Synthesis of enantiopure cyclopropyl esters from (-)-levoglucosenone

Article abstract of DOI:10.1039/c6ob00933f

The biorenewable chiral synthon (-)-levoglucosenone has been converted to enantiopure cyclopropyl esters using the base-promoted carbocyclisation of 4,5-epoxyvalerates. This protocol was applied to the enantiospecific synthesis of the GABA_c receptor agonist (1R,2R)-trans-2-aminomethylcyclopropanecarboxylic acid ((-)-TAMP) and its enantiomer. The process was also extended to generate 1,1,2- and 1,2,3-trisubstituted cyclopropanes resulting in a formal synthesis of the selective glutamate receptor antagonist PCCG-4.

Full text of DOI:10.1039/c6ob00933f

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Synthesis of enantiopure cyclopropyl esters from (-)D-OI: 10.1039/C6OB00933F
levoglucosenone.
Received 00th January 20xx,
Accepted 00th January 20xx
K. P. Stockton and B. W. Greatrex
The biorenewable chiral synthon (-)-levoglucosenone has been converted to enantiopure cyclopropyl esters using the
base-promoted carbocyclisation of 4,5-epoxyvalerates. This protocol was applied to the enantiospecific synthesis of the
GABAc receptor agonist (1R,2R)-trans-2-aminomethylcyclopropanecarboxylic acid ((-)-TAMP) and its enantiomer. The
process was also extended to generate 1,1,2- and 1,2,3-trisubstituted cyclopropanes resulting in a formal synthesis of the
selective glutamate receptor antagonist PCCG-4.
DOI: 10.1039/x0xx00000x
www.rsc.org/
affords 2-(hydroxymethyl)cyclopropyl esters21-25 or ketones26-28
when the appropriate 4,5-epoxycarbonyl derivative is treated
with base. Hindered bases including lithium diisopropylamide
Introduction
The cellulose pyrolysis product (-)-levoglucosenone (1) has
long been recognised as a versatile and potentially useful
chiral synthon.1,2 Availability has been an issue and recent
improvements in the production of 1 have only now made its
use in industry feasible.3 Consequently, we have begun to
develop methods for the conversion of 1 into new chiral
materials,4 and now disclose a general route to substituted
enantiopure cyclopropyl esters.
Cyclopropyl rings are commonly encountered in synthetic
bioactives due to their rigid bond angles which restrict
conformational freedom and promote selective interactions
with biological targets.5 An example of such a bioactive is
trans-(aminomethyl)cyclopropanecarboxylic acid ((-)-TAMP,
(LDA) and lithium hexamethyldisilazide (LHMDS) have been
reported in the case of ester cyclisations.29,30
A number of variations on the intramolecular cyclisation using
epoxides have been developed. The requisite 4,5-
epoxyenolates are most commonly prepared as intermediates
when malonates are treated with epichlorohydrin in the
presence of bases such as ethoxide and even
triethylamine.25,31,32 The reaction sequence can also be
initiated with the addition of a nucleophile to 4,5-epoxy-2,3-
dehydrovalerates.33
Throughout the 1990s, the group of Ebata used the Baeyer-
Villiger reaction on
1 and derivatives to prepare -
butyrolactones which can be converted into 4,5-epoxyesters
(Scheme 1).34-36 We demonstrate here that epoxide (S)-9a and
derivatives are suitable cyclopropanation substrates and can
be used in the synthesis of bioactive cyclopropanes.
(R,R)-2), which is a partial agonist of the GABAA (KD 55
2 GABAC (KD 2.6
M) receptors.6 The enantiomer (S,S)-2 is
also a partial agonist but has lower activity (KD 31 M) at
M) and


the2 GABAC receptors. Duke et al. suggested that the ability
of the cis- and trans-cyclopropyl isomers to selectively bind to
γ-aminobutyric acid (GABA) receptors was a function of their
rigid mimicry of the folded and extended conformations of
GABA.7 Other CNS active cyclopropane derivatives include the
serotonin-norepinephrine reuptake inhibitor milnacipran 3,8
and the glutamate receptor antagonist PCCG-4 4 (Figure 1).9
A variety of techniques5,10-12 have been developed for the
synthesis of cyclopropyl acids and derivatives of amino acids as
they are particularly well represented in the medicinal
chemistry literature.8,13-20 A less explored enantiospecific
method is the cyclisation of 4,5-epoxyenolates. The reaction
Results and Discussion
Starting with 1, both enantiomers of epoxyvalerate 9 were
synthesised as shown in Scheme 1. Hydrogenation of 1 and
Baeyer-Villiger
oxidation
afforded
hydroxymethyl-
butyrolactone (S)-7 in 91% overall yield for the two steps. The
Baeyer-Villiger reaction proceeded through the cyclic
orthoformate intermediate 6 to give (S)-7 and some of the
corresponding formate ester on the C-5 alcohol which was
hydrolysed with an aqueous HCl treatment. Ebata reported
that only 40% yield of butyrolactone (S)-7 was obtained if m-
CPBA was used as oxidant,37 however, when catalysed by p-
toluenesulfonic acid (TsOH) the reaction afforded an excellent
yield of (S)-7 in 16 hours. Mesylation generated (S)-8, and then
reaction with 1.05 equivalents of sodium ethoxide in ethanol
gave ethyl 4,5-epoxyvalerate (S)-9a in 58% yield for the 2-
steps. Due to the slight volatility of ethyl epoxyvalerate (S)-9a
and later products, the bulkier cyclohexyl epoxyvalerate (S)-9b
was also synthesised from (S)-8 using the lithium salt of
cyclohexanol. The enantiomer (R)-9b was prepared by the
cyclisation of epoxide (S)-9a to furnish the lactone (R)-7 which
was treated as per its enantiomer to give (R)-9b.
Figure 1. Some CNS active cyclopropyl amino acid derivatives.
a. School of Science and Technology, University of New England, Armidale, NSW,
Australia, 2351
The results of the base-promoted cyclisation reactions for
ester (S)-9a, (S)-9b and (R)-9b using LHMDS are shown in Table
1. The best yields were obtained at higher temperatures, while
Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra for
all new compounds. See DOI: 10.1039/x0xx00000x
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DOI: 10.1039/C6OB00933F
Scheme 1. Synthesis of enantiomers of 9a and 9b
.
Table 1: Base-promoted cyclopropanation reactions of (S)-9a and 9b
.
Entrya
Solvent
Substrate
Temp. (oC)
Yield 9b
1
2
THF
THF
Et2O
THF
THF
THF
THF
THF
THF
THF
(S)-9a
(S)-9a
(S)-9a
(S)-9a
(S)-9a
(S)-9b
(S)-9b
(S)-9b
(S)-9b
(S)-9b
(S)-9b
(S)-9b
(S)-9b
(R)-9b
25
-10
25
25
50
25
25
25
-78
-78 to 25
-78
80
50 (nd)
nd (36)
36 (nd)
47 (nd)
46 (nd)
53 (nd)d
58 (50)
38 (nd)
0 (0)
18 (nd)
13(nd)
30 (nd)
65 (nd)
(40)
3
4c
5
6
7
8e
9
at lower temperatures competing dimerisations dominated
giving complex mixtures (entries 2, 9, 10 and 13).
10
11f
12g
13
14
THF
Toluene
THF
The reaction at 50 °C afforded 65% of the trans-cyclopropane
1
10a as determined by H NMR with 1,3-diphenylbutadiene as
50
25
internal standard (entry 13). Only a single diastereomer was
isolated from the reactions and no other stereoisomers were
visible in the crude NMR or were isolated. To exclude the
possibility of lactone formation from the cis-cyclopropyl
isomer, (±)-3-oxabicyclo[3.1.0]hexan-2-one (11) was prepared
via the Simmons-Smith cyclopropanation of but-2-ene-1,4-diol
followed by oxidation with TEMPO/TCC. There was no
evidence of 11 in any GCMS chromatograms obtained from
crude reactions in Table 1.
THF
a Reactions were performed by the addition of 200 mg of epoxide to LHMDS (1.2 equiv)
in THF (15 mL) unless otherwise indicated. Conversion determined by 1H NMR with
b
1,3-diphenylbutadiene or p-dimethoxybenzene as internal standard. c 1.2 equiv KHMDS
d
e
f
g
was used. 5 mL total solvent volume. Inverse addition. 10 mol% BF3.Et2O. 1.0
equiv. of LHMDS was used in toluene (15 mL).
Scheme 2. Synthesis of both enantiomers of TAMP (2)
With adequate quantities of cyclopropane in hand, the
conversion to the GABAc receptor partial agonist (1S,2S)-2 was
examined (Scheme 2). Although less active, (1S,2S)-2 was
directly accessible from 1 without epimerisation and so its
synthesis was used to establish the methodology. Taking
alcohol (1S,2S)-10b through to (1S,2S)-2 was achieved by
mesylation to (1S,2S)-12, substitution with azide to furnish
(1S,2S)-13 and finally hydrogenation under acidic conditions to
give the amino acid in 82% yield for the three steps.
Attempted crystallisation of (1S,2S)-2 by vapour diffusion from
methanol/diethyl ether gave methyl ester (1S,2S)-14.
The enantiomer (1S,2S)-2 was synthesised starting with
epoxide (R)-9b which was treated with base to give
cyclopropane (1R,2R)-10b in 40% yield. Conversion of
cyclopropane (1R,2R)-10b through to (-)-TAMP (1R,2R)-2
proceeded in 79% combined yield via mesylate (1R,2R)-12 and
then azide (1R,2R)-13. For ease of comparison, (1R,2R)-2 was
also converted to the methyl ester (1R,2R)-14. It was found
that the magnitude of the optical rotations had excellent
agreement for the products as well as the intermediates
indicating that epimerisation did not occur at any stage of the
synthesis.
In order to expand the scope of the cyclopropanation to 1,1,2-
and 1,2,3-trisubstituted cyclopropanes, we applied the
methodology to substituted butyrolactones of type 16, 21 and
29 (Scheme 3). These butyrolactones can be accessed from 1
or the 3-iododerivative 15 using Heck, Suzuki and palladium-
mediated hydroarylation reactions followed by Baeyer-Villiger
oxidation.4 Thus, conversion of 16 to mesylate 17 and then
reaction with ethoxide afforded the epoxyvalerate 18 as a 1:1
mixture of diastereomers ready for cyclisation. Likewise, the
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epoxide 23 was prepared from the corresponding intermediate used in the synthesis of the metabotropic
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9
DOI: 10.1039/C6OB00933F
butyrolactone 21 by mesylation to give 22 and then reaction glutamate receptor antagonist PCCG-4 (4) and was obtained
with ethoxide in THF/ethanol. The diastereomer 28 was from ester 24 by hydrolysis and PyBOP coupling with
prepared as previously described4 using the Heck reaction of 1 morpholine in 89% yield for the two-steps. The sequence 1 to
with PhI followed by hydrogenation with Pd/C. Baeyer-Villiger 27 therefore represents a formal synthesis of 4.
oxidation afforded lactone 29 which was converted to epoxide The diastereomer 31 likewise proceeded with good selectivity
31 via mesylate 30.
in the cyclisation reaction and afforded lactone 32 in moderate
The reaction of phenyl-substituted epoxide 18 with LHMDS isolated yield. It was not possible to isolate the ester before
afforded the trans-isomer 19 and lactone 2038 formed from lactonisation occurred, a consequence of the syn-substitution
1
the cis-isomer in a 29:6 isolated yield ratio (5:1 by H NMR). of the alcohol and ester in the product.
The stereochemistry of 198 was confirmed on the basis of The product 24 formed from aryl substituted epoxide 23 had
crosspeaks in the NOESY spectrum between the phenyl and the ester group and hydroxymethyl group anti in the product
exocyclic hydroxymethylene resonances. Compound 20 has while cyclisation of epimer 31 had the two groups syn. The
been used for the preparation of the CNS drug milnacipran 3, ester and phenyl are anti in both products 24 and 32 indicating
however, the low yield obtained in the cyclisation and the that the enolate-phenyl relationship was likely a controlling
reaction selectivity would make the current synthesis element.
unfeasible.
To understand the interactions occurring in the transition
The cyclisation of 23 under the optimised conditions afforded states (TS) leading to the possible products, the E-enolates
24 in excellent yield with complete diastereoselectivity generated from 23 and 31 were modelled using Spartan ’14
(Scheme 3). A small amount of the O-silylated derivative 25 B3LYP/6311+G(d,p) and MP2/631G(d) in vacuum and the DFT
(10%) and traces of dimerised compound 26 arising from an TS structures found using each method are shown in Figure
intermolecular transesterification were also isolated from the 1.39,40 These levels of theory were chosen as they are
reaction mixture. The silylated adduct 25 was readily computationally affordable and reasonably reflect the relative
converted to 24 by stirring in ethanolic HCl confirming the energies in SN2 transition states compared to the best CCSD(T)
structural assignment. Morpholinamide 27 is an advanced calculations.41 Based upon the work of Ireland, the E-enolates
Scheme 3. Preparation of trisubstituted cyclopropanes
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of the methyl ester analogues of the starting enolates had
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bond angles supporting a Thorpe-Ingold-DtyOpI:e10r.a10te39a/Ccc6eOlBe0r0a9ti3o3nF
in the cyclisation. Unsubstituted enolate derived from 9 (R =
Me) had a calculated C2-C3-C4 bond angle of 112.5° while the
enolate derived from methyl ester analogue of 23 had a
calculated bond angle of 107.7° and the enolate obtained from
31 had a calculated bond angle of 109.5° (see electronic SI).
Conclusions
The procedures described in this report yielded both
enantiomers of the GABAc receptor antagonist TAMP with (+)-
TAMP synthesised in 8 steps from 1 in 35% overall yield, and
(-)-TAMP in 10 steps in 15% overall yield. We have also shown
that the products of palladium-catalysed cross coupling
reactions on 1 are suitable substrates for conversion through
to cyclopropyl esters via intramolecular ring-closure reactions.
The 3-substituted epoxy valerate 23 underwent cyclisation to
the corresponding 1,2,3-trisubstituted cyclopropane in
excellent yield leading to a formal synthesis of 4 and this
reaction bodes well for the synthesis of other 1,2,3-
trisubstituted cyclopropanes and potentially 1,2,2,3-
tetrasubstituted cyclopropanes.
Figure 2. Model DFT/B3LYP 6311+G(d,p) transition states leading to methyl ester
analogues of observed products 24 and 32
.
Table 2. Key bond distances and energies in 33, 34, 36 and 37 at B3LYP/6311+G(d,p)
and MP2/631-G(d).
TS
33
34
36
37
Interatomic Distances
Rel. Energies
(kcal.mol-1)
0.0
C2-C4
2.11
1.99
2.09
1.97
2.08
1.97
2.11
1.99
C4-O3
1.91
1.90
1.95
1.93
1.96
1.94
1.93
1.93
B3LYP
MP2
B3LYP
MP2
B3LYP
MP2
B3LYP
MP2
0.0
+5.6
+4.7
0.0
0.0
+2.0
+0.6
Experimental
(S)-5-(Hydroxymethyl)dihydrofuran-2(3H)-one ((S)-7).45 To a
stirred solution of 2,3-dihydrolevoglucosenone 5 (4.0 g, 31.2
mmol) in DCM (50 mL) cooled using a water bath was added
70% m-chloroperbenzoic acid (11.5 g, 47 mmol) then TsOH
(800 mg, 5.0 mmol). The mixture was stirred for 16 hours and
then the volatiles were removed under reduced pressure. To
the residue was added 1M HCl (20 mL) and the resulting
solution stirred overnight. The mixture was filtered, the
precipitate washed with water and the filtrate concentrated
under reduced pressure. Purification of the residue by flash
chromatography (ethyl acetate) to remove residual m-
chloroperbenzoic acid afforded the title compound (3.07 g,
85%); [α]D +50.0 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ
4.66-4.60 (m, 1H), 3.90 (dd, J = 12.5, 2.5 Hz, 1H), 3.64 (dd, J =
12.5, 4.5 Hz, 1H), 2.66-2.49 (m, 2H), 2.44 br s, 1H), 2.30-2.22
(m, 1H), 2.18-2.10 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.8,
80.9, 64.0, 28.7, 23.2; MS (EI) m/z 116.1 ([M]+, 0.5), 86 (12), 85
(100), 57 (10).
were expected when the esters were enolised with LHMDS in
THF.42 The geometry of the enolate was not expected to
greatly affect the reaction outcome as monomeric transition
states with a coordinated epoxide and enolate were not
possible. We have not probed the effects of enolate geometry
using calculations on the reaction outcome.
The transition states 33, 34, 36 and 37 exhibited single
imaginary frequencies and upon energy minimisation led to
the observed products or reactants. In both cases, the
observed product was correctly predicted by the calculated
energies using either level of theory. Using the B3LYP model,
transition state 34 leading to the all cis-cyclopropane 35 was
5.56 kcal.mol-1 less stable than the alternate 33 which led to
the observed cyclopropane 24. TS 36 leading to the observed
cyclopropane 32 following lactonisation was 1.7 kcal.mol-1
lower in energy than the alternate 37. The MP2 transition
states differed by 1.1 kcal.mol-1 and these structures
demonstrated a shorter C2-C4 bond and therefore later TS.
During the cyclisation, the ester enolate in 33 and 36 was on
the opposite face to the large phenyl substituent due to larger
steric interactions of the ester and phenyl compared to the
ester and epoxide. These results suggest that calculations
could be used to predict the outcomes of cyclisations of this
type.
(S)-5-(Methanesulfonyloxymethyl)dihydrofuran-2(3H)-one
((S)-8).46 To a solution of (S)-7 (5.08 g, 43.7 mmol) in DCM (50
mL) cooled using a water bath was added triethylamine (9.2
mL, 66 mmol) then methanesulfonyl chloride (4.7 mL, 61
mmol). The mixture was stirred for 3 hours then quenched
with a saturated solution of NH4Cl and the DCM removed
under reduced pressure. The aqueous layer was extracted
twice with ethyl acetate then the combined organic extracts
were dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by column chromatography
We attributed the increased yield of cyclised products from 23
and 31 relative to the unsubstituted epoxide 9 to a Thorpe-
Ingold effect and the closing of the C2-C3-C4 bond angle due
to the 
-phenyl group.43,44 The energy-minimised geometries
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23
(ethyl acetate) to give (S)-8 as a yellow syrup (7.38 g, 87%); spectroscopically identical to (S)-8 (762 mg, 89%); [α]D -30.0
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DOI: 10.1039/C6OB00933F
25
[α]D +33.3 (c 1.5, DCM); FT-IR (neat) 2940, 1769, 1164 cm-1; (c 1.1, DCM).
1H NMR (300 MHz, CDCl3) δ 4.88-4.71 (m, 1H), 4.43 (dd, J =
11.5, 3.0 Hz, 1H), 4.29 (dd, J = 11.5, 4.9 Hz, 1H), 3.07 (s, 3H), (R)-Cyclohexyl
3-(oxiran-2-yl)propanoate ((R)-9b). To
2.67-2.52 (m, 2H), 2.47-2.32 (m, 1H), 2.23-2.06 (m, 1H); 13C cyclohexanol (870 mg, 8.65 mmol) in dry THF (10 mL) cooled to
NMR (75 MHz, CDCl3) δ 176.0, 76.6, 69.7, 37.7, 27.9, 23.4; MS -60 °C was added a solution of n-butyl lithium in THF (1.6 M,
(EI) m/z 195.1 [M + H]+ 217.1 [M + Na]+.
4.73 mL, 7.57 mmol) and the mixture stirred for 10 minutes. To
this was added (R)-8 (1.05 g, 5.41 mmol) dissolved in THF
(5mL) and the mixture was allowed to come to room
(S)-Ethyl 3-(oxiran-2-yl)propanoate ((S)-9a).47,48 To
a
suspension of mesylate (S)-8 (1.80 g, 9.3 mmol) in dry EtOH (20 temperature over the course of 1.5 hours. The mixture was
mL) was added solid sodium ethoxide (0.70 g, 10.2 mmol) and quenched with a saturated solution of NH4Cl and extracted
the mixture was stirred for 3 hours. The mixture was quenched twice with ethyl acetate. The combined organic extracts were
with saturated NH4Cl and extracted three times with DCM. The dried (MgSO4), concentrated under reduced pressure and the
combined organic extracts were dried (MgSO4) and the DCM residue purified by column chromatography (1:9 ethyl
distilled. The residue was filtered through a bed of silica acetate/hexanes) to give (R)-9b as a colourless oil that was
22
eluting with 1:2 ethyl acetate/hexanes and the filtrate spectroscopically identical to (S)-9b (936 mg, 87%); [α]D
concentrated to give a colourless oil (0.88g, 67%); [α]D22 -14.8 +11.4 (c 1.32, EtOH).
1
(c 1.35, CHCl3); FT-IR (neat) 2982, 1730, 1179 cm-1; H NMR
(300 MHz, CDCl3) δ 4.14 (q, J = 7.0 Hz, 2H), 3.03-2.93 (m, 1H), (1S,2S)-Ethyl
2-(hydroxymethyl)cyclopropanecarboxylate
2.76 (dd, J = 4.4. 4.4 Hz, 1H), 2.50 (dd, J = 4.4, 2.8 Hz, 1H), 2.45 ((1S,2S)-10a).13 A solution of LHMDS in toluene (1 M, 1.82 mL)
(dd, J = 7.5, 7.5 Hz, 2H), 2.02-1.89 (m, 1H), 1.84-1.72 (m, 1H), was added to THF (3.2 mL) and the mixture cooled to -5 °C. To
1.25 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.7, 60.3, this was slowly added a solution (S)-9a (0.220 g, 1.53 mmol) in
51.0, 46.9, 30.3, 27.5, 14.0; MS (ESI) m/z 145.1 [M + H]+.
THF (5 mL) over the course of 10 minutes. The mixture was
quenched with 10% w/v NaH2PO4 (10 mL) and extracted with
(S)-Cyclohexyl
3-(oxiran-2-yl)propanoate ((S)-9b). To DCM (3 x 20 mL). The combined organic extracts were dried
cyclohexanol (1.25 g, 12.5 mmol) in dry THF (15 mL) cooled to (MgSO4) and concentrated under reduced pressure using a 20
-60 °C was slowly added a solution of MeLi in THF/cumene °C water bath and the residue purified by column
(0.83 M, 12.8 mL). The mixture was stirred for 10 minutes and chromatography (1:1 ethyl acetate/hexanes) to give (1S,2S)-
30
then a solution of (S)-8 (1.73 g, 8.91 mmol) in dry THF (15 mL) 10a as a colourless oil (85 mg, 39%); [α]D +57.5 (c 0.8, DCM);
1
was added and the mixture was allowed to come to room FT-IR (neat) 3424, 2981, 1721, 1177 cm-1; H NMR (300 MHz,
temperature over the course of an hour. The reaction was CDCl3) δ 4.11 (q, J = 7.0 Hz, 2H), 3.61 (dd, J = 11.3, 6.0 Hz, 1H),
quenched with a saturated solution of NH4Cl and extracted 3.47 (dd, J = 11.3, 6.8 Hz, 1H), 1.78-1.65 (m, 1H), 1.62 (br. s,
with ethyl acetate. The organic layer was dried (MgSO4) and 1H), 1.55 (app. td, J = 8.6, 4.3 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H),
concentrated and the residue purified by column 1.22- 1.14 (m, 1H), 0.84 (ddd, J = 8.3, 6.2, 4.5 Hz, 1H); 13C NMR
chromatography (1:9 ethyl acetate/hexanes) to give (S)-9b as a (75 MHz, CDCl3) δ 173.7, 64.6, 60.6, 24.2, 18.3, 14.2, 12.6; MS
33
colourless oil (1.51 g, 84%); [α]D -11.8 (c 1.52, EtOH); FT-IR (EI) m/z 144.1 ([M]+, trace), 101.1 (36), 99.1 (73), 98.1 (43),
1
(neat) 2934, 2858, 1727, 1176 cm-1; H NMR (300 MHz, CDCl3) 88.1 (64), 73.1 (100), 70.1 (39), 55.1 (98), 43.1 (27).
δ 4.77-4.58 (m, 1H), 2.95-2.81 (m, 1H), 2.66 (dd, J = 4.5, 4.5 Hz,
1H), 2.41 (dd, J = 5.0, 2.7 Hz, 1H), 2.35 (dd, J = 7.4, 7.4 Hz, 2H), (1S,2S)-Cyclohexyl
2-(hydroxymethyl)cyclopropane
2.01-1.53 (m, 6H), 1.52-1.08 (m, 6H); 13C NMR (75 MHz ,CDCl3) carboxylate ((1S,2S)-10b). Cyclohexyl ester (1S,2S)-9b (248
δ 172.0, 72.5, 51.0, 46.8, 31.4, 30.6, 27.6, 25.2, 23.5; MS (ESI) mg, 1.25 mmol) was treated as per the method for (1S,2S)-10a
m/z 221.1 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for except that the reaction was performed at room temperature
C11H18O3Na 221.1154; Found 221.1152.
and the column eluent was 2:3 ethyl acetate/hexanes to give
32
(1S,2S)-10b as a colourless oil (123 mg, 50%); [α]D +51.5 (c
(R)-5-(Hydroxymethyl)dihydrofuran-2(3H)-one
((R)-7).49 2.00, EtOH); FT-IR (neat) 3420, 2934, 2858, 1719, 1175 cm-1; 1H
o
Trifluoroacetic acid (5 mL) was cooled to -10 C and epoxide NMR (300 MHz, CDCl3) δ 4.77-4.57 (m, 1H), 3.54 (dd, J = 11.5,
(S)-9a (1.25 g, 8.67 mmol) was added. The mixture was stirred 6.2 Hz, 1H), 3.43 (dd, J = 11.5, 6.4 Hz, 1H), 2.48 (br. s., 1H),
at -10 °C for 20 minutes then the mixture was diluted with 1.86-1.58 (m, 5H), 1.54-1.43 (m, 2H), 1.43-1.09 (m, 6H), 0.80
toluene and concentrated under reduced pressure. The (ddd, J = 8.4, 6.2, 4.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
residue was purified by column chromatography (ethyl 173.3, 72.7, 64.3, 31.5, 25.3, 24.0, 23.6, 18.6, 12.6; MS (ESI)
acetate) to give (R)-7 as
a
colourless oil that was 221.1 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
spectroscopically identical to (S)-7 (715 mg, 71%); [α]D21 -50.5 C11H18O3Na 221.1154; Found 221.1178.
(c 1.5, CHCl3).
(1R,2R)-Cyclohexyl
2-(hydroxymethyl)cyclopropane
(R)-5-(Methanesulfonyloxymethyl)dihydrofuran-2(3H)-one
carboxylate ((1R,2R)-10b). (R)-9b (936 mg, 4.72 mmol) was
((R)-8). Methylhydroxy lactone (R)-7 (510 mg, 4.39 mmol) was treated as per the method for (1S,2S)-10b to give (1R,2R)-10b
treated as per the procedure for (S)-8 to give (R)-8 which was
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as a colourless oil that was spectroscopically identical to concentrated under reduced pressure then theVrieewsAidrtuiclee Ownlainse
26
DOI: 10.1039/C6OB00933F
(1S,2S)-10b (376 mg, 40%); [α]D -47.6 (c 1.26, EtOH).
suspended in 2M HCl (5 mL) and stirred at 50 °C overnight.
Removal of the volatiles under reduced pressure gave crude 2-
(1S,2S)-Cyclohexyl
2-(methanesulfonyloxymethyl)cyclo aminomethylcyclopropanecarboxylate hydrochloride (1S,2S)-2
propanecarboxylate ((1S,2S)-12). To a solution of (1S,2S)-10b (278 mg, 99%) which was recrystallised by vapour diffusion
(683 mg, 3.44 mmol) in DCM (10 mL) was added triethylamine from methanol/ether to give (1S,2S)-14 as translucent crystals
24
1
(720 µL, 5.17 mmol) then methanesulfonyl chloride (380 µL, (208 mg, 74%); mp 188-192 °C; [
]
D
+68.9 (c 1.03, H2O); H
4.82 mmol). The resulting mixture was stirred for 2 hours then NMR (300 MHz, D2O) δ 3.70 (s, 3H), 3.04 (dd, J = 13.4, 7.0 Hz,
quenched with a saturated solution of NH4Cl and extracted 1H), 2.95 (dd, J = 13.4, 7.9 Hz, 1H), 1.82 (ddd, J = 8.7, 4.7 4.7
with ethyl acetate. The organic phase was dried (MgSO4) then Hz, 1H), 1.78-1.66 (m, 1H), 1.32 (ddd, J = 9.8, 4.7, 4.7 Hz, 1H),
concentrated under reduced pressure and the residue purified 1.09 (ddd, J = 8.7, 6.4, 4.7 Hz, 1H); 13C NMR (75 MHz, D2O) δ
by column chromatography (3:7 ethyl acetate/hexanes) to give 176.5, 53.2, 42.8, 19.7, 19.5, 14.2; MS (ESI) m/z 116.0 [M]+.
(1S,2S)-12 as a colourless syrup that crystallised on standing
24
(829 mg, 87%); mp 62-64 °C; [α]D +47.3 (c 1.1, EtOH); FT-IR (1R,2R)-Methyl
2-aminomethylcyclopropanecarboxylate
(neat) 2944, 2861, 1710, 1161 cm-1; H NMR (300 MHz, CDCl3) hydrochloride ((1R,2R)-14).50 (1R,2R)-13 (344 mg, 1.54 mmol)
δ 4.85-4.61 (m, 1H), 4.15 (dd, J = 11.1, 6.8 Hz, 1H), 4.07 (dd, J = was treated as per the method for (1S,2S)-14 to give (1R,2R)-
11.1, 7.2 Hz, 1H), 3.01 (s, 3H), 1.90-1.60 (m, 6H), 1.58-1.15 (m, 14 as translucent crystals that were spectroscopically identical
7H), 0.93 (ddd, J = 8.5, 5.8, 4.9 Hz, 1H); 13C NMR (75 MHz, to (1S,2S)-14 (168 mg, 66%); [α]D26 -64.6 (c 0.43, EtOH).
CDCl3) δ 171.9, 73.2, 71.5, 38.0, 31.5, 25.3, 23.7, 20.1, 19.4,
1
13.0; MS (ESI) m/z 277.1 [M + H]+ 299.1 [M + Na]+; HRMS (ESI- (3S,5S)-5-(Methanesulfonyloxymethyl)-3-phenyldihydrofuran
TOF) m/z: [M + Na]+ Calcd for C12H20O5NaS 299.0929; Found -2(3H)-one (17). To a solution of 16 (414 mg, 2.16 mmol) in
299.0923.
DCM (5 mL) cooled in a water bath was added triethylamine
(0.45 mL, 3.2 mmol) then methanesulfonyl chloride (0.23 mL,
(1R,2R)-Cyclohexyl
2-(methanesulfonyloxymethyl)cyclo 3.0 mmol). The mixture was stirred for 1.5 hours then
propanecarboxylate ((1R,2R)-12). (1R,2R)-10b (487 mg, 2.46 quenched with saturated aqueous NH4Cl and extracted twice
mmol) was treated as per the method for (1S,2S)-12 to give with ethyl acetate. The combined organic extracts were dried
(1R,2R)-12 as a colourless oil that crystallised upon standing (MgSO4) and concentrated under reduced pressure and the
and was spectroscopically identical to (1S,2S)-12 (623 mg residue purified by column chromatography (3:2
30
92%); [α]D -44.2 (c 0.63, EtOH).
EtOAc/hexanes) to give 17 as a yellow syrup that crystallised
upon standing (591 mg, 100%); mp 102-104 °C; [α]D23 +50.8 (c
(1S,2S)-Cyclohexyl 2-(azidomethyl)cyclopropanecarboxylate 1.26, DCM); FT-IR (neat) 3032, 2978, 1736, 1344, 1180, 1141
1
((1S,2S)-13). To a solution of (1S,2S)-12 (555 mg, 2.01 mmol) in cm-1; H NMR (300 MHz, CDCl3) δ 7.56-7.09 (m, 5H), 4.95-4.81
DMF (10 mL) was added NaN3 (650 mg, 10.0 mmol) and the (m, 1H), 4.47 (dd, J = 11.5, 3.0 Hz, 1H), 4.36 (dd, J = 11.5, 4.5
mixture stirred at 60 °C overnight. The mixture was diluted Hz, 1H), 3.99 (dd, J = 9.8, 8.1 Hz, 1H), 3.09 (s, 3H), 2.67 (ddd, J =
with ethyl acetate and washed with three portions of 13.5, 9.8, 4.9 Hz, 1H), 2.55 (ddd, J = 13.4, 8.2, 8.1 Hz, 1H); 13C
saturated NH4Cl. The organic layer was dried (MgSO4) and NMR (75 MHz, CDCl3) δ 176.4, 136.6, 129.1, 127.9, 127.6, 74.8,
concentrated to give (1S,2S)-13 as a colourless oil which was 70.0, 45.2, 37.7, 32.5; MS (ESI) m/z 271.1 [M + H]+ 293.0 [M +
used without further purification (425 mg, 95%); [α]D29 +40.8 (c Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H14O5NaS
0.49, EtOH); FT-IR (neat) 2935, 2858, 2086, 1717, 1202, 1177 293.0460; Found 293.0468.
1
cm-1; H NMR (300 MHz, CDCl3) δ 4.83-4.61 (m, 1H), 3.19 (app.
d, J = 6.6 Hz, 2H), 1.89-1.61 (m, 5H), 1.59-1.14 (m, 8H), 0.85 (1S,2S)-Ethyl
2-(hydroxymethyl)-1-phenylcyclopropane
(ddd, J = 8.5, 6.0, 4.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ carboxylate (19).8 To a stirred solution of 17 (455 mg, 1.68
172.4, 72.9, 53.2, 31.5, 25.3, 23.6, 20.4, 18.9, 13.0; MS (ESI) mmol) in ethanol/THF (2:1, 15 mL) was added sodium ethoxide
m/z 246.1 [M + Na]+; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for (475 mg, 2.02 mmol). After
1 hour the reaction was
C11H18N3O2 224.1399; Found 224.1439.
neutralised with saturated NH4Cl and extracted twice with
DCM. The combined organic extracts were dried (MgSO4) and
(1R,2R)-Cyclohexyl 2-(azidomethyl)cyclopropanecarboxylate concentrated under reduced pressure and the residue purified
((1R,2R)-13). (1R,2R)-12 (581 mg, 2.10 mmol) was treated as by column chromatography (1:9 ethyl acetate/hexanes) to give
per the method for (1S,2S)-13 to give (1R,2R)-13 as a 18 as a 1:1 mixture of diastereomers (253 mg, 64%). A solution
colourless oil that was spectroscopically identical to (1S,2S)-13 of LHMDS in toluene (1.0 M, 712 µL) was added to THF (5 mL)
26
(408 mg, 87%);[α]D -37.6 (c 2.74, EtOH).
and a portion of 18 (112 mg, 0.508 mmol) in THF (5 mL) added
over the course of 10 minutes. The mixture was stirred for a
(1S,2S)-Methyl
2-aminomethylcyclopropanecarboxylate further 20 minutes then quenched with 10% w/v NaH2PO4 and
hydrochloride ((1S,2S)-14).50 To a solution of (1S,2S)-13 (414 extracted twice with DCM. The combined organic extracts
mg, 1.90 mmol) in 2:1 THF/2M HCl (9 mL) was added 5% Pd/C were dried (MgSO4) and concentrated and the residue purified
(40 mg) and the mixture stirred overnight under an by column chromatography (2:3 ethyl acetate/hexanes) to give
16
atmosphere of H2. The mixture was filtered through Celite and 19 (33 mg, 29%) and 20 (5 mg, 6%); 19: [α]D +12.5 (c 0.24,
6 | J. Name., 2016, 00, 1-3
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DCM); 1H NMR (300 MHz, CDCl3) δ 7.57-7.01 (m, 5H), 4.25-3.93 THF (1 M, 2.40 mL) was added to THF (17.6 mL) aVniedwaArsticoleluOtniolinne
(m, 2H), 3.39 (dd, J = 11.7, 5.8 Hz, 1H), 3.18 (dd, J = 11.7, 7.9 of 23 (441 mg, 2.0 mmol) in THF (10 DmOLI:)10w.1a0s39t/hCe6OnBa00d9d3e3dF
Hz, 1H), 2.18 (dddd, J = 9.2, 7.9, 6.6, 5.8 Hz, 1H), 1.70 (dd, J = rapidly. At the end of the addition the reaction was
9.2, 4.5 Hz, 1H), 1.47 (br. s., 1H), 1.27 (dd, J = 6.6, 4.5 Hz, 1H), immediately quenched with Amberlite® IRP-69 ion exchange
1.16 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) 173.8, 135.5, resin and filtered through Celite. The filtrate was concentrated
131.0, 128.2, 127.4, 62.4, 61.1, 33.8, 29.5, 18.1, 14.1; MS (ESI) and the residue purified by column chromatography (1:9 ethyl
m/z 221.1 [M + H]+ 243.1 [M + Na]+. (1R,5S)-1-Phenyl-3- acetate/hexanes) to give 24 (356 mg, 81%) as well as its O-
oxabicyclo[3.1.0]hexan-2-one (20)38: FT-IR (neat) 3060, 2973, trimethylsilyl ether derivative 25 (61 mg, 10%) as colourless
1
2907, 1758, 1602 cm-1; H NMR (300 MHz, CDCl3) δ 7.80-6.86 syrups; 24: [α]D17 -150 (c 1.70, DCM); FT-IR (neat) 3423, 3027,
(m, 5H), 4.47 (dd, J = 9.2, 4.7 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 2981, 1720, 1602, 1176 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.26-
2.55 (ddd, J = 7.9, 4.8, 4.7 Hz, 1H), 1.65 (dd, J = 7.9, 4.8 Hz, 1H), 7.20 (m, 2H), 7.20-7.10 (m, 3H), 4.10 (q, J = 7.2 Hz, 2H), 3.38
1.36 (dd, J = 4.8, 4.8 Hz, 1H); 13C NMR δ 175.9, 134.1, 128.6, (dd, J = 7.0, 7.0 Hz, 1H), 3.35 (dd, J = 7.0, 7.0 Hz, 1H), 2.81 (dd, J
128.3, 127.7, 68.0, 31.7, 25.1, 20.2; MS (ESI) m/z 175.0 [M + = 9.3, 5.3 Hz, 1H), 2.04 (dd, J = 5.3, 4.9 Hz, 1H), 2.01 (dddd, J =
H]+ 197.0 [M + Na]+.
9.3, 7.0, 7.0, 4.9 Hz, 1H), 1.48 (br. s., 1H), 1.22 (t, J = 7.2 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 173.0, 135.4, 128.7, 128.5,
(4R,5S)-5-(Methanesulfonyloxymethyl)-4-phenyldihydrofuran 126.9, 60.85, 60.8, 30.4, 30.0, 23.5, 14.2; MS (ESI) m/z 221.1
-2(3H)-one (22). To a solution of 21 (1.91 g, 9.94 mmol) was [M + H]+ 243.1 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
added triethylamine (2.07 mL, 14.9 mmol) then for C13H16O3Na 243.0997; Found 243.0988.
methanesulfonyl chloride (0.92 mL, 11.9 mmol) and the
mixture stirred for 3 hours. The reaction was quenched with (1S,2S,3R)-Ethyl
2-(trimethylsilyloxymethyl)-3-phenylcyclo
18
saturated NaHCO3 and extracted twice with ethyl acetate. The propanecarboxylate (25). [α]D -92.2 (c 0.51, DCM); FT-IR
combined organic extracts were dried (MgSO4) and (neat) 3072, 3023, 2956, 2871, 1727, 1251, 1179 cm-1; 1H NMR
concentrated under reduced pressure and the residue purified (500 MHz, C6D6) δ 7.11-6.96 (m, 5H), 3.99 (q, J = 7.1 Hz, 2H),
by column chromatography (1:1 ethyl acetate/hexanes) to give 3.31 (dd, J = 7.0, 7.0 Hz, 1H), 3.28 (dd, J = 7.0, 7.0 Hz, 1H), 2.98
22
22 as a pale yellow syrup (2.62 g, 98%); [α]D +47.4 (c 1.56, (dd, J = 9.5, 5.2 Hz, 1H), 2.23 (dddd, J = 9.5, 7.0, 7.0, 4.9 Hz,
DCM); FT-IR (neat) 3030, 2938, 1781, 1603, 1350, 1171 cm-1; 1H), 2.15 (dd, J = 5.2, 4.9 Hz, 1H), 0.98 (t, J = 7.2 Hz, 3H), -0.07
1H NMR (500 MHz, CDCl3) δ 7.38-7.30 (m, 2H), 7.29-7.23 (m, (s, 9H); 13C NMR (125 MHz, CDCl3) δ 173.2, 135.7, 129.0, 128.2,
1H), 7.22-7.16 (m, 2H), 4.61 (ddd, J = 8.1, 4.3, 2.4 Hz, 1H), 4.39 126.7, 60.7, 60.5, 30.8, 30.0, 23.7, 14.2, -0.7; MS (ESI) m/z
(dd, J = 11.9, 2.4 Hz, 1H), 4.26 (dd, J = 11.9, 4.3 Hz, 1H), 3.56 293.1 [M + H]+ 315.1 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+
(ddd, J = 9.8, 9.2, 8.1 Hz, 1H), 3.01 (s, 3H), 2.97 (dd, J = 18.0, Calcd for C16H24O3NaSi 315.1392; Found 315.1403.
9.2 Hz, 1H), 2.74 (dd, J = 18.0, 9.8 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 174.4, 137.8, 129.5, 128.3, 127.1, 83.0, 67.7, 42.7, ((1S,2S,3R)-2-(Hydroxymethyl)-3-phenylcyclopropyl)
37.8, 36.7; MS (ESI) m/z 271.1 [M + H]+ 293.1 [M + Na]+; HRMS (morpholino)methanone (27).9 To a solution of 24 (67 mg,
(ESI-TOF) m/z: [M + Na]+ Calcd for C12H14O5NaS 293.0460; 0.30 mmol) in 1:1 THF/H2O (2 mL) and NaOH added (25 mg,
Found 293.0446.
0.61 mmol) and the mixture heated for 20 minutes. A solution
of HCl (1 M, 3 mL) was added and then the mixture
(R)-Ethyl 3-((S)-oxiran-2-yl)-3-phenylpropanoate (23). To a concentrated under reduced pressure to give the crude
solution of 22 (2.60 g, 9.63 mmol) in 1:1 ethanol/THF (40 mL) carboxylic acid and NaCl. The residue was taken up in warm
was added sodium ethoxide (950 mg, 14.0 mmol) and the DCM (2 mL) and insoluble material removed by filtration. To
mixture stirred for 24 hours. The reaction was quenched with the solution of the carboxylic acid were added morpholine (35
saturated NH4Cl and extracted twice with DCM. The combined µL, 0.37 mmol), then PyBOP (190 mg, 0.37 mmol) and DIPEA
organic extracts were dried (MgSO4) and concentrated and the (140 µL, 0.84 mmol) and the reaction mixture immediately
residue purified by column chromatography (1:9 ethyl applied to
a column of silica and eluted with 3:17
acetate/hexanes) to give 23 as a pale yellow oil (1.72 g, 81%); methanol/ethyl acetate. Concentration of the appropriate
1
[α]D13 -4.8 (c 2.70, DCM); FT-IR (neat) 3063, 3030, 2981, 2927, fractions gave 27 as a colourless syrup (71 mg, 89%); H NMR
1
1729, 1602, 1251 cm-1; H NMR (500 MHz, CDCl3) δ 7.42-7.32 (500 MHz, CDCl3) δ 7.44-7.04 (m, 5H), 3.64 (br. s., 8H), 3.52
(m, 2H), 7.31-7.23 (m, 3H), 4.22-3.96 (m, 2H), 3.14 (ddd, J = (dd, J = 11.6, 7.0 Hz, 1H), 3.30 (dd, J = 11.6, 7.3 Hz, 1H), 2.81
7.2, 3.7, 2.4 Hz, 1H), 3.01 (ddd, J = 8.9, 7.2, 6.1 Hz, 1H), 2.92 (dd, J = 9.6, 4.6 Hz, 1H), 2.64 (br. s., 1H), 2.18 (dd, J = 4.6, 4.6
(dd, J = 15.3, 6.1 Hz, 1H), 2.79 (dd, J = 15.3, 8.9 Hz, 1H), 2.77 Hz, 1H), 2.02 (dddd, J = 9.5, 7.3, 7.0, 4.6 Hz, 1H); 13C NMR (125
(dd, J = 4.6, 3.7 Hz, 1H), 2.61 (dd, J = 4.6, 2.4 Hz, 1H), 1.17 (t, J = MHz, CDCl3) 170.5, 136.2, 128.6, 128.5, 126.8, 66.7 (2C), 60.8,
7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 171.5, 139.8, 128.6, 29.8, 29.3, 22.2.
127.7, 127.2, 60.4, 55.3, 46.9, 44.9, 37.6, 14.0; MS (ESI) m/z
221.1 [M + H]+ 243.1 [M + Na]+; HRMS (ESI-TOF) m/z: [M + (4S,5S)-5-(Hydroxymethyl)-4-phenyldihydrofuran-2(3H)-one
Na]+ Calcd for C13H16O3Na 243.0997; Found 243.1003.
(29). To a stirred solution of 28 (442 mg, 2.16 mmol) dissolved
in DCM (3 mL) was added 32% peracetic acid (600 µL, 2.78
(1S,2S,3R)-Ethyl
2-(hydroxymethyl)-3- mmol) and the mixture stirred overnight. The reaction was
phenylcyclopropanecarboxylate (24). A solution of LHMDS in quenched with 10% Pd/C (15 mg) and stirred for 20 minutes or
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until the evolution of O2 had ceased and a negative test for 137.2, 128.7, 127.1, 125.9, 69.7, 29.3, 27.4, 26.1; VMiewSA(rEticSleI)Omnli/nez
peroxides was obtained (starch/iodide). The mixture was then 197.1 [M + Na]+.
DOI: 10.1039/C6OB00933F
filtered through Celite, concentrated under reduced pressure
and taken up in 1:1 THF/1M HCl (12 mL) and stirred for 3
Acknowledgements
hours. The volatiles were removed under reduced pressure
and the residue purified by flash chromatography (1:1-7:3
ethyl acetate/hexanes) to give 29 as a crystalline solid (395 mg,
We gratefully acknowledge the donation of levoglucosenone
and productive discussions from Mr Tony Duncan and Dr
Warwick Raverty, Circa Group, Melbourne, Australia. We also
thank Assoc. Prof. Chris Fellows and Prof. Stephen Glover for
helpful comments regarding this manuscript.
27
95%); mp 97-99 °C (tol.); [α]D +172 (c 1.01, CHCl3); FT-IR
1
(neat) 3413, 3070, 3039, 2947, 1754, 1603 cm-1; H NMR (500
MHz, CDCl3) δ 7.42-7.34 (m, 2H), 7.34-7.28 (m, 1H), 7.28-7.21
(m, 2H), 4.80 (ddd, J = 7.6, 5.5, 3.7 Hz, 1H), 3.91 (ddd, J = 9.2,
8.2, 7.6 Hz, 1H), 3.53 (ddd, J = 12.5, 5.3, 3.7 Hz, 1H), 3.41 (br.
ddd, J = 12.5, 5.3, 5.3 Hz, 1H), 3.02 (dd, J = 17.4, 8.2 Hz, 1H),
2.89 (dd, J = 17.4, 9.2 Hz, 1H), 1.86 (br. dd, J = 5.3, 5.3 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 176.5, 136.4, 128.9, 127.9, 127.6,
83.2, 62.2, 43.1, 34.5; MS (ESI) m/z 193.1 [M + H]+ 215.1 [M +
Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H12O3Na
215.0684; Found 215.0675.
Notes and references
1. M. S. Miftakhov, F. A. Valeev and I. N. Gaisina, Russ. Chem.
Rev., 1994, 63, 869.
2. A. M Sarotti, M. M Zanardi, R. A Spanevello and A. G Suarez,
Curr. Org. Synth., 2012, 9, 439-459.
3. C. Lawrence, W. Raverty, A. Duncan, WO/2011/000030,
2011.
4. K. P. Stockton, C. M. Merritt, C. J. Sumby and B. W. Greatrex,
Eur. J. Org. Chem., 2015, 32, 6999-7008.
(4S,
5S)-5-(Methanesulfonyloxymethyl)-4-
phenyldihydrofuran-2(3H)-one (30). Alcohol 29 (245 mg, 1.28
mmol) was treated as per the method for 22 to give 30 as a
colourless crystalline solid (281 mg, 82%); mp 137-139 °C (tol.);
[α]D19 +152 (c 1.14, DCM); FT-IR (neat) 3032, 3015, 2961, 1766,
1763, 1600 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.50-7.31 (m,
3H), 7.25-7.14 (m, 2H), 4.99 (ddd, J = 7.2, 6.4, 3.1 Hz, 1H), 4.09
(dd, J = 11.6, 3.1 Hz, 1H), 3.95 (br. ddd, J = 8.9, 7.2, 6.4 Hz, 1H),
3.91 (dd, J = 11.6, 6.4 Hz, 1H), 3.00 (dd, J = 17.7, 8.9 Hz, 1H),
2.93 (s, 3H), 2.92 (dd, J = 17.7, 6.4 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 175.3, 135.7, 129.4, 128.5, 127.5, 79.7, 68.5, 42.6,
37.5, 34.6; MS (ESI) m/z 271.1 [M + H]+ 293.0 [M + Na]+. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C12H14O5NaS 293.0460;
Found 293.0455.
5. A. Mizuno, S. Miura, M Watanabe, Y. Ito, S. Yamada, T.
Odagami, Y. Kogami, M. Arisawa, and S. Shuto, Org. Lett.,
2013, 15, 1686-1689 and references cited therein.
6. G. A. Johnston, Curr. Top. Med. Chem., 2002, 2, 903-913.
7. R. K. Duke, M. Chebib, V. J. Balcar, R. D. Allan, K. N. Mewett
and G. A. Johnston, J. Neurochem., 2000, 75, 2602-2610.
8. B. Bonnaud, H. Cousse, G. Mouzin, M. Briley, A. Stenger, F.
Fauran and J. P. Couzinier, J. Med. Chem., 1987, 30, 318-325.
9. R. Pellicciari, M. Marinozzi, B. Natalini, G. Costantino, R.
Luneia, G. Giorgi, F. Moroni and C. Thomsen, J. Med. Chem.,
1996, 39, 2259-2269.
10. T. D. Avery, B. W. Greatrex, D. S. Pedersen, D. K. Taylor and
E. R. T. Tiekink, J. Org. Chem., 2008, 73, 2633-2640.
11. H. Xie, L. Zu, H. Li, J. Wang and W. Wang, J. Am. Chem. Soc.,
2007, 129, 10886-10894.
12. D. Y. K. Chen, R. H. Pouwer and J.-A. Richard, Chem. Soc.
Rev., 2012, 41, 4631-4642.
13. L. Amori, S. Katkevica, A. Bruno, B. Campanini, P. Felici, A.
Mozzarelli and G. Costantino, MedChemComm, 2012, 3,
1111-1116.
14. S. Shuto, S. Ono, Y. Hase, N. Kamiyama, H. Takada, K.
Yamasihita and A. Matsuda, J. Org. Chem., 1996, 61, 915-
923.
15. J. B. Schwarz, S. E. Gibbons, S. R. Graham, N. L. Colbry, P. R.
Guzzo, V.-D. Le, M. G. Vartanian, J. J. Kinsora, S. M. Lotarski
and Z. Li, J. Med. Chem., 2005, 48, 3026-3035.
16. A.-H. Li, L.-X. Dai and V. K. Aggarwal, Chem. Rev., 1997, 97,
2341-2372.
17. A. B. Charette and A. Beauchemin, Org. React., 2001.
18. M. P. Doyle, J. H. Griffin, V. Bagheri and R. L. Dorow,
Organometallics, 1984, 3, 53-61.
(R)-Ethyl
3-((S)-oxiran-2-yl)-3-phenylpropanoate
(31).
Mesylate 30 (250 mg, 0.93 mmol) was treated as per the
method for 23 to give 31 as a colourless oil (136 mg, 66%);
[α]D17 +11.0 (c 1.36, DCM); FT-IR (neat) 3067, 3032, 2981, 2923,
1731, 1602 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.39-7.31 (m,
2H), 7.30-7.20 (m, 3H), 4.18-4.03 (m, 2H), 3.32 (ddd, J = 7.6,
7.6, 5.6 Hz, 1H), 3.21 (ddd, J = 5.6, 4.0, 2.4 Hz, 1H), 2.78 (dd, J =
4.9, 4.0 Hz, 1H), 2.79 (dd, J = 15.6, 7.6 Hz, 1H), 2.68 (dd, J =
15.6, 7.6 Hz, 1H), 2.54 (dd, J = 4.9, 2.4 Hz, 1H), 1.20 (t, J = 7.2
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 171.5, 139.5, 128.5,
127.9, 127.2, 60.5, 54.6, 45.9, 43.1, 36.9, 14.0; MS (ESI) m/z
243.0 [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C13H16O3Na 243.0997; Found 243.0996.
(1R,5S,6S)-6-Phenyl-3-oxabicyclo[3.1.0]hexan-2-one
(32).51
Epoxide 31 (123 mg, 0.56 mmol) was treated as per the
method for 24 to give 31 as a crystalline solid (65 mg, 64%);
mp 122-123 °C; [α]D17 +130 (c 0.50, CHCl3); FT-IR (neat) 3068,
2963, 2905, 1737, 1602 cm-1; 1H NMR (500 MHz , CDCl3) δ
7.27-7.21 (m, 2H), 7.20-7.14 (m, 1H), 7.02-6.97 (m, 2H), 4.39
(dd, J = 9.5, 4.6 Hz, 1H), 4.34 (br. d, J = 9.5 Hz, 1H), 2.48-2.44
(m, 1H), 2.2 -2.23 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 174.9,
19. M. P. Doyle, A. B. Dyatkin, A. V. Kalinin, D. A. Ruppar, S. F.
Martin, M. R. Spaller and S. Liras, J. Am. Chem. Soc., 1995,
117, 11021-11022.
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
20. N. M. Roda, D. N. Tran, C. Battilocchio, R. Labes, R. J. Ingham, 47. S. Tsuboi, J. Sakamoto, T. Kawano, M. Utaka and A. Takeda, J.
View Article Online
DOI: 10.1039/C6OB00933F
J. M. Hawkins and S. V. Ley, Org. Biomol. Chem., 2015, 13,
2550-2554.
21. S. Takano, N. Sato, M. Akiyama and K. Ogasawara,
Heterocycles, 1985, 23, 2859-2872.
Org. Chem., 1991, 56, 7177-7179.
48. M. C. White, A. G. Doyle and E. N. Jacobsen, J. Am. Chem.
Soc., 2001, 123, 7194-7195.
49. Z.-Y. Liu, J.-X. Ji and B.-G. Li, J. Chem. Soc. Perkin Trans. 1,
2000, 3519-3521.
22. L. Tan, N. Yasuda, N. Yoshikawa, F. W. Hartner, K. K. Eng, W.
R. Leonard, F.-R. Tsay, R. P. Volante and R. D. Tillyer, J. Org. 50. K. Paulini and H. U. Reißig, Liebigs Ann. Chem., 1991, 455-
Chem., 2005, 70, 8027-8034. 461.
23. M. E. Senguel, A. Menzek, E. Sahin, M. Arik and N. Saracoglu, 51. J. V. Ruppel, X. Cui, X. Xu and X. P. Zhang, Org. Chem. Front.,
Tetrahedron, 2008, 64, 7289-7294.
2014, 1, 515-520.
24. K. Kuramochi, R. Matsui, Y. Matsubara, J. Nakai, T. Sunoki, S.
Arai, S. Nagata, Y. Nagahara, Y. Mizushina, M. Ikekita and S.
Kobayashi, Bioorg. Med. Chem., 2006, 14, 2151-2161.
25. M. V. Marques and M. M. Sá, J. Org. Chem., 2014, 79, 4650-
4658.
26. P. Crotti, V. Di Bussolo, L. Favero, F. Macchia, M. Pineschi and
E. Napolitano, Tetrahedron, 1999, 55, 5853-5866.
27. L. Dechoux, E. Doris, L. Jung and J. F. Stambach, Tetrahedron
lett., 1994, 35, 5633-5636.
28. L. Dechoux, L. Jung and J. F. Stambach, Synlett, 1994, 1994,
965-966.
29. C.-J. Koch, S. Šimonyiová, J. Pabel, A. Kärtner, K. Polborn and
Klaus T. Wanner, Eur. J. Org. Chem., 2003, 2003, 1244-1263.
30. S. Takano, N. Sato, M. Akiyama and K. Ogasawara,
Heterocycles, 1985, 23, 2859-2872.
31. T. Ok, A. Jeon, J. Lee, J. H. Lim, C. S. Hong and H.-S. Lee, J.
Org. Chem., 2007, 72, 7390-7393.
32. M. Tanabe, M. Watanabe, N. Hoshiya, A. Mizuno, H. Fukuda,
M. Arisawa and S. Shuto, J. Org. Chem., 2013, 78, 11714-
11720.
33. R. C. Dhakal and R. K. Dieter, J. Org. Chem., 2013, 78, 12426-
12439.
34. K. Koseki, T. Ebata, H. Kawakami, H. Matsushita, Y. Naoi and
K. Itoh, Heterocycles, 1990, 31, 423-426.
35. P.-T. Ho and N. Davies, Synthesis, 1983, DOI: 10.1055/s-1983-
30380, 462.
36. K. Matsumoto, T. Ebata, K. Koseki, K. Okano, H. Kawakami
and H. Matsushita, Bull. Chem. Soc. Japan, 1995, 68, 670-
672.
37. K. Koseki, T. Ebata, H. Kawakami, European Patent,
0418925B1, 1991.
38. M. P. Doyle, S. B. Davies and W. Hu, Org. Lett., 2000, 2, 1145-
1147.
39. Spartan ’14 software package Version 1.1.4, Wavefunction
Inc. CA 92612.
40. A. D. Becke, J. Chem. Phys., 1993, 98, 1372-1377.
41. M. Swart, M. Solà and F. M. Bickelhaupt, J. Comput. Chem.,
2007, 28, 1551-1560.
42. R. E. Ireland, P. Wipf and J. D. Armstrong III, J. Org. Chem.,
1991, 56, 650-657.
43. A. L. Ringer and D. H. Magers, J. Org. Chem., 2007, 72, 2533-
2537.
44. M. E. Jung and G. Piizzi, Chem. Rev., 2005, 105, 1735-1766.
45. Y. Nishida, M. Konno, Y. Fukushima, H. Ohrui and H. Meguro,
Agric. Biol. Chem., 1986, 50, 191-193.
46. T. Nakajima, D. Yamashita, K. Suzuki, A. Nakazaki, T. Suzuki
and S. Kobayashi, Org. Lett., 2011, 13, 2980-2983.
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