Studies towards the Leucetta-derived alkaloids spirocalcaridine A and B - Possible biosynthetic implications

Article abstract of DOI:10.1002/ejoc.201403650

An exploration of an abiotic approach to spirocalcaridines A and B is described centered on electrophile-induced dearomatizing spirocyclization of aryl enyne derivatives. Elaboration of the α-iodoenone through an Ullmann-like, copper-catalyzed amidation provided a formamide, which upon treatment with methylamine undergoes a dienol-arene rearrangement to provide the corresponding kealiinine-like framework. This observation suggests a possible biosynthetic links between the spirocalcaridine and naphthimidazole group of Leucetta alkaloids. A putative approach to the Leucetta-derived alkaloids predicated on the elaboration of spirofused cyclohexandienols is described. However, the strategy is compromised by rearrangement of key intermediates into corresponding naphthimidazole derivatives. This latter observation suggests a new hypothesis about the biosynthetic origins of this family of natural products.

Full text of DOI:10.1002/ejoc.201403650

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FULL PAPER
DOI: 10.1002/ejoc.201403650
Studies towards the Leucetta-Derived Alkaloids Spirocalcaridine A and B –
Possible Biosynthetic Implications
Panduka B. Koswatta,[a] Jayanta Das,[a] Muhammed Yousufuddin,[b] and Carl J. Lovely*[a]
Keywords: Synthetic methods / Cross-coupling / Rearrangement / Natural products / Alkaloids / Spiro compounds /
Nitrogen heterocycles
An exploration of an abiotic approach to spirocalcaridines A
and is described centered on electrophile-induced
dearomatizing spirocyclization of aryl enyne derivatives.
Elaboration of the α-iodoenone through an Ullmann-like,
copper-catalyzed amidation provided a formamide, which
upon treatment with methylamine undergoes a dienol-arene
rearrangement to provide the corresponding kealiinine-like
framework. This observation suggests a possible biosynthetic
links between the spirocalcaridine and naphthimidazole
group of Leucetta alkaloids.
B
alkaloids that belongs to this family of sponges is the most
highly oxygenated and includes calcaridine A (8),[8] spiro-
calcaridines A (9) and B (10),[8b] and spiroleucettadine
(11)[9] and spironaamidine (12) (Figure 1).[10]
Introduction
The Leucetta family of marine sponges produces a wide
variety of secondary metabolites, which includes a growing
number of 2-aminoimidazole alkaloids that have recently
been reviewed.[1] Many of these imidazole-containing
metabolites are biologically active and exhibit, amongst
others, anti-cancer and antibiotic activities, but their bio-
logical roles in nature have yet to be rigorously defined.[1b]
Structurally, these 2-aminoimidazoles fit into five broad
subclasses as a function of their substitution patterns and
oxidation levels. The simplest systems are characterized by
the presence of one benzyl moiety on the 2-aminoimidazole
framework, e.g., preclathridine A (1); oftentimes there is a
closely related congener in which the 2-amino moiety is
functionalized with methyl parabanic acid, e.g., clathridine
A (2).[2] Two groups contain two benzylic moieties; the
naamine/naamidine group is substituted with benzyl groups
at C4 and C5, e.g. naamidine H (3),[3] whereas the isona-
amine/isonaamidine group is functionalized at N1 and C4,
e.g., isonaamidine E (4).[4] The fourth group of Leucetta
alkaloids contains a naphthimidazole framework, such as
that found in the kealiinines, e.g., 5[5] and kealiiquinones,
e.g. 6[6] and 7.[7] The final and most recently isolated group of
To date, there have been no experimental studies directed
towards unraveling the biosynthetic pathways that lead to
the formation of these compounds. The lack of experimen-
tal support notwithstanding, obvious relationships can be
mapped out among the various family members (Figure 2).
The parent systems have been hypothesized to be derived
from either octapamine (13), tyramine (14) or p-hyd-
roxyphenyl pyruvate (16), which leads to 17 and the 4,5-
and 1,4-disubstituted systems result from elaboration of this
species.[1a] The remaining family members can then be de-
rived from naamine A (19) or closely related analogs. For
example, calcaridine A (8), which contains a 4,4-disubsti-
tuted 5-imidazolone fragment, derives from the oxidative
rearrangement of naamine derivative.[8a,8c,11] Spirocalcarid-
ines (9) and (10) can also be traced back to the same general
precursor through a dearomatizing alkylation and oxidation
of the resulting intermediate. Spiroleucettadine (11) and re-
lated spironaamidine (12) can be envisioned to derive from
the corresponding naamine derivative by oxidation of the
imidazole 4,5-bond followed by an oxidative dearomatiza-
tion. The final group of Leucetta-derived alkaloids that
originate from naamine-type precursors are the keali-
inines[5c] and kealiiquinones.[6,7] The former can be derived
from an intramolecular Friedel–Crafts-like process followed
by oxidation to deliver the kealiinines. Additional oxidation
would then permit entry to the kealiiquinones. Our group
has taken advantage of these putative relationships to ac-
complish the total syntheses of calcaridine A,[8a,8c] kealiin-
ines A–C,[5a,5b] kealiiquinone, and 2-deoxy-2-amino-
kealiiquinone.[12]
[a] Department of Chemistry and Biochemistry, The University of
Texas at Arlington,
700 Planetarium Place, Arlington, Texas 76019-0065, USA
E-mail: lovely@uta.edu
http://www.uta.edu/chemistry/faculty/directory/Lovely.php
[b] Center for Nanostructured Materials, The University of Texas
at Arlington,
700 Planetarium Place, Arlington, TX 76019-0065, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403650.
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P. B. Koswatta, J. Das, M. Yousufuddin, C. J. Lovely
FULL PAPER
Figure 1. Representative Leucetta alkaloids.
Figure 2. Putative biosynthesis and biosynthetic relationships among the Leucetta alkaloids.
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Towards the Leucetta-Derived Alkaloids Spirocalcaridine A and B
acetylide with Weinreb amide 27 (Scheme 1).[20] Gratify-
ingly, ynone 24 delivered spirofused triene dione 28 in 94%
yield upon treatment with trifluoroacetic acid (TFA).[18]
With the spiro derivative in hand, our plan involved the
selective epoxidation of the cyclopentenone followed by
isomerization to give the α-diketone.[18] However, attempts
to effect selective reduction of cyclopentenone were com-
promised by competitive reduction of the dienone carbonyl,
which resulted in a complex mixture of alcohols and
diols.[18] Presumably, the electron rich aryl ring retards the
reduction rate of the cyclopentenyl carbonyl and thus com-
petitive reduction of both enones occur. As a result, we di-
rected our attention towards the preparation of derivatives
already functionalized at the α-position.
Results and Discussion
In our studies towards both the Leucetta[13] and the
oroidin alkaloids[14] we have adopted a general strategy to
elaborate pre-existing imidazoles rather than the de novo
construction of the heterocycle and broadly bioinspired ap-
proaches to construct the key structural elements contained
within the alkaloid framework. Our attempts to execute
such a strategy towards the spirocalcaridines have been
largely unsuccessful and thus we have pursued an alterna-
tive abiotic approach.[15] The general plan depicted in retro-
synthetic form centered on the construction of key
spirofused framework 23 through an electrophile-induced
dearomatizing spirocyclization and then annulation of the
imidazole ring (23Ǟ22; Figure 3). Adjustment of the oxid-
ation state of the imidazole, if necessary, would be ac-
complished based on chemistry developed in our laboratory
by using N-sulfonyloxaziridines (21Ǟ9 or 10; Figure 3).[11]
This strategy was predicated on the availability of 23
through dearomatizing cyclization of aryl ynones, chemistry
developed independently by Larock[16] and Li[17], and sub-
sequently developed further by others.
Scheme 1.
Figure 3. A retrosynthetic analysis of spirocalcaridines A and B.
Larock has described previously the preparation of α-
In an initial foray towards these natural product targets, iodocyclopentenone 35 from the dearomatizing spirocycli-
we identified α-diketone 32 as a potentially useful interme- zation of 33 with N-iodosuccinimide (NIS).[16] Similarly, we
diate for further elaboration (Scheme 1). Taylor and co- found that the anisyl-substituted derivative led to related
workers have used a similar strategy in their recently pub- spirocycle 34 under similar conditions (Scheme 2). Brief
lished total synthesis of spirobacillene A.[18] To access this attempts were made to react these intermediates with either
material, spirofused derivative 28 was required, which in guanidine or urea as means to install the imidazole compo-
turn necessitated ynone 24 as a precursor (Scheme 1). This nent, but these experiments were unsuccessful. Similarly,
was accomplished from deprotonation of p-ethynylanisole attempts to introduce a nitrogen substituent in place of the
(26)[19] with nBuLi and by trapping the resulting lithium iodine through a variety of palladium[21] or copper-cata-
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lyzed cross-coupling reactions were unsuccessful (see stituted nitrogen through a cross-coupling strategy. Al-
Scheme 3 for successful implementation of this strategy).[22] though several options are available in a general sense, the
Although the failure of the direct installation of the imid- use of palladium catalysis was likely to be compromised by
azole moiety was not unexpected,[23] given the general the presence of the allylic acetate, and thus our efforts were
robustness of cross-coupling chemistry, we suspected the directed towards the use of copper-mediated methods.[22]
presence of the cyclohexadienone was the cause of the prob- The Buchwald group has demonstrated that cross-coupling
lems. As a result, we decided to investigate the correspond- reactions between vinyl iodides and acetamides occurs upon
ing dienol derivative, which would not be susceptible to treatment with 5 mol-% CuI, N,NЈ-dimethylethylenedi-
Michael addition reactions.
amine (DMEDA), Cs2CO3 in tetrahydrofuran (THF) at 50–
70 °C.[22a] Subjection of iodide 41 to these reaction condi-
tions but with the use of formamide resulted in the
formation of coupling product 42 in 50% yield along with
25% of 43 derived from the net reductive deiodination of
41 (Table 1, Entry 1; and Scheme 3).[24] A screen of various
solvents (Table 1, Entries 2–5) resulted in no improvement
in the cross-coupling yields, although it is of note that in
acetonitrile there is an increase in the amount of reduction
product 43. Attempts to improve the yield of cross-coupling
product 42 by using stoichiometric quantities of copper and
DMEDA were not successful (Table 1, Entry 6); reduction
of the reaction temperature with catalytic loadings of CuI
still resulted in appreciable reductive deiodination. By
changing the base to K2CO3 or the copper salt to the brom-
ide has little to no effect on the yield. We also briefly inves-
tigated other coupling partners under the best conditions,
but found that neither urea nor N-methylurea delivered the
cross-coupled product and only reductive deiodination was
observed.[25]
Scheme 2.
With formamide 42 in hand, we attempted to install the
remaining nitrogen atom in the basic alkaloid framework
ideally providing 44 (Scheme 4). Initial experiments were
conducted with methylamine, because this would provide
an avenue for the direct introduction of the methyl group
in a site-specific manner to provide 44. Subsequent regio-
selective and chemoselective hydration of the carbon-
carbon double bond in the cyclopentene would then
provide the entire AB-ring system of spirocalcaridine. How-
ever, when 42 was treated with methylamine·HCl in the
presence of K2CO3, hydrolysis of both the acetate and
formamide occurred, which provided amino alcohol 45 in
low, non-optimized yield. The efficiency notwithstanding,
we attempted to convert 45 into corresponding 2-amino-
imidazole 47 by treatment with cyanamide, but this resulted
in rearrangement of the spirofused system into amino-
naphthol derivative 46 rather than the desired 2-aminoimid-
azole (Scheme 4). A related rearrangement occurred upon
treatment of 42 with methylamine·HCl in the presence of
Scheme 3. Dearomatizing spirocyclization.
Initial studies were performed with diphenyl-substituted Et3N and EtOH at reflux, which provided aminonaphthol
derivative 40, because this could be prepared through derivative 48. Notably in this case the product does contain
known procedures from phenylacetylene. Treatment of alk- a methyl imidazole moiety, which suggests that it may be
ynone 40 with NIS in acetic acid provided spirocyclic enone possible to annulate 42 under the appropriate circumstances
41 as a 2:1 mixture of diastereomers (Scheme 3). The (see below).
stereochemistry of the major diastereomer was not assigned
Given that both spirocalcaridines A (9) and B (10)
and this mixture was used directly in the next step. Given possess a methoxy group on the aryl ring we prepared
that the acetoxy-bearing center would eventually be con- corresponding substrate 53 by iodine-induced ipso cycliza-
verted into a carbonyl in the synthetic scheme this stereo- tion reaction of known alkynone 52,[26] which delivered 53
isomeric mixture was of no consequence. It was our inten- in good yield as an almost 1:1 mixture of diastereomers
tion to use the iodo moiety as a means to introduce a sub- (Scheme 5). It is of note that the reaction temperature has
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Towards the Leucetta-Derived Alkaloids Spirocalcaridine A and B
Table 1. Optimization of the cross-coupling reaction of 41.
Entry
Solvent
Ligand
Base
Catalyst
Amide
Temp. [°C] Time [h] % Yield 42 % Yield 43
1
2
3
4
5
6
7
8
THF
10% DMEDA
10% DMEDA
10% DMEDA
10% DMEDA
10% DMEDA
1.5 equiv. Cs2CO3 5% CuI
2.0 equiv. Cs2CO3 5% CuI
1.5 equiv. Cs2CO3 5% CuI
1.5 equiv. Cs2CO3 5% CuI
1.5 equiv. Cs2CO3 5% CuI
formamide
formamide
formamide
formamide
formamide
formamide
formamide
formamide
formamide
formamide
formamide
formamide
urea
70
110
80
70
70
80
40
25
70
70
70
70
70
70
22
28
24
30
30
48
10
12
15
15
15
15
15
15
50
n.r.[a]
n.r.[a]
10
45
52
21
–
40
50
30
–
25
–
–
1,4-dioxane
toluene
DMF
CH3CN
THF
THF
THF
THF
THF
THF
THF
THF
THF
–
40
30
20
–
30
30
–
–
30
30
2 equiv. DMEDA 2 equiv. Cs2CO3
2 equiv. DMEDA 2 equiv. Cs2CO3
1 equiv. CuI
1 equiv. CuI
5% CuI
10% TMEDA
10% DMEDA
10% DMEDA
10% DMEDA
10% TMEDA
10% DMEDA
10% DMEDA
2 equiv. K2CO3
2 equiv. K2CO3
2 equiv. Cs2CO3
2 equiv. Cs2CO3
2 equiv. Cs2CO3
2 equiv. Cs2CO3
2 equiv. Cs2CO3
9
5% CuI
10
11
12
13
14
5% CuBr
5% CuI
5% CuCN
5% CuI
–
–
5% CuI
N-methylurea
[a] n.r.: no reaction, starting material recovered unreacted.
adjusted by reducing the C4–C8 double bond (spiro-
calcaridine numbering). A wide variety of conditions were
evaluated, but none of them delivered the reduction prod-
uct. An alternative strategy involved the formation and re-
duction of an imine (or iminium species), and an ensuing
cyclization would result in the formation of the key frame-
work elements found in spirocalcaridines A and B. How-
ever, we found that although an N-methylimidazole was
formed, the spiro ring system had again undergone re-
arrangement to form a naphthimidazole framework 58
(Scheme 5).
The tendency of these spiro systems to undergo re-
arrangement under acidic conditions or in the presence of
Lewis acid is not surprising given their close relationship to
substrates that participate in the cyclohexadienol-benzene
rearrangement. Mechanistically, we assume that the methyl-
amine reacts to form imine 60, which then undergoes re-
arrangement to form naphthyl framework 62 after acti-
vation by protonation via 61 (Scheme 6). Deprotonation
provides 63, which undergoes tautomerization and dehy-
drative cyclization to form the imidazole ring and 40.
This propensity to undergo rearrangement raises the pos-
sibility that the spirocalcaridines (and perhaps as yet un-
identified congeners) may serve as biosynthetic precursors
to the naphthimidazole group of Leucetta alkaloids
(Scheme 7). As a result the biosynthetic relationships
among the more highly functionalized congeners may re-
quire some reanalysis. Naamine A (65, X = Y = H) or na-
amine G (65, X = Y = MeO) derivatives after N-methyl-
ation may serve as precursors to spirofused derivative 66
through oxidative-dearomatizing spirocyclization. Subse-
Scheme 4. Attempted annulation of imidazole moiety.
to be controlled very carefully during the addition of NIS, quent rearrangement by hydrolytic ring opening, and ring-
otherwise formation of iodonaphthol 54 and diiodo- closure of the 2-aminoimidazole to the 2-imidazolone then
naphthol 55 are observed. An X-ray structure of 55 delivers the two spiroleucettadine congeners 11 and 12. The
unequivocally confirms the location of the iodides in the 14-functionalized naamine derivative (65, Z = OH) may
diiodinated naphthol (Figure 4; Scheme 5).[27] α-Iodoenone serve as a biosynthetic precursor to calcaridine A (8)
53 was subjected to the cross-coupling chemistry with CuI through O-methylation and oxidative rearrangement. It is
and formamide to provide corresponding amide 57 in 70% of note that we have accomplished the latter through the
yield along with 20% of reductively deiodinated product 56. use of an N-sulfonyloxaziridine.[11] The same precursor (65,
With formamide 57 in hand we explored a slightly different Z = OH) upon activation of the hydroxy group may engage
approach in which the oxidation state of the system was in a dearomatizing spirocyclization, which upon dihydrox-
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Scheme 6. Putative mechanism for the conversion of spirofused sys-
tem into the naphthimidazole framework.
to 65 (Z = OH) can serve as precursors to the naphthimid-
azole framework by electrophilic addition (Friedel–Crafts-
like) and subsequent oxidation. However, other pathways
are feasible, which includes ipso addition, followed by re-
arrangement via an intermediate related to 67 and then
oxidation.[5a] Our own studies with this system points to
another possibility in which spirocalcaridine (or closely re-
lated derivative) may undergo dehydration to 68; proton-
ation of the carbonyl oxygen primes the system for re-
arrangement by a dienone-phenol rearrangement (69Ǟ70,
Scheme 7). Rearomatization to 71 and a second dehy-
dration delivers the naphthimidazole derivatives, the keali-
inines. Alternatively, oxidation of 67 provides same interme-
diate 68 for the dienone-phenol rearrangement to deliver
70. Further oxidation of the naphthimidazole provides the
naphthoquinone derivatives kealiiquinone and 2-deoxy-2-
aminokealiiquinone. We note that we have recently ac-
complished the total synthesis of both kealiiquinone and 2-
aminokealiiquinone through oxidative functionalization of
kealiinine derivatives, thus there is a direct synthetic con-
nection between three types of Leucetta alkaloids.[12b] When
these results and ideas are taken in concert with our pre-
vious results, the direct connection between almost all the
Scheme 5. Attempted iodine-induced ipso addition reaction of alk-
yne 51. DMP = Dess–Martin periodinane.
Figure 4. X-ray crystal structure of diiodonaphthol derivative 55.
ylation would lead to the formation of the spirocalcaridine Leucetta alkaloids can be mapped out, specifically the
framework. It has been speculated that derivatives related relationship between the naamidine framework and the
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Towards the Leucetta-Derived Alkaloids Spirocalcaridine A and B
Scheme 7. Putative biosynthetic relationship between the naamine, calcaridines and the naphthimidazole group of Leucetta alkaloids.
other members can be envisioned. Only the feasibility of the dienone-phenol rearrangements, these results provide cir-
conversion of the naamine to spirocalcaridine framework cumstantial evidence for alternative biosynthetic relation-
remains to be demonstrated in the laboratory. This is a ships between the spirofused and naphthimidazole systems.
challenge that we are presently pursuing. It is important This type of rearrangement has been posited to account for
to note that Scheme 7 is purely hypothetical as far as the the biosynthesis of several aporphinoid alkaloids.[28] Recent
biosynthesis is concerned and there is no evidence for this results from our laboratory have demonstrated that oxid-
sequence in biological systems. Although our experiments ation of the kealiinine framework gives rise to the quinone
do not address the biosynthesis directly, we have a growing moiety within the kealiiquinone group and thus we have
body of evidence to suggest that the postulated transforma- demonstrated experimentally a link between four sub-
tions are feasible. Based on these hypotheses, it raises the families of these aminoimidazole natural products. Al-
possibility of additional family members related to 66, 67, though these results do not prove the biogenesis of these
and 68 in which X = Y = OMe, and non-symmetrical Leucetta alkaloids, it provides evidence that these pathways
variants in which either X = H and Y = OMe, or X = OMe are at least feasible.
and Y = H.
Experimental Section
Conclusions
General: All chemicals were obtained from commercial vendors
and were used as received unless stated otherwise. All reactions
were conducted under an atmosphere of dry nitrogen in oven-dried
In summary, we have described some exploratory experi-
ments towards the total synthesis of spirocalcaridine A and
B, and although these have not been successful owing to glassware. Solvents were dried by using a Pure-Solv 400 solvent
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purification system (Innovative Technology, Inc.), except for di-
methylformamide (DMF), which was dried with CaH2 and then
distilled under vacuum. The 1H NMR spectra were acquired at
500 MHz in CDCl3, unless indicated otherwise, by using residual
CHCl3 as a reference. 13C NMR spectra were obtained at 125 MHz
in CDCl3, unless otherwise indicated, by using the central ab-
sorbance of CDCl3 as an internal standard. In cases in which dia-
stereomers were isolated as inseparable mixtures, 1H NMR spectro-
scopic signals for related absorptions are integrated together and
the minor isomer signal is underlined. For 13C NMR spectroscopic
data, the minor isomer is reported in parentheses. High-resolution
mass spectra were obtained at the University of Florida by electro-
spray ionization (HRMS-ESI) or at the Shimadzu Center for Ad-
vanced Analytical Chemistry, University of Texas at Arlington.
Na2S2O3 (100 mL), extracted with ethyl acetate (3ϫ 100 mL), dried
with Na2SO4, and concentrated under vacuum. The crude material
thus obtained was purified by flash column chromatography (ethyl
acetate/hexane = 2.5:7.5) to afford compound 34 as a black solid
1
(1.16 g, 83%), m.p. 133–135 °C. H NMR (500 MHz, CDCl3): δ =
7.38 (d, J = 10.0 Hz, 2 H), 6.87 (d, J = 10.0 Hz, 2 H), 6.80 (d, J =
10.0 Hz, 2 H), 6.37 (d, J = 10.0 Hz, 2 H), 3.82 (s, 3 H), 2.93 (s, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 199.3, 184.5, 175.1,
161.5, 149.8, 130.5, 129.2, 126.3, 114.0, 104.3, 55.5, 54.3, 43.7 ppm.
FTIR (neat): ν = 2960, 2919, 2838, 1718, 1693, 1660, 1622, 1601,
˜
1562, 1503, 1415, 1293, 1247, 1178, 1024, 923, 857, 835, 766, 553,
524 cm–1. HRMS (m/z): calcd. for C17H13O3INa [M + Na]+
414.9802; found 414.9804.
2-Iodo-3-oxo-1-phenylspiro[4.5]deca-1,6,9-trien-8-yl Acetate (41):
1,4-Bis(4-methoxyphenyl)but-3-yn-2-one (24): To a solution of alk-
Alkynone 40 (1.35 g, 6.1 mmol) was dissolved in acetic acid (5 mL)
yne 26 (3.00 g, 22.7 mmol) in anhydrous THF (20 mL) at –78 °C followed by the careful addition of NIS (1.65 g, 7.3 mmol) to main-
was added n-butyllithium (2.5 m solution in hexane, 10.9 mL,
27.2 mmol). The yellow solution was stirred at –78 °C for 30 min,
before adding into a pre-cooled (–78 °C) solution of Weinreb amide
27 (5.22 g, 25.0 mmol) in anhydrous THF (20 mL) by cannula. The
mixture was stirred at –78 °C for 1 h, then the cooling bath was
removed and the mixture was stirred for another 15 min. The mix-
ture was then cooled to –78 °C and quenched with satd. aq. NH4Cl
(40 mL). Upon warming to room temperature the mixture was
diluted with water (100 mL) and extracted with ethyl acetate (3ϫ
100 mL), dried with Na2SO4 and concentrated under vacuum. The
obtained crude material was subjected to purification by flash col-
umn chromatography (ethyl acetate/hexane = 1:4) to afford desired
compound 24 as yellow solid (4.83 g, 76%), m.p. 78–80 °C. 1H
NMR (500 MHz, CDCl3): δ = 7.41 (d, J = 8.6 Hz, 2 H), 7.22 (d,
tain ambient temperature. After stirring the resulting mixture for
30 min, ethyl acetate was added to it followed by aqueous saturated
NaHCO3 to neutralize the reaction mixture. The EtOAc solution
was separated and the aqueous layer was extracted with EtOAc two
more times. The combined organic layers were dried (Na2SO4) and
concentrated to provide a crude product, which was separated
chromatographically (10% ethyl acetate in hexanes) to provide a ≈
1
2:1 mixture of 41 (1.46 g, 60%) as a pale brown oil: H NMR: δ =
7.42–7.35 (m, 3 H), 7.24–7.22 (m, 2 H), 5.95–5.88 (m, 2 H), 5.87–
5.81 (m, 2 H), 5.55, 5.25 (m, 1 H), 2.82, 2.76 (s, 2 H), 2.04, 1.94 (s,
3 H) ppm. 13C NMR: δ = 201.1 (201.0), 180.1 (178.9), 170.5
(170.5), 135.2 (135.0), 132.5 (133.8), 130.0 (129.9), 128.3 (128.0),
127.3 (127.9), 126.3 (125.4), 105.4 (104.8), 63.6 (63.4), 51.8 (51.4),
46.7 (47.6), 21.1 (21.0) ppm. IR (neat): ν = 3033, 2924, 1721, 1369,
˜
J = 8.6 Hz, 2 H), 6.90 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 1236, 1016, 928, 739, 698 cm–1. HRMS-ESI (m/z): calcd. for
H), 3.84 (s, 2 H), 3.82 (s, 3 H), 3.80 (s, 3 H) ppm. 13C NMR C18H15INaO3 [M + Na]+ 428.9958; found 428.9926.
(125 MHz, CDCl3): δ = 185.8, 161.8, 159.0, 135.3, 130.0, 125.6,
2-Formylamino-3-oxo-1-phenylspiro[4.5]deca-1,6,9-trien-8-yl Acet-
114.4, 111.7, 94.1, 87.8, 55.5, 55.4, 51.3 ppm. FTIR (neat): ν =
˜
ate (42): A 10 mL resealable, thick-walled tube was charged with
CuI (20 mg, 0.1 mmol), iodo-ketone 41 (841 mg, 2.1 mmol) and
Cs2CO3 (1.01 g, 3.1 mmol). The tube was evacuated and back filled
with nitrogen and N,NЈ-dimethylethylenediamine (0.02 mL,
0.2 mmol), formamide (0.10 mL, 2.5 mmol) and THF (5 mL) were
added under nitrogen. The pressure tube was sealed with a Teflon
cap, immersed in a preheated oil bath at 70 °C and the reaction
mixture was stirred for 48 h, and progress followed by TLC. After
the resulting pale blue suspension was allowed to reach room temp.,
EtOAc was added. The reaction mixture was filtered through a pad
of silica (EtOAc). The filtrate was concentrated and the residue was
purified by flash chromatography on silica gel (10% ethyl acetate
2964, 2936, 2899, 2839, 2188, 1667, 1599, 1508, 1462, 1439, 1396,
1297, 1247, 1173, 1068, 1020, 818, 795, 688, 567, 534 cm–1. HRMS
(m/z): calcd. for C18H15O3 [M – H]+ 279.1027; found 279.1020.
4-(4-Methoxyphenyl)spiro[4.5]deca-3,6,9-triene-2,8-dione (28): To a
solution of compound 24 (1.00 g, 3.57 mmol) in anhydrous CH2Cl2
(25 mL) at 0 °C was added TFA (5.5 mL, 71.35 mmol) and the re-
sulting solution was stirred at 0 °C for 3 h. During this time, the
reaction color changed to red wine from light yellow. The volatiles
were removed under vacuum, ethyl acetate (150 mL) was added
and the organic layer was washed with sat aq. NaHCO3 (100 mL),
dried with Na2SO4, and concentrated under vacuum. Obtained
crude material was purification by flash column chromatography
(ethyl acetate/hexane = 3:7) to afford compound 28 as a black solid
(0.90 g, 94%), m.p. 70–72 °C. 1H NMR (500 MHz, CDCl3): δ =
1
in hexanes) to provide 42 as brown oil (334 mg, 50%). H NMR:
δ = 8.88, 8.83 (d, J = 11.5 Hz, 1 H), 7.39 (s, 3 H), 7.34 (m, 1 H),
7.18 (m, 2 H), 5.95–5.90 (m, 2 H), 5.86–5.80 (m, 2 H), 5.59, 5.32
7.46 (d, J = 8.6 Hz, 2 H), 6.93 (d, J = 10.3 Hz, 2 H), 6.83 (d, J = (m, 1 H), 2.73, 2.67 (s, 2 H), 2.05, 1.95 (s, 3 H) ppm. 13C NMR: δ
8.6 Hz, 2 H), 6.60 (s, 1 H), 6.40 (d, J = 10.3 Hz, 2 H), 2.73 (s, 2
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 203.2, 184.9, 173.2,
162.5, 152.2, 129.8, 129.7, 127.6, 125.5, 114.5, 55.6, 51.1, 46.9 ppm.
= 199.9 (199.8), 170.5, 161.8 (162.0), 154.1 (153.5), 133.3
(134.5),133.9 (133.6), 132.3 (132.5), 129.6 (129.7), 129.1 (128.8),
127.6 (128.1), 126.1 (125.3), 63.6 (63.4), 47.4 (48.2), 46.2 (45.9),
FTIR (neat): ν = 3086, 3043, 2936, 2841, 2245, 1737, 1697, 1661,
21.2 (21.0) ppm. IR (neat): ν = 3195, 3023, 2917, 2850, 1667, 1494,
˜
˜
1583, 1509, 1397, 1308, 1245, 1185, 1041, 1020, 864, 836, 731, 592,
1441, 1221, 1097, 748, 698 cm–1. HRMS (m/z): calcd. for
509 cm–1. HRMS (m/z): calcd. for C17H14O3Na [M + Na]+ C19H16NO4 [M – H] 322.1085; found 322.1069.
289.0835; found 289.0824.
3-Oxo-1-phenylspiro[4.5]deca-1,6,9-trien-8-yl Acetate (43): From
4-(4-Methoxyphenyl)-3-iodospiro[4.5]deca-3,6,9-triene-2,8-dione
(34): To a solution of compound 24 (1.00 g, 3.57 mmol) in an-
hydrous acetonitrile (35 mL) at room temperature was added
the above reaction a second product 43 (87 mg, 15%) was isolated
as a dark brown oil: H NMR: δ = 7.75–7.72 (m, 1 H), 7.54–7.51
(m, 1 H), 7.43–7.32 (m, 3 H), 6.58, 7.51 (s, 1 H), 6.01–5.93. (m, 4
1
NaHCO3 (0.60 g, 7.13 mmol) followed by iodine (1.81 g, H), 5.78–5.77 (m, 1 H), 2.67, 2.60 (s, 2 H), 2.13, 2.11 (s, 3 H) ppm.
7.13 mmol). The resulting brown mixture was stirred at room tem-
perature for 30 min. The reaction was quenched with satd. aq.
13C NMR: δ = 205.8 (205.7), 176.9 (175.8), 170.8 (170.6), 135.4
(135.2), 133.9 (133.4), 131.0 (130.8), 129.9 (129.3), 128.7 (128.5),
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

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Date: 06-03-15 13:31:24
Pages: 12
Towards the Leucetta-Derived Alkaloids Spirocalcaridine A and B
128.5 (127.8), 124.4 (124.3), 64.2 (64.0), 51.3 (50.7), 48.5 (47.9),
(20% ethyl acetate in hexanes) to provide a 5:4 mixture of 53
(747 mg, 81%) as a reddish brown oil. 1H NMR: δ = 7.57, 7.32 (d,
J = 8.7 Hz, 2 H), 6.88, 6.87 (d, J = 8.7 Hz, 2 H), 5.95–5.92, 5.94–
5.91 (m, 2 H), 5.86–5.82, 5.85–5.80 (m, 2 H), 5.59, 5.39 (m, 1 H),
3.82, 3.82 (s, 3 H), 2.78, 2.71 (s, 2 H), 2.05, 2.01 (s, 3 H) ppm. 13C
NMR: δ = 201.1 (200.9), 179.1 (177.6), 170.5 (170.5), 161.1 (160.8),
133.3 (134.3), 129.2 (130.2), 127.3 (127.0), 125.8 (125.0), 113.7
(113.4), 104.2 (103.0), 63.8 (63.5), 55.3, 51.7 (51.3), 47.0 (47.9), 21.2
21.3 (21.3) ppm. IR (neat): ν = 3022, 1726, 1691, 1590, 1568, 1368,
˜
1229, 1012, 966, 863, 754, 647 cm–1. HRMS: calcd. for
C18H16O3Na [M + Na] 303.0992; found 303.0966.
3-Amino-8-hydroxy-4-phenylspiro[4.5]deca-3,6,9-trien-2-one
(45):
Methylamine hydrochloride (200 mg, 3.0 mmol) and K2CO3
(410 mg, 3.0 mmol) were added to a solution of 42 (192 mg,
0.6 mmol) in ethanol (10 mL) and the mixture was heated at reflux
overnight. Water was added to the reaction mixture after evaporat-
ing the solvent and the aqueous solution was extracted with EtOAc
(2ϫ 10 mL). The combined organic solutions were dried (Na2SO4)
and concentrated to provide a crude product, which was purified
(21.1) ppm. IR (neat): ν = 2930, 2837, 1728, 1704, 1603, 1504, 1330,
˜
1226, 1175, 1020, 900, 835, 760 cm–1. HRMS-ESI (m/z): calcd. for
C19H18IO4 [M + H]+ 437.0244; found 437.0243.
3-Iodo-4-(4-methoxyphenyl)naphthalen-2-ol (54) and 1,3-Diiodo-4-
by chromatography on silica gel (EtOAc/hexanes = 2:3) of to isolate
45 (30 mg, 20%) as a light brown solid. H NMR: δ = 7.40–7.38 2.1 mmol) was dissolved in acetic acid (5 mL) and NIS (577 mg,
(4-methoxyphenyl)naphthalen-2-ol (55): Alkynone 52 (530 mg,
1
(m, 2 H), 7.35–7.32 (m, 2 H), 7.28–7.27 (m, 1 H), 5.95 (dd, J = 3.2,
5.5 mmol) was added at once to the reaction at room temp. (the
10.1 Hz, 2 H), 5.72 (dd, J = 1.8, 10.1 Hz, 2 H), 4.37 (s, 1 H), 8.84 reaction mixture became warm). The resulting mixture was stirred
(s, 2 H), 2.58 (s, 2 H) ppm. 13C NMR: δ = 201.6, 140.7, 140.1,
135.0, 134.4, 128.7, 128.6,128.2, 127.5, 61.9, 48.0, 44.9 ppm.
for 15 min before usual workup provided the crude material, which
was purified with silica gel (EtOAc/hexanes = 1:9) to give 54
(245 mg, 31%) and 55 (179 mg, 17%).
3-Amino-4-phenyl-2-naphthol (46): Aminol 45 (23 mg, 0.1 mmol)
was added to a solution of cyanamide (90 mg, 2.1 mmol) in water.
This mixture was acidified to pH 4.5 by careful addition of 10%
HCl and the resulting mixture was heated at 90 °C for 3 h. After
cooling, the resulting mixture was made basic to pH 10 with 20%
NaOH and the aqueous layer was extracted with EtOAc (2ϫ
10 mL). The combined organic layers were dried (Na2SO4) and
concentrated to provide 46 (60%) as a brown solid, m.p. 162–
Characterization data for compound 54, reddish brown solid, m.p.
1
139–141 °C. H NMR: δ = 7.72 (d, J = 7.8 Hz, 1 H), 7.43 (t, J =
7.8 Hz, 2 H), 7.34 (d, J = 8.7 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 1 H),
7.18 (d, J = 8.7 Hz, 2 H), 7.06 (d, J = 8.7 Hz, 2 H), 5.66 (s, 1 H),
3.92 (s,3 H) ppm. 13C NMR (DEPT 135): δ = 159.4 (C), 151.1 (C),
146.2 (C), 138.9 (C), 134.7 (C), 131.0 (CH), 129.1 (C), 127.5 (CH),
127.2 (CH), 126.7 (CH), 124.4 (CH), 114.0 (CH), 108.9 (CH), 97.7
1
164 °C. H NMR ([D6]acetone): δ = 7.58–7.53 (m, 3 H), 7.46–7.43
(C), 55.4 (CH ) ppm. IR (neat): ν = 3478 (br.), 2954, 2833, 1604,
˜
3
(m, 1 H), 7.34–7.32 (m, 2 H), 7.17 (s, 1 H), 7.10–7.07 (m, 2 H), 1583, 1510, 1328, 1242, 1213, 1170, 1026, 872, 843, 795, 773,
7.06–7.03 (m, 1 H),4.25 (br. d, 2 H), 2.85 (br. d, 2 H) ppm. 13C 753 cm–1. HRMS-ESI (m/z): calcd. for C17H14IO2 [M + H]+
NMR ([D3]methanol): δ = 145.8, 137.5, 133.7, 130.6, 128.9, 128.8,
128.7, 127.2, 125.7, 123.5, 122.7, 122.1, 120.1, 107.6 ppm. HRMS
(m/z): calcd. for C16H12NO [M – H] 234.0924; found 234.0924.
377.0033; found 377.0046. calcd. for C17H13INaO2 [M + Na]+
398.9853; found 398.9867.
Characterization data for compound 55, reddish brown solid, m.p.
1
1-Methyl-4-phenyl-1H-naphtho[2,3-d]imidazole (48): Methylamine
hydrochloride (158 mg, 2.4 mmol) and Et3N (0.13 mL, 0.9 mmol)
were added to a solution of 42 (153 mg, 0.5 mmol) in ethanol
(5 mL), and the resulting mixture was heated at reflux temperature
overnight. Water was added to the reaction mixture after evapora-
tion of the solvent and the aqueous layer was extracted with EtOAc
(2ϫ 10 mL). The combined organic layers were dried (Na2SO4)
and concentrated to provide a crude product, which was purified
with silica gel (EtOAc/hexanes = 3:2) to produce 48 (43 mg, 35%)
as a green solid, m.p. 185–188 °C. 1H NMR: δ = 8.70 (d, J =
10.1 Hz, 1 H), 8.27 (d, J = 9.2 Hz, 1 H), 8.01 (s, 1 H), 7.97 (d, J =
104–106 °C. H NMR: δ = 8.06 (d, J = 8.7 Hz, 1 H), 7.53 (tt, J =
1.4, 7.8 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 1 H), 7.22 (tt, J = 1.4, 7.8 Hz,
1 H), 7.14 (d, J = 8.7 Hz, 2 H), 7.08 (d, J = 8.7 Hz, 2 H), 6.36 (s,
1 H), 3.92 (s,3 H) ppm. 13C NMR (DEPT 135): δ = 159.5 (C),
151.1 (C), 147.5 (C), 135.5 (C), 134.9 (C), 131.1 (CH), 131.0 (CH),
129.6 (C), 128.9 (CH), 128.5 (CH), 125.1 (CH), 114.1 (CH), 93.5
(C), 83.2 (C), 55.6 (CH ) ppm. IR (neat): ν = 3391 (br.), 3062, 2953,
˜
3
2840, 1605, 1511, 1486, 1371, 1234, 1171, 1027, 749 cm–1. HRMS-
ESI (m/z): calcd. for C17H13I2O2 [M + H]+ 502.9005; found
341.1512. calcd. for C17H12I2NaO2 [M + Na]+ 524.8824; found
363.1328. Observed ion consistent with MW of 340 Da. This struc-
7.8 Hz, 2 H), 7.54 (t, J = 7.8 Hz, 2 H), 7.47 (t, J = 10.1 Hz, 1 H), ture was confirmed by X-ray crystallography.
7.34 (t, J = 7.8 Hz, 1 H), 7.09 (t, J = 9.2 Hz, 1 H), 7.01 (t, J =
2-Formylamino-1-(4-methoxyphenyl)-3-oxospiro[4.5]deca-1,6,9-
10.1 Hz, 1 H), 4.21 (s, 3 H) ppm. 13C NMR: δ = 155.7, 147.1, 135.7,
135.4, 135.2, 133.9, 129.8, 128.8, 128.0, 126.8, 126.5, 122.7, 121.9,
trien-8-yl Acetate (57): By following the procedure for 42, CuI
(2 mg, 0.01 mmol), iodo-ketone 53 (102 mg, 0.23 mmol) and
Cs2CO3 (152 mg, 0.50 mmol), N,NЈ-dimethylethylenediamine
(0.01 mL, 0.02 mmol), formamide (0.02 mL, 0.50 mmol) and THF
(2 mL) were heated at reflux for 12 h. The crude product was puri-
fied with silica gel (EtOAc/hexanes = 1:1) to isolate a 1:1 mixture
of 57 (58 mg, 70%) as light brown oil. 1H NMR: δ = 8.87, 8.83
121.4, 117.1, 33.8 ppm. IR (neat): ν = 3039, 2918, 2844, 1607, 1592,
˜
1572, 1538, 1495, 1456, 1372, 1261, 1171, 1044, 896, 740 cm–1.
HRMS-ESI (m/z): calcd. for C18H14N2 [M + H]+ 259.1230; found
259.1227. calcd. for C36H29N4 [2M
517.2390.
+
H]+ 517.2387; found
2-Iodo-1-(4-methoxy-phenyl)-3-oxospiro[4.5]deca-1,6,9-trien-8-yl (two overlapping doublets, 1 H), 7.38, 7.38 (d, J = 8.5 Hz, 1 H),
Acetate (53): Alkynone 52 (530 mg, 2.1 mmol) was dissolved in
acetic acid (5 mL) followed by careful addition of NIS (577 mg,
5.5 mmol) to maintain ambient temperature. After stirring the re-
sulting mixture for 15 min, ethyl acetate (75 mL) was added, fol-
lowed by addition of sufficient satd. aq. NaHCO3 to neutralize
the reaction mixture. The organic solution was separated and the
7.19, 7.19 (d, J = 8.5 Hz, 2 H), 6.89, 6.89 (d, J = 8.5 Hz, 2 H),
5.98–5.90 (m, 2 H), 5.90–5.78 (m, 2 H), 5.64, 5.44 (s, 1 H), 3.81,
3.81 (s, 3 H), 2.69, 2.62 (s, 2 H), 2.06, 2.01 (s, 3 H) ppm. 13C NMR:
δ = 199.8 (199.7), 170.6 (170.5), 162.0 (162.3), 160.6 (160.8), 154.4
(153.9), 133.9 (134.8), 133.3 (132.7), 129.1 (129.8), 125.8 (125.7),
124.4 (124.5), 114.6 (114.3), 63.8 (63.6), 55.4 (55.4), 47.6 (48.5),
aqueous layer was extracted with ethyl acetate (2ϫ 75 mL). The 46.1 (45.7), 21.2 (21.1) ppm. IR (neat): ν = 3317, 3011, 2965, 2828,
˜
combined organic layers were dried (Na2SO4) and concentrated to
provide a crude product, which was separated chromatographically
1699, 1662, 1604, 1507, 1384, 1283, 1245, 1175, 1030, 804,
734 cm–1. HRMS-ESI (m/z): calcd. for C20H20NO5 [M + H]+
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O43650
/KAP1
Date: 06-03-15 13:31:24
Pages: 12
P. B. Koswatta, J. Das, M. Yousufuddin, C. J. Lovely
FULL PAPER
354.1341; found 354.1311. calcd. for C20H19NNaO5 [M + Na]+
376.1161; found 376.1129.
[1]
[2]
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528; b) J. D. Sullivan, R. L. Giles, R. E. Looper, Curr. Bioact.
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Coulon, M. L. Bourguet-Kondracki, Nat. Prod. Rep. 2012, 29,
739–751.
a) P. B. Koswatta, C. J. Lovely, Tetrahedron Lett. 2009, 50,
4998–5000; b) B. P. Zavesky, N. R. Babij, J. P. Wolfe, Org. Lett.
2014, 16, 4952–4955.
P. B. Koswatta, C. J. Lovely, Chem. Commun. 2010, 46, 2148–
2150.
H. M. Lima, B. J. Garcia-Barboza, N. N. Khatibi, C. J. Lovely,
Tetrahedron Lett. 2011, 52, 5725–5727.
1-(4-Methoxyphenyl)-3-oxospiro[4.5]deca-1,6,9-trien-8-yl
(56): From the above reaction a small amount of reductive dehalo-
genation product 56 (15 mg, 20%) was isolated as a 1:1 mixture of
Acetate
1
a dark brown solid, m.p. 92–95 °C. H NMR: δ = 7.72, 7.42 (d, J
= 8.8 Hz, 2 H), 6.75 (d, J = 8.3 Hz, 4 H), 6.37, 6.34 (s, 1 H), 5.89–
5.81 (m, 4 H), 5.74, 5.64 (m, 1 H), 3.70, 3.68 (s, 3 H), 2.49,2.42 (s,
2 H), 2.04,2.00 (s, 3 H) ppm. 13C NMR: δ = 205.6 (205.5), 176.0
(175.2), 170.9 (170.6), 161.9 (161.8), 136.1 (135.5), 130.5 (129.8),
127.7 (127.1), 126.2 (125.9), 124.1 (123.9), 114.2 (114.0), 64.3
[3]
[4]
[5]
(64.1), 55.5, 51.3 (50.8), 48.2 (47.7), 21.3 ppm. IR (neat): ν = 2841,
˜
a) J. B. Gibbons, K. M. Gligorich, B. E. Welm, R. E. Looper,
Org. Lett. 2012, 14, 4734–4737; b) J. Das, P. B. Koswatta, M.
Yousufuddin, J. D. Jones, C. J. Lovely, Org. Lett. 2012, 14,
6210–6213; c) W. Hassan, R. Edrada, R. Ebel, V. Wray, A.
Berg, R. Van Soest, S. Wiryowidagdo, P. Proksch, J. Nat. Prod.
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Stout, J. Clardy, J. Org. Chem. 1990, 55, 1944–1946.
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60, 497–498.
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Lett. 2008, 10, 5055–5058; b) R. A. Edrada, C. C. Stessman, P.
Crews, J. Nat. Prod. 2003, 66, 939–942; c) P. B. Koswatta, R.
Sivappa, H. V. R. Dias, C. J. Lovely, Synthesis 2009, 2970–
2982.
K. N. White, T. Amagata, A. G. Oliver, K. Tenney, P. J. Wenzel,
P. Crews, J. Org. Chem. 2008, 73, 8799–8722.
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5342–5344.
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48, 5771–5774.
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lington, 2010.
1728, 1680, 1600, 1585, 1508, 1238, 1176, 1022, 869, 806, 757 cm–1.
HRMS (m/z): calcd. for C19H18O4Na 333.1097; found 333.1072.
1-Methyl-4-(4-methoxyphenyl)-1H-naphth[2,3-d]imidazole (58):
A
solution of methylamine in methanol (8.03 m, 0.05 mL, 0.4 mmol)
was added to amide 58 (120 mg, 0.4 mmol) pre-absorbed on silica
gel (≈ 1 g). After stirring at room temp. overnight, Zn(BH4)2 in
THF (4.0 m, 0.10 mL, 0.4 mmol) was added to above reaction, and
stirred for 2 h. After removing the solvent, crude product was puri-
fied with silica gel (EtOAc/hexanes = 1:1) to isolate 59 (30 mg,
[6]
[7]
[8]
1
30%) as a light brown solid, m.p. 158–160 °C. H NMR: δ = 8.07
(d, J = 8.7 Hz, 1 H), 8.00 (d, J = 8.7 Hz, 2 H), 7.79 (s, 1 H), 7.57
(d, J = 8.7 Hz, 2 H), 7.45 (tt, J = 1.4, 7.3 Hz, 1 H), 7.35 (tt, J =
1.4, 7.3 Hz, 1 H), 7.12 (d, J = 8.7 Hz, 2 H), 3.92 (s, 3 H), 3.91 (s,
1 H) ppm. 13C NMR: δ = 159.1, 147.5, 142.5, 134.9, 132.3, 131.1,
129.6, 128.9, 128.3, 127.8, 126.5 124.4, 123.5, 114.0, 104.6, 55.4,
[9]
[10]
31.2 ppm. IR (neat): ν = 3054, 2920, 2844, 1667, 1513, 1241, 1174,
˜
1024, 828, 746 cm–1. HRMS (m/z): calcd. for C19H16ONa [M +
Na]+ 311.1155; found 311.1137.
[11]
[12]
X-ray Crystallographic Data: A suitable crystal covered with a layer
of hydrocarbon/paratone-N oil was selected and mounted on a
Cryo-loop, and immediately placed in the low temperature nitrogen
stream. The X-ray intensity data for 55 were measured at 100(2) K
on a SMART APEX CCD area detector system equipped with a
Oxford Cryosystems 700 series cooler, a graphite monochromator,
and a Mo-Kα fine-focus sealed tube (λ = 0.71073 Å). Intensity data
were processed by using the Saint Plus program. All the calcula-
tions for the structure determination were carried out by using the
SHELXTL package (version 6.14). Initial atomic positions were
located by direct methods by using XS, and the structure of the
compound was refined by the least-squares method by using XL.
Absorption correction was applied by using SADABS. Hydrogen
atoms were placed at calculated positions and refined riding on
the corresponding carbons. All non-hydrogen atoms were refined
anisotropically.
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gashira reaction between TMS-acetylene and p-iodoanisole fol-
lowed by base-induced desilylation.
Supporting Information Copies of H and 13C NMR spectra for all
new compounds.
1
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Acknowledgments
This work has been supported by the Robert A. Welch Foundation
(grant number Y-1362) and in part by the National Institutes of
Health (NIH) (GM065503). The National Science Foundation
(NSF) (CHE-0234811 and CHE-0840509) is thanked for funding
the purchase of the NMR spectrometers used in this research. The
authors acknowledge the Texas Advanced Computing Center
(TACC) at The University of Texas at Austin for providing re-
sources that have contributed to the research results reported
within this paper.
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10
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Job/Unit: O43650
/KAP1
Date: 06-03-15 13:31:24
Pages: 12
Towards the Leucetta-Derived Alkaloids Spirocalcaridine A and B
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[27] CCDC-1040263 contains the supplementary crystallographic
Received: December 18, 2014
data for compound 55. These data can be obtained free of
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O43650
/KAP1
Date: 06-03-15 13:31:24
Pages: 12
P. B. Koswatta, J. Das, M. Yousufuddin, C. J. Lovely
FULL PAPER
Natural Product Synthesis
A
putative approach to the Leucetta-
P. B. Koswatta, J. Das, M. Yousufuddin,
derived alkaloids predicated on the ela-
boration of spirofused cyclohexandienols is
described. However, the strategy is compro-
mised by rearrangement of key intermedi-
ates into corresponding naphthimidazole de-
rivatives. This latter observation suggests a
new hypothesis about the biosynthetic origins
of this family of natural products.
C. J. Lovely* ..................................... 1–12
Studies towards the Leucetta-Derived Alk-
aloids Spirocalcaridine A and B – Possible
Biosynthetic Implications
Keywords: Synthetic methods / Cross-cou-
pling / Rearrangement / Natural products /
Alkaloids / Spiro compounds / Nitrogen het-
erocycles
12
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