Highly Stereoselective Aldol Reactions by Memory of Chirality: Synthesis of Quaternary β-Hydroxy α-Amino Acids

Article abstract of DOI:10.1002/hlca.202100127

We describe here an asymmetric aldol reaction based on the principle of Memory of Chirality. From α-amino acids such as leucine and methionine, we have synthesized in two steps quaternary α-amino acid derivatives with high diastereoselectivity and enantioselectivity, using the chirality of the initial α-amino acid as the only chirality source. Furthermore, we were able to determine the relative and absolute configurations of the aldol products thanks to crystallographic structures and thus showed that the relative configuration depended on the aldehyde employed. We proposed a stereoselectivity explanation and obtained also quaternary β-hydroxy α-amino acids after acidic hydrolysis.

Full text of DOI:10.1002/hlca.202100127

doi.org/10.1002/hlca.202100127
FULL PAPER
Highly Stereoselective Aldol Reactions by Memory of Chirality:
Synthesis of Quaternary β-Hydroxy α-Amino Acids
Loïc Roupnel,a Régis Guillot,a Didier Gori+,b Baby Viswambharan,b Cyrille Kouklovsky,b and
Valérie Alezra*b
a
Institut de Chimie Moléculaire et des Matériaux d’Orsay – Services communs, CNRS, UMR 8182, Université
Paris-Saclay, FR-91405 Orsay, France
Institut de Chimie Moléculaire et des Matériaux d’Orsay – Méthodologie, Synthèse et Molécules Thérapeu-
b
tiques, CNRS, UMR 8182, Université Paris-Saclay, FR-91405 Orsay, France, e-mail: valerie.alezra@universite-paris-
saclay.fr
Dedicated to Prof. Ernst Peter Kündig, on the occasion of his 75th birthday
We describe here an asymmetric aldol reaction based on the principle of Memory of Chirality. From α-amino
acids such as leucine and methionine, we have synthesized in two steps quaternary α-amino acid derivatives
with high diastereoselectivity and enantioselectivity, using the chirality of the initial α-amino acid as the only
chirality source. Furthermore, we were able to determine the relative and absolute configurations of the aldol
products thanks to crystallographic structures and thus showed that the relative configuration depended on the
aldehyde employed. We proposed a stereoselectivity explanation and obtained also quaternary β-hydroxy α-
amino acids after acidic hydrolysis.
Keywords: aldol reaction, amino acids, asymmetric synthesis, memory of chirality, tertiary aromatic amides.
reaction intermediates, as in the synthesis of (À )-
Introduction
penibruguieramine A.[4,5] Because of their multiple
Quaternary α-amino acids are very interesting com- interests, many ways to access quaternary α-amino
pounds for their proven or potential biological acids have been developed.[6–10] Among these, meth-
activities. Examples of biologically active quaternary α- ods based on the principle of memory of chirality
amino acids are antibiotics, such as peptaibols,[1] (MOC)[11–24] use as the only source of chirality the
antihypertensive drug such as methyldopa or among chirality of a natural α-amino acid, the initial reactant,
β-hydroxy α-amino acids,[2] lactacystin, kaitocephalin, although it disappears transiently during the reaction.
calcaridine A or sphingofungins which have potent Our group has been interested in the development of
antifungal activities. They are also found in peptide asymmetric syntheses based on this principle for many
chemistry, because the presence of the quaternary years. We have developed a synthesis of quaternary α-
center induces a conformational change, even a amino acids by alkylation in only three steps,[25,26]
a
flexibility decrease of the structure, while increasing its method that we have applied to the synthesis of
metabolic stability.[3] They can furthermore be used as methyldopa[27] and to microflow reactors.[28] We also
extended this strategy to oxidative coupling of
enolate[29] and to the aldol reaction of alanine
+
derivatives.[30] In the latter case, we have been able to
Current address: Aix Marseille University - CNRS,
UMR7376, Laboratory of Environmental Chemistry, FR-
13331 Marseille, France
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/hlca.202100127
demonstrate a control of the second asymmetric
center by the nature of the aromatic aldehyde used
(Scheme 1). We wanted to know if this control was
specific to the alanine derivative or was also valid for
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Helv. Chim. Acta 2021, 104, e2100127
the face opposite to the naphthyl group, leading to a
global retention of configuration for the initial asym-
metric center (Scheme 1). It should be noted here that
the major (P,cis) conformer is not the only one present
but that we probably have a dynamic kinetic reso-
lution.
We thus synthesized the corresponding oxazolidi-
nones and used the reaction conditions developed for
the aldol reaction of alanine: mixing of the aromatic
aldehyde with the oxazolidinone (at room temperature
°
or low temperature), then slow addition at À 78 C of
the base – KHMDS (over two minutes) – to avoid
racemization due to heating of the medium; treatment
°
of the reaction at À 78 C with a 5% aqueous NaHCO3
solution to avoid hydrolysis of the oxazolidinone as
well as retro-aldol reaction. For leucine derivative 1-A,
we tested two types of conditions: a sequential
reaction (deprotonation for t1 minutes and then
addition of the aldehyde) and an in situ reaction
(mixing the aldehyde with the oxazolidinone at room
temperature, before lowering the temperature to
Scheme 1. Previous results for alkylation and aldol reactions by
Memory of Chirality.
°
À 78 C to perform the deprotonation). The results are
collected in Table 1. It appears that the aldol reaction
takes place in all cases with very good diastereomeric
other amino acids. We present here our latest results ratios, better than those observed for the alanine
concerning this MOC aldol reaction applied to other derivative (the assignments of the relative configura-
amino acids and thanks to some crystallographic tion were based on crystallographic structures of
structures of some major diastereomers, we were able major diastereomer of some aldol products – see
to confirm the dependence of the configuration of the below for determination and stereoselectivity explan-
second center with the nature of the aldehyde.
ation). The enantiomeric excesses are higher than 70%
in the optimized reactions and can go up to
enantiopure compounds, as in the case of compound
3 (the enantiomeric excess can also be improved by
recrystallization, Entry 7). We did not need to replace
Results and Discussion
We targeted mainly two amino acids, leucine, which THF with the ether/DME mixture that had been used
showed good results in alkylation reactions and for the alkylation reactions. In general, it is better to
methionine, as an example of functionalized amino perform the reaction in situ, to obtain better enantio-
acid. According to our previous strategy, an oxazolidi- meric excesses (Entries 1 and 4 or 9 and 11). This
none is formed without racemization in a single step probably limits the racemization of the enolate, which
from the sodium salt of the corresponding α-amino is trapped directly by the aldehyde. Some aldol
acid, acetone and naphthoyl chloride. The presence of products, such as the 3-pyridine compound have a
a tertiary aromatic amide function in the compound tendency to degrade rapidly, so it is sometimes
thus formed induces the creation of a dynamic axial simpler to acetylate them for purification (yields are in
chirality (these compounds are not planar and possess this case calculated on compound Ac-4, on two steps).
two slow rotations, the ArÀ CO and the NÀ CO The change in the amount of THF does not have a
rotations). The preferred orientation of the naphthyl great influence (Entries 1–3) and the introduction of
°
group is on the same side as the amino acid residue the aldehyde at À 78 C (Entries 6 and 10) generally
(major (P,cis) conformer) and it allows to preserve, at induces a decrease in yield, probably due to a
low temperature, the chiral information during the decrease in its solubility and consequently to a less
planar enolate formation step. This major conformer homogeneous mixture.
thus induces a stereoselective approach of the electro-
On the methionine derivative 1-B, we also tested
phile (whether it is an alkyl group or an aldehyde) by various aromatic aldehydes and the results are
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Table 1. Aldol reaction with Leucine oxazolidinone 1-A (in situ or sequential procedure).[a]
Entry
ArCHO
t1/t2 [min]
Comp.
dr[b]
ee[c] [%]
Yield[d] [%]
1
m-Br-C6H4CHO
m-Br-C6H4CHO
m-Br-C6H4CHO
m-Br-C6H4CHO
2-pyridine-CHO
3-pyridine-CHO
3-pyridine-CHO
3-pyridine-CHO
o-F-C6H4CHO
8/10
8/10
8/10
0/18
0/18
0/12
0/12
0/12
8/10
0/18
0/18
2
2
2
2
>99:1
>99:1
>99:1
>99:1
4:96
>99:1
>99:1
>99:1
97:3
69/–
64/–
59/–
72/–
92
63
84
95
56
48[i]
55[i]
38[i]
60
2[e]
3[f]
4
5
3[g]
Ac-4
Ac-4
Ac-4
5
>99/>99
48/–
6[h]
7
76[j]/–
80/–
8[k]
9
67/59
82/–
82/86
10[h]
11
o-F-C6H4CHO
o-F-C6H4CHO
5[l]
5
>99:1
96:4
61
81
[a] General procedure: In situ - to a stirred solution of oxazolidinone 1-A (100 mg) and aldehyde (5 equiv.) in THF (1.8 mL) cooled to
°
°
À 78 C was added a solution of KHMDS (1.5 equiv.) in THF dropwise (over 2 min) and the mixture was stirred for t2 min at À 78 C;
sequential - Identical to in situ procedure, except that KHMDS is added first and aldehyde is then added after t1 min. Unless
specified, absolute and relative configurations were assumed by analogy. [b] ratio a:b determined by chiral stationary-phase HPLC
on the crude product. [c] ee of a/b determined by chiral stationary-phase HPLC after purification. [d] combined yield of a and b. [e]
THF volume 1.2 mL instead of 1.8 mL. [f] THF volume 2.4 mL instead of 1.8 mL. [g] Absolute configuration of major diastereomer 3b
was assigned by X-Ray crystallography (Figure 1). [h] Aldehyde was added at À 78 C instead of r.t. [i] Yield calculated after acetylation
°
on two steps. [j] ee=91% after recrystallization. [k] Only 1 equiv. of KHMDS was used. [l] Absolute configuration of major
diastereomer 5a was assigned after acetylation by X-Ray crystallography (Figure 1).
collected in Table 2. We applied only the in situ
Consequently, we wanted to test the aldol reaction
conditions, the aldehyde being introduced prior to the with 2-pyridine carboxaldehyde on oxazolidinones
°
base, either at r.t. or at À 78 C depending on the case. derived from other amino acids. We thus tested the
°
By default, the aldehyde was added at À 78 C. valine and phenyl alanine derivatives (Table 3). The
However, when the enantiomeric excesses were low, valine derivative 1-C leads to the expected compound
probably due to a lack of solubility of the aldehyde, it with high diastereomeric ratio and enantiomeric
was then introduced at room temperature and the excess for the major diastereomer. In the case of
°
mixture cooled to À 78 C (Entries 1 and 2). The phenylalanine 1-D, we directly acetylated the reaction
observed diastereomeric ratios are always higher than product for ease of purification and product stability.
those of the alanine derivative. The enantiomeric The result was very disappointing, the diastereomeric
excesses are generally higher than 70%, except in the ratio and enantiomeric excesses being both low. This
disappointing case of ortho-bromobenzaldehyde (En- derivative was the one that already gave the worst
tries 3–6). For the latter, replacing THF with ether or results in the alkylation reactions. The presence of the
decreasing the number of aldehyde equivalents did benzyl group disturbs the conformer proportions
not result in a better enantiomeric excess (Entries 5 observed in NMR at low temperature (in THF, there
and 6). For 3-pyridine-carboxaldehyde, the enantio- was a (P,cis)/(M,cis) conformer ratio of 100/50 for this
meric excess could be improved by decreasing the derivative, compared to 100/29 for alanine and
amount of base employed and addition of the especially a cis/trans conformer ratio of 100/10
aldehyde at room temperature (Entries 11 and 12). compared to 100/2 in the case of alanine) and this
Changing the reaction time does not have a significant probably impairs the selectivity.[25] This is likely to be
influence on the enantiomeric excess (Entries 7 and 8, even more pronounced for aldol reactions, as the
or 9 and 10). Again, the best enantiomeric excess was aldehyde is an aromatic aldehyde, which can also
obtained with 2-pyridine carboxaldehyde (97% ee for interact with the benzyl group. We also tested 2-
the major diastereomer, Entry 7).
fluorobenzaldehyde on phenylalanine, but the enan-
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Table 2. Aldol reaction with Methionine oxazolidinone 1-B (in situ procedure).[a]
°
Entry
ArCHO
T[b] [ C]
t [min]
Comp.
dr[c]
ee[d] [%]
Yield[e] [%]
1
2
3
4
m-Br-C6H4CHO
m-Br-C6H4CHO
o-Br-C6H4CHO
o-Br-C6H4CHO
o-Br-C6H4CHO
o-Br-C6H4CHO
2-pyridine-CHO
2-pyridine-CHO
o-F-C6H4CHO
o-F-C6H4CHO
À 78
r.t.
r.t.
r.t.
r.t.
10
10
18
12
18
12
15
12
18
12
12
12
6
6
7
7
>99:1
>99:1
87:13
>99:1
>99:1
98:2
15:85
17:83
>99:1
>99:1
98:2
30/–
73/–
61/89
60/–
60/–
50/–
82/97
89/98
85/–
81/–
47/–
75/–
42
65
30[f]
72
50
73
65
65
99
92
80
88
5[g]
6[h]
7
7
r.t.
7
À 78
À 78
À 78
À 78
À 78
r.t.
8[i]
8
8
9
10
11
12[j]
9
9
10
10
3-pyridine-CHO
3-pyridine-CHO
98:2
[a]
°
General procedure: to a stirred solution of oxazolidinone 1-B (100 mg) and aldehyde (5 equiv.) in THF (1.8 mL) at À 78 C was
[b]
°
added a solution of KHMDS (1.5 equiv.) in THF dropwise (over 2 min) and the mixture was stirred for t min at À 78 C.
Temperature at which the aldehyde was added to the oxazolidinone. Unless specified, absolute and relative configurations were
assumed by analogy. [c] Ratio a:b determined by chiral stationary-phase HPLC on the crude product. [d] ee of a/b determined by
chiral stationary-phase HPLC after purification. [e] Combined yield of a and b. [f] Diastereomers are difficult to separate. [g] Diethyl
ether was used instead of THF. [h] Only 3 equiv. of aldehyde were used. [i] Absolute configuration of major diastereomer 8b was
assigned by X-Ray crystallography (Figure 1). [j] Only 1 equiv. of KHMDS was used.
Table 3. Aldol reaction with oxazolidinones 1 with 2-pyridine carboxaldehyde.[a]
Entry
R
t [min]
Comp.
dr[b]
ee[c] [%]
Yield[d] [%]
1
2
3
4
iBu
18
15
18
12
3[e]
4:96
15:85
7:93
56:44
>99/>99
82/97
45/90
56
65
CH2CH2SMe
8[e]
iPr
Bn
11[f]
47
Ac-12[g]
29/29
44[h]
[a]
°
General procedure: to a stirred solution of oxazolidinone 1-A (100 mg) and aldehyde (5 equiv.) in THF (1.8 mL) cooled to À 78 C
was added a solution of KHMDS (1.5 equiv.) in THF dropwise (over 2 min) and the mixture was stirred for t2 min at À 78 C. [b] Ratio
°
a:b determined by chiral stationary-phase HPLC on the crude product. [c] ee of a/b determined by chiral stationary-phase HPLC
after purification. [d] Combined yield of a and b. [e] Absolute configuration of major diastereomers 3b and 8b were assigned by X-
Ray crystallography (Figure 1). [f] Absolute and relative configuration of major diastereomer 11a were assumed by analogy. [g]
Relative configuration of major diastereomer Ac-12a was assigned by X-Ray crystallography (Figure 1). [h] Yield calculated after
acetylation on two steps.
tiomeric excess was only 34% (compound 13a was tiomeric excesses are comparable to those obtained
obtained with a very good diastereomeric ratio of during alkylation reactions. When the enantiomeric
98:2 and a yield of 52%). In all cases (except for the excess is lower, this is probably due to a decrease in
particular case of phenylalanine), the observed enan- the reactivity of the aldehyde, as in the case of ortho-
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bromobenzaldehyde, which is likely too hindered, or a better control of the stereoselectivity[31]) as in
in the case of poorly soluble aldehydes added at transition state II (Scheme 2). More surprisingly, the
°
À 78 C (Entry 6, Table 1 and Entry 1, Table 2). Thus, the crystallographic structure of the acetylated compound
enantiomeric excess is presumably kinetically con- Ac-5a is different from that observed for the major
trolled and not compromised by retro aldol reaction diastereomer in the reaction with the alanine deriva-
and subsequent enolate racemization.
tive. Therefore, there is probably no complexation
Regarding the control of the relative configuration with fluorine in this case. It can consequently be
of the aldol product by the substrate, we were able to assumed that for all compounds resulting from aldol
obtain crystallographic structures on major diaster- reaction with an aldehyde different from 2-pyridine-
eomer of some aldol products (Figure 1) and thus to carboxaldehyde, the absolute configuration of the
have access to the relative and possibly absolute new asymmetric center created is identical (major
configuration (when the latter is accessible, we diastereomer a). This corresponds to an aldol product
observe, as expected, the retention of configuration of controlled by a classical Zimmerman–Traxler transition
the initial α-amino acid). The crystallographic structure state (transition state I, Scheme 2). There is thus a
of the compounds 3b and 8b thus shows that the control of the second asymmetric center by the
relative configuration is identical to that obtained in aldehyde, phenomenon to our knowledge not de-
the case of the reaction of oxazolidinone derived from scribed in the literature (except in our previous
alanine with furan-2-carboxaldehyde (we had not publication).
performed the aldol reaction of the alanine derivative
The next step was the hydrolysis of the aldol
with 2-pyridine-carboxaldehyde). In the case of the products. This was performed on the products after
phenylalanine derivative (crystallographic structure of acetylation, to avoid any problem of degradation of
acetylated major diastereoisomer Ac-12a, Figure 1), the aldol compounds. We applied the conditions
the relative configuration of the major diastereomer developed previously in the laboratory (heating in a
does not correspond to that observed for the leucine mixture of 6 N hydrochloric acid and acetic acid) and
and methionine derivatives 3b and 8b. However, this obtained for leucine derivatives Ac-4a and Ac-5a the
does not seem significant to us, as the diastereomeric expected amino acids hydrochloride 14 and 15
ratio is close to 1:1. Thus, when 2-pyridinecarboxalde- (Scheme 3). On the other hand, for methionine deriva-
hyde is used, there is probably complexation of the tives (on the compound resulting from the reaction
potassium enolate by the pyridine nitrogen (pyridine, with 2-fluorobenzaldehyde 9a after acetylation), we
a good complexing agent, is regularly used to achieve observed the formation of a cyclic product 16, whose
sulfur is de-methylated, which we were able to
characterize by NMR (proton, carbon, HSQC) and mass,
but which we were unfortunately unable to isolate in
Figure 1. Crystallographic structures of compounds 3b (up left),
Ac-5a (up right), 8b (bottom left), Ac-12a (bottom right,
racemic).
Scheme 2. Proposed transition state for stereoselectivity ex-
planation: with most aldehydes (up) and with 2-pyridine
carboxaldehyde (bottom).
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solution (1 M). Flash chromatography was performed
on Kieselgel 60 (35–70 μm) silica gel. Infrared spectra
were recorded as thin films on NaCl plates using an
1
FT-IR spectrophotometer. H-NMR spectra were meas-
ured at 250, 300, 360 or 400 MHz using CDCl3, MeOD,
C6D6, toluene, CD2Cl2 or D2O as solvent. Chemical
shifts are reported in δ units to 0.01 ppm precision
with coupling constants reported to 0.1 Hz precision
using residual solvent as an internal reference. Multi-
plicities are reported as follows: s=singlet, d=doublet,
t=triplet, q=quadruplet, m=multiplet, br. s=broad
singlet, br. d=broad doublet. 13C-NMR spectra were
measured at 62.5, 75, 90 or 100 MHz using CDCl3,
MeOD, CD2Cl2 or D2O as solvent. Chemical shifts are
reported in δ units to 0.1 ppm precision using residual
solvent as an internal reference. Mass spectra were
Scheme 3. Hydrolysis of diastereopure acylated aldol com-
pounds.
pure form. This type of cyclization has already been measured on an ESI Q-Tof mass spectrometer Bruker at
described in the past.[32] We could consider deprotect- the Institut de Chimie Moléculaire et des Matériaux
ing the methionine derivatives using milder condi- (ICMMO) Mass Spectrometry Laboratory. HPLC Analy-
tions, as we described in the case of frozen chirality ses were performed on a Dionex instrument (Ultimate
(basic hydrolysis of oxazolidinone, esterification of the 3000) in our laboratory. This instrument is principally
acid, then reduction of the amide to imine by composed of gradient pump, a columns selector valve,
Schwartz’s reagent and mild hydrolysis),[33,34] in order Peltier effect column oven and diode array detector.
to retain the methyl group. This is currently under All enantiomeric excesses were determined by normal
investigation.
phase HPLC analyses with four different chiral sta-
tionary phase columns:
-
-
-
-
Daicel column, Chiralcel OJ-H (250 mm×4,6 mm
i.d.); particle size: 5 μm
Daicel column, Chiralpak AD-H (250 mm×4,6 mm
id); particle size: 5 μm
Daicel column, Chiralpak IC (250 mm×4,6 mm id);
particle size: 5 μm
Conclusions
In conclusion, we extended the aldol reaction by
Memory of Chirality that we had previously developed
to other amino acids. We observed better diastereose-
lectivity and good enantiomeric excesses. In the best
case, we were able to obtain the compound 3b in
enantiopure form. We also showed that there was a
control of the second asymmetric center which
Régis column Type ‘Pirkle’, (S,S) Whelk-O
(250 mm×4,6 mm id); particle size: 5 μm
1
Note: all the experimental procedures listed below
depended on the nature of the aldehyde employed. β- apply to both racemic and enantiomerically pure
Hydroxy α-amino acids were synthesized efficiently material. All aldol reaction for racemic compounds
from leucine. The application of this strategy to the were performed in two steps: first deprotonation with
°
total synthesis of active molecules is under study in KHMDS at À 78 C for 6 min and then addition of the
our laboratory.
aldehyde, in order to get both diastereomers. Only the
preparation of chiral compounds will be reported.
Experimental Section
For all the compounds, there exist at least two
conformers and were reported for the proton or
carbon NMR as major (M) and the minor (m).
General Information
Unless otherwise stated, all reactions were conducted
in oven dried glassware under an atmosphere of dry
argon gas. THF was distilled over sodium/benzophe-
General Procedure for Oxazolidinone Synthesis
none under argon. Acetone was purchased with water Procedure A. In a solution of amino acid salt (1 equiv.)
<50 ppm. All other reagents were used as received. and molecular sieves 4 Å (activated in the oven) in dry
°
Potassium bis(trimethylsilyl)amide was used as a THF acetone at 0 C under Ar was added, slowly, BF3 ·Et2O
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°
(0.06 equiv.). The mixture was stirred 5 min at 0 C and 2 M of aqueous solution of hydrochloric acid. The
overnight at room temperature. Then, 1-naphthoyl mixture was washed with a saturated sodium bicar-
chloride (1 equiv.) was added and the resulting bonate solution and the aqueous layer was extracted
solution was stirred 2 h. The mixture was filtered with ethyl acetate. The organic layer was dried over
through silica gel and washed twice with Et2O. The sodium sulfate, filtered, and then concentrated to give
solvents were concentrated, and the residue was dried the crude product which was then purified through
under vacuum. After dilution in ether and CH2Cl2, the column chromatography over silica gel to give the
organic phase was washed with saturated solution of desired product.
NaHCO3 and water. The crude product was obtained
after concentration.
General Procedure for the Hydrolysis of the Aldol Product
Procedure B. In a solution of amino acid salt The acetylated aldol product was suspended in a
(1 equiv.) and molecular sieves 4 Å (activated in the mixture of acetic acid (0.5 mL) and 6 N HCl (1 mL) and
°
°
oven) in dry acetone at 0 C under Ar was added, was heated to 125 C for 24 h. After cooling, the
slowly, AlMe3 (1 equiv., 2 M in toluene). The mixture mixture was then diluted with water and washed with
°
was stirred 5 min at 0 C and overnight at room diethyl ether. The aqueous phase was concentrated to
temperature. Then, 1-naphthoyl chloride (1 equiv.) was yield
added and the resulting solution was stirred 2 h. The acid derivatives as their hydrochloride salt.
mixture was filtered through silica gel and washed
2-amino-3-hydroxy-2-isobutyl-3-arylpropanoic
twice with Et2O. The crude product was obtained after
concentration.
(4S)-2,2-Dimethyl-4-(2-methylpropyl)-3-
(naphthalene-1-carbonyl)-1,3-oxazolidin-5-one (1-
A). Following the Procedure A, with sodium L-leucinate
salt (2.20 g, 14.38 mmol), BF3 ·Et2O (0.06 equiv., 100 μL,
0.82 mmol), and 1-naphthoyl chloride (1 equiv.,
2.16 mL, 14.38 mmol). The residue was purified by
General Procedure for Aldol Reaction of Oxazolidinone
with Aldehydes
To a stirred solution of starting N-(1-naphthoyl)- flash column chromatography over silica gel (toluene/
°
oxazolidinone in THF (1.8 mL) at À 78 C was added ethyl acetate 100:0 to 95:5) to give (4S)-2,2-dimethyl-
5 equiv. of the aldehyde (or in case of r.t. aldehyde 4-(2-methylpropyl)-3-(naphthalene-1-carbonyl)-1,3-ox-
addition, aldehyde was added prior to cooling). A azolidin-5-one (1-A; 2.21 g, 49%, ee>99%). All spec-
solution of potassium bis(trimethylsilyl)amide (1 M in troscopic data are in agreement with those previously
THF) was added dropwise over 2 min, and the reported.[25]
resulting mixture was stirred for desired time (total
°
reaction time including the base addition) at À 78 C.
(4S)-2,2-Dimethyl-4-[2-(methylsulfanyl)ethyl]-3-
The reaction was then quenched by the addition of (naphthalene-1-carbonyl)-1,3-oxazolidin-5-one (1-
1.0 mL of saturated ammonium chloride solution and B). Following the Procedure B, with sodium L-methioni-
diluted with 10 mL diethyl ether and 10 mL of ethyl nate salt (2.46 g, 14.38 mmol), AlMe3 (1 equiv., 7.2 mL
acetate. Excess ammonium chloride was washed with (2 M in toluene), 14.38 mmol), and 1-naphthoyl
5 mL of 5% sodium bicarbonate solution. The aqueous chloride (1 equiv., 2.16 mL, 14.38 mmol). The residue
layer is back extracted with 5 mL ethyl acetate. was purified by flash column chromatography over
Combined organic layers were washed with sat. NaCl, silica gel (cyclohexane/ethyl acetate/triethylamine
dried over sodium sulfate, filtered, and then concen- 90:10:1) to give(4S)-2,2-dimethyl-4-[2-(methylsulfanyl)
trated to give the crude product which was then ethyl]-3-(naphthalene-1-carbonyl)-1,3-oxazolidin-5-one
purified through column chromatography over silica (1-B; 2.25 g, 45%, ee>99%). All spectroscopic data
gel to give the desired product.
are in agreement with those previously reported.[25]
(4S)-2,2-Dimethyl-3-(naphthalene-1-carbonyl)-4-
(propan-2-yl)-1,3-oxazolidin-5-one (1-C). Following
General Procedure for the Acetylation Reaction
To a stirred solution of N-(1-naphthoyl)-oxazolidinone the Procedure A, with sodium L-valinate salt (2.00 g,
°
and 4-(dimethylamino)pyridine in THF at 0 C were 14.38 mmol),
BF3 ·Et2O
(0.06 equiv.,
100 μL,
added acetic anhydride and triethylamine. The result- 0.82 mmol), and 1-naphthoyl chloride (1 equiv.,
ing mixture was stirred for the night at room temper- 2.16 mL, 14.38 mmol). The residue was purified by
ature. The reaction was quenched by the addition of a flash column chromatography over silica gel (pentane/
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diethyl ether 80:20) to give (4S)-2,2-dimethyl-3- 131.6M+m; 132.8M; 132.9m; 133.2M; 133.5m; 143.2m;
(naphthalene-1-carbonyl)-4-(propan-2-yl)-1,3-oxazoli-
143.4M; 170.8M; 171.3m; 171.4m; 171.6M. HR-ESI-MS):
din-5-one (1-C; 3.28 g, 75%, ee>99%). All spectro- 510.1259 (C27H28BrNO4+, [M+H]+; calc. 510.1274),
scopic data are in agreement with those previously 532.1074 (C27H28BrNNaO4+, [M+Na]+; calc. 532.1094).
reported.[25]
(4R)-4-[(S)-Hydroxy(pyridin-2-yl)methyl]-2,2-
(4S)-4-Benzyl-2,2-dimethyl-3-(naphthalene-1-
carbonyl)-1,3-oxazolidin-5-one (1-D). Following the carbonyl)-1,3-oxazolidin-5-one (3b). Following the
General Procedure B, with sodium L-phenylalaninate General Procedure, (4S)-2,2-dimethyl-4-(2-meth-
dimethyl-4-(2-methylpropyl)-3-(naphthalene-1-
salt (2.69 g, 14.38 mmol), AlMe3 (1 equiv., 7.2 mL (2 M ylpropyl)-3-(naphthalene-1-carbonyl)-1,3-oxazolidin-5-
in toluene), 14.38 mmol), and 1-naphthoyl chloride one (1-A; 100 mg, 0.307 mmol), 2-pyridinecarboxalde-
(1 equiv., 2.16 mL, 14.38 mmol). The residue was hyde (5 equiv., 1.53 mmol, 146 μL) and KHMDS
purified by flash column chromatography over silica (1.5 equiv., 0.460 mmol, 460 μL (1 M in THF)) in THF
gel (cyclohexane/ethyl acetate/triethylamine 80:20:1) gave compound 3b after 18 min. The crude product
to give (4S)-4-Benzyl-2,2-dimethyl-3-(naphthalene-1- (dr=4:96) was then purified by column chromatog-
carbonyl)-1,3-oxazolidin-5-one (1-D; 3.14 g, 61%, ee> raphy over silica gel (cyclohexane/ethyl acetate 85:15
99%). All spectroscopic data are in agreement with to 30:70) to give diastereomer 3b (75 mg, 56%, ee>
those previously reported.[25]
99%). HPLC Analysis: Chiralpak AD-H, hexane/ethanol
°
95:5, 1 mL/min, T=35 C, λ=222 nm; retention times
(4R)-4-[(R)-(3-Bromophenyl)(hydroxy)methyl]-
of racemic mixture: major diastereomer 29.3 min and
2,2-dimethyl-4-(2-methylpropyl)-3-(naphthalene-1-
38.1 min (RR) ee=99% (minor diastereomer 14.6 min
carbonyl)-1,3-oxazolidin-5-one (2a). Following the (minor) and 29.3 min (major) ee>99%). 1H-NMR
General
Procedure,
(4S)-2,2-dimethyl-4-(2-meth- (300 MHz, 300 K, (D8)toluene): Conformer ratio major
(M)/minor (m): 1.0: 0.5: 0.50 (s, 3Hm); 0.74 (s, 3Hm);
ylpropyl)-3-(naphthalene-1-carbonyl)-1,3-oxazolidin-5-
one (1-A; 100 mg, 0.307 mmol), 3-bromobenzaldehyde 0.93 (s,3HM); 1.10 (s,3HM); 1.12–1.23 (m, 6HM+6Hm);
(5 equiv., 1.53 mmol, 180 μL) and KHMDS (1.5 equiv., 2.10–2.17 (m, 1HM+1Hm); 2.36–2.44 (m, 1HM+1Hm);
0.460 mmol, 460 μL (1 M in THF)) in THF gave com- 3.12 (dd, J=3.3, J=13.9, 1Hm); 3.28 (dd, J=1.2, J=
pound 2a after 18 min. The crude product was then 14.1, 1HM); 5.10 (d, J=8.7, 1HM); 5.19 (br. s, 1Hm); 5.53
purified by column chromatography over silica gel (d, J=8.7, 1HM); 5.82 (br. s, 1Hm); 6.56–6.64 (m, 1HM+
(heptane/THF 90:10 to 70:30) to give one diastereom- 1Hm); 6.95–7.52 (m, 8HM+8Hm); 7.93 (d, J=8.1,
er 2a (150 mg, 95%, ee=72%). HPLC Analysis: (S,S) 1HM); 8.10 (d, J=9.1, 1Hm); 8.25 (d, J=5.1, 1HM); 8.33
Whelk-O 1, hexane/ethanol 90:10, 1 mL/min, T=25 C, (d, J=4.2, 1Hm). 1H-NMR (400 MHz, 300 K, CDCl3):
°
λ=222 nm; retention times of racemic mixture: Conformer ratio major (M)/minor (m): 1.0:0.5: 0.89 (s,
12.2 min (minor) and 17.3 min (major RR) ee=72%. 3Hm); 1.09 (d, J=6.7, 3HM); 1.10 (d, J=6.7, 3Hm); 1.14
1H-NMR (360 MHz, 300 K, CDCl3): Conformer ratio (s, 3HM); 1.17 (d, J=6.7, 3Hm); 1.22 (d, J=6.7, 3HM);
major (M)/minor (m): 0.6:0.4: 0.42 (s, 3Hm); 0.54 (s, 1.25 (s, 3HM); 1.52 (s, 3Hm); 1.89–1.97 (m, 1Hm); 1.99–
3HM); 0.99 (s, 3HM); 1.10 (d, J=6.3, 3Hm); 1.11 (d, J= 2.08 (m, 1HM); 2.25–2.35 (m, 1HM+1Hm); 3.01 (dd, J=
6.5, 3HM); 1.20 (d, J=6.6, 3Hm); 1.28 (d, J=6.7, 3HM); 3.2, J=14.2, 1Hm); 3.18 (d, J=12.7, 1HM); 5.01 (d, J=
1.43 (s, 3Hm); 1.94–2.04 (m, 1Hm); 2.09 (dd, J=8.6, J= 9.1, 1HM); 5.06 (d, J=9.0, 1Hm); 5.43 (d, J=9.1, 1HM);
14.5, 1Hm); 2.13–2.18 (m, 1HM); 2.32 (dd, J=9.2, J= 5.66 (d, J=8.6, 1Hm); 7.29–7.36 (m, 2HM+1Hm); 7.41–
14.8, 1HM); 2.90 (dd, J=2.5, J=14.6, 1Hm); 3.06 (dd, 7.56 (m, 4HM+5Hm); 7.60 (d, J=7.6, 1HM); 7.70–7.93
J=2.1, J=14.8, 1HM); 5.33 (d, J=10.6, 1HM); 5.36 (d, (m, 3HM+4Hm); 8.61–8.67 (m, 1HM+ 1Hm). 13C-NMR
J=10.2, 1Hm); 6.51 (d, J=10.6, 1HM); 6.53 (d, J=10.2, (100 MHz, 300 K, CDCl3): 22.3M; 23.1m; 24.8M+m;
1Hm); 7.28–7.42 (m, 3HM+3Hm); 7.46–7.62 (m, 4HM 25.0M+m; 28.7m; 29.2M; 29.4M; 30.3m; 40.1m; 41.2M;
+4Hm); 7.72–7.76 (m, 2HM+2Hm); 7.87–7.96 (m, 72.5m; 72.8M; 76.0M; 76.4m; 96.5 M+m; 123.4 M;
2HM+2Hm). 13C-NMR (62.9 MHz, 300 K, CDCl3): 22.6M; 123.6m; 123.8 M+m; 124.0M+m; 125.0M; 125.4M;
22.9m; 24.5M; 24.7m; 25.4m; 25.5M; 28.5M; 28.6M+m; 125.6m; 126.0m; 126.5M+m; 127.3M; 128.4m; 128.6M;
30.1m; 40.7m; 40.8M; 75.8M; 76.2m; 78.4M+m; 96.4M; 129.8m; 130.0M*2+m*2; 133.3m; 133.4M; 134.1M;
96.5m; 123.1M; 123.2m; 123.7m; 124.2M; 124.4M; 134.3m; 136.4M+m; 148.8M+m; 157.6M; 158.2m;
125.5m; 125.6M; 126.0m; 126.2M; 126.4m; 126.8M; 169.0M+m; 172.4m; 172.7M. HR-ESI-MS: 433.2124
126.9m; 127.5M; 128.2m; 128.6m; 128.8M; 129.6M; (C26H29N2O4+, [M+H]+; calc. 433.2122), 455.1946
129.8m; 129.9M; 130.0M+m; 130.3M+m; 130.7m; (C26H28N2NaO4+, [M+Na]+; calc. 455.1941).
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(R)-[(4R)-2,2-Dimethyl-4-(2-methylpropyl)-3-
(naphthalene-1-carbonyl)-5-oxo-1,3-oxazolidin-4-
(5 equiv., 1.53 mmol, 160 μL) and KHMDS (1.5 equiv.,
0.460 mmol, 460 μL (1 M in THF)) in THF gave (4R)-4-
yl](pyridin-3-yl)methyl acetate (Ac-4a). Following [(R)-(2-fluorophenyl)(hydroxy)methyl]-2,2-dimethyl-4-
the General Procedure, (4S)-2,2-dimethyl-4-(2-meth- (2-methylpropyl)-3-(naphthalene-1-carbonyl)-1,3-oxa-
ylpropyl)-3-(naphthalene-1-carbonyl)-1,3-oxazolidin-5-
zolidin-5-one after 18 min. The crude product (dr=
one (1-A; 100 mg, 0.307 mmol), 3-pyridinecarboxalde- 96:4) was then purified by column chromatography
hyde (5 equiv., 1.53 mmol, 116 μL) and KHMDS over silica gel (heptane/THF 85:15) to give diaster-
(1.5 equiv., 0.460 mmol, 460 μL (1 M in THF)) in THF eomer 5a (113 mg, 81%, ee=82%). HPLC Analysis:
gave
(4R)-4-[(R)-hydroxy(pyridin-3-yl)methyl]-2,2- (S,S) Whelk-O 1, hexane/ethanol 90:10, 1 mL/min, T=
°
dimethyl-4-(2-methylpropyl)-3-(naphthalene-1-
25 C, λ=222 nm; retention times of racemic mixture:
carbonyl)-1,3-oxazolidin-5-one (4) after 12 min. Follow- 10.6 min (minor) and 24.9 min (major) ee=82% (minor
ing the General Procedure of Acetylation, compound 4 diastereomer 12.4 min (minor) and 16.4 min (major)
(crude product), 4-(dimethylamino)pyridine (0.1 equiv., ee=86%). 1H-NMR (300 K, CDCl3): Conformer ratio
0.03 mmol, 4 mg), acetic anhydride (5 equiv., major (M1): major (M2): major (M3):minor (m):
1.53 mmol,145 μL) and triethylamine (1 equiv., 0.6:0.6:0.6: 0.1 (not described): 0.85 (s, 3HM); 0.87 (d,
0.307 mmol, 410 μL) in THF (3 mL) gave compound J=6.0, 3HM); 0.98 (d, J=7.3, 3HM); 0.99 (br. s, 6HM);
Ac-4a after one night. The crude product was then 1.08 (d, J=5.8, 3HM); 1.14 (d, J=6.6, 3HM); 1.18 (s,
purified by column chromatography over silica gel 3HM); 1.27 (d, J=6.1, 3HM); 1.54 (s, 3HM); 1.80–1.67
(cyclohexane/ethyl acetate 60:40) to give diastereom- (m, 4HM); 2.19–2.12 (m, 5HM); 2.30 (s, 3HM); 2.94 (dd,
er Ac-4a (80 mg, 55%, ee=76%, and 91% after J=2.2, J=14.3, 1HM1); 3.17 (d, J=12.5, 1HM2 +1HM3);
recrystallization). HPLC Analysis: Chiralpak IC, hexane/ 4.59 (d, J=7.0, 1HM1); 4.69 (br. s, 1HM2); 5.67 (d, J=
°
ethanol 80:20, 1 mL/min, T=25 C, λ=222 nm; reten- 10.1, 1HM3); 5.68 (br. s, 1HM2); 5.76 (d, J=10.1, 1HM3);
tion times of racemic mixture: 14.0 min and 20.1 min 6.12 (d, J=6.2, 1HM1); 6.64 (t, J=9.2, 1HM); 8.01–7.00
1
(RS). ee=76%. H-NMR (250 MHz, 300 K, CD2Cl2): Con- (m, 32HM). 13C-NMR (75.5 MHz, 300 K, CDCl3): 3 con-
former ratio major (M)/minor (m): 0.7:0.3 (second formers 1 major (M) and 2 minor, same proportion (m):
minor, not described 0.2): 1.60 (d, J=6.5, 3HM); 1.77 (d, 21.7m; 22.7M; 23.2m; 24.0m; 24.6m*3; 24.9m; 25.2M;
J=6.7, 3HM); 1.85 (d, J=6.8, 3Hm); 1.91–1.94 (m, 25.7M; 27.0m; 28.6m; 28.8M; 28.9M; 30.5m; 39.9m;
3Hm); 1.93 (s, 3HM); 1.96 (s, 3Hm); 2.42 (s, 3Hm); 2.44 40.7M; 41.4m; 69.1m; 70.4m; 73.3m; 74.6m; 74.9M;
(s, 3HM); 2.51-2.64 (m, 1HM); 2.73–2.75 (m, 2Hm); 2.83 77.5M; 96.4M; 96.5m; 98.4m; 114.5m (d, J=23); 115.7m
(d, J=14.1, 1HM); 2.93 (s, 3HM); 3.00 (s, 3Hm); 3.48 (dd, (d, J=23); 116.2M (d, J=23); 123.4–134.1; 159.6m (d,
J=2.8, J=13.8, 1HM); 3.64 (dd, J=1.4, J=13.7, 1Hm); J=249); 160.1M (d, J=249); 160.2m (d, J=249);
7.58 (s, 1Hm); 7.83 (s, 1HM); 8.09–8.38 (m, 6HM+6Hm); 168.7m; 170.1M; 170.3m; 170.5m; 171.1M+m. HR-ESI-
8.66–8.79 (m, 3HM+3Hm); 9.29 (dd, J=1.5, J=4.9, MS: 450.2059 (C27H29FNO4+, [M+H]+; calc. 450.2075),
1HM+1Hm); 9.43 (d, J=1.6, 1HM+1Hm). 13C-NMR 472.1879 (C27H28FNNaO4+, [M+Na]+; calc. 472.1895).
(62.9 MHz, 300 K, CD2Cl2): 22.7M; 22.8m; 23.4m; 24.1M;
26.0M; 26.2m; 26.4M+m; 30.2M; 30.7m; 31.5m; 31.9M;
(4R)-4-[(R)-(3-Bromophenyl)(hydroxy)methyl]-
43.4M; 44.6m; 72.4M; 72.8m; 75.6m; 75.7M; 98.7M+m; 2,2-dimethyl-4-[2-(methylsulfanyl)ethyl]-3-
125.4M+m; 126.0m; 126.1M; 126.2M; 126.5m; 127.1M; (naphthalene-1-carbonyl)-1,3-oxazolidin-5-one (6a).
127.7m; 128.7m; 128.8M; 129.4M; 129.5m; 130.7M; Following the General Procedure, (4S)-2,2-dimethyl-4-
130.8m; 131.7m; 131.9M; 132.3M; 132.4m; 134.1M+m; [2-(methylsulfanyl)ethyl]-3-(naphthalene-1-carbonyl)-
135.2M; 135.3M; 135.4m; 135.5m; 139.0M; 139.2m; 1,3-oxazolidin-5-one (1-B; 100 mg, 0.290 mmol), 3-
151.1M; 151.2m; 151.3M+m; 171.5M; 171.6M; 171.7m; bromobenzaldehyde (5 equiv., 1.45 mmol, 170 μL) and
171.8m; 171.9M; 172.0m. HR-ESI-MS: 475.2240 KHMDS (1.5 equiv., 0.430 mmol, 430 μL (1 M in THF)) in
(C28H31N2O5+, [M+H]+; calc. 475.2227), 497.2046 THF gave compound 6a after 10 min. The crude
(C28H30N2NaO5+, [M+Na]+; calc. 497.2047).
product (single diastereomer) was then purified by
column chromatography over silica gel (PE/ethyl
acetate 100:0 to 70:30) to give diastereomer 6a
(100 mg, 65%, ee=73%). HPLC Analysis: (S,S) Whelk-O
(4R)-4-[(R)-(2-Fluorophenyl)(hydroxy)methyl]-
2,2-dimethyl-4-(2-methylpropyl)-3-(naphthalene-1-
carbonyl)-1,3-oxazolidin-5-one (5a). Following the 1, hexane/ethanol 90:10 for 30 min then with a
General
Procedure,
(4S)-2,2-dimethyl-4-(2-meth- gradient from 90:10 to 80:20 over 15 min and a step
°
ylpropyl)-3-(naphthalene-1-carbonyl)-1,3-oxazolidin-5-
one (1-A; 100 mg, 0.307 mmol), 2-fluorobenzaldehyde times of racemic mixture: 23.3 min (minor) and
of 35 min, 1 mL/min, T=25 C, λ=222 nm; retention
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1
26.6 min (major) ee=73%. H-NMR (250 MHz, 300 K, 137.6M; 138.5m2; 139.2m1; 168.5m1; 169.0M; 169.4m2;
CDCl3): Conformer ratio major (M)/minor (m): 0.7: 0.3: 169.5M; 170.3m1; 170.4m2. HR-ESI-MS: 528.0829
0.44 (s, 3Hm); 0.56 (s, 3HM); 0.99 (s, 3HM);1.47 (s, 3Hm); (C26H27BrNO4S+, [M+H]+; calc. 528.0839), 550.0647
2.25 (s, 3Hm); 2.31 (s, 3HM); 2.71–3.03 (m, 3HM (C26H26BrNNaO4S+, [M+Na]+; calc. 550.0658).
+4Hm); 3.07–3.17 (m, 1HM);5.37 (d, J=11.0, 1HM);
5.40 (d, J=11.1, 1Hm); 6.67 (d, J=11.1, 1HM); 6.71 (d,
(4R)-4-[Hydroxy(pyridin-2-yl)methyl]-2,2-
J=11.1, 1Hm); 7.25–7.42 (m, 3HM+3Hm); 7.45–7.75 dimethyl-4-[2-(methylsulfanyl)ethyl]-3-
(m, 6HM+6Hm); 7.86–7.99 (m, 2HM+2Hm). 13C-NMR (naphthalene-1-carbonyl)-1,3-oxazolidin-5-one (8).
(100.0 MHz, 300 K, CDCl3): 3 conformers M+2m: Following the General Procedure, (4S)-2,2-dimethyl-4-
14.6m; 15.5m; 15.6M; 26.2m; 27.0m; 28.3M+m; 28.7m; [2-(methylsulfanyl)ethyl]-3-(naphthalene-1-carbonyl)-
28.4 M+m; 28.9M; 30.4m; 32.4m; 32.9M; 33.1m; 56.5M 1,3-oxazolidin-5-one (1-B; 100 mg, 0.290 mmol), 2-
+2m; 75.4M; 75.6m; 76.1m; 96.7M; 96.8m; 98.2m; pyridinecarboxaldehyde (5 equiv., 1.45 mmol, 140 μL)
123.2–133.7; 137.3m; 142.8m 142.9M; 169.9 M; and KHMDS (1.5 equiv., 0.430 mmol, 430 μL (1 M in
170.3m*2; 170.6m; 171.2m; 171.5 M. HR-ESI-MS: THF)) in THF gave compound 8 after 15 min. The crude
528.0823 (C26H27BrNO4S+, [M+H]+; calc. 528.0839), product (dr=15:85) was then purified by column
550.0645
550.0658).
(C26H26BrNNaO4S+,
[M+Na]+;
calc. chromatography over silica gel (PE/ethyl acetate/Et3N
80:20:1 to 60:40:1) to give minor diastereomer 8a
(4 mg, 3%, ee=82%) and major diastereomer 8b
(85 mg, 65%, ee=97%). HPLC Analysis: Chiralpak AD-
(4R)-4-[(R)-(2-Bromophenyl)(hydroxy)methyl]-
°
2,2-dimethyl-4-[2-(methylsulfanyl)ethyl]-3-
(naphthalene-1-carbonyl)-1,3-oxazolidin-5-one (7a). 222 nm; retention times of racemic mixture: 62.1 min
Following the General Procedure, (4S)-2,2-dimethyl-4- (minor) and 67.8 min (major) ee=97% (isolated with
H, hexane/ethanol 95:5, 1 mL/min, T=38 C, λ=
[2-(methylsulfanyl)ethyl]-3-(naphthalene-1-carbonyl)-
ee>99%) (minor diastereomer 47.6 min (minor) and
1
1,3-oxazolidin-5-one (1-B; 100 mg, 0.290 mmol), 2- 56.8 min (major) ee=82%). Minor Diastereomer 8a. H-
bromobenzaldehyde (5 equiv., 1.45 mmol, 170 μL) and NMR (400 MHz, 300 K, CDCl3): Conformer ratio major
KHMDS (1.5 equiv., 0.430 mmol, 430 μL (1 M in THF)) in (M)/minor (m): 1.0:0.5: 0.87 (s, 3HM); 0.97 (s, 3Hm); 1.15
THF gave compound 7a after 12 min. The crude (mc, 3Hm); 1.74 (s, 3HM); 2.25 (s, 3HM); 2.30 (s, 3Hm);
product (single diastereomer) was then purified by 2.37–2.47 (m, 2Hm); 2.56–2.67 (m, 1Hm); 2.98–3.11
column chromatography over silica gel (PE/ethyl (m, 4HM); 3.15–3.34 (m, 1Hm); 5.53 (d, J=11.0, 1Hm);
acetate 100:0 to 70:30) to give diastereomer 7a 5.57 (d, J=11.7, 1HM); 6.04 (d, J=8.4, 1HM); 6.44 (d,
(110 mg, 72%, ee=60%). HPLC Analysis: (S,S) Whelk-O J=11.7, 1Hm); 6.51 (d, J=11.9, 1HM); 6.62 (d, J=6.2,
1, hexane/ethanol 88:12 for 30 min then with a 1Hm); 7.07–7.13 (m, 1HM); 7.31–7.98 (m, 8HM+9Hm);
gradient from 88:12 to 80:20 over 15 min and a step 8.57–8.60 (m, 1HM); 8.66–8.69 (m, 1Hm). 13C-NMR
°
of 40 min, 1 mL/min, T=25 C, λ=222 nm; retention (100.0 MHz, 300 K, CDCl3): 15.6M; 15.7m; 27.3M; 28.0M;
times of racemic mixture: 15.5 min (minor) and 28.1m; 28.6m; 29.7m; 30.4M; 33.6m; 34.5M; 72.6M;
41.5 min (major) ee=60% (minor diastereomer 73.3m; 74.9M; 76.1m; 96.2M+m; 121.2m; 121.4M;
11.9 min (minor) and 25.5 min (major) – other trials). 122.8M; 123.0m; 124.0M+m; 124.4M; 124.5m; 124.7M;
1H-NMR (300 MHz, 300 K, CDCl3): Conformer ratio 125.3m; 126.5M; 126.8m; 127.1M; 127.7m; 128.3M;
major (M):minor 1 (m1):minor 2 (m2): 0.4: 0.3: 0.2: 1.00 128.7m; 129.4m; 130.0M; 130.2M+m; 132.7m; 133.1M
(s, 3Hm1); 1.19 (s, 3Hm1); 1.25 (s, 3Hm2); 1.27 (s, 3Hm2); +m; 133.2M; 136.9M+m; 148.3M; 148.6m; 160.1m;
2.02 (s, 3HM); 2.03 (s, 3Hm1); 2.06 (s, 3Hm2); 2.19 (s, 160.2M; 169.6M; 170.0m; 174.4M; 170.5m. HR-ESI-MS:
3HM); 2.28 (s, 3HM); 2.37–2.88 (m, 3HM+3Hm1 + 451.1684 (C25H27N2O4S+, [M+H]+; calc. 451.1686),
3Hm2); 3.27–3.50 (m, 1HM+1Hm1 +1Hm2); 4.86 (d, J= 473.1503 (C25H26N2NaO4S+, [M+Na]+; calc. 473.1505).
7.3, 1Hm1); 4.96 (d, J=2.0, 1HM); 6.05 (d, J=7.1, 1Hm1); Major Diastereomer 8b. 1H-NMR (360 MHz, 300 K,
6.63 (d, J=3.2, 1Hm2); 6.97–7.04 (m, 1HM); 7.13–7.25 C6D6): Conformer ratio major (M)/minor (m): 1.0:0.5:
(m, 1HM+1Hm1 +2Hm2); 7.36–7.66 (m, 6HM+6Hm1 + 0.83 (s, 3Hm); 0.93 (s, 3HM); 1.22 (mc, 3HM+3Hm); 2.04
6Hm2); 7.24–7.36 (m, 1HM+1Hm1 +1Hm2); 7.85–7.98 (s, 3Hm); 2.10 (s, 3HM); 2.78–2.91 (m, 3Hm); 2.95–3.15
(3HM+3Hm1 +3Hm2). 13C-NMR (100.0 MHz, 300 K, (m, 3HM); 3.52–3.63 (m, 1Hm); 3.70–3.80 (m, 1HM);
CDCl3): 15.3m2; 15.4M+m1; 24.8M; 27.2M; 28.1m2; 5.33 (d, J=8.4, 1HM); 5.35 (d, J=8.3, 1Hm); 5.69 (d, J=
28.6m1; 28.7M; 28.9m1; 29.0m1; 29.4m2; 30.3m2; 30.6m2; 8.4, 1HM); 6.04 (d, J=8.3, 1Hm); 6.61–6.72 (m, 1HM+
32.2m1; 33.1M; 71.8m1; 72.3m2; 73.7M; 74.1m2; 74.2M; 1Hm); 7.02–7.10 (m, 2HM+2Hm); 7.13–7.23 (m, 2HM
74.3m1; 96.5M; 98.4m1 +m2; 123.2-134.2; 135.4m2; +3Hm); 7.24–7.36 (m, 1HM+1Hm); 7.44 (d, J=6.8,
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1HM); 7.53–7.74 (m, 2HM+2Hm); 7.96 (br. s, 1HM); (C26H27FNO4S+, [M+H]+; calc. 468.1639), 490.1451
8.07 (br. s, 1Hm); 8.30 (d, J=3.9, 1HM); 8.40 (d, J=3.7, (C26H26FNNaO4S+, [M+Na]+; calc. 490.1459).
1Hm). 1H-NMR (400 MHz, 300 K, CDCl3): Conformer
ratio major (M)/minor (m): 0.7:0.3: 0.87 (s, 3Hm); 1.11 (s,
(4R)-4-[(R)-Hydroxy(pyridin-3-yl)methyl]-2,2-
3HM); 1.28 (mc, 3HM); 1.51 (s, 3Hm); 2.21 (s, 3Hm); 2.26 dimethyl-4-[2-(methylsulfanyl)ethyl]-3-
(s, 3HM); 2.56–2.65 (m, 3Hm); 2.70–2.83 (m, 3HM); (naphthalene-1-carbonyl)-1,3-oxazolidin-5-one
3.20–3.30 (m, 1Hm); 3.40–3.50 (m, 1HM); 5.03 (br. s, (10a). Following the General Procedure, (4S)-2,2-
1HM+1Hm); 5.46 (br. s, 1HM); 5.71 (br. s, 1Hm); 7.26– dimethyl-4-[2-(methylsulfanyl)ethyl]-3-(naphthalene-1-
7.93 (m, 10HM+10Hm); 8.60–8.67 (m, 1HM+1Hm). carbonyl)-1,3-oxazolidin-5-one
(1-B;
100 mg,
13C-NMR (100.0 MHz, 300 K, CDCl3): 15.5M+m; 28.4m; 0.290 mmol), 3-pyridinecarboxaldehyde (5 equiv.,
29.0M; 29.6m; 29.7M*2; 30.5m; 31.5m; 32.4M; 72.3m; 1.45 mmol, 160 μL) and KHMDS (1 equiv., 0.290 mmol,
73.2M; 75.3M+m; 96.7M+m; 123.3M; 123.6m; 123.8M; 290 μL (1 M in THF)) in THF gave compound 10a after
123.9m; 124.1m; 124.2M; 124.8M; 125.4M; 125.6m; 12 min. The crude product (dr=98/2) was then
125.7m; 126.4m; 126.6M; 126.7m; 127.4M; 128.4m; purified by column chromatography over silica gel
128.7M; 129.8m; 129.9M; 130.0m; 130.2M; 133.3m; (cyclohexane/ethyl acetate 60:40 to 50:50) to give
133.4M; 133.8M; 134.1m; 136.6M+m; 148.9M+m; diastereomer 10a (115 mg, 88%, ee=75%). HPLC
157.2M; 158.0m; 169.1m; 169.3M; 171.4M; 172.0m. HR- Analysis: Chiralpak IC, hexane/ethanol 90:10, 1 mL/
ESI-MS: 451.1672 (C25H27N2O4S+, [M+H]+; calc. min, T=25 C, λ=222 nm; retention times of racemic
°
451.1686), 473.1500 (C25H26N2NaO4S+, [M+Na]+; calc. mixture: 30.1 min (minor) and 34.0 min (major) ee=
473.1505).
75% (minor diastereomer 38.3 min (minor) and
41.3 min (major)). 1H-NMR (400 MHz, 300 K, CDCl3):
Conformer ratio major (M)/minor (m): 0.7:0.3: 0.57 (s,
3HM+3Hm); 0.97 (s, 3HM); 1.51 (s, 3Hm); 2.19 (s, 3Hm);
(4R)-4-[(R)-(2-Fluorophenyl)(hydroxy)methyl]-
2,2-dimethyl-4-[2-(methylsulfanyl)ethyl]-3-
(naphthalene-1-carbonyl)-1,3-oxazolidin-5-one (9a). 2.27 (s, 3HM); 2.56–3.11 (m, 4HM +4Hm); 5.41 (d, J=
Following the General Procedure, (4S)-2,2-dimethyl-4- 10.4, 1HM); 5.59 (d, J=8.5, 1Hm); 6.23 (d, J=9.4, 1Hm);
[2-(methylsulfanyl)ethyl]-3-(naphthalene-1-carbonyl)-
6.58 (d, J=10.7, 1HM); 7.16 (d, J=7.0, 1HM); 7.37–7.76
1,3-oxazolidin-5-one (1-B; 100 mg, 0.290 mmol), 2- (m, 6HM+6Hm); 7.82–7.94 (m, 2HM+3Hm); 8.64–8.66
fluorobenzaldehyde (5 equiv., 1.45 mmol, 180 μL) and (m, 1HM+1Hm); 8.72 (br. s, 1HM); 8.79 (br. s, 1Hm).
KHMDS (1.5 equiv., 0.430 mmol, 430 μL (1 M in THF)) in 13C-NMR (100.0 MHz, 300 K, CDCl3): 15.5m; 15.6M;
THF gave compound 9a after 18 min. The crude 28.4M; 28.6M; 28.7m; 28.9M; 29.7m; 30.3m; 32.8m;
product (single diastereomer) was then purified by 32.9M; 74.1m; 74.8m; 75.2M; 75.5M; 96.7M; 96.8m;
column chromatography over silica gel (heptane/THF 123.2m; 123.5M; 123.9m; 124.1M+m; 124.2M; 125.2M;
90:10 to 75:25) to give one diastereomer 9a (135 mg, 125.6m; 126.9m; 127.0M; 127.5m; 127.8M; 128.6m;
99%, ee=85%). HPLC Analysis: (S,S) Whelk-O 1, 128.9M; 129.5M; 129.8m; 130.5M; 130.7m; 132.4M;
hexane/ethanol 88:12 for 30 min then with a gradient 132.8m; 133.1M; 133.4m; 134.7M; 135.1m; 135.7m;
from 88:12 to 80:20 over 15 min and a step of 40 min, 136.0M; 148.5M; 148.7m; 149.7m; 149.9M; 169.7M;
°
1 mL/min, T=25 C, λ=222 nm; retention times of 170.3m; 170.8m; 171.4M. HR-ESI-MS: 451.1676
racemic mixture: 15.8 min (minor) and 29.8 min (major) (C25H27N2O4S+, [M+H]+; calc. 451.1686), 473.1492
ee=85% (minor diastereomer 11.9 min and 25.6 min (C25H26N2NaO4S+, [M+Na]+; calc. 473.1505).
1
from racemic). H-NMR (400 MHz, 300 K, CDCl3): Con-
former ratio major (M)/minor (m): 0.6:0.3: 0.75 (s, 3HM);
(4R)-4-[(S)-Hydroxy(pyridin-2-yl)methyl]-2,2-
0.78 (s, 3Hm); 0.98 (s, 3HM); 1.52 (s, 3Hm); 2.20 (s, dimethyl-3-(naphthalene-1-carbonyl)-4-(propan-2-
3Hm); 2.32 (s, 3HM); 2.54–2.63 (m, 1Hm); 2.72–3.08 (m, yl)-1,3-oxazolidin-5-one (11b). Following the General
3Hm+4HM); 5.28 (d, J=9.4, 1Hm); 5.69 (d, J=11.1, Procedure,
1HM); 5.92 (d, J=9.3, 1Hm); 6.16 (d, J=11.0, 1HM); carbonyl)-4-(propan-2-yl)-1,3-oxazolidin-5-one
7.06–7.21 (m, 2HM+2Hm); 7.34–7.74 (m, 6HM+6Hm); 100 Mg, 0.320 mmol),
(4S)-2,2-dimethyl-3-(naphthalene-1-
(1-C;
2-pyridinecarboxaldehyde
7.06–7.95 (m, 3HM+3Hm). 13C-NMR (100.0 MHz, (5 equiv., 1.60 mmol, 152 μL) and KHMDS (1.5 equiv.,
300 K, CDCl3): 15.4m; 15.6M; 28.2m; 28.4M; 28.5M; 0.48 mmol, 480 μL (1 M in THF)) in THF gave com-
28.9m; 29.0M; 30.4m; 32.2m; 32.8M; 70.6m; 72.2M; pound 11b after 18 min. The crude product (dr=7:93)
74.0M; 74.4m; 96.4M+m; 115.7m (d, J=22); 116.0M (d, was then purified by column chromatography over
J=22); 124.1–133.4; 159.6M+m (d, J=248); 169.0M; silica gel (cyclohexane/ethyl acetate 85:15 to 30:70)
169.5m; 170.5m; 171.1M. HR-ESI-MS: 468.1623 to give diastereomer (63 mg, 47%, ee=90%). HPLC
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Analysis: Chiralpak AD-H, hexane/ethanol 90:10, 1 mL/ 55.6 min (major), ee=29%). First Diastereomer Ac-12a.
min, T=30 C, λ=222 nm; retention times of racemic 1H-NMR (400 MHz, 300 K, CDCl3): Conformer ratio
°
mixture: 12.9 min (minor) and 32.7 min (major) ee= major (M)/minor (m): 0.7:0.3: 0.19 (s, 3HM); 0.29 (s,
90% (minor diastereomer 19.2 min (minor) and 3Hm); 0.33 (s, 3HM); 0.76 (s, 3Hm); 2.28 (s, 3Hm); 2.29
1
39.2 min (major) ee=45%). H-NMR (400 MHz, 300 K, (s, 3HM); 3.85 (d, J=13.2, 1HM); 3.89 (d, J=13.1, 1Hm);
CDCl3): Conformer ratio major (M)/minor (m): 0.7:0.3: 4.21 (d, J=13.3, 1HM); 4.39 (d, J=13.4, 1Hm); 6.81 (s,
0.94 (s, 3Hm); 1.15 (s, 3HM); 1.28 (s, 3HM); 1.34 (d, J= 1Hm); 7.20 (d, J=7.1, 1HM); 7.30–7. 65 (m, 10HM+
6.9, 3HM); 1.35 (d, J=6.8, 3Hm); 1.50 (d, J=7.1, 3Hm); 12Hm); 7.69 (d, J=7.8, 1HM); 7.77–7.86 (m, 3HM+
1.51 (s, 3Hm); 1.61 (d, J=7.0, 3HM); 3.40 (sept, J=7.0, 3Hm); 8.41 (d, J=8.2, 1HM); 8.76 (d, J=3.9, 1HM+
1Hm); 3.70 (sept, J=7.0, 1HM); 5.74 (s, 1HM); 6.07 (s, 1Hm). 13C-NMR (100.0 MHz, 300 K, CDCl3): 21.1m;
1Hm); 7.23–7.56 (m, 7HM+6Hm); 7.67–7.80 (m, 2HM 21.2M; 27.5M; 28.5m; 29.0M+m; 37.4M; 39.3m; 73.1M;
+2Hm); 7.82–7.90 (m, 2HM+3Hm); 8.56 (d, J=4.6, 73.4m; 76.0M; 76.2m; 96.4M; 96.8m; 123.4m; 123.7M;
1HM); 8.63 (d, J=4.8, 1Hm). 13C-NMR (100.0 MHz, 123.8M; 123.9m; 124.3M; 125.1M; 125.9m; 126.2m;
300 K, CDCl3): 18.5M; 19.2m; 19.9m; 20.0M; 29.0M; 126.3m; 126.5M+m; 126.8M; 127.9m; 128.0M; 128.1M;
29.1m; 29.7M+m; 29.8M; 31.3m; 72.3M; 73.9m; 76.1m; 128.3m; 128.6M; 129.0M*2+m*2; 129.7m; 129.8M+m;
77.7M; 96.1m; 96.2M; 122.8M; 123.5m; 123.6m; 123.8M; 130.4m; 131.2M*2+m*2; 131.4M; 133.1M; 133.2m;
123.9 M+m; 125.2M; 125.7M; 125.8m; 125.9m; 126.4M; 134.0M; 134.1m; 135.4m; 135.7M; 136.9m; 137.0M;
126.5m; 126.7m; 127.2M; 128.4m; 128.5M; 129.9M+m; 149.3M; 149.5m; 156.0m; 156.1M; 169.2M; 169.4m;
130.0M; 130.1m; 133.4M+m; 134.5M+m; 136.5M+m; 169.5m; 169.7M; 169.8M; 170.5m. HR-ESI-MS: 509.2060
148.1M; 148.6m; 157.0M; 158.5m; 169.6M; 169.8m; (C31H29N2O5+, [M+H]+; calc. 509.2071), 531.1878
+
170.3M; 171.4m. HR-ESI-MS: 419.1959 (C25H27N2O4
[M+H]+; calc. 419.1965), 441.1777 (C25H26N2NaO4
[M+Na]+; calc. 441.1785).
,
,
(C31H28N2NaO5+, [M+Na]+; calc. 531.1890). Second
Diastereomer Ac-12b. H-NMR (400 MHz, 300 K, CDCl3):
+
1
Conformer ratio major (M)/minor (m): 0.8:0.2: 0.38 (s,
3Hm); 0.51 (s, 3HM); 1.02 (s, 3HM); 1.38 (s, 3Hm); 2.27 (s,
3HM); 2.33 (s, 3Hm); 2.87 (d, J=13.4, 1HM); 2.97 (d, J=
13.5, 1Hm); 4.40 (d, J=13.4, 1HM); 4.48 (d, J=13.8,
1Hm); 7.23–7.93 (m, 16HM+17Hm); 8.73 (d, J=4.1,
1HM). 13C-NMR (100.0 MHz, 300 K, CDCl3): only M
(R)-[4-Benzyl-2,2-dimethyl-3-(naphthalene-
1-carbonyl)-5-oxo-1,3-oxazolidin-4-yl](pyridin-2-yl)
methyl Acetate (Ac-12)
Following the general procedure, (4S)-4-benzyl-2,2- described: 21.3; 28.3; 28.6; 37.7; 73.0; 75.8; 96.6; 122.7;
dimethyl-3-(naphthalene-1-carbonyl)-1,3-oxazolidin-5- 123.5; 124.0; 124.6; 124.7; 126.6; 127.3; 127.9; 128.5;
one (1-D; 200 mg, 0.556 mmol), 2-pyridinecarboxalde- 128.8*2; 129.9; 130.7; 131.1*2; 133.2; 133.8; 135.7;
hyde (5 equiv., 2.78 mmol, 264 μL) and KHMDS 136.2; 148.9; 155.3; 168.5; 169.1; 169.3. HR-ESI-MS:
(1.5 equiv., 0.834 mmol, 834 μL (1 M in THF)) in THF 509.2051 (C31H29N2O5+, [M+H]+; calc. 509.2071),
(3 mL) gave (4R)-4-benzyl-4-[hydroxy(pyridin-2-yl) 531.1872 (C31H28N2NaO5+, [M+Na]+; calc. 531.1890).
methyl]-2,2-dimethyl-3-(naphthalene-1-carbonyl)-1,3-
oxazolidin-5-one (12) after 12 min. Following the
General Procedure of Acetylation, compound 12 (crude methyl]-2,2-dimethyl-3-(naphthalene-1-carbonyl)-
product 452 mg), 4-(dimethylamino)pyridine 1,3-oxazolidin-5-one (13a). Following the General
(0.1 equiv., 0.056 mmol, 7 mg), acetic anhydride Procedure, (4S)-4-benzyl-2,2-dimethyl-3-(naphthalene-
(4R)-4-Benzyl-4-[(R)-(2-fluorophenyl)(hydroxy)
–
(5 equiv., 2.78 mmol, 260 μL), triethylamine (1.5 equiv., 1-carbonyl)-1,3-oxazolidin-5-one
0.834 mmol, 116 μL) in THF (5.5 mL) gave compound 0.278 mmol),
Ac-12 after one night. The crude product (dr 56:44) 1.39 mmol,
(1-D;
2-fluorobenzaldehyde
146 μL) and KHMDS
100 mg,
(5 equiv.,
(1.5 equiv.,
was then purified by column chromatography over 0.417 mmol, 417 μL (1 M in THF)) in THF gave com-
silica gel (PE/ethyl acetate 80:20 to 70:30) then pound 13a after 15 min. The crude product (dr=98:2)
(CH2Cl2/ethyl acetate 95:5 at 90:10) to give two was then purified by column chromatography over
diastereomers Ac-12 (125 mg : first diastereomer Ac- silica gel (PE/ethyl acetate 100:0 to 80:20) to give
12a 54 mg, ee=29%, mixture 15 mg, second diaster- diastereomer 13a (70 mg, 52%, ee=34%). HPLC
eomer Ac-12b 56 mg, ee=29%, 44% in two steps). Analysis: Chiralpak IC, hexane/ethanol 90:10, 1 mL/
°
HPLC Analysis: Chiralpak IC, hexane/ethanol 90:10, min, T=25 C, λ=222 nm; retention times of racemic
°
1 mL/min, T=25 C, λ=222 nm; retention times of mixture: 6.5 min (major) and 7.4 min (minor) ee=34%
racemic mixture: 26.5 min (minor) and 28.2 min (major) (minor diastereomer 13.0 min and 15.3 min from
1
ee=29% (minor diastereomer 35.0 min (minor) and racemic). H-NMR (400 MHz, 300 K, CDCl3): Conformer
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ratio major (M)/minor (m): 1:0.3: 0.29 (s, 3Hm); 0.44 (s, 2Hm2). 13C-NMR (90 MHz, 300 K, CDCl3): 21.5M; 21.8m;
3HM); 0.78 (s, 3HM); 0.84 (s, 3Hm); 3.26 (d, J=13.7, 23.0M; 24.0m; 24.6m; 24.8M; 27.0m; 27.1M; 28.9M;
1HM); 3.57 (d, J=14.0, 1Hm); 4.29 (d, J=13.7, 1HM); 29.6m; 30.1m; 30.7M; 39.2M+m; 71.2M; 72.1m; 96.2M;
4.48 (d, J=7.3, 1HM); 4.53 (d, J=14.2, 1Hm); 5.18 (d, 98.2m; 115.5M (d; J=22); 124.0–134.2; 168.7m;
J=8.7, 1Hm); 5.92 (d, J=8.8, 1Hm); 6.34 (d, J=7.2, 168.8M; 169.0M+m; 170.0m; 170.1M (one carbon M
1HM); 7.11–7.20 (m, 1HM+1Hm); 7.24–7.60 (m, 11HM and m are under CDCl3 signal). HR-ESI-MS: 492.2174
+11Hm); 7.69–7.92 (m, 4HM+4Hm). 13C-NMR (C29H31FNO5+, [M+H]+; calc. 492.2181), 514.2003
(100.0 MHz, 300 K, CDCl3): 28.1M; 28.3m; 28.6M; 28.7m; (C29H30FNNaO4+, [M+Na]+; calc. 514.2000).
36.9M; 38.5m; 70.2M; 72.9m; 96.6M+m; 115.6M (d, J=
22); 115.9m (d, J=22); 123.9M+m; 124.0M; 124.3m;
2-Fluoro-β-hydroxy-α-(2-methylpropyl)-D–Phe-
125.3M; 125.6M; 125.8m; 126.1m; 126.5M+m; 126.7m; nylalanine–Hydrogen Chloride (14). Following the
126.8M (d, J=15); 127.0M; 127.2m (d, J=14); 128.0M; General Procedure, (R)-[(4R)-2,2-dimethyl-4-(2-meth-
128.1m; 128.4M; 128.7m; 128.8M*2+m*2; 129.9m; ylpropyl)-3-(naphthalene-1-carbonyl)-5-oxo-1,3-oxazo-
130.1M+m; 130.2M; 130.3M; 130.4m; 131.0M*2+m*2; lidin-4-yl](2-fluorophenyl)methyl
acetate
(Ac-5a;
131.3M; 133.3m; 133.1m; 133.3M; 133.6M+m; 135.3m; 30 mg, 0.061 mmol), acetic acid (0.5 mL) and 6 M HCl
135.9M; 160.1M+m (d, J=248); 169.9M; 170.2M; (1 mL) gave compound 14 after 24 h (10 mg, 56%).
170.3m; 171.6m (one carbon M and m are under CDCl3 1H-NMR (400 MHz, 300 K, CD3OD): 0.89 (d, J=5.4, 3H);
signal). HR-ESI-MS: 484.1908 (C30H27FNO4+, [M+H]+; 0.99 (d, J=5.4, 3H); 1.71–1.85 (m, 2H); 2.03 (d, J=8.8,
calc. 484.1919); 506.1727 (C30H26FNNaO4+, [M+Na]+; 1H); 5.19 (s, 1H); 7.09 (t, J=9.5, 1H); 7.20 (t, J=7.1, 1H);
calc. 506.1738).
7.37 (q, J=6.9, 1H); 7.60 (t, J=7.0, 1H). 13C-NMR
(100 MHz, 300 K, CD3OD): 22.7; 24.9; 25.2; 42.2; 68.8;
71.0; 116.0 (d, J=23); 125.1; 127.0 (d, J=14); 131.3;
131.5; 161.5 (d, J=244); 171.2. HR-ESI-MS: 256.1339
(R)-[(4R)-2,2-Dimethyl-4-(2-methylpropyl)-3-
(naphthalene-1-carbonyl)-5-oxo-1,3-oxazolidin-4-
yl](2-fluorophenyl)methyl Acetate (Ac-5a). To a (C13H19FNO3+, [M+H]+; calc. 256.1343); 278.1157
stirred solution of (4R)-4-[(R)-(2-fluorophenyl)(hydroxy) (C13H18FNNaO3+, [M+Na]+; calc. 278.1163).
methyl]-2,2-dimethyl-4-(2-methylpropyl)-3-
(naphthalene-1-carbonyl)-1,3-oxazolidin-5-one
(5a;
2-[(R)-Hydroxy(pyridin-3-yl)methyl]-L–Leucine–
120 mg, 0.222 mmol) and 4-(dimethylamino)pyridine Hydrogen Chloride (15). Following the general
(0.01 equiv., 0.0022 mmol, 0.27 mg) in CH2Cl2 (2.2 mL) procedure, (R)-[(4R)-2,2-dimethyl-4-(2-methylpropyl)-3-
°
at 0 C were added acetic anhydride (1.2 equiv., (naphthalene-1-carbonyl)-5-oxo-1,3-oxazolidin-4-yl](-
0.267 mmol, 25 μL) and triethylamine (1.2 equiv., pyridin-3-yl)methyl
acetate
(Ac-4a;
45 mg,
0.267 mmol, 37 μL). The resulting mixture was stirred 0.095 mmol), acetic acid (0.5 mL) and 6 M HCl (1 mL)
for 12h at room temperature. The reaction was gave compound 15 after 24 h (26 mg, quantitative
1
quenched by the addition of methanol. The mixture yield). H-NMR (400 MHz, 300 K, CD3OD): 0.90 (d, J=
was washed with a 1 M HCl solution and water. The 6.5, 3H); 1.03 (d, J=6.6, 3H); 1.69 (dd, J=9.4, J=14.3,
organic layer was dried over sodium sulfate, filtered, 1H); 1.82–1.96 (m, 1H); 2.21 (dd, J=3.1, J=14.3, 1H);
and then concentrated to give the crude product 5.28 (s, 1H); 8.14 (dd, J=5.1, J=7.9, 1H); 8.71 (d, J=7.9,
which was then purified through column chromatog- 1H); 8.90 (d, J=5.1, 1H); 8.96 (s, 1H). 13C-NMR
raphy over silica gel (PE/ethyl acetate 100:0 to 80:20) (100 MHz, 300 K, CD3OD): 22.3; 24.8; 25.1; 43.2; 68.1;
to give compound Ac-5a (75 mg, 69%). 1H-NMR 73.8; 127.9; 140.9; 142.7*2; 147.2; 171.0.
(250 MHz, 300 K, CDCl3): Conformer ratio major (M):
minor (m1): minor (m2): 0.5:0.3:0.2: À 0.30 (d, J=6.6,
3Hm2); 0.63 (d, J=6.4, 3Hm2); 0.89 (d, J=6.6, 3HM);
Supplementary Material
0.90 (s, 3Hm1); 0.83–0.93 (m, 1Hm1); 1.02 (d, J=6.4,
3Hm1); 1.06 (d, J=6.7, 3HM); 1.15 (d, J=6.8, 3Hm1); CCDC 2093028–2093030 and 2094493 contain the
1.19 (s, 3HM); 1.22 (s, 3Hm2); 1.33–1.45 (m, 1HM+ supplementary crystallographic data for compounds
1Hm2); 1.67 (s, 3Hm2); 1.69 (s, 3HM); 1.77–1.89 (m, 3b, Ac-5a, 8b and Ac-12a. These data can be obtained
1Hm1 +1Hm2); 2.06 (s, 3Hm1); 2.09–2.20 (m, 1HM+ free of charge from the Cambridge Crystallographic
1Hm1); 2.16 (s, 3HM); 2.21 (s, 3Hm1); 2.27 (s, 3Hm2); 2.99 Data Centre through https://www.ccdc.cam.ac.uk/
(br. d, J=13.9, 1HM); 3.13 (br. d, J=13.8, 1Hm2); 5.22 structures/.
(br. s, 1Hm2); 6.66 (t, J=9.4, 1Hm2); 6.80–7.78 (m,
10HM+10Hm1 +8Hm2); 7.82–8.04 (m, 2HM+ 2Hm1 +
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Helv. Chim. Acta 2021, 104, e2100127
[11] V. Alezra, T. Kawabata, ‘Recent Progress in Memory Of
Acknowledgements
Chirality (MOC): An Advanced Chiral Pool’, Synthesis 2016,
48, 2997–3016.
[12] T. Hardwick, N. Ahmed, ‘Memory of Chirality as
We thank the Marie Curie program for an IIF fellowship
(post-doctoral fellowship to B. V., grant PIIF-GA-2011-
300491). We also thank the synthesis support facility
(Pôle Synthèse) at ICMMO for their help.
a
Prominent Pathway for the Synthesis of Natural Products
through Chiral Intermediates’, ChemistryOpen 2018, 7,
484–487.
[13] S. Tan, F. Li, S. Park, S. Kim, ‘Carbocyclization of Hetero-
substituted Alkynes via the Memory of Chirality: Access to
Cα-Substituted Proline Derivatives’, J. Org. Chem. 2019, 84,
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Author Contribution Statement
L. R. and B. V. performed the experiments and analyzed
the data; R. G. was in charge of all the crystal analyses
and D. G. of HPLC analyses. C. K. helped to write the
paper. V. A. conceived and designed the experiments,
analyzed the data and wrote the paper.
[16] V. Veeraswamy, G. Goswami, S. Mukherjee, K. Ghosh, M. L.
Saha, A. Sengupta, M. K. Ghorai, ‘Memory of Chirality
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α-Amino Ester Enolates to Enones and Nitroalkenes’, J. Org.
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Received July 13, 2021
Accepted August 31, 2021
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