Design and synthesis of a conformationally rigid mimic of the dihydropyrimidine calcium channel modulator SQ 32,926

Article abstract of DOI:10.3390/50300227

A conformationally rigid polyheterocycle (3) which mimics the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators is prepared in a seven-step reaction sequence based on a Biginelli-type cyclocondensation reaction.

Full text of DOI:10.3390/50300227

Molecules 2000, 5, 227-239
molecules
ISSN 1420-3049
http://www.mdpi.org
Design and Synthesis of a Conformationally Rigid Mimic of the
Dihydropyrimidine Calcium Channel Modulator SQ 32,926‡
Birgit Jauk, Tetiana Pernat and C. Oliver Kappe*
Institute of Chemistry / Organic and Bioorganic Chemistry, Karl-Franzens-University Graz, Heinrich-
strasse 28, A-8010 Graz, Austria
Tel.: (43)-(316)-380-5352, Fax: (43)-(316)-380-9840, E-mail: oliver.kappe@kfunigraz.ac.at,
URL: http://www-ang.kfunigraz.ac.at/~kappeco
‡Presented in part at The First International Electronic Conference on Synthetic Organic Chemistry
(ECSOC-1), September, 1-30, 1997. URL: http://www.unibas.ch/mdpi/ecsoc/
Synthesis and Reactions of Biginelli Compounds, 21. For part 20, see [30].
*Author to whom correspondence should be addressed.
Received: 9 February 2000 / Accepted: 29 February 2000 / Published: 3 March 2000
Abstract: A conformationally rigid polyheterocycle (3) which mimics the putative receptor-
bound conformation of dihydropyridine-type calcium channel modulators is prepared in a
seven-step reaction sequence based on a Biginelli-type cyclocondensation reaction.
Keywords: Dihydropyrimidines, Biginelli reaction, isomünchnones, 1,3-dipolar cycloaddi-
tion reactions, AM1 calculations, conformation.
Introduction
4-Aryl-1,4-dihydropyridines (DHPs, e.g nifedipine, 1) are the most studied class of organic calcium
channel modulators and, since their introduction into clinical medicine in 1975, have become almost
indispensable for the treatment of cardiovascular diseases such as hypertension, cardiac arrhythmias,
or angina [1]. More than 25 years after the introduction of nifedipine (1), many DHP analogs have now
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

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Molecules 2000, 5
been synthesized and numerous second-generation commercial products have appeared on the market
[2].
In recent years interest has also focused on aza-analogs such as dihydropyrimidines of type 2
(DHPMs) which show a very similar pharmacological profile to classical dihydropyridine calcium
channel modulators [3-9]. Over the past few years several lead-compounds were developed (i.e. SQ
32,926) [6-8] that are superior in potency and duration of antihypertensive activity to classical DHP
drugs, and compare favorable with second-generation analogs such as amlodipine and nicardipine
[6,7]. These inherently asymmetric DHPM derivatives are not only very potent calcium channel
modulators, but also have been studied extensively to expand the existing structure-activity relation-
ships and to get further insight into molecular interactions at the receptor level [3-9].
O2N
O2N
O2N
O
i-PrO2C
i-PrO2C
CONH2
O
MeO2C
CO2Me
Me
N
N
CO2Me
O
Me
N
H
N
H
Me
Me
N
H
1
, nifedipine
2, SQ 32,926
3
DHP calcium channel antagonists (e.g. 1, nifedipine) are flexible molecules, in which the C4-aryl
moiety and the C3/C5 ester substituents can rotate, and the conformation of the 1,4-dihydropyridine
ring can change [10]. Despite many studies on the structure-activity relationships for DHPs and
DHPMs with respect to calcium channel antagonist-agonist modulation, there still remains debate on
the exact stereochemical/conformational requirements for activity [9-12]. It was recently proposed that
calcium channel modulation (antagonist vs. agonist activity) is dependent on the absolute configuration
at C4, whereby the orientation of the 4-aryl group (R- versus S-enantiomer) acts as a "molecular
switch" between antagonist and agonist activity [9]. In the receptor-bound conformation the substituted
aryl ring should be positioned axially, perpendicular to, and bisecting the boat-like dihydropyridine
ring, with the 4-aryl substituent (X) prefering the synperiplanar (sp) orientation relative to C4-H (Fig-
ure 1) [9].
(non-essential)
Right-hand side
X = sp
X
hydrogen bond
N H
H
O
Me
R
O
Left-hand side
(essential)
Figure 1. Proposed receptor-bound conformation of DHP/DHPM calcium channel modulators.

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Molecules 2000, 5
A cis-carbonyl ester orientation (with respect the C5=C6 bond) was also found mandatory for cal-
cium channel modulatory activity, whereas the right-hand side of the dihydropyridine ring was pro-
posed non-essential [9], providing a rationale for the similar pharmacological profile observed for
DHPs and DHPMs.
In the present article we detail the synthesis of the polycyclic DHPM derivative 3 that represents a
conformationally rigid analog of SQ 32,926 [6], "frozen" in the putative bioactive conformation shown
in Figure 1. All structural changes on 2 are made on the non-essential right hand side of the molecule,
thereby not interfering with the receptor-sensitive groups on the left-hand side.
Results and Discussion
The synthetic strategy towards the polycyclic DHPM derivative 3 is based on an intramolecular 1,3-
dipolar cycloaddition reaction of an o-alkenylaryl-tethered dihydropyrimidine-fused isomünchnone
dipole ("cyclization-cycloaddition cascade", see Scheme 1 [13]).
X
X
( )
n
( )
n
Biginelli-
condensation
RO2C
H
H
O
RO2C
Me
N
NH2
+
N
H
Me
O
O
H2N
O
4
1) protection
2) annulation/
dipole-formation
X
X
( )
n
O
_
( )
n
O
1) cycloaddition
2) deprotection
RO2C
Me
RO2C
Me
N
N
R
O
R
O
N
N
+
PG
5
H
6
Scheme 1.
In recent publications we have described model studies dealing with bimolecular and intramolecluar
dipolar cycloaddition reactions of a variety of dihydropyrimidine-fused mesomeric betaines, including
1,3-thiazolium-4-olates, 1,3-oxazolium-4-olates, and cross-conjugated heteroaromatic 1,3-thiazinium

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Molecules 2000, 5
betaines [14]. These studies have led to the synthesis of biologically inactive polyheterocycles of type
6 where the crucial N1 position of the pyrimidine nucleus (cf. Figure 1) is blocked by a methyl group
[14]. More recently we have devised a modified protection group strategy in order to access deriva-
tives where this position is unblocked [15]. These targets, however, still lacked the all important elec-
tron-withdrawing substituent on the aromatic ring (6, X = H) and therefore proved inactive.
In order to prepare a conformationally rigid mimic of the orally active antihypertensive agent and
calcium channel modulator SQ 32,926 (2) [6], a nitro group had to be introduced into the meta-
position of the aromatic ring. We initially considered to use the corresponding 5-nitro-2-
alkenylbenzaldehydes as suitable building blocks in a classical Biginelli-type cyclocondensation reac-
tion (Scheme 1, ® 4, X = NO2) [16]. Apparently, such aldehydes are too unstable and have never been
reported in the literature, and all our attempts to synthesize e.g. 5-nitro-2-vinyl-benzaldehyde failed.
We have therefore chosen to introduce the ortho-alkenyl tether required for the intramolecular 1,3-
dipolar cycloaddition at a later stage in the synthesis. The corresponding ortho-bromo substituted ana-
log 7 was readily prepared by Biginelli condensation of 2-bromo-5-nitrobenzaldehyde with isopropyl
acetoacetate and urea. Although a number of improved protocols for carrying out the one-pot Biginelli
reaction have recently been reported [17], the method described by Folkers et al. in 1932 using acetic
acid as solvent [18] proved to be superior to all other procedures, producing DHPM 7 in 66% yield. 2-
Bromo-5-nitrobenzaldehyde was readily available by nitration of commercially 2-bromo-benzaldehyde
with fuming HNO3/H2SO4 [19]. In the next step the allyl tether was introduced on the DHPM scaffold
via Stille reaction [20], using allyltributylstannane as reagent. The palladium-catalyzed cross coupling
process was best performed in refluxing toluene using tetrakis(triphenylphosphine)palladium, as cata-
lyst. Despite considerable variations in experimental conditions [20], the maximum yield of DHPM 8
obtained was 47%.
O2N
O2N
O2N
Br
Br
AcOH
HCl (cat)
Bu3Sn
O
H
i-PrO2C
H
O
H
i-PrO2C
i-PrO2C
N
N
NH2
+
D
Pd(PPh3)4
toluene, D
O
Me
N
H
Me
Me
N
H
O
H2N
O
8
7
Scheme 2.
In order to set up the cyclization-cycloaddition cascade for the construction of polycycle 3 the urea
moiety was functionalized at N3 by regioselective malonylacylation [21] with commercially available
methyl malonyl chloride. Even when a large excess of acylating reragent was used, the N3-acylated
product was obtained in a regiospecific manner, without any N1- or bis-acylation products being
formed. In a subsequent step the diazo functionality was introduced by standard diazo transfer with

231
Molecules 2000, 5
mesyl azide [22]. As we have previously noted, the protection of the N1 nitrogen at this stage of the
synthesis is crucial for the success of the cyclization-cycloaddition cascade [15]. In the absence of a
protective group the isomünchone intermediate (i.e., 5, PG = H, Scheme 1) will undergo a rapid, ther-
mally allowed 1,5-sigmatropic hydrogen shift to form an isomeric oxazole, which cannot participate in
the anticipated cycloaddition sequence 5 ® 6 [14]. In contrast to the CBZ-based (benzyloxycarbonyl)
protection method that we have devised in our model studies [15], we have now employed the N-BOC-
functionality (tert-butyloxycarbonyl) as protective group. The corresponding N1-BOC protected
DHPM 10 was synthesized in standard fashion by treatment of DHPM 9 with (BOC)2O/DMAP [23].
The advantage of this protection method is that the BOC group can easily be removed in the final
product (see below) under conditions that do not require palladium-catalyzed hydrogenolysis, which
here may not be compatible with the presence of a nitro group on the aromatic ring.
NO2
NO2
NO2
1) ClCO-CH2CO2Me
2) MesN3, TEA
(BOC)2O
DMAP
O
O
H
O
i-PrO2C
Me
CO2Me
CO2Me
i-PrO2C
Me
i-PrO2C
Me
t-BuO
N
N
N
O
N2
N2
N
H
8
N
H
9
O
N
O
10
Scheme 3.
The final steps in the synthesis, the cyclization-cycloaddition cascade, is shown in Scheme 4. De-
composition of the BOC-protected diazo imide precursor 10 with a catalytic amount of rhodium ace-
tate in refluxing benzene furnished directly the protected pentacyclic DHPM analog 12 in 55% yield,
without isolation of the initially generated transient isomünchone dipole 11. Note that in the absence of
suitable dipolarophiles (i.e. an internal p-bond) such cyclic carbonyl ylide dipoles 11 can be isolated,
and, in fact, are quite stable crystalline compounds [24]. In contrast to the cycloaddition reactions car-
ried out on the earlier model systems [14,15], here an isomeric pentacylce 13 was additionally isolated
in 38% yield. The formation of 13 can be rationalized in terms of a double bond isomerization in the
allyl-tethered side chain, probably catalyzed by the transition metal (Rh2+) present in the reaction me-
dium. Regardless of the choice of catalyst (rhodium acetate or rhodium perflurobutyrate) and reaction
conditions (e.g. inverse addition) the ratio of these cycloaddition products remained unchanged. The
1
13
structures of both cycloadducts were confirmed by comparison of their H and C NMR spectra with
spectroscopic data obtained for close analogs for which X-ray structure determinations had been car-
ried out [14]. For pentacycle 13, the position of the newly formed methyl group at C13 anti to the
bridged aryl substituent follows from the observed small coupling constant for the two vicinal hydro-
gen atoms at C12 and C13 (J = 2.9 Hz, torsion angle ca. 115°). Finally, gentle removal of the BOC
group in 12 was carried out by microwave-promoted deprotection following a recently reported proto-
col [25] to furnish the target compound 3 in 90% yield.

232
Molecules 2000, 5
NO2
NO2
O
O2N
O
O
CO2Me
i-PrO2C
Me
t-BuO
Rh2(OAc)4 i-PrO2C
i-PrO2C
N
O
_
N
O
N
O
CO2Me
N2
D
N
O
O
CO2Me
Me
N
O
+
Me
N
12
10
11
t-BuO
t-BuO
O2N
SiO2, mwave
O2N
O
O
i-PrO2C
i-PrO2C
N
O
N
CO2Me
CO2Me
O
Me
N
O
Me
N
H
Me
13
3
t-BuO
Scheme 4.
Molecular models based on semiempirical calculations of pentacycle 3 demonstrate that the ge-
ometry of this conformationally rigid DHPM derivative is very similar to the receptor-bound confor-
mation proposed in Figure 1 for DHP/DHPM calcium channel modulators (see Figure 3). The aryl
group is "tied" into the axial position and is (nearly) perpendicular to and bisecting the boatlike dihy-
dropyrimidine ring. The nitro substituent on the aromatic ring is forced into the synperiplanar (sp) ori-
entation relative to the C4-H atom. At the same time, the amide functionality on the right-hand side in
SQ 32,926 here is fixed into the trans position. Only the isopropyl ester moiety on the left-hand side
retains its conformational freedom (see Figure 2). According to semiempirical AM1 calculations, the
cis carbonyl ester orientation in 3 is favoured over the corresponding trans orientation by 1.68
kcal/mol. In DHPMs these energy differences are generally small, and the rotational barriers have also
been calculated to be relatively minor (2-4 kcal/mol) [26-28]. In a biological environment, both calcu-
lated mimium energy ester conformers therefore seem accessible.
9
8
O2N
O2N
10
11
12
7
i-Pr
i-Pr
6
O
O
O
O
16
H
3
17
4
5
14
N
H
5
6
O
N
2
O
4
N
13
3
1
2
15
CO2Me
1
O
18
Me
N
O
Me
N
H
H
2, SQ 32,926
3
Figure 2. Conformationally flexible bonds and functional groups in SQ 32,926 and DHPM 3.

233
Molecules 2000, 5
Figure 3. AM1 optimized geometry of the conformationally rigid pentacycle 3.
Figure 4. AM1 optimized geometries for the two lowest energy conformers of SQ 32,926 (cis/ap, left,
DHf = -109.55 kcal/mol; cis/sp, right, DHf = -109.11 kcal/mol).
For comparison purposes, we have calculated the minimum energy geometries for the conforma-
tionally non-restricted SQ 32,926. Based on the presence of three conformationally flexible bonds
(Figure 2) eight minimum conformers were located [26-28]. Since the intramolecular H-bond between
the N3-carbamoyl NH and the C2 carbonyl oxygen stabilized the trans carbonyl arrangement shown in
Figure 3 by at least 6 kcal/mol (AM1), the relatively high energy conformers with an N3 cis carbonyl
oriented carbamoyl functionality (strong dipole-dipole repulsion) were discounted. Of the remaining

234
Molecules 2000, 5
four conformers, the lowest energy conformer was the one having a C5 cis carbonyl oriented ester
group with the nitro group on the C4-aryl ring oriented in antiperiplanar (ap) orientation with respect
to C4-H (Figure 4). Note that his conformation does not correspond to the proposed bioactive cis/sp
arrangement shown in Figure 1. However, the putative bioactive cis/sp conformer (Figure 4) is only
0.44 kcal/mol higher in energy than the lowest energy cis/ap conformer. The respective trans C5 ester
carbonyl rotamers (not shown) were ca. 1.5-2.0 kcal/mol higher in energy than the corresponding cis
isomers.
In conclusion, we have reported the synthesis and structural characterization of a conformationally
rigid analog of the calcium channel modulator SQ 32,926. All modifications on the SQ 32,926 scaffold
were performed on the putative [9] nonessential right-hand side of the molecule, thereby not interfer-
ing with the receptor sensitive groups on the left hand side. The current model compound mimics the
proposed bioactive conformation of SQ 32,926 and therefore provides a tool to test the validity of the
currently accepted binding site model for DHP/DHPM calcium channel modulators [9]. Preliminary
electrophysiological measurements have confirmed that 3 has calcium channel antagonistic activity in
the micromolar range. Further structural modifications on these dihydropyrimidine analogs are cur-
rently being considered in our laboratory in order to increase their activity (modification of the right-
hand side). In addition, in order to the test the binding site model depicted in Figure 1 it will be neces-
sary to access enantiomerically pure 3 with known absolute configuration. Work along these lines is
currently in progress in our laboratories [29].
Experimental
General Procedures and Materials
Melting points were determined on a Gallenkamp melting point apparatus, Mod. MFB-595, and are
uncorrected. IR spectra were recorded on a Perkin-Elmer 298 spectrophotometer as KBr pellets. 1H and
13C NMR spectra were obtained on a Varian XL-200 Gemini instrument at 200 MHz and 50 MHZ, re-
spectively (J values are given in Hz). Microanalyses were obtained on a Fisons Mod. EA 1108 ele-
mental analyzer. Reactions were monitored by thin layer chromatography (TLC) on 0.2mm silica gel
F-252 (Merck) plates. Flash chromatography was performed with silica gel 60 (40-63 mm, Aldrich)
using mixtures of hexane and ethyl acetate as eluent. Methylene chloride, benzene, and THF were dis-
tilled and dried over 4 Å molecular sieves. Triethylamine was distilled from KOH before use. All
moisture-sensitive reactions were carried out under dry argon atmosphere employing flame-dried
glassware.
Computational Methods
Semiempirical AM1 calculations were carried out using the PC Spartan Pro package (Version 1.0.1)
on a Pentium PC. Starting geometries were obtained using Spartans interactive building mode, and

235
Molecules 2000, 5
preoptimized using the SYBYL force field. For pentacycle 3 the starting geometries were obtained
from X-ray structure coordinates of close analogs [14]. Geometries were completely optimized without
molecular mechanics corrections for amide bonds. Convergance was achieved in all optimizations.
2-Bromo-5-nitrobenzaldehyde
This material was prepared following a literature procedure [19]. 2-Bromobenzaldehyde (8.94 g, 48
mmol) was added dropwise under stirring at 5-10°C to a mixture of fuming HNO3 (4 mL) and concen-
trated H2SO4 (30 mL). The resulting yellow solution was allowed to warm to rt and subsequently was
1
poored onto ice-water, mp 98°C (cyclohexane); H NMR (CDCl3): d 7.89 (d, J = 8.5 Hz, 1H, C3-H),
8.30 (dd, J = 3.0 and 8.5 Hz, 1H, C4-H), 8.73 (d, J = 3.0 Hz, 1H, C6-H), 10.40 (s, 1H, CHO).
Isopropyl 4-(2-Bromo-5-nitrophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (7)
A mixture of isopropyl acetoacetate (2.30 g, 16 mmol), 2-bromo-5-nitrobenzaldehyde (2.43 g, 11
mmol), urea (0.95 g, 11 mmol), and acetic acid (20 mL) containing conc. HCl (100 mL, ca. 4 drops)
was heated under reflux for 24 h (after the first 6 h an additional quantity of conc HCl (100 mL) was
added). After the mixture was allowed to stand at rt overnight, the precipitate was filtered and recrys-
tallized from acetic acid to give 2.89 g (66%) of DHPM 7 as a colorless solid, mp 241°C; IR (KBr)
3380, 3080, 2950, 1710, 1650, 1520, 1450 cm-1; 1H NMR (DMSO-d6) d 0.79 and 1.12 (2 d, J = 6.4 Hz
each, 6H, CH(CH3)2), 2.36 (s, 3H, C6-CH3), 4.75 (m, J = 6.4 Hz, 1H, CH(CH3)2), 5.70 (s, 1H, C4-H),
7.80-8.10 (m, 4H, 3 ArH and N3-H), 9.45 (brs, 1H, N1-H) ppm. Anal. Calcd for C15H16BrN3O5: C,
45.20; H, 4.00; N, 10.60. Found: C, 45.58; H, 4.00; N, 10.24.
Isopropyl 4-(2-Allyl-5-nitrophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (8)
To a suspension of DHPM 7 (1.15 g, 2.9 mmol) in dry toluene (20 mL) was added allyltributylstan-
nane (0.95 g, 2.9 mmol), and Pd(PPh3)4 (67 mg, 2 mol%). The resulting mixture was heated at reflux
for 48 h under an argon atmosphere. After all starting material had been consumed (1H NMR analysis,
if necessary additional catalyst was added) the dark solution was filtered and washed successively with
3% HCl (2 x 10mL), H2O (2 x 10mL), and saturated NaHCO3 (2 x 10mL). The organic layer was dried
(Na2SO4) and toluene removed under reduced pressure. The crude material crystallized upon tituration
with hexane. Purification by silica gel flash chromatography (CHCl3/acetone 7:3) furnished 0.49 g
(47%) of DHPM 8 as a colorless solid, mp 175°C; IR (KBr) 3250, 3100, 2950, 1705, 1640, 1520, 1450
cm-1; 1H NMR (DMSO-d6) d 0.79 and 1.12 (2 d, J = 6.4 Hz each, 6H, CH(CH3)2), 2.34 (s, 3H, C6-CH3),
3.73 (m, 2H, CH2CH=CH2) 4.77 (m, J = 6.4 Hz, 1H, CH(CH3)2), 5.19 (m, 2H, CH2CH=CH2), 5.59 (s,
1H, C4-H), 5.95-6.18 (m, 1H, CH2CH=CH2), 7.41-8.17 (m, 4H, 3 ArH and N3-H), 9.38 (brs, 1H, N1-
H) ppm. Anal. Calcd for C18H21N3O5: C, 60.16; H, 5.88; N, 11.69. Found: C, 59.84; H, 5.91; N, 11.65.

236
Molecules 2000, 5
Isopropyl 4-(2-Allyl-5-nitrophenyl)-3-[2-diazo-2-[(methyloxy)carbonyl]acetyl]-6-methyl-2-oxo-
1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (9)
A mixture of DHPM 8 (1.08 g, 3.00 mmol), distilled methyl malonyl chloride (0.68 g, 5.00 mmol),
and benzene (30 mL) was heated at reflux for 2 h. After all starting material had been consumed
(TLC), the solution was cooled to ambient temperature. The solvent was evaporated under reduced
pressure and the crude product purified by silica gel flash chromatography (hexane/EtOAc 2:1) to
yield 980 mg (71%) of isopropyl 4-(2-allyl-2-nitrophenyl)-6-methyl-3-(2-methyloxycarbonylacetyl)-2-
oxo-1,2,3,4-tetrahydro-5-pyrimidine-carboxylate as colorless solid, mp 130°C; IR (KBr) 3260, 3150,
2960, 1760, 1740, 1705, 1640, 1520 cm-1; 1H NMR (DMSO-d6) d 1.08 and 1.20 (2 d, J = 6.4 Hz each,
6H, CH(CH3)2), 2.36 (s, 3H, C6-CH3), 3.54 (s, 2H, COCH2CO), 3.86 (s, 3H, OCH3), 3.73-4.00 (m, 2H,
CH2CH=CH2), 4.91 (m, J = 6.4 Hz, 1H, CH(CH3)2), 5.16-5.31 (m, 2H, CH2CH=CH2), 5.90-6.15 (m,
1H, CH2CH=CH2), 6.63 (s, 1H, C4-H), 7.45 (m, 1H, ArH), 8.12 (m, 2H, ArH), 10.56 (brs, 1H, N1-H)
ppm. Anal. Calcd for C22H25N3O8: C, 57.51; H, 5.48; N, 9.14. Found: C, 57.18; H, 5.54; N, 8.85.
A mixture of the above 1,3-dicarbonyl compound (460 mg, 1.00 mmol), mesyl azide (145 mg, 1.20
mmol), triethylamine (250 mg, 2.50 mmol), and methylene chloride (5 mL) was stirred in the dark at rt
for 24-48 h. After all starting material had been consumed (1H NMR), an addidional amount of solvent
was added and the diazo-transfer reaction mixture was washed rapidly with ice-cold 5% aq. KOH (3 x
5 mL) and brine (3 x 10 mL). The organic layer was dried (Na2SO4) and the solvent evaporated under
reduced pressure. The crude product was purified by flash chromatography (hexane/EtOAc, 1:1) to
yield the diazo imide 9 (460 mg, 95%) as a yellow oil that slowly crystallizes, mp 121-122°C; IR
1
(KBr) 3210, 3140, 2980, 2140, 1715, 1670, 1640, 1520 cm-1; H NMR (CDCl3) d 1.02 and 1.12 (2 d, J
= 6.4 Hz each, 6H, CH(CH3)2), 2.42 (s, 3H, C6-CH3), 3.82 (s, 3H, OCH3), 3.73-4.21 (m, 2H,
CH2CH=CH2), 5.00 (m, J = 6.4 Hz, 1H, CH(CH3)2), 5.22-5.36 (m, 2H, CH2CH=CH2), 5.93-6.15 (m,
1H, CH2CH=CH2), 6.31 (brs, 1H, C4-H), 7.35-8.28 (m, 4H, 3 ArH and N1-H) ppm, and minor rotam-
ers.
1-tert.-Butyl 5-Isopropyl 4-(2-Allyl-5-nitrophenyl)-6-methyl-3-[2-diazo-2-[(methyloxy)carbonyl]-
acetyl]-2-oxo-1,2,3,4-tetrahydro-1,5-pyrimidinedicarboxylate (10)
A solution of diazo imide 9 (340 mg, 0.70 mmol), 2.0 equiv. of (BOC)2O (320 mg, 1.40 mmol),
DMAP (90 mg, 0.70 mmol), and triethylamine (70 mg, 0.70 mmol) in dry CH2Cl2 (10 mL) was al-
lowed to stir at rt for 2 h. It was then washed with cold 1M HCl, brine, dried (Na2SO4), evaporated to
dryness and purified by silica gel flash chromatography (hexane/EtOAc 2:1) to yield 370 mg (90%) of
the protected DHPM 10 as a yellow oil, IR (film) 2980, 2140, 1770, 1720, 1700, 1670, 1640, 1520 cm-
1; 1H NMR (CDCl3) d 1.18 and 1.28 (2 d, J = 6.4 Hz each, 6H, CH(CH3)2), 1.67 (s, 9H, t-BuO), 2.54 (s,
3H, C6-CH3), 3.82 (s, 3H, OCH3), 3.73-4.20 (m, 2H, CH2CH=CH2), 5.05 (m, J = 6.4 Hz, 1H,
CH(CH3)2), 5.22-5.37 (m, 2H, CH2CH=CH2), 5.92-6.17 (m, 1H, CH2CH=CH2), 6.28 (brs, 1H, C4-H),

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Molecules 2000, 5
7.35-8.28 (m, 3H, ArH) ppm, and minor rotamers.
4-Isopropyl 15-Methyl 2-tert.-Butyl 3-Methyl-8-nitro-16-oxo-18-oxa-2,17-diazapentacyclo[13.2.1.01,13.
05,17.06,11]octadeca-3,6,8,10-tetraene-2,4,15-tricarboxylate (12)
A solution of diazo compound 10 (175 mg, 0.3 mmol) in dry benzene (10 mL) containing a cata-
lytic amount of rhodium acetate (< 5 mg) was heated at reflux under argon for 4 h. After all starting
material was consumed (TLC), the solvent was evaporated under reduced pressure and the crude prod-
uct purified by flash chromatography (hexane/EtOAc, 1:1) to give pentacycle 12 (Rf = 0.47, 92 mg,
55%) as a colorless solid, mp 170-172°C, and the isomeric pentacycle 13 (Rf = 0.55, 63 mg, 38%) as a
1
colorless solid, mp. 104-106°C; Data for 12: IR (KBr) 2980, 1770, 1750, 1590, 1520 cm-1; H NMR
(CDCl3) d 1.18 and 1.28 (2 d, J = 6.4 Hz each, 6H, CH(CH3)2), 1.43 (dd, J = 5.5 and 13.0 Hz, 1H, C14-
Ha), 1.67 (s, 9H, t-BuO), 2.43 (dd, J = 10.0 and 13.0 Hz, 1H, C14-Hb), 2.64 (3 H, s, C3-Me), 2.98 (dd,
J = 5.5 and 16.0 Hz, 1H, C12-Ha), 3.20 (m, 1H, C13-H), 3.37 (dd, J = 2.0 and 16.0 Hz, 1H, C12-Hb),
3.74 (3 H, s, OCH3), 4.98 (m, J = 6.4 Hz, 1H, CH(CH3)2), 5.79 (s, 1H, C5-H), 7.22 (d, J = 8.5 Hz, 1H,
13
C10-H), 8.04 (dd, J = 3.0 and 8.5 Hz, 1H, C9-H), 8.38 (d, J = 3.0 Hz, 1H, C7-H) ppm; C NMR
(CDCl3) d 18.6, 21.6, 22.0, 27.8, 31.5, 32.7, 41.9, 53.1, 54.2, 68.7, 85.0, 85.2, 97.9, 103.5, 122.9,
127.0, 133.6, 139.1, 141.6, 146.4, 147.2, 149.2, 164.2, 164.6, 166.5 ppm. Anal. Calcd. for C27H31N3O10:
C, 58.16; H, 5.60; N, 7.53. Found: C, 58.29; H, 5.70; N, 7.53. Data for 13: (KBr) 2980, 1770, 1750,
1590, 1520 cm-1; 1H NMR (CDCl3) d 1.44 (d, J = 7.0 Hz, 3H, C13-Me), 1.41 and 1.46 (2 d, J = 6.4 Hz
each, 6H, CH(CH3)2), 1.55 (s, 9H, t-BuO), 2.30 (dd, J = 2.9 and 7.0 Hz, 1H, C13-H), 2.46 (3 H, s, C3-
Me), 3.74 (d, J = 2.9 Hz, 1H, C12-H), 3.91 (3 H, s, OCH3), 5.22 (m, J = 6.4 Hz, 1H, CH(CH3)2), 6.04
(s, 1H, C5-H), 7.31 (d, J = 8.5 Hz, 1H, C10-H), 8.09 (dd, J = 3.0 and 8.5 Hz, 1H, C9-H), 8.41 (d, J =
3.0 Hz, 1H, C7-H) ppm; 13C NMR (CDCl3) d 16.7, 21.8, 22.1, 22.2, 28.1, 47.2, 48.9, 53.1, 53.5, 69.3,
85.3, 89.3, 97.2, 114.2, 122.6, 123.1, 130.4, 134.5, 139.9, 147.6, 150.0, 150.1, 163.2, 163.8, 166.6
ppm. Anal. Calcd. for C27H31N3O10: C, 58.16; H, 5.60; N, 7.53. Found: C, 58.40; H, 5.90; N, 7.23.
4-Isopropyl 15-Methyl 3-Methyl-8-nitro-16-oxo-18-oxa-2,17-diazapentacyclo[13.2.1.01,13.05,17.06,11]oc-
tadeca-3,6,8,10-tetraene-4,15-dicarboxylate (3)
To a solution of pentacycle 12 (56 mg, 0.1 mmol) in CH2Cl2 (10 mL) was added 1.50 g of silica gel
60. After evaporation of the solvent the dry powder was irradiated in a domestic microwave oven at
800 W for 3-5 min (TLC monitoring). Purification by silica gel flash chromatography provided 41 mg
(90%) of the target compound 3 as a colorless solid, mp 155-157°C; IR (KBr) 3550-3200, 2980, 1750,
1720, 1695, 1600, 1520 cm-1; 1H NMR (CDCl3) d 1.06 and 1.34 (2 d, J = 6.4 Hz each, 6H, CH(CH3)2),
1.47 (dd, J = 5.5 and 13.0 Hz, 1H, C14-Ha), 2.45 (dd, J = 10.0 and 13.0 Hz, 1H, C14-Hb), 2.46 (3 H, s,
C3-Me), 2.68 (m, 1H, C13-H), 2.99 (dd, J = 5.5 and 16.0 Hz, 1H, C12-Ha), 3.38 (dd, J = 2.0 and 16.0
Hz, 1H, C12-Hb), 3.86 (3 H, s, OCH3), 4.97 (m, J = 6.4 Hz, 1H, CH(CH3)2), 5.51 (s, 1H, N2-H), 5.79

238
Molecules 2000, 5
(s, 1H, C5-H), 7.23 (d, J = 8.5 Hz, 1H, C10-H), 8.01 (dd, J = 3.0 and 8.5 Hz, 1H, C9-H), 8.41 (d, J =
3.0 Hz, 1H, C7-H) ppm; 13C NMR (CDCl3) d 20.8, 21.8, 22.2, 31.4, 32.5, 43.8, 53.2, 53.9, 67.7, 86.1,
94.7, 96.2, 122.6, 126.9, 133.5, 140.7, 141.4, 146.4, 150.9, 164.7, 165.1, 166.0 ppm. Anal. Calcd. for
C22H23N3O8: C, 57.77; H, 5.07; N, 9.19. Found: C, 57.70; H, 5.00; N, 9.03.
Acknowledgements: This work was supported by the Austrian Academy of Sciences (APART 319) and
the Austrian Science Fund (FWF, Project P-11994-CHE).
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Samples Availability: Available from the authors.
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