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242 Chemistry and Biology of Beta-Lactams
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25. (a) Hehre, W. J.; Radom, L.; Schleyer, P. V. R.; Pople, A. J. Ab Initio Molecular Orbital Theory; Wiley,
New York, 1986, 76; (b) Ditcheld, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724; (c) Hehre,
W. J.; Ditcheld, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257.
26. Banik, B. K.; Banik, I.; Becker, F. F. Bioorg. Med. Chem. 2005, 13, 3611.
27. Doyle, T. W.; Belleau, B.; Luh, B. Y.; Ferraro, C. F. Can. J. Chem. 1977, 55, 468.
28. Domingo, L. R.; Ríos-Gutiérrez, M; Sáez, J. A. RSC Adv. 2015, 47, 37085.
29. Pahlavan, F; Moosavo, S. S.; Zolghadr, A. R.; Iranpoor, N. RSC Adv. 2023, 13 (48), 33854.
30. (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley, New York,
1994, 550–553; (b)Yamataka, H.; Ammal, S. C.; Asano, T.; Ohga, Y. Bull. Chem. Soc. Jpn. 2005, 78,
1851.
31. (a) Ojima, I.; Chen, H.-J. C. J. Chem. Soc. Chem. Commun. 1987, 625; (b) Ojima, I.; Chen, H.-J. C.;
Qui, X. Tetrahedron. 1988, 44, 5307; (c) Ojima, I.; Komata, T.; Qui, X. J. Am. Chem. Soc. 1990, 112,
770; (d) Hegedus, L. S.; Montgomery, J.; Narukawa, Y.; Snustad, D. C. J. Am. Chem. Soc. 1991, 113,
5784; (e) Evans, D. A.; Sjbgren, E. B. Tetrahedron Left. 1985, 26, 3783; (f) Evans, D. A.; Sjbgren, E. B.
Tetrahedron Left. 1985, 26, 3788; (g) Boger, D. L.; Myers, J. B., Jr. J. Org. Chem . 1991, 56, 5385.
32. (a) Khangarot, R. K.; Kaliappan, K. P. Eur. J. Org. Chem. 2013, 7664; (b) Stecko, S.; Furman, B.;
Chmielewski, M. Tetrahedron. 2014, 70, 7817; (c) Mandal, B.; Basu, B. Top. Heterocycl. Chem. 2013,
30, 85.
33. Ding, L. K.; Irwin, W. J. J. Chem. Soc. Perkin Trans. 1976, 1, 2382.
34. Pal, R.; Ghosh, S. C.; Chandra, K.; Basak, A. Synlett. 2007, 2321.
35. Ahn, C.; Kennington, J. W.; De Shong, P. J. Org. Chem. 1994, 59, 6282.
36. Santoro, S.; Liao, R.-Z.; Marcelli, T.; Hammar, P.; Himo, F. J. Org. Chem. 2015, 80, 2 649.
37. Okuro, K.; Enna, M.; Miura, M.; Nomura, M. J. Chem. Soc. Chem. Commun. 1993, 1107.
8
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Beta-Lactams as Synthons for Diverse Heterocycles
Bimal Krishna Banik1 and Aparna Das
1
Department of Mathematics and Natural Sciences, College of Sciences and
Human Studies, Deanship of Research Development, Prince Mohammad
Bin Fahd University, Al Khobar 31952, Kingdom of Saudi Arabia;
2
Department of Mathematics and Natural Sciences, College of Sciences and Human
Studies, Prince Mohammad Bin Fahd University, Al Khobar 31952, Kingdom of
Saudi Arabia; *Corresponding authors: Bimal Krishna Banik, email: bimalbanik10 @
gmail .c om, bbanik @pmu .edu .sa; Aparna Das, email: aparnadasam @gmail . com
2
8.1 Introduction
The β-lactam antibiotics are considered as a key milestone involving antimicrobial chemotherapy
research and application in the world. In fact, life was full of sadness and anxiety before the discovery
of efcient clinically active antibiotics. The role of β-lactams as different types of medicinally important compounds is extensively documented in this book. It is amazing that the four-membered ring has
also been exploited extensively as building materials for the preparation of many other compounds of
considerable biological and medicinal interests. In this chapter, we describe the use of β-lactams as the
starting materials for the preparation of various biologically active heterocyclic systems in chiral and
achiral forms.
8.2 Significance
A variety of β-lactams have been thoroughly explored in the synthesis of diverse racemic and optically
active heterocycles.1, 2 The strain in the four-membered ring of the β-lactams makes this skeleton reactive
toward cleavage of a specic bond. The specic bond breakage of the 2-azetidinone ring and subsequent
transformations of the intermediates produce interesting structural skeletons. Many compounds, for
example, α-amino acids, β-amino acids, indolizidines, bis-γ-lactam pyrrolizidines, eight-membered lactams, pyrrolidines, piperidines, enaminones, pyridones, oxazines, and oxazinones are obtained through
substituted β-lactams as the synthetic starting materials by chemical manipulations.
8.3 Different Bond Cleavage Reactions in β-Lactam System:
Synthesis of Biologically Active Compounds
The β-lactam ring underwent a variety of bond cleavages in the presence of other reactants because of
the high reactivity of the four-membered ring system (Figure 8.1). These ring-opening processes were
highly specic and spontaneous, and they produced diverse highly signicant compounds.
8.3.1 N1–C2 Bond Cleavage
Synthesis of natural enantiomer of medicinally active compounds is an attractive target. In many
instances, the synthesis of the nonnatural enantiomeric form is required for a comparative investigation.
DOI: 10.1201/9780367816339-8
243
244 Chemistry and Biology of Beta-Lactams
N1-C2 cleavage
C3-C4 cleavage
e
C2-C3 cleavag
HO
4
3
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OH
C4-N1 cleavag
HO
ii)
HO
H
H
H
NHBoc
OO
iii)
R
H
e
FIGURE 8.1 Diverse bond cleavage in β-lactam: four possibilities.
OO
H
H
H
HO
H
N
O
=
R
C
2
i) LiAlH
iii) NaIO
SCHEME 8.1 Synthesis of (-)-polyoxamic acid.
Ph
CH
OC(Ph)
2
OO H
H
H
NHBoc
; ii) a) Pd-C, HCO2NH4;b) NaOH, Boc2O;
4
, CH3CN, CCL4, RuCl
i)
R
3
R
iv)
H
HO
HN
HO
H
HO2C
R
H2N
iv) TFA, MeOH.
;
N
O
H
OO
H
R
H
Ph
R
OH
R
H
OH
H
Our exploratory research on β-lactams uses diverse carbohydrates. This endeavor culminated in the
synthesis of nonnatural enantiomer of biologically active polyoxamic acid through N1–C2 bond ssion
of β-lactam nucleus. An optically pure cis-α-hydroxy-β-lactams of predictable absolute conguration
was used for this synthesis considering the stereochemistry of the nal compounds (Scheme 8.1). The
starting β-lactam was synthesized via cycloaddition reaction of Schiff base obtained from a homochiral
aldose derived from mannitol and an achiral amine (for example, benzylamine) with benzyloxyacetyl
acid chloride.3 This synthesis was a multistep process, and these involve several protection–deprotection
steps. During the synthesis, effective catalytic transfer hydrogenation of N-benzyl and O-benzyl group
was realized. The knowledge captured during the synthesis was helpful to identify the precursors for the
natural isomer of polyoxamic acid.
In addition, a successful synthesis of this compound is helpful to identify effective routes for the
preparation of other natural and nonnatural amino acids and alkaloids. The ring cleavage of β-lactam
was conducted using excess lithium aluminum hydride under reux to produce the benzyl-protected
amino alcohol in excellent yield. Then Pd/ammonium formate-induced debenzylation (catalytic transfer hydrogenation) followed by a Boc protection of the amine gave protected amino alcohol. Sodium
periodate-induced oxidation of the diol produced the acid. A treatment by the strong acid Triuoroacetic
Acid (TFA) was helpful for the removal of all the protective groups to obtain the desired unnatural enantiomer of polyoxamic acid in excellent yield.
An efcient synthetic pathway4 toward the preparation of bis-γ-lactone, starting from a stereodened
bis-β-lactam, was available. The cycloaddition was highly specic and afforded substituted single dia-
stereomer of cis–cis-C4–C4’-bis-β-lactams. Bis-β-lactams on base-catalyzed rearrangement through a
ring expansion method afforded fused trans–trans-bis-γ-lactams (Scheme 8.2).
An initial bond breakage of bis-β-lactams by methoxide anion and an intramolecular ring-opening pro-
cess afforded the monocyclic β-lactams selectively. Finally, a ring closure took place by a further nucleophilic attack of nitrogen on ester carbonyl group to afford the product in excellent yield (Scheme 8.3).
O
H
Me
H
i) NaB
H H
R
2
O
O
1
i)
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1
R
N PMP
N
PMP
O
PMP = 4-methoxy phenyl
R2CH2COCl, Et3N; ii) MeONa.
SCHEME 8.2 Synthesis of bis-γ-lactams.
245Beta-Lactams as Synthons for Diverse Heterocycles
PMP
R
H
H H
i)
1
R
O
N
H
PMP
N
PMP
ii)
O
PMP
N
N
H
2
R
R
H
N
3
R
H
N
1
R
Ar
OMe
O
H
2
SCHEME 8.3 Formation of bis-γ-lactams.
2
1
R
R
OCHO
N
PMP
O
ii)
1
2
R
PMPHN
R
CHO
O
H4; ii) NaOH.
R
H
O
N
2
R
H
O
N
1
R
Ar
i)
3
R
H
1
Ar
R
H
H
R
N
O
2
1
R
R
N
3
H
OH
O
OMe
Me
O
O
R
H
O
PMPHN
H
2
N
PMP
O
2
R
H
N
2
3
R
H
1
Ar
R
NH
O
O
H
H
Ar
N
3
R
N
1
R
1
2
R
R
O
H
O
O
1
2
R
R
PMPHN
OH
O
SCHEME 8.4 Preparation of β-hydroxy amides and β -formyl amides.
Alcaide et al. disclosed the conversion of optically active 4-(formyloxy)-β-lactams into α-substituted-
β-hydroxy amides and β-formyl amides. This reaction suggested the importance of using structurally
dened β-lactams for the synthesis of nal products with a desired conguration. Sodium borohydride-
induced reduction of 4-(formyloxy)-β-lactams gave the α-substituted β-hydroxy amides. On reduction,
the formyloxy group gave α-formyl amides, tautomer of 4-hydroxy-β-lactams. This compound was
formed because of a reduction reaction due to the cleavage of N1–C2 bond (Scheme 8.4).5 β-Formyl
amides were obtained in good yield by sodium hydroxide treatment.
Synthesis of enaminones was conducted with sodium carbonate in methanol treatment on β-lactams
through an efcient ring enlargement reaction (Scheme 8.5).6 This was done by the selective cleavage of
the N1–C2 bond (Scheme 8.6).
Mechanistically, an E1 elimination and a ring-opening process followed by a trans-esterication reaction were responsible to produce the nal product, a ve-membered lactone (Scheme 8.6). An alternative
route indicated intramolecular lactonization process by the unstable hemiacetal.
246 Chemistry and Biology of Beta-Lactams
O
OMe
i) Na
O
O
R
3
R
3
OMe
Me
H
i) dipolarophile, AgOAc, Et3N; ii) HCl, 2-propanol; iii) HCl, MeOH.
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2
1
R
R
O
3
R
H
N
4
R
CO3, MeOH.
2
i)
SCHEME 8.5 Synthesis of enaminones.
2
1
R
R
3
R
Na
CO
2
H
N
4
R
3
2
1
R
R
N
O
2
R
O
O
SCHEME 8.6 Mechanism for the formation of enaminones.
R
NHR
R
OMe
2
R
O
O
4
4
NHR
3
R
O
2
R
O
O
N
4
R
MeOH
OH
4
3
R
4
3
R2NHR
O
OMe
MeO2C
H H
1
R
NCHCO
N
PMP
O
Me
2
2
R
i)
1
R
O
H
2
H
H
N
R
Me
CO
N
H
H
2
PMP
ii)
PMP
H H
1
R
H
O
N
H
N
O
Me
CO
2
2
R
PMPHN
H
1
R
H
H
N
O
CO
R
H
CO
2
Me
2
Me
2
MeO2C
H
H
1
R
+
H
N
PMP
O
PMPHN
H
1
R
H
O
2
R
CO
or
H
R
2
iii)
CO
CO
2
Me
2
Me
2
N
H
ii)
H
N
SCHEME 8.7 Synthesis of pyrrolizidines.
Pyrrolizidine alkaloids are biologically active naturally occurring compounds, found in plants and
insects. Therefore, synthesis of these types of compounds remains a challenge. The reaction of preformed aldimines with dipolarophile in the presence of silver acetate/triethylamine produced the pyrrolidine-based β-lactams selectively. Subsequently, these were converted to bi- and tricyclic pyrrolizidine
systems upon a reaction with hydrochloric acid through a β-lactam ring-opening reaction (Scheme 8.7).
A 3-unsubstituted-4-acyloxy-β-lactam was converted into 2-substituted 1,3-oxazin-6-one system by
treatment with acyl chlorides and DBU (Scheme 8.8).
8
7
247Beta-Lactams as Synthons for Diverse Heterocycles
O
O
i)
O
O
O
O
O
O
i) Sm
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O
1
R
NH
O
R2COCl, DBU, CH2Cl2.
SCHEME 8.8 Preparation of 1,3-oxazin-6-ones.
O
NH
SCHEME 8.9 Mechanism for the formation of 1,3-oxazin-6 -ones.
SCHEME 8.10 Synthesis of bridged δ-lactone proline derivatives.
2
R
COCl
1
R
O
EtO2C
I2, THF; ii) SmI2, tBuOH, THF.
O
N
O
H
O
N
Z
i)
DBU
1
R
2
R
or
i)
ii)
2
R
R
HN
EtO2C
N
O
N
.
2
O
O
O
H
N
2
R
O
The reaction proceeded through an electrocyclic ring opening through the N1–C2 bond cleavage followed by an electrocyclic ring closure (Scheme 8.9).
A samarium diiodide-induced transformation of 4-substituted β-lactams to the bridged δ-lactone, a
proline derivative, involving N1–C2 bond cleavage was reported10 (Scheme 8.10). It seemed that the reaction is not dependent on the nature of the solvents.
Indolizidine alkaloids have received attention of scientists due to their diverse pharmaceutical
signicances.
These types of molecules were prepared using β-lactams as starting materials. The reaction10 between
the 2-azetidinone-bound aryl imines and cyclopentadiene, catalyzed by indium trichloride, produced
the desired diastereomers in equal amounts (Scheme 8.11). Tetracyclic indolizidinones were obtained
through sodium methoxide-induced rearrangement reaction. A fused tricyclic tetrahydroquinoline
underwent PTSA-catalyzed cyclization to give tetracyclic system in excellent yield.
A γ-lactam was prepared efciently through intramolecular transamidation of a precursor amino compound, which was obtained from 4-methoxycarbonyl-3-vinyl-2-azetidinone (Scheme 8.12).11 A nucleophilic reaction by the primary amino group to the β-lactam carbonyl was involved in this process.
The uracil derivative was obtained12 involving reduction of a compound with sodium borohydride to
obtain the acyclic ureide with cis-stereochemistry. A subsequent sulfuric acid-mediated ring closure of
the primary alcohol was done leading to the desired uracil derivative in good yield (Scheme 8.13).
A few enantiopure 2,3-aziridino-γ-lactones were synthesized14 from mesylated 3-hydroxy β-lactams.
An acid-catalyzed intramolecular azetidinone ring opening followed by aziridine ring cyclization
through elimination of a mesylate was involved in the entire process (Scheme 8.14). The alcohol group
initiated the reaction upon protonation process.
Suitably substituted 4-(haloalkyl)azetidin-2-ones were a building block in organic synthesis by a
selective cleavage of the β-lactam ring.
4-(1-Chloroalkyl)-2-azetidinones and 4-(2-bromoalkyl)-2-azetidinones underwent efcient ring opening upon treatment with sodium methoxide base, to produce methyl 2-alkoxy-4-(alkylamino)-pentenoates
248 Chemistry and Biology of Beta-Lactams
MeO
OMe
3
BOMO
i) a) Ca(BH
4)2
.
O
HO
O
i) MeOCH=CHCONCO;
Ms
HO
R
1
2
i) HCl-MeOH.
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H H
O
PMPHN
i) InCl
PMP
N
+
N
PMP
H
H
N
H
MeO
, MeCN; ii) MeONa, MeOH; iii) PTSA, toluene.
O
i)
OMe
iii)
SCHEME 8.11 Synthesis of indolizidines.
H H
CO
2
Me
i)
N
PMP
O
NH
PMPHN
2
H H
O
MeO
MeO
N
O
PMP
H H
N
H
H
CO
OBOM
H
H
PMP
H
N
H
Me
2
H
OMe
H
N
H
ii)
+
OMe
PMPHN
PMP
HN
MeO
H
MeO
O
H H
H
H
H
N
H
H
N
PMP
ii)
OMe
H
N
O
ii)
O
N
H
; b) BOMCl, DIPEA; c) 9-BBN, THF, H2O2; d) MsCl, Et3N; e) NaN3; f) PPh3; ii) EtOH
SCHEME 8.12 Synthesis of γ-lactam.
O
NH
i)
O
MeO
ii) NaBH4; iii) H2SO4.
SCHEME 8.13 Synthesis of uracil derivatives.
SCHEME 8.14 Synthesis of 2,3-aziridino-γ-lactones.
O
NH
N
O
HO
NH
ii)
HN
iii)
O
O
H
NH
N
MeO
O
2
R
N
i)
N
1
R
O
O
R
O
249Beta-Lactams as Synthons for Diverse Heterocycles
R
Cl
OH
NHPMP
O
R
R
OH
Me
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and methyl 5-(alkylamino)-pentenoates, respectively (Scheme 8.15).13 The reaction took place via an
N1–C2 bond cleavage followed by an intramolecular nucleophilic substitution reaction to form azaheterocyclic intermediate, followed by a base-mediated elimination reaction to the nal products.
The application of N1–C2 bond ssion of β-lactam was demonstrated through a stereocontrolled syn-
thesis15 of 3,5-dialkyl and 3,4,5-trialkyl-4-aminopyrrolidinones from substituted azetidinones via a reaction with alcoholic hydrochloric acid (Scheme 8.16). The group at the C4 position of the β-lactam ring
was not stable under acidic conditions.
A reaction of 3-allyl-4-formyl-2-azetidinone with N-methylhydroxylamine produced the hydroxylamino nitrone (Scheme 8.17).16 The alkene and the aldehyde reacted to form an intermediate. This compound underwent intramolecular transesterication to an opened complex product, oxazinone nitrone.
Ban17 reported the synthesis of tricyclic cycloaromatized product through the intramolecular transamidation in bicyclic 2-azetidinone using cyclohexadiene (Scheme 8.18). A cleavage of the β-lactam
bond was responsible for the success of this reaction.
MeO
MeO
O
2
OR
O
2
OR
2
O
N
R
O
2
R
O
i)
1
Br
i)
N
1
R
O
i) MeONa.
SCHEME 8.15 Synthesis of alkylamino pentenoates.
O
2
Boc
Boc
N
O
HH
N
i)
R
O
Bn
N
O
HH
N
1
Ph
i)
O
NHBn
N
H
2
NHR
R
N
H
Ph
H
N
R
OH
1
OH
R
N
H
1
1
R
MeO
Et
O
i) and ii) HCl.
R
Boc
2
O
O
O
OR
N
HH
N
X
( )
n
NaOMe
N
1
R
MeOH
2
R
O
O
OMe
OMe
2
R
O
n
NHR
1
( )
2
O
O
R
Et
ii)
O
N
H
HN
H
OMe
X
n
( )
1
R
n
( )
N
1
R
PMP
SCHEME 8.16 Synthesis of alkyl-4-aminopyrrolidinones.
SCHEME 8.17 Synthesis of oxazinone nitrone.
H H
CHO
i)
N
PMP
O
i) MeNHOH.HCl; ii) CHCl3.
Me
O
H H
N
Me
PMP
Me
N
O
ii)
Me
Me
N
H
NHPMP
N
O
O
O
250 Chemistry and Biology of Beta-Lactams
O
OTBS
i) THF, 1.4-cyclohexadiene.
R
1
O
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A reaction of the haloalkyl-2-azetidinones with lithium aluminum hydride resulted in N1–C2 bond
cleavage of the β-lactam ring system, and this was followed by an intramolecular nucleophilic substitution of the halogen to form alkoxy-hydroxyethyl-aziridines.18 A further treatment with aluminum chloride trans-tetrahydrofuran was obtained. Aluminum chloride was capable of doing coordination with
nitrogen making the C–N bond unstable. A ring ssion was followed due to intramolecular nucleophilic
reaction by alcohol, leading to the formation of a cyclic amino ether (Scheme 8.19).
A ring opening of spiro-β-lactams using potassium cyanide led to the formation of β-amino esters, and
this reaction was possible due to an efcient nucleophilic pathway. The desired proline-based polypeptide was obtained through a series of chemical transformations (Scheme 8.20).
20
A few pyrrole derivatives were synthesized19 from substituted β-lactams tethered to allene. The ring
opening by sodium methoxide followed by intramolecular nucleophilic reaction on the electrophilic
allene center afforded the pyrrolines in good yields (Scheme 8.21). The pyrrolines were nally able to
aromatize to the pyrroles efciently by eliminating methanol.
Hydrogenolysis of 3-benzyloxy-azetidin-2-ones using palladium on activated carbon produced the
corresponding cis-3-hydroxy-β-lactams. This underwent triethylamine-mediated ring cyclization to
afford the cis-6-aza-2-oxabicyclo[3.2.0]heptan-7-ones (Scheme 8.22).21 3-Aminotetrahydrofuran derivative was obtained through a ring opening of bicyclic cis-β-lactams by means of hydrochloric acid.
OTBS
i)
NH
OTBS
O
N
NH
2
N
H
O
NH
N
H
SCHEME 8.18 Preparation of tricyclic cycloaromatized compound.
2
O
O
i) LiAlH4; ii) AlCl3.
2
R
O
O
AlH
Cl
i)
N
1
R
H
2
R
O
HO
Cl
N
1
R
3
2
R
O
O
AlH
1
N
R
ii)
Cl
Li
N
1
R
3
R
2
R
O
O
AlH
O
R
Li
1
NHR
Cl
1
NHOR
H
2
R
O
2
O
N
3
O
NHR
1
2
R
SCHEME 8.19 Synthesis of trans-tetrahydrofurans.
251Beta-Lactams as Synthons for Diverse Heterocycles
R
NHBoc
O
i) KCN, MeOH.
OMe
Ph
Me
i) MeONa, MeOH.
Bn
NHR
3
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An efcient synthesis of cyclic peptides was accomplished using substituted β-lactams.22 The key step
was an intramolecular nucleophilic ring opening of β-lactam by the free amine group of the amino acid
(Scheme 8.23).
An efcient strategy toward the synthesis of aminomethyl-butyrolactones using β-lactams was
reported.23 The base-induced ring opening of β-lactams followed by acid-induced lactonization of
hydroxyethyl-substituted β-lactams was involved in furnishing α-aminomethyl-γ-butyrolactones
(Scheme 8.24).
Racemic chloro-substituted β-lactams on reaction with sodium cyanide/methanol afforded ve-membered piperidine derivatives. The cyanide ion attacked the carbonyl group of the β-lactam ring, and the
resulting reactive species with a negative charge at the nitrogen displaced the chlorine (Scheme 8.25).
25
Optically active β-lactams were converted to chiral ve-membered lactones by treatment with triuoroacetic acid. The ketal ring was opened rst. The secondary hydroxyl group attacked the carbonyl of
the ring through a nucleophilic pathway, and it helped to form the lactone (Scheme 8.26).24 There was no
change of any stereocenters during this process.
Oxazines were prepared by the reduction of aryl nitro groups in β-lactams using indium metal and
ammonium chloride. The generated aromatic amine on nucleophilic ring-opening reaction afforded oxazine (Scheme 8.27).
26
N
N
Boc
O
SCHEME 8.20 Preparation of proline polypeptides.
SCHEME 8.21 Synthesis of pyrrole derivatives.
i)
MeO2C
RN
MeO2C
NHBoc
R3H
2
R
N
1
R
O
i)
OMe
R3H
2
R
N
1
R
Ph
Ph
.
O
Ph
Me
N
RN
H
n
R
R
R
2
MeO
R
2
N
RN
H
3
N
1
R
-MeOH
3
N
1
R
MeO2C
RN
.
i)
MeO2C
H
MeO2C
SCHEME 8.22 Synthesis of 3-aminotetrahydrofuran-2-carboxylate.
O
O
i) a) 10% Pd/C; b) Et
Br
N
R
i)
O
H H
O
N; ii) HCl, MeOH.
ii)
O
N
R
MeO
O
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