Aldol reactions with erythrulose derivatives: Stereoselective synthesis of differentially protected syn-α,β-dihydroxy esters

Article abstract of DOI:10.1016/S0040-4020(99)01041-8

Boron enolates of 1-O-silylated erythrulose 3,4-acetonides prepared with Brown's chloro-dicyclohexylborane/tertiary amine system have been shown to react with achiral aldehydes in a highly stereoselective way to yield a 1,2- syn/1,3-syn stereoisomer. Thro

Full text of DOI:10.1016/S0040-4020(99)01041-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 677–683
Aldol Reactions with Erythrulose Derivatives: Stereoselective
Synthesis of Differentially Protected syn-a,b-Dihydroxy Esters
a
a
a
a
b,
*
´
M. Carda, J. Murga, E. Falomir, F. Gonzalez and J. A. Marco
a
´
´
´
Departamento de Q. Inorganica y Organica, Universidad Jaume I, E-12080, Castellon, Spain
b
´
Departamento de Q. Organica, Universidad de Valencia, E-46100 Burjassot, Valencia, Spain.
Received 1 October 1999; revised 11 November 1999; accepted 25 November 1999
Abstract—Boron enolates of 1-O-silylated erythrulose 3,4-acetonides prepared with Brown’s chloro-dicyclohexylborane/tertiary amine
system have been shown to react with achiral aldehydes in a highly stereoselective way to yield a 1,2-syn/1,3-syn stereoisomer. Through
oxidative cleavage of the aldol adducts with periodic acid hydrate, enantiopure syn-a,b-dihydroxy esters with either hydroxyl group
differently protected have been prepared. These erythrulose derivatives therefore behave as a chiral hydroxy acetate (glycolate) enolate
equivalent. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
The aldol reaction1 has proven to be a powerful and general
method for the stereocontrolled construction of carbon–
carbon bonds and has relevant application in the synthesis
of natural polyoxygenated molecules such as macrolide and
polyether antibiotics.2 In connection with our current
interest in the development of erythrulose as a useful
C4-chiral building block for the stereocontrolled construc-
tion of polyfunctionalized structures,3 we envisaged the
enolization of protected l-(S)-erythrulose derivatives 1
(P0, P00, P000ˆprotecting groups) and the subsequent addition
of the resulting enolates to aldehydes. As shown in Scheme 1,
though synthetic equivalents of the d2 synthon hydroxy acet-
aldehyde enolate or its equivalent, the hydroxy acetic
(glycolic) acid enolate, have been described,4,5 there are
no counterparts for the d3 synthon a,b,-dihydroxy propanal
homoenolate equivalent.6 Furthermore, 1 could also act as
an a,b,g-trihydroxy butanal bishomoenolate equivalent (cf.
5). In such a process, 1 would function as a hitherto
unprecedented d4 synthon type with no loss of carbon,
thus maximizing atom economy.7 The synthetic utility of
erythrulose is therefore based on the fact that it may behave,
according to convenience, as a C4 chiral d2, d3 or d4 synthon.
Scheme 1.
further manipulation of the key aldol adduct 2 through prior
carbonyl reduction and selective cleavage of bonds a or b
would yield selectively protected a,b-dihydroxy aldehydes
3 or a,b,g-trihydroxy aldehydes 4, respectively. Even
With this idea in mind, we have investigated l-(S)-erythru-
lose 3,4-acetonide derivatives 6 bearing three different silyl
protecting groups (RˆTES, TBS and TBDPS).8 After initial
failures with several enolate types,9 we were eventually
successful through the use of the Brown dicyclohexylboron
chloride (Chx2BCl)/tertiary amine system.10 Aldol reactions
promoted by this reagent mixture led to aldol adducts 7 in
good chemical yields as an essentially single diastereo-
isomer (diastereomeric ratio, d.r.Ͼ95:5, as determined by
Keywords: aldol reactions; diastereoselection; hydroxy acids and deriva-
tives; oxidation.
* Corresponding author. Tel.: ϩ34-96-3864337; fax: ϩ34-96-3864328;
e-mail: alberto.marco@uv.es
13
1H and C NMR; 12 out of the 18 possible R/R0
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01041-8

678
M. Carda et al. / Tetrahedron 56 (2000) 677–683
esters 10.17 The formation of the O-formylated derivatives 8
in the oxidative cleavage of 7 with periodic acid can be
explained with the mechanism in Scheme 4.
Esters 9 and 10 should be amenable to conversion, via
appropriate nucleophilic substitution of hydroxyl groups,
into various compounds of pharmacological interest such
as, for example, b-hydroxy-a-amino acids, a-hydroxy-b-
amino acids or a,b-diamino acids.18 Furthermore, since
d-erythrulose acetonides enantiomeric to 6 are also easily
available,8 the preparation of compounds antipodal to those
depicted later is also feasible. Efforts in these directions are
presently underway in our group.
Scheme 2. RˆTES, TBS, TBDPS. 7: a R0ˆEt; b R0ˆiPr; c R0ˆPh; d
R0ˆ4-ClC6H4; e R0ˆ4-NO2C6H4; f R0ˆCH2vC(Me).
combinations in Scheme 2 were prepared, see Experi-
mental). Almost identical results were observed with all
three silyl protecting groups using three different tertiary
amines (Me2NEt, Et3N and iPr2NEt) in three different
solvents (Et2O, THF and CH2Cl2). The sterically hindered
pivaldehyde was the only aldehyde tested which did not
react under the conditions described.11,12
A further interesting question that has to be addressed is the
mechanistic basis of the unexpected stereochemical
outcome of aldol reactions with ketones 6 promoted by
Chx2BCl. Until our results, only a single case had been
described in which this reagent leads to the formation of
syn aldols,19 anti aldols being formed otherwise very pre-
dominantly.20 If the usually accepted cyclic transition state21
in the aldol addition itself is assumed, we should conclude
that a (Z) boron enolate was formed, in contrast to that
expected for Chx2BCl.20 In fact, recent computational calcu-
lations by our group22,23 support the conclusion that the
observed aldol adducts are formed through the (Z) boron
enolate participating in a chair-like transition state of the
Zimmerman–Traxler type.21 If this is the case, we must
explain why enolization with Chx2BCl gives rise here to a
(Z) boron enolate, rather than to the expected (E) enolate.24
Both theoretical and experimental work in this direction is
now underway and will be reported in due course.
The 2,4-syn/4,5-syn relative as well as the absolute config-
uration of the obtained aldol adducts was unequivocally
established by X-ray diffraction analysis of the enantiomer
of 7d (RˆTBS) and by a chemical correlation in the case of
7b (RˆTBS).11,12 In this paper, we give detailed reaction
conditions of the aforementioned aldol additions and
complete physical and spectral data of the aldol adducts.
Furthermore, we show that, as anticipated in our first
communication,11 erythrulose derivatives such as 6 behave
as an effective chiral equivalent of the d2 hydroxy acetic
(glycolic) acid enolate synthon. Our aldol methodology
therefore represents a useful tool in stereoselective organic
synthesis.
Aldols 7 proved sensitive to both strong acid and alkaline
conditions. After much experimentation, suitable conditions
were found for acetonide cleavage and selective elimination
of protecting groups (Scheme 3). Thus, compounds 7
(RˆTBS and R0ˆEt, iPr, Ph, p-ClC6H4)13 were treated
with periodic acid hydrate in ethyl acetate14 under carefully
controlled conditions (see Experimental). The acids formed
were isolated as their methyl esters and assigned structure 8
on the basis of spectroscopic findings and the subsequent
synthetic manipulations.15 Selective hydrolysis of the formyl
group in 8 took place under very mild basic conditions16 to
yield the monoprotected dihydroxy esters 9. Selective
cleavage of the silyl group in 8 without deformylation
proved infeasible. However, treatment of either 8, 9 or
their mixture15 with hydrogen fluoride16 provided dihydroxy
Experimental
NMR spectra were measured in a CDCl3 solution at 25ЊC
(Varian Unity 500 and 400 NMR spectrometers). Mass
spectra were run either by the electron impact (EIMS,
70 eV), chemical ionization (CIMS, CH4) or fast atom
bombardment mode (FABMS, m-nitrobenzyl alcohol
matrix) on a VG AutoSpec mass spectrometer. IR spectra
were recorded as oily films on NaCl plates (oils) or as KBr
pellets (solids). Optical rotations were measured at 22ЊC.
Reactions that required an inert atmosphere were carried
out under argon with flame-dried glassware. Commercial
Scheme 3. Reaction conditions. (a) H5IO6, EtOAc, room temperature, 2 h, then CH2N2. Yields: 8 (60–74%) and 9 (10–13%). (b) KHCO3/MeOH, 0ЊC, 1 h.
Yields: 80–85%. (c) HF-pyridine/MeCN, room temperature, 6 h. Yields: 75–85% (for the conversion 8!10).
Scheme 4.

M. Carda et al. / Tetrahedron 56 (2000) 677–683
679
reagents (Aldrich or Fluka) were used as received. Hexane
solutions of Chx2BCl were generated by hydroboration of
cyclohexene with monochloroborane as reported in the
literature.25 Et2O and THF were freshly distilled under Ar
from sodium-benzophenone ketyl. Dichloromethane was
Jˆ1.5 Hz, H-4), 4.60 (1H, dd, Jˆ7.5, 5.3 Hz, H-2), 4.18
(1H, dd, Jˆ8.8, 7.5 Hz, H-1), 4.12 (1H, dd, Jˆ8.8,
5.3 Hz, H-10), 3.63 (1H, br d, Jˆ9 Hz, H-5), 2.20 (1H, br
s, OH), 1.78 (1H, dqq, Jˆ9, 7, 7 Hz, H-6), 1.41, 1.36 (2×3H,
2×s, acetonide Me), 1.03, 0.95 (2×3H, 2×d, Jˆ7 Hz,
isopropyl Me), 0.95 (9H, t, Jˆ8 Hz, 3×SiCH2Me), 0.60
(6H, m, 3×SiCH2Me); 13C NMR (100 MHz): d 208.9
(C-3), 110.8 (acetonide C), 78.5 (C-2), 76.7 (C-5), 76.3
(C-4), 66.7 (C-1), 31.4 (C-6), 26.1, 24.8 (acetonide Me),
19.1, 19.0 (isopropyl Me), 6.7 (MeCH2Si), 4.9 (MeCH2Si).
˚
distilled from P2O5 and stored over 4 A molecular sieves.
Tertiary amines were distilled from CaH2. Unless detailed
otherwise, “work-up” means pouring the reaction mixture
into brine, extracting with the indicated solvent, additional
washing with 5% aq. NaHCO3 (if acids had been utilized in
the reaction) or with 5% aq. HCl (if bases had been utilized),
then again with brine, drying over anhydrous Na2SO4 or
MgSO4 and eliminating the solvent in vacuo. The obtained
material was then chromatographed on a silica gel column
(Su¨d-Chemie AG, 60-200) with the indicated eluant.
(2S,4R,5S)-4-O-Triethylsilyl-1,2-O-isopropylidene-1,2,4,5-
tetrahydroxy-5-phenylpentan-3-one, 7c (RˆTES). Oil,
[a]D Ϫ17.8 (CHCl3, c 1.5); IR nmax cmϪ1: 3420 (br, OH),
1736 (ketone CvO), 1372, 1256, 1073, 840; FABMS, m/z
403.1918
(MϩNaϩ).
Calc.
for
C20H32O5SiNa,
1
General procedure for aldol additions of erythrulose
derivatives 6 (all aldol reactions were performed under an
inert atmosphere). To a stirred solution of Chx2BCl (1.8 mL
of a 1 M hexane solution, 1.8 mmol) and Et3N (278 mL,
2 mmol) in anhydrous Et2O (6 mL) at Ϫ78ЊC was added
erythrulose derivative 68 (1 mmol) in anhydrous ether
(6 mL). After 10 min, the reaction mixture was warmed to
0ЊC for 1 h and then recooled to Ϫ78ЊC. A solution of the
aldehyde (5 mmol) in ether (6 mL) was added and after
10 min. at Ϫ78ЊC the reaction mixture was warmed to
0ЊC and stirred at this temperature for 5 h. Then pH 7 phos-
phate buffer (6 mL) and MeOH (6 mL) were added at 0ЊC
followed by 30% aq. H2O2 solution (3 mL). After stirring
for 1 h at room temperature, the mixture was worked up
(extraction with Et2O). Solvent removal in vacuo and
column chromatography of the residue on silica gel (hex-
ane–EtOAc 9:1 and then 4:1) afforded the aldol addition
product 7 as essentially one diastereoisomer. Chemical
yields: RˆTES, 7a (85%), 7b (77%), 7c (80%), 7d (87%);
RˆTBS, 7a (87%), 7b (86%), 7c (83%), 7d (86%), 7e
(89%), 7f (85%); RˆTPS, 7b (85%), 7c (78%). When
Et2O was replaced by THF or CH2Cl2, or when Et3N was
replaced by EtNMe2 or EtNiPr2, yields and d.r.’s remained
essentially unchanged.
Mˆ403.1916; H NMR (400 MHz): d 7.40–7.20 (5H, m,
aromatic), 5.26 (1H, br d, Jˆ2 Hz, H-5), 4.89 (1H, d,
Jˆ2 Hz, H-4), 4.64 (1H, dd, Jˆ7.8, 5.2 Hz, H-2), 4.22
(1H, dd, Jˆ8.8, 7.8 Hz, H-1), 4.10 (1H, dd, Jˆ8.8,
5.2 Hz, H-10), 1.50, 1.41 (2×3H, 2×s, acetonide Me), 0.74
(9H, t, Jˆ8 Hz, 3×SiCH2Me), 0.35 (6H, m, 3×SiCH2Me);
13C NMR (100 MHz): d 207.8 (C-3), 141.2, 128.1, 127.5,
125.7 (aromatic), 110.9 (acetonide C), 79.9 (C-4), 78.8
(C-2), 72.9 (C-5), 66.7 (C-1), 26.1, 24.9 (acetonide Me),
6.5 (MeCH2Si), 4.3 (MeCH2Si).
(2S,4R,5S)-4-O-Triethylsilyl-1,2-O-isopropylidene-1,2,4,5-
tetrahydroxy-5-(p-chlorophenyl)pentan-3-one, 7d (RˆTES).
Oil, [a]D Ϫ70.4 (CHCl3, c 1.8); IR nmax cmϪ1: 3420 (br,
OH), 1734 (ketone CvO), 1372, 1286, 1158, 840; FABMS,
m/z 437.1543 (MϩNaϩ). Calc. for C20H31O535ClSiNa,
1
Mˆ437.1527; H NMR (400 MHz): d 7.35–7.25 (4H, m,
aromatic), 5.22 (1H, br s, H-5), 4.84 (1H, d, Jˆ2 Hz, H-4),
4.64 (1H, dd, Jˆ7.7, 5.2 Hz, H-2), 4.23 (1H, dd, Jˆ8.8,
7.7 Hz, H-1), 4.10 (1H, dd, Jˆ8.8, 5.2 Hz, H-10), 1.49,
1.40 (2×3H, 2×s, acetonide Me), 0.75 (9H, t, Jˆ8 Hz,
3×SiCH2Me), 0.35 (6H, m, 3×SiCH2Me); 13C NMR
(100 MHz): d 207.5 (C-3), 139.9, 133.2, 128.3, 127.2
(aromatic), 111.0 (acetonide C), 79.6 (C-4), 78.7 (C-2),
72.3 (C-5), 66.7 (C-1), 26.1, 24.8 (acetonide Me), 6.4
(MeCH2Si), 4.4 (MeCH2Si).
(2S,4R,5S)-4-O-Triethylsilyl-1,2-O-isopropylidene-1,2,4,5-
tetrahydroxyheptan-3-one, 7a (RˆTES). Oil, [a]D Ϫ8.9
(CHCl3, c 6.5); IR nmax cmϪ1: 3420 (br, OH), 1728 (ketone
CvO), 1634, 1485, 1335, 850; CIMS, m/z 333.2104
(2S,4R,5S)-4-O-t-Butyldimethylsilyl-1,2-O-isopropylidene-
1,2,4,5-tetrahydroxyheptan-3-one, 7a (RˆTBS). Oil, [a]D
Ϫ47.4 (CHCl3, c 4.9); IR nmax cmϪ1: 3460 (br, OH), 1724
(ketone CvO), 1454, 1385, 1252, 1152, 1054, 837;
FABMS, m/z 333.2106 (MϩHϩ). Calc. for C16H33O5Si,
Mˆ333.2097; 1H NMR (400 MHz): d 4.66 (1H, d,
Jˆ2 Hz, H-4), 4.62 (1H, dd, Jˆ7.5, 5.3 Hz, H-2), 4.16
(1H, dd, Jˆ8.8, 7.5 Hz, H-1), 4.10 (1H, dd, Jˆ8.8,
5.3 Hz, H-10), 3.95 (1H, m, H-5), 2.10 (1H, br d,
Jˆ10.5 Hz, OH), 1.55 (2H, m, H-6), 1.40, 1.35 (2×3H,
2×s, acetonide Me), 0.97 (3H, t, Jˆ7.5 Hz, H-7), 0.89
(9H, s, SiCMe3), 0.06, Ϫ0.02 (2×3H, 2×s, SiMe2); 13C
NMR (100 MHz): d 208.5 (C-3), 110.7 (acetonide C),
78.5 (C-2), 77.9 (C-4), 73.1 (C-5), 66.5 (C-1), 27.4 (C-6),
26.0, 24.9 (acetonide Me), 25.7 (SiCMe3), 18.4 (SiCMe3),
10.3 (C-7), Ϫ4.6, Ϫ5.4 (SiMe2).
1
(MϩHϩ). Calc. for C16H33O5Si, Mˆ333.2097; H NMR
(400 MHz): d 4.67 (1H, d, Jˆ2.2 Hz, H-4), 4.64 (1H, dd,
Jˆ7.7, 5.3 Hz, H-2), 4.20 (1H, dd, Jˆ8.8, 7.7 Hz, H-1), 4.11
(1H, dd, Jˆ8.8, 5.3 Hz, H-10), 3.93 (1H, br m, H-5), 2.25
(1H, br d, Jˆ9 Hz, OH), 1.57 (2H, quint, Jˆ7.2 Hz, H-6),
1.42, 1.37 (2×3H, 2×s, acetonide Me), 0.99 (3H, t,
Jˆ7.2 Hz, H-7), 0.95 (9H, t, Jˆ8 Hz, 3×SiCH2Me), 0.60
(6H, 2×q, Jϳ8 Hz, 3×SiCH2Me); 13C NMR (100 MHz): d
208.5 (C-3), 110.7 (acetonide C), 78.5 (C-2), 77.8 (C-4),
73.1 (C-5), 66.4 (C-1), 27.2 (C-6), 26.0, 24.9 (acetonide
Me), 10.2 (C-7), 6.7 (MeCH2Si), 4.7 (MeCH2Si).
(2S,4R,5S)-4-O-Triethylsilyl-1,2-O-isopropylidene-1,2,4,5-
tetrahydroxy-6-methylheptan-3-one, 7b (RˆTES). Oil,
[a]D Ϫ15.4 (CHCl3, c 1.1); IR nmax cmϪ1: 3440 (br, OH),
1729 (ketone CvO), 1472, 1384, 1256, 1106, 838; CIMS,
m/z 347.2251 (MϩHϩ). Calc. for C17H35O5Si,
Mˆ347.2253; 1H NMR (400 MHz): d 4.90 (1H, d,
(2S,4R,5S)-4-O-t-Butyldimethylsilyl-1,2-O-isopropylidene-
1,2,4,5-tetrahydroxy-6-methylheptan-3-one, 7b (RˆTBS).
Oil, [a]D Ϫ16.5 (CHCl3, c 5.5); IR nmax cmϪ1: 3440 (br, OH),

680
M. Carda et al. / Tetrahedron 56 (2000) 677–683
1732 (ketone CvO), 1472, 1384, 1256, 1106, 838; FABMS,
m/z 369.2068 (MϩNa)ϩ. Calc. for C17H34O5SiNa,
Mˆ369.2073; 1H NMR (400 MHz): d 4.91 (1H, d,
Jˆ1.5 Hz, H-4), 4.59 (1H, dd, Jˆ7.4, 5.2 Hz, H-2), 4.18
(1H, dd, Jˆ8.8, 7.4 Hz, H-1), 4.12 (1H, dd, Jˆ8.8,
5.2 Hz, H-10), 3.63 (1H, br t, Jˆ9.5 Hz, H-5), 2.10 (1H,
br d, Jˆ9.5 Hz, OH), 1.78 (1H, dqq, Jˆ9, 7, 7 Hz, H-6),
1.41, 1.36 (2×3H, 2×s, acetonide Me), 1.03, 0.94 (2×3H,
2×d, Jˆ7 Hz, isopropyl Me), 0.90 (9H, s, SiCMe3), 0.08,
Ϫ0.01 (2×3H, 2×s, SiMe2); 13C NMR (100 MHz): d 208.9
(C-3), 110.8 (acetonide C), 78.5 (C-2), 76.7 (C-5), 76.3
(C-4), 66.7 (C-1), 31.4 (C-6), 26.1, 24.9 (acetonide Me),
25.8 (SiCMe3), 19.2, 19.0 (isopropyl Me), 18.4 (SiCMe3),
Ϫ4.3, Ϫ5.4 (SiMe2).
2×s, SiMe2); 13C NMR (100 MHz): d 207.0 (C-3), 149.2,
147.3, 126.6, 123.5 (aromatic), 111.3 (acetonide C), 79.7
(C-4), 78.7 (C-2), 72.1 (C-5), 66.8 (C-1), 26.3, 24.9 (aceto-
nide Me), 25.4 (SiCMe3), 18.2 (SiCMe3), Ϫ5.1, Ϫ5.9
(SiMe2). Elemental analysis: Found, C, 56.66%; H,
7.50%; N, 3.37. Calc. for C20H31NO7Si: C, 56.45%; H,
7.34%; N, 3.45%.
(2S,4R,5S)-4-O-t-Butyldimethylsilyl-1,2-O-isopropylidene-
1,2,4,5-tetrahydroxy-6-methylhept-6-en-3-one, 7f (RˆTBS).
Oil, [a]D Ϫ15.4 (CHCl3, c 1.5); IR nmax cmϪ1: 3450 (br,
OH), 1730 (ketone CvO), 1495, 1345, 1267, 790; EIMS,
m/z (% rel. int.): 329.1777 (MϪMeϩ, 2), 274 (23), 75 (100).
Calc. for C16H29O5Si, Mˆ329.1784; 1H NMR (400 MHz): d
5.03 (1H, br s, H-7), 4.97 (1H, q, Jˆ1.5 Hz, H-70), 4.84 (1H,
d, Jˆ2 Hz, H-4), 4.64 (1H, dd, Jˆ7.7, 5.2 Hz, H-2), 4.50
(1H, br s, H-5), 4.20 (1H, dd, Jˆ8.8, 7.7 Hz, H-1), 4.10 (1H,
dd, Jˆ8.8, 5.2 Hz, H-10), 1.78 (3H, br s, Me-C6), 1.44, 1.37
(2×3H, 2×s, acetonide Me), 0.86 (9H, s, SiCMe3), 0.04,
Ϫ0.05 (2×3H, 2×s, SiMe2); 13C NMR (100 MHz): d
208.2 (C-3), 143.6 (C-6), 111.9 (C-7), 110.9 (acetonide
C), 78.6 (C-2), 76.6 (C-4), 73.8 (C-5), 66.7 (C-1), 26.1,
24.9 (acetonide Me), 25.7 (SiCMe3), 19.2 (Me-C6), 18.4
(SiCMe3), Ϫ4.7, Ϫ5.5 (SiMe2).
(2S,4R,5S)-4-O-t-Butyldimethylsilyl-1,2-O-isopropylidene-
1,2,4,5-tetrahydroxy-5-phenylpentan-3-one, 7c (RˆTBS).
Oil, [a]D Ϫ9.6 (CHCl3, c 1.2); IR nmax cmϪ1: 3460 (br,
OH), 1731 (ketone CvO), 1450, 1250, 1080, 940;
FABMS, m/z 403.1928 (MϩNa)ϩ. Calc. for C20H32O5SiNa,
1
Mˆ403.1916; H NMR (400 MHz): d 7.35–7.25 (5H, m,
aromatic), 5.31 (1H, br d, Jˆ2 Hz, H-5), 4.88 (1H, d,
Jˆ2 Hz, H-4), 4.68 (1H, dd, Jˆ7.7, 5.2 Hz, H-2), 4.23
(1H, dd, Jˆ8.8, 7.7 Hz, H-1), 4.12 (1H, dd, Jˆ8.8,
5.2 Hz, H-10), 1.51, 1.42 (2×3H, 2×s, acetonide Me), 0.72
(9H, s, SiCMe3), Ϫ0.17, Ϫ0.40 (2×3H, 2×s, SiMe2); 13C
NMR (100 MHz): d 207.8 (C-3), 141.2, 128.1, 127.5,
125.7 (aromatic), 111.0 (acetonide C), 80.3 (C-4), 78.7
(C-2), 72.7 (C-5), 66.7 (C-1), 26.2, 24.9 (acetonide Me),
25.5 (SiCMe3), 18.2 (SiCMe3), Ϫ5.3, Ϫ6.0 (SiMe2).
(2S,4R,5S)-4-O-t-Butyldiphenylsilyl-1,2-O-isopropylidene-
1,2,4,5-tetrahydroxy-6-methylheptan-3-one,7b(RˆTBDPS).
Oil, [a]D Ϫ62.7 (CHCl3, c 1.4); IR nmax cmϪ1: 3470 (br,
OH), 1752 (ketone CvO), 1476, 1364, 1260, 1100;
FABMS, m/z 493.2392 (MϩNaϩ). Calc. for C27H38O5SiNa,
1
Mˆ493.2386; H NMR (400 MHz): d 7.70–7.60 (4H, m,
(2S,4R,5S)-4-O-t-Butyldimethylsilyl-1,2-O-isopropylidene-
1,2,4,5-tetrahydroxy-5-(p-chlorophenyl)pentan-3-one, 7d
(RˆTBS). Colourless needles, mp 110–112ЊC (from hex-
aromatic), 7.45–7.30 (6H, m, aromatic), 4.96 (1H, br s,
H-4), 4.38 (1H, dd, Jˆ7.7, 6.3 Hz, H-2), 3.88 (1H, dd,
Jˆ8.8, 7.7 Hz, H-1), 3.65 (1H, br t, Jϳ10.5 Hz, H-5),
3.10 (1H, dd, Jˆ8.8, 6.3 Hz, H-10), 2.20 (1H, d, Jˆ11 Hz,
OH), 1.92 (1H, dqq, Jˆ10.5, 7, 7 Hz, H-6), 1.23, 1.06
(2×3H, 2×s, acetonide Me), 1.10 (9H, s, SiCMe3), 1.07,
0.77 (2×3H, 2×d, Jˆ7 Hz, isopropyl Me); 13C NMR
(100 MHz): d 207.7 (C-3), 136.1, 136.0, 133.0, 129.8,
129.8, 127.7, 127.4 (aromatic), 110.7 (acetonide C), 78.6
(C-2), 76.7 (C-4, C-5), 66.3 (C-1), 31.6 (C-6), 27.2
(SiCMe3), 25.7, 25.0 (acetonide Me), 19.8 (SiCMe3), 19.4,
18.9 (isopropyl Me).
ane–CH2Cl2), [a]D Ϫ41.4 (CHCl3, c 0.8); IR nmax cmϪ1
:
3420 (br, OH), 1734 (ketone CvO), 1383, 1257, 1090, 838;
FABMS, m/z 437.1527 (MϩNa)ϩ. Calc. for C20H31O535Cl-
SiNa, Mˆ437.1527; 1H NMR (400 MHz): d 7.35–7.25
(4H, m, aromatic), 5.27 (1H, br d, Jˆ2 Hz, H-5), 4.83
(1H, d, Jˆ2 Hz, H-4), 4.67 (1H, dd, Jˆ7.7, 5.2 Hz, H-2),
4.24 (1H, dd, Jˆ8.8, 7.7 Hz, H-1), 4.13 (1H, dd, Jˆ8.8,
5.2 Hz, H-10), 1.50, 1.42 (2×3H, 2×s, acetonide Me), 0.74
(9H, s, SiCMe3), Ϫ0.14, Ϫ0.38 (2×3H, 2×s, SiMe2); 13C
NMR (100 MHz): d 207.5 (C-3), 139.9, 133.2, 128.3,
127.1 (aromatic), 111.1 (acetonide C), 80.0 (C-4), 78.7
(C-2), 72.2 (C-5), 66.7 (C-1), 26.2, 24.9 (acetonide Me),
25.5 (SiCMe3), 18.2 (SiCMe3), Ϫ5.2, Ϫ5.9 (SiMe2).
Elemental analysis: Found, C, 57.77%; H, 7.70%. Calc.
for C20H31O5ClSi: C, 57.88%; H, 7.53%.
(2S,4R,5S)-4-O-t-Butyldiphenylsilyl-1,2-O-isopropylidene-
1,2,4,5-tetrahydroxy-5-phenylpentan-3-one, 7c (RˆTBDPS).
Oil, [a]D Ϫ69.6 (CHCl3, c 0.8); IR nmax cmϪ1: 3460 (br,
OH), 1766 (ketone CvO), 1324, 1240, 1050, 938, 840;
FABMS, m/z 528.2316 (MϩHϩNa)ϩ. Calc. for
C30H37O5SiNa, Mˆ528.2308; 1H NMR (400 MHz): d
7.60–7.00 (15H, m, aromatic), 5.38 (1H, br s, H-5), 5.04
(1H, d, Jˆ1.5 Hz, H-4), 4.42 (1H, dd, Jˆ7.7, 6.5 Hz, H-2),
3.84 (1H, dd, Jˆ8.8, 7.7 Hz, H-1), 3.20 (1H, br s, OH), 2.92
(1H, dd, Jˆ8.8, 6.5 Hz, H-10), 1.31, 1.22 (2×3H, 2×s, aceto-
nide Me), 1.00 (9H, s, SiCMe3); 13C NMR (100 MHz): d
206.6 (C-3), 141.4, 136.3, 135.7, 132.7, 132.5, 129.9, 129.6,
128.4, 127.6, 127.5, 127.4, 125.8 (aromatic), 110.9 (aceto-
nide C), 80.3 (C-4), 78.7 (C-2), 72.3 (C-5), 66.2 (C-1), 26.9
(SiCMe3), 25.9, 25.0 (acetonide Me), 19.4 (SiCMe3).
(2S,4R,5S)-4-O-t-Butyldimethylsilyl-1,2-O-isopropylidene-
1,2,4,5-tetrahydroxy-5-(p-nitrophenyl)pentan-3-one, 7e
(RˆTBS). Yellowish needles, mp 124–125ЊC (from hex-
ane–CH2Cl2), [a]D Ϫ10.3 (CHCl3, c 3.5); IR nmax cmϪ1
:
3420 (br, OH), 1734 (ketone CvO), 1383, 1258,
838; FABMS, m/z 448.1775 (MϩNaϩ) Calc. for
C20H31NO7SiNa, Mˆ448.1767; 1H NMR (400 MHz): d
8.24 (2H, d, Jˆ8.8 Hz, aromatic), 7.56 (2H, d, Jˆ8.8 Hz,
aromatic), 5.41 (1H, br d, Jˆ9.5 Hz, H-5), 4.92 (1H, d,
Jˆ1.5 Hz, H-4), 4.72 (1H, dd, Jˆ7.7, 5 Hz, H-2), 4.28
(1H, dd, Jˆ8.8, 7.7 Hz, H-1), 4.17 (1H, dd, Jˆ8.8, 5 Hz,
H-10), 3.20 (1H, d, Jˆ9.5 Hz, OH), 1.54, 1.45 (2×3H, 2×s,
acetonide Me), 0.72 (9H, s, SiCMe3), Ϫ0.11, Ϫ0.40 (2×3H,
Periodic acid cleavage of aldols 7. The aldol (1 mmol) was
dissolved in EtOAc (10 mL) and treated with H5IO6
(800 mg, ca. 3.5 mmol). After stirring at room temperature

M. Carda et al. / Tetrahedron 56 (2000) 677–683
681
until consumption of 7 (ca. 2 h, TLC monitoring), solid
sodium thiosulfate (320 mg, ca. 2 mmol) was added. The
reaction mixture was stirred for 5 min, filtered and evapo-
rated in vacuo, and the oily residue was treated with ethereal
diazomethane. Column chromatography on silica gel (hex-
ane–Et2O 19:1, then 9:1) afforded 8 and 9. Chemical yields:
8a (60%), 8b (66%), 8c (74%), 8d (71%); 9a (10%), 9b
(11%), 9c (13%), 9d (12%).
Alkaline deformylation of esters 8. The ester (1 mmol)
was dissolved in dry MeOH (5 mL), cooled to 0ЊC and
treated with solid KHCO3 (110 mg, ca. 1.1 mmol). After
stirring at 0ЊC for ca. 1 h (TLC monitoring), the mixture
was worked up and chromatographed on silica gel (hex-
ane–EtOAc 9:1) to yield 9. Chemical yields: 9a (82%),
9b (80%), 9c (85%), 9d (85%).
Methyl (2R,3S)-2-O-t-butyldimethylsilyl-2,3-dihydroxy-
pentanoate, 9a. Oil, [a]D ϩ25.2 (CHCl3, c 0.9); IR nmax
cmϪ1: 3410 (br, OH), 1759, 1730sh (ester CvO), 1462,
1256, 1151, 838, 780; CIMS, m/z 263.1685 (MϩHϩ).
Methyl (2R,3S)-2-O-t-butyldimethylsilyl-3-O-formyl-2,3-
dihydroxypentanoate, 8a. Oil, [a]D Ϫ15.2 (CHCl3, c
1.1); IR nmax cmϪ1: 1760, 1729 (ester CvO), 1255, 1168,
1085, 838, 780; CIMS, m/z 291.1619 (MϩHϩ). Calc. for
1
Calc. for C12H27O4Si, Mˆ263.1678; H NMR (500 MHz):
1
C13H27O5Si, Mˆ291.1627; H NMR (500 MHz): d 8.06
d 4.09 (1H, d, Jˆ3 Hz, H-2), 3.70 (3H, s, OMe), 3.68 (1H,
br m, H-3), 2.20 (1H, br s, OH), 1.48 (2H, m, H-4), 0.94 (3H,
t, Jˆ7.5 Hz, H-5), 0.88 (9H, s, SiCMe3), 0.07, 0.02 (2×3H,
2×s, SiMe2); 13C NMR (125 MHz): d 172.7 (C-1), 74.8,
74.5 (C-2, C-3), 51.9 (OMe), 26.7 (C-4), 25.7 (SiCMe3),
18.3 (SiCMe3), 10.2 (C-5), Ϫ4.9, Ϫ5.5 (SiMe2).
(1H, s, OCHO), 5.10 (1H, dt, Jˆ4.5, 4 Hz, H-3), 4.28
(1H, d, Jˆ4 Hz, H-2), 3.70 (3H, s, OMe), 1.67 (2H, m,
H-4), 0.92 (3H, t, Jˆ7.5 Hz, H-5), 0.89 (9H, s, SiCMe3),
0.08, 0.04 (2×3H, 2×s, SiMe2); 13C NMR (125 MHz): d
171.4 (C-1), 160.6 (CHO), 76.1 (C-2), 73.0 (C-3), 52.1
(OMe), 25.7 (SiCMe3), 23.2 (C-4), 18.3 (SiCMe3), 9.9
(C-5), Ϫ4.9, Ϫ5.5 (SiMe2).
Methyl (2R,3S)-2-O-t-butyldimethylsilyl-2,3-dihydroxy-
4-methylpentanoate, 9b. Oil, [a]D ϩ31.1 (CHCl3, c 1.5);
IR nmax cmϪ1: 3420 (br, OH), 1760, 1730sh (ester CvO),
1470, 1390, 1364, 1256, 1150, 1109, 1007, 983, 838, 780;
CIMS, m/z 277.1833 (MϩHϩ). Calc. for C13H29O4Si,
Mˆ277.1835; 1H NMR (500 MHz): d 4.30 (1H, d,
Jˆ2.5 Hz, H-2), 3.72 (3H, s, OMe), 3.40 (1H, br d,
Jˆ2.5 Hz, H-3), 2.20 (1H, br s, OH), 1.72 (1H, m, H-4),
1.00, 0.91 (2×3H, 2×d, Jˆ7 Hz, H-5 and Me-C4), 0.90 (9H,
s, SiCMe3), 0.10, 0.04 (2×3H, 2×s, SiMe2); 13C NMR
(125 MHz): d 173.0 (C-1), 78.6 (C-3), 72.7 (C-2), 51.9
(OMe), 30.7 (C-4), 25.7 (SiCMe3), 19.2, 18.6 (C-5 and
Me-C4), 18.3 (SiCMe3), Ϫ4.7, Ϫ5.4 (SiMe2).
Methyl (2R,3S)-2-O-t-butyldimethylsilyl-3-O-formyl-2,3-
dihydroxy-4-methylpentanoate, 8b. Oil, [a]D Ϫ11.3
(CHCl3, c 1.3); IR nmax cmϪ1: 1759, 1729 (ester CvO),
1467, 1257, 1164, 1110, 836, 780; CIMS, m/z 305.1789
1
(MϩHϩ). Calc. for C14H29O5Si, Mˆ305.1784; H NMR
(500 MHz): d 8.07 (1H, s, OCHO), 4.97 (1H, dd, Jˆ7.3,
4.2 Hz, H-3), 4.36 (1H, d, Jˆ4.2 Hz, H-2), 3.67 (3H, s,
OMe), 2.00 (1H, dqq, Jˆ7.3, 7. 7 Hz, H-4), 0.94, 0.90
(2×3H, 2×d, Jˆ7 Hz, H-5 and Me-C4), 0.87 (9H, s,
SiCMe3), 0.07, 0.03 (2×3H, 2×s, SiMe2); 13C NMR
(125 MHz): d 171.6 (C-1), 160.6 (CHO), 79.1 (C-3), 72.2
(C-2), 52.0 (OMe), 28.1 (C-4), 25.6 (SiCMe3), 19.1,
17.9 (C-5 and Me-C4), 18.2 (SiCMe3), Ϫ4.8, Ϫ5.4
(SiMe2).
Methyl (2R,3S)-2-O-t-butyldimethylsilyl-2,3-dihydroxy-
3-phenylpropionate, 9c. Oil, [a]D ϩ27.5 (CHCl3, c 1.6);
IR nmax cmϪ1: 3390 (br, OH), 1757, 1734sh (ester CvO),
1452, 1437, 1255, 1143, 1057, 837, 780; CIMS, m/z
293.1568 (MϩHϩϪH2O). Calc. for C16H25O3Si,
Methyl (2R,3S)-2-O-t-butyldimethylsilyl-3-O-formyl-2,3-
dihydroxy-3-phenylpropionate, 8c. Oil, [a]D ϩ40.9
(CHCl3, c 1.7); IR nmax cmϪ1: 1759, 1734 (ester CvO),
1257, 1156, 1021, 837, 780; CIMS, m/z 293.1567
(MϩHϩϪHCOOH). Calc. for C16H25O3Si, Mˆ293.1572;
1H NMR (500 MHz): d 8.14 (1H, s, OCHO), 7.40–7.25
(5H, m, aromatic), 6.17 (1H, d, Jˆ4.3 Hz, H-3), 4.42 (1H,
d, Jˆ4.3 Hz, H-2), 3.65 (3H, s, OMe), 0.79 (9H, s, SiCMe3),
Ϫ0.13, Ϫ0.17 (2×3H, 2×s, SiMe2); 13C NMR (125 MHz): d
170.7 (C-1), 159.8 (CHO), 135.7, 128.6, 128.4, 127.1
(aromatic), 76.5 (C-3), 75.6 (C-2), 52.2 (OMe), 25.5
(SiCMe3), 18.3 (SiCMe3), Ϫ5.6, Ϫ5.7 (SiMe2).
1
Mˆ293.1572; H NMR (500 MHz): d 7.35–7.25 (5H, m,
aromatic), 5.01 (1H, br d, Jϳ3 Hz, H-3), 4.30 (1H, d,
Jˆ3.4 Hz, H-2), 3.72 (3H, s, OMe), 3.00 (1H, s, OH),
0.78 (9H, s, SiCMe3), Ϫ0.10, Ϫ0.25 (2×3H, 2×s, SiMe2);
13C NMR (125 MHz): d 172.0 (C-1), 140.4, 128.2, 127.7,
126.1 (aromatic), 76.9 (C-2), 75.1 (C-3), 52.1 (OMe), 25.5
(SiCMe3), 18.2 (SiCMe3), Ϫ5.5, Ϫ5.8 (SiMe2).
Methyl (2R,3S)-2-O-t-butyldimethylsilyl-2,3-dihydroxy-
3-(p-chlorophenyl)propionate, 9d. Oil, [a]D ϩ25.1
(CHCl3, c 3.6); IR nmax cmϪ1: 3470 (br, OH), 1760,
1735sh (ester CvO), 1493, 1463, 1437, 1409, 1362, 1257,
1145, 1092, 1065, 1015, 953, 835, 781; CIMS, m/z 327.1186
(MϩHϩϪH2O). Calc. for C16H24O3Si35Cl, Mˆ327.1183;
1H NMR (500 MHz): d 7.35–7.25 (4H, m, aromatic), 4.96
(1H, dd, Jˆ7, 3.3 Hz, H-3), 4.25 (1H, d, Jˆ3.3 Hz, H-2),
3.70 (3H, s, OMe), 3.10 (1H, d, Jˆ7 Hz, OH), 0.77 (9H, s,
SiCMe3), Ϫ0.08, Ϫ0.23 (2×3H, 2×s, SiMe2); 13C NMR
(125 MHz): d 171.7 (C-1), 138.9, 133.5, 128.3, 127.5
(aromatic), 76.7 (C-2), 74.5 (C-3), 52.1 (OMe), 25.5
(SiCMe3), 18.2 (SiCMe3), Ϫ5.4, Ϫ5.7 (SiMe2).
Methyl (2R,3S)-2-O-t-butyldimethylsilyl-3-O-formyl-2,3-
dihydroxy-3-(p-chlorophenyl)propionate, 8d. Oil, [a]D
ϩ44.8 (CHCl3, c 1.1); IR nmax cmϪ1: 1760, 1734 (ester
CvO), 1494, 1257, 1157, 1092, 1015, 837, 780;
CIMS, m/z327.1189 (MϩHϩϪHCOOH). Calc. for
C16H24O3Si35Cl, Mˆ327.1183; 1H NMR (500 MHz): d
8.09 (1H, s, OCHO), 7.35–7.25 (4H, m, aromatic), 6.12
(1H, d, Jˆ4.4 Hz, H-3), 4.38 (1H, d, Jˆ4.4 Hz, H-2), 3.64
(3H, s, OMe), 0.78 (9H, s, SiCMe3), Ϫ0.11, Ϫ0.18 (2×3H,
2×s, SiMe2); 13C NMR (125 MHz): d 170.4 (C-1), 159.6
(CHO), 134.5, 134.3, 128.6 (aromatic), 75.6 (C-2), 75.2
(C-3), 52.2 (OMe), 25.4 (SiCMe3), 18.2 (SiCMe3), Ϫ5.6,
Ϫ5.7 (SiMe2).
Deformylation/desilylation of 8 or desilylation of 9.
Either ester or their mixture15 (1 mmol) was dissolved in

682
M. Carda et al. / Tetrahedron 56 (2000) 677–683
´
acetonitrile (10 mL) and treated with 48% aq. HF (0.65 mL,
18 mmol). The reaction mixture was stirred at room
temperature for 6 h, poured onto 5% aq. NaHCO3 and
worked up. Column chromatography on silica gel (hex-
ane–EtOAc 1:1!EtOAc) provided dihydroxy esters 10.
Chemical yields for the direct conversion of 8 into 10:
10a (75%), 10b (78%), 10c (85%), 10d (81%).
Palomo and his group at the University of San Sebastian,
Spain, for their collaboration in part of the experimental
work.
References
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Methyl (2R,3S)-2,3-dihydroxypentanoate, 10a. Oil, [a]D
Ϫ7.5 (CHCl3, c 1.1); IR nmax cmϪ1: 3420 (br, OH), 1735
(ester CvO), 1639, 1453, 1377, 1260, 1095, 800; CIMS,
m/z 149.0812 (MϩHϩ). Calc. for C6H13O4, Mˆ149.0813;
1H NMR (500 MHz): d 4.12 (1H, br d, Jˆ2 Hz, H-2), 3.81
(3H, s, OMe), 3.12 (1H, m, H-3), 2.10 (1H, br s, OH), 1.63
(2H, quint, Jˆ7.4 Hz, H-4), 0.98 (3H, t, Jˆ7.4 Hz, H-5); 13C
NMR (125 MHz): d 174.2 (C-1), 74.0, 72.7 (C-2, C-3), 52.9
(OMe), 26.8 (C-4), 10.2 (C-5).
Methyl (2R,3S)-2,3-dihydroxy-4-methylpentanoate, 10b.
Oil, [a]D Ϫ6.9 (CHCl3, c 0.5); IR nmax cmϪ1: 3380 (br, OH),
1739 (ester CvO), 1441, 1272, 1222, 1141, 1094, 1048,
798; CIMS, m/z 163.0972 (MϩHϩ). Calc. for C7H15O4,
Mˆ163.0970; 1H NMR (500 MHz): d 4.29 (1H, d,
Jˆ1.5 Hz, H-2), 3.82 (3H, s, OMe), 3.49 (1H, dd, Jˆ8.5,
1.5 Hz, H-3), 1.87 (1H, m, H-4), 1.03, 0.97 (2×3H, 2×d,
Jˆ7 Hz, H-5 and Me-C4); 13C NMR (125 MHz): d 174.6
(C-1), 77.8 (C-3), 71.2 (C-2), 52.9 (OMe), 31.2 (C-4), 19.1,
19.0 (C-5 and Me-C4).
Methyl (2R,3S)-2,3-dihydroxy-3-phenylpropionate, 10c.
Colourless solid, mp 85–87ЊC (from hexane–CH2Cl2), lit.17
mp 84–86ЊC; [a]D ϩ13.3 (CHCl3, c 0.7), ϩ8.2 (EtOH, c
1.2), lit.17 [a]D ϩ3.4 (EtOH, c 1.19); IR nmax cmϪ1: 3390
(br, OH), 1736 (ester CvO), 1638, 1452, 1440, 1274, 1222,
1117, 1082, 1053, 1028; 1H NMR (500 MHz): d 7.40 – 7.25
(5H, m, aromatic), 4.99 (1H, d, Jˆ3 Hz, H-3), 4.34 (1H, d,
Jˆ3 Hz, H-2), 3.78 (3H, s, OMe), 3.30 (1H, br s, OH), 3.00
(1H, br s, OH); 13C NMR (125 MHz): d 173.2 (C-1), 139.9,
128.5, 128.0, 126.2 (aromatic), 74.8, 74.4 (C-2, C-3), 52.8
(OMe).
´
´
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nate, 10d: mp 120–122ЊC (from hexane–CH2Cl2), [a]D
ϩ6.3 (CHCl3, c 1.4); IR nmax cmϪ1: 3460 (br, OH), 1740
(ester CvO), 1492, 1440, 1400, 1337, 1225, 1105, 1054,
1014, 934, 780; EIMS, m/z (% rel. int.): 230.0339 (Mϩ, 1),
¨
Schollkopf, K., Schulz, B.-G., Eds.; Springer: Berlin, 1993; pp 63–
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related to 1, see: Loh, T.-P.; Chua, G.-L.; Vittal, J.-J.; Wong, M.-
W. Chem. Commun. 1998, 861–862.
6. For a conceptually related synthon based on a dihydroxyacetone
derivative, see: Enders, D.; Jegelka, U. Tetrahedron Lett. 1993,
2453–2456. For a recent review on chiral homoenolate equiva-
lents, see: Ahlbrecht, H.; Beyer, U. Synthesis 1999, 365–390.
7. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259–281.
8. For the preparation of variously protected d- and l-erythrulose
derivatives using chiral precursors other than erythrulose itself,
1
90 (100). Calc. for C10H11O435Cl, Mˆ230.0345; H NMR
(500 MHz): d 7.35–7.25 (4H, m, aromatic), 4.94 (1H, d,
Jˆ3 Hz, H-3), 4.28 (1H, d, Jˆ3 Hz, H-2), 3.75 (3H, s,
OMe), 3.30 (1H, br s, OH); 13C NMR (125 MHz): d
173.0 (C-1), 138.4, 133.8, 128.5, 127.7 (aromatic), 74.7
(C-3), 73.8 (C-2), 52.9 (OMe). Elemental analysis: Found,
C, 52.22%; H, 4.64%. Calc. for C10H11O4Cl: C, 52.08%; H,
4.81%.
´
´
Acknowledgements
see: Marco, J. A.; Carda, M.; Gonzalez, F.; Rodrıguez, S.;
Murga, J. Liebigs Ann. Chem. 1996, 1801–1810. For an improved
preparation of silylated l-erythrulose acetonides 6 (RˆTES, TBS,
The authors wish to acknowledge financial support by the
DGICYT (projects PB96-0760 and PB98-1438) and by the
Conselleria de Cultura de la Generalitat Valenciana (project
GV97-CB-11-77). E. F. thanks the latter institution for a
pre-doctoral fellowship. The authors further thank Prof. C.
´
TPS) from l-erythrulose hydrate, see: Carda, M.; Rodrıguez, S.;
¨
Murga, J.; Falomir, E.; Marco, J. A.; Roper, H. Synth. Commun.
1999, 29, 2601–2610.
9. The following enolization systems were tried without success

M. Carda et al. / Tetrahedron 56 (2000) 677–683
683
(either decomposition or recovery of starting material was
observed): (a) Sn(OTf)2/iPr2NEt: Mukaiyama, T. Aldrichimica
Acta 1996, 29, 59–76. (b) TiCl4/iPr2NEt: Evans, D. A.; Clark, J.
S.; Metternich, R.; Novack, V. J.; Sheppard, G. S. J. Am. Chem.
Soc. 1990, 112, 866–868. (c) SnCl4/iPr2NEt: Rossi, T.;
Marchioro, C.; Paio, A.; Thomas, R. J.; Zarantonello, P. J. Org.
Chem. 1997, 62, 1653–1661. (d) LDA or LDA/LiCl: Palomo, C.;
17. Dihydroxy ester 10 (R0ˆPh) showed NMR data identical with
those reported: Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B. J. Org.
Chem. 1994, 59, 5104–5105.
´
18. (a) Palomo, C.; Aizpurua, J. M.; Cabre, F.; Cuevas, C.; Munt,
S.; Odriozola, J. M. Tetrahedron Lett. 1994, 2725–2728. (b)
Ojima, I. Acc. Chem. Res. 1995, 28, 383–389. (c) Cativiela, C.;
´
´
Dıaz de Villegas, M. D.; Galvez, J. A. Tetrahedron: Asymmetry
1996, 7, 529–536. (d) Merino, P.; Castillo, E.; Franco, S.;
´
´
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Gonzalez, A.; Garcıa, J. M.; Landa, C.; Oiarbide, M.; Rodrıguez,
S.; Linden, A. Angew. Chem., Int. Ed. Engl. 1998, 37, 180–182,
and references cited therein. (e) n-Bu2BOTf/tertiary amine:
Mukaiyama, T.; Inoue, T. Bull. Chem. Soc. Jpn. 1980, 53, 174–
178. (f) n-BuBCl2/tertiary amine: Ramachandran, P. V.; Xu, W.-C.;
Brown, H. C. Tetrahedron Lett. 1997, 769–772.
´
Merchan, F. L.; Tejero, T. Tetrahedron 1998, 54, 12301–12322.
(e) Brackenridge, I., Davies, S. G.; Fenwick, D. R.; Ichihara, O.;
Polywka, M. E. C. Tetrahedron 1999, 55, 533–540. (f) Seki, M.;
Matsumoto, K. Synthesis 1999, 924.
´
19. Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron
10. Brown, H. C.; Ganesan, K.; Dhar, R. K. J. Org. Chem. 58,
147–153. For a general review on boron aldol additions, see:
Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1–200.
11. A preliminary account of the part of the work described here
has already appeared: Marco, J. A.; Carda, M.; Falomir, E.;
Palomo, C.; Oiarbide, M.; Ortiz, J. A.; Linden, A. Tetrahedron
Lett. 1999, 1065–1068. For the influence of the protecting groups
on the stereoselectivity, see: Carda, M.; Falomir, E.; Murga, J.;
Lett. 1994, 9083–9086.
20. For the enolization of ketones with Chx2BCl/tertiary amine to
yield E boron enolates, see Ref. 10 and: (a) Brown, H. C.; Dhar, R.
K.; Bakshi, R. K.; Pandiarajan, P. K.; Singaram, B. J. Am. Chem.
Soc. 1989, 111, 3441–3442. (b) Brown, H. C.; Dhar, R. K.;
Ganesan, K.; Singaram, B. J. Org. Chem. 1992, 57, 2716–2721.
(c) Brown, H. C.; Ganesan, K.; Dhar, R. K. J. Org. Chem. 1992, 57,
3767–3772. (d) Paterson, I.; Tillyer, R. D. J. Org. Chem. 1993, 58,
4182–4184. (e) Paterson, I.; Nowak, T. Tetrahedron Lett. 1996,
8243–8246.
´
Castillo, E.; Gonzalez, F.; Marco, J. A. Tetrahedron Lett. 1999,
6845–6848.
12. The complete details of all reaction conditions, chemical
correlations, X-ray diffraction analysis, computational calculations
and physical and spectral data of all intermediates are described in
21. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920–1923.
22. For recent theoretical studies on boron aldol reactions, see: (a)
Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Org. Chem. 1990, 55,
481–493. (b) Bernardi, A.; Capelli, A. M.; Comotti, A.; Gennari,
C.; Gardner, M.; Goodman, J. M.; Paterson, I. Tetrahedron 1991,
47, 3471–3484. (c) Gennari, C.; Vieth, S.; Comotti, A.; Vulpetti,
A.; Goodman, J. M.; Paterson, I. Tetrahedron 1992, 48, 4439–
4458. (d) Vulpetti, A.; Bernardi, A.; Gennari, C.; Goodman, J.
M.; Paterson, I. Tetrahedron 1993, 49, 685–696.
23. Computational ab initio calculations have been performed by
Dr J. Murga. The results will be disclosed in due time.
24. In the single case hitherto described of syn aldol formation of
an a-alkoxy ketone with Chx2BCl,19 it has been suggested that
initial formation of a five-membered chelate involving the boron
and the two oxygen atoms, followed by stereoselective deproto-
nation by the tertiary amine, explain the formation of the putative Z
enolate. This and other alternative explanations are now being
studied by us at both the theoretical and the experimental level.
25. Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister,
M. A. J. Am. Chem. Soc. 1994, 116, 11287–11314.
´
the PhD Thesis of E. Falomir (University of Castellon, 1998).
13. Even though any one of the three silyl groups (TES, TBS and
TBDPS) is suitable as a protecting group under the reaction con-
ditions of the sequence 7!8!9!10; here we describe only those
esters 8 and 9 bearing a TBS group.
14. (a) Wu, W.-L.; Wu, Y.-L. J. Org. Chem. 1993, 58, 3586–3588.
(b) Xie, M.; Berges, D. A.; Robins, M. J. J. Org. Chem. 1996, 61,
5178–5179.
15. The formation of small amounts of the deformylated ester 9
during the oxidative cleavage of 8 could not be avoided: shorter
reaction times only led to incomplete oxidation of 7. However, the
mixture of 8 and 9 may be used without separation in either of the
subsequent reactions, thus improving the overall yields.
16. The formylated derivatives 8 are quite sensitive to alkaline
media. Hydrolysis of 8 under even such mild conditions as
potassium carbonate in MeOH at 0ЊC caused decomposition. The
same result was observed when 8 (or 9) was treated with tetra-n-
butylammonium fluoride in THF.