Regio- And Stereoselective Addition of HO/OOH to Allylic Alcohols

Article abstract of DOI:10.1021/acs.joc.0c01280

A range of allylic alcohols are shown to readily react with ethereal H2O2 in the presence of catalytic amounts of Na2MoO4-gly or MoO2(acac)2, affording the C═C trans hydroxylation-hydroperoxylation products in good yields with high regio- and stereoselect

Full text of DOI:10.1021/acs.joc.0c01280

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Regio- and Stereoselective Addition of HO/OOH to Allylic Alcohols
Xiao-Tao Wang,‡ Wei-Bo Han,‡ Hui-Jun Chen, Qinghong Zha, and Yikang Wu*
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ABSTRACT: A range of allylic alcohols are shown to readily react with
ethereal H2O2 in the presence of catalytic amounts of Na2MoO4-gly or
MoO2(acac)2, affording the CC trans hydroxylation−hydroperox-
ylation products in good yields with high regio- and stereoselectivity.
Use of enantiomers of cyclic substrates resulted in corresponding
enantiopure diol-tert-hydroperoxides. The possibility of further con-
version of the diol-tert-hydroperoxides into triols or linear building blocks with an isolated tert-peroxy group containing a quaternary
center is also exemplified.
reaction. With the progress of the reaction, another two
products (2a and 3a) formed gradually. Further extension of
the reaction to 24 h led to complete disappearance of starting 1a
and the intermediate 4a, leaving only 2a and 3a as the major
species in the reaction mixture. The structures of 2a and 3a were
fully secured by 1H and 13C NMR, IR, and MS. Treatment of 2a
with Ph3P gave 3a, confirming the presence of the peroxy bond.
Later, the relative configuration of (racemic) 3a was established
by X-ray diffraction.6
Several other linear allylic alcohols of different alkene
geometry and/or different substitution patterns also reacted
smoothly under the same conditions,7 affording the expected
products (entries 2−8, Table 1). In the case of 1g and 1h, partial
relative configuration of the products was assigned by the NOE’s
observed with the acetonides (Figure 1, 3g′ and 3h′,
respectively) of 3g and 3h, respectively.
With the feasibility of the highly anticipated tandem
epoxidation−perhydrolysis achieved, we next turned our
attention to cyclic substrates, because in such conformation
restrained cases, the stereoselectivity might be even better, and
determination of relative configuration would be much easier.
More importantly, it would be more likely to acquire otherwise
not-so-easily attainable enantiopure tert-hydroperoxides (vide
infra).8
Allylic alcohols 1i−m (Figure 2) were first examined. The
substituent at the CC appeared to have critical influence on
the reaction. Conjugation of the double bond with a phenyl ring
(1i) or a vinyl group (1j) apparently complicated the reaction
(leading to complex mixtures), while an electron-withdrawing
ester group (1k) turned off the reaction completely; no products
INTRODUCTION
■
Perhydrolysis of epoxides is one of the reactions that allow for
facile incorporation of peroxy bonds into carbon frameworks
under mild conditions in synthetically useful yields, representing
a rather useful synthetic tool in peroxide chemistry.1 For this
reason, installation of epoxy functionality sometimes also
becomes an indispensable part of the whole synthetic plan and
thus holds, though in an inexplicit way, a special place in the
synthesis of organic peroxides. During the course of studies on
perhydrolysis of epoxides, we became aware of those protocols
of, e.g., Scettri (Ti(OiPr)4),2 Yamamoto (VO(OiPr)3,
WO2(acac)2),3 and Yamazaki (MTO, methyltrioxorhenium),4
where allylic or homoallylic alcohols reacted smoothly with
H2O2 in the presence of a proper transition metal catalyst to
furnish corresponding epoxides. These findings prompted us to
consider whether molybdenum species could also promote
epoxidation of alkenes in ethereal H2O2should it be possible
to form epoxides under the perhydrolysis conditions, the
epoxidation and the perhydrolysis might occur in one flask and
thus tremendously simplify the overall synthesis.
RESULTS AND DISCUSSION
■
One of our initial experiments is shown in Scheme 1, with 1a as
the substrate and Na2MoO4-gly5 as the catalyst. The expected
epoxide (4a) indeed was detectable on TLC (also verified
spectroscopically after chromatographic separation) after 1 h of
Scheme 1. Hydroxyhydroperoxylation of 1a
Received: May 29, 2020
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a
Table 1. Outline of the results with 1a−h
Figure 2. Some cyclic substrates initially tested (cf. the text).
a cyclic substrate should result in the corresponding optically
active tertiary hydroperoxide. Subsequent efforts were thus
made using optically active cyclic alcohols (obtained through
enzymatic resolution of the racemates, with tabular summary of
the resolution results shown in the Supporting Information).
With the optically active allylic alcohols as substrates, we
proceeded to examine their hydroxyhydroperoxylation under
the aforementioned conditions. Thus, (S)-1l furnished 2l in 82%
yield (Table 2, entry 1). The H-2/H-3 coupling constant of 2l
was found to be 3.1 Hz (equatorial/axial coupling),9 revealing a
cis relationship between the OH at C-2 and C-3 (cf. structure A
or B, Scheme 2). This is also fully consistent with the X-ray
analysis6 of racemic 2m. Selective protection of the OOH with
TBSCl followed by oxidative cleavage of the vicinal diol and
NaBH4 reduction of the dialdehyde afforded 5 (without any loss
of enantiopurity all the way from 2l). Conversion of 5 into the
known10 triol 6 finally verified the absolute configuration at the
C-1 of 2l.
By then, we had noticed that MoO2(acac)2 was particularly
potent in perhydrolysis of epoxides (compared with ketones and
ketals),11 and subsequent examination of MoO2(acac)2 showed
that the products were the same.12 Although the yields were
slightly lower, this disadvantage was compensated by the greatly
accelerated reaction rate as exemplified in entry 1 (Table 2).
Therefore, most other substrates were thus tested using
MoO2(acac)2 as the catalyst.13
We also examined 1y and 1z (Scheme 3), which gave a known
expoxide or triol and thus provided further evidence for the
stereochemical course of the formal hydroxyhydroperoxylation
reaction. These two substrates reacted substantially slower than
those simple ones listed in Table 2. Thus, after stirring at
ambient temperature for 12 h, the reaction mixture of 1y still
contained substantial amounts of unreacted/intermediate
epoxide 4y14a (isolated in 18% yield) in addition to the expected
product 2y and the known14b 3y. A similar phenomenon was
also observed with 1z. In this case, the reaction was further
extended to 42 h to allow for full consumption of 1z to be
converted into 2z and the known14b 3z.
a
Performed at rt in H2O2-saturated t-BuOMe with Na2MoO4-gly as
the catalyst. bRelative configuration deduced with reference to that of
3a, 3g, and 3h. cRelative configuration determined by X-ray
diffraction. dRelative configuration determined by NOE (cf. Figure 1).
It should be noted that although in some cases 3 is not listed in
Table 2 (entries 6−8 and 12, simply because of isolation/
characterization difficulty), formation of diol-hydroperoxide 2
was always accompanied by formation of triol 3. In an effort to
clarify the origin of 3, the isolated diol-hydroperoxide 2 was re-
exposed to the same ethereal H2O2/MoO2(acac)2 conditions
again for 12 h, and no 3 could be detected in the reaction
mixture. On the other hand, addition of activated powdered 4 Å
molecular sieves to the reaction system raised the ratio of 2/3
from 7:1 to 11:1.15 On the basis of these observations, it was
concluded that triol 3 must be generated via hydrolysis of the
intermediate epoxide 4 rather than deterioration of diol-
hydroperoxide 2.
Figure 1. NOE’s observed with acetonides 3g′ and 3h′.
were detected under the same conditions over 16 h of reaction.
However, both 1l and 1m reacted (separately) with H2O2
smoothly, affording the expected products in high yields with
high stereoselectivity. In the case of 1m, the hydroperoxy
product (racemic 2m) was a solid; its configuration was verified
by single crystal X-ray crystallographic analysis.6
The above results showed that the configurations of the two
newly installed stereogenic centers were controlled by the OH at
the allylic position. In other words, use of a single enantiomer of
B
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a
Table 2. Outline of the Results with 1l−u
Scheme 2. Elaboration of 2l into 5
Scheme 3. Hydroxyhydroperoxylation of 1y−z
the overall transformation: As illustrated in Scheme 4 with
conversion of 1l to 2l and 3l (part (A), the upper left scheme), in
the cyclic substrate cases the epoxidation occurred with a clear-
cut cis facial selectivity (cis to the allylic OH), strongly
suggesting that the reaction was mediated by a cyclic transition
state (which excluded epoxidation on the other face of the C
C) with both the allylic OH and the H2O2 (which eventually
oxidized the CC to give an epoxy ring) bound to the Mo
catalyst. The subsequent perhydrolysis also showed distinct
regio- as well as stereoselectivity; the attack by the OOH
exclusively occurred at the quaternary epoxy carbon center with
full configuration inversion, substantially better than the ca. 85%
inversion observed in the perhydrolysis16 of oxetanes. The
observation that no reaction (via path c) occurred at the other
epoxy carbon center (which was less substituted and thus would
be more suitable for SN2 substitution) suggested that the
inversion at the quaternary center was more likely to be achieved
via an SN1 ion pair mechanism (with one side of the planar
carbocation blocked by the counterion/leaving group) as
reasoned for the perhydrolysis of oxetanes in our previous16
work.
The knowledge from the cyclic substrates, together with the
structures as well as the configurations of the products from the
noncyclic substrates, also allowed us to get a stereochemical
overview (Scheme 4, exemplified with 1g, 1e, and 1h) of the
reaction for the open-chain cases. Thus, at the first step of
transformation (epoxidation) the open-chain substrates 1g, 1e,
a
Performed at rt in ethereal H2O2 in the presence of the indicated
catalyst (A = Na2MoO4-gly, B = MoO2(acac)2.
Isolation and full characterization of the diol-hydroperoxides
also made it possible to establish the stereochemical course of
C
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Scheme 4. Stereochemical Overview of the Addition of OH/OOH to Allylic Alcohols
and 1h must react in those conformations as depicted in Scheme
4 (parts (B), (C), and (D), respectively), and the regio- and
stereoselectivity in the subsequent perhydrolysis in each selected
case must be as depicted in the corresponding subschemes.
With the aid of the schematic summaries in Scheme 4, it
becomes much easier to identify the evidence for the dominating
perhydrolysis mechanism: In the case of 1g, the OOH attack
exclusively occurred at the more crowded quaternary epoxy
carbon center (with full configuration inversion) rather than the
less crowded tertiary epoxy carbon center. Therefore, the SN2
mechanism could be excluded, leaving the SN1 ion pair as the
only possible alternative. This conclusion is the same as what is
reached above for the cyclic substrates. However, it must be
noted that such preference for a SN1 ion pair perhydrolysis
mechanism at the quaternary epoxy carbon center holds only
when the quaternary center is not adjacent to the allylic center. If
the positions of the two epoxy carbon centers are “switched” as
in 1e (part (C), Scheme 4), the steric crowding around the
tertiary center becomes smaller (compared with that in 1g,
because the liner −CH2CH2Ph is smaller in size than the
branched −CH(OH)CH2CH2Ph); the SN2 substitution at the
tertiary epoxy carbon center not only is in operation, but also has
gained the upper hand in competition with the SN1 ion pair
mechanism at the quaternary center, providing 2e as the major
product (38%). Further reduction of the steric crowding around
the tertiary epoxy carbon center in 1e into a nonsubstituted CH2
(as the terminal epoxy center in 1h) leads to tremendous
facilitation of the SN2 substitution at this site; the perhydrolysis
exclusively occurred at the terminal center via the SN2
mechanism, giving 2h as the only product (part (C), Scheme
4).17
this case are disubstituted, the nucleophilic attacks took place
preferentially at the carbon center beta to the allylic OH,
confirming that the epoxy carbon center beta to allylic OH is
more susceptible to perhydrolysis. Besides, the slower reaction/
longer reaction time observed with 1d (compared with, e.g., 1a)
also indicated that the mechanism of the perhydrolysis of the
intermediate epoxide in this case must be different from that
with the substrates with a quaternary epoxy carbon center (such
as the intermediate epoxide derived from 1a).
It is perhaps noteworthy that the combination of
MoO2(acac)2 and H2O2 has been used by Su and Wang in a
recently18 reported protocol for the synthesis of triols from
alkenes, where the main reactions were completed in a (35%
aqueous H2O2−MeCN) biphasic system in the presence of an
additional (synthetic) ligand. Judging from the reaction
conditions, their crude product mixtures very likely contained
some hydroperoxides in addition to the triols directly formed
from the competing hydrolysis (which is expected to be much
more severe than observed in this work). However, because the
hydroperoxides were neither isolated nor characterized, but
directly reduced with Ph2S, it is not possible to assess the value of
that protocol in synthesis of hydroperoxides in comparison with
the present work.
CONCLUSIONS
■
A molybdenum mediated method for hydroxylation−hydro-
peroxylation of the CC in allylic alcohols has been developed.
With Na2MoO4-gly or MoO2(acac)2 as the catalyst, an array of
allylic alcohols were converted into the corresponding diol-
hydroperoxides in good yields. The reaction occurred in a highly
stereoselective manner, with the product configuration fully
controlled by the allylic OH of the substrates. As a consequence
of using ethereal H2O2 (instead of the previously18 aqueous
H2O2), the whole transformation did not require any additional
ligand. Competing hydrolysis at the perhydrolysis step was also
effectively suppressed. A range of diol-tert-hydroperoxides thus
become readily accessible. Isolation of the hydroperoxides also
In the case of 1d (Table 1), a disubstituted alkene, neither of
the two epoxy carbon centers of the intermediate epoxide are
quaternary. This made the SN1 ion pair mechanism strongly
disfavored. Therefore, the perhydrolysis/hydrolysis of the
epoxide derived from 1d most likely occurred through an SN2
mechanism, with full configuration inversion. What deserves
mentioning here is that although both epoxy carbon centers in
D
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1.64−1.56 (m, 3H), 1.47−1.34 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 138.5, 134.9, 128.3, 128.1, 127.6, 127.4, 72.8, 70.2, 68.5, 37.4,
29.6, 25.7, 22.0, 18.1; FT-IR (film) 3418, 3087, 3063, 3030, 2933, 2859,
2792, 2729, 1675, 1604, 1496, 1453, 1375, 1363, 1204, 1101, 1028, 908,
735, 697 cm−1. ESI-MS m/z 271.3 ([M + Na]+); ESI-HRMS calcd. for
C16H24O2Na ([M + Na]+) 271.1669, found 271.1663.
made it possible to look into the stereochemical course of the
tandem epoxidation−perhydrolysis reaction. As diol-hydro-
peroxides could be readily reduced to corresponding alcohols
in high yields, the present protocol also provides a stereo-
controlled approach to the corresponding triols with a newly
installed trans diol subunit, which are not accessible through,
e.g., conventional OsO4 cis19 dihydroxylation. Finally, as
illustrated through conversion of 2l into 5 (a flexible optically
active chiral tert-peroxy building block), this new access to 2 also
opens up an entry to the otherwise not-so-easily attainable
enantiopure peroxy group-containing isolated quaternary
stereogenic centers.20
5-Methyl-1-phenylhex-4-en-3-ol (1g). A commercially available
solution of 2-methylprop-1-enyl magnesium bromide (0.5 M, in THF,
14.4 mL, 7.2 mmol) was added to a solution of 3-phenylpropanal (0.8
mL, 6.0 mmol) in dry THF (24 mL) stirred in an ice−water bath under
N2 (balloon). After completion of the addition, stirring was continued
while the bath was allowed to warm to ambient temperature naturally.
When TLC showed completion of the reaction (ca. 3 h), aq. sat. NH4Cl
(10 mL) was added. The mixture was extracted with Et2O (30 mL × 3).
The combined organic layers were washed with brine (10 mL) and
dried over anhydrous Na2SO4. Removal of the drying agent by filtration
and the solvent by rotary evaporation gave an oily residue, which was
purified by column chromatography (15:1 PE/EtOAc) on silica gel to
EXPERIMENTAL SECTION
■
General Considerations. Although no explosions were experi-
enced in this work, generally speaking, organic peroxides are potentially
hazardous compounds and must be handled with great care: Avoid
direct exposure to strong heat or light, mechanical shock, oxidizable
organic materials, or transition metal ions. A safety shield should be
used for all reactions involving H2O2. All solvents and reagents were
used as received from commercial sources. Novozyme 43521 and Lipase
AK were purchased from Strem and Sigma, respectively. H2O2-
saturated Et2O (ethereal hydrogen peroxide) was prepared using a
literature procedure22 with a slight modification: Et2O (60 mL) was
placed in a separatory funnel and “washed” with three portions (20 mL
each) of NaCl-saturated H2O2 (prepared by stirring the commercially
available 30% aqueous hydrogen peroxide (60 mL) with an excess of
powdered NaCl (ca. 30 g) at ambient temperature until the initially
cloudy liquid phase became a clear solution; the supernatant was used;
performed behind a safety shield!). The ethereal layer was then dried
over anhydrous MgSO4 (ca. 2 g). The supernatant (ca. 1 M in H2O2 as
titrated with 0.1 M KMnO4) was used directly in the MoO2(acac)2
catalyzed hydroxylation−hydroperoxylation. H2O2-saturated t-BuOMe
was prepared similarly, except with t-BuOMe to replace Et2O. Column
chromatography was performed on silica gel (300−400 mesh) under
slightly positive pressure. PE stands for petroleum ether (chromatog-
raphy solvent, bp 60−90 °C).
1
afford 1g as a colorless oil (967 mg, 5.1 mmol, 85%). H NMR (400
MHz, CDCl3) δ 7.34−7.19 (m, 5H), 5.27−5.23 (m, 1H), 4.39 (dt, J =
8.8 Hz, 6.5 Hz, 1H), 2.76−2.63 (m, 2H), 2.00−1.90 (m, 1H), 1.83−
1.79 (m, 1H), 1.77 (s, 3H), 1.69 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 142.0, 135.4, 128.33, 128.26, 127.9, 125.7, 68.1, 39.1, 31.7,
25.7, 18.2; FT-IR (film) 3362, 3062, 3026, 2969, 2928, 2859, 1675,
1603, 1496, 1453, 1376, 1043, 1030, 1005, 914, 844, 747, 699 cm−1; EI-
MS m/z (%) 85 (100), 91 (37), 175 (36), 190 (M+, 33); EI-HRMS
calcd. for C13H18O (M+) 190.1358, found 190.1356.
General Procedure for Na2MoO4-gly Mediated Conversion of
1a−h into 2a−h. These experiments were mostly performed in H2O2-
saturated t-BuOMe using the general procedure shown below just to
illustrate that in case the more conventional H2O2-saturated Et2O
cannot be employed for safety reason, the reaction still can be carried
out to acquire the expected products.
The allyl alcohol 1 (0.3 mmol) was dissolved in freshly prepared16
H2O2-saturated t-BuOMe (3.0 mL). Na2MoO4-gly5 (11 mg, 0.03
mmol) was added. The mixture was stirred at ambient temperature
until TLC showed consumption of the starting 1. The mixture was
diluted with Et2O and washed with H2O. Phases were separated. The
aq. layer was back extracted with EtOAc (10 mL × 3). The combined
organic layers were washed in turn with H2O (5 mL) and brine (5 mL)
and dried over anhydrous Na2SO4. The drying agent was removed by
filtration. The filtrate was concentrated on a rotary evaporator. The
residue was purified by column chromatography on silica gel to give the
product 2 and 3.
Melting points were uncorrected (measured on a hot-stage melting
point apparatus equipped with a microscope). Optical rotations were
measured on an Anton Paar MCP5500 polarimeter. IR spectra were
measured with a Nicolet 380 infrared spectrophotometer. NMR spectra
were recorded with a Bruker Avance III 400 NMR spectrometer
(operating at 400 MHz for 1H) or a Bruker Avance III HD 500 NMR
(operating at 500 MHz for 1H) or a Bruker Avance III HD 600 NMR
Data for (2R*,3S*)-3-Hydroperoxy-3-methyl-5-phenylpentane-
1,2-diol (2a). 2a was obtained as a colorless oil, 33 mg, 73% from 1a,
along with 14% of recovered 1a, chromatography using 1:1 to 1:2 PE/
EtOAc; 1H NMR (400 MHz, CDCl3) δ 7.26−7.11 (m, 5H), 4.34 (br s,
1H), 3.90 (d, J = 5.5 Hz, 1H), 3.74 (d, J = 10.6 Hz, 1H), 3.64 (dd, J =
11.3 Hz, 7.5 Hz, 1H), 2.71 (td, J = 13.0, 4.5 Hz, 1H), 2.59 (td, J = 12.5,
5.0 Hz, 1H), 2.04 (td, J = 13.0, 4.3 Hz, 1H), 1.63 (td, J = 13.8, 5.2 Hz,
1H), 1.23 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.1, 128.4,
128.3, 125.9, 85.0, 75.8, 62.7, 35.2, 29.2, 18.5; FT-IR (film) 3365, 3089,
3062, 3028, 2979, 2939, 2864, 1602, 1496, 1454, 1367, 1205, 1151,
1090, 1028, 740, 699 cm−1. ESI-MS m/z 249.2 ([M + Na]+); ESI-
HRMS calcd. for C12H18O4Na ([M + Na]+) 249.1097, found 249.1102.
Data for (2R*,3S*)-3-Methyl-5-phenylpentane-1,2,3-triol (3a). 3a
was obtained as a white solid, 7 mg, 15% from 1a, chromatography
1
(operating at 600 MHz for H) instrument as stated below. ESI-MS
data were acquired with a Shimadzu LCMS-2010 eV mass spectrometer
or an Agilent Technologies 6120 Quadrupole LC/MS. ESI-HRMS data
were obtained with a Bruker Maxis 4 G TOF MS spectrometer or a
Thermo Scientific Q Exactive HF Orbitrap-FT MS.
Synthesis of Substrates 1a−h. Substrates 1a−c, 1e, and 1h are
known compounds and were prepared according to the literature.23
Substrate 1d is commercially available and was used as received.
8-(Benzyloxy)-2-methyloct-2-en-4-ol (1f). A commercially avail-
able solution of 2-methylprop-1-enyl magnesium bromide (0.5 M, in
THF, 2.4 mL, 1.2 mmol) was added to a solution of 5-
benzyloxypentanal (198 mg, 1.03 mmol) in dry THF (4 mL) stirred
in an ice−water bath under N2 (balloon). After completion of the
addition, stirring was continued while the bath was allowed to warm to
ambient temperature naturally. When TLC showed completion of the
reaction (ca. 5 h), aq. sat. NH4Cl (5 mL) was added. The mixture was
extracted with Et2O (10 mL × 3). The combined organic layers were
washed with brine (10 mL) and dried over anhydrous Na2SO4.
Removal of the drying agent by filtration and the solvent by rotary
evaporation gave an oily residue, which was purified by column
chromatography (5:1 PE/EtOAc) on silica gel to afford 1f as a colorless
oil (220 mg, 0.89 mmol, 87%). 1H NMR (400 MHz, CDCl3) δ 7.36−
7.24 (m, 5H), 5.15 (dd, J = 8.8, 1.3 Hz, 1H), 4.49 (s, 2H), 4.32 (dt, J =
8.5, 6.3 Hz, 1H), 3.46 (t, J = 6.6 Hz, 2H), 1.72 (s, 3H), 1.67 (s, 3H),
1
using 1:1 to 1:2 PE/EtOAc; mp 108−109 °C. H NMR (500 MHz,
CD3OD) δ 7.26−7.11 (m, 5H), 3.82 (dd, J = 10.5 Hz, 2.7 Hz, 1H),
3.59−3.51 (m, 2H), 2.75 (td, J = 12.7, 4.9 Hz, 1H), 2.67 (td, J = 13.2,
4.9 Hz, 1H), 1.86 (td, J = 13.2, 4.9 Hz, 1H), 1.72 (td, J = 12.8, 5.0 Hz,
1H), 1.19 (s, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 144.3,
129.35, 129.32, 126.6, 78.2, 74.7, 64.0, 42.5, 30.5, 22.2; FT-IR (film)
3197, 3024, 2999, 2941, 2961, 2887, 2863, 1605, 1494, 1453, 1368,
1314, 1196, 1087, 1063, 1029, 992, 949, 885, 789, 742, 721, 699 cm−1;
ESI-MS m/z 233.1 ([M + Na]+); ESI-HRMS calcd. for C12H18O3Na
([M + Na]+) 233.1148, found 233.1154.
Data for (2S*,3S*)-3-Hydroperoxy-3-methyl-5-phenylpentane-
1,2-diol (2b). 2b was obtained as a white solid, 48 mg, 77% from 1b,
E
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along with 7.5% of recovered 1b, chromatography using 1:1 to 1:2 PE/
EtOAc; mp 105−106 °C. 1H NMR (400 MHz, CD3OD) δ 7.35−7.10
(m, 5H), 3.86 (dd, J = 8.0, 2.9 Hz, 1H), 3.74 (dd, J = 11.5, 2.6 Hz, 1H),
3.53 (dd, J = 12.5 Hz, 5.0 Hz, 1H), 2.78−2.62 (m, 2H), 1.93−1.76 (m,
2H), 1.21 (s, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 144.1, 129.3,
126.7, 85.7, 76.4, 63.8, 37.2, 30.5, 18.0; FT-IR (film of a concd. solution
in CH2Cl2) 3366, 3060, 3026, 2941, 1603, 1496, 1454, 1377, 1188,
1090, 1062, 1030, 903, 747, 699, 668 cm−1; ESI-MS m/z 249.2 ([M +
Na]+); ESI-HRMS calcd. for C12H18O4Na ([M + Na]+) 249.1097,
found 249.1101.
Data for (2S*,3S*)-3-Methyl-5-phenylpentane-1,2,3-triol (3b). 3b
was obtaind as a white solid, 9 mg, 14% from 1b, chromatography using
1:1 to 1:2 PE/EtOAc; mp 105−106 °C. 1H NMR (500 MHz, CD3OD)
δ 7.26−7.11 (m, 5H), 3.77 (dd, J = 10.5 Hz, 2.7 Hz, 1H), 3.59−3.51 (m,
2H), 2.69 (t, J = 8.8 Hz, 2H), 1.89−1.81 (m, 1H), 1.76−1.68 (m, 1H),
1.22 (s, 3H); 13C{1H} NMR (125 MHz, CD3OD) δ 144.2, 129.3,
126.6, 78.6, 74.8, 63.9, 41.7, 30.9, 23.0; FT-IR (film of a concd. solution
in CH2Cl2) 3391, 3025, 2927, 1602, 1496, 1454, 1375, 1061, 1029, 747,
699 cm−1; ESI-MS m/z 233.1 ([M + Na]+); ESI-HRMS calcd. for
C12H18O3Na ([M + Na]+) 233.1148, found 233.1152.
Data for 1-(1-Hydroperoxycyclohexyl)ethane-1,2-diol (2c). 2c was
obtained as a colorless oil, 49 mg, 82% from 1c, chromatography using
1:1 to 1:2 and finally 1:3 PE/EtOAc; 1H NMR (400 MHz, CDCl3) δ
9.96 (s, 1H), 4.22 (s, 2H), 3.82−3.68 (m, 3H), 1.94 (d, J = 13.8 Hz,
1H), 1.87 (d, J = 13.9 Hz, 1H), 1.69−1.44 (m, 5H), 1.38−1.14 (m,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 83.8, 75.8, 62.5, 29.6, 28.7,
25.6, 21.1, 21.0; FT-IR (film) 3373, 2936, 2862, 1448, 1154, 1076,
1018, 929, 878, 819, 739 cm−1; ESI-MS m/z 221.1 ([M + COOH]−);
ESI-HRMS calcd. for C8H16O4Cl ([M + Cl]−) 211.0743, found
211.0744.
128.44 (CH), 126.0 (CH), 89.3 (CH), 75.0 (quat), 66.3 (CH2), 32.6
(CH2), 29.4 (CH2), 21.1 (CH3) (assigned with the aid of DEPT 135);
FT-IR (film) 3348, 3085, 3062, 3026, 2935, 2864, 1603, 1496, 1454,
1382, 1244, 1115, 1041, 918, 752, 700 cm−1; ESI-MS m/z 249.2 ([M +
Na]+); ESI-HRMS calcd. for C12H18O4Na ([M + Na]+) 249.1097,
found 249.1096.
Data for (2R*,3S*)-2-Hydroperoxy-2-methyl-5-phenylpentane-
1,3-diol (2e′). 2e was obtained as a colorless oil, 14 mg, 18% from
1e, chromatography using first 2:3, then 1:1 PE/EtOAc, and finally
1
EtOAc; H NMR (500 MHz, CDCl3) δ 9.34 (s, 1H), 7.30−7.17 (m,
5H), 3.91−3.84 (m, 2H), 3.78 (d, J = 12.7 Hz, 1H), 3.46 (br s, 2H),
2.97 (ddd, J = 13.7, 9.8 Hz, 4.9 Hz, 1H), 2.66 (ddd, J = 13.9, 9.3, 7.3 Hz,
1H), 1.90−1.74 (m, 2H), 1.07 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 141.7 (quat), 128.53 (CH), 128.47 (CH), 126.0 (CH), 85.8
(quat), 74.0 (CH), 64.7 (CH2), 33.5 (CH2), 32.7 (CH2), 16.4 (CH3)
(assigned with the aid of DEPT 135); FT-IR (film) 3365, 3086, 3062,
3026, 2929, 2860, 1603, 1496, 1454, 1376, 1257, 1223, 1044, 933, 751,
700 cm−1; ESI-MS m/z 249.1 ([M + Na]+); ESI-HRMS calcd. for
C12H18O4Na ([M + Na]+) 249.1097, found 249.1094.
Data for (2R*,3S*)-2-Methyl-5-phenylpentane-1,2,3-triol (3e). 3e
was obtained as a colorless oil, 19 mg, 30% from 1e, chromatography
using first 2:3, then 1:1 PE/EtOAc, and finally EtOAc; 1H NMR (400
MHz, CD3OD) δ 7.26−7.11 (m, 5H), 3.56 (d, J = 11.0 Hz, 1H), 3.51
(dd, J = 10.6, 1.3 Hz, 1H), 3.44 (d, J = 11.1 Hz, 1H), 2.91 (ddd, J = 13.4,
10.5, 4.6 Hz, 1H), 2.61 (ddd, J = 13.5, 10.0, 7.0 Hz, 1H), 2.02−1.93 (m,
1H), 1.69−1.59 (m, 1H), 1.08 (s, 3H); 13C{1H} NMR (100 MHz,
CD3OD) δ 143.8, 129.5, 129.3, 126.7, 75.6, 75.3, 68.8, 34.01, 34.00,
19.0; FT-IR (film) 3406, 3085, 3062, 3026, 2927, 1603, 1496, 1454,
1381, 1257, 1044, 941, 833, 750, 700 cm−1; ESI-MS m/z 233.2 ([M +
Na]+); ESI-HRMS calcd. for C12H18O3Na ([M + Na]+) 233.1148,
found 233.1150. (note that 3e = 3h.)
Data for (3R*,4S*)-8-(Benzyloxy)-2-hydroperoxy-2-methyloc-
tane-3,4-diol (2f). 2f was obtained as a colorless oil, 49 mg, 72%
from 1f, chromatography using 1:1 PE/EtOAc; 1H NMR (400 MHz,
CDCl3) δ 9.98 (s, 1H), 7.36−7.25 (m, 5H), 4.49 (s, 2H), 3.82 (dd, J =
7.5, 4.2 Hz, 1H), 3.49 (t, J = 6.3 Hz, 2H), 3.42−3.28 (m, 2H), 2.62 (br s,
1H), 1.74−1.59 (m, 3H), 1.57−1.38 (m, 3H), 1.29 (s, 3H), 1.23 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.1, 128.3, 127.7, 127.6,
84.8, 76.7, 72.9, 70.1, 69.4, 34.9, 29.3, 22.5, 20.9; FT-IR (film) 3388,
3092, 3059, 3030, 2980, 2939, 2863, 2798, 1603, 1496, 1454, 1365,
1206, 1151, 1100, 1074, 1028, 911, 737, 698 cm−1; ESI-MS m/z 321.2
([M + Na]+); ESI-HRMS calcd. for C16H26O5Na ([M + Na]+)
321.1673, found 321.1672.
Data for 1-(1-Hydroxycyclohexyl)ethane-1,2-diol (3c). 3c was
obtained as a white solid, 6 mg, 11% from 1c, chromatography using 1:1
1
to 1:2 and finally 1:3 PE/EtOAc; mp 111−112 °C. H NMR (400
MHz, CD3OD) δ 3.78 (dd, J = 11.3, 3.3 Hz, 1H), 3.55 (dd, J = 11.1, 7.8
Hz, 1H), 3.36 (dd, J = 8.0, 3.2 Hz, 1H), 1.71−1.43 (m, 9H), 1.29−1.18
(m, 1H); 13C{1H} NMR (100 MHz, CD3OD) δ 79.0, 74.0, 63.6, 34.6,
33.5, 27.0, 22.52, 22.48; FT-IR (film of a concd. solution in CH2Cl2)
3307, 2930, 2856, 1446, 1400, 1337, 1263, 1090, 1063, 1023, 971, 908,
879 cm−1; ESI-MS m/z 183.1 ([M + Na]+); ESI-HRMS calcd. for
C8H16O3Na ([M + Na]+) 183.0992, found 183.0998.
Data for (2R*,3S*)-3-Hydroperoxyheptane-1,2-diol (2d). 2d was
obtained as a colorless oil, 28 mg, 60% from 1d, chromatography using
1
1:1 to 1:2, then 1:3 PE/EtOAc, and finally MeOH; H NMR (500
Data for (3R*,4S*)-8-(Benzyloxy)-2-methyloctane-2,3,4-triol (3f).
3f was obtained as a colorless oil, 7 mg, 11% from 1f, chromatography
using 1:1 PE/EtOAc; 1H NMR (400 MHz, CDCl3) δ 7.36−7.27 (m,
5H), 4.50 (s, 2H), 3.98−3.92 (m, 1H), 3.49 (t, J = 6.4 Hz, 2H), 3.13−
3.08 (m, 1H), 3.01−2.72 (m, 3H), 1.73−1.61 (m, 3H), 1.59−1.40 (m,
3H), 1.28 (s, 3H), 1.27 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
138.4, 128.4, 127.7, 127.6, 76.4, 74.1, 72.9, 71.2, 70.2, 34.1, 29.5, 27.3,
26.2, 22.4; FT-IR (film) 3417, 3087, 3064, 3030, 2930, 2857, 2794,
1603, 1496, 1454, 1365, 1307, 1162, 1101, 1028, 949, 804, 736, 698
cm−1; ESI-MS m/z 305.2 ([M + Na]+); ESI-HRMS calcd. for
C16H26O4Na ([M + Na]+) 305.1723, found 305.1725.
MHz, CD3OD) δ 3.86 (q, J = 5.4 Hz, 1H), 3.77 (q, J = 5.1 Hz, 1H), 3.66
(dd, J = 11.3, 4.3 Hz, 1H), 3.58 (dd, J = 11.3, 6.8 Hz, 1H), 1.66−1.48
(m, 3H), 1.44−1.31 (m, 3H), 0.93 (t, J = 7.0 Hz, 3H); 13C{1H} NMR
(100 MHz, CD3OD) δ 86.9, 73.3, 64.6, 29.2, 28.6, 23.8, 14.4; FT-IR
(film) 3348, 2957, 2933, 2873, 1466, 1380, 1215, 1066, 988, 881 cm−1;
ESI-MS m/z 209.1 ([M + COOH]−); ESI-HRMS calcd. for
C7H16O4Na ([M + Na]+) 187.0941, found 187.0932.
Data for (2R*,3S*)-Heptane-1,2,3-triol (3d). 3d was obtained as a a
white solid, 9 mg, 20% from 1d, chromatography using first 1:1, then
1
1:2, and finally 1:3 PE/EtOAc and finally MeOH; mp 76−78 °C. H
NMR (400 MHz, CD3OD) δ 3.72 (dd, J = 11.2, 3.6 Hz, 1H), 3.56 (dd, J
= 11.2, 6.6 Hz, 1H), 3.52−3.41 (m, 2H), 1.72−1.64 (m, 1H), 1.58−
1.48 (m, 1H), 1.44−1.29 (m, 4H), 0.94 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (100 MHz, CD3OD) δ 76.3, 73.6, 64.7, 33.8, 29.1, 23.9, 14.5; FT-
IR (film of a concd. solution in CH2Cl2) 3260, 2953, 2938, 2914, 2872,
2856, 1487, 1458, 1439, 1315, 1083, 1042, 1005, 962, 888, 875, 730
cm−1; EI-MS m/z (%) 69 (100), 87 (62), 44 (33), 117 ([M −
CH2OH]+, 13), 147 ([M − H]+, 0.97); ESI-HRMS calcd. for C6H13O2
([M − CH2OH]+) 117.0916, found 117.0919.
Data for (3S*,4R*)-5-Hydroperoxy-5-methyl-1-phenylhexane-
3,4-diol (2g). 2g was obtained as a colorless oil, 53 mg, 74% from 1g,
1
chromatography using 2:1 to 3:2 PE/EtOAc; H NMR (400 MHz,
CDCl3) δ 9.80 (s, 1H), 7.29−7.14 (m, 5H), 3.86 (dd, J = 8.0, 5.3 Hz,
1H), 3.44 (s, 1H), 3.35 (s, 1H), 3.22 (s, 1H), 2.81−2.64 (m, 2H),
2.07−1.97 (m, 1H), 1.88−1.78 (m, 1H), 1.30 (s, 3H), 1.21 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 141.5, 128.39, 128.34, 125.9, 85.0,
76.7, 69.1, 36.8, 32.0, 22.4, 20.8; FT-IR (film) 3420, 3086, 3063, 3026,
2981, 2939, 2861, 1603, 1496, 1454, 1383, 1234, 1145, 1099, 1045, 997,
775, 748, 700 cm−1; ESI-MS m/z 263.2 ([M + Na]+); ESI-HRMS calcd.
for C13H20O4Na ([M + Na]+) 263.1254, found 263.1256.
Data for (3R*,4S*)-2-Methyl-6-phenylhexane-2,3,4-triol (3g). 3g
was obtained as a colorless oil, 16 mg, 24% from 1g, chromatography
using 2:1 to 3:2 PE/EtOAc; 1H NMR (400 MHz, CDCl3) δ 7.33−7.19
(m, 5H), 4.01 (dd, J = 8.0, 5.2 Hz, 1H), 3.37−3.04 (m, 4H), 2.83−2.67
(m, 2H), 2.07−1.97 (m, 1H), 1.91−1.81 (m, 1H), 1.31 (s, 3H), 1.27 (s,
Data for (2R*,3S*)-3-Hydroperoxy-2-methyl-5-phenylpentane-
1,2-diol (2e). 2e was obtained as a colorless oil, 20 mg, 38% from 1e,
chromatography using first 2:3, then 1:1 PE/EtOAc, and finally EtOAc;
1H NMR (400 MHz, CDCl3) δ 10.41 (br s, 1H), 7.30−7.15 (m, 5H),
3.90 (dd, J = 10.8, 2.3 Hz, 1H), 3.78 (d, J = 11.8 Hz, 1H), 3.66 (br s,
1H), 3.41 (d, J = 11.8 Hz, 1H), 2.97 (ddd, J = 13.6, 9.6, 4.8 Hz, 1H),
2.71 (dt, J = 13.6, 8.1 Hz, 1H), 1.94−1.74 (m, 2H), 1.06 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 141.6 (quat), 128.49 (CH),
F
https://dx.doi.org/10.1021/acs.joc.0c01280
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 141.6, 128.42, 128.38,
125.9, 76.6, 74.3, 70.6, 36.0, 31.9, 27.3, 26.1; FT-IR (film) 3398, 3084,
3062, 3026, 2974, 2927, 2859, 1603, 1496, 1454, 1386, 1158, 1096,
1044, 990, 949, 805, 749, 700 cm−1; ESI-MS m/z 247.1 ([M + Na]+);
ESI-HRMS calcd. for C13H20O3Na ([M + Na]+) 247.1305, found
247.1308.
Data for (2R*,3S*)-1-Hydroperoxy-2-methyl-5-phenylpentane-
2,3-diol (2h). 2h was obtained as a white solid, 17 mg, 25% from 1h,
along with 18 mg (33%) of unreacted 1h, chromatography using 1:1 to
1:2 PE/EtOAc; mp 62−63 °C. 1H NMR (400 MHz, CDCl3) δ 10.30 (s,
1H), 7.31−7.18 (m, 5H), 4.24 (d, J = 13.3 Hz, 1H), 3.91 (d, J = 13.3 Hz,
1H), 3.57 (t, J = 6.3 Hz, 1H), 3.06 (br s, 2H), 2.94 (dt, J = 13.5, 7.4 Hz,
1H), 2.68 (dt, J = 13.8, 8.1 Hz, 1H), 1.88−1.78 (m, 2H), 1.10 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 141.5, 128.52, 128.46, 126.1, 80.8,
76.7, 74.8, 32.87, 32.84, 21.3; FT-IR (film of a concd. solution in
CH2Cl2) 3398, 3085, 3061, 3026, 2927, 1603, 1496, 1454, 1381, 1257,
1043, 940, 749, 700 cm−1; ESI-MS m/z 249.2 ([M + Na]+; ESI-HRMS
calcd. for C12H18O4Na ([M + Na]+) 249.1097, found 249.1093.
Data for (2R*,3S*)-2-Methyl-5-phenylpentane-1,2,3-triol (3h =
3e). 3h = 3e was obtained as a colorless oil, 19 mg, 30% from 1h,
chromatography using 1:1 to 1:2 PE/EtOAc; cf. the data for 3e given
above immediately below the data for 2e′.
20.7, 18.1, −5.6, −5.7; FT-IR (film) 3465, 3085, 3063, 3027, 2954,
2929, 2857, 1604, 1496, 1471, 1463, 1389, 1362, 1329, 1256, 1087,
1006, 974, 938, 838, 778, 749 cm−1; ESI-MS m/z 347.3 ([M + Na]+);
ESI-HRMS calcd. for C18H32O3Na ([M + Na]+) 347.2013, found
347.2004.
The 3h-TBS (22 mg, 0.068 mmol) obtained above was dissolved in
acetone (2 mL). To this solution was added p-TsOH·H2O (1 mg, 0.006
mmol). The solution was stirred at ambient temperature for 3 h, when
TLC showed completion of the reaction. Aq. sat. NaHCO3 (2 mL) was
added. The mixture was extracted with Et2O (10 mL × 2). The
combined organic layers were washed with water (3 mL) and brine (3
mL) before being dried over anhydrous Na2SO4. Filtration and rotary
evaporation left an oily residue, which was purified by column
chromatography (5:1 PE/EtOAc) on silica gel to give acetonide 3h′ as
a colorless oil (25 mg, 0.068 mmol, 86%). 1H NMR (400 MHz, CDCl3)
δ 7.34−7.20 (m, 5H), 3.80 (t, J = 6.5 Hz, 1H), 3.69 (d, J = 9.8 Hz, 1H),
3.30 (d, J = 9.7 Hz, 1H), 2.93 (dt, J = 14.4, 7.3 Hz, 1H), 2.71 (dt, J =
14.3, 8.3 Hz, 1H), 2.01−1.93 (m, 2H), 1.46 (s, 3H), 1.39 (s, 3H), 1.28
(s, 3H), 0.89 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 141.9, 128.4, 128.3, 125.8, 106.7, 82.4, 81.6, 65.4, 33.2,
30.2, 28.6, 26.5, 25.8, 21.5, 18.1, −5.6, −5.7; FT-IR (film) 3086, 3064,
3028, 2984, 2956, 2931, 2858, 1604, 1497, 1471, 1455, 1377, 1369,
1296, 1252, 1216, 1194, 1095, 1045, 1002, 938, 837, 815, 776, 749
cm−1; ESI-MS m/z 387.4 ([M + Na]+); ESI-HRMS calcd. for
C21H36O3SiNa ([M + Na]+) 387.2326, found 387.2335.
Conversion of Hydroperoxide 2a into Triol 3a. Ph3P (31 mg,
0.118 mmol) was added to a solution of 2a (23 mg, 0.102 mmol) in
CH2Cl2 (2 mL) stirred at ambient temperature. After completion of the
addition, stirring was continued at the same temperature until TLC
showed completion of the reaction (ca. 1 h). The mixture was
concentrated on a rotary evaporator. The residue was purified by
column chromatography (first 2:1, then 1:1 PE/EtOAc) on silica gel to
give 3a as a white solid (21 mg, 0.999 mmol, 98%). Data for 3a: cf. those
given above under “Data for 3a”.
2-((4R*,5S*)-2,2-Dimethyl-5-phenethyl-1,3-dioxolan-4-yl)-
propan-2-ol (3g′). A small drop of concd. H2SO4 (ca. 10 mg) was
added to a mixture of 3g (59 mg, 0.26 mmol) in acetone (3 mL) stirred
at ambient temperature. Stirring was then continued for 12 h (when
TLC showed full consumption of the starting 3g). The reaction mixture
was poured into aq. sat. NaHCO3 (5 mL) and then extracted with Et2O
(10 mL × 3). The combined organic layers were washed with water (3
mL) and brine (3 mL) and dried over anhydrous Na2SO4. Removal of
the drying agent by filtration and the solvent by rotary evaporation gave
a residue, which was purified by column chromatography (6:1 PE/
EtOAc) on silica gel to afford 3g′ as a colorless oil (61 mg, 0.23 mmol,
88%). 1H NMR (400 MHz, CDCl3) δ 7.30−7.15 (m, 5H), 3.98 (td, J =
8.6, 3.0 Hz, 1H), 3.55(d, J = 7.8 Hz, 1H), 2.91 (ddd, J = 13.8, 10.3, 5.3
Hz, 1H), 2.70 (ddd, J = 13.8, 10.3, 6.6 Hz, 1H), 2.14 (s, 1H), 1.96−1.81
(m, 2H), 1.43 (s, 6H), 1.23 (s, 3H), 1.13 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3) δ 141.8, 128.36, 128.34, 125.9, 108.4, 86.8, 76.3, 69.7,
37.3, 32.6, 27.6, 27.5, 27.1, 24.6; FT-IR (film) 3481, 3087, 3063, 3027,
2984, 2932, 2858, 1604, 1496, 1455, 1379, 1370, 1250, 1216, 1170,
1061, 929, 874, 749, 700, 668 cm−1; ESI-MS m/z 287.1 ([M + Na]+);
ESI-HRMS calcd. for C16H24O3Na ([M + Na]+) 287.1618, found
287.1619.
tert-Butyldimethyl(((4R*,5S*)-2,2,4-trimethyl-5-phenethyl-1,3-
dioxolan-4-yl)methoxy)silane (3h′). A solution of triol 3h (21 mg, 0.1
mmol), TBSCl (18 mg, 0.12 mmol), imidazole (9 mg, 0.13 mmol) in
dry DMF (1 mL) was stirred in an ice−water bath for 20 min (TLC
showed completion of the reaction). Water (5 mL) was added to
quench the reaction. The mixture was extracted with Et2O (10 mL × 3).
The combined organic layers were washed with water (5 mL) and brine
(5 mL) before being dried over anhydrous Na2SO4. Filtration and
rotary evaporation left an oily residue, which was purified by column
chromatography (5:1 PE/EtOAc) on silica gel to furnish 3h-TBS (= 3e-
TBS; (2R*,3S*)-1-((tert-butyldimethylsilyl)oxy)-2- methyl-5-phenyl-
pentane-2,3-diol) as a colorless oil (28 mg, 0.86 mmol, 86%). 1H NMR
(400 MHz, CDCl3) δ 7.31−7.16 (m, 5H), 3.75 (d, J = 9.9 Hz, 1H),
3.53−3.47 (m, 1H), 3.47 (d, J = 9.8 Hz, 1H), 3.10 (s, 1H), 2.98 (ddd, J
= 13.6, 10.3, 4.9 Hz, 1H), 2.81 (d, J = 6.7 Hz, 1H), 2.67 (ddd, J = 13.6,
9.7, 7.0 Hz, 1H), 1.91−1.83 (m, 1H), 1.69−1.59 (m, 1H), 1.06 (s, 3H),
0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 142.1, 128.5, 128.4, 125.8, 76.9, 73.3, 68.4, 33.8, 33.0, 25.8,
Synthesis of Cyclic Substrates 1l−u. Cyclic (racemic) substrates
1l, 1m, 1n, 1o, 1p, 1q, 1r, and 1u are known compounds and were
prepared according to the literature procedures.24
Data for ( )-3-Ethylcyclohex-2-en-1-ol (1n). 1n was obtained as a
1
colorless oil, chromatography using 4:1 PE/EtOAc): H NMR (500
MHz, CDCl3) δ 5.48 (br s, 1H), 4.20 (br s, 1H), 2.03−1.85 (m, 4H),
1.84−1.68 (m, 2H), 1.62−1.50 (m, 3H), 1.00 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 144.1, 122.3, 65.9, 32.0, 30.2,
28.5, 19.1, 12.0. FT-IR (film) 3389, 2962, 2928, 2855, 1668, 1456, 1066
cm−1; EI-MS m/z (%) 126 (M+, 2), 108 (4), 97 (100), 91 (6), 79 (24),
67 (13), 55 (22), 41 (20), 39 (13); EI-HRMS calcd. for C8H14O (M+)
126.1039, found 126.1041.
Data for ( )-3-Methylcyclohept-2-en-1-ol (1r, No Data Available
in the Literature). 1r was obtained as a colorless oil, 603 mg, 4.8 mmol,
96% by NaBH4/CeCl3/MeOH reduction from the corresponding
ketone, chromatography using 3:1 PE/EtOAc): 1H NMR (500 MHz,
CDCl3) δ 5.48−5.45 (m, 1H), 4.35 (br s, 1H), 2.13−1.97 (m, 2H),
1.93−1.85 (m, 1H), 1.84−1.77 (m, 1H), 1.72 (s, 3H), 1.68 (br s, 1H),
1.66−1.56 (m, 3H), 1.39−1.30 (m, 1H); 13C{1H} NMR (126 MHz,
CDCl3) δ 138.7, 131.6, 71.4, 36.6, 34.0, 27.1, 26.3, 25.7. EI-MS m/z
(%) 126 (M+, 40), 111 (84), 97 (100), 83 (64), 69 (55), 55 (78), 43
(55), 41 (83); EI-HRMS calcd. for C8H14O (M+) 126.1039, found
126.1035.
( )-3-Allylcyclohept-2-en-1-ol (1s). CeCl3·7H2O (857 mg, 2.3
mmol) was added to a solution of the known25 ketone (320 mg, 2.1
mmol) in MeOH (5 mL). The mixture was stirred at ambient
temperature until a homogeneous solution was obtained. Stirring was
then continued in an ice−water bath, while NaBH4 (87 mg, 2.3 mmol)
was introduced. After completion of the addition, the mixture was
stirred at the same temperature for another 10 min (TLC showed
completion of the reaction). Water (5 mL) was then added to quench
the reaction. The mixture was extracted with EtOAc (20 mL × 3). The
combined organic layers were washed with brine (10 mL) and dried
over anhydrous Na2SO4. Removal of the drying agent by filtration and
the solvent by rotary evaporation gave 1s as a colorless oil (310 mg, 2.0
mmol, 95%). 1H NMR (500 MHz, CDCl3) δ 5.75 (ddt, J = 17.0, 10.1,
6.8 Hz, 1H), 5.50−5.47 (m, 1H), 5.05−4.99 (m, 2H), 4.37 (d, J = 7.7
Hz, 1H), 2.71 (d, J = 6.8 Hz, 2H), 2.10−1.99 (m, 2H), 1.94−1.85 (m,
1H), 1.84−1.74 (m, 2H), 1.67−1.53 (m, 3H), 1.34−1.21 (m, 1H);
13C{1H} NMR (125 MHz, CDCl3) δ 140.4, 136.3, 132.7, 116.2, 71.6,
44.4, 36.6, 32.4, 27.4, 26.0. FT-IR (film) 3349, 2924, 2853, 1445, 1260,
1030, 911, 801 cm−1; EI-MS m/z (%) 152 (M+, 4), 134 (5), 111 (100),
93 (40), 79 (20), 67 (35), 55 (56), 43 (20), 41 (37); EI-HRMS calcd.
for C10H16O (M+) 152.1196, found 152.1193.
G
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25
( )-5-Methyl-3,6-dihydro-2H-pyran-3-ol (1t). Alcohol 1t was
obtained using the same procedure above for “Synthesis of (racemic)
1s”, except the starting 7-membered cyclic ketone was replace with the
known26 5-methyl-2H-pyran-3(6H) -one. Data for 1t (a colorless oil,
using 4:1 PE/EtOAc; [α]D −50.8 (c 1.0 CHCl3), 98% ee as
determined by HPLC on a CHIRALPAK IB column (ϕ 0.46 × 25 cm,
particle size = 5 μm) eluting with 98:2 of n-hexane/i-PrOH at a flow
1
rate of 0.7 mL/min with UV detector set to 214 nm. H NMR (500
1
180 mg, 1.6 mmol, 72%; chromatography using 1:1 PE/EtOAc): H
MHz, CDCl3) δ 7.31−7.26 (m, 2H), 7.23−7.15 (m, 3H), 5.55 (br s,
1H), 4.22 (br s, 1H), 3.31 (d, J = 16.7 Hz, 1H), 3.28 (d, J = 15.7 Hz,
1H), 1.96−1.67 (m, 4H), 1.61−1.50 (m, 2H); 13C{1H} NMR (125
MHz, CDCl3) δ 141.6, 139.3, 128.9, 128.3, 126.1, 125.7, 66.0, 44.2,
31.8, 28.2, 19.1.
NMR (500 MHz, CDCl3) δ 5.70 (br s, 1H), 4.02−3.90 (m, 3H), 3.83
(br d, J = 11.7 Hz, 1H), 3.64 (dd, J = 11.7, 2.6 Hz, 1H), 1.65 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 137.8, 121.3, 70.6, 68.7, 63.0,
18.6; FT-IR (film) 3359, 2920, 2849, 1659, 1646, 1632, 1470, 668
cm−1; ESI-MS m/z 137.05 ([M + Na]+); ESI-HRMS calcd. for
C6H10O2Na ([M + Na]+) 137.0573, found 137.0575.
Data for (R)-3-Ethylcyclohex-2-en-1-ol ((R)-1n). (R)-1n was
obtained as a yellowish oil, 49 mg, 0.39 mmol, 39%; chromatography
25
using 4:1 PE/EtOAc; [α]D +73.4 (c 1.0 CHCl3), 96% ee as
Novozyme 435 Resolution of ( )-3-(3-Butenyl)-cyclohex-2-en-1-
ol (1p, Typical Procedure24a). Novezyme 435 (7.0 mg, ca. 2.2% of the
substrate weight) was added to a 1 M solution of racemic 1p (304 mg,
2.0 mmol) in n-hexane (2 mL) and vinyl butanoate (228 mg, 2 mol
equiv with respect to 1p). The mixture was stirred at ambient
temperature (ca. 24 °C) for about 5 h. The solid enzyme was filtered off
through Celite with suction. The filtrate was concentrated on a rotary
evaporator. The residue was subjected to column chromatography on
silica gel (10:1 to 4:1 PE/EtOAc) to give in turn the butanoate of (R)-
1p′ (along with some unreacted vinyl butanoate) and pure (S)-1p as a
colorless oil (147 mg, 0.96 mmol, 48% yield from racemic 1p 96% ee).
The ester (R)-1p′ (along with small amounts of 1p) was dissolved in
MeOH (2 mL), to which aq. NaOH (4 M, 0.5 mL, 2 mmol) was added.
The solution was stirred at ambient temperature until TLC showed
completion of the hydrolysis (the reaction mixture might turn yellowish
due to self-condensation of the acetaldehyde generated from the
hydrolysis of the unreacted vinyl butanoate). The mixture was extracted
with EtOAc (10 mL × 2). The combined organic layers were washed
with brine (10 mL) and dried over anhydrous Na2SO4. Removal of the
drying agent by filtration and the solvent by rotary evaporation gave an
oily residue, which was purified by column chromatography (4:1 PE/
EtOAc) on silica to give (R)-1p as a yellowish oil (135 mg, 0.88 mmol,
44%, 97% ee).
Substrates 1l, 1n, 1o, 1q, 1r, 1s, and 1t were all resolved using the
above procedure. Substrate 1m was resolved using the same procedure,
but with 2:1 n-hexane/EtOAc to replace n-hexane as the solvent.
Compound 1u was resolved using lipase AK according to the
literature.24f
Data for (R)-3-Methylcyclohex-2-en-1-ol ((R)-1l). (R)-1l was
obtained as a yellowish oil; 20.8 g, 185 mmol, 43%; chromatography
using 4:1 PE/EtOAc; [α]D25 +88.5 (c 1.0 CHCl3) (lit.24a [α]D22 +96.0
(c 0.423, CHCl3). 94% ee as determined by HPLC on a CHIRALPAK
AD-H column (ϕ 0.46 × 25 cm, particle size = 5 μm) eluting with 98:2
of n-hexane/i-PrOH at a flow rate of 0.7 mL/min with UV detector set
to 214 nm. 1H NMR (500 MHz, CDCl3) δ 5.48 (m, 1H), 4.16 (m, 1H),
1.83−1.96 (m, 2H), 1.70−1.81 (m, 2H), 1.67 (s, 3H), 1.52−1.61 (m,
2H).
determined by HPLC on a CHIRALPAK IG column (ϕ 0.46 × 25 cm,
particle size = 5 μm) eluting with 95:5 of n-hexane/i-PrOH at a flow
1
rate of 0.7 mL/min with UV detector set to 214 nm. H NMR (500
MHz, CDCl3) δ 5.48 (br s, 1H), 4.20 (br s, 1H), 2.04−1.54 (m, 9H),
1.00 (t, J = 7.5 Hz, 3H).
Data for (S)-3-Ethylcyclohex-2-en-1-ol ((S)-1n). (S)-1n was
obtained as a yellowish oil, 57 mg, 0.45 mmol, 45%; chromatography
using 4:1 PE/EtOAc; [α]D25 −62.2 (c 1.0 CHCl3) (lit.27 [α]D −27.9 (c
0.4, CHCl3); (lit.24b [α]D20 −61 (c unknown, CHCl3), 77% ee)), 87%
ee as determined by HPLC on a CHIRALPAK IG column (ϕ 0.46 × 25
cm, particle size = 5 μm) eluting with 95:5 of n-hexane/i-PrOH at a flow
1
rate of 0.7 mL/min with UV detector set to 214 nm. H NMR (500
MHz, CDCl3) δ 5.48 (br s, 1H), 4.20 (br s, 1H), 2.02−1.56 (m, 9H),
1.00 (t, J = 7.5 Hz, 3H).
Data for (R)-3-Allylcyclohex-2-en-1-ol ((R)-1o). (R)-1o was
obtained as a colorless oil, 190 mg, 1.37 mmol, 46%; chromatography
20
using 4:1 PE/EtOAc; [α]D +65.4 (c 1.0 CHCl3), 99% ee as
determined by GC on a DB-WAX quartz capillary column (ϕ 0.25 mm
× 30 m, df (dimension of film) = 0.25 μm) with the injector
temperature set to 250 °C, the column temperature changed from 50 to
250 °C at a rate of 10 °C/min, N2 as carrier gas (at a flow rate of 2 mL/
min), and the effluents detected using a H2 flame ionization detector.
1H NMR (500 MHz, CDCl3) δ 5.80 (ddt, J = 16.8, 10.3, 6.9 Hz, 1H),
5.56−5.53 (m, 1H), 5.08−5.05 (m, 1H), 5.04−5.03 (m, 1H), 4.21 (br s,
1H), 2.72 (d, J = 6.7 Hz, 1H), 2.01−1.86 (m, 2H), 1.85−1.70 (m, 2H),
1.63−1.55 (m, 2H), 1.49 (br s, 1H, −OH).
Data for (S)-3-Allylcyclohex-2-en-1-ol ((S)-1o). (S)-1o was
obtained as a colorless oil, 201 mg, 1.45 mmol, 48%; chromatography
20
using 4:1 PE/EtOAc; [α]D −54.9 (c 1.0 CHCl3), 91% ee as
determined by GC on a DB-WAX quartz capillary column (ϕ 0.25 mm
× 30 m, df (dimension of film) = 0.25 μm) with the injector
temperature set to 250 °C, the column temperature changed from 50 to
250 °C at a rate of 10 °C/min, N2 as carrier gas (at a flow rate of 2 mL/
min), and the effluents detected using a H2 flame ionization detector.
1H NMR (500 MHz, CDCl3) δ 5.83−5.73 (m, 1H), 5.53 (br s, 1H),
5.05 (br d, J = 7.8 Hz, 1H), 5.02 (br s, 1H), 4.20 (br s, 1H), 2.71 (d, J =
6.7 Hz, 2H), 2.01−1.85 (m, 2H), 1.83−1.69 (m, 2H), 1.63−1.53 (m,
2H).
Data for (S)-3-Methylcyclohex-2-en-1-ol ((S)-1l). (S)-1l was
obtained as a colorless oil, 22.9 g, 204 mmol, 48%; chromatography
using 4:1 PE/EtOAc; [α]D25 −92.6 (c 1.0 CHCl3) (lit.24a [α]D24 −96.3
(c 0.458, CHCl3)), 97% ee as determined by HPLC on a CHIRALPAK
AD-H column (ϕ 0.46 × 25 cm, particle size = 5 μm) eluting with 98:2
of n-hexane/i-PrOH at a flow rate of 0.7 mL/min with UV detector set
to 214 nm. 1H NMR (500 MHz, CDCl3) δ 5.48 (m, 1H), 4.16 (m, 1H),
1.83−1.96 (m, 2H), 1.70−1.81 (m, 2H), 1.67 (s, 3H), and 1.52−1.61
(m, 2H).
Data for (R)-3-(3-Butenyl)-cyclohex-2-en-1-ol ((R)-1p). (R)-1p was
obtained as a yellowish oil, 135 mg, 0.88 mmol, 44%; chromatography
using 10:1 PE/EtOAc for the corresponding butanoate and 4:1 PE/
25
EtOAc for the alcohol; [α]D +64.6 (c 1.0, CHCl3), 97% ee as
determined by HPLC on a CHIRALPAK IF3 column (ϕ 0.46 × 25 cm,
particle size = 3 μm) eluting with 98:2 of n-hexane/i-PrOH at a flow
1
rate of 0.7 mL/min with UV detector set to 214 nm. H NMR (500
Data for (R)-3-Benzylcyclohex-2-en-1-ol ((R)-1m). (R)-1m was
MHz, CDCl3) δ 5.80 (ddt, J = 17.0, 10.1, 6.5 Hz, 1H), 5.51 (br s, 1H),
5.01 (br d, J = 17.1 Hz, 1H), 4.95 (br d, J = 10.1 Hz, 1H), 4.19 (br s,
1H), 2.21−2.14 (m, 2H), 2.08−2.03 (m, 2H), 2.00−1.85 (m, 2H),
1.83−1.69 (m, 2H), 1.62−1.53 (m, 2H), 1.46 (br s, 1H); 13C{1H}
NMR (125 MHz, CDCl3) δ 141.7, 138.3, 124.0, 114.6, 65.9, 36.8, 31.9,
31.7, 28.5, 19.0.
obtained as a colorless oil, 162 mg, 0.86 mmol, 45%; chromatography
25
using 4:1 PE/EtOAc; [α]D +30.8(c 1.0 CHCl3), 92% ee as
determined by HPLC on a CHIRALPAK IB column (ϕ 0.46 × 25
cm, particle size = 5 μm) eluting with 98:2 of n-hexane/i-PrOH at a flow
1
rate of 0.7 mL/min with UV detector set to 214 nm. H NMR (500
MHz, CDCl3) δ 7.31−7.26 (m, 2H), 7.23−7.15 (m, 3H), 5.55 (br s,
1H), 4.22 (br s, 1H), 3.31 (d, J = 15.9 Hz, 1H), 3.28 (d, J = 16.6 Hz,
1H), 1.96−1.67 (m, 4H), 1.64 (br s, 1H), 1.61−1.50 (m, 2H); 13C{1H}
NMR (125 MHz, CDCl3) δ 141.6, 139.4, 128.9, 128.3, 126.1, 125.7,
66.0, 44.2, 31.8, 28.2, 19.1.
Data for (S)-3-Benzylcyclohex-2-en-1-ol ((S)-1m). (S)-1m was
obtained as a colorless oil, 145 mg, 0.77 mmol, 40%; chromatography
Data for (S)-3-(3-Butenyl)-cyclohex-2-en-1-ol ((S)-1p). (S)-1p was
obtained as a yellowish oil, 147 mg, 0.96 mmol, 48%; chromatography
25
using 4:1 PE/EtOAc; [α]D −66.5 (c 1.0, CHCl3), 96% ee as
determined by HPLC on a CHIRALPAK IF3 column (ϕ 0.46 × 25 cm,
particle size = 3 μm e) eluting with 98:2 of n-hexane/i-PrOH at a flow
1
rate of 0.7 mL/min with UV detector set to 214 nm. H NMR (500
MHz, CDCl3) δ 5.80 (ddt, J = 17.1, 10.2, 6.5 Hz, 1H), 5.51 (br s, 1H),
H
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5.01 (br d, J = 17.1 Hz, 1H), 4.95 (br d, J = 10.1 Hz, 1H), 4.19 (br s,
1H), 2.21−2.14 (m, 2H), 2.08−2.03 (m, 2H), 2.00−1.85 (m, 2H),
1.83−1.69 (m, 2H), 1.62−1.53 (m, 2H), 1.46 (br s, 1H); 13C{1H}
NMR (125 MHz, CDCl3) δ 141.7, 138.3, 124.0, 114.6, 65.9, 36.8, 31.9,
31.7, 28.5, 19.0.
Data for (R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-cyclohex-2-
en-1-ol ((R)-1q). (R)-1q was obtained as a yellowish oil, 140 mg, 0.58
mmol, 29%; chromatography using 5:1 PE/EtOAc; [α]D25 +34.4 (c 1.0,
CHCl3), 97% ee as determined by HPLC on a CHIRALPAK OD-H
column (ϕ 0.46 × 25 cm, particle size = 5 μm) eluting with 98:2 of n-
hexane/i-PrOH at a flow rate of 0.7 mL/min with UV detector set to
214 nm. 1H NMR (500 MHz, CDCl3) δ 5.77−5.74 (m, 1H), 4.23 (br s,
1H), 4.02 (s, 2H), 1.99−1.71 (m, 4H), 1.63−1.57 (m, 2H), 0.91 (s,
9H), 0.07 (s, 6H).
Data for (S)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-cyclohex-2-
en-1-ol ((S)-1q). (S)-1q was obtained as a yellowish oil, 241 mg, 0.99
mmol, 50%; chromatography using 5:1 PE/EtOAc; [α]D25 −28.5 (c 1.0,
CHCl3), 92% ee as determined by HPLC on a CHIRALPAK OD-H
column (ϕ 0.46 × 25 cm, particle size = 5 μm) eluting with 98:2 of n-
hexane/i-PrOH at a flow rate of 0.7 mL/min with UV detector set to
214 nm. 1H NMR (500 MHz, CDCl3) δ 5.77−5.74 (m, 1H), 4.23 (br s,
1H), 4.02 (s, 2H), 1.95−1.81 (m, 3H), 1.78−1.70 (m, 1H), 1.65−1.57
(m, 2H), 0.91 (s, 9H), 0.07 (s, 6H).
+206.1 (c 1.0, CHCl3), 94% ee as determined by HPLC on a
CHIRALPAK IE3 column (ϕ 0.46 × 25 cm, particle size = 3 μm)
eluting with 80:20 of n-hexane/i-PrOH at a flow rate of 0.7 mL/min
with UV detector set to 214 nm. 1H NMR (500 MHz, CDCl3) δ 5.69 (s,
1H), 4.02−3.89 (m, 3H), 3.82 (d, J = 11.6 Hz, 1H), 3.63 (d, J = 11.6 Hz,
1H), 2.00 (d, J = 4.8 Hz, 1H), 1.64 (s, 3H).
Data for (R)-5-Methyl-3,6-dihydro-2H-pyran-3-ol ((R)-1t). (R)-1t
was the enantiomer isolated directly from the enzyme resolution
mixture, a colorless oil, 187 mg, 1.64 mmol, 43%; chromatography
25
using 1:1 PE/EtOAc; [α]D −183.3 (c 0.5, CHCl3), 84% ee as
determined by HPLC on a CHIRALPAK IE3 column (ϕ 0.46 × 25 cm,
particle size = 3 μm) eluting with 80:20 of n-hexane/i-PrOH at a flow
1
rate of 0.7 mL/min with UV detector set to 214 nm. H NMR (500
MHz, CDCl3) δ 5.69 (br s, 1H), 3.99−3.87 (m, 3H), 3.80 (dd, J = 11.8,
1.3 Hz, 1H), 3.62 (dd, J = 11.7, 2.6 Hz, 1H), 2.25 (br s, 1H), 1.63 (s,
3H). The absolute configuration of (R)-1t was also confirmed by CBS
reduction of the corresponding ketone (using (R)- CBS-methyl-
oxazaborolidne/BH3), which according to the empirical rule, should
25
give (R)-1t, and the product showed a negative optical rotation [α]D
−117.4 (c 0.8, CHCl3).
Data for (S)-1-(Benzyloxycarbonyl)-3-hydroxy-5-methyl-1,2,3,6-
tetrahydro- pyridine ((S)-1u). (S)-1u was the enantiomer obtained
after hydrolysis of the ester, a colorless oil, 90 mg, 0.36 mmol, 36%;
25
Data for (R)-3-Methylcyclohept-2-en-1-ol ((R)-1r). (R)-1r was
chromatography using 2:1 PE/EtOAc; [α]D −81.3 (c 1.0, CHCl3),
25
obtained as a yellowish oil, 120 mg, 0.95 mmol, 33%; chromatography
[α]D −43.4 (c 1.3, EtOH), 99% ee as determined by HPLC on a
25
using 5:1 PE/EtOAc; [α]D +18.0 (c 1.0, CHCl3), 98% ee as
CHIRALPAK AD-H column (ϕ 0.46 × 25 cm, particle size = 5 μm)
eluting with 95:5 of n-hexane/i-PrOH at a flow rate of 0.7 mL/min with
UV detector set to 220 nm. 1H NMR (500 MHz, CDCl3) δ 7.39−7.28
(m, 5H), 5.64 (br s, 1H), 5.21−5.11 (m, 2H), 4.24−4.09 (m, 1H),
4.06−3.88 (m, 1H), 3.74−3.61 (m, 2H), 3.53−3.43 (m, 1H), 1.72 (s,
3H).
determined by HPLC on a CHIRALPAK IG column (ϕ 0.46 × 25 cm,
particle size = 5 μm) eluting with 95:5 of n-hexane/i-PrOH at a flow
1
rate of 0.7 mL/min with UV detector set to 214 nm. H NMR (500
MHz, CDCl3) δ 5.46 (br s, 1H), 4.35 (br s, 1H), 2.13−2.06 (m, 1H),
2.00 (dd, J = 14.9, 7.1 Hz, 1H), 1.93−1.86 (m, 1H), 1.84−1.78 (m,
1H), 1.72 (s, 3H), 1.67−1.51 (m, 4H), 1.40−1.29 (m, 1H); 13C{1H}
NMR (125 MHz, CDCl3) δ 138.7, 131.5, 71.4, 36.6, 34.0, 27.0, 26.3,
25.7.
Data for (R)-1-(Benzyloxycarbonyl)-3-hydroxy-5-methyl-1,2,3,6-
tetrahydro- pyridine ((R)-1u). (R)-1u was the enantiomer isolated
directly from the enzyme resolution mixture, a colorless oil, 130 mg,
0.53 mmol, 53%; chromatography using 2:1 PE/EtOAc; [α]D25 +60.1
Data for (S)-3-Methylcyclohept-2-en-1-ol ((S)-1r). (S)-1r was
(c 1.0, CHCl3), [α]D +38.3 (c 1.3, EtOH) (lit.24f [α]D +44 (c 1.3,
25
obtained as a yellowish oil, 186 mg, 1.47 mmol, 52%; chromatography
25
using 5:1 PE/EtOAc; [α]D −5.7 (c 1.0, CHCl3), 72% ee as
EtOH)), 79% ee as determined by HPLC on a CHIRALPAK AD-H
column (ϕ 0.46 × 25 cm, particle size = 5 μm) eluting with 95:5 of n-
hexane/i-PrOH at a flow rate of 0.7 mL/min with UV detector set to
220 nm. 1H NMR (500 MHz, CDCl3) δ 7.42−7.27 (m, 5H), 5.64 (br s,
1H), 5.20−5.11 (m, 2H), 4.16 (d, J = 28.1 Hz, 1H), 4.06−3.87 (m,
1H), 3.70 (d, J = 17.8 Hz, 2H), 3.55−3.42 (m, 1H), 1.72 (s, 3H).
Synthesis of Substrates 1v−z. These compounds were all
synthesized according to the literature.28
determined by HPLC on a CHIRALPAK IG column (ϕ 0.46 × 25
cm, particle size = 5 μm) eluting with 95:5 of n-hexane/i-PrOH at a flow
1
rate of 0.7 mL/min with UV detector set to 214 nm. H NMR (500
MHz, CDCl3) δ 5.47−5.44 (m, 1H), 4.34 (d, J = 7.1 Hz, 1H), 2.12−
2.05 (m, 1H), 2.03−1.96 (m, 1H), 1.92−1.85 (m, 1H), 1.8−1.75 (m,
1H), 1.71 (s, 3H), 1.69 (s, 1H), 1.64−1.55 (m, 3H), 1.39−1.29 (m,
1H); 13C{1H} NMR (125 MHz, CDCl3) δ 138.7, 131.6, 71.4, 36.6,
33.9, 27.1, 26.3, 25.7.
Data for (2R,4aR,5R)-5-((tert-butyldimethylsilyl)oxy)-4a-methyl-
2,3,4,4a,5,6,7,8-octahydronaphthalen-2-ol (1w). 1w was obtained as
a colorless oil, 340 mg, 1.15 mmol, chromatography using 4:1 PE/
EtOAc; [α]D25 −53.5 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3) δ
5.37 (br s, 1H), 4.16 (br s, 1H), 3.20 (dd, J = 10.8, 5.0 Hz, 1H), 2.17−
2.07 (m, 1H), 1.98−1.87 (m, 2H), 1.82−1.68 (m, 2H), 1.65−1.53 (m,
2H), 1.49−1.38 (m, 2H), 1.34−1.15 (m, 2H), 1.03 (s, 3H), 0.88 (s,
9H), 0.02 (s, 3H), 0.02 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
145.4, 125.5, 79.4, 67.8, 41.2, 34.1, 31.4, 31.3, 29.1, 25.8, 24.4, 18.1,
17.1, −3.9, −4.9.
Data for (R)-3-Allylcyclohept-2-en-1-ol ((R)-1s). (R)-1s was
obtained as a colorless oil, 80 mg, 0.53 mmol, 28%; chromatography
25
using 4:1 PE/EtOAc): [α]D +19.0 (c 1.0, CHCl3), 98% ee as
determined by HPLC on a CHIRALPAK AD-H column (ϕ 0.46 × 25
cm, particle size = 5 μm) eluting with 98:2 of n-hexane/i-PrOH at a flow
1
rate of 0.7 mL/min with UV detector set to 214 nm. H NMR (500
MHz, CDCl3) δ 5.76 (ddt, J = 16.9, 10.1, 6.8 Hz, 1H), 5.49 (br s, 1H),
5.07−5.00 (m, 2H), 4.39 (d, J = 6.9 Hz, 1H), 2.72 (d, J = 6.7 Hz, 2H),
2.12−1.99 (m, 2H), 1.96−1.87 (m, 1H), 1.86−1.76 (m, 1H), 1.72−
1.51 (m, 4H), 1.36−1.21 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3)
δ 140.5, 136.3, 132.6, 116.2, 71.7, 44.4, 36.6, 32.4, 27.3, 26.0.
Data for (2S,4R,4aS,6R)-4,4a-dimethyl-6-(prop-1-en-2-yl)-
2,3,4,4a,5,6,7,8-octahydronaphthalen-2-ol (1x). 1x was obtained as
a colorless oil, 918 mg, 4.17 mmol, 91% yield from corresponding
Data for (S)-3-Allylcyclohept-2-en-1-ol ((S)-1s). (S)-1s was
25
ketone, chromatography using 5:1 PE/EtOAc; [α]D +105.1 (c 1.0,
obtained as a colorless oil, 186 mg, 1.47 mmol, 52%; chromatography
CHCl3) (lit.29 [α]D +208 (c 1.1, CHCl3)). 1H NMR (500 MHz,
CDCl3) δ 5.32 (br d, J = 1.6 Hz, 1H), 4.70−4.66 (m, 2H), 4.28−4.21
(m, 1H), 2.37−2.21 (m, 2H), 2.11 (ddd, J = 14.1, 4.1, 2.6 Hz, 1H),
1.89−1.75 (m, 3H), 1.70 (s, 3H), 1.63 (s, 1H), 1.55−1.47 (m, 1H),
1.42−1.32 (m, 2H), 1.25−1.16 (m, 1H), 0.99 (s, 3H), 0.95 (t, J = 12.7
Hz, 1H), 0.89 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
150.2, 146.0, 124.2, 108.5, 68.0, 44.6, 40.8, 39.3, 38.2, 37.2, 32.9, 32.3,
20.8, 18.2, 15.4.
25
using 4:1 PE/EtOAc; [α]D −8.9 (c 1.0, CHCl3), 42% ee as
determined by HPLC on a CHIRALPAK AD-H column (ϕ 0.46 ×
25 cm, particle size = 5 μm) eluting with 98:2 of n-hexane/i-PrOH at a
flow rate of 0.7 mL/min with UV detector set to 214 nm. 1H NMR (500
MHz, CDCl3) δ 5.75 (ddt, J = 16.9, 10.1, 6.8 Hz, 1H), 5.48 (br s, 1H),
5.07−4.98 (m, 2H), 4.37 (d, J = 6.8 Hz, 1H), 2.70 (d, J = 6.7 Hz, 2H),
2.13−1.98 (m, 2H), 1.95−1.86 (m, 1H), 1.85−1.74 (m, 2H), 1.66−
1.53 (m, 3H), 1.34−1.20 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3)
δ 140.4, 136.3, 132.7, 116.2, 71.6, 44.4, 36.6, 32.4, 27.4, 26.0.
Data for Cholest-4-en-3β-ol (1y). 1y was obtained as a white solid,
189 mg, 0.48 mmol, chromatography using 6:1 PE/EtOAc; mp 133−
135 °C (lit.28e 135−136 °C). [α]D25 +56.1 (c 0.1, CHCl3) (lit.30 [α]D
+47.5 (c 1.0, CHCl3)). 1H NMR (500 MHz, CDCl3) δ 5.27 (br d, J =
Data for (S)-5-Methyl-3,6-dihydro-2H-pyran-3-ol ((S)-1t). (S)-1t
was the enantiomer obtained after hydrolysis of the ester, a colorless oil,
25
151 mg, 1.32 mmol, 35%; chromatography using 1:1 PE/EtOAc; [α]D
I
https://dx.doi.org/10.1021/acs.joc.0c01280
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1.5 Hz, 1H), 4.18−4.11 (m, 1H), 2.25−2.14 (m, 1H), 2.04−1.91 (m,
3H), 1.86−1.66 (m, 3H), 1.55−1.19 (m, 13H), 1.04 (s, 3H), 1.17−0.92
(m, 8H), 0.90 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H), 0.86 (d, J =
6.6 Hz, 3H), 0.76−0.70 (m, 1H), 0.67 (s, 3H).
[α]D25 −13.3 (c 1.0, MeOH). 1H NMR (500 MHz, CD3OD) δ 3.81−
3.76 (m, 1H), 3.73 (d, J = 2.7 Hz, 1H), 1.70 (q, J = 7.5 Hz, 2H), 1.64 (br
d, J = 13.8 Hz, 1H), 1.60−1.41 (m, 4H), 1.40−1.30 (m, 1H), 0.90 (t, J =
7.5 Hz, 3H); 13C{1H} NMR (125 MHz, CD3OD) δ 85.8, 70.1, 68.6,
27.3, 26.6, 25.5, 18.6, 5.4. FT-IR (film in CHCl3) 3374, 2940, 2880,
1459, 1382, 1069, 1042, 996, 829 cm−1; ESI-MS m/z 198.95 ([M +
Na]+); ESI-HRMS calcd. for C8H16O4Na ([M + Na]+) 199.0941,
found 199.0941.
Data for 7β-Hydroxycholest-5-en-3β-yl acetate (1z). 1z was
obtained as a white solid, 724 mg, 1.63 mmol, chromatography using
4:1 PE/EtOAc; mp 111−112 C (lit.28e 110−111 °C). [α]D25 −12.4 (c
0.1, CHCl3) (lit.30 [α]D −132.6 (c 0.1, CHCl3), lit.31 [α]D23 −9 (c 0.1,
CHCl3)). 1H NMR (500 MHz, CDCl3) δ 5.30 (br s, 1H), 4.66−4.55
(m, 1H), 3.89−3.82 (m, 1H), 2.38−2.28 (m, 2H), 2.02 (s, 3H), 1.93−
1.75 (m, 4H), 1.64−1.24 (m, 12H), 1.21−0.95 (m, 9H), 1.05 (s, 3H),
0.91 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz,
3H), 0.68 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 170.5, 142.3,
126.3, 73.4, 73.2, 55.9, 55.4, 48.1, 42.9, 40.7, 39.5, 37.6, 36.6, 36.5, 36.2,
35.7, 28.5, 28.0, 27.7, 26.3, 23.8, 22.8, 22.5, 21.4, 21.0, 19.1, 18.7, 11.8.
MoO2(acac)2 Mediated Formal Hydroxylation−Hydroperox-
ylation of 1l (Typical Procedure). To a solution of (S)-1l (449 mg,
4.0 mml) in freshly prepared H2O2-saturated Et2O (20 mL) was added
MoO2(acac)2 (65 mg, 0.2 mmol). The pale yellow−greenish
transparent solution was stirred at ambient temperature for 4 h (TLC
showed completion of the reaction). Aq. sat. NaCl (4 mL) was added to
quench the reaction. Phases were separated. The aq. layer was extracted
with EtOAc (20 mL × 5). The combined organic layers were dried over
anhydrous Na2SO4. Removal of the drying agent by filtration and the
solvent by rotary evaporation left an oily residue, which was purified by
column chromatography (1:1 PE/EtOAc) on silica gel to give diol-
hydroperoxide 2l (colorless sticky oil, 512 mg, 3.16 mmol, 79% from 1l)
and triol 3l (52 mg, 0.36 mmol, 9% from 1l).
Data for (1R,2R,3R)-1-Ethylcyclohexane-1,2,3-triol (3n). 3n was
obtained as a colorless oil, 560 mg, 3.5 mmol, 11%; more polar than 2n,
25
chromatography using 1:3 PE/EtOAc; [α]D −10.7 (c 1.0, MeOH).
1H NMR (500 MHz, CD3OD) δ 3.89 (ddd, J = 10.0, 5.5, 2.9 Hz, 1H),
3.51 (d, J = 2.7 Hz, 1H), 1.65−1.54 (m, 4H), 1.54−1.41 (m, 3H),
1.39−1.33 (m, 1H), 0.91 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (125 MHz,
CD3OD) δ 74.4, 73.2, 68.6, 31.5, 30.4, 27.5, 18.8, 5.4. FT-IR (film)
3396, 2940, 2880, 1459, 1395, 1151, 1069, 1041, 996, 962, 874, 834
cm−1; ESI-MS m/z 182.90 ([M + Na]+); ESI-HRMS calcd. for
C8H16O3Na ([M + Na]+) 183.0992, found 183.0994.
Data for (1S,2S,3R)-3-Allyl-3-hydroperoxycyclohexane-1,2-diol
(2o). 2o was obtained as a colorless sticky oil, 74 mg, 0.39 mmol,
25
78%; less polar than 3o, chromatography using 2:1 PE/EtOAc; [α]D
+9.4 (c 1.0, MeOH). 1H NMR (500 MHz, CD3OD) δ 6.00−5.90 (m,
1H), 5.10−5.02 (m, 2H), 3.84−3.77 (m, 2H), 2.51 (dd, J = 14.4, 6.8
Hz, 1H), 2.42 (dd, J = 14.4, 7.7 Hz, 1H), 1.62−1.35 (m, 6H); 13C{1H}
NMR (125 Hz, CD3OD) δ 133.8, 116.2, 85.4, 70.6, 68.5, 37.8, 27.2,
26.9, 18.5; FT-IR (film) 3348, 2943, 1051, 999, 668 cm−1; ESI-MS m/z
211.00 ([M + Na]+); ESI-HRMS calcd. for C9H16O4Na ([M + Na]+)
211.0941, found 211.0940.
Data for (1S,2S,3S)-3-Hydroperoxy-3-methylcyclohexane-1,2-
Data for (1R,2S,3S)-1-Allylcyclohexane-1,2,3-triol (3o). 3o was
diol (2l). 2l was obtained as a colorless sticky oil, 512 mg, 3.16 mmol,
obtained as a colorless sticky oil, 10 mg, 0.058 mmol, 11%; more polar
25
25
79%; less polar than 3l, chromatography using 1:1 PE/EtOAc; [α]D
than 2o, chromatography using 1:1 PE/EtOAc; [α]D +3.5 (c 0.5,
+18.9 (c 1.0, MeOH). 1H NMR (500 MHz, CD3OD) δ 3.85 (dt, J = 2.9,
7.6 Hz, 1H), 3.75 (d, J = 3.1 Hz, 1H), 1.59−1.42 (m, 6H), 1.28 (s, 3H);
13C{1H} NMR (125 MHz, CD3OD) δ 84.2, 72.0, 68.5, 29.1, 27.1, 20.7,
18.6; FT-IR (film) 3386, 2941, 1370, 1061 cm−1; ESI-MS m/z 185.10
([M + Na]+); ESI-HRMS calcd. for C7H14O4Na ([M + Na]+)
185.0784, found 185.0779.
MeOH). 1H NMR (500 MHz, CD3OD) δ 5.96−5.89 (m, 1H), 5.10−
5.04 (m, 2H), 3.82−3.87 (m, 1H), 3.49 (d, J = 2.5 Hz, 1H), 2.35 (dd, J =
14.0, 7.0 Hz, 1H), 2.26 (dd, J = 14.0, 7.8 Hz, 1H), 1.63−1.27 (m, 7H);
13C{1H} NMR (125 Hz, CD3OD) δ 133.5, 116.8, 74.2, 73.9, 68.5, 43.8,
30.4, 27.4, 18.7; FT-IR (film) 3393, 2939, 1049, 999, 669 cm−1; ESI-MS
m/z 194.95 ([M + Na]+); ESI-HRMS calcd. for C9H16O3Na ([M +
Na]+) 195.0992, found 195.0991.
Data for (1S,2S,3S)-1-methylcyclohexane-1,2,3-triol (3l). 3l was
obtained as a colorless sticky oil, 52 mg, 0.36 mmol, 9%; more polar
Data for (1R,2R,3S)-3-(But-3-en-1-yl)-3-hydroperoxycyclohex-
ane-1,2-diol (2p). 2p was obtained as a colorless sticky oil, 70 mg,
0.34 mmol, 69%; less polar than 3p, chromatography using 2:1 PE/
EtOAc; [α]D25 −14.3 (c 1.0, MeOH). 1H NMR (500 MHz, CD3OD) δ
5.87 (ddt, J = 17.0, 10.3, 6.6 Hz, 1H), 5.03 (ddt, J = 17.1, 1.9, 1.6 Hz,
1H), 4.91 (ddt, J = 10.2, 2.0, 1.0 Hz, 1H), 3.82−3.77 (m, 1H), 3.75 (d, J
= 2.5 Hz, 1H), 2.24−2.09 (m, 2H), 1.81−1.72 (m, 2H), 1.69−1.63 (m,
1H), 1.62−1.49 (m, 4H), 1.48−1.36 (m, 2H); 13C{1H} NMR (125 Hz,
CD3OD) δ 139.3, 112.8, 85.5, 70.4, 68.6, 32.6, 27.3, 27.0, 26.2, 18.6;
FT-IR (film) 3403, 2938, 1709, 1448, 1054, 997 cm−1; ESI-MS m/z
225.05 ([M + Na]+); ESI-HRMS calcd. for C10H18O4Na ([M + Na]+)
225.1097, found 225.1092.
25
than 2l, chromatography using 1:1 PE/EtOAc; [α]D +9.2 (c 1.0,
MeOH). 1H NMR (500 MHz, CD3OD) δ 3.94−3.89 (m, 1H), 3.43 (d,
J = 2.7 Hz, 1H), 1.62−1.45 (m, 5H), 1.35−1.27 (m, 2H), 1.22 (s, 3H);
13C{1H} NMR (125 MHz, CD3OD) δ 75.8, 72.6, 68.5, 32.2, 27.2, 26.3,
18.8; FT-IR (film) 3387, 2937, 1059, 1032 cm−1; ESI-MS m/z 169.00
([M + Na]+); ESI-HRMS calcd. for C7H14O3Na ([M + Na]+)
169.0835, found 169.0834.
Data for (1S,2S,3R)-3-Benzyl-3-hydroperoxycyclohexane-1,2-diol
(2m). 2m was obtained as a white solid, 96 mg, 0.40 mmol, 80%; less
polar than 3m, chromatography using 2:1 PE/EtOAc; mp 84−86 °C.
[α]D25 +29.2 (c 1.0, MeOH). 1H NMR (500 MHz, CD3OD) δ 7.37−
7.33 (m, 2H), 7.24−7.12 (m, 3H), 3.80 (ddd, J = 10.9, 5.2, 2.9 Hz, 1H),
3.64 (d, J = 2.6 Hz, 1H), 3.03 (d, J = 13.9 Hz, 1H), 2.98 (d, J = 13.9 Hz,
1H), 1.64−1.53 (m, 2H), 1.51−1.38 (m, 4H), 1.29 (br s, 1H); 13C{1H}
NMR (125 MHz, CD3OD) δ 137.4, 130.7, 127.1, 125.4, 85.8, 70.3,
68.6, 38.1, 27.1, 26.9, 18.5; FT-IR (KBr) 3347, 2925, 1455, 1031, 997,
730, 696, 660 cm−1; ESI-MS m/z 261.00 ([M + Na]+); ESI-HRMS
calcd. for C13H18O4Na ([M + Na]+) 261.1097, found 261.1098.
Data for (1R,2S,3S)-1-benzylcyclohexane-1,2,3-triol (3m). 3m was
obtained as a colorless sticky oil, 8 mg, 0.036 mmol, 7%; more polar
Data for (1S,2R,3R)-1-(But-3-en-1-yl)-cyclohexane-1,2,3-triol
(3p). 3p was obtained as a colorless sticky oil, 10 mg, 0.054 mmol,
25
10%; more polar than 2p, chromatography using 1:1 PE/EtOAc; [α]D
−31.7 (c 0.1, MeOH). 1H NMR (500 MHz, CD3OD) δ 5.86 (ddt, J =
16.9, 10.2, 6.6 Hz, 1H), 5.02 (ddt, J = 17.1, 2.0, 1.6 Hz, 1H), 4.91 (ddt, J
= 10.2, 2.1, 1.2 Hz, 1H), 3.90 (ddd, J = 9.7, 5.5, 2.9 Hz, 1H), 3.52 (d, J =
2.5 Hz, 1H), 2.24−2.09 (m, 2H), 1.71−1.45 (m, 6H), 1.41−1.27 (m,
2H); 13C{1H} NMR (125 Hz, CD3OD) δ 139.2, 112.9, 74.1, 73.6, 68.6,
38.7, 30.7, 27.4, 26.3, 18.7; FT-IR (film) 3393, 2937, 1709, 1447, 1053,
998 cm−1; ESI-MS m/z 208.95 ([M + Na]+); ESI-HRMS calcd. for
C10H18O3Na ([M + Na]+) 209.1148, found 209.1147.
25
than 2m, chromatography using 1:1 PE/EtOAc; [α]D +14.6 (c 0.5,
MeOH). 1H NMR (500 MHz, CD3OD) δ 7.28−7.22 (m, 4H), 7.19−
7.15 (m, 1H), 3.89−3.84 (m, 1H), 3.40 (d, J = 2.5 Hz, 1H), 2.88 (d, J =
13.5 Hz, 1H), 2.77 (d, J = 13.5 Hz, 1H), 1.65−1.44 (m, 5H), 1.33−1.24
(m, 2H); 13C{1H} NMR (125 MHz, CD3OD) δ 137.2, 130.7, 127.3,
125.6, 74.5, 73.5, 68.6, 45.1, 30.4, 27.2, 18.7; FT-IR (film) 3420, 2936,
2862, 1452, 997, 703 cm−1; ESI-MS m/z 244.95 ([M + Na]+); ESI-
HRMS calcd. for C13H18O3Na ([M + Na]+) 245.1148, found 245.1148.
Data for (1R,2R,3R)-3-ethyl-3-hydroperoxycyclohexane-1,2-diol
(2n). 2n was obtained as a white solid, 4.45 g, 25.3 mmol, 78%; less
polar than 3n, chromatography using 1:1 PE/EtOAc; mp 69−70 °C.
Data for (1S,2S,3R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-3-
hydro- peroxycyclohexane-1,2-diol (2q). 2q was obtained as a
colorless sticky oil, 33 mg, 0.11 mmol, 45%; chromatography using
25
1
1:1 PE/EtOAc; [α]D +5.0 (c 1.0, MeOH). H NMR (500 MHz,
CDCl3) δ 8.79 (s, 1H), 4.10 (br s, 1H), 4.01 (d, J = 10.7 Hz, 1H), 4.01−
3.96 (m, 1H), 3.87 (d, J = 10.6 Hz, 1H), 2.88 (br s, 1H), 2.03 (br s, 1H),
1.72−1.51 (m, 7H), 0.92 (s, 9H), 0.12 (s, 6H); 13C{1H} NMR (125
MHz, CDCl3) δ 85.0, 70.4, 69.1, 67.2, 28.2, 25.8, 25.4, 18.1, −5.6;
13C{1H} NMR (125 MHz, CD3OD) δ 85.9, 69.0, 68.5, 63.4, 27.5, 25.1,
J
https://dx.doi.org/10.1021/acs.joc.0c01280
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
23.8, 18.2, 17.9, −6.7; FT-IR (film) 3411, 2926, 2855, 1717, 1457,
1056, 1022 cm−1; ESI-MS m/z 315.10 ([M + Na]+); ESI-HRMS calcd.
for C13H28O5SiNa ([M + Na]+) 315.1598, found 315.1600.
MeOH). 1H NMR (600 MHz, MeOD) δ 7.39−7.26 (m, 5H), 5.19−
5.02 (m, 2H), 3.99−3.87 (m, 2H), 3.66 (d, J = 13.6 Hz, 1H), 3.50 (s,
1H), 3.10−2.90 (m, 2H), 1.23 and 1.21 (two singlets, 3H altogether).
13C{1H} NMR (150 MHz, CD3OD) δ 158.0 and 157.7, 138.2, 129.5,
129.0 and 129.0, 128.8, 75.4 and 75.3, 72.6 and 72.5, 68.3, 66.5 and
66.2, 50.2 and 50.2, 44.8 and 44.6, 24.0, and 23.9. FT-IR (film) 3399,
2930, 1681, 1434, 1094, 1056, 978, 697 cm−1; ESI-MS m/z 304.25 ([M
+ Na]+); ESI-HRMS calcd. for C14H19O5NNa ([M + Na]+) 304.1155,
found 304.1151.
Data for (1S,3aS,4S,5S,7aR)-1-((tert-butyldimethylsilyl)oxy)-3a-
hydroperoxy-7a-methyloctahydro-1H-indene-4,5-diol (2v). 2v was
obtained as a white solid, 145 mg, 0.44 mmol, 87%; less polar than 3v,
chromatography using 1:1 PE/EtOAc; mp 148−150 °C. [α]D25 +25.6
(c 1.0, MeOH). 1H NMR (500 MHz, CD3OD) δ 4.24 (d, J = 3.9 Hz,
1H), 4.15 (dd, J = 8.6, 6.4 Hz, 1H), 4.08 (ddd, J = 11.7, 5.3, 4.2 Hz, 1H),
2.17−2.08 (m, 1H), 2.06−1.93 (m, 2H), 1.79−1.68 (m, 1H), 1.66−
1.51 (m, 3H), 1.27−1.21 (m, 1H), 1.12 (s, 3H), 0.88 (s, 9H), 0.00 (d, J
= 8.2 Hz, 6H); 13C{1H} NMR (125 MHz, CD3OD) δ 94.7, 77.9, 69.2,
68.3, 46.8, 30.2, 27.7, 25.4, 24.9, 23.4, 17.5, 15.4, −5.7, −6.0. FT-IR
(KBr) 3463, 3250, 2955, 1467, 1391, 1250, 1126, 1094, 1030, 895, 832,
780 cm−1; ESI-MS m/z 355.15 ([M + Na]+); ESI-HRMS calcd. for
C16H32O5SiNa ([M + Na]+) 355.1911, found 355.1911.
Data for (1R,2R,3R)-3-Hydroperoxy-3-methylcycloheptane-1,2-
diol (2r). 2r was obtained as a colorless sticky oil, 18 mg, 0.10 mmol,
25
68%; chromatography using 1:1 PE/EtOAc; [α]D −5.8 (c 0.5,
MeOH). 1H NMR (500 MHz, CD3OD) δ 4.02 (br d, J = 9.8 Hz, 1H),
3.92 (br s, 1H), 1.98−1.88 (m, 1H), 1.77−1.70 (m, 1H), 1.67−1.42 (m,
6H), 1.31 (s, 3H); 13C{1H} NMR (125 MHz, CD3OD) δ 84.7, 77.7,
70.7, 34.3, 29.7, 23.6, 22.5, 20.9; FT-IR (film) 3340, 2931, 2868, 1456,
1101, 1034, 1009 cm−1; ESI-MS m/z 198.95 ([M + Na]+); ESI-HRMS
calcd. for C8H16O4Na ([M + Na]+) 199.0941, found 199.0932.
Data for (1R,2R,3S)-3-Allyl-3-hydroperoxycycloheptane-1,2-diol
(2s). 2s was obtained as a colorless sticky oil, 50 mg, 0.25 mmol, 62%;
chromatography using 1:1 PE/EtOAc; [α]D25 −29.2 (c 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 6.00−5.91 (m, 1H), 5.19−
5.09 (m, 2H), 4.15−4.07 (m, 2H), 3.43 (br s, 2H), 2.67 (dd, J = 14.8,
6.5 Hz, 1H), 2.48 (dd, J = 14.8, 7.7 Hz, 1H), 1.97−1.88 (m, 1H), 1.83−
1.76 (m, 1H), 1.74−1.62 (m, 2H), 1.61−1.45 (m,4H); 13C{1H} NMR
(125 MHz, CDCl3) δ 134.3, 118.0, 86.7, 77.4, 71.5, 39.0, 31.7, 29.8,
23.2, 20.9; FT-IR (film) 3371, 2933, 2866, 1457, 1093, 1003, 915 cm−1;
ESI-MS m/z 225.05 ([M + Na]+); ESI-HRMS calcd. for C10H18O4Na
([M + Na]+) 225.1097, found 225.1103.
Data for (1S,3aS,4S,5S,7aR)-1-((tert-Butyldimethylsilyl)oxy)-7a-
methyloctahydro-3aH-indene-3a,4,5-triol (3v). 3v was obtained as a
white solid, 12 mg, 0.038 mmol, 7%; more polar than 2v,
Data for (3R,4R,5R)-5-Hydroperoxy-5-methyltetrahydro-2H-
pyran-3,4-diol (2t). 2t was obtained as a colorless oil, 78 mg, 0.47
mmol, 84%; less polar than 3t, chromatography using 1:3 PE/EtOAc;
25
chromatography using 1:2 PE/EtOAc; mp 178−181 °C. [α]D
25
1
1
[α]D −31.9 (c 1.0, MeOH). H NMR (500 MHz, CD3OD) δ 3.91
(ddd, J = 9.5, 4.8, 3.3 Hz, 1H), 3.83 (d, J = 3.2 Hz, 1H), 3.59 (d, J = 12.1
Hz, 1H), 3.55 (dd, J = 10.7, 4.8 Hz, 1H), 3.46 (dd, J = 9.8, 9.8 Hz, 1H),
3.44 (d, J = 12.1 Hz, 1H), 1.21 (s, 3H); 13C{1H} NMR (125 MHz,
CD3OD) δ 82.6, 69.3, 67.3, 65.8, 65.3, 16.0; FT-IR (film) 3374, 2923,
1098, 1061 cm−1; ESI-MS m/z 186.95 ([M + Na]+); ESI-HRMS calcd.
for C6H12O5Na ([M + Na]+) 187.0577, found 187.0579.
+37.6 (c 0.33, MeOH). H NMR (500 MHz, CD3OD) δ 4.23 (dd, J
= 8.6, 6.5 Hz, 1H), 4.12−4.07 (m, 1H), 3.69 (d, J = 3.8 Hz, 1H), 2.30−
2.22 (m, 1H), 2.18−2.08 (m, 1H), 1.77−1.65 (m, 2H), 1.64−1.48 (m,
2H), 1.30−1.22 (m, 2H), 1.05 (s, 3H), 0.89 (s, 9H), 0.02 (d, J = 3.9 Hz,
6H); 13C{1H} NMR (125 MHz, CD3OD) δ 83.2, 78.2, 74.4, 68.6, 45.5,
30.0, 30.0, 28.0, 25.5, 25.0, 17.5, 14.5, −5.7, −6.0. FT-IR (KBr) 3427,
2954, 2857, 1472, 1250, 1088, 1061, 1027, 940, 903, 836, 776 cm−1;
ESI-MS m/z 339.20 ([M + Na]+); ESI-HRMS calcd. for C16H32O4SiNa
([M + Na]+) 339.1962, found 339.1964.
Data for (1R,2R,4aS,5R,8aR)-5-((tert-Butyldimethylsilyl)oxy)-8a-
hydroperoxy-4a-methyldecahydronaphthalene-1,2-diol (2w). 2w
was obtained as a white solid, 59 mg, 0.17 mmol, 42%; less polar
than 3w, chromatography using 1:1 PE/EtOAc; mp 190−192 °C.
[α]D25 −47.6 (c 0.25, MeOH). 1H NMR (500 MHz, CD3OD) δ 4.08−
4.00 (m, 2H), 3.79 (dd, J = 9.6, 6.1 Hz, 1H), 1.93−1.69 (m, 4H), 1.64−
1.41 (m, 6H), 1.36−1.26 (m, 2H), 1.14 (s, 3H), 0.87 (s, 9H), 0.01 (s,
3H), 0.00 (s, 3H); 13C{1H} NMR (125 MHz, CD3OD) δ 87.3, 73.3,
71.3, 67.9, 42.0, 30.3, 30.1, 25.0, 25.0, 24.3, 18.0, 17.5, 13.7, −5.3, −6.0;
FT-IR (KBr) 3536, 3437, 3129, 2936, 1458, 1251, 1092, 1053, 834, 773
cm−1; ESI-MS m/z 369.10 ([M + Na]+); ESI-HRMS calcd. for
C17H34O5SiNa ([M + Na]+) 369.2068, found 369.2065.
Data for (1S,2S,4R,4aS,6R,8aS)-8a-Hydroperoxy-4,4a-dimethyl-
6-(prop-1-en-2-yl)decahydronaphthalene-1,2-diol (2x). 2x was
obtained as a white solid, 72 mg, 0.27 mmol, 53% from 1x; less polar
than 3x, chromatography using 1:1 PE/EtOAc; mp 119−121 °C.
[α]D25 +58.7 (c 1.0, EtOAc). 1H NMR (500 MHz, CD3OD) δ 4.70 (br
s, 1H), 4.65 (br s, 1H), 4.12−4.04 (m, 2H), 2.27 (tt, J = 12.7, 4.0 Hz,
1H), 2.06−1.88 (m, 2H), 1.88−1.79 (m, 1H), 1.76 (dd, J = 13.0, 4.6
Hz, 1H), 1.71 (s, 3H), 1.59 (q, J = 12.5 Hz, 1H), 1.54−1.44 (m, 3H),
1.24 (dd, J = 12.4, 2.9 Hz, 1H), 1.09 (s, 3H), 0.75 (d, J = 6.9 Hz, 3H);
13C{1H} NMR (125 MHz, CD3OD) δ 150.6, 107.5, 85.3, 71.7, 67.5,
39.7, 39.5, 38.1, 34.1, 33.8, 25.4, 25.3, 19.5, 16.1, 13.9. FT-IR (KBr)
3527, 3200, 2949, 2611, 2379, 1453, 1133, 1038, 890 cm−1; ESI-MS m/
z 293.25 ([M + Na]+); ESI-HRMS calcd. for C15H30O4N ([M +
NH4]+) 288.2169, found 288.2170.
Data for (3R,4R,5R)-3-Methyltetrahydro-2H-pyran-3,4,5-triol (3t).
3t was obtained as a colorless oil, 10 mg, 0.067 mmol, 12%; more polar
than 2t, chromatography using 15:1 CH2Cl2/MeOH; [α]D25 −18.8 (c
1.0, MeOH). 1H NMR (500 MHz, CD3OD) δ 4.00 (ddd, J = 9.9, 4.9,
3.3 Hz, 1H), 3.58−3.54 (m, 2H), 3.48 (d, J = 11.7 Hz, 1H), 3.41 (dd, J =
10.3, 10.3 Hz, 1H), 3.27 (d, J = 11.6 Hz, 1H), 1.28 (br s, 2H), 1.14 (s,
3H); 13C{1H} NMR (125 MHz, CD3OD) δ 73.3, 71.0, 70.8, 65.7, 65.0,
20.8; FT-IR (film) 3386, 2924, 1095, 1058 cm−1; ESI-MS m/z 170.95
([M + Na]+); ESI-HRMS calcd. for C6H12O4Na ([M + Na]+)
171.0628, found 171.0623.
Data for (3R,4R,5R)-1-(Benzyloxycarbonyl)-3-hydroperoxy-4,5-
dihydroxy-3-methylpiperidine (2u). 2u was obtained as a colorless
oil, 54 mg, 0.18 mmol, 79%; chromatography using 1:1 PE/EtOAc;
25
25
[α]D −0.52 (c 1.0, MeOH), [α]D +0.43 (c 1.0, MeOH) (another
25
25
measurement at c 1.0 in MeOH), [α]D +1.1 (c 0.5 MeOH), [α]D
+1.7 (c 0.25 MeOH), 92% pure as determined by HPLC analysis on a
CHIRALPAK IC column (ϕ 0.46 × 25 cm, particle size = 5 μm) eluting
with 50:50 of n-hexane/i-PrOH at a flow rate of 0.7 mL/min with the
UV detector set to 214 nm. This compound in solution exists as a nearly
1:1 mixture of two conformers (cf. also the NMR at different
temperatures, Figure S5 in the Supporting Information) as shown by 1H
and 13C NMR. 1H NMR (500 MHz, CD3OD) δ 7.39−7.25 (m, 5H),
5.18−5.05 (m, 2H), 3.98−3.70 (m, 4H), 3.12−2.95 (m, 2H), 1.30 and
1.28 (two singlets, 3H altogether); 13C{1H} NMR (125 MHz,
CD3OD) δ 158.1 and 157.6, 138.1 and 137.9, 129.5 and 129.4, 129.1
and 128.9, 128.8 and 128.6, 84.4 and 83.9, 71.7 and 71.5, 68.5 and 68.4,
66.6 and 66.3, 46.7 and 46.6, 45.1 and 44.5, 18.8. FT-IR (film) 3401,
2939, 1678, 1437, 1221, 1096, 978, 698 cm−1; ESI-MS m/z 320.25 ([M
+ Na]+); ESI-HRMS calcd. for C14H19O6NNa ([M + Na]+) 320.1105,
found 320.1106. Reduction of this sample using Ph3P in CH2Cl2 gave
the corresponding triol in 100% yield, with 1H NMR in full consistence
Data for (1S,2S,4R,4aS,6R,8aS)-4,4a-Dimethyl-6-(prop-1-en-2-
yl)octahydronaphthalene-1,2,8a(1H)-triol (3x). 3x was obtained as
a white solid, 26 mg, 0.10 mmol, 20% from 1x; more polar than 2x,
chromatography using 1:2 PE/EtOAc; mp 138−140 °C. [α]D25 +31.4
(c 1.0 EtOAc). 1H NMR (500 MHz, CD3OD) δ 4.69 (br s, 1H), 4.65
(br s, 1H), 4.15−4.09 (m, 1H), 3.44 (d, J = 3.6 Hz, 1H), 2.32−2.21 (m,
2H), 1.95−1.85 (m, 1H), 1.80−1.70 (m, 1H), 1.71 (s, 3H), 1.62−1.43
(m, 4H), 1.32−1.24 (m, 2H), 1.04 (s, 3H), 0.77 (d, J = 7.0 Hz, 3H);
13C{1H} NMR (125 MHz, CD3OD) δ 150.6, 107.4, 77.4, 74.8, 67.7,
25
with that for 3u below and an optical rotation of [α]D +7.6 (c 0.5,
MeOH), confirming that the optical rotation of 2u is indeed very small
in magnitude.
Data for (3R,4R,5R)-1-(Benzyloxycarbonyl)-3,4,5-trihydroxy- 3-
methylpiperidine (3u). 3u was obtained as a colorless oil, 8 mg, 0.028
mmol, 12%; chromatography using 1:3 PE/EtOAc; [α]D25 +8.1 (c 0.5,
K
https://dx.doi.org/10.1021/acs.joc.0c01280
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
39.7, 38.4, 38.2, 34.3, 33.6, 31.5, 25.3, 19.5, 14.9, 13.9. FT-IR (KBr)
3342, 2945, 2480, 1641, 1458, 1376, 1145, 1039, 997, 951, 889 cm−1;
ESI-MS m/z 277.25 ([M + Na]+); ESI-HRMS calcd. for C15H30O3N
([M + NH4]+) 272.2220, found 272.2221.
ESI-MS m/z 501.65 ([M + Na]+); ESI-HRMS calcd. for C29H54O5N
([M + NH4]+) 496.3997, found 496.3997.
(S)-2-((tert-Butyldimethylsilyl)peroxy)-2-methylhexane-1,6-
diol (5). Elaboration of 2l into 6 via 5. Imidazole (4.5 g, 66 mmol)
was added to a solution of 2l (7.2 g, 44.3 mmol) in CH2Cl2 (180 mL)
and acetone (60 mL) stirred in an ice−water bath. The mixture was
stirred at the same temperature for 10 min. A solution of TBSCl (7.4 g,
48.8 mmol) in CH2Cl2 (30 mL) was introduced slowly over 30 min.
After completion of the addition, stirring was continued in the cooling
bath for another 4 h. Water (50 mL) was added to quench the reaction.
The mixture was extracted with CH2Cl2 (50 mL × 3). The combined
organic layers were dried over anhydrous Na2SO4. Removal of the
drying agent by filtration and the solvent by rotary evaporation left an
oily residue, which was purified by column chromatography (4:1 PE/
EtOAc) on silica gel to afford 2l′ as a colorless oil (8.6 g, 31.1 mmol,
70% from 2l) along with unreacted starting 2l (700 mg, 4.4 mmol,
10%). Data for 2l′: [α]D25 +5.8 (c 1.0, CHCl3). 1H NMR (500 MHz,
CDCl3) δ 4.01 (ddd, J = 6.9, 3.5, 3.4 Hz, 1H), 3.88 (d, J = 3.3 Hz, 1H),
3.05 (br s, 1H), 2.27 (br s, 1H), 1.75−1.66 (m, 1H), 1.63−1.41 (m,
5H), 1.36 (s, 3H), 0.93 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 84.9, 74.9, 69.3, 31.7, 28.7, 26.2, 19.8, 18.2,
18.2, −5.7; FT-IR (film) 3422, 2933, 1250, 1061, 834, 784 cm−1; ESI-
MS m/z 299.10 [M + Na]+); ESI-HRMS calcd. for C13H28O4SiNa ([M
+ Na]+) 299.1649, found 299.1650.
Data for Cholestane-5α-hydroperoxy-3β,4β-diol 2y). 2y was
obtained as a white solid, 58 mg, 0.13 mmol, 53% from 1y; less polar
than 3y, chromatography using 2:1 PE/EtOAc; Mp 164−166 °C.
[α]D25 +45.7 (c 1.0 THF). 1H NMR (500 MHz, d6-DMSO) δ 10.40 (s,
1H), 4.35 (d, J = 4.4 Hz, 1H), 3.95 (d, J = 7.3 Hz, 1H), 3.87−3.76 (m,
2H), 1.88 (d, J = 12.3 Hz, 1H), 1.75 (br s, 2H), 1.67−0.91 (m, 30H),
0.85 (d, J = 6.3 Hz, 3H), 0.82 (d, J = 6.4 Hz, 6H), 0.59 (s, 3H); 13C{1H}
NMR (125 MHz, d6-DMSO) δ 85.2, 71.8, 67.0, 56.5, 56.2, 46.1, 42.8,
40.2, 39.4, 39.3, 36.1, 35.7, 34.9, 31.4, 28.3, 27.9, 26.2, 25.8, 25.6, 24.2,
23.8, 23.1, 22.8, 20.6, 18.9, 16.9, 12.4. FT-IR (KBr) 3349, 2941, 2867,
1468, 1379, 1333, 1110, 1050, 1014, 951, 921, 831, 796 cm−1; ESI-MS
m/z 459.55 ([M + Na]+); ESI-HRMS calcd. for C27H48O4Na ([M +
Na]+) 459.3445, found 459.3448.
Data for Cholestane-3β,4β,5α-triol (3y). 3y was obtained as a white
solid, 16 mg, 0.038 mmol, 15% from 1y; more polar than 2y,
chromatography using 1:1 PE/EtOAc; mp 207−209 °C (lit.28b 211−
25
25
212 °C (EtOH)). [α]D +24.3 (c 0.5, MeOH), [α]D1 +40.8 (c 0.5,
pyridine) (lit.32 [α]D +43 (c unknown, pyridine)). H NMR (500
25
MHz, CD3OD) δ 4.05 (ddd, J = 12.1, 5.0, 4.1 Hz, 1H), 3.43 (d, J = 3.5
Hz, 1H), 2.19−2.11 (m, 1H), 2.00 (dt, J = 12.3, 3.1 Hz, 1H), 1.90−1.79
(m, 1H), 1.72 (dq, J = 3.8, 12.6 Hz, 1H), 1.64−0.98 (m, 27H), 1.15 (s,
3H), 0.92 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6
Hz, 3H), 0.68 (s, 3H); 13C{1H} NMR (125 MHz, CD3OD) δ 79.2,
76.7, 69.3, 57.7, 57.7, 47.6, 43.9, 41.5, 40.7, 39.4, 37.4, 37.2, 36.1, 32.4,
32.1, 29.4, 29.2, 26.8, 26.8, 25.2, 25.0, 23.2, 23.0, 21.7, 19.2, 16.2, 12.6.
ESI-MS m/z 443.60 ([M + Na]+).
The 2l′ (6.7 g, 24.2 mmol) obtained above was dissolved in a mixture
of THF (90 mL) and H2O (30 mL). The mixture was stirred at ambient
temperature, while powdered NaIO4 (10.3 g, 48.4 mmol) was added in
three portions (the clear solution became turbid with the addition).
After completion of the addition, the mixture was stirred at ambient
temperature for 1.5 h (TLC showed completion of the reaction). Solids
were filtered off through Celite (with suction). The filter cake was
washed with Et2O (30 mL). The combined filtrate and washing were
partially concentrated on a rotary evaporator to remove most of the
volatiles. The concentrated mixture was extracted with Et2O (30 mL ×
2). The combined organic layers were washed with brine (30 mL) and
dried over anhydrous Na2SO4. Removal of the drying agent by filtration
and the solvent by rotary evaporation gave the intermediate dialdehyde
as a colorless oil (6.5 g), which was immediately dissolved in EtOH
(120 mL). To this solution (stirred in an EtOH−dry ice bath, ca. −70
°C, to avoid side reactions) was added NaBH4 (1.83 g, 48.4 mmol). The
mixture was then stirred at the same temperature for another 30 min.
Water (30 mL) was added. The mixture was concentrated on a rotary
evaporator to remove most of the EtOH. The residue was extracted
with EtOAc (50 mL × 2). The combined organic layers were washed
with brine (30 mL) and dried over anhydrous Na2SO4. Removal of the
drying agent by filtration and the solvent by rotary evaporation left an
oily residue, which was purified by column chromatography (2:1 PE/
EtOAc) on silica gel to afford diol 5 as a colorless oil (5.0 g, 18.0 mmol,
Data for 4β,5β-Epoxycholestan-3β-ol (4y). 4y was obtained as a
white solid, 18 mg, 0.045 mmol, 18% from 1y): Mp 47−50 °C (lit.28e
25
25
mp 96−97 °C (EtOH)), [α]D −2.4 (c 1.0, CHCl3), [α]D −4.0 (c
0.7, CHCl3), [α]D −4.6 (c 0.5, CHCl3), (lit.33 [α]D +4 (c 1.4,
CHCl3), [α]D20 +5.4 (c 1.0, CHCl3), [α]D21 +4.3 (c 0.8, CHCl3)). 1H
NMR (500 MHz, CDCl3) δ 4.05 (br s, 1H), 3.13 (d, J = 4.4 Hz, 1H),
2.29 (br s, 1H), 2.10 (dt, J = 4.4, 13.6 Hz, 1H), 1.98 (dt, J = 12.7, 3.3 Hz,
1H), 1.88−1.72 (m, 2H), 1.62−1.48 (m, 3H), 1.45−1.21 (m, 11H),
1.18−0.92 (m, 14H), 0.90 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H),
0.86 (d, J = 6.6 Hz, 3H), 0.67 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 68.9, 64.2, 63.7, 56.2, 56.1, 47.0, 42.5, 39.7, 39.5, 36.1, 36.1,
35.7, 35.0, 31.1, 30.3, 28.2, 28.0, 26.1, 25.9, 24.3, 23.8, 22.8, 22.5, 21.3,
19.1, 18.6, 11.9.34
25
21
Data for 5α-Hydroperoxy-6β,7β-dihydroxycholestan-3β-yl Ac-
etate (2z). 2z was obtained as a white solid, 80 mg, 0.16 mmol, 65%
from 1z; mp 195−197 °C. [α]D25 +25.7 (c 0.5, EtOAc). 1H NMR (500
MHz, d6-DMSO) δ 10.82 (s, 1H), 5.04−4.96 (m, 1H), 4.69 (d, J = 5.0
Hz, 1H), 3.79 (br s, 1H), 3.51 (br s, 2H), 2.13−2.04 (m, 1H), 1.97 (s,
3H), 1.93−1.70 (m, 5H), 1.55−0.93 (m, 22H), 1.11 (s, 3H), 0.88 (d, J
= 6.4 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H), 0.62 (s,
3H); 13C{1H} NMR (125 MHz, d6-DMSO) δ 170.2, 86.1, 72.1, 71.5,
70.7, 55.9, 55.4, 44.3, 43.5, 39.4, 38.6, 38.2, 36.2, 35.8, 32.1, 31.5, 30.0,
28.8, 27.9, 27.3, 27.0, 23.8, 23.1, 22.9, 21.6, 21.2, 19.1, 18.2, 12.5; FT-IR
(KBr) 3409, 3184, 2944, 1719, 1469, 1366, 1261, 1131, 1086, 1031,
689 cm−1; ESI-MS m/z 517.65 ([M + Na]+); ESI-HRMS calcd. for
C29H54O6N ([M + NH4]+) 512.3946, found 512.3946.
25
74% from 2l′). Data for 5: [α]D −20.4 (c 1.0, CHCl3), 96% ee as
determined by HPLC on a CHIRALPAK AD-H column (ϕ 0.46 cm ×
25 cm, particle size 5 μm) eluting with 95:5 of n-hexane/i-PrOH at a
flow rate of 0.7 mL/min with UV detector set to 214 nm. 1H NMR (500
MHz, CDCl3) δ 3.65−3.59 (m, 3H), 3.56 (dd, J = 11.7, 6.9 Hz, 1H),
2.44 (t, J = 6.4 Hz, 1H), 1.84 (br s, 1H), 1.61−1.48 (m, 4H), 1.43−1.33
(m, 2H), 1.11 (s, 3H), 0.91 (s, 9H), 0.14 (s, 3H), 0.14 (s, 3H); 13C{1H}
NMR (126 MHz, cdcl3) δ 84.9, 67.5, 62.5, 33.6, 33.1, 26.1, 19.6, 18.5,
18.2, −5.7; FT-IR (film) 3365, 2931, 2859, 1250, 1054, 837, 784 cm−1;
ESI-MS m/z 301.20 [M + Na]+); ESI-HRMS calcd. for C13H30O4SiNa
([M + Na]+) 301.1806, found 301.1803.
Data for 5α,6β,7β-Trihydroxycholestan-3β-yl Acetate (3z). 3z was
obtained as a white solid, 26 mg, 0.054 mmol, 22% from 1z; mp 180−
182 °C (lit.14b 178−179 °C). [α]D +24.9 (c 1.0, EtOAc) (lit. [α]D
25
1
data not available). H NMR (500 MHz, CD3OD) δ 5.20−5.12 (m,
Part of 5 (25 mg, 0.09 mmol) obtaineda above was dissolved EtOH
(1 mL). Aq. HCl (2 N, 90 μL) was added. The mixture was stirred at
ambient temperature for 30 min (TLC showed completion of the
reaction). Anhydrous Na2SO4 was added (to remove the traces of water
in the mixture). The mixture was filtered and concentrated on a rotary
evaporator. The residue was dissolved in EtOAc (1 mL). Ph3P (31.5
mg, 0.12 mmol) was added. The mixture was then stirred at ambient
temperature for ca. 10 min (TLC showed completion of the reaction),
concentrated on a rotary evaporator, and purified by column
chromatography (1:15 MeOH/CH2Cl2) on silica gel to give the
known ((S)-2-methylhexane-1,2,6-triol (6) as a colorless oil (13 mg,
1H), 3.69 (dd, J = 10.1, 3.8 Hz, 1H), 3.38 (d, J = 3.6 Hz, 1H), 2.18 (t, J =
12.2 Hz, 1H), 2.00 (s, 3H), 1.94−1.79 (m, 3H), 1.70−0.99 (m, 23H),
1.15 (s, 3H), 0.94 (d, J = 6.2 Hz, 3H), 0.88 (d, J = 6.6 Hz, 6H), 0.71 (s,
3H); 13C{1H} NMR (125 MHz, CD3OD) δ 171.3, 77.8, 76.0, 72.3,
71.3, 55.6, 55.5, 43.9, 43.3, 40.1, 39.3, 38.1, 37.4, 36.8, 36.0, 35.8, 31.9,
28.4, 27.8, 26.7, 26.5, 23.6, 21.8, 21.6, 21.0, 19.9, 18.0, 16.2, 11.3;
13C{1H} NMR (125 MHz, d6-DMSO) δ 169.8, 77.1, 75.1, 71.3, 70.7,
55.4, 55.0, 43.3, 43.0, 38.9, 37.9, 37.2, 37.0, 35.7, 35.3, 31.7, 28.4, 27.4,
26.8, 26.6, 23.3, 22.7, 22.4, 21.1, 20.8, 18.7, 16.6, 12.0; FT-IR (KBr)
3443, 2951, 1737, 1467, 1383, 1240, 1132, 1078, 1029, 895, 709 cm−1;
L
https://dx.doi.org/10.1021/acs.joc.0c01280
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
0.088 mmol, 97% from 5). Data for 6: [α]D25 −3.1 (c 1.0, EtOAc) (lit.35
[α]D20 −2.1 (c 1.0, EtOAc)). 1H NMR (500 MHz, CD3OD) δ 3.56 (t, J
= 6.5 Hz, 2H), 3.35 (s, 2H), 1.57−1.37 (m, 6H), 1.12 (s, 3H); 13C{1H}
NMR (126 MHz, CD3OD) δ 72.2, 68.9, 61.5, 37.8, 32.9, 22.3, 19.5; 1H
NMR (500 MHz, d6-DMSO) δ 4.46 (t, J = 5.7 Hz, 1H), 4.35 (t, J = 5.2
Hz, 1H), 3.96 (s, 1H), 3.18−3.09 (m, 2H), 1.41−1.21 (m, 7H), 0.97 (s,
3H); 13C{1H} NMR (125 MHz, d6-DMSO) δ 71.5, 69.0, 60.9, 38.4,
33.5, 24.1, 19.7.
Conversion of (S)-1l into 3l (without Separation of the
Hydroperoxide 2l). To a solution of (S)-1l (224 mg, 2.0 mml) in
freshly prepared H2O2−saturated Et2O (10 mL) was added
MoO2(acac)2 (32.6 mg, 0.1 mmol). The pale yellow−greenish
transparent solution was stirred at ambient temperature for ca. 5 h
(TLC showed completion of the reaction). The flask was placed in an
ice−water bath. Me2S (0.73 mL, 10 mmol) was added slowly (the
yellow color of the reaction mixture gradually faded). The mixture was
then stirred at ambient temperature overnight.
Author Contributions
‡X.-T.W. and W.-B.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21672244, 21532002) and the Strategic
Priority Research Program of the Chinese Academy of Sciences
(XDB20020200).
REFERENCES
■
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The solvent was removed by rotary evaporation. The oily residue was
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on silica gel to give triol 3l (colorless sticky oil, 265 mg, 1.81 mmol, 91%
from 1l). Data for 3l: cf. those given above.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01280.
■
sı
1H and 13C{1H} NMR, IR spectra for all new compounds,
and tabular summary for enzymatic resolution of 1l−1u
(PDF)
X-ray crystallographic data for compounds 3a, 2v, 2m,
and 2x (CIF)
(2) Della Sala, G.; Giordano, L.; Lattanzi, A.; Proto, A.; Scettri, A.
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AUTHOR INFORMATION
Corresponding Author
■
Yikang Wu − State Key Laboratory of Bioorganic and Natural
Products Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry and the University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0003-4501-
5401; Email: yikangwu@sioc.ac.cn
(6) The crystallographic data for 3a, 2m, 2v, and 2x have been
deposited to the Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge CB2 1EZ, U. K.; e-mail: deposit@ccdc.cam.ac.uk
with the following identifying numbers: CCDC 1991655 (3a); CCDC
1991656 (2m); CCDC 1991657 (2v); CCDC 1991658 (2x)..
(7) In these experiments t-BuOMe was used to replace Et2O just to
show its experimental feasibility. In many cases we examined, H2O2-t-
BuOMe and H2O2-Et2O are interchangeable.
(8) Optically active sec-hydroperoxy centers could be generated by
Deng’s catalytic protocol, see: (a) Hu, L.; Lu, X.; Deng, L. Catalytic
Enantioselective Peroxidation of α,β-Unsaturated Aldehydes for the
Asymmetric Synthesis of Biologically Important Chiral Endoperoxides.
J. Am. Chem. Soc. 2015, 137, 8400−8403. However, optically active tert-
hydroperoxides are much more difficult to obtain. For a few precedents,
see (b) Dai, P.; Dussault, P. H. Intramolecular Reactions of
Hydroperoxides and Oxetanes: Stereoselective Synthesis of 1,2-
Dioxolanes and 1,2-Dioxanes. Org. Lett. 2005, 7, 4333−4335.
(c) Dai, P.; Trullinger, T. K.; Liu, X.; Dussault, P. H. Asymmetric
Synthesis of 1,2-Dioxolane-3-acetic Acids: Synthesis and Configura-
tional Assignment of Plakinic Acid A. J. Org. Chem. 2006, 71, 2283−
2292.
Authors
Xiao-Tao Wang − State Key Laboratory of Bioorganic and
Natural Products Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry and the
University of Chinese Academy of Sciences, Chinese Academy of
Sciences, Shanghai 200032, China
Wei-Bo Han − State Key Laboratory of Bioorganic and Natural
Products Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry and the University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China
Hui-Jun Chen − State Key Laboratory of Bioorganic and Natural
Products Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry and the University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China
Qinghong Zha − State Key Laboratory of Bioorganic and Natural
Products Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry and the University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China
(9) If the OH’s at the C-2 and C-3 were trans to each other as shown in
the (C) of Scheme 2, the coupling constant would be >10 Hz (not
observed).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01280
(10) Kolb, A.; Zuo, W.; Siewert, J.; Harms, K.; von Zezschwitz, P.
Improved Synthesis of Cyclic Tertiary Allylic Alcoholsby Asymmetric
M
https://dx.doi.org/10.1021/acs.joc.0c01280
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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16373.
O
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J. Org. Chem. XXXX, XXX, XXX−XXX