Hydrolytic and aminolytic kinetic resolution of terminal bis-epoxides

Article abstract of DOI:10.1021/jo3024335

Hydrolytic and aminolytic kinetic resolution of terminal bis-epoxides catalyzed by (salen)Co^III complexes affords epoxy-diols and N-protected epoxy-amino alcohols with excellent enantio- and diastereoselectivity and good yields. An operationall

Full text of DOI:10.1021/jo3024335

Article
pubs.acs.org/joc
Hydrolytic and Aminolytic Kinetic Resolution of Terminal Bis-
Epoxides
Jevgenia Bredihhina, Piret Villo, Karlis Andersons, Lauri Toom, and Lauri Vares*
̅
Institute of Technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia
S
* Supporting Information
ABSTRACT: Hydrolytic and aminolytic kinetic resolution of terminal bis-
epoxides catalyzed by (salen)CoIII complexes affords epoxy-diols and N-
protected epoxy-amino alcohols with excellent enantio- and diastereose-
lectivity and good yields. An operationally simple procedure gives instant
access to valuable building blocks containing two remote stereocenters in
highly enantioenriched form.
Scheme 1. Kinetic Resolution of Bis-Epoxides
INTRODUCTION
■
Asymmetric construction of vicinal amino alcohols and diols is
an important task due to the regular occurrence of such motifs
in biologically active compounds.1 Among the methods
available, the highly selective kinetic resolution of racemic
terminal epoxides catalyzed by Jacobsen’s (salen)CoIII catalyst
is frequently used both hydrolytically2 and aminolytically.3
Despite the progress with such methods, the construction of
secondary hydroxyl groups with a distal stereocenter is not
trivial to achieve with both high enantio- and diastereoselec-
tivity in a controlled manner. For instance, many representa-
tives of the bioactive Annonaceous acetogenins contain such
motifs (highlighted in Figure 1). Synthetic strategies for the
directional derivatization, rendering these building blocks
important and versatile intermediates.
Surprisingly, very limited attention has been paid to bis-
epoxides as substrates in kinetic resolution reactions. Jacobsen
and co-workers have resolved D,L-butadiene diepoxide6 with
high ee using water as a nucleophile,2c Chow and Kitching have
applied a similar strategy in the synthesis of insect
pheromones,7,8 although without directly measuring the ee of
the products, and dianhydro sugars have been used as
substrates by Yakota and Kakuchi.9 Furthermore, to date the
aminolytic kinetic resolution of terminal bis-epoxides has not
been explored.
Herein, we report the first hydrolytic kinetic resolution
(HKR) of aromatic bis-epoxides and the aminolytic kinetic
resolution (AKR) of bis-epoxides catalyzed by chiral (salen)-
CoIII complexes.
Figure 1. Acetogenins bearing remote hydroxy functionalities.
RESULTS AND DISCUSSION
■
We began our investigation with p- and m-bis(epoxyethyl)-
benzenes (Table 1), since the products could be easily
converted into useful building blocks and we expected that
the analysis of the resulting isomer composition would be
possible without further derivatizations.
assembly of such aliphatic units typically involve the synthesis
of two separate building blocks, each with the appropriate chiral
center, followed by the coupling of these two fragments.4
The hydrolytic and aminolytic kinetic resolution of terminal
epoxides is a highly stereoselective method for the formation of
1,2-diols and 1,2-amino alcohols in which up to half of the
material can be converted to the product with the desired
stereochemistry; in addition, the unreacted epoxide can be
recovered in enantioenriched form.5 In the case of terminal bis-
epoxides (1; Scheme 1) the situation is slightly different, as it
consists of three isomers: RS (meso), RR, and SS. The meso
isomer is expected to be resolved to afford 2 in up to 50% yield,
while the other two isomers yield diol 3 and unreacted bis-
epoxide 4, respectively. It was envisioned that epoxy-diols and
epoxy-amino alcohols of the type 2 would enable further two-
Addition of 1.0 equiv of H2O together with Jacobsen’s
catalyst (R,R)-5 (5 mol %) and AcOH (10 mol %) as an
oxidizing additive to p-bis(epoxyethyl)benzene 6 afforded the
desired epoxy-diol (R,S)-8a as a major product with essentially
complete enantioselectivity (Table 1, entry 1) along with the
(S,S)-tetrol and unreacted (R,R)-bis-epoxide. However, in
addition to compound 8a, a fair amount of diastereomer 8b
Received: November 20, 2012
© XXXX American Chemical Society
A
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a
Table 1. Kinetic Resolution of Bis-Epoxides 6 and 7
b
c
d
e
entry
1
product
cat. 5 confign
H2O (equiv)
yield (%)
er
dr
8
8
8
8
8
9
R,R
S,S
1.0
1.1
1.2
1.0
47
37
35
>99.9:0.1
<0.1:99.9
>99.9:0.1
>99.9:0.1
>99.9:0.1
<0.1:99.9
82.3:17.7
10.7:89.3
96.2:3.8
95.3:4.7
98.8:1.2
f
2
3
4
5
R,R
R,R
R,R
S,S
g
36
h
1 + 0.4
28
47
f
i
6
1.0
14:86
a
Experimental conditions: reactions were run on a 1.2 mmol scale in THF (4 M) at room temperature with 5 mol % of catalyst and 10 mol % of
b
c
d
AcOH. Amount (in equiv) of H2O used relative to bis-epoxide. Yield of isolated product based on bis-epoxide. Determined by chiral HPLC.
e
f
g
h
Determined by chiral HPLC. The opposite stereoisomeric series was obtained. Reaction time 96 h. After 16 h the product was isolated and
i
resubmitted to HKR conditions with an additional 0.4 equiv of H2O for another 16 h. Determined by NMR.
a
was formed. We speculated that 8b results from the incomplete
conversion of this particular isomer to the corresponding (S,S)-
tetrol and therefore expected that prolonged reaction time and/
or a small excess of water would improve the dr. Gratifyingly,
when 1.1 equiv of H2O was used the dr improved, while the
enantiomeric purity of epoxy-diol 8 remained unchanged (entry
2), and increasing the amount of water to 1.2 equiv further
improved the dr (entry 3). This observation is in accordance
with the model, developed by Schreiber et al. in 1987, which
estimates the effect of substrate and reagent concentrations of
group and face selective addition reactions leading to terminus
differentiation in a two-directional chain synthesis strategy.10
Running the reaction for 4 days with 1.0 equiv of H2O afforded
dr and er values similar to those obtained using excess water
(compare entries 4 and 3). After resubmitting the product from
entry 1 to the kinetic resolution conditions with 0.4 equiv of
water, the dr was improved up to 98.8:1.2, although at the cost
of the yield (entry 5). Similarly, when m-bis(epoxyethyl)-
benzene (7) was used as a substrate, epoxy-diol 9 was obtained
in excellent er and with high dr (entry 6).
Next we applied the HKR strategy to aliphatic substrates
(Table 2). The resolution of bis-epoxides 10−12 with 0.95−
1.15 equiv of water in the presence of Jacobsen’s catalyst 5
afforded the epoxy-diols 13a−15a, respectively, in good yields
(37−47%)11 and excellent enantio- and diastereoselectivity
(entries 1−4). In comparison to the aromatic bis-epoxides the
aliphatic substrates were more reactive, leading to shorter
reaction times and affording only a negligible amount of the
undesired diastereomer (13b−15b, respectively). It should be
noted that bis-epoxide 12 afforded the epoxy-diol 15a in
slightly lower enantioselectivity, but neither changing the
solvent to THF (entry 5) nor using TsOH as a catalyst
activator12 (entry 6) improved the situation. In addition, to
measure the mass balance of the reaction, for entry 5 we
isolated the unreacted enantiomerically enriched bis-epoxide 12
Table 2. HKR of Aliphatic Bis-Epoxides
b
H2O
(equiv)
yield
(%)
c
d
entry product
solvent
er
dr
1
2
3
4
5
6
13
14
15
15
15
15
1.0
iPrOH
iPrOH
iPrOH
iPrOH
THF
39
37
47
46
44
41
99.9:0.1
99.5:0.5
97:3
99.8:0.2
99.4:0.6
98.4:1.6
0.3:99.7
99.2:0.8
1.0
0.95
1.15
1.05
1.05
e
f
3:97
97:3
g
h
THF
7:93
nd
a
Experimental conditions: reactions were typically run on a 1 mmol
scale in the appropriate solvent (2 M) with 1−2 mol % of catalyst and
b
2−4 mol % of additive. Isolated yield of epoxy-diol based on bis-
c
d
epoxide. Determined by chiral HPLC. Determined by chiral HPLC.
e
f
(S,S)-5 was used. 2 mol % of (R,R)-5 and 4 mol % of additive were
used. 4 mol % TsOH was used as an additive together with 2 mol %
g
h
of (S,S)-5. Not determined.
in 16% yield and the corresponding tetradecane-1,2,13,14-tetrol
in 22% yield. In general, both iPrOH and THF performed well
as solvents and a high initial concentration of bis-epoxide (2 M)
was crucial for the success of the reaction.
Finally we investigated the AKR of aliphatic bis-epoxides.
Subjecting 10 to NH2Cbz, catalyst (R,R)-5, and AcOH gave
amino alcohol 16a in excellent er and good dr (Table 3, entry
1). However, the reaction was rather slow and required 5 days
to reach completion. As was the case in the HKR discussed
above, it is speculated that diastereomer 16b originates from
incomplete conversion into the corresponding (S,S)-bis-amino
alcohol. Bis-epoxide 11 afforded similar results with NH2Cbz as
the nucleophile (entry 2). Surprisingly, increasing the amount
B
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a
Table 3. AKR of Aliphatic Bis-Epoxides
Scheme 2. Diastereomer Analysis for Cbz-Protected AKR
Product 16
b
NH2R
(equiv)
time
(h)
yield
(%)
c
d
entry product
er
dr
f
1
2
3
4
5
6
16
17
17
18
18
18
NH2Cbz
120
120
120
16
37
38
37
39
45
39
>99.9:0.1
99.9:0.1
99.9:0.1
99.2:0.8
0.2:99.8
0.3:99.7
88:12
obtained enantiomers were analyzed by HPLC as a measure
of dr for the KR product under scrutiny. In order to achieve a
better separation on HPLC and to add UV activity when
needed, the remaining keto epoxide was opened unselectively
with 2-naphthalenethiol prior to analysis (compounds 23−25
in Scheme 3 and compounds 26 and 28 in Scheme 4).
(1.0)
f
f
NH2Cbz
(1.0)
91:9
NH2Cbz
(1.3)
88:12
99.3:0.7
1:99
g
g
g
NH2Boc
(1.05)
e
e
NH2Boc
(1.05)
16
CONCLUSION
■
We have demonstrated the efficient use of Jacobsen’s catalyst
for the highly enantio- and diastereoselective synthesis of
epoxy-diols and N-protected epoxy-amino alcohols. This novel
approach enables the construction of compounds with remote
stereocenters in enantiomerically pure form. We are currently
applying this methodology to the synthesis of biologically
valuable targets.
NH2Boc
(1.3)
16
0.9:99.1
a
Experimental conditions: reactions were typically run on a 1 mmol
scale in THF or MTBE (ca. 2 M) with 4 mol % of catalyst and 8 mol
b
% of additive. Isolated yield of N-protected epoxy-amino alcohol.
c
d
e
Determined by chiral HPLC. Determined by chiral HPLC. (S,S)-5
f
g
was used. AcOH was used as an additive. p-Nitrobenzoic acid was
used as an additive.
EXPERIMENTAL SECTION
■
1
General Considerations. The H and 13C NMR spectra were
of NH2Cbz did not improve the outcome, as had been seen in
HKR (entry 3).
recorded at 400.1 and 100.6 MHz, respectively. The chemical shifts for
1H and 13C are given in ppm relative to residual signals of solvents (for
1H, CDCl3 δ 7.27 ppm, DMSO-d6 δ 2.50 ppm, and for 13C, CDCl3 δ
77.0 ppm, DMSO-d6 δ 39.5 ppm). The following abbreviations are
used for multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; bs, broad singlet. Reactions were monitored by thin-layer
chromatography (TLC) and visualized either by UV detection or by
submerging into KMnO4 or phosphomolybdic acid solution.
Purification of reaction products was performed by flash chromatog-
raphy using silica gel 60 (0.040−0.063 mm, 230−400 mesh ASTM). In
HPLC analysis signals were detected by a diode-array detector. An
LTQ Orbitrap analyzer was used in HRMS analysis.
All reagents and solvents were obtained from commercial sources
and used without further purification. Aliphatic bis-epoxides were
prepared by m-CPBA oxidation of the corresponding alkenes. 1,4-
Bis(oxiran-2-yl)benzene and 1,3-bis(oxiran-2-yl)benzene were synthe-
sized according to the literature procedure.13 All HKR and AKR
reactions were repeated at least twice, and both catalyst enantiomers
((R,R)-5 and (S,S)-5) were used.
In order to improve the results, we then investigated the
effect of the N-protecting group by switching to NH2Boc as the
nucleophile. To our delight, the reaction with NH2Boc afforded
the product 18 (entries 4−6) with equally high enantiose-
lectivity and comparable yield. Notably, in this case, the
diastereoselectivity was significantly improved. We also tested
1.3 equiv of NH2Boc and varied the solvent, but these efforts
did not provide any significant change in results. Furthermore,
NH2Boc reacted much faster with the aliphatic bis-epoxides in
comparison to NH2Cbz (overnight vs 5 days), making it the
choice of nucleophile in AKR reactions.
To measure the er of aliphatic non-UV active products of
HKR and AKR, these compounds were first converted into UV
active derivatives via either tosylation (20−22, Scheme 3) or
benzylation (27, Scheme 4) and the er was determined by
HPLC on a chiral column by comparing with separately
synthesized reference materials.
However, the direct measurement of dr of aliphatic products
proved more complicated, and therefore a different strategy was
used. We reasoned that due to the excellent er of HKR and
AKR reactions the only diastereomer present in measurable
amount is that possessing the same chirality at the alcohol
center and opposite chirality at the epoxide center in
comparison to the major KR product. This diastereomer
results from the incomplete conversion to the corresponding
tetrol or bis-amino alcohol.
To verify this, we opened Cbz-protected epoxy-amino
alcohol 16 unselectively to yield 19 as a 88:12 mixture of
two diasteromers (Scheme 2) and compared this to the R,R and
S,S isomers of 19, which were synthesized separately. The
identity of the diastereomer detected in 16 was found to be S,S,
thus being in agreement with our reasoning. The other aliphatic
KR products were expected to show a similar diastereomeric
preference. Therefore, for the dr analysis we eliminated the
secondary hydroxyl center by oxidation to ketone. The
Determination of Absolute Configuration. We prepared
Mosher’s ester derivatives14 from (R)-23 and (S)-23, derived from
HKR products 13a and ent-13a, respectively, and from AKR products
1
18a and ent-18a. Analysis of H spectra indicated that the absolute
configuration was in agreement with previously published enantiopre-
ferences for HKR2c and AKR3c reactions. Other absolute config-
urations were assigned by analogy.
General Procedure for HKR of Terminal Bis-Epoxides.
Procedure for Aliphatic Substrates. To a 0.05 M solution of the
(R,R)- or (S,S)-(salen)CoII complex (1−2 mol %) in CH2Cl2 was
added AcOH (2−4 mol %). The mixture was stirred at room
temperature open to air for 0.5−1 h, during which time the color
turned from dark red to brown. Then the solution was concentrated to
dryness in vacuo. The crude solid was resolvated in THF or iPrOH
(see Table 2) and added to bis-epoxide (1.0 equiv). After the solution
was cooled to 0 °C, H2O was added (0.9−1.1 equiv; see Table 2). The
reaction was stirred overnight at room temperature. Then the solvent
was removed in vacuo and the residue purified by column
chromatography.
Procedure for Aromatic Substrates. Under the same conditions as
for aliphatic substrates, reagents used were as follows: (salen)CoII
C
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Scheme 3. Derivatization of Aliphatic HKR Products for Chiral HPLC Analysis
Scheme 4. Derivatization of AKR Products for Chiral HPLC Analysis
complex (5 mol %), additive AcOH (10 mol %), H2O (1.0−1.4 equiv;
see Table 1).
(ESI): calcd for C8H16O3 [M + Na]+ 183.0992, found 183.0985.
[α]25 −4.61 (c 0.76, MeOH).
(S)D-8-((R)-Oxiran-2-yl)octane-1,2-diol (14). This compound was
synthesized according to the general procedure for HKR of bis-
epoxides from 11 (401 mg, 2.35 mmol), (R,R)-5 (14.2 mg, 23 μmol),
AcOH (5 μL, 94 μmol), and H2O (42 μL, 2.35 mmol). Product 14
was isolated by flash chromatography (7:93 MeOH/CH2Cl2) as a pale
(S)-1-(4-((R)-Oxiran-2-yl)phenyl)ethane-1,2-diol (8). This com-
pound was synthesized according to the general procedure for HKR of
bis-epoxides from 6 (413 mg, 2.54 mmol), (R,R)-5 (60 mg, 99.3
μmol), AcOH (11 μL, 0.20 mmol), and H2O (45 μL, 2.54 mmol). The
product was isolated by flash chromatography (1:10 MeOH/CH2Cl2)
as a beige solid (162 mg, yield 36%). The er >99.9:0.1 and dr 95.3:4.7
were determined by HPLC analysis (CHIRALPAK IB column, 90:10
n-hexane/iPrOH, 1.0 mL/min, SR isomer 19.1 min (major), SS isomer
17.4 min (minor)). 1H NMR (400.1 MHz, CDCl3): δ 7.38−7.29 (m, 4
H), 4.84 (d, J = 8.0 Hz, 1H), 3.88 (dd, J = 3.8, 2.7 Hz, 1H), 3.76−3.78
(m, 1H), 3.64−3.68 (m, 1H), 3.17 (dd, J = 5.4, 4.1 Hz, 1H), 2.80−
2.83 (m, 1H), 2.73 (bs, 1H), 2.24 (bs, 1H). 13C NMR (100.6 MHz,
CDCl3): δ 140.6, 137.4, 126.3, 125.7, 74.4, 68.0, 52.1, 51.1. IR (ATR)
νmax (cm−1): 3377, 3238, 3043, 2965, 2918, 2870, 1464, 1421, 1383,
1335, 1308, 1267, 1080, 1051, 1019, 982, 897, 881, 831, 557. HRMS
1
yellow oil (161 mg, yield 37%). H NMR (400.1 MHz, CDCl3): δ
3.58−3.66 (m, 2H), 3.39 (dd, J = 11.1, 7.6 Hz, 1H), 3.01 (bs, 2H),
2.87−2.91 (m, 1H), 2.73 (dd, J = 5.0, 4.1 Hz, 1H), 2.45 (dd, J = 5.0
2.7 Hz, 1H), 1.26−1.58 (m, 12H). 13C NMR (100.6 MHz, CDCl3): δ
72.2, 66.7, 52.4, 47.1, 33.0, 32.3, 29.4, 29.2, 25.8, 25.4. IR (ATR) νmax
(cm−1): 3393, 2928, 2856, 1464, 1260, 1059, 914, 831, 733. HRMS
(ESI): calcd for C10H20O3 [M + H]+ 189.1485, found 189.1481. [α]25
D
−1.88 (c 0.75, MeOH).
(S)-12-((R)-Oxiran-2-yl)dodecane-1,2-diol (15). This com-
pound was synthesized according to the general procedure for HKR
of bis-epoxides from 12 (510 mg, 2.25 mmol), (S,S)-5 (14 mg, 22
μmol), AcOH (5 μL, 90 μmol), and H2O (38 μL, 2.14 mmol). The
product 15 was isolated by flash chromatography (4:96 EtOAc/n-
(ESI): calcd for C10H12O3 [M + H]+ 181.0859, found 181.0859. [α]25
D
+30.9 (c 1.25, MeOH). Mp: 53.2−54.4 °C.
(R)-1-(3-((S)-Oxiran-2-yl)phenyl)ethane-1,2-diol (9). This com-
pound was synthesized according to the general procedure for HKR of
bis-epoxides from 7 (276 mg, 1.70 mmol), (S,S)-5 (41 mg, 68 μmol),
AcOH (8 μL, 0.14 mmol) and H2O (30 μL, 1.70 mmol). The product
was isolated by flash chromatography (1:10 MeOH/CH2Cl2) as a
yellow oil (146 mg, yield 47%). The er >99.9:0.1 was determined by
HPLC analysis (CHIRALPAK IC column, 90:10 n-hexane/iPrOH, 1.0
mL/min; RS isomer 26.0 min). The dr 86:14 was determined by 13C
NMR analysis. 1H NMR (400.1 MHz, CDCl3): δ 7.20−7.36 (m, 4H),
4.79 (dd, J = 8.0, 3.1 Hz, 1H), 3.86 (dd, J = 4.1, 2.6 Hz, 1H), 3.73−
3.76 (m, 1H), 3.60−3.65 (m, 1H), 3.15 (bs, 1H), 3.14 (dd, J = 5.4, 4.1
Hz, 1H), 2.80 (dd, J = 5.4, 2.6 Hz, 1H), 2.66 (bs, 1H). 13C NMR
(100.6 MHz, CDCl3): δ 141.0, 137.9, 128.74 (major isomer), 128.72
(minor isomer), 125.98 (minor), 125.92 (major), 125.21 (minor),
125.16 (major), 123.17 (major), 123.09 (minor), 74.4, 68.0, 52.3, 51.1.
IR (ATR) νmax (cm−1): 3352, 3055, 2924, 2874, 1447, 1377, 1323,
1231, 1161, 1072, 1030, 876, 853, 799, 702. HRMS (ESI): calcd for
C10H12O3 [M + H]+ 181.0859, found 181.0852. [α]25D −35.8 (c 0.95,
MeOH).
1
hexane) as a white solid (250 mg, yield 44%). H NMR (400.1 MHz,
CDCl3): δ 3.64−3.72 (m, 2H), 3.41−3.46 (m, 1H), 2.91 (tdd, J = 5.5,
3.9, 2.7 Hz, 1H), 2.76 (dd, J = 5.0, 4.1 Hz, 1H), 2.47 (dd, J = 5.0 2.7
Hz, 1H), 2.17 (bs, 1H), 2.06 (bs, 1H), 1.26−1.56 (m, 20H). 13C NMR
(100.6 MHz, CDCl3): δ 72.3, 66.8, 52.4, 47.1, 33.2, 32.5, 29.6, 29.5,
29.4, 25.9, 25.5. IR (ATR) νmax (cm−1): 3476, 3314, 2916, 2851, 1470,
1072, 849. HRMS (ESI): calcd for C14H28O3 [M + H]+ 245.2111,
found 245.2106. [α]25 +6.0 (c 1.15, CHCl3). Mp: 60.0−61.3 °C.
General ProcedurDe for AKR of Terminal Bis-Epoxides. To a
0.05 M solution of the (R,R)- or (S,S)-(salen)CoII complex (4 mol %)
in CH2Cl2 was added AcOH (8 mol %) or p-nitrobenzoic acid (8 mol
%) as additive (see Table 3). The mixture was stirred at room
temperature open to air for 0.5−1 h, during which time the color
changed from dark red to brown. Then the solution was concentrated
to dryness in vacuo. The crude solid was resolvated in THF or MTBE
and added to bis-epoxide (1.0 equiv). After the solution was cooled to
0 °C, NH2Cbz or NH2Boc was added (1.0−1.3 equiv, see Table 3). In
the case of BocNH2 as nucleophile, the reaction mixture was stirred 16
h at room temperature, and with CbzNH2, 5 days. Then the mixture
was concentrated in vacuo and purified by flash chromatography.
Benzyl((S)-2-hydroxy-6-((R)-oxiran-2-yl)hexyl)carbamate
(16). This compound was synthesized according to the general
procedure for AKR of bis-epoxides from 10 (200 mg, 1.40 mmol),
(R,R)-5 (37 mg, 61 μmol), AcOH (7 μL, 0.12 mmol), and NH2Cbz
(212 mg, 1.40 mmol). The product 16 was isolated by flash
chromatography (1:1 n-hexane/EtOAc) as a beige solid (151 mg,
yield 37%). The er >99.9:0.1 was determined by HPLC analysis
(Phenomenex LUX Cellulose-1 column, 90:10 n-hexane/iPrOH, 1.5
(S)-6-((R)-Oxiran-2-yl)hexane-1,2-diol (13). This compound
was synthesized according to the general procedure for HKR of bis-
epoxides from 10 (259 mg, 1.82 mmol), (R,R)-5 (11 mg, 18 μmol),
AcOH (4 μL, 72 μmol), and H2O (33 μL, 1.82 mmol). The product
13 was isolated by flash chromatography (7:93 MeOH/CH2Cl2) as a
pale yellow oil (118 mg, yield 39%). 1H NMR (400.1 MHz, CDCl3): δ
3.70−3.59 (m, 2H), 3.43 (dd, J = 11.0, 7.4 Hz, 1H), 2.90 (m, 1H),
2.74 (dd, J = 5.0, 4.1 Hz, 1H), 2.46 (dd, J = 5.0, 2.7 Hz, 1H), 2.35 (bs,
1H), 2.19 (bs, 1H), 1.65−1.34 (m, 8H). 13C NMR (100.6 MHz,
CDCl3): δ 72.1, 66.7, 52.3, 47.0, 32.9, 32.3, 26.0, 25.3. IR (ATR) νmax
(cm−1): 3368, 2930, 2859, 1462, 1410, 1257, 1049, 914, 831. HRMS
1
mL/min, major isomer 20.6 min). H NMR (400.1 MHz, CDCl3): δ
7.30−7.36 (m, 5H), 5.26 (bs, 1H), 5.11 (s, 2H), 3.71 (bs, 1H), 3.34−
D
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Article
3.40 (m, 1H), 3.04−3.11 (m, 1H), 2.90 (bs, 1H), 2.75 (dd, J = 4.9, 4.0
Hz, 1H), 2.46 (dd, J = 4.9, 2.7 Hz, 1H), 2.42−2.43 (m, 1H), 1.45−
1.59 (m, 8H). 13C NMR (100.6 MHz, CDCl3): δ 157.1, 136.4, 128.5,
128.1, 128.0, 71.1, 66.9, 52.2, 47.0, 34.5, 32.2, 26.0, 25.2. IR (ATR)
νmax (cm−1): 3327, 3250, 3092, 3047, 3032, 2934, 2916, 2850, 1690,
1553, 1261, 1152, 1113, 1029, 972, 833, 756, 685. HRMS (ESI): calcd
for C16H23NO4 [M + H]+ 294.1700, found 294.1696. [α]25D +12.08 (c
1.59, CHCl3). Mp: 66.0−66.8 °C.
p-TsCl (144 mg, 0.75 mmol), Bu2SnO (5 mg, 22 μmol), and Et3N
(105 μL, 0.75 mmol). The product 20 was purified by flash
chromatography (1:15 MeOH/CH2Cl2) with a yield of 69% (164
mg). The er 99.9:0.1 was determined by HPLC analysis (CHIR-
ALPAK IA column, 85:15 n-hexane/iPrOH, 1.5 mL/min; minor
1
isomer 10.1 min, major isomer 14.9 min). H NMR (400.1 MHz,
CDCl3): δ 7.79−7.82 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.01−4.04
(m, 1H), 3.84−3.91 (m, 2H), 2.86−2.90 (m, 1H), 2.74 (dd, J = 5.0,
4.0 Hz, 1H), 2.44−2.45 (m, 4H), 2.24 (bs, 1H), 1.26−1.57 (m, 8H).
13C NMR (100.6 MHz, CDCl3): δ 145.0, 132.6, 129.9, 127.8, 73.8,
Benzyl((S)-2-hydroxy-8-((R)-oxiran-2-yl)octyl)carbamate
(17). This compound was synthesized according to the general
procedure for AKR of bis-epoxides from 11 (200 mg, 1.17 mmol),
(R,R)-5 (30 mg, 50 μmol), AcOH (5 μL, 94 μmol), and NH2Cbz (177
mg, 1.17 mmol). The product was isolated by flash chromatography
(1:1 n-hexane/EtOAc) as a white solid (143 mg, yield 38%). The er
99.9:0.1 was determined by HPLC analysis (Phenomenex LUX
Cellulose-1 column, 90:10 n-hexane/iPrOH, 1.5 mL/min, major
69.1, 52.1, 46.9, 32.5, 32.1, 25.7, 24.9, 21.5. HRMS (ESI): calcd for
C15H22O5S [M + H]+ 315.1260, found 315.1258.
(S)-2-Hydroxy-8-((R)-oxiran-2-yl)octyl-4-methylbenzenesul-
fonate (21). This compound was synthesized according to the general
procedure for tosylation of epoxy-diols from 14 (45 mg, 0.23 mmol),
p-TsCl (45 mg, 0.23 mmol), Bu2SnO (2 mg, 9 μmol), and Et3N (33
μL, 0.23 mmol). The product 21 was purified by flash chromatography
(1:15 MeOH/CH2Cl2) with a yield of 88% (71 mg). The er 99.5:0.5
was determined by HPLC analysis (Phenomenex LUX Cellulose-1
column, 90:10 n-hexane/iPrOH, 1.5 mL/min; minor isomer 15.2 min,
major isomer 23.2 min). 1H NMR (400.1 MHz, CDCl3): δ 7.77−7.80
(m, 2H), 7.32−7.36 (m, 2H), 4.01 (dd, J = 10.0, 2.9 Hz, 1H), 3.81−
3.89 (m, 2H), 2.86−2.90 (m, 1H), 2.72−2.74 (m, 1H), 2.43−2.46 (m,
4H), 2.30 (bs, 1H), 1.24−1.54 (m, 12H). 13C NMR (100.6 MHz,
CDCl3): δ 145.0, 132.7, 129.9, 127.9, 73.9, 69.4, 52.3, 47.0, 32.6, 32.3,
29.4, 29.2, 25.8, 25.0, 21.6. HRMS (ESI): calcd for C17H26O5S [M +
H]+ 343.1574, found 343.1571.
1
isomer 18.2 min, minor isomer 21.7 min). H NMR (400.1 MHz,
CDCl3): δ 7.31−7.37 (m, 5H), 5.18 (bs, 1H), 5.12 (s, 2H), 3.71 (bs,
1H), 3.36−3.42 (m, 1H), 3.04−3.11 (m, 1H), 2.88−2.93 (m, 1H),
2,75 (dd, J = 5.0, 4.0 Hz, 1H), 2.47 (dd, J = 5.0, 2.8 Hz, 1H), 2,14 (bs,
1H), 1.26−1.56 (m, 12H). 13C NMR (100.6 MHz, CDCl3): δ 157.1,
136.4, 128.5, 128.1, 71.3, 66.9, 52.3, 47.1, 47.0, 34.7, 32.4, 29.4, 29.3,
25.9, 25.3. IR (ATR) νmax (cm−1): 3385, 3304, 3088, 3062, 3035, 2914,
2851, 1713, 1666, 1560, 1285, 1265, 1155, 1096, 1024, 914, 839, 743,
697, 583. HRMS (ESI): calcd for C18H27NO4 [M + H]+ 322.2013,
found 322.2012. [α]25 +11.58 (c 1.33, CHCl3). Mp: 51.9−52.9 °C.
D
tert-Butyl((S)-2-hydroxy-6-((R)-oxiran-2-yl)hexyl)carbamate
(18). This compound was synthesized according to the general
procedure for AKR of bis-epoxides from 10 (159 mg, 1.12 mmol),
(S,S)-5 (20 mg, 33 μmol), p-nitrobenzoic acid (11 mg, 67 μmol), and
NH2Boc (138 mg, 1.18 mmol). The product was isolated by flash
chromatography (7:93 MeOH/CH2Cl2) as a pale yellow oil (133 mg,
yield 45%). 1H NMR (400.1 MHz, CDCl3): δ 5.06 (bs, 1H), 3.65 (bs,
1H), 3.24−3.29 (m, 1H), 2.83−2.91 (m, 2H), 2.73 (dd, J = 5.0, 4.1
Hz, 1H), 2.44 (dd, J = 5.0 2.7 Hz, 1H), 1.35−1.58 (m, 17H). 13C
NMR (100.6 MHz, CDCl3): δ 156.8, 79.5, 71.3, 52.2, 47.0, 46.6, 34.5,
32.2, 28.3, 25.9, 25.2. IR (ATR) νmax (cm−1): 3385, 2934, 2860, 1717,
1452, 1274, 1177, 1113, 1070, 1025, 713. HRMS (ESI): calcd for
(S)-2-Hydroxy-12-((R)-oxiran-2-yl)dodecyl-4-methylbenze-
nesulfonate (22). This compound was synthesized according to the
general procedure for tosylation of epoxy-diols from 15 (178 mg, 0.72
mmol), p-TsCl (145 mg, 0.76 mmol), Bu2SnO (3 mg, 14 μmol), and
Et3N (101 μL, 0.72 mmol). The product 22 was purified by flash
chromatography (1:50 MeOH/CH2Cl2) with a yield of 87% (253 mg).
The er 97:3 was determined by HPLC analysis (Phenomenex LUX
Cellulose-1 column, 90:10 n-hexane/iPrOH, 1.5 mL/min, major
1
isomer 8.83 min, minor isomer 9.94 min). H NMR (400.1 MHz,
CDCl3): δ 7.79−7.82 (m, 2H), 7.37−7.33 (m, 2H), 4.04 (dd, J = 9.5,
2.6 1H), 3.80−3.90 (m, 2H), 2.91 (tdd, J = 5.5, 3.9, 2.6 Hz, 1H), 2.76
(dd, J = 5.1, 3.9 Hz, 1H), 2.46−2.48 (m, 4H), 2.09 (d, J = 4.7 Hz, 1H),
1.25−1.63 (m, 20H). 13C NMR (100.6 MHz, CDCl3): δ 145.0, 132.7,
129.9, 127.9, 74.0, 69.5, 52.4, 47.1, 32.6, 32.5, 29.5, 29.4, 29.2, 25.9,
25.2, 21.6. HRMS (ESI): calcd for C21H34O5S [M + H]+ 399.2199,
found 399.2192.
General Procedure for Oxidation/Thiolation. To a 0.06 M
solution of epoxy-alcohol (1.0 equiv) in CH2Cl2 was added Dess−
Martin reagent (in excess, 1.5−6.0 equiv). The reaction was stirred
overnight at room temperature under an argon atmosphere. Then the
mixture was concentrated in vacuo and filtered through a silica plug.
The oxidized compound was then subjected to a thiolation reaction,
where to a 0.05 M solution of epoxide (1.0 equiv) and 2-
naphthalenethiol (in excess, 1.5−6.0 equiv) in MeOH was added
Et3N (in excess, 1.5−6.0 equiv). After the reaction mixture was stirred
overnight, it was concentrated in vacuo and purified by flash
chromatography.
C13H25NO4 [M + H]+ 260.1856, found 260.1852. [α]25 +16.0 (c
D
1.43, CHCl3).
Dibenzyl((2S,7R)-2,7-dihydroxyoctane-1,8-diyl)dicarbamate
(19). This compound was synthesized according to the general
procedure for AKR of bis-epoxides from 16 (55 mg, 0.18 mmol),
(R,R)-5 (5 mg, 8 μmol), (S,S)-5 (5 mg, 8 μmol), AcOH (1 μL, 17
μmol), and NH2Cbz (30 mg, 0.19 mmol). The product 19 was
isolated by flash chromatography (1:15 MeOH/CH2Cl2) with a yield
of 34% (28.8 mg). The retention time of 19 in HPLC analysis was
compared against the retention times of Cbz-protected (S,S)- and
(R,R)-bis-amino alcohols retrieved from the AKR reactions. The dr
88:12 was determined by HPLC analysis (Phenomenex LUX
Cellulose-1 column, 85:15 n-hexane/iPrOH, 1.5 mL/min, RS isomer
1
13.9 min (major), SS isomer 25.0 min (minor)). H NMR (400.1
MHz, DMSO-d6): δ 7.30−7.38 (m, 10H), 7.11 (dd, J = 5.7, 5.7 Hz,
2H), 5.01 (s, 4H), 4.53 (d, J = 5.1 Hz, 2H), 3.44 (bs, 2H), 2.90−3.01
(m, 4H), 1.17−1.40 (m, 8H). 13C NMR (100.6 MHz, DMSO-d6): δ
156.2, 137.2, 128.3, 127.7, 127.6, 69.0, 65.1, 46.9, 34.4, 25.2. HRMS
(ESI): calcd for C24H32N2O6 [M + H]+ 445.2333, found 445.2329.
General Procedure for Tosylation of Aliphatic Epoxy-
Diols.15 To a ∼0.35 M solution of epoxy-diol (1.0 equiv) in
CH2Cl2 was added Bu2SnO (0.02 − 0.04 equiv), Et3N (1.0 equiv), and
p-TsCl (1.0 equiv). The reaction was stirred overnight at room
temperature. Then the mixture was diluted with CH2Cl2 and added
NaHCO3 (saturated aqueous). The phases were separated, and the
aqueous phase was extracted with CH2Cl2. The collected organic
phases were washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography.
(R)-7-Hydroxy-1,8-bis(naphthalen-2-ylthio)octan-2-one (23).
This compound was synthesized according to the general procedure
for oxidation/thiolation from 20 (97 mg, 0.31 mmol) and Dess−
Martin periodinane (196 mg, 0.46 mmol) and continued with oxidized
product (82 mg, 0.26 mmol), 2-naphthalenethiol (255 mg, 1.59
mmol), and Et3N (220 μL, 1.58 mmol). The product 23 was purified
by flash chromatography (1:20 MeOH/CH2Cl2) with 75% yield (77
mg) over two steps. The er 99.8:0.2 was determined by HPLC analysis
and is referred to as the dr of 13 in Table 2 (CHIRALPAK IA column,
90:10 n-hexane/iPrOH, 1.5 mL/min, major isomer 30.3 min, minor
1
isomer 32.2 min). H NMR (400.1 MHz, CDCl3): δ 7.73−7.82 (m,
8H), 7.40−7.51 (m, 6H), 3.75 (s, 2H), 3.62−3.68 (m, 1H), 3.17 (dd, J
= 13.7, 3.5 Hz, 1H), 2.87 (dd, J = 13.7, 8.6 Hz, 1H), 2.61 (t, J = 7.1
Hz, 2H), 1.23−1.63 (m, 6H). 13C NMR (100.6 MHz, CDCl3): δ
205.4, 133.7, 132.6, 132.2, 132.0, 128.7, 128.6, 128.2, 127.8, 127.7,
127.2, 127.1, 126.7, 126.6, 126.1, 126.0, 69.2, 43.7, 42.1, 40.3, 35.7,
(S)-2-Hydroxy-6-((R)-oxiran-2-yl)hexyl-4-methylbenzenesul-
fonate (20). This compound was synthesized according to the general
procedure for tosylation of epoxy-diols from 13 (121 mg, 0.75 mmol),
E
dx.doi.org/10.1021/jo3024335 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
25.1, 23.6. HRMS (ESI): calcd for C28H28O2S2 [M − H]− 459.1458,
found 459.1446.
(m, 4H), 7.44−7.52 (m, 3H), 5.2 (bs, 1H), 3.98 (d, J = 4.4 Hz, 2 H),
3.68−3.74 (m, 1H), 3.22−3.26 (dd, J = 13.7, 3.4 Hz, 1H), 2.94 (dd, J
= 13.7, 8.7 Hz, 1H), 2.41 (t, J = 7.3, 2H), 1.27−1.67 (m, 15H). 13C
NMR (100.6 MHz, CDCl3): δ 205.6, 155.6, 133.7, 132.6, 132.1, 128.7,
128.4, 127.9, 127.7, 127.2, 126.7, 126.0, 79.8, 69.2, 50.3, 42.2, 39.8,
35.7, 28.3, 25.2, 23.5. HRMS (ESI): calcd for C23H31NO4S [M + Na]+
440.1866, found 440.1858.
(R)-9-Hydroxy-1,10-bis(naphthalen-2-ylthio)decan-2-one
(24). This compound was synthesized according to the general
procedure for oxidation/thiolation from 21 (22 mg, 66 μmol) and
Dess−Martin periodinane (41 mg, 99 μmol) and continued with
oxidized product (11 mg, 34 μmol), 2-naphthalenethiol (21 mg, 130
μmol), and Et3N (10 μL, 130 μmol). The product 24 was purified by
flash chromatography (2:3 EtOAc/n-hexanes) with 47% yield (7 mg)
over two steps. The er 99.4:0.6 was determined by HPLC analysis and
is referred to as the dr of 14 in Table 2 (Phenomenex LUX Cellulose-1
column, 70:30 n-hexane/iPrOH, 1.5 mL/min, major isomer 10.2 min,
minor isomer 12.4 min). 1H NMR (400.1 MHz, CDCl3): δ 7.73−7.83
(m, 8H), 7.40−7.51 (m, 6H), 3.74−3.77 (m, 2H), 3.64−3.71 (m, 1H),
3.22 (dd, J = 13.7, 3.5 Hz, 1H), 2.91 (dd, J = 13.7, 8.6 Hz, 1H), 2.59 (t,
J = 7.2 Hz, 2H), 1.22−1.58 (m, 10H). 13C NMR (100.6 MHz,
CDCl3): δ 205.7, 133.7, 132.7, 132.1, 132.0, 129.0, 128.7, 128.6, 128.3,
127.9, 127.7, 127.6, 127.5, 127.2, 127.1, 126.7, 126.6, 126.2, 126.0,
125.7, 69.4, 43.8, 42.2, 40.5, 36.0, 29.2, 28.9, 25.4, 23.6. MS (ESI) calcd
for C30H32O2S2 [M + H]+ 489.1917, found 489.1902.
(R)-13-Hydroxy-1,14-bis(naphthalen-2-ylthio)tetradecan-2-
one (25). This compound was synthesized according to the general
procedure for oxidation/thiolation from 22 (10 mg, 25 μmol) and
Dess−Martin periodinane (60 mg, 141 μmol) and continued with
oxidized product (4 mg, 10 μmol) and 2-naphthalenethiol (10 mg, 62
μmol). The product 25 was purified by flash chromatography (1:10:10
EtOAc/CH2Cl2/petroleum ether) with 78% yield (5 mg) over two
steps. The er 99.2:0.8 was determined by HPLC analysis and is
referred to as the dr of 15 in Table 2 (Phenomenex LUX Cellulose-1
column, 80:20 n-hexane/iPrOH, 1.5 mL/min, minor isomer 14.5 min,
major isomer 17.6 min). 1H NMR (400.1 MHz, CDCl3): δ 7.74−7.83
(m, 8H), 7.41−7.51 (m, 6H), 3.77 (s, 2H), 3.71 (m, 1H), 3.26 (dd, J =
13.7, 3.3 Hz, 1H), 2.94 (dd, J = 13.7, 8.7 Hz, 1H), 2.59−2.63 (m, 2H),
2.44 (d, J = 2.9 Hz, 1H), 1.20−1.59 (m, 18H). 13C NMR (100.6 MHz,
CDCl3): δ 205.8, 133.7, 132.7, 132.3, 132.0, 131.9, 128.7, 128.6, 128.2,
127.8, 127.7, 127.6, 127.2, 127.1, 126.7, 126.0, 125.9, 69.4, 43.8, 42.1,
40.7, 36.2, 29.5, 29.4, 29.3, 29.1, 25.6, 23.8. HRMS (ESI): calcd for
C34H40O2S2 [M − H]− 543.2397, found 543.2389.
tert-Butyl((S)-2-(benzyloxy)-6-((R)-oxiran-2-yl)hexyl)-
carbamate (27). To a solution of epoxy-amino alcohol 18 (20 mg, 77
μmol) in THF (1.5 mL) were added NaH (4.6 mg, 115 μmol), benzyl
bromide (12 μL, 100 μmol), and tetrabutylammonium iodide (5.7 mg,
15.4 μmol) under an argon atmosphere and stirred overnight. Then
the reaction was quenched with NaHCO3 (saturated aqueous) and
washed with brine. The organic phase was dried over MgSO4 and
concentrated in vacuo. The obtained crude product was purified by
flash chromatography (10:90 EtOAc/n-hexanes) to afford 14 mg of
the benzylated product 27 with 52% yield. The er 99.8:0.2 was
determined by HPLC analysis (CHIRALPAK IC column, 94:6 n-
hexane/iPrOH, 1.0 mL/min, minor isomer 24.4 min, major isomer
27.8 min). 1H NMR (400.1 MHz, CDCl3): δ 7.27−7.38 (m, 5H), 4.81
(bs, 1H), 4.51−4.58 (m, 2H), 3.45−3.54 (m, 1H), 3.35−3.41 (m, 1H),
3.11−3.17 (m, 1H), 2.88−2.92 (m, 1H), 2.75 (dd, J = 5.0, 3.9 Hz,
1H), 2.46 (dd, J = 5.0 2.7 Hz, 1H), 1.26−1.66 (m, 17H). 13C NMR
(100.6 MHz, CDCl3): δ 156.1, 138.5, 128.4, 127.8, 127.7, 79.2, 77.9,
71.3, 52.2, 47.0, 43.2, 32.3, 31.8, 28.4, 26.1, 25.1. HRMS (ESI): calcd
for C20H31NO4 [M + H]+ 350.2326, found 350.2320.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
1
Figures giving H and 13C NMR spectra, H data of Mosher
ester derivatives, and chromatograms from chiral HPLC
analysis. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lauri.vares@ut.ee.
■
(R)-Benzyl(9-hydroxy-10-(naphthalen-2-ylthio)-2-oxodecyl)-
carbamate (26). This compound was synthesized according to the
general procedure for oxidation/thiolation from 17 (86 mg, 0.24
mmol) and Dess−Martin periodinane (171 mg, 0.37 mmol) and
continued with oxidized product (53 mg, 0.16 mmol), 2-
naphthalenethiol (40 mg, 0.25 mmol), and Et3N (35 μL, 0.25
mmol). Product 26 was purified using flash chromatography (3:4
EtOAc/n-hexanes) with 88% yield over two steps (77 mg). The er
91.6:8.4 was determined by HPLC analysis and is referred to as the dr
of 17 in Table 3 (CHIRALPAK IB column, 85:15 n-hexane/iPrOH,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Archimedes Foundation (project no. 3.2.0501.10-
0004) and Estonian Ministry of Education (project no.
SF0180073s08) for financial support. We are grateful to Dr.
Tonis Pehk (National Institute of Chemical Physics and
̃
1
1.5 mL/min, major isomer 26.3 min, minor isomer 33.4 min). H
Biophysics, Tallinn, Estonia) for his help with NMR spectra
and Prof. Peter Somfai and Dr. Brinton Seashore-Ludlow for
critically reading the manuscript.
NMR (400.1 MHz, CDCl3): δ 7.75−7.84 (m, 4H), 7.44−7.51 (m,
3H), 7.31−7.37 (m, 5H), 5.48 (bs, 1H), 5.12 (s, 2H), 4.07 (d, J = 4.4
Hz, 2H), 3.71 (ddt, J = 8.7 5.9, 3.2 Hz, 1H), 3.25 (dd, J = 13.7, 3.2 Hz,
1H), 2.94 (dd, J = 13.7, 8.7 Hz, 1H), 2.4 (t, J = 7.5 Hz, 1H), 1.29−1.61
(m, 10H). 13C NMR (100.6 MHz, CDCl3): δ 205.2, 156.1, 136,3,
133.7, 132.7, 132.0, 128.6, 128.5, 128.2, 128.1, 128.0, 127.8, 127.7,
127.1, 126.6, 125.9, 69.4, 67.0, 50.5, 42.1, 39.9, 36.0, 29.2, 28.9, 25.4,
23.5. HRMS (ESI): calcd for C28H33NO4S [M + H]+ 480.2203, found
480.2184.
(R)-tert-Butyl(7-hydroxy-8-(naphthalen-2-ylthio)-2-
oxooctyl)carbamate (28). This compound was synthesized
according to the general procedure for oxidation/thiolation from 18
(16 mg, 63 μmol) and Dess−Martin periodinane (40 mg, 94 μmol)
and continued with oxidized product (7 mg, 27 μmol), 2-
naphthalenethiol (6 mg, 41 μmol), and Et3N (5 μL, 36 μmol).
Product 28 was purified using flash chromatography (3:4 EtOAc/n-
hexanes) with 63% yield over two steps (8 mg) (58% yield over two
steps). The er 99.3:0.7 was determined by HPLC analysis and is
referred to as the dr of 18 in Table 3 (Phenomenex LUX Cellulose-1
column, 85:15 n-hexane/iPrOH, 1.0 mL/min, minor isomer 17.3 min,
major isomer 19.9 min). 1H NMR (400.1 MHz, CDCl3): δ 7.75−7.84
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