Diastereoselective conjugate addition to chiral α,β-unsaturated carbonyl systems in aqueous media: An enantioselective entry to α- and γ-hydroxy acids and α-amino acids

Article abstract of DOI:10.1002/chem.200304790

The stereoselectivity of the ultrasonically induced zinc-copper conjugate addition of iodides to chiral α,βunsaturated carbonyl systems under aqueous conditions was studied. Alkyl iodides add diastereoselectively to methylenedioxolanone 1 and methyleneoxa

Full text of DOI:10.1002/chem.200304790

FULL PAPER
Diastereoselective Conjugate Addition to Chiral a,b-Unsaturated Carbonyl
Systems in Aqueous Media: An Enantioselective Entry to a- and g-Hydroxy
Acids and a-Amino Acids
Rosa M. Sua¬rez, Jose¬ Pe¬rez Sestelo,* and Luis A. Sarandeses*[a]
Abstract: The stereoselectivity of the
ultrasonically induced zinc copper con-
jugate addition of iodides to chiral a,b-
unsaturated carbonyl systems under
aqueous conditions was studied. Alkyl
iodides add diastereoselectively to
methylenedioxolanone 1 and methyle-
neoxazolidinone 2 to afford the 1,4-
addition products in good yields (38
95%) and with high diastereomeric
excess (44 90% de). The 1,4-addition
to chiral g,d-dioxolanyl-a,b-unsaturated
esters 3 5 also proceeds with good
yields (51 99%). The diastereoselectiv-
ity is dependent on the geometry of the
olefin: the Z isomer 3 gives high dia-
stereoselectivity, while the reactions
with the E isomer 4 are nonstereoselec-
tive. The reaction proceeds with excel-
lent chemoselectivity and allows the use
of iodides bearing ester, hydroxy, and
amino groups. Since the 1,4-addition
products can be readily hydrolyzed, this
methodology constitutes a novel entry
for the enantioselective synthesis of a-
and g-hydroxy acids and a-amino acids
in aqueous media. The results obtained
support the radical mechanism proposed
by Luche, and represent one of the few
examples of a radical stereoselective
conjugate addition in aqueous medium.
Keywords: aqueous media ¥ asym-
metric synthesis ¥ diastereoselectiv-
ity ¥ Michael addition ¥ radicals
nucleophiles such as organometallic species or radicals is of
current interest, but very few examples have been reported to
date.[6] Furthermore, stereoselective conjugate additions in
aqueous media remain practically unknown.[7]
One of the most important methods to perform conjugate
additions in aqueous media was discovered by Luche et al. in
1986.[8] Alkyl halides add regioselectively to electron-deficient
olefins in the presence of a zinc copper couple under ultra-
sonic irradiation (Scheme 1). This aqueous reaction combines
several advantages over other methods such as simplicity, mild
reaction conditions, and high chemoselectivity. Despite these
interesting features, the stereoselectivity of this reaction and its
utility in asymmetric synthesis has not been studied in detail.[9]
Introduction
Water is an attractive solvent for chemical reactions owing to
its low cost, safety, and environmental compatibility.[1] More-
over, the study of organic reactions in water is important to
gain an understanding of the basic mechanisms of life. During
the past decade, fundamental organic reactions such as
cyclizations, aldol reactions, allylations, oxidations, hydro-
genations and others have been performed in aqueous
media,[1] but aqueous stereoselective variants are still unde-
veloped in many cases.[2] Indeed, the majority of stereo-
selective processes is performed in apolar and aprotic media,
which precludes the use of water-soluble compounds and
requires the use of protecting groups.
The 1,4-conjugate addition reaction,[3] which is one of the
most important transformations in organic chemistry, has
been studied under aqueous conditions. The first break-
throughs in this area concerned Michael additions,[4] but more
recently this has been extended to other stabilized nucleo-
philes under different reaction conditions.[5] The use of other
Scheme 1. Luche×s conjugate addition.
The mechanism for the Zn(Cu) conjugate addition has been
a subject of study and debate. Although a mechanism
involving some type of organometallic species cannot be
discarded, the radical pathway shown in Scheme 2 has been
proposed.[8c] In the first step, a single-electron transfer (SET)
occurs from the metal surface to the carbon halogen bond,
which subsequently breaks to generate an adsorbed radical. In
the subsequent steps a radical 1,4-addition to the a,b-unsatu-
¬
[a] Dr. J. Perez Sestelo, Prof. Dr. L. A. Sarandeses
Departamento de QuÌmica Fundamental
Universidade da Corunƒa
15071 A Coruna (Spain)
ƒ
Fax: ( ‡34)981 167065
E-mail: sestelo@udc.es, qfsarand@udc.es
Supporting information for this article is available on the www under
http://www.chemeurj.org or from the author.
Chem. Eur. J. 2003, 9, 4179 4187
DOI: 10.1002/chem.200304790
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4179

¬
¬
J. Perez Sestelo L. A. Sarandeses and R. M. Suarez
FULL PAPER
g-hydroxy acids, a-amino acids, and complexnatural products.
The stereoselective conjugate addition of radicals in aqueous
media is also a relatively unexplored methodology.[15]
Conjugate addition to methylenedioxolanone 1 and methyl-
eneoxazolidinone 2: We started our investigation by studying
the reaction of various alkyl iodides (6a g, Table 1) with the
Seebach dioxolanone 1, which can be efficiently prepared in
enantiomerically pure form from (S)-lactic acid.[16] The radical
Scheme 2. Mechanism proposed for the zinc copper conjugate addition.
Table 1. Zinc copper-conjugate addition of iodides 6a g to methylene-
dioxolanone 1.
rated system is followed by additional SET, which gives rise to
an enolate that is protonated by the solvent. Evidence for the
enolate intermediate was provided by the use of deuterated
solvents, but the trapping of radical intermediates was
achieved with low yields only.[8c]
Since its discovery, Luche×s conjugate addition has been of
great utility in organic synthesis.[10] In particular, our group
soon found applications for this methodology in the synthesis
of vitamin D metabolites and analogues.[11] Later, we applied
this methodology for the stereoselective synthesis of 24-
hydroxyvitamin D metabolites[12] and 24-aminovitamin D
derivatives.[13] In a recent communication,[14] we reported the
diastereoselective ultrasonically induced zinc copper conju-
gate addition of achiral iodides to chiral a,b-unsaturated
systems in aqueous media. Herein, we summarize our studies
concerning the diastereoselectivity of this interesting reaction
discovered by Luche in the 1980s.
À
R I
Yield [%][a]
cis:trans[b]
1
2
3
4
5
6
7
nC5H11I (6a)
iC3H7I (6b)
cC6H11I (6c)
MeO2C(CH2)3I (6d)
HO(CH2)3I (6e)
HO(CH2)12I (6 f)
(S)-MeO2CCH(NHBoc)CH2I (6g)
75
65
95
65
45
57
72
93:7
95:5
92:8
92:8
92:8
92:8
92:8
[a] Yield of isolated product. [b] cis:trans ratio determined by 1H NMR
spectroscopy.
1,4-addition of alkyl iodides to methylenedioxolanone 1,
under classical reaction conditions (nBu3SnH, azobisisobutyr-
onitrile (AIBN), reflux), proceeds in good yield and with
moderate to good diastereoselectivity (60 75% de).[17] Fol-
lowing previous experimental procedures,[11] dioxolanone 1
was treated with 1-iodopentane (6a, 2 equiv), copper iodide
(2 equiv), and zinc (6 equiv) in EtOH/H2O (7:3). The mixture
was sonicated in an ultrasonic cleaning bath at room temper-
ature. After one hour of sonication it was found (TLC) that
dioxolanone 1 had been consumed and the 1,4-conjugate
addition product was isolated as a cis:trans mixture of
diastereomers in good yield (75%, Table 1, entry 1) and high
stereoselectivity (93:7, 86% de). Under the same experimen-
tal conditions, the reaction of secondary alkyl iodides such as
2-iodopropane (6b) and cyclohexyl iodide (6c) afforded the
conjugate addition products in excellent yield (65 95%) and
diastereoselectivity (84 90% de) (Table 1, entries 2 and 3).
The diastereomeric ratio was determined by integration of the
resonances of H2 and H5 in the 1H NMR spectra of the crude
products, and the stereochemistry of the major diastereomer
was assigned on the basis of NOE experiments, as described in
the literature.[17]
The chemoselectivity of the reaction was investigated by
studying the reactions of iodoester 6d and iodoalcohols 6e,f.
In these cases, the conjugate addition products were obtained
in reasonable yields (45 65%) and high stereoselectivities
(84% de) as the only reaction products (Table 1, entries 3 6).
We also explored the reactivity of more complex iodides
such as the enantiomerically pure serine derivative 6g,[18]
which bears an a-amino ester functionality and is useful in
the synthesis of a-amino acids (Scheme 3).[19] The Zn(Cu)-
Results and Discussion
Herein we describe the study of the stereoselectivity of the
1,4-conjugate addition reaction between organic halides and
chiral Michael acceptors (1 5). In accordance with the
mechanism proposed by Luche et al.(Scheme 2), stereoselec-
tivity could be achieved either in the nucleophilic addition by
using b-substituted Michael acceptors, or in the enolate
protonation step, if the a,b-unsaturated carbonyl system was
a-substituted. For the study of the protonation step we chose
methylenedioxolanone 1 and methyleneoxazolidinone 2,
whereas we chose the g,d-dioxolanyl-a,b-unsaturated esters
3
5 for the study of the nucleophilic-addition step. The
diastereoselective conjugate addition to these chiral a,b-
unsaturated systems was explored under different reaction
conditions using various types of nucleophiles. The results
should serve to establish comparisons and give additional data
about the mechanism of Luche×s conjugate addition. Further-
more, the 1,4-addition products are valuable intermediates in
the synthesis of important organic compounds such as a- and
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Chem. Eur. J. 2003, 9, 4179 4187

Diastereoselective Conjugated Addition
4179 4187
Table 2. Zinc copper conjugate addition of iodides 6a g to methyl-
eneoxazolidinone 2.
Scheme 3. Conjugate addition with serine derivative 6g.
Yield [%][a]
cis:trans[b]
À
R I
1
2
3
4
5
6
nC5H11I (6a)
cC6H11I (6c)
MeO2C(CH2)3I (6d)
HO(CH2)3I (6e)
HO(CH2)12I (6 f)
72
94
56
38
74
61
88:12
91:9
72:28
77:23
77:23
80:20
conjugate addition of iodide 6g (1.5 equiv) to methylenediox-
olanone 1 afforded the protected 5-hydroxyhomoglutamic
acid in good yield (72%, Table 1, entry 7 and Scheme 3) as a
separable mixture of cis:trans diastereomers in an 92:8 ratio
(7g:8g, 84% de). The diastereomeric excess, which is in the
same range as previous examples, indicates that the origin of
the stereoselectivity is the chirality of the dioxolanone.
According to the reaction mechanism proposed by Luche
et al. (Scheme 2), the stereochemistry of the major diaster-
eomer can be explained by stereoselective protonation of the
intermediate enolate generated in aqueous medium, and is
anti with respect to the tert-butyl group. The reaction is
probably under thermodynamic control; monitoring of the
reaction (1H NMR at different reaction times) shows that the
stereoselectivity is constant during the reaction time, that is
epimerization of the reaction products under the reaction
conditions is improbable. The stereochemical outcome of the
Zn(Cu)-conjugate addition is the same as that observed in
previous radical 1,4-additions to dioxolanone 1,[17] and that
observed by Seebach et al. in the alkylation of enolates of
2-tert-butyl-5-alkyl-1,3-dioxolan-4-ones.[16] In comparison
with other methodologies, Luche×s conjugate addition, be-
sides its experimental simplicity and the attractive character-
istics associated with aqueous media, shows excellent chemo-
selectivity with iodides bearing functional groups such as
hydroxy, amino, or ester groups (Table 1, entries 4 7).
Hydrolysis of the resulting addition products should provide
the corresponding enantiopure a-hydroxy acids,[20] a fact that
highlights this methodology as a formal and practical enan-
tioselective synthesis of a-hydroxy acids in aqueous media.
Encouraged by these results we decided to explore the
reactivity of methyleneoxazolidinone 2, a chiral a,b-unsatu-
rated system that has been previously used in radical
conjugate additions for the enantioselective synthesis of a-
amino acids.[21] Following the experimental procedure descri-
bed previously, the reaction of 1-iodopentane and cyclohexyl
iodide with oxazolidinone 2 afforded, after 45 min of soni-
cation, the conjugate addition products in good yields (72
94%) as a mixture of cis:trans diastereomers in 88:12
(76% de) and 91:9 (82% de) ratios, respectively (Table 2,
entries 1 and 2). The addition of iodoester 6d and iodoalco-
hols 6e, f proceeded with moderate yields and with good
stereoselectivities (Table 2, entries 3 5).
(S)-MeO2CCH(NHBoc)CH2I (6g)
[a] Yield of isolated product. [b] cis:trans ratio determined by 1H NMR
spectroscopy.
integration of the resonances in the region d ˆ 6.00 6.25 ppm
1
of the H NMR spectra; the assignments were made on the
basis of trans adducts having signals at lower field than their
cis isomers.[21] As in dioxolanone 1, the stereochemistry of the
major diastereomer was determined to be cis as a result of the
protonation of the enolate intermediate anti to the tert-butyl
group. The lower diastereoselectivity observed in the con-
jugate addition to oxazolidinone 2 (compare with dioxola-
none 1) can be attributed to the presence of the nitrogen atom
and its protecting group.[21] Interestingly, this stereochemical
outcome is opposite to that observed by Beckwith in 1,4-
conjugate additions under classical radical conditions
(nBu3SnH/AIBN),[21] but it is consistent with results obtained
by Seebach in the alkylation of enolates of 2-tert-butyl-5-
alkyl-1,3-oxazolidin-4-ones.[20] This result can be explained in
terms of the mechanism proposed by Luche (Scheme 2): a
nucleophilic radical mechanism for the initial step followed by
the protonation of an intermediate enolate. As in the case of
dioxolanone 1, hydrolysis of the conjugate addition products
should afford the corresponding enantiopure a-amino acids.
Therefore, the Zn(Cu) conjugate addition can be a useful
methodology for the enantioselective synthesis of a-amino
acids in aqueous media.[20]
Conjugate addition to g-oxy-a,b-unsaturated ester derivatives
3
5: Having determined the diastereoselectivity in the
Zn(Cu)-conjugate addition to 1 and 2 in the protonation
step, we proceeded to study the stereoselectivity in the
nucleophilic addition step. For this purpose we used acyclic
Michael acceptors bearing a chiral center at the g position,
such as g-oxy-a,b-unsaturated ester derivatives 3 5, derived
from (R)-2,3-O-isopropylideneglyceraldehyde.[23] The reactiv-
ity of these substrates in conjugate additions was studied with
a variety of nucleophiles. The stereochemical outcome is
dependent on the nature of the nucleophile and the geometry
of the double bond.[24]
The first series of experiments was performed with methyl
(S)-(2,2-dimethyl-1,3-dioxolane-4-yl)-cis-2-propenoate (3).
Under the same experimental conditions as for dioxolanone
1, we observed that the sonochemical conjugate addition of
iodides 6a e occurs in good yields (51 86%), although
The Zn(Cu)-conjugate addition of serine derivative 6g with
oxazolidinone 2 afforded the conjugate addition product 9g, a
protected derivative of diaminoadipic acid,[22] in 61% yield as
a separable mixture of cis:trans diastereomers in a 80:20 ratio
(Table 2, entry 6 and Scheme 3).
The diastereomeric ratio of the conjugate addition products
(9:10) was measured from the crude reaction mixture by
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¬
J. Perez Sestelo L. A. Sarandeses and R. M. Suarez
FULL PAPER
longer reaction times (3 h) and a larger excess of the iodide
(up to 6 equiv) were necessary to complete the reactions
(Table 3, entries 1 5). This lower reactivity is expected given
the substitution of the a,b-unsaturated system at the b-carbon
atom, which makes this center less reactive due to steric and
electronic effects. Nevertheless, the reactions exhibit high
stereoselectivity, affording a syn:anti diastereomeric mixture
in ratios from 86:14 to 96:4 (72 92% de).
sonication with sixequivalents of alkyl iodide, the reaction
was still incomplete (Table 2, entries 6 8). Additionally, we
Table 3. Zinc copper conjugate addition of iodides 6a e to the cis (3)
and trans (4) methyl (S)-(2,2-dimethyl-1,3-dioxolane-4-yl)-2-propenoate.
Scheme 5. Most stable conformers for cis alkene 3 and trans alkene 4.[24b]
found that the reactions were nonstereoselective, a situation
that indicates the importance of the geometry of the alkene in
the stereoselectivity. Similar behavior has previously been
observed in the 1,4-addition of alkyl radicals to these
substrates, and attributed to the fact that the 1,3-allylic strain
in the trans alkene 4 is very low, thus allowing the rotation of
À
R I
a,b-Unsaturated system Yield [%][a] syn:anti[b]
1
2
3
4
5
6
7
8
nC5H11I (6a)
iC3H7I (6b)
cC6H11I (6c)
MeO2C(CH2)3I (6d)
HO(CH2)3I (6e)
nC5H11I (6a)
iC3H7I (6b)
3
3
3
3
3
4
4
4
82
64
86
67
93:7
88:12
96:4
86:14
87:13
52:48
52:48
54:46
À
the C3 C4 bond and preventing the facial selection
(Scheme 5).
51
The stereochemical outcome of the zinc copper 1,4-
addition to 3 and 4 is the same as that obtained under the
classical radical conditions (nBu3SnH, AIBN), which pro-
ceeded with syn 1,2-stereoinduction for the Z isomer (2) but a
lack of stereoselectivity for the E isomer (3). Interestingly, the
results are contrary to those observed in the conjugate
addition of organocopper reagents (anti stereoselectivi-
ty),[24d, 26] a fact that supports the radical mechanism proposed
by Luche and co-workers.
In an attempt to increase the reactivity of the a,b-
unsaturated systems 3 and 4, we prepared a more electron-
deficient a,b-unsaturated carbonyl system bearing a diester
group at the a-position (5). The Michael acceptor 5 was
prepared by Knoevenagel condensation of (R)-2,3-O-isopro-
pylideneglyceraldehyde with diethyl malonate.[27] In accord-
47 (18)[c]
48 (30)[c]
48 (35)[c]
cC6H11I (6c)
[a] Yield of isolated product. [b] Diastereomeric ratio estimated by
quantitative 13C NMR spectroscopy. [c] Yields of recovered 4 in paren-
theses.
The diastereomeric excess was measured by integration of
the g-carbon signal (d ˆ 65.0 68.0 ppm) in quantitative
13C NMR spectra. The stereochemistries of the 1,4-addition
products (11a,b, 12a, b) derived from the addition of
1-iodopentane (6a) and isopropyl iodide (6b) to 3 were
determined by conversion to the known lactones 13a and 13b
(Scheme 4).[24a c] The stereochemistries of the other conjugate
addition products were determined by chemical correlation.
ance with our predictions, the reaction of iodides 6a
e
(2 equiv) with 5 proceeded to completion after less than
45 min of sonication (i.e. similar reaction times as 1 and 2) to
afford the conjugate addition products 15/16a e in excellent
Table 4. Zinc copper conjugate addition of iodides 6a e to (S)- g,d-
dioxolanyl-a,b-unsaturated ester 5.
Scheme 4. Lactonization of conjugate addition products obtained from 3.
The 1,2-stereoinduction obtained, which leads to the syn
adducts as the major diastereomers, can be explained by
assuming that, in the transition state, the alkene adopts a
conformation in which the 1,3-allylic strain is minimized
(Scheme 5).[25] The role of the geometry of the double bond in
the g-oxy-a,b-unsaturated ester 3 was studied by performing
the conjugate addition on the trans isomer 4. Under the same
reaction conditions, it was found that the trans alkene 4 has a
lower reactivity than the cis alkene 3. For example, after 3 h of
À
R I
Yield [%][a]
syn:anti[b]
1
2
3
4
5
nC5H11I (6a)
iC3H7I (6b)
cC6H11I (6c)
MeO2C(CH2)3I (6d)
HO(CH2)3I (6e)
96
70
99
72
52
87:13
88:12
84:16
83:17
83:17
[a] Yield of isolated product. [b] Diastereomeric ratio estimated by
quantitative 13C NMR spectroscopy.
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Chem. Eur. J. 2003, 9, 4179 4187

Diastereoselective Conjugated Addition
4179 4187
(1 mmol) and alkyl iodide (6a g, 2 6 mmol) in aqueous EtOH (5 mL,
70%) under ultrasonic irradiation. After few minutes, more aqueous EtOH
(5 mL, 70%) was added and sonication was continued for 45 90 min. In
the cases where the a,b-unsaturated system was not completely consumed
(TLC test), more CuI (1 mmol) and Zn (3 mmol) were added, and the
sonication was continued for 3 h. The
yields (up to 99%, Table 4). The stereoselectivity was of the
same order as those observed with cis alkene 3 (66 74% de).
As in the case of 3, the major diastereomer corresponds to
the product of syn addition. The stereochemistries of the
mixture was diluted with Et2O
(25 mL), sonicated a further 10 min,
and filtered through a short pad of
Celite. The solids were washed with
Et2O (3 Â 30 mL). The organic phase
was washed with brine (30 mL), dried
(Na2SO4 anhydrous), filtered, and con-
centrated under reduced pressure
Scheme 6. Lactonization of conjugate addition product 15a:16a derived from diester 5.
(20 30 mmHg). The residue was pu-
rified by flash chromatography to
afford, after concentration, the desired
1,4-addition product.
reaction products were determined by chemical correlation
or, in the case of 15a/16a, by transformation into the
corresponding lactone, analysis of the coupling constant,
and NOE experiments (Scheme 6).
(2S,5x)-2-(tert-Butyl)-5-hexyl-1,3-dioxolan-4-one (7a:8a): Following the
general experimental procedure, a mixture containing dioxolanone 1
(65 mg, 0.416 mmol) and 1-iodopentane (163 mL, 1.248 mmol) was treated
with CuI (158 mg, 0.832 mmol) and Zn (163 mg, 2.496 mmol) to give, after
column chromatography (10% EtOAc/hexanes), 7a:8a (71 mg, 75%, 93:7,
86% de) as a yellow oil. Rf ˆ 0.6 (30% EtOAc/hexanes); IR (neat): nÄ ˆ
In summary, the ultrasonically induced zinc copper con-
jugate addition of alkyl iodides to asymmetric a,b-unsatu-
rated carbonyl systems can be performed in a stereoselective
manner on methylenedioxolanone 1, methyleneoxazolidinone
2, and g,d-dioxolanyl-a,b-unsaturated esters 3 and 5. The
reaction proceeds in good yields (45 99%) and gives high
stereoselectivities (44 90% de). The results obtained support
the mechanism proposed by Luche and co-workers: the
nucleophilic addition seems to be performed by a radical
species and the final step is the protonation of an enolate. The
stereoselectivity is similar to that obtained with other
nucleophiles although the experimental simplicity, the aque-
ous medium and high chemoselectivity should be highlighted.
Since the conjugate addition products can be readily hydro-
lysed, the zinc copper conjugate addition provides a new
entry for the synthesis of a-amino acids, as well as a- and g-
hydroxy acids, in aqueous media.
2960 2873, 1802, 1197 1103 cmÀ1 1H NMR (200 MHz, CDCl3, 258C):
;
d ˆ 0.90 (t, J ˆ 6.8 Hz, 3H), 0.99 (s, 9H), 1.20 1.95 (m, 10H), 4.25 (ddd, J ˆ
6.8, 4.4, 1.0 Hz, 0.93H), 4.35 (ddd, J ˆ 6.8, 4.4, 1.0 Hz, 0.07H), 5.12 (d, J ˆ
1.5 Hz, 0.93H) 5.27 ppm (d, J ˆ 1.5 Hz, 0.07H); 13C NMR (50 MHz, CDCl3,
258C): d ˆ 14.0 (CH3), 22.5 (CH2), 23.4 (3  CH3), 24.9 (CH2), 28.8 (CH2),
30.6 (CH2), 31.5 (CH2), 34.2 (C), 75.1 (CH), 109.3 (CH), 173.7 ppm (C); MS
‡
‡
(FAB): m/z (%): 229 (13) [M ‡H], 228 (48) [M ], 149 (100); HRMS
‡
(FAB): m/z: calcd for C13H25O3: 229.1804 [M ‡H]; found: 229.1797.
(2S,5x)-2-(tert-Butyl)-5-(2-methylpropyl)-1,3-dioxolan-4-one (7b:8b):[16a]
Following the general experimental procedure, a mixture containing
dioxolanone
1 (100 mg, 0.64 mmol) and 2-iodopropane (192 mL,
1.92 mmol) was treated with CuI (244 mg, 1.28 mmol) and Zn (251 mg,
3.84 mmol) to give, after column chromatography (10% EtOAc/hexanes),
7b:8b (79 mg, 65%, 95:5, 90% de) as a yellow oil. Rf ˆ 0.5 (20% EtOAc/
hexanes); IR (neat): nÄ ˆ 2962 2875, 1797, 1197 1104 cmÀ1
;
1H NMR
(200 MHz, CDCl3, 258C): d ˆ 0.98 (s, 9H), 1.00 (s, 6H), 1.55 2.00 (m, 2H),
4.28 (ddd, J ˆ 10.3, 9.3, 4.9 Hz, 1H), 5.14 (d, J ˆ 1.0 Hz, 0.95H), 5.26 ppm
(d, J ˆ 1.0 Hz, 0.05H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 21.9 (CH3),
22.8 (CH3), 23.4 (3 Â CH3), 25.1 (CH), 34.2 (C), 39.7 (CH2), 73.7 (CH),
‡
109.4 (CH), 174.1 ppm (C); MS (FAB): m/z (%): 201 (14) [M ‡H], 200
‡
(78) [M ], 171 (36), 133 (100); HRMS (FAB): m/z: calcd for C11H21O3:
‡
201.1491 [M ‡H]; found: 201.1481.
Experimental Section
(2S,5x)-2-(tert-Butyl)-5-cyclohexylmethyl-1,3-dioxolan-4-one (7c:8c):[17]
Following the general experimental procedure, a mixture containing
General materials and methods: Unless otherwise stated, all reactions were
conducted in flame-dried glassware under a positive pressure of argon.
Reaction temperatures refer to external bath temperatures. All dry
solvents were distilled under argon immediately prior to use. Absolute
MeOH and EtOH were distilled from Mg turnings. For conjugate addition
reactions, Milli-Q water was used and the solvent mixture EtOH:H2O was
deoxygenated by bubbling a positive pressure of argon through for 10 min.
Zinc dust (325 mesh) was used without purification and copper iodide was
purified by recrystallization from saturated potassium iodide solution.[28]
All other reagents were commercial products and used as received.
Sonications were carried out in a Selecta SE3000513 (50 kHz, 150 W)
cleaning bath, filled with water and thermostated (18 208C) by running
tap water through a stainless steel coil. Thin-layer chromatography was
carried out on Merck silica gel 60 F254 (layer thickness 0.2 mm) and
components were located by observation under UV light and/or by treating
the plates with a phosphomolybdic acid or p-anisaldehyde reagent followed
by heating. Flash column chromatography was performed on Merck silica
gel 60 (230 400 mesh) by Still×s method.[29] [a]D: Jasco DIP-1000. UV:
dioxolanone
1 (100 mg, 0.64 mmol) and cyclohexyl iodide (248 mL,
1.92 mmol) was treated with CuI (244 mg, 1.28 mmol) and Zn (251 mg,
3.84 mmol) to give, after column chromatography (10% EtOAc/hexanes),
7c:8c (146 mg, 95%, 92:8, 84% de) as a yellow oil. Rf ˆ 0.6 (30% EtOAc/
hexanes); IR (neat): nÄ ˆ 2925 2853, 1799, 1216 1194 cmÀ1
;
1H NMR
(200 MHz, CDCl3, 258C): d ˆ 0.97 (s, 9H), 1.15 1.85 (m, 13H), 4.31 (ddd,
J ˆ 7.8, 3.9, 1.0 Hz, 0.92H), 4.42 (ddd, J ˆ 7.8, 3.9, 1.0 Hz, 0.08H), 5.12 (d,
J ˆ 1.0 Hz, 0.92H), 5.25 ppm (d, J ˆ 1.0 Hz, 0.08H); 13C NMR (50 MHz,
CDCl3, 258C): d ˆ 23.4 (3), 26.0, 26.1, 26.3, 32.6, 33.5, 34.3, 38.3, 73.4, 109.3,
‡
‡
174.1 ppm; MS (70 eV, EI): m/z (%): 241 (10) [M ‡H], 240 (61) [M ], 225
‡
(8) [M À CH3], 149 (100); HRMS (FAB): m/z: calcd for C14H25O3:
‡
241.1804 [M ‡H]; found: 241.1792.
Methyl
5-[(2S,4x)-2-(tert-butyl)-5-oxo-1,3-dioxolan-4-yl]pentanoate
mixture
(7d:8d): Following the general experimental procedure,
a
containing dioxolanone 1 (100 mg, 0.64 mmol) and methyl 4-iodobutyrate
(259 mL, 1.92 mmol) was treated with CuI (244 mg, 1.28 mmol) and Zn
(251 mg, 3.84 mmol) to give, after column chromatography (10% EtOAc/
hexanes), 7d:8d (107 mg, 65%, 92:8, 84% de) as a yellow oil. Rf ˆ 0.4
(30% EtOAc/hexanes); IR (neat): nÄ ˆ 2961 2874, 1799, 1739, 1197
1
Kontron Uvikon 941. IR: Matson FTIR. H NMR: 200 MHz, Bruker AC-
200F. 13C NMR: 50 MHz, Bruker AC-200F (DEPT was used to assign
carbon types). MS: Fisons VG-Quattro. HRMS: VG Autospec M.
1116 cmÀ1
;
1H NMR (200 MHz, CDCl3, 258C): d ˆ 0.98 (s, 9H), 1.50
General experimental procedure for conjugate addition of alkyl iodides
(6a g) to chiral a,b-unsaturated systems 1 5: CuI (2 mmol) and Zn
2.05 (m, 6H), 2.35 (dd, J ˆ 14.6, 7.3 Hz, 2H), 4.25 (dd, J ˆ 5.9, 4.4 Hz,
0.92H), 4.36 (dd, J ˆ 5.9, 4.4 Hz, 0.08H), 5.12 (d, J ˆ 1.0 Hz, 0.92H),
5.27 ppm (d, J ˆ 1.0 Hz, 0.08H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ
(6 mmol) were added to a solution of the chiral Michael acceptor 1
5
Chem. Eur. J. 2003, 9, 4179 4187 www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4183

¬
¬
J. Perez Sestelo L. A. Sarandeses and R. M. Suarez
FULL PAPER
1212 cmÀ1; 1H NMR (200 MHz, CDCl3, 258C): d ˆ 1.05 (s, 9H), 0.83 1.91
(m, 12H), 4.03 (dd, J ˆ 10.7, 2.9 Hz, 0.91H), 4.4 (dd, J ˆ 7.8, 2.4 Hz, 0.09H),
6.08 (s, 0.91H), 6.20 (s, 0.09H), 7.37 7.61 ppm (m, 5H); 13C NMR
(50 MHz, CDCl3, 258C): d ˆ 25.2 (3  CH3), 25.8 (CH2), 25.9 (CH2), 26.2
(CH2), 31.4 (CH2), 33.8 (CH2), 34.3 (CH), 36.9 (C), 42.6 (CH2), 55.7 (CH),
95.1 (CH), 126.5 (2 Â CH), 128.8 (2 Â CH), 130.4 (CH), 135.8 (C), 172.4 (C),
23.4 (3 Â CH3), 24.4 (CH2), 28.7 (CH2), 30.2 (CH2), 33.7 (CH2), 51.5 (CH3),
74.8 (CH), 109.3 (CH), 173.4 (C), 173.8 ppm (C); MS (70 eV, EI): m/z (%):
‡
258 (10) [M ], 111 (100); HRMS (FAB): m/z: calcd for C13H23O5: 259.1545
‡
[M ‡H]; found: 259.1545.
(2S,5x)-2-(tert-Butyl)-5-(4-hydroxybutyl)-1,3-dioxolan-4-one (7e:8e): Fol-
lowing the general experimental procedure, a mixture containing dioxo-
lanone 1 (150 mg, 0.96 mmol) and 3-iodo-1-propanol (275 mL, 2.88 mmol)
was treated with CuI (365 mg, 1.92 mmol) and Zn (377 mg, 5.76 mmol) to
give, after column chromatography (20% EtOAc/hexanes), 7e:8e (94 mg,
45%, 92:8, 84% de) as a yellow oil. Rf ˆ 0.2 (40% EtOAc/hexanes); IR
‡
‡
173.8 ppm (C); MS (70 eV, EI): m/z (%): 343 (2) [M ], 328 (2) [M À CH3],
‡
286 (78) [M À C4H9], 105 (100); HRMS (EI): m/z: calcd for C21H29NO3:
‡
343.2147 [M ]; found: 343.2147.
Methyl
5-[(2S,4x)-3-benzoyl-2-(tert-butyl)-5-oxo-4-oxazolidinyl]penta-
noate (9d:10d): Following the general experimental procedure, a mixture
containing 2 (80 mg, 0.308 mmol) and methyl 4-iodobutyrate (80 mL,
0.617 mmol) was treated with CuI (117 mg, 0.617 mmol) and Zn (121 mg,
1.848 mmol) to give, after column chromatography (15% EtOAc/hexanes),
9d:10d (56 mg, 56%, 72:28, 44% de) as a yellow oil. Rf ˆ 0.25 (30%
EtOAc/hexanes); IR (neat): nÄ ˆ 3017 2890, 1760, 1720, 1670, 1474 1456,
1215, 1183, 1162 cmÀ1; 1H NMR (200 MHz, CDCl3, 258C): d ˆ 1.03 (s, 9H),
1.22 1.98 (m, 6H), 2.16 (dd, J ˆ 15.6, 8.3 Hz, 2H), 3.64 (s, 3H), 3.9 (dd, J ˆ
10.3, 2.9 Hz, 0.72H), 4.42 (m, 0.28H), 6.06 (s, 0.72H), 6.18 (s, 0.28H), 7.37
7.65 ppm (m, 5H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 24.0 (CH2), 25.1
(3 Â CH3), 25.9 (CH2), 33.5 (CH2), 34.9 (CH2), 33.5 (CH2), 34.9 (CH2), 36.9
(C), 51.5 (CH3), 57.6 (CH), 95.4 (CH), 126.5 (2 Â CH), 128.8 (2 Â CH), 130.6
(CH), 135.6 (C), 172.2 (C), 173.4 (C), 173.5 ppm (C); MS (70 eV, EI): m/z
(neat): nÄ ˆ 3391, 2962 2874, 1796, 1201 1115 cmÀ1
;
1H NMR (200 MHz,
CDCl3, 258C): d ˆ 0.99 (s, 9H), 1.55 1.96 (m, 6H), 3.60 3.71 (m, 2H), 4.27
(ddd, J ˆ 6.8, 4.4, 1.0 Hz, 0.92H), 4.38 (ddd, J ˆ 6.8, 4.4, 1.0 Hz, 0.08H), 5.15
(d, J ˆ 1.5 Hz, 0.92H), 5.28 ppm (d, J ˆ 1.5 Hz, 0.08H); 13C NMR (50 MHz,
CDCl3, 258C): d ˆ 21.3 (CH2), 23.4 (3  CH3), 30.3 (CH2), 34.2 (C), 62.4
(CH2), 75.0 (CH), 109.3 (CH), 173.5 ppm (C); MS (FAB): m/z (%): 217 (54)
‡
[M ‡H], 147 (100); HRMS (FAB): m/z: calcd for C11H21O4: 217.1440
‡
[M ‡H]; found: 217.1447.
(2S,5x)-2-(tert-Butyl)-5-(13-hydroxytridecyl)-1,3-dioxolan-4-one (7 f:8 f):
Following the general experimental procedure, a mixture containing
dioxolanone 1 (100 mg, 0.64 mmol) and 12-iodo-1-dodecanol (600 mg,
1.92 mmol) was treated with CuI (244 mg, 1.28 mmol) and Zn (251 mg,
3.84 mmol) to give, after column chromatography (20% EtOAc/hexanes),
7 f:8 f (170 mg, 57%, 92:8, 84% de) as a yellow oil. Rf ˆ 0.5 (50% EtOAc/
‡
‡
‡
‡
(%): 362 (7) [M ‡H], 361 (10) [M ], 346 (14) [M À CH3), 330 (5) [M À
‡
CH3O], 304 (17) [M À C4H9], 105 (100); HRMS (EI): m/z: calcd for
hexanes); IR (neat): nÄ ˆ 3363, 2925 2854, 1800, 1197 cmÀ1
;
1H NMR
‡
C20H27NO5: 361.1889 [M ]; found: 361.1892; elemental analysis calcd (%)
(200 MHz, CDCl3, 258C): d ˆ 0.98 (s, 9H), 0.87 0.95 (m, 2H), 1.18 1.90
(m, 20H), 3.48 (q, J ˆ 6.8 Hz, 1H), 3.65 (t, J ˆ 6.3 Hz, 2H), 4.25 (ddd, J ˆ
11.7, 4.4, 1.5 Hz, 0.92H), 4.28 (ddd, J ˆ 11.7, 4.4, 1.5 Hz, 0.08H), 5.12 (d, J ˆ
1.5 Hz, 0.92H), 5.25 ppm (d, J ˆ 1.5 Hz, 0.08H); 13C NMR (50 MHz,
CDCl3, 258C): d ˆ 23.2 (CH2), 23.4 (3  CH3), 24.9 (CH2), 25.7 (CH2), 29.2
(CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.5 (CH2), 30.6 (CH2), 32.8
(CH2), 34.2 (C), 63.0 (CH2), 75.1 (CH), 109.3 (CH), 173.7 ppm (C); MS
for C20H27NO5 (361.4): C 66.46, H 7.53, N 3.88; found: C 66.17, H 7.52, N
3.71.
(2S,4x)-3-Benzoyl-2-(tert-butyl)-4-(4-hydroxybutyl)-5-oxazolidinone
(9e:10e): Following the general experimental procedure,
a mixture
containing (60 mg, 0.231 mmol) and 3-iodo-1-propanol (44 mL,
2
0.46 mmol) was treated with CuI (88 mg, 0.46 mmol) and Zn (91 mg,
1.39 mmol) to give, after column chromatography (40% EtOAc/hexanes),
9e:10e (28 mg, 38%, 77:23, 54% de) as a yellow oil. Rf ˆ 0.2 (50% EtOAc/
hexanes); IR (neat): nÄ ˆ 3647, 2980 2947, 1843, 1714, 1472 1456, 1253,
1213 cmÀ1; 1H NMR (200 MHz, CDCl3, 258C): d ˆ 1.03 (s, 9H), 1.43 2.02
(m, 6H), 3.50 (t, J ˆ 5.8 Hz, 2H), 3.91 (dd, J ˆ 10.3, 2.9 Hz, 0.77H), 4.44 (m,
0.23H), 6.07 (s, 0.77H), 6.19 (s, 0.23H), 7.38 7.65 ppm (m, 5H); 13C NMR
(50 MHz, CDCl3, 258C): d ˆ 22.8 (CH2), 25.1 (3  CH3), 31.6 (CH2), 35.0
(CH2), 36.9 (C), 57.7 (CH), 62.2 (CH2), 95.4 (CH), 126.5 (2 Â CH), 128.8
(2 Â CH), 130.6 (CH), 135.6 (C), 172.4 (C), 173.7 ppm (C); MS (70 eV, EI):
‡
(FAB): m/z (%): 343 (64) [M ‡H], 154 (100); HRMS (FAB): m/z: calcd
‡
for C20H39O4: 343.2848 [M ‡H]; found: 343.2836.
Methyl (2R)-2-[(tert-butoxycarbonyl)amino]-4-[(2S,4S)-2-(tert-butyl)-5-
oxo-1,3-dioxolan-4-yl]butanoate (7g): Following the general experimental
procedure, dioxolanone
1 (60 mg, 0.384 mmol) and 6g (242 mg,
0.768 mmol) was treated with CuI (219 mg, 1.152 mmol) and Zn (176 mg,
2.688 mmol) to give, after column chromatography (20% EtOAc/hexanes),
7g and 8g (91 mg and 8 mg, respectively, 72%, 92:8, 84% de) as colorless
oils. Rf ˆ 0.30 (7g) and 0.35 (8g) (30% EtOAc/hexanes); 7g: IR (neat): nÄ ˆ
2974 2876, 1797, 1745, 1714, 1199 1171 cmÀ1; 1H NMR (200 MHz, CDCl3,
258C): d ˆ 0.98 (s, 9H), 1.45 (s, 9H), 1.77 2.01 (m, 4H), 3.76 (s, 3H), 4.25
(m, 1H), 4.35 (m, 1H), 5.14 ppm (d, J ˆ 1.0 Hz, 1H); 13C NMR (50 MHz,
CDCl3, 258C): d ˆ 23.4 (3  CH3), 26.7 (CH2), 28.2 (CH2), 28.2 (3  CH3),
34.2 (C), 52.4 (CH3), 74.5 (CH), 109.4 (2 Â CH), 172.8 ppm (C); MS (CI):
‡
‡
‡
m/z (%): 320 (9) [M ‡H], 319 (11) [M ], 304 (16) [M À CH3], 262 (7)
‡
[M À C4H9), 105 (100); HRMS (EI): m/z: calcd for C18H25NO4: 319.1784
‡
[M ]; found: 319.1795.
(2S,4x)-3-Benzoyl-2-(tert-butyl)-4-(13-hydroxytridecyl)-5-oxazolidinone
(9 f:10 f): Following the general experimental procedure,
a mixture
containing (80 mg, 0.308 mmol) and 12-iodo-1-dodecanol (193 mg,
2
‡
m/z (%): 360 (16) [M ‡H], 260 (100); HRMS (CI): m/z: calcd for
0.617 mmol) was treated with CuI (117 mg, 0.617 mmol) and Zn (121 mg,
1.848 mmol) to give, after column chromatography (20% EtOAc/hexanes),
9 f:10 f (96 mg, 74%, 77:23, 54% de) as a yellow oil. Rf ˆ 0.15 (30%
EtOAc/hexanes); IR (neat): nÄ ˆ 3676, 2880 2850, 1780, 1675, 1485 1450,
1245, 1212 cmÀ1; 1H NMR (200 MHz, CDCl3, 258C): d ˆ 1.05 (s, 9H), 1.10
2.00 (m, 24H), 3.65 (t, J ˆ 6.3 Hz, 2H), 3.88 (dd, J ˆ 9.8, 2.9 Hz, 0.77H),
4.43 (m, 0.23H), 6.07 (s, 0.77H), 6.20 (s, 0.23H), 7.40 7.64 ppm (m, 5H);
13C NMR (50 MHz, CDCl3, 258C): d ˆ 24.7, 25.2, 25.7, 26.4, 28.7, 29.1, 29.3,
29.4, 29.4, 29.5, 29.6, 32.8, 35.4, 36.8, 39.8, 57.8, 63.0, 95.3, 126.5, 128.7, 129.0,
‡
C17H29NO7: 360.2022 [M ‡H]; found: 360.2025.
(2S,4x)-3-Benzoyl-2-(tert-butyl)-4-hexyl-5-oxazolidinone (9a:10a): Fol-
lowing the general experimental procedure, a mixture containing oxazo-
lidinone 2 (77 mg, 0.297 mmol) and 1-iodopentane (80 mL, 0.617 mmol) was
treated with CuI (117 mg, 0.617 mmol) and Zn (121 mg, 1.848 mmol) to
give, after column chromatography (12% EtOAc/hexanes), 9a:10a (71 mg,
72%, 88:12, 76% de) as a yellow solid. Rf ˆ 0.5 (30% EtOAc/hexanes);
m.p. 26 288C; IR (neat): nÄ ˆ 3043 2865, 1712, 1670, 1474 1458, 1257,
1213 cmÀ1; 1H NMR (200 MHz, CDCl3, 258C): d ˆ 0.84 (t, J ˆ 6.8 Hz, 3H),
1.04 (s, 9H), 0.94 2.04 (m, 10H), 3.88 (dd, J ˆ 10.2, 3.4 Hz, 1H), 6.06 (s,
0.88H), 6.19 ppm (s, 0.12H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 13.9
(CH3), 22.4 (CH2), 25.2 (3 Â CH3), 26.4 (CH2), 28.4 (CH2), 31.2 (CH2), 35.4
(CH2), 36.9 (C), 57.8 (CH), 95.4 (CH), 126.5 (2 Â CH), 128.7 (2 Â CH), 130.5
(CH), 135.7 (C), 172.4 (C), 173.8 ppm (C); MS (70 eV, EI): m/z (%): 332 (2)
‡
130.5, 135.7, 172.4, 173.8 ppm; MS (70 eV, EI): m/z (%): 446 (15) [M ‡H],
‡
‡
431 (8) [M À CH3], 388 (12) [M À C4H9], 105 (100); HRMS (EI): m/z:
‡
calcd for C27H43NO4: 445.3192 [M ]; found: 445.3193.
Methyl (2R)-4-[(2S,4S)-3-benzoyl-2-(tert-butyl)-5-oxo-4-oxazolidinyl]-2-
[(tert-butoxycarbonyl)amino]butanoate (9g): Following the general ex-
perimental procedure,
a mixture containing oxazolidinone 2 (95 mg,
‡
‡
[M ‡H], 316 (20) [M À CH3], 274 (100); HRMS (EI): m/z: calcd for
0.374 mmol) and 6g (200 mg, 0.634 mmol) was treated with CuI (142 mg,
0.748 mmol) and Zn (147 mg, 2.244 mmol) to give, after column chroma-
tography (25% EtOAc/hexanes), 9g and 10g (85 mg and 21 mg, respec-
tively, 61%, 80:20, 60% de) as pale yellow oils. 9g: Rf ˆ 0.2 (30% EtOAc/
hexanes); IR (neat): nÄ ˆ 3060 2875, 1789, 1743, 1712, 1667, 1512 1449,
1244, 1199 cmÀ1; 1H NMR (200 MHz, CDCl3, 258C): d ˆ 1.03 (s, 9H), 1.45
(s, 9H), 1.88 2.14 (m, 4H), 3.71 (s, 3H), 4.45 (m, 1H), 5.02 (m, 1H), 6.07 (s,
1H), 7.37 7.66 ppm (m, 5H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 25.1
(3 Â CH3), 28.3 (3 Â CH3), 30.1 (CH2), 31.5 (CH2), 36.8 (C), 36.9 (C), 52.4
‡
C20H29NO3: 331.2147 [M ]; found: 331.2150.
(2S,4x)-3-Benzoyl-2-(tert-butyl)-4-cyclohexylmethyl-5-oxazolidinone
(9c:10c):[17] Following the general experimental procedure, a mixture
containing
2 (80 mg, 0.308 mmol) and cyclohexyl iodide (80 mL,
0.617 mmol) was treated with CuI (117 mg, 0.617 mmol) and Zn (121 mg,
1.848 mmol) to give, after column chromatography (10% EtOAc/hexanes),
9c:10c (100 mg, 94%, 91:9, 82% de) as a yellow solid. Rf ˆ 0.55 (30%
EtOAc/hexanes); IR (neat): nÄ ˆ 2952 2879, 1877, 1712, 1480 1460, 1254,
4184
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 4179 4187

Diastereoselective Conjugated Addition
4179 4187
1H NMR (200 MHz, CDCl3, 258C): d ˆ 1.33 (s, 3H), 1.39 (s, 3H), 1.23
1.77 (m, 4H), 2.15 2.45 (m, 5H), 3.58 (dd, J ˆ 7.8, 7.3 Hz, 1H), 3.67 (s, 3H),
3.68 (s, 3H), 3.95 (dd, J ˆ 7.8, 6.3 Hz, 1H), 4.09 ppm (dq, J ˆ 7.3, 2.0 Hz,
1H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 22.2, 25.2, 26.3, 28.7, 30.1, 34.0,
34.6, 37.5, 51.6, 66.5:67.7 (86:14), 77.4, 108.8, 173.1, 173.7 ppm; MS (FAB):
(CH3), 57.5 (CH), 57.6 (CH), 95.6 (CH), 126.5 (2 Â CH), 128.9 (2 Â CH),
130.7 (CH), 135.3 (C), 171.9 (C), 172.0 (C), 173.6 (C), 173.7 ppm (C); MS
‡
(CI): m/z (%): 463 (7) [M ‡H], 106 (100); HRMS (CI): m/z: calcd for
‡
C24H35N2O7: 463.2444 [M ‡H]; found: 463.2431.
Methyl (3x)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]octanoate (11a:12a):
Following the general experimental procedure, a mixture containing 3 (150
mL, 0.805 mmol) and 1-iodopentane (630 mL, 4.833 mmol) was treated with
CuI (460 mg, 2.416 mmol) and Zn (464 mg, 7.249 mmol) to give, after
column chromatography (10% EtOAc/hexanes), 11a:12a (170 mg, 82%,
93:7, 86% de) as a yellow oil. Rf ˆ 0.6 (30% EtOAc/hexanes); IR (neat):
nÄ ˆ 2985 2861, 1740, 1370 1065 cmÀ1; 1H NMR (200 MHz, CDCl3, 258C):
d ˆ 0.85 (t, J ˆ 6.9 Hz, 3H), 1.27 (m, 8H), 1.32 (s, 3H), 1.38 (s, 3H), 2.23 (m,
2H), 2.45 (m, 1H), 3.63 (br t, J ˆ 7.8 Hz, 1H), 3.66 (s, 3H), 3.95 (dd, J ˆ 8.3,
6.3 Hz, 1H), 4.12 ppm (m, 1H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ
14.0, 22.5, 25.2, 26.3, 26.5, 30.6, 31.9, 34.6, 37.5, 51.5, 66.3:68.0 (93:7), 77.6,
‡
‡
m/z (%): 289 (38) [M ‡H], 273 (41) [M À CH3], 231 (100); HRMS (FAB):
‡
m/z: calcd for C14H25O6: 289.1651 [M ‡H]; found: 289.1643.
Methyl (3x)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-6-hydroxyhexanoate
(11e:12e): Following the general experimental procedure, a mixture
containing
3 (141 mL, 0.80 mmol) and 3-iodo-1-propanol (465 mL,
4.83 mmol) was treated with CuI (460 mg, 2.42 mmol) and Zn (474 mg,
7.25 mmol) to give, after column chromatography (75% EtOAc/hexanes),
11e:12e (82 mg, 51%, 87:13, 74% de) as a yellow oil. Rf ˆ 0.1 (50%
EtOAc/hexanes); IR (neat): nÄ ˆ 2986 2876, 1731, 1372 1061 cmÀ1
1H NMR (200 MHz, CDCl3, 258C): d ˆ 1.34 (s, 3H), 1.40 (s, 3H), 1.17
1.89 (m, 7H), 2.18 2.48 (m, 3H), 3.37 3.65 (m, 1H), 3.68 (s, 3H), 3.95
;
‡
‡
108.7, 173.5 ppm; MS (FAB): m/z (%): 259 (17) [M ‡H], 243 (70) [M À
4.15 ppm (m, 2H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 25.2 (CH2), 26.4
(CH2), 27.2 (CH3), 29.6 (CH3), 35.2 (CH), 38.3 (CH2), 51.6 (CH2), 62.5
(CH), 66.6 (0.87 Â CH), 67.8 (0.13 Â CH), 77.0 (CH2), 108.8 (C), 173.7 ppm
CH3], 201 (100); HRMS (FAB): m/z: calcd for C14H27O4: 259.1909
‡
[M ‡H]; found: 259.1905.
Following the general experimental procedure, a mixture containing 4
(139 mL, 0.805 mmol) and 1-iodopentane (630 mL, 4.833 mmol) was treated
with CuI (460 mg, 2.416 mmol) and Zn (474 mg, 7.249 mmol) to give, after
column chromatography (15% EtOAc/hexanes), 11a:12a (98 mg, 47%,
52:48, 4% de) as a yellow oil and 4 (28 mg, 18%).
‡
‡
(C); MS (70 eV, EI): m/z (%): 247 (1) [M ‡1], 231 (9) [M À CH3], 101
‡
(100); HRMS (FAB): m/z: calcd for C12H23O5: 247.1545 [M ‡H]; found:
247.1542.
(4x,5S)-4,5-Dihydroxy-5-pentylpentanoic acid g-lactone (13a:14a): HCl
(10%, 200 mL) was added to a solution of 11a:12a (40 mg, 0.15 mmol, 93:7)
in MeOH (1 mL). The reaction mixture was stirred for 1 h, concentrated
and purified by column chromatography (silica gel, 50% EtOAc/hexanes)
stopped with a short pad of NaHCO3 and Na2SO4, to give 13a:14a (24 mg,
86%, 93:7) as a colorless oil. 13a: Rf ˆ 0.3 (50% EtOAc/hexanes); IR
Methyl (3x)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-methylpentanoate
(11b:12b): Following the general experimental procedure, a mixture
containing
3 (141 mL, 0.805 mmol) and 2-iodopropane (483 mL,
4.833 mmol) was treated with CuI (460 mg, 2.416 mmol) and Zn (474 mg,
7.249 mmol) to give, after column chromatography (20% EtOAc/hexanes),
11b:12b (118 mg, 64%, 88:12, 76% de) as a yellow oil. Rf ˆ 0.6 (30%
(neat): nÄ ˆ 3470, 2931 2860, 1778, 1467 1050 cmÀ1
;
1H NMR (200 MHz,
CDCl3, 258C): d ˆ 0.89 (t, J ˆ 6.8 Hz, 3H), 1.17 1.57 (m, 6H), 1.82 (br s,
1H), 2.15 2.85 (m, 4H), 3.48 (dd, J ˆ 7.3, 6.8 Hz, 1H), 3.76 3.93 (m, 2H),
4.55 ppm (dd, J ˆ 7.3, 3.9 Hz, 1H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ
13.9, 22.4, 27.9, 28.8, 31.7, 34.6, 38.0, 61.7, 82.7, 177.5 ppm; MS (70 eV, EI):
EtOAc/hexanes); IR (neat): nÄ ˆ 2960 2877, 1739, 1437 1064 cmÀ1
;
1H NMR (200 MHz, CDCl3, 258C): d ˆ 0.88 (d, J ˆ 6.8 Hz, 3H), 0.90 (d,
J ˆ 7.2 Hz, 3H), 1.31 (s, 3H), 1.36 (s, 3H), 1.81 1.90 (m, 1H), 2.13 2.28 (m,
3H), 3.53 (dd, J ˆ 8.3, 7.8 Hz, 1H), 3.64 (s, 3H), 3.91 (dd, J ˆ 7.8, 5.9 Hz,
1H), 4.08 4.12 ppm (m, 1H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 18.7,
20.3, 25.3, 26.4, 28.4, 31.4, 43.2, 51.5, 66.8:68.6 (88:12), 76.6, 108.2,
‡
m/z (%): 187 (11) [M ‡1], 95 (100).
(4x,5S)-4,5-Dihydroxy-5-(1-methylethyl)pentanoic
acid
g-lactone
(13b:14b):[24b] HCl (10%, 310 mL) was added to a solution of 11b:12b
(53 mg, 0.23 mmol, 88:12) in MeOH (1 mL). The reaction mixture was
stirred for 1 h, concentrated, and purified by column chromatography
(silica gel, 50% EtOAc/hexanes) stopped with a short pad of NaHCO3 and
Na2SO4, to give 13b:14b (27 mg, 75%, 88:12) as a yellow oil. 13b: Rf ˆ 0.2
(50% EtOAc/hexanes); 1H NMR (200 MHz, CDCl3, 258C): d ˆ 0.98 (m,
6H), 1.73 1.90 (m, 4H), 2.28 2.67 (m, 3H), 4.59 ppm (dt, J ˆ 7.3, 4.4 Hz,
‡
174.3 ppm; MS (70 eV, EI): m/z (%): 215 (11) [M À CH3], 69 (100);
‡
HRMS (FAB): m/z: calcd for C12H23O4: 231.1596 [M À H]; found:
231.1606.
Following the general experimental procedure, a mixture containing 4 (185
mL, 1.074 mmol) and 2-iodopropane (644 mL, 6.44 mmol) was treated with
CuI (613 mg, 3.22 mmol) and Zn (843 mg, 9.67 mmol) to give, after column
chromatography (20% EtOAc/hexanes), 11b:12b (119 mg, 48%, 52:48,
4% de) as a yellow oil, and 4 (65 mg, 30%).
‡
‡
‡
1H); MS (70 eV, EI): m/z (%): 159 (8) [M ‡1], 158 (2) [M ], 145 (9) [M À
CH3], 127 (100).
Methyl (3x)-3-cyclohexyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]propio-
Diethyl
(15a:16a): Following the general experimental procedure, a mixture
containing (100 mg, 0.367 mmol) and 1-iodopentane (140 mL,
2-{(1x)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]hexyl}malonate
nate (11c:12c):[24c] Following the general experimental procedure,
a
mixture containing 3 (141 mL, 0.80 mmol) and cyclohexyl iodide (625 mL,
4.83 mmol) was treated with CuI (460 mg, 2.42 mmol) and Zn (474 mg,
7.25 mmol) to give, after column chromatography (10% EtOAc/hexanes),
11c:12c (188 mg, 86%, 96:4, 92% de) as a yellow oil. Rf ˆ 0.5 (30%
5
1.101 mmol) was treated with CuI (140 mg, 0.734 mmol) and Zn (144 mg,
2.202 mmol) to give, after column chromatography (75% EtOAc/hexanes),
15a:16a (121 mg, 96%, 87:13, 74% de) as a yellow oil. Rf ˆ 0.5 (50% Et2O/
EtOAc/hexanes); IR (neat): nÄ ˆ 2986 2854, 1738, 1370 1066 cmÀ1
1H NMR (200 MHz, CDCl3, 258C): d ˆ 1.28 (s, 3H), 1.34 (s, 3H), 0.84
;
hexanes); IR (neat): nÄ ˆ 2984 2934, 1733, 1370 1157 cmÀ1
;
1H NMR
(200 MHz, CDCl3, 258C): d ˆ 0.88 (t, J ˆ 6.8 Hz, 3H), 1.27 (s, 6H), 1.28 (t,
J ˆ 7.3 Hz, 6H), 1.22 1.46 (m, 8H), 2.48 (m, 1H), 3.49 (d, J ˆ 6.3 Hz, 1H),
3.65 (t, J ˆ 7.8 Hz, 1H), 3.99 (dd, J ˆ 7.8, 6.3 Hz, 2H), 4.21 ppm (q, J ˆ
1.5 Hz, 4H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 14.0 (CH3), 22.4 (CH2),
25.2 (CH3), 26.2 (CH3), 27.5 (CH2), 28.1 (CH2), 31.9 (CH2), 40.2 (CH3), 42.3
(CH3), 52.7 (CH), 61.3 (CH2), 66.8 (0.87 Â CH2), 68.3 (0.13 Â CH2), 76.4
(CH), 108.8 (C), 168.8 (C), 168.9 ppm (C); MS (FAB): m/z (%): 345 (11)
1.77 (m, 12H), 2.20 (m, 2H), 3.50 (dd, J ˆ 8.3, 7.8 Hz, 1H), 3.62 (s, 3H), 3.89
(dd, J ˆ 7.8, 6.3 Hz, 1H), 4.15 ppm (dq, J ˆ 12.2, 6.3 Hz, 1H); 13C NMR
(50 MHz, CDCl3, 258C): d ˆ 25.2, 26.4, 29.5, 30.8, 31.9, 32.8, 39.1, 40.3, 42.8,
43.9, 66.6:68.6 (96:4), 76.6, 108.6, 174.4 ppm; MS (FAB): m/z (%): 271 (14)
‡
‡
[M ‡H], 255 (72) [M À CH3], 213 (100); HRMS (FAB): m/z: calcd for
‡
C15H27O4: 271.1909 [M ‡H]; found: 271.1900; elemental analysis calcd (%)
for C15H26O4 (270.4): C 66.64, H 9.68; found: C 66.31, H 9.73.
‡
‡
[M ‡H], 329 (92) [M À CH3], 287 (100); HRMS (FAB): m/z: calcd for
‡
Following the general experimental procedure, a mixture containing 4 (139
mL, 0.80 mmol) and cyclohexyl iodide (625 mL, 4.83 mmol) was treated with
CuI (460 mg, 2.42 mmol) and Zn (474 mg, 7.25 mmol) to give, after column
chromatography (10% EtOAc/hexanes), 11c:12c (104 mg, 48%, 54:46,
8% de) as a yellow oil and 4 (52 mg, 35%).
C18H33O6: 345.2277 [M ‡H]; found: 345.2265.
Diethyl 2-{(1x)-1-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl}-2-methylpropyl]-
malonate (15b:16b): Following the general experimental procedure, a
mixture containing 5 (199 mg, 0.731 mmol) and 2-iodopropane (145 mL,
1.47 mmol) was treated with CuI (420 mg, 2.203 mmol) and Zn (336 mg,
5.14 mmol) to give, after column chromatography (10% EtOAc/hexanes),
15b:16b (162 mg, 70%, 88:12, 76% de) as a yellow oil. Rf ˆ 0.4 (20%
Dimethyl
(3x)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]heptanedioate
(11d:12d): Following the general experimental procedure, a mixture
containing 3 (141 mL, 0.805 mmol) and methyl 4-iodobutyrate (650 mL,
4.833 mmol) was treated with CuI (460 mg, 2.416 mmol) and Zn (474 mg,
7.249 mmol) to give, after column chromatography (15% EtOAc/hexanes),
11d:12d (155 mg, 67%, 86:14, 72% de) as a yellow oil. Rf ˆ 0.4 (40%
EtOAc/hexanes); IR (neat): nÄ ˆ 2983, 1732, 1370 cmÀ1
;
1H NMR
(200 MHz, CDCl3, 258C): d ˆ 0.97 (t, J ˆ 7.3 Hz, 6H), 1.26 (d, J ˆ 7.3 Hz,
3H), 1.29 (d, J ˆ 7.3 Hz, 3H), 1.34 (s, 3H), 1.39 (s, 3H), 2.09 2.21 (m, 1H),
2.44 2.52 (m, 1H), 3.54 (d, J ˆ 4.9 Hz, 1H), 3.63 (t, J ˆ 7.8 Hz, 1H), 4.01
(dd, J ˆ 7.8, 5.8 Hz, 1H), 4.19 (m, 4H), 4.32 ppm (m, 1H); 13C NMR
EtOAc/hexanes); IR (neat): nÄ ˆ 2987 2952, 1738, 1371 1064 cmÀ1
;
Chem. Eur. J. 2003, 9, 4179 4187
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4185

¬
¬
J. Perez Sestelo L. A. Sarandeses and R. M. Suarez
FULL PAPER
(50 MHz, CDCl3, 258C): d ˆ 14.0 (CH3), 20.4 (CH3), 20.8 (CH3), 26.1
(CH3), 27.6 (CH3), 28.2 (CH3), 41.6 (CH2), 46.3 (CH), 50.5 (CH), 61.3
(CH2), 67.4 (0.88 Â CH2), 69.5 (0.12 Â CH2), 75.2 (CH), 108.0 (C), 169.0 (C),
Acknowledgement
We are grateful to the Xunta de Galicia (PGIDT01PXI10307PR) for
financial support. R.M.S. thanks the Ministerio de Educacion Cultura y
Deporte (Spain) for a predoctoral (FPU) fellowship.
‡
‡
169.4 ppm (C); MS (FAB): m/z (%): 317 (10) [M ‡H], 301 (51) [M À
¬
CH3], 259 (100); HRMS (FAB): m/z: calcd for C16H29O6: 317.1964
‡
[M ‡H]; found: 317.1963.
Diethyl 2-{(1x)-1-cyclohexyl-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]me-
thyl}malonate (15c:16c): Following the general experimental procedure,
a mixture containing 5 (75 mg, 0.275 mmol) and cyclohexyl iodide (110 mL,
0.825 mmol) was treated with CuI (108 mg, 0.55 mmol) and Zn (110 mg,
1.65 mmol) to give, after column chromatography (15% EtOAc/hexanes),
15c:16c (100 mg, 99%, 84:16, 68% de) as a yellow oil. Rf ˆ 0.5 (30%
[1] a) A. Lubineau, J. Auge in Modern Solvents in Organic Synthesis (Ed.:
P. Knochel), Springer, Berlin, 1999, pp. 1 39; b) P. A. Grieco, Organic
Synthesis in Water, Blackie Academic & Professional, London, 1998;
c) C.-J. Li, T.-H. Chan, Organic Reactions in Aqueous Media, Wiley,
New York, 1997; d) C.-J. Li, Chem. Rev. 1993, 93, 2023 2035.
[2] U. M. Lindstrˆm, Chem. Rev. 2002, 102, 2751 2772.
[3] a) P. Perlmutter, Conjugate Addition in Organic Synthesis, Pergamon,
Oxford, 1992; b) B. E. Rossiter, N. M. Swingle, Chem. Rev. 1992, 92,
771 806; c) J. Leonard, E. Diez-Barra, S. Merino, Eur. J. Org. Chem.
1998, 2051 2061; d) N. Krause, A. Hoffmann-Rˆder, Synthesis 2001,
171 196.
EtOAc/hexanes); IR (neat): nÄ ˆ 2983 2854, 1732, 1369 1060 cmÀ1
;
1H NMR (200 MHz, CDCl3, 258C): d ˆ 1.22 (t, J ˆ 6.8 Hz, 6H), 1.27 (s,
3H), 1.32 (s, 3H), 1.38 (s, 3H), 0.96 1.42 (m, 2H), 1.55 1.75 (m, 8H), 2.48
(m, 1H), 3.58 (d, J ˆ 5.4 Hz, 1H), 3.65 (q, J ˆ 6.8 Hz, 1H), 4.00 (dd, J ˆ
14.2, 5.9 Hz, 1H), 4.20 (q, J ˆ 6.8 Hz, 2H), 4.35 ppm (q, J ˆ 7.3 Hz, 1H);
13C NMR (50 MHz, CDCl3, 258C): d ˆ 13.9, 14.0, 25.4, 26.4, 26.5, 26.7, 26.8,
30.6, 30.9, 38.4, 46.0, 50.9, 61.3, 61.4, 67.3:69.5 (84:16), 75.1, 108.0, 169.1,
‡
169.4 ppm; MS (70 eV, EI): m/z (%): 341 (19) [M À CH3], 101 (100);
[4] a) Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1612 1615; b) U.
Eder, G. Sauer, R. Wiechert, Angew. Chem. 1971, 83, 492 493;
Angew. Chem. Int. Ed. Engl. 1971, 10, 496 497; c) N. Harada, T.
Sugioka, H. Uda, T. Kuriki, Synthesis 1990, 53 56.
‡
HRMS (FAB): m/z: calcd for C19H33O6: 357.2277 [M ‡H]; found: 357.2277;
elemental analysis calcd (%) for C19H32O6 (356.5): C 64.02, H 9.05; found:
C 63.87, H 8.80.
[5] a) E. Keller, B. L. Feringa, Tetrahedron Lett. 1996, 37, 1879 1882;
b) E. Keller, B. L. Feringa, Synlett 1997, 842 844; c) Y. Mori, K.
Kakumoto, K. Manabe, S. Kobayashi, Tetrahedron Lett. 2000, 41,
3107 3111; d) S. Venkatraman, Y. Meng, C-J. Li, Tetrahedron Lett.
2001, 42, 4459 4462; e) S. Shimizu, S. Shirikawa, T. Suzuki, Y. Sasaki,
Tetrahedron 2001, 57, 6169 6173; f) D. Bensa, J.-M. Brunel, G. Buono,
J. Rodriguez, Synlett 2001, 715 717.
[6] a) T.-S. Huang, C.-J. Li, Org. Lett. 2001, 3, 2037 2039; b) T.-S. Huang,
C.-J. Li, Chem. Commun. 2001, 2348 2349; c) H. Miyabe, M. Ueda,
A. Nishimura, T. Naito, Org. Lett. 2002, 4, 131 134.
[7] F. M. da Silva, J. Jones, Jr., J. Braz. Chem. Soc. 2001, 12, 135.
[8] a) C. Petrier, C. Dupuy, J. L. Luche, Tetrahedron Lett. 1986, 27, 3149
3152; b) J. L. Luche, C. Allavena, Tetrahedron Lett. 1988, 29, 5369
5372; c) J. L. Luche, C. Allavena, C. Petrier, C. Dupuy, Tetrahedron
Lett. 1988, 29, 5373 5374.
[9] a) B. Giese, W. Damm, M. Roth, M. Zehnder, Synlett 1992, 441 443;
b) P. Erdmann, J. Sch‰fer, R. Springer, H.-G. Zeitz, B. Giese, Helv.
Chim. Acta 1992, 75, 630 644; c) M. Roth, W. Damm, B. Giese,
Tetrahedron Lett. 1996, 37, 351 354.
1-Ethyl 7-methyl (3x)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(ethoxy-
carbonyl)heptanedioate (15d:16d): Following the general experimental
procedure, a mixture containing 5 (100 mg, 0.367 mmol) and methyl
4-iodobutyrate (99 mL, 0.734 mmol) was treated with CuI (140 mg,
0.734 mmol) and Zn (144 mg, 2.202 mmol) to give, after column chroma-
tography (15% EtOAc/hexanes), 15d:16d (97 mg, 72%, 83:17, 66% de) as
a yellow oil. Rf ˆ 0.4 (40% EtOAc/hexanes); IR (neat): nÄ ˆ 2984 2939,
1739, 1371 1035 cmÀ1; 1H NMR (200 MHz, CDCl3, 258C): d ˆ 1.23 (t, J ˆ
6.8 Hz, 6H), 1.33 (s, 3H), 1.35 (s, 3H), 1.41 1.72 (m, 6H), 2.32 (m, 2H),
2.44 (m, 1H), 3.44 (d, J ˆ 6.3 Hz, 1H), 3.67 (s, 3H), 4.01 (dd, J ˆ 8.3, 6.4 Hz,
1H), 4.22 ppm (q, J ˆ 2.0 Hz, 4H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ
14.0 (CH3), 23.3 (CH2), 25.2 (CH3), 26.2 (CH3), 27.8 (CH2), 34.1 (CH2), 40.2
(CH3), 41.9 (CH3), 51.4 (CH), 52.6 (CH), 61.4 (CH2), 67.0 (0.83 Â CH2), 67.6
(0.17 Â CH2), 68.1 (CH2), 76.3 (CH), 108.9 (C), 168.6 (C), 168.7 (C),
‡
‡
173.7 ppm (C); MS (FAB): m/z (%): 375 (26) [M ‡H], 359 (76) [M À
CH3], 317 (100); HRMS (FAB): m/z: calcd for C18H31O8: 375.2019
‡
[M ‡H]; found: 375.2009.
Diethyl 2-{(1x)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-hydroxybutyl}-
malonate (15e:16e): Following the general experimental procedure, a
mixture containing 5 (100 mg, 0.367 mmol) and 3-iodo-1-propanol (105 mL,
1.101 mmol) was treated with CuI (140 mg, 0.734 mmol) and Zn (144 mg,
2.202 mmol) to give, after column chromatography (25% EtOAc/hexanes),
15e:16e (64 mg, 52%, 83:17, 66% de) as a yellow oil. Rf ˆ 0.2 (EtOAc); IR
[10] a) P. Cintas, J.-L. Luche in Synthetic Organic Sonochemistry (Ed.: J.-L.
Luche), Plenum, London, 1998, pp. 223 227. For more recent
applications see: b) R. Lavilla, O. Coll, J. Bosch, M. Orozco, F. J.
Luque, Eur. J. Org. Chem. 2001, 3719 3729; c) M. Okue, H.
Kobayashi, K. Shin-ya, K. Furihata, Y. Hayakawa, H. Seto, H.
Watanabe, T. Kitahara, Tetrahedron Lett. 2002, 43, 857 860.
[11] a) L. Castedo, J. L. Mascarenƒas, A. Mourinƒo, L. A. Sarandeses,
Tetrahedron Lett. 1988, 29, 1203 1206; b) J. L. Mascarenƒas, L. A.
Sarandeses, L. Castedo, A. Mourinƒo, Tetrahedron 1991, 47, 3485
(neat): nÄ ˆ 3443, 2985 2939, 1729, 1371 1059 cmÀ1
;
1H NMR (200 MHz,
CDCl3, 258C): d ˆ 1.21 (s, 3H), 1.26 (s, 3H), 1.30 (s, 3H), 1.37 (s, 3H), 1.50
1.72 (m, 5H), 1.97 (br s, 1H), 2.42 (m, 1H), 3.44 (d, J ˆ 5.9 Hz, 1H), 3.63 (m,
3H), 3.99 (dd, J ˆ 7.8, 5.9 Hz, 1H), 4.17 ppm (q, J ˆ 5.9 Hz, 4H); 13C NMR
(50 MHz, CDCl3, 258C): d ˆ 13.9 (CH), 14.0 (CH3), 24.6 (CH2), 25.2 (CH3),
26.2 (CH3), 30.8 (CH2), 39.8 (CH), 41.3 (CH3), 52.8 (CH), 61.4 (CH2), 62.3
(CH2), 67.2 (CH2), 68.1 (CH2), 76.9 (CH), 108.9 (C), 168.7 ppm (C); MS
¬
3498; c) J. L. Mascarenƒas, J. Perez Sestelo, L. Castedo, A. Mourinƒo,
¬
Tetrahedron Lett. 1991, 32, 2813 2816; d) J. Perez Sestelo, J. L.
Mascarenƒas, L. Castedo, A. Mourinƒo, J. Org. Chem. 1993, 58, 118
¬
123; e) J. Perez Sestelo, J. L. Mascarenƒas, L. Castedo, A. Mourinƒo,
‡
(FAB): m/z (%): 333 (30) [M ‡H], 275 (100); HRMS (FAB): m/z: calcd
Tetrahedron Lett. 1994, 35, 275 278.
‡
¬
for C16H29O7: 333.1913 [M ‡H]; found: 333.1924.
[12] J. Perez Sestelo, I. Cornella, O. de Unƒa, A. Mourinƒo, L. A. Sarandeses,
Chem. Eur. J. 2002, 8, 2747 2752.
¬
Ethyl (4x,5S)-tetrahydro-5-(hydroxymethyl)-4-pentyl-2-oxo-3-furancar-
boxylate (17a:18a): HCl (10%, 250 mL) was added to a solution of
15a:16a (65 mg, 0.189 mmol, 87:13) in MeOH (1 mL) at room temperature.
After stirring for 1 h, the reaction mixture was concentrated and purified by
column chromatography (silica gel, 50% EtOAc/hexanes) stopped with a
short pad of NaHCO3 and Na2SO4, to give 17a:18a (39 mg, 80%, 87:13) as
a yellow oil. 18a: Rf ˆ 0.2 (30% EtOAc/hexanes); 1H NMR (200 MHz,
CDCl3, 258C): d ˆ 0.88 (t, J ˆ 6.3 Hz, 3H), 1.31 (m, 6H), 1.63 (m, 2H), 1.77
(br s, 1H), 2.48 (m, 1H), 3.12 (dq, J ˆ 11.2, 7.8 Hz, 1H), 3.61 (d, J ˆ 11.7 Hz,
1H), 3.87 (qq, J ˆ 18.5, 2.4 Hz, 2H), 4.25 (q, J ˆ 7.3 Hz, 4H), 4.59 ppm (dt,
J ˆ 7.8, 2.9 Hz, 1H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 13.9, 14.0, 22.4,
27.5, 28.7, 31.6, 42.3, 52.4, 61.4, 62.0, 81.2, 168.6, 172.9 ppm; MS (FAB): m/z
[13] J. Perez Sestelo, O. de Unƒa, A. Mourinƒo, L. A. Sarandeses, Synlett
2002, 715 719.
¬
¬
[14] R. M. Suarez, J. Perez Sestelo, L. A. Sarandeses, Synlett 2002, 1435
1438.
[15] For reviews on radical reactions, see: a) N. A. Porter, B. Giese, D. P.
Curran, Acc. Chem. Res. 1991, 24, 163 171; b) N. A. Porter, B. Giese,
D. P. Curran, Stereochemistry of Radical Reactions, VCH, Weinheim,
1996; c) M. P. Sibi, N. A. Porter, Acc. Chem. Res. 1999, 32, 163 171,
d) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033 8061; e) H.
Yorimitsu, H. Shinokubo, K. Oshima, Synlett 2002, 674 686.
[16] a) D. Seebach, R. Naef, G. Calderari, Tetrahedron 1984, 40, 1313
1324; b) J. Zimmermann, D. Seebach, Helv. Chim. Acta 1987, 70,
1104 1114.
‡
(%): 259 (100) [M ‡H].
4186
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 4179 4187

Diastereoselective Conjugated Addition
4179 4187
[17] a) A. L. J. Beckwith, C. L. L. Chai, J. Chem. Soc. Chem. Commun.
1990, 1087 1088; b) G. Kneer, J. Mattay, Tetrahedron Lett. 1992, 33,
8051 8054; c) A. L. J. Beckwith, C. L. L. Chai, Tetrahedron 1993, 49,
7871 7882.
[18] T. Itaya, A. Mizutani, Tetrahedron Lett. 1985, 26, 347 350.
[19] a) M. J. Dunn, R. F. W. Jackson, J. Pietruzska, D. Turner, J. Org. Chem.
1995, 60, 2210 2215; b) R. F. W. Jackson, K. James, M. J. Wythes, A.
Wood, J. Chem. Soc. Chem. Commun. 1989, 644 655.
[20] D. Seebach, A. Fadel, Helv. Chim. Acta 1985, 68, 1243 1250.
[21] J. R. Axon, A. L. J. Beckwith, J. Chem. Soc. Chem. Commun. 1995,
549 550.
c) T. Moriwaka, Y. Washio, S. Harada, R. Hanai, T. Kayashita, H.
Nemoto, M. Shiro, T. Taguchi, J. Chem. Soc. Perkin Trans. 1 1995,
271 281; d) K. Nilsson, C. Ullenius, Tetrahedron 1994, 50, 13173
13180; e) M. Nomura, S. Kanemasa, Tetrahedron Lett. 1994, 35, 143
146; f) J. Leonard, G. Ryan, P. A. Swain, Synlett 1990, 613 614.
[25] a) R. W. Hoffmann, Chem. Rev. 1989, 89, 1841 1860; b) W. Smadja,
M. Zahouily, M. Malacria, Tetrahedron Lett. 1992, 33, 5511 5514;
c) T. Morikawa, Y. Washio, M. Shiro, T. Taguchi, Chem. Lett. 1993,
249 250; d) A. Mengel, O. Reiser, Chem. Rev. 1999, 99, 1191 1223.
[26] J. Leonard, S. Mohialdin, D. Reed, G. Ryan, P. A. Swain, Tetrahedron
1995, 51, 12843 12858.
[22] S. D. Bull, A. N. Chernega, S. G. Davies, W. O. Moss, R. M. Parkin
Tetrahedron 1998, 54, 10379 10388.
[27] A. Krief, L. Provins, A. Froidbise, Tetrahedron Lett. 1998, 39, 1437
1440.
[23] S. Takano, A. Kurotaki, M. Takahashi, K. Ogasawara, Synthesis 1986,
403 406.
[28] G. B. Kauffman, L. A. Teter, Inorg. Synth. 1963, 7, 9 12
[29] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923 2925.
[24] a) V. L. Patrocinio, P. R. R. Costa, C. R. D. Correia, Synthesis 1994,
474 476; b) J. S. Costa, A. G. Dias, A. L. Anholeto, M. D. Monteiro,
V. L. Patrocinio, P. R. R. Costa, J. Org. Chem. 1997, 62, 4002 4006;
Received: January 30, 2003 [F4790]
Chem. Eur. J. 2003, 9, 4179 4187
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¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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