An easy route toward enantio-enriched polycyclic derivatives via an asymmetric domino conjugate reduction-aldol cyclization catalyzed by a chiral Cu(I) complex

Article abstract of DOI:10.1016/j.tet.2011.07.039

A highly efficient reductive-aldol cyclization mediated by a chiral Cu(I) complex and an organosilane yielded to cyclic or polycyclic derivatives. An excellent control of the selectivities was reached in most cases (dr up to 100:0 and ee up to 95%). After

Full text of DOI:10.1016/j.tet.2011.07.039

Tetrahedron 68 (2012) 3457e3467
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An easy route toward enantio-enriched polycyclic derivatives via an asymmetric
domino conjugate reductionealdol cyclization catalyzed by a chiral Cu(I) complex
*
Julia Deschamp, Thomas Hermant, Olivier Riant
ꢀ
ꢀ
ꢀ
Unite de Chimie Organique et Medicinale, Universite catholique de Louvain, Place Louis Pasteur 1, Louvain-la-Neuve B-1348, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient reductive-aldol cyclization mediated by a chiral Cu(I) complex and an organosilane
yielded to cyclic or polycyclic derivatives. An excellent control of the selectivities was reached in most
cases (dr up to 100:0 and ee up to 95%). After developing the enantioselective intramolecular reductive-
aldol methodology, this strategy was successfully used for the synthesis of a key intermediate of a natural
diterpene in few steps.
Received 15 March 2011
Received in revised form 6 July 2011
Accepted 12 July 2011
Available online 21 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric Catalysis
Copper(I)
Reductive-aldol cyclization
Polycyclic compounds
1. Introduction
obtained with an excellent control of the diastereoselectivity10e13
and/or enantioselectivity.12d,14
Tandem, domino or cascade processes have been found as
powerful tools for the construction of chiral polycyclic building
blocks. The benefits of these reactions have been well-established
for the past decades in modern organic chemistry. Nowadays, the
developments of efficient and versatile methodologies dealing with
these demanding tasks are always an important area of research.1,2
Excellent progresses have been achieved in the field of in-
termolecular reductive-aldol reaction between a Michael acceptor
and an electrophilic partner catalyzed by various metal complexes
in presence of a reducing agent (Scheme 1).3,4 The obtention of
good to excellent levels of diastereo- and enantioselectivities was
observed with rhodium,5,6 iridium,7 cobalt,8 and indium9 com-
plexes. Furthermore, the intramolecular version catalyzed by rho-
dium,10,11 cobalt12 and copper13,14 complexes has also been
investigated. The corresponding cyclic or polycyclic structures were
Our team has recently described an efficient method for the
diastereo- and enantioselective domino reductive-aldol reaction
between methyl acrylate and a ketone15 or an aldehyde,16 catalyzed
by a copper(I) precursor combined with an appropriate chiral
diphosphane ligand and an organosilane as reducing agent. These
reactions are postulated to proceed by the in situ formation of
a copper enolate through the conjugated reduction of copper hy-
dride specie onto the Michael acceptor.17 Then, the in situ gener-
ated copper(I) enolate is trapped by the electrophile to form the
copper aldolate, which finally reacts with the silane through a s-
bond metathesis to deliver the silylated aldol adduct and re-
generates the copper(I) hydride catalyst.18 The domino reductive-
aldol reactions take the advantage of avoiding the pre-activation
of the nucleophile (metal/enolate) in an independent step in con-
trast to the Mukaïyama-type reactions.19 These results prompted us
to spread the scope of this methodology for the construction of
polycyclic compounds.20
In this paper, we unveil a more complete study of our work on
the intramolecular reductive-aldol cyclization and disclose an ap-
plication of this methodology toward the asymmetric synthesis of
a key intermediate of a natural product.
Scheme 1. General inter- and/or intramolecular reductive-aldol reaction in presence of
various catalysts and a hydride source.
2. Results and discussion
We initially focused our efforts on the reductive cyclization of
the diketo-ester 2a, which was easily obtained on a multi-gram
scale in a two steps synthesis starting from the commercially
* Corresponding author. Tel.: þ32 0 10 478 777; fax: þ32 0 10 474 168; e-mail
address: olivier.riant@uclouvain.be (O. Riant).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.039

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J. Deschamp et al. / Tetrahedron 68 (2012) 3457e3467
available 2-methylcyclohexane-1,3-dione.11a,21 The feasibility of the
reductive cyclization was first checked in presence of various well-
known catalysts and compared to our catalyst system (Table 1).
Following this preliminary study on the reactivity of our catalyst
system, we next investigated the influence of different parameters.
The most representative results were summarized in Table 2. We
first screened various atropochiral diphosphanes, and ferrocenyl li-
gands at different temperatures (Fig. 2). Although no improvement
was observed at room temperature by replacing S-BINAP S-L1 by S-
MeO/BIPHEP S-L2, an enhanced diastereoisomeric ratio of 76:24 was
obtained for this ligand at ꢀ50 ꢁC with a 70% ee on the major adduct
trans-3a (Table 2, entries 1e3). When the steric bulkiness was in-
creased around the phosphorus atom of the BIPHEP type ligand S-
L3, the four diastereoisomers were isolated with no enantiose-
lectivity (Table 2, entry 4). The use of R-Xylyl/P-PHOS R-L4 as chiral
diphosphane did not lead to better selectivities (entry 5).
Table 1
Reductive-aldol cyclization catalyzed by various catalysts and/or at various
temperature
Entry
1
Conditions
T (ꢁC)/t (h)
Conva (%)
100
trans-3a/cis-3aa
50:17 (8:25)b
Table 2
[PPh3CuH]6
(100 mol %)
25/2
Screening of chiral ligands at various temperaturesa
2
[RhCl(PPh3)3]
50/2
0
d
(3 mol %)/Et3SiH
1/rac-L1 (5 mol %)
1/S-L1 (1 mol %)c
1/rac-L1 (5 mol %)
1/rac-L1 (5 mol %)
1/rac-L1 (5 mol %)
1/rac-L1 (5 mol %)
3
4
5
6
7
8
25/2
25/2
0/2
ꢀ20/2
ꢀ60/2
ꢀ78/2
100
100
100
100
100
100
65:35
65:35
60:40
55:45
52:48
50:50
Entry
2aec
L*
T (ꢁC)
trans-3/
cis-3b
ee (trans-3)
a
The conversions and diastereoisomeric ratio were determined by GC.
The two other diastereoisomers were detected by GC.
In presence of 1 mol % 1/(S)-L1, trans-3a/cis-3a: 65/35, ee (trans-3a): 30% (de-
(%)/ee (cis-3) (%)b
b
c
1
2
3
4
2a
(S)-L1
(S)-L2
25
25
65:35
68:32
76:24
45:11
(14:30)c
75:25
54:46
63:37
37:63
68:32
49:51
43:57
32:68
18:82
27:73
28:72
0:100
0:100
0:100
0:100
30/nd
23/14
70/35
0/0
termined by chiral GC analysis).
ꢀ50
(S)-L3
ꢀ50
To our delight, we observed a total conversion onto the expected
cyclized adducts trans-3a and cis-3a22 in presence of the air-stable
precatalyst [CuF(PPh3)3$2MeOH]23 1, rac-BINAP rac-L1 and a stoi-
chiometric amount of phenylsilane at room temperature. Moreover,
only two diastereoisomers were isolated over the four possible
isomers. In contrast, the four possible diastereoisomers were
formed in presence of a stoichiometric quantity of the Stryker’s
catalyst,13b while no conversion was observed in presence of the
Wilkinson’s complex and triethylsilane (Table 1, entries 1e3).10 So,
our catalyst system seemed to be most efficient to promote the
domino conjugate reductionealdol cyclization of the diketo-ester
2a. Furthermore, in presence of [CuF(PPh3)3$2MeOH] 1/S-BINAP
S-L1 (1 mol %), the bicyclic compounds were obtained with any loss
of the diastereoselectivity and with an encouraging 30% enantio-
meric excess (Table 1, entry 4). The relative configuration was de-
termined by NOE experiments on each pure isolated isomers trans-
3a and cis-3a as shown in Fig. 1.22
5
6
7
8
(R)-L4
(R,S)-L5
(R,R)-L6
ꢀ50
ꢀ21/ꢀ1
4/17
16/13
68/45
19/5
25 or ꢀ50
25
ꢀ50
9
(R,S)-L7
(S,S)-L8
(S,S)-L9
25 or ꢀ50
25 or ꢀ50
25
10
11
12
13
14
15
16
17
18
19
5/16
47/82
63/89
33/92
ꢀ72/ꢀ91
60/84
86
ꢀ50
(S,S)-L10
(R,R)-L11
(S,S)-L10
(S,S)-L9
(S,S)-L10
(R,R)-L11
(R,R)-L12
ꢀ50
ꢀ50
2b
2c
ꢀ50
ꢀ50
ꢀ50
95
ꢀ50
ꢀ86
ꢀ50
ꢀ95
a
The reactions were carried out in a 0.10 M solution in toluene at the indicated
temperature under an oxygen free argon-atmosphere in presence of 2aec (1 mmol),
[CuF(PPh3)3$2MeOH]
1 (1 mol %)/chiral ligand L* (1 mol %), and phenylsilane
(1.4 equiv) for 2 h.
b
trans/cis and enantiomeric excesses were determined by chiral GC analysis.
The two other diastereoisomers were detected by GC.
c
We then tested the ferrocenyl diphosphane ligands that have
already shown their efficiency in various enantioselective catalytic
processes (Fig. 2).24 In presence of [CuF(PPh3)3$2MeOH] 1/Josiphos
L5, the cyclized adducts trans-3a and cis-3a were obtained with
a low diastereoisomeric ratio trans-3a/cis-3a of 54/46 with poor
enantiomeric excesses (Table 2, entry 6). Nevertheless, the dia-
stereoselectivity was reversed by using the Walphos ligand L6 at
room temperature and at ꢀ50 ꢁC (Table 2, entries 7 and 8). How-
ever, an improved enantiomeric excess of 68% were observed on
the major isomer cis-3a. The use of [CuF(PPh3)3$2MeOH] 1/Man-
dyphos L7 afforded to the expected compounds trans-3a and cis-3a
with a 68/32 dr and a low 19% ee on the major trans-3a adduct
(Table 2, entry 9). We then evaluated the Taniaphos diphosphane
ligands, which have revealed to be highly selective during our
studies on the intermolecular reductive-aldol reaction. Un-
fortunately, the use of [CuF(PPh3)3$2MeOH] 1 and the Taniaphos
ligand (S,S)-L8 yielded to poor selectivities at room temperature
Fig. 1. Relative configuration of bicyclic trans-3a and cis-3a.
We next evaluated the temperature dependence on the dia-
stereoselectivity (Table 1, entries 5e8). We noted a decrease of the
diastereoisomeric ratio (trans-3a/cis-3a: 65:35/50:50) when the
temperature was diminished from room temperature to ꢀ78 ꢁC.

J. Deschamp et al. / Tetrahedron 68 (2012) 3457e3467
3459
the Taniaphos ligand (S,S)-L10 in which the phosphorus atom is
sterically hindered, we were delighted to isolate the major adduct
cis-3a with a cis-3a/trans-3a diastereoisomeric ratio of 82:18 and
a high 92% ee (Table 2, entry 13). Moreover, it is important to note
the same diastereoselectivity was obtained in presence of the li-
gand (R,R)-L11 with the reverse major enantiomer cis-3a (Table 2,
entry 14).
We next investigated the influence of the steric hindrance on
the ester moiety of the diketo-ester 2aec. We indeed expected an
improvement of the selectivities by increasing the steric bulkiness
around the chiral copper enolate intermediate during the catalytic
process. To proof this hypothesis, we first carried out the reaction at
ꢀ50 ꢁC on the less hindered diketo-methyl ester 2b (R¼Me) in
presence of [CuF(PPh3)3$2MeOH] 1/(S,S)-L10 and phenylsilane, the
cyclized adducts were obtained as expected with a lower trans-3b/
cis-3b diastereoisomeric ratio of 28:72 and a 84% ee on the major
isomer. The domino process was then performed on the diketo-
tert-butyl ester 2c using the same conditions, and we were pleased
to note the formation of only one diastereoisomer cis-3c with an
excellent enantiomeric excess of 95% (Table 2, entries 15 vs 17). We
also evaluated the Taniaphos ligands (S,S)-L9-(R,R)-L12 on this
diketo-ester precursor 2c (Table 2, entries 16e19). In each case, the
same diastereoselectivity cis-3c/trans-3c: 100:0 was observed
whereas better enantiomeric excesses were obtained with the
steric bulkier ligands (S,S)-L10 and (R,R)-L12.
This reaction has proved to be highly reproducible also on
larger scale reactions at lower catalyst loading. A 10 mmol scale
reaction was indeed performed with a 0.5 mol % loading of
[CuF(PPh3)3$2MeOH] 1 and (S,S)-L10 and phenylsilane. A complete
conversion was so obtained within 15 min at ꢀ50 ꢁC with any loss
of selectivities, the sole adduct cis-3c was isolated with a high yield
of 80%.
We finally studied the scope of our methodology on the syn-
thesis of enantiomerically enriched bicyclic compounds bearing
various ring sizes and substitutions under the previous optimized
conditions (Table 3). The precursors 2aeh, which could generate
six-membered rings were synthesized in two steps starting from
Fig. 2. Chiral diphosphane ligands used in this study.
and at ꢀ50 ꢁC (Table 2, entry 10). Nevertheless, we observed the
formation of the cyclized compound cis-3a with an encouraging
enantiomeric excess of 82% by using the combined
[CuF(PPh3)3$2MeOH] 1/Taniaphos (S,S)-L9 albeit with a modest
diastereoisomeric ratio of 43:57. The diminution of the temperature
to ꢀ50 ꢁC led to a slight improvement of the both dia- and enan-
tioselectivities (Table 2, entries 11 and 12). When we finally tested
Table 3
Scope of the asymmetric intramolecular reductive-aldol cyclization catalyzed by [CuF(PPh3)3$2MeOH]/L10 in presence of phenylsilanea
Entry
1
Substrate
EWG
Product
Yield (%)
80
cis/transb
ee (cis)/ee (trans) (%)
2a
COOEt
3a
82:18
92/33
2
3
4
5
2b
2c
2d
2e
COOMe
COOt-Bu
CN
3b
3c
3d
3e
75
80
85
75
72:28
100:0
100:0
100:0
84/60
95
0
C(O)Me
65c
6
7
2f
COOEt
3f
78
80
88:12
89:11
92/60
97/72
2g
COOt-Bu
3g
8
2h
3h
85
100:0
95
(continued on next page)

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J. Deschamp et al. / Tetrahedron 68 (2012) 3457e3467
Table 3 (continued )
Entry
Substrate
EWG
Product
Yield (%)
70
cis/transb
ee (cis)/ee (trans) (%)
9
4
7
100:0
94
10
5a
8a
85
100:0
66
11
12
5b
5c
COOMe
8b
8c
70
85
70:30
94:6
88/66
80/85
COOt-Bu
13
6a
6b
9a
75
d
d
14
9b
75
d
d
a
The reactions were carried out in a 0.10 M solution in toluene at ꢀ50 ꢁC under an oxygen free argon-atmosphere in presence of substrate (1 mmol), [CuF(PPh3)3$2MeOH] 1
(1 mol %)/chiral ligand L* (1 mol %) and phenylsilane (1.4 equiv) for 1 h.
b
cis/trans and enantiomeric excesses were determined by chiral GC analysis.
The ketone was also reduced during the reaction.
c
commercially available precursors (Scheme 2). The treatment of 2-
methylalkane1,3-diones by acrolein in water gave quantitatively
the corresponding aldehydes, which were directly used without
any purification in a Wittig reaction in presence of the appropriate
after 24 h at room temperature the corresponding C-allylated
dione, which was then used in the two step procedure to give the
new diketo-ester in an overall yield of 45% after purification.25 Fi-
nally, the targeted compounds 5aec and 6a,b were, respectively,
obtained in two steps by C-alkylation of the corresponding 1,3-
dione followed by a cross metathesis coupling with an acrylate
ester in presence of a catalytic amount of Grubbs’ second genera-
tion catalyst. The precursors 5aec and 6a,b were isolated with
rather good yields (50e73%).26
ylides and benzoic acid in toluene at 80 ꢁC.21 The various
a,b-un-
saturated ester 2aeh were isolated with good to excellent yields
after purification. It was observed that a stoichiometric amount of
benzoic acid was necessary to obtain good yields.
As mentioned earlier, we have observed that the diaster-
eoselectivity was influenced by the ester moiety on the diketo-ester
(Table 3, entries 1e3). We then focused our interest on the for-
mation of various six-membered rings from precursors bearing
other electron withdrawing groups (Table 3, entries, 4 and 5). We
noted the formation of only one cis-isomer cis-3d by replacing the
ester by a nitrile group, but unfortunately, with no enantiose-
lectivity (Table 3, entry 4). In addition, we carried out the conju-
gated-reductionealdol cyclization on diketo-enone 2e and we
isolated only one cyclized adduct in which the ketone was also
reduced during the catalytic process (Table 3, entry 5). We next
performed the reaction on diketo-esters with various ring sizes
2feh on the monocyclic precursors with good cis-selectivities as
well as excellent enantiomeric excesses (entries 6e8). We also
checked the possibility to introduce an allyl group on the quater-
nary center of the precursor 4 (Table 3, entry 6); the reductive-aldol
reaction was thus performed and the resulting bicyclic adducts
were isolated as a sole cis-isomer 7 with a 94% ee and a 70% yield.
This substrate cis-7 behaved with equal efficiency compared to the
methyl analog cis-3c. Furthermore, the allyl moiety on the quater-
nary center could enable us to introduce various substituents on
this position and thus to synthesize manifold functionalized chiral
building blocks.
Scheme 2. Syntheses of the precursors.
The alkylation of the commercially available cyclohexane-1,3-
dione in presence of allyl bromide and triton B in water yielded
We then studied the construction of five-membered rings from
precursors 5aec (Table 3, entries 10e12). The 5,5-fused-junction

J. Deschamp et al. / Tetrahedron 68 (2012) 3457e3467
3461
bicycle cis-8a was formed as a single diastereoisomer albeit with
a 66% moderate ee. The 6,5-bicyclic adducts cis-8b and cis-8c were
obtained with reasonable to good diastereo- and enantioselectiv-
ities. Moreover, we have noticed an improvement of the di-
astereoisomeric ratio to 94:6 on the tert-butyl 6,5-bicycles
compound cis-8c as previously observed for the methyl- and tert-
butyl diketo-ester 2b and 2c. We also investigated the possibility to
generate larger seven- and eight-membered rings (Table 3, entries
13e14). The reaction, which was carried on the precursors 6a and
6b bearing longer lateral tethers unfortunately resulted in simple
reduction. The same reduced compounds 9a and 9b were obtained
at higher temperatures. Moreover, when the amount of silane was
increased, we also observed the reduction of a ketone.
We found that an optimized procedure was built up with an in
situ preformed catalyst prepared by a ligand exchange between the
air-stable precatalyst [CuF(PPh3)3$2MeOH] 1 and an appropriate
chiral diphosphane. As we already noticed, the copper hydride
species have shown a high level of reactivity toward the reductive-
aldol cyclization. The combination of a straightforward access to
the diketo-ester precursors, the low catalyst loading, a scalable
procedure and the high selectivities reached in most cases, should
enable to an easy access to new chiral building blocks for asym-
metric synthesis.
Scheme 3. Reagents and conditions. (a) Hoveyda’s catalyst (2 mol %), tert-butyl acry-
late (10 equiv), CH2Cl2, 40 ꢁC, 16 h. (b) 1/L10 (2 mol %), PhSiH3 (3.0 equiv), toluene,
ꢀ50 ꢁC, 16 h. (c) Grubbs’ II catalyst (1 mol %), tert-butyl acrylate (30 equiv), CH2Cl2,
40 ꢁC, 12 h.
especially for its antinociceptive and expectorant effects. More re-
cently, Quetin-Leclercq’s team has demonstrated the potent vaso-
relaxant activity of these two diterpenes (Scheme 4).29
We have next focused our interest to the construction of
polycyclic compounds in cascade or in sequence (Scheme 3). We
decided to start from the functionalized bicyclic compound cis-7,
which was obtained as a sole cis isomer with a 94% ee. A Michael
acceptor group was first introduced by cross metathesis coupling
of cis-7 and tert-butyl acrylate in presence of Hoveyda’s catalyst
and afforded the a,b-unsaturated ester 10 with a good yield of 85%.
Scheme 4.
The reductive-aldol cyclization was then performed on 10 in our
standard condition and we isolated the expected tricyclic com-
pound 11 and also the product resulting of the simple 1,4-
reduction. Moreover, a substantial amount of the starting mate-
rial 10 was recovered. Raising the amount of phenylsilane to
3 equiv allowed the full conversion of the starting material and
suppressed the formation of the reduction product. In that case,
we were pleased to observe only the formation of the tricyclic
compound 11 as a single diasteroisomer.27 We next considered
performing a double reductive-aldol cyclization on precursor 12,
which bears two Michael acceptors and which could directly yield
the angular tricyclic compound 11. The allyl-diketo-ester 4 reacted
with tert-butyl acrylate in presence of the second generation
Grubbs’ catalyst to lead to the expected di-ester 12. An optimum
yield of 80% was obtained in presence of 30 equiv of tert-butyl
acrylate in order to avoid the ring closing metathesis. As pre-
viously with substrate 10, several products including the expected
tricyclic compound 11 were formed when the reaction was con-
ducted in presence of [CuF(PPh3)3$2MeOH] 1/S,S-L10 and 1.4 or
2.0 equiv of phenylsilane. However, when 12 was reacted with
[CuF(PPh3)3$2MeOH] 1/S,S-L10 and 3.0 equiv of phenylsilane in
toluene at ꢀ50 ꢁC for 16 h, the expected tricyclic adduct 11 was
identified as the major product and isolated with a reasonable 46%
yield. We have also noticed the formation of reduced cyclized
compounds as minor products contrary to the sequence method.
We have found that the sequence and cascade methods surpris-
ingly led to the same isomer.28 This preliminary study has shown
the possibility to generate new angular tricyclic compounds in
sequence or in cascade with an excellent control of
diastereoselectivities.
To the best of our knowledge, only Mangoni et al.30 reported the
racemic synthesis of marrubiin in 24 steps starting from the well-
known WielandeMiescher ketone.31
Herein, we proposed a novel access to bicyclic scaffold 13 by
using the reductive-aldol cyclization strategy. According to the
retrosynthetic pathway described in Scheme 5, marrubiin, which
have already been obtained from the bicyclic ester 13 could be
synthesized starting from the diketo-ester 2. As mention earlier, the
bicyclic cis-3c and ent-cis-3c have been generated from the pre-
cursor 2c in presence of 0.5 mol % of [CuF(PPh3)3$2MeOH] 1 and,
respectively, with (S,S)-L10 and (R,R)-L12 within 15 min at ꢀ50 ꢁC
with excellent 95% and ꢀ95% ee and a 80% isolated yield. In our
previously report, we have surveyed the behavior of the 6,6-bicyclic
adducts 3aec toward dehydration.
Scheme 5. Retrosynthetic pathway to marrubiin.
Various conditions have been screened to optimize the de-
hydration yields (Scheme 6). It was found that mesyl chloride and
triethylamine reacted smoothly with the bicyclic adducts trans-3a
and trans-3b to give the conjugated unsaturated esters 14a,b in
good isolated yields. When those conditions were applied to the
bicyclic adducts cis-3aec, the dehydration occurred too, but the
non-conjugated alkenes 15aec were the sole products in those
reaction, and were isolated with 65% yields after purification.
Unfortunately, when the dehydration was conducted on a large
scale of cis-3c, the reaction was longer and sometimes not
reproducible.
After successfully developing the enantioselective intra-
molecular reductive-aldol methodology, we decided to use this
strategy for the synthesis of a key intermediate of marrubiin and
marrubenol, two natural diterpenes extracted from Marrubium
vulgare L. (Horehound, Lamiaceae). Indeed, the white horehound is
a widespread Mediterranean plant used in traditional medicine

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J. Deschamp et al. / Tetrahedron 68 (2012) 3457e3467
The use of the appropriate chiral ligand (R,R)-L12 in the intra-
molecular reductive cyclization will enable us to conduct to the
expected ester 13 and thus to the marrubiin (Scheme 8). Our
methodology takes advantage to lead to different enantiomers,
which could be an important tool for SAR studies.
Scheme 6. Dehydrations of bicyclic adducts 3aec. (a) MsCl (20 equiv), Et3N (25 equiv),
CH2Cl2, ꢀ20 ꢁC.
However, after several trial experiments, we were able to ach-
ieve this reaction on cis-3b instead of cis-3c in a reproducible way
by using thionyl chloride as the dehydrating agent. Firstly, cis-3c
was converted into cis-3b in two steps by treatment of TFA followed
by TMSCH2N2 with a good 91% yield. Then, the optimized condi-
tions of dehydration showed that cis-3b reacted smoothly with
SOCl2 at 0 ꢁC to give the expected non-conjugate ester 15b with
a 92% yield (Scheme 7).32 The introduction of the methyl sub-
stituent on 15b required the protection of the ketone group and this
step was achieved according to the Noyori’s conditions to yield the
dioxolane 17b, which could be crystallized and analyzed by X-ray
crystallography (Fig. 3).
Scheme 8. Access to epi-marrubiin and marrubiin via a diastereo- and enantiose-
lective reductive-aldol cyclization.
3. Conclusions
In summary, we have disclosed here a detailed study of the
intramolecular reductive-aldol cyclization on various diketo-esters
catalyzed by the air-stable [CuF(PPh3)3$2MeOH] 1 complex com-
bined with a chiral diphosphane in presence of a stoichiometric
amount of a silane as reducing agent. Manifold enantiomerically
enriched bicyclic and tricyclic adducts were generated with a high
level of diastereo- and enantiocontrol. Furthermore, this strategy
was employed toward the synthesis of a key intermediate of mar-
rubiine in fewer steps compared to the original synthesis. Current
efforts are focused in order to develop new applications to this
versatile methodology especially for the synthesis of new chiral
synthetic building blocks for asymmetric synthesis. Further studies
in this area will be reported in due course.
Scheme 7. Reagents and conditions. (a) TFA, CH2Cl2, 91%. (b) TMSCH2N2, MeOH/Et2O,
rt, 91%. (c) SOCl2, pyridine, CH2Cl2, 0 ꢁC, 92%. (d) TMSOTf, TMSOe(CH2)2eOTMS,
CH2Cl2, ꢀ78 ꢁC, 96%. (e) (i) LDA, HMPA, MeI, THF, ꢀ78 ꢁC to rt. (ii) HCl 4 M, THF, rt, 80%.
Fig. 3. ORTEP drawing of 17b and ent-13. The hydrogen atoms are omitted for the sake of clarity.
According to the literature procedure,30 the alkylation of the
protected ester 17b was then carried out in presence of LDA at
ꢀ78 ꢁC followed by the addition of methyl iodide. Two isomers
were formed with a ratio of 80/20 in favor of the trans product,
which yielded to the unsaturated ester ent-13 after deprotection by
HCl 4 M in an 80% yield.33,34 As previously observed, the diaster-
4. Experimental section
4.1. General
NMR spectra were recorded on Brucker spectrometers
(300 MHz and 500 MHz for 1H, 75 MHz and 125 MHz for 13C).
eoselectivity was explained by the
b
attack of the in situ enolate and
Chemical shifts are reported in
thylsilane with the solvent resonance as the internal standard for
1H NMR and chloroform-d ( 77.0 ppm) for 13C NMR. Coupling
constants (J) are given in hertz. Following abbreviations classify the
multiplicity:
m¼multiplet, br¼broad signal. The attribution of the different
protons was realized thanks to Jmod spectra, COSY and HMBC cor-
relations. The mass spectra and the high-resolution mass spectra
d parts per million from tetrame-
the stereochemistry was proved by X-ray crystallography (Fig. 3).30
We have demonstrated a straightforward accessibility to the
intermediate ent-13 in few steps starting from the diketo-ester 2c
by using the reductive-aldol cyclization to build the chiral bicyclic
scaffold with a 45% overall yield over eight steps starting from the
2-methylcyclohexane-1,3-dione (original racemic synthesis: 12
steps; 36% yield).
d
s¼singlet,
d¼doublet,
t¼triplet,
q¼quartet,

J. Deschamp et al. / Tetrahedron 68 (2012) 3457e3467
3463
(HRMS) were obtained, respectively, from the mass-service at
(CH2eCH3), 32.7 (CH2), 19.8 (CH2), 14.2 (CH3). m/z (ICþ, NH3) 239.3
(MHþ). HRMS (ICþ): MHþ, found 239.1286. C13H19O4 requires
239.1283.
ꢀ
Universite catholique de Louvain (Varian MAT-44 or FINNIGAN
ꢀ
MAT TSQ 70 spectrometers) and at Universite de Mons (Autospec
6F spectrometer). IR spectra were recorded on Shimadzu
FTIR-8400S spectrometer. ½a D20
ꢂ
values were measured on a Per-
4.3. Procedure for the synthesis of precursor 4
kineElmer 241 MC Polarimeter (concentration c are given in
g/100 mL). Analytical gas chromatography was performed on
a ThermoFinningan Trace GC using a CHIRALSIL-DEX CB (25 m,
To a solution of 1,3-cyclohexanedione (50 mmol) in water
(25 mL) was added at room temperature a solution of benzyl-
triethylammonium hydroxide in methanol (Triton B, 40% w/w,
50 mmol, 1 equiv) followed by allyl bromide (60 mmol, 1.2 equiv).
After stirring for 16 h at room temperature, the mixture was fil-
trated and the filtrate was extracted with dichloromethane
(3ꢃ20 mL). The combined organic phases were washed with brine
(2ꢃ20 mL), dried over MgSO4, and concentrated in vacuo. The
residue was treated by an aqueous sodium hydroxide (0.5 M,10 mL)
and then washed with diethyl ether (3ꢃ10 mL). An aqueous chlo-
rhydric acid (0.5 M, 10 mL) was added until a neutral pH, the so-
lution was then extracted with diethyl ether (3ꢃ10 mL). The
combined organic phases were dried over MgSO4, filtrated, and
evaporated under reduced pressure to afford yellow oil. To a solu-
tion of Grubbs’ second generation metathesis catalyst (0.01 mmol,
1 mol %) in distilled dichloromethane (2 mL) was added under ar-
gon a solution of the pure 2-allyl-2-methyl-1,3-cycloalkanedione
(1 mmol) and tert-butyl acrylate (4 mmol, 4 equiv) in distilled
dichloromethane (4 mL). the solution was refluxed under argon for
16 h. After reducing the solution to 1 mL, the residue was purified
by column chromatography (CH2Cl2/MeOH: 98/2) and led to a pale
0.25 mm, 25 mm). All reactions were carried out in flame-dried
glassware under an inert atmosphere of argon. Toluene was dis-
tilled under argon over sodium. CuF(PPh3)3$2MeOH was prepared
according to the reported procedure23. The following ligands were
generously provided by Hoffmann-La Roche (BIPHEP) and Solvias
(JosiPhos, WalPhos, MandyPhos, TaniaPhos).
4.2. General procedure for the synthesis of precursors 2aeh
To
a
suspension of the 2-methyl-1,3-cycloalkanedione
(50 mmol) in water (125 mL) was added acrolein (75 mmol,
1.5 equiv). The mixture was stirred at room temperature for 18 h.
Then, water and the excess of acrolein were evaporated under re-
duced pressure. The wet solid obtained was stirred with dichloro-
methane (50 mL). After 15 min, the slight suspension was filtered
and the filtrate is dried over MgSO4. After filtration, the solution
was concentrated in vacuo to afford the corresponding 2-methyl-2-
propionaldehyde-1,3-cycloalkane-dione (quantitative yields) of
a sufficient purity for the next step. The aldehyde (50 mmol) and
the appropriate Wittig reagent (75 mmol) were warmed at 80 ꢁC in
toluene (150 mL) in presence of benzoic acid (50 mmol) for 18 h.
The solution was successively washed with bicarbonate aqueous
solution and brine. The organic solution was then dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified via column chromatography (CH2Cl2/AcOEt:
98/2) to give a colorless oil (75e96% yields).
yellow oil in good yields. IR (film, cmꢀ1
1367, 1367, 1255, 1155. 1H NMR (300 MHz, CDCl3)
)
n
3025, 2935, 1708, 1652,
6.70 (1H, dt,
d
J¼15.6 and 6.1 Hz, CHalkene), 5.70 (1H, dt, J¼15.6 and 1.4 Hz, CHal-
kene), 5.55 (1H, ddt, J¼16.7, 10.3 and 7.4 Hz, CHalkene), 5.06 (2H, m,
CH2Alkene), 2.60 (4H, t, J¼7.2 Hz, 2ꢃ CH2), 2.47 (2H, d, J¼7.4 Hz, CH2),
1.93 (6H, m, 3ꢃ CH2), 1.46 (9H, s, 3ꢃ CH3). 13C NMR (75 MHz, CDCl3)
d
209.9 (2ꢃ C]Oketone), 165.7 (C]Oester), 146.1 (CHalkene), 131.9
The compounds 2aec, 2g, and 2h have already been described
(CHalkene), 123.6 (CHalkene), 119.6 (CH2alkene), 80.2 (Cquat), 68.2
(Cquat), 41.5 (CH2), 39.3 (2ꢃ CH2), 32.9 (CH2), 28.1 (3ꢃ CH3), 27.4
(CH2), 16.8 (CH2). m/z (ESIþ): 329.2 (MNaþ). HRMS (ESIþ) MHþ,
found 329.1729. C18H26O4Na requires 329.1729.
in our previous report.18
4.2.1. (E)-5-(1-Methyl-2,6-dioxocyclohexyl)pent-2-enenitrile 2d. IR
(liquid film, cmꢀ1
)
n
2975, 2933, 2050, 1720, 1650, 1319, 1284, 1255,
1155. 1H NMR (300 MHz, CDCl3)
d
6.64 (1H, dt, J¼16.2 and 6.6 Hz,
4.4. General procedure for the synthesis of precursors 5aec
CHalkene), 5.31 (1H, m, CHalkene), 2.77e2.57 (4H, m, 2ꢃ CH2),
2.03e1.91 (6H, m, 3ꢃ CH2), 1.30 (3H, s, CH3). 13C NMR (75 MHz,
To a solution of 2-methyl-1,3-cycloalkanedione (10 mmol) in
THF (30 mL) were successively added lithium iodide (11 mmol,
1.1 equiv) and DBU (11 mmol, 1.1 equiv). After several minutes,
a white precipitate was formed. After stirring for 30 min, allyl
bromide (20 mmol, 2 equiv) was added to the suspension, and then
the mixture was refluxed for 11 h. After cooling at room tempera-
ture, the mixture was poured on ice-water and was extracted with
ethyl acetate (4ꢃ5 mL). The combined organic phase was succes-
sively washed with water, a aqueous sodium thiosulfate solution
(5%) and brine, then was dried over MgSO4 and evaporated under
reduced pressure. The residue was purified by column chroma-
tography (cyclohexane/AcOEt: 70/30) to afford a colorless oil. The
metathesis between 2-allyl-2-methyl-1,3-cycloalkanedione and
tert-butyl acrylate gave the expected precursor 5aec according to
the previous above procedures.
CDCl3)
d 209.7 (C]Oketone), 154.6 (CHalkene), 100.3 (CHalkene), 64.6
(Cquat), 37.9 (2ꢃ CH2), 32.4 (CH2), 28.9 (CH2), 23.2 (CH3), 17.5 (CH2).
m/z (ICþ, NH3) 206.2 (MHþ). HRMS (ESIþ): MNaþ, found 228.0993.
C12H15NO2Na requires 228.1000.
4.2.2. (E)-6-(1-Methyl-2,6-dioxocyclohexyl)hex-3-en-2-one 2e. IR
(liquid film, cmꢀ1
)
n
2970, 2935, 1724, 1655, 1320, 1283, 1255, 1155.
1H NMR (300 MHz, CDCl3)
d
6.68 (1H, dt, J¼16.0 and 6.5 Hz, CHalkene),
6.00 (1H, dt, J¼16.0 and 1.3 Hz, CHalkene), 2.76e2.57 (4H, m, 2ꢃ CH2),
2.22 (3H, s, CH3), 2.04e1.93 (6H, m, 3ꢃ CH2), 1.29 (3H, s, CH3). 13
C
NMR (75 MHz, CDCl3)
d
209.9 (2ꢃ C]Oketone), 198.4 (C]Oketone),
146.8 (CHalkene), 131.6 (CHalkene), 64.7 (Cquat), 38.0 (2ꢃ CH2), 33.7
(CH2), 27.9 (CH2), 26.8 (CH3), 22.1 (CH3), 17.5 (CH2). m/z (ICþ, NH3)
223.1 (MHþ). HRMS (ESIþ): MNaþ, found 245.1145. C13H18O3Na re-
quires 245.1154.
The compounds 5a and 5c have already been described in our
previous report.18
4.2.3. Ethyl (E)-5-(1-methyl-2,6-dioxocyclopentyl)-pent-2-enoate
2f. IR (liquid film, cmꢀ1
)
n
2975, 2933, 1726, 1650, 1319, 1284,
4.4.1. Methyl (E)-4-(1-methyl-2,6-dioxycyclohexyl) -but-2-enoate
1255, 1155. 1H NMR (300 MHz, CDCl3)
d
6.79 (1H, dt, J¼15.7 and
5b. IR (liquid film, cmꢀ1
)
n
2952, 2908, 1716, 1693, 1656, 1456,
6.9 Hz, Halkene), 5.79 (1H, dt, J¼15.6 and J 1.5 Hz, Halkene), 2.08 (2H,
m, CH2), 1.81 (2H, m, CH2), 2.78 (4H, m, 2ꢃ CH2), 1.27 (3H, t,
J¼7.1 Hz, CH2eCH3), 1.15 (3H, s, CH3). 13C NMR (75 MHz, CDCl3)
1434, 1272, 1174. 1H NMR (300 MHz, CDCl3)
d
6.69 (1H, dt, J¼15.6
and 7.7 Hz, Halkene), 5.82 (1H, d, J¼15.6 Hz, Halkene), 3.69 (3H, s, CH3),
2.66 (6H, m, 3ꢃ CH2), 1.95 (2H, m, CH2), 1.32 (3H, s, CH3). 13C NMR
d
215.8 (2ꢃ C]Oketone), 171.2 (C]Oester), 146.7 (CHalkene), 122.3
(75 MHz. CDCl3)
d
209.1 (2ꢃ C]Oketone), 166.4 (C]Oester), 143.2
(CHalkene), 69.6 (Cquat), 56.1 (CH2eCH3), 35.0 (2ꢃ CH2), 27.2
(CHalkene), 124.6 (CHalkene), 64.5 (Cquat), 51.4 (CH3), 37.9 (2ꢃ CH2),

3464
J. Deschamp et al. / Tetrahedron 68 (2012) 3457e3467
37.2 (CH2), 22.6 (CH3), 17.3 (CH2). m/z (ICþ, NH3): 225.1 (MHþ).
4.7. General procedure for the catalytic reductive-aldol
cyclization
HRMS (ICþ): MHþ, found 225.1129. C12H17O4 requires 225.1127.
4.5. General procedure for the synthesis of precursors 6a,b
A 25 mL flame-dried round bottom flask equipped with a mag-
netic stirrer, was charged with [CuF(PPh3)3$2MeOH] (9.0 mg,
0.01 mmol), ligand (0.01 mmol) and toluene (10 mL). The catalyst
solution was stirred for 30 min at room temperature and phenyl-
To a solution of 2-methyl-1,3-cyclohexanedione (10 mmol) in
anhydrous DMF (50 mL) was added cesium carbonate (12 mmol,
1.2 equiv) at room temperature under argon. After stirring for 1 h,
a solution of the appropriate alkyl iodide (15 mmol, 1.5 equiv) in
DMF (5 mL) was added to the suspension, and then the mixture was
stirred at room temperature under argon for 24 h. The mixture was
poured on water and was extracted with diethyl ether. The organic
phase was washed with brine, then was dried over MgSO4, and
evaporated under reduced pressure. The residue was purified by
column chromatography (CH2Cl2/MeOH: 100/0/98/2) to afford
silane (180 mL, 1.40 mmol) was added at the same temperature.
After cooling the solution at ꢀ50 ꢁC, the appropriate substrate in
toluene (2 mL) was added to the solution. The mixture was stirred
for 2 h at ꢀ50 ꢁC under argon. Conversion, dr and ee were followed
by gas chromatography on an aliquot sample (hydrolysis by 1 mL of
aqueous HCl 3 M solution and filtered through a plug of silica). The
reaction mixture was quenched by adding an aqueous HCl solution
(3 M, 10 mL), which was vigorously stirred under air atmosphere
for 1e2 h. The aqueous layer was extracted by diethyl ether
(3ꢃ5 mL). Then, the combined organic layers were washed with
brine (20 mL), dried over anhydrous MgSO4, filtered and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography to yield the corresponding cyclized adduct.
a
colorless oil (40e46% yields). The metathesis between 2-
pentenyl-2-methyl-1,3-cyclohexanedione or 2-hexenyl-2-methyl-
1,3-cyclohexanedione and tert-butyl acrylate gave the expected
precursor 6a,b according to the previous above procedures.
4.5.1. tert-Butyl (E)-6-(1-methyl-2,6-dioxocyclo-hexyl)hex-2-enoate
6a. IR (liquid film, cmꢀ1
)
n
2974, 2937, 2879, 1697, 1654, 1456,
4.7.1. (1R,2S,6R) 2-Cyano-1-hydroxy-6-methylbi-cyclo[4.4.0]-decan-
1394, 1280, 1249, 1151. 1H NMR (300 MHz, CDCl3)
d
6.76 (1H, dt,
7-one cis-3d. IR (liquid film, cmꢀ1
)
n
2975, 2933, 2050, 1720, 1650,
J¼15.6 and 7.6 Hz, Halkene), 5.70 (1H, dt, J¼15.6 and 1.5 Hz, Halkene),
2.65 (4H, m, 2ꢃ CH2), 2.14 (2H, tdd/qd, J¼7.4 and 1.4 Hz, CH2), 1.97
(2H, m, CH2), 1.79 (2H, m, CH2), 1.47 (9H, s, 3ꢃ CH3), 1.24 (2H, m,
1319, 1284, 1255, 1155. 1H NMR (300 MHz, CDCl3)
d
2.67e2.59 (1H,
m, Ha of CH2), 2.55 (1H, dd, J¼12.0 and 4.2 Hz, CH), 2.31e2.16 (3H,
m, CH2 and Hb of CH2), 2.09e1.95 (4H, m, 2ꢃ CH2),1.75e1.52 (2H, m,
CH2), 1.49e1.39 (2H, m, CH2), 1.31 (3H, s, CH3). 13C NMR (75 MHz,
CH2), 1.23 (3H, s, CH3). 13C NMR (75 MHz, CDCl3)
d
210.2 (2ꢃ C]
Oketone), 165.8 (C]Oester), 146.5 (CHalkene), 123.6 (CHalkene), 80.1
(Cquat), 65.3 (Cquat), 38.0 (2ꢃ CH2), 36.3 (CH2), 32.1 (CH2), 28.1 (3ꢃ
CH3), 23.3 (CH2), 20.0 (CH3), 17.6 (CH2). m/z (ICþ, NH3): 295.2 (MHþ).
HRMS (ICþ): MHþ, found 295.1903. C17H27O4 requires 295.1909.
CDCl3)
d
212.1 (2ꢃ C]Oketone), 119.8 (CN), 74.2 (Cquat), 53.8 (Cquat),
36.6 (CH), 36.0 (CH2), 32.3 (CH2), 28.7 (CH2), 25.3 (CH2), 22.9 (CH3),
21.1 (CH2), 18.9 (CH2). m/z (ICþ, NH3) 208.1 (MHþ). HRMS (ESIþ):
MNaþ, found 230.1152. C12H17NO2Na requires 230.1157. Chiral GC
(oven: 170 ꢁC, flow: 1.4 mL/min) rt¼14.75 min and 15.64 min.
4.5.2. tert-Butyl (E)-7-(1-methyl-2.6-dioxocyclo-hexyl)hept-2-
enoate 6b. IR (liquid film, cmꢀ1
)
n
2975, 2935, 2868, 1693, 1650,
4.7.2. (1R,2S,6R) 1-Hydroxy-2-(1-hydroxy)ethyl-6-methylbicyclo
1456, 1425, 1367, 1284, 1257, 1151. 1H NMR (500 MHz, CDCl3)
d
6.80
[4.4.0]-decan-7-one cis-3e. IR (liquid film, cmꢀ1
)
n
3470, 2965,
(1H, dt, J¼15.6 and 7.6 Hz, Halkene), 5.70 (1H, dt, J¼15.6 and 1.5 Hz,
Halkene), 2.13 (2H, tdd/qd, J¼7.4 and 1.4 Hz, CH2), 2.65 (4H, m, 2ꢃ
CH2), 1.99 (1H, m, Ha of CH2), 1.80 (1H, m, Hb of CH2), 1.77 (2H, m,
CH2), 1.48 (9H, s, 3ꢃ CH3), 1.40 (2H, m, CH2), 1.22 (3H, s, CH3), 1.14
2930, 1725, 1710, 1445, 1370, 1350, 1195. 1H NMR (300 MHz, CDCl3)
d
4.37 (1H, qd, J¼6.4 and 1.7 Hz, CH(OH)eCH3), 3.92 (2H, br s, OH),
2.65e2.53 (1H, ddd, J¼8.0, 4.0, and 2.0 Hz, CH), 2.28e2.14 (4H, m, 2ꢃ
CH2), 1.98e1.95 (1H, m, 1H of CH2), 1.85e1.84 (1H, m, 1H of CH2),
1.65e1.55 (3H, m, CH2þ1H of CH2),1.45e1.30 (3H, m, CH2þ1Hof CH2),
1.17 (3H, s, CH3), 1.15 (3H, d, J¼6.3 Hz, CH(OH)eCH3). 13C NMR
(2H, m, CH2). 13C NMR (125 MHz, CDCl3)
d
210.4 (2ꢃ C]Oketone),
166.0 (C]Oester), 147.3 (CHalkene), 123.2 (CHalkene), 80.1 (Cquat), 65.5
(Cquat), 38.0 (2ꢃ CH3), 37.0 (CH2), 31.7 (CH2), 28.3 (CH2), 28.1 (3ꢃ
CH3), 24.4 (CH2), 19.5 (CH3), 17.6 (CH2).m/z (ICþ, NH3): 309.3 (MHþ).
HRMS (ICþ): MHþ, found 245.1145. C13H18O3 requires 245.1154.
(75 MHz, CDCl3) d 214.1 (C]Oketone), 66.6 (CH(OH)eCH3), 55.5 (Cquat),
53.4 (Cquat), 43.9 (CH), 30.1 (CH2), 29.6 (CH2), 22.7 (CH3), 21.8 (CH3),
21.7 (CH2), 18.9 (CH2), 17.9 (CH2). m/z (ICþ, NH3): 226.3 (MHþ). HRMS
(ICþ): MHþ, found 226.1565. C13H22O3 requires 226.1569. Chiral GC
(oven: 165 ꢁC, flow: 1.2 mL/min) rt¼16.75 min and 18.14 min.
4.6. Synthesis of the precursor 12
To a solution of Grubbs’ second generation metathesis catalyst
(0.01 mmol, 1 mol %) in distilled dichloromethane (2 mL) was
added under argon a solution of the pure compound 4 (1 mmol)
and tert-butyl acrylate (30 mmol, 30 equiv) in distilled dichloro-
methane (4 mL). The solution was refluxed under argon for 12 h.
After reducing the solution to 1 mL, the residue was purified by
column chromatography (CH2Cl2/MeOH: 98/2) and afforded a pale
4.7.3. (1R,2S,6R) 2-Ethoxycarbonyl-1-hydroxy-6-methylbicyclo
[4.3.0]-nonane-7-one trans-3f. ½a D20
þ75.0 (c 2.0 CH2Cl2). IR (liquid
ꢂ
film, cmꢀ1 3467, 2970, 2935, 1728, 1708, 1448, 1371, 1352, 1197. 1H
) n
NMR (300 MHz, CDCl3)
d
4.20 (2H, q, J¼7.1 Hz, CH2eCH3), 3.90 (1H,
br s, OH), 2.57 (1H, m, CH2), 2.28e2.05 (3H, m, CHþCH2), 2.00e1.80
(3H, m, 3ꢃ Ha of CH2), 1.55e1.80 (2H, m, 2ꢃ Hb of CH2), 1.30 (3H, t,
J¼7.3 Hz, CH2eCH3), 1.42e1.25 (2H, m, 2ꢃ Hb of CH2), 1.05 (3H, s,
yellow oil (80% yield). IR (liquid film, cmꢀ1
1690, 1650, 1456, 1425, 1367, 1284, 1257, 1151. 1H NMR (300 MHz,
CDCl3)
)
n
2972, 2936, 2865,
CH3). 13C NMR (75 MHz, CDCl3)
d 218.1 (C]Oketone), 176.0 (C]Oes-
ter), 74.0 (Cquat), 61.1 (CH2eCH3), 53.6 (Cquat), 47.7 (CH), 34.3 (CH2),
31.2 (CH2), 28.6 (CH2), 25.1 (CH2), 22.1 (CH2), 18.9 (CH3), 14.1
(CH2eCH3). m/z (ICþ, NH3): 241.3 (MHþ). Chiral GC (oven: 155 ꢁC,
flow: 1.2 mL/min) rt¼13.75 min and 14.14 min.
d
6.71 (1H, dt, J¼15.6 and 6.4 Hz, CHalkene), 6.53 (1H, dt,
J¼15.5 and 7.7 Hz, CHalkene), 5.73 (1H, dt, J¼15.5 and 1.2 Hz, CHal-
kene), 5.71 (1H, dt, J 15.6 and 1.2 Hz, CHalkene), 5.06 (2H, m, CH2), 2.62
(6H, m, 3ꢃ CH2),1.9 (6H, m, 3ꢃ CH2),1.47 (9H, s, 3ꢃ CH3),1.45 (9H, s,
3ꢃ CH3). 13C NMR (75 MHz, CDCl3)
d
209.1 (C]Oketone), 165.6 (C]
4.7.4. (1S,2S,6R) 2-Ethoxycarbonyl-1-hydroxy-6-methylbicyclo
Oester), 163.4 (C]Oester), 145.3 (CHalkene), 140.1 (CHalkene), 127.1
(CHalkene), 124.1 (CHalkene), 80.5 (Cquat), 80.5 (Cquat), 67.7 (Cquat), 39.1
(2ꢃ CH2), 37.3 (CH2), 34.3 (CH2), 28.1 (6ꢃ CH3), 27.1 (CH2), 16.8
(CH2). m/z (ICþ, NH3): 407.4 (MHþ). HRMS (ICþ): MHþ, found
407.2429. C23H35O6 requires 407.2434.
[4.3.0]-nonane-7-one cis-3f. ½a D20
ꢂ
82.4 (c 3.4, CH2Cl2). IR (liquid
film, cmꢀ1 3467, 2970, 2935, 1728, 1708, 1448, 1371, 1352, 1197. 1H
) n
NMR (300 MHz, CDCl3)
d
4.21 (2H, q, J¼7.1 Hz, CH2eCH3), 3.39 (1H,
br s, OH), 2.67 (1H, dd, J¼12.4 and 4.5 Hz, CH), 2.48e2.41 (2H, m,
0
CH2), 2.34e2.18 (1H, m, Ha of CH2), 2.11e2.03 (1H, m, Ha of CH2),

J. Deschamp et al. / Tetrahedron 68 (2012) 3457e3467
3465
1.93e1.84 (1H, ddd, J¼13.4, 10.8 and 2.8 Hz, Hb of CH2), 1.70e1.45
at 35 ꢁC for 4 h. The reaction was quenched with water, and the
aqueous layer was extracted with diethyl ether. The combined or-
ganic layers were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated under vacuum to afford to the acid 16
(91% yield). This residue was employed in the next reaction without
further purification.
0
00
00
(3H, m, Hb , 2ꢃ Ha of CH2), 1.32e1.25 (2H, m, 2ꢃ Hb of CH2), 1.30
(3H, t, J¼7.1 Hz, CH2eCH3), 1.09 (3H, s, CH3). 13C NMR (75 MHz,
CDCl3)
d 219.9 (C]Oketone), 174.0 (C]Oester), 79.4 (Cquat), 61.1
(CH2eCH3), 53.5 (Cquat), 47.5 (CH), 32.8 (CH2), 31.9 (CH2), 27.7 (CH2),
25.8 (CH2), 20.1 (CH2), 14.2 (CH2eCH3), 12.8 (CH3). m/z (ICþ, NH3):
241.3 (MHþ). HRMS (EIþ). HRMS (ICþ): MHþ, found 241.1438.
C13H21O4 requires 241.1440. Chiral GC (oven: 155 ꢁC, flow: 1.2 mL/
min) rt¼26.58 min and 29.65 min.
½
a 2D0
ꢂ
ꢀ34 (c 4.3 CH2Cl2). IR (liquid film, cmꢀ1
)
n
3473, 2950, 2875,
8.16
1780, 1693, 1448, 1384, 1319, 1211. 1H NMR (300 MHz, CDCl3)
d
(1H, br s, CO2H), 2.71 (1H, dd, J¼12.3 and 3.8 Hz, CH), 2.60e2.72
(1H, ddd/td, J¼14.1 and 6.99 Hz, Hb of CH2), 2.29e2.43 (2H, m, Ha
of CH2þHb of CH2), 1.85e2.2 (4H, m, CH2þ2ꢃ Hb of CH2), 1.59e1.85
(4H, m, CH2þ2ꢃ Ha of CH2), 1.38e1.43 (1H, d, J¼13.4 Hz, Ha of CH2),
4.7.5. (1R,2S,5R) 2-Ethoxycarbonyl-1-hydroxy-5-methylbicyclo
[4.3.0]-nonane-6-one trans-8b. ½a D20
þ21.2 (c 3.1, CH2Cl2). IR (liquid
ꢂ
film, cmꢀ1
)
n
3508, 2950, 1730, 1697, 1431, 1247, 1134. 1H NMR
1.23 (3H, s, CH3). 13C NMR (75 MHz, CDCl3)
d 217.4 (C]Oketone),
(300 MHz, CDCl3)
d
3.70 (3H, s, CH3), 3.60 (1H, br s, OH), 2.67e2.61
179.8 (C]Oacide), 80.0 (Cquat), 54.9 (Cquat), 48.5 (CH), 36.9 (CH2),
34.5 (CH2), 5.1 (CH2), 25.1 (CH2), 20.0 (CH2), 20.1 (CH2), 14.7 (CH3).
m/z (ICþ, NH3): 227.0 (MHþ). HRMS (ICþ): MHþ, found 227.1286
C12H19O4 requires 227.1283.
(1H, dd/t, J¼9.9 Hz, CH), 2.65e2.49 (1H, ddd, J¼15.3,13.8 and6.6 Hz,
Ha of CH2), 2.30e2.23 (1H, m, Hb of CH2), 2.01e1.89 (5H, m, CH2þ3ꢃ
Ha ofCH2),1.62e1.51 (3H, m, 3ꢃ Hb ofCH2),1.20 (3H, s, CH3).13C NMR
0
0
(75 MHz, CDCl3)
d 212.7 (C]Oketone), 175.3 (C]Oester), 83.5 (Cquat),
61.7 (Cquat), 52.0 (CH3), 47.6 (CH), 36.7 (CH2), 30.5; 29.6; 23.9 and 20.2
(4ꢃ CH2), 15.2 (CH3). m/z (ICþ, NH3): 227.2 (MHþ). Chiral GC (oven
160 ꢁC, flow: 1.2 mL/min) rt¼9.85 min and 10.21 min.
4.9. (1S,2S,6R) 2-Methoxycarbonyl-1-hydroxy-6-methyl
-bicyclo[4,4,0]-decan-7-one cis-3b
To a solution of the acid 16 (1.0 g, 4.42 mmol, 1 equiv) in diethyl
4.7.6. (1S,2S,5R) 2-Ethoxycarbonyl-1-hydroxy-5-methylbicyclo
ether were successively added methanol (2.7 mL, 66 mmol,
15 equiv) and trimethylsilydiazomethane (720 mL, 4.86 mmol,
[4.3.0]-nonane-6-one cis-8b. ½a D20
ꢂ
þ43.8 (c 4.0 CH2Cl2). IR (liquid
film, cmꢀ1
)
n
3508, 2950, 1730, 1697, 1431, 1247, 1134. 1H NMR
1.1 equiv) at 0 ꢁC. The reaction mixture was stirred for 15 min, and
then was quenched with saturated aqueous NaHCO3 solution. The
aqueous phase was extracted with diethyl ether. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under vacuum. The residue was
purified by flash chromatography to afford the ester cis-3b (91%
yield).
(300 MHz, CDCl3)
d 3.76 (3H, s, CH3), 3.39 (1H, br s, OH), 3.12 (1H,
dd, J¼10.1 and 9.2 Hz, CH), 2.60e2.48 (1H, ddd, J¼15.3, 13.1 and
6.1 Hz, Ha of CH2), 2.39e2.31 (1H, m, Hb of CH2), 2.19e2.09 (1H, 1H,
0
0
00
Ha of CH2), 2.07e1.97 (1H, m, Hb of CH2) 1.94e1.83 (2H, m, 2ꢃ Ha
00
of CH2), 1.32e1.25 (2H, m, 2ꢃ Hb of CH2), 1.59e1.51 (2H, m, CH2),
1.22 (3H, s, CH3). 13C NMR (75 MHz. CDCl3)
d 212.8 (C]Oketone),
173.3 (C]Oester), 85.3 (Cquat), 58.3 (Cquat), 53.5 (CH3), 51.9 (CH), 36.8
(CH2), 20.6 (CH2), 21.4 (CH2), 29.7 (CH2), 30.9 (CH2), 17.0 (CH3). m/z
(ICþ, NH3): 227.2 (MHþ). HRMS (EIþ). HRMS (ICþ): MHþ, found
227.1278. C12H19O4 requires 227.1283. Chiral GC (oven: 160 ꢁC, flow:
1.2 mL/min) rt¼18.70 min and 19.70 min.
½
a 2D0
ꢂ
ꢀ37.8 (c 2.1 CH2Cl2). IR (film, cmꢀ1
)
n
3392, 2941, 1693,
3.64
1726, 1434, 1317, 1249, 1209, 1157. 1H NMR (300 MHz, CDCl3)
d
(s, 1H, CO2Me), 2.71 (1H, dd, J¼12.3 and 3.8 Hz, CH), 2.54e2.65 (1H,
ddd/td, J¼14.1, 14.1 and 6.99 Hz, Hb of CH2), 2.23e2.33 (2H, m, Ha
of CH2þHb of CH2), 2.08e2.19 (1H, m, Hb of CH2), 1.92e2.05 (2H, m,
2ꢃ Hb of CH2), 1.77e1.90 (2H, m, Ha of CH2þHb of CH2), 1.65e1.72
(1H, m, Ha of CH2), 1.54e1.63 (1H, m, Ha of CH2), 1.46e1.51 (1H, m,
Ha of CH2), 1.32e1.37 (1H, d, J¼13.5 Hz, Ha of CH2), 1.20 (3H, s, CH3).
4.7.7. tert-Butyl 6-(1-methyl-2,6-dioxocyclohexyl) hexanoate 9a. IR
(liquid film, cmꢀ1
)
n
2975, 2940, 2880, 1695, 1652, 1456, 1392, 1280,
1249, 1151. 1H NMR (300 MHz, CDCl3)
d
2.68e2.59 (4H, m, 2ꢃ CH2),
NMR 13C (75 MHz, CDCl3)
d 217.4 (C]Oketone), 174.9 (C]Oester), 77.1
2.18e2.13 (2H, m, CH2), 2.20e1.73 (4H, m, 2ꢃ CH2), 1.55e1.43(3H,
m, CH2þ1H of CH2), 1.42 (9H, s, 3ꢃ CH3), 1.40e1.20 (3H, m, CH2þ1H
(Cquat), 54.5 (Cquat), 52.2 (CH3), 48.7 (CH), 36.9 (CH2), 34.2 (CH2),
28.4 (CH2), 25.2 (CH2), 20.0 (CH2), 20.2 (CH2), 14.8 (CH3). m/z (ICþ,
NH3): 241,04 (MHþ). m/z (ICþ, NH3): 241.1 (MHþ). HRMS (ICþ):
MHþ, found 241.1590 C13H20O4 requires 241.1596. Chiral GC (oven:
160 ꢁC, flow: 1.2 mL/min) rt¼47.92 min and 48.79 min.
of CH2), 1.18 (3H, s, CH3). 13C NMR (75 MHz, CDCl3)
d
210.2 (2ꢃ C]
Oketone), 174.0 (C]Oester), 80.0 (Cquat), 53.4 (Cquat), 37.9 (2ꢃ CH2),
37.4 (CH2), 35.2 (CH2), 29.2 (CH2), 28.1 (3ꢃ CH3), 24.6 (CH2), 24.3
(CH2), 18.9 (CH3), 17.6 (CH2). m/z (ICþ, NH3): 297.4 (MHþ). HRMS
(ICþ): MHþ, found 297.2063C17H29O4 requires 297.2066.
4.10. (6R,10S) 10-methoxycarbonyl-6-methylbicyclo[4,4,0]-
dec-1-en-5-one 15b
4.7.8. tert-Butyl 7-(1-methyl-2.6-dioxocyclohexyl) heptanoate 9b. IR
(liquid film, cmꢀ1
)
n
2978, 2942, 2879, 1696, 1650, 1456, 1390, 1280,
To a solution of cis-3b (870 mg, 3.62 mmol, 1 equiv) in pyridine
was dropwise added thionyl chloride (530 mL, 7.24 mmol, 2 equiv)
1249, 1151. 1H NMR (300 MHz, CDCl3)
d
2.67e2.58 (4H, m, 2ꢃ CH2),
2.17e2.12 (2H, m, CH2), 2.19e1.72 (4H, m, 2ꢃ CH2), 1.54e1.42 (3H,
m, CH2þ1H of CH2), 1.41 (9H, s, 3ꢃ CH3), 1.30e1.19 (3H, m, CH2þ1H
of CH2), 1.17 (3H, s, CH3) 1.17e1.10 (2H, m, CH2). 13C NMR (75 MHz,
at 0 ꢁC. The reaction mixture was stirred for 15 min, and then was
quenched with water. The aqueous phase was extracted with ethyl
acetate. The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered, and concentrated under
vacuum. The residue was purified by Flash chromatography to af-
ford the non-conjugated ester 15b (92% yield).
CDCl3)
d
210.4 (2ꢃ C]Oketone), 174.2 (C]Oester), 80.0 (Cquat), 53.4
(Cquat), 37.9 (2ꢃ CH2), 37.2 (CH2), 35.1 (CH2), 29.1 (CH2), 28.2 (3ꢃ
CH3), 24.4 (CH2), 24.2 (CH2), 18.8 (CH3), 17.5 (CH2). 16.9 (CH2). m/z
(ICþ, NH3): 311.4 (MHþ). HRMS (ICþ): MHþ, found 311.2220
C18H31O4 requires 311.2222.
½
a 2D0
ꢂ
ꢀ108.8 (c 1.6 CHCl3). IR (film, cmꢀ1
)
n
3392, 2941, 1726,
5.36
1693, 1434, 1317, 1249, 1209, 1157. NMR 1H (300 MHz, CDCl3)
d
(1H, s, CH), 3.24e3.28 (1H, m, CH), 2.54e2.63 (1H, ddd/dt, J¼13.8
and 7.2 Hz, Hb of CH2), 2.36e2.47 (3H, m, CH2þHa of CH2), 1.56e1.91
(4H, m, CH2þ2ꢃ Hb of CH2), 1.28 (3H, s, CH3), 1.38e1.48 (1H, dt,
4.8. (1S,2S,6R) 2-Carboxyl-1-hydroxy-6-methylbicyclo-[4,4,0]-
decan-7-one 16
J¼12.3 and 4.2 Hz, Ha of CH2), 1.21e1.35 (1H, m, Ha of CH2). NMR 13
C
To a solution of the cis-3c (1.54 g, 5.45 mmol, 1 equiv) in dry
DCM was dropwise added trifluoroacetic acid (6.3 mL, 81.8 mmol,
15 equiv) at room temperature. The mixture was stirred and heated
(75 MHz, CDCl3) d 214.3 (C]Oketone), 174.4 (C]Oester), 140.7 (Cquat),
118.9 (Calkene), 51.8 (CH3), 48.1 (Cquat), 46.4 (CH), 35.5 (CH2), 34.7
(CH2), 30.5 (CH2), 24.8 (CH2), 21.9 (CH3), 20.5 (CH2). m/z (ICþ, NH3) :

3466
J. Deschamp et al. / Tetrahedron 68 (2012) 3457e3467
223.4 (MHþ). HRMS (ICþ): MHþ, found 223.13440. C13H19O3 re-
quires 223.13342. Chiral GC (oven: 130/170 ꢁC, 0.5 ꢁC/min, flow:
1.2 mL/min) rt¼30.76 min and 34.22 min.
(oven: 130/170 ꢁC, 0.8 ꢁC/min, flow: 1.2 mL/min) rt¼29,31 min
and 30,42 min.
4.12.2. (6R,10S) 10-Methoxycarbonyl-6,10-dimethylbicyclo[4,4,0]dec-
1-en-5-one cis-13. ½a D20
ꢂ
þ64 (c 2.4 CH2Cl2). IR (film, cmꢀ1
) n 1726,
d 5.51 (1H, t,
4.11. (6R,10S) 5-(1,3-Dioxolanyl)-10-methoxycarbonyl-6-
methylbicyclo[4,4,0]-dec-1-ene 17b
1712, 1454, 1253, 1126. RMN 1H (500 MHz, CDCl3)
J¼3.6 Hz, CH), 3.67 (1H, s, CH3), 2.63e2.68 (1H, m, Hb of CH2),
2.43e2.50 (1H, m, Hb of CH2), 2.29e2.40 (2H, m, 2ꢃ Ha of CH2),
2.02e2.07 (1H, m, Hb of CH2), 1.77e1.80 (1H, m, Hb of CH2),
1.67e1.73 (2H, m, CH2), 1.50e1.58 (2H, m, 2ꢃ Ha of CH2), 1.44 (3H, s,
To a solution of ketone 15b (700 mg, 2.65 mmol, 1 equiv) in
dry dichloromethane was successfully added TMSOTf (24
mL,
0.13 mmol, 0.05 equiv) at ꢀ78 ꢁC followed by the silyl ether (1.0 g,
5.30 mmol, 2 equiv). The reaction mixture was stirred for 1 h at
ꢀ78 ꢁC and was then allowed to warm slowly to room tempera-
ture and was stirred for 12 h. After addition of pyridine, the re-
action mixture was quenched with a saturated aqueous NaHCO3
solution. The aqueous phase was extracted with DCM. The com-
bined organic layers were washed with brine, dried over anhy-
drous MgSO4, filtered, and concentrated under vacuum to
quantitatively yield to the protected ester 17b (96% yield). This
residue was used in the next reaction without further
purification.
H16), 1.32 (3H, s, H11). RMN 13C (75 MHz, CDCl3)
d 214.83 (C]Oke-
tone), 177.59 (C]Oester), 144.03 (Cquat), 122.48 (Calkene), 52.15 (CH3),
49.46 (Cquat), 47.34 (Cquat), 35.01 (CH2), 34.51 (CH2), 31.78 (CH2),
26.07 (CH3), 25.96 (CH3), 23.74 (CH2), 16.99 (CH2). m/z (ICþ, NH3):
237,00 (MHþ). HRMS (ICþ): MHþ, found 237.1502. C14H21O3 re-
quires 237.1491. Chiral GC (oven: 130/170 ꢁC, 0.8 ꢁC/min, flow:
1.2 mL/min) rt¼31.01 min and 32.35 min.
Acknowledgements
ꢀ
This work was supported by the Universite catholique de Lou-
½
a 2D0
ꢂ
þ57 (c 5.3 CH2Cl2). IR (film, cmꢀ1
)
n
2947, 2603, 2497, 1731,
5.10 (1H, s,
vain and FNRS. Dr. B. Pugin (Solvias) and Dr. R. Schmid (Hoffman-La
Roche) are gratefully acknowledged for the generous gift of chiral
ligands. SHIMADZU Benelux is gratefully acknowledged for finan-
cial support for the acquisition of an FTIR-8400S spectrometer.
Sonia Gharbi is gratefully acknowledged for the synthesis of the
precursor 4.
1442, 1375, 1311, 1263, 1201. NMR 1H (300 MHz, CDCl3)
d
CH), 3.89e4.03 (4H, m, 2ꢃ CH2), 3.69 (1H, s, CH3), 3.21e3.25 (1H, m,
CH), 2.03e2.29 (2H, m, CH2), 1.46e1.87 (8H, m, 4ꢃ CH2), 1.23 (3H, s,
CH3). NMR 13C (75 MHz, CDCl3)
d 175.1 (C]Oester), 140.0 (Cquat),
118.8 (Calkene), 112.0 (Cacetal), 65.5 (CH2), 64.9 (CH2), 51.7 (CH3), 47.4
(CH), 43.8 (Cquat), 30.4 (CH2), 30.4 (CH2), 26.9 (CH2), 24.1 (CH2), 21.9
(CH3), 20.8 (CH2). m/z (ICþ, NH3): 267.04 (MHþ). HRMS (ICþ): MHþ,
found 289.1418 C15H22O4Na requires 289.1416. Chiral GC (oven:
130/170 ꢁC, 0.5 ꢁC/min, flow: 1.2 mL/min) rt¼44.04 min and
45.05 min.
References and notes
1. Reviews on domino reaction: (a) Tietze, L. F. Chem. Rev. 1996, 96, 115e136; (b)
Fogg, D. E.; dos Santos, E. N. Coord. Chem. rev. 2004, 248, 2365e2379.
2. For reviews on domino, cascade reactions in total synthesis see: (a) Tietze, L. F.;
Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131e163; (b) Nicolaou, K. C.;
Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551e564; (c) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134e7186; (d)
Chapman, C. J.; Frost, C. G. Synthesis 2007, 1e21.
4.12. 10-Methoxycarbonyl-6,10-dimethylbicyclo[4,4,0]dec-1-
en-5-one trans-13 and cis-13
3. For reviews on reductive-aldol reactions see: (a) Chiu, P. Synthesis 2004,
2210e2215; (b) Nishiyama, H.; Shiomi, T. Top. Curr. Chem. 2007, 279, 105e137.
4. For initial works on reductive-aldol reaction catalyzed by different metals see:
[Rh] (a) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809e4812; (b) Matsuda,
I.; Takahashi, K.; Sato, S. Tetrahedron Lett. 1990, 31, 5331e5334; [Co] Isayama, S.;
Mukaiyama, T. Chem. Lett. 1989, 2005e2008; [Pd] Kiyooka, S.; Shimizu, A.; Torii,
S. Tetrahedron Lett. 1998, 39, 5237e5238; [Cu] Ooi, T.; Doda, K.; Sakai, D.;
Maruoka, K. Tetrahedron Lett. 1999, 40, 2133e2136; [Ni] Chrovian, C. C.;
Montgomery, J. Org. Lett. 2007, 9, 537e540.
5. Forintermolecular reductive-aldolmediated by rhodium complexesinpresenceof
organosilane see: (a) Taylor, S. J.; Morken, J. P. J. Am. Chem. Soc. 1999, 121,
12202e12203; (b) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc. 2000,
122, 4528e4529; (c) Zhao, C. X.; Bass, J.; Morken, J. P. Org. Lett. 2001, 3, 2839e2842;
(d) Russell, A. E.; Fuller, N. O.; Taylor, S. J.; Aurriset, P.; Morken, J. P. Org. Lett. 2004, 6,
2309e2312; (e) Fuller, N. O.; Morken, J. P. Synlett 2005,1459e1461; (f) Nishiyama,
H.; Shiomi, T.; Tsuchiya, Y.; Matsuda, I. J. Am. Chem. Soc. 2005, 127, 6972e6973; (g)
Shiomi, T.; Ito, J.-i.; Yamamoto, Y.; Nishiyama, H. Eur. J. Org. Chem. 2006,
5594e5600; (h) Shiomi, T.; Nishiyama, H. Org. Lett. 2007, 9, 1651e1654; (i) Nish-
iyama, H.; Ishikawa, J.; Shiomi, T. Tetrahedron Lett. 2007, 48, 7841e7844.
6. For intermolecular reductive-aldol reactions catalyzed by rhodium complexes in
presence of hydrogen see: (a) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am.
Chem. Soc. 2002, 124, 15156e15157; (b) Jung, C. K.; Garner, S. A.; Krische, M. J. Org.
Lett. 2006, 8, 519e522; (c) Han, S. B.; Krische, M. J. Org. Lett. 2006, 8, 5657e5660;
(d) Jung, C. K.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 17051e17056; (e) Garner,
S. A.; Krische, M. J. J. Org. Chem. 2007, 72, 5843e5846; (f) Bee, C.; Han, S. B.;
Hassan, A.; Lida, H.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 2746e2747.
7. (a) Zhao, C. X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett. 2001, 3,
1829e1831; (b) Townes, J. A.; Evans, M. A.; Queffelec, J.; Taylor, S. J.; Morken, J. P.
Org. Lett. 2002, 4, 2537e2540.
To
a freshly prepared solution of LDA (i-PrNH: 1.37 mL,
9.8 mmol, 4.5 equiv and n-BuLi 2.5 M: 3.48 mL, 8.7 mmol,
4 equiv) was added HMPA (1.89 mL, 10,0 mmol, 5 equiv) in THF at
0 ꢁC. The reaction mixture was stirred for 30 min, and then was
dropwise treated with a solution of ester 15b (580 mg, 2.18 mmol,
1 equiv). After stirring for 2 h at 0 ꢁC, methyl iodide (1.36 mL,
21.8 mmol, 10 equiv) was dropwise added at ꢀ78 ꢁC, the reaction
mixture was then allowed slowly to warm to room temperature
and stirred for 12 h. The solution was quenched with HCl 6 M for
2 h. The aqueous phase was extracted with diethyl ether. The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under vacuum. The
two diastereoisomers 13 and 130 were, respectively, isolated by
flash chromatography.
4.12.1. (6R,10R) 10-Methoxycarbonyl-6,10-dimethylbicyclo[4,4,0]dec-
1-en-5-one trans-13. ½a D20
ꢂ
ꢀ64 (c 2.9 CH2Cl2). IR (film, cmꢀ1
) n
1724, 1706, 1456, 1247, 1139. NMR 1H (500 MHz, CDCl3)
d 5.83 (1H,
s, CH), 3.62 (1H, s, CH3), 2.62e2.68 (1H, m, Hb of CH2), 2.46e2.54
(1H, m, Hb of CH2), 2.33e2.41 (2H, m, 2ꢃ Ha of CH2), 2.26e2.29
(1H, dq, J¼13.4 and 3.7 Hz, Hb of CH2), 1.80e1.88 (1H, qt, J¼13.8
and 3,7 Hz, Hb of CH2), 1.73e1.76 (1H, dq, J¼13.5 Hz and 2 Hz, Hb of
CH2), 1.54e1.57 (1H, m, Ha of CH2), 1.32e1.38 (1H, ddd/dt,
J¼13.5 and 4.2 Hz, Ha of CH2), 1.29 (3H, s, CH3), 1.07 (3H, s, CH3),
1.02e1.07 (1H, ddd/dt, J¼13.4 and 4.2 Hz, Ha of CH2). NMR 13C
8. Lumby, R. J. R.; Joensuu, P. M.; Lam, H. W. Org. Lett. 2007, 9, 4367e4370.
9. (a) Inoue, K.; Ishida, T.; Shibata, I.; Baba, A. Adv. Synth. Catal. 2002, 344,
283e287; (b) Shibata, I.; Kato, H.; Ishida, T.; Yasuda, M.; Baba, A. Angew. Chem.,
Int. Ed. 2004, 43, 711e714.
10. For diastereoselective intramolecular reductive aldol cyclizations catalyzed by
rhodium complexes in presence of organosilane see: (a) Emiabata-Smith, D.;
McKillop, A.; Mills, C.; Motherwell, W. B.; Whitehead, A. J. Synlett 2001,
1302e1304; (b) Freiria, M.; whitehead, A. J.; Tocher, D. A.; Motherwell, W. B.
Tetrahedron 2004, 60, 2673e2692.
(75 MHz, CDCl3)
d 214.95 (C]Oketone), 177.24 (C]Oester), 143.43
(Cquat), 122.07 (Calkene), 51.97 (CH3), 48.95 (Cquat), 46.80 (Cquat),
37.27 (CH2), 35.38 (CH2), 34.79 (CH2), 27.28 (CH3), 25.22 (CH2),
23.00 (CH3), 18.73 (C4). m/z (ICþ, NH3): 237.07 (MHþ). HRMS
(ICþ): MHþ, found 237.1497. C14H21O3 requires 237.1491. Chiral GC
11. For diastereoselective intramolecular reductive aldol cyclizations catalyzed by
rhodium complexes in presence of hydrogen see: (a) Huddleston, R. R.; Krische,

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experiments on each pure isolated isomers, for details see Ref. 20 (Supple-
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compound 14b by comparision of the optical rotation value of the latter with
the reported value (Yamazaki, J.; Bedekar, A. V.; Watanabe, T.; Tanaka, K.;
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ꢂ
20(ꢀ85.6 (c
3.4 in CHCl3) and ꢀ140 (c 2.1 in CHCl3) the configuration is S. For details see
Ref. 20 (Supplementary data).
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27. The relative configuration was determined by NOE experiment for details see
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antiomeric excess has not been determined.
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s
-bond metathesis see: (a) Rendler, S.; Plefka, O.; Karatas,
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33. The diastereoselective ratio was determined by GC analysis. The trans no-
menclature referred to the rˇ elation between the two methyl groups.
22. cis and trans nomenclature referred to the relation of the different substituents
on the bicyclic junction. The relative configuration was determined by NOE
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