Influence of the protecting groups on the syn/anti stereoselectivity of boron aldol additions with erythrulose derivatives. A theoretical and experimental study

Article abstract of DOI:10.1016/S0040-4020(02)01279-6

We have investigated a series of aldol additions of protected L-erythrulose derivatives mediated by dicyclohexyl boron chloride. The syn/anti stereoselectivity has been found to depend on the type of protecting groups on the hydroxyl functions at C-3 and

Full text of DOI:10.1016/S0040-4020(02)01279-6

Tetrahedron 58 (2002) 9697–9707
Influence of the protecting groups on the syn/anti stereoselectivity
of boron aldol additions with erythrulose derivatives.
A theoretical and experimental studyq
a
Juan Murga, Eva Falomir, Florenci Gonzalez, Miguel Carda and J. A. Marco
a
a
a
b
,
,
*
*
´
a
´
´
´
´
Depart. de Q. Inorganica y Organica, Univ. Jaume I, Castellon, E-12080 Castellon, Spain
´
Depart. de Q. Organica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
b
Dedicated to Professor Emanuel Vogel, former Director of the Institute of Organic Chemistry at the University of Cologne, Germany, on the occasion of his
75th birthday
Received 25 June 2002; revised 31 July 2002; accepted 7 October 2002
Abstract—We have investigated a series of aldol additions of protected L-erythrulose derivatives mediated by dicyclohexyl boron chloride.
The syn/anti stereoselectivity has been found to depend on the type of protecting groups on the hydroxyl functions at C-3 and C-4. Thus,
erythruloses benzylated at these hydroxyl groups gave only syn aldols while the corresponding benzoylated derivatives gave anti aldols under
the same reaction conditions. The resident chirality of the enolate promoted a complete internal 1,3-induction, which was syn in both aldol
types. Mechanistic proposals are advanced with support of both theoretical calculations and experimental data. q 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
(Chx2BCl) was used as the enolization reagent.5–8 The
boron enolates were then allowed to react with a range of
achiral aldehydes to yield aldol adducts of the general
formula 2 with a high degree of syn 1,2- and 1,3-induction
(which corresponds to the 2,4-syn/4,5-syn relationship in 2).
It is worth noting here that the observed syn 1,2-induction is
unexpected for Chx2BCl as the enolization reagent.5,6,9
Furthermore, we described the use of aldols 2 for the
preparation of selectively protected syn-a,b-dihydroxy
esters 3 in enantiopure form.8c Ketone 1 therefore behaves
here as a chiral synthetic equivalent of the d 2 synthon
hydroxyacetic (glycolic) acid enolate.10
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 Our current interest in the develop-
ment of erythrulose3 as a useful chiral C4 building block for
the stereocontrolled construction of polyfunctionalized
structures has prompted us to investigate the enolization
of protected derivatives thereof and the subsequent addition
of the resulting enolates to aldehydes. We recently reported
that L-erythrulose acetals of the general formula 1 (Scheme
1, protecting group P¼triethylsilyl, TES; t-butyldimethyl-
silyl, TBS; or t-butyldiphenylsilyl, TPS), readily prepared
in two steps from L-erythrulose,4 were transformed into
boron enolates provided that chlorodicyclohexylborane
A bibliographic review of the synthetic uses of Chx2BCl for
aldol additions revealed that, prior to our research, only one
case of a syn aldol addition had been reported with this
reagent. Paterson and co-workers described the use of
Scheme 1.
Keywords: erythrulose; boron aldol additions; stereoselectivity; influence of protecting groups; ab initio calculations.
*
Corresponding authors. Tel.: þ34-96-3864337; fax: þ34-96-3864328; e-mail: alberto.marco@uv.es
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01279-6

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J. Murga et al. / Tetrahedron 58 (2002) 9697–9707
hydroxyl functions at C-3 and C-4. In the present paper, we
disclose in full the experimental details of aldol reactions
previously reported in preliminary form.13 Furthermore, we
present the results of ab initio calculations aimed at a
mechanistic explanation of the observed experimental
results.
2. Results and discussion
We initially evaluated the 3,4-di-O-benzyl-L-erythrulose
derivative 4.4 As with 1, aldol additions of 4 using Chx2BCl
were fruitful, leading to aldol adducts 5 in good chemical
yields as essentially single diastereoisomers (Scheme 2 and
Table 1). The sterically hindered pivalaldehyde (tBuCHO)
was the only aldehyde tested which did not react under the
described conditions. The stereochemical course of the
reaction was the same as for 1, with only the 2,4-syn/4,5-syn
stereoisomer being detected.13 Thus, the change of the
acetonide moiety to benzyl protecting groups does not
change the stereochemical bias of the process. In line with
Paterson’s mechanistic reasoning, we subsequently investi-
gated the stereochemical outcome of aldol reactions with
1-O-t-butyldimethylsilyl-3,4-di-O-benzoyl-L-erythrulose 6,
readily prepared from L-ascorbic acid.4,8a,14 It turned out
that, under the same reaction conditions used for 1 and 4,
ketone 6 underwent aldol additions with aldehydes to give
aldol adducts 7 (relative configuration 2,4-syn/4,5-anti) with
high yield and stereoselectivity (dr’s were slightly lower
than with 4 but still .9:1, see Scheme 2 and Table 1).13,15
This result of the aldol reactions with ketone 6 is of great
potential use in organic synthesis. For example, oxidative
cleavage of the CO–C(OBz) bond under conditions similar
to those used in our previous report8c should lead to
selectively protected anti a,b-dihydroxy esters (Scheme
3).16 In fact, Forsyth and co-workers have recently used 6 in
just such a preparative role in their synthetic approach to
azaspiracid.17
Scheme 2. Aldol reactions of erythrulose derivatives 4 and 6.
Table 1. Aldol reactions of ketones 4 and 6 with aldehydes RCHO
R
Ketone (% yield of 5 or 7)
Et
4 (87)
6 (85)
iPr
tBu
4 (86)
6 (88)
No reaction
4 (83)
6 (85)
4 (86)
6 (89)
For reaction conditions, see Section 4. Dr’s (determined by means of 1H and
13C NMR) were always .9:1 (with 4, dr’s were most often .19:1).
an ethyl ketone bearing an a0-benzyloxy group, where a
syn aldol was formed with good diastereoselectivity
(diastereoisomeric ratio, dr .19:1).11 The authors related
this unanticipated syn bias to the formation of a Z enolate
instead of the expected E isomer, a feature attributed in turn
to the deprotonation step taking place in a chelate involving
the boron, carbonyl oxygen, and a-oxygen atoms.12 They
further reasoned that replacement of the benzyl by a benzoyl
group would make the a-oxygen atom electron-poorer and
thus inhibit the formation of such a chelate, with subsequent
reversal of the stereochemical course to the expected anti
aldol formation via an E enolate. Their conclusions were
subsequently supported by experimental results.11 How-
ever, if we assume that a Z enolate is also being formed in
our case, we would have to imply that the a-oxygen atom of
the acetal moiety in 1 participates in the formation of
chelates, a conclusion which does not agree with our
previous results concerning nucleophilic additions to the
carbonyl group of such ketones.3 In light of these findings,
we decided to investigate whether the syn/anti stereoselec-
tivity of our aldol reactions with erythrulose derivatives was
similarly amenable to modulation through the use of
protecting groups other than the acetal moiety on the
We were interested in understanding the mechanistic
aspects of these aldol reactions. The first question we
sought to answer concerned the actual configuration of the
intermediate enol borane. In the case of 1 (P¼TBS), this
configuration was unequivocally established as Z via
boron–silicon interchange as described by Evans and
co-workers18 (in all likelihood, the same result would be
observed with a-benzyloxy ketone 4). We also investigated
the influence of some experimental factors on the outcome
of the aldol reactions, using 1 (P¼TBS) or 4 and
benzaldehyde as the model reagents. The results of these
studies are shown in Table 2. Under the standard reaction
conditions (cond. 1),8 aldolizations take place smoothly
with high yields and only stereoisomers 2 or 5, respectively,
are detected (yields in Table 1). Neither the steric bulk of the
base nor the solvent (Et2O or CH2Cl2) plays a determinant
Scheme 3.

J. Murga et al. / Tetrahedron 58 (2002) 9697–9707
9699
Table 2. Influence of experimental factors on the outcome of boron aldol reactions with 1 or 4
Conditions
1a
2b
3c
4d
6e
7f
8g
Decomp.
Reaction product
2 or 5h
2 or 5h
2 or 5h
2 or 5h
Starting compounds
2 or 5h
a
Standard reaction conditions: (i) enolization, Et3N/1.8 equiv. Chx2BCl in Et2O, 08C, 30 min. (ii) Aldolization: 08C, 4 h.
As for cond. 1, but replacing EtNMe2 or EtNiPr2 as the base instead of Et3N, either with Et2O or with CH2Cl2 as the solvent.
As for cond. 1, but aldolization conducted for 5 h at 2788C.
As for cond. 1, but enolization conducted for 6 h at 2508C and aldolization for 5 h at 2788C.
As for cond. 1 but with #1.3 equiv. Chx2BCl.
As for cond. 1 but with 2.5 equiv. Chx2BCl.
b
c
d
e
f
g
h
As for cond. 1, but with $3 equiv. Chx2BCl.
Yields and dr’s are similar under all these conditions.
role in the outcome of the aldolization (cond. 2), yields and
stereoisomer would receive a qualitatively reasonable
explanation.18,21 The boron enolate of ketone 6, however,
behaves differently in that: (a) it gives rise to stereoisomer 7
(1,2-anti stereopreference). (b) It attacks the Si side of the
aldehyde carbonyl group (Scheme 2). The formation of an
anti aldol leads in principle to the suggestion that the enolate
of 6 has the E configuration. If we thus construct a chair-like
TS similar to that of the process 1 (4)!2 (5), we no longer
find all the favorable features which characterized those
TSs. Scheme 4 shows that there is a marked steric crowding
between one of the boron ligands and one of the bulky
groups at the stereogenic Ca carbon (OBz in the TS depicted
in the left). If we try to avoid this by rotation of the CO–Ca
bond, a considerable degree of A(1,3) strain23 appears
between the CH2OBz and OTBS groups (this factor is
much less a concern with the Z enolate, where an H atom
replaces the OTBS group). Among the various mechanistic
alternatives which may be proposed, one of them is that
aldol reactions of 6 may take place through a non-chair TS.
dr’s being the same. We have also found that the aldol
addition step takes place readily even at 2788C (cond. 3).
However, it is much more comfortable to perform the
reaction at 08C, and neither yields nor dr’s are compro-
mised. The enolization step turns out to be rate-determining
and requires temperatures $2508C to take place at an
acceptable rate (cf. cond. 4). Although the idea of the kinetic
formation of an E enolate, followed by rapid E!Z
isomerization, is conceivable in principle, such isomeriza-
tions have been found to take place at much higher
temperatures, so they may ruled out in the present case.18
The boron aldol reaction requires a minimum of about
1.7 equiv. of Chx2BCl to work efficiently (we routinely use
1.8 equiv.); an increase of the amount of chloroborane does
not change the final result and even begins to cause
decomposition above 3 equiv. (cond. 6–8).19
On the basis of these experimental facts, the 1,2-syn
stereopreference of the aldol processes with 1/4 can be
qualitatively explained by supposing the occurrence of a
cyclic, chair-like transition state (TS) of the Zimmermann–
Traxler type (Scheme 4),20 in which the chiral Z enolate
(more specifically the Re side of the reacting enolate carbon)
selectively attacks the Re side of the aldehyde carbonyl
group.21,22 This TS orients the C–O bond of the secondary
OBn group and the C–O bond of the enolate in the
electronically more favorable anti coplanar arrangement, in
which dipolar repulsions are minimized. Moreover, the
bulky groups at the stereogenic carbon (OBn and CH2OBn)
point away from the cyclohexyl groups on the boron atom.
In this manner, the formation of the 2,4-syn/4,5-syn
In order to find answers to these questions, we have
undertaken ab initio quantum-mechanical calculations.8a,24
In view of the high number of atoms involved in the
aldolization step, we used a somewhat reduced model for
these theoretical studies. Acetonide 1 (P¼SiMe3) was the
model ketone, whereas benzaldehyde was the reacting
aldehyde (see Scheme 5). For the enolization reagent, the
cyclohexyl groups were replaced by cyclopropyl (Cyp)
groups.25 In order to make a complete study, the two
possible boron enolates, E-1enolB and Z-1enolB, were included
in the calculations. The four diastereoisomeric aldols which
can be formed, or more precisely the cyclic boron aldolates,
Scheme 4. Tentative mechanistic proposals for aldol additions with ketones 1/4 and 6.

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J. Murga et al. / Tetrahedron 58 (2002) 9697–9707
Scheme 5. Aldolizations of ketone 1 (P¼TMS) and benzaldehyde mediated by Cyp2BCl (Cyp¼cyclopropyl).
were designated ss/aa and as/sa (Scheme 5; the stereo-
chemical descriptors s, syn, and a, anti, refer here in the
indicated order to the relative configurations at C2–C4 and
C4–C5).
vs 608 in an ideal chair). The other three TSs found consisted
of another half-chair and two boats of the ‘boat A’ type.8a,22c
The calculations further predict that the aa aldol is the
thermodynamically most stable adduct. All these data
confirm the conclusion that boron aldol additions with
ketone 1 and 4 are kinetically controlled processes which
yield ss aldols via the corresponding Z enolates.
We first studied the initial step of the aldol addition process,
i.e. the formation of the molecular complexes between
benzaldehyde and the two boron enolates. These molecular
complexes were found to be more stable than the starting
molecules, and their formation had a negligible activation
barrier. We then calculated the energy barriers of the TSs of
the key step, which leads from the molecular complexes to
the four boron aldolates. Table 3 shows the calculated
energy contents of each molecular complex and of the
respective TS, which leads to the final aldolate. The energy
barrier for the individual process is the difference between
these two energy contents. As shown, when enolate Z-1enolB
reacts with the aldehyde carbonyl, the calculations predict
that the lowest energy barrier (19.8 kcal/mol) is that leading
to the ss aldol, in complete agreement with experimental
results (Scheme 2). For the corresponding TS, our
calculations predict a half-chair geometry (Fig. 1, lower
right, and Table 4) very similar in its shape to the chair
depicted in Scheme 4 (CvC· · ·CvO dihedral angle, 70.88
Aldol reactions of a-benzoyloxy ketone 6 provide sa aldols
7. As commented above, this strongly suggests the
intermediacy of an E enolate5 and possibly a non-chair
geometry for the key TS. Several years ago, Paterson,
Gennari and their groups have performed computational
studies on aldol reactions of chiral E boron enolates of a0- or
b0-oxygenated ethyl ketones with the aid of force-field
analysis.11a,22g They concluded that such processes are
controlled by a range of competing factors such as non-
bonded interactions, A(1,3) strain, electrostatic repulsions
between lone pairs at the enolate and substituent oxygen
atoms, etc. The last factor was said by these authors to be
important, as it causes the oxygen-bearing substituent at Ca
to point inside the TS pseudocycle, away from the enolate
oxygen. They proposed for these aldol reactions two types
of competing TSs, one chair-like and another one which
Table 3. HF/6-31Gp//3-21G total (au) and relative energies (kcal/mol, in parentheses), relative to the sum enolateþbenzaldehyde, for the stationary points of
the reaction between enolates Z-1enolB or E-1enolB with benzaldehyde
Enolate
Aldol
Complexes
TS
Productsa
Z-1
enolB
Z-1
aa
as
sa
ss
aa
as
sa
ss
21579.292314 (216.6)
21579.288831 (214.4)
21579.288845 (214.4)
21579.277656 (27.4)
21579.281511 (29.2)
21579.291385 (215.4)
21579.283213 (210.3)
21579.276658 (26.2)
21579.237934 (þ17.5)
21579.242662 (þ14.4)
21579.245151 (þ13.0)
21579.246008 (þ12.4)
21579.247061 (þ12.4)
21579.244974 (þ13.7)
21579.251315 (þ9.7)
21579.228651 (þ23.9)
21579.323101 (235.9)
21579.309724 (227.5)
21579.300597 (221.8)
21579.297592 (219.9)
21579.323131 (235.3)
21579.309824 (227.0)
21579.300617 (221.2)
21579.297622 (219.3)
enolB
Z-1
enolB
Z-1
enolB
E-1
enolB
E-1
enolB
E-1
enolB
E-1
enolB
Total energies (hartrees) of the reactants are: Z-1
¼21235.833459; E-1
¼21235.834361; benzaldehyde¼2343.432438. Geometrical optimizations of
enolB
enolB
stationary points along the potential energy surface have been made at the HF level with the 3-21G basis set. Energy values were then computed at the HF level
with the 6-31Gp basis set. The energy barrier for each individual process is the difference between the energy contents of its respective TS and complex. All
calculations were carried out with the Gaussian 98 suite of programs.24
a
Boron aldolates.

J. Murga et al. / Tetrahedron 58 (2002) 9697–9707
9701
Figure 1. The four TSs for the aldol addition of the Z boron enolate of ketone 6 (R¼TMS) with benzaldehyde. Hydrogen atoms have been omitted for clarity.
The lowest energy barrier corresponds to the reaction leading to the ss boron aldolate.
˚
Table 4. HF/3-21G geometric parameters (lengths in A, angles in degrees) for all eight TSs
Z-1
E-1
enolB
enolB
aa
as
sa
ss
aa
as
sa
ss
Bond lengths
C· · ·C
B–Oenolate
B· · ·Oaldehyde
2.069
1.654
1.525
2.111
1.610
1.528
2.028
1.687
1.525
2.068
1.611
1.533
2.158
1.559
1.578
2.204
1.557
1.584
2.104
1.574
1.563
2.167
1.515
1.634
Dihedral angles
CvC· · ·CvOaldehyde
CvC–Oenolate–B
CvC· · ·C–Haldehyde
24.3
265.6
2120.8
267.5
251.7
55.4
2.0
284.4
119.5
70.8
46.9
251.4
73.2
18.9
248.1
45.3
29.3
164.0
278.0
217.2
43.1
256.4
214.5
2174.1

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J. Murga et al. / Tetrahedron 58 (2002) 9697–9707
Figure 2. The four TSs for the aldol addition of the E boron enolate of ketone 6 (R¼TMS) with benzaldehyde. Hydrogen atoms have been omitted for clarity.
The lowest energy barrier corresponds to the reaction leading to the sa boron aldolate.
could be either chair-like or boat-like, depending of the
nature of the groups at the stereogenic a carbon. For our
model reaction, Table 3 shows that the lowest energy barrier
leading to aldol sa is in fact that going through enolate
E-1enolB (20 kcal/mol). Furthermore, the corresponding TS
adopts a distorted geometry of the so-called ‘boat B’ type22c
(see Fig. 2, lower right, and Table 4). Three further high-
energy, boat-like TSs were found in our calculations but no
chair-like TSs.8a A plausible explanation for a boat-like TS
being energetically favored here is that it minimizes the A1,3
strain within the allylic moiety, as it is the H atom at Ca
which faces the enolate OTBS group (Scheme 6; for the TS
E-1enolB!aldol sa, the calculated H–Ca–CvC dihedral
angle is 26.28). The steric crowding which would exist in the
Scheme 6. TSs for the aldol addition step of the reaction between the E boron enolate of ketone 6 and aldehyde RCHO.

J. Murga et al. / Tetrahedron 58 (2002) 9697–9707
9703
chair TS between the OBz moiety and one of the boron
cyclohexyl ligands (Scheme 6, left part) is relieved through
the rotation of the two B–O bonds and the subsequent
spatial separation between these groups. Apparently, these
two favorable steric factors are quantitatively more
important than the less favourable, non-anticoplanar
alignment of the C–OBz and C–OB dipoles, which occurs
in the boat B TS (see also Scheme 4). However, the relative
importance of lone-pair repulsion in the different TSs is
difficult to estimate and may not be a decisive factor in
our case. In contrast with Paterson’s and Gennari’s
examples,11a,22g ketone 6 (and 4 as well) contains oxygen
atoms at both the Ca and Cb carbon atoms, so that a relative
vicinity of one of these oxygen atoms to the enolate oxygen
may be difficult to avoid.
data). Unambiguous assignments of 1H and 13C NMR
signals were made with a combination of spin decoupling,
DEPT and HMQC experiments. Mass spectra were run by
the electron impact (EIMS, 70 eV) or with the 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 258C.
Reactions which required an inert atmosphere were carried
out under argon with flame-dried glassware. Et2O was
freshly distilled from sodium-benzophenone ketyl. Dichloro-
methane was freshly distilled from CaH2. Tertiary amines
were freshly distilled from KOH. Toluene was freshly
distilled from sodium wire. Chx2BCl was generated by
hydroboration of cyclohexene with monochloroborane as
reported26 and used neat. Commercially available reagents
were used as received. Unless detailed otherwise, ‘work-up’
means pouring the reaction mixture into brine, extraction
with the indicated solvent, additional washing with 5%
aqueous NaHCO3, (if acids had been utilized in the reaction)
or with 5% aqueous HCl (if bases had been utilized), then
again with brine, drying over anhydrous Na2SO4 or MgSO4
and elimination of the solvent in vacuo. The obtained
material was then chromatographed on a silica gel column
(Su¨d-Chemie AG, 60–200 m) with the indicated eluent.
A last question to be addressed here is why the formation of
the aa aldol through a boat B TS is not favored in the case of
6. In fact, an examination of the corresponding TS in the
model reaction (Scheme 5, E-1enolB!aldol aa) does not
reveal a high degree of A(1,3) strain nor an important steric
crowding between the boron ligands and the dioxolane ring.
However, it reveals sizeable non-bonding interactions, not
present in the TS leading to aldol sa, between the dioxolane
ring and the OTMS group (the counterparts of the 1,2-di-
benzoyloxyethyl and OTBS moieties in 6). Attempts at
relieving this steric interaction through rotation of a C–C or
a C–O bond would make other sources of internal strain
(non-bonded interactions or dipolar repulsion within the
O–Ca–C–Oenolate fragment) to increase their value. It is
possible that the dioxolane ring of the model reaction is not
a sufficiently good surrogate for the 1,2-dibenzoyloxyethyl
moiety of 6, as the latter fragment is less rigid and more
capable of internal rotations. However, an ab initio
modelization of the full molecule of 6 with its 61 atoms is
beyond our computer capabilities.
4.1.1. Preparation of (S)-3,4-dibenzoyloxy-1-(tert-butyl-
dimethylsilyloxy)butan-2-one (6). A solution of L-threitol
1,2-acetonide (i)14 (4.86 g, ca. 30 mmol) in dry CH2Cl2
(75 mL) was ice-cooled under Ar and treated sequentially
with triethyl amine (8.5 mL, ca. 60 mmol), DMAP (36 mg,
0.3 mmol) and benzoyl chloride (8.1 mL, ca. 70 mmol).
After removal of the ice bath, the mixture was stirred
overnight at room temperature, then poured onto brine and
extracted with CH2Cl2. The combined organic layers were
washed with saturated aqueous ammonium chloride, then
again with brine and finally dried on anhydrous sodium
sulfate. Solvent removal in vacuo was followed by
chromatography on silica gel (hexane–EtOAc 9.1) to
furnish dibenzoate (ii) (10.2 g, 92%) as a colorless oil,
[a]D¼224.6 (c 1.5; CHCl3); 1H NMR (500 MHz) d 8.10–
8.00 (m, 4H), 7.60–7.35 (m, 6H), 5.62 (dt, 1H, J¼7,
4.2 Hz), 4.68 (dd, 1H, J¼11.8, 4.2 Hz), 4.64 (dd, 1H, J¼
11.8, 7 Hz), 4.52 (ddd, 1H, J¼6.8, 6, 4.2 Hz), 4.15 (dd, 1H,
J¼8.5, 6.8 Hz), 3.96 (dd, 1H, J¼8.5, 6 Hz); 13C NMR
(125 MHz) d 166.16, 166.0, 133.2, 133.1, 129.8, 129.7,
129.6, 128.4, 128.3, 110.0, 74.5, 71.2, 65.5, 63.5, 26.3, 25.2;
IR (NaCl) 3450 (br), 3064, 2988, 2937, 2890, 1724, 1602,
1585, 1452, 1382, 1372, 1316, 1284, 1264, 1110, 1070,
3. Conclusions
In summary, we have performed highly stereoselective aldol
additions of two readily available erythrulose derivatives
bearing different protecting groups. The nature of the latter
has been found to play a decisive role as regards the
sterochemical outcome of the process; when suitably
chosen, these protecting groups make possible the prepa-
ration of either syn or anti aldols, precursors in turn of
selectively protected syn or anti a,b-dihydroxy esters,
respectively: Erythrulose therefore turns out to behave here
as a synthetic equivalent of the chiral d 2 synthon
hydroxyacetic (glycolic) acid enolate. This opens a range
of synthetic possibilities which are currently being explored
within our group.
1026, 910, 847, 735, 712 cm21
.
4. Experimental
4.1. General
NMR spectra were measured at 400 or 500 MHz in CDCl3
solution at 258C. The signals of the deuterated solvent
(CDCl3) were taken as the reference (the singlet at d 7.25 for
1H NMR and the triplet centered at 77.00 ppm for 13C NMR

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J. Murga et al. / Tetrahedron 58 (2002) 9697–9707
Compound (ii) (10 g, 27 mmol) was dissolved in ice-cooled
1:1 aqueous trifluoroacetic acid (100 mL) and stirred at 08C
for 30 min (note of caution: if this time is exceeded,
migration of benzoyl groups may take place with the
corresponding decrease in the yield of (iii). The mixture was
then brought to neutral pH through slow and careful
addition of aqueous Na2CO3 at 08C (pH control!) and
subsequently poured onto brine. After extraction with
CH2Cl2, the organic layer was washed with brine and
dried on anhydrous Na2SO4. Column chromatography on
silica gel afforded L-threitol dibenzoate (iii) (7.4 g, 83%) as
a colorless oil, [a]D¼224 (c 1.1; CHCl3); 1H NMR
(400 MHz) d 8.10–8.00 (m, 4H), 7.60–7.35 (m, 6H), 5.59
(ddd, 1H, J¼6.9, 4.4, 3.8 Hz), 4.76 (dd, 1H, J¼11.8,
4.4 Hz), 4.64 (dd, 1H, J¼11.8, 6.9 Hz), 4.09 (m, 1H), 3.74
(m, 1H), 2.90 (br s, 1H), 2.60 (br s, 1H); 13C NMR
(100 MHz) d 166.6, 166.4, 133.6, 133.3, 129.9, 129.4,
129.2, 128.6, 128.5, 72.2, 71.0, 63.1, 63.0; IR (NaCl) 3450
(br), 3065, 3031, 2958, 1721, 1601, 1584, 1432, 1316, 1266,
1262, 1177, 1109, 1070, 1026, 838, 781, 709 cm21; HR
FABMS m/z 443.1899 [MþHþ], calcd for C24H31O6Si,
443.1890. Anal. Calcd for C24H30O6Si: C, 65.13; H, 6.83.
Found, C, 65.00; H, 6.99.
4.2. Experimental procedure for aldol additions of
ketones 4 or 6 promoted by dicyclohexyl boron chloride
Chx2BCl (395 mL, ca. 1.8 mmol) was added under Ar via
syringe to an ice-cooled solution of Et3N (280 mL, 2 mmol)
in anhydrous Et2O (5 mL). Erythrulose derivative 4 or 6
(1 mmol) was dissolved in anhydrous ether (5 mL) and
added dropwise via syringe to the reagent solution. The
reaction mixture was then stirred for 30 min. After addition
of a solution of the aldehyde (1.5 mmol) in ether (6 mL), the
reaction mixture was stirred at 08C for 4 h. Then phosphate
buffer solution (pH 7, 6 mL) and MeOH (6 mL) were added,
followed by 30% aqueous 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
(hexane–EtOAc 9:1, then 4:1) afforded the corresponding
aldol addition product 5 or 7. Chemical yields and dr are
given in the paper (Table 1). When Et2O was replaced by
THF or CH2Cl2, or when Et3N was replaced by EtNMe2 or
EtNiPr2, yields and dr’s remained essentially unchanged.
When the TBS group at C-1 was replaced by a TES or a TPS
group, yield and stereoselectivity also remained practically
unchanged, even though the reaction with the TPS
derivative was slower. The aldol addition step still takes
place at 2788C although it requires a longer time (about
6–8 h). This low temperature may become necessary in the
case of sensitive aldehydes.
1070, 803 cm21
.
The previous compound (6.6 g, ca. 20 mmol) was dissolved
under Ar in dry DMF (10 mL), cooled to 08C and treated
with imidazole (1.7 g, 25 mmol) and t-butyldimethylsilyl
chloride (3.32 g, ca. 22 mmol). The mixture was then stirred
for about 8 h at the same temp. (TLC monitoring!), poured
onto brine and extracted with Et2O. The combined organic
layers were washed with satd. aqueous ammonium chloride,
then again with brine and finally dried on anhydrous sodium
sulfate. Solvent removal in vacuo was followed by
chromatography on silica gel (hexane–EtOAc 9.1) to
yield the silylated derivative (iv) (8.09 g, 91%) as a
colorless oil, [a]D¼223.2 (c 1.2; CHCl3); 1H NMR
(500 MHz) d 8.10–8.00 (m, 4H), 7.60–7.35 (m, 6H), 5.64
(dt, 1H, J¼6.9, 4.2 Hz), 4.74 (dd, 1H, J¼12, 4.2 Hz), 4.64
(dd, 1H, J¼12, 6.9 Hz), 4.07 (ddd, 1H, m), 3.82 (dd, 1H,
J¼10, 4.5 Hz), 3.78 (dd, 1H, J¼10, 5.6 Hz), 0.90 (s, 9H),
0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz) d 166.3,
166.0, 133.26, 133.1, 129.9, 129.8, 129.7, 129.6, 128.4,
128.3, 72.1, 70.8, 63.7, 63.4, 25.8, 18.2, 25.6; IR (NaCl)
3450 (br), 3060, 3030, 2954, 1720, 1600, 1538, 1315, 1260,
4.2.1. (2S,4R,5S)-1,2-Bis(benzyloxy)-4-(t-butyldimethyl-
silyloxy)-5-hydroxyheptan-3-one (5, R5Et). Colorless
1
oil, [a]D¼261.4 (c 3.7; CHCl3); H NMR (400 MHz) d
7.35–7.25 (m, 10H), 4.75 (d, 1H, J¼11.5 Hz), 4.68 (d, 1H,
J¼2 Hz), 4.57 (d, 1H, J¼11.5 Hz), 4.56, 4.52 (AB system,
2H, J¼12 Hz), 4.29 (dd, 1H, J¼4.7, 3.3 Hz), 3.87 (dd, 1H,
J¼10.5, 3.3 Hz), 3.80 (m, 2H), 1.50 (m, 2H), 0.90 (s, 9H),
0.87 (t, 3H, J¼7.5 Hz), 0.05 (s, 3H), 20.02 (s, 3H); 13C
NMR (100 MHz) d 207.6, 137.8, 137.2, 128.5, 128.4, 128.3,
128.2, 128.0, 127.8, 127.7, 81.6, 77.9, 73.6, 73.1, 72.5, 69.4,
27.6, 25.8, 18.3, 10.2, 24.5, 25.4; IR (NaCl) 3470 (br),
3065, 3032, 2935, 2860, 1735, 1500, 1455, 1390, 1365,
1255, 1216, 1093, 1028, 887, 838, 780, 737, 700 cm21; HR
FABMS m/z 495.2530 [MþNaþ], calcd for C27H40O5NaSi,
495.2543. Anal. Calcd for C27H40O5Si: C, 68.61; H, 8.53.
Found, C, 68.81; H, 8.57.
1110, 1066, 700 cm21
.
A solution of oxalyl chloride (2.7 mL, ca. 30 mmol) in dry
CH2Cl2 (50 mL) was cooled under Ar to 2608C and treated
dropwise with a solution of DMSO (2.5 mL, ca. 35 mmol)
in dry CH2Cl2 (25 mL). The mixture was then stirred for
2 min at the same temperature and treated sequentially with
compound iv (6.67 g, ca. 15 mmol) dissolved in dry CH2Cl2
(50 mL) and, 15 min later, triethyl amine (10 mL, ca.
70 mmol). The mixture was stirred for 15 min a 2608C and
then for 1 h at 08C. After pouring onto brine and extraction
with CH2Cl2, the organic layer was washed with 5%
aqueous HCl, then again with brine, dried on anhydrous
Na2SO4, evaporated in vacuo and chromatographed on
silica gel (hexane–EtOAc 9.1). This furnished ketone 6
(5.31 g, 80%) as a colorless oil, [a]D¼225.3 (c 1; CHCl3);
1H NMR (500 MHz) d 8.10–8.00 (m, 4H), 7.60–7.40 (m,
6H), 5.98 (t, 1H, J¼4.1 Hz), 4.90 (m, 2H), 4.49 (s, 2H), 0.93
(s, 9H), 0.13 (s, 3H), 0.12 (s, 3H); 13C NMR (125 MHz) d
203.2, 166.0, 165.6, 133.6, 133.4, 130.0, 129.7, 129.4,
129.0, 128.5, 128.4, 75.0, 68.4, 62.7, 25.8, 18.3, 25.6; IR
(NaCl) 3440 (br), 3069, 2930, 2857, 1726, 1452, 1316,
4.2.2. (2S,4R,5S)-1,2-Bis(benzyloxy)-4-(t-butyldimethyl-
silyloxy)-5-hydroxy-6-methylheptan-3-one (5, R5iPr).
Colorless oil, [a]D¼234.8 (c 1.2; CHCl3); 1H NMR
(400 MHz) d 7.35–7.25 (m, 10H), 4.90 (d, 1H, J¼1 Hz),
4.77 (d, 1H, J¼11.2 Hz), 4.60–4.50 (m, 3H), 4.22 (dd, 1H,
J¼4.5, 3.1 Hz), 3.87 (dd, 1H, J¼10.5, 3.1 Hz), 3.81 (dd, 1H,
J¼10.5, 4.5 Hz), 3.48 (br d, 1H, J¼9 Hz), 1.70 (m, 1H),
0.96 (d, 3H, J¼6.5 Hz), 0.89 (s, 9H), 0.74 (d, 3H, J¼
6.5 Hz), 0.06 (s, 3H), 20.04 (s, 3H); 13C NMR (100 MHz) d
207.5, 137.8, 137.1, 128.5, 128.4, 128.3, 128.2, 127.8,
127.7, 81.9, 76.7, 76.4, 73.6, 72.5, 69.4, 31.5, 25.9, 19.3,
18.8, 18.4, 24.3, 25.4; IR (NaCl) 3450 (br), 3065, 3032,

J. Murga et al. / Tetrahedron 58 (2002) 9697–9707
9705
2930, 2860, 1732, 1497, 1455, 1389, 1362, 1255, 1107,
1028, 837, 779, 737, 698 cm21; HR FABMS m/z 509.2715
MþNaþ], calcd for C28H43O5NaSi, 509.2699. Anal. Calcd
for C28H42O5Si: C, 69.10; H, 8.70. Found, C, 69.00; H, 8.77.
1H), 1.00 (d, 6H, J¼6.5 Hz), 0.94 (s, 9H), 0.13 (s, 3H), 0.10
(s, 3H); 13C NMR (100 MHz) d 203.7, 166.3, 166.1, 133.7,
133.3, 130.0, 129.9, 129.8, 129.7, 129.5, 128.8, 128.6,
128.5, 79.9, 79.0, 76.6, 63.1, 29.5, 25.7, 19.8, 18.1, 17.9,
24.5, 24.8; IR (NaCl) 3470 (br), 3028, 2959, 1725, 1720sh,
1585, 1470, 1317, 1111, 840 cm21; HR FABMS m/z
515.2477 [MþHþ], calcd for C28H39O7Si, 515.2465.
Anal. Calcd for C28H38O7Si: C, 65.34; H, 7.44. Found, C,
65.47; H, 7.57.
4.2.3. (1S,2R,4S)-4,5-Bis(benzyloxy)-2-(t-butyldimethyl-
silyloxy)-1-hydroxy-1-phenylpentan-3-one (5, R5Ph).
Colorless oil, [a]D¼259 (c 4.3; CHCl3); 1H NMR
(400 MHz) d 7.40–7.20 (m, 15H), 5.18 (d, 1H, J¼
1.5 Hz), 4.89 (d, 1H, J¼2 Hz), 4.79 (d, 1H, J¼11.3 Hz),
4.60–4.50 (m, 3H), 4.28 (dd, 1H, J¼4.5, 3.1 Hz), 3.90 (dd,
1H, J¼10.5, 3.1 Hz), 3.84 (dd, 1H, J¼10.5, 4.5 Hz), 0.72 (s,
9H), 20.18 (s, 3H), 20.44 (s, 3H); 13C NMR (100 MHz) d
206.8, 141.4, 137.8, 137.2, 128.6, 128.5, 128.4, 128.2,
128.0, 127.8, 127.3, 125.7, 82.3, 80.3, 73.6, 72.7, 69.4, 25.6,
18.2, 25.2, 25.9; IR (NaCl) 3470 (br), 3065, 3032, 2927,
2929, 2857, 1703, 1598, 1584, 1496, 1455, 1390, 1313,
1255, 1204, 1112, 1026, 837, 780, 745, 699 cm21; HR
FABMS m/z 543.2531 [MþNaþ], calcd for C31H40O5NaSi,
543.2542. Anal. Calcd for C31H40O5Si: C, 71.50; H, 7.74.
Found, C, 71.70; H, 7.77.
4.2.7. (1R,2R,4S)-4,5-Bis(benzoyloxy)-2-(t-butyldi-
methylsilyloxy)-1-hydroxy-1-phenylpentan-3-one (7,
R5Ph). Colorless oil, [a]D¼222.7 (c 1.4; CHCl3); 1H
NMR (400 MHz) d 8.10–8.00 (m, 4H), 7.60–7.30 (m,
11H), 6.08 (dd, 1H, J¼6.5, 2.8 Hz), 5.00 (dd, 1H, J¼12.2,
2.8 Hz), 4.99 (d, 1H, J¼7.5 Hz), 4.77 (dd, 1H, J¼12.2,
6.5 Hz), 4.48 (d, 1H, J¼7.5 Hz), 0.79 (s, 9H), 20.10 (s, 3H),
20.45 (s, 3H); 13C NMR (100 MHz) d 203.4, 166.1, 166.0,
140.3, 133.7, 133.3, 130.0, 129.8, 129.5, 128.9, 128.6,
128.4, 128.3, 127.3, 81.4, 76.3, 75.1, 62.9, 25.7, 18.1, 24.9,
25.9; IR (NaCl) 3440 (br), 3065, 3032, 2958, 2859, 1732,
1704sh, 1472, 1455, 1384, 1256, 1106, 838, 779 cm21; HR
FABMS m/z 571.2135 [MþNaþ], calcd for C31H36O7NaSi,
571.2128. Anal. Calcd for C31H36O7Si: C, 67.86; H, 6.61.
Found, C, 68.00; H, 6.75.
4.2.4. (1S,2R,4S)-4,5-Bis(benzyloxy)-2-(t-butyldimethyl-
silyloxy)-1-hydroxy-1-(4-chlorophenyl)-pentan-3-one (5,
R54-chlorophenyl). Colorless oil, [a]D¼265.8 (c 0.8;
1
CHCl3); H NMR (400 MHz) d 7.40–7.30 (m, 10H), 7.17
(d, 2H, J¼8.5 Hz), 7.03 (d, 2H, J¼8.5 Hz), 5.14 (d, 1H,
J¼1 Hz), 4.83 (d, 1H, J¼1.5 Hz), 4.81 (d, 1H, J¼11 Hz),
4.60–4.50 (m, 3H), 4.30 (dd, 1H, J¼4.3, 3.2 Hz), 3.91 (dd,
1H, J¼10.5, 3.2 Hz), 3.84 (dd, 1H, J¼10.5, 4.3 Hz), 0.72 (s,
9H), 20.16 (s, 3H), 20.43 (s, 3H); 13C NMR (100 MHz) d
206.5, 140.2, 137.7, 137.1, 133.0, 128.7, 128.6, 128.5,
128.4, 128.1, 127.8, 127.2, 82.5, 80.1, 73.7, 72.7, 72.1, 69.2,
25.6, 18.2, 25.1, 25.9; IR (NaCl) 3450 (br), 3030, 2930,
4.2.8. (1R,2R,4S)-4,5-Bis(benzoyloxy)-2-(t-butyldi-
methylsilyloxy)-1-hydroxy-1-(4-chlorophenyl)-pentan-3-
one (7, R54-chlorophenyl). Colorless oil, [a]D¼230.2 (c
1
0.8; CHCl3); H NMR (400 MHz) d 8.10–8.00 (m, 4H),
7.60–7.30 (m, 10H), 6.03 (dd, 1H, J¼6.5, 2.8 Hz), 4.99 (dd,
1H, J¼12.1, 2.8 Hz), 4.97 (d, 1H, J¼7.5 Hz), 4.75 (dd, 1H,
J¼12.1, 6.5 Hz), 4.40 (d, 1H, J¼7.5 Hz), 0.81 (s, 9H),
20.07 (s, 3H), 20.41 (s, 3H); 13C NMR (100 MHz) d 203.0,
166.2, 166.1, 138.6, 134.1, 133.8, 133.3, 130.0, 129.7,
129.4, 128.6, 128.5, 128.4, 81.5, 75.6, 75.0, 62.8, 25.7, 18.1,
24.8, 25.8; IR (NaCl) 3490 (br), 3059, 2956, 2931, 2887,
2858, 1727 (br), 1602, 1584, 1493, 1452, 1265, 1177, 1110,
1094, 1015, 840, 781, 712 cm21; HR FABMS m/z 583.1944
2857, 1730, 1575, 1495, 1360, 1254, 1090, 940, 780 cm21
;
HR FABMS m/z 577.2169 [MþNaþ], calcd for
35
39
C31H ClO5NaSi, 577.2153. Anal. Calcd for C31H39ClO5Si:
C, 67.07; H, 7.08. Found, C, 67.00; H, 7.21.
[MþHþ], calcd for C31H ClO7Si, 583.1919. Anal. Calcd
35
36
4.2.5. (2S,4R,5R)-1,2-Bis(benzoyloxy)-4-(t-butyldi-
methylsilyloxy)-5-hydroxyheptan-3-one (7, R5Et).
Colorless oil, [a]D¼þ27.1 (c 5.2; CHCl3); 1H NMR
(400 MHz) d 8.10–8.00 (m, 4H), 7.60–7.30 (m, 6H), 6.01
(dd, 1H, J¼5.6, 2.5 Hz), 4.96 (dd, 1H, J¼12.3, 2.5 Hz), 4.80
(dd, 1H, J¼12.3, 5.6 Hz), 4.30 (d, 1H, J¼4.7 Hz), 3.80 (m,
1H), 3.10 (br s, 1H), 1.70–1.50 (m, 2H), 1.02 (t, 3H,
J¼7.5 Hz), 0.94 (s, 9H), 0.14 (s, 3H), 0.10 (s, 3H); 13C
NMR (100 MHz) d 203.3, 166.3, 166.1, 133.7, 133.3, 130.0,
129.9, 129.7, 129.4, 128.7, 128.5, 128.4, 81.3, 76.3, 75.9,
63.0, 25.8, 25.7, 18.2, 10.4, 24.5, 24.8; IR (NaCl) 3490
(br), 3019, 2958, 2931, 2859, 1725 (br), 1602, 1452, 1264,
1216, 1112, 1070, 1026, 840, 757, 712 cm21; HR FABMS
m/z 501.2306 [MþHþ], calcd for C27H37O7Si, 501.2308.
Anal. Calcd for C27H36O7Si: C, 64.77; H, 7.25. Found, C,
64.81; H, 7.37.
for C31H35ClO7Si: C, 63.85; H, 6.05. Found, C, 64.00; H,
6.20.
Acknowledgements
Financial support for this project was provided through the
Spanish Ministry of Science and Technology (DGICYT
project PB98-1438) and by BANCAJA (project P1B99-18).
´
¨
The authors thank Dr H. Roper, Eridania Beghin-Say,
Vilvoorde, Belgium, for a very generous supply of
L-erythrulose. One of the authors (J. M.) thanks the Spanish
´
Ministry of Science and Technology for a Ramon y Cajal
fellowship.
4.2.6. (2S,4R,5R)-1,2-Bis(benzoyloxy)-4-(t-butyldi-
methylsilyloxy)-5-hydroxy-6-methylheptan-3-one (7,
R5iPr). Colorless oil, [a]D¼þ20.5 (c 3.2; CHCl3); 1H
NMR (400 MHz) d 8.10–8.00 (m, 4H), 7.60–7.30 (m, 6H),
6.04 (dd, 1H, J¼6, 2.4 Hz), 4.98 (dd, 1H, J¼12.2, 2.4 Hz),
4.80 (dd, 1H, J¼12.2, 6 Hz), 4.49 (d, 1H, J¼4.8 Hz), 3.51
(dt, 1H, J¼7.5, 4.8 Hz), 3.00 (br d, 1H, J¼7.5 Hz), 1.83 (m,
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Lett. 1994, 35, 9083–9086. (b) Paterson, I.; Wallace, D. J.;
Cowden, C. J. Synthesis 1998, 639–652. After our results, a
further example of preparation of syn aldols using Chx2BCl
´
has appeared in the literature: (c) Galobardes, M.; Gascon, M.;
´
Mena, M.; Romea, P.; Urpı, F.; Vilarrasa, J. Org. Lett. 2000, 2,
2599–2602.
12. Recent experimental findings of our group seem to indicate
that this behavior may be general with a-oxygenated ketones,
even in cases where the formation of chelates is unlikely:
´
´
3. Marco, J. A.; Carda, M.; Gonzalez, F.; Rodrıguez, S.; Castillo,
E.; Murga, J. J. Org. Chem. 1998, 63, 698–707, and references
cited therein.
´
Murga, J.; Falomir, E.; Carda, M.; Gonzalez, F.; Marco, J. A.
Org. Lett. 2001, 3, 901–904.
13. Carda, M.; Falomir, E.; Murga, J.; Castillo, E.; Gonzalez, F.;
´
4. For an improved preparation of silylated L-erythrulose
acetonides 1 (P¼TES, TBS, TPS) from L-erythrulose hydrate,
Marco, J. A. Tetrahedron Lett. 1999, 40, 6845–6848. The
configurations of all aldol adducts were established through
chemical correlations described in this paper.
´
see: (a) Carda, M.; Rodrıguez, S.; Murga, J.; Falomir, E.;
¨
Marco, J. A.; Roper, H. Synth. Commun. 1999, 29,
2601–2610. For the preparation of protected D- and
L-erythrulose derivatives using chiral precursors other than
14. L-Ascorbic acid was first converted into L-threitol 1,2-aceto-
nide as reported: (a) Wei, C. C.; De Bernardo, S.; Tengi, J. P.;
Borgese, J.; Weigele, M. J. Org. Chem. 1985, 50, 3462–3467.
(b) Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.;
Mikkilineni, A. B.; Wu, D. C.-J.; Saibaba, R.; Panzica, R. P.
J. Org. Chem. 1988, 53, 2598–2602. L-Threitol 1,2-acetonide
was then converted into 6 as described in Section 4.
´
erythrulose itself, see: (b) Marco, J. A.; Carda, M.; Gonzalez,
´
F.; Rodrıguez, S.; Murga, J. Liebigs Ann. Chem. 1996,
1801–1810.
5. For a general review of boron aldol reactions: Cowden, C. J.;
Paterson, I. Org. React. 1997, 51, 1–200.
15. Like 1, ketones 4 and 6 did not yield aldol products with
Sn(OTf)2/EtNiPr2, TiCl4/EtNiPr2, LDA or LDA/LiCl; instead,
either decomposition or recovery of the starting product was
observed. Aldolizations with n-Bu2BOTf or n-BuBCl2 failed
also with 4 and 6. In contrast to 1, however, aldolizations
performed with SnCl4 in the presence of a tertiary amine7c
were successful with 4 and afforded aldols 5. Yields and
6. For the enolization of ketones with Chx2BCl/tertiary amine to
yield E boron enolates, see, for example: (a) Brown, H. C.;
Ganesan, K.; Dhar, R. K. J. Org. Chem. 1993, 58, 147–153.
(b) Paterson, I.; Nowak, T. Tetrahedron Lett. 1996, 37,
8243–8246.
7. Aldol reactions with 1 proved unfeasible with the following
enolization systems: (a) Sn(OTf)2/iPr2NEt: Mukaiyama, T.

J. Murga et al. / Tetrahedron 58 (2002) 9697–9707
9707
´
stereoselectivities were similar to those observed with
Chx2BCl.8a
Romea, P.; Urpı, F.; Vilarrasa, J. Tetrahedron Lett. 1997, 38,
1637–1640. (e) Gennari, C.; Moresca, D.; Vulpetti, A.; Pain,
G. Tetrahedron 1997, 53, 5593–5608. See also Refs. 5, 18 and
22.
16. There are not many alternatives in the literature for the
preparation of such esters in enantiopure form. See, for
example: (a) Andrus, M. B.; Sekhar, B. B. V. S.; Meredith,
E. L.; Dalley, N. K. Org. Lett. 2000, 2, 3035–3037. (b) Dixon,
D. J.; Ley, S. V.; Polara, A.; Sheppard, T. Org. Lett. 2001, 3,
3749–3752. For previous work, see references cited in these
papers.
22. For computational studies on boron aldol reactions, see, for
example: (a) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Org.
Chem. 1990, 55, 481–493. (b) Goodman, J. M.; Kahn, S. D.;
Paterson, I. J. Org. Chem. 1990, 55, 3295–3303. (c) Bernardi,
A.; Capelli, A. M.; Gennari, C.; Goodman, J. M.; Paterson, I.
J. Org. Chem. 1990, 55, 3576–3581. (d) Bernardi, A.; Capelli,
A. M.; Comotti, A.; Gennari, C.; Gardner, M.; Goodman, J. M.;
Paterson, I. Tetrahedron 1991, 47, 3471–3484. (e) Bernardi,
F.; Robb, M. A.; Suzzi-Valli, G.; Tagliavini, E.; Trombini, C.;
Umani-Ronchi, A. J. Org. Chem. 1991, 56, 6472–6475.
(f) Gennari, C.; Vieth, S.; Comotti, A.; Vulpetti, A.; Goodman,
J. M.; Paterson, I. Tetrahedron 1992, 48, 4439–4458.
(g) Vulpetti, A.; Bernardi, A.; Gennari, C.; Goodman, J. M.;
Paterson, I. Tetrahedron 1993, 49, 685–696.
´
17. Forsyth, C. J.; Hao, J.; Aiguade, J. Angew. Chem. Int. Ed.
2001, 40, 3663–3667.
18. Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am.
Chem. Soc. 1981, 103, 3099–3111(b) Enol borane formation
from 1 (P¼TBS) under the standard conditions was followed
by addition of BuLi at 2788C and capture of the intermediate
enol borate with trimethylsilyl chloride at the same tempera-
ture. Examination of the NMR spectra of the crude mixture
showed the presence of only one enol silane. Its structure was
determined from the spectral properties, whereas its configu-
ration was ascertained by means of NOE experiments. We
have also tried to perform an E!Z isomerization in our
substrates. A solution of 1 (P¼TBS) in hexanes was thus
enolized under the standard conditions, and the solution was
then heated at reflux for 3 h. However, extensive decompo-
sition was the only result observed
23. (a) Johnson, F. Chem. Rev. 1968, 68, 375–413. (b) Hoffmann,
R. W. Chem. Rev. 1989, 89, 1841–1860.
24. Calculations have been carried out with the Gaussian 98 suite
of programs: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseris, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrezewski,
V. G.; Montgomery, J. A.; Stratmann, R. E.; Burant, J. C.;
Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.;
Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.;
Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford,
S.; Ochterski, J.; Peterson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, R.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
´
M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.;
Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen, W.;
´
Wong, M. W.; Andres, J. L.; Head-Gordon, M.; Replogle,
E. S.; Pople, J. A. Gaussian 98 (Revision A.1); Gaussian Inc.:
Pittsburgh, PA, 1998.
25. While the size of the boron-bonded alkyl groups has been
shown to have a marked influence on the outcome of the
enolization step,5,9 this is not the case with the aldol addition
step.18,21,22 It may also be assumed that the size of these boron
ligands is more decisive than its electronic nature in
determining the energy of the TS of the aldol addition step.
For this reason, we considered that a cyclopropyl group was a
suitable model for a cyclohexyl group, even if they have
different electronic features. We further considered that the
dioxolane moiety of 1 (P¼TMS) was an acceptable surrogate
for either the bisbenzyloxyethyl fragment of 4 or the
bisbenzoyloxyethyl of 6 and would simplify the calculations,
as it contains fewer atoms.
19. Before the result of the boron–silicon interchange experiment
was known, we had considered the possibility of a non-cyclic,
extended TS with participation of an E enolate and two
molecules of Chx2BCl (see: Walker, M. A.; Heathcock, C. H.;
J. Org. Chem. 1991, 56, 5747–5750). This alternative was
made unlikely by the results of Table 2 and definitively ruled
out after the Z enolate configuration was secured.
20. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920–1923.
21. For discussions on mechanistic models of aldol reactions with
chiral enolates, see: (a) Evans, D. A.; Nelson, J. V.; Taber,
T. R. Top. Stereochem. 1982, 13, 1–115. (b) Heathcock, C. H.
Aldrichim. Acta 1990, 23, 99–111. (c) Van Draanen, N. A.;
Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H. J. Org.
26. Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister,
M. A. J. Am. Chem. Soc. 1994, 116, 11287–11314.
´
Chem. 1991, 56, 2499–2506. (d) Figueras, S.; Martın, R.;