Aldol reactions between L-erythrulose derivatives and chiral α-amino and α-fluoro aldehydes: Competition between felkin-anh and cornforth transition states

Article abstract of DOI:10.1002/chem.200800956

Both matched and mismatched diastereoselection have been observed in aldol reactions of a boron enolate of a protected L-erythrulose derivative with several chiral α-fluoro and α-amino aldehydes. Strict adherence to the Felkin-Anh model for the respective transition structures does not account satisfactorily for all the observed results, as previously observed in the case of α-oxygenated aldehydes. In some cases, only the Cornforth model provides a good explanation. The factors that influence this dichotomy are discussed and a general mechanistic model is proposed for aldol reactions with α-heteroatom-substituted aldehydes. Additional support for the model was obtained from density functional calculations.

Full text of DOI:10.1002/chem.200800956

DOI: 10.1002/chem.200800956
Aldol Reactions between l-Erythrulose Derivatives and Chiral a-Amino and
a-Fluoro Aldehydes: Competition between Felkin–Anh and Cornforth
Transition States
Santiago Díaz-Oltra,[a] Miguel Carda,*[a] Juan Murga,[a] Eva Falomir,[a] and
J. Alberto Marco*[b]
Abstract: Both matched and mis-
matched diastereoselection have been
observed in aldol reactions of a boron
enolate of a protected l-erythrulose
derivative with several chiral a-fluoro
and a-amino aldehydes. Strict adher-
ence to the Felkin–Anh model for the
respective transition structures does
not account satisfactorily for all the ob-
served results, as previously observed
in the case of a-oxygenated aldehydes.
In some cases, only the Cornforth
model provides a good explanation.
The factors that influence this dichoto-
my are discussed and a general mecha-
nistic model is proposed for aldol reac-
tions with a-heteroatom-substituted al-
dehydes. Additional support for the
model was obtained from density func-
tional calculations.
Keywords: aldol reaction · boron
enolates · density functional calcu-
lations · fluorine · transition states
Introduction
mation of syn-aldols 2 via the (Z)-enolate 1B in reactions
with achiral aldehydes RCHO (Scheme 1).[4]
The aldol reaction is a powerful and general method for the
stereocontrolled construction of carbon–carbon bonds.[1]
Among the many enolate types investigated thus far, boron
enolates have proven to be particularly versatile because of
their good reactivity and excellent stereoselectivity.[2] In
recent years, we have investigated the outcome of aldol re-
actions of boron enolates generated from suitably protected
l-erythrulose derivatives such as 1 and dicyclohexylboron
chloride (Chx2BCl).[3] With this class of ketone substrates,
the latter reagent gives rise to the highly stereoselective for-
Subsequent to these initial studies, we wondered whether
or not the facial bias of chiral enolate 1B would be strong
enough to overcome the inherent facial preferences of the
carbonyl group in a-chiral aldehydes (double diastereoselec-
tion).[1a–e] Therefore, we investigated the aldol reactions of
1B with a range of a-chiral aldehydes in both antipodal
forms. These aldehydes had either only carbon substituents
[a] Dr. S. Díaz-Oltra, Prof. Dr. M. Carda, Dr. J. Murga, Dr. E. Falomir
Depart. de Q. Inorgµnica y Orgµnica, Univ. Jaume I
Avda. Sos Baynat s/n, 12071 Castellón (Spain)
Fax : (+34)964-728214
E-mail: mcarda@qio.uji.es
[b] Prof. Dr. J. A. Marco
Depart. de Q. Orgµnica, Univ. de Valencia
c/D. Moliner, 50, 46100 Burjassot, Valencia (Spain)
Fax : (+34)96-3544328
E-mail: alberto.marco@uv.es
Supporting Information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800956. It contains experi-
mental procedures for configurational assignments of the aldol ad-
ducts, the spectral data of compounds and correlation intermediates
and copies of the NMR spectra.
Scheme 1. Aldol additions of a boron enolate of ketone 1 to achiral alde-
hydes (TBS=tert-butyldimethylsilyl; Chx=cyclohexyl).
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FULL PAPER
(a-methyl aldehydes 3a and 3b) or else one oxygen atom
(a-alkoxy aldehydes 4a–c) bound to the a-carbon atom. The
results of these aldol reactions are summarized in
Scheme 2.[5] In all successful reactions, the enolate Re face
attacks the aldehyde carbonyl Re face.
TS-2 involves approach of a nucleophile to the carbonyl
carbon atom along a trajectory that is not anticoplanar to
the bulkiest substituent at the a-carbon atom (the CH2OP
moiety). This has been called a “non-Anh” TS.[13] However,
because both reactions take place easily under the usual
conditions, the latter features
seem to be minor factors here.
For a-oxygenated aldehydes,
however, a strict adherence to
the Felkin–Anh model does not
provide a satisfactory explana-
tion of the observed results.[5]
We thus proposed that in such
aldehydes, which contain an
electronegative oxygen atom at
the a-carbon atom, dipolar re-
pulsions in the transition states
become meaningful. Conse-
quently, Cornforth-like transi-
tion states were proposed, in
Scheme 2. Aldol additions of enolate 1B to aldehydes (R)- and (S)-3, and (R)- and (S)-4 (Bn=benzyl; TPS=
tert-butyldiphenylsilyl).
which the aldehyde C=O and
ꢀ
Ca O bonds are in an essential-
It is generally accepted that aldehydes react with boron
enolates via cyclic, six-membered transition states (TS) of
the Zimmerman–Traxler type (Scheme 1).[1–3,6,7] Enolate 1B
displays a marked diastereofacial preference whereby exclu-
sively its Re face attacks the Re face of the aldehyde carbon-
yl. This diastereofacial bias is attributed to the presence of a
ꢀ
ꢀ
dipolar repulsion between the C Oenolate and the Ca
O
bonds, which compels them to orientate in an anticoplanar
fashion (Scheme 1).[1e,8] As a result, the enolate Re face is
sterically more accessible than the Si face, the latter now be-
coming blocked by the bulky dioxolane ring.[3c] For the alde-
hyde, the R group preferentially adopts an equatorial orien-
tation in the chair-like TS. This causes its carbonyl Re face
to be more reactive in these aldol reactions. On the basis of
this reasoning, we proposed a mechanistic explanation for
the difference in behavior between a-methyl and a-oxygen-
ated aldehydes in our previous paper.[5] In addition to the
aforementioned electronic and steric factors, a no-less-im-
portant element is the avoidance of steric repulsions of the
so-called syn-pentane type between the OTBS group at the
enolate C=C bond and one substituent at the stereogenic a-
aldehyde carbon atom (Scheme 3). This feature,[1a,5,9,10] often
present in aldol transition states involving (Z)-enolates, is
believed to be a key stereocontrol element that determines
aldehyde p-facial selectivities in many cases. For a-methyl
aldehydes 3a and 3b, the concomitant influence of all these
factors led to the proposal of transition state TS-1 for the
aldol reactions of (S)-3, and TS-2 for those of (R)-3
(Scheme 3), in either case with avoidance of syn-pentane in-
teractions. The former belongs to the Felkin–Anh (FA) type
TS,[11] even though a spatial approach at the Bürgi–Dunitz
angle implies here that the nucleophile is closer to the
methyl group than the hydrogen atom.[7,11,12] The alternative
Scheme 3. Proposed transition states for the aldol additions of enolate 1B
to aldehydes (R)- and (S)-3.
ly anticoplanar orientation (Scheme 4).[14] Indeed, such types
of transition states had already been proposed for various
carbonyl addition reactions, including aldol reactions with
cyclic transition states.[15,16] The Cornforth TS-3, which does
not show noticeable negative features of either steric or
electronic nature, was therefore proposed for aldol reactions
of aldehydes (S)-4, in which aldols 7 are formed with good
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J. A. Marco, M. Carda et al.
Figure 1. Chiral a-fluoro and a-amino aldehydes used in this study.
porting Information).[3,5] We started with the aldol reactions
of enolate 1B with a-fluoro aldehydes (R)- and (S)-8. The re-
sults are shown in Scheme 5 and indicate that the a-fluori-
Scheme 4. Proposed transition states for the aldol additions of enolate 1B
to aldehydes (R)- and (S)-4.
yield and excellent stereoselectivity. Aldehydes (R)-4, how-
ever, must react through either the Felkin–Anh TS-4 of in-
trinsically higher energy than a Cornforth-type TS (higher
dipolar repulsion) or through the Cornforth TS-5, which ex-
hibits a strong syn-pentane steric interaction between the R
and OTBS groups. Both transition states therefore are
higher in energy than TS-3 and the reaction turns out to be
slow and unselective. Besides, the alternative attack of the
enolate on the aldehyde Si face does not alleviate the situa-
tion, either, because other negative factors (see above)
would then emerge.[5]
With the aim of investigating the relative importance of
dipolar versus steric or stereoelectronic factors, we have
now extended our study to the case of aldehydes containing
other heteroatoms at the a-carbon atom, more specifically
a-fluoro and a-amino aldehydes. The former have the most
electronegative atom and therefore the strongest dipolar re-
pulsion factor in the transition states.[17] The latter have a
much less electronegative atom, a feature which suggests
that steric and dipolar repulsions may be of comparable
magnitude. The results of the aldol reactions of the afore-
mentioned aldehydes with boron enolate 1B and the discus-
sion of the observed results are one main subject of the
present paper. In addition, we have performed the same
type of study on two other enolizable compounds, both
chiral and achiral, which we consider to be useful models to
give a firmer basis to our mechanistic conclusions.[18]
Scheme 5. Aldol additions of enolate 1B to a-fluoro aldehydes (R)- and
(S)-8.
nated aldehydes react in essentially the same way as those
containing a-oxygen atoms. The reactions with aldehydes
(S)-8 were relatively rapid (total conversion in 5–6 h) and
completely diastereoselective insofar as can be detected by
NMR spectroscopic methods (d.r. >95:5). Aldols 10 were
thus formed[19] via enolate attack on the Re aldehyde car-
bonyl face. In contrast, aldehydes (R)-8 did not react with
enolate 1B. Ketone 1 was recovered unchanged, together
with decomposition products from the aldehyde.
The similarity of the results of the aldol reactions of 1
with a-oxygenated and a-fluorinated aldehydes suggests the
same type of mechanistic explanation. Dipolar repulsions
are presumably very strong here, due to the high electrone-
gativity of fluorine. Thus, the successful reaction of alde-
hydes (S)-8 to yield aldols 10 can be explained through as-
sumption of the Cornforth transition state TS-6, with mini-
mized dipolar repulsion and the absence of steric syn-pen-
tane crowding (Scheme 6). In contrast, aldehydes (R)-8 are
confronted with the choice between the Felkin–Anh TS-7,
which shows noticeable dipolar repulsion, and the Cornforth
TS-8, which shows a marked steric syn-pentane interaction.
Results and Discussion
Aldol reactions with chiral ketone 1: For the purposes de-
scribed in the preceding section, the enantiomerically pure
aldehydes 8a–b and 9a–c (Figure 1) were prepared in both
antipodal forms according to described procedures.[19]
The aldol additions were performed under the previously
reported conditions (for experimental details, see the Sup-
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Boron Aldol Reactions with a-Heteroatom-Substituted Aldehydes
FULL PAPER
ꢀ
the nitrogen atom, the dipolar repulsion of the C=O and C
N bonds is not very strong. Thus, steric syn-pentane interac-
tions are in all likelihood the dominant factor of stereocon-
trol. Accordingly, TS-9 and TS-10, both devoid of such inter-
actions (Scheme 8), are proposed to be reasonable transition
structures for the reactions of aldehydes (S)- and (R)-9, re-
spectively. Transition structure TS-9 belongs to the Corn-
forth type whereas TS-10 is clearly a Felkin–Anh TS, with
attack of the enolate on the carbonyl carbon atom taking
ꢀ
place in an almost antiperiplanar orientation to the C N
bond, itself arranged in a perpendicular fashion to the car-
bonyl plane.
Scheme 6. Proposed transition states for aldol additions of enolate 1B to
a-fluoro aldehydes (R)- and (S)-8.
Both alternative transition states therefore show an in-
creased energy content, which explains the failure of the
corresponding aldol reactions. Furthermore, this indicates
that the magnitude of the syn-pentane steric factor in the
present case is comparable with, or possibly higher than, the
ꢀ
dipolar repulsion of the C=O/Ca X bonds, even in the case
of the very electronegative fluorine atom.
The results of the aldol reactions of 1 with a-amino alde-
hydes 9a–c are shown in Scheme 7. As previously observed
with a-methyl aldehydes,[5] both the S and the R enantio-
mers react with 1B and provide aldols 11 and 12, respective-
ly, with a good stereoselectivity (d.r. >95:5).
Scheme 8. Proposed transition states for aldol additions of enolate 1B to
a-amino aldehydes (R)- and (S)-9.
Aldol reactions with achiral ketone 13: The previous aldol
reactions show the combined effects of the stereochemical
biases of either chiral component (double diastereoselec-
tion).[1c] To gain an insight into the intrinsic diastereofacial
bias of the chiral aldehydes used in this study, we investigat-
ed their aldol reactions with achiral ketone 13, a dihydrox-
yacetone derivative structurally related to 1, which also
forms a (Z)-enolate with Chx2BCl.[3d] Scheme 9 shows the
results of its reactions with aldehydes 3a, 4c, 8b, and 9b (re-
actions were performed with either enantiomer but only the
R antipode is depicted in Scheme 9). For aldehydes contain-
ing a nitrogen atom or no heteroatoms in the a position, the
reaction showed a moderate diastereoselectivity, with diaste-
reomeric ratios being about 4–5:1 (the major syn aldol is
that depicted in Scheme 9). The reaction also displayed a
similar diastereoselectivity in the case of the a-oxygenated
aldehydes. However, it was very stereoselective for a-fluori-
nated aldehydes, with only one aldol being detected (d.r.
>95:5).
Scheme 7. Aldol additions of enolate 1B to a-amino aldehydes (R)- and
(S)-9.
These results contrast with those of the previously dis-
cussed a-heteroatom-substituted aldehydes. Indeed, they in-
dicate that dipolar repulsions are here of a much lesser mag-
nitude. Due to the comparatively low electronegativity of
These results can be explained within the same mechanis-
tic frame detailed above, in which the main factor is again
the avoidance of syn-pentane steric interactions in the tran-
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J. A. Marco, M. Carda et al.
Scheme 9. Aldol additions of enolate 13B to aldehydes (R)-3a, (R)-4c, (R)-8a and (R)-9b (major aldol depicted in each case).
sition states (Scheme 10). Accordingly, (R)-aldehydes with-
out a-heteroatoms react through the Felkin–Anh TS-11
(attack on the aldehyde Si face) in preference to the non-
Anh TS-12 (attack on the aldehyde Re face). Polar effects
are negligible here so that the sterically less congested TS-
11 (attack anti to the bulky CH2OP) takes over. This ex-
plains the formation of the observed major aldol 14 and the
moderate diastereoselectivity (Scheme 9).
For aldehydes containing a-heteroatoms the situation was
found to be different. In the case of (R)-a-amino aldehydes,
the choice is between the Felkin–Anh TS-13 (attack on the
aldehyde Re face) and the Cornforth TS-14 (attack on the
aldehyde Si face), both of which are devoid of syn-pentane
interactions (Scheme 10). In our mechanistic view, the major
product 16 is that formed through the Felkin–Anh TS-13 be-
cause the electronegativity of the nitrogen atom is not very
high. This reduces, therefore, the dipolar repulsion compo-
nent and makes the Cornforth TS-14 comparatively less
preferent.
With (R)-aldehydes containing a-heteroatoms of high
electronegativity (O, F), the relative energy of Cornforth
and Felkin–Anh transition states undergoes a complete re-
versal (Scheme 11). Compound 15 was the major isomer
when oxygen was the a-heteroatom, and its counterpart 17
was the only aldol formed in the case of the (R)-a-fluoro al-
dehyde. In our mechanistic model, both compounds are
formed through the Cornforth-type TS-15, which is favored
here due to the high electronegativity of O and F and the
correspondingly high dipolar repulsion factor in TS-16, most
particularly in the case of the fluorine atom (Scheme 11).
We may now conclude that the diastereofacial bias of
chiral ketone 1, although a strong and dominant factor with
many aldehyde types, is not able to overcome the intrinsic
facial bias of aldehydes containing very electronegative
atoms (O, F, and perhaps Cl) on the a-carbon atom. In such
cases, matched and mismatched situations will arise, the
latter being associated with slow and unselective reactions
(see Scheme 2 and 5).
Scheme 10. Proposed transition states for aldol additions of enolate 13B to aldehydes (R)-3a and (R)-9b.
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Boron Aldol Reactions with a-Heteroatom-Substituted Aldehydes
FULL PAPER
Scheme 12. Aldol additions of enolate 18B to aldehydes (R)-/(S)-4a and
(R)- and (S)-8b.
Following the mechanistic concepts disclosed above, these
results may be explained as depicted in Scheme 13. It is
known that enolate 18B displays a strong bias towards at-
tacking the Si face of aldehyde carbonyl groups.[1a,i,2a]
Indeed, this is what happens with the a-oxygenated alde-
hydes (R)- and (S)-4a, as well as with the a-fluorinated al-
dehyde (R)-8b. However, the aldol reaction with (S)-8b
turns out to be so slow that decomposition of the unstable
aldehyde is the only observed result. Scheme 13 shows the
proposed transition states for these reactions. Addition of
18B to the (R)-aldehydes takes place via attack on the car-
bonyl Si face through the Cornforth TS-17, devoid of syn-
pentane interactions. This type of steric crowding would be
present, however, in the alternative Felkin–Anh TS-18,
which becomes therefore much less favorable. In the case of
Scheme 11. Proposed transition states for aldol additions of enolate 13B
to aldehydes (R)-4c and (R)-8a.
Aldol reactions with oxazolidinone 18: In relation to the
latter issue and to complete our study, we wanted to com-
pare the strength of the stereochemical bias of our ketone 1
with that of other well-established chiral auxiliaries of wide-
spread use in aldol reactions such as, for example, Evans ox-
azolidinone 18.[1a,i,2a] Thus, aldol reactions of a (Z)-boron
enolate of this compound (18B) were allowed to react with
(R)- and (S)-a-oxygenated and a-fluorinated aldehydes of
the type used above.[20,21] The results are shown in
Scheme 12.
Scheme 13. Proposed transition states for aldol additions of enolate 18B to aldehydes (R)- and (S)-4a and (R)- and (S)-8b.
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J. A. Marco, M. Carda et al.
the (S)-aldehydes, however, syn-pentane interaction is no-
ticeable when the reaction goes through the Cornforth TS-
20. Avoidance of this steric interaction by means of appro-
tions of boron enolates to aldehydes.[7h] The stationary
points were characterized by frequency calculations to
verify that minima and transition states have either zero or
one imaginary frequency. Energy values were computed at
08C, a temperature frequently used in these aldol reactions.
For calculations of energies, we have considered only
those transition states with chair-like geometries with the R
group of the aldehyde (RCHO) in an equatorial arrange-
ment. The obtained energies have been found to be related
to two specific dihedral angles f1 and f2, which are defined
in Figure 3.[26] The FA model is based on transition states in
ꢀ
priate C C bond rotation leads to the Felkin–Anh TS-19.
Obviously, this increases the energy of the TS because of
the higher dipolar repulsion. Nevertheless, this seems to still
be energetically feasible for the a-oxygenated aldehyde (S)-
4a, which reacts to give aldol 20 as essentially a single ste-
reoisomer. However, the a-fluorinated aldehyde (S)-8b
does not react at all, even after prolonged reaction times.
The only reasonable explanation for this is that both alter-
native transition states (TS-19 and TS-20) have now under-
gone marked increases in their energy contents; the Felkin–
Anh TS-19, apparently devoid of unfavorable steric features,
is destabilized by the high dipolar repulsion between the C=
ꢀ
O and C F bonds, whereas the Cornforth TS-20 is destabi-
lized by the syn-pentane interaction between the Me and R
groups.
Figure 3. Definition of f1 and f2 dihedral angles. f1 =C1-C2-C3-X. R,
R’=H, Me.
Quantum-mechanical calculations: In relation to the previ-
ously discussed experimental results, we wished to under-
score our mechanistic proposals with the aid of quantum-
mechanical calculations. For that purpose, and in view of the
large number of atoms involved in the aldol reactions with
our substrates, the simplified model molecules shown in
which the principal stabilizing interaction is a hyperconjuga-
ꢀ
tive delocalization of the forming C Nu bond (HOMO)
ꢀ
with the best vicinal acceptor, here the Ca
X
bond
(LUMO). This hyperconjugative interaction will be maxi-
ꢀ
ꢀ
mized when the forming C Nu bond and the Ca X bond
are antiperiplanar (f1 =1808). Because the Bürgi–Dunitz
angle[12] has to be taken into account, f1 should differ from
the ideal angle of 1808 by no more than 10–208 (i.e. ꢁ160–
1708). Accordingly, f2 should not be far away from ꢁ908. I n
contrast, Cornforth transition states involve minimization of
ꢀ
the dipolar repulsion between the C=O and Ca X bond.
Figure 2. Model molecules used in the quantum-mechanical calculations.
Consequently, f1 should be less than ꢁ908 and f2 should
differ from 1808 by no more than 10–208.
The Cartesian coordinates for all atoms in the different
transition states are given in the Supporting Information.
Table 1 shows some relevant geometrical features of these
Figure 2 were studied. Erythrulose enolate 1B was replaced
by the boron (Z)-enolate 22, which contains a methyl group
instead of the bulky OTBS fragment. This change is justified
by the fact that boron aldolization reactions carried out with
an ethyl ketone very similar to 1 gave essentially the same
results as 1 itself.[4a] Furthermore, the boron cyclohexyl
groups have been replaced by methyl groups because al-
though the size of the boron ligands is important for the ste-
reochemical outcome of the enolization step,[22] it does not
exert a decisive influence on that of the aldol addition
step.[3c] Finally, the a,b-O,O-isopropylidene moiety was re-
placed by an a-methoxy group. Compounds (R)-23 and (S)-
23 were chosen as the model a-chiral aldehydes. These alde-
hydes are the same as those used by Evans and co-workers
in their theoretical calculations on boron aldol reactions
with achiral enolates.[7h]
ꢀ
transition states. The extent of C C bond formation in tran-
sition states can be generally assessed by determining the
distance between the reacting carbon atoms of the aldehyde
and the enol borane. In the cases under study here, the
ꢀ
lengths of the forming C C bonds are mainly in the range
of 2.25–2.50 Š. There are three notable exceptions in the
case of fluorinated aldehydes, in which these bonds are dis-
tinctly longer (>2.60 Š), which indicates earlier transition
states (see below).[27]
Transition-state structures for addition of 22 to a-amino al-
dehydes (R)- and (S)-23a: As mentioned above, the addi-
tion of erythrulose boron enolate 1B to a-amino aldehydes
(R)- and (S)-9 exhibits good stereocontrol and only yields
aldols formed by the attack of the enolate to the Re face of
the aldehyde carbonyl (Scheme 7). As for the model reac-
tions, the calculated transition states for the addition of 22
to the Re face of aldehydes (S)-23a and (R)-23a are shown
in Figure 4 and Figure 5, respectively (in this and the follow-
All calculations were carried out with the Gaussian 98
suite of programs.[23] The B3LYP exchange-correlation func-
tional method[24] with the 6–31G** basis set[25] was used, as
Evans and co-workers have shown that B3LYP is a reliable
method for determining transition state structures in addi-
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Boron Aldol Reactions with a-Heteroatom-Substituted Aldehydes
Table 1. Calculated dihedral angles f1 and f2, and lengths of the forming
FULL PAPER
nistic proposals (Scheme 7 and Scheme 8). The Felkin–Anh
(FA) TS-1B is here approximately 0.4 kcalmolꢀ1 higher in
energy (Figure 4). The Cornforth TS-1A contains an ar-
ꢀ
C C bonds of the transition states of all aldol reactions with the model
molecules from Figure 2.
Transition structure[a]
f1 [8]
48.4
f2 [8]
154.8
ꢀ110.3
C1 C2 (Š)
ꢀ
2.43
2.27
ꢀ
rangement of the C=O and C N bonds (dihedral angle f2 =
TS-1A (C)
TS-1B (F)
154.88) which, although not fully antiparallel, reduces the di-
polar repulsion in a marked proportion. However, the calcu-
lated f1 angle in the FA TS-1B is 139.78, much lower than
anticipated (see comments above). This deviation is due to
the existence of a syn-pentane repulsion between the eno-
late olefinic methyl and aldehyde a-methyl group (Figures 3
139.7
TS-2A (C)
TS-2B (F)
45.7
174.9
155.1
ꢀ77.1
2.33
2.27
TS-3A (C)
TS-3B (F)
TS-3C (C)
TS-3D (F)
49.9
149.7
155.3
ꢀ101.4
ꢀ164.9
78.1
2.43
2.37
2.40
2.35
ꢀ
and 4). Rotation around the C2 C3 bond alleviates in part
ꢀ57.9
this steric interaction and causes at the same time a reduc-
ꢀ175.0
tion of f1.
TS-4A (C)
TS-4B (F)
TS-4C (C)
TS-4D (F)
37.3
173.9
147.1
ꢀ79.0
ꢀ173.4
99.1
2.34
2.37
2.40
2.50
ꢀ
The degree of involvement of the C N bond in the Nu!
s*Cꢀ hyperconjugative interaction, which is believed to sta-
N
ꢀ68.2
ꢀ
bilize the FA TS-1B, can be estimated by comparing the C
N bond lengths in the TS and in the reactant aldehyde. As a
ꢀ158.2
TS-5A (C)
TS-5B (F)
63.6
139.2
165.1
ꢀ113.9
2.84
2.39
ꢀ
matter of fact, the C N bond in TS-1B has a calculated
length of 1.474 Š whereas in the reactant aldehyde (S)-23a
this distance lies in the range between 1.468 Š (f2 =1808,
Cornforth-type conformation) and 1.476 Š (f2 =908, Felkin–
Anh-type conformation). This close similarity strongly sug-
TS-6A (C)
TS-6B (F)
68.1
167.9
170.2
ꢀ91.0
2.64
2.74
[a] Cornforth-type transition states are labeled with C, whereas those of
the Felkin–Anh type are labeled with F. For absolute energy contents of
all transition states, see Supporting Information. Energy differences be-
tween comparable transition states are given in kcalmolꢀ1 in Figures 4–9.
gests that a Nu!s*Cꢀ hyperconjugative interaction is
N
almost absent in TS-1B, this being likely related to the
rather low value of f1 (see above). Thus, this paradigmatic,
energetically favourable feature of all FA transition states is
absent here. All these features explain why the Cornforth
TS-1A is the most favourable TS in the addition of 22 to a-
amino aldehyde (S)-23a.
In the case of the addition of 22 to (R)-23a, the FA TS-
2B is now the lowest lying one, with the Cornforth TS-2A
being higher in energy by approximately +0.9 kcalmolꢀ1.
Again, this is in line with our experimental observations and
qualitative mechanistic proposals (Scheme 7 and Scheme 8).
It is now worth noting that TS-2B has a f1 angle of ꢂ1758,
a value much more similar to that expected for a FA transi-
ꢀ
tion structure. However, the C N bond length (1.481 Š) is
Figure 4. Transition states for the addition of 22 to (S)-23a (relative ener-
ꢀ
only slightly higher than the length of the C N bond in the
gies in kcalmolꢀ1).
reactant aldehyde (range of values between 1.468 and
1.476 Š), a circumstance which, once again, does not suggest
a sizeable Nu!s*Cꢀ hyperconjugative interaction in the
N
TS. As regards the Cornforth TS-2A, it has a dihedral angle
f2 =155.18, a value similar to that calculated for TS-1A.
However, TS-2A exhibits a Me–Me syn-pentane repulsion
of the aforementioned type that destabilizes it in relation to
TS-2B.
The conclusion to be drawn from these calculations is es-
sentially the same we had qualitatively derived from the ex-
perimental results with enolate 1B (Scheme 7). The electro-
negativity of the nitrogen atom is not high enough to en-
force an antiperiplanar arrangement of the aldehyde C=O
Figure 5. Transition states for the addition of 22 to (R)-23a (relative ener-
gies in kcalmolꢀ1).
ꢀ
and C N bonds in the transition states of the aldol reac-
tions. In fact, Evans and co-workers predicted by means of
theoretical calculations that the ground-state conformation
ing figures, the lowest-lying TS is assigned the relative
energy 0 kcalmolꢀ1). For the addition of 22 to (S)-23a the
lowest-lying TS is the Cornforth-type TS-1A, in agreement
with our experimental observations and qualitative mecha-
ꢀ
of a-amino aldehydes shows a C=O···C N dihedral angle
(f2 in the present paper) of nearly 1508, a value very similar
to that found for the Cornforth TS-1A. However, the ener-
Chem. Eur. J. 2008, 14, 9240 – 9254
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9247

J. A. Marco, M. Carda et al.
getic cost necessary for bringing it to about 908 is not too
high (< 2 kcalmolꢀ1).[7h] This means that either Cornforth
or FA transition states may be available with similar ease in
nucleophilic additions to a-amino aldehydes.
the earliest one. In addition, it does not show any syn-pen-
tane repulsion. However, f2 is 155.38, a value very similar to
that predicted for the Cornforth TS-1A with an a-amino al-
dehyde (Table 1). This somewhat low value is perhaps unex-
pected for an a-oxygenated aldehyde, which contains the
more electronegative oxygen atom. In fact, the aforemen-
tioned calculations by Evans and co-workers[7h] predict a
value f2 of approximately 1808 for a-alkoxy aldehydes in
the ground-state conformation.[28] Moreover, and in contrast
with a-amino aldehydes, the energetic cost necessary for
bringing it to about 908 is high (>3 kcalmolꢀ1).[7h] However,
rotation to an angle f2 ꢂ1558 is not so costly
(ꢂ0.5 kcalmolꢀ1) and may be easily achieved. The discrep-
ancy between the anticipated antiperiplanar and the calcu-
lated arrangement may possibly be due to a steric repulsion
between the aldehyde O-methyl group and the atoms at the
stereogenic carbon center of the enolate, an interaction alle-
Transition-state structures for addition of 22 to a-oxygenat-
ed aldehydes (R)- and (S)-23b: The addition of erythrulose
enolate 1B to a-oxygenated aldehydes was found to exhibit a
high degree of stereocontrol in the reaction with (S)-a-
alkoxy aldehydes (Scheme 2). In contrast, the reaction with
(R)-a-alkoxy aldehydes provides a mixture of aldols, togeth-
er with decomposition products. These results suggest that,
in contrast to the other aldehyde types, the attack of the er-
ythrulose enolate may take place here competitively on
either face of the aldehyde carbonyl group. Therefore, we
studied here the transition states, which result from the
attack of the enolate on either the Re or the Si face of the
aldehydes.
ꢀ
viated in part through C2 C3 bond rotation. As regards the
Figure 6 shows the transition states for additions of 22 to
the Re and the Si face of aldehyde (S)-23b. From the transi-
tion states associated with attack on the Re face, the Corn-
FA TS-3B, the f1 angle is 149.78, this somewhat low value
being related to the presence of a Me–Me syn-pentane inter-
action, which is the main factor responsible for its increased
energy content in comparison with TS-3A.
Quantum-mechanical calculations for the additions of 22
to the Re and Si faces of aldehyde (R)-23b (Figure 7) show
that the FA TS-4B, associated with attack on the aldehyde
Re face, has now the lowest energy content. The second-
lowest energy content TS is the Cornforth TS-4C, corre-
sponding to attack on the aldehyde Si face, which is relative-
ly destabilized by 2.3 kcalmolꢀ1. Still higher by 2.6 kcalmolꢀ1
is TS-4A (attack on the aldehyde Re face). Finally, the FA
TS-4D is the TS with the highest energy content (+
4.3 kcalmolꢀ1). As a matter of fact, TS-4B shows no unfav-
Figure 6. Transition states for the addition of 22 to (S)-23b (relative ener-
gies in kcalmolꢀ1).
forth TS-3A is the most favorable TS here, with the FA TS-
3B being 1.1 kcalmolꢀ1 higher in energy. As before, this
agreed well with our experimental observations and qualita-
tive mechanistic proposals (Scheme 2 and Scheme 4). Addi-
tions to the Si face must go through markedly higher energy
barriers. Indeed, the Cornforth TS-3C and the FA TS-3D
are 2.6 and 1.3 kcalmolꢀ1, respectively, higher in energy
than TS-3A.
From all four transition states, TS-3A shows the longest
Figure 7. Transition states for the addition of 22 to (R)-23b (relative ener-
length for the forming C C bond (2.43 Š) and is therefore
gies in kcalmolꢀ1).
ꢀ
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Chem. Eur. J. 2008, 14, 9240 – 9254

Boron Aldol Reactions with a-Heteroatom-Substituted Aldehydes
FULL PAPER
orable interactions of either electronic or steric kind. In con-
trast, TS-4A is destabilized by a syn-pentane interaction,
and perhaps also by a steric repulsion between the aldehyde
O-methyl group and the atoms at the stereogenic carbon
atom of the enolate. The latter feature is suggested by the
midalization of this atom in the TS. In addition to the afore-
mentioned features, TS-5A does not exhibit unfavorable
syn-pentane repulsions and is thus by far the preferred TS.
This is in complete agreement with our experimental obser-
vations and qualitative mechanistic proposals (Scheme 5 and
Scheme 6).
Aside from the unfavorable dipolar repulsion factor dis-
cussed above, the FA TS-5B shows in addition a Me–Me
syn-pentane interaction. This explains why this TS turns out
to be higher in energy than TS-5A by the appreciable
amount of 2.3 kcalmolꢀ1 (Figure 8).
In contrast to (S)-a-fluoro aldehydes 8, the R enantiomers
do not react with erythrulose enolate 1B at all (Scheme 5).
When applied to model aldehyde (R)-23c, our theoretical
calculations predict that the Cornforth TS-6A and the FA
TS-6B have approximately the same energy content
(Figure 9). Indeed, TS-6A exhibits a destabilizing syn-pen-
ꢀ
low value of the dihedral f2 angle C=O···C O (147.18).
The aforementioned calculations would lead to the pre-
diction that (R)-a-alkoxy aldehydes react through a Felkin–
Anh TS to yield mainly one diastereoisomer, different from
that obtained with the S aldehydes. Indeed, this happens
with Evans chiral enolate 18B (Scheme 12) but not when
enolate 1B is used (Scheme 2), as we only observed a slow
and non-selective reaction. This result would suggest the ex-
istence of several competitive transition states (Scheme 4).
However, whether the discrepancy results from the inade-
quacy of our model reaction or from the calculation level
used here is not clear.[29]
Transition-state structures for addition of 22 to a-fluoro al-
dehydes (R)- and (S)-23c: The lowest energy TS in the addi-
tion of 22 to aldehyde (S)-23c is the Cornforth TS-5 A
ꢀ
(Figure 8). Here, the dihedral C=O···C F angle f2 =165.18,
Figure 9. Transition states for the addition of 22 to (R)-23c (relative ener-
gies in kcalmolꢀ1).
tane interaction that overcomes even the favorable factor of
a Cornforth-type conformation (f2 =170.28). As regards TS-
6B, it adopts a FA conformation (f1 =167.98) but the struc-
Figure 8. Transition states for the addition of 22 to (S)-23c (relative ener-
gies in kcalmolꢀ1).
ꢀ
ture is destabilized here by a strong C=O/C F dipolar repul-
a value very close to that calculated by Evans and co-work-
ers (1668) for the reaction of 23c with a simple achiral enol-
borane. This indicates that the dipolar repulsion component
is markedly reduced in this TS. This is a particularly relevant
feature because the same group has shown that there is a
high energetic cost (ca. 3.5 kcalmolꢀ1) for bringing the C=
sion, which causes it to have more or less the same energy
content as TS-6A. This alone does not explain the observed
absence of reactivity but it is worth noting that, if we com-
pare the absolute energy contents of TS-6A or TS-6B with
that of TS-5A (see Supporting Information), we observe
that TS-6A and TS-6B are destabilized by approximately
2.8 kcalmolꢀ1 relative to TS-5A. This fact may explain the
lack of reactivity of (R)-a-fluoro aldehydes in this reaction
because the reactions must traverse high energy barriers in
any case. Again, this agrees very well with our qualitative
mechanistic proposals (Scheme 5 and 6). It is also worth
noting here that the same behavior is observed with Evans
chiral enolate 18B, which reacts very well with a-fluoro alde-
hydes of one configuration (R in this case) but not at all
with the S antipodes (Scheme 12).
ꢀ
O···C F dihedral angle in 2-fluoropropanal from its ground-
state value of nearly 1808 to about 908.[7h] In the case of the
aforementioned aldol reaction, this means that the stereo-
electronic advantage associated with FA transition states
ꢀ
(C F perpendicular to C=O) is not able to compensate the
energetic penalty of the necessary conformational change. It
ꢀ
is also worth mentioning that the length of the forming C C
bond in TS-5A (2.84 Š) is markedly higher than in all other
transition states, a feature which indicates that this TS is
very early. In all likelihood, this is related to the high elec-
trophilicity of the carbonyl group in a-fluoro aldehydes, due
in turn to the high electronegativity of the fluorine atom. In
fact, an inspection of the bond angles around the boron
atom (see Supporting Information) reveals a distinct pyra-
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9249

J. A. Marco, M. Carda et al.
except where otherwise indicated. The non-quaternary signals were as-
signed by means of 2D HMQC experiments. Solvent signals taken as ref-
erence were 1H (d=7.25) and 13C (d=77). 19F NMR d values are refer-
enced to CFCl3 (d=0) but the internal standard used was C6F6 (d=
ꢀ162.3 ppm).[30] Mass spectra were run in either the electron impact
(EIMS, 70 eV) or the fast atom bombardment mode (FABMS, m-nitro-
benzyl alcohol matrix). IR data, which were measured as films on NaCl
plates (oils) or as KBr pellets (solids), are given only when relevant func-
tions (C=O, OH) are present. Optical rotations were measured at 258C.
Reactions which required an inert atmosphere were carried out under
dry N2 with flame-dried glassware. Commercial reagents were used as re-
ceived. THF and Et2O were freshly distilled from sodium-benzophenone
ketyl. Dichloromethane was freshly distilled from CaH2. Tertiary amines
were freshly distilled from KOH. Unless detailed otherwise, “work-up”
means pouring the reaction mixture into satd. aqueous NH4Cl (basic re-
action media) or NaHCO3 (acid reaction media), extraction with the indi-
cated solvent, additional washing with 5% aq NaHCO3 or 5% aq HCl,
respectively, then again with brine, drying over anhydrous Na2SO4 or
MgSO4 and solvent removal under reduced pressure. This was followed
by chromatography of the residue on a silica gel column (60–200 mm)
with the indicated solvent mixture. Where solutions were filtered through
a Celite pad, the pad was additionally rinsed with the same solvent used,
and the washing solutions were incorporated into the main organic layer.
Conclusion
The doubly diastereoselective aldol reactions of a (Z)-boron
enolate of chiral ketone 1 with a-chiral aldehydes have been
investigated from the experimental point of view. As in the
recent disclosure on achiral enolates by Evans and co-work-
ers,[7h] cyclic transition states of the Zimmerman–Traxler
type have been assumed with no chelation issues involved.
Relying upon the experimental findings with this and other
enolizable compounds, and on the theoretical calculations
on model reactions, we have summarized the results of the
aforementioned reactions within a unified general concept
in which several factors must be taken into account. These
factors are:
1) Syn-pentane steric repulsions between the OTBS group
on the enolate and one aldehyde non-hydrogen a-sub-
stituent are energetically important interactions that
ꢀ
must be avoided through appropriate C C bond rota-
tion.
General experimental procedure for aldol additions of ketone 1 mediated
by dicyclohexyl boron chloride: Chx2BCl (neat, 395 mL, ca. 1.8 mmol)
was added under Ar by syringe to an ice-cooled solution of Et3N
(280 mL, 2 mmol) in anhydrous Et2O (5 mL). Erythrulose derivative 1
(1 mmol) was dissolved in anhydrous Et2O (5 mL) and added dropwise
by syringe to the reagent solution. The reaction mixture was then stirred
for 30 min. After dropwise addition of a solution of the appropriate alde-
hyde (freshly prepared, 4 mmol) in anhydrous ether (6 mL), the reaction
mixture was stirred at 08C for 6 h. Then, phosphate buffer solution (pH
7, 6 mL) and MeOH (6 mL) were added, followed by 30% aq H2O2 solu-
tion (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 (hexanes/EtOAc mixtures)
afforded the aldol addition product. Chemical yields and d.r. values are
given in the main text.
2) For aldehydes a-substituted with very electronegative
heteroatoms (F, O), Cornforth-type dipolar repulsions
during the TS are energetically more important than the
stereoelectronic advantage associated with the Felkin–
Anh conformation. Thus, the shapes of the transition
states are likely dictated by ground-state conformational
factors of the aldehydes, where such dipolar repulsions
are of paramount importance.
3) For aldehydes containing less electronegative a-heteroa-
toms (N), either Felkin–Anh or Cornforth transition
states may dominate according to the particular situa-
tion. For those containing only carbon a-substituents, the
Felkin–Anh p-facial bias is not very strong, and the ste-
reocontrol is mostly exerted by the chiral enolate. Again,
the stereochemical course is dictated here by the need to
avoid syn-pentane steric repulsions.
(2R,3R,4S)-5-(Benzyloxy)-2-(tert-butyldimethylsilyloxy)-1-{(S)-2,2-di-
methyl-1,3-dioxolan-4-yl)}-4-fluoro-3-hydroxypentan-1-one (10a): oil;
[a]D =ꢀ63.3 (c=0.98 in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.35–
7.25 (br m, 5H; aromatic), 5.09 (br s, 1H; H-2), 4.65 (br s, 2H;
OCH2Ph), 4.60–4.50 (partly overlapped m, 1H; H-4), 4.60 (dd, J=7,
5 Hz, 1H; H-4’), 4.36 (br t, J ꢂ10 Hz, 1H; H-3), 4.22 (dd, J=8.5, 7 Hz,
1H; H-5’a), 4.11 (dd, J=8.5, 5 Hz, 1H; H-5’b), 3.91 (ddd, 3JH,F =27.5 Hz,
J=12, 2 Hz, 1H; H-5a), 3.81 (ddd, 3JH,F =29 Hz, J=12, 5 Hz, 1H; H-5b),
2.40 (d, J=10 Hz, 1H; OH), 1.47 (s, 3H; acetonide Me), 1.39 (s, 3H; ace-
tonide Me), 0.95 (s, 9H; Me3CSi), 0.12 (s, 3H; MeSi), 0.05 ppm (s, 3H;
MeSi); 13C NMR (125 MHz, CDCl3): d=208.0 (C-1), 137.9 (aromatic Cq),
128.4 (ꢁ 2), 127.7, 127.6 (ꢁ 2) (aromatic CH), 111.2 (acetonide Cq), 91.5/
In the cases under study in the present paper with ketone
1 as the enol-forming compound, factor 1) can be consid-
ered dominant in general terms and determines the reaction
course for aldehydes containing nitrogen or only-carbon a-
substituents, with either R or S configuration. For aldehydes,
which contain a-fluorine or a-oxygen atoms, factors 1) and
2) are comparable in magnitude and one is unable to domi-
nate the other. In the case of the S enantiomers both factors
cooperate (matched pairs) and give rise to highly stereose-
lective reactions. For the R enantiomers, however, both fac-
tors counteract each other (mismatched pairs), resulting in
slow and unselective reactions.
1
90.1 (d, JC,F ꢂ179 Hz, C-4), 78.6 (C-4’), 74.7 (br s, C-2), 73.6 (OCH2Ph),
2
2
69.5 (d, JC,F ꢂ19.2 Hz, C-5), 68.7 (d, JC,F ꢂ26.6 Hz, C-3), 66.7 (C-5’),
26.0 (acetonide Me), 25.7 (ꢁ 3, Me3CSi), 24.9 (acetonide Me), 18.4 (Cq-
Si), ꢀ4.7 (MeSi), ꢀ5.6 ppm (MeSi); 19F NMR (470 MHz, CDCl3): d=
ꢀ192.8 ppm (dt, Jꢂ49, 27.5 Hz); IR: n˜ =3460 (br, OH), 1735 (C=O)
cmꢀ1; HRMS (EI): m/z: calcd for C23H37FO6SiꢀMe: 441.2108; found:
441.2098 ([M+ꢀMe], 2), 399 (1), 341 (7), 159 (15), 101 (22), 91 (100); ele-
mental analysis calcd (%) for C23H37FO6Si: C 60.50, H 8.17; found: C
60.68, H 8.31.
(2R,3R,4S)-2-(tert-Butyldimethylsilyloxy)-1-{(S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)}-4-fluoro-3-hydroxy-5-phenylpentan-1-one (10b): oil; [a]D =
ꢀ75.3 (c=0.95 in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.35–7.25 (br
m, 5H; aromatic), 5.09 (br s, 1H; H-2), 4.60 (dtd, 2JH,F =48 Hz, J=8.3,
2.6 Hz, 1H; H-4), 4.59 (dd, J=7.6, 5.2 Hz, 1H; H-4’), 4.21 (dd, J=9,
7.6 Hz, 1H; H-5’a), 4.12 (overlapped m, 1H; H-3), 4.11 (dd, J=9, 5.2 Hz,
Experimental Section
General methods: 1H and 13C NMR spectra were recorded at 500 MHz
and 125 MHz, respectively, in CDCl3 solution at 258C. 19F NMR spectra
were recorded at 470.25 MHz. 13C NMR signal multiplicities were deter-
mined with the DEPT pulse sequence. 13C signals are sharp singlets,
2
1H; H-5’b), 3.30 (ddd, JH,F =35 Hz, J=15, 2.6 Hz, 1H; H-5a), 3.00 (ddd,
2JH,F =24.6 Hz, J=15, 8.3 Hz, 1H; H-5b), 2.50 (d, J=11 Hz, 1H; OH),
1.43 (s, 3H; acetonide Me), 1.37 (s, 3H; acetonide Me), 0.94 (s, 9H;
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Boron Aldol Reactions with a-Heteroatom-Substituted Aldehydes
FULL PAPER
Me3CSi), 0.11 (s, 3H; MeSi), 0.03 ppm (s, 3H; MeSi); 13C NMR
(125 MHz, CDCl3): d=208.1 (C-1), 137.1 (aromatic Cq), 129.5 (ꢁ 2),
(2R,3S,4R)-2-(tert-Butyldimethylsilyloxy)-4-(dibenzylamino)-1-{(S)-2,2-
dimethyl-1,3-dioxolan-4-yl)}-3-hydroxypentan-1-one (12a): oil; [a]D =
ꢀ52.7 (c=1.56 in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.35–7.20 (br
m, 10H; aromatic), 4.78 (br s, 1H; H-2), 4.60 (dd, J=7.5, 5 Hz, 1H; H-
4’), 4.20 (dd, J=8.5, 5 Hz, 2H; H-5’a/OH), 4.08 (m, 2H; H-3/H-5’b), 3.87
(br d, J=13.2 Hz, 2H; NCH2Ph), 3.40 (br d, J=13.2 Hz, 2H; NCH2Ph),
3.05 (dq, J=9.5, 6.6 Hz, 1H; H-4), 1.43 (s, 3H; acetonide Me), 1.40 (s,
3H; acetonide Me), 1.12 (d, J=6.6 Hz, 3H; H-5), 0.74 (s, 9H; Me3CSi),
0.03 (s, 3H; MeSi), ꢀ0.11 ppm (s, 3H; MeSi); 13C NMR (125 MHz,
CDCl3): d=207.7 (C-1), 138.7 (ꢁ 2) (aromatic Cq), 128.9 (ꢁ 4), 128.5 (ꢁ
4), 127.3 (ꢁ 2) (aromatic CH), 110.5 (acetonide Cq), 78.6 (C-2 or C-4’),
76.1 (C-4’ or C-2), 71.6 (C-3), 66.2 (C-5’), 54.0 (C-4), 53.5 (ꢁ 2, NCH2Ph),
26.1 (acetonide Me), 25.8 (ꢁ 3, Me3CSi), 25.1 (acetonide Me), 18.3 (Cq-
Si), 8.0 (C-5), ꢀ4.3 (MeSi), ꢀ5.4 ppm (MeSi); IR: n˜ =3400 (br, OH), 1738
1
128.4 (ꢁ 2), 126.6 (aromatic CH), 111.2 (acetonide Cq), 92.6/91.2 (d, JC,F
3
2
ꢂ178 Hz, C-4), 78.7 (C-4’), 74.7 (d, JC,F ꢂ2.2 Hz, C-2), 71.3 (d, JC,F
2
ꢂ26.5 Hz, C-3), 66.8 (C-5’), 38.0 (d, JC,F ꢂ19.7 Hz, C-5), 25.9 (acetonide
Me), 25.7 (ꢁ 3, Me3CSi), 24.9 (acetonide Me), 18.4 (Cq-Si), ꢀ4.7 (MeSi),
ꢀ5.6 ppm (MeSi); 19F NMR (470 MHz, CDCl3): d=ꢀ188.2 ppm (ddd, J
ꢂ48, ꢂ35, ꢂ24.5 Hz); IR: n˜ =3550 (br, OH), 1735 (C=O) cmꢀ1; HRMS
(EI): m/z: calcd for C22H35FO5SiꢀMe: 411.2003 [M+ꢀMe]; found:
411.2010 ([M+ꢀMe], 2), 369 (10), 311 (12), 159 (45), 129 (82), 101 (100),
91 (83); elemental analysis calcd (%) for C22H35FO5Si: C 61.94, H 8.27;
found: C 61.77, H 8.49.
(2R,3S,4S)-2-(tert-Butyldimethylsilyloxy)-4-(dibenzylamino)-1-{(S)-2,2-
dimethyl-1,3-dioxolan-4-yl)}-3-hydroxypentan-1-one (11a): oil; [a]D =
(C=O) cmꢀ1
;
HRMS (FAB): m/z: 528.3142 [M+H+]; calcd for
1
ꢀ47.6 (c=1.88 in CHCl3); H NMR (500 MHz, CDCl3): d=7.45–7.20 (m,
C30H46NO5Si, 528.3145; elemental analysis calcd (%) for C30H45NO5Si: C
68.27, H 8.59; found: C 68.41, H 8.66.
10H, aromatic), 4.95 (br s, 1H; H-2), 4.60 (br t, J ꢂ6.5 Hz, 1H; H-4’),
4.22 (m, 1H; H-3), 4.20 (m, 2H; H-5a/5b), 3.80 (br d, J=14 Hz, 2H;
NCH2Ph), 3.63 (br d, J=14 Hz, 2H; NCH2Ph), 3.07 (quint, J ꢂ6.5 Hz,
1H; H-4), 2.40 (br s, 1H; OH), 1.49 (s, 3H; acetonide Me), 1.46 (s, 3H;
acetonide Me), 1.16 (d, J=6.5 Hz, 3H; H-5), 0.86 (s, 9H; Me3CSi), 0.03
(s, 3H; MeSi), ꢀ0.20 ppm (s, 3H; MeSi); 13C NMR (125 MHz, CDCl3):
d=207.7 (C-1), 140.2 (ꢁ 2, aromatic Cq), 128.7 (ꢁ 4), 128.2 (ꢁ 4),126.9 (ꢁ
2) (aromatic CH), 110.7 (acetonide Cq), 78.3 (C-2 or C-4’), 78.0 (C-4’ or
C-2), 72.7 (C-3), 66.3 (C-5’), 56.5 (C-4), 54.0 (ꢁ 2, NCH2Ph), 26.0 (aceto-
nide Me), 25.8 (ꢁ 3, Me3CSi), 25.0 (acetonide Me), 18.3 (Cq-Si), 9.7 (C-5),
(2R,3S,4R)-2-(tert-Butyldimethylsilyloxy)-4-(dibenzylamino)-1-{(S)-2,2-
dimethyl-1,3-dioxolan-4-yl)}-3-hydroxy-5-phenylpentan-1-one (12b): oil;
[a]D =ꢀ50.2 (c=1.5 in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.45–
7.20 (br m, 15H; aromatic), 5.10 (d, J=2.5 Hz, 1H; H-2), 4.50 (br s, 1H;
OH), 4.44 (dd, J=7.5, 5 Hz, 1H; H-4’), 4.25 (dd, J=8.6, 5 Hz, 1H; H-
5’a), 4.17 (dd, J=9.5, 2.5 Hz, 1H; H-3), 4.10 (dd, J=8.6, 7.5 Hz, 1H; H-
5’b), 4.00–3.90 (br m, 2H; NCH2Ph), 3.60–3.50 (br m, 2H; NCH2Ph),
3.35 (td, J=9.5, 3.6 Hz, 1H; H-4), 3.22 (dd, J=14.3, 3.6 Hz, 1H; H-5a),
3.06 (dd, J=14.3, 9.5 Hz, 1H; H-5b), 1.52 (s, 3H; acetonide Me), 1.50 (s,
3H; acetonide Me), 0.91 (s, 9H; Me3CSi), 0.10 (s, 3H; MeSi), 0.00 ppm (s,
3H; MeSi); 13C NMR (125 MHz, CDCl3): d=207.7 (C-1), 139.9, 138.8
(br,ꢁ2) (aromatic Cq), 129.8 (ꢁ 2), 129.2 (ꢁ 4), 128.5 (ꢁ 2), 128.3 (ꢁ 4),
127.2 (ꢁ 2), 126.4 (aromatic CH), 110.5 (acetonide Cq), 78.9 (C-2 or C-
4’), 76.0 (C-4’ or C-2), 71.5 (C-3), 65.8 (C-5’), 59.8 (C-4), 53.8 (br,ꢁ2,
NCH2Ph), 34.2 (C-5), 26.2 (acetonide Me), 25.9 (ꢁ 3, Me3CSi), 25.0 (ace-
tonide Me), 18.3 (Cq-Si), ꢀ4.4 (MeSi), ꢀ5.0 ppm (MeSi); IR: n˜ =3340 (br,
OH), 1736 (C=O) cmꢀ1; HRMS (EI): m/z: calcd for C36H49NO5SiꢀtBu:
546.2675; found: 546.2628 ([M+ꢀtBu], 1), 300 (71), 91 (100); elemental
analysis calcd (%) for C36H49NO5Si: C 71.60, H 8.18, found: C 71.70, H
8.32.
ꢀ4.6 (MeSi), ꢀ5.4 ppm (MeSi); IR: n˜ =3550 (br, OH), 1733 (C=O) cmꢀ1
;
HRMS (FAB): m/z: calcd for C30H46NO5Si: 528.3145, [M+H+]; found:
528.3147; elemental analysis calcd (%) for C30H45NO5Si: C 68.27, H 8.59;
found: C 68.47, H 8.49.
(2R,3S,4S)-2-(tert-Butyldimethylsilyloxy)-4-(dibenzylamino)-1-{(S)-2,2-
dimethyl-1,3-dioxolan-4-yl)}-3-hydroxy-5-phenylpentan-1-one (11b): oil;
[a]D =ꢀ52.3 (c=1.04 in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.35–
7.20 (br m, 15H; aromatic), 4.88 (d, J=3 Hz, 1H; H-2), 4.35–4.30 (m,
2H; H-3/H-4’), 4.15 (d, J=6.6 Hz, 2H; H-5’a/5’b), 3.82 (d, J=14.3 Hz,
2H; NCH2Ph), 3.68 (d, J=14.3 Hz, 2H; NCH2Ph), 3.22 (m, 1H; H-4),
3.12 (dd, J=14, 8.4 Hz, 1H; H-5a), 2.96 (dd, J=14, 5.7 Hz, 1H; H-5b),
2.40 (d, J=9 Hz, 1H; OH), 1.55 (s, 3H; acetonide Me), 1.46 (s, 3H; ace-
tonide Me), 0.82 (s, 9H; Me3CSi), ꢀ0.02 (s, 3H; MeSi), ꢀ0.23 ppm (s,
3H; MeSi); 13C NMR (125 MHz, CDCl3): d=207.9 (C-1), 140.6, 139.8 (ꢁ
2) (aromatic Cq), 129.8 (ꢁ 2), 128.8 (ꢁ 4), 128.2 (ꢁ 4), 128.1 (ꢁ 2), 126.8
(ꢁ 2), 125.8 (aromatic CH), 110.9 (acetonide Cq), 78.5 (C-2 or C-4’), 76.8
(C-4’ or C-2), 70.9 (C-3), 66.5 (C-5’), 61.5 (C-4), 54.1 (ꢁ 2, NCH2Ph), 32.4
(C-5), 26.2 (acetonide Me), 25.8 (ꢁ 3, Me3CSi), 24.9 (acetonide Me), 18.2
(Cq-Si), ꢀ4.8 (MeSi), ꢀ5.2 ppm (MeSi); IR: n˜ =3540 (br, OH), 1733 (C=
O) cmꢀ1; HRMS (EI): m/z: calcd for C36H49NO5SiꢀMe: 588.3145 [M+
ꢀMe]; 588.3107 ([M+ꢀMe], 1), 300 (36), 91 (100); elemental analysis
calcd (%) for C36H49NO5Si: C 71.60, H 8.18; found: C 71.45, H 8.35.
(2R,3S,4R)-2-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxy)-
4-(dibenzylamino)-1-{(S)-2,2-dimethyl-1,3-dioxolan-4-yl)}-3-hydroxypen-
tan-1-one (12c): oil; [a]D =ꢀ40.2 (c=1.28 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.80–7.75 (m, 4H; aromatic), 7.55–7.40 (m, 6H;
aromatic), 7.30–7.20 (br m, 10H; aromatic), 4.78 (br s, 1H; H-2), 4.50 (br
t, J ꢂ6 Hz, 1H; H-4’), 4.30 (br s, 1H; OH), 4.25–4.20 (m, 2H; H-3/H-
5’a), 4.14 (br d, J=11.6 Hz, 1H; H-5a), 4.10–4.00 (m, 3H; H-5’b/
NCH2Ph), 3.84 (dd, J=11.6, 6.8 Hz, 1H; H-5b), 3.77 (br d, J=13.3 Hz,
2H; NCH2Ph), 3.15 (m, 1H; H-4), 1.33 (s, 6H; 2ꢁacetonide Me), 1.22 (s,
9H; Me3CSi), 0.62 (s, 9H; Me3CSi), ꢀ0.06 (s, 3H; MeSi), ꢀ0.26 ppm (s,
3H; MeSi); 13C NMR (125 MHz, CDCl3): d=206.6 (C-1), 139.0 (ꢁ 2),
135.9 (ꢁ 4), 133.0, 132.8 (aromatic Cq), 130.0, 129.9, 129.1 (ꢁ 4), 128.6 (ꢁ
4), 127.9 (ꢁ 2), 127.8 (ꢁ 2), 127.2 (ꢁ 2) (aromatic CH), 110.4 (acetonide
Cq), 78.4 (C-4’), 76.0 (C-2), 67.4 (C-3), 65.5 (C-5’), 60.5 (C-5), 59.1 (C-4),
54.7 (ꢁ 2, NCH2Ph), 27.2 (ꢁ 3, Me3Si), 26.0 (acetonide Me), 25.8 (ꢁ 3,
Me3Si), 24.9 (acetonide Me), 19.2, 18.2 (Cq-Si), ꢀ4.5 (MeSi), ꢀ5.4 ppm
(MeSi); IR: n˜ =3365 (br, OH), 1737 (C=O) cmꢀ1; HRMS (FAB): m/z:
calcd for C46H64NO6Si2: 782.4272 [M+H+]; found: 782.4275; elemental
analysis calcd (%) for C46H63NO6Si2: C 70.64, H 8.12; found: C 70.51, H
8.22.
(2R,3S,4S)-2-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphenylsilyloxy)-
4-(dibenzylamino)-1-{(S)-2,2-dimethyl-1,3-dioxolan-4-yl)}-3-hydroxypen-
tan-1-one (11c): oil; [a]D =ꢀ22.4 (c=1.34 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.80–7.75 (m, 4H; aromatic), 7.50–7.35 (br m,
10H; aromatic), 7.30–7.20 (m, 6H; aromatic), 5.17 (br s, 1H; H-2), 4.50
(br t, J ꢂ6.5 Hz, 1H; H-4’), 4.35 (br t, J ꢂ8.5 Hz, 1H; H-3), 4.20–4.05
(br m, 3H; H-5a/H-5’a/H-5’b), 4.00 (br d, J=14 Hz, 2H; NCH2Ph), 3.98
(overlapped m, 1H; H-5b), 3.85 (br d, J=14 Hz, 2H; NCH2Ph), 3.23 (br
td; J ꢂ6.5, 5 Hz, 1H; H-4), 2.60 (d, J=10 Hz, 1H; OH), 1.43 (s, 3H; ace-
tonide Me), 1.42 (s, 3H; acetonide Me), 1.14 (s, 9H; Me3CSi), 0.85 (s,
9H; Me3CSi), 0.04 (s, 3H; MeSi), ꢀ0.18 ppm (s, 3H; MeSi); 13C NMR
(125 MHz, CDCl3): d=207.6 (C-1), 140.1 (ꢁ 2), 135.8 (ꢁ 2), 135.7 (ꢁ 2),
133.3, 133.1 (aromatic Cq), 129.8, 129.7, 128.8 (ꢁ 4), 128.2 (ꢁ 4), 127.8 (ꢁ
2), 127.7 (ꢁ 2), 127.0 (ꢁ 2) (aromatic CH), 110.8 (acetonide Cq), 78.1 (C-
2 or C-4’), 77.0 (C-4’ or C-2), 71.7 (C-3), 66.1 (C-5’), 62.4 (C-5), 62.1 (C-
4), 55.1 (ꢁ 2, NCH2Ph), 27.0 (ꢁ 3, Me3Si), 26.0 (ꢁ 3, Me3CSi), 25.9 (aceto-
nide Me), 25.1 (acetonide Me), 19.2, 18.4 (Cq-Si), ꢀ4.3 (MeSi), ꢀ5.0 ppm
(MeSi); IR: n˜ =3550 (br, OH), 1733 (C=O) cmꢀ1; HRMS (FAB): m/z:
calcd for C46H64NO6Si2: 782.4272, [M+H+]; found: 782.4310; elemental
analysis calcd (%) for C46H63NO6Si2: C 70.64, H 8.12; found: C 70.78, H
8.01.
(3S,4S,5R)-1,3-Bis(tert-butyldimethylsilyloxy)-6-benzyloxy-5-fluoro-4-hy-
droxyhexan-2-one (17): oil; [a]D =+7.8 (c=1.6 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.35–7.25 (br m, 5H; aromatic), 4.88 (br s, 1H;
H-3), 4.62 (s, 2H; H-1a/H-1b), 4.60–4.45 (br m, 1H; H-5), 4.43 (AB
system, J=18 Hz, 2H; OCH2Ph), 4.20 (br t, J ꢂ10 Hz, 1H; H-4), 3.88
(ddd, 3JH,F =26 Hz, J=11.7, 2 Hz, 1H; H-6a), 3.78 (ddd, 3JH,F =29.5 Hz,
J=11.7, 5 Hz, 1H; H-6b), 2.50 (d, J=10 Hz, 1H; OH), 0.97 (s, 9H;
Me3CSi), 0.94 (s, 9H; Me3CSi), 0.12 (s, 3H; MeSi), 0.10 (s, 6H; MeSi),
0.09 ppm (s, 3H; MeSi); 13C NMR (125 MHz, CDCl3): d=208.7 (C-2),
137.8 (aromatic Cq), 128.3 (ꢁ 2), 127.6 (ꢁ 2), 127.5 (aromatic CH), 91.0/
1
2
89.6 (d, JC,F ꢂ178 Hz, C-5), 74.8 (C-3), 73.5 (OCH2Ph), 69.7/69.5 (d, JC,F
Chem. Eur. J. 2008, 14, 9240 – 9254
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9251

J. A. Marco, M. Carda et al.
2
ꢂ26 Hz, C-4), 69.4/69.2 (C-6, d, JC,F ꢂ19.5 Hz), 68.3 (C-1), 25.7 (ꢁ 6,
G. Peris, from the Serveis Centrals de Instrumentaciꢂ of the University
Jaume I, for their collaboration in some X-ray diffraction analyses.
Me3CSi), 18.2, 18.1 (Cq-Si), ꢀ4.9 (MeSi), ꢀ5.6 (MeSi), ꢀ5.7 (MeSi),
ꢀ5.8 ppm (MeSi); 19F NMR d=ꢀ192.4 ppm (dt, Jꢂ47, ꢂ28 Hz); IR: n˜ =
3460 (br, OH), 1735 (C=O) cmꢀ1
; HRMS (EI): m/z: calcd for
C25H45FO5Si2ꢀHF: 480.2727; 480.2769 ([M+-HF], 1), 311 (30), 129 (30),
91 (100); elemental analysis calcd (%) for C25H45FO5Si2: C 59.96, H 9.06;
found: C 60.10, H 9.22.
[1] a) D. A. Evans, J.V. Nelson, T. R. Taber, Top. Stereochem. 1982, 13,
1–115; b) T. Mukaiyama, Org. React. 1982, 28, 203–331; c) S. Masa-
mune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem. 1985, 97, 1–
31; Angew. Chem. Int. Ed. Engl. 1985, 24, 1–30; d) C. H. Heathcock,
in Asymmetric Synthesis, Vol. 3 (Ed.: J. D. Morrison), Academic
Press, Orlando, 1984, pp. 111–212; e) C. H. Heathcock, Aldrichimica
Acta 1990, 23, 99–111; f) Comprehensive Organic Synthesis, Vol. 2
(Eds.: B. M. Trost, I. Fleming, E. Winterfeldt), Pergamon Press,
Oxford, 1993; g) H. B. Mekelburger, C. S. Wilcox in Comprehensive
Organic Synthesis, Vol. 2 (Eds.: B. M. Trost, I. Fleming, E. Winter-
feldt), Pergamon Press, Oxford, 1993, pp. 99–131; h) C. H. Heath-
cock in Comprehensive Organic Synthesis, Vol. 2 (Eds.: B. M. Trost,
I. Fleming, E. Winterfeldt), Pergamon Press, Oxford, 1993, pp. 133–
179 and 181–238; i) B. M. Kim, S. F. Williams, S. Masamune in Com-
prehensive Organic Synthesis, Vol. 2 (Eds.: B. M. Trost, I. Fleming,
E. Winterfeldt), Pergamon Press, Oxford, 1993, pp. 239–275;
j) M. W. Rathke, P. Weipert in Comprehensive Organic Synthesis,
Vol. 2 (Eds.: B. M. Trost, I. Fleming, E. Winterfeldt), Pergamon
Press, Oxford, 1993, pp. 277–299; k) I. Paterson in Comprehensive
Organic Synthesis, Vol. 2 (Eds.: B. M. Trost, I. Fleming, E. Winter-
feldt), Pergamon Press, Oxford, 1993, pp. 301–319; l) A. S. Franklin,
I. Paterson, Contemp. Org. Synth. 1994, 1, 317–338; m) M. Braun, in
Houben-Weylꢀs Methods of Organic Chemistry, Stereoselective Syn-
thesis, Vol. 3, (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E.
Schaumann), Thieme, Stuttgart, 1996, pp. 1603–1666 and 1713–
1735; n) R. Mahrwald, Chem. Rev. 1999, 99, 1095–1120; o) C.
Palomo, M. Oiarbide, J. M. García, Chem. Eur. J. 2002, 8, 36–44;
p) C. Palomo, M. Oiarbide, J. M. García, Chem. Soc. Rev. 2004, 33,
65–75; q) Modern Aldol Reactions (Ed.: R. Mahrwald), Wiley-
VCH, Weinheim, 2004; r) E. M. Carreira, A. Fettes, C. Marti, Org.
React. 2006, 67, 1–216; s) D. A. Evans, G. Helmchen, M. Ruping, J.
Wolfgang, in Asymmetric Synthesis, (Eds.: M. Christmann, S. Brꢄse),
Wiley-VCH, Weinheim, 2007, pp. 3–9.
(S)-4-Benzyl-3-{(2S,3S,4R)-4-(tert-butyldiphenylsilyloxy)-3-hydroxy-2-
methylpentanoyl}oxazolidin-2-one (19): oil; [a]D =+36.7 (c=2.64 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=7.80–7.75 (m, 4H; aromatic),
7.50–7.25 (br m, 11H; aromatic), 4.67 (m, 1H; H-4), 4.20–4.15 (m, 3H;
H-2’/H-5a/H-5b), 3.96 (m, 1H; H-3’), 3.90 (quint, apparent J ꢂ6.3 Hz,
1H; H-4’), 3.26 (dd, J=13.4, 3.3 Hz, 1H; CHPh), 3.20 (br s, 1H; OH),
2.81 (dd, J=13.4, 9.4 Hz, 1H; CHPh), 1.30 (d, J=7 Hz, 3H; H-5’ or Me-
C2’), 1.13 (d, overlapped, 3H; Me-C2’ or H-5’), 1.13 ppm (s, 9H; Me3CSi);
13C NMR (125 MHz, CDCl3): d=177.4 (C1’), 152.5 (C2), 135.9 (ꢁ 4),
135.1, 134.4, 133.3 (aromatic Cq), 129.7, 129.5, 129.4 (ꢁ 2), 128.9 (ꢁ 2),
127.6 (ꢁ 2), 127.4 (ꢁ 2), 127.3 (aromatic CH), 75.5 (C3’ or C4’), 69.9 (C4’
or C3’), 66.0 (C5), 55.0 (C4), 39.0 (C2’), 37.7 (CH2Ph), 26.9 (ꢁ 3,
Me3CSi), 19.5 (C5’ or MeC2’), 19.1 (Cq-Si), 11.6 ppm (MeC2’ or C5’); IR:
n˜ =3530 (br, OH), 1787, 1678 (C=O) cmꢀ1; HRMS (EI): m/z: calcd for
C32H39NO5SiꢀtBu: 488.1893; 488.1896 ([M+ꢀtBu], 38), 311 (50), 255
(100), 199 (90), 178 (77); elemental analysis calcd (%) for C32H39NO5Si:
C 70.43, H 7.20; found: C 70.20, H 7.22.
(S)-4-Benzyl-3-{(2S,3S,4S)-4-(tert-butyldiphenylsilyloxy)-3-hydroxy-2-
methylpentanoyl}oxazolidin-2-one (20): oil; [a]D =+14.4 (c=0.72 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=7.75–7.70 (m, 4H; aromatic),
7.45–7.20 (br m, 11H; aromatic), 4.50 (m, 1H; H-4), 4.15–4.05 (m, 2H;
H-5a/H-5b), 4.00–3.85 (br m, 3H; H-2’/H-3’/H-4’), 3.25 (dd, J=13.3,
3 Hz, 1H; CHPh), 2.75 (dd, J=13.3, 9.5 Hz, 1H; CHPh), 2.70 (br d, J=
6.5 Hz, 1H; OH), 1.33 (d, J=6.7 Hz, 3H; H-5’ or Me-C2’), 1.20 (d, J=
6.2 Hz, 3H; Me-C2’ or H-5’), 1.13 ppm (s, 9H; Me3CSi); 13C NMR
(125 MHz, CDCl3): d=175.1 (C1’), 152.5 (C2), 135.7 (ꢁ 4), 135.1, 133.9,
133.0 (aromatic Cq), 129.6, 129.5, 129.2 (ꢁ 2), 128.7 (ꢁ 2), 127.6 (ꢁ 2),
127.3 (ꢁ 2), 127.1 (aromatic CH), 75.4 (C3’ or C4’), 70.9 (C4’ or C3’),
65.8 (C5), 55.0 (C4), 40.5 (C2’), 37.5 (CH2Ph), 26.9 (ꢁ 3, Me3CSi), 20.1
(C5’ or Me-C2’), 19.0 (Cq-Si), 12.7 ppm (Me-C2’ or C-5’); IR: n˜ =3540 (br,
OH), 1783, 1694 (C=O) cmꢀ1
;
HRMS (EI): m/z: calcd for
[2] a) C. J. Cowden, I. Paterson, Org. React. 1997, 51, 1–200; b) A.
Abiko, Acc. Chem. Res. 2004, 37, 387–395.
C32H39NO5SiꢀtBu: 488.1893; 488.1897 ([M+ꢀtBu], 24), 255 (55), 199
(100), 178 (51); elemental analysis calcd (%) for C32H39NO5Si: C 70.43,
H 7.20; found: C 70.52, H 7.37.
[3] a) M. Carda, J. Murga, E. Falomir, F. Gonzµlez, J.A. Marco, Tetrahe-
dron 2000, 56, 677–683; b) J. Murga, E. Falomir, M. Carda, J.A.
Marco, Tetrahedron: Asymmetry 2002, 13, 2317–2327; c) J. Murga,
E. Falomir, F. Gonzµlez, M. Carda, J.A. Marco, Tetrahedron 2002,
58, 9697–9707; d) See also: J. Murga, E. Falomir, M. Carda, F. Gon-
zµlez, J.A. Marco, Org. Lett. 2001, 3, 901–904.
[4] Other ketones structurally related to erythrulose behave in the same
way: a) M. Carda, J. Murga, E. Falomir, F. Gonzµlez, J.A. Marco,
Tetrahedron: Asymmetry 2000, 11, 3211–3220; b) M. Carda, F. Gon-
zµlez, R. Sµnchez, J.A. Marco, Tetrahedron: Asymmetry 2002, 13,
1005–1010.
(S)-4-Benzyl-3-{(2S,3S,4R)-4-fluoro-3-hydroxy-2-methyl-5-phenylpenta-
noyl}oxazolidin-2-one (21): oil; [a]D =+52.2 (c=1.8 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.35–7.20 (br m, 10H; aromatic), 4.66 (m, 1H; H-
4), 4.62 (dtd partially overlapped by the signal at d 4.66, 2JH,F =47.5 Hz,
J=7.6, 3 Hz, 1H; H-4’), 4.20–4.15 (m, 2H; H-5a/H-5b), 4.00 (m, 2H; H-
2’/H-3’), 3.30–3.20 (m, 2H; H-5’a/CHPh), 2.98 (ddd, 3JH,F =26 Hz, J=15,
7.3 Hz, 1H; H-5’b), 2.80 (dd, J=13.5, 9.5 Hz, 1H; CHPh), 1.35 ppm (d,
J=7 Hz, 3H; Me-C2’); 13C NMR (125 MHz, CDCl3): d=177.5 (C1’),
152.6 (C2), 136.9, 135.0 (aromatic Cq), 129.8 (ꢁ 2), 129.4 (ꢁ 2), 129.0 (ꢁ
1
[5] J.A. Marco, M. Carda, Díaz-Oltra, S. J. Murga, E. Falomir, H.
Roeper, J. Org. Chem. 2003, 68, 8577–8582.
[6] H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79, 1920–
1923.
2), 128.3 (ꢁ 2), 127.5, 126.6 (aromatic CH), 93.0/91.7 (C4’, d, JC,F
2
ꢂ172.5 Hz), 71.5/71.3 (C3’, d, JC,F ꢂ25.3 Hz), 66.2 (C5), 55.0 (C4), 38.7
2
(C2’), 37.9/37.8 (C5’, d, JC,F ꢂ15.5 Hz), 37.8 (CH2Ph), 11.0 ppm (Me-C2’);
19F NMR d=ꢀ190.8 ppm (dt, Jꢂ47.5, ꢂ26 Hz); IR: n˜ =3500 (br, OH),
1781, 1690 (C=O) cmꢀ1; HRMS (FAB): m/z: calcd for C22H25FNO4:
386.1767 [M+H+]; found: 386.1773; elemental analysis calcd (%) for
C22H24FNO4: C 68.56, H 6.28; found: C 68.52, H 6.39.
[7] For theoretical studies on boron aldol reactions, see: a) Y. Li, M. N.
Paddon-Row, K. N. Houk, J. Org. Chem. 1990, 55, 481–493; b) J. M.
Goodman, S. D. Kahn, I. Paterson, J. Org. Chem. 1990, 55, 3295–
3303; c) A. Bernardi, A. M. Capelli, C. Gennari, J. M. Goodman, I.
Paterson, J. Org. Chem. 1990, 55, 3576–3581; d) A. Bernardi, A. M.
Capelli, A. Comotti, C. Gennari, M. Gardner, J. M. Goodman, I. Pa-
terson, Tetrahedron 1991, 47, 3471–3484; e) F. Bernardi, M.A.
Robb, G. Suzzi-Valli, E. Tagliavini, C. Trombini, A. Umani-Ronchi,
J. Org. Chem. 1991, 56, 6472–6475; f) C. Gennari, S. Vieth, A. Co-
motti, A. Vulpetti, J. M. Goodman, I. Paterson, Tetrahedron 1992,
48, 4439–4458; g) A. Vulpetti, A. Bernardi, C. Gennari, J. M. Good-
man, I. Paterson, Tetrahedron 1993, 49, 685–696; h) V. J. Cee, C. J.
Cramer, D. A. Evans, J. Am. Chem. Soc. 2006, 128, 2920–2930.
[8] N. A. Van Draanen, S. Arseniyadis, M. T. Crimmins, C. H. Heath-
cock, J. Org. Chem. 1991, 56, 2499–2506. For another example
Acknowledgements
Financial support has been granted by the Spanish Ministry of Education
and Science (projects CTQ2005–06688-C02–01 and CTQ2005–06688-
C02–02) and by the Fundació Caixa Castellꢂ-Universitat Jaume I(proj-
ects PI-IB-2005–30 and PI-IA-2005–15). S. D.-O. thanks the University
Jaume Ifor a postdoctoral contract. The authors further thank X. Fontro-
dona, from the Serveis Tꢃcnicos de Recerca, University of Girona, and
9252
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Chem. Eur. J. 2008, 14, 9240 – 9254

Boron Aldol Reactions with a-Heteroatom-Substituted Aldehydes
FULL PAPER
which shows the importance of dipole alignment in aldol transition
states, see: R. K. Boeckman Jr. , B. T. Connell, J. Am. Chem. Soc.
1995, 117, 12368–12369.
Yamamoto, T. Kitazume, J. Org. Chem. 1989, 54, 83–91. The reac-
tions give, however, very variable yields and show, in general, a
medium-to-low stereoselectivity. They are assumed to take place
through open transition states, either chelated or unchelated. The
other report describes low-yielding reactions with the boron enolate
of a chiral a-acyloxy ketone: S. L. Less, P. F. Leadlay, C. J. Dutton, J.
Staunton, Tetrahedron Lett. 1996, 37, 3519–3520.
[9] W. R. Roush, J. Org. Chem. 1991, 56, 4151–4157. The quantitative
importance of the syn-pentane interactions is underscored in our
cases by the fact that enolate 1B does not react with pivalaldehyde,
see ref. [3]. Indeed, if a TS is drawn for the aldol reaction with this
aldehyde, a steric interaction of the aforementioned type will always
[18] For nucleophilic additions to aldehydes containing other types of a-
heteroatoms, see, for example: a) D. Enders, O. Piva, F. Burkamp,
Tetrahedron 1996, 52, 2893–2908 (a-sulphenyl aldehydes); b) D.
Enders, J. Adam, D. Klein, T. Otten, Synlett 2000, 1371–1384 (a-
silyl aldehydes); see also: D. Enders, F. Burkamp, Collect. Czech.
Chem. Commun. 2003, 68, 975–1006.
[19] Details of the preparation of aldehydes 8a,b and 9a–c as well as of
the structural elucidation of the new aldols are given in the Support-
ing Information.
ꢀ
be present for all rotamers around the tBu CO bond.
[10] The various factors which may influence the stereochemical out-
come of aldol reactions have been analyzed in detail by Danishefsky
and co-workers: C. B. Lee, Z. Wu, F. Zhang, M. D. Chappell, S. J.
Stachel, T.-C. Chou, Y. Guan, S. J. Danishefsky, J. Am. Chem. Soc.
2001, 123, 5249–5259.
[11] In all discussions in this paper, no specific differentiation has been
made between the purely steric Felkin–Anh model (for aldehydes
containing all-carbon substituents) and the stereoelectronic “polar
Felkin–Anh” model (for aldehydes containing a-heteroatoms):
a) M. Chꢃrest, H. Felkin, N. Prudent, Tetrahedron Lett. 1968, 9,
2199–2204; b) N. T. Anh, Top. Curr. Chem. 1980, 88, 145–162; c) A.
Mengel, O. Reiser, Chem. Rev. 1999, 99, 1191–1223. See also: R. J.
Smith, M. Trzoss, M. Bühl, S. Bienz, Eur. J. Org. Chem. 2002, 2770–
2775.
[12] a) H. B. Bürgi, J. D. Dunitz, E. Shefter, J. Am. Chem. Soc. 1973, 95,
5065–5067; b) H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff, Tetra-
hedron 1974, 30, 1563–1572; c) R. E. Gawley, J. Aubꢃ, Principles of
Asymmetric Synthesis, Pergamon, 1996, Chapters 4 and 5.
[13] E. P. Lodge, C. H. Heathcock, J. Am. Chem. Soc. 1987, 109, 3353–
3361. The “non-Anh” label refers to transition structures in which
attack takes place anti to a substituent which neither has the lowest
lying s*C-X orbital (for a-heteroatom-substituted aldehydes) nor is
the sterically bulkiest one (for aldehydes not containing a-hetero-
atoms). See also ref. [12c].
[14] a) J. W. Cornforth, R. H. Cornforth, K.K. Mathew, J. Chem. Soc.
1959, 112–127; for theoretical refinements of the model, see:
b) M. N. Paddon-Row, N. G. Rondan, K. N. Houk, J. Am. Chem.
Soc. 1982, 104, 7162–7166; c) K. N. Houk, M. N. Paddon-Row, N. G.
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R. J. Longarich, Science 1986, 231, 1108–1117.
[15] Cornforthꢅs model has been previously applied to reactions of a-
oxygenated aldehydes with achiral allylboron compounds: a) W. R.
Roush, M.A. Adam, A. E. Walts, D. J. Harris, J. Am. Chem. Soc.
1986, 108, 3422–3434; b) H. Brinkmann, R. W. Hoffmann, Chem.
Ber. 1990, 123, 2395–2401; c) A. N. Thadani, R. A. Batey, Tetrahe-
dron Lett. 2003, 44, 8051–8055; d) The higher stability of Cornforth-
like transition structures in some additions of allylboron reagents to
a-oxygenated aldehydes has also received theoretical support: B. W.
Gung, X. Xue, Tetrahedron: Asymmetry 2001, 12, 2955–2959; e) For
more detailed accounts of the diastereoselective reactions of allyl-
boron compounds, see: W. R. Roush in Comprehensive Organic Syn-
thesis, Vol. 2 (Eds.: B. M. Trost, I. Fleming, E. Winterfeldt), Perga-
mon Press, Oxford, 1993 pp. 1–54, and: W. R. Roush, in Houben-
Weylꢀs Methods of Organic Chemistry, Stereoselective Synthesis, Vol.
3 (Eds: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann),
Thieme, Stuttgart, 1996, pp. 1410–1486, and references therein;
f) for a related situation in the addition of an allenylstannane, see:
J.A. Marshall, X.-J. Wang, J. Org. Chem. 1991, 56, 3211–3213.
[16] When we were performing our investigations with ketone 1, a paper
by Evans and co-workers appeared in which the modified Cornforth
model was applied to provide a good explanation of the sterochemi-
cal outcome of aldol reactions of achiral ketones with a-hetero-
atom-substituted aldehydes: D. A. Evans, S. J. Siska, V. J. Cee,
Angew. Chem. 2003, 115, 1803–1807; Angew. Chem. Int. Ed. 2003,
42, 1761–1765.
[20] We did not deem it necessary to extend the study of 18B to a-amino
aldehydes or to aldehydes having all-carbon a-substituents, as it has
been established that aldol reactions of boron enolates of Evans ox-
azolidinones with such aldehydes are stereocontrolled in almost all
cases by the chiral enolate. See refs. [1 and 2] and also: a) K. Haya-
shi, Y. Hamada, T. Shioiri, Tetrahedron Lett. 1991, 32, 7287–7290;
b) T. Owa, H. Haupt, M. Otsuka, S. Kobayashi, N. Tomioka, A. Itai,
M. Ohno, T. Shiraki, M. Uesugi, Y. Sugiura, K. Maeda, Tetrahedron
1992, 48, 1193–1208; c) T. Shioiri, K. Hayashi, Y. Hamada, Tetrahe-
dron 1993, 49, 1913–1924; d) D. L. Boger, S. L. Colletti, T. Honda,
R. F. Menezes, J. Am. Chem. Soc. 1994, 116, 5607–5618; e) G. R.
Pettit, D. D. Burkett, J. Barkóczy, G. L. Breneman, W. E. Pettit, Syn-
thesis 1996, 719–725; f) M. J. Rishel, S. M. Hecht, Org. Lett. 2001, 3,
2867–2869; g) A. N. Hulme, C. H. Montgomery, Tetrahedron Lett.
2003, 44, 7649–7653; h) E. M. Rosser, S. Morton, K. S. Ashton, P.
Cohen, A. N. Hulme, Org. Biomol. Chem. 2004, 2, 142–149.
[21] Aldol reactions of boron enolates of Evans oxazolidinones with a-
oxygenated aldehydes also are often stereocontrolled by the chiral
enolate. However, at least one case is known where the strong
Felkin stereofacial bias of the aldehyde overcame that of a chiral N-
acyloxazolidinone and forced the formation of an anti aldol from
the (Z)-boron enolate: D. A. Evans, S. W. Kaldor, T. K. Jones, J.
Clardy, T. J. Stout, J. Am. Chem. Soc. 1990, 112, 7001–7031.
[22] J. Murga, E. Falomir, M. Carda, J.A. Marco, Tetrahedron 2001, 57,
6239–6247, and references therein.
[23] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseris, M.A.
Robb, J. R. Cheeseman, V. G. Zakrezewski, J.A. Montgomery, R. E.
Stratmann, J. C. Burant, S. Dapprich, J. M. Millam, A. D. Daniels,
K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi,
R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, S. Clifford, J. Och-
terski, G. A. Peterson, P. Y. Ayala, Q. Cui, K. Morokuma, D. K.
Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. Cioslow-
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Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A.
Al-Laham, C. Y. Peng, A. Nanayakkara, C. Gonzµlez, M. Challa-
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Chem. Phys. 1993, 98, 5648–5652; d) P. J. Stephens, F. J. Devlin,
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[25] W. J. Hehre, L. Radom, P. von R. Schleyer, J. A. Pople, Ab Initio
Molecular Orbital Theory, Wiley, New York, 1986.
[26] The angles f1 and f2 are not defined here in the same manner as in
reference [7h].
[27] For most transition structures described here, the calculated angle of
attack of the nucleophile to the carbonyl group lies in the range 97–
1008. Notable exceptions were found in some transition states with
fluorinated aldehydes, where the calculated angles were markedly
smaller (< 958).
[17] Stereoselective aldol reactions with a-fluoro aldehydes (excluding
a,a-difluoro aldehydes) are almost unknown. We have found only
two reports in the bibliography, both of them referring to chiral a-
fluoro-a-methylaldehydes. One is the reaction of such aldehydes
with achiral enolsilanes under Lewis acid catalysis: T. Yamazaki, T.
Chem. Eur. J. 2008, 14, 9240 – 9254
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www.chemeurj.org
9253

J. A. Marco, M. Carda et al.
[28] The solvent may impart some additional stability to synperiplanar
conformations (f2 =0) of a-oxygenated aldehydes, see: B. Lecea, A.
Arrieta, F. P. Cossío, J. Org. Chem. 1997, 62, 6485–6492, and refer-
ences therein.
1. However, the results were essentially the same as with 22 and
therefore the calculations were not continued with the other alde-
hydes.
[30] a) M. J. S. Dewar, J. Kelemen, J. Chem. Phys. 1968, 49, 499–508;
b) K. Kushida, A. Watanabe, Proton and Fluorine Magnetic Reso-
nance Spectral Data, 1988, Japan Halon Co. Ltd., Tokyo, 1988.
[29] After these results were obtained,
the calculations were repeated
for a-alkoxy aldehydes (R)- and
(S)-23b and a model ketone eno-
Received: May 20, 2008
late i, closer to the actual reagent
Published online: August 29, 2008
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Chem. Eur. J. 2008, 14, 9240 – 9254