Covering: July 1998 to June 1999. Previous review: 1999, 16, 697.
1 Quinoline alkaloids
1.2 Non-terpenoid quinoline and quinolinone alkaloids from higher plants
Bioactivity-guided fractionation of an ethyl acetate extract of the seeds of
Casimiroa edulis, a medicinal and food plant of Mexico and Central America, showed that the antimutagenic activity was due to the known alkaloid casimiroine
1, among other metabolites.
1
Casimiroine not only inhibited 7,12-dimethylbenz[
a]anthracene (DMBA)-induced mutation of
Salmonella typhimurium, but also displayed promising chemopreventive activity against cancer by significantly inhibiting DMBA-induced lesions in mouse mammary gland cultures.
Two investigations on the constituents of Angostura bark (
Galipea officinalis), published within a few months of each other, have brought to light the new 1,2,3,4-tetrahydroquinoline alkaloid
2. The earlier publication assigned the name galipinine to the compound,
5
while the later publication, in which the isolation was based on bioactivity-guided fractionation against
Mycobacterium tuberculosis, named it allocuspareine.
6
The former name should thus take precedence. The NMR spectroscopic data in the two publications are in broad agreement (
H ± 0.3 ppm,
C ± 2 ppm), although there are discrepancies in the assignment of signals. While galipinine was shown to be laevorotatory in the earlier study ([
]
D
33.4,
c 0.0055, CHCl
3), a full CD spectrum reported in the latter study additionally proved that the new compound belongs to the same enantiomeric series as the related alkaloid cuspareine
3, the absolute configuration of which is not known. Cuspareine was in fact also isolated in both investigations, as well as two other well-known alkaloids, cusparine
4 and galipine
5. In addition, the presence of demethoxycusparine
6, not previously known from this plant source, was reported in the earlier article, while 4-methoxy-2-pentylquinoline
7 and
N-methylquinolin-2-one
8 were detected in the latter investigation. Despite the authors
claims to the contrary, alkaloid
8 is not a new natural product–it was, in fact, first detected in extracts of
G. officinalis almost thirty years ago.
24
Both articles give previously unreported NMR spectroscopic data for cuspareine
3 and galipine
5. As a postscript in the second investigation, the quinoline alkaloids were found to be more active against
M. tuberculosis than the tetrahydroquinoline alkaloids, but the bulk of the activity resided in the unidentified polar basic fraction from the bark extract.
Although quinolin-4-one alkaloids bearing hydrocarbon chains at C-2 are not uncommon metabolites of certain rutaceous plants, the chains invariably possess an odd number of carbon atoms. A suite of quinolin-4-one alkaloids
9–16 isolated from
Ruta graveolens is thus unusual in including all chain lengths between C
7 and C
11.
15
The
n-octyl and
n-decyl compounds
10,
12 and
15 are new natural products, while 2-heptylquinolin-4-one
9 was previously known only as a metabolite of microorganisms of the genus
Pseudomonas. Not all of the alkaloids were separable, but MS measurements in some cases, and reversed-phase HPLC–MS in others, provided good evidence for the structures.
In last year
s review,
25a
it was pointed out that the ostensibly new alkaloid transitorine
17 from
Ephedra transitoria was, in fact, merely the keto tautomer of the well-known compound kynurenic acid. This fact has now been recognised by the authors,
26
who have withdrawn the trivial name transitorine (which actually appeared as
transtorine
in the original publication
27
) from the literature.
Oxidation of 2-aryl-1,2,3,4-tetrahydroquinolin-4-ones with a relatively safe hypervalent iodine reagent, [hydroxy(tosyloxy)iodo]benzene, in trimethyl orthoformate containing a trace of perchloric acid as catalyst provides a simple route to 2-aryl-4-methoxyquinolines, including the alkaloids
18 and
19 (graveolinine).
28
Radical cyclisation of the
cis-stilbene-like precursor
20 with tributyltin hydride and AIBN in boiling benzene produced an equal mixture of the methyl ether
21 of the unusual benzo[
h]quinoline alkaloid toddaquinoline and its regioisomer
22 in 58% yield.
29
(+)-Tortuosamine
23 and its
N-formyl analogue
24 are atypical alkaloids from the genus
Sceletium (Amaryllidaceae). New enantioselective syntheses of these tetrahydroquinolines proceeded through the (
)-alcohol
25, for which three different routes from the corresponding achiral 1-arylcyclohexene were developed.
30
Some significant later steps in the synthesis are shown in
Scheme 1. One of these is the free radical cyclisation and oxidation of the bromoacetal
26, which stereoselectively introduced the side chain adjacent to the aromatic ring into the product
27. After a series of functional group interconversions and transpositions, the
-iodo enone
28 was subjected to palladium-mediated coupling with the diethyl acetal of propynal to give enyne
29, partial hydrogenation of which over Lindlar catalyst produced a mixture of dienes
30. Condensation of this mixture with ammonium acetate in acetic acid completed the construction of the tetrahydroquinoline core of the product
31, which was readily converted into the target alkaloids (+)-
23 and (+)-
24.
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Scheme 1
Reagents: i, H2C CHOEt, NBS, Et2O, 0 °C to rt; ii, Bu3SnCl (cat.), NaBH4, AIBN (cat.), ButOH, reflux; iii, MCPBA, BF3·Et2O, CH2Cl2, rt; iv, Me2NH2Cl, Me3Al, THF, reflux; v, Swern oxidation; vi, LiAlH4, THF, reflux; vii, MeOCOCl, Et3N, CH2Cl2, rt; viii, CS2, NaH, MeI, THF, rt; ix, 1,2-Cl2C6H4, reflux; x, CrO3, 3,5-dimethylpyrazole, CH2Cl2, 15 °C; xi, I2, pyridine, CCl4, rt; xii, HC CCH(OEt)2, PdCl2(Ph3P)2 (cat.), CuI (cat.), Pri2NH, THF, 0 °C; xiii, H2, Lindlar catalyst, EtOAc, rt; xiv, NH4OAc, AcOH, 100 °C; xv, 50% KOH–EtOH (1 2) reflux; xvi, AcOCHO, 0 °C.
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1.3 Terpenoid quinoline alkaloids, tricyclic derivatives and dimeric analogues
The ostensibly new alkaloid 2-hydroxy-4-methoxy-3-prenylquinoline
32, isolated along with several known quinoline and carbazolo[1,2-
b]quinazoline alkaloids from the fruits of
Evodia officinalis,
4
is actually the hydroxy tautomer of the rather rare quinolin-2-one alkaloid atanine
33. Confusion between hydroxyquinoline and quinolinone tautomers is a common pitfall for the unwary (
cf.transitorine
in the previous section), and the prevailing tautomer depends on the medium in which spectra are recorded. The alkaloids isolated in this study (see
Table 1) showed marginal cytotoxic activity against both human lung and colon carcinoma cells, but were inactive as topoisomerase inhibitors. Atanine from
Zanthoxylum integrifolium has also proved to be a good inhibitor of platelet aggregation
in vitro, and exhibited a strong vasorelaxing effect on the contraction of rat aorta induced by potassium ions or norepinephrine.
21
Severibuxine
34, a new member of the extremely rare class of monoterpenoid quinolinone alkaloids, is the first quinolinone alkaloid to have been found in the Chinese plant
Severinia buxifolia (
Atalantia buxifolia).
16
The usual metabolites from this source are acridone alkaloids, a number of which were also isolated on this occasion. The new compound and its acetate derivative were characterised spectroscopically. Severibuxine proved to be cytotoxic against P-388 murine leukaemia and various other cell lines, as were most of the accompanying acridones.
Aerial parts of
Skimmia laureola, a medicinal plant native to Kashmir and northern Pakistan, yielded the new dihydrofuro[2,3-
b]quinoline alkaloid (+)-methylisoplatydesmine
35, which was characterised fully by spectroscopic techniques.
17
Its absolute configuration was not ascertained.
Two dimeric quinolinone alkaloids, melicobisquinolinones A and B,
36 and
37, were isolated from leaf extracts of the Vietnamese medicinal plant
Melicope ptelefolia together with one of the constituent moieties,
N-methylflindersine
38.
11
Dimers of prenylated quinolinone alkaloids are extremely uncommon, and most of them can be envisaged as formal Diels–Alder adducts formed from
monomers
such as
N-methylflindersine and a prenylquinolinone precursor
39, as in the case of melicobisquinolinone A. Indeed, the new alkaloid
36 is a regioisomer of paraensidimerine D
40, another formal Diels–Alder adduct of
38 and
39, which has been known for almost two decades. Both
36 and
37 were characterised with the help of very thorough NMR spectroscopic studies in which two-dimensional correlations and NOE effects were used to establish connectivities and spatial relationships, as well as the half-chair or twisted conformations for the dihydropyran rings. Since neither of the bismelicoquinolinones showed Cotton effects in their CD spectra, they are thought to be racemic. Alkaloids
37 and
38 inhibited mycelial growth of the fungus
Cladosporium cucumerinum at nanomolar concentrations, but
36 was inactive.
1.4 Furoquinoline alkaloids
The simple new furoquinoline alkaloids dictangustine-A
41 and iso-
-fagarine
42 were isolated from the root bark of Chinese
Dictamnus angustifolius together with several other more common members of this class.
3
The positions of the substituents on ring A were determined by means of NOESY experiments.
Dictamnine
43,
-fagarine
44 and haplopine
45, isolated from
Toddalia asiatica by bioassay-guided fractionation, showed complete inhibitory activity at 100
g ml
1 towards arachidonic acid-induced platelet aggregation
in vitro.
20
A new synthetic approach to the furoquinoline alkaloids in which the key step involves rhodium-mediated dipolar cycloaddition of diazoquinolinediones is exemplified by the synthesis of isodictamnine
46 (
Scheme 2).
31
Cycloaddition of the diazo compound
47 with trimethylsilylacetylene was catalysed by rhodium pivalate and a few drops of ethanolic hydrochloric acid in fluorobenzene at 55 °C, and gave the
angular
adduct
48 and the desired
linear
adduct
49 in yields of 57% and 18% respectively. Desilylation of the separable adducts with tetrabutylammonium fluoride afforded the unnatural compound pseudoisodictamnine
50 (87%) and the target alkaloid
46 (61%). In general, the ratio of angular to linear adducts was found to vary markedly depending on the diazo compound, the dipolarophile and the presence of hydrochloric acid. The method is thus unlikely to be generally useful for preparing naturally occurring furo[2,3-
b]quinolines and related 2,3-dihydro analogues.
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|
Scheme 2
Reagents: i, Et3N, MeSO2N3, EtOH, 0 °C to rt; ii, HCCSiMe3, Rh2(OCOCMe3)4 (0.01 mol%), cat. HCl in Et2O (1 M), C6H5F, 55 °C; iii, Bu4NF, THF (1 M), rt.
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1.5 Decahydroquinoline alkaloids of the genus Lycopodium
Most of the alkaloids belonging to the genus
Lycopodium (club-mosses) are polycyclic compounds commonly possessing C
10N, C
16N
2 or C
30N
3 skeletons. However, several decahydroquinolines bearing additional heterocyclic rings as substituents are known. The structures of two of these compounds, lucidine A and oxolucidine A, have hitherto been only partially elucidated because of the complexity of their NMR spectra. A recent reinvestigation of the extracts of
L. lucidulum has now resulted in the almost complete assignment of the structures.
32
Separation of four alkaloids, lucidines A and B and oxolucidines A and B, was achieved by countercurrent distribution followed by chromatography on alumina and, finally, reversed-phase HPLC. A chemical correlation between lucidines A and B and the two oxolucidines was established by formation of the latter two from the former on exposure to air. Oxolucidine A was reduced to a dihydro derivative upon treatment with sodium borohydride in methanol. An unusual tris(
p-bromobenzoate) derivative of the reduced product gave crystals suitable for X-ray diffraction analysis, which revealed the structure
51, the absolute configuration of which is as depicted. The structures of lucidine A and oxolucidine A were thus inferred to be
52 and
53, respectively, and the only remaining uncertainty is the configuration of lucidine A at C-14. The structures of the compounds in the B series remain undetermined.
The simpler
Lycopodium alkaloid
Na-acetyl-
Nb-methylphlegmarine
54 has been synthesised by Comins and co-workers by a route involving two different applications of their well-known methodology based on the use of chiral
N-acylpyridinium salts as precursors for the preparation of versatile dihydropyridone intermediates (
Scheme 3).
33
Firstly, stereoselective addition of (
R)-2-methylpent-4-enylmagnesium chloride to the salt
55 gave the
N-acyldihydropyridone
56 in 76% yield. Significant later steps included acid-induced intramolecular aldol condensation of keto-aldehyde
57 to create the hexahydroquinolin-4(1
H )-one
58, stereoselective introduction of an axial substituent at C-5 by conjugate addition and trapping of the enolate to form the silylated enol triflate
59, and defunctionalisation of
59 with a palladium(0) catalyst and formic acid to yield the bridgehead alkene
60. The ensuing hydrogenation of the alkene took place predominantly (89
11) on the face opposite to the silyl substituent, giving a
trans-fused decahydroquinoline containing four of the target alkaloid
s five stereogenic centres. Oxidative desilylation of
61 and manipulation of substituents then completed the synthesis of the key 5-iodomethyldecahydroquinoline
62. Experience gained with model studies
34
suggested the transformation of
62 into the organomagnesium reagent
63, which was added to a second equivalent of the salt
55 to produce the new dihydropyridone
64 in 50% yield along with the product of methyl addition (50%). A single crystal X-ray structure determination of
64 confirmed that all five stereogenic centres had been correctly installed. The synthesis of alkaloid
54 was completed as shown in
Scheme 3. This route, the first asymmetric synthesis of (
)-
Na-acetyl-
Nb-methylphlegmarine, established the (2
S, 4a
R,5
S,7
R,8a
R) absolute configuration of the alkaloid.
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|
Scheme 3
Reagents: i, (R)-H2CCHCH2CH(Me)CH2MgCl, THF, 78 to 42 °C, then 10% aq. HCl; ii, NaOMe in MeOH (4.37 M), reflux; iii, 10% aq. HCl, THF, rt; iv, BuLi, THF, 78 °C; v, PhOCOCl, THF, 78 °C; vi, L-Selectride, BF3·Et2O, THF, 78 °C; vii, O3, MeOH, 78 °C, then Me2S, 78 °C to rt; viii, p-TsOH·H2O, C6H6, 40–50 °C; ix, PhMe2SiCH2MgCl, CuI, Et2O–THF, 0 °C to rt; x, N-(5-chloro-2-pyridyl)triflimide, DMPU, Et2O–THF, heat; xi, Bu3N, HCO2H, Ph3P, Pd(OAc)2, DMF, 60 °C; xii, KOH, PriOH–H2O, reflux; xiii, H2 (1 atm), 5% Pd/C, AcOH, EtOH, rt; xiv, BnOCOCl, NaOH (1 M), 0 °C to rt; xv, 35% MeCO3H in AcOH, Hg(OAc)2, rt; xvi, LiAlH4, THF, reflux; xvii, (Ph2PCH2)2, (CH2I)2, CH2Cl2, rt to reflux; xviii, ButLi (2 equiv.), Et2O, 78 to 45 °C; xix, MeMgBr (1 equiv.), Et2O; xx, salt 55, PhMe, 78 °C; xxi, AcCl, K2CO3, THF, rt; xxii, H2 (1 atm), 5% Pd/C, Li2CO3, EtOAc.
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1.6 Quinoline alkaloids from fungal and microbial sources
It has been suggested that the biogenesis of the
Streptomyces metabolite benzastatin D
65 from the simpler benzastatin A
66 is
via an epoxide such as
67, which can undergo cyclisation to give either
65 or the alternative metabolite benzastatin E
68.
35
In model studies designed to probe these options, the epoxides
69 and
70 were found to give exclusively the indoline products
71 and
72 after catalytic hydrogenation over a 10% palladium-on-carbon catalyst. However, it is possible that benzastatins D and E interconvert through an aziridine intermediate. This hypothesis was tested by the model reaction sequence shown in
Scheme 4. Treatment of the aniline derivative
73 with iodine yielded the 3-iodotetrahydroquinoline
74, which was converted into the aziridine
75 when exposed to DBU in toluene at 100 °C. Solvolysis of
75 with silver tetrafluoroborate in aqueous acetone yielded only the tetrahydroquinolin-3-ol
76, but treatment with anhydrous hydrogen chloride produced a 1
1 mixture of the alternative products
77 and
78.
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|
Scheme 4
Reagents: i, I2, Na2CO3, CH2Cl2, rt; ii, DBU, PhMe, 100 °C; iii, AgBF4, Me2CO–H2O, rt; iv, dry HCl, CH2Cl2, rt.
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Further studies aimed at the total synthesis of the broad-spectrum antibiotic and antitumour compound streptonigrin
79 have focused on coupling strategies for building the CD ring system.
36
The best results were achieved by means of Suzuki coupling between the boronic ester
80 and 4-chloro-3-nitropyridine [Pd(Ph
3P)
4, K
2CO
3, DME, reflux], which gave the model biaryl system
81 in 81% yield.
The first total synthesis of luzopeptins A–C
82–84, potent antitumour antibiotics isolated from the microorganism
Actinomadura luzonensis almost twenty years ago, has been communicated by Boger and co-workers.
37
The challenges posed by the construction of the symmetrical decadepsipeptide core, obviously the main feature of the synthesis, will not be described here since they are only peripheral to the topic of this review. At the end of the synthesis, 3-hydroxy-6-methoxyquinoline-2-carboxylic acid was attached to free amine groups on the depsipeptide core by conventional amide formation to give luzopeptin C in 80% yield . Peracetylation followed by mild basic hydrolysis then yielded a mixture of luzopeptins A (50%) and B (20%). Ciufolini and co-workers have also described a synthetic approach to the luzopeptins in which the main objective was the assembly of the key tripeptide
85 in multigram amounts.
38
Boger and Saionz have reported further studies on the DNA-binding properties of the antitumour antibiotic sandramycin
86 and 23 synthetic analogues in which the intercalation chromophore was systematically varied
39
(
cf. ref.
25b
). The surface plasmon resonance technique was used to establish binding constants to the high-affinity bis-intercalation binding site 5
-(GCATGC)
2, and to evaluate the preference for sandramycin binding to 5
-d(GCXXGC)
2 (X = AT, TA, CG, GC). In general, results paralleled those previously obtained by fluorescence quenching measurements, but in addition it was found that complexes formed at the high-affinity bis-intercalation sites were exceptionally stable, as judged by the unusually slow off rates for binding dissociation. This feature appears to correlate with previously observed cytotoxicity.
1.7 Quinoline alkaloids from animals
(+)-Halitulin, a marine metabolite possessing the unique 3,4-bis(quinolin-5-yl)pyrrole structure
87 (absolute configuration unknown), was isolated from the sponge
Haliclona tulearensis collected in Sodwana Bay near Durban, South Africa.
9
This astonishing structure was revealed by a combination of spectroscopic and chemical analyses. In particular, the 7,8-dihydroxyquinoline unit, unprecedented in a natural product, was suggested by the formation of an unstable
ortho-quinone on treatment with sodium periodate. Its position of attachment was inferred from NOE effects between 2-H on the pyrrole ring and 4-H and 6-H on the quinoline system. The azacyclodecane and aliphatic components were deduced after spectroscopic comparisons with haliclorensin
88, a simpler metabolite recently reported from the same sponge. Halitulin forms an unstable tetraacetate, and is oxidised on exposure to air and light to a mixture of two azacyclodecane
N-oxides, after which quinone formation apparently occurs. The new alkaloid showed cytotoxic activity towards cell cultures of P-388 murine leukaemia, A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human melanoma (IC
50 0.025, 0.012, 0.012 and 0.025
g cm
3, respectively).
The much simpler alkaloid
N-methylquinolinium-2-carboxylate
89, a natural betaine isolated from whole-body extracts of the firefly
Photuris versicolor, appears to participate in the insects
arsenal of chemical defences against predators.
14
This is the first time that this known compound has been found as a natural product. The structure was deduced on the basis of its spectroscopic properties, and confirmed by synthesis following a reported procedure.
40
Jineol (quinoline-3,8-diol)
90, a cytotoxic alkaloid isolated from the centipede
Scolopendra subspinipes, has been synthesised by a route in which directed
ortho-lithiation of a 2-chloroquinoline is the principal step (
Scheme 5).
41
8-Methoxyquinolin-2-one
91, prepared in three steps from
o-anisidine, was converted into the 2-chloro derivative
92 by treatment with phosphorus oxychloride, following which lithiation with lithium tetramethylpiperidide and treatment with trimethyl borate afforded the quinoline-3-boronic acid
93 in 82% overall yield. Oxidation with peracetic acid to give the quinolin-3-ol
94 proceeded in excellent yield. Dechlorination of
94 with zinc in acetic acid followed by demethylation gave a poor overall yield (21%) of the target alkaloid
90, but the yield was improved to 46% by forming the methyl ether of
94 before carrying out the defunctionalisations. A number of ethers of jineol were also prepared for biological screening by alkylating
90 with haloalkanes in dimethyl sulfoxide containing powdered potassium hydroxide.
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Scheme 5
Reagents: i, POCl3, pyridine (cat.), C6H5Cl, reflux; ii, LiTMP, THF, 75 °C; iii, B(OMe)3, THF, 75 °C, then H2O–THF; iv, MeCO3H (32%), HOAc, 0 °C to rt, then NaHSO3, H2O; v, Me2SO4, K2CO3, Me2CO, reflux; vi, Zn, HOAc, H2O, 70 °C; vii, pyridine·HCl, 200–220 °C.
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1.8 Decahydroquinoline alkaloids from ants and amphibians
A major new survey of the alkaloidal constituents isolated from the skins of frogs, toads and related amphibians by Daly, Garraffo and Spande provides a snapshot of the current state of knowledge in this rapidly expanding area of investigation.
42
The section on 2,5-disubstituted
cis- and
trans-decahydroquinoline alkaloids, almost 40 of which have been partially or fully characterised to date, covers the occurrence, biological activity, synthesis and spectroscopic identification of these compounds, and gives valuable information on their IR and MS behaviour in particular. Also mentioned briefly are some tentative tetrahydroquinoline and octahydroquinoline variants, and putative Diels–Alder dimers of the latter. The smaller family of gephyrotoxins, which possess a perhydropyrrolo[1,2-
a]quinoline core, is dealt with separately.
The hypothesis that most of the skin alkaloids of amphibians are derived from dietary sources has received a fillip from the discovery of decahydroquinoline alkaloids in ants, reported in two recent papers. Extracts from virgin queens of the myrmicine ant
Solenopsis (
Diplorhoptrum)
azteca from Puerto Rico contained two new caste-specific alkaloids of molecular mass 275 in the ratio 1
9.
18
Mass spectrometric fragmentation patterns and FTIR spectra showed beyond doubt that these were decahydroquinolines bearing unsaturated side chains – the first compounds of this class ever detected in ants. Two related alkaloids of the same molecular mass isolated from Costa Rican populations of the frog
Dendrobates pumilio had been known for some years, but had never previously been obtained in sufficient quantity for characterisation. Valuable spectroscopic comparisons between the four compounds proved that they were diastereomeric; in particular, the stereochemical relationships were inferred largely on the basis of Bohlmann bands and fingerprint absorptions in the IR spectra. The upshot is that the frog alkaloids (decahydroquinolines
cis-275B and
cis-275B
) have been assigned the structures
95 and
96, respectively, while the new ant alkaloids (coded as 5-
epi-
cis-275B
and 5-
epi-trans-275B) are
97 and
98. A substantial
1H and
13C NMR spectroscopic study of
cis-275B
95 and its deuterium chloride salt, and extensive comparisons with synthetic model systems, permitted the determination of an
N-endo conformation, as illustrated in
99.
Furthermore, accumulated experience and recent advances in spectroscopic interpretation also allowed the authors to clarify the structures of several other amphibian decahydroquinolines that have hitherto been only tentatively identified.
13C NMR spectroscopic data were obtained for the first time for
cis-243A
100 from
D. auratus; the
N-exo conformation
101, with the C-2 substituent equatorial and the C-5 substituent axial, appears to be favoured. The structure of
trans-269AB from
D. pumilio and various populations of
D. histrionicus– actually, an inseparable mixture of
102 and its C-5 epimer
103– was also based partly on NMR spectroscopic measurements, and is comparatively secure. Several minor stereoisomers in the 269AB complex have not yet been clarified, although a related compound from Costa Rican
D. granuliferus seems to be an isomer of
cis-269AB
104. Some residual uncertainty also hangs over the configuration at C-5 of alkaloids
trans-269A
105 and
trans-269B
106 from
D. auratus. A population of
D. pumilio from Isla Colón, Panama produced the partly characterised
cis-267L
107, while a suite of decahydroquinolines of molecular mass 271 from
D. granuliferus appeared to include
cis-271D
108 and
trans-271D
109 (in both of which the C-2 and C-5 side-chains might be interchanged), and
iso-5-epi-
trans-271D
110. The paper contains a useful list of 36 known and tentative decahydroquinoline alkaloids and their amphibian sources.
A Brazilian myrmicine ant species belonging to the
Solenopsis (
Diplorhoptrum) sp.
picea group was found to contain three structurally isomeric alkaloids in the ratio 3
1
1.
10
The major component proved to be identical to a known amphibian 4-methyl-6-propylquinolizidine (also known as quinolizidine 195C). The minor components, characterised by GC-MS behaviour and FTIR spectroscopy, proved to be the well-known frog alkaloid
cis-195A
111 (the inappropriately-named pumiliotoxin C, or
cis-fused 5-methyl-2-propyldecahydroquinoline;
vide infra) and a hitherto unknown stereoisomer. This isomer showed fingerprint absorptions in the IR spectrum typical of a
cis-fused decahydroquinoline, as well as a Bohlmann band pattern indicative of
cis-disposed hydrogen substituents at C-2 and C-8. The relative stereochemistry at C-5 was not determined. Structure
112 was proposed for the new product, which has been assigned the code designation
cis-195J. Significantly, small quantities of the same triad of alkaloids have been found, among several others, in a number of populations of the Madagascan mantelline frog
Mantella betsileo, which strongly suggests that ants related to the Brazilian species are likely dietary sources of the sequestered skin alkaloids.
An important communication by the Daly team describes the use of chemical ionisation tandem mass spectrometry (CI-MS/MS) with ammonia as the reagent gas for elucidating the structures of several classes of monocyclic and bicyclic amphibian alkaloids, including decahydroquinolines.
43
The collision-induced dissociation of the initially generated [M + H]
+ ion, which is incapable of releasing a radical, results in markedly different fragmentation pathways when compared to conventional electron-impact methods, and casts new light on the structures of the alkaloids. The CI-MS/MS spectra of
cis-195A
111 and
cis-219A
113 were given to illustrate the application of the technique to decahydroquinoline systems.
Decahydroquinoline
cis-195A, still referred to as pumiliotoxin C by most synthetic chemists (to the chagrin of the Daly group
42
), is the prototypical decahydroquinoline alkaloid from the skin secretions of dendrobatid frogs, and it remains a very popular target for synthesis. Some years ago, Back and Nakajima reported a short synthesis of the racemic alkaloid
44
(
cf. ref.
25c
); this route has now been modified as shown in
Scheme 6 to yield the (
)-enantiomer
111.
45
The key to enantioselectivity lay in the selective hydrolysis of the racemic diester
114 with pig liver esterase to give a 1
1 mixture of the two half-esters
115 and
116. Although these compounds were difficult to separate, a combination of chemical transformations and recycling allowed recovery of the latter in a total yield of 67%. The (
)-half ester
116 was converted in four steps into the (
)-amino ester
117, following which syntheses of (
)-
111 and the epimeric compound 2-
epi-pumiliotoxin C
118 were completed
via the bicyclic enaminone (+)-
119 by means of the methodology previously used for making the racemic compounds.
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|
Scheme 6
Reagents: i, pig liver esterase, phosphate buffer (pH 8), rt; ii, CH2N2 in Et2O, MeOH; iii, NaOH, H2O, reflux, then HCl; iv, Ph2PON3, Et3N, PhMe, reflux; v, BnOH, pyridine, reflux; vi, H2 (1 atm), 10% Pd/C, HCO2H, MeOH, rt; vii, EtOH, rt; viii, LDA, THF, 78 °C to rt; ix, Tf2O, CH2Cl2, reflux; x, H2 (100 atm), PtO2, MeOH, 6 d; xi, BnOCOCl, aq. K2CO3, CHCl3; xii, 5% Na–Hg, Na2HPO4, MeOH–THF (11), rt; xiii, H2 (1 atm), 10% Pd/C, EtOH, rt.
|
Short complementary syntheses of (
)-pumiliotoxin C and several of its stereoisomers, devised by Habermehl and co-workers,
46
are illustrated in
Scheme 7. Condensation of the kinetically-generated enolate of (
R)-(+)-3-methylcyclohexanone
120 with diethyl carbonate yielded the keto ester
121, after which reaction with (
S)-(+)-3-aminohexanol
122 produced the 3-aminoacrylate
123. Sequential replacement of the hydroxy group by tosylate and bromide gave
124, stereoselective cyclisation of which was effected in 87% yield merely by heating in degassed DMF at 100 °C. The stereochemistry at C-4a in the product
125 is probably a result of steric effects during cyclisation. Removal of the ethoxycarbonyl blocking group was accomplished by heating
125 under reflux in a mixture of acetic acid, hydrochloric acid and pyridine. The imine functionality of the product
126 was hydrogenated over palladium on charcoal to produce a mixture of (
)-pumiliotoxin C
111 and the (
)-
trans-fused epimer
127 in a ratio of about 1
0.64 and an overall yield of 57% based on
123. Epimerisation of the propyl chain in the latter product was probably caused by isomerisation of the imine in the presence of the palladium catalyst. The products could be separated by chromatography on alumina, but characterisation, including X-ray crystallographic analysis, was performed on the more stable hydrochloride salts. The
trans compound would appear to be the same as the minor frog alkaloid
trans-195A, the stereochemistry at C-5 of which was previously undetermined, but which has now apparently been clarified.
42
In the same manner, the aminoacrylate
128, prepared from (
R)-(+)-3-methylcyclohexanone
120 and (
R)-(
)-3-aminohexanol
ent-
122, was transformed into a mixture of
127 and the new
cis-fused pumiliotoxin C isomer
129. Finally, aminoacrylate
130, derived from (
S)-(
)-3-methylcyclohexanone
ent-
120 and (
S)-(+)-3-aminohexanol
122, yielded another new
cis-fused stereoisomer
131 as well as
ent-
127, the enantiomer of the
trans-fused product.
|
|
Scheme 7
Reagents: i, (EtO)2CO, LDA, THF, 78 °C to rt; ii, TFA (cat.), 4Å molecular sieves, PhMe, 100 °C; iii, p-TolSO2Cl, DMAP, CH2Cl2, rt; iv, NaBr, DMF, rt; v, DMF, 4Å molecular sieves, 100 °C; vi, HOAc, pyridine, 20% aq. HCl, reflux; vii, H2, 10% Pd/C, EtOH, then chromatography on Al2O3 (activity grade III).
|
Another approach that resulted in the synthesis of both
cis-and
trans-fused decahydroquinolines of the pumiliotoxin C class employed 2,3,4,6-tetra-
O-pivaloyl-
-
D-galactosamine
132 as an unusual chiral auxiliary (
Scheme 8).
47
The imine
133 derived from reaction between this sugar derivative and hex-5-enal underwent a stereoselective Diels–Alder cycloaddition with 1-methoxy-3-trimethylsilyloxybutadiene to give the dihydropiperidin-4-one
134 in 68% yield and a diastereomeric ratio (dr) of better than 40
1. A sequence of reactions similar to those used in the Comins
Lycopodium synthesis (
cf. Section 1.5,
Scheme 3) produced the pivotal bicyclic enone
135, after which stereoselective conjugate addition with lithium dimethylcuprate in the presence of trimethylsilyl chloride afforded the
trans-fused decahydroquinolin-4-one
136 (81%, dr > 15
1). The structure of this product was substantiated by X-ray crystallography. The chiral auxiliary was removed with aqueous acid, after which standard transformations completed the synthesis of the hydrochloride salt of
137, which is yet another stereoisomer of pumiliotoxin C. The interesting feature of this route is that the chiral auxiliary apparently steers the protonation of the enolate formed from
135 by conjugate addition. When the sugar moiety of
135 was replaced by phenoxycarbonyl to give
138, the subsequent reaction with methylcuprate yielded the
cis-fused product
139 in 82% yield and a dr of 4.5
1. Both
138 and
139 had previously featured in a synthesis of pumiliotoxin C by Comins and Dehghani.
48
|
|
Scheme 8
Reagents: i, hex-5-enal, 4Å molecular sieves, pentane; ii, 1-methoxy-3-trimethylsilyloxybutadiene, ZnCl2·Et2O, THF, 20 °C; iii, PrMgCl, CuCl, BF3·Et2O, THF, 78 °C; iv, NaIO4, K2OsO4 (cat.), aq. dioxane; v, NaOH, dibenzo-18-crown-6, C6H6; vi, Me2CuLi, Me3SiCl, THF, 78 °C; vii, Bu4NF; viii, HCl (1 M), aq. MeOH (15); ix, BnOCOCl, NaHCO3; x, (CH2SH)2, BF3·Et2O; xi, H2, Raney Ni; xii, HCl; xiii, PhOCOCl.
|
The first enantioselective total synthesis of the marine decahydroquinoline alkaloid lepadin B
140, a metabolite of the tunicate (sea-squirt)
Clavelina lepadiformis, has been achieved by Toyooka
et al. as shown in
Scheme 9.
49
These workers once again commenced with the chiral building block
141, which has featured in several of their previous alkaloid syntheses. In this case, the building block was converted in a number of steps into the vinyl triflate
142 (48% overall yield), which underwent palladium-catalysed methoxycarbonylation to produce the unsaturated ester
143. The ensuing conjugate addition of a vinyl group gave the 2,3-
trans-substituted ester
144 as a single isomer. After a series of standard transformations, the crucial intramolecular aldol condensation of keto-aldehyde
145 was achieved with DBU in boiling benzene. Some epimerisation of the aldehyde also occurred under these conditions, and the
cis-fused bicyclic enone
146 was isolated in 60% yield as a 14
1 mixture with the
trans-fused isomer. Conjugate addition of phenylthiomethyl phenyl sulfone at C-5 was followed by a series of defunctionalisations to give the sulfone-containing decahydroquinoline
147. To complete the synthesis, Julia coupling of
147 with 2-heptenal followed by removal of the remaining protecting groups yielded lepadin B
140. The spectra of the laevorotatory trifluoroacetate salt of the synthetic product ([
]
D
26
92.6, MeOH) were identical with those of the salt of natural lepadin B ([
]
D96, MeOH). This synthesis verifies the (2
S,3
S,4a
S,5
S,8a
R) absolute configuration of (
)-
140.
|
|
Scheme 9
Reagents: i, Pd(PPh3)4, PPh3, Et3N, MeOH, CO (balloon), DMF, rt; ii, H2CCHLi, CuI, Et2O, 78 to 30 °C; iii, LiOH·H2O, MeOH–H2O (31), 60 °C; iv, EtOCOCl, Et3N, THF, 0 °C; v, CH2N2, Et2O; vi, PhCO2Ag, Et3N, Et2O; vii, Im2CO, Et3N, MeONHMe·HCl, CH2Cl2, 0 °C to rt; viii, MeMgBr, THF, 0 °C to rt; ix, OsO4, NaIO4, dioxane–H2O (11), rt; x, DBU (4 equiv.), C6H6, reflux; xi, PhSCH2SO2Ph, BuLi, THF, 78 to 10 °C; xii, Bu3SnH, AIBN, C6H6, reflux; xiii, NaBH4, MeOH–CH2Cl2 (110), 0 °C; xiv, Im2CS, (CH2Cl)2, reflux; xv, Bu3SnH, PhMe, reflux; xvi, PrSLi, HMPA–THF, rt; xvii, (Boc)2O, C6H6, reflux; xviii, BuLi, THF, 78 °C, then 2-heptenal, 78 to 50 °C; xix, Na–Hg, Na2HPO4, MeOH, rt; xx, conc. HCl, MeOH, reflux.
|
2 Quinazoline alkaloids
2.1 Occurrence, characterisation and biological activity
New quinazoline alkaloids isolated during the period under review are listed in
Table 2 together with known alkaloids isolated from new sources.
4,21,50–56
Table 2
Isolation and detection of quinazoline alkaloids
Species
|
Alkaloid
a
|
Ref
|
|
Aspergillus ochraceus |
()-Circumdatin C
b
151 |
50 |
|
|
()-Circumdatin D
b
152 |
51 |
|
|
()-Circumdatin E
b
153 |
|
|
|
()-Circumdatin F
b
154 |
|
|
Calanthe aristurifera, |
Tryptanthrin 165 |
52 |
|
C. discolor, C. reflexa |
|
|
|
Evodia officinalis |
Evodiamine |
4 |
|
|
Rutaecarpine 161 |
|
|
Glycosmis cf. chlorosperma |
(E )-Bogorin
b
150 |
53 |
|
|
(Z )-Bogorin
b
148 |
|
|
Penicillium sclerotigenum |
Sclerotigenin
b
157 |
54 |
|
Penicillium thymicola |
(+)-Alantrypinone
b
158 |
55 |
|
|
()-Fumiquinazoline F 159 |
|
|
Phellodendron amurense |
()-7,8-Dihydroxyrutaecarpine
b
|
56 |
|
(callus cultures) |
162 |
|
|
|
(+)-7-Hydroxyrutaecarpine 161 |
|
|
Zanthoxylum integrifolium |
14-Formylrutaecarpine |
21 |
|
a
Only new alkaloids and new records for a given species are listed in the table. Structures of most known alkaloids may be found in previous reviews in this series. b
New alkaloids. |
(
Z )-Bogorin
148, a new quinazolone alkaloid isolated from Javanese
Glycosmis cf. chlorosperma, was obtained in quantities too small for confirmation of its structure by two-dimensional NMR spectroscopic experiments.
53
The putative structure was therefore substantiated by the short synthesis shown in
Scheme 10. Base-induced elimination of hydrogen chloride from
149 produced exclusively (
E )-bogorin
150, which proved to be identical to another trace alkaloid in the plant extract. Photochemical isomerisation of
150 yielded a separable 1
1 mixture of (
E )- and (
Z )-bogorins, the latter of which gave
1H and
13C NMR spectroscopic signals identical to those of natural
148. (
Z )-Bogorin showed antifungal activity towards
Cladosporum herbarium (IC
50 40
g cm
3), and was moderately cytotoxic towards
Artemia salina (brine shrimp). The (
E )-isomer and the synthetic precursors were significantly less active.
|
Scheme 10
Reagents: i, 130 °C, 2.5 h; ii, styrene oxide, pyridine (cat.), PriOH, reflux; iii, SOCl2, C6H6, reflux; iv, DBU, C6H6, reflux; v, h (high pressure Hg lamp), cyclohexane, rt.
|
New peptide-like quinazolinone alkaloids derived from anthranilic acid together with other simple amino acids continue to turn up in fungal extracts. Circumdatin C
151 and the minor metabolites
152–154, named circumdatins D, E and F respectively, are quinazolino[3,2-
a][1,4]benzodiazepinediones from a terrestrial isolate of
Aspergillus ochraceus (subgenus
Circumdati, section
Circumdati).
50,51
The compounds, formally biosynthesised from two substituted anthranilate units and either
L-alanine or
L-proline, were accompanied by two unusual zwitterionic benzodiazepines, circumdatins A
155 and B
156. All structures were elucidated on the basis of spectroscopic measurements, with two-dimensional NMR experiments playing the expected dominant role. The simpler quinazolinobenzodiazepine sclerotigenin
157, obtained from extracts of the sclerotia (reproductive structures) of
Penicillium sclerotigenum, is derived from anthranilic acid and glycine.
54
This compound, which first appeared in the literature over twenty years ago as a purely synthetic material,
57
gave NMR spectra at ambient temperatures consistent with the presence of atropisomers, a phenomenon that has been observed with related 1,4-benzodiazepines. Variable temperature NMR measurements indicated an interconversion barrier of about 20 kcal mol
1. Sclerotigenin appears to be largely responsible for the observed antiinsectan activity of the fungal extract towards the crop pest
Helicoverpa zea (the corn earworm).
Two major metabolites isolated from a new
Penicillium species,
P. thymicola, are the novel alkaloid, (+)-alantrypinone
158 and a known compound, fumiquinazoline F
159.
55
In addition to the usual complement of spectroscopic methods used for characterising the new compound, X-ray crystallographic analysis revealed the (3
R,14
R) absolute configuration shown in
158. The implication is that alantrypinone incorporates
L-alanine and the unusual amino acid
D-tryptophan, as do fumiquinazoline F and the closely related spiroquinazoline
160. The authors feel, however, that modular peptide synthases are probably responsible for the biosynthesis of these compounds, and that the configuration of the more likely precursor
L-tryptophan is reversed during an enzymatic reaction.
Callus cultures of
Phellodendron amurense, the bark of which is used as a traditional medicine in China, produce indolopyridoquinazoline alkaloids related to the well-known compound rutaecarpine
161. In the latest investigation of the chemical constituents of the cultures, the new metabolite (
)-7,8-dihydroxyrutaecarpine
162 and a known alkaloid, (+)-7-hydroxyrutaecarpine
163, were isolated from methanolic extracts of callus tissue.
56
The only noteworthy feature in an otherwise unexceptional spectroscopic structural elucidation was the relatively small coupling constant between 7-H and 8-H (
J 2 Hz), which suggests a
trans-diequatorial arrangement of these protons, and hence a
trans-diaxial arrangement of the two hydroxy groups.
The rather uncommon quinazoline alkaloid arborine
164 has been identified as the component responsible for the inhibition of juvenile hormone III-biosynthesis in the field cricket (
Gryllus bimaculatus) by leaf extracts of
Glycosmis pentaphylla.
58
A review on the search for natural products and analogues with antitubercular activity has once again highlighted the importance of tryptanthrin
165 as a lead compound.
59
2.2 Structural and synthetic studies
A recent book chapter dealing with applications of transition metal-catalysed carbonylations in the synthesis of alkaloids includes a short section on quinazoline alkaloids.
60
In 1996 Joshi
et al. indisputably demonstrated the (3
S) absolute configuration of (
)-vasicinone
166 by means of X-ray crystallography, but reported that NMR spectroscopic analysis of the (+)- and (
)-Mosher
s esters of the alkaloid gave a contradictory result
61
(
cf. ref.
25d
). They have now acknowledged that they fell into the trap of assuming that, for example, the (
R)-Mosher
s acid chloride [
-methoxy-
-(trifluoromethyl)phenylacetyl chloride] gives rise to an ester that also has the (
R) configuration.
62
In fact, in terms of the Cahn–Ingold–Prelog sequence rules, the ester must have (
S) configuration because the priorities of the substituents change once chlorine is replaced by oxygen. There is thus no contradiction in the results from the spectroscopic analysis of the Mosher
s esters, and the (3
S) configuration of (
)-vasicinone has been fully vindicated. NMR spectroscopic analysis of the (+)- and (
)-Mosher
s esters of (
)-vasicine
167 likewise confirms that this alkaloid, too, has the (3
S) configuration.
The alkaloids febrifugine and isofebrifugine, first reported over fifty years ago, have moved into the limelight recently in view of their powerful antimalarial activity. The natural products have long been assumed to have the (2
S,3
R) and (2
R,3
R) absolute configurations, respectively. However, the first asymmetric total synthesis of the two alkaloids, by Kobayashi
et al., has now shown that these absolute configurations must be reversed.
63
Part of their synthesis of (2
S,3
R)-febrifugine is shown in
Scheme 11. Condensation between 2-methoxyaniline, 2-methoxypropene and the (
R)-aldehyde
168 (prepared by an enantioselective tin-mediated aldol condensation) was catalysed by ytterbium(III) triflate in aqueous medium, and gave the Mannich-type adducts
169 and
170 in 92% yield and a ratio of 33
67. The
anti adduct
169 was converted in several steps into the bromomethyl ketone
171, reaction of which with the anion of 4(3
H )-quinazolinone (4-hydroxyquinazoline) followed by removal of the protecting groups completed the synthesis of the (
)-enantiomer of febrifugine,
ent-
172. Natural febrifugine is dextrorotatory, and therefore must have the (2
R,3
S) configuration. By commencing with the (
S)-enantiomer of aldehyde
168, the authors were able to prepare (2
R,3
S)-(+)-febrifugine
172, the data for which were identical in all respects with those reported for the natural product. A similar sequence of reactions on the
syn-diastereomer
170 led to the formation of unnatural (2
R,3
R)-isofebrifugine
ent-
173, while the natural enantiomer
173 was once again obtained when the (
S)-aldehyde
ent-
168 was used in the synthesis.
|
|
Scheme 11
Reagents: i, Yb(OTf )3 (10%), THF–H2O (91), 0–5 °C; ii, HF, THF; iii, Ph3P, CBr4, CH2Cl2; iv, CAN, MeCN, H2O, 0 °C; v, Boc2O; vi, LiN(SiMe3)2, THF, then Me3SiCl; vii, MCPBA, CH2Cl2; viii, 4-hydroxyquinazoline, KOH; ix, HCl (6 M), reflux; x, Br2, HBr, HOAc.
|
The synthesis of racemic febrifugine and isofebrifugine by Takeuchi and co-workers shown in
Scheme 12 employed an unusual Claisen rearrangement for the construction of the piperidinol segment.
64
The allyl enol ether
174, prepared in four steps from 3-hydroxypyridine, rearranged in 74% yield to give the 2-allylpiperidin-3-one
175 merely on treatment with boron trifluoride etherate in acetonitrile at room temperature; rearrangement of the endocyclic double bond obviously precedes the Claisen rearrangement. Reduction of
175 with sodium borohydride in methanol gave the
cis-2,3-disubstituted piperidin-3-ol
176 as the sole product. Bromoetherification then afforded the bicyclic compound
177 as a 3
1 mixture of diastereomers, an unimportant factor in view of the subsequent dehydrobromination to
178 under basic conditions. Bromohydration of
178 and reaction with 4(3
H )-quinazolinone followed by removal of protecting groups completed the synthesis of (±)-isofebrifugine
rac-
173, following which thermal equilibration in boiling ethanol afforded (±)-febrifugine
rac-
172.
|
|
Scheme 12
Reagents: i, PhCH2Cl, PhMe, reflux; ii, H2CCHCH2Br, NaH, MeOH, reflux; iii, NaBH4, MeOH, 0 °C; iv, BnOCOCl, THF, rt; v, BF3·Et2O, MeCN, rt; vi, NBS, dry MeCN, rt; vii, ButOK, THF, reflux; viii, NBS, MeCN, H2O, rt; ix, 4(3H )-quinazolinone, K2CO3, DMF, rt; x, H2, 20% Pd(OH)2/C, MeOH, rt; xi, EtOH, reflux, 2 h.
|
The recently discovered quino[2
,3
3,4]pyrrolo[2,1-
b]quinazolinone alkaloid luotonin A
179 bears a striking structural similarity to the topoisomerase I inhibitor camptothecin
180, derivatives of which are used clinically for cancer chemotherapy. This structural similarity seems to underlie recent interest in the new alkaloid, which is effective against the murine leukaemia P-388 cell line (
cf. ref.
25e
). Luotonin A has rapidly succumbed to synthesis, and two short approaches published during the period under review are shown in
Scheme 13. The first, by Wang and Ganesan,
65
employed the known lactam
181, made in five steps and 9% overall yield from 2-nitrobenzaldehyde. Simple treatment of the anion of
181 with 2-sulfinylaminobenzoyl chloride
182 gave the target alkaloid
179 in 85% yield. The route devised by Kelly and co-workers
66
commenced with synthetic vasicinone (±)-
166, prepared according to reported methods. Oxidation with Jones reagent afforded dione
183, which underwent a Friedlander condensation with 2-aminobenzaldehyde to give luotonin A
179 in 36% yield.
|
|
Scheme 13
Reagents: i, LiN(SiMe3)2 (4.9 equiv.), THF, 182 (2.1 equiv.), rt, 2 h, then LiN(SiMe3)2 (2.5 equiv.), 182 (1.1 equiv.), rt, 1 h; ii, Jones oxidation; iii, 2-aminobenzaldehyde, Triton B, EtOH, reflux.
|
Syntheses of (
)-benzomalvin A
184 and benzomalvin B
185 by Eguchi and co-workers featured what has become known as the
Eguchi protocol
(acylation of suitable precursors with 2-azidobenzoyl chloride
186 followed by intramolecular aza-Wittig reaction) to construct both heterocyclic rings (
Scheme 14).
67
The present work expands on a previously published communication
68
(
cf. ref.
25f
), but includes noteworthy new results. In brief, reaction of
186 with
N-methyl-
L-phenylalanine methyl ester
187 yielded the intermediate azide
188 (ee 99.7%), after which treatment with tributylphosphine in boiling toluene followed by acidic work-up yielded the (
)-benzodiazepinedione
189 in 87% yield and undiminished optical purity. A second application of the
Eguchi protocol
completed the synthesis of (
)-benzomalvin A
184 ([
]
D
21
109.8,
c 1.0, MeOH). Incidentally, the claim that this is the first total synthesis of (
)-benzomalvin A is incorrect (
vide infra). Benzomalvin B
185 was prepared from benzomalvin A as a mixture of (
E ) and (
Z ) isomers by a benzylic bromination–dehydrobromination sequence. An interesting feature of this study is that the conformation of benzomalvin A was found to change with time when studied by NMR spectroscopy, eventually attaining an equilibrium ratio of 76
24. The major conformer was identical with the natural product. NOE interactions between the
N-methyl group and H-7 suggested the conformations shown in
190 and
191 for the major and minor invertomers respectively. Furthermore, an X-ray crystallographic study on a crystal of the minor conformer, which proved to be dextrorotatory ([
]
D
23
+77.1,
c 1.0, MeOH), confirmed the relative orientation of the diazepinone ring. The energy barrier between the two conformers was determined to be 5.9 kcal mol
1 by PM3 calculations. What is not clear from this work is whether the minor conformer is actually the same as (+)-benzomalvin D, a minor
Penicillium metabolite reported in 1995
69
(
cf. ref.
25g
). Benzomalvin D was reported as displaying exactly the same kind of conformational interconversion with natural and synthetic samples of (
)-benzomalvin A as described by the Eguchi group, and conformational representations essentially the same as those illustrated in
190 and
191 (which are, in effect, atropisomers) were proposed. The authors of the present publication seem not to have been aware of these results, and it appears that they may have unwittingly synthesised benzomalvin D in the course of their work.
|
|
Scheme 14
Reagents: i, Et3N, THF, 0 °C to rt; ii, Bu3P, PhMe, rt to reflux; iii, TFA–H2O–THF (1112.5), rt; iv, KN(SiMe3)2, THF, 78 °C; v, 186, THF, 78 °C to rt; vi, Ph3P, PhMe, rt to reflux; vii, NBS, AIBN, CCl4, reflux; viii, DBU, PhMe, reflux.
|
Wang and Ganesan recently reported a synthesis of fumiquinazoline G
192 in which cyclisation of the
N-acylanthranilamide
193 to the 4-quinazolinone
194 was the key step
70
(
cf. ref.
25f
). He and Snider have now shown that the cyclisation does
not produce the lactam
194, but instead gives the lactim ether
195 (
Scheme 15).
71
However, this does not invalidate the earlier study, since removal of the Fmoc protecting group with piperidine followed by chromatography on silica gel was accompanied by spontaneous cyclisation to yield fumiquinazoline G. Interestingly, removal of the Fmoc group with 4-dimethylaminopyridine yielded a free primary amine that failed to cyclise to the target alkaloid. With the aid of model studies, He and Snider were able to demonstrate that piperidine plays a role in the cyclisation over and above that of a deprotection agent. In their hands, an amidine carboxamide
196 proved to be an isolable intermediate. Exposure of this compound to silica gel induced spontaneous cyclisation to fumiquinazoline G through the putative quinazolinone intermediate
197.
|
|
Scheme 15
Reagents: i, Ph3P, I2, Pri2NEt, CH2Cl2, rt; ii, 20% piperidine in CH2Cl2, rt, then preparative TLC on SiO2; iii, piperidine, EtOAc, rt; iv, SiO2, EtOAc–MeOH (21), rt.
|
Several model studies designed to explore aspects of the synthesis of complex quinazoline alkaloids should be mentioned in conclusion. Synthetic approaches to the pyrazino[2,1-
b]quinazoline core found in the ardeemins, fiscalins and fumiquinazolines have been evaluated by Cledera
et al., who showed that the
Eguchi protocol
was the best of the four approaches studied for making products such as
198.
72
Hart and Magomedov have examined an unusual cascade reaction in which the sulfoxide
199 rearranged to a mixture of products that included the spiroindoline
200 upon treatment with trifluoroacetic acid in chloroform.
73
The ultimate intention is to apply the novel process to the synthesis of the alkaloid spiroquinazoline
160. On a simpler note, the benzodiazepinediones
201 were found to undergo rearrangement to the vasicinone-like carboxylic acids
202 in yields of 70–80% when heated in concentrated hydrochloric acid for a few minutes.
74
-fagarine
b
42
