Efficient synthesis of an enantiopure β-lactam as an advanced precursor of thrombin and tryptase inhibitors

Article abstract of DOI:10.1021/jo020617u

A new and efficient synthesis of a β-lactam that is an advanced precursor of inhibitors of thrombin and tryptase is reported. The reaction sequence is based on the use of an inexpensive enantiomerically pure starting material and is designed to allow acce

Full text of DOI:10.1021/jo020617u

CHART 1. Str u ctu r es of Th r om bin a n d Tr yp ta se
In h ibitor s 1 a n d 2 a n d of Com m on P r ecu r sor 3
Efficien t Syn th esis of a n En a n tiop u r e
â-La cta m a s a n Ad va n ced P r ecu r sor of
Th r om bin a n d Tr yp ta se In h ibitor s
Rita Annunziata,† Maurizio Benaglia,*,†
Mauro Cinquini,†,‡ Franco Cozzi,†,‡
Francesco Maggioni,† and Alessandra Puglisi†
Dipartimento di Chimica Organica e Industriale and
CNR-ISTM, Universita’ degli Studi di Milano,
Via Golgi 19 - 20133 Milano, Italy
maurizio.benaglia@unimi.it
Received September 20, 2002
SCHEME 1. Syn th esis of â-La cta m s 6ts a n d 6cs
a n d of Diols 7ts a n d 7cs
Abstr a ct: A new and efficient synthesis of a â-lactam that
is an advanced precursor of inhibitors of thrombin and
tryptase is reported. The reaction sequence is based on the
use of an inexpensive enantiomerically pure starting mate-
rial and is designed to allow access to both enantiomers of
the target molecules by epimerization of a side-product
obtained along the synthesis. An improved procedure for the
epimerization step that takes advantage of the use of a
polymer-supported and recyclable phase-transfer catalyst is
described.
The synthesis of â-lactams has witnessed a resurgence
of interest since the discovery that several representa-
tives of this class of compounds can effectively inhibit
proteases.1,2 In particular, azetidinone 1 (Chart 1) was
identified3 as a powerful and selective inhibitor of throm-
bin, a serine protease involved in both venous and
arterial thrombotic episodes.4 More recently, â-lactam 2
(Chart 1) was found to display inhibition of tryptase at
the subnanomolar level and suppress induced inflam-
mation in animal lungs.5 These compounds featured an
ω-guanidyl-substituted n-propyl side chain at C-3 and a
carboxylic residue at C-4, both essential for biological
activity. The thrombin inhibitor 1 was prepared in
racemic form by assembling the â-lactam ring via the
condensation between the enolate of methyl 5-[N′,N′′-bis-
(carbobenzyloxy)guanidino]pentanoate and the N-tri-
methylsilylimine derived from cinnamaldehyde, followed
by oxidative degradation of the styryl residue to establish
the carboxy function at C-4.3 The tryptase inhibitor 2 was
prepared in enantiopure form starting from unnatural
and relatively expensive D-ornithine, which was trans-
formed into a N-protected R-bromoacid to be used in an
intramolecular R-bromoamide/aminomalonate condensa-
tion as the crucial â-lactam forming reaction.5 We rea-
soned that the stereoisomerically pure trans compound
3 (Chart 1) could represent a convenient, advanced
precursor of 1 and 2 and differently N-substituted
derivatives thereof. Here, we report a concise, new
synthesis of 3 (R ) Boc) by a route that starts from
readily available and inexpensive D-glyceraldehyde and
opens access to both enantiomers of the target molecules
in enantiopure form.
The synthetic plan was centered on the condensation
between S-2-pyridylthio 5-(4-methoxyphenoxy)pentanoate
4 and the N-4-methoxyphenylimine derived from O,O-
cyclohexylidene D-glyceraldehyde, (S)-5 (Scheme 1). Com-
pound 4 was readily obtained in four steps from δ-vale-
rolactone by methanolysis (MeOH, catalytic pTSA, reflux,
18 h, 100% yield based on the crude product), etherifi-
cation (4-methoxyphenol, PPh3, diisopropylazodicarbox-
ylate, DCM, rt, 48 h, 90% yield), basic hydrolysis to the
acid (1 M KOH, 1:1 MeOH/water, rt, 24 h, 100% yield
based on the crude product), and thioester formation
(2,2′-dipyridyl disulfide, PPh3, DCM, rt, 15 h, 97.5%
yield). The overall isolated yield for 4 was 87.8% from
δ-valerolactone.
* Corresponding author. Fax: ++39/02/50314159.
† Dipartimento di Chimica Organica e Industriale.
‡ CNR-ISTM.
(1) Wilmouth, R. C.; Kassamally, S.; Westwood, N. J .; Sheppard, R.
J .; Claridge, T. D. W.; Aplin, R. T.; Wright, P. A.; Pritchard, G. J .;
Schofield, C. J . Biochemistry 1999, 38, 7989-7998.
(2) Yoakim, C.; Ogilvie, W. W.; Cameron, D. R.; Chabot, C.; Guse,
I.; Hache’, B.; Naud, J .; O’Meara, J . A.; Plante, R.; Deziel, R. J . Med.
Chem. 1998, 41, 2882-2891.
(3) Han, W. T.; Trehan, A. K.; Wright, J . J . K.; Federici, M. E.; Seiler,
S. M.; Meanwell, N. A. Bioorg. Med. Chem. 1995, 3, 1123-1143.
(4) Talbot, M. D.; Butler, K. D. Drug News Perspect. 1992, 3, 357-
363.
(5) Qian, X.; Zheng, B.; Burke, B.; Saindane, M. T.; Kronental, D.
R. J . Org. Chem. 2002, 67, 3595-3600.
Reaction of the titanium enolate of this thioester (TiCl4,
TEA, DCM, -78 °C)6 with imine (S)-5 (from -78 °C to
rt, 18 h) afforded a 1:1 mixture of â-lactams 3,4-trans-
4,4′-syn 6ts and 3,4-cis-4,4′-syn 6cs in 55% yield (see
Scheme 1 for numbering). The trans/cis stereochemical
assignment was based on the value of the HC-3/HC-4
coupling constant values (J cis ) 5.0-6.0 Hz; J trans ) 2.0-
(6) Review: Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J . Org. Chem.
2000, 563-572. This review also reports models of stereoselections
rationalizing the observed trans/cis and syn stereoselectivity.
10.1021/jo020617u CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/26/2003
2952
J . Org. Chem. 2003, 68, 2952-2955

SCHEME 2. Syn th esis of P r ecu r sor 3 fr om Diol 7ts
SCHEME 3. Ep im er iza tion of Ald eh yd e 15 to en t-8
in th e P r esen ce of Su p p or ted Ca ta lysts 16 a n d 17
As mentioned above, the thrombin inhibitor 2 has been
described so far only in the racemic form and, to the best
of our knowledge, no stereochemistry/activity relationship
has been reported. Therefore, the possibility of obtaining
both enantiomers of 3 was worth investigating. Among
the precursors of â-lactam 3, it was anticipated that the
“useless” cis isomer 7cs could provide an easy entry to
the required compound. In this line, oxidation of 7cs
afforded aldehyde cis-15 (95% yield, Scheme 3) featuring
a stereocenter at C-4 that should be readily epimerized
under basic conditions13 to afford the more stable trans-
configurated â-lactam ent-8. Unfortunately, neither the
described procedure (40% aqueous dimethylamine, 5%
benzyl tributylammonium bromide, benzene, rt, 18-48
h)13 nor modification of solvent, reaction temperature, or
reaction time produced appreciable epimerization in 15,
which was recovered in 30-75% yield. However, replace-
ment of the phase-transfer catalyst with its poly(ethylene
glycol)-supported analogue 1614 (10% of catalyst, DCM,
rt, 18 h) improved the trans/cis ent-8/15 ratio to 90:10
and the recovery yield to 94%. Eventually, the use of the
poly(ethylene glycol)-supported tetrakis ammonium cata-
lyst 1715 (2.5% catalyst, DCM, rt, 18 h) in the same
process resulted in the isolation of the pure trans-
configurated aldehyde ent-8 in 95% yield. Remarkably,
catalyst 17 was readily recovered by precipitation and
filtration15 and recycled for two additional epimerization
reactions (ent-8/15 ratio ) 90:10, g90% yield). Conversion
of aldehyde ent-8 to amine ent-14 was then accomplished
in an overall yield very similar to that reported in Scheme
2.
2.5 Hz); the complete syn stereoselectivity at C-4/C-4′,
expected on the basis of our previous experience in
analogous condensations involving a variety of thioesters
and imine 5,6-10 was suggested by comparison of NMR
chemical shift trends for diagnostic protons in similar
products7-10 and confirmed by the conversion of 6ts to
adduct 3 (see below). To obtain stereochemically pure
compounds, â-lactams 6ts and 6cs were deprotected (1:1
TFA/water, from 0 °C to rt, 55 min) and readily separated
by flash chromatography (∆Rf g 0.2 in 6:4 hexane/AcOEt)
to afford diol 7ts (39%) and 7cs (39%).
The conversion of pure 7ts into the target molecule 3
was performed as described in Scheme 2. Stepwise
oxidation of the diol function afforded first aldehyde 8
(NaIO4, 1:1 AcOEt/water, rt, 1 h, 90% yield) and then
acid 9 (KMnO4, 1:1 acetone/water, rt, 50 min), which was
isolated as its methyl ester 10 (diazomethane, diethyl
ether, 1.5 h, 85% overall yield from 8). Alternatively,
direct conversion of diol 7ts to acid 9 was performed in
72% yield by reaction with NaIO4 and KMnO4 in 1:1
acetone/water at rt for 1 h. The 4-methoxyphenyl protect-
ing groups were then simultaneously removed (CAN, 3:1
acetonitrile/water, from -45 to -15 °C, 45 min) to afford
alcohol 11 in 66% yield. Standard manipulation of the
hydroxy function, involving formation of mesylate 12
(MsCl, TEA, DCM, from 0 °C to rt, 15 h), synthesis of
azide 13 (NaN3, DMF, rt, 20 h), and hydrogenation (10%
Pd/C, H2, MeOH, rt, 5 h), afforded amine 14 in 62%
overall yield from 11. The introduction of the protected
guanidino group was performed following a procedure
recently developed by Goodman et al.11 by reaction of 14
with N,N′-di-Boc-N′′-trifylguanidine12 and TEA (DCM, rt,
4 h) that afforded 3 (R ) Boc) in 91% yield. The overall
yield of stereoisomerically pure adduct 3 from thioester
4 and imine 5 was 6.1% after 10 steps requiring 6
chromatographic purifications.
In conclusion, both enantiomers of a â-lactam that is
an advanced precursor of powerful inhibitors of thrombin
and tryptase have been synthesized by a new approach
based on the use of an inexpensive enantiomerically pure
starting material. The stereodivergency of the synthesis
is made possible by an improved procedure that allows
complete epimerization of one of the azetidinone stereo-
centers by the use of a recyclable polymer-supported
(7) For a recent example of a completely syn-stereoselective con-
densation similar to that here described, see: Annunziata, R.; Benaglia,
M.; Cinquini, M.; Cozzi, F.; Puglisi, A. Bioorg. Med. Chem. 2002, 10,
1813-1818.
(8) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G. J . Org.
Chem. 1992, 57, 4155-4162.
(12) Tamaki, M.; Han, G.; Hruby, V. J . J . Org. Chem. 2001, 66,
1038-1042.
(9) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Ponzini,
F. J . Org. Chem. 1993, 58, 4746-4748.
(13) Alcaide, B.; Aly, M. F.; Rodriguez-Vicente, A. Tetrahedron Lett.
1998, 39, 5865-5866.
(10) Annunziata, R.; Cinquini, M.; Cozzi, F.; Molteni, V.; Schupp,
O. J . Org. Chem. 1996, 61, 8293-8296.
(14) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Tocco,
G. Org. Lett. 2000, 2, 1737-1739.
(11) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J . Org.
Chem. 1998, 63, 3804-3805.
(15) Benaglia, M.; Cinquini, M.; Cozzi, F.; Tocco, G. Tetrahedron Lett.
2002, 43, 3391-3393.
J . Org. Chem, Vol. 68, No. 7, 2003 2953

4.22 (dd, 1H, J ) 6.7, 6.0 Hz, one H of CH-CH2-O), 4.15 (dd,
1H, J ) 6.0, 5.5 Hz, H-C4), 4.00 (m, 2H, Ar-O-CH2), 3.82 (s,
3H, one of two MeO), 3.79 (s, 3H, one of two MeO), 3.72 (dd,
1H, J ) 6.7, 6.0 Hz, one H of CH-CH2-O), 3.40 (m, 1H,
H-C3),1.33-2.00 (m, 14H, CH2-CH2 of the side chain at C-3
and cyclohexyl protons). 13C NMR: δ 167.6, 156.3, 153.2, 153.1,
131.6, 120.2, 114.9, 114.8, 113.8, 110.8, 76.6, 67.9, 66.6, 58.9,
55.9, 55.6, 50.4, 36.6, 34.6, 27.8, 25.2, 24.1, 23.9, 22.7. Com -
catalyst. Extension of this chemistry to the synthesis of
other â-lactams endowed with protease inhibition proper-
ties is under investigation in our laboratories.
Exp er im en ta l Section
Gen er a l. 1H NMR spectra were recorded at 300 MHz in
chloroform-d (CDCl3) unless otherwise stated and were refer-
enced to tetramethylsilane (TMS) at 0.00 ppm; peak assignments
were based on direct and long-range C-H correlations as well
as on two-dimensional experiments. 13C NMR spectra were
recorded at 75 MHz and were referenced to 77.0 ppm in CDCl3.
Optical rotations were measured at the Na D-line in a 1 dm cell
at 22 °C. IR spectra were recorded on thin film or as solutions
in DCM. 5-(4-Methoxyphenoxy)pentanoic acid16 and imine (S)-5
1
p ou n d 6ts. H NMR: δ 7.57 (B part of an AB system, 2H, J )
9.0 Hz, H ortho to N in N-PMP), 6.86 (m, 6H, remaining
aromatic protons), 4.43 (t, 1H, J ) 6.7 Hz, H-C4′), 4.08 (dd,
1H, J ) 8.7, 6.5 Hz, one H of CH-CH2-O), 4.00 (m, 2H, Ar-
O-CH2), 3.88 (dd, 1H, J ) 6.5, 2.4 Hz, H-C4), 3.82 (s, 3H, one
of two MeO), 3.78 (s, 3H, one of two MeO), 3.76 (dd, 1H, J )
6.7, 6.0 Hz, one H of CH-CH2-O), 3.00 (m, 1H, H-C3),1.33-
2.00 (m, 14H, CH2-CH2 of side chain at C-3 and cyclohexyl
protons). 13C NMR: δ 166.8, 156.3, 154.2, 154.0, 131.7, 119.3,
115.5, 115.4, 114.0, 111.3, 76.7, 68.0, 65.5, 60.3, 55.9, 55.6, 51.3,
8
were known compounds.
S-2-P yr idylth io 5-(4-Meth oxyph en oxy)pen tan oate 4. This
compound was prepared according to a described procedure.17
To a stirred solution of 5-(4-methoxyphenoxy)pentanoic acid
(0.628 g, 2.8 mmol) in dry DCM (10 mL) were added 2-pyridyl
disulfide (0.801 g, 3.64 mmol) and PPh3 (1.027 g, 3.92 mmol),
each in 5 mL of dry DCM. The yellow solution was stirred for
15 h at rt. The reaction was quenched by the addition of water
(10 mL). The organic phase was separated, and the aqueous
phase was extracted three times with DCM. The combined
organic phases were dried over sodium sulfate, filtered, and
concentrated under vacuum. The crude product was purified by
flash chromatography with a 1:1 hexane/EtOAc mixture as the
eluant to give the title compound in 97.5% yield (0.866 g) as a
yellow thick oil that solidified upon standing in the freezer. IR
36.7, 34.5, 27.8, 27.1, 25.2, 24.1, 23.9. Anal. Calcd for C28H35
-
NO6: C, 69.83; H, 7.33; N, 2.91. Found: C, 70.12; H, 7.44; N,
2.76.
(3S,4R,4′S)- a n d (3R,4R,4′S)-1-(4-Meth oxyp h en yl)-3-[3-(4-
m et h oxyp h en oxy)p r op -1-yl]-4-(1,2-d ih yd r oxyet h yl)a zet i-
d in -2-on e 7. To a stirred suspension of the diastereoisomeric
mixture of compounds 6cs and 6ts (0.200 g, 0.415 mmol) in
water (5 mL) cooled to 0 °C was slowly added TFA (5 mL). The
resulting solution was allowed to warm to room temperature,
and the reaction was monitored by TLC. After disappearance of
the starting material (ca. 55 min), the reaction was quenched
by the cautious addition of a saturated aqueous solution of
potassium carbonate (10 mL). The aqueous phase was extracted
with DCM (3 × 15 mL), dried over a mixture of potassium
carbonate and sodium sulfate, filtered, and concentrated under
vacuum. The residue was purified by flash chromatography with
hexane/EtOAc mixtures of increasing polarity (from 6:4 to 1:1
to 1:9) as the eluants. Diol 7cs, mp 115-117 °C, was obtained
in 39% yield (0.065 g). [R]D 33.3 (c 0.3, DCM). IR (DCM): 3400,
1719, 1510 cm-1. 1H NMR: δ 7.40 (B part of an AB system, 2H,
J ) 9.0 Hz, H ortho to N in N-PMP), 6.89 (A part of an AB
system, 2H, J ) 9.0 Hz, H meta to N in N-PMP), 6.85 (s, 4H,
O-Ar-O), 4.30 (t, 1H, J ) 5.7 Hz, H-C4), 4.04 (m, 3H, CH-OH
and CH2-OAr), 3.80 (s, 3H, one MeO), 3.78 (s, 3H, one MeO),
3.67 (m, 2H, CH2-OH), 3.42 (dt, 1H, J ) 7.0, 5.7 Hz, H-C3),
2.40 (bs, 2H, OH), 1.92-2.25 (m, 4H, CH2- CH2). 13C NMR: δ
167.5, 156.4, 153.7, 152.9, 131.1, 120.4, 115.3, 114.6, 114.0, 71.6,
67.9, 64.5, 55.6, 55.5, 55.3, 50.6, 27.7, 22.0. Diol 7ts, a low-
melting material, was obtained in 39% yield (0.065 g). [R]D 29.8
(thin film): 1695 cm-1 1H NMR: δ 8.62 (dd, 1H, J ) 3.6, 2.0
.
Hz, H-C6 of pyridine), 7.74 (dt, 1H, J ) 5.7, 2.0 Hz, H-C4 of
pyridine), 7.62 (dd, 1H, J ) 5.8, 1.0 Hz, H-C3 of pyridine), 7.29
(m, 1H, H-C5 of pyridine), 6.84 (s, 4H, C6H4), 3.95 (t, 2H, J )
6.0 Hz, OCH2), 3.78 (s, 3H, OMe), 2.81 (t, 2H, J ) 7.3 Hz, CH2Cd
O), 1.90 (m, 4H, CH2-CH2). 13C NMR: δ 196.4, 153.9, 153.2,
151.7, 150.5, 137.2, 130.2, 123.6, 115.6, 114.8, 68.0, 55.8, 43.8,
28.7, 22.3. Anal. Calcd for C17H19NO3S: C, 64.33; H, 6.03; N,
4.41. Found: C, 64.08; H, 6.13; N, 4.33.
(3S,4R,4′S)- a n d (3R,4R,4′S)-1-(4-Meth oxyp h en yl)-3-[3-(4-
m et h oxyp h en oxy)p r op -1-yl]-4-(1,4-d ioxa sp ir o[4.5]d ec-2-
yl)a zetid in -2-on e 6. To a stirred solution of thioester 4 (0.100
g, 0.315 mmol) in dry DCM (2 mL) cooled at -78 °C and kept
under nitrogen was added dropwise a 1 M DCM solution of
titanium tetrachloride (0.347 mL, 0.347 mmol). After 5 min of
stirring, TEA (0.052 mL, 0.378 mmol) was added dropwise and
stirring was continued for 20 min. A DCM (2 mL) solution of
imine 5 (0.043 g, 0.158 mmol) was then added, and the reaction
mixture was allowed to slowly warm to room temperature. After
a total reaction time of 18 h, the reaction was quenched by
addition of a saturated aqueous solution of sodium bicarbonate
(5 mL). The resulting mixture was filtered through a Celite cake;
the organic phase was separated, and the aqueous phase was
extracted with DCM (2 × 10 mL). The combined organic phases
were concentrated under vacuum, and the residue was dissolved
in THF (5 mL) and treated with 5 mL of a 1 M aqueous solution
of KOH (2 mL) to hydrolyze the unreacted thioster. After 1 h
stirring at room temperature, EtOAc (5 mL) was added and the
organic phase was separated, washed with water, dried over
sodium sulfate, filtered, and concentrated under vacuum. 1H
NMR analysis of the crude reaction mixture revealed the
presence of a 1:1 mixture of diastereoisomers. The mixture was
purified by flash chromatography with a 6:4 hexane/EtOAc
mixture as the eluant to afford the title compounds (0.083 g) in
55% yield as a thick pale yellow oil. IR (thin film): 1742, 1510,
(c 0.5, DCM). IR (DCM): 3430, 1720, 1510 cm-1 1H NMR: δ
.
7.45 (B part of an AB system, 2H, J ) 8.9 Hz, H ortho to N in
N-PMP), 6.88 (A part of an AB system, 2H, J ) 8.9 Hz, H meta
to N in N-PMP), 6.85 (s, 4H, O-Ar-O), 4.03 (m, 1H, CH-OH),
3.97 (m, 3H, H-C4 and CH2-OAr), 3.79 (s, 3H, one MeO), 3.77
(s, 3H, one MeO), 3.69 (m, 2H, CH2-OH), 3.17 (dt, 1H, J ) 6.7,
2.0 Hz, H-C3), 2.40 (bs, 2H, OH), 1.88-2.10 (m, 4H, CH2-CH2).
13C NMR: δ 167.5, 156.4, 153.6, 152.9, 131.2, 119.7, 115.5, 114.7,
114.3, 73.4, 68.2, 63.3, 59.9, 55.7, 55.5, 50.6, 26.9, 25.7. Anal.
Calcd for C22H27NO6: C, 65.82; H, 6.78; N, 3.49. Found: C, 65.52;
H, 6.54; N, 3.65.
(3S,4R)-1-(4-Meth oxyp h en yl)-3-[3-(4-m eth oxyp h en oxy)-
p r op -1-yl]-4-for m yl-a zetid in -2-on e 8. To a solution of com-
pound 7ts (0.020 g, 0.05 mmol) in a mixture of EtOAc (2 mL)
and water (2 mL) cooled to 0 °C was added sodium metaperio-
date (0.042 g, 0.2 mmol) in one portion. The reaction was
monitored by TLC. After the mixture was stirred for 1.5 h, the
phases were separated, and the aqueous phase was extracted
with EtOAc (2 × 10 mL). The combined organic phases were
dried over sodium sulfate, filtered, and concentrated under
vacuum to afford the crude product (0.017 g, 90% yield) as a
low-melting material that was used without further purification.
1
1231 cm-1. Com p ou n d 6cs. H NMR: δ 7.65 (B part of an AB
system, 2H, J ) 9.0 Hz, H ortho to N in N-PMP), 6.86 (m, 6H,
remaining aromatic protons), 4.36 (t, 1H, J ) 6.0 Hz, H-C4′),
[R]D 47.3 (c 0.9, DCM). IR (DCM): 1740, 1690, 1510 cm-1 1H
.
NMR: δ 9.75 (d, 1H, J ) 4.3 Hz, CHO), 7.26 (B part of an AB
system, 2H, J ) 9.0 Hz, H ortho to N in N-PMP), 6.88 (A part
of an AB system, 2H, J ) 9.0 Hz, H meta to N in N-PMP), 6.83
(s, 4H, O-Ar-O), 4.17 (dd, 1H, J ) 4.3, 2.5 Hz, H-C4), 3.96 (t,
(16) Corrie, J . E. T.; Barth, A.; Papageorgiou, G. J . Labelled Compd.
Pharm. 2001, 44, 619-626.
(17) Kobayashi, S.; Iimori, T.; Izawa, T.; Ohno, M. J . Am. Chem.
Soc. 1981, 103, 2406-2407.
2954 J . Org. Chem., Vol. 68, No. 7, 2003

2H, J ) 6.8 Hz, CH2-OAr), 3.79 (s, 3H, one MeO), 3.65 (s, 3H,
one MeO), 3.43 (m, 1H, H-C3), 1.83-2.08 (m, 4H, CH2-CH2).
13C NMR: δ 198.5, 165.1, 156.6, 154.0, 152.9, 131.2, 117.6, 115.4,
114.7, 114.6, 70.5, 62.9, 55.7, 55.5, 52.7, 26.9, 25.2. Anal. Calcd
for C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.53; H,
6.47; N, 3.58.
(3S,4R)-3-Am in op r op -1-yl-4-ca r b om et h oxy-a zet id in -2-
on e 14: Syn th esis of Mesyla te 12. To a stirred solution of
alcohol 11 (0.038 g, 0.2 mmol) and TEA (0.033 mL, 0.24 mmol)
in DCM (2 mL) cooled at 0 °C was added mesyl chloride (0.017
mL, 0.22 mmol) in DCM (2 mL). Stirring was continued for 6 h
at 0 °C and then for 12 h at rt. The reaction mixture was then
transferred to a separatory funnel and washed with cold water
(5 mL). The aqueous phase was extracted with DCM (2 × 5 mL),
and the combined organic phases were dried over sodium sulfate,
filtered, and concentrated under vacuum. 1H NMR analysis of
the crude product was consistent with the formation of mesylate
12, which was used as such. Syn th esis of Azid e 13. To a stirred
solution of the crude mesylate in DMF (1 mL) was added sodium
azide (0.026 g, 0.4 mmol) in one portion. The mixture was stirred
24 h at rt, and water (1 mL) was added. This mixture was then
transferred to a distillation apparatus with DCM (5 mL), and
the organic solvents and water were removed by evaporation
under vacuum to afford a pale yellow residue. 1H NMR analysis
of the crude product was consistent with the formation of azide
13, which was used as such. Hyd r ogen a tion . A suspension of
the crude azide and 10% Pd/C (0.010 g) in EtOH (5 mL) was
stirred under a hydrogen atmosphere for 6 h at rt. The catalyst
was removed by filtration on Celite, and the filtrate was
concentrated under vacuum. The resulting residue was dissolved
in AcOEt and purified by filtration on a short plug of silica gel
with a 98:2 AcOEt/MeOH mixture as the eluant. The product
(0.023 g) was obtained in 62% overall yield from alcohol 11.
Mp: 64-66 °C. [R]D -12.1 (c 0.3, DCM). IR (DCM): 3350,1745,
(3R,4R)-1-(4-Meth oxyp h en yl)-3-[3-(4-m eth oxyp h en oxy)-
p r op -1-yl]-4-for m yl-a zetid in -2-on e 15 was similarly obtained
in 95% yield from 7cs. Mp: 98-100 °C. [R]D 92.2 (c 1.3, DCM).
1
IR (DCM): 1731, 1691, 1509 cm-1. H NMR: δ 9.88 (d, 1H, J )
3.4 Hz, CHO), 7.25 (B part of an AB system, 2H, J ) 9.0 Hz, H
ortho to N in N-PMP), 6.87 (A part of an AB system, 2H, J )
9.0 Hz, H meta to N in N-PMP), 6.84 (s, 4H, O-Ar-O), 4.52
(dd, 1H, J ) 6.0, 3.4 Hz, H-C4), 3.96 (t, 2H, J ) 6.8 Hz, CH2-
OAr), 3.80 (s, 3H, one MeO), 3.78 (s, 3H, one MeO), 3.72 (m,
1H, J ) 6.0, 4.0 Hz, H-C3), 1.83-2.10 (m, 4H, CH2-CH2). 13C
NMR: δ 199.9, 165.6, 156.6, 153.0, 152.9, 131.1, 117.3, 115.4,
114.7, 114.6, 67.5, 60.3, 55.7, 55.5, 53.6, 27.4, 22.6.
(3S,4R)-1-(4-Meth oxyp h en yl)-3-[3-(4-m eth oxyp h en oxy)-
p r op -1-yl]-4-ca r b om et h oxy-a zet id in -2-on e 10: Ald eh yd e
Oxid a tion . To a stirred solution of aldehyde 8 (0.097 g, 0.242
mmol) in acetone (2 mL) was added potassium permanganate
(0.020 g, 0.126 mmol) in water (2 mL). The reaction was
monitored by TLC analysis, which showed complete disappear-
ance of the starting material after 50 min. The reaction was
quenched by the addition of solid sodium sulfite. The resulting
slurry was filtered through a Celite cake that was repeatedly
washed with 5 mL portions of DCM, chloroform, and EtOAc.
The resulting mixture was concentrated as such under vacuum,
and the residue was washed several times with DCM (5 mL
portions). The combined organic phases were dried over sodium
sulfate, filtered, and concentrated under vacuum to afford the
crude acid 9 as a low-melting solid. This was used as such for
the conversion to the ester. Ester ifica tion . To a stirred suspen-
sion of the acid in diethyl ether (5 mL) was added dropwise an
ethereal solution of diazomethane. After the mixture was stirred
for 1.5 h, the excess diazomethane was decomposed by addition
of a few drops of acetic acid. The residue obtained by evaporation
of the solvent under vacuum was purified by flash chromatog-
raphy with a 1:1 hexane/EtOAc mixture as the eluant to afford
the product (0.082 g) as a thick oil in 85% overall yield from the
aldehyde. [R]D 33.6 (c 0.7, DCM). IR (DCM): 1749, 1740, 1509
cm-1. 1H NMR: δ 7.27 (B part of an AB system, 2H, J ) 9.0 Hz,
H ortho to N in N-PMP), 6.88 (A part of an AB system, 2H, J
) 9.0 Hz, H meta to N in N-PMP), 6.85 (s, 4H, O-Ar-O), 4.23
(d, 1H, J ) 2.4 Hz, H-C4), 3.99 (t, 2H, J ) 5.6 Hz, CH2-OAr),
3.80 (s, 6H, two MeO), 3.78 (s, 3H, one MeO), 3.43 (m, 1H,
H-C3), 1.88-2.18 (m, 4H, CH2-CH2).13C NMR: δ 170.4, 165.3,
156.4, 153.9, 153.0, 131.0, 117.8, 115.4, 114.7, 114.4, 67.7, 66.9,
55.7, 55.5, 55.3, 52.7, 26.9, 25.5. Anal. Calcd for C22H25NO6: C,
66.15; H, 6.31; N, 3.51. Found: C, 66.44; H, 6.57; N, 3.68.
1
1740 cm-1. H NMR: δ 6.00 (bs, 1H, NH), 3.83 (d, 1H, J ) 2.5
Hz, H-C4), 3.78 (s, 3H, OMe), 3.38 (m, 2H, CH2-NH2), 3.29
(m, 1H, H-C3), 1.72-1.93 (m, 4H, CH2-CH2). 13C NMR: δ 173.1,
165.4, 55.7, 52.2, 50.6, 39.3, 26.8, 25.1. Anal. Calcd for
C8H14N2O3: C, 51.60; H, 7.58; N, 15.04. Found: C, 51.29; H,
7.75; N, 14.89.
(3S,4R)-3-(N′,N′′-Di-ter t-b u t yloxyca r b on ylgu a n id in o)-
p r op -1-yl-4-ca r bom eth oxy-a zetid in -2-on e 3. To a stirred
solution of amine 14 (0.016 g, 0.086 mmol) and TEA (0.015 mL,
0.107 mmol) in DCM (2 mL) was added N,N′-di-Boc-N′′-tri-
fylguanidine12 (0.038 g, 0.1 mmol) in DCM (1 mL). The mixture
was stirred at room temperature for 4 h, and the reaction was
quenched by the addition of a saturated aqueous solution of
sodium bicarbonate (2 mL). The organic phase was eparated,
and the aqueous phase was extracted with DCM (3 × 5 mL).
The combined organic phases were dried over sodium sulfate,
filtered, and concentrated under vacuum. The residue was
purified by flash chromatography with EtOAc as the eluant to
afford the product (0.034 g) in 91% yield. Mp: 135-137 °C. [R]D
1
-6.5 (c 0.1, DCM). IR (DCM): 3340,1755, 1736, 1660 cm-1. H
NMR: δ 11.50 (s, 1H, BocNH), 8.37 (t, 1H, J ) 5.0 Hz, NH-
CH2), 6.17 (bs, 1H, lactam NH), 3.88 (d, 1H, J ) 2.5 Hz, H-C4),
3.77 (s, 3H, OMe), 3.58 (m, 2H, CH2-NH), 3.33 (m, 1H, H-C3),
1.82-2.05 (m, 4H, CH2-CH2). 13C NMR: δ 174.2, 168.7, 166.6,
166.1, 156.3, 79.3, 78.1, 55.0, 51.1, 50.5, 42.7, 28.2, 27.8, 26.0,
25.1. Anal. Calcd for C19H32N4O7: C, 53.26; H, 7.53; N, 13.08.
Found: C, 53.51; H, 7.69; N, 12.86.
(3S,4R)-3-Hyd r oxyp r op -1-yl-4-ca r bom eth oxy-a zetid in -2-
on e 11. To a stirred solution of ester 10 (0.050 g, 0.125 mmol)
in acetonitrile (6 mL) cooled to -40 °C was added a solution of
CAN (0.548 g, 1 mmol) in water (2 mL). The reaction temper-
ature is allowed to slowly rise to -15 °C. After the mixture was
stirred for 45 min, the reaction was quenched by the addition of
saturated aqueous solutions of sodium sulfite and sodium
bicarbonate. The resulting slurry, warmed to room temperature,
was filtered through a Celite cake, and the filter was washed
with EtOAc (25 mL). The organic phase was separated, and the
aqueous phase was extracted with AcOEt (2 × 10 mL) and DCM
(2 × 10 mL). The combined organic phases were dried over
sodium sulfate, filtered, and concentrated under vacuum. The
residue was purified by flash chromatography with EtOAc as
the eluant to afford the product (0.016 g) in 66% yield. Mp: 98-
100 °C. [R]D -13.5 (c 0.4, DCM). IR (DCM): 3450,1746, 1741
Ep im er iza tion of (3R,4R)-15 to (3R,4S)-8. To a stirred
solution of aldehyde 15 (0.037 g, 0.1 mmol) and dimethylamine
(0.4 mL of a 40% solution in water) in DCM (2 mL) was added
catalyst 17 (0.014 g, 0.0025 mmol). After the mixture was stirred
for 48 h at room temperature, the solvent was evaporated under
vacuum, and to the residue was added diethyl ether (10 mL).
The catalyst was filtered off, and the solvent was evaporated to
afford the pure trans title aldehyde in 95% yield (0.035 g). The
product had [R]D -48.3 (c 0.2, DCM) and was identical by 1H
NMR to (3S,4R)-8.
Ack n ow led gm en t. This work was supported by
MIUR (Progetto Nazionale Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni) and CNR.
cm-1 1H NMR: δ 6.10 (bs, 1H, NH), 3.83 (d, 1H, J ) 2.5 Hz,
.
H-C4), 3.70 (s, 3H, OMe), 3.61 (t, 2H, J ) 6.0 Hz, CH2-OH),
3.24 (m, 1H, H-C3), 1.65-2.00 (m, 4H, CH2-CH2).13C NMR: δ
171.4, 166.1, 60.3, 58.1, 54.2, 51.6, 27.9, 24.4. Anal. Calcd for
C8H13NO4: C, 51.33; H, 7.00; N, 7.48. Found: C, 51.55; H, 6.87;
N, 7.61.
Su p p or tin g In for m a tion Ava ila ble: Spectra and experi-
mental details. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O020617U
J . Org. Chem, Vol. 68, No. 7, 2003 2955