One-step preparation of O-(α-bromoacyl) cyanohydrins by minor enantiomer recycling: Synthesis of 4-amino-2(5H)-furanones

Article abstract of DOI:10.1021/jo401401c

O-(α-Bromoacyl) cyanohydrins were prepared in a single step from a range of different aldehydes in combination with α-bromoacyl cyanides. By the use of a cyclic procedure where the two minor diastereoisomers from a chiral Lewis acid-catalyzed reaction und

Full text of DOI:10.1021/jo401401c

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Article
One-Step Preparation of O-(alpha-Bromoacyl) cyanohydrins by
Minor Enantiomer Recycling - Synthesis of 4-Amino-2(5H)-furanones
Robin Hertzberg, and Christina Moberg
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401401c • Publication Date (Web): 27 Aug 2013
Downloaded from http://pubs.acs.org on September 2, 2013
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diastereoselectivites. The synthetic importance of these compounds was demonstrated by the
synthesis of 4-amino-2(5H)-furanones, a class of compounds which has shown both biological
activity and utility as synthetic intermediates. This transformation was achieved by an
intramolecular Blaise reaction which gave the products in high to excellent yields and
enantiomeric ratios.
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INTRODUCTION
The 2(5H)-furanone structural motif (Figure 1) is found in a wide range of compounds, many of
which exhibit interesting biological properties.1 For this reason, extensive efforts have been
devoted to syntheses of furanone derivatives.2 Among these, 4-amino-substituted furanones are of
particular interest due to their importance as synthetic intermediates as well as for their biological
activity. The introduction of an amino group in the furanone part of the natural product
squamocin, for example, gave a product with increased cytotoxic activity, which was found to
inhibit both mitochondrial complexes I and III.3 Betulin derivatives functionalized with different
4-amino-2(5H)-furanones showed in several cases higher cytotoxic activity to human cancer cell
lines than the native compound.4 4-Amino-2(5H)-furanones were used as intermediates in the
synthesis of (+)-eldanolide5 as well as in the synthesis of the antibiotic virginiamycin M2.6
Furthermore, five-membered amino-substituted lactones have acted as starting materials for the
synthesis of several β-lactams and β-amino esters.7
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Figure 1. The 2(5H)-furanone structural motif
Diverse methodologies have been developed for the synthesis of aminofuranones. Achiral 3-
substituted aminofuranones have been obtained by electrocyclic ring opening of 4-hydroxy-3-
aminocyclobutenones,8 and racemic 5,5-disubstituted derivatives from 3-hydroxyalkynes via
sequential Pd-catalyzed oxidative carbonylation, conjugate addition, and lactonization.9
Enantioenriched aminofuranones have been prepared by diastereoselective alkylation of lithium
enolates of vinylogous urethanes,10 as well as by enantioselective alkyne additions to aldehydes,
using (S)-BINOL for the chiral induction, followed by conjugate addition of an amine; this latter
method afforded 4-amino-2(5H)-furanones with 84–90% ee.11 A similar procedure was used for
the synthesis of enantioenriched tetronic acids (4-hydroxy-2(5H)-furanones or tetrahydrofuran-
2,4-diones).12
Cyanohydrins derived from both aldehydes and ketones have frequently been employed as
starting materials for the preparation of aminofuranones. In the presence of strong base, such as
LiN(SiMe3)2, ester enolates of O-acylated racemic13 or enantioenriched14 cyanohydrins, the latter
obtained via kinetic resolution of the acylated ketone cyanohydrins14a or via enzyme catalyzed
HCN addition to ketones,14b cyclize to aminofuranones. An alternative procedure, consisting of
the addition of a Reformatsky reagent to TMS-protected cyanohydrins (Blaise reaction15)
followed by deprotection and lactonization was applied to the synthesis of both tetronic acids16
and 4-aminobutyrolactones.17 The latter type of products were also shown to be accessible by
cyclization of 3-acetamido-4-acetoxyalkanoic acids, in turn obtained via a reaction sequence
consisting of the initial addition of an allyl Grignard reagent to the same cyanohydrins.18
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Enantioenriched O-(α-bromoacyl) cyanohydrins have also been used in an intramolecular Blaise
reaction to give 4-amino- and 4-hydroxyfuranones.19 A derivative of the latter type was recently
employed as starting material for the preparation of a compound originally assumed to be
identical to Gobienine A.20
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We have previously developed a convenient method for a one-step synthesis of highly
enantioenriched O-acylated cyanohydrins from aldehydes and acyl cyanides employing a dual
activation catalytic system consisting of a chiral titanium salen dimer 121 and a Lewis base, such
as a tertiary amine, at –40 °C.22
Enantiomeric ratios were generally in the range 95:5 to 98:2,22 but lower selectivites were
observed for products which undergo racemization in the presence of the base needed for the
catalytic reaction.23 In order to further increase the enantioselectivity and at the same time avoid
problems connected to the presence of base, we developed a recycling procedure involving two
chiral catalysts. Here the minor enantiomer from the product-forming catalytic reaction, by the
use of a second chiral catalyst, undergoes a reversed process to restore the prochiral starting
material, thereby establishing a cyclic process. With the combination of the titanium salen dimer
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1 and a biocatalyst, highly enantioenriched O-acylated cyanohydrins were obtained, in most cases
in high yields, from the reaction between aldehydes and acyl cyanides.24 A thermodynamic
driving force maintaining a unidirectional cycle is secured by a constant feed of acyl cyanide and
the irreversible formation of carboxylate ions.
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We anticipated that a direct route for the preparation of O-(-bromoacyl) cyanohydrins,
avoiding the intermediacy of racemization-prone cyanohydrins, would constitute an attractive
initial step towards the preparation of enantioenriched aminofuranones. The use of α-bromoacyl
cyanides in the cyanation of aldehydes would give direct access to the products needed for the
subsequent Blaise cyclizations.19
RESULTS AND DISCUSSION
The required bromoacyl cyanides (2a and 2b) were synthesized (2a in racemic form) from the
appropriate acyl bromides and TMSCN according to a literature procedure.25 Compound 2a could
also be prepared using the less expensive CuCN as source of cyanide (Scheme 1).
Scheme 1. Synthesis of Acyl Cyanides 2
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We first attempted our standard acylcyanation conditions22 for the reaction of benzaldehyde
(3a) with acyl cyanide 2a at –20 °C in dichloromethane, employing a catalytic system consisting
of the titanium salen dimer 1 and triethylamine (Scheme 2). Not surprisingly, due to the high
reactivity of acyl bromides with triethylamine,26 low conversion of the aldehyde and only minor
amounts of product were observed. The minor enantiomer recycling procedure does not require
the presence of base, and was therefore assumed to be more beneficial.
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Scheme 2. Attempted Acylcyanation of 3a Using the Dual Activation Procedure
By using a combination of the (S,S)-Ti catalyst 1 and Candida antarctica lipase B (CALB) in
a two-phase system consisting of toluene and aqueous buffer, the desired products were indeed
obtained (Table 1). Since racemic 2a was used, four stereoisomers of the product were expected
to form. Whereas the stereocenter in the acyl part of the product would be lost in the subsequent
Blaise reaction, the configuration at the C–O stereocenter was crucial. When using benzaldehyde
(3a) as a substrate, excellent selectivity for the isomers with R absolute configuration at the C–O
stereocenter was observed, and products (R,R)- and (R,S)-4a were isolated in good combined
yield (Table 1, entry 1). High yields and selectivities were observed for both electron rich (entries
3 and 5) and electron deficient substrates (entries 2 and 4). The product from (E)-butenal (3f,
containing ca 5% of the Z-isomer) was obtained in somewhat lower yield due to the presence of
non-acylated cyanohydrin (5f), but still with high selectivity (entry 6). The E/Z ratio of the
products were essentially the same as that of the starting material.
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In the reaction with pentanal (entry 7), both the yield of product 4g and the [(R,R)+(R,S)] to
[(S,R)+(S,S)] isomer ratio increased as expected during the initial part of the reaction, whereafter
a slight decline in isomeric ratio was observed. We assumed that this effect was due to enzyme
inhibition, leading to a lower rate of hydrolysis of (S,R)- and (S,S)-4g; the enzyme was indeed
shown to exhibit decreased activity towards these minor 4g isomers in the presence of 2a. A
gradual decrease in the rate of addition of 2a served to maintain a balance between the rates of
the product-forming forward reaction and the reverse hydrolysis, whereby the decrease in
stereoselectivity could be avoided (see Supporting Information). However, a more convenient
synthetic procedure consists of the addition of the acyl cyanide 2a over 8 hours, which gave the
products with a diastereomeric ratio of 80:20, followed by kinetic resolution, achieved by
continued stirring in the presence of the enzyme. In this way 65% yield of 4g with a
diastereomeric ratio of 99:1 could be isolated.
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Table 1. Synthesis of O-Acylated Cyanohydrins 4 via Minor Enantiomer Recycling
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[(R,S)+(R,R)] /
[(S,R) + (S,S)]b
99.4:0.6
Yield a (%)
Entry
Product
R
1
2
3
4
5
6
7
C6H5
64
78
64
80
68
51
65
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4a
4b
4c
4d
4e
4f
4-Cl-C6H4
98.6:1.4
4-MeO-C6H4
4-Br-C6H4
~98:2c
96.1:3.9
4-Me-C6H4
(E)-CH3CH=CH
97.2:2.8
97.4:2.6
n-C4H9
99.0:1.0
4g
aIsolated yield. Determined by chiral GC or HPLC. Measured between two peaks only due to
b
c
poor separation.
The enantioenriched products 4 obtained from the minor enantiomer recycling were then
subjected to an intramolecular Blaise reaction, using metallic zinc in THF at 65 °C followed by
quenching with NH4Cl (aq.), to afford 4-amino-2(5H)-furanones 6 (Table 2). The reaction
resulted in most cases in high yields and no or little racemization. The small differences observed
in isomeric ratios between starting materials and products in a few cases (4d and 4f) could be the
result of slightly different reactivities of the diastereomeric O-acyl cyanohydrins (Table 2, entries
4 and 6).
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Table 2. Synthesis of Aminofuranones (R)-6 via Intramolecular Blaise Reaction
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Yielda (%)
Erb
Entry
Product
6a
R
1
2
3
4
5
6
7
C6H5
86
97
98
73
93
94
71
98.6:1.4
98.4:1.6
97.9:2.1
97.3:2.7
97.3:2.7
95.4:4.6
98.8:1.2
4-Cl-C6H4
4-MeO-C6H4
4-Br-C6H4
4-Me-C6H4
(E)-CH3CH=CH
n-C4H9
6b
6c
6d
6e
6f
6g
aIsolated yield. bDetermined by chiral GC or HPLC.
We then proceeded with the synthesis of the O-(-bromo)acetylated cyanohydrin 7. Due to
poor solubility of 2b in toluene, this reaction was run in the more polar cyclopentyl methyl ether,
1
which has a boiling point similar to that of toluene. However, as shown by H NMR
spectroscopy, large amounts of free cyanohydrin (8) were present and, as a consequence, low
yields of the acylated products were obtained. These problems were solved when 2b dissolved in
cyclopentyl methyl ether was added to the reaction mixture in toluene. Under these conditions,
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the desired product (R)-7 from benzaldehyde (3a) and acyl cyanide 2b was obtained with
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excellent er (99:1) and in good yield (62%), (Scheme 3).
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Scheme 3. Synthesis of (R)-7 via Minor Enantiomer Recycling
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To verify the absolute configuration at the C–O stereocenter of the products, the O-acylated
product 4a was cleaved by p-TsOH in EtOH to give cyanohydrin 5a (Scheme 4). This
cyanohydrin was then acetylated using acetic anhydride to give the known compound (R)-9.
Comparison of the sign of the optical rotation of (R)-9 with literature data27 unambiguously
confirmed the absolute configuration to be R. Products 4b–g and 7 were treated in the same way
to give the corresponding acetylated compounds. The HPLC retention order of the products
derived from 4b,28a 4c,28b and 4d28a were compared to literature data, which showed the absolute
configuration of the C–O stereocenter in all cases to be R. To assign the configuration of 4e,28c
4f,24c and 4g,28d the GC or HPLC retention times of the acetylated compounds were compared to
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samples known to have R configuration; these samples were obtained by previously described
enzyme-catalyzed hydrolysis of the racemic compounds. The GC retention time of the acetylated
compound derived from 7 was shown to be the same as that of (R)-9.
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Scheme 4. Synthesis of (R)-9 for Determination of Absolute Configuration
CONCLUSION
O-(-Bromoacyl) cyanohydrins with high diasteromeric purity were obtained by a one-step
recycling procedure consisting of acylcyanation of prochiral aldehydes and regeneration of
starting material from the minor, undesired diastereomers of the product. When the reverse
reaction, which is a kinetic resolution, is allowed to continue after terminated addition of acyl
cyanide, the two minor diastereomers are completely consumed. The O-(-bromoacyl)
cyanohydrins obtained were transformed to (R)-4-amino-2(5H)-furanones, which serve as
starting materials for a variety of biologically active compounds, in high yields. High
enantiomeric purities of the cyclized products were observed. This is particularly important for
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synthetic applications where no additional stereogenic centers are present in the target
compounds, since cumbersome separation of enantiomers is avoided.
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EXPERIMENTAL SECTION
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General. Dry dichloromethane and THF were taken from a Glass Contour solvent dispensing
system. Oven or flame dried glassware was used when necessary. (S,S)-[(4,6-
bis(tbutyl)salen)Ti(µ-O)]2 (1) was prepared according to a published procedure.21 Immobilized
(acrylic resin, >5000 U/g) Candida antarctica lipase B (CALB) and zinc powder (<10 µm) were
purchased from Sigma Aldrich. Benzaldehyde, 4-methoxybenzaldehyde, 4-methylbenzaldehyde,
(E)-2-butenal and pentanal were distilled, and 4-chlorobenzaldehyde and 4-bromobenzaldehyde
were recrystallized from EtOH/H2O 3:1 prior to use. 1H NMR spectra were recorded at 500 MHz
and 13C NMR spectra at 125 MHz. The 1H and 13C chemical shifts are reported in ppm relative to
residual CHCl3 or CD2HOD in CDCl3 and CD3OD, respectively. GC analyses were conducted
with a FID-detector and a chiral column (CYCLOSIL B, 30 m x 0.25 mm x 0.25 µm). HPLC
analyses were conducted with a UV-detector and chiral column (Daicel Chiralpak IC, 0.46 cm x
25 cm and Daicel Chiralcel OD-H, 0.46 cm x 25 cm).
2-Bromopropanoyl cyanide (2a). 2-Bromopropionyl bromide (4.0 mL, 38.2 mmol) was
added to a two-necked flask containing CuCN (3.87 g, 43.2 mmol) under nitrogen, the mixture
was stirred at 125 °C for 2 h 15 min. Vacuum distillation (~9 mbar) directly from the reaction
flask at 60 °C gave 2a (2.50 g, 40%) as a pale yellow liquid. 1H NMR (500 MHz, CDCl3): δ 4.56
(q, J = 6.8 Hz, 1 H), 1.89 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 170.5, 111.7, 46.4,
18.8.
General Procedure for the Minor Enantiomer Recycling. Aldehyde (1 equiv) and (S,S)-
[(salen)Ti(µ-O)]2 (5-10 mol %) (1) were dissolved in toluene, and CALB and phosphate buffer
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were added. The mixture was stirred at room temperature or 40 °C while acyl cyanide 2a (3
equiv), dissolved in toluene, was added to the organic phase over 24–50 h using a syringe pump.
When the addition was complete, the phases were separated and the aqueous phase was extracted
with Et2O. The combined organic phases were dried over MgSO4 and the solvents evaporated.
The crude product was purified by flash chromatography.
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(R)-Cyano(phenyl)methyl 2-bromopropanoate (4a). The general procedure was followed
using benzaldehyde (240 µL, 2.36 mmol), CALB (200 mg) and (S,S)-[(salen)Ti(µ-O)]2 (144 mg,
0.118 mmol) in toluene (10 mL) and 2M pH 6 buffer (10 mL) at 40 °C. 2a (1.15 g, 7.10 mmol)
in toluene (2.5 mL total volume) was added over 50 h. Flash chromatography (hexanes/EtOAc
39:1 to 19:1, Rf = 0.24 hexanes/EtOAc 19:1) gave 4a (406 mg, 64%, [(RS+RR)/(SR+SS)] =
99.4:0.6) as a colorless oil. HPLC (Daicel Chiralpak IC, hexanes/2-propanol 99.5:0.5, flow 0.6
ml/min, detection at 220 nm): tR (minor) 26.0 min, tR (major) 27.8 min, tR (minor) 31.1 min, tR
21
(major) 39.1 min; [α]D +7.4 (c 1.0, CHCl3); IR: 2965, 2360, 2343, 1760, 1210, 1142, 757, 696
cm-1; Mixture of diastereoisomers: 1H NMR (500 MHz, CDCl3): δ 7.52–7.57 (m, 2H), 7.45–7.51
(m, 3H), 6.44 and 6.45 (s, 1H), 4.43 and 4.41 (q, J = 6.9 Hz, 1H), 1.87 and 1.85 (d, J = 6.9 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ 168.6 and 168.5, 131.2 and 131.1, 130.9 and 130.8, 129.51
and 129.48, 128.1 and 127.9, 115.7 and 115.5, 64.3 and 64.2, 38.5 and 38.4, 21.4 and 21.3;
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C11H11BrNO2 267.9968; Found 267.9960.
(R)-Cyano(4-chlorophenyl)methyl 2-bromopropanoate (4b). The general procedure was
followed using 4-chlorobenzaldehyde (337 mg, 2.40 mmol), CALB (200 mg) and (S,S)-
[(salen)Ti(µ-O)]2 (146 mg, 0.120 mmol) in toluene (10 mL) and 2M pH 7 buffer (10 mL) at 40
°C. 2a (1.17 g, 7.25 mmol) in toluene (2.5 mL total volume) was added over 24 h. Flash
chromatography (hexanes/EtOAc 19:1 to 9:1, Rf = 0.24 hexanes/EtOAc 19:1) gave 4b (567 mg,
78%, [(RS+RR)/(SR+SS)] = 98.6:1.4) as a colorless oil. HPLC (Daicel Chiralpak IC and Daicel
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Chiralcel OD-H in series, hexanes/2-propanol 99:1, flow 0.4 ml/min, detection at 220 nm): tR
(major) 83.8 min, tR (minor) 114.7 min, tR (minor) 123.1 min, tR (major) 134.8 min; [α]D21 –3.0 (c
1.0, CHCl3); IR: 2978, 2931, 2360, 2342, 1757, 1494, 1140, 1093, 822 cm-1; Mixture of
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diastereoisomers: H NMR (500 MHz, CDCl3): δ 7.49 (d, J = 8.6 Hz, 2H), 7.44–7.47 (m, 2H),
6.42 and 6.40 (s, 1H), 4.43 and 4.40 (q, J = 6.9 Hz, 1H), 1.86 and 1.85 (d, J = 7.1 Hz, 3H); 13C
NMR (125 MHz, CDCl3): δ 168.5 and 168.3, 137.2 and 137.1, 129.82 and 129.80, 129.7 and
129.6, 129.5 and 129.3, 115.3 and 115.1, 63.6 and 63.5, 38.4 and 38.2, 21.4 and 21.3; HRMS
(ESI-Orbitrap) m/z: [M + Na]+ Calcd for C11H9BrClNO2Na 323.9397; Found 323.9390.
(R)-Cyano(4-methoxyphenyl)methyl 2-bromopropanoate (4c). The general procedure was
followed using 4-methoxybenzaldehyde (290 µL, 2.38 mmol), CALB (200 mg) and (S,S)-
[(salen)Ti(µ-O)]2 (290 mg, 0.238 mmol) in toluene (10 mL) and 2M pH 7 buffer (10 mL) at room
temperature. 2a (1.16 g, 7.15 mmol) in toluene (2.5 mL total volume) was added over 50 h. Flash
chromatography (first one separation with hexanes/EtOAc 9:1 then one with 100%
dichloromethane as eluent, Rf = 0.23 hexanes/EtOAc 9:1) gave 4c (452 mg, 64%,
[(RS+RR)/(SR+SS)] = ~98:2) as a pale yellow oil. HPLC (Daicel Chiralpak IC, hexanes/2-
propanol 99.5:0.5, flow 0.6 ml/min, detection at 220 nm): tR (major and minor overlapped) 42.1
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min, tR (minor) 54.4 min, tR (major) 59.5; [α]D –10.9 (c 1.0, CHCl3); IR: 2963, 2937, 2840,
2360, 2342, 1752, 1611, 1515, 1255, 1141, 831 cm-1; Mixture of diastereoisomers: 1H NMR (500
MHz, CDCl3): δ 7.47 (dd, J = 1.8, 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.39 and 6.38 (s, 1H),
4.40 and 4.38 (q, J = 6.9 Hz, 1H), 3.84 (s, 3H), 1.85 and 1.83 (d, J = 6.9 Hz, 3H); 13C NMR (125
MHz, CDCl3): δ 168.7 and 168.5, 161.51 and 161.47, 129.9 and 129.7, 123.2 and 123.1, 115.9
and 115.7, 114.80 and 114.79, 64.1 and 64.0, 55.60 and 55.59, 38.6 and 38.5, 21.40 and 21.35;
HRMS (ESI-Orbitrap) m/z: [M + Na]+ Calcd for C12H12BrNO3Na 319.9893; Found 319.9887.
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(R)-Cyano(4-bromophenyl)methyl 2-bromopropanoate (4d). The general procedure was
followed using 4-bromobenzaldehyde (178 mg, 0.963 mmol), (S,S)-[(salen)Ti(µ-O)]2 (58.4 mg,
0.0480 mmol) and CALB (80 mg) in toluene (4 mL) and 2M pH 7 buffer (4 mL) at room
temperature. 2a (465 mg, 2.87 mmol) in toluene (1 mL total volume) was added over 50 h. Flash
chromatography (hexanes/EtOAc 39:1 to 19:1, Rf = 0.32 hexanes/EtOAc 19:1) gave 4d (266 mg,
80%, [(RS+RR)/(SR+SS)] = 96.1:3.9) as a colorless oil. HPLC (Daicel Chiralpak IC and Daicel
Chiralcel OD-H in series, hexanes/2-propanol 98.5:1.5, flow 0.4 ml/min, detection at 220 nm): tR
(major) 75.1 min, tR (minor) 99.6 min, tR (minor) 106.1 min, tR (major) 121.2 min; [α]D21 –5.0 (c
0.66, CHCl3); IR: 2961, 2931, 2360, 2343, 1756, 1490, 1140, 1073, 871 cm-1; Mixture of
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diastereoisomers: H NMR (500 MHz, CDCl3): δ 7.60–7.63 (m, 2H), 7.41–7.44 (m, 2H), 6.40
and 6.39 (s, 1H), 4.42 and 4.40 (q, J = 6.9 Hz, 1H), 1.86 and 1.85 (d, J = 7.1 Hz); 13C NMR (125
MHz, CDCl3): δ 168.5 and 168.3, 132.79 and 132.77, 130.2 and 130.1, 129.6 and 129.5, 125.4
and 125.3, 115.2 and 115.1, 63.7 and 63.5, 38.4 and 38.1, 21.4 and 21.3; HRMS (ESI-Orbitrap)
m/z: [M + H]+ Calcd for C11H10Br2NO2 347.9052; Found 347.9041.
(R)-Cyano(4-methylphenyl)methyl 2-bromopropanoate (4e). The general procedure was
followed using 4-methylbenzaldehyde (285 µL, 2.42 mmol), CALB (201 mg) and (S,S)-
[(salen)Ti(µ-O)]2 (147 mg, 0.121 mmol) in toluene (10 mL) and 2M pH 7 buffer (10 mL) at 40
°C. 2a (1.18 g, 7.32 mmol) in toluene (2.5 mL total volume) was added over 50 h. Flash
chromatography (hexanes/dichloromethane 1:1, Rf = 0.38) gave 4e (466 mg, 68%,
[(RS+RR)/(SR+SS)] = 97.2:2.8) as a colorless oil. HPLC (Daicel Chiralpak IC and Daicel
Chiralcel OD-H in series, hexanes/2-propanol 99:1, flow 0.4 ml/min, detection at 220 nm): tR
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(major) 63.2 min, tR (minor) 84.8 min, tR (major) 88.2 min, tR (minor) 96.0 min; [α]D –0.88 (c
1.0, CHCl3); IR: 2978, 2928, 2360, 2343, 1755, 1209, 1142, 814 cm-1; Mixture of
1
diastereoisomers: H NMR (500 MHz, CDCl3): δ 7.43 (d, J = 7.0 Hz, 2H), 7.27 (d overlapped
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with CHCl3, 2H), 6.41 and 6.40 (s, 1H), 4.41 and 4.39 (q, J = 6.9 Hz, 1H), 2.40 (s, 3H), 1.84 and
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1.86 (d, J = 6.9 Hz, 3H); C NMR (125 MHz, CDCl3): δ 168.6 and 168.5, 141.2 and 141.1,
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130.14 and 130.12, 128.3 and 128.14, 128.09 and 127.9, 115.8 and 115.6, 64.3 and 64.2, 38.6 and
38.5, 21.5, 21.40 and 21.35; HRMS (ESI-Orbitrap) m/z: [M + Na]+ Calcd for
C12H12BrNO2Na 303.9944; Found 303.9938.
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(R)-1-Cyano-[(E)-1-propenyl]methyl 2-bromopropanoate (4f). The general procedure was
followed using (E)-2-butenal (200 µL, 2.41 mmol), CALB (201 mg) and (S,S)-[(salen)Ti(µ-O)]2
(147 mg, 0.121 mmol) in toluene (10 mL) and 2M pH 7 buffer (10 mL) at 40 °C. 2a (1.18 g, 7.32
mmol) in toluene (2.5 mL total volume) was added over 50 h. Flash chromatography
(hexanes/EtOAc 9:1, Rf = 0.39) gave 4f (284 mg, 51%, [(RS+RR)/(SR+SS)] = 97.4:2.6) as an
orange oil. GC-FID (CYCLOSIL B, flow 1.0 ml/min, 60 °C for 10 min, 5 °C/min to 100 °C, hold
30 min, 0.5 °C/min to 122 °C): tR (major) 84.0 min, tR (major) 86.4 min, tR (minor) 88.1 min, tR
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(minor) 89.6 min; [α]D –12.5 (c = 1.0, CHCl3); IR: 2979, 2948, 2360, 2343, 1752, 1144 cm-1;
Mixture of diastereoisomers: 1H NMR (500 MHz, CDCl3): δ 6.23 (dq, J = 6.7, 13.5 Hz, 1H), 5.83
(dd, J = 6.0, 11.9 Hz, 1H), 5.60 (split dd, J = 6.8, 15.3 Hz, 1H), 4.39 and 4.38 (q, J = 6.9 Hz, 1H),
1.86 (d, J = 7.0 Hz, 3H), 1.83 (dd, J = 0.7, 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 168.6
and 168.5, 136.9 and 136.8, 120.8 and 120.6, 115.3 and 115.1, 62.9 and 62.8, 38.6 and 38.5,
21.44 and 21.40, 17.9; HRMS (ESI-Orbitrap) m/z: [M
C8H10BrNO2Na 253.9787; Found 253.9777.
+
Na]+ Calcd for
(R)-1-Cyanohexyl 2-bromopropanoate (4g). Pentanal (255 µL, 2.40 mmol) and (S,S)-
[(salen)Ti(µ-O)]2 (146 mg, 0.120 mmol) were dissolved in toluene (10 mL), and CALB (200 mg)
and 2M pH 7 buffer (10 mL) were added. The mixture was stirred at room temperature while 2a
(1.17 g, 7.22 mmol) in toluene (2.5 mL total volume) was added over 8 h using a syringe pump.
After the addition was finished, the mixture was allowed to continue stirring. After 17 h another
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portion of CALB (100 mg) was added and the stirring was continued for 7 h. The phases were
separated and the aqueous phase was extracted with Et2O. The combined organic phases were
dried over MgSO4 and the solvents evaporated. The crude product was purified by flash
chromatography (petroleum ether/EtOAc 19:1, Rf = 0.47) to give 4g (384 mg, 65%,
[(RS+RR)/(SR+SS)] = 99.0:1.0) as a pale yellow oil. GC-FID (CYCLOSIL B, flow 2.0 ml/min, 60
°C for 10 min, 10 °C/min to 100 °C, hold 10 min, 1 °C/min to 150 °C): tR (major) 56.0 min, tR
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(major) 57.2 min, tR (minor) 58.0 min, tR (minor) 60.0 min; [α]D +48.0 (c 1.0, CHCl3); IR:
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2960, 2934, 2873, 1755, 1212, 1150 cm-1; Mixture of diastereoisomers: H NMR (500 MHz,
CDCl3): δ 5.37 and 5.36 (t, J = 6.8 Hz, 1H), 4.40 and 4.39 (q, J = 6.9 Hz, 1H), 1.94-1.98 (m, 2
H), 1.86 and 1.85 (d, J = 6.9 Hz, 3H), 1.47–1.55 (m, 2H), 1.40 (sextet, J = 7.3 Hz, 2H), 0.94 (t, J
= 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 168.9 and 168.7, 116.5 and 116.3, 62.6 and 62.5,
38.7 and 38.4, 31.99, 26.62 and 26.56, 22.05 and 22.03, 21.5 and 21.3, 13.9; HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C9H15BrNO2 248.0281; Found 248.0272.
General Procedure for the Blaise Cyclisation. The Zn powder was activated prior to use by
washing with 3 M HCl (aq.), distilled water until neutral, acetone, and dry Et2O. The activated Zn
was dried under vacuum at 100 °C and stored under nitrogen.
Activated Zn and THF were added to a vial under nitrogen and the vial was sealed. The
mixture was stirred at 65 °C in an oil bath while 4 dissolved in THF was added dropwise using a
syringe. When the reaction was finished, the mixture was cooled to –78 °C and NH4Cl (aq. sat.)
was added. The mixture was allowed to reach room temperature and was then extracted with
EtOAc. The combined organic phases were dried over MgSO4 and the solvents evaporated. The
crude product was purified by flash chromatography.
(R)-4-Amino-3-methyl-5-phenylfuran-2(5H)-one (6a). The general procedure was followed
using Zn (146 mg, 2.24 mmol) in THF (0.3 mL) and 4a (201 mg, 0.750 mmol) in THF (0.15+0.1
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mL). NH4Cl (aq. sat.) (0.3 mL) was added after 2 h reaction. Flash chromatography
(hexanes/EtOAc 1:4, Rf = 0.46) gave 6a (122 mg, 86%, 98.6:1.4 er) as a white solid. Mp = 160–
172 °C; GC-FID (CYCLOSIL B, flow 2.0 ml/min, 60 °C for 1 min, 10 °C/min to 100 °C, hold 5
min, 5 °C/min to 200 °C, hold 45 min): tR (major) 68.3 min, tR (minor) 73.1 min; [α]D20 –98.5 (c
1.3, EtOH); IR: 3444, 3304, 3193, 1716, 1646, 1617 cm-1; 1H NMR (500 MHz, CD3OD): δ 7.38–
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7.43 (m, 3H), 7.30–7.32 (m, 2H), 5.64 (s, 1H), 1.72 (s, 3H); C NMR (125 MHz, CD3OD): δ
179.2, 168.4, 137.4, 130.4, 129.9, 128.5, 89.6, 81.1, 6.2; HRMS (ESI-Orbitrap) m/z: [M + H]+
Calcd for C11H12NO2 190.0863; Found 190.0854.
(R)-4-Amino-5-(4-chlorophenyl)-3-methylfuran-2(5H)-one (6b). The general procedure
was followed using Zn (132 mg, 2.02 mmol) in THF (0.3 mL) and 4b (200 mg, 0.662 mmol) in
THF (0.15+0.15 mL). NH4Cl (aq. sat.) (0.2 mL) was added after 1.5 h reaction. Flash
chromatography (hexanes/EtOAc 1:2, Rf = 0.43) gave 6b (144 mg, 97%, 98.4:1.6 er) as a white
solid. Mp = 132-140 °C; HPLC (Daicel Chiralcel OD-H, hexanes/2-propanol 85:15, flow 0.6
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ml/min, detection at 254 nm): tR (minor) 24.1 min, tR (major) 58.8 min; [α]D –94.3 (c 1.0,
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EtOH); IR: 3459, 3297, 3198, 1720, 1635, 1610, 1597 cm-1; H NMR (500 MHz, CD3OD): δ
7.40–7.43 (m, 2H), 7.29–7.32 (m, 2H), 5.64 (s, 1H), 1.71 (s, 3H); 13C NMR (125 MHz, CD3OD):
δ 178.9, 168.0, 136.3, 136.2, 130.1, 130.0, 89.8, 80.2, 6.2; HRMS (ESI-Orbitrap) m/z: [M + H]+
Calcd for C11H11ClNO2 224.0473; Found 224.0468.
(R)-4-Amino-5-(4-methoxyphenyl)-3-methylfuran-2(5H)-one (6c). The general procedure
was followed using Zn (140 mg, 2.14 mmol) in THF (0.3 mL) and 4c (206 mg, 0.691 mmol) in
THF (0.15+0.15 mL). NH4Cl (aq. sat.) (0.2 mL) was added after 2 h reaction. Flash
chromatography (hexanes/EtOAc 1:4, Rf = 0.41) gave 6c (149 mg, 98%, 97.9:2.1 er) as a
colorless gum. HPLC (Daicel Chiralcel OD-H, hexanes/2-propanol 85:15, flow 0.6 ml/min,
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detection at 254 nm): tR (minor) 36.6 min, tR (major) 74.7 min; [α]D –54.0 (c 1.1, EtOH); IR:
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3344, 3213, 2936, 1723, 1646, 1610, 1515 cm-1; H NMR (500 MHz, CD3OD): δ 7.22–7.24 (m,
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2H), 6.94–6.96 (m, 2H), 5.59 (s, 1H), 3.80 (s, 3H), 1.71 (s, 3H); 13C NMR (125 MHz, CD3OD): δ
179.2, 168.4, 162.0, 130.0, 129.1, 115.3, 89.8, 80.9, 55.8, 6.2; HRMS (ESI-Orbitrap) m/z: [M +
H]+ Calcd for C12H14NO3 220.0968; Found 220.0963.
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(R)-4-Amino-5-(4-bromophenyl)-3-methylfuran-2(5H)-one (6d). The general procedure
was followed using Zn (42.2 mg, 0.645 mmol) in THF (0.1 mL) and 4d (75.0 mg, 0.215 mmol)
in THF (0.1 mL). Additional THF (0.3 mL) was added to facilitate stirring during the reaction.
NH4Cl (aq. sat.) (0.2 mL) was added after 4.5 h reaction. Flash chromatography (hexanes/EtOAc
1:2, Rf = 0.38) gave 6d (42.1 mg, 73%, 97.3:2.7 er) as a white solid. Mp = 170–180 °C; HPLC
(Daicel Chiralcel OD-H, hexanes/2-propanol 85:15, flow 0.6 ml/min, detection at 254 nm): tR
(minor) 23.5 min, tR (major) 58.4 min; [α]D22 –88.3 (c 0.20, EtOH); IR: 3452, 3293, 3193, 1731,
1720, 1634, 1610, 1591 cm-1; 1H NMR (500 MHz, CD3OD): δ 7.56 (d, J = 8.4 Hz, 2H), 7.24 (d,
J = 8.4 Hz, 2H), 5.63 (s, 1H), 1.71 (s, 3H); 13C NMR (125 MHz, CD3OD): δ 178.9, 168.0, 136.7,
133.1, 130.4, 124.2, 89.7, 80.2, 6.24; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C11H11BrNO2 267.9968; Found 267.9966.
(R)-4-Amino-3-methyl-5-(4-methylphenyl)furan-2(5H)-one (6e). The general procedure
was followed using Zn (140 mg, 2.14 mmol) in THF (0.3 mL) and 4e (201 mg, 0.714 mmol) in
THF (0.15+0.15 mL). NH4Cl (aq. sat.) (0.3 mL) was added after 2 h reaction. Flash
chromatography (hexanes/EtOAc 1:4, Rf = 0.42) gave 6e (134 mg, 93%, 97.3:2.7 er) as a
colorless gum. HPLC (Daicel Chiralcel OD-H, hexanes/2-propanol 85:15, flow 0.6 ml/min,
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detection at 254 nm): tR (minor) 22.4 min, tR (major) 56.4 min; [α]D –74.3 (c 1.0, EtOH); IR:
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3342, 3212, 2922, 1725, 1652, 1646 cm-1; H NMR (500 MHz, CD3OD): δ 7.22 (d, J = 8.1 Hz,
2H), 7.17–7.20 (m, 2H), 5.60 (s, 1H), 2.35 (s, 3H), 1.71 (s, 3H); 13C NMR (125 MHz, CD3OD): δ
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179.3, 168.5, 140.5, 134.3, 130.5, 128.5, 89.6, 81.0, 21.3, 6.2; HRMS (ESI-Orbitrap) m/z: [M +
H]+ Calcd for C12H14NO2 204.1019; Found 204.1012.
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(R)-4-Amino-3-methyl-5-((E)-prop-1-en-1-yl)furan-2(5H)-one (6f). The general procedure
was followed using Zn (220 mg, 3.36 mmol) in THF (0.3 mL) and 4f (154 mg, 0.665 mmol) in
THF (0.15+0.15 mL). NH4Cl (aq. sat.) (0.2 mL) was added after 2 h reaction. Flash
chromatography (hexanes/EtOAc 1:4, Rf = 0.37) gave 6f (95.5 mg, 94%, 95.4:4.6 er) as a yellow
gum. GC-FID (CYCLOSIL B, flow 1.0 ml/min, 60 °C for 10 min, 10 °C/min to 100 °C, hold 5
min, 3 °C/min to 200 °C, hold 20 min): tR (major) 63.8 min (E+Z), tR (minor) 64.4 min (Z) and
65.2 min (E); [α]D22 –36.5 (c 1.1, EtOH); IR: 3346, 3215, 1724, 1652, 1646 cm-1; 1H NMR (500
MHz, CD3OD): δ 6.00 (dq, J = 6.6, 13.2 Hz, 1H), 5.34 (ddq, J = 1.7, 8.0, 15.2 Hz, 1H), 5.04 (d, J
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= 8.0 Hz, 1H), 1.77 (dd, J = 1.6, 6.6 Hz, 3H), 1.62 (s, 3H); C NMR (125 MHz, CD3OD): δ
179.0, 168.3, 134.2, 127.3, 88.9, 80.3, 17.9, 6.2; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C8H12NO2 154.0863; Found 154.0856.
(R)-4-Amino-5-butyl-3-methylfuran-2(5H)-one (6g). The general procedure was followed
using Zn (150 mg, 2.29 mmol) in THF (0.2 mL) and 4g (190 mg, 0.766 mmol) in THF (0.2+0.2
mL). NH4Cl (aq. sat.) (0.6 mL) was added after 4 h reaction. Flash chromatography (petroleum
ether/EtOAc 1:3, Rf = 0.44) gave 6g (91.9 mg, 71%, 98.8:1.2 er) as a colorless oil. GC-FID
(CYCLOSIL B, flow 2.0 ml/min, 60 °C for 1 min, 10 °C/min to 100 °C, hold 5 min, 5 °C/min to
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180 °C, hold 60 min): tR (major) 57.9 min, tR (minor) 59.1 min; [α]D +26.9 (c 1.0, EtOH); IR:
3347, 3217, 2957, 2931, 1716, 1647, 1616 cm-1; 1H NMR (500 MHz, CDCl3): δ 4.68 (split d, J =
5.1 Hz, 1H), 4.44 (bs, 1H), 4.38 (bs, 0.6 H), 1.82-1.90 (m, 1H), 1.67 (s, 3H), 1.51-1.58 (m, 1H),
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1.30-1.45 (m, 4H), 0.90 (t, J = 7.1 Hz, 3H); C NMR (125 MHz, CDCl3): δ 175.6, 163.5, 93.2,
77.5, 32.7, 26.3, 22.6, 14.0, 6.4; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C9H16NO2 170.1176; Found 170.1169.
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(R)-Cyano(phenyl)methyl 2-bromoacetate (7). Benzaldehyde (150 µL, 1.48 mmol) and
(S,S)-[(salen)Ti(µ-O)]2 (90 mg, 0.074 mmol) were dissolved in toluene (6 mL), and CALB (123
mg) and 1M pH 8 buffer (6 mL) were added. 2b (1.10 g, 7.43 mmol) dissolved in cyclopentyl
methyl ether (1.58 mL total volume) was added to the organic phase over 50 h at 40 °C. When
the addition was finished the phases were separated and the organic phase was extracted with
Et2O. The combined organic phases were dried over MgSO4 and the solvents evaporated. The
crude product was purified by flash chromatography (hexanes/EtOAc 9:1, Rf = 0.28) to give 7
(233 mg, 62%, 99:1 er) as a pale yellow oil. GC-FID (CYCLOSIL B, flow 2.0 ml/min, 60 °C for
10 min, 20 °C/min to 100 °C, hold 5 min, 5 °C/min to 160 °C, hold 32 min): tR (major) 52.4 min,
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tR (minor) 58.0 min; [α]D –4.1 (c 1.0, CHCl3); IR: 3036, 2960, 2360, 2342, 1756, 1255, 1131,
1
761, 697 cm-1; H NMR (500 MHz, CDCl3): δ 7.52–7.56 (m, 2H), 7.46–7.51 (m, 3H), 6.45 (s,
1H), 3.92 (A-part of AB, J = 12.7 Hz, 1H), 3.90 (B-part of AB, J = 12.7 Hz, 1H); 13C NMR (125
MHz, CDCl3): δ 165.6, 131.1, 130.9, 129.5, 128.1, 115.5, 64.5, 24.5; HRMS (ESI-Orbitrap) m/z:
[M + Na]+ Calcd for C10H8BrNO2Na 275.9631; Found 275.9619.
(R)-2-Hydroxy-2-phenylacetonitrile (5a). Compound 4a (47.5 mg, 0.177 mmol) was
dissolved in EtOH (1.1 mL), p-TsOH·H2O (41.0 mg, 0.216 mmol) was added and the solution
was stirred at room temperature. After four days the solvent was evaporated. The crude product
was purified by flash chromatography (hexanes/EtOAc 9:1, Rf = 0.25) to give 5a (13.6 mg, 58%)
as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.53–7.57 (m, 2H), 7.43–7.49 (m, 3H), 5.56 (d,
J = 7.0 Hz, 1H), 2.54 (d, J = 7.2 Hz, 1H).
(R)-Cyano(phenyl)methyl acetate (9). Compound 5a (13.6 mg, 0.102 mmol) was dissolved
in dichloromethane (0.2 mL). Acetic anhydride (20 µL, 0.21 mmol), pyridine (25 µL, 0.31
mmol), and DMAP (1.3 mg, 0.011 mmol) were added to the solution which was stirred at room
temperature for 30 min. NH4Cl (aq. sat.) was added and the aqueous phase was extracted with
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dichloromethane. The combined organic phases were dried over MgSO4 and the solvent was
evaporated. The crude product was purified by flash chromatography (hexanes/EtOAc 9:1, Rf =
0.36) to give 9 (8.0 mg, 45%, 99.4:0.6 er) as a colorless oil. GC-FID (CYCLOSIL B, flow 2.0
ml/min, 60 °C for 10 min, 10 °C/min to 100 °C, hold 5 min, 5 °C/min to 200 °C, hold 1 min): tR
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(major) 31.4 min, tR (minor) 32.9 min; [α]D +4.9 (c 0.54, CHCl3) (lit.27 [α]D +4.5 (c 1.8,
1
CHCl3, >99% ee)); H NMR (500 MHz, CDCl3): δ 7.50–7.54 (m, 2H), 7.43–7.48 (m, 3H), 6.42
(s, 1H), 2.17 (s, 3H).
ASSOCIATED CONTENTS
Supporting Information
Copies of 1H NMR and 13C NMR spectra of all compounds, GC and HPLC chromatograms of
enantioenriched compounds and hydrolysis curves for 4g and a graph showing product formation
and changes in ee over time in the reaction with 4g with gradual decrease in addition rate of 2a.
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
*E-mail: kimo@kth.se
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
Financial support from the Swedish Research Council (grant 621-2012-3391) is gratefully
acknowledged. We are grateful to Inanllely Gonzalez, Alexis Bordet, and Robin Lafficher for
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their skillful experimental work, and to professor Karl Hult, Department of Biochemistry, KTH,
for valuable discussions.
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