Three-component Staudinger-type stereoselective synthesis of C-glycosyl-β-lactams and their use as precursors for C-glycosyl isoserines and dipeptides. A polymer-assisted solution-phase approach

Article abstract of DOI:10.1002/adsc.200404100

A collection of 4-(C-galactosyl)- and 4-(C-ribosyl)-β-lactams featuring different substituents at C-3 and N-1 was prepared by combining in a one-pot procedure a formyl C-glycoside, a primary amine, and a substituted acetyl chloride in the presence of base

Full text of DOI:10.1002/adsc.200404100

FULL PAPERS
Three-Component Staudinger-Type Stereoselective Synthesis of
C-Glycosyl-b-lactams and their Use as Precursors for C-Glycosyl
Isoserines and Dipeptides. A Polymer-Assisted Solution-Phase
Approach
Alessandro Dondoni,a,* Alessandro Massi,a Simona Sabbatini,a Valerio Bertolasib
a
`
Laboratorio di Chimica Organica, Dipartimento di Chimica, Universita di Ferrara, Via L.Borsari 46, 44100 Ferrara, Italy
Fax: (þ39)-0532-291167, e-mail: adn@dns.unife.it
b
`
Centro di Strutturistica Diffrattometrica, Dipartimento di Chimica, Universita di Ferrara, Via L.Borsari 46,
44100 Ferrara, Italy
Received: April 2, 2004; Accepted: June 25, 2004
th
Dedicated to Professor J.Mulzer on the occasion of his 60 birthday.
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A collection of 4-(C-galactosyl)- and 4-(C- formed into C-glycosyl-N-Boc-b-amino-a-hydroxy es-
ribosyl)-b-lactams featuring different substituents at ters (C-glycosyl isoserines) and a C-ribosyl dipeptide
C-3 and N-1 was prepared by combining in a one- via base-promoted heterocycle ring opening by meth-
pot procedure a formyl C-glycoside, a primary amine, anol and l-phenylalanine methyl ester, respectively.
and a substituted acetyl chloride in the presence of
base (Staudinger-type reaction).Sulfonyl chloride
and aminomethylated resins were used in sequence Keywords: [2þ2] cycloaddition; C-glycosides; C-gly-
to remove excess of components and by-products. cosyl amino acids; b-lactams; multicomponent reac-
Two pure C-glycosyl-b-lactams were effectively trans- tion
Introduction
tigen, human cytomegalovirus protease, thrombin, hu-
man leukocyte elastase, cholesterol absorption, and b-
In the course of our study on stereoselective multicom- lactamase.[4] Another aspect underlying the importance
ponent reactions (SMCRs) as a tool for the rapid con- of b-lactams in the strictly related domains of organic
struction of chiral heterocycle C-glycoconjugate sys- synthesis and medicinal chemistry is their application
tems with improved or new biological properties,[1] we to the synthesis of other classes of biologically active
became interested in the synthesis of 4-(C-glycosyl)-2- compounds, especially densely functionalized b-amino
azetidinones IV, i.e., anomerically coupled sugar/b-lac- acids, via the so-called b-lactam synthon methodology
tam constructs (Figure 1).It is worth mentioning that
(b-LSM).[5] Hence, we were spurred to develop a chemi-
the b-lactam skeleton is the key structural motif of sev- cally effective and operatively simple entry to the hither-
eral classes of antibiotics[2,3] such as penicillins, cephalo- to unreported class[6] of b-lactam C-glycoconjugates IV
sporins, thienamycins, and various monobactams, whose bearing the substituents R, R’, and the sugar moiety as
potency as inhibitors of different bacteria including the elements of diversity, with the hope that these com-
widely diffused Staphylococcus aureus, has been con- pounds would display new biological properties and
veniently exploited for more than sixty years.Unfortu-
serve as precursors for C-glycosyl-b-amino acids and/
nately, the longstanding use and abuse of these antibiot- or unnatural glycopeptides.
ics have lead to the emergence of bacterial strain resist-
ance to these drugs so that the design and synthesis of
new families of b-lactam-containing molecules are being Results and Discussion
actively pursued.There is also a renewed interest in b-
lactam derivatives, especially synthetic products, as Since the Staudinger [2þ2] imine-ketene cycloaddition
non-antibiotic agents since compounds of this type is by far the most versatile and simplest entry to the b-
have been shown to be inhibitors of prostate-specific an- lactam system,[7] we envisaged the synthesis of IV by
Adv. Synth. Catal. 2004, 346, 1355–1360
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Alessandro Dondoni et al.
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combining reagents which could generate in situ the
above cycloaddition partners, thus giving rise to a one-
pot, multicomponent reaction system.To this aim, the
starting materials were easily identified as the commer-
cially available substituted acetyl chlorides III and pri-
mary amines II as well as the readily available anomeric
sugar aldehydes (formyl C-glycosides, I).[8]
According to the above synthetic plan, a chiral C-gly-
cosylimine was generated in CH2Cl2 by mixing the b-C-
galactosyl formaldehyde[8] 1 with an excess (1.5 equivs.)
of p-methoxybenzylamine (R1 ¼PMB) (Scheme 1).
These unusual reaction conditions[9] ensured the com-
plete consumption of the most costly reagent 1.The un-
reacted alkylamine was easily removed from the solu-
tion by treatment with resin-supported sulfonyl chlor-
ide.The resulting heterogeneous mixturewas then treat-
ed with (acetoxy)acetyl chloride (R2 ¼Ac) (3.5 equivs.)
and triethylamine (6 equivs.) to produce the correspond-
ing acetoxy ketene.[10] After a suitable period of time
(see Experimental Section) the reaction mixture was
Scheme 1. Reagents and conditions: (i) R1NH2 (1.5 equivs.),
4 Š MS, CH2Cl2, 08C, 1 h, then polymer-bound sulfonyl
chloride, 08C, 45 min; (ii) Et3N (6.0 equivs.), (a-oxy)acetyl
chloride (3.5 equivs.), CH2Cl2, ꢀ508C to r.t., 12 h, then ami-
nomethylated polystyrene, r.t., 4 h.
treated with nucleophilic aminomethylated resin which yield (Scheme 2).Subsequent oxidative b-lactam ring
served to remove the excess of ketene and its unreacted enlargement to the a-amino acid N-carboxy anhydride
precursor acetyl chloride, as well as the acid arising from (NCA) 6, followed by ring opening by methanol, and fi-
decomposition of the latter.Furthermore, the same res-
nal switching of the nitrogen protective group yielded
in allowed the sequestering of aldehyde 1 which resulted the a-amino ester 8.This compound was proved to be
from the partial hydrolysis of the C-galactosyl imine. identical in all respects (NMR spectra and optical rota-
Simple work-up (filtration and washing with water) of tion value) to known (2S)-N-Boc-C-galactosylglycine
the resulting suspension and solvent evaporation afford- methyl ester previously synthesized in our laboratory.[11]
ed a mixture of 4-(C-galactosyl)-b-lactams (3R,4S)-3a
Next, following the above optimized cyclocondensa-
and (3S,4R)-3a (for yield and ratio, see Table 1), slightly tion protocol, also the C-ribosyl formaldehyde[8] 2 was
contaminated by the carboxylic acid amide [AcOCH2 effectively transformed (see Table 1) into the corre-
C(O)NHPMB].The major stereoisomer (3 R,4S)-3a sponding4-(C-ribosyl)-b-lactam (3R,4S)-4a(Scheme 1).
shown in Scheme 1 was isolated in the pure state by
chromatography.
While the conservation of the b-linkage at the anome-
ric carbon of the sugar moiety and the cis-relationship of
the C3 and C4 protons of the b-lactam ring were easily
established by 1H NMR analysis, the absolute configura-
tion of the latter carbon atom was assigned by chemical
correlation of (3R,4S)-3a with a known compound.
Thus, following the same reaction sequence described
by Palomo and co-workers,[6] removal of the O-acetyl
group from (3R,4S)-3a afforded 5 in almost quantitative
Scheme 2. Reagents and conditions: (i) LiOH (2.0 equivs.),
30% H2O2 (6.0 equivs.), THF-H2O (3:1), 08C, 2 h; (ii) TEM-
PO (1.0 equiv.), NaOCl, KBr, buffer phosphate solution,
CH2Cl2, 08C, 15 min; (iii) MeOH, 508C, 8 h; (iv) Boc2O
Figure 1. Reagents I – III for a multicomponent synthesis of
C-glycosyl-b-lactams IV.
(2.0 equivs.), dioxane, r.t. 24 h; then CAN (3.0 equivs.),
MeCN-H2O (4:1), r.t., 2 h.
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The structure of this product was established by X-ray This reaction afforded the C-galactosyl isoserine methyl
crystallography of the C3-OH-free derivative (see Sup- ester 10 in excellent isolated yield.No evidence of the
porting Information).[12] Other reactions were carried presence of the C2 epimer was provided by NMR anal-
out using the above anomeric sugar aldehydes 1 and 2 ysis of the crude reaction mixture.In the same way com-
and various pairs of primary amine and (alkoxy)acetyl pound (3R,4S)-4b was transformed into the correspond-
chloride.In this way a small collection of ten 4-( C-glyco- ing ester 12 in high yield and without the formation of
syl)-b-lactams 3a – g and 4a – c was prepared in satisfac- the C2 epimer.In the same vein, another important
tory yields and selectivities (Table 1).Suitable protec-
transformation of (3R,4S)-4b was demonstrated to oc-
tive groups were introduced at N1 and C3 of the b-lac- cur efficiently.In fact, b-lactams are known to be direct
tam ring in view of the elaboration of these compounds precursors for dipeptides containing b-amino-a-hy-
toward fully deprotected systems for biological assays[13] droxy acid fragments upon coupling with a-amino es-
and open-chain products via the b-LSM.[5] It is worth ters.[15] Accordingly, treatment of the N-Boc protected
pointing out that the use of polymer-bound reagents is derivative 11 with l-phenylalanine methyl ester in the
central to the effectiveness of this solution-phase chem- presence of DMAP afforded the C-ribosyl dipeptide
istry.Their important function consists in removing the
excess of reactants employed to draw key-steps to com-
pletion, thus allowing a one-pot, two-step, three-compo-
13 in excellent yield.
nent reaction to be carried out efficiently and enabling Conclusion
the facile isolation of the final product(s) in an almost
pure state.
This explorative work on the potential of 4-(C-glycosyl)-
Within the concept of b-LSM,[5] the ring opening of 3- b-lactams as precursors for unnatural C-glycosylamino
alkoxy-b-lactams to give b-amino-a-hydroxy esters (iso- acids and small peptides needs further research.In our
serines) has been amply demonstrated.[5b] Accordingly, laboratory this is being intensely pursued by addressing
4-(C-glycosyl)-b-lactams were envisaged as precursors different modifications of the b-lactam ring and im-
for a new family of C-glycosylamino acids, i.e., C-glyco- proved reaction conditions towards a fully automatized
syl isoserines, and artificial glycopeptides.Examples of
procedure suitable for parallel syntheses.The glycocon-
these transformations were carried out starting from ap- jugate library generation by combinatorial strategies [16]
propriate N- and O-protected galactosyl and ribosyl de- is, in fact, one of the topics of major interest in modern
rivatives (3R,4S)-3e and (3R,4S)-4b (Scheme 3).Very
mild conditions were required in the basic alcoholysis
of these b-lactams in order to avoid considerable loss
of the configurational integrity of C3 as well as of the
corresponding carbon atom in the resulting esters.
Hence, taking advantage of the extensive experience
of Palomo and co-workers in this chemistry,[14] the N-
PMP group of (3R,4S)-3e was replaced by N-Boc and
the resulting product 9 was subjected to Et3N and
DMAP-promoted methanolysis at room temperature.
carbohydrate chemistry in the service of glycobiology.
Table 1. 4-C-Glycosylated b-lactams prepared by one-pot,
two-step Staudinger reaction.
Entry
R1
R2
Yield [%][a]
de [%][b]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
PMB
PMB
Bn
Ac
Bn
Ac
Bn
Ac
Bn
Me
Ac
Ac
Bn
94
90
92
88
68
65
75
92
70
68
70
60
70
70
50
20
50
90
88
75
Bn
PMP
PMP
PMB
PMB
PMP
PMP
Scheme 3. Reagents and conditions: (i) CAN (4.5 equivs.),
MeCN-H2O (4:1), ꢀ108C, 2 h; (ii) Boc2O (1.5 equivs.), Et3N
(3.0 equivs.), DMAP (cat.), CH2Cl2 , r.t., 12 h; (iii) Et3N (5.0
equivs.), DMAP (3.0 equivs.), MeOH, r.t., 48 h; (iv) H-Phe-
OMe.HCl (2.0 equivs.), Et3N (4.5 equivs.), DMAP (0.5
equivs.), CH2Cl2, r.t., 48 h.
10
[a]
Overall yield of the mixture of diastereoisomers.
[b]
Diastereomeric excess determined by 1H NMR analysis of
the crude reaction mixture
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1.90 (s, 3H, CH3); 13C NMR: d¼170.0, 162.2, 156.1, 137.7,
137.8, 138.0, 131.0, 129.0–127.0 (m, 15 C), 120.0, 111.9, 81.7,
80.0, 78.8, 77.2, 73.7, 73.0, 72.1, 71.9, 69.8, 59.0, 55.8, 20.3; MAL-
DI-TOF MS: m/z¼638.7 (Mþ þH), 660.5 (Mþ þNa); anal.
calcd.for C 38H39NO8 (637.72): C 71.57, H 6.16, N 2.20; found:
C 71.60, H 6.18, N 2.25.
Experimental Section
General Remarks
All moisture-sensitive reactions were performed under a nitro-
gen atmosphere using oven-dried glassware.Solvents were
dried over standard drying agents and freshly distilled prior
to use.Commercially available powdered 4 Š molecular sieves
(5 mm average particle size) were used without further activa-
Eluted second was (3S,4R)-4b (10 mg, 3%) slightly contami-
nated by (3R,4S)-4b.
tion.Reactions were monitored by TLC on silica gel 60 F
254
with detection by charring with sulfuric acid.Flash column
chromatography was performed on silica gel 60 (230–400
mesh).Optical rotations were measured at 20 ꢁ28C in the stat-
Conversion of the 4-(C-Galactosyl)-b-lactam (3R,4S)-
3a into the (2S)-N-Boc-C-galactosylglycine Methyl
Ester 8
1
ed solvent. H (300 MHz) and 13C (75 MHz) NMR spectra
were recorded for CDCl3 solutions at room temperature unless
otherwise specified.Assignments were aided by homo- and
heteronuclear two-dimensional experiments.MALDI-TOF
mass spectra were acquired using a-cyano-4-hydroxycinnamic
acid as the matrix.
General procedures for all synthetic steps are described here
while characterization data are reported only for representa-
tive ribo derivatives.Aldehydes 1 and 2 were prepared as de-
scribed.[8] The C-galactosylglycine 8 is a known compound.[11]
(3R,4R)-4-(2’,3’,4’,6’-Tetra-O-benzyl-b-d-galactopyranosyl)-
3-hydroxy-1-(4-methoxybenzyl)-azetidin-2-one (5): To
a
cooled (08C), stirred solution of (3R,4S)-3a (386 mg,
0.50 mmol) in THF (3 mL) and H2O (1 mL) were added
LiOH (24 mg, 1.00 mmol), and a 30% solution of H2O2
(0.30 mL, 3.00 mmol). The resulting mixture was stirred at
the same temperature for 2 h, and then diluted with a 1.5 M sol-
ution of Na2S2O3 (5 mL).Most of the THF was removed under
vacuum from the mixture, which was then diluted with CH2Cl2
(100 mL), and washed with saturated aqueous NaHCO3 (3ꢂ
5 mL).The organic layer was dried (Na SO4), concentrated,
2
and eluted from a column of silica gel with 2:1 cyclohexane-
AcOEt to give 5 as a colorless syrup; yield: 346 mg (95%);
[a]D: ꢀ53.3 (c 0.4, CHCl3); 1H NMR (CDCl3 þD2O): d¼
7.40–7.10 and 6.90–6.80 (2 m, 24H, Ph), 4.95 and 4.58 (2d,
2H, J¼11.2 Hz, PhCH2), 4.87 and 4.53 (2d, 2H, J¼11.0 Hz,
PhCH2), 4.73 and 4.61 (2d, 2H, J¼11.8 Hz, PhCH2), 4.52 (d,
1H, J3,4 ¼5.0 Hz, H-3), 4.42 and 4.38 (2d, 2H, J¼12.0 Hz,
PhCH2), 4.30 and 4.22 (2d, 2H, J¼14.0 Hz, PhCH2), 4.14 (dd,
General Procedure for Staudinger Reactions
A mixture of aldehyde 1 or 2 (0.50 mmol), activated 4 Š pow-
dered molecular sieves (200 mg), and anhydrous CH2Cl2
(5 mL) was stirred at room temperature for 15 min and then
cooled to 08C.To the mixture was slowly added the primary
amine (0.75 mmol) and the suspension was stirred for an addi-
tional 1 h.Then polymer-bound sulfonyl chloride (500 mg,
1.00 mmol of a 2.0 mmol gꢀ1 resin) was added in one portion
and the mixture stirred at 08C for 45 min.The mixture was
then cooled to ꢀ508C and Et3N (418 mL, 3.00 mmol) and the
(a-oxy)acetyl chloride (1.75 mmol) were added in this se-
quence.The resulting mixture was stirred overnight at room
temperature and then aminomethylated polystyrene (555 mg,
1.50 mmol of a 2.7 mmol gꢀ1 resin) was added in one portion.
The suspension was stirred for additional 4 h then molecular
sieves and resins were filtered off through a pad of Celite and
washed thoroughly with CH2Cl2.The combined filtrates were
washed with water (3ꢂ15 mL), dried (Na2SO4), concentrated,
and eluted from a column of silica gel with the suitable elution
system to give the corresponding 4-C-glycosyl-b-lactam.
1H, J1’,2’ ¼9.0 Hz, J2’,3’ ¼9.2 Hz, H-2’), 3.96 (dd, 1H, J3’,4’
¼
2.5 Hz, J4’,5’ ~ 0.5 Hz, H-4’), 3.76 (s, 3H, OCH3), 3.75 (dd, 1H,
J4,1’ ¼1.5 Hz, H-4), 3.48 (dd, 1H, H-3’), 3.47 (dd, 1H, J5’,6’a
¼
8.0 Hz, J6’a,6’b ¼9.0 Hz, H-6’a), 3.40 (dd, 1H, J5’,6’b ¼5.0 Hz, H-
6’b), 3.38 (dd, 1H, H-1’), 3.18 (ddd, 1H, H-5’); MALDI-TOF
MS: m/z¼730.5 (Mþ þH), 752.8 (Mþ þNa); anal.calcd.for
C45H47NO8 (729.86): C 74.05, H 6.49, N 1.92; found: C 74.10,
H 6.52, N 1.90.
Methyl 3,7-Anhydro-4,5,6,8-tetra-O-benzyl-2-((4-methox-
ybenzyl)amino)-2-deoxy-d-threo-L-galacto-octanoate (7): To
a stirred solution of 5 (365 mg, 0.50 mmol) in CH2Cl2 (4 mL)
were added 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO;
78 mg, 0.50 mmol), and
a solution of KBr (6.0 mg,
0.05 mmol) in H2O (0.1 mL). The solution was then cooled to
08C, and aqueous NaOCl (5 mL) buffered at pH 7 (by the ad-
dition of 1 M phosphate buffer) was added.The resulting mix-
ture was stirred at the same temperature for an additional
15 min, then diluted with CH2Cl2 (100 mL), and washed with
a 10% solution of HCl (10 mL containing 125 mg of KI), a
10% solution of Na2S2O3 (5 mL), and H2O (5 mL).The organic
layer was dried (Na2SO4), and concentrated to give the a-ami-
no acid N-carboxy anhydride 6 as a crude material; yield:
353 mg (~95%); selected 1H NMR data: d¼7.40–7.10 and
6.90–6.80 (2 m, 24H, Ph), 4.52 and 4.48 (2d, 2H, J¼12.0 Hz,
PhCH2), 4.30 (dd, 1H, J1’,2’ ¼9.0 Hz, J2’,3’ ¼9.2 Hz, H-2’), 4.03
(dd, 1H, J3’,4’ ¼2.5 Hz, J4’,5’ ~ 0.5 Hz, H-4’), 3.80 (s, 3H,
OCH3), 3.70 (dd, 1H, H-3’).
(3R,4S)-3-Acetoxy-4-(2’,3’,5’-tri-O-benzyl-b-d-
ribofuranosyl)-1-(4-methoxyphenyl)-azetidin-2-one
[(3R,4S)-4b]
Column chromatography with 5:2 cyclohexane-AcOEt af-
forded first (3R,4S)-4b; yield: 212 mg (67%) as a yellow syrup;
[a]D: 5. 5 (c 0.9, CHCl3); 1H NMR: d¼7.40–7.20 and 6.80–6.60
(2 m, 19H, Ph), 6.02 (d, 1H, J3,4 ¼5.0 Hz, H-3), 4.57 and 4.53
(2d, 2H, J¼12.0 Hz, PhCH2), 4.56 and 4.29 (2d, 2H, J¼
11.5 Hz, PhCH2), 4.46 (s, 2H, PhCH2), 4.44 (dd, 1H, J4,1’
¼
6.0 Hz, H-4), 4.35 (dd, 1H, J1’,2’ ¼6.2 Hz, H-1’), 4.20 (ddd, 1H,
J3’,4’ ¼5.0 Hz, J 4’,5’a ¼3.5 Hz, J4’,5’b ¼4.5 Hz, H-4’), 3.96 (dd, 1H,
J2’,3’ ¼5.5 Hz, H-3’), 3.88 (dd, 1H, H-2’), 3.74 (s, 3H, OCH3),
3.43 (dd, 1H, J5’a,5’b ¼10.0 Hz, H-5’a), 3.37 (dd, 1H, H-5’b),
A solution of the above crude anhydride 6 (353 mg,
~0.48 mmol) in MeOH (4 mL) was stirred at 508C for 8 h,
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Stereoselective Synthesis of C-Glycosyl-b-lactams and their Use
FULL PAPERS
then cooled to room temperature, and concentrated.The resi-
due was eluted from a column of silica gel with 2.5:1 toluene-i-
Pr2Otogive 7 asa whitefoam;yield:293 mg (80%from 5); [a]D:
19.3 (c 0.7, CHCl3); 1H NMR (C6D6): d¼7.40–7.00 and 6.80–
6.70 (2 m, 24H, Ph), 5.03 and 4.84 (2d, 2H, J¼11.0 Hz,
PhCH2), 4.95 and 4.54 (2d, 2H, J¼11.5 Hz, PhCH2), 4.52 (dd,
1H, J3,4 ¼9.0 Hz, J4.5 ¼9.2 Hz, H-4), 4.35 and 4.31 (2d, 2H, J¼
11.2 Hz, PhCH2), 4.28 and 4.24 (2d, 2H, J¼12.0 Hz, PhCH2),
4.04 (dd, 1H, J2,3 ¼1.5 Hz, H-3), 3.96 (d, 1H, H-2), 3.94 and
3.86 (2d, 2H, J¼13.5 Hz, PhCH2), 3.84 (dd, 1H, J5,6 ¼2.5 Hz,
J6,7 ~ 0.5 Hz, H-6), 3.65 (dd, 1H, J7,8a ¼7.5 Hz, J8a,8b ¼9.0 Hz,
H-8a), 3.59 (dd, 1H, J7.8b ¼5.5 Hz, H-8b), 3.51 (ddd, 1H, H-7),
3.28 (s, 3H, OCH3), 3.26 (s, 3H, OCH3); MALDI-TOF MS:
m/z¼732.9 (Mþ þH), 754.9 (Mþ þNa), anal.calcd.for
C45H49NO8 (731.87): C 73.85, H 6.75, N 1.91; found: C 73.88,
H 6.70, N 1.93.
(3R,4S)-3-Acetoxy-4-(2’,3’,5’-tri-O-benzyl-b-d-ribofurano-
syl)-1-(tert-butoxycarbonyl)-azetidin-2-one (11): Column
chromatography with 5:2 cyclohexane-AcOEt afforded 11 as
a yellow syrup; yield: 291 mg (92%); [a]D: 3. 5 (c 0.9, CHCl3);
1H NMR: d¼7.50–7.20 (m, 15H, Ph), 5.92 (d, 1H, J3,4
¼
6.0 Hz, H-3), 4.62 and 5.57 (2d, 2H, J¼11.0 Hz, PhCH2), 4.59
(s, 2H, PhCH2), 4.55 (s, 2H, PhCH2), 4.46 (dd, 1H, J4,1’
¼
2.0 Hz, H-4), 4.39 (dd, 1H, J2’,3’ ¼5.0 Hz, J1’,2’ ¼7.0 Hz, H-2’),
4.25 (ddd, 1H, J3’,4’ ¼5.5 Hz, J4’,5’a ¼4.5 Hz, J4’,5’b ¼5.5 Hz, H-
4’), 4.10 (dd, 1H, H-1’), 3.92 (dd, 1H, H-3’), 3.55 (dd, 1 H,
J5’a,5’b ¼10.5 Hz, H-5’a), 3.43 (dd, 1H, H-5’b), 2.10 (s, 3H,
CH3), 1.42 (s, 9H, t-Bu); MALDI-TOF MS: m/z¼632.5 (Mþ
þH), 654.5 (Mþ þNa), 670.3 (Mþ þK); anal.calcd.for
C36H41NO9 (631.71): C 68.45, H 6.54, N 2.22; found: C 68.48,
H 6.55, N 2.25.
Methyl 3,7-Anhydro-4,5,6,8-tetra-O-benzyl-2-[(tert-butoxy-
carbonyl)amino]-2-deoxy-d-threo-L-galacto-octanoate (8):
To a stirred solution of 7 (73 mg, 0.10 mmol) in dioxane
(2 mL) was added di-tert-butyl dicarbonate (Boc2O) (44 mg,
0.20 mmol) in one portion. The solution was stirred at room
temperature for 24 h, and then concentrated.The residue
was suspended with CH2Cl2 (50 mL) and washed with a 10%
solution of citric acid (2ꢂ5 mL).The organic layer was dried
(Na2SO4), and concentrated to give a ~1:1 mixture of the start-
ing amino ester 7 and its N-Boc derivative.
To a stirred solution of the above crude mixture in MeCN
(2 mL) and H2O (0.5 mL) was added ceric ammonium nitrate
(CAN) (164 mg, 0.30 mmol) in one portion. The resulting mix-
ture was vigorously stirred at room temperature for 2 h, and
then neutralized with a few drops of Et3N.Most of the
MeCN was removed under vacuum from the mixture, which
was then diluted with CH2Cl2 (50 mL) and washed with a
10% solution of Na2S2O3 (5 mL), and brine (5 mL).The organ-
ic layer was dried (Na2SO4), concentrated, and eluted from a
column of silica gel with 1.5:1 toluene-i-Pr2O to give 8 as an
oil; yield: 36 mg (50% from 7); [a]D: ꢀ3.0 (c 1.2, CHCl3);
lit.[11] [a]D: ꢀ2.6 (c 1.2, CHCl3).
General Procedure for the Synthesis of C-Glycosyl-N-
Boc-b-amino-a-hydroxy Esters
To
a
stirred solution of 3-acetoxy-1-N-Boc-b-lactam
(0.20 mmol) and DMAP (73 mg, 0.60 mmol) in CH3OH
(5 mL) was slowly added Et3N (139 mL, 1.00 mmol) at room
temperature.The mixture was stirred at room temperature
for 48 h, then the solvent was removed under reduced pressure
and aqueous saturated NH4Cl solution (8 mL) was added.The
reaction mixture was then extracted with CH2Cl2 (3ꢂ20 mL),
and the combined extracts were dried (Na2SO4), concentrated,
and eluted from a column of silica gel with the suitable elution
system to give the corresponding C-glycosyl-N-Boc-b-amino-
a-hydroxy methyl ester.
(2R,3R)-3-(2’,3’,5’-Tri-O-benzyl-b-d-ribofuranosyl)-3-tert-
butoxycarbonylamino-2-hydroxypropionic acid methyl ester
(12): Column chromatography with 2:1 cyclohexane-AcOEt
afforded 12 as a yellow foam; yield: 117 mg (94%); [a]D:
1
ꢀ16.5 (c 0.4, CHCl3); H NMR: d¼7.50–7.20 (m, 15H, Ph),
5.65 (d, 1H, J3,NH ¼10.0 Hz, NH), 4.62 and 4.55 (2d, 2H, J¼
10.5 Hz, PhCH2), 4.58 and 4.44 (2d, 2H, J¼12.0 Hz, PhCH2),
4.53 and 4.44 (2d, 2H, J¼11.5 Hz, PhCH2), 4.40 (d, 1H, J2,3
¼
3.5 Hz, H-2), 4.35 (dd, 1H, J1’,2’ ¼6.0 Hz, J3,1’ ¼3.0 Hz, H-1’),
4.27 (ddd, 1H, H-3), 4.17 (ddd, 1H, J3’,4’ ¼5.0 Hz, J4’,5’a
3.5 Hz, J4’,5’b ¼3.0 Hz, H-4’), 3.95 (dd, 1H, J2’,3’ ¼5.0 Hz, H-2’),
3.90 (dd, 1H, H-3’), 3.78 (s, 3H, OCH3), 3.55 (dd, 1H, J5’a,5’b
¼
General Procedure for the Preparation of 3-Acetoxy-
1-N-Boc-b-lactams
¼
10.0 Hz, H-5’a), 3.41 (dd, 1H, H-5’b), 3.30 (bs, 1H, OH), 1.42
(s, 9H, t-Bu); MALDI-TOF MS: m/z¼622.5 (Mþ þH), 644.3
(Mþ þNa), 660.8 (Mþ þK); anal.calcd for C 35H43NO9
(621.72): C 67.62, H 6.97, N 2.25; found: C 67.65, H 6.98, N 2.20.
To a cooled (ꢀ108C), stirred solution of N-PMP-b-lactam
(0.50 mmol) in CH3CN (20 mL) and H2O (5 mL) was slowly
added
a solution of ceric ammonium nitrate (1.23 g,
2.25 mmol) in H2O (18 ml).The solution was stirred at
ꢀ108C for 2 h then was quenched with aqueous saturated
Na2SO3 solution (15 mL).The aqueous layer was extracted
with AcOEt (3ꢂ40 mL), and the combined organic layer was
washedwithNa2SO3 solution, dried(Na2SO4), andconcentrated
to give the corresponding N-H-b-lactam as crude material.
To a stirred solution of the above crude N-H-b-lactam
(~0.50 mmol), di-tert-butyl dicarbonate (164 mg, 0.75 mmol),
and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (5.0 mL) was slowly
added Et3N (209 mL, 1.50 mmol) at room temperature. The
mixture was stirred for 18 h at room temperature then
quenched with aqueous saturated NH4Cl solution (15 mL).
The mixture was extracted with AcOEt (3ꢂ30 mL).The com-
bined extracts were dried (Na2SO4), concentrated, and eluted
from a column of silica gel with the suitable elution system to
give the corresponding 1-N-Boc-4-C-glycosyl-b-lactam.
Procedure for the Synthesis of Dipeptide 13
(2S)-2-[(2’R,3’S)-2’-Acetoxy-3’-(2’’,3’’,5’’-tri-O-benzyl-b-d-ri-
bofuranosyl)-3’-tert-butoxycarbonylaminopropionylamino]-
3-phenylpropionic acid methyl ester (13): To a stirred solution
of 11 (126 mg, 0.20 mmol), DMAP (12 mg, 0.10 mmol), and l-
phenylalanine methyl ester hydrochloride (86 mg, 0.40 mmol)
in CH2Cl2 (5 mL) was slowly added Et3N (125 mL, 0.90 mmol)
at room temperature.The mixture was stirred at room temper-
ature for 48 h, then the solvent was removed under reduced
pressure and aqueous saturated NH4Cl solution (8 mL) was
added.The reaction mixture was then extracted with CH Cl2
(3ꢂ20 mL), and the combined extracts were dried (Na2SO4),
2
Adv. Synth. Catal. 2004, 346, 1355–1360
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co.KGaA, Weinheim
1359

Alessandro Dondoni et al.
FULL PAPERS
concentrated, and eluted from a column of silica gel with 2:1
bide, A.Esnal, A.Landa, J.I.Miranda, A.Linden,
J.
Org. Chem. 1998, 63, 5838–5846; and more recently by
Indian researchers: M.Arun, S.N.Joshi, V.G.Puranik,
cyclohexane-AcOEt to give 13 as a yellow foam; yield:
1
128 mg (92%); [a]D: 17.7 (c 0.9, CHCl3); H NMR: d¼7.50–
7.20 and 7.15–7.00 (2 m, 20H, Ph), 6.57 (d, 1H, J2,NH ¼8.0 Hz,
B.M. Bhawal, A.R.A.S. Deshmukh,
Tetrahedron
NH), 5.74 (d, 1H, J3’,N’H ¼10.0 Hz, N’H), 5.38 (d, 1H, J2’,3’
5.0 Hz, H-2’), 4.90 (ddd, 1H, J2,3 ¼7.0 Hz, J2,3a ¼6.5 Hz, J2,3b
¼
¼
2003, 59, 2309–2316.
[7] For reviews, see: a) G.I.Georg, V.T.Ravikumar, in: The
Organic Chemistry of b-Lactams, (G.I. Georg), VCH,
New York, 1993, pp.295–368; b) C.Palomo, J.M. Aiz-
6.5 Hz, H-2), 4.60 and 4.54 (2d, 2H, J¼11.5 Hz, PhCH2), 4.54
and 4.45 (2d, 2H, J¼12.0 Hz, PhCH2), 4.54 and 4.42 (2d, 2H,
J¼12.0 Hz, PhCH2), 4.36–4.28 (m, 2H, H-3’, H-1’’), 4.08
(ddd, 1H, J3’’,4’’ ¼5.0 Hz, J4’’,5’’a ¼3.5 Hz, J4’’,5’’b ¼4.0 Hz, H-4’’),
purua, I.Ganboa, M.Oiarbide,
Eur. J. Org. Chem.
1999, 3223–3235.
3.88 (dd, 1H, J2’’,3’’ ¼5.5 Hz, H-3’’), 3.83 (dd, 1 H, J1’’,2’’
¼
¼
[8] a) A.Dondoni, M.-C Scherrmann, J. Org. Chem. 1994, 59
, 6404–6412; b) A.Dondoni, Pure Appl. Chem. 2000, 72,
1577–1588; c) A.Dondoni, P.Formaglio, A.Marra, A.
Massi, Tetrahedron 2001, 57, 7719–7727.
[9] In general an excess of aldehyde is employed for the in
situ generation of the imine.These conditions are used
to avoid the presence of unreacted amine which sub-
tracts part of the ketene.
5.5 Hz, H-2’’), 3.72 (s, 3H, OCH3), 3.52 (dd, 1H, J5’’a,5’’b
10.0 Hz, H-5’’a), 3.37 (dd, 1H, H-5’’b), 3.14 (d, 1H, 2 H-3),
1.98 (s, 3H, CH3), 1.42 (s, 9H, t-Bu); MALDI-TOF MS: m/
z¼695.9 (Mþ þH), 717.8 (Mþ þNa), 733.9 (Mþ þK); anal.
calcd.for C 41H44NO9 (694.79): C 70.88, H 6.38, N 2.02; found:
C 70.90, H 6.41, N 2.05.
[10] For a fully automatable procedure, the ketene genera-
tion was also carried out by using the highly basic (but
quite expensive) BEMP resin (polymer-bound triamino-
phosphonamide imine) that removes the trialkylammo-
nium salt by-products and therefore simplifies considera-
bly the work-up procedure.Full details of this methodol-
ogy will be reported in a forthcoming paper.For the ear-
lier use of the BEMP resin for ketene generation, see:
A.E.Taggi, A.M.Hafez, H.Wack, B.Young, D.Ferra-
ris, T.Lectka, J. Am. Chem. Soc. 2002, 124, 6626–6635.
[11] A.Dondoni, F.Junquera, F.L.Merchan, P.Merino, M-.
Acknowledgements
We gratefully acknowledge MIUR (COFIN 2002) for financial
support.
References and Notes
[1] a) A.Dondoni, A.Massi, S.Sabbatini, V.Bertolasi,
Org. Chem. 2002, 67, 6979–6994; b) A.Dondoni, A.
Massi, E.Minghini, V.Bertolasi, Helv. Chim. Acta
J.
C.Scherrmann, T.Tejero,
5484–5496.
J. Org. Chem. 1997, 62,
2002, 85, 3331–3348; c) A.Dondoni, A.Massi, E.Min-
ghini, S.Sabbatini, V.Bertolasi, J. Org. Chem. 2003, 68,
[12] Crystallographic data (excluding structure factors) for
the structure reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication no.CCDC 235150.Copies
of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax.: (internat.) þ44 1223/336–033; e-mail: depos-
it@ccdc.cam.ac.uk]. For enquires contact V. B. at the in-
dicated address or by e-mail.
[13] The ease of removal of all protective groups from the b-
lactam ring and sugar residue by CAN oxidation and hy-
drogenolysis was demonstrated in compounds (3R,4S)-
3b and (3R,4S)-4c.
6172–6183; d) A.Dondoni, A.Massi,
Mol. Diversity
2003, 6, 261–270; e) A.Dondoni, A.Massi, E.Minghini,
V.Bertolasi, Tetrahedron 2004, 60, 2311–2326.
[2] For reviews, see: a) The Organic Chemistry of b-Lactams,
(Ed.: G. I. Georg), VCH, New York, 1993; b) M.Kidwai,
P.Sapra, K.R.Bhushan, Curr. Med. Chem. 1999, 6, 195–
215.
[3] For several articles devoted to b-lactam chemistry and
synthesis, see the thematic issue of Tetrahedron 2000,
56, 5553–5742.
[4] M.Carina, L.Delpiccolo, M.A.Fraga, E.G.Mata,
J.
Comb. Chem. 2003, 5, 208–210, and references cited
therein.
[14] C.Palomo, J.M.Aizpurua, C.Cuevas, A.Mielgo, R.
Galarza, Tetrahedron Lett. 1995, 36, 9027–9030.
[15] a) I.Ojima, C.M.Sun, Y.H.Park, J. Org. Chem. 1994, 59,
[5] a) I.Ojima, in: The Organic Chemistry of b-Lactams,
(Ed.: G. I. Georg), VCH, New York, 1993, pp.197–255;
b) I.Ojima, S.Lin, J. Org. Chem. 1998, 63, 224–225,
and references cited therein.
1249–1250; b) C.Palomo, J.M.Aizpurua, C.Cuevas,
J.
Chem. Soc. Chem. Commun. 1994, 1957–1958.
[6] The stereoselective synthesis of non-anomeric sugar b-
lactams via [2þ2] cycloaddition of achiral ketenes to chi-
ral imines derived from cyclic dialdoses was reported
earlier by Palomo and co-workers: C.Palomo, M.Oiar-
[16] a) P.M.St.Hilaire, M.Meldal,
2000, 39, 1162–1179; b) A.Barkley, P.Arya,
Eur. J. 2001, 7, 555–563.
Angew. Chem. Int. Ed.
Chem.
1360
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asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1355–1360