A unifying stereochemical analysis for the formation of halogenated C 15-acetogenin medium-ring ethers from laurencia species via intramolecular bromonium ion assisted epoxide ring-opening and experimental corroboration with a model epoxide

Article abstract of DOI:10.1021/jo301580c

A unifying stereochemical analysis for the formation of the constitutional isomeric halogenated C₁₅-acetogenin medium-ring ether natural products from Laurencia species is presented, where an intramolecular bromonium ion assisted epoxide ring-o

Full text of DOI:10.1021/jo301580c

Article
pubs.acs.org/joc
A Unifying Stereochemical Analysis for the Formation of
Halogenated C15-Acetogenin Medium-Ring Ethers From Laurencia
Species via Intramolecular Bromonium Ion Assisted Epoxide Ring-
Opening and Experimental Corroboration with a Model Epoxide
Karl J. Bonney and D. Christopher Braddock*
Department of Chemistry, Imperial College London, London, SW7 2AZ, U. K.
S
* Supporting Information
ABSTRACT: A unifying stereochemical analysis for the
formation of the constitutional isomeric halogenated C15-
acetogenin medium-ring ether natural products from Laurencia
species is presented, where an intramolecular bromonium ion
assisted epoxide ring-opening reaction of enantiomerically
pure epoxides can account for ring-size, the position of the
halogen substituents, and relative and absolute configurations
of the known natural products. Experimentally, a model
epoxide corroborates the feasibility of this process for
concurrent formation of 7-, 8- and 9-ring ethers corresponding to the halogenated medium-ring ethers of known metabolites
from Laurencia species.
INTRODUCTION
■
Since the isolation and structural elucidation of laurencin (1a)
in the 1960s,1 a dazzlingly diverse array of diastereo- and
constitutional isomers of halogenated C15-acetogenin medium-
ring ethers have been isolated from species of the marine red
algae Laurencia (Figures 1, 2).2 These metabolites are either 7-,
8- or 9-membered ring ethers (often incorporating a second
oxygen-containing ring as an oxetane, tetrahydrofuran or
tetrahydropyran) with a characteristic C-12 or C-13 bromide
substituent, oxygenated at C-6 and C-7 (Figure 1) or with a
chloride substituent at one of these positions (Figure 2), along
with an enyne or bromoallene side-chain.3−5 The synthetic
challenges of medium-ring ether formation, control of the cis-
or trans-α,α′ ether stereochemistry, stereoselective halide
incorporation and selective enyne or bromoallene formation
has resulted in much synthetic interest, and state-of-the-art total
syntheses over the past five decades have been continually
reported.6−20
The generally accepted biogenesis of this class of metabolites
finds its origins in the isolation of C15-(3E,6R,7R)-laurediol 18
and its oppositely configured diol (3Z,6S,7S)-18 by Irie in
1972.21 Later studies by Murai and co-workers22 showed that
Figure 1. Diastereo- and constitutional isomers of the formula
C15H21BrO2 (1b, 3) and C15H20Br2O2 (2, 4−11) of halogenated
medium-ring ethers from Laurencia species that are oxygenated at both
C-6 and C-7. Laurencin (1a) is related as the acetate of 1b.
the constitutional isomeric eight-membered medium-ring
ethers deacetyllaurencin (1b) and prelaureatin (3) (with
molecular formulas of C15H21BrO2) were formed, albeit in
very low yields, from the two diols respectively via
lactoperoxidase (LPO) and (partially purified) bromoperox-
idase (BPO)-catalyzed bromoetherifications with no apparent
crossover between the two series (Scheme 1).23,24 Subsequent
intramolecular bromoetherification events, involving the
formation of favored ring-sizes, allows for the formation of
the constitutional isomeric bicyclic dibromides 4, 6 and 7 (with
molecular formulas of C15H20Br2O2).22,24,25 However, the
Received: July 25, 2012
© XXXX American Chemical Society
A
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RESULTS AND DISCUSSION
■
Our stereochemical analysis commences by correlating the
medium-ring ethers shown in Figure 1 with enantiomerically
pure (3E or 3Z,6S,7R)-epoxide 19, and not the laurediols,29 via
intramolecular bromonium ion assisted epoxide ring-opening,27
with water functioning as an external nucleophile (Scheme 2).28
Scheme 2. Unifying Stereochemical Analysis for the
Medium-Ring Ethers of Figure 1 via Bromonium Ion
a
Assisted Ring-Opening of Epoxide 19
Figure 2. Diastereo- and constitutional isomers of the formula
C15H20BrClO (12−17) of halogenated medium-ring ethers from
Laurencia species that are chlorinated at either C-6 or C-7.
Scheme 1. Irie−Murai Biogenesis
biogenesis of the equally ubiquitous 7- or 9-membered
medium-ring ethers of the family has yet to be elucidated,
nor has a nonenzymatic direct bromonium-induced cyclization
of a linear precursor been reported for any member of the
family regardless of ring size.26 Other cyclization pathways not
involving intramolecular bromoetherification reactions with
alcohols as the nucleophile to access such eight-membered ring
systems may also be possible. Given also their common
molecular formulas, the identification of a single potential
biogenetic precursor would be intellectually and scientifically
satisfying. By the same token, identification of such a species
could allow for a laboratory synthesis of all the isomeric
members of the family from a single precursor (albeit
necessarily as a mixture of isomers).
Herein, we present a stereochemical analysis that correlates
these medium-ring ethers with an enantiomerically pure
epoxide via intramolecular bromonium ion assisted epoxide
ring-opening,27 with water (for the medium-ring ethers shown
in Figure 1) or chloride (for the medium-ring ethers shown in
Figure 2) functioning as external nucleophiles.28 Experimen-
tally, we show with a model epoxide the feasibility of an
intramolecular bromonium ion assisted epoxide ring-opening
for the concurrent formation of 7-, 8- and 9-ring ethers
corresponding to the halogenated medium-ring ethers of
known metabolites from Laurencia species. This also
constitutes the first time that the medium-ring of any of
these natural products has been constructed by a nonenzymatic
bromonium-induced cyclization process from a linear pre-
cursor.
a
Medium-ring ethers 20−22 are unknown compounds but are
implicated as plausible naturally occurring compounds by the isolation
of 5,3a 9,5b and 11,5d respectively. 12,13-epi-1b, 12,13-epi-3 and 12,13-
epi-20 are unknown compounds.
Here we invoke bromonium ion formation on either face of the
C(12)−C(13) alkene of epoxyalkene 19 (giving intermediates
A and B) and subsequent nucleophilic attack by the epoxide at
either the C-12 or C-13 position of the bromonium ions
(stereospecifically with inversion of stereochemistry at that
position), where the subsequent oxonium ions (intermediates
C−F) are attacked by water at either the C-6 or C-7 position
(also stereospecifically with inversion of stereochemistry). By
invoking this reaction mechanism, a single epoxide precursor
can be correlated to eight diastereo- and constitutional isomers
with molecular formulas of C15H21BrO2. It leads to two 7-, four
8- and two 9-membered medium-rings (and no other ring-
sizes), where the molecular diversity arises from the non-
regioselectivity of the process, while the final absolute and
relative stereochemistries at the C-6, C-7, C-12 and C-13
positions for each compound are controlled by the diaster-
eospecific nature of the two ring-opening steps as defined by
B
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a
the original absolute stereochemistry of the epoxide, and the
initial (E)-geometry of the C(12)−C(13) alkene. For the eight
medium-ring ethers to arise from this analysis, two of these are
the known eight-membered medium-ring ethers (1b and 3),
three (20, 21 and 22) are plausible precursors to other known
compounds (5, 9 and 11, respectively) by further intra-
molecular bromoetherification, and three more (12,13-epi-1b,
12,13-epi-3 and 12,13-epi-20) are unknown. Leaving aside for
the moment the question of enzymatic control, this analysis can
unify ring-size, the position of the halogen substituents, and
absolute and relative configurations for the halogenated
medium-ring ether metabolites.30
Scheme 4. Preparation of Cyclization Precursors 30 and 31
A similar analysis is applicable for the chlorine-containing
medium-ring ether natural products shown in Figure 2 of
formula C15H20BrClO (12−17) isolated from Laurencia
species, where chloride now functions as the external
nucleophile (Scheme 3).28 Analysis of the C-12 and C-13
a
Conditions: (a) PPh3Br2, pyridine, CH2Cl2, 0 °C to room
i
temperature (rt), 1.5 h, 81%; (b) propargyl alcohol, PrMgCl, THF,
0−70 °C, 1.5 h, then CuCl, 25, Et2O, 0−70 °C, 3 h, 92%; (c) CBr4,
PPh3, CH2Cl2, −15 °C to rt, 2 h; (d) 3-butyn-1-ol, K2CO3, CuI, NaI,
acetone, 0−70 °C, 22 h, 39% (2 steps); (e) 5% Pd-BaSO4, quinoline,
H2, 1:1 MeOH/cyclohexene, rt, 2.5 h, 68%; (f) Zr(OtBu)4, (+)-DBTA,
CHP, 4 Å MS, CH2Cl2, −40 °C, 44 h, 82%, 78:22 (3S,4R):(3R,4S);
(g) Boc2O, NEt3, DMAP, PhMe, 0 °C to rt, 16 h, 56% (31a 32%).
Scheme 3. Unifying Stereochemical Analysis for the
Medium-Ring Ethers of Figure 2 via Bromonium Ion
a
Assisted Ring-Opening of Epoxide 23
double bonds of epoxide 19. Epoxide 31 represents an “armed”
version of alcohol 30, where the tert-butyl carbonate is
positioned as an intramolecular nucleophile27c,d to terminate
an intramolecular bromonium ion assisted epoxide ring-
opening reaction (and a cyclic carbonate should result).
Accordingly, readily available (E)-2-penten-1-ol (24) was
converted through a known sequence with minor modifications
to bromide 27.32 A second copper-mediated coupling33 with 3-
butyn-1-ol gave oxygen-sensitive enediyne 28.34 Enediyne 28
was chemoselectively hydrogenated to afford (E,Z,Z)-doubly
skipped triene 29 using hydrogen gas and a quinolone-
poisoned palladium on barium sulfate catalyst35 where the use
of sacrificial cyclohexene in methanol solution was critical to
avoid over-reduction. Regioselective catalytic asymmetric
epoxidation of the homoallylic alcohol in 29 was achieved
using Onaka’s conditions,36 providing (S,R)-epoxy-diene 30.37
“Armed” substrate 31 was obtained by treating alcohol 30 with
Boc-anhydride, triethylamine and catalytic DMAP, along with
unavoidable formation of pseudo dimer 31a.38
a
Medium-ring ethers 12,13-epi-12 and 12,13-epi-16 are unknown
compounds.
Attempts to induce an intramolecular bromonium ion
assisted epoxide ring-opening of substrate 30 using our
previously developed conditions,28 with NBS and water as
the nucleophile (and solvent), was unsuccessful, and instead a
variety of bromohydrin regioisomers, dibromides and dibro-
motetrahydrofurans were obtained 30a−d, (Scheme 5).39 The
use of Jamison’s conditions (NBS, hexafluoroisopropanaol, 4 Å
MS)27d to induce intramolecular bromonium ion assisted
epoxide ring-opening of “armed” substrate 31 was also
unsuccessful. Much to our delight, the application of Snyder’s
highly reactive Et2SBr·SbCl5Br reagent (BDSB)40 to induce
intramolecular bromonium ion assisted epoxide ring-opening of
“armed” substrate 31 gave carbonates 32−37, which were
hydrolyzed in quantitative yields to medium-ring ethers 39−44
(Scheme 6).41 Thus, six42 of the eight anticipated diastereo-
and constitutional isomeric medium-ring ethers (two 7-, two 8-
and two 9-ring) are formed by this intramolecular bromonium
ion assisted epoxide ring-opening reaction, and these correlate
to the known natural products as shown in Scheme 6.
stereochemistries of these compounds reveals that they must
arise from electrophilic bromination of a (Z)-configured alkene
at C(12)−C(13), rather than (E): epoxide 23 emerges as the
precursor.31 As before, eight possible diastereo- and constitu-
tional isomers arise, with two 7-, four 8- and two 9-ring systems
possible. Remarkably, these map onto all six of the known
natural products with formula C15H20BrClO (12−17) with
complete fidelity and where 12,13-epi-12 and 12,13-epi-16 are
unknown compounds.
From a reactivity standpoint, the bromonium ion assisted
epoxide ring-opening reaction27,28 benefits enthalpically from
the opening of two small rings. For the systems above, along
with the conformational constraint provided by the Z-
configured C(9)−C(10) olefin, this feature may counterbalance
the unfavorable entropic restrictions associated with medium-
ring ether formation.
In order to investigate the feasibility of the above cyclizations,
a model compound of epoxide 19 was required, and epoxides
30 and 31 were targeted (Scheme 4). The substrates both
feature the requisite (S,R)-epoxide, to be installed by directed
asymmetric epoxidation of Z homoallylic alcohol 29, and the
two olefins matching the C(9)−C(10) Z and C(12)−C(13) E
None of the cyclic medium-ring ether compounds isolated in
this study proved to be crystalline, and so the structures of
diastereo- and constitutional isomeric carbonates 32−36 and
diols 39−45 was achieved using 2D COSY, DEPT-135, HSQC
C
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ppm, whereas the exocyclic resonances were observed ca. 62
Scheme 5. Unsuccessful Attempt at Bromonium Ion Assisted
Epoxide Ring-Opening of ( )-30
a
ppm (Table 1). The 13C NMR CO carbonate resonances
Table 1. 13C NMR Shifts of Carbon-Bearing Bromide in
a
Carbonates 32−36 and Diols 39−44
b
entry
ether
32
δC CHBr
1
56.0 (C-12)
61.9 (C-13)
62.8 (C-13)
56.8 (C-12)
56.8 (C-12)
55.7 (C-12)
55.2 (C-12)
62.5 (C-13)
62.8 (C-13)
57.7 (C-12)
55.2 (C-12)
2
33
3
34
4
35 or 36
35 or 36
39
5
6
7
40
8
41
9
42
10
11
43 or 44
a
Conditions: (a) H2O, NBS, TMG, rt, 65 h: 30a and 30b, 10%; 30c,
43 or 44
1%; 30d, 2%; other dibromohydrins, 10%; other bromohydrin
regioisomers, 4%.
a
b
All spectra recorded in CDCl3. Chemical shift reported in ppm. The
C-12 or C-13 descriptor in parentheses refers to the carbon number to
which the bromide is attached.
Scheme 6. Intramolecular Bromonium Ion Assisted Epoxide
Ring-Opening of 31 to Form Medium-Ring Ethers and
Subsequent Hydrolysis
a
were likewise characteristic at ca. 149 ppm for a six-membered
carbonate (Table 2, entries 1−3) and ca. 154 ppm for a seven-
Table 2. 13C NMR Shifts of CO in Cyclic Carbonates 32−
a
36
b
entry
ether
32
δC CHBr
1
2
3
4
5
148.5
148.9
148.9
154.2
154.2
33
34
35 or 36
35 or 36
a
b
All spectra recorded in CDCl3. Chemical shift reported in ppm.
ring system (entries 4−5).44 These observations in conjunction
allow assignment of the compounds as either 7- 8- or 9-
membered ring ethers. HMBC correlations were also observed
between H-7 and C-13 of 39 and also H-7 and C-12 of 33, thus
inherently confirming the formation of the medium-ring itself
and also supporting the assignment of 8- and 7-membered ring
ethers respectively. The absolute and relative stereochemistry at
the C-6 and C-7 positions in all cases was deduced by
consideration of the (6S,7R)-configuration of the initial
epoxide, which must undergo bromonium ion assisted epoxide
ring-opening27,28 with inversion of configuration at the center
attacked by the carbonate (as inferred from the carbonate ring-
size). The relative stereochemistry of the C-12 and C-13
positions was also set as either (12R,13S) or (12S,13R) due to
the initial trans-geometry of the C(12)−C(13) alkene of
substrate 31: the bromonium ion must be formed with either
the (12R,13R)- or (12S,13S)-configuration followed by stereo-
specific attack leading to stereochemical inversion at the C-12
or C-13 position. Therefore only the relative stereochemistry
across the ether oxygen and the ring size (as deduced by the
position of the bromine at C-12 or C-13 and the original ring-
size of the carbonate) needs to be known in order to be able to
assign the overall absolute and relative stereochemistry for
these compounds.
a
Conditions: (a) Et2SBr·SbCl5Br, NO2Me, rt, 1 h: 32, 4.1%; 33, 1.4%;
34, 1.2%; 35 and 36, 1.8%; 37, 3.5%; 38, 5.8%; (b) column
chromatography; (c) preparative HPLC; (d) NaOH, MeOH, rt, 2 h.
and HMBC NMR experiments (see Supporting Information for
spectra). The CHBr 13C NMR resonance for each compound
was readily identified in this manner as at either C-12 (and
hence endocyclic) or C-13 (and hence exocyclic).43 A strong
correlation between CHBr 13C NMR resonances emerged
where all endocyclic CHBr resonances were observed at ca. 56
For 7- and 8-membered medium-ring ethers, it was found
that there is a correlation between the 1H NMR chemical shifts
of the flanking ether protons and the relative stereochemistry
D
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across the ether oxygen (Table 3). For the cis-α,α′ ether
compounds the C(9)−C(10) alkene evidently shields these
medium-ring ethers prepared in this study by the intra-
molecular bromonium ion assisted ring-opening of epoxide 31.
A 15:2 mixture of diastereomeric cyclopropanes 45 was also
isolated from the bromonium ion assisted epoxide ring-opening
reaction of epoxide 31 with BDSB, followed by hydrolysis
(Scheme 6). They were identified using NMR methods (see
Supporting Information), where C-10 diastereotopic methylene
cyclopropane resonances were apparent at δH 0.95 and 0.39
ppm, C-13 was found to be the bromine bearing carbon (δC 61
ppm), a HMBC correlation between C-7 and H-12 confirmed
the presence of a cyclic ether and defined the ring-size. As for
the medium-ring ethers, the absolute stereochemistry at C-6
and C-7 is controlled by the original configuration of the
epoxide. However, cis-α,α′ or trans- α,α′ ether stereochemistry
could not be established, and the absolute stereochemistry of
the other stereocenters remains unknown. A plausible
mechanism (Scheme 7) to form carbonate 38 invokes an
Table 3. Comparison of 1H NMR Shifts of trans- and cis-α,α′
a
Ether Protons of Carbonates 32−36 and Diols 39−44
b
entry
ether
32
δH CHOCH
1
3.51−3.45 (H-7 and H-13)
3.65 (H-12), 3.59 (H-7)
4.28 (H-7), 4.22 (H-12)
4.58 (H-6), 4.16 (H-13)
4.60 (H-6), 4.17 (H-13)
3.76 (H-13), 3.55 (H-7)
3.97 (H-13), 3.82 (H-7)
3.75 (H-12), 3.34 (H-7)
4.10−3.97 (H-7 and H-12)
4.15 (H-13), 3.76 (H-6)
4.18 (H-13), 3.79 (H-6)
2
33
3
34
4
35 or 36
35 or 36
39
5
6
7
40
8
41
9
42
10
11
43 or 44
43 or 44
a
b
All spectra recorded in CDCl3. Chemical shift(s) reported in ppm.
Scheme 7. Plausible Mechanism of Cyclopropane 38
Formation from Bromonium Ion A
The descriptors in parentheses are the designation of the α,α′ protons
according to the note on numbering of compounds reported in the
Supporting Information.
protons resulting in an upfield shift of both protons compared
to the trans-α,α′ compounds. This is exemplified by the direct
comparison of the chemical shifts of the cis-α,α′carbonate 33
(entry 2) and trans-α,α′ carbonate 34 (entry 3) for 7-
membered medium-ring ethers [Δδ ca. 0.6 ppm], and by
comparison of cis-α,α′diol 39 (entry 6) and trans-α,α′ diol 40
(entry 7) for 8-membered medium-ring ring ethers [Δδ ca. 0.3
1
ppm]. The H NMR spectra of structurally related natural
products exhibit the same trans-α,α′ versus cis-α,α′ effect,
supporting the assignments made.45 In the case of 8-membered
ring ether 39, an NOE was also observed between H-7 and H-
13, confirming the cis-α,α′ relationship. For the 9-membered
ring-ethers, both as carbonates 35 and 36, and diols 43 and 44
(Table 3, entries 4, 5, 10 and 11), the above effect was not
1
evident with the H NMR spectra being markedly similar, and
the two possible (6S,7S,12R,13S) and (6S,7S,12S,13R)
diastereoisomers could not be distinguished.
initial intramolecular attack of a bromonium ion A of epoxide
31 by the C(9)−C(10) olefin,48 subsequent rearrangement of
cyclopropyl cation B via cyclobutyl cation C,49 followed by
bromonium ion assisted epoxide ring-opening26,27 on the new
bromonium ion D, where the newly formed cyclopropane may
provide a beneficial conformational constraint to favor ring-
closure. The sequence is completed by intramolecular attack of
oxonium ion E by the tert-butyl carbonate.
A comparison of the 13C NMR data for carbon atoms C-5 to
C-15 of monocyclic 8-membered medium-ring ether 39 with
laurencin (1a)46 is shown in Table 4.47 The root-mean-square
of Δδ of 1.0 ppm is an excellent fit and provides further
corroboration of the structure of 39, and hence all the other
Table 4. Comparison of the 13C NMR Shifts for C-5 to C-15
a
for Monocyclic Ether 39 and Laurencin (1a)
CONCLUSIONS
b
bc
,
■
entry
carbon no.
39 δC
1a δC
33.8
Δδ
In conclusion, we have shown that an “armed” epoxide 31 is a
viable precursor for an intramolecular bromonium ion assisted
epoxide ring-opening process using Snyder’s powerful BDSB
reagent, providing concurrently six medium-ring ether prod-
ucts, which correlate to several medium-ring natural products of
formulas C15H21BrO2 and C15H20Br2O2 from Laurencia species.
This experimental corroboration using a model epoxide raises
an important and interesting question. Does this represent a
possible biogenetic pathway to the medium-ring ethers from
Laurencia species from epoxides 19 and 23? If so, since the
stereochemical information contained in the epoxides is
translated to the four stereocenters of the medium-ring
products by the stereospecific nature of the process, the ability
of an enzyme to provide an asymmetric environment may not
1
5
6
34.9
74.2
84.6
32.3
128.8
129.4
30.4
55.7
83.8
25.8
9.3
+1.1
−2.5
0.0
2
76.7
84.6
32.3
128.9
129.2
29.7
56.0
81.8
25.8
9.3
3
7
4
8
0.0
5
9
−0.1
+0.2
+0.7
−0.3
+2.0
0.0
6
10
11
12
13
14
15
7
8
9
10
11
0.0
a
b
All spectra recorded in CDCl3. Chemical shift reported in ppm.
c
Data taken from ref 8j.
E
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4:1); IR (neat) 2963, 1459, 1419, 1208, 1143, 966 cm−1; H NMR
(400 MHz, CDCl3) δ 5.77−5.70 (m, 1H), 5.43−5.36 (m, 1H), 3.98 (t,
J = 2.2 Hz, 2H), 3.00−2.98 (m, 2H), 2.10−2.03 (m, 2H), 1.01 (t, J =
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 134.3, 122.2, 85.7, 76.8,
25.3, 22.1, 15.5, 13.5; MS (EI) m/z 187 (M + H)+. The crude product
was used in the next step without further purification. A solution of 3-
butyn-1-ol (11.0 mL, 146 mmol, 1.0 equiv) in acetone (500 mL) was
added to a solution of bromide 27 (146 mmol, 1.0 equiv) in acetone
(100 mL) at 0 °C. Potassium carbonate (40.3 g, 292 mmol, 2.0 equiv),
sodium iodide (43.8 g, 292 mmol, 2.0 equiv) and copper(I) iodide
(27.7 g, 146 mmol, 1.0 equiv) were added, and the cloudy yellow
mixture was heated at 70 °C for 22 h. The reaction mixture was
subsequently concentrated to approximately 100 mL, and ethyl acetate
(400 mL) was added. The mixture was washed with saturated aqueous
ammonium chloride solution (2 × 200 mL) and water (2 × 200 mL).
The aqueous washings were combined, extracted with ethyl acetate (3
× 400 mL), and the organics were combined, dried over sodium
sulfate and filtered. The solvent was removed under reduced pressure,
and the product was purified by column chromatography (petroleum
spirit:ethyl acetate, 4:1) to give alcohol 28 (10.0 g, 39% over 2 steps) as
a yellow oil: Rf 0.21 (petroleum spirit:ethyl acetate, 4:1); IR (neat)
1
be necessary.50 Furthermore, the stereochemical analysis of
such intramolecular bromonium ion assisted epoxide ring-
opening processes for epoxides 19 (Scheme 2) and 23 (Scheme
3) shows that there are eight such medium-ring ethers possible
from each epoxide, where 12,13-epi-1b, 12,13-epi-3, 12,13-epi-
12, 12,13-epi-16, 20, 12,13-epi-20, 21 and 22 may therefore
represent the cores of as yet undiscovered naturally occurring
medium-ring ethers from Laurencia species.51
EXPERIMENTAL SECTION
■
(E)-Oct-5-en-2-yn-1-ol (26). A solution of bromine (20.5 g, 128
mmol, 1.1 equiv) in dichloromethane (40 mL) was added dropwise to
a solution of triphenylphosphine (33.6 g, 128 mmol, 1.1 equiv) in
dichloromethane (140 mL) at 0 °C. The orange-yellow triphenyl-
phosphine dibromide suspension was stirred at 0 °C for 30 min, and
pyridine (10.1 g, 128 mmol, 1.1 equiv) was added, followed by a
solution of alcohol 24 (10.0 g, 116 mmol, 1.0 equiv) in dichloro-
methane (60 mL). The reaction mixture was allowed to warm to room
temperature and stirred for 1.5 h. The mixture was washed with 1 M
hydrochloric acid (2 × 100 mL), and the layers were separated. The
aqueous portion was extracted with dichloromethane (2 × 50 mL), the
organics were combined and dried over sodium sulfate. The solvent
and product were distilled away from the triphenylphosphine oxide
under reduced pressure, and collected using a cold trap. The
triphenylphosphine oxide was washed thoroughly with pentane,
which was combined with the solution of the product in dichloro-
methane. The solvent was carefully removed by distillation, to provide
the known bromide32e 25 (14.0 g, 81%) as a pale brown liquid,
contaminated with small quantities of triphenylphosphine oxide and
dichloromethane: Rf 0.62 (petroleum spirit:ethyl acetate, 4:1); IR
(neat) 2964, 2932, 1660, 1459, 1436, 1203, 962 cm−1; 1H NMR (400
MHz, CDCl3) δ 5.88−5.81 (m, 1H), 5.75−5.67 (m, 1H), 3.98 (d, J =
8.0 Hz, 2H), 2.15−2.08 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 138.1, 125.4, 33.4, 25.1, 13.0; MS (EI+) m/z 147
(M+.). The crude bromide was used in the next step without further
purification. A solution of isopropylmagnesium chloride in THF (200
mL, 2.0 M, 397 mmol, 2.5 equiv) was added dropwise to a stirred
solution of propargyl alcohol (12.0 mL, 206 mmol, 1.3 equiv) in THF
(100 mL) at 0 °C, heated to 70 °C for 1.5 h and recooled to 0 °C.
Copper(I) chloride (3.14 g, 32 mmol, 0.2 equiv) was added, followed
by dropwise addition of a solution of bromide 25 (23.6 g, 159 mmol,
1.0 equiv) in diethyl ether (170 mL). The mixture was heated at 70 °C
for 3 h, allowed to cool to room temperature, and the mixture was
washed with saturated ammonium chloride solution (2 × 200 mL).
The aqueous layer was separated and extracted with ethyl acetate (4 ×
150 mL). The organics were combined, washed with brine (2 × 200
mL) and dried over sodium sulfate. After removal of the solvent under
reduced pressure, the residue was purified by column chromatography
(petroleum spirit:ethyl acetate, 4:1) to give the known propargylic
alcohol32a 26 (18.1 g, 92%) as a pale yellow oil: Rf 0.20 (petroleum
spirit:ethyl acetate, 4:1); IR (neat) 3600−3050, 2964, 2873, 1463,
1373, 1009, 965 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.76−5.70 (m,
1H), 5.45−5.38 (m, 1H), 4.31 (t, J = 2.2 Hz, 2H) 2.98−2.96 (m, 2H),
2.10−2.03 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 134.1, 122.6, 84.1, 79.9, 51.4, 25.3, 22.0, 13.5; MS (CI) m/z
142 (M + NH4)+; HRMS (Magnetic Sector CI+, NH3) m/z calcd for
C8H16NO (M + NH4)+ 142.1232, found 142.1236.
3650−3100, 2963, 1670, 1419, 1314, 1041, 966 cm−1; H NMR (400
1
MHz, CDCl3) δ 5.75−5.66 (m, 1H), 5.42−5.35 (m, 1H), 3.70 (t, J =
6.3 Hz, 2H), 3.18−3.14 (m, 2H), 2.90−2.88 (m, 2H), 2.47−2.43 (m,
2H), 2.16 (br s, 1H), 2.07−2.00 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 133.8, 123.0, 78.4, 76.9, 76.7, 75.7, 61.1,
25.3, 23.1, 21.9, 13.5, 9.8; MS (CI) m/z 194 (M + NH4)+; HRMS
(Magnetic Sector CI+, NH3) m/z calcd for C12H20NO (M + NH4)+
194.1545, found 194.1539.
(3Z,6Z,9E)-Dodeca-3,6,9-trien-1-ol (29). 5% Pd-BaSO4 (0.80 g)
and quinoline (2.0 mL) were added to a solution of dienyne 28 (2.0 g,
11.4 mmol) in methanol/cyclohexene (1/1, 100 mL). The mixture
was stirred vigorously under hydrogen gas (1 atm). After 2.5 h the
reaction mixture was filtered through a short plug of silica, and the
solvent removed under reduced pressure. The crude mixture was
subjected to column chromatography (petroleum spirit:acetone, 4:1)
to give product 29 (1.40 g, 68%) as a pale yellow oil: Rf 0.48
(petroleum spirit:acetone, 2:1); IR (neat) 3600−3020, 3013, 2962,
2933, 1647, 1439, 1396 cm−1; H NMR (400 MHz, CDCl3) δ 5.57−
1
5.35 (m, 6H), 3.65 (t, J = 6.5 Hz, 2H), 2.86−2.82 (m, 2H), 2.79−2.75
(m, 2H), 2.39−2.33 (m, 2H), 2.05−1.90 (m, 3H), 0.99 (t, J = 3.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 132.5, 131.0, 128.3, 128.0,
126.9, 125.6, 62.1, 30.8, 30.4, 25.6 (x2), 13.8; MS (CI+) m/z 198 (M +
NH4)+; HRMS (Magnetic Sector CI+, NH3) m/z calcd for C12H24NO
(M + NH4)+ 198.1858, found 198.1838.
(3S*,4R*,6Z,9E)-3,4-Epoxydodeca-6,9-dien-1-ol ( -30). tert-
Butyl hydroperoxide (0.36 mL) was added dropwise to a solution of
triene 29 (129 mg, 0.72 mmol, 1.0 equiv) and vanadyl acetylacetonate
(10 mg, 0.04 mmol, 5 mol %) in dichloromethane (10 mL) at 0 °C.
The mixture was stirred at room temperature for 16 h, diluted with
dichloromethane (10 mL) and washed with 10% w/w aqueous sodium
sulfite solution (10 mL). The layers were separated, and the aqueous
portion was extracted with diethyl ether (2 × 10 mL). The combined
organics were washed with brine (20 mL), dried over sodium sulfate,
and purified by column chromatography to give epoxide ( )-30 (68
mg, 48%) as a colorless oil: Rf 0.19 (petroleum spirit:ethyl acetate,
2:1); IR (neat) 3600−3050, 3010, 2964, 2930, 2874, 1455, 1385 cm−1;
1H NMR (400 MHz, CDCl3) δ 5.62−5.38 (m, 4H), 3.94−3.85 (m,
2H), 3.13 (dt, J = 7.8, 4.5 Hz, 1H), 3.00 (td, J = 6.4, 4.1 Hz, 1H), 2.77
(app t, J = 6.4 Hz, 2H), 2.48−2.39 (m, 1H), 2.29−2.20 (m, 1H),
2.07−2.00 (m, 2H), 1.97−1.73 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 132.9, 130.8, 126.6, 124.1, 60.8, 56.0, 55.0,
30.6, 30.5, 26.3, 25.5, 13.8; MS (CI) m/z 214 (M + NH4)+; HRMS
(Magnetic Sector CI+, NH3) m/z calcd for C12H24NO2 (M + NH4)+
214.1807, found 214.1803.
(E)-Dodec-9-ene-3,6-diyn-1-ol (28). Carbon tetrabromide (58.3
g, 175 mmol, 1.2 equiv) was added to a solution of propargylic alcohol
26 (18.1 g, 146 mmol, 1.0 equiv) in dichloromethane (500 mL) at
−15 °C. A solution of triphenylphosphine (49.8 g, 190 mmol, 1.3
equiv) in dichloromethane (200 mL) was added dropwise, and the
mixture was allowed to warm to room temperature and stirred for 2 h.
The mixture was concentrated to approximately 100 mL, petroleum
spirit (400 mL) was added, cooled to −78 °C, filtered through a short
plug of silica (to remove triphenylphosphine oxide and bromoform),
and the solvent was removed under reduced pressure to give the
known product bromide32e 27 as a pale yellow oil, contaminated with
a small quantity of bromoform: Rf 0.55 (petroleum spirit:ethyl acetate,
(3S,4R,6Z,9E)-3,4-Epoxydodeca-6,9-dien-1-ol (30). Zirconium-
(IV) t-butoxide (1.58 mL, 10.2 mmol, 0.40 equiv) was added to
(2R,3R)-N,N′-dibenzyl-2,3-dihydroxybutanediamide (2.01 g, 6.1
mmol, 0.60 equiv) and activated 4 Å molecular sieves (1.03 g) in
dichloromethane (75 mL) at room temperature. The mixture was
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The Journal of Organic Chemistry
Article
stirred for 2 h, cooled to −40 °C, and cumene hydroperoxide (3.77
mL) was added dropwise, followed by dropwise addition of a solution
of (3Z,6Z,9E)-dodeca-3,6,9-trien-1-ol (29) (1.84 g, 10.2 mmol, 1.0
equiv) in dichloromethane (5 mL). After 20 h, further cumene
hydroperoxide (1.80 mL) was added, and after a further 24 h aqueous
sodium sulfite (10 mL) and diethyl ether (100 mL) were added, and
the reaction mixture was allowed to warm to room temperature.
Sodium sulfate (40.0 g) and silica (4.0 g) were added, and the mixture
was stirred for 30 min before passing through a plug of silica, eluting
with ethyl acetate (200 mL). The solvent was removed under reduced
pressure, and the crude mixture was subjected to column
chromatography (petroleum spirit:ethyl acetate, 2:1), providing
Diastereomer 2: Isolated as a single diastereomer, with the overall
relative stereochemistry unassigned: 55 mg, 5.1% as a colorless oil; IR
1
(KBr) 3750−3100, 2978, 2818, 1641, 1421, 1265 cm−1; H NMR
(400 MHz, CDCl3) δ 5.69−5.60 (m, 2H), 4.16−4.10 (m, 1H), 3.93−
3.81 (m, 2H), 3.70 (dt, J = 8.8, 3.9 Hz, 1H), 3.13 (dt, J = 7.7, 4.4 Hz,
1H), 3.03 (dt, J = 6.4, 4.4 Hz, 1H), 2.73−2.61 (m, 2H), 2.45−2.27 (m,
2H), 1.98−1.87 (m, 1H), 1.81−1.54 (m, 3H), 1.03 (t, J = 7.4, 3H);
13C NMR (100 MHz, CDCl3) δ 129.0, 126.7, 76.1, 62.0, 60.6, 55.9,
55.2, 31.4, 30.6, 26.7, 26.6, 10.3; MS (CI+, NH3) 310 (M + NH4)+;
HRMS (Magnetic Sector CI+, NH3) m/z calcd for C12H25NO379Br (M
+ NH4)+ 310.1018, found 310.1021; HPLC (n-hexane:i-propanol,
95:5), 4.00 mL/min, 240 nm, tR 24.5 min. (3R*,4S*,6Z,9S*,10R*)-
1 0 - B r o m o - 3 , 4 - e p o x y d o d e c - 6 - e n e - 1 , 9 - d i o l a n d
(3R*,4S*,6Z,9R*,10S*)-10-Bromo-3,4-epoxydodec-6-ene-1,9-diol
(30b). Diastereomer 1: Isolated as a single diastereomer, with the
overall relative stereochemistry unassigned: 10 mg, 0.9% as a colorless
epoxide 30 (1.64 g, 82%) as a colorless oil: [α]20 −8.9 (c 0.87,
D
CH2Cl2) [where the trityl derivative recorded an e.r. of 78:22, (3S,4R):
(3R,4S); see below]; all other data was identical with that reported
above.
1
oil; IR (KBr) 3700−3050, 2850, 2770, 1642, 1404 cm−1; H NMR
(3S,4R,6Z,9E)-3,4-Epoxydodeca-6,9-dien-1-yl trityl ether.
Triethylamine (0.07 mL, 0.51 mmol, 2.0 equiv) and trityl chloride
(78 mg, 0.28 mmol, 1.1 equiv) were added to a solution of epoxide 30
(50 mg, 0.24 mmol, 1.0 equiv) in dichloromethane (2.5 mL) at room
temperature. The mixture was stirred for 18 h, diluted with
dichloromethane (15 mL) and washed with water (15 mL). The
aqueous phase was extracted with dichloromethane (3 × 15 mL), and
the combined organics were washed with brine (20 mL). The organics
were dried over sodium sulfate, filtered, and the solvent was removed
under reduced pressure. The crude mixture was subjected to column
chromatography (petroleum spirit:ethyl acetate, 20:1) to provide the
product (82 mg, 73%) as a colorless oil: Rf 0.38 (petroleum spirit:ethyl
(400 MHz, CDCl3) δ 5.75−5.63 (m, 2H), 4.07 (ddd, J = 9.7, 5.0, 3.4
Hz, 1H), 3.95−3.79 (m, 3H), 3.18−3.14 (m, 1H), 3.09−3.04 (m, 1H),
2.52−2.31 (m, 4H), 2.04−1.76 (m, 4H), 1.12 (t, J = 7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 127.6, 127.4, 74.0, 64.7, 60.5, 56.0, 55.6,
31.8, 30.6, 27.0, 26.5, 12.5; MS (CI+, NH3) 310 (M + NH4)+; HRMS
(Magnetic Sector CI+, NH3) m/z calcd for C12H22O379Br (M + H)+
293.0752, found 293.0750; HPLC (n-hexane:i-propanol, 95:5), 4.00
mL/min, 240 nm, tR 27.5 min. Diastereomer 2: Isolated as a single
diastereomer, with the overall relative stereochemistry unassigned: 8
mg, 0.7% as a colorless oil; IR (KBr) 3700−3050, 2850, 2771, 1642,
1402 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.77−5.63 (m, 2H), 4.12−
4.05 (m, 1H), 3.96−3.85 (m, 2H), 3.74 (dt, J = 8.2, 4.4 Hz, 1H), 3.20
(dt, J = 7.8, 4.5 Hz, 1H), 3.10−3.05 (m, 1H), 2.51−2.29 (m, 4H),
2.02−1.65 (m, 5H), 1.12 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 127.9, 127.6, 73.6, 65.1, 60.6, 56.0, 31.9, 30.7, 27.3, 26.2,
12.5; MS (CI+, NH3) 310 (M + NH4)+; HRMS (Magnetic Sector CI+,
NH3) m/z calcd for C12H22O379Br (M + H)+ 293.0752, found
293.0766; HPLC (n-hexane:i-propanol, 95:5), 4.00 mL/min, 240 nm,
tR 28.5 min. (3R*,4S*,6Z,9R*,10S*)-9,10-Dibromo-3,4-epoxydo-
dec-6-en-1-ol and (3R*,4S*,6Z,9S*,10R*)-9,10-Dibromo-3,4-epox-
ydodec-6-en-1-ol (30c). Isolated as a mixture of two diastereomers (it
acetate, 10:1); [α]20 −0.9 (c 0.98, CH2Cl2); IR (neat) 3063, 3026,
D
2963, 2926, 2875, 1490, 1447, 1068 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.53−7.48 (m, 6H), 7.38−7.32 (m, 6H), 7.31−7.26 (m,
3H), 5.62−5.37 (m, 4H), 3.33 (t, J = 6.5 Hz, 2H), 3.20−3.15 (m, 1H),
3.01 (td, J = 6.4, 4.3 Hz, 1H), 2.79 (app t, J = 6.3 Hz, 2H), 2.45−2.37
(m, 1H), 2.30−2.22 (m, 1H), 2.10−2.01 (m, 2H), 1.98−1.81 (m, 2H),
1.01 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.2, 132.8,
130.6, 128.7, 127.8, 127.0, 126.7, 124.5, 86.8, 61.1, 56.4, 54.9, 30.6,
28.7, 26.3, 25.6, 13.9; MS (ESI) m/z 461 (M + Na)+; HRMS (ES-
ToF) m/z calcd for C31H34O2Na (M + Na)+ 461.2457, found
461.2451; e.r. = 78:22, (3S,4R):(3R,4S); HPLC (ChiralPak AD), n-
hexane:i-propanol = 99.75:0.25, wavelength = 200 nm; injection
volume = 10 μL, flow rate = 0.25 mL/min, tR = 105.7 min (3S,4R), tR
= 93.9 min (3R,4S).
1
was not possible to estimate the ratio from the H NMR spectrum):
10 mg, 0.9% as a colorless oil; IR (KBr) 3650−3050, 1717, 1350, 1054
cm−1; 1H NMR (400 MHz, CDCl3) δ 5.73−5.66 (m, 4H), 4.26−4.14
(m, 4H), 3.96−3.85 (m, 4H), 3.16 (dt, J = 7.8, 4.5 Hz, 2H), 3.08−2.97
(m, 4H), 2.92−2.84 (m, 2H), 2.51−2.21 (m, 6H), 2.07−1.90 (m, 4H),
1.83−1.55 (m, 4H), 1.12 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 127.7, 127.6, 127.4, 127.3, 60.7, 60.6, 60.4, 57.5, 57.3, 55.9,
55.8, 55.1, 55.0, 35.2, 35.1, 30.6, 30.5, 30.3, 29.7, 11.1; MS (CI+, NH3)
372 (M + NH4)+; HRMS (Magnetic Sector CI+, NH3) m/z calcd for
C12H24NO279Br2 (M + NH4)+ 372.0174, found 372.0157; HPLC (n-
hexane:i-propanol, 98.5:1.5), 3.50 mL/min, 206 nm, tR 40.5 min.
(3R*,4S*,6R*)-6-Bromo-6-[(2R*,4S*,5R*)-4-bromo-5-ethyltetra-
hydrofuran-2-yl]-3,4-epoxy-hexan-1-ol, (3R*,4S*,6R*)-6-Bromo-6-
[(2R*,4R*,5S*)-4-bromo-5-ethyltetrahydrofuran-2-yl]-3,4-epoxy-
hexan-1-ol, (3R*,4S*,6S*)-6-Bromo-6-[(2S*,4S*,5R*)-4-bromo-5-
ethyltetrahydrofuran-2-yl]-3,4-epoxyhexan-1-ol and (3R*,4S*,6S*)-
6-Bromo-6-[(2S*,4R*,5S*)-4-bromo-5-ethyltetrahydrofuran-2-yl]-
3,4-epoxyhexan-1-ol (30d). Diastereomers 1 and 2: Isolated as a
mixture of two diastereomers in a ratio of 1.2:1.0 (found by integration
of the signals at 4.36 and 4.27 ppm): 15 mg, 1.1% as a colorless oil; IR
(KBr) 3600−3100, 2974, 1715, 1640, 1445, 1379, 1098, 948 cm−1; 1H
NMR (400 MHz, CDCl3) δ 4.40−4.36 (m, 1H), 4.31−4.27 (m, 1H),
4.25−4.18 (m, 2H), 4.08−4.04 (m, 4H), 3.94−3.84 (m, 4H), 3.29−
3.19 (m, 3H), 3.18−3.14 (m, 1H), 2.53−2.46 (m, 2H), 2.40−2.19 (m,
4H), 2.08−2.02 (m, 2H), 1.98−1.57 (m, 8H), 1.03 (t, J = 7.4 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 88.7, 88.6, 79.9, 79.0, 60.5, 60.4, 55.6,
55.1, 54.9, 54.8, 54.6, 53.2, 48.3, 48.2, 40.4, 40.2, 34.0, 33.7, 31.0, 30.6,
26.4, 26.3, 10.0, 9.9; MS (CI+, NH3) 370 (M + H)+; HRMS (ES-ToF)
m/z calcd for C12H21O379Br2 (M + H)+ 370.9857, found 370.9860.
Diastereomers 3 and 4: Isolated as a mixture of two diastereomers (it
was not possible to estimate the ratio from the 1H NMR spectrum due
to overlapping resonances): 16 mg, 1.2% as a colorless oil; IR (KBr)
Procedure for the Treatment of Epoxide ( )-30 with NBS
and Water. Tetramethylguanidine (23 mg, 0.2 mmol, 5 mol %) and
NBS (0.65 g, 3.7 mmol, 1.0 equiv) were added to a stirred solution of
epoxide ( )-30 (0.72 g, 3.7 mmol, 1.0 equiv) in water (370 mL). The
mixture was stirred at room temperature for 3 days, and the products
were extracted with ethyl acetate (3 × 100 mL). The organics were
combined and washed with 10% w/w aqueous sodium sulfite solution
(2 × 100 mL) and brine (100 mL). The organics were dried over
sodium sulfate, and the solvent was removed under reduced pressure
to give a colorless oil. Separation of products and purification was
achieved by column chromatography (petroleum spirit:ethyl acetate,
2:1, to 100% ethyl acetate) and HPLC (n-hexane/i-propanol) where
a p p r o p r i a t e t o g i v e t h e f o l l o w i n g c o m p o u n d s .
(3R*,4S*,6Z,9S*,10R*)-9-Bromo-3,4-epoxydodec-6-ene-1,10-diol
and (3R*,4S*,6Z,9R*,10S*)-9-Bromo-3,4-epoxydodec-6-ene-1,10-
diol (30a). Diastereomer 1: Isolated as a single diastereomer, with
the overall relative stereochemistry unassigned: 32 mg, 3.0% as a
colorless oil; IR (KBr) 3700−3100, 2967, 2880, 1643, 1438, 1385
cm−1; 1H NMR (400 MHz, CDCl3) δ 5.75−5.64 (m, 2H), 4.16−4.07
(m, 1H), 3.93−3.83 (m, 2H), 3.67 (ddd, J = 8.8, 5.8, 3.3 Hz, 1H), 3.18
(dt, J = 7.6, 4.6 Hz, 1H), 3.07 (dt, J = 7.0, 5.0 Hz, 1H), 2.86−2.76 (m,
1H), 2.63−2.57 (m, 1H), 2.45−2.37 (m, 1H), 2.33−2.26 (m, 1H),
1.98−1.89 (m, 1H), 1.84−1.69 (m, 2H), 1.62−1.51 (m, 1H), 1.02 (t, J
= 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 128.3, 126.9, 75.0,
60.6, 60.5, 56.1, 55.7, 31.3, 30.6, 26.8, 26.7, 10.1; MS (CI+, NH3) 310
(M + NH4)+; HRMS (Magnetic Sector CI+, NH3) m/z calcd for
C12H25NO379Br (M + NH4)+ 310.1018, found 310.1018; HPLC (n-
hexane:i-propanol, 95:5), 4.00 mL/min, 240 nm, tR 22.5 min.
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3600−3050, 2969, 2916, 1712, 1641, 1379, 1260, 1051 cm−1; 1H
NMR (400 MHz, CDCl3) δ 4.27−4.21 (m, 3H), 4.18−4.12 (m, 1H),
4.07−4.01 (m, 2H), 3.94- 3.86 (m, 6H), 3.30−3.25 (m, 2H), 3.24−
3.20 (m, 1H), 3.18−3.13 (m, 1H), 2.76−2.68 (m, 2H), 2.40−2.19 (m,
4H), 2.12−2.05 (m, 2H), 1.99−1.50 (m, 8H), 1.03 (t, J = 7.4 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 87.4, 87.3, 79.5, 79.1, 60.6, 60.4, 55.6,
HRMS (Magnetic Sector CI+, NH3) m/z calcd for C13H23NO479Br (M
+ NH4)+ 336.0810, found 336.0807; HPLC (n-hexane:i-propanol,
94:6); 1.05 mL/min; 203 nm; tR 148 min. (4R)-4-{(2R,7S)-7-[(1R)-
1-bromopropyl]-2,3,6,7-tetrahydrooxepin-2-yl}-1,3-dioxan-2-one
(33). Colorless oil (containing 27% by mole of an unidentified
saturated compound, found by relative integration of the resonance at
3.70 ppm with the resonance at 3.65 ppm): [α]23 +22.6 (c 0.30,
55.1, 54.9, 54.8, 54.5, 53.4, 46.7, 46.5, 40.4, 40.2, 33.4, 33.1, 31.0, 30.6,
25.3, 25.2, 9.9, 9.8; MS (CI+, NH3) 370 (M + H)+; HRMS (ES-ToF)
m/z calcd for C12H21O379Br2 (M + H)+ 370.9857, found 370.9867.
tert-Butyl (3S,4R,6Z,9E)-3,4-epoxydodeca-6,9-dienyl carbo-
nate (31). Triethylamine (3.83 mL, 27.7 mmol, 2.0 equiv) and DMAP
(337 mg, 2.8 mmol, 0.2 equiv) were added to a solution of epoxide 30
(2.71 g, 13.8 mmol, 1.0 equiv) in toluene (50 mL) at 0 °C. Di-t-butyl
dicarbonate (4.28 mL, 18.7 mmol, 1.35 equiv) was added dropwise,
and the reaction mixture was allowed to warm to room temperature.
After stirring at room temperature for 16 h, the solvent was removed
under reduced pressure, and the mixture was immediately subjected to
column chromatography (petroleum spirit:ethyl acetate, 9:1), to give
first 31 (2.30 g, 56%) as a colorless oil: Rf 0.59 (petroleum spirit:ethyl
D
CH2Cl2); IR (neat) 2970, 2931, 1747, 1407, 1251, 1192, 1124 cm−1;
1H NMR (400 MHz, CDCl3) δ 5.83−5.80 (m, 2H), 4.55−4.46 (m,
2H), 4.39−4.32 (m, 1H), 3.96−3.90 (m, 1H), 3.65 (ddd, J = 9.9, 4.5,
2.0 Hz, 1H), 3.59 (ddd, J = 10.7, 3.4, 1.6 Hz, 1H), 2.65−2.56 (m, 1H),
2.52−2.30 (m, 2H), 2.29−2.24 (m, 2H), 2.09−1.72 (m, 3H), 1.06 (t, J
= 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 148.9, 129.1, 128.8,
83.3, 80.6, 79.6, 66.8, 61.9, 34.2, 31.9, 26.5, 23.4, 12.4; MS (CI) m/z
336 (M + NH4)+; HRMS (Magnetic Sector CI+, NH3) m/z calcd for
C13H23NO479Br (M + NH4)+ 336.0810, found 336.0811; HPLC (n-
hexane:i-propanol, 94:6); 1.50 mL/min; 203 nm; tR 140 min. (4R)-4-
{(2R,7R)-7-[(1S)-1-Bromopropyl]-2,3,6,7-tetrahydrooxepin-2-yl}-
1,3-dioxan-2-one (34). The product was isolated as a colorless oil
(containing 9% of 32 and 20% of 33, found by relative integration of
the resonance at 5.95 ppm with the resonance at 5.76 ppm and the
acetate, 2:1); [α]20 −3.8 (c 1.05, CH2Cl2); IR (neat) 2973, 1739,
D
1
1457, 1395, 1370, 1276, 1252, 1159, 1102, 967 cm−1; H NMR (400
resonance at 5.74 ppm): [α]26 −9.0 (c 0.20, CH2Cl2); IR (neat)
MHz, CDCl3) δ 5.62−5.35 (m, 4H), 4.31−4.23 (m, 2H), 3.12−3.05
(m, 1H), 3.00 (td, J = 6.4, 4.1 Hz, 1H), 2.81−2.74 (m, 2H), 2.45−2.35
(m, 1H), 2.29−2.19 (m, 1H), 2.08−1.81 (m, 4H), 1.51 (s, 9H), 0.98
(t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 153.4, 132.9,
130.8, 126.6, 124.1, 82.2, 64.3, 56.2, 54.0, 30.6, 27.8, 27.6, 26.1, 25.6,
13.8; MS (CI) m/z 314 (M + NH4)+; HRMS (Magnetic Sector CI+,
NH3) m/z calcd for C17H32NO4 (M + NH4)+ 314.2331, found
314.2323. The second, bis(3R,4S,6Z,9E)-3,4-epoxydodeca-6,9-dien-
yl carbonate (31a), was given as a pale yellow oil (0.93 g, 32%): Rf
D
2925, 2857, 1748, 1410, 1249, 1191, 1119 cm−1; 1H NMR (400 MHz,
CDCl3) δ 5.73−5.70 (m, 2H), 4.54 (ddd, J = 10.8, 5.0, 3.4 Hz, 1H),
4.46 (ddd, J = 10.2, 4.3, 2.5 Hz, 1H), 4.35 (td, J = 11.1, 3.6 Hz, 1H),
4.28 (dt, J = 11.7, 1.8 Hz, 1H), 4.22 (ddd, J = 10.5, 4.3, 1.7 Hz, 1H),
4.03 (dt, J = 9.7, 4.0 Hz, 1H), 2.85−2.78 (m, 1H), 2.67−2.54 (m, 1H),
2.38−2.17 (m, 3H), 2.09−2.01 (m, 1H), 1.93−1.72 (m, 2H), 1.10 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 148.5, 127.8, 127.7,
80.9, 77.9, 75.5, 66.8, 62.8, 30.5, 30.2, 28.3, 23.3, 12.4; MS (CI+, NH3)
m/z 336 (M + NH4)+; HRMS (Magnetic Sector CI+, NH3) m/z calcd
for C13H23NO479Br (M + NH4)+ 336.0810, found 336.0807; HPLC
(n-hexane:i-propanol, 94:6); 1.50 mL/min; 203 nm; tR 145 min.
(5aS,7R,8S,10Z,12aS)-8-Bromo-7-ethyl-4,5,5a,7,8,9,12,12a-
octahydro[1,3]dioxepino[5,4-b]oxonin-2-one (35) and
(5aS,7S,8R,10Z,12aS)-8-Bromo-7-ethyl-4,5,5a,7,8,9,12,12a-
octahydro[1,3]dioxepino[5,4-b]oxonin-2-one (36). Diastereomer
1: Colorless oil (containing 16% by mole of an unidentified
compound, found by relative integration of the resonance at 4.40
ppm with the resonance at 4.50 ppm): [α]26D +15.0 (c 0.20, CH2Cl2);
IR (neat) 2925, 1790, 1171, 1055 cm−1; 1H NMR (500 MHz, CDCl3)
δ 5.84−5.75 (m, 1H), 5.69−5.61 (m, 1H), 4.62−4.46 (m, 2H), 4.26−
4.20 (m, 1H), 4.19−4.13 (m, 1H), 3.92−3.84 (m, 2H), 3.04−2.84 (m,
2H), 2.71−2.55 (m, 2H), 2.33−2.20 (m, 1H), 2.09−1.94 (m, 3H),
1.12 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 154.2, 129.6,
124.8, 81.9, 79.3, 60.5, 58.2, 56.8, 36.1, 35.1, 31.6, 30.4, 11.0; MS (ESI)
m/z 319 (M + H)+; HPLC (n-hexane:i-propanol, 94:6); 1.50 mL/min;
203 nm; tR 97 min. It was not possible to obtain high resolution mass
spectrometry data for this compound using either CI or ESI modes of
ionization. Diastereomer 2: Colorless oil (containing ca. 20% of
Diastereomer 1, found by relative integration of the alkene resonances
in the 13C NMR spectrum): [α]24D +18.5 (c 0.20, CH2Cl2); IR (neat)
0.49 (petroleum spirit:ethyl acetate, 2:1): [α]20 −6.4 (c 1.57,
D
CH2Cl2); IR (neat) 2963, 1745, 1461, 1403, 1251, 966 cm−1; 1H
NMR (400 MHz, CDCl3) δ 5.62−5.35 (m, 8H), 4.38−4.31 (m, 4H),
3.08 (dt, J = 7.1, 4.5 Hz, 2H), 3.01 (td, J = 6.4, 4.2 Hz, 2H), 2.80−2.74
(m, 4H), 2.46−2.37 (m, 2H), 2.28−2.19 (m, 2H), 2.06−1.97 (m, 6H),
1.93−1.84 (m, 2H), 0.98 (t, J = 7.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 155.0, 132.9, 130.9, 126.6, 124.0, 65.4, 56.2, 53.8, 31.4, 27.5,
26.1, 25.5, 13.8; MS (CI) m/z 436 (M + NH4)+; HRMS (Magnetic
Sector CI+, NH3) m/z calcd for C25H42NO5 (M + NH4)+ 436.3063,
found 436.3056.
Procedure for Cyclization of Carbonate 31 and Subsequent
Hydrolysis. A solution of Et2SBr·SbCl5Br (885 mg, 1.61 mmol, 1.0
equiv) in nitromethane (1 mL) was added rapidly to a solution of
carbonate 31 (477 mg, 1.61 mmol, 1.0 equiv) in nitromethane (80
mL) at room temperature. After 1 h the reaction mixture was diluted
with ethyl acetate (200 mL) and washed with a mixture of aqueous
sodium sulfite solution (100 mL) and saturated aqueous sodium
bicarbonate solution (100 mL). The layers were separated, and the
aqueous phase was extracted with ethyl acetate (4 × 100 mL). The
organics were combined, washed with brine (200 mL), dried over
sodium sulfate, filtered, and the solvent was removed under reduced
pressure. The crude mixture was subjected to column chromatography
(petroleum spirit:ethyl acetate, 3:1 to 1:2) to give two components,
first Mixture A (105 mg) as a pale yellow oil and second Mixture B
(91 mg) as a colorless oil. Mixture A: Rf 0.35 (ethyl acetate:petroleum
1
2968, 1793, 1385, 1174, 1054 cm−1; H NMR (400 MHz, CDCl3) δ
5.85−5.77 (m, 1H), 5.69−5.61 (m, 1H), 4.64−4.57 (m, 1H), 4.53−
4.47 (m, 1H), 4.27−4.21 (m, 1H), 4.20−4.14 (m, 1H), 3.93−3.84 (m,
2H), 3.05−2.84 (m, 2H), 2.70−2.50 (m, 2H), 2.31−2.24 (m, 1H),
2.06−1.94 (m, 3H), 1.12 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100
MHz, CDCl3) δ 154.2, 130.0, 124.4, 81.1, 78.6, 60.5, 58.2, 56.8, 36.2,
35.2, 31.3, 30.4, 11.0; MS (ESI) m/z 319 (M + H)+; HPLC (n-
hexane:i-propanol, 94:6); 1.50 mL/min; 203 nm; tR 102 min. It was
not possible to obtain high resolution mass spectrometry data for this
compound using either CI or ESI modes of ionization. Mixture B: Rf
1
spirit, 3:1). Analysis of the H NMR spectrum provides the following
calculated yields from carbonate 31:32 (21 mg, 4.1%), 33 (7 mg,
1.4%), 34 (6 mg, 1.2%), 35 and 36 (9 mg, 1.8%). These compounds
were separated by preparative HPLC. (4R)-4-[(2R,4Z,7S,8R)-7-
Bromo-8-ethyl-3,6,7,8-tetrahydro-2H-oxocin-2-yl]-1,3-dioxan-2-
one (32). Colorless oil (containing 12% of compound 34, found by
relative integration of the resonance at 5.95 ppm with the resonance at
5.74 ppm): [α]26 +20.0 (c 1.20, CH2Cl2); IR (neat) 2967, 2923,
1
0.29 (ethyl acetate:petroleum spirit, 3:1). Analysis of the H NMR
D
1748, 1449, 1408, 1248, 1192, 1124, 1093 cm−1; 1H NMR (400 MHz,
CDCl3) δ 6.03−5.91 (m, 2H), 4.55 (dt, J = 11.1, 3.7 Hz, 1H), 4.52−
4.35 (m, 2H), 4.04 (dt, J = 9.9, 3.4 Hz, 1H), 3.51−3.45 (m, 2H), 3.17
(ddd, J = 14.1, 8.5, 3.6 Hz, 1H), 2.60−2.46 (m, 2H), 2.23−2.13 (m,
2H), 2.09−1.97 (m, 2H), 1.56−1.49 (m, 1H), 0.99 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 148.5, 129.3, 128.9, 85.2, 81.1, 80.2,
67.0, 56.0, 32.3, 28.7, 26.0, 22.7, 9.8; MS (CI) m/z 336 (M + NH4)+;
spectrum provides the following calculated yields from tert-butyl
(3R,4S,6Z,9E)-epoxydodeca-6,9-dienyl carbonate 31:37 (18 mg, 3.5%)
and 38 (30 mg, 5.8%). This mixture of carbonates was subjected to
basic hydrolysis. Sodium hydroxide (171 mg, 4.28 mmol. 15.0 equiv)
was added to a solution of Mixture B (91 mg, 0.29 mmol, 1.0 equiv) in
methanol at room temperature. After 2 h saturated aqueous
ammonium chloride solution (136 mg, 2.54 mmol, 9.0 equiv) was
H
dx.doi.org/10.1021/jo301580c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
added, and the mixture was stirred for an additional 10 min. The crude
mixture was filtered through a plug of silica, eluting with diethyl ether
(100 mL), and the solvent was subsequently evaporated under
reduced pressure to provide Mixture C (75 mg) as a colorless oil.
Mixture C: Rf 0.31 (ethyl acetate:petroleum spirit, 3:1). These
compounds were separated by preparative HPLC. (1R)-1-
[(2R,4Z,7R,8S)-7-Bromo-8-ethyl-3,6,7,8-tetrahydro-2H-oxocin-2-
yl]propane-1,3-diol (40). Colorless oil (containing 7% by mole of an
unidentified compound, found by relative integration of the resonance
(Magnetic Sector CI+, NH3) m/z calcd for C12H25NO379Br (M +
NH4)+ 310.1018, found 310.1021.
(1R)-1-{(2R,7R)-7-[(1S)-1-Bromopropyl]-2,3,6,7-tetrahy-
drooxepin-2-yl}propane-1,3-diol (42). The product was isolated as
a white solid (containing 9% of 39 and 20% of 41, in accordance with
what was found for compound 34): [α]28D −10.0 (c 0.01, CH2Cl2); IR
(neat) 3650−3000, 2926, 1639, 1455, 1055 cm−1; 1H NMR (400
MHz, CDCl3) δ 5.78−5.68 (m, 2H), 4.30−4.24 (m, 1H), 4.10−3.97
(m, 2H), 3.91−3.84 (m, 2H), 3.83−3.75 (m, 1H), 2.93 (d, J = 4.5 Hz,
1H), 2.74−2.64 (m, 1H), 2.57−2.53 (m, 1H), 2.36−2.20 (m, 2H),
1.98−1.65 (m, 4H), 1.10 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 128.2, 127.6, 78.0, 77.9, 74.2, 62.8, 61.2, 35.1, 31.2, 31.0,
27.4, 12.6; MS (CI) m/z 310 (M + NH4)+; HRMS (Magnetic Sector
CI+, NH3) m/z calcd for C12H25NO379Br (M + NH4)+ 310.1018,
found 310.1021. Insufficient material was available to record a melting
point.
at 4.26 ppm with the resonance at 4.20 ppm): [α]26 −25.5 (c 1.00,
D
CH2Cl2); IR (neat) 3600−3050, 2933, 1457, 1386, 1152, 1046 cm−1;
1H NMR (400 MHz, CDCl3) δ 5.81−5.71 (m, 2H), 4.20 (ddd, J =
10.0, 7.5, 2.9 Hz, 1H), 3.97 (ddd, J = 9.8, 6.7, 3.2 Hz, 1H), 3.93−3.81
(m, 4H), 3.13−3.05 (m, 1H), 2.83 (br s, 1H), 2.74−2.65 (m, 1H),
2.57 (br s, 1H), 2.44−2.29 (m, 2H), 2.05−1.94 (m, 1H), 1.93−1.82
(m, 1H), 1.81−1.67 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 128.1, 127.7, 78.3, 77.7, 73.0, 61.1, 55.2, 35.3, 34.9,
29.8, 26.2, 9.0; MS (CI) m/z 310 (M + NH4)+; HRMS (ES-ToF) m/z
calcd for C12H22O379Br (M + H)+ 293.0752, found 293.0742; HPLC
(n-hexane:i-propanol, 94:6); 4.00 mL/min; 203 nm; tR 48 min. 1-[2-
(1-Bromopropyl)-3-oxabicyclo[4.1.0]hept-4-yl]propane-1,3-diol
(45). Colorless oil (two diastereomers in a ratio of 15:2, found by
relative integration of the resonance at 0.25 ppm with the resonance at
0.40 ppm; the following resonances given are for the major
(2S,3S,5Z,8S,9R)-8-Bromo-9-ethyl-2-(2-hydroxyethyl)-
2,3,4,7,8,9-hexahydrooxonin-3-ol (43) and (2S,3S,5Z,8R,9S)-8-
Bromo-9-ethyl-2-(2-hydroxyethyl)-2,3,4,7,8,9-hexahydrooxo-
nin-3-ol (44). Diastereomer 1: Off-white solid (containing 16% by
mole of an unidentified compound, in accordance with what was found
for Diastereomer 1 of compound 35 or 36): [α]28 +1.0 (c 0.02,
D
CH2Cl2); IR (neat) 3650−3000, 2923, 1642, 1457, 1262, 1057 cm−1;
1H NMR (400 MHz, CDCl3) δ 5.72−5.65 (m, 2H), 4.22 (td, J = 8.8,
3.4 Hz, 1H), 4.17−4.12 (m, 1H), 3.93−3.86 (m, 2H), 3.80−3.72 (m,
1H), 3.60−3.53 (m, 1H), 3.02−2.79 (m, 2H), 2.40−1.92 (m, 4H),
1.85−1.72 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 128.7, 127.9, 73.9, 73.5, 61.2, 60.6, 57.7, 35.2, 35.0, 32.1,
30.3, 11.1; MS (CI) m/z 310 (M + NH4)+; HRMS (Magnetic Sector
CI+, NH3) m/z calcd for C12H25NO379Br (M + NH4)+ 310.1018,
found 310.1018. Insufficient material was available to record a melting
point. Diastereomer 2: White solid (containing 21% of Diastereomer
1, in accordance with what was found for Diastereomer 2 of
compound 35 or 36): [α]28D −1.0 (c 0.01, CH2Cl2); IR (neat) 3600−
diastereomer): [α]26 +7.7 (c 1.90, CH2Cl2); IR (neat) 3600−3000,
D
1
2928, 1460, 1066 cm−1; H NMR (400 MHz, CDCl3) δ 4.29 (td, J =
8.8, 3.1 Hz, 1H), 3.93 (dd, J = 8.8, 2.1 Hz, 1H), 3.85 (app t, J = 5.1 Hz,
2H), 3.53 (ddd, J = 12.7, 6.4, 2.1 Hz, 1H), 3.31 (ddd, J = 11.3, 6.5, 4.5
Hz, 1H), 2.81 (d, J = 2.4 Hz, 1H), 2.66 (br s, 1H), 2.19−2.05 (m, 1H),
1.98−1.83 (m, 2H), 1.75−1.64 (m, 2H), 1.38−1.27 (m, 2H), 1.16−
1.08 (m, 4H), 0.90−0.81 (m, 1H), 0.39 (dd, J = 10.7, 5.3 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 75.4, 74.6, 70.9, 61.1, 60.8, 34.0, 27.5,
24.8, 11.8, 11.3, 11.2, 7.0; MS (CI) m/z 310 (M + NH4)+; HRMS (ES-
ToF) m/z calcd for C12H22O379Br (M + H)+ 293.0752, found
293.0739; HPLC (n-hexane:i-propanol, 94:6); 4.00 mL/min; 203 nm;
tR 42 min.
General Procedure for the Hydrolysis of the Cyclic
Carbonates Isolated from Mixture A. Sodium hydroxide (15.0
equiv) was added to a solution of carbonate 32, 33, 34, 35 or 36 (1.0
equiv) in methanol (42 mM) at room temperature. After stirring for 2
h ammonium chloride (9.0 equiv) was added and stirred for a further
10 min. The mixture was filtered through a plug of silica, eluting with
diethyl ether, and the solvent was subsequently removed under
reduced pressure to provide the product 39, 41, 42, 43 or 44,
respectively, in quantitative yield.
1
3050, 2928, 1671, 1458, 1061 cm−1; H NMR (500 MHz, CDCl3) δ
5.73−5.67 (m, 2H), 4.27−4.22 (m, 1H), 4.21−4.16 (m, 1H), 3.97−
3.87 (m, 2H), 3.83−3.76 (m, 1H), 3.64−3.57 (m, 1H), 3.04−2.83 (m,
2H), 2.45−1.95 (m, 4H), 1.92−1.75 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 128.5, 128.1, 73.9, 73.5, 61.1, 60.6,
57.8, 35.2, 35.1, 32.1, 30.3, 11.1; MS (CI) m/z 310 (M + NH4)+;
HRMS (Magnetic Sector CI+, NH3) m/z calcd for C12H25NO379Br (M
+ NH4)+ 310.1018, found 310.1021. Insufficient material was available
to record a melting point.
ASSOCIATED CONTENT
■
S
* Supporting Information
(1R)-1-[(2R,4Z,7S,8R)-7-Bromo-8-ethyl-3,6,7,8-tetrahydro-
2H-oxocin-2-yl]propane-1,3-diol (39). Colorless oil (containing
12% of 42, in accordance with what was found for compound 32):
General experimental; copies of H and 13C NMR spectra for
1
26, 28, 29, 30, 31, 31a and trityl derivative of 30; HPLC
[α]28 +11.0 (c 1.20, CH2Cl2); IR (neat) 3650−3050, 2922, 1649,
chromatogram of the racemic and enantioenriched trityl
D
1
derivative of 30; H and 13C NMR spectra of compounds
1447, 1055 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.02−5.89 (m, 2H),
4.10 (dt, J = 9.9, 3.4 Hz, 1H), 3.92−3.84 (m, 2H), 3.79−3.73 (m, 1H),
3.58−3.53 (m, 1H), 3.29−3.15 (m, 2H), 2.92 (d, J = 2.9 Hz, 1H),
2.56−2.48 (m, 1H), 2.44−2.35 (m, 1H), 2.22−2.13 (m, 1H), 2.10−
1.98 (m, 1H), 1.82−1.75 (m, 2H), 1.69−1.59 (m, 1H), 1.01 (t, J = 7.5
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 129.4, 128.8, 84.6, 83.9,
74.3, 61.4, 55.7, 34.9, 32.3, 30.4, 25.8, 9.3; MS (CI) m/z 310 (M +
NH4)+; HRMS (Magnetic Sector CI+, NH3) m/z calcd for
C12H22O379Br (M + H)+ 293.0752, found 293.0745.
30a−d, including Br-induced isotopic shift for compounds 30a
1
(Diastereomer 1) and 30b (Diastereomers 1 and 2); H NMR
spectrum of Mixture A before preparative HPLC. HPLC
chromatogram of Mixture A and C; note on numbering of
1
compounds; copies of H, 13C, DEPT-135, COSY and HSQC
NMR spectra for carbonates 32, 33, 34, 35 and 36, and HMBC
1
NMR spectrum of 33; copies of H, 13C, DEPT-135, COSY
and HSQC NMR spectra for diols 39, 40, 41, 42, 43, 44 and
45, and HMBC and NOESY NMR spectra of 39 and 45;
comparison of 1H NMR spectrum of 32 with 1a. This material
is available free of charge via the Internet at http://pubs.acs.org.
(1R)-1-{(2R,7S)-7-[(1R)-1-Bromopropyl]-2,3,6,7-tetrahy-
drooxepin-2-yl}propane-1,3-diol (41). Colorless oil (containing
27% by mole of an unidentified saturated compound, in accordance
with what was found for compound 33): [α]28 +43.0 (c 0.20,
D
CH2Cl2); IR (neat) 3600−3050, 2929, 1667, 1423, 1260, 1059 cm−1;
1H NMR (400 MHz, CDCl3) δ 5.80−5.76 (m, 2H), 4.01−3.95 (m,
1H), 3.88−3.83 (m, 2H), 3.79−3.70 (m, 2H), 3.38−3.30 (m, 1H),
2.61−2.57 (m, 1H), 2.54−2.46 (m, 1H), 2.37−2.25 (m, 2H), 2.00−
1.78 (m, 2H), 1.76−1.70 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 128.8, 128.4, 83.9, 83.0, 74.6, 62.5, 61.2, 34.7,
34.2, 32.8, 26.4, 12.6; MS (CI) m/z 310 (M + NH4)+; HRMS
AUTHOR INFORMATION
Corresponding Author
*E-mail: c.braddock@imperial.ac.uk.
■
Notes
The authors declare no competing financial interest.
I
dx.doi.org/10.1021/jo301580c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(10) (+)-Laureatin: (a) Sugimoto, M.; Suzuki, T.; Hagiwara, H.;
Hoshi, T. Tetrahedron Lett. 2007, 48, 1109−1112. (b) Kim, H.; Lee,
H.; Lee, D.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2007, 129, 2269−2274.
(11) (+)-Isolaureatin: (a) Fukuzawa, A.; Kurosawa, E.; Irie, T. J. Org.
Chem. 1972, 37, 680−682. (b) see ref 9b.
ACKNOWLEDGMENTS
■
We thank the EPSRC (Grant No. EP/F034253/1 to D.C.B.)
and for a DTA (to K.J.B.). We thank P. R. Haycock for NMR
experiments.
(12) (+)-Laurallene: (a) see ref 9a. (b) Saitoh, T.; Suzuki, T.;
Sugimoto, M.; Hagiwara, H.; Hoshi, T. Tetrahedron Lett. 2003, 44,
3175−3178. (c) Sasaki, M.; Hashimoto, A.; Tanaka, K.; Kawahata, M.;
Yamaguchi, K.; Takeda, K. Org. Lett. 2008, 10, 1803−1806. (d) see ref
9b.
(13) (−)-Isolaurallene: (a) Crimmins, M. T.; Emmitte, K. A. J. Am.
Chem. Soc. 2001, 123, 1533−1534. (b) Crimmins, M. T.; Emmitte, K.
A.; Choy, A. L. Tetrahedron 2002, 58, 1817−1834.
(14) (+)-Itomanallene A: Jeong, A. W.; Kim, M. J.; Kim, H.; Kim, S.;
Kim, D.; Shin, K. J. Angew. Chem., Int. Ed. 2010, 49, 752−756.
(15) ent-(+)-Neolaurallene: see ref 14.
(16) (+)-Isolaurepinnacin: (a) Berger, D.; Overman, L. E.; Renhowe,
P. A. J. Am. Chem. Soc. 1993, 115, 9305−9306. (b) Berger, D.;
Overman, L. E.; Renhowe, P. A. J. Am. Chem. Soc. 1997, 119, 2446−
2452. (c) Suzuki, T.; Matsumara, R.; Oku, K.-I.; Taguchi, K.;
Hagiwara, H.; Hoshi, T.; Ando, M. Tetrahedron Lett. 2001, 42, 65−67.
(17) (+)-Rogioloxepane A: (a) Matsumara, R.; Suzuki, T.; Hagiwara,
H.; Hoshi, T.; Ando, M. Tetrahedron Lett. 2001, 42, 1543−1546.
(b) Crimmins, M. T.; DeBaillie, A. C. Org. Lett. 2003, 5, 3009−3011.
(18) (+)-Pinnatifidenyne: Kim, H.; Choi, W. J.; Jung, J.; Kim, S.;
Kim, D. J. Am. Chem. Soc. 2003, 125, 10238−10240.
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(25) (a) Fukuzawa, A.; Aye, M.; Nakamura, M.; Tamura, M.; Murai,
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(26) Snyder has recently reported syntheses of halogenated 8- and 9-
membered medium-ring ethers resembling those of the Laurencia
acetogenins by a bromonium-induced ring expansion process involving
intramolecular capture of a bromonium ion with the oxygen of a
tetrahydrofuran and/or tetrahydropyran: Snyder, S. A.; Treitler, D. S.;
Brucks, A. P.; Sattler, W. J. Am. Chem. Soc. 2011, 133, 15898−15901.
(27) For the original report of an intramolecular bromonium ion
assisted epoxide ring-opening reaction using molecular bromine where
necessarily present bromide anion functions as the external
nucleophile on the resulting oxonium ion, see: (a) Davies, S. G.;
Polywka, M. E. C.; Thomas, S. E. Tetrahedron Lett. 1985, 26, 1461−
1464. (b) Davies, S. G.; Polywka, M. E. C.; Thomas, S. E. J. Chem. Soc.,
Perkin Trans. 1 1986, 1277−1282. For processes terminated by an
intramolecularly positioned nucleophile, see: (c) Bravo, F.; McDonald,
F. E.; Neiwert, W. A.; Hardcastle, K. I. Org. Lett. 2004, 6, 4487−4489.
(d) Tanwidjaja, J.; Ng, S.; Jamison, T. F. J. Am. Chem. Soc. 2009, 131,
(9) (+)-Prelaureatin: (a) Crimmins, M. T.; Tabet, E. A. J. Am. Chem.
Soc. 2000, 122, 5473−5476. (b) Fujiwara, K.; Souma, S.-I.; Mishima,
H.; Murai, A. Synlett 2002, 1493−1495. (c) Sasaki, M.; Oyamada, K.;
Takeda, K. J. Org. Chem. 2010, 75, 3941−3943.
J
dx.doi.org/10.1021/jo301580c | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
12084−12085. For the intermolecular capture of a bromonium ion by
an epoxide, see: (e) Zhou, L.; Tan, C. K.; Zhou, J.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2010, 132, 10245−10247. For the intramolecular capture
of a bromonium ion by the oxygen of a tetrahydrofuran, see:
(f) Braddock, D. C.; Millan, D. S.; Perez-Fuertes, Y.; Pouwer, R.;
Sheppard, R. N.; Solanki, S.; White, A. J. P. J. Org. Chem. 2009, 74,
1835−1841. (g) See also ref 26. (h) For the intramolecular capture of
a bromonium ion by the oxygen of an oxetane, see: Keshipeddy, S.;
Martínez, I.; Castillo, B. F., II; Morton, M. D.; Howell, A. R. J. Org.
Chem. 2012, 77, 7883−7890.
(28) For an intramolecular bromonium ion assisted epoxide ring-
opening reaction with capture of the oxonium ion with an added
external nucleophile, see: Bonney, K. J.; Braddock, D. C.; White, A. J.
P.; Yaqoob, M. J. Org. Chem. 2011, 76, 97−104.
(29) Laurediols R,R-18 and S,S-18 could both arise from stereo-
specific ring-opening of the 6S,7R-epoxide 19 with water at the C-6
and C-7 positions, respectively. Murai proposed an epoxide to be a
plausible precursor of the laurediols; see ref 22.
(30) The natural products neoisoprelaurefucin (7-membered ring,
see refs 3d and 7) and neolaurallene (9-membered ring, see refs 5c and
15) would arise from a (6R,7S)-configured epoxide instead of the
(6S,7R)-epoxide of 19 by this analysis. The former epoxide has been
invoked in the proposed biogenesis of the obtusallene family of natural
products from Laurencia species: Braddock, D. C. Org. Lett. 2006, 8,
6055−6058.
studies (ref 28), but complicated mixtures of inseparable bromoace-
tates were obtained when they were applied to substrate 30.
(40) (a) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009, 48,
7899−7903. (b) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am.
Chem. Soc. 2010, 132, 14303−14314. (c) Snyder, S. A.; Treitler, D. S.
Org. Synth. 2011, 88, 54−69.
(41) The separation of these constitutional and diastereomeric
medium-ring ethers with the same molecular formulas was challenging,
and perfect separation was not obtained; the yields reported in Scheme
6 are based on a 1H NMR analysis before separation (see the
Supporting Information).
(42) A medium-ring ether with the prelaureatin (3) motif could not
be detected.
(43) For a note on numbering in these systems, see the Supporting
Information.
(44) The IR stretching frequency of the carbonate CO was also
found to be diagnostic for the size of the cyclic carbonate. Compounds
with a 6-membered carbonate were found to have an IR absorption at
1748 cm−1, whereas for a 7-membered carbonate the absorption due
to CO was at 1793 cm−1.
(45) For example, 7-membered medium-ring cis-α,α′ ether
1
isolaurepinnacin (15) (ref 3b) has H NMR (CDCl3) resonances at
3.52 and 3.59 ppm for its H-7 and H-12 protons respectively. Epimeric
trans-α,α′ ether rogioloxepane A (13) (ref 3c) has its resonances
(CDCl3) at 4.32 and 4.24 ppm, respectively.
(46) 13C NMR data for deacetyllaurencin (1b) has not been reported
in the literature.
(31) The (12Z)-geometrical laurediol isomer has been isolated from
Laurencia species: Fukuzawa, A.; Honma, T.; Takasugi, Y.; Murai, A.
Phytochemistry 1993, 32, 1435−1438.
(47) As shown in Figure 1, all the other naturally occurring medium-
ring ethers, apart from prelaureatin (3) (see also ref 42), that are
oxygenated at C-6 and C-7 are bicyclic, and so a meaningful
comparison of their shifts with those of monocyclic ethers 39−44 is
not feasible. A meaningful comparison with the monocyclic ethers 12−
17 is also not feasible since they are necessarily epimeric at C-12 or C-
13.
(48) For cyclopropane formation by attack of a bromonium ion by an
alkene, see: (a) Simsek, N.; Arici, C.; McKee, M. L.; Ulku, D.; Balci, M.
Struct. Chem. 2001, 12, 305−311. (b) Katsushima, T.; Maki, K.;
Yamaguchi, R.; Kawanisi, M. Bull. Chem. Soc. Jpn. 1980, 53, 2031−
2035.
(49) The interconversion between cyclopropylalkyl, cyclobutyl and
allylic carbocations has been well documented, especially for the
C4H7+ system: (a) Staral, J. S.; Yavari, I.; Roberts, J. D.; Prakash, G. K.
S.; Donovan, D. J.; Olah, G. A. J. Am. Chem. Soc. 1978, 100, 8016−
8018. (b) Staral, J. S.; Roberts, J. D. J. Am. Chem. Soc. 1978, 100,
8018−8020. (c) Brittain, W. J.; Squillacote, M. E.; Roberts, J. D. J. Am.
Chem. Soc. 1984, 106, 7280−7282.
(50) For a review on halogenating enzymes, see: Vaillancourt, F. H.;
Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.; Walsh, C. T. Chem.
Rev. 2006, 106, 3364−3378.
(32) (a) Loreau, O.; Maret, A.; Poullain, D.; Chardigny, J. M.;
́ ́ ̀
Sebedio, J. L.; Beaufrere, B.; Noel, J. P. Chem. Phys. Lipids 2000, 106,
̈
65−78. See also: (b) Young, W. G.; Richards, L.; Azorlosa, J. J. Am.
Chem. Soc. 1939, 61, 3070−3074. (c) Cossío, F. P.; Ganboa, I.;
Palomo, C. Tetrahedron Lett. 1985, 26, 3041−3044. (d) Smith, L. M.;
Smith, R. G.; Loehr, T. M.; Daves, G. D., Jr.; Daterman, G. E.; Wohleb,
R. H. J. Org. Chem. 1978, 43, 2361−2366. (e) Anorbe, B.; Martin, V.
̃
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4994.
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(33) Villalva-Servin, N. P.; Laurent, A.; Fallis, A. G. Can. J. Chem.
2004, 82, 227−239.
(34) The moderate yield for this two-step process is a reflection of
the chromatographic purification of the desired linear product away
from branched isomers. The branched isomers originate from
competing SN2′ processes/isomerization pathways in steps a and b
of Scheme 4.
(35) For a representative example see: Miyaoka, H.; Tamura, M.;
Yamada, Y. Tetrahedron 2000, 56, 8083−8094.
(36) Okachi, T.; Murai, N.; Onaka, M. Org. Lett. 2003, 5, 85−87.
(37) The e.r. of 30 was determined by chiral HPLC methods to be
78:22 (see the Supporting Information). This was achieved by
tritylation of the primary alcohol and comparison with a racemic
sample obtained by epoxidation of triene 29 (followed by tritylation)
using 5 mol% vanadyl acetylacetonate and stoichiometric TBHP
according to the method of Mihelich: Mihelich, E. D.; Daniels, K.;
Eickhoff, D. J. J. Am. Chem. Soc. 1981, 103, 7690−7692. The absolute
configuration of 30 was assigned by reference to Onaka’s work (ref 36)
using cis-hexen-3-ol and the published conditions (0.20 equiv of
Zr(OtBu)4, 0.22 equiv of (+)-DBTA, PhCl, 4 Å MS, −40 °C, 40 h)
which in our hands gave the (3S,4R)-epoxide in 47% ee (100%
conversion). Our modified conditions (0.40 equiv of Zr(OtBu)4, 0.60
equiv of (+)-DBTA, CH2Cl2, 4 Å MS, −40 °C, 18 h) gave the same
(3S,4R)-epoxide in 71% ee (100% conversion) with the same sense of
asymmetric induction.
(51) Studies on bromonium ion induced transannular oxonium ion
formation-fragmentation in model obtusallene systems (ref 27f),
resulted in the formation of a [5.5.1]bicyclotridecane, and we
speculated that it may represent the core of an undiscovered natural
product from Laurencia species. New natural products with exactly this
core have since been reported: Gutierrez-Cepeda, A.; Fernandez, J. J.;
Norte, M.; Souto, M. L. Org. Lett. 2011, 13, 2690−2693.
(38) Evidently, Boc-protected alcohol 31 is more reactive to a second
nucleophilic attack by 30 than Boc2O itself. Experiments using large
excesses of Boc2O increased the ratio of desired product 31 relative to
31a, but removal of excess Boc2O was problematic.
(39) The combination of NBS, a carboxylic acid and catalytic TMG
in dichloromethane solution had also proven effective in our previous
K
dx.doi.org/10.1021/jo301580c | J. Org. Chem. XXXX, XXX, XXX−XXX