Spiro[3.5]nonenyl Meroterpenoid Lactones, Cryptolaevilactones G-L, an Ionone Derivative, and Total Synthesis of Cryptolaevilactone M from Cryptocarya laevigata

Article abstract of DOI:10.1021/acs.jnatprod.8b00732

A CH₃OH-CH₂Cl₂ (1:1) extract (N025439) of the leaves and twigs of Cryptocarya laevigata furnished eight new compounds, 1-8. Based on extensive 1D and 2D NMR spectroscopic data examination, the new δ-lactone derivatives 1-6 are monoterpene-polyketide hybrids containing a unique spiro[3.5]nonenyl moiety. Their trivial names, cryptolaevilactones G-L, follow those of the related known meroterpenoids cryptolaevilactones A-F. Cryptolaevilactone L (6) contains 11,12-cis-oriented substituents, while the other cryptolaevilactones contain trans-oriented groups. The structure of the linear δ-lactone 7, cryptolaevilactone M, was characterized from various spectroscopic data analysis, and the absolute configuration was determined by total synthesis through stereoselective allylation and Grubbs olefin metathesis. Compound 8 was elucidated to be an ionone derivative with a 3,4-syn-diol functionality.

Full text of DOI:10.1021/acs.jnatprod.8b00732

Article
pubs.acs.org/jnp
Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
Spiro[3.5]nonenyl Meroterpenoid Lactones, Cryptolaevilactones G−
L, an Ionone Derivative, and Total Synthesis of Cryptolaevilactone M
from Cryptocarya laevigata
Fumika Tsurumi,† Yuta Miura,†,# Misaki Nakano,†,# Yohei Saito,† Shuichi Fukuyoshi,†
Katsunori Miyake,‡ David J. Newman,§ Barry R. O’Keefe,⊥ Kuo-Hsiung Lee,∥,¶
and Kyoko Nakagawa-Goto*,†,∥
†School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa,
920-1192, Japan
‡Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
§NIH Special Volunteer, Wayne, Pennsylvania 19087, United States
⊥Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, and Molecular
Targets Program, Center for Cancer Research, National Cancer Institute, NCI at Frederick, Frederick, Maryland 21702-1201,
United States
∥Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel
Hill, North Carolina 27599-7568, United States
¶Chinese Medicine Research and Development Center, China Medical University and Hospital, 2 Yuh-Der Road, Taichung, 40447,
Taiwan
S
* Supporting Information
ABSTRACT: A CH3OH−CH2Cl2 (1:1) extract (N025439)
of the leaves and twigs of Cryptocarya laevigata furnished eight
new compounds, 1−8. Based on extensive 1D and 2D NMR
spectroscopic data examination, the new δ-lactone derivatives
1−6 are monoterpene−polyketide hybrids containing a
unique spiro[3.5]nonenyl moiety. Their trivial names,
cryptolaevilactones G−L, follow those of the related known
meroterpenoids cryptolaevilactones A−F. Cryptolaevilactone
L (6) contains 11,12-cis-oriented substituents, while the other
cryptolaevilactones contain trans-oriented groups. The
structure of the linear δ-lactone 7, cryptolaevilactone M, was
characterized from various spectroscopic data analysis, and the absolute configuration was determined by total synthesis through
stereoselective allylation and Grubbs olefin metathesis. Compound 8 was elucidated to be an ionone derivative with a 3,4-syn-
diol functionality.
include not only 6-alkyl-δ-lactones3−11,14 but also tetrahydro-
lant derived δ-lactones with an alkyl or arylalkyl group at
PC-6 are produced by a limited number of genera, flavanones16−19 and their dimers,5,18,20 as well as pavine
alkaloids.21−23 Our previous study of C. laevigata disclosed the
unique monoterpene−polyketide hybridized δ-lactones, named
cryptolaevilactones A−F.14 Although the biosynthetic pathway
is not clear, their spiro[3.5]nonene moiety is probably
biosynthesized through hetero [2 + 2] cycloaddition of a
monoterpene, β-phellandrene, and a polyketide δ-lactone
containing a double bond. Our continuing research has now
furnished six new spiro[3.5]nonenyl meroterpenoid lactones
(1−6), a new linear lactone (7), and an ionone derivative (8)
with a 3,4-syn-diol functionality (Figure 1), together with eight
known compounds, caryophyllene oxide,24 (−)-boscialin,25
including Aniba (Lauraceae),1 Goniothalamus (Annonaceae),
Piper (Piperaceae), and Psilotum and Tmesipteris (Psilota-
ceae).2 The genus Cryptocarya (Lauraceae) is also known to
produce δ-lactone derivatives such as cryptocaryone,3,4
obolactone,5 cryptolatifolione,6,7 cryptomoscatones,8 rugulac-
tone,9 cryptocaryols,10 and cryptoconcatones.11 These lactones
exhibit a wide range of bioactivities such as antitumor,5
antitrypanosomal,12 antimalarial,13 and inhibitory effects on
NF-κB activation.9
During a phytochemical study on rainforest plants,14,15
a
50% MeOH−CH2Cl2 extract of the leaves and twigs of
Cryptocarya laevigata (Lauraceae), provided by the U.S.
National Cancer Institute (code # N025439), was investigated.
The characteristic secondary metabolites of Cryptocarya
Received: August 29, 2018
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.8b00732
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
212.0 to δC 200.0) was likely due to conjugation with a
neighboring double bond. Based on these data, a trans-Δ8(9)
olefinic moiety was assigned in 1. HMQC, 1H−1H COSY, and
HMBC data (Figure 2) provided support for the C-8−C-10
α,β-unsaturated carbonyl moiety, which might be produced by
dehydration at C-8−C-9 of cryptolaevilactone B.14 The
molecular formula of C29H34O3 (HRFABMS m/z 431.2598
[M + H]+) also suggested a dehydrated molecule relative to
cryptolaevilactone B. The two compounds were assigned the
same relative configuration on the bases of the NOESY
correlations between H-11/H-13, H-12/H-7′α, H-12/H-2′, H-
13/H-6′β, H-5′α/H-6′α, and H-5′α/H-4′α (Figure 2), as well
as the 1H NMR coupling constants of a pseudoaxial H-5′β [δH
1.31 (1H, dddd, J = 13.4, 13.4, 10.7, 2.1 Hz)] in 1. The ECD
spectrum of 1 displayed a curve similar to that of the (11S,
12R, 1′S, 4′S) isomer based on time-dependent density
functional theory/electronic circular dichroism (TDDFT-
ECD) calculations.33 As shown in Figure 3, the experimental
ECD curve was slightly closer to the curve calculated for (6S)
(α-orientation of H-6) than the one computed for (6R) (β-
orientation of H-6); however, the similarity was not sufficient
for an unequivocal assignment. Finally, the (6S) configuration
was suggested based upon the absolute configuration of 7, the
likely biosynthetic precursor of 1. Accordingly, the absolute
configuration of 1 was postulated to be (6S, 11S, 12R, 1′S,
4′S). Because the shapes of the ECD spectra of 1 and
cryptolaevilactone B were similar, the absolute configuration of
cryptolaevilactone B might be (6R, 8R, 11S, 12R, 1′S, 4′S), of
which only a relative configuration was proposed in the
previous paper.14 Thus, cryptolaevilactone G (1) is the 8,9-
dehydrated analogue of cryptocaryalactone B.
Figure 1. Structures of compounds 1−8 from the leaves and twigs of
C. laevigata. The absolute configuration of compound 6 was proposed
from other cryptolaevilactones.
(−)-13aα-antofine,26 (−)-crychine,27 N-trans-feruloyl 3′-O-
methyldopamine,28 epicatechin,29 quercitrin,30 and lutein.31,32
RESULTS AND DISCUSSION
■
Compounds 2 and 4−6 were isolated as mixtures of
diastereomers. The small amounts of 2 (0.4 mg), 4 (0.8 mg), 5
(0.5 mg), and 6 (0.4 mg) from the limited plant extract (10.5
g) caused difficulty in further purifications of these interesting
secondary metabolites. However, individual structure elucida-
tions could be made based on the intensities of the signals in
the NMR spectra.
The EtOAc-soluble portion of the 50% MeOH−CH2Cl2
extract of the leaves and twigs of C. laevigata (N025439)
was separated by a combination of column chromatography
and preparative HPLC methods, using silica gel, octadecylsilyl
(ODS), and chiral-phase columns (CHIRAL ART Cellulose-
SC).
Compound 1 was obtained as an optically active colorless,
amorphous solid, [α]24D +208 (c 0.05, CHCl3). The 1H NMR
data of 1 (Table 1) indicated the presence of a mono-
substituted phenyl moiety [δH 7.34 (2H, brd, J = 7.6 Hz), 7.29
(2H, dd, J = 7.6, 7.2 Hz), 7.20 (1H, tt, J = 7.2, 1.0 Hz)], two
sets of Z-olefinic protons [6.70 (1H, ddd, J = 9.6, 5.5, 3.1 Hz)
and 5.94 (1H, ddd, J = 9.6, 2.6, 1.4 Hz); 5.57 (1H, brd, J =
10.1 Hz) and 5.53 (1H, brd, J = 10.1 Hz)], two sets of E-
olefinic protons [δH 6.75 (1H, ddd, J = 16.2, 7.9, 6.9 Hz) and
6.17 (1H, ddd, J = 16.2, 1.4, 1.0 Hz); 6.35 (1H, d, J = 15.8 Hz)
and 6.29 (1H, dd, J = 15.8, 7.9 Hz)], and an oxymethine
proton [δH 4.42 (1H, m)]. Other assignable aliphatic protons,
including 14 methylenes or methines and two methyls [δH 0.84
(3H, d, J = 6.5 Hz), 0.87 (3H, d, J = 6.9 Hz)], were also
observed. The 13C NMR data of 1 (Table 2) included signals
for 27 carbons (two overlapped), including those for a
carbonyl carbon (δC 200.0), a lactone carbonyl carbon (δC
163.7), 14 sp2 carbons, and an oxymethine carbon (δC 76.0).
The proton and carbon signals were similar to those of
cryptolaevilactone B, which also contains a unique spiro[3.5]-
nonenyl moiety.14
Compound 2 showed a protonated molecular ion at m/z
431.2588 in the HRFABMS, corresponding to the same
molecular formula, C29H35O3, as 1. Although the compound
was isolated as a mixture with a small amount of a
1
diastereomer and, thus, purification was difficult, its H and
13C NMR data (Tables 1 and 2) were quite close to those of 1.
NOESY correlations of H-11 with H-7′α/H-14 and H-12 with
H-7′β/H-2′ indicated that H-11 and H-12 were α- and β-
oriented, respectively (Figure 2). The coupling constants of H-
5′α (dddd, J = 12.7, 12.7, 8.9, 3.8 Hz) and H-6′α (ddd, J =
14.1, 5.2, 3.8 Hz) suggested a half-chair conformation of the
cyclohexene portion of the spiro moiety with H-4′β, 5′α, and
6′β in pseudoaxial and H-5′β and 6′α in pseudoequatorial
positions. Additionally, a β-orientation was assigned to H-4′
based on a NOESY correlation between H-13 and H-5′α/6′α.
These results indicated that compound 2 has the opposite
configurations at C-11, C-12, and C′-1 as 1, and its spiro
moiety has the same relative configuration as in cryptolaevi-
lactone A.14 The absolute configuration of 2 was concluded as
(6S, 11R, 12S, 1′R, 4′S) based on comparison of experimental
and calculated33 ECD data (Figure 3). Accordingly, the
structure of cryptolaevilactone H (2) was defined as the 8,9-
dehydrated analogue of cryptolaevilactone A. This also
permitted assignment of the (6R,8R,11R,12S,1′R,4′S) absolute
configuration of cryptolaevilactone A.14
However, the spectra of 1 did not show signals for an OH
group at C-8 and methylene at C-9 but did contain olefinic
signals at δH 6.75 (1H, ddd, J = 16.2, 7.9, 6.9 Hz) and 6.17
(1H, ddd, J = 16.2, 1.4, 1.0 Hz) as well as carbons at δC 140.6
and 132.7. The observed upfield shift of the C-10 carbonyl (δC
B
DOI: 10.1021/acs.jnatprod.8b00732
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
1
Table 1. H NMR Spectroscopic Data of Compounds 1−7 (600 MHz, CDCl3)
1
2
3
4
5
6
7
position
3
δH (J in Hz)
δH (J in Hz)
δH (J in Hz)
δH (J in Hz)
δH (J in Hz)
δH (J in Hz)
δH (J in Hz)
5.94, ddd (9.6, 2.6, 5.92, ddd (9.6, 2.4, 5.92, 9.6, 2.4, 1.0) 5.93, ddd (9.8, 2.1, 5.97, ddd (9.8, 2.7, 5.91, ddd (9.6, 2.7, 6.03, dt (9.8,
1.4) 1.0) 1.4) 1.0) 0.9) 1.7)
4
5
6.70, ddd (9.6, 5.5, 6.65, ddd (9.6, 5.2, 6.66, ddd (9.6, 5.5, 6.67, ddd (9.8, 5.2, 6.81, ddd (9.8, 6.0, 6.67, ddd (9.6, 6.2, 6.89, dt (9.8,
3.1)
3.1)
3.1)
3.4)
2.4)
2.4)
4.3)
2.25, m
2.23, m
2.25, m
2.23, m
2.30, dddd (18.2,
11.7, 2.7, 2.4)
1.84, dddd (18.4,
11.9, 2.7, 2.4)
2.42, m
2.44, dddd (18.2,
6.0, 3.8, 1.0)
2.08, dddd (18.4,
6.2, 3.6, 0.9)
6
7
4.42, m
4.47, m
4.47, m
4.38, m
4.49, m
4.58, dddd (11.9,
4.71, m
6.2, 6.2, 3.6)
h
2.55, dddd (15.1,
7.9, 5.8, 1.0)
2.67, dddd (15.1,
6.9, 6.2, 1.4)
2.61, dd (7.2, 6.2) 2.61, dddd (15.9,
7.2, 1.7, 1.7)
2.53, dddd (15.0,
7.9, 5.8, 1.0)
2.67, dddd (15.0,
6.5, 6.5, 1.4)
1.94, ddd (14.8, 6.2, 1.56, m
3.8)
2.12, ddd (14.8, 7.9, 1.78, m
6.9)
1.81, ddd (14.5,
5.8, 3.8)
2.02, ddd (14.5,
8.1, 6.9)
i
2.63, dddd (15.9,
7.6, 2.1, 1.4)
8
9
6.75, ddd (16.2, 7.9, 6.76, dt (15.8, 7.2) 6.77, ddd (16.0,
6.73, ddd (15.8, 7.9, 5.41, m
6.2)
6.16, ddd (15.8, 1.4, 2.71, dd (17.2, 6.9) 2.45, dd (17.9, 8.6) 2.70, m
1.0)
4.03, m
4.32, m
6.9)
7.6, 7.2)
6.17, ddd (16.2, 1.4, 6.17, brd (15.8)
1.0)
6.19, brd (16.0)
2.77, dd (17.2, 6.5) 2.55, dd (17.6, 3.1)
11
12
13
14
16
17
18
19
20
3.45, ddd (9.7, 9.3, 3.46, ddd (9.6, 9.1, 3.51, ddd (9.6, 9.3, 3.46, ddd (10.0, 8.9, 3.21, ddd (9.8, 8.9, 3.57, ddd (10.0, 9.3, 2.65, t (7.1)
8.6)
8.2)
8.9)
8.6)
8.8)
8.2)
3.02, dd (9.3, 7.9)
2.94, dd (9.1, 8.2) 2.91, dd (9.3, 7.2) 2.90, dd (8.9, 8.2)
2.96, dd (8.8, 8.2)
3.20, dd (11.0, 10.0) 2.51, tdd (7.1,
6.9, 1.4)
6.29, dd (15.8, 7.9) 6.31, dd (15.8, 8.2) 6.31, dd (15.8, 7.2) 6.27, dd (15.8, 8.2) 6.28, dd (15.8, 8.2) 6.15, dd (15.7, 11.0) 6.18, dt (15.8,
6.9)
6.35, d (15.8)
6.36, d (15.8)
6.34, d (15.8)
6.31, d (15.8)
6.41, d (15.8)
6.35, d (15.7)
7.28, d (4.1)
7.28, d (4.1)
6.41, brd
(15.8)
7.33, dd (7.6,
1.4)
7.29, dd (7.6,
7.2)
7.21, tt (7.2,
1.4)
7.29, dd (7.6,
7.2)
7.33, dd (7.6,
1.4)
e
7.34, brd (7.6)
7.29, dd (7.6, 7.2)
7.20, tt (7.2, 1.0)
7.29, dd (7.6, 7.2)
7.34, brd (7.6)
7.34, brd (7.4)
7.34, brd (7.8)
7.27−7.33, m
7.37, d (7.8)
e
7.30, dd (7.4, 7.4) 7.29, dd (7.8, 7.2) 7.27−7.33, m
7.31, dd (7.8, 7.6)
7.22, tt (7.6, 1.0)
7.31, dd (7.8, 7.6)
7.37, d (7.8)
j
7.22, tt (7.4, 1.4)
7.20, tt (7.2, 1.0)
7.19, tt (6.9, 1.7)
7.26, m
e
7.30, dd (7.4, 7.4) 7.29, dd (7.8, 7.2) 7.27−7.33, m
7.28, d (4.1)
7.28, d (4.1)
e
7.34, brd (7.4)
7.34, brd (7.8)
7.27−7.33, m
2′
3′
4′
5′α
5.57, brd (10.1)
5.53, brd (10.1)
5.58, d (11.2)
5.56, d (11.2)
1.85, m
1.30, dddd (12.7,
12.7, 8.9, 3.8)
6.00, dd (10.3, 1.4) 5.90, brd (10.5)
5.66, dd (10.3, 1.7) 5.71, brd (10.5)
5.55, d (10.9)
5.53, d (10.9)
1.87, m
5.63, brd (10.0)
5.54, brd (10.0)
1.93, m
a
1.86, m
1.68, m
1.86, m
1.55, mc
1.94, m
b
g
1.31, dddd (13.4,
13.1, 10.7, 2.4)
1.50, mf
1.66, m
1.29, dddd (13.1,
12.9, 10.0, 2.7)
k
5′β
6′α
6′β
7′α
1.31, dddd (13.4,
13.4, 10.7, 2.1)
1.51, m overlap
1.28, dddd (12.7,
12.4, 9.3, 3.3)
1.29, dddd (12.0,
12.0, 10.3, 1.9)
1.62, m
b
g
1.68, m
2.20, ddd (14.1,
5.2, 3.8)
1.61, ddd (13.1,
12.4, 2.7)
1.79, brd (13.1)
1.65, m
1.98, brd (12.7)
a
d
1.86, m
1.51, m
1.70, ddd (13.1,
5.2, 3.3)
1.61, ddd (13.4,
13.1, 3.1)
1.80, ddd (12.0, 4.5, 1.65, ddd (12.9,
k
1.9)
12.7, 2.7)
i
2.15, ddd (11.3, 9.7, 1.84, dd (11.5, 8.2) 2.15, dd (11.0, 9.6) 2.18, dd (11.2, 10.0) 2.15, dd (11.3, 9.8) 1.77, dd (13.4, 8.2)
1.0)
7′β
8′
1.89, dd (11.3, 8.6) 2.25, dd (11.5, 9.6) 1.97, dd (11.0, 8.9) 1.89, dd (11.2, 8.6) 1.87, dd (11.3, 8.9) 2.64, dd (13.4, 9.3)
d
c
f
h
1.54, m
1.51, m
1.55, m
1.50, m
1.53, m
1.53, m
9
10
OH
0.84, d (6.5)
0.87, d (6.9)
0.78, d (6.9)
0.80, d (6.9)
0.85, d (6.5)
0.88, d (6.5)
0.75, d (6.9)
0.78, d (6.9)
0.84, d (6.5)
0.86, d (6.9)
0.76, d (6.5)
0.80, d (6.9)
3.52, d (1.7)
3.28, brs
OAc
2.02, s
a−k
Overlapping signals.
The HRFABMS protonated molecular ion of cryptolaevi-
lactone I (3) was observed at m/z 431.2596 [M + H]+; thus,
the molecular formula of C29H35O3 is the same as those of 1
correlations between H-11/H-7′α, H-12/H-7′β, H-12/H-6′β,
H-7′α/H-2′, H-5′α/H-6′α, and H-4′α/H-5′α (Figure 2), as
1
well as the following H NMR coupling constants [δH 1.70
1
and 2. The H and 13C NMR data of 3 showed similar, but
(1H, ddd, J = 13.1, 5.2, 3.3 Hz, H-6′β), 1.61 (1H, ddd, J =
13.1, 12.4, 2.7 Hz, H-6′α), 1.28 (1H, dddd, J = 12.7, 12.4, 9.3,
3.3 Hz, H-5′β)]. Comparison of the experimental and
slightly shifted, signal patterns compared to those of 1,
consistent with 3 being a diastereomer (Tables 1 and 2). The
relative configuration of 3 was determined from the NOESY
C
DOI: 10.1021/acs.jnatprod.8b00732
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
Table 2. 13C NMR Spectroscopic Data of Compounds 1−7 (150 MHz, CDCl3)
1
2
3
4
5
6
7
position
δC
δC
δC
δC
δC
δC
δC
2
3
4
5
163.7
121.3
144.4
28.9
163.8
121.2
144.5
28.8
163.8
121.3
144.5
28.8
163.7
121.3
144.4
28.9
no data
121.2
144.9
29.1
164.1
121.0
145.1
28.5
no data
121.3
145.5
26.8
6
76.0
76.0
76.0
76.0
74.8
75.6
75.5
7
37.7
37.6
37.7
37.7
38.9
40.7
40.5
8
9
140.6
132.7
200.0
43.7
140.4
132.9
200.0
43.7
140.5
132.9
199.9
43.6
140.8
132.7
199.8
43.5
66.9
45.2
207.9
46.3
52.0
128.0
132.0
137.0
126.3
128.6
127.5
128.6
126.3
40.6
64.6
48.3
212.2
45.2
54.4
127.8
132.3
136.9
126.2
128.6
127.4
128.6
126.2
40.0
64.4
48.8
211.0
43.0
29.1
128.3
131.1
137.2
126.0
128.6
127.2
128.6
126.0
10
11
12
13
14
15
16
17
18
19
20
1′
2′
3′
4
52.0
51.2
51.7
54.3
128.3
131.9
137.0
126.2
128.6
127.4
128.6
126.2
40.8
128.1
132.0
137.1
126.2
128.7
127.4
128.7
126.2
40.5
129.0
131.6
137.1
126.3
128.6
127.3
128.6
126.3
41.5
131.0
131.3
137.1
126.1
128.6
127.2
128.6
126.1
41.3
136.0
131.4
42.1
135.8
131.2
41.3
131.2
131.5
41.7
131.8
132.4
41.8
135.8
131.6
42.1
133.1
132.5
41.7
5′
6
22.4
30.0
22.9
30.3
22.4
36.6
21.9
37.8
22.3
29.8
22.1
36.6
7
33.9
34.7
35.1
33.1
33.4
31.3
8
31.9
31.7
31.9
31.8
31.9
31.8
9
19.3
19.4
19.4
19.1
19.3
19.0
10
OAc
19.6
19.6
19.7
19.4
19.6
21.1
19.5
170.5
calculated33 ECD data supported the (6S, 11R, 12S, 1′S, 4′S)
absolute configuration (Figure 3).
assignment was supported by the COSY and HMBC analyses
(Figure 2). The relative configuration of the spiro portion was
identical to that of 1, by comparison of the NMR spectra and
NOESY correlations. The orientation of the styrenyl unit at C-
12 and carbonyl chromophore at C-11 could be expected to
dominate the ECD spectrum. Thus, the ECD is governed
mainly by the C-11 and C-12 stereogenic centers and might be
sensitive to the populations of rotamers along the σ-bonds
between C-12 and C-13 as well as C-10 and C-11. Accordingly,
the absolute configuration of 5 was postulated as (6R, 8R, 11S,
12R, 1′S, 4′S) based on the similarities of the ECD spectra of 5
and cryptolaevilactone B14 (Figure 4). Cryptolaevilactone K
(5) was concluded to be the 8-O-acetyl derivative of
cryptolaevilactone B and was isolated as a mixture with a
small amount of a diastereomer.
The 1H NMR data of 4 and 3 (Table 1) were quite similar;
however, the signals related to the spiro moiety, H-2′−H-4′ as
well as H-5′α,β and H-6′α,β, were shifted, suggesting a different
configuration at C-1′. Other NMR spectroscopic data,
including 2D, coupled with the HRFABMS ion peak at m/z
431.2585 [M + H]+ suggested that compound 4 was the C-4′
epimer of 3. The β-orientation of H-4′ was determined from
the NOESY correlations between H-4′/H-5′β, H-4′/H-6′β, H-
5′α/H-12, and H-6′α/H-12 (Figure 2), as well as the coupling
constants for H-5′α (dddd, J = 13.4, 13.1, 10.7, 2.4 Hz), H-6′α
(brd, J = 13.1 Hz), and H-6′β (ddd, J = 13.4, 13.1, 3.1 Hz).
Based on these results, cryptolaevilactone J (4) has the same
2D structure as 1−3 but a different relative configuration. The
ECD spectra of compounds 1 and 4 showed highly similar
Cotton effects, while those of compounds 2 and 3 displayed
similar shapes (Figure 3). The (6S, 11S, 12R, 1′R, 4′S)
absolute configuration was confirmed by the calculated ECD
data33 (Figure 3).
Compound 6 was isolated as a mixture of diasteromers in a
ca. 4:1 ratio. The HRFABMS ion at m/z 449.2695 [M + H]+
was consistent with the molecular formula C29H36O4 found for
cryptolaevilactones A−C.14 The H and 13C NMR data of 6
1
were highly similar to those of cryptolaevilactones A−C
(Tables 1 and 2). Thus, compound 6 is likely a diastereomer of
cryptolaevilactones A−C. The (11R*, 12R*, 1′R*, 4′S*)
relative configuration of the spiro moiety was established from
NOESY correlations (H-11/H-12, H-11/H-7′α, H-13/H-7′β,
H-13/H-2′, H-7′β/H-2′, H-12/H-5′α, H-12/H-6′α, H-11/H-
6′α, Figure 2) and 1H NMR coupling constants [H-5′α (dddd,
J = 13.1, 12.9, 10.0, 2.7 Hz), H-6′α (brd, J = 12.7 Hz), and H-
The HRFABMS ion, m/z 491.2798 [M + H]+, of 5 was
different from those of 1−4. The presence of an acetoxy group
was supported by the molecular formula, C31H38O5, and an
1
acetoxy methyl resonance at δH 2.02 (3H, s) in the H NMR
data of 5 (Table 1). Proton signals for a methylene group at δH
2.71 and 2.77 and a low field shifted oxymethine at δH 5.41
indicated that the acetoxy group was located at C-8. This
D
DOI: 10.1021/acs.jnatprod.8b00732
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
Figure 2. Selected HMBC correlations (arrows), COSY connectivities (bold line), and key NOESY correlations for 1−8.
Figure 3. Experimental and calculated ECD spectra of compounds 1−4 in MeCN.
6′β (ddd, J = 12.9, 12.7, 2.7 Hz)]. The (11R, 12R, 1′R, 4′S)
absolute configuration of the spiro moiety was defined by
comparison of experimental and calculated ECD data (Figure
5). Thus, the C-11 and C-12 substituents are cis in compound
6 (cryptolaevilactone L), but trans in all related spiro[3.5]-
nonenyl meroterpenoid lactones (cryptolaevilactones A−K).
Because the two stereogenic centers at C-6 and C-8 contribute
less to the overall shape of the ECD curve, their absolute
configurations at C-6 and C-8 could not be determined from
the TDDFT-ECD calculation (Figure 5) but are most likely
(6R, 8R) based on the absolute configurations of other
cryptolaevilactones.
Compound 7 showed a protonated molecular ion at m/z
315.1590 in the HRFABMS, corresponding to the molecular
formula C19H22O4. The 1H NMR data displayed similar signals
to those of cryptolaevilactone A;14 however, the 18 proton
signals for the spiro moiety were not observed (Table 1).
Instead, four aliphatic hydrogens were detected at δH 2.65 (2H,
E
DOI: 10.1021/acs.jnatprod.8b00732
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
was prepared from ethylene glycol,34 was converted to allyl
alcohol 10 through a stereoselective Keck allylation. An
1
enantiomeric excess (ee) of >99% was confirmed by the H
NMR spectrum of its Mosher ester 10a (Figure S59,
Supporting Information). Silyl protection of the hydroxy
group, followed by oxidative cleavage of the terminal olefinic
group, afforded aldehyde 12, which was transformed under
Brown conditions into 1334 in 91% de. After removal of the
unwanted diastereomer, compound 13 was treated with
acryloyl chloride and cyclized by Grubbs olefin metathesis.
The resulting lactone 15 was converted to aldehyde 16
through deprotection of the primary alcohol and 2-
iodobenzoic acid (IBX) oxidation. Treatment of 16 with
phenylbutenyl-MgBr prepared from (E)-4-phenylbut-3-enoic
acid (20) in three steps gave alcohol 17 as a diastereomer
mixture, which was oxidized to generate ketone 18. Careful
reaction, workup, and purification conditions were required to
remove the tert-butyldiphenylsilyl (TBDPS) protecting group,
because the target compound 7 cyclizes readily to form 19.
Finally, deprotection was achieved successfully by treatment
with tetra-n-butylammonium fluoride (TBAF) and purification
without the use of acidic silica gel to furnish compound 7 with
Figure 4. Experimental ECD spectrum of compound 5 in MeCN.
1
(6R, 8R) configuration. Because the H NMR (Figure S60,
Supporting Information) and ECD (Figure 6) spectra of
synthesized 7 were identical with those of isolated 7, the
structure of cryptolaevilactone M (7) was elucidated as (R)-6-
[(R,E)-2-hydroxy-4-oxo-8-phenyloct-7-en-1-yl]-5,6-dihydro-
2H-pyran-2-one.
Figure 5. Experimental and calculated ECD spectra of compound 6
(11R, 12R, 1′R, 4′S) in MeCN.
Compound 8 was isolated as a colorless oil with an
HRFABMS ion at m/z 227.1631 [M + H]+, indicating a
molecular formula of C13H22O3. The 1H NMR data (Table 3)
revealed four methyl groups (three singlets at δH 0.85, 1.11,
and 2.28; a doublet at δH 0.92), two trans olefinic protons (δH
t, J = 7.1 Hz) and 2.51 (2H, tdd, J = 7.1, 6.9, 1.4 Hz),
suggesting the presence of a 1,2-disubstituted 11,12-ethyl unit.
The 1H−1H COSY and HMBC data of 7 (Figure 2) supported
the 2D structure shown in Figure 1. The absolute configuration
was proved by total synthesis (Scheme 1). Aldehyde 9, which
a
Scheme 1. Stereoselective Total Synthesis of 7
a
Reagents and conditions: (a) (R)-BINOL, Ti(OiPr)4, 4 Å MS, allylSnBu3, anhydrous toluene, −20 °C, 70%; (b) TBDPSCl, imidazole, anhydrous
CH2Cl2, rt, 4 h, 97%; (c) OsO4, NMO, tBuOH−H2O (3:1), rt, 2 h, 99%; (d) NaIO4, THF−H2O (3:1), rt, 2 h, 99% for 2 steps; (e)
(+)-IPc2B(allyl), anhydrous Et2O, −78 °C, 4 h; (f) acryloyl chloride, Et3N, anhydrous CH2Cl2, 0 °C, 2 h, 76% for 2 steps; (g) second Grubbs
catalyst, anhydrous CH2Cl2, reflux, 3 h, 93%; (h) p-TsOH·H2O, THF−H2O (3:1), rt, 21 h, 99%; (i) IBX, anhydrous CH2Cl2, anhydrous DMSO,
rt, 11 h, 96%; (j) 22, Mg, anhydrous THF, −40 °C to rt, 4 h, 42%; (k) IBX, anhydrous CH2Cl2, anhydrous DMSO, rt, 4 h, 82%; (l) TBAF,
anhydrous THF, rt, 19 h, 61%; (m) LAH, anhydrous THF, 0 °C to rt, 1 h, 87%; (n) CBr4, PPh3, imidazole, anhydrous CH2Cl2, rt, 1 h, 83%; (o)
(S)-MTPA-Cl, Et3N, DMAP, CH2Cl2, 40 °C, 1 h, 88%.
F
DOI: 10.1021/acs.jnatprod.8b00732
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
Figure 6. Experimental ECD spectra of isolated and synthesized 7 in MeCN.
1
Table 3. H and 13C NMR Spectroscopic Data of
Compound 8 (CDCl3)
δH (J in Hz)
δC
position
600 MHz
150 MHz
1
2ax
2eq
3
4
5
6
7
8
9
10
1ax-Me
1eq-Me
5-Me
OH
OH
33.5
44.7
1.46, dd (15.0, 3.1)
1.85, dd (15.0, 3.1)
4.03, q (3.1)
3.18, dd (10.3, 3.1)
1.92, ddd (10.3, 10.7, 6.5)
1.66, dd (10.7, 10.3)
6.56, dd (16.0, 10.3)
6.03, d (16.0)
69.8
76.7
32.5
56.7
148.2
133.6
198.2
27.1
23.6
31.8
16.6
Figure 7. Calculated and experimental ECD spectra of compound 8
in MeCN.
2.28, s
1.11
0.85
0.92, d (6.5)
2.03, br s
2.12, br s
HRFABMS, and ECD, revealed the structures of the new
compounds 1−6. While the new cryptolaevilactones G−K (1−
5) and the known analogues14 contain trans-oriented cyclo-
butane rings, the new cryptolaevilactone L (6) contains a cis
moiety. Cryptolaevilactone M (7) was characterized as a
related δ-lactone without a spiro[3.5]nonane moiety. The
absolute configuration was defined by total synthesis through
stereoselective allylation and Grubbs olefin metathesis.
Compound 8 was defined as an ionone derivative with a 3,4-
syn-diol moiety.
6.03, d, J = 16.0 Hz and δH 6.56, dd, J = 16.0, 10.3 Hz), and
two oxymethine protons (δH 3.18, dd, J = 10.3, 3.1 Hz and δH
4.03, q, J = 3.1 Hz). The 13C NMR data (Table 3) suggested
the presence of a conjugated carbonyl carbon at δC 198.2 in
addition to the aforementioned groups. Based on the HMQC
and COSY analyses (Figure 2), the 2D structure of 8 was
assigned to be an ionone derivative; its 4-epimer was derived
artificially from natural (3S,4S,5S,6S,9R)-3,4-dihydroxy-5,6-
dihydro-β-ionol.35 A NOESY correlation between H-3 and
H-4 suggested that the two hydroxy groups were syn-oriented,
which was supported by the coupling constant of 3.1 Hz.
Additional correlations of H-4 with H-2β and H-6, H-2β, with
H-6 and of 1α-Me with H-5 and H-2α established the (3S*,
4R*, 5S*, 6S*) configuration. Subsequently, the (3R, 4S, 5R,
6R) absolute configuration was defined via the ECD spectrum,
which agreed with the calculated spectrum (Figure 7).
In conclusion, six monoterpene−polyketide hybrids con-
taining a unique spiro[3.5]nonane moiety, cryptolaevilactones
G−L, were found in a CH3OH−CH2Cl2 (1:1) extract
(N025439) of the leaves and twigs of C. laevigata. Although
some analytical difficulty precluded complete structure
elucidation, extensive spectroscopic and spectrometric experi-
ments, including 1H/13C NMR, HMBC, COSY, NOESY,
In our previous paper,14 the absolute configurations of the
pyrone moiety of cryptolaevilactones A−C were proposed
based on their ECD Cotton effects. However, the recent
TDDFT-ECD calculations clearly indicated that the chirality of
the pyrone moiety results in a minor contribution to the ECD
spectrum. Accordingly, cryptolaevilactones A−F14 are likely to
have an identical absolute configuration at C-6, namely, 6R for
cryptolaevilactones A−C and 6S for cryptolaevilactones D−F.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Optical rotations were
measured on a JASCO P-2200 digital polarimeter. ECD spectra
were recorded on a JASCO J-820 spectrometer. Infrared spectra (IR)
were recorded on a Thermo Fisher Scientific NICOLET iS5 FT-TR
spectrometer with samples in CH2Cl2. NMR spectra were obtained on
JEOL JMN-ECA600 and JMN-ECS400 NMR spectrometers with
tetramethylsilane as an internal standard, and chemical shifts are
indicated as δ values. HRMS data were recorded on a JEOL JMS-700
(FAB) mass spectrometer. MPLC was performed with C18 cartridges
(ODS-25, YMC-DispoPack). Preparative HPLC was conducted on a
GL Science recycling system using an InertSustain C18 column (5 μm,
G
DOI: 10.1021/acs.jnatprod.8b00732
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
20 × 250 mm) and a CHIRAL ART Cellulose-SC column (5 μm, 10
× 250 mm, YMC).
Cryptolaevilactone L (6): colorless oil; 1H and 13C NMR, see
Tables 1 and 2; HRFABMS m/z 449.2695 [M + H]+ (calcd for
C29H37O4, 449.2692).
Plant Material. A crude CH2Cl2−CH3OH (1:1) extract
(N025439) of C. laevigata leaves and twigs was provided by the
NCI Natural Products Branch (Developmental Therapeutics Branch,
Frederick, MD, USA). The plants were collected in The Philippines
by D. D. Soejarto, E. Reynoso, E. Sagcal, and R. Edrada in March
1990. The taxonomic determination of the plant material was
confirmed by J. C. Regalado in 1994. A voucher specimen
(#U44Z.1628) was deposited at the Smithsonian Institution
(Washington, DC, USA), and reference samples of N025439 were
deposited at NCI-Frederick and Kanazawa University (Kanazawa,
Japan).
1
Cryptolaevilactone M (7): colorless oil; H and 13C NMR, see
Tables 1 and 2; HRFABMS m/z 315.1590 [M + H]+ (calcd for
C19H23O4, 315.1596).
(3R,4S,5R,6R)-3,4-Dihydroxy-4,5-dihydro-α-ionone (8): colorless
oil; [α]27 +12 (c 0.1, CHCl3); 1H and 13C NMR, see Table 3;
D
HRFABMS m/z 227.1631 [M + H]+ (calcd for C13H23O3, 227.1647).
Stereoselective Total Synthesis of Cryptolaevilactone M (7).
3-[(tert-Butyldimethylsilyl)oxy]propanal (9). To a suspension of
NaH (60%, 508 mg, 12.7 mmol) in anhydrous tetrahydrofuran (THF,
12.5 mL) was added dropwise 1,3-propanediol (899 mg, 11.8 mmol)
in anhydrous THF (12.5 mL) at 0 °C. The suspension was stirred for
45 min at room temperature (rt), tert-butyldimethylsilyl chloride
(1.87 g, 12.4 mmol) in anhydrous THF (5.0 mL) was added dropwise
at 0 °C, and the resulting mixture was stirred at rt for 2 h. The mixture
was quenched with saturated NaHCO3 at 0 °C and extracted with
Et2O, washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified with column chromatog-
raphy to afford 3-(tert-butyldimethylsilanyloxy)propan-1-ol (1.82 g,
81%) as a colorless oil.
Extraction and Isolation. The extract, N025439 (10.5 g), was
partitioned between EtOAc and H2O. The EtOAc-soluble fraction
(5.0 g) was chromatographed on silica gel using n-hexane−EtOAc
(1:0−0:1) and MeOH as eluents to give six fractions, F1−F6. F2
(1.37 g) was separated by silica gel column chromatography (CC)
eluted with n-hexane−acetone (5:1−0:1) to furnish five subfractions,
SF2a−e. SF2a was purified by recycling preparative HPLC with
MeOH−H2O (9.5:0.5) to provide caryophyllene oxide (1.2 mg). F4
(620 mg) was separated by silica gel CC eluted with CH2Cl2−acetone
(1:0−0:1) to provide four subfractions, SF4a−d. SF4a (70.5 mg) was
subjected to silica gel CC eluted with n-hexane−EtOAc (5:1−0:1)
and MeOH to yield seven subfractions, SF4a1−4a7. SF4a6 (7.0 mg)
was purified by MPLC on ODS-25 (YMC-DispoPack AT 12 g) with
MeOH−H2O (9:1−1:0), followed by repeated recycling preparative
HPLC with MeOH−H2O (9:1) and CHIRAL column HPLC with n-
hexane−iPrOH (1:2) to provide compounds 1 (0.9 mg), 2 (1.2 mg),
3 (0.4 mg), 4 (0.8 mg), and 5 (0.5 mg). SF4b (72.6 mg) was
separated by repeated recycling preparative HPLC with MeCN−H2O
(7:3−0:1) to provide (−)-crychine (3.0 mg). SF4d was subjected to
recycling preparative HPLC with MeCN−H2O (8.5:1.5−0:1) to give
lutein (2.1 mg). F5 (448 mg) was chromatographed on silica gel
eluted with CH2Cl2−MeOH (40:1−0:1), leading to seven sub-
fractions, SF5a−g. SF5c (64.3 mg) was subjected to MPLC with
MeCN−acetone−MeOH−H2O (1:2:1:2), followed by repeated
recycling preparative HPLC with acetone−H2O (3:1), to afford
compound 6 (0.4 mg). SF5d (65.9 mg) was separated by MPLC with
acetone−H2O (4:1−1:0), followed by repeated recycling preparative
HPLC with MeOH−H2O (1:1), to afford compound 8 (1.3 mg).
SF5f (225.3 mg) was subjected to MPLC with MeCN−H2O (1:4−
0:1), followed by repeated recycling preparative HPLC with MeOH−
H2O (1:1−0:1), to afford (−)-boscialin (1.2 mg), N-trans-feruloyl 3′-
O-methyldopamine (1.5 mg), and epicatechin (2.4 mg). F6 (1.78 g)
was chromatographed on silica gel using n-hexane−acetone (3:1−0:1)
and MeOH as eluents to yield seven subfractions, SF6a−g. SF6d
(97.1 mg) was subjected to MPLC with MeCN−H2O (2:3−0:1) to
give five subfractions, SF6d1−6d5. SF6d1 was purified by recycling
preparative HPLC with MeOH−H2O (13:7) to furnish compound 7
(0.4 mg).
To a solution of 3-(tert-butyldimethylsilanyloxy)propan-1-ol (432
mg, 2.27 mmol) in EtOAc (4.0 mL) was added IBX (1.51 g 5.39
mmol), and the mixture was refluxed at 80 °C for 3.5 h. Subsequently,
the mixture was cooled to rt and filtered. The organic phase was
washed with saturated NaHCO3 and brine, dried over Na2SO4, and
concentrated under reduced pressure. The title aldehyde (9, 399 mg,
2.12 mmol) was obtained as a colorless oil without further
1
purification. H NMR (400 MHz, CDCl3) δ 0.07 (s, 6H), 0.88 (s,
9H), 2.60 (dt, J = 2.0 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H), 9.81 (t, J =
2.4 Hz, 1H).
(R)-1-[(tert-Butyldimethylsilyl)oxy]hex-5-en-3-ol (10). A mixture
of (R)-1,1′-bi-2-naphthol (BINOL) (388 mg, 1.36 mmol) and Ti(Oi-
Pr)4 (0.19 mL, 0.65 mmol) in anhydrous toluene (6.0 mL) in the
presence of 4 Å molecular sieves (600 mg) was stirred at rt. After 3 h,
a solution of aldehyde 9 (499 mg, 2.66 mmol) in anhydrous toluene
(1.0 mL) was added, and the resulting mixture was stirred for 10 min.
The mixture was cooled to −78 °C, and allyltributyltin (2.4 mL, 7.8
mmol) was added. The stirring was continued at −20 °C for 35 h.
After completion of the reaction (detected by TLC), the reaction was
quenched with saturated NaHCO3 and stirred for an additional 30
min. The solution was extracted with CH2Cl2, washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. The
residue was purified with silica gel column chromatography (n-
1
hexane−EtOAc, 10:1) to afford 10 (431 mg, 70%, > 99% ee by H
NMR spectroscopy of its MTPA ester; see Supporting Information)
1
as a colorless oil: H NMR (600 MHz, CDCl3) δ 0.08 (s, 6H), 0.90
(s, 9H), 1.69−1.65 (m, 2H), 3.37 (d, J = 2.4 Hz, 1H), 3.84−3.78 (m,
1H), 3.93−3.88 (m, 2H), 5.13−5.08 (m, 2H), 5.90−5.80 (m, 1H).
(R)-1-[(tert-Butyldimethylsilyl)oxy]hex-5-en-3-yl-(R)-3,3,3-tri-
fluoro-2-methoxy-2-phenylpropanoate (10a). To a solution of (R)-
1-[(tert-butyldimethylsilyl)oxy]hex-5-en-3-ol (10, 1.8 mg, 6.4 μmol)
in CH2Cl2 (0.4 mL) were added Et3N (3.1 μL, 23 μmol), 4-
dimethylaminopyridine (DMAP) (3.3 mg, 27 μmol), and (S)-
(+)-MTPA-Cl (4.1 μL, 23 μmol). The reaction mixture was stirred
for 1 h at 40 °C, and the reaction was quenched with water. The
aqueous phase was extracted with EtOAc, the combined organic
extracts were dried over Na2SO4 and filtered, and the solvent was
removed under reduced pressure. The crude product was purified by
silica gel column chromatography (n-hexane−EtOAc, 5:1) to afford
Cryptolaevilactone G (1): colorless, amorphous solid; [α]28D +208
(c 0.1, CHCl3); IR νmax (CH2Cl2) 2955, 2929, 2864, 1724, 1691,
1664, 1385, 1245, 1145, 1044, 969, 815, 758, 743, 696 cm−1; 1H and
13C NMR, see Tables 1 and 2; HRFABMS m/z 431.2598 [M + H]+
(calcd for C29H35O3, 431.2586).
Cryptolaevilactone H (2): colorless, amorphous solid; [α]27 +43
D
(c 0.02, CHCl3); IR νmax (CH2Cl2) 2955, 2927, 2870, 1725, 1664,
1632, 1388, 1247, 1047, 965, 820, 747, 698 cm−1; 1H and 13C NMR,
see Tables 1 and 2; HRFABMS m/z 431.2596 [M + H]+ (calcd for
C29H35O3, 431.2586).
1
Cryptolaevilactone I (3): pale yellow oil; H and 13C NMR, see
1
Mosher ester 10a as a colorless oil (2.8 mg, 88%): H NMR (600
Tables 1 and 2; HRFABMS m/z 431.2588 [M + H]+ (calcd for
MHz, CDCl3) δ 0.03 (s, 6H), 0.89 (s, 6H), 1.81−1.90 (m, 2H),
2.36−2.46 (m, 2H), 3.54 (s, 3H), 3.61−3.68 (m, 2H), 5.02−5.04 (m,
2H), 5.29−5.33 (m, 2H), 5.62−5.69 (m, 1H), 7.38−7.41 (m, 3H),
7.53−7.54 (m, 2H).
(3R)-1-[(tert-Butyldimethylsilyl)oxyl]-3-[(tert-butyldiphenyl)oxyl]-
hex-5-ene (11). To a stirred solution of alcohol 10 (386 mg, 1.68
mmol) in anhydrous CH2Cl2 (6.0 mL) was added imidazole (348 mg,
5.12 mmol) followed by TBDPSCl (0.86 mL, 3.3 mmol) at rt. After
C29H35O3, 431.2586).
1
Cryptolaevilactone J (4): pale yellow oil; H and 13C NMR, see
Tables 1 and 2; HRFABMS m/z 431.2585 [M + H]+ (calcd for
C29H35O3, 431.2586).
Cryptolaevilactone K (5): colorless oil; 1H and 13C NMR, see
Tables 1 and 2; HRFABMS m/z 491.2798 [M + H]+ (calcd for
C31H39O5, 491.2797).
H
DOI: 10.1021/acs.jnatprod.8b00732
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
stirring for 4 h, the reaction was quenched with water. The aqueous
phase was extracted with CH2Cl2, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (n-hexane−EtOAc, 30:1) to give
67.5, 75.2, 121.2, 127.6, 127.7, 129.72, 129.75, 133.94, 133.98, 135.8,
135.9, 144.9, 164.4; HRMS-FAB (m/z) [M + H]+ calcd for
C31H47O4Si2, 539.3013; found, 539.3002.
(3S,5R)-3-[(tert-Butyldiphenyl)oxyl]oct-7-ene-1-ol-5-yl Acrylate.
To a solution of 15 (152 mg, 0.283 mmol) in 20:1 THF−H2O
(2.0 mL) was added TsOH·H2O (7.1 mg, 0.037 mmol). The resulting
solution was stirred at rt for 21 h. Saturated NaHCO3 was added, and
the mixture was extracted with EtOAc. The combined organic extracts
were washed with brine, dried over Na2SO4, and concentrated in
under reduced pressure. The residue was purified by silica gel column
chromatography (n-hexane−EtOAc, 5:1) to give the title compound
(118 mg, 99%) as a colorless oil: [α]25D +44 (c 0.3, CHCl3); 1H NMR
(600 MHz, CDCl3) δ 1.07 (s, 1H), 1.76−1.81 (m, 2H), 1.91−2.44
(m, 4H), 3.66−3.73 (m, 2H) 4.18−4.24 (m, 1H), 4.48−4.55 (m,
1H), 4.37 (s, 1H), 5.92 (d, J = 9.6 Hz, 1H), 6.68−6.73 (m, 1H),
7.38−7.47 (m, 6H), 7.67 (d, J = 7.2 Hz, 4H); 13C NMR (600 MHz,
CDCl3) δ 19.3, 26.9, 29.2, 41.5, 50.2, 65.6, 74.3, 121.2, 127.9, 130.04,
130.08, 133.2, 133.3, 135.79, 135.83, 144.9, 163.9, 201.2; HRMS (m/
z) [M + H]+ calcd for C25H33O4Si, 425.2148; found, 425.2136.
(R)-3-[(tert-Butyldiphenylsilyl)oxy]-4-[(R)-6-oxo-3,6-dihydro-2H-
pyran-2-yl]butanal (16). A solution of (3S,5R)-3-[(tert-
butyldiphenyl)oxyl]oct-7-ene-1-ol-5-yl acrylate (83 mg, 0.28 mmol)
in anhydrous CH2Cl2 (4.0 mL) was added to 2-iodoxybenzoic acid
(83 mg, 0.30 mmol) in anhydrous dimethyl sulfoxide (DMSO) (2.0
mL). The mixture was stirred at rt for 11 h and filtered through a pad
of Celite. The organic filtrates were washed with saturated NaHCO3
and brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (n-hexane−EtOAc,
1
silyl ether 11 (759 mg, 97%) as a colorless oil: H NMR (600 MHz,
CDCl3) δ 0.03 (d, J = 3.6 Hz, 6H), 0.83 (s, 9H), 1.68−1.72 (m, 2H),
2.14−2.23 (m, 2H), 3.57−3.67 (m, 2H), 3.91−3.94 (m, 1H), 4.88−
4.96 (m, 2H), 5.69−5.73 (m, 1H), 7.35−7.42 (m, 6H), 7.67 (d, J =
6.0 Hz, 4H).
(S)-5-[(tert-Butyldimethylsilyl)oxy]-3-[(tert-butyldiphenylsilyl)-
oxy]pentanal (12). To a solution of silyl ether 11 (351 mg, 0.750
t
mmol) in BuOH−H2O (3:1, 12.0 mL) were added N-methylmor-
pholine-N-oxide (NMO) (50% in water, 0.48 mL, 0.23 mmol) and
microencapsulated OsO4 (ca. 10%, 93.0 mg, 0.037 mmol). The
resulting solution was stirred at rt for 33 h; then excess solid Na2SO3
was added. The mixture was diluted with EtOAc, and the layers were
separated. The aqueous phase was extracted with EtOAc. The
combined organic phases were washed with brine, dried over Na2SO4,
and concentrated in vacuo. The resulting oil was dissolved in THF−
H2O (3:1, 12.0 mL), to which NaIO4 (470 mg, 2.20 mmol) was
added. The reaction mixture was stirred at rt for 2 h and diluted with
H2O. The whole solution was extracted with EtOAc, washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (n-
hexane−EtOAc, 10:1) to obtain 12 (348 mg, 99%) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 0.05 (d, J = 5.2 Hz, 6H), 0.81 (s, 9H),
1.04 (s, 9H), 1.73−1.83 (m, 2H), 2.48 (ddd, J = 3.2, 6.0, 16 Hz, 1H),
2.58 (ddd, J = 2.4, 5.6, 16 Hz, 1H), 3.53−3.63 (m, 2H), 4.36−4.42
(m, 1H), 7.36−7.45 (m, 6H), 7.66 (d, J = 6.0 Hz, 4H), 9.67 (t, J = 2.4
Hz, 1H).
3:1) to give 16 (77 mg, 96%) as a colorless oil: [α]25 +46 (c 2.0,
D
CHCl3); 1H NMR (600 MHz, CDCl3) δ 1.05 (s, 9H), 1.73−1.79 (m,
1H), 1.89−1.96 (m, 1H), 2.01−2.10 (m, 2H), 2.63−2.68 (m, 1H),
2.78−2.84 (m, 1H), 4.45−4.50 (m, 1H), 4.53−4.60 (m, 1H), 5.93−
5.96 (m, 1H), 6.70−6.75 (m, 1H), 7.38−7.47 (m, 6H), 7.63−7.66
(m, 4H), 9.71 (s 1H); 13C NMR (600 MHz, CDCl3) δ 19.2, 27.0,
29.3, 38.3, 41.2, 59.4, 68.2, 74.8, 121.2, 127.78, 127.81, 129.9, 133.4,
133.6, 135.9, 144.8, 164.1.
(4R, 6S)-8-[(tert-Butyldim ethylsilyl)oxy]-6-[(tert-
butyldiphenylsilyl)oxy]oct-1-en-4-ol (13). To a solution of
(+)-Ipc2B(allyl) (1.0 M, 0.82 mL, 0.82 mmol) in anhydrous Et2O
(6.0 mL) was added dropwise aldehyde 12 (277 mg, 0.589 mmol) in
anhydrous Et2O (4.0 mL) at −78 °C under Ar. The reaction mixture
was stirred for 4 h at −78 °C and quenched with 3N aqueous NaOH
(0.70 mL) and 30 wt % aq H2O2 (0.35 mL). The resulting mixture
was stirred overnight at rt. The mixture was extracted with EtOAc,
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude product (304 mg) was used without
further purification.
(6R)-6-{(2S,E)-2-[(tert-Butyldiphenylsilyl)oxy]-4-hydroxy-8-phe-
nyloct-7-en-1-yl}-5,6-dihydro-2H-pyran-2-one (17). To a stirred
suspension of Mg (turnings) (493 mg, 20.5 mmol) in anhydrous THF
(2.0 mL) was added dropwise a solution of 22 (1.43 g, 6.79 mol) in
anhydrous THF (4.0 mL) at rt and refluxed for 1 h. The resulting
alkenyl Grignard reagent was added dropwise to 16 (51 mg, 0.12
mmol) dissolved in anhydrous THF (1.5 mL) at −40 °C, and the
reaction mixture was stirred at 0 °C for 3 h and at rt for 1 h, then
quenched with saturated aqueous NH4Cl and extracted with EtOAc.
The combined organic phases were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified by column chromatography (n-hexane−EtOAc, 4:1) to give
17 (28 mg, 42%) as a colorless oil. Diastereomeric mixture: 1H NMR
(600 MHz, CDCl3) major δ 1.06 (s, 9H), 1.50−1.55 (m, 2H), 1.59−
1.91 (m, 4H), 1.93−2.03 (m, 2H), 2.19−2.32 (m, 2H), 3.81−3.86
(m, 1H), 4.24−4.30 (m, 1H), 4.51−4.56 (m, 1H), 5.90−5.92 (m,
1H), 6.31−6.21 (m, 1H), 6.37 (t, J = 17.4 Hz, 1H), 6.67−6.70 (m,
1H), 7.19 (t, J = 7.2 Hz 1H), 7.28−7.33 (m, 4H), 7.37−7.47 (m,
6H), 7.65−7.68 (m, 4H): minor δ 1.06 (s, 9H), 1.50−1.55 (m, 2H),
1.59−1.91 (m, 4H), 1.93−2.03 (m, 2H), 2.19−2.32 (m, 2H), 3.81−
3.86 (m, 1H), 4.24−4.30 (m, 1H), 4.38−4.42 (m, 1H), 5.87−5.89
(m, 1H), 6.31−6.21 (m, 1H), 6.37 (t, J = 17.4 Hz, 1H), 6.61−6.64
(m, 1H), 7.19 (t, J = 7.2 Hz 1H), 7.28−7.33 (m, 4H), 7.37−7.47 (m,
6H), 7.65−7.68 (m, 4H).
(3S,5R)-1-[(tert-Butyldimethylsilyl)oxyl]-3-[(tert-butyldiphenyl)-
oxyl]oct-7-ene-5-yl Acrylate (14). To a solution of alcohol 13 (304
mg, 0.594 mmol) in anhydrous CH2Cl2 (4.0 mL) at 0 °C were added
Et3N (0.42 mL, 3.0 mmol) and acroylyl chloride (0.20 mL, 2.5
mmol). The reaction mixture was stirred at 0 °C for 2 h and diluted
with CH2Cl2 and saturated aqueous NaHCO3. The mixture was
extracted with CH2Cl2. The combined organic phases were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (n-hexane−
Et2O, 10:1) to give ester 14 (246 mg, 74% in 2 steps) as a colorless
1
oil: H NMR (600 MHz, CDCl3) δ −0.04 (d, J = 4.2 Hz, 6H), 0.83
(s, 9H), 1.05 (s, 9H), 1.69−1.83 (m, 4H), 2.08−2.21 (m, 2H), 3.63
(ddt, J = 17.2, 6.8, 3.2 Hz, 2H), 3.93−3.97 (m, 1H), 4.91−4.97 (m,
2H), 5.06−5.10 (m, 1H), 5.54−5.63 (m, 1H), 5.73 (d, J = 10.8 Hz,
1H), 5.93 (dd, J = 10.8, 17.6 Hz, 1H), 6.23 (d, J = 17.2 Hz, 1H),
7.35−7.44 (m, 6H), 7.65−7.69 (m, 4H).
(4R, 6S)-8-[(tert-Butyldim ethylsilyl)oxy]-6-[(tert-
butyldiphenylsilyl)oxy]oct-1-en-4-yl Acrylate (15). To a solution of
14 (99 mg, 0.18 mmol) in degassed CH2Cl2 (25 mL) at rt was added
the second-generation Grubbs catalyst (13 mg, 0.017 mmol). The
reaction mixture was refluxed for 3 h. The solvent was evaporated and
the residue was purified by silica gel column chromatography (n-
hexane−EtOAc, 10:1) to give 15 (93 mg, 96%) as a pale, yellow oil:
[α]25D +47 (c 2.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ −0.03 (d,
J = 2.0, 6H), 0.82 (s, 9H), 1.05 (s, 9H), 1.71−1.91 (m, 4H), 1.95−
2.05 (m, 2H), 3.45−3.51 (m, 2H), 3.58−3.59 (m, 2H), 4.11−4.17
(m, 1H), 4.51−4.58 (m, 1H), 5.90−5.93 (m, 1H), 6.64−6.68 (m,
1H), 7.37−7.45 (m, 6H), 7.63−7.67 (m, 4H); 13C NMR (600 MHz,
CDCl3) δ −5.45, −5.42, 18.2, 19.4, 25.9, 27.0, 29.1, 39.4, 41.2 59.4,
(R)-6-{(R,E)-2-[(tert-Butyldiphenylsilyl)oxy]-4-oxo-8-phenyloct-7-
en-1-yl}-5,6-dihydro-2H-pyran-2-one (18). A solution of alcohol 17
(16 mg, 0.028 mmol) in anhydrous CH2Cl2 (4.0 mL) was added to
IBX (30 mg, 0.107 mmol) in anhydrous DMSO (2.0 mL). The
mixture was stirred at rt for 4 h and filtered through a pad of Celite.
The combined organic filtrates were washed with saturated aqueous
NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by silica gel column chromatography (n-
hexane−EtOAc, 3:1) to give 18 (13 mg, 96%) as a colorless oil:
1
[α]25 +44 (c 0.4, CHCl3); H NMR (600 MHz, CDCl3) δ 1.04 (s,
D
I
DOI: 10.1021/acs.jnatprod.8b00732
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
1H), 1.69−1.73 (m, 1H), 1.83−1.88 (m, 1H), 1.97−2.07 (m, 2H),
2.36−2.39 (m, 2H), 2.45−2.50 (m, 1H), 2.58−2.64 (m, 1H), 2.67
(dd, J = 4.8, 16.8 Hz, 1H), 2.85 (dd, J = 7.2, 16.2 Hz, 1H), 4.41−4.53
(m, 1H), 4.59−4.64 (m, 1H), 5.91−5.93 (m, 1H), 6.01−6.14 (m,
1H), 6.34 (d, J = 15.6 Hz, 1H), 6.68−6.71 (m, 1H), 7.18−7.21 (m,
1H), 7.28−7.30 (m, 4H), 7.36−7.45 (m, 6H), 7.62−7.65 (m, 4H);
13C NMR (600 MHz, CDCl3) δ 19.3, 26.7, 27.0, 41.0, 43.3, 49.2, 66.4,
74.5, 121.1, 126.0, 127.0, 127.77, 127.82, 128.4,128.9, 129.94, 129.97,
130.6, 133.49, 133.54, 135.8, 145.1, 164.1, 208.5; HRMS (m/z) [M +
H]+ calcd for C35H41O4Si, 553.2774; found, 553.2739.
Cryptolaevilactone M (7). To a stirred solution of 18 (4.6 mg, 8.3
μmol) in THF (1.0 mL) was added TBAF (1.0 M in THF) (9 μL, 9
μmol) at 0 °C. The reaction mixture was stirred for 40 min at the
same temperature. HOAc (0.4 μL, 7 μmol) was added, and upon
stirring for 35 min, additional TBAF (1.0 M in THF) (27 μL, 27
μmol) and HOAc (1.5 μL, 26 μmol) were added. The reaction
mixture was warmed to rt over 25 min, stirred for 19 h, and quenched
with saturated NaHCO3. The aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine and
dried over Na2SO4. The filtrate was concentrated under reduced
pressure, and the resulting residue was purified by HPLC to give 7 as
with the CAM-B3LYP functional and TZVP basis set. The calculation
was performed using the conformers within 2 kcal/mol predicted in
MeCN. The solvent effect was introduced by the conductor-like
polarizable continuum model (CPCM). The DFT optimization and
TDDFT-ECD calculation were performed using Gaussian09
(Gaussian, Inc., Wallingford, CT, USA). The calculated spectrum
was displayed using GaussView 5.0.920 with the peak half-width at
half-height being 0.333 eV. The Boltzmann-averaged spectrum at
298.15 K was calculated using Excel 2016 (Microsoft Co., Redmond,
WA, USA). The calculations were reoptimized according to the
literature.33
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.8b00732.
NMR spectra for 1−8, experimental details for the
synthesis of 7, and comparison of 1H NMR spectrum for
synthesized and isolated 7 (PDF)
a colorless solid (1.6 mg, 61%), which cyclized gradually to form
1
compound 19. 7: [α]25 +49 (c 0.03, CHCl3); H NMR (600 MHz,
D
AUTHOR INFORMATION
Corresponding Author
*Tel: +81-76-264-6305. E-mail: kngoto@p.kanazawa-u.ac.jp.
CDCl3) δ 1.79−1.83 (m, 1H), 2.00−2.05 (m, 1H), 2.41−2.43 (m,
2H), 2.48−2.52 (m, 2H), 2.65 (t, J = 7.2 Hz, 2H), 2.70−2.71 (m,
2H), 3.27 (d, J = 3.0 Hz, 1H), 4.30−4.33 (m, 1H), 4.69−4.73 (m,
1H), 6.02−6.04 (m, 1H), 6.15−6.20 (m, 1H), 6.41 (d, J = 15.6 Hz,
1H), 6.88−6.91 (m, 1H), 7.20−7.22 (m, 1H), 7.28−7.34 (m, 1H);
HRMS (m/z) [M + H]+ calcd for C19H23O4, 315.1596; found,
■
ORCID
Yohei Saito: 0000-0003-2313-8339
Shuichi Fukuyoshi: 0000-0002-9015-0920
Katsunori Miyake: 0000-0001-6199-8781
David J. Newman: 0000-0002-4959-2428
Barry R. O’Keefe: 0000-0003-0772-4856
Kuo-Hsiung Lee: 0000-0002-6562-0070
Kyoko Nakagawa-Goto: 0000-0002-1642-6538
315.1595.
1
Compound 19: [α]25 +32 (c 0.1, CHCl3); H NMR (600 MHz,
D
CDCl3) δ 1.61−1.66 (m, 1H), 1.89−1.93 (m, 1H), 1.97−2.01 (m,
1H), 2.05−2.10 (m, 1H), 2.46−2.51 (m, 3H), 2.62 (t, J = 7.2 Hz,
2H), 2.69 (dd, J = 7.8, 15.6 Hz, 1H), 2.77 (dd, J = 5.4, 19.2 Hz, 1H),
2.91 (d, J = 18.6 Hz, 1H), 4.28−4.33 (m, 2H), 4.87−4.90 (m, 1H),
6.18 (dt, J = 6.6, 15.6 Hz, 1H), 6.40 (d, J = 16.2 Hz, 1H), 7.18−7.22
(m, 1H), 7.27−7.34 (m, 4H); 13C NMR (400 MHz, CDCl3) δ 26.8,
29.5, 36.2, 36.3, 43.2, 48.4, 62.6, 65.9, 72.6, 126.0, 127.1, 128.5, 128.7,
130.8, 169.3, 206.8; HRMS (m/z) [M + H]+ calcd for C19H23O4,
315.1596; found, 315.1579.
Author Contributions
#Y.M. and M.N. contributed equally to this work.
Notes
(E)-4-Phenylbut-3-en-1-ol (21). To a solution of trans-styrylacetic
acid (20, 201 mg, 1.24 mmol) in anhydrous THF (6.0 mL) was added
dropwise lithium aluminum hydride (LAH, 1.9 mL, 1.9 mmol, 1 M
solution in THF) at 0 °C. The reaction was stirred at 0 °C for 20 min
and at rt for 60 min, then quenched with H2O, followed by a 10%
NaOH aqueous solution. The reaction mixture was filtered through
Celite, extracted with EtOAc, washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (n-hexane−EtOAc, 5:1) to give 21
(160 mg, 87%) as a yellow oil: 1H NMR (600 MHz, CDCl3) δ 2.48−
2.51 (m, 2H), 3.77 (t, J = 6.0 Hz, 2H), 6.21 (dt, J = 7.2, 15.6 Hz, 1H),
6.51 (d, J = 15.6 Hz, 1H), 7.18−7.23 (m, 1H), 7.30 (t, J = 7.8 Hz,
2H), 7.36 (d, J = 7.2 Hz, 2H).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate the critical comments, suggestions, and editing
of the manuscript by Dr. Susan L. Morris-Natschke at the
University of North Carolina at Chapel Hill. This work was
supported by JSPS KAKENHI grant numbers 25293024 and
18H02583 awarded to K.N.G. Partial support is also
acknowledged from NIH Grant CA177584 awarded to
K.H.L. We also thank the Natural Products Support Group,
Leidos Biomedical Inc., for plant extraction. This project has
been funded in whole or in part with federal funds from the
National Cancer Institute, National Institutes of Health
(NIH), under contract HHSN261200800001E. The content
of this publication does not necessarily reflect the views or
policies of the Department of Health and Human Services, nor
does mention of trade names, commercial products, or
organizations imply endorsement by the U.S. Government.
This project has also been supported in part by the Intramural
Research Program of the NIH, National Cancer Institute,
Center for Cancer Research.
(E)-(4-Bromobut-1-en-1-yl)benzene (22). To a solution of CBr4
(5.3 g, 16 mmol) in CH2Cl2 (25 mL) was added PPh3 (4.2 g, 16
mmol) at rt for 10 min. 21 (789 mg, 5.33 mmol) in CH2Cl2 was
added dropwise over 15 min and stirred for 1 h. The reaction mixture
was poured into water and extracted with CH2Cl2. The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (n-hexane−EtOAc, 3:1) to give 22
1
(930 mg, 83%) as a colorless oil: H NMR (600 MHz, CDCl3) δ
2.76−2.80 (m, 2H), 3.48 (t, J = 7.2 Hz, 2H), 6.19 (dt, J = 7.2, 15.6
Hz, 1H), 6.49 (d, J = 16.2 Hz, 1H), 7.22−7.24 (m, 1H), 7.31 (t, J =
7.8 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H).
Calculation of ECD Spectra. Preliminary conformational analysis
of each compound was performed by using CONFLEX8 with the
MMFF94 force field. The conformers were further optimized in
MeCN by the DFT method with the B3LYP functional and 6-31(d)
basis set. The ECD spectrum was calculated by the TDDFT method
REFERENCES
■
(1) Franca, N. C.; Gottlieb, O. R.; Suarez, A. M. P. Phytochemistry
1973, 12, 1182−1184.
(2) Davies-Coleman, M. T.; Rivett, D. E. A. Progress in the Chemistry
of Organic Natural Products 1989, 55, 1−35.
J
DOI: 10.1021/acs.jnatprod.8b00732
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
(3) Govindachari, T. R.; Parthasarathy, P. C. Tetrahedron Lett. 1972,
13, 3419−3420.
(4) Maddry, J. A.; Joshi, B. S.; Newton, M. G.; Pelletier, S. W.;
Partasarathy, P. C. Tetrahedron Lett. 1985, 26, 5491−6492.
(5) Dumontet, V.; Hung, N. V.; Adeline, M. T.; Riche, C.; Chiaroni,
́
́
A.; Sevenet, T.; Gueritte, F. J. Nat. Prod. 2004, 67, 858−862.
(6) Drewes, S. E.; Horn, M. M.; Wijewardene, C. S. Phytochemistry
1996, 41, 333−334.
(7) Novaes, L. F. T.; Sarotti, A. M.; Pilli, R. A. RSC Adv. 2015, 5,
53471−53476.
(8) Cavalheiro, A. J.; Yoshida, M. Phytochemistry 2000, 53, 811−819.
(9) Meragelman, T. L.; Scudiero, D. A.; Davis, R. E.; Staudt, L. M.;
McCloud, T. G.; Cardellina, J. H., II; Shoemaker, R. H. J. Nat. Prod.
2009, 72, 336−339.
(10) Grkovic, T.; Blees, J. S.; Colburn, N. H.; Schmid, T.; Thomas,
C. L.; Henrich, C. J.; McMahon, J. B.; Gustafson, K. R. J. Nat. Prod.
2011, 74, 1015−1020.
(11) Yang, B. Y.; Kong, L. Y.; Wang, X. B.; Zhang, Y. M.; Li, R. J.;
Yang, M. H.; Luo, J. G. J. Nat. Prod. 2016, 79, 196−203.
(12) Davis, R. A.; Demirkiran, O.; Skyes, M. L.; Avery, V. M.;
Suraweera, L.; Fechner, G. A.; Quinn, R. J. Bioorg. Med. Chem. Lett.
2010, 20, 4057−4059.
(13) Liu, Y.; Rakotondraibe, H.; Brodie, P. J.; Wiley, J. D.; Cassera,
M. B.; Miller, J. S.; Ratovoson, F.; Rakotobe, E.; Rasamison, V. E.;
Kingston, D. G. I. J. Nat. Prod. 2015, 78, 1330−1338.
(14) Tsurumi, F.; Miura, Y.; Saito, Y.; Miyake, K.; Fujie, T.;
Newman, D. J.; O’Keefe, B. R.; Lee, K. H.; Nakagawa-Goto, K. Org.
Lett. 2018, 20, 2282−2286.
(15) Aimaiti, S.; Suzuki, A.; Saito, Y.; Fukuyoshi, S.; Goto, M.;
Miyake, K.; Newman, D. J.; O’Keefe, B. R.; Lee, K. H.; Nakagawa-
Goto, K. J. J. Org. Chem. 2018, 83, 951−963.
(16) Chou, T. H.; Chen, J. J.; Lee, S. J.; Chiang, M. Y.; Yang, C. W.;
Chen, I. S. J. Nat. Prod. 2010, 73, 1470−1475.
(17) Feng, R.; Wang, T.; Wei, W.; Tan, R. X.; Ge, H. M.
Phytochemistry 2013, 90, 147−153.
(18) Feng, R.; Guo, Z. K.; Yan, C. M.; Li, E. G.; Tan, R. X.; Ge, H.
M. Phytochemistry 2012, 76, 98−105.
(19) Ren, Y.; Yuan, C.; Qian, Y.; Chai, H. B.; Chen, X.; Goetz, M.;
Kinghorn, A. D. J. Nat. Prod. 2014, 77, 550−556.
(20) Dumontet, V.; Gaspard, C.; Hung, N. V.; Fahy, J.; Tchertanov,
́
́
L.; Sevenet, T.; Gueritte, F. Tetrahedron 2001, 57, 6189−6196.
(21) Wu, T. S.; Lin, F. W. J. Nat. Prod. 2001, 64, 1404−1407.
(22) Lin, F. W.; Wang, J. J.; Wu, T. S. Chem. Pharm. Bull. 2002, 50,
157−159.
(23) Lin, F. W.; Wu, P. L.; Wu, T. S. Chem. Pharm. Bull. 2001, 49,
1292−1294.
(24) Heyman, H.; Tezuka, Y.; Kikuchi, T.; Supriyatna, S. Chem.
Pharm. Bull. 1994, 42, 138−146.
́
(25) Busch, J.; Grether, Y.; Ochs, D.; Sequin, U. J. Nat. Prod. 1998,
61, 591−597.
(26) Stærk, D.; Lykkeberg, A. K.; Christensen, J.; Budnik, B. A.; Abe,
F.; Jaroszewski, J. W. J. Nat. Prod. 2002, 65, 1299−1302.
(27) Lee, S. S.; Liu, Y. C.; Chen, C. H. J. Nat. Prod. 1990, 53, 1267−
1271.
(28) Cutillo, F.; D’Abrosca, B.; DellaGreca, M.; Marino, C. D.;
Golino, A.; Previtera, L.; Zarrelli, A. Phytochemistry 2003, 64, 1381−
1387.
(29) Romani, A.; Zuccaccia, C.; Cleenti, C. Dyes Pigm. 2006, 71,
218−223.
(30) Davis, A. L.; Cai, Y.; Davies, A. P.; Lewis, J. R. Magn. Reson.
Chem. 1996, 34, 887−890.
̋
́
́
(31) Molnar, P.; Deli, J.; Osz, E.; Zsila, F.; Simonyi, M.; Toth, G.
Helv. Chim. Acta 2004, 87, 2159−2168.
(32) Li, S. H.; Zhang, H. J.; Niu, X. M.; Yao, P.; Sun, H. D.; Fong, H.
H. S. J. Nat. Prod. 2003, 66, 1002−1005.
(33) Pascitelli, G.; Bruhn, T. Chirality 2016, 28, 466−474.
(34) Zhang, J.; Li, Y.; Wang, W.; She, X.; Pan, X. J. Org. Chem. 2006,
71, 2918−2921.
(35) Perez, C.; Trujillo, J. J. Nat. Prod. 1996, 59, 69−72.
K
DOI: 10.1021/acs.jnatprod.8b00732
J. Nat. Prod. XXXX, XXX, XXX−XXX