Antifungal diterpene alkaloids from the Caribbean sponge Agelas citrina: Unified configurational assignments of agelasidines and agelasines

Article abstract of DOI:10.1002/ejoc.201200572

Three new diterpene alkaloids - the hypotaurocyamines, (-)-agelasidines E and F (5, 6), and an adeninium salt, agelasine N (9) - were isolated from the Caribbean sponge Agelas citrina along with six known natural products: agelasines B-E (7, 10-12), 2-oxo-agelasine B (8), and (-)-agelasidine C (3). The chemical structures of 5, 6, and 9 were elucidated by NMR spectroscopy and mass spectrometry. This represents the first report of natural products from the sponge A. citrina. Unified assignment of the absolute configurations of the new compounds and known compounds was achieved by chemical correlation, quantitative measurements of molar rotations, and comparative analysis by van't Hoff's principle of optical superposition. (-)-Agelasidine C (3) exhibited potent antifungal and modest cytotoxic activity against human chronic lymphocytic leukemia (CLL) cells. Copyright

Full text of DOI:10.1002/ejoc.201200572

Job/Unit: O20572
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Date: 25-06-12 11:41:18
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200572
Antifungal Diterpene Alkaloids from the Caribbean Sponge Agelas citrina:
Unified Configurational Assignments of Agelasidines and Agelasines
E. Paige Stout,[a] Lily C. Yu,[a] and Tadeusz F. Molinski*[a,b]
Dedicated to Professor Ernesto Fattorusso on the occasion of his 75th birthday
Keywords: Natural products / Alkaloids / Circular dichroism / Terpenoids
Three new diterpene alkaloids – the hypotaurocyamines,
(–)-agelasidines E and F (5, 6), and an adeninium salt, agelas-
ine N (9) – were isolated from the Caribbean sponge Agelas
citrina along with six known natural products: agelasines B–
E (7, 10–12), 2-oxo-agelasine B (8), and (–)-agelasidine C (3).
The chemical structures of 5, 6, and 9 were elucidated by
NMR spectroscopy and mass spectrometry. This represents
the first report of natural products from the sponge A. citrina.
Unified assignment of the absolute configurations of the new
compounds and known compounds was achieved by chemi-
cal correlation, quantitative measurements of molar rota-
tions, and comparative analysis by van’t Hoff’s principle of
optical superposition. (–)-Agelasidine C (3) exhibited potent
antifungal and modest cytotoxic activity against human
chronic lymphocytic leukemia (CLL) cells.
cyamine and adeninium alkaloids, respectively, and are the
first natural products reported from A. citrina, a species
endemic to the Caribbean Sea. A unifying chiroptical analy-
Introduction
A growing class of nitrogenous diterpenes that include
co-occurring hypotaurocyamines (e.g., 1–4) and N9-adenin-
ium alkaloids from marine sponges of the genus Agelas
have been shown to exhibit a wide range of biological ac-
tivities, including antineoplastic,[1] antimicrobial,[2] and
Na+,K+-adenosine triphosphatase (ATPase) inhibitory
properties.[3] As a part of ongoing investigations into bio-
active chemical constituents of Caribbean sponges, we ex-
plored the constituents of the potently antifungal extracts
of the marine sponge Agelas citrina, which inhibited growth
of several strains of Candida and the pernicious pathogens
Cryptococcus var grubii and Cryptococcus var gattii. Here
we report the isolation and structure elucidation of three
new and six known alkaloid diterpenes – two hypotaurocy-
amine diterpenes, agelasidines E and F (5, 6), one N9-meth-
yladeninium diterpene, agelasine N (9) – in addition to
known compounds agelasines B–E (7, 10–12),[3] 2-oxo-agel-
asine B (8),[4] and (–)-agelasidine C (3)[5] (Figure 1). Com-
pounds 5, 6, and 9 expand the observed range of new oxi-
dation motifs in the diterpenoid scaffold of the hypotauro-
[a] Department of Chemistry and Biochemistry, University of
California,
San Diego, 9500 Gilman Drive MC0358, La Jolla, CA 92093-
0358, USA
Fax: +1-858-822-0386
E-mail: tmolinski@ucsd.edu
[b] Skaggs School of Pharmacy and Pharmaceutical Sciences,
University of California,
Figure 1. Agelasidines A–F (1–6); agelasines B (7), C (10), D (11),
and E (12), (–)-2-oxo-agelasine B (8), and (+)-agelasine N (9); and
synthetic compounds 14 and 15.[15a] Guanidinium groups are de-
picted as a free-base.
San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200572.
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E. P. Stout, L. C. Yu, T. F. Molinski
SHORT COMMUNICATION
sis of the natural products by application of van’t Hoff’s
principle of optical superposition, completed assignment of
their absolute configurations.
Results and Discussion
A MeOH extract of the Caribbean sponge A. citrina was
subjected to solvent partitioning and chromatography to
yield compounds 3 and 5–12 (Figure 1), which represent the
first natural products reported from A. citrina.
Compound (–)-3 {HRMS (ESI): m/z = 424.2993 [M +
H]+, C23H41N3O2S} displayed 1H NMR chemical shifts
identical to the first reported values for (+)-agelasidine C
[(+)-3],[2a] but the sign of the specific rotation {[α]2D5 = –12
(c = 2.0, MeOH)} was opposite {[α]2D5 = +8.5 (c = 2.0,
MeOH)}.[2a] Conversion of (–)-3 into the corresponding
4,6-dimethylpyrimidine derivative by reaction of the guan-
idine (pentane-2,4-dione, pyridine; Supporting Information,
Scheme S1), followed by reductive ozonolysis according to
the procedure of Nakamura and co-workers[2a] gave deriva-
tives from (–)-3 (Supporting Information) that were enan-
tiomeric with those obtained from (+)-3.[2a] Consequently,
the (5R,6S) configuration was assigned to the sample of
(–)-3 obtained from A. citrina.
Figure 2. Key 1H–1H COSY/TOCSY (bold line) and HMBC
(arrow) correlations for agelasidine E (5) and agelasine N (9).
Stereochemical assignments at C-13 for 5 and 6 were
made by chemical degradation and comparison of the prod-
ucts with known compounds (Scheme 1a). Ozonolysis of
either 5 or 6 (O3, –78 °C, MeOH), followed by reductive
workup (NaBH4) and acetylation (Ac2O, pyridine), gave
tetraacetyl derivative (+)-13 {[α]2D5 = +6.7 (c = 0.2, CHCl3)},
reported earlier from degradation of 2.[2a] Consequently,
both 5 and 6 are (13R).
Mass spectrometric measurements of agelasidine E (5),
isolated as a colorless oil, gave HRMS (ESI): m/z =
440.2940 [M + H]+, and suggested a molecular formula of
C23H41N3O3S; one oxygen more than agelasines B and C
1
(2, 3). Analysis of the H and 13C NMR spectra of 5 (Sup-
porting Information, Table S3) identified a terminal methyl-
ene at H2-15 (δH = 5.50, 5.57 ppm) and a quaternary C-13
(δC = 68.9 ppm), which supported the branched hypotauro-
cyamine moiety similar to 2. Lack of one of the methyl
singlets and appearance of low-field diastereotopic methyl-
ene proton signals (δH = 3.97, 4.07 ppm) were consistent
with an oxidation product of 2 formed by the replacement
of a CH3 group with a CH2OH group. The location of the
OH group in 5 was secured through detailed examination
of the TOCSY and HMBC spectra (Figure 2). Interpret-
Scheme 1. (a) Chemical degradation of agelasidine E (5) to (R)-
13.[2a] (b) Key NOEs (double-headed arrows) are shown for (+)-
agelasine N (9).
The configurations of C5 and C6 in the cyclohexene seg-
ation of collective long-range 1H–13C correlations from H2- ments of 5 and 6 were solved independently by global esti-
16 to C-3 (δC = 124.7 ppm) and C-4 (δC = 143.6 ppm); H3- mations of molar rotation, [f], by employing the principle
18 (δH = 0.95 ppm) to C-4, C-5 (δC = 40.4 ppm), C-6 (δC
34.4 ppm), and C-7 (δC = 36.1 ppm); and H-3 (δH
=
=
of optical superposition, first proposed by van’t Hoff[12]
based on canonical observations by Le Bel. The power of
5.79 ppm) to C-2 (δC = 25.7 ppm) and C-5 supported the the method has been nicely demonstrated by Wipf and Be-
placement of the hydroxy group at C-16 (δC = 63.1 ppm). ratan in applications to natural product assignments of ab-
Unlike 5, which showed no absorption in the UV/Vis solute and relative configurations of relatively complex nat-
spectrum above 210 nm, agelasidine F (6) contained a chro- ural products.[13a,13c,14] In its simplest interpretation, the
mophore (λmax = 240 nm). Analysis of the HRMS (ESI) molar rotation is the summation of independent atomic
data (m/z = 438.2786 [M + H]+, C23H39N3O3S) and 1H contributions to optical rotatory power – both positive and
NMR signals of 6 (Supporting Information, Table S3) sug- negative angles – from isolated centers of asymmetry, which
gested the presence of a conjugated olefin associated with in turn are dependent upon polarizability. Molar rotations
a new downfield proton signal (δH = 9.32 ppm, s) that was can be calculated by DFT methods,[13b] but it is not trivial
readily assigned to an α,β-unsaturated aldehyde (δC
=
and requires formidable computational power. More conve-
196.8 ppm). Differences in the NMR chemical shifts be- niently, global contributions to molar rotation [f]D mea-
tween 5 and 6 near the cyclohexene ring (Supporting Infor- sured at the sodium D-line emission, can be approximated
mation, Table S3) and similarities of the remaining COSY from the measured molar rotations of simpler analogs
and HMBC correlations allowed placement of the CH=O {derived from [α]D according to Equation (1), where M is
group at C-16.
the molar mass}, each containing isolated chiral molecular
2
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Antifungal Diterpene Alkaloids from Agelas citrina
segments. In practice, this empirical approach is valid and serve to illustrate the power of optical superposition and
van’t Hoff’s rule can be applied if stereocenters are sepa- molar rotations[13] and underscore a reminder of the in-
rated by one or more methylene units and non-bonded in- herent risk of over-reliance on the sign of [α]D alone.[4]
teractions are negligible.[13a]
Agelasine N (9), an amorphous white solid, revealed a
formula of C26H42N5O from the HRMS (ESI) data (m/z =
440.3386 [M + H]+) and upon comparison with those of
known agelasines 7 and 10–12, indicating the addition of
H2O. The 1H NMR spectroscopic data of 9 were consistent
with a hydroxy-substituted clerodane ring system. HMBC
correlations from both H3-17 (δH = 0.94 ppm) and H3-19
(δH = 0.89 ppm) to C-10 (δC = 80.6 ppm) supported a terti-
ary alcohol by placement of the OH group at C-10 (Fig-
ure 2). NOE correlations of 9 allowed assignment of the
relative configuration at all stereogenic centers in a trans-
fused clerodane bicyclic ring system through observation of
syn-facial NOEs (Scheme 1b). The paucity of available sam-
ple (≈0.5 mg, 9) precluded determination of absolute con-
figuration; consequently, the depicted configuration of 9 is
arbitrary.
[α]D ϫ M
[f]D
=
(1)
100
To test the applicability of the method in the context of
5 and 6, we calculated the values of all four stereoisomers
of agelasidine B (2; Table 1, Entries 6–9) by superposition
of combinations of both enantiomers of 1 and 3 and com-
pared them to the measured value (Table 1, Entry 2; [f]D
=
–11.5 degmol–1 dm3 cm–1). A good fit of the calculated
value (Table 1, Entry 9; [f]D = –19.7) was obtained only for
the known (5S,6R,13R) configuration of (–)-2, indepen-
dently derived by Nakamura by using chemical degrada-
tion.[2a]
Table 1. Measured and Calculated molar rotations[a] [f]D
(degmol–1 dm3 cm–1) by van’t Hoff’s principle of optical superposi-
tion.[12,13]
The reported absolute configurations of agelasines A–F
were determined through stepwise chemical degradation,
followed by comparison of the products to known com-
pounds by optical rotation and CD.[3] Total syntheses of
agelasines A,[6] B,[7] D,[8] and E[9] supported the assign-
ments, or – in the case of the synthesis of agelasine C (10)
[b]
Entry
Compound
[f]D meas.
[f]D calcd.
1
2
3
4
5
6
7
8
(+)-(13S)-1
(–)-(5S,6R,13R)-2
(–)-(5R,6S)-14[b]
(–)-(5R,6S,13R)-5
(–)-(5R,6S,13R)-6
(5R,6S,13S)-2a
(5R,6S,13R)-2b
(5S,6R,13S)-2c
(5S,6R,13R)-2d
(5R,6S,13S)-5a
(5R,6S,13R)-5b
(5S,6R,13S)-5c
(5S,6R,13R)-5d
74.9
–11.5
–15.9
–44.3
–59.7
[10]
– led to revision of the originally assigned absolute con-
figuration. Subsequent configurational assignments of new
agelasines were heavily reliant upon comparisons of [α]D
values with those of known agelasines (Table 2), despite sig-
nificant structural differences, including variable counteri-
+19.7
–130.1
+130.1
–19.7
+56.3
–93.4
+93.4
–56.3
9
–
–
ons (HCO2 , CF3CO2 , Cl–) that result from purification of
quaternary N9-methyl adeninium or guanidinium salts un-
der different protocols, or the use of different solvents for
optical rotation measurements.[4,11] The inherent danger in
the incorrect assignment of the absolute configuration
through reliance on optical rotation alone is well known
10
11
12
13
[a] Calculated from [α]D values (MeOH, see Table 2) of the corre-
sponding Cl– salts. [b] See ref.[15a]
The method was applied next to agelasidine E [(–)-5] by but may be compounded further by variables in measure-
combinations of [f]D for 1 and 15 (Figure 1, [α]D = –8.2) ment of α, especially highly charged or polar compounds.
prepared in optically pure form reported by Paquette and For example, the [α]D of sceptrin, a pyrrole-aminoimidazole
co-workers as an intermediate in the synthesis of (+)-cleo- alkaloid from several different Agelas spp., was shown to
meolide A.[15] Again, the best fit for the measured molar be highly variable and dependent – both in sign and magni-
rotation of (–)-5 ([f]D = –44.3) was obtained for the calcu- tude – on concentration and, particularly, on the nature of
lated value (5d, [f]D = –56.3) of the (5S,6R,13R) configura- the counterion.[16]
tion of the natural product. This also matches agelasidine F
To resolve lingering concerns of assignments of configu-
[(–)-6] ([f]D = –59.7) although, strictly, the molecular struc- ration in the agelasine/agelasidine family of adeninium al-
ture comparison here is not as valid as with (–)-5. In any kaloids based on optical activity, we undertook measure-
case, as co-occurrence of (–)-5 with (–)-6 likely results from ments of [α]D of (–)-agelasine B (7) and (–)-agelasidine C (3)
the latter being the oxidation product of the former; both after ion exchange with Cl– or HCOO– while using a fixed
are expected to share the same absolute configuration. concentration (c) close to the literature reported values[2,3]
Comparisons of [f]D by using a different synthetic analog or varying c over a range of values (Supporting Infor-
14[15a] and a synthetic compound[15b] lacking the allylic OH mation). Neither the counterion (Cl–, HCOO–) or variation
group [cf., (–)-3] gave a poor fit ([f]D = –9.4 and +1.8, of c across the range 0.03–3.0 g/100 mL appeared to affect
respectively; Supporting Information, Table S1). Despite the sign or magnitude of [α]D, within experimental error
the levorotatory nature of (–)-3, (–)-5, and (–)-6 obtained (Supporting Information, Table S2).
from the same sample of Agelas citrina, the configurations
Nevertheless, an examination of the reported specific ro-
at C5 and C6 of the latter two are opposite to the former, tations of the same compound (Table 2) isolated from dif-
which reveals the dominant rotatory power of the allylic ferent Agelas specimens from different geographic locations
C-13 quaternary hypotaurocyamine group. These examples reveals variable optical activity.
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E. P. Stout, L. C. Yu, T. F. Molinski
SHORT COMMUNICATION
Table 2. [α]D (MeOH) of salts of agelasines A–N and agelasid-
ines A–F.
Natural products 3, 5–8, 10, and 12 were tested for ac-
tivity against the fungal pathogen Candida albicans and hu-
man chronic lymphocytic leukemia (CLL) cells. (–)-Agelasi-
dine C (3) exhibited modest cytotoxicity against CLL (IC50
= 10 μm) and potent antifungal activity (MIC = 0.5 μg/mL).
Other agelasidines showed less potent antifungal activity (5,
8.0 and 6, 4.0 μg/mL), whereas the other compounds were
less active (8 and 10 Ͼ32; 12, 16.0 μg/mL).
Entry Compound
[α]D
Counterion
c
Ref
(g/100 mL)
[3a]
[3a]
[a]
1
2
3
4
5
6
7
8
agelasine A
agelasine B
–31.3
–21.5
–20
–6.1
–7.4
Cl–
Cl–
HCO2
0.59
1.0
1.5
0.3
0.5
2.04
1.1
1.0
1.88
1.7
2.55
0.02
0.36
0.2
0.46
0.11
1.0
0.8
0.5
0.5
1.0
0.43
2.0
7.2
(–)-7
(–)-7
(–)-8
–
–
[4]
2-oxo-7
HCO2
–
[a]
HCO2
[3a]
[3a]
[a]
agelasine C
agelasine D (+)-11 +10.4
(–)-11 –5.1
(–)-10 –55.1
Cl–
Cl–
–
HCO2
Conclusions
[3b]
[a]
9
agelasine E
(–)-12 –17.1
(+)-12 +1.7
–5.5
Cl–
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
HCO2
In conclusion, we describe three new alkaloid diterpenes,
(–)-agelasidines E and F (5, 6) and (+)-agelasine N (9), pro-
viding the first report of natural products from the Carib-
bean sponge Agelas citrina. Experimental evidence suggests
that the counterion and the concentration have negligible
effects on the sign and magnitude of [α]D for members in
this family of nitrogenous diterpenoid natural products.
[3b]
[1]
agelasine F[b]
agelasine G
agelasine H
agelasine I
agelasine J
agelasine K
agelasine L
agelasine M
agelasine N
Cl–
–85
–63.9
–2.5
+14
+60
–3.2
+208
+6.4
+5.6
Cl–
–
[11a]
[11a]
[11b]
[11b]
[11b]
[4]
HCO2
HCO2
HCO2
HCO2
–
–
–
–
HCO2
–
HCO2
[a]
(+)-9
(+)-9
Cl–
–
[a]
HCO2
[2a]
[2a]
[2a]
[5]
agelasidine A (+)-1 +19.1
Cl–
Cl–
Cl–
Cl–
Cl–
agelasidine B (–)-2
agelasidine C (+)-3
(–)-3
–2.5
+8.5
–5.6
–12.2
–11.8
–3.6
Experimental Section
General Experimental Procedures: General experimental procedures
are described elsewhere.[17a]
[a]
(–)-3
(–)-3
2.0
2.0
2.75
1.0
2.0
–
[a]
HCO2
(–)-Agelasidine C (3): Pale yellow oil. [α]2D5 = –12 (c = 2.0, MeOH).
[5]
agelasidine D (–)-4
agelasidine E (–)-5
agelasidine F (–)-6
Cl–
Cl–
[a]
FTIR (ATR, ZnSe): ν = 3234 (br.), 2966, 2935, 1633, 1572, 1450,
˜
–9.3
–12.6
1380, 1297, 1120 cm–1. HRMS (ESI): m/z = 424.2993 [M + H]+
(calcd. for C23H42N3O2S, 424.2998); NMR spectroscopic data are
in agreement with the literature;[2a,5] [α]D is opposite in sign to the
enantiomer reported by Nakamura and co-workers from Agelas
mauritiana,[2a] but the same as that reported by Rodriguez[5] from
a sample of A. clathrodes (see Table 2).
–
[a]
HCO2
[a] This report. [b] = ageline A.
Agelasines B (7) and C (10) and 2-oxo-agelasine B (8)
from Agelas citrina displayed specific rotations consistent
with earlier reports;[3a,4] however, agelasines D (11) and E
(12) were both opposite in sign with different magnitudes
(Table 2, Entries 7/8 and 9/10, respectively), and conse-
quently, are antipodal to the originally reported natural
products. It is also of interest to note that the [α]D value of
(–)-agelasidine C (3) originally reported from A.
clathrodes[5] has approximately half the magnitude of our
observed value for (–)-3 (Table 2, Entries 22 and 23, respec-
tively) suggesting not only the occurrence of enantiomeric
modifications from different geographically disparate
sources but the possibility of heterogeneous composition (%
ee) as non-racemic mixtures of enantiomers.
However, enantiomeric heterogeneity is still rare among
marine natural products. The origins of optical purity in
marine natural products have been the subject of discussion
and speculation.[17,18] One explanation for the biosynthesis
of antipodal C5, C6 configurations between (–)-3 and (–)-
5/6 is that both enantiomers of 3 may be formed with less
(–)-Agelasidine E (5): Colorless oil. [α]2D5 = –9.3 (c = 1.0, MeOH).
FTIR (ATR, ZnSe): ν = 3350 (br.), 3173 (br.), 2958, 2928, 1672,
˜
1633, 1458, 1373, 1281, 1135, 1082, 1005 cm–1. HRMS (ESI): m/z
= 440.2940 [M + H]+ (calcd. for C23H42N3O3S, 440.2941). NMR
spectroscopic data, see the Supporting Information.
(–)-Agelasidine F (6): Colorless oil. [α]2D5 = –12.6 (c = 2.0, MeOH).
UV (MeOH): λ (logε) = 229 (4.60), 273 (3.60) nm. CD (MeOH): λ
= 320 (Δε +0.78), 220 (Δε –4.4). FTIR (ATR, ZnSe): ν = 3350 (br.),
˜
3165 (br.), 2965, 2928, 1680, 1625, 1572, 1458, 1373, 1343, 1289,
1135 cm–1. HRMS (ESI): m/z = 438.2786 [M + H]+ (calcd. for
C23H40N3O3S, 438.2785).
(–)-Agelasine B (7): White amorphous powder. [α]2D5 = –20 (c = 1.5,
MeOH). NMR spectroscopic data are in agreement with the litera-
ture.[3a]
(–)-2-Oxo-agelasine B (8): Pale yellow oil. [α]2D5 = –7.4 (c = 0.5,
MeOH). NMR spectroscopic data are in agreement with the litera-
ture.[4]
(+)-Agelasine N (9): Amorphous white solid. [α]2D5 = +5.6 (c = 0.5,
MeOH). UV (MeOH): λ (ε) = 210 (4.03), 273 (3.67) nm. FTIR
stringent asymmetric control (a promiscuous terpene cy- (ATR, ZnSe): ν = 2952, 2925, 2357, 1658, 1586, 1462, 1384,
˜
1344 cm–1. HRMS (ESI): m/z = 440.3386 [M + H]+ (calcd. for
C26H43N5O, 440.3389). NMR spectroscopic data, see Supporting
Information.
clase, or two independent cyclases, as seen with independent
α- and β-pinene biosynthesis in Salvia officinalis[19]) and
that 5 and 6 arise through an independent oxidoreductase
that effects kinetic resolution during allylic hydroxylation
under more stringent control.
(–)-Agelasine C (10): Pale yellow oil. [α]2D5 = –12 (c = 1.0, MeOH).
NMR spectroscopic data are in agreement with the literature.[3a]
4
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Antifungal Diterpene Alkaloids from Agelas citrina
(–)-Agelasine D (11): Amorphous solid. [α]2D5 = –5.1 (c = 1.0,
MeOH). NMR spectroscopic data are in agreement with the litera-
ture.[3a]
[6] E. Piers, M. L. Breau, Y. X. Han, G. L. Plourde, W. L. Yeh, J.
Chem. Soc. Perkin Trans. 1 1995, 963–966.
[7] E. Piers, J. Y. Roberge, Tetrahedron Lett. 1992, 33, 6923–6926.
[8] B. T. Utenova, L. L. Gundersen, Tetrahedron Lett. 2004, 45,
4233–4235.
(+)-Agelasine E (12): Amorphous solid. [α]2D5 = +1.7 (c = 2.0,
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Acknowledgments
We are grateful for funding from the National Institutes of Health
(NIH AI 100776, AI039987 to T. F. M) and a Ruth L. Kirschstein
National Research Service Award (NIH T32 CA009523 to E. P. S.).
The 500 MHz NMR spectrometer was purchased with a grant from
National Science Foundation (NSF) (CRIF, CHE0741968). We
thank Y. Su (UCSD) for HRMS measurements, D. Dalisay and R.
Andersen (University of British Columbia) for antifungal assays,
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Received: May 1, 2012
Published Online: ᭿
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5

Job/Unit: O20572
/KAP1
Date: 25-06-12 11:41:18
Pages: 6
E. P. Stout, L. C. Yu, T. F. Molinski
SHORT COMMUNICATION
Marine Natural Products
Chiroptical methods, including molar ro-
tations and application of van’t Hoff’s
principle of optical superposition, were ap-
plied to solve the configurations of two new
diterpenoid alkaloids isolated from Agelas
citrina, a sponge endemic to the Bahamas.
E. P. Stout, L. C. Yu,
T. F. Molinski* .................................. 1–6
Antifungal Diterpene Alkaloids from the
Caribbean Sponge Agelas citrina: Unified
Configurational Assignments of Agelasid-
ines and Agelasines
Keywords: Natural products / Alkaloids /
Circular dichroism / Terpenoids
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0