Synthetic strategy toward γ-KETO NITRILES and their Biocatalytic conversion to asymmetric γ-lactones

Article abstract of DOI:10.1055/s-0033-1339282

Asymmetric γ-hydroxy nitriles are valuable intermediates because hydrolysis of the nitriles can result in an intramolecular cyclization to chiral γ-lactones, which have a variety of biological uses. Starting with an assortment of different aldehydes (alkyl and aryl) a 4-step synthesis of γ-keto nitriles was developed. These prochiral substrates were then screened against a library of ketoreductases for their ability to stereoselectively reduce the carbonyl. Enzymes from the short chain dehydrogenase family showed activity and these enzymatic reactions were scaled up to produce a diverse set of chiral γ-lactones.

Full text of DOI:10.1055/s-0033-1339282

PAPER
▌2171
paper
Synthetic Strategy toward γ-Keto Nitriles and Their Biocatalytic Conversion
to Asymmetric γ-Lactones
Synthesis of Asymmetric γ-Lactones
Sarah E. Franz,1,a Richard R. Watkins,1,a Laura A. Wright,a Blair A. Weaver,a Ramon C. Hartage,a Ion Ghiviriga,b
Giuseppe Gumina,c Brent D. Feske*a
a
Department of Chemistry and Physics, Armstrong Atlantic State University, 11935 Abercorn St., Savannah, GA 31419, USA
b
Department of Chemistry, University of Florida, PO Box 117200, Gainesville, FL 32611, USA
c
Department of Chemistry, Georgia Southern University, PO Box 8064, Statesboro, GA 30460, USA
Fax +1 (912)3443433; E-mail: brent.feske@armstrong.edu
Received: 04.04.2013; Accepted after revision: 22.05.2013
Bakers’ yeast (Saccharomyces cerevisiae) has been a pop-
Abstract: Asymmetric γ-hydroxy nitriles are valuable intermedi-
ular biocatalytic tool for the organic chemist. It has been
ates because hydrolysis of the nitriles can result in an intramolecular
shown to catalyze a variety of reactions; however, it is
cyclization to chiral γ-lactones, which have a variety of biological
uses. Starting with an assortment of different aldehydes (alkyl and
most prevalently used for its proficiency to reduce ketones
aryl) a 4-step synthesis of γ-keto nitriles was developed. These pro- to asymmetric alcohols.12 Its ability to reduce a diverse
chiral substrates were then screened against a library of ketoreduc-
tases for their ability to stereoselectively reduce the carbonyl.
collection of ketones can be explained by the many keto-
reductases (KREDs) it contains and that many of these en-
Enzymes from the short chain dehydrogenase family showed activ-
zymes have been characterized to be very promiscuous.13
ity and these enzymatic reactions were scaled up to produce a di-
Unfortunately, the use of wild type bakers’ yeast frequent-
verse set of chiral γ-lactones.
ly leads to a combination of products often formed by
Key words: lactones, enzymes, reduction, asymmetric synthesis,
competing enzymes. To circumvent this problem, gluta-
asymmetric catalysis
thione S-transfersae (GST)-ketoreductase chimeras were
engineered and placed into Escherichia coli (E. coli) cre-
ating a bakers’ yeast KRED library.14–16 This system can
Chiral lactones are compounds that have shown medicinal
be used to screen the stereospecificity of these KREDs for
importance as anticancer agents, antibiotic agents, antivi-
a given substrate by use of the pure fusion protein or in
ral agents, and as antidepressants.2–4 The nonmedicinal
whole cells.15–18
uses include insect pheromones, flavor components, and
perfumes.2–4 While the first lactone synthesis was report-
ed in 1883,5 there has been a lack of asymmetric methods
to produce these compounds, especially methods utilizing
biocatalysis.6 Some biocatalytic methods have used
Baeyer–Villiger monooxygenases to oxidize cyclic ke-
tones yielding lactones,7 the oxidation of 1,4-diols,8,9 and
more popular routes utilize lipase chemistry to afford en-
antioselectivity via kinetic resolution.10 Similarly, Taylor
et al. used an approach to react γ-hydroxy nitriles with the
nitrilase found in Rhodococcus rhodochrous.11 Unfortu-
nately, the use of kinetically-resolving enzymes such as
nitrilase and lipase is inherently limited to a 50% yield
when the substrate is a racemic mixture (Scheme 1).
Recently we investigated the reduction of β-keto nitriles
with the above mentioned KRED library.17 These sub-
strates gave very interesting results such as high stereose-
lectivity, enzyme promiscuity, and the library’s synthetic
diversity affording both R or S alcohols in pure form for
most substrates. As a result, γ-keto nitriles were an obvi-
ous next substrate target to continue the investigation of
the KRED library. This comes with the additional benefit
that the enzymatic products (γ-hydroxy nitriles) can be
easily converted to asymmetric γ-lactones (Scheme 2). γ-
Lactones are one of the most commonly found lactones in
nature and they have been shown to be medicinally impor-
tant as DNA polymerase inhibitors, NF-κB activity regu-
lators, and microtubule assembly inhibitors, among many
other forms of pharmacological activity.19 These com-
pounds have also been found to act as insect pheromones
such as (R)-γ-caprolactone [(R)-γ-c] (beetle pheromone),
(R)-4-nonanolide [(R)-4-n] (rice weevil attractant), (R)-4-
dodecanolide [(R)-4-d] (beetle defense chemical), (S)-4-
hexanolide [(S)-4-h] (synthetic intermediate for beetle
O
Rhodococcus
OH
OH
*
rhodochrous
O
+
[nitrilase]
R
CN
R
CN
*
R
Scheme 1 Previous studies using nitrilase enzymes to kinetically re-
solve the alcohol can only give a 50% yield
O
1. acid or base
hydrolysis
OH
O
R
CN
2. H3O+ workup
(cyclization)
R
SYNTHESIS 2013, 45, 2171–2178
Advanced online publication: 25.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Scheme 2 Hydrolysis of γ-hydroxy nitriles followed by acidification
will afford a spontaneous cyclization to the γ-lactone
DOI: 10.1055/s-0033-1339282; Art ID: SS-2013-M0268-OP
© Georg Thieme Verlag Stuttgart · New York

2172
S. E. Franz et al.
PAPER
pheromone), and (R)-eldanolide [(R)-e] (moth phero- achieved by simple treatment with iodine and NaHCO3 af-
mone) (Figure 1), so a single strategy to synthesize a vari- fording the γ-keto nitriles in high yield.
ety of asymmetric γ-lactones would be beneficial.
The aforementioned KRED enzyme library was then
screened for its ability to reduce the γ-keto nitriles 5a–g to
O
O
O
O
O
the corresponding alcohol 6a–g (Scheme 4 and Table 1).
The percentages represent enantiomeric excesses, and to
better represent and compare any spatial tendencies the
absolute stereochemistry is represented in L and D Fischer
projections (with the more oxidized nitrile at the top and
R group at the bottom of the projection). These results
show that every substrate can be reduced by at least two
enzymes. For 6a, 6b, 6d, and 6g, this library can produce
either the L or the D stereoisomer by varying the enzyme
that is used (with variable ee), which potentially allows
for the synthesis of a variety of γ-lactone stereoisomers.
The enzyme YOL151w reduces every substrate, which is
no surprise since this enzyme has the highest promiscuity
out of the KRED enzyme library (it has at least 26 known
substrates at this time).15–18,21,22 Since this library of en-
zymes originated from bakers’ yeast (BY), these sub-
strates were also screened with bakers’ yeast to compare
its reduction capabilities. Interestingly, products obtained
from bakers’ yeasts’ ee was quite high; however, the over-
all conversion was extremely low (1 to 3% as shown by
GC) for a 1 mM substrate concentration. This low conver-
sion continues to support why the engineered E. coli is su-
perior when compared to wild type bakers’ yeast.
O
O
O
O
O
C5H11
(R)-4-n
C8H17
(R)-4-d
(R)-γ-c
(S)-4-h
(R)-e
Figure 1 Examples of several biologically active γ-lactones
To begin this approach a small library of γ-keto nitriles
must be synthesized. In addition, our goal was to develop
a substrate library that contains a balance of aliphatic and
aromatic substituents with varying size and electronics.
Unfortunately, most of the γ-keto nitrile substrates that we
wanted to investigate were not commercially available,
except for 5d, which was purchased from Sigma-Aldrich.
Current literature has shown that single synthetic strate-
gies toward these substrates are limited, so we developed
a four-step procedure that could be applied to both alkyl
and aryl groups as long as the aldehyde is commercially
available (Scheme 3).
The synthesis of the 1,3-dithianes 2 was easily accom-
plished in high yields. The aliphatic derivatives were usu-
ally oils that were purified through a bed of Celite using
vacuum filtration. Most of the aromatic compounds were
solids and could be purified simply by rinsing the solids
with EtOAc. The next step utilized the popular umpolung
chemistry demonstrated by Seebach and Corey.20 The al-
kylation was less favorable with the alkyl substituents
when compared to the aryl counterparts. In all cases, the
reaction temperature was kept at –78 °C to minimize the
competing β-elimination mechanism. Elimination prod-
ucts and 3a, 3b, and 3c were very difficult to separate ei-
ther by silica gel chromatography or fractional distillation.
Chromatography was ineffective due to their extremely
low polarity: the use of neat hexanes and pentane did not
afford sufficient separation and the addition of small
amounts of a discriminating eluent such as ethyl acetate
produced excessively polar mixtures. Fortunately the cy-
ano substitution could be effectively executed with the
crude mixture, followed by successful purification of the
more polar products 4 by flash chromatography. Aromatic
compounds 4 could simply be purified by rinsing the sol-
ids with EtOAc. Lastly, deprotection of 4a–g was
O
OH
*
KRED
library
R
CN
R
CN
5a–g
6a–g
Scheme 4 General reaction catalyzed by the ketoreductase enzyme
This KRED enzyme library is composed of enzymes from
four different families; the D-hydroxy dehydrogenase,
medium chain dehydrogenase, short chain dehydroge-
nase, and the aldose reductase family. In a recent publica-
tion,18 we had investigated the reduction of β-keto nitriles
and data analysis of the results showed that even though
the protein YNL331c had been classified as part of the al-
dose reductase family it showed substrate promiscu-
ity/similarity to those of the short chain dehydrogenase
family. This led to building a phylogenetic tree to check
the relationship of these enzymes. Analysis of this tree
suggested that the protein YNL331c was more closely re-
lated to the short chain dehydrogenase family and not the
aldose reductase family. Interestingly, we continue to see
O
HSCH2CH2CH2SH
NBS
H
BuLi
NaCN, DMSO
I2, NaHCO3
O
S
R
S
H
S
R
S
S
R
S
18-crown-6
100 °C, 4 h
BrCH2CH2Cl
THF, –78 °C, 4 h
acetone, H2O, 0 °C
R
R
CN
Cl
CN
4
1
2
3
5
Alkyl
Aryl
1a: R = Et
1b: R = Bu
1c: R = n-C6H13
1d: R = Ph
1e: R = 4-MeOC6H4
1f: R = 4-MeC6H4
1g: R = 4-ClC6H4
Scheme 3 Synthetic strategy developed to synthesize a variety of γ-keto nitriles
Synthesis 2013, 45, 2171–2178
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Asymmetric γ-Lactones
2173
Table 1 Results from the Screening of the Enzyme Library
Gene
6a
6b
6c
6d
6e
6f
6g
YOL151w
YGL039w
76% L
70% D
92% D
13% L
43% D
17% D
90% D
7% L
80% D
16% D
16% L
4% L
33% L
14% D
CH2CH2CN
L
D
YGL157w
50% D
96% D
99% D
55% L
6% L
36% L
R
YNL331c
BY
99% L
99% L
15% D
90% D
84% L
95% L
30% L
88% D
99% D
data to support this theory. As seen in Table 1, the enzyme easier to purify and afforded higher yields. Particularly,
YOL151w, YGL039w, and YGL157w are members of for the synthesis of 3a–c, we were unable to purify the
the short chain dehydrogenase family. None of the en- product and a lower conversion was observed when com-
zymes from the D-hydroxy dehydrogenase, medium chain pared to the aryl counterparts. Ultimately, several γ-keto
dehydrogenase, and the aldose reductase family displayed nitriles were synthesized and these putative substrates
any activity towards these substrates. Thus, we are con- were screened against the library of bakers’ yeast KREDs.
tinuing to see a relationship between substrate acceptance Interestingly, among this library of enzymes (that is com-
and enzyme family.
posed of enzymes from four different families) only the
short-chain dehydrogenase enzyme family showed activi-
ty towards this substrate. These results can lend more in-
formation into fully understanding these enzyme families
and their relationships.
After each screening, the enzyme that displayed the high-
est enantioselectivity was chosen for scaleup. The scaleup
was conducted using whole-cells suspended in a non-
–
growing buffer (100 mM PO4 , pH 7.4, 5 g/L glucose,
OD600 = 18, 28 °C), which are conditions that have been
previously optimized.18 These reactions were conducted
in 500 mL batches shaken in a 2 L baffled flask. The typ-
ical product concentration for these whole cell biocatalyt-
ic conversions was from 70–150 mg/L with a conversion
usually near 100% (as determined by GC analysis). In a
scaleup multiple flasks were used, which resulted in sev-
eral hundred milligrams of crude 6a–g. A continuous liq-
uid-liquid extractor was used to extract the cell cultures.
Lastly, the conversion of the γ-hydroxy nitrile to the
asymmetric γ-lactone 7a–g was achieved in high yield by
base-catalyzed hydrolysis, followed by acidic workup
(Scheme 5). It should be mentioned that initially a heated
strong acid-catalyzed hydrolysis procedure was utilized;
however, it was found that racemization occurred under
these vigorous conditions, particularly for the aryl sub-
strates. In addition, for the strongly electron-donating p-
methoxy-substituted 7f the acidic workup was still too
strong and it resulted in the racemic lactone.
Starting materials and solvents were obtained from Fisher Scientific
and used without further purification. IR spectra were recorded on
a PerkinElmer, Spectrum 100 FT-IR spectrometer. 1H NMR and 13
C
NMR were recorded on an Oxford NMR 300 MHz spectrometer in
CDCl3. Mass spectra were obtained using an Agilent Technologies
7890A (G3440A) GC system with a 5975C VL MSD and a triple-
axis detector and for asymmetric separation a Hewlett Packard HP
6890 series GC system with a 5973 mass selector detector equipped
with a β-cyclodextrin column. HRMS data were collected on an
ABsciex Q-star Elite. Optical rotations were measured on an Anton
Paar MCP 200 polarimeter at 20 °C. OD600 data were measured on
a Hewlett Packard Diode Array UV/Vis (8453). Percent enantio-
meric excess (% ee) was determined by area peaks on the Hewlett
Packard GCMS (above). Chromatography columns were packed
from Sorbent Technologies silica gel.
2-Alkyl-1,3-dithianes 2a–c; General Procedure
A 250 mL round-bottomed flask was placed in the dark before add-
ing NBS (2.36 g, 0.095 equiv) to a stirred solution of 1 (10.0 mL, 1
equiv) and propane-1,3-dithiol (15.98 mL, 1.15 equiv) at r.t. After
20 min, the mixture was partitioned between Et2O (50 mL) and H2O
(50 mL). The aqueous layer was extracted with Et2O (2 × 50 mL)
and the combined organic layers were concentrated under reduced
pressure, and the residue was filtered through Celite using hexanes
to give pure 2.
O
OH
*
1. H2O2, NaOH (aq)
2. H3O+ workup
O
*
R
CN
2-Ethyl-1,3,-dithiane (2a)
Yield: 19.2 g (93%); yellow oil.
R
6
7
1H NMR (300 MHz, CDCl3): δ = 1.07 (3 H, t, J = 7.41 Hz), 1.84 (3
H, m), 2.11 (1 H, m), 2.86 (4 H, m), 3.98 (1 H, t, J = 6.74 Hz).
Scheme 5 Basic conditions were used to hydrolyze the nitrile
13C NMR (300 MHz, CDCl3): δ = 11.6, 26.1, 28.9, 30.5, 49.4.
In summary, we have demonstrated a novel synthetic
route to γ-lactones utilizing a biocatalytic reduction as the
key asymmetry-generating step. A four-step procedure
was developed to build a variety of aryl and alkyl γ-keto
nitriles. In this process, the aryl substrates were generally
GCMS: m/z = 148, 119, 106, 85, 74, 59.
2-Butyl-1,3-dithiane (2b)
Yield: 16.1 g (98%); yellow oil.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2171–2178

2174
S. E. Franz et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 0.90 (3 H, t, J = 7.29 Hz), 1.35 (3
H, m), 1.50 (2 H, m), 1.88 (4 H, m), 2.85 (4 H, m), 4.05 (1 H, t, J =
6.87 Hz).
13C NMR (300 MHz, CDCl3): δ = 47.8, 35.3, 30.6, 28.9, 26.2, 22.4,
15.0.
cooled down to –78 °C. After stirring for 3 h of at –78 °C, the solu-
tion was removed from the cooling bath, and vented for 5 min. Sat.
aq NH4Cl (100 mL) and EtOAc (100 mL) were added, the layers
were separated, and the aqueous layer was extracted with EtOAc (3
× 100 mL). The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure resulting in a yellow solid. Ice
cold EtOAc (3 × 20 mL) was added and the resulting suspension
was filtered using vacuum filtration. The filtrate was concentrated
under reduced pressure resulting in 3.
GCMS: m/z = 176, 133, 119, 101, 87, 73, 60.
2-Aryl-1,3-dithianes 2e–g; General Procedure
NBS (1.68 g, 0.095 equiv) was added to a stirred solution of 1 (13.0
g, 1 equiv) and propane-1,3-dithiol (11.4 mL, 1.15 equiv) in the
dark. The solution stirred for 15 min at r.t. whereupon a yellow solid
resulted. EtOAc (100 mL) was added to dissolve the solid and an
equal volume of H2O was added to remove any salts. The layers
were separated and the aqueous layer was extracted with EtOAc (2
× 50 mL). The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure resulting in a yellow solid. The
yellow solid was rinsed with ice cold EtOAc (3 × 10 mL) and vac-
uum filtered resulting in a white solid.
2-(2-Chloroethyl)-2-(4-methoxyphenyl)-1,3-dithiane (3e)
Yield: 5.9 g (45%); yellow solid; mp 46–50 °C.
1H NMR (300 MHz, CDCl3): δ = 7.76 (2 H, m), 6.91 (2 H, m), 3.83
(3 H, m), 3.43 (2 H, m), 2.73 (4 H, m), 2.52 (2 H, m), 1.94 (2 H, m).
13C NMR (300 MHz, CDCl3): δ = 158.9, 132.7, 129.7, 114.1, 56.8,
55.4, 46.8, 39.9, 27.7, 25.0.
GCMS: m/z = 288, 252, 225, 214, 179, 151, 103, 77.
2-(2-Chloroethyl)-2-p-tolyl-1,3-dithiane (3f)
2-(4-Methoxyphenyl)-1,3-dithiane (2e)
Yield: 14.1 g (85%); yellow solid; mp 51–54 °C.
Yield: 13.5 g (60%); white solid; mp 92–97 °C.
1H NMR (300 MHz, CDCl3): δ = 7.74 (2 H, m), 7.20 (2 H, m), 3.42
(2 H, m), 2.71 (4 H, m), 2.51 (2 H, m), 2.36 (3 H, s), 1.94 (2 H, m).
13C NMR (300 MHz, CDCl3): δ = 137.8, 137.4, 129.6, 128.3, 57.1,
46.8, 39.1, 27.6, 24.9, 21.0.
1H NMR (300 MHz, CDCl3): δ = 7.39 (2 H, m), 6.86 (2 H, m), 5.12
(1 H, s), 3.78 (3 H, s), 3.05 (2 H, m), 2.89 (2 H, m), 2.15 (1 H, m),
1.90 (1 H, m).
13C NMR (300 MHz, CDCl3): δ = 159.7, 131.4, 129.0, 114.2, 55.4,
50.8, 32.3, 25.2.
GCMS: m/z = 272, 209, 163, 135, 115, 77.
GCMS: m/z = 226, 152, 121, 108, 77, 65.
2-(2-Chloroethyl)-2-(4-chlorophenyl)-1,3-dithiane (3g)
Yield: 2.8 g (26%); yellow solid; mp 58–60 °C.
2-p-Tolyl-1,3-dithiane (2f)
Yield: 10.6 g (51%); white solid; mp 70–72 °C.
1H NMR (300 MHz, CDCl3): δ = 7.35 (2 H, m), 7.14 (2 H, m), 5.14
(1 H, s), 2.97 (4 H, m), 2.33 (3 H, s), 2.16 (1 H, m), 1.92 (1 H, m).
13C NMR (300 MHz CDCl3): δ = 138.2, 136.1, 129.5, 127.7, 51.3,
32.2, 25.2, 21.3.
1H NMR (300 MHz, CDCl3): δ = 7.81 (2 H, m), 7.34 (2 H, m), 3.41
(2 H, m), 2.68 (4 H, m), 2.45 (2 H, m), 1.93 (2 H, m).
13C NMR (300 MHz, CDCl3): δ = 139.7, 133.6, 130.1, 129.0, 56.9,
47.0, 39.6, 27.6, 24.7.
GCMS: m/z = 292, 229, 218, 183, 155, 115, 75.
GCMS: m/z = 210, 136, 105, 91, 77.
Alkyl-Substituted Propanenitriles 4a–c; General Procedure
NaCN (1.95 g, 2 equiv) and 18-crown-6 (10.55 g, 2 equiv) were
added to crude 3 (4.76 g) and placed under argon before adding
DMSO (35 mL). The solution was allowed to react for 4 h at 100 °C
while stirring. The flask was allowed to cool to r.t. before extracting
with Et2O (50 mL) and H2O (50 mL). The organic layer was washed
with brine (30 mL) and H2O (30 mL) before concentrating under re-
duced pressure. Silica gel column chromatography using hexanes as
eluent gave pure 4.
2-(4-Chlorophenyl)-1,3-dithiane (2g)
Yield: 9.4 g (42%); white solid; mp 84–86 °C.
1H NMR (300 MHz, CDCl3): δ = 7.40 (2 H, m), 7.29 (2 H, m), 5.12
(1 H, s), 2.95 (4 H, m), 2.15 (1 H, m), 1.90 (1 H, m).
13C NMR (300 MHz, CDCl3): δ = 137.7, 134.2, 129.3, 129.0, 50.7,
32.1, 25.1.
GCMS: m/z = 230, 165, 156, 105, 74.
3-(2-Ethyl-1,3-dithian-2-yl)propanenitrile (4a)
2-Alkyl-2-(2-chloroethyl)-1,3-dithianes 3a–c; General Proce-
dure
Yield: 0.5 g (11%); yellow oil.
IR (neat): 2249 cm–1 (CN).
A solution of 2 (12.04 g, 1 equiv) in THF (140 mL) at a final con-
centration of 0.1–0.5 M was placed under argon and cooled to
–40 °C in a dry ice acetone bath. A 1.6 M solution of n-BuLi in hex-
anes (42.68 mL) was added slowly while stirring and the flask was
allowed to warm up to –10 °C and allowed to remain at that temper-
ature for 1 h. After reaching –78 °C, 1-bromo-2-chloroethane
(11.32 mL, 2 equiv) was added and the flask was allowed to warm
up to –20 °C and allowed to remain at that temperature for 24–72 h.
After warming up to r.t., sat. aq NH4Cl (140 mL) was added to
quench any leftover base. The product was extracted with Et2O (60
mL) and combined organic extracts were concentrated under re-
duced pressure. Silica gel column chromatography and distillation
were unable to purify 3, but the impurities did not affect the next re-
action step.
1H NMR (300 MHz, CDCl3): δ = 1.02 (3 H, t, J = 7.41 Hz), 1.85 (2
H, q, J = 7.50 Hz), 1.98 (2 H, m), 2.30 (2 H, m), 2.51 (2 H, m), 2.78
(4 H, m).
13C NMR (300 MHz, CDCl3): δ = 8.5, 13.2, 14.3, 25.0, 26.0, 29.9,
31.8, 33.3, 52.4.
GCMS: m/z = 201, 172, 147, 127, 98, 74, 58.
3-(2-Butyl-1,3-dithian-2-yl)propanenitrile (4b)
Yield: 0.8 g (7%); yellow oil.
IR (neat): 2245 cm–1 (CN).
1H NMR (300 MHz, CDCl3): δ = 0.92 (3 H, t, J = 7.14 Hz), 1.25 (2
H, t, J = 7.01 Hz), 1.39 (3 H, m), 1.75 (2 H, m), 1.92 (1 H, m), 2.32
(2 H, m), 2.51 (2 H, m), 2.74 (2 H, m), 2.84 (2 H, m).
13C NMR (300 MHz, CDCl3): δ = 13.3, 14.0, 22.9, 25.0, 25.9, 26.1,
33.6, 38.7, 51.9, 119.7.
2-Aryl-2-(2-chloroethyl)-1,3-dithianes 3e–g; General Procedure
Compound 2 (10.0 g, 1 equiv) was dissolved in anhyd THF (90 mL)
under argon. The solution was cooled to –40 °C and 1.6 M n-BuLi
(31 mL, 1 equiv) was added under an inert atmosphere. The solution
was warmed to –20 °C and stirred for 1 h at –20 °C. 1-Bromo-2-
chloroethane (4.5 mL, 1.1 equiv) was added after the solution was
GCMS: m/z = 229, 172, 154, 126, 113, 98, 86, 74, 58.
Synthesis 2013, 45, 2171–2178
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PAPER
Synthesis of Asymmetric γ-Lactones
2175
3-(2-Hexyl-1,3-dithian-2-yl)propanenitrile (4c)
1H NMR (300 MHz, CDCl3): δ = 1.08 (3 H, t, J = 7.29 Hz), 2.47 (2
H, q, J = 7.32 Hz), 2.58 (2 H, t, J = 7.14 Hz), 2.80 (2 H, t, J = 7.14
Hz).
Yield: 0.6 g (9%); yellow oil.
IR (neat): 2246 cm–1 (CN).
13C NMR (300 MHz, CDCl3): δ = 7.7, 11.5, 35.7, 37.3, 119.3, 206.9.
1H NMR (300 MHz, CDCl3): δ = 0.86 (3 H, t, J = 6.52 Hz), 1.26 (6
H, m), 1.42 (2 H, m), 1.72 (2 H, m), 1.95 (2 H, m), 2.32 (2 H, t), 2.49
(2 H, t, J = 7.73 Hz), 2.77 (4 H, m).
13C NMR (300 MHz, CDCl3): δ = 13.3, 14.1, 22.6, 23.7, 30.0, 26.1,
27.4, 31.6, 33.7, 39.0, 52.0, 119.8.
GCMS: m/z = 111, 96, 82, 68, 57.
4-Oxooctanenitrile (5b)
Yield: 75 mg (99%); yellow oil.
IR (neat): 2253.2 (CN), 1714 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): δ = 0.90 (3 H, t, J = 7.28 Hz), 1.31 (2
H, m, J = 7.42 Hz), 1.58 (2 H, q, J = 7.49 Hz), 2.44 (2 H, t, J = 7.41
Hz), 2.57 (2 H, t, J = 7.14 Hz), 2.79 (2 H, t, J = 7.14 Hz).
13C NMR (300 MHz, CDCl3): δ = 11.4, 13.9, 22.3, 25.8, 38.0, 42.3,
119.2, 206.5.
GCMS: m/z = 257, 203, 172, 142, 113, 74.
Aryl-Substituted Propanenitriles 4e–g; General Procedure
NaCN (676 mg, 2 equiv), 18-crown-6 (3.64 g, 2 equiv), and 3 (2.01
g, 1 equiv) were added to a 50 mL round-bottomed flask and then
flushed with argon before adding anhyd DMSO (15 mL). The solu-
tion was stirred for 4 h at 100 °C. The solution was then cooled to
r.t. and EtOAc (75 mL) and deionized (DI) H2O (75 mL) were add-
ed. The layers were separated and the organic layer was washed
with DI H2O and brine (25 mL each), dried (MgSO4), and concen-
trated under reduced pressure. The resulting oil was purified by sil-
ica gel column chromatography (9:1 hexanes–EtOAc), resulting in
4 as a yellow oil.
GCMS: m/z: 139, 124, 110, 97, 85, 69, 57.
4-Oxodecanenitrile (5c)
Yield: 0.6 g (82%); yellow oil.
IR (neat): 2250 (CN), 1715 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): δ = 0.89 (3 H, m), 1.26 (6 H, m), 1.58
(2 H, m), 2.43 (2 H, t, J = 10.65 Hz), 2.57 (2 H, t, J = 7.04 Hz), 2.78
(2 H, t, J = 7.22 Hz).
13C NMR (300 MHz, CDCl3): δ = 11.4, 14.1, 22.5, 23.7, 28.8, 31.6,
37.7, 42.6, 119.2, 206.5.
3-[2-(4-Methoxyphenyl)-1,3-dithian-2-yl]propanenitrile (4e)
Yield: 2.7 g (47%); yellow oil.
IR (neat): 2253 cm–1 (CN).
1H NMR (300 MHz, CDCl3): δ = 7.72 (2 H, m), 6.91 (2 H, m), 3.83
GCMS: m/z = 167, 138, 113, 98, 82, 69, 54.
(3 H, s), 2.74 (4 H, m), 2.43 (2 H, m), 2.32 (2 H, m), 1.95 (2 H, m).
13C NMR (300 MHz, CDCl3): δ = 159.2, 131.8, 129.6, 119.3, 114.3,
56.6, 55.4, 39.5, 27.6, 24.8 13.0.
Aryl-Substituted γ-Keto Nitriles 5e–g; General Procedure
NaHCO3 (3.8 g, 6.7 equiv), DI H2O (4.8 mL), and I2 (5.6 g, 6.6
equiv) were added to a solution of 4 (1.9 g, 1 equiv) dissolved in
acetone (15 mL) at 0 °C. The solution was stirred at 0 °C for 2 h and
then aq 10% Na2S2O3 and EtOAc (50 mL) were added. The layers
were separated and the organic layer was washed with aq 10%
Na2S2O3 until the dark color of I2 had disappeared (ca. 200 mL). The
organic layer was then washed with brine (100 mL), dried (MgSO4),
and concentrated under reduced pressure affording pure 5.
GCMS: m/z = 279, 225, 205, 172, 151, 133, 108, 77.
3-(2-p-Tolyl-1,3-dithiane-2-yl)propanenitrile (4f)
Yield: 7.9 g (72%); yellow oil.
IR (neat): 2245 cm–1 (CN).
1H NMR (300 MHz, CDCl3): δ = 7.69 (m, 2 H), 7.20 (m, 2 H), 2.725
(m, 4 H), 2.38 (s, 3 H), 1.92 (m, 2 H), 1.23 (m, 2 H), 0.84 (m, 2 H).
13C NMR (300 MHz, CDCl3): δ = 137.8, 137.0, 127.8, 128.2, 119.7,
56.9, 39.5, 27.6, 24.8, 21.0, 13.0.
4-(4-Methoxyphenyl)-4-oxobutanenitrile (5e)
Yield: 1.1 g (99%); white solid; mp 90–93 °C.
IR (neat): 2253 (CN), 1676 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): δ = 7.92 (2 H, m), 6.95 (2 H, m), 3.88
(3 H, s), 3.33 (2 H, t, J = 7 Hz), 2.76 (2 H, t, J = 7 Hz).
13C NMR (300 MHz, CDCl3): δ = 194.0, 164.1, 130.4, 128.8, 119.6,
114.1, 55.7, 33.9, 11.9.
GCMS: m/z = 263, 209, 174, 135.
3-[2-(4-Chlorophenyl)-1,3-dithian-2-yl]propanenitrile (4g)
Yield: 1.9 g (72%); yellow oil.
IR (neat): 2249 cm–1 (CN).
1H NMR (300 MHz, CDCl3): δ = 7.79 (2 H, m), 7.36 (2 H, m), 2.71
(4 H, m), 2.36 (4 H, m), 1.94 (2 H, m).
13C NMR (300 MHz, CDCl3): δ = 139.0, 134.0, 130.0, 129.2, 119.0,
56.7, 39.8, 27.6, 24.6, 13.0.
GCMS: m/z = 189, 135, 107, 92, 77.
4-Oxo-4-p-tolylbutanenitrile (5f)
Yield: 1.6 g (30%), white solid; mp 61–63 °C.
IR (neat): 2249 (CN) 1677 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): δ = 7.84 (2 H, m), 7.27 (2 H, m), 3.35
(2 H, t, J = 7 Hz), 2.76 (2 H, t, J = 7 Hz), 2.42 (3 H, s).
13C NMR (300 MHz, CDCl3): δ = 195.2, 144.9, 133.3, 129.6, 128.2,
119.5, 34.2, 21.8, 11.9.
GCMS: m/z = 283, 229, 209, 174, 155, 137, 74.
Alkyl-Substituted γ-Keto Nitriles 5a–c; General Procedure
In a 100 mL round-bottomed flask, 4 (273 mg, 1 equiv) and
NaHCO3 (670 mg, 6.7 equiv) were dissolved in acetone (6.5 mL)
and H2O (0.65 mL). The flask was placed in an ice bath and I2 (1.3
g, 8.4 equiv) was added while stirring. The solution was allowed to
react until GCMS showed completion. At times more I2 (0.2 equiv)
was added to complete the reaction. Aq 10% Na2S2O3 (100 mL) was
added to remove the black color and extracted with EtOAc (2 × 50
mL). The combined organic layers were washed with brine (75 mL)
and aq 10% Na2S2O3 (75 mL), and concentrated under reduced
pressure to give pure 5.
GCMS: m/z = 173, 119, 91, 77, 65, 51.
4-(4-Chlorophenyl)-4-oxobutanenitrile (5g)
Yield: 1.2 g (89%), white solid; mp 58–61 °C.
IR (neat): 2253 (CN), 1675 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): δ = 7.87 (2 H, m), 7.44 (2 H, m), 3.34
(2 H, t, J = 7 Hz), 2.75 (2 H, t, J = 7 Hz).
4-Oxohexanenitrile (5a)
Yield: 0.3 g (54%); yellow oil.
13C NMR (300 MHz, CDCl3): δ = 194.3, 140.5, 134.0, 129.5, 129.3,
119.2, 34.3, 11.9.
IR (neat): 2249 (CN), 1714 cm–1 (C=O).
GCMS: m/z = 193, 139, 111, 75, 57.
© Georg Thieme Verlag Stuttgart · New York
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2176
S. E. Franz et al.
PAPER
Enzymatic Reduction of γ-Keto Nitriles; Scaleup of Ketoreduc-
tases (KREDs) on Alkyl-Substituted γ-Keto Nitriles 5a–c; Gen-
eral Procedure
LB (lysogeny broth) medium with 30 μg/mL kanamycin was inoc-
ulated with a single colony of E. coli (containing the appropriate
overexpressed gene) and shaken for 15 h at 37 °C. This preculture
was diluted 1:100 into 1 L of the same medium and shaken for 2.5
(S)-4-Hydroxy-4-phenylbutanenitrile (6d)
Yield: 57 mg (15.8%); colorless oil; [α]D –19.5.
IR (neat): 3428 (OH, alcohol), 2247 cm–1 (CN).
1H NMR (300 MHz, CDCl3): δ = 7.35 (5 H, m), 4.83 (1 H, dd, J =
9, 5 Hz), 2.48 (2 H, m), 2.06 (2 H, m), 1.88 (1 H, s).
13C NMR (300 MHz, CDCl3): δ = 143.1, 128.9, 128.4, 125.7, 119.6,
72.5, 34.3, 13.9.
h at 37 °C with a stirring rate of 220 rpm. Upon reaching an OD600
=
0.2 the cell culture was cooled to 20 °C, and isopropylthio-β-D-ga-
lactoside was added to a final concentration of 100 μM and shaken
for 14 h. Cells were collected by centrifugation (5000 g for 10 min
at 4 °C) and then resuspended in 500 mL of 100 mM phosphate buf-
fer (pH 7.4) containing 5 g/L glucose. The bioconversion was car-
ried out at 28 °C with a stirring rate of 220 rpm. Portions of neat 5
(100 mg) were added in small increments and monitored by GCMS
for conversion. The product was extracted with CH2Cl2 (3 × 50 mL)
and the combined extracts were concentrated under reduced pres-
sure to give the crude 6. Silica gel column chromatography with 8:1
hexanes–EtOAc as eluent afforded pure 6.
GCMS: m/z = 161, 107, 79, 51, 91, 63.
(S)-4-Hydroxy-4-(4-methoxyphenyl)butanenitrile (6e)
Yield: 90 mg (67%); colorless oil; [α]D –7.8.
IR (neat): 3445 (OH), 2255 cm–1 (CN).
1H NMR (300 MHz, CDCl3): δ = 7.23 (2 H, m), 6.86 (2 H, m), 4.71
(1 H, dd, J = 8, 5 Hz), 3.77 (3 H, s), 2.41 (2 H, m), 1.98 (2 H, m).
13C NMR (300 MHz, CDCl3): δ = 159.5, 135.2, 127.0, 119.8, 114.2,
72.0, 55.4, 34.2, 13.9.
GCMS: m/z = 191, 137, 109, 94, 77.
(S)-4-Hydroxyhexanenitrile (6a)
Yield: 0.2 g (74%); yellow oil; [α]D +29.7.
(R)-4-Hydroxy-4-p-tolylbutanenitrile (6f)
Yield: 120 mg (99%); colorless oil; [α]D +8.0.
IR (neat): 3394 (OH), 2248 cm–1 (CN).
IR (neat): 3414 (OH), 2250 cm–1 (CN).
1H NMR (300 MHz, CDCl3): δ = 0.94 (3 H, t, J = 7.4 Hz), 1.49 (2
H, m), 1.75 (2 H, m), 2.48 (2 H, t, J = 7.0 Hz), 3.62 (1 H, m).
1H NMR (300 MHz, CDCl3): δ = 7.21 (4 H, m), 4.77 (1 H, dd, J =
13C NMR (300 MHz, CDCl3): δ = 9.9, 13.8, 30.3, 32.1, 71.3, 120.1.
8, 5 Hz), 2.44 (2 H, m), 2.35 (3 H, s), 2.01 (2 H, m).
13C NMR (300 MHz, CDCl3): δ = 140.1, 138.1, 129.5, 125.7, 119.8,
72.3, 34.2, 21.2, 13.9.
GCMS: m/z = 112, 98, 84, 66, 59, 55.
(S)-4-Hydroxyoctanenitrile (6b)
Yield: 84 mg (44%); yellow oil; [α]D +24.0.
GCMS: m/z = 175, 121, 93, 77, 65.
IR (neat): 3423 (OH), 2248 cm–1 (CN).
1H NMR (300 MHz, CDCl3): δ = 0.89 (3 H, t, J = 7.04 Hz), 1.35 (6
H, m), 1.70 (2 H, m), 2.48 (2 H, t, J = 7.38 Hz), 3.68 (1 H, m).
13C NMR (300 MHz, CDCl3): δ = 13.8, 14.1, 22.7, 27.7, 32.6, 37.2,
70.1, 120.1.
(R)-4-(4-Chlorophenyl)-4-hydroxybutanenitrile (6g)
Yield: 141 mg (79%); colorless oil; [α]D +8.7.
IR (neat): 3411 (OH), 2251 cm–1 (CN).
1H NMR (300 MHz, CDCl3): δ = 7.30 (4 H, m), 4.78 (1 H, dd, J =
8, 5.5 Hz), 2.45 (2 H, m), 1.97 (2 H, m).
13C NMR (300 MHz, CDCl3): δ = 141.6, 133.9, 129.0, 127.1, 119.6,
71.6, 34.3, 13.8.
GCMS: m/z = 140, 122, 87, 84, 69, 66, 55.
(R)-4-Hydroxydecanenitrile (6c)
Yield: 70 mg (89%); yellow oil; [α]D –12.5.
GCMS: m/z = 195, 141, 113, 77, 51.
IR (neat): 3412 (OH), 2249 cm–1 (CN).
1H NMR (300 MHz, CDCl3): δ = 0.86 (3 H, m), 1.22 (8 H, m), 1.42
(2 H, m), 1.69 (2 H, m), 2.48 (2 H, t, J = 7.38 Hz), 3.68 (1 H, m).
13C NMR (300 MHz, CDCl3): δ = 13.8, 14.2, 22.7, 25.6, 29.3, 31.8,
32.6, 37.5, 70.1, 120.1.
Alkyl-Substituted γ-Lactones 7a–c; General Procedure
A 25 mL round-bottomed flask containing a solution of 6 (63 mg, 1
equiv) in H2O (1.67 mL) and aq 3 M NaOH (1.64 mL, 11 equiv) was
attached to a water jacketed condenser. After the addition of H2O2
(1.45 mL, 30%), the solution was heated to 70 °C for 2 h, and al-
lowed to cool to r.t. H2O (10 mL) was added and the pH was deter-
mined to be ~10. The mixture was extracted with CH2Cl2 (10 mL)
to remove any impurities. Aq 6 M HCl was added until the pH was
between 2–3 to cyclize the lactone. The product was extracted with
CH2Cl2 (3 × 10 mL) and the combined organic layers were concen-
trated under reduced pressure to give pure 7.
GCMS: m/z = 201, 172, 147, 127, 98, 74, 58.
Enzymatic Reduction of γ-Keto Nitriles; Scaleup of Ketoreduc-
tases (KREDs) on Aryl-Substituted γ-Keto Nitriles 5d–g; Gen-
eral Procedure
LB medium with 30 μg/mL kanamycin was inoculated with a single
colony of E. coli (containing the appropriate overexpressed gene)
and shaken for 15 h at 37 °C. This preculture was diluted 1:100 into
1 L of the same medium and shaken for 2.5 h at 37 °C with a stirring
rate of 220 rpm. Upon reaching an OD600 = 0.2 the cell culture was
cooled to 20 °C, and isopropylthio-β-D-galactoside was added to a
final concentration of 100 μM and shaken for 14 h. Cells were col-
lected by centrifugation (5000 g for 10 min at 4 °C) and then resus-
pended in 500 mL of 100 mM phosphate buffer (pH 7.4) containing
5 g/L glucose. The bioconversion was carried out at 28 °C with a
stirring rate of 220 rpm. Portions of neat 5 (350 mg) were added in
small increments and monitored by GCMS for conversion. After
extraction with CH2Cl2 (3 × 50 mL), the combined organic layers
were dried (MgSO4), and concentrated under reduced pressure. The
resulting oil was purified using silica gel column chromatography
(2:1 hexanes–EtOAc) affording 6 as a colorless oil.
(S)-γ-Hexalactone (7a)
Yield: 30 mg (56%); yellow oil; [α]D –14.4.
IR (neat): 1766 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): δ = 0.97 (3 H, t, J = 7.55 Hz), 1.70 (3
H, m), 2.29 (1 H, m, J = 6.59 Hz), 2.51 (2 H, q, J = 8.07 Hz), 4.41
(1 H, q, J = 6.87 Hz).
13C NMR (300 MHz, CDCl3): δ = 9.5, 27.6, 28.6, 29.0, 82.3, 117.4.
GCMS: m/z = 114, 97, 85, 70, 57.
HRMS (ESI): m/z calcd for C6H11O2 [M + H]+: 115.0754; found:
115.0691.
(S)-γ-Octalactone (7b)
Yield: 46 mg (79%); yellow oil; [α]D –28.9.
IR (neat): 1769 cm–1 (C=O).
Synthesis 2013, 45, 2171–2178
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Asymmetric γ-Lactones
2177
1H NMR (300 MHz, CDCl3): δ = 0.89 (3 H, t, J = 9.11 Hz), 1.54 (7
H, m), 2.39 (3 H, m), 4.46 (1 H, q, J = 6.87 Hz).
HRMS (ESI): m/z calcd for C11H12O2 [M + H]+: 177.0910; found:
177.0920.
13C NMR (300 MHz, CDCl3): δ = 13.99, 22.50, 27.42, 28.08, 28.96,
35.33, 81.20, 117.53.
(R)-5-(4-Chlorophenyl)dihydrofuran-2(3H)-one (7g)
Yield: 48 mg (81%); white solid; mp 45–55 °C; [α]D +16.1.
IR (neat): 1770 cm–1 (C=O).
1H NMR (300 MHz, CD3CN): δ = 7.36 (4 H, m), 5.45 (1 H, dd, J =
GCMS: m/z = 141, 114, 100, 85, 70, 57.
HRMS (ESI): m/z calcd for C8H15O2 [M + H]+: 143.1067; found:
143.0996.
9, 5.8 Hz), 2.58 (3 H, m), 2.05 (1 H, m).
13C NMR (300 MHz, CD3CN): δ = 176.9, 139.1, 133.6, 128.8,
127.5, 80.5, 30.6, 28.8.
(R)-γ-Decalactone (7c)
Yield: 29 mg (64%); yellow oil; [α]D +14.5.
IR (neat): 1708 cm–1 (C=O).
GCMS: m/z = 196, 161, 141, 117, 75, 56.
1H NMR (300 MHz, CDCl3): δ = 0.87 (3 H, t, J = 7.14 Hz), 1.57 (11
H, m), 2.40 (3 H, m), 4.47 (1 H, q, J = 6.78 Hz).
HRMS (ESI): m/z calcd for C10H10ClO2 [M + H]+: 197.0364; found:
197.0362.
13C NMR (300 MHz, CDCl3): δ = 14.1, 22.6, 25.3, 28.1, 29.1, 29.8,
31.7, 35.7, 81.2, 117.6
Acknowledgment
GCMS: m/z = 169, 128, 100, 85, 70, 55.
This work was supported by NSF-RUI grant CHE-0848708 from
the Organic and Macromolecular Chemistry Program and NSF-
MRI CHE-0923153. Student support was also provided by the Na-
tional Science Foundation’s STEP Program under Award No. DUE-
0856593. Any opinions, findings, and conclusions or recommenda-
tions expressed in this material are those of the author(s) and do not
necessarily reflect the views of the NSF. Additional thanks to Dr.
Jon Stewart at the University of Florida for donating the enzyme li-
brary.
HRMS (ESI): m/z calcd for C10H19O2 [M + H]+: 171.1385; found:
171.1409.
Aryl-Substituted γ-Lactones; 7d–g; General Procedure
H2O2 (1.9 mL, 30%) was added through a jacketed condenser to a
70 °C solution of 6 (103 mg, 1 equiv) and NaOH (2.2 mL, 3 M) dis-
solved in DI H2O (2.2 mL) kept in a 25 mL round-bottomed flask.
The solution was stirred at 70 °C for 2 h, then cooled to r.t., diluted
with DI H2O (20 mL) and extracted with CH2Cl2 (2 × 45 mL). The
organic layers were discarded and aq 6 M HCl was added to the
aqueous layer until a pH of 2–3 was achieved causing cyclization of
the lactone, which was extracted with CH2Cl2 (3 × 45 mL). The
combined organic layers were dried (MgSO4) and concentrated un-
der reduced pressure. The resulting oil was purified by silica gel col-
umn chromatography (2:1 hexanes–EtOAc) to afford 7.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
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1265.
Yield: 43 mg (96%); white solid; mp 32–34 °C; [α]D –18.6.
IR (neat): 1767 cm–1 (C=O, lactone).
1H NMR (300 MHz, CDCl3): δ = 7.37 (5 H, m), 5.52 (1 H, dd, J =
8.0, 6.3 Hz), 2.67 (3 H, m), 2.20 (1 H, m).
13C NMR (300 MHz, CD3CN): δ = 177.0, 139.5, 128.9, 128.5,
125.4, 81.3, 60.5, 31.0, 29.0.
GCMS: m/z = 117, 107, 91, 77, 56.
HRMS (ESI): m/z calcd for C10H11O2 [M + H]+: 163.0759, found:
163.0764.
5-(4-Methoxyphenyl)dihydrofuran-2(3H)-one (7e)
Yield: 40 mg (38%); white solid; mp 38–40 °C; [α]D +0.2.
IR (neat): 1760 cm–1 (C=O).
(8) Moreno-Horn, M.; Martinez-Rojas, E.; Gorisch, H.; Tressl,
R.; Garbe, L. A. J. Mol. Catal. B: Enzym. 2007, 49, 24.
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1H NMR (300 MHz, CD3CN): δ = 7.29 (2 H, m), 6.91 (2 H, m), 5.39
(1 H, dd, J = 9.6, 6.0 Hz), 3.75 (3 H, s), 2.57 (3 H, m), 2.11 (1 H, m).
13C NMR (300 MHz, CD3CN): δ = 177.2, 159.9, 131.8, 127.6,
114.0, 81.5, 55.0, 30.5, 29.1.
GCMS: m/z = 192, 148, 137, 109, 77.
HRMS (ESI): m/z calcd for C11H12O3 [M + H]+: 193.0859; found:
193.0863.
(R)-5-p-Tolyldihydrofuran-2(3H)-one (7f)
Yield: 67 mg (65%); white solid; mp 48–50 °C; [α]D +13.0.
IR (neat): 1760 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): δ = 7.21 (4 H, m), 5.47 (1 H, dd, J =
8, 6 Hz), 2.63 (3 H, m), 2.35 (3 H, s), 2.18 (1 H, m).
13C NMR (300 MHz, CDCl3): δ = 177, 138, 136, 129.5, 125.4, 81.4,
31, 29.1, 21.2.
GCMS: m/z = 176, 161, 121, 117, 91, 77, 56.
© Georg Thieme Verlag Stuttgart · New York
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S. E. Franz et al.
PAPER
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