Double diastereoselection in anti aldol reactions mediated by dicyclohexylchloroborane between an l-erythrulose derivative and chiral aldehydes

Article abstract of DOI:10.1039/c2ob25803j

Anti aldol reactions of an l-erythrulose derivative with several α-chiral aldehydes mediated by dicyclohexylboron chloride are examined. Good yields and stereoselectivities are observed. The results are best explained when the reactions are assumed to occ

Full text of DOI:10.1039/c2ob25803j

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PAPER
Double diastereoselection in anti aldol reactions mediated by
dicyclohexylchloroborane between an L-erythrulose derivative and chiral
aldehydes†‡
Santiago Díaz-Oltra,a Purificación Ruiz,a Eva Falomir,a Juan Murga,a Miguel Carda*a and J. Alberto Marco*b
Received 26th April 2012, Accepted 21st June 2012
DOI: 10.1039/c2ob25803j
Anti aldol reactions of an L-erythrulose derivative with several α-chiral aldehydes mediated by
dicyclohexylboron chloride are examined. Good yields and stereoselectivities are observed. The results
are best explained when the reactions are assumed to occur via boat-like transition states with
minimization of 1,3-allylic strain and avoidance of syn pentane interactions.
Introduction
The aldol reaction is a powerful and general method for the
stereocontrolled construction of carbon–carbon bonds.1 It may
be performed through the use of various types of metal enolates
or also in an organocatalytic, metal-free manner.2,3 From the
many enolate types investigated thus far, boron enolates have
proven to be particularly versatile because of their good reactiv-
ity and high stereoselectivity.4 In the last decade, we have been
investigating the outcome of aldol reactions of boron enolates of
protected L-erythrulose derivatives such as 1, generated with
Chx2BCl (dicyclohexylboron chloride).5 With these ketones, the
latter reagent gives rise to the highly stereoselective formation of
syn aldols 2 via the Z enolate6 1B in reactions with achiral alde-
hydes RCHO (Scheme 1).7
Subsequent to these initial investigations, we wondered
Scheme 1 Aldol additions of a Z boron enolate of chiral ketone 1 to
achiral aldehydes via a chair-like transition state (TS) (Chx = cyclohexyl;
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 aldehydes having a stereocentre in the
α-carbon atom (double diastereoselection).1a–e Therefore, we
investigated the aldol reactions of 1B with a range of α-chiral
aldehydes in both antipodal forms. In the initial study, the
TBS = tert-butyldimethylsilyl).
aldehydes had only carbon substituents (α-methyl aldehydes 3)
or else one oxygen (α-alkoxy aldehydes 4) bound to the
α-carbon atom (in all these aldehydes, P is a protecting group,
and R is a variable fragment).8
The study was subsequently extended to the case of α-amino
and α-fluoro aldehydes.9 The results of all these aldol reactions
are summarized in Scheme 2. The aldols depicted are the only
diastereomers detected in the aldol reaction mixture by means of
NMR (d.r. > 95 : 5). In all successful cases, a practically exclu-
sive attack of the enolate Re face on the aldehyde carbonyl
Re face was observed.10 We explained the stereochemical course
of these aldol reactions by assuming the generally accepted
model of cyclic, six-membered transition states of the Zimmer-
man–Traxler type (Scheme 1).11,12 In the case of α-chiral alde-
hydes, where issues of double diastereoselection are at work,1a–c
we completed the mechanistic paradigm with the inclusion of
the Felkin–Anh model and its subsequent refinements.13,14 As
aDepart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Castellón,
E-12071 Castellón, Spain.
E-mail: mcarda@qio.uji.es; Fax: +34-964-728214;
Tel: +34 -964-728242
bDepart. de Q. Orgánica, Univ. de Valencia, E-46100 Burjassot,
Valencia, Spain. E-mail: alberto.marco@uv.es; Fax: +34-96-3544328;
Tel: +34 -96-3544337
†Dedicated to the memory of Prof. Dr emerit. E. Vogel, University of
Cologne, Germany, deceased March 31, 2011.
‡Electronic supplementary information (ESI) available: Additional
experimental procedures and tabulated spectral data of all correlation
intermediates. Graphical NMR spectra of all new compounds (three PDF
files). CCDC 285438, 762867, 762868, 764882, 764883, 766571. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob25803j
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Scheme 3 Anti aldol additions of boron enolates of chiral ketones 13
and 15 to achiral aldehydes (Bz = benzoyl).
Scheme 2 Aldol additions of enolate 1B to aldehydes (R)/(S)-3,
(R)/(S)-4, (R)/(S)-8 and (R)/(S)-9 (Bn = benzyl).
Fig. 1 α-Chiral aldehydes used in this study (TPS
butyldiphenylsilyl).
= tert-
matters evolved, however, we found that strict adherence to this
model did not allow for a satisfactory account of all observed
results, most particularly with aldehydes having highly electro-
negative atoms (F,O) bound to the α-carbon. In such cases, it
was found that additional inclusion of features of the Cornforth
model15–17 provided a much better explanation.8,9 This con-
clusion was further supported by means of density functional
calculations.9
15, which is easier to prepare and yields anti aldols 16 with
similar degrees of stereoselectivity.20
The purpose of the present investigation is the study of the
double diastereoselection in anti aldol reactions of ketone 15
with α-chiral aldehydes.
Results and discussion
Shortly after beginning our research on boron aldol reactions
with ketone 1, and relying on findings of Paterson and co-
workers,6a we wondered whether the replacement of one or more of
the electron-donating O-protecting groups of 1 by electron-with-
drawing counterparts would change the stereochemical course of
the aldol reaction from syn to anti. Indeed, and in line with Pater-
son’s idea, chiral ketone 13, which bears two benzoyl protecting
groups, was found to stereoselectively give anti aldols 14 with
achiral aldehydes (Scheme 3),18 most likely through the corres-
ponding E boron enolate.19 Later quantum-mechanical studies of
our group provided the theoretical basis for this mechanistic
assumption.5d In a more recent development, the dibenzoylated
ketone 13 has been replaced by its monobenzoylated counterpart
The α-chiral aldehydes (R)/(S)-3, (R)/(S)-4 and (R)/(S)-9, used in
the present study (Fig. 1), are also those of our previous publi-
cations8,9 and have been prepared by means of the same pro-
cedures (α-fluoro aldehydes 8 have not been included in the
present study). The results of the aldol reactions are presented in
Scheme 4.
Ketone 15 is assumed to be first converted into E enolate 15B.
The latter then reacts with the aldehydes to yield the anti aldols
17–20, obtained as essentially single diastereoisomers in the
majority of cases. Exceptions to this behaviour were aldehydes
(R)-3a,b and (S)-4a,b, which gave complex mixtures,
accompanied
by
ill-defined
decomposition
products.
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If we wish to extend this mechanistic view to the aldol reac-
tions of ketone 15 with α-chiral aldehydes (Scheme 4), it is also
necessary to add to the general model all the other factors which
were taken into account in our previous papers8,9 on aldol reac-
tions of ketone 1, i.e. the Felkin–Anh and Cornforth
models.13–17
The case of α-methyl aldehydes (R)- and (S)-3a,b will be
studied first. According to Scheme 4, aldehydes (S)-3a,b reacted
with enolate 15B to yield anti aldols 17a,b with good yields and
excellent diastereoselectivity. In contrast, the same reaction with
aldehydes (R)-3a,b only gave aldol mixtures, accompanied by
decomposition products.
If the stereochemical model of Scheme 5 is applied to the
reactions of 15B with aldehydes (R)- and (S)-3a,b, we obtain the
four boat-like transition structures (TS-1 to TS-4) depicted in
Scheme 6. The formation of aldols 17a,b in the case of (S)-3a,b
can be reasonably explained with transition structure TS-1. It
can be seen that the spatial arrangement of the three groups at
the α-carbon of the aldehyde (H, Me, CH2OP) closely adheres to
the Felkin–Anh model (anti orientation of the bulky CH2OP
group and the attacking nucleophile). Since no unfavourable
steric features are present in TS-1, it is not surprising that these
reactions take place with good results, both in terms of yield and
stereoselectivity, to yield anti aldols 17a,b. Rotation of the alde-
hyde Cα–CO bond in TS-1 gives rise to the alternative transition
structure TS-2, which would yield the same final product.
However, this TS is markedly higher in energy contents, as it
shows two unfavourable features: (a) a non-Anh arrangement22
of the three groups at the α-carbon of the aldehyde. (b) a syn
pentane interaction23,24 between the Me and OTBS groups. Par-
ticularly the latter effect has been shown to be quantitatively
very important in aldol and allylation reactions, often overriding
the stereoelectronic preference associated with a Felkin–Anh
geometry.8,9,23 In consequence, we may assume than the aldol
reactions of 15B with aldehydes (S)-3a,b take place only through
TS-1.
Scheme 4 Aldol additions of an E enolate of ketone 15 to aldehydes
(R)/(S)-3a,b, (R)/(S)-4a,b and (R)/(S)-9a,b,c. d.r. > 95 : 5 unless other-
wise stated (for the meaning of P and R, see Fig. 1).
The situation is different in the case of aldehydes (R)-3a,b,
which react with 15B to give mixtures of aldols together with
decomposition products (Scheme 4). In Scheme 6, a plausible
explanation for this result is proposed. The reaction may take
place through either TS-3 or TS-4: TS-3 is of the Felkin–Anh
type but also shows an unfavourable syn pentane interaction,
whereas TS-4 is of the non-Anh type. Both reactions therefore
must traverse unfavourable transition structures and become
accordingly slower, with the expected loss of stereoselectivity
and increased probability of decomposition pathways.
A similar situation is found in the case of α-oxygenated alde-
hydes (R)- and (S)-4a,b, even though the R enantiomers are
those reacting efficiently here, whereas the S enantiomers give
complex aldol mixtures and decomposition products (Scheme 4).
As above, four boat-like transition structures (TS-5 to TS-8),
depicted in Scheme 7, may be drawn for these reactions. In the
same line of reasoning as above, the successful reactions of alde-
hydes (R)-4a,b are proposed to occur through transition struc-
tures like TS-6, which is of the Felkin–Anh type and does not
display unfavourable steric features. In contrast, TS-5 shows an
unfavourable syn pentane effect. The same effects are also seen
in transition structures TS-7 and TS-8, which should be relevant
for the reactions of aldehydes (S)-4a,b. It is thus not surprising
Scheme 5 Proposed TS for the aldol addition step of the E boron
enolate of ketone 13 and achiral aldehydes RCHO.
Furthermore, aldol 19a was obtained as an 88 : 12 mixture (for
the methods used to establish the stereostructures of these aldols,
see the ESI†).
For a mechanistic explanation of the stereochemical course of
these reactions, we cannot directly adapt the chair-like Zimmer-
man–Traxler model used in our previous publications that dis-
cussed the formation of syn aldols via Z enolates.8,9 Indeed,
theoretical calculations of our group have led to the proposal that
anti aldol reactions of ketone 13 with achiral aldehydes mediated
by Chx2BCl take place through a transition structure (TS) of the
“boat B” type (Scheme 5).5d,12g One salient feature of this TS is
the arrangement of the groups around the stereocentre in the
enolate moiety in such a way as to minimize the 1,3-allylic
strain21 within the enolate E olefinic moiety. As a consequence,
the benzoate points inside the cyclic TS but, due to the boat
shape of the latter, this does not lead to a steric crowding with
the cyclohexyl ligands at the boron atom (compare with the
chair-like TS in Scheme 1).
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Scheme 6 Proposed TSs for the aldol addition step of boron enolate 15B to α-methyl aldehydes (R)- and (S)-3a,b.
Scheme 7 Proposed TSs for the aldol addition step of boron enolate 15B to α-oxygenated aldehydes (R)- and (S)-4a,b.
that the latter reactions yield complex aldol mixtures and
decomposition products. It is also worth mentioning that, while
TS-8 belongs to the Felkin–Anh type13 (see above), TS-5 and
TS-7 belong to the Cornforth type (anti orientation of the elec-
tronegative OP group and the aldehyde CvO bond).15–17 None-
theless, the energetically important contribution of the syn
pentane interaction is able to override the aforementioned
effects.
The aldol reactions of the α-amino aldehydes 9a,b,c showed a
difference with the previous ones. In this case, both (R)- and
(S)-9a,b,c reacted with enolate 15B to yield aldol adducts (19
and 20, respectively) with good yields and, in most cases, high
diastereoselectivity. An application of the previous models to the
reactions of these aldehydes would yield the transition structures
TS-9 to TS-12, all of them depicted in Scheme 8. The aldol
reactions of aldehydes (R)-9a,b,c to yield 19a,b,c can be thought
to occur via TS-10, which is of the Felkin–Anh type and does
not display unfavourable steric features. The alternative, Corn-
forth-type TS-9 shows a syn pentane effect and can thus be ruled
out.
For the aldol reactions of aldehydes (S)-9a,b,c, TS-11 (Corn-
forth) and TS-12 (Felkin–Anh) might be considered suitable
TSs. However, both show a syn pentane interaction. Accordingly,
and as observed for aldehydes (S)-4a,b, only complex aldol mix-
tures and decomposition products should be expected. In contrast
with this prediction, aldols 20a,b,c are diastereoselectively
formed with good yields.
A plausible explanation for this result is the assumption of the
alternative TS-13, which is devoid of the energetically unfavour-
able syn pentane effects, even if it shows neither the
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Scheme 8 Proposed TSs for the aldol addition step of boron enolate 15B to α-amino aldehydes (R)- and (S)-9a,b,c.
stereoelectronic benefit of the Felkin–Anh geometry nor the
favourable Cornforth-like anti arrangement of the polar CvO
and C–N bonds. Nevertheless, it has been commented above that
syn pentane effects have been shown to be quantitatively very
important in aldol and allylation reactions, often overriding the
stereoelectronic preference associated to a Felkin–Anh geome-
try.8,9,23 Moreover, the lower electronegativity of nitrogen as
compared with oxygen makes the energetic advantage of the
Cornforth geometry in α-amino aldehydes less important than in
α-oxygenated aldehydes. Indeed, as previously observed in the
aldol additions of the Z enolate 1B, Cornforth-like TSs were
found relevant mainly for aldehydes bearing highly electronega-
tive atoms (O,F) in the α carbon but even in that case, the mini-
mization of the dipolar repulsion was not able to override a syn
pentane interaction.8,9
25 °C. Reactions which required an inert atmosphere (all except
those involving water in the reaction medium) were carried out
under dry N2 with flame-dried glassware. Commercial reagents
were used as received. THF and Et2O were freshly distilled from
sodium-benzophenone ketyl. Dichloromethane was freshly dis-
tilled from CaH2. Toluene was freshly distilled from sodium
wire. Tertiary amines were freshly distilled from KOH. Unless
detailed otherwise, “work-up” means pouring the reaction
mixture into brine, followed by extraction with the solvent indi-
cated in parenthesis. If the reaction medium was acidic, an
additional washing of the organic layer with 5% aq NaHCO3
was performed. If the reaction medium was basic, an additional
washing with aq NH4Cl was performed. Where solutions were
filtered through a Celite pad, the pad was additionally washed
with the same solvent used, and the washings combined with the
main organic layer. The latter was dried over anhydrous Na2SO4
and the solvent was eliminated under reduced pressure. Column
chromatography of the residue on
(60–200 μm) was performed with elution with the indicated
a silica gel column
Experimental
General
solvent mixture.
NMR spectra were recorded at 500 MHz (1H NMR) and
125 MHz (13C NMR) in CDCl3 solution at 25 °C, if not other-
General experimental procedure for aldol additions of ketone
15 mediated by dicyclohexylboron chloride. Chx2BCl (neat,
395 μL, ca. 1.8 mmol) was added under Ar via syringe to an
ice-cooled solution of Et3N (280 μL, 2 mmol) in anhydrous
Et2O (5 mL). Erythrulose derivative 15 (453 mg, 1 mmol) was
dissolved in anhydrous Et2O (5 mL) and added dropwise via
syringe to the reagent solution. The reaction mixture was then
stirred for 30 min and then cooled to −78 °C. After dropwise
addition of a solution of the appropriate aldehyde8,9 (4 mmol) in
wise indicated, with the solvent signals as internal reference. 13
C
NMR signal multiplicities were determined with the DEPT pulse
sequence. Mass spectra were run in the EI (70 eV), the FAB
(m-nitrobenzyl alcohol matrix) or the electrospray (ESMS) mode. IR
data, which were measured as films on NaCl plates (oils) or as
KBr pellets (solids), are given only when relevant functions
(CvO, OH) are present. Optical rotations were measured at
This journal is © The Royal Society of Chemistry 2012
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anhydrous ether (6 mL), the reaction mixture was stirred at
−78 °C for 5 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). Removal of vola-
tiles under reduced pressure and column chromatography of the
residue on silica gel (hexanes–EtOAc mixtures) afforded the
aldol addition product. Yields and diastereoisomeric ratios are
indicated in Scheme 4.
2× MeSi), 0.07 (3H, s; MeSi); 13C NMR (125 MHz) δ 205.8,
165.9, 134.2, 133.2, 129.6, 19.2, 18.3, 18.0 (quat C), 135.7 (×4),
129.9 (×2), 129.7, 129.5 (×2), 128.4 (×2), 127.6 (×2), 127.5
(×2), 79.0, 78.0, 76.6, 69.7 (CH), 62.2 (CH2), 26.9 (×3,
Me3CSi), 25.8 (×6, 2 Me3CSi), 16.9 (C7), −4.4 (MeSi), −5.0
(MeSi), −5.4 (×2, 2 MeSi); HR EIMS m/z (% rel. int.) 707.3249
(M+ − tBu, 1), 255 (90), 105 (100). Calcd for C42H64O7Si3 −
tBu, 707.3255.
(2S,4R,5R,6R)-2-(Benzoyloxy)-6-(benzyloxy)-1,4-bis-(tert-butyl-
dimethylsilyloxy)-5-hydroxyheptan-3-one (18b). Oil: [α]D −11.2
(c 1.15; CHCl3); IR νmax (cm−1): 3470 (br, OH), 1727 (br,
(2S,4R,5R,6S)-2-(Benzoyloxy)-1,4-bis-(tert-butyldimethylsilyl-
oxy)-7-(tert-butyldiphenylsilyloxy)-5-hydroxy-6-methylheptan-
3-one (17a). Oil: [α]D +2.2 (c 1.1; CHCl3); IR νmax 3490 (br,
1
CvO); H NMR (500 MHz) δ 8.10 (2H, br d, J ∼ 7.5 Hz; aro-
1
OH), 1728 (br, CvO) (cm−1); H NMR δ 8.10 (2H, br d, J ∼
matic), 7.60 (1H, br t, J ∼ 7.5 Hz; aromatic), 7.48 (2H, br t, J ∼
7.5 Hz; aromatic), 7.35–7.25 (5H, br m; aromatic), 5.65 (1H, dd,
J = 5.5, 3 Hz; H-2), 4.75 (1H, d, J = 4.4 Hz; H-4), 4.46 (1H, d,
J = 11.7 Hz; benzyl), 4.32 (1H, d, J = 11.7 Hz; benzyl), 4.04
(1H, dd, J = 11.3, 5.5 Hz; H-1), 3.96 (1H, dd, J = 11.3, 3 Hz;
H-1′), 3.91 (1H, br td, J ∼ 8.5, 4.4 Hz; H-5), 3.56 (1H, br dq,
J = 8.5, 6.5 Hz; H-6), 2.60 (1H, d, J = 9 Hz; OH), 1.24 (3H, d,
J = 6.5 Hz; H-7), 0.98 (9H, s; Me3CSi), 0.85 (9H, s; Me3CSi),
0.18 (3H, s; MeSi), 0.12 (3H, s; MeSi), 0.03 (3H, s; MeSi), 0.00
(3H, s; MeSi); 13C NMR (125 MHz) δ 203.2, 165.8, 138.2,
129.5, 19.2, 18.3, 18.2 (quat C), 133.3, 129.8 (×2), 128.5 (×2),
128.2 (×2), 128.0 (×2), 127.5, 78.8, 78.4, 76.2, 70.6 (CH), 74.0,
62.3 (CH2), 25.9 (×3, Me3CSi), 25.7 (×3, Me3CSi), 15.9 (C7),
−4.4 (MeSi), −5.1 (MeSi), −5.4 (×2, 2 MeSi); HR FABMS m/z
617.3353 (M + H+). Calcd for C33H53O7Si2, 617.3329.
7.5 Hz; aromatic), 7.70–7.65 (4H, m; aromatic), 7.57 (1H, br t,
J ∼ 7.5 Hz; aromatic), 7.45–7.35 (8H, br m; aromatic), 5.81 (1H,
dd, J = 6.3, 3.3 Hz; H-2), 4.47 (1H, d, J = 8 Hz; H-4), 4.25–4.20
(2H, m; H-1/H-5), 4.12 (1H, dd, J = 11.2, 6.3 Hz; H-1′), 3.76
(1H, dd, J = 10, 4.3 Hz; H-7), 3.70 (1H, dd, J = 10, 5.5 Hz;
H-7′), 3.30 (1H, br s; OH), 2.05 (1H, br m; H-6), 1.06 (9H, s;
Me3CSi), 0.96 (3H, d, J = 7 Hz; Me-C6), 0.92 (9H, s; Me3CSi),
0.88 (9H, s; Me3CSi), 0.10 (3H, s; MeSi), 0.09 (3H, s; MeSi),
0.08 (3H, s; MeSi), 0.07 (3H, s; MeSi); 13C NMR δ 206.5,
166.1, 133.3, 133.2, 129.4, 19.2, 18.3, 18.1 (quat C), 135.6 (×2),
135.5 (×2), 133.2 (×2), 129.9 (×2), 129.7 (×2), 128.4 (×2),
127.7 (×3), 78.2, 77.6, 75.0, 35.7 (CH), 68.3, 62.4 (CH2), 26.9
(×3, Me3CSi), 25.8 (×6, 2 Me3CSi), 9.6 (Me-C6), −4.4 (MeSi),
−5.0 (MeSi), −5.4 (×2, 2 MeSi); HR EIMS m/z (% rel. int.)
721.3425 (M+ − tBu, 2), 269 (22), 105 (100), calcd for
C43H66O7Si3 − tBu, 721.3412.
(2S,4R,5R,6R)-2-(Benzoyloxy)-1,4-bis-(tert-butyldimethylsilyloxy)-
6-(N,N-dibenzylamino)-5-hydroxyheptan-3-one (19a)
(2S,4R,5R,6S)-2-(Benzoyloxy)-7-(benzyloxy)-1,4-bis-(tert-butyl-
dimethylsilyloxy)-5-hydroxy-6-methylheptan-3-one (17b). Oil:
[α]D −2.2 (c 1.4; CHCl3); IR νmax (cm−1): 3490 (br, OH), 1726
Obtained as an 88 : 12 mixture with a diastereoisomer. Chroma-
tographic separation gave the major diastereoisomer 20a: oil:
[α]D +11.5 (c 1.18; CHCl3); IR νmax (cm−1): 3460 (br, OH),
1
(br, CvO); H NMR (500 MHz) δ 8.10 (2H, br d, J ∼ 7.5 Hz;
aromatic), 7.57 (1H, br t, J ∼ 7.5 Hz; aromatic), 7.41 (2H, br t,
J ∼ 7.5 Hz; aromatic), 7.40–7.25 (5H, br m; aromatic), 5.79 (1H,
br t, J ∼ 4.3 Hz; H-2), 4.50–4.45 (3H, m; H-4/benzyl),
4.15–4.10 (3H, m; H-1/H-1′/H-5), 3.55–3.50 (2H, m; H-7/H-7′),
3.20 (1H, d, J = 5 Hz; OH), 2.08 (1H, br m; H-6), 0.97 (3H, d,
J = 7 Hz; Me-C6), 0.88 (9H, s; Me3CSi), 0.86 (9H, s; Me3CSi),
0.08 (6H, s; 2 MeSi), 0.06 (3H, s; MeSi), 0.05 (3H, s; MeSi);
13C NMR (125 MHz) δ 206.6, 166.0, 138.3, 129.5, 18.3, 18.1
(quat C), 133.3 (×2), 130.0 (×2), 128.4 (×3), 127.6 (×3), 78.6,
78.1, 74.6, 34.3 (CH), 74.3, 73.2, 62.7 (CH2), 25.8 (×6, 2
Me3CSi), 10.5 (Me-C6), −4.4 (MeSi), −5.0 (MeSi), −5.4 (×2, 2
MeSi); HR FABMS m/z 631.3476 (M + H+). Calcd for
C34H55O7Si2, 631.3486.
1
1726 (br, CvO); H NMR (500 MHz) δ 8.19 (2H, br d, J ∼ 8
Hz; aromatic), 7.66 (1H, br t, J ∼ 7.5 Hz; aromatic), 7.54 (2H,
br t, J ∼ 7.5 Hz; aromatic), 7.35–7.15 (10H, br m; aromatic),
5.77 (1H, br t, J ∼ 4 Hz; H-2), 4.44 (1H, m; H-5), 4.30 (1H, d,
J = 7.3 Hz; H-4), 4.18 (1H, dd, J = 11, 4.8 Hz; H-1), 4.11 (1H,
dd, J = 11, 3.5 Hz; H-1′), 3.86 (2H, d, J = 14.2 Hz, N-benzyl
CH2), 3.68 (2H, d, J = 14.2 Hz, N-benzyl CH2), 3.30 (1H, br s;
OH), 3.05 (1H, qd, J = 6.8, 2.5 Hz; H-6), 1.13 (3H, d, J = 6.8 Hz;
H-7), 0.90 (9H, s; Me3CSi), 0.73 (9H, s; Me3CSi), 0.12 (3H, s;
MeSi), 0.09 (3H, s; MeSi), −0.07 (3H, s; MeSi), −0.13 (3H, s;
MeSi); 13C NMR (125 MHz) δ 206.0, 165.8, 140.5 (×2), 129.5,
18.3, 18.0 (quat C), 133.5, 130.0 (×2), 128.5 (×2), 128.4 (×4),
128.1 (×4), 126.5 (×2), 79.9, 78.1, 75.0, 53.2 (CH), 63.3, 54.6
(×2) (CH2), 25.7 (×6, 2 Me3CSi), 8.0 (C7), −4.8 (MeSi), −5.1
(MeSi), −5.5 (×2, 2 MeSi); HR FABMS m/z 706.3971
(M + H+). Calcd for C40H60NO6Si2, 706.3959.
(2S,4R,5R,6R)-2-(Benzoyloxy)-1,4-bis-(tert-butyldimethylsilyloxy)-
6-(tert-butyldiphenylsilyloxy)-5-hydroxyheptan-3-one (18a). Oil:
[α]D −2 (c 2.2; CHCl3); IR νmax (cm−1): 3470 (br, OH), 1729
1
(br, CvO); H NMR (500 MHz) δ 8.11 (2H, br d, J ∼ 7.5 Hz;
aromatic), 7.72 (2H, br t, J ∼ 7 Hz; aromatic), 7.60 (1H, br t,
J ∼ 7.5 Hz; aromatic), 7.50–7.25 (10H, br m; aromatic), 5.85
(1H, br t, J ∼ 4.5 Hz; H-2), 4.70 (1H, d, J = 7 Hz; H-4),
4.20–4.15 (2H, m; H-1/H-1′), 4.10 (1H, br quint, J ∼ 5.5 Hz;
H-6), 3.90 (1H, br t, J ∼ 5.5 Hz; H-5), 2.90 (1H, br s; OH), 1.08
(9H, s; Me3CSi), 1.05 (3H, d, J = 6.5 Hz; H-7), 0.92 (9H, s;
Me3CSi), 0.86 (9H, s; Me3CSi), 0.13 (3H, s; MeSi), 0.10 (6H, s;
(2S,4R,5R,6R)-2-(Benzoyloxy)-1,4-bis-(tert-butyldimethylsilyl-
oxy)-6-(N,N-dibenzylamino)-5-hydroxy-7-phenylheptan-3-one
(19b). Oil: [α]D +7.4 (c 1.65; CHCl3); IR νmax (cm−1): 3430 (br,
1
OH), 1727 (br, CvO); H NMR (500 MHz) δ 8.20 (2H, br d,
J ∼ 7.5 Hz; aromatic), 7.64 (1H, br d, J ∼ 7.5 Hz; aromatic),
7.53 (2H, br t, J = 7.5 Hz; aromatic), 7.30–7.00 (15H, br m; aro-
matic), 5.84 (1H, br t, J ∼ 4 Hz; H-2), 4.70 (1H, d, J = 8 Hz;
6942 | Org. Biomol. Chem., 2012, 10, 6937–6944
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H-4), 4.34 (1H, br d, J = 8 Hz; H-5), 4.26 (1H, dd, J = 10.8, 4
Hz; H-1), 4.14 (1H, dd, J = 10.8, 4 Hz; H-1′), 3.95 (2H, d, J ∼
14.7 Hz, N-benzyl CH2), 3.60 (2H, br d, J ∼ 14.7 Hz, N-benzyl
CH2), 3.50 (1H, br s; OH), 3.22 (1H, br dd, J ∼ 10.2, 4.1 Hz;
H-6), 3.10 (1H, dd, J = 14.3, 10.2 Hz; H-7), 2.94 (1H, dd, J =
14.3, 4.1 Hz; H-7′), 0.95 (9H, s; Me3CSi), 0.71 (9H, s; Me3CSi),
0.18 (3H, s; MeSi), 0.14 (3H, s; MeSi), −0.09 (3H, s; MeSi),
−0.14 (3H, s; MeSi); 13C NMR (125 MHz) δ 206.6, 165.6,
140.4, 140.2 (×2), 129.4, 18.4, 18.1 (quat C), 133.6, 130.1,
130.0, 128.6 (×2), 128.3 (×4), 128.0 (×5), 127.9 (×3), 126.4
(×2), 125.8, 80.1, 77.6, 71.5, 59.2 (CH), 63.5, 54.3 (×2), 31.2
(CH2), 25.9 (×3, Me3CSi), 25.8 (×3, Me3CSi), −4.7 (MeSi),
−5.0 (MeSi), −5.4 (MeSi) −5.5 (MeSi); HR EIMS m/z (% rel.
int.) 724.3553 (M+ − tBu, 1), 300 (76), 91 (100). Calcd for
C46H63NO6Si2 − tBu, 724.3616.
J ∼ 7.5 Hz; aromatic), 7.62 (1H, br d, J ∼ 7.5 Hz; aromatic),
7.48 (2H, br t, J = 7.5 Hz; aromatic), 7.40 (4H, m; aromatic),
7.30–7.10 (11H, br m; aromatic), 5.95 (1H, br t, J ∼ 4 Hz; H-2),
4.74 (1H, d, J = 2 Hz; H-4), 4.50 (1H, br s; OH), 4.20 (1H, dd,
J = 11.3, 5.3 Hz; H-1), 4.15 (1H, dd, J = 11.3, 3 Hz; H-1′), 4.00
(1H, dd, J = 9.5, 2 Hz; H-5), 3.75 (2H, br d, J ∼ 13 Hz,
N-benzyl CH2), 3.41 (1H, br td, J ∼ 9.5, 3 Hz; H-6), 3.33 (2H,
br d, J ∼ 13 Hz, N-benzyl CH2), 2.86 (1H, dd, J = 14, 3 Hz;
H-7), 2.78 (1H, dd, J = 14, 10 Hz; H-7′), 0.92 (9H, s; Me3CSi),
0.88 (9H, s; Me3CSi), 0.12 (3H, s; MeSi), 0.09 (3H, s; MeSi),
0.05 (3H, s; MeSi), −0.10 (3H, s; MeSi); 13C NMR (125 MHz)
δ 205.3, 165.4, 140.2, 139.0 (×2), 129.6, 18.3, 18.2 (quat C),
133.1, 130.0 (×2), 129.7 (×2), 129.2 (×4), 128.4 (×2), 128.3
(×2), 128.2 (×4), 127.1 (×2), 126.3, 79.9, 78.0, 72.0, 61.0 (CH),
62.6, 54.1 (×2), 33.9 (CH2), 25.9 (×3, Me3CSi), 25.7 (×3,
Me3CSi), −4.8 (MeSi), −5.1 (MeSi), −5.5 (×2, 2 MeSi); HR
EIMS m/z (% rel. int.) 724.3692 (M+ − tBu, 9), 300 (32), 91
(100). Calcd for C46H63NO6Si2−tBu, 724.3616.
(2S,4R,5R,6R)-2-(Benzoyloxy)-1,4-bis-(tert-butyldimethylsilyloxy)-
7-(tert-butyldiphenylsilyloxy)-6-(N,N-dibenzylamino)-5-hydroxyhep-
tan-3-one (19c). Oil: [α]D −6 (c 1.3; CHCl3); IR νmax (cm−1):
1
(2S,4R,5R,6S)-2-(Benzoyloxy)-1,4-bis-(tert-butyldimethylsilyloxy)-
7-(tert-butyldiphenylsilyloxy)-6-(N,N-dibenzylamino)-5-hydroxy-
heptan-3-one (20c). Oil: [α]D −2 (c 1.1; CHCl3); IR νmax
(cm−1): 3460 (br, OH), 1726 (br, CvO); 1H NMR (500 MHz) δ
8.08 (2H, br d, J ∼ 8 Hz; aromatic), 7.72 (4H, br d, J ∼ 7 Hz;
aromatic), 7.58 (1H, br t, J = 7.5 Hz; aromatic), 7.50–7.40 (8H,
br m; aromatic), 7.20–7.10 (10H, br m; aromatic), 5.76 (1H, br t,
J ∼ 4 Hz; H-2), 4.47 (1H, br d, J ∼ 2.5 Hz; H-4), 4.40 (1H, br s;
OH), 4.10–4.00 (2H, m; H-1/H-1′), 3.91 (1H, dd, J = 11.2, 3.3
Hz; H-7), 3.83 (1H, m; H-7′), 3.82 (2H, d, J = 13.2 Hz, N-
benzyl CH2), 3.70 (1H, dd, J = 8.8, 2.7 Hz; H-5), 3.63 (2H, d, J
= 13.2 Hz, N-benzyl CH2), 3.16 (1H, br td, J = 8.8, 3.3 Hz;
H-6), 1.16 (9H, s; Me3CSi), 0.80 (9H, s; Me3CSi), 0.75 (9H, s;
Me3CSi), 0.00 (3H, s; MeSi), −0.04 (3H, s; MeSi), −0.06 (3H,
s; MeSi), −0.27 (3H, s; MeSi); 13C NMR (125 MHz) δ 205.0,
165.2, 139.3 (×2), 133.1 (×2), 129.9, 19.2, 18.2, 18.1 (quat C),
136.0 (×2), 135.9 (×2), 130.0 (×3), 129.8, 129.2 (×4), 128.4
(×4), 128.3 (×3), 127.7 (×4), 127.1 (×2), 79.3, 78.5, 68.8, 60.8
(CH), 62.5, 62.3, 54.8 (×2) (CH2), 27.2 (×3, Me3CSi), 25.8 (×3,
Me3CSi), 25.7 (×3, Me3CSi), −4.8 (MeSi), −4.9 (MeSi), −5.4
(×2) (MeSi); HR FABMS m/z 960.5054 (M + H+). Calcd for
C56H78NO7Si3, 960.5087.
3460 (br, OH), 1725 (br, CvO); H NMR (500 MHz) δ 8.22
(2H, br d, J ∼ 8 Hz; aromatic), 7.80 (4H, br d, J ∼ 7.5 Hz; aro-
matic), 7.70–7.20 (19H, br m; aromatic), 5.94 (1H, br t, J ∼ 4.5 Hz;
H-2), 4.58 (2H, m; H-4/H-5), 4.22 (2H, m; H-1/H-1′), 4.17
(1H, dd, J = 11.5, 6 Hz; H-7), 4.08 (1H, dd, J = 11.5, 4 Hz;
H-7′), 3.97, 3.93 (4H, AB system, J = 14.5 Hz, 2 N-benzyl
CH2), 3.60 (1H, br s; OH), 3.25 (1H, m; H-6), 1.18 (9H, s;
Me3CSi), 0.95 (9H, s; Me3CSi), 0.80 (9H, s; Me3CSi), 0.17 (3H,
s; MeSi), 0.14 (3H, s; MeSi), −0.01 (3H, s; MeSi), −0.12 (3H, s;
MeSi); 13C NMR (125 MHz) δ 205.4, 165.7, 140.1 (×2), 132.9,
132.8, 129.7, 19.0, 18.3, 18.1 (quat C), 135.7 (×4), 133.3, 130.0
(×4), 128.4 (×4), 128.1 (×4), 127.6 (×4), 126.5 (×4), 79.8, 78.2,
74.0, 58.9 (CH), 62.8, 62.2, 55.3 (×2) (CH2), 26.9 (×3,
Me3CSi), 25.8 (×6, 2 Me3CSi), −4.8 (MeSi), −4.9 (MeSi), −5.4
(×2) (MeSi); HR ESMS m/z 960.5086 (M + H+). Calcd for
C56H78NO7Si3, 960.5087.
(2S,4R,5R,6S)-2-(Benzoyloxy)-1,4-bis-(tert-butyldimethylsilyl-
oxy)-6-(N,N-dibenzylamino)-5-hydroxyheptan-3-one (20a). Oil:
[α]D + 35.1 (c 2.25; CHCl3); IR νmax (cm−1): 3420 (br, OH),
1
1724 (br, CvO); H NMR (500 MHz) δ 8.11 (2H, br d, J ∼
7.5 Hz; aromatic), 7.58 (1H, br t, J ∼ 7.5 Hz; aromatic), 7.46
(2H, br t, J ∼ 7.5 Hz; aromatic), 7.30–7.20 (10H, br m; aromatic),
5.97 (1H, br t, J ∼ 4 Hz; H-2), 4.60 (1H, br s; H-4), 4.20 (1H, br
s; OH), 4.18 (1H, dd, J = 11.3, 5 Hz; H-1), 4.09 (1H, dd, J =
11.3, 2.7 Hz; H-1′), 4.02 (1H, br d, J = 9.5 Hz; H-5), 3.77 (2H,
d, J = 13.2 Hz, N-benzyl CH2), 3.30 (2H, d, J = 13.2 Hz,
N-benzyl CH2), 2.94 (1H, dq, J = 7.5, 6.8 Hz; H-6), 0.97 (3H, d,
J = 6.8 Hz; H-7), 0.85 (9H, s; Me3CSi), 0.83 (9H, s; Me3CSi),
0.06 (6H, s; 2 MeSi), 0.02 (3H, s; MeSi), −0.28 (3H, s; MeSi);
13C NMR (125 MHz) δ 204.8, 165.5, 138.9 (×2), 129.8, 18.2
(×2) (quat C), 133.2, 129.9 (×2), 129.2 (×4), 128.4 (×4), 128.3
(×2), 127.7 (×2), 79.8, 77.9, 72.5, 55.0 (CH), 62.5, 53.4 (×2)
(CH2), 25.9 (×3, Me3CSi), 25.7 (×3, Me3CSi), 8.5 (C7), −4.6
(×2, 2 MeSi), −5.4 (×2, 2 MeSi); HR FABMS m/z 706.3947
(M + H+). Calcd for C40H60NO6Si2, 706.3959.
Acknowledgements
Financial support has been granted by the Spanish Ministry of
Science and Technology (projects CTQ2005-06688-C02-01 and
CTQ2005-06688-C02-02) and by the BANCAJA-UJI foun-
dation (project PI-1B2011-37).
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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6937–6944 | 6943

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hedron: Asymmetry, 2002, 13, 2317–2327; (d) J. Murga, E. Falomir,
F. González, M. Carda and J. A. Marco, Tetrahedron, 2002, 58, 9697–
9707.
6 (a) Prior to our work,5 only a single precedent of formation of Z boron
enolates of ketones with Chx2BCl had been reported: I. Paterson,
D. J. Wallace and S. M. Velázquez, Tetrahedron Lett., 1994, 35, 9083–
9086; (b) We have produced evidence that this phenomenon may be
general with suitably protected α-oxygenated ketones: J. Murga,
E. Falomir, M. Carda, F. González and J. A. Marco, Org. Lett., 2001, 3,
901–904.
7 Other ketones structurally related to erythrulose behave in the same way:
(a) M. Carda, J. Murga, E. Falomir, F. González and J. A. Marco, Tetra-
hedron: Asymmetry, 2000, 11, 3211–3220; (b) M. Carda, F. González,
R. Sánchez and J. A. Marco, Tetrahedron: Asymmetry, 2002, 13, 1005–
1010; (c) S. Díaz-Oltra, J. Murga, E. Falomir, M. Carda, G. Peris and
J. A. Marco, J. Org. Chem., 2005, 70, 8130–8139.
8 J. A. Marco, M. Carda, S. Díaz-Oltra, J. Murga, E. Falomir and
H. Roeper, J. Org. Chem., 2003, 68, 8577–8582.
9 S. Díaz-Oltra, M. Carda, J. Murga, E. Falomir and J. A. Marco, Chem.–
Eur. J., 2008, 14, 9240–9254.
21 R. W. Hoffmann, Chem. Rev., 1989, 89, 1841–1860.
22 E. P. Lodge and 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 σ*C–X
orbital (for α-heteroatom-substituted aldehydes) nor is the sterically bulk-
iest one (for aldehydes not bearing α-heteroatoms). See also ref. 13c.
23 W. R. Roush, J. Org. Chem., 1991, 56, 4151–4157. The quantitative
importance of the syn pentane interactions is underscored in the cases
under study here by the fact that enolate 1B does not react with pivalalde-
hyde.5 Indeed, if a TS is drawn for the aldol reaction with this aldehyde,
a syn pentane interaction will always be present for all rotamers around
the tBu–CO bond.
10 The same stereochemical course was also observed in aldol reactions of
other ketones related to 17.
11 H. E. Zimmerman and M. D. Traxler, J. Am. Chem. Soc., 1957, 79,
1920–1923.
12 For theoretical studies on the transition states of boron aldol reactions,
see: (a) Y. Li, M. N. Paddon-Row and K. N. Houk, J. Org. Chem., 1990,
24 For two interesting reviews on the conformational aspects of open-chain
carbon backbones, see: (a) R. W. Hoffmann, M. Stahl, U. Schopfer and
G. Frenking, Chem.–Eur. J., 1998, 4, 559–566; (b) R. W. Hoffmann,
Angew. Chem., Int. Ed., 2000, 39, 2054–2070.
6944 | Org. Biomol. Chem., 2012, 10, 6937–6944
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