One-pot hydrosilylation-RCM-protodesilylation: Application to the synthesis of ω-alkenyl α,β-unsaturated lactones

Article abstract of DOI:10.1055/s-0028-1087910

A simple and efficient one-pot procedure has been developed for the synthesis of α,β-unsaturated lactones bearing a pendant E-olefin. This new methodology, which features a hydrosilylation, a ring-closing metathesis (RCM) and a protodesilylation reaction,

Full text of DOI:10.1055/s-0028-1087910

LETTER
565
One-Pot Hydrosilylation–RCM–Protodesilylation: Application to the
Synthesis of w-Alkenyl a,b-Unsaturated Lactones
Synthesis of
w-A
y
lkenyl
a
,
b
-U
r
nsaturate
i
d Lac
t
l
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
Received 23 October 2008
containing substrates such as III (Scheme 1, eq 2). In
Kobayashi’s synthesis of phoslactomycin B for instance,
RCM performed on V using Grubbs first- and second-
generation catalyst under various conditions appeared to
Abstract: A simple and efficient one-pot procedure has been devel-
oped for the synthesis of a,b-unsaturated lactones bearing a pendant
E-olefin. This new methodology, which features a hydrosilylation,
a ring-closing metathesis (RCM) and a protodesilylation reaction,
allows to perform RCM on substrates containing an alkyne moiety. be completely unsuccessful (Scheme 1, eq 3).8 This fail-
The utility of this methodology was further demonstrated in the
ure is supposedly due to a chelation that occurs between
total synthesis of (+)-goniothalamin and (–)-pironetin, two natural
the alkyne moiety and the catalyst which inhibits the reac-
products with interesting biological activities.
tion.
Key words: hydrosilylation, ring-closing metathesis, protodesily-
lation, a,b-unsaturated lactones, goniothalamin, pironetin
One way to prevent catalyst deactivation in a RCM pro-
cess, which involves an alkyne-containing substrate, is to
protect the triple bond. This can either be done by intro-
ducing a bulky silylated group as shown by Panek9 in his
w-Alkenyl a,b-unsaturated lactones are present in a
synthesis of (–)-callystatin A, or by complexating the
wide range of biologically active natural products such
alkyne moiety using hexacarbonyldicobalt.10 These meth-
as (+)-goniothalamin,1 (–)-pironetin,2,3 (–)-callystatin A,4
ods, however, have the disadvantage of requiring either
(–)-cryptocaryalactone,5 or phoslactomycin B6 (Figure 1).
unnecessary steps or harsh conditions that are not compat-
ible with most substrates.11
OH
O
O
In our quest to develop chemoselective methods to syn-
thesize polyfunctional compounds of type VII starting
from readily accessible substrates such as III, we became
interested in a simple and efficient one-pot procedure fea-
turing a hydrosilylation, a RCM, and a protodesilylation
(Scheme 2).
O
(–)-callystatin A
Me
O
O
O
OMe OH
In order to establish the viability of the sequence, each
step was carried out separately on a model substrate of
type III: compound 1a (Scheme 2). Hence, compound 1a
[R1 = Pr, R2 = H, n = 0] was first hydrosilylated under the
conditions developed by Trost and Ball12 using HSi(OEt)3
in the presence of 1 mol% of [Cp*Ru(MeCN)3]PF6 in
CH2Cl2. These conditions led to the corresponding silylat-
ed product of type VIII (3a), which was obtained in 90%
yield as a mixture of regioisomers but with complete
chemoselectivity. The latter was then subjected to stan-
dard RCM conditions {Grubbs second-generation catalyst
[Ru]-II (5 mol%), CH2Cl2, 40 °C} to afford the corre-
sponding a,b-unsaturated d-lactone IX (4a) in a moderate
45% yield. Finally, compound 4a was protodesilylated
under the conditions developed by Fürstner et al.13 using
AgF in a MeOH–H2O–THF (1:1:10) mixture at room tem-
perature to afford the desired (E)-w-alkenyl a,b-unsaturat-
ed lactone in 72% yield. Hence, compound 2a could be
obtained in three steps and 29% overall yield (Scheme 2).
OAc
O
Ph
(–)-cryptocaryalactone
(–)-pironetin
O
O
HO
O
O
P
OH
OH
O
O
Ph
HO
OH
NH2
(+)-goniothalamin
phoslactomycin B
Figure 1 Structure of various natural products containing an w-al-
kenyl a,b-unsaturated lactone
Whilst ring-closing metathesis (RCM) has proven to be a
useful reaction to access the a,b-unsaturated lactone motif
II from the corresponding diene I (Scheme 1, eq 1),7 it ap-
pears that this reaction fails when applied to alkyne-
In order to avoid the time and yield loss usually associated
with the isolation and purification of intermediates in a
multistep sequence, a one-pot, three-step reaction was
examined.14 Thus, 1a was treated with 1 mol% of
[Cp*Ru(MeCN)3]PF6 in the presence of HSi(OEt)3 (1.2
SYNLETT 2009, No. 4, pp 0565–0568
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087910; Art ID: G35308ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9

566
C. Bressy et al.
LETTER
O
O
RCM
O
O
(eq 1)
R1
R1
n
n
R2
O
R2
O
I
II
O
O
RCM
RCM
R1
R1
(eq 2)
(eq 3)
n
n
R2
R2
III
IV
O
O
TBSOOPMB
O
TBSOOPMB
TESO
O
TESO
OTBS
OTBS
V
VI
Scheme 1 Synthesis of a,b-unsaturated lactones via RCM
O
O
O
R1
O
one-pot reaction
R1
n
n
R2
R2
III (1a R1= Pr, R2 = H, n = 0)
VII (2a R1 = Pr, R2 = H, n = 0; 72%)
N
N
Mes
Cl
Cl
Mes
AgF
[Cp*Ru(MeCN)3]PF6
HSi(OEt)3, CH2Cl2, 0 °C to r.t.
Ru
THF–MeOH–H2O, r.t.
Ph
PCy3
[Ru]-II
O
O
O
O
(EtO)3Si
R1
(EtO)3Si
R1
Grubbs II
CH2Cl2, 40 °C
n
n
R2
R2
VIII (3a R1 = Pr, R2 = H, n = 0; 90%)
IX (4a R1 = Pr, R2 = H, n = 0; 45%)
Scheme 2 One-pot hydrosilylation–RCM–protodesilylation
equiv) in CH2Cl2. After complete conversion of the start- As a general trend, all the w-alkenyl a,b-unsaturated lac-
ing material,15 [Ru]-II (5 mol%) was added and stirring tones were obtained in good yields ranging from 35–82%,
was continued at 40 °C. Once the RCM was over,15 the and complete control of the stereoselectivity of the exocy-
reaction mixture was allowed to reach room temperature clic double bound as (E)-alkenyl products were exclusive-
before AgF (2.4 equiv) was added along with MeOH ly formed. The alkyne position (Table 1, entries 1–3) or
(0.01 M), H2O (0.01 M), and THF (0.1 M). Stirring was the substitution pattern at the a-position of the ester
then continued in the absence of light until complete con- (Table 1, entries 1 and 4) did not seem to tremendously
sumption of the silylated intermediate.15 To our delight, affect the reactivity. It is noteworthy that while five-
the desired (E)-w-alkenyl a,b-unsaturated lactone 2a was membered ring lactones could be obtained though in a
isolated in 80% yield which compared favorably with the slightly lower yield (Table 1, entry 5), the access to seven-
29% yield obtained previously in a sequential fashion.16
membered ring lactones failed at the RCM stage (Table 1,
entry 6).
With these conditions in hand, a close examination of the
reaction scope was then undertaken with a set of alkyne- Following these initial results, we were particularly inter-
containing dienes. The results are reported in Table 1.
ested in applying this synthetic methodology to a,b-unsat-
urated d-lactone-containing natural products.
Synlett 2009, No. 4, 565–568 © Thieme Stuttgart · New York

LETTER
Synthesis of w-Alkenyl a,b-Unsaturated Lactones
567
Table 1 One-Pot Hydrosilylation–RCM–Protodesilylation Scopea
[Cp*Ru(MeCN)3]PF6, HSi(OEt)3
O
O
then
Grubbs II
then
R1
O
O
AgF
R1
one-pot reaction
n
n
R2
R2
Entry
1
Olefin
Product
Yield (%)b E/Z (%)c
O
O
O
( )-1a
( )-2a
80
>20/1
O
O
O
O
O
2
3
( )-1b
( )-1c
( )-2b
( )-2c
82
50
>20/1
–
O
O
O
O
O
O
O
O
4
5
6
( )-1d
( )-1e
( )-1f
( )-2d
( )-2e
( )-2f
60
35
–
>20/1
O
O
O
O
–
–
O
O
O
O
a Reactions conditions: HSi(OEt)3 (1.2 equiv), CH2Cl2, 0 °C, Cp*Ru(MeCN)3PF6 (1 mol%), 0 °C to r.t., Grubbs II (5 mol%), 40 °C, AgF (2.4
equiv), MeOH–H2O–THF, r.t.
b Isolated yield.
c The E/Z ratio was determined by 1H NMR of the crude reaction mixture.
Our first target was (+)-goniothalamin,1 which exhibits We next turned our attention to (–)-pironetin,2,3 another
interesting antifungal,17 immunosuppressive, and anti- a,b-unsaturated d-lactone-containing natural product
inflammatory activities.18 Hence, by applying our one- which displays plant-growth regulatory20 as well as im-
pot, three-step sequence to compound 5, we were able to munosuppressive activities (Scheme 4).21 Hence, by sub-
isolate the desired natural product in 65% yield jecting compound 622 to our one-pot hydrosilylation–
(Scheme 3). Its spectroscopic and physical data were in RCM–protodesilylation reaction conditions, we were able
accordance with those reported for the natural product to access simultaneously the a,b-unsaturated d-lactone
{[a]D20 +168.2 (c 1.40, CHCl3); lit. [a]D22 +170.3 (c 1.38, and the olefin with the E-configuration in 78% isolated
CHCl3)}.19
yield. A final deprotection of the alcohol at C6 using
aqueous HF led to the desired natural product in 82%
yield (Scheme 4). The spectroscopic and physical data of
the synthesized (–)-pironetin were in accordance with
[Cp*Ru(MeCN)3]PF6, HSi(OEt)3
O
O
then
Grubbs II
then
20
those reported for the natural product {[a]D –133.6 (c
O
O
AgF
0.35, CDCl3); lit. [a]D22 –137.5 (c 0.34, CDCl3)}.2,3
Ph
65%
In conclusion, we have developed a new straightforward
methodology which allows not only to perform RCM on
alkyne-containing substrates, but also to reduce the triple
bond in a stereoselective fashion. With this highly
Ph
5
(+)-goniothalamin
Scheme 3 Total synthesis of (+)-goniothalamin
Synlett 2009, No. 4, 565–568 © Thieme Stuttgart · New York

568
C. Bressy et al.
LETTER
O
O
[Cp*Ru(MeCN)3]PF6, HSi(OEt)3
then
Grubbs II
then
OMe OTBS
O
OMe OR
O
AgF
Me
Me
7 R = TBS
HF aq
64% (from 6)
6
(–)-pironetin R = H
Scheme 4 Total synthesis of (–)-pironetin
(15) The reaction was monitored by TLC.
(16) General Procedure for the One-Pot Hydrosilylation–
RCM–Protodesilylation
chemoselective one-pot procedure, w-alkenyl a,b-unsat-
urated lactones were obtained in moderate to good yields
under mild conditions. Finally, this methodology was
used as a key step in the total syntheses of (+)-gonio-
thalamin and (–)-pironetin, two natural products with in-
teresting biological activities. Further applications of this
methodology to targets of major interest will be described
in due course.
To a solution of alkyne (1 equiv) in CH2Cl2 (0.1 M solution)
at 0 °C was added triethoxysilane (1.2 equiv) followed by
Cp*Ru(MeCN)3PF6 (0.01 equiv). The flask was
immediately allowed to warm to r.t. and stirred until
complete conversion of the starting material. Grubbs’
second-generation catalyst was then added (0.05 equiv), and
the reaction mixture was stirred at 40 °C until complete
conversion. The reaction mixture was then allowed to reach
r.t. before AgF (2.4 equiv) was added followed by MeOH
(0.01 M), H2O (0.01 M), and THF (0.1 M). Stirring was
continued in the absence of light until complete consumption
of the silylated intermediate, and the reaction mixture was
filtered through Celite, extracted with CH2Cl2, dried over
MgSO4, and evaporated under reduced pressure. The crude
residue was purified by flash column chromatography on
SiO2 using a gradient of eluents to afford the desired lactone.
Representative Characterization Data for Selected
Products
Acknowledgment
We would like to gratefully acknowledge Bayer CropScience and
CDP-Innovation for financial support.
References and Notes
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Compound 2a: IR: 2960, 2920, 2870, 1720, 1380, 1240, 980,
820 cm–1. 1H NMR (400 MHz, CDCl3): d = 6.81 (dt, J = 9.6,
4.3 Hz, 1 H), 6.07 (dt, J = 9.6, 1.8 Hz, 1 H), 5.82 (dtd,
J = 15.4, 5.8, 1.0 Hz, 1 H), 5.58 (ddt, J = 15.4, 6.6, 1.5 Hz,
1 H), 4.87 (qapp, J = 7.3 Hz, 1 H), 2.45–2.39 (m, 2 H), 2.04
(qapp, J = 6.8 Hz, 2 H), 1.41 (happ, J = 7.3 Hz, 2 H), 0.90 (t,
J = 7.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 164.2 (s),
144.7 (d), 135.5 (d), 126.9 (d), 121.6 (d), 78.3 (d), 34.2 (t),
29.8 (t), 21.9 (t), 13.6 (q). ESI-HRMS: m/z calcd for
C10H14NaO2 [M + Na]+: 189.0891; found: 189.0886.
Compound 2c: IR: 2920, 1720, 1640, 1390, 1250, 820 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.87 (ddd, J = 9.8, 5.0, 3.0
Hz, 1 H), 6.01 (dt, J = 9.8, 2.0 Hz, 1 H), 5.78 (ddt, J = 17.2,
10.1, 6.6 Hz, 1 H), 5.01 (dqapp, J = 17.2, 2.0 Hz, 1 H), 5.01
(dqapp, J = 10.1, 3.3 Hz, 1 H), 4.41 (m, 1 H), 2.35–2.29 (m, 2
H), 2.14–2.01 (m, 2 H), 1.86–1.71 (m, 1 H), 1.70–1.56 (m, 2
H), 1.56–1.42 (m, 1 H). 13C NMR (100 MHz, CDCl3): d =
163.5 (s), 144.0 (d), 137.0 (d), 120.4 (d), 114.0 (t), 76.8 (d),
32.3 (t), 31.2 (t), 28.4 (t), 22.9 (t). ESI-HRMS: m/z calcd for
C10H14NaO2 [M + Na]+: 189.0891; found: 189.0886.
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