Electrocyclic ring-opening reactions may cause failure of enolate alkylation of 1,4-oxazin-2-one based chiral glycine equivalents

Article abstract of DOI:10.1016/j.tet.2008.03.059

Attempted monoalkylation of 6-methyl-5,6-diphenyl-1,4-oxazin-2-one that had been designed as a chiral glycine equivalent gave even under optimized conditions only minute amounts of the desired monoalkylation product whereas an acyclic ketone was obtained repeatedly as the major product. This result indicates that the enolate of the chiral glycine equivalent is prone to an electrocyclic ring-opening reaction. This hypothesis could be further supported by additional experiments. Based on these results, it is reasonable to assume that electrocyclic ring-opening reactions are also the cause for the failure of alkylation reactions of structurally related glycine equivalents reported in the literature.

Full text of DOI:10.1016/j.tet.2008.03.059

Tetrahedron 64 (2008) 5107–5110
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Electrocyclic ring-opening reactions may cause failure of enolate
alkylation of 1,4-oxazin-2-one based chiral glycine equivalents
ˇ
*
ˇ
´
Sona Simonyiova, Klaus T. Wanner
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universita¨t Mu¨nchen, Butenandtstr. 7, Haus C, 81377 Munich, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Attempted monoalkylation of 6-methyl-5,6-diphenyl-1,4-oxazin-2-one that had been designed as a chi-
ral glycine equivalent gave even under optimized conditions only minute amounts of the desired
monoalkylation product whereas an acyclic ketone was obtained repeatedly as the major product. This
result indicates that the enolate of the chiral glycine equivalent is prone to an electrocyclic ring-opening
reaction. This hypothesis could be further supported by additional experiments. Based on these results, it
is reasonable to assume that electrocyclic ring-opening reactions are also the cause for the failure of
alkylation reactions of structurally related glycine equivalents reported in the literature.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 25 February 2008
Accepted 17 March 2008
Available online 21 March 2008
Dedicated to Professor H. No¨th with best
wishes on the occasion of his 80th birthday
Keywords:
Oxazinones
Enolate
Alkylation
Electrocyclic ring-opening reaction
Chiral glycine equivalents
1. Introduction
as a result of its synthesis from alanine (Scheme 1). This method is
therefore less flexible with respect to the substitution pattern of the
Asymmetric syntheses of a-amino acids are a broad and well
established field in organic chemistry. As non-natural a-amino
acids often exhibit remarkable pharmacological and conforma-
tional propertiesdwhether as free amino acids or as part of bio-
active peptidesdthe area of research still grows at a rapid and
constant pace.1 In contrast to the numerous methods available for
the asymmetric synthesis of a-monosubstituted a-amino acids,
only a limited number exist for the synthesis of their a,a-
disubstituted counterparts.2
final compound, i.e., the a-quaternary a-amino acid.5
OMe
N
Ph
Ph
O
O
O
N
O
OMe
N
N
Z
O
N
Boc
Ph
Me
O
1
3
4
2
Scheme 1.
The diastereoselective alkylation of a chiral glycine equivalent in
the form of an enolate is certainly one of the most popular synthetic
concepts applied to the preparation of a-monosubstituted a-amino
acids.1 High versatility and efficiency of the overall process are
characteristics of many chiral glycine equivalents developed on the
basis of this concept. Accordingly, a related strategy can also be
expected to be a highly effective method for the synthesis of a,a-
disubstituted a-amino acids. The chiral tert-butyl imidazole-1-
carboxylate 13 and the chiral oxazinone 24 are well established
examples developed in this field, i.e., the synthesis of a-quaternary
a-amino acids. A further case is the oxazinone 3 in which one
substituent of the final amino acid is already present in the scaffold
2. Results and discussion
In a previous article, we introduced the 1,4-oxazinone 4 as a new
chiral glycine equivalent for the preparation of a-monoalkylated as
well as a,a-dialkylated a-amino acids. Alkylation reactions of 4
proceeded smoothly and with high diastereoselectivities for a wide
variety of electrophiles and a final hydrolysis gave the target
compounds in good yields.6
We now planned to extend our studies to the 1,4-oxazinone
(rac)-7, which we expected to be of special value as a chiral glycine
equivalent. As for related structures, alkylation reactions of the
anion of (rac)-7 can be expected to proceed with high diaste-
reoselectivities. Just as important is the fact that the final amino
acids should be easy to liberate as well. Mild acidic conditions
* Corresponding author. Tel.: þ49 89 2180 77249; fax: þ49 89 2180 77247.
E-mail address: klaus.wanner@cup.uni-muenchen.de (K.T. Wanner).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.059

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S. Simonyiova, K.T. Wanner / Tetrahedron 64 (2008) 5107–5110
5108
should suffice to remove the chiral auxiliary. Where appropriate,
a hydrogenolytic procedure could be applied instead of a hydro-
lytic. The feasibility of the latter is the result of the benzylic posi-
tions of the two heteroatoms in the 1,4-oxazinone ring in (rac)-7,
which was actually also an important facet in the design of (rac)-7
as a chiral glycine equivalent (Scheme 2).
Searching for an explanation of this puzzling result, we won-
dered whether the side product (rac)-10 possibly formed in-
dependently from the alkylation process simply as a consequence
of treating (rac)-7 with a base. To support our theory, (rac)-7 was
only reacted with s-BuLi and with NaHMDS. After aqueous workup,
this led indeed to (rac)-10 in each case though in varying amounts
and with some starting material, (rac)-7, still present. When opti-
mized (NaHMDS 1.1 equiv, THF, ꢀ78 ꢁC, 4 days), the reaction went
to completion providing (rac)-10 after purification on silica gel in
a 79% yield (Scheme 4).
Ph
Ph
Ph
Ph
Ph
Ph
O
N
O
a
b, c
NHBoc
H3C
H3C
O
O
H3C
OH
O
O
Ph
Ph
CH3
Ph
N
(rac)-7
(rac)-6
(rac)-5
a
Ph
H3C
Scheme 2. (a) Boc-glycine, DCC, 4-DMAP, CH2Cl2, rt, 24 h, 37%; (b) TFA, CH2Cl2, rt,14 h;
(c) acetate buffer pH 5, CH2Cl2, rt, 8 h, 79%.
O
O
O
(rac)-7
(rac)-10
The synthesis of the chiral glycine equivalent (rac)-7 was per-
formed according to the synthetic sequence outlined in Scheme 2
starting from 2-hydroxy-1,2-diphenylpropan-1-one [(rac-5]). For
the sake of simplicity, we decided to synthesize 7 in its racemic
form [(rac)-7] as neither of the two enantiomers of the chiral
auxiliary present in (rac)-7, the a-hydroxyketone (R)-5 or (S)-5,
were available commercially. In the early phase of this study, there
was yet no need to work with the chiral glycine equivalent in
enantiopure form. Important characteristics, e.g., like its efficiency
with respect to the asymmetric induction, could, of course, also be
obtained from the racemic compound (rac)-7.
As the first step of the synthesis of (rac)-7, the racemic a-
hydroxyketone (rac)-5 was reacted in the presence of catalytic
amounts of DMAP with Boc protected glycine activated with DCC to
give the glycine ester (rac)-6 in a 37% yield. In order to initiate the
cyclization, (rac)-6 was deprotected by treatment with trifluoro-
acetic acid and the reaction mixture brought to a pH of 5 where-
upon the desired chiral glycine equivalent (rac)-7 was formed in
a 79% yield (Scheme 2).
Scheme 4. (a) NaHMDS, THF, ꢀ78 ꢁC, 4 days, 79%.
An explanation for the formation of (rac)-10 could be an elec-
trocyclic ring-opening reaction. This seemed probable as, according
to literature reports, double unsaturated six membered heterocy-
clic ring systems can undergo spontaneous ring-opening reactions
depending on their substitution pattern.8
When the enolate 11, which is the result of treating (rac)-7 with
a base, undergoes an electrocyclic ring-opening reaction the salt of
the carboxylic acid 12 will form (Scheme 5). The higher thermo-
dynamic stability of the carboxylic acid salt 12 compared to the
enolate 11 can be considered as the driving force for the ring-
opening reaction.
Ph
Ph
N
Ph
Ph
Ph
N
N
Ph
Base
H3C
O
H3C
O
O-
O-
O
O
As alkylation reactions of (rac)-7 could be expected to proceed
quite smoothly, our interest was largely focused on the asymmetric
induction this process would proceed with. However, when (rac)-7
was treated under standard conditions with 1.1 equiv of s-BuLi at
ꢀ78 ꢁC in THF followed by benzyl bromide as a model electrophile
no alkylation product could be detected. Only the starting material
and some decomposition product were present. Consequently, we
varied the reaction conditions, i.e., the base (s-BuLi, NaHMDS, P4-t-
Bu, BTPP, BEMP, phase transfer reaction with KOH and Bu4NBr in
CH2Cl2, H2O), the reaction temperature (ꢀ78 ꢁC to 0 ꢁC) and the
solvent (THF, DME, CH2Cl2). The results, however, remained dis-
appointing as either no alkylation product or only the double
alkylated derivative (rac)-9 was found (Scheme 3). In very few
cases, in addition to the dibenzyl derivative (rac)-9 and the starting
material some of the desired monobenzylated compound (rac)-8
(stereochemistry not assigned) was present in the crude reaction
product (e.g., with BTPP) (Scheme 3). However, interestingly, for
most of the performed alkylation reactions, no matter how the
reaction conditions were adjusted, the same side product was
observed, which was finally identified as the diphenylpropanone
derivative (rac)-10.7
(rac)-7
12
11
CH3
+
Ph
Ph
N
Ph
H2O
H
Ph
O
OH
O
13
(rac)-10
Ph
Ph
H2O
N
N
Ph
Ph
+
O
O
CH3
(rac)-14
CH3
O
O
(rac)-15
Scheme 5.
In the presence of water, 12, as a 2-azadiene, can be expected to
undergo a hydrolytic cleavage, which is likely to first effect the
imino subunit and subsequently the remaining enamine moiety. In
any case, in addition to ammonia and glyoxalic acid, the ketone
(rac)-10 should form, the compound frequently found during the
reactions above mentioned.
Ph
Ph
Ph
Ph
Ph
CH3
N
N
N
H
Ph
Ph
Ph
a) Base
Ph
+
+
Ph
H3C
Ph
b) BnBr (3.0 equiv.)
H3C
H3C
O
O
O
O
O
O
O
(rac)-7
(rac)-10
(rac)-8
Scheme 3.
(rac)-9

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S. Simonyiova, K.T. Wanner / Tetrahedron 64 (2008) 5107–5110
5109
A number of additional experiments were performed to gain
more evidence whether the reaction mechanism proceeds as pro-
posed above. Our aim was to prove the formation of the primary
product of the ring-opening reaction: the carboxylic acid salt 12.
For the first experiment, the deprotonation was carried out in
analogy to the set up described above, which had yielded (rac)-10
in high amounts (NaHMDS 1.1 equiv, THF, ꢀ78 ꢁC, 4 days). But the
mixture was then liberated from solvent (at ꢀ40 ꢁC) and the re-
sidue treated with trifluoroacetic acid (TFA, 1.1 equiv in CH2Cl2).
These conditions were chosen to rule out any hydrolysis of 12 and
to transform it in the free acid 13. However, in the resulting reaction
mixture significant amounts of the hydrolysis product (rac)-10
(w25%) were again present in addition to a mixture of two new
stereoisomeric compounds. Under modified conditions (s-BuLi
1.1 equiv, THF, ꢀ78 ꢁC, 6 days, removal of the solvent at ꢀ50 ꢁC, TFA
1.0 equiv in MeOH at rt), the formation of (rac)-10 could at last be
significantly reduced (w2%). This was a significant improvement as
the two newly formed diastereomeric compounds underwent
decomposition when subjected to column chromatography at silica
gel or aluminium oxide for purification and therefore had to be
characterized as a mixture of diastereomers out of the crude
reaction mixture (1H NMR, 13C NMR, IR, HRMS). These compounds
were found to be the oxazolinones (rac)-14 and (rac)-15. Upon
generation by protonation of 12, the free acid 13 had apparently
undergone a ring closure reaction by addition of the carboxylate
function to the enamine moiety. In contrast to their precursors, the
diastereomers (rac)-14 and (rac)-15 were sufficiently stable for
isolation even though they underwent hydrolysis during chroma-
tography and could also be completely converted to the ketone
(rac)-10 when treated with TFA (in H2O).
ring-opening reaction of the enolate is slowed down in comparison
to the alkylation reaction, which allows the latter to proceed. This is
probably the reason why literature almost exclusively describes
alkylation reactions of this type of chiral amino acid equivalents in
which the first substituent in the a-positions of the carbonyl group
is already present and a second is introduced.
3. Conclusion
In summary, the 1,4-oxazinone (rac)-7 has been synthesized
and evaluated for its suitability as a chiral glycine equivalent for
the synthesis of a-substituted a-amino acids. But attempted
monoalkylation reactions provided only minute amounts of the
desired monoalkylation products if at all. Instead of significant
amounts of a decomposition product, the ketone (rac)-10 was
found indicating that the enolate of the oxazinone (rac)-7 had
undergone an electrocyclic ring-opening reaction. This assumption
was further supported by additional experiments in which a mix-
ture of the diastereomeric oxazolidinones (rac)-14 and (rac)-15
was isolated. Obviously, under the workup conditions chosen, the
initial product of the ring-opening reaction, the carboxylic acid
salt 12, undergoes a subsequent ring closure providing these
compounds. The electrocyclic ring-opening reactions is likely to
also be responsible for the failure of monoalkylation reactions of
related chiral glycine equivalents, i.e., 16 and 17, reported in the
literature.
4. Experimental
4.1. General remarks
Although the expected carboxylic acid 13 could not be detected,
the results of these experiments, the formation of the diastereomers
(rac)-14 and (rac)-15 as reaction products, clearly support our
hypothesis on the nature of the reaction mechanism as proposed
above.
All experiments were carried out in oven-dried glassware under
a dry N2 atmosphere. Standard vacuum techniques were used for
handling air-sensitive materials. Solvents were dried, kept under N2
and freshly distilled before use. Reagents were used as commer-
cially available. Mp (uncorrected values): melting point apparatus
according to Dr. Tottoli (Bu¨chi no. 510). NMR spectra: Jeol Eclipse
þ400 and Jeol Eclipse þ500, chemical shifts (d) are reported in parts
per million. IR: FT-IR spectrometer Paragon 1000 (Perkin–Elmer),
KBr pellets. MS: 5989 mass spectrometer with 59980 B Particle
Beam LC/MS Interface (Hewlett–Packard). Combustion analysis:
CHN Rapid (Fa. Heraeus). Column chromatography: on silica gel
((Merck 60) 0.040–0.063 mm). TLC plates 60 F-254, detection with
UV (l¼254 nm) or with ammonium cerium(IV) heptamolybdate.
Monosubstituted 1,4-oxazinone derivatives like 3 and pyr-
azinone analogues have been used quite extensively and with great
success for enolate alkylation and the preparation of a-quaternary
amino acids.5,9 In contrast, for the parent compounds, the chiral
glycine equivalents 16 and 17 (Fig. 1), only casual remarks have
been reported about attempts of enolate alkylation reactions.
According to these they end up with the dialkylation instead of the
monoalkylation products only.10,11 These results are similar to our
observations for (rac)-7 (see above), in which as far as alkylation
reactions took place at all, the disubstituted derivative (rac)-9 was
found as the major product but still in low yields. As also outlined
above, all attempts to optimize the reaction conditions for the
formation of the monosubstituted derivative of (rac)-7, (rac)-8,
remained fruitless. According to our results, the reason for this is
the electrocyclic ring-opening reaction of the enolate 11, which
efficiently competes with the alkylation reaction. The same is likely
to be true for the alkylation reactions of the oxazinone 16 and the
pyrazinone 17, too.
4.1.1. (rac)-(1-Methyl-2-oxo-1,2-diphenylethyl) 2-[N-(1,1-dimethyl-
ethyloxycarbonyl)amino]ethanoate (rac)-6
N-tert-Butyloxycarbonylglycine (1.769 g, 10.10 mmol, 2.0 equiv),
2-hydroxy-1,2-diphenylpropan-1-one (1.142 g, 5.049 mmol) and
DMAP (61.7 mg, 0.505 mmol, 0.1 equiv) were added to a solution of
DCC (2.084 g,10.10 mmol, 2.0 equiv) in CH2Cl2 (70 mL). The mixture
was stirred for 72 h at rt. The solid material was filtered off and
washed with CH2Cl2. The organic layer was washed with H2O, dried
over Na2SO4, filtrated and concentrated in vacuo. CC (heptane/
EtOAc¼8:2). Yield: 708.6 mg (37%), colourless crystals, mp 128–
129 ꢁC. TLC Rf¼0.23 (heptane/EtOAc¼8:2). 1H NMR (400 MHz,
CD2Cl2) d¼1.41 (s, 9H, (CH3)3C), 1.92 (s, 3H, CH3), 3.71 (dd, J¼18.3,
5.1 Hz, 1H, CH2), 3.98 (dd, J¼18.3, 6.2 Hz, 1H, CH2), 4.77–4.86 (br s,
1H, NH), 7.26–7.80 (m, 10H, Haromat) ppm. 13C NMR (100 MHz,
CD2Cl2) d¼27.0 (CH3), 28.6 ((CH3)3C), 43.5 (CH2), 80.4 ((CH3)3C),
88.4 (CH3CO), 124.7 (CHaromat), 128.7 (CHaromat), 128.8 (CHaromat),
129.6 (CHaromat), 129.6 (CHaromat), 133.0 (CHaromat), 135.1 (Caromat),
140.6 (Caromat), 156.0 (NHC]O), 169.7 (CH2C]O), 196.6
(PhC]O) ppm. MS (CI, CHþ5 ), m/z (%): 384 (16) [MþH]þ, 209 (100).
IR (KBr): ~n¼3326, 1734, 1678, 1527, 1310 cmꢀ1. C22H25NO5 (383.45)
calcd: C 68.91, H 6.57, N 3.65; found: C 68.80, H 6.65, N 3.58.
Interestingly, in the cases of 1,4-oxazinones and pyridazinones,
as, for example, 16 and 17, the ring-opening reaction of the in-
dividual enolates must be so fast that it does not allow an efficient
subsequent trapping reaction by an electrophile, e.g., alkyl halide.
But this changes when an a-substituent, as in 3, is present. Then the
Boc
N
O
O
N
O
Ph
N
Ph
17
16
Figure 1.

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S. Simonyiova, K.T. Wanner / Tetrahedron 64 (2008) 5107–5110
5110
4.1.2. (rac)-6-Methyl-5,6-diphenyl-3,6-dihydro-2H-1,4-oxazin-
2-one (rac)-7
4.1.5. (2RS)-2-Phenyl-2-((1RS)-1-phenylethyl)oxazol-5(2H)-
one (rac)-14 and (2RS)-2-phenyl-2-((1SR)-1-phenylethyl)-
oxazol-5(2H)-one (rac)-15
TFA (664 mg, 448 mL, 5.82 mmol, 10.0 equiv) was added to a
solution of (rac)-6 (223.0 mg, 0.5822 mmol) in CH2Cl2 (5.8 mL). The
mixture was stirred for 14 h at rt. The solvent was evaporated in
vacuo. The residue was dissolved in CH2Cl2 (2.4 mL), acetate buffer
pH 5 (4.8 mL) was added and the mixture was stirred at rt for 14 h.
The organic layer was separated and the aqueous solution was
extracted with CH2Cl2. The organic layer was dried over Na2SO4,
filtrated and concentrated in vacuo. CC (heptane/EtOAc¼7:3). Yield:
121.1 mg (79%), colourless oil. TLC: Rf¼0.28 (iso-hexane/EtOAc¼7:3).
1H NMR (400 MHz, CDCl3) d¼1.92 (s, 3H, CH3), 4.07 (d, J¼21.0 Hz,1H,
CH2), 4.75 (d, J¼21.0 Hz, 1H, CH2), 7.33–7.49 (m, 10H, Haromat) ppm.
13C NMR (100 MHz, CD2Cl2) 27.5 (CH3), 52.3 (CH2), 86.2 (C), 126.8
(CHaromat), 128.7 (CHaromat), 129.8 (CHaromat), 130.0 (CHaromat), 130.4
(CHaromat), 138.0 (Caromat), 139.6 (Caromat), 168.3 (C]O), 171.1
(C]O) ppm. MS (CI, CHþ5 ), m/z (%): 266 (7) [MþH]þ, 211 (87), 209
(100). IR (KBr): ~n¼3060, 1752, 1445, 1265 cmꢀ1. HRMS (EIþ, 70 eV)
calcd for C17H15NO2: 265.1103; found: 265.1111. C17H15NO2 (265.31)
calcd: C 76.96, H 6.70, N 5.28; found: C 76.45, H 5.76, N 5.17.
(A) NaHMDS (53 mL, 0.11 mmol, 2.0 M solution in THF, 1.1 equiv)
was added to a solution of (rac)-7 (25.3 mg, 0.0954 mmol) in
THF (1.0 mL) at ꢀ78 ꢁC. The mixture was stirred for 4 days at
ꢀ78 ꢁC. The solvent was evaporated in vacuo. TFA (1.05 mL,
1.05 mmol, 0.1 M in CH2Cl2, 1.1 equiv) was added and the
mixture was concentrated in vacuo. The oily residue was
measured by 1H NMR spectroscopy in CDCl3. The ratio of [(rac)-
14þ(rac)-15]/(rac)-7 was 75:25.
(B) s-BuLi (45 mL, 0.0634 mmol, 1.4 M solution, in cyclohexane
1.1 equiv) was added to
a solution of (rac)-7 (15.3 mg,
0.0577 mmol) in THF (0.6 mL) at ꢀ78 ꢁC and stirred for 6 days
at ꢀ78 ꢁC. Then the solvent was removed at ꢀ50 ꢁC in vacuo.
TFA (577 mL, 0.0577 mmol, 0.1 M in MeOH 1.0 equiv) was added
at rt, the solvent was evaporated in vacuo and the residue was
measured by 1H NMR spectroscopy in CDCl3. The ratio of [(rac)-
14þ(rac)-15]/(rac)-7 was 98:2.
4.1.3. (rac)-3,3-Dibenzyl-6-methyl-5,6-diphenyl-3,6-dihydro-
2H-1,4-oxazin-2-one (rac)-9
(rac)-14þ(rac)-15, colourless oil. TLC: Rf¼0.26 (heptane/
EtOAc¼8:2). 1H NMR (400 MHz, CD2Cl2)12 d¼1.27 (d, J¼7.2 Hz, 3H,
CH3), 1.28 (d, J¼7.2 Hz, 3H, CH3), 3.67 (q, J¼7.2 Hz, 1H, CH), 3.69 (q,
J¼7.2 Hz, 1H, CH), 7.06–7.62 (m, 20H, Haromat), 7.38 (s, 1H, CH]N),
7.67 (s, 1H, CH]N) ppm. 13C NMR (100 MHz, CD2Cl2)12 d 15.1(CH3),
15.3 (CH3), 49.2 (CH), 49.4 (CH), 111.8 (C(O)N), 112.1 (C(O)N),
126.3 (CHaromat), 126.6 (CHaromat), 127.3 (CHaromat), 127.5 (CHaromat),
127.8 (CHaromat), 128.0 (CHaromat), 128.2 (CHaromat), 128.4
(CHaromat), 128.6 (CHaromat), 128.8 (CHaromat), 129.5 (CHaromat), 129.8
(CHaromat), 137.4 (Caromat), 137.6 (Caromat), 138.26 (Caromat), 138.31
(Caromat), 151.0 (C]N), 152.8 (C]N), 163.9 (C]O), 164.5
(C]O) ppm. MS (CI, CHþ5 ), m/z (%): 266 (100) [MþH]þ. IR (KBr):
~n¼3442, 3062, 2979,1785,1683,1450,1214 cmꢀ1. HRMS (EIþ, 70 eV)
calcd for C17H15NO2: 265.1103, found: 265.1104.
KOH (8.4 mg, 0.15 mmol, 4.0 equiv), Bu4NBr (1.2 mg,
0.004 mmol, 0.1 equiv) and benzyl bromide (19.2 mg, 13 mL,
0.112 mmol, 3.0 equiv) were added to a solution of (rac)-7 (9.9 mg,
0.037 mmol) in CH2Cl2 (0.6 mL) at 0 ꢁC. The mixture was stirred for
5 h at 0 ꢁC. Phosphate buffer (pH 7) was added, the organic layer
was separated and the liquid phase extracted with CH2Cl2. The
combined organic layers were dried over Na2SO4, filtered and
concentrated in vacuo. CC (heptane/EtOAc¼7:3). Yield: 5.1 mg
(31%), colourless crystals, mp: 188–190 ꢁC. TLC: Rf¼0.44 (iso-hex-
ane/EtOAc¼7:3). 1H NMR (500 MHz, CD2Cl2) d¼0.67 (s, 3H, CH3),
3.31 (d, J¼12.8 Hz, 1H, CH2), 3.36 (d, J¼12.8 Hz, 1H, CH2), 3.70 (d,
J¼12.8 Hz, 1H, CH2), 3.76 (d, J¼12.8 Hz, 1H, CH2), 5.93–5.97 (m, 2H,
Haromat), 6.85–6.88 (m, 2H, Haromat), 6.89–6.94 (m, 2H, Haromat), 7.10
(t, J¼7.4 Hz, 1H, Haromat), 7.12–7.17 (m, 2H, Haromat), 7.23–7.40 (m,
11H, Haromat) ppm. 13C NMR (125 MHz, CD2Cl2) d¼24.0 (CH3), 47.8
(CH2), 47.9 (CH2), 68.2 (CCH2Ph), 87.5 (CH3C), 128.1 (CHaromat), 129.1
(CHaromat), 129.3 (CHaromat), 129.4 (CHaromat), 129.9 (CHaromat),
129.9 (CHaromat), 130.0 (CHaromat), 130.2 (CHaromat), 130.3 (CHaromat),
130.6 (CHaromat), 132.8 (CHaromat), 133.1 (CHaromat), 138.0 (Caromat),
138.1 (Caromat), 138.7 (Caromat), 140.5 (Caromat), 166.2 (C]N), 168.7
(C]O) ppm. MS (CI, CHþ5 ), m/z (%): 446 (27) [MþH]þ, 266 (100). IR
(KBr): ~n¼2921, 1721, 646, 1350, 1091, 702, 695 cmꢀ1. HRMS (EIþ,
70 eV) calcd for C31H27NO2: 445.2042, found: 445.2054.
Acknowledgements
We thank Monika Simon for her assistance with editing and
proofreading.
References and notes
1. Williams, R. M. Synthesis of Optically Active a-Amino Acids; Pergamon: Oxford,
1989.
2. (a) Vogt, H.; Bra¨se, S. Org. Biomol. Chem. 2007, 5, 406–430; (b) Cativiela, C.;
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Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645–732.
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4.1.4. (rac)-1,2-Diphenylpropan-2-one (rac)-10
NaHMDS (33 mL, 0.066 mmol, 2.0 M solution in THF, 1.1 equiv)
was added to a solution of (rac)-7 (15.9 mg, 0.060 mmol) in THF
(0.7 mL) at ꢀ78 ꢁC. The mixture was stirred for 96 h at ꢀ78 ꢁC.
Phosphate buffer was added, the organic layer was separated and
the liquid phase extracted with CH2Cl2. The combined organic layers
were dried over Na2SO4, filtered and concentrated in vacuo. CC
(heptane/EtOAc¼7:3). Yield: 10 mg (79%),7 colourless oil. TLC: Rf¼
0.5 (heptane/EtOAc¼7:3). 1H NMR (500 MHz, CDCl3) d¼1.54 (d, J¼
6.9 Hz, 3H, CH3), 4.70 (q, J¼6.9 Hz,1H, CH), 7.17–7.22 (m,1H, Haromat),
7.27–7.30 (m, 4H, Haromat), 7.37–7.40 (m, 2H, Haromat), 7.45–7.49 (m,
1H, Haromat), 7.93–7.96 (m, 2H, Haromat) ppm. 13C NMR (125 MHz,
CDCl3) d 19.5 (CH3), 47.9 (CH),126.9 (CHaromat),127.8 (CHaromat),128.0
(CHaromat), 128.8 (CHaromat), 129.0 (CHaromat), 132.8 (CHaromat), 136.5
(Caromat),141.5 (Caromat), 200.3 (C]O) ppm. MS (CI, CHþ5 ), m/z (%): 211
(100) [MþH]þ. IR (KBr): ~n¼2973, 2927, 1677, 1447, 1224 cmꢀ1. HRMS
(EIþ, 70 eV) [MþH]þ calcd for C15H14O: 210.1045; found: 210.1057.
36, 995–997.
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6. (a) Koch, C. J.; Simonyiova, S.; Pabel, J.; Kartner, A. R.; Polborn, K.; Wanner, K. T.
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Wanner, K. T. Eur. J. Org. Chem. 2003, 2233–2242.
7. Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473–1478.
8. Pericyclic ReactionsdA Textbook; Sankararam, S., Ed.; Wiley-VCH: Weinheim,
2005.
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2211–2214.
10. Abella´n, T.; Chinchilla; Galindo, N.; Guillena, G.; Na´jera, C.; Sansano, J. M.
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Chem. 2000, 4, 57–103.
12. The assignments of 1H and 13C NMR chemical shifts were obtained by means of
2D NMR techniques, including HSQC and HMBC.