Enantioselective direct aldol reactions of achiral ketones with racemic enolizable α-substituted aldehydes: Scope and limitations

Article abstract of DOI:10.1055/s-0030-1259525

Aldol reactions of racemic enolizable dioxolan-protected α-substituted-β-ketoaldehydes with representative achiral ketones catalyzed by proline or 5-(2-pyrrolidine-2-yl)-1H-tetrazole in wet DMSO proceed with dynamic kinetic resolution (or via DYKAT with an α-substituted- β-alkoxyaldehyde) to give adducts with high dr and ee. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259525

508
CLUSTER
Enantioselective Direct Aldol Reactions of Achiral Ketones with Racemic
Enolizable a-Substituted Aldehydes: Scope and Limitations
E
nantioselective
A
a
ldol Reacti
l
ons of
e
a
-
Substituted
(
)-
E
A
ldehyde
s
. Ward,* Vishal Jheengut, Garrison E. Beye, H. Martin Gillis, Athanasios Karagiannis,
Fabiola Becerril-Jimenez
Department of Chemistry, University of Saskatchewan, Saskatoon, SK, S7N 5C9, Canada
Fax +1(306)9664730; E-mail: dale.ward@usask.ca
Received 7 December 2010
In a preliminary study, we established that proline-cata-
Abstract: Aldol reactions of racemic enolizable dioxolan-protected
a-substituted-b-ketoaldehydes with representative achiral ketones
catalyzed by proline or 5-(2-pyrrolidine-2-yl)-1H-tetrazole in wet
DMSO proceed with dynamic kinetic resolution (or via DYKAT
lyzed aldol reactions of 1 with simple achiral aldehydes in
DMF or DMSO (with controlled amounts of water) are
highly diastereo- and enantioselective.4 This was signifi-
with an a-substituted-b-alkoxyaldehyde) to give adducts with high cant because 3-pentanone is a poor substrate in proline-
catalyzed aldol reactions.2 Among the scattered examples
dr and ee.
of proline-catalyzed aldol reactions of chiral aldehydes,5
Key words: aldol reaction, chiral aldehydes, kinetic resolution, or-
ganocatalysis, polypropionates
generally moderate levels of enantiotopic group
selectivity6 (or double stereodifferentiation)7 were ob-
served. Nonetheless, we reasoned that because of its near
exclusive Felkin diastereoface selectivity, racemic alde-
hyde ( )-2a would be a good candidate to undergo pro-
line-catalyzed direct aldol with 1 with high enantiotopic
group selectivity (i.e., kinetic resolution6).8 Under opti-
mized conditions, (–)-5a was obtained essentially as a sin-
gle stereoisomer in a process that proceeded via dynamic
kinetic resolution (DKR,9 Scheme 1).8 In this paper, we
report the extension of this concept to other ketones and
aldehydes and simple procedures for the preparation of 5a
on >30 gram scale.
The first examples of proline-catalyzed enantioselective
direct intermolecular aldol reactions were reported in a
landmark paper by List, Lerner, and Barbas in 2000.1 In
the ensuing decade, this reaction has been extensively
studied by numerous research groups, and remarkable
progress has been achieved.2 Despite the impressive stereo-
selectivity that has been obtained in many examples and
with diverse organocatalysts, a continuing limitation to
synthetic applications of this process has been the rather
narrow substrate scope; that is, few competent ketone
donors and mainly simple achiral or aromatic aldehyde
acceptors. Our interest in this process stemmed from its
possible application to our thiopyran-based synthetic
route to polypropionates via stereoselective sequential
two-directional aldol reactions of 1 and 2a (Scheme 1).3
We next investigated the efficacy of the more soluble cat-
alyst 6.10 Aldol reactions of 1 with ( )-2a, benzaldehyde
(2c), and isobutyraldehyde (2d) catalyzed by 6 (0.2 equiv)
were conducted under the conditions previously opti-
mized using 4 (0.5 equiv) revealing that 6 was the superior
catalyst for the reactions with ( )-2a and 2c, (Table 1; cf.
entries 1, 2, 4, 5, and 7, 8). The individual reactions were
optimized by examining the effects of various reaction pa-
rameters including the amount of added water,4 stoichio-
metry, catalyst loading, and reaction time. A solvent
screen revealed that DMF was superior for 2c and DMSO
for 2d and ( )-2c.11 The addition of controlled amounts of
water improved all reactions and the adducts 5a, 5c, and
5d were obtained with excellent diastereo- and enantiose-
lectivities.4 Despite extensive efforts, the conversion of 2c
to 5c could not be improved beyond 85%, and this was at-
tributed to the reversibility of the reaction.12 The reaction
of 1 with 2d catalyzed by 4 in DMSO without added water
works exceptionally well (Table 1, entry 4).4 The same re-
action catalyzed by 6 proceeded poorly in dry DMSO and
even with added water, additional 1 was required to reach
80% conversion to 5d (Table 1, entries 5 and 6). Whereas
(–)-5a was relatively stable to 4 in wet DMSO,8a signifi-
cant retro-aldol (but with negligible erosion of dr or ee)
occurred on exposure to 6 under these conditions.13 Ap-
plying that knowledge, excellent yields of (–)-5a were ob-
tained by carefully controlling the reaction conditions and
by using a large excess of 1 (Table 1, entries 8–15).
O
O
OH
O
HO
O
O
O
O
O
O
2 aldol
reactions
H
+
S
S
S
S
S
1
( )-2a
3 (20 possible diastereomers)
H
O
DMSO
+ H2O
N
OH
H
polypropionates
(S)-proline (4)
O
HO
O
O
4
fast relative to
aldol reaction
with 1
56%
(dr >20)
(–)-2a
(+)-2a
(ee >98%)
DMSO
+ H2O
S
S
(–)-5a
Scheme 1 Proline-catalyzed reaction of 1 with ( )-2a via DKR8a
SYNLETT 2011, No. 4, pp 0508–0512
x
x.
x
x.
2
0
1
1
Advanced online publication: 02.02.2011
DOI: 10.1055/s-0030-1259525; Art ID: Y02310ST
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Enantioselective Aldol Reactions of a-Substituted ( )-Aldehydes
509
Table 1 Aldol Reactions of Ketones 1, 7–9 with Aldehydes 2a–d Catalyzed by 4 or 6
H
H
O
N
N
N
(S)
(S)
or
N
H
OH
N
H
N
H
O
OH
R3
O
O
4
6
O
O
O
O
a R3
=
b R3
=
+
H
R3
r.t.
R1
R2
R1
R2
1 R1–R2 = -CH2SCH2-
7 R1–R2 = -(CH2)3-
8 R1 = R2 = H
5 R1–R2 = -CH2SCH2-
10 R1–R2 = -(CH2)3-
11 R1 = R2 = H
2
S
c R3 = Ph
d R3 = c-Pr
9 R1 = H; R2 = Me
12 R1 = H; R2 = Me
13 R1 = Me; R2 = H
Entry Catalyst
(equiv)a
Ketone Solvent
(equiv)a
H2O
RCHO
Time Product
drd
ee
(equiv)a (M)b
(d)
4
1
2
4
2
3
2
4
2
3
4
3
3
3
4
2
2
3
4
3
3
2
2
3
3
7
7
2
(yield)c
(%)e
1f 4 (0.5)
1 (3)
1 (3)
1 (3)
1 (3)
1 (3)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (12)
1 (12)
7 (6)
7 (12)
DMF
1
1
2c (2)
2c (2)
2c (2)
2d (1)
2d (1)
2d (1)
5c (92% isolated)
14
9
96
2
3
6 (0.2)
6 (0.2)
DMF
5c (85%, 82% isolated)
5c (50%)
>95
n.d.g
>98
n.d.
>98
>98
>98
n.d.
n.d.
n.d.
n.d.
n.d.
>98
>98
n.d.
93
DMF
0
7
4f 4 (0.5)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
5d (96% isolated)
5d (35%)
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
10
5
6
6 (0.2)
6 (0.2)
0
1
5d (80%, 73% isolated)
5a (56% isolated)
5a (76% isolated)
5a (55%)
7h 4 (0.5)
8
( )-2a (1)
( )-2a (1)
( )-2a (1)
( )-2a (1)
( )-2a (1)
( )-2a (1)
( )-2a (1)
( )-2a (1)
8
9
6 (0.2)
6 (0.5)
8
8
10 6 (0.5)
11 6 (0.5)
12 6 (0.5)
13 6 (0.5)
14 6 (0.5)
15 6 (0.5)
16 4 (0.5)
17 4 (0.5)
8
5a (75%)
8
5a (55%)
4
5a (60%)
12
8
5a (45%)
5a (76% isolated)
5a (86% isolated)
10a (25%)
8
( )-2a (0.5)
( )-2a (1)
( )-2a (1)
( )-2a (1)
( )-2a (1)
( )-2a (0.5)
( )-2a (0.5)
( )-2a (1)
( )-2a (1)
( )-2a (1)
( )-2a (1)
( )-2a (1)
( )-2a (1)
( )-2b (0.5)
8
8
10a (66% isolated)
ent-10a (80%)
ent-10a (85%, 77% isolated)
11a (72% isolated)i
11a (57% isolated)i
18 ent-6 (0.5) 7 (6)
19 ent-6 (0.5) 7 (12)
8
n.d.
>95
90f
8
20 4 (0.5)
21 4 (0.5)
8 (20)
8 (20)
0
0.5
13
83
22 ent-6 (0.5) 8 (20)
23 ent-6 (0.5) 8 (20)
0
ent-11a (55% + 20% enone, 48% isolated)i 11
92
4
ent-11a (45% + 45% enone)i
12a/13a, 1:1 (20%)
11
n.d.
n.d.
n.d.
n.d.
>20
>20
n.d.
n.d.
n.d.
n.d.
24 4 (0.5)
25 4 (0.5)
9 (20)
9 (20)
0
0.5
0
12a/13a, 2:1 (20%)
26 ent-6 (0.5) 9 (20)
27 ent-6 (0.5) 9 (20)
ent-12a/ent-13a, 1:1.7 (25%)
ent-12a/ent-13a, 1.6:1 (36% isolated)
5b (47% isolated)
0.5
8
92 (ent-12a)
>95
28 4 (0.5)
29 6 (0.5)
1 (6)
1 (11)
8
( )-2b (0.5 M) 2
5b (63% isolated)
>95
Synlett 2011, No. 4, 508–512 © Thieme Stuttgart · New York

510
D. E. Ward et al.
CLUSTER
Table 1 Aldol Reactions of Ketones 1, 7–9 with Aldehydes 2a–d Catalyzed by 4 or 6 (continued)
H
H
O
N
N
N
(S)
(S)
or
N
H
OH
N
H
N
H
O
OH
R3
O
O
4
6
O
O
O
O
a R3
=
b R3
=
+
H
R3
r.t.
R1
R2
R1
R2
1 R1–R2 = -CH2SCH2-
7 R1–R2 = -(CH2)3-
8 R1 = R2 = H
5 R1–R2 = -CH2SCH2-
10 R1–R2 = -(CH2)3-
11 R1 = R2 = H
2
S
c R3 = Ph
d R3 = c-Pr
9 R1 = H; R2 = Me
12 R1 = H; R2 = Me
13 R1 = Me; R2 = H
Entry Catalyst
(equiv)a
Ketone Solvent
(equiv)a
H2O
RCHO
Time Product
(d)
drd
ee
(equiv)a (M)b
(yield)c
(%)e
30 4 (0.5)
8 (20)
8 (20)
8 (20)
DMSO
DMSO
DMSO
0
8
8
( )-2b (0.5)
( )-2b (0.5)
( )-2b (0.5)
2
11b (72% + 9% enone isolated)
11b (35%, <2% enone)
15
15
9
91
31 4 (0.5)
2
n.d.
n.d.
32 6 (0.5)
2
11b (38% + 35% enone)
a Relative to RCHO.
b Nominal concentration relative to the volume of solvent used but not accounting for the amounts any of the other reagents.
c Unless otherwise indicated, determined by 1H NMR of the reaction mixture after work up using an internal standard.
d Determined by 1H NMR of the crude reaction mixture.
e See Supporting Information for details.
f Taken from ref. 4a.
g Not determined.
h Taken from ref. 8a.
i An inseparable mixture of diastereomers.
As described above, aldol reactions of ( )-2a with 1 cata- ( )-2a, control experiments indicated that ( )-14 was
lyzed by 4 or 6 are remarkably stereoselective and pro- transformed within 12 hours into a 1–2:1 mixture of ( )-
ceed via DKR to give (–)-5a essentially as a single 14 and ( )-15, respectively, and 16; the latter becoming
stereoisomer (four diastereomers possible; dr >20, ee >95% of the mixture after several days. Considering that
>98%). The scope of this process was evaluated by exam- Felkin selectivity was observed in aldol reactions of the
ining the reactions of 7, 8, and 9 with ( )-2a (Table 1, en- Li-enolate of 1 with both ( )-14 [to give ( )-17, dr 3.3:1]
tries 16–27) and of 1 and 8 with ( )-2b (Table 1, entries and ( )-15 [to give ( )-18, dr >20:1],17 and that 4 or 6 de-
28–32) under similar conditions.14 The corresponding al- rived enamines of 1 are very selective for re-face addition
dol adducts were obtained with excellent stereoselectivi- of aldehydes with anti relative topicity, it can be predicted
ties and in good yields (with the exception of 12a and 13a) that (1R)-14 is ‘partially matched’19 and (1R)-15 ‘fully
demonstrating that the thiopyran motif is not a required matched’19 for reaction with these enamines to give ad-
structural element. Despite extensive efforts at optimiza- ducts 17 and 18, respectively.3c In the event, moderate
tion, only low levels of regioselectivity and poor yields yields of a ca. 1:2 mixtures of 17 and 18, respectively,
could be realized from the reaction of 9 with ( )-2a; how- were obtained. However, starting with a preformed mix-
ever, the major adduct 12a was formed with high stereo- ture of ( )-14 and ( )-15 (and 16) produced 1:5 mixtures
selectivity.15 Reactions of 8 with ( )-2a or ( )-2b worked of 17 and 18, respectively. In both cases, 18 was obtained
best without added water but gave significant amounts of with excellent enantioselectivity and use of 6 provided
the enones (not shown) resulting from dehydration of ad- somewhat better results than 4.20 The preferential reaction
ducts 11a and 11b, respectively, especially when 6 was with (1R)-15 can be rationalized by its ‘fully matched’19
used as catalyst (Table 1, entries 20–23 and 30–32).16 Ad- status.3c
dition of water suppressed the dehydration when using 4
Returning to the synthesis of 5a, a versatile intermediate
(but not with 6) but gave lower yields with some erosion
of stereoselectivity (Table 1, cf. entries 20, 21, and 30,
31).
for polypropionate synthesis,8b,21 we were motivated to
develop a procedure that required less 1 and was more
amenable to scale-up. Initially, we attempted to optimize
As shown previously,17 the dioxolan group in 2a (and 2b) the preparation of ( )-5a using ( )-4 (Table 3).22
imparts a very strong Felkin bias for addition to the carbo- Sonication23 did not improve our previously optimized
nyl, and this feature is essential for effective kinetic reso- conditions (1 M in DMSO) and reactions without
lution.3c To test this aspect, we attempted the reaction of 1 solvent23b,24 did not proceed at 22 °C (<10% conversion in
with ( )-14 in hopes of effecting a type III dynamic kinet- 1 d). However, excellent results were obtained under sol-
ic asymmetric transformation (DYKAT,18 Table 2). Un- vent-free conditions by sonication of the mixture at 38 °C
der the conditions optimized for the reactions of 1 with (Table 3, entry 1).25 Surprisingly, the use of (S)-proline
Synlett 2011, No. 4, 508–512 © Thieme Stuttgart · New York

CLUSTER
Enantioselective Aldol Reactions of a-Substituted ( )-Aldehydes
511
Table 2 Aldol Reactions of 1 with ( )-14 Catalyzed by 4 or 6a
Table 3 Optimization of the Syntheses of ( )-5a and (–)-5a from
Reaction of 1 and ( )-2a Catalyzed by 4 (0.5 equiv) or 6 (0.2 equiv)
O
"partially matched" "partially mismatched"
OMOM
1
O
OMOM
Entry Catalyst 1
Additives
Temp Time Conv ee of 5a
(°C) (d)
(%)b (%)c
O
H
(equiv)a(equiv)a
4 (or 6)
1
1
H
H
wet
DMSO
r.t.
S
1d
2d
3d
4d
5
( )-4
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
H2O (2)
38
38
38
38
22
22
38
22
22
22
3
3
94
92
–
10
16
+
S
S
(1R)-14
(1S)-14
4
4
4
4
4
4
6
6
6
H2O (1)
O
HO
OMOM
H2O (1)
1.5 50
0.5 27
45
OMOM
O
OMOM
O
H2O (1)
55
S
S
1
1
17
+
H
H
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
none
2
7
55
90
95
65
50
85
25
OMOM
O
HO
S
S
6
20
(1S)-15
(1R)-15
"fully matched"
"fully mismatched"
7
2
<5
85
S
S
8
10
10
8
18
9
2
H2O (1)
90
Entry
Catalyst
[CHO]b 17/18
Yield (%)c ee of 18 (%)d
10e
2
H2O (1)
DMSO (1.5)
>98
1
4
0.5
1
1:2.3
1:2
37
31
28
33
42
42
92
95
2
4
a Relative to ( )-2a.
b [5a]/([2a] + [5a]) × 100; relative concentrations determined by 1
NMR of the crude product.
H
3e
4
4
0.5
0.5
0.8
0.8
1:5
n.d.
n.d.
>95f
>95
c Determined by optical rotation assuming (ee, %) = optical purity
6
1:2
(%). For all reactions, the dr was >20 by 1 H NMR of the crude prod-
uct.
5
ent-6
1:2f
1:5
d Reaction sonicated in thermostated ultrasonic cleaning bath.
e Taken from ref. 8b; 75% isolated yield after chromatography.
6e
6
a Reactions for 4 d: 1 (12 equiv), H2O (8 equiv), cat. (0.5 equiv).
b Nominal starting concentration of ( )-14 based on the volume of
DMSO used but not accounting for the amounts of other reagents.
c Isolated yield of 17 + 18 (separable by careful chromatography).
d See the Supporting Information.
or 6 proceed with DKR (or DYKAT) to give adducts with
high diastereo- and enantioselectivity if the aldehyde pos-
sesses significant diastereoface selectivity [e.g., ( )-2a
and ( )-2b]. Adducts 5a, 5b, 11a, and 11b are useful in
polypropionate synthesis. Simple scalable procedures for
the preparation of racemic or enantiopure (>98% ee) 5a
from simple precursors without chromatography are pre-
sented.
e Starting with a 3:1:0.7 mixture of 14, 15, and 16, respectively.
f Products are ent-17 and ent-18.
(4) under the same conditions gave nearly racemic 5a but
with excellent dr (>20:1). A time course study revealed a
steady erosion of the ee (but not dr) of 5a with increasing
conversion suggesting that racemization of ( )-2a was
slow under these conditions (Table 3, entries 2–4). Addi-
tion of AcOH4b,c allowed the reaction to proceed at room
temperature without sonication to give 5a in low ee but
without an apparent conversion dependence (Table 3, en-
tries 5–6). At 38 °C, the procedure was more convenient
and easily scalable to give near racemic 5a without chro-
matography (81% yield on 10 g scale; dr >20; ee <5%).
Under solvent-free conditions, reactions catalyzed by 6
were faster and much more enantioselective than with 4
(Table 3 entries 8 and 9). Addition of small amounts of
water suppressed the reaction but improved the ee. Includ-
ing a small amount of DMSO gave acceptable reactivity
and restored the excellent enantioselectivity observed at
lower concentrations.26 This procedure was easily scal-
able to give (–)-5a without chromatography (72% yield on
35 g scale; dr >20; ee >98%).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial support from the Natural Sciences and Engineering
Research Council (Canada) and the University of Saskatchewan is
gratefully acknowledged.
References
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In conclusion, aldol reactions of achiral ketones with ra-
cemic enolizable a-substituted aldehydes catalyzed by 4
Synlett 2011, No. 4, 508–512 © Thieme Stuttgart · New York

512
D. E. Ward et al.
CLUSTER
(3) (a) Ward, D. E.; Man, C. C.; Guo, C. Tetrahedron Lett. 1997,
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(14) After 2 d, a solution of ( )-2b in DMSO containing D2O
(20 equiv) and either 4 or 6 (0.5 equiv) showed >90%
deuteration of the a-CH confirming racemization under
these conditions.
(15) We were unable to determine the ee for 13a.
(16) Subjecting 11a or 11b to the reaction conditions confirmed
their susceptibility to elimination, particularly in the
presence of 6.
(17) Ward, D. E.; Sales, M.; Man, C. C.; Shen, J.; Sasmal, P. K.;
Guo, C. J. Org. Chem. 2002, 67, 1618.
(5) Recent examples with chiral aldehyde acceptors:
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Ramachary, D. B.; Barbas, C. F. III. Org. Lett. 2005, 7,
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(d) Calderon, F.; Doyaguez, E. G.; Cheong, P. H.-Y.;
Fernandez-Mayoralas, A.; Houk, K. N. J. Org. Chem. 2008,
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Synth. Catal. 2006, 348, 211. (f) Grondal, C.; Enders, D.
Tetrahedron 2006, 62, 329. (g) Alcaide, B.; Almendros, P.;
Luna, A.; Torres, M. R. J. Org. Chem. 2006, 71, 4818.
(h) Cordova, A.; Ibrahem, I.; Casas, J.; Sunden, H.;
Engqvist, M.; Reyes, E. Chem. Eur. J. 2005, 11, 4772.
With (dynamic) kinetic resolution: (i) Chercheja, S.;
Nadakudity, S. K.; Eilbracht, P. Adv. Synth. Catal. 2010,
352, 637. (j) Reyes, E.; Cordova, A. Tetrahedron Lett. 2005,
46, 6605. Dynamic kinetic resolution with chiral ketone
acceptors: (k) Wang, Y.; Zhang, Y. Chin. J. Chem. 2010, 28,
1267. (l) Yang, J.; Wang, T.; Ding, Z.; Shen, Z.; Zhang, Y.
Org. Biomol. Chem. 2009, 7, 2208. (m) Wang, Y.; Shen, Z.;
Li, B.; Zhang, Y.; Zhang, Y. Chem. Commun. 2007, 1284;
for citations to early examples, see ref. 8a.
(6) Kinetic resolution of racemic substrates is equivalent to an
enantiotopic-group-selective reaction, i.e., groups on
enantiomeric substrates are enantiotopic by external
comparison. See: Mislow, K.; Raban, M. Top. Stereochem.
1967, 1, 1.
(7) Reviews on double stereodifferentiation: (a) Masamune, S.;
Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed.
Engl. 1985, 24, 1. (b) Kolodiazhnyi, O. I. Tetrahedron
2003, 59, 5953.
(18) Review: (a) Steinreiber, J.; Faber, K.; Griengl, H. Chem.
Eur. J. 2008, 14, 8060. Accordingly, DYKAT involves the
overall resolution of racemic (types I and II) or
diastereomeric (types III and IV) mixtures involving
interconverting diastereomeric intermediates (cf. DKR of
enantiomeric intermediates). Type III involves
interconversion of diastereomers by epimerization while in
type IV diastereomers are interconverted via achiral
intermediates. We are unaware of previous examples of type
III DYKAT via an aldol reaction. For examples involving
DYKAT via aldol–retroaldol mechanism (type IV), see ref.
5h, 5j, and: (b) Yamaguchi, A.; Matsunaga, S.; Shibasaki,
M. J. Am. Chem. Soc. 2009, 131, 10842. (c) Steinreiber, J.;
Schurmann, M.; Wolberg, M.; van Assema, F.; Reisinger,
C.; Fesko, K.; Mink, D.; Griengl, H. Angew. Chem. Int. Ed.
2007, 46, 1624.
(19) (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L.
J. Am. Chem. Soc. 1995, 117, 9073. (b) Evans, D. A.; Dart,
M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996,
118, 4322.
(20) We were unable to determine the ee for 17. 1H NMR of the
crude product suggested the possible presence of minor
amounts of other adducts arising from 14 but these could not
be quantified or isolated. The maximum yield of enantiopure
18 from this reaction is 50%.
(21) (a) Beye, G. E.; Ward, D. E. J. Am. Chem. Soc. 2010, 132,
7210. (b) Jheengut, V.; Ward, D. E. J. Org. Chem. 2007, 72,
7805.
(22) Compound ( )-5a is also a useful intermediate: Ward, D. E.;
Gillis, H. M.; Akinnusi, O. T.; Rasheed, M. A.; Saravanan,
K.; Sasmal, P. K. Org. Lett. 2006, 8, 2631.
(8) (a) Ward, D. E.; Jheengut, V.; Akinnusi, O. T. Org. Lett.
2005, 7, 1181. (b) Ward, D. E.; Jheengut, V.; Beye, G. E.
J. Org. Chem. 2006, 71, 8989.
(23) (a) Izquierdo, I.; Plaza, M. T.; Robles, R.; Mota, A. J.;
Franco, F. Tetrahedron: Asymmetry 2001, 12, 2749.
(b) Shigehisa, H.; Mizutani, T.; Tosaki, S.-Y.; Ohshima, T.;
Shibasaki, M. Tetrahedron 2005, 61, 5057.
(9) Pellissier, H. Tetrahedron 2008, 64, 1563.
(10) Review: Longbottom, D. A.; Franckevicius, V.; Kumarn, S.;
Oelke, A. J.; Wascholowski, V.; Ley, S. V. Aldrichimica
Acta 2008, 41, 3.
(24) Rodriguez, B.; Bruckmann, A.; Bolm, C. Chem. Eur. J.
2007, 13, 4710.
(25) The mixture is initially homogeneous but becomes solid as
5a precipitates. Diastereoselectivity was improved with
small amounts of water (2 equiv, dr >20; 0 equiv, dr = 13)
but the reaction was suppressed with larger amounts (ref. 4).
(26) Presumably by increasing the solubility of 6 and increasing
the rate of racemization of 2a.
(11) Little or no aldol adducts were observed in CHCl3, MeCN,
or THF.
(12) A solution of 5c (2 M in DMF), H2O (1 equiv), and 6 (0.2
equiv) at r.t. for 2 d gave a 1:1.1 mixture (by 1H NMR) of 2c
and 5c (46% isolated; dr = 20, ee >95%).
(13) A DMSO solution of (–)-5a, H2O (8 equiv), and 6 (0.2 equiv)
at r.t. for 4 d gave a 1:1.8 mixture (by 1H NMR) of ( )-2a and
(–)-5a (43% isolated; dr >20, ee >95%).
Synlett 2011, No. 4, 508–512 © Thieme Stuttgart · New York

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