(α-aminoacyl)amino-substituted heterocycles and related compounds

Article abstract of DOI:10.1021/jo8007379

(Chemical Equation Presented) N-Protected-(aminoacyl)benzotriazoles 1a-e,g,i,j,1a′-c′ convert heterocyclic amines of the following series: thiazoles (3a and 3a′), benzothiazoles (3b and 3b′), benzimidazoles (3c and 3c′), thiadiazoles (3d), pyrimidones (9a

Full text of DOI:10.1021/jo8007379

(r-Aminoacyl)amino-Substituted Heterocycles and Related
Compounds
Alan R. Katritzky,* Bahaa El-Dien M. El-Gendy, Ekaterina Todadze, and
Ashraf A. A. Abdel-Fattah
Center for Heterocyclic Compounds, Department of Chemistry, UniVersity of Florida, GainesVille,
Florida 32611-7200
katritzky@chem.ufl.edu
ReceiVed April 2, 2008
N-Protected-(aminoacyl)benzotriazoles 1a-e,g,i,j,1a′-c′ convert heterocyclic amines of the following
series: thiazoles (3a and 3a′), benzothiazoles (3b and 3b′), benzimidazoles (3c and 3c′), thiadiazoles
(3d), pyrimidones (9a,b,a′), pyrazoles (11a,b), and pyridines (13a-g, 13d′) under microwave irradiation,
into N-substituted amides in yields of 40-98% (average 76%). N-Protected peptidoylbenzotriazoles 6a,b
similarly afforded C-terminal N-protected dipeptidoyl amides 7a,b (52-60%).
Introduction
N-Acylbenzotriazoles15 have been employed for (i) N-
acylation16 in the preparation of primary, secondary, tertiary,17
and Weinreb amides;18 (ii) C-acylation for the preparation of
ꢀ-ketosulfones19 primary and secondary R-cyanonitriles,20 R-ni-
troketones,21 ketones,22 and R-ketoazines;23 and (iii) O-acylation
of aldehydes24 and of steroids25 to give esters.
N-Substituted heterocycles show anti-inflammatory,1 anti-
proliferative,2 antithrombotic,3 antifungal,4 and antineurological
biological activities.5 Such units occur in diverse pharmacologi-
cally active molecules including cell adhesion inhibitors,6
platelet-activating factor (RAF), or angiotensin II antagonists,7
mitogen-activated protein (MAP) kinase,8 and mitotic kinesin
KSP inhibitors.9 (R-Aminoacyl)amino-substituted heterocycles
are useful synthetic intermediates (Figure 1) for endomorphin-2
(EM-2) analogues (1),10 bacterial RND efflux pump inhibitors
(EPIs) such as MC-04,124 (2)11 and MC-02,595 (3),12 γ-secre-
tase inhibitor LY411575 (4),13 and inhibitors of tumor necrosis
factor-R converting enzyme (TACE) GW 3333 (5).14
N-(Boc-aminoacyl)benzotriazoles and chiral amines give N-(Boc-
R-amino)amides with no detectable racemization.26 Numerous
N-(protected-R-aminoacyl)benzotriazoles couple with unprotected
amino acids in mixed organic/aqueous solution with complete
(11) Watkins, W. J.; Landaverry, Y.; Leger, R.; Litman, R.; Renau, T. E.;
Williams, N.; Yen, R.; Zhang, J. Z.; Chamberland, S.; Madsen, D.; Griffith, D.;
Tembe, V.; Huie, K.; Dudley, M. N. Bioorg. Med. Chem. Lett. 2003, 13, 4241–
4244.
(1) Zablocki, J. A.; Tarlton, E.; Rizzi, J. P.; Manto,N. B. PCT Int. Appl.
9822457 1998; Chem. Abstr. 1998, 129, 27933.
(2) Hoffmann, M.; Grauert, M.; Brandl, T.; Steegmaier, M.; Hauptmann, R.
U.S. Patent 009457 2006; Chem. Abstr. 2006, 144, 1299006.
(3) Klein, S. I.; Molino, B. F.; Czekaj, M.; Gardner, C. J. U.S. Patent 5780590
1998; Chem. Abstr. 1998, 129, 122869.
(12) Renau, T. E.; Le´ger, R.; Filonova, L.; Flamme, E. M.; Wang, M.; Yen,
R.; Madsen, D.; Griffith, D.; Chamberland, S.; Dudley, M. N.; Lee, V. J.;
Lomovskaya, O. L.; Watkins, W. J.; Ohta, T.; Nakayama, K.; Ishida, Y. Bioorg.
Med. Chem. Lett. 2003, 13, 2755–2758.
(13) Fuwa, H.; Okamura, Y.; Morohashi, Y.; Tomita, T.; Iwatsubo, T.; Kan,
T.; Fukuyama, T.; Natsugari, H. Tetrahedron Lett. 2004, 45, 2323–2326.
(14) Rabinowitz, M. H.; Andrews, R. C.; Becherer, J. D.; Bickett, D. M.;
Bubacz, D. G.; Conway, J. G.; Cowan, D. J.; Gaul, M.; Glennon, K.; Lambert,
M. H.; Leesnitzer, M. A.; McDougald, D. L.; Moss, M. L.; Musso, D. L.;
Rizzolio, M. C. J. Med. Chem. 2001, 44, 4252–4267.
(15) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synlett 2005, 11, 1656–1665.
(16) Katritzky, A. R.; Khelashvili, L.; Mohapatra, P. P.; Steel, P. J Synth.
2007, 23, 3673–3677.
(4) Giori, P.; Vertuani, G.; Mazzotta, D.; Guarneri, M.; Pancaldi, d.; Brunelli,
A. Farmaco 1982, 37, 450–458.
(5) Brodney, M. A.; Coffman, K. J.; Kleinman, E. F.; O’neill, B. T.; Chen,
Y. L. U.S. Patent 066613 1998; Chem. Abstr. 2007, 146, 359172.
(6) Hagmann, W. D.; Delaszlo, S. E.; Doherty, G.; Chang, L. L.; Yang, G. X.
PCT Int. Appl. 012183 2001; Chem. Abstr. 2001, 134, 193737.
(7) Bowles, S. A.; Floyd, C. D.; Miller, A.; Whittaker, M.; Wood, L. M.
PCT Int. Appl. 9314069 1993; Chem. Abstr. 1993, 120, 77276.
(8) Kubo, A.; Imashiro, R.; Sakurai, H.; Miyoshi, H.; Ogasawara, A.;
Hiramatsu, H. PCT Int. Appl. 035638 2003; Chem. Abstr. 2003, 138, 353990.
(9) Dhanak, D.; Knight, S. D.; Lu, P.; Morgans, D.; Yao, B. PCT Int. Appl.
10.575 2003; Chem. Abstr. 2003, 140, 42200.
(17) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210–
8213.
(18) Katritzky, A. R.; Yang, H.; Zhang, S.; Wang, M. ARKIVOC 2002, xi,
39–44.
(19) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem. 2003,
68, 1443–1446.
(10) Fujita, Y.; Tsuda, Y.; Li, T.; Motoyama, T.; Takahashi, M.; Shimizu,
Y.; Yokoi, T.; Sasaki, Y.; Ambo, A.; Kita, A.; Jinsmaa, Y.; Bryant, S. D.;
Lazarus, L. H.; Okada, Y. J. Med. Chem. 2004, 47, 3591–3599.
(20) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem. 2003,
68, 4932–4934.
5442 J. Org. Chem. 2008, 73, 5442–5445
10.1021/jo8007379 CCC: $40.75 2008 American Chemical Society
Published on Web 06/11/2008

(R-Aminoacyl)amino-Substituted Heterocycles
SCHEME 1
TABLE 1. Preparation of Acylaminothiazoles, -benzothiazoles,
-benzimidazoles, and -thiadiazoles
FIGURE 1. Biologically active (R-aminoacyl)amino-substituted
heterocycles.
preservation of the original chirality.27 In continuation of this
research, we now report the synthesis of N-substituted amides
3a-d, 3a′*-c′, 9a,b, 9a′, 11a,b, 13a-g, 13d′ and N-protected
dipeptidoyl amides 7a,b by treatment of the corresponding
N-(protected-aminoacyl)benzotriazoles 1a-e,g,i,j, 1a′-c′, N-
acylbenzotriazoles 1f,h or N-(protected-peptidoyl)benzotriazoles
6a,b with heterocyclic amines under microwave irradiation.
Result and Discussions
I. Preparation of Acylaminothiazoles, -benzothiazoles,
-benzimidazoles, and -thiadiazoles. The starting N-(protected-
aminoacyl)benzotriazoles 1a-d, 1a′, 1b′, 1c′ were prepared
from N-protected amino acids following our published one-step
procedure.28,29
a Isolated yield. b From ref 32.
Treatment of 2-aminothiazole (2a), 2-amino-6-methoxyben-
zothiazole (2b), N-benzyl-2-aminobenzimidazole (2c), and
5-amino-3-methoxy-1,2,4-thiadiazole (2d) and N-(protected-R-
aminoacyl)benzotriazoles 1a-d, 1a′, 1b′, 1c′ under microwave
irradiation at 70 °C for 30 min (150 min for 2d with 1d) gave
the N-substituted amides 3a-d, 3a′, 3b′, and 3c′ in 50-98%
yields (Scheme 1 and Table 1).
The enantiopurity of compounds 3a-c was confirmed by
HPLC analysis. As expected, HPLC analysis of enantiopure
3a-c gave a single peak for each compound. In contrast, two
peaks were observed for the corresponding racemic N-substi-
tuted heterocycles 3a′, 3b′, and 3c′ (Table 1).
L-Met-Bt (1e) with unprotected L-Ala (4a) in aqueous acetoni-
trile) was treated with benzotriazole and SOCl2 to provide
N-(protected-dipeptidoyl)benzotriazole Cbz-L-Met-L-Trp-Bt
(6a). Compound 6a was reacted with 2a under microwave
irradiation (100 W) in DMF at 70 °C for 30 min to give
dipeptidoyl amide 7a in 60% yield (Scheme 2). Dipeptidoyl
amide 7b was prepared by coupling of 6-methoxybenzothiazol-
2-amine (2b) with Cbz-L-Phe-L-Ala-Bt (6b) as described above
in 52% (Scheme 2).
Few literature reports describe the preparation of carboxa-
mides of type 3. Kraus et al.30,31 investigated the coupling
reaction between amino acids and weakly nucleophilic het-
eroaromatic amines including substituted 2-aminothiazole and
substituted 2-aminobenzothiazole using four different coupling
reagents such as (i) DCC/HOBt, (ii) EDC, (iii) HBTU, (iv)
benzotriazole-1-yloxytris(dimethylamino)phosphonium hexaflu-
orophosphate (BOP), and (v) phosphorus oxychloride POCl3/
pyridine. Use of the uronium coupling reagent HBTU failed.
The best literature yields (41-93%) were achieved with the
POCl3 in pyridine. These authors conclude30 “the N-acylation
of weakly nucleophilic heterocyclic amines by protected amino
As a further application of this synthetic approach, Cbz-L-
Met-L-Trp-OH (5a) (prepared as reported27b by coupling of Cbz-
(21) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Gromova, A.; Witek, R.; Steel,
J. S. J. Org. Chem. 2005, 70, 9211–9214.
(22) Katritzky, A. R.; Khanh, N., B.; Le, Khelashvili, L.; Mohapatra, P. P.
J. Org. Chem. 2006, 71, 9861–9864.
(23) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Akhmedova, R. G. ARKIVOC
2005, Vi, 329–338.
(24) Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J. Heterocycl. Chem.
1999, 36, 777–781.
(25) Katritzky, A. R.; Angrish, P. Steroids 2006, 71, 660–669.
(26) Katritzky, A. R.; Wang, M.; Yang, H.; Zhang, S.; Akhmedov, N. G.
ARKIVOC 2002, Viii, 134–142.
(27) (a) Katritzky, A. R.; Todadze, E.; Angrish, P.; Draghici, B. J. Org. Chem.
2007, 72, 5794–5801. (b) Katritzky, A. R.; Suzuki, K.; Singh, S. K. Synthesis
2004, 2645–2652.
(30) Quelever, G.; Burlet, S.; Garino, C.; Pietrancosta, N.; Laras, Y.; Kraus,
J. J. Comb. Chem. 2004, 6, 695–698.
(28) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003, 2795–2798.
(29) Katritzky, A. R.; Angrish, P.; Suzuki, K. Synthesis 2006, 411–424.
(31) Laras, Y.; Quelever, G.; Garino, C.; Pietrancosta, N.; Sheha, M.; Bihel,
F.; Wolfe, M. S.; Kraus, J. Org. Biomol. Chem 2005, 3, 612–618.
J. Org. Chem. Vol. 73, No. 14, 2008 5443

Katritzky et al.
SCHEME 2
SCHEME 4
SCHEME 5
III. Acylation of Aminopyrazoles. N-Substituted pyrazoles
were prepared in yields of 23-89% and reaction times of 5-10
h from activated aromatic acids and N-protected amino acids
via isolated intermediates utilizing acyl chlorides37 or N-
protected aminoacyl chlorides4 (not easily storable and sensitive
to degradation and racemization.38 Literature couplings without
isolation of intermediates include activation by (HCTU)/
(HATU),39 EDC/HOBt,39 or phosponate anhydrides (T3P)39 in
yields ranging of up to 42% in reaction times up to 16 h.
We successfully coupled 4-ClPhCOBt 1f and Cbz-Gly-Bt 1g
with 5-amino-3-methyl-1-phenylpyrazole (10a) in DMF under
microwave irradiation (100 W, 70 °C) during 30 min (Scheme
4) to obtain 11a,b (40 and 75%, respectively). Our N-
(aminoacyl)benzotriazoles are stable, easy to handle reagents
and can be stored at 20 °C for months.
IV. Preparation of (Acylamino)pyridines. Microwave ir-
radiation of 1f and 2-aminopyridine (12a) at 70 °C for 30 min
gave N-(4-chloropyridin-2-yl)benzamide (13a) in 94% yield
(heating 1f and 12a in DMF at 100 °C for 6 h gave 13a in
75%). The microwave conditions were applied to the reactions
of N-acylbenzotriazoles 1d,e,g-j and 1d′ with 2-aminopyridine
(12a), 2-amino-4-methylpyridine (12b), and 2-amino-4,6-dim-
ethylpyridine (12c), thus providing 55-98% of the correspond-
ing heteroaryl carboxamides 13b-g and 13d′ (Scheme 5 and
Table 2).
SCHEME 3
acids is not a straight-forward reaction which could be achieved
under any standard coupling conditions”. Other literature
methods utilizing DCC/HOBt32 or EDC14 as coupling reagents
reported yields of 27-36% and reaction times of 4-16 h.
II. Preparation of (Acylamino)pyrimidones. Procedures
similar to those of Section I above coupled Cbz-L-Ala-Bt 1b,
Cbz-DL-Ala-Bt 1b′, and 4-ClPhCOBt 1f, with 4-amino-1-
benzylpyrimidin-2-one (8a) under microwave irradiation to give
novel 9a,b and 9a′ in 76-98% yields (Scheme 3). The structures
of compounds 9a,b and 9a′ were supported by spectroscopic
data together with microanalyses. The 13C NMR and 1H NMR
spectra of N-substituted amides 9a,b and 9a′ showed charac-
teristic signals in the regions of 165.9-175.2 and 10.94-11.31
ppm which were assigned to the N-heteroaryl amide carbonyl
carbon and the proton of the NH, respectively.
The absence of racemization was confirmed for 13d by HPLC
analysis, which showed a single peak at 3.66 min, while two
peaks of equal intensity at retention times 3.63 and 5.74 min
were observed for the racemic Cbz-DL-Phe-NHPy-2 (13d′).
This methodology is advantageous compared to several recent
approaches to (R-aminoacyl)amino-substituted pyridines in
yields from unreported to 77% and reaction times from
unreported to 54 h, using (i) N,N′-dicyclohexylcarbodiimide
(DCC) and 1-hydroxybenzotriazole HOBt,40 (ii) 1-ethyl-3-(3-
Previous preparations of N-substituted aminopyrimidones
reported yields of 19-79% and reaction times of 17-40 h using
carbodiimide-based reagents such as DCC,33 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDAC),34 or (1-ethyl-3-(3′-
dimethylaminopropyl)carbodiimide (EDCI)35 in the presence of
HOBt. Kenner et al.36 acylated 3-methylcytosine with benzoyl
chloride in pyridine at 100 °C (1.5 h) in 65% yield.
(32) Leung-Toung, R.; Wodzinska, J.; Li, W.; Lowrie, J.; Kukreja, R.;
Desilets, D.; Karimian, K.; Tam, T. F. Bioorg. Med. Chem. 2003, 11, 5529–
5537.
(33) Camplo, M.; Niddam, V.; Barthelemy, P.; Faury, P.; Mourier, N.; Simon,
V.; Charvet, A. S.; Trabaud, C.; Graciet, J. C. Eur. J. Med. Chem. 1995, 30,
789–800.
(37) (a) Daidone, G.; Bajardi, M. L.; Plescia, S.; Raffa, D.; Schillaci, D.;
Maggio, B.; Benetollo, F.; Bombieri, G. Eur. J. Med. Chem. 1996, 31, 461–
468. (b) Daidone, G.; Maggio, B.; Plescia, S.; Raffa, D.; Musiu, C.; Milia, C.;
Perra, G.; Marongiu, M. Eur. J. Med. Chem. 1998, 33, 375–382.
(34) Manfredini, S.; Marastoni, M.; Tomatis, R.; Durini, E.; Spisani, S.; Pani,
A.; Marceddu, T.; Musiu, C.; Marongiu, M. E.; La Colla, P. Bioorg. Med. Chem.
2000, 8, 539–547.
(38) (a) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R. H. J. Am.
Chem. Soc. 1990, 112, 9651–9652. (b) Bertho, J.-N.; Loffet, A.; Pinel, C.;
Reuther, F.; Sennyey, G. Tetrahedron Lett. 1991, 32, 1303–1306.
(39) Rzepecki, P.; Gallmeier, H.; Geib, N.; Cernovska, K.; Koenig, B.;
Schrader, T. J. Org. Chem. 2004, 69, 5168–5178.
(35) Balajthy, Z.; Aradi, J.; Kiss, I. T.; Elodi, P. J. Med. Chem. 1992, 35,
3344–3349.
(36) Kenner, G. W.; Reese, C. B.; Todd, A. R. J. Chem. Soc. 1955, 855–
859.
(40) Molard, Y.; Parrot-Lopez, H. Tetrahedron Lett. 2001, 42, 4799–4802.
5444 J. Org. Chem. Vol. 73, No. 14, 2008

(R-Aminoacyl)amino-Substituted Heterocycles
TABLE 2. Preparation of (Acylamino)pyridines from N-Acyl and
N-(Aminoacyl)benzotriazoles
13g, which was prepared in high yield (98%) by our alternative
methodology, demonstrating the wide scope of the benzotriazole
approach.
Conclusions
In summary, a general and convenient route has been
developed for the preparation of N-substituted amides derived
from diverse heterocyclic amines and carboxylic acids under
simple reaction conditions.
Experimental Section
General Procedure for the Preparation of N-Substituted
Amides 3a-d, 3a′-c′, 9a,b, 9a′, 11a,b, 13a-g, 13d′, and
Dipeptide Amides 7a,b. A dried heavy-walled Pyrex tube contain-
ing a small stir bar was charged with benzotriazole adduct (0.25
mmol) and aminoheterocycle 1 (0.25 mmol) dissolved in DMF (1
mL). The reaction mixture was exposed to microwave irradiation
(100 W) for 30 min at a temperature of 70 °C. The mixture was
allowed to cool through an inbuilt system until the temperature
had fallen below 30 °C (ca. 10 min). The reaction mixture was
quenched with water and extracted with EtOAc (3 × 25 mL). The
extracts were washed with (10%) Na2CO3 (3 × 50 mL) and water
(3 × 50 mL) and dried (MgSO4). The solvent was removed under
reduced pressure, and the residue was subjected to silica gel column
using EtOAc/hexane (1:1) as an eluent to give the corresponding
N-substituted amide.
Benzyl N-[(1S)-1-(1H-indol-3-ylmethyl)-2-oxo-2-(1,3-thiazol-
2-ylamino)ethyl]carbamate (3a): White microcrystals (81%), mp
1
94-96 °C, [R]25 ) -39.8 (c 1.7, CHCl3); H NMR (300 MHz,
CDCl3) δ 4.84-D4.86 (m, 1H), 3.21-3.35 (m, 2H), 5.06 (d, J )
12.1 Hz, 1H), 5.11 (d, J ) 12.5 Hz, 1H), 5.90 (d, J ) 8.0 Hz, 1H),
6.76 (s, 2H), 6.95 (t, J ) 7.1 Hz, 1H), 7.08 (t, J ) 7.5 Hz, 1H),
7.19-7.32 (m, 7H), 7.45 (d, J ) 7.6 Hz, 1H), 8.00 (s, 1H), 11.73
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 29.0, 55.6, 67.2, 109.5,
111.2, 113.7, 118.4, 119.7, 122.3, 123.0, 127.1, 128.0, 128.2, 128.5,
135.9, 136.9, 156.1, 158.3, 170.0. Anal. Calcd for C22H20N4O3S:
C, 62.84; H, 4.79; N, 13.32. Found: C, 62.65; H, 4.74; N, 13.14.
Benzyl {(S)-1-[(S)-1-(6-Methoxybenzothiazol-2-ylcarbamoyl)-
ethylcarbamoyl]-2-phenylethyl}carbamate (7b): White prisms
(52%), mp 190-192 °C, [R]25D ) -68.8 (c 2.3, CHCl3); 1H NMR
δ 12.05 (br s, 1H), 8.15 (d, J ) 8.9 Hz, 1H), 7.90 (d, J ) 8.4 Hz,
1H), 7.61 (d, J ) 8.8 Hz, 1H), 7.27-7.23 (m, 6H), 7.03-7.00 (m,
5H), 6.86 (dd, J ) 8.9, 2.3 Hz, 1H), 5.42-5.35 (m, 2H), 5.12 (d,
J ) 12.6 Hz, 1H), 5.03 (dd, J ) 16.2, 8.4 Hz, 1H), 3.85 (s, 3H),
3.13-2.98 (m, 2H), 1.49 (d, J ) 6.6 Hz, 3H); 13C NMR δ 172.8,
170.7, 156.8, 156.7, 156.0, 142.5, 136.6, 136.0, 133.2, 129.3, 128.3,
127.8, 127.7, 126.9, 121.9, 115.1, 103.9, 103.3, 66.9, 56.5, 55.7,
48.7, 39.9, 19.2. Anal. Calcd for C28H28N4O5S: C, 63.14; H, 5.30;
N, 10.52. Found: C, 62.77; H, 5.34; N, 10.34.
a Isolated yield. b HPLC for 13d: 3.66 min. c HPLC for 13d′: 3.63
and 5.74 min. d From ref 44a. e From ref 44b. f From ref 10. g From ref
42. h No yield stated from ref 43.
dimethylaminopropyl)carbodiimide (EDC) and HOBt,41 (iii)
1,1′-carbonyldiimidazole (CDI),42 (iv) ethyl chloroformate,43 (v)
phosphorus trichloride (PCl3),10 and (vi) acid chloride method.44
Our approach provides known compounds 13a,b,d,f,g in
better or comparable yields to those reported in the literature
(Table 2) and afforded previously unreported N-substituted
amides 13c, 13d′, 13e, and 7b in isolated yields of 52-98%.
The method quoted in ref 42, that is, activating the correspond-
ing N-protected amino acids with CDI followed by treatment
with 2-amino-4,6-dimethylpyridine is advantageous for N-
substituted amides from 2-amino-4,6-dimethylpyridine, and we
prepared 13f (68%, cf. 77%) by this procedure. However, similar
treatment of 2-amino-4-methylpyridine failed to yield compound
Acknowledgment. We thank Dr. C. D. Hall for help with
the preparation of this manuscript.
(41) Pratt, L. M.; Beckett, R. P.; Bellamy, C. L.; Corkill, D. J.; Cossins, J.;
Courtney, P. F.; Davies, S. J.; Davidson, A. H.; Drummond, A. H.; Helfrich,
K.; Lewis, C. N.; Mangan, M.; Martin, F. M.; Miller, K.; Nayee, P.; Ricketts,
M. L.; Thomas, W.; Todd, R. S.; Whittaker, M. Bioorg. Med. Chem. Lett. 1998,
8, 1359–1364.
Supporting Information Available: Compound character-
ization data for 3b-d, 3a′-c′, 7a, 9a,b, 9a′, 11a,b, 13a-g,
13d′. This material is available free of charge via the Internet
at http://pubs.acs.org.
(42) Duflos, M.; Courant, J.; Le Baut, G.; Grimaud, N.; Renard, P.; Manechez,
D.; Caignard, D.-H. Eur. J. Med. Chem. 1998, 33, 635–645.
(43) He, L. Acta Crystallogr. 2006, E62, o3947–o3948.
(44) (a) Vaughan, J.; Smith, P. A. S. J. Org. Chem. 1958, 23, 1909–1912.
(b) Jozwiak, A.; Brzezinski, J. Z.; Plotka, M. W.; Szczesniak, A. K.; Malinowski,
Z.; Epsztajn, J. Eur. J. Org. Chem. 2004, 33, 3254–3261.
JO8007379
J. Org. Chem. Vol. 73, No. 14, 2008 5445