Diastereoselectivity in the boron aldol reaction of α-alkoxy and α,β-bis-alkoxy methyl ketones

Article abstract of DOI:10.1039/c9ob00358d

In this work, using DFT calculations, we investigated the 1,4 and 1,5 asymmetric induction in boron enolate aldol reactions of α-alkoxy and α,β-bisalkoxy methyl ketones. We evaluated the steric influence of alkyl substituents at the α position and the stereoelectronic influence of the oxygen protecting groups at the α and β positions. Theoretical calculations revealed the origins of the 1,4 asymmetric induction in terms of the nature of the β-substituent. The synergistic effect between the α,β-syn and α,β-anti-bisalkoxy stereocenters was elucidated. In the presence of the β-alkoxy center, the reaction proceeds through the Goodman-Paton 1,5-stereoinduction model, experiencing a minor influence of the α-alkoxy center.

Full text of DOI:10.1039/c9ob00358d

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Diastereoselectivity in the Boron Aldol Reaction of -Alkoxy and ,-Bis-Alkoxy
Methyl Ketones
Alessandra A. G. Fernandes,† Ives A. Leonarczyk,†† Marco A. B. Ferreira,††* Luiz Carlos Dias,†*
†† Centre of Excellence for Research in Sustainable Chemistry (CERSusChem), Department of Chem-
istry, Federal University of São Carlos − 13565-905, Brazil.
† Institute of Chemistry, University of Campinas, Campinas −13083-970, Brazil.
Corresponding Authors *Email: marco.ferreira@ufscar.br (M. A. B. Ferreira), ldias@iqm.unicamp.br
(L. C. Dias) Tel.: +55-19-35213097.
ABSTRACT
In this work, using DFT calculations, we investigated the 1,4 and 1,5 asymmetric induction presented
in boron enolate aldol reactions of -alkoxy and ,-bisalkoxy methyl ketones. We evaluated the steric
influence of alkyl substituents at the α position as well as the stereoelectronic influence of the oxygen
protecting groups at the  and  positions. Theoretical calculations revealed the origins of 1,4 asym-
metric induction in terms of the nature of the β-substituent. The synergistic effect between the ,-syn
and ,-anti-bisalkoxy stereocenters were elucidated. In the presence of the β-alkoxy center the reaction
course goes through the Goodman-Paton 1,5-stereoinduction model, experiencing a minor influence of
the -alkoxy center.
dipole minimization
steric effect
O
OH
R
H
O
OH
4
R
PG
4
H
H
O
PG
R
1
R
O
R'
O
1
R'
L
H
L
O
OP
1,4-anti
OP
1,4-syn
B
B
O
L
L
O
R'
TS1'-A
R'
favorable for
R = i-Pr, t-Bu
favorable for
R = Me
TS1-A
PG = protecting group

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INTRODUCTION:
The boron-mediated aldol reaction is one of the most versatile and efficient methods for the
formation of C-C bonds with regio-, diastereo- and enantioselective control.1 The application of this
reaction is accompanied by the presence of powerful predictive models constructed over the last few
decades, allowing its safe application in the preparation of complex molecules, remarkably so for the
synthesis of natural products.1,2 In particular, for metal-mediated aldol reactions of -alkoxy ethyl ke-
tones a reasonable set of evidence properly justifies their stereoselectivities.3 For boron and tita-
nium(IV) enolates it is presumed that the stereoselectivity proceeds through the Zimmerman-Traxler
chair-like transition state (Figure 1A, TSA), in which the both C-O bonds assume an antiperiplanar
orientation for dipolar reasons. The RL- substituent in the chiral -position is arranged outside of the
cyclic transition states to minimize 1,3-diaxial interactions, and determines the approach of aldehyde,
furnishing the 1,4-syn aldol adduct with high diastereoselectivities. The 1,2-relative stereochemistry is
determined by the enolate geometry. However, metals like lithium and magnesium are involved in a
chelated transition state to afford the opposite diastereoselectivity (Figure 1A, TSB). For benzyl pro-
tecting groups and specific conditions with titanium(IV)4 the 1,4-anti product is observed supposedly
through TSB.
2

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Figure 1. Stereoinduction involving -alkoxy and ,-bisalkoxy methyl ketones.
3

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Despite the success of the boron-mediated propionate aldol reactions, the acetyl analogue has
proved to be more challenging. These enolborinates preferably react via a boat-like transition state in
which the 1,3-diaxial interactions are much reduced.5 In particular, the presence of -alkoxy and ,-
bisalkoxy stereocenters in methyl ketones, desirable in the construction of polyhydroxylated natural
products, makes its lack of development especially puzzling. The well known Goodman-Paton model
describes successfully the remote asymmetric 1,5-induction in boron mediated aldol reactions of -
alkoxy methyl ketones (Figure 1B). These findings showed that the transition state responsible for the
stereodeterminant step keeps the -OPG group towards to the C-H formyl bond and participates in a
stabilizing hydrogen bond (H-bond) with the lone pairs of the -oxygen. The nature of protecting group
is critical for the observed high levels of the observed 1,5-anti asymmetric induction and involves a
puzzling non-covalent interactions balance between the -substituents, C-H formyl, and boron ligands.6
Conversely, as unraveled by DFT calculations, except for large protecting groups (OSiR3, OCR3) and
bulky -alkyl substituents, the Goodman-Paton model is often predominant over other models to ex-
,
plain the observed stereoinduction.6 17 However, to date, no successful model has been presented ex-
plaining the role of the -alkoxy center (Figure 1C).
Some examples involving asymmetric 1,4-induction of -alkoxy and ,-bisalkoxy methyl ke-
tones have been reported. In 1999, Evans and coworkers disclosed the first evidence of a remote 1,4-
asymmetric induction in aldol reactions involving boron enolates of α-alkoxy methyl ketones and alde-
hydes, as part of the total synthesis of C23-C24 bond of Bryostatin 2 (Figure 2A).7 Low levels of dia-
stereoselectivities were obtained using (c-Hex)2BCl, although useful levels of 1,4-syn and 1,4-anti
asymmetric induction were observed using chiral boranes. Other more recent contributions were made
by Fürstner8 (Figure 2B), Kalesse9 (Figure 2C), and Burch10 (Figure 2D) in the context of total synthesis,
similarly showing in the most cases modest 1,4-anti diastereoselectivities. It is worth mentioning that
synthetically useful results can be achieved using titanium(IV)11.
4

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Figure 2: Representative examples of 1,4-Asymmetric induction in aldol reactions involving boron
enolates of α-alkoxy methyl ketones.
Due to the lack of detailed studies regarding the factors that influence the 1,4-asymmetric in-
duction in boron-mediated aldol reactions of chiral -alkoxy methyl ketones and the synergic effects in
,-bisalkoxy methyl ketones, we decided to study the influence of the alkyl substituents at the -
position as well as the nature of the oxygen protecting groups at the  and  positions using DFT
calculations.
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RESULTS AND DISCUSSION
Computational details. All DFT calculations were performed with Gaussian 09 using an ultrafine
grid.12 The choice of the level of theory followed previous results from literature,6 using the B3LYP
functional13 along with 6-31g(d,p) basis set in vacuum for geometry optimization, and the Grimme’s
D3 dispersion version.14. We also truncate the boron ligands aiming reduction of computational costs,
since previous work shows no relative energy or geometry changes. The structures were visualized
using the beta version of CYLview.15 The frequency calculations (295.15 K at 1 atm) confirmed that
the calculated stationary points denote either minima (no imaginary frequency) or transition states (sin-
gle imaginary frequency) on the potential-energy surface, furnishing also the zero-point vibrational en-
ergies, and the thermal and entropic correction from which the Gibbs free energies were determined.
To refine the electronic energies, single-point calculations were performed at B3LYP/6-31g(d,p)/IEF-
PCM level of theory employing the B3LYP/6-31g(d,p) geometries. The natural bond orbital (NBO)
was calculated using NBO 6.0,16 at B3LYP/6-31g(d,p)/IEF-PCM level of theory. The second-order per-
turbation analysis (E2PERT=0.05 keyword) estimates the electron delocalization LPO → σ*C-H associ-
ated to the hydrogen bonds stabilization energies.
Initial considerations. We considered in our calculations the well known Goodman-Paton model to
describe the remote asymmetric 1,5-induction in boron mediated aldol reactions of methyl ketones.6
Only boat-like transition state geometries were considered, which prevent 1,3-diaxial-type interaction
presented in the chair-like conformations. The input geometries for the diastereoisomeric competing
transition states TS1 and TS1’ were designed considering the rotation of dihedral Φ1 generating 3 start-
ing geometries for each diastereoisomers (Scheme 1A). For the α,β-bisalkoxy methyl enolates, addi-
tional “in” and “out” conformers were included, generating at least 9 starting geometries for each dia-
stereoisomer by rotation of dihedral Φ2 and Φ3. The Scheme 1B describes the boron enolates of the α,β-
syn-bisalkoxy methyl ketones. The index “in” and “out” refers to the relative position of the beta-sub-
stituent and the ring in the transition state. We assumed simplifications on the molecular structures by
shortening some substituents aiming to reduce the computational costs, but without compromising the
quality of the results. Based on the previous literature reports,6,17 we truncated the boron ligands, replac-
ing c-Hex- by Me-. Other simplifications involved the change of more traditional protecting group (PG)
substituents TBS- and PMB- by TMS- and Bn-, respectively. Since the diastereoselectivity was mainly
controlled by the features of methyl ketones, we choose acetaldehyde in the calculations.
6

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A) α-alkoxy methyl ketone
R
H
OPG
PGO
H
R
O
OH
O
OH
H
H
O
Me
Me
Me
Me
O
Φ
1
Φ
1
4
4
vs
vs
vs
R
R
B
B
1
1
Me
Me
O
O
OPG
1,4-anti
OPG
1,4-syn
Me
Me
R = Me, t-Bu
PG = Bn, TMS
TS1
TS1'
B) α,β-syn-bisalkoxy methyl ketone
Me
H
Φ2
H
OPG'
H
H
Me
Me
OPG
OPG
PG'O
Φ
3
H
H
O
Me
Me
O
B
B
Me
O
O
Me
Me
PGO
O
OH
PGO
O
OH
in-TS2
in-TS2'
4
4
5
1
1
Me
Me
Me
Me
5
OPG'
1,4-anti, 1,5-anti
OPG'
1,4-syn, 1,5-syn
OPG
OPG
H OPG'
H
Me
OPG'
H
H
H
Me
H
Me
Me
Me
O
O
B
B
Me
O
O
Me
Me
out-TS2'
PG = PG' = Bn, TMS
out-TS2
Scheme 1. Conformations and substituents considered in the transition states calculations.
Since boron mediated aldol reactions are typically kinetically governed, to evaluate the theo-
retical diastereoselectivity we computed the equilibrium ratio between diastereoisomer [A]:[B] consid-
ering the Boltzmann distribution associated with the Gibbs energies (eqn (1)).18 A1 is the most stable
transition state conformation among all conformers i and j.
‡
‡
‡
‡
‡
‡
ꢈ∆ꢉ
‡
ꢌ∆ꢉ
‡
ꢎ/ꢏꢐ
ꢌ∆ꢉ
ꢌ∆ꢉ
‡
ꢅꢆꢇꢈ∆ꢉ
ꢎ/ꢏꢐꢆꢇꢈ∆ꢉ
ꢎ/ꢏꢐꢆ⋯ ꢇ
ꢊꢋ
ꢊꢋ
ꢊꢍ
ꢑꢋ
ꢊꢒ
ꢑꢓ
ꢎ/ꢏꢐ
ꢀ ꢂ
ꢁ
ꢄ
(1)
‡
‡
‡
ꢈ∆ꢉ
ꢌ∆ꢉ
ꢀꢃꢂ
ꢌ∆ꢉ
ꢌ∆ꢉ
ꢇꢈ∆ꢉ
ꢎ/ꢏꢐꢆꢇꢈ∆ꢉ
ꢎ/ꢏꢐꢆ⋯ ꢇ
ꢊꢋ
ꢕꢖ
ꢊꢋ
ꢔꢋ
ꢑꢋ
ꢔꢍ
We validated our theoretical models using experimental selectivities obtained from selected
reactants (Figure 3). Although we can find some precedents in literature involving asymmetric induc-
tion with α-alkoxy and α,β-bisalkoxy methyl ketones, these findings are generally sparse and the em-
ployed ketones are structurally diverse, and/or involve double stereodifferentiation with chiral alde-
hydes, and therefore do not allow a straightforward rationalization about the importance of stereoelec-
tronic effects. We address this issue by conducting a series of experiments with methyl ketones 10-21
(Figure 3A), from which we systematically evaluate the nature of the protecting groups, and alkyl sub-
stituents at - and -positions. The same attention was taken with the set of employed achiral aldehydes
7

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22a-h (Figure 3B), presenting a logical variation in their steric and electronic properties. See in the
Electronic Supporting Information file all details of these reactions, including preparation of methyl
ketones, and proof of stereochemistry of aldol adducts.
A)
α-alkoxy methyl ketones
α,β-syn-bisalkoxy methyl ketones
PG = PMB, PG' = PMB (16)
α,β-anti-bisalkoxy methyl ketones
PG = PMB, R = Me (10)
PG = PMB, PG' = PMB (19)
PG = PMB, PG' = TBS (20)
PG = TBS, PG' = TBS (21)
O
PGO
O
PGO
Me
O
PG = TBS, R = Me (11)
PG = PMB, R = i-Pr (12)
PG = TBS, R = i-Pr (13)
PG = PMB, R = t-Bu (14)
PG = TBS, R = t-Bu (15)
PG = PMB, PG' = TBS (17)
PG = TBS, PG' = TBS (18)
R
Me
Me
Me
OPG'
Me
OPG'
OPG
B)
aldehydes
(22e)
R' = CH2CH
R' = Ph
R' = p-NO2-C6H4
R' = Me (22a)
R' = Et (22b)
R' = i-Pr (22c)
R' = t-Bu(22d)
O
(22f)
(22g)
R'
H
R' = p-OMe-C6H
4 (22h)
Figure 3. A: Employed -alkoxy and ,-bisalkoxy methyl ketones. B: Employed achiral aldehydes.
Aldol reactions with -alkoxy methyl ketones. The enolates were prepared in situ using (c-Hex)2BCl,
Et3N and the corresponding -alkoxy methyl ketones 10-15 in Et2O at 30 ºC. The aldol reactions with
the achiral aldehydes 20a−h provided the corresponding 1,4-anti and 1,4-syn aldol adducts (Figure 4).
Analyzing the results, we noted that the experimental diastereoselectivities were slightly influenced by
the nature of protecting groups and aldehydes. The size of the R-substituent in these cases plays a major
role in determining the ratio of the products. With R = Me, we observed low to moderate diastereose-
lectivities favoring the 1,4-anti isomer (dr = 52:46 to 76:24). Increasing the bulkiness of R group the
aldol reaction increases the sense of induction in favor of the 1,4-syn isomer, from dr = 48:52 to 29:71
(R = i-Pr) and dr = 11:89 to 28:72 (R = t-Bu).
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Figure 4. Diastereoselectivities in the Boron-Mediated Aldol Reactions of Methyl Ketones 10-15.
Our theoretical investigation began by locating the transition states for the 1,4-syn and 1,4-anti
products presented in Scheme 1A. We adopted TS1 and TS1’ for 1,4-anti and 1,4-syn diastereoisomeric
transition structures, respectively. We located the transition states for R = Me and PG = Bn (TS1Me,Bn
and TS1’Me,Bn), for R = t-Bu and PG = Bn (TS1t-Bu,Bn and TS1’t-Bu,Bn), for R = Me and PG = TMS
(TS1Me,TMS and TS1’Me,TMS), and for R = t-Bu and PG = TMS (TS1t-Bu,Bn and TS1’t-Bu,Bn). The results
of these calculations are summarized in Table 1, and same selected transition structures in Figure 5.
Our theoretical calculations (Table 1) produced the same qualitative trends and predicted correctly the
major diastereoisomer for 3 cases (PG = Bn for R = Me, t-Bu; PG = TMS for R = Me) but failed for the
most hindered system (PG = TMS for R = t-Bu) indicating no theoretical diastereoselectivity (53:47).
Probably in this specific case the steric demand of the protecting group and borane ligands would be
necessary to better describe the stereodifferentiation.
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Table 1. Relative Gibbs (∆∆Grel) energies (kcal mol-1), theoretical diastereoselectivities and total dipo-
lar moment for calculated -alkoxy methyl ketones.
O
OH
O
OH
OBMe2
O
4
R
4
R
R
1
Me
+
1
Me
+
H
Me
OPG
OPG
OPG
1,4-anti
1,4-syn
drtheor(1,4-
anti:1,4:syn)
∆∆Grel
(kcal/mol)
Enolate
Dipole (D)
[exp]
TS1Me,Bn-a (1,4-anti)
TS1Me,Bn-b (1,4-anti)
TS1Me,Bn-c (1,4-anti)
TS1’Me,Bn-a (1,4-syn)
TS1t-Bu,Bn-a (1,4-anti)
TS1t-Bu,Bn-b (1,4-anti)
TS1’t-Bu,Bn-a (1,4-syn)
TS1’t-Bu,Bn-b (1,4-syn)
TS1Me,TMS-a (1,4-anti)
TS1Me,TMS-b (1,4-anti)
TS1’Me,TMS-a (1,4-syn)
TS1’Me,TMS-b (1,4-syn)
TS1’Me,TMS-c (1,4-syn)
TS1t-Bu,TMS-a (1,4-anti)
TS1t-Bu,TMS-b (1,4-anti)
1.4
1.4
0.0
1.3
1.3
1.4
7.3
0.0
0.0
0.6
2.8
0.1
1.6
1.3
0.0
0.0
4.4
1.9
4.8
6.0
4.0
5.0
3.8
3.8
3.8
5.4
4.2
6.4
5.6
4.2
4.5
6.1
4.0
5.3
4.4
5.4
R = Me, PG = Bn
96:4 [52:48]
6:94 [21:88]
R = t-Bu, PG = Bn
R = Me, PG = TMS
62:38 [53:47]
53:47 [14:86]
R = t-Bu, PG = TMS TS1’t-Bu,TMS-a (1,4-syn)
TS1’t-Bu,TMS-b (1,4-syn)
TS1’t-Bu,TMS-c (1,4-syn)
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TS1Me,Bn-b
TS1Me,Bn-c
TS1’Me,Bn-a
TS1t-Bu,Bn-a
TS1’t-Bu,Bn-b
TS1Me,TMS-a
TS1’Me,TMS-b
TS1t-Bu,TMS-b
TS1’t-Bu,TMS-a
Figure 5. Representative transition state structures for calculated -alkoxy methyl ketones.
A more in-depth analysis reveals the same non-expected conformations, which present a similar
“in” conformation as depicted by the Goodman-Paton model in β-alkoxy methyl ketones transition
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structure, and responsible for 1,5-diastereoinduction.5 Taking as an example the TS1Me,Bn-b (Figure 5),
this structure keeps the -OPG group towards to the C-H formyl bond, and participates in a stabilizing
hydrogen bond (H-bond) of 2.3 kcal.mol-1 between the lone pairs of the α-oxygen (LPO1 and LPO2) and
the σ*C−H formyl. Nevertheless, this interaction is not enough to stabilize this transition state, being 1.4
kcal.mol-1 higher in energy than TS1Me,Bn-c. Similar structures found in other systems also did not pre-
sent themselves as a minimum in terms of relative energy.
A general analysis of the results showed that the lowest energy diastereoisomeric transition
states, conducting to the products 1,4-anti and 1,4-syn, are those where the both C-O bonds assume an
antiperiplanar orientation (Table 1 and Figure 5), very similar to the chair-like chiral -OPG ethyl ke-
tone transition states, probably for the same dipolar reasons. The NBO analysis showed in all the cases
a very close stabilization energy (0.4-0.8 kcal.mol-1) between the LPO of -OPG and vinyl σ*C−H, there-
fore not explaining this energetic preference. Considering the magnitude of the molecular dipole (Table
1), we conclude that dipole minimization plays a major role in the antiperiplanar orientation of C-O
bonds, which in most cases the C-O antiperiplanar conformers possess the lowest dipole moments.
Another general observation of lowest energy transition state relates to the orientation of the α-
R group that can be pointed into the transition state ring (Scheme 2). This orientation differs greatly
from the established models involving ethyl ketones. This is made possible because the boat type con-
formation drastically reduces the 1,3-diaxial repulsive interactions. A more detailed analysis also shows
that the α-O-PG and α-C-R bonds move as far apart as possible each other, preventing severe vicinal
repulsive interactions, and in some cases assuming an antiperiplanar conformation. Thus, from the the-
oretical results, we conclude that the formation of the 1,4-anti and 1,4-syn diastereoisomers is a conse-
quence of the relative energies between TS1-A and TS1'-A, respectively, as represented in Scheme 2.
The preference between them varies according to the steric nature between R and P - the small group
being turned towards the transition state cycle, which is the most crowded position. Consequently, in
steric terms, when R = Me we have R < α-OPG, favoring TS1-A over TS1’-A, producing the 1,4-anti
product. In the case of R = i-Pr, t-Bu, we have that R > α-OPG since the ∠C-(α-C)-O-PG dihedral can
be adjusted in order to minimize the steric repulsions of the protecting group with the transition state
ring. In this situation, the opposite stereoselectivity is expected - 1,4-syn product - and TS1'-A becomes
smaller in energy. By this model, better levels of selectivities depend solely on the difference in steric
volume of groups α-R and α-OPG, that are not usually as large as the systems studied in this work and
present in the literature.
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H
O
OH
PG
R
O
O
4
R
favorable for
R = Me
H
L
1
R'
B
OPG
L
O
1,4-anti
R'
TS1-A
R
H
O
O
PG
O
OH
H
L
favorable for
R = i-Pr, t-Bu
4
R
B
1
R'
O
L
OPG
R'
1,4-syn
TS1'-A
Scheme 2. Proposed induction model for α-alkoxy methyl ketones.
Aldol reactions with ,-bisalkoxy methyl ketones. Once the basis for understanding the diastere-
oselection of α-alkoxy methyl ketones was formed, our next incursion sought to unravel the synergism
between α-alkoxy and β-alkoxy stereocenters. We obtained the experimental selectivities for aldol re-
actions of ,-syn (16-18) and ,-anti (19-21) bisalkoxy methyl ketones, by first generating the eno-
lates in situ using (c-Hex)2BCl, Et3N in Et2O at 30 ºC, and the aldol reactions with the achiral alde-
hydes 20a−h provided the corresponding aldol adducts (Figure 6).
The high diastereoselectivities (dr > 95:05) for ,-syn-bisalkoxy methyl ketones 16-17 suggest
that the PMB protecting group at the  position is critical for the high levels of the observed 1,5-anti
selectivities. The presence of TBS group at β-position caused an erosion of the selectivity (dr = 59:41
,21
to 51:49). Several studies have already been published by Paterson19, Evans20 and Dias17 on aldol
reactions of boron enolates of β-alkoxy methyl ketones showing major influence of beta substituents on
the 1,5-diastereoselectivity. In the present case the β-position overcomes the 1,4-syn sense of induction
of -position. Intriguingly, the aldol adducts from ,-anti-bisalkoxy methyl ketones (18-21) showed
lower diastereoselectivities when compared with their ,-syn analogues (16-18) showing that the rel-
ative stereochemistry between the alkoxy substituents influences the reaction pathway.
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Figure 6. Diastereoselectivities in the Boron-Mediated Aldol Reactions of Methyl Ketones 16-21.
Following the protocol outlined in Scheme 1, we mapped all relevant transition states, including
α,β-syn-bisalkoxy methyl ketones, with the most important results shown in Table 2 and Figure 7 (for
energies of all found diastereoisomeric transition states, see the SI).
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Table 2. Relative Gibbs (∆∆Grel) energies (kcal mol-1), and theoretical diastereoselectivities for calcu-
lated α,β-syn-bisalkoxy methyl ketones.
drtheor(1,5-anti:1,5:syn)*
Enolate
∆∆Grel (kcal/mol)
[exp]
in-TS2Bn,Bn-syn-c (1,5-anti)
in-TS2'Bn,Bn-syn-a (1,5-syn)
in-TS2TMS,Bn-syn-c (1,5-anti)
in-TS2'TMS,Bn-syn-a (1,5-syn)
in-TS2TMS,TMS-syn-c (1,5-anti)
in-TS2'TMS,TMS-syn-a (1,5-syn)
0.0
1.9
0.0
1.9
0.0
0.3
α-OBn,β-OBn-syn
α-OTMS,β-OBn-syn
>99:5 [>95:05]
>99:5 [>95:05]
74:26 [56:44]
α-OTMS,β-OTMS-
syn
*Determined considering the Boltzmann distribution associated with the Gibbs energies of all observed dia-
stereoisomeric transition states.
in-TS2Bn,Bn-syn-c
in-TS2'Bn,Bn-syn-a
in-TS2TMS,Bn-syn-c
in-TS2'TMS,Bn-syn-a
in-TS2TMS,TMS-syn-c
in-TS2'TMS,TMS-syn-a
Figure 7. Representative calculated transition state geometries for the α,β-syn-bisalkoxy methyl ke-
tones.
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The results presented in Table 2 show an excellent correlation between the experimental and
theoretical diastereoselectivities. A remarkable fact was that for the three investigated ketones - α-
OBn,β-OBn-syn, α-OTMS,β-OBn-syn, and α-OTMS,β-OTMS-syn – the transition states in-TS2 and
in-TS2’ presented the lower energies, providing the 1,5-anti and 1,5-syn diastereoisomers, respectively.
The analysis of their geometries (Figure 7) reveals that these transitions states fit with the Goodman-
Paton model for 1,5-anti selectivity.5 As discussed before, in this model the lower energy transition
states, which provide the 1,5-anti and 1,5-syn aldol adducts, is organized in such a way that it keeps the
-OPG group pointing towards to the C-H formyl and participating in a stabilizing H-bond. The pref-
erence for the 1,5-anti product is given because the lowest energy transition state orientates the β-R
group further from the borane ligands than the competitive 1,5-syn transition state. In particular, the
transition states in-TS2Bn,Bn-syn-c and in-TS2TMS,Bn-syn-c of lowest energies were located for α-OBn,β-
OBn-syn and α-OTMS,β-OBn-syn ketones, respectively, predicting the 1,5-anti as the major product.
NBO analysis allows for calculation of the energy associated with the stabilizing H-bond of around 5
kcal.mol-1. Another feature of these reactions that we could theoretically describe is the non-influence
of the α-alkoxy protecting group in determining diastereoselectivity. This can be appreciated by the
same relative energy (1.9 kcal.mol-1) between the lowest energy transition states in-TS2 and in-TS2’
for α-OBn,β-OBn-syn and α-OTMS,β-OBn-syn ketones (Table 2). A further insight obtained from the
theoretical results has shown that the C-O bonds of the enolate/α-alkoxy are in an antiperiplanar orien-
tation in both in-TS2Bn,Bn-syn-c and in-TS2TMS,Bn-syn-c which configures a match case in which the 1,5-
anti induction is reinforced by the α-alkoxy center. Conversely, in the higher energy transition states
in-TS2'Bn,Bn-syn-a and in-TS2'TMS,Bn-syn-a, these same bonds are less favorably oriented, cancelling out
the stabilizing effect of dipole minimization. In contrast, the loss of diastereoselectivity for the α-
OTMS,β-OTMS-syn ketone can be understood in a manner analogous to that already seen in the Good-
man-Paton model, where β-OSiR3 protecting groups exert severe steric repulsion with the ring and bo-
rane ligands, in both "in" transition states, generating the drop in the diastereoselectivity. We were able
to capture this effect, as can be seen, in the energy difference of 0.3 kcal.mol-1 between in-TS2TMS,TMS-
syn-c and in-TS2'TMS,TMS-syn-a. The model depicted in Scheme 3 summarizes all previous observations
regarding the synergistic effect between the α,β-syn-bisalkoxy stereocenters.
Our next step involved the study of α,β-anti-bisalkoxy methyl ketones, aiming to find the ori-
gins for the drop of 1,5-anti diastereoselectivity (Figure 6). The most important results can be seen in
Table 3 and Figure 8 (for energies of all found diastereoisomeric transition states, see the SI).
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Table 3. Relative Gibbs (∆∆Grel) energies (kcal mol-1), and theoretical diastereoselectivities for calcu-
lated α,β-anti-bisalkoxy methyl ketones.
drtheor(1,5-anti:1,5:syn)*
Enolate
∆∆Grel (kcal/mol)
[exp]
in-TS3Bn,Bn-anti-c (1,5-anti)
in-TS3'Bn,Bn-anti-b (1,5-syn)
in-TS3TMS,Bn-anti-b (1,5-anti)
in-TS3'TMS,Bn-anti-a (1,5-syn)
0.0
0.6
0.0
0.7
α-OBn,β-OBn-anti
77:23 [68:32]
α-OTMS,β-OBn-
anti
70:30 [80:20]
*Determined considering the Boltzmann distribution associated with the Gibbs energies of all observed dia-
stereoisomeric transition states.
2.220 Å
2.240 Å
4.4 kcal.mol‐1
4.1 kcal.mol‐1
in-TS3Bn,Bn-anti-c
in-TS3'Bn,Bn-anti-b
2.230 Å
2.280 Å
3.6 kcal.mol‐1
4.1 kcal.mol‐1
in-TS3TMS,Bn-anti-b
in-TS3'TMS,Bn-anti-a
Figure 8. Representative calculated transition state geometries for the α,β-anti-bisalkoxy methyl ke-
tones.
The most important previous features for α,β-syn-bisalkoxy ketones were observed for the α,β-
anti-bisalkoxy ketones. The analysis of lowest energies in-TS3 and in-TS3’ geometries reveals that
these transitions states also fit with the Goodman-Paton model for 1,5-anti selectivity, presenting sta-
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bilizing H-bond (around 4.1 kcal.mol-1 for 1,5-anti and 3.6-4.4 kcal.mol-1 for 1,5-syn), with non-influ-
ence of the α-alkoxy protecting group, and predicting the experimental selectivities in reasonable agree-
ment (Table 3, Figure 8). The origins for the drop of 1,5-anti diastereoselectivity for α,β-anti-bisalkoxy
ketones can be understood considering that the α-alkoxy center in-TS3 transition state orientates the C-
O bonds of the enolate/α-alkoxy in a less favorable way in relation to dipole minimization effect. The
opposite is expected for in-TS3', helping to stabilize this transition state which would supposedly be
responsible for the 1,5-syn product and so lead to decrease the 1,5-anti experimental diastereoselectiv-
ity. The model depicted in Scheme 3 summarizes all previous observations regarding the synergistic
effect between the α,β-syn-bisalkoxy and α,β-anti-bisalkoxy stereocenters.
Scheme 3: Proposed induction model for synergistic effect between the α,β-syn-bisalkoxy stereocen-
ters in methyl ketones.
Previously, the Goodman-Paton model was used to rationalize the 1,4-syn diastereoselectivity
of α-methyl methyl ketones bearing a β-alkoxy group.6 This diastereoisomeric differentiation originates
from the steric interaction between the enolate double bond and the α-methyl group. A final incursion
in our theoretical work regard to investigate the effects of 1,4-induction of α-alkoxy,α-methyl methyl
ketones, as described in Figure 2B. We considered in our calculations two model, α,β-bisalkoxy,α-
methyl and α,β-bisalkoxy methyl ketones, as described in Table 4 and Figure 9.
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Table 4. Relative Gibbs (∆∆Grel) energies (kcal mol-1), and theoretical diastereoselectivities for calcu-
lated α,β-bisalkoxy methyl ketones.
drtheor(1,5-anti:1,5:syn)*
Enolate
R = H
∆∆Grel (kcal/mol)
[exp]
in-TS4Bn,Bn-a (1,4-anti)
in-TS4'Bn,Bn-a (1,4-syn)
in-TS5Bn,Bn-a (1,4-anti)
in-TS5'Bn,Bn-a (1,4-syn)
0.0
2.0
0.0
2.7
99:1 [not reported]
R = Me
>99:1 [89:11]
*Determined considering the Boltzmann distribution associated with the Gibbs energies of all observed dia-
stereoisomeric transition states.
2.120 Å
2.250 Å
6.2 kcal.mol‐1
4.0 kcal.mol‐1
in-TS4Bn,Bn-a (1,4-anti)
in-TS4'Bn,Bn-a (1,4-syn)
2.150 Å
5.2 kcal.mol‐1
2.100 Å
6.5 kcal.mol‐1
in-TS5Bn,Bn-a (1,4-anti)
in-TS5'Bn,Bn-a (1,4-syn)
Figure 9. Representative calculated transition state geometries for the α,β-bisalkoxy methyl ketones.
In our first model, we excluded the α-methyl substituent, and the results indicated the preva-
lence of the Goodman-Paton model to describe the selectivity. The transition states in-TS4Bn,Bn-a of
lowest energies was located predicting the 1,4-anti as the major product. This geometry turns of the O-
P group eclipsed to the enolate double bond, in order to reduce the dipole of the system, reflecting the
dipolar effect discussed before. In the case of α,β-bisalkoxy,α-methyl methyl ketone, the calculations
reveal the in-TS5Bn,Bn-a as the lowest in energy and predicts the 1,4-anti as the major disatereoisomer.
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As expected, the additional α-methyl group reinforces the 1,4-anti sense of induction with preference
for an orthogonal alignment in relation to the enolate double bond, in line with similar transition states
reported in literature.6,22 We conclude that the in-TS5'Bn,Bn-a is 2.7 kcal mol-1 higher in energy than in-
TS5Bn,Bn-a due to steric and dipolar reasons. All these observations are depicted in Scheme 4.
Scheme 4: Proposed induction model for synergistic effect between the α-alkoxy,α-methyl stereocen-
ters in methyl ketones.
CONCLUSION
In this work, we investigated the 1,4 and 1,5 asymmetric induction presented in boron enolates aldol
reactions of -alkoxy and ,-bisalkoxy methyl ketones with commercially available achiral aldehydes.
The steric influence of the alkyl substituents at the α position as well as the stereoelectronic influence
of the oxygen protecting groups at the  and  positions were theoretically and experimentally investi-
gated. Our findings uncover the origins of 1,4 asymmetric induction in terms of the nature of β-substit-
uent. In the presence of the β-alkoxy stereocenter, theoretical calculations help to understand the syn-
ergistic effect between the ,-syn and ,-anti-bisalkoxy stereocenters. In these cases, the reaction
course goes through the Goodman-Paton 1,5-stereoinduction model, experiencing only a minor influ-
ence of the -alkoxy group.
CONFLICTS OF INTEREST
There are no conflicts to declare.
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ACKNOWLEDGEMENTS
Authors acknowledge CNPq, and CAPES for the fellowships conceded. We also gratefully
acknowledge financial support from FAPESP (14/50249-8, 15/08541-6) and GlaxoSmithKline (GSK).
We are in debit with Prof. Cláudio F. Tormena for computational facilities.
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22
If we consider the stereochemistry of α-methyl stereocenter, the in-TS5Bn,Bn-a produce the 1,4-syn
diastereoisomer, in line with previous results as depicted in reference 6.
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Table of content
dipole minimization
steric effect
O
OH
R
H
O
OH
4
R
PG
4
H
H
O
PG
R
1
R
O
R'
O
1
R'
L
H
L
O
OP
OP
B
B
1,4-anti
1,4-syn
O
L
L
O
R'
R'
favorable for
R = i-Pr, t-Bu
favorable for
R = Me
TS1'-A
TS1-A
PG = protecting group
We investigated the asymmetric induction in boron enolate aldol reactions of -alkoxy
and ,-bisalkoxy methyl ketones, and elucidate the synergistic effect between the
stereocenters.