Chiral base-catalyzed enantioselective synthesis of 4-aryloxyazetidinones and 3,4-benzo-5-oxacephams

Article abstract of DOI:10.1021/jo900821b

(Chemical Equation Presented) Readily available 4-formyloxyazetidinone was enantioselectively transformed into 3, 4-benzo-2-hydroxy-5-oxacephams and 4-phenyloxyazetidinones upon treatment with 0.1 equiv of the cinchona alkaloid in toluene via intermolecul

Full text of DOI:10.1021/jo900821b

pubs.acs.org/joc
The main strategies of the synthesis of cephalosporin
Chiral Base-Catalyzed Enantioselective Synthesis of
4-Aryloxyazetidinones and 3,4-Benzo-5-oxacephams
and penicillin congeners make use of 6-aminopenicil-
lanic acid (6-APA) and 7-aminocephalosporinic acid
(7-ACA) as readily available chiral starting materials.
Nevertheless, this biosynthetic approach is limited, and
many novel β-lactam therapeutics are obtained via total
synthesis.4
Anna Koziol,† Bartlomiej Furman,† Jadwiga Frelek,†
†
Magdalena Woznica, Elisa Altieri, and
‡
ꢀ
Marek Chmielewski*,†
†Institute of Organic Chemistry Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland, and ‡Dip. di
Chimica Organica e Biologica, Universitaꢁ, Vill. S. Agata,
I 98166 Messina, Italy
In 1974, Clauss, Grimm, and Prossel5 reported that the 4-
acetoxyazetidin-2-one undergoes a nucleophilic displace-
ment of an acetoxy group with variety of nucleophiles. This
observation prompted many laboratories to use racemic or
chiral 4-acyloxyazetidinones as substrates for the synthesis
of variety of β-lactam antibiotics.6
chmiel@icho.edu.pl
For several years, our laboratory has been interested in
the synthesis of oxygen analogues of penicillin and cepha-
losporin. We have reported attractive diastereoselective
approaches to clavams and oxacephams starting from the
carbohydrate precursors.7 The present paper describes
for the first time an enantioselective approach to the con-
struction of 3,4-benzo-2-hydroxy-5-oxacephams (3) and
4-phenoxyazetidinones (5). This new approach is based
on the chiral Lewis base-promoted intermolecular nucleo-
philic substitution at C-4 of 4-formyloxyazetidinone (1)
(Scheme 1).
Received April 21, 2009
Recently, the racemic 3,4-benzo-2-hydroxy-5-oxacep-
hams (3) have been synthesized by the base-catalyzed
(NaOH or EtONa/EtOH) condensation of a salicylaldehyde
(2a) or o-hydroxyphenones (2) with the 4-acetoxyazetidi-
none.8 It appears to be a stepwise process, which occurs via
the nucleophilic substitution of acetoxy group followed by
the addition of β-lactam NH group to the carbonyl group of
the phenone (Scheme 2). In the case of salicylaldehyde (2a),
despite two new stereogenic centers being formed (C-2 and
C-6), the hydroxy group is always syn located to the bridge-
head proton.8
Both acid- and base-catalyzed nucleophilic substitutions
at C-4 of the azetidinone ring proceed via flat intermediates,
an acyliminium cation in the case of the acid-catalyzed
process, or a neutral 1,2-dehydro-azetidin-4-one (6) in the
case of the base-catalyzed one, i.e. through the SN1 or the
Readily available 4-formyloxyazetidinone was enantio-
selectively transformed into 3,4-benzo-2-hydroxy-5-oxa-
cephams and 4-phenyloxyazetidinones upon treatment
with 0.1 equiv of the cinchona alkaloid in toluene via
intermolecular nucleophilic trapping of N-acyliminium
intermediate by the hydroxyl moiety of phenols or
o-hydroxybenzaldehydes. Additionally, the absolute con-
figuration of title compounds was established by CD
spectroscopy.
β-Lactam antibiotics represent the most powerful tool
against bacterial infections.1 Recently, β-lactams also have
been observed to display interesting activity against non-
bacterial diseases.2 Owing to these attractive biological
properties, the synthesis of mono- and polycyclic systems con-
taining the β-lactam ring has been extensively investigated.3
(4) The Organic Chemistry of β-Lactams; Wild, H., Georg, G. I., Ed.;
VCH Publishers: Weinheim, 1993; p 49.
(5) Clauss, K.; Grimm, D.; Prossel, G. Liebigs Ann. Chem. 1974, 539.
(6) (a) Hungerbuhler, E.; Biollaz, M.; Ernest, I.; Kalvoda, J.; Lang, M.;
Schneider, P.; Sedelmeier, G. In New Aspects of Organic Chemistry I; Yoshida,
Z.; Shiba, T.; Ohshiro, Y., Eds.; VCH Publishers: Weinheim, 1989; p 419.
(b) De Bernardo, S.; Tengi, J. P.; Sasso, G. J.; Weigele, M. J. Org. Chem. 1985,
50, 3457. (c) M€uller, J. C.; Toome, V.; Pruess, D. L.; Blount, J. F.; Weigele, M. J.
Antibiot. 1983, 36, 217. (d) Hoppe, D.; Hilpert, T. Tetrahedron 1987, 43, 2467.
(1) (a) Chemistry and Biology of β-Lactam Antibiotics; Morin, R. B.,
Gorman, M., Eds.; Academic Press: New York, 1982; (b)Frontiers of Antibiotics
Research; Umezwa, H., Eds.; Academic Press: Tokio, 1987; (c) Recent Progress
in the Chemical Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer:
Berlin, 1990. (d) Lysek, R.; Borsuk, K.; Furman, B.; Kaluz_a, Z.; Kazimierski, A.;
Chmielewski, M. Curr. Med. Chem. 2004, 11, 1813.
_
(7) (a) Kaluza, Z.; Furman, B.; Patel, M.; Chmielewski, M. Tetrahedron:
_
Asymmetry 1994, 5, 2719. (b) Kaluza, Z.; Furman, B.; Chmielewski, M.
Tetrahedron: Asymmetry 1995, 6, 1719. (c) Chmielewski, M.; Kaluza, Z.;
_
_
ꢀ
Abramski, W.; Belzecki, C.; Grodner, J.; Mostowicz, D.; Urbanski, R.
Synlett 1994, 539. (d) Kaluza, Z.; Furman, B.; Chmielewski, M. J. Org.
_
_
Chem. 1997, 62, 3135. (e) Kaluza, Z.; Lysek, R. Tetrahedron: Asymmetry
(2) Veinberg, G.; Vorona, M.; Shestakova, I.; Kanepe, I.; Lukevics, E.
_
_
Curr. Med. Chem. 2003, 10, 1741.
1997, 8, 2553. (f) Kaluza, Z. Tetrahedron Lett. 1998, 39, 8349. (g) Kaluza, Z.
€
_
(3) (a) Comprehensive Heterocyclic Chemistry II; Katrizky A. R., Rees C.
W., Scriven E. F., Eds.; Pergamon: New York, 1996; Chapters 1.18-1.20; (b)
Ojima, I.; Delaloge, F. Chem. Rev. Soc. 1997, 26, 377. (c) Ojima, I. Acc. Chem.
Res. 1995, 28, 383. (d) Magriotis, P. A. Angew. Chem., Int. Ed. 2001, 40, 4377.
(e) Synthesis of β-Lactam Antibiotics, Chemistry, Biocatalysis and Process
Integration; Bruggink, A., Eds.; Kluwler: Dordrecht, The Netherlands, 2001.
Tetrahedron Lett. 1999, 40, 1025. (h) Furman, B.; Thurmer, R.; Kaluza, Z.;
Lysek, R.; Voelter, W.; Chmielewski, M. Angew. Chem, Int. Ed. 1999, 38,
1121.
(8) (a) Campbell, M. M.; Nelson, K. H.; Cameron, A. F. J. Chem. Soc.,
Chem. Commun. 1979, 532. (b) Arnoldi, A.; Merlini, L.; Scaglioni, L.
J. Heterocycl. Chem. 1987, 75.
DOI: 10.1021/jo900821b
r
Published on Web 07/02/2009
J. Org. Chem. 2009, 74, 5687–5690 5687
2009 American Chemical Society

Koziol et al.
JOCNote
SCHEME 1. Synthetic Strategy
TABLE 1. Evaluation of Conditions for the Reaction of Azetidinone 1
with Salicylaldehyde (2a) in the Presence of Quinidine (7) as a Catalyst
(All Reactions Were Carried out at Room Temperature)
entry
solvent
catalyst (equiv) timea (h) yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
10
THF
THFd
CH2Cl2
Et2O
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.1
0.1
48
96
24
24
48
48
48
48
48
12
77
70
83
65
78
40
78
76
77
65
31
33
24
6
51
0
toluene
DMF
DMFe
toluene
toluene
toluenef
0
SCHEME 2. Base-Catalyzed Formation of Substituted 3,4-Ben-
zo-2-hydroxy-5-oxacephams
48
49
49
aThe reaction was carried out until disappearance of substrate
1 (TLC). bIsolated yield determined after flash chromatography on
c
SiO2. The enantiomeric excess was determined by chiral HPLC. dAt
e
f
ꢀ
˚
0 °C. In the presence of molecular sieves 4 A. 5 equiv of CaCO3 was
added.
phenylethanol the expected cepham (3a) is formed in a good
yield but as a racemic mixture. However, when quinidine (7)
was used, the condensation reaction went smoothly to give
3a in 77% yield with 31% ee (Table 1, entry 1).
Note that when the reaction temperature was decreased to
0 °C, the same enantioselectivity was observed (entry 2). If
dichloromethane or diethyl ether were used as solvents, the
yield of reaction was unchanged but the enantioselectivity
was reduced to 24% and 6%, respectively. The lack of
enantioselectivity was noticed when DMF was used as a
solvent. With toluene as solvent, the enantiomeric excess
increased to 51% (entry 5). It is interesting that with 0.1 equiv
of the quinidine (7) in toluene, the product was obtained with
a similar yield and enantioselectivity (entry 9). As a general
trend, it was found that the reaction rate increased upon the
addition of CaCO3 (5 equiv, entry 10). The enantiomeric
excess was unchanged but the yield was reduced to 65%. A
control experiment showed that CaCO3 itself was not re-
sponsible for the activation of 1, but it trapped formic acid
liberated during substitution reaction.13
This initial positive result prompted us to further investi-
gate the enantioselective condensation by varying cincho-
nine type chiral amines (Table 2). Due to the use of
pseudoenantiomeric pairs of cinchonine alkaloids, the ob-
served product enantiomeric excess is comparable but not
the same. When (DHQD)2PHAL (11) was used, ent-3a was
obtained in 52% yield with 46% ee (entry 5). Introduction of
N-BOC-protected amine in the place of the hydroxy group
diminished both chemical yield and the enantioselectivity
(entry 6). No condensation occurred when catalyst contained
an acyl- or silyl-protected hydroxy group or a free amino
function in the place of the hydroxyl group (entries 7-10).
Subsequently, we analyzed the scope of this asymmetric
reaction with various o-hydroxybenzaldehydes and ketones.
As shown in Table 3, the enantiomeric excess as well as the
product’s yield depended on the nature of substituent in the
phenol ring. In all cases only one diastereomer was formed in
a good yield and with a moderate enantioselectivity.
elimination-addition mechanism, respectively.9 The discri-
mination of the enantiotopic faces of the intermediate by a
chiral nucleophile-catalyst complex should lead to the
optically enriched product. This assumption prompted us
to investigate the chiral Lewis acid catalyzed intramolecular
formation of the 3,4-benzo-5-oxacepham.10 The observed
moderate yield which had not exceeded 50%, but a high
asymmetric induction, suggested a kinetic resolution (asym-
metric destruction) of the initially formed racemic oxacep-
ham.10
Presently, we decided to investigate whether chiral Lewis
bases could be used as catalysts in the asymmetric version of
the same nucleophilic displacement reaction.11 Among the
well-known chiral Lewis bases the cinchonine alkaloids play
a central role in the field of asymmetric catalysis.12 The
cinchonine alkaloid family consists of two pairs of diaster-
eomers, often termed “pseudoenantiomeric” because the
respective carbinolamine fragments have an enantiomeric
relationship.
The 4-formyloxyazetidinone (1) undergoes condensation
with the salicylaldehyde (2a) in the presence of catalytic
amount of DBU and DABCO providing product rac-3a in
80% and 84% yield, respectively. This observation
prompted us to check whether chiral amines could promote
the same reaction in an enantioselective way. Our initial
studies indicated that in the presence of (-)-sparteine,
N-benzylprolinol, or nonracemic 2-dimethylamino-1,2-di-
(9) Nagaraja Rao, S.; More O’Ferral, R. A. J. Am. Chem. Soc. 1990, 112,
2729.
ꢀ
(10) Koziol, A.; Frelek, J.; Woznica, M.; Furman, B.; Chmielewski, M.
Eur. J. Org. Chem. 2009, 338.
(11) (a) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev.
2003, 103, 2985. (b) Chen, Y.; McDaid, P.; Deng, L. Chem. Rev. 2003, 103,
2965.
The assignment of absolute configuration at the bridge-
head carbon atom (C-6) was made by the electronic circular
(12) (a) Pracejus, H. Forschr. Chem. Forsch. 1967, 8, 493. (b) Kacprzak,
ꢀ
K.; Gawronski, J. Synthesis 2001, 7, 961. (c) Tian, S.-K.; Chen, Y.; Hang, J.;
Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621. (d) Palomo,
(13) Combinations of a catalytic amount of quinidine 7 and different
inorganic and organic bases (K2CO3, NaHCO3, MgCO3, Et3N) were tested.
In all cases, the expected 3,4-benzo-2-hydroxy-5-oxacepham 3a was formed
in good yield, but enantioselectivity was considerably reduced.
ꢀ
C.; Oiarbide, M.; Lopez, R. Chem. Soc.Rev. 2009, 38, 632.
5688 J. Org. Chem. Vol. 74, No. 15, 2009

Koziol et al.
JOCNote
TABLE 2. Chiral Base Evaluation Studies for an Enantioselective Forma-
tion of 3a from 1 and 2a in the Presence of 0.1 Equiv of Chiral Lewis Base (7-
16, Toluene, rt, 48 h)
TABLE 3. Scope and Limitation of Reaction between 1 and Substituted
o-Hydroxyphenones 2a-f in the Presence of 0.1 Equiv of Quinidine 7
(Toluene, rt, 48 h)
entry
catalyst
yielda (%)
eeb (%)
1
7
8
9
10
11
12
13
14
15
16
77
46
69
63
52
36
0
0
0
0
49 (3a)
14 (ent-3a)
14 (3a)
6 (ent-3a)
46 (ent-3a)
16 (3a)
2c
3c
4c
5
6
7
8
9
10
entry
phenone
product
yielda (%)
eeb (%)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
77
76
89
75
92
79
48
40
32
16
43
24
aIsolated yield determined after flash chromatography on silica gel.
Reaction was carried out until disappearance of substrate 1 (TLC); bThe
enantiomeric excess was determined by chiral HPLC; cReaction per-
formed in THF.
aIsolated yield determined after flash chromatography on SiO2.
Reaction was carried out until disappearance of substrate 1 (TLC). bThe
enantiomeric excess was determined by chiral HPLC.
dichroism spectroscopy (CD) applying the helicity rule
developed previously for oxacephams.14 According to the
rule, the positive sign of Cotton effect (CE) arising at around
220 nm corresponds to the (R) absolute configuration at the
ring junction while it is negative for the (S) configuration at
the same carbon atom. The positive sign of the CE at 221 nm
obtained for compound 3a and the negative one at 222 nm
for ent-3a allowed us to establish the absolute configuration
as (R) and (S), respectively. The very good agreement
between the experimental and simulated CD spectrum ob-
tained by the TDDFT quantum chemical calculations pro-
vided an additional corroboration of the configurational
assignment (Figure 1). For compound 3d, the configuration
at the N,O-hemiacetal center (C-2) was established by the
NOE experiments, which showed a spin-spin interaction
between the hydroxy group proton and the bridgehead
proton (H-6), whereas protons of CH3 group did not show
such interaction.
FIGURE 1. Experimental CD spectrum of 3a (green line) and
simulated CD spectrum of 3a (red line). Molecular structure presents
the lowest energy conformer of 3a calculated at the B3LYP/6-31
G (d,p) level.
under the same conditions a good chemical yield was found.
Reaction of 1 with 4d led probably to intramolecular N-
acylation and formation of the unstable oxacepham-2-one,
which underwent a rapid opening of the β-lactam ring and
subsequently further decomposition.15 The observed enan-
tioselectivity (Table 4) was also similar to that found for the
reactions with hydroxyphenones (Table 3). This result sug-
gests that in the case of hydroxyphenones the first step of the
reaction is not an acetal formation, but it involves a nucleo-
philic substitution via the elimination/addition mechanism,
and consequently, the enantioselectivity is created by the
intermolecular process. The second step leading to the ring
closure is under the thermodynamic control and as such is
The scope of the base-catalyzed nucleophilic substitution
at C-4 of 1 was further extended to the reaction leading to the
4-aryloxy compounds 5 (Table 4). Practically in all cases,
(15) (a) Chitwood, J. L.; Gott, P. G.; Martin, J. C. J. Org. Chem. 1971, 36,
_
_
ꢀ
2228. (b) Chmielewski, M.; Kaluza, Z.; Belzecki, C.; Salanski, P.; Jurczak, J.;
Adamowicz, H. Tetrahedron 1985, 41, 2441. (c) Mostowicz, D.; Belzecki, C.;
_
Chmielewski, M. J. Carbohydr. Chem. 1988, 7,805. (d)Mostowicz,D.;Zegrocka,
O.; Chmielewski, M. Carbohydr. Res. 1991, 212, 283. (e) Chmielewski, M.;
_
ꢀ
(14) (a) Lysek, R.; Borsuk, K.; Chmielewski, M.; Kaluza, Z.; Urbanczyk-
Lipkowska, Z.; Klimek, A.; Frelek, J. J. Org. Chem. 2002, 67, 1472. (b)
ꢀ
Frelek, J.; Kowalska, P.; Masnyk, M.; Kazimierski, A.; Korda, A.; Woznica,
_
ꢀ
Kaluza, Z.; Grodner, J.; Urbanski, R. ACS Symp. Ser. Guiliano, R., Ed. 1992,
494, 50. (f) Chmielewski, M.; Kaluz_a, Z.; Furman, B. Chem. Commun. 1996,
2689.
M.; Chmielewski, M.; Furche, F. Chemistry - Eur. J. 2007, 13, 6732.
J. Org. Chem. Vol. 74, No. 15, 2009 5689

Koziol et al.
JOCNote
TABLE 4. Scope and Limitation of Reaction between 1 and Substituted
o-Hydroxyphenols 4a-i in the Presence of 0.1 Equiv of Quinidine 7
(Toluene, rt, 48 h)
is described. The key step of this method is based on the
chiral Lewis base mediated, enantioselective intermolecular
alkylation of the phenol hydroxy group which proceeds via
the elimination/addition mechanism. It is important to note
that the chiral Lewis base is used in catalytic amounts with-
out affecting yield and enantioselectivity. It is in contrast
with the previously described chiral Lewis acid mediated
alkylation of the phenol hydroxy group by the N-acylimi-
nium ion generated from the 4-formyloxyazetidinone (1).
The latter reaction requires always an equimolar amount of
promoter and proceeds in a low yield but with a high
asymmetric induction as the intramolecular process or in a
good yield but with a low asymmetric induction as the
intermolecular process.10
entry
phenol
R
product
yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
2-Me
2-t-Bu
2-CH2CO2Me
2-CO2Me
3-NO2
2-Me, 4-Ph
2-Me, 6-OMe
2-Me, 4-Br
5a
5b
5c
5d
5e
5f
77
54
65
0
82
77
69
74
48
46
11
Moreover, it should be noted that the present method can
be applied to the synthesis of various phenoxy substituted
azetidinones potentially having a biological activity.16
43
50
46
24
4g
4h
5g
5h
aIsolated yield determined after flash chromatography on SiO2.
Reaction was carried out until disappearance of substrate 1 (TLC). bThe
enantiomeric excess was determined by chiral HPLC.
Experimental Section
Typical Procedure for Enantioselective Formation of 5a. To
the solution of 1 (30 mg, 0.26 mmol, 1.0 equiv) and o-cresol (4a)
(42 mg, 0.39 mmol, 1.5 equiv) in toluene (5 mL) at room
temperature was added quinidine (7) (9 mg, 0.1 equiv) under
argon atmosphere. The reaction mixture was stirred for 48 h
until disappearance of starting material and diluted with water
(5 mL). The aqueous phase was extracted with ether (3ꢀ10 mL).
The organic extracts were combined and dried over Na2SO4.
The solution was filtered and the filtrate evaporated. The crude
product was purified by column chromatography (silica gel, 2:3
hexanes/diethyl ether) to yield 41 mg (0.23 mmol) of 5a as yellow
preferentially leading to the exo location of the N,O-acetal
hydroxy group.
To shed more light on the reaction mechanism, we per-
formed experiments using 1 equiv of 1, 1.5 equiv of 4a, and
1.5 equiv of 4e. As result, only compound 5e was obtained in
82% yield and 43% ee. This may indicate that the phenolate
anion, not the phenol itself, is an active reagent that ap-
proaches the neutral intermediate 6. The more acidic m-
nitrophenol wins the competition to form the phenolate
anion. The enantioselectivity is probably induced by the
counterion, the protonated chiral base, which accompanies
the phenolate anion.
crystals: yield 77%, 48% ee; mp 99-100 °C; IR (film) 1786 cm-1
;
1H NMR (500 MHz, CDCl3) δ 2.24 (s, 3H, CH3), 3.13 (dt, J=
15.0, 1.3 Hz, 1H, CH2), 3.35 (ddd, J = 15.0, 3.8, 2.4 Hz, 1H,
CH2), 5.65 (dd, J=3.8, 1.3 Hz, 1H, CH-O), 6.58 (s, 1H, NH),
6.69 (d, J=8.0 Hz, 1H, Ar), 7.96 (td, J=7.5, 1.1 Hz, 1H, Ar),
7.15 (td, J=8.0, 1.8 Hz, 1H, Ar), 7.19 (d, J=7.5 Hz, 1H, Ar); 13
C
In conclusion, the enantioselective approach to the synth-
esis of 3,4-benzo-5-oxacephams and 4-aryloxyazetidinones
NMR (125, CDCl3) δ 16.2, 46.3, 76.3, 112.8, 122.4, 126.9,
127.9, 131.5, 154.1, 166.0; HR MS (ESI) calcd for [MþNa]þ
C10H11NO2Na 200.0682, found 200.0686; HPLC [OD-H, hex-
anes/IPA 8:2, 0.5 mL/min, tR[S] = 24.2 (minor), tR[R] = 32.0
(major)].
(16) (a) Shah, S. K.; Dorn, C. P.; Finke, P. E.; Hale, J. J.; Halmann, W.
K.; Krause, K. A.; Handler, G. O.; Kissinger, A. L.; Ashe, B. M.; Weston, H.;
Knight, W. B.; Maycock, A. L.; Dellea, P. S.; Fletcher, D. S.; Hand, K. M.;
Mumford, R. A.; Underwood, D. J.; Doherty, J. B. J. Med. Chem. 1992, 35,
3745. (b) Doherty, J. B.; Shah, S. K.; Finke, P. E.; Dorn, C. P.; Halmann, W.
K.; Hale, J. J.; Kissinger, A. L.; Thompson, K. R.; Krause, K.; Handler, G.
O.; Knight, W. B.; Maycock, A. L.; Ashe, B. M.; Gale, P.; Mumford, R. A.;
Andersen, O. F.; Williams, H. R.; Nolan, T. E.; Frankenfield, D. L.;
Underwood, D.; Vyas, K. P.; Kari, P. H.; Dahlgren, M. E.; Mao, J.; Fletcher,
D. S.; Dellea, P. S.; Hand, K. M.; Osinga, D. G.; Petersom, L. B.; Williams,
D. T.; Metzger, J. M.; Bonney, R. J.; Humes, J. L.; Pacholok, S. P.; Halon,
W. A.; Opas, E.; Stolk, J.; Davies, P. Proc. Natl. Acad. Sci. U.S.A. 1993, 93,
8727. (c) Knight, W. B.; Greek, B. G.; Chabin, R. M.; Gale, P.; Maycock, A.
L.; Weston, H.; Kuo, D. W.; Westler, W. M.; Dorn, C. P.; Finke, P. E.;
Halmann, W. K.; Hale, J. J.; Liesch, J.; MacCoss, M.; Nadia, M. A.; Shah, S.
K.; Underwood, D.; Doherty, J. B. Biochemistry 1992, 31, 8160. (d) Borth-
wick, A. D.; Weingarten, G.; Haley, T. M.; Tomaszewski, M.; Wang, W.; Hu,
Z.; Bedard, J.; Jin, H.; Yuen, L.; Mansour, T. S. Bioorg. Med. Chem. Lett.
1998, 8, 365.
Acknowledgment. This work was supported by the Min-
istry of Education and Science, Grant No. PBZ-KBN-126/
T09/08/2004. We acknowledge a grant (no. G 32-15) for
computational time at the Warsaw Supercomputing Centre
(ICM), Poland. A.K. thanks the Head of the Polish Acad-
emy of Sciences for a doctoral fellowship.
Supporting Information Available:
Experimental proce-
dures and characterization data of compounds 3 and 5. This
material is available free of charge via the Internet at http://
pubs.acs.org
5690 J. Org. Chem. Vol. 74, No. 15, 2009