Expanding the utility of Bronsted base catalysis: Biomimetic enantioselective decarboxylative reactions

Article abstract of DOI:10.1002/chem.201100687

As a result of the low reactivity of simple esters, the use of them as nucleophiles in direct asymmetric transformations is a long-standing challenge in synthetic organic chemistry. Nature approaches this difficulty through a decarboxylative mechanism, which is used for polyketide synthesis. Inspired by nature, we report guanidine-catalyzed biomimetic decarboxylative C-C and C-N bond-formation reactions. These highly enantioselective decarboxylative Mannich and amination reactions utilized malonic acid half thioesters as simple ester surrogates. It is proposed that nucleophilic addition precedes decarboxylation in the mechanism, which has been investigated in detail through the identification of intermediates by using electrospray ionization (ESI) mass-spectrometric analysis and DFT calculations. Copyright

Full text of DOI:10.1002/chem.201100687

FULL PAPER
DOI: 10.1002/chem.201100687
Expanding the Utility of Brønsted Base Catalysis: Biomimetic
Enantioselective Decarboxylative Reactions
Yuanhang Pan,[a] Choon Wee Kee,[a] Zhiyong Jiang,[b] Ting Ma,[a] Yujun Zhao,[a]
Yuanyong Yang,[a] Hansong Xue,[a] and Choon-Hong Tan*[a]
In memory of Professor Keith Fagnou
À
À
Abstract: As a result of the low reac-
tivity of simple esters, the use of them
as nucleophiles in direct asymmetric
transformations is a long-standing chal-
lenge in synthetic organic chemistry.
Nature approaches this difficulty
through a decarboxylative mechanism,
which is used for polyketide synthesis.
Inspired by nature, we report guani-
dine-catalyzed biomimetic decarboxy-
lative C C and C N bond-formation
reactions. These highly enantioselective
decarboxylative Mannich and amina-
tion reactions utilized malonic acid half
thioesters as simple ester surrogates. It
is proposed that nucleophilic addition
precedes decarboxylation in the mech-
anism, which has been investigated in
detail through the identification of in-
termediates by using electrospray ioni-
zation (ESI) mass-spectrometric analy-
sis and DFT calculations.
Keywords: amination · biomimetic
synthesis · decarboxylation · density
functional calculations · Mannich
reaction · organocatalysis
Introduction
quires either strong bases or Lewis acids in the form of
metal complexes.[2]
The ability of nature to form carbon–carbon bonds under
mild conditions has been an inspiration and motivation for
synthetic chemists. For example, the biosynthesis of poly-
ketides requires the generation of ester enolates under phys-
iological conditions, which forbids the use of strong bases.[1]
This feat is achieved through the decarboxylation of a ma-
lonic acid half thioester (MAHT), a process catalyzed by
polyketide synthase (PKS). The weakly basic histidine motif
of PKS activates the MAHT toward decarboxylation, and
the resulting thioester enolate undergoes electrophilic trap-
ping with an acyl unit to furnish the Claisen condensation
product (Scheme 1a).[1c] The attention of chemists is drawn
toward such strategy and the use of MAHTs and malonic
acid half oxyesters (MAHOs) as the precursors of ester eno-
lates. This elegant strategy allows a mild base to form eno-
lates of simple esters, the activation of which usually re-
More than thirty years ago, Kobuke and Yoshida first
demonstrated a decarboxylative Claisen condensation with
magnesium acetate and imidazole under enzyme-free condi-
tions.[3a,b] Ytterbium triflates were then shown to catalyze a
Knoevenagel condensation between MAHTs and aldehy-
des.[3c] Subsequently, a Cu-catalyzed enantioselective thioest-
er aldol reaction[4a–c] and enantioselective decarboxylative
Michael reaction catalyzed by using a heterobimetallic Ni/
La–N,N’-bis(salicylidene)ethylenediamine (salen) complex
were developed.[4d] However, Brunner et al. made an impor-
tant observation that a base alone is sufficient to drive de-
carboxylation reactions of MAHOs.[5] Following this report,
several metal-free decarboxylative reactions have been de-
veloped.[6] Recently, enantioselective decarboxylation cata-
lyzed by Cinchona alkaloid derivatives were investigated by
Ricci et al.[6e] and Wennemers and Lubkoll[6f] for the addi-
tion of MAHTs to imines and nitro-olefins, respectively. De-
spite these investigations, the development of highly enan-
tioselective decarboxylative reactions that can tolerate a
wide range of substrates is still highly desirable.
[a] Y. Pan, C. W. Kee, T. Ma, Y. Zhao, Y. Yang, H. Xue, Prof. C.-H. Tan
Department of Chemistry
We are keen to develop chiral guanidines[7,8] as general
catalysts for Brønsted base-catalyzed reactions. We have
been successful with several reactions that utilize nucleo-
philes with relatively acidic protons (Figure 1).[9] However,
there is an inherent limit to the range of nucleophiles suita-
ble because of the basicity of the guanidine catalyst. One
possible strategy to circumvent this issue is to activate a
simple ester by using the soft enolization strategy.[10] Soft
enolization occurs when a relatively weak amine base and
an electrophile-activating component act in concert, thus ef-
National University of Singapore (NUS)
3 Science Drive 3, 117543 (Singapore)
Fax : (+65)6779-1691
E-mail: chmtanch@nus.edu.sg
[b] Prof. Z. Jiang
Provincial Key Laboratory of Natural Medicine and
Immuno-Engineering
Jinming Campus, Henan University
Kaifeng, Henan, 475004 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100687.
Chem. Eur. J. 2011, 17, 8363 – 8370
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8363

Results and Discussion
An initial study shows that in
the presence of
a catalytic
amount of bicyclic guanidine 3,
the reaction between MAHT
1a and N-tosyl imine 2a pro-
ceeds smoothly in excellent
yield (Table 1, entry 1). From
our previous experience with
bicyclic guanidine-catalyzed re-
actions, we know that increas-
ing the steric bulk of the sub-
strate increases the enantiose-
lectivity of the product.
A
Scheme 1. a) Claisen condensation in polyketide biosynthesis.[1c,6f] b) Biomimetic decarboxylative Mannich re-
much higher enantiomeric
excess (ee) was obtained when
tert-butyl-substituted MAHT
1c (Table 1, entry 3) was used
as the donor. Among the sol-
vents tested (Table 1, en-
tries 3–7), diethyl ether afford-
ed the best ee value, but a low
yield of the adduct was ob-
tained (Table 1, entry 4). Low-
ering the reaction temperature
to 08C did not improve the
enantioselectivity significantly
(Table 1, entries 8–10). Howev-
er, an excellent enantiomeric
excess of 92% ee was achieved
at À208C, albeit in a low yield
of 21%, after 5 days (Table 1,
entry 11). We attributed the
low yield to a competing reac-
tion, that is, the unproductive
decarboxylation of MAHTs.
This side reaction cannot be
eliminated even at a low reac-
tion temperature. As a com-
promise between the yield and
action. Asn=asparagine, CoA=coenzyme A, Cys=cysteine, His=histidine, Phe=phenylalanine, Ts=N-tosyl.
Figure 1. The pKa values of bicyclic guanidinium and nucleophiles in aqueous or DMSO solution.[13] DMSO=
dimethyl sulfoxide.
fecting reversible deprotonation.[10c] An excellent alternative
strategy is to mimic the polyketide biosynthetic pathway.
The bifunctional nature of a bicyclic guanidine[11] catalyst
should be appropriate for a proximity-assisted decarboxyla-
tive strategy (Scheme 1b).
Herein, we report a highly enantioselective guanidine-cat-
alyzed biomimetic decarboxylative Mannich[12] reaction with
MAHTs. High yield and enantioselectivity in a decarboxyla-
tive Mannich reaction for MAHTs without a group substi-
tuted on the a-carbon atom are difficult to attain with an or-
ganocatalyst[6e,f] and the use of a-alkyl-substituted MAHTs
in an organocatalytic decarboxylative Mannich reaction has,
to the best of our knowledge, not previously been reported.
ee values, THF was chosen as the solvent for further optimi-
zation. Good yields and excellent ee values could be simulta-
neously achieved when the reaction was conducted at
À108C (Table 1, entry 12). An excess of imine 2a was re-
quired to increase the imine concentration, which should en-
hance the rate of the Mannich reaction but not the unpro-
ductive decarboxylation.
With the optimal reaction conditions developed, the sub-
strate scope was evaluated (Table 2). We examined the per-
formance of MAHT 1c with a series of N-tosyl (Ts) imines
in the presence of 10 mol% catalyst 3. Good yields and ex-
cellent ee values were obtained with imines bearing both
electron-withdrawing and -donating aryl groups as well as
(hetero)aryl groups (up to 85% yield, up to 97% ee;
Table 2, entries 1–9). As a result of the difficulties in the
preparation and the low reactivities of a-alkyl-substituted
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Chem. Eur. J. 2011, 17, 8363 – 8370

Enantioselective Decarboxylative Mannich and Amination Reactions
FULL PAPER
Table 1. Decarboxylative Mannich reactions of MAHTs 1a–c.[a]
Table 2. Highly enantioselective decarboxylative Mannich reaction be-
tween MAHTs 1c–g and imines 2a–i.
Entry
1 [R]
2 [Ar]
4
Yield
[%][c]
ee
[%][d]
1[a]
2[a]
1c [H]
1c [H]
1c [H]
1c [H]
1c [H]
1c [H]
1c [H]
1c [H]
2a [4-ClC6H4]
2b [4-BrC6H4]
2c [C6H5]
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
72
85
68
74
82
43
50
76
92
92
95
90
95
91
94
97
Entry
1 [R]
T
[8C]
t
Solvent
4
Yield
[%][b]
ee
[h]
[%][c]
3[a]
1
2
3
4
5
6
7
8
9
1a [Ph]
1b [Bn]
1c [tBu]
1c [tBu]
1c [tBu]
1c [tBu]
1c [tBu]
1c [tBu]
1c [tBu]
1c [tBu]
1c [tBu]
1c [tBu]
25
25
25
25
25
25
25
0
24
THF
THF
THF
Et2O
TBME
toluene
CH2Cl2
Et2O
TBME
THF
4a
4b
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
>95
92
89
30
40
62
23
33
34
60
21
72
15
33
57
80
77
40
32
80
82
65
92
92
4[a]
2d [2-napthyl]
2e [3-OMeC6H4]
2 f [4-NO2C6H4]
2g [4-MeC6H4]
2h [4-PhC6H4]
2i [2-thioenyl]
2a [4-ClC6H4]
2b [4-BrC6H4]
2c [C6H5]
2d [2-napthyl]
2 f [4-NO2C6H4]
2a [4-ClC6H4]
2a [4-ClC6H4]
2a [4-ClC6H4]
24
30
30
30
30
30
96
96
48
120
96
5[a]
6[a,h]
7[a]
8[a]
9[a]
1c [H]
75
85
10[b]
11[b]
12[b]
13[b]
14[b]
15[b]
16[b]
17[b]
1d [Me]
1d [Me]
1d [Me]
1d [Me]
1d [Me]
1e [Et][i]
1 f [allyl][i]
1g [Bn][i]
64(27)[e]
68(28)[e]
69(24)[e]
63(24)[e]
70(28)[e]
60(24)[e]
52(22)[e]
37(35)[f]
96(68)[g]
97(70)[g]
98(67)[g]
98(65)[g]
94(74)[g]
98(22)[g]
96(40)[g]
90(11)[g]
0
0
10
11
12[d]
À20
THF
THF
À10
[a] The reaction was performed with 1.5 equiv of 1 and 1.0 equiv of 2.
[b] Yield of the isolated product. [c] Determined by HPLC. [d] The reac-
tion was performed with 1.0 equiv of 1 and 1.5 equiv of 2. TBME=tert-
butyl methyl ether.
[a] Reaction was performed in THF (0.1m) at À108C with 1.0 equiv of 1
and 1.5 equiv of 2. [b] Reaction was performed in TBME (0.05m) at
room temperature with 1.5 equiv of 1 and 1.0 equiv of 2. [c] Yield of the
isolated product. [d] Determined by HPLC analysis. [e] Yield of the iso-
lated syn isomer; anti/syn=7:3. [f] Yield of the isolated syn isomer; anti/
syn=1:1. [g] The ee value of the syn isomer. [h] Reaction was performed
at À258C. [i] Catalyst loading: 20 mol% 3.
MAHTs, their use in the decarboxylative reaction was limit-
ed.[4b] We developed a simple method for the synthesis of a-
alkyl-substituted MAHTs through the monoesterification of
various malonic acids catalyzed by 4-dimethylaminopyridine
(DMAP; see the Supporting Information for the synthetic
route). Unfortunately, the earlier result was poor when an
a-alkyl-substituted MAHT was subjected to the previous op-
timal conditions. After a short optimization (see the Sup-
porting Information), we set up the reaction at room tem-
perature in TBME. Excellent yields and ee values can be
achieved with various a-substituted MAHTs (Table 2, en-
tries 10–17). Although moderate diastereomeric ratios were
obtained and attempts to improve the diastereoselectivity
were not successful, the two diastereoisomers can be easily
separated by using flash column chromatography. The rela-
tive and absolute stereochemistry was determined from X-
ray analysis of 4m. To the best of our knowledge, this exam-
ple is the first of a decarboxylative Mannich reaction with
a-alkyl-substituted MAHTs.
in good yields with good ee values when a-alkyl-substituted
MAHTs 5a–c add to diethyl azodicarboxylate 6 in the pres-
ence of 5 or 20 mol% of catalyst 3 (Scheme 2). The use of
bulkier MAHTs 5a–c is necessary, whereas MAHT 1d gave
an unsatisfactory ee value. With simple deprotection and hy-
drolysis of product 7a–c, alkyl-substituted a-amino acids can
be obtained easily. This method could provide a new syn-
thetic route toward unnatural a-amino acids.
Two possible reaction pathways can be envisaged: 1) A
decarboxylation/nucleophilic addition pathway in which a
MAHT undergoes decarboxylation first to form a thioester
enolate and 2) a nucleophilic addition/decarboxylation
mechanism in which nucleophilic addition precedes decar-
boxylation. The latter is supported by previous studies.[6d,15]
In this study, we chose a transition-state (TS) structure in
which 3 binds to the imine and enol of MAHT through hy-
drogen bonds (Figure 2b) because we have previously show
that such a side-on TS structure is more favorable than the
b-Amino acid derivatives are useful building blocks in the
preparation of natural products, pharmaceutical targets, and
polypeptides with unique structural properties. The decar-
boxylative Mannich reaction,
described above, allows access
to valuable enantiopure b-
amino thioesters. We realized
that we can also prepare a-
amino acid derivatives by using
decarboxylative
a-amina-
tion.[14] Alkyl-substituted a-
amino thioesters were obtained
Scheme 2. Enantioselective decarboxylative amination of MAHTs 5a–c with azodicarboxylate 6.
Chem. Eur. J. 2011, 17, 8363 – 8370
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8365

C.-H. Tan et al.
thioester functional group, tosyl
protecting group, and carboxyl-
ate group). We assumed that
the highly negatively charged
carboxylate group will form a
stronger hydrogen-bonding in-
teraction with 3+H, therefore
we restricted our present com-
putational study to the side-on
conformation as shown in Fig-
ure 2b.
On the basis of DG° values,
DFT calculations indicate that
nucleophilic addition precedes
decarboxylation. Decarboxyla-
tion of MAHT has a barrier of
18.5 kcalmolÀ1
(Figure 2a),
which is substantially higher
than both the barriers for the
Mannich reaction (Figure 2b)
and
tautomerization
(Fig-
ure 2c). In addition, under the
reaction conditions, the anion
that is relevant to intermediate-
3 was characterized by using
electrospray ionization (ESI)
mass-spectrometric
analysis.
The mass-to-charge ratio (m/z)
and isotopic patterns are consis-
tent with the proposed anionic
species 8 (Figure 3). Our results
strongly support a mechanism
in which nucleophilic addition
precedes
decarboxylation.
Rouden and co-workers report-
ed a similar observation in trie-
thylamine-catalyzed decarboxy-
lative Mannich reactions.[17]
DFT calculations suggest that
the barrier to decarboxylation
is fairly independent of the
chemical environment of the
TS structure. The DG° value
for the decarboxylation of inter-
mediate-3 is only 0.2 kcalmolÀ1
lower than that for MAHT
(Figure 2d). On the basis of the
relevant DG° values given in
Figure 2, the rate-determining
step is the decarboxylation,
thus future attempts to increase
the reaction rate should focus
on tuning properties that can
Figure 2. a)–d) Possible pathways (see text for details). DG° is the difference in Gibbs free energy between
the transition states and the reactants. DG is the difference in Gibbs free energy between the molecules on the
right side of the chemical equation and those on the left. All units are given in kcalmolÀ1. DG° for the step
linking intermediates-1 and -2 is +0.39 kcalmolÀ1. G=E+thermal correction to Gibbs free energy, where E is
the electronic energy at CPCM/RM06-2X/6-311++G
ACHTUNGTREN(NUGN 2df,2p)//RM06-2X/6-31G(d) and the thermal correction
to Gibbs free energy is derived from the frequency calculation at RM06-2X/6-31G(d). Ar=4-ClC6H5.
corresponding face-on TS structure.[11,16] In this case, several
conformations can be conceived for the side-on TS structure
because of the presence of multiple hydrogen-bond acceptor
sites on the enol of the MAHT (i.e., the O atoms in the
lower the DG° value of decarboxylation.
Our calculations are further validated because the high
enantioselectivity could be predicted by comparing the
DGMannich° value (Figure 2b). The product derived from TS-
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Chem. Eur. J. 2011, 17, 8363 – 8370

Enantioselective Decarboxylative Mannich and Amination Reactions
FULL PAPER
perature for 10 min, followed by the
addition of MAHT 1d (14.3 mg,
0.075 mmol, 1.5 equiv). The reaction
mixture was stirred at room tempera-
ture and monitored by TLC analysis.
Upon complete consumption of 2a
after 96 h, the reaction solvent was re-
moved in vacuo and the crude product
was directly loaded onto
a short
column of silica gel, followed by gradi-
ent elution with hexane/ethyl acetate
mixtures (20:1–6:1). After removing
the solvent, the products were ob-
tained as white solids (20.2 mg in total,
92%). The syn and anti isomers were
separated by flash chromatography.
Representative procedure for decar-
boxylative
amination
between
MAHTs 5a–c and diethyl azodicarbox-
ylate 6 catalyzed by 3: Diethyl azodi-
carboxylate (6; 23.7 mL, 0.15 mmol,
3.0 equiv)
and
3
(0.56 mg,
Figure 3. Detection of counteranions of 8 by direct injection mass-spectrometric (ESI) analysis.
0.0025 mmol, or 0.05 equiv for 5a and
0.2 equiv for 5b,c) were dissolved in
TBME (5.0 mL), followed by the addi-
tion of MAHT
5
(0.05 mmol,
1(1R,2S) is consistent with experimental absolute configura-
1.0 equiv). The reaction mixture was stirred at room temperature and
monitored by TLC analysis. Upon complete consumption of 5 after 48 h,
the solvent was removed in vacuo and the crude product was directly
loaded onto a short column of silica gel, followed by gradient elution
with hexane/ethyl acetate mixtures (20:1–6:1). After removing the sol-
vent, product 7 was obtained as a colorless oil.
4c: White solid; m.p. 132–1348C; 92% ee; 1H NMR (500 MHz, CDCl3):
d=7.56 (d, J=8.2 Hz, 2H), 7.20–7.09 (m, 4H), 7.02 (d, J=8.5 Hz, 2H),
5.84 (d, J=7.0 Hz, 1H), 4.66 (dd, J=12.8, 6.5 Hz, 1H), 2.85 (dd, J=15.2,
6.6 Hz, 1H), 2.76 (dd, J=15.3, 5.8 Hz, 1H), 2.38 (s, 3H), 1.34 ppm (s,
9H); 13C NMR (75.5 MHz, CDCl3): d=198.0, 143.6, 137.9, 137.4, 133.7,
129.7, 128.7, 128.3, 127.3, 54.8, 50.0, 49.2, 29.7, 21.7 ppm; LRMS (ESI):
m/z: 448.0 [M+Na+]; HRMS (ESI): m/z: calcd for C20H24ClNO3S2Na:
448.0778 [M+Na+]; found: 448.0765.
tion, whereas the DDG° value between TS-1(1R,2S) and TS-
1(1S,2R) of 4.95 kcalmolÀ1 is consistent with the high ee value.
Conclusion
In conclusion, we have developed a bicyclic guanidine-cata-
lyzed enantioselective biomimetic decarboxylative Mannich
reaction and a decarboxylative amination reaction. Good
yields and excellent enantioselectivities (up to 90% yield,
up to 98% ee) were obtained for a wide range of MAHTs.
Experimental characterization of the intermediates and the-
oretical calculations indicate that nucleophilic addition pre-
cedes decarboxylation. Both b-amino acid derivatives and a-
amino acid derivatives can be obtained by using this meth-
odology. Further investigations of other variants of enantio-
selective decarboxylative reactions are underway in our lab-
oratory.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (70:30); flow rate: 1.0 mLminÀ1
;
258C; l=230 nm; retention time: 9.0 min (major), 12.1 min (minor).
4d: White solid; m.p. 144–1468C; 92% ee; 1H NMR (500 MHz, CDCl3):
d=7.55 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H), 7.16 (d, J=7.9 Hz,
2H), 6.96 (d, J=8.2 Hz, 2H), 5.85 (d, J=6.9 Hz, 1H), 4.65 (dd, J=12.8,
6.4 Hz, 1H), 2.84 (dd, J=15.3, 6.6 Hz, 1H), 2.76 (dd, J=15.3, 5.7 Hz,
1H), 2.38 (s, 3H), 1.34 ppm (s, 9H); 13C NMR (75.5 MHz, CDCl3): d=
198.1, 143.6, 138.4, 137.4, 131.7, 129.7, 128.6, 127.3, 121.9, 54.9, 49.9, 49.2,
29.7, 21.7 ppm; LRMS (ESI): m/z: 492.0 [M+Na+]; HRMS (ESI): m/z:
calcd for C20H24BrNO3S2Na: 492.0273 [M+Na+]; found: 492.0270.
Experimental Section
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (70:30); flow rate: 1.0 mLminÀ1
;
Representative procedure for the reaction between MAHT 1c and N-
tosyl imine 2a catalyzed by 3 (conditions a): N-Tosyl imine 2a (22.0 mg,
0.075 mmol, 1.5 equiv) and 3 (1.12 mg, 0.005 mmol, 0.1 equiv) were dis-
solved in THF (0.5 mL, 0.1m). The reaction mixture was cooled to
À108C for 15 min. MAHT 1c (8.8 mg, 0.05 mmol, 1.0 equiv) was added
to the reaction mixture, which was stirred at À108C for 96 h. The solvent
was removed in vacuo and the crude product was directly loaded onto a
short column of silica gel. Flash chromatography was performed with a
gradient elution with hexane/ethyl acetate mixtures (20:1–6:1). After re-
moving the solvent, product 4c was obtained as a white solid (15.3 mg,
72%).
258C; l=254 nm; retention time: 9.7 min (major), 13.6 min (minor).
4e: White solid; m.p. 118–1208C; 95% ee; 1H NMR (500 MHz, CDCl3):
d=7.59 (d, J=8.2 Hz, 2H), 7.23–7.12 (m, 5H), 7.11–7.01 (m, 2H), 5.66
(d, J=6.8 Hz, 1H), 4.68 (dd, J=12.8, 6.5 Hz, 1H), 2.90 (dd, J=15.2,
6.7 Hz, 1H), 2.80 (dd, J=15.2, 5.8 Hz, 1H), 2.37 (s, 3H), 1.34 ppm (s,
9H); 13C NMR (75.5 MHz, CDCl3): d=198.2, 143.4, 139.3, 137.6, 129.6,
128.7, 127.9, 127.4, 126.8, 55.4, 50.3, 49.0, 29.7, 21.7 ppm; LRMS (ESI):
m/z:: 414.0 [M+Na+]; HRMS (ESI): m/z:: calcd for C20H26NO3S2Na:
414.1168 [M+Na+]; found: 414.1167.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
((i.d.)0ꢁ250 mm); hexane/2-propanol (70:30); flow rate: 1.0 mLminÀ1
;
Representative procedure for the reaction between MAHT 1d and N-
tosyl imine 2a catalyzed by 3 (condition b): N-Tosyl imine 2a (14.6 mg,
0.05 mmol, 1.0 equiv) and 3 (1.12 mg, 0.005 mmol, 0.1 equiv) were dis-
solved in TBME (1.0 mL). The reaction mixture was stirred at room tem-
258C; l=230 nm; retention time: 7.6 min (major), 9.0 min (minor).
4 f: White solid; m.p. 134–1368C; 90% ee; 1H NMR (500 MHz, CDCl3):
d=7.84–7.60 (m, 1H), 7.54 (d, J=8.2 Hz, 2H), 7.50–7.40 (m, 3H), 7.24–
Chem. Eur. J. 2011, 17, 8363 – 8370
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8367

C.-H. Tan et al.
7.15 (m, 1H), 7.00 (d, J=8.0 Hz, 2H), 5.85 (d, J=6.9 Hz, 1H), 4.87 (dd,
J=12.8, 6.5 Hz, 1H), 2.99 (dd, J=15.2, 6.7 Hz, 1H), 2.89 (dd, J=15.2,
5.8 Hz, 1H), 2.22 (s, 3H), 1.33 ppm (s, 9H); 13C NMR (75.5 MHz,
CDCl3): d=198.2, 143.4, 137.5, 136.4, 133.2, 133.0, 129.5, 128.6, 128.1,
127.7, 127.3, 126.4, 126.3, 126.1, 124.4, 55.7, 50.2, 49.1, 29.7, 21.5 ppm;
LRMS (ESI): m/z: 464.0 [M+Na+]; HRMS (ESI): m/z: calcd for
C24H27NO3S2Na: 464.1315 [M+Na+]; found: 464.1311
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (70:30); flow rate: 1.0 mLminÀ1
;
258C; l=230 nm; retention time: 8.5 min (major), 10.3 min (minor).
4l: White solid; m.p. 144–1468C; 96% ee; 1H NMR (500 MHz, CDCl3):
d=7.48 (d, J=8.2 Hz, 2H), 7.13–7.03 (m, 4H), 6.94 (d, J=8.3 Hz, 2H),
6.05 (d, J=8.3 Hz, 1H), 4.46 (dd, J=8.1, 5.9 Hz, 1H), 2.83–2.73 (m, 1H),
2.34 (s, 3H), 1.34 (s, 9H), 1.14 ppm (d, J=7.0 Hz, 3H); 13C NMR
(75.5 MHz, CDCl3): d=203.7, 143.3, 138.0, 137.8, 133.4, 129.42, 128.5,
128.3, 127.1, 77.6, 77.2, 76.8, 60.3, 53.4, 49.1, 29.6, 21.6, 16.5 ppm; LRMS
(ESI): m/z: 462.0 [M+Na+]; HRMS (ESI): m/z: calcd for
C21H26ClNO3S2Na: 460.0935 [M+Na+]; found: 462.0932.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (70:30); flow rate: 1.0 mLminÀ1
;
258C; l=254 nm; retention time: 9.5 min (major), 10.6 min (minor).
4g: White solid; m.p. 98–1008C; 95% ee; 1H NMR (500 MHz, CDCl3):
d=7.59 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.10 (t, J=7.9 Hz,
1H), 6.75–6.65 (m, 2H), 6.57 (s, 1H), 5.68 (d, J=6.8 Hz, 1H), 4.66 (q, J=
6.5 Hz, 1H), 3.68 (s, 3H), 2.89 (dd, J=15.2, 6.7 Hz, 1H), 2.80 (dd, J=
15.2, 5.8 Hz, 1H), 2.36 (s, 3H), 1.35 ppm (s, 9H); 13C NMR (75.5 MHz,
CDCl3): d=198.2, 159.8, 143.4, 140.9, 137.6, 129.7, 129.6, 127.4, 119.1,
113.7, 112.2, 55.4, 55.3, 50.3, 49.0, 29.8, 21.6 ppm; LRMS (ESI): m/z:
444.1 [M+Na+]; HRMS (ESI): m/z: calcd for C21H27NO4S2Na: 444.1274
[M+Na+]; found: 444.1266.
The ee value was determined by HPLC analysis. Chiralpak AD-H
(4.6 mm (i.d.)ꢁ250 mm); hexane/2-propanol (75:25); flow rate:
1.0 mLminÀ1; 258C; l=230 nm; retention time: anti isomer: 10.9 min
(major), 24.3 min (minor); syn isomer: 6.6 min (minor), 8.1 min (major).
4m: White solid; m.p. 145–1478C; 97% ee; 1H NMR (500 MHz, CDCl3):
d=7.48 (d, J=8.3 Hz, 2H), 7.26–7.22 (m, 2H), 7.08 (d, J=8.0 Hz, 2H),
6.87 (d, J=8.3 Hz, 2H), 6.01 (d, J=8.3 Hz, 1H), 4.43 (dd, J=8.2, 5.7 Hz,
1H), 2.85–2.73 (m, 1H), 2.35 (s, 3H), 1.34 (s, 9H), 1.15 ppm (d, J=
7.0 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): d=203.8, 143.3, 138.4, 138.0,
131.5, 129.4, 128.7, 127.1, 121.6, 60.4, 53.3, 49.1, 29.7, 21.6, 16.5 ppm;
LRMS (ESI): m/z: 506.0 [M+Na+]; HRMS (ESI): m/z: calcd for
C21H26BrNO3S2Na: 506.0430 [M+Na+]; found: 506.0427
The ee value was determined by HPLC analysis. Chiralpak AD-H
(4.6 mm (i.d.)ꢁ250 mm); hexane/2-propanol (70:30); flow rate:
1.0 mLminÀ1
; 258C; l=254 nm; retention time: 10.3 min (major),
11.2 min (minor).
The ee value was determined by HPLC analysis. Chiralpak AD-H
(4.6 mm (i.d.)ꢁ250 mm); hexane/2-propanol (75:25); flow rate:
1.0 mLminÀ1; 258C; l=230 nm; retention time: anti isomer: 12.2 min
(major), 29.2 min (minor); syn isomer: 7.4 min (minor), 9.1 min (major).
4n: White solid; m.p. 179–1818C; 98% ee; 1H NMR (500 MHz, CDCl3):
d=7.49 (d, J=8.2 Hz, 2H), 7.16–7.09 (m, 3H), 7.05 (d, J=8.1 Hz, 2H),
7.02–6.97 (m, 2H), 5.97 (d, J=8.4 Hz, 1H), 4.49 (dd, J=8.4, 5.9 Hz, 1H),
2.87–2.79 (m, 1H), 2.31 (s, 3H), 1.34 (s, 9H), 1.14 ppm (d, J=7.0 Hz,
3H); 13C NMR (126 MHz, CDCl3): d=203.7, 142.9, 139.3, 138.3, 129.3,
128.40, 127. 6, 127.2, 126.9, 60.9, 53.8, 48.9, 29.7, 21.6, 16.4 ppm; LRMS
(ESI): m/z: 428.1 [M+Na+]; HRMS (ESI): m/z: calcd for
C21H27NO3S2Na: 428.1325 [M+Na+]; found: 428.1318.
4h: White solid; m.p. 145–1478C; 91% ee; 1H NMR (500 MHz, CDCl3):
d=8.05 (d, J=8.7 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.6 Hz,
2H), 7.18 (d, J=8.0 Hz, 2H), 6.03 (d, J=6.8 Hz, 1H), 4.77 (dd, J=12.4,
6.4 Hz, 1H), 2.86 (dd, J=15.4, 6.6 Hz, 1H), 2.78 (dd, J=15.4, 5.4 Hz,
1H), 2.37 (s, 3H), 1.33 ppm (s, 9H); 13C NMR (75.5 MHz, CDCl3): d=
197.8, 147.5, 146.8, 144.0, 137.2, 129.8, 127.8, 127.3, 123.8, 54.8, 49.5, 49.5,
29.7, 21.7 ppm; LRMS (ESI): m/z: 459.0 [M+Na+]; HRMS (ESI): m/z:
calcd for C20H24N2O5S2Na: 459.1019; [M+Na+]; found: 459.1014.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (70:30); flow rate: 1.0 mLminÀ1
;
258C; l=254 nm; retention time: 15.4 min (major), 16.8 min (minor).
4i: White solid; m.p. 131–1338C; 94% ee; 1H NMR (500 MHz, CDCl3):
d=7.59 (d, J=8.1 Hz, 2H), 7.16 (d, J=7.9 Hz, 2H), 6.98 (q, J=8.2 Hz,
4H), 5.59 (d, J=6.6 Hz, 1H), 4.63 (q, J=6.4 Hz, 1H), 2.90 (dd, J=15.3,
6.7 Hz, 1H), 2.79 (dd, J=15.2, 5.9 Hz, 1H), 2.38 (s, 3H), 2.27 (s, 3H),
1.35 ppm (s, 9H); 13C NMR (75.5 MHz, CDCl3): d=198.2, 143.3, 137.7,
137.6, 136.4, 129.6, 129.3, 127.4, 126.7, 55.2, 50.4, 48.9, 29.76, 21.7,
21.2 ppm; LRMS (ESI): m/z: 428.1 [M+Na+]; HRMS (ESI): m/z: calcd
for C21H27NO3S2Na: 428.1325 [M+Na+]; found: 428.1336.
The ee value was determined by HPLC analysis. Lux 5u Cellulose-2
(4.6 mm (i.d.)ꢁ250 mm); hexane/2-propanol (90:10); flow rate:
1.0 mLminÀ1; 258C; l=230 nm; retention time: anti isomer: 17.2 min
(minor), 21.4 min (major); syn isomer: 19.0 min (minor), 28.1 min
(major).
4o: White solid; m.p. 136–1388C; 98% ee; 1H NMR (500 MHz, CDCl3):
d=7.78–7.70 (m, 1H), 7.64–7.56 (m, 2H), 7.48–7.38 (m, 4H), 7.35 (s,
1H), 7.15–7.08 (m, 1H), 6.85 (d, J=8.0 Hz, 2H), 6.06 (d, J=8.4 Hz, 1H),
4.64 (dd, J=8.3, 6.0 Hz, 1H), 3.03–2.82 (m, 1H), 2.10 (s, 3H), 1.32 (s,
9H), 1.20 ppm (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3): d=
203.8, 143.0, 138.1, 136.2, 133.1, 132.86, 129.2, 128.4, 128.1, 127.7, 127.1,
126.4, 126.3, 126.1, 124.6, 61.2, 53.56, 49.0, 29.7, 21.4, 16.6 ppm; LRMS
(ESI): m/z: 478.1 [M+Na+]; HRMS (ESI): m/z: calcd for
C25H29NO3S2Na: 478.1471 [M+Na+]; found: 478.1479
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (70:30); flow rate: 1.0 mLminÀ1
;
258C; l=230 nm; retention time: 8.5 min (major), 10.8 min (minor).
4j: White solid; m.p. 137–1398C; 97% ee; 1H NMR (500 MHz, CDCl3):
d=7.60 (d, J=8.1 Hz, 2H), 7.51 (d, J=7.6 Hz, 2H), 7.47–7.37 (m, 4H),
7.37–7.30 (m, 1H), 7.23–7.12 (m, 4H), 5.78 (d, J=6.9 Hz, 1H), 4.75 (dd,
J=12.8, 6.5 Hz, 1H), 2.94 (dd, J=15.3, 6.8 Hz, 1H), 2.85 (dd, J=15.3,
5.7 Hz, 1H), 2.34 (s, 3H), 1.36 ppm (s, 9H); 13C NMR (75.5 MHz,
CDCl3): d=198.2, 143.4, 140.8, 140.7, 138.3, 137.6, 129.6, 129.0, 127.6,
127.4, 127.3, 127.2, 55.2, 50.2, 49.0, 29.8, 21.6 ppm; LRMS (ESI): m/z:
490.1 [M+Na+]; HRMS (ESI): m/z: calcd for C26H29NO3S2Na: 490.1481
[M+Na+]; found: 490.1480.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (90:10); flow rate: 1.0 mLminÀ1
;
258C; l=254 nm; retention time: anti isomer: 18.4 min (major), 32.4 min
(minor); syn isomer: 15.0 min (major), 23.2 min (minor).
4p: White solid; m.p. 155–1578C; 94% ee; 1H NMR (500 MHz, CDCl3):
d=8.01 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.7 Hz,
2H), 7.11 (d, J=8.1 Hz, 2H), 6.25 (d, J=8.3 Hz, 1H), 4.58 (dd, J=8.2,
5.2 Hz, 1H), 2.87–2.80 (m, 1H), 2.33 (s, 3H), 1.31 (s, 9H), 1.17 ppm (d,
J=7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3): d=203.5, 147.4, 146.9,
143.7, 137.8, 129.59, 127.9, 127.1, 123.6, 60.2, 53.0, 49.4, 29.6, 21.6,
16.6 ppm; LRMS (ESI): m/z: 473.0 [M+Na+]; HRMS (ESI): m/z: calcd
for C21H26N2O5S2Na: 473.1175 [M+Na+]; found: 473.1167.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (80:20); flow rate: 1.0 mLminÀ1
;
258C; l=254 nm; retention time: 16.7 min (major), 18.5 min (minor).
1
4k: White solid; m.p. 97–998C; 85% ee; H NMR (500 MHz, CDCl3): d=
7.66 (d, J=8.2 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 7.11 (dd, J=5.0, 1.1 Hz,
1H), 6.83–6.78 (m, 1H), 6.78–6.74 (m, 1H), 5.72 (d, J=7.9 Hz, 1H), 4.99
(dd, J=13.4, 5.8 Hz, 1H), 3.02 (dd, J=15.7, 5.6 Hz, 1H), 2.93 (dd, J=
15.7, 5.9 Hz, 1H), 2.39 (s, 3H), 1.38 ppm (s, 9H); 13C NMR (75.5 MHz,
CDCl3): d=198.0, 143.5, 143.2, 137.6, 129.7, 127.3, 126.8, 125.4, 125.4,
51.1, 50.3, 49.1, 29.8, 21.7 ppm; LRMS (ESI): m/z: 420.0 [M+Na+];
HRMS (ESI): m/z: calcd for C18H23NO3S3Na: 420.0732 [M+Na+]; found:
420.0733
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (70:30); flow rate: 1.0 mLminÀ1
;
258C; l=230 nm; retention time: anti isomer: 16.6 min (major), 28.6 min
(minor); syn isomer: 7.1 min (minor), 9.2 min (major).
4q: White solid; m.p. 139–1418C; 98% ee; 1H NMR (500 MHz, CDCl3):
d=7.47 (d, J=8.3 Hz, 2H), 7.14–7.00 (m, 4H), 6.90 (d, J=8.4 Hz, 2H),
8368
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8363 – 8370

Enantioselective Decarboxylative Mannich and Amination Reactions
FULL PAPER
6.10 (d, J=8.5 Hz, 1H), 4.54 (dd, J=8.4, 5.0 Hz, 1H), 2.59–2.52 (m, 1H),
2.34 (s, 3H), 1.80–1.69 (m, 1H), 1.54–1.47 (m, 1H), 1.32 (s, 9H),
0.93 ppm (t, J=7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3): d=203.8,
143.2, 138.2, 137.9, 133.3, 129.41, 128.5, 128.2, 127.1, 60.8, 58.6, 49.3, 29.6,
24.3, 21.6, 11.9 ppm; LRMS (ESI): m/z: 476.1 [M+Na+]; HRMS (ESI):
m/z: calcd for C22H28ClNO3S2Na: 476.1091 [M+Na+]; found: 476.1080.
Procedure for the determination of intermediate by MS (ESI): N-Tosyl
imine 2a (22.0 mg, 0.075 mmol, 1.5 equiv) and 3 (1.12 mg, 0.005 mmol,
0.1 equiv) were dissolved in THF (0.5 mL). The mixture was cooled
down to À108C, and after 15 min MAHT 1c (8.8 mg, 0.05 mmol,
1.0 equiv) was added. The reaction mixture was stirred at À108C, and the
mass spectra (ESI) were recorded at intervals of 10 h. The anion of inter-
mediate-3 was characterized by using MS (ESI): the m/z values and iso-
topic patterns are consistent with the proposed anionic species 8.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (90:10); flow rate: 1.0 mLminÀ1
;
258C; l=210 nm; retention time: anti isomer: 14.2 min (major), 30.0 min
(minor); syn isomer: 10.8 min (minor), 11.9 min (major).
Computational detail: All the calculations were performed on 64-bit
Linux systems in the High-Performance Computing (HPC) Center in the
National University of Singapore. Gaussian 09[18] was used for all the cal-
culations. Geometry optimization was performed at RM06–2X[19]/6–
31G(d)[20] with tight convergence criteria through “opt=tight” and inte-
gration grid specified through “int=ultrafine”.[21] Frequency calculations
were performed on all the stationary points to verify their nature. Single-
point calculations (the int=ultrafine option was used) on RM06–2X/6–
31G(d) optimized stationary points were performed at RM06–2x/6–311+
4r: White solid; m.p. 132–1348C; 96% ee; 1H NMR (500 MHz, CDCl3):
d=7.47 (d, J=8.2 Hz, 2H), 7.13–7.01 (m, 4H), 6.89 (d, J=8.4 Hz, 2H),
6.15 (d, J=8.6 Hz, 1H), 5.79–5.64 (m, 1H), 5.14–5.02 (m, 2H), 4.57 (dd,
J=8.7, 4.7 Hz, 1H), 2.74–2.61 (m, 1H), 2.48–2.40 (m, 1H), 2.34 (s, 3H),
2.32–2.26 (m, 1H), 1.31 ppm (s, 9H); 13C NMR (75 MHz, CDCl3) d=
203.2, 143.3, 138.2, 137.7, 133.8, 133.4, 129.4, 128.5, 128.2, 127.1, 118.7,
58.7, 58.3, 49.5, 35.2, 29.6, 21.6 ppm; LRMS (ESI): m/z: 488.0 [M+Na+];
HRMS (ESI): m/z: calcd for C23H28ClNO3S2Na: 488.1091 [M+Na+];
found: 488.1087.
+GACTHNUTRGNEUNG
(2df,2p),[22] and the conductorlike polarizable continuum model
(CPCM)[23] solvation model was used to estimate the effect of THF on
the energetics of the stationary points. Intrinsic reaction coordinate
(IRC) calculations on all the transition states were performed with the
following combination of keywords “irc=(maxpoints=500, recalc=20,
calcfc, maxcycle=100, tight) M062x/6–31G(d) geom=connectivity, int=
ultrafine”. The minima found by the IRC calculations were reoptimized
and single-point calculations were performed as described above.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (90:10); flow rate: 1.0 mLminÀ1
;
258C; l=230 nm; retention time: anti isomer: 14.7 min (major), 27.7 min
(minor); syn isomer: 11.5 min (major), 13.2 min (minor).
4s: White solid; m.p. 164–1668C; 90% ee; 1H NMR (500 MHz, CDCl3):
d=7.46 (d, J=8.2 Hz, 2H), 7.31–7.19 (m, 3H), 7.13 (d, J=7.2 Hz, 2H),
7.08–7.01 (m, 4H), 6.83 (d, J=8.4 Hz, 2H), 6.30 (d, J=8.7 Hz, 1H), 4.54
(dd, J=8.7, 3.9 Hz, 1H), 3.02 (dd, J=15.8, 10.1 Hz, 2H), 2.90–2.81 (m,
2H), 2.34 (s, 3H), 1.25 ppm (s, 9H); 13C NMR (75 MHz, CDCl3 ppm) d=
203.6, 143.3, 138.2, 137.7, 137.6, 133.4, 129.4, 129.4, 128.8, 128.5, 128.2,
127.1, 127.0, 61.0, 58.4, 49.3, 37.1, 29.4, 21.6 ppm; LRMS (ESI): m/z:
538.1 [M+Na+]; HRMS (ESI): m/z: calcd for C27H30ClNO3S2Na:
538.1248 [M+Na+]; found: 538.1240.
Acknowledgements
This work was supported by grants (R-143–000–337–112 and R-143–000–
376–112) and a research scholarship (Y.P.) from the National University
of Singapore.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (90:10); flow rate: 1.0 mLminÀ1
;
258C; l=230 nm; retention time: anti isomer: 26.8 min (major), 46.3 min
(minor); syn isomer: 23.6 min (major), 34.2 min (minor).
[1] a) D. OꢂHagan, The Polyketide Metabolites, Ellis Horwood, Chiches-
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[3] a) Y. Kobuke, J.-i. Yoshida, Tetrahedron Lett. 1978, 19, 367–370;
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1
7a: Colorless oil; 88% ee; H NMR (500 MHz, CDCl3): d=6.69–6.23 (m,
1H), 5.08–4.63 (m, 1H), 4.32–4.10 (m, 4H), 1.83 (s, 2H), 1.55 (d, J=
3.6 Hz, 6H), 1.44 (d, J=6.2 Hz, 3H), 1.30–1.22 (m, 6H), 1.01 ppm (s,
9H); 13C NMR (126 MHz, CDCl3 ppm) d=200.8, 156.1, 63.2, 62.4, 53.8,
53.7, 32.9, 31.8, 29.9, 14.6 ppm; LRMS (ESI): m/z: 399.0 [M+Na+];
HRMS (ESI): m/z: calcd for C17H32N2O5SNa: 399.1924 [M+Na+]; found:
399.1933.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (92:08); flow rate: 0.8 mLminÀ1
;
258C; l=230 nm; retention time: 9.1 min (minor), 13.1 min (major).
1
7b: Colorless oil; 85% ee; H NMR (500 MHz, CDCl3): d=6.67–6.33 (m,
1H), 4.84–4.39 (m, 1H), 4.29–4.11 (m, 4H), 1.94 (br, 1H), 1.82 (s, 2H),
1.75 (br, 1H), 1.54 (s, 6H), 1.27 (t, J=7.0 Hz, 6H), 1.09 (br, 3H),
1.00 ppm (s, 9H); 13C NMR (75 MHz, CDCl3) d=200.1, 156.7, 70.5, 69.3,
63.2, 62.2, 54.0, 53.6, 32.9, 31.8, 29.9, 29.8, 22.6, 14.6, 11.3 ppm; LRMS
(ESI): m/z: 413.0 [M+Na+]; HRMS (ESI): m/z: calcd for
C18H34N2O5SNa: 413.2081 [M+Na+]; found: 413.2094.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
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258C; l=230 nm; retention time: 7.5 min (minor), 9.5 min (major).
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7c: Colorless oil; 90% ee; H NMR (500 MHz, CDCl3): d=6.69–6.28 (m,
1H), 4.97–4.49 (m, 1H), 4.28–4.11 (m, 4H), 1.87 (br, 1H), 1.82 (s, 2H),
1.73 (br, 1H), 1.54 (s, 6H), 1.50–1.29 (m, 4H), 1.27 (t, J=7.1 Hz, 6H),
1.00 (s, 9H), 0.90 ppm (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3
ppm) d=200.4, 156.65, 68.7, 67.7, 63.2, 62.2, 54.0, 53.6, 32.9, 31.8, 29.9,
29.8, 28.8, 28.4, 22.5, 14.6, 14.0 ppm; LRMS (ESI): m/z: 441.0 [M+Na+];
HRMS (ESI): m/z: calcd for C20H38N2O5SNa: 441.2394 [M+Na+]; found:
441.2392.
The ee value was determined by HPLC analysis. Chiralpak IA (4.6 mm
(i.d.)ꢁ250 mm); hexane/2-propanol (92:08); flow rate: 0.8 mLminÀ1
;
258C; l=230 nm; retention time: 6.7 min (minor), 8.8 min (major).
Chem. Eur. J. 2011, 17, 8363 – 8370
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Received: March 4, 2011
Published online: June 15, 2011
8370
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8363 – 8370