α-EWG-substituted enones: Suitable substrates for ring-closing metathesis

Article abstract of DOI:10.1055/s-2006-950274

The A-ring of hexacyclinic acid has been synthesised, using a ring-closing metathesis involving an α-EWG-substituted enone as the key step. We have then explored the scope of this reaction, which gives access to various 5- and 6-membered rings. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950274

LETTER
2807
a-EWG-Substituted Enones: Suitable Substrates for Ring-Closing Metathesis
a
-EW
G
-S
u
ubstituted En
l
one
s
ie Toueg,* Joëlle Prunet
Laboratoire de Synthèse Organique, UMR CNRS 7652, Ecole Polytechnique, DCSO, 91128 Palaiseau, France
Fax +33(1)69333851; E-mail: julie.toueg@polytechnique.org
Received 13 July 2006
O
Abstract: The A-ring of hexacyclinic acid has been synthesised,
OH
OTBS
using a ring-closing metathesis involving an a-EWG-substituted
enone as the key step. We have then explored the scope of this re-
action, which gives access to various 5- and 6-membered rings.
H
O
O
H
H
AcO
A
H
A
O
H
O
H
H
H
HO
B
B
C
C
Key words: metathesis, ring-closure, enones, natural products
H
H
H
HO2C
2
1
Hexacyclinic acid (1) was isolated from Streptomyces cel-
lulosae subsp. griseorubiginosus (strain S1013), and was
shown to have some cytotoxic activity on three cell lines
(HM02, HEPG2 and MCF7).1 It reveals a unique hexacy-
clic carbon skeleton, whose structure is very close, and
probably biosynthetically related to that of FR182877
(Figure 1), isolated from Streptomyces sp. No.9885 by
Fujisawa Pharmaceutical Company in 1998.2
OTBS
OTBS
O
H
O
O
O
H
EtO2C
H
H
EtO2C
5
H
H
4
3
Scheme 1 Retrosynthetic analysis of the ABC-rings of 1
O
O
OH
OH
H
H
O
O
O
O
H
H
AcO
We first focused on the synthesis of 5-membered ring
enone 5. Surprisingly, very few methods exist for the syn-
thesis of cyclic a-carbalkoxyenones that do not require the
use of selenium derivatives, even though such motives
have proved to be valuable synthetic intermediates for to-
tal synthesis.8 Noteworthy though is the work of Ikeda9
that uses a rhodium-catalysed C–H insertion followed by
spontaneous elimination on silica gel, intramolecular
Knoevenagel condensations with titanium chloride lead-
ing to a variety of carbocycles,10 and the study of
Rodrigo11 involving palladium carboxylation of the a-
iodo enone. Unfortunately, these methods lack generality
or require precursors, which are uneasy to handle.
H
HO
H
H
H
H
HO
H
H
H
H
HO2C
Hexacyclinic acid 1
FR182877
Figure 1 Structures of hexacyclinic acid and FR182877
The complex and challenging structure of these molecules
has drawn interest among several groups, leading to di-
verse strategies towards the FR182877 ring system,3 and
two biomimetic total syntheses.4 In spite of the similari-
ties between FR182877 and hexacyclinic acid, the latter
has not yet succumbed to total synthesis. However,
Clarke5 has reported the synthesis of the AB- and DEF-
ring systems, while Landais6 and Kalesse7 recently pub-
lished routes to ABC tricycles.
We envisioned that these compounds could be formed by
a ring-closing metathesis (RCM), in spite of the steric hin-
drance and electron deficiency of the a-carbalkoxyenone
involved in this reaction (Equation 1), that could favour
dimerisation of the terminal olefin over ring-closure. To
the best of our knowledge, only examples of RCM with
alkyl a-substituted enones have been reported so far.12
Our strategy for the synthesis of the ABC-ring system of
hexacyclinic acid is shown in Scheme 1. Compound 2
would arise from compound 3 via a retro-Diels–Alder re-
action, followed by a Mn(OAc)3-mediated radical cyclisa-
tion, and decarboxylation of the ester group. Compound 3
would in turn result from a diastereoselective Michael ad-
dition of ketone 4 to enone 5.
O
O
R
O
O
n
catalyst
X = CH2, O, NPG
Y = Me, OEt
Y
X
X
Y
n
R
Equation 1
SYNLETT 2006, No. 17, pp 2807–2811
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950274; Art ID: D20206ST
1
7
.1
0
.2
0
0
6
We thus prepared the precursor for this challenging ring-
closing-metathesis reaction. Known aldol 613 was protect-
© Georg Thieme Verlag Stuttgart · New York

2808
J. Toueg, J. Prunet
LETTER
O
O
ed as its TBS ether 7 (Scheme 2). Reduction of the thi-
azolidinethione auxiliary13 furnished the corresponding
aldehyde, which was directly transformed into b-keto es-
ter 8.14 This compound underwent a Knoevenagel conden-
sation with acetaldehyde to afford diene 9 as a 1:1 mixture
of E/Z isomers.15
O
O
i) or ii)
R
EtO
EtO
d 30%
e 34%
O
O
Br
iii)
R
RX : a
EtO
10
b
d
e
Br
OH
OTBS
S
S
O
O
TBSOTf
2,6-lutidine
Br
I
a 69%
N
N
S
S
b 68%
d 55%
e 67%
CH2Cl2
90%
6
7
Ph
Ph
Scheme 3 Synthesis of precursors 10a,b and 10c,d. Reagents and
conditions: i) LDA (2 equiv), 1 h, 0–20 °C, then d (1.3 equiv), THF;
ii) NaH (1 equiv), 10 min, then n-BuLi (1 equiv), 10 min, 0–20 °C,
then e (1.3 equiv), THF; iii) acetaldehyde (4.5 equiv), TiCl4 (1.8
equiv), pyridine (3.5 equiv), THF, 0–20 °C, overnight.
1) DIBAL-H (2 equiv)
CH2Cl2, –78 °C, 5 min
O
O
OTBS
OTBS
84%
EtO
EtO
2) N2CHCO2Et,
SnCl2, CH2Cl2
3 h, 20 °C
8
74%
O
O
O
R
O
O
O
O
n
R'O
R'O
TiCl4, pyridine
THF, 0–20 °C
overnight
n
R
10a–e
11a–c
9
85%
Equation 3 RCM leading to carbocycles.
Scheme 2 Synthesis of diene 9
With compounds 10a–e in hand, we tested the RCM step
(Equation 3). The reaction proved very efficient for 5- and
6-membered ring formation (11a–c), with even a quanti-
tative yield in the case of 11c (Table 1). Unfortunately, we
observed only dimers with compounds 10d and even 10e,
where we had hoped the methyl substituent would favour
the formation of the 7-membered ring.
Diene 9 was engaged in the metathesis step. To our de-
light, the reaction proceeded smoothly in refluxing dichlo-
romethane and furnished the desired cyclopentenone 5
after 24 hours in 51% yield with only 1 mol% of Grubbs’
second-generation catalyst16 (Equation 2). The yield im-
proved to 65% with an increased amount of catalyst (10
mol%).
We then focused on the formation of lactones and lactams.
The precursors were prepared in two steps from the corre-
sponding alcohol or amine, as shown in Scheme 4.
O
OTBS
O
O
OTBS
Grubbs II (n mol%)
EtO
CH2Cl2, 0.03 M,
reflux, 24 h
EtO2C
O
O
i) or ii)
O
O
9
5
n = 1
yield = 51%
yield = 60%
yield = 65%
XR
n = 5
O
n = 10
12
a
b
c
d
e
commercially available
Equation 2 RCM leading to 5
78%
81%
37%
65%
We then decided to explore the scope of this RCM, which
is a new selenium-free access to cyclic a-carbalkoxy-
enones.
RXH =
a
HO
HO
HO
b
c
O
O
We first focused on the synthesis of carbocycles. Dienes
10a,b were prepared in one step from ethyl 3-oxohept-6-
enoate17 and 3-oxooct-7-enoate,17 respectively, and 10d,e
were prepared in two steps from ethyl acetoacetate, as
shown in Scheme 3. Alkylation with the required halides
furnished the b-keto esters d and e in modest yields, and
Knoevenagel condensations15 proved efficient to form the
enones. Diene 10c was prepared by a Baylis–Hillman re-
action of methyl acrylate with o-allylbenzaldehyde fol-
lowed by oxidation.18
iii)
XR
13
d
e
BocHN
CbzHN
a
b
c
d
e
81%
91%
85%
43%
56%
Ph
Scheme 4 Synthesis of precursors 13a–e. Reagents and conditions: i)
b–d (1 equiv), xylene, 150 °C, 30 min; ii) e (0.6 equiv), toluene, ref-
lux, overnight; iii) acetaldehyde (4.5 equiv), TiCl4 (1.8 equiv), pyridi-
ne (3.5 equiv), THF, 0–20 °C, overnight.
Synlett 2006, No. 17, 2807–2811 © Thieme Stuttgart · New York

LETTER
a-EWG-Substituted Enones
2809
Table 1 Ring-Closing-Metathesis Step with Compounds 10a–e Leading to Carbocyclesa
Precursor
Product
Time (h)
Yield (%)
O
O
O
O
EtO
O
0.5
82
EtO
EtO
11a
10a
O
O
O
EtO
4
3
62
10b
11b
O
O
OH
O
MeO
Quant.
MeO
11c
10c
10d
10e
O
O
EtO
EtO
Dimers only
Dimers only
24
24
–
–
O
O
a Reagents and conditions: 1 mol% Grubbs II, CH2Cl2, 0.03 M, reflux.
Reaction of alcohols on 2,2,6-trimethyl-1,3-dioxin-4-one much more reactive than in the case of carbocycles, so
proved very efficient, whereas the reaction with monopro- that dimerisation is much favoured. The only way to over-
tected amines was low-yielding.19 Knoevenagel conden- come this issue is to introduce a steric bias to form the g-
sation occurred uneventfully with esters and amides, but lactone and g-lactam. Dienes 13b and 13e, which possess
only one diastereoisomer was obtained with the latter sub- allylic substituents, led to lactone 14b and lactam 14e in
strates. Considering the steric hindrance generated by the 70% and 30% yields, respectively. However, example 13c
trisubstituted nitrogen in compounds 13d and 13e, it was shows that formation of a tetrasubstituted olefin is not
assumed that the E-isomers were obtained in both cases.
possible with such an a-carboxy-substituted enone.
Contrasting results were obtained when compounds Finally, we tested the reactivity of an a-carbalkoxyenone
13a–e were submitted to standard RCM conditions in enyne RCM. We thus prepared precursor 16 from
(Equation 4, Table 2).
known b-keto ester 1520 (Scheme 5). No reaction occurred
under our standard reaction conditions, or in refluxing
1,2-dichloroethane. Only when refluxed under an ethyl-
ene atmosphere in 1,2-dichloroethane with 5 mol% cata-
lyst in the presence of Ti(Oi-Pr)4,21 4% of cyclised
product could be isolated; the major compound 17 result-
ed from cross metathesis of 16 with ethylene, and no start-
ing material was recovered. Ethylene atmosphere was
required for any reaction to occur, but the same results
were obtained when the reaction was run without Ti(Oi-
Pr)4, except that the yield of the cyclised compound was
even lower.
O
O
O
R
O
n
X
n
X = O or NPG
R'O
X
R'O
R
13a–e
14b,e
Equation 4 RCM leading to lactones and lactams
Reaction of dienes 13a and 13d only furnished traces of
the desired 5-membered rings, the major products being
dimers in both cases. Indeed, the terminal olefin here is
Synlett 2006, No. 17, 2807–2811 © Thieme Stuttgart · New York

2810
J. Toueg, J. Prunet
LETTER
Table 2 Ring-Closing Metathesis with Compounds 13a–e Leading to Lactones and Lactamsa
Precursor
Product
Time (h)
24
Yield (%)
O
O
O
O
O
O
Tracesb
O
O
14a
13a
O
O
O
3
70c
O
13b
14b
O
O
O
No reaction
24
24
–
13c
O
O
O
O
Tracesb
N
NBoc
Boc
14d
13d
O
O
O
O
Ph
30c
NCbz
19
N
Cbz
Ph
13e
14e
a Reagents and conditions: 1 mol% Grubbs II, CH2Cl2, 0.01 M, reflux.
b Dimers are the major products.
c Estimated from the NMR spectrum of the unpurified product as it decomposes on silica gel.
Typical Procedure for RCM
O
O
O
O
O
Diene 10b (88 mg, 0.42 mmol) was dissolved in 14 mL (0.03M) of
dry CH2Cl2. Then Grubbs II catalyst was added (3.5 mg, 1 mol%)
and the solution was refluxed for 4 h. The mixture was concentrated
in vacuo. Purification on silica gel (PE–EtOAc, 7:3) afforded 44 mg
(62%) of 11b as a yellow oil.
EtO
EtO
TiCl4, pyridine
THF, 0–20 °C
overnight
15
16
85%
IR (thin film): 1737, 1687, 1372, 1269, 1223, 1058, 551, 515, 486
Grubbs II (5 mol%)
ethylene
Ti(Oi-Pr)4 0.3 equiv
O
O
O
1
cm–1. H NMR (400 MHz, CDCl3): d = 1.32 (t, 3 H, J = 7.2 Hz,
EtO2C
OCH2CH3), 2.01–2.10 (m, 2 H, H5), 2.48–2.57 (m, 4 H, H4 and
H6), 4.27 (q, 2 H, J = 7.2 Hz, OCH2CH3), 7.66 (t, 1 H, J = 4.4 Hz,
H3). 13C NMR (100 MHz, CDCl3): d = 14.3 (OCH2CH3), 22.3 (C5),
26.3 (C4), 38.9 (C6), 61.3 (OCH2CH3), 133.5 (C2), 155.8 (C3),
164.9 (CO2Et), 194.6 (C1). MS (GC, CI NH3): m/z = 186 [M +
EtO
DCE, reflux, 24 h
17 20%
18 4%
Scheme 5 Enyne ring-closing metathesis.
+
NH4 ], 169 [M + H+]. HRMS: m/z calcd for C9H12O3: 168.0787;
found: 168.0788.
In conclusion, we have demonstrated that a-carbalkoxy-
enones are suitable substrates for ring-closing metathesis
under very mild conditions, leading to 5- and 6-membered
carbocycles, naphthols, and g-substituted g-lactones and
lactams. Enyne RCM is also possible with these precur-
sors, but the yield of the desired diene is very low. This
methodology has allowed us to synthesise the enantiopure
A-ring of hexacyclinic acid.
Acknowledgment
We gratefully acknowledge the CNRS (UMR 7652) and the Ecole
Polytechnique for financial support. J. T. thanks the Ecole Polytech-
nique for a fellowship, and Dr Gagosz and Dr Grimaud for helpful
discussions.
Synlett 2006, No. 17, 2807–2811 © Thieme Stuttgart · New York

LETTER
a-EWG-Substituted Enones
2811
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Synlett 2006, No. 17, 2807–2811 © Thieme Stuttgart · New York