Synthesis and determination of the absolute configuration of (-)-(5R,6Z)-dendrolasin-5-acetate from the nudibranch Hypselodoris jacksoni

Article abstract of DOI:10.3762/bjoc.9.329

A small sample of (-)-(5R,6Z)-dendrolasin-5-acetate, which was fully characterized by 2D NMR studies, was isolated from the nudibranch Hypselodoris jacksoni, along with the sesquiterpenes (+)-agassizin, (-)-furodysinin, (-)-euryfuran, (-)-dehydroherbadysidolide and (+)-pallescensone. A synthetic sample ([α]_D -8.7) of the new metabolite was prepared by [1,2]-Wittig rearrangement of a geranylfuryl ether followed by acetylation of purified alcohol isomers. The absolute configuration at C-5 was established as R by the analysis of MPA ester derivatives of (Z)-5-hydroxydendrolasin obtained by preparative enantioselective HPLC.

Full text of DOI:10.3762/bjoc.9.329

Synthesis and determination of the absolute
configuration of (−)-(5R,6Z)-dendrolasin-5-acetate
from the nudibranch Hypselodoris jacksoni
I. Wayan Mudianta1, Victoria L. Challinor1, Anne E. Winters2,
Karen L. Cheney2, James J. De Voss1 and Mary J. Garson*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2925–2933.
1School of Chemistry and Molecular Biosciences, The University of
Queensland, Brisbane QLD 4072, Australia and 2School of Biological
Sciences, The University of Queensland, Brisbane QLD 4072,
Australia
doi:10.3762/bjoc.9.329
Received: 11 September 2013
Accepted: 21 November 2013
Published: 23 December 2013
Email:
Mary J. Garson* - m.garson@uq.edu.au
This article is part of the Thematic Series "Natural products in synthesis
and biosynthesis".
* Corresponding author
Guest Editor: J. S. Dickschat
Keywords:
enantioselective HPLC; E/Z-isomers; Hypselodoris; natural products;
© 2013 Mudianta et al; licensee Beilstein-Institut.
License and terms: see end of document.
nudibranch; sesquiterpene
Abstract
A small sample of (−)-(5R,6Z)-dendrolasin-5-acetate, which was fully characterized by 2D NMR studies, was isolated from the
nudibranch Hypselodoris jacksoni, along with the sesquiterpenes (+)-agassizin, (−)-furodysinin, (−)-euryfuran,
(−)-dehydroherbadysidolide and (+)-pallescensone. A synthetic sample ([α]D −8.7) of the new metabolite was prepared by [1,2]-
Wittig rearrangement of a geranylfuryl ether followed by acetylation of purified alcohol isomers. The absolute configuration at C-5
was established as R by the analysis of MPA ester derivatives of (Z)-5-hydroxydendrolasin obtained by preparative enantioselect-
ive HPLC.
Introduction
Marine organisms have been proven a prolific source of natural that use small molecules for a variety of purposes, including
products that potentially can be used as lead compounds or communication, reproduction, and defense against predation
which have inspired synthetic chemists as synthetic targets [1]. [4,5]. These molecules have been extensively studied and as of
Similarly, extensive studies of marine chemical ecological inter- 2012, seven out of the 20 natural products of marine origin
actions have enriched our knowledge of biological and evolu- (either directly or as a derivative) that have been approved for
tionary patterns, and of the role of small molecules in chemical FDA use as a drug or are in clinical trials were first isolated
defensive strategies underwater [2,3]. Nudibranchs (Mollusca: from molluscs. For some of these bioactives, the actual biosyn-
Gastropoda: Opisthobranchia) are a group of marine animals thetic source is a microorganism [6].
2925

Beilstein J. Org. Chem. 2013, 9, 2925–2933.
Within the Nudibranchia, the genus Hypselodoris is generally along with two alkene signals [δH 5.15 (1H), 5.07 (1H); δC
characterized by sesquiterpene chemistry, as evidenced by a 123.7, 123.9]. Signals for three methyl groups were observed at
number of studies on European [7-13], Indian [14], South δH 1.72, 1.67, and 1.59 and were linked to signals at δC 23.3,
African [15], Brazillian [16], and Indo-Pacific specimens [17- 25.7, and 17.6, respectively, by HSQC. There were also signals
20]. During a comparative biogeographical study on opistho- characteristic of an acetate group [δH 2.01 (s, 3H); δC 21.4].
branch molluscs from South East Queensland, Australia, we en- These partial NMR assignments were comparable to those of
countered the new sesquiterpene (−)-(5R,6Z)-dendrolasin-5- the known dendrolasin (3), a sesquiterpene previously isolated
acetate (1) in specimens of H. jacksoni along with the other from Hypselodoris cantabrica [9] and H. californiensis [18].
known sesquiterpene metabolites (+)-agassizin, (−)-furodysinin, However, the signal corresponding to H-5 in dendrolasin (3)
(−)-euryfuran, (−)-dehydroherbadysidolide, (+)-pallescensone. was reported to be a multiplet (2H) resonating at δH 2.21 [24]
The new metabolite 1 has never been identified from natural whereas that in 1 was shifted to δH 5.64 (brdt, J = 6.4, 9.3 Hz,
sources, although the 6E-isomer 2 was previously reported in 1H). The gCOSY spectrum of 1 showed cross peaks from H-5
racemic form during the synthesis of naturally occurring to H-4/H-6, between the furan signals H-1/H-2 and between
dendrolasin (3) by Tsubuki et al. in 2009 [21] (Figure 1). H-8/H-9/H-10. The H-5 proton was attached to an oxymethine
Dendrolasin (3) itself has been isolated from both terrestrial and carbon at δC 70.7 based on HSQC data and showed HMBC
marine sources, including from the nudibranchs Chromodoris correlations to neighbouring carbons including C-3 (δC 120.2),
lochi [22], from three Hypselodoris spp. [18], and from the C-7 (δC 141.5), and the OAc carbonyl (δC 170.2) (Figure 2).
marine sponge Dictyodendrilla sp. [23]. The current study HMBC correlations observed from the alkene proton H-6 (δH
reports the isolation and synthesis of (−)-(5R,6Z)-dendrolasin-5- 5.15) to C-4, C-7, and CH3-14 secured the position of the
acetate (1), with the determination of the absolute configuration double bond between C-6 and C-7. A second double bond was
at C-5 by spectroscopic analysis of the methoxyphenylacetic positioned between C-10 and C-11 based on HMBC correla-
acid (MPA) derivative.
tions from the alkene proton H-10 (δH 5.07) to CH3-12 and C-8.
The C-6/C-7 configuration was revealed as Z rather than the
E-configuration anticipated, based on 1D nOe experiments in
which the signal intensity of H3-14 increased when the signal
attributed to H-6 was irradiated (mixing time 60 ms). 1D nOe
irradiation of H-10 provided assignment of the signals corres-
ponding to CH3-12.
Figure 1: (−)-(5R,6Z)-Dendrolasin-5-acetate (1), its 6E derivative and
naturally occuring dentrolasin (3).
Results and Discussion
Isolation and structure elucidation of natural
product 1
Eight individuals of H. jacksoni were collected by SCUBA
from two locations in SE Queensland. Owing to their small size
(21–40 mm), the specimens were not examined individually.
Extraction into acetone followed by partitioning into diethyl
ether gave an extract which was fractionated first by normal
phase (NP) flash chromatography and then by preparative NP
HPLC to give (+)-agassizin, (−)-furodysinin, (−)-euryfuran,
(−)-dehydroherbadysidolide, (+)-pallescensone, and the new
sesquiterpene 1.
Figure 2: Selected HMBC, COSY, and nOe correlations of 1.
Total synthesis of (−)-(5R,6Z)-dendrolasin-5-
acetate (1)
In view of the small sample (0.1 mg) of natural material avail-
able, a synthetic study was undertaken to provide stereochem-
ical characterization of 1, in particular the configuration at C-5.
The synthesis, which was completed in five steps, involved
Compound 1, [α]D −53 (c 0.006, CHCl3), displayed a (+)- preparation of 3-furylmethanol (4) and of geranyl bromide (5),
HRESIMS ion adduct at m/z 299.1624 [M + Na]+ consistent etherification, [1,2]-Wittig rearrangement of geranyl 3-furyl-
with the molecular formula C17H24O3. The 1H NMR spectrum methyl ether (6) to produce 7a/b, and acetylation to obtain
(CDCl3, 500 MHz) of 1 showed diagnostic signals for a furan target 1. The overall synthesis (Scheme 1) was adapted from
[δH 7.33 (1H), 7.23 (1H), 6.27 (1H); δC 142.7, 140.1, 111.8] Tsubuki et al. [21].
2926

Beilstein J. Org. Chem. 2013, 9, 2925–2933.
Scheme 1: Synthetic route to sesquiterpene 1.
Furan-3-ylmethanol (4) was prepared in 78% yield by reduc- In principle, the rearrangement of 6 could afford either [1,2]-
tion of 2-furoic acid with LiAlH4 in dry diethyl ether, whereas rearranged products (e.g. 7a/b or 8) or [2,3]-rearranged prod-
geranyl bromide (5) was obtained through bromination of ucts such as 9 or 10 depending on which site adjacent to the
geraniol with carbon tetrabromide and triphenylphosphine in ether oxygen is preferentially deprotonated (Scheme 2). A ther-
90% yield. The 1H NMR spectrum of the geraniol sample used modynamic optimization study on the Wittig rearrangement of
indicated the presence of traces of nerol, the Z-isomer of allyl 3-furylmethyl ether by Tsubuki et al. has revealed that
geraniol. Etherification of furan-3-ylmethanol (4) with the deprotonation occurs mainly at the α-position [21]. The results
geranyl/neryl bromide mixture (5) in the presence of NaH of this theoretical study are fully consistent with our synthetic
furnished the 3-furylmethyl ether 6 (65% yield) as an E/Z mix- work since the mixture of 7a/b was the sole [1,2]-Wittig
ture (3:1). The H-5 signal for the minor Z-isomer of 6 resonated rearrangement product obtained.
at δH 3.90 (d, J = 6.8 Hz) compared to that of the E-isomer
(δH 4.00, d, J = 6.8 Hz). Irradiation of the H-5 signal of the Racemic 5-hydroxydendrolasin (7a/b) was next subjected to
Z-isomer increased the intensity of the signal associated with HPLC (hexanes/EtOAc, 90:10) to provide the individual E- (7a)
the adjacent methyl (CH3-14), confirming the Z double bond at and Z-isomers (7b) that were each carefully characterised by
C6/C7. The isomeric mixture of 6 was immediately subjected to 1H NMR and 1D nOe experiments. Assignment of the upfield
[1,2]-Wittig rearrangement with t-BuLi (4 equiv) and LDA at signals corresponding to the three methyl groups attached to the
−78 °C to afford racemic 5-hydroxydendrolasin (39% yield), double bonds (Figure 3) was made using HMBC and nOe data.
again as an E/Z mixture (7a/b) for which a 3:1 ratio was deter- The signal for CH3-14 in the Z-isomer resonated downfield
mined by 1H NMR comparison with data for the individual (δH 1.74) compared to that in the E-isomer (δH 1.65) while the
stereoisomers (see below). The 3:1 ratio of E/Z-isomers was signal for H-5 appeared slightly upfield (δH 4.48) in the
confirmed via analytical HPLC.
Z-isomer compared to that in its E counterpart (δH 4.51).
Scheme 2: Mechanism of Wittig rearrangement [21].
2927

Beilstein J. Org. Chem. 2013, 9, 2925–2933.
Figure 3: (a) NP HPLC trace showing separation of racemic 5-hydroxydendrolasin (7a/b) using hexanes/EtOAc (90:10; flow rate 2 mL/min over
60 minutes (x axis)) and refractive index detection (y axis); (b) 1H NMR spectroscopic comparison of (6E)-5-hydroxydendrolasin (7a) (i) and (6Z)-5-
hydroxydendrolasin (7b) (ii); × = water signals.
1D NOESY irradiation of the CH3-14 signal for the Z-isomer [α]D +13 for its acetate derivative). As anticipated, the 1H NMR
resulted in enhancement of the alkene signal at δH 5.24 (H-6), spectrum (CDCl3, 500 MHz) of the synthetic sample of
fully consistent with the Z configuration; there was no corres- (−)-(6Z)-1 was fully superimposable with that of the sample of
ponding nOe between CH3-14 and H-6 in the E-isomer, (6Z)-dendrolasin-5-acetate isolated from H. jacksoni (Figure 5).
although such data must be interpreted with care.
Absolute configurational assignment of (6Z)-
With the individual characterization of the E/Z-isomers accom- dendrolasin-5-acetate (1)
plished, preparative enantioselective HPLC separation of It remained to determine the absolute configuration of C-5 in
racemic (Z)-5-hydroxydendrolasin (7b) was next undertaken the natural acetate derivative. A portion of the racemic mixture
(Figure 4) and provided samples of both of the (+)-7b and of 7b was esterified with (R)-MPA acid in the presence of
(−)-7b isomers, respectively. Treatment of each enantiomer of DMAP and DCC at room temperature to give a mixture of
7b with acetic anhydride and pyridine gave their acetate deriva- diastereomeric (R,R)-11 and (R,S)-11, which was separated by
tives. Surprisingly, (+)-7b ([α]D +9.3) gave an acetate deriva- reversed phase (RP) HPLC (MeCN/H2O; 63:35) (Figure 6). The
tive with [α]D −8.7 and vice versa ([α]D –12 for (−)-7b and H-6 protons in (R,R)-11 and (R,S)-11 resonated at δH 5.04 and
Figure 4: Analytical enantioselective HPLC trace showing separation of individual enantiomers of (6Z)-5-hydroxydendrolasin (Chiralpak AD column,
250 × 4.6 mm, 2% IPA in n-hexane at 0.5 mL/min, UV detection at 214 nm).
2928

Beilstein J. Org. Chem. 2013, 9, 2925–2933.
Figure 5: The 1H NMR (CDCl3, 500 MHz) spectroscopic comparison of (6Z)-dendrolasin-5-acetate (1): (a) sample isolated from H. jacksoni; (b) syn-
thetic sample of (−)-(6Z)-1.
Figure 6: RP HPLC trace showing separation of the MPA esters (R,R)-11 and (R,S)-11 (MeCN/H2O, 63:35 over 50 minutes, Phenomenex C-18
column, 250 × 4.60 mm, UV detection at 254 nm).
at δH 5.13, respectively, in agreement with H-6 of the (R,R)- was identical to that of the synthetic (R,R)-11 and established
isomer positioned in the shielding cone of the aryl ring of the that (+)-5-hydroxydendrolasin (7) has an R configuration. Like-
MPA moiety [25]. The diastereotopic H-4 signals in (R,S)-11 at wise, the 1H NMR spectrum of the MPA ester of (−)-7b was
δH 2.51 and 2.58 were shielded compared to those in (R,R)-11 identical to that of the synthetic diastereomer (R,S)-11. Taking
(δH 2.64, 2.74). Likewise, the furan proton signals were shifted into account the change in sign of [α]D between the alcohol and
upfield in the (R,S)-isomer compared to the (R,R)-isomer. These its acetate derivative, these data verified that the naturally-
data were in agreement with the configurations depicted in occurring (−)-acetate 1 had a 5R configuration.
Figure 6. The MPA ester spectra acted as reference data for
determination of the absolute configuration of the natural Specific rotation values for 1 were measured as [α]D −53 for the
sample of dendrolasin-5-acetate (1). The individually-purified natural sample and −8.7 for the synthetic sample. Despite
enantiomers of synthetic (6Z)-5-hydroxydendrolasin were each having the same negative sign of specific optical rotation, the
treated with (R)-MPA to give their respective MPA ester [α]D values of the natural sample was considerably larger than
derivatives. The 1H NMR spectra of the MPA ester of (+)-7b that of the synthetic sample. Although a partial explanation for
2929

Beilstein J. Org. Chem. 2013, 9, 2925–2933.
the difference in values was apparent, namely that the natural (6Z)-5-hydroxydendrolasin purified by preparative enantiose-
sample size was small (0.1 mg) compared to the synthetic lective HPLC.
sample size (0.9 mg), better experimental evidence of their
stereochemical uniformity was desirable. Enantioselective Experimental
HPLC analyses run under identical conditions using 5% Isolation of (−)-(5R,6Z)-dendrolasin-5-acetate (1) from
isopropanol in n-hexane were carried out on the synthetic Hypselodoris jacksoni: Eight individuals of H. jacksoni
sample of racemic 1, the two synthetically prepared R and S (21–40 mm in length) were collected from various dive sites in
enantiomers of 1, and the natural sample as shown in Figure 7. South East Queensland (specimens #243, 244 Mudjimba Island,
The data revealed a clear separation of the individual enan- Mooloolaba S26°36’54”, E153°06’49”; #75–77 and #125–127
tiomers of 1 (shown in trace (a)), and that the (+)-enantiomer Shag Rock, North Stradbroke Island S27°24'49" E153°31'30”)
elutes before the (−)-enantiomer (traces (b) and (c)). Finally, the between March and October of 2012. The whole animals were
natural sample has the same retention time as the (−)-enan- chopped, macerated in acetone (20 mL), sonicated for 2 min
tiomer (trace (d)). A co-injection experiment performed on a before being filtered through a cotton plug. The resulted filtrate
mixture of the synthetic (+)-enantiomer and the natural sample was combined, concentrated under reduced pressure and parti-
consistently displayed two peaks in which the former com- tioned between Et2O (3 × 20 mL) and water. The Et2O crude
pound eluted before the natural sample.
fraction (39.2 mg) was resolved by NP flash column chroma-
tography eluted with gradient solvent from 100%
hexanes→100% EtOAc to give ten fractions. The first and the
Conclusion
Chemical investigation of H. jacksoni collected from Queens- second fraction (coded as HJF1–2) (21.3 mg) were combined
land yielded a new sesquiterpene (5R,6Z)-dendrolasin-5-acetate based on their TLC profile, and yielded the major metabolites
(1) whose structure and stereochemistry were confirmed by (−)-furodysinin (3.8 mg), (+)-agassizin (2.5 mg) and (−)-eury-
means of a five-step synthesis involving [1,2]-Wittig rearrange- furan (0.8 mg) following NP HPLC separation using 100%
ment of geranyl furyl ether (6) followed by acetylation of the hexanes. The fourth fraction coded as HJF4 (1.8 mg) was
purified alcohol products. The absolute configuration in 1 was subjected to NP HPLC eluting with 2.5% EtOAc/hexanes to
established as 5R by detailed comparison with MPA ester give (−)-dehydroherbadysidolide (0.1 mg), (+)-pallescensone
derivatives prepared from individual enantiomers of synthetic (0.2 mg), and the new sesquiterpene (−)-(5R,6Z)-dendrolasin-5-
Figure 7: Enantioselective HPLC profiles (5% isopropanol in n-hexane) of 1: (a) synthetic (±) mixture; (b) synthetic (+)-enantiomer; (c) synthetic (−)-
enantiomer; (d) natural sample from H. jacksoni.
2930

Beilstein J. Org. Chem. 2013, 9, 2925–2933.
acetate (1, 0.1 mg).
−53 (c 0.006, CHCl3); 1H NMR 13.6 Hz, 1H, H-5), 2.66 (dd, J = 7.1, 14.4 Hz, 1H, H-4a), 2.59
(CDCl3, 500 MHz) δH 7.33 (bs, 1H, H-1), 7.23 (bs, 1H, H-15), (dd, J = 7.1, 14.4 Hz, 1H, H-4b), 2.12–2.01 (m, 4H, H-8 and
6.27 (s, 1H, H-2), 5.64 (bdt, J = 6.4, 9.3 Hz, 1H, H-5), H-9), 1.65 (d, J = 1.1 Hz, 3H, CH3-14), 1.69 (s, 3H, CH3-12),
5.15 (d, J = 9.3 Hz, 1H, H-6), 5.07 (brt, J = 6.9 Hz, 1H, H-10), 1.60 (s, 3H, CH3-13); 13C NMR (CDCl3, 125 MHz) δC 142.9
2.73 (dd, J = 6.7, 14.5 Hz, 1H, H-4a), 2.63 (dd, J = 6.0, 14.5 (C-1), 140.3 (C-15), 139.5 (C-7), 131.8 (C-11), 127.0 (C-3),
Hz, 1H, H-4b), 2.15–1.95 (overlapping, m, 4H, H-8, H-9), 124.0 (C-10), 120.9 (C-6), 111.7 (C-2), 68.5 (C-5), 39.6 (C-8),
1.72 (s, 3H, H-14), 1.67 (s, 3H, H-12), 1.59 (s, 3H, H-13); 33.3 (C-4), 26.4 (C-9), 25.7 (C-12), 17.8 (C-13), 16.7 (C-14);
13C NMR (CDCl3, 125 MHz) δC 142.7 (C-1), 141.5 (C-7), (+)-LRESIMS m/z: 257 [M + Na]+.
140.1 (C-15), 132.0 (C-11), 123.9 (C-10), 123.7 (C-6), 120.2
(C-3), 111.8 (C-2), 70.7 (C-5), 32.5 (C-8), 30.7 (C-4), 26.5 (±)-(Z)-1-(furan-3-yl)-4,8-dimethylnona-3,7-dien-2-ol (7b):
(C-9), 25.7 (C-12), 23.3 (C-14), 17.6 (C-13); (+)-HRESIMS Colorless glass; 1H NMR (CDCl3, 500 MHz) δH 7.37 (s, 1H,
m/z: [M + Na]+ calcd. for C17H24NaO3, 299.1618; found, H-1), 7.29 (s, 1H, H-15), 6.32 (s, 1H, H-2), 5.24 (d, J = 8.8 Hz,
299.1624.
1H, H-6), 5.07 (brt, J = 5.4 Hz, 1H, H-10), 4.48 (q, J = 6.7, 13.6
Hz, 1H, H-5), 2.65 (dd, J = 7.2, 14.4 Hz, 1H, H-4a), 2.58 (dd, J
Procedure for Wittig rearrangement of 3-furylmethyl ether = 7.2, 14.4 Hz, 1H, H-4b), 2.12–2.01 (m, 4H, H-8 and H-9),
(6) [21]: To a solution of (E/Z)-3-furylmethyl ether (6, 200 mg) 1.74 (d, J = 1.1 Hz, 3H, CH3-14), 1.69 (s, 3H, CH3-12), 1.60 (s,
in THF (10 mL) was added dropwise first LDA (3.64 mL, 3H, CH3-13); 13C NMR (CDCl3, 125 MHz) δC 142.9 (C-1),
10 wt % suspension in hexane) followed by t-BuLi (2.5 mL, 140.3 (C-15), 139.5 (C-7), 132.6 (C-11), 128.0 (C-3), 124.0
1.6 M in hexanes;) at −78 °C under Ar. After stirring for 1 h (C-10), 121.1 (C-6), 111.7 (C-2), 68.1 (C-5), 33.2 (C-8), 32.5
(the reaction mixture was allowed to warm to 0 °C), the reac- (C-4), 26.6 (C-9), 25.8 (C-12), 23.5 (C-14), 17.8 (C-13); (+)-
tion mixture was quenched with sat. aq NH4Cl solution and the HRESIMS m/z: [M + Na]+ calcd for C15H22NaO2, 257.1512;
solvent was removed under vacuum. The residue was extracted found, 257.1515.
with pentane/Et2O (1:1, v/v). The extract was washed with
brine and dried over Na2SO4. Evaporation of the solvent gave a Procedure for acetylation of (±)-(Z)-1-(furan-3-yl)-4,8-
residue, which was chromatographed on silica gel (5.0 g, dimethylnona-3,7-dien-2-ol (7b): A portion of 7b (8.4 mg)
hexanes/AcOEt 95:5) to afford the desired product (E/Z ratio was dissolved in dry pyridine (0.5 mL) and cooled in an ice
~3:1) as a mixture of enantiomers (83 mg, 39% yield). The E- bath. After the addition of acetic acid anhydride (1.5 mL) the
and Z-isomers of 5-hydroxydendrolasin were then separated by mixture brought to rt and stirred for 1.5 hours. Toluene
NP HPLC (hexanes/EtOAc 90:10, flow rate 2 mL/min, refrac- (0.5 mL) was added and the resulting azeotrope was evaporated
tive index detection, Waters μPorasilTM column 10 μm, under reduced pressure to give (±)-(6Z)-dendrolasin-5-acetate
300 × 7.8 mm) to give the individual 6E ((7a); 25.2 mg; tR = (1) (6.4 mg); 1H and 13C NMR data (CDCl3, 500 MHz) are
50.0 min) and 6Z ((7b); 8.4 mg; tR = 40.0 min) isomers. Analyt- identical to those of 1. (+)-LRESIMS m/z 299 [M + Na]+.
ical enantioselective HPLC separation of the Z-isomer of
5-hydroxydendrolasin (7b) was performed on an Agilent 1200 Procedure for acetylation of the (+) isomer of 7b: A portion
series liquid chromatography system (isocratic conditions of 2% of the (+) isomer of 7b (1.3 mg) was acetylated using the same
isopropanol in n-hexane, flow rate of 0.5 mL min−1) equipped procedure as for 7b to obtain (−)-(6Z)-dendrolasin-5-acetate (1,
with UV (214 nm) and ALP (Advanced Laser Polarimeter, 0.9 mg); Colorless glass; [α]D −8.7 (c 0.06, CHCl3); 1H and
PDR-Chiral Inc.) detectors and a Chiralpak AD column 13C NMR data (CDCl3, 500 MHz) are the same as those of the
(250 × 4.6 mm, Daicel Chemical Industries Ltd.). The prepara- 1. (+)-LRESIMS m/z: 299 [M + Na]+.
tive enantioselective HPLC purification of 7b used isocratic
conditions (1.5% isopropanol in n-hexane, flow rate of 10 mL Procedure for acetylation of the (−)-isomer of 7b: A portion
min−1) with UV detection at 220 nm and a Chiralpak AD of the (−)-isomer of 7b (1.3 mg) was acetylated using the same
column (250 × 20 mm, Daicel Chemical Industries Ltd.) to give procedure as for 7b to obtain (+)-(6Z)-dendrolasin-5-acetate (1,
the (+)-enantiomer (2.7 mg); (−)-enantiomer (2.6 mg). The 1.1 mg); Colorless glass; [α]D +12.9 (c 0.07, CHCl3); 1H and
retention times were: 29.5 min ((+)-enantiomer); 32.1 min ((−)- 13C NMR (CDCl3, 500 MHz) are identical to those of 1. (+)-
enantiomer).
LRESIMS m/z: 299 [M + Na]+.
(±)-(E)-1-(furan-3-yl)-4,8-dimethylnona-3,7-dien-2-ol (7a) Procedure for preparation of (R)- and (S)-MPA esters of
[21]: Colorless glass; 1H NMR (CDCl3, 500 MHz) δH 7.37 (s, racemic (6Z)-5-hydroxydendrolasin (7b): (±)-(6Z)-5-
1H, H-1), 7.29 (s, 1H, H-15), 6.32 (s, 1H, H-2), 5.24 (d, J = 8.5 Hydroxydendrolasin (2.0 mg) was dissolved in dry DCM
Hz, 1H, H-6), 5.07 (brt, J = 7.1 Hz, 1H, H-10), 4.51 (q, J = 7.1, (0.2 mL) to which (R)-methoxyphenylacetic acid (MPA)
2931

Beilstein J. Org. Chem. 2013, 9, 2925–2933.
(0.83 mg in 0.1 mL of DCM) was added, followed by DCC the (R,S,6Z)-dendrolasin MPA ester (11b). [α]D −22 (c 0.07,
(2 equiv, 1.03 mg in 0.1 mL of DCM) and DMAP (2 equiv, CHCl3); (+)-LRESIMS m/z: 405 [M + Na]+.
0.61 mg in 0.1 mL of DCM). The reaction was stirred at rt for
16 h and then filtered through a cotton wool plug. The solvent Enantioselective HPLC experiments: Enantioselective HPLC
was removed by rotary evaporation and the residue passed analysis of the (±)-(6Z)-dendrolasin-5-acetate (1) racemic mix-
through a pipette silica column eluted with hexanes/EtOAc ture, the individual 5R- and 5S-enantiomers of (6Z)-dendro-
(95:5) to give a racemic MPA ester (0.8 mg). The racemic MPA lasin-5-acetate, and the natural sample of (−)-(5R,6Z)-dendro-
ester was subsequently subjected to RP HPLC (MeCN/H2O, lasin-5-acetate, were performed using an Agilent 1200 series
60:40; flow rate 1 mL/min, UV detection at 254 nm, liquid chromatography system (isocratic conditions, 5%
Phenomenex Gemini 5 μ C18 110 Å, 250 × 4.60 mm) to give isopropanol in n-hexane, flow rate of 0.5 mL min−1) equipped
the R,R (0.2 mg) and R,S diastereomers (0.2 mg).
with UV (220 nm) and ALP (Advanced Laser Polarimeter,
PDR-Chiral Inc.) detectors and a Chiralpak OJ column (4.6 ×
(R,R)-(6Z)-dendrolasin MPA ester (11a): Colorless glass; 250 mm, Daicel Chemical Industries Ltd.). Retention times
[α]D +10.1 (c 0.01, CHCl3); 1H NMR (CDCl3, 500 MHz) δH were: (+)-enantiomer, >97% ee 8.3 min; (–)-enantiomer,
7.38–7.30 (m, 5H, MPA phenyl protons), 7.28 (brs, 1H, H-1), >98.5% ee 9.4 min; natural sample 9.4 min.
7.14 (s, 1H, H-15), 6.20 (s, 1H, H-2), 5.66 (m, 1H, H-5), 5.04
(d, J = 9.8 Hz, 1H, H-6), 5.02 (brt, 1H, H-10), 4.70 (s, 1H, CH
Supporting Information
of MPA), 3.37 (s, 3H, OMe of MPA), 2.73 (dd, J = 7.2, 14.7
Hz, 1H, H-4a), 2.63 (dd, J = 7.2, 14.7 Hz, 1H, H-4b), 2.16–2.10
Supporting Information File 1 contains experimental details
(m, 1H, H-8a), 1.98–1.86 (m, 1H, H-8b and 2H, m, H-9), 1.64
for the preparation of compound 6, spectroscopic data and
(s, 6H, CH3-14 and CH3-12), 1.56 (s, 3H, CH3-13); (+)-
other relevant information for compounds 1, 7b, 11a, and
HRESIMS m/z: [M + Na]+ calcd for C24H30NaO4, 405.2036;
11b.
found, 405.2038.
Supporting Information File 1
Experimental details and spectroscopic data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-329-S1.pdf]
(R,S)-(6Z)-dendrolasin MPA ester (11b): Colorless glass;
[α]D +10.7 (c 0.01, CHCl3); 1H NMR (CDCl3, 500 MHz) δH
7.38−7.36 (m, 5H, MPA phenyl protons), 7.17 (bs, 1H, H-1),
6.83 (s, 1H, H-15), 5.95 (s, 1H, H-2), 5.68 (m, 1H, H-5), 5.12
(d, J = 9.4 Hz, 1H, H-6), 5.04 (brt, J = 7.3 Hz, 1H, H-10), 4.68
(s, 1H, CH of MPA), 3.36 (s, 3H, OMe of MPA), 2.58 (dd, J = Acknowledgements
7.0, 14.7 Hz, 1H, H-4a), 2.51 (dd, J = 7.0, 14.7 Hz, 1H, H-4b), We thank the Australian Research Council and The University
2.24–2.20 (m, 1H, H-8a), 2.06–1.92 (m, 1H, H-8b and m, 2H, of Queensland for financial support, and Deb Aston for photog-
H-9), 1.71 (d, J = 1.0 Hz, 3H, CH3-14), 1.67 (s, 3H, CH3-12), raphy and her assistance with sample collections.
1.58 (m, 3H, CH3-13); (+)-HRESIMS m/z: [M + Na]+ calcd for
References
1. Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
C24H30NaO4, 405.2036; found, 405.2043.
Prinsep, M. R. Nat. Prod. Rep. 2013, 20, 1–48. doi:10.1039/b207130b
Procedure for preparation of MPA ester of the (+)-isomer of
2. Paul, V. J.; Ritson-Williams, R.; Sharp, K. Nat. Prod. Rep. 2011, 28,
7b: A portion of the (+)-isomer of 7b (1.3 mg) was treated with
345–387. doi:10.1039/c0np00040j
(R)-MPA (0.83 mg in 0.1 mL of DCM) using the same proce-
3. Pawlik, J. R. Antipredatory Defensive Roles of Natural Products from
dure as for the preparation of MPA ester of the racemic (6Z)-5-
hydroxydendrolasin (7b) to obtain the (+)-MPA ester (1.2 mg).
The 1H NMR data (CDCl3, 500 MHz) were identical to those
for the (R,R,6Z)-dendrolasin MPA ester (11a). [α]D −93 (c 0.08,
CHCl3); (+)-LRESIMS m/z: 405 [M + Na]+.
Marine Invertebrates. In Handbook of Marine Natural Products;
Fattorusso, E.; Gerwick, W. H.; Taglialatela-Scafati, O., Eds.; Springer:
London, 2012; pp 677–710. doi:10.1007/978-90-481-3834-0_12
4. Cimino, G.; Ghiselin, M. T. Chemoecology 1998, 8, 51–60.
doi:10.1007/PL00001804
5. Cimino, G.; Ghiselin, M. T. Proc. Calif. Acad. Sci. 2009, 60, 175–422.
6. Gerwick, W. H.; Moore, B. S. Chem. Biol. 2012, 19, 85–98.
doi:10.1016/j.chembiol.2011.12.014
Procedure for preparation of MPA ester of the (−)-isomer of
7b: A portion of the (−)-isomer of 7b (1.3 mg) was treated with
(R)-MPA (0.83 mg in 0.1 mL of DCM) using the same proce-
dure as for the preparation of MPA ester of the racemic (6Z)-5-
hydroxydendrolasin (7) to obtain the (−)-MPA ester (1.0 mg).
The 1H NMR data (CDCl3, 500 MHz) are identical to those of
7. Grode, S. H.; Cardellina, J. H., II. J. Nat. Prod. 1984, 47, 76–83.
doi:10.1021/np50031a009
8. Avila, C.; Cimino, G.; Fontana, A.; Gavagnin, M.; Ortea, J.;
Trivellone, E. J. Chem. Ecol. 1991, 17, 625–636.
doi:10.1007/BF00982131
2932

Beilstein J. Org. Chem. 2013, 9, 2925–2933.
9. Fontana, A.; Avila, C.; Martinez, E.; Ortea, J.; Trivellone, E.; Cimino, G.
J. Chem. Ecol. 1993, 19, 339–356. doi:10.1007/BF00993700
10.Cimino, G.; Fontana, A.; Giménez, F.; Marin, A.; Mollo, E.;
Trivellone, E.; Zubía, E. Experientia 1993, 49, 582–586.
doi:10.1007/BF01955168
11.Fontana, A.; Giménez, F.; Marin, A.; Mollo, E.; Cimino, G. Experientia
1994, 50, 510–516. doi:10.1007/BF01920760
12.Fontana, A.; Trivellone, E.; Mollo, E.; Cimino, G.; Avila, C.;
Martinez, E.; Ortea, J. J. Nat. Prod. 1994, 57, 510–513.
doi:10.1021/np50106a011
13.da Cruz, J. F.; Gaspar, H.; Calado, G. Chemoecology 2012, 22, 47–53.
doi:10.1007/s00049-011-0097-z
14.Fontana, A.; Ciavatta, M. L.; D'Souza, L.; Mollo, E.; Naik, C. G.;
Parameswaran, P. S.; Wahidulla, S.; Cimino, G. J. Indian Inst. Sci.
2001, 81, 403–415.
15.McPhail, K.; Davies-Coleman, M. T.; Coetzee, P. J. Nat. Prod. 1998,
61, 961–964. doi:10.1021/np980051y
16.Pereira, F. R.; Berlinck, R. G. S.; Filho, E. R.; Veloso, K.;
Ferreira, A. G.; Padula, V. Quim. Nova 2012, 35, 2194–2201.
doi:10.1590/S0100-40422012001100018
17.Schulte, G.; Scheuer, P. J.; McConnell, O. J. Helv. Chim. Acta 1980,
63, 2159–2167. doi:10.1002/hlca.19800630805
18.Hochlowski, J. E.; Walker, R. P.; Ireland, C.; Faulkner, D. J.
J. Org. Chem. 1982, 47, 88–91. doi:10.1021/jo00340a018
19.Schulte, G. R.; Scheuer, P. J. Tetrahedron 1982, 38, 1857–1863.
doi:10.1016/0040-4020(82)80034-3
20.Karuso, P.; Scheuer, P. J. Molecules 2002, 7, 1–6.
doi:10.3390/70100001-rev
21.Tsubuki, M.; Okita, H.; Kaneko, K.; Shigihara, A.; Honda, T.
Heterocycles 2009, 77, 433–444. doi:10.3987/COM-08-S(F)40
22.Kakou, Y.; Crews, P.; Bakus, G. J. J. Nat. Prod. 1987, 50, 482–484.
doi:10.1021/np50051a023
23.Tran, N. H.; Hooper, J. N. A.; Capon, R. J. Aust. J. Chem. 1995, 48,
1757–1760. doi:10.1071/CH9951757
24.Chakraborty, A.; Kar, G. K.; Ray, J. K. Tetrahedron 1997, 53,
8513–8518. doi:10.1016/S0040-4020(97)00509-7
25.Freire, F.; Calderón, F.; Seco, J. M.; Fernandez-Mayoralas, A.;
Quinõá, E.; Riguera, R. J. Org. Chem. 2007, 72, 2297–2301.
doi:10.1021/jo061939r
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.9.329
2933