Novel synthesis of sterically hindered N-substituted lactams from imides

Article abstract of DOI:10.1016/j.tetlet.2006.05.037

An efficient and practical synthesis of sterically hindered N-substituted lactams has been developed starting from simple starting materials. The stereochemistry of the synthetically useful N,N acetal intermediate has been established.

Full text of DOI:10.1016/j.tetlet.2006.05.037

Tetrahedron Letters 47 (2006) 4877–4880
Novel synthesis of sterically hindered N-substituted lactams
from imides
Mousumi Sannigrahi,* Patrick Pinto, T. M. Chan, Neng-Yang Shih and F. George Njoroge
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States
Received 21 February 2006; revised 3 May 2006; accepted 8 May 2006
Abstract—An efficient and practical synthesis of sterically hindered N-substituted lactams has been developed starting from simple
starting materials. The stereochemistry of the synthetically useful N,N acetal intermediate has been established.
Ó 2006 Elsevier Ltd. All rights reserved.
Pyridones are well known pharmacophores and have
emerged as potent antitumor, antiviral, and antimicro-
bial agents over the last decade.1 During the course of
our chemistry program there was a need to synthesize
and incorporate these moieties in our scaffold. Unsubsti-
tuted pyridones are generally prepared via nucleophilic
displacement of an appropriate bromide or mesylate by
hydroxypyridine.2 In our case we used mesylate 1 as the
leaving group but the presence of an adjacent tert-butyl
group created a rather sterically hindered environment.
OH
NHBoc
MsO
N
+
1
(a)
O
N
NHBoc
NBoc
The reaction proceeded through intramolecular aziridine
formation followed by the opening of aziridine 2, to give
the desired pyridone 3, albeit in low yields (Scheme 1).
3
2
Scheme 1. Reagents and conditions: (a) TBAB, KOH; 30%.
It was envisioned that reduction of pyridone 3 to the
corresponding lactam would give us access to another
biologically and pharmacologically important class of
compounds.3 Unfortunately this methodology was
unsuitable for the synthesis of substituted lactams that
were required in our project. Due to the ubiquity of lac-
tams in alkaloids, there are several synthetic routes that
have been reported in literature.
conditions that were applied we avoided using this
protocol.
Oxidation of cyclic amines to amides is another com-
monly used route to access asymmetrically substituted
amides.5 However, in our case due to the symmetrical
nature of our starting amine and the eminent lack of reg-
ioselectivity during oxidation made this method unat-
tractive for our synthesis.
Recently, Milewska and co-workers outlined a general
method to make lactams starting from a diimide.4 In this
case the diimide, analogous to compound 4, was treated
with Lawesson’s reagent to afford the corresponding
monothioamide which was subsequently reduced with
Raney-Nickel at elevated temperature. Due to the toxic
nature of Lawesson’s reagent and harsh reaction
Although there was ample precedence in the literature for
N-alkylation’s of amides through displacement of
primary or secondary halides,6 there have been no
reported cases where the halide carries a substitution at
the b position. When we tried to alkylate 5 with the
b-substituted mesylate 6; none of 7 was isolated (Scheme 2).
*
On the other hand, a wide variety of imides are commer-
cially available and can be readily converted to
Corresponding author. Tel.: +1 908 740 4403; fax: +1 908 740 7305/
7152; e-mail: mousumi.sannigrahi@spcorp.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.037

4878
M. Sannigrahi et al. / Tetrahedron Letters 47 (2006) 4877–4880
O
N
O
O
NHBoc
MsO
O
O
NHBoc
NH
(a)
NH
N
H2N
NHBoc
6
O
O
O
4
5
(b)
9
(a)
O
8
OBEt3Li
NHBoc
+
NHBoc
N
NHBoc
N
7
O
O
Scheme 2. Reagents and conditions: (a) DIBAL-H, CH2Cl2; NaC-
NBH3, AcOH; (b) K2CO3, TBAB, PhMe, H2O.
11
10
N-substituted imides containing the amino acid deriva-
tive through Mitsunobu chemistry on the corresponding
amino alcohol. Imides such as 9 could also be obtained
from condensation of amino acid derived diamines of
type 8 with the corresponding anhydride. The ease of
synthesis of the starting imide from relatively simple
starting materials made this an attractive starting point.
Boc
N
NHBoc
N
11
N
(b)
O
O
12
7
Scheme 3. Reagents and conditions: (a) LiEt3BH, CH2Cl2, À78 °C,
15 min; (b) NaCNBH3, CH3CN; AcOH.
Addition of alkyl magnesium bromides to these N-
substituted imides seemed to be a straightforward way
of introducing the alkyl units alpha to the tertiary nitro-
gen. However, attempts to carry out this reaction by
treating imide 9 with 2 equiv of methyl magnesium bro-
mide never proceeded beyond the monoaddition of the
methyl group to the carbonyl imide. Similar observa-
tions have been precedented in the literature.7
CF3CO2H and NaCNBH3 to give the corresponding
N-methyl amide have been reported in the literature.9
To further explore the generality of our methodology,
we applied the same synthetic sequence to the geminally
substituted lactam 13 and observed the expected cyclized
product 14 obtained through the reduction of the less
sterically hindered imide carbonyl. The bicyclic interme-
diate 14 was efficiently converted to the desired lactam
15 as shown in Scheme 4.
A more commonly used route involved the reduction of
a suitably substituted imide to the corresponding hydr-
oxy lactam using a hydride donating reducing agent,
followed by the generation of the N-acyliminium ion
using boron trifluoroetherate and in situ quenching
with triethylsilane.8
Next, we proceeded to study the effect of the nucleo-
philicity of the secondary amine 16 on the cyclization
reaction leading to 17 (Scheme 5) by varying the electron
inducting nature of the N-protecting group. Replacing
the t-Boc group on the amine with benzoyl, methylsulf-
onamide, acetamide, and trifluoroacetamide not only
served the above purpose but also allowed us to study
the steric effect of these groups on the stereoselectivity
of the cyclization reaction.
In an attempt to evaluate this concept, we started out
with the imide 9 and treated it with LiEt3BH with the
expectation of generating the required hydroxy lactam
intermediate 10 as shown in Scheme 3. To our surprise
we isolated a separable mixture of product with a mass
difference of 18 units from the expected product 10.
After thorough analysis the products were confirmed
to be a diastereomeric mixture of N,N acetal 12. Replac-
ing super hydride with DIBAL-H gave identical results.
This unexpected outcome prompted us to investigate the
generality of this reaction.
Much to our satisfaction, the conversion of imides 16a–e
to the corresponding N-substituted cyclic acetals 17a–e
proceeded efficiently and the variation in nucleophilicity
of the N-protecting group of the imide seemed to have
little effect on the yield of the reaction (Table 1). Inter-
estingly these variations did have an impact on the ste-
reochemical outcome of the formation of acetals 17a–e
We envisioned that 12 being an N,N acetal, ring opening
to generate the acyliminium ion should be feasible using
a mild acid, such as, acetic acid, which in the presence of
excess NaCNBH3 should give 7. Indeed, when 12 was
treated under refluxing conditions in the presence of
the hydride donating agent, as expected, compound 7
was obtained in good yield.
O
N
Boc
N
NHBoc
N
NHBoc
(a)
N
(b)
O
O
O
To the best of our knowledge this reaction sequence is
unprecedented in literature. However, a related reaction
involving reduction of an acyliminium ion generated
in situ on treatment of an amido methylol with
13
14
15
Scheme 4. Reagents and conditions: (a) LiEt3BH, CH2Cl2, À78 °C,
15 min; 80%; (b) NaCNBH3, CH3CN; AcOH; 82%.

M. Sannigrahi et al. / Tetrahedron Letters 47 (2006) 4877–4880
4879
R
O
MOMO
MOMO
+
O
N
H
N
(a)
(b)
CO2Me
2
4
2
H
(a)
(b)
NHR
NHR
N
N
O
N
O
HN
HN
19
NH2
H2N
O
O
17S
21
(65:35)
16
20
+
R
H
N
Scheme 6. Reagents and conditions: (a) (s)-HbHNl, HCN, pH = 4.5;
MeOCH2OMe, P2O5; (b) H2, Pd/C, MeOH.
4
2
N
O
N
O
17R
18
nature of the N-methylsulfonamide group had a pro-
nounced effect on the outcome. Using the same argu-
ments as before it was apparent that conformer B,
where the steric interaction between the N-sulfonamide
and the tert-leucine was minimized, should be the
favored one in this case.
Scheme 5. Reagents and conditions: (a) LiEt3BH, CH2Cl2, À78 °C; (b)
NaCNBH3, CH3CN; AcOH.
Table 1. Conversion of imide 16 to lactam 18 via acetal 17
Furthermore, when isomers 17a (R) and 17a (S) were
individually subjected to the exact reaction conditions
(Scheme 5, step b) no interconversion was observed,
leading us to believe that their formation is indeed kinet-
ically controlled.
Imide
R
Ratio 17(a–e)
2S,4S:2S,4R
17(a–e) R +
17(a–e) S (%)
18 (%)
16a
16b
t-Boc
CBz
75:25
74:26
77
75
90
93
16c
16d
C(O)CH3
C(O)CF3
61:39
56:44
63
68
81
84
The diastereomers of acetal 17 (2S, 4R and 2S, 4S) were
easily separable by column chromatography thereby
facilitating in the characterization. Thus, 2D NMR
analysis (HSQC, HSQCTOXY, HMBC, and COSY)
was used to establish the connectivity of proton and car-
bon nuclei. NOE experiments unambiguously estab-
lished the trans relationship between the protons H-2
and H-4 for the major product of entry 17a–d and a
cis-relationship for the minor isomer.
16e
SO2Me
39:61
87
88
as shown in Table 1. In each case, with the exception of
16e, the secondary nitrogen favored attack on the (Si)-
face of the imine 11 (Scheme 3). The stereochemical bias
of the reaction was an interplay between the gem-di-
methyl, the tert-leucine unit and the protecting group
on the nitrogen of the secondary amine which could
be explained on the basis of the possible transition states
shown in Figure 1.
Cores similar to 17, had been previously observed dur-
ing the hydrogenation of cyanogroups in the presence
of (R)-valine derived diamine 20 by Vink et al. (Scheme
6).10 However, the stereochemical outcome of the acetals
21 was dependent on the stereochemistry of the pro-
tected hydroxyl group of the starting cyanohydrin,
which was introduced by enzymatic asymmetric addi-
tion of HCN to the corresponding aldehyde, making
the route undesirable.
The loss of stereoselectivity observed in 17c or 17d is
presumably due to the increased steric interaction be-
tween the tert-leucine and the acetamide moiety. For
the carbamates 17a and 17b, the oxygen atom in N-pro-
tecting group R next to the carbonyl occupied the same
space as that of the bulky CH3 and CF3 of 17c and 17d,
making the conformer A relatively less favorable in the
latter case due to the proximity of the adjacent tert-leu-
cine group. Although the aforementioned interaction
was minimized in conformer B, the interaction between
the axial methyl and the tert-leucine, which was absent
in conformer A, was a key steric interaction here
(Fig. 1). In the anomalous case of 17e, the tetrahedral
Our present methodology provides ready access to either
diastereoisomer of the pyridone N,N, acetal which can
be further functionalized to provide important interme-
diates for medicinal chemistry. Importantly, a practical
and efficient route to synthesize functionalized lactams
where the nitrogen is attached to a sterically hindered
unit, which was not accessible through any other known
approaches, has been developed.11 It is reasonable to as-
sume that this methodology could be extended to other
ring sizes although with a possibility of different stereo-
chemical outcome. The practicality of this route has
been established by applying the sequence to multigram
(100 g) scale synthesis of compound 18a successfully.
O
+
N
R
O
N
O
+
N
N
O
R
H
References and notes
Conformer A
Conformer B
1. Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 17,
Figure 1. Proposed transition states for cyclization of 16 to 17.
1757–1779.

4880
M. Sannigrahi et al. / Tetrahedron Letters 47 (2006) 4877–4880
2. Orjales, A.; Mosquera, R.; Toledo, A.; Pumar, C.;
stirred for 1.5 h. Satd NH4Cl (3.5 mL) was added at
(À78 °C) and the reaction mixture allowed to warm up to
room temperature. The reaction mixture was extracted
with CH2Cl2. The organic layer was dried over MgSO4,
filtered, concentrated and purified over silica gel using 0–
20% ethyl acetate in CH2Cl2 to yield 17a (R) and 17a (S).
Either the crude diastereomeric mixture of 17 or the
separated isomers 17a (R) or 17a (S) could be used in the
next step. To a solution of 17a (1.0 mmol) in CH3CN
(9.0 mL) and glacial acetic acid (3 mL) was added NaC-
NBH3 (3.0 mmol) and the reaction mixture was heated at
55 °C for 12 h, cooled to RT, evaporated to dryness and
redissolved in CH2Cl2. The organic layer was washed with
1N NaOH, brine and filtered through Na2SO4, concen-
trated and purified over silica gel using 50% EtOAc in
hexanes to yield 18a. Spectral data were obtained for all
new compounds. Analytical and 1H NMR data for some
representative compounds are included below. Compound
17a (S) (major isomer): mp 147–150 °C. MS (ES) calcd for
C18H32N2O3 (M+H)+ 324.2, found 324.2; 1H NMR
(400 MHz, CD3OD): d ppm: 0.94 (s, 9H); 0.95 (s, 3H);
0.96 (s, 3H); 1.04 (s, 9H); 1.58 (m, 1H); 1.98 (m, 1H); 2.19
(m, 2H); 3.25 (m, 2H); 3.78 (m, 1H); 5.02 (m, 1H).
Compound 17a (R) (minor isomer): mp 132–136 °C. MS
(ES) calcd for C18H32N2O3 (M+H)+ 324.2, found 324.2;
1H NMR (400 MHz, CD3OD): d ppm: 0.95 (s, 12H); 1.04
(s, 3H); 1.38 (s, 9H); 1.6 (m, 1H); 1.98 (m, 1H); 2.20 (m,
2H); 3.39 (m, 1H); 3.70 (m, 1H); 4.05 (m, 1H); 5.02 (m,
1H). Compound 18a: mp 116–118 °C. MS (ES) calcd for
C18H34N2O3 (M+H)+ 327.2, found 327.2; 1H NMR
(400 MHz, CDCl3): d ppm: 0.97 (s, 12H); 1.38 (s, 9H);
1.57 (s, 3H); 2.14 (s, 2H); 2.62 (m, 1H); 3.15 (m, 1H); 3.51
(m, 1H); 3.71 (9m, 1H); 4.30 (t, 1H, J = 12.8 Hz); 4.71 (d,
1H, J = 10.2 Hz).
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4. Milewska, M.; Bytner, T.; Polonski, T. Synthesis 1996,
1485–1488.
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2264–2267; (b) Moehrle, H.; Jeandree, M.; Breitmaier, E.;
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M. K.; Peter, S. K. J. Med. Chem. 1991, 38, 887–900; (b)
Butler, D. E.; Nordin, I. C.; L’Italien, Y. J.; Zweisler, L.;
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11. Representative procedure to obtain 18: Superhydride
(2.2 mmol, 1 M soln in THF) was added to a cooled
(À78 °C) solution of the imide 16a (1.0 mmol) in anhy-
drous CH3CN (5.0 mL) and the reaction mixture was