The role of β-bulky substituents in aldol reactions of boron enolates of methylketones with aldehydes: Experimental and theoretical studies by DFT analysis

Article abstract of DOI:10.1021/jo2023119

In this work, we show the influence of the volume of the β-substituents on the levels of 1,5-stereoselectivities of aldol reactions of boron enolates generated from β-alkoxy methylketones with aldehydes. Excellent levels of 1,5-syn stereoinduction were obtained when the β-protecting group is a silicon ether. This remarkable selectivity is attributed to the volume of the β-bulky substituent of the corresponding boron enolate. We have investigated a stereochemical model using DFT analysis to rationalize the sense of 1,5-syn stereoselectivities of β-alkyl-β- alkoxy methylketones.

Full text of DOI:10.1021/jo2023119

Article
pubs.acs.org/joc
The Role of β-Bulky Substituents in Aldol Reactions of Boron
Enolates of Methylketones with Aldehydes: Experimental and
Theoretical Studies by DFT Analysis
Luiz C. Dias,* Emílio C. de Lucca, Jr., Marco A. B. Ferreira, Danilo C. Garcia, and Claudio F. Tormena
́
Chemistry Institute, State University of Campinas, UNICAMP, 13083-970, C.P. 6154, Campinas, SP, Brazil
S
* Supporting Information
ABSTRACT: In this work, we show the influence of the
volume of the β-substituents on the levels of 1,5-stereo-
selectivities of aldol reactions of boron enolates generated
from β-alkoxy methylketones with aldehydes. Excellent levels
of 1,5-syn stereoinduction were obtained when the
β-protecting group is a silicon ether. This remarkable selectivity
is attributed to the volume of the β-bulky substituent of the corresponding boron enolate. We have investigated a stereochemical
model using DFT analysis to rationalize the sense of 1,5-syn stereoselectivities of β-alkyl-β-alkoxy methylketones.
our collective understanding of the factors that govern this
substrate-controlled stereoinduction.
INTRODUCTION
■
The aldol reaction is a fundamental methodology employed in
the construction of carbon−carbon bonds in synthetic organic
chemistry. This reaction is useful in the total synthesis of natural
products, in particular for the creation of the 1,3-dioxygen
relationship in organic molecules with biological and pharmaco-
logical significance.1
The 1,5-remote asymmetric induction in the reaction of
boron enolates generated from β-alkoxy methylketones and
aldehydes was first observed by Masamune and co-workers in
1989 in their work toward the total synthesis of the C1−C16
fragment of briostatin 1 (Scheme 1).2
In this work, the authors observed that the addition of the
boron enolate prepared from methylketone 1 to aldehyde 2
provided the aldol adduct 3 with 1,5-anti relationship between
the new created stereogenic center and the β-alkoxy group of
the boron enolate. This methodology proved to be dependent
on the nature of the employed boron reagent. With Et2BOTf,
the authors achieved a 67:33 ratio in favor of the 1,5-anti
diastereomer. Using the chiral borane C, the diastereoselectivity
was 86:14 in favor of the 1,5-anti aldol adduct, which showed
that higher levels of 1,5-anti stereocontrol are possible through
the reinforcing influence of the boron enolate. Moreover,
Masamune and co-workers have demonstrated the difficulties in
obtaining good levels of selectivities in favor of the 1,5-syn aldol
adduct using chiral borane B.
The possible transition states (TS) that lead to the formation
of 1,5-anti and 1,5-syn aldol adducts from aldol reactions of
boron enolates of methylketones and aldehydes have been
studied by Paton and Goodman.8 The authors showed that the
aldol reactions of the boron enolates of β-alkoxy methylketones
undergo a six-membered cyclic transition state with preference
for the boat conformation because the 1,3-diaxial interactions
are minimized between one of the ligands of the boron and the
ring substituents. They proposed that the β-alkoxy substituent
of the enolate is directed into the six-membered ring and parti-
cipates in a stabilizing H-bond with the aldehyde formyl hydro-
gen, which leads to further stabilization of the “in” transition
state over the “out” transition state (Scheme 2).
For an alkyl protecting group at the β-oxygen, the high
preference for the in-1,5-anti transition state over the in-1,
5-syn is due to the decrease in the steric interactions between the
β-alkyl substituent and one of the ligands on boron. However,
the in-1,5-syn transition states are only slightly lower in energy
when compared with the in-1,5-anti when silicon ethers are
used at the β-position because of the decrease in the steric re-
pulsions between the protecting group and the β-alkyl substituent.
In order to achieve the stereocenter C47 of the C27−C51
fragment of altohyrtin A (spongistatin 1), Paterson and co-
workers demonstrated a notable example where the more
complex boron enolate 4 overrides the 1,5-anti stereoinduction
typically observed for boron aldol reactions of simple β-alkoxy
methylketones, providing the aldol adduct 6 with extraordinary
levels of 1,5-syn diastereoselectivity (Scheme 3).3f This was the
first example that good levels of 1,5-syn stereoinduction were
achieved involving boron enolates of methylketones and was
attributed to the more remote stereocenters of the ketone.
The seminal contributions of Paterson3 and Evans,4 who
independently developed the 1,5-anti aldol reaction to a variety
of β-alkoxy methylketones, transformed the initial discovery of
Masamune in a powerful and synthetically useful aldol method-
ology widely used in the total synthesis of natural polyketides.
From these studies, very high diastereoselectivities (often >20:1)
could be obtained from a variety of β-alkoxy methylketones
using readily prepared boron enolates. Subsequently, Denmark,5
Dias,6 and others7 have made numerous contributions to advance
Received: November 10, 2011
Published: January 10, 2012
© 2012 American Chemical Society
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Scheme 1
Scheme 2
mediated by L-proline, provided the hydroxyketone 20 in 63%
yield and 90% ee, as determined by Mosher ester analysis.10
The conversion of hydroxyketone 20 into the PMB ether using
4-methoxybenzyl 2,2,2-trichloroacetimidate (PMBTCA) gave
the methylketone 11 in 90% yield.11 The protection of the
hydroxyl of 20 using TBSCl and imidazole led to the formation
of methylketone 12 in 78% yield (Scheme 5).12
Aldol Reactions of Boron Enolates of Methylketones
11 and 12. We consequently investigated the aldol reactions
between methylketones 11 or 12 and aldehydes 23a−h using
(c-Hex)2BCl and Et3N in Et2O to generate the kinetic boron
enolates (Table 1).
As evident from the results presented in Table 1, for boron
enolate 21 (P = PMB, R = t-Bu), the aldol adducts 24a−g and
25a−g were obtained in good to excellent yields and with
diastereoselectivities on the order of 80:20 in favor of the 1,
5-syn diastereomer. The levels of selectivity decrease as the
steric size of the R group of the aldehyde is increased (entries 1,
4, and 6).
The aldol reactions between the boron enolate 22 (P = TBS,
R = t-Bu) and aldehydes 23a−h provided the aldol adducts
26a−h and 27a−h in good yields. The diastereoselectivities
ranged from 62:38 to 74:26, and the 1,5-syn diastereomer is the
main observed product. As seen in entries 2, 5, and 7, the
diastereoselectivities increase as the steric size of the aldehyde is
decreased.
On the basis of these results, we hypothesized that the
greatest contribution to the sense of 1,5-syn stereoinduction in
aldol reactions that involve boron enolates of β-bulky alkyl
methylketones is related to the stereo effect of the alkyl
substituent at the β-position. However, the electronic effect is
not negligible because the sense of 1,5-syn induction was lower
for enolates 21 (P = PMB, R = t-Bu) and 22 (P = TBS, R = t-Bu)
compared with that for methylketones 10 (P = Bn, R = CCl3)
and 9 (P = TBS, R = CCl3).
A comparison of the results for methylketone 12 (P = TBS,
R = t-Bu) with those of previous studies described in the
literature reveals a close relationship between the increase in
the size of the β-substituent and the increase in the levels of
selectivities in favor of the 1,5-syn diastereomer (Scheme 6).
The same comparison for methylketone 11 (P = PMB, R =
t-Bu) in Scheme 7 suggests no change in 1,5-anti selectivities
when the size of the β-alkyl substituent is varied (entries 1−4).
However, with a further increase in the size of the β-substituent
(entries 5 and 6), as in this study, we obtained a sharp reversal
in selectivity in favor of the 1,5-syn aldol adduct.
Recently, we demonstrated that good diastereoselectivities in
favor of the 1,5-syn aldol adducts are possible (Scheme 3).6c,d
With both CF3 and CCl3 substituents, the 1,5-syn remote asy-
mmetric induction occurred independently of the stereo-
electronic nature of the β-alkoxy protecting group. Although
the best levels of 1,5-syn asymmetric induction were obtained
with a β-CCl3 group, these results suggest that the joint action
of stereo and electronic character of the β-trihalomethyl groups
in the methylketones 7−10 should be the factor responsible for
the observed sense of 1,5-syn induction.
To understand the stereo and electronic effects of the
β-substituents in boron-mediated aldol reactions of β-alkyl-β-
alkoxy methylketones, we decided to report an extension of our
previous work.9 Here, we report our investigation of the influ-
ence of 1,5-induction by varying the sizes of the β-alkyl groups
(Me, t-Bu, p-NO2C6H4, Ph3C) in combination with several
protecting groups at the β-oxygen (P = TBS, PMB, Tr, and
TPS, triphenylsilyl) 11−19 (Scheme 4).
RESULTS AND DISCUSSION
■
Preparation of Methylketones 11 and 12. The pre-
paration of methylketone 11 (P = PMB, R = t-Bu) and 12
(P = TBS, R = t-Bu) began with the preparation of β-hydroxyketone
20. The aldol reaction between acetone and pivalaldehyde,
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Scheme 3
Scheme 4
Scheme 5
Proof of the Relative Stereochemistry of Aldol Ad-
ducts Derived from Methylketones 11 and 12. To prove
the relative stereochemistry of aldol adducts obtained from
methylketone 12 (P = TBS, R = t-Bu) in Table 1, we chose to
derivatize the separable mixture of aldol adducts 26c and 27c
obtained from the aldol reaction between enolate 22 (P = TBS,
R = t-Bu) and pivalaldehyde (23c) (entry 7, Table 1). A simple
analysis of the deviation from the plane of polarized light would
be sufficient to determine the relative stereochem-
istry and hence the absolute stereochemistry. After the TBS
protecting group was removed from aldol adduct 26c (major
product), the resulting diol was a meso compound, as demon-
strated by its lack of optical activity. Nevertheless, the removal
of the TBS group from aldol adduct 27c (minor product) led to
the formation of a diol with a C2 symmetry axis, a sufficient
condition for this compound to be optically active.
The treatment of 26c with HF in acetonitrile provided
the meso 1,5-diol 35. The removal of the TBS group from
27c generated the C2-symmetric 1,5-diol 36, [α]D +50
(c 0.45, CH2Cl2), as required by a 1,5-anti relationship
(Scheme 8).
To determine the relative stereochemistry of the aldol
adducts obtained from methylketone 11 (P = PMB, R = t-Bu),
the 78:22 mixture of 24c and 25c (entry 6, Table 1) was treated
with DDQ, which provided diols 35 and 36 in 78% yield
(Scheme 9).
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Table 1. Aldol Reactions of Methylketones 11 and 12
a
b
c
entry
enolate (P)
aldehyde (R)
i-Pr (23a)
dr (1,5-syn:1,5-anti)
yield (%)
1
2
PMB (21)
TBS (22)
TBS (22)
PMB (21)
TBS (22)
PMB (21)
TBS (22)
PMB (21)
TBS (22)
PMB (21)
TBS (22)
PMB (21)
TBS (22)
PMB (21)
TBS (22)
TBS (22)
80:20
65:35
65:35
82:18
74:26
78:22
66:34
81:19
72:28
83:17
68:32
75:25
62:38
79:21
68:32
65:35
91
98
79
85
92
80
98
86
86
95
71
85
90
86
86
88
i-Pr (23a)
i-Pr (23a)
Et (23b)
d
3
4
5
Et (23b)
6
t-Bu (23c)
t-Bu (23c)
7
8
CH2C(Me) (23d)
CH2C(Me) (23d)
Ph (23e)
9
10
11
12
13
14
15
16
Ph (23e)
p-NO2C6H4 (23f)
p-NO2C6H4 (23f)
p-OMeC6H4 (23g)
p-OMeC6H4 (23g)
PhCH2CH2 (23h)
a
b
Liquid aldehydes were added without prior dilution. p-Nitrobenzaldehyde (23f) was dissolved in 1.0 mL of CH2Cl2. Ratio was determined by 1H
c
and 13C NMR analyses of the diastereoisomeric mixture of aldol adducts. Isolated yields of both syn and anti isomers after SiO2 gel flash column
chromatography. CH2Cl2 as solvent. All reactions were quenched by the addition of methanol.
d
Scheme 6
1
The H and 13C NMR spectra of a mixture of diols 35 and
36 prepared by the removal of the PMB protecting group
(Scheme 9) were identical with those of diols 35 and 36
obtained by the removal of the TBS protecting group (Scheme 8).
We therefore conclude that the diastereomer 1,5-syn was also
the major product in aldol reactions that involved methylketone
11 (P = PMB, R = t-Bu).
Preparation of Methylketones 13, 14, 15, 16, 17, and
18. At this point, we decided to investigate the influence of
bulky protecting groups such as triphenylmethyl (Tr, trityl) and
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Scheme 7
Scheme 8
Protection of the hydroxyl group of 20 using TPSCl in the
presence of AgOTf led to the formation of methylketone 14
(P = TPS, R = t-Bu) in 82% yield.13
The preparation of methylketones 15 (P = Tr, R = Me) and
16 (P = TPS, R = Me) was made by a slight modification of the
protocol of Lundquist and co-workers,13b using equimolar
amounts of diol 37, AgOTf, and TrCl or TPSCl. Alcohol 38
was thus obtained in 78% yield. The methylketone 15 (P = Tr,
R = Me) was obtained in 86% yield by oxidation of alcohol 38
under Swern conditions. Similarly, alcohol 39 was submitted
under Swern conditions to provide methylketone 16 (P = TPS,
R = Me) in 60% yield (two steps).
Using the same protocol as that used for the preparation of
methylketones 13−16, the treatment of hydroxyketone 40 with
AgOTf and TrCl lead to methylketone 17 (P = Tr, R =
p-NO2C6H4) in 51% yield. In the same way, hydroxyketone
40 was treated with AgNO3 and TPSCl to provide 18 (P = TPS,
R = p-NO2C6H4) in 73% yield (Scheme 10).
Scheme 9
Aldol Reactions of Boron Enolates of Methylketones
13−18. To examine the influence of larger protecting groups
(with different electronic properties), we investigated the aldol
reactions that involve boron enolates 41 (P = Tr, R = t-Bu),
42 (P = Tr, R = Me), 43 (P = Tr, R = p-NO2C6H4), 44 (P = TPS,
R = t-Bu), 45 (P = TPS, R = Me), and 46 (P = TPS, R =
p-NO2C6H4) under the same conditions previously employed
(Table 2).
triphenylsilyl (TPS) at the β-oxygen. Protection of compound
20 using TrCl in the presence of AgOTf led to the formation of
methylketone 13 (P = Tr, R = t-Bu) in 88% yield (Scheme 10).
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Scheme 10
As seen in Table 2, the aldol reactions between the boron
enolates 41 (P = Tr, R = t-Bu), 42 (P = Tr, R = Me), and 45
(P = TPS, R = Me) with aldehydes provided the corresponding
aldol adducts in good yields in an equimolar ratio of the 1,5-anti
and 1,5-syn diastereoisomers. Moreover, the aldol reactions that
involved the boron enolate 44 (P = TPS, R = t-Bu) with the
corresponding aldehydes gave the aldol adducts in good yields
and in diastereoselectivities that ranged from 63:37 to 70:30,
where the 1,5-syn diastereomer was the major product. A clear
decrease in the sense of 1,5-syn induction was observed when
Tr and TPS were employed as protecting groups.
The boron enolates 43 (P = Tr, R = p-NO2C6H4) and
46 (P = TPS, R = p-NO2C6H4) gave aldol adducts in good
yields and, unexpectedly, in 1,5-anti selectivity. In previous
work,6c,d we showed that aldol reactions that involved methyl-
ketone 33 (P = PMB, R = p-NO2C6H4) gave aldol adducts in
high 1,5-anti selectivities, whereas the use of bulkier protecting
groups at the β-oxygen, as in methylketone 30 (P = TBS, R =
p-NO2C6H4), led to poor 1,5-syn selectivities.
case; the diols 59 and 60 were obtained in a quantitative yields
(Scheme 12).
After comparing the previously reported spectroscopic data
of diols 59 and 60,6c,d we concluded that the diastereomers in
major proportion in the aldol reactions that involve the methyl-
ketone 17 (P = Tr, R = p-NO2C6H4) and 18 (P = TPS, R =
p-NO2C6H4) were 1,5-anti aldol adducts.
Preparation of Methylketone 19. As shown in Scheme 6,
the aldol reactions that involve boron enolates generated from
β-OTBS methylketones show an interesting relationship: an
increase in the volume of the β-alkyl substituent leads to an
increase in the levels of 1,5-syn selectivities. In this context, we
decided to prepare methylketone 19 (P = TBS, R = Ph3C) to
confirm the proposed trend.
Thus, we first prepared methylketone 19 by reducing the
acid 61 with LiAlH4 to provide alcohol 62 in 69% yield
(Scheme 13).14 Aldehyde 63 was then prepared by oxidation of
62 under Swern conditions in 96% yield.15 The Weinreb amide
64 was enolized with LDA, followed by the addition of
aldehyde 63, to provide 65 in 99% yield.4c Protection of the
hydroxyl group in 65 with TBSOTf gave the silicon ether 66
in 85% yield,16 which, after reaction with MeLi, provided
methylketone 19 in 99% yield.6e
Aldol Reactions of the Boron Enolate of Methylke-
tone 19. We next investigated the aldol reactions involving
boron enolate 67 (P = TBS, R = Ph3C) under the same con-
ditions employed previously (Table 3).
As observed in Table 3, the aldol reactions between the
boron enolate 67 (P = TBS, R = Ph3C) and the corresponding
aldehydes led to the formation of aldol adducts 68a−g and
69a−g in high 1,5-syn selectivities and in good yields. These
results clearly show that the steric size of β-bulky substituents in
β-alkoxy methylketones plays a major role in the 1,5-syn stereo-
chemical sense.
Proof of the Relative Stereochemistry of Aldol
Adducts Derived from Methylketone 19. To determine
the relative stereochemistry of the aldol adducts obtained from
the reactions involving boron enolate 67 (P = TBS, R = Ph3C),
we applied a methodology described by Kishi and co-workers.17
These results suggest a more complicated relationship be-
tween the increased volume of the protecting group and the
size of the β-alkyl groups in the 1,5-remote induction.
Proof of the Relative Stereochemistry of Aldol
Adducts Derived from Methylketones 14, 17, and 18.
To determine the relative stereochemistry of aldol adducts ob-
tained from methylketone 14 (P = TPS, R = t-Bu), the mixture
of aldol adducts 53c and 54c was treated with HF in aceto-
nitrile to provide diols 35 and 36 in quantitative yields (Scheme 11).
The 1H and 13C NMR spectra of the mixture of diols 35 and
36 prepared by the removal of the TPS protecting group
(Scheme 11) were identical with those of diols 35 and 36
obtained from the removal of the TBS protecting group
(Scheme 8). The major aldol adduct observed in the aldol
reactions that involved methylketone 14 (P = TPS, R = t-Bu)
was also the 1,5-syn aldol adduct.
The relative stereochemistries for the aldol adducts obtained
from methylketones 17 (P = Tr, R = p-NO2C6H4) and 18
(P = TPS, R = p-NO2C6H4) were confirmed after the corre-
sponding protecting groups were removed using HF in each
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Table 2. Aldol Reactions of Methylketones 13−18
a
b
c
entry
enolate
aldehyde (R′)
i-Pr (23a)
dr (1,5-syn:1,5-anti)
yield (%)
1
P = Tr, R = t-Bu (41)
50:50
50:50
50:50
50:50
50:50
27:73
40:60
30:70
33:67
30:70
65:35
63:37
70:30
50:50
50:50
50:50
39:61
33:67
46:54
71
95
95
95
77
51
55
98
76
76
88
86
68
90
83
71
69
74
78
2
P = Tr, R = t-Bu (41)
Ph (23e)
i-Pr (23a)
3
P = Tr, R = Me (42)
4
P = Tr, R = Me (42)
CH2C(Me) (23d)
5
P = Tr, R = Me (42)
Ph (23e)
6
P = Tr, R = p-NO2C6H4 (43)
P = Tr, R = p-NO2C6H4 (43)
P = Tr, R = p-NO2C6H4 (43)
P = Tr, R = p-NO2C6H4 (43)
P = Tr, R = p-NO2C6H4 (43)
P = TPS, R = t-Bu (44)
P = TPS, R = t-Bu (44)
P = TPS, R = t-Bu (44)
P = TPS, R = Me (45)
i-Pr (23a)
7
Et (23b)
8
CH2C(Me) (23d)
9
Ph (23e)
10
11
12
13
14
15
16
17
18
19
p-NO2C6H4 (23f)
i-Pr (23a)
t-Bu (23c)
Ph (23e)
i-Pr (23a)
P = TPS, R = Me (45)
CH2C(Me) (23d)
P = TPS, R = Me (45)
Ph (23e)
P = TPS, R = p-NO2C6H4 (46)
P = TPS, R = p-NO2C6H4 (46)
P = TPS, R = p-NO2C6H4 (46)
i-Pr (23a)
Et (23b)
Ph (23e)
a
b
Liquid aldehydes were added without prior dilution. p-Nitrobenzaldehyde (23f) was dissolved in 1.0 mL of CH2Cl2. Ratio was determined by 1H
c
and 13C NMR analyses of the diastereoisomeric mixture of aldol adducts. Isolated yields of both syn and anti isomers after SiO2 gel flash column
chromatography. All reactions were quenched by the addition of methanol.
Scheme 11
spectroscopic analysis of the corresponding 1,3-acetonide 71,19
which was prepared in 95% yield from diol 70. The removal of
the TBS protecting group from diol 70 with HF in CH3CN led
to the formation of triol 72 in quantitative yield (Scheme 14).
Based on the analysis of the 13C NMR spectrum of triol 72 in
CD3OD, the chemical shift value for carbon C3 is 71.8 ppm,
which is slightly higher than the shift expected for a syn/syn triol
(70.7 ppm, according to the Kishi database). However, this
value is far from the expected chemical shift for an anti/syn triol
(68.6 ppm). Therefore, we believe this result confirms the rela-
tive stereochemistry for aldol adducts obtained from methyl-
ketone 19 (P = TBS, R = Ph3C) as 1,5-syn.
We thus converted the aldol adduct 68b into two different
triols (Scheme 14 and 15). Initially, the aldol adduct 68b was
subjected to 1,3-syn carbonyl reduction,18 which led to the
formation of diol 70 in 84% yield and high selectivity (dr >
95:05). The 1,3-syn stereochemistry of the secondary alcohols
in 70 was determined on the basis of Rychnovsky 13C NMR
To reinforce this conclusion, we prepared triol 75. The aldol
adduct 68b was subjected to 1,3-anti carbonyl reduction,20
which led to the formation of a mixture of diols 73 and 70 in
50% yield and in 37:63 selectivity that favors the 1,3-syn isomer.
The relative stereochemistry for the secondary alcohol 73 was
determined on the basis of Rychnovsky 13C NMR spectroscopic
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Scheme 12
Scheme 13
Table 3. Aldol Reactions of Methylketone 19
a
b
c
entry
aldehyde (R)
i-Pr (23a)
dr (1,5-syn:1,5-anti)
yield (%)
1
2
3
4
5
6
7
>95:05
>95:05
>95:05
>95:05
91:09
95
92
98
94
89
84
78
Et (23b)
t-Bu (23c)
CH2C(Me) (23d)
Ph (23e)
p-NO2C6H4 (23f)
p-OMeC6H4 (23g)
>95:05
91:09
a
b
Liquid aldehydes were added without prior dilution. p-Nitrobenzaldehyde (23f) was dissolved in 1.0 mL of CH2Cl2. Ratio was determined by 1H
c
and 13C NMR analyses of the diastereoisomeric mixture of aldol adducts. Isolated yields of both syn and anti isomers after SiO2 gel flash column
chromatography. All reactions were quenched by the addition of methanol.
analysis of the corresponding 1,3-acetonide 74 (dr = 37:63),19
which was prepared in 95% yield from diol 73. The removal of
the TBS protecting group of 73 with HF led to the formation
of triol 75 (dr = 37:63) in quantitative yield (Scheme 15).
From the analysis of the 13C NMR spectrum of triol 75, the
chemical shift for carbon C3 was 66.7 ppm, which is close to
the expected values for anti/anti triols according to the Kishi
database (66.3 ppm). Thus, we confirmed, unequivocally, that
the 1,5-diastereomer obtained in higher proportion in aldol
reactions that involved the methylketone 19 (P = TBS, R =
Ph3C) was the 1,5-syn aldol adduct.
Rationalization Model. All the boron aldol reactions were
conducted under conditions of kinetic control. Because this
step is irreversible, the competing boron aldol transition struc-
tures in which a new stereocenter is formed allowed us to
compare the energies of the aldol transition structures to
investigate the effects of β-bulky groups with respect to the
1,5-stereoselectivity.
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Scheme 14
Scheme 15
Aldol reactions of β-alkoxy methylketones (R = CF3, CCl3,
and t-Bu) with TBS or PMB protecting groups and β-bulky
alkyl groups showed good 1,5-syn selectivities. In addition,
a further increase in the steric size of the β-substituent
(R = Ph3C) gave only 1,5-syn aldol adducts, which reinforced
this induction.
On the basis of our experimental results, we conclude that
the stereochemical model proposed by Goodman and Paton
works only for methylketones with small and medium β-alkyl
substituents such as -Me, -CH2R, -i-Pr, Ar, etc.
We propose a complementary stereochemical model of
induction that includes the volume effect of the β-substituent
and the protecting groups at the β-oxygen of β-alkoxy methyl-
ketones. In the case of β-bulky substituted methylketones (t-Bu,
-CX3, and Ph3C-) with protecting groups of intermediate size
such as benzylic (P = Bn and PMB) and silicon (P = TBS)
derivatives, the relative energies of the “in” transition states that
involve formyl H-bonds are higher than those of the “out”
transition states because of the steric repulsions OP ⇔ R for
TS-in-1,5-anti and L ⇔ R for TS-in-1,5-syn.
Thus, we postulate that the lower-energy “out” transition
state should keep the β-bulky substituent as far as possible from
the ring and the ligands of boron. The competitive transition
states TS-out-1,5-anti-a and TS-out-1,5-syn-a assume this
conformation, as depicted in Scheme 16. The orientation of
the -OP group in the transition state TS-out-1,5-anti-a implies
greater repulsion with boron ligands and brings together the
oxygens of the protecting group and the enolate. Thus, the 1,
5-syn stereoinduction arises from the transition state TS-out-1,
5-syn-a, which is the lowest-energy transition state; this transition
state guides the -OP group in the direction opposite the C−O
enolate bond, which partially reduces the steric repulsions and
the dipole moment of the system.
However, this sense of induction is lost when larger pro-
tecting groups such as Tr (Ph3C-) and TPS (Ph3Si-) are employed.
In these cases, new repulsive interactions are introduced into the
system, which reduces the difference in the relative energies of the
competing transition states.
Theoretical calculations involving these systems were made
to support the proposed theoretical model and to give support
to the conclusions presented.
THEORETICAL ANALYSIS
■
Computational Methods. Theoretical calculations of the
transition states of aldol reactions that involve boron enolates
were performed to investigate this reverse substrate-based 1,5-
syn stereocontrol. All structures were fully optimized through
the Gaussian03 or Gaussian09 program.21 The 6-31G(d,p)
basis sets were applied for this purpose. Single-point calcu-
lations (in CH2Cl2 or Et2O) using the default Gaussian09
IEF-PCM22 (UFF radii) or Truhlar SMD23 solvation models
from the optimized gas-phase transition-state geometries were
performed to evaluate the relative energies using the B3LYP24
hybrid density functional in combination with the 6-31+G(d,p)
basis set.25 The Cartesian coordinates are supplied in the
Supporting Information. Paton and Goodman8 have observed
that the full optimization geometry and energy in solvents are
very similar to single-point solvation. We wished to adopt boat-
like starting geometries, which have been previously shown by
Goodman to be the more favorable conformers. The boat-like
transition state prevents 1,3-diaxial-type interactions that occur
in the corresponding chairlike transition structures. Frequency
calculations ensured that the stationary points represent a
maximum on the potential-energy surface, and the correspond-
ing eigenvectors were inspected to confirm the expected aldol
reaction coordinates.
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Analysis of the relative energies of the transition states in
Table 4 indicated the transition states out-1,5-syn-a (0.0 kcal/
mol) as being the most stable for methylketones 9 (P = TBS,
R = CCl3) and 7 (P = TBS, R = CF3), which led to similar
relative energies for the two solvation models employed. This
result qualitatively predicts the preferential formation of the
1,5-syn aldol adducts, in agreement with our experimental
results. We believe that the low energy for the out-1,5-syn-a
conformer is due to the β-trihalomethyl and β-OTMS sub-
stituents being directed as far from the ring as possible.
In addition, the “in” transition states of methylketones 7 and
9 were found to have greater energies than the out-1,5-syn-a
transition states. The NBO analysis showed small energy values
(all below 1 kcal/mol) for the H-bonds between the lone pairs
of the β-oxygen (LPO1 and LPO2) and the C−H formyl
(σ*C−H) in the “in” transition states. These values are closely
related with conformational restrictions imposed by strong
repulsions between OP ⇔ R and L ⇔ R for the in-1,
5-anti and in-1,5-syn transition states, respectively. The long
lengths of the H-bonds (rO−HC), which range from 2.6 to 2.8 Å,
and the low values of the matrix overlap S<O−H‑C> result in the
low H-bond energies (for reference, we have included in
Supporting Information, section S3, the rO−HC and S<O−H‑C>
values for the competitive transition states of methylketone
34). Surprisingly, the “in-syn” transition states exhibited
H-bonds between the lone pairs of F and Cl atoms and the
C−H formyl (σ*C−H) in the range of 1−2 kcal/mol, which is
greater than the energies of the previously discussed oxygen
H-bonds. However, this additional stabilization is not sufficient
to offset the strong β-CX3 ⇔ B-L repulsions responsible for the
high energy of these conformers.
Scheme 16. 1,5-Stereochemical Model for β-Bulky-
Substituted Methylketones
The “X-in” transition states were also characterized. In these
cases, despite the stabilization of the X−HC H-bonds (in the
range of 1.6−3.4 kcal/mol), the CX3-oriented groups on the
ring increase the relative energy of these conformers.
The next step was to investigate the transition states using
models for methylketones 10 (P = Bn, R = CCl3) and 8 (P =
Bn, R = CF3). The results are shown in Scheme 19 and Table 5
(the energies of all characterized conformers can be found in
Tables S4 and S5 in the Supporting Information).
The natural bond orbital (NBO) energies were calculated at
the B3LYP/6-31G(d,p) level using NBO 5.0.26 These
delocalization energies were calculated by second-order
perturbation theory analysis using the E2PERT=0.05 keyword
to reduce the threshold for donor−acceptor delocalization
energy interactions from 0.5 kcal mol−1 to 0.05 kcal mol−1. We
examined the overlap matrix (S<i−j>) in the overlap of
preorthogonal natural bond orbital (SPNBO) analysis that
provided the NBO overlap.
The initial geometries in the diastereoisomeric transition
states were generated by rotating the Φ1 dihedral for “out”
conformers, as shown in Scheme 17. Additionally, we generated
the “X-in” transition states for the transition states of
trihalomethyl methylketones. In the studied models, we
replaced the PMB, TBS, and c-Hex groups with Bn, TMS,
and Me groups, respectively.
β-Trihalomethyl Methylketones. Initially, we investigated
the transition states using models for methylketones 9
(P = TBS, R = CCl3) and 7 (P = TBS, R = CF3). The initial
geometries were generated as shown in Scheme 17. The
most significant transition states are shown in Scheme 18 and
Table 4 (see Tables S1 and S2 in the Supporting Information
for all energies of the observed transition states).
Analysis of the characterized transition states for methyl-
ketone 10 (P = Bn, R = CCl3) indicated that the out-1,5-syn-a
conformers had the lowest relative energy (0.0 kcal/mol),
irrespective of the employed solvation model. The out-1,5-syn-
a transition states led to preferential formation of the 1,5-syn
aldol adducts, in agreement with our experimental results.
In the case of methylketone 8 (P = Bn, R = CF3), the exper-
imental results were dr ∼ 65:35 (1,5-syn:1,5-anti).6d Because of
these results, competitive transition states with highly similar
relative energies are expected. As depicted in Table 5 (X = F),
with the IEF-PCM solvation method, the relative energies for
the competitive transition states in-1,5-anti-b (0.0 kcal/mol)
and out-1,5-syn-a (0.3 kcal/mol) are in disagreement with our
experimental results. We believe this difference is associated
with a deficiency in the IEF-PCM model for predicting the
theoretical solvation energy for polyfluorinated molecules.27
However, an inversion in the relative stabilities was observed
when the solvation model developed by Truhlar (SMD) was
applied. This model significantly improved the solvation energy
calculation, and the out-1,5-syn-a (0.0 kcal/mol) transition
state become more stable than the in-1,5-anti-b (0.4 kcal/mol)
transition state.
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Scheme 17
Scheme 18. Aldol Transition Structures of β-Trihalomethyl-β-Trimethylsilyloxy Dimethyl Boron Enolate and Ethanal
The results described in Table 5 support our model (Scheme 16).
Moreover, similar to methylketones 7 and 9 (P = TBS),
methylketones 8 and 10 (P = PMB) had “in” transition-state
energies higher than those of out-1,5-syn-a, as well as low H-
bond (O−HC) energies that ranged from 0.78 to 1.8 kcal/mol.
This result is interesting because β-OBn methylketones have
traditionally been associated with high 1,5-anti selectivities
precisely because of the stabilization that arises from the H-
bonds (O−HC). However, the conformational constraints
in our system in the “in” transition states impose strong
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Table 4. Aldol Transition Structures Calculated at B3LYP and with Basis Set 6-31G(d,p), the SCRF in B3LYP/6-31+G(d,p) and
IEF-PCM (UFF Radii) or SMD Solvation Models, and the Delocalization Energies and NBO Overlap Matrix (S) of the
Stabilizing H-Bond
repulsions between β-OBn ⇔ β-CX3 and L ⇔ β-CX3, which
leads to greater H-bond (rO−HC) distances, in the range of
2.5−2.7 Å, and low matrix overlap S<O−H‑C> values. Moreover,
despite the high energy associated with the stabilizing halogen
H-bond (X−HC) (1.2−4.5 kcal/mol), the “X-in” transition
states had high relative energies because of the orientation of
the β-CX3 groups on the ring.
transition states. For the “in” conformers, the long lengths of
the H-bonds (rO−HC), which are in the range of 2.7 to 3.0 Å,
and the low matrix overlap S<O−H‑C> values lead to low H-bond
energies that range from 0.16 to 0.54 kcal/mol.
For the study of methylketone 19 (P = TBS, R = Ph3C), we
considered all six conformers related to the C−Ph and C−C
sigma-bond rotations of the trityl protecting group (see the
Supporting Information, section S9, for further details). The
structures with the lowest energies are shown in Scheme 21 and
Table 7 (for visualization of all characterized structures see
Supporting Information, Table S8).
As shown in Table 7, the large gap between the competitive
transition states out-1,5-syn-a-i (0.0 kcal/mol) and out-1,5-
anti-a-v (3.4 and 3.6 kcal/mol for IEF-PCM and SMD
solvation models, respectively) suggests the exclusive formation
of the 1,5-syn aldol adduct, which is consistent with the
experimental diastereoselectivity (dr > 95:05, 1,5-syn:1,5-anti).
The energy difference between the competitive transition states
of all other aldol reactions studied in this work are in the range
of 0.4−1.7 kcal/mol and in low-to-moderate experimental 1,5-
syn selectivities. Thus, the proposed induction model (Scheme
16) helps explain the high 1,5-syn selectivity obtained, which
occurred via the lowest-energy conformer out-1,5-syn-a-i. This
conformer minimizes the steric repulsions between the β-Ph3C
and β-OTMS groups and the ring and the boron ligands.
Therefore, our expectation was that a higher selectivity would
be achieved when a bulkier β-group, such as β-Ph3C, was
β-tert-Butyl Methylketones and β-Triphenylmethyl
Methylketones. We hypothesized that the 1,5-syn selectivity
would arise from the stereo effect of β-bulky substituents based
on the results obtained with the methylketones 11 (P = PMB,
R = t-Bu) and 12 (P = TBS, R = t-Bu) (Table 1). This stereo
effect led to 1,5-syn selectivities similar to those obtained using
methylketones 9 (P = TBS, R = CCl3) and 10 (P = Bn, R =
CCl3). We continued our theoretical study using models for
methylketones 11 and 12 as represented in Scheme 20 and
Table 6 (Tables S7 and S8 in the Supporting Information
describe the energies of all the characterized transition states).
According to Table 6, the out-1,5-syn-a conformers for
methylketones 11 and 12 showed the lowest relative energies
(∼1 kcal/mol more stable than out-1,5-anti-b), which predicts
the 1,5-syn selectivity of the aldol adducts. These results agree
perfectly with our model (Scheme 16) and are related to steric
minimization between the β-t-Bu and β-OP groups and the ring
and the boron ligands. The high energy of the “in” transition
states arise from the severe repulsions between the OP ⇔ t-Bu
and L ⇔ t-Bu groups in the in-1,5-anti and in-1,5-syn
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Scheme 19. Aldol Transition Structures of β-Trihalomethyl-β-Benzyloxy Dimethyl Boron Enolate and Ethanal
employed. Interestingly, the volume of the β-Ph3C group
strongly intervened in the “in” transition states via the severe
OP ⇔ β-Ph3C repulsion because TS-in-1,5-anti-iii (6 kcal/mol
more energetic than out-1,5-syn-a-i) showed no H-bonds
(rO−HC of 3.45 Å). In addition, the severe repulsion between
the L ⇔ β-Ph3C groups prevented the formation of the in-1,5-
syn transition state, which could not be characterized.
Role of Oxygen Steric Repulsion in β-Bulky Methyl-
ketones. As previously discussed, the bulky β-group orients
itself as far as possible from the ring in the transition states.
Therefore, independent of the conventional protecting groups
such as TBS and PMB, the out-1,5-syn-a conformers possess
the lowest energy. However, the TS-out-1,5-anti-a conformers
also satisfy this condition (Figure 1). Moreover, steric repul-
sions involving the protecting groups are present in both
conformations.
C−O enolate bond, which leads to a strong minimization of the
dipole moment and steric repulsion in the system.28
β-Triphenylmethoxy Methylketones. According to the
data presented in Table 2, the sense of 1,5-syn induction of β-
bulky methylketones is lost when a highly bulky protecting
group is used, such as in the case of 13 (P = Tr, R = t-Bu), 15
(P = Tr, R = Me), and 16 (P = TPS, R = Me). These results
demonstrate that the β-OP (P = Tr or TPS) substituent does
not provide induction.
Initially, we ascertained the volume effect in the protecting
groups of β-bulky-substituted methylketones using the model
system of methylketone 13 (P = Tr, R = t-Bu). Theoretical
calculations were performed, and the lowest-energy transition
states are shown in Scheme 22 and Table 8. We considered
two conformers related to the C-Ph sigma-bond rotations
(for details, see the Supporting Information, section S9).
Analysis of the relative energies of the transition states related
to methylketone 13 (P = Tr, R = t-Bu) presented in Table 8
show that the competitive transition states out-1,5-anti-b-i
(0.0 kcal/mol) and out-1,5-syn-b-i (0.3 and 0.2 kcal/mol for
IEF-PCM and SMD solvation models, respectively) are similar
in energy, which indicates poor 1,5-selectivity. In fact, selectivity
for this reaction was not experimentally observed (dr = 50:50,
As is evident in the graphic in the Figure 1, the TS-out-1,5-
anti-a conformers were between 1.7 and 3.6 kcal/mol higher in
energy than the out-1,5-syn-a conformers. This large energy
difference is attributed to the interaction between the enolate
bond (C−O) and the β-oxygen. The conformer out-1,5-syn-a
drives the β-OP group in the opposite direction from the
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Table 5. Aldol Transition Structures Calculated at B3LYP and with Basis Set 6-31G(d,p), the SCRF Calculated in B3LYP/6-
31+G(d,p) and IEF-PCM (UFF Radii) or SMD Solvation Model, and the Delocalization Energies and NBO Overlap Matrix (S)
of the Stabilizing H-Bond
1,5-anti:1,5-syn), which underscores the volume effect of the
β-OTr group in the erosion of the 1,5-selectivity. In addition,
the volume of the β-OTr group induced strong repulsions
that prevented the formation of H-bonds in the high-energy “in”
conformers.
The effect of the protecting group becomes more evident by
analysis of the relative energies of the “out” transition states
of the β-t-Bu methylketones in Figure 2. The same energy
profile was obtained for TMS- and Bn-protected methylke-
tones. However, with the trityl protecting group, the energies
of the out-1,5-anti-b and out-1,5-syn-b transition states were
lowered.
In view of these results, the loss of 1,5-syn selectivity of
methylketone 13 (P = Tr, R = t-Bu) is reasonably assumed to
arise from the new repulsive interactions introduced into the
system from the trityl protecting group. Analysis of the
geometries presented in Scheme 22 indicates that the trityl
group, which is bulkier than a tert-butyl group, justifies the
1 kcal/mol stability of out-1,5-syn-b-i over out-1,5-syn-a-i
(Table 8). Therefore, the out-1,5-syn-b-i conformer keeps the
β-OTr group far from the ring in the transition state but drives
the β-tert-butyl group in the direction of the ring and the boron
ligands. A similar situation occurs with the out-1,5-anti-b-i con-
former, which keeps the β-OTr group away from the ring while
directing the β-t-Bu group with the π-system enolate. Thus, the
transition states out-1,5-syn-b-i and out-1,5-anti-b-i have
lower relative energies; however, because of the unfavorable
interactions from the β-t-Bu group, there is no energetic dis-
crimination between them.
The transition states related to the models of the β-alkoxy-
β-methyl methylketones that involve Bn, TMS, and Tr protecting
groups were also studied (see the Supporting Information,
sections S10, S11, and S12, for the relative energies of all the
transition states and for values of the lowest energies and
geometries). The transition-state energies for these systems are
represented in Figure 3.
As expected, the methylketones that contain a small β-Me
substituent and a benzyl protecting group behave according to
Goodman’s induction model, which leads to high 1,5-anti
selectivities because the in-1,5-anti is the lowest-energy
conformation and because the transition state contains a
stabilizing H-bond (rO−HC = 2.35 Å and EHB = 3.0 kcal/mol).
The competitive TS-out-1,5-syn-a conformer was 0.8 kcal/mol
more energetic than the in-1,5-anti conformer. Experimentally,
we obtained 1,5-anti adducts in high selectivities (dr > 95:05),6d
which is in accordance with the theoretical results. However,
β-methyl methylketones with bulky protecting groups such as
TBS, Tr, and TPS led to equimolar mixtures of the 1,5-anti and
1,5-syn adducts. This scenario occurred for β-OTMS β-methyl
methylketone because the lowest-energy transition-states con-
formers (out-1,5-anti-b and out-1,5-syn-a) showed relative
energies of 0 kcal/mol. The system that contained a β-OTr pro-
tecting group exhibited similar relative energies of 0 kcal/mol
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Scheme 20. Aldol Transition Structures of β-tert-Butyl Dimethyl Boron Enolate and Ethanal
Table 6. Aldol Transition Structures Calculated at B3LYP and with Basis Set 6-31G(d,p), the SCRF in B3LYP/6-31+G(d,p) and
IEF-PCM (UFF Radii) or SMD Solvation Models, and Delocalization Energies and NBO Overlap Matrix (S) of the Stabilizing
H-Bond
for out-1,5-syn-b and 0.3 kcal/mol for out-1,5-anti-b, which is
in agreement with our experimental results.
benzylic protecting group is present and to poor 1,5-syn
selectivities when bulky protective groups such as TBS and
t-Bu6c,d are used. Furthermore, β-alkyl-β-OTr methylketones
did not exhibit 1,5-induction sense.
Thus, for the methylketone 15 (P = Tr, R = Me), the out-
1,5-syn-b and out-1,5-anti-b transition states represent the
conformation in which the β-OTr substituent is as far as
possible from the ring. No energetic discrimination between the
conformations occurred because of the identical β-Me repulsive
interactions with the ring; this situation is identical to that of
methylketone 13 (P = Tr, R = t-Bu).
β-Aryl-β-Triphenylmethoxy Methylketones. The aldol
reactions involving the methylketones 17 (P = Tr, R =
p-NO2C6H4) and 18 (P = TPS, R = p-NO2C6H4) showed 1,
5-anti induction. This result was unexpected because β-alkoxy-
β-aril methylketones lead to high 1,5-anti selectivities when a
Theoretical calculations were performed to investigate the
effect of β-OBn, β-OTMS, and β-OTr as protecting groups
in β-aril methylketones (sections S13, S14, and S15 in the
Supporting Information contain the energies of all the transi-
tion states and the values for the lowest energies). Figure 4
shows the relative energies of the found transition states.
In the case of methylketone 33 (P = Bn, R = p-NO2C6H4),
the competitive transition states were characterized, and the
TS-in-1,5-anti (0 kcal/mol) conformer was found to be lower
in energy than the Ts-out-1,5-syn-a conformer by 1.0 kcal/mol.
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Scheme 21. Aldol Transition Structures of β-Triphenylmethyl-β-Trimethylsilyloxy Dimethyl Boron Enolate and Ethanal
Table 7. Aldol Transition Structures Calculated at B3LYP and with Basis Set 6-31G(d,p), the SCRF in B3LYP/6-31+G(d,p) and
IEF-PCM (UFF Radii) or SMD Solvation Models, and the Delocalization Energies and NBO Overlap Matrix (S) of the
Stabilizing H-Bond
Figure 1. Energy profiles of the out-1,5-anti-a and out-1,5-syn-a transition states of β-bulky methylketones.
This large energy difference is in agreement with the experi-
mental results (dr > 95:05, 1,5-anti:1,5-syn) and with the initial
model of Goodman, in which the TS-in-1,5-anti transition state
and in-1,5-syn (0 kcal/mol) in an energy profile that represents
a reversal in selectivity and a modest 1,5-syn aldol adduct pre-
ference. This result is in perfect agreement with the experi-
mentally obtained results (dr ∼ 70:30, 1.5-syn:1,5-anti) and also
in accordance with the model proposed by Goodman.
contains stabilizing H-bonds (rO−HC = 2.39 Å and EHB
=
2.8 kcal/mol). Additionally, the TMS protecting group in the
same substitution pattern (β-p-NO2C6H4) leads to the lower-
energy competitive transition states out-1,5-anti-b (0.4 kcal/mol)
The model used in the study of methylketone 17 (P = Tr,
R = p-NO2C6H4) led to the lowest-energy competitive
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These results are in agreement with our experimental results
(dr ∼ 80:20, 1,5-anti:1,5-syn).
Scheme 22. Aldol Transition Structures of β-tert-Butyl-β-
triphenylmethoxy Dimethyl Boron Enolate and Ethanal
As shown in Scheme 23, in the TS-out-1,5-syn-b-ii transition
state, the highly polarized p-NO2C6H4 group eclipses the
oxygen enolate, which leads to steric repulsions between these
substituents and raises the energy of the system. However,
the more energetically favorable TS-out-1,5-anti-b-ii keeps the
β-p-NO2C6H4 substituent in a position opposite the enolate
oxygen, which minimizes the dipole moment and reduces
the steric repulsions of the system. In addition, this conformer
allows a π-stacking stabilization between the aromatic ring sys-
tems and the enolate.
The out-1,5-anti-b conformation is always lower in energy
than the out-1,5-syn-b conformation, irrespective of the pro-
tecting group for p-NO2C6H4-substituted methylketones.
This situation is not true for β-alkyl-substituted methylketones
(R = Me and t-Bu), which reinforces the premise of greater
polarizability of the aromatic system.
CONCLUSIONS
■
From this systematic study involving aldol reactions of boron
enolates of methylketones (with different stereoelectronic
properties in the β-alkyl substituents and in the β-protecting
groups) and several achiral aldehydes (aliphatic, α,β-unsatu-
rated, and aromatic aldehydes), we conclude that the levels of
selectivity observed also depend on the nature of the β-alkyl
substituents and not only on the electronic nature of the
β-protecting group, as previously described. These observations
were corroborated by theoretical studies conducted using DFT.
New studies are still required in order to investigate the
generality of the 1,5-syn induction. We speculate that the results
presented by Paterson in the synthesis of the C27−C51
fragment of spongistatin 13f (Scheme 3) are included in the
induction model proposed in this paper. The highly substituted
F-subunit should provide the required β-substituent volume
that direct the stereochemical bias to 1,5-syn selectivity. New
efforts are underway in the direction of a full comprehension of
the factors that govern the 1,5-syn selectivity and the deve-
lopment of a 1,5-syn aldol methodology with synthetic utility.
Table 8. Aldol Transition Structures Calculated at B3LYP
and with Basis Set 6-31G(d,p), the SCRF in B3LYP/
6-31+G(d,p) and IEF-PCM (UFF Radii) or SMD Solvation
Model, and the Delocalization Energies and NBO Overlap
Matrix (S) of the Stabilizing H-Bond
EXPERIMENTAL SECTION
■
Materials and Methods. Unless noted, all reactions were
performed under an atmosphere of argon in flame-dried glassware
with magnetic stirring. Dichloromethane, triethylamine (Et3N), 2,6-
lutidine, and dimethylformamide (DMF) were distilled from CaH2.
Dimethyl sulfoxide (DMSO) was distilled under reduced pressure
from CaH2 and stored over molecular sieves. THF and diethyl ether
were distilled from sodium/benzophenone. Oxalyl chloride was disti-
lled immediately prior to use. The purification of reaction products
was performed by flash column chromatography using silica gel (230−
400 mesh). Analytical thin-layer chromatography was performed on
silica- gel 60 and GF (5−40-μm thickness) plates. Visualization was
accomplished with UV light and phosphomolybdic acid followed by
heating. Optical rotations were measured with a sodium lamp and are
reported as follows: [α]T°CD (c g/100 mL, solvent). Melting points are
uncorrected. For the Infrared spectra, wavelengths of maximum
absorbance (max) are quoted in wavenumbers (cm−1). 1H and proton-
decoupled 13C NMR spectra were taken in C6D6, CDCl3 or CD3OD at
250 MHz (1H) and 62.5 MHz (13C), 400 MHz (1H) and 100 MHz
(13C) or at 500 MHz (1H) and 125 MHz (13C). The chemical
shifts (δ) are reported in ppm using solvent as an internal standard
(C6D6 at 7.16 ppm, CDCl3 at 7.26 ppm, and CD3OD at 3.30 ppm
transition states out-1,5-anti-b and out-1,5-syn-b with energy
values of 0 and 0.9 kcal/mol, respectively. These conformations
keep the β-OTr substituent as far from the ring as possible,
thereby reducing the system energy. However, unlike the
situation with the β-alkyl substituted methylketones (R = Me
and t-Bu), here we observe a strong energy discrimination
between the out-1,5-anti-b and out-1,5-syn-b conformers, with
a preference for the formation of the 1,5-anti aldol adduct.
1
for H NMR spectra and C6D6 at 128.0 ppm, CDCl3 at 77.0 ppm,
and CD3OD at 49.0 ppm for 13C NMR spectra). Data are reported as
follows: s = singlet, d = doublet, t = triplet, q = quartet, quint =
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Figure 2. Relative transition-state energies (IEF-PCM) of β-t-Bu-substituted methylketones.
Figure 3. Relative transition-state energies (IEF-PCM) of β-Me-substituted methylketones.
Figure 4. Relative transition-state energies (IEF-PCM) of β-p-NO2C6H4-substituted methylketones.
quintuplet, sext = sextet, br s = broad singlet, dd = doublet of doublets,
dt = doublet of triplets, ddd = doublet of doublet of doublets, tt =
triplet of triplets, m = multiplet; coupling constant(s) in Hz; integration.
The signals of the minor isomers are stated in brackets. High-resolution
mass spectrometry (HRMS) were measured using electrospray ioniza-
tion (ESI) or using electron ionization (EI). The parent ions ([M +
H]+, [M + Na]+, [M − CH3]+, [M − C4H9]+, [M − C6H5]+) are
quoted. The preparation of methylketones 11, 12, 13, 15, 17 and the
1782
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(dd, J = 6.1 and 15.6 Hz, 1H); 4.54 (sext, J = 6.1 Hz, 1H); 7.16−7.23
(m, 9H); 7.14−7.79 (m, 6H). 13C NMR (125 MHz; C6D6) δ 24.0;
30.3; 52.9; 66.8; 128.2; 130.3; 135.1; 135.9; 205.0. HRMS (EI TOF-
MS): calcd for C17H19O2Si [M − C6H5]+ 283.1154; found 283.1162.
(RS)-4-(4-Nitrophenyl)-4-(triphenylsilyloxy)butan-2-one (18). To
a solution of alcohol 40 (1.01 g; 4.78 mmol) in DMF (15 mL) under
argon atmosphere was added pyridine (3.85 mL; 47.8 mmol) followed
by AgNO3 (3.25 g; 19.1 mmol), and the mixture was stirred until the
solid was completely dissolved. Then, TPSCl (5.63 g; 19.1 mmol) was
added in one portion, and the resulting suspension was stirred for 18 h
at room temperature. After this period, the crude reaction was filtered,
and the white solid was washed with Et2O. The organic phase was
washed with water (2 × 25 mL) and brine (2 × 25 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The resi-
due was purified by flash column chromatography (silica gel 200−400
mesh) using a mixture of hexane/dichloromethane/ethyl acetate
(50:40:10) as the eluent, which provided 1.63 g (73%) of 18 as a pale
Scheme 23
aldol adducts 24a−g, 25a−g, 26a−h, 27a−h, 47a−e, 48a−e, 49a−e,
50a−e, 51a−f, 52a−f is described in ref 9.
Preparation of Methylketones. (+)-(R)-5,5-Dimethyl-4-
(triphenylsilyloxy)hexan-2-one (14). A solution of alcohol 20
(200 mg, 1.39 mmol), AgOTf (426 mg, 3.53 mmol), and 2,6-lutidine
(0.24 mL, 2.02 mmol) in anhydrous CH2Cl2 (10 mL) was cooled to
0 °C. TPSCl (1.04 g, 3.53 mmol) was added, and the resulting
suspension was stirred for 5 min at 0 °C and 1 h at room temperature.
After this period, the crude reaction was filtered through a pad of
Celite. The filtrate was washed with saturated aqueous NaHCO3 (2 ×
50 mL) and then with brine (2 × 50 mL). The organic phase was
subsequently dried over MgSO4 and concentrated. The residue was
purified by flash column chromatography (silica gel 200−400 mesh)
using a mixture of hexane/ethyl acetate (90:10) as eluent, which
1
yellow solid. Rf 0.80 (hexane/CH2Cl2/EtOAc, 50:10:40). H NMR
(250 MHz; C6D6) δ 1.61 (s, 3H); 2.28 (dd, J = 5.5 and 16.3 Hz, 1H);
2.75 (dd, J = 7.0 and 16.4 Hz, 1H); 5.53 (t, J = 5.5 Hz, 1H); 7.01
(d, J = 8.7 Hz, 2H); 7.22 (m, 9H); 7.71 (m, 6H); 7.80 (d, J = 8.7 Hz,
2H). 13C NMR (62.5 MHz; C6D6) δ 30.4; 53.2; 71.6; 123.4; 127.1;
128.2; 130.5; 134.0; 135.8; 147.5; 150.6; 203.7. HRMS (ESI TOF-
MS): calcd for C28H26NO4Si 468.1631; found 468.1647.
(RS)-3-Hydroxy-N-methoxy-N-methyl-4,4,4-triphenylbutanamide
(65). Lithium diisopropylamide (LDA) was generated by the addition
of n-butyllithium (4.7 mL, 7.33 mmol, 1.6 M solution in hexanes) to a
solution of diisopropylamine (1.00 mL, 7.3 mmol) in THF (5.0 mL)
at −78 °C. After 10 min, a solution of Weinreb amide 64 (0.8 mL,
7.3 mmol) in THF (2.5 mL) was added via cannula, and the resulting
solution was stirred at −78 °C for 30 min. A solution of aldehyde 63
(1.0 g, 3.65 mmol) in THF (5.0 mL) was added via cannula, and the
solution was stirred at −78 °C for 40 min. The reaction was quenched
at −78 °C by the addition of saturated aqueous NH4Cl (10 mL), and
the mixture was warmed to room temperature. The mixture was dilu-
ted with EtOAc. The aqueous washings were extracted with EtOAc
(3 × 50 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 (2 × 50 mL) and brine (2 × 50 mL),
dried over MgSO4, filtered, and concentrated under reduced pressure,
which provided 1.37 g (99%) of 65 as a white solid. Rf 0.30 (30%
EtOAc in hexane). Mp 117−120 °C. IR (neat) 3450, 3088, 3057,
3034, 3020, 2970, 2937, 1645, 1597, 1495, 1447, 1423, 1389, 1267,
provided 461 mg (82%) of 14 as a white solid. [α]20 +4.0 (c 1.31;
D
CHCl3). Rf 0.53 (10% EtOAc in hexane). Mp 73−76 °C. IR (neat)
3070, 3051, 2962, 2908, 2870, 1717, 1711, 1589, 1479, 1468, 1429,
1394, 1366, 1292, 1265, 1161, 1117, 1086, 1074, 1022, 997, 878, 739,
710, 700 cm−1. H NMR (250 MHz; C6D6) δ 0.85 (s, 9H); 1.40 (s,
1
3H); 2.21 (dd, J = 3.0 and 17.8 Hz, 1H); 2.53 (dd, J = 7.1 and 17.8 Hz,
1H); 4.49 (dd, J = 3.0 and 7.1 Hz, 1H); 7.16−7.23 (m, 9H); 7.84−
7.90 (m, 6H). 13C NMR (62.5 MHz; C6D6) δ 26.1; 29.8; 35.6; 47.3;
76.2; 128.0; 130.0; 135.6; 136.2; 204.9. HRMS (ESI TOF-MS): calcd
for C26H31O2Si 403.2093; found 403.2056.
(RS)-4-(Triphenylsilyloxy)pentan-2-one (16). A solution of alcohol
37 (730 mg, 7.0 mmol), AgOTf (1.80 g, 7.0 mmol), and 2,6-lutidine
(1.0 mL, 8.6 mmol) in anhydrous CH2Cl2 (12 mL) was cooled to
0 °C. TPSCl (2.06 g, 7.0 mmol) was added, and the resulting suspension
was stirred for 5 min at 0 °C and 1 h at room temperature. After this
period, the crude reaction was filtered through a pad of Celite, and the
filtrate was washed with saturated aqueous NaHCO3 (2 × 50 mL) and
then with brine (2 × 50 mL). The organic phase was subsequently
dried over MgSO4 and concentrated. The residue was purified by flash
column chromatography (silica gel 200−400 mesh) using a mixture of
hexane/ethyl acetate (80:20) as eluent, which provided the compound
39 as an oil.
1
1180, 1107, 1088, 1036, 1001, 991, 895, 737, 706, 652, 640 cm−1. H
NMR (400 MHz; CDCl3) δ 2.06 (dd, J = 10.7 and 16.1 Hz, 1H), 2.77
(d, J = 16.1 Hz, 1H), 3.04 (d, J = 3.7 Hz, 1H), 3.15 (s, 3H), 3.43
(s, 3H), 5.84 (dd, J = 3.7 and 9.5 Hz, 1H), 7.18 (t, J = 7.4 Hz, 3H),
7.27 (t, J = 7.4 Hz, 6H), 7.39 (d, J = 7.4 Hz, 6H). 13C NMR (62.5
MHz; CDCl3) δ 32.0; 36.0; 61.0; 61.3; 70.2; 126.2; 127.7; 129.9;
144.5; 173.5. HRMS (ESI TOF-MS): calcd for C24H26NO3 376.1913;
found 376.1879.
(RS)-3-(tert-Butyldimethylsilyloxy)-N-methoxy-N-methyl-4,4,4-tri-
phenylbutanamide (66). TBSOTf (0.7 mL, 3.1 mmol) was added
dropwise to a solution of alcohol 65 (1.0 g, 2.7 mmol) and 2,6-lutidine
(0.5 mL, 3.9 mmol) in CH2Cl2 (5.0 mL). After 1 h, the reaction was
quenched by the addition of water (10 mL). The phases were
separated, and the aqueous phase was extracted with EtOAc (3 ×
50 mL). The organic phase was washed with water (2 × 25 mL) and
brine (2 × 25 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (silica gel 200−400 mesh) using a mixture of hexane/
ethyl acetate (80:20) as the eluent, which provided 1.13 g (85%) of 66
as a white solid. Rf 0.48 (30% EtOAc in hexane). Mp 179−181 °C. IR
(neat) 3055, 2957, 2930, 2856, 1659, 1597, 1495, 1472, 1447, 1421,
1389, 1265, 1180, 1101, 993, 959, 897, 831, 777, 739, 706 cm−1.
1H NMR (400 MHz; CDCl3) δ −0.07 (s, 3H), −0.04 (s, 3H), 0.59
(s, 9H), 1.94 (dd, J = 5.3 and 17.2 Hz, 1H), 2.58 (d, J = 17.2 Hz, 1H),
3.15 (s, 3H), 3.35 (s, 3H), 6.12 (d, J = 7.8 Hz, 1H), 7.11 (br s, 3H),
7.23 (br s, 6H), 7.39 (br s, 6H). 13C NMR (62.5 MHz; CDCl3)
δ −5.6; −4.4; 18.1; 25.5; 32.3; 39.3; 60.8; 62.2; 71.3; 125.7; 127.9;
DMSO (1.19 mL, 16.8 mmol) was added dropwise to a stirred
solution of oxalyl chloride (0.76 mL, 8.61 mmol) in CH2Cl2 (43 mL)
at −78 °C, and the mixture was stirred for 30 min. A solution of
the alcohol 39 (2.54 g, 7.0 mmol) in CH2Cl2 (18 mL) was added
dropwise via cannula, and the mixture was stirred at −78 °C for
30 min. Et3N (4.9 mL, 35.0 mmol) was added dropwise. The suspension
was allowed to slowly warm to room temperature and was stirred for
1 h. The reaction was quenched with the addition of a saturated aqueous
NH4Cl solution (20 mL). The phases were separated, and the aqueous
phase was extracted with EtOAc (3 × 50 mL). The organic phase
was washed with water (2 × 25 mL) and brine (2 × 25 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (silica gel
200−400 mesh) using a mixture of hexane/ethyl acetate (80:20) as
eluent, which provided 1.51 g (60%, two steps) of 16 as a white solid.
Rf 0.54 (20% EtOAc in hexane). Mp 55−58 °C. IR (neat) 3070, 3051,
2972, 2930, 1715, 1589, 1485, 1429, 1375, 1337, 1265, 1117, 1086,
1020, 901, 739, 712, 702 cm−1. 1H NMR (250 MHz; C6D6) δ 1.14 (d,
J = 6.1 Hz, 3H); 1.62 (s, 3H); 2.13 (dd, J = 6.1 and 15.6 Hz, 1H); 2.49
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129.1; 146.6; 172.9. HRMS (ESI TOF-MS): calcd for C30H40NO3Si
490.2777; found 490.2766.
and 18.1 Hz, 1H)); 2.60 (dd, J = 7.3 and 18.1 Hz, 1H); (2.70 (br s,
1H)); (3.26 (d, J = 10.3 Hz, 1H)); 3.48 (d, J = 10.3 Hz, 1H); 4.42
(dd, J = 2.5 and 7.5 Hz, 1H); (4.48 (dd, J = 2.3 and 7.5 Hz, 1H));
7.19−7.25 (m, 9H); 7.84−7.87 (m, 6H). 13C NMR (62.5 MHz; C6D6)
δ 25.8; (25.9); (26.2); 26.2; (34.1); 34.2; (35.5); 35.7; 44.7; (44.8);
47.5; (47.7); (74.1); 74.5; (75.6); 75.8; 128.1; (128.5); (130.0); 130.1;
135.6; (135.7); 136.1; (209.7); 210.0. HRMS (ESI TOF-MS): calcd
for C31H40O3SiNa 511.2644; found 511.2639.
(RS)-4-(tert-Butyldimethylsilyloxy)-5,5,5-triphenylpentan-2-one
(19). To a solution of Weinreb amide 66 (50 mg, 0.10 mmol) in THF
(1.8 mL) was added MeLi (0.71 mL, 0.50 mmol, 0.70 M in Et2O)
dropwise at −78 °C. The reaction mixture was stirred for 40 min. The
reaction was quenched at −78 °C by the addition of saturated aqueous
NH4Cl (5 mL), and the mixture was warmed to room temperature.
The mixture was diluted with EtOAc. The aqueous washings were
extracted with EtOAc (3 × 5 mL). The combined organic layers were
washed with brine (2 × 10 mL), dried over MgSO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash
column chromatography (silica gel 200−400 mesh) using a mixture of
hexane/ethyl acetate (80:20) as the eluent, which provided 46 mg
(99%) of 19 as a yellow solid. Rf 0.79 (20% EtOAc in hexane). Mp
171−174 °C. IR (neat) 3057, 2955, 2928, 2854, 1715, 1495, 1447,
(1S,5R)-1-Hydroxy-6,6-dimethyl-1-phenyl-5-(triphenylsilyloxy)-
heptan-3-one (53e) and (1R,5R)-1-Hydroxy-6,6-dimethyl-1-phenyl-
5-(triphenylsilyloxy)heptan-3-one (54e). The mixture of aldol
adducts 53e and 54e (68%, 72 mg, 0.14 mmol) was obtained as a
yellow oil (70:30 diastereoselectivity) after purification by flash column
chromatography (silica gel 200−400 mesh) using a mixture of hexane/
ethyl acetate (80:20) as the eluent. Rf 0.50 (20% EtOAc in hexane). IR
(neat) 3568, 3051, 2962, 2907, 2872, 1707, 1589, 1479, 1454, 1429, 1394,
1
1364, 1265, 1194, 1115, 1088, 1028, 932, 739, 702 cm−1. H NMR
1
1360, 1265, 1103, 1005, 835, 739, 704 cm−1. H NMR (250 MHz;
(500 MHz; C6D6) δ 0.83 (s, 9H); (0.83 (s, 9H)); (1.99 (dd, J = 2.3
and 17.5 Hz, 1H)); 2.12−2.19 (m, 2H); (2.22 (dd, J = 2.3 and 18.0 Hz,
1H)); 2.25 (dd, J = 2.9 and 18.2 Hz, 1H); (2.30 (dd, J = 7.5 and 17.5 Hz,
1H)); 2.54 (dd, J = 7.7 and 18.2 Hz, 1H); (2.54 (dd, J = 7.7 and
18.0 Hz, 1H)); 2.68 (br s, 1H); (3.01 (br s, 1H)); 4.41 (dd, J = 2.9 and
7.6 Hz, 1H); (4.49 (dd, J = 2.3 and 7.8 Hz, 1H)); (4.65 (dd, J = 2.0 and
10.1 Hz, 1H)); 4.82 (dd, J = 4.7 and 7.7 Hz, 1H); 7.09−7.30 (m, 14H);
7.85−7.89 (m, 6H). 13C NMR (62.5 MHz; C6D6) δ (26.1); 26.1; (35.5);
35.6; 47.3; (47.4); 52.1; (52.1); (69.2); 69.7; (75.6); 75.7; (125.9); 126.1;
(127.4); 127.5; (128.1); 128.1; 128.4; (128.5); (130.1); 130.1; 135.6;
(135.6); 136.1; 143.9; 208.5; (208.7). HRMS (ESI TOF-MS): calcd for
C33H37O3Si 509.2512; found 509.2532.
(2RS,6RS)-6-Hydroxy-7-methyl-2-(triphenylsilyloxy)octan-4-one
(55a) and (2RS,6SR)-6-Hydroxy-7-methyl-2-(triphenylsilyloxy)-
octan-4-one (56a). The mixture of aldol adducts 55a and 56a
(90%, 84 mg, 0.19 mmol) was obtained as a yellow oil (50:50 dia-
stereoselectivity) after purification by flash column chromatography
(silica gel 200−400 mesh) using a mixture of hexane/ethyl acetate
(80:20) as the eluent. Rf 0.44 (20% EtOAc in hexane). IR (neat) 3545,
3070, 3053, 2966, 2930, 1963, 1894, 1828, 1778, 1589, 1466, 1429,
1379, 1265, 1117, 1080, 997, 895, 748, 719 cm−1. 1H NMR (400 MHz;
C6D6) δ (0.80 (d, J = 6.8 Hz, 3H)); 0.81 (d, J = 6.8 Hz, 3H); 0.87
(d, J = 6.8 Hz, 3H); 1.11−1.13 (m, 3H); 1.43−1.51 (m, 1H); 2.04−
2.22 (m, 3H); 2.47−2.52 (m, 1H); 2.83 (br s, 1H); 3.64−3.69 (m,
1H); 4.49−4.60 (m, 1H); 7.20−7.21 (m, 9H); 7.75−7.77 (m, 6H).
13C NMR (62.5 MHz; C6D6) δ 17.6; (17.6); 18.7; (18.7); 24.0;
(33.3); 33.3; (47.3); 47.6; 52.9; (53.0); (66.7); 66.7; 71.8; (71.9);
128.2; (130.3); 130.3; (135.0); 135.1; 135.9; (209.7); 209.8. HRMS
(ESI TOF-MS): calcd for C27H33O3Si 433.2199; found 433.2199.
(2RS,6RS)-6-Hydroxy-7-methyl-2-(triphenylsilyloxy)oct-7-en-4-
one (55d) and (2RS,6SR)-6-Hydroxy-7-methyl-2-(triphenylsilyloxy)-
oct-7-en-4-one (56d). The mixture of aldol adducts 55d and 56d
(83%, 84 mg, 0.20 mmol) was obtained as a white oil (50:50 di-
astereoselectivity) after purification by flash column chromatography
(silica gel 200−400 mesh) using a mixture of hexane/ethyl acetate
(80:20) as the eluent. Rf 0.45 (20% EtOAc in hexane). IR (neat) 3481,
3070, 3051, 2974, 2930, 1963, 1894, 1826, 1707, 1653, 1589, 1485,
1429, 1377, 1265, 1186, 1117, 1090, 1020, 995, 905, 744, 702 cm−1.
1H NMR (400 MHz; C6D6) δ (1.12 (d, J = 6.3 Hz, 3H)); 1.12 (d, J =
6.3 Hz, 3H); 1.57 (s, 3H); 2.12−2.23 (m, 2H); 2.27−2.38 (m, 1H);
2.48−2.54 (m, 1H); 2.88 (br s, 1H); 4.35−4.41 (m, 1H); 4.48−4.60
(m, 1H); 4.77 (s, 1H); 5.00−5.01 (m, 1H); 7.20−7.22 (m, 9H);
7.74−7.77 (m, 6H). 13C NMR (62.5 MHz; C6D6) δ (18.3); 18.4; 23.9;
(48.7); 49.1; (52.9); 53.0; 66.6; (66.7); (71.0); 71.1; 110.7; (110.7);
128.2; 130.3; (130.3); (135.0); 135.1; 135.9; 146.5; (146.5); 208.7;
(208.7). HRMS (ESI TOF-MS): calcd for C27H31O3Si: 431.2043;
found 431.2047.
CDCl3) δ −0.08 (s, 3H), −0.07 (s, 3H), 0.59 (s, 9H), 1.98 (dd, J = 6.5
and 19.1 Hz, 1H), 2.03 (s, 3H), 2.72 (d, J = 19.1 Hz, 1H), 6.10 (d, J =
6.5 Hz, 1H), 7.00−7.47 (m, 15H). 13C NMR (62.5 MHz; CDCl3)
δ −5.7; −4.4; 18.0; 25.6; 30.8; 51.3; 61.9; 70.1; 125.9; 127.7; 129.0;
146.6; 206.9. HRMS (EI TOF-MS): calcd for C25H27O2Si [M − C4H9]+
387.1780; found 387.1762.
General Procedure for Methylketone Aldol Reactions. To a
solution of the methylketone (1.0 equiv, 0.21 mmol) in Et2O (5.5 mL)
at −30 °C was carefully added (c-Hex)2BCl (2.0 equiv, 0.42 mmol),
followed by the addition of Et3N (2.1 equiv, 0.44 mmol). After the
addition of Et3N was complete (the formation of a white cloud was
observed at this point), the reaction medium was immediately cooled
to −78 °C. The corresponding aldehyde (4.0 equiv, 0.84 mmol) was
added dropwise to this slurry, and the resulting mixture was stirred for
1 h. The reaction was quenched by the addition of MeOH (4.0 mL),
and the resulting solution was stirred at room temperature for 30 min.
The solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography (silica gel 200−400 mesh),
which provided the aldol adducts.
(3R,7S)-7-Hydroxy-2,2,8-trimethyl-3-(triphenylsilyloxy)nonan-5-
one (53a) and (3R,7R)-7-Hydroxy-2,2,8-trimethyl-3-
(triphenylsilyloxy)nonan-5-one (54a). The mixture of aldol adducts
53a and 54a (88%, 85 mg, 0.18 mmol) was obtained as a yellow oil
(65:35 diastereoselectivity) after purification by flash column chro-
matography (silica gel 200−400 mesh) using a mixture of hexane/
ethyl acetate (80:20) as the eluent. Rf 0.56 (20% EtOAc in hexane). IR
(neat) 3580, 3070, 3053, 2962, 2908, 2874, 1709, 1589, 1479, 1470,
1429, 1394, 1366, 1265, 1115, 1088, 1063, 1028, 999, 897, 748, 710
1
cm−1. H NMR (250 MHz; C6D6) δ 0.81−0.91 (m, 15H); 1.33−1.51
(m, 1H); 1.76 (dd, J = 1.4 and 17.6 Hz, 1H); 1.81−1.97 (m, 1H); 2.06
(dd, J = 10.1 and 17.6 Hz, 1H); (2.22 (dd, J = 2.0 and 18.0 Hz, 1H));
2.34 (dd, J = 2.6 and 18.1 Hz, 1H); 2.41 (br s, 1H); 2.52−2.63 (m,
1H); (3.29 (dd, J = 4.1 and 9.2 Hz, 1H)); 3.56 (m, 1H); 4.41 (dd, J =
2.8 and 7.1 Hz, 1H); (4.48 (dd, J = 2.3 and 7.8 Hz, 1H)); 7.18−7.23
(m, 9H); 7.83−7.88 (m, 6H). 13C NMR (62.5 MHz; C6D6) δ 17.5;
(17.6); 18.7; (18.8); (26.2); 26.2; (33.2); 33.2; (35.5); 35.7; 46.8;
(47.3); 47.4; (71.2); 71.6; (75.7); 75.8; (128.0); 128.1; (130.0); 130.1;
135.6; (135.6); 136.1; 209.6; (209.6). HRMS (ESI TOF-MS): calcd
for C30H39O3Si 475.2668; found 475.2666.
(3S,7R)-3-Hydroxy-2,2,8,8-tetramethyl-7-(triphenylsilyloxy)-
nonan-5-one (53c) and (3R,7R)-3-Hydroxy-2,2,8,8-tetramethyl-7-
(triphenylsilyloxy)nonan-5-one (54c). The mixture of aldol adducts
53c and 54c (86%, 87 mg, 0.18 mmol) was obtained as a yellow oil
(63:37 diastereoselectivity) after purification by flash column chro-
matography (silica gel 200−400 mesh) using a mixture of hexane/
ethyl acetate (80:20) as eluent. Rf 0.68 (20% EtOAc in hexane) IR
(neat) 3543, 3070, 3053, 2962, 2907, 2872, 1963, 1904, 1828, 1778,
1709, 1653, 1589, 1479, 1468, 1429, 1394, 1366, 1308, 1265, 1186,
(1RS,5RS)-1-Hydroxy-1-phenyl-5-(triphenylsilyloxy)hexan-3-one
(55e) and (1SR,5RS)-1-Hydroxy-1-phenyl-5-(triphenylsilyloxy)-
hexan-3-one (56e). The mixture of aldol adducts 55e and 56e
(71%, 70 mg, 0.15 mmol) was obtained as a colorless oil (50:50 di-
astereoselectivity) after purification by flash column chromatography
(silica gel 200−400 mesh) using a mixture of hexane/ethyl acetate
(80:20) as the eluent. Rf 0.38 (20% EtOAc in hexane). IR (neat) 3522,
1
1115, 1084, 1028, 999, 943, 937, 897, 741, 710 cm−1. H NMR (400
MHz; C6D6) δ 0.85 (s, 9H); (0.85 (s, 9H)); 0.86 (s, 9H); (0.87 (s,
9H)); 1.88 (dd, J = 10.4 and 17.2 Hz, 1H); (1.88 (dd, J = 1.5 and 17.2
Hz, 1H)); 2.04−2.11 (m, 1H); (2.26 (dd, J = 2.2 and 18.2 Hz, 1H));
2.36 (dd, J = 2.6 and 18.3 Hz, 1H); 2.52 (br s, 1H); (2.59 (dd, J = 7.5
1784
dx.doi.org/10.1021/jo2023119 | J. Org. Chem. 2012, 77, 1765−1788

The Journal of Organic Chemistry
Article
3069, 3053, 2974, 2930, 2899, 1963, 1894, 1828, 1778, 1707, 1589,
1495, 1454, 1429, 1379, 1265, 1186, 1117, 1090, 1067, 1030, 916, 895,
739, 702 cm−1. 1H NMR (400 MHz; C6D6) δ 1.09 (d, J = 6.0 Hz, 3H);
2.02−2.10 (m, 1H); 2.26−2.37 (m, 1H); 2.39−2.52 (m, 2H); (3.13
(br s, 1H)); 3.22 (br s, 1H); 4.44−4.57 (m, 1H); 4.97−5.03 (m, 1H);
7.07−7.11 (m, 1H); 7.15−7.26 (m, 13H); 7.74−7.77 (m, 6H).
13C NMR (62.5 MHz; C6D6) δ 23.9; 52.3; (52.6); (52.8); 52.9; 66.6;
(66.7); (69.7); 69.8; (126.0); 126.0; 127.4; 128.2; 128.5; (130.3);
130.3; (135.0); 135.0; 135.9; 143.9; 208.7; (208.8). HRMS (ESI TOF-
MS): calcd for C30H30O3SiNa 489.1862; found 489.1842.
895, 837, 777, 741, 704, 633 cm−1. 1H NMR (400 MHz; C6D6) δ 0.05
(s, 3H); 0.06 (s, 3H); 0.74 (d, J = 6.8 Hz, 3H); 0.75 (s, 9H); 0.79 (d,
J = 6.8 Hz, 3H); 1.31−1.41 (m, 1H); 1.82 (d, J = 17.6 Hz, 1H); 1.92
(dd, J = 9.5 and 17.6 Hz, 1H); 2.05 (dd, J = 7.0 and 19.2 Hz, 1H); 2.82
(d, J = 19.2 Hz, 1H); 2.94 (br s, 1H); 3.67−3.71 (m, 1H); 6.36 (d, J =
7.0 Hz, 3H); 6.92 (br s, 3H); 7.06 (br s, 6H); 7.50 (br s, 6H). 13C
NMR (62.5 MHz; C6D6) δ −5.3; −4.0; 17.3; 18.4; 18.7; 26.0; 33.2;
47.3; 51.6; 62.5; 70.5; 71.8; 126.3; 129.5; 132.5; 147.2; 210.5. HRMS
(ESI TOF-MS): calcd for C33H44O3SiNa 539.2957; found 539.2933.
(2SR,6RS)-2-(tert-Butyldimethylsilyloxy)-6-hydroxy-1,1,1-triphe-
nyloctan-4-one (68b). The aldol adduct 68b (92%, 51 mg, 0.10
mmol) was obtained as a white solid (>95:05 diastereoselectivity) after
purification by flash column chromatography (silica gel 200−400
mesh) using a mixture of hexane/ethyl acetate (80:20) as the eluent. Rf
0.57 (20% EtOAc in hexane). Mp 145−148 °C. IR (neat) 3599, 3053,
3036, 2959, 2928, 2897, 2854, 1699, 1597, 1495, 1470, 1448, 1389,
1360, 1265, 1176, 1130, 1036, 999, 953, 833, 779, 743, 706, 629 cm−1.
1H NMR (500 MHz; C6D6) δ 0.04 (s, 3H); 0.05 (s, 3H); 0.75 (s, 9H);
0.82 (t, J = 7.5 Hz, 3H); 1.06−1.14 (m, 1H); 1.19−1.28 (m, 1H); 1.68
(dd, J = 2.7 and 17.8 Hz, 1H); 1.80 (dd, J = 9.3 and 17.8 Hz, 1H); 1.98
(dd, J = 7.0 and 19.3 Hz, 1H); 2.76 (d, J = 19.3 Hz, 1H); 2.81 (br s,
1H); 3.70−3.78 (m, 1H); 6.34 (d, J = 7.0 Hz, 1H); 6.92 (br s, 3H);
7.06 (br s, 6H); 7.50 (br s, 6H). 13C NMR (100 MHz; C6D6) δ −5.3;
−4.0; 9.8; 18.4; 25.9; 29.6; 49.6; 51.5; 62.4; 68.6; 70.3; 126.2; 129.4;
132.8; 147.2; 210.2. HRMS (ESI TOF-MS): calcd for C32H42O3SiNa
525.2801; found 525.2835.
(1SR,5SR)-5-Hydroxy-6-methyl-1-(4-nitrophenyl)-1-
(triphenylsilyloxy)heptan-3-one (57a) and (1SR,5RS)-5-Hydroxy-6-
methyl-1-(4-nitrophenyl)-1-(triphenylsilyloxy)heptan-3-one (58a).
The mixture of aldol adducts 57a and 58a (69%, 0.112 g, 0.18 mmol)
was obtained as a pale yellow oil (61:39 diastereoselectivity) after puri-
fication by flash column chromatography (silica gel 200−400 mesh)
using a mixture of hexane/dichloromethane/ethyl acetate (50:40:10)
as the eluent. Rf 0.50 (hexane/CH2Cl2/EtOAc 5:4:1). 1H NMR
(250 MHz, C6D6) δ 0.78 (d, J = 6.8 Hz, 3H); (0.78 (d, J = 6.8 Hz,
3H)); 0.84 (d, J = 6.8 Hz, 3H); (0.84 (d, J = 6.8 Hz, 3H)); 1.34−1.53
(m, 1H); (1.90−2.01 (dd, J = 2.4 and 17.1 Hz, 1H)); 1.91−2.29
(m, 3H); 2.43−2.52 (m, 1H); 2.74 (dd, J = 7.6 and 16.4 Hz, 1H);
(2.76 (dd, J = 7.6 and 16.4 Hz, 1H)); 3.55−3.67 (m, 1H); 5.41−5.51
(m, 1H); 6.92 (d, J = 8.5 Hz, 2H); (6.97 (d, J = 8.5 Hz, 2H)); 7.09−
7.23 (m, 9H); 7.57−7.68 (m, 6H); 7.73 (d, J = 8.5 Hz, 2H); 7.75 (d,
J = 8.5 Hz, 2H). 13C NMR (62.5 MHz, C6D6) δ 17.5; 18.5; 33.3; (47.6);
47.9; 53.4; (71.4); 71.6; 71.8; (71.9); 123.5; 127.0; (127.1); 127.8; 128.2;
130.5; (134.0); 134.0; 135.8; 147.6; 150.4; (150.4); (208.0); 208.1. HRMS
(ESI TOF-MS): calcd for C32H33NO5SiNa 562.2026; found 562.2052.
(1SR,5RS)-5-Hydroxy-1-(4-nitrophenyl)-1-(triphenylsilyloxy)-
heptan-3-one (57b) and (1SR,5SR)-5-Hydroxy-1-(4-nitrophenyl)-1-
(triphenylsilyloxy)heptan-3-one (58b). The mixture of aldol adducts
57b and 58b (74%, 0.116 g, 0.22 mmol) was obtained as a pale yellow
oil (67:33 diastereoselectivity) after purification by flash column
chromatography (silica gel 200−400 mesh) using a mixture of hexane/
dichloromethane/ethyl acetate (50:40:10) as the eluent. Rf 0.40
(2SR,6RS)-2-(tert-Butyldimethylsilyloxy)-6-hydroxy-7,7-dimethyl-
1,1,1-triphenyloctan-4-one (68c). The aldol adduct 68c (98%, 57 mg,
0.11 mmol) was obtained as a white solid (>95:05 diastereoselectivity)
after purification by flash column chromatography (silica gel 200−400
mesh) using a mixture of hexane/ethyl acetate (80:20) as the eluent. Rf
0.73 (20% EtOAc in hexane). Mp 181−184 °C. IR (neat) 3589, 3090,
3059, 3032, 3018, 2951, 2932, 2903, 2857, 1709, 1597, 1582, 1495,
1470, 1447, 1398, 1366, 1304, 1265, 1252, 1186, 1113, 1088, 1036,
1
1007, 955, 918, 835, 777, 739, 702, 631 cm−1. H NMR (500 MHz;
1
C6D6) δ 0.04 (s, 3H); 0.08 (s, 3H); 0.74 (s, 9H); 0.76 (s, 9H); 1.99
(dd, J = 9.5 and 17.8 Hz, 1H); 2.05 (dd, J = 3.0 and 17.8 Hz, 1H); 2.12
(dd, J = 6.8 and 19.1 Hz, 1H); 2.88 (d, J = 19.1 Hz, 1H); 3.08 (d, J =
3.0 Hz, 1H); 3.66 (dt, J = 3.0 and 9.5 Hz, 1H); 6.38 (d, J = 6.8 Hz,
1H); 6.94 (br s, 3H); 7.08 (br s, 6H); 7.50 (br s, 6H). 13C NMR (62.5
MHz; C6D6) δ −5.3; −4.0; 18.4; 25.6; 26.0; 34.1; 45.2; 51.6; 62.4;
70.7; 74.5; 126.3; 129.4; 132.2; 147.1; 211.0. HRMS (ESI TOF-MS):
calcd for C34H46O3SiNa 553.3114; found 553.3110.
(hexane/CH2Cl2/EtOAc 50:40:10). H NMR (250 MHz, C6D6) δ
0.82 (t, J = 7.4 Hz, 3H); 1.08−1.32 (m, 2H); (1.97 (dd, J = 2.8 and
17.2 Hz, 1H)); 1.99−2.25 (m, 3H); 2.35−2.40 (m, 1H); 2.70 (dd, J =
7.4 and 16.3 Hz, 1H); (2.72 (dd, J = 7.1 and 16.3 Hz, 1H)); 3.62−3.77
(m, 1H); 5.40−5.50 (m, 1H); 6.89 (d, J = 8.7 Hz, 2H); (6.91 (d, J =
8.4 Hz, 2H)); 7.09−7.23 (m, 9H); 7.58−7.67 (m, 6H); 7.73 (d, J =
8.7 Hz, 2H); (7.74 (d, J = 8.4 Hz, 2H)). 13C NMR (125 MHz, C6D6) δ
(9.9); 9.9; (29.7); 29.7; (50.1); 50.4; 53.3; 68.6; (68.7); (71.4); 71.6;
123.5; 127.0; (127.1); 127.9; 128.2; 128.3; 128.5; 130.5; (130.5);
(134.0); 134.0; 135.8; 147.6; 150.4 (150.4); (207.5); 207.7. HRMS (ESI
TOF-MS): calcd for C31H32NO5Si 526.2050; found 526.2037.
(2SR,6RS)-2-(tert-Butyldimethylsilyloxy)-6-hydroxy-7-methyl-
1,1,1-triphenyloct-7-en-4-one (68d). The aldol adduct 68d (94%,
53 mg, 0.10 mmol) was obtained as a white solid (>95:05 di-
astereoselectivity) after purification by flash column chromatography
(silica gel 200−400 mesh) using a mixture of hexane/ethyl acetate
(80:20) as the eluent. Rf 0.48 (20% EtOAc in hexane). Mp 65−67 °C.
IR (neat) 3501, 3090, 3057, 3034, 3020, 2953, 2928, 2897, 2856, 1707,
1653, 1597, 1495, 1472, 1447, 1394, 1362, 1265, 1105, 1036, 1003,
(1SR,5SR)-1-Hydroxy-5-(4-nitrophenyl)-1-phenyl-5-
(triphenylsilyloxy)pentan-3-one (57e) and (1RS,5SR)-1-Hydroxy-5-
(4-nitrophenyl)-1-phenyl-5-(triphenylsilyloxy)pentan-3-one (58e).
The mixture of aldol adducts 57e and 58e (78%, 0.141 g, 0.24 mmol)
was obtained as a pale yellow oil (54:46 diastereoselectivity) after puri-
fication by flash column chromatography (silica gel 200−400 mesh)
using a mixture of hexane/dichloromethane/ethyl acetate (50:40:10)
1
951, 906, 837, 775, 741, 704, 631 cm−1. H NMR (500 MHz; C6D6)
δ 0.06 (s, 3H); 0.07 (s, 3H); 0.75 (s, 9H); 1.49 (s, 3H); 1.94 (dd, J =
2.9 and 17.4 Hz, 1H); 2.04 (dd, J = 6.4 and 19.2 Hz, 1H); 2.06 (dd, J =
9.4 and 17.4 Hz, 1H); 2.65 (d, J = 2.9 Hz, 1H); 2.82 (d, J = 19.2 Hz,
1H); 4.38 (d, J = 9.4 Hz, 1H); 4.71−4.72 (m, 1H); 4.88−4.89 (m,
1H); 6.36 (d, J = 6.4 Hz, 1H); 6.93 (br s, 3H); 7.07 (br s, 6H); 7.51
(br s, 6H). 13C NMR (62.5 MHz; C6D6) δ −5.2; −4.0; 18.1; 18.4;
26.0; 48.6; 51.7; 62.5; 70.4; 71.1; 110.9; 126.3; 129.5; 132.5; 146.2;
146.9; 209.3. HRMS (ESI TOF-MS): calcd for C33H43O3Si 515.2982;
found 515.2953.
(1RS,5SR)-5-(tert-Butyldimethylsilyloxy)-1-hydroxy-1,6,6,6-tetra-
phenylhexan-3-one (68e) and (1SR,5SR)-5-(tert-Butyldimethylsily-
loxy)-1-hydroxy-1,6,6,6-tetraphenylhexan-3-one (69e). The mixture
of aldol adducts 68e and 69e (89%, 54 mg, 0.10 mmol) was obtained
as a white solid (91:09 diastereoselectivity) after purification by flash
column chromatography (silica gel 200−400 mesh) using a mixture of
hexane/ethyl acetate (80:20) as the eluent. Rf 0.50 (20% EtOAc in
hexane). Mp 87−89 °C. IR (neat) 3499, 3090, 3057, 3034, 2955,
2930, 2897, 2856, 1707, 1597, 1495, 1472, 1448, 1391, 1362, 1265,
1
as the eluent. Rf 0.60 (hexane/CH2Cl2/EtOAc 50:40:10). H NMR
(250 MHz, C6D6) δ 2.12−2.55 (m, 3H); 2.60−2.80 (m, 2H); 4.87−
4.97 (m, 1H); 5.39−5.49 (m, 1H); 6.85 (d, J = 8.7 Hz, 2H); (6.87
(d, J = 8.7 Hz, 2H)); 7.03−7.33 (m, 9H); 7.56−7.68 (m, 6H); 7.71 (d,
J = 8.7 Hz, 2H). 13C NMR (125 MHz, C6D6) δ 30.0; (30.2); (52.7);
52.8; (53.3); 53.3; 69.7; (69.8); (71.4); 71.5; 123.5; 125.8; (125.9);
127.0; (127.1); 128.2; (128.5); 128.6; 130.5; (133.9); 134.0; 135.8;
(143.6); 143.7; 147.5; 150.3; (206.7); 207.0. HRMS (ESI TOF-MS):
calcd for C35H30NO4Si 556.1944; found 556.1977.
(2SR,6RS)-2-(tert-Butyldimethylsilyloxy)-6-hydroxy-7-methyl-
1,1,1-triphenyloctan-4-one (68a). The aldol adduct 68a (95%,
54 mg, 0.10 mmol) was obtained as a white solid (>95:05
diastereoselectivity) after purification by flash column chromatography
(silica gel 200−400 mesh) using a mixture of hexane/ethyl acetate
(80:20) as the eluent. Rf 0.68 (20% EtOAc in hexane). Mp 89−91 °C.
IR (neat) 3556, 3090, 3057, 3036, 3020, 2959, 2930, 2895, 2856, 1705,
1597, 1495, 1472, 1447, 1389, 1362, 1265, 1099, 1036, 1003, 957, 910,
1785
dx.doi.org/10.1021/jo2023119 | J. Org. Chem. 2012, 77, 1765−1788

The Journal of Organic Chemistry
Article
1
1103, 1036, 953, 837, 775, 741, 704, 633 cm−1. H NMR (500 MHz;
C6D6) δ (0.05 (s, 3H)); 0.06 (s, 3H); (0.06 (s, 3H)); 0.07 (s, 3H);
(0.75 (s, 9H)); 0.76 (s, 9H); 1.91−2.01 (m, 2H); 2.16 (dd, J = 9.2 and
17.8 Hz, 1H); 2.72 (d, J = 19.0 Hz, 1H); (2.72 (d, J = 19.0 Hz, 1H));
(2.91 (d, J = 2.5 Hz, 1H)); 3.00 (d, J = 2.5 Hz, 1H); 4.96 (dt, J = 2.5
and 9.2 Hz, 1H); (5.04−5.06 (m, 1H)); 6.34 (d, J = 6.4 Hz, 1H);
6.95−7.52 (m, 20H). 13C NMR (62.5 MHz; C6D6) δ −5.3; (−4.2);
−4.0; 18.4; 26.0; 51.5; (51.9); 52.1; (62.3); 62.4; 69.8; (69.9); 70.3;
(70.5); (126.0); 126.1; 126.2; 127.5; 128.5; 129.4; 132.7; 143.5;
(143.7); 147.0; 209.3. HRMS (ESI TOF-MS): calcd for C36H43O3Si
551.2982; found 551.3027.
NaHCO3, filtered, and concentrated under reduced pressure to give
26 mg (99%) of diols 59 and 60 as a yellow solid. Rf 0.38 (20% EtOAc
in hexane). (1SR,5SR)-1,5-Dihydroxy-6-methyl-1-(4-nitrophenyl)-
heptan-3-one (59): 1H NMR (500 MHz; C6D6) δ 0.78 (d, J =
6.8 Hz, 3H); 0.83 (d, J = 6.8 Hz, 3H); 1.34−1.54 (m, 1H); 1.97 (dd,
J = 2.5 and 16.4 Hz, 1H); 2.10 (dd, J = 3.0 and 17.1 Hz, 1H); 2.21 (dd,
J = 9.8 and 16.4 Hz, 1H); 2.28 (dd, J = 9.6 and 17.1 Hz, 1H); 2.59
(br s, 1H); 3.41 (br s, 1H); 3.63−3.75 (m, 1H); 4.90 (dd, J = 3.0 and
9.6 Hz, 1H); 6.99 (d, J = 8.5 Hz, 2H); 7.90 (d, J = 8.5 Hz, 2H).
(1SR,5RS)-1,5-Dihydroxy-6-methyl-1-(4-nitrophenyl)heptan-3-one
(60): 1H NMR (500 MHz; C6D6) δ 0.79 (d, J = 6.8 Hz, 3H); 0.84 (d,
J = 6.8 Hz, 3H); 1.34−1.54 (m, 1H); 1.99 (dd, J = 2.4 and 16.6 Hz,
1H); 2.09 (dd, J = 2.9 and 17.2 Hz, 1H); 2.17 (dd, J = 9.3 and 16.6 Hz,
1H); 2.39 (dd, J = 9.6 and 17.2 Hz, 1H); 2.59 (br s, 1H); 3.41 (br s,
1H); 3.63−3.75 (m, 1H); 4.84−4.94 (m, 1H); 7.01 (d, J = 8.5 Hz,
2H); 7.90 (d, J = 8.5 Hz, 2H).
(1RS,5SR)-5-(tert-Butyldimethylsilyloxy)-1-hydroxy-1-(4-nitro-
phenyl)-6,6,6-triphenylhexan-3-one (68f). The aldol adduct 68f
(84%, 55 mg, 0.09 mmol) was obtained as a white solid (>95:05
diastereoselectivity) after purification by flash column chromatography
(silica gel 200−400 mesh) using a mixture of hexane/ethyl acetate
(80:20) as the eluent. Rf 0.17 (20% EtOAc in hexane). Mp 174−177 °C.
IR (neat) 3472, 3055, 2986, 2957, 2930, 2897, 2854, 1707, 1599, 1522,
1495, 1447, 1389, 1348, 1265, 1194, 1165, 1097, 1038, 987, 951, 897,
852, 837, 741, 706 cm−1. 1H NMR (400 MHz; CDCl3) δ −0.11 (s, 3H);
−0.03 (s, 3H); 0.61 (s, 9H); 1.98 (dd, J = 6.9 and 19.4 Hz, 1H); 2.60
(dd, J = 9.2 and 18.1 Hz, 1H); 2.70 (dd, J = 2.9 and 18.1 Hz, 1H); 2.80
(d, J = 19.4 Hz, 1H); 3.68 (d, J = 2.9 Hz, 1H); 5.28 (d, J = 9.2 Hz, 1H);
6.11 (d, J = 6.9 Hz, 1H); 7.00−7.46 (m, 15H); 7.50 (d,
J = 8.8 Hz, 1H); 8.18 (d, J = 8.8 Hz, 1H). 13C NMR (100 MHz;
CDCl3) δ −5.6; −4.3; 18.1; 25.6; 51.3; 51.4; 61.9; 68.9; 69.7; 123.7
126.0; 126.4; 127.8; 128.9; 146.4; 147.3; 149.7; 209.2. HRMS (ESI
TOF-MS): calcd for C36H41NO5SiNa 618.2652; found 618.2668.
(1RS,5SR)-5-(tert-Butyldimethylsilyloxy)-1-hydroxy-1-(4-methoxy-
phenyl)-6,6,6-triphenylhexan-3-one (68g) and (1SR,5SR)-5-
(tert-Butyldimethylsilyloxy)-1-hydroxy-1-(4-methoxyphenyl)-6,6,6-
triphenylhexan-3-one (69g). The mixture of aldol adducts 68g and
69g (78%, 50 mg, 0.09 mmol) was obtained as a yellow oil (91:09
diastereoselectivity) after purification by flash column chromatography
(silica gel 200−400 mesh) using a mixture of hexane/ethyl acetate
(80:20) as the eluent. Rf 0.43 (20% EtOAc in hexane). IR (neat) 3483,
3090, 3057, 3034, 3020, 2955, 2928, 2901, 2854, 1707, 1612, 1514,
1495, 1472, 1464, 1447, 1396, 1304, 1250, 1175, 1101, 1036, 953, 835,
775, 739, 704, 633 cm−1. 1H NMR (500 MHz; C6D6) δ (0.06 (s, 3H));
0.07 (s, 3H); 0.08 (s, 3H); (0.74 (s, 9H)); 0.76 (s, 9H); 1.98 (dd, J =
6.8 and 19.3 Hz, 1H); 2.06 (dd, J = 3.4 and 17.2 Hz, 1H); 2.25 (dd, J =
9.2 and 17.2 Hz, 1H); 2.71 (d, J = 19.3 Hz, 1H); (2.76 (d, J = 19.3 Hz,
1H)); 2.89 (br s, 1H); 3.33 (s, 3H); (3.34 (s, 3H)); 4.96 (dd, J = 3.4
and 9.2 Hz, 1H); (5.05 (dd, J = 1.5 and 8.8 Hz, 1H)); 6.34 (d, J =
6.8 Hz, 1H); 6.76 (dt, J = 2.2 and 8.8 Hz, 1H); 6.93 (br s, 3H); 7.06
(dt, J = 2.2 and 8,8 Hz, 1H); 7.19 (br s, 6H); 7.51 (br s, 6H). 13C
NMR (62.5 MHz; C6D6) δ −5.2; (−4.1); −4.0; 18.4; 26.0; 51.6;
(52.1); (52.1); 52.3; 54.8; (62.3); 62.4; 69.6; (69.7); 70.3; (70.5);
113.9; 126.2; (127.2); 127.4; 129.4; 132.7; 135.7; (135.8); 147.1;
159.5; 209.2 (209.3). HRMS (ESI TOF-MS): calcd for C37H43O3Si
563.2982; found 563.2946.
Stereochemistry proofs. (3R,7S)-3,7-Dihydroxy-2,2,8,8-tetra-
methylnonan-5-one (35) and (3R,7R)-3,7-Dihydroxy-2,2,8,8-tetra-
methylnonan-5-one (36). Aldol adducts 53c and 54c (12 mg, 0.02
mmol) were dissolved in 1.0 mL of acetonitrile at 0 °C. To the
resulting solution were added four drops of aqueous 48% HF solution.
The mixture was stirred for 5 min at 0 °C, then for 1.5 h at room
temperature. The reaction was quenched by the addition of solid
NaHCO3, filtered, and concentrated under reduced pressure to give
6 mg (100%) of 35 and 36 as a yellow solid. Rf 0.38 (20% EtOAc
in hexane). 1H NMR (250 MHz; C6D6) δ (0.86 (s, 18H)); 0.87
(s, 18H); 2.10−2.19 (m, 2H); 2.23−2.35 (m, 2H); (2.90 (br s, 2H));
3.09 (br s, 2H); 3.67−3.73 (m, 2H). 13C NMR (62.5 MHz; C6D6)
δ 25.8; (34.3); 34.4; (45.4); 45.7; (74.9); 75.2; (213.1); 213.5.
(1SR,5SR)-1,5-Dihydroxy-6-methyl-1-(4-nitrophenyl)heptan-3-
one (59) and (1SR,5RS)-1,5-Dihydroxy-6-methyl-1-(4-nitrophenyl)-
heptan-3-one (60). The inseparable aldol adduct 61a and 62a (50 mg,
0.093 mmol) was dissolved in MeCN/CH2Cl2 1:1 (4.0 mL) at 0 °C.
Four drops of aqueous 48% HF solution were added to the resulting
solution. The mixture was stirred for 5 min at 0 °C, then for 3 h at
room temperature. The reaction was quenched by the addition of solid
(2SR,4SR,6SR)-2-(tert-Butyldimethylsilyloxy)-1,1,1-triphenyloc-
tane-4,6-diol (70). To a solution of aldol adduct 68b (100 mg,
0.20 mmol) in THF/MeOH 4:1 (1.0 mL) at −60 °C was added
Et2BOMe (0.10 mL, 0.72 mmol) dropwise, and the resulting solution
was stirred for 15 min. A solution of LiBH4 (0.36 mL, 0.72 mmol,
2.0 M in THF) was added dropwise, and the resulting solution was
stirred for 2 h at −60 °C. The mixture was allowed to warm to −40 °C,
and the reaction was then quenched by the addition of pH 7.0 aqueous
phosphate buffer solution (8 mL). Then, MeOH (15 mL) and H2O2
30% (6 mL) were added dropwise at 0 °C. The resulting mixture was
stirred for 1 h at 0 °C, after which MeOH was removed by reduced
pressure. The solution was diluted with H2O (10 mL), the phases
were separated, and the aqueous phase was extracted with EtOAc
(4 × 30 mL). The organic phase was washed with water (2 × 25 mL)
and brine (2 × 25 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (silica gel 200−400 mesh) using a mixture of hexane/
ethyl acetate (80:20) as the eluent, which provided 84 mg (84%,
dr > 95:05) of 70 as a colorless oil. Rf 0.36 (20% EtOAc in hexane).
IR (neat) 3387, 3090, 3057, 3034, 3020, 2959, 2930, 2856, 1597, 1495,
1472, 1464, 1447, 1265, 1136, 1103, 1036, 1003, 945, 905, 835, 775,
1
741, 706 cm−1. H NMR (250 MHz; C6D6) δ −0.08 (s, 3H); 0.25
(s, 3H); 0.81 (t, J = 7.6 Hz, 3H); 0.85 (s, 9H); 1.23−1.53 (m, 5H);
2.07 (ddd, J = 2.8; 6.6 and 14.7 Hz, 1H); 2.51 (br s, 1H); 3.04 (br s,
1H); 3.47−3.55 (m, 1H); 3.87−3.95 (m, 1H); 5.56 (dd, J = 2.8 and
5.7 Hz, 2H); 7.01 (t, J = 7.5 Hz, 3H); 7.13 (t, J = 7.5 Hz, 6H); 7.54
(d, J = 7.5 Hz, 6H). 13C NMR (62.5 MHz; C6D6) δ −4.3; −3.5; 9.7;
18.8; 26.4; 31.3; 42.9; 45.6; 64.0; 71.2; 74.1; 74.4; 126.2; 127.7; 130.9;
145.9. HRMS (ESI TOF-MS): calcd for C32H44O3SiNa: 527.2957;
found 527.2989.
tert-Butyl((SR)-3-((4SR,6SR)-6-ethyl-2,2-dimethyl-1,3-dioxan-4-
yl)-1,1,1-triphenylpropan-2-yloxy)dimethylsilane (71). PPTS was
added in catalytic amounts at room temperature to a solution of
diol 70 (19 mg, 0.04 mmol) in 2,2-dimethoxypropane (1.0 mL). The
reaction mixture was stirred for 2 h and quenched by the addition of
solid NaHCO3, filtered, and concentrated under reduced pressure to
give 20 mg (95%) of 71 as a yellow oil. Rf 0.79 (20% EtOAc in
hexane). IR (neat) 3090, 3057, 3034, 2993, 2961, 2935, 2856, 1597,
1493, 1464, 1448, 1381, 1265, 1202, 1169, 1146, 1107, 1034, 1003,
1
959, 835, 775, 744, 706 cm−1. H NMR (250 MHz; C6D6) δ −0.03
(s, 3H); 0.24 (s, 3H); 0.84 (s, 9H); 0.92 (t, J = 7.4 Hz, 3H); 1.06−1.66
(m, 5H); 1.30 (s, 3H); 1.51 (s, 3H); 2.21 (ddd, J = 3.6; 6.5 and
15.0 Hz, 1H); 3.48−3.58 (m, 1H); 3.62−3.73 (m, 1H); 5.47 (t, J =
4.5 Hz, 1H); 7.00 (t, J = 7.4 Hz, 3H); 7.11 (t, J = 7.4 Hz, 6H); 7.52
(d, J = 7.4 Hz, 6H). 13C NMR (62.5 MHz; C6D6) δ −4.5; −3.5; 9.6;
18.7; 20.2; 26.3; 29.7; 30.5; 37.5; 44.2; 64.0; 68.0; 70.3; 73.3; 98.6;
126.2; 127.7; 131.1; 145.6. HRMS (EI TOF-MS): calcd for C34H45O3Si
[M − CH3]+ 529.3138; found 529.3130.
(2SR,4SR,6SR)-1,1,1-Triphenyloctane-2,4,6-triol (72). Four drops
of aqueous 48% HF solution were added at 0 °C to a solution of diol
70 (20 mg, 0.04 mmol) in acetonitrile (0.5 mL). The mixture was
stirred for 5 min at 0 °C for 2 days at room temperature and quenched
by the addition of solid NaHCO3. The solution was then filtered and
concentrated under reduced pressure to give 16 mg (100%) of 72 as a
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The Journal of Organic Chemistry
Article
colorless oil. Rf 0.36 (20% EtOAc in hexane). IR (neat) 3429, 3088,
3057, 2962, 2928, 2876, 2854, 1597, 1495, 1447, 1441, 1265, 1134,
1097, 1036, 845, 739, 702 cm−1. 1H NMR (250 MHz; CD3OD) δ 0.92
(t, J = 7.4 Hz, 3H); 1.36−1.71 (m, 5H); 1.86 (dd, J = 4.7 and 14.4 Hz, 1H);
3.59−3.69 (m, 1H); 4.10−4.20 (m, 1H); 5.50 (d, J = 9.6 Hz, 1H);
7.14 (t, J = 7.0 Hz, 3H); 7.23 (t, J = 7.0 Hz, 6H); 7.33 (d, J =
7.0 Hz, 6H). 13C NMR (62.5 MHz; CD3OD) δ 10.1; 31.2; 42.1; 44.4;
63.3; 71.8; 72.9; 73.6; 127.0; 128.6; 131.3; 146.6. HRMS (ESI TOF-MS):
calcd for C26H30O3Na 413.2093; found 413.2098.
a mixture of diols 73 and 70 (24 mg, 0.05 mmol) in acetonitrile
(1.2 mL). The mixture was stirred for 5 min at 0 °C for 4 days at room
temperature, quenched by the addition of solid NaHCO3, filtered, and
concentrated under reduced pressure to give 21 mg (100%) of 75 and
72 as a colorless oil. Rf 0.36 (20% EtOAc in hexane). IR (neat) 3425,
3088, 3057, 2962, 2930, 1597, 1495, 1447, 1265, 1134, 1095, 1036,
1
895, 845, 739, 704 cm−1. H NMR (400 MHz; CD3OD) δ 0.89−2.29
(m, 9H); 3.61−3.71 (m, 1H); 4.06−4.18 (m, 1H); 5.50 (d, J = 9.6 Hz,
1H); (5.65 (d, J = 10.0 Hz, 1H)); 7.13−7.16 (m, 3H); 7.21−7.24 (m,
6H); 7.32−7.37 (m, 6H). 13C NMR (100 MHz; CD3OD) δ 10.1;
(10.3); 31.2; (31.7); 42.1; (43.7); 44.4; (45.6); (63.1); 63.3; (66.7);
(70.8); (70.8); 71.7; 72.9; 73.6; (126.8); 126.9; 128.5; 131.2; 146.6.
HRMS (ESI TOF-MS): calcd for C26H31O3 391.2273; found
391.2256.
(2SR,4RS,6SR)-2-(tert-Butyldimethylsilyloxy)-1,1,1-triphenyloc-
tane-4,6-diol (73) and (2SR,4SR,6SR)-2-(tert-Butyldimethylsilyloxy)-
1,1,1-triphenyloctane-4,6-diol (70). Acetic acid (0.6 mL) was added
to a stirring suspension of Me4NHB(OAc)3 (422 mg, 1.6 mmol) in
THF (0.6 mL) at room temperature. The resulting mixture was stirred
for 30 min and was cooled to −40 °C. The aldol adduct 68b (100 mg,
0.20 mmol) in THF (0.6 mL) was added via cannula. Then, a solution
of CSA (23 mg, 0.10 mmol) in acetic acid/THF 1:1 (1.2 mL) was
added, and the mixture was stirred for 3 days at −22 °C. The reaction
was quenched by the addition of a saturated aqueous solution of
NaHCO3 (15 mL) followed by the addition of a potassium tartrate
aqueous solution (15 mL) and Et2O (50 mL). The mixture was stirred
vigorously at room temperature for 8 h. The phases were separated,
and the aqueous phase was extracted with Et2O (4 × 20 mL). The
organic phase was washed with brine (2 × 25 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica gel 200−400 mesh)
using a mixture of hexane/ethyl acetate (80:20) as the eluent, which
provided 53 mg of 73 and 70 (50%, dr = 35:65, 73:70) as a colorless
oil. Rf 0.36 (20% EtOAc in hexane). IR (neat) 3393, 3090, 3057, 3034,
3020, 2959, 2930, 2856, 1597, 1495, 1472, 1462, 1447, 1256, 1101,
1036, 1003, 947, 833, 773, 743, 704 cm−1. 1H NMR (250 MHz; C6D6)
δ (−0.29 (s, 3H)); −0.08 (s, 3H); 0.25 (s, 3H); (0.32 (s, 3H)); (0.62
(t, J = 7.3 Hz, 3H)); 0.81 (t, J = 7.6 Hz, 3H); 0.85 (s, 9H); (0.88 (s,
9H)); 0.99−1.58 (m, 5H); 2.07 (ddd, J = 2.8; 6.6 and 14.7 Hz, 1H);
(2.19−2.29 (m, 1H)); (3.34−3.43 (m, 1H)); 3.47−3.55 (m, 1H);
3.85−3.96 (m, 1H); (4.35 (t, J = 9.1 Hz, 1H)); 5.56 (dd, J = 2.8 and
5.7 Hz, 2H); (6.07 (d, J = 8.5 Hz, 1H)); 7.01 (t, J = 7.5 Hz, 3H); 7.13
(t, J = 7.5 Hz, 6H); 7.52 (d, J = 7.5 Hz, 6H) (7.72 (d, J = 6.8 Hz, 6H)).
13C NMR (62.5 MHz; C6D6) δ (−4.4); −4.3; (−4.3); −3.5; 9.7;
ASSOCIATED CONTENT
* Supporting Information
■
S
1H NMR, 13C NMR, IR, and HRMS spectra for the prepared
compounds and Cartesian coordinates of transition structures
with gas-phase and solution-phase SCF absolute energies. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ldias@iqm.unicamp.br.
■
ACKNOWLEDGMENTS
■
We are grateful to FAEP-UNICAMP, FAPESP, CNPq and
INCT-INOFAR (Proc. CNPq 573.564/2008-6) for financial
support and to Prof. Carol H. Collins (IQ-UNICAMP) for
helpful suggestions about English grammar and style.
REFERENCES
■
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(s, 3H)); 2.16−2.24 (m, 1H); 3.48−3.56 (m, 1H); 3.64−3.71 (m,
1H); (4.20−4.27 (m, 1H)); 5.48 (dd, J = 4.0 and 5.0 Hz, 1H); (5.74
(d, J = 8.0 Hz, 1H)); 7.01 (t, J = 7.4 Hz, 3H); 7.11 (t, J = 7.4 Hz, 6H);
7.53 (d, J = 7.4 Hz, 6H) (7.67 (br s, 6H)). 13C NMR (100 MHz;
C6D6) δ (−4.7); −4.5; (−4.3); −3.5; 9.6; (9.8), 18.7; (19.0); 20.1;
(25.7); (26.2); 26.3; (26.6); (29.1); 29.7; 30.5; 37.5; (38.1); 44.2;
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(99.9); (125.8); 126.2; 127.9; 131.1; 145.5. HRMS (EI TOF-MS):
calcd for C34H45O3Si [M − CH3]+ 529.3138; found 529.3147.
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