Synthesis of (+)-luzofuran and (-)-ancistrofuran

Article abstract of DOI:10.1021/jo402790x

The first synthesis of the furan-containing snyderane, (+)-luzofuran, is reported. The key step in this approach was an electrophilic brominative cyclization, which was accomplished using a nucleophilic N-heterocycle-flanked phosphoramidite catalyst in combination with the common laboratory reagent N-bromosuccinimide.

Full text of DOI:10.1021/jo402790x

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pubs.acs.org/joc
Synthesis of (+)-Luzofuran and (−)-Ancistrofuran
Carl Recsei, Bun Chan,*,† and Christopher S. P. McErlean*
School of Chemistry, University of Sydney, Sydney 2006, Australia
†ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, University of Melbourne, Victoria 3010, Australia
S
* Supporting Information
ABSTRACT: The first synthesis of the furan-containing snyderane,
(+)-luzofuran, is reported. The key step in this approach was an
electrophilic brominative cyclization, which was accomplished using a
nucleophilic N-heterocycle-flanked phosphoramidite catalyst in combi-
nation with the common laboratory reagent N-bromosuccinimide.
fused snyderanes by electrophilic bromination or any other
means. This paper details our first foray into the chemistry of
snyderane natural products, the total synthesis of the 6,5-fused
snyderane luzofuran (3).
INTRODUCTION
■
More than 750 bromine-containing compounds have been
isolated from Laurencia species of marine algae, making them
the single largest source of brominated natural products yet
known.1 While there have been a vast number of innovative
approaches to access the most abundant halogenated natural
products, the C15-acetogenins, other classes have served less
often as synthetic targets. Take, for instance, the second largest
family of halogenated sesquiterpenes isolated from Laurencia,1
the snyderanes (Figure 1). Characterized by a bromocyclohex-
ane ring with halogen incorporation at C10, this family of
compounds includes members with acyclic side chains (1 and
2) as well as a variety of ring fusions, including 6,5-, 6,6- and
6,7-fused compounds (3−6). Their biogenesis likely involves
an asymmetric brominative cyclization of nerolidol (7)
followed by postcyclization modifications.2
Despite the synthetic attractiveness of such a simple
approach, the enantioselective electrophilic bromination of
unactivated alkenes remains a major challenge in organic
chemistry.3−10 For instance, no catalytic methods exist for the
enantioselective electrophilic brominative cyclization of poly-
enes.11−13 Several strategies have been employed to circumvent
this limitation,14−18 and there is one report of a stoichiometric
brominating reagent capable of delivering moderate levels of
enantioselectivity.19 It is therefore unsurprising that only a
handful of reports utilizing electrophilic brominative ap-
proaches to the snyderanes have been disclosed.
Luzofuran (3) was isolated from an Okinawan collection of
the red alga Laurencia luzonensis by Kuniyoshi and co-workers
in 2005.26 With only 3.8 mg being isolated from 1.1 kg of the
predried alga, it is unsurprising that there are as yet no literature
reports regarding any biological activities of the compound.
We elected to employ a biomimetically inspired brominative
cyclization to access the 6,5-fused ring system. We anticipated
that the electrophilic brominating reagent could be generated in
situ from an unreactive but economical bromonium source and
engage in a diastereoselective cyclization. Our approach was
inspired by two considerations: (1) the seminal work of
Ishihara and co-workers who developed a stoichiometric
brominating reagent19 and (2) the highly conserved histidine
and arginine-rich active site of the vanadium haloperoxidase
class of enzymes that are responsible for in vivo brominative
cyclizations.2,27−29 We sought to combine the attributes from
both systems to give a catalytically active molecule that could
function as a bromonium shuttle in the manner depicted in
Figure 2.
Phosphoramidites chelate to metal centers exclusively via the
tetrahedral phosphorus atom,30 and they likewise protonate on
phosphorus,31 so a BINOL-based phosphoramidite seemed the
most appropriate molecule to function as a bromonium shuttle.
The use of phosphorus(III) in this catalytic role has precedent
in iodolactonizations.32 To this end, we recently reported the
development of a library of N-heterocycle-substituted phos-
phoramidites.33,34 The required balance between oxidative
stability versus catalytic activity led us to settle upon the 2,4,5-
trichlorophenyltriazole (TCPT)-flanked catalyst 8 for this work
(Figure 3).
The parent α- and β-snyderols (1 and 2) have been
synthesized in ca. 2% yield by an electrophilic bromination of
nerolidol (7).20,21 A similar strategy was used to synthesize the
6,6-fused 8-bromo-epi-capirrappi oxide (4) in a more palatable
30% yield.21 An electrophilic brominative strategy to the 6,7-
fused compound aplysistatin (5)22 gave the desired compound
in ca. 2% yield. Consequently, total syntheses of aplysistatin
(5)23,24 and palisadin (6)25 using tin- and mercury-based
methods, respectively, have been reported. To the best of our
knowledge, there are no reports detailing the synthesis of 6,5-
Received: December 17, 2013
© XXXX American Chemical Society
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Figure 1. Examples of snyderane natural products.
Figure 2. Proposed in situ activation of a bromonium source with a phosphoramidite.
Scheme 1. Synthesis of ( )-Luzofuran (3)
Figure 3. 2,4,5-Trichlorophenyltriazole-flanked catalyst 8 (TCPT).
RESULTS AND DISCUSSION
■
As shown in Scheme 1, our synthesis began with the
organometallic union of the geranyl fragment 9 and the furan
fragment 10. Organobarium reagents are well-known to give
extremely high levels of α-selectivity in reaction with
aldehydes,35−37 and polyene-containing organobarium reagents
can be made with complete retention of alkene geometry.38 As
such, reaction of geranyl chloride 9 with activated barium gave
an organobarium reagent, which reacted with 3-furancarbox-
aldehyde 10 to give alcohol 11. Treatment of 11 with 1 equiv of
the cheap and readily available N-bromosuccinimide (NBS)
and a catalytic amount of TCPT 8 furnished ( )-luzofuran (3)
in 17% yield and ( )-4-epi-luzofuran (epi-3) in 4% yield.39
The relative stereochemistry of synthetic ( )-luzofuran (3)
was assigned on the basis of the NOE enhancements between
the hydrogens shown in Scheme 1 (see the Supporting
Information), which necessitates the relative configuration
depicted. This is in excellent agreement with Kuniyoshi’s
assignment of the natural product stereochemistry.26 However,
1
a comparison of the H and 13C NMR shifts for naturally
occurring luzofuran and our synthetic ( )-luzofuran revealed
an anomaly (Table 1).
As depicted graphically in Figure 4, the 1H NMR shifts were
in almost perfect agreement, differing by no more than 0.08
ppm. Similarly, the 13C NMR shifts differed by no more than
0.08 ppm with the exception of C7. At that center there was a
marked difference between our observed chemical shift (80.15
ppm) and the reported value (78.1 ppm). We could not easily
reconcile this unexpected outcome with the NOE data shown
in Scheme 1.
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C7 would affect the ring conformation such that the coupling
constants around the bicyclic structure would be perturbed.
The diagnostic signal for the hydrogen appended to C4 was
most useful for monitoring this process. Of the available
possibilities (see the Supporting Information), the only
diastereomer that had matching (predicted) coupling constants
and that could possess the observed NOE interactions was the
(4S*,6S*,7S*,10S*) isomer. This supported our assignment of
the relative stereochemistry of ( )-luzofuran 3.41 Unambiguous
confirmation of the relative stereochemistry was secured by
conversion of 3 (and epi-3) into known compounds (vide
infra).
The structure of the minor product, ( )-epi-luzofuran (epi-
3) differs from the natural product at C4 only (Scheme 2). The
4:1 diastereomeric ratio of the products may reflect a Stork−
Eschenmoser scenario in which cyclization occurs more readily
when the acyclic precursor is in the appropriate conforma-
tion.42,43 Concerted cyclizations of this fashion have been
proposed for other snyderanes.44,45 Although a single
enantiomer of TCPT 8 was employed in the cyclization, the
production of a racemate convinced us that the level of
diastereoselection was substrate rather than catalyst-controlled,
and that the ratio of products reflected the thermodynamic
preference for the furyl unit to be pseudoaxial, as in 12, rather
than pseudoequatorial as in 13. The most direct way to probe
this hypothesis was to generate the cyclization precursor as a
single enantiomer and measure the diastereomeric ratio of the
ensuing product mixture.
Table 1. . NMR Comparison of Synthetic and Isolated
( )-Luzofuran
reported26
synthetic
differences
carbon no.
δH
δC
δH
δC
ΔH
ΔC
1
7.39
6.32
143.5
108.4
128.7
70.4
7.38
6.32
143.47
108.47
128.76
70.47
0.01
0.00
0.03
−0.07
−0.06
−0.07
−0.07
0.00
2
3
4
5.10
1.80
2.30
1.70
5.08
1.81
2.27
1.70
0.02
−0.01
0.03
5
32.7
32.77
5
6
55.1
78.1
39.5
55.12
80.15
39.58
0.00
−0.02
−2.05
−0.08
0.00
7
8
1.60
1.90
2.10
2.35
3.95
1.59
1.91
2.08
2.27
3.95
0.01
−0.01
0.02
8
9
32.6
32.66
−0.06
0.00
9
0.08
10
11
12
13
14
15
65.5
38.7
30.3
17.0
20.3
138.9
65.55
38.71
30.32
17.01
20.37
138.90
0.00
−0.05
−0.01
−0.02
−0.01
−0.07
0.00
1.01
0.99
1.21
7.36
1.05
0.98
1.25
7.35
−0.04
0.01
−0.04
0.01
The enantioselective synthesis of (+)-luzofuran (+)-3
required the corresponding (S)-configured alcohol (+)-11.
We anticipated that this could be generated by an
enantioselective reduction of the corresponding ketone 14
(Scheme 3). As such, the racemic alcohol 11 was oxidized with
the Dess−Martin periodinane to give 14.46,47 Enantioselective
transfer hydrogenation with Noyori’s (S,S)-RuTsDPEN catalyst
proceeded in excellent yield.48 The enantiomeric ratio was
1
determined by H NMR analysis of the corresponding O-
methyl mandalate 15 to be 95:5.
Figure 4. Chemical shift comparison between natural and synthetic
( )-luzofuran (3). δH or δC = [reported shift]−[observed shift]
(ppm).
Compound (+)-11 was treated with 1 equiv of NBS and a
catalytic amount of TCPT 8 to furnish (+)-luzofuran (+)-(3) in
29% yield and (4S,6R,7R,10R)-epi-luzofuran (+)-(epi-3) in 7%
yield. Comparison of product ratio of luzofuran and 4-epi-
luzofuran revealed that the cyclization was indeed immune to
the absolute stereochemistry of the C4 center, ruling out a
matched, mis-matched catalyst−substrate explanation for the
observed 4:1 product ratio. Rather, that unaltered product ratio
We therefore performed a J-value comparison using the
reported data,26 our observed values, and those predicted for
the low energy conformations of all diastereomers about the
luzofuran core (see the Supporting Information).40 We
anticpated that any alteration in the chemical environment of
Scheme 2. Stork−Eschenmoser-Type Cyclization
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Scheme 3. Synthesis of (+)-Luzofuran (+)-3.
lends weight to the hypothesized Stork−Eschenmoser cycliza-
tion depicted in Scheme 2.
trofuran (17) in good yield.49,50 As shown in Table 2 and Table
3, comparison of the NMR chemical shifts of 16 and 17 with
The value of optical rotation for this synthetic sample of
luzofuran was identical in both magnitude and direction to that
reported for the natural product. This necessitates the absolute
stereochemistry of naturally occurring luzofuran to be
(4S,6S,7S,10S). Final confirmation of the relative and absolute
stereochemistry of the products was attained by conversion into
the known compounds ( )-epi-ancistrofuran 16 and (−)-an-
cistrofuran 17.
Ancistrofuran was isolated from the defensive secretions of
the West African termite Ancistrotermes cavithorax by Baker,
Evans and co-workers.49 A combination of spectroscopic
techniques and chemical derivatization was employed to
elucidate the gross structure of ancistrofuran. Several total
syntheses have subsequently confirmed the relative stereo-
chemistry of the natural product, and although the absolute
stereochemistry remains undetermined both enantiomers of
ancistrofuran have been synthesized.50−53
As depicted in Scheme 4, radical-mediated debromination of
( )-luzofuran ( )-(3) gave ( )-epi-ancistrofuran ( )-16.
Employing the same protocol on (4S,6R,7R,10R)-epi-luzofuran
(epi-3) gave (−)-ancistrofuran, but the sample was contami-
nated with traces of an inseparable byproduct. We were pleased
to find that debromination of (4S,6R,7R,10R)-epi-luzofuran
(epi-3) with activated magnesium smoothly gave (−)-ancis-
Table 2. NMR Comparison of (−)-Ancistrofuran
reported54
synthetic
differences
carbon
no.
δH
7.36
δC
δH
7.37
δC
ΔH
ΔC
1
143.1
109.1
129.3
71.6
32.9
32.9
57.4
81.0
40.8
40.8
33.2
33.2
39.1
39.1
31.4
23.4
21.3
20.4
138.8
143.1
109.1
129.3
71.6
32.9
32.9
57.4
81.0
40.9
40.9
33.2
33.2
39.2
39.2
31.5
23.4
21.4
20.5
138.8
−0.01
−0.01
0.0
0.0
2
6.37
6.38
3
0.0
4
4.91
4.91
2.20
1.80
1.63
0.00
0.0
5
2.19
−0.01
0.0
5
1.97−1.32
1.97−1.32
0.0
6
0.0
7
0.0
8
1.24−1.16
1.97−1.32
1.97−1.32
1.97−1.32
1.97−1.32
1.97−1.32
1.26−1.94
1.26−1.94
1.26−1.94
1.26−1.94
1.26−1.94
1.26−1.94
−0.1
−0.1
0.0
8
9
9
0.0
10
10
11
12
13
14
15
−0.1
−0.1
−0.1
0.0
0.98
0.86
1.13
7.36
0.99
0.87
1.14
7.37
−0.01
−0.01
−0.01
−0.01
−0.1
−0.1
0.0
Scheme 4. Synthesis of ( )-epi-Ancistrofuran (16) and
(−)-Ancistrofuran (17)
the literaure values showed excellent agreement. The successful
synthesis of ( )-epi-ancistrofuran ( )-16 and (−)-ancistrofur-
an (17) confirms the relative stereochemistry of epi-luzofuran
(epi-3) and luzofuran (3).
Our attention then turned to gaining a mechanistic
understanding of how the TCPT catalyst (8) affects the
brominative cyclization. The importance of the catalyst
structure was illustrated by the observations that are
summarized in Scheme 5. First, the cyclization of substrate
11 did not proceed in the absence of TCPT (8). Second,
attempted cyclization using a phosphine catalyst was
unsuccessful. Third, cyclization with a catalytic loading of a
BINOL−phosphoramidite lacking only the pendant N-hetero-
cycles (MorfPhos) was completely ineffective. Even when a
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N-heterocycle-flanked phosphoramidite 8 enabled us to
perform a diastereoselective brominative cyclization using the
common laboratory reagent NBS. We anticipate that this
strategy will provide general access to the snyderane class of
natural products.
Table 3. NMR Comparison of ( )-epi-Ancistrofuran
reported51
synthetic
differences
ΔH
carbon no.
δH
δH
1
7.38
7.35−7.37
6.34
−0.02
−0.02
−0.03
2
6.36
EXPERIMENTAL SECTION
4
5.06
5.03
■
( )-9-Hydroxydendrolasin (11).55 To a suspension of anhy-
drous barium iodide (3.12 g, 7.97 mmol, 4.5 equiv) in THF (30 mL)
was added a solution of lithium biphenylide, prepared by stirring (2 h)
freshly cut lithium pieces (110 mg, 15.9 mmol, 9.0 equiv) and biphenyl
(2.44 g, 15.8 mmol, 9.0 equiv) in THF (30 mL). This mixture was
stirred (1 h) and then cooled to −78 °C, and a solution of (E)-geranyl
chloride (9) (620 mg, 3.59 mmol, 1.0 equiv) in THF (20 mL) was
added over 1.5 h. The resulting mixture was stirred (1 h) at −78 °C,
and then a solution of 3-furancarboxaldehyde (310 μL, 3.58 mmol, 1.0
equiv) in THF (10 mL) added over 10 min. The mixture was stirred
(0.5 h) at −78 °C and then quenched via the addition of hydrochloric
acid (0.2 M, 100 mL). The aqueous phase was extracted with Et2O (2
× 50 mL), and the organic extracts were combined with the organic
partition of the reaction mixture, washed with water (2 × 200 mL) and
brine (100 mL), dried over sodium sulfate, and concentrated. Column
chromatography (ethyl acetate/light petroleum 5/95) gave 11 (494
mg, 2.11 mmol, 58%) as a colorless oil: Rf 0.50 (ethyl acetate/hexanes
5
1.4−2.3
1.4−2.3
1.4−2.3
1.4−2.3
1.4−2.3
1.4−2.3
1.4−2.3
1.4−2.3
1.4−2.3
0.94
2.16
5
1.3−1.95
1.3−1.95
1.3−1.95
1.3−1.95
1.3−1.95
1.3−1.95
1.3−1.95
1.3−1.95
0.93
6
8−10
8−10
8−10
8−10
8−10
8−10
12
−0.01
0.01
13−14
13−14
15
0.88
0.89
1.20
1.16
−0.04
−0.02
7.38
7.35−7.37
stoichiometric quantity of MorfPhos was employed for
extended reaction times (3 h), the reaction was extremely
low yielding (<5%). And finally, in line with Snyder’s
observations, the unprotected alcohol of compound 11
rendered it incompatible with the potently electrophilic reagent
BDSB.11,12
Quantum mechanical calculations at the M06-2X/6-311+G-
(3df,2p)//M05-2X/6-31G(d) level of theory with the inclusion
of solvation effects using the SMD continuum model (see the
Supporting Information) show that the bromine atom is indeed
transferred from NBS onto the phosphorus atom of the TCPT
catalyst (Figure 5). Subsequent transfer of the catalyst-bound
bromine onto the alkene is acompanied by succinimide
deprotonation of the alcohol which assists cyclization. The
involvement of the bromonium shuttle in the delivery of the
bromine atom to the alkene renders the process substantially
more energetically favorable than the uncatalyzed process.
Instructively, no carbocation intermediates were detected
during these computational studies.
1/9); IR (cm−1) 3383, 2917, 1108, 1024, 787; H NMR (300 MHz;
1
CDCl3) 7.39 (2 H, m), 6.41 (1 H, m), 5.16 (1 H, ddd, J 7.9, 6.8, 0.9),
5.06 (1 H, m), 4.66 (1 H, ddd, J 7.2, 5.8, 3.9), 2.45−2.49 (2 H, m),
2.03−2.10 (4 H, m), 1.91 (1 H, d, J 4.0), 1.68 (3 H, s), 1.64 (3 H, s),
1.60 (3 H, s); 13C NMR (75 MHz; CDCl3) 143.3 (CH), 139.7 (CH),
139.2 (C), 131.9 (C), 128.8 (C), 124.2 (CH), 119.5 (CH), 108.8
(CH), 68.9 (CH), 40.0 (CH2), 36.9 (CH2), 26.6 (CH2), 25.8 (CH3),
17.8 (CH3), 16.5 (CH3); MS (EI) m/e (relative intensity) 216 (25),
201 (16), 147 (100), 129 (70), 95 (81), 91 (64); HRMS (ESI) m/e
[M + Na] calcd for C15H22O2Na 257.15120, obsd 257.15130.
(E)-9-Oxodendrolasin (14).56 Sodium hydrogen carbonate (200
mg, 2.38 mmol, 3.46 equiv) was added to a solution of the Dess−
Martin periodinane (335 mg, 789 μmol, 1.15 equiv) in CH2Cl2 (5 mL)
and the mixture stirred (5 min) with cooling to 0 °C. A solution of 11
(150 mg, 687 μmol, 1.00 equiv) in CH2Cl2 (5 mL) was added slowly,
and the mixture was stirred and allowed to warm to 15 °C. Stirring was
continued (1 h), a solution of sodium sulfite (5% in water, 20 mL) was
added, the aqueous phase was extracted with CH2Cl2 (2 × 5 mL), and
the organic extracts combined with the organic partition of the
reaction mixture and washed with water (2 × 50 mL), brine (50 mL),
dried over sodium sulfate, and concentrated. Column chromatography
(ether/light petroleum 5/95) gave 14 (137 mg, 92%) as a slightly
yellow oil: Rf 0.48 (ether/hexanes 1/9); IR (cm−1) 2947, 1678, 1154,
873, 743; 1H NMR (300 MHz; CDCl3) 8.02 (1 H, m), 7.41 (1 H, m),
6.75 (1 H, m), 5.40 (1 H, app t J 7.0), 5.04 (1 H, m), 3.44 (2 H, d J
7.0), 1.96−2.11 (4 H, m), 1.67 (3 H, s), 1.64 (3 H, s), 1.57 (3 H, s);
13C NMR (75 MHz; CDCl3) 193.4 (C), 147.3 (CH), 144.1 (CH),
139.2 (C), 131.7 (C), 127.5 (C), 124.0 (CH), 116.2 (CH), 108.9
(CH), 40.5 (CH2), 39.7 (CH2), 26.5 (CH2), 25.7 (CH3), 17.7 (CH3),
CONCLUSION
■
We report the first synthesis of the 6,5-fused snyderane,
luzofuran (3), in both racemic and enantioenriched form.
Excision of the halogen from epi-3 gave the insect-derived
natural product (−)-ancistrofuran (17), while debromination of
( )-luzofuran (3) gave the known compound ( )-epi-
ancistrofuran ( )-16. The heightened nucleophilicity of the
Scheme 5. Attempted Catalyst-Free Cyclizations
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Figure 5. Calculated schematic energy profiles for the catalyzed brominative cyclization of (+)-11.
16.6 (CH3); MS (ESI) m/e (relative intensity) 271 (100, MK+);
HRMS (ESI) m/e [M + Na] calcd for C15H20O2Na 255.13555, obsd
255.13551.
J 7.66), 1.67 (3 H, s), 1.57 (3 H, s), 1.46 (3 H, s); 13C NMR (75 MHz;
CDCl3) 170.3 (C), 143.2 (CH), 140.5 (CH), 138.6 (C), 136.5 (C),
131.6 (C), 128.8 (CH), 128.7 (CH), 128.7, (CH), 127.4 (CH), 127.4
(CH), 124.6 (C), 124.2 (CH), 118.3 (CH), 109.2 (CH), 82.8 (CH),
69.6 (CH), 57.5 (CH), 39.7 (CH2), 33.3 (CH2), 26.6 (CH2), 25.8
(CH3), 17.8 (CH3), 16.3 (CH3); MS (ESI) m/e (relative intensity)
787 (100), 405 (MNa+, 30); HRMS (ESI) m/e [M + Na] Calcd for
C24H30O4Na 405.20363, obsd 405.20367. A diasteromeric mixture was
synthesized according to the above procedure, using ( )-11. (S)-
((R,E)-1-(furan-3-yl)-4,8-dimethylnona-3,7-dien-1-yl) 2-methoxy-2-
phenyl acetate (epi-15) showed key signals: IR (cm−1) 2915, 1732,
1197, 1108, 1023, 874, 791, 726; 1H NMR (500 MHz; CDCl3) 7.09 (1
H, m), 6.11 (1 H, m), 5.79 (1 H, app t, J 6.8), 4.76 (1 H, s), 3.40 (3 H,
s); 13C NMR (125 MHz; CDCl3) 170.1 (C), 143.0 (CH), 140.0
(CH), 138.6 (C), 136.3 (C), 131.5 (C), 128.8 (CH), 128.7 (2 C, CH),
127.4 (2 C, CH), 124.5 (C), 124.2 (CH), 118.5 (CH), 108.8 (CH),
82.8 (CH), 69.7 (CH), 57.4 (CH), 39.8 (CH2), 33.7 (CH2), 26.6
(CH2), 25.8 (CH3), 17.8 (CH3), 16.4 (CH3). Integration of the peaks
of the major and minor diastereomers in the 1H NMR spectrum of 15
indicated a 95:5 diasteromeric ratio of esters.
(S)-9-Hydroxydendrolasin ((S)-11). Dichloro(p-cymene)-
ruthenium(II) dimer (36 mg, 59 μmol, 0.051 equiv) and (S,S)-
TsDPEN (51 mg, 0.14 mmol, 0.12 equiv) were heated to reflux (1 h)
in degassed CH2Cl2 (20 mL). The solvent was removed under a
stream of argon, and a solution of sodium formate (800 mg, 11.8
mmol, 10 equiv) in degassed, deionized water (15 mL) and then a
solution of cetyltrimethylammonium bromide (16 mg, 44 μmol, 0.04
equiv) and 14 (250 mg, 1.16 mmol, 1.0 equiv) in degassed ethyl
acetate (8 mL) were added. The mixture was stirred at room
temperature (16 h) and then poured onto water (100 mL), and
saturated aqueous ammonium chloride (100 mL) was added. The
mixture was extracted with ether/hexanes 1/1 (3 × 50 mL), the
combined organic extracts were passed through a plug of Celite,
washing with ether/hexanes:1/1 (100 mL), and the filtrate was
concentrated. Column chromatography (ethyl acetate/light petro-
leum: 5/95) gave (S)-11 (199 mg, 79%) as a colorless oil: [α]2D0−6.2 (c
2.1, THF).
(S)-((S,E)-1-(Furan-3-yl)-4,8-dimethylnona-3,7-dien-1-yl) 2-
methoxy-2-phenyl Acetate (15). To a solution of (S)-11 (20 mg,
85 μmol, 1.0 equiv) in CH2Cl2 (5 mL) were added DCC (18 mg, 87
μmol, 1.0 equiv), then (S)-(+)-α-methoxyphenylacetic acid (14.5 mg,
8.73 μmol, 1.0 equiv), and then 4-dimethylaminopyridine (1.0 mg, 8.2
μmol, 0.10 equiv). The mixture was stirred (8 h) and then filtered,
washing with CH2Cl2 (5 mL), and the filtrate concentrated. Column
chromatography (ether/light petroleum 7/93) gave 15 (30 mg, 92%):
[α]2D0 + 2.2 (c 0.054, CHCl3); Rf 0.35 (ether/hexanes 1/9); IR (cm−1)
( )-Luzofuran (3).26 A solution of ( )-11 (120 mg, 512 μmol,
1.00 equiv) and (S)-TCPT catalyst 8 (90 mg, 0.10 mmol, 0.200 equiv)
in CH2Cl2 (10 mL) was stirred (7 h) over activated 4 Å molecular
sieves (0.5 g). The mixture was cooled to −78 °C, and a solution of N-
bromosuccinimide (92 mg, 517 μmol, 1.01 equiv) in CH2Cl2 (7 mL)
was added over 5 min. The solution was stirred (10 min) at −78 °C
then quenched via the addition of a solution of sodium sulfite (5% in
water, 20 mL) and allowed to warm to room temperature. The
aqueous phase was extracted with CH2Cl2 (2 × 5 mL), and the organic
extracts were combined with the organic partition of the reaction
mixture, washed with water (50 mL) and brine (50 mL), dried over
sodium sulfate, and concentrated. Column chromatography (ether/
light petroleum 7/93) gave ( )-luzofuran (3) as a colorless oil (27
1
2924, 1747, 1171, 1106, 1023, 874; H NMR (500 MHz; CDCl3)
7.42−7.44 (2 H, m), 7.32−7.37 (5 H, m), 6.36 (1 H, m), 5.79 (1 H,
app t J 6.8), 5.00 (1 H, app tt, J 10.4, 1.4), 4.81 (1 H, dddd J 7.2, 7.0,
1.3, 1.2), 4.73 (1 H, s), 3.39 (3 H, s), 2.47 (1 H, ddd, J 14.5, 7.2, 6.8),
2.40 (1 H, ddd, J 14.5, 6.8, 6.4), 1.90−1.96 (2 H, m), 1.82 (2 H, app t,
F
dx.doi.org/10.1021/jo402790x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
1
mg, 17%) and (4S*,6R*,7R*,10R*)-2-(furan-3-yl)-7,11,11-trimethy-
loctahydrobenzofuran (4-epi-3) as a colorless solid (8.0 mg, 4%).
(S)-(+)-Luzofuran (3).26 A solution of (S)-11 (200 mg, 853 μmol,
1.00 equiv) and (S)-TCPT catalyst 8 (161 mg, 183 μmol, 0.200 equiv)
in CH2Cl2 (14 mL) was stirred (7 h) over activated 4 Å molecular
sieves (0.5 g). The mixture was cooled to −78 °C, and a solution of N-
bromosuccinimide (165 mg, 927 μmol, 1.01 equiv) in CH2Cl2 (10
mL) was added over 5 min. The solution was stirred (10 min) at −78
°C, quenched via the addition of a solution of sodium sulfite (5% in
water, 20 mL), and allowed to warm to room temperature. The
aqueous phase was extracted with CH2Cl2 (2 × 5 mL), and the organic
extracts were combined with the organic partition of the reaction
mixture, washed with water (50 mL) and brine (50 mL), dried over
sodium sulfate, and concentrated. Column chromatography (ether/
light petroleum 7/93) gave (+)-luzofuran (3) as a colorless oil (44 mg,
15%): [α]2D0 + 5.1 (c 0.18, CHCl3); Rf 0.53 (ethyl acetate/hexanes 1/
1/19); IR (neat) νmax/cm−1 2931, 1461, 1261, 1158, 1025, 874; H
NMR (300 MHz; CDCl3) 7.35−7.37 (2 H, m), 6.34 (1 H, m), 5.03 (1
H, ddd, J 9.2, 2.5, 0.4), 2.16 (1 H, ddd, J 13.6, 11.6, 9.3) 1.88−1.95 (1
H, m), 1.75 (1 H, dddd, J 11.6, 7.0, 2.7, 0.5), 1.3−1.65 (6 H, m), 1.16
(3 H, d, J 0.6), 0.93 (3 H, s), 0.89 (3 H, s); 13C NMR (75 MHz;
CDCl3) 143.4 (CH), 139.1 (CH), 129.5 (C), 108.8 (CH), 81.4 (C),
69.5 (CH), 55.6 (CH), 41.2 (CH2), 39.0 (CH2), 33.3 (C), 32.9
(CH3), 31.7 (CH2), 21.3 (CH2), 20.5 (CH3), 20.1 (CH3); MS (ESI;
MeOH/LiCl) m/e (relative intensity) 241 (100); HRMS (ESI) m/e
7
[M + Li] calcd for C15H22O2 Li 241.17744, obsd 241.17763, calcd for
7
C30H44O4 Li 475.33942, obsd 475.33942.
(−)-Ancistrofuran ((−)-17).50 Lithium (5.0 mg, 0.72 mmol, 23
equiv), anhydrous magnesium chloride (30 mg, 0.32 mmol, 10 equiv),
and naphthalene (13 mg, 0.10 mmol, 3.3 equiv) were taken up in THF
(1.5 mL) and stirred vigorously (3 h). The resulting black suspension
of active magnesium was cooled to −78 °C, and a solution of (S)-4-
epi-3 (10 mg, 3.1 μmol, 1.0 equiv) in THF (1.0 mL) added over 0.5 h.
The solution was stirred, allowing to warm to −65 °C (16 h). A
solution of tert-butyl alcohol (10% in THF, 3.0 mL) was added slowly
and the solution stirred at −65 °C (0.5 h). Isopropyl alcohol (5 mL)
was added, the reaction partitioned between ether (10 mL) and water
(50 mL), and the aqueous partition extracted with ether (10 mL). The
combined organic extracts were washed with water (3 × 50 mL), dried
over sodium sulfate, and concentrated. Column chromatography
(ether/light petroleum 7/93) gave (S)-(−)-17 (6.4 mg, 86%) as a
colorless oil: Rf 0.35 (ether/hexanes 1/19); [α]2D0 −2.6 (c 0.20,
CHCl3); IR (neat) νmax/cm−1 2865, 1458, 1374, 1259, 1156, 1049,
1
9); IR (neat) νmax/cm−1 2955, 1458, 1157, 1023, 896, 599; H NMR
(500 MHz; CDCl3) 7.38 (1 H, m), 7.35 (1 H, m), 6.32 (1 H, m), 5.08
(1 H, dd J 9.2, 2.4), 3.94, (1 H, dd J 12.5, 4.6), 2.21−2.33 (2 H, m),
2.08 (1 H, dddd J 14.4, 13.6, 12.5, 4.0), 1.91 (1 H, ddd J 12.4, 4.0, 3.1),
1.81 (1 H, ddd J 9.8, 7.0, 2.6), 1.70 (1 H, dd J 13.2, 7.0), 1.60 (1 H,
dddd J 13.5, 12.5, 4.4, 0.9), 1.25 (3 H, d J 0.9), 1.05 (3 H, s), 0.98 (3
H, s); 13C NMR (125 MHz; CDCl3) 143.5 (CH), 138.9 (CH), 128.8
(C), 108.5 (CH), 80.2 (C), 70.5 (CH), 65.6 (CH), 55.1 (CH), 39.6
(CH2), 38.7 (CH2), 32.8 (C), 32.7 (CH2), 30.3 (CH3), 20.4 (CH3),
17.0 (CH3); MS (EI) m/e (relative intensity) 299 (6), 297 (6), 219
(12), 217 (12), 137 (64), 121 (57), 95 (48), 81 (100); HRMS (ESI)
m/e [M + Na] calcd for C15H2179BrO2Na 335.06171, obsd 335.06174,
calcd for C15H2181BrO2Na 337.05967, obsd 337.05968.
1
1024; H NMR (300 MHz; CDCl3) 7.37 (2 H, m), 6.38 (1 H, m),
4.91 (1 H, dd, J 9.1, 6.8), 2.20 (1 H, dddd, J 11.6, 6.4, 4.8, 0.7) 1.87−
1.94 (1 H, m), 1.80 (1 H, ddd, J 13.7, 11.2, 9.1), 1.63 (1 H, dd, J 13.7,
5.2), 1.26−1.74 (6 H, m), 1.14 (3 H, d, J 0.7), 0.99 (3 H, s), 0.87 (3 H,
s); 13C NMR (75 MHz; CDCl3) 143.1 (CH), 138.8 (CH), 129.3 (C),
109.1 (CH), 81.0 (C), 71.6 (CH), 57.4 (CH), 40.9 (CH2), 39.2
(CH2), 33.2 (C), 32.9 (CH3), 31.5 (CH2), 23.4 (CH3), 21.4 (CH2),
20.5 (CH3); MS (ESI; MeOH/LiCl) m/e (relative intensity) 241
(4S,6R,7R,10R)-2-(Furan-3-yl)-7,11,11-trimethyloctahydrobenzofuran
20
(4-epi-3) was also obtained as a colorless solid (11 mg, 4%): Δε
261
−4.38 (THF); mp 40−44 °C; Rf 0.45 (ethyl acetate/hexanes 1/9); IR
(neat) νmax/cm−1 2922, 1488, 1185, 1161, 956, 752, 687; H NMR
1
(300 MHz; CDCl3) 7.36−7.39 (2 H, m), 6.37 (1 H, m), 4.99 (1 H,
ddd, J 9.2, 6.8, 0.95), 3.94 (1 H, dd, J 12.5, 4.8), 2.21−2.32 (2 H, m),
2.07 (1 H, dddd, J 14.3, 13.5, 12.5, 4.1), 1.76 (1 H, dd, J 13.4, 5.2),
1.58 (1 H, dddd J 13.5, 12.5, 4.3, 0.95), 1.20 (3 H, d J 0.95), 1.12 (3 H,
s), 0.98 (3 H, s); 13C NMR (75 MHz; CDCl3) 143.4 (CH), 139.0
(CH), 128.9 (C), 109.0 (CH), 80.1 (C), 72.8 (CH), 65.6 (CH), 57.0
(CH), 40.2 (CH2), 39.0 (C), 33.2 (CH2), 32.7 (CH2), 30.6 (CH3),
23.6 (CH3), 17.7 (CH3); MS (EI) m/e (relative intensity) 299 (32),
297 (29), 219 (16), 217 (16), 137 (62), 121 (74), 95 (53), 81 (100);
MS (ESI; MeOH/LiCl) m/e (relative intensity) 241 (100), 257 (48),
319 (20), 321 (21); HRMS (ESI) m/e [M + Li] calcd for
C15H2179BrO27Li 319.08795, obsd 319.08811, calcd for
7
(100); HRMS (ESI) m/e [M + Li] Calcd for C15H22O2 Li 241.17744,
obsd 241.17764, calcd for C30H44O4 Li 475.33942, obsd 475.33948.
7
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra, coupling constant analysis, and
computational details. This material is available free of charge
via the Internet at http://pubs.acs.org.
7
C15H2181BrO2 Li 321.08590, obsd 321.08603. Elution with ethyl
AUTHOR INFORMATION
Corresponding Authors
*E-mail: bun.chan@sydney.edu.au.
*E-mail: christopher.mcerlean@sydney.edu.au.
■
acetate allowed recovery of the catalyst as the phosphoramidate (160
mg, 98% recovery). When the catalyst/substrate system is prepared by
addition of a solution of the (S)-TCPT catalyst 8 in CH2Cl2 (2 mL) to
a solution of the substrate in nitroethane (20 mL), followed by drying
over activated 4 Å molecular sieves and proceeding as above the
reaction gives luzofuran (3) (84 mg, 29%) and 4-epi-3 (21 mg, 7%)
with recovery of the unreacted substrate (65 mg, 33%).
Notes
The authors declare no competing financial interest.
epi-Ancistrofuran (( )-16).57 To a solution of ( )-3 (7.0 mg, 22
μmol, 1.0 equiv) in fluorobenzene (1 mL) was added tributyltin
hydride (13 μL, 48 μmol, 2.1 equiv) and the mixture heated to 50 °C.
A solution of VA-044 (7.1 mg, 22 μmol, 1.0 equiv) in methanol (1
mL) was added over 10 h. After the solution was stirred at 50 °C (6 h)
TLC analysis showed incomplete conversion. Tributyltin hydride (5.0
μL, 19 μmol, 2 equiv) and VA-044 (2.0 mg, 6.2 μmol, 0.28 equiv) in
methanol (0.5 mL) were added, and stirring was continued at 50 °C (8
h). The solution was cooled to room temperature and partitioned
between ether (10 mL) and a solution of potassium fluoride (5% in
water, 10 mL), and then the aqueous partition was extracted with ether
(10 mL). The combined organic extracts were washed with water (50
mL), a solution of potassium fluoride (5% in water, 10 mL), and a
saturated solution of ammonium chloride (10 mL), dried over sodium
sulfate, and concentrated. Column chromatography with 10%
potassium carbonate on silica (ethyl acetate/light petroleum 1/19)
gave ( )-16 (4.1 mg, 84%) as a colorless oil: Rf 0.25 (ether/hexanes
ACKNOWLEDGMENTS
■
C.R. acknowledges receipt of a University of Sydney
Postgraduate Award. B.C. acknowledges grants of computer
time from the NCI National Facility and Intersect Australia,
Ltd.
REFERENCES
■
(1) Wang, B.-G.; Gloer, J. B.; Ji, N.-Y.; Zhao, J.-C. Chem. Rev. 2013,
113, 3632.
(2) Carter-Franklin, J. N.; Butler, A. J. Am. Chem. Soc. 2004, 126,
15060.
(3) Murai, K.; Fujioka, H. Heterocycles 2013, 87, 763.
(4) Tan, C. K.; Yeung, Y. Y. Chem. Commun. 2013, 49, 7985.
(5) Castellanos, A.; Fletcher, S. P. Chem.Eur. J. 2011, 17, 5766.
(6) Chen, G. F.; Ma, S. M. Angew. Chem., Int. Ed. Engl. 2010, 49,
8306.
G
dx.doi.org/10.1021/jo402790x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(7) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int.
Ed. Engl. 2012, 51, 10938.
(8) Hennecke, U. Chem.Asian J. 2012, 7, 456.
(9) Tan, C. K.; Zhou, L.; Yeung, Y. Y. Synlett 2011, 1335.
(10) Mendoza, A.; Fananas, F. J.; Rodriguez, F. Curr. Org. Synth.
2013, 10, 384.
(44) Kuniyoshi, M.; Marma, M. S.; Higa, T.; Bernardinelli, G.;
Jefford, C. W. Chem. Commun. 2000, 1155.
(45) Kuniyoshi, M.; Marma, M. S.; Higa, T.; Bernardinelli, G.;
Jefford, C. W. J. Nat. Prod. 2001, 64, 696.
(46) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(47) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(48) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521.
(11) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009, 48,
7899.
(49) Baker, R.; Briner, P. H.; Evans, D. A. J. Chem. Soc., Chem.
Commun. 1978, 410.
(50) Baker, R.; Briner, P. H.; Evans, D. A. J. Chem. Soc., Chem.
(12) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc.
2010, 132, 14303.
(13) Sawamura, Y.; Nakatsuji, H.; Sakakura, A.; Ishihara, K. Chem. Sci.
Commun. 1978, 981.
2013, 4, 4181.
(51) Baker, R.; Cottrell, I. F.; Ravenscroft, P. D.; Swain, C. J. J. Chem.
Soc., Perkin Trans. 1 1985, 2463.
(52) Baker, R.; Ravenscroft, P. D.; Swain, C. J. J. Chem. Soc., Chem.
Commun. 1984, 74.
(14) Snyder, S. A.; Treitler, D. S.; Schall, A. Tetrahedron 2010, 66,
4796.
(15) Braddock, D. C.; Marklew, J. S.; Foote, K. M.; White, A. J. P.
Chirality 2013, 25, 692.
(53) Mori, K.; Suzuki, N. Liebigs Ann. Chem. 1990, 287.
(54) Palombo, E.; Audran, G.; Monti, H. Tetrahedron 2005, 61, 9545.
(55) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481.
(56) Hoppmann, A.; Weyerstahl, P. Tetrahedron 1978, 34, 1723.
(57) Hoye, T. R.; Caruso, A. J. J. Org. Chem. 1981, 46, 1198.
(16) Braddock, D. C.; Marklew, J. S.; Thomas, A. J. F. Chem.
Commun. 2011, 47, 9051.
(17) Braddock, D. C.; Hermitage, S. A.; Kwok, L.; Pouwer, R.;
Redmond, J. M.; White, A. J. P. Chem. Commun. 2009, 1082.
(18) Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc.
2010, 132, 1232.
(19) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900.
(20) Kato, T.; Ichinose, I.; Kamoshida, A.; Kitahara, Y. J. Chem. Soc.,
Chem. Commun. 1976, 518.
(21) Kato, T.; Ishii, K.; Ichinose, I.; Nakai, Y.; Kumagai, T. J. Chem.
Soc., Chem. Commun. 1980, 1106.
(22) Shieh, H.-M.; Prestwich, G. D. Tetrahedron Lett. 1982, 23, 4643.
(23) Gosselin, P.; Rouessac, F. Tetrahedron Lett. 1983, 24, 5515.
(24) Couladouros, E. A.; Vidali, V. P. Chem.Eur. J. 2004, 10, 3822.
(25) Tanaka, A.; Suzuki, M.; Yamashita, K. Agric. Biol. Chem. 1986,
50, 1069.
(26) Kuniyoshi, M.; Wahome, P. G.; Miono, T.; Hashimoto, T.;
Yokoyama, M.; Shrestha, K. L.; Higa, T. J. Nat. Prod. 2005, 68, 1314.
(27) Carter-Franklin, J. N.; Parrish, J. D.; Tschirret-Guth, R. A.;
Little, R. D.; Butler, A. J. Am. Chem. Soc. 2003, 125, 3688.
(28) Littlechild, J.; Rodriguez, E. G.; Isupov, M. J. Inorg. Biochem.
2009, 103, 617.
(29) Messerschmidt, A.; Prade, L.; Wever, R. Biol. Chem. 1997, 378,
309.
(30) Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49,
2486.
(31) Nurminen, E. J.; Mattinen, J. K.; Lonnberg, H. J. Chem. Soc.,
Perkin Trans. 2 2000, 2238.
(32) Sakakura, A.; Shomi, G.; Ukai, A.; Ishihara, K. Heterocycles 2010,
82, 249.
(33) Recsei, C.; McErlean, C. S. P. Tetrahedron 2012, 68, 464.
(34) Recsei, C.; McErlean, C. S. P. Tetrahedron: Asymmetry 2010, 21,
149.
(35) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am. Chem. Soc.
1991, 113, 8955.
(36) Yanagisawa, A.; Habaue, S.; Yasue, K.; Yamamoto, H. J. Am.
Chem. Soc. 1994, 116, 6130.
(37) Sparling, B. A.; Moebius, D. C.; Shair, M. D. J. Am. Chem. Soc.
2013, 135, 644.
(38) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc.
2002, 124, 3647.
(39) The major byproducts resulted from bromination of the internal
alkene to yield an inseparable diasteromeric mixture of prenylated
tetrahydrofurans.
(40) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C.
Tetrahedron 1980, 36, 2783.
(41) Requests for copies the original spectra or an authentic sample
of luzofuran have thus far gone unanswered. At this stage, we conclude
that the single anomaly in the reported 13C NMR data reflects a
typographical error.
(42) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77, 5068.
(43) Eschenmoser, A.; Ruzicka, L.; Jeger, O.; Arigoni, D. Helv. Chim.
Acta 1955, 38, 1890.
H
dx.doi.org/10.1021/jo402790x | J. Org. Chem. XXXX, XXX, XXX−XXX