The dynamic kinetic resolution of azlactones with thiol nucleophiles catalyzed by arylated, deoxygenated cinchona alkaloids

Article abstract of DOI:10.1021/jo202662d

A significant improvement of the available organocatalytic methods (in terms of product substrate scope and product enantiomeric excess) for the generation of enantioenriched α-amino acid thioesters via the dynamic kinetic resolution of azlactones is reported. C-9 arylated cinchona alkaloid catalysts have been found to be considerably superior to other bifunctional alkaloid catalysts as the promoters of this asymmetric process.

Full text of DOI:10.1021/jo202662d

Article
pubs.acs.org/joc
The Dynamic Kinetic Resolution of Azlactones with Thiol
Nucleophiles Catalyzed by Arylated, Deoxygenated Cinchona
Alkaloids
Zaida Rodríguez-Docampo, Cormac Quigley, Sean Tallon, and Stephen J. Connon*
School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity Biomedical Sciences Institute, University of Dublin,
Trinity College, Dublin 2, Ireland
S
* Supporting Information
ABSTRACT: A significant improvement of the available organo-
catalytic methods (in terms of product substrate scope and product
enantiomeric excess) for the generation of enantioenriched α-amino
acid thioesters via the dynamic kinetic resolution of azlactones is
reported. C-9 arylated cinchona alkaloid catalysts have been found
to be considerably superior to other bifunctional alkaloid catalysts as
the promoters of this asymmetric process.
alcohols are ostensibly quite similar, the considerably higher
acidity and longer bond lengths associated with thiols make
them considerably more challenging substrates in this reaction.
However, it is still perhaps surprising that no highly effective
method of thiolysis has been established, given the potential
application of such a process to the synthesis of enantioen-
riched peptide thioesters for native chemical ligation (NCL), a
well-established coupling technique used to construct large
peptide structures through the coupling of two smaller peptides
via the reaction between N-terminal cysteine and C-terminal
thioester units (usually derived from either aromatic or primary
alkyl thiols), followed by an S → N acyl shift.8 One of the
challenges associated with NCL is the synthesis of the peptidic
thioesters,9 which is sometimes accompanied by epimerization
at the amino acid derived α-chiral center via either azlactone
formation or enolization of the relatively acidic (when com-
pared to ester or amide analogues) thioester.10,11 This compro-
mises the process and limits the practical application of the
archetypal NCL reaction to coupling at faster reacting, less
hindered amino acid thioesters (e.g., Ala or the achiral Gly) at
the C-terminal partner. Undoubtedly, the synthesis of peptide
thioesters for use in NCL is still an unsolved problem, and
numerous examples aimed at the circumvention of this issue
have recently appeared.8d−i,9
INTRODUCTION
■
The catalytic dynamic kinetic resolution (DKR) of
α-substituted azlactones by alcoholysis is a valuable route for
the facile, enantioselective synthesis of N-protected α-amino
acid derivatives.1 In this process, one enantiomer of the racemic
azlactone reacts preferentially (in the presence of a chiral cata-
lyst) with the alcohol. The acidity of the α-hydrogen of the
azlactone (pKa ∼ 9, H2O, 25 °C)2 allows the continuous
regeneration of the fast reacting azlactone enantiomer, if the
catalyst is capable of accelerating the rate of racemization to a
greater degree than the alcoholysis of the slow reacting azlactone
enantiomer (i.e., kfast ≫ kslow and krac ≫ kslow, Scheme 1).
Scheme 1. DKR of Azlactones
Exploratory attempts to perform DKR on azlactones by
thiolysis were performed in 2008 using urea-based catalyst 2
(Scheme 2).6e,12 Under optimized conditions (which result in
Whereas the selective DKR of azlactones with alcohols
has been widely studied, leading to the disclosure of several
examples of very efficient processes, including the use of
enzymes,3 Ti-complexes,4 and organocatalysts,5−7 the thiolysis
of azlactones still remains relatively unexplored. While thiols and
Received: January 11, 2012
Published: February 22, 2012
© 2012 American Chemical Society
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distance/relative orientations of the quinuclidine base and the
hydrogen-bond-donating phenolic hydroxyl groups can be
systematically varied), of which 7, 8, and 9 are representative.
These materials were found to be capable of promoting the
selective DKR of azlactones using allyl alcohol as the nucleo-
phile, with levels of product ee up to 92% possible.6g Since
these promoters possess distinct steric- and hydrogen-bond-
donating/accepting characteristics to either 2 or 5, yet have
been shown to be catalytically competent in azlactone DKR
processes, we were encouraged to investigate their potential
for application to the formation of enantiomerically enriched
thioesters by DKR.
Scheme 2. The First Example of the DKR of Azlactones
Mediated by Thiols
The catalysts were evaluated in the addition of the primary
thiol 4 to the alanine-derived azlactone 1 in dichloromethane.
This has traditionally proven to be a particularly challenging
substrate due to the relatively small steric requirement of the
methyl moiety at the acidic α-carbon. In our previous alcohol-
ysis study,6g we observed that the steric and electronic nature of
the product N-protecting group13 has a profound influence
over both the rate and the enantioselectivity of the DKR process
catalyzed by amines, such as 7−9. It was, therefore, considered
prudent to include azlactones 10, 11, and 12 (which incor-
porate relatively electron-deficient, electron-rich, and hetero-
cyclic aromatic functionalities, respectively) in our preliminary
survey (Table 1).
high levels of product ee in the corresponding alcoholysis
reactions), the DKR of alanine-derived azlactone 1 with cyclo-
hexanethiol catalyzed by the bifunctional urea-based catalyst 2
resulted in the formation of thioester 3 in 50% ee at ambient
temperature (64% ee was possible at −30 °C). This repre-
sented the first example of this class of reaction. However, the
requirement for the use of a secondary thiol (lower enantio-
selectivity resulted with more synthetically useful primary thiol
nucleophiles) and low reaction temperatures limited possible
future application of the method.
Table 1. Initial Substrate and Catalyst Screening
RESULTS AND DISCUSSION
■
In a preliminary attempt to improve the efficacy of this process,
we evaluated the DKR of azlactone 1 with the benzyl thiol 4
catalyzed by 5: the benchmark literature catalyst developed by
Song et al.6f for the DKR of azlactones by alcoholysis (Scheme 3).
Scheme 3. DKR by Thiolysis Catalyzed by Squaramide 5
a
b
entry
azlactone
catalyst
conv. (%)
ee (%)
abs. config.
1
2
1
1
7
8
9
7
8
9
7
8
9
7
8
9
5
8
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
25
20
17
16
35
8
S
R
S
S
R
S
S
R
S
3
1
4
10
10
10
11
11
11
12
12
12
12
12
5
6
Under identical conditions to those outlined in Scheme 2,
efficient, but largely unselective, catalysis was observed. Given
the failure of the known (thio)urea and squaramide-based
bifunctional organocatalysts for alcoholysis reactions to mediate
the analogous thiolysis chemistry selectively, it seemed clear
that, in order to improve the utility of the thiolysis protocol, a
significant departure in terms of catalyst design was required.
Recently, we developed a small library (nine members) of
cinchona alkaloid-based catalysts. These are characterized by
the presence of a phenolic substituent at C-9 (in which the
7
20
15
11
0
8
9
10
11
12
13
43
4
R
S
10
S
c
14
>98
53
R
a
b
Determined by 1H NMR spectroscopy. Determined by CSP-HPLC.
c
Reaction carried out at an equilibrated temperature of 19−20 °C.
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The thiolysis of 1 with 4 (which does not occur in the
absence of catalyst) proceeded smoothly and cleanly to full
conversion in the presence of 10 mol % 7−9 with low levels of
enantiomeric excess (entries 1−3). We were pleased to observe
that (as was the case in the alcoholysis study) that a degree of
conformational control over the stereochemical outcome of the
reaction was possible:6g that is, catalysts 7 and 8 (both quinine-
derived) promote the thiolysis reaction to furnish 6 with similar
levels of product ee; however, while 7 favors (S)-6 (entry 1),
catalysis involving the 1,2-substituted naphthol derivative 8
leads to preferential formation of the (R)-product antipode
(entry 2). While the same trends were observed in reactions
involving the activated and deactivated azlactones 10 and 11,
respectively, no significant general increase in the enantio-
selectivity of the process was discernible (entries 4−9). However,
the analogous reactions involving the N-furyl-substituted azlac-
tone 12 were intriguing. While catalysts 7 and 9 appear not
to efficiently differentiate between the enantiomers of (rac)-12
(entries 10 and 12), the 1,2-naphthol 8 promoted the same
reaction with 43% ee. Interestingly, this recognition appears to
be confined to catalyst 8: the same reaction promoted by
the squaramide catalyst 5 resulted in poor product ee (entry
13). We also observed that the enantioselectivity of the reaction
of 12 with 4 catalyzed by 8 exhibited subtle temperature
dependencecareful equilibration of the temperature between
19 and 20 °C led to an increase in product ee from 43 to 53%
(entries 11 and 14).
With the optimum catalyst and N-protecting group identi-
fied, the optimization of the reaction conditions was then
undertaken (Table 2). Starting with the best conditions iden-
tified in our preliminary study (entry 1), it was found that
carrying out the reaction at either lower or higher tempera-
tures reduces the enantioselectivity of the process (entries 2−4).
Using fewer equivalents of the nucleophile led to slower
conversion and slightly lower product ee (entry 5), while varia-
tion of either the catalyst loading (entries 6−7) or the reaction
solvent (entries 8−10) also failed to impact the enantio-
selectivity positively. Dilution of the reaction did allow for more
effective DKR (entries 11−14): the product ee increased
significantly from 53% at 0.4 M in dichloromethane solvent
(entry 1) to 73% ee at 0.04 M (entry 12). This concentration
proved optimalfurther dilution resulted in longer reaction
times (entries 13−14). It is noteworthy that, under these
optimized conditions, the thiolysis process is considerably more
enantioselective (using a more NCL compatible thiol at lower
loadings) at ambient temperature than the literature benchmark
reaction, which was carried out at −30 °C.
The scope of the method was next probed through the
thiolytic DKR of other amino acid derived azlactones (Table 3).
Emphasis was placed on the investigation of substrates derived
from α-unbranched amino acids more usually employed at the
C-terminus of a peptide coupling partner in NCL processes.
Gratifyingly, the thiolysis of azlactones derived from racemic
versions of the naturally occurring amino acids alanine, phenyl-
alanine, methionine, and leucine resulted in the formation of
the N-furoyl amino acid thioesters 15−18, respectively, in
good to excellent isolated yield and 66−73% ee (entries 1−4).
The synthesis of thioesters 19−21 formally derived from un-
natural amino acids was also possible (entries 5−7) with similar
enantioselectivity. We also evaluated the considerably more
hindered (and less practical from the standpoint of application
to NCL) valine-derived azlactone variantthis served as a very
poor substrate, which converted to 22 slowly and with low
levels of enantiodiscrimination (entry 8).
While the absolute configuration at the stereocenter in
these thiolysis products is the same as that obtained in our
earlier alcoholysis study, it is interesting to note that the
sensitivity of the catalyst to steric bulk at the α-carbon (i.e.,
higher levels of product ee from less-hindered substrates) is
the opposite of that observed with an allyl alcohol as the
nucleophile. This strongly suggests that the pretransition state
assemblies of the thiolysis and alcoholysis DKR processes
catalyzed by 8 may be analogous, but far from identical,15
which leads to the conclusion that these two reactions must be
studied separately.
Table 2. Optimization of the Reaction Conditions
a
b
entry
1
concn (M)
solvent
X (equiv)
Y (mol %)
time (h)
conv. (%)
ee (%)
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.1
0.04
0.02
0.01
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MTBE
PhMe
2
2
2
2
1
2
2
2
2
2
2
2
2
2
10
10
10
10
10
5
20
26
>98
>98
>98
>98
80
53
12
36
45
42
38
42
21
35
21
56
73
71
69
c
2
d
3
21
e
4
21
5
6
20
20
>98
>98
85
7
20
10
10
10
10
10
10
10
20
8
21
9
48
23
10
11
12
13
14
CDCl3
CH2Cl2
CH2Cl2
CH2Cl2
48
50
20
93
70
72
120
120
50
CH2Cl2
30
a
b
c
d
e
1
Determined by H NMR spectroscopy. Determined by CSP-HPLC. Reaction at −25 °C. Reaction at 0 °C. Reaction at 30 °C.
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Table 3. Substrate Scope Evaluation
a
b
Isolated yields. Determined by CSP-HPLC.
To eliminate the possibility that the catalyst is capable
the asymmetric induction derives only from the DKR addition
process. It, therefore, seems likely that, if the enantioselectivity
of these reactions can be improved, catalysts, such as 8,
could hold promise for the in situ generation of thioesters
for the synthesis of hydrophobic proteins via NCL in organic
solvents.14
of influencing the product absolute configuration through
thioester deprotonation/reprotonation, (rac)-15 was exposed
to the catalyst (10 mol %) and the thiol 4 (1.0 equiv) in
CH2Cl2 (0.04 M) for 70 h at ambient temperature: no change
in the thioester ee was detected. Thus, it can be inferred that
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(m, 1H), 6.64 (dd, 1H, J2 = 3.4, 1.5 Hz), 7.15 (d, 1H, J2 = 3.4 Hz),
7.20−7.23 (m, 1H), 7.26−7.34 (m, 4H), 7.87 (bs, 1H), 8.58 (d, 1H,
J2 = 8.3 Hz), 12.90 (bs, 1H); 13C NMR (100 Hz, d6-DMSO) δ 37.0,
54.3, 112.8, 114.8, 127.4, 129.2, 130.0, 139.0 (C), 146.2, 148.3 (C),
158.7 (C), 173.9 (C); IR (neat) νmax/cm−1 3328, 2820, 2516, 1916,
1727, 1608, 1593, 1566, 1530, 1353, 1253, 1232, 1196, 988, 763,
752, 697; HRMS (ESI) m/z calculated for C14H13NNaO4, [M + Na]+
282.0742; found, 282.0737.
CONCLUSION
■
Where “traditional” urea- and squaramide-based cinchona
alkaloid derived organocatalystswhich mediate highly selec-
tive DKR reactions of azlactones with alcohol nucleophiles
failed to promote the DKR of azlactones by thiolysis (with
unhindered thiols) with synthetically useful levels of product ee,
it has been found that the recently reported C-9 arylated
phenolic variants are capable of promoting the most enantio-
selective DKR reactions of azlactones by thiolysis to date. Other
significant improvements over the literature benchmark include
the possibility of using primary thiol nucleophiles (essential if
the technology is eventually to be applied to NCL processes) at
lower loadings than previously required, and a catalyst that
operates optimally at ambient temperature in conjunction with
azlactones derived from less-hindered amino acids most suit-
able for selection as the C-terminal peptide thioester coupling
partner in NCL reactions. The levels of enantioselectivity asso-
ciated with the DKR reactions (65−73% ee) are lower than
those usually obtained in the corresponding alcoholysis reactions.
An investigation to uncover the origins of this discrepancy with a
view toward the design of one-pot NCL-type coupling reactions
(which will naturally involve the use of a more easily cleaved
N-protecting group) involving azlactones is underway.
N-2-Furoylmethionine (25): Cream solid (0.90 g, 75%), mp 128−
1
130 °C; H NMR (400 Hz, d6-DMSO) δ 2.04−2.12 (m, 5H), 2.47−
2.64 (m, 2H), 4.48−4.55 (dd, 1H, J2 = 14.5, 7.7 Hz), 6.66−6.69 (m,
1H), 7.21 (d, 1H, J2 = 3.4 Hz), 7.90 (bs, 1H), 8.59 (d, 1H, J2 =
8.0 Hz), 12.78 (bs, 1H); 13C NMR (100 Hz, d6-DMSO) δ 15.5, 31.0
(2 × CH2), 51.8, 112.8, 114.8, 146.2, 148.4 (C), 158.9 (C), 174.3 (C);
IR (neat) νmax/cm−1 3414, 2922, 1729, 1639, 1597, 1529, 1476, 1188,
1009, 880, 765, 746; HRMS (ESI) m/z calculated for C10H13NO4SNa,
[M + Na]+ 266.0463; found, 266.0461.
N-2-Furoylleucine (26): Off-white hygroscopic solid (0.71 g, 63%),
1
mp 75−77 °C; H NMR (400 Hz, d6-DMSO) δ 0.89 (d, 3H, J2 =
6.3 Hz), 0.94 (d, 3H, J2 = 6.4 Hz), 1.54−1.73 (m, 2H), 1.75−1.84 (m,
1H), 4.39−4.47 (m, 1H), 6.65−6.68 (m, 1H), 7.21 (d, 1H, J2 = 3.4
Hz), 7.89 (bs, 1H), 8.51 (d, 1H, J2 = 8.1 Hz); 13C NMR (100 Hz, d6-
DMSO) δ 22.0, 23.9, 25.4, 40.3, 51.03, 112.8, 114.8, 146.1, 148.4 (C),
158.8 (C), 175.0 (C); IR (neat) νmax/cm−1 3415, 3118, 2959, 1737,
1645, 1595, 1532, 1472, 1397, 1182, 1148, 1004, 926, 841, 754, 748,
657; HRMS (ESI) m/z calculated for C11H15NO4Na, [M + Na]+
248.0899; found, 248.0894.
EXPERIMENTAL SECTION
N-2-Furoylallylglycine (27): White hygroscopic solid (0.93 g, 89%),
■
1
mp 79−81 °C; H NMR (400 Hz, d6-DMSO) δ 2.55−2.67 (m, 2H),
General Methods. All the DKR reactions were carried out in
oven-dried glassware and under an argon atmosphere. Unless
otherwise stated, all chemicals were commercially sourced and used
without purification. The 4-tert-butylbenzyl mercaptan was distilled
under low pressure prior to use. The catalyst 8 was prepared following
literature procedures.6g The azlactones were immediately used after
preparation. NMR spectra were internally referenced to residual
solvent signals (CHCl3 or DMSO).
General Procedure for the Synthesis of the N-2-Furoyl
Amino Acids. The commercially available racemic amino acid
(5 mmol) was dissolved or suspended in an aqueous solution of
NaOH (25 mL, 0.93 M, 11.6 mmol, 2.33 equiv.) and the solution or
suspension cooled down to 0 °C with an ice/water bath. 2-Furoyl
chloride (0.5 mL, 5 mmol, 1.00 equiv) was added slowly via a syringe.
The resulting mixture was allowed to warm to room temperature and
stirred overnight.
For alanine, phenylalanine, methionine, and valine: a solution of
aqueous HCl (approx. 1 mL, 36% conc.) was added until a precipitate
was formed and the pH of the solution was approximately 2. The
mixture was filtered (frit nb 3) and solids extensively washed with cold
water (15 mL) and Et2O (15 mL). The resulting white solids were
dried under high vacuum.
For leucine, nor-leucine, allylglycine, and 2-aminobutiric acid: a
solution of aqueous HCl (approx. 1 mL, 36% conc.) was added until a
precipitate was formed and the pH of the solution was approximately
2. The precipitate formed an oily residue that was dissolved with
CH2Cl2 (10 mL). The aqueous layer was then extracted with more
CH2Cl2 (15 mL × 3). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo to afford oils that solidified
(hygroscopic) after drying under high vacuum.
4.42−4.49 (m, 1H), 5.07 (d, 1H, Jcis = 10.2 Hz), 5.15 (d, 1H, Jtrans
=
17.2 Hz), 5.76−5.88 (m, 1H), 6.63−6.67 (m, 1H), 7.20 (d, 1H, J2 =
3.4 Hz), 7.87 (bs, 1H), 8.43 (d, 1H, J2 = 7.4 Hz); 13C NMR (100 Hz,
d6-DMSO) δ 36.0, 52.7, 113.0, 115.0, 118.7, 135.5, 146.3, 148.5 (C),
158.8 (C), 174.0 (C); IR (neat) νmax/cm−1 3374, 2895, 2549, 1721,
1594, 1528, 1473, 1234, 1209, 1191, 1017, 993, 943, 919, 885, 756,
695; HRMS (ESI) m/z calculated for C10H11NO4Na, [M + Na]+
232.0586; found, 232.0589.
N-2-Furoylnorleucine (28): Off-white solid (0.95 g, 83%), mp 94−
1
96 °C; H NMR (400 Hz, d6-DMSO) δ 0.86 (t, 3H, J2 = 7.2 Hz),
1.22−1.39 (m, 4H), 1.69−1.85 (m, 2H), 4.27−4.35 (m, 1H), 6.64 (dd,
1H, J2 = 1.8, 3.5 Hz), 7.19 (dd, 1H, J2 = 3.5 Hz, J3 = 0.8 Hz), 7.86 (dd,
1H, J2 = 1.8 Hz, J3 = 0.8 Hz), 8.44 (d, 1H, J2 = 8.2 Hz); 13C NMR
(100 Hz, d6-DMSO) δ 13.8, 21.7, 27.9, 30.2, 51.8, 111.8, 113.8, 145.2,
147.4 (C), 157.9 (C), 173.7 (C); IR (neat) νmax/cm−1 3370, 2952,
2870, 1734, 1715, 1625, 1596, 1530, 1479, 1416, 1288, 1200, 1151,
1007, 870, 790, 748; HRMS (ESI) m/z calculated for C11H15NO4Na,
[M + Na]+ 248.0899; found, 248.0905.
N-2-Furoyl-2-aminobutiric acid (29): Off-white hygroscopic solid
(0.93 g, 95%), mp 105−108 °C; 1H NMR (400 Hz, d6-DMSO) δ 0.95
(app t, 3H, J2 = 7.4 Hz), 1.72−1.83 (m, 1H), 1.85−1.95 (m, 1H),
4.25−4.33 (m, 1H), 6.65−6.68 (m, 1H), 7.23 (d, 1H, J2 = 3.4 Hz),
7.88 (bs, 1H), 8.43 (d, 1H, J2 = 7.7 Hz); 13C NMR (100 Hz, d6-
DMSO) δ 11.8, 24.9, 54.4, 112.9, 114.8, 146.2, 148.5 (C), 158.9 (C),
174.5 (C); IR (neat) νmax/cm−1 3339, 2973, 1731, 1636, 1592, 1528,
1473, 1414, 1294, 1182, 1128, 1076, 1013, 885, 757, 748, 670; HRMS
(ESI) m/z calculated for C9H11NO4Na, [M + Na]+ 220.0586; found,
220.0582.
N-2-Furoylvaline (30): Bright white solid (0.61 g, 58%), mp 113−
1
114 °C; H NMR (400 Hz, d6-DMSO) δ 0.96 (d, 3H, J2 = 2.9 Hz),
N-2-Furoylalanine (23): White solid (0.46 g, 51%), mp 173−
1
174 °C; H NMR (400 Hz, d6-DMSO) δ 1.40 (d, 3H, J2 = 7.4 Hz),
0.97 (d, 3H, J2 = 2.9 Hz), 2.15−2.26 (m, 1H), 4.25−4.31 (m, 1H),
6.67 (dd, 1H, J2 = 3.5, 1.8 Hz), 7.28 (d, 1H, J2 = 3.5 Hz), 7.89 (m,
1H), 8.21 (d, 1H, J2 = 8.3 Hz), 12.78 (bs, 1H); 13C NMR (100 Hz, d6-
DMSO) δ 18.6, 19.3, 29.6, 57.5, 111.8, 114.0, 145.3, 147.3 (C), 158.0
(C), 173.0 (C); IR (neat) νmax/cm−1 3363, 2961, 1708, 1618, 1593,
1532, 1478, 1394, 1328, 1295, 1228, 1196, 1020, 926, 885, 803, 770,
758, 740; HRMS (ESI) m/z calculated for C10H13NO4Na, [M + Na]+
234.0742; found, 234.0740.
4.40 (app. qn, 1H), 6.67 (dd, 1H, J2 = 3.5, 1.5 Hz), 7.20 (d, 1H, J2 =
3.5 Hz), 7.89 (m, 1H), 8.56 (d, 1H, J2 = 7.5 Hz), 12.65 (bs, 1H); 13
C
NMR (100 Hz, d6-DMSO) δ 17.9, 48.4, 112.8, 114.7, 146.1, 148.5
(C), 158.5 (C), 175.0 (C); IR (neat) νmax/cm−1 3316, 2497, 1713,
1592, 1564, 1525, 1471, 1219, 1190, 1162, 1123, 937, 884, 761;
HRMS (ESI) m/z calculated for C8H9NNaO4, [M + Na]+ 206.0429;
found, 206.0424.
N-2-Furoylphenylalanine (24): White solid (0.88 g, 68%), mp
153−154 °C; 1H NMR (400 Hz, d6-DMSO) δ 3.10 (dd, 1H, J1 = 14.0
Hz, J2 = 4.51 Hz), 3.21 (dd, 1H, J1 = 14.0 Hz, J2 = 10.4 Hz), 4.59−4.65
General Procedure for the Synthesis of the N-2-Furoyl
Azlactones. A solution of N,N'-dicyclohexylcarbodiimide (DCC,
0.95 mmol, 0.95 equiv) in CH2Cl2 (2 mL) was added slowly via a syringe
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to a solution/suspension of the corresponding N-2-furoyl amino acid
(1 mmol) in dry CH2Cl2 (10 mL). The reaction was stirred overnight
at room temperature under an Ar atmosphere. The resulting sus-
pension was filtered and the solids washed with CH2Cl2 (10 mL × 2).
The filtrate was concentrated in vacuo to afford an oily residue that
was passed through a short silica column and eluted with a mixture of
10−20% EtOAc in hexane. The solvent was removed and the products
dried under high vacuum to afford either waxy solids or clear oils that
were used immediately in the next step.
NMR (100 Hz, CDCl3) δ 9.5, 24.9, 65.7, 112.0, 116.9, 140.8 (C),
146.8, 153.9 (C), 177.2 (C); IR (neat) νmax/cm−1 3288, 3136, 3113,
2938, 2878, 2856, 1830, 1806, 1681, 1661, 1555, 1471, 1400, 1235,
1179, 1146, 1111, 1074, 1065, 1042, 1008, 976, 909, 869, 767, 723,
715; HRMS (ESI) m/z calculated for C9H8NO3, [M − H]− 178.0504;
found, 178.0506.
N-2-Furoylvaline Azlactone (37): Off-white waxy solid (139.5 mg,
1
76%), mp 72−74 °C; H NMR (400 Hz, CDCl3) δ 1.02 (d, 3H, J2 =
6.8 Hz), 1.15 (d, 1H, J2 = 6.8 Hz), 2.33−2.44 (m, 1H), 4.26−4.29 (m,
1H), 6.57−6.60 (m, 1H), 7.11 (d, 1H, J2 = 3.3 Hz), 7.66 (bs, 1H); 13
C
N-2-Furoylalanine Azlactone (12): Off-white waxy solid (136.5 mg,
1
87%), mp 54−56 °C; H NMR (400 Hz, CDCl3) δ 1.59 (d, 3H, J2 =
NMR (100 Hz, CDCl3) δ 17.5, 18.8, 31.2, 70.0, 112.0, 116.9, 140.8
(C), 146.8, 153.9 (C), 176.7 (C); IR (neat) νmax/cm−1 3123, 3095,
2982, 2931, 1813, 1669, 1559, 1477, 1398, 1336, 1326, 1234, 1172,
1145, 1077, 1063, 1036, 1014, 918, 882, 873, 850, 774, 719; HRMS
(ESI) m/z calculated for C10H10NO3, [M − H]− 192.0661; found,
192.0666.
7.6 Hz), 4.44, (q, 1H, J2 = 7.6 Hz), 6.58 (m, 1H), 7.11 (d, 1H, J2 =
3.4 Hz), 7.66 (bs, 1H); 13C NMR (100 Hz, CDCl3) δ 16.9, 60.3,
112.1, 117.0, 140.8 (C), 146.9, 153.8 (C), 177.9 (C); IR (neat)
νmax/cm−1 3146, 3122, 3086, 1820, 1808, 1675, 1661, 1556, 1478,
1402, 1323, 1255, 1179, 1147, 1106, 1079, 1067, 1026, 1002, 933, 906,
882, 869, 852, 807, 774, 728, 714, 658; HRMS (ESI) m/z calculated
for C8H6NO3, [M − H]− 164.0348; found, 164.0340.
Dynamic Kinetic Resolution Using 4-tert-Butylbenzyl Mer-
captan. General Procedure for Table 1. The freshly made
azlactone (0.2 mmol) was placed into a dry graduated reaction
vial previously flushed with Ar and equipped with a magnetic
stirring bar. 4-tert-Butylbenzyl mercaptan (75 μL, 0.4 mmol,
2.0 equiv) was added, and the volume of the reaction was
completed with dry CH2Cl2 up to 0.5 mL (0.4 M). After 10 min,
the corresponding catalyst (5, 7−9) (0.02 mmol, 0.1 equiv) was
added, and the reaction was stirred at room temperature and
under Ar for 20 h. The reaction was directly poured onto a
column of silica gel and the product purified by flash chroma-
tography using a mixture of 12−15% EtOAc in hexane as
eluent. Stereochemical assignment for 15 was determined after
hydrolysis to the corresponding acid (see the Determination of
the Absolute Configuration at the end of the section). Com-
pound 6 was assigned according to the literature.6e 13 and 14
were assigned by analogy.
General Procedure for Table 2. The freshly prepared azlactone 12
(0.2 mmol) was placed in a dry graduated reaction vial previously
flushed with Ar and equipped with a magnetic stirring bar. The rest of
the experimental procedure is analogous to the one described in the
section above, but adjusting the relative amounts of catalyst 8, 4-tert-
butylbenzyl mercaptan, and the various solvents according to the levels
indicated in Table 2.
N-2-Furoylphenylalanine Azlactone (31): Off-white waxy solid
1
(139.8 mg, 61%), mp 88−89 °C; H NMR (400 Hz, CDCl3) δ 3.21
(dd, 1H, J1 = 14.0 Hz, J2 = 6.45 Hz), 3.36 (dd, 1H, J1 = 14.0 Hz, J2 =
5.0 Hz), 4.68 (app t, 1H, J = 5.6 Hz), 6.52−6.55 (m, 1H), 7.00 (d, 1H,
J2 = 3.4 Hz), 7.19−7.33 (m, 5H), 7.63 (bs, 1H); 13C NMR (100 Hz,
CDCl3) δ 37.2, 65.8, 112.0, 117.0, 127.2, 128.5, 129.6, 134.9 (C),
140.6 (C), 146.9, 153.8 (C), 176.4 (C); IR (neat) νmax/cm−1 3123,
3092, 2923, 1813, 1800, 1665, 1559, 1477, 1401, 1320, 1268, 1246,
1169, 1145, 1078, 1049, 1017, 972, 925, 882, 841, 778, 734, 715, 698,
658; HRMS (ESI) m/z calculated for C14H10NO3, [M − H]−
240.0661; found, 240.0662.
N-2-Furoylmethionine Azlactone (32): Off-white waxy solid
1
(139.1 mg, 65%), mp 45−46 °C; H NMR (400 Hz, CDCl3) δ 2.11
(s, 3H), 2.12−2.18 (m, 1H), 2.28−2.36 (m, 1H), 2.74 (app t, 2H),
4.60 (app t, 1H), 6.59 (m, 1H), 7.12 (bs, 1H), 7.26 (bs, 1H);
13C NMR (100 Hz, CDCl3) δ 15.0, 30.0, 30.3, 62.9, 112.1, 117.1, 140.8
(C), 147.0, 154.2 (C), 177.3 (C); IR (neat) νmax/cm−1 3121, 2913, 1806,
1660, 1553, 1575, 1446, 1401, 1325, 1251, 1167, 1089, 1065, 1041, 1014,
977, 927, 903, 883, 857, 798, 773, 718, 654; HRMS (ESI) m/z calculated
for C10H11NO3S, [M − H]− 224.0381; found, 224.0378.
N-2-Furoylleucine Azlactone (33): Off-white waxy solid (128.0 mg,
1
61%), mp 39−42 °C; H NMR (400 Hz, CDCl3) δ 0.99 (d, 3H, J2 =
6.6), 1.23 (d, 3H, J2 = 6.6 Hz), 1.63−1.72 (m, 1H), 1.77−1.86 (m,
1H), 2.02−2.14 (m, 1H), 4.40 (dd, 1H, J2 = 9.2, 5.4 Hz), 6.56−6.59
(m, 1H), 7.10 (d, 1H, J2 = 3.4 Hz), 7.65 (bs, 1H); 13C NMR (100 Hz,
CDCl3) δ 21.8, 22.8, 25.0, 40.8, 63.1, 112.0, 116.8, 140.9 (C), 146.8,
153.7 (C), 177.9 (C); IR (neat) νmax/cm−1 3112, 2964, 1821, 1668,
1557, 1474, 1398, 1321, 1275, 1236, 1179, 1144, 1055, 1007, 922, 894,
771, 720, 654; HRMS (ESI) m/z calculated for C11H12NO3, [M −
H]− 206.0817; found, 206.0813.
General Procedure for Table 3. The freshly made azlactone
(0.4 mmol) was placed into a dry reaction vial previously flushed with
Ar and equipped with a magnetic stirring bar. 4-tert-Butylbenzyl
mercaptan (150 μL, 0.8 mmol, 2.0 equiv) was added, and the volume
of the reaction was made up with dry CH2Cl2 to 10 mL (0.04 M). This
solution was warmed to 19−21 °C. After 10 min, catalyst 8 (18.10 mg,
0.04 mmol, 0.1 equiv) was added, and the reaction was stirred at 19−
21 °C under Ar for the times indicated in Table 3. The reaction was
quenched with an aqueous solution of HCl (2 M, 5 mL), and the
aqueous phase was extracted with CH2Cl2 (5 mL × 2). The combined
organic layers were successively washed with an aqueous saturated
solution of NaHCO3 (5 mL) and brine (5 mL). The organic layer was
dried (MgSO4), filtered, and concentrated to afford an oily residue.
The residue was purified by silica flash chromatography using a
mixture of 12−15% EtOAc in hexane as eluent.
N-2-Furoylallylglycine Azlactone (34): Clear oil (167.1 mg, 92%);
1H NMR δ (400 Hz, CDCl3) 2.58−2.67 (m, 1H), 2.75−2.83 (m, 1H),
4.47 (app t, 1H), 5.15 (d, 1H, Jcis = 10.0 Hz), 5.23 (dd, 1H, Jtrans
=
17.0 Hz), 5.70−5.84 (m, 1H), 6.56 (dd, 1H, J2 = 3.4, 1.7 Hz), 7.09 (1H,
d, J2 = 3.4 Hz), 7.64 (bs, 1H); 13C NMR (100 Hz, CDCl3) δ 35.2, 64.6,
112.0, 117.0, 119.9, 131.1, 140.6 (C), 146.9, 153.9 (C), 176.5 (C); IR
(neat) νmax/cm−1 3288, 2926, 2855, 1824, 1673, 1624, 1530, 1476, 1400,
1314, 1235, 1045, 1011, 918, 884, 756, 715, 674; HRMS (ESI) m/z
calculated for C10H8NO3, [M − H]− 190.0504; found, 190.0504.
N-2-Furoylnorleucine Azlactone (35): Off-white waxy solid (120.2
N-2-Furoylalanine, 4-tert-Butylbenzyl Thioester (15): White solid
20
546
(56.6 mg, 86%, 73% ee), mp 99−101 °C; [α] −47.6 (c 0.105,
CHCl3); 1H NMR (400 Hz, CDCl3) δ 1.29 (s, 9H), 1.52 (d, 3H, J2 =
7.1 Hz), 4.07−4.17 (m, 2H), 4.88−4.97 (m, 1H), 6.49−6.62 (m, 1H),
6.84 (d, 1H, J2 = 7.8 Hz), 7.15 (d, 1H, J2 = 3.5 Hz), 7.21 (d, 2H, J2 =
8.2 Hz), 7.31 (d, 2H, J2 = 8.2 Hz), 7.46 (bs, 1H); 13C NMR (100 Hz,
CDCl3) δ 19.0, 31.2, 32.9, 34.4 (C), 54.4, 112.2, 115.03, 125.6, 128.5,
133.5 (C), 144.3, 147.2 (C), 150.4 (C), 157.7 (C), 200.2 (C);
IR (neat) νmax/cm−1 3351, 2958, 1678, 1651, 1517, 1294, 1200,
1100, 1027, 967, 939, 905, 827, 763, 702, 659; HRMS (ESI) m/z
calculated for C19H23NO3SNa, [M + Na]+ 368.1296; found, 368.1291.
CSP-HPLC analysis: Chiralcel OD-H (4.6 mm × 25 cm), 90:10
hexane/IPA, 1 mL/min, 254 nm; tR = 12.8 min (major enantiomer)
and 17.1 min (minor enantiomer).
1
mg, 58%), mp 48−50 °C; H NMR (400 Hz, CDCl3) δ 0.94 (t, 3H,
J2 = 7.2 Hz), 1.35−1.57 (m, 4H), 1.82−1.93 (m, 1H), 2.00−2.11 (m,
1H), 4.42 (dd, 1H, J2 = 5.5, 7.3 Hz), 6.61 (dd, 1H, J2 = 1.7, 3.4 Hz),
7.13 (d, 1H, J2 = 3.4 Hz), 7.69 (d, 1H, J2 = 1.7 Hz); 13C NMR
(100 Hz, CDCl3) δ 13.3, 21.8, 26.9, 30.9, 64.2, 111.6, 116.5, 140.4 (C),
146.4, 153.4 (C), 177.0 (C); IR (neat) νmax/cm−1 3284, 2959, 2872,
1742, 1649, 1516, 1467, 1299, 1184, 1011, 885, 748; HRMS (ESI)
m/z calculated for C11H14NO3, [M + H]+ 208.974; found, 208.0979.
N-2-Furoyl-2-aminobutyric acid Azlactone (36): Off-white waxy
1
solid (119.1 mg, 70%), mp 52−55 °C; H NMR (400 Hz, CDCl3) δ
1.06 (app t, 3H), 1.87−2.0 (m, 1H), 2.02−2.14 (m, 1H), 4.37 (app t,
1H), 6.57−6.60 (m, 1H), 7.11 (d, 1H, J2 = 3.4 Hz), 7.66 (bs, 1H); 13
C
2412
dx.doi.org/10.1021/jo202662d | J. Org. Chem. 2012, 77, 2407−2414

The Journal of Organic Chemistry
Article
N-2-Furoylphenylalanine, 4-tert-Butylbenzyl Thioester (16):
1 mL/min, 254 nm; tR = 7.74 min (major enantiomer) and 9.19 min
(minor enantiomer).
20
White solid (162.0 mg, 96%, 66% ee), mp 121−126 °C; [α]
346
1
+13.95 (c 1.62, CHCl3); H NMR (400 Hz, CDCl3) δ 1.31 (s, 9H),
N-2-Furoyl-2-aminobutyric acid, 4-tert-Butylbenzyl Thioester
20
546
(21): Yellow oil (114.0 mg, 80%, 71% ee); [α] −22.36 (c 1.10,
3.23 (app d, 2H), 4.10 (bs, 2H), 5.12−5.21 (m, 1H), 6.46−6.50 (dd,
1H, J2 = 3.4, 1.8 Hz), 6.70 (d, 1H, J2 = 8.6 Hz), 7.08−7.13 (m, 3H),
7.19 (d, 2H, J2 = 8.2 Hz), 7.22−7.26 (m, 3H), 7.32 (d, 2H, J2 =
8.2 Hz), 7.42 (d, 1H, J2 = 1.3 Hz); 13C NMR (100 Hz, CDCl3) δ 31.3,
33.0, 34.5 (C), 38.4, 58.9, 112.2, 115.1, 125.5, 127.1, 128.6 (2 × CH),
129.4, 133.6 (C), 135.2 (C), 144.4 (C), 147.1 (C), 150.4 (C), 157.8
(C), 199.2 (C); IR (neat) νmax/cm−1 3375, 2960, 1661, 1592,
1518, 1475, 1279, 1177, 1070, 1009, 928, 884, 839, 761, 751, 703;
HRMS (ESI) m/z calculated for C25H27NO3SNa, [M + Na]+
444.1609; found, 444.1608. CSP-HPLC analysis: Chiralcel OD-H
(4.6 mm × 25 cm), 95:5 hexane/IPA, 1 mL/min, 254 nm; tR = 22.0 min
(major enantiomer) and 25.3 min (minor enantiomer).
CHCl3); 1H NMR (400 Hz, CDCl3) δ 0.98 (app t, 3H), 1.29 (s, 9H),
1.73−1.87 (m, 1H), 1.99−2.13 (m, 1H), 4.12 (bs, 2H), 4.81−4.90 (m,
1H), 6.51 (dd, 1H, J2 = 3.5, 1.6 Hz), 6.78 (d, 1H, J2 = 8.5 Hz), 7.15 (d,
1H, J2 = 3.5 Hz), 7.20 (d, 2H, J2 = 8.2 Hz), 7.31 (d, 2H, J2 = 8.2 Hz),
7.47 (bs, 1H); 13C NMR (100 Hz, CDCl3) δ 9.6, 26.3, 31.3, 32.9,
34.5 (C), 59.6, 112.3, 115.0, 125.6, 128.5, 133.6 (C), 144.2, 147.3 (C),
150.4 (C), 158.0 (C), 199.6 (C); IR (neat) νmax/cm−1 3282, 2947,
1670, 1650, 1593, 1515, 1475, 1322, 1278, 1180, 1106, 1057,
1004, 917, 882, 833, 751, 695; HRMS (ESI) m/z calculated for
C20H25NO3SNa, [M + Na]+ 382.1453; found, 382.1441. CSP-HPLC
analysis: Chiralcel OD-H (4.6 mm × 25 cm), 90:10 hexane/IPA,
1 mL/min, 254 nm, tR = 9.4 min (major enantiomer) and 11.9 min
(minor enantiomer).
N-2-Furoylmethionine, 4-tert-Butylbenzyl Thioester (17): Clear oil
20
546
1
(156.2 mg, 96%, 73% ee); [α] −7.49 (c 1.56, CHCl3); H NMR
(400 Hz, CDCl3) δ 1.29 (s, 9H), 2.02−2.13 (m, 4H), 2.24−2.35 (m,
1H), 2.54−2.59 (m, 2H), 4.12 (bs, 2H), 5.01−5.08 (m, 1H), 6.51 (dd,
1H, J2 = 3.4, 2.0 Hz), 7.09 (d, 1H, J2 = 8.4 Hz), 7.15 (d, 1H, J2 =
3.4 Hz), 7.20 (d, 2H, J2 = 8.3 Hz), 7.31 (d, 2H, J2 = 8.3 Hz), 7.47 (bs,
1H); 13C NMR (100 Hz, CDCl3) δ 15.4, 29.9, 31.2, 32.0, 33.0, 34.4
(C), 57.8, 112.3, 115.2, 125.5, 128.5, 133.4 (C), 144.4, 147.1 (C),
150.4 (C), 157.9 (C), 199.2 (C); IR (neat) νmax/cm−1 3240, 2963,
1682, 1639, 1592, 1568, 1535, 1471, 1312, 1015, 934, 885, 833, 783,
760; HRMS (ESI) m/z calculated for C21H27NO3S2Na, [M + Na]+
428.1330; found, 428.1326. CSP-HPLC analysis: Chiralcel OD-H
N-2-Furoylvaline, 4-tert-Butylbenzyl Thioester (22): Oily solid
20
1
(123.0 mg, 82%, 28% ee); [α] −15.5 (c 0.20, CHCl3); H NMR
546
(400 Hz, CDCl3) δ 0.94 (d, 3H, J2 = 7.0 Hz), 1.02 (d, 3H, J2 =
6.9 Hz), 1.29 (s, 9H), 2.35−2.47 (m, 1H), 4.12 (bs, 2H), 4.81−4.89
(m, 1H), 6.52 (dd, 1H, J2 = 3.5, 1.8 Hz), 6.77 (d, 1H, J2 = 9.3 Hz),
7.15 (d, 1H, J2 = 3.5 Hz), 7.20 (d, 2H, J2 = 8.2 Hz), 7.31 (d, 2H, J2 =
8.2 Hz), 7.47 (bs, 1H); 13C NMR (100 Hz, CDCl3) δ 16.9, 19.5, 31.3,
31.5, 33.0, 34.5 (C), 63.0, 112.3, 115.1, 125.6, 128.5, 133.6 (C), 144.3,
147.3 (C), 150.4 (C), 158.2 (C), 199.4 (C); IR (neat) νmax/cm−1 3278,
2961, 1682, 1648, 1590, 1517, 1467, 1318, 1286, 1077, 1009, 929, 883,
806, 757, 697; HRMS (ESI) m/z calculated for C21H27NO3SNa, [M +
Na]+ 396.1609; found, 396.1597. CSP-HPLC analysis: Chiralcel OD-H
(4.6 mm × 25 cm), 90:10 hexane/IPA, 1 mL/min, 254 nm, tR = 7.1 min
(major enantiomer) and 8.6 min (minor enantiomer).
(4.6 mm × 25 cm), 90:10 hexane/IPA, 1 mL/min, 254 nm; tR
9.6 min (major enantiomer) and 11.6 min (minor enantiomer).
=
N-2-Furoylleucine, 4-tert-Butylbenzyl Thioester (18): Yellow oil
20
546
1
(150.0 mg, 97%, 70% ee); [α] −18.6 (c 1.50, CHCl3); H NMR
(400 Hz, CDCl3) δ 0.95 (bs, 3H), 0.97 (bs, 3H), 1.29 (s, 9H), 1.58−
1.87 (m, 3H), 4.10 (bs, 2H), 4.89−4.96 (m, 1H), 6.50−6.53 (m, 1H),
6.63 (d, 1H, J2 = 8.8 Hz), 7.16 (d, 1H, J2 = 3.9 Hz), 7.20 (d, 2H, J2 =
8.0 Hz), 7.31 (d, 2H, J2 = 8.0 Hz), 7.47 (bs, 1H); 13C NMR (100 Hz,
CDCl3) δ 21.5, 23.1, 24.8, 31.3, 33.0, 34.5 (C), 41.9, 57.1, 112.3, 115.1,
125.6, 128.5, 133.6 (C), 144.3, 147.2 (C), 150.3 (C), 158.0 (C), 200.3
(C); IR (neat) νmax/cm−1 3285, 2958, 1649, 1592, 1516, 1471, 1365,
1289, 1183, 1074, 1009, 933, 884, 834, 758; HRMS (ESI) m/z
calculated for C22H29NO3SNa, [M + Na]+ 410.1766; found, 410.1746.
CSP-HPLC analysis: Chiralcel OD-H (4.6 mm × 25 cm), 90:10
hexane/IPA, 1 mL/min, 254 nm; tR = 7.3 min (major enantiomer) and
8.2 min (minor enantiomer).
Determination of the Absolute Configuration. The config-
uration at the chiral center was assigned by comparison of the sign of
the specific rotation determined for enantiomerically pure synthesized
N-furoyl L-alanine and N-furoyl L-phenylalanine (following the general
procedure reported for the synthesis of the N-2-Furoyl amino acids)
and the respective products of the hydrolyzed N-furoyl-alanine (15)
and N-furoyl-phenylalanine thioesters (16) resulting from the
organocatalytic reactions. The hydrolysis was carried out by dissolving
the corresponding thioester (0.39 mmol) into a NaOH (0.88 mmol,
2.25 equiv) solution in 1:1 THF/H2O water (1 mL). The THF was
removed in vacuo and the resulting liquid acidified with concentrated
HCl until persistent cloudiness appeared (pH ∼ 2). The mixture was
transferred to a separating funnel and extracted with CHCl3 (3 ×
2 mL). The combined organic layers were evaporated and the resulting
solid washed with hexane until the thiol/disulfide was completely
removed (monitored by TLC). The resulting solid was thoroughly
dried under high vacuum. The optical rotation of enantiomerically
N-2-Furoylallylglycine, 4-tert-Butylbenzyl Thioester (19): Yellow-
20
546
1
ish oil (142.2 mg, 95%, 72% ee); [α] −5.77 (c 0.711, CHCl3); H
NMR (400 Hz, CDCl3) δ 1.29 (s, 9H), 2.63−2.71 (m, 2H), 4.12 (bs,
2H), 4.97 (dd, 1H, J2 = 14.0, 6.8 Hz), 5.15 (bs, 1H), 5.19 (br. d, 1H),
5.65−5.79 (m, 1H), 6.50−6.52 (m, 1H), 6.77 (bd, 1H, J2 = 8.3 Hz),
7.15 (d, 1H, J2 = 3.3 Hz), 7.20 (d, 2H, J2 = 7.5 Hz), 7.31 (d, 2H, J2 =
7.5 Hz), 7.46 (s, 1H); 13C NMR (100 Hz, CDCl3) δ 31.2, 33.0, 34.5
(C), 37.0, 57.5, 112.3, 115.1, 119.8, 125.6, 128.5, 131.7, 133.5 (C),
144.3, 147.2 (C), 150.4 (C), 157.8 (C), 199.2 (C); IR (neat)
νmax/cm−1 3282, 2948, 1670, 1649, 1593, 1515, 1475, 1392, 1057, 1004,
917, 882, 833, 751; HRMS (ESI) m/z calculated for C21H25NO3SNa,
[M + Na]+ 394.1453; found, 394.1462. CSP-HPLC analysis: Chiralcel
OD-H (4.6 mm × 25 cm), 90:10 hexane/IPA, 1 mL/min, 254 nm, tR =
8.1 min (major enantiomer) and 9.8 min (minor enantiomer).
20
20
pure N-furoyl L-alanine was [α] +15.2 (c 0.25, MeOH) vs [α]
546
546
−7.33 (c 0.30, MeOH) obtained for hydrolyzed thioester 15. The
optical rotation of enantiomerically pure N-furoyl L-phenylalanine was
20
20
546
[α] −62 (c 0.10, MeOH) vs [α] +17.5 (c 0.20, MeOH) obtained
546
for hydrolyzed thioester 16.
ASSOCIATED CONTENT
■
N-2-Furoylnorleucine, 4-tert-Butylbenzyl Thioester (20): Yellow
S
* Supporting Information
20
oil (136.0 mg, 91%, 65% ee); [α] −9.29 (c 0.42, CHCl3); 1H NMR
546
Selected NMR spectra and HPLC chromatograms. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(400 Hz, CDCl3) δ 0.91 (t, 3H, J2 = 7.2 Hz), 1. 30−1.43 (m, 13H),
1.71−1.82 (m, 1H), 1.98−2.08 (m, 1H), 4.14 (s, 2H), 4.91 (dt, 1H,
J2 = 4.8, 8.4 Hz), 6.54 (dd, 1H, J2 = 1.8, 3.6 Hz), 6.76 (d, 1H, J2 =
8.4 Hz), 7.18 (d, 1H, J2 = 3.6 Hz), 7.23 (d, 2H, J2 = 8.4 Hz), 7.33
(d, 2H, J2 = 8.4 Hz), 7.49 (d, 1H, J2 = 1.8 Hz); 13C NMR (100 Hz,
CDCl3) δ 13.4, 21.9, 26.9, 30.9, 32.2, 32.5, 34.1 (C), 58.2, 111.9, 114.7,
125.2, 128.1, 133.3 (C), 143.9, 146.9 (C), 149.4 (C), 157.6 (C), 199.5
(C); IR (neat) νmax/cm−1 3289, 2958, 1865, 1651, 1591, 1568, 1515,
1473, 1302, 1180, 1009, 934, 884,756; HRMS (ESI) m/z calculated for
C22H29NO3SNa, [M + Na]+ 410.1766; found, 410.1773. CSP-HPLC
analysis: Chiralcel OD-H (4.6 mm × 25 cm), 90:10 hexane/IPA,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: connons@tcd.ie.
Notes
The authors declare no competing financial interest.
2413
dx.doi.org/10.1021/jo202662d | J. Org. Chem. 2012, 77, 2407−2414

The Journal of Organic Chemistry
Article
D. A.; Kitagaki, S.; Utsumi, N.; Barbas, C. F. III Angew. Chem., Int. Ed.
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2011, 50, 5553. (e) Capitta, F.; Frongia, A.; Piras, P. P.; Pitzanti, P.;
Secci, F. Org. Biomol. Chem. 2012, 10, 490.
ACKNOWLEDGMENTS
■
We are grateful to Science Foundation Ireland, the Irish
Research Council for Science, Engineering and Technology,
and The European Research Council for financial support.
(12) (a) Terada, M.; Nii, H. Chem.Eur. J. 2011, 17, 1760.
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(b) Frebault, F.; Luparia, M.; Oliveira, M. T.; Goddard, R.; Maulide,
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