Enantioselective Organocatalyzed Bromolactonizations: Applications in Natural Product Synthesis

Article abstract of DOI:10.1021/acs.joc.6b01375

Asymmetric bromolactonization reactions of δ-unsaturated carboxylic acids have been investigated in the presence of 10 chiral squaramide hydrogen-bonding organocatalysts. The best catalyst enabled the cyclization of several 5-arylhex-5-enoic acids into th

Full text of DOI:10.1021/acs.joc.6b01375

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Article
Enantioselective Organocatalyzed Bromolactonizations:
Applications in Natural Product Synthesis
Marius Aursnes, Jørn E. Tungen, and Trond Vidar Hansen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01375 • Publication Date (Web): 26 Aug 2016
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Enantioselective Organocatalyzed Bromolactonizations: Applications
in Natural Product Synthesis
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Marius Aursnes, Jørn E. Tungen and Trond V. Hansen*
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Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, P.O. Box 1068,
Blindern, N-0316 Oslo, Norway
Received Date (will be automatically inserted after manuscript is accepted)
ABSTRACT: Asymmetric bromolactonization reactions of δꢀunsaturated carboxylic
acids have been investigated in the presence of 10 chiral squaramide hydrogenꢀ
bonding organocatalysts. The best catalyst enabled the cyclization of several 5ꢀ
arylhexꢀ5ꢀenoic acids into the corresponding bromolactones with up to 96% ee and in
high to excellent chemical yields. The reported catalysts are prepared in a
straightforward manner in two steps from dimethyl squarate. The utility of the
developed protocol was demonstrated in highly enantioselective syntheses of the
sesquiterpenoids (ꢀ)ꢀgossoronol and (ꢀ)ꢀboivinianin B. Both natural products were
obtained in ≥ 99% enantiomeric excess
.
INTRODUCTION
Halogenation of olefins followed by an intramolecular ring opening of the halonium
intermediate by a carboxylic acid, known as halolactonization, is a very effective
method for the preparation of synthetically useful products and intermediates.1 In
recent years, the development of asymmetric versions of such lactonization reactions
has received increased attention, resulting in several advances.2 For both bromoꢀ3 and
iodolactonization4 of alkenoic acids, Lewis acids and organocatalysts have been
employed in enantioselective protocols.2 Recently, we reported a highly
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stereoselective iodolactonization protocol of 5ꢀarylhexꢀ5ꢀenoic acids utilizing chiral
squaramides such as 1b and 1dꢀ1f (Figure 1).4b
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O
O
9
R
N
N
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H
H
N(Pent)2
1a-g
O2N
F3C
O2N
F3C
1a, R =
1c, R =
1b, R =
1d, R =
NO2
CF3
F3C
1g, R = H
1f, R =
1e, R =
F3C
CF3
NO2
NO2
O
O
N
O
O
N
N
O2N
N
O2N
N
N
H
H
H
2
3
CF3
O
C
F3C
N
N
H
H
N(Pent)2
4
Figure 1. Squaramide catalysts investigated in this study.
The presence of a Hꢀbonding motif on the arylꢀsubstituent in these catalysts was
reported necessary for achieving high asymmetric induction with δꢀunsaturated
carboxylic acids as substrates. The Hꢀbonding properties that most chiral squaramide
catalysts display have been deemed important for catalysis.5 Until now, no studies
have applied chiral squaramides in enantioselective bromolactonization reactions. As
a consequence of the greater chemical stability of the CꢀBr bond relative to the CꢀI
bond,6 the chiral bromolactones offer many advantages compared to their iodoꢀ
congeners, such as increased overall stability, ease of purification and longꢀterm
storage. Herein, our investigations towards the development of an enantioselective
organocatalyzed bromolactonization protocol employing squaramides as Hꢀbonding
catalysts are reported.
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RESULTS AND DISCUSSION
The chiral squaramide catalysts 1aꢀg4b and 2ꢀ4 depicted in Figure 1 were easily
prepared in two steps,4a,4b and the δꢀunsaturated acid 5a (R = H) was used for protocol
development (Table 1).
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Table 1. Screening of Squaramide Catalysts in the Asymmetric Bromolactonization
Reaction.
entrya
catalyst
yieldb
(%)
eec
(%)
1
2
1a
1b
1c
1d
1e
1f
1g
2
93
74
34
50
73
73
68
71
84
86
55
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5
0
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2
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0
9
3
0
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aThe reactions were performed on a 0.2 mmol scale of 5a. bIsolated material. cDetermined by HPLC analysis using
commercial chiral columns.
First, the reaction was conducted with 5a and 1.5 equivalents of Nꢀbromosuccinimide
o
at ꢀ78 C for 24 hours with a fixed starting concentration of 0.1 M of 5a in each
individual experiment in the presence of 15 mol% of catalyst loading of 1aꢀg and 2ꢀ4.
Based on our initial report,4b a 1:1 ratio of dichloromethane:acetone was chosen as the
solvent mixture. Under these conditions, see Table 1, the two squaramides 1a and 1b
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returned moderate eeꢀvalues of 55% and 54%, respectively, accompanied with high to
excellent yields (entry 1 and 2). Among the other squaramides explored, only catalyst
4 returned any reasonable enantioselectivity (35% ee), see entry 10. The absolute
configuration of 6a was determined to be S in all cases based on comparison with
optical rotation values and literature data.3aꢀ3c,3f Since a better yield was observed in
the presence of squaramide 1a compared to 1b, the previously unknown catalyst 1a
was chosen for further selectivity enhancement studies. Subsequently, different
commercially available Br+ꢀsources were investigated using otherwise the same
conditions as above (Table 2).
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Table 2. Screening of Br+ꢀsource in the Asymmetric Bromolactonization Reaction.
entrya
Br+
yieldb
(%)
eec
(%)
1
2
3
4
5
6
NBSd
Br2/NBS
NBPe
93
92
88
93
0
55
39
65
DBHf
52
TABCOg
Br2
n.d.h
0
42
aThe reactions were performed on a 0.2 mmol scale of 5a. bIsolated material. cDetermined by HPLC analysis using
commercial chiral columns. dNꢀbromosuccinimide. eNꢀbromophtalimide. f1,3ꢀdibromoꢀ5,5ꢀdimethylhydantoin. g2,4,4,6ꢀ
tetrabromoꢀ2,5ꢀcyclohexadienone. h Not determined.
The use of Br2 together with NBS proved to be less selective (entry 2), or ineffective
alone, as racemic 6a was obtained (entry 6). When Nꢀbromophtalimide (NBP) was
employed, a slight enhancement in the enantioselectivity was observed (65% ee),
compared to the results discussed above. Pleasantly, the product 6a was obtained in a
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high yield of 88% (entry 3). In the presence of 1,3ꢀdibromoꢀ5,5ꢀdimethylhydantoin
(DBH) a moderate eeꢀvalue of 52% was returned (entry 4). When 2,4,4,6ꢀtetrabromoꢀ
2,5ꢀcyclohexadienone (TABCO) was used as the Br+ꢀsource, no conversion to 6a was
observed as 5a was recovered unreacted (entry 5).
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Thereafter we turned our attention to a limited solvent screen (Table 3).
Table 3. Screening of Conditions in the Asymmetric Bromolactonization Reaction.
entrya
altered
yieldb
(%)
eec
variables
(%)
1
2
acetone/CH2Cl2
acetone
88
86
84
89
62
88
78
85
86
92
65
76
52
76
74
80
68
76
76
7
3
CH2Cl2
4
3.0 equiv. NBP
1.0 equiv. NBP
30 mol% cat.
7.5 mol% cat.
c = 0.2 M
5
6
7
8
9
c = 0.05 M
10
T = 25 °C
b
c
aThe reactions were performed on a 0.2 mmol scale of 5a. Isolated material. Determined by HPLC analysis using commercial
chiral columns.
When acetone was used as the solvent, an enhancement in the selectivity was
observed (76% ee) with almost similar yields as before (86%), entry 2.
Dichloromethane as the only solvent slightly reduced the selectivity (entry 3).
Acetone was chosen for altering the reaction conditions with the aim of improving the
enantioselectivity further (Table 3). The amount of NBP was first changed. Doubling
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the amount of NBP to a total of three equivalents (entry 4) gave no improvement in
the enantioselectivity of 6a (76% ee) with the same chemical yield as earlier. When
equimolar amounts of substrate and NBP were used with acetone as the solvent and
15 mol% of 1a, a reduction in the yield was obtained. However, essentially the same
enantioselectivity was observed (entry 5). A twoꢀfold increase in the catalyst loading
to 30 mol% gave an enhancement in the eeꢀvalue to 80% with basically the same
chemical yield of 88% (entry 6). Decreasing the catalyst loading diminished both the
selectivity and the chemical yield, see entry 7. Increasing or decreasing the
concentration of 5a returned similar results as before with respect to both selectivity
and chemical yields (entries 8 and 9). Performing the reaction at 25 oC gave an almost
racemic product 6a (entry 10). Overall, acetone as the solvent with 30 mol% of
catalyst 1a gave the best results.
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To test the substrate scope of the reaction, the optimized conditions were next applied
to a range of substrates (Figure 2).
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NBP (1.5 equiv.),
cat. 1a (30 mol%)
3
4
CO2H
O
O
R
R
acetone
Br
5
6
(c = 0.1 M)
-78 °C, 24 h
5a-l
6a-l
7
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9
O
O
O
O
O
O
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Br
Br
Br
Me
6a
88%, 80% ee
6b
6c
94%, 92% ee
91%, 79% ee
O
O
O
O
O
O
Br
Br
Br
F
Cl
MeO
6e
6f
6d
93%, 92% ee
96%, 86% ee
90%, 9% ee
F
O
O
O
O
O
O
Br
Br
Br
Br
F3C
6g
6h
91%, 91% ee
6i
87%, 80% ee
84%, 70% ee
O
O
O
O
O
O
Br
Br
Br
O2N
6l
6k
95%, 21% ee
6j
94%, 96% ee
88%, 24% ee
aThe reactions were performed on a 0.2 mmol scale of 5a-l. bIsolated material. cDetermined by HPLC analysis using
commercial chiral columns.
Figure 2. Scope of the Asymmetric Bromolactonization Reaction.
Several of the substituted 5ꢀarylꢀ5ꢀhexenoic acids reacted in a highly enantioselective
fashion. Using the 2ꢀnapthtyl substituted 5ꢀhexenoic acid 5b, a high enantiomeric
excess of 92% and a near quantitative yield of the corresponding product 6b was
obtained. The paraꢀtolyl substituted acid 6c was isolated in 91% chemical yield with
comparable results for the enantioselectivity, 79% ee, as for 6a. Disappointingly, with
an electronꢀdonating methoxy group in the paraꢀposition, almost no enantioinduction
was seen. With a halogenꢀsubstituent in the paraꢀposition of the bromolactones 6eꢀ6g,
high asymmetric inductions were observed. Notably, a nitroꢀgroup in the paraꢀ
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position gave the highest selectivity (96% ee) among all substrates investigated.
When using the metaꢀfluoro substituted acid 5h, the product 6h was observed to have
ee of 91%. In the case of a CF3ꢀsubstituent in the paraꢀposition, diminished selectivity
(ee = 70%) was obtained. Since the products 6bꢀ6j prepared by this protocol were
obtained as solids, the enantiomeric excess of these bromolactones can easily be
enhanced by a simple recrystallization. However, when the arylꢀmoiety was replaced
with a cyclohexylꢀ or an isopropylꢀsubstituent, 6k and 6l, respectively, the
enantioselectivity was significantly reduced. For such substrates, similar trends were
also observed with squaramide 1b as the catalyst in the previously reported
iodolactonization protocol.4b In summary, the enantioinduction in the
bromolactonization reaction is consistently high for aryl moieties of low to moderate
electron density, with high to excellent chemical yields of the obtained products.
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When we utilized the squaramide 1a on a γꢀunsaturated acid substrate, low
stereodifferentiation occurred (18% ee, see Supporting Information). This may be due
to reasons of kinetics,7 since these types of substrates are more challenging to engage
in asymmetric transformations.2 Thus, the protocol reported herein does not translate
directly to efficient asymmetric bromolactonization of γꢀunsaturated carboxylic acids.
The use of chiral squaramides in catalysis has attracted increased interest as Hꢀ
bonding catalophores,8,9 and the catalysts employed herein display such properties.
The enantioenriched bromolactones prepared through the described catalytic process
may in turn be elaborated in several ways.1 To give just a few examples, the
functionalized aryl moiety present in 6aꢀ6g may undergo electrophilic substitution
reactions, transition metalꢀbased coupling protocols or may be transformed to a
carboxylic acid by oxidation.10 The alkyl bromide moiety may undergo substitution
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reactions or be used for carbonꢀcarbon bond formation by radical or organopalladium
chemistry.1
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9
In order to further demonstrate the synthetic potential of the described protocol, it was
employed in the total synthesis of natural products. The bisabolane sesquiterpene (ꢀ)ꢀ
gossonorol (7),11,12 as well as the related natural products yingzhaosu C (8)13,14 and (ꢀ
)ꢀboivinianin B (9),15,16 were selected as suitable targets, due to their interesting
biological activities against fungi, cancer and malaria. Furthermore, the developed
bromolactonization protocol offers the possibility of controlling the absolute
configuration of the benzylic position in 7ꢀ9 and the tertiary alcohol moiety of 8 and
9, making it an interesting tool for establishing the mentioned target molecules. Thus,
seeing that enantiomerically pure lactone 6c could be a useful intermediate for 7ꢀ9,
we employed the catalyst 1a on a large scale. First, a preparative scale synthesis of 5c
was performed as outlined in Scheme 1. Then 5 grams of 5c were reacted in the
presence of 30 mol% of 1a utilizing the same conditions as in Figure 2. This afforded
6.45g of 6c in 93% yield and in 81% ee. Radical reduction of 6c with
tris(trimethylsilyl)silane17 in the presence of AIBN afforded compound 12 in 89%
yield, and the solid material was recrystallized at this stage (heptane:EtOAc, 95:5),
raising the enantiomeric excess to > 99%. Alternatively, as a proof of concept, the
recrystallization procedure may be performed directly on bromolactone 6c
(heptane:EtOAc, 92:8), improving the enantiopurity to 96% ee. The lactone 12 was
then reacted with an excess of MeLi at ꢀ78o C to afford 13 in 75% yield over two
steps. The chemoselective elimination of the aliphatic tertiary alcohol in the presence
of the chiral, tertiary benzylic alcohol remained. This challenge was realized after
several different dehydration conditions were investigated (see Supporting
Information). The best conditions with respect to the chemical yield of (ꢀ)ꢀgossonorol
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(7) without any loss of stereochemical integrity, were observed when performing the
reaction in the presence of phosphorous oxychloride in pyridine at 0 oC (Scheme 1).
Scheme 1. Applications in natural product synthesis.
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O
O
BBr3
OMe
Br
OMe
p-tolylboronic acid,
Pd(PPh3)4, K2CO3
toluene, 80 °C
96%
CH2Cl2
-78 °C
82%
methyl hex-5-ynoate
10
O
OMe
11c
O
LiOH
OH
THF-H2O-MeOH
0 °C, 96%
Me
5c
Me
NBP, 30 mol% cat. 1a
acetone, -78 °C
93 %
5 g scale
(Me3Si)3SiH, AIBN
O
O
O
O
toluene, 80 °C
89%
Br
Me
Me
12
6c
81% ee
81% ee
recryst.
recryst.
96% ee, 86%
>99% ee, 94%
MeLi
Et2O, -78 °C to rt.
90%
OH
OH
OH
POCl3
Me
pyridine, 0 °C
64%
13
Me
(-)-gossonorol (7)
ref. 14b
Shi catalyst., Bu4NHSO4,
OH
Me
oxone® in aq. Na2(EDTA), K2CO3
Na2B4O7 10H2O in aq. Na2(EDTA)
acetonitrile-DMM 1:2
O
O
68%
Me
yingzhaosu C (8)
OH
O
H
Me
(-)-boivinianin B (9)
Hence, starting from the commercially available ester methyl hexꢀ5ꢀynoate, (ꢀ)ꢀ
gossoronol (7) was prepared over seven steps and in 34% yield and > 99% ee. All
physical and spectral data were in accordance with naturally occurring and synthetic
material of 7.11,12 In addition, these efforts also constitute a formal synthesis of
yingzhaosu C (8).14b (ꢀ)ꢀGossoronol (7) was then further elaborated into (ꢀ)ꢀ
boivinianin B (9) through the use of the Shi epoxidation reaction.18 Thus, treating 7
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with Oxone® in the presence of 30 mol% of Dꢀepoxone under basic conditions, lead
to the introduction of the required epoxide moiety, which was then followed by an
intramolecular acid catalyzed cyclization to afford (ꢀ)ꢀboivinianin B (9) in 23%
overall yield, see Scheme 1. All physical and spectral data for 9 were in accordance
with published values.15,16
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CONCLUSIONS
To conclude, we have developed a highly enantioselective organocatalyzed
bromolactonization protocol of arylꢀsubstituted δꢀunsaturated acids using the
squaramide 1a. Consistently high yields of 87ꢀ96% and enantiomeric excess in the
range of 70ꢀ96% were observed for electron poor and moderately electron rich
substrates. Usually, bromolactones are solid compounds that can easily be
recrystallized in order to increase an already good to excellent enantiomeric excess. In
addition, the greatly improved stability of the bromolactones, compared to the
corresponding iodoꢀcongeners, allows this purification process to occur without
decomposition or formation of byproducts. We have demonstrated that squaramides
are easy to prepare, handle and apply in highly enantioselective, preparative protocols.
These features were demonstrated in the preparation of (ꢀ)ꢀgossonorol (7) and (ꢀ)ꢀ
boivinianin B (9). Often the carbonꢀhalogen bond is seen merely as a functional
handle that allows further chemical manipulations. However, the organohalogen
constellation is in fact found in over 4700 natural products and in a significant
number of drugs.19 Hence, enantioselective and catalytic processes that forge the
formation of sp3 hybridized carbonꢀhalogen bonds are of considerable value. Towards
these ends, applications of the disclosed protocol and the novel catalyst 1a will be
investigated.
EXPERIMENTAL SECTION
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Unless stated otherwise, all commercially available reagents and solvents were used
in the form they were supplied without any further purification. The stated yields are
based on isolated material. Thin layer chromatography was performed on silica gel 60
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254 aluminumꢀbacked plates. Flash column chromatography was performed on silica
gel 60 (40ꢀ63 µm). NMR spectra were recorded at 400 MHz or 300 MHz respectively
for H NMR and at 100 MHz or 75 MHz respectively for 13C NMR. Coupling
1
constants (J) are reported in hertz and chemical shifts are reported in parts per million
1
(δ) relative to the central residual protium solvent resonance in H NMR (CDCl3 = δ
7.27, DMSOꢀd6 = δ 2.50 and TFAꢀd = δ 11.50) and the central carbon solvent
resonance in 13C NMR (CDCl3 = δ 77.00 ppm and DMSOꢀd6 = δ 39.43). Mass spectra
were recorded using ESI as the method of ionization. HRMSꢀESI spectra were
measured with a QTOF instrument. Optical rotations were measured using a 0.7 mL
cell with a 1.0 dm path length. HPLC analyses were performed with a diode array
detector set at 217 nm and equipped with a chiral stationary phase (ADꢀH 5 ꢁm 4.6 x
250 mm or ODꢀH 5 ꢁm 4.6 x 250 mm) or a C18 stationary phase (5ꢁm 4.6 × 150
mm), applying the conditions stated. The GC analyses were performed using a C18
GC column (20 m, i.d. = 0.18 mm) with FID detector.
Synthesis of squaramide catalysts.
The catalysts 1a-1g4b and 24a-4 were prepared according to literature procedures. Data
and spectra for known catalysts have been reported before,4a,4b while the data for the
novel catalysts 1a, 1c, 1g, 2 and 3 are given below.
3-((3,5-Dinitrophenyl)amino)-4-(((1R,2R)-2-(dipentylamino)cyclohexyl)amino)-
cyclobut-3-ene-1,2-dione (1a).
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Catalyst 1a was obtained as a yellow amorphous solid. Yield 1.10 g (43% over two
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steps). M.p.: 181ꢀ183 °C, decomp.. [α] ꢀ 95.6 (c = 0.14, CHCl3). H NMR (400
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MHz, TFAꢀd) δ 8.86 (s, 1H), 8.77 (s, 2H), 4.79 – 4.65 (m, 1H), 3.78 – 3.56 (m, 2H),
3.49 – 3.37 (m, 1H), 3.30 – 3.18 (m, 1H), 3.05 – 2.92 (m, 1H), 2.37 (d, J = 12.8 Hz,
1H), 2.23 (d, J = 11.9 Hz, 1H), 2.12 – 1.60 (m, 8H), 1.60 – 1.26 (m, 10H), 0.91 (s,
3H), 0.89 (s, 3H). 13C NMR (101 MHz, DMSOꢀd6) δ 184.7, 179.8, 169.9, 161.0,
148.8 (2C), 141.8, 117.2 (2C), 110.4, 64.1 (2C), 54.9, 49.3, 34.1, 29.1 (2C), 28.5
(2C), 24.8, 24. 5, 23.8, 22.1 (2C), 13.9 (2C). HRMS (ESI): Exact mass calculated for
C26H37N5O6Na [M+Na]+: 538.2636, found 538.2634.
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3-(((1R,2R)-2-(Dipentylamino)cyclohexyl)amino)-4-((4-nitrophenyl)amino)cyclobut-
3-ene-1,2-dione (1c)
Catalyst 1c was obtained as an orangeꢀbrown solid. Yield 0.93 g (54% over two
1
steps). Mp.: 172 ꢀ 176 °C, decomp.. H NMR (400 MHz, TFAꢀd) δ 8.41 (d, J = 7.6
Hz, 2H), 7.76 (d, J = 7.3 Hz, 2H), 5.04 – 3.98 (m, 2H), 3.78 – 2.87 (m, 4H), 2.31 –
1.20 (m, 19H), 1.06 – 0.77 (m, 7H). 13C NMR (101 MHz, TFAꢀd) δ 186.2, 174.9,
151.0, 136.5, 128.0 (2C), 127.0 (2C), 124.4, 122.0, 81.7, 68.3 (2C), 56.0, 53.6, 35.9,
33.9, 30.7 (2C), 27.9, 24.9, 24.5, 22.1 (2C), 14.1 (2C). [α] = ꢀ 35 (c = 0.9, CHCl3).
HRMS (TOF ES+): exact mass calculated for C26H39N4O4 [M + H]+: 471.2971, found
471.2975.
3-Amino-4-(((1R,2R)-2-(dipentylamino)cyclohexyl)amino)cyclobut-3-ene-1,2-dione
(1g).
Catalyst 1g was obtained as a white solid. Yield 0.32 g (69% over two steps). Mp.:
1
225ꢀ230 °C, decomp.. [α] = + 8.6 (c = 0.8, CHCl3). H NMR (400 MHz, TFAꢀd) δ
6.57 (bs, 1H, NH), 4.63 (bs, 1H), 3.73 – 3.55 (m, 2H), 3.42 (t, J = 11.3 Hz, 1H), 3.24
(bs, 1H), 2.97 (bs, 1H), 2.37ꢀ2.28 (m, 1H), 2.27 – 2.15 (m, 1H), 2.12 – 1.59 (m, 8H),
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1.58 – 1.14 (m, 10H), 0.99 – 0.78 (m, 6H). 13C NMR (101 MHz, TFAꢀd) δ 183.5,
180.4, 170.4, 169.3, 67.0, 54.6, 53.6 (d, J = 297.5 Hz), 34.4, 28.9 (2C), 25.9 (d, J =
82.3 Hz), 23.9, 23.8 (d, J = 48.4 Hz), 22.3 (d, J = 9.5 Hz), 12.7 (d, J = 2.3 Hz).
HRMS (TOF ES+): exact mass calculated for C20H36N3O2 [M + H]+: 350.2802, found
350.2802.
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(S)-3-((3,5-Dinitrophenyl)amino)-4-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-
yl)cyclobut-3-ene-1,2-dione (2)
Catalyst 2 was obtained as an orange solid. Yield 0.56 g (84% over two steps). Mp.:
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236ꢀ238 °C, decomp.. [α] = ꢀ 234.0 (c = 1.0, acetone). H NMR (400 MHz, TFAꢀ
d) δ 8.87 (bs, 1H), 8.68 (bs, 2H), 4.93 (bs, 1H), 4.21 – 3.82 (m, 4H), 3.83 – 3.65 (m,
1H), 3.53 (bs, 1H), 3.41 (bs, 1H), 3.27 (bs, 1H), 2.45 (bs, 1H), 2.27 (app. d, J = 26.4
Hz, 7H). 13C NMR (101 MHz, TFAꢀd) δ 185.5, 180.1, 168.5, 165.0, 149.7, 139.8,
122.0, 115.7, 60.7, 59.6, 57.3, 56.9, 50.5, 30.7, 23.8, 23.3, 23.2. HRMS (TOF ES+):
exact mass calculated for C19H21N5NaO6 [M + Na]+: 438.1384, found 438.1384.
(S)-3-((3,5-Dinitrophenyl)amino)-4-(((1-ethylpyrrolidin-2-yl)methyl)amino)cyclobut-
3-ene-1,2-dione (3)
Catalyst 3 was obtained as a brown solid. Yield 0.16 g (71% over two steps). Mp.:
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193ꢀ196 °C. [α] = ꢀ 87.1 (c = 1.0, acetone). H NMR (400 MHz, TFAꢀd) δ 8.89 –
8.83 (m, 1H), 8.80 – 8.74 (m, 2H), 7.94 (bs, 1H), 4.39 – 4.15 (m, 2H), 4.02 – 3.85 (m,
2H), 3.69 – 3.56 (m, 1H), 3.37 – 3.19 (m, 2H), 2.51 (dq, J = 14.2, 7.0 Hz, 1H), 2.24
(tt, J = 13.6, 6.9 Hz, 2H), 2.08 (dq, J = 15.3, 7.8 Hz, 1H), 1.44 (t, J = 7.2 Hz, 3H). 13C
NMR (101 MHz, DMSOꢀd6) δ 184.9, 180.3, 170.1, 161.7, 148.7, 141.6, 117.4, 110.4,
79.1, 62.8, 47.8, 45.8, 27.2, 22.5, 13.4. HRMS (TOF ES+): exact mass calculated for
C17H20N5O6 [M + H]+: 390.1408, found 390.1408.
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Preparation of starting materials
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General method A
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Methyltriphenylphosphonium bromide (1.3 equiv.) was suspended in THF (0.75 M)
and cooled to 0 °C, whereupon KHMDS (0.5 M in toluene, 1.3 equiv.) was added via
syringe. The resulting mixture was stirred for 1 hour then cooled to ꢀ78 °C and a
solution of the 5ꢀarylꢀ5ꢀoxohexanoic acid (1.0 equiv.) in THF (~0.25 M) was added in
a dropwise manner. Cooling was discontinued and the resulting mixture was stirred at
ambient temperature until TLC indicated full conversion of the starting material. The
mixture was treated with sat. aq. NH4Cl and extracted with EtOAc. The combined
organic extracts were dried over MgSO4, filtered and the solvent was evaporated in
vacuo. The residue was purified by flash chromatography on silica (hexanes, followed
by hexanes/EtOAc in various proportions) to afford the corresponding 5ꢀarylhexꢀ5ꢀ
enoic acids 5aꢀ5c, 5e, 5gꢀ5i and 5kꢀ5m.
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General method B
Step 1. Commercially available methyl hexꢀ5ꢀynoate (2.00 g, 15.9 mmol, 1.0 equiv)
was added dropwise to a 1 M solution of boron tribromide (3.96 g, 15.9 mmol, 1.0
equiv) at ꢀ78 °C. The resulting solution was allowed to warm to room temperature
over 3 h. Glacial acetic acid (16 mL) was carefully added to the mixture and stirred
for 1 hour. This mixture was quenched with water, extracted with CH2Cl2 (2 x 45 mL)
and dried (MgSO4). The residue was purified by flash chromatography on silica (10%
EtOAc in hexane) to afford the corresponding methyl 5ꢀbromohexꢀ5ꢀenoate (10) with
physical and spectral data in accord with literature.20 Step 2. Methyl 5ꢀbromohexꢀ5ꢀ
enoate (10, 100 mg, 0.48 mmol, 1.0 equiv.), the specific 4ꢀarylboronic acid (0.58
mmol. 1.2 equiv.), Pd(PPh3)4 (5.6 mg, 0.005 mmol, 1 mol%), 2.0 M Na2CO3 aq.
solution (1.5 mL, 3.0 mmol) and toluene (2.5 mL) were placed in a round bottom
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flask under argon atmosphere. The reaction mixture was stirred at 80 °C until TLC
indicated full conversion. The mixture was treated with sat. aq. NH4Cl (10 mL) and
extracted with Et2O (3 x 10 mL). The combined organic extracts were washed with
brine and dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The
residue was purified by flash chromatography on silica (hexanes/EtOAc in various
proportions) to afford the corresponding methyl 5ꢀarylhexꢀ5ꢀenoates 11d, 11f and 11j
with physical and spectral data in accord with literature.20 The chemical yields for
11d, 11f and 11j were 78 mg (96%), 144 mg (96%) and 82 mg (50%), respectively.
Step 3.To a solution of the methyl esters (1.0 equiv.) in THF/MeOH/H2O (2/2/1, c =
0.14 M), solid LiOH (20 equiv.) was added at 0 °C. The mixture was was allowed to
warm up to room temperature and stirred until TLC indicated full conversion. The
solution was acidified with sat. aq. NaH2PO4 (5 mL) and then EtOAc (5 mL) was
added. The layers were separated and the water phase was extracted with EtOAc (2 x
4 mL). The combined organic layer was washed with brine, dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by column chromatography on
silica (hexanes/EtOAc in various proportions) to afford in individual experiments the
corresponding 5ꢀarylhexꢀ5ꢀenoic acids 5d, 5e and 5j.
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5-Phenylhex-5-enoic acid (5a)
Prepared according to the general method A. Yield 1.65 g (96%). Physical and
spectral data were in accord with literature.4b 1H NMR (400 MHz, CDCl3) δ 11.82 (s,
1H), 7.15 – 7.63 (m, 5H), 5.34 (s, 1H), 5.11 (s, 1H), 2.61 (t, J = 7.5 Hz, 2H), 2.41 (t, J
= 7.4 Hz, 2H), 1.83 (p, J = 7.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 180.2, 147.3,
140.7, 128.3 (2C), 127.5, 126.1 (2C), 113.1, 34.4, 33.3, 23.0.
5-(Naphthalen-2-yl)hex-5-enoic acid (5b)
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Prepared according to the general method A. Yield 0.14 g (70%). Physical and
spectral data were in accord with literature.4b 1H NMR (300 MHz, CDCl3) δ 11.23
(bs, 1H), 7.77– 7.96 (m, 4H), 7.61 (dd, J = 8.6, 1.8 Hz, 1H), 7.42 – 7.56 (m, 2H), 5.51
(d, J = 1.3 Hz, 1H), 5.23 (d, J = 1.5 Hz, 1H), 2.73 (t, J = 7.5 Hz, 2H), 2.45 (t, J = 7.4
Hz, 2H), 1.89 (p, J = 7.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 180.1, 147.1, 137.9,
133.4, 132.8, 128.1, 127.9, 127.5, 126.1, 125.8, 124.7, 124.5, 113.6, 34.4, 33.3, 23.1.
5-(p-Tolyl)hex-5-enoic acid (5c)
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Prepared according to the general method A. Yield 0.13 g (53%). Physical and
spectral data of 5c were in accord with literature.4b 1H NMR (400 MHz, DMSOꢀd6) δ
7.34 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 5.29 (d, J = 2.0 Hz, 1H), 5.01 (d, J
= 1.9 Hz, 1H), 2.48 (t, J = 7.4 Hz, 2H), 2.29 (s, 3H), 2.22 (t, J = 7.4 Hz, 2H), 1.60 (p,
J = 7.4 Hz, 2H). 13C NMR (101 MHz, DMSOꢀd6) δ 174.3, 147.0, 137.2, 136.8, 129.0
(2C), 125.7 (2C), 111.8, 33.8, 33.0, 23.2, 20.7.
5-(4-Methoxyphenyl)hex-5-enoic acid (5d)
Prepared according to the general method B. Yield 0.16 g (83% over two steps).
Physical and spectral data were in accord with literature.4b 1H NMR (300 MHz,
CDCl3) δ 7.31 – 7.41 (m, 2H), 6.84 – 6.91 (m, 2H), 5.25 (d, J = 1.4 Hz, 1H), 5.01 (d,
J = 1.4 Hz, 1H), 3.82 (s, 3H), 2.56 (t, J = 7.4 Hz, 2H), 2.39 (t, J = 7.4 Hz, 2H), 1.81
(p, J = 7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 179.5, 159.1, 146.5, 133.1, 127.2
(2C), 113.7 (2C), 111.5, 55.3, 34.5, 33.2, 23.1.
5-(4-Fluorophenyl)hex-5-enoic acid (5e)
Prepared according to the general method A. Yield 0.36 g (81%). Physical and
spectral data were in accord with literature.4b 1H NMR (300 MHz, CDCl3) δ 11.35
(bs, 1H), 7.32 – 7.45 (m, 2H), 6.97 – 7.08 (m, 2H), 5.24 – 5.30 (m, 1H), 5.04 – 5.11
(m, 1H), 2.56 (t, J = 7.5 Hz, 1H), 2.39 (t, J = 7.5 Hz, 1H), 1.80 (p, J = 7.5 Hz, 1H).
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13C NMR (75 MHz, CDCl3) δ 180.0, 162.3 (d, 1JCF = 246 Hz), 146.3, 136.7 (d, 4JCF
=
3.3 Hz), 127.7 (d, 3JCF = 7.9 Hz, 2C), 115.2 (d, 2JCF = 21.3 Hz, 2C), 113.0, 34.5, 33.2,
22.9.
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5-(4-Chlorophenyl)hex-5-enoic acid (5f)
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Prepared according to the general method B. Yield 0.24 g (91% over two steps).
Physical and spectral data were in accord with literature.4b 1H NMR (400 MHz,
CDCl3) δ 9.76 (bs, 1H), 7.28 – 7.38 (m, 4H), 5.31 (d, J = 1.3 Hz, 1H), 5.11 (d, J = 2.0
Hz, 1H), 2.55 (t, J = 7.5 Hz, 2H), 2.39 (t, J = 7.4 Hz, 2H), 1.79 (p, J = 7.4 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ 179.6, 146.2, 139.1, 133.3, 128.5 (2C), 127.4 (2C),
113.6, 34.3, 33.2, 22.9.
5-(4-Bromophenyl)hex-5-enoic acid (5g)
Prepared according to the general method A. Yield 0.38 g (77%). Physical and
spectral data were in accord with literature.21 1H NMR (300 MHz, CDCl3) δ 11.44 (bs,
1H), 7.42– 7.52 (m, 2H), 7.24 – 7.33 (m, 2H), 5.33 (s, 1H), 5.12 (s, 1H), 2.56 (t, J =
7.5 Hz, 2H), 2.40 (t, J = 7.4 Hz, 2H), 1.80 (p, J = 7.4 Hz, 2H). 13C NMR (75 MHz,
CDCl3) δ 180.0, 146.2, 139.5, 131.4 (2C), 127.7 (2C), 121.4, 113.6, 34.2, 33.2, 22.9.
5-(3-Fluorophenyl)hex-5-enoic acid (5h)
Prepared according to the general method A. Yield 0.45 g (91%). Physical and
spectral data were in accord with literature.4c 1H NMR (400 MHz, CDCl3) δ 7.36 –
7.26 (m, 1H), 7.23 – 7.17 (m, 1H), 7.12 (dt, J = 10.4, 2.1 Hz, 1H), 6.99 (tdd, J = 8.2,
2.6, 0.9 Hz, 1H), 5.36 (s, 1H), 5.15 (s, 1H), 2.57 (t, J = 7.5 Hz, 2H), 2.41 (t, J = 7.4
Hz, 2H), 1.82 (p, J = 7.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 180.0, 163.1 (d,
4
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1JCF = 245.1 Hz), 146.4 (d, JCF = 2.1 Hz), 143.2 (d, JCF = 7.3 Hz), 129.9 (d, JCF
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=
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8.3 Hz), 121.9 (d, JCF = 2.8 Hz), 114.4 (d, JCF = 21.2 Hz), 114.2, 113.2 (d, JCF
21.8 Hz), 34.5, 33.2, 23.1.
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5-(4-(Trifluoromethyl)phenyl)hex-5-enoic acid (5i)
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Prepared according to the general method A. Yield 0.12 g (93%). Physical and
spectral data were in accord with literature.4b 1H NMR (400 MHz, CDCl3) δ 7.58
(apparently d, J = 8.1 Hz, 2H), 7.49 (apparently, J = 8.5 Hz, 2H), 5.38 (s, 1H), 5.19 (s,
1H), 2.59 (t, J = 7.6 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 1.79 (p, J = 7.5 Hz, 2H). 13C
NMR (100 MHz, CDCl3): 178.2, 146.5, 144.5, 129.6 (q, 2JCF = 31.9 Hz), 126.6, 125.5
(q, 3JCF = 3.8 Hz), 124.2 (q, 1JCF = 270 Hz), 115.2, 34.5, 33.0, 23.0.
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5-(4-Nitrophenyl)hex-5-enoic acid (5j)
Prepared according to the general method B. 65 mg (46% over two steps). Physical
and spectral data were in accord with literature.4b Mp.: 105ꢀ106 °C. TLC
(heptane/EtOAc 7:3, KMnO4 stain): Rf = 0.17. 1H NMR (400 MHz, CDCl3) δ 8.19 (d,
J = 8.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 5.46 (s, 1H), 5.28 (d, J = 1.2 Hz, 1H), 2.61
(t, J = 7.6 Hz, 1H), 2.41 (t, J = 7.3 Hz, 2H), 1.80 (p, J = 7.4 Hz, 2H). HRMS (ESI+):
Exact mass calculated for C12H13NO4Na [M+Na]+: 258.0737, found 258.0737.
5-Cyclohexylhex-5-enoic acid (5k)
Prepared according to the general method A. Yield 0.42 g (85%). Physical and
spectral data were in accord with literature.4d 1H NMR (400 MHz, CDCl3) δ 4.78 (s,
1H), 4.72 (d, J = 1.3 Hz, 1H), 2.39 (t, J = 7.5 Hz, 2H), 2.10 (t, J = 7.6 Hz, 2H), 1.91 –
1.65 (m, 8H), 1.36 – 1.07 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 180.2, 154.1,
107.8, 44.1, 34.3, 33.8, 32.6 (2C), 26.9 (2C), 26.5, 23.2.
6-Methyl-5-methyleneheptanoic acid (5l)
Prepared according to the general method A. Yield 0.46 g (94%). Physical and
spectral data were in accord with literature.4b 1H NMR (300 MHz, CDCl3) δ 11.09 (bs,
1H), 4.76 – 4.83 (m, 1H), 4.67 – 4.74 (m, 1H), 2.38 (t, J = 7.5 Hz, 2H), 2.24 (hept, J =
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7.0 Hz, 1H), 2.09 (t, J = 7.5 Hz, 2H), 1.80 (p, J = 7.5 Hz, 2H), 1.03 (d, J = 7.0 Hz,
6H). 13C NMR (75 MHz, CDCl3) δ 180.3, 154.6, 107.1, 33.6 (3C), 23.0, 21.8 (2C).
4-(4-Chlorophenyl)pent-4-enoic acid (5m)
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Prepared according to the general method A. Yield 0.21 g (85%). Physical and
spectral data were in accord with literature.3a 1H NMR (300 MHz, CDCl3) δ 10.60
(bs, 1H), 7.28 – 7.38 (m, 4H), 5.32 (s, 1H), 5.14 (s, 1H), 2.83 (t, J = 7.7 Hz, 1H), 2.54
(t, J = 7.7 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 179.3, 145.4, 138.8, 133.5, 128.6
(2C), 127.4 (2C), 113.5, 32.8, 30.0.
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General procedure for asymmetric bromolactonization with chiral squaramides.
The procedure is given for the acid 5a and is typical: Nꢀbromophthalimide (1.5
equiv.) was dissolved in acetone (0.1 M) and cooled to ꢀ78 °C. Subsequently, a
solution of acid 5a (40 mg, 0.21 mmol, 1.0 equiv.) and the individual squaramides
catalyst (0.3 equiv.) in acetone (0.10 M) was added and the resulting mixture was
stirred at ꢀ78 °C for 24 hours. The reaction mixture was treated with sat. aq. Na2S2O3
(5 ml) while still in the cooling bath, allowed to equilibrate to ambient temperature
and then EtOAc (5 ml) was added. The phases were separated and the organic phase
was washed with aq. NaOH (2 x 5 ml, 1.0 M) and brine (5 ml). The organic phase
was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by
column chromatography on silica (hexanes/EtOAc 4:1) to afford the bromolactone 6a.
(S)-6-(Bromomethyl)-6-phenyltetrahydro-2H-pyran-2-one (6a)
The product 6a was prepared according to the general procedure for asymmetric
bromolactonization using 5ꢀphenylhexꢀ5ꢀenoic acid (5a) as the starting material.
Spectroscopic data is in agreement with literature.3a,3b The enantiomeric excess (80%
ee) was determined by chiral HPLC analysis (Chiralpak ADꢀH, hexanes/iPrOH 95:5,
1 mL/min, 217 nm): tr(e1, major) = 14.37 min and tr(e2, minor) = 15.55 min. Yield: 49
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mg (88%) of colorless oil. TLC (hexanes/EtOAc 6:4): Rf = 0.27, visualized with
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CAM stain. [α] = + 9.4 (c = 1.00, CHCl3); H NMR (400 MHz, CDCl3) δ 7.44 –
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7.31 (m, 5H), 3.75 – 3.55 (q, J = 11.2 Hz, 2H), 2.56 – 2.32 (m, 4H), 1.89 – 1.77 (m,
2H), 1.66 – 1.52 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 170.6, 140.4, 129.1 (2C),
128.7, 125.5 (2C), 85.3, 41.7, 30.2, 29.2, 16.4.
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(S)-6-(Bromomethyl)-6-(naphthalen-2-yl)tetrahydro-2H-pyran-2-one (6b)
Prepared according to the general procedure using 5ꢀ(naphthalenꢀ2ꢀyl)hexꢀ5ꢀenoic
acid (5b) as starting material. Spectroscopic data is in agreement with literature.3a,3b
The enantiomeric excess (92% ee) was determined by chiral HPLC analysis
(Chiralpak ADꢀH, hexanes/iPrOH 93:7, 1 mL/min, 217 nm): tr(e1, minor) = 17.64 min
and tr(e2, major) = 19.53 min. Yield: 67 mg (94%) of pale yellow solid. Mp.: 116ꢀ118
°C. TLC (hexanes/EtOAc 7:3): Rf = 0.35, visualized with CAM stain. [α] = + 35.8 (c
1
= 0.21, CHCl3). H NMR (400 MHz, CDCl3) δ 7.93 – 7.83 (m, 4H), 7.57 – 7.50 (m,
2H), 7.43 (dd, J = 8.7, 2.0 Hz, 1H), 3.75 (d, J = 0.7 Hz, 2H), 2.59 – 2.43 (m, 4H),
1.92 – 1.82 (m, 1H), 1.69 – 1.57 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 170.6,
137.7, 133.2, 133.1, 129.2, 128.5, 127.7, 127.1, 127.0, 125.5, 122.6, 85.4, 41.5, 30.2,
29.3, 16.4.
(S)-6-(Bromomethyl)-6-(p-tolyl)tetrahydro-2H-pyran-2-one (6c)
Prepared according to the general procedure using 5ꢀ(pꢀtolyl)hexꢀ5ꢀenoic acid (5c) as
starting material. Spectroscopic data is in agreement with literature.3a,3b The
enantiomeric excess (79% ee) was determined by chiral HPLC analysis (Chiralpak
ADꢀH, hexanes/iPrOH 93:7, 1 mL/min, 217 nm): tr(e1, major) = 11.39 min and tr(e2,
minor) = 12.30 min. Yield: 50 mg (91%) of white solid. Mp.: 59ꢀ61 °C. TLC
(hexanes/EtOAc 6:4): Rf = 0.35, visualized with CAM stain. [α] = +17.7 (c = 1.10,
1
CHCl3). H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 6.5 Hz, 2H), 7.21 (d, J = 8.1 Hz,
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2H), 3.64 (q, J = 11.1 Hz, 2H), 2.57 – 2.28 (m, 7H), 1.88 – 1.77 (m, 1H), 1.68 – 1.51
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(m, 1H). C NMR (101 MHz, CDCl3) δ 170.7, 138.6, 137.4, 129.8 (2C), 125.4 (2C),
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85.3, 41.8, 30.1, 29.2, 21.2, 16.4. As a proof of concept, the bromolactone 6c with
79% ee (50 mg) was recrystallized from EtOAc in heptane (2:98) to afford 6c with
enantiomeric excess of 96% ee and with 86% recovery (43 mg).
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(S)-6-(Bromomethyl)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (6d)
Prepared according to the general procedure using 5ꢀ(4ꢀmethoxyphenyl)hexꢀ5ꢀenoic
acid (5d) as starting material. Spectroscopic data is in agreement with literature.3a,3b
The enantiomeric excess (9% ee) was determined by chiral HPLC analysis (Chiralpak
ADꢀH, hexanes/iPrOH 90:10, 1 mL/min, 217 nm): tr(e1, major) = 13.36 min and tr(e2,
minor) = 14.33 min. Yield: 49 mg (90%) of white solid. Mp.: 83ꢀ84 °C. TLC
(hexanes/EtOAc 7:3): Rf = 0.17, visualized with CAM stain. [α] = ˗2.0 (c = 0.71,
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CHCl3). H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz,
2H), 3.82 (s, 3H), 3.69 – 3.55 (m, 2H), 2.55 – 2.29 (m, 4H), 1.89 – 1.78 (m, 1H), 1.70
– 1.58 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 170.6, 159.8, 132.3, 126.9 (2C), 114.5
(2C), 85.1, 55.5, 41.9, 30.0, 29.2, 16.4.
(S)-6-(Bromomethyl)-6-(4-fluorophenyl)tetrahydro-2H-pyran-2-one (6e)
Prepared according to the general procedure using 5ꢀ(4ꢀfluorophenyl)hexꢀ5ꢀenoic acid
(5e) as starting material. Spectroscopic data is in agreement with literature.3a,3b The
enantiomeric excess (92% ee) was determined by chiral HPLC analysis (Chiralpak
ADꢀH, hexanes/iPrOH 90:10, 1 mL/min, 217 nm): tr(e1, major) = 10.23 min and tr(e2,
minor) = 11.99 min. Yield: 52 mg (93%) of white solid. Mp.: 97ꢀ99 °C. TLC
(hexanes/EtOAc 7:3): Rf = 0.34, visualized with CAM stain. [α] = + 13.0 (c = 0.57,
CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.28 (m, 2H), 7.08 – 6.98 (m, 2H), 3.54
(q, J = 11.2 Hz, 2H), 2.50 – 2.22 (m, 4H), 1.85 – 1.73 (m, 1H), 1.60 – 1.49 (m, 1H).
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13C NMR (101 MHz, CDCl3) δ 170.1, 162.6 (d, 1JCF = 248.7 Hz), 136.1 (d, 4JCF = 2.9
Hz), 127.4 (d, 3JCF = 8.2 Hz, 2C), 116.0 (d, 2JCF = 21.6 Hz, 2C), 84.8, 41.4, 30.1, 29.1,
16.2.
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(S)-6-(Bromomethyl)-6-(4-chlorophenyl)tetrahydro-2H-pyran-2-one (6f)
Prepared according to the general procedure using 5ꢀ(4ꢀchlorophenyl)hexꢀ5ꢀenoic
acid (5f) as starting material. Spectroscopic data is in agreement with literature.3a,3b
The enantiomeric excess (86% ee) was determined by chiral HPLC analysis
(Chiralpak ADꢀH, hexanes/iPrOH 90:10, 1 mL/min, 217 nm): tr(e1, major) = 10.42
min and tr(e2, minor) = 12.64 min. Yield: 52 mg (96%) of white solid. Mp.: 102ꢀ104
°C. TLC (hexanes/EtOAc 7:3): Rf = 0.15, visualized with CAM stain. [α] = + 13.2 (c
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= 0.93, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.32 (m, 4H), 3.62 (q, J = 11.1
Hz, 2H), 2.56 – 2.30 (m, 4H), 1.91 – 1.81 (m, 1H), 1.67 – 1.55 (m, 1H), 13C NMR
(101 MHz, CDCl3) δ 170.1, 139.0, 134.9, 129.3 (2C), 127.1 (2C), 84.9, 41.3, 30.3,
29.2, 16.4.
(S)-6-(Bromomethyl)-6-(4-bromophenyl)tetrahydro-2H-pyran-2-one (6g)
Prepared according to the general procedure using 5ꢀ(4ꢀbromophenyl)hexꢀ5ꢀenoic
acid (5g) as starting material. Spectroscopic data is in agreement with literature.3a The
enantiomeric excess (80% ee) was determined by chiral HPLC analysis (Chiralpak
ADꢀH, hexanes/iPrOH 93:7, 1 mL/min, 217 nm): tr(e1, major) = 13.86 min and tr(e2,
minor) = 16.94 min. Yield: 45 mg (87%) of white solid. Mp.: 180ꢀ182 °C decomp..
TLC (hexanes/EtOAc 7:3): Rf = 0.33, visualized with CAM stain. [α] = + 11.1 (c =
1
1.34, CHCl3). H NMR (400 MHz, CDCl3) δ 7.60 – 7.44 (m, 2H), 7.31 – 7.26 (m,
2H), 3.62 (q, J = 11.1 Hz, 2H), 2.60 – 2.25 (m, 4H), 1.94 – 1.78 (m, 1H), 1.65 – 1.50
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(m, 1H). C NMR (101 MHz, CDCl3) δ 170.1, 139.5, 132.3 (2C), 127.4 (2C), 123.0,
85.0, 41.2, 30.2, 29.2, 16.4.
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(S)-6-(Bromomethyl)-6-(3-fluorophenyl)tetrahydro-2H-pyran-2-one (6h)
Prepared according to the general procedure using 5ꢀ(3ꢀfluorophenyl)hexꢀ5ꢀenoic acid
(5h) as starting material. The enantiomeric excess (91% ee) was determined by chiral
HPLC analysis (Chiralpak ODꢀH, hexanes/iPrOH 90:10, 1 mL/min, 217 nm): tr(e1,
major) = 16.76 min and tr(e2, minor) = 20.82 min. Yield: 50 mg (91%) of colorless
solid. Mp.: 90ꢀ91 °C. TLC (hexanes/EtOAc 7:3): Rf = 0.35, visualized with CAM
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stain. [α] = + 10.4 (c = 0.78, CHCl3). H NMR (400 MHz, CDCl3) δ 7.39 (td, J =
8.1, 5.9 Hz, 1H), 7.18 (ddd, J = 7.9, 1.8, 0.9 Hz, 1H), 7.12 (dt, J = 10.0, 2.2 Hz, 1H),
7.06 (tdd, J = 8.2, 2.5, 0.9 Hz, 1H), 3.66 (d, J = 11.2 Hz, 1H), 3.61 (d, J = 11.2 Hz,
1H), 2.58 – 2.30 (m, 4H), 1.92 – 1.81 (m, 1H), 1.67 – 1.56 (m, 1H). 13C NMR (101
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MHz, CDCl3) δ 170.0, 163.2 (d, 1JCF = 247.6 Hz), 143.2 (d, JCF = 6.8 Hz), 130.8 (d,
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3JCF = 8.2 Hz), 121.2 (d, JCF = 3.0 Hz), 115.7 (d, JCF = 21.1 Hz), 113.1 (d, JCF
=
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23.4 Hz), 84.8 (d, JCF = 1.9 Hz), 41.2, 30.4, 29.3, 16.4. HRMS (ESI+): Exact mass
calculated for C12H12BrFO2Na [M+Na]+: 308.9897, found 308.9896.
(S)-6-(Bromomethyl)-6-(4-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-2-one
(6i)
Prepared according to the general procedure using 5ꢀ(4ꢀ(trifluoromethyl)phenyl)hexꢀ
5ꢀenoic acid (5i) as starting material. Spectroscopic data is in agreement with
literature.3a,3b The enantiomeric excess (70% ee) was determined by chiral HPLC
analysis (Chiralpak ADꢀH, hexanes/iPrOH 90:10, 1 mL/min, 217 nm): tr(e1, major) =
11.34 min and tr(e2, minor) = 13.51 min. Yield: 47 mg (84%) of pale yellow solid.
Mp.: 171ꢀ173 °C. TLC (hexanes/EtOAc 6:4): Rf = 0.23, visualized with CAM stain.
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[α] = + 9.6 (c = 0.60, CHCl3). H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 8.6 Hz,
2H), 7.55 (d, J = 8.3 Hz, 2H), 3.65 (q, J = 11.2 Hz, 2H), 2.58 – 2.37 (m, 4H), 1.93 –
1.84 (m, 1H), 1.60 – 1.52 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 169.9, 144.5, 131.0
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(q, JCF = 32.8 Hz), 126.2 (2C), 126.1 (q, JCF = 3.8 Hz), 123.9 (q, JCF = 272.1 Hz),
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(S)-6-(Bromomethyl)-6-(4-nitrophenyl)tetrahydro-2H-pyran-2-one (6j)
Prepared according to the general procedure using methyl 5ꢀ(4ꢀnitrophenyl)hexꢀ5ꢀ
enoate (5j) as starting material. The enantiomeric excess (96% ee) was determined by
chiral HPLC analysis (Chiralpak ADꢀH, hexanes/iPrOH 85:15, 1 mL/min, 217 nm):
tr(e1, major) = 17.29 min and tr(e2, minor) = 21.08 min. Yield: 50 mg (94%) of pale
yellow solid. Mp.: 110ꢀ111 °C. TLC (hexanes/EtOAc 7:3): Rf = 0.14, visualized with
CAM stain. [α] = + 10.4 (c = 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J
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= 8.9 Hz, 2H), 7.62 (d, J = 8.9 Hz, 2H), 3.71 – 3.62 (m, 2H), 3.68 (d, J = 11.2 Hz,
1H), 3.65 (d, J = 11.2 Hz, 1H), 2.48 – 2.39 (m, 2H), 1.97 – 1.87 (m, 1H), 1.64 – 1.54
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(m, 1H). C NMR (101 MHz, CDCl3) δ 169.4, 148.1, 147.6, 126.9 (2C), 124.2 (2C),
84.9, 40.4, 30.7, 29.3, 16.5. HRMS (ESI+): Exact mass calculated for C12H12BrNO4Na
[M+Na]+: 335.9842, found 335.9840. The absolute configuration was assigned based
on analogy with the other lactones formed.
(S)-6-(Bromomethyl)-6-cyclohexyltetrahydro-2H-pyran-2-one (6k)
Prepared according to the general procedure using methyl 5ꢀcyclohexylhexꢀ5ꢀenoic
acid (5k) as starting material Spectroscopic data is in agreement with literature.3a,3b
The enantiomeric excess (21% ee) was determined by chiral HPLC analysis
(Chiralpak ODꢀH, hexanes/iPrOH 90:10, 1 mL/min, 217 nm): tr(e1, major) = 11.26
min and tr(e2, minor) = 12.01 min. Yield: 53 mg (95%) of colorless oil. TLC
(hexanes/EtOAc 7:3): Rf = 0.41, visualized with CAM stain. [α] = + 1.6 (c = 0.88,
CHCl3). 1H NMR (400 MHz, CDCl3) δ 3.56 (s, 2H), 2.60 – 2.48 (m, 1H), 2.47 – 2.36
(m, 1H), 2.09 – 1.65 (m, 9H), 1.36 – 1.03 (m, 6H). 13C NMR (101 MHz, CDCl3) δ
170.9, 85.7, 45.5, 38.1, 30.0, 26.9, 26.6, 26.5, 26.5, 26.3, 26.2, 17.2.
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(S)-6-(Bromomethyl)-6-isopropyltetrahydro-2H-pyran-2-one (6l)
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Prepared according to the general procedure using methyl 6ꢀmethylꢀ5ꢀ
methyleneheptanoic acid (5l) as starting material. Spectroscopic data is in agreement
with literature.3b The enantiomeric excess (24% ee) was determined by chiral HPLC
analysis (Chiralpak ODꢀH, hexanes/iPrOH 90:10, 1 mL/min, 217 nm): tr(e1, major) =
12.33 min and tr(e2, minor) = 13.25 min. Yield: 53 mg (88%) of colorless oil. TLC
(hexanes/EtOAc 7:3): Rf = 0.37, visualized with CAM stain. [α] = + 1.7 (c = 0.66,
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CHCl3). 1H NMR (400 MHz, CDCl3) δ 3.56 (s, 2H), 2.61 – 2.49 (m, 1H), 2.48 – 2.36
(m, 1H), 2.18 (hept, J = 6.9 Hz, 1H), 2.10 – 2.01 (m, 1H), 1.95 – 1.78 (m, 3H), 1.01
(t, J = 6.4 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 170.8, 85.9, 37.6, 35.2, 29.9, 25.9,
17.1, 16.9, 16.7.
(S)-5-(Bromomethyl)-5-(4-chlorophenyl)dihydrofuran-2(3H)-one (6m)
Prepared according to the general procedure using methyl 4ꢀ(4ꢀchlorophenyl)pentꢀ4ꢀ
enoic acid (5f). Spectroscopic data is in agreement with literature.3a The enantiomeric
excess (24% ee) was determined by chiral HPLC analysis (ODꢀH, hexanes/iPrOH
90:10, 1 mL/min, 217 nm): tr(e1, major) = 12.33 min and tr(e2, minor) = 13.25 min.
Yield: 43 mg (94%) of colourless oil. TLC (hexanes/EtOAc 7:3). Rf = 0.33, visualized
with CAM stain. [α] = ˗4.8 (c = 0.37, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.39 –
7.30 (m, 4H), 3.69 (d, J = 11.4 Hz, 1H), 3.65 (d, J = 11.4 Hz, 1H), 2.86 – 2.72 (m,
2H), 2.59 – 2.44 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 175.2, 139.3, 134.8, 129.1
(2C), 126.5 (2C), 86.1, 40.7, 32.5, 29.1.
Preparative scale synthesis of methyl 5-bromohex-5-enoate (10)
Commercially available methyl hexꢀ5ꢀynoate (20.0 g, 159 mmol, 1.0 equiv) was
added dropwise to a 1 M solution of boron tribromide in CH2Cl2 (159 mL, 159 mmol,
1 equiv) at ꢀ78 °C. The resulting solution was allowed to warm to room temperature
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over 3 h. Glacial acetic acid (316 mL) was carefully added to the mixture and stirred
for 1 hour. This mixture was quenched with water (150 mL), extracted with CH2Cl2
(3 x 50 mL) and dried (MgSO4). The residue was purified by flash chromatography
on silica (heptane/EtOAc 90:10) to afford 10 as a yellow oil. Yield: 26.9 g (82%). The
spectroscopic data were in accord with literature.20 TLC (heptane/EtOAc 85:15): Rf =
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0.47, visualized with KMnO4 stain. H NMR (400 MHz, CDCl3) δ 5.58 (q, J = 1.1
Hz, 1H), 5.43 (d, J = 1.6 Hz, 1H), 3.68 (s, 3H), 2.47 (t, J = 7.2 Hz, 2H), 2.34 (t, J =
7.4 Hz, 2H), 1.90 (p, J = 7.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 173.7, 133.4,
117.6, 51.7, 40.6, 32.5, 23.1.
Preparative scale synthesis of methyl 5-(p-tolyl)hex-5-enoate (11c)
Prepared according to the general method B. pꢀTolylboronic acid (11.0 g, 80.9 mmol,
1.20 equiv.) and methyl 5ꢀbromohexꢀ5ꢀenoate (10) (14.0 g, 67.6 mmol, 1.00 equiv.)
were added to a roundꢀbottom flask. Toluene (335 mL) was added and the flask was
evacuated and filled with argon. Next, solid Pd(PPh3)4 (1.56 g, 1.35 mmol, 2 mol%)
was added followed by addition of a degassed aq. solution of 2.0 M Na2CO3 (200 mL,
400 mmol) and the setup was again evacuated and filled with argon (3x). The reaction
mixture was subsequently stirred at 80 °C until TLC indicated full conversion. The
mixture was treated with sat. aq. NH4Cl (675 mL) and extracted with Et2O (3 x 100
mL). The combined organic extracts were washed with brine (100 mL) and dried
(Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified
by flash chromatography on silica (heptane/EtOAc 85:15) to afford 11c as a pale
yellow solid with physical and spectral data in accord with literature.4b Yield: 8.99 g
(96%). Mp.: 66ꢀ67 °C. TLC (heptane/EtOAc 85:15): Rf = 0.33, visualized with
KMnO4 stain. 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 7.9
Hz, 2H), 5.28 (d, J = 1.3 Hz, 1H), 5.02 (d, J = 1.3 Hz, 1H), 3.66 (s, 3H), 2.54 (t, J =
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7.9 Hz, 2H), 2.35 (s, 3H), 2.32 (d, J = 7.5 Hz, 2H), 1.79 (p, J = 7.5 Hz, 2H). 13C NMR
(101 MHz, CDCl3) δ 174.1, 147.4, 138.0, 137.3, 129.2 (2C), 126.1 (2C), 112.3, 51.6,
34.7, 33.5, 23.6, 21.2.
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Methyl 5-(4-nitrophenyl)hex-5-enoate (11j)
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Prepared according to the general method B. Yield: 82 mg (50%). TLC
(heptane/EtOAc 85:15, KMnO4 stain): Rf = 0.24, 1H NMR (400 MHz, CDCl3) δ 8.19
(d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 5.45 (d, J = 0.9 Hz, 1H), 5.27 (d, J = 1.1
Hz, 1H), 3.67 (s, 3H), 2.69 – 2.49 (m, 2H), 2.35 (t, J = 7.3 Hz, 2H), 1.79 (p, J = 7.4
Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 173.8, 147.6, 147.3, 146.1, 127.0, 123.9,
116.5, 51.7, 34.5, 33.4, 23.4. HRMS (ESI+): Exact mass calculated for C13H15NO4Na
[M+Na]+: 272.0893, found 272.0894.
(S)-6-Methyl-6-(p-tolyl)tetrahydro-2H-pyran-2-one (12)
Preparative scale synthesis of 6c: The bromolactone 6c was prepared according to the
general procedure for asymmetric bromolactonization using 5c (5g, 26.3 mmol) that
afforded 6.93g (93%) of 6c with enantiomeric excess of 81% ee. The enantiomeric
excess was determined by HPLC analysis (Chiralpak ADꢀH, hexanes/iPrOH 93:7, 1.0
mL/min): tr(e1, major) = 11.84 min and tr(e2, minor) = 12.81 min. Then the
bromolactone 6c (3.00 g, 10.6 mmol, 1.00 equiv.) was dissolved in toluene (210 mL),
tris(trimethylsilyl)silane (10.0 g, 40.2 mmol, 2.70 equiv) and AIBN (578 mg, 3.52
mmol) were added and the setup was evacuated and filled with argon (3x). The
reaction mixture was then heated to 80 °C overnight. Next, the reaction mixture was
cooled to room temperature, concentrated in vacuo and the material thus obtained
purified by flash column chromatography on silica (15% EtOAc in heptane) to give
12 as a colorless oil which quickly solidified. The crystals were recrystallized from
EtOAc in heptane (5:95). The enantiomeric excess (> 99% ee) was determined by
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HPLC analysis (Chiralpak ODꢀH, hexanes/iPrOH 99:1, 0.9 mL/min, 217 nm): tr(e1,
minor) = 20.82 min and tr(e2, major) = 21.73 min. Yield: 1.81 g (84%) over two steps
from acid 5c of white crystals. Mp.: 101 ꢀ102 °C. TLC (hexanes/EtOAc 75:15): Rf =
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0.24, visualized with CAM stain. [α]
= ̶ 38.0 (c = 0.17, MeOH). H NMR (400
MHz, CDCl3) δ 7.25 – 7.18 (m, 2H), 7.18 – 7.14 (m, 2H), 2.51 – 2.35 (m, 2H), 2.33
(s, 3H), 2.29 (dt, J = 14.2, 4.8 Hz, 1H), 1.97 (ddd, J = 14.2, 11.4, 4.4 Hz, 1H), 1.83 –
1.72 (m, 1H), 1.65 (s, 3H), 1.65 – 1.53 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 171.7,
141.7, 137.1, 129.4 (2C), 124.4 (2C), 85.4, 34.4, 31.5, 29.1, 21.0, 16.7. HRMS (ESI+):
Exact mass calculated for C13H16O2Na [M+Na]+: 227.1043, found 227.1043.
(S)-2-Methyl-6-(p-tolyl)heptane-2,6-diol (13)
Methyllitium in Et2O (1.6 M, 59.5 mL, 95.2 mmol, 12.00 equiv.) was added to a
solution of lactone 12 (1.62 g, 7.93 mmol, 1.00 equiv.) dissolved in Et2O (35 mL) at ꢀ
78 °C. The solution was allowed to warm up to room temperature overnight. The
solution was added dropwise to a flask with water (100 mL) at 0 °C. The phases were
separated and the aqueous phase was extracted with Et2O (2 x 40 mL). The combined
organic extracts were washed with brine (30 mL), dried (Na2SO4), filtered and the
solvent was evaporated in vacuo. The residue was purified by flash chromatography
on silica (hexanes/EtOAc 1:1) to yield 13 as colorless oil. Yield: 1.67 g (90%). TLC
(hexanes/EtOAc 1:1): Rf = 0.27, visualized with CAM stain. [α]
= ̶ 8.5 (c = 0.14,
MeOH). 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.3 Hz,
2H), 2.33 (s, 3H), 1.86 – 1.71 (m, 2H), 1.54 (s, 3H), 1.47 – 1.20 (m, 4H), 1.15 (s, 6H).
13C NMR (101 MHz, CDCl3) δ 145.2, 136.2, 129.0 (2C), 124.8 (2C), 74.7, 71.2, 44.7,
44.2, 30.4, 29.4 (2C), 21.1, 18.9. HRMS (ESI+): Exact mass calculated for
C15H24O2Na [M+Na]+: 259.1669, found 259.1669.
Synthesis of (-)-gossonorol (7)
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