Highly stereoselective titanium-mediated aldol reactions from chiral α-silyloxy ketones. A reliable tool for the synthesis of natural products

Article abstract of DOI:10.1016/j.tet.2011.06.019

Chiral α-silyloxy ketones participate in highly stereoselective TiCl₄-mediated aldol reactions that afford diastereomerically pure syn-syn adducts in high yield irrespective of the R¹ and R ² substituents flanking the carbonyl or the silicon protecting group. Further manipulation of the resulting aldol adducts provide in a straightforward manner highly functionalized fragments that facilitate the synthesis of natural products.

Full text of DOI:10.1016/j.tet.2011.06.019

Tetrahedron 67 (2011) 6045e6056
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Highly stereoselective titanium-mediated aldol reactions from chiral
ketones. A reliable tool for the synthesis of natural products
a-silyloxy
*
*
ꢀ
ꢁ
Judit Esteve, Carme Jimenez, Joaquim Nebot, Javier Velasco, Pedro Romea , Felix Urpí
ꢁ
ꢀ
Departament de Química Organica, Universitat de Barcelona, Martí i Franques 1e11, 08028 Barcelona, Catalonia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2011
Received in revised form 6 June 2011
Accepted 9 June 2011
Available online 16 June 2011
Chiral a-silyloxy ketones participate in highly stereoselective TiCl4-mediated aldol reactions that afford
diastereomerically pure synesyn adducts in high yield irrespective of the R1 and R2 substituents flanking
the carbonyl or the silicon protecting group. Further manipulation of the resulting aldol adducts provide
in a straightforward manner highly functionalized fragments that facilitate the synthesis of natural
products.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective reactions
Aldol reactions
Titanium enolates
Chiral ketones
Natural product synthesis
1. Introduction
provide an appropriate entry to the syn arrays embedded in a wide
number of natural products.
The synthesis of increasingly complex natural products has
stimulated the continuous development of synthetic methodolo-
gies with greater selectivity and efficiency.1e3 Particularly, there is
a need for selective and high yielding transformations in the cou-
pling of elaborate fragments in advanced steps of a synthetic se-
quence, where the constraints imposed by the structure of the
reaction partners hinder existing methodologies. Stereoselective
aldol reactions are a good example of these challenges,4 in which
the concurrent construction of a new carbonecarbon bond and the
introduction of one or two new stereocenters often depend on
accurate substrate-controlled processes.5 Therefore, successful ap-
plication of these reactions requires reliable knowledge of their
scope and mechanistic basis in order to predict the outcome of any
transformation. In this context, we reported that the titanium-
mediated aldol reactions from (S) 2-tert-butyldimethylsilyloxy-3-
pentanone give the corresponding synesyn adducts in a highly
stereoselective manner.6,7 However, the influence of structural el-
O
OH
R
HO
R1
O
OH
O
OH
O
R2
R2
TiL4, R3N
RCHO
R1
R2
R
R
R3SiO
R1
R1
R3SiO
R : alkyl, vinyl
R : alkyl
syn-syn
OH OH
R2
R
R1
R3SiO
Scheme 1. Titanium-mediated aldol reactions of chiral a-silyloxy ketones and further
transformations.
2. Results and discussion
2.1. Influence of R1 group
ements of other a
-silyloxy ketones, such as R1, R2 or the protecting
Our previous findings on the enolization of (S)-tert-butyldime-
thylsilyloxy-3-pentanone (1 in Scheme 2) with TiL4/i-Pr2NEt and
the subsequent aldol additions of the resulting titanium enolates to
a large set of aldehydes led us to assess the influence of R1 group on
parallel titanium-mediated aldol reactions based on lactate-
silicon group on the stereochemical outcome of related reactions
was unclear (Scheme 1).8,9 Here, we document a comprehensive
study of titanium-mediated aldol reactions from chiral a-silyloxy
ketones. Our results demonstrate that these transformations
derived
a-tert-butyldimethylsilyloxy ketones 2e5. Alkyl ketones
1e4 were easily prepared by acylation of the corresponding alkyl
lithium reagents with amide 6 (Scheme 2).10 However, allyl coun-
terparts were too reactive and ketone 5 was obtained in low yields
* Corresponding authors. E-mail addresses: pedro.romea@ub.edu (P. Romea),
felix.urpi@ub.edu (F. Urpí).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.019

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J. Esteve et al. / Tetrahedron 67 (2011) 6045e6056
because of the formation of the undesired tertiary alcohol de-
rivative even at ꢀ100 ꢁC. Finally, (S)-2-tert-butyldimethylsilyloxy-
5-hexen-3-one (5) was prepared by addition of allyl magnesium
chloride to Weinreb amide 77 in an excellent yield (Scheme 2).
enolizations even at longer reaction times and gave moderate
yields of 9a (entries 5e7 in Table 1). These results restrict the
application of TiCl3(i-PrO) to ketone 1, although it was also suc-
cessful in the addition of propyl ketone 3, which holds a small R1
group (R1: Me for 1, R1: Et for 3), to chiral aldehyde b (Scheme 3).
On this occasion, long enolization and reaction times allowed an
85% yield of diastereomerically pure aldol 10b, an advanced in-
termediate in the synthesis of 11, the C1eC17 fragment of sali-
nomycin (Scheme 3, see also Scheme 10).11
In spite of this result, TiCl4 appeared to be a more general and
reliable titanium Lewis acid and was chosen for the following
studies. The optimized conditions were then used for the aldol
additions of ketones 2e4 to representative aldehydes. The results
are summarized in Table 2.
O
O
1) Pyrrolidine
R1CH2Li
THF, –78 °C
77–88%
R1
N
2) TBSCl, Et3N
TBSO
TBSO
1 R1: Me 2 R1: n-Pr
O
6
3 R1: Et 4 R1: n-Hex
OEt
HO
O
O
1) MeNHOMe·HCl
Ethyl lactate
i-PrMgCl
MgCl
THF, –78 °C
95%
N
OMe
2) TBSCl, Et3N
TBSO
TBSO
7
5
Scheme 2. Lactate-derived a-tert-butyldimethylsilyloxy ketones.
Our findings show that titanium-mediated aldol reactions from
Given that the success of the titanium-mediated aldol reactions
from ethyl ketone 1 relies to some extent on the titanium Lewis
acid, we first surveyed the enolization of model ketone 2 with
several Lewis acids and the addition of the resulting titanium
enolate to isobutyraldehyde (a). The results are summarized in
Table 1.
lactate-derived
a-tert-butyldimethylsilyloxy ketones 1e4 are
highly stereoselective transformations that deliver the corre-
sponding 2,4-syn-4,5-syn adducts 8e10, and 12 in a simple and
efficient manner irrespective of the R1 group. This methodology has
already been used in the key step of the synthesis of NFX-2 and
antimycinone (13 and 14, respectively, in Scheme 4), where the
Table 1
Titanium-mediated aldol reactions from lactate-derived a-tert-butyldimethylsilyloxy ketones
Entry
Ketone
Lewis acid
tenol (h)
treac (h)
Conversion (%)a
Aldol
dra
Yield (%)b
1
2
3
4
5
6
7
8
1
1
1
2
2
2
2
2
TiCl4
0.5
0.5
1.5
0.5
0.5
0.5
1.5
1.5
0.5
0.5
2.0
0.5
0.5
1.5
0.5
2.0
100
>95
40
100
80
80
90
<30
8a
8a
8a
9a
9a
9a
9a
9a
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
nd
85
85
35
81
63
67
75
nd
TiCl3(i-PrO)
TiCl2(i-PrO)2
TiCl4
TiCl3(i-PrO)
TiCl3(i-PrO)
TiCl3(i-PrO)
TiCl2(i-PrO)2
a
Determined by 1H NMR.
Isolated yield.
b
As expected, aldol reactions from ketones 1 and 2 were sim-
addition of the titanium enolate from ketone 4 to just 1.25 equiv of
aldehyde d gives a single diastereomer of aldol 12d in 84% yield (see
also Scheme 9).12
Having confirmed the success of the aldol methodology with
several lactate-derived alkyl ketones, we tackled the reactivity of
allyl ketone 5. We were especially interested in this ketone because
it was expected to be more easily enolizable than 1e4 and the
resulting titanium enolates would contain two reacting positions,
ilar. The enolization of these two ketones with TiCl4 for 30 min
and addition of the resulting enolate to 1.5 equiv of iso-
butyraldehyde for 30 min at ꢀ78 ꢁC furnished 2,4-syn-4,5-syn
adducts 8a and 9a as a single diastereomer (dr>97:3) in high
yields (see entries 1 and 4 Table 1). In turn, mild Lewis acid
TiCl2(i-PrO)2 proved unsuitable since longer enolization and re-
action times did not promote their quantitative enolization (see
entries 3 and 8 in Table 1). Ketone 2, which holds a larger R1
group than ketone 1 (R1: Me for 1, R1: Pr for 2), required a strong
Lewis acid like TiCl4, because TiCl3(i-PrO) provided partial
a
and
vinylogous aldol adducts, depending on the predominant reacting
position, or
, respectively (Scheme 5).13
g. These offered the possibility of accessing 2,4-syn-4,5-syn or
a
g
OH
O
O
1) TiCl3(i-PrO), i-Pr2NEt, CH2Cl2, 1.5 h, –78 °C
OBn
O
(b) , 2 h, –78 °C
2)
TBSO
TBSO
H
OBn
3
Single diastereomer
85%
10b
OTBS
O
OH
O
17
OBn
MeO
O
1
H
H
11
C1–C17 Fragment of salinomycin
Scheme 3. TiCl3(i-PrO)-Mediated aldol reaction of ketone 3.

J. Esteve et al. / Tetrahedron 67 (2011) 6045e6056
6047
Table 2
TiCl4-Mediated aldol reactions from ketones 2e4
Entry
Ketone
R1
Aldehyde
R
Equiv
Aldol
dra
Yield (%)b
1
2
3
4
5
2
2
3
3
4
Pr
Pr
Et
Et
a
c
a
c
a
i-Pr
Ph
i-Pr
Ph
1.5
1.2
1.5
1.2
1.5
9a
9c
10a
10c
12a
>97:3
>97:3
>97:3
>97:3
>97:3
81
77
89
75
87
Hex
i-Pr
a
Determined by 1H NMR.
Isolated yield.
b
1) TiCl4, i-Pr2NEt
CH2Cl2, –78 °C
O
O
OH
Keeping in mind this possibility, the reaction mixtures were
carefully monitored. However, we did not observe the formation
of the vinylogous adducts and the titanium-mediated aldol re-
action from lactate-derived allyl ketone 5 consistently proceeded
Hex
2) 1.25 equiv
O
OTBDPS
Hex
TBSO
TBSO
4
Single diastereomer
84%
12d
through the
a position. Moreover, the higher acidity of ketone 5
H
was not sufficient and TiCl4 or TiCl3(i-PrO) were once again the
most appropriate Lewis acids. The results are summarized in
Table 3.
(d)
OTBDPS
O
O
As for simple alkyl ketones 1 and 2, TiCl2(i-PrO)2 was too mild to
adequately enolize the more acidic ketone 5 and longer enolization
and reaction times produced 2,4-syn-4,5-syn aldol 15a only in low
yield (compare entries 1e3 in Table 3). In turn, TiCl4 and TiCl3(i-
PrO) gave similar results and furnished 15a as a single diastereomer
in acceptable yields (see entries 1 and 2 in Table 3). The application
of the TiCl4-procedure to other aliphatic aldehydes afforded a single
diastereomer in acceptable to high yields (entries 4 and 5 in Table
3), but parallel additions to benzaldehyde and crotonaldehyde
were troublesome (entries 6 and 7 in Table 3). Analysis of the re-
action mixture from benzaldehyde showed that the corresponding
aldol 15c was obtained as a single diastereomer in ca. 80% yield
(entry 6 in Table 3); however, our attempts to purify the reaction
OR
13 R: H NFX-2
14 R: COi-Bu Antimycinone
Scheme 4. Aldol step from ketone 4 towards NFX-2 and antimycinone.
O
TBSO
5
mixture by column chromatography were unsuccessful and
a,b-
TiL4, i-Pr2NEt
unsaturated ketone 16 was obtained instead (Scheme 6). In turn,
the expected aldol adduct 15g from crotonaldehyde was not ob-
served in the reaction mixtures and conjugated ketone 16 was also
isolated as the only product (entry 7 in Table 3). These results
suggest that aldol adducts 15c and 15g are thermodynamically
TiLn
O
OH
O
O
OH
RCHO
RCHO
2
4
5
R
R
α
γ
TBSO
TBSO
TBSO
γ attack
α attack
2,4-syn-4,5-syn
unstable and that they decompose to deliver the a,b-unsaturated
ketone 16, which should be considered for further applications of
Scheme 5. Alternative aldol reactions of titanium enolate from ketone 5.
related methodologies.
Table 3
Titanium-mediated aldol reactions from allyl ketone 5
Entry
Lewis acid
tenol (h)
treac(h)
Aldehyde
R
Equiv
Aldol
dra
Yield (%)b
1
2
3
4
5
6
7
TiCl4
0.5
0.5
1.5
0.5
0.5
0.5
0.5
0.5
0.5
2.0
0.5
0.5
0.5
0.5
a
a
a
e
f
i-Pr
i-Pr
i-Pr
i-Bu
Et
Ph
1.5
1.5
1.5
1.5
1.5
1.2
1.2
15a
15a
15a
15e
15f
15c
15g
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
d
74
75
35
TiCl3(i-PrO)
TiCl2(i-PrO)2
TiCl4
TiCl4
TiCl4
80
67
c
g
(80)c
d
TiCl4
(E) CH]CHCH3
a
Determined by 1H NMR.
Isolated yield.
Crude yield.
b
c

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J. Esteve et al. / Tetrahedron 67 (2011) 6045e6056
M
4). These observations confirm the efficient enolization provided
O
O
by TiCl4/i-Pr2NEt and the high reactivity of the ensuing titanium
enolate. In contrast, parallel reactions from ketone 18 containing an
R2-isopropyl group were more sluggish. Short reaction times pro-
duced the expected aldol adducts 20 in a highly stereoselective way
but in moderate yields, since relatively large amounts of the
starting ketone 18 were isolated for isobutyraldehyde as well as
benzaldehyde (30% and 20%, respectively, see entries 4 and 6 in
Table 4). These figures were improved by extending reaction times
(compare entries 4e7 in Table 4). This finding proved that titanium-
M: H, TiL4
TBSO
M
O
O
+
H
TBSO
mediated aldol reactions from a-tert-butyldimethylsilyloxy ketones
are as sensitive to the steric hindrance of R2 group as they are to
the R1 group.
O
TBSO
16
Scheme 6. Decomposition of conjugated aldol adducts from allyl ketone 5.
2.3. Influence of the silicon protecting group
Finally, we studied the effect of the silicon group on the ste-
reochemical outcome of these reactions. Although the tert-butyl-
dimethylsilyl-protecting group (TBS) used up to this point is
probably the most common protecting group of alcohols, we tested
the stability and influence of other silicon groups on these
titanium-mediated aldol reactions. We were particularly aware of
the labile triethylsilyl group (TES), which is often used in the syn-
thesis of natural products. Therefore, lactate-derived ethyl ketones
21e23 possessing sensitive and robust silicon protecting groups,
from TES to TIPS, were submitted to the same enolization condi-
tions and the resulting titanium enolates underwent aldol addi-
tions to 1.5 equiv of isobutyraldehyde (a) for 1 h. The results are
summarized in Table 5.
2.2. Influence of R2 group
Having established the generality of the aldol methodology
based on lactate-derived ketones, we examined the effect of R2
group. For this purpose and in order to expand the scope of this
reaction to any a-silyloxy ketone, we studied the aldol reactions of
a
-tert-butyldimethylsilyloxy ethyl ketones 17 and 18, which hold R2
groups of diverse steric hindrance (R2: Bn and i-Pr, respectively, see
Fig. 1).14
O
O
O
R2
OTBS
OTBS
TBSO
Table 5
α-OTBS ethyl
17
18
TiCl4-Mediated aldol reactions of ethyl
a
-silyloxy ketones 21e23
ketones
Fig. 1. Chiral a-tert-butyldimethylsilyloxy ethyl ketones.
The closeness of bulky R2 groups to the carbonyl led us to test
carefully the experimental conditions of the TiCl4-mediated aldol
reactions from these ketones with model aldehydes, such as iso-
butyraldehyde (a) and benzaldehyde (c). The results are summa-
rized in Table 4.
Entry
Ketone
R3Si
Aldol
dra
Yield (%)b
Our results reveal that the experimental conditions optimized
for lactate-derived ethyl ketone 1 can be safely exported to ketone
17, thereby allowing diastereoselectively aldol adducts 19 in yields
up to 87% (see entries 1 and 3 in Table 4). Indeed, no starting ketone
17 was observed in the crude reaction mixtures and longer reaction
times did not improve the yield (compare entries 1 and 2 in Table
1
2
3
21
22
23
TES
TBDPS
TIPS
24a
25a
26a
>97:3
>97:3
>97:3
82
79
80
a
Determined by 1H NMR.
Isolated yield.
b
Table 4
Titanium-mediated aldol reactions from ethyl ketones 17 and 18
Entry
Ketone
tenol (h)
treac (h)
Aldehyde
R
Equiv
Aldol
dra
Yield (%)b,c
1
2
3
4
5
6
7
17
17
17
18
18
18
18
0.5
1.5
0.5
0.5
1.5
0.5
1.5
0.5
2.0
0.5
0.5
1.0
0.5
1.0
a
a
c
a
a
c
c
i-Pr
i-Pr
Ph
i-Pr
i-Pr
Ph
1.5
1.5
1.2
1.5
1.5
1.2
1.2
19a
19a
19c
20a
20a
20c
20c
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
87
86
82
52 (30)
70
64 (20)
75
Ph
a
Determined by 1H NMR.
Isolated yield.
Into parentheses, recovered ketone 18.
b
c

J. Esteve et al. / Tetrahedron 67 (2011) 6045e6056
6049
The silicon protecting groups had no effect on the titanium-
mediated aldol additions from -silyloxy ketones. The diaster-
eoselectivity and the yield of these transformations and those de-
scribed for -OTBS ketone 1 were similar (compare entry 1 in Table
1 and entries 1e3 in Table 5). Even the sensitive TES group was
stable under the reaction conditions and the corresponding adduct
24a was isolated in high yield (entry 1 in Table 5). These observa-
tions indicate that the transformations are highly flexible, and so
they are suitable for advanced steps of a synthetic sequence.
2.5. Synthetic applications
Having demonstrated that the titanium-mediate aldol reactions
a
a
based on chiral a-silyloxy ketones occur in a highly stereoselective
manner irrespective of the R1, R2 and silicon protecting groups, we
next explored the conversion of the ensuing adducts into arrays
embedded in the structure of natural products. Our first target dealt
with the removal of the original Ca stereocenter.
Masamune proved that removal of the hydroxyl protecting
group of this sort of aldol adducts followed by the oxidation of the
resulting
a-hydroxy ketone delivers enantiomerically pure b-hy-
2.4. Stereochemistry and mechanism
droxy carboxylic acids in good yields.9a This synthetic sequence was
used to confirm the configuration of the aldol adducts shown in
Scheme 7. Moreover, it was successfully applied to the synthesis of
NFX-2 and antimycinone (Scheme 9).19,20 Treatment of aldol 12d
The absolute configuration of aldol products 8 resulting from
ethyl ketone 1 was firmly established through chemical correlation,
NMR and X-ray diffraction studies.7,15 Taking advantage of these
results, the stereochemistry of aldol adducts 9, 10, 12 and 15 from
lactate-derived ketones 2e5 was initially assigned as 2,4-syn-4,5-
syn and was later confirmed during the application to the synthesis
of natural products. In turn, the absolute configuration of aldol
adducts from ketones containing bulky R2 groups, 19ae20a, or
different silicon protecting groups, 24ae26a, was confirmed by
chemical correlation. Thus, removal of the protecting groups and
subsequent oxidation of the resulting dihydroxy ketones furnished
(see Scheme 4) with HF in CH3CN led to
a-hydroxy ketone 28,
which was oxidized and deprotected to afford NFX-2 (13 in Scheme
9) in 60% yield. Alternatively, acylation of 12d and simultaneous
TBS and TBDPS deprotection of the resulting keto ester 29 furnished
a mixture of hemiketals 30, which was smoothly oxidized with
NaIO4 to produce antimycinone (14 in Scheme 9) in quantitative
yield. Thus, these synthetic sequences from chiral ketone 4 furnish
enantiomerically pure metabolites 13 and 14 in four steps and 46%
and 71% yield, respectively, from
the high efficiency of the titanium-mediated aldol reaction based
a
-OTBS ketone 4,21 which prove
b
-hydroxy carboxylic acid 27, whose spectroscopic data matched
those reported in the literature for (2R,3S) 3-hydroxy-
2,4-dimethylpentanoic acid (Scheme 7).9c,16
on
a
-silyloxy ketones.
OH
OH
O
OH
O
O
1) HF–CH3CN
2) NaIO4, MeOH–H2O
40–55%
1) HF–CH3CN
2) NaIO4, MeOH–H2O
55–60%
R2
HO
TBSO
R3SiO
19a, 20a
27
24a–26a
R2: Bn, i-Pr
R3Si: TES; TBDPS; TIPS
[α]D = + 9.8 to +11.4 (c 0.65 –1.0, CHCl3)
Heathcock9c [α]D = + 9.1 (c 2.2, CHCl3)
Palomo16 [α]D = + 10.8 (c 1.0, CHCl3)
Scheme 7. Chemical correlation to (2R,3S) 3-hydroxy-2,4-dimethylpentanoic acid.
This information and the stereochemical outcome of the reactions
reported so far support a common mechanistic picture for these
The selective removal of the a-OSiR3 functionality without af-
fecting the carbon skeleton was our next objective. Preliminary
experiments with SmI2 proved that it was impossible to carry out
this reduction on unprotected aldol adducts. In contrast, TBS-
transformations in which the enolization of an
a-silyloxy ketone
produces a Z-enolate that evolves through a cyclic six-membered
transition state. Remarkably, no vinylogous aldol adducts were ob-
served from allyl ketone 5, thereby ruling out alternative open tran-
sition states. In such a scenario, the antiperiplanar distribution of
R3SiOeC and CeOTi bonds wouldbethekeyelementdetermining the
stereochemical outcome of the reaction since the preferred chair
transition state places the less sterically demanding substituent (H vs
protection of the b-hydroxyl group of 8a followed by treatment of
the resulting aldol with SmI2 nicely furnished ethyl ketone 31 in
82% yield (Scheme 10).22,23 This sequence was applied to aldol 10b
(see Scheme 3) for the preparation of ketone 32, an advanced in-
termediate for the synthesis of the C1eC17 fragment of salinomycin
11 (Scheme 10).11
Me, Bn, or i-Pr) of the C
a
stereocenter pointing towards the inside of
We also addressed the stereoselective reduction of the carbonyl
bond to obtain enantiomerically pure 1,2,4-triols. Taking advantage
the ring (Scheme 8), as previously proposed for related systems.9c,17,18
of well established stereoselective reductions of
b-hydroxy ke-
TiCln
tones,24 we first assessed the anti reduction of the C]O bond of
model aldol adducts 8a and 8h25 (R: i-Pr, C(CH3)C]CH2, re-
spectively, Scheme 11). In spite of our attempts, neither the classical
EvanseChapmaneCarreira26 reduction nor other substrate-
controlled methodologies succeeded,27 affording mixtures of anti
and syn diols 33 and 34 in a poor diastereomeric ratio.
O
O
TiCl4, i-Pr2NEt
R2
R1
R2
R1
R3SiO
R3SiO
H
R3SiO
R
R2
TiClm
O
RCHO
The low stereocontrol observed for these reductions can be
O
traced to the protected hydroxyl group at the
a-position to the
R1
carbonyl. The rationale for the expected anti stereochemistry of this
reduction assumes that the internal hydride delivery proceeds
through a six-membered transition state in which the activated
carbonyl group is placed at an axial position (I in Scheme 11).
However, the antiperiplanar arrangement of the electron-
withdrawing OTBS group relative to the C]O bond forces the hy-
dride to follow the less favoured trajectory according to the
O
OH
R2
R
R3SiO
R1
Scheme 8. Mechanism for the titanium-mediated aldol reactions based on a-silyloxy
ketones.

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J. Esteve et al. / Tetrahedron 67 (2011) 6045e6056
O
O
OH
O
OH
HF–CH3CN, rt
92%
1) NaIO4, MeOH–H2O, rt
2) HF–CH3CN, rt
O
OTBDPS
Hex OTBDPS
TBSO
Hex
12d
HO
OH
60%
28
13 NFX-2
OH
i-BuCOCl, py
CH2Cl2
O
OH
OR
O
Hex
TBAF–AcOH
NaIO4
O
O
94%
THF, rt
91%
MeOH–H2O, rt
100%
TBSO
Hex
OTBDPS
O
OR
30 R: COi-Bu
29 R: COi-Bu
O
14 Antimycinone
Scheme 9. Synthesis of NFX-2 and antimycinone from aldol 12d.
O
OH
O
OTBS
1) TBSOTf, 2,6-lutidine, CH2Cl2, rt
2) SmI2,THF–MeOH, 0 °C
82%
TBSO
OH
8a
31
O
O
OTBS
1) TBSOTf, 2,6-lutidine, CH2Cl2, rt
2) SmI2,THF–MeOH, 0 °C
85%
OBn
OBn
TBSO
10b
32
OTBS
O
OH
O
OBn
MeO
O
H
H
11
C1–C17 Fragment of salinomycin
Scheme 10. Removal of the -OTBS group by reduction with SmI2.
a
Cornforth model.28,29 Thus, alternative transition state II (Scheme
11) can contribute to the reaction and the sterically favoured
transition state I cannot override the electronically favoured II,
which may explain the dramatic loss of stereocontrol observed in
the reduction of aldol products 8a and 8h.
In contrast, parallel reductions directed towards syn-diols
proceeded with excellent diastereoselectivity. Thus, the Nar-
asakaePrasad30 procedure delivered diols 34 as a single di-
astereomer in high yields. As shown in Scheme 12, this
methodology was used for the stereoselective reduction of ent-
8h25 leading to diol ent-34h as a single diastereomer (dr>97:3) in
an excellent 94% yield. Treatment of ent-34h with BH3 followed by
oxidative work-up furnished a 4:1 mixture of diastereomers,
which was purified to deliver all-syn triol 35 in 60% yield. Selective
protection of primary alcohol with pivaloyl chloride and the
resulting diol with Me2C(OMe)2 afforded acetonide 36 in 61% yield
over two steps. Finally, removal of the silicon protecting group at
C6 and DesseMartin oxidation31 of the ensuing alcohol afforded
the C1eC7 fragment of erythronolides 37 in 70% yield.32 Once
again, the Ca stereocenter in the starting a-silyloxy ketone ent-1
becomes the key element to install all the stereocenters to finally
afford the desired fragment in a straightforward and efficient
manner.
Given that the highly stereoselective reduction of 2,4-syn-4,5-
syn aldol ent-8h to syn-diol ent-34 presumably proceeded through
the chelated boron aldolate shown in Scheme 12, we envisaged that
a sequential transformation based on a titanium-mediated aldol
reaction from ketone 1 followed by reduction of the resultant ti-
tanium aldolate with LiBH4 might also occur. This approach was
right and provided straightforward access to the desired syn-diols
34 in a one-pot transformation.15 In view of this successful trans-
formation, we studied a similar procedure from allyl ketone 5 that
would supply highly functionalized syn-diols 38. The results are
summarized in Table 6.
O
OH
The stereochemical outcome of these reactions confirm the
synthetic potential of the sequential aldol-reduction trans-
R
TBSO
TBS
formations based on chiral
a-silyloxy ketones. As for ketones 1,
OAc
B
8a R: i-Pr 8h R: C(CH3)=CH2
O
O
H
OAc
B
O
Me
H
H
diastereomerically pure syn-diols 38 were obtained in good to high
yields in a straightforward manner.33 Remarkably, diol 38c derived
from benzaldehyde was isolated in 80% yield. This observation
implies that the titanium aldolate shows enough stability to be
trapped by the reducing agent. In contrast, diol 38g from croto-
naldehyde was not observed in the reaction mixtures. The absence
of the reduced product demonstrates that the aldol of allyl ketone 5
and crotonaldehyde is not produced as expected. With this ex-
ception, the reduction of the C]O bond of titanium aldolates from
R
H
O
OAc
Me4N HB(OAc)3
CH3CN/AcOH
R
OAc
H
Me
Me
O
Me
OTBS
H
OH
OH
OH
OH
I
II
+
R
R
TBSO
TBSO
anti
syn
33
34
33a R: i-Pr 86% dr 55:45
33h R: C(CH3)=CH2 95% dr 78:22
a-silyloxy ketones furnished the corresponding syn-diols in
a highly stereoselective manner.
Scheme 11. Substrate-controlled synthesis of anti-diols from aldol adducts.

J. Esteve et al. / Tetrahedron 67 (2011) 6045e6056
6051
O
OH
OH OH
O
O
Me
Et
Et2BOMe
THF
LiBH4
B
Et
TBSO
TBSO
TBSO
H
H
ent-8h
Single diastereomer
94%
ent-34h
OH OH
1) PivCl, Et3N, CH2Cl2, rt
2) Me2C(OMe)2, rt
61%
BH3.SMe2, THF
H2O2, OH–
OH
TBSO
(dr 4:1) 60%
35
O
O
O
O
OPiv
TBSO
36
1) TBAF,THF, rt
2) DMP, CH2Cl2, rt
70%
PivO
O
37
C1–C7 fragment of erythronolides
Scheme 12. Substrate-controlled synthesis of syn-diols from aldol adducts.
Table 6
Sequential TiCl4-mediated aldol reaction and LiBH4 reduction from allyl ketone 5
a PerkineElmer 241 MC polarimeter. IR spectra were recorded on
a Nicolet 510FT spectrometer and only the more representative
frequencies are reported. 1H NMR (300 MHz) and 13C NMR
(75.4 MHz) spectra were recorded on a Varian Unity Plus spec-
trometer; 1H NMR (400 MHz) spectra were recorded on a Varian
Mercury; 1H NMR (500 MHz) spectra were recorded on a Varian-
Entry
Aldehyde
R
Equiv
Diol
dra
Yield (%)b
500 VXR; chemical shifts (
d
) are quoted in parts per million and
1
2
3
4
5
a
e
i
c
g
i-Pr
i-Bu
(CH2)12CH3
Ph
(E) CH]CHCH3
1.5
1.5
1.5
1.2
1.2
38a
38e
38i
38c
38g
>97:3
>97:3
>97:3
>97:3
d
72
66
83
80
d
referenced to internal TMS for 1H NMR and CDCl3
(d
77.0) for 13C
NMR; where appropriate, 2D techniques were also used to assist in
structural elucidation. Mass spectra were obtained from the Centro
ꢀ
de Apoio Científico e Tecnoloxico a Investigacion (CACTI), Uni-
a
Determined by 1H NMR.
Isolated yield.
versidade de Vigo and from the Servei d’Espectrometria de Masses,
Universitat de Barcelona. Flash chromatography was performed on
b
SDS silica gel (35e70 mm). Analytical thin layer chromatography
3. Conclusions
was carried out on Merck Kieselgel 60 F254 plates. The following
solvents and reagents were purified and dried according to the
standard procedures: CH2Cl2, THF and i-Pr2NEt. All other reagents
were used as received.
In summary, titanium enolates from a broad scope of chiral
-silyloxy ketones participate in highly stereoselective aldol
a
reactions. Our systematic study of the influence of a range of struc-
tural and experimental variables on the stereochemical outcome of
these substrate-controlled reactions has established that the corre-
sponding synesyn adducts can be obtained as a single diastereomer
in high yield irrespective of the R1 and R2 substituents flanking the
carbonyl or the silicon protecting group. In turn, these adducts can be
converted into highly functionalized fragments in a straightforward
4.2. (S)-2-tert-Butyldimethylsilyloxy-5-hexen-3-ona (5)
A 1.7 M C3H5MgCl in THF (3.5 mL, 6 mmol) was carefully added
to a solution of 7 (1.58 g, 6 mmol) in dry THF (90 mL) under N2 at
ꢀ78 ꢁC. The resulting mixture was stirred for 15 min at ꢀ78 ꢁC and
quenched by addition of sat NH4Cl. It was partitioned with Et2O and
H2O, the organic layer was washed with brine, dried and concen-
trated to afford an oil, which was purified by flash chromatography
(95:5 hexanes/EtOAc) to give 1.30 g (5.7 mmol, 95% yield) of ketone
manner. A remarkable example is the lactate-derived a-silyloxy allyl
ketone, which undergoes highly efficient sequential transformations
that lead to high yields of enantiomerically pure syn diols containing
three new stereocenters. Hence, the titanium-mediated aldol re-
actions from chiral a-silyloxy ketones are a reliable and powerful
tool for the synthesis of natural products.
5 as a colourless oil; Rf (95:5 hexanes/EtOAc) 0.40; [
a
]
20 ꢀ1.2 (c 1.1,
D
CHCl3); nmax (liquid film) 3082, 2956, 2931, 2859, 1731, 1644, 1472,
1254, 1118 cmꢀ1
; dH (300 MHz, CDCl3) 5.94 (1H, ddt, J 17.2, 10.3,
4. Experimental
6.9 Hz, CH]CH2), 5.20e5.09 (2H, m, CH]CH2), 4.18 (1H, q, J 6.9 Hz,
CHOSi), 3.42 (1H, ddt, J 17.9, 6.9, 1.3 Hz, COCHxHy), 3.33 (1H, ddt, J
17.9, 6.9, 1.3 Hz, COCHxHy), 1.29 (3H, d, J 6.9 Hz, MeCHOSi), 0.92 (9H,
s, SiCMe3), 0.09 (6H, s, 2ꢂ SiMe); dC (75.4 MHz, CDCl3) 211.9, 130.7,
118.5, 74.7, 41.7, 25.7, 20.9, 18.0, ꢀ4.8, ꢀ5.1; HRMS (ESI): [MH]þ,
found 229.1612, C12H25O2Si requires 229.1618.
4.1. General information
Melting points were taken on an Electrothermal apparatus and
are uncorrected. Specific rotations were determined at 20 ꢁC on

6052
J. Esteve et al. / Tetrahedron 67 (2011) 6045e6056
4.3. General TiCl4-aldol procedure for
a
-silyloxy ketones
11.9, ꢀ4.6, ꢀ4.7; HRMS (ESI): [MNa]þ, found 359.2004,
C19H32NaO3Si requires 359.2012.
Neat TiCl4 (0.12 mL, 1.1 mmol) is added slowly to a solution of
an
a
-silyloxy ketone (1.0 mmol) in CH2Cl2 (5 mL) at ꢀ78 ꢁC under
4.3.5. (2S,4R,5S)-2-tert-Butyldimethylsilyloxy-4-hexyl-5-hydroxy-6-
N2. The resulting yellow mixture is stirred for 3e4 min and i-
Pr2NEt (0.19 mL, 1.1 mmol) is added dropwise. The resulting dark
red solution is stirred for 30 min at ꢀ78 ꢁC and, after the drop-
wise addition of freshly distilled aldehyde (1.5 or 1.2 equiv),
stirring is continued for 30 min at ꢀ78 ꢁC. The reaction is
quenched by the addition of sat NH4Cl (5 mL) and vigorously
stirred at room temperature. The mixture is diluted with Et2O,
washed with H2O, sat NaHCO3 and brine. The aqueous layers are
extracted with Et2O, and the combined organic extracts are dried
(MgSO4) and concentrated. The resulting oil is analyzed by 1H
NMR and purified by flash chromatography (hexanes/EtOAc or
CH2Cl2).
methyl-3-heptanone (12a). Colourless oil. Rf (95:5 hexanes/EtOAc)
20
0.10; [
a
]
ꢀ15.9 (c 1.1, CHCl3); nmax (liquid film) 3510 (br), 2960,
D
2940, 2860, 1710, 1465, 1120 cmꢀ1
; dH (300 MHz, CDCl3) 4.23 (1H, q,
J 6.7 Hz, CHOSi), 3.45e3.30 (2H, m, COCHCHOH), 1.80e1.65 (2H, m,
COCHCHxHy and CHMe2), 1.60e1.45 (1H, m, COCHCHxHy), 1.32 (3H,
d, J 6.7 Hz, MeCHOSi), 1.30e1.20 (8H, m, (CH2)4Me), 1.01 (3H, d, J
6.7 Hz, CHMe), 0.93 (9H, s, SiCMe3), 0.89 (3H, d, J 6.7 Hz, CHMe), 0.87
(3H, t, J 6.7 Hz, CH2Me), 0.10 (6H, s, 2ꢂ SiMe); dC (75.4 MHz, CDCl3)
218.5, 76.2, 74.9, 46.9, 31.6, 31.2, 29.7, 28.1, 25.8, 25.1, 22.6, 20.5,19.4,
19.2, 18.1, 14.0, ꢀ4.6 (ꢂ 2); HRMS (ESI): [MNa]þ, found 381.2805,
C20H42NaO3Si requires 381.2801.
4.3.6. (2S,4R,5S,6S)-2-tert-Butyldimethylsilyloxy-6-tert-butyldiphe-
4.3.1. (2S,4R,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-6-methyl-
nylsilyloxy-4-hexyl-5-hydroxy-3-heptanone (12d). Colourless oil. Rf
20
4-propyl-3-heptanone (9a). Colourless oil. Rf (90:10 hexanes/
(60:40 hexanes/CH2Cl2) 0.15; [
a
]
ꢀ7.9 (c 2.0, CHCl3); nmax (liquid
D
EtOAc) 0.25; [
a]
20 ꢀ22.2 (c 1.3, CHCl3); nmax (liquid film) 3524 (br),
film) 3510 (br), 3080, 3060, 2960, 2920, 2850, 1710, 1595, 1470,
D
2958, 2932, 2859, 1701, 1470, 1256, 1115 cmꢀ1
;
dH (400 MHz, CDCl3)
1250, 1110 cmꢀ1
;
dH (500 MHz, CDCl3) 7.70e7.60 (4H, m, ArH),
4.23 (1H, q, J 6.8 Hz, CHOSi), 3.45e3.39 (1H, m, COCHCHOH), 3.36
(1H, dd, J 8.4, 2.7 Hz, CHOH), 1.80e1.65 (2H, m, CHMe2 and
CHxHyCH2Me), 1.55e1.43 (1H, m, CHxHyCH2Me), 1.35e1.15 (2H, m,
CH2CH2Me), 1.32 (3H, d, J 6.8 Hz, MeCHOSi), 1.01 (3H, d, J 6.4 Hz,
CHMe), 0.93 (9H, s, SiCMe3), 0.90 (3H, t, J 7.2 Hz, CH2Me), 0.89 (3H, d,
J 6.8 Hz, CHMe), 0.10 (6H, s, 2ꢂ SiMe); dC (100.6 MHz, CDCl3) 218.6,
76.2, 74.9, 46.7, 31.2, 27.2, 25.8, 21.3, 20.5, 19.4, 19.1, 18.1, 14.4, ꢀ4.6,
ꢀ4.7; HRMS (ESI): [MNa]þ, found 339.2326, C17H36NaO3Si requires
339.2325.
7.50e7.30 (6H, m, ArH), 4.07 (1H, q, J 7.0 Hz, CHOTBS), 3.72e3.68
(1H, m, CHOH), 3.67 (1H, quint, J 6.0 Hz, CHOTBDPS), 3.38e3.34 (1H,
m, COCHCH2), 1.64e1.54 (1H, m, COCHCHxHy), 1.39e1.31 (1H, m,
COCHCHxHy), 1.23 (3H, d, J 7.0 Hz, MeCHOTBS), 1.21e1.04 (8H, m,
(CH2)4Me), 0.99 (9H, s, SiCMe3), 0.95 (3H, d, J 6.0 Hz, TBDPSOCHMe),
0.85 (9H, s, SiCMe3), 0.79 (3H, t, J 7.0 Hz, CH2Me), 0.08 (3H, s, SiMe),
0.08 (3H, s, SiMe); dC (75.4 MHz, CDCl3) 216.4, 135.9, 135.8, 134.2,
133.2, 129.8, 129.6, 127.7, 127.4, 75.3, 74.6, 70.0, 46.9, 31.6, 29.7, 27.2,
27.1, 26.3, 25.8, 22.6, 20.6, 19.2, 19.1, 18.1, 14.1, ꢀ4.6, ꢀ4.7; HRMS
(ESI): [MNa]þ, found 621.3785, C35H58NaO4Si2 requires 621.3771.
4.3.2. (1R,2R,4S)-4-tert-Butyldimethylsilyloxy-1-hydroxy-1-phenyl-
2-propyl-3-pentanone (9c). Colourless oil. Rf (90:10 hexanes/EtOAc)
4.3.7. (2S,4R,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-6-methyl-
20
0.20; [
a
]
D
ꢀ15.0 (c 0.9, CHCl3); nmax (liquid film) 3488 (br), 2957,
4-vinyl-3-heptanone (15a). Colourless oil. Rf (95:5 hexanes/EtOAc)
2931, 2858, 1709, 1455, 1254, 1117 cmꢀ1
;
dH (300 MHz, CDCl3)
0.25; [
a
]
D
20 þ195.6 (c 1.0, CHCl3); nmax (liquid film) 3522 (br), 3081,
7.35e7.30 (5H, m, ArH), 4.95 (1H, d, J 4.5 Hz, CHOH), 4.02 (1H, q, J
6.9 Hz, CHOSi), 3.53e3.46 (1H, m, COCHCHOH), 1.78e1.64 (1H, m,
CHxHyCH2Me),1.57e1.40 (3H, m, CHxHyCH2Me),1.23 (3H, d, J 6.9 Hz,
MeCHOSi), 0.93 (9H, s, SiCMe3), 0.80 (3H, t, J 7.3 Hz, CH2Me), 0.09
(3H, s, SiMe), 0.08 (3H, s, SiMe); dC (75.4 MHz, CDCl3) 217.2, 142.0,
128.2, 127.4, 126.1, 75.0, 73.2, 52.3, 28.7, 25.8, 20.9, 20.1, 18.1, 14.3,
ꢀ4.6, ꢀ4.7; HRMS (ESI): [MNa]þ, found 373.2172, C20H34NaO3Si
requires 373.2169.
2957, 2931, 2859, 1700, 1633, 1472, 1256, 1116, 1085 cmꢀ1
;
dH
(300 MHz, CDCl3) 5.93e5.81 (1H, m, CH]CH2), 5.34e5.28 (1H, m,
CH]CH2), 4.25 (1H, q, J 6.9 Hz, CHOSi), 4.03 (1H, dd, J 9.2, 3.1 Hz,
CHOH), 3.51 (1H, dd, J 8.2, 2.9 Hz, CHCH]CH2), 1.70e1.60 (1H, m,
CHMe2), 1.33 (3H, d, J 6.9 Hz, MeCHOSi), 0.99 (3H, d, J 6.6 Hz, CHMe),
0.92 (9H, s, SiCMe3), 0.87 (3H, d, J 6.7 Hz, CHMe), 0.08 (3H, s, SiMe),
0.07 (3H, s, SiMe); dC (75.4 MHz, CDCl3) 215.5,131.7,120.9, 76.2, 74.7,
52.3, 30.8, 25.7, 21.9, 18.9, 18.7, 18.1, ꢀ4.8, ꢀ4.9; HRMS (ESI):
[MNa]þ, found 323.2013, C16H32NaO3Si requires 323.2012.
4.3.3. (2S,4R,5S)-2-tert-Butyldimethylsilyloxy-4-ethyl-5-hydroxy-6-
methyl-3-heptanone (10a). Colourless oil. Rf (90:10 hexanes/EtOAc)
4.3.8. (2S,4R,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-7-methyl-
20
0.25; [
a
]
ꢀ19.9 (c 1.0, CHCl3); nmax (liquid film) 3521 (br), 2960,
4-vinyl-3-octanone (15e). Colourless oil. Rf (95:5 hexanes/EtOAc)
D
2932, 2859, 1705, 1472, 1464, 1256, 1117 cmꢀ1
;
dH (400 MHz, CDCl3)
0.25; [
a]
20 þ128.9 (c 1.1, CHCl3); nmax (liquid film) 3737, 2956, 2931,
D
4.22 (1H, q, J 6.8 Hz, CHOSi), 3.41e3.30 (2H, m, CHOH and COCH-
CHOH), 1.85e1.55 (3H, m, CHMe2 and CH2Me), 1.32 (3H, d, J 6.8 Hz,
MeCHOSi), 1.00 (3H, d, J 6.6 Hz, CHMe), 0.93 (9H, s, SiCMe3), 0.89
(3H, d, J 6.6 Hz, CHMe), 0.87 (3H, t, J 7.5 Hz, CH2Me), 0.11 (6H, s, 2ꢂ
SiMe); dC (100.6 MHz, CDCl3) 218.4, 76.1, 74.9, 48.4, 31.1, 25.8, 20.4,
19.2 (ꢂ 2), 18.2, 18.1, 12.4, ꢀ4.6, ꢀ4.7; HRMS (ESI): [MNa]þ, found
325.2174, C16H34NaO3Si requires 325.2169.
2859, 1701, 1635, 1472, 1258, 1115 cmꢀ1
;
dH (300 MHz, CDCl3) 5.84
(1H, ddd, J 17.1, 10.1, 9.5 Hz, CH]CH2), 5.35e5.25 (1H, m, CH]CH2),
4.24 (1H, q, J 6.9 Hz, CHOSi), 3.98 (1H, dt, J 9.4, 3.8 Hz, CHOH), 3.73
(1H, dd, J 9.5, 3.8 Hz, CHCH]CH2), 1.87e1.70 (1H, m, CHMe2), 1.44
(1H, ddd, J 13.7, 9.3, 5.3 Hz, CHxHyCHMe2), 1.31 (3H, d, J 6.9 Hz,
MeCHOSi), 1.06 (1H, ddd, J 13.7, 8.8, 4.0 Hz, CHxHyCHMe2), 0.92 (9H,
s, SiCMe3), 0.92e0.90 (3H, buried d, CHMe), 0.90 (3H, d, J 6.4 Hz,
CHMe), 0.08 (3H, s, SiMe), 0.07 (3H, s, SiMe); dC (75.4 MHz, CDCl3)
214.8, 132.3, 121.1, 74.7, 69.0, 55.8, 43.4, 25.8, 24.3, 23.4, 21.8, 21.5,
18.1, ꢀ4.8, ꢀ4.9; HRMS (ESI): [MNa]þ, found 337.2175,
C17H34NaO3Si requires 337.2170.
4.3.4. (1R,2R,4S)-4-tert-Butyldimethylsilyloxy-2-ethyl-1-hydroxy-1-
phenyl-3-pentanone (10c). Colourless oil. Rf (90:10 hexanes/EtOAc)
0.22; [
a
]
D
20 ꢀ18.4 (c 1.05, CHCl3); nmax (liquid film) 3488 (br), 2956,
2931, 2858, 1709, 1462, 1255, 1120 cmꢀ1
;
dH (300 MHz, CDCl3)
7.35e7.26 (5H, m, ArH), 4.96 (1H, dd, J 5.1, 2.2 Hz, CHOH), 4.00 (1H,
q, J 6.7 Hz, CHOSi), 3.44 (1H, ddd, J 9.2, 5.1, 4.0 Hz, COCHCHOH),
1.85e1.68 (1H, m, CHxHyMe), 1.67e1.50 (1H, m, CHxHyMe), 1.22 (3H,
d, J 6.7 Hz, MeCHOSi), 0.93 (9H, s, SiCMe3), 0.79 (3H, t, J 7.5 Hz,
CH2Me), 0.08 (3H, s, SiMe), 0.07 (3H, s, SiMe); dC (75.4 MHz, CDCl3)
216.8, 142.1, 128.2, 127.4, 126.1, 75.0, 73.1, 53.8, 25.8, 20.0, 19.6, 18.1,
4.3.9. (2S,4R,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-4-vinyl-3-
20
heptanone (15f). Colourless oil. Rf (95:5 hexanes/EtOAc) 0.20; [a]
D
þ143.8 (c 1.1, CHCl3); nmax (liquid film) 3529 (br), 2958, 2932, 2859,
1712, 1635, 1473, 1255, 1118 cmꢀ1
dH (300 MHz, CDCl3) 5.84 (1H,
;
ddd, J 17.0, 10.3, 9.1 Hz, CH]CH2), 5.35e5.25 (1H, m, CH]CH2), 4.25
(1H, q, J 6.9 Hz, CHOSi), 3.85e3.75 (2H, m, COCHCHOH), 1.60e1.27

J. Esteve et al. / Tetrahedron 67 (2011) 6045e6056
6053
(2H, m, CH2Me), 1.32 (3H, d, J 6.9 Hz, MeCHOSi), 0.94 (3H, t, J 7.5 Hz,
CH2Me), 0.92 (9H, s, SiCMe3), 0.08 (3H, s, SiMe), 0.07 (3H, s, SiMe); dC
(75.4 MHz, CDCl3) 214.9, 131.9, 121.1, 74.7, 72.5, 54.8, 27.1, 25.7, 21.6,
18.1, 10.1, ꢀ4.8, ꢀ4.9; HRMS (ESI): [MNa]þ, found 309.1861,
C15H30Na3Si requires 309.1856.
CHMe), 0.97 (9H, t, J 7.9 Hz, Si(CH2Me)3), 0.86 (3H, d, J 6.6 Hz,
CHMe), 0.63 (6H, q, J 7.9 Hz, Si(CH2Me)3); dC (75.4 MHz, CDCl3)
219.4, 76.1, 74.3, 41.3, 30.4, 21.4, 19.3, 18.8, 9.4, 6.7, 4.8; HRMS (ESI):
[MNa]þ, found 311.2013, C15H32NaO3Si requires 311.2012.
4.3.15. (2S,4R,5S)-2-tert-Butyldiphenylsilyloxy-5-hydroxy-4,6-
20
4.3.10. (2S,4R,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-4,6-
dimethyl-3-heptanone (25a). Colourless oil. Rf (CH2Cl2) 0.20; [a]
D
dimethyl-1-phenyl-3-heptanone (19a). Colourless oil. Rf (90:10
þ5.1 (c 1.0, CHCl3); nmax (liquid film) 3525 (br), 2962, 1700, 1474,
1428, 1113 cmꢀ1
dH (300 MHz, CDCl3) 7.66e7.60 (4H, m, ArH),
20
hexanes/EtOAc) 0.35; [
a
]
þ7.0 (c 1.2, CHCl3); nmax (liquid film)
;
D
3530 (br), 3087, 3064, 3031, 2960, 2711,1697,1604,1496, 1474,1407,
7.48e7.33 (6H, m, ArH), 4.27 (1H, q, J 7.0 Hz, CHOSi), 3.33e3.25 (1H,
m, CHOH), 3.22 (1H, qd, J 7.0, 2.1 Hz, COCHMe), 1.70e1.54 (1H, m,
CHMe2), 1.28 (3H, d, J 7.0 Hz, MeCHOSi), 1.11 (9H, s, SiCMe3), 1.03
(3H, d, J 7.0 Hz, COCHMe), 0.97 (3H, d, J 6.7 Hz, CHMe), 0.75 (3H, d, J
6.7 Hz, CHMe); dC (75.4 MHz, CDCl3) 219.2, 135.8, 133.4, 132.7, 130.0,
127.8, 127.7, 75.9, 75.1, 41.7, 30.2, 26.9, 21.4, 19.5, 19.2, 18.7, 9.2;
HRMS (FAB): [MH]þ, found 413.2507, C25H37O3Si requires 413.2511.
1389, 1362, 1324, 1257, 1195, 1109, 1039 cmꢀ1
;
dH (300 MHz, CDCl3)
7.32e7.16 (5H, m, ArH), 4.26 (1H, dd, J 8.5, 4.0 Hz, CHOSi), 3.41 (1H,
dd, J 9.1, 1.9 Hz, CHOH), 3.20 (1H, qd, J 7.3, 1.9 Hz, COCHMe), 3.01
(1H, dd, J 13.4, 4.0 Hz, PhCHxHy), 2.85 (1H, dd, J 13.4, 8.5 Hz,
PhCHxHy), 1.74e1.60 (1H, m, CHMe2), 1.05 (3H, d, J 7.3 Hz, COCHMe),
1.02 (3H, d, J 6.6 Hz, CHMe), 0.86 (9H, s, SiCMe3), 0.86 (3H, d, J
6.8 Hz, CHMe), ꢀ0.08 (3H, s, SiMe), ꢀ0.36 (3H, s, SiMe); dC
(75.4 MHz, CDCl3) 219.2, 137.2, 130.0, 128.3, 126.8, 79.9, 75.9, 41.9,
41.8, 30.3, 25.7, 19.6, 18.7, 18.0, 8.7, ꢀ5.1, ꢀ5.7; HRMS (ESI): [MH]þ,
found 365.2504, C21H37O3Si requires 365.2506.
4.3.16. (2S,4R,5S)-5-Hydroxy-4,6-dimethyl-2-triisopropylsilyloxy-3-
heptanone (26a). Colourless oil. Rf (CH2Cl2) 0.25; [
a]
20 þ30.1 (c 1.1,
D
CHCl3); nmax (liquid film) 3529 (br), 2946, 1700, 1465, 1119 cmꢀ1
;
dH
(300 MHz, CDCl3) 4.35 (1H, q, J 6.9 Hz, CHOSi), 3.49e3.43 (1H, m,
CHOH), 3.40 (1H, qd, J 7.2, 2.1 Hz, COCHMe), 1.78e1.60 (1H, m,
CHMe2), 1.40 (3H, d, J 6.9 Hz, MeCHOSi), 1.16 (3H, d, J 7.2 Hz,
COCHMe), 1.10e1.05 (21H, m, Si(CHMe2)3), 1.03 (3H, d, J 6.4 Hz,
CHMe), 0.83 (3H, d, J 6.7 Hz, CHMe); dC (75.4 MHz, CDCl3) 220.7,
76.0, 75.1, 41.1, 30.2, 22.2, 19.6, 18.7, 18.0, 17.9, 12.2, 9.3; HRMS (ESI):
[MH]þ, found 331.2665, C18H39O3Si requires 331.2663.
4.3.11. (1R,2R,4S)-4-tert-Butyldimethylsilyloxy-1-hydroxy-2-methyl-
1,5-diphenyl-3-pentanone (19c). Colourless oil. Rf (50:50 hexanes/
CH2Cl2) 0.25; [
a]
20 þ8.7 (c 1.0, CHCl3); nmax (liquid film) 3502 (br),
D
3063, 3030, 2954, 2929, 2885, 2857, 1699, 1454, 1255, 1115 cmꢀ1
;
dH
(300 MHz, CDCl3) 7.36e7.15 (10H, m, ArH), 5.05 (1H, d, J 3.2 Hz,
CHOH), 4.28 (1H, dd, J 8.5, 4.0 Hz, CHOSi), 3.24 (1H, qd, J 7.3, 3.2 Hz,
COCHMe), 2.95 (1H, dd, J 13.5, 4.0 Hz, PhCHxHy), 2.77 (1H, dd, J 13.5,
8.5 Hz, PhCHxHy), 0.98 (3H, d, J 7.3 Hz, CHMe), 0.84 (9H, s, SiCMe3),
ꢀ0.06 (3H, s, SiMe), ꢀ0.32 (3H, s, SiMe); dC (75.4 MHz, CDCl3) 218.0,
141.6, 137.2, 129.9, 128.3, 128.2, 127.2, 126.8, 125.9, 79.7, 72.4, 47.6,
41.4, 25.7, 18.0, 9.8, ꢀ5.1, ꢀ5.6; HRMS (ESI): [MNa]þ, found
421.2169, C24H34NaO3Si requires 421.2169.
4.4. Synthetic applications
4.4.1. (2S,4R,5S,6S)-6-tert-Butyldiphenylsilyloxy-4-hexyl-2,5-
dihydroxy-3-heptanone (28). A solution of 12d (695 mg, 1.16 mmol)
and 48% aq HF (0.13 mL, 3.83 mmol) in CH3CN (12 mL) was stirred at
room temperature under a N2 for 1 h. It was diluted with CH2Cl2
(100 mL), washed with sat NaHCO3 (2ꢂ30 mL), dried (Na2SO4) and
concentrated. Purification of the residue by column chromatogra-
phy (80:20 hexanes/EtOAc) afforded 515 mg (1.06 mmol, 92% yield)
4.3.12. (3S,5R,6S)-3-tert-Butyldimethylsilyloxy-6-hydroxy-2,5,7-
trimethyl-4-octanone (20a). Colourless oil. Rf (90:10 hexanes/
20
EtOAc) 0.30; [
a
]
D
ꢀ1.9 (c 1.3, CHCl3); nmax (liquid film) 3524 (br),
29.59, 2858, 1699, 1472, 1253, 1071 cmꢀ1
;
dH (300 MHz, CDCl3) 3.91
of 28 as a colourless oil. Rf (80:20 hexanes/EtOAc) 0.35; [
a
]
20 þ11.1
D
(1H, d, J 5.1 Hz, CHOSi), 3.40 (1H, dt, J 8.3,1.6 Hz, CHOH), 3.14 (1H, qd, J
7.2, 1.6 Hz, COCHMe), 2.10e1.90 (1H, m, Me2CHCHOSi), 1.80e1.60
(1H, m, HOCHCHMe2), 1.09 (3H, d, J 7.2 Hz, COCHMe), 1.03 (3H, d, J
6.5 Hz, CHMe), 0.96 (3H, d, J 6.5 Hz, CHMe), 0.94 (9H, s, SiCMe3), 0.89
(3H, d, J 6.7 Hz, CHMe), 0.84 (3H, d, J 6.7 Hz, CHMe), 0.05 (3H, s, SiMe),
0.03 (3H, s, SiMe); dC (75.4 MHz, CDCl3) 218.9, 83.0, 76.0, 41.3, 32.1,
30.4, 25.8, 19.7, 19.4, 18.8, 18.2, 17.4, 9.3, ꢀ4.5, ꢀ5.1; HRMS (ESI):
[MNa]þ, found 339.2328, C17H36NaO3Si requires 339.2325.
(c 1.7, CHCl3); nmax (liquid film) 3450 (br), 3060, 2960, 2920, 2860,
1700,1590,1460 cmꢀ1
; dH (300 MHz, CDCl3) 7.70e7.60 (4H, m, ArH),
7.50e7.30 (6H, m, ArH), 4.23 (1H, qd, J 7.2, 4.8 Hz, MeCHOH),
3.83e3.72 (2H, m, CHOHCHOTBDPS), 3.18e3.12 (1H, m, COCHCH2),
1.73e1.57 (1H, m, COCHCHxHy), 1.50e1.37 (1H, m, COCHCHxHy), 1.34
(3H, d, J 7.2 Hz, MeCHOH), 1.32e1.10 (8H, m, (CH2)4Me), 1.07 (9H, s,
SiCMe3), 1.04 (3H, d, J 5.8 Hz, TBDPSOCHMe), 0.87 (3H, t, J 6.9 Hz,
CH2Me), 0.08 (3H, s, SiMe), 0.08 (3H, s, SiMe); dC (75.4 MHz, CDCl3)
217.0, 135.9, 135.8, 134.0, 133.1, 129.9, 129.7, 127.8, 127.5, 74.1, 73.4,
69.8, 47.4, 31.5, 29.6, 27.1, 27.0, 22.6, 20.6, 19.6, 19.2, 18.8, 14.0.
4.3.13. (1R,2R,4S)-4-tert-Butyldimethylsilyloxy-1-hydroxy-2,5-
dimethyl-1-phenyl-3-hexanone (20c). Colourless oil. Rf (CH2Cl2)
20
0.25; [
a
]
ꢀ20.5 (c 1.1, CHCl3); nmax (liquid film) 3502 (br), 2958,
4.4.2. (2R,3R,4S)-2-Hexyl-3-hydroxy-4-methylbutyrolactone, NFX-2
(13). A solution of 28 (460 mg, 0.95 mmol) and NaIO4 (2 g,
9.5mmol)in2:1 MeOH/H2O(12mL)wasstirredatroom temperature
for 1.5 h. It was diluted with CH2Cl2 and washed with 0.5 M HCl. The
aqueous layers were extracted with CH2Cl2. The combined organic
extracts were dried (Na2SO4) andconcentrated to afford 424 mg of an
oil that was used in the next step without further purification.
A solution of this oil and 48% aq HF (0.25 mL, 7.3 mmol) in
CH3CN (15 mL) was stirred at room temperature under N2 for three
days. Application of the work-up described in Section 4.4.1 afforded
furnished 115 mg (0.57 mmol, 60% yield) of 13 as a white solid. Rf
D
2930, 2857, 1717, 1456, 1252, 1071, 1004 cmꢀ1
; dH (300 MHz, CDCl3)
7.35e7.23 (5H, m, ArH), 5.06 (1H, d, J 2.9 Hz, CHOH), 3.96 (1H, d, J
4.9 Hz, CHOSi), 3.18 (1H, qd, J 7.2, 2.9 Hz, COCHMe), 2.05e1.95 (1H, m,
CHMe2), 1.01 (3H, d, J 7.2 Hz, COCHMe), 0.95 (3H, d, J 6.6 Hz, CHMe),
0.94 (9H, s, SiCMe3), 0.79 (3H, d, J 6.6 Hz, CHMe), 0.06 (3H, s, SiMe),
0.05(3H, s, SiMe);dC (75.4MHz, CDCl3)217.9,141.5,128.2,127.2,125.9,
82.7, 72.5, 46.9, 31.9, 25.8,19.6,18.2,17.0,10.3, ꢀ4.5, ꢀ5.1;HRMS(ESI):
[MNa]þ, found 373.2169, C20H34NaO3Si requires 373.2169.
4.3.14. (2S,4R,5S)-5-Hydroxy-4,6-dimethyl-2-triethylsilyloxy-3-
heptanone (24a). Colourless oil. Rf (CH2Cl2) 0.20; [
a]
20 þ18.8 (c 1.0,
(2:1 hexanes/EtOAc) 0.30; mp 58.0e59.5 ꢁC [lit.34 mp 57.0e58.5 ꢁC;
D
20
CHCl3); nmax (liquid film) 3529 (br), 2960, 1702, 1459, 1368, 1121,
lit.35 mp 60e62 ꢁC]. Rf (80:20 hexanes/EtOAc) 0.35; [
a
]
ꢀ13.5 (c
D
20
21
1105 cmꢀ1
;
dH (300 MHz, CDCl3) 4.24 (1H, q, J 6.9 Hz, CHOSi), 3.45
1.2, MeOH) [lit.34
[
a]
ꢀ11.9 (c 1.0, MeOH); lit.35
[a
]
ꢀ14 (c 1.0,
D
D
(1H, dd, J 8.5, 2.6 Hz, CHOH), 3.36 (1H, qd, J 7.2, 2.6 Hz, COCHMe),
1.69 (1H, dhept, J 8.6, 6.6 Hz, CHMe2), 1.35 (3H, d, J 6.9 Hz,
MeCHOSi), 1.12 (3H, d, J 7.2 Hz, COCHMe), 1.02 (3H, d, J 6.6 Hz,
MeOH)]; nmax (KBr) 3473 (br), 2952, 2930, 2850, 1735, 1395, 1210,
1187, 1063 cmꢀ1
MeCHO), 3.89e3.79 (1H, m, CHOH), 2.56 (1H, ddd, J 8.5, 7.2, 5.7 Hz,
; dH (300 MHz, CDCl3) 4.20 (1H, quint, J 6.4 Hz,

6054
J. Esteve et al. / Tetrahedron 67 (2011) 6045e6056
COCHCH2), 1.90e1.20 (10H, m, (CH2)5Me), 1.45 (3H, d, J 6.4 Hz,
MeCHO), 0.89 (3H, t, J 6.7 Hz, CH2Me); dC (75.4 MHz, CDCl3) 176.4,
80.1, 79.0, 48.6, 31.5, 29.2, 28.5, 26.7, 22.5, 18.2, 14.0.
MeOH (3.6 mL) at 0 ꢁC under N2. The dark green mixture was stirred
for 10 min at 0 ꢁC and was quenched by addition of sat Na2CO3
(12 mL). It was then partitioned with Et2O and sat Na2CO3 and the
aqueous layer was further extracted with Et2O. The combined or-
ganic extracts were dried (MgSO4) and concentrated. The resulting
oil was purified by column chromatography (90:10 hexanes/EtOAc)
to afford 50 mg (0.18 mmol, 91% yield, 82% yield over two steps) of
4.4.3. (2S,3R,4R,6S)-6-tert-Butyldimethylsilyloxy-2-tert-butyldiphe-
nylsilyloxy-4-hexyl-5-oxo-3-heptanyl 3-methylbutanoate (29). A
solution of 12d (843 mg, 1.4 mmol), pyridine (0.57 mL, 7.0 mmol), 3-
methylbutanoyl chloride (0.84 mL, 7.0 mmol) and DMAP (25 mg)
were stirred overnight at room temperature under N2. It was diluted
with CH2Cl2, washed with 1 M HCl, sat NaHCO3 and H2O, dried
(Na2SO4) and concentrated. The residue was purified by column
chromatography (95:5 hexanes/EtOAc) to afford 907 mg (1.33 mmol,
94% yield) of 29 as a colourless oil. Rf (95:5 hexanes/EtOAc) 0.50;
31 as a colourless oil. Rf (90:10 hexanes/EtOAc) 0.60; [
a
]
D
20 ꢀ18.4 (c
0.9, CHCl3); nmax (liquid film) 2960, 2860, 1715, 1465, 1254,
1054 cmꢀ1
; dH (300 MHz, CDCl3) 3.78 (1H, dd, J 6.0, 4.1 Hz, CHOSi),
2.69 (1H, qd, J 7.0, 6.0 Hz, COCHMe), 2.60e2.39 (2H, m, CH2CO),1.64
(1H, heptd, J 6.9, 4.1 Hz, CHMe2), 1.08 (3H, d, J 7.0 Hz, COCHMe), 1.03
(3H, t, J 7.2 Hz, MeCH2CO), 0.90 (9H, s, SiCMe3), 0.90 (3H, d, J 6.9 Hz,
CHMe), 0.84 (3H, d, J 6.9 Hz, CHMe), 0.06 (3H, s, SiMe), 0.02 (3H, s,
SiMe); dC (75.4 MHz, CDCl3) 214.2, 77.5, 49.9, 35.5, 32.8, 26.1, 19.9,
18.4, 17.5, 13.6, 7.7, ꢀ3.9, ꢀ4.1; HRMS (FAB): [MH]þ, found 273.2245,
C15H33O2Si requires 273.2250.
[a]
20 ꢀ18.4 (c 1.6, CHCl3); nmax (liquid film) 3081, 3035, 2961, 2933,
D
2850, 1740, 1700, 1472, 1364, 1254, 1113 cmꢀ1
;
dH (500 MHz, CDCl3)
7.70e7.60 (4H, m, ArH), 7.50e7.30 (6H, m, ArH), 5.31 (1H, dd, J 6.9,
4.2 Hz, CHOCO), 4.18 (1H, q, J 6.7 Hz, CHOTBS), 3.70 (1H, dq, J 6.9,
6.3 Hz, CHOTBDPS), 3.66 (1H, ddd, J 10.4, 4.2, 3.0 Hz, COCHCH2),
2.15e1.95 (3H, m, COCH2CHMe2), 1.67e1.57 (1H, m, COCHCHxHy),
1.30e1.20 (1H, m, COCHCHxHy), 1.20e1.10 (7H, m, CHxHy(CH2)3Me),
1.23 (3H, d, J 6.7 Hz, MeCHOTBS), 1.04 (9H, s, SiCMe3), 0.95 (3H, d, J
6.3 Hz, MeCHOTBDPS), 0.95 (9H, s, SiCMe3), 0.90e0.88 (1H, m,
CHxHy(CH2)3Me), 0.89 (3H, d, J 6.3 Hz, CHMe), 0.88 (3H, d, J 6.3 Hz,
CHMe), 0.85 (3H, t, J 7.0 Hz, CH2Me), 0.15 (3H, s, SiMe), 0.12 (3H, s,
SiMe); dC (75.4 MHz, CDCl3) 213.0, 172.1, 136.0 (ꢂ2), 134.0, 133.0,
129.8, 129.6, 127.6, 127.4, 75.2, 74.9, 68.9, 45.7, 43.5, 31.7, 29.7, 27.4,
27.1, 26.0, 25.4, 25.0, 22.6, 22.4, 20.8, 20.2, 19.2, 18.1, 14.1, ꢀ4.5 (ꢂ2).
4.4.6. (2R,3R,4R,5S)-2-tert-Butyldimethylsilyloxy-4,6-dimethyl-6-
hepten-3,5-diol (ent-34h). Et2BOMe (1 M) in THF (3.0 mL,
3.0 mmol) was added to a solution of ent-8h (505 mg, 1.75 mmol) in
THF (12.5 mL) at ꢀ78 ꢁC under N2. This mixture was stirred at
ꢀ78 ꢁC for 20 min. Solid NaBH4 (80 mg, 2.1 mmol) was then added
and the reaction mixture was stirred for 3 h at ꢀ78 ꢁC, quenched
with AcOH (3.5 mL) and vigorously stirred at room temperature. It
was partitioned with CH2Cl2 and H2O, the aqueous layer was
extracted with CH2Cl2, and the combined organic extracts were
washed with 1 M NaOH and dried (Na2SO4). The volatiles were
removed in vacuo and the resulting oil was treated with 33% w/v
H2O2 (7 mL) in 1 M NaOAc in 9:1 MeOH/H2O (50 mL) for 1 h at room
temperature. It was partitioned with CH2Cl2 and H2O, the aqueous
layer was extracted with CH2Cl2, and the combined organic extracts
were dried (Na2SO4) and concentrated. Purification of the resulting
oil by column chromatography (90:10 hexanes/EtOAc) afforded
4.4.4. (2R,3R,4S)-2-Hexyl-4-methyl-3-[3-methylbutanoyloxy]butyr-
olactone, antimycinone (14). A solution of 29 (200 mg, 0.29 mmol),
AcOH (33 mL, 0.58 mmol), 1 M TBAF in THF (1.75 mL, 1.75 mmol) in
THF (5 mL) was stirred under N2 for 1 h at 0 ꢁC and 2 h at room
temperature. It was diluted with Et2O, washed with 10% NaHSO4,
sat NaHCO3 and H2O, dried (MgSO4). Purification of the resulting oil
by column chromatography (85:15 hexanes/EtOAc) furnished
88 mg (0.27 mmol, 91% yield) of a 4:1 mixture (1H NMR analysis) of
hemiketals 30 as a white solid.
477 mg (1.65 mmol, 94% yield) of ent-34h as a colourless oil. Rf
20
(95:5 hexanes/EtOAc) 0.15; [
a
]
þ7.2 (c 2.1, CHCl3); nmax (liquid
D
film) 3448 (br), 2956, 2932, 1654 cmꢀ1
; dH (500 MHz, CDCl3)
A mixture of this solid and NaIO4 (560 mg, 2.7 mmol) in 2:1
MeOH/H2O (3.4 mL) was stirred at room temperature for 4 h. It was
diluted with CH2Cl2, washed with 0.5 M HCl, dried (Na2SO4) and
concentrated. The residue was purified by column chromatography
(80:20 hexanes/EtOAc) to afford 75 mg (0.27 mmol, 100% yield) of
5.11e5.10 (1H, m, C]CHxHy), 4.96e4.92 (1H, m, C]CHxHy),
4.26e4.23 (1H, m, CH2]CCHOH), 3.76 (1H, dq, J 7.7, 6.0 Hz, CHOSi),
3.50 (1H, dd, J 7.7, 2.3 Hz, SiOCHCHOH), 1.78e1.22 (1H, m, CHMe),
1.70e1.68 (3H, m, MeC]CH2), 1.13 (3H, d, J 6.0 Hz, MeCHOSi), 0.91
(9H, s, SiCMe3), 0.83 (3H, d, J 7.0 Hz, CHMe), 0.11 (3H, s, SiMe), 0.10
(3H, s, SiMe); dC (75.4 MHz, CDCl3) 144.7, 111.1, 80.4, 78.8, 70.3, 35.7,
25.8, 19.8, 19.5, 18.0, 5.3, ꢀ4.0, ꢀ4.8; HRMS (FAB): [MH]þ, found
290.2226, C15H33O3Si requires 290.2232.
antimycinone 14 as a colourless oil. Rf (80:20 hexanes/EtOAc) 0.55;
21
[
a]
20 þ13.1 (c 1.5, CHCl3) [lit.36
[
a
]
20 þ10.6 (c 1.0, CHCl3); lit.20
[
a
]
D
D
D
þ10.1 (c 1.5, CHCl3)];; nmax (liquid film) 2959, 2930, 2873, 1785,
1744, 1468, 1294, 1252, 1181, 1121 cmꢀ1
; dH (300 MHz, CDCl3) 4.94
(1H, dd, J 5.6, 4.6 Hz, CHOCO), 4.36 (1H, qd, J 6.6, 4.6 Hz, MeCHO),
2.68 (1H, dt, J 8.2, 5.6 Hz, COCHCH2), 2.22 (2H, d, J 7.2 Hz, COCH2),
2.18e2.03 (1H, m, CHMe2), 1.92e1.79 (1H, m, COCHCHxHy),
1.73e1.56 (1H, m, COCHCHxHy), 1.50e1.20 (8H, m, (CH2)4Me), 1.47
(3H, d, J 6.6 Hz, MeCHO), 0.97 (6H, d, J 6.6 Hz, CHMe2), 0.88 (3H, t, J
6.8 Hz, CH2Me); dC (75.4 MHz, CDCl3) 175.9, 172.4, 79.4, 78.4, 46.4,
43.1, 31.5, 29.3, 28.9, 26.8, 25.7, 22.5, 22.3, 19.4, 14.0.
4.4.7. (2S,3R,4S,5R,6R)-6-tert-Butyldimethylsilyloxy-2,4-dimethyl-
1,3,5-heptanetriol (35). BH3$THF (1 M) in THF (1.6 mL, 1.6 mmol)
was carefully added to a solution of ent-34h (150 mg, 0.52 mmol) in
THF (5 mL) at 0 ꢁC under N2. The resulting solution was stirred at
room temperature for 2 h, cooled at 0 ꢁC, diluted with 1:1 THF/
MeOH (5.8 mL), and treated with 33% w/v H2O2 (1.6 mL) and 3 M
NaOH (4.8 mL). The reaction mixture was then stirred for 2 h at
room temperature. It was partitioned with EtOAc and H2O, the
aqueous layer was extracted with EtOAc and the combined organic
extracts were dried (MgSO4) and concentrated. Purification of the
resulting oil by column chromatography (from CH2Cl2 to 95:5
CH2Cl2/i-PrOH) afforded 153 mg (96% yield) of a 4:1 mixture of two
diastereomers according to its 1H NMR analysis. Further purifica-
tion by MPLC (95:5 CH2Cl2/i-PrOH) provided 96 mg (0.31 mmol,
4.4.5. (3R,4S)-5-tert-Butyldimethylsilyloxy-4,6-dimethyl-3-
heptanone (31). A mixture of 8a (330 mg, 1.15 mmol), 2,6-lutidine
(0.20 mL, 1.72 mmol) and TBSOTf (0.33 mL, 1.44 mmol) in CH2Cl2
(4 mL) was stirred for 15 min at 0 ꢁC and overnight at room tem-
perature under N2. It was partitioned with Et2O and sat NH4Cl and
the organic layer was washed with H2O. The aqueous layers were
extracted with Et2O and the combined organic extracts were dried
(MgSO4) and concentrated. The residue was purified by column
chromatography (99:1 hexanes/EtOAc) to afford 414 mg
(1.03 mmol, 90% yield) of the fully protected aldol adduct.
60% yield) of diastereomerically pure triol 35 as a colourless oil. Rf
20
(95:5 CH2Cl2/i-PrOH) 0.75; [
a
]
ꢀ14.5 (c 2.0, CHCl3); nmax (liquid
D
film) 3394 (br), 2956, 2933, 1381 cmꢀ1
; dH (500 MHz, CDCl3) 3.81
(1H, dd, J 5.4, 4.4 Hz, CHOHCHCH2OH), 3.75 (1H, dq, J 8.1, 6.3 Hz,
CHOSi), 3.66 (2H, d, J 4.8 Hz, CH2OH), 3.41 (1H, dd, J 8.2, 2.2 Hz,
SiOCHCHOH), 2.00e1.90 (1H, m, CHMe), 1.77e1.72 (1H, m,
A 0.2 M SmI2 in THF (3.5 mL, 0.7 mmol) was slowly added via
canula to a solution of that adduct (81 mg, 0.20 mmol) in 2:1 THF/

J. Esteve et al. / Tetrahedron 67 (2011) 6045e6056
6055
CHCH2OH), 1.11 (3H, d, J 6.3 Hz, MeCHOSi), 1.03 (3H, d, J 7.0 Hz,
CHMe), 0.96 (3H, d, J 7.0 Hz, CHMe), 0.90 (9H, s, SiCMe3), 0.11 (6H, s,
2ꢂ SiMe); dC (75.4 MHz, CDCl3) 79.2, 77.2, 70.4, 66.7, 37.2, 36.0, 25.8,
19.6, 17.9, 11.5, 7.2, ꢀ4.1, ꢀ4.8; HRMS (FAB): [MH]þ, found 307.2318,
C15H35O4Si requires 307.2304.
solution was stirred for 30 min at ꢀ78 ꢁC, freshly distilled aldehyde
was added and stirring continued for 30 min at ꢀ78 ꢁC. Then, 2 M
LiBH4 in THF (1.0 mL, 2.0 mmol) was added carefully and the re-
action mixture was stirred for 1 h at ꢀ78 ꢁC. Finally, the reaction
was quenched by slow addition of AcOH (1 mL), followed by sat
NH4Cl (5 mL). The mixture was partitioned with Et2O and H2O, and
the organic layer was washed with sat NaHCO3 and brine, dried
(MgSO4) and concentrated. The residue was purified by column
chromatography (90:10 hexanes/EtOAc) to give the corresponding
diol.
4.4.8. (2S,3R,4S,5R,6R)-6-tert-Butyldimethylsilyloxy-3,5-
isopropylidenoxy-2,4-dimethyl-1-heptyl pivalate (36). Freshly dis-
tilled pivaloyl chloride (0.28 mL, 2.3 mmol) was added to a solution
of 35 (154 mg, 0.46 mmol), Et3N (0.32 mL, 2.3 mmol) and DMAP
(cat) in CH2Cl2 (4.5 mL) at 0 ꢁC under N2. The reaction mixture was
stirred for 1 h at 0 ꢁC and overnight at room temperature. It was
diluted with CH2Cl2, washed with 1 M HCl, sat NaHCO3 and H2O,
dried (MgSO4) and concentrated. The residue was filtered through
a pad of silica (99:1 CH2Cl2/MeOH) to afford a colourless oil, which
was used immediately in the next step.
4.5.1. (2S,3S,4R,5S)-2-tert-Butyldimethylsilyloxy-6-methyl-4-vinyl-
3,5-heptanediol (38a). Colourless oil. Rf (90:10 hexanes/EtOAc)
20
0.25; [
a]
þ18.7 (c 1.1, CHCl3); nmax (liquid film) 3527 (br), 3073,
D
2956, 2931, 2858, 1637, 1472, 1463, 1387, 1255, 1133, 1073 cmꢀ1
; dH
(300 MHz, CDCl3) 6.01 (1H, dt, J 17.4, 10.4 Hz, CH]CH2), 5.25 (1H,
dd, J 10.4, 2.2 Hz, CH]CHxHy), 5.05 (1H, dd, J 17.4, 2.2 Hz, CH]
CHxHy), 3.68 (1H, dq, J 8.1, 6.0 Hz, CHOSi), 3.55e3.40 (2H, m, 2ꢂ
CHOH), 2.30e2.20 (1H, m, CHCH]CH2), 1.85e1.65 (1H, m, CHMe2),
1.10 (3H, d, J 6.0 Hz, MeCHOSi), 0.98 (3H, d, J 6.6 Hz, CHMe), 0.90
(9H, s, SiCMe3), 0.88 (3H, d, J 6.9 Hz, CHMe), 0.09 (3H, s, SiMe), 0.08
(3H, s, SiMe); dC (75.4 MHz, CDCl3) 133.3,118.8, 80.0, 79.6, 70.5, 47.2,
30.6, 25.8, 19.3, 19.2, 18.4, 18.0, ꢀ4.1, ꢀ4.8; HRMS (ESI): [MH]þ,
found 303.2352, C16H35O3Si requires 303.2350.
A solution of this oil and PPTS (cat) in 1:1 CH2Cl2/Me2C(OMe)2
(5 mL) was stirred overnight at room temperature under N2. Re-
moval of the volatiles and purification of the residue by column
chromatography (CH2Cl2) gave 121 mg (0.28 mmol, 61% yield) of 36
as a colourless oil. Rf (CH2Cl2) 0.70; [
a
]
20 þ9.5 (c 1.25, CHCl3); nmax
D
(liquid film) 2965, 2933, 1732 cmꢀ1
;
dH (500 MHz, CDCl3) 4.00 (1H,
dd, J 11.1, 4.1 Hz, CHxHyOPiv), 3.89 (1H, dd, J 11.1, 5.7 Hz, CHxHyOPiv),
3.71 (1H, dq, J 8.2, 6.2 Hz, CHOSi), 3.56 (1H, dd, J 9.7, 2.0 Hz,
CHOCHCH2O), 3.49 (1H, dd, J 8.2, 2.0 Hz, SiOCHCHOH), 1.98e1.90
(1H, m, CHCH2O), 1.45 (1H, qt, J 6.7, 2.0 Hz, CHMe), 1.39 (3H, s,
O2CMe), 1.38 (3H, s, O2CMe), 1.19 (9H, s, CMe3), 1.05 (3H, d, J 6.2 Hz,
MeCHOSi), 1.02 (3H, d, J 6.6 Hz, MeCHCH2), 0.87 (9H, s, SiCMe3), 0.85
(3H, d, J 6.7 Hz, CHMe), 0.06 (3H, s, SiMe), 0.04 (3H, s, SiMe); dC
(75.4 MHz, CDCl3) 178.5, 99.0, 78.9, 75.6, 69.2, 65.6, 38.9, 33.9, 31.1,
29.8, 27.2, 25.8, 19.3, 18.8, 18.3, 14.5, 5.4, ꢀ4.3, ꢀ5.0; HRMS (FAB):
[MH]þ, found 431.3191, C23H47O5Si requires 431.3192.
4.5.2. (1R,2R,3S,4S)-4-tert-Butyldimethylsilyloxy-1-phenyl-2-vinyl-
1,3-pentanediol (38c). Colourless oil. Rf (90:10 hexanes/EtOAc)
20
0.20; [
a
]
þ30.3 (c 1.0, CHCl3); nmax (liquid film) 3737, 3688 (br),
D
3072, 2955, 2929, 2857, 1636, 1472, 1256, 1085 cmꢀ1
; dH (300 MHz,
CDCl3) 7.40e7.20 (5H, m, ArH), 6.05 (1H, dt, J 17.4, 10.2 Hz, CH]
CH2), 5.23 (1H, dd, J 10.2, 2.1 Hz, CH]CHxHy), 4.95 (1H, d, J 5.9 Hz,
CHOHPh), 4.91 (1H, ddd, J 17.4, 2.1, 0.5 Hz, CH]CHxHy), 3.63 (1H, dq,
J 8.3, 6.0 Hz, CHOSi), 3.32 (1H, dd, J 8.2, 2.3 Hz, CHOSiCHOH),
2.30e2.23 (1H, m, CHCH]CH2),1.00 (3H, d, J 6.0 Hz, MeCHOSi), 0.89
(9H, s, SiCMe3), 0.08 (3H, s, SiMe), 0.06 (3H, s, SiMe); dC (75.4 MHz,
CDCl3) 142.2, 132.9, 128.0, 127.3, 126.7, 120.1, 77.7, 75.9, 70.7, 53.6,
25.8, 19.0, 18.0, ꢀ4.1, ꢀ4.8; HRMS (ESI): [MNa]þ, found 359.2011,
C19H32NaO3Si requires 359.2012.
4.4.9. (2S,3R,4S,5R)-3,5-Isopropylidenoxy-2,4-dimethyl-6-oxo-1-
heptyl pivalate (37). TBAF (2 M) in THF (0.6 mL, 1.2 mmol) was
added to a solution of 36 (49 mg, 0.11 mmol) in THF (1.5 mL) at 0 ꢁC
under N2 and the reaction mixture was stirred at room temperature
for 20 min. It was diluted with CH2Cl2, washed with H2O and brine,
dried (Na2SO4) and concentrated. The residue was purified by col-
umn chromatography (75:25 hexanes/EtOAc) to afford 29 mg of an
oil. A solution of this oil in CH2Cl2 (1 mL) was added via canula (þ
0.8 mL CH2Cl2) to a solution of DMP (90 mg, 0.21 mmol) and pyr-
4.5.3. (2S,3S,4R,5S)-2-tert-Butyldimethylsilyloxy-7-methyl-4-vinyl-
3,5-octanediol (38e). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.25;
20
[a
]
ꢀ0.5 (c 1.1, CHCl3); nmax (liquid film) 3534 (br), 3073, 2955,
D
idine (41
m
L, 0.51 mmol) in CH2Cl2 (1 mL) at 0 ꢁC under N2, and the
2930, 2859, 1637, 1471, 1256, 1134, 1084 cmꢀ1
; dH (300 MHz, CDCl3)
reaction mixture was stirred overnight at room temperature. The
resulting white suspension was diluted with EtOAc, washed with
H2O, sat NaHCO3 and Na2S2O3 and dried (MgSO4). Removal of the
volatiles afforded a residue that was purified by column chroma-
6.00 (1H, dt, J 17.4, 10.2 Hz, CH]CH2), 5.26 (1H, dd, J 10.2, 2.3 Hz,
CH]CHxHy), 5.03 (1H, dd, J 17.4, 2.3 Hz, CH]CHxHy), 4.00e3.93
(1H, m, CHOHCH2), 3.67 (1H, dq, J 8.2, 6.0 Hz, CHOSi), 3.58e3.52
(1H, m, CHOSiCHOH), 2.01e1.94 (1H, m, CHCH]CH2), 1.86e1.70
(1H, m, CHMe2), 1.45 (1H, ddd, J 13.8, 8.9, 5.4 Hz, CHOHCHxHy),
1.12e1.10 (1H, m, CHOHCHxHy), 1.09 (3H, d, J 6.0 Hz, MeCHOSi), 0.92
(3H, d, J 6.6 Hz, CHMe), 0.92 (3H, d, J 6.6 Hz, CHMe), 0.90 (9H, s,
SiCMe3), 0.09 (3H, s, SiMe), 0.09 (3H, s, SiMe); dC (75.4 MHz, CDCl3)
133.0, 119.2, 79.7, 72.3, 70.5, 50.4, 43.8, 25.8, 24.3, 23.4, 22.1, 19.1,
18.0, ꢀ4.1, ꢀ4.8; HRMS (ESI): [MH]þ, found 317.2512, C17H37O3Si
requires 317.2514.
tography (90:10 hexanes/EtOAc) to give 25 mg (79 mmol, 70% yield)
of keto ester 37 as a colourless oil. Rf (90:10 hexanes/EtOAc) 0.15;
[
a]
20 þ27.5 (c 1.2, CHCl3); nmax (liquid film) 2975, 2933, 1728 cmꢀ1
;
D
dH (500 MHz, CDCl3) 4.25 (1H, d, J 2.4 Hz, MeCOCHO), 4.06 (1H, dd, J
11.1, 4.5 Hz, CHxHyOPiv), 3.85 (1H, dd, J 11.1, 6.0 Hz, CHxHyOPiv), 3.66
(1H, dd, J 9.9, 2.1 Hz, CHOCHCH2O), 2.18 (3H, s, MeCO), 2.06e2.00
(1H, m, CHMe), 2.00e1.92 (1H, m, CHCH2O), 1.49 (3H, s, O2CMe),
1.42 (3H, s, O2CMe), 1.21 (9H, s, CMe3), 1.01 (3H, d, J 6.6 Hz, CHMe),
0.86 (3H, d, J 6.9 Hz, CHMe); dC (75.4 MHz, CDCl3) 209.5, 178.4, 99.5,
79.3, 75.1, 65.4, 38.9, 34.1, 32.5, 29.8, 27.2, 27.1, 19.0, 14.2, 6.4; HRMS
(FAB): [MH]þ, found 315.2174, C17H31O5 requires 315.2171.
4.5.4. (2S,3S,4R,5S)-2-tert-Butyldimethylsilyloxy-4-vinyl-3,5-
octadecanediol (38i). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.30;
20
[a
]
þ2.9 (c 1.0, CHCl3); nmax (liquid film) 3536 (br), 3073, 2926,
D
2855, 1636, 1463, 1255, 1087 cmꢀ1
; dH (300 MHz, CDCl3) 6.00 (1H,
4.5. Sequential aldol and reduction transformation from allyl
ketone 5
dt, J 17.3, 10.3 Hz, CH]CH2), 5.26 (1H, dd, J 10.3, 2.1 Hz, CH]CHxHy),
5.03 (1H, dd, J 17.4, 2.1 Hz, CH]CHxHy), 3.86e3.83 (1H, m,
CHOHCH2), 3.66 (1H, dq, J 8.0, 6.0 Hz, CHOSi), 3.54e3.49 (1H, m,
CHOSiCHOH), 2.07e2.00 (1H, m, CHCH]CH2), 1.25 (24H, br s,
(CH2)12Me), 1.09 (3H, d, J 6.0 Hz, MeCHOSi), 0.90 (9H, s, SiCMe3),
0.90e0.88 (3H, buried m, (CH)12Me), 0.09 (3H, s, SiMe), 0.09 (3H, s,
SiMe); dC (75.4 MHz, CDCl3) 133.0, 119.2, 79.7, 74.6, 70.5, 49.9, 34.7,
Neat TiCl4 (0.12 mL, 1.1 mmol) was added slowly to a solution of
5 (228 mg, 1.0 mmol) in CH2Cl2 (5 mL) at ꢀ78 ꢁC under N2. The
resulting yellow suspension was stirred for 3e4 min and i-Pr2NEt
(0.19 mL, 1.1 mmol) was added dropwise. The resulting dark red

6056
J. Esteve et al. / Tetrahedron 67 (2011) 6045e6056
ꢀ
12. Esteve, C.; Ferrero, M.; Romea, P.; Urpí, F.; Vilarrasa, J. Tetrahedron Lett. 1999, 40,
5083e5086.
31.9, 29.7e29.6 (ꢂ8), 29.3, 25.8, 22.7, 19.2, 18.0, 14.1, ꢀ4.1, ꢀ4.8;
HRMS (ESI): [MH]þ, found 443.3916, C26H55O3Si requires 443.3915.
13. For a recent review on vinylogous aldol reaction, see: Casiraghi, G.; Battistini, L.;
Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076e3154.
14. Ketones 17 and 18 were prepared by acylation of EtLi with pyrrolidine amides
Acknowledgements
derived from the corresponding a-hydroxy acids, as described in Scheme 2 for
ketones 1e4. See also Ref. 10.
15. Esteve, J.; Matas, S.; Pellicena, M.; Velasco, J.; Romea, P.; Urpí, F.; Font-Bardia, M.
Financial support from the Spanish Ministerio de Ciencia e
Eur. J. Org. Chem. 2010, 3146e3151.
ꢀ
Innovacion (MICINN) and Fondos EU FEDER (Grants CTQ2006-
ꢀ
ꢀ
16. Palomo, C.; Oiarbide, M.; Gomez-Bengoa, E.; Mielgo, A.; Gonzalez-Rego, M. C.;
13249/BQU and CTQ2009-09692) and the Generalitat de Catalunya
(2009SGR825), as well as a doctorate studentship (Universitat de
Barcelona) to J.N., are acknowledged.
ꢀ
~
García, J. M.; Gonzalez, A.; Odriozola, J. M.; Banuelos, P.; Linden, A. ARKIVOC
2005, 377e392.
17. (a) Bernardi, A.; Capelli, A. M.; Comotti, A.; Gennari, C.; Gardner, M.; Goodman,
J. M.; Paterson, I. Tetrahedron 1991, 47, 3471e3484; (b) Bernardi, A.; Gennari, C.;
Goodman, J. M.; Paterson, I. Tetrahedron: Asymmetry 1995, 6, 2613e2636.
18. This mechanism can also be applied to a
-OTBS ketones containing other R1
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