Solvent- and structure-dependent regioselectivity in the boron-mediated aldol reaction of 2-(1,3-dioxolan-2-yl)ethyl ethyl ketones

Article abstract of DOI:10.1002/ejoc.200700320

The regioselectivity of the Chx₂BCl/Et₃N-mediated (Chx = cyclohexyl) aldol reactions of ketones of general structure 2 has been studied and was shown to depend on both ketone structure and solvent. Useful levels of regioselectivity in favour of any of the two possible regioisomers were obtained in either pentane or diethyl ether. The relative configuration of the aldol products was assigned by ¹H NMR studies of six-membered-ring derivatives. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700320

FULL PAPER
DOI: 10.1002/ejoc.200700320
Solvent- and Structure-Dependent Regioselectivity in the Boron-Mediated Aldol
Reaction of 2-(1,3-Dioxolan-2-yl)ethyl Ethyl Ketones
Steve Lanners,[a] Hassan Norouzi-Arasi,[a] Naima Khiri,[a] and Gilles Hanquet*[a]
Keywords: Aldol reactions / Boron / Regioselectivity / Ketones / Solvent effects
The regioselectivity of the Chx2BCl/Et3N-mediated (Chx =
cyclohexyl) aldol reactions of ketones of general structure 2
has been studied and was shown to depend on both ketone
structure and solvent. Useful levels of regioselectivity in fav-
our of any of the two possible regioisomers were obtained in
either pentane or diethyl ether. The relative configuration of
the aldol products was assigned by 1H NMR studies of six-
membered-ring derivatives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
During our synthetic studies on Pamamycin-607 (1)[1–3]
we became interested in the study of ketone 2a as a possible
precursor of the C(1)–C(18) fragment (3) of Pamamycin-
607, by an aldol reaction with the C(8)–C(18) fragment al-
dehyde 4.[1] The desired aldol product 5 possesses a 2,3-anti-
3,4-syn relationship between the newly formed stereogenic
centres (Scheme 1).
This relative configuration arises from a Felkin–Anh[4–5]
addition of the (E)-enolate of ketone 2a to α-chiral aldehyde
4. While some methods for the generation of lithium (E)-
enolates are reported in the literature, they involve the use
of strongly basic hindered lithium amides, and the lithium
enolates generated by these methods often display moderate
π-facial selectivities. On the other hand, boron enolates are
known to react with high π-facial selectivities. Furthermore,
the use of the Chx2BCl/Et3N (Chx = cyclohexyl) system
developed by Brown,[6–7] which has been widely used in nat-
ural product synthesis,[8] is known to afford excellent (E)
selectivity in the enolisation step. Furthermore, boron (E)-
enolates display very high Felkin–Anh selectivity [in con-
trast with their (Z) isomers which lead to anti-Felkin–Anh
products].[9] We thus decided to use the Chx2BCl/Et3N sys-
tem for our synthetic purposes.
We reasoned that, in addition to the diastereoselectivity
issues mentioned above, the substitution pattern of ketone
2a might give rise to the formation of two regioisomeric
enolates. Indeed, high to total regioselectivities are reported
in the literature for the enolisation of α- or β-branched ethyl
ketones, but little was known about ethyl ketones with more
remote functionality (γ functionalisation in our case).
Scheme 1. Retrosynthetic analysis of Pamamycin-607.
In order to examine the behaviour of ketone 2a during
enolisation and subsequent aldol reaction, we decided to
use aldehyde (R)-6 as a model for the C(8)–C(18) aldehyde
4 (Figure 1).
[a] Laboratoire de Stéréochimie associé au CNRS, ECPM, Uni-
versité Louis Pasteur,
25 rue Becquerel, 67087 Strasbourg, France
Fax: +33-3-90242742
E-mail: ghanquet@chimie.u-strasbg.fr
Figure 1. Choice of the model aldehyde.
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Indeed, (R)-6 bears the same α-methyl group and Lewis- dation in the last step was more convenient and reliable in
basic β-oxygen substitution pattern as aldehyde 4 and seems our hands than the Swern oxidation used in previous syn-
to be an ideal model to verify π-facial selectivity. Alterna- theses of (R)-6.[11] The resulting crude aldehyde was used
tively, the use of racemic aldehyde (Ϯ)-6 was sufficient in in the aldol reaction without further purification to avoid
many cases.
racemisation.
We describe the synthesis of ketone 2a (Figure 2) and its
analogues 2b–d, and their behaviour in the boron-mediated
aldol reaction with model aldehydes (R)-6 or (Ϯ)-6.
Scheme 2. Preparation of model aldehyde (R)-6.
The racemic aldehyde was easily prepared on
a
Figure 2. Structures of the studied ethyl ketones.
multigram scale from commercially available diol 10 by sil-
ver(I)-mediated monobenzylation[12] followed by a Parikh–
Doering oxidation (Scheme 3).
Results and Discussion
While one possible approach to ketone 2a relied on the
The chiral nonracemic aldehyde (R)-6 was available in ring opening of γ-caprolactone,[13] the most reliable and
three steps from commercially available methyl (R)-3-hy- scalable synthesis of 2a proved to be a 5-step procedure
droxy-2-methylpropionate (7) according to literature pro- starting from commercially available 4-pentenoic acid
cedures (Scheme 2). The use of the Parikh–Doering[10] oxi- (Scheme 4). Ketones 2c and 2d were prepared using the
Scheme 3. Preparation of model aldehyde (Ϯ)-6.
Scheme 4. Preparation of ketones 2a, 2c and 2d.
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Boron-Mediated Aldol Reaction of 2-(1,3-Dioxolan-2-yl)ethyl Ethyl Ketones
FULL PAPER
same sequence. The starting 4-pentenoic acid was converted stereomers. At this stage, the use of the lithium enolate of
into the corresponding N-acylimidazole which was treated ketone 2a was investigated. However, the use of a strong
in situ with the lithium enolate of tert-butyl propionate, amide base (LiTMP) led to the decomposition of the ketone
tert-butyl acetate or tert-butyl butyrate to afford β-keto es- by a competing deprotonation α to the ester group followed
ters 14a,c,d in good yield. Alternatively, β-keto esters by ring opening of the dioxolane. On the other hand, the
14a,c,d were also available from diethyl malonate and allyl use of the milder base LiHMDS led to the same side reac-
bromide[14] through ester 13.[15] The ketone group was then tion, albeit to a lesser extent. In view of these results, the
protected as a dioxolane in compounds 15a,c,d and the use of lithium enolates was abandoned.
double bond was oxidised with mCPBA to afford epoxides
The relative configuration of the desired aldol product
16a,c,d. The secondary alcohols 17a,c,d were obtained by 22a has subsequently been ascertained by the debenzylation
opening of the epoxide using lithium dimethylcuprate, and of 22a using hydrogen gas and Pd/C in methanol
subsequent oxidation afforded ketones 2a,c,d in an overall (Scheme 7).
yield of 49–67%.
Ketone 2b was obtained in good overall yields from 5-
hexen-2-one as illustrated in Scheme 5.
Scheme 7. Formation of ketal 23a.
1
The H NMR spectroscopic data of the cyclic ketal 23a
are in good agreement with those of a similar compound
of the same relative configuration described by Gennari et
al.[16] Furthermore, the selective decoupling and NOESY
experiments are in agreement with the 2,3-anti-3,4-syn rela-
tive configuration in a chair configuration, as depicted in
Figure 3.
Scheme 5. Preparation of ketone 2b.
With ketones 2a–d and model aldehydes (Ϯ)-6 and (R)-
6 in hand, we embarked on the study of the aldol reaction.
Our first attempts using ketone 2a employed the optimised
conditions described by Brown;[6–7] the highest (E) selectiv-
ity during enolisation was obtained by using nonpolar sol-
vents (of which pentane proved to be the best) at low con-
centrations (ideally 0.05 ). When ketone 2a was enolised
in pentane at 0 °C and subsequently treated with (R)-6 at
–78 °C, our first runs consistently afforded a mixture of two
regioisomeric products in a combined yield of 65%. Sur-
prisingly, aldol product 21a, arising from the internal en-
olisation of 2a, appeared to be the major product (21a/22a
was approximately 4:1). On the other hand, when the en-
olisation and aldol reaction were conducted at the same
temperatures and concentrations in diethyl ether, we were
delighted to find that aldol product 22a, arising from the
enolisation of the ethyl group, was the major product (21a/
22a = 3:1 in a combined yield of 78%, Scheme 6). Both
aldol products 21a and 22a were isolated as pure dia-
Figure 3. Characteristic NMR spectroscopic data for ketal 23a.
Unfortunately, the determination of the relative configu-
ration of regioisomer 21a failed as its derivatization to cy-
clic compounds (i.e. the acetonide or cyclic ketal) was
impossible in our hands. The Prasad–Narasaka re-
duction,[17–20] or catecholborane[21] reduction, which should
give the corresponding 1,3-syn-diol, were ineffective.
Access to 1,3-anti-diol using Evans–Carreira[22] or Evans–
Tishchenko[23] conditions was also denied.
In order to examine the influence of the structure of the
ketone, we extended the study to ketones 2a, 2b, 2c and 2d
using the same reaction conditions described before. The
use of isobutyraldehyde as the electrophile resulted in a sig-
1
nificant simplification of the H NMR signals and allowed
Scheme 6. Aldol reaction of ketone 2a with aldehyde (R)-6 (Chx =
cyclohexyl).
a determination of the regioisomer ratios (24/25) by 1H
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NMR spectroscopy of the crude reaction mixture. The cor- those of isolated and fully characterised 24b,c and 25b,c. In
responding results are summarised in Table 1. contrast with aldol products 21a, 24b–d and 25b–d could
In this simplified case, the simple diastereoselectivity of now be smoothly reduced to the corresponding 1,3-syn-di-
the aldol reaction seemed slightly reduced, and small ols. Whereas 21a required the use of catecholborane,[21]
amounts of compounds assigned as diastereomers of each 24b–d and 25b–d reacted smoothly under Narasaka–Prasad
regioisomer could be detected in most reaction mixtures. In conditions[17–20] (Scheme 8). In both cases, the correspond-
this case, the use of more polar solvents (MTBE, DME, ing acetonides 26b–d and 27b–d were obtained using stan-
or THF) was also examined, but generally resulted in the dard reaction conditions.
complete loss of regio- and diastereoselectivity, and the lat-
The relative configuration of the cyclic derivatives can be
1
ter solvents were considered unsuitable. However, the major determined by H NMR spectroscopy. For all compounds
diastereomers of compounds 24b–d and 25b–d could be iso- 26b–d and 27b–d, the signal of the proton in position 5 of
lated. We did not succeed in the separation of 24a and 25a the dioxane ring is split by the coupling with two other
as pure samples; nevertheless, the regio- and diastereomeric protons, giving coupling constants of 11–12 Hz each. These
1
ratio was determined from characteristic signals in the H compounds are known to exist predominantly in a chair
NMR spectra (CH-OH, and CH2-H) by comparison with conformation which explains the characteristic 13C chemi-
Table 1. Boron-mediated aldol reaction of ketones 2a–d with isobutyraldehyde.[a]
Entry
Ketone
R
Solvent
Relative amount
Regioisomer 24
Regioisomer 25
syn[b]
anti
syn[b]
anti
1
2
3
4
5
6
7
8
2a
2a
2b
2b
2c
2c
2d
2d
Me
Me
–
–
H
H
Et
Et
pentane
diethyl ether
pentane
diethyl ether
pentane
diethyl ether
pentane
diethyl ether
7
4
8
6
0
0
6
4
63
25
38
34
69
46
35
18
10
12
11
12
0
8
15
16
20
59
43
48
31
46
44
62
[a] A solution of the ketone was added to a mixture of borane and triethylamine at 0 °C, followed by cooling to –78 °C and the addition
of the aldehyde (0.33 equiv.). [b] The diastereomeric ratios were determined by integration of characteristic signals of the 1H NMR spectra
of the crude reaction mixtures.
Scheme 8. syn-Selective reduction and acetonide formation.
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Boron-Mediated Aldol Reaction of 2-(1,3-Dioxolan-2-yl)ethyl Ethyl Ketones
FULL PAPER
cal shift of the acetonide methyl groups.[24,25] Assuming this
chair conformation, the splitting of the signal of the proton
in position 5 is consistent with an axial position and two
axial-axial couplings with the protons in positions 4 and 6
on the ring. This allows us to assign a 2,3-anti relationship
to all the major aldol products 24b–d and 25b–d. Thus, the
simple diastereoselectivity of the aldol reaction was not al-
tered by changing the solvent, allowing the assumption that
This surprising solvent effect, by which the intrinsic regio-
chemical preference of a ketone for enolisation is inverted,
is, to the best of our knowledge, unprecedented in the litera-
ture. While a strong influence of remote substitution on al-
dol regioselectivity has been mentioned in one example by
Heathcock,[26] we found no reports on relevant changes of
regioselectivity in different solvents.
The regio- and stereoselectivity observed during the for-
the (E)-enol borinate was formed predominantly in all the mation of enol borinates is commonly rationalised by the
reactions.
model proposed by Paterson and Goodman.[27] This model
The regioselectivities observed with ketone 2d (Table 1, is based on the conformational preference of the ketone–
Entries 5 and 6) confirmed the surprising solvent effect pre- borane adduct, governed by a strong anomeric effect and
viously described with ketone 2a (Scheme 6 and Table 1, the ability of the α-carbon atom to stabilise a negative
Entries 1 and 2). This effect was clearly structure-depend- charge. For the ketones examined in our study, we reckoned
ent. Ketone 2b which was not substituted with a propionate that there should be no significant difference in the ability
or a butyrate unit gave similar ratios of regioisomers 24b of either α position to stabilise a negative charge. However,
and 25b in either solvent (Table 1, Entries 3 and 4). An ace- steric interactions based on the remote substitution should
tate substituent α to the dioxolane (ketone 2c) led to a favour complexation of the borane on the least-hindered
stronger preference for regioisomer 24c when the aldolis- side and thus trigger deprotonation of the ethyl substituent.
ation was performed in pentane (Table 1, Entry 5). This This seems to apply only to the simplest substrate, ketone
preference dropped significantly in diethyl ether (Table 1, 2b, which shows a slight preference for enolate formation
Entry 6).
on the least-hindered side in all cases. In the case of the
Finally, we confirmed these results by performing the al- more complex substrates (ketones 2a, 2c and 2d) and in
dolisation between the racemic aldehyde (Ϯ)-6 and ketone pentane, the deprotonation of the internal position is fav-
2b or 2d (Table 2).
oured. As in all cases the (E)-enol borinate is still formed
The 2,3-anti-3,4-syn relative configuration of aldol 22d selectively; we assume that the Paterson–Goodman model
was confirmed by the preparation of the corresponding cy- is still applicable, but that the complexation of the borane
clic ketal 23d using the previously described conditions takes place preferentially on the internal position. This pref-
(Scheme 7 and Figure 3).
erence is unlikely to be governed by steric factors, but could
These results are in agreement with those observed in be controlled by dipole interactions which are in turn, of
Table 1 and confirm the solvent effect on the regioselectivity course, determined by the orientation of the dioxolane and
of the reaction. The more bulky ethyl group of ketone 2d ester substituents (i.e. the conformation of the ketone sub-
compared to the methyl group in 2a increases slightly the strate). We propose that it is the change of this conforma-
regioselectivity of the aldol reaction in diethyl ether but de- tion in a more polar solvent like diethyl ether that is the
creases the regioselectivity in pentane (see also Table 1, En- cause for the reversal of regioselectivity that is observed
tries 1, 2 7, and 8).
when the latter solvent is used.
Table 2. Boron-mediated aldol reaction of ketones 2b,d with model aldehyde (Ϯ)-6.[a]
Entry
Ketone
Solvent
Relative amount
Combined isolated yield [%]
Regioisomer 21[b]
Regioisomer 22
1
2
3
4
2b
2b
2d
2d
pentane
diethyl ether
pentane
75
79
72
75
40
35
55
22
60
65
45
78
diethyl ether
[a] A solution of the ketone was added to a mixture of borane and triethylamine at 0 °C, followed by cooling to –78 °C and the addition
of the aldehyde (0.33 equiv.). [b] Attempts to determine the relative configuration of the major diastereomer of 21 failed.
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S. Lanners, H. Norouzi-Arasi, N. Khiri, G. Hanquet
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ether, and the organic phases were purified by distillation to afford
a colourless oil (2.6 g) in 82% yield. B.p. 40 °C/25 Torr. H NMR
Conclusions
1
We have studied the regioselectivity of the aldol reaction
(300 MHz, CDCl3): δ = 5.81–5.67 (m, 1 H), 5.00–4.86 (m, 2 H),
of 2-(1,3-dioxolan-2-yl)ethyl ethyl ketones. This regioselec- 4.05 (t, J = 7.2 Hz, 2 H), 2.32–2.27 (m, 4 H), 1.17 (t, J = 7.17 Hz,
3 H) ppm.
tivity seems to be influenced strongly by remote substitu-
tion and by the nature of the solvent used. The experimen-
tal results lead us to propose that it is likely to be controlled
by polar interactions. More importantly, we have observed
that the conformational changes induced by a change of
solvent can have a significant influence on the regioselectiv-
ity of enol formation. While the influence of the solvent
on the stereoselectivity of enol borinate formation has been
examined most thoroughly in the past,[6,7] our results show
that it is important to consider its influence on regioselec-
tivity as well. This solvent-mediated regiochemical control
has also enabled us to develop a viable aldol-based ap-
proach to the convergent assembly of the C(1)–C(18) frag-
ment of Pamamycin-607 (1) using ketone 2a.
General Procedure for the Preparation of tert-Butyl β-Keto Esters
14a,c,d: To a stirred solution of diisopropylamine (11.4 mL,
81.2 mmol) in dry THF (80 mL) and HMPA (30 mL) under argon
was added dropwise n-butyllithium (55.8 mL of a 1.6  solution in
hexane, 89.3 mmol) at –78 °C. The solution was stirred for 30 min,
and then a solution of tert-butyl acetate, propionate or butyrate
(74.9 mmol) in dry THF (20.0 mL) was added dropwise. After the
addition, the solution was stirred for 1 h, and a solution of ethyl
4-pentanoate (13) (4.0 g, 31.2 mmol) in dry THF (50 mL) was
added. The reaction mixture was then warmed to room tempera-
ture and stirred overnight. The reaction was quenched by the ad-
dition of saturated aq. NH4Cl (200 mL). The mixture was extracted
with AcOEt (3ϫ100 mL), the combined organic layers were
washed with brine and dried with MgSO4, and the solvents were
removed in vacuo. The crude product was purified by flash
chromatography on silica gel (hexane/AcOEt, 5:1) to afford the
tert-butyl β-keto esters 14a,c,d as colourless oils in 82–86% yield.
Experimental Section
Preparation of β-Keto Esters 14a,c,d from 4-Pentenoic Acid: To a
stirred solution of 4-pentenoic acid (4.94 g, 49.3 mmol, 1 equiv.) in
dry THF (50 mL) under argon, was added slowly carbonyldiimid-
azole (8 g, 49.3 mmol, 1 equiv.). The mixture was stirred at room
temperature for 1 h. To a stirred solution of diisopropylamine
(20 g, 197.3 mmol, 4 equiv.) in dry THF (20 mL) under argon was
added dropwise n-butyllithium (123 mL of a 1.6  solution in hex-
ane, 197.4 mmol, 4 equiv.) at –78 °C. The solution was stirred at
–78 °C for 30 min, and then a solution of tert-butyl acetate, propi-
onate or butyrate (98.65 mmol, 2 equiv.) in dry THF (15.0 mL) was
added dropwise. After stirring at 78 °C for another 30 min, this
solution was transferred by cannula to the imidazolide solution and
the mixture cooled to –78 °C. After 15 min at –78 °C, the reaction
mixture was then warmed to room temperature and stirred for 2 h.
A white precipitate appeared, and the reaction was quenched by
the addition of saturated aq. NH4Cl (300 mL). The mixture was
extracted with diethyl ether (2ϫ100 mL), the combined organic
layers were washed with brine and dried with MgSO4, and the sol-
vents were removed in vacuo. The crude product was purified by
flash chromatography on silica gel (hexane/MTBE, 15:1) to afford
the tert-butyl β-keto esters 14a,c,d as colourless oils in 86–92%
yield.
General: Unless otherwise stated, reagents and solvents were pur-
chased as reagent grade and used without further purification.
THF was distilled from sodium benzophenone ketyl. CH2Cl2 was
distilled from CaH2. Column chromatography was performed with
silica gel 60 (230–400 mesh, 0.040–0.063 mm), purchased from E.
Merck. Thin-layer chromatography (TLC) was performed with
glass sheets coated with silica gel 60 F254 (unless otherwise stated),
purchased from E. Merck, and visualization was effected by UV
light and/or appropriate staining reagents. IR (cm–1) spectra were
recorded using Universal ATR sampling accessories with a Perkin–
Elmer Spectrum One spectrometer. NMR spectra (1H and 13C)
were recorded with a Bruker AC200 (200 MHz) or a Bruker Avance
(300 MHz or 400 MHz) spectrometer. Chemical shifts are reported
in ppm relative to the residual solvent (CHCl3) resonance at δ =
1
7.26 ppm in the H spectra and relative to the central CDCl3 reso-
nance at δ = 77.0 ppm in the 13C spectra. Data are reported as: s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br.
s = broad singlet; integration; coupling constant(s) in Hz.
Preparation of Ketones 2a–d
Preparation of β-Keto Esters 14a,c,d from Allyl Bromide
Diethyl Allylmalonate (12): To a suspension of NaH (0.92 g, 55%
in oil, 21.0 mmol) in THF (50 mL) was added dropwise diethyl
malonate (3.20 g, 20.0 mmol) at 0 °C. The reaction mixture was
warmed to room temperature and stirred for 1 h. Allyl bromide
(2.90 g, 24.0 mmol) was added, and the resulting solution was
stirred overnight. After the addition of H2O (100 mL) and extrac-
tion with diethyl ether, the organic layer was washed with brine,
dried with MgSO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography (hexane/
diethyl ether, 10:1) to afford 12 (3.44 g) in 86% yield. 1H NMR
(300 MHz, CDCl3): δ = 5.85–5.71 (m, 1 H), 5.16–5.03 (m, 2 H),
4.20 (q, J = 7.17 Hz, 2 H), 4.19 (q, J = 7.17 Hz, 2 H), 3.42 (t, J =
7.7 Hz, 1 H), 2.67–2.61 (m, 2 H), 1.26 (t, J = 7.17 Hz, 6 H) ppm.
tert-Butyl 2-Methyl-3-oxohept-6-enoate (14a): Pale yellow oil; Rf =
1
0.42 (hexane/AcOEt, 9:1). H NMR (300 MHz, CDCl3): δ = 5.88–
5.27 (m, 1 H), 5.09–4.94 (m, 2 H), 3.42 (q, J = 7.1 Hz, 1 H), 2.70–
2.45 (m, 2 H), 2.40–2.26 (m, 2 H), 1.45 (s, 9 H), 1.28 (d, J = 7.1 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 205.9, 172.1, 136.2,
117.6, 81.6, 56.4, 40.0, 28.6, 28.0, 12.9 ppm.
tert-Butyl 3-Oxohept-6-enoate (14c): Pale yellow oil; Rf = 0.44 (hex-
1
ane/AcOEt, 9:1). H NMR (300 MHz, CDCl3): δ = 5.88–5.75 (m,
1 H), 5.01–4.97 (m, 2 H), 3.35 (s, 2 H), 2.64 (t, J = 7.5 Hz, 2 H),
2.38–2.31 (m, 2 H), 1.47 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 202.4, 166.4, 136.7, 115.5, 50.7, 41.9, 27.96, 27.42 ppm.
Ethyl 4-Pentenoate (13): To a solution of diethyl allylmalonate (12)
(5 g, 25 mmol, 1 equiv.) in DMSO (25 mL) was added NaCl
(2.19 g, 37 mmol, 1.5 equiv.) and H2O (20 mL). The reaction mix-
ture was refluxed (160–180 °C) for 8 h. The ester was isolated by
the addition of H2O to the reaction mixture and separation of the
ester-containing layer. The aqueous layer was extracted with diethyl
tert-Butyl 2-Ethyl-3-oxohept-6-enoate (14d): Colourless oil; Rf =
1
0.40 (hexane/AcOEt, 9:1). H NMR (300 MHz, CDCl3): δ = 5.87–
5.74 (m, 1 H), 5.07–4.96 (m, 2 H), 3.26 (t, J = 7.3 Hz, 1 H), 2.67–
2.51 (m, 2 H), 2.38–2.31 (m, 2 H), 1.84 (m, 2 H), 1.45 (s, 9 H), 0.92
(t, J = 7.3 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 204.8,
168.9, 136.9, 115.3, 81.7, 61.8, 40.9, 27.9, 26.9, 21.5, 11.9 ppm.
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FULL PAPER
Preparation of 2-(1,3-Dioxolan-2-yl) Esters 15a,c,d and Dioxolane
18: To a solution of β-oxo esters 14a,c,d or 2-oxo-1-hexene
(20 mmol, 1 equiv.) in dry CH2Cl2 (200 mL) under argon was
added ethylene glycol (200 mmol, 10 equiv.). Ethyl orthoformate
(30 mmol, 1.5 equiv.) and camphorsulfonic acid (2 mmol,
0.1 equiv.) were then added, and the reaction mixture was stirred
at room temperature for 1 d. The reaction was quenched with satu-
rated aq. NaHCO3 (200 mL). The mixture was extracted with di-
ethyl ether (3ϫ200 mL). The combined organic layers were washed
with brine, dried with Na2SO4, and the solvent was evaporated in
vacuo. The products were purified by flash chromatography.
9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.7, 108.9, 80.7,
65.1, 52.1, 47.1, 43.7, 38.7, 33.6, 28.0, 26.7 ppm.
tert-Butyl 2-{2-[2-(Oxiran-2-yl)ethyl]-1,3-dioxolan-2-yl}butanoate
(16d): Yield: 4.17 g (89%). Colourless oil. Rf = 0.44 (hexane/
AcOEt, 4:1). 1H NMR (300 MHz, CDCl3): δ = 4.05–3.94 (m, 4 H),
2.96–2.88 (m, 1 H), 2.75–2.71 (m, 1 H), 2.51–2.44 (m, 2 H), 2.09–
1.51 (m, 7 H), 1.46 (s, 9 H), 0.89 (t, J = 7.5 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 171.9, 110.7, 80.4, 65.3, 55.9, 52.2,
47.2, 30.6, 27.9, 25.9, 21.0, 12.4 ppm.
2-Methyl-2-[2-(oxiran-2-yl)ethyl]-1,3-dioxolane (19): Yield: 1.8 g
(80%). Viscous colourless oil obtained by chromatography (hexane/
AcOEt, 5:1). H NMR (300 MHz, CDCl3): δ = 3.95 (m, 4 H), 2.85
(m, 1 H), 2.54 (dd, J = 5.6, 2.8 Hz, 2 H), 1.69 (m, 4 H), 1.32 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 109.5, 64.7, 52.2, 47.2,
35.1, 27.1, 23.9 ppm.
tert-Butyl 2-[2-(But-3-enyl)-1,3-dioxolan-2-yl]propanonate (15a):
Yield: 4.5 g (88%). Colourless oil obtained by chromatography
(hexane/diethyl ether, 10:1). Rf = 0.38 (hexane/AcOEt, 9:1). 1H
NMR (300 MHz, CDCl3): δ = 5.91–5.77 (m, 1 H), 5.07–4.94 (m, 2
H), 4.06–3.95 (m, 4 H), 2.73 (q, J = 7.1 Hz, 1 H), 2.25–2.05 (m, 2
H), 2.0–1.65 (m, 2 H), 1.46 (s, 9 H), 1.16 (d, J = 7.1 Hz, 3 H) ppm.
1
Preparation of Alcohols 17a,c,d and 20: To a suspension of CuI
13C NMR (75 MHz, CDCl3): δ = 174.0, 139.4, 122.6, 114.6, 77.9, (41 mmol, 2 equiv.) in dry diethyl ether (100 mL) at 0 °C under
64.4, 45.2, 33.0, 31.0, 29.5, 12.1 ppm.
argon, was added dropwise MeLi (52 mL, 1.6  in diethyl ether,
82 mmol, 4 equiv.). A solution of epoxides 16a,c,d (20 mmol,
0.95 equiv.) in diethyl ether (50 mL) was then added dropwise. The
reaction was monitored by TLC until the disappearance of the
starting material (50–60 min). Saturated aq. NH4Cl (75 mL) was
then added, and the mixture was extracted with diethyl ether
(3ϫ100 mL). The combined organic layers were washed with brine
and dried with MgSO4, and the solvent was evaporated in vacuo.
The products were purified by flash column chromatography (cy-
clohexane/AcOEt, 2:1).
tert-Butyl 2-[2-(But-3-enyl)-1,3-dioxolan-2-yl]acetate (15c): Yield:
4.5 g (93%). Colourless oil obtained by chromatography (cyclohex-
ane/AcOEt, 2:1). Rf = 0.41 (hexane/AcOEt, 9:1). 1H NMR
(300 MHz, CDCl3): δ = 5.91–5.77 (m, 1 H), 5.06–4.92 (m, 2 H),
4.04–3.94 (m, 4 H), 2.56 (s, 2 H), 2.21–2.14 (m, 2 H), 1.94–1.88 (m,
2 H), 1.46 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.7,
138.3, 114.3, 109.2, 80.6, 65.0, 43.8, 36.8, 28.1, 27.9 ppm.
tert-Butyl
2-[2-(But-3-enyl)-1,3-dioxolan-2-yl]butanoate
(15d):
Yield: 4.37 g (81%). Colourless oil obtained by chromatography
(hexane/diethyl ether, 10:1). Rf = 0.39 (hexane/AcOEt, 9:1). 1H
NMR (300 MHz, CDCl3): δ = 5.87–5.74 (m, 1 H), 5.07–4.96 (m, 2
H), 3.26 (t, J = 7.3 Hz, 1 H), 2.67–2.51 (m, 2 H), 2.38–2.31 (m, 2
H), 1.84 (m, 2 H), 1.45 (s, 9 H), 0.92 (t, J = 7.3 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 204.8, 168.9, 136.9, 115.3, 81.7, 61.8,
40.9, 27.9, 26.9, 21.5, 11.9 ppm.
tert-Butyl 2-[2-(3-Hydroxypentyl)-1,3-dioxolan-2-yl]propanoate (17a):
Yield: 4.2 g (90%). Colourless oil. Rf = 0.32 (hexane/AcOEt, 2:1).
1H NMR (300 MHz, CDCl3): δ = 4.10–3.92 (m, 4 H), 3.54–3.43
(m, 1 H), 2.74 (q, J = 7.1 Hz, 0.5 H, diastereomer A), 2.73 (q, J =
7.1 Hz, 0.5 H, diastereomer B), 2.1–1.65 (m, 4 H), 1.53–1.33 (m, 2
H), 1.44 (s, 9 H), 1.14 (d, J = 7.1 Hz, 3 H), 0.93 (t, J = 7.3 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.0, 122.7, 77.9, 72.0,
64.4, 44.9, 31.6, 30.7, 30.2, 29.5, 12.1, 9.7 ppm.
2-(But-3-enyl)-2-methyl-1,3-dioxolane (18): Yield: 2.35 g (96%). Vis-
cous yellow oil obtained by chromatography (hexane/AcOEt, 5:1).
1H NMR (300 MHz, CDCl3): δ = 5.68 (m, 1 H), 4.99 (dd, J = 10.5,
2 Hz, 1 H), 4.92 (dd, J = 18, 2 Hz, 1 H), 3.95 (m, 4 H), 2.19 (m, 2
H), 1.96 (m, 2 H), 1.35 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 139.9, 114.5, 110.5, 64.6, 35.6, 29.6, 23.8 ppm.
tert-Butyl 2-[2-(3-Hydroxypentyl)-1,3-dioxolan-2-yl]acetate (17c):
Yield: 3.9 g (88%). Colourless oil. Rf = 0.3 (hexane/AcOEt, 2:1).
1H NMR (300 MHz, CDCl3): δ = 4.06–3.96 (m, 4 H), 3.57–3.49
(m, 1 H), 2.58 (s, 2 H), 2.06–1.88 (m, 3 H), 1.71–1.59 (m, 1 H),
1.57–1.48 (m, 3 H), 1.46 (s, 9 H), 0.95 (t, J = 7.5 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 168.8, 109.5, 80.7, 73.1, 65.0,
64.9, 43.6, 33.7, 30.7, 30.2, 28.0, 9.9 ppm.
Preparation of Epoxides 16a,c,d and 19: To a solution of tert-butyl
ester 15a,c,d or dioxolane 18 (16.5 mmol, 1 equiv.) in dry CH2Cl2
(400 mL) was added m-CPBA (77%, 19.8 mmol, 1.2 equiv. of active
oxygen). The reaction mixture was stirred at room temperature
overnight. Saturated aq. K2CO3 (100 mL) was then added, and the
mixture was extracted with CH2Cl2 (3ϫ100 mL). The combined
organic layers were washed with brine and dried with MgSO4, and
the solvents were evaporated in vacuo. The products were purified
by flash column chromatography (cyclohexane/AcOEt, 10:3).
tert-Butyl 2-[2-(3-Hydroxypentyl)-1,3-dioxolan-2-yl]butanoate (17d):
Yield: 4.45 g (90%). Colourless oil. Rf = 0.35 (hexane/AcOEt, 2:1).
1H NMR (300 MHz, CDCl3): δ = 4.05–3.94 (m, 4 H), 3.51–3.43
(m, 1 H), 2.50 (dd, J = 3.6, 11.5 Hz, 1 H), 2.1 (br. s, 1 H), 2.06–
1.96 (m, 1 H), 1.83–1.47 (m, 7 H), 1.44 (s, 9 H), 0.91 (t, J = 7.4 Hz,
3 H), 0.87 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 171.9, 111.3, 80.4, 73.1, 65.2, 65.1, 55.9, 30.7, 30.2, 29.9, 28.0,
21.0, 12.3, 9.8 ppm.
tert-Butyl 2-{2-[2-(Oxiran-2-yl)ethyl]-1,3-dioxolan-2-yl}propanoate
(16a): Yield: 4.23 g (95%). Colourless oil. Rf = 0.44 (hexane/Ac-
1
1-(2-Methyl-1,3-dioxolan-2-yl)pentan-3-ol (20): Yield: 2.3 g (92%).
Yellow oil obtained by chromatography (hexane/AcOEt, 4:1). Rf =
0.53 (hexane/AcOEt, 4:1). 1H NMR (300 MHz, CDCl3): δ = 3.9
(m, 4 H), 3.45 (m, 1 H), 2.5 (m, 1 H), 1.7 (m, 2 H), 1.6 (m, 2 H),
1.55 (m, 2 H), 1.3 (s, 3 H), 0.85 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 110.1, 73.24, 64.6, 35.3, 31.1, 30.1, 23.7, 10
ppm.
OEt, 4:1). H NMR (300 MHz, CDCl3): δ = 4.05–3.95 (m, 4 H),
2.98–2.90 (m, 1 H), 2.78–2.72 (m, 1 H), 2.72 (q, 1 H), 2.3 (m, 1 H),
2.09–1.53 (m, 4 H) 1.46 (s, 9 H), 1.17 (d, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 174.0, 122.8, 77.9, 64.4, 59.7, 46.5, 44.9,
30.9, 30.1, 29.5, 12.1 ppm.
tert-Butyl
2-{2-[2-(Oxiran-2-yl)ethyl]-1,3-dioxolan-2-yl}acetate
(16c): Yield: 3.88 g (92%). Colourless oil. Rf = 0.40 (hexane/
AcOEt, 4:1). 1H NMR (300 MHz, CDCl3): δ = 3.95–3.84 (m, 4 H),
2.89–2.83 (m, 1 H), 2.66 (dd, J = 4.9, 3.3 Hz, 2 H), 2.39 (dd, J =
4.9, 3.3 Hz, 2 H), 1.93–1.86 (m, 2 H), 1.61–1.53 (m, 2 H), 1.37 (s,
Preparation of Ketones 2a,b,c,d: To a solution of alcohols 17a,c,d
(3.2 mmol, 1 equiv.) in DMF was added PDC (pyridinium dichro-
mate) portionwise (3.66 g, 9.73 mmol, 3 equiv.). The reaction mix-
Eur. J. Org. Chem. 2007, 4065–4075
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4071

S. Lanners, H. Norouzi-Arasi, N. Khiri, G. Hanquet
FULL PAPER
ture was stirred at room temperature under argon overnight. H2O
(20 mL) and diethyl ether (20 mL) were then added. The reaction
mixture was stirred at 0 °C for 15 min and extracted with diethyl
ether (3ϫ50 mL). The combined organic layers were washed with
saturated aq. NH4Cl (2ϫ50 mL) and then with brine (50 mL) and
dried with MgSO4. The solvents were evaporated in vacuo, and the
product was purified by flash column chromatography (cyclo-
hexane/EtOAc, 3:1).
MgSO4. The solvent was evaporated, and the crude product was
subjected to flash chromatography (gradient elution).
Aldol Adduct 21a: Obtained from a reaction in pentane and a puri-
fication using a cyclohexane Ǟ cyclohexane/diisopropyl ether (2:1)
gradient. Yield: 240 mg (52%). Colourless oil. Rf = 0.12 (hexane/
diethyl ether, 1:1). 1H NMR (400 MHz, CDCl3): δ = 7.40–7.28 (m,
5 H), 4.53 (A of AB system, both diastereomers, JAB = 11.9, ∆ν =
10 Hz, 1 H), 4.48 (B of AB system, one diastereomer, JAB = 11.9,
∆ν = 10 Hz, 0.5 H), 4.47 (B of AB system, one diastereomer, JAB
= 11.9, ∆ν = 12 Hz, 0.5 H), 4.01–3.85 (m, 5 H), 3.60–3.48 (m, 2
H), 2.91 (d, one diastereomer, J = 3.8 Hz, 0.5 H), 2.84 (d, one
diastereomer, J = 4.2 Hz, 0.5 H), 2.87–2.72 (m, 1 H), 2.70 (q, one
diastereomer, J = 7.1 Hz, 0.5 H), 2.69 (q, one diastereomer, J =
7.2 Hz, 0.5 H), 2.61–2.49 (m, 2 H), 2.50–2.24 (m, 1 H), 2.06–1.79
(m, 1 H), 1.95–1.85 (m, 1 H), 1.46 (s, 9 H), 1.16 (d, one dia-
stereomer, J = 7.4 Hz, 1.5 H), 1.14 (d, one diastereomer, J = 7.4 Hz,
1.5 H), 1.04 (t, one diastereomer, J = 7.3 Hz, 1.5 H), 1.02 (t, one
diastereomer, J = 7.1 Hz, 1.5 H), 1.01 (d, one diastereomer, J =
7.1 Hz, 1.5 H), 1.01 (d, one diastereomer, J = 7.2 Hz, 1.5 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 215.4, 215.0, 172.7, 172.5, 138.3,
128.8, 128.1, 128.0, 111.1, 110.9, 81.0, 80.9, 77.6, 76.2, 75.8, 75.7,
75.5, 65.4, 65.3, 65.2, 65.1, 50.0, 49.6, 47.8, 47.3, 37.4, 36.4, 36.0,
35.8, 33.9, 33.6, 28.4, 28.4, 13.2, 12.9, 10.6, 10.4, 7.9, 7.8 ppm.
tert-Butyl 2-[2-(3-Oxopentyl)-1,3-dioxolan-2-yl]propanoate (2a):
Yield: 0.82 g (91%). Colourless oil. Rf = 0.32 (hexane/AcOEt, 2:1).
1H NMR (400 MHz, CDCl3): δ = 4.04–3.92 (m, 4 H), 2.74 (q, J =
7.1 Hz, 1 H), 2.55–2.39 (m, 4 H), 2.19 (A part of ABXY, JAB
=
14.8, JAX =, JAY = 6.5, ∆ν = 47 Hz, 1 H), 2.08 (B part of ABXY,
JAB = 14.8, JBX = 6.2, JBY = 6.2, ∆ν = 47 Hz, 1 H), 1.46 (s, 9 H),
1.17 (d, J = 7.1 Hz, 3 H), 1.05 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 210.5, 174.0, 122.3, 77.9, 64.4, 43.9, 38.2,
36.0, 30.5, 29.5, 12.1, 7.8 ppm. C15H26O5 (286.36): calcd. C 62.91,
H 9.15; found C 62.57, H 9.19.
1-(2-Methyl-1,3-dioxolan-2-yl)pentan-3-one (2b): Yield: 0.83 g
(96%). Colourless oil. Rf = 0.51 (hexane/AcOEt, 3:1). 1H NMR
(300 MHz, CDCl3): δ = 4 (m, 4 H), 2.46 (t, J = 7.4 Hz, 2 H), 2.25
(q, J = 8 Hz, 2 H), 1.75 (t, J = 7.5 Hz, 2 H), 1.35 (s, 3 H), 0.93 (t,
J = 8 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 210.5, 109.4,
64.7, 36.9, 35.8, 32.8, 23.9, 7.8 ppm. C9H16O3 (172.2): calcd. C
62.77, H 9.36; found C 62.87, H 9.29.
Aldol Adduct 21b: Obtained from a reaction in pentane and a puri-
fication using a cyclohexane Ǟ cyclohexane/diisopropyl ether (2:1)
gradient. Yield: 98 mg (28%). Colourless oil. Rf = 0.26 (hexane/
diethyl ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 7.37–7.17 (m,
5 H), 4.48 (AB, J = 12.06, ∆υ = 13.72 Hz, 2 H), 3.97–3.86 (m, 5
H), 3.58–3.48 (m, 2 H), 2.88–2.79 (m, X part of ABX system, 1
tert-Butyl 2-[2-(3-Oxopentyl)-1,3-dioxolan-2-yl]acetate (2c): Yield:
0.89 g (93%). Colourless oil. Rf = 0.31 (hexane/AcOEt, 2:1). 1H
NMR (300 MHz, CDCl3): δ = 4.03–3.92 (m, 4 H), 2.55 (s, 2 H),
2.50 (t, J = 6.9 Hz, 2 H), 2.43 (q, J = 7.3 Hz, 2 H), 2.19–2.15 (m,
2 H), 1.45 (s, 9 H), 1.06 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 210.7, 168.5, 108.8, 80.8, 65.0, 43.9, 36.6,
35.6, 31.6, 7.8 ppm. C14H24O5 (272.3): calcd. C 61.74, H 8.88;
found C 61.89, H 8.99.
H), 2.62–2.47 (m, 4 H), 2.33 (dd, A part of ABX system, JAX
=
10.3, JAB = 14.5 Hz, 1 H,), 2.00 (dd, B part of ABX system, JBX
= 2.4, JAB = 14.5, ∆υ = 103.7 Hz, 1 H), 1.94–1.87 (m, 1 H), 1.02
(t, J = 7.5 Hz, 3 H), 1.00 (d, J = 7.1 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 214.9, 168.4, 137.9, 128.4, 127.7, 108.4, 80.8,
75.7, 73.5, 64.8, 64.6, 43.9, 37.1, 36.6, 35.4, 28.0, 10.1, 7.4 ppm.
tert-Butyl 2-[2-(3-Oxopentyl)-1,3-dioxolan-2-yl]butanoate (2d):
Yield: 0.43 g (89%). Colourless oil. Rf = 0.33 (hexane/AcOEt, 2:1).
1H NMR (300 MHz, CDCl3): δ = 4.04–3.91 (m, 4 H), 2.50–2.39
(m, 5 H), 2.22 (ddd, J = 7, 8.15, 14.9 Hz, 1 H), 2.04 (ddd, J = 7,
8.15, 14.7 Hz, 1 H), 1.83–1.67 (m, 1 H), 1.61–1.46 (m, 1 H), 1.46
(s, 9 H), 1.04 (t, J = 7 Hz, 3 H), 0.89 (t, J = 7.5 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 211.1, 171.7, 110.7, 80.5, 65.2, 65.1,
55.9, 36.3, 35.4, 29.7, 28.1, 21.0, 12.4, 7.9 ppm. C16H28O5 (300.4):
calcd. C 63.97, H 9.40; found C 63.79, H 9.19.
Aldol Adduct 21d: Obtained from a reaction in pentane and a puri-
fication using a cyclohexane Ǟ cyclohexane/diisopropyl ether (2:1)
gradient. Yield: 190 mg (40%). Colourless oil. Rf = 0.14 (hexane/
diethyl ether, 1:1). 1H NMR (400 MHz, CDCl3): δ = 7.40–7.26 (m,
5 H), 4.51 (A of AB system, both diastereomers, JAB = 12, ∆ν =
10 Hz, 1 H), 4.47 (B of AB system, one diastereomer, JAB = 12, ∆ν
= 10 Hz, 0.5 H), 4.46 (B of AB system, one diastereomer, JAB
=
12, ∆ν = 12 Hz, 0.5 H), 4.07–3.88 (m, 5 H), 3.61–3.5 (m, 2 H), 2.9
(m, one diastereomer, J = 6 Hz, 0.5 H), 2.87 (m, one diastereomer,
J = 6 Hz, 0.5 H), 2.87–2.72 (m, 1 H), 2.74 (t, one diastereomer, J
= 7.5 Hz, 0.5 H), 2.71 (t, one diastereomer, J = 7.5 Hz, 0.5 H), 2.6–
2.47 (m, 2 H), 2.52–2.2 (m, 1 H), 2.1–1.82 (m, 1 H), 1.96–1.83 (m,
1 H), 1.44 (s, 9 H), 1.68 (td, one diastereomer, J = 7.5, 7.2 Hz, 1
H), 1.64 (td, one diastereomer, J = 7.5, 7.2 Hz, 1 H), 1.06 (t, one
diastereomer, J = 7 Hz, 1.5 H), 1.04 (t, one diastereomer, J =
7.3 Hz, 1.5 H), 1.02 (d, one diastereomer, J = 7 Hz, 1.5 H), 1.01
(d, one diastereomer, J = 7.2 Hz, 1.5 H), 0.99 (t, one diastereomer,
J = 7.2 Hz, 1.5 H), 0.97 (t, one diastereomer, J = 7.2 Hz, 1.5 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 213.4, 213.0, 174.5, 173.5,
138.3, 128.8, 128.1, 128.0, 110.1, 110.0, 81.0, 80.9, 75.6, 75.2, 74.9,
74.7, 74.5, 65.4, 65.3, 65.2, 65.1, 50.2, 49.6, 48.8, 48.3, 37.3, 36.4,
36.0, 35.6, 33.9, 33.6, 28.4, 28.4, 12.2, 11.9, 11.6, 11.4, 8.0, 7.9 ppm.
General Procedure for the Aldol Reactions: To a stirred solution of
Chx2BCl (1.31 mmol, 290 µL, 1.3 equiv.) in pentane or diethyl
ether (15 mL) at 0 °C under argon, was added dropwise a solution
of ketones 2a–d (1 mmol, 1 equiv.) in the same solvent (10 mL),
and the enolate was generated rapidly with concurrent formation
and precipitation of Et3N·HCl. The reaction mixture was stirred
at 0 °C for 2 h. To this mixture was added dropwise the aldehyde
[0.82 mmol, neat in the case of isobutyraldehyde and dissolved in
the reaction solvent (5 mL) for aldehyde 6] at –78 °C. The reaction
mixture was stirred at this temperature for 3 h, and then tightly
sealed and stored in the freezer (–23 °C) overnight. Then a pH = 7
phosphate buffer solution (10 mL) was added, and the aqueous
layer was extracted with diethyl ether (3ϫ30 mL). The organic lay-
ers were combined and concentrated, and methanol (20 mL), pH
= 7 phosphate buffer (5 mL) and finally H2O2 (35% in H2O,
10 mL) were added at 0 °C. The mixture was stirred at room tem-
perature for 2 h. Thereafter, distilled H2O (10 mL) was added, and
the mixture was extracted with CH2Cl2 (3ϫ50 mL). The organic
layers were combined, washed with brine (50 mL), and dried with
Aldol Adduct 22a: Obtained from a reaction in diethyl ether and a
purification using a cyclohexane Ǟ cyclohexane/diisopropyl ether
(1:1) gradient. Yield: 243 mg (52%). Colourless oil. Rf = 0.10 (hex-
ane/diethyl ether, 1:1). 1H NMR (400 MHz, CDCl3): δ = 7.39–7.29
(m, 5 H), 4.56–4.48 (m, 2 H), 4.15–3.85 (m, 5 H), 3.62–3.54 (m, 2
4072
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Eur. J. Org. Chem. 2007, 4065–4075

Boron-Mediated Aldol Reaction of 2-(1,3-Dioxolan-2-yl)ethyl Ethyl Ketones
FULL PAPER
H), 2.93 (d, one diastereomer, J = 2.5 Hz, 0.5 H), 2.92 (d, one
diastereomer, J = 2.5 Hz, 0.5 H), 2.90–2.50 (m, 3 H), 2.72 (q, J = NMR (75 MHz, CDCl3): δ = 212.3, 170.4, 109.5, 78.9, 76.7, 69.7,
(m, 6 H), 1.47 (s, 9 H), 1.46 (s, 9 H), 1.05–0.86 (m, 18 H) ppm. 13
C
7.2 Hz, 1 H), 2.24–2.02 (m, 2 H), 1.98–1.85 (m, 1 H), 1.46 (s, 9 H),
1.18 (d, J = 7.3 Hz, 3 H), 1.17 (t, one diastereomer, J = 7.1 Hz,
1.5 H), 1.05 (t, one diastereomer, J = 7.0 Hz, 1.5 H), 1.03 (d, one
diastereomer, J = 7.1 Hz, 1.5 H), 0.98 (d, one diastereomer, J =
7.0 Hz, 1.5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 215.3,
215.2, 172.7, 138.5, 128.8, 128.1, 128.0, 111.3, 110.9, 80.9, 77.9,
76.6, 75.6, 75.5, 75.2, 75.2, 65.8, 65.6, 49.5, 49.3, 47.9, 47.8, 37.4,
37.3, 37.1, 37.0, 36.4, 35.4, 28.4, 15.8, 19.4, 14.2, 12.9, 10.3 ppm.
68.6, 49.7, 37.7, 37.3, 31.4, 29.0, 19.9, 16.7, 11.2, 7.4 ppm.
Aldol Adduct 25b (anti): 1H NMR (300 MHz, CDCl3): δ = 3.98–
3.91 (m, 4 H), 3.51–3.45 (m, 1 H), 2.84–2.74 (m, 1 H), 2.67–2.56
(m, 2 H), 2.53 (d, 1 H, OH), 2.03–197 (m, 2 H), 1.82–1.71 (m, 1
H), 1.34 (s, 3 H), 1.12 (d, J = 7.2 Hz, 3 H), 0.98 (d, J = 6.9 Hz, 3
H), 0.92 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 215.6, 109.3, 78.3, 64.6, 48.7, 37.4, 32.2, 30.4, 23.9, 20.0, 15.7,
14.4 ppm.
Aldol Adduct 22b: Obtained from a reaction in pentane and a puri-
fication using a cyclohexane Ǟ cyclohexane/diisopropyl ether (2:1)
gradient. Yield: 173 mg (47%). Colourless oil. Rf = 0.19 (hexane/
diethyl ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 7.36–7.28 (m,
5 H), 4.5 (s, 2 H), 4.02–3.92 (m, 5 H), 3.62–3.52 (m, 2 H), 2.90–
2.68 (m, 1 H), 2.65–2.57 (m, 2 H), 2.55 (d, 1 H), 2.18–2.12 (m, 2
H), 1.95–1.86 (m, 1 H), 1.46 (s, 3 H), 0.98 (d, J = 6.9 Hz, 3 H),
0.97 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 Hz, CDCl3): δ = 211,
137.4, 128.8, 127.4, 109.1, 76.5, 71.2, 70.3, 49.3, 35.5, 35.3, 26.9,
26.3, 10.2, 9.3 ppm.
Aldol Adduct 25c (anti): 1H NMR (300 MHz, CDCl3): δ = 4.00–
3.95 (m, 4 H), 3.46 (dd, J = 7, 4.5 Hz, 1 H), 2.82–2.73 (m, 1 H),
2.66–2.51 (m, 4 H), 2.19–2.13 (m, 2 H), 2.03–1.97 (m, 2 H), 1.80–
1.71 (m, 1 H), 1.45 (s, 9 H), 1.11 (d, J = 7.3 Hz, 3 H), 0.96 (d, J =
7 Hz, 3 H), 0.90 (d, J = 7 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 215.4, 168.5, 108.7, 80.8, 78.2, 65.0, 64.6, 48.3, 43.9,
37.1, 30.9, 30.4, 28.0, 20.0, 15.8, 14.4 ppm.
Aldol Adduct 25c (syn): 1H NMR (400 MHz, CDCl3): δ = 4.04–
3.96 (m, 4 H), 3.54 (dd, J = 6.4, 2.6 Hz, 1 H), 2.78 (dq, J = 7.3,
2.6 Hz,1 H), 2.64–2.59 (m, 1 H), 2.57 (s, 2 H), 2.54–2.42 (m, 1 H),
2.23–2.15 (m, 2 H), 1.69 (dd, J = 6.7, 2.0 Hz, 1 H), 1.47 (s, 9 H),
1.14 (d, J = 7.3 Hz, 3 H), 1.04 (d, J = 6.4 Hz, 3 H), 0.87 (d, J =
6.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 215.7, 168.9,
109.1, 81.3, 76.7, 65.4, 65.3, 47.8, 44.2, 36.1, 30.9, 28.4, 19.6, 19.4,
14.1 ppm.
Aldol Adduct 22d: Obtained from a reaction in diethyl ether and a
purification using a cyclohexane Ǟ cyclohexane/diisopropyl ether
(1:1) gradient. Yield: 158 mg (32%). Colourless oil. Rf = 0.12 (hex-
ane/diethyl ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 7.36–7.28
(m, 5 H), 4.53–4.49 (m, 2 H), 4.1–3.83 (m, 5 H), 3.63–3.55 (m, 2
H), 2.91 (d, one diastereomer, J = 2.5 Hz, 0.5 H), 2.89 (d, one
diastereomer, J = 2.5 Hz, 0.5 H), 2.90–2.50 (m, 3 H), 2.75 (t, J =
7 Hz, 1 H), 2.21–2.05 (m, 2 H), 1.98–1.86 (m, 1 H), 1.45 (s, 9 H),
1.15 (t, one diastereomer, J = 6.9 Hz, 1.5 H), 1.06 (t, one dia-
stereomer, J = 7.0 Hz, 1.5 H), 1.04 (d, one diastereomer, J = 7 Hz,
1.5 H), 0.96 (d, one diastereomer, J = 7.0 Hz, 1.5 H), 0.95 (t, one
diastereomer, J = 7.1 Hz, 1.5 H), 0.94 (t, one diastereomer, J =
7.1 Hz, 1.5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 215.8,
215.4, 173.1, 138.5, 128.8, 128.0, 127.9, 111.3, 110.9, 80.9, 77.9,
76.7, 75.6, 75.5, 75.2, 75.1, 65.8, 65.6, 65.5, 65.4, 49.5, 49.3, 47.4,
47.3, 37.4, 37.2, 37.1, 37.0, 36.4, 35.4, 28.4, 15.8, 14.2, 14.1, 11.2,
10.0 ppm.
Aldol Adduct 24b (anti): 1H NMR (300 MHz, CDCl3): δ = 3.97–
3.83 (m, 4 H), 3.39–3.43 (m, 1 H), 2.96 (ddd, X part of ABX sys-
tem, J = 3.1, 5.9, 9.9 Hz, 1 H), 2.69–2.46 (m, 2 H), 2.42 (br. s, 1
H), 2.30 (dd, A part of ABX system, JAX = 9.9, JAB = 14.8 Hz, 1
H), 1.86 (dd, B part of ABX system, JBX = 3.1, JAB = 14.8, ∆υ =
182.6 Hz, 1 H), 1.63 (m, 1 H), 1.36 (s, 3 H), 1.06 (t, J = 7.4 Hz, 3
H), 0.98 (d, J = 5.4 Hz, 3 H), 0.96 (d, J = 5.4 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 216.3, 109.0, 78.8, 64.3, 48.9, 39.3,
38.0, 31.4, 23.9, 19.8, 16.6, 7.3 ppm.
Aldol Adduct 25d (anti, two diastereomers): 1H NMR (300 MHz,
CDCl3): δ = 4.11–3.92 (m, 4 H), 3.49–3.44 (m, 1 H), 2.83–2.74 (m,
1 H), 2.66–2.46 (m, 4 H), 2.29–1.99 (m, 2 H), 1.83–1.53 (m, 3 H),
1.48 (s, 9 H), 1.12 (d, J = 7.1 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H),
0.92 (d, J = 6.8 Hz, 3 H), 0.91 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 213.8, 172.1, 111.8, 78.5, 77.0, 64.8, 51.1,
48.2, 37.2, 29.6, 29.1, 28.1, 19.3, 18.1, 17.7, 14.2 ppm.
Aldol adduct 25d (syn, two diastereomers): 1H NMR (400 MHz,
CDCl3): δ = 4.11–3.92 (m, 4 H), 3.52 (dd, J = 8.5, 2.5 Hz, 1 H),
2.83–2.75 (m, 1 H), 2.64–2.47 (m, 4 H), 2.31–2.0 (m, 2 H), 1.83–
1.63 (m, 3 H), 1.48 (s, 9 H), 1.45 (s, 9 H), 1.13 (d, J = 7 Hz, 3 H),
1.12 (d, J = 7 Hz, 3 H), 1.04 (d, J = 6.5 Hz, 3 H), 1.03 (d, J =
6.5 Hz, 3 H), 0.92 (t, J = 7 Hz, 3 H), 0.9 (t, J = 7 Hz, 3 H), 0.88
(d, J = 6.5 Hz, 3 H), 0.87 (d, J = 7 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 213.2, 173.1, 113.8, 77.9, 76.9, 64.2, 51.0,
48.8, 36.9, 29.9, 29.3, 28.8, 19.4, 18.0, 17.3, 14.6 ppm.
Cyclic Ketals 23a,d: To
a rapidly stirred solution of 22a,d
(0.07 mmol) in dry MeOH (0.5 mL) was added Pd/C (5 mg, 5%
w/w). The flask was purged with hydrogen gas and stirred at room
temperature under hydrogen overnight. The reaction mixture was
then filtered through Celite, which was copiously washed with di-
ethyl ether. The solvents were removed in vacuo. The residue was
purified by flash column chromatography (hexane/diethyl ether,
2:3) to afford a colourless oil. Rf = 0.15 (hexane/diethyl ether, 2:3).
Aldol Adduct 24c (anti): 1H NMR (300 MHz, CDCl3): δ = 3.91–
3.81 (m, 4 H), 3.31 (dd, J = 6, 6.1 Hz, 1 H), 2.83 (ddd, X part of
ABX system, J = 3, 6.42, 9.42 Hz, 1 H), 2.56–2.42 (m, 4 H), 2.35
(dd, A part of ABX system, JAX = 9.9, JAB = 14.9 Hz, 1 H), 2.06
(dd, B part of ABX system, JBX = 3, JAB = 14.9, ∆υ = 93.1 Hz, 1
H), 1.65–1.50 (m, 1 H), 1.38 (s, 3 H), 0.95 (t, J = 7.3 Hz, 3 H), 0.88
(d, J = 6.8 Hz, 3 H), 0.86 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 216.0, 168.4, 108.5, 80.9, 78.7, 67.7, 64.6,
48.7, 43.8, 37.7, 37.3, 31.4, 28.0, 19.9, 16.7, 7.4 ppm.
1
23a: Yield: 20 mg (99%). H NMR (400 MHz, CDCl3): δ = 4.09–
3.95 (m, 4 H), 3.89–3.81 (m, 1 H), 3.54 (dd, J = 11, 5.4 Hz, 1 H),
3.17 (t, J = 10.5 Hz, 1 H), 3.15 (s, 3 H), 2.71 (q, one diastereomer,
J = 7.2 Hz, 0.5 H), 2.70 (q, one diastereomer, J = 7.2 Hz, 0.5 H),
2.02–1.93 (m, 1 H), 1.90–1.74 (m, 3 H), 1.71–1.51 (m, 2 H), 1.47
Aldol Adduct 24d (anti): 1H NMR (300 MHz, CDCl3): δ = 4.10– (s, 9 H), 1.17 (d, 3 H), 0.97 (d, J = 7.1 Hz, 3 H,), 0.90 (d, J =
3.86 (m, 8 H), 3.40–3.34 (m, 2 H), 2.95–2.88 (m, X part of ABX
system of one diastereomer, 1 H), 2.84–2.78 (m, X part of ABX
system of the other diastereomer, 1 H), 2.62–2.42 (m, 8 H), 2.36–
2.25 (m, 3 H), 2.12 (dd, B part of ABX system of one diastereomer,
JBX = 2.6, JAB = 15 Hz, 1 H), 1.93 (dd, B part of ABX system of
6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.4, 111.3,
111.2, 104.1, 104.0, 80.3, 80.2, 77.2, 65.8, 65.7, 65.6, 65.6, 65.5,
48.2, 48.0, 47.2, 47.2, 39.7, 39.6, 31.9, 31.9, 28.0, 27.8, 27.6, 25.2,
13.2, 12.7, 12.6, 8.0 ppm. 23d: Yield: 22 mg (98%). 1H NMR
(400 MHz, CDCl3): δ = 4.09–3.95 (m, 4 H), 3.9–3.8 (m, 1 H), 3.55
the other diastereomer, JBX = 3, JAB = 14.9 Hz, 1 H), 1.81–1.56 (dd, J = 11, 5.6 Hz, 1 H), 3.2 (t, J = 10.5 Hz, 1 H), 3.16 (s, 3 H),
Eur. J. Org. Chem. 2007, 4065–4075
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4073

S. Lanners, H. Norouzi-Arasi, N. Khiri, G. Hanquet
FULL PAPER
2.68 (t, one diastereomer, J = 5.2 Hz, 0.5 H), 2.68 (t, one dia-
washed with brine and dried with MgSO4 and concentrated in
stereomer, J = 5.2 Hz, 0.5 H), 2.04–1.98 (m, 1 H), 1.90–1.75 (m, 3 vacuo. The resulting oils were purified by flash chromatography
H), 1.7–1.51 (m, 2 H), 1.65 (m, 2 H), 1.49 (s, 9 H), 1.05 (d, J = (diethyl ether/cyclohexane, 1:1) to give pure acetonides 27b,c.
6.5 Hz, 2 H), 0.97 (d, J = 7.0 Hz, 3 H), 0.91 (d, J = 6.5 Hz, 3 H)
1
ppm. 13C NMR (100 MHz, CDCl3): δ = 172.3, 111.8, 111.6, 104.0,
104.0, 80.9, 80.7, 77.2, 65.8, 65.7, 65.6, 65.6, 65.5, 49.4, 49.1, 48.8,
48.8, 39.6, 39.5, 31.9, 31.9, 28.5, 27.7, 27.5, 25.2, 19.4, 14.5, 13.2,
8.3 ppm.
Acetonide 27b (anti-anti): H NMR (300 MHz, CDCl3): δ = 3.89–
3.84 (m, 4 H), 3.38–3.31 (m, 1 H), 3.22 (dd, J = 2.28, 10.17 Hz, 1
H), 1.87–1.35 (m, 6 H), 1.29 (s, 3 H), 1.26 (s, 3 H), 1.25 (s, 3 H),
0.86 (d, J = 6.8 Hz, 3 H), 0.76 (d, J = 6.8 Hz, 3 H), 0.67 (d, J =
6.75 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 110.2, 97.6,
77.7, 74.2, 64.6, 35.8, 34.5, 30.1, 28.2, 27.7, 26.9, 23.8, 20.1, 19.6,
14.3, 11.8 ppm.
Catecholborane Reduction of 24b–d and Acetonide 26b–d Formation:
A typical experimental procedure is as follows. The hydroxy ketone
24b,c (1 mmol) was dissolved in anhydrous THF (10.0 mL) in a dry
round-bottomed flask under argon. The solution was chilled in an
MeOH/ice bath (–10 °C) and charged with catecholborane (1 
solution in THF, 5.1 mL, 5.1 mmol, 5 equiv.). After 24 h, the reac-
tion was quenched by the addition of anhydrous MeOH (2.0 mL)
and saturated aq. sodium potassium tartrate (2.0 mL). This mix-
ture was stirred at 25 °C for 2 h, and the desired product was iso-
lated by a standard extractive isolation procedure. The crude mix-
ture was placed in acetone (5 mL) in the presence of dimethoxypro-
pane (2 mmol) and of camphorsulfonic acid (0.1 mmol). The mix-
ture was stirred overnight, neutralised with saturated aq. NaHCO3
and extracted with CH2Cl2 (3ϫ10 mL). The combined organic lay-
ers were washed with brine, dried with MgSO4 and concentrated
in vacuo. The resulting oils were purified by flash chromatography
(diethyl ether/cyclohexane, 1:1) to give pure acetonides 26b,c.
1
Acetonide 27c (anti-anti): H NMR (400 MHz, CDCl3): δ = 4.04–
4.00 (m, 4 H), 3.40–3.35 (m, 1 H), 3.33 (dd, J = 1.52, 10.68 Hz, 1
H), 2.49 (s, 2 H), 2.03 (dd, J = 1.52, 7.04 Hz, 1 H), 1.92–1.82 (m,
1 H), 1.74–1.72 (m, 2 H), 1.47 (s, 9 H), 1.45–1.42 (m, 1 H), 1.39 (s,
3 H), 1.37 (s, 3 H), 1.34–1.32 (m, 1 H), 0.96 (d, J = 6.52 Hz, 3 H),
0.93 (t, J = 7.52 Hz, 3 H), 0.84 (d, J = 6.52 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 168.7, 108.9, 97.2, 80.7, 77.8, 75.6,
64.7, 64.6, 45.1, 35.5, 34.9, 30.0, 29.7, 28.0, 27.6, 25.8, 20.9, 19.5,
14.5, 10.1 ppm.
[1] G. Solladié, X. J. Salom-Roig, G. Hanquet, Tetrahedron Lett.
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1
Acetonide 26b (anti-anti): H NMR (400 MHz, CDCl3): δ = 3.99–
[3] For a review on the synthetic efforts towards the Pamamycins,
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Kim, J. Crawford, J. Org. Chem. 2003, 68, 6096–6107.
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3.95 (m, 4 H), 3.39–3.34 (m, 1 H), 3.32 (dd, J = 1.56, 10.84 Hz, 1
H), 2.02 (dd, J = 1.60, 7.0 Hz, 1 H), 1.91–1.81 (m, 1 H), 1.50 (d, J
= 3.52 Hz, 2 H), 1.47–1.40 (m, 2 H), 1.39 (s, 3 H), 1.38 (s, 3 H),
1.30 (s, 3 H), 0.96 (d, J = 6.96 Hz, 3 H), 0.94 (t, J = 7.32 Hz, 3 H),
0.86 (d, J = 6.69 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 215.4, 109.2, 76.3, 64.3, 48.7, 36.3, 35.5, 31.0, 23.9, 19.2, 18.3,
7.5 ppm.
1
Acetonide 26c (anti-anti): H NMR (400 MHz, CDCl3): δ = 4.04–
4.00 (m, 4 H), 3.46–3.41 (m, 1 H), 3.31 (dd, J = 2.5, 10.5 Hz, 1 H),
2.58 (s, 2 H), 2.13–2.05 (m,1 H), 1.87 (dd, J = 2.5, 7.05 Hz, 1 H),
1.82–1.73 (m, 1 H), 1.48 (s, 9 H), 1.46–1.40 (m, 2 H), 1.39–1.36 (m,
1 H), 1.38 (s, 3 H), 1.34 (s, 3 H), 0.95 (d, J = 7.05 Hz, 3 H), 0.85
(d, J = 7.05 Hz, 3 H), 0.77 (d, J = 7.05 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.8, 109.7, 97.6, 80.5, 77.7, 74.2, 65.0,
43.9, 35.8, 33.2, 30.1, 28.1, 28.0, 27.1, 20.1, 19.6, 14.3, 11.8 ppm.
Prasad-Narasaka Reduction of 25b–d and Acetonide Formation: A
typical experimental procedure is as follows. The hydroxy ketones
25b,c (1 mmol) were dissolved in a mixture of anhydrous THF/
MeOH (8:2, 10.0 mL) in a dry round-bottomed flask under argon.
The solution was charged at –78 °C with diethyl(methoxy)borane
(1  solution in THF, 1.1 mmol, 1 equiv.) and stirred for 45 min,
at which time NaBH4 (1.1 mmol, 1.1 equiv.) was added portion-
wise. The reaction mixture was stirred at –78 °C for 5 h, quenched
with aq. acetic acid (1 , 6 mL), and allowed to warm to room
temperature. The mixture was neutralised with saturated aq.
NaHCO3, and AcOEt (20 mL) was added. The mixture was stirred
for 30 min, the aqueous phase was acidified by the addition of aq.
sulfuric acid (10% w/w), and the mixture was extracted with AcOEt
(3ϫ50 mL). The combined organic layers were washed with brine,
dried with MgSO4 and concentrated in vacuo. Finally, boronic ester
hydrolysis was achieved by adding MeOH and distilling the re-
sulting MeOH/Et2BOMe azeotrope. The crude mixture was placed
in acetone (5 mL) in the presence of dimethoxypropane (2 mmol)
and camphorsulfonic acid (0.1 mmol). The mixture was stirred
overnight, neutralised with saturated aq. NaHCO3, and extracted
with CH2Cl2 (3ϫ10 mL). The combined organic layers were
[15] P. A. Krapcho, J. A. Lovey, Tetrahedron Lett. 1973, 12, 957–
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Eur. J. Org. Chem. 2007, 4065–4075

Boron-Mediated Aldol Reaction of 2-(1,3-Dioxolan-2-yl)ethyl Ethyl Ketones
FULL PAPER
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Received: April 10, 2007
Published Online: July 3, 2007
Eur. J. Org. Chem. 2007, 4065–4075
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4075