Acid-catalysed intramolecular addition of β-ketoesters to 1,3-dienes

Article abstract of DOI:10.1039/c6ob02122k

1,3-Dienyl β-keto esters are cyclised into bicyclolactones using the Bi(OTf)₃/TfOH catalytic system. This reaction represents a rare case of simultaneous C-C and C-O bond formation at positions 1 and 3 of a 1,3-diene. Application to the synthesis of ramulosin is presented.

Full text of DOI:10.1039/c6ob02122k

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ARTICLE
Acid-catalysed intramolecular addition of -ketoesters to 1,3-
dienes
Marie Vayer,a Weizhen Fang,a Régis Guillot,a Sophie Bezzenine-Lafollée,a Christophe Bour*a and
Received 00th January 20xx,
Accepted 00th January 20xx
Vincent Gandon*a
DOI: 10.1039/x0xx00000x
1,3-Dienyl -keto esters are cyclised into bicyclolactones using the Bi(OTf)3/TfOH catalytic system. This reaction represents
a rare case of simultaneous C-C and C-O bond formation at positions 1 and 3 of a 1,3-diene. Application to the synthesis of
ramulosin is presented.
www.rsc.org/
acts as a dinucleophile through the methylene carbon and one
oxygen, and the 1,3-diene as a dielectrophile, giving rise to
synthetically useful bicyclolactones of type hexahydro-1H-
isochromene-1,8(8aH)-dione. This diketo framework or the
corresponding keto-enol form, as well as closely related ones
such as the octahydro-1H-isochromen-1-one motif can be
found in a variety of natural products including ramulosin,5a
terretonin C,5b ricciocarpin A,5c actinobolin,5d bactobolin5e and
salvinorin,5f which exhibit a broad spectrum of antibiotic and
neurobiological activities (Scheme 2).
Introduction
Controlling the reactivity of ambident nucleophiles with
ambident electrophiles remains a great challenge in organic
synthesis.1 We have recently shown that the sequential calcium-
catalysed/organocatalysed condensation of propargyl alcohols
tethered to
compounds by selecting the nucleophilic site, i.e. a carbon or an
oxygen of the -keto ester, and the electrophilic site, i.e. an
-keto esters could lead to valuable cyclic

alkyne or the hydroxylated carbon of the propargyl alcohol
moiety (Scheme 1, eq (1)).2 Here, we describe a rare type of 1,3-
addition
hydroalkylation/hydroalkoxylation tandem reaction of 1,3-
dienyl
-keto esters (Scheme 1, eq (2)).3
to
1,3-dienes
resulting
from
the

Scheme 1. Condensation of -keto esters to propargyl alcohols (eq (1)) and to 1,3-
dienes (eq (2)).
Scheme 2. Natural compounds containing the octahydro-1H-isochromen-1-one
framework.
The two-step addition of carboxylic acids to conjugated dienes
to give lactones has been previously described under harsh and
not catalytic reaction conditions, using sodium and then excess
Results and discussion
H2SO4 in refluxing benzene.4 In our case, the
-keto ester moiety
Our model compound to develop the proposed condensation
was the oxo-dienoate
from commercially available (2E,4E)-hexa-2,4-dien-1-ol,
converted into the corresponding bromide with PBr3, and
methyl 4-methyl-3-oxopentanoate
3 (Scheme 3). It was readily obtained
a.Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Univ.
Paris-Sud, Université Paris-Saclay, bâtiment 420, 91405 Orsay cedex (France).
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
1
2
.
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wet 1,2-dichloroethane (DCE, up to 1780 ppm oVfiewwaArtteicrle),Ontlhinee
proportion of
5
dropped to 17% (entrDyO3I:)1.0T.1h0e39/NCi6gOgBe0m21a2n2nK
catalytic system Ca(NTf2)2/nBu4PF6,9 which we had used
previously as in Scheme 1, eq (1)2 or in other transformations,10
did not lead to
tested in wet toluene (entries 5-10). Among them, Bi(OTf)3 gave
the best ratio for (entry 10, 29/71). The superiority of Bi(OTf)3
5 (entry 4). A series of metal triflates was next
5
over other metal triflates for the activation of polyenes11
especially 1,3-dienes has also been observed in
dihydroarylation reactions.12 Lowering the temperature to 80 °C
Scheme 3. Typical synthesis of a 1,3-dienyl -keto ester.
resulted in the exclusive formation of
Dealkylating lactonisations with an excess of TfOH have been
reported.13 In the present case, the use of only 5 mol% TfOH in
5 in 80% yield (entry 11).
Various catalytic conditions were screened (Table 1). Following
our study on the hydroalkylation of unactivated alkenes with
keto amides,6 the (JohnPhos)AuCl/Cu(OTf)2 catalytic system7
was first tested in toluene at 110 °C (entry 1). Product , arising
from the hydroalkylation of the internal diene double bond by
the -keto ester, was accompanied by the desired lactonisation
product , yet as minor component of the mixture (80/20).

-
wet toluene at 110 °C furnished
(entry 12). On the other hand,
5
4
as a sole product in 65% yield
was obtained selectively with
4
Tf2NH in 99% yield (entry 13). The yield of 5 could be appreciably

increased to 76% by using a catalytic mixture of Bi(OTf)3 and
TfOH (entry 14). With other Brønsted acids, the level of
selectivity was lower (entries 15-18). Lastly, it should be
mentioned that the reaction does not work with the 1,3-dienyl
5
Table
1.
Optimisation
studies
for
the
intramolecular
tandem
hydroalkylation/hydroalkoxylation of the 1,3 dienyl -keto ester 3.a

-keto acid corresponding to
3, nor the corresponding benzyl
amide.
On the basis of this optimisation study, the Bi(OTf)3/TfOH
catalytic system was selected and the reaction of
monitored by GC. It revealed that full conversion of into
achieved within 15 min. After 3 h, the
and after 8 h, only was detected as an 86/14 mixture of
stereoisomers (Table 2, entry 1). The structure of the major
diastereomer of could be unambiguously established by 2D
NOE NMR experiments and also by an X-ray diffraction study
(Figure 1).‡ Substrate was then tested (entry 2). It differs from
regarding the position of the diene fragment, which is internal
in and terminal in . However, the same product was
3
4
was
was
Entry
Cat.
Solvent
tolf
T °C
4/5b
% Yield
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Au/Cuc
110
110
80
80/20
47/53
83/17
100/0
41/59
66/34
88/12
78/22
86/14
29/71
100/0
0/100
100/0
0/100
86/14
82/18
40/60
4/5 ratio became 30/70,
Au/Cuc
wet tolg
wet DCEh
wet tolg
wet tolg
wet tolg
wet tolg
wet tolg
wet tolg
wet tolg
wet tolg
wet tolg
wet tolg
wet tolg
wet tolg
wet tolg
wet tolg
5
Au/Cuc
d
Ca(NTf2)2/nBu4PF6
Cu(OTf)2
110
110
110
110
110
110
110
80
110
110
110
110
110
110
5
AgOTf
Al(OTf)3
Ga(OTf)3
In(OTf)3
Bi(OTf)3
Bi(OTf)3
TfOH
Tf2NH
6
3
3
6
5
obtained, albeit in lower yield.§ Similarly, the intramolecular
tandem hydroalkylation/hydroalkoxylation of the constitutional
isomers 7 and 9 gave the same product 8 in 58% and 79% yield
80
65
99
76
respectively at 80 °C (entries 3 and 4). Changing the gem-
dimethyl carbon tether by a cyclohexyl as in 10 resulted in the
formation of 11, isolated in 53% yield as a single diastereomer
(entry 5). When only one methyl is present in the carbon tether,
as in 12, the conversion into 13 is moderate (entry 6). This is
likely to be due to the absence of gem-dialkyl (or Thorpe-Ingold)
effect. The major diastereomers remain trans as noted.
Complete diastereoselectivity was observed from substrate 14
(entry 7). On the other hand, but not surprisingly, no
Bi(OTf)3/TfOHe
Bi(OTf)3/Tf2NHe
Bi(OTf)3/PTSAe
Bi(OTf)3/MsOHe
a Reactions were run in the presence of 5 mol% catalyst at c = 0.15 M, unless stated
otherwise. b Ratio determined by 1H NMR. c (JohnPhos)AuCl (5 mol%), Cu(OTf)2 (10
mol%). d Ca(NTf2)2 (5 mol%), nBu4PF6 (7 mol%). e 5 mol% each. Karl Fischer titrations
(highest of 3 measurements), water content: f < 5 ppm, g < 290 ppm, h < 1780 ppm.
diastereoselection occurred between alkyl groups in 17 and 19
,
Since the formation of 5 likely involves the loss of methanol, we
which were obtained in 71% and 42% yield respectively in a 1/1
ratio (entries 8-9). Nevertheless, these examples show that the
title reaction is able to generate quaternary centers from 1,3-
dienes. The structure of one of the diastereomer of 17 was
ascertained by X-ray analysis (Figure 1).‡ Lastly, with compound
20, which is a homolog of 5 and 8, the expected product 21 was
obtained in 52% yield with a good diastereoselectivity (entry
10).
reasoned that the presence of exogenous water would favour
it.8 Adding controlled amounts of water directly in toluene (1,
10 and 100 equiv) increased indeed the proportion of
5 but it
went along with extensive decomposition. To avoid the
presence of droplets of water, toluene was humidified in a
separatory funnel by vigorous shaking with water, decanted,
collected, and used as such. This technique gave a water
content up to 290 ppm against 5 ppm for distilled toluene (Karl
Fischer titration). With this wet toluene, the ratio was still in
favour of 5 (47/53) and no decomposition occurred (entry 2). In
2 | J. Name., 2012, 00, 1-3
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Table 2. Scope studies of Bi(OTf)3/TfOH-catalysed intramolecular addition of -keto
esters to 1,3-dienes.a
View Article Online
DOI: 10.1039/C6OB02122K
En
try
Substrate
Product
(major
isomer)
% Yield
(d.r.)b
Time
(h)
T °C
110
76
(86/14)
Figure 1. Crystal structures of the major diastereomer of
5 (left) and of one
1
2
3
8
8
9
diastereomer of 17 (right) (thermal ellipsoids at 50% probability level).
3
6
5
5
Of note, the analog of 20 with a phenyl group instead of a
methyl group at the terminal diene position decomposed under
reaction conditions. Degradation of the substrate was also
observed with a methyl group at the activated methylene
54
(82/18)
110
80
fragment of the
Interestingly, compounds

-keto ester framework.
14 and 4 others have been used
58
(-)
6, 9,
as substrates for oxidative Pd(OAc)2-catalysed intramolecular
cyclopropanation (Scheme 4, eq (1)).14 Under similar conditions,
1,2-aminoalkylation of 1,3-dienes such as 23 have been
described (eq (2)).15 In the two cases, the coordination of Pd to
the internal diene double bond triggers first a nucleophilic
attack (of the activated methylene in eq (1) and of the amino
8
8
7
9
84
(-)
4
5
6
7
80
110
110
80
5
group in eq (2)) which results in the formation of a
-allyl
53
(100/0)
12
24
24
palladium species. Then, it undergoes a second nucleophilic
attack, by the same nucleophile in the first example and by the
activated methylene group in the second one.
10
11
31
(80/20)
12
14
13
15
67
(100/0)
71
(50/50)
8
80
4
17
19
16
Scheme 4. Pd-catalysed cyclopropanation of 1,3-dienyl
12) and 1,2-aminoalkylation of 1,3-dienes (eq (2), ref 13).
-keto esters (eq (1), ref
42
(50/50)
9
50
5
18
20
Our method, which transforms the two double bonds of the
dienes, is thus complementary to these two reactions and
further expands the scope of 1,3-dienyl -keto esters. To show
its utility, the title reaction was applied to the synthesis of a
natural product: ramulosin, which is a metabolite from an
endophytic fungus (Scheme 5).16 Because substrate 25 does not
benefit from a gem-dialkyl effect to assist its cyclisation, side
52
(90/10)
10
110
24
21
a See Supporting Information for details on substrate synthesis. Reactions were run
in the presence of 5 mol% Bi(OTf)3 and 5 mol% TfOH in wet toluene (0.15 M) at 110
°C, see note §§. b Diastereomeric ratio determined by 1H NMR; structure of the reactions took place leading to extensive decomposition with
major isomer obtained by X-ray crystallography for 5, 17, and by NOESY
the Bi(OTf)3/TfOH catalytic system. Nevertheless, using TfOH as
catalyst, the 26/27 diastereomeric mixture was isolated in a
experiments for the others.
reasonable 44% yield. The major isomer proved to be ramulosin
as desired.
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Conclusions
We have developed a new transformation of 1,3-dienyl
View Article Online

DOI: 10.1039/C6OB0-2k1e22toK
esters which exploits two nucleophilic sites of the -keto ester
fragment (C and O) and two not contiguous nucleophilic sites of
the diene moiety. The result is a rare type of simultaneous C-C
and C-O bond formation at positions 1 and 3 of 1,3-dienes
leading to an interesting scaffold that can be found in natural
products such as ramulosin and its derivatives. Efforts directed
towards the enantioselective version of this reaction are
underway.
Scheme 5. Synthesis of ramulosin.
A mechanistic scenario for the title reaction shown in Scheme
6. From
A
, we postulate the formation of the regioisomeric allyl
or
by addition of Bi3+ or H+ to the diene fragment.17
, which is the most highly substituted regioisomer, is
expected to prevail. This would explain why compounds and
transform into the same products. Attack of the activated
methylene fragment would then lead to and possibly after
cations
B
C
If R = H,
C
3/6
Experimental
Procedures for intramolecular tandem hydroalkylation
/hydroalkoxylation of the 1,3-dienyl -keto esters: In air, a 10 mL
7/9
D
E
regeneration of the catalyst. Alternatively, the ester
functionality may attack the complexed alkene to furnish the
tube equipped with a Teflon-coated magnetic stir bar was
charged with Bi(OTf)3 (0.05 equiv), TfOH (0.05 equiv) and wet
toluene (c = 0.15 M, see note §§). The substrate (0.2 mmol, 1
equiv) was added and the tube was sealed with a plastic stopper.
The tube was immersed and stirred in a preheated oil bath at 110
°C for 24 h. Then, the reaction mixture was cooled to room
temperature and quenched with satd aq NaHCO3 (5 mL). The
organic layer was extracted with Et2O, washed with brine, dried
over MgSO4, filtered through a short pad of Celite, rinsed with
Et2O and evaporated to afford the crude product. Purification by
flash chromatography (cyclohexane/AcOEt, 90/10) afforded the
desired product.
oxonium
and rationalize the role of water at the same time: (i) the
attack of water giving and then after loss of MeOH and
regeneration of the catalyst (red pathway) or (ii) dealkylation by
a triflate ion to give and TfOMe (blue pathway). The reaction
F. Two pathways may account for its dealkylation into
H
G
H
G
of TfOMe with water would give MeOH and regenerate TfOH,
as proposed by Muñoz and Lloyd-Jones.13
Acknowledgements
We thank CNRS, Ministère de l’Enseignement Supérieur et de
la Recherche, Université Paris-Sud and Institut Universitaire
de France (IUF) for the support of this work
.
Notes and references
‡ CDC 1001233 and 1497250 contains the supplementary
crystallographic data for this paper.
§ With Bi(OTf)3 alone, a 44/65 mixture of
4
and
5 was obtained.
With TfOH alone, a 14/86 mixture of
4 and 5 was obtained.
§§ Preparation of wet solvents: Wet DCE or toluene were
prepared by vigorous shaking of bulk DCE or toluene with distilled
water in a separatory funnel. The wet solvents were collected and
used as such.
Scheme 6. Mechanistic proposal ([Y]+ = Bi3+ or H+).
1
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To distinguish between the two pathways, the reaction of
carried out in toluene humidified with 18OH2 (Scheme 7). It
allowed us to detect the presence of 18O-
by mass
spectrometry, yet the incorporation was very as low as 10%.
Thus, pathway (ii) seems more likely.
3 was
2
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5
Scheme 7. Cyclization of 3
carried out in toluene humidified with 18OH2.
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