Addition of kinetic boron enolates generated from β-alkoxy methyl ketones to aldehydes. Density functional theory calculations on the transition structures

Article abstract of DOI:10.1016/j.tet.2009.08.042

Herein we report that good to excellent levels of 1,5-anti stereoinduction are obtained in boron enolate aldol reactions of 1,2-syn β-alkoxy methyl ketones with achiral aldehydes, when the β-alkoxy protecting group is part of a benzylidene acetal. We have

Full text of DOI:10.1016/j.tet.2009.08.042

Tetrahedron 65 (2009) 8714–8721
Contents lists available at ScienceDirect
Tetrahedron
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Addition of kinetic boron enolates generated from
b-alkoxy methyl ketones to
aldehydes. Density functional theory calculations on the transition structures
,
a
a
a
a
Luiz C. Dias a , Savio M. Pinheiro , Vanda M. de Oliveira , Marco A.B. Ferreira , Claudio F. Tormena ,
*
´
´
Andrea M. Aguilar b, Julio Zukerman-Schpectorc, Edward R.T. Tiekink c
a Institute of Chemistry, University of Campinas, UNICAMP, PO Box 6154, 13084-971 Campinas, SP, Brazil
b Universidade Federal de S˜ao Paulo, UNIFESP, Campus Diadema, Departamento de Cieˆncias Exatas e da Terra, R. Prof. Artur Ridel, 275, 09972-270 Diadema, SP, Brazil
c Universidade Federal de S˜ao Carlos, LaCrEMM-DQ, CP 676, 13565-905, S˜ao Carlos-SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2009
Received in revised form 17 August 2009
Accepted 17 August 2009
Available online 21 August 2009
Herein we report that good to excellent levels of 1,5-anti stereoinduction are obtained in boron enolate
aldol reactions of 1,2-syn
group is part of a benzylidene acetal. We have also investigated the effects of the ligands on boron, the
-, and -substituents and the -alkoxy protecting group on the boron enolates, using density functional
theory (B3LYP) and Møller–Plesset perturbation theory (MP2) calculations.
Ó 2009 Elsevier Ltd. All rights reserved.
b
-alkoxy methyl ketones with achiral aldehydes, when the
b-alkoxy protecting
a-,
b
g
b
Keywords:
Aldol reactions
Boron enolates
Theoretical calculations
Natural bond orbital analysis
1,5-Stereoinduction
1. Introduction
reactions, we wish to describe here the use of chiral
a,b-di-
substituted and
a,b,g
-trisubstituted methyl ketones.11 The scope of
The aldol reaction of the kinetic boron enolates of methyl ketones
isa powerful methodfor C–C bond construction.1 Theboronenolates
the reaction was explored using methyl ketones with tert-butyldi-
methylsilyl (TBS), p-methoxybenzyl (PMB) as well as with benzy-
generated from
a-methyl methyl ketones need the use of chiral
lidene acetal protecting groups at the b-position.
ligands on boron in order to afford useful levels of 1,4-syn asym-
metric induction.2 On the other hand, the use of boron enolates of
2. Results and discussion
b
-alkoxy methyl ketones affords the corresponding aldol products
with moderate to high levels of 1,5-anti stereoinduction.1 The first
report on 1,5-anti stereoinduction in boron enolate aldol reactions of
Our studies began by investigating the aldol reactions of 1,2-syn
disubstituted methyl ketones 1 and 5, containing a TBS protected
b
-alkyloxy methyl ketones was described by Masamune and co-
hydroxyl group at the
enolization (Scheme 1). Initially, we examined the aldol reaction of
the less-substituted boron enolate formed from -trisubstituted
b-position, using (c-Hex)2BCl/Et3N in Et2O for
workers3 in 1989. More recently, the research groups of Paterson,4
Evans,5 Dias,6 and Goodman7 made very important contributions.
The levels of selectivity are heavily dependent on the nature of the
a,b,g
methyl ketone 1 with aldehyde 2a, which gave a 52:48 mixture of
1,5-anti and 1,5-syn aldol adducts 3 and 4, respectively, in 79%
yield.12
b
-alkoxy substituent and high degrees of 1,5-anti selectivities are
obtained when the -alkoxy protecting group is an alkyloxy group,
a benzyloxy group (OBn, OPMB) or part of a benzylidene acetal.4–9
b
As shown in Scheme 1, the boron-mediated aldol reaction of the
boron enolate prepared from 1,2-syn methyl ketone 5 showed only
modest 1,5-stereoinduction upon addition of isobutyraldehyde (2b)
to give a 70:30 mixture of 1,5-anti and 1,5-syn aldol adducts 6 and 7,
Usually, the use of a b-silicon protecting group gives little or no
selectivity, with a few exceptions.6,10
In continuation of our efforts to understand the factors con-
trolling the 1,5-stereoinduction in these boron-mediated aldol
respectively, in 69% yield.12,13 These findings with
b-OTBS protect-
ing groups are in agreement with literature results.6,10
Based on these results, we decided to explore the influence of
a p-methoxybenzyl (PMB) group at the
ketone 8 in reactions with aldehydes 2b–f (Scheme 2 and Table 1).
b-position in 1,2-syn methyl
* Corresponding author. Fax: þ55 19 3521 3023.
E-mail address: ldias@iqm.unicamp.br (L.C. Dias).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.042

L.C. Dias et al. / Tetrahedron 65 (2009) 8714–8721
8715
1,5-anti
1,5-syn
PMP
O
PMP
O
1,5-anti
PMP
O
O
1,5-syn
TBS
PMBO
TBS
PMBO
TBS
PMBO
1) c-Hex2BCl, Et3N
Et2O, −78 °C, 1h
O
O
OH
O
O
OH
O
O
O
O
H
R
O
O
OH
(c-Hex)2BCl
Et2O, Et3N
O
O
OH
R
+
2b-g
+
Me
Me
Me 11
R
O
−78 °C
Me Me
Me Me
Me Me
2)
−30 °C
3
−78 °C
4
12
13
1
Me
Me
H
OBn
OBn
Me
1,2-syn-2,3-anti
ds 52:48 (79%)
2a
Scheme 3. Aldol reactions of the boron enolate prepared from 1,2-syn
ketone 11.
b-alkoxy methyl
OBn
1,5-anti
1,5-syn
1) c-Hex2BCl, Et3N
TBSO
Me
TBSO
Me
O
O
OH
TBSO
Me
O
OH
Et2O, −78 °C, 1h
Me
Table 2
Me
O
+
2)
Aldol reactions of the boron enolate generated from methyl ketone 11
Me Me
5
Me Me
Me
Me Me
Me
Me
Me
6
7
H
Entry
Aldehyde (R)
Solvent
dsa 1,5-anti/1,5-syn
Yieldb (%)
2b
1,2-syn
ds 70:30 (69%)
−78 °C to −30 °C
i
1
2
3
4
5
6
2b, Pr
2c, Et
2d, Ph
2e, p-MeOC6H4
2f, p-NO2C6H4
2g, C(Me)]CH2
Et2O
Et2O
Et2O
Et2O
86:14
80:20
86:14
87:13
80:20
85:15
83
84
95
82
52
67
Scheme 1. Aldol reactions of the boron enolates generated from 1,2-syn
methyl ketones 1 and 5.
b-alkoxy
Et2O/CH2Cl2
Et2O
1,5-anti
1,5-syn
1. c-Hex2BCl
PMBO
Me
O
PMBO
Me
O
OH
R
PMBO
Me
O
OH
Diastereoselectivity was determined by 1H and 13C NMR analysis of the crude
mixture of products.
Combined yields for both 1,5-syn and 1,5-anti isomers after purification by flash
column chromatography.
a
Et3N, Et2O, -78 °C
Me
R
Me
b
Me Me
8
Me
Me
Me
1,5-anti
O
2.
9
10
1,5-syn
H
R
2b-f
The 1,5-anti relationship for aldol adduct 12e (R¼p-MeOC6H4)
was confirmed by a single-crystal X-ray diffraction analysis, as
shown in Figure 1.14
Scheme 2. Aldol reactions of the boron enolate generated from 1,2-syn
methyl ketone 8.
b-alkoxy
Table 1
Aldol reactions of the boron enolate generated from methyl ketone 8
Entry
Aldehyde (R)
dsa 1,5-anti/1,5-syn
Yieldb (%)
i
1
2
3
4
5
2b, Pr
53:47
67:33
56:44
50:50
67:33
88
90
88
94
82
2c, Et
2d, Ph
2e, p-MeOC6H4
2f, p-NO2C6H4
a
Diastereoselectivity was determined by 1H and 13C NMR analysis of the crude
mixture of products.
b
Combined yields for both 1,5-syn and 1,5-anti isomers after purification by flash
column chromatography.
Surprisingly, the reactions presented in Scheme 2 and Table 1
resulted in low levels of diastereoselectivities favoring the corre-
sponding 1,5-anti aldol adducts. In contrast to what was expected,
the aldol addition of methyl ketone 8 showed that the stereo-
Figure 1. ORTEP3 diagram of the single-crystal X-ray structure of aldol adduct 12e.14
induction from the
addition, we believe that the
b
-alkoxy stereocenter is almost nonexistent. In
The intrinsic facial selectivity of the boron enolate generated from
a,b,g-trisubstituted methyl ketone 14 was investigated before in our
a-methyl stereocenter exhibited
laboratories.6f For this purpose, we reacted the kinetic boron enolate
generated from 14 with achiral aromatic, olefinic, and aliphatic al-
dehydes. We were delighted to find that this reaction led to the for-
mation of 1,5-anti products 15 as the major isomers (up to >95:5
diastereoselectivity) (Scheme 4 and Table 3).6f,12 These studies
a modest, intrinsic 1,4-syn stereoinduction. The relative stereo-
chemistries for the major products 6 (Scheme 1) and 9b (R¼iPr)
(Scheme 2) were assigned by transformation to the corresponding
diols after removal of the TBS and PMB protecting groups,
respectively, whose spectroscopic properties compared very well
with literature data (see Supplementary data for additional details).13
We next examined the use of 1,2-syn methyl ketones containing
showed a remarkable influence of the resident
b-alkoxyand g-methyl
stereocenters on the stereochemical course of these aldol reactions.6
a b-alkoxy substituent as a part of a benzylidene acetal. It should be
noted that we tested a new experimental procedure for the aldol
reactions of methyl ketones 11 (Scheme 3) and 17 (see Scheme 5). We
found out that there is no need to wait additional time for the eno-
lization and the aldehyde is added immediately after addition of
(c-Hex)2BCl and Et3N to a solution of the corresponding methyl
ketone in Et2O as solvent at ꢀ78 ꢁC. This leads to better results in
terms of yields when compared with the normal enolization
procedure, although the levels of diastereoselectivities are the same.
Following this protocol, aldol reactions of 1,2-syn methyl ketone 11,
PMP 1,5-anti
PMP
O
PMP
O
1,5-syn
O
O
O
OH
O
O
O
OH
O
O
(c-Hex)2BCl
Et2O, Et3N
+
H
R
R
R
16
Me
14
15
0 °C
Me Me
−78 °C
Me
Me
Me Me
Scheme 4. Aldol reactions of the boron enolate prepared from 1,2-syn
ketone 14.6f
b-alkoxy methyl
The configurational assignment of the major isomer as 1,5-anti
was confirmed by a single-crystal X-ray structure determination of
aldol adduct 15h (R¼Me).6f
lacking the methyl group in g-position relative to the carbonyl group,
with aldehydes 2b–g, at ꢀ78 ꢁC, provided the corresponding 1,5-anti
(12b–g) and 1,5-syn (13b–g) aldol adducts (Scheme 3, Table 2).12 The
boron-mediated aldol reactions of methyl ketone 11 were found to
proceed with good yields and good levels of remote 1,5-anti ster-
eoinduction. The best selectivity was observed with p-methoxy-
benzaldehyde (entry 4, 1,5-anti/1,5-syn¼87:13).
With these encouraging results in hand, we next moved to in-
vestigate the aldol reactions of all-syn-trisubstituted methyl ketone
17, where the absolute stereochemistry of the g-stereocenter has
been changed when compared with methyl ketone 14. The aldol
reactions of the 1,2-syn methyl ketone 17 with aldehydes 2b–k

8716
L.C. Dias et al. / Tetrahedron 65 (2009) 8714–8721
Table 3
PMP
PMP
O
Aldol reactions of the boron enolate generated from methyl ketone 146f
TBS
O
TBS
DIBAL-H
CH2Cl2
TBSOTf
2,6-lutidine
CH2Cl2, 0 °C
87%
O
O
OH OH
O
O
O
Entry
Aldehyde (R)
Solvent
dsa 1,5-anti/1,5-syn
Yieldb (%)
Me
Me
0 °C, 85%
1
2
3
4
5
2a, m-BnOC6H4
2b, Pr
2d, Ph
2g, C(Me)]CH2
2h, Me
Et2O
Et2O
Et2O
Et2O
Et2O
>95:05
>95:05
>95:05
>95:05
>95:05
82
77
77
75
89
22
i
Me Me 20
Me Me
PMB
Me
Me
PMB
TBS
TBS
O
TBS
BnBr
TBS
OH
O
O
O
OBn O
NaH, DMF
0 °C, 53%
TBAF 1M
THF, 89%
a
Diastereoselectivity was determined by 1H and 13C NMR analysis of the crude
Me
Me
Me
Me
mixture of products.
23
24
Me Me
b
Me Me
Combined yields for both 1,5-syn and 1,5-anti isomers after purification by flash
column chromatography.
PMP
PMB
OBn O
DDQ
MS 4Å
CH2Cl2
44%
a
OH OH
OBn O
O
OH
were investigated using (c-Hex)2BCl and Et3N in Et2O as solvent, to
give the 1,5-anti and 1,5-syn aldol adducts 18 and 19, respectively
(Scheme 5, Table 4). As observed before, these boron-mediated
aldol reactions were found to proceed with good yields and good
degrees of remote 1,5-anti stereoinduction. Especially noteworthy
is that this methyl ketone afforded lower levels of 1,5-anti dia-
stereoselectivity when compared with methyl ketone 14. These
results clearly demonstrate, for the first time, that even the ste-
b
d
Me
Me
c
Me Me 25
26
Me
Me Me
Me
Hc
R2
OBn
O
Me
PMP
J
b,c= 12.0 Hz R1
=
O
Hd
Me
J
c,d= 2.0 Hz
Hb
R1
nOe 5.96%
OH
26 Ha
Me
R2
=
Me
reochemistry of the
g-stereocenter plays a significant role in the
aldol addition reactions of these particular methyl ketones.
Scheme 7. Proof of stereochemistry for aldol adduct 18b.
acetal 21 in 85% yield (Scheme 6). Analysis of the 13C NMR spectra
PMP
O
PMP 1,5-anti
PMP
O
1,5-syn
O
O
O
O
O
O
OH
showed resonances at
d 19.1, 30.1, and 98.2 for 21, as expected for
O
O
OH
H
R
+
c-Hex2BCl, Et3N
Et2O, −30 °C
a 1,3-cis acetonide.15
2b-k
Me
17
R
R
19
− 78 °C
18
Me Me
Having ascertained the relative stereochemistry for the 1,3-diol
unit in diol 20, we next moved to establish its relation with the
stereocenters originally present in the boron enolate. Protection of
20 with TBSOTf gave the corresponding bis-silyl ether 22 in 87%
yield, which, after treatment with DIBAL-H in CH2Cl2 provided
primary alcohol 23 in 85% yield (Scheme 7). Alcohol 23 was pro-
tected as its benzyl ether (53%) and treated with TBAF to remove
both TBS protecting groups to give diol 25 in 89% yield. Treatment
of 25 with DDQ in CH2Cl2 in the presence of molecular sieves gave
benzylidene acetal 26 in 44% yield (Scheme 7). Analysis of the 1H
NMR coupling constants for 26, specifically JHb–Hc¼12.0 Hz and
JHc–Hd¼2.0 Hz, together with the NOE interaction between Ha and
Hb, proved that Ha, Hb, and Hc are all axial (Scheme 7), confirming
the 1,5-anti stereochemistry for aldol adducts 18b–k.
Me Me
Me
Me
Scheme 5. Aldol reactions of the boron enolate prepared from 1,2-syn
ketone 17.
b-alkoxy methyl
Table 4
Aldol reactions of the boron enolate generated from methyl ketone 17
Entry
R
Solvent
dsa 1,5-anti/1,5-syn
Yieldb (%)
i
1
2
3
4
5
6
7
8
9
2b, Pr
2c, Et
2d, Ph
2e, p-MeOC6H4
2f, p-NO2C6H4
2g, C(Me)]CH2
2h, Me
2i, CH2CH2Ph
2j, CH]CH2
2k, p-FC6H4
Et2O
Et2O
Et2O
Et2O
Et2O/CH2Cl2
Et2O
Et2O
Et2O
Et2O
86:14
88:12
72:28
86:14
>95:05
78:22
89:11
90:10
86:14
86:14
97
51
69
70
55
89
65
94
72
59
10
Et2O
3. Aldol transition structures
3.1. Computational methods
a
Diastereoselectivity was determined by 1H and 13C NMR analysis of the crude
mixture of products.
b
Combined yields for both 1,5-syn and 1,5-anti isomers after purification by flash
column chromatography.
All structures were fully optimized through the Gaussian03
program,16 applying the B3LYP hybrid functional17 and 6-31G(d,p)
basis sets. For purposes of comparison, in some cases we calculated
the single-point energies from these optimized structures applying
the functional B3LYP hybrid in combination with 6-311þþG(d,p)
basis set, and the second-order Møller–Plesset perturbation theory
(MP2)18 in combination with 6-31þG(d,p). The relative energies for
the transition structures were evaluated by single-point calcula-
tions (in Et2O) from the gas-phase optimized geometries (PCM
method).19 The Cartesian coordinates are supplied in Supplemen-
tary data. In previous works, Paton and Goodman7 observed that
the single-point solvation energies and geometries were very
similar to those obtained from a full optimization in solvents. The
NBO delocalization energies (stabilizing energies calculated by
second-order perturbation theory analysis) were calculated at the
B3LYP/6-31G(d,p) level using NBO 5.0.20,21 The frequency calcula-
tions for the observed transition structures were conducted to
check for the presence of a single imaginary frequency and the
corresponding eigenvector inspected to confirm the expected aldol
reaction coordinate.
The 1,5-anti relative stereochemistry for aldol adducts 18b–k
was unambiguously established after conversion of 18b (R¼iPr) to
the corresponding acetals 21 and 26 (Schemes 6 and 7). Selective
reduction of 18b performed very well to give the 1,3-syn diol 20
(83% yield). This was followed by treatment of 20 with Me2C(OMe)2
in the presence of catalytic amounts of CSA to give isopropylidene
PMP
O
PMP
O
Et2BOMe, LiBH4
THF:MeOH (4:1)
O
O
OH
O
OH OH
Me
Me
−78 °C, 83%
Me Me
Me
Me Me
Me
18b
20
δ 30.3
δ 98.2
δ 30.1
δ 98.8
δ 19.1
Me Me
Me Me
δ 19.7
O
O
O
O
Me2C(OMe)2
Me
CSAcat., rt, 85%
Me Me
Me
21
Scheme 6. Preparation of isopropylidene acetal 21.

L.C. Dias et al. / Tetrahedron 65 (2009) 8714–8721
8717
3.2. Simple 1,2-syn
b
-alkoxy methyl ketones
Wehaveobserved anenergeticpreferenceforthe[in-anti]and[in-
syn] conformers with a stabilizing formyl H-bond with delocalization
energies of 3.1 and 2.9 kcal/mol, respectively (see Supplementary
data for additional details).23 This leads to a shorter O–H distance in
the 1,5-anti transition structure (2.354 Å) as well as to a higher
delocalization energy when compared with the 1,5-syn transition
structure (2.372 Å).7,20,21 Transition state [in-anti], which gives the
1,5-anti isomer, is lower in energy when compared with transition
state [in-syn], which gives the 1,5-syn aldol adduct. This difference of
0.5 kcal/mol leads to a Boltzmann distribution of 8:2 at ꢀ78 ꢁC, in
favor of the 1,5-anti diastereoisomer. The A1,3 type interaction of the
We were intrigued by the fact that 1,2-syn methyl ketone 8,
containing a -alkoxy PMB protecting group, led to low levels of
b
diastereoselection (Scheme 2, Table 1).
Recently, Paton and Goodman7 published very interesting the-
oretical studies in order to explain the origins of the 1,5-anti
asymmetric induction in boron-mediated aldol reactions of methyl
ketones. They concluded that these reactions proceed via boat-like
transition states and, based on Natural Bond Orbital analysis, pro-
posed that a stabilizing formyl hydrogen bond favors the formation
of the 1,5-anti aldol product.7,20–22 Due to the lower basicity of the
a
-Me group and one of the hydrogens of the enolate double bond
seems to disfavor transition state [in-anti], while the steric interaction
between the -Me group in pseudo-axial position and one of the
b
-oxygen, it is proposed that silyl protecting groups prevent this
formyl hydrogen bonding and led to the lower levels of observed
selectivities. However, the lower basicity of the oxygen attached to
the silicon may not be the only effect responsible for the observed
lower selectivities as steric effects may play a very important role in
controlling the observed sense of stereoinduction.10a We have
b
methyl ligands on boron disfavors transition state [in-syn].
These theoretical results are consistent with our experimental
results using the boron enolate generated from methyl ketone 8 as
they show a tendency to form the 1,5-anti aldol adduct as the major
isomer (Scheme 1 and Table 1).
observed that the use of a
1,5-syn isomers in similar levels of diastereoselectivities when
compared with
-OTBS protecting groups.6a,b
b
-OtBu protecting group also gives the
Although Paton and Goodman7b stated that a similar model also
rationalizes the excellent levels of 1,4-syn selectivities observed in
b
Based on these results, we have performed theoretical calcula-
tions on the competing transition structures leading to both 1,5-
anti and 1,5-syn aldol adducts. We based our work in the previous
theoretical studies of Paton and Goodman7 and only the boat-like
transition structures were considered, as they are energetically
more favorable because of the 1,3-diaxial type interactions present
in the corresponding chair-like transition structures.22
the reactions of a-methyl boron enolates, and correctly predicts the
outcome of competition between 1,4- and 1,5-stereoinduction,
where the latter dominates, we observed that this is not the case
with a,b-syn disubstituted boron enolates of methyl ketones like 8.
Due to the lower energy difference observed between transition
states, it looks like this is the case of a mismatched relationship as
there is
a
competition between 1,4-syn induction from the
-alkoxy
-OTBS methyl
Initially, we studied the simple aldol transition structures for
a-methyl stereocenter and 1,5-anti induction from the b
a
,b
-dimethyl-b-methoxy dimethylboron enolate 8a and acetalde-
stereocenter. This should also be the case with the b
hyde (Fig. 2). A summary of the low-energy structures is presented
in Figure 2 (Fig. S1 in Supplementary data shows all the successfully
optimized structures).
ketone 5 (Scheme 1).
At this point, we turned our attention to investigate the corre-
sponding transition structures by replacing the -Me group by
-OBn group.
-methyl- -isopropyl-
-benzyloxy dimethylboron enolate 8b are shown in Figure 3 (see in
b
a
b
-iPr group and the
The lower energy transition states for the
b-OMe substituent by a b
a
b
b
OMe OB(Me)2
MeO
Me
O
OH
Me
1,5-anti
MeO
Me
O
OH
Me
1,5-syn
+
+
MeCHO
Me
8a
OBn OB(Me)2
BnO
O
OH
Me
1,5-anti
BnO
O
OH
Me
1,5-syn
Me
Me
Me
+
Me
8b
Me
Me
+
MeCHO
Me Me
Me Me
Me Me
Figure 2. Aldol transition structures for
a
,
b-dimethyl-b-methoxy dimethylboron
Figure 3. Aldol transition structures for a-methyl-b-isopropyl-b-benzyloxy dime-
enolate 8a and acetaldehyde, leading to 1,5-anti and 1,5-syn aldol adducts (relative
thylboron enolate 8b and acetaldehyde, leading to 1,5-anti and 1,5-syn aldol adducts
energies in kcal/mol calculated in Et2O at B3LYP/6-31G(d,p)).
(NBO energy in kcal/mol at B3LYP/6-31G(d,p)).

8718
L.C. Dias et al. / Tetrahedron 65 (2009) 8714–8721
OBn OB(c-Hex)2
BnO
O
OH
Me
1,5-anti
BnO
O
OH
Me
1,5-syn
Supplementary data, Fig. S2 with all observed structures). The anal-
ysis of the relative energies of these transition structures (Table 5)
proved that the density functional B3LYP shows relative energies
favoring the corresponding [out-anti] transition structure, thus pre-
venting the formyl H-bond. There was also a large energy difference
between the competitive transition state [out-anti], of lower energy
and which leads to 1,5-anti diastereoisomer, and [out-syn] leading to
1,5-syn diastereoisomer, a situation which is inconsistent with our
experimental results, as well as with the results described earlier by
Paton and Goodman.7
+
Me
Me
Me
+
MeCHO
8c
Me Me
Me Me
Me Me
Table 5
Relative energies (in kcal/mol calculated in Et2O) of aldol transition structures for
a
-methyl-b-isopropyl-b-benzyloxy dimethylboron enolate 8b and acetaldehyde
TS
B3LYP/6-31G B3LYP/6-311þþg
MP2/6-31þg
(d,p) (d,p)//B3LYP/6-31G(d,p) (d,p)//B3LYP/6-31G(d,p)
in-anti-a 1.2
1.8
0.0
2.7
1.3
0.0
2.3
0.8
4.2
out-anti
in-syn-a
out-syn
0.0
1.9
1.3
The single-point energy calculation at the B3LYP/6-311þþG(d,p)
level did not lead to significant changes in the relative energies.
However, the same single-point calculation using MP2/6-
31þG(d,p) theory revealed now a lower energetic preference for
the [in-anti-a] and [in-syn-a] conformers, which contain a stabiliz-
ing formyl H-bond. The O–H distance in the [in-anti-a] transition
structure (2.389 Å) is shorter when compared with the [in-syn-a]
transition structure (2.404 Å), with delocalization energies of 2.2
and 2.4 kcal/mol, respectively. In this case, the [in-anti-a], which
gives the 1,5-anti isomer, is lower in energy when compared with
transition state [in-syn-a], which gives the 1,5-syn aldol adduct.
This difference of 0.8 kcal/mol leads to a Boltzmann distribution of
9:1 at ꢀ78 ꢁC, in favor of the 1,5-anti diastereoisomer. The results
presented in Figure 3 and Table 5 seem to be in agreement with our
experimental results.
Figure 4. Aldol transition structures for
hexyl boron enolate 8c and acetaldehyde, leading to 1,5-anti and 1,5-syn aldol adducts
(NBO energies in kcal/mol at B3LYP/6-31G(d,p)).
a-methyl-b-isopropyl-b-benzyloxy dicyclo-
In these cases, the cyclohexyl groups are not responsible for the
diastereodifferentiation, but they keep the ring in a rigid boat-like
conformation, avoiding the 1,3-diaxial interactions between the
boron and the ring substituents.
3.3. Boron enolates of
methyl ketone
b-benzylidene acetal-substituted
A possible explanation for these controversial results is on the
employed DFT theory for calculation of the transition state relative
energies. Recent publications show that for steric hindered systems
the density functional B3LYP led to good quality geometries, but to
poor quality relative energies.7,24 Therefore, analysis of the com-
petitive transition states that involves small differences in relative
energies, provide discrepant quantitative results and it is necessary
to use high level non-DFT methods to compute single-point energy
from DFT-optimized structures, as recommended by Schreiner and
co-workers.24a In this case, we believe that the steric energy be-
In the case of b-benzylidene acetal-substituted boron enolates,
Paton and Goodman7 observed that the favored transition structure
has the six-membered acetal ring in a chair-like conformation, with
the substituents in equatorial positions. The preferred 1,5-anti
transition structure has the acetal oxygen oriented toward the
formyl hydrogen.
3.3.1. 1,2-syn-a-Methyl,b-alkoxy dimethylboron enolate (8d). In or-
tween the eclipsed a-Me and b
-iPr groups was super estimated in
[in-anti-a] and [in-syn-a] conformers.
der to better understand the results described in Schemes 3–5, we
decided to examine the corresponding transition structures, starting
with boron enolate 8d (calculated for a more simple system in which
the PMB group is replaced by a phenyl group) (Fig. 5).
In order to obtain more information on these transition struc-
tures, we next examined the influence of dicyclohexyl substituents
using the boron enolate 8c. As shown in Table 6, the insertion of
cyclohexyl groups do not generate significant differences in the
relative energies of the observed transition states, independent on
the theory level employed when compared to the previous case
(Fig. 4, Table 5), in agreement with the observed results presented
in Table 1.
Toward that end, as can be observed from Figure 7 and Table 5,
different results were obtained depending on the employed theory
level. Using B3LYP/6-31G(d,p) the [in-syn] transition state leading
to 1,5-syn aldol adduct is lower in energy, although this is not the
observed major product. The single-point energy calculation at the
B3LYP/6-311þþG(d,p) level led to the [in-anti] and [out-anti] low-
energy transition structures. As noted earlier, the density func-
tional B3LYP did not furnish an accurate determination of the
relative energy.7,24 The single-point analysis employing a higher
theory level (MP2/6-31þG(d,p)) showed that only the transition
states [in-anti] and [in-syn] containing a stabilizing hydrogen bond
are lower in energy (Table 7). The O–H distance in the [in-anti]
transition structure (2.332 Å) is shorter when compared with the
[in-syn] transition structure (2.383 Å), with delocalization energies
of 3.3 and 2.3 kcal/mol, respectively.
Table 6
Relative energies (in kcal/mol calculated in Et2O) of aldol transition structures for
a
-methyl-b-isopropyl-b-benzyloxy dicyclohexyl boron enolate 8c and acetaldehyde
TS
B3LYP/
6-31G(d,p)
B3LYP/6-311þþg(d,p)//
MP2/6-31þg(d,p)//
B3LYP/6-31G(d,p)
B3LYP/6-31G(d,p)
in-anti-a
out-anti
in-syn-a
out-syn
1.2
0.0
2.3
1.4
2.1
0.0
3.0
1.2
0.0
2.6
0.7
4.9

L.C. Dias et al. / Tetrahedron 65 (2009) 8714–8721
Ph
Ph
8719
Ph
Ph
Ph
Ph
O
O
OB(Me)2
O
O
O
OH
Me
O
O
O
OH
Me
1,5-syn
O
O
OB(Me)2
O
O
O
OH
Me
O
O
O
OH
Me
1,5-syn
+
MeCHO
+
+
MeCHO
+
Me
Me
Me
Me Me
Me Me
Me Me
8e
8d
1,5-anti
1,5-anti
Figure 5. Aldol transition structures for 1,2-syn-a-methyl,b-alkoxy dimethylboron
enolate 8d and acetaldehyde, leading to 1,5-anti and 1,5-syn aldol adducts (NBO en-
ergies in kcal/mol at B3LYP/6-31G(d,p)).
Figure 6. Aldol transition structures for 1,2-syn-2,3-anti-a,g-methyl,b-alkoxy dime-
thylboron enolate 8e and acetaldehyde, leading to 1,5-anti and 1,5-syn aldol adducts
(NBO energies in kcal/mol at B3LYP/6-31G(d,p)).
In this case, the [in-anti], which gives the 1,5-anti isomer, is
lower in energy (0.1 kcal/mol) when compared with transition
state [in-syn], which gives the 1,5-syn aldol adduct.
Table 8
This indicates a possible competition between 1,4- and 1,5-
asymmetric induction, leading to a Boltzmann distribution of 6:4 at
ꢀ78 ꢁC, favoring the 1,5-anti diastereoisomers. These qualitative
results are in accordance with our experimental results. Again, the
Relative energies (in kcal/mol calculated in Et2O) of aldol transition structures for
1,2-syn-2,3-anti-
a
,
g
-methyl,
b
-alkoxy dimethylboron enolate 8e and acetaldehyde
TS
B3LYP/6-31G B3LYP/6-311þþg
MP2/6-31þg
(d,p)
(d,p)//B3LYP/6-31G(d,p) (d,p)//B3LYP/6-31G(d,p)
A1,3 type interaction of the a-Me group and the one of the hydro-
in-anti
out-anti 2.6
in-syn
out-syn
0.0
0.0
2.1
2.7
1.6
0.0
5.0
2.3
5.5
gens of the enolate double bond seems to disfavor transition state
[in-anti], while steric interactions between the ligands on boron
and the benzylidene acetal substituents disfavor transition state
[in-syn] (Table 7).
1.9
2.2
Table 7
The 1,5-anti [in-anti] transition structure is 2.3 kcal/mol more
stable than the 1,5-syn [in-syn], leading to a 10:0 Boltzmann distri-
bution at ꢀ78 ꢁC by using the MP2/6-31þG(d,p) single-point analy-
sis. This result is in perfect agreement with our experimental
observations. The high-energy difference of these conformers is
Relative energies (in kcal/mol calculated in Et2O) of aldol transition structures for
1,2-syn-a-methyl,b-alkoxy dimethylboron enolate 8d and acetaldehyde
TS
B3LYP/6-31G B3LYP/6-311þþg
MP2/6-31þg
(d,p)
(d,p)//B3LYP/6-31G(d,p)
(d,p)//B3LYP/6-31G(d,p)
in-anti
out-anti 0.9
in-syn
out-syn
0.2
0.2
0.0
0.7
1.3
0.0
3.0
0.1
4.8
probably due to the severe repulsive interactions between
a and
g-methyl groups at the axial positions in transition structure [in-syn].
0.0
2.1
3.3.3. 1,2,3-syn-
vestigated the transition structure for
a
,
g
-Methyl,
b
-alkoxy boron enolate. Finally, we in-
-trisubstituted boron
a,b,g
3.3.2. 1,2-syn-2,3-anti-
a
,
g
-Methyl,
b
-alkoxy dimethylboron enolate
enolate 8f (calculated for a simpler system in which the PMB group
is replaced by a phenyl group) (Fig. 7, Table 9). Furthermore, the
benzylidene acetal ring (see Supplementary data in Fig. S7 and
Table S11, for additional information) shows a preference for
a chair-like conformation with all bulky substituents in pseudo-
(8e). We next moved to investigate the transition structures for
-trisubstituted boron enolate 8e (calculated for a simpler
a,b,g
system in which the PMB group is replaced by a phenyl group,
keeping the acetal ring in a chair-like conformation, with all
bulky substituents in pseudo-equatorial positions) (Fig. 6, Table 8).
We have observed a preference for the transition structure [in-
anti], independent on the theory level employed. The formyl hy-
drogen bond (H–O) is shorter in transition structure [in-anti]
(2.332 Å) when compared with 2.457 Å observed for the [in-syn]
transition structure, with delocalization energies of 3.3 and
1.7 kcal/mol, respectively.
equatorial positions and the
g-methyl group in a pseudo-axial
position. The competitive transition structures are shown in Fig-
ure 7 (see Supplementary data in Fig. S8 and Table S13, for all the
observed structures).
It is interesting to observe that the most stable transition state
conformers are [out-anti-d] and [out-syn-c], and the conformers
[in-anti] and [in-syn] containing a stabilizing hydrogen bond are

8720
L.C. Dias et al. / Tetrahedron 65 (2009) 8714–8721
Ph
Ph
Ph
is part of a benzylidene acetal. The strong internal stereoinduction
of the -alkoxy stereocenter of the boron enolates dominates the
overall stereochemical outcome of the corresponding aldol addition
b
O
O
OB(Me)2
O
O
O
OH
Me
O
O
O
OH
Me
1,5-syn
+
MeCHO
+
Me
Me
Me
reactions, leading to the 1,5-anti products with high diaster-
Me
Me
Me
8f
1,5-anti
eoselectivities. Even with the use of
a-methyl-b-alkoxy methyl
ketones, the -stereocenter plays a dominant role in determining
b
the sense of 1,5-anti asymmetric induction. The examples presented
in this work show that the levels of facial selection are dependent
on the absolute stereochemistries of the chiral boron enolates. In
order to gain insight on the stereochemical outcome of these aldol
couplings, we have performed theoretical calculations on the
kinetic boron enolates generated from
b-alkoxy methyl ketones
with acetaldehyde using density functional theory by means of
B3LYP and ab initio MP2 method. The magnitude of the formyl
hydrogen bond has been evaluated using NBO perturbation theory
analysis. In some cases, different results were obtained depending
on the employed theory level. Further studies in this direction, es-
pecially in order to stress the importance of a competing 1,4-syn
induction are underway and will be described in due course.
Acknowledgements
We are grateful to FAEP-UNICAMP, FAPESP (Fundaça˜o de
`
˜
Amparo a Pesquisa do Estado de Sao Paulo), CNPq (Conselho
´
´
Nacional de Desenvolvimento Cientıfico e Tecnologico), and INCT-
INOFAR Proc. CNPq 573.564/2008-6 for financial support. We thank
also Prof. Carol H. Collins for helpful suggestions about English
grammar and style and Prof. Jonathan M. Goodman for useful
comments on the theoretical calculations.
Supplementary data
Figure 7. Aldol transition structures for all-syn-a,g-methyl,b-alkoxy boron enolate 8f
and acetaldehyde, leading to 1,5-anti and 1,5-syn aldol adducts (NBO energies in
kcal/mol at B3LYP/6-31G(d,p)).
Spectroscopic data for the prepared compounds, crystallo-
graphic data for aldol 12e, and Cartesian coordinates of all transi-
tion structures with gas-phase and solution-phase SCF absolute
energies. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2009.08.042.
Table 9
Relative energies (in kcal/mol calculated in Et2O) of aldol transition structures for
all-syn-
a
,
g
-methyl,
b
-alkoxy boron enolate 8f and acetaldehyde
TS
B3LYP/6-31G B3LYP/6-311þþg
MP2/6-31þg
References and notes
(d,p)
(d,p)//B3LYP/6-31G(d,p) (d,p)//B3LYP/6-31G(d,p)
in-anti
out-anti-d 0.0
in-syn
out-syn-c
2.3
2.4
0.0
4.2
0.9
0.5
0.0
0.8
0.6
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M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.;
Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J.
B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu,
23. As suggested by Paton and Goodman (Ref. 7), we label these structures as
‘in’ and ‘out’ to signify whether the
b
ꢀalkoxy substituent points in toward
the approaching aldehyde (with a stabilizing formyl hydrogen bond), or out
and away from the aldehyde (absence of
bond).
a stabilizing formyl hydrogen
24. (a) Schreiner, P. R.; Folkin, A. A.; Pascal, R. A.; Meijere, A. Org. Lett. 2006, 8,
3635; (b) Grimme, S. Angew. Chem., Int. Ed. 2006, 45, 4460; (c) Zhao, Y.;
Truhlar, D. G. Org. Lett. 2006, 8, 5753; (d) Wodrich, M. D.; Corminboeuf, C.;
Schereiner, P. R.; Fokin, A. A.; Schleyer, P. v. R. Org. Lett. 2007, 9, 1851;
(e) Schreiner, P. R. Angew. Chem., Int. Ed. 2007, 46, 4217; (f) Zhao, Y.; Truhlar, D.
G. Acc. Chem. Res. 2008, 41, 157.