Enantioselective synthesis of the strigolactone mimic (+)-GR24

Article abstract of DOI:10.1021/jo402722p

A short and cost-effective synthesis of the important strigolactone analogue (+)-GR24 is described. Central to this new approach is the concise, enantioselective synthesis of the A-C ring system.

Full text of DOI:10.1021/jo402722p

Note
pubs.acs.org/joc
Enantioselective Synthesis of the Strigolactone Mimic (+)-GR24
Liam J. Bromhead, Johan Visser, and Christopher S. P. McErlean*
School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
S
* Supporting Information
ABSTRACT: A short and cost-effective synthesis of the important
strigolactone analogue (+)-GR24 is described. Central to this new approach
is the concise, enantioselective synthesis of the A−C ring system.
trigolactones are a family of plant signaling molecules at the
center of intense applied research.1−4 These molecules
Scheme 1. Strategies to (+)-GR24 (3)
S
mediate vital biological functions in plants, including seed-
germination, inhibition of shoot-branching,5 and root-colo-
nization by symbiotic arbuscular mycorrhizal fungi, which
enable soil−plant nutrient transfer.6 The agrichemical potential
of strigolactones is vast. The parent member of the class, strigol
(1) (Figure 1), was isolated from cotton roots in 1966, and
Figure 1. Strigol (1) and synthetic analogue GR24.
catalyst;13 coupling of racemic A−C fragment ( )-4 with an
enantiomerically pure D ring (+)-6;14 or coupling of an
enantiomerically pure A−C fragment (+)-4 to racemic D-ring
( )-6.14,15 Zwanenburg and co-workers utilized a palladium
coupling to unite ( )-4 and ( )-5 using Trost’s ligand.13 While
the ee of the product was excellent, an almost 1:1 mixture of
diastereomers was produced. Synthesis of enantiomerically pure
D-ring (+)-6 is laborious. The most attractive strategy therefore
involves the enantiomerically pure A−C fragment (+)-4.
Zwanenburg reported that microcrystalline cellulose triace-
tate (CTA) was effective for the chromatographic resolution to
give (+)-4 and (−)-4 (Scheme 2),14 but the yield of such
resolutions are limited to 50%. Given the importance of
(+)-GR24 (3) over the past thirty years and its widespread
application across the plant sciences, it is surprising to find that
an enantioselective synthesis of the A−C fragment (+)-4 was
not reported until 2012.15 Utilizing (2R,5R)-2,5-dimethylpyr-
rolidine as a chiral auxiliary to dictate the stereochemical course
of an intramolecular [2 + 2] ketene-iminium cyclization,
researchers from Syngenta Crop Protection were able to
since that time a further 17 strigolactones have been isolated.7
Frustratingly, these root exudates occur in extremely low
natural abundance curtailing assessment of their biological
functions and, in many instances, preventing unambiguous
stereochemical assignment of their structures.4 For this reason,
simplified strigolactones have been the target of much synthetic
effort. The most widely applicable of the synthetic analogues,
( )-GR24 (2) (Figure 1), was developed by Johnson and co-
workers and is routinely used as a positive control in plant- and
fungi-based assays.8
Since the initial report, the synthesis of ( )-GR24 (2) has
been steadily improved upon, most notably by Zwanenburg and
co-workers.9,10 Indeed it was Zwanenburg who identified that
the most active component of the racemate for seed
germination in the parasitic weeds Striga hermonthica and
Orobanche crenata possessed the same stereochemistry as
naturally occurring strigol (1) (Figure 1).11 Commercial
( )-GR24 (2) is routinely subjected to a time-consuming
enantioselective HPLC separation prior to biological applica-
tion.12 Therefore the asymmetric synthesis of (+)-GR24 (3) is
an important goal. As depicted in Scheme 1, published
approaches fall into one of three categories: coupling two
racemic fragments ( )-4 and ( )-5 with an enantioselective
Received: December 8, 2013
Published: January 14, 2014
© 2014 American Chemical Society
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Note
batches. The aldehyde 11 readily participated in an intra-
molecular Stetter reaction to give the indanone 13 in good
yield. Although asymmetric variants of the intramolecular
Stetter reaction are known,22,23 we were concerned that the
lability of the hydrogen appended to C2 of the indanone 13
may diminish the level of enantiocontrol by facile epimeriza-
tion. Rather than tempering the reactivity at that position, we
elected to embrace it to facilitate a DKR. Treatment of 13 with
Noyori’s (S,S)-RuTsDPEN catalyst under transfer hydro-
genation conditions delivered the bicyclic ketone (+)-4 in
90% yield and 92% ee, which was improved to >99% ee after a
single recrystallization (see Supporting Information). The
lactone was formylated, and the D-ring ( )-6 was appended
to deliver (+)-GR24 (3) and epi-(+)-GR24 (15).
Scheme 2. Previous Enantioselective Synthesis of (+)-GR24
(3)
As depicted in Scheme 4, the corresponding (R,R)-
RuTsDPEN catalyst was employed with equal facility to deliver
Scheme 4. Enantioselective Synthesis of (−)-GR24 (17)
generate the desired isomer in 8 steps and 92% ee. (Scheme 2).
It is clear that if (+)-GR24 (3) were to be used on a large scale,
a more practical synthesis would need to be developed. We
now detail a rapid, scalable, and enantioselective synthesis of
(+)-GR24 (3).
As strigolactones have recently demonstrated promise in
medicinal settings,16 we anticipated that access to both
enantiomers of GR24 may be beneficial for future SAR
investigations and that any route that we developed ought to
be flexible enough to allow the generation of substituted
analogues. As such we elected to employ a dynamic kinetic
resolution (DKR) as the enantioselective step in our strategy.17
As shown in Scheme 3, readily available and inexpensive indene
(10) was subjected to ozonolytic cleavage, and the correspond-
ing dialdehyde engaged in a chemoselective Wittig olefination
to give the product in 56% overall yield (based on the
phosphorane).18−21 In this way 11 could be accessed in >2.5 g
lactone (−)-4,24 which was elaborated to (−)-GR24 (16) and
epi-(−)-GR24 (17) by the same sequence of reactions.
Finally, we united the enantiomerically pure A−C fragment
(+)-4 with the D-ring ( )-5 using Trost’s stereoselective
palladium coupling protocol employing both enantiomers of
the DACH-phenyl ligand.13,25,26 As shown in Scheme 5, there
was a clear matched, mismatched scenario in which the level of
diastereoselectivity was greater for the formation of epi-
(+)-GR24 (15). The same trend was observed when (−)-4
was employed for the coupling. However, as both reactions
Scheme 3. Enantioselective Synthesis of (+)-GR24 (3)
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Note
Scheme 5. Enantioselective Synthesis of (−)-GR24 (17)
chromatography, eluting with 10% ethyl acetate in hexanes, to give
returned a diastereomeric mixture, this protocol offers little
advantage over the method outlined in Schemes 3 and 4.
In conclusion, we report a short, scalable, enantioselective
synthesis of the synthetic strigolactone (+)-GR24 (3). By
utilizing a Noyori asymmetric reduction for a DKR, the
generation of either enantiomer of the A−C fragment (+)-4 or
(−)-4 can be achieved in just 4 synthetic operations. The D-
ring ( )-5 can be appended under classical or catalytic
conditions to deliver enantiomerically pure (+)-GR24 (3).
Any other isomer of this important plant-signaling mimic can
be generated using a common synthetic sequence. The
resolution bottleneck has been circumvented, and the routine
application of single enantiomer (+)-GR24 (3) as a positive
control across the plant sciences is now possible.
13 (1.23 g, 95%) as a yellow oil: IR (cm−1) 2983, 1708, 1609, 1466,
1
1373, 1294, 1279, 1217, 1174, 1029; H NMR (300 MHz; CDCl3)
7.77 (1 H, d, J 7.5), 7.59 (1 H, m), 7.45 (1 H, d, J 7.8), 7.37 (1 H, m),
4.13 (2 H, q, J 7.2), 3.45 (1 H, dd, J 7.8, 17.1), 3.06−2.85 (3 H, m),
2.62 (1 H, dd, J 16.2, 8.1), 1.21 (3 H, t, J 7.2); 13C NMR (75 MHz;
CDCl3) 206.9 (C), 172.1 (C), 153.4 (C), 136.5 (C), 135.0 (CH),
127.6 (CH), 126.6 (CH), 124.1 (CH), 60.9 (CH2), 43.7 (CH), 35.4
(CH2), 33.1 (CH2), 14.3 (CH3); HRMS (ESI) Found MNa+
241.08317, C13H14O3 + Na requires 241.08352.
(3aR,8bS)-3,3a,4,8b-Tetrahydro-2H-indeno[1,2-b]furan-2-
one (+)-4. Dichloro(p-cymene)ruthenium(II) dimer (84 mg, 0.14
mmol) and (1S,2S)-(+)-N-p-tosyl-1,2-diphenylethylenediamine (100
mg, 0.27 mmol) were taken up in isopropanol (7 mL). Triethylamine
(77 μL, 0.55 mmol) was added, and the reaction mixture was stirred at
80 °C for 1.5 h. The solvent was removed in vacuo to give (S,S)-
RuTsDPEN, which was used in the following step. Formic acid (1.30
mL) and Hunig’s base (2.39 mL) were mixed at 0 °C. After 15 min, a
̈
EXPERIMENTAL SECTION
■
solution of ketone (1.50 g, 6.9 mmol) in dichloromethane (7 mL) was
added via cannula, followed by a solution of (S,S)-RuTsDPEN,
prepared above, in dichloromethane (5 mL). The dichloromethane
was removed under nitrogen flow, and the solution was stirred
overnight at 40 °C. Saturated aqueous sodium hydrogen carbonate was
added (15 mL). The aqueous phase was extracted with ethyl acetate
(3× 15 mL). The combined organic extracts were then washed with
brine and dried over anhydrous Na2SO4, and the solvent was removed
in vacuo. The residue was taken up in dichloromethane (10 mL),
pyridinium para-toluenesulfonate (170 mg) was added, and the
reaction mixture was heated at reflux overnight. The solvent was
removed in vacuo, and the residue was purified by column
chromatography, eluting with 20% ethyl acetate in hexanes, to give
(+)-4 (1.08 g, 90%) as colorless crystals, which were recrystallized
High resolution mass spectra were recorded on a Fourier transform
ion cyclotron resonance mass spectrometer with a 7.0 T magnet, fitted
with an off-axis electrospray source. The enantiopurity of compounds
was determined by chiral HPLC analysis using an AD-H or OD-H
column, and a dual λ absorbance detector (254 and 270 nm).
(E)-Ethyl 4-(2-formylphenyl)but-2-enoate (11). Indene (5.08 g,
43.7 mmol) was taken up in dichloromethane (70 mL) and treated
with ozone at −78 °C for 7 h. Triphenylphosphine (17.2 g, 65.6
mmol) was added, and the solution was stirred overnight. The solvent
was removed in vacuo. The residue was taken up in fresh
dichloromethane (80 mL), phosphonium ylide (6.94 g, 19.9 mmol)
was added, and the solution was stirred overnight. The solvent was
removed in vacuo, and the residue was purified by column
chromatography, eluting with pure hexanes followed by 10% diethyl
ether in hexanes, to give an inseparable 7:1 mixture of 11 and the bis-
alkene (2.9 g, 72%; 11 56%) as a pale yellow oil: IR (cm−1) 2983,
1711, 1694, 1651, 1599, 1574, 1368, 1267, 1158, 1037, 983; 1H NMR
(300 MHz; CDCl3) 10.08 (1 H, s), 7.76 (1 H, d, J 7.5), 7.43 (2 H, m),
7.20 (1 H, d, J 7.2), 7.06 (1 H, dt, J 15.6, 6.3), 5.64 (1 H, d, J 15.6),
4.08 (2 H, q, J 6.9), 3.90 (2 H, d, J 7.2), 1.18 (3 H, t, J 7.2); 13C NMR
(75 MHz; CDCl3) 192.5 (CH), 166.3 (C), 146.6 (CH), 139.8 (C),
134.0 (CH), 133.8 (C), 133.7 (CH), 131.5 (CH), 127.5 (CH), 122.7
(CH), 60.3 (CH2), 35.2 (CH2), 14.2 (CH3); HRMS (ESI) Found
MNa+ 241.08336, C13H14O3 + Na requires 241.08352. Minor isomer:
1H NMR (300 MHz; CDCl3) 6.28 (1 H, J 15.9), 4.19 (2 H, J 7.2),
3.58 (2 H, J 6.3), 1.26 (3 H, J 7.2).
Ethyl 2-(1-oxo-2,3-dihydro-1H-inden-2-yl)acetate (13). Tri-
azolium salt 12 (255 mg, 0.70 mmol) was taken up in THF (20 mL),
and the solution was bubbled with argon for 15 min. Triethylamine
(100 μL, 0.72 mmol) was added, and the solution was bubbled with
argon for an additional 5 min. A 7:1 mixture of 11 and the bis-alkene
(1.52 g; 5.97 mmol of 11) in THF (20 mL), which had been bubbled
with argon for 20 min, was added via cannula, and the solution was
stirred overnight. The reaction was quenched with saturated aqueous
ammonium chloride (20 mL). The aqueous phase was extracted with
ethyl acetate (3 × 20 mL). The combined organic extracts were
washed with brine and dried over anhydrous Na2SO4, and the solvent
was removed in vacuo. The residue was purified by column
from methanol: mp 93 °C; [α]D20 +110 (c 0.985, CHCl3), lit.14 [α]D
20
−107.0 (c 0.4, CHCl3); IR (cm−1) 2954, 1753, 1610, 1450, 1349,
1250, 1145, 990; H NMR (300 MHz; CDCl3); 7.49 (1 H, d, J 6.6),
1
7.38−7.29 (3 H, m), 5.90 (1 H, d, J 6.9), 3.41−3.28 (2 H, m), 2.96−
2.86 (2 H, m), 2.39 (1 H, dd, J 18.3, 5.4); 13C NMR (75 MHz;
CDCl3) 176.9 (C), 142.5 (C), 138.8 (C), 130.0 (CH), 127.6 (CH),
126.4 (CH), 125.3 (CH), 87.7 (CH), 37.9 (CH2), 37.3 (CH), 35.7
(CH2); HRMS (ESI) Found MNa+ 197.05728, C11H10O2 + Na
requires 197.05730.
(3aS,8bR)-3,3a,4,8b-Tetrahydro-2H-indeno[1,2-b]furan-2-
one (−)-4. Dichloro(p-cymene)ruthenium(II) dimer (34 mg, 5.6 ×
10−5 mol) and (1R,2R)-(+)-N-p-tosyl-1,2-diphenylethylenediamine
(40 mg, 0.11 mmol) were taken up in isopropanol (3 mL).
Triethylamine (31 μL, 0.22 mmol) was added, and the reaction
mixture was stirred at 80 °C for 1.5 h. The solvent was removed in
vacuo to give (R,R)-RuTsDPEN, which was used in the following step.
Formic acid (0.52 mL) and Hunig’s base (0.96 mL) were mixed at 0
̈
°C. After 15 min, a solution of ketone (600 mg, 2.75 mmol) in
dichloromethane (5 mL) was added via cannula, followed by a solution
of (R,R)-RuTsDPEN, prepared above, in dichloromethane (5 mL).
The dichloromethane was removed under nitrogen flow, and the
solution was stirred overnight at 40 °C. Saturated aqueous sodium
hydrogen carbonate (10 mL) was added. The aqueous phase was
extracted with ethyl acetate (3× 10 mL). The combined organic
extracts were then washed with brine and dried over anhydrous
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Note
Na2SO4, and the solvent was removed in vacuo. The residue was taken
up in dichloromethane (10 mL), pyridinium para-toluenesulfonate (70
mg) was added, and the reaction mixture was heated at reflux
overnight. The solvent was removed in vacuo, and the residue was
purified by column chromatography, eluting with 20% ethyl acetate in
hexanes, to give (−)-4 (380 mg, 80%) as colorless crystals, which were
ethyl acetate in hexanes. Recrystallization with ethyl acetate and
hexanes gave (−)-16 as colorless crystals (89 mg, 37%): mp 150−151
°C, lit.14 152.5−154.5 °C; lit.14 [α]D −451 (c 0.52, CHCl3), [α]D
20
20
−446 (c 0.25, CHCl3); IR (cm−1) 1780, 1746, 1681, 1349, 1327, 1209,
1182, 1159, 1090, 1046, 1017, 952; 1H NMR (300 MHz; CDCl3) 7.50
(2 H, m), 7.36−7.22 (3 H, m), 6.97 (1 H, s), 6.18 (1 H, s), 5.95 (1 H,
d, J 7.8), 3.94 (1 H, m) 3.44 (1 H, dd, J 16.8, 9.3), 3.10 (1 H, dd, J
17.0, 3.0), 2.04 (3 H, s); 13C NMR (75 MHz; CDCl3) 171.2 (C),
170.2 (C), 151.0 (CH), 142.6 (C), 140.9 (CH), 138.9 (C), 136.0 (C),
130.0 (CH), 127.5 (CH), 126.5 (CH), 125.1 (CH), 113.3 (C), 100.6
(CH), 85.9 (CH), 38.9 (CH), 37.3 (CH2), 10.7 (CH3); HRMS (ESI)
Found MNa+ 321.07341, C17H14O5 + Na requires 321.07334. (−)-17
as colorless crystals (100 mg, 42%): mp 130−131 °C, lit.14 133.5−134
°C; [α]D20 −285 (c 0.5, CHCl3), lit.14 [α]D20 −272 (c 0.2, CHCl3); IR
(cm−1) 1783, 1747, 1681, 1347, 1327, 1208, 1182, 1153, 1089, 1045,
1019, 952; 1H NMR (300 MHz; CDCl3) 7.49 (2 H, m), 7.36−7.22 (3
H, m), 6.97 (1 H, s), 6.19 (1 H, s), 5.95 (1 H, d, J 8.1), 3.93 (1 H, m)
3.42 (1 H, dd, J 17.1, 9.3), 3.09 (1 H, dd, J 16.8, 3.0), 2.03 (3 H, s);
13C NMR (75 MHz; CDCl3) 171.3 (C), 170.3 (C), 151.1 (CH), 142.7
20
recrystallized from methanol: mp 93 °C; [α]D −109 (c 0.985,
CHCl3), lit.14 [α]D +102.5 (c 0.4, CHCl3); H NMR (300 MHz;
CDCl3); 7.49 (1 H, d, J 7.2), 7.38−7.29 (3 H, m), 5.89 (1 H, d, J 6.9),
3.43−3.28 (2 H, m), 2.95−2.86 (2 H, m), 2.39 (1 H, dd, J 18.0, 5.4);
13C NMR (75 MHz; CDCl3) 176.8 (C), 142.5 (C), 138.8 (C), 130.0
(CH), 127.6 (CH), 126.4 (CH), 125.3 (CH), 87.7 (CH), 37.9 (CH2),
37.3 (CH), 35.7 (CH2).
20
1
(+)-GR24 (3) and (+)-epi-GR24 (15). To a solution of (+)-4 (650
mg, 3.73 mmol) in methyl formate (20 mL) was added potassium tert-
butoxide (2.1 g 18.7 mmol), in two portions, under nitrogen flow, at 0
°C. The reaction mixture was stirred overnight. The reaction was
quenched with hydrochloric acid (1.0 M, 25 mL), and the aqueous
phase was extracted with ethyl acetate (3 × 25 mL). The combined
organic extracts were then washed with brine and dried over
anhydrous Na2SO4, and the solvent was removed in vacuo. The
colorless solid residue and potassium carbonate (570 mg, 4.12 mmol)
were taken up in DMF (8 mL), and a solution of the ( )-6 (990 mg,
5.60 mmol), in DMF (5 mL), was added via cannula at 0 °C. The
solution was stirred overnight. The reaction was quenched with
saturated aqueous ammonium chloride (20 mL). The aqueous phase
was extracted with ethyl acetate (3 × 20 mL). The combined organic
extracts were then washed with water (2 × 30 mL) and brine and dried
over anhydrous Na2SO4, and the solvent was removed in vacuo. The
residue was purified by column chromatography, eluting with 50%
ethyl acetate in hexanes, to give (+)-3 as colorless crystals (418 mg,
(C), 141.1 (CH), 138.8 (C), 135.8 (C), 130.0 (CH), 127.5 (CH),
126.4 (CH), 125.3 (CH), 113.4 (C), 100.7 (CH), 85.9 (CH), 38.8
(CH), 37.4 (CH2), 10.7 (CH3); HRMS (ESI) Found MNa+
321.07336, C17H14O5 + Na requires 321.07334.
(+)-GR24 (3) and (+)-epi-GR24 (15) via an Asymmetric O-
Alkylation Procedure.13 To a solution of (+)-4 (110 mg, 0.63
mmol) in methyl formate (7 mL) was added potassium tert-butoxide
(360 mg 3.20 mmol) at 0 °C. The reaction mixture was stirred
overnight. The reaction was quenched with hydrochloric acid (1.0 M;
10 mL), and the aqueous phase was extracted with ethyl acetate (3 ×
15 mL). The combined organic extracts were then washed with brine
and dried over anhydrous Na2SO4, and the solvent was removed in
vacuo. The residue was purified by column chromatography, eluting
with 30% ethyl acetate in hexanes, to give the desired enol (118 mg
38%): mp 151−152 °C, lit.14 154−155 °C; [α]D +443 (c 0.51,
20
CHCl3), lit.14 [α]D +436 (c 0.25, CHCl3); IR (cm−1) 1781, 1746,
20
20
1681, 1344, 1327, 1208, 1181, 1154, 1089, 1044, 1017, 952; 1H NMR
(300 MHz; CDCl3) 7.49 (2 H, m), 7.35−7.22 (3 H, m), 6.97 (1 H, s),
6.19 (1 H, s), 5.93 (1 H, d, J 8.1), 3.93 (1 H, m) 3.43 (1 H, dd, J 17.1,
9.3), 3.10 (1 H, dd, J 16.8, 3.0), 2.02 (3 H, s); 13C NMR (75 MHz;
CDCl3) 171.3 (C), 170.3 (C), 151.1 (CH), 142.6 (C), 141.1 (CH),
138.9 (C), 135.9 (C), 130.0 (CH), 127.5 (CH), 126.4 (CH), 125.2
(CH), 113.2 (C), 100.7 (CH), 85.9 (CH), 38.9 (CH), 37.3 (CH2),
10.7 (CH3); HRMS (ESI) Found MNa+ 321.07335, C17H14O5 + Na
requires 321.07334. (+)-15 as colorless crystals (529 mg, 48%): mp
131−132 °C, lit.14 133.5−134.5 °C; [α]D20 +292 (c 0.50, CHCl3), lit.14
[α]D20 +273 (c 0.2, CHCl3); IR (cm−1) 1781, 1746, 1680, 1338, 1326,
1208, 1181, 1154, 1086, 1046, 1017, 951; 1H NMR (300 MHz;
CDCl3) 7.49 (2 H, m), 7.36−7.22 (3 H, m), 6.97 (1 H, s), 6.18 (1 H,
s), 5.95 (1 H, d, J 8.1), 3.94 (1 H, m) 3.42 (1 H, dd, J 16.8, 9.3), 3.09
(1 H, dd, J 17.0, 3.0), 2.03 (3 H, s); 13C NMR (75 MHz; CDCl3)
171.3 (C), 170.3 (C), 151.1 (CH), 142.6 (C), 141.1 (CH), 138.8 (C),
135.9 (C), 130.0 (CH), 127.5 (CH), 126.4 (CH), 125.2 (CH), 113.4
(C), 100.7 (CH), 85.9 (CH), 38.8 (CH), 37.4 (CH2), 10.7 (CH3);
HRMS (ESI) Found MNa+ 321.07326, C17H14O5 + Na requires
321.07334.
92%) as a colorless solid: mp 126−127 °C; [α]D +439 (c 0.5,
MeOH); IR (neat)/cm−1 3027 (br), 2739, 1706, 1622, 1605, 1481,
1460, 1412, 1381, 1343, 1330, 1200, 1154, 1080; 1H NMR (300 MHz;
DMSO-d6) 11.24 (1 H, br), 7.51 (1 H, d, J 2.1), 7.45 (1 H, d, J 7.2),
7.31 (3 H, m), 5.91 (1 H, d, J 7.8), 3.90 (1 H, m), 3.36 (1 H, dd, J 9.0,
17.0), 3.03 (1 H, dd, J 2.4, 17.0); 13C NMR (75 MHz; DMSO-d6)
172.1 (C), 154.0 (CH), 143.0 (C), 139.8 (C), 129.5 (CH), 127.0
(CH), 126.0 (CH), 125.3 (CH), 105.9 (C), 84.4 (CH), 38.1 (CH),
37.0 (CH2); m/z (ESI) 203 (MH+, 100%), 220 ([M + H2O]+, 58). A
solution of ( )-5 (106 mg, 0.49 mmol), tris(dibenzylideneacetone)
dipalladium(0) (6.8 mg, 7.4 × 10−6 mol) and either (S,S) or (R,R)-
DACH-phenyl-Trost ligand (16.2 mg, 2.2 × 10−5 mol) in dichloro-
methane (1 mL) was degassed, and the solution was stirred for 20 min.
Triethylamine (35 μL, 0.25 mmol) and the synthesized enol (50 mg,
0.25 mmol) were added, and the reaction mixture was stirred for 1 h.
The mixture was purified directly by column chromatography, eluting
with 40% ethyl acetate in hexanes, to give (+)-GR24 (3) (39 mg, 53%
with (S,S) ligand; 5 mg, 7% with (R,R) ligand) and (+)-epi-GR24 (15)
(9 mg, 12% with (S,S) ligand; 45 mg, 61% with (R,R) ligand).
(−)-GR24 (16) and (−)-epi-GR24 (17) via an Asymmetric O-
Alkylation Procedure.13 To a solution of (−)-4 (247 mg, 1.42
mmol) in methyl formate (12 mL) was added potassium tert-butoxide
(955 mg 8.51 mmol), at 0 °C. The reaction mixture was stirred
overnight. The reaction was quenched with hydrochloric acid (1.0 M;
20 mL), and the aqueous phase was extracted with ethyl acetate (3 ×
20 mL). The combined organic extracts were then washed with brine
and dried over anhydrous Na2SO4, and the solvent was removed in
vacuo. The residue was purified by column chromatography, eluting
with 30% ethyl acetate in hexanes, to give the desired enol (266 mg,
(−)-GR24 (16) and (−)-epi-GR24 (17). To a solution of (−)-4
(140 mg, 0.80 mmol) in methyl formate (7 mL) was added potassium
tert-butoxide (450 mg, 4.0 mmol) under nitrogen flow, at 0 °C. The
reaction mixture was stirred overnight. The reaction was quenched
with hydrochloric acid (1 M, 10 mL), and the aqueous phase was
extracted with ethyl acetate (3 × 10 mL). The combined organic
extracts were then washed with brine and dried over anhydrous
Na2SO4, and the solvent was removed in vacuo. The colorless solid
residue and potassium carbonate (122 mg, 0.88 mmol) were taken up
in DMF (3 mL), and a solution of ( )-6 (213 mg, 1.2 mmol), in DMF
(2 mL), was added via cannula at 0 °C. The solution was stirred
overnight. The reaction was quenched with saturated aqueous
ammonium chloride (10 mL). The aqueous phase was extracted
with ethyl acetate (3 × 10 mL). The combined organic extracts were
then washed with water (2 × 20 mL) and brine and dried over
anhydrous Na2SO4, and the solvent was removed in vacuo. The
residue was purified by column chromatography, eluting with 50%
20
93%) as a colorless solid: mp 129−131 °C; [α]D − 479 (c 0.5,
MeOH); IR (neat)/cm−1 3027 (br), 2738, 1700, 1671, 1605, 1480,
1460, 1440, 1409, 1381, 1343, 1330, 1266, 1241, 1205, 1189, 1153,
1083; 1H NMR (300 MHz; DMSO-d6) 11.24 (1 H, br), 7.51 (1 H, d, J
2.1), 7.45 (1 H, d, J 7.2), 7.31 (3 H, m), 5.91 (1 H, d, J 7.8), 3.90 (1 H,
m), 3.36 (1 H, dd, J 9.0, 17.0), 3.03 (1 H, dd, J 2.4, 17.0); 13C NMR
(75 MHz; DMSO-d6) 172.1 (C), 153.9 (CH), 143.0 (C), 139.8 (C),
129.5 (CH), 127.0 (CH), 126.0 (CH), 125.3 (CH), 105.9 (C), 84.4
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dx.doi.org/10.1021/jo402722p | J. Org. Chem. 2014, 79, 1516−1520

The Journal of Organic Chemistry
Note
(CH), 38.1 (CH), 37.0 (CH2); m/z (ESI) 203 (MH+, 100%), 220
([M + H2O]+, 75). A solution of ( )-5 (106 mg, 0.49 mmol),
tris(dibenzylideneacetone) dipalladium(0) (6.8 mg, 7.4 × 10−6 mol)
and either (S,S) or (R,R)-DACH-phenyl-Trost ligand (16.2 mg, 2.2 ×
10−5 mol) in dichloromethane (1 mL) was degassed, and the solution
was stirred for 20 min. Triethylamine (35 μL, 0.25 mmol) and the
synthesized enol (50 mg, 0.25 mmol) were added, and the reaction
mixture was stirred for 1 h. The mixture was purified directly by
column chromatography, eluting with 40% ethyl acetate in hexanes, to
give (−)-GR24 (16) (5 mg, 7% with (S,S) ligand; 40 mg, 54% with
(R,R) ligand) and (−)-epi-GR24 (17) (46 mg, 62% with (S,S) ligand;
9 mg, 12% with (R,R) ligand).
(20) Schnatter, W. F. K.; Almarsson, O.; Bruice, T. C. Tetrahedron
1991, 47, 8687.
̈
(21) The level of chemoselectivity for this Wittig reaction displayed
an inverse temperature effect that we do not yet understand. At room
temperature 11 was the sole product, whereas at lower temperature,
mixtures of 11 and the corresponding diester were obtained in ratios
ranging from 5:1−1:4.
(22) de Alaniz, J. R.; Rovis, T. Synlett 2009, 1189.
(23) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606.
(24) The measured values of optical rotation for compounds(+)-4
and (−)-4 were of opposite sign to that reported in ref 14. Since all
other compounds were in excellent agreement with the values reported
in ref 13 and ref 14, and since compound (+)-4 was unambiguously
transformed into (+)-GR24 and (−)-4 was transformed into
(−)-GR24, we attribute this minor inconsistency to a typographical
error. See the Supporting Information.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra, HPLC traces. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) Trost, B. M.; Vanvranken, D. L.; Bingel, C. J. Am. Chem. Soc.
1992, 114, 9327.
(26) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
AUTHOR INFORMATION
Corresponding Author
*Fax: +61 2 9351 3329. Tel: +61 2 9351 3970. E-mail:
christopher.mcerlean@sydney.edu.au.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Australian Research Council
(DP120102466) for financial support and Prof. Koichi
Yoneyama for useful discussions. L.J.B. acknowledges receipt
of an Australian Postgraduate Award.
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