Preparation of oxocene terpenes. the first enantiospecific synthesis of cytotoxic arenaran A

Article abstract of DOI:10.1039/c6ob01640e

The first syntheses of cytotoxic marine arenarans A and B starting from commercial (-)-sclareol are reported. The oxocene ring of the target compound is formed via ring-closing metathesis, a process that depends on certain structural requirements. The tra

Full text of DOI:10.1039/c6ob01640e

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DOI: 10.1039/C6OB01640E.
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DOI: 10.1039/C6OB01640E
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Preparation of oxocene terpenes. First enantiospecific synthesis
of cytotoxic arenaran A
Received 00th January 20xx,
Accepted 00th January 20xx
Alejandro Torres,a Pilar Gutierrez,a Ramón Alvarez‐Manzaneda,b Rachid Chahboun*a and
Enrique Alvarez‐Manzaneda*a
DOI: 10.1039/x0xx00000x
First syntheses of cytotoxic marine arenarans A and B starting from commercial (‐)‐sclareol, are reported. The oxocene ring
of the target compound is formed via a ring‐closing metathesis, a process that depends on certain structural requirements.
The trans‐fused structure of the natural product is confirmed by comparison with the cis‐fused isomer, also synthesized.
This synthetic strategy is also aplicable to the synthesis of other oxocene terpenes.
www.rsc.org/
some cases, no syntheses of these oxocane terpenes have yet
Introduction
Although terpenes containing eight‐membered ether rings are
been reported. The structure of arenaran A (
established in 2D NMR experiments, utilizing mainly H‐C COSY
correlations ( = 140 and = 9 Hz); however, this result is
insufficient to characterise the trans‐fused union assigned.
1) has been
J
J
infrequent in nature, their biological activities are of interest.
Arenaran A (
from the marine sponge Dysidea arenaria, belong to this type
of compound. Compound is in vitro‐active against several
types of cancer cells, with reported IC50 values ( g/mL) of 9.51
(A‐549, human lung carcinoma), 9.11 (HT‐29, human colon
adenocarcinoma), 5.28 (HCT‐29, human colon
1) and B (2), two sesquiterpene ethers isolated
Moreover, the absolute configuration of natural terpene
remains unknown.
1
1
μ
Results and discussion
These considerations, together with the possibility of
preparing large quantities of arenaran A ( ) in order to conduct
an in‐depth study of its biological activity, encouraged us to
develop a synthetic route towards compound and related
adenocarcinoma) and 3.17 (P‐388 murine leukemia). Another
example of oxocane terpene is the labdane type brominated
diterpene 3, isolated from the red alga Laurencia obtuse.2
1
1
terpenes. In this respect, the only relevant antecedent is a
study aimed at the synthesis of arenaran A reported by
Reggelin et al.3 These authors essayed the construction of the
O
13
1
8
bicyclic oxocene structure of
1 based on the intramolecular
O
O
O
2
3
9
7
attack of an allyl alcohol on an alkenyl sulfoximine. The failure
of their attempt highlights the difficulty of forming an eight‐
membered ring. In view of this outcome, we planned to create
the oxocene ring via a ring‐closing metathesis (RCM) process,
as shown in Scheme 1.
O
6
11
10
12
Br
H
H
4
H
14
5
15
3
2
1
Figure 1. Natural oxocane terpenes.
Despite the rare structure of this type of compound, which is
biogenetically related to aplysistatins and other bioactive
metabolites, and the relevant biological activity observed in
O
OH
O
RCM
H
1
5
4
a. Departamento de Química Orgánica, Facultad de Ciencias, Instituto de
Biotecnología, Universidad de Granada, 18071 Granada, Spain.
E‐mail: rachid@ugr.es; eamr@ugr.es
Scheme 1. Retrosynthesis of arenaran A (
1
)
via ring‐closing metathesis.
b. Area de Química Orgánica, Departamento de Química y Física, Universidad de
Almería, 04120 Almería, Spain
Electronic Supplementary Information (ESI) available: Copy of 1H and 13C NMR
spectra for all new compounds. See DOI: 10.1039/x0xx00000x
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Scheme 3. Synthesis of epi‐arenaran A (13) from alcohol 10
.
In order to determine the reaction conditions, we first
investigated the use of ‐ionone ( ) as a starting material.
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DOI: 10.1039/C6OB01640E
At this point, it is very important to note that the preparation
α
6
Considering the chemical behaviour of compound
6 previously
of alcohol
), from
diatereoisomer of epoxyketone
5
α
in enantiopure form, the precursor of arenaran A
‐ionone ( ) can be achieved via the corresponding
, with the epoxy group on the
side; however, the preparation of this epoxyketone from
reported,4 the utilization of this terpene as the synthetic
(1
6
precursor should provide alcohol 10, the epimer of compound
8
5
, and consequently the complete sequence should lead to the
corresponding cis‐fused epi‐arenanan A (13). Scheme 2 shows
the synthesis of alcohol 10 from ‐ionone ( ). Epoxydation of
dihydro‐ ‐ionone ( ) gave the expected epoxyketone , which
after methylenation and treatment with LiAlH4 provided
alcohol 10
α
α‐
ionone (6), reported by Serra, involves a very long synthetic
α
6
sequence (10 steps), including a low yield lipase‐mediated
α
7
8
acetylation reaction.4
Taking into account these difficulties, we investigated the
.
preparation of enantiopure alcohol
for obtaining this alcohol from commercial (+)‐sclareolide (16
is depicted in scheme 4. Alcohol is obtained from ketoester
5. A first synthetic proposal
)
5
O
MCPBA
H2, Ni Raney
14, resulting from the Baeyer‐Villiger oxidation of diketone
derived from alkene 15, which is easily prepared from lactone
THF, rt, 1 h
(83%)
CH2Cl2, 0 ºC
30 min (86%)
O
O
O
16.
6
7
8
MePh3P+ Br-
n-BuLi, THF
0 ºC, 2.5 h
(91%)
O
OH
O
O
LiAlH4, THF
O
OH
0 ºC - reflux
30 min (85%)
O
10
9
H
H
O
14
15
from (+)‐sclareolide (16
5
16
Scheme 4. Retrosynthesis of alcohol
5
)
Scheme 2. Synthesis of alcohol 10 from
α
‐ionone (
6
).
This alcohol was then transformed into epi‐arenaran A (13),
following the above retrosynthetic plan (Scheme 3). The
reaction of alcohol 10 with allyl bromide under basic
conditions leads to ether 11, which unexpectedly failed to give
the desired RCM after treatment with second‐generation
Grubbs catalyst, instead generating alcohol 10. Under these
reaction conditions, ether 12, derived from dimethylallyl
bromide, underwent the desired ring‐closing metathesis,
affording compound 13, the cis‐fused stereoisomer of
arenaran A.
Scheme 5 shows the synthetic sequence for the intended
synthesis of ketoester 14 from lactone 16. Reduction of iodide
17 with Raney Ni, following a procedure developed in our
laboratory, gave alkene 15, which was then converted into
diketone 18. However, all attempts at obtaining the desired
ketoester 14, via a Baeyer‐Villiger oxidation of diketone
utilizing a variety of reaction conditions were unsuccessful,
producing instead the ketoester 19. These results highlight the
difficulty of achieving oxidation of the ketone group linked to
the quaternary carbon, probably due to steric hindrance. This
outcome contrasts with that of the related, but more rigid 1‐
decalones;5 however, the possibility of utilizing these ketones
NaH, THF, Allyl bromide
O
OH
as a starting material for preparing alcohol
5 must be
THF, reflux
discarded due to the further difficulties arising from the
tendency of the subsequent reduction products to dehydrate,
affording bicyclic enol ethers.
24 h (93%)
2nd generation
Grubbs catalyst
11
10
CH2Cl2, reflux
48 h
NaH, THF
Br
reflux
24 h (92%)
2nd generation
Grubbs catalyst
O
O
CH2Cl2, reflux
48 h (84%)
H
13
12
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DOI: 10.1039/C6OB01640E
O
NaH, THF
OH
Allyl bromide
reflux 20 h
(90%)
5
4
NaH, THF
2nd generation
Grubbs catalyst
CH2Cl2, reflux
2 h
Br
reflux
24 h (92%)
O
2nd generation
Grubbs catalyst
O
O
MCPBA
O
CH2Cl2, reflux
3 h (91%)
CH2Cl2, 0ºC
1 h (93%)
H
Scheme 5. Attempts at preparing ketoester 14 from (+)‐sclareolide (16
)
2
1
23
Scheme 7. Synthesis of arenaran A (1) and B (2) from alcohol 5.
The above difficulties were circumvented by utilizing
commercial (‐)‐sclareol (20) as a starting material. Thus,
alcohol
5 was prepared from this diterpene, via ketoester 22,
As mentioned above, the structural elucidation performed by
Crews et al. for the natural arenaran A, based on 2D NMR
experiments, does not allow us to establish unequivocally the
trans‐fused union proposed by these authors.1 However, after
preparing both stereoisomers, we will be able to confirm this
resulting from the Baeyer‐Villiger oxidation of ketoaldehyde
21, utilizing a procedure developed in our laboratory7 (see
Scheme 6). At this point, it is interesting to note the different
behaviour of the aldehyde group attached to the quaternary
carbon, present in the compound 21, from that of the ketone
group joined to the same carbon atom, which has compound
18; the first of these undergoes Baeyer‐Villiger oxidation in
good yield, under the usual reaction conditions, and so
methylenation of ketoester 22 leads in good yield to the
1
proposal. Tables 1 and 2 show the 13C and H NMR chemical
shifts for epi‐arenaran A (13) (with the cis‐fused union), for the
synthetic arenaran A (
arenaran A. NMR data for the synthetic and natural arenarans
B ( ) are shown in table 3.
1), reported here, and for the natural
2
desired alcohol 5.
Table 1. 13C NMR chemical shifts for epi‐arenaran A (13) and for the synthetic and
natural arenarans A (1).
epi‐Arenaran A
(13)a
Synthetic
Synthetic
Natural
Arenaran A (1)a Arenaran A (1)b Arenaran A (1)b
OH
OH
Ref. 7
CHO
OCHO
O
MCPBA
(ref. 1)
CH2Cl2, reflux
1.5 h (93%)
(Ref. 7)
140.6 (C)
123.6 (CH)
77.4 (C)
56.4 (CH2)
55.5 (CH)
42.8 (CH2)
41.9 (CH2)
35.5 (CH2)
34.1 (C)
31.4 (CH3)
25.2 (CH2)
24.6 (CH3)
21.1 (CH3)
18.0 (CH2)
15.1 (CH3)
132.9 (C)
123.3 (CH2)
80.2 (C)
61.1 (CH)
45.4 (CH2)
41.9 (CH)
35.2 (CH3)
34.0 (C)
32.3(CH2)
28.9 (CH3)
25.0(CH2)
24.1 (CH3)
21.9 (CH2)
21.0 (CH2)
19.7 (CH3)
133.1 (C)
124.7 (CH)
79.5 (C)
61.8 (CH2)
46.1 (CH)
42.6 (CH2)
35.7 (CH2)
34.5 (C)
33.4 (CH3)
29.7 (CH2)
26.4 (CH3)
24.9 (CH2)
23.2 (CH3)
22.1 (CH3)
20.5 (CH2)
132.8 (C)
124.5 (CH)
79.3 (C)
61.5 (CH2)
45.9 (CH)
42.4 (CH2)
35.5 (CH2)
34.3 (C)
33.1 (CH3)
29.5 (CH2)
26.1 (CH3)
24.7 (CH2)
23.0 (CH3)
21.9 (CH3)
20.1 (CH2)
6 steps
(67%)
H
O
20
22
21
MePh3P+ Br-
n-BuLi, THF
0 ºC, 3 h (86%)
OH
5
Scheme 6. Synthesis of alcohol
5 from (‐)‐sclareol (20)
Alcohol
similar procedure to that utilized for the cis‐fused isomer 13.
First, the O‐allyl ether was prepared, but this dialkene also
5 was then transformed into arenaran A (1) following a
4
aCD3OD, bC6D6
failed to give the metathesis process. However, the O‐
dimethylallyl ether 23 underwent the desired reaction,
affording arenaran A (
that ether 23 undergoes the RCM much faster than its epimer
12. The further epoxidation of compound gave arenaran B
) (Scheme 7).
1). At this point it is important to note
1
(2
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Table 2. 1H NMR chemical shifts for epi‐arenaran A (13) and for the synthetic and
natural arenarans A (1).
As can be seen in tables 1 and 2, there is an excellent
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correlation of spectral data between tDhOeI:s1y0n.1t0h3e9/tCic6OaBn0d16t4h0eE
natural arenaran A (1), while those of the cis‐fused
steroisomer (epi‐arenaran A, 13) are very discordant. This
finding corroborates the trans‐fused stereochemistry
proposed for natural arenaran A by Crews et al. On the other
epi‐Arenaran A
(13)a
Synthetic
Synthetic
Natural
Arenaran A (1)a Arenaran A (1)b Arenaran A (1)b
(ref. 1)
5.06 (br s)
4.06 (br s)
hand, the
arenaran A has been confirmed on the basis of the observed
NOE effect between Me‐12 ( 1.68) and H‐2 ( 5.07) (see
Electronic Supplementary Information). The NMR data of the
synthetic and natural arenarans B ( ), which are placed in
order of decreasing in table 3, showed some discrepancies.
In order to dispel doubts, a thorough study on the structure of
synthetic arenaran B ( ) has been conducted. This includes 1D
Z configuration of the carbon‐carbon double bond of
5.43 (t, J=6.9)
3.96 (dd,
J=7.0,13.8)
3.76 (dd,
5.15 (br s)
4.22 (dd,
J=2.1,18.4)
4.03 (d, J=18.4)
5.07 (br s)
4.11 (br s)
δ
δ
3.68 (ddd,
J=19.5, 11.3)
3.67 (ddd,
J=19.9,11.5.
1.3)
1.68 (m)
1.67 (s)
J=6.9,13.8)
2
δ
2.40‐2.03 (m)
1.96 (ddd,
J=3.1,13.1)
1.87 (m)
1.76 (ddd,
J=3.3,13.4)
1.71 (s)
1.45‐1.40 (m)
1.34 (d, J=3.0)
1.20 (m)
3.37 (m)
1.76 (ddd,
J=4.5,12.7)
1.69 (s)
1.68 (m)
1.68 (s)
2
and 2D NMR spectra at 500 MHz (TOCSY, COSY, HSQC, HMBC
and NOESY experiments). This allowed us to corroborate
unequivocally the proposed structure for this compound, and
1.63 (m)
1.63 (m)
1.65 (m)
to assign correctly the 1H and 13C NMR signals (Table 4). The
β
1.61‐1.58 (m)
1.55 (m)
1.51 (m)
1.62 (m)
1.52 (m)
1.35 (m)
1.31 (m)
1.62 (m)
1.51 (m)
1.34 (m)
1.31 (m)
disposition of the epoxide group has been confirmed on the
basis of the observed NOE effect between H‐2 ( 2.79) and H‐6
1.50). All these experiments are included in the Electronic
Supplementary Information. With respect to the
δ
(δ
1.46 (dt,
J=3.0,13.5)
1.35‐1.32 (m)
1.25 (s)
absolute stereochemistry of natural arenaran A, it should
be noted that the optical rotation for the natural
1.13 (s)
1.08 (dd,
J=4.0,13.4)
1.03 (s)
1.29 (s)
1.25 (m)
1.26 (s)
1.25 (m)
1.16 (ddd,
J=4.1,13.3)
0.91 (s)
0.86 (s)
0.78 (s)
0.85 (s)
0.79 (s)
Table 4. 1H and 13C NMR assignments for synthetic arenaran B (2).
0.89 (s)
Carbon or
Proton
1
1H
13C
aCD3OD, bC6D6
4.03 (dd, J=15.9, 2.3)
3.90 (d, J=15.9)
2.79 (d, J=2.3)
58.2 (CH2)
Table 3. 1H and 13C NMR data in CDCl3 for the synthetic and natural arenarans B (2).
2
3
4
64.2 (CH)
60.9 (C)
32.0 (CH2)
Synthetic
Arenaran B (2)
Natural
Arenaran B (2)
(ref. 1)
4.02 (dd,
J=15.6, 2.1)
3.89 (d, J=15.6)
2.79 (d, J=2.1)
2.41 (dt,
J=13.5, 5.1)
1.86 (dt,
J=13.5, 3.6)
1.67 (m)
1.58 (m)
1.50 (m)
1.45 (m)
1.40 (m), 1.21
(m)
Synthetic
Arenaran B (2)
Natural
Arenaran B (2)
(ref. 1)
2.43 (ddd, J=13.4, 4.3, 4.3)
1.88 (ddd, J=13.4, 13.4, 4.3)
1.68 (tt, J=13.4, 4.3)
1.61 (tdd, J=13.4, 4.3, 4.3)
1.50 (dd, J=13.4, 4.3)
4.02 (dd,
J=17.6, 1.7)
3.90 (d, J=17.6)
2.79 (s)
80.0 (C)
80.0 (C)
5
22.2 (CH2)
64.1 (CH)
60.8 (C)
58.1 (CH2)
64.1 (CH)
60.8 (C)
58.2 (CH2)
6
7
8
44.9 (CH)
80.2 (C)
36.1 (CH2)
2.42 (dt,
J=13.4, 4.9)
1.86 (dt,
J=13.2, 3.9)
1.67 (m)
1.58 (m)
1.50 (m)
1.45 (m)
1.40 (m), 1.21
(m)
1.35 (m)
1.29 (s)
1.16 (s)
0.98 (s)
0.85 (s)
1.72 (ddd, J=13.5, 3.8, 3.8)
1.33 (ddd, J=13.5, 13.5, 3.8)
1.55 (dp, J=13.5, 3.8)
1.45 (ddd, J=13.5, 3.8, 3.8)
1.39 (ddd, J=13.5, 3.8, 3.8)
1.19 (ddd, J=13.5, 13.5, 3.8)
44.7 (CH)
45.0 (CH)
9
20.0 (CH2)
42.4 (CH2)
42.2 (CH2)
35.9 ((CH2)
34.7 (C)
33.2 (CH3)
31.8 (CH2)
42.4 (CH2)
36.0 ((CH2)
35.5 (C)
33.3 (CH3)
32.7 (CH2)
10
11
12
13
14
15
34.8 (C)
1.30 (s)
1.16 (s)
0.85 (s)
0.98 (s)
23.1 (CH3)
22.7 (CH3)
21.7 (CH3)
33.4 (CH3)
1.35 (m)
1.21 (s)
1.16 (s)
0.97 (s)
22.9 (CH3)
22.5 (CH3)
22.0 (CH2)
21.5 (CH3)
19.9 (CH2)
23.0 (CH3)
22.6 (CH3)
22.1 (CH2)
21.9 (CH3)
20.0 (CH2)
0.84 (s)
compound ([α]
25: +154.0; c 0.01, CHCl3) is very discordant
D
from that measured in our laboratory for synthetic arenaran A
([
25: ‐32.1; c 0.01, CHCl3); however, the optical rotation of
synthetic arenaran B (
α
]
D
2
) ([α]
25: ‐24.9; c 0.2, CHCl3) is very
D
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similar to that described for the natural epoxyde ([
c 0.23, CHCl3). This finding leads us to believe that the [
value previously reported for natural arenaran A (
mistaken, and that the absolute stereochemistry proposed by
Crews et al for this compound is correct, because of its
correlation with (‐)‐sclareol (20).
ARTICLE
α
]
25: ‐24.4;
D
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DOI: 10.1039/C6OB01640E
NaH, THF
reflux
25
α]
D
O
OH
1) might be
H
H
Br
26
27
24 h (92%)
2nd generation
Grubbs catalyst
CH2Cl2, reflux
Utilizing a similar strategy, commercial (‐)‐sclareol (20) was
transformed into the oxocene epoxide 29, via alcohol 26
4 h (84%)
(Scheme 9). This was synthesized in two alternative ways. First,
methylenation of ketoester 24, whose efficient preparation in
one step from (‐)‐sclareol (20) has been developed by our
group,8 gave in high yield alcohol 26. Alternatively, aldehyde
25, previously synthesised in our laboratory,9 was converted
into this alcohol under the Wolff‐Kishner conditions; to the
O
O
O
MCPBA
CH2Cl2, 0 ºC
1.h (93%)
H
H
best of our knowledge, this transformation of
a α‐
28
29
hydroxyaldehyde into an alkene has not yet been described
(Scheme 8).
Scheme 9. Synthesis of oxocene epoxide 29 from alcohol 26.
Experimental
Materials and methods
Unless stated otherwise, reactions were performed in oven‐
dried glassware under an argon atmosphere using dry
solvents. Solvents were dried as follows: THF over Na–
benzophenone, and DCM and MeOH over CaH2. Thin‐layer
chromatography (TLC) was performed using F254 precoated
plates (0.25 mm) and visualized by UV fluorescence quenching
and phosphomolybdic acid solution staining. Flash
chromatography was performed on silica gel (230‐400 mesh).
Chromatography separations were carried out by conventional
column on silica gel 60 (230‐400 Mesh), using Hexanes‐EtOAc
mixtures of increasing polarity.1H and 13C NMR spectra were
recorded at 400 MHz and 100 MHz, respectively. CDCl3 was
Scheme 8. Synthesis of alcohol 26 from (‐)‐sclareol (20
)
treated with K2CO3. Chemical shifts (δ H) are quoted in parts
per million (ppm) referenced to the appropriate residual
1
solvent peak and tetramethylsilane. Data for H NMR spectra
Next, alcohol 26 was transformed into the oxocene epoxide
29 the 3‐debromoderivative of marine metabolite
are reported as follows: chemical shift (δ ppm) (multiplicity,
coupling constant (Hz), integration), with the abbreviations s,
br s, d, br d, t, q, and m denoting singlet, broad singlet,
doublet, broad doublet, triplet, quartet and multiplet
,
3.
Treatment of dimethylallyl ether 27 with second‐generation
Grubbs catalyst afforded in good yield oxocene 28, which
underwent stereoselective epoxydation, after reaction with
MCPBA at 0 °C, to give epoxide 29, the 3‐debromoderivative of
respectively.
J
= coupling constant in Hertz (Hz). Data for 13C
natural terpene
bicyclic ether moiety of epoxyde 29 are similar to that
reported for natural terpene
3
. The 13C NMR chemical shifts of carbons of
NMR spectra are reported in terms of chemical shift relative to
Me4Si (δ 0.0) and the signals were assigned utilizing DEPT
experiments and on the basis of heteronuclear correlations.
Infrared spectra (IR) were recorded as thin films or as solids on
a FTIR spectrophotometer with samples between sodium
chloride plates or as potassium bromide pellets and are
reported in frequency of absorption (cm–1). Only selected
3.
absorbances (νmax) are reported. ([α
]D) measurements were
carried out in a polarimeter; utilizing a 1dm length cell and
CHCl3 as a solvent. Concentration is expressed in mg/mL.
HRMS were recorded on a spectrometer, using FAB with
thioglicerol or glycerol matrix doped in NaI 1%.
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
water (3 x 30 mL) and brine (2 x 30 mL), dried over anhydrous
View Article Online
Synthetic procedures
Na2SO4, and evaporated to give alcoholD1O0I: (120..110539g/,C86O5%B0)16a4s0aE
1
yellow oil. H RMN (CDCl3, 400 MHz):
δ 0.87 (s, 3H), 0.97 (s,
4‐(2,6,6‐trimethylcyclohex‐2‐enyl)butan‐2‐one (7). Ni Raney
(50% in water, 6 mL) was added to a solution of
3H), 1.17 (s, 3H), 1.25 (br s, 2H), 1.33‐1.47 (m, 4H), 1.53‐1.65
α‐ionone
(m, 2H), 1.75 (m, 1H), 1.75 (s, 3H), 2.05 (m, 2H), 4.69 (s, 2H).
(6)(10.0 g, 52 mmol) in THF (120 mL), and the mixture was
13C RMN (CDCl3, 101 MHz):
δ 18.3 (CH2), 21.4 (CH3), 22.5 (CH3),
stirred under an ordinary hydrogen pressure (balloon) at room
temperature for 1 h. Then, the reaction mixture was filtered
through a silicagel‐Na2SO4 pad (100 g), eluting with acetone
(100 mL). After evaporation of the solvent under vacuum,
24.3 (CH2), 30.8 (CH3), 32.0 (CH3), 34.7 (C), 41.1 (CH2), 41.7
(CH2), 41.8 (CH2), 54.0 (CH), 73.0 (C) 109.5 (CH2), 146.5 (C). IR
(film): 757, 884, 909, 930, 1024, 1042, 1099, 1178, 1214, 1378,
1386, 1454, 1648, 3072, 3400‐3600 cm‐1. HRMS (FAB) m/z
calcd for C14H26ONa (M + Na+) 233.1881, found 233.1876.
ketone
7 (8.39 g, 83%) was obtained, as a colourless oil.
Compound
7 showed identical spectroscopic properties to
those reported in the literature.10,11
(1R, 2S)‐1‐(Allyloxy)‐1,3,3‐trimethyl‐2‐(3‐methylbut‐3‐en‐1‐
yl)cyclohexane (11). NaH (208 mg, 5.20 mmol, 60% dispersion
in mineral oil) was added to a solution of alcohol 10 (470 mg,
2.238 mmol) in anhydrous THF (20 mL) at 0 °C under an argon
atmosphere, and allyl bromide (0.4 mL, 4.62 mmol) was added,
and the reaction mixture was kept stirring at reflux for 24 h, at
which time TLC showed no 10 remaining. The mixture was
poured into ice and the solvent was evaporated under
vacuum. Then ether (50 mL) was added and the organic phase
was washed with water (3 x 15 mL) and brine (2 x 15 mL), dried
over anhydrous Na2SO4, and evaporated to give a crude
residue, which, after column chromatography on silica gel (5%
EtOAc/hexane), afforded ether 11 (520 mg, 93%) as a colorless
4‐((1S,2S,6R)‐1,3,3‐trimethyl‐7‐oxa‐bicyclo[4.1.0]heptan‐2‐
yl)butan‐2‐one (8).
20.00 mmol) was added to a solution of dihydro‐
)(3.52 g, 18.11 mmol) in dichloromethane (70 mL), cooled at
m
‐Chloroperbenzoic acid (70%, 4.92 g,
α‐ionone
(7
0 °C, and the reaction mixture was stirred for 30 min. Then, a
10% Na2SO3 solution (10 mL) was added, and the mixture was
extracted with EtOAc (3 x 20 mL). The organic phase was
successively washed with sat. NaHCO3 (3 x 30 mL) and brine (2
x 30 mL), and dried over anhydrous Na2SO4. After evaporation
of the solvent under vacuum, compound
obtained as a colourless syrup. Compound
8
8
(3.27 g, 86%) was
exhibited identical
properties to those reported in the literature.4
oil. 1H NMR (CDCl3, 400 MHz):
(dd, = 14.1, 3.8 Hz, 1H), 1.12 (s, 3H), 1.16 (dd,
1H), 1.27‐1.34 (m, 2H), 1.36‐1.45 (m, 2H), 1.53‐1.64 (m, 2H),
1.75 (s, 3H), 1.93‐2.12 (m, 3H), 3.82 (d, = 4.8 Hz, 2H), 4.68
(d, = 5.0 Hz, 2H), 5.9 (m, 1H), 5.27 (d, = 17.2 Hz, 1H), 5.05 (d,
= 10.5 Hz, 1H). 13C NMR (CDCl3, 100 MHz):
18.4 (CH2), 22.5
δ
0.86 (s, 3H), 0.99 (s, 3H), 1.07
= 13.4, 3.6 Hz,
J
J
(1S,6R)-1,3,3-Trimethyl-2-(3-methylbut-3-en-1-yl)-7-
oxabicyclo[4.1.0]heptane (9). 2M n‐BuLi in cyclohexane (7.8
J
mL, 15.7 mmol) was added to
a
solution of
J
J
methyltriphenylphosphonium bromide (5.59 g, 15.7 mmol) in
anhydrous THF (75 mL), and the mixture was stirred at 0 ºC
under an argon atmosphere for 15 min. Then, a solution of
J
δ
(CH3), 24.1 (CH2), 24.5 (CH3), 32.2 (CH3), 34.9 (C), 34.93 (CH),
41.8 (CH2), 42.2 (CH2), 56.0 (CH), 61.6 (CH2), 22.1 (CH3), 76.7
(C), 109.3 (CH2), 114.1 (CH2), 136.6 (CH), 146.9 (C). IR (film):
917, 1065, 1075, 1154, 1171, 1264, 1372, 1454, 1647 cm‐1.
HRMS (FAB) m/z calcd for C17H30ONa (M + Na+) 273.2194,
found 273.2201.
ketone
8 (3 g, 14.26 mmol) in anhydrous THF (2 mL) was
added, and the resulting mixture was kept stirring for 2.5 h.
Then, the reaction was carefully quenched with water (10 mL),
and the solvent was evaporated. Then, ether (100 mL) was
added and the organic phase was washed with water (3 x 30
mL) and brine (2 x 30 mL), dried over anhydrous Na2SO4 and
evaporated to afford a crude product that was purified by
Treatment of ether 11 with 2nd Generation Grubbs catalyst.
Obtention of alcohol 10. 2nd Generation Grubbs catalyst (20
mg). was added to a solution of ether 11 (170 mg, 0.68 mmol)
in anhydrous CH2Cl2 (30 mL), and the mixture was kept stirring
at reflux under an argon atmosphere for 48 h. Then, solvent
was evaporated and the crude product was purified by column
chromatography (20% EtOAc/hexane) to yield alcohol 10 (124
mg, 87%).
column chromatography on silica gel (10% EtOAc/hexane) to
1
yield epoxide
9
(2.67 g, 91%) as a colourless oil. H NMR
(CDCl3, 400 MHz): δ 0.82 (s, 3H), 0.88 (s, 3H), 1.28 (m, 1H), 1.33
(s, 3H), 1.46‐1.58 (m, 2H), 1.37 (m, 1H), 1.75 (s, 3H), 1.83 (m,
1H), 1.92 (dd, J = 15.5, 6.1 Hz, 1H), 2.05 (m, 1H), 2.29 (m, 1H),
2.93 (s, 1H), 4.71 (s, 2H). 13C NMR (CDCl3, 100 MHz): δ 22.3
(CH2), 22.8 (CH3), 25.8 (CH2), 27.1 (CH3), 27.1 (CH2), 27.5 (CH3),
27.9 (CH), 31.6 (C), 37.7 (CH2), 46.9 (CH3), 59.8 (C), 60.3 (CH),
109.7 (CH2), 146.8 (C). IR (film): 756, 884, 1095, 1182, 1216,
1366, 1376, 1449, 1649, 3073 cm‐1.HRMS (FAB) m/z calcd for
C14H24ONa (M + Na+) 231.1725, found 231.1733.
(2S, 3R)‐1,1,3‐Trimethyl‐3‐((3‐methylbut‐2‐en‐1‐yl)oxy)‐2‐(3‐
methylbut‐3‐en‐1‐yl)cyclohexane (12). NaH (208 mg, 5.2
mmol, 60% dispersion in mineral oil) was added to a solution
of alcohol 10 (0.5 g, 2.38 mmol) in anhydrous THF (20 mL) at 0
°C under an argon atmosphere, and 3,3‐dimethylallyl bromide
(0.4 mL, 3.46 mmol) was added, and the reaction mixture was
kept stirring at reflux for 24 h, at which time TLC showed no 10
remaining. The mixture was poured into ice and the solvent
was evaporated under vacuum. The aqueous phase was
extracted with ether (2 x 30 mL) and the organic phase was
(1R,2S)‐1,3,3‐Trimethyl‐2‐(3‐methylbut‐3‐en‐1‐yl)
cyclohexan‐1‐ol (10). LiAlH4 (130 mg, 3.43 mmol) was added to
a solution of epoxide
(50 mL) at 0 °C. The mixture was stirred at reflux under an
argon atmosphere for 30 min, at which time TLC showed no
9 (2.5 g, 12.00 mmol) in anhydrous THF
9
remaining. Then, the mixture was poured into ice and the
solvent was evaporated. Ether (100 mL) was added and the
phases were shaken. The organic phase was washed with
6 | J. Name., 2012, 00, 1‐3
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Journal Name
ARTICLE
washed with water (3 x 15 mL) and brine (2 x 15 mL), dried 4‐((1S,6S)‐2,2,6‐trimethyl‐6‐propionylcyclohexyl)butan‐2‐one
View Article Online
over anhydrous Na2SO4, and evaporated to give a crude (18). O3/O2 was bubbled through a soluDtOioI:n10o.1f0c3o9/mC6pOoBu0n1d64105E
residue, which, after column chromatography on silica gel (5% (2.0 g, 9.09 mmol) in CH2Cl2 (60 mL) cooled at ‐78 °C for 1 h,
EtOAc/hexane), afforded ether 12 (0.61 g, 92%) as a colorless after which time TLC showed no remaining starting material.
oil. 1H NMR (CDCl3, 400 MHz):
(dd, = 13.9, 3.8 Hz, 1H), 1.12 (s, 3H), 1.15 (dd,
δ
0.85 (s, 3H), 0.97 (s, 3H), 1.05 Then, argon was bubbled through the solution for 5 min, and
= 13.3, 3.6 Hz, triphenylphosphine (2.6 g, 9.9 mmol) was added, and the
J
J
1H), 1.27‐1.33 (m, 2H), 1.34‐1.42 (m, 2H), 1.63 (s, 3H), 1.69 (s, mixture was further stirred at room temperature for 5 h. After
1H), 1.71 (s, 3H), 1.75 (s, 3H), 1.96‐2.01 (m, 2H), 2.04 (m, 2H), evaporation of the solvent under vacuum, the resulting crude
3.79 (d,
6.3, 1.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz):
(CH2), 22.0 (CH3), 22.5 (CH3), 24.2 (CH2), 24.6 (CH3), 25.7 (CH3), colourless syrup. [α]D ‐16.8 (
32.2 (CH3), 34.9 (C), 35.0 (CH2), 41.9 (CH2), 42.4 (CH2), 56.0 400 MHz): 0.87 (s, 3H), 0.88 (s, 3H), 0.98 (t,
(CH), 57.7 (CH2), 76.5 (C), 109.3 (CH2), 123.3 (CH), 133.3 (C), 1.18 (s, 3H), 1.18 (m, 1H), 1.28 – 1.75 (m, 8H), 2.05 (s, 3H), 2.25
147.0 (C). IR (film): 909, 1029, 1106, 1374, 1450, 1648 cm‐1 – 2.68 (m, 4H). 13C NMR (CDCl3, 100 MHz):
8.5 (CH3), 17.2
HRMS (FAB) m/z calcd for C19H34ONa (M + Na+) 301.2507, (CH3), 18.2 (CH2), 22.1 (CH2), 22.5 (CH3), 29.8 (CH3), 30.6 (CH2),
J
= 6.2 Hz, 2H), 4.68 (d,
J
= 10.0 Hz, 2H), 5.28 (tt,
J
=
product was purified by column chromatography on silica gel
δ
18.0 (CH3) 18.5 (25% EtOAc/ hexane) giving diketone 18 (1.95 g, 85 %), as a
20
c
0.9, CHCl3). 1H NMR (CDCl3,
= 7.2 Hz, 3H),
δ
J
.
δ
found 301.2498.
33.4 (CH3), 34.3 (C), 37.1 (CH2), 41.2 (CH2), 45.5 (CH2), 47.7
(CH), 52.8 (C), 209.0 (C), 217.6 (C). IR (film): 772, 957, 1161,
1355, 1460, 1697, 1715 cm‐1. HRMS (FAB) m/z calcd for
(6aS,10aR,Z)‐4,7,7,10a‐Tetramethyl‐5,6,6a,7,8,9,10,10a‐
octahydro‐2H‐benzo[b]oxocine (epi‐arenaran A) (13). 2nd C16H28O2Na (M + Na+) 275.1987, found 275.1979.
Generation Grubbs catalyst (20 mg) was added to a solution of
ether 12 (200 mg, 0.72 mmol) in anhydrous CH2Cl2 (40 mL), 2‐((1S,6S)‐2,2,6‐trimethyl‐6‐propionylcyclohexyl)ethyl acetate
and the reaction mixture was kept stirring at reflux under an (19).
m‐Chloroperbenzoic acid (70%, 493 mg, 2.158 mmol) was
argon atmosphere for 48 h. Then, the solvent was evaporated added to a solution of compound 18 (272 mg; 1.079 mmol) in
and the crude product was purified by column chloroform (10 mL), and the reaction mixture was stirred at
chromatography (3% EtOAc/hexane) to yield ether 13 (0.13 g, reflux for 3 days, at which TLC showed no remaining starting
1
84%). H NMR (CD3OD, 400 MHz):
δ
0.89 (s, 3H), 1.03 (s, 3H), material. Then, a 10% Na2SO3 solution (1 mL) was added, and
= 13.4, 4.0 Hz, 1H), 1.13 (s, 3H), 1.20 (m, 1H), 1.34 the mixture was stirred for an additional 15 min. Then the
= 3.0 Hz, 2H), 1.40‐1.45 (m, 2H), 1.71 (s, 3H), 1.76 (dd, reaction was extracted with EtOAc (3 x 10 mL) and the organic
13.4, 3.3 Hz, 1H), 1.87 (m, 1H), 1.96 (dd, = 13.1, 3.1 Hz, 1H), phase was successively washed with sat. NaHCO3 (5 x 10 mL)
2.03‐2.40 (m, 2H), 3.76 (dd, = 13.8, 6.9 Hz, 1H), 3.96 (dd, and brine (2 x 10 mL), and dried over anhydrous Na2SO4 and
13.8, 7.0 Hz, 1H), 5.43 (t,
= 6.9 Hz, 1H). 13C NMR (CD3OD, 100 evaporated to give a crude residue, which, after column
MHz): 15.1 (CH3), 18.0 (CH2), 21.1 (CH3), 24.6 (CH3), 25.2 chromatography on silica gel (10% EtOAc/hexane), afforded 19
(CH2), 31.4 (CH3), 34.1 (C), 35.5 (CH2), 41.9 (CH2), 42.8 (CH2), (234 mg, 81%) as a colourless syrup. [α]D20 ‐13.3 (
1.0, CHCl3).
55.5 (CH), 56.4 (CH2), 77.4 (C), 123.6 (CH), 140.6 (C). IR (film): 1H NMR (CDCl3, 400 MHz):
0.89 (s, 3H), 0.90 (s, 3H), 1.00 (t,
1.08 (dd,
(d,
J
J
J =
J
J
J =
J
δ
c
δ
J
1052, 1071, 1095, 1153, 1176, 1212, 1364, 1386, 1454, 1475, = 7.2 Hz, 3H), 1.18 (s, 3H), 1.18 – 1.74 (m, 9H), 1.99 (s, 3H),
1671 cm‐1. HRMS (FAB) m/z calcd for C15H26ONa (M + Na+) 2.40 – 2.56 (m, 2H), 3.79 – 3.97 (m, 2H). 13C NMR (CDCl3, 100
245.1881, found 245.1876.
MHz): δ 8.5 (CH3), 17.5 (CH3), 18.2 (CH2), 21.0 (CH3), 22.7 (CH2),
27.2 (CH2), 30.5 (CH2), 33.1 (CH3), 34.0 (C), 36.3 (CH2), 40.8
(CH2), 44.7 (CH), 52.5 (C), 65.1 (CH2), 170.9 (C), 216.9 (C). IR
(4aS,8aS)‐8‐ethyl‐4,4,7,8a‐tetramethyl‐1,2,3,4,4a,5,6,8a‐
octahydronaphthalene (15). 5 mL of an aqueous suspension of (film): 957, 1096, 1355, 1459, 1697, 1714, 3072 cm‐1. HRMS
Raney nickel (Aldrich, cat. 221678) was added to a stirred (FAB) m/z calcd for C16H28O3Na (M + Na+) 291.1936, found
solution of 17 (2.5 g, 7.22 mmol) in THF (30 mL) and the 291.1944.
mixture was further stirred at room temperature for 1h, under
an ordinary hydrogen pressure (balloon). Then the mixture (1S,2S)‐1,3,3‐Trimethyl‐2‐(3‐oxobutyl) cyclohexyl formate
was diluted with diethyl ether (50 mL) and filtered on silca gel (22).
–Na2SO4 mixture (10: 16 g) column, washed with diethyl ether NaHCO3 (0.56 g, 6.69 mmol) was added to a solution of
(10 mL) to yield 15 as colorless oil (1.42 g, 89%). [α]D20 +67.1 (
ketoaldehyde 21 (0.5 g, 2.23 mmol) in CH2Cl2 (50 mL) and the
1.1, CHCl3). 1H NMR (CDCl3, 400 MHz):
0.82 (s, 3H), 0.87 (s, mixture was stirred under reflux for 1.5 h. Then, 10% aq
3H), 0.92 (s, 3H), 0.96 (t, = 7.5 Hz, 3H), 1.56 (s, 3H), 0.99 – Na2SO3 (5 mL) was added and the mixture was further stirred
1.70 (m, 8H), 1.75 – 2.08 (m, 5H). 13C NMR (CDCl3, 100 MHz):
at room temperature for 15 min. Then, EtOAc (20 mL) was
m‐Chloroperbenzoic acid (70%, 1.37 g, 5.58 mmol) and
c
δ
J
δ
15.1 (CH3), 19.07 (CH3), 19.09 (CH3), 19.3 (CH2), 20.0 (CH2), 20.5 added and the organic phase was washed with water (3 x 20
(CH3), 21.7 (CH2), 33.3 (CH2), 33.61 (C), 33.63 (CH3), 36.9 (CH2), mL) and brine (2 x 20 mL), dried over anhydrous Na2SO4, and
1
39.1 (C), 41.8 (CH2), 51.9 (CH), 125.0 (C), 142.3 (C). IR (film): evaporated to give formate 22 (0.49 g, 93%). H NMR (CDCl3,
1374, 1457, 1644 cm‐1. HRMS (FAB) m/z calcd for C16H28Na (M 400 MHz):
δ
0.88 (s, 3H), 0.98 (s, 3H), 1.14‐1.28 (m, 1H), 1.30‐
+ Na+) 243.2089, found 243.2093.
1.40 (m, 1H), 1.43‐1.50 (m, 1H), 1.50‐1.60 (m, 3H), 1.55 (s, 3H),
1.60‐1.75 (m, 3H), 2.16 (s, 3H), 2.48 (dt, J = 12.0, 3.0 Hz, 1H),
2.51‐2.59 (m, 1H), 2.65‐2.73 (m, 1H), 8.05 (s, 1H). 13C NMR
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 7
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
(CDCl3, 100 MHz):
δ
19.8 (CH2), 20.2 (CH2), 20.9 (CH3), 21.7 Treatment of ether 4 with 2nd Generation Grubbs catalyst. 2nd
View Article Online
DOI: 10.1039/C6OB01640E
(CH3), 30.0 (CH3), 32.7 (CH3), 35.8 (C), 38.6 (CH2), 40.6 (CH2), Generation Grubbs catalyst (22 mg). was added to a solution
45.9 (CH2), 53.2 (CH), 88.9 (C), 209.3 (C), 160.5 (CH). HRMS of ether
4 (187 mg, 0.75mmol) in anhydrous CH2Cl2 (30 mL),
(FAB) m/z calcd for C14H24O3Na (M + Na+) 263.1623, found and the mixture was kept stirring at reflux under an argon
263.1619.
atmosphere for 2 h. Then, solvent was evaporated affording a
crude product, which consists of a complex mixture and
(1S,2S)‐1,3,3‐Trimethyl‐2‐(3‐methylbut‐3‐en‐1‐yl) cyclohexan‐ starting material.
1‐ol (5). 2M ‐BuLi in cyclohexane (1.25 mL, 2.5 mmol) was
n
added to a solution of methyltriphenylphosphonium bromide (2S,3S)‐1,1,3‐Trimethyl‐3‐((3‐methylbut‐2‐en‐1‐yl)oxy)‐2‐(3‐
(0.91 g, 2.5 mmol, 98%) in anhydrous THF (25 mL), and the methylbut‐3‐en‐1‐yl)cyclohexane (23). NaH (34 mg, 0.86
mixture was stirred at 0 °C under an argon atmosphere for 15 mmol, 60% dispersion in mineral oil) was added to a solution
min. Then, a solution of ketoester 22 (0.3 g, 1.25 mmol) in of alcohol
5 (147 mg, 0.7 mmol) in anhydrous THF (12.5 mL) at
anhydrous THF (0.3 mL) was added, and the resulting mixture 0 °C under an argon atmosphere, and 3,3‐dimethylallyl
was kept stirring for 3 h. Then, the reaction was carefully bromide (0.24 mL, 20.77 mmol) was added, and the reaction
quenched with water (0.5 mL). The solvent was evaporated mixture was kept stirring at reflux for 24 h, at which time TLC
and ether was added (25 mL), and the organic phase was showed no
5 remaining. The mixture was poured into ice and
washed with water (3 x 10 mL) and brine (2 x 10 mL), dried the solvent was evaporated under vacuum. Then ether (25 mL)
over anhydrous Na2SO4 and evaporated to afford a crude was added and the organic phase was washed with water (3 x
product that was purified by column chromatography on silica 10 mL) and brine (2 x 10 mL), dried over anhydrous Na2SO4,
gel (20% EtOAc/hexane) to yield alcohol
5 (0.23 g, 86%) as a and evaporated to give a crude residue, which, after column
20
yellow oil. [α]D +6.5 (
MHz): 0.83 (s, 3H), 0.95 (s, 3H), 1.11 (t,
(s, 3H), 1.21 (dd,
1.31 (dd,
2H), 1.75 (s, H), 2.11 (m, 1H), 2.20 (m, 1H), 4.70 (s, 2H). 13C 1.43‐1.46 (m, 2H), 1.56‐1.59 (m, 3H), 1.64 (s, 3H), 1.71 (s, 3H),
NMR (CDCl3, 100 MHz): 20.5 (CH2), 21.4 (CH3), 22.6 (CH3), 1.73 (s, 3H), 2.03 (m, 1H), 2.24 (m, 1H), 3.82‐3.90 (m, 2H), 4.67
23.2 (CH3), 24.4 (CH2), 32.8 (CH3), 35.6 (C), 40.9 (CH2), 41.5 (s, 2H), 5.27 (t,
= 6.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz):
c
1.2, CHCl3). 1H NMR (CDCl3, 400 chromatography on silica gel (3% EtOAc/hexane), afforded
δ
J
= 4.5 Hz, 1H), 1.17 ether 23 (179 mg, 92%) as a colorless oil. [α]D20 +21.2 (
c
0.9,
1
J
= 13.0, 4.0 Hz, 1H), 1.25 (s, 1H), 1.37 (m, 1H), CHCl3). H NMR (CDCl3, 400 MHz):
δ
0.86 (s, 3H), 0.97 (s, 3H),
J
= 12.3, 4.1 Hz, 1H), 1.40‐1.50 (m, 2H), 1.52‐1.64 (m, 1.17 (s, 3H), ), 1.26 (s, 1H), 1.31‐1.33 (m, 2H), 1.36 (m, 1H),
δ
J
δ
(CH2), 43.6 (CH2), 56.8 (CH), 74.1 (C), 109.7 (CH2), 147.1 (C). IR 18.02 (CH3), 20.0 (CH2), 20.3 (CH3), 22.3 (CH3), 22.6 (CH3), 25.2
(film): 883, 911, 1063, 1100, 1161, 1373, 1388, 1459, 1648, (CH2), 25.8 (CH3), 32.9 (CH3), 35.4 (C), 37.3 (CH2), 40.5 (CH2),
1714, 3072, 3300‐3600 cm‐1.HRMS (FAB) m/z calcd for 41.2 (CH2), 53.0 (CH), 56.8 (CH2), 78.2 (C), 108.9 (CH2), 122.8
C14H26ONa (M + Na+) 233.1881, found 233.1890.
(CH), 134.4 (C), 147.6 (C). IR (film): 754, 960, 1074, 1124, 1276,
1721 cm‐1. HRMS (FAB) m/z calcd for C19H34ONa (M + Na+)
(1S, 2S)‐1‐(Allyloxy)‐1,3,3‐trimethyl‐2‐(3‐methylbut‐3‐en‐1‐ 301.2507, found 301.2509.
yl)cyclohexane (4). NaH (250 mg, 6.24 mmol, 60% dispersion
in mineral oil) was added to a solution of alcohol
5 (564 mg,
2.70 mmol) in anhydrous THF (20 mL) at 0 °C under an argon Arenaran A (1). 2nd Generation Grubbs catalyst (10 mg) was
atmosphere, and allyl bromide (0.5 mL, 5.54 mmol) was added, added to a solution of ether 23 (62 mg, 0.223 mmol) in
and the reaction mixture was kept stirring at reflux for 20 h, at anhydrous CH2Cl2 (30 mL), and the mixture was kept stirring at
which time TLC showed no
poured into ice and the solvent was evaporated under evaporated and the crude product was purified by column
vacuum. Then ether (50 mL) was added and the organic phase chromatography (3% AcOEt/hexane) to yield (45 mg, 91%).
was washed with water (3 x 20 mL) and brine (2 x 20 mL), dried [α]D20 ‐32.1 ( 0.01, CHCl3). 1H NMR (CD3OD, 400 MHz):
0.91
over anhydrous Na2SO4, and evaporated to give a crude (s, 3H), 1.16 (ddd, = 13.3, 4.1 Hz, 1H), 1.25 (s, 3H), 1.35‐1.32
residue, which, after column chromatography on silica gel (5% (m, 2H), 1.46 (dt, J = 13.5, 3.0 Hz, 1H), 1.51 (m, 2H), 1.55 (m,
EtOAc/hexane), afforded ether (618 mg, 90%) as a colorless 2H), 1.61‐1.58 (m, 2 H), 1.65 (m, 2H), 1.69 (s, 3H), 1.76 (ddd,
oil. H NMR (400MHz, CDCl3) δ 5.87 (m, 1H), 5.25 (dd, =1.7, 12.7, 4.5 Hz), 3.37 (m, 2H), 4.03 (d, J = 18.4 Hz), 4.22 (dd, J =
17.2 Hz, 1H), 5.05 (dd, 19.7
=1.7, 10.4 Hz, 1H), 4.65 (s, 2H), 3.92‐ 18.4, 2.1 Hz), 5.15 (br s). 13C NMR (CD3OD, 100 MHz):
5 remaining. The mixture was reflux under an argon atmosphere for 3 h. Then, solvent was
1
c
δ
J
4
J
1
J
=
J
δ
3.83 (m, 2H), 2.22 (m, 1H), 2.01 (m, 1H), 1.72 (s, 3H), 1.65‐1.52 (CH3), 21.0 (CH2), 21.9 (CH2), 24.1 (CH3), 25.0 (CH2), 28.9 (CH3),
(m, 2H), 1.41‐1.28 (m, 5H), 1.24 (s, 1H), 1.19 (m, 1H), 1.14 (s, 32.3 (CH2), 34.0 (C), 35.2 (CH3), 41.9 (CH), 45.4 (CH2), 61.1 (CH),
1
3H), 0.95 (s, 3H), 0.84 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 80.2 (C), 123.3 (CH2), 132.9 (C). H NMR (CDCl3, 400 MHz):
δ
147.4 (C), 136.5 (CH), 114.6 (CH2), 108.9 (CH2), 78.5 (C), 60.9 0.86 (s, 3H), 0.91 (s, 3H), 1.16 (dd,
(CH2), 53.5 (CH), 41.2 (CH2), 40.7 (CH2), 37.7 (CH2), 35.4 (C), 3H), 1.32‐1.35 (m, 2H), 1.46 (dt,
32.9 (CH3), 25.2 (CH2), 22.6 (CH3), 22.1 (CH3), 19.9 (CH2), 19.8 1H), 1.55 (m, 1H), 1.58‐1.61 (m, 2H), 1.65 (m, 1H), 1.69 (s, 3H),
(CH3). IR (film): 1074, 1155, 1264, 1374, 1455, 1648 cm‐1. 1.76 (dd,
= 12.7, 4.5 Hz, 1H), 3.37 (m, 1H), 4.03 (d, = 18.4 Hz,
HRMS (FAB) m/z calcd for C17H30ONa (M + Na+) 273.2194, 1H), 4.22 (dd, = 18.4, 2.1 Hz, 1H), 5.15 (br s, 1H).13C NMR
(CDCl3, 100 MHz): 20.1 (CH2), 22.0 (CH3), 22.9 (CH3), 24.5
J
= 13.3, 4.1 Hz, 1H), 1.25 (s,
J
= 13.5, 3.0 Hz, 1H), 1.51 (m,
J
J
J
found 273.2185.
δ
(CH2), 26.3 (CH3), 29.4 (CH2), 33.3 (CH3), 34.5 (C), 35.5 (CH2),
8 | J. Name., 2012, 00, 1‐3
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42.3 (CH2), 45.7 (CH), 61.5 (CH2), 79.8 (C), 123.7 (CH), 133.3 (C). (CH2), 42.0 (CH2), 44.6 (CH2), 56.2 (CH), 61.5 (CH), 74.1 (C),
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HRMS (FAB) m/z calcd for C15H26ONa (M + Na+) 245.1881, 109.6 (CH2), 147.1 (C). IR (film): 882, 968, 1083, 1103, 1386,
DOI: 10.1039/C6OB01640E
found 245.1893.
1455, 1648, 1727, 3300‐3500 cm‐1. HRMS (FAB) m/z calcd for
C19H34ONa (M + Na+) 301.2507, found 301.2499.
Arenaran B (2).
m‐Chloroperbenzoic acid (70%, 50.0 mg, 0.20
mmol) was added to a solution of compound
1
(28 mg, 0.126 Treatment of aldehyde 25 with N2H4‐KOH. Obtention of
mmol) in CH2Cl2 (12.5 mL) at 0 °C, and the mixture was stirred alcohol 26. Hydrazine (2 mL, 41.2 mmol) was added to a
for 1 h. Then a 10% Na2SO3 solution (5 mL) was added and the solution of aldehyde 25 (2.0 g, 6.5 mmol) in triethyleneglycol
mixture was further stirred for 15 min. Then, EtOAc (10 mL) dimethyl ether (20 mL) and the mixture was stirred under
was added, and the organic phase was washed with sat reflux for 1 h, then KOH (2.31 g, 41.25 mol) was added and the
NaHCO3 (3 x 10 mL) and brine (2 x 10 mL), and dried over anh mixture was stirred at reflux for an additional 11h. Then, the
Na2SO4. Evaporation of the solvent under vacuum gave finally mixture was kept at room temperature and H2O (10 mL) was
epoxide
2
(28 mg, 93%) as a low m.p. solid. [
α
]
25: ‐24.9 (
c
0.2, added. EtOAc (50 mL) was added and the organic phase was
δ
D
1
CHCl3) (lit.1: ‐24.4 (
c
0.23, CHCl3). H NMR (CDCl3, 400 MHz): washed with H2O (10 x 20 mL) and brine (3 x 20 mL), dried over
0.85 (s, 3H), 0.98 (s, 3H), 1.16 (s, 3H), 1.29 (s, 3H), 1.21 (m, 1H), anhydrous Na2SO4 and evaporated to give a crude product
1.40 (m, 1H), 1.45 (m, 1H), 1.50 (m, 1H), 1.58 (m, 1H), 1.67 (m, which after column chromatography on silica gel (10%
1H), 1.86 (dt,
1H), 2.79 (s 1H), 3.90 (d,
Hz, 1H). 13C NMR (CDCl3, 100 MHz):
J
= 13.2, 3.9 Hz, 1H), 2.42 (dt,
= 17.6 Hz, 1H), 4.02 (dd,
19.9 (CH2), 21.5 (CH3),
J
= 13.4, 4.9 Hz, EtOAc/hexane), afforded alcohol 26 (1.6 g, 81%) as a colourless
J
J
= 17.6, 1.7 oil.
δ
22.0 (CH2), 22.5 (CH3), 22.9 (CH3), 31.8 (CH2), 33.2 (CH3), 34.7 (4aS,5R,6R,8aS)‐1,1,4a,6‐Tetramethyl‐6‐((3‐methylbut‐2‐en‐1‐
(C), 35.9 ((CH2), 42.2 (CH2), 44.7 (CH), 58.1 (CH2), 60.8 (C), 64.1 yl)oxy)‐5‐(3‐methylbut‐3‐en‐1‐yl)decahydronaphthalene (27).
(CH), 80.0 (C). 1H NMR (CDCl3, 500 MHz):
δ 0.85 (s, 3H), 0.98 (s, NaH (100 mg, 2.5 mmol, 60% dispersion in mineral oil) was
3H), 1.16 (s, 3H), 1.19 (ddd, J = 13.5, 13.5, 3.8 Hz, 1H), 1.30 (s, added to a solution of alcohol 26 (180 mg, 0.647 mmol) in
3H), 1.33 (ddd, J = 13.5, 13.5, 3.8 Hz, 1H), 1.39 (ddd, J = 13.5, anhydrous THF (100 mL) at 0 °C under an argon atmosphere,
3.8, 3.8 Hz, 1H), 1.45 (ddd, J = 13.5, 3.8, 3.8 Hz, 1H), 1.50 (dd, J and 3,3‐dimethylallyl bromide (0.2 mL, 1.73 mmol) was added,
= 13.4, 4.3 Hz, 1H), 1.55 (dp, J = 13.5, 3.8 Hz, 1H), 1.61 (tdd, J = and the reaction mixture was kept stirring at reflux for 24 h, at
13.4, 4.3, 4.3 Hz, 1H), 1.68 (tt, J = 13.4, 4.3 Hz, 1H), 1.72 (ddd, J which time TLC showed no 26 remaining. The mixture was
= 13.5, 3.8, 3.8 Hz, 1H), 1.88 (ddd, J = 13.4, 13.4, 4.3 Hz, 1H), poured into ice and the solvent was evaporated under
2.43 (ddd, J = 13.4, 4.3, 4.3 Hz, 1H), 2.79 (d, J = 2.3 Hz, 1H), vacuum. Then, ether (100 mL) was added and the organic
3.90 (d, J = 15.9 Hz, 1H), 4.03 (dd, J = 15.9, 2.3 Hz, 1H). 13C NMR phase was washed with water (3 x 30 mL) and brine (2 x 30
(CDCl3, 125 MHz): δ 20.0 (CH2), 21.7 (CH3), 22.2 (CH2), 22.7 mL), dried over anhydrous Na2SO4, and evaporated to give a
(CH3), 23.1 (CH3), 32.0 (CH2), 33.4 (CH3), 34.8 (C), 36.1 (CH2), crude residue, which, after column chromatography on silica
42.4 (CH2), 44.9 (CH), 58.2 (CH2), 60.9 (C), 64.2 (CH), 80.2 (C).
gel (5% EtOAc/hexane), afforded ether 27 (206 mg, 92%).
[α]D20 ‐7.1 ( 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz):
0.79 (s,
(1R,2R,4aS,8aS)‐2,5,5,8a‐Tetramethyl‐1‐(3‐methylbut‐3‐en‐1‐ 3H), 0.83 (s, 3H), 0.85 (s, 3H), 0.90 (dd, = 12.3, 2.2 Hz, 1H),
yl)decahydronaphthalen‐2‐ol (26). 2 M ‐BuLi in cyclohexane 0.97 (dd, = 12.9, 3.6 Hz, 1H), 1.14 (s, 3H), 1.25 (s, 2H), 1.35‐
(1.7 mL, 3.3 mmol) was added to solution of 1.44 (m, 2H), 1.54‐1.61 (m, 4H), 1.63 (s, 3H), 1.65‐1.68 (m, 3H),
methyltriphenylphosphonium bromide (15.75 g, 60 mmol, 1.71 (s, 3H), 1.72 (s, 3H), 1.84 (dt,
98%) in anhydrous THF (75 mL), and the mixture was stirred at (dd, = 13.6, 4.6 Hz, 1H), 2.17 (dd,
c
δ
J
n
J
a
J
J
= 12.2, 3.3 Hz, 1H), 2.01
J
= 13.3’ 4.6 Hz, 1H), 3.81‐
‐78ºC under an argon atmosphere for 15 min. Then, a solution 3.90 (m, 2H), 4.65 (br s, 2H), 5.25 (tt,
of ketoester 24(3.8 g, 12 mmol) in anhydrous THF (2 mL) was NMR (CDCl3, 100 MHz): 15.9 (CH3), 18.1 (CH3), 18.5 (CH2),
J
= 6.4, 1.4 Hz, 1H). 13C
δ
added, and the resulting mixture was kept stirring for 45 min. 20.1 (CH2), 20.8 (CH3), 21.5 (CH3), 22.6 (CH3), 24.3 (CH2), 25.8
Then, the reaction was carefully quenched with water (5 mL), (CH3), 33.2 (C), 33.4 (CH3), 38.5 (CH3), 39.2 (C), 40.1 (CH2),
and the solvent was evaporated. Then, ether (100 mL) was 41.0(CH2), 42.1 (CH2), 56.1 (CH), 56.8 (CH2), 58.1 (CH), 78.3 (C),
added, and the organic phase was washed with water (3 x 30 108.9 (CH2), 122.9 (CH), 134.3 (C), 147.6 (C). IR (film): 973,
mL) and brine (2 x 30 mL), dried over anhydrous Na2SO4 and 1035, 1058, 1079, 1131, 1386, 1446, 1647 cm‐1. HRMS (FAB)
evaporated to afford a crude product that was purified by m/z calcd for C24H42ONa (M + Na+) 369.3133, found 369.3141.
column chromatography on silica gel (20% EtOAc/hexane) to
yield alcohol 26 (3.4 g, 91%). [α]D20 +8.5 (
(CDCl3, 400 MHz): 0.79 (s, 3H), 0.80 (s, 3H), 0.86 (s, 3H), 0.92 2,3,6a,7,8,8a,9,10,11,12,12a,12b‐dodecahydro‐1H‐
(dd, = 12.1, 2.3 Hz, 1H), 0.97 (dd,
= 12.7, 3.8 Hz, 1H), 1.05 (t, naphtho[2,1‐b]oxocine (28). 2nd Generation Grubbs catalyst
= 4.0 Hz, 1H), 1.14 (s, 3H), 1.25 (br s, 1H), 1.28 (s, 1H), 1.35‐ (30 mg) was added to a solution of ether 27 (310 mg, 0.895
1.40 (m, 2H), 1.41 (s, 1H), 1.43 (m, 1H), 1.53‐1.61 (m, 2H), mmol) in anhydrous CH2Cl2 (40 mL). The mixture was kept
1.62‐1.67 (m, 3H), 1.73 (s, 3H), 1.86 (dt, = 12.2, 3.1 Hz, 1H), stirring at reflux under an argon atmosphere for 4 h. Then, the
2.04‐2.14 (m, 2H), 4.69 (br s, 2H). 13C NMR (CDCl3, 100 MHz):
solvent was evaporated and the crude product was purified by
c
0.8, CHCl3). 1H NMR (6aR,8aS,12aS,12bR,Z)‐4,6a,9,9,12a‐Pentamethyl‐
δ
J
J
J
J
δ
15.5 (CH3), 18.5 (CH2), 20.6 (CH2), 21.5 (CH3), 22.6 (CH3), 23.6 column chromatography (3% AcOEt/hexane) to yield 28 (218
20
1
(CH2), 23.9 (CH3), 33.3 (C), 33.4 (CH3), 39.2 (C), 39.7 (CH2), 41.3 mg, 84%). [α]D +40.4 (
c
0.9, CHCl3). H NMR (CD3OD, 400
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J. Name., 2013, 00, 1‐3 | 9
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MHz):
3H), 0.88 (s, 3H), 1.13 (dd,
1.30 (dd, = 12.6, 3.5 Hz, 1H), 1.34‐1.43 (m, 3H), 1.50 (dd,
12.0, 3.8 Hz, 1H), 1.54‐1.58 (m, 2H), 1.60‐1.66 (m, 3H), 1.68 (br financial support and assistance provided to the FQM‐348
d, = 1.5 Hz, 3H), 1.70‐1.73 (m, 2H), 1.82 (dd, = 13.1, 4.5 Hz, group. This research is a part of the Doctoral Thesis of P.
1H), 3.37 (dd, = 12.7, 4.4 Hz, 1H), 4.03 (d, = 18.4 Hz, 1H), Gutierrez.
4.23 (dd,
= 18.4, 2.0 Hz, 1H), 5.15 (s, 1H). 13C NMR (CD3OD,
100 MHz): 15.8 (CH3), 18.8 (CH2), 20.1 (CH2), 21.8 (CH3), 23.4
δ
0.80 (s, 3H), 0.82 (dd,
J
= 12.2, 2.5 Hz, 1H), 0.87 (s, The authors thank the Spanish Ministry of EVcioewnoArmticlye Oanlninde
DOI: 10.1039/C6OB01640E
J
= 13.3, 3.8 Hz, 1H), 1.24 (s, 3H), Competitiveness (Project CTQ2014‐56611‐R/BQU) and the
J
J
=
Regional Government of Andalucia (Project P11‐CTS‐7651) for
J
J
J
J
J
δ
(CH2), 23.9 (CH3), 26.2 (CH3), 29.2 (CH2), 33.3 (C), 33.6 (CH3),
36.3 (CH2), 38.0 (C), 40.6 (CH), 41.8 (CH), 50.3 (CH), 55.9 (CH),
61.7 (CH2), 79.9 (C), 123.5 (CH), 133.7 (C). IR (film): 1052, 1111,
1127, 1218, 1384, 1450 cm‐1. HRMS (FAB) m/z calcd for
C20H34ONa (M + Na+) 313.2507, found 313.2516.
Notes and references
1
2
P. A. Horton and P. Crews, J. Nat. Prod. 1995, 58, 44.
D. Iliopoulou, N. Mihopoulou, V. Roussis and C.Vagias, J.
Nat. Prod. 2003, 66, 1225.
M. Reggelin, M. Gerlach and M Vogt, Eur. J. Org. Chem. 1999,
1011.
3
4aS,6aR,8aS,9aR,11bS)‐4,4,6a,9a,11b‐
Pentamethyltetradecahydro‐1H‐naphtho[2,1‐b]oxiren[2,3‐
4
5
S. Serra and V. Lissoni, Eur. J. Org. Chem. 2015, 2226‐2234.
F. W. J. Demnitz, S. Freiberg and H.‐ P. Weber, Helv. Chim.
Acta 1995, 78, 887.
E. Alvarez‐Manzaneda, R. Chahboun, E. Cabrera, E. Alvarez,
A. Haidour, J. M. Ramos, R. Alvarez‐Manzaneda, M.
Hmamouchi and H. Es‐Samti, Chem. Commun. 2009, 592.
(a) A. F. Barrero, E. Alvarez‐Manzaneda, R. Chahboun and M.
C. Páiz, Tetrahedron Lett. 1998, 39, 9543; (b) A. F. Barrero, E.
Alvarez‐Manzaneda, R. Alvarez‐Manzaneda, R. Chahboun, R.
Menenes and M. Aparicio, Synlett 1999, 713.
f]oxocane (29).
m‐Chloroperbenzoic acid (70%, 147 mg, 0.6
6
mmol) was added to a solution of compound 28 (125 mg,
0.431 mmol) in dichloromethane (10 mL), cooled at 0 °C, and
the reaction mixture was stirred for 1 h, at which TLC showed
no remaining starting material. Then, a 10% Na2SO3 solution
(10 mL) was added, and the mixture was stirred for an
additional 15 min. Then the reaction was extracted with EtOAc
(3 x 20 mL). The organic phase was successively washed with
sat. NaHCO3 (3 x 30 mL) and brine (2 x 30 mL), and dried over
anh Na2SO4 and evaporated to give a crude residue, which,
after column chromatography on silica gel (5% EtOAc/hexane),
7
8
9
E. Alvarez‐Manzaneda, R. Chaboun, E. Alvarez, A. Fernández,
R. Alvarez‐Manzaneda, A. Haidour, J. M. Ramos and A.
Akhaouzan, Chem. Commun. 2012, 48, 606.
A. F. Barrero, E. Alvarez‐Manzaneda, R. Chahboun and A. F.
Arteaga Synth. Commun. 2004, 34, 3631.
1
10 Y. X. Tang and T. Suga, T. Phytochemistry 1994, 37, 737.
11 B. A. Baker, Z. V. Boskovic and B. H. Lipshutz, Org. Lett. 2008,
10, 289.
afforded epoxyde 29 (2.3 g, 93%) as a colourless oil. H NMR
(CDCl3, 400 MHz):
(s, 3H), 1.29 (s, 3H), 1.90 – 1.21 (m, 15H), 2.44 (dd,
Hz, 1H), 2.80 (d, = 2.0 Hz, 1H), 3.89 (d, = 15.8 Hz, 1H), 4.03
(dd, 15.33
= 15.8, 2.2 Hz, 1H). 13C NMR (CDCl3, 125 MHz) :
δ
0.81 (s, 3H), 0.86 (s, 3H), 0.90 (s, 3H), 1.16
J
= 13.3, 5.5
J
J
J
δ
(CH3), 18.96 (CH2), 20.02 (CH2), 20.82 (CH2), 21.95 (CH3), 23.09
(CH3), 23.68 (CH3), 31.72 (CH2), 33.47 (C), 33.77 (CH3), 36.93
(CH2), 38.35 (C), 40.88 (CH2), 41.84 (CH2), 49.51 (CH), 56.17
(CH), 58.31 (CH2), 61.10 (C), 64.22 (CH), 80.33 (C). HRMS (FAB)
m/z calcd for C20H34O2Na (M + Na+) 329.2457, found 329.2461.
Conclusions
In summary, the first synthesis of arenaran A (1) and B (2),
utilizing a ring‐closing metathesis (RCM) process, starting from
commercial (‐)‐sclareol (20) is reported. For the RCM process
to be successfully applied, some structural requirements must
be met. The trans‐fused structure of the natural products is
corroborated by comparison of their spectroscopic data with
those of the cis‐fused isomer (epi‐arenaran A, 13), which was
also synthesized. This strategy can also be utilized for
preparing other natural oxocene terpenes. Thus, the epoxide
29, the 3‐debromoderivative of the natural terpene 3, has
been synthesized from the diterpene 20
.
Acknowledgements
10 | J. Name., 2012, 00, 1‐3
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