Enantioselective synthesis of (+)-petromyroxol, enabled by rhodium-catalyzed denitrogenation and rearrangement of a 1-sulfonyl-1,2,3-triazole

Article abstract of DOI:10.1021/acs.joc.5b00399

Petromyroxol is a nonracemic mixture of enantiomeric oxylipids isolated from water conditioned with larval sea lamprey. The (+)-antipode exhibits interesting biological properties, but only 1 mg was isolated from >100000 L of water. Recently, transition-m

Full text of DOI:10.1021/acs.joc.5b00399

Note
pubs.acs.org/joc
Enantioselective Synthesis of (+)-Petromyroxol, Enabled by
Rhodium-Catalyzed Denitrogenation and Rearrangement of a
1‑Sulfonyl-1,2,3-Triazole
Alistair Boyer*
School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow G12 8QQ, U.K.
S
* Supporting Information
ABSTRACT: Petromyroxol is a nonracemic mixture of
enantiomeric oxylipids isolated from water conditioned with
larval sea lamprey. The (+)-antipode exhibits interesting
biological properties, but only 1 mg was isolated from
>100 000 L of water. Recently, transition-metal-catalyzed
denitrogenation of 1-sulfonyl-1,2,3-triazoles has emerged as a
powerful strategy for the synthesis of value-added products,
including efficient diastereocontrolled construction of tetrahy-
drofurans. This methodology enabled the rapid development
of the first synthesis of (+)-petromyroxol in 9 steps and 20%
overall yield from a readily accessible starting material.
etromyroxols are tetrahydrofuran-containing natural prod-
novel aquatic pest-control strategies, including the study of
aquatic pheromones.3 Importantly, although it is the less-
abundant enantiomer, (+)-petromyroxol (1) was demonstrated
to trigger a significant olfactory response in the sea lamprey.1
However, the possibility of further study of the biochemistry of
(+)-petromyroxol was hampered because only 2.9 mg of the
enantiomeric mixture were isolated from over 100 000 L of
water.1
P
ucts that were first described in December 2014 (Scheme
1a).1 They were isolated as a nonracemic 64:36 mixture of
Scheme 1. Introduction (Photo credit: T. Lawrence, Great
Lakes Fishery Commission)
Petromyroxol is a tetrahydrofuran diol from the acetogenin4
family and one of the vast array of natural compounds that
contain a tetrahydrofuran.5 The prevalence of this fundamental
motif has driven the creation of a wide range of innovative and
novel methodology for its construction.6 Recently, this set was
expanded to include an efficient stereocontrolled syntheses of
substituted THFs, capitalizing on the reactivity of a 1-sulfonyl-
1,2,3-triazole (1-ST) motif.7 Within 1-STs (e.g., 2, Scheme 1b),
the incorporation of a sulfonyl group fine-tunes the reactivity of
a 1,2,3-triazole so that, in the presence of a transition metal
catalyst, a Dimroth equilibrium can be established (2⇌2′). The
catalyst promotes denitrogenation, forming an α-imino
carbenoid 3. Overall, this strategy has been successfully
demonstrated by the transformation of readily accessible
building blocks into value-added products.8 In the case of 1-
STs bearing a pendant allyl ether (e.g., 4), the corresponding
carbenoid 4a can trap an oxygen lone pair to form an oxonium
ylide 4b. The charge is neutralized by [2,3]-sigmatropic
rearrangement9 to form a new C−C bond with high levels of
efficiency and stereocontrol.7
(−)/(+) enantiomers, and their structure was deduced by a
combination of detailed NMR studies, comparison with known
substituted tetrahydrofurans, and Mosher ester analysis. The
natural products were isolated from water conditioned with
larvae of the sea lamprey, Petromyrzon marinus L. The sea
lamprey is a parasitic fish that has invaded the Great Lakes and,
having no natural predator, has caused serious damage to the
fish population, harming the ecosystem and economy of the
region.2 This problem has spurred the investigation of several
This manuscript describes the application of this potent
approach toward THF construction to the first total synthesis
Received: February 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00399
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
of (+)-petromyroxol. The completion of the synthesis not only
confirms the structure of the natural product but also provides
valuable access to material required for further investigation of
the biology of this fascinating creature.
Scheme 3. Synthesis
The keystone to developing a synthesis strategy came with
recognition that the central THF motif could be constructed by
diastereoselective rhodium-catalyzed denitrogenation and re-
arrangement of the β-allyloxy-1-ST 7 into a trans-2,5-
disubstituted dihydrofuran-3-one 8 (Scheme 2).7a
Scheme 2. Retrosynthetic Analysis
The resulting heterocycle 8 would act as a suitable building
block for the remainder of the synthesis, with ketone and allyl
groups providing excellent handles for further manipulation.
The ketone 8 could be reduced diastereoselectively10 to give an
alcohol with the correct geometry as found in the natural
compound. The allyl group would allow introduction of the
remaining carbon atom through cross metathesis (6).
Importantly, the 1-ST substrate 7 for the pivotal transformation
would be accessible from the corresponding alkyne 9, which
could in turn come from the O-allylation of the product of
acetylide epoxide ring opening of appropriately protected 1,2-
epoxy-3-octanol 10.
with the desired trans-2,5-configuration. In contrast to previous
observations,7a during this reaction baseline impurities were
observed. It is suggested that the unhindered7b benzyl ether
presents a number of alternative reaction pathways including
[1,2]-sigmatropic shift and C−H bond functionalization.
However, formation of the five-membered oxonium inter-
mediate species and rearrangement to give the dihydrofuran-3-
one was the major pathway giving the heterocyclic scaffold 8 in
67% isolated yield of the desired isomer. The final stereocenter
within the target molecule was installed under substrate control,
with a hydride delivered opposite to the allyl substituent with
>10:1 selectivity (8 → 14).10 Cross-metathesis between the
Type I terminal alkene and Type II benzyl acrylate using
Grubb’s second generation catalyst proceeded in excellent yield
accomplishing installation of the one remaining carbon atom
(14 → 6).9g,16 Finally, the homologated compound 6 was
treated with hydrogen and palladium on carbon to effect
concomitant reduction of the alkene and hydrogenolysis of the
benzyl ether and benzyl ester to complete the synthesis of
(+)-petromyroxol (1) in excellent yield. The NMR spectra and
optical rotation data were in excellent agreement with those
reported for the naturally sourced compound, unambiguously
confirming the structure.
The synthesis commenced with formation of the requisite
epoxide (Scheme 3). Sharpless dihydroxylation11 of readily
accessible trans-1-chloro-2-octene (11)12 led to the 1,2-diol 12
with excellent yield (95%) and enantioselectivity (>95% ee).13
Treatment of the diol 12 with 2 equiv of base followed by
benzyl bromide led to tandem epoxide formation−protection
of the secondary alcohol (i.e., 10). The key alkyne motif for 1-
ST formation was installed by nucleophilic opening of the
epoxide with an aluminum acetylide14 to give the requisite
terminal alkyne (i.e., 13). Then, the free alcohol was smoothly
converted to the allyl ether under standard conditions (8 → 9).
The triazole motif was installed under anionic conditions by
treatment of the terminal alkyne with nBuLi followed by TsN3,
resulting in efficient and regioselective formation of the 5-
substituted-1-ST 7.15
Overall, the first enantioselective synthesis of (+)-petromyr-
oxol was completed in only 9 steps with an overall yield of 20%
from a readily accessible allylic chloride. The core tetrahy-
drofuran motif within the natural product was formed by
denitrogenation and rearrangement of a 1-ST. This synthesis
The conditions developed previously,7a namely 5 mol %
rhodium(II) acetate in toluene at reflux, were used to promote
denitrogenation and rearrangement to form the furanone 8
B
DOI: 10.1021/acs.joc.5b00399
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The Journal of Organic Chemistry
Note
min−1, 205 nm, major enantiomer tret = 9.5 min, minor enantiomer tret
= 11.5 min).
exemplifies the versatile reactivity of the 1-ST motif as a tool for
enabling rapid construction of valuable molecular architecture.
(−)-(R,R)-5-Benzyloxydec-1-yn-4-ol (13). n-Butyllithium (2.2 M
solution in hexanes, 2.2 cm3, 4.9 mmol, 1.3 equiv) was added to a
stirred solution of ethynyltrimethylsilane (0.79 cm3, 5.6 mmol, 1.5
equiv) in diethyl ether (25 cm3) at −78 °C. The mixture was stirred
for 15 min at −78 °C, then trimethylaluminum (2 M in toluene, 2.4
cm3, 4.9 mmol, 1.3 equiv) was added, and the mixture stirred for 0.5 h
at −78 °C and then 0.5 h at −45 °C. The mixture was recooled to −78
°C, and a solution of epoxide 10 (875 mg, 3.7 mmol, 1.0 equiv) in
diethyl ether (5 cm3 with washings) was added followed by BF3·OEt2
(0.51 cm3, 4.1 mmol, 1.1 equiv) down the cold flask wall. The reaction
mixture was stirred for 1 h at −78 °C, and then the reaction was
quenched by the addition of methanol (1.5 cm3). The mixture was
allowed to warm to ambient temperature, and saturated aqueous
ammonium chloride (30 cm3) was added. The aqueous layer was
extracted with ethyl acetate (2 × 30 cm3), dried (MgSO4), filtered, and
concentrated in vacuo. The crude mixture was dissolved in THF (30
cm3), and nBuN4F (1 M in THF, 7.5 cm3, 7.5 mmol, 2.0 equiv) was
added. The mixture was stirred for 16 h at ambient temperature and
then washed with half saturated brine (30 cm3). The organic layer was
dried (MgSO4), filtered, and concentrated in vacuo. The crude product
was purified by flash column chromatography (10% Et2O in petrol) to
EXPERIMENTAL SECTION
■
General Considerations. 1H chemical shift data are given in units
δ relative to the residual protic solvent where δ(CDCl3) = 7.26 ppm, s.
13C chemical shift data were recorded with broad-band proton
decoupling and are given in units δ relative to the solvent where
δ(CDCl3) = 77.0 ppm, t. Peak assignments were made using 2D
COSY, HSQC, and HMBC experiments. IR spectra were recorded as
thin films using an ATR accessory. Where appropriate, reactions were
performed in oven-dried glassware under an an argon atmosphere.
Purification was performed using Merck Geduran Si 60 (40−63 μm)
silica gel. THF, Et2O, and toluene were passed through a column of
activated alumina under nitrogen before use. Petrol refers to fractions
of petroleum ether collected between 40 and 60 °C.
(+)-(R,R)-1-Chlorooctane-2,3-diol (12). A suspension of potas-
sium hexacyanoferrate(III) (8.98 g, 27.3 mmol, 4.0 equiv), potassium
carbonate (3.77 g, 27.3 mmol, 4.0 equiv), methanesulfonamide (649
mg, 6.8 mmol, 1.0 equiv), (DHQD)2PHAL (69 mg, 0.09 mmol, 1.3
mol %), and osmium tetroxide (2.5 wt % in tBuOH, 0.42 cm3, 0.04
mmol, 0.6 mol %) in tBuOH (25 cm3) and water (25 cm3) was stirred
at ambient temperature for 0.5 h. The mixture was cooled to 0 °C, and
(E)-1-chlorooct-2-ene 1112 (1.00 g, 6.8 mmol, 1.0 equiv) was added.
The reaction mixture was stirred at 0 °C for 18 h, and then the
reaction was quenched by the addition of sodium sulfite (13.8 g, 109
mmol, 16 equiv) and stirred at ambient temperature for 2 h. The
mixture was diluted with water (25 cm3) and extracted with ethyl
acetate (5 × 50 cm3). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. The crude product
(main contaminant MeSO2NH2) was purified by flash column
chromatography (gradient from 10 to 20% EtOAc in petrol) to
yield the title compound 12 (1.18 g, 95%) as a white crystalline solid.
23
yield the title compound 13 (807 mg, 83%) as a colorless oil. [α]D
−40.4 (c 1.0, CHCl3); νmax 3451br, 3308, 2951, 2930, 2859, 1454,
1069, and 1028 cm−1; δH(400 MHz; CDCl3): 7.40−7.27 (5 H, m, Ph),
4.68 (1 H, d, J 11.3 Hz, benzyl OCHA), 4.54 (1 H, d, J 11.3 Hz, benzyl
OCHB), 3.75 (1 H, dtd, J 6.7, 6.3, and 4.1 Hz, CH−OH), 3.56 (1 H,
td, J 6.1 and 4.1 Hz, CH−OBn), 2.50 (1 H, ddd, J 16.8, 6.3, and 2.7
Hz, CHACC), 2.44 (1 H, ddd, J 16.8, 6.3, and 2.7 Hz, CHBCC),
2.39 (1 H, br d, J 6.7 Hz, OH), 2.03 (1 H, t, J 2.7 Hz, CCH), 1.71−
1.56 (2 H, m, CH2), 1.44−1.24 (6 H, m, CH2) and 0.89 (3 H, t, J 6.9
Hz, CH3); δC(101 MHz; CDCl3): 138.2 (Ph), 128.5 (2 × Ph), 127.9
(2 × Ph), 127.8 (Ph), 80.9 (CC), 80.1 (CH−OBn), 72.6 (benzyl
OCH2), 71.0 (CH−OH), 70.3 (CC), 32.0 (CH2), 30.2 (CH2), 24.9
(CH2), 23.8 (CH2CC), 22.6 (CH2) and 14.0 (CH3); m/z (ESI-Qq-
20
Mp 66−67 °C; [α]D +13.3 (c 1.5, MeOH); νmax 3310br, 3219br,
2957, 2936, 2861, 1458, and 1126 cm−1; δH(400 MHz; CDCl3): 3.71−
3.59 (4 H, m, 2 × CH−OH and CH2Cl), 2.53 (1 H, d, J 4.5 Hz, OH),
2.03 (1 H, d, J 4.9 Hz, OH), 1.62−1.23 (8 H, m, CH2) and 0.90 (3 H,
t, J 6.8 Hz, CH3); δC(101 MHz; CDCl3): 73.7 (CH−OH), 71.6 (CH−
OH), 47.0 (CH2Cl), 33.7 (CH2), 31.7 (CH2), 25.2 (CH2), 22.6
(CH2), and 14.0 (CH3). The enantiomeric excess (>95% ee) was
determined for the subsequent compound 10. Data consistent with
previously reported values.11c
+
TOF) 283.1681 ([M + Na]+ = C17H24NaO2 requires 283.1669).
(−)-(R,R)-4-Allyloxy-5-benzyloxydec-1-yne (9). Sodium bis(tri-
methylsilyl)amide (1 M solution in THF, 4.1 cm3, 4.1 mmol, 1.5
equiv), followed by allyl bromide (0.35 cm3, 4.1 mmol, 1.5 equiv) and
tetrabutylammonium iodide (300 mg, 0.8 mmol, 0.3 equiv), was added
to a stirred solution of alcohol 13 (705 mg, 2.7 mmol, 1.0 equiv) in
DMF (25 cm3) at 0 °C. The mixture was stirred for 12 h, allowing the
mixture to reach ambient temperature, and then the reaction was
quenched by the addition of saturated aqueous ammonium chloride
(30 cm3). The mixture was extracted with diethyl ether (3 × 30 cm3),
and the combined organic layers were washed with aqueous lithium
chloride (10 wt %/vol, 70 cm3) dried (MgSO4), filtered, and
concentrated in vacuo. The crude product was purified by flash
column chromatography (gradient from 1 to 2% Et2O in petrol) to
(+)-(R,R)-3-Benzyloxy-1,2-epoxyoctane (10). Sodium bis(tri-
methylsilyl)amide (2 M solution in THF, 5.6 cm3, 11.2 mmol, 2.02
equiv) was added to a solution of diol 12 (1.00 g, 5.6 mmol, 1.0 equiv)
and tetrabutylammonium iodide (410 mg, 1.1 mmol, 0.2 equiv) in
DMF (50 cm3) at 0 °C. The mixture was stirred at 0 °C for 1 h, then
benzyl bromide (1.3 cm3, 11.1 mmol, 2.0 equiv) was added, and the
mixture was stirred at ambient temperature for 18 h. The reaction was
quenched by the addition of saturated aqueous ammonium chloride
(25 cm3) and extracted with diethyl ether (3 × 50 cm3). The
combined organic layers were washed with aqueous lithium chloride
(10 wt %/vol, 50 cm3) dried (MgSO4), filtered, and concentrated in
vacuo. The crude product was purified by flash column chromatog-
raphy (gradient from 1 to 2% EtOAc in petrol) to yield the title
23
yield the title compound 9 (766 mg, 94%) as a colorless oil. [α]D
−8.8 (c 0.85, CHCl3); νmax 3310, 2953, 2926, 2857, 1454, 1085, and
1074 cm−1; δH(400 MHz; CDCl3): 7.39−7.26 (5 H, m, Ph), 5.93 (1
H, ddt, J 17.2, 10.3, and 5.8 Hz, allyl =CH), 5.28 (1 H, ddt, J 17.2, 1.6,
and 1.4 Hz, allyl =CHZ), 5.18 (1 H, ddt, J 10.3, 1.6, and 1.4 Hz, allyl
=CHE), 4.65 (1 H, d, J 11.4 Hz, benzyl OCHA), 4.59 (1 H, d, J 11.4
Hz, benzyl OCHB), 4.21 (1 H, ddt, J 12.7, 5.8, and 1.4 Hz, allyl
OCHA), 4.08 (1 H, ddt, J 12.7, 5.8, and 1.4 Hz, allyl OCHB), 3.62−
3.53 (2 H, m, CH−OBn and CH−Oallyl), 2.57 (1 H, ddd, J 17.0, 5.3,
and 2.7 Hz, CHACC), 2.40 (1 H, ddd, J 17.0, 6.4, and 2.7 Hz,
CHBCC), 1.98 (1 H, t, J 2.7 Hz, CCH), 1.67−1.19 (8 H, m,
CH2), and 0.88 (3 H, t, J 6.9 Hz, CH3); δC(101 MHz; CDCl3): 138.7
(Ph), 135.0 (allyl =CH), 128.3 (2 × Ph), 128.0 (2 × Ph), 127.5 (Ph),
117.1 (allyl =CH2), 81.8 (CC), 79.7 (CH−OBn), 78.4 (CH−
Oallyl), 72.9 (benzyl OCH2), 71.9 (allyl OCH2), 69.6 (CC), 31.9
(CH2), 29.8 (CH2), 25.5 (CH2), 22.6 (CH2), 20.3 (CH2CC) and
23
compound 10 (1.02 g, 78%) as a colorless oil. [α]D +32.2 (c 1.6,
CHCl3); νmax 2955, 2930, 2859, 1454, 1090, and 1071 cm−1; δH(400
MHz; CDCl3): 7.40−7.26 (5 H, m, Ph), 4.84 (1 H, d, J 11.9 Hz,
benzyl OCHA), 4.58 (1 H, d, J 11.9 Hz, benzyl OCHB), 3.08−3.00 (2
H, m, CH−OBn and epoxide CH), 2.78 (1 H, dd, J 4.8 and 4.1 Hz,
epoxide CHA), 2.49 (1 H, dd, J 4.8 and 2.4 Hz, epoxide CHB), 1.72−
1.18 (8 H, m, CH2) and 0.88 (3 H, t, J 7.1 Hz, CH3); δC(101 MHz;
CDCl3): 138.7 (Ph), 128.3 (2 × Ph), 127.8 (2 × Ph), 127.4 (Ph), 80.5
(CH−OBn), 71.6 (benzyl OCH2), 55.1 (epoxide CH), 43.1 (epoxide
CH2), 32.3 (CH2), 31.8 (CH2), 25.2 (CH2), 22.5 (CH2), and 14.0
14.0 (CH3); m/z (ESI-Qq-TOF) 323.1967 ([M + Na]+
C20H28NaO2 requires 323.1982).
=
+
(CH3); m/z (ESI-Qq-TOF) 257.1504 ([M + Na]+ = C15H22NaO2
+
requires 257.1512). The enantiomeric excess was determined to be
(+)-(R,R)-5-(2-Allyloxy-3-benzyloxyoctyl)-1-tosyl-1,2,3-tria-
>95% (Chiralpak AD-H, 0.46Ø × 25 cm, 0.5% iPrOH/hexane, 1 cm3
zole (7). n-Butyllithium (2.5 M solution in hexanes, 0.44 cm3, 1.1
C
DOI: 10.1021/acs.joc.5b00399
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Note
mmol, 1.1 equiv) was added to a stirred solution of alkyne 9 (300 mg,
1.0 mmol, 1.0 equiv) in THF (5 cm3) at −78 °C. The mixture was
stirred for 0.5 h at −78 °C, then p-toluenesulfonyl azide17 (1.6 M
solution in THF, 0.69 cm3, 1.1 mmol, 1.1 equiv) was added, and the
mixture stirred for 0.5 h at −78 °C. The reaction was quenched by the
addition of saturated aqueous ammonium chloride (10 cm3), diluted
with ethyl acetate (10 cm3), and allowed to warm to ambient
temperature. The aqueous layer was extracted with ethyl acetate (2 ×
10 cm3), and the combined organic layers were dried (MgSO4),
filtered, and concentrated in vacuo. The crude mixture was purified by
flash column chromatography (rapid: <20 min, <20 fractions, gradient
from 10 to 20% EtOAc in petrol) to yield the title compound 7 (442
mg, 89%) as a colorless oil. N.B. When neat, 1-STs can undergo
isomerization and decomposition;15,18 this compound was stored as
aqueous layer was extracted with ethyl acetate (2 × 5 cm3). The
combined organic layers were dried (MgSO4), filtered, concentrated in
vacuo, and purified by flash column chromatography (gradient from
5% to 10% to 20% EtOAc in petrol) to give a small amount of the
undesired diastereoisomer (<1:10) followed by the title compound 14
22
(60 mg, 79%) as a white solid. Mp 39−41 °C; [α]D +18.2 (c 0.89,
CHCl3); νmax 3437br, 2953, 2930, 2859, 1454, 1090, 1067, and 1028
cm−1; δH(400 MHz; CDCl3): 7.38−7.24 (5 H, m, Ph), 5.88 (1 H,
dddd, J 17.1, 10.2, 7.5, and 6.5 Hz, allyl =CH), 5.19 (1 H, ddt, J 17.1,
1.8, and 1.6 Hz, allyl =CHZ), 5.09 (1 H, ddt, J 10.2, 1.8, and 1.2 Hz,
allyl =CHE), 4.71 (1 H, d, J 11.6 Hz, benzyl OCHA), 4.63 (1 H, d, J
11.6 Hz, benzyl OCHB), 4.33 (1 H, ddd, J 9.1, 6.8, and 5.7 Hz, furan 5-
H), 4.28−4.23 (1 H, m, furan 3-H), 3.89 (1 H, ddd, J 7.2, 7.2, and 2.8
Hz, furan 2-H), 3.32 (1 H, ddd, J 7.2, 5.7, and 5.2 Hz, CH−OBn),
2.54−2.35 (2 H, m, allyl CH2), 1.97 (1 H, ddd, J 13.5, 6.8, and 1.4 Hz,
furan 7-HA), 1.92 (1 H, ddd, J 13.5, 9.1, and 4.3 Hz, furan 7-HB), 1.69
(1 H, d, J 5.8 Hz, OH), 1.55−1.20 (8 H, m, CH2) and 0.88 (3 H, t, J
7.0 Hz, CH3); δC(101 MHz; CDCl3): 138.9 (Ph), 134.8 (allyl =CH),
128.2 (2 × Ph), 127.9 (2 × Ph), 127.4 (Ph), 117.0 (allyl =CH2), 81.6
(furan 2-H), 81.0 (CH−OBn), 79.3 (furan 3-H), 72.9 (furan 5-H),
72.7 (benzyl OCH2), 37.5 (furan 4-H2), 33.8 (allyl CH2), 31.9 (CH2),
30.5 (CH2), 25.3 (CH2), 22.6 (CH2), and 14.0 (CH3); m/z (ESI-Qq-
21
solution before use. [α]D +53.6 (c 0.5, CHCl3); νmax 2955, 2930,
2861, 1389, 1196, 1182, and 1086 cm−1; δH(400 MHz; CDCl3): 7.92
(2 H, d, J 8.4 Hz, Ts Ar), 7.41−7.28 (8 H, m, Ts Ar, Ph and triazole-
H), 5.63 (1 H, ddt, J 17.2, 10.3, and 5.8 Hz, allyl =CH), 5.12 (1 H, ddt,
J 17.2, 1.5, and 1.3 Hz, allyl =CHZ), 5.08 (1 H, ddt, J 10.3, 1.5, and 1.3
Hz, allyl =CHE), 4.66 (1 H, d, J 11.5 Hz, benzyl OCHA), 4.58 (1 H, d,
J 11.5 Hz, benzyl OCHB), 3.91 (1 H, ddt, J 12.5, 5.8, and 1.3 Hz, allyl
OCHA), 3.78 (1 H, ddd, J 9.7, 4.1, and 3.2 Hz, CH−Oallyl), 3.76 (1 H,
ddt, J 12.5, 5.8, and 1.3 Hz, allyl OCHB), 3.51 (1 H, ddd, J 8.3, 4.1, and
4.0 Hz, CH−OBn), 3.29 (1 H, ddd, J 15.2, 3.2, and 0.5 Hz, CHA-
triazole), 3.02 (1 H, dd, J 15.2 and 9.7 Hz, CHB-triazole), 2.43 (3 H, s,
Ts Me), 1.72−1.20 (8 H, m, CH2), and 0.90 (3 H, t, J 7.0 Hz, CH3);
δC(101 MHz; CDCl3): 146.9 (Ts Ar), 138.4 (Ph), 137.6 (triazole),
134.4 (Ts Ar), 134.2 (allyl =CH), 133.8 (triazole-H), 130.3 (2 × Ts
Ar), 128.6 (2 × Ts Ar), 128.4 (2 × Ph), 128.1 (2 × Ph), 127.8 (Ph),
117.5 (allyl =CH2), 79.1 (CH−OBn), 77.8 (CH−Oallyl), 72.5 (benzyl
OCH2), 71.9 (allyl OCH2), 31.9 (CH2), 29.1 (CH2), 25.8 (CH2), 25.0
(CH2−triazole), 22.6 (CH2), 21.8 (Ts Me) and 14.0 (CH3); m/z
(ESI-Qq-TOF) 520.2234 ([M + Na]+ = C27H35N3NaO4S+ requires
520.2240).
+
TOF) 341.2073 ([M + Na]+ = C20H30NaO3 requires 341.2087).
(+)-2,3-Dehydro-1,9-O,O-dibenzylpetromyroxol (6). A solu-
tion of alkene 14 (58 mg, 0.18 mmol, 1.0 equiv) and benzyl acrylate
(236 mg, 1.5 mmol, 8.0 equiv) in dichloromethane (3 cm3) was
degassed (bubbling Ar, 5 min), then Grubb’s second generation
catalyst (15 mg, 0.02 mmol, 10 mol %) was added, and the reaction
mixture was stirred at 50 °C. After 2.5 h the reaction was quenched by
the addition of methanol (0.1 cm3) and concentrated in vacuo. The
crude product was purified by flash column chromatography (25%
EtOAc in petrol) to give the title compound 6 (68 mg, 82%) as a
19
colorless oil. [α]D +7.4 (c 1.0, CHCl3); νmax 3439br, 2951, 2930,
2859, 1721, 1657, 1454, 1377, 1317, 1263, 1163, 1092, 1069, 1042,
and 1026 cm−1; δH(400 MHz; CDCl3): 7.38−7.23 (10 H, m, Ph), 7.06
(1 H, dt, J 15.6 and 7.1 Hz, 3-H), 6.02 (1 H, dt, J 15.6 and 1.5 Hz, 2-
H), 5.17 (2 H, s, CO2Bn), 4.67 (1 H, d, J 11.6 Hz, 9-OCHAPh), 4.62
(1 H, d, J 11.6 Hz, 9-OCHBPh), 4.32 (1 H, td, J 7.9 and 5.6 Hz, 8-H),
4.26 (1 H, ddt, J 6.1, 3.0, and 2.8 Hz, 6-H), 3.94 (1 H, td, J 6.9 and 3.0
Hz, 5-H), 3.30 (1 H, ddd, J 7.1, 5.6, and 5.5 Hz, 9-H), 2.60 (1 H,
dddd, J 14.7, 7.1, 6.9, and 1.5 Hz, 4-HA), 2.55 (1 H, dddd, J 14.7, 7.1,
6.9, and 1.5 Hz, 4-HB), 1.95 (2 H, dd, J 7.9 and 2.8 Hz, 7-H2), 1.72 (1
H, d, J 6.1 Hz, 6-OH), 1.55−1.20 (8 H, m, 10−13-H2) and 0.88 (3 H,
t, J 7.0 Hz, 14-H3); δC(101 MHz; CDCl3): 166.2 (C1), 145.9 (C3),
138.8 (Ph), 136.0 (Ph), 128.5 (2 × Ph), 128.2 (2 × Ph), 128.2 (2 ×
Ph), 128.1 (Ph), 127.9 (2 × Ph), 127.5 (Ph), 122.9 (C2), 80.9 (C9),
80.7 (C5), 79.4 (C8), 72.8 (C6), 72.7 (benzyl OCH2), 66.1 (benzyl
OCH2), 37.8 (C7), 32.3 (C4), 31.9 (C10−C13), 30.5 (C10−C13),
25.3 (C10−C13), 22.6 (C10−C13), and 14.0 (C14); m/z (ESI-Qq-
(−)-(2S,5R)-2-Allyl-5-((R)-1-benzyloxyhexyl)dihydrofuran-3-
one (8). Rhodium(II) acetate dimer (9 mg, 0.02 mmol, 5 mol %) was
added to a stirred solution of 1-tosyl-1,2,3-triazole 7 (210 mg, 0.42
mmol, 1.0 equiv) in toluene (17 cm3). The reaction mixture was
heated under reflux for 0.5 h and then cooled to ambient temperature.
Alumina (Basic, pH 9.5, Brockmann activity III, i.e. 6 wt % H2O, 4.2 g)
was added, and the reaction mixture was stirred at ambient
temperature for 0.5 h. The mixture was directly purified by flash
column chromatography (gradient from 10 to 20% EtOAc in petrol)
19
to give the title compound 8 (89 mg, 67%) as a colorless oil. [α]D
−89.3 (c 1.1, CHCl3); νmax 2953, 2928, 2859, 1757, 1454, and 1071
cm−1; δH(400 MHz; CDCl3): 7.37−7.31 (2 H, m, Ph), 7.31−7.25 (3
H, m, Ph), 5.82 (1 H, ddt, J 17.1, 10.2, and 6.9 Hz, allyl =CH), 5.14 (1
H, ddt, J 17.1, 1.9, and 1.5 Hz, allyl =CHZ), 5.10 (1 H, ddt, J 10.2, 1.9,
and 1.1 Hz, allyl =CHE), 4.62 (1 H, d, J 11.5 Hz, benzyl OCHA), 4.47
(1 H, d, J 11.5 Hz, benzyl OCHB), 4.44 (1 H, ddd, J 8.2, 3.8, and 3.2
Hz, furanone 5-H), 4.13 (1 H, dd, J 6.9 and 4.7 Hz, furanone 2-H),
3.33 (1 H, td, J 6.6 and 3.2 Hz, CH−OBn), 2.49−2.42 (1 H, m, allyl
CHA), 2.47 (1 H, dd, J 17.8 and 8.2 Hz, furanone 4-HA), 2.34−2.26 (1
H, m, allyl CHB), 2.31 (1 H, dd, J 17.8 and 3.8 Hz, furanone 4-HB),
1.77−1.64 (2 H, m, CH2), 1.47−1.24 (6 H, m, CH2), and 0.90 (3 H, t,
J 6.9 Hz, CH3); δC(101 MHz; CDCl3): 215.6 (CO), 138.1 (Ph),
133.2 (allyl =CH), 128.4 (2 × Ph), 127.9 (2 × Ph), 127.7 (Ph), 118.0
(allyl =CH2), 81.8 (CH−OBn), 79.4 (furanone 2-H), 76.1 (furanone
5-H), 72.5 (benzyl OCH2), 39.4 (furanone 4-H2), 36.0 (allyl CH2),
32.0 (CH2), 30.0 (CH2), 25.3 (CH2), 22.6 (CH2), and 14.0 (CH3);
+
TOF) 475.2442 ([M + Na]+ = C28H36NaO5 requires 475.2455).
(+)-Petromyroxol (1). A mixture of benzyl ester 6 (65 mg, 0.14
mmol, 1.0 equiv) and palladium (10 wt % on carbon, 15 mg, 0.01
mmol, 10 mol %) in ethyl acetate (1 cm3) was evacuated and refilled
with hydrogen (3×) and stirred under an atmosphere of hydrogen for
36 h. The reaction vessel was purged, and the crude mixture was
purified by flash column chromatography (5% AcOH in EtOAc) to
give (+)-petromyroxol 1 (35 mg, 89%) as an amorphous solid. Mp
19
51−53 °C; [α]D +20.5 (c 1.7, CHCl3); νmax 3404br, 2952, 2932,
2871, 2860, 1710, 1408, 1292, 1249, 1070, and 1060 cm−1; δH(500
MHz; CDCl3): 5.04 (3 H, br, OH), 4.28 (1 H, dd, J 4.5 and 2.9 Hz, 6-
H), 4.05 (1 H, ddd, J 9.3, 6.9, and 6.5 Hz, 8-H), 3.77 (1 H, td, J 6.5,
6.5, and 2.9 Hz, 5-H), 3.38 (1 H, ddd, J 7.3, 6.9, and 4.0 Hz, 9-H), 2.40
(1 H, dt, J 16.3 and 5.9 Hz, 2-HA), 2.37 (1 H, dt, J 16.3 and 5.6 Hz, 2-
HB), 2.02 (1 H, dd, J 13.5 and 6.5 Hz, 7-HA), 1.85 (1 H, ddd, J 13.5,
9.3, and 4.5 Hz, 7-HB), 1.74−1.60 (4 H, m, 3-H2 and 4-H2), 1.54−1.46
(1 H, m, 11-HA), 1.43−1.21 (7 H, m, 10-H2, 11-HB, 12-H2, and 13-
H2) and 0.88 (3 H, t, J 6.9 Hz, 14-H3); δC(126 MHz; CDCl3): 178.3
(C1), 82.4 (C5), 80.6 (C8), 74.2 (C9), 73.1 (C6), 37.5 (C7), 33.9
(C2), 33.0 (C10), 31.9 (C12), 28.1 (C4), 25.2 (C11), 22.6 (C13),
21.2 (C3) and 14.0 (C14); m/z (ESI-Qq-TOF+) 297.1658 ([M +
+
m/z (ESI-Qq-TOF) 339.1915 ([M + Na]+ = C20H28NaO3 requires
339.1931).
(+)-(2S,3S,5R)-2-Allyl-5-((R)-1-benzyloxyhexyl)tetrahydro-
furan-3-ol (14). Lithium tri-sec-butylborohydride (1 M in THF, 0.47
cm3, 0.47 mmol, 2.0 equiv) was added to a stirred solution of furan-3-
one 8 (75 mg, 0.24 mmol, 1.0 equiv) in THF (2.5 cm3) at −78 °C.
The reaction mixture was stirred for 2.5 h, and the reaction was
quenched by the addition of water (0.2 cm3), H2O2 (30 vols, 0.2 cm3),
and NaOH (1 M, 0.02 cm3) and stirred at ambient temperature for 16
h. Ethyl acetate (5 cm3) and brine (5 cm3) were added, and the
D
DOI: 10.1021/acs.joc.5b00399
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
+
Na]+ = C14H26NaO5 requires 297.1672); m/z (ESI-Qq-TOF−)
J. 2014, 20, 12881−12888. (i) Clark, J. S.; Hansen, K. E. Chem.Eur.
J. 2014, 20, 5454−5459. (j) Clark, J. S.; Romiti, F. Angew. Chem., Int.
Ed. 2013, 52, 10072−10075.
−
273.1709 ([M − H]− = C14H25O5 requires 273.1707). The NMR
peaks were sensitive to sample concentration; data reported for ca. 15
mg·cm−3. Data consistent with those reported for the natural
compound;1 see Supporting Information for further comparison.
(10) (a) Fernan
́
dez de la Pradilla, R.; Castellanos, A.; Osante, I.;
Colomer, I.; San
(b) Williams, D. R.; Harigaya, Y.; Moore, J. L.; D’Sa, A. J. Am. Chem.
Soc. 1984, 106, 2641−2644.
́
chez, M. I. J. Org. Chem. 2008, 74, 170−181.
ASSOCIATED CONTENT
* Supporting Information
NMR Spectra for compounds 6−14, HPLC chromatogram for
compound 10, TLC data, and a detailed comparison of data
collected for natural and synthetic petromyroxol 1. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
(11) (a) Vanhessche, K. P. M.; Wang, Z.-M.; Sharpless, K. B.
Tetrahedron Lett. 1994, 35, 3469−3472. (b) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483−
2547. (c) Zhang, Z.-B.; Wang, Z.-M.; Wang, Y.-X.; Liu, H.-Q.; Lei, G.-
X.; Shi, M. J. Chem. Soc., Perkin Trans. 1 2000, 53−57.
(12) Glueck, S. M.; Fabian, W. M. F.; Faber, K.; Mayer, S. F. Chem.
Eur. J. 2004, 10, 3467−3478.
S
(13) The ee was determined after the next step, for epoxide 10.
́ ́
(14) (a) Skrydstrup, T.; Benechie, M.; Khuong-Huu, F. Tetrahedron
AUTHOR INFORMATION
Corresponding Author
*E-mail: alistair@boyer-research.com.
Notes
■
Lett. 1990, 31, 7145−7148. (b) Fried, J.; Sih, J. C.; Lin, C. H.; Dalven,
P. J. Am. Chem. Soc. 1972, 94, 4343−4345. (c) Trost, B. M.; Machacek,
M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006, 128, 6745−6754.
(15) (a) Meza-Avina, M. E.; Patel, M. K.; Lee, C. B.; Dietz, T. J.;
̃
Croatt, M. P. Org. Lett. 2011, 13, 2984−2987. (b) Meza-Avina, M. E.;
̃
The authors declare no competing financial interest.
Patel, M. K.; Croatt, M. P. Tetrahedron 2013, 69, 7840−7846.
(16) (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360−11370. (b) Scholl, M.; Ding, S.;
Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953−956.
(17) Curphey, T. J. Org. Prep. Proced. Int. 1981, 13, 112−115.
(18) Yamauchi, M.; Miura, T.; Murakami, M. Heterocycles 2009, 80,
177−181.
ACKNOWLEDGMENTS
■
The author gratefully acknowledges support from the Ramsay
Memorial Fellowships Trust and the University of Glasgow,
School of Chemistry as well as valuable discussions with Prof. J.
Stephen Clark, Filippo Romiti, and Prof. Weiming Li.
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