Enantioselective addition of β-functionalized allylboronates to aldehydes and aldimines. Stereocontrolled synthesis of α-methylene-γ-lactones and lactams

Article abstract of DOI:10.1016/j.tet.2007.12.046

We report results regarding the development of condensations of chiral β-alkoxycarbonylallylboronates on aldehydes and imines. These allylboronates add in a highly enantioselective and diastereospecific manner to afford biologically and synthetically useful chiral α-methylene-γ-butyrolactones and lactams. The nature of the electrophile (aldehyde vs imine) is shown to have a dramatic influence on the mechanism of the reaction, probably directing the stereoselectivity of the process through different transition states.

Full text of DOI:10.1016/j.tet.2007.12.046

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2441e2455
www.elsevier.com/locate/tet
Enantioselective addition of b-functionalized allylboronates
to aldehydes and aldimines. Stereocontrolled synthesis
of a-methylene-g-lactones and lactams
,y
*
Isabelle Chataigner , Franc¸oise Zammattio, Jacques Lebreton, Jean Villieras
´
Universite´ de Nantes, Nantes Atlantique Universite´, CNRS, Faculte´ des Sciences et des Techniques, Laboratoire de Synthe`se Organique (LSO),
UMR CNRS 6513, 2 rue de la Houssinie`re, BP 92208, F-44322 Nantes Cedex 3, France
Received 12 November 2007; received in revised form 19 December 2007; accepted 20 December 2007
Available online 15 January 2008
Abstract
We report results regarding the development of condensations of chiral b-alkoxycarbonylallylboronates on aldehydes and imines. These
allylboronates add in a highly enantioselective and diastereospecific manner to afford biologically and synthetically useful chiral a-methyl-
ene-g-butyrolactones and lactams. The nature of the electrophile (aldehyde vs imine) is shown to have a dramatic influence on the mechanism
of the reaction, probably directing the stereoselectivity of the process through different transition states.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the toxicity. In this context, the isosteric replacement of the
oxygen by a nitrogen atom is of interest, as it leads to a less
reactive and hopefully more selective system. In addition, the
supplementary nitrogen atom allows for a large variety of modu-
lations by its substitution with electron-withdrawing groups or
lipophilic chains for instance. Even if known in the natural
world, the a-methylene-g-butyrolactam moiety is much scarcer
than the lactone one (Fig. 1).1c,4
Various synthetic strategies have described an access to
these molecules in literature.1,5 A classical route is based on
the a-methylenation of a preformed lactone.5b Alkoxycarbo-
nylallylation reactions have also been largely studied to
The a-methylene-g-butyrolactone framework is widely
found in naturally occuring compounds (Fig. 1).1 In 1985,
Hoffmann already reported that more than 2000 natural deriv-
atives featured this moiety and evaluated that 10% of the reg-
istered products contained this structural motif.1a The ability
of the methylene group of the g-lactone to act as a highly
reactive Michael acceptor is the basis of its role as a physiolog-
ically important building block. Nucleophiles such as L-cyste-
ine or sulfhydryl containing enzymes add in vivo to the
unsaturated lactone part, thus inhibiting the incorporation of
several aminoacids into proteins.1,2 The toxicity often associ-
ated to their significant in vivo activity has, however, limited
the clinical use of these products.3 Modulations are thus
needed to improve the pharmacological properties and decrease
HOOC
O
R
H3CO
N
O
R
O
O
O
N
O
Me
O
O
3
1a: R = C5H11
1b: R = C13H27
2a: R = H
2b: R = CH3
* Corresponding author.
E-mail address: isabelle.chataigner@univ-rouen.fr (I. Chataigner).
y
´
Present address: Universite de Rouen, INSA de Rouen, CNRS UMR 6014,
Figure 1. Examples of naturally occuring a-methylene-g-lactones and lactams:
methylenelactocin (1a), protolichesterinic acid (1b), ambrosin (2a), parthenin
(2b), and pukelimid E (3).
`
C.O.B.R.A., I.R.C.O.F., 1 rue Tesnieres, 76131 Mont Saint Aignan Cedex,
France.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.046

2442
I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
assemble these frameworks (Scheme 1). The latter approach is
clearly attractive since it provides a convenient and attractive
route to both the methylene-lactone and -lactam skeletons by
simply changing the electrophilic partner from an aldehyde
to an aldimine substrate.
enough to be purified either by distillation under reduced pres-
sure or by flash chromatography on neutralized silica.
DIBAL
COOR1
R2
R3
HMPA
R2
COOR1
Toluene
0 °C
Al(iBu)2
R3
R2
Met
O
OR1
R3
2 R3
*
R2
R
*
6
*
*
R4
9a: R1 = Et, R2 = H
9b: R1 = R2 = Me
10a: R1 = Et, R2 = R3 = H
10b: R1 = R2 = Me, R3 = H
10c: R1 = R3 = Me, R2 = H
O
R4
O
+
X
XH OR1
R4
X = O, N-R3
7
X
4
5
O
Cl
a
B
O
Scheme 1.
11
R2
R3
COOR1
The asymmetric versions of this allylation reaction have
been mainly envisaged by introduction of the chiral part on
the alkoxycarbonyl group of the organometallic or on the elec-
trophile.6 The inherent lack of flexibility of these strategies
and the increasing efficiency of chiral allylmetals has led to
the development of substrates bearing a chiral auxiliary on
the metal center. This attractive route avoids the long and
sometimes tedious deprotection of substrates and allows for
the recycling of the chiral inductor. Among allylmetal re-
agents, organoboranes have proven their efficiency in the ster-
eocontrolled construction of several adjacent chiral centers
and have become invaluable tools in the organic chemists’
toolbox.7 In this context, we have been interested, for several
years, in the development of chiral b-alkoxycarbonylallylboro-
nates and have studied their reactivity toward various electro-
philes such as aldehydes and aldimines.8 We report herein
results regarding the stereochemical course of these condensa-
tions and show that the mechanism involved in the process
depends on the nature of the electrophile.
O
B
(95%)
O
12a: R1 = Et, R2 = R3 = H
12b: R1= R2 = Me, R3 = H
12c: R1 = R3 = Me, R2 = H
12b/12c: 65/35
a MeCu was added in the case of 10b and 10c.
Scheme 2.
The g-substituted crotylboronate derivatives could be ac-
cessed in a similar way, starting from methyl but-2-ynoate.
DIBAL reduction of methyl but-2-ynoate 9b expectedly fur-
nished the E-vinylalane 10b, in accordance with Tsuda’s
work.10 The presence of the supplementary methyl substituent,
however, significantly reduced the reactivity of the vinylalane
intermediate and after treatment with 11, the corresponding
crotylboronate was isolated in poor yield. This problem was
circumvented by addition of a catalytic amount of MeCu
that allowed to increase the overall yield to 95%. The pinacol
b-methoxycarbonylcrotyl-boronates 12b and 12c were iso-
lated as a mixture of diastereomers in a 65:35 (Z/E) ratio
(Scheme 2).
2. Results and discussion
2.1. Preparation of b-functionalized allylboronates
We next studied the replacement of the achiral pinacol moi-
ety by a chiral diol. Roush and Chemler have extensively
proven the efficiency of tartrate derivatives in enantioselective
allylations involving unfunctionalized boronates.7a However,
disappointing results had been observed in the b-alkoxycarb-
onyl series with these chiral auxiliaries, as well as with the
commercially available pinanediol (ee¼6e20% in the conden-
sation on aldehydes).8b We have thus turned our attention to
other chiral diols and have considered (ꢀ)-(1R,2R,3R,4S)-2-
endo-phenyl-2,3-bornanediol 14,8cee,9a initially described by
Hoffmann (Scheme 3).11 Thus, boronates 12 were cleaved
into the corresponding acids 13 by oxidative treatment of the
pinacol ester compounds using sodium periodate in a water/
acetone mixture. This procedure involves a concomitant
oxidation of the liberated pinacol, preventing its interference
in the following steps. Problems of reproducibility led us to
consider the modified procedure described by Coutts et al.,
who replaced water by an aqueous solution of ammonium
acetate.12 Under these conditions, acids 13 proved unstable
but their immediate esterification with diol 14 afforded
A few methods of b-alkoxycarbonylallylboronates prepara-
tion have been reported in literature.8a,9 In 1993, we first
described the synthesis of the achiral allylboronate 12a by
condensation of a vinylalane derivative on pinacol chlorome-
thylboronate in the presence of HMPA.8a More recently,
Hall et al. have described the related reaction between vinyl-
copper(I) intermediate and iodomethylboronate to yield g,g0-
disubstituted allylboronates.9a,b Ramachandran and Kabalka
have independently developed an alternative strategy based
0
on a palladium-catalyzed SN2 reaction of allylacetates with
bisdiboron compounds.9c,d Our own methodology relies on
treatment of ethylpropiolate 9a with diisobutylaluminium
hydride in the presence of HMPA leading to a vinylalane inter-
mediate 10a, which in turn was reacted in situ with pinacol
chloromethylboronate 11 to furnish pinacol b-ethoxycarbonyl-
allylboronate 12a, isolated in 95% yield (Scheme 2). In con-
trast to the unfunctionalized allylboronate derivatives, known
to be sensitive species, 12a eventually proved to be stable

I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
2443
chiral b-alkoxycarbonylallylboronates 15 in excellent yields
(Scheme 3). Once again, these boronates revealed quite robust
and were purified by chromatography on neutralized silica. It
allowed the concomitant separation of the Z/E mixture, in the
crotylboronate series, giving access to each diastereomer 15b
and 15c.
aminoalcohols could be beneficial to the chiral induction by
freezing the conformation of the chiral species through intra-
molecular hydrogen bonding (Scheme 4). Thus, the chiral
substrate derived from norephedrine, 16b, was prepared in
a similar manner. These new b-allyloxazaborolidine deriva-
tives 16a,b, however, proved unstable and were thus used as
such in the following step without further purification.
Having successfully synthesized various chiral allylboron
reagents, enantioselective allylboration reactions of aldehydes
and imines were next undertaken.
R2
R3
COOR1
R2
R3
COOR1
OH
NaIO4
O
aq. NH4OAc
acetone
B
B
O
OH
12a : R1= Et, R2 = R3 = H
12b: R1= R2 = Me, R3 = H
12c: R1 = R3 = Me, R2 = H
13a : R1 = Et, R2 = R3 = H
13b: R1 = R2 = Me, R3 = H
13c: R1 = R3 = Me, R2 = H
2.3. Reactivity of chiral b-ethoxycarbonylallylboron reagents:
the case of achiral aldehydes
Ether
MgSO4
r.t.
OH
OH
2.3.1. Case of ephedrine as chiral auxiliary
Reacting the chiral allyloxazaborolidine 16a with 3,4,5-
trimethoxybenzaldehyde 17a, chosen as a model substrate,
led to the formation of the expected homoallylic alcohol
18a, isolated in 60% overall yield (Scheme 5 and Table 1,
entry 1). With this b-ethoxycarbonyl substituted allylboron
derivative, the condensation required one week at room tem-
perature to reach completion and confirmed its sluggish char-
acter when compared to reactions in the unfunctionalized
series. Conjugation of the allyl unit to the ester, by lowering
the nucleophilicity of the allylboron moiety, may account
for this fact. Acidic catalyses (both by Lewis and Brønsted
acids) of similar condensations have been recently reported
in the literature.14e16 They have proven highly efficient on ac-
celerating the reaction and diminishing reaction times to one
day. However, they have also shown detrimental effects on
the stereoselectivity of the process, especially on the enantio-
selectivity.14b In our case, the enantioselectivity of the
Ph
(-)-14
COOR1
O
O
B
R3 R2
Ph
15a : R1 = Et, R2 = R3 = H (99%)
15b: R1= R2 = Me, R3 = H
(99%)
15c: R1 = R3 = Me, R2 = H
Scheme 3.
2.2. Preparation of b-functionalized allyloxazaborolidines
As Reetz and Itsuno have reported good results for similar
reactions when using unfunctionalized allyloxazaborolidine
derivatives,13 we decided to extend our method to the prepara-
tion of chiral b-alkoxycarbonyl substituted allyloxazaborol-
idines. The synthetic strategy used to access the chiral boron
species was similar to the one described above with chiral di-
ols. Thus, boronate 12a was cleaved with sodium periodate
and the resulting boronic acid 13a was immediately reacted
with ephedrine in the presence of magnesium sulfate. Disap-
pearance of 13a and generation of a new product was moni-
tored by TLC. Mass spectrometry analysis of the crude
mixture indicated the formation of the expected allylboron de-
rivative 16a (Scheme 4). We anticipated that the use of free
COOEt
R4
*
X
COOEt
i) r.t., 1 week
ii) hydrolysis
+ R4CHO
B
HO
O
17
18
a : R4 = 3,4,5-(OMe)3C6H2
b : R4 = C6H5
15a : X = O
16a : X = NMe
16b : X = NH
c : R4 = Et
d : R4 = iPr
e : R4 = CO2Et
Scheme 5.
COOEt
COOEt
OH
NaIO4
Table 1
Reaction between chiral allylboron substrates and achiral aldehydes
O
aq. NH4OAc
acetone
B
B
O
OH
Entry Allylboron substrate R4CHO Solvent Adduct Yield (%) eea (%)
12a
13a
RHN
HO
1
16a
16b
15a
15a
15a
15a
15a
15a
15a
15a
15a
17a
17a
17a
17a
17a
17a
17a
17b
17c
17d
17e
Toluene 18a
Toluene 18a
Toluene 18a
CH2Cl2 18a
60
60
88
63
91
99
89
95
99
80
90
6
30
82
82
80
76
71
80
78
72
78
Ether
MgSO4
r.t., 24h
2
Ph
3
EtO
4
O
B
COOEt
5
THF
Et2O
18a
18a
H
R
6
N
N
B
7
Pentane 18a
Toluene 18b
Toluene 18c
Toluene 18d
Toluene 18e
*
O
O
8
Ph
9
10
11
a
16a: R = Me
16b: R = H
Enantiomeric excess.
Scheme 4.

2444
I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
1
O
uncatalyzed process, evaluated by H NMR of the derived
O-methylmandelic and O-acetylmandelic esters,17 led to the
conclusion that ephedrine was a poor chiral inductor for this
reaction. Condensing 16b on 17a led to a significant increase
of the enantiomeric excess (ee) (entry 2) and came to support
the initial hypothesis on the positive impact of the free amino
group on the rigidity of the reactive conformation. However,
in both cases, the enantioselectivities remained modest, possi-
bly because of the remote position of the chiral centers with
respect to reactive sites.
R4
*
COOEt
a or b
O
*
90-99%
HO
R4
18
19
a : R4 = (OMe)3C6H2
b : R4 = C6H5
c : R4 = Et
e : R4 = CO2Et
Scheme 6. Reagents and conditions: (a) NaH, THF, 0 ꢁC (18aec); (b) PTSA,
Toluene, D (18e).
7, Table 2). L and D-glyceraldehyde acetonide derivatives 17f
and 17g were chosen as model chiral electrophiles since these
aldehydes have been used as classical probes.21 Both R and S
enantiomers were prepared in two steps starting, respectively,
from D-mannitol and L-gulonolactone, according to Schmidt
and Bradley’s procedure.22,23
2.3.2. Case of the (ꢀ)-(1R,2R,3R,4S)-2-endo-phenyl-2,3-
bornanediol chiral auxiliary
We were pleased to find that chiral allylboronate 15a bear-
ing a phenylbornanediol as chiral auxiliary provided good
level of enantioselectivity in the allylation reactions of alde-
hyde 17a (Table 1, entry 3). After the reaction, chiral diol auxi-
liary 14 could be recovered in quantitative yields. The absolute
R
R
1
stereochemistry, reliably assigned by H NMR spectrometry
O
after derivatization of the alcohols into mandelate esters,17
showed an R configuration for the major enantiomer. Note
that important solvent effects had been observed in the unfunc-
tionalized series.11b,18 The influence of this parameter on the
course of the reaction revealed insignificant when using the
b-ethoxycarbonyl substituted derivatives (compare entries
3e7). Toluene proved, however, to be the solvent of choice,
leading to the best yields and selectivities. Condensing the chi-
ral allylboronate 15a on benzaldehyde led to similar results,
leading to 18b in 95% yield and 80% ee (entry 8). Examina-
tion of the reactivity of 15a included the study of the conden-
sation with aliphatic aldehydes. Thus, using n-propanal 17c
furnished alcohol 18c, isolated in excellent yield and 78% ee
(entry 9). More hindered isobutyraldehyde 17d led to a small
decrease in enantioselectivity (entry 10). Finally, the conden-
sation of 15a on an ester substituted aldehyde 17e furnished
18e in 90% yield and 78% ee (entry 11). We thus showed
that the nature of the aldehydic component has only little in-
fluence on the course of the allylboration reaction. In contrast
to tartrate or pinanediol derived allylboronates, results ob-
served here with 14 are comparable to the ones reported in
the unfunctionalized series,11b and remain the best enantiose-
lectivities observed for condensations involving achiral alde-
hydes and b-alkoxycarbonylallylboronate reagents with
chirality borne by the boron atom.19,8cee,9a
R
O
R
O
O
*
*
CO2Et
COOEt
i) r.t., 1 week
ii) hydrolysis
O
+
B
*
O
HO
OHC
12a :
17f : R = CH3
18f : R = CH3
O
17g : R = -(CH2)3-
18g : R = -(CH2)3-
B
O
O
Ph
O
B
NaH, THF
0 °C
15a :
(95%)
*
*
O
O
O
O
R
R
19f : R = CH3
Scheme 7.
Reacting the achiral b-ethoxycarbonylallylboronate 12a
with aldehyde (R)-17f in toluene furnished homoallylic alco-
hol 18f, isolated in 89% yield (Scheme 7) (Table 2, entry 1).
The reaction showed moderate diastereoselectivity (40% de),
the major diastereomer having an (S,R) configuration.24 Simi-
larly, condensation of 12a on the (S)-17g led to an increased
but still modest stereoselectivity (entry 2). Reaction between
chiral boronate 15a and chiral aldehyde 17f of (R) configura-
tion led to a poorer diastereoselectivity, showing that these two
chiral entities have opposite stereochemical influences (entry
3). In contrast, the reaction between 15a and aldehyde 17f
The homoallylic alcohols 18 were then easily cyclized to
furnish the corresponding a-methylene-g-butyrolactones 19
in high yields (Scheme 6). Lactonizations were run either un-
der basic (18ec) or acidic (18e) conditions. Comparison of the
optical rotation of lactone 19b ([a]D ꢀ15.2 (c 1, CHCl3)) with
the literature data20 confirmed the R absolute configuration of
the major enantiomer.
Table 2
Reaction between chiral allylboron substrates and chiral aldehydes
Entry
Allylboron
substrate
Aldehyde
Adduct
Yield (%)
dea (%)
1
2
3
4
5
a
12a
12a
15a
15a
15a
(R)-17f
(S)-17g
(R)-17f
(S)-17f
(S)-17g
18f
18g
18f
18f
18g
89
99
99
99
97
40
56
2.4. Reactivity of chiral b-ethoxycarbonylallylboronate: the
case of chiral aldehydes
30
>95
>95
The double asymmetric induction phenomenon was also
examined by means of reaction with chiral aldehydes (Scheme
Diastereomeric excess.

I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
2445
Table 3
Reaction between chiral crotylboron substrates and aldehydes
possessing an (S) configuration led to the formation of a unique
diastereomer 18f bearing an (R,S) configuration (entry 4). The
phenomenon was confirmed when condensing boronate 15a
on chiral (S)-17g (entry 5). Both chiral entities have thus fully
synergical effects in these cases and allow for a totally diaster-
eoselective process. The resulting homoallylic alcohol 18f was
then cyclized into the corresponding lactone 19f in high yield
(Scheme 7).
Entry Allylic
substrate
R4CHO Adduct Yield (%) dra syn:anti Select.b (%)
1
2
3
4
5
6
7
15c
15c
15c
15b
15b
15b
15b
17b
17c
17e
17b
17c
17e
20a
20b
20c
20d
21e
20f
95
85
92
86
90
92
85
>19:1
>19:1
>19:1
>1:19
>1:19
>1:19
>1:19
50c
80c
35c
75c
85c
70c
>95d
(S)-17f 20g
Diastereomeric ratio determined by 1H NMR on the crude mixture.
Enantiomeric excess or diastereomeric excess.
1
Enantiomeric excess determined by H NMR spectrometry of the derived
a
b
c
2.5. Reactivity of chiral (E)-b-methoxycarbonylcrotyl-
boronate: the case of achiral aldehydes
mandelic esters.
d
Diastereomeric excess.
Reacting chiral (E)-15c with benzaldehyde 17b in toluene
furnished the corresponding homoallylic alcohol 20a in 95%
yield (Scheme 8) (Table 3, entry 1). The diastereoselectivity
of the reaction was complete and expectedly the syn diastereo-
mer was found to have formed, on basis of the 1H NMR
(vide infra). While, the acid-catalyzed condensations have
been shown to lead to mixtures of diastereomers, no isomeriza-
tion was observed under these non-acidic reaction condi-
tions.14d,15a,b A lower enantioselectivity was observed here,
probably because of the steric hindrance imposed by the methyl
group; this decrease in the asymmetric induction when compar-
ing allylboron with crotylboron reagents had already been
observed in the case of unfunctionalized reagents.7a,25 Next,
(E)-crotylboronate 15c was reacted with aldehyde 17c. Similar
results were observed in terms of yield and diastereoselectivity
but the level of asymmetric induction was significantly in-
creased with this aliphatic aldehyde (entry 2). In contrast, the
condensation of 15c on glyoxylic aldehyde 17e appeared less
enantioselective (entry 3).
2.6. Reactivity of chiral (Z)-b-methoxycarbonylcrotyl-
boronate: the case of aldehydes
Reacting chiral (Z)-crotylboronate 15b with aldehydes in
toluene furnished the expected homoallylic alcohols 20deg
and corresponding cyclized lactones 21deg (Scheme 8). The
diastereoselectivity of the reaction also appears to be com-
plete, leading to anti-alcohols 20deg and corresponding
trans-lactones 21deg (vide infra).26 Enantiomeric excesses
were higher with this (Z)-crotylboronate stereoisomer and
values appeared similar to those obtained previously in the
allylic series, in the 70e85% range (Table 3, entries 4e6).
Condensation of boronate 15b on chiral aldehyde (S)-17f simi-
larly led to a completely diastereoselective reaction, giving
access to the (3R,4R,5S) enantiomer of alcohol 20g, isolated
in 85% yield (entry 7).
Ph
MeO2C
OH
CO2Me
R3
R4CHO
17
O
B
R2
+
R4
a
O
R3
R2
17b : R4 = C6H5
17c : R4 = Et
(Z)-15b: R2 = Me, R3 = H
(E)-15c: R2 = H, R3 = Me
20a: R2 = H, R3 = Me, R4 = Ph
20b: R2 = H, R3 = Me, R4 = Et
17e : R4 = CO2Et
20c: R2 = H, R3 = Me, R4 = CO2Et
20d: R2 = Me, R3 = H, R4 = Ph
(S)-17f : R4 = CH(-OCMe2OCH2-)
20e: R2 = Me, R3 = H, R4 = Et
20f: R2 = Me, R3 = H, R4 = CO2Et
20g: R2 = Me, R3 = H, R4 = CH(-OCMe2OCH2-)
b or c
O
R4
R2
O
R3
21a: R2 = H, R3 = Me, R4 = Ph
21b: R2 = H, R3 = Me, R4 = Et
21c: R2 = H, R3 = Me, R4 = CO2Et
21d: R2 = Me, R3 = H, R4 = Ph
21e: R2 = Me, R3 = H, R4 = Et
21f: R2 = Me, R3 = H, R4 = CO2Et
21g: R2 = Me, R3 = H, R4 = CH(-OCMe2OCH2-)
Scheme 8. Reagents and conditions: (a) toluene, rt; (b) NaH, THF, 0 ꢁC (20a,b,d,e,g); (c) PTSA, toluene, D (20cef).

2446
I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
Lactonization of homoallylic alcohols 20aeg was effected
observed in all these allylation reactions (Scheme 9). The dia-
stereoselectivities observed in the case of double asymmetric in-
duction are in complete agreement with the proposed transition
state. Assuming that CeO bonds of the dioxolane and the form-
ing CeC bond are antiperiplanar,21b a mismatched effect is ex-
pected when using an R aldehyde, while the aldehyde of S
configuration should lead to synergical effects and formation
of a unique diastereomer. The complete diastereoselectivity
observed in the case of crotylboronate species is also in full
agreement with the proposed mechanism, since the (Z)-crotyl-
boronate leads to the formation of anti-homoallylic alcohols
and corresponding trans-lactones, while the (E)-crotylboronate
furnishes syn-alcohols and corresponding cis-lactones. In the
latter case, a disfavoring 1,2-interaction between the methyl
moiety of the crotylboronate and the R substituent of the alde-
hyde can account for the lower selectivity observed in some
cases.
in conditions similar to those described above (Scheme 8). The
cis/trans stereochemistry of the obtained lactones 21aeg was
assigned on the basis of NMR spectrometry and comparison
with previously reported data.14,15,27 Accordingly, the respec-
tive syn/anti stereochemistry of the corresponding precursory
alcohols 20aeg could be attributed.
The process thus appears to be stereospecific: thegeometry of
isomeric crotylboronates (E)-15b and (Z)-15c was transfered,
respectively, into diastereomeric anti- and syn-homoallylic al-
cohols and further into trans- and cis-lactones with no apparent
loss of selectivity. This constitutes the first enantioselective ver-
sion of condensations of crotylboronates bearing an alkoxycarb-
onyl moiety in b-position. While the enantioselectivity of this
process is moderate with (E)-crotylboronate, it reaches values
in 80% range with (Z)-crotyl species.
We have then tried to understand the sense of asymmetric
induction observed in these allylation reactions. A two-step
mechanism is generally proposed: after coordination of the
aldehydic oxygen to the0 boron, condensation happens with
allylic transposition (SE2 ), involving a six-membered cyclic
ZimmermanneTraxler type transition state.7a The first coordi-
nation step is the one that allows for discrimination of both
prochiral faces of the aldehyde and thus sets the enantioselec-
tivity of the process. When cyclic boronates are considered,
Roush proposed a prefered ‘axial’ coordination of the aldehy-
dic oxygen to boron atom, which could lead to a conformation
stabilized by nes* interactions between the axial lone pairs of
boronate oxygen atoms and the forming BeO bond, evoking
an anomeric effect centered on boron.28 A possible attractive
interaction between the aldehydic proton and the oxygen
atom borne by boron,29 associated to steric effects led us to
consider that the aldehydic hydrogen atom should be posi-
tioned toward the oxygen boronate. Taking into account these
considerations, two complexes A and B are to be considered
(Fig. 2). Hoffmann hypothesized that induction observed
with unfunctionalized allylboronates derived from phenylbor-
nanediol is based on aldehydic C]O double bond that should
be parallel to the phenyl moiety, the aldehydic hydrogen being
positioned on the phenyl side to avoid disfavored interactions
with the camphor moiety.11b In our case, this would lead to
a preferred complexation of the aldehyde on its Si face (com-
plex A on Fig. 1).
*
O
O
R1O2C
OH
O
B
R1O2C
O
R3
O
R3
R3
H
H C
R4
R2
R4
R2
R4
R2
C
Scheme 9.
2.7. Reactivity of chiral b-ethoxycarbonylallylboronate: the
case of aldimines
Reports on allylboration reactions with aldimines are much
seldom reported in the literature.30 This is probably due to
their trans-geometry that imposes the coordination of the ni-
trogen atom syn to the R4 group and, consequently, their
poor reactivity in allylation reactions. Interestingly, catalytic
asymmetric alkoxycarbonylallylstannation of aldimines was
recently reported in the presence of chiral bis-p-allylpalla-
dium complex.31 In our case, this reaction would lead to func-
tionalized a-methylene-g-lactams of interest.4 Furthermore,
imines derived from glyoxylate would produce chiral a-ami-
noesters bearing a functionalized allylic moiety. Reacting chi-
ral allylboronate 15a with imines led to a set of results
summarized in Table 4 (Scheme 10). No reaction was found
to occur with the sterically hindered imine 23a, bearing
a tert-butyl moiety (entry 1). In contrast, condensation of
15a on imine 23b, derived from glyoxylate led to the expected
a-aminoester 24b in good yield (entry 2). The lower reactivity
of aldimines when compared to aldehydes explains that the re-
action required two weeks to reach completion. This inertness
was, however, beneficial to enantioselectivity that reached
94%, a value higher than that measured in the case of achiral
aldehydes (compare entries 3, 8e11 of Table 1 with entries 2,
3 of Table 4). The generated homoallylic amine could be cy-
clized in 93% yield using PTSA in toluene. Condensation of
allylboronate 15a on aldimine 23c, bearing a p-methoxybenzyl
group on the nitrogen atom directly led to lactam 25c (entry
3). Enantioselectivity proved even higher in this case and led
Once this discriminative complexation has occurred,
the complex evolves to the reactive conformation. A chair-like
transition state C, for which the aldehydic R4 moiety adopts
a preferred pseudo-equatorial orientation in order to avoid
1,2-interactions, can thus account for the enantioselectivity
O
O
O O
All
H
All
B
B
H
O
O
R4
R4
A
B
favored complex
Figure 2.

I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
2447
Table 4
Reaction between chiral allylboron 15a and aldimines
proved to be the trans-lactam by comparison with reported
data.34 Additionally, condensing (E)-crotylboronate 15c with
23g led to the unique formation of the cis-lactam 27. The enan-
tiomeric excess of lactams 26 and 27, determined by NMR
spectrometry in the presence of Eu(hfc)3, proved to be superior
to 95% in both cases, confirming the good chiral transfer men-
tioned abovewith imines. This latter pair of examples highlights
the power of this approach at affording excellent diastereo-
and enantiocontrol in the formation of a-methylene-g-
butyrolactams.
Entry
Imine
Adduct
Yield (%)
eea (%)
1
2
3
4
5
6
a
23a
23b
23c
23d
23e
23f
d
d
73
65
92
58
61
d
94
24b
25c
25d
25e
25f
>95
>95
>95
>95
Enantiomeric excess determined by 1H NMR using Eu(hfc)3 as chiral shift.
to the isolation of a single enantiomer (ee>95%). The use of
silylated aldimines was also envisaged since they would
have the advantage of furnishing directly N-deprotected
derivatives after hydrolysis of the medium. Highly sensitive
aldimines 23def were accessed by condensing hexamethyldi-
silylazane amide on the corresponding aromatic aldehydes.32
Reacting these silylated imines on chiral allylboronate 15a di-
rectly led to the corresponding secondary lactams 25def after
acidic hydrolysis of the reaction medium (entries 4e6). Here
again, the condensations proved efficient and completely
enantioselective (ee>95%), leading to only one detectable en-
antiomeric secondary lactam. Optical rotations of lactams 25d
and 25e were indicative of their R configuration.33
Ph
N
MeO2C
R2
N
O
B
O
Ph
R2
Toluene
r.t., 14 d.
+
O
R3
R3
15b: R2 = Me, R3 = H
15c: R2 = H, R3 = Me
26: R2 = H, R3 = Me
23g
27: R2 = Me, R3 = H
Scheme 11.
The formation of lactams of R absolute configuration in-
volves an exclusive attack at the Re face of the aldimine
and thus contrasts dramatically with the similar reaction In-
volving aldehydes. A different pathway is to be considered
here. Because of the s-trans nature of imines, their coordina-
tion to the boron atom may occur in a different manner, as
described in Figure 3. Steric and electronic repulsions
between the R4 group and phenyl group of the chiral auxiliary
on one side and between R5 and the bornanediol moiety
on the other side may greatly disfavor the formation of
complex D.
Two transition states are then to be considered, involving
either a chair-like or a boat-like conformation (Scheme 12).
The respective formation of the trans- and cis-lactams from
the (Z)- and (E)-crotylboronate suggests that a boat-like tran-
sition state may be preferred in this case. A strong 1,3-diaxial
interaction between the ester group of the allylboronate and
the R4 group on the imine may, in this case, greatly disfavor
the chair-like conformation E over the boat-like one F. This
is in agreement with some results from the literature, which
propose boat-like transition states in the allylboration of
imine.35 These results, however, contrast with those previously
obtained in these laboratories with b-alkoxycarbonyl crotyl-
zinc derivatives, which furnish, respectively, cis- or trans-
lactam from (Z) or (E) substrates34 and thus furnishes a
complementary methodology to access a-methylene-g-
lactams on demand.
Ph
EtO2C
R4
O
B
N R5
COOEt
Toluene
r.t.
R4
+
B
O
N
Ph
R5
15a
R4
COOEt
23a : R4 = CO2Et, R5 = tBu
23b : R4 = CO2Et, R5 = cC6H11
HN
R5
23c : R4 = CO2Et, R5 = p(OMe)C6H4-CH2-
23d : R4 = C6H5, R5 = SiMe3
24b : R4 = CO2Et
23e : R4 = 3,4,5-(OMe)3C6H2, R5 = SiMe3
23f : R4 = p-ClC6H4, R5 = SiMe3
R5 = cC6H11
PTSA
Toluene
O
R5
N
R4
25a : R4 = CO2Et, R5 = tBu
25b : R4 = CO2Et, R5 = cC6H11
25c : R4 = CO2Et, R5 = p(OMe)C6H4
25d : R4 = C6H5, R5 = H
25e : R4 = 2,4,6-(OMe)3C6H2, R5 = H
25f : R4 = p-ClC6H4, R5 = H
Scheme 10.
O
O
O
H
O
2.8. Reactivity of chiral b-methoxycarbonylcrotylboronate:
the case of aldimines
All
R4
All
B
N
B
N
R4
R5
R5
H
Reacting chiral (Z)-crotylboronate 15b with aldimine 23g in
toluene furnished lactam 26 (Scheme 11). The diastereomeric
excess was determined by NMR spectrometry on the crude sam-
ple and showed the formation of only one stereoisomer, which
D
E
favored complex
Figure 3.

2448
I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
R1O2C
of DIBAL in toluene (113 mL, 110 mmol). The mixture was
BL2
CO2R1
R5
N
R5
R4
stirred at this temperature for 2 h. Ethylpropiolate (6.82 g,
71 mmol) was additioned dropwise and the reaction mixture
was stirred at 0 ꢁC overnight. Pinacol chloromethylboronate
11 (15 g, 85 mmol) was introduced and stirring was main-
tained at room temperature for 24 h. After dilution with ether
(230 mL), the reaction mixture was quenched with a 1 M so-
lution of HCl (60 mL). The organic layer was then succes-
sively washed with 1 M HCl (60 mL, three times), saturated
sodium bicarbonate (60 mL), and water (60 mL, twice). After
drying over MgSO4 and evaporation of the solvents the prod-
uct was purified by distillation under reduced pressure
(Eb¼80e85 ꢁC/1 mmHg) to give a colorless liquid (16.2 g,
95%). 1H NMR (200 MHz) 1.25 (s, 12H), 1.29 (t, 3H,
J¼7.1), 1.91 (br s, 2H), 4.19 (q, 2H, J¼7.1), 5.54 (dt, 1H,
J¼1.5, 1.4), 6.09 (dt, J¼1.5, 0.8). 13C NMR (50 MHz) 14.2,
17.2, 24.7 (4C), 60.7, 83.4 (2C), 124.1, 137.8, 167.3. MS
(EI) m/z: 240, 225, 182, 153, 141, 83. IR (film, cmꢀ1):
1720, 1625, 1350.
*
O
B
R4
N
O
R2
O
H
R4
N
R2
H
R2 R3
H
R5
R3
R3
trans when R2 = H, R3 = Me
E
cis when R2 = Me, R3 = H
R3
R4
R2 R3
*
R3
R2
O
B
H
R4
O
R2
CO2R1
H
N
N
R5
H
O
BL2
R5
R4
N
R1O2C
R5
F
cis when R2 = H, R3 = Me
trans when R2 = Me, R3 = H
Favored TS
Scheme 12.
3. Conclusion
Asymmetric b-alkoxycarbonylallylboration reactions offer
an easy and rapid access to chiral a-methylene-g-butyro-lac-
tones and lactams. The presence of an ester function in b-po-
sition of the nucleophilic allylic species, however, introduces
severe constraints as compared to classical unfunctionalized
allylmetal reagents, leading to less reactive reagents. The reac-
tions are thus rather slow but they are operationally simple.
Phenylbornanediol constitutes, to date, the best chiral auxili-
ary for b-alkoxycarbonylallylboration reactions and allows
a good to complete enantioselection and quantitative recycling
of the chiral entity. Discriminative complexation of aldehydes
to boron implicates a reaction on its Si face. In the case of al-
dimines, addition of a substituent on the heteroatom induces
new steric constraints and completely modifies the system,
the reaction taking place at the Re face of the imine. The pro-
cess appears to be completely stereospecific, depending on the
stereochemistry of the starting allylboronate species. (E)- and
(Z)-Crotylboronate, respectively, lead to cis- and trans-lac-
tones when reacted with aldehydes and a classical chair-like
transition state is proposed to account for these results. In con-
trast, the interaction of imines with (E)- and (Z)-crotylboronate
yields cis- and trans-lactam, suggesting a boat-like transition
state in this case. This methodology will now be used in the
synthesis of natural products and will be reported in due time.
4.1.2. Synthesis of methyl 2-((4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)methyl)but-2-enoate (12b and 12c)
To a stirred solution of CuI (192 mg, 1 mmol) in dry THF
(10 mL), cooled down to ꢀ30 ꢁC, was added a 1 M solution
of methyllithium in ether (1 mL, 1 mmol). After 20 min stir-
ring at this temperature, dry toluene (20 mL) and HMPA
(3.4 mL, 19.6 mmol) were added to this mixture. A 1 M solu-
tion of DIBAL in toluene (15 mL, 15 mmol) was then addi-
tioned dropwise and the reaction mixture was stirred at
ꢀ30 ꢁC for 2 h. Methyl but-2-ynoate (1 mL, 10 mmol) was
added and the reaction mixture was stirred at ꢀ20 ꢁC for an
additional 5 h. A solution of pinacol chloromethylboronate
11 (2.12 g, 12 mmol) was introduced and stirring was main-
tained at room temperature overnight. After dilution with ether
(30 mL), the reaction mixture was slowly quenched with a 1 M
solution of HCl (10 mL). The organic layer was then succes-
sively washed with 1 M HCl (10 mL, three times), saturated
sodium bicarbonate (10 mL), and water (10 mL, twice). After
drying over MgSO4 and evaporation of the solvents, a colorless
liquid (2.28 g, 95%) was obtained as 35:65 mixture of E/Z dia-
stereomers. Major diastereomer, 12b: 1H NMR (200 MHz)
1.24 (s, 12H), 1.83 (br s, 2H), 2.00 (dt, 3H, J¼7.3, 1.2),
3.71 (s, 3H), 6.06 (qt, 1H, J¼7.3, 1.3). 13C NMR (50 MHz)
15.8, 24.7 (4C), 51.0, 83.1 (2C), 128.7, 137.7, 168.2. Minor
4. Experimental section
1
diastereomer, 12c: H NMR (200 MHz) 1.24 (s, 12H), 1.78
4.1. General
(dt, 3H, J¼7.0, 0.8), 1.85 (br s, 2H), 3.71 (s, 3H), 6.83 (qt,
1H, J¼7.0, 1.1). 13C NMR (50 MHz) 14.4, 24.7 (4C), 51.5,
83.2 (2C), 129.9, 135.7, 168.3. MS (EI) m/z (%): 368 (1),
285 (7), 258 (100), 141 (64), 82 (52). IR (film, cmꢀ1): 2956,
1721, 1644, 1350, 1197.
1
Unless otherwise stated, H NMR (400 or 200 MHz) and
13C NMR (100 or 50 MHz) spectra were recorded in deuter-
ated chloroform relative to (CH3)4Si and CDCl3, respectively.
Chemical shifts are expressed in parts per million (ppm). Mass
spectra were recorded on a H.P. 5889 A spectrometer. IR spec-
tra were recorded on a Bruker IFS WHR spectrometers.
4.1.3. Synthesis of ethyl 2-[4-methyl-4,7-[dimethylmethano-
1,3-dioxo-2-boraperhydroinden-2-yl]methyl]prop-2-
enoate (15a)
Sodium periodate (3.85 g, 18 mmol) was added to a mixture
of pinacol allylboronate 12a (1.44 g, 6 mmol) in acetone
(160 mL) and 0.1 M solution of aqueous ammonium acetate
4.1.1. Synthesis of ethyl 2-((4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)methyl)acrylate (12a)
To a stirred solution of HMPA (37 mL, 210 mmol) in dry
toluene (230 mL) was added dropwise at 0 ꢁC a 1 M solution

I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
2449
(130 mL). Stirring was maintained at room temperature for
4.2. General procedure for the synthesis of homoallylic
24 h. Acetone was removed and the aqueous layer was ex-
tracted three times with ether. The organic layer was dried
over MgSO4 and partially evaporated until 40 mL of ether
are left. Phenylbornandiol 14 (1.086 g, 6 mmol) in ether
(40 mL) and MgSO4 (2 g) were added to this solution. After
24 h stirring, the magnesium sulfate was filtered and the
solvent removed under reduced pressure. The residue was
purified by flash chromatography (hexane/EtOAc/Et3N
95:5:0.001) to give 15a as a colorless oil (2.2 g, quantitative
yield). 1H NMR (200 MHz) 0.80e1.90 (m, 4H), 0.92 (s,
3H), 0.93 (s, 3H), 1.02 (t, 3H, J¼7.1), 1.23 (s, 3H), 1.93 (br
s, 2H), 2.13 (d, 1H, J¼5.2), 3.84 (dq, 1H, J¼ꢀ10.8, 7.1),
3.98 (dq, 1H, J¼ꢀ10.8, 7.1), 4.72 (s, 1H), 5.44 (dd, 1H,
J¼1.4, 2.9), 5.44 (d, 1H, J¼1.4), 7.20e7.50 (m, 5H). 13C
NMR (50 MHz) 9.3, 13.8, 17.1, 20.7, 23.5, 24.6, 29.5, 48.7,
50.1, 51.9, 60.4, 88.7, 95.7, 124.0, 126.6 (2C), 127.1, 127.3
(2C), 137.0, 141.6, 167.2. MS (EI) m/z (I%): 368 (1), 258
(100), 230 (28), 141 (34), 105 (21), 95 (19), 68 (23). IR
(film, cmꢀ1): 3060, 2984, 2963, 2898, 1718, 1635, 1372.
[a]D 46.2 (c 1.59, CHCl3). Anal. Calcd for C22H29BO4: C,
71.75; H, 7.94. Found: C, 71.79; H, 7.88.
alcohols 18 (typically on 1 mmol scale)
The desired aldehyde (1 equiv) was added to a stirred solu-
tion of phenylbornandiol 2-ethoxycarbonylallylboronate 15a
(1 mmol) in the appropriate solvent (2 M). Stirring was
maintained at room temperature under inert atmosphere for
one week (monitored by TLC). The reaction mixture was
quenched with water and extracted three times with ether. Af-
ter drying over MgSO4, solvents were removed under reduced
pressure. The residue was purified by flash chromatography,
allowing separation of the chiral auxiliary (quantitative recov-
ering yield) and the desired homoallylic alcohol (63e99%
yield).
4.2.1. Ethyl 4-hydroxy-2-methylene-4-(3,4,5-trimethoxy-
phenyl) butanoate (18a)
1H NMR (200 MHz) 1.32 (t, 3H, J¼7.1), 2.64 (ddd, 1H,
J¼0.6, 8.2, ꢀ14.0), 2.76 (br s, 1H), 2.80 (ddd, 1H, J¼0.9,
4.0, ꢀ14.0), 3.83 (s, 3H), 3.87 (s, 6H), 4.23 (q, 2H, J¼7.1),
4.83 (dd, 1H, J¼4.0, 8.2), 5.65 (m, 1H, J¼0.6, 0.9, 1.4),
6.26 (d, 1H, J¼1.4), 6.60 (s, 2H). 13C NMR (50 MHz) 13.9,
42.3, 55.8 (2C), 60.5, 60.8, 72.9, 102.4, 127.8 (2C), 137.0,
139.8, 152.9 (3C), 167.5. MS (EI) m/z (I%): 310 (5), 264
(68), 197 (100). IR (film, cmꢀ1): 3510e3420, 3006, 2940,
1710, 1620. Anal. Calcd for C16H22O6: C, 61.92; H, 7.14.
Found: C, 61.57; H, 7.38.
4.1.4. Synthesis of methyl 2-[4-methyl-4,7-[dimethyl-
methano-1,3-dioxo-2-boraperhydroinden-2-yl]-
methyl]but-2-enoate (15b and 15c)
Sodium periodate (2.77 g, 12.9 mmol) was added to
a 65:35 mixture of pinacol crotylboronate 12b/12c (1.037 g,
4.3 mmol) in acetone (57 mL) and 0.1 M solution of aqueous
ammonium acetate (48 mL). Stirring was maintained at room
temperature overnight. Acetone was removed and the aqueous
layer was extracted three times with ether. The organic layer
was dried over MgSO4 and partially evaporated until 30 mL
of ether are left. Phenylbornandiol 14 (1.65 g, 4.3 mmol) in
ether (30 mL) and MgSO4 (10 g) were added to this solution.
After 24 h stirring, the MgSO4 was filtered and the solvent re-
moved under reduced pressure to give a colorless oil (1.58 g,
quantitative yield) containing a 65:35 mixture of Z/E diaste-
reomers. They were separated by flash chromatography on
silica (hexane/EtOAc/Et3N 98:2:0.001) to give 15b and 15c
as colorless oils. Major diastereomer, first eluted, 15b: 1H
NMR (200 MHz) 0.90e1.25 (m, 4H), 0.92 (s, 3H), 0.94 (s,
3H), 1.21 (s, 3H), 1.82 (br s, 2H), 1.98 (dt, 3H, J¼7.2, 1.2),
2.13 (d, 1H, J¼5.1), 3.26 (s, 3H), 4.72 (s, 1H), 5.98 (qt, 1H,
J¼7.2, 1.3), 7.20e7.50 (m, 5H). 13C NMR (50 MHz) 9.2,
14.6, 19.5, 20.8, 23.5, 24.6, 29.4, 48.7, 50.1, 50.4, 51.8,
88.6, 95.8, 126.6 (2C), 127.1, 127.3 (2C), 128.3, 137.5,
141.8, 167.8. [a]D 95.5 (c 1.0, CHCl3). Minor diastereomer,
4.2.2. Ethyl4-hydroxy-2-methylene-4-phenyl butanoate (18b)
1H NMR (200 MHz) 1.31 (t, 3H, J¼7.1), 2.66 (ddd, 1H,
J¼0.9, 8.2, ꢀ13.9), 2.70 (br s, 1H), 2.80 (ddd, 1H, J¼1.1,
4.3, ꢀ13.9), 4.22 (q, 2H, J¼7.1), 4.89 (dd, 1H, J¼4.3, 8.2),
5.59 (m, 1H, J¼0.9, 1.1, 1.3), 6.23 (d, 1H, J¼1.3), 7.2e7.4
(m, 5H). 13C NMR (50 MHz) 14.0, 42.2, 60.8, 72.8, 125.6
(2C), 127.2, 127.9, 128.1 (2C), 137.0, 143.9, 167.5. MS (EI)
m/z (I%): 220 (1), 203 (20), 174 (14), 107 (100). IR (film,
cmꢀ1): 3510e3420, 3006, 2980, 1710, 1620. Anal. Calcd
for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.47; H, 7.43.
4.2.3. Ethyl 4-hydroxy-2-methylenehexanoate (18c)
1H NMR (200 MHz) 0.97 (t, 3H, J¼7.4), 1.31 (t, 3H,
J¼7.1), 1.50 (m, 2H, J¼7.4), 2.29 (br s, 1H), 2.33 (ddd, 1H,
J¼0.9, 8.3, 14.0), 2.59 (ddd, 1H, J¼1.1, 3.7, ꢀ14.0), 3.66
(m, 1H, J¼3.7, 8.3), 4.22 (q, 2H, J¼7.1), 5.66 (m, 1H,
J¼0.9, 1.1, 1.5), 6.25 (d, 1H, J¼1.5). 13C NMR (50 MHz)
9.9, 14.1, 29.9, 39.9, 60.9, 71.9, 127.3, 137.8, 167.7. MS
(EI) m/z (I%): 172 (1), 126 (10), 59 (100). IR (film, cmꢀ1):
3510, 2980, 2962, 1710, 1620. Anal. Calcd for C9H16O3: C,
62.77; H, 9.36. Found: C, 62.59; H, 9.50.
1
second eluted, 15c: H NMR (200 MHz) 0.90e1.25 (m, 4H),
0.92 (s, 3H), 0.93 (s, 3H), 1.22 (s, 3H), 1.70 (d, 3H, J¼7.0),
1.87 (br s, 2H), 2.12 (d, 1H, J¼5.2), 3.39 (s, 3H), 4.71 (s,
1H), 6.81 (q, 1H, J¼7.0), 7.20e7.50 (m, 5H). 13C NMR
(50 MHz) 9.2, 11.4, 14.3, 20.7, 23.5, 24.6, 29.4, 48.7, 50.1,
51.1, 51.8, 88.7, 95.6, 126.6, 127.1, 127.3, 129.5, 135.6,
141.7, 168.2. [a]D 58.7 (c 1.0, CHCl3). MS (EI) m/z: 368
(1), 285 (7), 258 (100), 141 (64), 82 (52). IR (film, cmꢀ1):
2956, 1721, 1644, 1350, 1197.
4.2.4. Ethyl 4-hydroxy-5-methyl-2-methylenehexanoate(18d)
1H NMR (400 MHz) 0.96 (d, 6H, J¼6.7), 1.30 (t, 3H,
J¼7.1), 1.67 (m, 1H), 2.29 (dd, 1H, J¼9.4, ꢀ14.0), 3.50
(ddd, 1H, J¼1.0, 2.7, ꢀ14.0), 3.50 (ddd, 1H, J¼2.7, 5.3,
9.4), 4.22 (q, 2H, J¼7.2), 5.66 (m, 1H), 6.25 (d, 1H, J¼1.4).
13C NMR (50 MHz) 14.1, 17.3, 18.5, 33.6, 37.2, 60.9, 75.4,

2450
I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
127.1, 138.3, 167.8. MS (CI NH3) m/z: 187. IR (film, cmꢀ1):
3520, 2950, 1710, 1620.
was purified by flash chromatography to give a white solid
(95% yield).
4.3.1. 3-Methylene-5-(30,40,50-trimethoxyphenyl) tetra-
hydrofuran-2-one (19a)
4.2.5. Ethyl 4-hydroxy-2-methylene penta-1,5-dioate (18e)
1H NMR (200 MHz) 1.29 (t, 3H, J¼7.1), 1.30 (t, 3H,
J¼7.1), 2.64 (dd, 1H, J¼8.0, ꢀ14.0), 2.86 (ddd, 1H, J¼0.9,
4.5, ꢀ14.0), 3.16 (d, 1H, J¼6.6), 4.23 (q, 4H, J¼7.1), 4.39
(ddd, 1H, J¼4.5, 6.6, 8.0), 5.72 (m, J¼0.9, 1.2 Hz), 6.29 (d,
J¼1.2). 13C NMR (50 MHz) 13.5 (2C), 36.5, 60.3, 60.7,
69.0, 127.5, 135.4, 166.3, 173.6. MS (CI CH4) m/z: 217. IR
(film, cmꢀ1): 3470, 2980, 1740, 1630.
1H NMR (200 MHz) 2.88 (m, 1H, J¼2.6, 2.9, 6.9, ꢀ17.0),
3.40 (m, 1H, J¼2.0, 2.6, 8.0, ꢀ17.0), 3.84 (s, 3H), 3.86 (s,
6H), 5.45 (dd, 1H, J¼6.9, 8.0), 5.70 (dd, 1H, J¼2.0, 2.6),
6.30 (dd, 1H, J¼2.6, 2.9 Hz), 6.52 (s, 2H). 13C NMR
(50 MHz) 36.4, 56.3 (2C), 60.9, 78.0, 122.5, 133.7 (2C),
134.4 (3C), 138.3, 153.7, 168.2. MS (EI) m/z (I%): 264 (11),
97 (100), 197 (73). IR (film, cmꢀ1): 3040, 2972, 1760, 1560.
4.2.6. Ethyl 2,20-dimethyl-10,30-(dioxolan-4-yl)-4-hydroxy-2-
methylene butanoate (18f)
4.3.2. 3-Methylene-5-phenyl tetrahydrofuran-2-one (19b)
1H NMR (200 MHz) 2.91 (dddd, 1H, J¼2.5, 2.9, 6.5,
ꢀ17.1), 3.41 (dddt, 1H, J¼2.5, 2.9, 8.0, ꢀ17.1), 5.53 (dd,
1H, J¼6.5, 8.0), 5.69 (dd, 1H, J¼2.5, 2.9), 6.31 (dd, 1H,
J¼2.5, 2.9 Hz), 7.20e7.40 (m, 5H). 13C NMR (50 MHz)
36.1, 77.9, 122.3, 125.3 (2C), 128.5, 128.7 (2C), 134.2,
139.8, 167.9. MS (EI) m/z (I%): 174 (8), 97 (100), 77 (18),
68 (38). IR (film, cmꢀ1): 3020, 2960, 1772, 1642.
1
(R,S) or (S,R) isomer: H NMR (400 MHz) 1.21 (t, 3H,
J¼7.1), 1.25 (s, 3H), 1.32 (s, 3H), 2.26 (ddd, 1H, J¼0.9,
8.6, ꢀ14.3), 2.61 (ddd, 1H, J¼1.1, 3.3, ꢀ14.3), 3.6e4.0 (m,
4H), 4.12 (q, 2H, J¼7.1), 5.63 (m, 1H), 6.18 (d, 1H, J¼1.4).
13C NMR (50 MHz) 14.2, 25.3, 26.2 36.2, 61.1, 66.7, 71.2,
1
78.3, 109.4, 128.0, 137.2, 168.0. (R,R) or (S,S) isomer: H
NMR (400 MHz) 1.21 (t, 3H, J¼7.1), 1.26 (s, 3H), 1.34 (s,
3H), 2.34 (ddd, 1H, J¼0.9, 8.4, ꢀ14.2), 2.40 (ddd, 1H,
J¼1.0, 4.1, ꢀ14.2), 3.6e4.0 (m, 4H), 4.11 (q, 2H, J¼7.1),
5.62 (m, 1H), 6.17 (d, 1H, J¼1.4). 13C NMR (50 MHz)
14.2, 25.3, 26.3, 36.7, 60.9, 66.7, 71.2, 78.5, 109.2, 127.8,
137.9, 167.3. MS (EI) m/z (I%): 244 (1), 229 (37), 199 (4),
143 (100), 113 (16), 123 (98), 73 (24). IR (film, cmꢀ1):
3471, 2980e2920, 1714, 1632, 1066.
4.3.3. 3-Methylene-5-ethyl tetrahydrofuran-2-one (19c)
1H NMR (200 MHz) 1.00 (t, 3H, J¼7.3), 1.72 (qd, 2H,
J¼7.3, 7.4), 2.58 (dddd, 1H, J¼2.6, 2.9, 6.2, ꢀ17.0), 3.06
(dddd, 1H, J¼2.0, 2.6, 7.6, ꢀ17.0), 4.70 (ddd, 1H, J¼6.2,
7.4, 7.6), 5.63 (dd, 1H, J¼2.0, 2.6), 6.21 (dd, 1H, J¼2.6,
2.9). 13C NMR (50 MHz) 8.9, 29.0, 32.9, 78.6, 121.7, 134.7,
162.2. MS (EI) m/z (I%): 126 (21), 97 (100), 69 (48). IR
(film, cmꢀ1): 2980, 2962, 1772, 1645.
4.2.7. Ethyl 4-(1,4-dioxaspiro [4,5] decanyl)-4-hydroxy-2-
methylene butanoate (18g)
4.3.4. 3-Methylene-5-ethoxycarbonyltetrahydrofuran-2-
one (19e)
1
(R,S) or (S,R) isomer: H NMR (400 MHz) 1.32 (t, 3H,
J¼7.1), 1.35e1.75 (m, 10H), 2.39 (ddd, 1H, J¼0.7, 8.5,
ꢀ14.3), 2.72 (ddd, 1H, J¼0.9, 3.4, ꢀ14.3), 3.66e4.00 (m,
4H), 4.23 (q, 2H, J¼7.1), 5.74 (m, 1H), 6.29 (d, 1H, J¼1.4).
13C NMR (50 MHz) 14.0, 23.6 (2C), 25.0, 34.7 (2C), 36.1,
60.9, 65.6, 71.2, 77.6, 109.6, 127.8, 137.0, 167.8. (R,R) or
(S,S) isomer: 1H NMR (400 MHz) 1.31 (t, 3H, J¼7.1),
1.35e1.75 (m,10H), 2.48 (ddd, 1H, J¼0.7, 8.0, ꢀ14.0), 2.51
(ddd, 1H, J¼0.9, 4.0, ꢀ14.0), 3.63e4.00 (m, 4H), 4.22 (q,
2H, J¼7.1), 5.73 (m, 1H), 6.28 (d, 1H, J¼1.5). 13C NMR
(50 MHz) 14.0, 23.0 (2C), 24.8, 34.7 (2C), 35.7, 60.9, 65.1,
69.4, 79.4, 110.0, 127.8, 137.0, 168.0. MS (CI NH3) m/z:
302 (MþNH3þ1). IR (film, cmꢀ1): 3470, 2972e2920, 1716,
1628, 1100.
To a solution of the hydroxyester 18e (216 mg, 1 mmol) in
toluene (5 mL) was added a catalytic quantity of monohy-
drated PTSA (19 mg, 0.1 mmol). The reaction mixture was
heated to reflux overnight and the water trapped in a Dean-
Stark apparatus. The solution was quenched with water, ex-
tracted with CH2Cl2, dried over MgSO4. After removal of
the solvents, the residue was purified by flash chromatography
1
(hexane/EtOAc 60:40) to give 19e (168 mg, 99% yield). H
NMR (200 MHz, CDCl3) 1.31 (t, 3H, J¼7.2), 3.01 (dddd,
1H, J¼2.4, 2.8, 4.7, ꢀ17.5), 3.28 (dddd, 1H, J¼2.4, 2.8, 9.3,
ꢀ17.5), 4.26 (q, 2H, J¼7.2), 4.96 (dd, 1H, J¼4.7, 9.3), 5.73
(dd, 1H, J¼2.4, 2.8), 6.30 (dd, 1H, J¼2.4, 2.8). 13C NMR
(50 MHz) 13.6, 30.7, 61.7, 72.5, 122.9, 131.5, 168.9, 169.3.
MS (EI) m/z (I%): 170 (1), 141 (7), 124 (18), 97 (100), 69
(43), 41 (46). IR (film, cmꢀ1): 2981 (CeH), 1783, 1748,
1654. Anal. Calcd for C8H10O4: C, 56.47; H, 5.92. Found:
C, 56.02; H, 6.20.
4.3. General procedure for the synthesis of a-methylene-g-
lactones 19
A solution of the hydroxyester 18 (1 equiv) in dry THF
(1 M solution) was added dropwise to a cooled (0 ꢁC) suspen-
sion of sodium hydride (1.1 equiv) in THF (1 M solution). The
reaction mixture was stirred for several minutes (monitored by
TLC), then worked up with a phosphate buffered solution
(pH¼7). After extraction with ether (three times), drying
over MgSO4, and evaporation of the solvents, the residue
4.3.5. 5-(2,20-Dimethyl-1,3-dioxolan-4-yl)-3-methylene-tetra-
hydro-2-furanone (19f)
1
(R,S) or (S,R) isomer: H NMR (400 MHz) 1.26 (s, 3H),
1.34 (s, 3H), 2.83 (dddd, 1H, J¼2.6, 2.9, 4.9, ꢀ17.5), 2.97
(dddd, 1H, J¼2.6, 2.9, 8.1, ꢀ17.5), 3.80e3.85 (m, 1H),
3.95e4.10 (m, 2H), 4.34 (ddd, 1H, J¼4.9, 6.9, 8.1), 5.59

I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
2451
(dd, 1H, J¼2.6, 2.9), 6.17 (dd, 1H, J¼2.6, 2.9). 13C NMR
(50 MHz) 24.9, 26.5, 29.8, 66.6, 76.6, 76.7, 110.1, 122.7,
133.6, 169.8. (R,R) or (S,S) isomer: 1H NMR (400 MHz)
1.36 (s, 3H), 1.39 (s, 3H), 2.83 (m, 1H), 2.97 (dddd, 1H,
J¼2.6, 2.9, 8.1, ꢀ17.5), 3.70e4.10 (m, 3H), 4.35e4.50 (m,
1H), 5.56 (dd, 1H, J¼2.6, 2.9), 6.16 (dd, 1H, J¼2.6, 2.9).
13C NMR (50 MHz) 25.3, 25.9, 29.5, 65.0, 75.1, 76.9, 110.2,
121.9, 133.8, 170.0. MS (EI) m/z (I%): 198 (1), 183 (24),
123 (16), 101 (41), 43 (100). IR (film, cmꢀ1): 2980e2920,
1774, 1667.
6.31 (ddd, 1H, J¼3.2, 0.9, 0.9), 7.38 (m, 5H). 13C NMR
(50 MHz) 15.7, 24.7, 51.4, 85.8, 120.9, 125.8, 128.7 (4C),
136.6, 140.4, 170.0. MS (EI) m/z (I%) 220 (2), 114 (100),
107 (72), 79 (79). IR (film, cmꢀ1): 3481, 3040e3029, 2976,
2940, 1772, 1718, 1636.
4.4.5. anti-1-Ethyl 5-methyl 2-hydroxy-3-methyl-4-methyl-
enepentanedioate (20f)
1H NMR (400 MHz) 1.31 (t, 3H, J¼7.2), 1.40 (d, 3H,
J¼6.9), 3.56 (m, 1H), 3.71 (s, 3H), 4.16 (dq, 1H, J¼7.2,
ꢀ10.8), 4.21 (dq, 1H, J¼7.2, ꢀ10.8), 4.34 (d, 1H, J¼6.3),
5.65 (d, 1H, J¼2.5), 6.31 (d, 1H, J¼2.8). 13C NMR
(100 MHz) 12.6, 18.6, 38.2, 51.1, 61.8, 71.9, 126.3, 140.9,
168.6, 174.0. MS (CI, NH3) m/z 234, 217. IR (film, cmꢀ1):
3487, 2981, 1777, 1719, 1628.
4.4. General procedure for the synthesis of homoallylic
alcohols 20 (typically on 1 mmol scale)
The desired aldehyde (1 equiv) was added to a stirred solu-
tion of the desired phenylbornandiol 2-methoxycarbonyl-
crotyl-boronate 15b or 15c (1 mmol) in dry toluene (2 M).
Stirring was maintained at room temperature under inert atmo-
sphere for one week (monitored by TLC). The reaction mix-
ture was quenched with water and extracted three times with
ether. After drying over MgSO4, solvents were removed under
reduced pressure. The residue was purified by flash chroma-
tography, allowing separation of the chiral auxiliary (quantita-
tive recovering yield) and the desired homoallylic alcohol
(85e95% yield).
4.5. General procedure for the synthesis of a-methylene-g-
lactones 21
A solution of the hydroxyester 20 (1 equiv) in dry THF
(1 M solution) was added dropwise to a cooled (0 ꢁC) suspen-
sion of sodium hydride (1.1 equiv) in THF (1 M solution). The
reaction mixture was stirred for several minutes (monitored by
TLC), then worked up with a phosphate buffered solution
(pH¼7). After extraction with ether (three times), drying
over MgSO4, and evaporation of the solvents, the residue
was purified by flash chromatography on silica to give the
desired lactone (90e99% yield).
4.4.1. syn-Methyl 4-hydroxy-3-methyl-2-methylene-4-
phenylbutanoate (20a)
1H NMR (400 MHz) 0.97 (d, 3H, J¼7.2), 2.71 (d, 1H,
J¼4.4), 3.06 (m, 1H), 3.71 (s, 3H), 4.64 (dd, 1H, J¼8.0,
4.4), 5.60 (mzd, 1H, J¼0.8), 6.23 (m, 1H), 7.31 (m, 5H).
13C NMR (50 MHz) 16.5, 43.5, 52.0, 78.1, 125.7, 126.6
(2C), 127.7, 128.2 (2C), 136.6, 142.9, 168.3. MS (EI) m/z
(I%): 220 (7), 114 (100), 79 (47). IR (film, cmꢀ1): 3481,
3064, 3029, 2973, 1772, 1715.
4.5.1. cis-4-Methyl-3-methylene-5-phenyl-dihydrofuran-
2(3H)-one (21a)
1H NMR (400 MHz) 0.76 (d, 3H, J¼7.1), 3.42 (m, 1H),
5.55 (d, 1H, J¼2.6), 5.60 (d, 1H, J¼8.1), 6.29 (d, 1H,
J¼3.2), 7.30e7.40 (m, 5H). 13C NMR (50 MHz) 15.4, 38.9,
82.1, 121.7, 126.0 (2C), 128.4, 128.5 (2C), 136.6, 140.0,
170.1. MS (EI) m/z (I%) 188 (10), 143 (30), 82 (100), 54
(95). IR (film, cmꢀ1): 2968, 2932, 1769, 1752, 1663.
4.4.2. syn-Methyl 4-hydroxy-3-methyl-2-methylene-
hexanoate (20b)
1H NMR (200 MHz) 0.93 (t, 3H, J¼7.4), 1.06 (d, 3H,
J¼7.2), 1.43 (m, 2H), 2.20 (br s, 1H), 2.80 (m, 1H), 3.52
(m, 1H), 3.73 (s, 3H), 5.60 (s, 1H), 6.23 (s, 1H). 13C NMR
(50 MHz) 10.4, 12.8, 27.4, 40.0, 51.8, 74.6, 125.3, 143.2,
168.0. MS (CI, NH3) m/z: 190, 173. IR (film, cmꢀ1): 3453,
2978, 2966, 1718, 1636.
4.5.2. cis-5-Ethyl-4-methyl-3-methylene-dihydrofuran-
2(3H)-one (21b)
1H NMR (400 MHz) 1.03 (t, 3H, J¼7.4), 1.23 (d, 3H,
J¼6.8), 1.68 (m, 2H), 2.68 (m, 1H), 3.93 (m, 1H), 5.52 (d,
1H, J¼2.8), 6.20 (d, 1H, J¼3.1). 13C NMR (50 MHz) 9.5,
17.2, 27.7, 39.4, 86.2, 120.7, 141.1, 170.3.
4.4.3. syn-1-Ethyl 5-methyl 2-hydroxy-3-methyl-4-methyl-
enepentanedioate (20c)
4.5.3. cis-Ethyl 3-methyl-4-methylene-5-oxo-tetrahydrofuran-
2-carboxylate (21c)
1H NMR (400 MHz) 1.24 (t, 3H, J¼7.1), 1.33 (d, 3H,
J¼6.9), 3.06 (m, 1H), 4.04 (q, 2H, J¼7.1), 4.40 (d, 1H,
J¼5.9), 5.60 (m, 1H), 6.25 (m, 1H). 13C NMR (50 MHz)
14.6, 18.7, 38.3, 66.8, 80.0, 122.8, 138.1, 169.0, 172.7.
1H NMR (400 MHz) 1.10 (d, 3H, J¼7.2), 1.27 (t, 3H, J¼7.2),
3.65 (m, 1H), 3.71 (s, 3H), 4.16 (dq, 1H, J¼7.2, ꢀ10.8), 4.21
(dq, 1H, 7.2, ꢀ10.8), 4.45 (d, 1H, J¼5.9), 5.73 (s, 1H), 6.30
(s, 1H). 13C NMR (100 MHz) 13.9, 16.1, 38.6, 51.1, 61.1,
73.3, 126.9, 140.0, 169.0, 174.0. MS (CI, NH3) m/z 234, 217.
4.5.4. trans-4-Methyl-3-methylene-5-phenyl-dihydrofuran-
2(3H)-one (21d)
1H NMR (400 MHz) 1.32 (d, 3H, J¼6.7), 2.95 (m, 1H),
4.90 (d, 1H, J¼7.6), 5.59 (d, 1H, J¼2.9), 6.31 (d, 1H,
J¼3.2), 7.30e7.42 (m, 5H). 13C NMR (100 MHz) 15.9,
4.4.4. anti-Methyl 4-hydroxy-3-methyl-2-methylene-4-
phenylbutanoate (20d)
1H NMR (200 MHz) 1.32 (d, 3H, J¼6.7), 2.96 (m, 1H),
3.71 (s, 3H), 4.91 (d, 1H, J¼7.6), 5.59 (dd, 1H, J¼3.2, 1.1),

2452
I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
43.4, 85.9, 121.0, 125.9 (2C), 128.7, 128.8 (2C), 136.4, 140.5,
170.0. MS (EI) m/z (I%) 188 (6), 143 (23), 82 (100), 54 (89).
IR (film, cmꢀ1): 3068, 3035, 2968, 2932, 1766, 1693.
(t, 1H, J¼1.7). 13C NMR (50 MHz) 14.1, 55.3, 61.8, 63.9,
114.2 (2C), 129.9 (2C), 153.9, 157.5 (2C), 171.3. MS (EI)
m/z (I%) 221 (15), 192 (17), 148 (53), 121 (100). IR (film,
cmꢀ1): 2978, 2936, 2836, 1745, 1634.
4.5.5. trans-5-Ethyl-4-methyl-3-methylene-dihydrofuran-
2(3H)-one (21e)
4.7. General procedure for the syntheis of silylated imines
1H NMR (200 MHz) 1.05 (t, 3H, J¼7.4), 1.25 (d, 3H,
J¼6.8), 1.68 (m, 2H), 2.70 (m, 1H), 3.95 (m, 1H), 5.55 (d,
1H, J¼2.7), 6.23 (d, 1H, J¼3.1). 13C NMR (50 MHz) 9.2,
17.0, 27.4, 39.2, 86.0, 120.4, 140.9, 170.0. MS (EI) m/z (I%)
140 (1), 111 (33), 82 (100), 54 (59). IR (film, cmꢀ1): 2968,
2935, 2881, 1762, 1685.
23de23f (typically on 15 mmol scale)
To a solution of hexamethyldisilylazane (1 equiv) in dry
THF (0.25 M) was added dropwise at room temperature
a 2 M n-BuLi solution in hexanes (1.25 equiv). The reaction
mixture was stirred at room temperature for 1 h before being
cooled to 5 ꢁC. The freshly distilled aldehyde (1 equiv) was
added dropwise and after 1 h stirring at 5 ꢁC, the reaction mix-
ture was filtered over Celite under inert atmosphere and then
over a classical filter to remove the salts. Evaporation of the
solvents led to the crude imine used for allylation reaction
(70% yield).
4.5.6. trans-Ethyl 3-methyl-4-methylene-5-oxo-tetra-
hydrofuran-2-carboxylate (21f)
1H NMR (400 MHz) 1.23 (t, 3H, J¼7.1), 1.36 (d, 3H,
J¼6.9), 3.12 (m, 1H), 4.20 (q, 2H, J¼7.1), 4.44 (d, 1H,
J¼6.0), 5.61 (m, 1H), 6.24 (m, 1H). 13C NMR (50 MHz)
14.0, 18.7, 38.3, 62.1, 79.4, 123.0, 137.9, 168.9, 172.7.
4.7.1. N-Trimethylsilyl benzylidenamine (23d)
4.5.7. trans-5-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-methyl-3-
methylene-dihydrofuran-2(3H)-one (21g)
1H NMR (200 MHz) 0.20 (s, 9H), 7.38 (m, 3H), 7.74 (m,
2H), 8.92 (s, 1H). 13C NMR (50 MHz) ꢀ1.2 (3C), 128.4
(2C), 128.5, 131.2 (2C), 138.8, 168.5. MS (EI) m/z (I%) 177
(44), 162 (100), 135 (27), 73 (53), 59 (81), 45 (14).
1H NMR (400 MHz) 1.33 (d, 3H, J¼6.9), 1.35 (s, 3H), 1.44
(s, 3H), 3.01 (m, 1H), 3.88e4.19 (m, 4H), 5.61 (d, 1H, J¼2.6),
6.26 (d, 1H, J¼3.0). 13C NMR (50 MHz) 19.1, 24.9, 26.6,
37.2, 66.8, 77.1, 83.9, 110.0, 122.0, 140.0, 169.6. MS (EI)
m/z (I%) 213 (1), 197 (87), 101 (81), 43 (100). IR (film,
cmꢀ1): 2940, 2901, 1770, 1726.
4.7.2. N-Trimethylsilyl-3,4,5-trimethoxybenzylidenamine (23e)
1H NMR (200 MHz) 0.25 (s, 9H), 3.74 (s, 3H), 3.93 (s,
6H), 7.06 (s, 2H), 8.86 (s, 1H). 13C NMR (50 MHz) ꢀ1.3
(3C), 56.0 (2C), 60.6, 131.5, 134.3 (2C), 140.7, 153.2,
157.8, 168.5.
4.6. General procedure for the synthesis of ethylglyoxylate
derived imines 23aec (typically on 10 mmol scale)
4.7.3. N-Trimethylsilyl-4-chlorobenzylidenamine (23f)
1H NMR (400 MHz) 0.25 (s, 9H), 7.40 (d, 2H, J¼7.0), 7.73
(d, 2H, J¼7.0), 8.92 (s, 1H). 13C NMR (50 MHz) ꢀ1.3 (3C),
128.8 (3C), 129.6 (2C), 137.2, 166.8. MS (EI) m/z (I%)
211e213 (1), 196e198, 169e171, 139e141, 73 (68), 59
(100).
To a 0.5 M solution of ethylglyoxylate (1 equiv) in dry
ether was added MgSO4. A solution of the corresponding
amine (1 equiv) in ether (0.5 M) was then added. The mixture
was stirred overnight under inert atmosphere at room temper-
ature before filtration and removal of the solvent. When neces-
sary, the imine was purified by flash chromatography on
neutralized silica (90% yield).
4.8. General procedure for the synthesis of homoallylic
amines
4.6.1. Ethyl N-tert-butyl-imino-ethanoate (23a)
1H NMR (200 MHz) 1.23 (s, 9H), 1.30 (t, 3H, J¼7.2), 4.30
(q, 2H, J¼7.2), 7.60 (s, 1H). 13C NMR (50 MHz) 13.9 (3C),
28.7, 61.3, 65.5, 148.5, 171.3. MS (EI) m/z (I%): 157 (1),
142 (2), 84 (15), 57 (100), 29 (18). IR (film, cmꢀ1):
2972e2874, 1752, 1748, 1648.
The desired imine (1.1 mmol) in dry toluene (0.5 mL) was
added to a solution of 2-ethoxycarbonylallylboronate 15a
(240 mg, 1 mmol) in toluene (0.5 mL). The reaction mixture
was stirred under inert atmosphere at room temperature for
two weeks (monitored by TLC), before being hydrolyzed
with water. After extraction with ether, drying over MgSO4
and evaporation of the solvents, the residue was purified by
flash chromatography, allowing separation of the chiral auxil-
iary 14 (quantitative recovering yield) and the desired homo-
allylic amine (73% yield).
4.6.2. Ethyl N-cyclohexyl-imino-ethanoate (23b)
1HNMR(200 MHz)1.00e2.00(m, 10H), 1.35(t, 3H, J¼7.2),
3.27 (m, 1H), 4.35 (q, 2H, J¼7.2), 7.73 (s, 1H). 13C NMR
(50 MHz) 14.2, 24.4 (2C), 25.4, 33.5 (2C), 61.7, 69.8, 151.4,
164.4. MS (EI) m/z (I%) 183 (1), 154 (11), 137 (14), 100 (30),
83 (100). IR (film, cmꢀ1): 2984e2857, 1747, 1723, 1646, 1242.
4.8.1. Ethyl N-cyclohexylamine-2-methylenepenta-1,5-
dioate (24b)
1H NMR (400 MHz) 0.80e2.00 (m, 10H), 1.27 (t, 3H,
J¼7.1), 1.33 (t, 3H, J¼7.1), 2.37 (m, 1H), 2.51 (dd, 1H,
J¼7.5, ꢀ13.7), 2.69 (ddd, 1H, J¼0.9, 7.1, ꢀ13.7), 3.64 (dd,
4.6.3. Ethyl N-p-methoxybenzyl-imino-ethanoate (23c)
1H NMR (200 MHz) 1.36 (t, 3H, J¼7.2), 3.81 (s, 3H), 4.34
(q, 2H, J¼7.2), 4.81 (d, 2H, J¼1.7), 6.80e7.20 (m, 4H), 7.69

I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
2453
1H, J¼7.1, 7.5), 4.14 (q, 2H, J¼7.1 Hz), 4.22 (q, 2H, J¼7.1),
4.9.2. (ꢀ)-(R)-3-Methylene-5-phenyl pyrrolidin-2-one (25d)
1
5.60 (dd, 1H, J¼0.9, 1.5), 6.19 (d, 1H, J¼1.5). 13C NMR
(50 MHz) 14.1 (2C), 24.5, 24.8, 25.9, 32.7, 34.0, 36.7, 55.0,
57.5, 60.4, 60.6, 126.9, 137.0, 165.6, 175.2. MS (EI) m/z
(I%) 298 (100), 224 (15), 184 (8), 96 (5), 55(6), 29 (47). IR
(film, cmꢀ1): 2982, 2940, 1742, 1640. Anal. Calcd for
C16H27NO4: C, 64.62; H, 9.15. Found: C, 64.46; H, 9.09.
Mp: 191 ꢁC, H NMR (400 MHz) 2.68 (dddd, 1H, J¼2.7,
2.7, 4.7, ꢀ17.1), 3.30 (dddd, 1H, J¼2.4, 2.4, 8.2, ꢀ17.1),
4.75 (dd, 1H, J¼4.7, 8.2), 5.37 (m, 1H), 6.04 (dd, 1H,
J¼2.4, 2.7), 6.55 (br s, 1H), 7.2e7.8 (m, 5H). 13C NMR
(100 MHz) 36.8, 54.8, 116.6, 125.7 (2C), 128.0, 129.0 (2C),
138.7, 142.6, 170.8. MS (EI) m/z (I%): 173 (69), 144 (20),
104 (33), 68 (49), 40 (100). IR (film, cmꢀ1): 3220, 1690,
1665, 1640. [a]D ꢀ15.0 (c 0.5, CHCl3). Anal. Calcd for
C11H11NO: C, 76.28; H, 6.40. Found: C, 76.38; H, 6.41.
4.8.2. 1-Cyclohexyl-5-ethoxycarbonyl-3-methylene pyrrolidin-
2-one (25b)
To a solution of the homoallylic amine 24b (297 mg,
1 mmol) in toluene (5 mL) was added a catalytic quantity of
PTSA (19 mg, 0.1 mmol). The reaction mixture was heated
to reflux overnight and the water trapped in a Dean-Stark ap-
paratus. The solution was quenched with water, extracted with
CH2Cl2, and dried over MgSO4. After removal of the solvents,
the residue was purified by flash chromatography to give 25b
4.9.3. (ꢀ)-(R)-3-Methylene-5-(3,4,5-trimethoxyphenyl)
pyrrolidin-2-one (25e)
Mp: 141 ꢁC, 1H NMR (400 MHz) 2.69 (dddd, 1H, J¼2.4, 2.8,
4.9, ꢀ17.2), 3.30 (dddd, 1H, J¼2.4, 2.4, 8.1, ꢀ17.2), 3.83 (s,
3H), 3.85 (s, 6H), 4.69 (dd, 1H, J¼4.9, 8.1), 5.40 (m, 1H),
6.08 (dd, 1H, J¼2.7, 2.4), 6.29 (br s, 1H), 6.48 (s, 2H). 13C
NMR (50 MHz) 36.7, 55.0, 56.0 (2C), 60.7, 102.4 (2C),
116.3, 138.3, 138.8 (3C), 153.5, 170.8. MS (EI) m/z (I%): 263
(100), 232 (62), 204 (13), 40 (24), 28 (24). IR (film, cmꢀ1):
3158, 3074, 2885, 1704, 1666. [a]D ꢀ20.0 (c 1.20, CHCl3).
1
(93% yield). H NMR (200 MHz) 1.00e1.83 (m, 10H), 1.29
(t, 3H, J¼7.1), 2.69 (dddd, 1H, J¼2.1, 2.1, 4.2, ꢀ17.0), 3.00
(dddd, 1H, J¼3.0, 3.0, 9.4, ꢀ17.0), 3.96 (tt, 1H, J¼3.7,
12.0), 4.17 (qd, 1H, J¼7.1, ꢀ14.2), 4.23 (qd, 1H, J¼7.1,
ꢀ14.2), 4.24 (dd, 1H, J¼4.2, 9.4), 5.33 (m, 1H), 6.01 (m,
1H). 13C NMR (50 MHz) 14.0, 25.5, 25.6, 29.2, 30.0, 30.3,
30.4, 52.9, 55.0, 61.6, 115.7, 137.9, 168.0, 172.9. MS (EI)
m/z (I%): 251 (14), 178 (100), 96 (91), 53 (19). IR (film,
cmꢀ1): 2975, 2932, 1740, 1734, 1669.
4.9.4. (ꢀ)-3-Methylene-5-p-chlorophenyl pyrrolidin-2-
one (25f)
1H NMR (400 MHz) 2.64 (dddd, 1H, J¼2.3, 2.7, 4.6,
ꢀ17.2), 3.31 (dddd, 1H, J¼2.3, 2.7, 8.2, ꢀ17.2), 4.74 (dd,
1H, J¼4.6, 8.2), 5.40 (dd, 1H, J¼2.3, 2.3), 6.07 (dd, 1H,
J¼2.7, 2.7), 6.73 (s, 1H), 7.22 (ddd, 2H, J¼2.0, 2.4, 8.5),
7.34 (ddd, 2H, J¼2.0, 2.4, 8.5). 13C NMR (50 MHz) 36.7,
54.2, 116.9, 127.1 (2C), 129.1 (2C), 133.6, 138.3, 141.2,
170.8. MS (EI) m/z (I%): 209e207 (63), 172 (100), 138
(29), 68 (74). IR (film, cmꢀ1): 3237, 3090, 2925, 1697,
1676. [a]D ꢀ21.9 (c 0.64, CHCl3).
4.9. General procedure for the synthesis of lactams 25
The desired imine (2 equiv) was added to a solution of 2-
ethoxycarbonylallylboronate 15a (1 equiv) in dry toluene
(2 M). Stirring was maintained at room temperature under in-
ert atmosphere for one week (monitored by TLC). The reac-
tion mixture was quenched with water and extracted with
ether. When homoallylic amine remained, an acido-basic treat-
ment of the crude mixture (HCl/NaOH) led to completion of
the cyclization. After drying of the organic layer over
MgSO4 and removal of the solvents, the residue was chroma-
tographed, allowing separation of the chiral auxiliary 14
(quantitative recovering yield) and the desired lactam
(58e92% yield).
4.9.5. 1,4-Dimethyl-3-methylene-5-phenylpyrrolidin-2-
one (26)
1H NMR (200 MHz) 1.26 (d, 3H, J¼7.0), 2.71 (m, 1H),
2.74 (s, 3H), 3.96 (d, 1H, J¼5.1), 5.29 (d, 1H, J¼2.4), 6.07
(d, 1H, J¼2.8), 7.3 (m, 5H). 13C NMR (50 MHz) 18.0, 28.8,
42.3, 70.5, 114.7, 127.0 (2C), 128.6, 129.3 (2C), 140.1,
145.2, 168.7. MS (EI) m/z (I%): 201 (100), 124 (69). [a]D
ꢀ21.0 (c 1.50, CHCl3).
4.9.6. 1,4-Dimethyl-3-methylene-5-phenylpyrrolidin-2-
one (27)
4.9.1. (ꢀ)-(R)-5-Ethoxycarbonyl-3-methylene-1-(4-methoxy-
benzyl) pyrrolidin-2-one (25c)
1H NMR (200 MHz) 0.75 (d, 3H, J¼7.1), 2.82 (s, 3H), 3.28
(m, 1H), 4.60 (d, 1H, J¼8.3), 5.22 (d, 1H, J¼2.9), 6.07 (d, 1H,
J¼3.1), 7.00 (m, 2H), 7.30 (m, 3H). 13C NMR (50 MHz) 14.2,
28.8, 35.6, 66.5, 114.5, 126.9, 127.4, 128.1, 128.6 (2C), 136.9,
144.6, 168.8. MS (EI) m/z (I%): 201 (100), 124 (69). Anal.
Calcd for C13H15NO: C, 77.58; H, 7.51. Found: C, 77.55; H,
7.17. [a]D ꢀ59.0 (c 0.32, CHCl3).
1H NMR (400 MHz) 1.18 (t, 3H, J¼7.1), 2.68 (dddd, 1H,
J¼2.2, 2.6, 3.4, ꢀ17.2), 2.89 (dddd, 1H, J¼2.2, 2.6, 9.4,
ꢀ17.2), 3.72 (s, 3H), 3.90 (dd, 1H, J¼3.4, 9.4), 4.00 (d, 1H,
J¼ꢀ14.7), 4.08 (qd, 2H, J¼7.1, 1.8), 5.02 (d, 1H, J¼ꢀ14.7),
5.32 (dd, 1H, J¼2.2, 2.2), 6.01 (dd, 1H, J¼2.6, 2.6), 6.77
(d, 2H, J¼8.6), 7.08 (d, 2H, J¼8.6). 13C NMR (50 MHz)
13.8, 28.8, 55.0, 55.5, 61.3, 74.6, 113.9, 116.5 (2C), 127.2,
129.8 (2C), 137.0, 159.1, 167.7, 170. MS (EI) m/z (I%): 289
(8), 216 (10), 121 (100). IR (film, cmꢀ1): 3470, 2981, 2937,
1740, 1734, 1669. [a]D ꢀ85.2 (c 2.03, CHCl3).
Acknowledgements
We thank the ‘Centre National de la Recherche Scientifi-
`
que’, the ‘Ministere de l’Education Nationale de la Recherche

2454
I. Chataigner et al. / Tetrahedron 64 (2008) 2441e2455
´
Durand, D.; Guingant, A.; Villieras, J. Tetrahedron Lett. 1998, 39,
et de la Technologie’ for a doctoral fellowship for I.C. and the
´
‘Universite de Nantes’ for supporting this work.
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