αβ-Unsaturated δ-valerolactones through RCM-isomerization sequence

Article abstract of DOI:10.1055/s-0031-1290488

αβ-Unsaturated δ-lactones are accessible via a sequential ring-closing metathesis (RCM) double-bond migration reaction starting from butenoates of allyl alcohols. This approach proceeds efficiently with lower catalyst loadings and higher initial substrate concentrations compared to the alternative RCM of acrylates derived from homoallylic alcohols. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0031-1290488

LETTER
▌851
lαet,teβr -Unsaturated δ-Valerolactones through RCM–Isomerization Sequence
α-Pyrones through RCM–Isomerization Sequence
Bernd Schmidt,* Oliver Kunz
Universität Potsdam, Institut für Chemie (Organische Synthesechemie), Karl-Liebknecht-Straße 24-25, 14476 Potsdam-Golm, Germany
Fax +49(331)9775059; E-Mail: bernd.schmidt@uni-potsdam.de
Received: 11.01.2012; Accepted after revision: 03.02.2012
Lewis acidic co-catalyst, occasionally very high catalyst
loadings of up to 20 mol% were reported for the synthesis
of α-pyrones.10 A further drawback is the necessity to ap-
ply high- or pseudo-high-dilution conditions in these
Abstract: α,β-Unsaturated δ-lactones are accessible via a sequen-
tial ring-closing metathesis (RCM) double-bond migration reaction
starting from butenoates of allyl alcohols. This approach proceeds
efficiently with lower catalyst loadings and higher initial substrate
concentrations compared to the alternative RCM of acrylates de- transformations, because exceeding a certain critical ini-
rived from homoallylic alcohols.
tial substrate concentration, normally ca. 0.01 M, will in-
evitably lead to incomplete conversion and very low
isolated yields, presumably due to irreversible inhibition
of the catalyst.11 For these reasons, tactics were developed
to circumvent this difficult metathesis step: for instance,
Metz et al. demonstrated that the RCM of a mixed acrole-
in acetal 312,13 proceeds without any solvent using very
small amounts of the first-generation catalyst A. Mo(VI)-
catalyzed or Cr(VI)-mediated oxidation of the intermedi-
ate dihydropyran acetal yields the desired α-pyrone 1.4 A
sequence of RCM and allylic oxidation has also been ap-
plied to allyl ethers 4, either as a two-step procedure, us-
ing stoichiometric amounts of Cr(VI) reagents for the
allylic oxidation,14,15 or as a Ru-catalyzed tandem se-
quence.16,17 We thought that the problems arising from the
insufficient reactivity of electron-deficient C–C double
bonds might also be solved by using butenoates 5 instead
of acrylates 2 as RCM precursors. Subsequent isomeriza-
tion of the intermediate β,γ-unsaturated lactones 6 to α,β-
unsaturated lactones should be facile because a conjugat-
ed π-system is established in this step (Scheme 1).
Key words: ruthenium, lactones, tandem reactions, metathesis,
esters
The ring-closing metathesis (RCM) of acrylates 2 derived
from homoallylic alcohols yields α,β-unsaturated δ-lac-
tones (α-pyrones, 1). This transformation has not only
been used for the total synthesis of numerous natural
products, such as umuravumbolide1 or strictifolione,2,3 but
also to obtain intermediates en route to the synthesis of
other naturally occurring compounds, such as ricciocarpin
A4 or laulimalide5,6 (Figure 1).
O
O
AcO
O
O
OH OH
umuravumbolide
(+)-strictifolione
O
O
H
O
O
O
H
O
RCM
RCM–
O
O
isomerization
(this work)
ricciocarpin A
O
R
5
O
O
O
O
acrylate
RCM
(laulimalide intermediate)
isomeri-
zation
O
O
O
OBn
R
R
R
Figure 1 Natural products synthesized through RCM of acrylates
6
1
2
OMe
O
Unfortunately, the high synthetic value of acrylate RCM
is somewhat tainted by the comparatively low reactivity
of electron-deficient alkenes in olefin-metathesis reac-
tions.7 This problem has been addressed by using either
first-generation Grubbs catalyst [Cl2(PCy3)2Ru=CHPh]
(A) in combination with Lewis acids, for example, Ti(Oi-
Pr)4,8 or the more reactive second-generation catalyst B.9
Although this catalyst can be used without addition of a
O
RCM–allylic
oxidation
R
R
3
4
MesN
NMes
Ph
PCy3
Cl
Cl
Ph
Ru
B
A
Cl
Cl
Ru
PCy3
PCy3
SYNLETT 204012, 236, 0851–0854
Advanced online publication: 16.03.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290488; Art ID: ST-2012-B0026-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthetic routes to α-pyrones (1) based on RCM

852
B. Schmidt, O. Kunz
LETTER
Compared to the number of examples reported in the lit- tion time had to be increased to 48 hours at 40 °C. The ob-
erature for RCM of acrylates 2 to α-pyrones 1 there are servation of a concomitant hydrogenation of the C–C
only few examples for the cyclization of butenoates 5 to double bond was not fully unexpected in light of a report
lactones 6.18–22 An organocatalytic synthesis of unsaturat- by Cossy and Dalko, who described a one-flask RCM–re-
ed lactones 6 has very recently been reported,23 and previ- duction sequence using triethylsilane in fivefold excess.39
ous syntheses rely on tartrate- or carbohydrate-derived Gratifyingly, we were able to suppress the undesired for-
aldehydes which are Z-selectively olefinated and subse- mation of 8a completely by reducing the amount of trieth-
quently cyclized.24 It has been shown that unsaturated lac- ylsilane to 0.2 equivalents, resulting in an isolated yield of
tones 6 undergo a base-mediated double-bond migration α-pyrone 1a of 85% (Table 1, entry 10).
to α-pyrones 1, with DBU20–22,24–27 or KOt-Bu23 being the
Table 1 Optimization of Conditions
most commonly used reagents. In order to avoid the use of
these basic reagents and to reduce the number of workup
O
steps, we investigated an assisted tandem RCM–isomeri-
zation approach to accomplish the synthesis of α-pyrones
catalyst (n mol%), toluene (x mol/L), 80 °C;
O
then chemical trigger, 110 °C
from butenoates. Like assisted tandem catalytic trans-
Ph
formations in general,28 the RCM–isomerization
5a
sequence29,30 relies on the presence of a ‘chemical trig-
O
O
O
O
ger’28 which is required to induce in situ the transforma-
tion of a Ru carbene into a Ru hydride,31 which then
catalyzes the double-bond isomerization step. Snapper et
al.32 and we have introduced a variety of chemical triggers
for the synthesis of cyclic enol ethers via a catalytic
RCM–isomerization sequence of allyl ethers. In particu-
lar, our group proposed inorganic hydrides,33 2-propanol
plus sodium hydroxide,34 ethyl vinyl ether,35,36 or
triethylsilane36 as additives to achieve the crucial in situ
conversion of the carbene into a hydride complex.
O
O
OH
O
+
+
+
Ph
Ph
Ph
Ph
7a
1a
6a
8a
Entry
Catalyst
(mol%)
c (mol/L) Chemical trigger
Yield of 6
(%)
(equiv)
1a
2
A (5.0)
B (1.0)
B (5.0)
B (5.0)
B (2.0)
B (5.0)
B (5.0)
B (2.0)
B (2.0)
B (1.0)
0.01
0.10
0.05
0.05
0.10
0.05
0.05
0.10
0.10
0.10
none
6a 42
6a 93
6a
none
At the beginning of this study we investigated the possi-
bility to replace the more expensive second-generation
catalyst B by the first-generation catalyst A. It has previ-
ously been noted that the use of A for substrates 5 requires
the addition of Ti(Oi-Pr)4.18 As this Lewis acid might in-
hibit most of our isomerization-inducing additives, we in-
vestigated phenol as a co-catalyst,37 unfortunately to no
avail as the isolated yield of 6a was only 42% (Table 1,
entry 1). In contrast, with the second-generation catalyst
B a yield of 93% was obtained with a much lower catalyst
loading of just 1.0 mol% and at significantly higher initial
substrate concentration (Table 1, entry 2). This prompted
us to use B in all further experiments. In the next step, we
investigated various chemical triggers: while no isomeri-
zation was observed with NaBH4 (Table 1, entry 3), even
at an increased catalyst loading, the two basic additives
sodium hydroxide with 2-propanol and sodium hydride
lead to a rapid base-induced ring-opening reaction which
gives 2Z,4E-dienoic acids in good yields and high stereo-
selectivities (Table 1, entries 4 and 5).38 With ethyl vinyl
ether, we could indeed detect significant amounts of isom-
erized lactone 1a, however, conversion was incomplete,
and an unidentified byproduct was formed in significant
amounts (Table 1, entries 6 and 7). For these reasons tri-
ethylsilane was tested. With one equivalent, the desired
isomerization was indeed accomplished, but a small
amount of saturated lactone 8a was formed as a byproduct
upon heating the reaction mixture after addition of the si-
lane for 1.5 hours (Table 1, entry 8). This problem became
more pronounced when dichloromethane was used as a
solvent (Table 1, entry 9), presumably because the reac-
3b
4
NaBH4 (0.5)
2-PrOH; NaOH (0.5) 7a 44
5
NaH (1.2)
7a 80
6a/1a
6a/1a
1a 71
1a 76
1a 85
6c
7c
8d
9e
10
H2C=CHOEt (3)
H2C=CHOEt (10)
Et3SiH (1.0)
Et3SiH (1.0)
Et3SiH (0.2)
a Phenol (0.5 equiv) was added to the RCM reaction.
b No product apart from 6a was detected.
c Heating to reflux for 16 hours after addition of H2C=CHOEt; 6a and
1a are formed in a 1:1 ratio, along with unidentified byproducts.
d Approximately 10% of 8a as a byproduct.
e CH2Cl2 was used as a solvent, heating to 40 °C after addition of si-
lane for 48 h; approximately 25% of 8a as a byproduct.
We applied these optimized conditions to several other
butenoates 5b–j, which were synthesized from the corre-
sponding allylic alcohols as described previously.38 In
most cases, the desired α-pyrones 1 were obtained in high
yields and excellent selectivity. In all cases, no products
resulting from hydrogenation or ring opening of the lac-
tone could be detected. There is also no indication that γ,δ-
unsaturated isomers, that is, cyclic enol ethers, are
formed, which might have been an additional complica-
tion in those cases where the substituent R is sterically less
Synlett 2012, 23, 851–854
© Georg Thieme Verlag Stuttgart · New York

LETTER
α-Pyrones through RCM–Isomerization Sequence
853
demanding, such as 1e with R = Me. Haloarenes (e.g., 1b
and 1c) tolerate the reductive reaction conditions, as we
did not find any products resulting from a reductive deha-
logenation (Scheme 2).
O
O
OH
OH
O
(2.2 equiv)
DCC (2.2 equiv), DMAP (0.2 equiv)
OH
CH2Cl2, 20 °C (87%)
B (1.0 mol%), toluene (0.1 mol/L),
O
O
O
80 °C, 0.5–1 h;
then Et3SiH
(0.2 equiv), 110 °C, 3–6 h
9
10
O
O
O
B (2.0 mol%), toluene (0.1 mol/L),
80 °C, 0.5–1 h;
O
R
R
O
then Et3SiH
1
5
(0.4 equiv), 110 °C, 3–6 h (85%)
O
O
O
O
O
11
O
F
O
O
Scheme 3 Tandem double RCM–isomerization of tetraene 10;
Bonds formed through RCM are highlighted in bold
1b (89%)
1c (86%)
1a (85%)
Br
O
O
O
O
In summary, we disclose herein that triethylsilane is a
suitable additive in RCM reactions to trigger the in situ
conversion of the metathesis catalyst to an isomerization
catalyst. This opens up a route to circumvent the disad-
vantageous acrylate RCM for the synthesis of α-py-
rones.46
O
O
1e (86%)
1f (94%)
1d (39%)
OMOM
O
O
O
O
O
O
O
O
Acknowledgment
This work was generously supported by the Deutsche Forschungs-
gemeinschaft (DFG grant Schm 1095/6-1). Generous donations of
solvents by Evonik Oxeno is gratefully acknowledged.
OTBS
1g (92%)
1h (85%)
1i (85%)
1j (80%)
Scheme 2 Synthesis of α-pyrones 1 from butenoates 5; bonds
formed through RCM are highlighted in bold
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmornifaItngoniSmuortinfaopnrtIgiSutpor
Finally, we investigated the possibility to extend a double
RCM reaction by a sequential double isomerization reac-
tion. Double or multiple RCM reactions have emerged as
a valuable approach for the rapid assembly of bi- or poly-
cyclic molecules.40 However, in order to obtain syntheti-
cally useful yields of bicyclic products and to avoid
laborious separation of the target molecule from unreact-
ed starting material or monocyclic intermediates, it is nec-
essary that all RCM steps proceed in very high yields and
selectivities. This prerequisite is even more important for
the envisaged tandem double RCM–isomerization, be-
cause every molecule will undergo four transformations,
calling for a yield >99% for each Ru-catalyzed step if a
conversion of more than 95% to the target molecule is in-
tended (Scheme 3).
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 851–854

854
B. Schmidt, O. Kunz
LETTER
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A solution of 5i (200 mg, 0.7 mmol) in toluene (7.0 mL) was
preheated to 80 °C, and catalyst B (6.0 mg, 1.0 mol%) was
added. After the starting material was fully consumed (TLC,
approx. 30 min), Et3SiH (22 μL, 0.14 mmol) was added, and
the solution was heated to reflux for 1 h. All volatiles were
evaporated, and the residue was purified by chromatography
on silica (eluent: hexane–MTBE = 5:1) to give α-pyrone 1i
(152 mg, 85%) as a colorless oil. [α]24D +117.3 (c 0.56,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 6.90 (ddd,
J = 9.6, 5.8, 2.7 Hz, 1 H), 6.00 (dm, J = 9.7 Hz, 1 H), 4.19
(dt, J = 11.1, 5.0 Hz, 1 H), 4.00 (qm, J = 6.3 Hz, 1 H), 2.57–
2.35 (2 H), 1.22 (d, J = 6.3 Hz, 3 H), 0.88 (9 H), 0.09 (3 H),
0.08 (3 H). 13C NMR (75 MHz, CDCl3): δ = 168.5 (0), 145.1
(1), 121.1 (0), 81.7 (1), 69.3 (1), 25.8 (3), 24.3 (2), 20.2 (3),
18.0 (0), –4.5 (3), –4.7 (3). IR (neat): ν = 2957 (m), 2931 (m),
2897 (w), 1723 (s), 1383 (m), 1249 (s), 1075 (s). ESI-MS:
m/z = 239 (5), 257 (35), 279 (100) [M + Na]+. ESI-HRMS:
m/z calcd for C13H24NaO3Si+ [M + Na]+: 279.1392; found:
279.1375. Anal. Calcd (%) for C13H24O3Si (256.41): C, 60.9,
H, 9.4. Found: C, 60.7; H, 9.6.
Synlett 2012, 23, 851–854
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