Organocatalytic mannich reactions on a carbapenem core - Synthesis of mannich bases and bicyclic diazanonanes

Article abstract of DOI:10.1002/ejoc.201301823

An efficient diastereoselective synthesis of carbapenem Mannich bases was developed using organocatalysis. This method also provides a route to new highly functionalized diazabicyclo[4.2.1]nonanes of proposed biological significance.

Full text of DOI:10.1002/ejoc.201301823

FULL PAPER
DOI: 10.1002/ejoc.201301823
Organocatalytic Mannich Reactions on a Carbapenem Core – Synthesis of
Mannich Bases and Bicyclic Diazanonanes
Zamani E. D. Cele,[a] Sachin A. Pawar,[a] Tricia Naicker,[a] Glenn E. M. Maguire,[a]
Per I. Arvidsson,[a,b] Hendrik G. Kruger,*[a] and Thavendran Govender*[a]
Keywords: Organocatalysis / Nitrogen heterocycles / Lactams / Carbapenems / Mannich bases
An efficient diastereoselective synthesis of carbapenem
Mannich bases was developed using organocatalysis. This
method also provides a route to new highly functionalized
diazabicyclo[4.2.1]nonanes of proposed biological signifi-
cance.
The provision of well-defined mechanistic insight was cru-
cial for the widespread recognition of this concept. Since
then, several organocatalytic approaches to Mannich-type
reactions have been successfully developed.[9] Nevertheless,
applications of organocatalytic Mannich reactions for the
derivatization of β-lactam scaffolds are rare.[10]
Introduction
The Mannich reaction is one of the most important C–
C bond formation reactions used for the construction of
nitrogenous molecules in organic syntheses.[1] This reaction
is useful for the preparation of synthetically and biolo-
gically significant optically enriched β-amino carbonyl com-
pounds.[2] The Mannich reaction has also received con-
tinuous attention because the aminocarbonyl products can
also undergo transformations to give useful β-peptides and
β-lactams, which are present in several biologically active
molecules.[3] Despite the immense importance of the direct-
type Mannich reaction, it suffers from a number of limita-
tions. The challenge of controlling the roles of the three
components in one reaction vessel, i.e., the carbonyl donor,
amine, and aldehyde, may lead to competitive side-reactions
and consequently lower yields.[4]
Furthermore, only ketones or aldehydes can be used as
enolate precursors, as other carbonyl groups such as esters
and amides are inert to aminomethylation.[5] These limita-
tions may be partially overcome by using preformed imines
and enolates, and through the appropriate use of catalysts
and reaction conditions.[6]
Traditionally, small organometallic catalysts were used to
mediate asymmetric Mannich reactions.[7] List and co-
workers developed the first organocatalytic asymmetric
Mannich reaction, which was based on enamine activation
of carbonyl compounds, and catalysed by l-proline.[1a,6a,8]
β-Lactam-containing substances, with their characteristic
four-membered ring system, represent a highly desirable
target for preparative organic chemistry. Firstly, β-lactam
antibiotics, especially from the carbapenem class, play an
immensely important role in the treatment of serious infec-
tions caused by extended-spectrum beta-lactamase (ESBLs)
producing organisms.[11] The global challenge of microbial
resistance[12] has triggered massive efforts to find new anti-
bacterial agents, even among known classes such as β-lact-
ams.[13] Secondly, the enhanced reactivity of β-lactams ren-
ders them useful as chiral building blocks for organic syn-
thesis.[14] Medium-ring heterocycles, commonly encoun-
tered structural elements in biologically active natural prod-
ucts, may be prepared by ring expansion of β-lactams with
neighbouring nitrogen nucleophiles.[15]
In this paper, we show how an organocatalytic Mannich
reaction of a key β-lactam intermediate effectively leads to
products that fall within both of the focus areas outlined
above. Initially, we explored the substrate scope of the mild
organocatalytic asymmetric Mannich reaction to synthesize
β-lactam carbapenem intermediates of potential value for
the preparation of new antibacterial agents. During this
work, we discovered a new intramolecular rearrangement
that leads to a class of hitherto unreported diazabicy-
clononanes with natural-product-like complexity.
[a] Catalysis and Peptide Research Unit, University of KwaZulu
Natal,
Durban, South Africa
E-mail: govenderthav@ukzn.ac.za
http://cpru.ukzn.ac.za
[b] Science for Life Laboratory, Drug Discovery and Development
Platform, and Division of Translational Medicine and Chemical
Biology, Department of Medical Biochemistry and Biophysics,
Karolinska Institutet,
Results and Discussion
We recently reported the mild completely stereoselective
organocatalytic C–C bond functionalization of the carb-
apenem intermediate 4-nitrobenzyl (2S,5R,6S)-6-[(R)-1-
Stockholm, Sweden
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301823.
Eur. J. Org. Chem. 2014, 2253–2260
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H. G. Kruger, T. Govender et al.
Table 1. Optimization of the catalytic asymmetric three-component Mannich reaction (PNB = para-nitrobenzyl).
FULL PAPER
Entry[a]
Catalyst/additive
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
l-proline
l-proline
l-proline
d-proline
phenylalanine
pyrrolidine
pyrrolidine/benzoic acid
l-proline/acetic acid
l-proline/formic acid
l-proline/benzoic acid
DMSO
DMF
55
23
11
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
53
n.r.
n.r.
15
50
43
25
[a] Unless otherwise noted, the reaction conditions were: carbapenem 1 (0.287 mmol), formaldehyde 3a (2.0 equiv.), p-anisidine
(2.0 equiv.), DMSO, room temp., 24 h. [b] Yield of isolated product.
hydroxyethyl]-3,7-dioxo-1-azabicyclo-[3.2.0]heptane-2-carb-
Brønsted acids were then evaluated as co-catalysts to try
oxylate (1), based on enamine-activated aldol, Mannich, to improve the reactivity and yield. Unfortunately, there
and Michael reactions.[10c] In this paper, we fully explore was no improvement in the yield of the Mannich product
the substrate scope of the Mannich reaction.
(Table 1, entries 7–10). Encouraged by the results obtained
Initially, p-anisidine (2a) and formaldehyde (3) were se- under the initial conditions (Table 1, entry 1), the substrate
lected for a model three-component Mannich reaction with scope of the three-component Mannich reaction was exam-
4-nitrobenzyl (2S,5R,6S)-6-[(R)-1-hydroxyethyl]-3,7-dioxo- ined using different amines and formaldehyde (Table 2). In
1-azabicyclo-[3.2.0]heptane-2-carboxylate (1; carbapenem general, regardless of the electronic properties of the sub-
intermediate), using l-proline as a catalyst in DMSO. As stituents on the aromatic ring of aniline, the Mannich bases
previously established,[10c] the reaction proceeded by en- could be obtained in moderate yields and with excellent dia-
amine catalysis, and the new C–C bond was formed on the stereoselectivities (Table 2, entries 1–4). Notably, even a
carbon α to the carbonyl (ketone), resulting in the forma- condensed-ring amine (2-naphthylamine) performed well to
tion of Mannich base 4a in 53% yield (Table 1, entry 1). As give the corresponding product in 52% yield and with a dr
reported, this reaction was completely regio- and stereo- of Ͼ99:1 (Table 2, entry 5). We observed the formation of
selective.[10c] In this case, the relative configuration of Man- the aldol addition product as a result of an expected side-
nich product 4a was confirmed to be (S) by 2D NMR spec- reaction, which also occurs under similar conditions,[10c]
troscopy.
and this explains the reduced yields.[1a,18]
Solvent screening did not give any improvement in the
Table 2. Substrate scope of the catalytic asymmetric three-compo-
nent Mannich reaction using aromatic amines.[a]
yields, and DMSO was still the best solvent for this reaction
(Table 1, entry 1 vs. entries 2 and 3). d-Proline gave results
similar to those with l-proline in terms of yield and dia-
stereoselectivity (Table 1, entries 1 and 4). This result shows
that the carbapenem substrate (i.e., 1) rather than the cata-
lyst controls the stereochemical outcome of the reaction,
and therefore the cheaper l-proline was preferred as the or-
ganocatalyst for the reaction. Similar results have been re-
ported for the direct aldol and nitroaldol reactions between
enantiopure azetidine-2,3-diones (β-lactams) and ketones
or nitromethane.[16] It was reported in that paper that the
use of either enantiomer of proline or of N-methylephedrine
as the organocatalyst resulted in an identical level of
Entry[a]
R
Product Yield [%][b]
dr[c]
1
2
3
4
5
4-MeOC6H4
Ph
4-MeC6H4
4-BrC6H4
2-naphthyl
4a
4b
4c
4d
4e
55
55
53
55
52
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
[a] Unless otherwise noted, the reaction conditions were: carbap-
enem intermediate 1 (0.287 mmol), formaldehyde 3 (2.0 equiv.),
amine derivative (2.0 equiv.), DMSO, room temp., 24 h. [b] Yield
1
of isolated product. [c] Determined by H NMR spectroscopy.
In contrast to the results with aromatic amines, when
sterecontrol in these reactions. Neither pyrrolidine Ϫ an benzyl and aliphatic amines were tested in the three-compo-
achiral secondary amine, nor phenylalanine Ϫ a primary nent Mannich reaction with formaldehyde, aldol reaction
amine, catalysed the reaction (Table 1, entries 5 and 6).[17]
products were formed almost exclusively. Fortunately, these
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Organocatalytic Mannich Reactions on a Carbapenem Core
amines can form stable imines by treatment with paraform- new bond and the nucleophilicity of the amine. No re-
aldehyde and magnesium sulfate in CHCl3 (Table 3). Sur- arranged products were observed for the aromatic amines
prisingly, and to our delight, the two-component Mannich tested, and we attribute this to the lower pKa of these
reaction of benzyl imine 5b with carbapenem intermediate groups. The decreased basicity of the NH functionality ren-
1 resulted in the formation of diazabicyclo[4.2.1]nonane ders it less nucleophilic, but this can also negate the proxim-
compound 7b in one pot. We propose that this reaction ity effect by hydrogen bonding to the ketone.
occured via Mannich base intermediate 6b, as may be seen
To establish whether the reaction proceeds by intramo-
in the plausible catalytic cycle shown in Scheme 1. We attri- lecular rearrangement of intermediate 6b, we then used N-
bute this result to a combination of the proximity of the methyl benzylamine as an amine component in the Man-
nich reaction (Scheme 2). In this case, only the anticipated
Mannich base (i.e., 8a) was obtained in acceptable yield
(42%) and with excellent diastereoselectivity (Ͼ99%),
which gives further support for postulated intermediate 6b.
This reaction also demonstrated the successful use of sec-
ondary amines in the organocatalytic two-component Man-
nich reaction. The secondary amine N-methyl aniline was
also tested in the organocatalytic three-component reaction
(Scheme 2), and it gave a good yield (51%) of tertiary Man-
nich base 8b.
Table 3. Substrate scope of the catalytic asymmetric two-compo-
nent Mannich reaction using aliphatic amines.[a]
Entry[a] R1
Product
Yield [%][b]
dr[c]
The diazabicyclo[4.2.1]nonane ring system in 7 repre-
sents an interesting molecular skeleton.
1
2
3
4
5
6
7
8
4-MeOC7H6
Bn
7a
7b
7c
7d
7e
7f
58
61
54
52
58
60
57
46
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
4-ClC7H6
4-BrC7H6
2-picolyl
Ph-Et
(S)-1-Ph-Et
nBu
7g
7h
The bicyclic diazabicyclo[4.2.1]nonane core has been re-
ported in patents and papers relating to compounds with
various biological effects, e.g., as histamine H3 inverse ago-
nists and antagonists, dual orexin receptor antagonists, and
opioid receptor agonists.[19] To the best of our knowledge,
[a] Unless otherwise noted, the reaction conditions were: amine
(1.0 mmol), paraformaldehyde (1.0 mmol), MgSO4 (1.0 g), CHCl3,
r.t., 7 h, and 1 (0.5 equiv.). [b] Yield of isolated product. [c] Deter-
1
mined by H NMR spectroscopy.
Scheme 1. Catalytic cycle of the proline-catalysed Mannich reaction of carbapenem core 1.
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H. G. Kruger, T. Govender et al.
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Scheme 2. Organocatalytic Mannich reaction.
only one paper discussing the organocatalytic asymmetric cyclo[4.2.1]nonanes. These compounds appears to represent
synthesis of an all-carbon bicyclononane ring system has a privileged molecular scaffold for the preparation of biolo-
been published, which makes both the synthetic route and gically active compounds.
the highly functionalized diazabicyclo scaffold novel.[20]
NMR correlations observed in the spectra of the prod-
Excited by the rather unexpected and efficient formation ucts revealed some interesting features. The spectra of com-
of highly functionalized analogues of this valuable molecu- pound 4b (HMBC: H-18–C-9, purple arrow; and NOE: H-
lar scaffold, we explored this reaction further, and the re- 18–H-4, green arrow) clearly confirmed the presence of the
sults are given in Table 3.
β-lactam ring and the relative stereoselectivity at C-8 in the
All the diazabicyclo[4.2.1]nonanes were obtained in good structure (Figure 2). The NMR spectrum of compound 7b
yields and with excellent diastereoselectivities, regardless of (HMBC: H-17–C-2 and H-18–C-2) verified the formation
the electronic nature of the aryl ring of the benzylamines of the bicyclic ring, which is consistent with the crystal data
(Table 3, entries 1–4). Similary, if a heteroaromatic imine (Figure 1). We observed an upfield shift for the ketone
such as that obtained from picolylamine was used, the cor- (C=O) signal of compounds 4a–4e in their 13C NMR spec-
responding Mannich base was obtained with excellent dia- tra (compared to compound 1). This may be attributed to
stereoselectivity and with no effect on the yield (Table 3, intramolecular hydrogen bonding between the oxygen of
entry 5). The imines of aliphatic amines such as phenyleth- the carbonyl group and the amine group attached to the
ylamine and n-butylamine also reacted with 1 to give the aromatic ring. When N-methylaniline was used as a sub-
corresponding diazabicyclo[4.2.1]nonanes with excellent strate, resulting in Mannich base product 8a, no upfield
diastereoselectivities and with no significant change in yield shift was observed for the carbonyl signal, which indicates
(Table 3, entries 6–8).
the importance of the postulated hydrogen bonding
The structures of diazabicyclo[4.2.1]nonane products 7a– (Scheme 2).
7h were confirmed by 2D NMR measurements, and a sin-
gle-crystal X-ray structure of 7b was obtained (Figure 1).
Figure 2. β-Lactam Mannich base 4b and bicyclo[4.2.1]nonane 7b.
Figure 1. Single-crystal X-ray structure of 7b. Displacement ellip-
soids are scaled to the 50% probability level.
Conclusions
In summary, the two-component organocatalytic Man-
In summary, we have demonstrated that it is possible to
nich reaction provides a unique method for the construc- alter the reactivity patterns of a β-lactam substrate in its
tion of highly functionalized, natural-product like diazabi- organocatalytic Mannich reaction with formaldehyde and
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Organocatalytic Mannich Reactions on a Carbapenem Core
4-Nitrobenzyl (2S,5R,6S)-6-[(R)-1-Hydroxyethyl]-3,7-dioxo-2-
[(phenylamino)methyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate
(4b): The crude product was purified by column chromatography
(EtOAc/hexane, 80:20; Rf = 0.4) to give the product (403 mg, 55%)
as a semisolid. [α]2D0 = –30.0 (c = 0.1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.21 (d, J = 8.64 Hz, 2 H), 7.70 (s, 1 H), 7.51 (d, J =
8.60 Hz, 2 H), 7.45 (d, J = 7.88 Hz, 2 H), 7.30 (t, J = 7.82 Hz, 2
H), 7.12 (t, J = 7.38 Hz, 1 H), 6.14 (s, 1 H), 6.04 (s, 1 H), 5.29 (d,
J = 9.72 Hz, 2 H), 4.60 (m, 1 H), 4.17 (m, 1 H), 3.06 (m, 1 H),
3.04 (m, 1 H), 2.66 (dd, J = 15.84, 9.52 Hz, 1 H), 1.37 (d, J =
anilines/aliphatic amines. Carbapenem intermediate 1 reacts
with formaldehyde and anilines to produce β-lactam Man-
nich bases, while reaction with aliphatic or benzylic amines
results in the formation of diazabicyclo[4.2.1]nonane prod-
uct(s) in one pot. Highly distereoselective diazabicy-
clo[4.2.1]nonane formation was observed in all reactions of
aliphatic amines, and this led to highly functionalized ana-
logues of compounds with postulated biological signifi-
cance. The reported organocatalytic functionalization of
carbapenem intermediate 1 may be used to access new β- 6.16 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.33,
165.58, 162.15, 148.06, 142.21, 137.22, 130.88, 129.21, 128.69,
125.10, 124.09, 120.23, 115.72, 66.93, 66.02, 64.82, 55.78, 40.24,
21.62 ppm. HRMS (ESI+): calcd. for C23H23N3O7 [M + H]+
454.1608; found 454.2985.
lactams, as well as new highly functionalized diazabicy-
clo[4.2.1]nonanes Both of these compound classes are
highly valuable as starting points for the synthesis of com-
pounds with biologically important features.
4-Nitrobenzyl (2S,5R,6S)-6-[(R)-1-Hydroxyethyl]-2-[(4-methoxy-
phenylamino)methyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carb-
oxylate (4a): The crude product was purified by column
chromatography (EtOAc/hexane, 80:20; Rf = 0.4) to give the prod-
uct (431 mg, 55%) as a semisolid. [α]2D0 = –50.0 (c = 0.1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 8.72 Hz, 2 H), 7.66
(d, J = 8.72 Hz, 2 H), 7.40 (d, J = 9.00 Hz, 2 H), 6.83 (d, J =
9.00 Hz, 2 H), 5.83 (d, J = 9.96 Hz, 2 H), 5.31 (s, 2 H), 5.03 (d, J
= 4.40 Hz, 2 H), 4.53–4.49 (m, 1 H), 3.97 (q, J = 5.44 Hz, 1 H),
3.69 (s, 3 H), 3.11 (dd, J = 5.30, 2.38 Hz, 1 H), 2.77–2.69 (m, 2 H),
1.10 (d, J = 6.32 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 167.57, 166.04, 161.87, 155.25, 147.11, 143.23, 131.91, 131.55,
128.53, 123.51, 120.77, 113.75, 113.56, 65.40, 63.47, 62.74, 55.08,
53.45, 40.11, 21.61 ppm. HRMS (ESI+): calcd. for C24H25N3O8
[M + H]+ 484.1714; found 484.1712.
Experimental
General Methods: Reagents and solvents were purchased from Ald-
rich, Merck, and Fluka. All solvents were dried using standard
procedures. Thin layer chromatography (TLC) was carried out
using Merck Kieselgel 60 F254. Crude compounds were purified
by column chromatography using silica gel (60–200 mesh unless
otherwise stated). NMR spectra were recorded with Bruker
AVANCE III 400 or 600 MHz instruments at room temperature.
Chemical shifts are expressed in ppm downfield from tetramethyl-
silane, which was used as an internal standard, and coupling con-
stants are reported in Hz. Optical rotations were recorded with a
Perkin–Elmer Polarimeter (model 341). High-resolution mass spec-
trometric data were obtained using a Bruker micrOTOF-Q II in-
strument operating at ambient temperatures, with a sample concen-
tration of approximately 1 ppm.
4-Nitrobenzyl (2S,5R,6S)-6-[(R)-1-Hydroxyethyl]-3,7-dioxo-2-[(p-
tolylamino)methyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (4c):
The crude product was purified by column chromatography
(EtOAc/hexane, 70:30; Rf = 0.4) to give the product (400 mg, 53%)
as a brown solid. [α]2D0 = +5.0 (c = 0.1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.20 (d, J = 7.64 Hz, 2 H), 7.51 (d, J =
7.72 Hz, 2 H), 7.33 (d, J = 7.28 Hz, 2 H), 7.08 (d, J = 7.08 Hz, 2
H), 6.11 (s, 1 H), 6.04 (s, 1 H), 5.28 (q, J = 7.32 Hz, 2 H), 4.59 (s,
1 H), 4.15 (s, 1 H), 3.02 (m, 2 H), 2.65 (dd, J = 15.15, 9.83 Hz, 1
H), 2.28 (s, 3 H), 1.34 (d, J = 4.96 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.23, 165.55, 162.02, 147.87, 142.16,
134.65, 130.34, 129.34, 128.54, 123.92, 120.24, 115.55, 66.71, 65.88,
64.59, 42.66, 21.47, 20.87 ppm. HRMS (ESI+): calcd. for
C24H25N3O7 [M + H]+ 468.1765; found 468.1770.
Representative Procedure for the Mannich Reaction of Aromatic
Amines with Carbapenem: A substituted aniline (2 equiv.) was
added to a stirred solution of formaldehyde (36% aqueous solu-
tion; 0.574 mmol) in DMSO (3 mL) at ambient temperature. After
4 h, carbapenem intermediate 1 (0.1 g, 0.287 mmol) and a catalytic
amount of l-proline (30 mol-%) were added. The reaction mixture
was stirred at room temperature for 20 h and monitored by TLC.
The reaction mixture was then quenched by the addition of PBS
(phosphate-buffered saline) buffer (0.01 m; 1 mL) and water
(3 mL). The aqueous phase was extracted with EtOAc (3ϫ). The
combined organic extracts were dried with anhydrous MgSO4,
which was subsequently removed by filtration. The solvent was re-
moved under reduced pressure, and the crude product mixture was
purified by silica gel column chromatography.
4-Nitrobenzyl (2S,5R,6S)-2-[(4-Bromophenylamino)methyl]-6-[(R)-
1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate
(4d): The crude product was purified by column chromatography
(EtOAc/hexane, 80:20; Rf = 0.4) to give the product (473 mg, 55%)
as a semisolid. [α]2D0 = –70.0 (c = 0.1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.23 (d, J = 8.52 Hz, 2 H), 7.78 (s, 1 H), 7.52 (d, J =
8.52 Hz, 2 H), 7.41–7.35 (m, 4 H), 6.17 (s, 1 H), 6.06 (s, 1 H), 5.29
(q, J = 13.2 Hz, 2 H), 4.61–4.59 (m, 1 H), 4.20–4.16 (m, 1 H), 3.06
(dd, J = 19.26, 11.34 Hz, 1 H), 2.68–2.64 (m, 2 H), 1.37 (d, J =
6.12 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.26,
165.47, 162.17, 148.09, 142.16, 136.36, 132.20, 130.78, 128.67,
124.12, 121.74, 117.72, 115.84, 66.98, 64.79, 55.64, 40.41,
21.69 ppm. HRMS (ESI–): calcd. for C23H22BrN3O7 [M – H]–
530.0557; found 530.0612.
Representative Procedure for the Preparation of Imines: A literature
procedure was followed.[21]
Representative Procedure for the Mannich Reaction of Imines with
Carbapenems: l-Proline (30 mol-%) and the respective imine
(2 equiv.) were added to a solution of carbapenem intermediate 1
(562 mg, 1.62 mmol) in DMSO (15 mL). The solution was stirred
at room temperature for Ͼ20 h and monitored by TLC. The reac-
tion mixture was then quenched by the addition of PBS buffer
(0.01 m; 10 mL) and water (15 mL). The aqueous phase was ex-
tracted with EtOAc (3ϫ). The combined organic extracts were
dried with anhydrous MgSO4, which was subsequently removed by
filtration. The solvent was removed under reduced pressure, and
the crude product mixture was purified by silica gel column
chromatography.
4-Nitrobenzyl (2S,5R,6S)-6-[(R)-1-Hydroxyethyl]-2-[(naphthalen-1-
ylamino)methyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carb-
oxylate (4e): The crude product was purified by column chromatog-
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H. G. Kruger, T. Govender et al.
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raphy (EtOAc/hexane, 80:20; Rf = 0.4) to give the product (392 mg,
product was purified by column chromatography (EtOAc/hexane,
70:30; Rf = 0.4) to give the product (468 mg, 53%) as a brown
crystalline solid. [α]2D0 = –10.0 (c = 0.1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.23 (d, J = 8.64 Hz, 2 H), 7.42 (d, J =
1
48%) as a brownish oil. [α]2D0 = –45.0 (c = 0.1, CHCl3). H NMR
(400 MHz, CDCl3): δ = 8.22 (d, J = 8.72 Hz, 2 H), 7.51 (d, J =
8.68 Hz, 2 H), 5.33 (d, J = 3.48 Hz, 2 H), 4.37 (m, 1 H), 4.21 (m,
1 H), 4.04 (d, J = 8.72 Hz, 1 H), 3.69 (m, 1 H), 3.31 (t, J = 8.16 Hz, 11.10, 8.50 Hz, 4 H), 7.13 (d, J = 8.28 Hz, 2 H), 5.14 (d, J =
2 H), 2.73 (dd, J = 18.6, 8.10 Hz, 1 H) 2.50 (t, J = 5.20 Hz, 1 H), 3.24 Hz, 2 H), 4.91 (d, J = 14.72 Hz, 1 H), 4.44 (dd, J = 6.54,
2.28 (d, J = 18.65 Hz, 1 H), 1.45–1.25 (m, 4 H), 1.23 (d, J =
3.38 Hz, 1 H), 4.27 (q, J = 7.44, 6.04 Hz, 1 H), 4.16 (d, J =
6.48 Hz, 3 H), 0.86 (t, J = 7.26 Hz, 3 H) ppm. 13C NMR (100 MHz, 14.73 Hz, 1 H), 4.01 (d, J = 15.68 Hz, 1 H), 3.59 (d, J = 15.64 Hz,
CDCl3): δ = 210.05, 174.03, 167.13, 148.11, 141.83, 128.65, 124.08, 1 H), 2.73 (dd, J = 18.65, 8.04 Hz, 1 H) 2.53 (q, J = 5.44, 3.48 Hz,
70.57, 66.89, 66.76, 58.28, 51.19, 49.36, 47.67, 43.65, 29.63, 21.02,
20.16, 13.85 ppm. HRMS (ESI+): calcd. for C27H25N3O7 [M +
H]+ 504.1765; found 504.1792.
1 H), 2.30 (d, J = 18.69 Hz, 1 H), 1.25 (d, J = 6.56 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 209.92, 175.09, 166.75, 148.31,
141.85, 135.61, 132.08, 130.76, 128.71, 124.28, 122.09, 70.51, 67.06,
57.73, 51.63, 50.14, 47.75, 44.23, 20.99 ppm. HRMS (ESI+): calcd.
for C24H24BrN3O7 [M + H]+ 546.0870; found 546.0854.
4-Nitrobenzyl (1R)-3-Benzyl-5-[(R)-1-hydroxyethyl]-4,8-dioxo-3,9-
diazabicyclo[4.2.1]nonane-1-carboxylate (7b): The crude product
was purified by column chromatography (EtOAc/hexane, 70:30; Rf
4-Nitrobenzyl (1R)-5-[(R)-1-Hydroxyethyl]-4,8-dioxo-3-(pyridin-2-
ylmethyl)-3,9-diazabicyclo[4.2.1]nonane-1-carboxylate (7e): The
crude product was purified by column chromatography (EtOAc/
hexane, 80:20; Rf = 0.3) to give the product (440 mg, 58%) as a
white crystalline solid. [α]2D0 = –10.0 (c = 0.1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.27 (d, J = 4.44 Hz, 1 H), 8.15 (d, J =
8.68 Hz, 2 H), 7.63 (m, 1 H), 7.42 (d, J = 8.64 Hz, 2 H), 7.21 (d, J
= 7.84 Hz, 1 H), 7.10 (t, J = 6.90, 5.34 Hz, 1 H) 5.43 (d, J =
16.20 Hz, 1 H), 5.16 (s, 2 H), 4.40 (dd, J = 6.62, 2.70 Hz, 1 H),
4.31–4.21 (m, 2 H), 4.12 (d, J = 16.21 Hz, 1 H), 3.74 (d, J =
15.61 Hz, 1 H), 3.68 (d, J = 7.00 Hz, 1 H), 2.88 (dd, J = 18.19,
7.38 Hz, 1 H), 2.51 (q, J = 5.76, 2.64 Hz, 1 H), 2.31 (d, J =
18.17 Hz, 1 H), 1.21 (d, J = 6.88 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 208.93, 174.67, 168.04, 155.82, 148.72,
142.28, 137.19, 128.35, 123.79, 122.56, 122.23 70.27, 66.47, 66.24,
57.04, 53.74, 52.16, 46.91, 44.64, 20.03 ppm. HRMS (ESI+): calcd.
for C23H24N4O7 [M + H]+ 469.1717; found 469.1756.
= 0.4) to give the product (491 mg, 61%) as a white solid. [α]2D0
=
1
–30.0 (c = 0.1, CHCl3). H NMR (400 MHz, CDCl3): δ = 8.24 (d,
J = 8.60 Hz, 2 H), 7.45 (d, J = 8.52 Hz, 2 H), 7.25–7.34 (m, 5 H),
5.17 (q, J = 13.6 Hz, 2 H), 4.92 (d, J = 14.6 Hz, 1 H), 4.51–4.45
(m, 1 H), 4.32–4.28 (m, 2 H), 4.06 (d, J = 15.68 Hz, 1 H), 3.64 (d,
J = 15.64 Hz, 1 H), 2.76 (dd, J = 18.61, 8.00 Hz, 1 H), 2.57 (q, J
= 5.24, 3.72 Hz, 1 H) 2.34 (d, J = 18.61 Hz, 1 H), 1.29 (d, J =
6.60 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 209.64,
174.72, 166.65, 141.76, 136.34, 128.79, 128.67, 128.42, 127.88,
124.00, 70.24, 66.70, 66.68, 57.62, 51.94, 49.95, 47.50, 43.98,
20.79 ppm. HRMS (ESI+): calcd. for C25H27N3O8 [M + H]+
498.1870; found 498.1878.
4-Nitrobenzyl (1R)-5-[(R)-1-Hydroxyethyl]-3-(4-methoxybenzyl)-
4,8-dioxo-3,9-diazabicyclo[4.2.1]nonane-1-carboxylate (7a): The
crude product was purified by column chromatography (EtOAc/
hexane, 80:20; Rf = 0.4) to give the product (438 mg, 58%) as a
yellow crystalline solid. [α]2D0 = –20.0 (c = 0.1, CHCl3). H NMR
1
4-Nitrobenzyl (1R)-5-[(R)-1-Hydroxyethyl]-4,8-dioxo-3-phenethyl-
3,9-diazabicyclo[4.2.1]nonane-1-carboxylate (7f): The crude product
was purified by column chromatography (EtOAc/hexane, 70:30; Rf
= 0.3) to give the product (452 mg, 58%) as a white crystalline
solid. [α]2D0 = –20.0 (c = 0.1, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 8.18 (d, J = 8.64 Hz, 1 H), 7.77 (d, J = 8.56 Hz, 2 H), 7.23 (d,
J = 6.76 Hz, 2 H), 7.18 (m, 1 H), 7.11 (d, J = 7.01 Hz, 2 H), 5.29 (s,
2 H), 4.33 (dd, J = 6.48, 4.16 Hz, 1 H), 4.19 (q, J = 7.48, 6.00 Hz, 1
H), 3.96 (d, J = 15.52 Hz, 1 H), 3.69–3.57 (m, 2 H), 3.53–3.45 (m,
1 H), 2.82–2.72 (m, 1 H), 2.71–2.63 (m, 2 H), 2.45 (q, J = 5.16,
4.48 Hz, 1 H), 2.26 (d, J = 18.61 Hz, 1 H), 1.19 (d, J = 6.56 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 210.02, 174.06, 167.13,
148.11, 141.75, 138.47, 128.67, 126.72, 124.09, 66.92, 66.57, 58.19,
51.64, 51.44, 47.66, 43.71, 33.96, 20.93 ppm. HRMS (ESI+): calcd.
for C25H27N3O7 [M + H]+ 482.1921; found 482.1891.
(400 MHz, CDCl3): δ = 8.21 (d, J = 8.68 Hz, 2 H), 7.42 (d, J =
8.68 Hz, 2 H), 7.16 (d, J = 8.64 Hz, 2 H), 6.80 (d, J = 8.60 Hz, 2
H), 5.14 (q, J = 6.68 Hz, 2 H), 4.84 (d, J = 14.44 Hz, 1 H), 4.43
(dd, J = 6.58, 3.46 Hz, 1 H), 4.24 (q, J = 7.34, 6.14 Hz, 1 H), 4.18
(d, J = 14.44 Hz, 1 H), 4.02 (d, J = 15.72 Hz, 1 H), 3.78 (s, 3 H)
3.58 (d, J = 15.64 Hz, 1 H), 2.73 (dd, J = 18.57, 7.96 Hz, 1 H), 2.73
(q, J = 18.57, 7.96 Hz, 1 H), 2.34 (s, 1 H), 2.29 (d, J = 18.49 Hz, 1
H), 1.24 (d, J = 6.64 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 209.55, 174.59, 166.62, 159.22, 141.74, 130.02, 128.30, 128.23,
123.88, 114.04, 70.13, 66.51, 57.49, 55.24, 51.16, 49.66, 47.39,
43.89, 20.66 ppm. HRMS (ESI+): calcd. for C24H25N3O7
[M + H]+ 468.1765; found 468.1772.
4-Nitrobenzyl (1R)-3-(4-Chlorobenzyl)-5-[(R)-1-hydroxyethyl]-4,8-
dioxo-3,9-diazabicyclo[4.2.1]nonane-1-carboxylate (7c): The crude
product was purified by column chromatography (EtOAc/hexane,
70:30; Rf = 0.38) to give the product (430 mg, 53%) as a white
crystalline solid. [α]2D0 = –25.0 (c = 0.1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.16 (d, J = 8.40 Hz, 2 H), 7.32 (d, J =
8.40 Hz, 2 H), 7.18 (d, J = 6.08 Hz, 2 H), 7.14 (s, 2 H), 5.07 (q, J
= 3.44 Hz, 2 H), 4.84 (d, J = 14.69 Hz, 2 H), 4.38 (m, 1 H), 4.21
(t, J = 12.76 Hz, 1 H), 4.12 (d, J = 14.72 Hz, 1 H), 3.96 (d, J =
15.65 Hz, 1 H), 3.53 (d, J = 15.65 Hz, 1 H) 2.67 (dd, J = 18.67,
7.90 Hz, 1 H), 2.46 (s, 1 H), 2.24 (d, J = 18.65 Hz, 1 H), 1.19 (d, J
= 6.44 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 209.51,
174.72, 166.41, 141.50, 134.76, 133.67, 130.09, 128.79, 123.95,
70.18, 66.74, 66.71, 57.41, 51.28, 49.82, 47.44, 43.89, 20.66 ppm.
HRMS (ESI+): calcd. for C24H24ClN3O7 [M + H]+ 502.1375; found
502.1384.
4-Nitrobenzyl (1R)-5-[(R)-1-Hydroxyethyl]-4,8-dioxo-3-(1-phenyl-
ethyl)-3,9-diazabicyclo[4.2.1]nonane-1-carboxylate (7g): The crude
product was purified by column chromatography (EtOAc/hexane,
70:30; Rf = 0.35) to give the product (444 mg, 57%) as a white
crystalline solid. [α]2D0 = +15.0 (c = 0.1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.22 (d, J = 8.24 Hz, 2 H), 7.39 (d, J =
8.16 Hz, 2 H), 7.33 (m, 5 H), 6.12 (d, J = 6.67 Hz, 1 H), 4.93 (m,
2 H), 4.46 (m, J = 3.48 Hz, 1 H), 4.26 (t, J = 13.01 Hz, 1 H), 3.87
(d, J = 15.85 Hz, 1 H), 3.40 (d, J = 15.88 Hz, 1 H), 2.71 (dd, J =
18.37, 7.60 Hz, 1 H), 2.45 (s, 1 H), 2.29 (d, J = 18.45 Hz, 1 H),
1.48 (d, J = 6.84 Hz, 3 H), 1.24 (d, J = 6.32 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 210.20, 174.56, 166.37, 142.16,
139.88, 128.43, 127.99, 124.16, 70.34, 66.66, 66.53, 57.45, 51.42,
47.44, 45.62, 45.07, 20.71, 16.70 ppm. HRMS (ESI+): calcd. for
C25H27N3O7 [M + H]+ 482.1921; found 482.1815.
4-Nitrobenzyl (1R)-3-(4-Bromobenzyl)-5-[(R)-1-hydroxyethyl]-4,8-
dioxo-3,9-diazabicyclo[4.2.1]nonane-1-carboxylate (7d): The crude
2258
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2253–2260

Organocatalytic Mannich Reactions on a Carbapenem Core
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4-Nitrobenzyl (1R)-3-Butyl-5-[(R)-1-hydroxyethyl]-4,8-dioxo-3,9-di-
azabicyclo[4.2.1]nonane-1-carboxylate (7h): The crude product was
purified by column chromatography (EtOAc/hexane, 80:20; Rf =
0.4) to give the product (337 mg, 48%) as a brownish oil. [α]2D0
=
+37.0 (c = 0.1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.22 (d,
J = 8.72 Hz, 2 H), 7.51 (d, J = 8.68 Hz, 2 H), 5.33 (d, J = 3.48 Hz,
2 H), 4.37 (m, 1 H), 4.21 (m, 1 H), 4.04 (d, J = 8.72 Hz, 1 H), 3.69
(m, 1 H), 3.31 (t, J = 8.16 Hz, 2 H), 2.73 (dd, J = 18.6, 8.10 Hz, 1
H) 2.50 (t, J = 5.20 Hz, 1 H), 2.28 (d, J = 18.65 Hz, 1 H), 1.45–
1.25 (m, 4 H), 1.23 (d, J = 6.48 Hz, 3 H), 0.86 (t, J = 7.26 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 210.05, 174.03, 167.13,
148.11, 141.83, 128.65, 124.08, 70.57, 66.89, 66.76, 58.28, 51.19,
49.36, 47.67, 43.65, 29.63, 21.02, 20.16, 13.85 ppm. HRMS (ESI+):
calcd. for C21H28N3O7 [M + H]+ 434.1927; found 434.1450.
[4]
[5]
[6]
4-Nitrobenzyl (2S,5R,6S)-2-{[Benzyl(methyl)amino]methyl}-6-[(R)-
1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate
(8a): The crude product was purified by column chromatography
(EtOAc/hexane, 80:20; Rf = 0.4) to give the product (42%) as a
semisolid. [α]2D0 = +65.0 (c = 0.1, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.45 (d, J = 8.25 Hz, 2 H), 7.66 (d, J = 54 Hz, 2 H),
7.40 (d, J = 8.8 Hz, 2 H), 6.83 (m, 3 H), 5.83 (d, J = 9.96 Hz, 2
H), 5.31 (s, 2 H), 5.03 (d, J = 4.40 Hz, 2 H), 4.53–4.49 (m, 1 H),
3.97 (q, J = 16.24, 5.44 Hz, 1 H), 3.69 (s, 3 H), 3.11 (dd, J = 5.30,
2.38 Hz, 1 H), 2.77–2.69 (m, 2 H), 1.10 (d, J = 6.37 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 168.57, 168.04, 161.87, 155.25,
142.11, 143.23, 131.91, 133.55, 128.53, 123.51, 118.77, 113.75,
112.56, 64.40, 63.47, 63.74, 55.08, 53.45, 40.21, 21.61 ppm. HRMS
(ESI+): calcd. for C25H27N3O7 [M + H]+ 482.1921; found 482.1881.
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(phenyl)amino]methyl}-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carb-
oxylate (8b): The crude product was purified by column
chromatography (EtOAc/hexane, 70:30; Rf = 0.4) to give the prod-
uct (51%) as a semisolid. [α]2D0 = +65.0 (c = 0.1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.23 (d, J = 8.72 Hz, 2 H), 7.48 (d, J =
8.56 Hz, 2 H), 7.20 (m, 3 H), 6.93 (d, J = 8.24 Hz, 2 H), 5.29 (s, 2
H), 5.08 (d, J = 12.28 Hz, 1 H), 4.93 (d, J = 14.16 Hz, 1 H), 4.70
(q, J = 6.88 Hz, 1 H), 4.61 (d, J = 12.25 Hz, 1 H), 4.27 (dd, J =
8.02, 4.18 Hz, 1 H), 4.10 (d, J = 14.16 Hz, 1 H), 3.73 (q, J =
7.01 Hz, 1 H), 3.01 (dd, J = 18.99, 8.18 Hz, 1 H), 2.78 (d, J =
4.12 Hz, 1 H), 2.57 (d, J = 19.01 Hz, 1 H), 2.35 (s, 3 H), 1.59 (d, J
= 6.96 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 207.83,
173.67, 166.90, 142.67, 137.35, 128.24, 123.91, 72.80, 71.41, 71.11,
66.29, 55.75, 53.78, 47.47, 41.35, 21.09, 16.96 ppm. HRMS (ESI+):
calcd. for C24H25N3O7 [M + H]+ 468.1765; found 468.1783.
[10]
[11]
[12]
[13]
Supporting Information (see footnote on the first page of this arti-
cle): General methods, representative procedure for the Mannich
reaction of aromatic amines with carbapenem; representative pro-
cedure for the preparation of imines; representative procedure for
the Mannich reaction of imines with carbapenems; copies of NMR
spectra of products; copies of HRMS spectra of products.
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The authors thank the National Research Foundation (South
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Received: December 6, 2013
Published Online: February 6, 2014
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