Studies of Azetidin-2-one as a Reactive Enolate Synthon of β-Alanine for Condensations with Aldehydes and Ketones

Article abstract of DOI:10.1021/acs.joc.6b01585

Studies describe formation of the lithium enolate of N-(4-methoxybenzyloxy)azetidin-2-one (1) and characterization of representative aldol reactions with aldehydes and ketones. Diastereoselectivity features the production of anti-aldol adducts from α,β-unsaturated ketones and α-branched aliphatic aldehydes. The stereoselectivity is rationalized via closed, six-membered transition-state arrangements leading to the formation of Felkin-Anh and anti-Felkin products. Examples illustrate the direct incorporation of monocyclic β-lactams into a variety of molecular architectures. The utility of 1 as an enolate synthon of homoglycine (β-alanine) is illustrated by the efficient synthesis of novel β-amino acid derivatives, including complex 4-hydroxy-2-pyridinones.

Full text of DOI:10.1021/acs.joc.6b01585

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Article
Studies of Azezidin-2-one-as a Reactive Enolate Synthon of
beta-Alanine for Condensations with Aldehydes and Ketones
David R. Williams, Andrew F. Donnell, David C Kammler, Sarah A. Ward, and Levin Taylor
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01585 • Publication Date (Web): 14 Sep 2016
Downloaded from http://pubs.acs.org on September 16, 2016
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Studies of Azetidin-2-one as a Reactive Enolate Synthon of β-Alanine for
Condensations with Aldehydes and Ketones
†
David R. Williams,* Andrew F. Donnell, David C. Kammler, Sarah A. Ward
and Levin Taylor, IV
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Department of Chemistry, Indiana University, Bloomington, Indiana 47405, USA
CH3
LiHMDS
O
THF, –78 °C
O
H C
3
N
HO
(R)-carvone
N
OPMB
OPMB
1
21 (82%)
(15 examples)
ABSTRACT: Studies describe formation of the lithium enolate of N-(4-
methoxybenzyloxy)azetidin-2-one (1), and characterization of representative aldol
reactions with aldehydes and ketones. Diastereoselectivity features the production of
anti-aldol adducts from α,β-unsaturated ketones and α-branched aliphatic aldehydes.
The stereoselectivity is rationalized via closed, six-membered transition state
arrangements leading to the formation of Felkin-Anh and anti-Felkin products. Examples
illustrate the direct incorporation of monocyclic β-lactams into a variety of molecular
architectures. The utility of 1 as an enolate synthon of homoglycine (β-alanine) is
illustrated by the efficient synthesis of novel β-amino acid derivatives, including complex
4
-hydroxy-2-pyridinones.
INTRODUCTION
Small ring heterocycles have been widely utilized as reactive intermediates for the
synthesis of complex heterocyclic systems. Azetidin-2-ones (β-lactams) are especially
significant as an essential motif in penicillin and cephalosporin antibiotics. Recent
methodology toward the synthesis of β-lactams has impressively advanced the Staudinger
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reaction of ketenes with various N-substituted imines for the preparation of 3,4-
,
1
2
disubstituted and 4-monosubstituted examples. In this manner, catalytic processes have
been devised for the production of β-lactams with cis- and trans-diastereoselectivity, as
0
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9
0
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0
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well as high enantioselectivity. However, these advances have not proven useful for the
synthesis of 3-monosubstituted-2-azetidinones. Methods that feature the preparation of
4
related azetidines as reactive species have also recently received attention, and studies
5
for the selective ring opening of the β-lactam have been reported. The reactivity of
azetidin-2-one provides for the design of peptidomimetics via the incorporation of a
homoglycine (β-alanine) subunit within the amido backbone. For these examples, the
introduction of substitution at the α-carbon (3-position) of the β-lactam ring can prove
useful for the design of unnatural β-aminoamides as isosteric bioactive equivalents. In
6
the course of our investigations leading to the total synthesis of apiosporamide, we have
explored the aldol reactions of N-(4-methoxybenzyloxy)azetidin-2-one (1) as an effective
general strategy for the synthesis of complex, nonracemic 4-hydroxy-2-pyridinones, as
7
exemplified by 2 and related natural products (Eq. 1). Herein, we describe a full account
of our investigations of aldol reactions of 1 and describe the contributing factors leading
to the observed stereoselectivity of these processes.
O
HO
CH3
O
OH
O
O
H
H
(1)
N
HO
H
OPMB
N
H
H C
1
(PMB = CH C H OMe)
3
2
6 4
2
((+)-Apiosporamide)
These studies have demonstrated a kinetic enolization of 1 and the reactivity of the
resulting lithium enolate with a selection of aldehydes and ketones. Our efforts present a
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method for the direct incorporation of the intact β-lactam into complex molecular
architectures which may serve as probes of biological targets.
RESULTS AND DISCUSSION
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Studies of aldol reactions involving azetidin-2-one substrates have been
associated, in large measure, with installation of the hydroxylethyl side chain of
8,9
thienamycin and related penem derivatives. The condensation of the enolate of 3 with
acetaldehyde yields the adducts 4a-d (Scheme 1). Chirality at C-4 of the starting
azetidinone 3 determines the C-3 stereochemistry (4ab:4cd ratio 89:9), whereas only
modest asymmetric induction is observed for introduction of chirality at the site of the
secondary alcohol (4a:4b ratio 50:39). In related reports of acyclic systems, a
stereoselective C-alkylation of the lithium enolate, derived from the deprotonation of
1
0
methyl-3-aminobutyrate, has been shown to produce anti-stereoselectivity.
Scheme 1. Aldol Reaction of 3 with Acetaldehyde
HO
H H
H C
3
N
O
O
H C CH3
3
4
a/4b
H
N
LDA, THF
78 °C, MeCHO
(major)
–
O
9
8% yield
HO
O
[dr 50:39:9:0.2]
H H
H C CH3
3
H C
3
3
N
O
O
H C CH3
3
4
c/4d
(minor)
Our initial attempts to explore kinetic enolate formation of the parent azetidin-2-
one examined several standard choices for nitrogen protection, and these derivatives
failed to provide solutions of enolates consistent with stable, albeit reactive, species.
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1
1
Based on literature reports by Miller and coworkers regarding the preparation and
bioactivity of N-alkoxyazetidin-2-ones, we have found that the presence of the N-O bond
in the hydroxamic acid PMB (para-methoxybenzyl) derivative 1 leads to useful solutions
of highly reactive enolates at –78 °C. The azetidin-2-one 1 is obtained by adapting the
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0
1
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report of Reinhoudt for intramolecular N-alkylation of 4-(4-methoxybenzyloxy)-3-
chloropropionamide 5 using sodium hydride in DMF at 60 °C (Eq. 2). Small amounts of
the acrylamide 6 are occasionally observed in the reaction, but the desired β-lactam 1 is
O
O
O
NaH, DMF
° → 60 °C
OPMB
OPMB
Cl
N
H
N
H
6
N
0
(
2)
OPMB
5
1 (52%)
readily purified by flash chromatography and stored under anhydrous conditions as a
crystalline solid (mp 46–47 °C). Studies for the kinetic deprotonation of 1 have
measured deuterium incorporation to quantify enolate formation by the integration of the
1
α-hydrogen signal in H NMR spectra following the d
4
-methanol quench. As
summarized in Table 1, the choice of the base is significant for achieving complete
deprotonation as LDA has proven to be less effective than LiHMDS (entries 1 and 2)
whereas LiHMDS is superior to the use of the corresponding NaHMDS and KHMDS
13
bases. Notably, solutions of enolate show evidence of decomposition as temperatures
are increased from –78 °C to –40 °C or above (entries 6 and 8).
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Table 1. Deprotonation Studies of 1
O
D
O
base, THF (0.1 M)
N
N
then CD OD
3
OPMB
OPMB
1
1a
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entry
base
equiv
1.1
time
1 h
temp
% d-incorporation
69% D
1
2
3
4
5
6
7
8
LDA
–78 °C
–78 °C
–78 °C
–78 °C
–78 °C
LiHMDS
NaHMDS
KHMDS
NaHMDS
NaHMDS
LiHMDS
LiHMDS
1.1
1 h
90% D
1.1
1 h
79% D
1.1
1 h
12% D
1.5
1 h
83% D
1.1
1.3 h
2 h
–78 °C to 0 °C
–78 °C
decomp
100% D
decomp
1.1
0.93
2.2 h
–78 °C to –40 °C
By employing our optimized conditions, the enolate of 1 affords a facile
condensation with the nonracemic enone 7 to produce nearly equal amounts of the anti-
diastereomers 8 and 9 in 95% yield (Eq. 3). No products resulting from 1,4-conjugate
addition are observed. Fortunately, the chromatographic separation of these
diastereomers provides suitable crystals leading to simple derivatives of each alcohol for
1
4
unambiguous assignments of stereochemistry via X-ray crystallographic analysis.
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TBSO
O
HO
N
OPMB
LiHMDS
THF, –78 °C
O
8
0
1
2
3
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8
9
0
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9
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9
0
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9
0
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2
3
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6
7
8
9
0
N
(3)
TBSO
TBSO
OPMB
7
O
1
O
HO
[95% (dr 1.2:1)]
N
OPMB
9
Our mechanistic rationale of this aldol reaction considers four closed transition states as
illustrated in Figure 1. The anti-products 8 and 9 arise via the Zimmerman–Traxler
arrangements of 10 and 11, respectively, whereas 12 and 13 lead to the unobserved syn-
adducts 14 and 15. Unfavorable steric interactions of the C-4 methylene of the enolate of
1
1
with the saturated methylene carbons of the starting cyclohexenone are destabilizing in
2 and 13. This condition is remedied by the presence of the planar C=C moiety in both
10 and 11, and a slight preference for formation of 8 is attributed to axial addition to the
cyclohexenone carbonyl versus equatorial addition as featured in 11.
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H
TBSO
OPMB
TBSO
O
N
Li
HO
O
N
OPMB
O
anti-8
H
1
0
OPMB
10
11
12
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TBSO
N
H
O
Li
TBSO
O
O
HO
N
OPMB
H
anti-9
11
OPMB
TBSO
N
TBSO
H
O
Li
O
O
HO
N
OPMB
syn-14
H
1
2
TBSO
H
TBSO
OPMB
Li
N
O
HO
O
N
O
OPMB
H
syn-15
13
Figure 1. Zimmerman–Traxler arrangements leading to anti- and syn-aldol products of 1.
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The total synthesis of (+)-apiosporamide has utilized anti-8, and further studies
have sought reaction conditions to maximize the production of the desired diastereomer.
The addition of an equivalent of HMPA or 12-crown-4 into solutions of the lithium
enolate, followed by reactions with enone 7, result in a slight increase in the formation of
8
(dr 1.4:1). However, attempts to generate a boron enolate by the direct treatment of 1
with n-Bu BOTf and Et N or by the transmetalation of the lithium enolate upon the
addition of n-Bu BOTf or 9-BBNOTf have led to the recovery of starting materials. The
literature describes an example of an aldol competent boron enolate derived from the C-4
2
3
2
1
5
substituted-N-silyl β-lactam 16 (Eq 4). Deprotonation with LDA at low temperature is
followed by addition of 9-BBNOTf with warming to –20 °C. Subsequent introduction of
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5
6
acetaldehyde yields 17 (80%). Unfortunately, in our studies, the recovery of starting 1 is
1
6
observed by application of these conditions.
HO
O
H
LDA, Et O, –78 °C
O
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
then 9-BBNOTf
H C
(4)
3
N
N
t
Si BuPh2 –78 °C → –20 °C
then add
t
H
Si BuPh
2
H C
3
H C
3
1
6
MeCHO
17
We have also investigated the use of Lewis acids for precomplexation of enone 7
as a means to modulate the outcome of our key aldol reaction. In fact, chiral Lewis acids
would incorporate an additional element of stereocontrol for access to the desired facial
selectivity. For these experiments, a concentrated solution of enone 7 and Lewis acid is
premixed at –78 °C, and this solution is then transferred via cannula into a cold solution
of the lithium enolate of 1. Unoptimized results are summarized in Table 2 and feature a
facile aldol condensation with minimal changes in stereoselectivity. Furthermore, the use
of chiral Lewis acids (entries 5, 6, 7 and 8) indicate a slight increase in the preference for
the anti-diastereomer 8 irrespective of the chirality of the Lewis acid. This behavior
suggests small improvements in the reaction profile for axial versus equatorial addition,
while elements of asymmetry in the Lewis acid do not affect the facial selectivity.
Table 2. Aldol Reactions Using Precomplexed Ketone 7
TBSO
TBSO
LiHMDS
O
THF, –78 °C
O
O
N
then 7
OPMB Lewis Acid
solution
HO
HO
N
N
1
8
OPMB
9
OPMB
entry
Lewis acid
8:9 ratio
1
2
3
EtAlCl
BF •OEt
MgBr •OEt
2
57:43
55:45
57:43
3
2
2
2
8
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Ti(O-i-Pr)
4
59:41
75:25
67:33
Ti(O-i-Pr)
Ti(O-i-Pr)
4
/(S)-BINOL (2 equiv)
/(R)-BINOL (2 equiv)
4
Ph
Ph
10
11
12
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7
8
N
N
66:34
68:32
Ts
Ts
B
Br
Ph
Ph
N
N
Ts
Ts
B
Br
We have subsequently surveyed the scope of the aldol reaction using the lithium
enolate of N-(4-methoxybenzyloxy)-azetidin-2-one (1) in reactions with a variety of
aldehydes and ketones. A compilation of examples is shown in Table 3 based upon the
application of the previous reaction conditions affording 8 and 9.
Table 3. A Survey of Aldol Reactions of 1.
OH
O
LiHMDS, THF, –78 °C
O
O
3
R
5
N
N
OPMB
then
18
OPMB
R1
R2
1
19
c
a
yield
dr ratio
ratio of
entry
1
substrate
major product
b
d
(
%)
(anti:syn) anti-isomers
CH3
CH3
O
O
H C
3
H C
3
HO
N
82
100:0
94:6
>96:4
n.a.
OPMB
2
0
21
OH
O
O
H C
3
H C
3
H
2
97
CH3
N
CH3
OPMB
22
2
3
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1
1
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2
2
2
2
2
2
2
2
3
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3
3
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5
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OH
O
O
H
3
4
86
95:5
n.a.
n.a.
N
OPMB
24
25
H C
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
1
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9
0
1
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3
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9
0
1
2
3
4
5
6
7
8
9
0
H C
3
O
72
85
75:25
HO
O
N
2
6
OPMB
27
O
OH
H
H
O
N
O
O
H
5
81:19
94:6
OBn
OBn
OPMB
TBDPSO
TBDPSO
2
8
29
OH
BnO
O
BnO
H C
O
O
H
O
H C
3
6
7
8
9
3
94
80
81
80
90
93
>96:4
>96:4
80:20
>96:4
70:30
80:20
75:25
58:42
65:35
53:47
n.a.
CH3
N
CH3
OPMB
3
0
2
31
OH
O
O
TBDPSO
TBDPSO
H
CH3
N
CH3
OPMB
3
3
OH
3
5
7
9
1
O
O
H C
3
H C
3
H
BnO
N
BnO
OPMB
34
3
OH
O
O
Ph
TBSO
Ph
H
N
TBSO
OPMB
O
3
6
3
HO
O
Ph
1
0
1
Ph
H
N
OPMB
38
3
OH
O
O
H
1
n.a.
N
OPMB
4
0
4
1
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OH
O
O
O
O
H
1
1
2
3
93
80
87
83:17
88:12
n.a.
n.a.
n.a.
N
OPMB
4
2
43
OH
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H C
3
H C
H
N
3
OPMB
44
4
4
5
7
OH
O
O
TBDPSO
TBDPSO
14
89:11
H
N
OPMB
4
6
a
b
In each example, the major product was isolated and characterized as a pure sample. Yields are based upon
an initial flash chromatography to provide the crude aldol adducts as a mixture of isomers which were
c
separated from remaining starting substrates. The ratios of diastereomers were determined by an integration
d
of selected hydrogen signals. Anti-isomers are characterized by larger JH3–JH5 coupling constants in the 6–9
Hz range as compared to syn-isomers JH3–JH5 = 1–4 Hz). Using simple aldehydes and ketones, a racemic
product is obtained and n.a. is symbolized to indicate not applicable dr data in these cases.
Upon complete deprotonation of 1 using LiHMDS at –78 °C in THF, the reactive enolate
provides for a rapid condensation upon introduction of the carbonyl substrate.
Nucleophilic additions generally proceed in good to excellent yields. In these products, a
significant pathway for decomposition is available through nucleophilic opening of the β-
lactam ring. Thus, it is important to quench these aldol reactions with a pH 7 buffer, and
to avoid prolonged reaction times since initially formed alkoxides, particularly those
derived from starting aldehydes, can lead to O-acylation via intermolecular reactions at –
7
8 °C. To achieve successful aldol reactions, anhydrous conditions are required and the
starting β-lactam 1 should be free of impurities. We have noted that samples of 1, which
are stored for 7 days, often contain small amounts of impurities. The use of these
samples without repurification lead to poor outcomes or failed reaction attempts. Our
conditions have used a slight excess of the enolate of 1, and the carbonyl substrate is
generally consumed within 30 minutes at –78 °C. No evidence is observed for competing
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
processes of deprotonation that lead to the reisolation of starting material, as might be
anticipated in the case of 3-methylcyclopentenone 26. Likewise, epimerization is not
observed in the reactions of aldehydes 28, 30, 32, 34, and 36. The aldol reaction of the
enolate of 1 with aldehydes leads to the anti-products with good to excellent
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
stereoselectivity for substrates that display increasing steric hindrance as a result of α-
substitution (entries 2–9). In some cases, the corresponding syn-adducts are found as
minor products. The assignment of relative stereochemistry is determined by an analysis
1
of vicinal H coupling constants. Isomers with the anti-stereochemistry show large (JH3
–
J
H5) coupling in the range of 6–9 Hz compared to small coupling constants (JH3–JH5 of 1–
1
7
4 Hz) for the corresponding syn-diastereomers. Thus, ratios of anti- to syn-
diastereomers, derived from aldehyde substrates, can often be determined by an
1
integration of selected H NMR signals of samples of aldol product mixtures. In all
cases, major products are fully characterized following an initial chromatography leading
to isolation of the mixture of aldol adducts and repurification via flash (silica gel)
chromatography. Attempts for preparative HPLC separations of diastereomers have
displayed evidence of decomposition, which is not encountered in the flash
chromatography efforts. Our studies of chiral, nonracemic aldehydes provide β-lactams
with modest levels of asymmetric induction as a result of substrate control (Table 3;
entries 5–9). For the products of representative examples (entries 7 and 8), the chirality
1
8
of the secondary alcohol is confirmed via the Mosher ester analysis, and closely related
products (entries 6 and 9) were recognized by the similarities of features and coupling
constants in the analysis of their proton NMR spectra. In the case of tertiary alcohol 21
(entry 1), additional information is obtained upon treatment with N-bromosuccinimide
1
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(
NBS) in THF at 22 °C (Eq 5). Cyclization proceeds to afford the bromide 48 as a single
diastereomer in 73% yield, establishing the cis-stereochemistry of the starting alcohol and
the isopropenyl substituent in 21. NOESY studies have led to the assignment of the
newly established stereogenic carbon by the observed crosspeak for the indicated
hydrogens shown in 48. The anti-stereochemistry of the major product 27 from ketone
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
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39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
6 (entry 4) is assumed by analogy to similarities with related products 8, 9, and 21.
H
CH3
H
CH3
NBS (1.5 equiv)
THF
O
O
H C
(5)
3
H
H
HO
O
N
N
2
2 °C
CH3
Br
OPMB
OPMB
2
1
48
We have considered these results through the evolution of Felkin-Anh and anti-
Felkin arrangements which lead to diastereomeric transition states. Thus, the major
adduct 33 (dr 58:42) in entry 7 (Table 3) is rationalized by the Felkin–Anh model 49
(Figure 2), whereas its accompanying minor diastereomer 33a is produced from the anti-
Felkin arrangement 50, which is modified by a C–C bond rotation to avoid the syn-
pentane interaction with the C-4 methylene of the enolate. For the minimal energetic
costs imposed by the C–C rotation in 50, the anti-Felkin product is achieved with
comparable steric effects as found in 49. Similarly, the presence of α-benzyloxy
substitution in nonracemic aldehyde 34 provides major adducts as predicted via the polar
Felkin model 51 as well as the competing anti-Felkin 52 with a minimization of steric
interactions (Figure 2). The competing aldol reactions, described by 51 and 52, lead to
the production of the major product 35 as well as the alternative anti-isomer 35a (dr
6
5:35 for the anti-isomers).
1
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2
3
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
PMBO
N
H
H
H
OH
O
Li
H
O
TBDPSO
H
N
H
H
H C
3
O
OPMB
TBDPSO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH3
33
4
9 (Felkin-Anh)
OPMB
N
H
H
H
H
OH
O
Li
TBDPSO
O
H
H
N
H C
CH3
O
3
H
OPMB
33a
OTBDPS
50 (anti-Felkin)
PMBO
N
H
H
H
H
OH
O
Li
H C
3
O
H
H
H
BnO
N
O
O
OPMB
Bn
3
5
CH3
5
1 (Polar-Felkin)
OPMB
N
H
H
H
H
OH
O
H C
3
Li
a
O
H
H
BnO
N
CH3
O
H b
OPMB
OBn
5
2 (anti-Felkin with
35a
C –C rotation)
a
b
Figure 2. Considerations of asymmetric induction for reactions of α-substituted
aldehydes with 1.
The extent to which syn-aldol adducts are formed in certain cases was not
anticipated. Our studies have found that aromatic and heteroaromatic aldehydes and
straight chain aliphatic aldehydes usually indicate the production of syn-diastereomers,
comprising as much as 12%–25% of the observed product mixture (Table 3; entries 10–
1
4). We speculate that syn-products may arise from a closed boat-like transition state
1
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(
TS) 53 or from a competing periplanar open transition state 54 as illustrated for the
formation of syn-41a (Scheme 2). The open TS arrangement 54 orients the aldehydic
Scheme 2. Open Transition State Arrangements
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
O
H
O
OH
H
H
Ph
O Li
O
H
R
N
N
OPMB
N
OLi
PMBO
5
3
OPMB
syn-41a
54
hydrogen over the β-lactam ring to minimize steric interactions. This may explain the
absence of syn-adducts in the aldol reactions of 1 with many ketones. In addition, the
presence of α-branching in aldehyde substrates increases the effective steric bulk of R,
which may destabilize 54 relative to the closed TS arrangements due to nonbonded
interactions with the lithium enolate.
The enolate methodology of β-lactam 1 offers a valuable technique for providing
access to the preparation of unique β-alanine (homoglycine) derivatives. By ring
opening, these aldol products lead to an efficient synthesis of a variety of β-amino esters.
Illustrations are shown in Scheme 3 using simple alcohols such as methanol and allyl
alcohol to generate 55, 56 and 57, respectively. The formation of methyl esters from 29
and 43 (examples 1 and 2 of Scheme 3) are readily accomplished using methanol and
potassium carbonate to achieve high yields of the respective esters without the need for
protection of the secondary alcohol. Products 55 and 56 present an available amino
function for further acylation. Example 3 (Scheme 3) demonstrates mild conditions for
the incorporation of an alkoxide leading to the allyl ester 57. We have also documented
the N-acylation required for the synthesis of peptidomimetic substances as shown in the
1
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reaction of 29 to yield 58 via the incorporation of the tert-butyl ester of L-alanine. This
directly provides an available β-amino group in 58 for further elaboration.
A significant goal of our studies sought to utilize our azetidin-2-ones for the
preparation of β-amido esters as key intermediates for the construction of highly
substituted 4-hydroxy-2-pyridinones. In fact, simple dihydropyridin-2-one derivatives
have been obtained via the one-pot N-acylation of N-(4-methoxybenzyloxy)amine 57
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 2
upon treatment with diketene in CH Cl followed by an intramolecular Claisen
condensation in the presence of 4-dimethylaminopyridine (DMAP). This general concept
is demonstrated in Scheme 4 for the synthesis of the complex 4-hydroxy-2-pyridinone 62.
In this case, the allyl ester 57 leads to amide 60 via N-acylation using the nonracemic
6
carboxylic acid 59 and benzotriazol-1-yloxytris(dimethylamino) phosphonium
19
hexafluorophosphate (BOP). Deprotection of the allyl ester provides an unstable
20
carboxylic acid 61 for acyl activation (BOP, DBU) allowing for the ring closure to
3
proceed at –20 °C. Subsequently, a mild oxidation with BrCCl affords the 5-substituted-
,
2
1 22
2-pyridinone 62.
Our example shows that, N-acylations are feasible using the standard
conditions that are compatible with demanding strategies for synthesis of
peptidomimetics via these experiments.
1
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Scheme 3. Transformations of Selected Azetidin-2-ones to Esters and Amides
Example 1
O
BnO OH
BnO OH
H
H
O
K
2
CO
3
; MeOH TBDPSO
TBDPSO
OMe
NH
O
(93%)
O
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
5
OPMB
2
9
OPMB
Example 2
HO
HO
O
O
O
O
K CO ; MeOH
2
3
OCH3
2
2 °C
N
(87%)
N H
OPMB
56
4
3
OPMB
Example 3
TBSO
1
) TESOTf, pyr
TBSO
O
O
CH Cl
2
2
0 °C → rt (96%)
nBuLi, THF TESO
–78 °C → rt (83%)
O
,
2
)
HO
HO
N
N H
57
OPMB
9
OPMB
Example 4
O
H C
O
CH3
O
3
BnO OH
H
BnO OH
H
O
O
H
O
NH2
Me Al; CH Cl
2
TBDPSO
TBDPSO
N
H
NH
O
3
2
O
N
0
° → 22 °C
5
8
OPMB
2
9
(56%)
OPMB
1
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 4. The Use of 1 in the Synthesis of 4-Hydroxy-2-pyridinones
TBSO
BOP, Et N
MeCN
TBSO
3
O
OR
O
O
H
H
(93%)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
TESO
TESO
PMBO
H
O
H
H
N H
N
5
7
OPMB
H
HOOC
5
9
6
6
0 (R = C H )
3 5
1 (R = H)
1
) Pd(PPh3)4
pyrrolidine
PMBO
H
H
CH Cl (89%)
N
O
O
2
2
H
H
2) BOP, DBU
CH3 CH Cl at –20 °C
H
2
2
(40%)
TBSO
TESO
OH
3) BrCCl , TMG
3
H
CH Cl (72%)
2
2
CH3
6
2
CONCLUSION
In conclusion, our investigations have described aldol reactions using the reactive
lithium enolate derived from N-(4-methoxybenzyloxy)-2-acetidinone (1) at –78 °C.
Facile condensations with α,β-unsaturated enones and α-branched aldehydes produce
good to excellent yields of 3-substituted-2-azetidinones. We have postulated that these
reactions proceed via closed, six-membered transition states leading to anti-
diastereoselection. Major adducts stemming from chiral, nonracemic α-substituted
aldehydes feature three contiguous stereocenters corresponding to Felkin-Anh and anti-
Felkin addition products. Unbranched aliphatic and aromatic or heteroaromatic
aldehydes provide high yields of aldol products as mixtures of anti- and syn-
diastereomers. Finally, we have illustrated opportunities for applications of these
reactive β-lactams for the synthesis of complex substances containing C-linked β-amino
acid derivatives, and further transformations produce C-5 substituted 4-hydroxy-pyridin-
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2
-ones. The aldol products derived from 1 may prove useful for the synthesis of novel
peptidomimetics or C-linked glycopeptides via the incorporation of an unnatural β-
alanine subunit. In this manner, the azetidinone 1 serves as a valuable β-homoglycine
equivalent which allows for an efficient assembly of molecular complexity.
EXPERIMENTAL SECTION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Methods. All reactions were conducted in flame- or oven-dried
glassware under an atmosphere of argon unless otherwise noted. All reagents and
solvents were reagent grade and used as received with the following exceptions: Bulk
grade hexanes and ethyl acetate (EtOAc) were distilled before use. Diethyl ether (Et
tetrahydrofuran (THF), dimethylformamide (DMF), toluene, acetonitrile, and
dichloromethane were degassed and passed through activated alumina columns in a
2
O),
commercial solvent purification system. Triethylamine (Et
distilled from CaH under dry air immediately before use. Allyl alcohol was distilled
from magnesium turnings under Ar. Bromotrichloromethane (BrCCl ) was distilled from
CaH under Ar. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and triethylsilyl
trifluoromethanesulfonate (TESOTf) were distilled from CaH
under Ar. Dimethylsulfoxide (DMSO) was distilled from CaH
3
N), and pyridine were
2
3
2
2
under vacuum and stored
under vacuum and stored
2
over 4Å molecular sieves under Ar. 1,1,3,3-Tetramethylguanidine (TMG) was distilled
from BaO under Ar. Tetrakis(triphenylphosphine)palladium(0) [Pd(PPh ] was washed
with degassed ethanol and degassed ether, then dried in vacuo overnight in the absence of
3 4
)
23
light. Commercial solutions of n-butyllithium (n-BuLi) were titrated with menthol in
THF using 2,2'-bipyridine as an indicator. Commercial solutions of lithium 1,1,3,3-
2
4
hexamethyldisilazane (LiHMDS) were titrated according to the method of Ireland.
1
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
5
Dess–Martin periodinane (DMP) was prepared according to the literature procedure. In
addition to those defined above, the following reagents are referred to by their
abbreviations: dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP),
benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), and
tetra-n-butylammonium fluoride (TBAF).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Reactions were monitored by analytical thin-layer chromatography (TLC) using
glass-backed 0.25 mm thickness silica gel 60 (F254) plates, which were visualized under
UV light and/or by staining with ethanolic p-anisaldehyde. Preparative TLC was
performed on 0.5 mm thickness 20 cm × 20 cm glass-backed silica gel 60 (F254) plates.
Flash chromatography was performed using silica gel 60 (230–400 mesh ASTM).
2
Amounts of silica used are reported as volume (mL) of SiO . The sample was loaded as a
solution in the minimum amount of the mobile phase, unless otherwise noted, and
pressure was obtained using an airline bleed. Solvents were removed by rotary
evaporation under aspirator vacuum, and all non-volatile samples were dried under high
vacuum (0.1–0.2 mmHg) at rt.
Melting points were determined using a capillary melting point apparatus and are
uncorrected. Optical rotations were obtained on a polarimeter at 589 nm (sodium D line)
using a 10 cm path length and a 1.0 mL volume. Concentrations (c) are given in g/100
–
1
mL in the specified solvent. Infrared spectra are reported in wavenumbers (cm ). Oils
were analyzed as films on sodium chloride plates; solids were analyzed on a diamond
plate (ATR) or as films on sodium chloride plates. Proton and carbon nuclear magnetic
1
13
resonance ( H NMR and C NMR) spectra were measured on 400 or 500 MHz
spectrometers. The spectra were acquired as solutions in deuterated chloroform (CDCl
3
),
2
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methanol (CD
3 3 2
OD), or acetone ((CD ) CO) and are reported in parts per million (δ, ppm)
downfield using residual non-deuterated solvent as an internal standard set to δ 7.26,
1
13
1
3
.23, and 2.05 for H NMR and δ 77.16, 49.00, and 29.84 for C NMR, respectively. H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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60
NMR data are reported in the form: chemical shift (multiplicity, coupling constants,
number of protons). Multiplicities are recorded by the following abbreviations: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Mass spectral data (MS and
HRMS) were recorded by use of electron impact (EI), fast atom bombardment (FAB) or
electrospray ionization (ESI) with time-of-flight (TOF) analyzer. Data are reported in the
form: m/z (relative intensity).
N-(4-Methoxybenzyloxy)azetidin-2-one (1). N-(4-methoxybenzyloxy)amine
2 2
(4.225 g, 27.58 mmol, 1 equiv) was dissolved in CH Cl (92 mL, 0.3 M), cooled to 0 °C,
and pyridine (2.35 mL, 29.05 mmol, 1.06 equiv) was added rapidly. To this clear,
colorless solution was added 3-chloropropionyl chloride (2.80 mL, 29.3 mmol, 1.06
equiv) dropwise over 5 min. A white precipitate rapidly appeared, and then gradually
disappeared before addition was complete, leaving a clear yellow solution. The cooling
bath was removed and the reaction was allowed to warm to rt over 15 min. The reaction
was diluted with pentane (200 mL), causing precipitation of a white solid. The yellow-
white suspension was washed with water (1 x 50 mL), then 1 M HCl (1 x 10 mL), and the
combined aqueous washes were extracted with CH
organic layers were washed with saturated aqueous NaHCO
aqueous NaCl (1 x 25 mL), dried (MgSO ), filtered, and concentrated in vacuo to give a
cream-colored solid. The crude material was purified by flash chromatography using
diethyl ether to yield a thick oil. This oil was redissolved in CH Cl , an equal volume of
2
Cl
2
(1 x 50 mL). The combined
3
(1 x 25 mL), saturated
4
2
2
2
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Et
2
O was added, and then carefully concentrated in vacuo to precipitate 6.355 g (95%) of
N-(4-methoxybenzyloxy)amide in a 2:1 mixture of amide rotamers as a fluffy white solid.
This material could be recrystallized from CH Cl /hexanes, albeit in slightly reduced
yields to give white crystals: mp 80–81 °C; R 0.1 [hexanes/EtOAc (2:1)]; IR (ATR)
3209 (br), 3031, 2952, 1653, 1607, 1515, 1238, 1033, 1014, 823 cm ; H NMR (400
MHz, CDCl ) δ 8.04 (s, br, 0.67H), 7.82 (s, br, 0.33H), 7.27–7.38 (m, br 2H), 6.88–6.96
(m, 2H), 4.88 (s, 1.33H), 4.77 (s, br, 0.67H), 3.82 (s, 3H), 3.80 (s, br, 2H), 2.82 (s, br,
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
–
1 1
3
1
3
0
1
3
.67H), 2.49 (s, br 1.33H); C NMR (101 MHz, CDCl δ 173.5, 167.3, 160.2, 159.9,
31.0, 127.1, 126.1, 114.0, 113.8, 79.1, 77.8, 77.2, 55.2, 39.7, 38.5, 36.2, 34.6, 29.6; MS
+
(FAB, NBA, Na ) 244 (100), 209 (60), 195 (43), 151 (28), 137 (69); HRMS m/e [M +
+
H] calcd for C11
H
15ClNO
3
244.0741, found 244.0744; Anal. calcd for C11
H
14ClNO
3
C
54.22, H 5.79, N 5.75, found C 54.17, H 5.77, N 5.68.
Sodium hydride (0.174 g of 60% dispersion in mineral oil, 4.36 mmol, 1.05
equiv) was slurried in DMF (1.4 mL) and cooled to 0 °C. A solution of the amide
described above (1.01 g, 1 equiv) in DMF (4.0 mL) was added dropwise over 10 min
with vigorous stirring. The reaction was stirred at 0 °C for 20 min, the cooling bath was
removed, and the reaction was allowed to warm to rt over 10 min, during which time the
suspension became a clear pale yellow solution. The reaction was then immersed in a
pre-heated 60 °C oil bath and heated for 1 hr, during which time it became an opaque
1
yellow suspension. Reaction progress was monitored by H NMR spectroscopy (400
MHz, CDCl
1:1 hexanes/EtOAc) followed by concentration. The reaction was cooled to rt and then
loaded directly onto a plug of silica, using small quantities of CH Cl to aid transfer
3 2
), and samples were prepared by filtration of a small aliquot through SiO
(
2
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(
100% Et
2
O). Following concentration, the wet, impure product was stirred under high
vacuum for 4 hr to remove residual DMF resulting in a thick yellow oil. The crude
material was purified by flash silica gel chromatography (100% Et O) to yield 0.506 g of
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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a mixture of the desired β-lactam (1) containing small amounts of N-(4-
methoxybenzyloxy)acrylamide (ratio 12:1). This viscous oil was purified by flash
chromatography using diethyl ether, which led to crystallization of pure 1 upon
concentration of the combined fractions as white needles (475 mg, 53% yield): mp 46–
4
2
7
2
1
7 °C; R
967, 1763, 1610, 1586, 1512, 1247, 1035 cm ; H NMR (400 MHz, CDCl
.32, δ = 6.89, JAB = 8.7 Hz, 4H), 4.86 (s, 2H), 3.80 (s, 3H), 3.21 (t, J = 4.2 Hz, 2H),
.61 (t, J = 4.2 Hz, 2H); C NMR (101 MHz, CDCl
f
0.33 [hexanes/EtOAc (1:1)], 0.45 (100% Et
2
O); IR (neat) 3076, 3041, 3002,
–
1 1
3
δ AB (δ =
A
B
1
3
3
) δ 164.4, 160.1, 130.7, 127.2,
13.9, 77.3, 55.2, 44.9, 31.9; MS (CI/CH
4
) 208 (1), 135 (19), 122 (45), 121 (100), 91
+
(
27), 78 (33), 77 (39); HRMS m/e [M + H] calcd for C11
H
14NO
3
208.0974, found
208.0970; Anal. calcd for C11
.76.
3
H13NO C 63.76, H 6.32, N 6.76, found C 63.42, H 6.32, N
6
(
R)-3-[(1S,4S)-4-(tert-Butyldimethylsilanoxy)-1-hydroxycyclohex-2-enyl]-1-
(4-methoxybenzyloxy)azetidin-2-one (8) and (S)-3-[(1R,4S)-4-(tert-Butyldimethyl-
silanoxy)-1-hydroxycyclohex-2-enyl]-1-(4-methoxybenzyloxy)azetidin-2-one (9). To a
–
78 °C solution of β-lactam 1 (6.76 g, 32.6 mmol) in THF (326 mL) was added LiHMDS
(27.4 mL of a 1.0 M solution in THF, 31.0 mmol) dropwise. The clear, yellow solution
6
was stirred at –78 °C for 2 h, then a solution of ketone 7 (3.51 g, 15.5 mmol) in THF (26
mL) was added dropwise. The reaction was stirred at –78 °C for 30 min, then it was
4 2
quenched by the addition of saturated aqueous NH Cl (200 mL) and extracted with Et O
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5
6
(
2 × 200 mL). The combined organic layers were washed with saturated aqueous
NaHCO
and concentrated in vacuo to a yellow solid. NMR indicated a 1.2:1.0 ratio of 8:9. The
crude material was purified by flash chromatography (1 L SiO , 9:1 CH Cl –Et O) to
provide alcohol 8 (3.55 g, 51%) and alcohol 9 (2.94 g, 44%), both as white solids.
For characterization of the major diastereomer 8: mp 112–113 °C; R 0.28
O (9:1)]; [α] –9.10 (c 0.714, CHCl ); IR
3 4
(100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO , filtered,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
1
2
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8
9
0
1
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8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
2
f
2
D
2
[hexanes/EtOAc (1.5:1)], 0.2 [CH
2
Cl
2
/Et
2
3
–1
(film) 3420 (br), 3070, 2945, 2853, 1745, 1620, 1515, 1251, 1040, 875, 829, 776 cm ;
1
H NMR (400 MHz, CDCl
.6 Hz, 2H), 5.74 (dd, J = 10.2, 3.0 Hz, 1H), 5.39 (d, J = 10.2 Hz, 1H), 4.87 (A of AB,
AB = 11.4 Hz, 1H), 4.87 (B of AB, JBA = 11.4 Hz, 1H), 4.19 (dddd, J = 8.3, 3.3, 3.3, 1.6
Hz, 1H), 3.81 (s, 3H), 3.33 (dd, J = 4.3, 2.6 Hz, 1H), 3.23 (dd, J = 5.4, 4.4 Hz, 1H), 3.07
3
) δ 7.34 (A of AB, JAB = 7.34 Hz, 2H), 6.89 (B of AB, JBA =
8
J
(
dd, J = 5.4, 2.6 Hz, 1H), 2.21 (ddd, J = 13.1, 7.9, 2.6 Hz, 1H), 2.06 (br s, 1H), 1.96
dddd, J = 13.0, 7.8, 4.9, 3.1 Hz, 1H), 1.71 (ddd, J = 13.6, 10.7, 2.9 Hz, 1H), 1.52 (dddd,
(
1
3
J = 13.4, 10.2, 7.0, 3.1 Hz, 1H), 0.87 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); C NMR (101
MHz, CDCl ) δ 164.2, 160.1, 134.7, 130.9, 130.0, 127.2, 113.9, 77.5, 69.0, 65.8, 55.2,
3
52.9, 47.4, 32.4, 29.6, 25.8, 18.1, –4.6, –4.7; MS (CI) 416 (1), 376 (14), 122 (37), 121
+
(100), 73 (17); HRMS (EI) m/z [M – OH] calcd for C23
H34NO
4
Si 416.2257, found
4
5
16.2251; Anal. calcd for C23H35NO Si C 63.71, H 8.14, N 3.23, found C 63.83, H 8.17,
N 3.22.
For characterization of the minor diastereomer 9: mp 73–75 °C; R
f
0.25
2
D
2
[hexanes/EtOAc (1.5:1)], 0.1 (9:1 CH
2
Cl
2
–Et
2
O); [α] –27.9 (c 0.562, CHCl ); IR (film)
3
–
1 1
3
440 (br), 2932, 2846, 1759, 1614, 1581, 1508, 1258, 1093, 869, 829, 770 cm ; H NMR
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(
400 MHz, CDCl
3
) δ 7.34 (A of AB, JAB = 8.5 Hz, 2H), 6.89 (B of AB, JBA = 8.5 Hz,
2H), 5.77 (d, J = 10.1 Hz, 1H), 5.41 (d, J = 10.1 Hz, 1H), 4.87 (A of AB, JAB = 11.6 Hz,
H), 4.87 (B of AB, JBA = 11.6 Hz, 1H), 4.12 (dddd, J = 8.5, 6.0, 2.0, 2.0 Hz, 1H), 3.81
s, 3H), 3.26–3.19 (m, 2H), 2.95 (dd, J = 5.1, 2.5 Hz, 1H), 2.05 (br s, 1H), 2.02–1.95 (m,
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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48
49
50
51
52
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57
58
59
60
(
1
1
H), 1.86–1.77 (m, 1H), 1.71 (dddd, J = 12.4, 12.4, 9.0, 2.8 Hz, 1H), 1.58 (ddd, J = 13.0,
13
3
3.0, 3.0 Hz, 1H), 0.88 (s, 9H), 0.07 (s, 6H); C NMR (101 MHz, CDCl ) δ 163.9,
160.1, 136.8, 130.9, 129.1, 127.2, 113.9, 77.5, 67.9, 67.2, 55.2, 53.9, 47.3, 32.0, 28.4,
2
7
5.8, 18.1, –4.6, –4.8; MS (CI) 416 (1), 197 (44), 122 (40), 121 (100), 105 (40), 75 (62),
+
3 (30); HRMS (EI) m/z [M – OH] calcd for C23
H
34NO
4
Si 416.2257, found 416.2262;
5
Anal. calcd for C23H35NO Si C 63.71, H 8.14, N 3.23, found C 63.86, H 8.19, N 3.22.
General procedure for aldol reactions of Table 3 using β-lactam 1. To a –78
°
C solution of β-lactam 1 (1.6 equiv) in THF (0.1 M) was added LiHMDS (2.0 equiv of a
1.0 M solution in THF) dropwise over 5 min. The clear, yellow solution was stirred at –
8 °C for 2 h. Ketone or aldehyde substrate (1.0 equiv) was then added dropwise. The
reaction was stirred at –78 °C for 15 to 30 min, or until the disappearance of the starting
material by TLC. Reactions were quenched by the addition of saturated aqueous NH Cl
or by pH 7 aqueous buffer, and extracted with Et O. The combined organic layers were
4
washed with saturated aqueous NaHCO and saturated aqueous NaCl, dried over Na SO ,
7
4
2
3
2
filtered, and concentrated in vacuo. Ratios were determined by the integration of selected
1
H NMR signals of the crude mixture of isomeric products, which were then purified by
silica gel flash chromatography leading to spectroscopic characterizations of the major
product diastereomers.
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(
S)-3-((1S,5R)-1-Hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-1-
((4-methoxybenzyl)oxy)azetidin-2-one (21) (Table 3, entry 1). By application of the
general procedure for the low temperature generation of the enolate of 1 (520 mg, 2.5
mmol), the reaction of (R)-carvone (180 mg, 1.2 mmol) in THF (25 mL; 0.1 M) gave the
product lactam 21 as a colorless oil (385 mg, 90%), characterized a single diastereomer.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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4
5
6
7
8
9
0
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9
0
1
2
3
4
5
6
7
8
9
0
20
D
R
f
0.78 [hexanes/EtOAc (6:4)]; [α] –51.0 (c 0.70, CDCl
3
); IR (film) 3436, 3130, 2924,
) δ 7.32
d, J = 8.2, Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 5.53–5.46 (m, 1H), 4.85 (q, J = 11.1 Hz,
–
1 1
1760, 1613, 1515, 1252, 1176, 1034, 821, 459 cm ; H NMR (600 MHz, CDCl
3
(
2
5
1
H), 4.73 (d, J = 12.6 Hz, 2H), 3.80 (s, 3H), 3.49 (dd, J = 4.3, 2.6 Hz, 1H), 3.25 (dd, J =
.5, 4.3 Hz, 1H), 3.09 (dd, J = 5.5, 2.6 Hz, 1H), 2.35 (dt, J = 12.6, 2.2, 1H), 2.24 (dt, J =
5.1, 10.4 Hz, 1H), 2.12–2.05 (m, 2H), 1.94 (ddt, J = 17.9, 10.4, 2.2 Hz, 1H), 1.72 (d, J =
1
3
14.1 Hz, 3H), 1.65 (s, 3H); C NMR (101 MHz, CDCl
3
) δ 165.1, 160.1, 148.3, 135.7,
1
1
3
30.8, 127.3, 125.8, 113.9, 109.6, 77.5, 72.6, 55.3, 52.7, 48.3, 40.6, 38.5, 30.8, 20.8,
+
7.8; HRMS (ESI-TOF) m/z [M + Na] calcd for C21
H
27NO
4
Na 380.1838, found
80.1837.
3
-(1-Hydroxy-2-methylpropyl)-1-(4-methoxybenzyloxy)azetidin-2-one (23)
(Table 3, entry 2). Following the general procedure for the low temperature generation
of the enolate of 1 (132 mg; 0.64 mmol), the aldehyde 22 (36.3 µL, 0.40 mmol) was
introduced into the reaction at –78 °C. After stirring for 30 min, the reaction was
quenched by the addition of aqueous NH
Combined organic extracts were washed with aqueous NaHCO
NaCl, dried (Na SO ), filtered and concentrated in vacuo to a thick oil. Flash silica gel
chromatography using 40% EtOAc in hexanes afforded the crude product (109 mg, 0.39
4
Cl (6 mL) and extracted with ether (2 x 15 mL).
3
, then aqueous, saturated
2
4
2
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mmol 97% yield) which proved to be principally one diastereomer (dr 94:6). Further
purification by flash chromatography using 25% EtOAc in hexanes provided a pure
sample of 23. For characterization of the anti-diastereomer 23: R
6:4)]; IR (film) 3470, 2962, 1756, 1612, 1515, 1253, 1033, 822, 559 cm ; H NMR (400
MHz, CDCl ) δ 7.34 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.89 (A of AB, JAB
1.2 Hz, 1H), 4.86 (B of AB, JBA = 11.2 Hz, 1H), 3.82 (s, 3H), 3.45 (td, J = 6.7, 3.3 Hz,
H), 3.27 (t, J = 4.9 Hz, 1H), 3.10 (dd, J = 4.7, 2.5 Hz, 1H), 3.00 (ddd, J = 7.5, 5.3, 2.5
f
0.24 [hexanes/EtOAc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–
1 1
(
3
=
1
1
Hz, 1H), 2.38 (d, J = 3.5 Hz, 1H), 1.81–1.68 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H), 0.89 (d, J
13
=
6.8 Hz, 3H); C NMR (101 MHz, CDCl
3
) δ 165.9, 160.2, 130.9, 127.2, 114.0, 77.5,
+
75.6, 55.3, 48.9, 47.9, 33.1, 18.6, 17.8; HRMS (ESI-TOF) m/z [M + Na] calcd for
C
15
H
21NO
4
Na 302.1368, found 302.1376.
3
-[Cyclohexyl(hydroxy)methyl]-1-(4-methoxybenzyloxy)azetidin-2-one (25)
(Table 3, entry 3). The aldol adduct 25 was prepared according to the general procedure
for formation of the enolate from 1 (132 mg, 0.64 mmol) via introduction of aldehyde 24
(
48.1 µl, 0.40 mmol) into the reaction at –78 °C. Flash chromatography[EtOAc/hexanes
4:6)] resulted in a pure sample of 25 from the crude product mixture (86%, 95:5 ratio of
(
anti–syn isomers). A flash chromatograph of this product gave a sample of the pure
diastereomer 25: R 0.44 [hexanes/EtOAc (6:4)]; IR (film) 3478, 2928, 1744, 1612, 1516,
f
–
1 1
1
8
252, 856, 550 cm ; H NMR (600 MHz, CDCl
3
) δ 7.33 (d, J = 8.6 Hz, 2H), 6.89 (d, J =
.7 Hz, 2H), 4.87 (A of AB, JAB = 11.3 Hz, 1H), 4.85 (B of AB, JBA = 11.3 Hz, 1H), 3.81
(s, 3H), 3.45 (t, J = 6.7 Hz, 1H), 3.26 (t, J = 5.0 Hz, 1H), 3.10 (dd, J = 4.6, 2.6 Hz, 1H),
3
1
.00 (ddd, J = 7.5, 5.2, 2.4 Hz, 1H), 2.45 (s, 1H), 1.85 (d, J = 13.0 Hz, 1H), 1.72 (m, 2H),
.64 (d, J = 12.0 Hz, 1H), 1.57 (d, J = 12.6 Hz, 1H), 1.48–1.38 (m, 1H), 1.27–1.04 (m,
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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3
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5
5
5
5
5
5
5
5
5
5
6
1
3
3
3
H), 1.04–0.87 (m, 2H); C NMR (101 MHz, CDCl ) δ 166.0, 160.2, 130.9, 127.2,
114.0, 77.5, 74.9, 55.3, 54.1, 48.9, 47.8, 42.8, 28.8, 28.4, 26.3, 26.0, 25.8; HRMS (ESI-
+
TOF) m/z [M + Na] calcd for C18
H25NO
4
Na 342.1681, found 342.1666.
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
S)-3-((R)-1-Hydroxy-3-methylcyclopent-2-en-1-yl)-1-((4-
methoxybenzyl)oxy)azetidin-2-one (27) (Table 3, entry 4). Following the general
procedure for the low temperature generation of the enolate of β-lactam 1 (124 mg; 0.60
mmol), the ketone 26 (28 mg, 0.29 mmol) was introduced into the reaction at –78 °C.
After stirring for 30 min, the reaction was quenched by the addition of aqueous NH
mL) and extracted with ether (2 x 8 mL). Combined organic extracts were washed with
aqueous NaHCO , then aqueous, saturated NaCl, dried (Na SO ), filtered and
4
Cl (6
3
2
4
concentrated in vacuo to a thick oil. Flash silica gel chromatography using diethylether
afforded the crude product (63 mg, 72% yield) which proved to be principally the crude
anti-adduct 27 containing small amounts of more polar syn-isomer (approximate dr
7
5:25). Rechromatography using Et
2
O provided the pure anti-27 (34 mg) which was
O; 2 elutions]; IR (film) 3435, 2937, 1757, 1612,
515, 1252, 1032, 822 cm ; H NMR (500 MHz, CDCl ) δ 7.38–7.28 (m, 2H), 6.95–
characterized as follows: R 0.40 [Et
f
2
–1
1
1
6
5
3
.84 (m, 2H), 5.20 (d, J = 1.7 Hz, 1H), 4.88 (d, J = 3.1 Hz, 2H), 3.82 (s, 4H), 3.26 (t, J =
.2 Hz, 1H), 3.11 (m, 2H), 2.47–2.38 (m, 1H), 2.26–2.13 (m, 1H), 2.05 (dd, J = 8.8, 4.5
13
3
Hz, 1H), 1.96 (d, J = 4.5 Hz, 1H), 1.75 (t, J = 1.7 Hz, 3H) ; C NMR (126 MHz, CDCl )
δ 164.7, 160.1, 147.0, 130.8, 127.3, 127.0, 114.0, 84.4, 77.7, 55.3, 53.2, 48.1, 37.4, 35.3,
+
1
3
6.8; HRMS (ESI-TOF) m/z [M + Na] calcd for C17
H
21
O
4
NNa 326.1368, found
26.1364.
2
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The Journal of Organic Chemistry
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A pure sample of the minor product (3.0 mg) was characterized as the
1
corresponding syn-isomer 27a: R
f
0.45 [Et
2
O; 2 elutions]; H NMR (500 MHz, CDCl
3
) δ
7
3
1
.38–7.28 (m, 2H), 6.95–6.84 (m, 2H), 5.42 (d, J = 1.2 Hz, 1H), 4.88 (d, J = 3.1 Hz, 2H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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56
57
58
59
60
.82 (s, 3H), 3.29 (t, J = 5.2 Hz, 1H), 3.11 (m, 2H), 2.47–2.38 (m, 1H), 2.26–2.13 (m,
H), 2.10–2.07 (m, 1H), 1.97 (d, J = 4.7 Hz, 1H), 1.75 (t, J = 1.2 Hz, 3H). Small
13
quantities of 27a proved insufficient for C NMR analysis. HRMS (ESI-TOF) m/z [M +
+
Na] calcd for C17
H
21
O
4
NNa 326.1368, found 326.1367.
(
R)-3-((S)-((2R,3S,4S)-3-(Benzyloxy)-4-((tert-
butyldiphenylsilyl)oxy)tetrahydrofuran-2-yl)(hydroxy)methyl)-1-(4-
methoxybenzyloxy)azetidin-2-one (29) (Table 3, entry 5). Following the general
procedure for the low temperature generation of the enolate of 1 (50 mg, 0.24 mmol),
aldehyde 28 (69 mg, 0.15 mmol) was introduced into the reaction at –78 °C. After
stirring for 40 minutes, the reaction was quenched by the addition of aqueous pH 7 buffer
(
10 mL) and extracted with Et
Na SO ), filtered, and concentrated in vacuo to give a thick, colorless oil. An initial
O provided three product diastereomers (90 mg; dr
6:18:7) in approximately 90% yield. A subsequent flash chromatography (10% EtOAc
in CH Cl ) gave 60 mg of the major product 29, and additional fractions of inseparable
2
O (2 x 8 mL). Combined organic extracts were dried
(
2
4
flash chromatography using Et
2
7
2
2
mixtures (total 20 mg) that contained the minor anti-adduct together with a small amount
of an uncharacterized syn-isomer (ratio 2:1). The major azetidinone anti-29 was
characterized as follows: R
f
2 2
0.66 [EtOAc/CH Cl (1:9)]; IR (film) 3443, 3070, 2933,
–1
1
1
756, 1612, 1515, 1252, 1112, 1076, 823, 735, 702, 614 cm ; H NMR (400 MHz,
3
CDCl ) δ 7.70 (dt, J = 6.5, 1.6 Hz, 2H), 7.67–7.60 (dt, J = 6.5, 1.6 Hz, 2H), 7.50–7.37
2
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