Mimicking Halimane Synthases: Monitoring a Cascade of Cyclizations and Rearrangements from Epoxypolyprenes

Article abstract of DOI:10.1021/acs.joc.9b01996

We have developed and rationalized a biomimetic transformation mimicking halimane synthases based on a Lewis acid-catalyzed cascade of cyclizations and rearrangements of epoxypolyprenes. Two rings, three stereogenic centers, and a new double bond were generated in a single chemical operation. Based on this cascade transformation, we achieved a unified strategy toward the stereoselective total syntheses of halimene-type terpenoids and analogues as a proof-of-concept study. This method has been applied to the rapid synthesis of diterpene isotuberculosinol, a virulence factor of Mycobacterium tuberculosis as a representative example.

Full text of DOI:10.1021/acs.joc.9b01996

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Article
Mimicking Halimane-Synthases: Monitoring a Cascade of
Cyclizations plus Rearrangements from Epoxypolyprenes
José F. Quilez del Moral, Victoriano Domingo, Alvaro Perez, Kevin A. Martinez Andrade,
Lourdes Enriquez, Martin Jaraiz, José Luis López-Pérez, and Alejandro F. Barrero
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01996 • Publication Date (Web): 27 Sep 2019
Downloaded from pubs.acs.org on September 28, 2019
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Mimicking Halimane-Synthases: Monitoring a Cascade of
Cyclizations plus Rearrangements from Epoxypolyprenes.
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José F.Quilez del Moral *, Victoriano Domingo , Álvaro Pérez , Kevin A. Martínez Andrade , Lourdes
‡
‡
‖,
†,
Enríquez , Martín Jaraiz , José Luis López-Pérez *, and Alejandro F. Barrero *
†Department of Organic Chemistry, Institute of Biotechnology, University of Granada, 18071 Granada,
Spain.
‡Department of Electronics, University of Valladolid, 47011 Valladolid, Spain.
‖Department of Pharmaceutical Sciences, IBSAL-CIETUS, University of Salamanca, 37007 Salamanca,
Spain. Department of Pharmacology, Faculty of Medicine, University of Panama, Republic of Panama.
TOC GRAPHIC
ABSTRACT: We have developed and rationalized a biomimetic transformation mimicking halimane-
synthases based on a Lewis acid-catalyzed cascade of cyclizations plus rearrangements of
epoxypolyprenes. Two rings, three stereogenic centers and a new double bond were generated in a
single chemical operation. Based on this cascade transformation, we achieved a unified strategy toward
the stereoselective total syntheses of halimene–type terpenoids and analogues as a proof–of–concept
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study. This method has been applied to the rapid synthesis of diterpene isotuberculosinol, a virulence
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factor of Mycobacterium tuberculosis as representative example.
INTRODUCTION
Biomimetic strategies allow the construction of complex natural products in a minimum of steps. The
benefits of these processes are recognized worldwide, with the ‘‘atom and step economy’’ approach of
green chemistry which are of special interest. 1–4 In the field of terpenoid biogenesis, the generation of
the hopanoid skeleton by squalene cyclases, where five new cycles and up to nine stereogenic centers
are created constitutes an excellent example of the spectacular and potentiality of this process.3,5
Challenged by these fascinating transformations, researchers have been trying to replicate the action of
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these enzymes for over a century. Although the use of either Brönsted or Lewis acids have been by far
the most common method to achieve biomimetic polycyclizations of isoprenoids in the lab,3,6–16 other
astonishing protocols including those involving enzymes17–20 and radical cyclizations have also been
reported.21–23 An outstanding milestone in this synthetic effort was the achievement of enantioselective
cyclization protocols of some polyenes.24–29
Often oxidosqualene- and other terpene cyclases, in addition to cyclization processes, give rise to a
series of hydride and methyl shifts before releasing the final natural product. Up to seven of these
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rearrangements take place in the biosynthesis of triterpene cucurbitanes. Obviously, the difficulty of
reproducing these processes using chemical reagents involving cyclizations and rearrangements
increases significantly. In this regard, van Tamelen and Sharpless reported in 1969 that the treatment of
squalene 2,3-oxide with stannic chloride led to a mixture of cyclized products, including a rearranged
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bicyclic alcohol possessing the halimane core. Apart from van Tamelen´s seminal work, to the best of
our knowledge, no precedents exist on addressing rationalized synthesis of “rearranged terpenes” using
this approach. However, efficient rearrangements of carbocations generated on previously cyclized
structures can be found in the literature.31–37 Some of these non-enzymatic rearrangements can be
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considered as nice examples of the minimal-enzymatic-assistance hypothesis,4,38 thus encouraging the
biomimetic pursuit of these complex reactions.
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The bicyclic backbone B present in diterpene halimene–type skeleton is a common molecular
fragment conserved in important biologically active natural products39–44 (Figure 1a). Biosynthetically, it
must be derived from (E,E,E)-geranylgeranyl diphosphate through “halimane synthases” catalysis. This
process starts with a class II diterpene cyclase (DTC) mediated protonation of the terminal
isopropylidene to give a bicyclic carbocation intermediate which later suffers several rearrangements of
hydride and methyl groups.45 Other common DTCs (such as copalyl synthases for example) only
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produce diterpenes as labdanes by deprotonation of the labda-13-en-8-yl intermediate A. Among the
many substances presenting the halimene framework, diterpenes such as isotuberculosinol (1) and 1-
tuberculosinyladenosine were reported to be the virulence factors42 isolated from Mycobacterium
tuberculosis the causative agent of the human disease tuberculosis, a worldwide health threat
responsible for approximate 1.7 million deaths annually.46 Due to their interest and structural
complexity of these substances, multistep synthesis or semi-synthesis has been developed.47–48
Here, we describe our efforts to know to what extent the action of “halimane synthases” can be
mimicked in the laboratory in vitro, that is, to generate the bicyclic halimene skeleton starting from a
simple acyclic epoxypolyprene in a one-step cascade process including two head-tail cyclizations and
two or three 1,2-Wagner-Meerwein rearrangements (Figure 1b).
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Figure 1. Accessing to the halimane skeleton. a, Biosynthesis of the halimanes: some representative
halimane–type terpenoids. b, Bionspired synthesis of halimanes: Is it achievable a tandem cyclization-
rearrangement process leading to halimenes?
Taking advantage of the tremendous effort devoted by chemists for decades to comprehend
carbocationic polycyclizations and before starting any experimental tests, we evaluated and analysed the
possible requirements that each of the agents involved in the cyclization process. Selection of the
oxyrane group as an initiator is fundamental in this strategy because it must provide the selective and
soft formation of the initial acyclic carbocation by oxyrane opening. Concerning the structural
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requirements the acyclic precursor, the presence of unsaturations in the terminal “R” moiety, as in the
case of C20 geranylgeraniol derivatives or longer polyprenes, or functions containing heteroatoms
located close to the C–8 carbocation II should be avoided since they could favour subsequent
cyclizations or E1 deprotonations respectively (Figure 1b).26,49 With regard to the reaction medium, the
use of non-basic and poor nucleophilic solvents and low temperatures should help to induce the
rearrangement process by avoiding the E1 processes. Finally, considering the requirements for the acid
that mediates the process, it should be a Lewis acid that, after coordination to the oxirane, should permit
its opening and subsequent cyclization, and most importantly, should prevent any fast ligand
dissociation in the generated intermediate zwitterionic species resulting from the oxyrane opening (II,
Figure 1b). This zwitterion possesses a carbocation and a metalanion-alkoxide, which will bear the
negative charge during the whole process. Thus, when the cyclization is over, the cation at C–8 in the
absence of any base or nucleophile could evolve to the rearranged products if the process is
energetically favourable. Although different rearrangements could be conceivable, the series of 1,2-
migrations of hydride and methyl groups leading to the different expected halimene skeletons seems to
be, a priori, stereoelectronically favoured (Scheme 2). Additionally, in our opinion, the negative charge
located at the metal bound to the oxygen may exert an electrostatic attraction on the bicyclic cation at
C–8, thus-favouring those rearrangements that bring the charges closer. This reasoning regarding the
role that the Lewis acid should exert in this process parallels the interesting rationalization provided by
Shenvi to account for their results on the aluminium Lewis acids-mediated tail-to-head transformations
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of a nerolidol-based vinyl epoxide, mimicking class I terpene cyclases. Thus, the authors claim that
key to the success of their approach was the “sequestration of the counteranion using non-dissociating
ligands”. Eventually, and after prolonged reaction times, the dissociation of a chloride ion from the
aluminate anion could be responsible for the ultimate deprotonation leading to the halimene skeleton.
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RESULTS AND DISCUSSION
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To verify the experimental viability of our hypothesis, we started this biomimetic approach by
choosing the monoepoxide of farnesylbutane 2 as a simple model of a starting material. For the Lewis
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DCM (0.1 M) for 40 min, an equimolecular mixture of epimers at C–8, 3a–3b possessing the rearranged
skeleton of halima-5-ene and syn- halima-5-ene was obtained in 51% yield (Table 1, entry 1), together
with minor proportions of the non-rearranged monocyclic (7b) and bicyclic products (8b) (3% and 2%,
respectively), as well as the acyclic aldehyde 6 (1.5%). The different mechanistic steps rationalizing the
generation of the products obtained in this transformation are depicted in Scheme 1.
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Scheme 1. Mechanistic Steps Leading to the Generation of 3–9.
Compound 3b turned out to present a restricted conformational equilibrium at rt on ring B and as
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consequence the resolution of NMR spectra, especially in C NMR, is low. A complete characterization
of this isomer was only possible after conducting the NMR experiences at 90 ºC in deuterated DMSO.
Molecular Mechanics conformational search first and quantum chemical calculations then performed on
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a and 3b revealed the existence of two pairs of main conformers of similar stability (≤1 kcal/mol) for
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each epimer. The energetic barrier calculated for 3a (7.2 Kcal/mol) supports a rapid rate of
interconversion in agreement with the experimental data in NMR, whereas the interconversion barrier
between the two conformers of 3b (14.0 kcal/mol) may well account for a slow conformational
equilibrium between these two species (see Supplementary Information). This phenomenon was
reported in related natural products presenting the stereochemistry assigned to 3b.19,40a
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In order to gain a comprehensive mechanistic and energetic understanding of the different steps of the
bicyclization-rearrangement cascade from 2 to 3a–3b, quantum chemical calculations were carried out
using 14,15-epoxygeranylcitronelene (I) as a diterpene model and Me AlCl as a catalyst. Previous
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inexpensive SCW calculations allowed us to find two main productive prochiral conformations (Ia and
Ib) of the acyclic precursor, namely, chair-boat and chair-chair conformations, both possessing similar
stabilities (difference 0.3 Kcal/mol, Figure 2). The results obtained from the computational study of the
entire process are represented in Figure 2 (see Supplementary Information for details).
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Figure 2. Energy diagram for the formation of species I–X leading to halimenes 3a–b. Relative energies [kcalmol, B3LYP/6-31+G(d,p) empirical
dispersion=gd3b], in normal text for SMD solvation model by a single point energy calculation, and in brackets for calculations in vacuo. Selected
distances in Å in TSs. For simplification of the figure, the moiety ClMe Al-O appears represented by L, and R stands for n-butyl.
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Calculations showed differing results considering the generation of the labdan-8-yl cationic
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intermediate III. Thus, whereas the calculations performed in vacuum showed that the two cyclizations
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were stepwise, no minimum of energy was found for this first cyclization when the calculations were
performed considering the presence of CH
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(concerted process). Although the concerted
asynchronous processes were the result obtained when the solvent was included in the calculations,51–52
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the feasibility of a stepwise scenario should not be ruled out, mainly when this mechanism would well
account for the generation of minor monocyclic products 4, 5, 7 and aldehyde 6, found in the reaction of
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After the formation of bicyclic cations IIIa and IIIb, one 1,2 hydride C
1,2-methyl C10 → C migration were predicted to take place, overcoming small barriers leading to the
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haliman-10-yl carbocations Va and Vb. Rearranged intermediates Va and Vb undergo a ring A
conformational change implying a variation of the space disposition of the dimethylcholoroaluminate
group from equatorial towards an axial arrangement. As consequence of this conformational change, the
chlorine atom gradually approaches to C–10 carbocation, thus contributing to the stabilization of the
intermediates VII due to the favourable electrostatic interactions between the negative charge of the
chlorine atom partially detached from the alcoxyaluminate and the carbocation at C–10. In fact, the
initial distance of Al–Cl, (2.27Å) when the aluminate was equatorially disposed, is gradually lengthened
to 2.53Å when it is axial in both intermediates VIIa and VIIb, while the distance C10–Cl, 1.99Å, is still
far from the 1.85Å of a typical Csp3–Cl bond. The fact that the chlorine atom is not completely detached
from the aluminate anion is of paramount importance, since it not only permits the cascade of Warner-
Meerwein rearrangements of the molecule to continue; but it also favours the interconversion of
carbocations VII to VIII through C → C10 hydride shift from the alpha face of the halimane skeleton, a
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process thermodynamically favourable in 6 kcal/mol. Subsequently, the C3–C4 bond of VIII undergoes
a gradual elongation until it breaks to give a 10-12 Kcal/mol more stable seco-3,4-halimane monocyclic
aldehyde complex intermediates IX.
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+
In this regard, a related A contraction of a halima-13E-en-15-PP-5-yl intermediate was proposed to
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occur in the biosynthesis of premutilin, proposal that was supported by quantum chemical
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calculations. All that led us to hypothesize that the theoretically-proposed route to aldehydes IX may
constitute a possible biosynthetic pathway to natural 3,4-seco-halimanes such as secochiliotrin methyl
ester or secochiliolide aldehyde.67
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The unsaturated aldehydes IX suffer a concerted process with activation energy near to 10 kcal/mol
where A ring is regenerated through a intramolecular Prins reaction with a simultaneous proton transfer
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from C–6 (H-6) to O–3 to produce the final ∆ halimanes X. It is worth noting that the particular
space orientation of the oxygen atom resulted in the Prins process in TSIX–X, which facilitated the final
proton transfer.
These computational calculations are consistent with those recently reported on biosynthetic studies
of halimenes not oxigenated at C319,55 and, more significantly, they shed some light on the three most
relevant figures of our cyclization-rearrangement experimental process. Thus, the solvent CH
2
Cl plays
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an important role provoking a significant decrease in the energetic barriers to cyclizations and
rearrangements, probably as consequence of carbocation stabilization. Secondly, the formation of two
stereoisomers at C8, 3a and 3b, is a consequence of the co-existence of a pre-chair-boat Ia acyclic
precursor competing against the pre-chair-chair Ib precursor (both initial precursors and transition-states
structures for the first cyclization step were predicted to be almost isoenergetic, see Supplementary
Information). Furthermore, the role played by the oxygen and chlorine atoms in the non-detached
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alkoxyaluminate anion, possibilitating the A ring opening and the ensuing concerted Prins reaction and
H6-deprotonation, supported the high selectivity observed toward haliman-5-enes among all the
possible olefinic regioisomers and also versus other kinds of rearranged products. Finally, the recovery
of the Lewis acid unaltered renders the process susceptible to catalysis by the Lewis acid.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Once we proved that the mechanism and the energetic barriers calculated for the cyclization and
rearrangement processes supported the experimental results obtained with model 2, we focused our
efforts on optimizing the experimental conditions for this transformation. To this end, a screening of
different Lewis acids, concentrations, temperatures and solvents was achieved (Table 1).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 1. Screen of the Cyclization-Rearrangement Experimental Conditions of Epoxide 2
temp
(ºC), C
solvent
7a, 7b
yield
(ratio)
time
3a, 3b
4, 5, 6
8a, 8b, 8c
yield (ratio)
entry
equiv/LA
(
min) yield (ratio) yield (ratio)
(
mM)
1
2
1/Me
1/Et
2
AlCl
-78, 0.03
-78, 0.03
Reflux,
DCM
DCM
45
45
51% (1:1)
2% (0:0:1)
3% (1:0)
2% (1:0:0)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0%
2
AlCl
54% (1:1.1) 3% (1:0:0.2)
ND
(
0:0.6:1)
3
4
0.1/Bi(OTf)
1/Cu(OTf)
3
DCM
DCM
DCM
40
30
ND
ND
4% (1:0:0)
ND
4% (1:0)
23% (1:0:0)
0
.03
19%
17%
(5.7:0.2:1)
2
-78, 0.03
(
1:0.3)
1
3%
5a
1/InBr
1/InBr
0.5/Et
1.5/Et
-78, 0.03
RT, 0.03
300
27% (1:0.8)
4% (1:0:0)
ND
3
(
0:0.3:1)
6b
7
DCM
DCM
DCM
100
100
50
37% (1:0.4)
53% (1:1)
59% (1:1)
7% (1:0:0)
ND
9% (1:0.2) 9% (0:0.8:1)
ND
3% (1:0)
3
2
AlCl -78, 0.03
ND
2% (1:0:0)
8
2
AlCl
-78, 0.03
ND
1
0%
9
2/Et
2
AlCl
-78, 0.03
DCM
45
71% (1:1.1)
6% (1:0:1)
ND
(
0:0.6:1)
1
1
0
1
3/Et
5/Et
2
2
AlCl
AlCl
-78, v
-78, 0.03
DCM
DCM
40
35
65% (1:1)
59% (1:1)
34% (1:1)
5% (1:0:0.4)
ND
ND
ND
4% (0:0.3:1)
ND
-100,
12
2/Et
2
AlCl
DCM
60
ND
ND
ND
0
.03
1
14
3
2/Et
2/Et
2
2
AlCl
AlCl
0, 0.03
-78, 0.3
-78,
DCM
DCM
30
25
50% ((1:1)
63% (1:1)
7% (1:0:0.2)
ND
ND
3% (1:0)
13% (0:0:1)
ND
15
2/Et
2
AlCl
DCM
50
58% (1:1)
2% (1:0:0)
ND
ND
0.003
1
6c
2/Et
2/Et
2/Et
2/Et
2/Et
2/Et
2/Et
2/Et
2/Et
2
2
2
2
2
2
2
2
2
AlCl
AlCl
AlCl
AlCl
AlCl
AlCl
AlCl
AlCl
AlCl
-78, 0.03 Hexane
10, 0.03 Bencene
-78, 0.03 Toluene
-78, 0.03
-78, 0.03
-30, 0.03
-20, 0.03
-60, 0.03
60
45
45
50
210
30
30
70
65
27% (1:1)
54%(1:0.8)
68% (1:1)
4% (1:1)
ND
40% (1:1.2)
56% (1:0.8)
59% (1:1.1)
ND
ND
5%(0.7:1:0)
2%(1:0:0)
ND
4 (1:0:1)
ND
5%(1:0:0)
2(1:0:0)
ND
ND
ND
ND
ND
ND
ND
1
1
1
7
8
9
TBME
THF
DCE
57 (1:1.3) 21%(0:1.6:1)
4 (1.1:1)
ND
d
20
ND
2
2
2
1
2
3
7 (0:1:0)
3 (0:0:1)
7 (0:0:1)
22 (1:0:0)
CCl
CHCl
4
ND
ND
ND
3
e
24
-40, 0.03 CH
3
CN
a
b
Compound 9a was obtained in 14% yield. Minor proportions of its epimer at C8 was detected by NMR from the mixture.
c
Compound 9a was obtained in 15% yield. Its epimer at C8 was detected by NMR from the mixture. 60% recovered starting
material. Compound 10 was obtained in 91% yield Compound 11 was obtained in 43% yield.
d
e
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To start, several Lewis acids were tested to trigger the cyclization-rearrangement process (Table 1,
1
2
entries 1–6). Although the two alkyl aluminum Lewis acids used led to acceptable yields of 3a and 3b,
comparatively slight yield improvements were found when Et AlCl was used (Table 1, entry 2).
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
Copper(II) and bismuth(III) triflates failed to produce the desired halimane derivatives, and a complex
mixture of non-rearranged monocyclic and bicyclic structures was observed (Table 1, entries 3–4). The
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
results obtained with InBr
halim-5-ene derivatives 3a and 3b, the formation of haliman-1(10)-enes 9a and 9b was observed (Table
, entries 5–6). The greater volume of the Lewis acid in this case, hampering its approach to C–10 and
3
deserve a special mention, where together with the previously generated
1
therefore the stabilization of the carbocation at this position, may be postulated to rationalize these
results.
All in all, Et
2
AlCl was selected as catalyst of choice. Variations in the quantity of Et
2
AlCl used (Table
1
, entries 7–11) caused an improvement in the efficiency of the process. Thus, up to a 71% yield of the
desired halim-5-enes was obtained when 2 equivalents of Lewis acid were used (Table 1, entry 9).
Changes in the temperature do not produce significant yield differences (Table 1, entries 9, 12–13), with
the best results being obtained when the reaction was conducted at -78º C. Furthermore, the influence of
molar concentration on production of 3a and 3b was also moderate as can be concluded from the results
obtained in entries 9, 14 and 15 of the Table 1.
Finally, significant alterations of the reaction outcome were revealed when different solvents were
tested. Thus, the use of hexane as a solvent slowed down the process significantly, and after 1h, most of
the starting material remained mainly unaltered (Table 1, entry 16). Good yields were obtained in
benzene and toluene (54% and 68%, respectively) (Table 1, entries 17–18), probably due to the
stabilization of carbocation intermediates. The effect of ethereal solvents was counter-productive and
mainly regular mono- and unrearranged bicyclization products 7 and 8 were obtained (Table 1, entries
1
9–20). Easy deprotonation of the corresponding bicyclic cations by solvents acting as Brønsted bases
may account for the observed reactivity. The use of THF provoked the production of acyclic ketone 10
as major product as result of a 1,2-hydride shift of the initial acyclic carbocation. Other halogenated
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solvents were also tested and, although acceptable yields of the target 3a and 3b were produced (Table
, entries 21–23), the efficiency of the process was slightly worse when compared to that found when
using DCM. To conclude, a polar aprotic solvent such as CH CN was also made to react with epoxide 2
Table 1, entry 24) and the initial carbocation was neutralized by a molecule of acetonitrile leading to
the hydroxyacetamide 11 as a major product after work-up.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Once the experimental conditions were optimized (Table 1, entry 9), we proceeded to study the scope
of the process by altering the side chain of the epoxypolyprene (Table 2)
Table 2. Scope of the Biomimetic Cyclization–Rearrangement of Epoxypolyenes.a
a
Conditions: epoxypolyene (0.01 M), Et
2
AlCl (2-3 equiv), CH
Cl
2 2
, -78ºC, 45 min. The epimeric mixtures were separated by
b
semipreparative HPLC. Minor proportions of the corresponding epimer at C8 was detected by NMR from the mixture.
First of all the reaction of the tert-butyldimethylsilylderivative of 10,11-epoxyfarnesol 12 with
Et
2
ClAl in CH
Cl
2 2
only resulted in a mixture of bicyclization compounds, where no concomitant
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rearrangement were produced, in agreement with previous reported results.13,56 The presence of a
silyloxy group at C13 in compound 13 considerably reduced the efficiency of the process towards the
halimene type products 14b (20%), whilst when a double bond is located at C–14, as happens in 15, an
acceptable yield was again obtained (55% of halima-5-enes 16a–b). In both cases, a certain degree of
diastereoselectivity was noticed, favouring the rearranged structured derived from the chair-boat
conformation of the starting epoxide (methyl groups at C8 and C9: anti). In the reaction of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
epoxypreoleanatetraene 17 with Et AlCl, a good 75 % of a 1:1.3 mixture of the corresponding
2
tetracyclic derivatives (18a–b) was obtained, which evidenced a high energetic barrier for a third
cyclization in this case.57
When the monoepoxy derivative of methyl geranylgeraniate (19) was used as a starting material, the
diastereomer 20b resulting from the expected cyclization-rearrangement was obtained in a 29% yield. It
should be noted that the monocyclic ketone 21 (5.5%) was also obtained.
Perhaps the most elegant demonstration of the utility of this cascade of cyclizations plus
rearrangements strategy is displayed in the straightforward synthesis of the interesting halim-5-ene
isotuberculosinol (1). We also anticipated that, while addressing the synthesis of tuberculosinol, the
59
natural halimene viterofolin E, isolated from Vitex rotundifolia, could be produced en route (Scheme
2
). With these targets in mind, we treated the monoepoxy derivative of geranyllinalool (22) with
Et ClAl in DCM at -78 ºC. Unsurprisingly, the presence of a free hydroxyl group prevented the
2
cyclization-rearrangement process to take place efficiently, and only 12% of the corresponding halim-5-
enes (23) were produced. However, if the monoepoxy derivative of geranyllinalool acetate 24 was
subjected to the same conditions, an acceptable 53% yield of diastereoisomers 25 (1: 2.5) was obtained,
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Page 16 of 52
together minor proportions of 26 and 27. Of these two diastereomers, compound 25a presents the same
stereochemistry at C–8 and C–9 as that exhibited by isotuberculosinol (1) (Scheme 2), whereas the
second distereomer, 25b, shares the stereochemistry at C–8 and C–9 with viterofolin E. Reduction of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
5b with LAH allowed to complete the synthesis of viterofolin E as a mixture of epimers at C–13 (23b)
in only two steps and 34% yield from epoxide 24.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Continuing with the synthesis of isotuberculosinol, the pair of epimers 25 was deoxygenated
following the modified Barton-McCombie procedure, and then reduced with LAH. Isotuberculosinol 1
was thus obtained in 65% yield for the last three steps and in an overall 10% yield from
monoepoxyderivative 24. The spectroscopic data of synthetic isotuberculosinol matched completely
4
7
with those reported for the natural substance. Together with isotuberculosinol, its 8-epi-isomer 1b was
isolated in 25% yield. Although this substance has not been described as natural product so far, it was
enzymatically produced.60
Scheme 2. Synthesis of (±) isotuberculosinol.
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Once we proved that rearranged diterpenes can be produced after a tandem process of cyclization and
rearrangements, we turned back (our attention) to one of the conclusions inferred from the
computational calculations, namely, (that) the process is susceptible to catalysis by the Lewis acid.
Thus, we treated epoxide to substoichiometric quantities of different Lewis acids (Table 3). Although
the use of 50% mmol of dimethylaluminium chloride also produced 3a and 3b with acceptable yield
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(table 3, entry 1), when the quantity of dimethylaluminium chloride was lowered up to 0.2 equiv, the
process showed no completion after 5h of reaction time, and 31% of starting material remained
66
unaltered (Table 3, entry 2). We decided then to test different gallium and indium halides. Although
the use of indium halides (Table 3, entries 3–4) led to low yields of the rearranged products 3a and 3b,
the use of 0.2 equiv of different gallium halides led, gratifyingly, to acceptable yields of the desired
halim-5-ene derivatives (Table 3, entries 5–7). We finally found that the quantity of GaCl could be
3
reduced to 0.01 equiv without decreasing the yield of the halim-5-enes produced (Table 3, entry 8).
Table 3. Generation of Halim-5-enes derivatives (3a–
3b) from Epoxide 2 Using Catalytic Quantities of
Lewis Acidsa
temp (ºC),
time (min)
3a, 3b
yield (ratio)
entry equiv/LA
1
0.5/Me
0.2/Me
2
2
AlCl
AlCl
-78, 100
-78, 180
rt, 15
rt, 55
rt, 5
53% (1:1)
32% (1:1.7)
28 %(1:0.8)
12% (1:2)
56% (1:1)
53% (1:1)
54% (1:1)
55% (1:1)
51% (1:1)
b
2
3
4
5
6
7
8
9
0.2/InI
0.2/InCl
0.2/GaCl
0.2/GaI
0.2/GaBr
0.1/GaCl
0.01/GaCl
3
3
3
3
rt, 5
3
rt, 5
3
rt, 5
3
rt, 5
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a
b
DCM was used as solvent, 0.03 C (mM). ·31% of starting material
was recovered.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Finally, considering both the enormous biosynthetic importance of the cyclization of squalene-2,3-oxide
and the fact that its cyclization with SnCl supposed the only precedent so far reported of cyclization
and rearrangement to produce halim-5-enes, we decided to study the behavior of squalene-2,3-oxide
28) in the presence of aluminium and gallium Lewis acids. The results obtained are summarized in
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
Scheme 3.
Scheme 3. Cyclization of oxidoaqualene with Et
2
AlCl and GaCl .
3
a
Minor proportions of the corresponding epimer at C8 was detected by NMR from the mixture.
Although no reported by van Tamelen, monocycles 29 and 30 were found previously in the
cyclizations of 28, either triggered by different acids or in processes involving cyclases.62,63 Aldehyde
1
3
1 was described for the first time. Halim-5-ene 32 presented the same H NMR signals to that of the
halimene described by van Tamelem, which allowed us to assign unambiguously the stereochemistry of
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the product reported by these authors. It should be noted that van Tamelen and Sharpless suggested the
opposite configuration at C9 for this compound in their seminal contribution. Finally, the rearranged
malabaricanes thalianol (33) and 14-epithalianol (34) were also produced in these transformations.64,68
Although van Tamelen amazingly assigned in 1966 the same rearranged malabaricane to the tricyclic
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
compound generated in the reaction of squalene-2,3-oxide with SnCl
4
, our work suggest that the same
-mediated cyclization.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mixture of thalianol and 14-epithalianol could have been generated in the SnCl
4
To conclude, the yields of 32-34 and their corresponding stereochemistries seem to indicate that, on the
one hand, the bicyclic cation derived from the chair-chair conformation of squalene-2,3-oxide evolves
via a third cyclization to produce the rearranged malabaricanes 33 and 34, after a hydride and methyl
shift, and a proton elimination (Scheme 4). On the other hand, the bicyclic intermediated derived from
chair-boat conformation of the acyclic precursor would undergo the corresponding 1,2-shifts to generate
the halim-5-ene derivative 32.
Scheme 4. Formation of 32-34 from epoxide 28.
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CONCLUSIONS
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Nature produces numerous examples of rearranged diterpenes and triterpenes. In this regard, we prove
that rearranged halima-5-enes can be produced in a single synthetic step by reacting monoepoxy-
geranylgeraniol derivatives with appropriate Lewis acids, via a cascade of two cyclizations and three
rearrangements. The fact that we were capable to generate “in vitro” the halima-5-ene skeleton
constitutes a nice illustration of the theory of “minimal enzymatic assistance”, which was postulated to
define the action of cyclases in the generation of related natural products. Quantum chemical
calculations revealed, on the one hand, that the energetic barriers calculated for the cyclization and
rearrangements processes were low enough to support our mechanistic proposal and, on the other hand,
that the process was susceptible to catalysis by the Lewis acid. This last inference was confirmed
experimentally, and acceptable yields of rearranged halim-5-ene derivatives could be produced after
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
employing 0.01 equiv of GaCl .
3
EXPERIMENTAL SECTION
General Remarks.
All air- and water-sensitive reactions were performed in flaks flame-dried under a positive flow of
argon and conducted under an argon atmosphere. The solvents used were purified according to standard
literature techniques and stored under argon. Anhydrous dichloromethane was distilled from calcium
hydride (5 % w/v) under positive pressure of nitrogen. THF was freshly distilled immediately prior to
use from sodium/benzophenone and strictly deoxygenated for 30 min under Argon. Reagents were
purchased at the higher commercial quality and used without further purification, unless otherwise
stated. Silica gel SDS 60 (35-70 m) was used for flash column chromatography. Reactions were
monitored by thin layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-
2
54) using UV light as the visualizing agent and solutions of phosphomolybdic acid in ethanol. HPLC
with UV detection was used. Semi-preparative HPLC separation were carried out on a column (5 m
Silica, 10 X 250 mm) at a flow rate of 2.0 mL/min in an Agilent Series 1100 instrument. NMR spectra
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1
13
were performed with a Varian Direct Drive 600 ( H 600 MHz/ C 150 MHz), Varian Direct Drive 500
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(1
H 500 MHz/ C 125 MHz), Varian Direct Drive 400 ( H 400 MHz/ C 100 MHz) and Varian Inova
13
1
13
1
13
Unity ( H 300 MHz/ C 75 MHz) spectrometers. High-resolution MS were determined on an Autospec-
Q VG-Analytical (FISONS) mass spectrometer. DEPT 135 and two-dimensional (COSY, HSQC,
HMBC, NOESY) NMR spectroscopy were used where appropriate to assist the assignment of signals in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
the H and C NMR spectra.
Preparation of polyenic precursors 35–38.
(
6E,10E)-2,6,10-Trimethylhexadeca-2,6,10-triene (35). To a solution of farnesyl acetate (1000 mg,
3.78 mmol) in 20 mL of THF cooled at 0ºC was added 3.8 mL of Li CuCl (0.38 mmol). The resulting
solution was cooled at -30 ºC and then, 2.83 mL of butylmagnesium chloride were added dropwise
5.67 mmol). After stirring for 4 h, the reaction mixture was diluted with tertbutyl methyl ether (MTBE)
(120 mL) and then washed with saturated aqueous NH Cl and brine. The organic layer was then dried
2
4
(
4
with anhydrous Na
2
SO
4
and concentrated under reduced pressure. Purification by flash chromatography
1
with hexane (H) provided 971 mg of compound 35 (97%). Colourless oil. H NMR (400 MHz, CDCl
3
):
δ 5.15–5.08 (m, 3H), 2.11–2.04 (m, 4H), 2.01–1.97 (m, 6H), 1.68 (s, 3H), 1.60 (s, 9H), 1.36–1.26 (m,
1
3
1
6
H), 0.88 (t, J = 7.0 Hz, 3H); C{ H} NMR (101 MHz, CDCl
24.8 (CH), 124.4 (CH), 124.3 (CH), 39.7 (CH ), 39.7 (CH ), 31.5 (CH
), 17.7 (CH ), 16.0 (CH ), 15.9 (CH
35 263.2739, found 263.2732.
3
): δ 134.8 (C), 134.7 (C), 131.2 (C),
), 29.6 (CH ), 27.9 (CH ), 26.8
), 14.1 (CH ); HRMS
1
2
2
2
2
2
(CH
2
), 26.6 (CH
2
), 25.7 (CH
3
), 22.6 (CH
2
3
3
3
3
+
(ESI–QTOF) m/z: [M + H] Calcd for C19
H
Tert-butyldimethyl(((5E,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-yl)oxy)silane (36). To
a
solution of farnesyl ketone (1147 mg, 4.38 mmol) in 24 mL of THF cooled at 0ºC was added 141 mg of
LAH (3.72 mmol). The resulting solution was stirred for 20 min, and then, diluted with MTBE. To this
solution, 0.1 mL of H
2
O, 0.1 mL of 5N NaOH and 0.3 mL of H
2
O were added successively. The
resulting mixture was filtrated through a pad Na
2
SO and silica gel and concentrated under reduced
4
pressure. To a stirred solution of this reaction crude oil in 70 mL of DMF were added imidazole (627
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mg, 9.2 mmol) and TBSCl (1384 mg, 9.2 mmol). After consumption of the starting product (12 h), the
mixture was diluted with MTBE and water and extracted with MTBE. The combined organic layer was
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
washed with 2N HCl and brine, dried over anhydrous Na
2
SO and concentrated under reduced pressure.
4
Purification by flash chromatography (H:MTBE, 3:1) afforded 1460 mg of compound 36 (88%).
1
Colourless oil. H NMR (500 MHz, CDCl
3
): δ 5.17–5.08 (m, 3H), 3.80 (sext, J = 6.1 Hz, 1H), 2.12–
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
.92 (m, 10H), 1.69 (s, 3H), 1.61 (s, 9H), 1.53–1.67 (m, 2H), 1.14 (d, J = 6.1 Hz, 3H), 0.90 (s, 9H), 0.06
1
3
1
(
s, 6H); C{ H} NMR (125 MHz, CDCl
3
): δ 135.0 (C), 134.9 (C), 131.2 (C), 124.4 (CH), 124.3 (CH),
), 39.7 (CH ), 39.7 (CH ), 26.8 (CH ), 26.6 (CH ), 25.9 (3 x CH ),
), 23.8 (CH ), 18.2 (C), 17.7 (CH ), 16.0 (CH ), 16.0 (CH ), -4.4 (CH ), -4.7
); HRMS (ESI–QTOF) m/z: [M + H] Calcd for C24 47OSi 379.3396, found 379.3391.
6E,10E)-3,7,11,15-Tetramethylhexadeca-1,6,10,14-tetraene (37). A mixture of Cp TiCl
6.56 mmol) and Mn dust (3163 mg, 57.61 mmol) in deoxygenated THF 100 mL) was stirred at rt until
the red solution turned green, under an argon atmosphere. Then, a solution of geranylgeraniol (2092 mg,
.2 mmol) in strictly deoxygenated THF (5.0 mL) was added to the solution of Cp TiCl . The reaction
1
24.2 (CH), 68.4 (CH), 39.9 (CH
5.7 (CH ), 24.3 (CH
2
2
2
2
2
3
2
3
2
3
3
3
3
3
+
(CH
3
H
(
2
2
(4124 mg,
1
7
2
2
mixture was refluxed for 20 h. Then, the solution was diluted with MTBE, filtrated and the solid washed
with ethyl acetate. The organic layer was washed with HCl 2N, then with brine, dried over anhydrous
Na
2
SO
4
and concentrated in vacuo. The resulting crude was flash chromatographed (H) to give 1007 mg
1
(
51%) of compound 37. Colourless oil. H NMR (400 MHz, CDCl
3
): δ 5.71 (ddd, J = 17.2, 10.3, 7.5 Hz,
1
H), 5.16–5.08 (m, 3H), 4.96 (ddd, J = 17.2, 2.0, 1.2 Hz, 1H), 4.92 (ddd, J = 10.3, 2.0, 0.9 Hz, 1H),
13
1
2.17–1.96 (m, 11H), 1.68 (s, 3H), 1.60 (s, 9H), 1.38–1.27 (m, 2H), 0.97 (d, J = 6.7 Hz, 3H); C{ H}
NMR (75 MHz, CDCl ): δ 145.0 (CH), 135.1 (C), 131.5 (C), 124.8 (CH), 124.7 (CH), 124.5 (CH),
18.5 (C), 112.7 (CH ), 46.0 (CH), 40.0 (CH
(CH ), 25.9 (CH ), 20.4 (CH ), 17.9 (CH ), 16.3 (CH
Calcd for C20 35 275.2739, found 275.2727.
Methyl (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenoate (38). To a stirred solution
of geranylgeraniol (1000 mg, 3.45 mmol) in 40 mL in CH Cl under Argon was added Dess-Martin
3
1
2
2
), 37.6 (CH
3
), 37.0 (CH
2
), 27.0 (CH
2
), 26.9 (CH ), 26.0
2
), 16.3 (CH
3
); HRMS (ESI–QTOF) m/z: [M + H]+
3
2
3
3
3
H
2
2
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reagent (2925 mg, 6.9 mmol). After 2 h at rt the reaction was quenched with a saturated solution of
Na –NaHCO that was added slowly to the mixture, the combined organic layer was washed with
brine and dried over anhydrous Na SO and concentrated under reduced pressure. Filtration on silica gel
H: MTBE, 1:2) afforded the allylic aldehyde, which was dissolved in 30 mL of tert-butyl alcohol and
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
S
2
O
3
3
2
4
(
1
5 mL of 2-methyl-2-butene. A solution of sodium chlorite (1910 mg, 21.22 mmol) and sodium
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
dihydrogenphosphate (2200 mg, 15.92 mmol) in 15 mL of water was added dropwise over a 25 min
period. The pale yellow reaction mixture was stirred at room temperature for 2 h. Volatile components
were then removed under vacuum. The residue was dissolved in 150 mL of water and extracted with
two 100 mL portions of MTBE. The combined organic layers were washed with brine, dried and
concentrated. To a stirred solution of this reaction crude oil in 8.5 mL of benzene and 2.1 mL of MeOH,
1
.6 mL (3.2 mmol) of a 2M solution of TMSCH
2
2
N in hexanes was added dropwise. After consumption
of the starting product (30 min), the mixture was concentrated under reduced pressure. Purification by
flash chromatography (H/MTBE, 10:1) afforded 556 mg of compound 38 (51%). The spectroscopic data
of compound 38 coincide with those reported in the literature.58
General procedure for the synthesis of epoxy-derivatives 2, 13, 15 and 19
Powdered NBS (1.1 mmol) was added to a solution of the corresponding polyene (35–38) (1.0 mmol)
in a mixture of THF:H
washed with water, dried with anhydrous Na
The residue was dissolved in 8 mL of MeOH containing 1.2 mmol of K
min. The methanolic solution was then diluted with MTBE, washed with water, brine, dried with
anhydrous Na SO and the solvent removed, giving a residue which was flash chromatographed to give
the corresponding epoxides.
3-((3E,7E)-3,7-Dimethyltrideca-3,7-dien-1-yl)-2,2-dimethyloxirane (2). Following the general
2
O (12 mL, 5:1) at 0 ºC. The mixture was stirred for 30 min, diluted with MTBE,
SO and the solvent concentrated under reduced pressure.
CO (20 mL) and stirred for 10
2
4
2
3
2
4
(
procedure, successive reaction of polyene 28 with NBS and K
2
CO
3
/MeOH provided compound 2
1
(
45%). This compound was separated by flash chromatography (H:MTBE, 95:5). Colourless oil. H
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NMR (300 MHz, CDCl
3
): δ 5.17–5.11 (m, 2H), 2.70 (t, J = 6.2 Hz, 1H), 2.19–2.06 (m, 4H), 2.04–1.94
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(m, 4H), 1.70–1.63 (m, 2H), 1.62 (s, 3H), 1.59 (s, 3H), 1.33–1.27 (m, 6H), 1.30 (s, 3H), 1.26 (s, 3H),
1
3
1
0.88 (t, J = 6.5 Hz, 3H); C{ H} NMR (75 MHz, CDCl
CH), 64.2 (CH), 58.3 (C), 39.6 (CH ), 36.3 (CH ), 31.5 (CH
), 18.7 (CH ), 16.0 (CH ), 15.9 (CH
35O 279.2688, found 279.2681.
3
): δ 134.5 (C), 133.9 (C), 124.9 (CH), 124.9
), 29.5 (CH ), 27.9 (CH ), 27.5 (CH ),
), 14.1 (CH ); HRMS (ESI–
(
2
2
2
2
2
2
2
6.6 (CH
2
), 24.9 (CH
3
), 22.6 (CH
2
3
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
QTOF) m/z: [M + H] Calcd for C19
H
Tert-butyl(((5E,9E)-12-(3,3-dimethyloxiran-2-yl)-6,10-dimethyldodeca-5,9-dien-2-yl)oxy)dimethyl
silane (13). Following the general procedure, successive reaction of polyene 29 with NBS and
K
2
CO
3
/MeOH provided compound 13 (45%). This compound was separated by flash chromatography
1
(H:MTBE, 95:5). Colourless oil. H NMR (500 MHz, CDCl
3
): δ 5.17 (bt, J = 6.8 Hz, 1H), 5.13 (bt, J =
6
.9 Hz, 1H), 3.80 (sext, J = 6.0 Hz, 1H), 2.71 (t, J = 6.3 Hz, 1H), 2.19–1.92 (m, 8H), 1.71–1.57 (m, 2H),
.63 (s, 3H), 1.61 (s, 3H), 1.53–1.39 (m, 2H), 1.31 (s, 3H), 1.27 (s, 3H), 1.14 (d, J = 6.1 Hz, 3H), 0.90
1
1
3
1
(s, 9H), 0.6 (s, 6H); C{ H} NMR (75 MHz, CDCl
8.4 (CH), 64.2 (CH), 58.3 (C), 39.8 (CH ), 39.6 (CH
CH ), 24.9 (CH ), 24.3 (CH ), 23.8 (CH
.7 (CH
3
): δ 134.9 (C), 134.0 (C), 124.9 (CH), 124.4 (CH),
), 36.3 (CH ), 27.5 (CH ), 26.6 (CH ), 25.9 (3 x
), 18.2 (C), 16.0 (CH ), 16.0 (CH ), -4.4 (CH ), -
Si 395.3345, Found 395.3355.
6
2
2
2
2
2
3
3
2
3
), 18.8 (CH
3
3
3
3
+
4
3
); HRMS (ESI–QTOF) m/z: [M + H] Calcd for C24
H
47
O
2
2
,2-Dimethyl-3-((3E,7E)-3,7,11-trimethyltrideca-3,7,12-trien-1-yl)oxirane (15). Following the general
procedure, successive reaction of polyene 30 with NBS and K
2
CO
3
/MeOH provided compound 15
1
(58%). This compound was separated by flash chromatography (H:MTBE, 95:5). Colourless oil. H
NMR (300 MHz, CDCl ): δ 5.74–5.63 (m, 1H), 5.17–5.08 (m, 2H), 4.97–4.89 (m, 2H), 2.69 (t, J = 6.2
3
Hz, 1H), 2.15–2.04 (m, 6H), 2.00–1.92 (m, 5H), 1.66–1.63 (m, 2H), 1.61 (s, 3H), 1.58 (s, 1H), 1.35–
1
3
1
1
.30 (m, 2H), 1.29 (s, 3H), 1.25 (s, 3H), 0.98 (d, J = 6.7 Hz, 3H); C{ H} NMR (75 MHz, CDCl ): δ
3
145.0, 135.0, 134.2, 125.1, 124.9, 112.7, 64.4, 58.5, 39.9, 37.6, 37.0, 36.6, 27.7, 26.8, 25.9, 25.1, 20.4,
+
1
9.0, 16.3, 16.2; HRMS (ESI–QTOF) m/z: [M + H] Calcd for C20
H
35O 291.2688, Found 291.2677.
(19).
/MeOH
Methyl
(2E,6E,10E)-13-(3,3-dimethyloxiran-2-yl)-3,7,11-trimethyltrideca-2,6,10-trienoate
Following the general procedure, successive reaction of polyene 31 with NBS and K
2
CO
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provided compound 19 (34%). This compound was separated by flash chromatography (H:MTBE,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
0:1). Colourless oil. H NMR (500 MHz, CDCl
3
): δ 5.68 (bs, 1H) 5.15 (bt,J = 6.9 Hz, 1H), 5.10 (m,
1H), 3.69 (s, 3H), 2.71 (t, J = 6.2 Hz, 1H), 2.19–1.97 (m, 10H), 2.17 (d, J = 1.3 Hz, 3H), 1.67–1.59 (m,
1
3
1
2
H), 1.62 (s, 3H), 1.61 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H); C{ H} NMR (125 MHz, CDCl
3
): δ 167.2
(
(
C), 160.1 (C), 136.1 (C), 134.1 (C), 124.7 (CH), 122.9 (CH), 115.2 (CH), 64.2 (CH), 58.3 (C), 50.8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH
8.7 (CH
Found 335.2593.
3
), 40.9 (CH
2
), 39.6 (CH
2
), 36.3 (CH
2
), 27.5 (CH
2
), 26.6 (CH
2
), 25.9 (CH
2
), 24.9 (CH
3
), 18.8 (CH
3
),
+
1
3
), 16.0 (CH
3
), 16.0 (CH
3
); HRMS (ESI–QTOF) m/z: [M + H] Calcd for C21
H
35
O
3
335.2586,
Epoxides 12, 17, 22, 24 and 28 were obtained following methods previously reported in the
literarure.13, 57, 61, 65
General procedure for the cyclization plus rearrangement of epoxypolyprenes 2, 12, 13, 15, 17, 19,
24 and 26.
A solution of starting material (0.5 mmol) in dry DCM (50 mL) was cooled at -78 ºC, To a separate
flask was added dry DCM (15 mL) followed by 1 mL of a 1M solution Et
solution of Et AlCl was slowly added to a cooled solution of starting material (approximately for 1h).
The reaction crude oil was further stirred until disappearance of the starting material. Then, 1.5 mL of
Et N and 0.7 mL of a 4:1 mixture of MeOH/H O were added. The reaction mixture was taken out of the
cooling bath and a saturated solution of NH Cl (60 mL) was then added. After separation of the organic
layer, the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layer was washed
2
AlCl in DCM (1 mmol). This
2
3
2
4
with brine (3 x 50 mL), dried over Na
column chromatography.
2
SO , concentrated under reduced pressure and then purified by
4
Cyclization of epoxypolyprene 2
Using DCM as solvent
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Following the general procedure, reaction of epoxide 2 with Et AlCl at -78 ºC for 1 h provided after
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
flash chromatography (H:MTBE, 6:1) compounds 3a and 3b (71%, 1:1 ratio), compound 4 (3%),
compound 6 (3%) and compounds 8b and 8c (10%, 0.6:1 ratio). Ratios were determined by integration
1
of the H NMR spectrum of the mixture.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(2S,4aS,5R,6S)-1,1,5,6-Tetramethyl-5-pentyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol
(3a).
A
fraction enriched in 3a was subjected to HPLC (normal phase, H:TBME 19:1, Rt = 50.1 min) to give
1
pure 3a. Colourless oil. H NMR (600 MHz, CDCl
3
): δ 5.53 (dt, J = 5.1, 2.2 Hz, 1H), 3.47 (t, J = 2.8
Hz, 1H), 2.27 – 2.22 (m, 1H), 1.92 – 1.85 (m, 2H), 1.79 (dddd, J = 17.7, 10.6, 3.5, 2.3 Hz, 1H), 1.70
(dq, J = 14.0, 3.5 Hz, 1H), 1.57–1.45 (m, 3H), 1.36 – 1.17 (m, 8H), 1.14 (s, 3H), 1.06 (s, 3H), 0.90 (t, J
1
3
1
=
7.3 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H), 0.66 (s, 3H); C{ H} NMR (150 MHz, CDCl
), 33.5 (CH), 32.8 (CH
), 20.0 (CH ), 16.3 (CH ), 15.1 (CH
35O 279.2688, Found 279.2682.
3
): δ 142.4 (C),
), 31.8 (CH ),
), 14.1
1
2
20.8 (CH), 76.4 (CH), 41.3 (C), 38.8 (CH), 37.0 (C), 36.8 (CH
2
2
2
8.3 (CH
3
), 28.3 (CH
2
), 25.5 (CH
3
), 22.7 (CH
2
), 22.2 (CH
2
2
3
3
+
(CH
3
); HRMS (ESI–QTOF) m/z: [M + H] Calcd for C19
H
(2S,4aS,5R,6R)-1,1,5,6-Tetramethyl-5-pentyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-ol (3b). A
fraction enriched in 3b was subjected to HPLC (normal phase, H:MTBE 19:1, Rt = 50.1 min) to give
1
pure 3b. Colourless oil. H NMR (600 MHz, DMSO–d
6
, 85 ºC): δ 5.27 (bt, J = 3.9 Hz, 1H, H6), 3.32
(
t, J = 3.1 Hz, 1H, H3), 2.06 (bd, J = 17.4 Hz, 1H, H7a), 1.98 (bd, J = 12.2 Hz, 1H, H10), 1.92 (tdd, J
= 13.2, 4.9, 2.6 Hz, 1H, H2a), 1.68 – 1.55 (m, 3H, H7b, H8, H2b), 1.52 – 1.40 (m, 2H, H1), 1.31 –
.13 (m, 8H, H11, H12, H13, H14), 1.01 (s, 3H, H19), 0.98 (s, 3H, H18), 0.85 (t, J = 7.1 Hz, 3H,
1
1
3
1
H15), 0.78 (s, 3H, H20), 0.75 (d, J = 6.7 Hz, 3H, H17); C{ H} NMR (150 MHz, DMSO–d
6
, 85 ºC):
δ 148.6 (C6), 121.7 (C5), 80.2 (C3), 45.8 (C4), 45.1 (C10), 41.0 (C9), 39.7 (C11), 37.8 (C8), 37.7
(
CH
2
), 36.0 (C7), 34.8 (C2), 32.3 (C18), 30.2 (C19), 27.6 (CH
2
), 27.2 (CH
2
), 27.0 (C20), 26.7 (C1),
35O 279.2688; Found
+
1
9.7 (C17), 19.0 (C15); HRMS (ESI–QTOF) m/z: [M + H] Calcd for C19
H
2
79.2679.
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(
1R,4S)-1,3,3-Trimethyl-2-((E)-3-methylnon-3-en-1-yl)-7-oxabicyclo[2.2.1]heptane (4). Colourless
1
2
1
oil. H NMR (600 MHz, CDCl
3
): δ 5.17 (tm, J = 6.9 Hz, 1H), 3.70 (d, J = 5.4 Hz, 1H), 2.00 – 1.86 (m,
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5H), 1.69 – 1.63(m, 1H), 1.57 (s, 3H), 1.50 – 1.22 (m, 10H), 1.31 (s, 3H), 1.17 (dd, J = 8.7, 5.8 Hz, 1H),
1
3
1
1
1
2
.03 (s, 3H), 1.00 (s, 3H), 0.88 (t, J = 7.1 Hz, 3H); C{ H} NMR (150 MHz, CDCl
33.8 (C), 125.0 (CH), 88.7 (C), 86.0 (CH), 55.1 (CH), 45.2 (C), 39.8 (CH ), 39.0 (CH
), 22.6 (CH ), 18.9 (CH
35O 279.2688, Found 279.2710.
3
): δ 135.0 (C),
), 31.5 (CH ),
), 15.9
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9.5 (CH
2
), 27.8 (CH
2
), 26.1 (CH
2
), 26.1 (CH
3
), 25.7 (CH
2
), 23.9 (CH
3
2
3
+
(CH
3
), 14.1 (CH
3
); HRMS (ESI–QTOF) m/z: [M + H] Calcd for C19
H
(
R,E)-4,8-Dimethyl-5-(propan-2-ylidene)tetradec-8-enal (6). Aldehyde 6 was purified and
characterized as its primary alcohol derivative 6a. To a solution of a fraction enriched in 6 (18 mg) in 5
mL of MeOH:H O (4:1 ratio) was added 3 mg of NaBH and the mixture was stirred for1 h 30 min at
ºC. The reaction was concentrated under reduced pressure and the residue dissolved in MTBE and
2
4
0
washed with water, quenched with acetone, and concentrated under reduced pressure. The organic layer
was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
The resulting crude was purified by HPLC (H:MTBE, 6:1) to afford 12 mg of primary alcohol 6a.
1
Colourless oil. H NMR (500 MHz, CDCl
3
): δ 5.15 (t, J = 7.1 Hz, 1H), 3.62 (t, J = 6.7 Hz, 2H), 2.71 (h,
J = 7.1 Hz, 1H), 2.06 – 1.93 (m, 4H), 1.68 (s, 3H), 1.65 (s, 3H) 1.63 (s, 3H), 1.55 – 1.25 (m, 10 H), 0.98
1
3
1
(
d, J = 6.9 Hz, 3H),0.90 (t, J = 7.0 Hz, 3H); C{ H} NMR (75 MHz, CDCl
25.2 (C), 124.3 (CH), 63.4 (CH ), 40.4 (CH ), 35.6 (CH), 31.6 (CH ), 31.6 (CH
), 21.0 (CH ), 20.1 (CH ), 19.7 (CH ), 16.0 (CH
35 263.2739, Found 263.2745.
3
): δ 135.7 (C), 135.6 (C),
), 31.2 (CH ), 29.6
), 14.1 (CH );
1
2
2
2
2
2
(CH
2
), 27.9 (CH
2
), 27.0 (CH
2
), 22.6 (CH
2
3
3
3
3
3
+
HRMS (ESI–QTOF) m/z: [M – OH] Calcd for C19
H
(2S,4aR,5S,8aR)-1,1,4a-Trimethyl-6-methylene-5-pentyldecahydronaphthalen-2-ol (8b). A fraction
enriched in 8b was subjected to HPLC (normal phase, H:MTBE 9:1, Rt = 22.7 min) to give pure 8b.
1
Colourless oil. H NMR (500 MHz, CDCl
3
): δ 4.83 (d, J = 1.7 Hz, 1H), 4.53 (d, J = 1.7 Hz, 1H), 3.27
(dd, J = 11.8, 4.4 Hz, 1H), 2.43 – 2.38 (m, 1H), 1.99 (td, J = 13.1, 5.0 Hz, 1H), 1.81 (dt, J = 13.1, 3.6
Hz, 1H), 1.77 – 1.06 (m, 15H), 1.01 (s, 3H), 0.92 (s, 1H), 0.88 (t, J = 7.1 Hz, 3H), 0.78 (s, 3H), 0.68 (s,
1
3
1
3
H); C{ H} NMR (126 MHz, CDCl
3
): δ 148.4 (C), 106.5 (CH ), 78.9 (CH), 56.6 (CH), 54.6 (CH),
2
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Page 28 of 52
3
9.3 (C), 39.1 (C), 38.2 (CH
3.7 (CH ), 22.7 (CH ), 15.4 (CH
33 261.2582, Found 261.2597.
2S,4aR,5S,8aR)-1,1,4a,6-Tetramethyl-5-pentyl-1,2,3,4,4a,5,8,8a-octahydronaphthalen-2-ol (8c). A
2
), 37.1 (CH
2
), 32.5 (CH
2
), 28.4 (CH
2
), 28.3 (CH
3
), 28.0 (CH
2
), 24.0 (CH
2
),
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
2
3
), 14.4 (CH
3
), 14.1 (CH
3
); HRMS (ESI–QTOF) m/z: [M – OH]+
Calcd for C19
H
(
fraction enriched in 8c was subjected to HPLC (normal phase, H:MTBE 9:1, Rt = 21.5 min) to give pure
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
8
c. Colourless oil. H NMR (600 MHz, CDCl
3
): δ 5.39 (bs, 1H), 3.26 (dd, J = 11.2, 4.5 Hz, 1H), 2.00 –
1
.94 (m, 2H), 1.91 (dt, J = 13.3, 3.6 Hz, 2H), 1.69 (s, 3H), 1.67 – 1.57 (m, 3H), 1.52 (s, 2H), 1.42 – 1.10
13
1
(
m, 8H), 0.98 (s, 3H), 0.90 (t, J = 7.1 Hz, 3H), 0.87 (s, 3H), 0.76 (s, 3H); C{ H} NMR (126 MHz,
CDCl ): δ 135.6 (C), 121.7 (CH), 79.2 (CH), 54.9 (CH), 49.6 (CH), 38.7 (C), 37.3 (CH ), 36.5 (C), 32.5
(CH ), 31.9 (CH ), 27.9 (CH ), 27.4 (CH ), 27.2 (CH ), 23.5 (CH ), 22.6 (CH ), 21.9 (CH ), 15.1 (CH ),
4.1 (CH ), 13.5 (CH ); HRMS (ESI–QTOF) m/z: [M – OH] Calcd for C19 33 261.2582, Found
61.2608.
3
2
2
2
3
2
2
2
2
3
3
+
1
2
3
3
H
Using MTBE as solvent
Following the general procedure, reaction of epoxide 2 with Et AlCl, using MTBE as a solvent for 1 h
2
provided after flash chromatography (H:MTBE, 9:1) compounds 3a and 3b (4%, 1:1 ratio), compounds
7a and 7b (57%, 1:1.3 ratio) and compounds 8b and 8c (21%, 1.6:1 ratio). Ratios were determined by
1
integration of the H NMR spectrum of the mixture.
(1S,5R)-4,6,6-Trimethyl-5-((E)-3-methylnon-3-en-1-yl)cyclohex-3-en-1-ol (7a). A fraction enriched in
7
a was subjected to HPLC (normal phase, H:MTBE 9:1, Rt = 20.8 min) to give pure 7a. Colourless oil.
1H NMR (600 MHz, CDCl
): δ 5.23 (bs, 1H), 5.13 (t, J = 6.8 Hz, 1H), 3.45 (dd, J = 8.1, 5.5 Hz, 1H),
3
2.26 – 2.19 (m, 1H), 2.15 (ddd, J = 15.1, 10.9, 5.2 Hz, 1H), 1.99 – 1.93 (m, 4H), 1.75 – 1.68 (m, 1H),
.71 (s, 4H), 1.63 (bs, 1H), 1.60 (s, 3H), 1.37 – 1.23 (m, 7H), 0.95 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H), 0.82
1
1
3
1
(s, 3H); C{ H} NMR (151 MHz, CDCl
3
): δ 137.1 (C), 135.0 (C), 125.3 (CH), 118.2 (CH), 75.0 (CH),
), 31.6 (CH ), 29.5 (CH ), 27.9 (CH ), 27.2 (CH ), 27.0
48.8 (CH), 42.0 (CH ), 38.1 (C), 31.8 (CH
2
2
2
2
2
2
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The Journal of Organic Chemistry
(
CH), 25.3 (CH
3
), 22.6 (CH
3
), 16.2 (CH
3
), 16.0 (CH
3
), 14.1 (CH
); HRMS (ESI–QTOF) m/z: [M + H]+
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Calcd for C19
H35O 279.2688, Found 279.2690.
(1S,3R)-2,2-Dimethyl-4-methylene-3-((E)-3-methylnon-3-en-1-yl)cyclohexan-1-ol (7b). A fraction
enriched in 7b was subjected to HPLC (normal phase, H:MTBE 9:1, Rt = 22.6 min) to give pure 7b.
1
Colourless oil. H NMR (600 MHz, CDCl
3
): δ 5.10 (t, J = 7.3 Hz, 1H), 4.88 (s, 1H), 4.61 (s, 1H), 3.41
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(dd, J = 9.9, 4.2 Hz, 1H), 2.33 (dt, J = 13.2, 4.8 Hz, 1H), 2.08 (ddd, J = 13.6, 9.6, 4.2 Hz, 2H), 2.02–
1
.94 (m, 3H), 1.88 – 1.77 (m, 2H), 1.67 – 1.46 (m, 4H), 1.59 (s, 3H), 1.35 – 1.24 (m, 6H), 1.03 (s, 3H),
13
1
0
.89 (t, J = 6.9 Hz, 3H), 0.72 (s, 3H); C{ H} NMR (151 MHz, CDCl
), 80.0 (CH), 53.4 (CH), 43.2 (C), 41.2 (CH ), 35.8 (CH
), 30.5 (CH ), 28.5 (CH ), 26.3 (CH ), 25.3 (CH ), 18.6 (CH ), 18.1 (CH
33 261.2582, Found 261.2578.
3
): δ 149.9 (C), 137.7 (C), 127.6
(CH), 111.0 (CH
2
2
2
), 34.9 (CH
2
), 34.2 (CH
2
),
);
32.2 (CH
2
2
3
2
2
3
3
), 16.8 (CH
3
+
HRMS (ESI–QTOF) m/z: [M – OH] Calcd for C19
H
Using benzene as solvent
Following the general procedure, reaction of epoxide 2 with Et AlCl, using benzene as a solvent at 10ºC
2
for 45 minutes provided after flash chromatography (H:MTBE, 9:1) compounds 3a and 3b (54%, 1:0.8
1
ratio), compound 4 (2%) and compound 5 (3%). Ratios were determined by integration of the H NMR
spectrum of the mixture.
1
(2R,3S,4R)-2,3,4-Trimethyl-3-((E)-3-methylnon-3-en-1-yl)cyclohexan-1-one (5). Colourless oil. H
NMR (500 MHz, CDCl
3
): δ 5.16 (t, J = 7.1 Hz, 1H), 2.50 (q, J = 6.7 Hz, 1H), 2.37 – 2.33 (m, 2H), 2.14
– 1.80 (m, 6H), 1.68 – 1.55 (m, 1H), 1.63 (s, 3H), 1.48 – 1.23 (m, 8H), 0.94 (d, J = 6.7 Hz, 3H), 0.91 (d,
1
3
1
J = 10.2 Hz, 3H), 0.91 (t, J = 3.5 Hz, 3H), 0.59 (s, 3H); C{ H} NMR (126 MHz, CDCl
3
) δ 214.1 (C),
), 31.6 (CH ),
), 7.6
1
34.8 (C), 124.9 (CH
1.0(CH ), 29.5(CH
2
), 50.5 (CH), 43.5 (C), 41.6 (CH
2
), 36.1(CH), 36.0 (CH
), 16.2 (CH ), 15.4 (CH ), 15.0 (CH
35O 279.2688, Found 279.2687.
2
), 32.6 (CH
2
2
3
2
2
), 28.0 (CH
2
), 22.6 (CH
2
3
3
3
), 14.1 (CH
3
+
(CH
3
); HRMS (ESI–QTOF) m/z: [M + H] Calcd for C19
H
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