Diastereoselective methyl orthoformate alkylations of chiral N-acylthiazolidinethiones catalyzed by nickel(II) complexes

Article abstract of DOI:10.1002/adsc.201300521

The completely diastereoselective silyl triflate-mediated methyl orthoformate alkylation of chiral N-acyl-4-isopropyl-1,3-thiazolidine-2-thiones catalyzed by commercially available nickel(II) complexes is reported. The simple experimental procedure requires 2.5-5 mol% of bis(phosphine)nickel dichloride [(R₃P)₂NiCl₂] complexes, proceeds under very mild conditions, and covers a wide array of acyl groups. Furthermore, it can potentially be expanded to different electrophiles.

Full text of DOI:10.1002/adsc.201300521

COMMUNICATIONS
DOI: 10.1002/adsc.201300521
Diastereoselective Methyl Orthoformate Alkylations of Chiral
N-Acylthiazolidinethiones Catalyzed by Nickel(II) Complexes
Juan Manuel Romo,a Erik Gꢀlvez,a Ignasi Nubiola,a Pedro Romea,a,* Fꢁlix Urpꢂ,a,*
and Max Kindreda
a
Departament de Quꢂmica Orgꢃnica, Universitat de Barcelona, Carrer Martꢂ i Franquꢄs 1-11, 08028 Barcelona, Catalonia,
Spain
Fax : (+34)-9-3339-7878; phone: (+34)-9-3403-9106 (PR), (+34)-9-3401-1247 (FU); e-mail: pedro.romea@ub.edu or
felix.urpi@ub.edu
Received: June 14, 2013; Revised: July 25, 2013; Published online: October 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300521.
Abstract: The completely diastereoselective silyl tri-
flate-mediated methyl orthoformate alkylation of
chiral N-acyl-4-isopropyl-1,3-thiazolidine-2-thiones
catalyzed by commercially available nickel(II) com-
plexes is reported. The simple experimental proce-
dure requires 2.5–5 mol% of bis(phosphine)nickel
dichloride [(R3P)2NiCl2] complexes, proceeds under
very mild conditions, and covers a wide array of
acyl groups. Furthermore, it can potentially be ex-
panded to different electrophiles.
chiral catalyst requires careful preparation and the
use of dry-box techniques, which have probably ham-
pered further applications to related transformations.
Inspired by this example and taking advantage of
our experience with carbon-carbon bond forming pro-
cesses based on the Lewis acid-mediated addition of
titanium enolates from chiral N-acyl-1,3-thiazolidine-
2-thiones to acetals[7] and glycals,[8,9] we envisaged that
such heterocycles might become an excellent chiral
platform to promote diastereoselective additions to
oxocarbenium intermediates catalyzed by structurally
simple metal complexes. The stereocontrol provided
by such chiral auxiliaries might facilitate the installa-
tion of both one and two vicinal chiral centers pro-
moted by catalytic amounts of achiral metal com-
plexes.[10,11]
Keywords: alkylation; diastereoselectivity; nickel;
synthetic methods; thiazolidinethiones
Herein, we report the entirely diastereoselective
The stereoselective construction of carbon-carbon Lewis acid-mediated addition of (S)-N-acyl-4-isopro-
bonds through an SN1-like mechanism is a promising pyl-1,3-thiazolidine-2-thiones 1[12] to methyl orthofor-
approach to the synthesis of compounds with structur- mate catalyzed by commercially available nickel(II)
ally complex molecular architecture.[1] To date, the ad- complexes (Scheme 1), which could be expanded to
dition of nucleophiles to chiral oxocarbenium ions has more complex reagents.
played a key role in the chemistry of carbohydrates
Preliminary studies using the conditions reported
and has been much exploited in the development of by Evans showed that nickel(II) chloride complexes
routes for the synthesis of natural products.[2] More were unable to promote the addition of (S)-N-prop-
recently, the need for more efficient processes has
anoyl-4-isopropyl-1,3-thiazolidine-2-thione
1a
to
stimulated the development of new stereoselective methyl orthoformate (entry 1 in Table 1). It was nec-
additions of carbon nucleophiles to oxocarbenium essary to replace the chlorines by sulfonate ligands to
and carbenium intermediates,[3] but there is still a lack obtain the desired adducts. Indeed, freshly prepared
of methods for carrying out such transformations
using easily available catalysts in a straightforward
manner.[4,5]
Some years ago, Evans reported that the (Tol-
BINAP)NiACHTUNGTRENNUNG(OTf)2 complex triggered the reaction of
N-acyl-1,3-thiazolidine-2-thiones with methyl ortho-
formate activated by BF3·OEt2 to provide the corre-
sponding 3,3-dimethoxy adducts in high yields and
Scheme 1. Lewis acid-mediated additions of 1 to methyl or-
with high enantioselectivities.[6] Unfortunately, that thoformate catalyzed by nickel(II) complexes.
Adv. Synth. Catal. 2013, 355, 2781 – 2786
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2781

Juan Manuel Romo et al.
COMMUNICATIONS
Table 1. BF3·OEt2-mediated addition of 1a to HC
catalyzed by nickel(II) complexes.
(OMe)3
Table 2. Silyl triflate-mediated addition of 1a to HCACHTUNGTRENNUNG(OMe)3
with (Ph3P)2NiCl2.
Entry
Catalyst
T [8C]
t [h]
2a [%][a]
Entry Catalyst
(mol%)
R3SiOTf
T
[8C]
t
2a
[h][a] [%][b]
1
2
3
4
5
6
A
E
E
E
G
C
20
20
0
À20
À20
À20
96
16
16
16
48
16
–
E
E
E
R
14
24
52
72
36
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
10
TMSOTf À20
16
16
72
72
16
3
20
33
44
36
75
77
77
51
TMSOTf
TMSOTf
0
0
TMSOTf 20
C
TESOTf
TESOTf
TIPSOTf
TESOTf[c]
0
0
0
0
[a]
Isolated yield after column chromatography.
3
3
[a]
[b]
[c]
The mixture was initially stirred for 20 min at À208C.
Isolated yield after column chromatography.
1.3 equivalents of TESOTf were used
(Ph3P)2NiACHTUNGTRENNUNG(OMs)2 produced adduct 2a as a single dia-
stereomer in yields of up to 72% provided that the re-
action was carried out at low temperatures to avoid
the formation of decomposition products (compare
entries 2–5 in Table 1). These results confirmed our
hypotheses about the feasibility of such a process and
the absolute control over the configuration of the a-
stereocenter imparted by the thiazolidinethione scaf-
fold.[13] Interestingly, the putatively more active
Table 3. Silyl triflate-mediated addition of 1b to HCACHTUNGTRENNUNG(OMe)3
with (Ph3P)2NiCl2.
(Ph3P)2NiACHTUNGTRENNUNG(OTf)2 complex furnished 2a but in a low
yield (entry 6 in Table 1), which suggests that the ap-
propriate preparation of the active species is crucial
for the overall process.
Entry Catalyst (mol%) R3SiOTf Equiv. t [h][a] 2b [%][b]
Thus, considering that the need to prepare mois-
ture-sensitive catalysts and the use of large amounts
of reagents were major hurdles in developing
a straightforward and highly efficient method, we
paid special attention to Sodeokaꢆs findings regarding
the replacement of chlorine via the treatment of nick-
el(II) chloride complexes with silyl triflates.[14] Since
those Lewis acids could generate the catalytic species
and the oxocarbenium intermediate simultaneously,
we next assessed the influence of several silyl triflates
on the reaction of 1a with methyl orthoformate
(Table 2). Early experiments with TMSOTf showed
1
2
3
4
5
6
7
8
20
20
20
10
5
2.5
1.5
1.0
TMSOTf 1.5
TESOTf 1.5
TIPSOTf 1.5
TESOTf 1.3
TESOTf 1.2
TESOTf 1.15
TESOTf 1.1
TESOTf 1.1
3
3
3
1
1
1
1
5
75
86
76
85
90
94
91
77
[a]
[b]
The mixture was initially stirred for 20 min at À208C.
Isolated yield after column chromatography.
that this procedure produced adduct 2a as a single a single diastereomer with a 94% yield (entries 4–6 in
diastereomer even though the yields were low (en- Table 3). Furthermore, smaller amounts of the cata-
tries 1–4 in Table 2). Furthermore, we were pleased to lyst also afforded 2b in yields of up to 91% (entries 7
observe that other silyl triflates such as TESOTf or and 8 in Table 3) but the results proved to be more
TIPSOTf turned out to be much more suitable and difficult to reproduce.
produced 2a in high yields (entries 5–7 in Table 2)
provided that 20 mol% of the nickel(II) complex was dure, the influence of other bases and catalysts was
used (compare entries 7 and 8 in Table 2). next evaluated. We were especially interested in im-
Having found a highly efficient and reliable proce-
Parallel studies of more acidic N-phenylacetylthia- proving the results from 1a, since the more acidic 1b
zolidinethione 1b were much more successful, as high already produced a single diastereomer very efficient-
yields of adduct 2b were obtained at 08C irrespective ly under the aforementioned mild conditions. Thus,
of the silyl triflate (entries 1–3 in Table 3). Remarka- a large number of tertiary amines and nickel(II) com-
bly, just 2.5 mol% of (Ph3P)2NiCl2 and 1.15 equiva- plexes were tested. Surprisingly, none of the bases
lents of TESOTf were enough to deliver adduct 2b as used in the study produced yields better than or com-
2782
asc.wiley-vch.de
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2781 – 2786

Diastereoselective Methyl Orthoformate Alkylations of Chiral N-Acylthiazolidinethiones
Table 4. Catalytic addition of 1a to HCACTHNURGTNEUNG(OMe)3.
and significant catalytic activity was observed with
complexes possessing basic and unhindered phosphine
ligands. Indeed, the sterically hindered complex con-
taining bulky Cy3P did not yield adduct 2a at all
(entry 4 in Table 4), but Bu3P and Me3P counterparts
with catalyst loadings of 5–2.5 mol% furnished 2a in
high yields provided that the reaction was carried out
at À208C (compare entries 5–9 in Table 4). Finally,
the more acidic (DME)NiCl2 complex was completely
ineffective and no traces of 2a were observed after
long reaction times (entry 10 in Table 4). These results
led us to adopt (Me3P)2NiCl2 as the complex of
choice for the less reactive substrates such as 1a
(Method A), whereas (Ph3P)2NiCl2 could be safely
used for the more reactive substrates derived from N-
arylacetyl groups such as 1b (Method B).
The scope of the process was next examined with
several N-acylthiazolidinethiones using the conditions
optimized for both 1a and 1b (Methods A and B, re-
spectively, see the Experimental Section). As shown
in Table 5, application of Method A to substrates 1c–
e with alkyl R groups smoothly produced the corre-
sponding adducts 2c–e, although a certain loss of yield
was observed as the steric hindrance of R increased
(compare entries 1–4 in Table 5). An acyl chain pos-
Entry LnNiCl2
mol% T [8C] t [h][a] 2a [%][b]
1[c]
2[c]
3[e]
4[c]
5[c]
6[c]
7[d]
8[d]
9[e]
10[c]
C
20
20
20
20
0
0
0
0
0
0
À20
À20
À20
0
3
3
3
3
3
3
3
1.5
1.5
4
77
80
79
–
79
76
78
87
81
–
5
5
[a]
The mixture was initially stirred for 20 min at À208C.
Isolated yield after column chromatography.
1.5 equivalents of TESOTf were used.
1.2 equivalents of TESOTf were used.
1.15 equivalents of TESOTf were used.
[b]
[c]
[d]
[e]
parable to that of 2,6-lutidine,[15] but some nickel(II) sessing a methyl ester as well as the introduction of
complexes containing trialkylphosphines were fairly an oxygenated substituent at the a-position were tol-
active and delivered adduct 2a in high yields.[16] The erated and the corresponding adducts were obtained
results summarized in Table 4 indicated that com- as a single diastereomer in high yields (entries 5 and 6
plexes containing arylphosphines gave almost identi- in Table 5). The latter result is particularly significant,
cal results without observing any beneficial effects of since it represents a fruitful example of the uncertain
using bidentate ligands (compare entries 1–3 in glycolate reaction.[17]
Table 4). Longer reaction times did not improve these
In turn, Method B was successfully applied to sub-
results either. Nevertheless, complexes with alkyl- strates 1h–k irrespective of the electronic character of
phosphines behaved very differently and a promising the aryl group, although yields were slightly lower for
Table 5. TESOTf-mediated catalyzed addition of 1 to HCACTHNUTRGNEUNG(OMe)3.
Entry
1
R
Catalyst
mol%
TESOTf (equiv.)
T [8C]
t [h]
2 [%][a]
1
2
3
4
5
6
7
8
a
c
d
e
f
g
b
h
i
Me
Pr
Bn
iPr
N
5
5
5
5
5
5
2.5
2.5
2.5
2.5
2.5
1.2
1.2
1.2
1.2
1.2
1.2
1.15
1.15
1.15
1.15
1.15
À20
À20
À20
À20
À20
À20
0
0
0
0
0
1.5
1.5
1.5
1.5
1.5
3
87
81
73
66
67
82
94
88
91
71
74
A
OPiv
Ph
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
2,4-F2C6H3
1[b]
1[b]
1[b]
1[b]
1[b]
9
10
11
j
k
[a]
Isolated yield after column chromatography.
The mixture was initially stirred for 20 min at À208C.
[b]
Adv. Synth. Catal. 2013, 355, 2781 – 2786
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2783

Juan Manuel Romo et al.
COMMUNICATIONS
those containing electron-withdrawing substituents
(compare entries 7–11 in Table 5).[18]
Once the scope of this Lewis acid-mediated addi-
tion of N-acylthiazolidinethiones to methyl orthofor-
mate had been established, we speculated about the
possibility of adapting such a transformation to differ-
ent chiral auxiliaries.[19] Related oxazolidinones and
oxazolidinethiones were promising candidates since
Scheme 3. Removal of the chiral auxiliary.
their structures are very similar to those of thiazolidi- mediates, we finally explored such alkylation reac-
nethiones and therefore could result in an extension tions with the different electrophiles represented in
of the synthetic potential of the reported alkylation.
Scheme 4. Preliminary studies on the addition of 1b
Following this approach, the optimized experimen- to 1,3-benzodithiolylium tetrafluoroborate,[21] N,N-di-
tal conditions were applied to N-propanoyl- and N- methylmethyleneiminium chloride,[22] and benzalde-
phenylacetyloxazolidinones and -oxazolidinethiones, 3 hyde dimethyl acetal gave encouraging results, since
and 4, respectively (Scheme 2). The initial results the expected adducts 8–10 were obtained for all of
from oxazolidinones 3 were disappointing. Indeed, these reagents.[23] As they encompass intermediates
stabilized by sulfur, nitrogen, and oxygen atoms, and
they involve the generation of one or two new stereo-
centers, these results suggest that the method previ-
ously developed could be useful for a larger set of
transformations that proceed through SN1-like mecha-
nisms.
In summary, the commercially available and easily
to handle nickel(II) complexes (Me3P)2NiCl2 and
(Ph3P)2NiCl2 trigger the completely diastereoselective
TESOTf-mediated addition of chiral N-acyl-4-isopro-
pyl-1,3-thiazolidine-2-thiones to methyl orthoformate
under very mild conditions. This methodology could
be expanded to cover other reactions that proceed
through oxocarbenium or carbenium intermediates.
Scheme 2. Influence of different chiral auxiliaries.
the N-propanoyloxazolidinone 3a did not react at all,
whereas the more acidic N-phenylacetyl counterpart
3b produced adduct 5b with a 65% yield but as a mix-
ture of diastereomers (dr 87:13). In contrast, oxazoli-
dinethiones 4 were reactive enough and adducts 6
were obtained in a diastereomerically pure form
albeit in moderate yields. Careful analyses of the re-
action mixtures showed that the yield losses com-
pared to the thiazolidinethione counterparts 1 were
due to the partial conversion of the oxazolidinethione
scaffold into the corresponding oxazolidinone one.
Therefore, these experiments prove that the exocyclic
C=S bond is necessary to achieve highly stereocon-
trolled transformations, whereas the endocyclic sulfur
heteroatom is required to avoid undesired decomposi-
tions.[20]
Scheme 4. Further transformations.
The choice of a thiazolidinethione chiral auxiliary
was also supported by the mild conditions required Experimental Section
for its removal. For instance, enantiomerically pure
mandelic-like thioester 7 was obtained with a 77% General Procedures
yield by simple treatment of adduct 2b with 1-dodec-
ACHTUNGTRENNUNG
Method A: Solid (Me3P)2NiCl2 (7.0 mg, 25 mmol) was added
to a solution of 1 (0.5 mmol) and HC(OMe)3 (83 mL,
0.75 mmol) in dry CH2Cl2 (1 mL) at room temperature
AHCTUNGTRENNUNG
2784
asc.wiley-vch.de
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2781 – 2786

Diastereoselective Methyl Orthoformate Alkylations of Chiral N-Acylthiazolidinethiones
and TESOTf (136 mL, 0.6 mmol) and 2,6-lutidine (88 mL,
0.75 mmol) were added dropwise after 3 and 7 min, respec-
tively. The reaction mixture was stirred at À208C, quenched
with saturated NH4Cl solution (1.2 mL), and diluted in H2O.
The aqueous layer was extracted with CH2Cl2, the combined
organic layers were washed with brine, dried and concen-
trated. The residue was purified by column chromatography
on deactivated silica gel to give the desired adduct 2.
Method B: The reaction was carried out as in Method A
using (Ph3P)2NiCl2 (8.2 mg, 12.5 mmol) and TESOTf
(130 mL, 0.575 mmol). Furthermore, the reaction mixture
was stirred at À208C for 20 min and in an ice bath for 1 h.
Chem. Int. Ed. 2010, 49, 9685–9688; e) R. Sinisi, M. V.
Vita, A. Gualandi, E. Emer, P. G. Cozzi, Chem. Eur. J.
2011, 17, 7404–7408.
[6] D. A. Evans, R. J. Thomson, J. Am. Chem. Soc. 2005,
127, 10506–10507.
[7] a) A. Cosp, P. Romea, P. Talavera, F. Urpꢂ, J. Vilarrasa,
M. Font-Bardia, X. Solans, Org. Lett. 2001, 3, 615–617;
b) A. Cosp, I. Larrosa, I. Vilasꢂs, P. Romea, F. Urpꢂ, J.
Vilarrasa, Synlett 2003, 1109–1112; c) B. Checa, E.
Gꢀlvez, R. Parellꢇ, M. Sau, P. Romea, F. Urpꢂ, M.
Font-Bardia, X. Solans, Org. Lett. 2009, 11, 2193–2196.
[8] I. Larrosa, P. Romea, F. Urpꢂ, D. Balsells, J. Vilarrasa,
M. Font-Bardia, X. Solans, Org. Lett. 2002, 4, 4651–
4654.
[9] For recent applications of these reactions to the synthe-
sis of natural products, see: a) I. Larrosa, P. Romea, F.
Urpꢂ, Org. Lett. 2006, 8, 527–530; b) M. T. Crimmins,
A.-M. R. Dechert, Org. Lett. 2009, 11, 1635–1638;
c) T. J. Harrison, S. Ho, J. L. Leighton, J. Am. Chem.
Soc. 2011, 133, 7308–7311; d) K. K. Pulukuri, T. K.
Chakraborty, Org. Lett. 2012, 14, 2858–2861.
Acknowledgements
Financial support from the Spanish Ministerio de Economꢀa
y Competitividad (Grant No. CTQ2012-31034), and the Gen-
eralitat de Catalunya (2009SGR825) as well as doctorate stu-
dentships to J. M. R. (FPU, Ministerio de Educaciꢁn) and E.
G. (Universitat de Barcelona) are acknowledged.
[10] For pioneering studies on SN1-like alkylation reactions
of titanium enolates from chiral N-acyloxazolidinones,
see: D. A. Evans, F. Urpꢂ, T. C. Somers, J. S. Clark,
M. T. Bilodeau, J. Am. Chem. Soc. 1990, 112, 8215–
8216.
[11] For examples of stereoselective additions of chiral tita-
nium enolates to five-membered oxocarbenium inter-
mediates, see: a) G. Jalce, M. Seck, X. Franck, R. Hoc-
quemiller, B. Figadꢁre, J. Org. Chem. 2004, 69, 3240–
3241; b) R. A. Pilli, V. B. Riatto, J. Braz. Chem. Soc.
2008, 19, 583–599.
[12] For the preparation of 1, see: E. Gꢀlvez, P. Romea, F.
Urpꢂ, Org. Synth. 2009, 86, 70–80.
[13] The configuration of adduct 2a was established by con-
version into (R)-3,3-dimethoxy-2-methylpropanoic acid
described by Evans in ref.[6] For further details, see the
Supporting Information.
[14] a) T. Suzuki, Y. Hamashima, M. Sodeoka, Angew.
Chem. 2007, 119, 5531–5535; Angew. Chem. Int. Ed.
2007, 46, 5435–5439; b) Y. Hamashima, T. Nagi, R. Shi-
mizu, T. Tsuchimoto, M. Sodeoka, Eur. J. Org. Chem.
2011, 3675–3678.
[15] Pyridine, 2,6-di-tert-butyl-4-methylpyridine, and DBU
did not provide adduct 2a at all, whereas tertiary
amines like Et3N or (i-Pr)2NEt afforded 2a in low
yields.
References
[1] a) E. Emer, R. Sinisi, M. G. Capdevila, D. Petruzziello,
F. De Vincentiis, P. G. Cozzi, Eur. J. Org. Chem. 2011,
647–666; b) A. Gualandi, P. G. Cozzi, Synlett 2013, 281–
296.
[2] a) K. Toshima, K. Tatsuta, Chem. Rev. 1993, 93, 1503–
1531; b) S. J. Danishefsky, M. T. Bilodeau, Angew.
Chem. 1996, 108, 1482–1522; Angew. Chem. Int. Ed.
Engl. 1996, 35, 1380–1419; c) K. C. Nicolaou, H. J.
Mitchell, Angew. Chem. 2001, 113, 1624–1672; Angew.
Chem. Int. Ed. 2001, 40, 1576–1624; d) H. Pellissier,
Tetrahedron 2005, 61, 2947–2993.
[3] For accounts on the reactivity of carbocations, see:
a) G. A. Olah, J. Org. Chem. 2001, 66, 5943–5957; b) H.
Mayr, T. Bug, M. F. Gotta, N. Hering, B. Irrgang, B.
Janker, B. Kempf, R. Loos, A. R. Ofial, G. Remenni-
kov, H. Schimmel, J. Am. Chem. Soc. 2001, 123, 9500–
9512; c) R. Lucius, R. Loos, H. Mayr, Angew. Chem.
2002, 114, 97–102; Angew. Chem. Int. Ed. 2002, 41, 91–
95; d) P. G. Cozzi, F. Benfatti, Angew. Chem. 2010, 122,
264–267; Angew. Chem. Int. Ed. 2010, 49, 256–259.
[4] For insightful analyses on the addition of nucleophiles
to cyclic oxocarbenium ions, see: a) L. Ayala, C. G.
Lucero, J. A. C. Romero, S. A. Tabacco, K. A. Woerpel,
J. Am. Chem. Soc. 2003, 125, 15521–15528; b) C. H.
Larsen, B. H. Ridgway, J. T. Shaw, D. M. Smith, K. A.
Woerpel, J. Am. Chem. Soc. 2005, 127, 10879–10884;
c) J. R. Krumper, W. A. Salamant, K. A. Woerpel, J.
Org. Chem. 2009, 74, 8039–8050.
[5] For examples on catalytic stereoselective additions to
oxocarbenium and carbenium intermediates, see:
a) S. E. Reisman, A. G. Doyle, E. N. Jacobsen, J. Am.
Chem. Soc. 2008, 130, 7198–7199; b) P. G. Cozzi, F.
Benfatti, L. Zoli, Angew. Chem. 2009, 121, 1339–1342;
Angew. Chem. Int. Ed. 2009, 48, 1313–1316; c) A. R.
Brown, W.-H. Kuo, E. N. Jacobsen, J. Am. Chem. Soc.
2010, 132, 9286–9288; d) G. Bergonzini, S. Vera, P. Mel-
chiorre, Angew. Chem. 2010, 122, 9879–9882; Angew.
[16] Nickel(II) complexes were purchased from Aldrich and
used as received.
[17] For recent examples on the addition of glycolate eno-
lates to oxocarbenium intermediates, see: a) J. Baiget,
M. Caba, E. Gꢀlvez, P. Romea, F. Urpꢂ, M. Font-
Bardia, J. Org. Chem. 2012, 77, 8809–8814; b) E.
Gꢀlvez, M. Sau, P. Romea, F. Urpꢂ, M. Font-Bardia,
Tetrahedron Lett. 2013, 54, 1467–1470.
[18] The configuration of adduct 2i was secured through
correlation with a compound previously reported by
Evans in ref.[6] For further details, see the Supporting
Information.
[19] For the influence of chiral auxiliaries on the Lewis
acid-mediated addition of titanium enolates to acetals,
Adv. Synth. Catal. 2013, 355, 2781 – 2786
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2785

Juan Manuel Romo et al.
COMMUNICATIONS
see: J. Baiget, A. Cosp, E. Gꢀlvez, L. Gꢇmez-Pinal, P.
Romea, F. Urpꢂ, Tetrahedron 2008, 64, 5637–5644.
[20] Remarkably, Sodeoka reported that the thiazolidine-
thione and oxazolidinethione heterocycles cannot be
used in related asymmetric fluorination reactions be-
cause of the high reactivity of the C=S group towards
the electrophilic fluorine atom (see ref.[14a]), which
proves the crucial role of the auxiliary in this sort of
transformations.
Cozzi, Angew. Chem. 2011, 123, 7988–7992; Angew.
Chem. Int. Ed. 2011, 50, 7842–7846.
[22] For overviews on the Mannich reaction, see: a) M.
Arend, B. Westermann, N. Risch, Angew. Chem. 1998,
110, 1096–1122; Angew. Chem. Int. Ed. 1998, 37, 1044–
1070; b) S. Mukherjee, J. W. Yang, S. Hoffmann, B.
List, Chem. Rev. 2007, 107, 5471–5569.
[23] It was impossible to isolate the adduct derived from
N,N-dimethylmethyleneiminium chloride, so it was con-
verted into amide 9 by in situ treatment of the putative
adduct with (S)-PhCHMeNH2 (see the Supporting In-
formation).
[21] For examples of asymmetric reactions with this cation,
see: A. Gualandi, E. Emer, M. G. Capdevila, P. G.
2786
asc.wiley-vch.de
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2781 – 2786