Diastereoselective synthesis of 2-substituted-piperidin-4-ones as convenient precursors for an asymmetric approach to carbacephams

Article abstract of DOI:10.1016/j.tet.2003.08.060

Optically active carbacephams can be efficiently prepared generating the β-lactam ring on 2-substituted-piperidin-4-ones. These can, in turn, be prepared diastereoselectively through a Michael-Michael reaction sequence initiated by benzylamine on precursors derived by Wittig reaction between serinals and 4-[(4-methylphenyl)sulfonyl]-1-(triphenylphosphoranylidene)-2-butanone.

Full text of DOI:10.1016/j.tet.2003.08.060

Tetrahedron 59 (2003) 8439–8444
Diastereoselective synthesis of 2-substituted-piperidin-4-ones
as convenient precursors for an asymmetric approach
to carbacephams
a
b
Achille Barco,a Nikla Baricordi,b Simonetta Benetti,a Gisella Biondini, Carmela De Risi
,
*
and Gian Piero Pollinib
a
`
Dipartimento di Chimica, Universita di Ferrara, Via Luigi Borsari 46, 44100 Ferrara, Italy
`
Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, Via Fossato di Mortara 19, 44100 Ferrara, Italy
b
Received 22 May 2003; revised 2 July 2003; accepted 30 July 2003
Abstract—Optically active carbacephams can be efficiently prepared generating the b-lactam ring on 2-substituted-piperidin-4-ones. These
can, in turn, be prepared diastereoselectively through a Michael–Michael reaction sequence initiated by benzylamine on precursors derived
by Wittig reaction between serinals and 4-[(4-methylphenyl)sulfonyl]-1-(triphenylphosphoranylidene)-2-butanone.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
been recently reported by Avenoza et al.6 who accom-
plished a short and efficient asymmetric approach to the
carbacepham derivative 4, involving as the key step
the asymmetric hetero Diels–Alder reaction between the
benzylimine 1, derived from the Garner’s aldehyde, and
Danishefsky’s diene (Scheme 1). The diastereomeric
mixture of the appropriately substituted six-membered
ring systems 2 and 3 was separated by column chromatog-
raphy and the major cyclo-adduct 3 was eventually utilized
for the subsequent construction of the b-lactam ring of 4,
which represents a useful building block for further
modifications.
The extensive use of common b-lactam antibiotics has
resulted in an increasing number of resistant strains of
bacteria through mutation and b-lactamase gene transfer,
thus triggering a continuous interest in the synthesis of new
b-lactam systems.1 Over the past few years, the literature
has indicated a growing interest in the preparation and
biological evaluation of carbacephalosphorins (carbace-
phems), and one of them, loracarbef, has been developed
and marketed.2 Most of the synthetic approaches to the basic
skeleton of carbacepham nucleus relied on the construction
of the six-membered ring system into the existing b-lactam
ring, usually obtained through classical Staudinger reac-
tion.3 Recently, synthetic pathways involving the construc-
tion of the six-membered ring system followed by formation
of the b-lactam ring have been successfully exploited as
alternative approaches to the asymmetric synthesis of
carbacephams.4,5 An example of the latter strategy has
2. Results and discussion
We have recently introduced7 4-[(4-methylphenyl)sulfo-
nyl]-1-(triphenylphosphoranylidene)-2-butanone 5 as a
readily available four-carbon synthon for substituted divinyl
Scheme 1.
Keywords: carbacephams; diastereoselection; 2-substituted-piperidin-4-ones.
*
Corresponding author. Tel.: þ39-532-291174; fax: þ39-532-240709; e-mail: bns@ifeuniv.unife.it
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.060

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A. Barco et al. / Tetrahedron 59 (2003) 8439–8444
Our own approach to the preparation of 4 calls for both
compound 8 and 9 as the requisite starting materials. These
were readily obtained in 80% yield by reaction between the
synthon 57 and both the Garner aldehyde 69 and the N-Boc-
O-tert-butyldimethylsilyl (O-TBDMS) protected serinal 710
(Scheme 2).
Figure 1.
ketones, the two double bonds adjacent to the central
carbonyl group being generated by Wittig reaction of the
stabilized ylide function with a suitable aldehyde and
through a base-promoted b-elimination of the sulfone
moiety, respectively (Fig. 1).
The reaction of 8 with benzylamine (Scheme 3) proceeded
uneventfully through two sequential Michael reactions
producing a diastereomeric mixture of the piperidones 10a
and 10b, the relative stereochemistry for both compounds
being assigned on the basis of the results obtained only in a
later stage of the synthesis. In particular, a 6:4 epimeric
mixture of piperidones 10a and 10b was obtained at room
temperature for 48 h, while a 9:1 ratio was observed when
the reaction was carried out at 08C for 6 days, the
diastereomeric ratio being determined in all cases through
HPLC analysis.
The derived divinyl ketones are able to take part to domino
reaction sequences leading to an efficient construction of
2-substituted 4-piperidone ring systems when nitrogen
nucleophiles (e.g. benzylamine) were used as the initiators.8
We wish to report in this paper a convenient alternative
approach to the asymmetric synthesis of 4 which we
envisaged as an extension of our own interest in the
synthesis of piperidine derivatives via tandem Michael–
Michael reactions.7
In order to increase the diastereoselectivity of the process,
we examined the reaction of 8 with chiral amines, such as
(þ) and (2)-phenylethylamine, instead of benzylamine,
Scheme 2.
Scheme 3.

A. Barco et al. / Tetrahedron 59 (2003) 8439–8444
8441
Scheme 4.
under the same conditions as above. Disappointingly, the
expected epimeric piperidinones were formed in the same
6:4 ratio as when the reaction was performed at room
temperature, while no reaction was observed at 08C.
(Scheme 5). The primary alcohol group of the prevalent
isomer was then oxidized by means of Jones reagent
producing the known acid 15, already transformed by
Avenoza6 into the interesting carbacepham derivative 4.
The mixture of N-benzyl derivatives 10a and 10b was
subsequently transformed in quantitative yield into the
corresponding mixture of N-Cbz derivatives 11a and 11b,
which could be separated by flash chromatography.
Interestingly, a reversal of the diastereoselectivity was
observed when the tandem Michael reaction sequence was
performed on the precursor 9, deriving from the reaction of
the differently protected serinal 7 (N-Boc-O-TBDMS) with
phosphorane 5. Indeed, when 9 was exposed to reaction with
benzylamine at 08C, an inseparable 2:10 mixture of the
piperidones 12a and 12b (HPLC ratio) was obtained. Clean
separation was then accomplished by flash chromatography
after transformation into the corresponding N-Cbz deriva-
tives 13a and 13b (Scheme 4).
Moreover, submitting compound 13b and 13a to the action
of tetrabutylammonium fluoride, the O-silyl protective
group was smoothly removed to furnish the primary
alcohols 14b and 14a, the latter being easily converted to
the acid 15 (Scheme 6), possessing spectroscopic and
optical features identical to those reported by Avenoza et al.6
3. Conclusions
In summary, we have shown that it is possible to obtain
optically active functionalized carbacephams using the
Wittig reaction between serinals and 4-[(4-methylphenyl)-
sulfonyl]-1-(triphenylphosphoranylidene)-2-butanone 5 as a
tool to prepare the required precursors able to participate to
a domino reaction sequence initiated by benzylamine for the
generation of the suitable substituted six-membered ring on
which the b-lactam ring could be subsequently constructed.
These results emphasize once more the versatility of the
Cleavage of the N,O-acetal of the intermediates 11a and
11b, easily achieved by treatment with acetic acid/water,
gave the 1,2-amino alcohols 14a and 14b, respectively, the
mild acid hydrolysis preserving the N-Boc protecting group
Scheme 5.

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A. Barco et al. / Tetrahedron 59 (2003) 8439–8444
Scheme 6.
building block 5 as a valuable tool for the construction of
functionalized carbon frameworks particularly useful as
precursors of substituted piperidine ring systems, one of the
commonest structural sub-units in biologically active
natural compounds. We believe that the asymmetric
synthesis of carbacephams described in this paper, which
compares well with the Avenoza’s in terms of steps and
overall yield, could be considered of high potential value for
the stereocontrolled route to piperidine systems.
was refluxed for 20 h, then concentrated in vacuo. The oily
residue was purified by flash-chromatography (eluent:
EtOAc/cyclohexane 1:1), affording the title compound 8
(1.11 g, 80%) as an oil. LRMS (EI): found 437.4;
C22H31NO6S requires 437.2. [Found: C, 60.29; H, 7.05.
C22H31NO6S requires C, 60.39; H, 7.14%]. [a]2D0¼þ58.5
(c 0.65, CHCl3). nmax (liquid film) 1690, 1680, 1625,
1590 cm21; dH (300 MHz, DMSO-d6, 1208C) 1.42 (9H, s,
3Me), 1.48 (3H, s, Me), 1.55 (3H, s, Me), 2.42 (3H, s,
PhMe), 2.97 (2H, t, J¼7.08 Hz, CH2SO2), 3.49 (2H, t, J¼
7.08 Hz, CH2CO), 3.80 (1H, dd, J¼9.1, 2.7 Hz, CHaHbO),
4.10 (1H, dd, J¼9.1, 6.6 Hz, CHaHbO), 4.47 (1H, m,
CHNBoc), 6.15 (1H, dd, J¼15.9, 1.2 Hz, HCvCH–CO),
6.70 (1H, dd, J¼15.9, 6.3 Hz, HCvCH–CO), 7.45 (2H, d,
J¼8.1 Hz, arom.), 7.80 (2H, d, J¼8.1 Hz, arom.); dC
(50 MHz, CDCl3, 258C) 21.5, 24.5, 26.4, 28.3, 32.9, 50.6,
58.1, 67.2, 77.1, 80.8, 94.5, 127.9, 129.2, 135.9, 144.9,
145.5, 151.9, 194.9.
4. Experimental
4.1. General remarks
Melting points were determined on a Bu¨chi–Tottoli
apparatus and are uncorrected. Infrared (IR) spectra were
recorded on a FT-IR Bruker IFS 88 spectrometer. Nuclear
magnetic resonance (1H NMR and 13C NMR) spectra were
taken on a Bruker AC spectrometer (200 and 50 MHz) and
on a Varian 300 Unity spectrometer (300 and 75 MHz) for
solutions in CDCl3 unless otherwise noted. Chemical shifts
are given in parts per million downfield from tetramethyl-
silane as the internal standard and coupling constants are
given in Hertz. Optical rotations were measured with a
Perkin–Elmer 241 MC polarimeter. Diastereomeric ratios
were determined through HPLC analyses, in normal phase
on silica gel and isopropanol/water 80:20 as eluant, in
reverse phase on C18 and acetonitrile/water concentration
gradient, using a DG 1680-54 JASCO UV 1575 instrument.
Organic solutions were dried over anhydrous magnesium
sulfate and evaporated with a rotary evaporator. Light
petroleum refers to the fractions boiling in the range 40–
608C and ether to diethyl ether. Flash-chromatography was
carried out with Merck silica gel (230–400 mesh). All
reactions were performed under N2 or Ar atmosphere.
Elemental analyses were effected by the micro analytical
laboratory of Dipartimento di Chimica, University of
Ferrara.
4.1.2. (4S,20R)-4-(10-Benzyl-40-oxo-piperidin-20-yl)-3-
(tert-butoxycarbonyl)-2,2-dimethyl-oxazolidine (10a)
and (4S,20S)-4-(10-benzyl-40-oxo-piperidin-20-yl)-3-(tert-
butoxycarbonyl)-2,2-dimethyl-oxazolidine (10b). Benzyl-
amine (0.81 g, 7.60 mmol) was added to a solution of 8
(1.66 g, 3.80 mmol) in THF (10 mL), the mixture stirred at
08C for 6 days, then concentrated in vacuo. The oily residue
was dissolved in EtOAc (20 mL), washed with NaHCO3
solution (2£10 mL, sat. aq.) and brine (2£10 mL). The dried
organic extracts were concentrated and the residue purified
by flash chromatography (eluent: EtOAc/cyclohexane 1:4)
affording the oily mixture of the title compounds 10a and
10b (1.03 g, 70%) in 9:1 ratio (HPLC analysis). A pure
fraction of 10a could be obtained and characterized. LRMS
(EI): found 388.1; C22H32N2O4 requires 388.2. [Found: C,
67.94; H, 8.27. C22H32N2O4 requires C, 68.01; H, 8.30%].
[a]2D0¼þ28.5 (c 0.40, CHCl3). nmax (liquid film) 1710,
1680 cm21; dH (300 MHz, DMSO-d6,1608C) 1.40 (9H, s,
3Me), 1.45 (3H, s, Me), 1.58 (3H, s, Me), 2.30–2.38 (2H, m,
CH2CO), 2.40–2.49 (2H, m, COCH2), 3.10–3.23 (2H, m,
CH2N), 3.31–3.40 (1H, m, CHN), 3.60 (1H, d, J¼14.0 Hz,
CHaHbPh), 3.96 (1H, dd, J¼9.5, 3.0 Hz, CHaHbO), 4.05
(1H, d, J¼14.0 Hz, CHaHbPh), 4.10 (1H, dd, J¼9.5, 2.0 Hz,
CHaHbO), 4.27 (1H, m, CHNBoc), 7.15–7.45 (5H, m,
arom.).
4.1.1. (4S)-4-[3-Oxo-5-(40-methylphenylsulfonyl)-1-pen-
tenyl]-3-(tert-butoxycarbonyl)-2,2-dimethyl-oxazolidine
(8). A mixture of phosphorane 57 (1.55 g, 3.18 mmol) and
the aldehyde 6 (0.73 g, 3.18 mmol) in dry CHCl3 (10 mL)

A. Barco et al. / Tetrahedron 59 (2003) 8439–8444
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4.1.3. (4S,20R)-4-(10-Benzyloxycarbonyl-40-oxo-piperi-
din-20-yl)-3-(tert-butoxycarbonyl)-2,2-dimethyl-oxazoli-
dine (11a) and (4S,20S)-4-(10-benzyloxycarbonyl-40-oxo-
piperidin-20-yl)-3-(tert-butoxycarbonyl)-2,2-dimethyl-
oxazolidine (11b). A solution of the 9:1 mixture 10a/10b
(1.20 g, 3.09 mmol) in MeOH (30 mL) was hydrogenated at
50 psi with Pd(OH)2 (100 mg) in a Parr apparatus at 258C.
After 20 h, the catalyst was removed by filtration through
Celite and the solvent evaporated. The crude oily residue
(0.90 g) was dissolved in a 5:1 THF/H2O mixture (30 mL)
and treated with Na2CO3·10H2O (1.14 g, 4 mmol) and
benzylchloroformate (0.68 g, 4 mmol). After being stirred
for 16 h at room temperature, the reaction mixture was
diluted with brine (20 mL) and extracted with EtOAc
(2£20 mL). Evaporation of the dried organic extracts
furnished an oil that was purified by flash chromatography
(eluent: ether/light petroleum 2:1) affording the title com-
pound 11a (1.07 g, 80%) as an oil. LRMS (EI): found 432.3;
C23H32N2O6 requires 432.2. [Found: C, 63.80; H, 7.39.
C23H32N2O6 requires C, 63.87; H, 7.46%]. [a]2D0¼þ30.5 (c
0.95, CHCl3). nmax (liquid film) 1715, 1680 cm21; dH
(300 MHz, DMSO-d6, 1608C) 1.40 (9H, s, 3Me), 1.45 (3H, s,
Me), 1.57 (3H, s, Me), 2.38–2.45 (2H, m, CH2CO), 2.52–
2.68 (2H, m, COCH2), 3.56–3.75 (1H, m, CHaHbO), 3.80–
3.98 (2H, m, CH2NCbz), 4.05–4.30 (2H, m, CHaHbO and
CHNBoc), 4.54–4.64 (1H, m, CHNCbz), 5.15 (2H, J¼
12.0 Hz, AB system, OCH2Ph), 7.23–7.42 (5H, m, arom.),
and the title compound 11b (0.14 g, 10%) as an oil.
LRMS (EI): found 432.1; C23H32N2O6 requires 432.2.
[Found: C, 63.80; H, 7.39. C23H32N2O6 requires C, 63.87;
H, 7.46%]. [a]2D0¼þ9.5 (c 0.82, CHCl3). nmax (liquid film)
butyl ester (12b). Benzylamine (0.56 g, 5.24 mmol) was
added to a solution of compound 9 (1.34 g, 2.62 mmol) in
THF (7 mL), the reaction mixture stirred at 08C for 5 days,
then concentrated in vacuo. The residual oil was dissolved
in EtOAc (20 mL), washed with NaHCO3 solution
(2£20 mL, sat. aq.) and brine (2£20 mL). The dried organic
extracts were concentrated and the residue purified by flash
chromatography (eluent: EtOAc/cyclohexane 1:3) affording
the oily mixture of the title compounds 12a and 12b
(0.85 g, 70%) in 1:5 ratio (HPLC analysis). A pure
fraction of 12b could be obtained and characterized.
LRMS (EI): found 462.1; C25H42N2O4Si requires 462.3.
[Found: C, 64.81; H, 9.09. C25H42N2O4Si requires C, 64.89;
H, 9.15%]. [a]2D0¼ 29.4 (c 0.33, CHCl3). nmax (liquid film)
3250, 1710, 1680 cm21; dH (200 MHz, CDCl3, 258C)
0.05–0.07 (6H, m, Me2Si), 0.82–0.87 (9H, m, Me3CSi),
1.40–1.45 (9H, m, Me3C), 1.80–2.45 (4H, m, CH2COCH2),
2.80–3.40 (4H, m, CHNCH2, PhCHaHbN), 3.40–3.85
(3H, m, CH2OSi, PhCHaHbN), 3.90–4.01 (1H, m,
CHNHBoc), 5.20 (1H, br, J¼7.0 Hz, NH), 7.20–7.40
(5H, m, arom).
4.1.6. (1S,20R)-(10-Benzyloxycarbonyl-40-oxo-piperidin-
20-yl)-2-(tert-butyldimethylsilylethyl)carbamic acid tert-
butyl ester (13a) and (1S,20S)-(10-benzyloxycarbonyl-40-
oxo-piperidin-20-yl)-2-(tert-butyldimethylsilylethyl)car-
bamic acid tert-butyl ester (13b). A solution of piperidones
12a and 12b (1.00 g, 2.16 mmol) in MeOH (30 mL) was
hydrogenated at 50 psi with Pd(OH)2 (100 mg) in a Parr
apparatus at 258C. After 20 h the reaction mixture was
filtered through Celite and the solvent evaporated. The
residual oil was dissolved in a 5:1 mixture THF/H2O
(25 mL) and treated with Na2CO3·10H2O (0.65 g,
2.28 mmol) and benzylchloroformate (0.39 g, 2.28 mmol).
After being stirred for 12 h at room temperature, the mixture
was diluted with brine (30 mL) and extracted with EtOAc
(2£20 mL). Evaporation of the dried organic extracts and
purification of the oily residue by flash chromatography
(eluent: EtOAc/cyclohexane 1:3) afforded the title com-
pound 13a (0.20 g, 18%) as an oil. LRMS (EI): found 506.5;
C26H42N2O6Si requires 506.3. [Found: C, 61.59; H, 8.30;
C26H42N2O6Si requires C, 61.63; H, 8.35%]. [a]2D0¼þ25.3
1715, 1680 cm21
; dH (300 MHz, DMSO-d6, 1208C)
1.32 (3H, s, Me), 1.36 (3H, s, Me), 1.45 (9H, s, 3Me),
2.38–2.46 (2H, m, CH2CO), 2.52–2.58 (2H, m, COCH2),
3.80–3.95 (3H, m, CHaHbO, CH2NCbz), 4.11–4.20 (2H, m,
CHaHbO, CHNBoc), 4.50–4.55 (1H, m, CHNCbz), 5.19
(2H, J¼16 Hz, AB system, OCH2Ph), 7.25–7.42 (5H, m,
arom.).
4.1.4. (6S)-7-(tert-Butyldimethylsilyloxy)-6-(tert-butoxy-
carbonylamino)-1-(p-toluensulfonyl)-4-hepten-3-one (9).
A mixture of 57 (1.70 g, 3.50 mmol) and 7 (1.06 g,
3.50 mmol) in dry CHCl3 (10 mL) was stirred at 258C for
30 h, then concentrated in vacuo and the residue purified
by flash chromatography (eluent: EtOAc/cyclohexane 1:2)
affording the title compound 9 (1.43 g, 80%) as an oil.
LRMS (EI): found 511.0; C25H41NO6SSi requires 511.2.
[Found: C, 58.60; H, 7.99. C25H41NO6SSi requires C, 58.67;
H, 8.08%]. [a]2D0¼27.2 (c 0.50, CHCl3). nmax (liquid film)
3300, 1690, 1680, 1625, 1590 cm21; dH (200 MHz, CDCl3,
258C) 0.06 (6H, s, Me2Si), 0.89 (9H, s, Me3CSi), 1.44
(9H, s, Me3C), 2.44 (3H, s, PhMe), 3.10 (2H, t, J¼8.8 Hz,
CH2SO2), 3.39 (2H, t, J¼8.8 Hz, CH2CO), 3.60–3.85
(2H, m, CH2OSi), 4.40 (1H, m, CHNHBoc), 4.95 (1H,
br d, J¼7.0 Hz, NH), 6.20 (1H, dd, J¼15.9, 1.8 Hz,
HCvCH–CO), 6.80 (1H, dd, J¼15.9, 5.5 Hz, HCvCH–
CO), 7.38 (2H, d, J¼8.0 Hz, arom.), 7.80 (2H, d, J¼8.0 Hz,
arom.).
(c 0.07, CHCl3). nmax (liquid film) 3250, 1710, 1680 cm21
;
dH (300 MHz, DMSO-d6, 1208C) 0.05 (6H, s, Me2Si), 0.85
(9H, m, Me3CSi), 1.38 (9H, m, Me3C), 2.37 (1H, dt, J¼16.0,
5.0 Hz, HCHCO), 2.43 (1H, dd, J¼10.0, 5.0 Hz, HCHCO),
2.52 (1H, dd, J¼10.0, 5.0 Hz, HCHCO), 2.68 (1H, dd, J¼
16.0, 7.8 Hz, HCHCO), 3.48 (1H, ddd, J¼14.0, 11.5,
5.1 Hz, HCHNCbz), 3.62–3.75 (3H, m, CH2OSi,
HCHNCbz), 4.15–4.24 (1H, m, CHNHBoc), 4.52–4.62
(1H, m, CHNCbz), 5.17 (2H, s, OCH2Ph), 5.40–5.51 (1H,
br, NH), 7.25–7.42 (5H, m, arom.), and the title compound
13b (0.79 g, 72%) as an oil. LRMS (EI): found 506.2;
C26H42N2O6Si requires 506.3. [Found: C, 61.59; H, 8.30;
C26H42N2O6Si requires C, 61.63; H, 8.35%]. [a]2D0¼213.0
(c 0.23, CHCl3). nmax (liquid film) 3250, 1710, 1680 cm21
;
dH (300 MHz, DMSO-d6, 1208C) 0.06 (6H, s, Me2Si), 0.87
(9H, m, Me3CSi), 1.40 (9H, m, Me3C), 2.30–245 (3H, m,
HCHCO, CH2CO), 2.64 (1H, dd, J¼16.5, 6.8 Hz, HCHCO),
3.40–3.85 (4H, m, CH2NCbz, CH2OSi), 4.20–4.30 (1H, m,
CHNHBoc), 4.65–4.78 (1H, m, CHNCbz), 5.24 (2H, J¼
15.5 Hz, AB system, OCH2Ph), 6.05 (1H, br, NH) 7.25–
7.42 (5H, m, arom.).
4.1.5. (1S,20R)-(10-Benzyl-40-oxo-piperidin-20-yl)-2-(tert-
butyldimethylsilyloxyethyl)carbamic acid tert-butyl
ester (12a) and (1S,20S)-(10-benzyl-40-oxo-piperidin-20-
yl)-2-(tert-butyldimethylsilyloxyethyl)carbamic acid tert-

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A. Barco et al. / Tetrahedron 59 (2003) 8439–8444
4.1.7. (1S,20R)-1-(10-Benzyloxycarbonyl-40-oxo-piperi-
din-20-yl)-2-(hydroxyethyl)carbamic acid tert-butyl
ester (14a) and (1S,20S)-1-(10-benzyloxycarbonyl-40-oxo-
piperidin-20-yl)-2-(hydroxyethyl)carbamic acid-tert-
butyl ester (14b). Method A. A solution of 11a (0.46 g,
1.06 mmol) in acetic acid (4 mL) containing H2O (1 mL)
was stirred at room temperature for 32 h, then evaporated in
vacuo. The residue was dissolved in EtOAc (10 mL) and
washed with NaHCO3 solution (10 mL, sat. aq.). Evapo-
ration of the dried organic extracts afforded the title
compound 14a (0.40 g, 97%) as an oil.
excess of oxidant was destroyed with 2-propanol (10 mL).
The reaction mixture was dried, filtered trough Celite and
concentrated in vacuo. The residual oil was dissolved in
CHCl3 (20 mL), washed with water (2£10 mL) and the
organic extracts were dried and evaporated. Purification of
the residue by flash chromatography (eluent: EtOAc
containing 0.1% acetic acid) afforded the title compound
15 (0.34 g, 83%) as a colorless oil. LRMS (EI): found 406.1;
C20H26N2O7 requires 406.2. [Found: C, 59.03; H, 6.39.
C20H26N2O7 requires C, 59.10; H, 6.45%]. [a]2D0¼þ16.1
(c 2.28, MeOH) (lit.6 [a]2D0¼þ16.0 (c 0.84, MeOH)).
nmax (liquid film) 3450, 1715, 1680 cm21; dH (300 MHz,
DMSO-d6, 1208C) 1.39 (9H, s, 3Me), 2.36 (1H, dt, J¼15.8,
4.9 Hz, HCHCO), 2.44 (1H, dd, J¼10.5, 7.8 Hz, HCHCO),
2.54 (1H, dd, J¼10.5, 3.5 Hz, HCHCO), 2.68 (1H, dd,
J¼15.8, 6.84 Hz, HCHCO) 3.40–3.65 (2H, m, CH2NCbz),
4.08–4.20 (1H, m, CHNHBoc), 4.55–4.65 (1H, m,
CHNCbz), 5.15 (2H, s, OCH2Ph), 5.62–5–78 (1H, d, J¼
8.0 Hz, NH) 7.25–7.42 (5H, m, arom.).
Method B. A solution of 13a (0.16 g, 0.31 mmol) and
tetrabutylammonium fluoride trihydrate (0.39 g,
1.24 mmol) in THF (5 mL) was stirred at room temperature
overnight, then the solvent was evaporated under reduced
pressure. The residual oil was dissolved in EtOAc (20 mL)
and washed with water (2£20 mL). Evaporation of the dried
organic extracts gave the title compound 14a as an oil
(0.11 g, 94%), which was pure enough to be used in the next
step without purification.
Acknowledgements
In both cases, a sample was purified by flash chroma-
tography (eluent: EtOAc/cyclohexane 1:1) for analytical
purposes. LRMS (EI): found 392.3; C20H28N2O6 requires
392.2. [Found: C, 61.12; H, 7.14. C20H28N2O6 requires C,
61.21; H, 7.19%]. [a]2D0¼þ27.7 (c 1.64, CHCl3). nmax
(liquid film) 3450, 1715, 1680 cm21; dH (300 MHz,
DMSO-d6, 1208C) 1.40 (9H, s, 3Me), 2.38–2.58 (2H, m,
CH2CO), 2.51–2.72 (2H, m, COCH2), 3.38–3.65 (4H,
m, CH2OH, CH2NCbz), 4.08–4.20 (1H, m, CHNHBoc),
4.55–4.65 (1H, m, CHNCbz), 5.19 (2H, s, OCH2Ph),
5.62–5.78 (1H, br, NH), 7.25–7.42 (5H, m, arom.).
We thank MIUR (PRIN 2002) for financial support.
References
´
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The same procedures were applied to 12b and 13b to give
14b. LRMS (EI): found 392.1; C20H28N2O6 requires 392.2.
[Found: C, 61.12; H, 7.14. C20H28N2O6 requires C, 61.21;
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