Stereoselective titanium-mediated aldol reactions of α-benzyloxy methyl ketones

Article abstract of DOI:10.1016/j.tet.2012.09.096

Good levels of 1,4-anti asymmetric induction are obtained in the TiCl ₃(i-PrO)-mediated aldol reaction of chiral α-benzyloxy methyl ketones with a wide array of aldehydes. This methodology represents a new approach to substrate-controlled acetate aldol reactions capable of providing highly functionalized fragments in a straightforward manner, which may be useful in the design of more efficient syntheses.

Full text of DOI:10.1016/j.tet.2012.09.096

Tetrahedron 68 (2012) 10338e10350
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Stereoselective titanium-mediated aldol reactions of a-benzyloxy methyl ketones
*
*
ꢀ
Miquel Pellicena, Joan G. Solsona, Pedro Romea , Felix Urpí
ꢀ
ꢁ
Departament de Química Organica, Universitat de Barcelona, Carrer Martí i Franques 1-11, 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:
Good levels of 1,4-anti asymmetric induction are obtained in the TiCl3(i-PrO)-mediated aldol reaction of
Received 1 August 2012
Received in revised form 20 September
2012
Accepted 25 September 2012
Available online 3 October 2012
chiral a-benzyloxy methyl ketones with a wide array of aldehydes. This methodology represents a new
approach to substrate-controlled acetate aldol reactions capable of providing highly functionalized
fragments in a straightforward manner, which may be useful in the design of more efficient syntheses.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective reactions
Acetate aldol reactions
Titanium enolates
Chiral ketones
Synthesis of natural products
1. Introduction
configuration of the new stereocenter become much more difficult
than in related aldol reactions from ethyl ketones.11
The development of highly stereoselective aldol methods and
their successful application to the synthesis of structurally complex
natural products has placed the aldol reaction among the most im-
portant carbonecarbon bond-forming processes.1,2 Nevertheless,
the solutions to some issues, such as stereocontrol in acetate aldol
reactions,3 remain elusive. It is certainly true that recent advances in
catalytic asymmetric-based4 and chiral auxiliary-based1,5 ap-
proaches provide excellent levels of stereocontrol for a remarkable
range of acetate aldol reactions, but these are still unable to facilitate
the coupling of elaborate fragments in advanced steps of the syn-
thesis of complex natural products.6 Indeed, such transformations
usually require highly reactive species capable of overcoming op-
posing trends due to the reacting partners, so they are commonly
carried out using Mukaiyama7 or metal enolate-mediated aldol
variants.8,9 In particular, substrate-controlled aldol reactions based
on metal enolates from chiral methyl ketones represent an appeal-
ing alternative to accomplish such challenging transformations
provided that thorough knowledge of the asymmetric induction
imparted by the enolate and the aldehyde is available.9,10 Un-
fortunately, metal enolate-mediated acetate aldol reactions can
proceed through several six-membered cyclic transition states of
similar energy and both stereocontrol and prediction of the
In this context, we have unravelled the complex structure of tita-
nium(IV) enolates of chiral
a
-alkoxy ketones12 and have clearly
established the crucial influence of titanium Lewis acid on the ste-
reochemical outcome of their aldol reactions. Thus, lactate-derived
-benzyloxy ethyl ketone affords 2,4-syn-4,5-syn or 2,4-anti-4,5-syn
a
aldol adducts depending on the stoichiometry and the titanium(IV)
Lewis acid employed in the enolization step (Eq. 1 in Scheme 1).13,14
Keeping in mind such precedents, we envisaged that related a-alk-
oxy methyl ketones might also furnish 1,4-syn or 1,4-anti aldol ad-
ducts in a straightforward and stereoselective manner (Eq. 2 in
Scheme 1).15,16 Herein, we report our findings for the substrate-con-
trolled titanium-mediated aldol reactions of chiral
a-benzyloxy
methyl ketones, which prove that the appropriate choice of the tita-
nium(IV) Lewis acid affords 1,4-anti aldol adducts in moderate to high
diastereoselectivity, and provide valuable knowledge for devising
more efficient syntheses of complex natural products.
2. Results and discussion
2.1. Preliminary results
Initially, we chose lactate-derived
and 2 as models to assess the feasibility of the proposed acetate
aldol reaction and, later on, related -benzyloxy methyl ketones
a-alkoxy methyl ketones 1
a
* Corresponding authors. Tel.: þ34 93 4039106; fax: þ34 93 3397878 (P.R.); tel.:
þ34 93 4021247; fax: þ34 93 3397878 (F.U.); e-mail addresses: pedro.romea@
ub.edu (P. Romea), felix.urpi@ub.edu (F. Urpí).
3e5 were prepared in order to test the scope of such substrate-
controlled titanium-mediated aldol reactions (Fig. 1).17
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.096

M. Pellicena et al. / Tetrahedron 68 (2012) 10338e10350
10339
2 equiv TiCl4 or 1 equiv TiCl3(i-PrO)
i-Pr2NEt
O
OH
O
O
OH
TiCl4, i-Pr2NEt
R1CHO
2
4
2
4
(1)
(2)
Ref. 13
5
R1
5
R1
R1CHO
BnO
BnO
BnO
2,4-anti-4,5-syn
2,4-syn-4,5-syn
O
OH
R1
O
O
OH
R1
TiL4, i-Pr2NEt
R1CHO
TiL4, i-Pr2NEt
1
1
R
R
R
This study
4
4
R1CHO
ArCH2O
ArCH2O
ArCH2O
1,4-anti
1,4-syn
Scheme 1. Titanium-mediated aldol reaction of chiral a-benzyloxy ketones.
titanium Lewis acid was found to be important. As expected, parent
titanium(IV) Lewis acid, namely TiCl4, was unsuitable for our pur-
poses because it produced a partial removal of the PMB protecting
group. Instead, TiCl3(i-PrO)afforded 15a inahighdiastereomericratio
and yield (dr 86:14, 80% yield, see entry 1), whereas the softer
TiCl2(i-PrO)2 displayed reduced stereocontrol but an excellent yield
(dr 70:30, 90% yield, see entry 2). Moreover, the bulkiness of alkoxy
ligands had a minor effect, as the less bulky TiCl3(n-PrO) afforded
a slightly lower diastereoselectivity and a similar yield (compare
entries 1 and 3). Further optimization of the experimental conditions
revealed that the enolization step was fairly fast and could be reduced
to 0.5 h, and that the amount of aldehyde could safely be reduced to
1.2 equiv without reducing the yield (see entry 4).
Having established the feasibility of the process, we turned our
attention to the more robust Bn-protected ketone 2 (see entries
5e9 in Table 1). Almost no diastereoselectivity was observed with
TiCl4 (see entries 5 and 6), but better levels of stereocontrol were
achieved either with 2.1 equiv of TiCl4 (see entry 7) or softer Lewis
acids, such as TiCl3(i-PrO) or TiCl2(i-PrO)2 (see entries 8 and 9).
Indeed, as had been previously observed for PMB-protected ke-
tone 1, the best diastereoselection in the titanium-mediated aldol
reaction of 2 was achieved with TiCl3(i-PrO), likewise in compara-
ble yields (compare entries 4 and 8 in Table 1).
O
O
PMBO
BnO
1
2
O
O
O
BnO
3
BnO
4
BnO
5
Fig. 1. Chiral a-benzyloxy methyl ketones.
Methyl ketones 1e5 were easily prepared in an enantiomerically
pure form through acylation of methyl organometallic reagents
(MeM, M¼Li, MgBr) with N-acyl pyrrolidines 6e9 derived from the
corresponding
stirring of
a
-hydroxy esters (Scheme 2).17 Remarkably, simple
a
-hydroxy esters and pyrrolidine in a solvent free process
allowed the formation of hydroxy amides 6e9, which were used in
the next step without further purification. Then, benzylation under
basic conditions gave the resulting benzyloxy amides 10e14, whose
treatment with MeM (M¼Li, MgBr) provided the desired ketones
1e5 in good overall yields (39e66%). Eventually, (R)-3-benzyloxy-
2-butanone (ent-2) was likewise obtained from the commercially
available (R) isobutyl lactate.
With a straightforward and reliable multigram supply of the re-
quired methyl ketones to hand, we first evaluated the influence of the
enolization conditions on the titanium-mediated aldol reaction of
model ketones 1 and 2 with isobutyraldehyde (a). The results are
summarized inTable 1. Takingadvantageofourownexperienceinthe
2.2. Scope of the TiCl3(i-PrO)-mediated aldol reactions of
lactate-derived ketones 1 and 2
Next, these experimentally simple conditions were applied to
other aliphatic, aromatic and a,b-unsaturated aldehydes. The re-
titanium-mediated aldol reaction of
a
-hydroxy ketones,13 we initially
sults are summarized in Table 2 and prove that the lactate-derived
methyl ketone 1 affords anti aldol adducts 15 from aldehydes aef in
good yields and diastereomeric ratios (see entries 1e6). Signifi-
cantly, diastereoselectivity for aliphatic aldehydes was not seri-
ously affected by steric bulk (compare entries 1e4), ranging from dr
86:14 for isobutyraldehyde (a) to dr 82:18 for 3-phenylpropanal (c).
Benzaldehyde (e) provided similar results, but both the di-
carried out the enolization of 1 with several titanium Lewis acids
(1.1equiv)andi-Pr2NEt(1.1 equiv)for1.5 hatꢀ78ꢁCandtheresulting
enolate was allowed to react with isobutyraldehyde (a, 1.5 equiv) for
0.5 h at the same temperature (see entries 1e4 in Table 1). As ex-
pected, the stereochemical outcome of these reactions was highly
dependent on the titanium Lewis acid used, but on this occasion the
major diastereomer obtained across all the optimization experiments
was anti adduct 15a (Table 1). Remarkably, the strength of the
astereomeric ratio and the yield dropped for
a,b-unsaturated
methacrolein (f), which afforded anti adduct 15f in dr 75:25 and
O
O
O
O
a
b
R
c
R
R
R
N
OEt
N
80–99%
74–92%
PGO
PGO
58-91%
HO
HO
6 R: Me
7 R: i-Bu
8 R: Bn
9 R: i-Pr
10 PG: PMB, R: Me
11 PG: Bn, R: Me
12 PG: Bn, R: i-Bu
13 PG: Bn, R: Bn
14 PG: Bn, R: i-Pr
1 PG: PMB, R: Me
2 PG: Bn, R: Me
3 PG: Bn, R: i-Bu
4 PG: Bn, R: Bn
5 PG: Bn, R: i-Pr
Scheme 2. Reagents and conditions: (a) pyrrolidine, rt (R: Me, i-Bu, Bn) or 45 ꢁC (R: i-Pr). (b) ArCH2Cl, NaOH, [Oct3NMe]Cl, toluene (R: Me) or CH2Cl2 (R: Bn, i-Bu, i-Pr), rt. (c) MeLi,
THF, ꢀ78 ꢁC (R: Me, Bn) or MeMgBr, THF, 0 ꢁC (R: i-Bu, i-Pr).

10340
M. Pellicena et al. / Tetrahedron 68 (2012) 10338e10350
Table 1
Titanium-mediated aldol reaction of ketones 1 and 2 with isobutyraldehyde
O
O
OH
O
OH
1) TiL4, i-Pr2NEt, CH2Cl2, tenol
, 78 C
2) i-PrCHO (a), 0.5 h, 78 C
PGO
PGO
PGO
1
PG: PMB
PG: Bn
15a PG: PMB
17a PG: Bn
16a PG: PMB
18a PG: Bn
2
Entry
Ketone
TiL4 (equiv)
tenol (h)
dra (15a:16a)
dra (17a:18a)
Yieldb (%)
1c
2c
3c
4
5
6
7
8
9
1
1
1
1
2
2
2
2
2
TiCl3(i-PrO) (1.1)
TiCl2(i-PrO)2 (1.1)
TiCl3(n-PrO) (1.1)
TiCl3(i-PrO) (1.1)
TiCl4 (1.1)
1.5
1.5
1.5
0.5
0.5
0.5
0.5
0.5
0.5
86:14
70:30
83:17
86:14
80
90
71
80
90
71
77
80
80
57:43
51:49
71:29
85:15d
73:27
TiCl4 (1.1)þTHF (1.1)
TiCl4 (2.1)
TiCl3(i-PrO) (1.1)
TiCl2(i-PrO)2 (1.1)
a
Determined by 1H NMR analysis of the reaction mixture.
Isolated yield of the aldol mixture.
Aldehyde (1.5 equiv) were used.
b
c
d
Determined by HPLC.
Table 2
TiCl3(i-PrO)-mediated aldol reactions of ketones 1 and 2
O
O
OH
R1
O
OH
R1
1) TiCl3(i-PrO), i-Pr2NEt, CH2Cl2, 0.5 h, 78 C
2) R1CHO, 0.5 h, 78
C
PGO
PG: PMB
PG: Bn
PGO
PGO
1
15 PG: PMB
17 PG: Bn
16 PG: PMB
18 PG: Bn
2
Entry
Ketone
Aldehyde
R1
dra (15:16)
dra (17:18)
Yieldb (%)
1
2
3
4
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
g
a
b
h
e
i
i-Pr
i-Bu
Ph(CH2)2
Et
Ph
H2C]C(CH3)
t-Bu
i-Pr
i-Bu
Pr
86:14
83:17
82:18
86:14
82:18
75:25
80
81
72
70
70
65
72
80
76
67
66
67
68
67
58
56
5
6c
7
93:7
8
9
85:15d
85:15
80:20
83:17
74:26
73:27
75:25
69:31
55:45
10
11
12e
13
14e
15c
16c
Ph
4-NO2ePh
4-MeOePh
4-BrePh
H2C]C(CH3)
(E) CH3CH]CH
j
k
f
l
a
Determined by 1H NMR analysis of the reaction mixture.
Isolated yield of the aldol mixture.
The aldehyde was not distilled.
b
c
d
e
Determined by HPLC.
A solution of aldehyde in CH2Cl2 (1.0 mL) was added via cannula (0.5 mL rinse) to the solution of enolate in CH2Cl2 (3.5 mL).
a 65% yield (compare entries 5 and 6). In the same way, the ster-
eocontrol achieved from Bn-protected ketone 2 was highly de-
pendent on the aldehyde partner (see entries 7e16 in Table 2).
Indeed, the steric bulk of aliphatic aldehydes affected the diaster-
eoselectivity of these transformations (compare entries 7e10), the
best diastereomeric ratio (dr 93:7, entry 7) being provided by piv-
alaldehyde (g). Moreover, ketone 2 afforded comparable stereo-
control with benzaldehyde (e), but it was eroded when either
electron-withdrawing or electron-donating substituents were
The absolute stereochemistry of the major diastereomer was se-
cured through analysis of the spectroscopic data for 17e10c and
chemical correlation for aldols 15a and 17a (Scheme 3). Our previous
experience in the removal of the a-OTBS functionality in similar aldol
adducts18 prompted us to test the same strategy for the chemical
correlation of15a. Thisinvolved a three-step sequence inwhich SmI2-
mediated reductive elimination of the
a-OPMB group was the
key step (Eq. 1 in Scheme 3). Thus, TBS-protection of 15a furnished
19, which was subsequently treated with SmI2 to provide ethyl
ketone 20.19 Finally, TBS deprotection afforded (S)-5-hydroxy-6-
methylheptan-3-one (21 in Scheme 3) in a 44% overall yield.
present in the aromatic ring (see entries 12e14). Finally, a,b-un-
saturated aldehydes offered the poorest diastereoselection (see
entries 15 and 16), which was almost non-existent in the case of
E-crotonaldehyde (l).
Moreover, 17a was converted into the corresponding
b-hydroxy
carboxylic acid 22 (Eq. 2 in Scheme 3). Hence, hydrogenolysis of the

M. Pellicena et al. / Tetrahedron 68 (2012) 10338e10350
10341
results prove that such acetate aldol reactions consistentlyafford the
1,4-anti adduct, but the availability of various transition states pre-
vents prediction of the diastereoselectivity of a particular reaction.
2.4. Double asymmetric aldol reactions
Although a simple theoretical model for these transformations is
still elusive, the aforementioned results prove that the titanium-
mediated aldol reaction of
a-benzyloxy methyl ketones can be use-
ful for the stereoselective construction of
b-hydroxy carbonyl sub-
units in advanced steps of a synthesis. Therefore, considering that
these reactions usually involve chiral aldehydes, we next assessed the
ability of lactate-derived ketones 1 and 2 to govern the stereochem-
Scheme 3. Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 71%. (b) SmI2,
2:1 THF/MeOH, 0 ꢁC, 89%. (c) HF, CH3CN, rt, 70%. (d) H2, Pd/C, EtOH, rt. (e) NaIO4, 2:1
MeOH/H2O, rt; 50% over two steps.
ical outcome in double asymmetric processes21 with model chiral
b-
and a
-hydroxy aldehydes, such as 2922 and 3023 (Fig. 2).
benzyl ether followed by oxidative cleavage of the resulting dihy-
droxy ketone afforded (S)-3-hydroxy-4-methylpentanoic acid (22
in Scheme 3) in a 50% overall yield. Spectroscopic and physical data
for 21 and 22 matched those previously reported in the literature
and confirmed the configuration assigned to aldols 15a and 17a.20
Fig. 2. Chiral b- and a-hydroxy aldehydes.
2.3. TiCl3(i-PrO)-mediated aldol reactions of ketones 3e5
Conventional wisdom accepts that nucleophilic additions to
chiral -methyl aldehydes without other chelating functional
Having established the generality of the aldol methodology
based on lactate-derived ketones, we examined the stereocontrol
a
groups usually render the corresponding Felkin adduct.1,2,9,24 Thus,
it was not surprising to observe that matched pairs involving ke-
tones 1 and 2 with aldehyde 29 afforded the corresponding Felkin
adducts 31 and 33 in excellent diastereoselectivities (Scheme 4),
whereas enantiomeric ketone ent-2 overcame the stereochemical
bias imparted by aldehyde 29 and afforded an 80:20 mixture of
diastereomers (35 and 36) in an 81% yield.
imparted by other a-benzyloxy methyl ketones. In particular, we
studied the aldol reaction of ketones 3e5, containing different R
chains (R: i-Bu, Bn and i-Pr, respectively, see Fig. 1), with some
representative aldehydes, such as isobutyraldehyde (a), benzalde-
hyde (e) and methacrolein (f). The results are summarized inTable 3.
These results reveal that the titanium aldol chemistry optimized
for lactate-derived ketones can be expanded to other a-benzyloxy
Likewise, double asymmetric processes with chiral
aldehydes were next addressed. Pioneering studies by Heathcock
on the aldol additions of achiral and chiral -hydroxy methyl and
a-hydroxy
methyl ketones with some caution. Indeed, the data summarized in
Tables 2 and 3 show that yields from ketones 3e5 are always much
better than those obtained from 1 and 2 while changes in diaster-
eoselectivity do not seem to follow any pattern. For instance, iso-
butyraldehyde (a) participates in highly diastereoselective aldol
reactions with ketones 2e4 (dr 85:15), but a significant loss of
stereocontrol is observed for bulky ketone 5 (dr 67:33). In turn, the
best results for benzaldehyde (e) are obtained with bulky ketones 4
and 5, whereas the worst diastereomeric ratios for conjugated
methacrolein (f) are achieved both with the least and the most bulky
ketones, 2 and 5, respectively. From a general point of view, these
a
ethyl ketones to a-hydroxy aldehydes early proved the Cornforth-
like stereochemical induction of these aldehydes.25,26 More re-
cently, this trend has been definitely established by Evans in
a comprehensive study on the aldol reaction of methyl ketones
with
additions of ketones 1 and 2 to chiral aldehydes 30 and ent-30
containing an oxygenated C stereocenter would proceed with
a different diastereoselectivity.
a
-hydroxy aldehydes.27,28 Thus, we anticipated that the aldol
a
Table 3
TiCl3(i-PrO)-mediated aldol reactions of ketones 3, 4 and 5
O
O
OH
R1
O
OH
R1
1) TiCl3(i-PrO), i-Pr2NEt, CH2Cl2, 0.5 h, 78 C
R
R
R
2) R1CHO, 0.5 h, 78 C
BnO
BnO
BnO
3
4
5
R: i-Bu
R: Bn
R: i-Pr
23 R: i-Bu
25 R: Bn
27 R: i-Pr
24 R: i-Bu
26 R: Bn
28 R: i-Pr
Entry
Ketone
Aldehyde
R1
Aldols
dra
Yieldb (%)
1
3
3
3
4
4
4
5
5
5
a
e
f
a
e
f
a
e
f
i-Pr
Ph
H2C]C(CH3)
i-Pr
23a:24a
23e:24e
23f:24f
25a:26a
25e:26e
25f:26f
27a:28a
27e:28e
27f:28f
85:15
75:25
81:19
85:15
88:12
83:17
67:33
87:13
64:36
93
94
85
92
96
78
90
97
80
2
3c
4
5
Ph
6c
7
H2C]C(CH3)
i-Pr
Ph
8
9c
H2C]C(CH3)
a
Determined by 1H NMR analysis of the reaction mixture.
Isolated yield of the aldol mixture.
The aldehyde was not distilled.
b
c

10342
M. Pellicena et al. / Tetrahedron 68 (2012) 10338e10350
Scheme 4. Reagents and conditions: (a) (i) TiCl3(i-PrO), i-Pr2NEt, CH2Cl2, ꢀ78 ꢁC; (ii) 29, ꢀ78 ꢁC.
According to the Cornforth model, reactions of ketones 1 and 2
Having demonstrated that the titanium-mediated aldol
reactions of chiral -benzyloxy methyl ketones proceed in a highly
stereoselective manner in double asymmetric processes, we next
explored the conversion of the ensuing adducts into arrays
with aldehyde 30 gave aldol adducts 37 and 39 in high di-
astereomeric ratios (Scheme 5). Nevertheless, we were completely
taken aback when the aldol reaction of either ketone 1 or 2 with
a
Scheme 5. Reagents and conditions: (a) (i) TiCl3(i-PrO), i-Pr2NEt, CH2Cl2, ꢀ78 ꢁC; (ii) 30 or ent-30, ꢀ78 ꢁC.
ent-30 furnished a single diastereomer (41 and 42, respectively) in
remarkable yields (Scheme 5). Thus, the diastereoselectivity ach-
ieved in both reactions represented in Scheme 5 was astonishingly
high and the anti-Cornforth adducts 41 and 42 were even more
favoured than their Cornforth counterparts 37 and 39.29 Faced with
such a puzzling result, a verification of the stereochemistry was
considered inavoidable. Hence, the configuration of aldols 39 and
42 was firmly established through the sequential removal of pro-
tecting groups to obtain the corresponding lactones (Scheme 6).
Hydrogenolysis of the benzyl ether followed by oxidative cleavage
embedded in the structure of natural products. Our target was the
C12eC16 fragment of epothilone B (Scheme 7),32 the synthesis of
which had already been addressed by Mulzer several years ago.33
In fact, any structure having the same carbon backbone with the
desired configuration at C13 and C15 stereocenters would serve as
a synthetic analogue of Mulzer’s C12eC16 fragment. So, provided
that the aldol reaction of ketone
1 with aldehyde 30 had
delivered adduct 37 diastereoselectively (dr 95:5) in a high yield
(see Scheme 5), we envisaged that it could lead to the desired
C12eC16 fragment in a straightforward manner. Hence, stereo-
of the resulting dihydroxy ketone afforded
b
-hydroxy acids 44 and
selective syn reduction of b-hydroxy ketone 37 under Kiyooka con-
47, respectively. Then, TBDPS deprotection gave lactones 45 and 48
in good overall yields. Their spectroscopic and physical data
matched those previously reported in the literature30,31 and con-
firmed the configuration assigned to aldols 39 and 42.
ditions34 afforded the desired syn diol 49 (dr 88:12), which was
isolated as a single diastereomer in a 78% yield after purification.
Finally, protection of the diol as isopropylidene acetal under standard
conditions delivered 50 in an 82% yield.35 Therefore, a stereoselective
Scheme 6. Reagents and conditions: (a) H2, Pd/C, EtOH, rt. (b) NaIO4, 2:1 MeOH/H2O, rt. (c) HF, CH3CN, rt; 40% overall yield for 45, 50% overall yield for 48.

M. Pellicena et al. / Tetrahedron 68 (2012) 10338e10350
10343
and only the more representative frequencies (
n
) are reported.1H NMR
(500, 400 or 300 MHz) and 13C NMR (100.6 or 75.4 MHz) spectra were
recorded on Varian spectrometers. Chemical shifts (
parts per million and referenced to internal TMS (
0.00 for 1H NMR),
DMSO-d6 ( 77.0 for
2.50 for 1H NMR and 39.5 for 13C NMR) or CDCl3 (
d) are quoted in
d
d
d
13C NMR); coupling constants (J)arequoted inHertz;data arereported
as follows: s, singlet; d, doublet; t, triplet; q, quartet; p, quintet; sept,
septuplet; 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 d’Espectrometria de Masses, Universitat de Barcelona.
4.2. Preparation of methyl ketones 1e5
4.2.1. (S)-3-(p-Methoxybenzyloxy)-2-butanone (1). A 1.6 M solution
of MeLi in Et2O (3.8 mL, 6.1 mmol) was added dropwise to a solu-
tion of 10 (1.58 g, 6.0 mmol) in THF (60 mL) at ꢀ78 ꢁC under N2. The
resulting mixture was stirred for 5 min at ꢀ78 ꢁC, quenched by
addition of satd NH4Cl (10 mL), and vigorously stirred at rt for
10 min. The mixture was diluted with Et2O and the organic layer
was washed with satd NH4Cl, brine, dried (MgSO4) and concen-
trated. The resulting oil was purified by column chromatography
Scheme 7. Reagents and conditions: (a) DIBALH, THF, ꢀ78 ꢁC; 78%. (b) 1:1 Me2
-
C(OMe)2/CH2Cl2, cat PPTS, rt, 82%.
(90:10 hexanes/EtOAc) to afford 1.12 g (89% yield) of 1 as a colour-
20
less oil. Rf (90:10 hexanes/EtOAc) 0.20. [
a
]
ꢀ35.5 (c 4.5, CHCl3)
D
synthesis of the C12eC16 fragment of epothilone B was accom-
plished in three steps in a 48% overall yield starting from ketone 1.
This example demonstrates that our substrate-controlled aldol re-
action methodology based on chiral a-benzyloxy methyl ketones is
a useful tool for the synthesis of natural products.
[lit.10a ent-1 [
a]
20 þ33.1 (c 4.11, CHCl3)]. IR (film)
n 2934, 2838, 1717,
D
1613, 1515, 1250, 1175, 1111, 1034 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
7.29e7.24 (2H, m, ArH), 6.91e6.86 (2H, m, ArH), 4.49 (1H, d,
J¼11.3, PhCHxHy), 4.42 (1H, d, J¼11.3, PhCHxHy), 3.88 (1H, q, J¼6.9,
CHOPMB), 3.80 (3H, s, MeO), 2.18 (3H, s, COMe), 1.32 (3H, d, J¼6.9,
CHMe). 13C NMR (75.4 MHz, CDCl3)
d 211.3,159.4, 129.6, 129.4, 113.9,
80.5, 71.5, 55.2, 24.9, 17.2. HRMS (þFAB): MHþ, found 209.1178,
3. Conclusions
C12H17O3 requires 209.1178.
In summary, the titanium-mediated aldol reaction of chiral
a
-benzyloxy methyl ketones is highly sensitive to the titanium
4.2.2. (S)-3-Benzyloxy-2-butanone (2). The abovementioned ex-
perimental procedure was applied to 11 (1.64 g, 7.0 mmol) to af-
Lewis acid used in the enolization step. High yields and a remark-
able 1,4-anti induction have been obtained for aliphatic and aro-
matic aldehydes when the reaction is carried out with TiCl3(i-PrO).
Moreover, high diastereoselectivities have been achieved in double
ford 898 mg (72% yield) of 2 as a colourless oil. Rf2(485:15 hexanes/
20
EtOAc) 0.30. [
a]
ꢀ38.7 (c 1.0, CHCl3) [lit.10c
[
a
]
D
ꢀ35.2 (c 2.51,
D
CHCl3)]. IR (film)
n 3031, 2982, 2868, 1718, 1497, 1454, 1355, 1116,
1065 cmꢀ1
.
1H NMR (300 MHz, CDCl3)
d 7.40e7.27 (5H, m, ArH),
asymmetric processes with chiral a- and b-oxygenated aldehydes
and an example of application in the synthesis of the C12eC16
fragment of epothilone B has been described. Thus, the titanium-
based methodology reported here represents a new approach to
the substrate-controlled acetate aldol reaction, which may be
helpful to design more efficient syntheses.
4.59 (1H, d, J ¼11.7, PhCHxHy), 4.49 (1H, d, J¼11.7, PhCHxHy), 3.91
(1H, q, J¼6.9, CHOBn), 2.20 (3H, s, COMe), 1.35 (3H, d, J¼6.9,
CHMe). 13C NMR (75.4 MHz, CDCl3)
d 211.2, 137.5, 128.5, 127.9,
127.7, 80.8, 71.8, 25.0, 17.2. HRMS (þESI): MNaþ, found 201.0894,
C11H14NaO2 requires 201.0886.
4. Experimental section
4.1. General information
4.2.3. (S)-3-Benzyloxy-5-methyl-2-hexanone (3). A 1.4 M solution
of MeMgBr in 75:25 toluene/THF (5.7 mL, 8.0 mmol) was added
dropwise to a solution of 12 (1.11 g, 4.0 mmol) in THF (40 mL) at
0 ꢁC under N2. The resulting mixture was stirred for 30 min at 0 ꢁC,
then quenched and worked-up as in the previous case to afford
889 mg (91% yield) of 3 as a colourless oil. Rf (85:15 hexanes/
Unless otherwise noted, all oxygen and moisture-sensitive re-
actions were conducted in oven-dried glassware under a N2 atmo-
spherewith anhydrous solvents. The solvents and reagents were dried
and purified when necessary according to standard procedures. All
commercial reagents were used as received. Melting points were de-
termined with a Gallenkamp apparatus and are uncorrected. Analyt-
ical 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.
Flash Column chromatographies were performed on SDS silica gel 60
20
20
EtOAc) 0.35. [
a
]
ꢀ79.9 (c 1.0, CHCl3) [lit.36 ent-3 [
a
]
þ83 (c 1.0,
D
D
CHCl3, 96% ee)]. IR (film)
n 3025, 2952, 2927, 2862, 1712, 1450,
1348, 1124, 1091 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d 7.39e7.24 (5H,
m, ArH), 4.58 (1H, d, J¼11.8, PhCHxHy), 4.39 (1H, d, J¼11.8,
PhCHxHy), 3.81 (1H, dd, J¼9.5, 4.2, CHOBn), 2.18 (3H, s, COMe),
1.89e1.75 (1H, m, CHMe2), 1.64 (1H, ddd, J¼13.9, 9.5, 5.2,
CHxHyCHMe2), 1.35 (1H, ddd, J¼13.9, 8.8, 4.2, CHxHyCHMe2), 0.92
(3H, d, J¼6.8, CHMe), 0.85 (3H, d, J¼6.8, CHMe). 13C NMR
(35e70
mm). High-pressure liquid chromatography (HPLC) analyses
(100.6 MHz, CDCl3) d 211.9, 137.4, 128.5, 128.0, 83.8, 72.5, 41.0, 24.9,
were performed under isocratic conditions with a Tracer Spherisorb
24.5, 23.2, 21.7. HRMS (þESI): MNaþ, found 243.1362, C14H20NaO2
S3 W column with a 0.9 mL minꢀ1 flow at rt; the eluent and the re-
requires 243.1355.
tention time are specified for each case. Specific rotations ([a]D) were
determinedat20ꢁConaPerkineElmer241MCpolarimeter. IRspectra
were recorded on a Nicolet 6700 FT-IR Thermo Scientific spectrometer
4.2.4. (S)-3-Benzyloxy-4-phenyl-2-butanone (4). Experimental pro-
cedure described for 1 was applied to 13 (1.90 g, 6.0 mmol) with

10344
M. Pellicena et al. / Tetrahedron 68 (2012) 10338e10350
a reaction time of 30 min to afford 902 mg (58% yield) of 4 as a col-
CHOH), 2.86 (1H, br s, CHOH), 2.77 (1H, dd, J¼17.6, 2.4, COCHxHy),
2.63 (1H, dd, J¼17.6, 9.8, COCHxHy), 1.77e1.64 (1H, m, CHMe2), 1.35
(3H, d, J¼6.8, CHMe), 0.94 (3H, d, J¼6.8, CHMe), 0.92 (3H, d, J¼6.8,
ourless oil. Rf (70:30 hexanes/EtOAc) 0.40. [
IR (film)
1099 cmꢀ1. 1H NMR (300 MHz, CDCl3)
a
]
20 ꢀ60.8 (c 1.0, CHCl3).
D
n
3086, 3063, 3024, 2919, 2864, 1713, 1495, 1453, 1352,
d
7.38e7.12 (10H, m, ArH), 4.52
CHMe). 13C NMR (100.6 MHz, CDCl3)
d 214.4, 137.4, 128.5, 128.0,
(1H, d, J¼11.7, PhCHxHyO), 4.36 (1H, d, J¼11.7, PhCHxHyO), 3.99 (1H,
dd, J¼8.1, 4.8, CHOBn), 3.01 (1H, dd, J¼14.1, 4.8, PhCHxHy), 2.93 (1H,
dd, J¼14.1, 8.1, PhCHxHy), 2.13 (3H, s, COMe). 13C NMR (75.4 MHz,
127.8, 80.6, 72.1, 71.9, 41.2, 33.1, 18.4, 17.7, 17.2. HRMS (þESI): MNaþ,
found 273.1467, C15H22NaO3 requires 273.1461.
Minor aldol (18a). HPLC (98:2 hexanes/i-PrOH) tR¼14.8 min. 1H
CDCl3)
d
210.8, 137.3, 137.0, 129.5, 128.4, 127.8, 127.7, 126.7, 85.9, 72.6,
NMR (400 MHz, CDCl3)
d
3.94 (1H, q, J¼6.8, CHOBn), 2.70 (1H, dd,
38.5, 26.0. HRMS (þESI): MNaþ, found 277.1204, C17H18NaO2 re-
J¼17.6, 3.6, COCHxHy), 2.64 (1H, dd, J¼17.6, 8.8, COCHxHy), 0.91 (3H,
quires 277.1199.
d, J¼6.8, CHMe). 13C NMR (100.6 MHz, CDCl3)
d 80.8, 72.2, 71.9, 41.1,
33.2, 17.2.
4.2.5. (S)-3-Benzyloxy-4-methyl-2-pentanone (5). The experimen-
tal procedure described for 3 was applied to 14 (1.30 g, 5.0 mmol) to
afford 722 mg (71% yield) of 5 as a colourless oil. Rf (85:15 hexanes/
4.3.3. (2S,5R)-5-Hydroxy-2-(p-methoxybenzyloxy)-7-methyl-3-
octanone (15b). Colourless oil. Rf (70:30 hexanes/EtOAc) 0.25. IR
EtOAc) 0.35. [
a]
20 ꢀ88.4 (c 1.0, CHCl3). IR (film)
n
3030, 2960, 2870,
(film)
NMR (400 MHz, CDCl3) d 7.28e7.25 (2H, m, ArH), 6.91e6.87 (2H, m,
n
3473 (br), 2956, 1716, 1613, 1514, 1466, 1248, 1036 cmꢀ1. 1H
D
1710, 1455, 1351, 1090, 1073 cmꢀ1
.
1H NMR (300 MHz, CDCl3)
d
7.40e7.24 (5H, m, ArH), 4.58 (1H, d, J¼11.7, PhCHxHy), 4.39 (1H, d,
ArH), 4.50 (1H, d, J¼11.3, ArCHxHy), 4.45 (1H, d, J¼11.3, ArCHxHy),
4.16e4.05 (1H, m, CHOH), 3.90 (1H, q, J¼6.8, CHOPMB), 3.81 (3H, s,
MeO), 2.88 (1H, d, J¼3.3, CHOH), 2.76 (1H, dd, J¼18.0, 2.7, COCHxHy),
2.61 (1H, dd, J¼18.0, 9.0, COCHxHy), 1.86e1.73 (1H, m, CHMe2), 1.49
(1H, ddd, J¼13.7, 9.0, 5.5, CHxHyCHMe2), 1.33 (3H, d, J¼6.8,
MeCHOPMB), 1.15 (1H, ddd, J¼13.7, 8.8, 4.5, CHxHyCHMe2), 0.92
(3H, d, J¼6.6, CHMe), 0.91 (3H, d, J¼6.8, CHMe). 13C NMR
J¼11.7, PhCHxHy), 3.43 (1H, d, J¼6.6, CHOBn), 2.16 (3H, s, COMe),
2.10e1.91 (1H, m, CHMe2), 0.99 (3H, d, J¼6.6, CHMe), 0.91 (3H, d,
J¼6.9, CHMe). 13C NMR (75.4 MHz, CDCl3)
d 211.7, 137.6, 128.4, 127.9,
127.8, 90.6, 72.9, 30.9, 25.8, 18.7, 18.1. HRMS (þESI): MNaþ, found
229.1202, C13H18NaO2 requires 229.1199.
4.3. General procedure for the TiCl3(i-PrO)-mediated aldol
reaction
(100.6 MHz, CDCl3) d 214.2, 159.4, 129.6, 129.5, 113.9, 80.2, 71.5,
65.6, 55.2, 45.7, 44.7, 24.3, 23.3, 22.0, 17.1. HRMS (þFAB): MHþ,
found 295.1898, C17H27O4 requires 295.1909.
Freshly distilled Ti(i-PrO)4 (80
mL, 0.27 mmol) was added
Minor aldol (16b). 1H NMR (400 MHz, CDCl3)
d
2.86 (1H, d, J¼3.6,
dropwise to a solution of TiCl4 (90
mL, 0.82 mmol) in CH2Cl2
CHOH),1.32 (3H, d, J¼6.9, MeCHOPMB), 0.91 (3H, d, J¼6.7, CHMe).13C
(1.0 mL) at 0 ꢁC under N2. The resulting white mixture was stirred
for 15 min at 0 ꢁC and 10 min at rt. It was diluted with CH2Cl2
(1.0 mL), and the resulting colourless solution was added via
cannula (2ꢂ0.5 mL rinse) to a solution of the ketone (1.0 mmol) in
CH2Cl2 (2.0 mL) at ꢀ78 ꢁC under N2. The resulting yellow solution
NMR (100.6 MHz, CDCl3) d 129.4, 80.4, 71.6, 45.5, 44.5, 23.8, 21.6.
4.3.4. (2S,5R)-5-Hydroxy-2-(p-methoxybenzyloxy)-7-phenyl-3-
heptanone (15c). Colourless oil. Rf (75:25 hexanes/EtOAc) 0.20. IR
(film)
n
3473 (br), 3032, 2937, 1716, 1612, 1514, 1455, 1302, 1250,
was stirred for 5 min and i-Pr2NEt (190
m
L, 1.1 mmol) was added
1036 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d
7.30e7.12 (7H, m, ArH),
dropwise. The resulting dark red solution was stirred for 30 min
at ꢀ78 ꢁC and after the dropwise addition of the aldehyde
(1.2 mmol), stirring was continued for 30 min at ꢀ78 ꢁC. The re-
action was quenched by addition of satd NH4Cl (5 mL) and vig-
orously stirred at rt for 10 min. The mixture was diluted with Et2O
and the organic layer was washed with H2O, satd NaHCO3,
and brine, dried (MgSO4) and concentrated. The reaction crude
was analyzed by NMR or HPLC and purified by column
chromatography.
6.89e6.87 (2H, m, ArH), 4.48 (1H, d, J¼11.2, ArCHxHy), 4.44 (1H, d,
J¼11.2, ArCHxHy), 4.09e3.98 (1H, m, CHOH), 3.88 (1H, q, J¼6.8,
CHOPMB), 3.80 (3H, s, MeO), 2.85e2.78 (1H, m, CHxHyPh), 2.79 (1H,
dd, J¼18.0, 2.6, COCHxHy), 2.72e2.65 (1H, m, CHxHyPh), 2.64 (1H,
dd, J¼18.0, 9.2, COCHxHy), 1.88e1.78 (1H, m, CHxHyCH2Ph),
1.75e1.66 (1H, m, CHxHyCH2Ph), 1.30 (3H, d, J¼6.8, CHMe). 13C NMR
(100.6 MHz, CDCl3)
125.8, 113.9, 80.2, 71.6, 66.8, 55.2, 44.2, 38.2, 31.7, 17.1.
Minor aldol (16c). 1H NMR (400 MHz, CDCl3)
1.31 (3H, d, J¼6.8,
CHMe). 13C NMR (100.6 MHz, CDCl3)
80.4, 44.1.
d
214.2, 159.5, 141.8, 129.5, 129.3, 128.4 (ꢂ2),
d
d
4.3.1. (2S,5S)-5-Hydroxy-2-(p-methoxybenzyloxy)-6-methyl-3-
heptanone (15a). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.30. IR
4.3.5. (2S,5R)-5-Hydroxy-2-(p-methoxybenzyloxy)-3-heptanone
(15d). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.20. IR (film)
3488 (br), 2936, 1715, 1612, 1514, 1463, 1249, 1109, 1034 cmꢀ1. 1H
NMR (400 MHz, CDCl3) 7.29e7.25 (2H, m, ArH), 6.91e6.87 (2H, m,
(film)
n
3514 (br), 2961, 1716, 1613, 1514, 1466, 1250, 1111 cmꢀ1. 1H
n
NMR (400 MHz, CDCl3)
d
7.29e7.25 (2H, m, ArH), 6.91e6.87 (2H, m,
ArH), 4.51 (1H, d, J¼11.4, PhCHxHy), 4.45 (1H, d, J¼11.4, PhCHxHy),
3.91 (1H, q, J¼6.9, CHOPMB), 3.85e3.80 (1H, m, CHOH), 3.80 (3H, s,
MeO), 2.75 (1H, dd, J¼17.8, 2.4, COCHxHy), 2.61 (1H, dd, J¼17.8, 9.7,
COCHxHy), 1.75e1.64 (1H, m, CHMe2), 1.33 (3H, d, J¼6.9,
MeCHOPMB), 0.94 (3H, d, J¼6.9, CHMe), 0.92 (3H, J¼6.9, CHMe). 13C
d
ArH), 4.50 (1H, d, J¼11.2, PhCHxHy), 4.45 (1H, d, J¼11.2, PhCHxHy),
3.99e3.93 (1H, m, CHOH), 3.90 (1H, q, J¼6.8, CHOPMB), 3.81 (3H, s,
MeO), 2.79 (1H, dd, J¼18.0, 2.6, COCHxHy), 2.61 (1H, dd, J¼18.0, 9.2,
COCHxHy),1.59e1.41 (2H, m, CH2Me),1.32 (3H, d, J¼6.8, CHMe), 0.95
NMR (100.6 MHz, CDCl3)
d
214.5, 159.4, 129.5, 129.4, 113.9, 80.2,
(3H, t, J¼7.4, CH2Me). 13C NMR (100.6 MHz, CDCl3)
d 214.2, 159.5,
72.1, 71.6, 55.2, 41.1, 33.1, 18.3, 17.7, 17.2. HRMS (þFAB): MHþ, found
129.5, 129.4, 113.9, 80.2, 71.5, 68.9, 55.2, 43.7, 29.4, 17.1, 9.8.
281.1747, C16H25O4 requires 281.1753.
Minor aldol (16d). 1H NMR (400 MHz, CDCl3)
CHOPMB), 2.71 (1H, dd, J¼18.0, 3.2, COCHxHy), 0.94 (3H, t, J¼7.4,
CH2Me). 13C NMR (100.6 MHz, CDCl3)
214.3, 80.4, 71.6, 43.6.
d
3.91 (1H, q, J¼6.8,
Minor aldol (16a). 1H NMR (400 MHz, CDCl3)
d
3.92 (1H, q, J¼6.9,
CHOPMB), 2.62 (1H, dd, J¼17.7, 10.7, COCHxHy). 13C NMR
d
(100.6 MHz, CDCl3)
d 80.5, 72.2, 71.6, 41.0, 33.2.
4.3.6. (1S,4S)-1-Hydroxy-4-(p-methoxybenzyloxy)-1-phenyl-3-
4.3.2. (2S,5S)-2-Benzyloxy-5-hydroxy-6-methyl-3-heptanone
pentanone (15e). Colourless oil. Rf (75:25 hexanes/EtOAc) 0.30. IR
(17a). Colourless oil. Rf (75:25 hexanes/EtOAc) 0.25. HPLC (98:2
(film)
n
3475 (br), 3032, 2935, 1717, 1612, 1514, 1454, 1302, 1248,
hexanes/i-PrOH) tR¼13.8 min. IR (film)
1454, 1367, 1113, 1053, 1026 cmꢀ1
7.40e7.28 (5H, m, ArH), 4.58 (1H, d, J¼11.6, PhCHxHy), 4.52 (1H, d,
J¼11.6, PhCHxHy), 3.94 (1H, q, J¼6.8, CHOBn), 3.89e3.75 (1H, m,
n
3495 (br), 2957, 2871,1714,
1033 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d
7.36e7.22 (7H, m, ArH),
.
1H NMR (400 MHz, CDCl3)
6.89e6.86 (2H, m, ArH), 5.16 (1H, dd, J¼7.5, 4.9, CHOH), 4.48 (1H, d,
J¼11.3, ArCHxHy), 4.42 (1H, d, J¼11.3, ArCHxHy), 3.90 (1H, q, J¼6.8,
CHOPMB), 3.80 (3H, s, MeO), 3.03e2.92 (2H, m, COCH2), 1.30 (3H, d,
d

M. Pellicena et al. / Tetrahedron 68 (2012) 10338e10350
10345
J¼6.8, CHMe). 13C NMR (100.6 MHz, CDCl3)
d
213.3, 159.5, 142.9,
4.3.11. (1S,4S)-4-Benzyloxy-1-hydroxy-1-phenyl-3-pentanone
(17e). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.15. IR (film) 3463
(br), 3085, 3058, 3026, 2976, 2862,1710,1601,1492,1451,1023 cmꢀ1
1H NMR (500 MHz, CDCl3)
7.40e7.26 (10H, m, ArH), 5.18 (1H, dd,
129.6,129.4,128.5,127.7,125.7,113.9, 80.2, 71.6, 69.9, 55.3, 46.2,17.0.
n
Minor aldol (16e). 1H NMR (400 MHz, CDCl3)
d
5.12 (1H, dd,
.
J¼9.2, 3.2, CHOH), 3.01 (1H, dd, J¼17.6, 9.2, COCHxHy), 2.87 (1H, dd,
d
J¼17.6, 3.2, COCHxHy). 13C NMR (100.6 MHz, CDCl3)
d
80.4, 71.7, 46.1.
J¼8.6, 3.8, CHOH), 4.57 (1H, d, J¼11.7, PhCHxHy), 4.49 (1H, d, J¼11.7,
PhCHxHy), 3.93 (1H, q, J¼6.8, CHOBn), 3.03 (1H, dd, J¼17.9, 8.3,
COCHxHy), 2.99 (1H, dd, J¼17.9, 4.3, COCHxHy), 1.33 (3H, d, J¼6.8,
4.3.7. (2S,5S)-5-Hydroxy-2-(p-methoxybenzyloxy)-6-methyl-6-
hepten-3-one (15f). Colourless oil. Rf (75:25 hexanes/EtOAc) 0.30. IR
CHMe). 1H NMR (400 MHz, DMSO-d6)
d 7.38e7.20 (10H, m, ArH),
(film)
n
3486 (br), 3074, 2936, 1717, 1612, 1514, 1456, 1302, 1248,
5.38 (1H, d, J¼4.4, CHOH), 5.09e5.02 (1H, m, CHOH), 4.51 (1H, d,
J¼11.6, PhCHxHy), 4.37 (1H, d, J¼11.6, PhCHxHy), 3.97 (1H, q, J¼6.8,
CHOBn), 2.95 (1H, dd, J¼16.0, 8.4, COCHxHy), 2.77(1H, dd, J¼16.0, 4.4,
COCHxHy), 1.17 (3H, d, J¼6.8, CHMe). 13C NMR (75.4 MHz, CDCl3)
1035 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d
7.29e7.25 (2H, m, ArH),
6.91e6.87 (2H, m, ArH), 5.02e5.01 (1H, m, C]CHxHy), 4.87e4.86 (1H,
m, C]CHxHy), 4.51 (1H, d, J¼11.2, ArCHxHy), 4.46 (1H, d, J¼11.2,
ArCHxHy), 3.92 (1H, q, J¼6.8, CHOPMB), 3.81e3.78 (1H, m, CHOH),
3.80(3H, s,MeO), 2.84e2.77(2H, m,COCH2),1.74(3H, brs,MeC]CH2),
d
213.1, 142.9, 137.3, 128.5, 128.0, 127.8, 127.7, 125.7, 80.5, 71.9, 69.9,
46.2,17.0.13C NMR (100.6 MHz, DMSO-d6)
d 209.9,145.3,138.1,128.3,
1.33 (3H, d, J¼6.8, CHMe). 13C NMR (100.6 MHz, CDCl3)
d
213.4,159.5,
128.1, 127.7, 127.6, 127.0, 125.8, 80.0, 70.8, 68.6, 47.4, 16.6. HRMS
145.8, 129.6, 129.4, 113.9, 111.2, 80.2, 71.6, 70.9, 55.3, 42.8, 18.3, 17.1.
(þESI): MNaþ, found 307.1311, C18H20NaO3 requires 307.1304.
Minor aldol (16f). 1H NMR (400 MHz, CDCl3)
d
3.93 (1H, q, J¼6.8,
Minor aldol (18e). 1H NMR (500 MHz, CDCl3)
d
5.15 (1H, dd, J¼8.6,
CHOPMB), 2.71 (1H, dd, J¼17.2, 3.2, COCHxHy), 1.73 (3H, br s, MeC]
3.8, CHOH), 3.95 (1H, q, J¼6.8, CHOBn), 2.92 (1H, dd, J¼17.7, 3.1,
CH2). 13C NMR (100.6 MHz, CDCl3)
71.0, 42.7.
d 213.5, 145.9, 111.1, 80.4, 71.7,
COCHxHy), 1.33 (3H, d, J¼6.8, CHMe). 1H NMR (400 MHz, DMSO-d6)
d
5.37 (1H, d, J¼4.4, CHOH), 5.04e4.99 (1H, m, CHOH), 4.45 (1H, d,
J¼11.6, PhCHxHy), 4.39 (1H, d, J¼11.6, PhCHxHy), 4.01 (1H, q, J¼6.8,
CHOBn), 2.98 (1H, dd, J¼16.0, 8.8, COCHxHy), 2.67(1H, dd, J¼16.0, 4.4,
COCHxHy), 1.20 (3H, d, J¼6.8, CHMe). 13C NMR (75.4 MHz, CDCl3)
4.3.8. (2S,5S)-2-Benzyloxy-5-hydroxy-6,6-dimethyl-3-heptanone
20
(17g). Colourless oil. Rf (75:25 hexanes/EtOAc) 0.25. [
1.2, CHCl3, 86% de). IR (film) 3518 (br), 2955, 2869, 1715, 1456,
1365, 1113, 1081 cmꢀ1. 1H NMR (400 MHz, CDCl3)
7.40e7.25 (5H,
a]
ꢀ60.1 (c
D
n
d d 80.2, 68.8, 47.4, 16.6.
80.7, 46.1. 13C NMR (100.6 MHz, DMSO-d6)
d
m, ArH), 4.56 (1H, d, J¼11.6, PhCHxHy), 4.52 (1H, d, J¼11.6,
PhCHxHy), 3.94 (1H, q, J¼6.8, CHOBn), 3.73 (1H, ddd, J¼10.4, 3.2, 2.0,
CHOH), 2.78 (1H, d, J¼3.2, CHOH), 2.77 (1H, dd, J¼17.6, 2.0,
COCHxHy), 2.59 (1H, dd, J¼17.6, 10.4, COCHxHy), 1.35 (3H, d, J¼6.8,
4.3.12. (1S,4S)-4-Benzyloxy-1-hydroxy-1-(p-nitrophenyl)-3-
pentanone (17i). White solid. Mp 54e56 ꢁC. Rf (75:25 hexanes/
EtOAc) 0.10. IR (KBr)
n
3433 (br), 1709, 1598, 1509, 1449, 1347, 1077,
8.28e8.10 (2H, m, ArH),
1012 cmꢀ1 1H NMR (400 MHz, CDCl3)
.
d
CHMe), 0.91 (9H, s, CMe3). 13C NMR (75.4 MHz, CDCl3)
d
214.5, 137.4,
7.60e7.44 (2H, m, ArH), 7.42e7.28 (5H, m, ArH), 5.25 (1H, dd, J¼9.1,
3.1, CHOH), 4.56 (1H, d, J¼12.0, PhCHxHy), 4.52 (1H, d, J¼12.0,
PhCHxHy), 3.95 (1H, q, J¼6.8, CHOBn), 3.04 (1H, dd, J¼18.1, 3.1,
COCHxHy), 2.93 (1H, dd, J¼18.1, 9.1, COCHxHy), 1.35 (3H, d, J¼6.8,
128.5, 128.0, 127.9, 80.7, 74.8, 71.9, 39.2, 34.3, 25.6, 17.2. HRMS
(þESI): MHþ, found 265.1801, C16H25O3 requires 265.1798.
Minor aldol (18g). 1H NMR (400 MHz, CDCl3)
d 3.95 (1H, q,
J¼6.8, CHOBn), 2.81 (1H, d, J¼3.2, CHOH), 2.71 (1H, dd, J¼17.6,
CHMe). 13C NMR (75.4 MHz, CDCl3)
d 212.6, 150.1, 147.3, 137.1, 128.6,
2.0, COCHxHy), 0.90 (9H, s, CMe3). 13C NMR (75.4 MHz, CDCl3)
128.1, 127.8, 126.4, 123.7, 80.4, 71.9, 68.9, 46.0, 16.9.
d
74.9, 17.1.
Minor aldol (18i). 1H NMR (400 MHz, CDCl3)
d
5.20 (1H, dd, J¼8.8,
3.3, CHOH), 4.58 (1H, d, J¼11.6, PhCHxHy), 4.50 (1H, d, J¼11.6,
PhCHxHy), 3.96 (1H, q, J¼6.8, CHOBn), 2.99 (1H, dd, J¼18.0, 8.8,
COCHxHy), 2.91 (1H, dd, J¼18.0, 3.3, COCHxHy), 1.33 (3H, d, J¼6.8,
4.3.9. (2S,5R)-2-Benzyloxy-5-hydroxy-7-methyl-3-octanone
(17b). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.20. IR (film) 3470
(br), 2949, 2924, 2861, 1714, 1452, 1110, 1064 cmꢀ1 1H NMR
(400 MHz, CDCl3)
7.40e7.28 (5H, m, ArH), 4.58 (1H, d, J¼11.5,
n
.
CHMe). 13C NMR (75.4 MHz, CDCl3)
d 80.7.
d
PhCHxHy), 4.52 (1H, d, J¼11.5, PhCHxHy), 4.18e4.08 (1H, m, CHOH),
3.92 (1H, q, J¼6.8, CHOBn), 2.75 (1H, dd, J¼18.0, 3.0, COCHxHy), 2.61
(1H, dd, J¼18.0, 9.0, COCHxHy), 1.86e1.74 (1H, m, CHMe2), 1.49 (1H,
ddd, J¼13.7, 9.0, 5.4, CHxHyCHMe2), 1.35 (3H, d, J¼6.8, CHMe), 1.16
(1H, ddd, J¼13.7, 8.8, 4.5, CHxHyCHMe2), 0.92 (3H, d, J¼6.7, CHMe),
4.3.13. (1S,4S)-4-Benzyloxy-1-hydroxy-1-(p-methoxyphenyl)-3-
pentanone (17j). Yellowish oil. Rf (80:20 hexanes/EtOAc) 0.10. IR
(film)
n
3467 (br), 1714, 1608, 1511, 1452, 1300, 1245, 1173,
1030 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d
7.39e7.24 (7H, m, ArH),
6.91e6.85 (2H, m, ArH), 5.13 (1H, dd, J¼8.4, 4.4, CHOH), 4.56 (1H, d,
J¼11.6, PhCHxHy), 4.48 (1H, d, J¼11.6, PhCHxHy), 3.92 (1H, q, J¼6.8,
CHOBn), 3.80 (3H, s, MeO), 3.09 (1H, br s, CHOH), 3.07e2.84 (2H, m,
COCH2), 1.32 (3H, d, J¼6.8, CHMe). 13C NMR (75.4 MHz, CDCl3)
0.91 (3H, d, J¼6.7, CHMe). 13C NMR (75.4 MHz, CDCl3)
d 214.1, 137.4,
128.5, 128.0, 127.8, 80.5, 71.9, 65.6, 45.7, 44.7, 24.4, 23.3, 22.0, 17.1.
HRMS (þESI): MNaþ, found 287.1621, C16H24NaO3 requires 287.1617.
Minor aldol (18b). 1H NMR (400 MHz, CDCl3)
d
3.93 (1H, q, J¼6.8,
d 213.0, 159.1, 137.4, 135.1, 128.5, 127.9, 127.8, 126.9, 113.9, 80.5, 71.8,
CHOBn), 1.35 (3H, d, J¼6.8, CHMe). 13C NMR (75.4 MHz, CDCl3)
69.5, 55.2, 46.2, 17.0.
d
214.2, 80.8, 44.6.
Minor aldol (18j). 1H NMR (400 MHz, CDCl3)
d
5.09 (1H, dd, J¼9.2,
3.2, CHOH), 1.33 (3H, d, J¼6.8, CHMe). 13C NMR (75.4 MHz, CDCl3)
4.3.10. (2S,5R)-2-Benzyloxy-5-hydroxy-3-octanone
(17h).
d 80.7, 71.9, 69.5, 46.1, 17.0.
Colourless oil. Rf (75:25 hexanes/EtOAc) 0.20. IR (film)
n
3453 (br),
2956, 2926, 2866, 1714, 1454, 1110, 1063 cmꢀ1. 1H NMR (400 MHz,
4.3.14. (1S,4S)-4-Benzyloxy-1-(p-bromophenyl)-1-hydroxy-3-
CDCl3)
d
7.40e7.28 (5H, m, ArH), 4.58 (1H, d, J¼11.6, PhCHxHy), 4.52
pentanone (17k). Colourless oil. Rf (70:30 hexanes/EtOAc) 0.30. IR
(1H, d, J¼11.6, PhCHxHy), 4.10e3.98 (1H, m, CHOH), 3.92 (1H, q,
J¼6.8, CHOBn), 2.88 (1H, br s, CHOH), 2.80 (1H, dd, J¼18.0, 2.7,
COCHxHy), 2.63 (1H, dd, J¼18.0, 9.2, COCHxHy), 1.58e1.30 (4H, m,
(CH2)2), 1.35 (3H, d, J¼6.8, CHMe), 0.93 (3H, t, J¼7.0, CH2Me). 13C
(film)
(300 MHz, CDCl3)
n .
3446 (br), 1716, 1487, 1456, 1071, 1009 cmꢀ1 1H NMR
d
7.50e7.07 (9H, m, ArH), 5.15e5.07 (1H, m,
CHOH), 4.54 (1H, d, J¼11.7, PhCHxHy), 4.49 (1H, d, J¼11.7, PhCHxHy),
3.92 (1H, q, J¼6.8, CHOBn), 3.28 (1H, br s, CHOH), 3.03e2.73 (2H, m,
COCH2), 1.32 (3H, d, J¼6.8, CHMe). 13C NMR (75.4 MHz, CDCl3)
NMR (75.4 MHz, CDCl3) d 214.1, 137.4, 128.5, 128.0, 127.8, 80.6, 71.9,
67.3, 44.2, 38.7, 18.7, 17.2, 13.9.
d 212.9, 141.9, 137.2, 131.6, 128.5, 128.0, 127.8, 127.4, 121.4, 80.5, 71.9,
Minor aldol (18h). 1H NMR (400 MHz, CDCl3)
d
3.93 (1H, q, J¼6.8,
69.2, 46.1, 17.0.
CHOBn), 2.72 (1H, dd, J¼17.9, 3.4, COCHxHy). 13C NMR (75.4 MHz,
Minor aldol (18j). 1H NMR (300 MHz, CDCl3)
3.4, CHOH), 4.53 (1H, d, J¼11.9, PhCHxHy), 4.48 (1H, d, J¼11.9,
d
5.07 (1H, dd, J¼8.9,
CDCl3)
d
80.8, 44.1.

10346
M. Pellicena et al. / Tetrahedron 68 (2012) 10338e10350
PhCHxHy), 3.93 (1H, q, J¼6.8, CHOBn). 13C NMR (75.4 MHz, CDCl3)
hexanes/EtOAc) 0.30. [
a
]
20 ꢀ41.9 (c 1.0, CHCl3, 72% ee) [lit.37 ent-20
D
d
141.9, 80.7, 72.0, 46.0.
[a
]
20 þ53.5 (c 0.85, CHCl3)]. IR (film)
n 2960, 2933, 2860, 1719, 1474,
D
1252, 1088, 1053 cmꢀ1 1H NMR (400 MHz, CDCl3)
. d 4.06 (1H, dt,
4.3.15. (2S,5S)-2-Benzyloxy-5-hydroxy-6-methyl-6-hepten-3-one
(17f). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.15. IR (film) 3475
(br), 2977, 2930, 2862, 1713, 1447, 1083 cmꢀ1 1H NMR (300 MHz,
CDCl3) 7.42e7.24 (5H, m, ArH), 5.04e5.00 (1H, m, C]CHxHy),
J¼8.0, 3.9, CHOTBS), 2.55 (1H, dd, J¼14.8, 8.0, CHxHyCHOTBS), 2.45
(2H, q, J¼7.2, CH2CH3), 2.32 (1H, dd, J¼14.8, 3.9, CHxHyCHOTBS),
1.71 (1H, septd, J¼6.8, 3.9, CHMe2), 1.03 (t, J¼7.2, CH2Me), 0.88 (3H,
d, J¼6.8, CHMe), 0.85 (9H, s, CMe3), 0.83 (3H, d, J¼6.8, CHMe), 0.04
(3H, s, SiMe), ꢀ0.03 (3H, s, SiMe). 13C NMR (100.6 MHz, CDCl3)
n
.
d
4.89e4.84 (1H, m, C]CHxHy), 4.59 (1H, d, J¼11.7, PhCHxHy),
4.54e4.45 (1H, m, CHOH), 4.52 (1H, d, J¼11.7, PhCHxHy), 3.95 (1H, q,
J¼6.9, CHOBn), 2.89e2.69 (3H, m, COCH2 & CHOH), 1.74 (3H, br s,
MeC]C), 1.36 (3H, d, J¼6.9, CHMe). 13C NMR (75.4 MHz, CDCl3)
d
210.9, 73.2, 45.6, 37.8, 33.8, 25.8, 18.0, 17.7, 17.2, 7.5, ꢀ4.7 (Χ2).
HRMS (þFAB): MHþ, found 259.2091, C14H31O2Si requires
259.2093.
d
213.2, 145.8, 137.4, 128.5, 128.0, 127.9, 111.2, 80.6, 71.9, 71.0, 42.8,
18.3, 17.1.
4.4.3. (S)-5-Hydroxy-6-methyl-3-heptanone (21). A 48% aqueous
solution of HF (19 mL, 0.52 mmol) was added dropwise to a solution
Minor aldol (18f). 1H NMR (300 MHz, CDCl3)
d
3.96 (1H, q, J¼6.9,
CHOBn). 13C NMR (75.4 MHz, CDCl3)
42.8, 18.0.
d
145.9, 111.2, 80.8, 71.9, 71.0,
of 20 (41 mg, 0.16 mmol) in CH3CN (1.8 mL) at rt. The reaction
mixture was stirred for 3.5 h and diluted with CH2Cl2 (25 mL).
The organic layer was washed with satd NaHCO3, dried (MgSO4)
and concentrated. The resulting oil was purified by column
chromatography (85:15 hexanes/EtOAc) to afford 16 mg (70% yield)
of 21 (er 86:14) as a colourless oil. Rf (85:15 hexanes/EtOAc) 0.20.
4.3.16. (2S,5S,6E)-2-Benzyloxy-5-hydroxy-6-octen-3-one
(17l). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.10. IR (film) 3451
(br), 2917, 2861, 1713, 1454, 1115 cmꢀ1. 1H NMR (300 MHz, CDCl3)
n
d
7.40e7.27 (5H, m, ArH), 5.72 (1H, dqd, J¼15.4, 6.4, 1.1, CH]CHMe),
[a
]
ꢀ46.7 (c 1.6, CHCl3, 72% ee) [lit.37 ent-21 [
a
]
þ53.5 (c 0.83,
20
20
D
D
5.50 (1H, ddq, J¼15.4, 6.6, 1.6, CH]CHMe), 4.58 (1H, d, J¼11.7,
PhCHxHy), 4.57e4.46 (1H, m, CHOH), 4.50 (1H, d, J¼11.7, PhCHxHy),
3.92 (1H, q, J¼6.8, CHOBn), 2.88e2.67 (3H, m, COCH2 & CHOH),
1.69e1.67 (3H, m, CH]CHMe), 1.34 (3H, d, J¼6.8, CHMe). 13C NMR
CHCl3)]. IR (film) n 3477 (br), 2964, 1710, 1465, 1412, 1380,
1115 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d
3.82 (1H, ddd, J¼9.6, 5.8, 2.4,
CHOH), 2.59 (1H, dd, J¼17.2, 2.4, CHxHyCHOH), 2.50 (1H, dd, J¼17.2,
9.6, CHxHyCHOH), 2.48 (2H, q, J¼7.2, CH2CH3), 1.74e1.63 (1H, m,
CHMe2), 1.07 (3H, t, J¼7.2, CH2Me), 0.94 (3H, d, J¼6.8, CHMe), 0.92
(75.4 MHz, CDCl3)
d 213.2, 137.4, 132.1, 128.5, 128.0, 127.8, 127.1,
80.6, 71.9, 68.5, 44.3, 17.6, 17.1.
(3H, d, J¼6.8, CHMe). 13C NMR (100.6 MHz, CDCl3)
d 213.1, 72.3, 45.6,
Minor aldol (18l). 1H NMR (300 MHz, CDCl3)
d
5.71 (1H, dqd,
36.8, 33.0, 18.3, 17.8, 7.6.
J¼15.4, 6.4, 1.1, CH]CHMe), 5.49 (1H, ddq, J¼15.4, 6.6, 1.6, CH]
CHMe), 4.56 (1H, d, J¼11.8, PhCHxHy), 4.51 (1H, d, J¼11.8, PhCHxHy),
3.93 (1H, q, J¼6.8, CHOBn), 1.71e1.69 (3H, m, CH]CHMe). 13C NMR
4.5. Synthesis of carboxylic acid 22 from 17a
(75.4 MHz, CDCl3)
d
213.2, 132.1, 127.1, 80.7, 71.9, 68.4, 44.2, 17.0.
A mixture of 17a (293 mg, 1.17 mmol, dr 85:15) and 10% Pd/C
(300 mg) in EtOH (50 mL) was hydrogenated with H2 (1 atm) at rt
for 3 h. The reaction mixture was filtered on CeliteÒ, eluted with
CH2Cl2 and concentrated to obtain 178 mg (1.11 mmol) of a colour-
less oil, which was used in the next step without further purifica-
tion. A mixture of this oil and NaIO4 (1.95 g, 9.0 mmol) in 2:1
MeOH/H2O (10 mL) was stirred for 1 h at rt. Then, it was diluted
with Et2O (10 mL), cooled to 0 ꢁC and 0.5 M HCl was slowly added to
reach pH 1. The mixture was partitioned with Et2O (10 mL) and H2O
(10 mL), and the aqueous layer was extracted with Et2O (4ꢂ10 mL).
The combined organic extracts were dried (MgSO4) and concen-
trated. The residue was purified by column chromatography (95:5
4.4. Synthesis of ketone 21 from 15a
4.4.1. (2S,5S)-5-(tert-Butyldimethylsilyloxy)-2-(p-methox-
ybenzyloxy)-6-methyl-3-heptanone (19). A mixture of 15a (134 mg,
0.48 mmol, dr 86:14), 2,6-lutidine (83
mL, 0.72 mmol) and TBSOTf
(140 L, 0.60 mmol) in CH2Cl2 (1.8 mL) was stirred at rt overnight. It
m
was diluted with CH2Cl2, washed with satd NH4Cl, satd NaHCO3,
brine, dried (MgSO4) and concentrated. The resulting oil was pu-
rified by column chromatography (95:5 hexanes/EtOAc) to afford
134 mg (71% yield) of 19 (dr 86:14) as a colourless oil. Rf (95:5
hexanes/EtOAc) 0.45. IR (film)
n
2958, 2933, 2858, 1719, 1613, 1515,
7.29e7.25 (2H, m,
CH2Cl2/MeOH) to afford 70 mg (49% overall yield) of 22 (er 85:15)
20
1250, 1040 cmꢀ1 1H NMR (400 MHz, CDCl3)
.
d
as a colourless oil. Rf (95:5 CH2Cl2/MeOH) 0.20. [
a
]
ꢀ25.3
D
25
ArH), 6.90e6.87 (2H, m, ArH), 4.52 (1H, d, J¼11.4, ArCHxHy), 4.39
(1H, d, J¼11.4, ArCHxHy), 4.17e4.13 (1H, m, CHOTBS), 3.88 (1H, q,
J¼6.8, CHOPMB), 3.80 (3H, s, MeO), 2.80 (1H, dd, J¼17.2, 7.6,
COCHxHy), 2.43 (1H, dd, J¼17.2, 4.4, COCHxHy), 1.73 (1H, septd,
J¼6.8, 3.6, CHMe2), 1.30 (3H, d, J¼6.8, MeCHOPMB), 0.89 (3H, d,
J¼6.8, CHMe), 0.84 (9H, s, CMe3), 0.83 (3H, J¼6.8, CHMe), 0.06 (3H, s,
(c 1.2, CHCl3, 70% ee) [lit.20b
3293 (br), 2960, 2931, 2876, 2637, 1715, 1407, 1286, 1182 cmꢀ1. 1H
NMR (300 MHz, CDCl3)
[a
]
ꢀ40.7 (c 3.0, CHCl3)]. IR (film)
n
D
d
3.81 (1H, ddd, J¼9.1, 5.9, 3.2, CHOH), 2.58
(1H, dd, J¼16.4, 3.2, COCHxHy), 2.48 (1H, dd, J¼16.4, 9.1, COCHxHy),
1.82e1.68 (1H, m, CHMe2), 0.97 (3H, d, J¼6.9, Me), 0.95 (3H, d, J¼6.9,
Me). 13C NMR (100.6 MHz, CDCl3)
d 178.1, 72.8, 38.4, 33.2, 18.3, 17.7.
SiMe), ꢀ0.01 (3H, s, SiMe). 13C NMR (100.6 MHz, CDCl3)
d 211.8,
159.4, 129.7, 129.6, 113.9, 80.5, 71.9, 71.5, 55.3, 40.7, 33.6, 25.9, 18.0,
4.6. Spectroscopic data of aldols from ketones 3e5
17.5, 17.3, 17.1, ꢀ4.5, ꢀ4.8.
4.6.1. (3S,6S)-6-Benzyloxy-3-hydroxy-2,8-dimethyl-5-nonanone
4.4.2. (S)-5-(tert-Butyldimethylsilyloxy)-6-methyl-3-heptanone
(20). A 0.2 M solution of SmI2 in THF (6.1 mL, 1.2 mmol) was slowly
added via cannula to a solution of 19 (121 mg, 0.31 mmol) in 2:1
THF/MeOH (6.1 mL) at 0 ꢁC under N2. The dark green mixture was
stirred for 1.5 h at 0 ꢁC, quenched by addition of satd NaHCO3
(10 mL) and vigorously stirred at rt for 10 min. Then it was parti-
tioned with CH2Cl2 (50 mL) and satd NaHCO3 (50 mL), and the
aqueous layer was extracted with CH2Cl2. The combined organic
extracts were dried (MgSO4) and concentrated. The resulting oil
was purified by column chromatography (95:5 hexanes/EtOAc) to
afford 70 mg (89% yield) of 20 (er 86:14) as a colourless oil. Rf (95:5
(23a). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.30. IR (film)
3501 (br), 2956, 2927, 2869, 1714, 1467, 1451, 1095, 1045, 1027 cmꢀ1
1H NMR (400 MHz, CDCl3)
7.40e7.27 (5H, m, ArH), 4.60 (1H, d,
n
.
d
J¼11.4, PhCHxHy), 4.40 (1H, d, J¼11.4, PhCHxHy), 3.84 (1H, dd, J¼9.5,
4.2, CHOBn), 3.83e3.78 (1H, m, CHOH), 2.87 (1H, d, J¼3.2, CHOH),
2.71 (1H, dd, J¼17.7, 2.4, COCHxHy), 2.60 (1H, dd, J¼17.7, 9.4,
COCHxHy), 1.89e1.76 (1H, m, CH2CHMe2), 1.76e1.64 (1H, m, CH(OH)
CHMe2), 1.62 (1H, ddd, J¼13.9, 9.5, 5.2, CHxHyCHMe), 1.36 (1H, ddd,
J¼13.9, 8.8, 4.2, CHxHyCHMe), 0.94 (3H, d, J¼6.4, CH(OH)CHMe),
0.93 (3H, d, J¼6.8, CH2CHMe), 0.92 (3H, d, J¼6.8, CH(OH)CHMe),
0.85 (3H, d, J¼6.4, CH2CHMe). 13C NMR (100.6 MHz, CDCl3)
d 215.3,

M. Pellicena et al. / Tetrahedron 68 (2012) 10338e10350
10347
137.3, 128.5, 128.1 (ꢂ2), 83.6, 72.7, 72.1, 41.1, 41.0, 33.1, 24.5, 23.2,
21.6, 18.4, 17.7. HRMS (þESI): MHþ, found 293.2115, C18H29O3 re-
quires 293.2111.
5.07e5.00 (1H, m, CHOH), 4.50 (1H, d, J¼11.6, PhCHxHyO), 4.36 (1H,
d, J¼11.6, PhCHxHyO), 4.03 (1H, dd, J¼7.7, 4.4, CHOBn), 3.21 (1H, d,
J¼3.2, CHOH), 3.01 (1H, dd, J¼14.1, 4.4, PhCHxHy), 2.91 (1H, dd,
J¼14.1, 7.7, PhCHxHy), 2.91 (1H, dd, J¼18.0, 9.4, COCHxHy), 2.76 (1H,
Minor aldol (24a). 1H NMR (400 MHz, CDCl3)
d 4.55 (1H, d,
J¼11.6, PhCHxHy), 2.69 (1H, dd, J¼17.6, 2.4, COCHxHy), 2.57 (1H, dd,
dd, J¼18.0, 3.1, COCHxHy). 13C NMR (100.6 MHz, CDCl3)
d 213.1,
J¼17.6, 9.6, COCHxHy). 13C NMR (100.6 MHz, CDCl3)
d
84.0, 72.8,
142.8, 137.1, 136.6, 129.6, 128.5, 128.4, 127.9, 127.8, 127.6, 126.8,
125.6, 85.5, 72.7, 69.7, 47.3, 38.3. HRMS (þESI): MNHþ4 , found
378.2068, C24H28NO3 requires 378.2064.
72.2, 40.9.
4.6.2. (1S,4S)-4-Benzyloxy-1-hydroxy-6-methyl-1-phenyl-3-
heptanone (23e). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.20. IR
4.6.6. (2S,5S)-2-Benzyloxy-5-hydroxy-6-methyl-1-phenyl-6-hepten-
(film)
n
3465 (br), 3027, 2957, 2929, 2867, 1714, 1556, 1494, 1456,
7.39e7.25
3-one (25f). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.20. IR (film)
1383, 1087, 1051, 1025 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d
n
3475 (br), 3062, 3023, 2916, 2860, 1709, 1648, 1493, 1450, 1081,
(10H, m, ArH), 5.17 (1H, ddd, J¼8.8, 3.6, 3.4, CHOH), 4.57 (1H, d,
J¼11.6, PhCHxHy), 4.35 (1H, d, J¼11.6, PhCHxHy), 3.83 (1H, dd, J¼9.6,
4.4, CHOBn), 3.21 (1H, d, J¼3.4, CHOH), 3.00 (1H, dd, J¼17.8, 8.8,
COCHxHy), 2.91 (1H, dd, J¼17.8, 3.6, COCHxHy), 1.85e1.72 (1H, m,
CHMe2), 1.64e1.54 (1H, m, CHxHyCHMe2), 1.32 (1H, ddd, J¼14.0, 8.6,
4.4, CHxHyCHMe2), 0.90 (3H, d, J¼6.8, CHMe), 0.82 (3H, d, J¼6.4,
1025 cmꢀ1 1H NMR (400 MHz, CDCl3)
.
d
7.34e7.13 (10H, m, ArH),
4.98e4.95 (1H, m, C]CHxHy), 4.85e4.81 (1H, m, C]CHxHy), 4.54
(1H, d, J¼11.6, PhCHxHyO), 4.40 (1H, d, J¼11.6, PhCHxHyO),
4.46e4.37 (1H, m, CHOH), 4.04 (1H, dd, J¼8.0, 4.4, CHOBn), 3.05
(1H, dd, J¼14.0, 4.4, PhCHxHy), 2.93 (1H, dd, J¼14.0, 8.0, PhCHxHy),
2.85 (1H, d, J¼3.2, CHOH), 2.71 (1H, dd, J¼17.8, 9.2, COCHxHy), 2.61
(1H, dd, J¼17.8, 3.2, COCHxHy), 1.66 (3H, br s, MeC]CH2). 13C NMR
CHMe). 13C NMR (75.4 MHz, CDCl3)
d
213.9, 142.9, 137.3, 128.5 (ꢂ2),
128.0 (ꢂ2), 127.7, 125.7, 83.5, 72.6, 69.9, 46.0, 40.8, 24.4, 23.2, 21.6.
Minor aldol (24e). 1H NMR (400 MHz, CDCl3)
5.13 (1H, ddd,
(100.6 MHz, CDCl3)
127.9, 127.8, 126.8, 111.1, 85.5, 72.7, 70.7, 43.9, 38.3, 18.3.
Minor aldol (26f). 1H NMR (400 MHz, CDCl3)
4.99e4.97 (1H, m,
d
213.2, 145.7, 137.1, 136.7, 129.6, 128.4 (ꢂ2),
d
J¼8.8, 3.6, 3.4, CHOH), 4.51 (1H, d, J¼11.6, PhCHxHy), 4.37 (1H, d,
J¼11.6, PhCHxHy), 3.84 (1H, dd, J¼9.6, 4.0, CHOBn), 3.18 (1H, d,
J¼3.4, CHOH), 2.97 (1H, dd, J¼17.6, 8.8, COCHxHy), 2.87 (1H, dd,
J¼17.6, 3.6, COCHxHy), 0.90 (3H, d, J¼6.4, CHMe), 0.82 (3H, d, J¼6.8,
d
C]CHxHy), 4.86e4.84 (1H, m, C]CHxHy), 4.49 (1H, d, J¼11.6,
PhCHxHyO), 4.39 (1H, d, J¼11.6, PhCHxHyO), 2.79 (1H, d, J¼3.2,
CHOH), 1.69 (3H, br s, MeC]CH2).
CHMe). 13C NMR (75.4 MHz, CDCl3)
d 213.8, 127.7, 125.6, 83.8, 72.7,
40.7, 24.4, 23.1, 21.7.
4.6.7. (3S,6S)-3-Benzyloxy-6-hydroxy-2,7-dimethyl-4-octanone
(27a). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.25. IR (film)
(br), 2956, 2930, 2873, 1712, 1468, 1455, 1387, 1091, 1070,
1028 cmꢀ1 1H NMR (400 MHz, CDCl3)
7.40e7.26 (5H, m, ArH),
4.58 (1H, d, J¼11.6, PhCHxHy), 4.40 (1H, d, J¼11.6, PhCHxHy),
3.86e3.73 (1H, m, CHOH), 3.48 (1H, d, J¼6.8, CHOBn), 2.96 (1H, d,
J¼3.4, CHOH), 2.66 (1H, dd, J¼17.9, 3.0, COCHxHy), 2.59 (1H, dd,
J¼17.9, 8.9, COCHxHy), 2.08e1.95 (1H, m, BnOCHCHMe2), 1.76e1.63
(1H, m, CHOHCHMe2), 0.98 (3H, d, J¼6.7, BnOCHCHMe), 0.95 (9H,
m, BnOCHCHMe & CHOHCHMe2). 13C NMR (100.6 MHz, CDCl3)
n 3501
4.6.3. (3S,6S)-6-Benzyloxy-3-hydroxy-2,8-dimethyl-1-nonen-5-one
(23f). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.25. IR (film) 3485
(br), 2955, 2928, 2867, 1715, 1454, 1385, 1367, 1087, 1027 cmꢀ1. 1H
NMR (400 MHz, CDCl3) 7.42e7.26 (5H, m, ArH), 5.03 (1H, br s, C]
n
.
d
d
CHxHy), 4.87 (1H, br s, C]CHxHy), 4.61 (1H, d, J¼11.4, PhCHxHy),
4.55e4.49 (1H, m, CHOH), 4.40 (1H, d, J¼11.4, PhCHxHy), 3.85 (1H,
dd, J¼9.5, 4.4, CHOBn), 2.89 (1H, d, J¼3.2, CHOH), 2.85e2.70 (2H, m,
COCH2), 1.89e1.75 (1H, m, CHMe2), 1.75 (3H, br s, MeC]CH2), 1.62
(1H, ddd, J¼13.9, 9.5, 5.2, CHxHyCHMe2), 1.37 (1H, ddd, J¼13.9, 8.7,
4.4, CHxHyCHMe2), 0.93 (3H, d, J¼6.4, CHMe), 0.85 (3H, d, J¼6.8,
d
215.2, 137.4, 128.4, 128.0 (ꢂ2), 90.3, 73.1, 72.0, 41.8, 33.1, 31.0, 18.8,
18.3, 18.1, 17.7.
CHMe). 13C NMR (75.4 MHz, CDCl3)
d
214.1, 145.8, 137.3, 128.5, 128.1,
Minor aldol (28a). 1H NMR (400 MHz, CDCl3)
d 4.55 (1H, d,
128.0, 111.2, 83.5, 72.6, 71.0, 42.6, 41.0, 24.5, 23.2, 21.6, 18.3.
J¼11.6, PhCHxHy), 3.46 (1H, d, J¼6.8, CHOBn), 2.91 (1H, d, J¼3.4,
CHOH), 2.73 (1H, dd, J¼17.9, 2.0, COCHxHy), 2.48 (1H, dd, J¼17.9, 9.9,
COCHxHy), 0.99 (3H, d, J¼6.6, BnOCHCHMe). 13C NMR (100.6 MHz,
Minor aldol (24f). 1H NMR (400 MHz, CDCl3)
d
4.56 (1H, d, J¼11.6,
PhCHxHy), 3.90 (1H, dd, J¼9.4, 4.2, CHOBn), 2.87 (1H, d, J¼3.2,
CHOH), 1.74 (3H, br s, MeC]CH2). 13C NMR (75.4 MHz, CDCl3)
CDCl3)
d
215.1, 128.5, 128.0 (ꢂ2), 90.8, 73.2, 72.1, 41.7, 33.1, 30.9, 18.6,
d
111.2, 83.9, 72.8, 40.8.
18.2, 17.7.
4.6.4. (2S,5S)-2-Benzyloxy-5-hydroxy-6-methyl-1-phenyl-3-
4.6.8. (1S,4S)-4-Benzyloxy-1-hydroxy-5-methyl-1-phenyl-3-
heptanone (25a). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.20. IR
hexanone (27e). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.20. IR
(film)
n
3498 (br), 3024, 2956, 2926, 2871, 1710, 1492, 1453, 1381,
(film)
n
3467 (br), 2961, 2930, 2899, 2870, 1715, 1496, 1452, 1384,
1086 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d
7.35e7.13 (10H, m, ArH),
1069, 1027 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d
7.40e7.22 (10H, m,
4.53 (1H, d, J¼11.6, PhCHxHyO), 4.40 (1H, d, J¼11.6, PhCHxHyO), 4.03
(1H, dd, J¼8.6, 4.4, CHOBn), 3.78e3.66 (1H, m, CHOH), 3.04 (1H, dd,
J¼14.0, 4.4, PhCHxHy), 2.93 (1H, dd, J¼14.0, 8.6, PhCHxHy), 2.80 (1H,
d, J¼3.6, CHOH), 2.65e2.47 (2H, d, COCH2), 1.69e1.56 (1H, m,
CHMe2), 0.87 (3H, d, J¼6.4, CHMe), 0.84 (3H, d, J¼6.8, CHMe). 13C
ArH), 5.17 (1H, d, J¼8.8, CHOH), 4.58 (1H, d, J¼11.6, PhCHxHy), 4.34
(1H, d, J¼11.6, PhCHxHy), 3.47 (1H, d, J¼6.8, CHOBn), 3.30 (1H, br s,
CHOH), 3.02 (1H, dd, J¼18.0, 9.2, COCHxHy), 2.86 (1H, dd, J¼18.0,
3.0, COCHxHy), 2.06e1.92 (1H, m, CHMe2), 0.96 (3H, d, J¼6.8,
CHMe), 0.88 (3H, d, J¼6.8, CHMe). 13C NMR (100.6 MHz, CDCl3)
NMR (100.6 MHz, CDCl3)
d
214.3, 137.1, 136.8, 129.5, 128.4 (ꢂ2),
d
213.9, 142.9, 137.4, 128.5, 128.4, 127.9 (ꢂ2), 127.7, 125.7, 90.1, 73.0,
127.9, 127.8, 126.7, 85.6, 72.8, 71.9, 42.3, 38.4, 33.0, 18.3, 17.7. HRMS
69.8, 46.8, 31.0, 18.7, 18.1. HRMS (þESI): MNHþ4 , found 330.2066,
(þESI): MNHþ4 , found 344.2221, C21H30NO3 requires 344.2220.
C20H28NO3 requires 330.2064.
Minor aldol (26a). 1H NMR (400 MHz, CDCl3)
d
4.47 (1H, d,
Minor aldol (28e). 1H NMR (400 MHz, CDCl3)
d
4.51 (1H, d, J¼11.6,
J¼11.6, PhCHxHyO), 4.39 (1H, d, J¼11.6, PhCHxHyO), 2.77 (1H, d,
PhCHxHy), 3.23 (1H, br s, CHOH), 0.88 (3H, d, J¼6.8, CHMe). 13C NMR
J¼3.6, CHOH). 13C NMR (100.6 MHz, CDCl3)
d
129.5, 127.9, 85.9, 72.9,
(100.6 MHz, CDCl3) d 127.6, 125.7, 90.5, 73.1, 69.8, 30.8, 18.6, 18.2.
72.1, 42.2, 38.5, 33.1, 18.3.
4.6.9. (3S,6S)-3-Benzyloxy-6-hydroxy-2,7-dimethyl-7-octen-4-one
(27f). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.25. IR (film) 3482
(br), 2961, 2929, 2911, 2872,1710,1454,1386,1071,1027cmꢀ1.1HNMR
(400 MHz, CDCl3) 7.40e7.26 (5H, m, ArH), 5.02 (1H, br s, C]CHxHy),
4.86 (1H, br s, C]CHxHy), 4.63 (1H, d, J¼11.6, PhCHxHy), 4.56e4.44
4.6.5. (1S,4S)-4-Benzyloxy-1-hydroxy-1,5-diphenyl-3-pentanone
(25e). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.15. IR (film) 3464
(br), 3057, 3028, 2862, 1713, 1696, 1650, 1557, 1493, 1455, 1086,
1026 cmꢀ1 1H NMR (400 MHz, CDCl3)
7.40e7.10 (15H, m, ArH),
n
n
d
.
d

10348
M. Pellicena et al. / Tetrahedron 68 (2012) 10338e10350
(1H, m, CHOH), 4.40 (1H, d, J¼11.6, PhCHxHy), 3.49 (1H, d, J¼6.8,
CHOBn), 2.97 (1H, d, J¼3.2, CHOH), 2.80 (1H, dd, J¼18.0, 9.4,
COCHxHy), 2.68 (1H, dd, J¼18.0, 2.8, COCHxHy), 2.10e1.95 (1H, m,
CHMe2), 1.74 (3H, br s, MeC]CH2), 0.98 (3H, d, J¼6.4, CHMe), 0.91
3.96 (1H, q, J¼6.9, CHOBn), 2.83 (1H, dd, J¼17.1, 9.4, COCHxHy), 2.58
(1H, dd, J¼17.1, 3.0, COCHxHy), 1.05 (9H, s, CMe3), 0.91 (3H, d, J¼7.0,
CHMe). 13C NMR (75.4 MHz, CDCl3)
d 213.1, 80.8, 68.7, 67.2, 13.1.
(3H, d, J¼6.8, CHMe).13C NMR (100.6 MHz, CDCl3)
d
214.1, 145.8, 137.4,
4.8. Spectroscopic data for aldols from aldehydes 30 and
ent-30
128.4, 128.0 (ꢂ2), 111.2, 90.2, 73.0, 70.9, 43.4, 31.0, 18.7, 18.3, 18.1.
Minor aldol (28f). 1H NMR (400 MHz, CDCl3)
d
4.56 (1H, d, J¼11.6,
PhCHxHy), 3.48 (1H, d, J¼6.8, CHOBn), 2.91 (1H, d, J¼3.2, CHOH),
4.8.1. (2S,5S,6R)-6-(tert-Butyldiphenylsilyloxy)-5-hydroxy-2-(p-me-
1.73 (3H, br s, MeC]CH2), 0.99 (3H, d, J¼6.4, CHMe). 13C NMR
thoxybenzyloxy)-3-heptanone (37). Colourless oil. Rf (85:15 hex-
(100.6 MHz, CDCl3)
18.3, 18.2.
d
213.9, 128.5, 111.1, 90.6, 73.2, 43.4, 30.8, 18.6,
anes/EtOAc) 0.15. [
a
]
20 ꢀ29.0 (c 1.2, CHCl3, 90% de). IR (film)
n 3521
D
(br), 2934, 1716, 1612, 1427, 1110 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d
7.70e7.66 (4H, m, ArH), 7.44e7.34 (6H, m, ArH), 7.26e7.24 (2H, m,
4.7. Spectroscopic data for aldols from aldehyde 29
ArH), 6.87e6.85 (2H, m, ArH), 4.50 (1H, d, J¼11.3, PhCHxHy), 4.41
(1H, d, J¼11.3, PhCHxHy), 4.05e4.01 (1H, m, CHOH), 3.88 (1H, q,
J¼6.8, CHOPMB), 3.79 (3H, s, MeO), 3.89e3.81 (1H, m, CHOSi),
2.74e2.72 (2H, m, COCH2), 1.28 (3H, d, J¼6.8, MeCHOPMB), 1.07
(9H, s, CMe3), 1.02 (3H, d, J¼6.4, CHMe). 13C NMR (100.6 MHz, CDCl3)
4.7.1. (2S,5S,6S)-7-(tert-Butyldiphenylsilyloxy)-5-hydroxy-2-(p-me-
thoxybenzyloxy)-6-methyl-3-heptanone (31). Colourless oil. Rf
20
(75:25 hexanes/EtOAc) 0.30. [
(film)
1111, 1036 cmꢀ1
a
]
D
ꢀ29.8 (c 1.3, CHCl3, 86% de). IR
n
3507 (br), 3071, 2933, 1716, 1612, 1514, 1391, 1366, 1249,
d 213.0, 159.4, 135.9, 134.2, 133.5, 129.8, 129.7, 129.6, 129.5, 127.7,
.
1H NMR (400 MHz, CDCl3)
d
7.68e7.64 (4H, m,
127.5,113.9, 80.2, 72.1, 71.6, 71.5, 55.3, 39.8, 27.0,19.3,18.3,17.1. HRMS
ArH), 7.45e7.36 (6H, m, ArH), 7.28e7.24 (2H, m, ArH), 6.88e6.85
(2H, m, ArH), 4.51 (1H, d, J¼11.2, PhCHxHy), 4.43 (1H, d, J¼11.2,
PhCHxHy), 4.40e4.30 (1H, m, CHOH), 3.91 (1H, q, J¼6.8, CHOPMB),
3.79 (3H, s, MeO), 3.71 (1H, dd, J¼10.0, 4.7, CHxHyOSi), 3.66 (1H, dd,
J¼10.0, 6.1, CHxHyOSi), 3.05 (1H, br s, CHOH), 2.81 (1H, dd, J¼17.5,
9.2, COCHxHy), 2.67 (1H, dd, J¼17.5, 3.3, COCHxHy), 1.80e1.71 (1H,
m, CHCH2OSi), 1.31 (3H, d, J¼6.8, CHMe), 1.06 (9H, s, CMe3), 0.93
(þFAB): MHþ, found 521.2706, C31H41O5Si requires 521.2723.
4.8.2. (2S,5S,6R)-2-Benzyloxy-6-(tert-butyldiphenylsilyloxy)-5-
hydroxy-3-heptanone (39). Colourless oil. Rf (80:20 hexanes/EtOAc)
20
0.25. [
a
]
ꢀ30.1 (c 1.4, CHCl3, 82% de). IR (film)
n
3511 (br), 2930,
7.69e7.62
D
2852, 1713, 1425, 1106 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d
(4H, m, ArH), 7.44e7.25 (11H, m, ArH), 4.55 (1H, d, J¼11.5, PhCHxHy),
4.47 (1H, d, J¼11.5, PhCHxHy), 4.04e3.99 (1H, m, CHOH), 3.89 (1H, q,
J¼6.8, CHOBn), 3.82 (1H, qd, J¼6.3, 4.0, CHOSi), 2.79e2.61 (2H, m,
COCH2),1.29 (3H, d, J¼6.8, MeCHOBn),1.04 (9H, s, CMe3),1.00 (3H, d,
(3H, d, J¼7.0, CHMe). 13C NMR (100.6 MHz, CDCl3)
d 213.3, 159.4,
135.6, 135.5, 133.3, 133.2, 129.7 (ꢂ2), 129.6, 129.5, 127.7, 113.9, 80.3,
71.5, 68.9, 67.2, 55.3, 41.9, 39.8, 26.9, 19.2, 17.2, 10.9. HRMS (þFAB):
MHþ, found 535.2869, C32H43O5Si requires 535.2880.
J¼6.3, CHMe). 13C NMR (75.4 MHz, CDCl3)
212.8, 137.5, 135.9 (ꢂ2),
d
Minor aldol (32). 1H NMR (400 MHz, CDCl3)
d
3.78 (3H, s, MeO),
134.1, 133.5, 129.8, 129.7, 128.5, 127.9, 127.8, 127.7, 127.5, 80.6, 72.1,
71.8, 71.6, 39.8, 27.0, 19.3, 18.4, 17.1. HRMS (þESI): MNHþ4 , found
508.2867, C30H42NO4Si requires 508.2877.
1.88e1.78 (1H, m, CHCH2OSi), 0.87 (3H, d, J¼7.0, CHMe). 13C NMR
(100.6 MHz, CDCl3)
d 80.4, 71.0, 67.5, 67.1, 42.2, 40.2, 17.1, 13.3.
4.7.2. (2S,5S,6S)-2-Benzyloxy-7-(tert-butyldiphenylsilyloxy)-5-
4.8.3. (2S,5S,6S)-6-(tert-Butyldiphenylsilyloxy)-5-hydroxy-2-(p-me-
hydroxy-6-methyl-3-heptanone (33). Colourless oil. Rf (80:20 hex-
thoxybenzyloxy)-3-heptanone (41). Colourless oil. Rf (80:20 hex-
20
20
anes/EtOAc) 0.25. [
a
]
ꢀ24.5 (c 1.1, CHCl3, 82% de). IR (film)
n
3512
1H NMR (400 MHz,
7.70e7.64 (4H, m, ArH), 7.46e7.26 (11H, m, ArH), 4.59 (1H, d,
anes/EtOAc) 0.15. [
a
]
ꢀ40.0 (c 1.0, CHCl3). IR (film)
n
3500 (br),
1H NMR
d 7.70e7.62 (4H, m, ArH), 7.47e7.32 (6H, m, ArH),
D
D
(br), 2928, 1715, 1469, 1452, 1427, 1109 cmꢀ1
CDCl3)
.
2928, 2853, 1715, 1614, 1512, 1250, 1109, 1032 cmꢀ1
(400 MHz, CDCl3)
.
d
J¼11.6, PhCHxHy), 4.50 (1H, d, J¼11.6, PhCHxHy), 4.39e4.31 (1H, m,
CHOH), 3.93 (1H, q, J¼6.8, CHOBn), 3.70 (1H, dd, J¼10.2, 4.8,
CHxHyOSi), 3.66 (1H, dd, J¼10.2, 6.2, CHxHyOSi), 3.08 (1H, br s, CHOH),
2.82 (1H, dd, J¼17.4, 9.3, COCHxHy), 2.68 (1H, dd, J¼17.4, 3.2,
COCHxHy), 1.81e1.71 (1H, m, CHCH2OSi), 1.34 (3H, d, J¼6.8, CHMe),
1.05 (9H, s, CMe3), 0.92 (3H, d, J¼7.0, CHMe). 13C NMR (75.4 MHz,
7.29e7.22 (2H, m, ArH), 6.91e6.83 (2H, m, ArH), 4.49 (1H, d, J¼11.2,
PhCHxHy), 4.41 (1H, d, J¼11.2, PhCHxHy), 4.05e3.95 (1H, m, CHOH),
3.90 (1H, q, J¼6.8, CHOPMB), 3.87e3.81 (1H, m, CHOSi), 3.80 (3H, s,
MeO), 2.76e2.70 (2H, d, COCH2), 1.29 (3H, d, J¼6.8, MeCHOPMB),
1.05 (9H, s, CMe3), 1.04 (3H, d, J¼6.8, CHMe). 13C NMR (75.4 MHz,
CDCl3)
d
213.0, 159.4, 135.8 (ꢂ2), 134.0, 133.4, 129.8, 129.7, 129.6,
CDCl3)
d
213.2,137.5,135.6 (ꢂ2),133.3,133.2,129.8,129.7,128.5,127.9,
129.5, 127.7, 127.5, 113.9, 80.4, 71.7, 71.5, 71.2, 55.3, 39.9, 27.0, 19.3,
18.6, 17.2. HRMS (þESI): MNaþ, found 543.2528, C31H40O5NaSi re-
quires 543.2537.
127.8, 127.7 (ꢂ2), 80.6, 71.9, 69.0, 67.3, 42.0, 39.8, 26.9, 19.2, 17.2, 11.0.
HRMS (þESI): MHþ, found: 505.2772, C31H41O4Si requires 505.2768.
Minor aldol (34). 1H NMR (400 MHz, CDCl3)
d
3.98 (1H, q, J¼6.9,
CHOBn), 2.65 (1H, dd, J¼16.8, 2.8, COCHxHy). 13C NMR (75.4 MHz,
4.8.4. (2S,5S,6S)-2-Benzyloxy-6-(tert-butyldiphenylsilyloxy)-5-
CDCl3)
d
80.6, 71.0, 42.1, 40.1.
hydroxy-3-heptanone (42). Colourless oil. Rf (80:20 hexanes/EtOAc)
0.20. [
a]
20 ꢀ41.9 (c 1.1, CHCl3). IR (film)
n
3504 (br), 2923, 2851,1710,
7.69e7.63 (4H, m,
D
4.7.3. (2R,5R,6S)-2-Benzyloxy-7-(tert-butyldiphenylsilyloxy)-5-
1420, 1108 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d
hydroxy-6-methyl-3-heptanone (35). Colourless oil. Rf (80:20 hex-
ArH), 7.46e7.27 (11H, m, ArH), 4.57 (1H, d, J¼11.6, PhCHxHy), 4.48
(1H, d, J¼11.6, PhCHxHy), 4.04e3.96 (1H, m, CHOH), 3.92 (1H, q,
J¼6.8, CHOBn), 3.83 (1H, qd, J¼6.0, 4.8, CHOSi), 2.82e2.68 (3H, m,
COCH2 & CHOH), 1.32 (3H, d, J¼6.8, MeCHOBn), 1.05 (9H, s, CMe3),
anes/EtOAc) 0.25. IR (film)
n
3499 (br), 2929, 1715, 1472, 1454, 1424,
7.71e7.62 (4H, m, ArH),
1106 cmꢀ1 1H NMR (400 MHz, CDCl3)
.
d
7.47e7.26 (11H, m, ArH), 4.61 (1H, d, J¼11.7, PhCHxHy), 4.50 (1H, d,
J¼11.7, PhCHxHy), 4.20e4.12 (1H, m, CHOH), 3.96 (1H, q, J¼6.8,
CHOBn), 3.73 (1H, dd, J¼10.3, 4.8, CHxHyOSi), 3.66 (1H, dd, J¼10.3,
6.6, CHxHyOSi), 3.55 (1H, d, J¼3.2, CHOH), 2.79e2.75 (2H, m,
COCH2), 1.91e1.79 (1H, m, CHCH2OSi), 1.34 (3H, d, J¼6.8, CHMe),
1.05 (9H, s, CMe3), 0.87 (3H, d, J¼6.9, CHMe). 13C NMR (75.4 MHz,
1.04 (3H, d, J¼6.0, MeCH). 13C NMR (75.4 MHz, CDCl3)
d 212.9, 137.5,
135.9, 135.8, 134.0, 133.4, 129.8, 129.7, 128.5, 127.9, 127.8, 127.7,
127.6, 80.7, 71.8, 71.7, 71.2, 40.0, 27.0, 19.3, 18.7, 17.2. HRMS (þESI):
2MNaþ, found 1003.4963, C60H76O8NaSi2 requires 1003.4970.
CDCl3)
d
213.3,137.6,135.6,133.2,129.7,128.5,127.8,127.7, 80.7, 71.8,
4.9. Synthesis of lactones 45 and 48
70.8, 67.2, 42.1, 40.2, 26.8, 19.2, 17.2, 13.2.
Minor aldol (36). 1H NMR (400 MHz, CDCl3)
PhCHxHy), 4.50 (1H, d, J¼11.8, PhCHxHy), 4.35e4.28 (1H, m, CHOH),
d
4.56 (1H, d, J¼11.8,
4.9.1. (3S,4R)-3-Hydroxy-4-methyl-
procedure described for the synthesis of 22 was applied to 39
g-butyrolactone (45). Experimental

M. Pellicena et al. / Tetrahedron 68 (2012) 10338e10350
10349
(243 mg, 0.50 mmol, dr 91:9) to afford 159 mg (0.43 mmol) of 44
as a brownish oil, which was used in the next step without further
purification. A 48% aqueous solution of HF (0.15 mL, 4.3 mmol) was
added dropwise to a solution of 44 in CH3CN (4.0 mL) at rt. The reaction
mixture was stirred for 24 h and diluted with CH2Cl2 (30 mL). Then
2 M HCl was slowly added to reach pH 1 and the mixture was
concentrated. It was treated again with CH2Cl2, dried (MgSO4) and
further concentrated. The resulting brownish oil was purified by
column chromatography (hexanes/EtOAc from 65:35 to 35:65) to
afford 20 mg (40% overall yield) of 45 (dr 91:9) as a colourless oil. Rf
chromatography (95:5 hexanes/EtOAc) afforded 54 mg (82% yield)
of 50 as a colourless oil. Rf (95:5 hexanes/EtOAc) 0.15. [
2.1, CHCl3). IR (film)
1252, 1111 cmꢀ1 1H NMR (300 MHz, CDCl3)
a
]
20 ꢀ8.2 (c
D
n
2988, 2960, 2931, 2891, 2854,1514,1427,1375,
.
d
7.76e7.66 (4H, m,
ArH), 7.47e7.31 (6H, m, ArH), 7.31e7.22 (2H, m, ArH), 6.92e6.83
(2H, m, ArH), 4.57 (1H, d, J¼11.4, PhCHxHy), 4.47 (1H, d, J¼11.4,
PhCHxHy), 3.89e3.78 (1H, m, CHOSi), 3.80 (3H, s, MeO), 3.79e3.63
(2H, m, 2ꢂ CHOH), 3.39 (1H, p, J¼6.2, CHOPMB), 1.69 (1H, dt, J¼12.7,
2.4, CHeqHax), 1.29e1.13 (1H, m, CHeqHax), 1.31 (3H, s, MeCO2), 1.29
(3H, s, MeCO2), 1.18 (3H, d, J¼6.2, MeCHOPMB), 1.08 (9H, s, CMe3),
(50:50 hexanes/EtOAc) 0.10. [
a
]
20 þ10.3 (c 0.9, CHCl3, 82% de) [lit.30
[
a
]
1.04 (3H, d, J¼6.4, MeCHOSi). 13C NMR (75.4 MHz, CDCl3)
d 159.1,
D
D
þ10.87 (c 2.42, CHCl3); lit.30
[a
]D þ10.0 (c 1.59, CHCl3); lit.30
[
a
]
25 þ10.91
136.0 (ꢂ2), 134.6, 134.5, 130.9, 129.4 (ꢂ2), 129.3, 127.4, 127.3, 113.7,
98.4, 77.3, 72.8, 72.4, 71.5, 71.1, 55.2, 29.9, 27.3, 27.0, 19.5 (ꢂ2), 18.0,
16.2. HRMS (þESI): MNH4þ, found 580.3433, C34H50O5NSi requires
580.3452.
D
(c 1.27, CHCl3)]. IR (film)
n
3429 (br), 1766, 1173, 1052 cmꢀ1. 1H NMR
(300 MHz, CDCl3)
d
4.50 (1H, qd, J¼6.6, 3.1, MeCH), 4.25 (1H, ddd, J¼6.6,
3.9, 3.1, CHOH), 2.86 (1H, dd, J¼17.9, 6.6, COCHxHy), 2.52 (1H, dd, J¼17.9,
3.9, COCHxHy), 1.38 (3H, d, J¼6.6, Me). 13C NMR (75.4 MHz, CDCl3)
d
175.0, 83.9, 72.9, 37.4, 18.5.
Acknowledgements
4.9.2. (3S,4S)-3-Hydroxy-4-methyl-g-butyrolactone (48). Experimental
Financial support from the Spanish Ministerio de Ciencia e
procedure described for the synthesis of 45 was applied to 42
(347 mg, 0.71 mmol) to afford 41 mg (50% overall yield) of 48
ꢁ
Innovacion (MICINN), Fondos FEDER (Grant No. CTQ2009-09692),
and the Generalitat de Catalunya (2009SGR825) as well as doctor-
as a colourless oil. Rf (50:50 hexanes/EtOAc) 0.10. [a D20
]
ꢀ72.4 (c 0.5,
ꢁ
ate studentships to M.P. and J.G.S. (Ministerio de Educacion and
CHCl3) [lit.31
1766, 1167, 1054 cmꢀ1
[
a
]
D
ꢀ60.0 (c 1.57, CHCl3, 78% ee)]. IR (film)
n
3432 (br),
25
Universitat de Barcelona, respectively) are acknowledged.
.
1H NMR (300 MHz, CDCl3)
d 4.58 (1H,
qd, J¼6.5, 3.7, MeCH), 4.24 (1H, ddd, J¼5.6, 3.7, 1.2, CHOH), 2.81 (1H,
dd, J¼17.7, 5.6, COCHxHy), 2.57 (1H, dd, J¼17.7, 1.2, COCHxHy), 1.44
References and notes
(3H, d, J¼6.5, Me). 13C NMR (75.4 MHz, CDCl3)
d 176.6, 81.1, 69.4,
1. (a) Braun, M. In Houben-Weyl; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Thieme: Stuttgart, 1995; Vol. E21b, p 1603; (b) Cowden,
C. J.; Paterson, I. Org. React. 1997, 51, 1; (c) Palomo, C.; Oiarbide, M.; García, J.
M. Chem.dEur. J. 2002, 8, 36; (d) Palomo, C.; Oiarbide, M.; García, J. M. Chem.
Soc. Rev. 2004, 33, 65; (e) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-
VCH: Weinheim, 2004; (f) Geary, L. M.; Hultin, P. G. Tetrahedron: Asymmetry
2009, 20, 131.
39.3, 13.6.
4.10. Synthesis of C12eC16 fragment of epothilone B
4.10.1. (2S,3S,5R,6S)-2-(tert-Butyldiphenylsilyloxy)-6-(p-methox-
ybenzyloxy)-3,5-heptanediol (49). 1.0 M solution of DIBALH in
2. (a) Yeung, K.-S.; Paterson, I. Angew. Chem., Int. Ed. 2002, 41, 4632; (b) Yeung, K.-S.;
hexanes (450 mL, 0.45 mmol) was added dropwise to a solution of
Paterson, I. Chem. Rev. 2005, 105, 4237; (c) Schetter, B.; Mahrwald, R. Angew.
Chem., Int. Ed. 2006, 45, 7506; (d) Brodmann, T.; Lorenz, M.; Schackel, R.; Simsek,
€
37 (82 mg, 0.16 mmol) in THF (3.2 mL) at ꢀ78 ꢁC under N2. The
reaction mixture was stirred at ꢀ78 ꢁC for 2 h, quenched by a slow
addition of MeOH (0.25 mL) and vigorously stirred for 10 min
at ꢀ78 ꢁC. Then a 1 M solution of sodium potassium tartrate (3 mL)
was added followed by vigorous stirring at rt for 30 min. It was
diluted with H2O (15 mL), the layers were separated and the
aqueous layer was extracted with EtOAc (3ꢂ15 mL). The combined
organic extracts were washed with brine, dried (MgSO4) and con-
centrated. 1H NMR analysis of the resulting oil showed the presence
of 49 as a 88:12 mixture of diastereomers, which were separated by
column chromatography (75:25 hexanes/EtOAc) to obtain 64 mg
S.; Kalesse, M. Synlett 2009, 174; (e) Li, J.; Menche, D. Synthesis 2009, 2293.
3. The term acetate aldol reaction refers to any aldol transformation involving
unsubstituted enolates, which encompasses the reactions of acetate esters,
other carboxylic derivatives and methyl ketones.
ꢁ
ꢁ
4. (a) Pellissier, H. Tetrahedron 2007, 63, 9267; (b) Guillena, C.; Najera, C.; Ramon,
D. J. Tetrahedron: Asymmetry 2007, 18, 2249; (c) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (d) Trost, B. M.; Brindle, C. S.
Chem. Soc. Rev. 2010, 39, 1600; (e) Kumagai, N.; Shibasaki, M. Angew. Chem., Int.
Ed. 2011, 50, 4760.
5. For recent advances in chiral auxiliaries-based acetate aldol reactions, see:
Khatik, G. L.; Kumar, V.; Nair, V. A. Org. Lett. 2012, 14, 2442 and references
therein.
6. For examples illustrating the complexity of acetate aldol reactions, see: (a)
Paterson, I.; Findlay, A. D.; Anderson, E. A. Angew. Chem., Int. Ed. 2007, 46, 6699;
(78% yield) of diastereomerically pure 49 as a colourless oil. Rf
€
ꢁ
(b) Furstner, A.; Bouchez, L. C.; Funel, J.-A.; Liepins, V.; Poree, F.-H.; Gilmour, R.;
Beaufils, F.; Laurich, D.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46, 9265; (c)
Lorenz, M.; Kalesse, M. Org. Lett. 2008, 10, 4371; (d) Paterson, I.; Findlay, A. D.;
20
(75:25 hexanes/EtOAc) 0.15. [
a
]
D
ꢀ3.4 (c 0.9, CHCl3). IR (film)
n
3417 (br), 2957, 2926, 2888, 2854,1614,1513,1469, 1456,1425,1247,
ꢁ
ꢁ
Noti, C. Chem.dAsian J. 2009, 4, 594; (e) Guerinot, A.; Lepesqueux, G.; Sable, S.;
Reymond, S.; Cossy, J. J. Org. Chem. 2010, 75, 5151; (f) Dieckmann, M.;
Kretschmer, M.; Li, P.; Rudolph, S.; Herkommer, D.; Menche, D. Angew. Chem.,
Int. Ed. 2012, 51, 5667.
1107, 1081, 1035 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
7.76e7.62 (4H,
m, ArH), 7.48e7.31 (6H, m, ArH), 7.28e7.18 (2H, m, ArH), 6.92e6.82
(2H, m, ArH), 4.54 (1H, d, J¼11.2, PhCHxHy), 4.42 (1H, d, J¼11.2,
PhCHxHy), 3.90e3.73 (2H, m, 2ꢂ CHOH), 3.78 (3H, s, MeO),
3.73e3.62 (1H, m, CHOSi), 3.43 (1H, qd, J¼6.3, 4.5, CHOPMB), 3.30
(2H, br s, 2ꢂ OH), 1.75 (1H, dt, J¼14.3, 2.4, CHxHy), 1.46 (1H, dt,
J¼14.3, 10.0, CHxHy), 1.17 (3H, d, J¼6.3, MeCHOPMB), 1.06 (9H, s,
7. (a) Gennari, C. In Comprehensive Organic Synthesis Series; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1992; Vol. 2, pp 629e660; (b) Nelson, S. G. Tetrahedron:
Asymmetry 1998, 9, 357; (c) Mahrwald, R. Chem. Rev.1999, 99,1095; (d) Carreira, E.
M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin,1999; Vol. 3, p 996; (e) Carreira, E. M.; Fettes, A.; Marti, C. Org.
React. 2006, 67, 1.
8. The term metal enolate is used in a broad sense. It refers to enolates from alkaline,
boron, titanium, tin and other elements that participate in aldol reactions pro-
ceeding through cyclic transition states.
CMe3), 1.02 (3H, d, J¼6.2, MeCH). 13C NMR (75.4 MHz, CDCl3)
d 159.1,
135.8 (ꢂ2), 134.0, 133.5, 130.6, 129.8, 129.7, 129.2, 127.7, 127.5, 113.8,
77.4, 76.4, 74.4, 72.5, 70.6, 55.2, 33.5, 27.0, 19.3, 18.7, 14.6. HRMS
(þESI): 2MNaþ, found 1067.5501, C62H84O10NaSi2 requires
1067.5495.
9. For a recent review, see: Ariza, X.; Garcia, J.; Romea, P.; Urpí, F. Synthesis 2011,
2175.
10. For studies on stereoselective aldol reactions from
a-hydroxy methyl
ketones, see: (a) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.;
Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540; (b) Palomo, C.;
Oiarbide, M.; Aizpurua, J. M.; Gonzalez, A.; García, J. M.; Landa, C.; Odrio-
4.10.2. (2S,3R,5S,6S)-6-(tert-Butyldiphenylsilyloxy)-3,5-O-iso-
propylidene-2-(p-methoxybenzyloxy)-3,5-heptanediol (50). A solu-
tion of 49 (61 mg, 0.12 mmol) and PPTS (cat.) in 1:1
Me2C(OMe)2/CH2Cl2 (1.2 mL) was stirred at rt overnight. Removal
of the volatiles and purification of the residue by column
ꢁ
zola, I.; Linden, A. J. Org. Chem. 1999, 64, 8193; (c) Denmark, S. E.; Stavenger,
€
R. A. J. Am. Chem. Soc. 2000, 122, 8837; (d) Furstner, A.; Kattnig, E.; Lepage,
O. J. Am. Chem. Soc. 2006, 128, 9194; (e) Lorenz, M.; Bluhm, N.; Kalesse, M.
Synthesis 2009, 3061; (f) Lorente, A.; Pellicena, M.; Romea, P.; Urpí, F. Tet-
rahedron Lett. 2010, 51, 942.

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11. (a) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Org. Chem. 1990, 55, 481; (b)
Goodman, J. M.; Kahn, S. D.; Paterson, I. J. Org. Chem. 1990, 55, 3295; (c)
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€
Romea, P.; Urpí, F. Org. Lett. 2003, 5, 4681; (b) Pellicena, M.; Kramer, K.; Romea,
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pentanone to
a
-hydroxy aldehydes also unveiled their remarkable Cornforth
ꢁ
p-facial selectivity, see: Esteve, C.; Ferrero, M.; Romea, P.; Urpí, F.; Vilarrasa, J.
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b
-benzyloxy methyl ketones, see: Zambrana, J.; Romea,
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ꢁ
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ꢁ
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ꢁ
18. Esteve, J.; Jimenez, C.; Nebot, J.; Velasco, J.; Romea, P.; Urpí, F. Tetrahedron 2011,
€
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€
20. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127; (b) Yan, T.
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