Stereoselective acetate aldol reactions of α-silyloxy ketones

Article abstract of DOI:10.1016/j.tet.2014.12.099

TiCl₄-mediated aldol reactions of chiral methyl α-silyloxy ketones with a variety of aldehydes provide the corresponding 1,4-syn aldol adducts with moderate to high stereocontrol. This transformation represents a new approach to substrate-controlled acetate aldol reactions and complements the 1,4-anti asymmetric induction produced by the related α-benzyloxy ketones. This new approach could be useful in the design of more efficient syntheses of natural products.

Full text of DOI:10.1016/j.tet.2014.12.099

Accepted Manuscript
Stereoselective acetate aldol reactions of α-silyloxy ketones
Adriana Lorente, Miquel Pellicena, Pedro Romea, Fèlix Urpí
PII:
S0040-4020(14)01829-8
10.1016/j.tet.2014.12.099
TET 26320
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 November 2014
Revised Date: 18 December 2014
Accepted Date: 29 December 2014
Please cite this article as: Lorente A, Pellicena M, Romea P, Urpí F, Stereoselective acetate aldol
reactions of α-silyloxy ketones, Tetrahedron (2015), doi: 10.1016/j.tet.2014.12.099.
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Stereoselective acetate aldol reactions of α-
silyloxy ketones
Adriana Lorente, Miquel Pellicena, Pedro Romea, and Fèlix Urpí
Departament de Química Orgànica and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Carrer Martí i
Franquès, 1-11, 08028 Barcelona, Catalonia, Spain

1
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Tetrahedron
journal homepage: www.elsevier.com
Stereoselective acetate aldol reactions of α-silyloxy ketones
Adriana Lorente, Miquel Pellicena, Pedro Romea, and Fèlix Urpí
Departament de Química Orgànica and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Carrer Martí i Franquès, 1-
11, 08028 Barcelona, Catalonia, Spain
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
TiCl4–Mediated aldol reactions of chiral methyl α-silyloxy ketones with a variety of aldehydes
provide the corresponding 1,4-syn aldol adducts with moderate to high stereocontrol. This
transformation represents a new approach to substrate-controlled acetate aldol reactions and
complements the 1,4-anti asymmetric induction produced by the related α-benzyloxy ketones.
This new approach could be useful in the design of more efficient syntheses of natural products.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Stereoselective reactions
Acetate aldol reactions
Titanium enolates
Chiral ketones
1. Introduction
much more demanding than it is in related processes from ethyl
ketones since metal enolate-mediated aldol reactions involving
chiral methyl ketones can proceed through several six-membered
cyclic transition states of similar energy.13 Therefore, prediction
of the stereochemical outcome of these reactions is always
problematic and requires comprehensive analysis of the influence
of both the ketone and the aldehyde on the configuration of the
new stereocentre.
The coupling of elaborate fragments in the advanced steps of a
synthesis requires full knowledge of the particular trends of the
reacting species.1,2 This is especially important in asymmetric
synthesis, in which the configurations of the new chirality centres
usually rely on subtle steric and electronic influences due to
several groups within the reactants.3 Acetate aldol reactions
illustrate such a scenario.4,5 Indeed, the resultant β-hydroxy
carbonyl structures are found in a large array of natural products
and, in principle, they could be easily synthesized by aldol
addition of methyl ketones to aldehydes.5,6 Nevertheless, and
despite recent advances in catalytic asymmetric-based5g-h,7 and
chiral auxiliary-based5g-h,8 approaches, there is still a shortage of
methods to achieve such transformations both in structurally
simple as well as structurally complex intermediates in advanced
steps of a synthesis.9 Thus, substrate-controlled aldol reactions
based on metal enolates from chiral methyl ketones are an
appealing way to address this challenge provided that one has a
thorough understanding of the asymmetric induction that the
enolate and the aldehyde undergo.5g-h,10,11,12 Unfortunately, this is
Keeping these challenges in mind, some years ago we
launched a project to develop stereoselective aldol reactions from
titanium(IV) enolates of chiral methyl ketones.14,15 These
titanium(IV) enolates can be prepared by simple treatment of
methyl ketones with titanium(IV) Lewis acids in the presence of
a tertiary amine,16,17 and they can react with a large array of
aldehydes under mild conditions. Furthermore, we envisaged that
the relatively short Ti–O distances and the possibility of
attaching different ligands to the metal might furnish the tight
transition states that are essential for highly stereocontrolled
transformations.18 This proved to be the case in the aldol
additions of β- as well as α-benzyloxy methyl ketones (see
———
Corresponding author. Tel.: +34 93 4039106; fax: +34 93 3397878 (P.R.); e-mail:pedro.romea@ub.edu (P. Romea)
Corresponding author. Tel.: +34 03 4021247; fax: +34 93 3397878 (F.U.); e-mail: felix.urpi@ub.edu (F. Urpí)

2
Tetrahedron
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Scheme 1. Titanium–mediated substrate–controlled aldol reactions from chiral β- and α-hydroxy methyl ketones.
equation 1 and 3 in Scheme 1).14,15 A parallel process based on β-
silyloxy methyl ketones turned out to be non stereoselective
(equation 2 in Scheme 1), so the benzyl protecting group seemed
to be crucial for the success of these reactions. Nevertheless,
preliminary studies of the addition of titanium(IV) enolates from
α-tert-butyldimethylsilyloxy methyl ketones to aliphatic,
aromatic, and α,β-unsaturated aldehydes showed that the
corresponding 1,4-syn aldols could be obtained in good yields
(see equation 4 in Scheme 1).19 Encouraged by these results, we
have now carried out a comprehensive analysis of such a
transformation that complements the 1,4-anti induction observed
for the related α-benzyloxy methyl ketones (compare equation 3
and 4 in Scheme 1). Herein, we report our findings on the
substrate-controlled titanium-mediated aldol reactions of α-
silyloxy methyl ketones that produce 1,4-syn aldol adducts with
moderate to high diastereoselectivity depending on the steric
hindrance of the R group and the aldehyde. On the whole, these
studies provide valuable knowledge for devising more efficient
synthesis routes for complex natural products.
titanium-mediated aldol reaction of 1 with isobutyraldehyde (a).
These preliminary experiments were disappointing; experimental
conditions optimized for related ethyl ketones based on the
enolization of 1 with mild Lewis acids such as (i-PrO)2TiCl2 and
(i-PrO)TiCl3 yielded the self-condensation adduct 5 as the major
component of the reacting mixtures instead of 1,4-syn aldol 2a
(entry 1 and 2 in Table 1).21 This suggested that the enolization
step was slow enough to allow the resulting enolate to attack the
activated ketone and produce the undesired aldol 5. Even the
stronger TiCl4 produced a significant amount of this adduct at –
78 °C (entry 3 in Table 1). The formation of 5 was finally
minimized by lowering the enolization temperature to –94 °C and
carrying out the aldol reaction at –78 °C.22 Thereby, aldols 2a
and 3a (1,4-syn and 1,4-anti, respectively) were obtained with a
71% overall yield as well as tiny amounts of hemiacetal 4a,
which was isolated as
a
single diastereomer after
chromatographic purification (entry 4 in Table 1). Hence, the
diastereoselectivity of the formation of 2a was established as dr
77:23 assuming that 4a results from 2a (entry 4 in Table 1).
2.2. TiCl4-Mediated aldol reactions of lactate-derived ketone 1
2. Results and discussion
Having established the feasibility of the titanium–mediated
aldol addition of 1 to isobutyraldehyde (a), we next examined
parallel reactions with other aldehydes under the previously
optimized experimental conditions. The results summarized in
Table 2 prove that the TiCl4-mediated aldol reactions of 1 with
aliphatic aldehydes a–g are fairly diastereoselective (entries 1–7
2.1. Preliminary results
Lactate-derived α-tert-butyldimethylsilyloxy methyl ketone
120 was chosen to assess the feasibility of stereoselective acetate
aldol reactions. Considering the influence of titanium(IV) Lewis
acids on the stereochemical outcome of related processes,18 we
initially studied the effect of the enolization conditions on the
Table 1
Influence of titanium(IV) Lewis acids on the aldol reaction of 1 and isobutyraldehyde (a)
a) 1.1 eq TiL4, 1.1 eq i-Pr2NEt, CH2Cl2, Tenol, 30 min. b) 1.5 eq i-PrCHO, –78 °C, 30 min
Entry
TiL4
Tenol (°C)
–78
dr (2a+4a):3aa
75:25
Yield 2a and 3a (%)b
Yield 4a (%)b
Yield 5 (%)b
1
2
3
4
Ti(i-PrO)2Cl2
Ti(i-PrO)Cl3
TiCl4
5
–
68
29
15
–
–78
76:24
27
65
71
ndc
ndc
5
–78
74:26
TiCl4
–94
77:23
a) Determined by 1H NMR analysis of isolated products.
b) Isolated yield.
c) Not determined.

3
Table 2
ACCEPTED MANUSCRIPT
TiCl4-Mediated aldol reactions of 1 with achiral aldehydes
a) 1.1 eq TiCl4, 1.1 eq i-Pr2NEt, CH2Cl2, –94 °C, 30 min. b) 1.5 eq R 1CHO, –78 °C, 30 min
Entry
Aldehyde
R1
Yield 4 (%)a
Yield 2 and 3 (%)a
dr (2+4):3
77:23b
76:24b
76:24b
71:29c
78:22c
77:23c
80:20c
55:45c
65:35c
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
i-Pr
5
71
63
65
73
71
72
68
75
80
i-Bu
19
18
–
n-Pr
Me
CH2OTIPS
CH2CH2OTIPS
CH2CH2NPhth
Ph
–
–
g
h
i
–
–
C(CH3)=CH2
–
a) Overall isolated yield.
b) Determined by 1H NMR analysis of isolated products.
c) Determined by 1H NMR analysis of the reaction mixture.
in Table 2). Indeed, 1,4-syn aldols 2a–g were isolated in good
yields and diastereomeric ratios close to 80:20 irrespective of the
steric bulk of the R1 group. Even aldol adduct 2d from the
smallest acetaldehyde (d) was obtained with a reasonably good
diastereomeric ratio and yield (dr 71:29 and 73%, entry 4 in
Table 2). It is noteworthy that significant amounts of hemiacetals
4b and 4c from isovaleraldehyde and butanal were isolated after
chromatographic purification (entries 2 and 3 in Table 2
respectively), whereas the corresponding hemiacetals from
acetaldehyde or aldehydes e–g containing other functional groups
in R1 were never observed (entries 4–7 in Table 2). Benzaldehyde
(h) and methacrolein (i) did not form such hemiacetals either
The isolation of hemiacetals 4a–c as a single diastereomer
indicated that kinetic discrimination was operating on the mixture
of aldol diastereomers,23,24 so there was room to improve the
isolation of pure 1,4-syn adducts 2 provided that 4 could be
obtained in good yields to be subsequently converted back into 2.
Thus, we were pleased to observe that the use of two equivalents
of butanal (c) yielded up to 45% of pure hemiacetal 4c. Higher
loadings were not necessary, as three equivalents afforded a
similar yield (compare entries 1–3 in Table 3). Finally, stirring 4c
and a catalytic amount of p-TsOH in THF/MeOH at room
temperature produced 2c with a 98% yield (entry 3 in Table 3).
Application of this experimental procedure to isovaleraldehyde
(b) allowed us to isolate diastereomerically pure 1,4-syn aldol 2b
(entries
8
and
9
in Table 2). Unfortunately, the
diastereoselectivity for these conjugated aldehydes was poorer
than that achieved with the aliphatic counterparts, being
particularly low with benzaldehyde (dr 55:45, entry 8 in Table 2).
in a straightforward manner (entry 4 in Table 3), but
isobutyraldehyde (a) turned out to be less amenable and
produced hemiacetal 4a in a low yield (entry 5 in Table 3).
Table 3
Synthesis and hydrolysis of hemiacetals 4
a) 1.1 eq TiCl4, 1.1 eq i-Pr2NEt, CH2Cl2, –94 °C, 30 min. b) n eq R 1CHO, –78 °C, 30 min. c) cat p-TsOH, 4:1 THF/MeOH, rt, 20 min
Entry
Aldehyde
R1
Equivalents
Hemiacetal
dra 4
Yield 4 (%)b
Aldol
2c
Yield 2 (%)b
1
2
3
4
5
c
c
c
b
a
n-Pr
n-Pr
n-Pr
i-Bu
i-Pr
1.5
2
4c
4c
4c
4b
4a
>97:3
>97:3
>97:3
>97:3
>97:3
18
45
43
42
17
–
2c
–
3
2c
98
84
–
2
2b
2
2a
a) The minor diastereomer was not detected in the isolated products by 1H NMR analysis (400 MHz).
b) Isolated yield.

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Tetrahedron
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Therefore, while it is true that such a protocol is restricted to
certain aliphatic aldehydes, it easily produces configurationally
pure 1,4-syn aldol adducts which are difficult to obtain by other
methods. Moreover, it also suggests that subtle structural details
can determine the outcome of these aldol reactions.
2.3. TiCl4-Mediated aldol reaction of chiral α-silyloxy methyl
ketones
The aim of expanding the scope of such a substrate-controlled
transformation led us to test the reaction of other α-tert-
butyldimethylsilyloxy methyl ketones with several representative
aldehydes. Thus, ketones 6–8 were prepared in an
enantiomerically pure form through acylation of MeLi with N-
acyl pyrrolidines 9–11 derived from the corresponding α–
hydroxy esters, as shown in Scheme 2.25 Moreover, 6 and 8 were
also obtained by treatment of the corresponding Weinreb amides
12 and 13 with MeMgBr.26
Scheme 2. Synthesis of α-OTBS ketones 6–8. Reagents and conditions: a)
With a straightforward and reliable multigram supply of α-
tert-butyldimethylsilyloxy methyl ketones to hand, we evaluated
their titanium-mediated aldol reactions with isobutyraldehyde
(a), benzaldehyde (h), and methacrolein (i) under the previously
optimized experimental conditions. The results are summarized
in Table 4, including those for lactate-derived ketone 1.
C4H9N, rt. b) TBSCl, Et3N, DMAP, THF, rt. c) MeLi, THF, –78 °C. d)
MeONHMe·HCl, i-PrMgCl, THF, –20 °C. e) MeMgBr, THF, 0 °C.
Table 4
TiCl4-Mediated aldol reactions of α-OTBS methyl ketones
a) 1.1 eq TiCl4, 1.1 eq i-Pr2NEt, CH2Cl2, –94 °C, 30 min. b) 1.5 eq R 1CHO, –78 °C, 30 min
Entry
1
Ketone
R
Aldehyde R1
i-Pr
Ph
Adduct
2a
dra (1,4-syn/1,4-anti)
77:23c
Yield (%)b
71
1
Me
a
2
1
1
6
6
6
7
7
7
8
8
8
Me
Me
i-Bu
i-Bu
i-Bu
Bn
h
2h
55:45
65:35
73:27
72:28
64:36
77:23
75:25
68:32
96:4
75
80
95
75
74
95
94
93
85
84
83
3
i
C(Me)=CH2
2i
4
a
h
i
i-Pr
14a
14h
14i
16a
16h
16i
18a
18h
18i
5
Ph
6
C(Me)=CH2
i-Pr
7
a
h
i
8
Bn
Ph
9
Bn
C(Me)=CH2
i-Pr
10
11
12
i-Pr
i-Pr
i-Pr
a
h
i
Ph
83:17
90:10
C(Me)=CH2
a) Determined by 1H NMR analysis of the reaction mixture
b) Overall isolated yield. Diastereomeric aldol adducts can not be separated by column chromatography
c) Determined by 1H NMR analysis of isolated products

5
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Table 5
Influence of the protecting group on the TiCl4-mediated aldol reactions of α-silyloxy ketones
(a) 1.1 eq TiCl4, 1.1 eq i-Pr2NEt, CH2Cl2, –94 °C, 30 min. b) 1.5 eq i-PrCHO ( a), –78 °C, 30 min
Entry
Ketone
R3Si
Adduct
16a
dra (1,4-syn/1,4-anti)
77:23c
Yield (%)b
1
2
3
7
TBS
95
91
98
20
21
TES
22a
76:24
80:20
TBDPS
24a
a) Determined by 1H NMR analysis of the reaction mixture
b) Overall isolated yield. Diastereomeric aldol adducts can not be separated by column chromatography
c) Determined by 1H NMR analysis of isolated products
Most of these acetate aldol reactions provided the
corresponding 1,4-syn aldol adducts in high yields and with
moderate to excellent diastereoselectivities. Lactate-derived
the resultant α-hydroxy ketones gave the corresponding β-
hydroxy acids 26 and 27 (Scheme 3).
methyl ketone
reactions, whereas the valine–derived ketone
1
underwent the poorest stereocontrolled
produced
8
diastereomeric ratios of up to 96:4 (compare entries 1–3 and 10–
12 in Table 4). Thus, the steric bulk of the R group plays a
crucial role in the diastereoselectivity of the reaction, although
the pace at which the latter increases also depends on aldehyde.
Indeed, aldol reactions of 1, 6, and 7 with isobutyraldehyde (a)
and methacrolein (i) produce similar diastereomeric ratios
(approximately dr 75:25 and 65:35 respectively, compare entries
1, 4, and 7 with 3, 6, and 9) whereas similar reactions of 8 result
in much better stereocontrol (dr 96:4 and 90:10 respectively,
entries 10 and 12 in Table 4). In contrast, the diastereomeric
ratios for benzaldehyde steadily increase from 55:45 to 83:17
(compare entries 2, 5, 8, and 11 in Table 4). All together, these
results show that α-OTBS methyl ketones with a bulky R group
can participate in highly diastereoselective acetate aldol reactions
and provide access to 1,4-syn diastereomers that are difficult to
obtain by any other synthetic method.5g-h,27
a) 48% HF, CH3CN, rt, 2.5 h. b) NaIO4, 2:1 MeOH/H2O, rt, 1 h
Scheme 3. Chemical correlation of aldols 2 and 18.
Comparison of the physical and spectroscopic data for the
carboxylic acids 26 and 27 with those previously reported in the
literature proved the 1,4-syn configuration of the aldol adducts
(Scheme 4).
Finally, the influence of other silyl protecting groups was also
tested. To this end, α-silyloxy methyl ketones 20 and 21 were
prepared25 as was
7
and their aldol reactions with
isobutyraldehyde (a) were examined. Importantly, the results
summarized in Table 5 show that all those ketones produced
excellent yields (91–98%) and diastereoselectivities close to
80:20. Therefore, the silyl-protecting groups have no influence
on such reactions and even the labile TES can safely be used. In
short, TiCl4-mediated acetate aldol additions of α-silyloxy
methyl ketones to a wide array of achiral aldehydes provide the
corresponding 1,4-syn aldol adducts with remarkable
stereocontrol
.
2.4. Configuration
Scheme 4. 1,4-syn Configuration of aldols 2 and 18.
The stereochemical outcomes of such titanium-mediated aldol
reactions of α-silyloxy methyl ketones were established by
chemical correlation of the aldol adducts 2a, 18a, and 18h.
Removal of the TBS protecting group and further oxidation of

6
Tetrahedron
ACCEPTED MANUSCRIPT
The moderate to high 1,4-syn stereochemical induction
To gain further insight into such unforeseen behaviour, we
provided by such a wide range of α-silyloxy ketones is a pleasing
complement to the 1,4-anti trend observed for related α-
benzyloxy ketones.14 So titanium-mediated aldol reactions from
α-hydroxy methyl ketones can provide either configuration
merely by a change of the protecting group (Scheme 1).18 This is
especially remarkable since most of the acetate aldol reactions
from α-hydroxy methyl ketones supply the corresponding 1,4-
anti configuration.27 Therefore, these substrate-controlled aldol
reactions from α-silyloxy methyl ketones may be a valuable tool
for the total synthesis of natural products. With this in mind, we
finally tested the reactions in a more complex scenario involving
chiral aldehydes.
assessed double asymmetric aldol reactions of methyl ketones 1
and 8 with chiral α-OTBDPS aldehydes 33 and ent-33.32 These
are known to impart a remarkable Felkin bias and are often
employed as probes to evaluate such transformations.33.34.35 As
shown in Scheme 6, these aldehydes confirmed the trend
observed in the former reactions. Indeed, the putative matched
pair involving lactate–derived ketone 1 and chiral aldehyde 33
produced a roughly equimolecular mixture of two diastereomers
in an excellent yield (see equation 7 in Scheme 6). Instead, anti-
Felkin aldol adduct 36 was obtained from ent-33 with a high
diastereomeric ratio (dr 80:20) and with a 92% yield (see
equation 8 in Scheme 6). Valine–derived methyl ketone 8
exhibited the same trend. Contrary to what was expected, its
addition to 33 produced Felkin adduct 38 in
a 84:16
2.5. Double asymmetric aldol reactions
diastereomeric ratio with a 93% yield whereas the parallel
reaction with ent-33 produced anti-Felkin adduct 40 in a higher
diastereomeric ratio (dr 93:7) than with a 95% yield (compare
equation 9 and equation 10 in Scheme 6).
Conventional wisdom states that double asymmetric reactions
become more or less diastereoselective than those of the two
reacting depending on the stereochemical induction imparted by
each of them. Thus, if they cooperate and produce the same
diastereomer (matched case) the stereocontrol increases; whereas
in the opposite situation (mismatched case) the stereocontrol is
reduced.29 This occurs for most aldol additions of chiral enolates
to chiral aldehydes and it is currently used in the accounts of such
reactions. Nonetheless, we had previously observed that double
asymmetric acetate aldol reactions from α–benzyloxy methyl
ketones are highly diastereoselective, irrespective of the
configuration of the ketone and the aldehyde.14b Therefore, the
stereochemical outcome of this sort of reactions deserve to be
examined carefully.
These puzzling results highlight the difficulty in providing a
simple mechanistic model that accounts for the overall
transformations and reveal the necessity of further studies to shed
light on the intricacies of these reactions. In turn, they also
emphasize the fact that sterically hindered α-OTBS methyl
ketones are an excellent platform from which 1,4-syn aldol
adducts can be obtained in a highly diastereoselective and
straightforward manner irrespective of the configuration of the
aldehyde, which can be exploited to devise more efficient
synthesis.
Keeping such precedents in mind, we examined the TiCl4-
mediated aldol reaction of lactate-derived ketone 1 with α-Me
chiral aldehydes 28 and ent-28 (Scheme 5).30 Since it is well
documented that chiral aldehydes favour the Felkin diastereomer
in acetate aldol reactions under non-chelating conditions,5,10,31
aldehyde 28 was expected to produce the most diastereoselective
process. Surprisingly, just the contrary was observed: the
3. Conclusions
To summarize, TiCl4-mediated acetate aldol reactions of
chiral α-silyloxy methyl ketones with a variety of aldehydes
produce the corresponding 1,4-syn adducts with moderate to high
diastereoselectivities and yields. Importantly, sterically hindered
α-silyloxy methyl ketones participate in highly stereocontrolled
transformations irrespective of the aldehyde; this nicely
complements the 1,4-anti induction provided by related α-
benzyloxy methyl ketones. Thus, the titanium–based
methodology reported here represents a new and complimentary
approach to substrate-controlled acetate aldol reactions, which
may be helpful to design more efficient syntheses.
enantiomer of aldehyde 28, ent-28, produced
a better
diastereomeric ratio (dr 72:28 versus 62:38) with a higher yield
(81% versus 67%, see equations 5 and 6 in Scheme 5). Moreover,
the diastereoselectivity of the putative matched pair was slightly
lower than that with isobutyraldehyde (dr 77:23), which is the
most similar achiral aldehyde used in previous experiments (see
Table 2).
a) 1.1 eq TiCl4, 1.1 eq i-Pr2NEt, CH2Cl2, –94 °C, 30 min. b) 1.2 eq 28 or ent-28, –78 °C, 30 min
Scheme 5. Double asymmetric aldol reactions with chiral α–Me aldehydes.

7
ACCEPTED MANUSCRIPT
a) 1.1 eq TiCl4, 1.1 eq i-Pr2NEt, CH2Cl2, –94 °C, 30 min. b) 1.2 eq RCHO, –78 °C, 30 min
Scheme 6. Double asymmetric aldol reactions with chiral α–OTBDPS aldehydes.
4. Experimental Section
4.2. Synthesis of (S)-tert-butyldimethylsilyloxy-2-butanone (1)
MeLi (1.6 M in THF, 4.0 mL, 6.5 mmol) was added dropwise
4.1. General information
Unless otherwise noted, all oxygen and moisture-sensitive
reactions were conducted in oven-dried glassware under inert
atmosphere of N2 with anhydrous solvents. The solvents and
reagents were dried and purified when necessary according to
standard procedures. All commercial reagents were used as
received. Analytical thin-layer chromatography (TLC) was
carried out on Merck silica gel 60 F254 plates and analyzed by UV
(254 nm) and stained with p-anisaldehyde or phosphomolybdic
acid; Rf values are approximate. Column chromatographies were
carried under low pressure (flash) conditions and performed on
SDS silica gel 60 (35–70 µm). Specific rotations ([α]D) were
determined at 20 ºC on a Perkin-Elmer 241 MC polarimeter. IR
spectra were recorded on a Nicolet 6700 FT-IR Thermo
Scientific spectrometer and only the more representative
to
a
solution of (S)-2-tert-butyldimethylsilyloxy-N,N-
tetramethylenpropanamide (1.12 g, 4.4 mmol) in THF (40 mL) at
–78 °C. The resulting mixture was stirred at –78 °C for 45 min,
quenched by addition of saturated NH4Cl (10 mL) and vigorously
stirred at room temperature for 10 min. The mixture was diluted
with Et2O (60 mL) and the layers were separated. The organic
layer was washed with saturated NH4Cl (30 mL), brine (30 mL),
dried (MgSO4), and carefully concentrated at 0 °C (Alert:
concentration at higher temperatures led to lower yields due to
the volatility of compound). The resulting oil was purified by
column chromatography (50:50 hexanes/CH2Cl2) to afford 707
mg (80% yield) of (S)-tert-butyldimethylsilyloxy-2-butanone (1)
as a colourless oil. Rf (50:50 hexanes/CH2Cl2) 0.35. [α]D –6.8 (c
1.0, CHCl3) [lit.12d [α]D –7.1 (c 2.16, CHCl3)]. IR (film) ν 2956,
2931, 2887, 2858, 1720, 1254, 1125. 1H NMR (400 MHz,
CDCl3) δ 4.11 (1H, q, J = 6.8, CHOTBS), 2.18 (3H, s, COCH3),
1.27 (3H, d, J = 6.8, CH3CHOTBS), 0.90 (9H, s, (CH3)3C), 0.08
(6H, s, Si(CH3)2). 13C NMR (100.6 MHz, CDCl3) δ 212.6 (C),
75.0 (CH), 25.7 (CH3), 24.8 (CH3), 20.6 (CH3), 18.0 (C), –4.7
(CH3), –5.1 (CH3).
frequencies (ν) are reported in cm–1. 1H NMR (400 MHz) and 13
C
NMR (100.6 MHz) spectra were recorded on a Varian Mercury
400. Chemical shifts (δ) are quoted in ppm and referenced to
1
internal TMS (δ 0.00 for H NMR), or CDCl3 (δ 77.0 for 13C
NMR); coupling constants (J) are quoted in Hz; data are reported
as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet
(and their corresponding combinations); where necessary, 2D
techniques (NOESY, COSY, HSQC) were also used to assist on
structure elucidation. High resolution mass spectra (HRMS) were
obtained with an Agilent 1100 spectrometer by the Unitat
4.3. General procedure for the TiCl4-mediated aldol reaction
Neat TiCl4 (120 ꢀL, 1.1 mmol) was added dropwise to a
solution of the corresponding α-silyloxy methyl ketone (1.0
d’Espectrometria de Masses at the Centres Científics
Tecnològics de la Universitat de Barcelona (CCiTUB).
i

8
Tetrahedron
1
mmol) in CH2Cl2 (5.0 mL) at –94 ºC, and the mixture was
Minor aldol (3b). H NMR (400 MHz, CDCl3) δ 2.82 (1H,
dd, J = 18.4, 2.8, COCHxHy), 2.58 (1H, dd, J = 18.4, 9.2,
COCHxHy), 1.29 (3H, d, J = 6.8, CH3CHOTBS), 0.09 (3H, s,
SiCH3), 0.08 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ
215.9, 74.9, 65.6, 45.7, 44.4, 24.4, 23.3, 22.0, 18.0, –4.7, –5.1.
ACCEPTED MANUSCRIPT
stirred for 5 min. Then, anhydrous i-Pr2NEt (190 ꢀL, 1.1 mmol)
was added dropwise and the resulting dark red solution was
stirred for 30 min at –94 ºC. After dropwise addition of the
freshly distilled aldehyde (1.5 mmol), stirring was continued for
30 min at –78 ºC. The reaction was quenched by the addition of
saturated NH4Cl (5 mL) and vigorously stirred at room
temperature for 10 min. Then it was diluted with Et2O (50 mL),
and washed with H2O (50 mL), saturated NaHCO3 (50 mL), and
brine (50 mL). The combined organic extracts were dried
(MgSO4) and concentrated. The resulting crude was analysed by
1H NMR and purified by column chromatography.
4.4.4.
(2S,4S,6S)-4[(S)-1-tert-Butyldimethylsilyloxyethyl]-2,6-
(90:10
diisobutyl-1,3-dioxan-4-ol (4b). Colourless oil. Rf
hexanes/EtOAc) 0.85. [α]D –20.7 (c 1.0, CHCl3). IR (film) ν
3522 (br), 2955, 2929, 2897, 2869, 1470, 1377, 1251, 1155,
1120, 1080, 1004. 1H NMR (400 MHz, CDCl3) δ 4.73 (1H, dd,
J = 6.4, 4.8, OCHO), 4.01–3.92 (1H, m, CH2CHO), 3.67 (1H, q,
J = 6.4, CHOTBS), 3.47 (1H, d, J = 2.4, OH), 1.88–1.76 (2H, m,
CH2), 1.52–1.36 (3H, m, O2CCHxHy & CH2), 1.28–1.22 (1H, m,
O2CCHxHy), 1.20–1.12 (2H, m, 2 × CH(CH3)2), 1.04 (3H, d, J =
6.4, CH3CHOTBS), 0.92–0.89 (12H, m, 4 × CH3), 0.89 (9H, s,
(CH3)3C), 0.08 (3H, s, SiCH3), 0.07 (3H, s, SiCH3). 13C NMR
(100.6 MHz, CDCl3) δ 96.4, 93.9, 73.5, 70.4, 45.2, 43.4, 37.0,
25.8, 24.0, 23.9, 23.2, 22.9, 22.6, 22.1, 18.1, 17.5, –4.6, –4.9.
HRMS (+ESI): m/z calcd. for C20H42NaO4Si [M+Na]+: 397.2744,
found: 397.2751.
4.4. TiCl4-Mediated aldol reactions of lactate–derived ketone 1
4.4.1. (2S,5R)-2-tert-Butyldimethylsilyloxy-5-hydroxy-6-methyl-
3-heptanone (2a). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.25.
[α]D +9.2 (c 1.0, CHCl3, 50% de). IR (film) ν 3487 (br), 2957,
2935, 2858, 1714, 1471, 1366, 1254, 1120, 1044. 1H NMR
(400 MHz, CDCl3) δ 4.14 (1H, q, J = 6.9, CHOTBS), 3.82–3.72
(1H, m, CHOH), 2.78 (1H, dd, J = 17.9, 3.0, COCHxHy), 2.66
(1H, dd, J = 17.9, 9.3, COCHxHy), 1.80–1.64 (1H, m, CH(CH3)2),
1.29 (3H, d, J = 6.9, CH3CHOTBS), 0.96 (3H, d, J = 6.9, CH3),
0.92 (9H, s, (CH3)3C), 0.91 (3H, d, J = 6.9, CH3), 0.09 (3H, s,
SiCH3), 0.08 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ
215.9, 75.0, 72.1, 40.6, 33.2, 25.6, 20.6, 18.2, 18.1, 17.9, –4.7, –
5.0. HRMS (+ESI): m/z calcd. for C14H31O3Si [M+H]+: 275.2036,
found: 275.2035.
4.4.5. (2S,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-3-octanone
(2c). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.35. [α]D +18.7
(c 1.0, CHCl3). IR (film) ν 3473 (br), 2958, 2932, 2859, 1716,
1472, 1464, 1367, 1255, 1120, 1006. 1H NMR (400 MHz,
CDCl3) δ 4.13 (1H, q, J = 6.8, CHOTBS), 4.07–3.98 (1H, m,
CHOH), 2.76 (1H, dd, J = 18.2, 3.2, COCHxHy), 2.67 (1H, dd, J
= 18.2, 8.8, COCHxHy), 1.57–1.32 (4H, m, (CH2)2CH3), 1.28
(3H, d, J = 6.8, CH3CHOTBS), 0.93 (3H, t, J = 6.9, CH3), 0.91
(9H, s, (CH3)3C), 0.08 (3H, s, SiCH3), 0.07 (3H, s, SiCH3). 13C
NMR (100.6 MHz, CDCl3) δ 215.5, 75.0, 67.1, 43.6, 38.7, 25.7,
20.6, 18.7, 18.0, 14.0, –4.7, –5.1. HRMS (+ESI): m/z calcd. for
C14H31O3Si [M+H]+: 275.2036, found: 275.2045.
Minor aldol (3a). 1H NMR (400 MHz, CDCl3) δ 2.84 (1H, dd,
J = 18.1, 2.3, COCHxHy), 2.58 (1H, dd, J = 18.1, 9.8, COCHxHy),
0.09 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 74.9, 40.9,
17.6.
4.4.2.
(2S,4S,6R)-4[(S)-1-tert-Butyldimethylsilyloxyethyl]-2,6-
Minor aldol (3c). 1H NMR (400 MHz, CDCl3) δ 2.85 (1H, dd,
J = 18.4, 2.4, COCHxHy), 2.58 (1H, dd, J = 18.4, 9.2, COCHxHy),
1.28 (3H, d, J = 6.8, CH3CHOTBS), 0.09 (3H, s, SiCH3), 0.08
(3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 215.6, 74.9,
67.2, 43.8, 38.7, 18.6.
diisopropyl-1,3-dioxan-4-ol (4a). Colourless oil. Rf (90:10
hexanes/EtOAc) 0.85. [α]D –18.4 (c 0.25, CHCl3). IR (film) ν
3532 (br), 2958, 2858, 1472, 1377, 1363, 1252, 1105, 1016. 1H
NMR (400 MHz, CDCl3) δ 4.73 (1H, d, J = 5.2, OCHO), 3.69
(1H, q, J = 6.4, CHOTBS), 3.54 (1H, ddd, J =11.7, 6.8, 2.5,
CH2CHO), 3.44 (1H, d, J = 2.3, OH), 1.80–1.69 (1H, m,
CH(CH3)2), 1.69–1.58 (1H, m, CH(CH3)2), 1.51 (1H, dd, J =
12.7, 2.5, CHxHyCHO), 1.20 (1H, ddd, J = 12.7, 11.7, 2.3,
CHxHyCHO), 1.06 (3H, d, J = 6.4, CH3CHOTBS), 0.95 (3H, d, J
= 6.7, CH3), 0.92 (3H, d, J = 6.9, CH3), 0.91 (3H, d, J = 6.9,
CH3), 0.90 (9H, s, (CH3)3C), 0.88 (3H, d, J = 6.8, CH3), 0.10 (3H,
s, SiCH3), 0.09 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ
98.3, 96.5, 76.8, 73.5, 33.4, 33.1, 32.4, 25.8, 18.1(×2), 18.0, 17.6,
17.4, 16.8, –4.6, –4.8. HRMS (+ESI): m/z calcd. for
C18H38NaO4Si [M+Na]+: 369.2431, found: 369.2435.
4.4.6.
(2S,4S,6S)-4[(S)-1-tert-Butyldimethylsilyloxyethyl]-2,6-
(90:10
dipropyl-1,3-dioxan-4-ol (4c). Colourless oil. Rf
hexanes/EtOAc) 0.90. [α]D –20.9 (c 1.0, CHCl3). IR (film) ν
3520 (br), 2958, 2930, 2874, 2858, 1464, 1377, 1253, 1148,
1119, 1005. 1H NMR (400 MHz, CDCl3) δ 5.03 (1H, t, J = 5.3,
OCHO), 3.91–3.83 (1H, m, CH2CHO), 3.68 (1H, q, J = 6.4,
CHOTBS), 3.46 (1H, d, J = 2.3, OH), 1.62–1.32 (9H, m,
O2CCHxHy & 4 × CH2), 1.27–1.18 (1H, m, O2CCHxHy), 1.05
(3H, d, J = 6.4, CH3CHOTBS), 0.94–0.88 (6H, m, 2 × CH2CH3),
0.89 (9H, s, (CH3)3C), 0.08 (3H, s, SiCH3), 0.07 (3H, s, SiCH3).
13C NMR (100.6 MHz, CDCl3) δ 96.3, 94.8, 73.4, 71.9, 38.3,
36.8, 36.4, 25.8, 18.3, 18.1, 17.5, 17.4, 14.0 (×2),–4.6,–4.9.
HRMS (+ESI): m/z calcd. for C18H38NaO4Si [M+Na]+: 369.2431,
found: 369.2436.
4.4.3. (2S,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-7-methyl-3-
octanone (2b). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.30.
[α]D +9.7 (c 1.15, CHCl3). IR (film) ν 3475 (br), 2956, 2931,
2859, 1715, 1471, 1367, 1259, 1121. 1H NMR (400 MHz,
CDCl3) δ 4.13 (1H, q, J = 6.8, CHOTBS), 4.15–4.05 (1H, m,
CHOH), 2.74 (1H, dd, J = 18.4, 3.2, COCHxHy), 2.67 (1H, dd, J
= 18.4, 8.8, COCHxHy), 1.88–1.74 (1H, m, CH(CH3)2), 1.55–1.45
(1H, m, CHxHyCH(CH3)2), 1.28 (3H, d, J = 6.8, CH3CHOTBS),
1.20–1.12 (1H, m, CHxHyCH(CH3)2), 0.93 (3H, d, J = 6.1, CH3),
0.91 (3H, d, J = 6.1, CH3), 0.91 (9H, s, (CH3)3C), 0.08 (3H, s,
SiCH3), 0.08 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ
215.8, 75.0, 65.5, 45.7, 44.0, 25.7, 24.4, 23.3, 22.0, 20.6, 18.0, –
4.7, –5.1. HRMS (+ESI): m/z calcd. for C15H32NaO3Si [M+Na]+:
311.2013, found: 311.2009.
4.4.7. (2S,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-3-hexanone
(2d). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.20. IR (film) ν
3448 (br), 2957, 2931, 2897, 2859, 1716, 1472, 1463, 1368,
1258, 1119, 1058. 1H NMR (400 MHz, CDCl3) δ 4.25–4.16
(1H, m, CHOH), 4.13 (1H, q, J = 6.8, CHOTBS), 2.77 (1H, dd, J
= 18.2, 3.2, COCHxHy), 2.68 (1H, dd, J = 18.2, 8.6, COCHxHy),
1.29 (3H, d, J = 6.8, CH3CHOTBS), 1.22 (3H, d, J = 6.3,
CHOHCH3), 0.92 (9H, s, (CH3)3C), 0.09 (3H, s, SiCH3), 0.08

9
(3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 215.4, 74.9,
hexanes/EtOAc) 0.25. IR (film) ν 3481 (br), 2955, 2930, 2895,
A
CCEPTED MANUSCRIPT
63.6, 45.1, 25.7, 22.5, 20.7, 18.0, –4.7, –5.1.
2858, 1717, 1472, 1463, 1363, 1254, 1159, 1118, 1090. 1H
NMR (400 MHz, CDCl3) δ 7.42–7.25 (10H, m, 2×ArH), 5.17–
5.10 (1H, m, 2×CHOH), 4.16 (1H, q, J = 6.9, 2×CHOTBS), 3.05
(1H, dd, J = 17.9, 9.1, COCHxHy), 3.04 (1H, dd, J = 18.1, 3.5,
COCHxHy), 2.97 (1H, dd, J = 18.1, 8.8, COCHxHy), 2.95 (1H,
Minor aldol (3d). 1H NMR (400 MHz, CDCl3) δ 2.86 (1H, dd,
J = 18.4, 2.8, COCHxHy), 2.58 (1H, dd, J = 18.4, 9.0, COCHxHy),
1.21 (3H, d, J = 6.8, CH3CHOTBS), 0.92 (9H, s, (CH3)3C), 0.09
(3H, s, SiCH3), 0.09 (3H, s, SiCH3). 13C NMR (100.6 MHz,
CDCl3) δ 74.8, 63.8, 45.2, 22.4.
dd, J
= 17.9, 3.2, COCHxHy), 1.27 (3H, d, J = 6.9,
CH3CHOTBS), 1.21 (3H, d, J = 6.9, CH3CHOTBS), 0.83–0.82
(18H, m, 2× (CH3)3C), 0.07 (3H, s, SiCH3), 0.06 (6H, s, SiCH3),
0.06 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 214.3,
214.1, 143.0, 142.9, 128.5, 128.5, 127.6, 127.5, 125.7, 125.6,
75.0, 74.9, 69.8, 69.7, 45.7, 45.5, 25.7 (×2), 20.6, 20.5, 18.0 (×2),
–4.7 (×2), –5.0 (×2).
4.4.8.
(2S,5R)-2-tert-Butyldimethylsilyloxy-5-hydroxy-6-
triisopropylsilyloxy-3-hexanone (2e). Colourless oil. Rf (90:10
hexanes/EtOAc) 0.30. IR (film) ν 3487 (br), 2943, 2893, 2866,
1717, 1464, 1387, 1367, 1254, 1121. 1H NMR (400 MHz,
CDCl3) δ 4.19–4.08 (1H, m, CHOH), 4.16 (1H, q, J = 6.8,
CHOTBS), 3.72–3.62 (2H, m, CH2OTBDPS), 2.87 (1H, dd, J =
18.0, 7.8, COCHxHy), 2.77 (1H, dd, J = 18.0, 4.5, COCHxHy),
1.29 (3H, d, J = 6.8, CH3CHOTBS), 1.15–1.03 (21H, m,
Si(CH(CH3)2)3), 0.91 (9H, s, (CH3)3C), 0.08 (3H, s, SiCH3), 0.07
(3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 214.0, 75.0,
68.1, 66.6, 40.4, 25.7, 20.6, 17.9, 17.8, 11.9, –4.5, –5.1.
4.4.12. (2S,5R)-2-tert-Butyldimethylsilyloxy-5-hydroxy-6-methyl-
6-hepten-3-one (2i). Colourless oil. Rf (90:10 hexanes/EtOAc)
0.30. IR (film) ν 3482 (br), 2956, 2931, 2887, 2858, 1717, 1472,
1
1463, 1389, 1367, 1256, 1161, 1119, 1006. H NMR (400 MHz,
CDCl3) δ 5.05–5.02 (1H, m, =CHxHy), 4.89–4.87 (1H, m,
=CHxHy), 4.52–4.46 (1H, m, CHOH), 4.16 (1H, q, J = 6.8,
CHOTBS), 2.86 (1H, dd, J = 17.8, 8.5, COCHxHy), 2.79 (1H, dd,
J = 17.8, 3.7, COCHxHy), 1.76 (3H, s, H2C=CCH3), 1.30 (3H, d,
J = 6.8, CH3CHOTBS), 0.93 (9H, s, (CH3)3C), 0.09 (6H, s,
SiCH3), 0.08 (6H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ
214.7, 145.8, 111.0, 75.0, 70.8, 42.3, 25.7, 20.5, 18.4, 18.0, –4.7,
–5.1.
Minor aldol (3e). 1H NMR (400 MHz, CDCl3) δ 2.92 (1H, dd,
J = 17.9, 4.5, COCHxHy), 2.77 (1H, dd, J = 17.9, 8.0, COCHxHy),
1.29 (3H, d, J = 6.8, CH3CHOTBS), 0.92 (9H, s, (CH3)3C), 0.09
(3H, s, SiCH3), 0.09 (3H, s, SiCH3). 13C NMR (100.6 MHz,
CDCl3) δ 74.9, 68.0, 66.5, 40.6, –4.7, –5.1.
Minor aldol (3i). 1H NMR (400 MHz, CDCl3) δ 4.16 (1H, q, J
= 6.8, CHOTBS), 2.91 (1H, dd, J = 18.0, 2.8, COCHxHy), 2.76
(1H, dd, J = 18.0, 9.4, COCHxHy), 1.31 (3H, d, J = 6.8,
CH3CHOTBS), 0.92 (9H, s, (CH3)3C), 0.10 (3H, s, SiCH3), 0.09
(6H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 145.8, 111.2,
74.9, 70.9, 42.6, 20.6, 18.3, –4.7.
4.4.9.
(2S,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-7-
triisopropylsilyloxy-3-heptanone (2f). Colourless oil. Rf (90:10
hexanes/EtOAc) 0.35. IR (film) ν 3489 (br), 2943, 2892, 2866,
1716, 1464, 1388, 1366, 1254, 1115. 1H NMR (400 MHz,
CDCl3) δ 4.34–4.27 (1H, m, CHOH), 4.15 (1H, q, J = 6.8,
CHOTBS), 3.92–3.86 (2H, m, CH2OTBDPS), 2.85 (1H, dd, J =
17.8, 7.8, COCHxHy), 2.70 (1H, dd, J = 17.8, 4.6, COCHxHy),
1.79–1.65 (2H, m, CH2CH2OTBDPS), 1.29 (3H, d, J = 6.8,
CH3CHOTBS), 1.15–1.03 (21H, m, Si(CH(CH3)2)3), 0.91 (9H, s,
(CH3)3C), 0.08 (6H, s, Si(CH3)2). 13C NMR (100.6 MHz, CDCl3)
δ 213.6, 75.0, 67.0, 62.0, 44.0, 38.6, 25.7, 21.1, 20.6, 18.0, 11.8,
–4.7, –5.1.
4.5. Hydrolysis of hemiacetals 4a–c
A mixture of hemiacetal 4a–c (0.1 mmol) and p-TsOH·H2O
(25 µmol) in 4:1 THF/H2O (1.5 mL) was stirred at room
temperature for 20 min. Then, it was partitioned with Et2O and
saturated NaHCO3. The organic layer was washed with brine,
dried (MgSO4), and concentrated. The resulting crude was
purified by column chromatography (90:10 hexanes/EtOAc) to
afford pure aldol adducts 2a–c.
Minor aldol (3f). 1H NMR (400 MHz, CDCl3) δ 4.14 (1H, q, J
= 6.8, CHOTBS), 2.85 (1H, dd, J = 18.4, 5.8, COCHxHy), 2.73
(1H, dd, J = 18.4, 7.4, COCHxHy), 1.28 (3H, d, J = 6.8,
CH3CHOTBS), 0.92 (9H, s, (CH3)3C), 0.09 (6H, s, Si(CH3)2). 13
NMR (100.6 MHz, CDCl3) δ 74.9, 67.0, 62.0, 44.3, 38.5, 11.9.
C
4.6. Synthesis of α–OTBS methyl ketones 6–8
4.4.10. (2S,5S)-7-Amino-2-tert-butyldimethylsilyloxy-5-hydroxy-
N-phtaloyl-3-heptanone (2g). Colourless oil. Rf (60:40
4.6.1. Acylation of pirrolidine–amides 9–11
Experimental procedure reported for methyl ketone 1 was
used for the acylation of pirrolidine–amides 9–11,20 with the
following results.
hexanes/EtOAc) 0.60. IR (film) ν 3519 (br), 2954, 2930, 2895,
2857, 1772, 1715, 1468, 1443, 1397, 1372, 1253, 1121, 1089. 1H
NMR (400 MHz, CDCl3) δ 7.87–7.82 (2H, m, ArH), 7.74–7.68
(2H, m, ArH), 4.13 (1H, q, J = 6.8, CHOTBS), 4.12–4.03 (1H,
m, CHOH), 3.86 (2H, t, J = 6.6, CH2NPhth), 2.83 (1H, dd, J =
18.0, 8.9, COCHxHy), 2.66 (1H, dd, J = 18.0, 3.2, COCHxHy),
4.6.1.1.
(S)-3-tert-Butyldimethylsilyloxy-5-methyl-2-hexanone
(6). Starting from 9 (585 mg, 2.0 mmol), the acylation was
carried out for 1.5 h to afford 200 mg (42% yield) of 6 as a
colourless oil. Rf (CH2Cl2) 0.65. [α]D −31.3 (c 1.1, CHCl3). IR
(film) ν 2953, 2928, 2897, 2857, 1716, 1474, 1351, 1255, 1140,
1.81 (2H, q, CH2CH2NPhth), 1.27 (3H, d,
J = 6.8,
CH3CHOTBS), 0.89 (9H, s, (CH3)3C), 0.06 (3H, s, SiCH3), 0.05
(3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 213.9, 168.6,
133.9, 132.0, 123.2, 74.9, 64.8, 43.7, 35.3, 34.6, 25.6, 20.5, 18.0,
–4.7, –5.1.
1
1092. H NMR (400 MHz, CDCl3) δ 4.02 (1H, dd, J = 8.4, 4.9,
CHOTBS), 2.15 (3H, s, COCH3), 1.79–1.67 (1H, m, CH(CH3)2),
1.52 (1H, ddd, J = 13.5, 8.4, 5.5, CHxHy), 1.35 (1H, ddd, J =
13.5, 8.2, 4.9, CHxHy), 0.93 (3H, d, J = 7.0, CH3), 0.92 (9H, s,
(CH3)3C), 0.91 (3H, d, J = 7.0, CH3), 0.06 (3H, s, SiCH3), 0.04
(3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 212.3 (C), 77.6
(CH), 43.7 (CH2), 25.7 (CH3), 24.6 (CH3), 23.9 (CH), 23.3 (CH3),
22.0 (CH3), 18.1 (C), −4.9 (CH3), −5.1 (CH3). HRMS (+ESI): m/z
calcd. for C13H29O2Si [M+H]+: 245.1931, found: 245.1928.
Minor aldol (3g). 1H NMR (400 MHz, CDCl3) δ 2.81 (1H, dd,
J = 18.1, 3.4, COCHxHy), 2.70 (1H, dd, J = 18.1, 8.6, COCHxHy),
0.07 (3H, s, SiCH3), 0.06 (3H, s, SiCH3). 13C NMR (100.6 MHz,
CDCl3) δ 74.8, 64.8, 43.9, 35.2, 20.6.
4.4.11. (1R,4S) and (1S,4S)-5-tert-Butyldimethylsilyloxy-1-
hydroxy-3-pentanone (2h and 3h). Colourless oil. Rf (90:10

10
Tetrahedron
(CH), 72.1 (CH), 43.7 (CH2), 40.2 (CH2), 33.1 (CH), 25.7 (CH3),
ACCEPTED MANUSCRIPT
24.0 (CH), 23.2 (CH3), 22.1 (CH3), 18.3 (CH3), 18.1 (C), 18.0
(CH3), –4.8 (CH3), –5.0 (CH3).
4.6.1.2. (S)-3-tert-Butyldimethylsilyloxy-4-phenyl-2-butanone (7).
Starting from 10 (3.18 g, 9.5 mmol), the acylation was carried
out for 15 min to afford 1.28 g (48% yield) of 7 as a colourless
oil. Rf (CH2Cl2) 0.65. [α]D –45.0 (c 1.0, CHCl3). IR (film) ν
2953, 2929, 2854, 1714, 1651, 1557, 1470, 1453, 1255, 1099.
1H NMR (400 MHz, CDCl3) δ 7.34–7.14 (5H, m, ArH), 4.15
(1H, dd, J = 8.3, 4.0, CHOTBS), 2.91 (1H, dd, J = 13.4, 4.0,
PhCHxHy), 2.79 (1H, dd, J = 13.4, 8.3, PhCHxHy), 2.11 (3H, s,
COCH3), 0.84 (9H, s, (CH3)3C), –0.11 (3H, s, SiCH3), –0.29
(3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 212.0 (C),
137.3 (C), 137.0 (C), 129.9 (CH), 128.2 (CH), 126.6 (CH),
80.2 (CH), 41.2 (CH2), 25.7 (CH3), 25.5 (CH3), 18.0 (C), –5.3
1
Minor aldol (15a). H NMR (400 MHz, CDCl3) δ 4.07 (1H,
dd, J = 8.0, 5.0, CHOTBS), 3.07 (1H, br s, CHOH), 2.76 (1H, dd,
J = 18.1, 2.2, COCHxHy), 2.57 (1H, dd, J = 18.1, 9.9, COCHxHy),
0.93 (9H, s, (CH3)3C), 0.06 (6H, s, Si(CH3)2). 13C NMR (100.6
MHz, CDCl3) δ 216.0 (C), 77.5 (CH), 72.1 (CH), 43.9 (CH2),
40.7 (CH2), 33.0 (CH), 25.7 (CH3), 24.0 (CH), 23.2 (CH3), 22.1
(CH3), 18.3 (CH3), 18.1 (C), 18.0 (CH3), –4.8 (CH3), –4.9 (CH3).
4.7.2. (1R,4S)-4-tert-Butyldimethylsilyloxy-1-hydroxy-6-methyl-
1-phenyl-3-heptanone (14h). Colourless oil. Rf (CH2Cl2) 0.35. IR
(film) ν 3456 (br), 2956, 2927, 2893, 2856, 1718, 1470,
(CH3), –5.6 (CH3). HRMS (
[M
+ESI): m/z calcd. for C16H27O2Si
1
+
H]+: 279.1775, found: 279.1773.
1389,1363, 1253, 1092, 1056. H NMR (400 MHz, CDCl3) δ
7.38–7.26 (5H, m, ArH), 5.15 (1H, dd, J = 8.7, 3.3, CHOH), 4.07
(1H, dd, J = 8.3, 5.2, CHOTBS), 3.35 (1H, br s, OH), 2.99 (1H,
dd, J = 18.0, 3.3, COCHxHy), 2.91 (1H, dd, J = 18.0, 8.7,
COCHxHy), 1.75–1.62 (1H, m, CH(CH3)2), 1.48 (1H, ddd, J =
13.8, 8.3, 5.8, CHxHyCHOTBS), 1.33 (1H, ddd, J = 13.8, 8.0, 5.2,
CHxHyCHOTBS), 0.91 (3H, d, J = 6.7, CH3), 0.89 (9H, s,
(CH3)3C), 0.88 (3H, d, J = 6.3, CH3), 0.05 (3H, s, SiCH3), 0.03
(3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 214.2 (C), 143.0
(C), 128.5 (CH), 127.5 (CH), 125.5 (CH), 77.6 (CH), 69.8 (CH),
45.3 (CH2), 43.5 (CH2), 25.7 (CH3), 23.9 (CH), 23.2 (CH3), 22.1
(CH3), 18.1 (C), –4.8 (CH3), –5.0 (CH3).
4.6.1.3.
(S)-3-tert-Butyldimethylsilyloxy-4-methyl-2-pentanone
(8). Starting from 11 (1.42 g, 5.0 mmol), the acylation was
carried out for 1 h at –40 °C to afford 565 mg (49% yield) of 8 as
a colourless oil. Rf (95:5 hexanes/EtOAc) 0.35. [α]D –49.6 (c
0.9, CHCl3). IR (film) ν 2960, 2930, 2857, 1715, 1471, 1252,
1
1088. H NMR (400 MHz, CDCl3) δ 3.68 (1H, d, J = 5.8,
CHOTBS), 2.14 (3H, s, COCH3), 1.97–1.84 (1H, m,
CH(CH3)2), 0.94 (9H, s, (CH3)3C), 0.91 (3H, d, J = 6.7, CH3),
0.89 (3H, d, J = 6.9, CH3), 0.05 (3H, s, SiCH3), 0.02 (3H, s,
SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 212.4 (C), 83.8
(CH), 32.8 (CH), 25.8 (CH3), 25.7 (CH3), 18.8 (CH3), 18.1
(C), 17.5 (CH3), –4.9 (CH3), –5.1 (CH3). HRMS (
calcd. for C12H27O2Si [M
1
Minor aldol (15h). H NMR (400 MHz, CDCl3) δ 5.12 (1H,
dd, J = 7.5, 4.9, CHOH), 4.08 (1H, dd, J = 8.2, 5.1, CHOTBS),
3.33 (1H, br s, OH), 3.02–2.92 (2H, m, COCH2), 0.90 (9H, s,
(CH3)3C), 0.05 (6H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ
214.2 (C), 142.9 (C), 128.5 (CH), 127.6 (CH), 125.8 (CH), 77.5
(CH), 69.9 (CH), 45.7 (CH2), 43.7 (CH2), 25.7 (CH3), 23.9 (CH),
23.2 (CH3), 22.1 (CH3), 18.1 (C), –4.8 (CH3), –5.0 (CH3).
+ESI): m/z
+
H]+: 231.1775, found: 231.1772.
4.6.2. Acylation of Weinreb–amides 12–13
4.6.2.1. (S)-2-tert-Butyldimethylsilyloxy-5-methyl-2-hexanone
(6). A 1.4 M solution of MeMgBr in 75:25 toluene/THF (3.0
mL, 4.1 mmol) was added dropwise to a solution of 12 (396 mg,
4.7.3.
(3R,6S)-6-tert-Butyldimethylsilyloxy-3-hydroxy-2,8-
dimethyl-1-nonen-5-one (14i). Colourless oil. Rf (90:10
hexanes/EtOAc) 0.25. IR (film) ν 3487 (br), 2955, 2929, 2896,
2858, 1711, 1468, 1386, 1257, 1095. 1H NMR (400 MHz, CDCl3)
δ 5.04–5.02 (1H, m, C=CHxHy), 4.89–4.85 (1H, m, C=CHxHy),
4.51–4.46 (1H, m, CHOH), 4.07 (1H, dd, J = 8.3, 4.8, CHOTBS),
3.01 (1H, d, J = 3.4, OH), 2.84 (1H, dd, J = 17.9, 2.6, COCHxHy),
2.71 (1H, dd, J = 17.9, 9.5, COCHxHy), 1.77–1.67 (1H, m,
CH(CH3)2), 1.75 (3H, br s, CH3C=CH2), 1.57–1.48 (1H, m,
CHxHyCHOTBS), 1.43–1.34 (1H, m, CHxHyCHOTBS), 0.93
(3H, d, J = 6.4, CH3), 0.92 (9H, s, (CH3)3C), 0.91 (3H, d, J = 6.5,
CH3), 0.07 (3H, s, SiCH3), 0.04 (3H, s, SiCH3). 13C NMR (100.6
MHz, CDCl3) δ 214.7 (C), 145.7 (C), 111.0 (CH2), 77.6 (CH),
70.8 (CH), 43.6 (CH2), 42.1 (CH2), 25.7 (CH3), 23.9 (CH), 23.2
(CH3), 22.1 (CH3), 18.5 (CH3), 18.0 (C), –4.8 (CH3), –5.0 (CH3).
1.4 mmol) in THF (3.0 mL) at
stirred at °C for 2 h, quenched by addition of saturated NH4Cl
0 °C. The resulting mixture was
0
(5 mL) and vigorously stirred at room temperature for 10 min.
The layers were separated and the aqueous layer was extracted
with Et2O (2 × 10 mL) and CH2Cl2 (2 × 10 mL). The combined
organic extracts were dried (MgSO4) and concentrated. The
resulting oil was purified by column chromatography (CH2Cl2) to
afford 282 mg (84% yield) of 6.
4.6.2.2.
(S)-3-tert-Butyldimethylsilyloxy-4-methyl-2-
pentanone (7). The aforementioned experimental procedure
was followed, starting from 1310c (1.94 g, 7.0 mmol) to afford
1.39 g (86% yield) of 7.
1
Minor aldol (15i). H NMR (400 MHz, CDCl3) δ 5.03–5.00
(1H, m, C=CHxHy), 4.48–4.44 (1H, m, CHOH), 4.08 (1H, dd, J =
8.2, 4.9, CHOTBS), 3.10 (1H, d, J = 3.2, OH), 2.82 (1H, dd, J =
18.1, 3.2, COCHxHy), 2.74 (1H, dd, J = 18.1, 9.0, COCHxHy),
0.93 (3H, d, J = 6.3, CH3), 0.92 (9H, s, (CH3)3 C), 0.92 (3H, d, J
= 6.5, CH3), 0.07 (6H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3)
δ 214.8 (C), 145.8 (C), 111.3 (CH2), 77.4 (CH), 71.0 (CH), 43.8
(CH2), 42.4 (CH2), 25.7 (CH3), 24.0 (CH), 23.2 (CH3), 22.1
(CH3), 18.2 (CH3), 18.1 (C), –4.8 (CH3), –5.0 (CH3).
4.7. TiCl4-Mediated aldol reactions of α–OTBS methyl ketones
4.7.1.
(3R,6S)-6-tert-Butyldimethylsilyloxy-3-hydroxy-2,8-
(90:10
dimethyl-5-nonanone (14a). Colourless oil. Rf
hexanes/EtOAc) 0.35. IR (film) ν 3479 (br), 2954, 2928, 2897,
2855, 1711, 1472, 1255, 1089, 1042, 1003. 1H NMR (400
MHz, CDCl3) δ 4.05 (1H, dd, J = 8.4, 5.0, CHOTBS), 3.82–3.73
(1H, m, CHOH), 2.99 (1H, br s, CHOH), 2.82 (1H, dd, J = 18.1,
2.0, COCHxHy), 2.53 (1H, dd, J = 18.1, 9.9, COCHxHy), 1.78–
1.64 (2H, m, 2×CH(CH3)2), 1.58–1.48 (1H, m, CHxHyCHOTBS),
1.43–1.33 (1H, m, CHxHyCHOTBS), 0.95 (3H, d, J = 6.8, CH3),
0.93 (3H, d, J = 6.5, CH3), 0.92 (9H, s, (CH3)3C), 0.91 (3H, d, J =
6.6, CH3), 0.91 (3H, d, J = 7.3, CH3), 0.07 (3H, s, SiCH3), 0.04
(3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 215.9 (C), 77.7
4.7.4. (2S,5R)-2-tert-Butyldimethylsilyloxy-5-hydroxy-6-methyl-
1-phenyl-3-heptanone (16a). Colourless oil. Rf (90:10
hexanes/EtOAc) 0.20. IR (film) ν 3492 (br), 2953, 2927, 2887,
2856, 1712, 1466, 1257, 1094, 1044. 1H NMR (400 MHz,
CDCl3) δ 7.31–7.16 (5H, m, ArH), 4.17 (1H, dd, J = 8.6, 4.1,
CHOTBS), 3.78 (1H, ddd, J = 9.8, 5.8, 1.9, CHOH), 2.97–2.76

11
(3H, m, COCHxHy & PhCH2), 2.89 (1H, br s, OH), 2.57–2.45
=
18.3, 10.1,
COCHxHy),
2.00–1.86
(1H,
m,
ACCEPTED MANUSCRIPT
(1H, m, COCHxHy), 1.74–1.62 (1H, m, CH(CH3)2), 0.93 (3H, d, J
= 6.8, CH3), 0.89 (3H, d, J = 6.8, CH3), 0.84 (9H, s, (CH3)3C), –
0.12 (3H, s, SiCH3), –0.32 (3H, s, SiCH3). 13C NMR (100.6 MHz,
CDCl3) δ 215.2 (C), 136.9 (C), 129.9 (CH), 128.3 (CH), 126.7
(CH), 80.3 (CH), 71.9 (CH), 41.3 (CH2), 41.1 (CH2), 33.1 (CH),
25.7 (CH3), 18.2 (CH3), 18.0 (C), 17.9 (CH3), –5.3 (CH3), –5.6
(CH3).
TBSOCHCH(CH3)2), 1.77–1.63 (1H, m, CHOHCH(CH3)2), 0.95
(3H, d, J = 6.8, CH3), 0.94 (9H, s, (CH3)3C), 0.92 (3H, d, J = 6.8,
CH3), 0.91 (3H, d, J = 6.6, CH3), 0.89 (3H, d, J = 6.6, CH3), 0.06
(3H, s, SiCH3), 0.01 (3H, s, SiCH3). 13C NMR (100.6 MHz,
CDCl3) δ 215.8 (C), 83.9 (CH), 72.1 (CH), 41.3 (CH2), 33.1
(CH), 32.5 (CH), 25.7 (CH3), 18.6 (CH3), 18.2 (CH3), 18.1 (C),
18.0 (CH3), 17.6 (CH3), –4.8 (CH3), –5.1 (CH3). HRMS (+ESI):
m/z calcd. for C32H68NaO6Si2 [2M+Na]+: 627.4447, found:
627.4441.
1
Minor aldol (17a). H NMR (400 MHz, CDCl3) δ 4.22 (1H,
dd, J = 7.5, 4.1, CHOTBS), 3.65 (1H, ddd, J = 8.7, 5.5, 3.2,
CHOH), 3.02 (1H, br s, OH), 1.67–1.57 (1H, m, CH(CH3)2), 0.87
1
Minor aldol (19a). H NMR (400 MHz, CDCl3) δ 2.72 (1H,
dd, J = 18.4, 2.0, COCHxHy), 2.53 (1H, dd, J = 18.4, 9.9,
COCHxHy), 0.04 (3H, s, SiCH3).
(9H, s, (CH3)3C), –0.06 (3H, s, SiCH3), –0.23 (3H, s, SiCH3). 13
C
NMR (100.6 MHz, CDCl3) δ 215.9 (C), 136.7 (C), 129.9 (CH),
128.2 (CH), 126.7 (CH), 79.8 (CH), 71.7 (CH), 41.7 (CH2), 41.4
(CH2), 32.9 (CH), 25.7 (CH3), 18.2 (CH3), 17.7 (CH3), –5.2
(CH3), –5.4 (CH3).
4.7.8. (1R,4S)-4-tert-Butyldimethylsilyloxy-1-hydroxy-5-methyl-
1-phenyl-3- hexanone (18h). Colourless oil. Rf (90:10
hexanes/EtOAc) 0.20. IR (film) ν 3471 (br), 2953, 2925, 2891,
2857, 1715, 1474, 1388, 1252, 1073. 1H NMR (400 MHz,
CDCl3) δ 7.41–7.23 (5H, m, ArH), 5.16 (1H, dd, J = 9.4, 2.8,
CHOH), 3.72 (1H, d, J = 6.2, CHOTBS), 3.03 (1H, dd, J = 18.2,
2.8, COCHxHy), 2.84 (1H, dd, J = 18.2, 9.4, COCHxHy), 1.99–
1.84 (1H, m, CH(CH3)2), 0.91 (9H, s, (CH3)3C), 0.90 (3H, d, J =
6.3, CH3), 0.88 (3H, d, J = 6.9, CH3), 0.05 (3H, s, SiCH3), 0.01
(3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 214.2 (C), 143.0
(C), 128.5 (CH), 127.5 (CH), 125.5 (CH), 83.9 (CH), 69.7 (CH),
46.4 (CH2), 32.4 (CH), 25.7 (CH3), 18.6 (CH3), 18.1 (C), 17.6
(CH3), –4.8 (CH3), –5.1 (CH3).
4.7.5.
(1R,4S)-4-tert-Butyldimethylsilyloxy-1-hydroxy-1,5-
diphenyl-3-pentanone (16h). Colourless oil. Rf (90:10
hexanes/EtOAc) 0.20. IR (film) ν 3449 (br), 2953, 2924, 2858,
1717, 1454, 1256, 1093. 1H NMR (400 MHz, CDCl3) δ 7.30–
7.06 (10H, m, ArH), 5.09–5.02 (1H, m, CHOH), 4.11 (1H, dd, J
= 8.6, 4.2, CHOTBS), 3.18 (1H, d, J = 3.2, CHOH), 2.93–2.65
(4H, m, COCH2 & PhCH2), 0.73 (9H, s, (CH3)3C), –0.22 (3H, s,
SiCH3), –0.40 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ
213.6 (C), 143.0 (C), 136.7 (C), 129.9 (CH), 128.5 (CH), 128.3
(CH), 127.6 (CH), 126.7 (CH), 125.6 (CH), 80.3 (CH), 69.6
(CH), 46.1 (CH2), 41.0 (CH2), 25.7 (CH3), 18.0 (C), –5.3 (CH3),
–5.6 (CH3).
1
Minor aldol (19h). H NMR (400 MHz, CDCl3) δ 5.12 (1H,
dd, J = 9.0, 3.2, CHOH), 3.77 (1H, d, J = 5.6, CHOTBS), 2.99
(1H, dd, J = 18.4, 9.0, COCHxHy), 2.89 (1H, dd, J = 18.4, 3.2,
COCHxHy), 0.92 (9H, s, (CH3)3C), 0.03 (3H, s, SiCH3). 13C NMR
(100.6 MHz, CDCl3) δ 127.6 (CH), 125.8 (CH), 83.5 (CH), 46.8
(CH2), 32.6 (CH), 18.8 (CH3), 17.4 (CH3).
1
Minor aldol (17h). H NMR (400 MHz, CDCl3) δ 4.95–4.88
(1H, m, CHOH), 4.16 (1H, dd, J = 7.7, 4.1, CHOTBS), 3.24 (1H,
d, J = 2.6, CHOH), 0.75 (9H, s, (CH3)3C), –0.16 (3H, s, SiCH3),
–0.32 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 129.9
(CH), 128.4 (CH), 128.3 (CH), 126.8 (CH), 125.7 (CH), 79.8
(CH), 69.6 (CH), 46.7 (CH2), 41.3 (CH2), 25.7 (CH3).
4.7.9.
(3S,6R)-3-tert-Butyldimethylsilyloxy-6-hydroxy-2,7-
4.7.6. (2S,5R)-2-tert-Butyldimethylsilyloxy-5-hydroxy-6-methyl-
1-phenyl-6-hepten- 3-one (16i). Colourless oil. Rf (90:10
hexanes/EtOAc) 0.15. IR (film) ν 3486 (br), 2950, 2926, 2855,
dimethyl-7-octen-4-one (18i). Colourless oil. Rf (90:10
hexanes/EtOAc) 0.25. [α]D –26.7 (c 1.0, CHCl3, 80% de). IR
(film) ν 3486 (br), 2955, 2931, 2892, 2860, 1715, 1471, 1386,
1252, 1071. 1H NMR (300 MHz, CDCl3) δ 5.03 (1H, br s,
C=CHxHy), 4.87 (1H, br s, C=CHxHy), 4.49 (1H, d, J = 9.1,
CHOH), 3.72 (1H, d, J = 6.0, CHOTBS), 3.00 (1H, br s, OH),
2.87 (1H, dd, J = 18.2, 2.4, COCHxHy), 2.62 (1H, dd, J = 18.2,
9.6, COCHxHy), 2.03–1.85 (1H, m, CH(CH3)2), 1.75 (3H, br s,
CH3C=CH2), 0.93 (9H, s, (CH3)3C), 0.92 (3H, d, J = 6.4, CH3),
0.90 (3H, d, J = 6.5, CH3), 0.06 (3H, s, SiCH3), 0.02 (3H, s,
SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 214.6 (C), 145.8 (C),
110.9 (CH2), 83.8 (CH), 70.7 (CH), 43.1 (CH2), 32.5 (CH), 25.7
(CH3), 18.7 (CH3), 18.5 (CH3), 18.1 (C), 17.5 (CH3), –4.8 (CH3),
–5.1 (CH3). HRMS (+ESI): m/z calcd. for C32H64NaO6Si2
[2M+Na]+: 623.4134, found: 623.4125.
1
1713, 1468, 1256, 1096. H NMR (400 MHz, CDCl3) δ 7.31–
7.16 (5H, m, ArH), 5.02 (1H, br s, C=CHxHy), 4.87 (1H, br s,
C=CHxHy), 4.48 (1H, d, J = 9.5, CHOH), 4.19 (1H, dd, J = 8.7,
4.1, CHOTBS), 3.06 (1H, br s, CHOH), 2.99–2.56 (4H, m,
COCH2 & PhCH2), 1.73 (3H, br s, CH3C=CH2), 0.84 (9H, s,
(CH3)3C), –0.12 (3H, s, SiCH3), –0.32 (3H, s, SiCH3). 13C NMR
(100.6 MHz, CDCl3) δ 214.0 (C), 145.8 (C), 136.8 (C), 129.9
(CH), 128.3 (CH), 126.7 (CH), 111.0 (CH2), 80.3 (CH), 70.7
(CH), 42.9 (CH2), 41.1 (CH2), 25.7 (CH3), 18.4 (CH3), 18.0 (C),
–5.3 (CH3), –5.6 (CH3).
Minor aldol (17i). 1H NMR (400 MHz, CDCl3) δ 4.96 (1H, br
s, C=CHxHy), 4.83 (1H, br s, C=CHxHy), 4.34 (1H, dd, J = 8.6,
2.3, CHOH), 4.24 (1H, dd, J = 7.6, 4.1, CHOTBS), 1.66 (3H, br
s, CH3C=CH2), 0.87 (9H, s, (CH3)3C), –0.05 (3H, s, SiCH3), –
0.23 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 214.8 (C),
145.6 (C), 136.6 (C), 129.9 (CH), 128.3 (CH), 126.8 (CH), 111.1
(CH2), 79.8 (CH), 70.7 (CH), 43.5 (CH2), 41.3 (CH2), 25.7 (CH3),
18.2 (CH3), 18.0 (C), –5.2 (CH3), –5.4 (CH3).
Minor aldol (19i). 1H NMR (300 MHz, CDCl3) δ 5.01 (1H, br
s, C=CHxHy), 4.45 (1H, d, J = 4.3, CHOH), 3.78 (1H, d, J = 5.4,
CHOTBS), 0.94 (9H, s, (CH3)3C), 0.05 (3H, s, SiCH3). 13C NMR
(100.6 MHz, CDCl3) δ 111.3 (CH2), 83.4 (CH), 43.5 (CH2), 32.7
(CH), 18.9 (CH3), 18.2 (C), 17.3 (CH3), –4.8 (CH3), –5.0 (CH3).
4.8. TiCl4-Mediated aldol reactions of α–silyloxy methyl ketones
4.7.7.
(3S,6R)-3-tert-Butyldimethylsilyloxy-6-hydroxy-2,7-
dimethyl-4-octanone (18a). Colourless oil. Rf (90:10
hexanes/EtOAc) 0.30. [α]D –17.0 (c 1.1, CHCl3, 92% de). IR
(film) ν 3510 (br), 2955, 2930, 2879, 2859, 1707, 1475, 1388,
1252, 1089. H NMR (400 MHz, CDCl3) δ 3.79 (1H, ddd, J =
10.1, 5.9, 1.9, CHOH), 3.70 (1H, d, J = 6.0, CHOTBS), 3.02 (1H,
br s, OH), 2.85 (1H, dd, J = 18.3, 1.9, COCHxHy), 2.45 (1H, dd, J
4.8.1. (2S,5R)-2-Triethylsilyloxy-5-hydroxy-6-methyl-1-phenyl-3-
heptanone (22a). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.25.
IR (film) ν 3503 (br), 2955, 2937, 2908, 2887, 1709, 1468, 1239,
1102, 1004. H NMR (400 MHz, CDCl3) δ 7.31–7.16 (5H, m,
ArH), 4.23 (1H, dd, J = 8.1, 4.6, CHOTES), 3.79–3.72 (1H, m,
CHOH), 3.03–2.74 (4H, m, OH & COCHxHy & PhCH2), 2.52–
1
1

12
Tetrahedron
ACCEPTED MANUSCRIPT
2.42 (1H, m, COCHxHy), 1.73–1.62 (1H, m, CH(CH3)2), 0.92
(CH3)3C), 0.92 (9H, s, (CH3)3C), 0.90 (3H, d, J = 6.9,
(3H, d, J = 6.8, CH3), 0.89 (3H, d, J = 6.3, CH3), 0.84 (9H, t, J =
7.9, Si(CH2CH3)3), 0.48–0.38 (6H, m, Si(CH2CH3)3). 13C NMR
(100.6 MHz, CDCl3) δ 215.1 (C), 136.8 (C), 129.7 (CH), 128.3
(CH), 126.7 (CH), 80.1 (CH), 72.0 (CH), 41.4 (CH2), 41.1 (CH2),
33.1 (CH), 18.2 (CH3), 17.9 (CH3), 6.6 (CH3), 4.5 (CH2). HRMS
(+ESI): m/z calcd. for C20H34NaO3Si [M+Na]+: 373.2169, found:
373.2184; m/z calcd. for C40H68NaO6Si2 [2M+Na]+: 723.4447,
found: 723.4453.
CH3CHCH2), 0.09 (3H, s, SiCH3), 0.08 (3H, s, SiCH3). 13C NMR
(100.6 MHz, CDCl3) δ 214.7 (C), 135.6 (2 × CH), 133.3 (2×C),
129.6 (CH), 75.0 (CH), 70.2 (CH), 66.9 (CH2), 41.7 (CH2), 40.3
(CH), 26.8 (CH3), 25.7 (CH3), 20.6 (CH3), 13.1 (CH3), –4.7
(CH3), –5.0 (CH3).
4.9.2.
(2S,5R,6S)-2-tert-Butyldimethylsilyloxy-7-tert-
(31).
butyldiphenylsilyloxy-5-hydroxy-6-methyl-3-heptanone
Colourless oil. Rf (90:10 hexanes/EtOAc) 0.35. IR (film) ν 3511
(br), 3069, 3047, 2960, 2927, 2889, 2856, 1714, 1469. H NMR
Minor aldol (23a).1H NMR (400 MHz, CDCl3) δ 4.27 (1H,
dd, J = 7.1, 4.5, CHOTES), 3.66–3.59 (1H, m, CHOH), 1.68–
1.58 (1H, m, CH(CH3)2), 0.53–0.45 (6H, m, Si(CH2CH3)3). 13C
NMR (100.6 MHz, CDCl3) δ 215.9 (C), 136.6 (C), 129.8 (CH),
128.2 (CH), 126.7 (CH), 79.6 (CH), 71.8 (CH), 41.7 (CH2), 41.5
(CH2), 32.9 (CH), 18.2 (CH3), 17.7 (CH3), 6.7 (CH3), 4.6 (CH2).
1
(400 MHz, CDCl3) δ 7.69–7.64 (4H, m, ArH), 7.45–7.35 (6H, m,
ArH), 4.16 (1H, q, J = 6.8, CHOTBS), 4.14–4.07 (1H, m,
CHOH), 3.73 (1H, dd, J = 10.2, 5.1, CHxHyOSi), 3.67 (1H, dd, J
= 10.2, 6.0, CHxHyOSi), 3.49 (1H, d, J = 3.4, OH), 2.90–2.60
(2H, m, COCH2), 1.90–1.78 (1H, m, CHCH2OSi), 1.29 (3H, d, J
= 6.8, CH3CHOTBS), 1.05 (9H, s, (CH3)3C), 0.91 (9H, s,
(CH3)3C), 0.89 (3H, d, J = 7.0, CH3CHCH2), 0.08 (3H, s, SiCH3),
0.07 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 214.6 (C),
135.6 (2×CH), 134.7 (CH), 133.3 (2.C), 129.7 (2×CH), 127.7
(CH), 75.1 (CH), 70.1 (CH), 66.9 (CH2), 41.5 (CH2), 40.3 (CH),
26.8 (CH3), 25.7 (CH3), 20.6 (CH3), 19.2 (C), 18.0 (C), 13.4
(CH3), –4.7 (CH3), –5.0 (CH3).
4.8.2. (2S,5R)-2-tert-Butyldiphenylsilyloxy-5-hydroxy-6-methyl-
1-phenyl-3-heptanone (24a). Colourless oil. Rf (90:10
hexanes/EtOAc) 0.30. IR (film) ν 3512 (br), 3074, 2955, 2930,
2893, 2856, 1707, 1469, 1427, 1112, 1046. 1H NMR (400 MHz,
CDCl3) δ 7.60–7.55 (2H, m, ArH), 7.45–7.21 (11H, m, ArH),
7.15–7.10 (2H, m, ArH), 4.35 (1H, t, J = 6.4, CHOTBDPS),
3.32–3.26 (1H, m, CHOH), 2.91–2.83 (2H, m, PhCH2), 2.67 (1H,
d, J = 3.1, OH), 2.40 (1H, dd, J = 18.2, 1.9, COCHxHy), 2.11 (1H,
dd, J = 18.2, 10.0, COCHxHy), 1.52–1.41 (1H, m, CH(CH3)2),
1.08 (9H, s, (CH3)3C), 0.76 (3H, d, J = 6.8, CH3), 0.72 (3H, d, J =
6.8, CH3). 13C NMR (100.6 MHz, CDCl3) δ 214.3 (C), 136.4 (C),
135.9 (CH), 135.8 (CH), 132.9 (C), 132.6 (C), 130.1 (CH), 130.0
(CH), 129.8 (CH), 128.4 (CH), 127.9 (CH), 127.6 (CH), 126.8
(CH), 80.5 (CH), 71.5 (CH), 41.5 (CH2), 41.4 (CH2), 32.8 (CH),
26.9 (CH3), 19.1 (C), 18.0 (CH3), 17.8 (CH3). HRMS (+ESI): m/z
calcd. for C60H76NaO6Si2 [2M+Na]+: 971.5073, found: 971.5079.
Minor aldol (25a).1H NMR (400 MHz, CDCl3) δ 4.39 (1H, t,
J = 5.7, CHOTBDPS), 3.40–3.34 (1H, m, CHOH), 2.74 (1H, d, J
= 2.8, OH), 2.15–2.05 (2H, m, COCH2), 1.09 (9H, s, (CH3)3C),
0.73 (3H, d, J = 6.8, CH3), 0.69 (3H, d, J = 6.8, CH3). 13C NMR
(100.6 MHz, CDCl3) δ 214.6 (C), 136.3 (C), 135.9 (CH), 132.8
(2×C), 130.1 (CH), 129.9 (CH), 128.3 (CH), 127.9 (CH), 127.7
(CH), 79.7 (CH), 71.4 (CH), 42.3 (CH2), 41.2 (CH2), 32.7 (CH),
26.9 (CH3), 19.2 (C), 17.9 (CH3), 17.7 (CH3).
1
Minor aldol (32). H NMR (400 MHz, CDCl3) δ 4.36–4.29
(1H, m, CHOH), 4.15 (1H, q, J = 6.8, CHOTBS), 3.68 (2H, d, J
= 5.6, CH2OSi), 3.10 (1H, d, J = 3.3, OH), 1.81–1.71 (1H, m,
CHCH2OSi), 1.29 (3H, d, J = 6.8, CH3CHOTBS), 1.05 (9H, s,
(CH3)3C), 0.93 (3H, d, J = 7.0, CH3CHCH2), 0.91 (9H, s,
(CH3)3C), 0.08 (6H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ
214.5 (C), 135.6 (CH), 135.5 (CH), 133.4 (C), 133.3 (C), 129.6
(CH), 75.0 (CH), 68.6 (CH), 67.3 (CH2), 41.8 (CH2), 39.8 (CH),
26.9 (CH3), 20.6 (CH3), 10.9 (CH3).
4.9.3.
(2S,5R,6S)-2-tert-Butyldimethylsilyloxy-6-tert-
butyldiphenylsilyloxy-5-hydroxy-3-heptanone (34). Colourless
oil. Rf (hexanes/EtOAc 90:10) 0.20. IR (film) ν 3511 (br), 2956,
2931, 2894, 2858, 1716, 1472, 1463, 1428, 1390, 1363, 1254,
1
1112. H NMR (400 MHz, CDCl3) δ 7.73–7.63 (4H, m, ArH),
7.46–7.34 (6H, m, ArH), 4.15 (1H, q, J = 6.8, CHOTBS), 4.05–
3.95 (1H, m, CHOH), 3.91–3.83 (1H, m, CHOTBDPS), 2.67
(1H, dd, J = 17.8, 9.2, COCHxHy), 2.67 (1H, dd, J = 17.8, 3.2,
COCHxHy), 2.70 (1H, d, J = 3.8, OH), 1.28 (3H, d, J = 6.8,
CH3CHOTBS), 1.07 (9H, s, (CH3)3C), 0.99 (3H, d, J = 6.3,
CH3CHOTBDPS), 0.90 (9H, s, (CH3)3C), 0.07 (3H, s, SiCH3),
0.05 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 213.8 (C),
135.8 (2×CH), 134.3 (C), 133.5 (C), 129.7 (CH), 129.6 (CH),
127.7 (CH), 127.5 (CH), 75.0 (CH), 72.1 (CH), 71.4 (CH), 39.3
(CH2), 27.0 (CH3), 25.7 (CH3), 20.6 (CH3), 19.3 (C), 18.4 (CH3),
18.0 (C), –4.7 (CH3), –5.0 (CH3).
4.9. Double asymmetric aldol reactions
4.9.1.
(2S,5R,6R)-2-tert-Butyldimethylsilyloxy-7-tert-
(29).
butyldiphenylsilyloxy-5-hydroxy-6-methyl-3-heptanone
Colourless oil. Rf (90:10 hexanes/EtOAc) 0.25. IR (film) ν 3516
(br), 3070, 3048, 2955, 2933, 2886, 2856, 1712, 1468. H NMR
1
(400 MHz, CDCl3) δ 7.69–7.63 (4H, m, ArH), 7.45–7.35 (6H, m,
ArH), 4.36–4.26 (1H, m, CHOH), 4.15 (1H, q, J = 6.8,
CHOTBS), 3.69 (2H, d, J = 5.6, CH2OSi), 3.11 (1H, d, J = 3.5,
OH), 2.85 (1H, dd, J = 17.7, 9.3, COCHxHy), 2.64 (1H, dd, J =
17.7, 3.2, COCHxHy), 1.83–1.72 (1H, m, CHCH2OSi), 1.29 (3H,
d, J = 6.8, CH3CHOTBS), 1.06 (9H, s, (CH3)3C), 0.93 (3H, d, J =
7.0, CH3CHCH2), 0.91 (9H, s, (CH3)3C), 0.08 (3H, s, SiCH3),
0.07 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 214.4 (C),
135.6 (CH), 135.5 (CH), 134.8 (CH), 133.4 (C), 133.2 (C), 129.7
(2.CH), 127.7 (CH), 75.1 (CH), 68.7 (CH), 67.2 (CH2), 41.3
(CH2), 39.8 (CH), 26.9 (CH3), 25.7 (CH3), 20.6 (CH3), 19.2 (C),
18.0 (C), 10.9 (CH3), –4.7 (CH3), –5.0 (CH3).
Minor aldol (35). 1H NMR (400 MHz, CDCl3) δ 2.95 (1H, dd,
J = 17.8, 3.1, COCHxHy), 2.85 (1H, dd, J = 17.8, 9.3, COCHxHy),
2.81 (1H, d, J = 4.7, OH), 1.27 (3H, d, J = 6.8, CH3CHOTBS),
1.06 (9H, s, (CH3)3C), 1.02 (3H, d, J = 6.3, CH3CHOTBDPS),
0.92 (9H, s, (CH3)3C), 0.09 (6H, s, SiCH3). 13C NMR (100.6
MHz, CDCl3) δ 214.5 (C), 135.8 (CH), 135.7 (CH), 134.1 (C),
133.5 (C), 129.8 (CH), 129.7 (CH), 127.7 (CH), 74.9 (CH), 71.4
(CH), 71.0 (CH), 39.4 (CH2), 20.7 (CH3), 19.3 (C), –4.7 (CH3).
1
4.9.4. (5R,6S)-6-tert-Butyldiphenylsilyloxy-5-hydroxy-2-methyl-
3-heptanone (36). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.30.
IR (film) ν 3480 (br), 3068, 2961, 2928, 2892, 2855, 1705, 1470,
Minor aldol (30). H NMR (400 MHz, CDCl3) δ 4.18–4.08
(1H, m, CHOH), 4.16 (1H, q, J = 6.8, CHOTBS), 3.73 (1H, dd, J
= 10.2, 5.0, CHxHyOSi), 3.65 (1H, dd, J = 10.2, 6.2, CHxHyOSi),
3.49 (1H, d, J = 3.4, OH), 2.87 (1H, dd, J = 17.7, 3.0, COCHxHy),
2.67 (1H, dd, J = 17.7, 9.2, COCHxHy), 1.91–1.79 (1H, m,
CHCH2OSi), 1.29 (3H, d, J = 6.8, CH3CHOTBS), 1.05 (9H, s,
1
1426, 1384, 1115, 1092. H NMR (400 MHz, CDCl3) δ 7.71–
7.64 (4H, m, ArH), 7.46–7.34 (6H, m, ArH), 4.00–3.93 (1H, m,
CHOH), 3.84 (1H, dq, J = 12.4, 6.2, CHOTBDPS), 2.84 (1H, d, J

13
= 4.5, OH), 2.68–2.48 (3H, m, COCH2 & CH(CH3)2), 1.09 (3H,
6.9, CH3), 0.04 (3H, s, SiCH3), 0.03 (3H, s, SiCH3). 13C NMR
ACCEPTED MANUSCRIPT
d, J = 6.9, CH3), 1.07 (3H, d, J = 6.9, CH3), 1.06 (9H, s,
(CH3)3C), 1.05 (3H, d, J = 6.2, CH3CHO). 13C NMR (100.6
MHz, CDCl3) δ 215.0 (C), 135.8 (CH), 135.7 (CH), 134.0 (C),
133.5 (C), 129.8 (CH), 129.7 (CH), 127.7 (CH), 127.5 (CH), 71.4
(CH), 71.3 (CH), 42.1 (CH2), 41.5 (CH), 27.0 (CH3), 19.3 (C),
18.5 (CH3), 18.0 (2×CH3).
(100.6 MHz, CDCl3) δ 134.5 (C), 130.0 (CH), 129.9 (CH), 127.8
(CH), 83.5 (CH), 40.6 (CH2), 32.7 (CH), 26.9 (CH3), 26.6 (CH3).
4.10. Chemical Correlation
48% HF (0.32 mL, 10 mmol) was added dropwise to a
solution of aldols 2 or 18 (1 mmol) in CH3CN (10 mL) at room
temperature. The reaction mixture was stirred for 2.5 h and
partitioned with CH2Cl2 (50 mL) and saturated NaHCO3 (25 mL).
The layers were separated and the organic layer was washed with
NaHCO3 (2 × 25 mL), dried (MgSO4) and concentrated to obtain
of a colourless oil, which was used in the next step without
further purification. A mixture of this oil and NaIO4 (2.25 g, 10
mmol) in 2:1 MeOH/H2O (9 mL) was stirred at room temperature
for 1 h. Then, it was diluted with Et2O (20 mL), cooled to 0 °C
and 1 M HCl was slowly added to reach pH 1. The mixture was
partitioned with Et2O (10 mL) and H2O (10 mL), the layers were
separated and the aqueous layer was extracted with Et2O (4 × 10
mL). The combined organic extracts were dried (MgSO4) and
concentrated. The residue was purified by column
chromatography to afford β–hydroxy acids 26 or 27.
1
Minor aldol (37). H NMR (400 MHz, CDCl3) δ 3.86–3.79
(1H, m, CHOTBDPS), 2.87 (1H, d, J = 3.4, OH), 1.07 (9H, s,
(CH3)3C), 1.04 (3H, d, J = 6.2, CH3CHO). 13C NMR (100.6
MHz, CDCl3) δ 215.0 (C), 135.8 (CH), 134.2 (C), 133.5 (C),
129.8 (CH), 129.7 (CH), 127.7 (CH), 72.0 (CH), 71.9 (CH), 42.4
(CH2), 41.5 (CH), 19.3 (C), 18.6 (CH3), 18.0 (CH3), 17.9 (CH3).
4.9.5.
(3S,6R,7S)-3-tert-Butyldimethylsilyloxy-7-tert-
(38).
butyldiphenylsilyloxy-6-hydroxy-2-methyl-4-octanone
Colourless oil. Rf (90:10 hexanes/EtOAc) 0.35. IR (film) ν 3527
(br), 3068, 2957, 2931, 2893, 2855, 1708, 1471, 1428, 1388,
1
1254, 1140, 1111, 1087. H NMR (400 MHz, CDCl3) δ 7.72–
7.62 (4H, m, ArH), 7.46–7.34 (6H, m, ArH), 4.07–4.01 (1H, m,
CHOH), 3.87 (1H, qd, J = 6.3, 4.1, CHOTBDPS), 3.71 (1H, d, J
= 5.8, CHOTBS), 2.72 (1H, d, J = 3.3, OH), 2.71 (1H, dd, J =
18.0, 9.1, COCHxHy), 2.61 (1H, dd, J = 18.0, 3.0, COCHxHy),
1.98–1.88 (1H, m, CH(CH3)2), 1.07 (9H, s, (CH3)3C), 0.99 (3H,
d, J = 6.3, CH3CHOTBDPS), 0.92 (9H, s, (CH3)3C), 0.90 (3H, d,
J = 6.7, CH3), 0.90 (3H, d, J = 6.6, CH3), 0.04 (3H, s, SiCH3), –
0.02 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ 213.5 (C),
135.9 (2×CH), 134.3 (C), 133.5 (C), 129.7 (CH), 129.6 (CH),
127.7 (CH), 127.5 (CH), 83.8 (CH), 72.2 (CH), 71.3 (CH), 40.1
(CH2), 32.4 (CH), 27.0 (CH3), 25.8 (CH3), 19.3 (C), 18.8 (CH3),
18.3 (CH3), 18.1 (C), 17.4 (CH3), –4.8 (CH3), –5.1 (CH3). HRMS
(+ESI): m/z calcd. for C62H100NaO8Si4 [2M+Na]+: 1107.6387,
found: 1107.6377.
4.10.1. (R) 3-Hydroxy-4-methylpropanoic acid (26). Colourless
oil. Rf (95:5 CH2Cl2/MeOH) 0.25. From 2a [α]D +18.1 (c 1.0,
CHCl3, 48% ee) [lit.28 [α]D +39.8 (c 1.0, CHCl3)]. From 18a [α]D
33.9 (c 0.9, CHCl3, 92% ee) IR (film) ν 3270 (br), 1715, 1418,
1
1182, 1044. H NMR (400 MHz, CDCl3) δ 3.86–3.79 (1H, m,
CHOH), 2.57 (1H, dd, J = 16.5, 3.2, COCHxHy), 2.45 (1H, dd, J
= 16.5, 9.3, COCHxHy), 1.80–1.69 (1H, m, CH(CH3)2), 0.95 (6H,
m, 2 × CH3). 13C NMR (100.6 MHz, CDCl3) δ 178.0 (C), 72.8
(CH), 38.3 (CH2), 33.2 (CH), 18.3 (CH3), 17.7 (CH3).
1
Minor aldol (39). H NMR (400 MHz, CDCl3) δ 4.01–3.95
(1H, m, CHOH), 3.93–3.88 (1H, m, CHOTBDPS), 3.75 (1H, d, J
= 5.4, CHOTBS), 2.97 (1H, d, J = 3.9, OH), 2.89 (1H, dd, J =
18.1, 2.3, COCHxHy), 2.60 (1H, dd, J = 18.1, 8.0, COCHxHy),
1.05 (9H, s, (CH3)3C), 1.02 (3H, d, J = 6.3, CH3CHOTBDPS),
0.96 (9H, s, (CH3)3C), 0.89 (3H, d, J = 6.8, CH3), 0.89 (3H, d, J =
6.7, CH3), 0.06 (6H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) δ
215.3 (C), 135.7 (2×CH), 134.8 (C), 130.0 (CH), 129.9 (CH),
127.8 (2×CH), 83.5 (CH), 70.9 (CH), 70.6 (CH), 39.7 (CH2),
32.7 (CH), 26.9 (CH3), 19.2 (C), 18.9 (CH3), 17.8 (CH3), 17.3
(CH3), –5.0 (CH3).
4.10.2. (R) 3-Hydroxy-3-phenylpropanoic acid (27). Viscous oil.
Rf (20:80 hexanes/EtOAc) 0.30. From 18h [α]D +10.7 (c 1.2,
EtOH, 66% ee) [lit.12c [α]D +15.5 (c 0.9, EtOH)]. IR (film) ν
1
3286 (br), 2926 (br), 1695, 1454, 1275, 1212, 1057, 1017. H
NMR (400 MHz, CDCl3) δ 7.41–7.28 (5H, m, ArH), 5.17 (1H,
dd, J = 9.1, 3.7, CHOH), 2.85 (1H, dd, J = 16.6, 9.1, COCHxHy),
2.78 (1H, dd, J = 16.6, 3.7, COCHxHy). 13C NMR (100.6 MHz,
CDCl3) δ 177.1 (C), 142.0 (C), 128.7 (CH), 128.1 (CH), 125.7
(CH), 70.2 (CH), 43.0 (CH2).
4.9.6.
(3S,6R,7R)-3-tert-Butyldimethylsilyloxy-7-tert-
(40).
Acknowledgements
butyldiphenylsilyloxy-6-hydroxy-2-methyl-4-octanone
Colourless oil. Rf (90:10 hexanes/EtOAc) 0.25. [α]D +5.2 (c 1.1,
EtOH, 86% de). IR (film) ν 3486 (br), 3070, 2958, 2929, 2890,
2856, 1713, 1470, 1428, 1389, 1363, 1253, 1112, 1088. 1H NMR
(400 MHz, CDCl3) δ 7.70–7.63 (4H, m, ArH), 7.46–7.34 (6H, m,
ArH), 4.10–4.03 (1H, m, CHOH), 3.85 (1H, qd, J = 6.3, 4.6,
CHOTBDPS), 3.75 (1H, d, J = 5.7, CHOTBS), 2.80–2.62 (3H,
m, COCH2 & OH), 1.99–1.89 (1H, m, CH(CH3)2), 1.05 (9H, s,
(CH3)3C), 1.01 (3H, d, J = 6.3, CH3CHOTBDPS), 0.93 (9H, s,
(CH3)3C), 0.91 (3H, d, J = 6.9, CH3), 0.91 (3H, d, J = 6.7, CH3),
0.05 (3H, s, SiCH3), 0.01 (3H, s, SiCH3). 13C NMR (100.6 MHz,
CDCl3) δ 214.0 (C), 135.8 (2×CH), 134.1 (C), 133.4 (C), 129.8
(CH), 129.7 (CH), 127.7 (CH), 127.5 (CH), 83.7 (CH), 71.5
(CH), 70.7 (CH), 40.4 (CH2), 32.5 (CH), 27.0 (CH3), 25.8 (CH3),
19.3 (C), 18.8 (CH3), 18.3 (CH3), 18.1 (C), 17.4 (CH3), –4.8
(CH3), –5.1 (CH3). HRMS (+ESI): m/z calcd. for C31H54NaO4Si2
[M+NH4]+: 560.3586, found: 560.3578.
Financial support from the Spanish Ministerio de Ciencia e
Innovación (Grant No. CTQ2009-09692/BQU), Ministerio de
Economía y Competitividad (Grant No. CTQ2012-31034), and
the Generalitat de Catalunya (2009SGR825), as well as doctorate
studentship to M. P. (FPU, Ministerio de Educación) is
acknowledged.
References and Notes
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1
Minor aldol (41). H NMR (400 MHz, CDCl3) δ 3.74 (1H, d,
J = 5.4, CHOTBS), 0.88 (3H, d, J = 6.8, CH3), 0.88 (3H, d, J =

14
Tetrahedron
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ACCEPTED MANUSCRIPT
37, 8949.
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