Asymmetric synthesis of the four stereoisomers of 5-deoxystrigol

Article abstract of DOI:10.1016/j.tetlet.2014.10.040

Two approaches to the strigolactone tricyclic lactone skeleton 2 were investigated using ketene/ketene-iminium cycloaddition to olefins. Finally, the first enantioselective access to the four stereoisomers of 5-deoxystrigol 1 is reported using an intramolecular [2+2] cycloaddition of homochiral ketene-iminium salts 5. Very high asymmetric control was achieved with C-2 symmetric pyrrolidines as chiral auxiliary.

Full text of DOI:10.1016/j.tetlet.2014.10.040

Tetrahedron Letters 55 (2014) 6577–6581
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of the four stereoisomers of 5-deoxystrigol
⇑
Mathilde Lachia, Pierre-Yves Dakas, Alain De Mesmaeker
Syngenta Crop Protection AG, Crop Protection Research, Research Chemistry, Schaffhauserstrasse 101, CH-4332 Stein, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2014
Revised 1 October 2014
Accepted 7 October 2014
Available online 13 October 2014
Two approaches to the strigolactone tricyclic lactone skeleton 2 were investigated using ketene/ketene-
iminium cycloaddition to olefins. Finally, the first enantioselective access to the four stereoisomers of
5-deoxystrigol 1 is reported using an intramolecular [2+2] cycloaddition of homochiral ketene-iminium
salts 5. Very high asymmetric control was achieved with C-2 symmetric pyrrolidines as chiral auxiliary.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Ketene/ketene-iminium
Strigolactone
Total synthesis
[2+2] Cycloaddition
Cyclobutanone
Strigolactones are a family of plant hormones, whose first mem-
ber, strigol, was isolated in the sixties for its effect on the germina-
tion of Striga seeds, a parasitic weed.1 Recently, their role as
signaling molecules in the rhizosphere and as plant hormone was
unveiled and strigolactones were found to be involved in control-
ling plant architecture (shoot and root branching), root growth,
secondary growth as well as germination.2
Strigolactones are derived from the carotenoid pathway, with
carlactone identified in 2012 as a key intermediate in the biosyn-
thesis, which is later converted to 5-deoxystrigol, the alleged par-
ent of the different members of the strigolactone family.3 Although
first isolated only in 2005 from Lotus japonicus,4 5-deoxystrigol 1
was prepared for the first time as an intermediate in the synthesis
of strigol in 1991, wherein the tricyclic lactone skeleton was
accessed by a Nazarov type cyclization.5 Since then, two other
approaches were reported involving also a Nazarov cyclization6
or a reductive carbon–carbon bond formation.7 However, to the
best of our knowledge, the enantioselective synthesis of 5-deoxy-
strigol has never been described.
which would result from the cycloaddition of a ketene 4 or
ketene-iminium salt 5 derived from the acid 6 or the amide 7.
Thus, commercially available 2,2-dimethylcyclohexanone 8 was
alkylated with allyl bromide. Then, the olefination of the ketone 9
is required to get the a,b-unsaturated ester. The standard Horner–
Wadsworth–Emmons reaction with phosphonate ester gave only
recovery of the starting material. Similar results were obtained
when attempting a Peterson olefination, due to the high hindrance
of the ketone 9. Recently, Dudley et al. have reported a two-step
procedure for the olefination of bulky ketones, based on
a
Meyer–Schuster rearrangement.9 The acetylenic organolithium
obtained by deprotonation of ethoxyacetylene was added to the
ketone 9, providing alcohol 10 in high yield. Then, the Lewis
acid-catalyzed Meyer–Schuster rearrangement afforded the
desired
a,b-unsaturated ester 11 as a 1:1 mixture of E and Z iso-
mers, which were easily separated by chromatography on silica
gel. Both AuCl3 and Sc(OTf)3 were very efficient as Lewis acids in
promoting this reaction. Esters-11 were hydrolyzed separately
without isomerization to acids (E)-6 and (Z)-6, which were coupled
with pyrrolidine to afford the corresponding amides (E)-7a and (Z)-
7a (see Scheme 2).
The [2+2] intramolecular cycloaddition of ketene-iminium salts
derived from amides 7a was attempted at first, because ketene-
iminium salts are more reactive than the corresponding ketenes.10
Unfortunately, starting material was recovered for both diastereo-
isomers (Scheme 3).
We have previously reported the use of asymmetric [2+2] cyclo-
addition to access (+)-GR-248 and we report here the extension of
this methodology to the asymmetric synthesis of the four stereo-
isomers of 5-deoxystrigol.
Our retrosynthetic analysis of (+)-5-deoxystrigol 1 and related
stereoisomers is depicted in Scheme 1. Lactone 2 could be accessed
via a regioselective Baeyer–Villiger oxidation of cyclobutanone 3,
The formation of ketene-iminium salts involving
tion of ,b-unsaturated amides has never been reported in the lit-
erature. On the contrary, reactions involving ,b-unsaturated
ketenes are well studied, in particular in the case of cyclopentene11
c-deprotona-
a
⇑
a
Corresponding author. Tel.: +41 628 660 268.
E-mail address: alain.de_mesmaeker@syngenta.com (A. De Mesmaeker).
http://dx.doi.org/10.1016/j.tetlet.2014.10.040
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6578
M. Lachia et al. / Tetrahedron Letters 55 (2014) 6577–6581
O
O
Me Me
O
Me Me
Me Me
O
O
O
Me Me
O
Me Me
C
X
X
O
O
Me
(+)-5-deoxystrigol 1
2
3
X=O (4) or
N+R1R2 (5)
X=OH (6)
or NR1R2 (7)
Scheme 1. Retrosynthetic analysis of (+)-5-deoxystrigol 1.
Me Me
O
Me Me
Me Me
OH
Me Me
Me Me
O
O
a
b
OEt
a, b
a, b
CO2H
8
9
10
(E)-6
3
CO2Et
Me Me
Me Me
O
O
Me Me
CO2H
O
Me Me
Me Me
c
d
CO2Et
+
c
(Z)-11
(E)-11
2
(Z)-6
3
Scheme 4. Intramolecular [2+2] cycloaddition of the ketene and synthesis of the
racemic lactone 2. Reagents and conditions: (a) Me2C@CClNMe2 (Ghosez reagent),
CH2Cl2; (b) Et3N (2.0 equiv), DMAP (1.0 equiv), CH2Cl2, reflux, 46%; (c) H2O2, AcOH,
92%.
Me Me
Me Me
O
OH
N
e
O
(E)-6 or (Z)-6
(E)-7a or (Z)-7a
and the acid chloride induces the rotation of the carbonyl group
out of the plane of the C@C bond, which results in their partial
deconjugation. This hypothesis is supported by the observed differ-
ence in stretching frequencies of the C@O in the IR spectra
(Scheme 5, compound (Z)-6 versus 12 and (E)-6 versus 13)19. Con-
Scheme 2. Preparation of the precursors for the intramolecular cycloaddition.
Reagents and conditions: (a) LiHMDS, allyl bromide, THF, ꢀ78 °C, 65%; (b)
ethoxyacetylene, n-BuLi, THF, ꢀ78 °C, then 9; 77%; (c) Sc(OTf)3 (5%), CH2Cl2, EtOH,
82%, E/Z = 1/1, separation of isomers; or AuCl3 (5%), CH2Cl2, EtOH, 90%; (d) NaOH,
THF/H2O, 95% (E)-11; quant. (Z)-11; (e) PyBop (1.1 equiv), pyrrolidine (1.1 equiv),
Hunig’s base (3.0 equiv), DMF, 87% (E)-7a or (Z)-7a.
sequently, the lower acidity of the
c proton disfavors the formation
of the ketene. In the case of the E isomer, we postulate that, due to
steric repulsion between the carbonyl and the allyl group, the lat-
ter adopts an axial orientation, reducing considerably the acidity of
Me Me
N
the
c proton, preventing the formation of the corresponding
ketene.
O
A solution to facilitate the formation of the ketene/ketene-imin-
ium salt would be to start from the deconjugated acid 12 or amides
O
Me Me
(E)-7a
Tf2O, collidine
CH2Cl2, r.t.
or
O
N
O
O
Me
H
Me Me
Me Me
Me Me
3
Me
C
C
O
O
γ
(E)-6
HO
ν= 1686 cm-1
O
4
3
IR (C=O)
(Z)-7a
Scheme 3. Attempted [2+2] cycloaddition of the ketene-iminium salts from amide
(E)-7a or (Z)-7a.
Me
H
Me Me
Me Me
Me HO
or cyclohexene ring.12 Thus, the cycloaddition of the ketene was
attempted on both (E)-6 and (Z)-6 separately (Scheme 4). After for-
mation of the acid chloride with Ghosez reagent, the ketene was
formed by deprotonation with triethylamine. To our surprise, the
E isomer did not react under these conditions and the starting acid
(E)-6 was recovered. Under the same conditions b the Z isomer
afforded cyclobutanone 3 in low yield, which could be further
improved up to 28% adding DMAP (Scheme 4).
The Baeyer–Villiger oxidation was nevertheless carried out and
the tricyclic lactone core structure 2 was obtained. At this stage,
our data fully matched the one reported in the literature.5
Although successful, this route was limited by the low yield of
the intramolecular ketene cycloaddition. In the case of the Z iso-
mer, we suspect that repulsion between the gem-dimethyl group
γ
O
O
(Z)-6
IR (C=O)
ν= 1693 cm-1
4
3
Me Me
O
OH
OH
12
13 (ref 19)
IR (C=O)
IR (C=O)
ν= 1700 cm-1
ν= 1688 cm-1
Scheme 5. Plausible conformational restrictions for ketene formation.

M. Lachia et al. / Tetrahedron Letters 55 (2014) 6577–6581
6579
21a–f. Unfortunately, we were not able to form the desired decon-
jugated ester 20 from neither E nor Z ester 11 under various reac-
tion conditions (including enolate formation followed by kinetic
protonation). Consequently, we considered a novel approach to
acid 12 from the commercially available Hagemann’s ester 14
(Scheme 6). Alkylation of ester 14 with ethyl bromoacetate was
straightforward13 and the resulting diester 15 was decarboxylated
in 2 steps: saponification of the ethyl esters followed by thermal
decarboxylation of the diacid. Attempts to carry out the 2 steps
in one pot failed in our hands, contrary to what was reported in
the literature.13 After protection of 16 as a benzyl ester 17 to secure
deprotection under neutral conditions avoiding any C@C bond
isomerization, addition of the lithium dimethyl cuprate allowed
the introduction of the gem-dimethyl group, and was followed
by in situ quench of the copper enolate with N-(5-chloro-2-pyri-
dyl)bis(trifluoromethane-sulfonimide) (Comins’ reagent).14 During
lithium dimethyl cuprate addition, low temperature (ꢀ20 °C) and
ether as the solvent induced the precipitation of the copper enolate
necessary to avoid the formation of lactone 19. Lowering the reac-
tion temperature below ꢀ20 °C prevents the reaction to occur. In
contrast, at room temperature the formation of 19 was observed
as minor component. Then, addition of THF as the co-solvent dur-
ing the reaction with Comins’ reagent allowed to restore the solu-
bility of the copper enolate and improved yield. Although sensitive
to solvents and temperature, high yields of the triflate 18 were
obtained, even on multi-gram scale. The triflate 18 was engaged
in a Stille coupling with allyltributyl stannane (Scheme 6). The
addition of LiCl was required to activate the stannane during the
transmetallation step and the reaction was best carried out in diox-
ane. The benzyl ester was then saponified to the acid 12.
When attempting the key cycloaddition step, we were delighted
that cyclobutanone 3 was formed in 82% yield (Scheme 7, condi-
tions a), confirming the hypothesis that the formation of the ketene
from acid 6 was the limiting step in our first approach (Scheme 4).
Encouraged by this result, we then considered the intramolecular
cycloaddition of the corresponding ketene-iminium salts because
asymmetric version of this reaction would provide an enantiose-
lective access to the tricyclic lactone 2. Asymmetric cycloadditions
of ketene-iminium salts were reported using pyrrolidine deriva-
tives with very high stereocontrol and in particular, C-2 symmetric
pyrrolidines were preferred in the case of intramolecular reac-
tion.15 Thus, acid 12 was coupled to different secondary amines
in good yields and the resulting amides 21a–f were submitted to
the conditions of the cycloaddition (Scheme 7 and Table 1). After
hydrolysis of the iminium salt, cyclobutanone 3 was converted to
lactone 2 as the enantiomeric excess was assessed at this stage.
To our delight, chiral induction was observed with substituted pyr-
rolidine derivatives and in particular (S,S)-2,5-bis(methoxy-
methyl)-pyrrolidine amide (S,S)-21f gave excellent control of the
selectivity (Table 1). Increasing the bulk of the amide led to very
long reaction time, with only 40% of the desired cylobutanone 3
isolated after 48 h from 21f and almost no conversion observed
after 2 days with the even more bulky (S,S)-2,5-bis(phenyl) -pyr-
rolidine amide 21e.
Consequently, the conditions were optimized on amide 21f to
improve its conversion. Increasing the temperature had no
O
O
O
O
a
b, c
CO2H
Me
d
CO2Bn
Me
e
CO2Et
Me
CO2Et
CO2Et
14
15
16
17
O
OTf
O
f
g
CO2Bn
12
+
CO2Bn
Me
Me
Me
Me
Me
Me
18
19
20
Scheme 6. Synthesis of the acid 12; Reagents and conditions: (a) NaOH, EtOH; then BrCH2CO2Et, quant.; (b) NaOH, EtOH/water; then HCl, quant.; (c) toluene/DMF, reflux,
quant.; (d) Cs2CO3, BnBr, DMF, 86%; (e) MeLi, CuI, Et2O, ꢀ20 °C to 0 °C, 30 min; then 17, ꢀ20 °C, 20 min; then N-(5-chloro-2-pyridyl)bis(trifluoromethane-sulfonimide), THF,
ꢀ20 °C to 0 °C, 15 min, quant; (f) allyltributyl stannane, Pd(PPh3)4, LiCl, dioxane reflux, 90%; (g) NaOH, dioxane/water, reflux, 86%.
O
O
O
Me Me
Me Me
Me Me
CO2H
O
O
Me Me
Me Me
O
O
O
a
e
+
+
+
O
O
12
3
23
2
24
Me Me
O
Me Me
O
b
d
+
R1
NR1R2
O
N+
R2
Me Me
Me Me
25
26
c
21a-f
22a-f
Scheme 7. Cycloaddition of ketene and ketene-iminium salts from acid 12; Reagents and conditions: (a) Me2C@CClNMe2 (Ghosez reagent), CH2Cl2, rt; then Et3N, reflux, 82%
(3 only); (b) R1R2NH, N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide hydrochloride, 1-hydroxy-7-azabenzotriazole, Et3N, CH2Cl2, rt; (c) Tf2O (2.0 equiv), collidine
(2.1 equiv), rt, CH2Cl2, 12 h; (d) H2O, CCl4, reflux; (e) H2O2, AcOH, rt.

6580
M. Lachia et al. / Tetrahedron Letters 55 (2014) 6577–6581
Table 1
Screening of different chiral amines for the asymmetric intramolecular cycloaddition of ketene-iminium salts from amides 21a–f
Amide
NR1R2
Yield of 21
Yield of 3+23
Ratio 3/23
ee of 2c
21a
82%
81%
11/1
—
N
MeO
21b
21c
76%
55%
58%
68%
10/1
11/1
46%
25%
N
Me
N
Ph
21d
95%
93%
11/1
0%
Me
Me
N
N
21e
81%
85%
85%
85%
<5%a
40%a
85%b
83%b
—
—
Ph
Ph
MeO
OMe
OMe
OMe
(S,S)-21f
(S,S)-21f
(R,R)-21f
5/1
5/1
5/1
91%
91%
89%
N
MeO
MeO
N
N
a
b
c
The reaction was carried out for 48 h.
2.0 equiv 2-fluoropyridine was used as a base.
Determined by chiral HPLC analysis.
dramatic effect on the reaction but increasing the reaction time up
to 10 days gave 3 in 69%. Formation of the ketene-iminium salt was
very slow and collidine could trap it reversibly and slow down the
overall reaction. Indeed, replacing collidine by the more bulky
2,6-di-tert-butyl-4-methylpridine or the non-nucleophilic 2-fluo-
ropyridine16 dramatically improved the conversion with a reaction
completed after 12 h and up to 85% of cyclobutanone 3 was
isolated with ee over 90%. As already observed in our previous
studies but nevertheless surprising,8 the ketene-iminium salt
cycloaddition was not completely regioselective and compound
23 was also formed. In addition, during the Baeyer–Villiger
oxidation, small amounts of epoxide 25 and 26 were also isolated
(up to 15%). In the case of amide (S,S)- or (R,R)-21f, the ratio
between 2:25:24 and 26 is 4.35:1:1.
stereochemistry was assigned by comparison with reported [a]
D
for lactone 2 and matched the expected stereochemistry reported
for these chiral lactones.17 The synthesis of the four stereoisomers
of the 5-deoxystrigol was completed in good yield and the diaste-
reoisomeric mixture of (+)-1 and (+)-epi-1 and of (ꢀ)-ent-1 and
(ꢀ)-ent-20-epi-1 were separated by reverse phase HPLC. Good
correlation was obtained between the [a]D values for the four ster-
eoisomers using our procedure and the ones from the literature.18
In contrast, significant decomposition of the compounds was
observed when silica gel was used during the final purification,
confirming the high sensitivity of 5-deoxystrigol to hydrolysis.
In summary, the cycloaddition methodology we developed pre-
viously for the synthesis of (+)-GR-24 and analogs proved success-
ful to access the natural product (+)-5-deoxystrigol. Indeed, we
report here the first enantioselective access to all four stereoiso-
mers of 5-deoxystrigol in 12 steps using easily scalable processes.
Finally, with these optimal conditions, both enantiomers of
lactone (+)- and (ꢀ)-2 were prepared (Scheme 8). The absolute
OMe
O
O
O
O
Me Me
Me Me
O
O
O
Me Me
O
c
a, b
O
N
Me Me
+
O
O
OMe
O
O
Me
Me
(S,S)-21f
(+)-2
91% ee
(+)-1
(+)-2'-epi-1
OMe
O
O
O
Me Me
Me Me
O
O
O
Me Me
O
a, b
c
O
N
Me Me
+
O
O
O
OMe
O
O
Me
Me
(R,R)-21f
(-)-2
89% ee
(-)-ent-1
(-)-ent-2'-epi-1
Scheme 8. Synthesis of the four isomers of 5-deoxystrigol. Reagents and conditions: (a) Tf2O (1.5 equiv), 2-fluoropyridine (2.0 equiv), CH2Cl2, rt, 12 h; then) H2O, CCl4, reflux,
12 h, 83–85%; (b) H2O2, AcOH, 0 °C to rt, 12 h, 92%; (c) t-BuOK, ethyl formate, THF, rt, 12 h; then 5-chloro-3-methyl furanone, rt, 2 h, 80–85%.

M. Lachia et al. / Tetrahedron Letters 55 (2014) 6577–6581
6581
5. (a) Frischmuth, K.; Samson, E.; Kranz, A.; Welzel, P.; Meuer, H.; Sheldrick, W. S.
Tetrahedron 1991, 47, 9793–9806; (b) MacAlpine, G.; Raphael, R. A.; Shaw, A.;
Taylor, A. W.; Wild, H. J. Chem. Soc., Perkin Trans. 1 1976, 410–416.
6. Reizelman, A.; Scheren, M.; Nefens, G. H. L.; Zwanenburg, B. Synthesis 2000, 13,
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Acknowledgement
We sincerely thank Juliane Huber for very skillful HPLC analyses
and separations.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
10.040.
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17. (+)-2 [a]D +33.8 (c, 0.433, CHCl3, 21 °C) measured for the sample with ee = 91%;
(ꢀ)-2
[
a
]
ꢀ31.2 (c, 0.633, CHCl3, 21 °C) measured for the sample with
D
ee = 89%. Hirayama, K.; Mori, K. Eur. J. Org. Chem. 1999, 2211–2217 (+)-2 [
a]
D
+45.0 (c, 0.630, CHCl3, 21 °C) reported with ee = 99.2%..
18. (+)-1 [
CH3CN, 32 °C); (ꢀ)-ent-1 [
ꢀ141.8 (c 0.533, CH3CN, 32 °C) measured for samples with ee = 100%.
a] a] +142.3 (c 0.363,
+225.4 (c 0.363, CH3CN, 32 °C); (+)-20-epi-1 [
D
D
a]
ꢀ242.2 (c 0.497, CH3CN, 32 °C); (ꢀ)-ent-2’-epi-1
D
[a]
D
Akiyama, K.; Ogasawara, S.; Ito, S.; Hayashi, H. Plant Cell Physiol. 2010, 5, 1104–
1117 (+)-1 [
a]D +296 (c 0.0453, CH3CN, 32 °C); (+)-2’-epi-1 [a]D +184 (c 0.0426,
CH3CN, 32 °C); (ꢀ)-ent-1 [
a
]
D
ꢀ294 (c 0.0462, CH3CN, 32 °C); (ꢀ)-ent-20-epi-1
[
a
]
ꢀ168 (c 0.0520, CH3CN, 32 °C) reported with ee = >99%..
D
19. Palaty, J.; Abbott, F. S. J. Med. Chem. 1995, 38, 3398–3406.