Copper-Catalyzed Asymmetric Conjugate Addition to α-Alkylidene Cycloalkanones

Article abstract of DOI:10.1055/s-0034-1380165

The asymmetric copper-catalyzed conjugate addition to α-alkylidene cycloalkanones, substituted at their terminal position with aromatic and aliphatic groups, is reported. While high enantioselectivity is reached using chiral phosphoramidite ligands, with R₃Al reagents, moderate diastereoselectivity was observed upon hydrolysis of the aluminium enolates. A Grignard reagent also react with high diastereoselectivity.

Full text of DOI:10.1055/s-0034-1380165

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 901–906
letter
901
P. Garcia et al.
Letter
Synlett
Copper-Catalyzed Asymmetric Conjugate Addition to
α-Alkylidene Cycloalkanones
Pierre Garciaa
Nicolas Germaina
Simon Woodwardb
Alexandre Alexakis*a
O
R2
R3
O
(R2)3Al
R1
R1
cat. CuI/L*
n
n
then R3 electrophile
10 examples
57–95% ee
dr 1:1 to 4:1
a Department of Organic Chemistry, University of Geneva, Quai Ernest
Ansermet, 30, 1211 Geneva 4, Switzerland
alexandre.alexakis@unige.ch
b School of Chemistry, The University of Nottingham, University Park,
NG7 2RD Nottingham, UK
n
= 1, 2
R1 = alkyl, aryl
Received: 26.11.2014
Accepted after revision: 22.01.2015
Published online: 17.02.2015
[Cu], L*
MAlkn
O
O
Alk
R = H, Alk, Ar
X = H, Alk, Ar,
OR, NR
R
X
DOI: 10.1055/s-0034-1380165; Art ID: st-2014-b0974-l
R
X
Abstract The asymmetric copper-catalyzed conjugate addition to α-
alkylidene cycloalkanones, substituted at their terminal position with
aromatic and aliphatic groups, is reported. While high enantioselectivi-
ty is reached using chiral phosphoramidite ligands, with R3Al reagents,
moderate diastereoselectivity was observed upon hydrolysis of the alu-
minium enolates. A Grignard reagent also react with high diastereo-
selectivity.
known
O
O
[Cu], L*
MAlkn
R = H, Alk, Ar
X = CH2, O, NR
X
X
( )n
( )n
Alk
[Cu], L*
MAlkn
O
O
Alk
Key words α-alkylidene cycloalkanones, conjugate addition, copper,
trialkylaluminium reagents, Grignard reagents
this work
R = Alk, Ar
X = CH2
( )n
n = 1, 2
*
X
X
*
R
R
( )n
Scheme 1 Copper-catalyzed conjugate additions
The synthesis of optically active compounds is of prime
importance for pharmaceutical needs and is therefore a re-
search field where asymmetric conjugate addition is a key
strategy.1 From a synthetic view point, the use of copper-
catalyzed conjugated-addition strategies (Scheme 1) en-
ables the easy introduction of molecular complexity: gener-
ation of one or two stereocenters2 and additional possibili-
ties for further functionalization thanks to the remaining
carbonyl group. General approaches for conjugated addition
of carbon nucleophiles rely on the use of acyclic or cyclic
substrates (Scheme 1, top) and very few approaches for the
functionalization of alkylidene cycloalkanones have been
reported (Scheme 1, bottom).3
Asymmetric conjugate addition of alkyl nucleophiles
onto α-alkylidene cycloalkanones have been reported for
diastereoselective processes, mainly using a stoichiometric
amount of copper.4,5 An enantioselective version of this
transformation employing a catalytic loading of copper salt
and chiral ligand would therefore facilitate the synthesis
of complex molecules. After a first proof of concept by
Woodward in 2001 where the enantioselectivity of the cop-
per-catalyzed addition of diethylzinc onto (E)-2-hex-
ylidenecyclopentanone was determined after derivatiza-
tion, albeit in a rather broad window (72–86% ee),6 we re-
port herein a specific study devoted to the enantioselective
conjugate addition of alkyl nucleophile (Me3Al, Et3Al) onto a
broad range of α-alkylidene cycloalkanones.
The screening of the reaction conditions (Table 1) con-
sisted of a library of copper salts and chiral ligands, diethyl
ether being the preferred solvent as reactions run in THF,
dichloromethane, or toluene showed a significant amount
of 1,2-addition adduct. In order to gain insights on the en-
antioselectivity of the transformation, and reduce the num-
ber of stereocenters to only one, once the conjugate addi-
tion was completed (ca. 2 h), trapping of the resulting eno-
late was realized with trifluoroacetic acid anhydride and
the crude mixture analyzed by chiral GC.
Using ethylmagnesium bromide as nucleophile (Table 1,
entries 1–4) did not provide any detectable enantioselectiv-
ity, although the conversion toward the expected com-
pound was total.7 While the use of diethylzinc did not show
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 901–906

902
P. Garcia et al.
Letter
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Table 1 Optimization of the Reaction Conditionsa
O
TFAA
O
CF3
Et
*
O
Et
*
O[Al]
[Cu]( 5 mol%)
L* (5 mol%)
(2 equiv)
+ EtnM
Ph
Ph
Ph
Et2O, –30 °C
1.4 equiv
2a
1a
CuCl
CuTc
Cu(MeCN)4BF4
[CF3SO3Cu]2⋅C6H6
[Cu]
L*
Cu-1
Cu-2
Cu-3
Cu-4
O
O
O
P
N
P
N
P
N
O
O
O
L-1
L-2
L-3
OMe
O
O
O
O
P
N
P
N
P
N
OMe
L-4
L-5
L-6
Entry
[Cu]
Cu-1
L*
EtnM
eeb,c
1
2
L-1
L-2
L-2
L-1
L-1
L-1
L-1
L-1
L-2
L-3
L-4
L-5
L-6
EtMgBr
EtMgBr
EtMgBr
EtMgBr
Et2Zn
Et3Al
0
Cu-1
Cu-2
Cu-3
Cu-4
Cu-3
Cu-4
Cu-2
Cu-2
Cu-2
Cu-2
Cu-2
Cu-2
0
0
3
4
0
5
0
6
56
33
67
84
55
–77
70
4
7
Et3Al
8
Et3Al
9
Et3Al
10
11
12
13
Et3Al
Et3Al
Et3Al
Et3Al
a Reaction conditions: 1a (0.27 mmol), EtnM (0.37 mmol), CuTc (0.013 mmol), L* (0.013 mmol), Et2O (3 mL).
b Full conversion in all cases; determined by GC.
c Determined by chiral GC on 2a.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 901–906

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Table 2 (continued)
Entry R1
any improved conditions (Table 1, entry 5), switching to tri-
ethylaluminium provided an initial enantioselective conju-
gate addition example (56% ee, Table 1, entry 6). In accord
with literature suggestions, copper thiophene-2-carboxyl-
ate (CuTc) was identified as the best copper catalyst after
further evaluation (Table 1, entries 7 and 8).8 With the ap-
propriate catalyst in hand, the last parameter screened was
the influence of the ligand. A remarkable improvement was
reached using the diastereoisomer of ligand L-1: L-2 pro-
vided a high enantioselectivity of 84% enantiomeric excess
(Table 1, entry 9).9 Removal of the chirality at the aryloxy
backbone (L-3) or the use of bulkier aryl groups at the ami-
do part of the phosphoramidite ligand L-4 were detrimen-
tal with 55% and 77% enantiomeric excess, respectively (Ta-
ble 1, entries 10 and 11). Finally, use of related L-5, with o-
methoxy group, did not yield improved conditions (Table 1,
entry 12) while the use of the phosphanamine L-6 afforded
almost a racemate (Table 1, entry 13).10
Having determined our best conditions (Table 1, entry
9), the scope of application of this procedure was evaluated
(Table 2) using trimethylaluminium and triethylaluminium
as nucleophiles and a broad range of α-alkylidene cyclohex-
anones or cyclopentanones substituted with either aromat-
ic or aliphatic groups. As we were most interested in reach-
ing functionalized cycloalkanones, quench of the reaction
mixture was realized using 1.2 M HCl in MeOH.
n
R2
Product
drb
eec
O
4
4-F3CC6H4
2
Me
2.2:1
92
F
F
F
3d
O
O
5
6
7
3-thienyl
3-thienyl
Ph
2
2
1
Me
Et
3.1:1
1.2:1
2.3:1
82
68
57
S
3e
S
3f
O
Me
3g
3h
3i
O
8
9
n-Pr
i-Pr
1
1
Me
Me
2:1
94
94
Table 2 Substrate Scopea
O
O
O
O
R2
CuTc (5 mol%)
L-2 (5 mol%)
4.2:1
R23Al
*
+
R1
*
R1
Et2O, –30 °C
R1 = Alk, Ar
1.4 equiv
( )n
( )n
1a–g
3a–j
Entry R1
n
R2
Product
drb
eec
10
i-Pr
1
Et
1:1
77
O
O
3j
a Reaction conditions: 1a–g (0.27 mmol), AlAlk3 (0.37 mmol), CuTC (0.013
mmol), L-2 (0.013 mmol), Et2O (3 mL)
1
2
3
Ph
Ph
2
Et
1.3:1
2.1:1
1.7:1
84
b Full conversion in all cases; determined by GC.
c Determined by chiral GC.
3a
3b
3c
When the optimal reaction conditions of Table 1 were
used, a diastereomeric ratio of 1.3:1 (Table 2, entry 1) was
obtained. Interestingly, using Me3Al instead of Et3Al al-
lowed access to a higher enantioselectivity of 90% enantio-
meric excess and a rather increased diastereoselectivity of
2.1:1 (Table 2, entry 2). In both cases, the enantioselectivity
of the two diastereomers was identical, showing that the
protonation of the enolates is not affected by the chiral li-
gand. Keeping Me3Al as the nucleophile, the influence of
the substitution at the para position was briefly studied.
Thus, either 4-Me (95% ee, 1.7:1 dr) or 4-CF3 (92% ee, 2.2:1
dr) groups furnished the target product in similar enantio-
2
2
Me
Me
90
95
O
4-MeC6H4
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selectivity and diastereoselectivity to 3b (Table 2, entries 3
and 4). After the evaluation of the influence of the aromatic
group at the alkene terminus, the influence of an hetero-
aromatic group was studied using a 3-thienyl group. As for
previous cases, higher enantioselectivity and diastereo-
selectivity was observed when Me3Al was used instead of
Et3Al (Table 2, entries 5 and 6). Notably, here the presence
of a sulfur atom interfered only slightly with the reaction
performance as the enantioselectivity of 82% reached for
3e11 remained high.
Contracting the cyclohexanone framework to cyclopen-
tanone, the enantioselectivity of the addition of Me3Al
dropped dramatically from 90% to 57% (Table 2, entries 2 vs.
7) while a similar diastereoselectivity (2.1:1 vs. 2.3:1) was
attained. Gratifyingly, in the presence of an alkyl terminus,
instead of the aromatic one previously discussed, an excel-
lent enantiomeric excess of 94% was reached even though a
low diastereomeric ratio of 2:1 was still observed (3h, Table
2, entry 8). Changing from n-Pr to i-Pr group yielded 3i12
with the same enantioselectivity of 94% but pleasingly with
a higher diastereoselectivity of 4.2:1 (Table 2, entry 9).
Again, the use of Et3Al furnished 3j with lower enantiomer-
ic excess and diastereomeric ratio (entry 10).
were identified: requirement of additional HMPA and MeLi
in THF along with reactive electrophiles such as methyl io-
dide, allyl iodide, or benzyl iodide.
Unfortunately, the trapping reaction, generating the
quaternary center α to the tertiary center built during the
nucleophilic attack, showed very poor reproducibility. In-
deed, despite extended efforts to optimize this step, vari-
able and significant amounts of the product from simple
hydrolysis were always present in the crude mixture.15 We
reasoned that this could arise from enolate equilibration
between the transient enolate and the final compound.
Notwithstanding this drawback, the diastereoselectivity of
the trapping was reproducible. However, as this was rather
low, similar to those observed during the direct hydrolysis
of the transient aluminium enolate (max. 3:1), we did not
pursue this investigation.
We eventually studied the influence of a stereogenic
center onto the substrate (Scheme 3). We anticipated, based
on literature precedent, that substituting the cycle may
have an effect on the outcome of the title reaction.4,5 For ex-
ample, asymmetric conjugate addition of dimethylzinc to 4
followed by zinc enolate trapping with benzaldehyde and
subsequent elimination afforded 6 in 42% isolated yield af-
ter three steps, and >99% enantiomeric excess.16,17 We
therefore attempted different catalytic systems but none of
them was as reactive except copper iodide promoted 1,4-
addition of Grignard reagents. Starting from a racemic mix-
ture of 6, we managed to isolate a mixture of diastereomers
of 7 in 88:12 diastereomeric ratio. The same ratio was ob-
served after reaction with enantiomerically pure unsatu-
rated ketone 6: only one enantiomer of each diastereomer
While the addition of Me3Al enabled very high enanti-
oselectivities to be reached, simple hydrolysis of the tran-
sient enolate furnished a tertiary center with only modest
diastereoselectivity. Therefore, we questioned whether the
use of other electrophiles than TFAA (Table 1) or H+ (Table
2) would provide greater stereoselection at the quaternary
center through C-alkylation (Scheme 2).13 After optimiza-
tion, reaction conditions close to those reported by Cramer14
HMPA (2 equiv)
O
CuTc (5 mol%)
L-2 (5 mol%)
Me
MeLi (2 equiv)
O
R2
O[Al]
( )n
Me
R1
R2I (10 equiv)
R1
R1
+ Me3Al
THF, r.t.
Et2O, –30 °C
1.4 equiv
( )n
1a–g
( )n
R1 = Alk, Ar
Scheme 2 Attempted C-alkylation of the transient aluminium enolate
R2 = Me, allyl, Bn
O
O
OH
Ph
O
1) L-4 (4 mol%), CuTc (2 mol%)
Me2Zn (1,1 equiv)
Et2O, –30 °C, 4 h
DBU
(0.6 equiv)
Ph
THF, r.t., 16 h
2) PhCHO (1.1 equiv)
–30 °C to r.t., 15 min
Me
Me
6 (42 %)
4
5
O
O
F3C
O
Et
1) CuI (5 mol%)
EtMgBr (1.2 equiv)
Ph
MTBE, –4 °C, 6 h
Ph
2) (F3CCO)2O (10 equiv)
THF, –30 °C, 30 min
then 0 °C, 16 h
Me
Me
7 (71%)
9:1 dr
6
Scheme 3 Conjugate addition to chiral substrates
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 901–906

905
P. Garcia et al.
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Synlett
was observed (90:10 dr). Even if we were not able to de-
duce the absolute configuration of the new stereogenic car-
bon, the presence of a stereodefined tertiary center at this
position lead to a diastereoselective conjugate addition to
proximal exo-methylanated ketones. The development of a
new catalyst could allow us to study match and mismatch
cases associated to the asymmetric conjugate addition to
enantiopure unsaturated ketones. Furthermore, the synthe-
sis of 7 was a model considered en route to more complex
systems. Indeed, we could trap the magnesium enolate
with allyl chloroformate and thus prepare the correspond-
ing allyl enol carbonate (not shown). By looking at the pal-
ladium-catalyzed decarboxylative allyl alkylation18 for this
system and the different catalyst–substrate combination,
we would have access to three contiguous stereogenic cen-
ters.
In conclusion, we have developed a general method for
the enantioselective conjugate addition of trialkylalumini-
um reagents onto α-alkylidene cycloalkanones using CuTc
as catalyst and phosphoramidite ligand L-2. Trimethylalu-
minium provides better enantioselectivity than triethylalu-
minium (up to 95% ee). α-Alkylidene cyclohexanones and
cyclopentanones are suitable substrates and these can be
substituted with the olefin termini being aromatic, het-
eroaromatic, or alkyl groups. While the nucleophilic addi-
tion is stereocontrolled, trapping of the transient alumini-
um enolate showed a low diastereoselectivity using either
H+ or alkylating reagent. Further development for such
transformation would therefore overcome the observed
limitation for the diastereoselectivity as well as direct use
in the synthesis of biorelevant targets.
(d) Naasz, R.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Chem.
Commun. 2001, 735. (e) Knopff, O.; Alexakis, A. Org. Lett. 2002,
4, 3835. (f) Hayashi, T.; Tokunaga, N.; Yoshida, K.; Han, J. J. Am.
Chem. Soc. 2002, 124, 12102. (g) Alexakis, A.; March, S. J. Org.
Chem. 2002, 67, 8753. (h) Yoshida, K.; Ogasawara, M.; Hayashi,
T. J. Org. Chem. 2003, 68, 1901. (i) Dijk, E. W.; Panella, L.; Pinho,
P.; Naasz, R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahe-
dron 2004, 60, 9687. (j) Guo, H. C.; Ma, J. A. Angew. Chem. Int. Ed.
2006, 45, 354. (k) Rathgeb, X.; March, S.; Alexakis, A. J. Org.
Chem. 2006, 71, 5737. (l) Welker, M.; Woodward, S.; Alexakis, A.
Org. Lett. 2010, 12, 576. (m) Kenjiro, K.; Hitomi, F.; Masahiko, H.
Bull. Chem. Soc. Jpn. 2011, 84, 640. (n) Mendoza, A.; Ishihara, Y.;
Baran, P. S. Nat. Chem. 2012, 4, 21. (o) Galeštoková, Z.; Šebesta,
R. Eur. J. Org. Chem. 2012, 6688. (p) Gopala, K. J.; Chunyin, Z.;
Silas, P. C. Eur. J. Org. Chem. 2012, 1712. (q) Germain, N.;
Guénée, L.; Mauduit, M.; Alexakis, A. Org. Lett. 2014, 16, 118.
(r) Germain, N.; Schlaefli, D.; Chellat, M.; Rosset, S.; Alexakis, A.
Org. Lett. 2014, 16, 2006.
(3) Copper-Catalyzed Asymmetric Synthesis; Alexakis, A.; Krause, N.;
Woodward, S., Eds.; Wiley-VCH: Weinheim, 2014.
(4) For α-alkylidene cyclopentanones, see: (a) Schmuff, N. R.; Trost,
B. M. J. Org. Chem. 1983, 48, 1404. (b) Reusch, W.; Wang, W. Y.
Tetrahedron 1988, 44, 1014. (c) La Clair, J. J.; Lansbury, P. T.; Zhi,
B.-x.; Hoogsteen, K. J. Org. Chem. 1995, 60, 4822. (d) Yu, W.; Jin,
Z. J. Am. Chem. Soc. 2001, 124, 6576. (e) Taber, D. F.; Jiang, Q.;
Chen, B.; Zhang, W.; Campbell, C. L. J. Org. Chem. 2002, 67, 4821.
(f) Stellfeld, T.; Bhatt, U.; Kalesse, M. Org. Lett. 2004, 6, 3889.
(g) Hua, Z.; Carcache, D. A.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J.
J. Org. Chem. 2005, 70, 9849.
(5) For α-alkylidene cyclohexanones, see: (a) Paquette, L. A.; Wang,
X. J. Org. Chem. 1994, 59, 2052. (b) Fleming, I.; Ramarao, C.
Chem. Commun. 2000, 2185. (c) Fleming, I.; Maiti, P.; Ramarao,
C. Org. Biomol. Chem. 2003, 1, 3989. (d) Oballa, R. M.; Carson, R.;
Lait, S.; Cadieux, J. A.; Robichaud, J. Tetrahedron 2005, 61, 2761.
(e) Pronin, S. V.; Shenvi, R. A. J. Am. Chem. Soc. 2012, 134, 19604.
(6) Börner, C.; Dennis, M. R.; Sinn, E.; Woodward, S. Eur. J. Org.
Chem. 2001, 2435.
(7) Other conditions with CuI and Tol-BINAP were evaluated
without success. For a leading reference, see: Wang, S.-Y.; Ji,
S.-J.; Loh, T.-P. J. Am. Chem. Soc. 2012, 134, 19604.
(8) Vuagnoux-d’Augustin, M.; Alexakis, A. Chem. Eur. J. 2007, 13,
9647.
Acknowledgment
The authors thank Stéphane Rosset for technical help and Noé Mage
for preparation of 1d and BnI.
(9) Recent report discussing similar behavior: Li, H.; Alexakis, A.
Angew. Chem. Int. Ed. 2012, 51, 1055.
(10) Recent report on the use of phosphanamine as ligand for CuTc-
catalyzed asymmetric conjugate addition of alane: Müller, D.;
Alexakis, A. Chem. Eur. J. 2013, 19, 15226.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380165.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(11) General Procedure
In a Schlenk tube, to a solution of α-alkylidene cyclohexanone
1d (51.5 mg, 0.27 mmol), CuTc (2.5 mg, 0.013 mmol), L-2 (7.0
mg, 0.013 mmol) in Et2O (3 mL) at –30 °C was added dropwise a
solution of Me3Al (2.0 M in heptane, 188 μL, 0.37 mmol), and
the reaction was stirred for 2 h. At this point, an aliquot was
taken and quenched with Ac2O to determine the enantioselec-
tivity. After addition of 2 mL of 1.2 M HCl in MeOH the reaction
was stirred at r.t., and a saturated solution of Rochelle’s (or Sei-
gnette) salt was added (5 mL). After extraction of the aqueous
phase with Et2O, the combined organic phases were washed
with brine, dried over MgSO4, filtered, and concentrated in
vacuo. GC analysis was used to determine the conversion and
purification on silica gel (cyclohexane–EtOAc, 99:1) afforded 3e
as colorless oil in 70% yield. Mixture of diastereomers = 3.1:1;
dias indicates signals due to both. 1H NMR (400 MHz, CDCl3): δ
References and Notes
(1) For Cu-catalyzed processes, see: (a) Jerphagnon, T.; Pizzuti, M.
G.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2009, 38, 1039.
(b) Alexakis, A.; Bäckvall, J.; Krause, N.; Pàmies, O.; Diéguez, M.
Chem. Rev. 2008, 108, 2796. (c) Alexakis, A.; Benhaim, C. Eur. J.
Org. Chem. 2002, 3221. For Rh, see: (d) Fagnou, K.; Lautens, M.
Chem. Rev. 2003, 103, 169. (e) Yamasaki, K.; Hayashi, T. Chem.
Rev. 2003, 103, 2829. (f) Koripelly, G.; Rosiak, A.; Rössle, M.;
Christoffers, J. Synthesis 2007, 1279.
(2) (a) Petrier, C.; Barbosa, J. C. D.; Dupuy, D.; Luche, J. L. J. Org.
Chem. 1985, 50, 5761. (b) Naasz, R.; Arnold, L. A.; Pineschi, M.;
Keller, E.; Feringa, B. L. J. Am. Chem. Soc. 1999, 121, 1104.
(c) Hirao, T.; Takada, T.; Sakurai, H. Org. Lett. 2000, 2, 3659.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 901–906

906
P. Garcia et al.
Letter
Synlett
= 1.14–1.23 (m, 4.5 H, 2 dias), 1.44–1.53 (m, 1.5 H, 2 dias), 1.59–
1.73 (m, 3.1 H, 2 dias), 1.78–1.98 (m, 1.7 H, 2 dias), 2.15–2.38
(m, 3.1 H, 2 dias), 2.43–2.48 (m, 1 H, dia minor), 3.26–3.34 (m, 1
H, dia major), 3.47–3.53 (m, 1 H, dia minor), 6.86–6.89 (m, 2 H,
2 dias), 7.15–7.18 (m, 1 H, 2 dias). 13C NMR (100 MHz, CDCl3): δ
= 16.3, 20.7, 24.3, 24.9, 27.7, 28.2, 28.4, 31.9, 32.9, 34.2, 42.2,
42.3, 56.5, 57.7, 119.9, 120.6, 125.2, 125.4, 127.2, 127.5, 145.6,
146.9, 211.9, 213.3. IR (ATR): 3100, 2936, 2867, 1705, 1450,
1129, 785 cm–1. HRMS (EI): m/z calcd for C12H16OS: 208.09164;
found: 208.09173.
(13) Germain, N.; Guénée, L.; Mauduit, M.; Alexakis, A. Org. Lett.
2014, 16, 118.
(14) Ngoc, D. T.; Albicker, M.; Schneider, L.; Cramer, N. Org. Biomol.
Chem. 2010, 8, 1781.
(15) Attempts to trap the transient enolate with allyl chloroformate
to obtain a derivatizable allyl vinyl carbonate were unsuccess-
ful. For recent leading references, see: (a) Liu, W.-B.; Reeves, C.
M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 10626.
(b) See ref. 2q and references cited therein.
(16) For seminal work on asymmetric conjugate addition–aldolisa-
tion–elimination sequence, see: (a) Feringa, B. L.; Pineschi, M.;
Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2620. (b) Nicolaou, K. C.; Tang, W.; Dagneau, P.;
Faranoni, R. Angew. Chem. Int. Ed. 2005, 44, 3874.
(17) For previous racemic syntheses of analogous substrates, see:
(a) Falck, J. R.; He, A.; Reddy, M. L.; Kundu, A.; Barma, D. K.;
Bandyopadhyay, A.; Kamila, S.; Akella, R.; Bejot, R.; Mioskowski,
C. Org. Lett. 2006, 8, 4645. (b) Iqbal, M.; Duffy, P.; Evans, P.;
Cloughley, G.; Allan, B.; Lledό, A.; Verdaguer, X.; Riera, A. Org.
Biomol. Chem. 2008, 6, 4649.
(12) 3i: Colourless oil. Mixture of diastereomers = 4.2:1. 1H NMR
(400 MHz, CD2Cl2): δ = 0.71 (d, J = 6.9 Hz, 1 H, dia minor), 0.81
(d, J = 6.8 Hz, 3 H, dia major), 0.85 (d, J = 6.8 Hz, 3 H, dia major),
0.90 (d, J = 6.7 Hz, 2 H, dia minor), 0.93 (d, J = 6.9 Hz, 3 H), 1.49–
1.55 (m, 1.3 H, 2 dias), 1.61–1.81 (m, 4.3 H, 2 dias), 1.93–2.03
(m, 3.2 H, 2 dias), 2.05–2.13 (m, 1.9 H, 2 dias), 2.18–2.29 (m, 1.7
H, 2 dias). 13C NMR (100 MHz, CD2Cl2): δ = 13.4, 13.7, 18.3, 20.5,
21.1, 21.2, 21.3, 22.0, 24.7, 28.2, 30.4, 32.2, 38.8, 39.4, 39.6, 39.7,
52.6, 53.7, 220.0 (dia major), 221.7 (dia minor). IR (ATR): 2960,
2875, 1734, 1464, 1150 cm–1. HRMS (EI): m/z calcd for C10H18O:
154.13522; found: 154.13513.
(18) Hong, A. Y.; Stoltz, B. M. Eur. J. Org. Chem. 2013, 2745.
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