Highly stereoselective titanium-mediated aldol reaction from (S)-4-benzyloxy-3-methyl-2-butanone

Article abstract of DOI:10.1021/jo201021z

Substrate-controlled titanium-mediated aldol reactions from (S)-4-benzyloxy-3-methyl-2-butanone provide satisfactory levels of 2,5-syn asymmetric induction if they are carried out in the presence of a second equivalent of TiCl₄. Such reactions

Full text of DOI:10.1021/jo201021z

FEATURED ARTICLE
pubs.acs.org/joc
Highly Stereoselective Titanium-Mediated Aldol Reaction
from (S)-4-Benzyloxy-3-methyl-2-butanone†
Joana Zambrana, Pedro Romea,* Fꢀelix Urpí,* and Cristina Lujꢁan
Departament de Química Orgꢀanica, Universitat de Barcelona, Carrer Martí i Franquꢁes 1-11, 08028 Barcelona, Catalonia, Spain
S Supporting Information
b
ABSTRACT: Substrate-controlled titanium-mediated aldol re-
actions from (S)-4-benzyloxy-3-methyl-2-butanone provide sa-
tisfactory levels of 2,5-syn asymmetric induction if they are
carried out in the presence of a second equivalent of TiCl4. Such
reactions give high yields and excellent diastereoselectivity with
a wide array of achiral and chiral aldehydes without needing
other sources of chirality. This procedure is thus of interest for the synthesis of natural products. Furthermore, spectroscopic studies
and analyses of the reacting species have revealed a possible mechanism to account for the experimental results.
Scheme 1. Acetate and Propionate Aldol Reactions
’ INTRODUCTION
Since pioneering studies in the 1970s, recent decades have
witnessed the development of a large number of highly stereo-
selective aldol methodologies.1 These have been used to synthe-
size structurally complex natural products, which have placed
aldol reactions among the most important carbonꢀcarbon bond-
forming processes.2 In spite of these accomplishments, some
issues are still a matter of concern. One of them is the acetate
aldol reaction.3,4 Indeed, early reports by Evans5 and Masamune6
showed that the stereochemical control on the acetate aldol
reaction was much more challenging than that on the apparently
similar propionate counterpart (Scheme 1). This difference in
behavior is due to the close energy of alternative transition state
geometries for acetate aldol reactions, which hampers the
differentiation of the two faces of the π CdO bond by the
unsubstituted enolate.7
Scheme 2. Titanium-Mediated Aldol Reactions from Pro-
tected (S)-4-Hydroxy-3-methyl-2-butanone
This challenge is usually countered by the use Mukaiyama-
like8 and organocatalytic approaches.9 Unfortunately, some of
these methodologies can only be applied to a narrow set of
substrates, and for this reason, it has always been highly desirable
to develop parallel transformations from metal enolates. Hence,
it is not surprising that a large set of chiral auxiliaries,10 stoichio-
metric and catalytic Lewis acids,11,12 and catalytic Lewis bases13
have been reported. This is particularly significant for aldol
reactions of methyl ketones in the advanced steps of synthesis,
where constraints are imposed by the structure of the reaction
partners.14 Therefore, a better understanding of the stereoselec-
tivity imparted by chiral methyl ketones in substrate-controlled
aldol reactions becomes crucial.15 In this scenario, Paterson
established that high diastereoselectivity could be achieved in
boron-mediated aldol reactions with chiral ketones derived from
Roche ester. Notably, the ethyl ketones give excellent levels of
substrate-controlled 1,4-syn stereoinduction with cyclohexyl
ligands on boron, which are reduced for the corresponding
methyl ketone. In the latter case, chiral Ipc ligands on boron
are then used to enhance the 1,4-syn stereoinduction to equally
high levels.1b,15a,16 Looking for a different approach, we envisaged
that titanium(IV) Lewis acids might provide such levels of stereo-
control and offer an appealing alternative to chiral boron Lewis
acids. Our previous experience in related processes indicated that
the appropriate choice of the protecting group and the titanium
Lewis acid might afford highly diastereoselective aldol reactions
in a straightforward manner.17,18 Herein, we document our
studies on the titanium-mediated aldol reactions of protected
(S)-4-hydroxy-3-methyl-2-butanone (Scheme 2) with achiral
and chiral aldehydes, which give access to the corresponding
2,5-syn adducts in high yields and diastereoselectivity.
Received: May 20, 2011
Published: July 08, 2011
r
2011 American Chemical Society
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Table 1. Influence of the Hydroxyl Protecting Group and the Titanium(IV) Lewis Acid on the Aldol Reaction of Methyl Ketones 1
and 2
entry
ketone
PG
TiL4
TiL4 (equiv)
dr (syn/anti)a
yieldb (%)
1
2
3
4
5
6
7
8
1
1
1
2
2
2
2
2
TBDPS
TBDPS
TBDPS
Bn
TiCl3(i-PrO)
TiCl4
1
1
2
1
1
1
2
2
64:36
64:36
61:39
67:33
83:17
68:32
77:23
95:5
32
77
78
35
92
81
67
89
TiCl4
TiCl2(i-PrO)2
TiCl3(i-PrO)
TiCl4
Bn
Bn
Bn
TiCl3(i-PrO)
TiCl4
Bn
a Established by 1H NMR analysis. b Overall isolated yield.
Table 2. Influence of Lewis Acids on the Titanium-Mediated
’ RESULTS AND DISCUSSION
Aldol Reaction from 2
Preliminary Experiments. Since the titanium-mediated aldol
reactions from R- and β-hydroxy chiral ketones are sensitive to
the hydroxyl protecting group and the titanium(IV) Lewis acid
engaged in the enolization, we initially assessed the aldol addi-
tions of Roche ester-derived methyl ketones 1 and 2 possessing
different protecting groups (PG = TBDPS and Bn respectively,
see Table 1) to isobutyraldehyde (a) using several titanium Lewis
acids. The results are summarized in Table 1.
The aldol reactions from TBDPS-ketone 1 proceeded in a low
diastereomeric ratio irrespective of the titanium Lewis acid (see
entries 1 and 2 in Table 1). Taking into account that bulky silicon
protecting groups do not facilitate coordination to Lewis acids,
the low stereocontrol provided by 1 may be attributable to the
fact that the carbon substituents at the R-stereocenter are
sterically too similar (Me versus CH2OTBDPS) to permit
effective π-facial differentiation of the CdO bond at the transi-
tion state. Otherwise, the chelating ability of the β-benzyl ether
confirmed the strong influence of titanium Lewis acids on the
substrate-controlled aldol reactions of methyl ketone 2, being
particularly remarkable the diastereoselectivity achieved with
TiCl3(i-PrO) (compare entries 4ꢀ6 in Table 1). Taking
advantage of our experience with other benzyl-protected chiral
ketones, we also examined the effect of an excess of Lewis
acid on these reactions.19 Such conditions were inappropriate
for ketone 1 (see entry 3 in Table 1), but the use of two
equivalents of TiCl4 on ketone 2 provided 2,5-syn aldol 5a in
high yield and a high diastereomeric ratio (dr 95:5 and 89%
yield, see entry 8 in Table 1). Interestingly, two equivalents of
TiCl3(i-PrO) were less suitable and aldol 5a was isolated in a
lower yield and in a lower diastereomeric ratio (compare entries
5, 7, and 8 in Table 1).
entry
Lewis acid, LA
dr (syn/anti)a
yieldb (%)
1
2
3
4
5
6
TiCl4
95:5
89
TiCl3(i-PrO)
Ti(i-PrO)4
SnCl4
85:15
68:32
92:8
68 (6)
36 (5)
57 (18)
79
Et2AlCl
92:8
BF3 OEt2
62:38
91
3
aEstablished by 1H NMR analysis. b Overall isolated yield. Yield of
recovered methyl ketone 2 is shown in parentheses.
The stereochemical outcome of such an aldol reaction de-
pends on the second Lewis acid. Thus, the bias imparted by
titanium(IV) Lewis acids is enlightening: TiCl4 furnishes an
exceptional dr 95:5 (see entry 1 in Table 2) and the mildest Ti-
(i-PrO)4 gives values (dr 68:32 and 36% yield, see entry 3 in
Table 2) that are almost identical to those observed for TiCl2-
(i-PrO)2 (dr 67:33 and 35% yield, see entry 4 in Table 1), while
TiCl3(i-PrO) as a second Lewis acid affords better diastereos-
electivities (dr 85:15, see entry 2 in Table 2) than the process that
involves 1 or 2 equiv of TiCl3(i-PrO) (dr 83:17 and 77:23, see
entries 5 and 7 in Table 1 respectively). On the other hand, SnCl4
and Et2AlCl gave poorer yields than TiCl4 but similar diastereos-
electivities (compare entries 1, 4, and 5 in Table 2), while
The data summarized in Table 1 show that the appropriate
choice of the protecting group and the enolization conditions of
chiral ketones derived from Roche ester secured highly stereo-
selective aldol transformations. In this context, the significant rise
in the diastereoselectivity of the titanium-mediated aldol addition
of ketone 2 to isobutyraldehyde due to the presence of a second
equivalent of TiCl4 led us to evaluate the influence of other Lewis
acids. The results are summarized in Table 2.
BF3 OEt2 seemed to have no influence and provided mixtures
3
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Table 3. Different Methods for the Titanium-Mediated Aldol
Addition of Ketone 2
entry
methoda
dr (syn/anti)b
yieldc (%)
Figure 1. Influence of the additional equivalents of TiCl4 on the yield
and diastereoselectivity of the aldol addition of 2 to isobutyraldehyde.
1
2
3
4
A
B
95:5
94:6
93:7
97:3
89
75
C
D
33 (52)
86
of both aldols in good yields but poor diastereomeric ratios (see
entry 6 in Table 2).
aMethod A: (i) TiCl4 (1 equiv), i-Pr2NEt (1.1 equiv), CH2Cl2, ꢀ78 °C,
30 min; (ii) TiCl4 (1 equiv), 10 min c) i-PrCHO (1.5 equiv), ꢀ78 °C,
30 min. Method B: (i) TiCl4 (2 equiv), i-Pr2NEt (1.1 equiv), CH2Cl2,
ꢀ78 °C, 30 min; (ii) i-PrCHO (1.5 equiv), ꢀ78 °C, 30 min. Method C:
(i) TiCl4 (1 equiv), i-Pr2NEt (1.1 equiv), CH2Cl2, ꢀ78 °C, 30 min;
(ii) TiCl4 (1.2 equiv)ꢀi-PrCHO (1.2 equiv), ꢀ78 °C, 30 min. Method
D: (i) TiCl4 (1 equiv), i-Pr2NEt (1.1 equiv), CH2Cl2, ꢀ78 °C, 30 min;
(ii) TiCl4 (1.2 equiv)ꢀi-PrCHO (1.2 equiv), ꢀ78 °C, 30 min (inverse
addition). b Established by HPLC analysis. c Overall isolated yield. The
yield of recovered methyl ketone 2 is shown in parentheses.
The enhanced diastereoselectivity observed in entry 1 of Table 2
raised the question of the amount of extra Lewis acid required to
achieve such levels of stereocontrol, so the influence of TiCl4
equivalents on the diastereoselectivity and yield of this transfor-
mation was next investigated. As shown in Figure 1, addition of
increasing amounts of TiCl4 to the reaction mixture did not
significantly affect the yield (81ꢀ90%), but the diastereoselec-
tivity was steadily improved from dr 68:32 to 95:5. Interestingly,
the diastereoselectivity did not change but the yield dropped
when more than 1 equiv of TiCl4 was added (Figure 1). These
results indicate that the additional 1 equiv of TiCl4 is necessary
for highly stereocontrolled aldol additions, which points to a
dramatic change in the structure of the reacting species and the
transition state involved in transformations of this sort.
Optimization. Once the ketone and the appropriate titanium-
(IV) Lewis acid required to achieve highly stereocontrolled aldol
reactions had been ascertained, we examined some experimental
aspects of the process. Initially, we focused on the way in which
the second equivalent of TiCl4 is added to the reaction mixture.
Thus, four protocols were evaluated. In method A, the enolization of
ketone 2 was carried out according to the procedure described in
the preliminary experiments, and the second equivalent of TiCl4
was then added, followed 10 min later by the aldehyde. In
method B, 2 equiv of TiCl4 were added simultaneously to ketone
2 at the beginning of the enolization, and the reaction was carried
out according to the general procedure. In method C, the aldehyde
was precomplexed with TiCl4, and this mixture was added to the
titanium enolate from 2. Finally, in method D the enolate from 2
was added to a mixture containing the isobutyraldehyde pre-
complexed with TiCl4 (inverse addition). The results summar-
ized in Table 3 show that high levels of stereocontrol can be
achieved irrespective of how the second equivalent of TiCl4 is
added to the reaction mixture. Importantly, the good results
given by method B (see entry 2 in Table 3) show that the
presence of a second equivalent of TiCl4 does not prevent a
proper enolization (no starting ketone was recovered), whereas
the high diastereoselectivities provided by methods C and D (see
entries 3 and 4 in Table 3) are more difficult to explain (see
further comments).20 The diastereoselectivity obtained in method
D was particularly outstanding (dr 97:3, see entry 4 in Table 3),
which illustrates how slight changes in the experimental procedure
can tune the diastereoselectivity. These findings prompted us to
study methods A and D in more detail in order to identify the key
features responsible for the greater stereocontrol.
We first examined method A. We assessed the influence of the
enolization and reaction times (tenol and treac respectively), as
well as the time elapsed (telap) from the addition of the second
equivalent of TiCl4 and the aldehyde, on the outcome of the aldol
reaction. The results (see Table 4) show that it is worth adding
the second equivalent of TiCl4 when the enolization is over and
then the aldehyde some minutes later. This procedure does not
affect the yield but increases the diastereoselectivity (compare
entries 1ꢀ3 in Table 4). We then examined the enolization and
the reaction times. These two variables seemed to have less
influence on the reaction, but the yield decreased when the
enolization time was reduced to 15 min (compare entries 4 and 5
in Table 4). Otherwise, the aldol addition to isobutyraldehyde
turned out to be very fast, and the same yield was obtained when
the reaction time was shortened to 15 min (compare entries 2
and 6 in Table 4). Finally, we also examined the use of fewer
equivalents of the aldehyde, observing a loss of yield when just
1.2 equiv of isobutyraldehyde were added to the reaction mixture
(compare entries 2 and 6 in Table 4).
In view of these results, we considered that the most appropriate
conditions would involve enolization for 30 min, followed by the
addition of a second equivalent of TiCl4, stirring the reaction
mixture for 10 min, addition of 1.5 equiv of aldehyde, and further
reaction for 30 min at ꢀ78 °C (see entry 2 of Table 4).
Moreover, these enolization and reaction times optimized
for method A were also deemed suitable for method D.
Therefore, we recognized that the best conditions for method
D would involve enolization for 30 min, followed by the
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Table 4. Optimization of the Titanium-Mediated Aldol Addition of 2 to Isobutyraldehyde (a)
entry
tenol (min)
telap (min)
treac (min)
i-PrCHO (equiv)
dr (syn/anti)a
yieldb (%)
1
2
3
4
5
6
30
30
30
15
30
30
0
10
20
10
10
10
30
30
30
15
15
30
1.5
1.5
1.5
1.5
1.5
1.2
90:10
95:5
95:5
95:5
94:6
95:5
94
89
91
83
89
68
a Established by HPLC analysis. b Overall isolated yield.
addition of the resulting solution to a mixture of 1.2 equiv
of TiCl4ꢀaldehyde complex and further reaction for 30 min
at ꢀ78 °C.
Having established that method A provided highly diastereo-
selective aldol additions of methyl ketone 2 to a broad range of
aldehydes (dr g90:10), we turned our attention to method D.
Although preliminary experiments with isobutyraldehyde had
shown that it furnished slightly better diastereoselectivities than
method A (compare entries 1 and 4 in Table 3), we were
concerned that the inverse addition required by the former could
jeopardize the generality of our approach. Thus, we decided to
test the scope of this methodology with the same aldehydes aꢀi.
The results of this study are summarized in Table 6.
These reactions show an improved diastereoselectivity. Re-
markably, aliphatic aldehydes aꢀc afforded excellent diastereo-
meric ratios, and even the sterically unhindered butanal delivered
2,5-syn aldol 5c in dr 96:4 and 88% yield (see entry 3 in Table 6).
Among the R,β-unsaturated aldehydes, reactions of methacro-
lein (d) and crotonaldehyde (e) were also successful and
provided the 2,5-syn aldols 5d and 5e, respectively, in high yields
and as a single diastereomer (dr 97:3, see entries 4 and 5 in
Table 6). Parallel additions to highly conjugated aldehydes such
as cinnamaldehyde (f) or aromatic aldehydes hꢀi also proceeded
in excellent diastereomeric ratios but in somewhat lower yields
(see entries 6ꢀ9 in Table 6). The reasons for these low yields are
still unclear, but they may be attributable to the formation of
Scope. The experimental procedures optimized for the tita-
nium-mediated aldol addition of ketone 2 to isobutyraldehyde
(a) were next applied to other achiral aliphatic, R,β-unsaturated
and aromatic aldehydes. The results summarized in Table 5
demonstrate the excellent stereocontrol achieved by this trans-
formation using method A. Remarkably, aliphatic aldehydes aꢀc
gave the corresponding 2,5-syn aldols 5aꢀc in high yields and
diastereomeric ratios depending on their steric hindrance. In-
deed, isobutyraldehyde furnished 5a almost as a single diaster-
eomer (dr 95:5) in 89% yield (see entry 1 in Table 5), while
n-butanal afforded 5c in a somewhat less stereoselective way (dr
90:10 and 78% yield, see entry 3 in Table 5). In turn, R,β-
unsaturated aldehydes as methacrolein, crotonaldehyde, or cin-
namaldehyde (dꢀf respectively) provided comparable results,
and 2,5-syn aldols 5dꢀf were obtained in 77ꢀ80% yield and
diastereomeric ratios ranging from 90:10 to 95:5 (compare
entries 4ꢀ6 in Table 5). Finally, aromatic aldehydes gꢀi afforded
2,5-syn aldols 5gꢀi in high yields and diastereomeric ratios
irrespective of the electronic character of the aldehyde (com-
pare entries 8ꢀ10 in Table 5).
Table 5. Titanium-Mediated Aldol Reactions of 2 (Method A)
entry
aldehyde
R
dr (syn/anti)a
yield (%)b
1
2
a
b
c
d
e
f
i-Pr
95:5
89
86
78
78
80
77
93
81
91
i-Bu
n-Pr
92:8
3
90:10
95:5
4
H2CdC(CH3)
(E) CH3CHdCH
(E) PhCHdCH
Ph
5
93:7
90:10c
6
7d
8d
9d
g
h
i
92:8
4-NO2Ph
94:6
4-MeOPh
90:10
a Established by HPLC analysis. b Overall isolated yield. c Established by 1H NMR analysis d 1.2 equiv of aldehyde were used.
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Table 6. Titanium-Mediated Aldol Reactions of 2 (Method D)
entry
aldehydea
R
yield of 7 (%)
dr (syn/anti)b
yield of 5c (%)
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
i-Pr
97:3
96:4
96:4
97:3
97:3
95:5d
97:3
96:4
91:9
86
86
i-Bu
n-Pr
88
H2CdC(CH3)
(E) CH3CHdCH
(E) PhCHdCH
Ph
<5
<5
22
21
34
<5
81
80
22 (43)
68
g
h
i
4-NO2Ph
60
4-MeOPh
35 (40)
a 1.2 equiv of aldehyde were used. b Established by HPLC analysis. c Overall isolated yield. The yield of recovered methyl ketone 2 is shown in
parentheses. d Established by 1H NMR analysis.
bond is not formed in the stereochemical-determining step.
From a synthetic point of view, these results bear out the high
levels of 2,5-syn asymmetric induction provided by the methyl
ketone 2 on the titanium-mediated acetate aldol reaction with a
broad array of achiral and chiral aldehydes in a simple and reliable
manner.
Stereochemistry. The syn asymmetric induction imparted by
ketone 2 was initially established by reduction of aldols 5a and 5g
to the corresponding diols 14a and 14g (Scheme 4). The relative
configuration of these diols was secured through conversion into
acetonides 15, which were studied by 1D and 2D NMR
Figure 2. Chiral aldehydes.
experiments.24 The configuration of the new stereocenter C3
was pivotal in our strategy, since it was connected with the
original C2 stereocenter to establish the absolute configuration
of aldols 5. Indeed, DDQ oxidation of diols 14 delivered
nonproductive aldehyde-Lewis acid complexes and the conver-
sion of the putative titanium aldolate to R,β-unsaturated ketone
7 (see entries 6ꢀ8 in Table 6).
benzylidene acetals 16 as a single diastereomer.
In spite of such failures, the scope of this procedure is not
Then, comprehensive analyses of diagnostic geminal (2J1ꢀ1
,
0
seriously affected, and we conclude that the titanium-mediated
acetate aldol reactions of ketone 2 and achiral aldehydes through
method A or D proceed in high yields and excellent diastereo-
meric ratios.
Double-Stereodifferentiating Reactions. Once the feasibil-
ity of the substrate-controlled aldol addition of ketone 2 to a wide
set of achiral aldehydes aꢀi had been demonstrated, we pro-
ceeded to test such reactions with protected chiral R- and
β-hydroxy aldehydes represented in Figure 2.21,22
Current models of double-stereodifferentiating reactions pre-
dict that one of the enantiomers should reinforce the stereo-
chemical bias imparted by the chiral ketone, while the other
would act in the opposite sense.23 Therefore, we expected the
former to deliver the 2,5-syn aldol as a single diastereomer and
the latter to reduce the stereocontrol. Surprisingly, the diaster-
eoselectivities observed for the four aldehydes shown in Figure 2
were similar.
Indeed, the double-stereodifferentiating titanium-mediated
aldol additions of ketone 2 gave high yields (77ꢀ90%) and
excellent diastereomeric ratios (from dr 92:8 to 94:6) of 2,5-syn
aldols 10ꢀ13 irrespective of the configuration of the chiral
aldehyde (Scheme 3). The lack of influence of chiral R- and
β-hydroxy aldehydes on the diastereoselectivity of such aldol
reactions hints at a mechanism in which the new carbonꢀcarbon
see Figure 3) and vicinal coupling constants (3J1ꢀ2 and 3J1 -2, see
0
1
Figure 3) on their H NMR spectra and key NOE experiments
madeclear the 2,5-syn configuration of aldols 5. Importantly, such
stereochemistry was later confirmed by comparison of spectro-
scopic features of aldol 5a with those reported in the literature.1b
Mechanistic Hypothesis. The experimental evidence pre-
sented so far demonstrates that the second Lewis acid plays a key
role in the stereochemical outcome of the titanium-mediated
aldol reaction from benzyl-protected methyl ketone 2. Indeed, it
wholly determines the diastereoselectivity.
From a mechanistic point of view, we first envisaged that the
titanium-mediated aldol reactions from 2 in the presence of a
second Lewis acid might proceed through an open transition
state. This assumption was inspired by Heathcock’s seminal
report on the preparation of syn- and anti-aldols by addition of
boron enolates from chiral N-propanoyl-1,3-oxazolidinones to
aldehydes in the presence of different Lewis acids.25 The
rationale for the observed diastereoselectivity relied on the steric
bulk of Lewis acids: small Lewis acids prefer transition state A
because it minimizes gauche interactions about the forming
bond, whereas transition state B becomes competitive for large
Lewis acids in order to avoid methylꢀLewis acid interactions
(Scheme 5).
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Scheme 3. Double-Stereodifferentiating Aldol Reactions
Scheme 4. Elucidation of the Configuration of Aldols 5
Scheme 5. Heathcock’s Proposal for Transition States in
Lewis Acid Mediated Propionate Aldol Reactions
Scheme 6. Hypothetical Open Transition States for the
Titanium-Mediated Acetate Aldol Reactions from 2
Figure 3. NMR diagnostic features of benzylidene acetals 16.
in the presence of a second equivalent of TiCl4 (Scheme 6).
Indeed, the lack of a methyl on the enolate should have produced
similar diastereoselectivities in Table 2 irrespective of the Lewis
However, this model does not account for the stereochemical
outcome of titanium-mediated aldol reactions from 2 carried out
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Figure 4. Titration of 2. 1H NMR spectra (250 MHz, CDCl3, ꢀ10 °C) of TiCl4ꢀ2 complex.
acid used because the same HꢀLA interactions appear in
transition states leading to syn or anti aldol adducts. Furthermore,
these open transition states fail to explain why chiral aldehydes
do not affect the stereochemical outcome of double-stereodiffer-
entiating reactions represented in Scheme 3.
is placed in a pseudoequatorial position. However, significant
changes were observed in the H NMR spectrum when the
1
titanium enolate was prepared with 2 equiv of TiCl4 or when the
second one was added to the titanium enolate. Indeed, the clear
1H NMR spectrum collapsed, and we only observed broad bands
which we could not easily explain. Thus, the enolate underwent a
change upon addition of a second Lewis acid, but it is still
unknown what sort of intermediate results from such interaction.
Trying to shed light on this issue, we carried out some aldol
reactions involving benzyl-protected R- and β-hydroxy alde-
hydes 17 and 18 (Scheme 7). These aldehydes are structurally
akin to 8 (and ent-8) and 9 (and ent-9) represented in Figure 2,
but the higher chelating ability of OBn group should alter the
structure of the reacting species and affect the stereochemical
outcome of the aldol reaction. This hypothesis was confirmed,
since the diastereoselectivity of the aldol reactions involving
these aldehydes was dramatically eroded to such an extent that
almost equimolecular mixtures of diastereomers were obtained
in high yields (Scheme 7).
Alternatively, other authors reporting on titanium-mediated
aldol reactions claim that the presence of a second equivalent of
TiCl4 modifies the structure of the titanium enolate. For
instance, Crimmins suggested that the second molecule of
TiCl4 acts as a chlorine scavenger from the hexacoordinated
titanium enolate of a N-propanoyl-1,3-oxazolidine-2-thione,26
while Ghosh assumed that it binds to other centers of the enolate
and changes the geometry of the transition state.27 In an attempt
to test such hypotheses in our system and to gain insight into the
structure of the titanium enolate from ketone 2, we carried out
NMR experiments on TiCl4ꢀ2 complexes and the ensuing
1
enolate. The corresponding H NMR spectra are shown in
Figures 4 and 5.
As expected, the titration of 2 with increasing amounts of
TiCl4 revealed the formation of a 1:1 chelated TiCl4ꢀ2 complex
(see, for instance, the dramatic low field shifts of PhCH2OCH2
protons from δ 4.5 to 5.5 ppm, in Figure 4), which was the only
species observed in the presence of 1 equiv of TiCl4.28 Moreover,
we did not observe significant changes in these chemical shifts
after the addition of a second equivalent of TiCl4, so the position
of this additional TiCl4 remained unclear.
The data presented so far suggest that a complex mechanism
operates in this aldol reaction. Unfortunately, studies on the
structure of the titanium enolates are scarce, which makes it
difficult to offer explanations for their reactions.29
However, it is well-known that RR0CdOꢀTiCl4 complexes
exist as octahedral 2:1 RR0CdOꢀTiCl4 adducts or centrosym-
metric dimeric species resulting from the formation of chlorine
bridges in the case of 1:1 stoichiometry (I in Figure 6).30 In turn,
Sharpless epoxidation is thought to be governed by a catalytic
species containing a four-membered ring with two titanium atoms
connected by bridging oxygens (II in Figure 6).31 Hence, bimetallic
Otherwise, the behavior of the titanium enolate was surprising.
1
Clear NMR spectra registered for this intermediate (for H
NMR, see Figure 5) also pointed to a chelated structure that
adopts a half-chair-like conformation in which the methyl group
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FEATURED ARTICLE
Figure 5. 1H NMR (500 MHz, CD2Cl2, ꢀ78 °C) of the titanium enolate of 2 (b, i-Pr2NEt peaks).
Scheme 7. Titanium-Mediated Aldol Reactions of 2 with R- and β-Benzyloxy Aldehydes
invoked an eight-membered cyclic transition state with a chlorine
bridge between titanium and silicon atoms to account for the
high selectivity observed in a Mukaiyama-like aldol reaction of a
lactate-derived methyl ketone (see eq 1 in Scheme 8).32 More
recently, Wang speculated that a complex with two chlorine
atoms bridging two titanium atoms could be responsible of the
highly regioselective 1,4-addition of a titanium enolate to an
activated enone (see eq 2 in Scheme 8).33 Finally, Liotta depicted
a transition state that involves a chlorine bridge to rationalize the
stereoselective formation of a carbonꢀcarbon bond through the
addition of a titanium enolate to O-methyl oximes activated by
TiCl4 (see eq 3 in Scheme 8).34
Keeping all these models in mind, the observation that the
second equivalent of TiCl4 affects the structure of the titanium
enolate and it is required to achieve high stereocontrol suggests
that these aldol reactions proceed through a bimetallic enolate. It
is likely that the titanium enolate is a hexacoordinated species and
Figure 6. Bimetallic titanium complexes.
four-membered cyclic structures with two titanium atoms con-
nected through a chlorine and an oxygen atom are often invoked
to explain the structure of this sort of reacting species.
Moreover, several mechanistic proposals to account for the
stereochemical outcome of different processes based on titanium
enolates also involve bimetallic-like species. For instance, Trost
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Scheme 8. Transition States Involving Titanium Enolates Proposed for Different CarbonꢀCarbon Bond-Forming Reactions
FEATURED ARTICLE
enolates, although we are aware that it is just a working hypothesis.
It obviously requires much more experimental and theoretical
support, but we consider that this proposal may be useful to guide
further advances in this field.
Scheme 9. Proposed Mechanism for the Titanium-Mediated
Aldol Reaction from Ketone 2
’ CONCLUSIONS
A systematic study of the substrate-controlled titanium-
mediated aldol reactions of methyl ketones derived from Roche
esters has established that this transformation is sensitive to the
hydroxyl protecting group, the titanium Lewis acid engaged in
the enolization step, and the addition of another Lewis acid to
the reacting mixture. The best results were obtained when the
TiCl4-mediated aldol reaction of (S)-4-benzyloxy-3-methyl-2-
butanone was carried out in the presence of a second equivalent
of TiCl4. Then, high yields (77ꢀ93%) and diastereomeric ratios
up to 98:2 were obtained with a wide array of achiral aliphatic,
R,β-unsaturated, and aromatic aldehydes, as well as chiral R- and
β-OTBDPS aldehydes. The mechanism of this highly stereocon-
trolled reaction is still unclear, but experimental and spectro-
scopic evidence suggests that it might proceed through a cyclic
transition state in which an oxygen and a chlorine act as bridges
between two titanium atoms. Irrespective of the theoretical
background of such a process, the reported transformation is
simple and does not need other sources of chirality, and both
enatiomeric starting methyl ketones are easily available from the
corresponding Roche esters.
the second TiCl4 equivalent binds to this enolate to give a more
complex one containing two titanium atoms. Then, the interac-
tion of this bimetallic enolate and an aldehyde could take
advantage of the higher reactivity of the outer titanium atom to
produce an intermediate, which would evolve through a cyclic
six-membered transition state shown in Scheme 9. According to
this mechanism, the stereochemical-determining step of the
titanium-mediated aldol addition of methyl ketone 2 to alde-
hydes in the presence of a second equivalent of TiCl4 would not
involve the carbon-forming step but instead the coordination of
the aldehyde to the bimetallic enolate complex. Such an
approach is compatible with the stereochemistry of the result-
ing adducts obtained in methods A and D and explains the
indifference toward the configuration of chiral aldehydes.
Furthermore, aldehydes possessing R- and β-benzyloxy groups
like 17 and 18 prevent this sort of interaction because they
favor the formation of a hexacoordinated chelated RCHOꢀ
TiCl4 complex, which would react through less stereoselective
pathways.
In summary, these features and the above-mentioned high
levels of stereocontrol achieved with a wide array of aldehydes,
provided that they are not sensitive to Lewis acids or they do not
contain chelating groups, confer to the reported methodology an
appealing interest to the synthesis of natural products.
’ EXPERIMENTAL SECTION
1. General Experimental Methods. Specific rotations were
determined at 20 °C. IR data only show the most representative
frequencies (cmꢀ1). Chemical shifts (δ are quoted in ppm and refer-
This rationale is based on the structure of titanium complexes
and has precedents in related processes involving titanium
enced to internal TMS (δ 0 for 1H NMR, and CDCl3 (δ 77.0) for 13
C
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FEATURED ARTICLE
NMR; data are reported as follows: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad. Where appropriate, 2D techniques were
also used to assist in structure elucidation. Flash chromatography was
performed on 35ꢀ70 μm silica gel. Analytical thin-layer chromatogra-
phy was carried out on silica gel 60 F254 plates. HPLC analyses of aldols
products were carried out with a Chiralcel OD-H column at 0.9 mL
minꢀ1 flow.
All reactions were conducted in oven-dried glassware under inert
atmosphere of nitrogen with anhydrous solvents. The solvents and
reagents were purified and dried according to standard procedures.
Chiral ketone 2 and aldehydes (8, ent-8, 9, ent-9) were prepared
according to reported procedures.15a,21,22
2. General Procedure for Aldol Reactions from Ketone 2
(Method A). Neat TiCl4 (110 μL, 1.0 mmol) was added dropwise to a
solution of ketone 2 (1.0 mmol) in CH2Cl2 (5 mL) at ꢀ78 °C under N2,
and the resulting yellow mixture was stirred for 2ꢀ3 min. Then,
i-Pr2NEt (190 μL, 1.1 mmol) was carefully added, and the ensuing dark
red solution was stirred for 30 min at ꢀ78 °C followed by addition of
neat TiCl4 (110 μL, 1.0 mmol). After the solution was stirred for 10 min,
aldehyde (1.5 mmol) was added, and the reaction mixture was stirred for
30 min at ꢀ78 °C.
72.4, 65.8, 49.7, 47.0, 45.7, 24.6, 23.5, 22.3, 13.4; IR (film) ν 3472, 2955,
2869, 1708, 1454, 1367, 1099, 1028. HRMS (+ESI) m/z calcd for
C17H26NaO3 [M + Na]+ 301.1774, found 301.1779.
(2S,5S)-1-Benzyloxy-5-hydroxy-2-methyl-3-octanone (5c): yellow-
ish oil; Rf = 0.40 (hexane/EtOAc 7:3); HPLC (hexane/i-PrOH 95:5)
tR = 12.2 min; [R]D +41.0 (c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.36ꢀ7.27 (m, 5H), 4.50 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H),
4.10ꢀ4.04 (m, 1H), 3.62 (dd, J = 9.0, 8.2 Hz, 1H), 3.49 (dd, J = 9.0, 5.1
Hz, 1H), 3.09 (s, 1H), 2.94ꢀ2.85 (m, 1H), 2.70 (dd, J = 17.5, 2.6 Hz,
1H), 2.54 (dd, J = 17.5, 9.2 Hz, 1H), 1.53ꢀ1.41 (m, 2H), 1.39ꢀ1.30 (m,
2H), 1.07 (d, J = 7.0 Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H); 13C NMR (100.6
MHz, CDCl3) δ 214.9, 138.0, 128.6, 128.0, 127.9, 73.6, 72.4, 67.4, 49.2,
47.0, 38.7, 18.9, 14.2, 13.4; IR (film) ν 3471, 3031, 2959, 2932, 2872,
1708, 1454, 1375, 1099, 1028; HRMS (+ESI) m/z calcd for
C16H24NaO3 [M + Na]+ 287.1618, found 287.1621.
(2S,5R)-1-Benzyloxy-5-hydroxy-2,6-dimethyl-6-hepten-3-one (5d):
yellowish oil; Rf = 0.30 (hexane/EtOAc 7:3); HPLC (hexane/i-PrOH
95:5) tR = 19.2 min; [R]D +51.6 (c 1.15, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.36ꢀ7.27 (m, 5H), 5.01ꢀ4.99 (m, 1H), 4.86ꢀ4.84 (m, 1H),
4.52 (dd, J = 9.0, 2.8 Hz, 1H), 4.50 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.0
Hz, 1H), 3.62 (dd, J = 9.0, 8.3 Hz, 1H), 3.50 (dd, J = 9.0, 5.1 Hz, 1H),
3.11 (s, 1H), 2.96ꢀ2.87 (m, 1H), 2.77 (dd, J = 17.4, 3.1 Hz, 1H), 2.69
(dd, J = 17.4, 9.1 Hz, 1H), 1.72 (s, 3H), 1.08 (d, J = 7.0 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 214.2, 145.9, 138.0, 128.6, 128.0, 127.9,
111.2, 73.6, 72.4, 71.1, 47.8, 47.1, 18.6, 13.3; IR (film) ν 3462, 3030,
2972, 2862, 1710, 1652, 1496, 1454, 1370, 1092; HRMS (+ESI) m/z
calcd for C16H22NaO3 [M + Na]+ 285.1461, found 285.1460.
(2S,5R,6E)-1-Benzyloxy-5-hydroxy-2-methyl-6-octen-3-one (5e):
yellowish oil; Rf = 0.30 (hexane/EtOAc 7:3); HPLC (hexane/i-PrOH
95:5) tR = 15.6 min; [R]D +33.5 (c 1.15, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.36ꢀ7.27 (m, 5H), 5.70 (dqd, J = 15.3, 6.5, 1.1 Hz, 1H), 5.48
(ddq, J = 15.3, 6.5, 1.6 Hz, 1H), 4.55ꢀ4.52 (m, 1H), 4.50 (d, J = 12.1 Hz,
1H), 4.46 (d, J = 12.1 Hz, 1H), 3.62 (dd, J = 9.0, 8.1 Hz, 1H), 3.49 (dd,
J = 9.0, 5.2 Hz, 1H), 3.06 (s, 1H), 2.93ꢀ2.85 (m, 1H), 2.73 (dd, J = 17.4,
3.7 Hz, 1H), 2.66 (dd, J = 17.4, 8.3 Hz, 1H), 1.68 (ddd, J = 6.5, 1.6, 0.9
Hz, 3H), 1.07 (d, J = 7.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ
213.9, 137.8, 131.9, 128.4, 127.7, 127.6, 126.9, 73.3, 72.1, 68.4, 48.8, 46.9,
17.7, 13.1; IR (film) ν 3454, 3030, 2858, 1709, 1496, 1454, 1376, 1098,
1028; HRMS (+ESI) m/z calcd for C16H22NaO3 [M + Na]+ 285.1461,
found 285.1459.
The mixture was quenched by addition of saturated NH4Cl (5 mL),
diluted with Et2O (50 mL), and washed with H2O (20 mL), saturated
NaHCO3 (20 mL), and brine (20 mL). The aqueous layers were
extracted with Et2O (2 ꢁ 30 mL), and the combined organic extracts
were dried (MgSO4) and concentrated. The resulting oil was analyzed
by HPLC and NMR and purified by column chromatography.
3. General Procedure for Aldol Reactions from Ketone 2
(Method D). Neat TiCl4 (120 μL, 1.1 mmol) was added dropwise to a
solution of ketone 2 (1.0 mmol) in CH2Cl2 (2 mL) at ꢀ78 °C under N2,
and the resulting yellow mixture was stirred for 2ꢀ3 min. i-Pr2NEt (190
μL, 1.1 mmol) was carefully added, and the dark red solution was stirred
for 30 min at ꢀ78 °C.
At the same time, neat TiCl4 (130 μL, 1.2 mmol) was added dropwise
to a solution of aldehyde (1.2 mmol) in CH2Cl2 (2 mL) in another
round-bottom flask at ꢀ78 °C under N2. The resulting mixture was
stirred for 10 min at ꢀ78 °C, and then the enolate solution was added
dropwise to the solution of precomplexed aldehyde via cannula. The
resulting solution was stirred for 30 min at ꢀ78 °C, quenched, and
purified as in the former method.
(2S,5R,6E)-1-Benzyloxy-5-hydroxy-2-methyl-7-phenyl-6-hepten-3-
one (5f): yellowish solid; mp = 70ꢀ72 °C; Rf = 0.30 (hexane/EtOAc
4. Physical and Spectroscopic Data of Aldols 5 and
10ꢀ13. (2S,5R)-1-Benzyloxy-5-hydroxy-2,6-dimethyl-3-heptanone
(5a): yellowish oil; Rf = 0.50 (hexane/EtOAc 7:3); HPLC (hexane/
i-PrOH 95:5) tR = 13.1 min; [R]D +56.5 (c 1.0, CHCl3) [lit.1b ent-3a [R]D
ꢀ50.5 (c 0.27, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.36ꢀ7.26 (m,
5H), 4.50 (d, J = 12.1 Hz, 1H), 4.46 (d, J = 12.1 Hz, 1H), 3.83 (ddd, J =
9.7, 5.7, 2.3 Hz, 1H), 3.62 (dd, J = 9.0, 8.3 Hz, 1H), 3.49 (dd, J = 9.0, 5.1
Hz, 1H), 3.06 (s, 1H), 2.96ꢀ2.88 (m, 1H), 2.69 (dd, J = 17.4, 2.3 Hz,
1H), 2.54 (dd, J = 17.4, 9.7 Hz, 1H), 1.73ꢀ1.61 (m, 1H), 1.07 (d, J = 7.0
Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 214.9, 137.8, 128.4, 127.7, 127.6, 73.3, 72.2,
72.1, 46.8, 46.0, 33.0, 18.4, 17.8, 13.2; IR (film) ν 3491, 2962, 1708,
1454, 1367, 1098; HRMS (+ESI) m/z calcd for C16H24NaO3 [M + Na]+
287.1618, found 287.1623.
(2S,5S)-1-Benzyloxy-5-hydroxy-2,7-dimethyl-3-octanone (5b): yel-
lowish oil; Rf = 0.50 (hexane/EtOAc 7:3); HPLC (hexane/i-PrOH
95:5) tR = 10.0 min; [R]D +35.4 (c 1.15, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.36ꢀ7.26 (m, 5H), 4.50 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.0
Hz, 1H), 4.17ꢀ4.11 (m, 1H), 3.62 (dd, J = 9.0, 8.3 Hz, 1H), 3.49 (dd, J =
9.0, 5.1 Hz, 1H), 3.07 (s, 1H), 2.91ꢀ2.88 (m, 1H), 2.68 (dd, J = 17.5, 2.7
Hz, 1H), 2.53 (dd, J = 17.5, 9.1 Hz, 1H), 1.82ꢀ1.72 (m, 1H), 1.45 (ddd,
J = 13.7, 8.9, 5.6 Hz, 1H), 1.12 (ddd, J = 13.7, 8.5, 4.5 Hz, 1H), 1.07 (d, J
= 7.0 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 214.9, 138.0, 128.6, 128.0, 127.9, 73.6,
1
7:3); [R]D +21.0 (c 0.8, CHCl3); H NMR (400 MHz, CDCl3) δ
7.37ꢀ7.21 (m, 10H), 6.62 (dd, J = 15.9, 1.1 Hz, 1H), 6.19 (dd, J = 15.9,
5.9 Hz, 1H), 4.81ꢀ4.75 (m, 1H), 4.51 (d, J = 12.1 Hz, 1H), 4.47 (d, J =
12.1 Hz, 1H), 3.63 (dd, J = 9.0, 8.2 Hz, 1H), 3.52 (dd, J = 9.0, 5.1 Hz,
1H), 3.24 (d, J = 3.5 Hz, 1H), 2.97ꢀ2.89 (m, 1H), 2.85 (dd, J = 17.5,
3.4 Hz, 1H), 2.76 (dd, J = 17.5, 8.6 Hz, 1H), 1.09 (d, J = 7.0 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 213.6, 137.8, 136.6, 130.2, 130.2, 128.5,
128.4, 127.8, 127.7, 126.5, 73.4, 72.1, 68.3, 48.8, 46.9, 13.1; IR (film) ν
3494, 3030, 2978, 2933, 2861, 1705, 1684, 1653, 1496, 1420, 1118;
HRMS (+ESI) m/z calcd for C21H24NaO3 [M + Na]+ 347.1618, found
347.1621.
(1R,4S)-5-Benzyloxy-1-hydroxy-4-methyl-1-phenyl-3-pentanone
(5g): yellowish oil; Rf = 0.30 (hexane/EtOAc 7:3); HPLC (hexane/
i-PrOH 85:15) tR = 10.5 min; [R]D +42.0 (c 1.15, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.38ꢀ7.24 (m, 10H), 5.16 (dd, J = 7.9, 4.4 Hz, 1H),
4.49 (d, J = 11.8 Hz, 1H), 4.46 (d, J = 11.8 Hz, 1H), 3.61 (dd, J = 9.1, 8.1
Hz, 1H), 3.50 (dd, J = 9.1, 5.1 Hz, 1H), 3.47 (s, 1H), 2.98ꢀ2.82 (m, 3H),
1.07 (d, J = 7.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 213.7, 142.9,
137.8, 128.9, 128.4, 127.7, 127.6, 127.5, 125.6, 73.3, 72.1, 69.7, 50.9, 46.8,
13.0; IR (film) ν 3460, 3062, 3030, 2972, 2862, 1709, 1495, 1454, 1365,
1094, 1028; HRMS (+ESI) m/z calcd for C19H22NaO3 [M + Na]+
321.1461, found 321.1467.
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(1R,4S)-5-Benzyloxy-1-hydroxy-4-methyl-1-(4-nitrophenyl)-3-pen-
tanone (5h): yellowish oil; Rf = 0.25 (hexane/EtOAc 6:4); HPLC
(hexane/i-PrOH 85:15) tR = 28.1 min; [R]D +28.4 (c 1.15, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 8.16ꢀ8.14 (m, 2H), 7.45ꢀ7.43 (m, 2H),
7.37ꢀ7.26 (m, 5H), 5.24 (dt, J = 9.4, 2.8 Hz, 1H), 4.48 (s, 2H),
3.78ꢀ3.69 (m, 1H), 3.64ꢀ3.51 (m, 2H), 2.95 (dd, J = 17.7, 2.8 Hz, 1H),
2.95ꢀ2.87 (m, 1H), 2.80 (dd, J = 17.7, 9.4 Hz, 1H), 1.07 (d, J = 7.0 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) δ 213.4, 150.2, 147.2, 137.6,
128.5, 127.9, 127.7, 126.4, 126.3, 123.6, 73.4, 72.3, 68.8, 50.7, 46.7, 12.8;
IR (film) ν 3469, 2862, 1710, 1604, 1519, 1347, 1078; HRMS (+ESI)
m/z calcd for C19H21NNaO5 [M + Na]+ 366.1312, found 366.1316.
(1R,4S)-5-Benzyloxy-1-hydroxy-1-(4-methoxyphenyl)-4-methyl-3-
pentanone (5i): yellowish oil; Rf (hexane/EtOAc 6:4) = 0.35; HPLC
(hexane/i-PrOH 85:15) tR = 18.2 min; [R]D +25.2 (c 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.36ꢀ7.23 (m, 7H), 6.87ꢀ6.85 (m, 2H),
5.11 (td, J = 6.2, 2.6 Hz, 1H), 4.49 (d, J = 12.3 Hz, 1H), 4.46 (d, J = 12.3
Hz, 1H), 3.79 (s, 3H), 3.61 (dd, J = 9.0, 8.2 Hz, 1H), 3.50 (dd, J = 9.0, 5.2
Hz, 1H), 3.38 (d, J = 2.6 Hz, 1H), 2.95ꢀ2.80 (m, 3H), 1.07 (d, J = 7.0
Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 213.8, 159.0, 137.8, 135.0,
128.4, 127.7, 127.6, 126.9, 126.9, 113.8, 73.3, 72.1, 69.3, 55.3, 50.9, 46.9,
29.7, 13.1; IR (film) ν 3462, 2924, 2854, 1709, 1612, 1514, 1248, 1034;
HRMS (+ESI) m/z calcd for C20H24NaO4 [M + Na]+ 351.1567, found
351.1559.
(2S,5R,6R)-1-Benzyloxy-6-tert-butyldiphenylsilyloxy-5-hydroxy-2-
methyl-3-heptanone (10): colorless oil; Rf = 0.50 (hexane/EtOAc 7:3);
HPLC (hexane/i-PrOH 95:5) tR = 8.9 min; [R]D +21.3 (c 1.2, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.68ꢀ7.65 (m, 5H), 7.45ꢀ7.25 (m,
10H), 4.48 (d, J = 12.3 Hz, 1H), 4.44 (d, J = 12.3 Hz, 1H), 4.04ꢀ3.99
(m, 1H), 3.84 (qd, J = 6.3, 4.6 Hz, 1H), 3.61 (dd, J = 9.1, 7.7 Hz, 1H),
3.45 (dd, J = 9.1, 5.4 Hz, 1H), 2.91ꢀ2.85 (m, 1H), 2.85 (d, J = 4.3 Hz,
1H), 2.69 (dd, J = 17.2, 3.9 Hz, 1H), 2.63 (dd, J = 17.2, 8.7 Hz, 1H), 1.07
(d, J = 7.0 Hz, 3H), 1.05 (s, 9H), 1.02 (d, J = 6.3 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 213.3, 137.9, 135.8, 135.8, 134.0, 133.5, 129.8,
129.7, 128.4, 127.7, 127.7, 127.6, 127.5, 73.2, 72.0, 71.5, 71.1, 47.0, 44.1,
27.0, 19.3, 18.4, 13.3; IR (film) ν 3491, 3070, 2932, 2858, 1710, 1472,
1454, 1428, 1375, 1111; HRMS (+ESI) m/z calcd for C31H44NO4Si
[M + NH4]+ 522.3034, found 522.3025.
(2S,5R,6S)-1-Benzyloxy-6-tert-butyldiphenylsilyloxy-5-hydroxy-2-
methyl-3-heptanone (11): colorless oil; Rf = 0.55 (hexane/EtOAc 7:3);
[R]D +9.5 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.71ꢀ7.64
(m, 5H), 7.45ꢀ7.24 (m, 10H), 4.47 (d, J = 12.1 Hz, 1H), 4.43 (d, J =
12.1 Hz, 1H), 4.04ꢀ3.98 (m, 1H), 3.82 (qd, J = 6.3, 4.6 Hz, 1H), 3.58
(dd, J = 9.1, 7.9 Hz, 1H), 3.46 (dd, J = 9.1, 5.3 Hz, 1H), 2.90ꢀ2.82 (m,
1H), 2.85 (d, J = 3.3 Hz, 1H), 2.70 (dd, J = 17.2, 3.2 Hz, 1H), 2.58 (dd, J
= 17.2, 9.0 Hz, 1H), 1.06 (s, 9H), 1.04 (d, J = 7.1 Hz, 3H), 1.00 (d, J = 6.3
Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 213.3, 137.9, 135.9, 134.2,
133.6, 129.8, 129.6, 128.4, 127.7, 127.6, 127.5, 73.3, 72.1, 72.0, 71.6, 46.9,
44.6, 27.0, 19.3, 18.5, 13.2; IR (film) ν 3499, 3070, 2932, 2857, 1710,
1472, 1454, 1428, 1375, 1111; HRMS (+ESI) m/z calcd for
C31H44NO4Si [M + NH4]+ 522.3034, found 522.3029.
(2S,5R,6R)-1-Benzyloxy-7-tert-butyldiphenylsilyloxy-5-hydroxy-2,6-
dimethyl-3-heptanone (12): colorless oil; Rf = 0.55 (hexane/EtOAc
7:3); HPLC (hexane/i-PrOH 95:5) tR = 8.3 min; [R]D +11.4 (c 1.25,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.68ꢀ7.65 (m, 5H),
7.45ꢀ7.24 (m, 10H), 4.49 (d, J = 12.1 Hz, 1H), 4.45 (d, J = 12.1 Hz,
1H), 4.35ꢀ4.30 (m, 1H), 3.68 (dd, J=9.3, 4.2Hz, 1H), 3.65(dd, J= 9.3, 5.2
Hz, 1H), 3.62 (dd, J = 9.0, 8.0 Hz, 1H), 3.47 (dd, J = 9.0, 5.3 Hz, 1H), 3.15
(d, J= 3.3 Hz, 1H), 2.94ꢀ2.85 (m, 1H), 2.71 (dd, J= 17.1, 9.1 Hz, 1H), 2.61
(dd, J = 17.1, 3.4 Hz, 1H), 1.78ꢀ1.70 (m, 1H), 1.07 (d, J = 7.2 Hz, 3H),
1.06ꢀ1.05 (s, 9H), 0.91 (d, J = 7.0 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3) δ 213.7, 137.9, 135.6, 135.6, 133.4, 133.3, 129.7, 128.4, 127.7,
127.6, 73.3, 72.1, 68.9, 67.1, 46.9, 46.8, 39.7, 26.9, 19.2, 13.2, 11.0; IR (film) ν
3512, 3070, 2931, 2858, 1709, 1472, 1454, 1428, 1362, 1112; HRMS
(+ESI) m/z calcd for C32H42O4Si [M + H]+ 519.2925, found 519.2922.
(2S,5R,6S)-1-Benzyloxy-7-tert-butyldiphenylsilyloxy-5-hydroxy-2,6-
dimethyl-3-heptanone (13): colorless oil; Rf = 0.50 (hexane/EtOAc
7:3); HPLC (hexane/i-PrOH 95:5) tR = 8.7 min; [R]D +24.0 (c 1.3,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.68ꢀ7.65 (m, 5H),
7.44ꢀ7.25 (m, 10H), 4.49 (d, J = 12.1 Hz, 1H), 4.45 (d, J = 12.1 Hz,
1H), 4.17ꢀ4.11 (m, 1H), 3.71 (dd, J = 10.2, 5.0 Hz, 1H), 3.66 (dd, J =
10.2, 6.1 Hz, 1H), 3.62 (dd, J = 9.0, 8.0 Hz, 1H), 3.51 (d, J = 3.3 Hz, 1H),
3.47 (dd, J = 9.0, 5.3 Hz, 1H), 2.95ꢀ2.87 (m, 1H), 2.73ꢀ2.62 (m, 1H),
1.85ꢀ1.75 (m, 1H), 1.07 (d, J = 7.0 Hz, 3H), 1.05 (s, 9H), 0.88 (d, J = 7.0
Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 213.9, 137.9, 135.6, 133.3,
129.7, 128.4, 127.7, 127.6, 73.3, 72.1, 70.3, 66.7, 46.9, 46.8, 40.2, 26.9,
19.2, 13.3, 13.3; IR (film) ν 3497, 3070, 2961, 2931, 2858, 1709, 1472,
1428, 1112; HRMS (+ESI) m/z calcd for C32H42O4Si [M + H]+
519.2925, found 519.2925.
5. PROOF OF THE STEREOCHEMISTRY FOR ALDOLS 5
5.1. Stereoselective Reduction of Aldols 5. A 1 M solution
of Et2BOMe (1.7 mL, 1.7 mmol) in THF was added dropwise to
a 0.15 M solution of aldol 5a or 5g (1 mmol) in THF at ꢀ78 °C
under N2, and the resulting mixture was stirred for 20 min at
ꢀ78 °C. NaBH4 (46 mg, 1.2 equiv) was quickly added, and the
reaction mixture was further stirred for 3 h at ꢀ78 °C under N2.
The reaction was quenched by addition of AcOH (2 mL), and
the mixture was allowed to warm to room temperature. The
mixture was partitioned with CH2Cl2 and H2O, and the aqueous
layer was extracted with CH2Cl2. The combined organic extracts
were washed with 1 M NaOH, dried (MgSO4), and concen-
trated. The residue was diluted in a 1 M solution of NaOAc in 9:1
MeOH/H2O (25 mL) and treated with 33% w/v H2O2 (4 mL)
at room temperature for 1 h.
The reaction mixture was partitioned with CH2Cl2 and H2O,
and the aqueous layer was extracted with CH2Cl2. The combined
organic extracts were dried (MgSO4), and the solvent was
removed in vacuo. The resultant oil was purified by column
chromatography (hexane/EtOAc) to afford syn 1,3-diols 14a and
14g in 92ꢀ95% yield.
(2S,3S,5R)-1-Benzyloxy-2,6-dimethyl-3,5-heptanediol (14a):
colorless oil; Rf = 0.20 (hexane/EtOAc 7:3); [R]D +30.3 (c 1.2,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.28 (m, 5H),
4.53 (d, J = 11.8 Hz, 1H), 4.50 (d, J = 11.8 Hz, 1H), 4.01 (dt, J =
9.7, 2.7 Hz, 1H), 3.63 (ddd, J = 9.0, 5.0, 2.6 Hz, 1H), 3.54 (dd, J =
9.1, 5.0 Hz, 1H), 3.51 (dd, J = 9.1, 6.5 Hz, 1H), 1.97ꢀ1.90 (m,
1H), 1.71ꢀ1.60 (m, 1H), 1.53ꢀ1.44 (m, 2H), 0.94 (d, J = 7.2
Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 138.0, 128.7, 128.1, 127.9, 77.9,
76.2, 74.5, 73.8, 38.9, 36.0, 34.3, 18.5, 17.8, 11.6; IR (film) ν 3410,
2950, 2874, 1450, 1410, 1384, 1365, 1329, 1098, 1028; HRMS
(+ESI) m/z calcd for C16H26NaO3 [M + Na]+ 289.1774, found
289.1767.
(2S,3S,5R)-1-Benzyloxy-2-methyl-5-phenyl-3,5-pentanediol
(14g): colorless oil; Rf = 0.30 (hexane/EtOAc 7:3); [R]D +22.6
1
(c 0.7, CHCl3); H NMR (400 MHz, CDCl3) δ 7.407.27 (m,
10H), 4.95 (dd, J = 10.0, 2.6 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H),
4.50 (d, J = 12.1 Hz, 1H), 4.14 (dt, J = 10.83, 2.17 Hz, 1H), 3.56
(dd, J = 9.1, 4.6 Hz, 1H), 3.51 (dd, J = 9.1, 6.9 Hz, 1H),
1.99ꢀ1.92 (m, 1H), 1.88 (ddd, J = 14.3, 10.8, 10.0 Hz, 1H), 1.66
(ddd, J = 14.3, 2.7, 2.0 Hz, 1H), 0.92 (d, J = 7.1 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 144.9, 128.8, 128.6, 128.1, 127.9,
127.6, 125.9, 75.9, 75.5, 74.5, 73.8, 42.5, 38.7, 11.7; IR (film) ν
3396, 2916, 2857, 1454, 1100, 1061; HRMS (+ESI) m/z calcd
for C19H24NaO3 [M + Na]+ 323.1618, found 323.1612.
8585
dx.doi.org/10.1021/jo201021z |J. Org. Chem. 2011, 76, 8575–8587

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FEATURED ARTICLE
5.2. Protection of Diols 14. A mixture of a syn 1,3-diol 14 (0.2
mmol) and a catalytic amount of PPTS in 1:1 CH2Cl2/
(MeO)2CMe2 (5 mL) was stirred at room temperature for 24
h under N2. The solvent was removed in vacuo, and the resultant
white residue was purified by column chromatography (hexane/
EtOAc) to afford isopropylidene ketals 15a and 15g as a colorless
oil in 95% and 88% yield, respectively.
1.80ꢀ1.85 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H); 13C NMR (100.6
MHz, CDCl3) δ 197.9, 138.8, 137.3, 133.5, 129.0, 128.8, 128.4,
128.4, 126.3, 102.1, 76.3, 73.8, 41.8, 31.7, 11.7; IR (film) ν 2965,
2918, 2850, 1686, 1597, 1449, 1374, 1213, 1119, 1001; HRMS
(+ESI) m/z calcd for C19H20NaO3 [M + Na]+ 319.1305, found
319.1296.
(2S,3S,5R)-1-Benzyloxy-3,5-isopropylidenedioxy-2,6-di-
methylheptane (15a): colorless oil; Rf = 0.80 (hexane/EtOAc
7:3); [R]D +24.6 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.40ꢀ7.20 (m, 5H), 4.51 (d, J = 12.1 Hz, 1H), 4.48 (d, J = 12.1
Hz, 1H), 3.88 (ddd, J = 11.7, 4.8, 2.5 Hz, 1H), 3.47 (dd, J = 9.1,
6.5 Hz, 1H), 3.44 (dd, J = 9.1, 4.7 Hz, 1H), 3.34 (dd, J = 9.1, 5.8
Hz, 1H), 1.84ꢀ1.73 (m, 1H), 1.65ꢀ1.55 (m, 1H), 1.39 (s, 3H),
1.35 (s, 3H), 1.37ꢀ1.33 (m, 1H), 1.26ꢀ1.16 (m, 1H), 0.96 (d,
J = 6.9 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H);
13C NMR (100.6 MHz, CDCl3) δ 138.9, 128.5, 127.8, 127.7,
98.4, 74.4, 73.3, 72.5, 69.8, 38.9, 33.3, 31.1, 30.4, 20.1, 18.7, 17.9,
12.4; IR (film) ν 2990, 2959, 2872, 1378, 1257, 1201, 1171, 1098;
HRMS (+ESI) m/z calcd for C19H30NaO3 [M + Na]+ 329.2087,
found 329.2084.
(1R,3S,4S)-5-Benzyloxy-1,3-isopropylidenedioxy-4-methyl-1-
phenylpentane (15g): colorless oil; Rf = 0.80 (hexane/EtOAc
7:3); [R]D +22.2 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.38ꢀ7.25 (m, 10H), 4.88 (dd, J = 11.3, 2.9 Hz, 1H), 4.49 (s,
2H), 4.08 (ddd, J = 11.3, 4.9, 2.5 Hz, 1H), 3.49 (dd, J = 9.1, 6.4
Hz, 1H), 3.35 (dd, J = 9.1, 5.6 Hz, 1H), 1.87ꢀ1.77 (m, 1H), 1.63
(dt, J = 12.9, 2.8 Hz, 1H), 1.59ꢀ1.50 (m, 1H), 1.53 (s, 3H), 1.47
(s, 3H), 0.98 (d, J = 6.9 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
δ 142.9, 138.8, 128.6, 128.6, 127.8, 127.7, 127.7, 126.1, 99.2, 73.4,
72.2, 71.9, 69.9, 38.8, 36.9, 30.5, 20.1, 12.4; IR (film) ν 3029,
2991, 2919, 2856, 1453, 1379, 1254, 1201, 1169, 1098; HRMS
(+ESI) m/z calcd for C22H28NaO3 [M + Na]+ 363.1931, found
363.1927.
5.3. Oxidation of Diols 14. A mixture of diol 14 (0.2 mmol),
DDQ (179 mg, 0.75 mmol), and 4 Å molecular sieves in CH2Cl2
(5 mL) was stirred under N2 at room temperature for 24 h. The
mixture was then filtered through Celite, eluted with CH2Cl2,
and washed with H2O. The aqueous layer was extracted with
CH2Cl2, the combined organic extracts were washed with H2O
and dried (MgSO4), and the solvent was removed in vacuo. The
resultant oil was purified by column chromatography (hexane/
EtOAc) to afford benzylidene acetals 16a and 16g as a colorless
oil in 23% and 33% yield, respectively.
(2R,4S,5S)-4-[(2R)-2-Hydroxy-3-methyl-1-butyl]-5-methyl-2-
phenyl-1,3-dioxane (16a): orange oil; Rf = 0.50 (hexane/EtOAc
6:4); [R]D ꢀ10.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.86ꢀ7.26 (m, 5H), 5.56 (s, 1H), 4.24 (ddd, J = 9.74, 3.43, 2.35
Hz, 1H), 4.13 (dd, J = 11.3, 2.4 Hz, 1H), 4.03 (dd, J = 11.2, 1.3
Hz, 1H), 3.63 (ddd, J = 10.1, 5.3, 1.8 Hz, 1H), 1.82ꢀ1.52 (m,
4H), 1.23 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.92 (d, J =
6.8 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 138.4, 129.2,
128.5, 126.3, 102.1, 81.4, 76.7, 74.1, 36.5, 34.1, 32.5, 18.6, 17.8,
11.7; IR (film) ν 3525, 2961, 2929, 2873, 1466, 1389, 1375, 1165,
1113, 1003; HRMS (+ESI) m/z calcd for C16H23O2 [M ꢀ OH]+
247.1693, found 247.1693.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra of
S
b
aldols adducts 5 and 10ꢀ13 and acetals 15 and 16. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: felix.urpi@ub.edu; pedro.romea@ub.edu.
’ ACKNOWLEDGMENT
Financial support from the Spanish Ministerio de Ciencia e
Innovaciꢁon (MICINN), Fondos FEDER (Grant No. CTQ2009-
09692), and the Generalitat de Catalunya (2009SGR825) as well
as a doctorate studentship (FPU, Ministerio de Educaciꢁon) to
J.Z. are acknowledged.
’ DEDICATION
†This paper is dedicated to Professor Carmen Nꢁajera on the
occasion of her 60th birthday.
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