Aldol Additions of Titanium and Boron Enolates of Achiral and Chiral δ-Lactones to Achiral Model Aldehydes: Simple and Induced Diastereoselectivities

Article abstract of DOI:10.1002/ejoc.201501128

We studied the steric course of aldol additions of CpTiCl₂ (novel) or Bu₂B enolates of the unsubstituted δ-lactone and of the four monomethylated δ-lactones to isobutyraldehyde, crotonaldehyde, and para-bromobenzaldehyde. The titanium enolates reacted syn-selectively with >95:5 ds in most cases. The boron enolates reacted anti-selectively without exception (ds = 98:2 to 92:8). These selectivities paired with a preferred trans-orientation of the α-hydroxyalkyl substituents relative to the lactone's β- or γ-methyl group and with a preferred cis-orientation relative to the lactone's δ-methyl group. Our preparation of γ-methyl-δ-lactone (20) features a tandem glycol cleavage/lactol → lactone conversion with cat. TEMPO/stoichiom. PhI(OAc)₂, which we believe is novel. Aldol additions of CpTiCl₂ and Bu₂B enolates of δ-lactone and its monomethyl derivatives to model aldehydes were studied. The CpTiCl₂ enolates reacted syn-selectively (ds >95:5), the Bu₂B enolates anti-selectively (ds up to 98:2). The α-hydroxyalkyl groups were oriented trans relative to the lactone's β- or γ-methyl group but cis relative to the lactone's δ-methyl group.

Full text of DOI:10.1002/ejoc.201501128

FULL PAPER
DOI: 10.1002/ejoc.201501128
Aldol Additions of Titanium and Boron Enolates of
Achiral and Chiral δ-Lactones to Achiral Model Aldehydes:
Simple and Induced Diastereoselectivities
[a]
[a]
[a]
[b]
Fabian Weber, Fabian Becker, Manfred Keller, Harald Hillebrecht, and
Reinhard Brückner*[
a]
Dedicated to Dr. Klaus Brückner at the occasion of his 90th anniversary
Keywords: Aldol reactions / β-Hydroxy esters / δ-Lactones / Boron enolates / Titanium enolates / Diastereoselectivity /
Configuration determination
We studied the steric course of aldol additions of CpTiCl
novel) or Bu B enolates of the unsubstituted δ-lactone and
2
ferred trans-orientation of the α-hydroxyalkyl substituents
relative to the lactone’s β- or γ-methyl group and with a
preferred cis-orientation relative to the lactone’s δ-methyl
group. Our preparation of γ-methyl-δ-lactone (20) features a
tandem glycol cleavage/lactolǞlactone conversion with cat.
(
2
of the four monomethylated δ-lactones to isobutyraldehyde,
crotonaldehyde, and para-bromobenzaldehyde. The titanium
enolates reacted syn-selectively with Ͼ95:5 ds in most cases.
The boron enolates reacted anti-selectively without excep-
tion (ds = 98:2 to 92:8). These selectivities paired with a pre-
2
TEMPO/stoichiom. PhI(OAc) , which we believe is novel.
Introduction
diastereomers if at least one reactant is chiral. This is be-
cause aldol additions can proceed with or without simple
diastereoselectivity (no matter which reactants) and with or
without induced diastereoselectivity (if at least one reactant
is chiral). High simple diastereoselectivity is rarely encoun-
The aldol addition is an exceedingly powerful tool in or-
ganic synthesis.[ Among its many specialized applications
is the aldol addition of δ-lactones to aldehydes.
duces an α-hydroxyalkyl group at C-α of a δ-lactone.
Thereby, the latter is incorporated into more complex struc-
tures. Analogous aldol additions allow functionalization of
1]
[
2–9]
It intro-
[1]
tered in aldol additions of acyclic lithium enolates. Cyclic
lithium enolates are not generally exempt from this rule. Ac-
cordingly, lithium enolates of the six-membered rings enu-
merated in the first paragraph – and of δ-lactones, which
are the focus of this paper, in particular – aldol-add with
“δ-lactone variants”, such as those that contain two hetero-
[
10–14]
atoms in the cycle rather than one.
Conversely, cyclo-
hexanones represent isocyclic variants of δ-lactones. Their
[2]
little or without simple diastereoselectivity. A few excep-
enolates aldol-add to aldehydes, too.[
15,16]
The enolates of
[15d,15e]
tions are known, though.
For δ-lactone enolates this
“heterocyclic cyclohexanones” such as pyran-4-ones (= 4-
is exemplified in the upper third of Scheme 1. The lithium
[17]
oxacyclohexanones),
piperidin-4-ones (= 4-azacyclohex-
enolate of lactone 1 aldol-adds to an α,β-unsaturated alde-
[
18]
[19]
anones),
,3-dioxane-5-ones (= 3,5-dioxacyclohexanones)[
likewise.
thian-4-ones (= 4-thiacyclohexanones),
and
[3]
hyde with perfect syn selectivity. In contrast the lithium
20]
1
react
enolate of lactone 2 and a variety of aldehydes give anti-
[11a]
aldols with up to 100% ds.
Each of the aldol additions mentioned above may form,
in principle, a maximum of at least two diastereomers, if
the reactants are achiral, and a maximum of at least four
The only syn-selective aldol additions of α-unsubstituted
δ-lactones described to date, to the best of our knowledge,
have been performed in our group and proceed via
IV
[9,21]
CpCl Ti enolates.
Arguably, the most (and only?) reli-
2
[
a] Institut für Organische Chemie der
able method of making anti-aldols from α-unsubstituted δ-
Albert-Ludwigs-Universität,
[
4]
Albertstraße 21, 79104 Freiburg, Germany
E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
http//www.brueckner.uni-freiburg.de
lactones is via their dialkylboron enolates. This propensity
extends to anti-selective aldol additions from δ-lactone ana-
[b] Institut für Anorganische und Analytische Chemie der
Albert-Ludwigs-Universität,
logues with an extra heteroatom in the six-membered
[10,13,14]
ring.
Scheme 1 illustrates these selectivities in lines 3
Albertstraße 21, 79104 Freiburg, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501128.
[
9b]
[4d]
and 4, starting from the chiral δ-lactones 5 and 6. The
syn and anti selectivities of these aldol additions were per-
7892
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7892–7918

Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
IV
anone enolates (Scheme 1, bottom): the (Et N) Ti enolate
2
3
of the cyclohexanone aldol-adds to benzaldehyde with 97:3
[
15b]
syn/anti selectivity.
The cyclopentyl(tert-hexyl)boron
enolate reacts analogously with more than 96:4 anti/syn
[
15a]
selectivity.
Little to nothing is known about the scope of these meth-
ods of simple diastereocontrol. Turning from aldol ad-
ditions of α-unsubstituted δ-lactones (cf. above) to aldol ad-
ditions of α-substituted δ-lactones, the upper part of
[
12,7]
Scheme 2 shows two pertinent examples.
anti-selective and yet proceed via enolates strikingly dif-
They are both
[
4d]
ferent from the Bu B enolate of lactone 6,
which forms
2
the aldol anti-8 of Scheme 1. The anti-addition of lactone
[
12]
11
was effected via the potassium enolate, the anti-ad-
[
7]
dition of lactone 13 via the silver enolate. Of course, these
findings imply nothing about what the syn/anti selectivities
of the corresponding CpCl Ti and Bu B enolates would
IV
2
2
have been. Nonetheless it must be pointed out that there
need not be a Ti versus B dichotomy of the simple dia-
stereoselectivity as lines 3–5 of Scheme 1 might suggest: the
IV
(
(
iPrO) Ti and the Bu B enolate of α-methylcyclohexanone
3 2
both accessed from the silyl enol ether 16, namely by an
indirect and by a direct transmetalation, respectively) aldol-
added to benzaldehyde with high anti selectivity.[ Dif-
ferently expressed, the aldol additions of six-membered cy-
clic α-substituted ester and ketone enolates as represented
in Scheme 2 tend to give anti-configured aldol adducts no
16]
IV
matter what the counterion is. The CpCl Ti and Bu B
2
2
enolates of α-methyl-δ-lactone revealed anti preferences –
or at least only a small syn preference – in their aldol ad-
ditions as well (see below).
Scheme 1. Highly diastereoselective aldol additions of α-unsubsti-
tuted six-membered ring enolates from the literature. Considering
them pairwise reveals their synthetic value but also suggests the
absence of easy explanations for the respective kind of stereocon-
trol. One suspects a medley of factors, which – in the absence of
high-caliber calculational support – looks intractable. Reagents and
conditions: a) LDA (0.25 m in THF, 3 equiv.), THF, –78 °C, 1 h;
aldehyde (1.5 equiv.), –78 °C, 2 h; 50%;[ b) LiHMDS (1.0 m in
3]
hexane, 1.1 equiv.), THF, –78 °C 15 min; aldehyde (1.0 equiv.),
11a]
–
(
78 °C, 30 min; 79%;[
c) iPr
2
NH (1.3 equiv.), nBuLi
O, 2 h; ad-
(1.4 equiv.), 24 [ h; addition of hexanal
1.25 equiv.), Et
dition of CpTiCl
2.2 equiv.), 24 h; 82%, anti/syn 100:0;
nBu BOTf (1.5 equiv.), CH Cl , room temp.Ǟ–78 °C; 6, CH
78 °C, 2 h; addition of PMBO-CH -CHO (2.0 equiv.), –78 °C, 3 h;
aq. H (30%), MeOH, room temp., 14 h; 71%, syn/anti 100:0;
e) LDA, THF, –78 °C; BrTi(NEt , –78 °C; solvent removed at
2 2
O, –78 °C, 60 min; addition of 5, Et
3
9b]
(
d) iPr
2
NEt (1.6 equiv.),
Cl
2
2
2
2
2
,
–
2
[4d]
2
O
2
Scheme 2. Highly diastereoselective aldol additions of α-substituted
six-membered ring enolates from the literature. Reagents and con-
ditions: a) KHMDS (1.05 equiv.), THF, –78 °C, 15 min; propanal
2 2
)
room temp.; redissolved in pentane and cooled to –78 °C; benzalde-
hyde, –78 °C; Ͼ70%; syn/anti 97:3 (no more details given);[
15b]
[12]
(
2.0 equiv.), –78 °C, 1 h; 53%, only anti;
6
b) DBU/AgPF /(R)-
f) iPrNEt
2
(1.1 equiv.), c-C
78 °C, 30 min, PhCHO (1.0 equiv.) 30 min, –78 °C, 1 h, 0 °C;
5 9 6
H (tC H13)BOTf (1.1 equiv.), THF,
MeO-BIPHEP (3 mol-% each), toluene, –50 °C, 15 h, 92%, anti/syn
–
[7]
Ͼ95:5, 99% ee; c) for the Ti(OiPr)
(
2
3
enolate: 16 (1.1 equiv.), BuLi
1.1 equiv.), THF, 0 °C, 30 min; TiCl(OiPr) (1.1 equiv.) –72 °C,
h; solvent exchanged for hexane; –72 °C, benzaldehyde, 1 h; 94%,
enolate reacted with benzaldehyde at –72 °C
1
73%, no syn diastereomer detected in the H NMR spectrum of
3
[
15a]
the crude product.
anti/syn 95:5; the TiCl
in CH Cl for 1 h: 29%, anti/syn 88:12; d) the BBu
acted at –72 °C in Et O for 2 h: 60%, anti/syn 99.5:0.5.
3
[16]
2
2
2
[1e6n]olate re-
fect – as perfect as the respective induced diastereoselecitivi-
ties, which arose additionally.
2
The dichotomy of the syn- versus anti-selective aldol ad-
Bearing in mind the facts delineated so far we wondered
ditions of the titanium versus boron enolates of the substi- what the scope of our syn- versus anti-favoring aldol ad-
[
9b]
[4d]
tuted δ-lactones of Scheme 1 is complemented by a related ditions 5Ǟsyn-7 and 6Ǟanti-8 from Scheme 1 would
dichotomy of aldol additions of the unsubstituted cyclohex- be (Figure 1). Would the simple diastereoselectivity vary if
Eur. J. Org. Chem. 2015, 7892–7918
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7893

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
our enolates originated from unsubstituted δ-lactone (17)
or α-methyl-δ-lactone (18): that is, from δ-lactones, which
would aldol-add without the interference of induced dia-
stereoselectivity? Or, if our enolates were derived from β-
(19), γ- (20) or δ-monomethyl-δ-lactone (21): that is, from
δ-lactones that would aldol-add such that simple diastereo-
selectivity might be reinforced or attenuated by the inter-
ference of induced diastereocontrol? We addressed these
questions by employing isobutyraldehyde (22), crotonalde-
hyde (23), and 4-bromobenzaldehyde (24) as representative
electrophiles. We opted for 4-bromobenzaldehyde rather
than benzaldehyde hoping that the aldol adducts obtained
from the former would crystallize and therefore lend them-
selves for structure elucidation by X-ray crystallography.
Scheme 3. Synthesis of the methyl-δ-lactones that were not ob-
tained commercially. Reagents and conditions: a) iPrNH
2
(
1.1 equiv.), BuLi (1.1 equiv.), THF, –78 °C, 30 min; addition of 17,
–78 °C, 30 min; MeI (1.5 equiv.), –78 °C, 30 min, –35 °C, 1 h; 42%;
b) TEMPO (5 mol-%), bleach (total content of chlorine approx.
1
0%, approx. 2.0 equiv.), KBr (15 mol-%), CH
NaHCO
2.0 equiv.), MeOH, room temp., 1 h; 89% (ref. with NaBH
EtOH: 93%); d) K OsO (OH) (0.2 mol-%), (DHQ)
0.4 mol-%), K Fe(CN) (2.2 equiv.), K CO (2.2 equiv.), Me-
SO NH (1.0 equiv.), tBuOH/H O (1:1), room temp. 1 d; 72%;
e) TEMPO (10 mol-%), PhI(OAc) (2.2 equiv.), NaHCO
20 equiv.), CH Cl , room temp., 30 min; 68%.
2 2
Cl /satd. aq.
3
solution, room temp., 30 min; [ 58%; c) NaBH
4
in
27]
(
4
2
2
4
2
PHAL
(
3
6
2
3
2
2
2
2
3
(
2
2
with this reagent mix is unprecedented to the best of our
knowledge. We had found these conditions “accidentally” –
when trying to oxidize a different secondary/tertiary glycol
to the corresponding tert-hydroxy ketone and achieving a
[
29]
glycol cleavage instead.
Figure 1. Substrates of the aldol additions of this study.
Results and Discussion
Synthesis of the δ-Lactone Starting Materials
Being in possession of the desired δ-lactones 17–21 (cf.
Of the δ-lactones required for this study (Figure 1), the Figure 1) we investigated how their CpCl Ti and Bu B enol-
2
2
parent compound 17 and δ-methyl-δ-lactone (21) were ates aldol-add to the aldehydes 22–24. As a rule, these
commercially available. α-Methyl-δ-lactone (18), β-methyl- CpCl Ti enolate additions proceeded well under the condi-
2
δ-lactone (19), and γ-methyl-δ-lactone (20) were synthe- tions of the corresponding prototypical aldol addition
[
9b]
sized as shown in Scheme 3.
5Ǟsyn-7
(Scheme 1). An exception was found in the
(
1) We obtained α-methyl-δ-lactone (18) in 42% yield by CpCl Ti enolate aldol additions of α-methyl-δ-lactone (18),
2
methylating the lithium enolate of δ-lactone (17) with as detailed below. The Bu B enolate aldol additions of the
2
[
22,23]
methyl iodide.
δ-lactones 17–21 required modifying the conditions of the
(
2) The synthesis of β-methyl-δ-lactone (19) by the oxid- prototypical aldol addition 6Ǟanti-8[4d] (Scheme 1). Ori-
ation of 3-methylpentane-1,5-diol (25) with MnO was de- enting additions of the boron enolate of β-methyl-δ-lactone
2
scribed in the literature (81% yield).[ In our hands this (19) to 4-bromobenzaldehyde (24) led to no more than 30%
24]
[
30]
[4d]
reaction gave irreproducible results (Ǟ 46–82% 19 plus up conversion under the previously described conditions.
to 54% of the corresponding lactol, which proved insepa- Under otherwise identical conditions we had much better
rable by flash chromatography[ ). We achieved the same levels of conversion
25]
[30]
– and isolated an 82% yield of the
oxidation reproducibly in 58% yield by using catalytic aldol adduct 38 – by combining the metal source and the
[
26]
TEMPO and stoichiometric bleach as the oxidants.
3) We synthesized γ-methyl-δ-lactone (20) via the sur- with the previously used lactone 6. Originally, we had added
mised intermediacy of the lactol 29. For 29 a two-step ac- Bu BOTf to a solution of NEt in CH Cl at –5 °C, cooled
base in a different order with the present lactone 19 than
(
2
3
2
2
cess from melonal (26) via the unsaturated alcohol 27 had that solution to –78 °C, and then added the lactone. Now,
[
27]
been described.
Melonal (26) gave an 89% yield of this we mixed the lactone and Bu BOTf at –78 °C and added
2
alcohol 27 after treatment with NaBH in MeOH. The ole- NEt 15 min later.
4
3
fin moiety of 27 was dihydroxylated.[ This provided a
28]
The outcomes of the 30 lactone enolate aldol additions
and that we undertook are compiled in Tables 1 and 2. Table 1
[26a]
7
2
2% yield of the triol 28. This, 10 mol-% TEMPO,
equiv. of PhI(OAc)2[26b] were subjected to a glycol cleav- contains the results of the 2ϫ6 aldol additions delivering
age (Ǟ lactol 29) / oxidation (Ǟ lactone 20) tandem reac- aldol adducts with two stereocenters; Table 2 represents the
tion in 68% yield. Effecting such an overall transformation outcome of the 2ϫ9 aldol additions that furnished aldol
7894
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7892–7918

Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
adducts with three stereocenters. Differently expressed, the ments of the aldol adducts 30 and 31 (Entries 1 and 2,
aldol additions of this study’s lactone enolates, which are Table 1) are based on the following analogies:
achiral – and hence cannot be subject to induced dia-
(1) The diastereoselectivities of the formation reactions
stereocontrol – are compiled in Table 1. The aldol additions were stereocomplementary starting from CpCl Ti versus
2
of this study’s lactone enolates, which are chiral – and, Bu B enolates, and uniformly high. This fits well with the
2
hence, may experience induced diastereocontrol – are the assumption that the titanium enolates of Entries 1–3 of
topic of Table 2.
Adding unsubstituted δ-lactone (17) to the aldehydes 22– boron enolates anti-selectively.
4 afforded the aldols 30–32 (Table 1, Entries 1–3). They (2) If so assigned, the ring-protons 3-H (numbering:
were diastereomerically almost pure, the CpCl Ti enolate of Table 1) of the aldol adducts 30–32 are deshielded in the
Table 1 aldol-add syn-selectively and the corresponding
2
2
[
31]
1
7 reacting with syn/anti Ͼ95:5 to 97:3 and the Bu B enol- three pairs of syn versus anti diastereomers.
2
ate with anti/syn 93:7 to 96:4.
The aldol adducts 30–32 derived from the unsubstituted
This stereocomplementarity and the separability of all δ-lactone (17) and the aldehydes 22–24 (Table 1, Entries 1–
[25]
syn,anti mixtures by flash chromatography allowed us to 3) are sterically less hindered than the aldol adducts 33–
1
gain 400 MHz H NMR spectra of the six pure aldol dia- 35 (Table 1, Entries 4–6). The latter compounds contain a
stereomers. This allowed us to assess the syn/anti ratios in quaternary stereocenter and are the result of adding α-
1
the crude aldol products H-NMR-spectroscopically. We es- methyl-δ-lactone (18) to the same three aldehydes. The
tablished the syn configuration of the major aldol dia- titanium-mediated aldol additions of α-methyl-δ-lactone
stereomer syn-32 (Table 1, Entry 3, left) from the CpCl Ti (18) responded to the increased hindrance by the loss – or,
2
enolate of δ-lactone (17) and para-bromobenzaldehyde (24) as assessed later (see below), the partial reversal (from a syn
[
32]
by X-ray crystallography (Figure 2, first line, left). Making to an anti preference ) – of simple diastereocontrol. In
doubly sure, we established the anti configuration of the contrast, the boron-mediated aldol additions of the same
major aldol diastereomer anti-32 (Table 1, Entry 3, right), hindered lactone 18 were nearly as diastereoselective (ds =
which resulted from the Bu B enolate of δ-lactone (17) and 92:8 to Ͼ95:5; Table 1, Entries 4–6) as the analogous reac-
2
para-bromobenzaldehyde (24), by X-ray crystallography, tions of the unsubstituted lactone 17 (ds = 93:7 to 96:4;
too (Figure 2, first line, right). The syn versus anti assign- Table 1, Entries 1–3).
Table 1. Simple diastereoselectivity in the aldol additions of titanium and boron enolates of the achiral δ-lactones of Figure 1. The 3D
structure of each aldol adduct whose compound number is highlighted by a grey background was determined by an X-ray crystal
structural analysis (cf. Figure 2).
[
(
a] Reagents and conditions: iPr
1.4 equiv.), –78 °C, 18 h; aldehyde 22–24 (2.0 equiv.), –78 °C, 24 h. [b] Reagents and conditions: Lactone 17 or 18, Bu
CH Cl , –78 °C, 15 min; NEt (1.6 equiv.),–78 °C, 1 h; aldehyde 22–24 (2.0 equiv.), –78 °C, 3 h. [c] Determined by integrating baseline-
separated signals in the 400 MHz H NMR spectrum of the crude product (which signals these were is specified in the Experimental
2
NH (1.2 equiv.), BuLi (1.1 equiv.), Et
2
O, –78 °C, 1 h; addition of lactone 17 or 18, –78 °C, 1 h; CpTiCl
3
2
BOTf (1.6 equiv.),
2
2
3
1
[f]
Section). [d] Yields without parentheses are either the yield of the only isolated diastereomer or the combined yield of the separated
[25]
diastereomers, always after purification by flash chromatography on silica gel. The yield with parentheses refers to the syn-30/anti-30
[25]
mixture isolated after purification by flash chromatography on silica gel. [e] Crude “30” was so contaminated by side products that its
4
00 MHz 1H NMR spectrum did not allow the diastereomeric composition to be determined. Therefore, “30” was purified by flash
[25]
chromatography on silica gel “to some extent”. This means that we combined all fractions that contained the product (according to
TLC analysis) with the three fractions that eluted before the product and with the three fractions that eluted after the product. The
diastereomer ratio in the Table refers to the chromatographed product just described. [f] No H NMR signal corresponding to the
minor diastereomer was detected. [g] Isolated yield of a pure 65:35 mixture of the diastereomers.
[
f]
1
Eur. J. Org. Chem. 2015, 7892–7918
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7895

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
Table 2. Simple and induced diastereoselectivity in the aldol additions of titanium and boron enolates of the chiral δ-lactones of Figure 1.
The 3D structure of each aldol adduct whose compound number is highlighted by a grey background was determined by an X-ray crystal
structural analysis (cf. Figure 2).
[
–
a] Reagents and conditions: iPr
78 °C, 18 h; aldehyde (2.0 equiv.), –78 °C, 24 h. [b] Reagents and conditions: Bu
2
NH (1.2 equiv.), BuLi (1.1 equiv.), Et
2
O (0.16 m), –78 °C, 1 h; lactone, –78 °C, 1 h; CpTiCl
BOTf (1.6 equiv.), CH Cl (0.16 m), –78 °C, 15 min;
3
(1.6 equiv.), –78 °C, 1 h; aldehyde (2.0 equiv.), –78 °C, 3 h. [c] Determined by integrating baseline-separated signals in the 400 MHz
3
(1.4 equiv.),
2
2
2
NEt
1
H NMR spectrum of the crude product (which signals these were is specified in the Experimental Section). [d] Yields without parentheses
[25]
refer to the pure main diastereomer isolated after purification by flash chromatography on silica gel.
If a mixture of cis,trans dia-
stereomers was isolated, its yield is given in parentheses. [e] Crude “syn,trans-36”, crude “39”, and crude “42” were so contaminated by
side products that the corresponding 400 MHz 1H NMR spectrum did not allow the diastereomeric composition to be determined.
[25]
Therefore, “36”, “39”, and “42” were purified by flash chromatography on silica gel “to some extent”. This means that we combined
all respective fractions that contained the product (according to TLC analysis) with the three fractions that eluted before the product
f
and with the three fractions that eluted after the product. The respective diastereomer ratios in the Table refer to the chromatographed
1
products just described. [f] No H NMR signal corresponding to the indicated minor diastereomer was detected. [g] Three diastereomers
from this aldol adduct portfolio were subjected to X-ray crystallography: anti,trans-41 (Figure 2), syn,trans-41 (Figure 2), and a co-crystal
of syn,trans-41 and anti,trans-41 (Figure 3). [h] 12% of a mixture of diastereomers were isolated separately, as were 17% syn,trans-44; the
total yield of aldol adduct was 81%.
The near-identical magnitudes of simple diastereocontrol
Table 2 summarizes the 18 aldol additions altogether of
in the boron-mediated aldol additions of lactones 18 versus the CpCl Ti enolates (“left-bound” reactions) and of the
2
1
7 suggested that the directions of simple diastereocontrol Bu B enolates (“right-bound” reactions) of β- (19, En-
2
were identical, too. Consequently, the major diastereomers tries 1–3), γ- (20, Entries 4–6), and δ-methyl-δ-lactone (21,
of the boron-based aldol adducts 33–35 were considered Entries 6–9) to our aldehydes 22–24. Each of these ad-
anti diastereomers. This notion was corroborated by crys- ditions might have led, in principle, to up to four dia-
tallizing the major diastereomer of the boron- and para- stereomers. The corresponding ratios of syn- to anti-aldol(s)
bromobenzaldehyde-based aldol adduct 35. An X-ray crys- measure the extent of simple diastereocontrol, and the ra-
tal structure analysis confirmed its anti configuration (Fig- tios of cis- to trans-(hydroxyalkyl)methyl-δ-lactone(s) gauge
ure 2, second line, right). If the configurations of anti-33 the degree of induced diastereoselectivity. In the actual
1
and anti-34 were assigned correctly for analogy (see above), experiments, we identified – H-NMR-spectroscopically
the syn,anti selectivity of each of the titanium-mediated (400 MHz, CDCl ) – as few as two aldol adducts in eight
3
aldol additions of α-methyl-δ-lactone (18) could be quanti- aldol additions, three aldol adducts in six aldol additions,
1
fied H NMR spectroscopically as follows (Table 1, En- and the maximum number of four aldol adducts in four
tries 4–6): the titanium enolate of lactone 18 added to iso- aldol additions. Overall, Table 2 documents the obtention
butyraldehyde (22) with a weak anti preference (Ǟanti/syn of 31 of the 36 conceivable different aldol products. The
63:37), to crotonaldehyde (23) with a weak syn preference content of the major diastereomer in the crude aldol mix-
(Ǟsyn/anti 59:41), and to 4-bromobenzaldehyde (24) with tures ranged from 66% (syn,trans-41) to 98% (anti,trans-
no preference at all (Ǟsyn/anti 50:50). This contrasts with 36). From 11 of our total of 18 aldol additions the major
the Ͼ95:5 syn selectivities of the aldol additions of the tita- diastereomer was isolated as a pure product. In one
nium enolate of the unhindered lactone 17 to the same alde- case (syn,cis-44) the second most abundant diastereomer
[
33]
hydes.
(syn,trans-44) was also isolated as a pure compound. From
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Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
Figure 2. Elucidation of the configurations of the main diastereomers by X-ray structural analysis: the 4-bromobenzaldehyde adducts
[
41]
[42]
[43]
[44]
[45]
[46]
[47][a]
[48]
syn-32, anti-32, anti-35, syn,trans-38, syn,trans-41, anti,trans-41, and syn,cis-44,
the isobutanal adduct anti,trans-36,
and the 4-bromobenzoate anti,cis-45[ of the isobutanal adduct anti,cis-42. [a] Compound syn,cis-44 crystallized in an acentric space
group. Its X-ray structure has been inverted in the presentation in this Figure for the sake of endowing the stereocenter at C-α of each δ-
lactone consistently with an S configuration. The genuine X-ray structure is shown in the Supporting Information.
49]
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F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
the remaining seven aldol additions we could only isolate stereomer with the constitution 41. Accordingly, when the
two-compound mixtures consisting of the major cis and the aldol 41 resulted from the titanium enolate, the major
[
34]
major trans isomer.
(syn,trans-41) and the second most abundant diastereomer
The configurational assignments of the 18 major dia- (syn,cis-41) were trans,cis isomers. So were the major
stereomers of the aldol products 36–44 of Table 2 began (anti,trans-41) and the second most abundant diastereomer
with assigning the syn configuration to each major aldol (anti,cis-41) of the aldol 41 formed from the boron enolate.
product from the CpCl Ti enolates of lactones 19–21 and These findings suggest that the second most abundant dia-
2
the aldehydes 22–24 (“left-bound” reactions); of these stereomers in the γ-methyl-δ-lactone-derived aldols 39 and
aldols, we recognized syn-36–41 as syn,trans-36–41 and syn- 40 are cis isomers of the dominating trans species. This in-
1
[39]
4
2–44 as syn,cis-42–44. Similarly, we assigned the anti con- terpretation is corroborated by H NMR analogies.
figuration to each major aldol product 36–44 from the cor- The aldol additions of δ-methyl-δ-lactone (21) furnished
responding Bu B enolates and the same set of aldehydes a full set of the 12 conceivable aldol adducts, too (42–44,
2
(
Table 2, “right-bound” reactions); of these, we recognized Table 2, Entries 7–9). The 3D structures of the six major
anti-36–41 as anti,trans-36–41 and anti-42–44 as anti,cis-42– diastereomers were elucidated by X-ray crystallography
4. Six of the 18 preceding attributions are based on X-ray (syn,cis-44, para-bromobenzoate anti,cis-45 of aldol anti,cis-
4
crystallographic evidence (Figure 2, lines 3–5); twelve are 42) or plausible analogies as described above. Moreover, we
extrapolated by analogy. Each extrapolation concerned an reasoned similarly as when we considered each second most
enolate, which, by adding to one aldehyde, had afforded abundant aldol 39–41 as the cis isomer of the trans-config-
crystals that had been subjected to X-ray crystallography. ured major aldol. However, in the aldols 42–44 we classified
Accordingly, we did not go beyond assuming that the iden- the second most abundant diastereomers as trans isomers
tical enolate added to the other two aldehydes essentially of the dominating cis isomers. These assignments were cor-
1
[39,40]
with the identical stereoselectivity.
roborated by H NMR analogies.
In a nutshell, the stereoselectivities of Table 2 can be de-
The titanium and boron enolates of β-methyl-δ-lactone
(19) afforded a total of seven aldol adducts (Table 2, En- scribed as follows:
tries 1–3). Six of them yielded their stereostructures either
(1) The CpCl Ti enolate additions of Table 2 gave syn-
2
to X-ray analyses (anti,trans-36, syn,trans-38) or to the al- aldols with ds = 93:7 to 99:1. This resembles the syn selec-
ready mentioned assumption that the identical enolates tivity of the aldolizations of the CpCl Ti enolate of the un-
2
added to the other two aldehydes essentially with identical substituted δ-lactone (17; syn/anti Ͼ95:5 to 97:3; Table 1,
stereoselectivities. The seventh aldol product was identified Entries 1–3).
1
H-NMR-spectroscopically as anti,cis-38 in the aldol mix-
(2) The Bu B enolate additions of Table 2 gave anti-aldol
2
ture obtained from Bu B-19 and para-bromobenzaldehyde products with ds = 93:7 to 98:2. This is akin to the anti
2
35]
(
24; Table 2, Entry 3, right).[
selectivity of the aldolizations of the Bu B enolate of the
2
The aldol additions of γ-methyl-δ-lactone (20) led to all unsubstituted δ-lactone (17; anti/syn 92:8 to ca. 96:4;
2 conceivable aldol adducts 39–41 (Table 2, Entries 4–6). Table 1, Entries 1–3).
1
The stereostructures of the six major diastereomers were
(3) The aldol additions of the CpCl Ti and the Bu B
2 2
[36,37]
recognized directly by X-ray analyses (syn,trans-41
and enolate of β-methyl-δ-lactone (19) were highly trans-selec-
[
37,38]
anti,trans-41
) or indirectly by extrapolating the under- tive (trans/cis Ͼ94:6; Table 2, Entries 1–3). The underlying
lying selectivities to the analogous aldolizations (see above). 1,2-asymmetric inductions appears plausible in terms of a
Additionally, we possessed an X-ray structural analysis of repulsive steric effect of the neighboring methyl group.
[
37,38]
a mixture of the aldols syn,cis-41 and syn,trans-41
(4) The aldol additions of the CpCl Ti and the Bu B
2 2
(Figure 3). By the exclusion principle this allowed us to as- enolate of γ-methyl-δ-lactone (20) were moderately trans-
sign stereostructure anti,cis-41 to the fourth aldol dia- selective (trans/cis = 68:32 to 78:22; Table 2, Entries 4–6).
Figure 3. Along with the thin flat needles of the aldol adduct syn,trans-41[37] (X-ray structure: Figure 2) we found one large plate-like
crystal. It turned out to be a co-crystal of the same aldol adduct syn,trans-41 and its diastereomer syn,cis-41 in a 1:2 ratio. The X-ray
[
50]
structure
of this crystal is shown here. In the first analysis (not depicted), the nucleus C-8 (ϵ X-ray numbering for the methyl-
substituted carbon atom) was refined as an unexplainably elongated ellipsoid. This could be resolved into two distinct positions: C-8A
and C-8B, with site occupation factors in a ratio of 2 (for syn,cis-41) to 1 (for syn,trans-41). Obviously, very small amounts of residual
syn,cis-41 co-precipitated with syn,trans-41 in a 2:1 ratio towards the end of the crystallization of what had been the 33:67 (!) syn,cis-41/
syn,trans-41 mixture, which we had isolated from our titanium-mediated aldol addition.
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Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
The respective 1,3-asymmetric induction seems inexplicable boat-48b might act in favor of an equatorial aldehyde sub-
in terms of a direct interaction with the methyl group, stituent in the respective transition state (not depicted in
Figure 4) and the formation of an anti-aldol, accordingly.[
32]
which looks fairly remote.
(
5) The aldol additions of the CpCl Ti and the Bu B Of course, one may speculate whether a CpCl Ti(enolate)
2
2
2
enolate of δ-methyl-δ-lactone (21) were moderately cis-se- is too weak a Lewis acid for capturing an aldehyde in a
lective (cis/trans = 73:27 to 76:24), reaching 86:14 in one Zimmerman–Traxler transition state. A hint in that direc-
instance (Table 2, Entries 7–9). Superficially, the underlying tion might be that CpTiCl scarcely releases HCl fumes
3
1,4-asymmetric induction looks contrasteric, but evidently when handled in laboratory air. In any event an alternative
the methyl group at C-δ and a suitably oriented incoming is that our CpCl Ti enolates aldol-add via an acyclic transi-
2
[
52]
aldehyde should be separated too much from one another tion state.
for any steric interaction to occur. Figure 5 is an attempt at interpreting the induced dia-
A straightforward interpretation – at least to an extent – stereoselectivities of the aldol additions of our chiral enol-
of the dichotomy of the simple diastereoselectivities of our ates. The respective stereocontrol is independent of the
titanium- versus boron-mediated aldol additions is based metal moiety. Accordingly, the partaking CpCl Ti and Bu B
2
2
on the assumption that they proceed via cyclic transition enolates are condensed to single formulas 52c–e in Figure 5.
states. There is no reason to doubt that, in compliance with The structure variation c–e is the locant variation of the
[
51]
the Zimmerman–Traxler model,
the Bu B enolates, methyl group. In the CpCl Ti and Bu B enolates 52c the
2
2
2
β
γ
which must be “trans”-configured, react via chair-like tran- methyl group resides at C , in the enolates 52d at C , and
δ
sition states chair-51a–e (Figure 4). In these “chairs”, the in the enolates 52e at C . We presume that each enolate
aldehyde substituent R is oriented equatorially. Thus, these 52c–e represents either the best “half-chair”-like[ sub-
53]
additions should lead to boron aldolates anti-50a–e. This is structure 52chalf-chair–ehalf-chair of the transition state of its
[
54]
true no matter whether or where the lactone is methylated. aldol additions or the best “half-boat”-like
substructure
If (!) the syn selectivity of the aldol additions of the CpCl Ti 52c
enolates 46a and 46c–e is also determined in six-membered ditions.
–ehalf-boat of the transition state of its aldol ad-
We cannot assess what the favored structure
2
half-boat
55]
[
cyclic transition states 48a and 48c–e, the latter must ac- might be, because we are even unaware of δ-lactone enolate
commodate the aldehyde substituent axially (Figure 4). This equilibrium structures. How the hybridization of the endo-
is a necessity both if these transitions states represent chairs cyclic O atom and the associated ring-strain add up to an
48a and 48c–e or boats 48a and 48c–e. We believe it is more optimized transition state structure must be considered an
likely that the CpCl Ti enolates 46a and 46c–e react via the unknown. Be this as it may, we suppose that, moreover,
2
transition states boat- rather than chair-48a and 48c–e. This the carbonyl group of the incoming aldehyde targets the
α
is because the α-methylated CpCl Ti enolate 46b does not nucleophilic center C of the relevant enolate 52c–e via an
2
exhibit the syn selectivity of all other CpCl Ti enolates (46a axial trajectory. This is inferred from understanding the
2
and 46c–e). α-Methylation should destabilize specifically HOMO of these enolates as a π-type orbital and from opti-
the transition state boat-48b by allyl1,3 strain, while no com- mizing its overlap with the LUMO of the incipient alde-
α
parable effect would be expected in a chair-like transition hyde. An axial attack of the aldehyde upon C looks least
state. The selective destabilization of the transition state hindered by a methyl group at the immediately neighboring
Figure 4. Aldol additions of the titanium and boron enolates of the unsubstituted δ-lactone (17) and the analogous δ-lactones methylated
at C-α (18), C-β (19), C-γ (20), or C-δ (21) to isobutyraldehyde (22), crotonaldehyde (23), and 4-bromobenzaldehyde (24): interpretation
of the metal-dependent – and in one case (CpCl Ti enolate 46b) methyl-dependent – simple diastereoselectivities (details: see text).
2
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7899

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
β
β
C if this attack is antiperiplanar to the C –Me bond. This
would be tantamount to a preference of the enolates 52chalf-
or 52chalf-boat for forming aldolates 53c (Figure 5). That
chair
is, the high trans selectivity of the aldol additions of β-
methyl-δ-lactone (19; Table 2, Entries 1–3) would be a steric
effect. In contrast, the induced diastereoselectivities of the
aldol additions of γ-methyl-δ-lactone (20; Table 2, En-
tries 4–6) and δ-methyl-δ-lactone (21; Table 2, Entries 7–9)
are moderate – and diverging: 20 reacts with a trans prefer-
ence while 21 shows a cis preference. Our speculation is that
the trans preference of the aldol additions of the enolates
52dhalf-chair or 52dhalf-boat and the cis preference of the aldol
additions of the enolates 52ehalf-chair or 52ehalf-boat are a con-
formational effect. As Figure 5 points out, the trans prefer-
γ
ence of the aldol additions 52dǞ53d allows the C –Me
bond to be oriented (pseudo)equatorially both in the enol-
ate subunit 52d of the transition state and in the initially
formed half-chair conformer 53d of the aldol adduct. Simi-
larly, the cis preference of the aldol additions 52eǞ53e al-
δ
lows the C –Me bond to be oriented (pseudo)equatorially
both in the enolate subunit 52e of the transition state and
in the initially formed half-chair conformer 53e of the aldol
adduct.
Experimental Section
General Working Technique and Analytic Techniques
Working Technique: All reactions that did not require water were
carried out under dry N
65 °C) and under reduced pressure with a heat gun prior to use.
Liquids were added with syringe and cannula through a rubber
septum. Solids were added in a countercurrent of dry N . Reactions
2
. Reaction flasks were dried in an oven
(
2
that were conducted in the presence of water were carried out with-
out inert gas atmosphere. Solvents: tetrahydrofuran (THF) was dis-
tilled from potassium and dichloromethane (CH
under dry N prior to use. Other solvents, which were obtained
commercially as “dry” or “extra dry” solvents, were used without
further purification. Cyclohexane (c-C 12), ethyl acetate (EtOAc),
methanol (MeOH), ethanol (EtOH), dichloromethane (CH Cl ),
2 2 2
Cl ) over CaH
2
6
H
2
2
and tert-butyl methyl ether (TBME) for workup and column
chromatography were distilled prior to use with a rotary evaporator
2
to remove high-boiling fractions. Diethyl ether (Et O), pentane,
and chloroform (CHCl ) for workup and column chromatography
3
were obtained as p.a. grade solvents and used without further puri-
fication. Grignard reagents were stored in a freezer in Schlenk flasks
Figure 5. Aldol additions of the titanium and boron enolates of the
unsubstituted δ-lactone (17) and the analogous δ-lactones methyl-
with PTFE screw caps and PTFE valves. Prior to use, they were
ated at C-β (19), C-γ (20), or C-δ (21) to isobutyraldehyde (22), titrated with salicylaldehyde phenylhydrazone.[ Chromatography:
56]
crotonaldehyde (23), and 4-bromobenzaldehyde (24): conformation-
based hypotheses for explaining the metal-independent induced dia-
stereoselectivities (details: see text). [a] The term “half-chair” has a
substrate-dependent meaning in conformational analysis. In the
enolates labeled “half-chair” here, we use the term as for cyclohex-
ene; this understanding was extended to δ-lactones (see the reference
cited in ref. 40); the identical conformation was used – its conforma-
tional preference being corroborated by molecular mechanics calcu-
Thin layer chromatography (TLC) on Merck silica plates with glass
as supporting material (TLC Silicagel 60 F254) was used to monitor
reactions and assess purification procedures. If possible, chromato-
grams were marked in UV light at 254 nm and subsequently stained
with permanganate stain (2 g KMnO
4
3
, 4 g NaHCO , 100 mL of
H
H
2
O) or vanillin stain (4.5 g vanillin, 75 mL EtOH, 4 mL conc.
®
2
4
SO ). Macherey–Nagel & Co silica gel 60 (230–400 mesh) was
[25]
lations – for δ-lactone enolates in ref.[55]. [b] The term “half-boat” is
used for flash column chromatography. Chromatography condi-
tions are documented at the respective experiment in the following
manner: dϫ h (cm), V (mL), solv1:solv2, a:b to c:d, Fx–Fy. This
used here to describe a conformation in which five ring-atoms are
coplanar and one atom projects out of the plane. This structure is
homologous to the envelope conformation of a five-membered ring. means: a column with the inner diameter d cm was packed with
7
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Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
h cm silica gel. Fractions of the size V mL were collected. The
product was eluted with the solvents solv1 and solv2 in the ratio
a:b. The ratio – if not stated otherwise – was changed every 12
fractions in the following series (a:b marks the starting point, c:d
marks the end point): 100:0, 100:1, 50:1, 20:1, 10:1, 5:1, 3:1, 2:1,
at –78 °C. After the system had been stirred for 15 min at –78 °C,
NEt (0.22 mL, 0.16 g, 1.6 mmol, 1.6 equiv.) was added and the
solution was stirred for 1 h at –78 °C. The appropriate aldehyde
(2.0 mmol, 2.0 equiv.) was added to this solution, either as a solu-
3
tion in CH
2 2
Cl (1 mL) within 1 h by syringe pump [isobutyral-
1:1, 1:2, 1:3, 0:100. Fx–Fy were the fractions containing the prod-
dehyde (22)] or in one portion [crotonaldehyde (23), 4-bromobenz-
uct. Melting points were determined with a Büchi melting point aldehyde (24)] at –78 °C. After the system had been stirred for 3 h
apparatus and use of open glass capillaries.[ Nuclear magnetic
resonance spectroscopy: NMR spectra were recorded by Dr. M.
Keller, F. Reinbold, and M. Schonhard with a Bruker Avance 400
57]
at –78 °C the reaction was quenched by addition of aqueous phos-
phate buffer (20 mm, pH 7, 4 mL), MeOH (2 mL), and H (30%,
1 mL). The mixture was warmed to room temperature and stirred
for 1 h at room temperature. CH Cl (10 mL) was added to the
edHSQC, and HMBC experiments] and a Bruker DRX 500 spec- mixture, the organic layer was separated, and the aqueous layer
2
O
2
1
13
spectrometer [ H (400 MHz),
C
(100 MHz), DQF-COSY,
2
2
1
13
trometer [ H (500 MHz), C (126 MHz), DQF-COSY, edHSQC was washed with CH
"C,H-COSY"), and HMBC experiments] or with an automated ers were washed with saturated aqueous Na
and dried with MgSO , and the solvent was evaporated under re-
2
Cl
2
(3ϫ 10 mL). The combined organic lay-
(
2
SO solution (5 mL)
3
1
Varian Mercury VX 300 spectrometer [ H (300 MHz)]. Spectra
were referenced internally by the H and C NMR signals of the
solvent [CDCl
4
1
13
duced pressure. The anti-aldols were obtained as colorless oils,
1
13
1
[25]
3
: 7.26 ppm ( H) and 77.10 ppm ( C)]. H NMR
which were purified by flash chromatography.
spectroscopic data are reported as follows: chemical shift (δ in
ppm), multiplicity (s for singlet; d for doublet; t for triplet; m for
rel-(S)-3-[(R)-1-Hydroxy-2-methylpropyl]-3,4,5,6-tetrahydro-2H-
pyran-2-one (syn-30)
c
multiplet; m for symmetrical multiplet; br. for broad signal), cou-
3
pling constant(s) (Hz; J couplings unless otherwise noted), inte-
gral, and specific assignment. 13C NMR spectroscopic data are re-
ported in terms of chemical shift and assignment. For AB signals
the high-field part was named A and the low-field part B. The
atom numbering used for NMR assignments follows the IUPAC
nomenclature. IR spectra were recorded with a Perkin–Elmer Para-
gon 1000 FT-IR spectrometer for a film of the substance on an
NaCl plate. High-resolution mass spectra (HRMS) were recorded
by Dr. J Wörth and C. Warth with a Thermo Exactive mass spec-
trometer equipped with an orbitrap analyzer. Ionization methods:
electron spray ionization (ESI; spray voltage: 4–5 kV) or atmo-
spheric pressure chemical ionization (APCI; spray current: 5 μA).
Elemental analyses were obtained by F. Tönnies and A. Siegel with
an Elementar Vario El CHNS analyzer. X-ray crystal structure
analyses were conducted by Dr. M. Keller with a Nonius Kappa-
CCD diffractometer and by Prof. Dr. H. Hillebrecht with a Bruker
Following the General Procedure A the title compound was pre-
pared from δ-lactone (17, 100 mg, 1.00 mmol) and isobutyr-
aldehyde (22, 144 mg, 2.00 mmol, 2.0 equiv.). Purification by flash
chromatography[ (2.0ϫ15 cm, 15 mL, c-C
25]
H12/EtOAc 3:1 to 1:1,
6
1
5–20) rendered the product as a colorless oil (124 mg, 72 %).
1
syn/anti Ͼ95:5. [The 300 MHz H NMR spectrum of the crude
product was too contaminated by byproducts to integrate any sig-
nals. A short column chromatographic separation (2.0 ϫ10 cm,
1
6
5 mL, c-C H12/EtOAc 3:1 to 1:1, 9–18) was conducted to get rid
1
of most byproducts. The 400 MHz H NMR spectrum of the prod-
uct thus obtained still contained no baseline-separated signals of
anti-30. Integration of the signals at δ = 4.25–4.35 (6-H
2
, both dia-
stereomers) versus δ = 3.85–3.94 (1ЈH, syn-30) resulted in syn/anti
α
SMART APEX2 CCD diffractometer and use of Mo-K radiation
1
[
58]
100:0]. H NMR (400.13 MHz, CDCl ): δ = 0.87 (d, J
2Ј-Me,2Ј
=
from a microsource.
3
6
J
4
3
6
3
.8 Hz, 3 H, 2Ј-Me), 1.05 (d, J3Ј,2Ј = 6.5 Hz, 3 H, 3Ј-H ), 1.69 (dqq,
2Ј,1Ј = 9.8 Hz, J2Ј,3Ј = J2Ј,2Ј-Me = 6.6 Hz, 1 H, 2Ј-H), 1.89–1.99 (m,
General Procedure A – Titanium-Mediated Preparation of syn-Ald-
ols: A solution of LDA was prepared by adding BuLi (2.2–2.4 m in
A
H, 4-H
2
, 5-H
2
) , 2.46 (br. s, 1 H, OH), 2.67–2.73 (m, 1 H,
hexane, 1.1 mmol, 1.1 equiv.) to a stirred solution of iPr
0.16 mL, 0.12 g, 1.2 mmol, 1.2 equiv.) in Et O (6 mL) at –78 °C.
After the system had been stirred for 1 h at –78 °C a solution of
the appropriate δ-lactone (1.0 mmol) in Et O (1 mL) was added
within 30 min by syringe pump at –78 °C. After the system had
been stirred for 1 h at –78 °C, solid CpTiCl (0.31 g, 1.4 mmol,
.4 equiv.) was added in one portion. Upon addition of CpTiCl
2
NH
A
-H) , 3.89 (br. d, J1Ј,2Ј = 9.5 Hz, 1 H, 1Ј-H), 4.30–4.34 (m, 2 H,
(
2
A
-H
2
) ppm; the indicated protons were distinguished in a DQF-
)]
by their crosspeaks with protons that previously had been assigned
unequivocally [δ (previously assigned) ↔ δ (distinguished)]: δ =
.98 (1Ј-H) ↔ δ = 2.67–2.73 (3-H); δ = 2.67–2.73 (3-H) ↔ δ =
.89–1.99 (4-H , 5-H ) and δ = 4.30–4.34 (6-H ) ↔ δ = 1.89–1.99
) ppm. 13C NMR (100.62 MHz, CDCl
, 5-H ): δ = 17.27 (C-
) , 18.88 (C-2-Me) , 19.76 (C-3Ј) , 22.38 (C-5) , 29.91 (C-2Ј) ,
COSY spectrum [“H,H-COSY spectrum” (400.13 MHz, CDCl
3
2
H
H
3
3
1
1
3
2
2
2
the clear solution turns red and after stirring overnight at –78 °C
a colorless precipitate forms. The appropriate aldehyde (2.0 mmol,
(
4-H
2
2
3
A
A
A
A
A
4
4
2.0 equiv.) was added at –78 °C, either as a solution in Et
2
O (1 mL)
A
A
A
A
3.14 (C-3) , 68.66 (C-6) , 75.85 (C-1Ј) , 174.96 (C-2) ppm. The
within 1 h by syringe pump [isobutyraldehyde (22)] or in one por-
tion [crotonaldehyde (23), 4-bromobenzaldehyde (24)]. After the
system had been stirred overnight at –78 °C the reaction was
indicated nuclei – they are non-quaternary – were identified in an
edHSQC spectrum [“short-range C,H-COSY spectrum” (100.62/
4
00.13 MHz, CDCl
3
)] by their crosspeaks with directly bonded pro-
quenched by addition of a saturated aqueous NH
4
Cl solution
13
tons (these had previously been assigned unequivocally) [δ
↔
C
( C)
, downfield
in the DQF-COSY spectrum);
δ = 18.88 (C-2-Me) ↔ δ = 0.87 (2-Me); δ = 19.76 (C-3Ј) ↔ δ =
.05 (3Ј-H ); δ = 22.38 (C-5) ↔ δ = 1.89–1.99 (4-H , 5-H , highfield
part which has a crosspeak to 6-H in the DQF-COSY spectrum);
δ = 29.91 (C-2Ј) ↔ δ = 1.69 (2Ј-H); δ = 43.14 (C-3) ↔ δ = 2.67–
2.73 (3-H); δ = 68.66 (C-6) ↔ δ = 4.30–4.34 (6-H ); δ = 75.85 (C-
BOTf (0.36 mL, 0.41 g, 1.5 mmol, 1.5 equiv.) was added to a 1Ј) ↔ δ = 3.89 (1Ј-H) ppm. IR (film): ν˜ = 3450, 2960, 1720, 1475,
(
2 mL) at –78 °C. The mixture was warmed to room temperature,
1
δ
H
( H)]: δ = 17.27 (C-4) ↔ δ = 1.89–1.99 (4-H
2 2
, 5-H
®
diluted with Et
2
O (10 mL), and filtered through a pad of celite .
O (50 mL). The combined filtrates
and the solvent was evaporated under re-
duced pressure. The syn-aldols were obtained as colorless oils,
part which has no crosspeak to 6-H
2
The residue was washed with Et
were dried with MgSO
2
4
1
3
2
2
2
[25]
which were purified by flash chromatography.
General Procedure B – Boron-Mediated Preparation of anti-Aldols:
Bu
solution of the appropriate δ-lactone (1.0 mmol) in CH
2
2
–
1
2
Cl
2
(6 mL)
1400, 1260, 1170, 1080, 995, 910, 740 cm . HRMS (pos. APCI,
Eur. J. Org. Chem. 2015, 7892–7918
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7901

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
+
1
MeOH): calcd. for C
+0.3 ppm). C
2.51, H 9.43.
9
H
17
O
3
[M + H] 173.11722; found 173.11728
uct contained no signals clearly attributable to anti-31]. H NMR
(
6
9
H
16
O
3
(172.22): calcd. C 62.77, H 9.36; found C (400.13 MHz, CDCl
3
): δ = 1.68 (m
c
, possibly interpretable as ddd,
4Ј,3Ј = 6.5 Hz, J4Ј,2Ј = 1.6 Hz, J4Ј,1Ј = 0.9 Hz, 3 H, 4Ј-H ), 1.70–
)A, 2.66 (m
, 1
, possibly interpretable as br. d, JOH,1Ј = 5.0 Hz,
H, OH) , 4.21–4.33 (m, 2 H, 6-H ), 4.47 (br. s, 1 H, 1Ј-H), 5.47
, possibly interpretable as ddq, J2Ј,3Ј = 15.3 Hz, J2Ј,1Ј = 6.8 Hz,
4
5
J
1
3
1
A
2
.81 (m, 1 H, 4-H ) , 1.83–1.96 (m, 3 H, 4-H , 5-H
2
c
rel-(S)-3-[(S)-1-Hydroxy-2-methylpropyl]-3,4,5,6-tetrahydro-2H-
pyran-2-one (anti-30)
A
H, 3-H) , 3.17 (m
c
A
1
2
(
m
c
A
J
6
2Ј,4Ј = 1.6 Hz, 1 H, 2Ј-H) , 5.73 (dq, J3Ј,2Ј = 15.3 Hz, J3Ј,4Ј =
.5 Hz, 1 H, 3Ј-H) ppm. The indicated protons were distinguished
A
in a DQF-COSY spectrum [“H,H-COSY spectrum” (400.13 MHz,
CDCl )] by their crosspeaks with protons that previously had been
assigned unequivocally [δ
Following the General Procedure B the title compound was pre-
pared from δ-lactone (17, 100 mg, 1.00 mmol) and isobutyr-
aldehyde (22, 144 mg, 2.00 mmol, 2.0 equiv.). Purification by flash
3
1
1
H
( H) ↔ δ ( H)]: δ = 4.47 (1Ј-H) ↔ δ =
H
5.47 (2Ј-H); δ = 4.47 (1Ј-H) ↔ δ = 3.17 (OH); δ = 4.47 (1Ј-H) ↔
[
25]
1
chromatography (2.0ϫ15 cm, 15 mL, c-C
6
H12/EtOAc 3:1 to 1:1,
δ = 2.66 (3-H); δ = 2.66 (3-H) ↔ δ = 1.70–1.81 (4-H ); δ = 2.66 (3-
2
13
1
2
3–17) rendered the product as a colorless oil (115 mg, 67 %). H) ↔ δ = 1.83–1.96 (4-H , 5-H ) ppm. C NMR (100.62 MHz,
A
A
A
syn/anti 4:96 [determined by integration of the signals at δ = 2.57
3
CDCl ): δ = 17.73 (C-4Ј) , 19.69 (C-4) , 22.25 (C-5) , 45.75 (C-3)
A
A
A
A
A
(
3-H, anti-30) vs. δ = 2.67–2.73 (3-H, syn-30) in the 400 MHz
H NMR spectrum of the crude product]. H NMR (400.13 MHz,
, 69.07 (C-6) , 72.10 (C-1Ј) , 128.67 (C-3Ј) , 129.69 (C-2Ј) ,
173.90 (C-2) ppm. The indicated nuclei – they are non-quater-
1
1
A
CDCl
=
=
3
): δ = 0.91 (d, J2Ј-Me,2Ј = 6.8 Hz, 3 H, 2Ј-Me), 1.03 (d, J3Ј,2Ј
6.8 Hz, 3 H, 3Ј-H ), 1.58 (m , possibly interpretable as ddt, Jgem
13.2 Hz, J4-H(1),3 = 11.8 Hz, J4-H(1),5 = 7.2 Hz, 1 H, 4-H ) , 1.86
nary – were identified in an edHSQC spectrum [“short-range C,H-
COSY spectrum” (100.62/400.13 MHz, CDCl )] by their cross-
3
peaks with directly bonded protons (these had previously been as-
3
c
1
A
1
3
1
(
qqd, J2Ј,2Ј-Me = J2Ј,3Ј = 6.8 Hz, J2Ј,1Ј = 3.8 Hz, 1 H, 2Ј-H), 1.93
, 2 H, 5-H , possibly interpretable as ddt, Jgem
)A, 2.02 [m
3.3 Hz, J4-H(2),3 = 8.0 Hz, J4-H(2),5 = 6.6 Hz, 1 H, 4-H ] , 2.56 (4-H , 5-H
signed unequivocally) [δ
C
( C) ↔ δ
H
( H)]: δ = 17.73 (C-4Ј) ↔ δ =
1
(m
c
2
c
=
1.68 (4Ј-H
3
); δ = 19.69 (C-4) ↔ δ = 1.70–1.81 (4-H ) and 1.83–1.96
2
A
2
2
1
2
); δ = 22.25 (C-5) ↔ δ = 1.83–1.96 (4-H , 5-H
45.75 (C-3) ↔ δ = 2.66 (3-H); δ = 69.07 (C-6) ↔ δ = 4.21–4.33 (6-
); δ = 72.10 (C-1Ј) ↔ δ = 4.47 (1Ј-H); δ = 128.67 (C-3Ј) ↔ δ =
2
); δ =
A
[ddd, J3,4-H(1) = 11.8 Hz, J3,4-H(2) = J3,1Ј = 7.8 Hz, 1 H, 3-H] , 3.57
A
(ddd, J1Ј,3 = 7.6 Hz, J1Ј,OH = J1Ј,2Ј = 3.8 Hz, 1 H, 1Ј-H) , 3.76 (d,
H
2
A
A
JOH,1Ј = 3.4 Hz, 1 H, OH), 4.29–4.34 (m, 2 H, 6-H
2
)
ppm. The 5.73 (3Ј-H); δ = 129.69 (C-2Ј) ↔ δ = 5.47 (2Ј-H) ppm. IR (film): ν˜
= 3445, 2975, 2880, 1725, 1450, 1400, 1350, 1260, 1165, 1080, 970,
indicated protons were distinguished in a DQF-COSY spectrum
“H,H-COSY spectrum” (400.13 MHz, CDCl )] by their cross- 735, 645 cm . HRMS (CI, NH
171.10212; found 171.10290 (+1.3 ppm).
–
1
+
[
3
3 9 15 3
): calcd. for C H O [M + H]
peaks with protons that previously had been assigned unequivo-
1
1
cally [δ
H
( H) ↔ δ
H
( H)]: δ = 1.87 (2Ј-H) ↔ δ = 3.58 (1Ј-H); δ =
rel-(S)-3-[(S,trans)-1-Hydroxybut-2-enyl]-3,4,5,6-tetrahydro-2H-
pyran-2-one (anti-31)
1
3.58 (1Ј-H) ↔ δ = 3.57 (3-H); δ = 3.57 (3-H) ↔ δ = 1.59 (4-H ); δ
2
1
=
2
3.57 (3-H) ↔ δ = 2.03 (4-H ); δ = 1.59 (4-H ) ↔ δ = 1.93 (5-H )
2
and δ = 2.03 (4-H ) ↔ δ = 1.93 (5-H
2
); δ = 1.93 (5-H
2
) ↔ δ =
4.29–4.37 (6-H
2
) ppm. 13C NMR (100.62 MHz, CDCl
3
): δ = 15.00
A
A
A
A
(
(
C-2Ј-Me) , 20.19 (C-3Ј) , 21.34 (C-4) , 21.93 (C-5) , 29.30
C-2Ј) , 43.03 (C-3) , 68.15 (C-6) , 75.85 (C-1Ј) , 175.95 (C-
A
A
A
A
A
Following the General Procedure B the title compound was pre-
pared from δ-lactone (17, 100 mg, 1.00 mmol) and crotonaldehyde
2
) ppm. The indicated nuclei – they are non-quaternary – were
identified in an edHSQC spectrum [“short-range C,H-COSY spec-
trum” (100.62/400.13 MHz, CDCl )] by their crosspeaks with di-
rectly bonded protons (these had previously been assigned unequiv-
(
23, 140 mg, 2.00 mmol, 2.0 equiv.). Purification by flash
3
[25]
chromatography (2.0ϫ15 cm, 15 mL, c-C
12–16) rendered the product as a colorless oil (109 mg, 64%, anti-
1/syn-31 93:7). syn/anti 7:93 [determined by integration of the sig-
nals at δ = 2.52 (3-H, anti-31) vs. δ = 2.71 (3-H, syn-31) in the
6
H12/EtOAc 3:1 to 1:1,
1
3
1
ocally) [δ
C
( C) ↔ δ
H
( H)]: δ = 15.00 (C-2Ј-Me) ↔ δ = 0.92 (2Ј-
); δ = 21.34 (C-4) ↔ δ =
.59 (4-H ) and 2.03 (4-H ); δ = 21.93 (C-5) ↔ δ = 1.93 (5-H ); δ
29.30 (C-2Ј) ↔ δ = 1.87 (2Ј-H); δ = 43.03 (C-3) ↔ δ = 3.57 (3-
3
Me); δ = 20.19 (C-3Ј) ↔ δ = 1.04 (3Ј-H
1
=
3
1
2
2
1
1
4
00 MHz H NMR spectrum of the crude product]. H NMR
400.13 MHz, CDCl , contains 7% syn-31): δ = 1.50 [m , possibly
interpretable as dddd, Jgem = 13.2 Hz, J4-H(1),3 = 11.8 Hz, J4-H(1),5
(
3
c
H); δ = 68.15 (C-6) ↔ δ = 4.29–4.37 (6-H ); δ = 75.85 (C-1Ј) ↔ δ
2
=
3.58 (1Ј-H) ppm. IR (film): ν˜ = 3440, 2960, 2360, 2340, 1710,
1
A
4
=
7.6 and 7.1 Hz, 1 H, 4-H ] , 1.72 (ddd, J4Ј,3Ј = 6.5 Hz, J4Ј,2Ј =
1
6
475, 1400, 1315, 1265, 1220, 1195, 1085, 1055, 1000, 940,
5
,
–1
1.7 Hz, J
= 0.5 Hz, 3 H, 4Ј-H ), 1.86–2.04 (m, 3 H, 5-H 4-
55 cm . HRMS (pos. APCI, MeOH): calcd. for C
9
H
O
17
O
3
[M +
4Ј,1Ј
3
2
2
A
+
H ) , 2.50 [m , possibly interpretable as ddd, J
J
= 11.8 Hz,
H] 173.11777; found 173.11800 (+1.3 ppm). C
calcd. C 62.77, H 9.36; found C 62.68, H 9.42.
9
H
16
3
(172.22):
c
3,4-H(1)
A
3,4-H(2) = J3,1Ј = 7.9 Hz, 1 H, 3-H] , 3.98 (br. s, 1 H, OH), 4.24
(
br. dd, J1Ј,3 = J1Ј,2Ј = 7.9 Hz, 1 H, 1Ј-H), 4.29–4.33 (m, 2 H, 6-
rel-(S)-3-[(R,trans)-1-Hydroxybut-2-enyl]-3,4,5,6-tetrahydro-2H-
pyran-2-one (syn-31)
4
2
H ), 5.46 (ddq, J2Ј,3Ј = 15.2 Hz, J2Ј,1Ј = 7.8 Hz, J2Ј,4Ј = 1.7 Hz, 1
H, 2Ј-H), 5.77 (dqd, J3Ј,2Ј = 15.3 Hz, J3Ј,4Ј = 6.5 Hz, J3Ј,1Ј = 0.9 Hz,
1
4
A
H, 3Ј-H) ppm. The indicated protons were distinguished in a
DQF-COSY spectrum [“H,H-COSY spectrum” (400.13 MHz,
CDCl
3
)] by their crosspeaks with protons that previously had been
1
1
assigned unequivocally [δ
2.51 (3-H); δ = 2.51 (3-H) ↔ δ = 1.51 (4-H ); δ = 2.51 (3-H) ↔ δ
= 1.87–2.05 (5-H
H
( H) ↔ δ
H
( H)]: δ = 4.25 (1Ј-H) ↔ δ =
1
Following the General Procedure A the title compound was pre-
pared from δ-lactone (17, 100 mg, 1.00 mmol) and crotonaldehyde
2
2
13
4-H ); δ = 4.30–4.34 (6-H
2
) ↔ δ = 1.87–2.05 (5-
3
2
(
23, 140 mg, 2.00 mmol, 2.0 equiv.). Purification by flash
H
2
4-H ) ppm. C NMR (100.62 MHz, CDCl , contains 7% syn-
[
25]
A
A
A
A
chromatography (2.0ϫ15 cm, 15 mL, c-C
6
H12/EtOAc 3:1 to 1:1,
31): δ = 17.80 (C-4Ј) , 21.59 (C-4) , 21.83 (C-5) , 45.21 (C-3) ,
68.51 (C-6) , 73.53 (C-1Ј) , 129.87 (C-2Ј) , 129.96 (C-3Ј) , 175.26
(C-2) ppm. The indicated nuclei – they are non-quaternary – were
A
A
A
A
2
0–26) rendered the product as a colorless oil (110 mg, 65 %).
1
A
syn/anti Ͼ95:5 [the 400 MHz H NMR spectrum of the crude prod-
902
7
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7892–7918

Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
identified in an edHSQC spectrum [“short-range C,H-COSY spec-
aldehyde (24, 370 mg, 2.00 mmol, 2.0 equiv.). Purification by flash
chromatography[ (2.0ϫ15 cm, 15 mL, c-C
25]
H12/EtOAc 3:1 to 1:1,
trum” (100.62/400.13 MHz, CDCl
3
)] by their crosspeaks with di-
6
rectly bonded protons (these had previously been assigned unequiv-
15–20) rendered the product as a colorless solid (206 mg, 72%).
13
1
ocally) [δ
C
( C) ↔ δ
H
( H)]: δ = 17.80 (C-4Ј) ↔ δ = 1.73 (4Ј-H
3
); δ syn/anti 5:95 [determined by integration of the signals at δ = 2.69
1
2
1
=
21.59 (C-4) ↔ δ = 1.51 (4-H ) and 1.87–2.05 (5-H
2
4-H ); δ = (3-H, anti-32) vs. δ = 2.78 (3-H, syn-32) in the 400 MHz H NMR
4-H ); δ = 45.21 (C-3) ↔ δ = spectrum of the crude product], m.p. 66 °C. H NMR
2
1
21.83 (C-5) ↔ δ = 1.87–2.05 (5-H
2.51 (3-H); δ = 68.51 (C-6) ↔ δ = 4.30–4.34 (6-H
1Ј) ↔ δ = 4.25 (1Ј-H); δ = 129.87 (C-2Ј) ↔ δ = 5.47 (2Ј-H); δ =
129.96 (C-3Ј) ↔ δ = 5.78 (3Ј-H) ppm. IR (film): ν˜ = 3430, 2915, 7.7 Hz, 1 H, 4-H ] , 1.50 [m
2360, 1720, 1450, 1400, 1255, 1220, 1165, 1080, 1030, 970, 770,
40 cm–1. HRMS (CI, NH [M + H]+
6 ): calcd. for C
171.10212; found 171.10220 (+0.5 ppm).
2
2
); δ = 73.53 (C- (400.13 MHz, CDCl ): δ = 1.38 [m , possibly interpretable as dddd,
3
c
J
gem = 13.7 Hz, J4-H(1),3 = 12.1 Hz, J4-H(1),5-H(1) = J4-H(1),5-H(2)
=
1
A
c
, possibly interpretable as dddd, Jgem
= 14.1 Hz, J4-H(2),3 = 7.3 Hz, J4-H(2),5-H(1) = 6.6 Hz, J4-H(2),5-H(2)
=
4
2 A
3
9
H
15
O
3
6.0 Hz, J4-H(2),6-H(2) = 0.7 Hz, 1 H, 4-H ] , 1.74–1.91 (m, 2 H, 5-
)A, 2.67 [ddd, J3,4-H(1) = 12.0 Hz, J3,1Ј = 8.7 Hz, J3,4-H(2)
.8 Hz, 1 H, 3-H], 4.25–4.36 (m, 2 H, 6-H ), 4.60 (br. s, 1 H, OH),
.80 (d, J1Ј,3 = 8.7 Hz, 1 H, 1Ј-H), 7.25 (m , 2 H, 2ϫortho-H), 7.49
, 2 H, 2ϫmeta-H) ppm. The indicated protons were distin-
guished in a DQF-COSY spectrum [“H,H-COSY spectrum”
H
2
=
7
4
(m
c
2
rel-(S)-3-[(S)-(4-Bromophenyl)(hydroxy)methyl]-3,4,5,6-tetrahydro-
H-pyran-2-one (syn-32)
c
2
A
(
400.13 MHz, CDCl
3
)] by their crosspeaks with protons that pre-
1
1
viously had been assigned unequivocally [δ
2
=
(
(
H
( H) ↔ δ
H
( H)]: δ =
1
2
.67 (3-H) ↔ δ = 1.38 (4-H ); δ = 2.67 (3-H) ↔ δ = 1.50 (4-H ); δ
1
3
4.25–4.36 (6-H
2
2
) ↔ δ = 1.74–1.91 (5-H ) ppm. C NMR
Following the General Procedure A the title compound was pre-
pared from δ-lactone (17, 100 mg, 1.00 mmol) and 4-bromobenz-
aldehyde (24, 370 mg, 2.00 mmol, 2.0 equiv.). Purification by flash
A
A
3
100.62 MHz, CDCl ): δ = 21.65 (C-4) , 21.71 (C-5) , 46.59
A
A
A
C-3) , 68.58 (C-6) , 74.46 (C-1Ј) , 122.23 (C-4ЈЈ), 128.79
[
25]
(C-2ЈЈ, C-6ЈЈ), 131.74 (C-3ЈЈ, C-5ЈЈ), 139.23, (C-1ЈЈ), 175.31 (C-
chromatography (2.0ϫ15 cm, 15 mL, c-C
4–21) rendered the product as a colorless solid (189 mg, 66%).
syn/anti 97:3 [determined by integration of the signals at δ = 4.80
6
H12/EtOAc 3:1 to 1:1,
A
2
) ppm. The indicated nuclei – they are non-quaternary – were
identified in an edHSQC spectrum [“short-range C,H-COSY spec-
trum” (100.62/400.13 MHz, CDCl )] by their crosspeaks with di-
rectly bonded protons (these had previously been assigned unequiv-
1
1
3
(
1Ј-H, anti-32) vs. δ = 5.47 (1Ј-H, syn-32) in the 400 MHz H NMR
1
spectrum of the crude product], m.p. 71 °C. H NMR
400.13 MHz, CDCl ): δ = 1.48–1.58 (m, 1 H, 4-H ) , 1.73–1.91
3
1
3
1
A
1
1
A
ocally) [δ
C
( C) ↔ δ ( H)]: δ = 21.65 (C-4) ↔ δ = 1.38 (4-H )
A
H
(
(
2
2
A
and 1.50 (4-H ); δ = 21.71 (C-5) ↔ δ = 1.74–1.91 (5-H
4
2
); δ =
6.59 (C-3) ↔ δ = 2.67 (3-H); δ = 68.58 (C-6) ↔ δ = 4.25–4.36
m, 3 H, 4-H , 5-H
2 c
) , 2.77 (m , possibly interpretable as ddd, J3,4
A
A
=
10.4 and 7.8 Hz, J3,1Ј = 2.6 Hz, 1 H, 3-H), 3.26 (d, JOH,1Ј
=
A
(
6-H
2
); δ = 74.46 (C-1Ј) ↔ δ = 4.80 (1Ј-H) ppm. IR (film): ν˜ =
4.6 Hz, 1 H, OH), 4.23–4.32 (m, 2 H, 6-H
2
), 5.47 (dd, J1Ј,OH = J1Ј,3
3
440, 2960, 1715, 1490, 1400, 1350, 1265, 1165, 1085, 1070, 1010,
=
2
3.3 Hz, 1 H, 1Ј-H), 7.23 (m
c
, 2 H, 2ϫortho-H), 7.47 (m
ϫmeta-H) ppm. The indicated protons were distinguished in a
DQF-COSY spectrum [“H,H-COSY spectrum” (400.13 MHz,
c
, 2 H,
–
1
A
965, 840, 775, 735 cm . HRMS (pos. APCI, MeOH): calcd. for
C H O
12 14 3
Br [M + H]+ 285.01263; found 285.01300 (+1.3 ppm).
CDCl
3
)] by their crosspeaks with protons that previously had been
rel-(S)-3-[(S)-1-Hydroxy-2-methylpropyl]-3-methyl-3,4,5,6-tetra-
hydro-2H-pyran-2-one (anti-33) by Ti-Mediated Aldol Addition
1
1
assigned unequivocally [δ
H
( H) ↔ δ
H
( H)]: δ = 2.77 (3-H) ↔ δ =
1
2
1.48–1.58 (4-H ); δ = 2.77 (3-H) ↔ δ = 1.73–1.91 (4-H , 5-H
2
); δ
2
13
=
4.23–4.32 (6-H
2
), ↔ δ = 1.73–1.91 (4-H , 5-H
2
) ppm. C NMR
A
A
(
(
100.62 MHz, CDCl
3
): δ = 17.80 (C-4) , 22.19 (C-5) , 47.13
A
A
A
C-3) , 69.07 (C-6) , 71.22 (C-1Ј) , 121.24 (C-para), 127.56 (2ϫC-
A
A
ortho) , 131.48 (2ϫC-meta) , 139.97 (C-ipso), 173.93 (C-2) ppm.
Following the General Procedure A the title compound was pre-
pared from α-methyl-δ-lactone (18, 114 mg, 1.00 mmol) and iso-
A
The indicated nuclei – they are non-quaternary – were identified
in an edHSQC spectrum [“short-range C,H-COSY spectrum”
butyraldehyde (22, 144 mg, 2.00 mmol, 2.0 equiv.). Purification by
(
100.62/400.13 MHz, CDCl
3
)] by their crosspeaks with directly
[25]
2
flash chromatography (2.0ϫ20 cm, 15 mL, pentane/Et O 1:2, 8–
bonded protons (these had previously been assigned unequivocally)
2
3
0) rendered the product as a colorless oil (112 mg, 60%). syn/anti
7:63 [determined by integration of the signals at δ = 1.39 (3-Me,
1
3
1
1
[δ
C
( C) ↔ δ ( H)]: δ = 17.80 (C-4) ↔ δ = 1.48–1.58 (4-H ) and
2 2
H
1
H
4
.73–1.91 (4-H , 5-H
2
); δ = 22.19 (C-5) ↔ δ = 1.73–1.91 (4-H , 5-
); δ = 47.13 (C-3) ↔ δ = 2.77 (3-H); δ = 69.07 (C-6) ↔ δ = 4.23–
); δ = 71.22 (C-1Ј) ↔ δ = 5.47 (1Ј-H); δ = 127.56 (2ϫC-
ortho) ↔ δ = 7.23 (2ϫortho-H); δ = 131.48 (2ϫC-meta) ↔ δ =
1
anti-33) vs. δ = 1.42 (3-Me, syn-33) in the 400 MHz H NMR spec-
trum of the crude product]. H NMR (400.13 MHz, CDCl ,
3
2
1
.32 (6-H
2
syn/anti 37:63 mixture of diastereomers): δ = 0.87 [d, J2Ј-Me,2Ј
=
6.8 Hz, 3 H, 2Ј-Me (syn-33)], 0.98 [d, J2Ј-Me,2Ј = 6.9 Hz, 3 H, 2Ј-
7.47 (2ϫmeta-H) ppm. IR (film): ν˜ = 3450, 2965, 1720, 1490, 1460,
Me (anti-33)], 1.02 [d, J3Ј-H3,2Ј = 6.6 Hz, 3 H, 3Ј-H
3
(anti-33)], 1.05
–
1
1
400, 1350, 1250, 1165, 1070, 1030, 1010, 960, 830, 775 cm
.
4
[
d, J3Ј-H3,2Ј = 6.8 Hz, 3 H, 3Ј-H
3
(syn-33)], 1.39 [d, J3-Me,4 = 0.4 Hz,
HRMS (pos. APCI, MeOH): calcd. for C13
99.02773; found 299.02774 (Ϯ0.0 ppm).
16 3
H O
Br [M + H]+
3
H, 3-Me (anti-33)], 1.41 [s, 3 H, 3-Me (syn-33)], 1.55–1.62 [m, 1
2
1
1
H, 4-H (syn-33)], 1.69–1.77 [m, 1 H, 4-H (anti-33)], 1.80–1.91 [m,
2
1
rel-(S)-3-[(R)-(4-Bromophenyl)(hydroxy)methyl]-3,4,5,6-tetrahydro- 3 H, probably 4-H (anti-33), 5-H (both diastereomers), 2Ј-H (anti-
2
2
2H-pyran-2-one (anti-32)
33)], 1.91–2.10 [m, 3 H, probably 4-H (syn-33), 5-H (both dia-
stereomers), 2Ј-H (syn-33)], 2.87 [d, JOH,1Ј-H = 4.0 Hz, 1 H, OH
(
J
=
6
anti-33)], 3.24 [d, JOH,1Ј = 8.4 Hz, 1 H, OH (syn-33)], 3.51 [dd,
1Ј,OH = 8.5 Hz, J1Ј,2Ј = 2.9 Hz, 1 H, 1Ј-H (syn-33)], 3.70 [dd, J1Ј,2Ј
4.8 Hz, J1Ј,OH = 4.0 Hz, 1 H, 1Ј-H (anti-33)] 4.24–4.33 [m, 1 H,
1
2
-H (both diastereomers)], 4.39–4.47 [m, 1 H, 6-H (both dia-
Following the General Procedure B the title compound was pre-
pared from δ-lactone (17, 100 mg, 1.00 mmol) and 4-bromobenz-
stereomers)] ppm. IR (film): ν˜ = 3445, 2975, 2880, 1725, 1450,
1400, 1350, 1260, 1165, 1080, 970, 735, 645 cm . HRMS (pos.
–
1
Eur. J. Org. Chem. 2015, 7892–7918
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7903

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
APCI, MeOH): calcd. for C
9
H
19
O
3
[M + H]+ 187.13342; found fication by flash chromatography[25] (2.5ϫ20 cm, 15 mL, pentane/
1
87.13320 (–1.2 ppm). C
9
H
18
O
3
(174.24): calcd. C 64.49, H 9.74;
Et
an off-white solid (145 mg, 61 %, syn-34/anti-34 64:36). syn/anti
9:41 [determined by integration of the signals at δ = 1.26 (3-Me,
syn-34) vs. δ = 1.32 (3-Me, anti-34) in the 300 MHz H NMR spec-
trum of the crude product], m.p. (for the syn-34/anti-34 64:36 mix-
ture): 53 °C. An analytical sample of syn-34 (!) was obtained by
flash chromatography (cf. footnote 33); it eluted slightly faster than
2
O 1:2, fractions 14–27) rendered a mixture of diastereomers as
found C 64.22, H 10.02.
5
rel-(S)-3-[(S)-1-Hydroxy-2-methylpropyl]-3-methyl-3,4,5,6-tetra-
hydro-2H-pyran-2-one (anti-33) by B-Mediated Aldol Addition
1
anti-34 and was obtained as a colorless oil. Analytical data for syn-
1
3
4 (!): H NMR (400.13 MHz, CDCl
3
): δ = 1.26 (s, 3 H, 3-Me),
Following the General Procedure B the title compound was pre-
pared from α-methyl-δ-lactone (18, 114 mg, 1.00 mmol) and iso-
1.49 [dddd, Jgem = 13.3 Hz, J4-H(1),5-H(2) = 5.0 Hz, J
=
=
4-H(1),5-H(1)
1
A
3.6 Hz, J
6.5 Hz, J
4
-H(1),6-H(2)
= 2.0 Hz, 1 H, 4-H ] , 1.73 (ddd, J
4Ј,3Ј
4
= 1.7 Hz, 5J4Ј,1Ј = 0.5 Hz, 3 H, 4Ј-H ), 1.83 [dddd,
butyraldehyde (22, 144 mg, 2.00 mmol, 2.0 equiv.). Purification by
4
Ј,2Ј
3
flash chromatography[ (2.0ϫ20 cm, 15 mL, pentane/Et
25]
O 1:1,
2
Jgem = 14.2 Hz, J5-H(1),4-H(1) = 8.5 Hz, J
5-H(1),4-H(2)
= 4.1 Hz,
= 14.4 Hz,
1
A
1
1–30) rendered the product as a colorless oil (157 mg, 84 %).
J5-H(1),6-H(1) = 4.0 Hz, 1 H, 5-H ] , 1.95 [ddddd, J
gem
1
syn/anti Ͻ5:95 [the 400 MHz H NMR spectrum of the crude prod-
uct contained no signals clearly attributable to syn-33]. H NMR
J5-H(2),4-H(2) = 11.7 Hz, J5-H(2),6-H(1) = 10.6 Hz, J
4.4 Hz, J5-H(2),6-H(2) = 3.9 Hz, 1 H, 5-H ] , 2.10 [ddd, J
=
5-H(2),4-H(1)
1
2 A
gem
=
2
(
400.13 MHz, CDCl
.99 (d, J3Ј,2Ј = 6.6 Hz, 3 H, 3Ј-H
3
): δ = 0.92 (d, J2Ј-Me,2Ј = 6.9 Hz, 3 H, 2Ј-Me), 13.2 Hz, J
-H(2),5-H(2)
= 11.9 Hz, J4-H(2),5-H(1) = 4.1 Hz, 1 H, 4-H ]
OH,1Ј
= 5.9 Hz, 1 H, OH), 4.22 (dd, J1Ј,2Ј = 7.3 Hz,
4
), 1.36 (d, 4J3-Me,4 = 0.4 Hz, 3 H,
A
0
3
2
J
J
3
A
, 2.68 (d, J
-Me), 1.66–1.74 (m, 1 H, 4-H ) , 1.77–1.88 (m, 3 H, 4-H , 5-H , J1Ј,OH = 5.6 Hz, 1 H, 1Ј-H)A superimposed by 4.26 [m , possibly
1
2
1
c
A
2 A
Ј-H) , 1.93–2.05 (m, 1 H, 5-H ) , 3.00 (br. s, 1 H, OH), 3.67 (d,
1Ј,2Ј = 5.1 Hz, 1 H, 1Ј-H), 4.24 [m , possibly interpretable as ddd,
gem = 11.3 Hz, J6-H(1),5 = 11.3 Hz and 3.5 Hz
interpretable as ddd, J
3.5 Hz, 1 H, 6-H ], 4.38 [dddd, J
= J6-H(1),5-H(2) = 10.9 Hz, J6-H(1),5-H(1)
=
=
gem
1
c
gem
= 10.9 Hz, J6-H(2),5-H(1)
1
2
,
1 H, 6-H ], 4.41 [m
c
,
4.5 Hz, J6-H(2),5-H(2) = 3.5 Hz, J6-H(2),4-H(1) = 2.1 Hz, 1 H, 6-H ],
possibly interpretable as dddd, Jgem = 11.1 Hz, J6-H(1),5 = 4.9 Hz
and 2.8 Hz, J6-H(1),4-H(1) = 2.2 Hz, 1 H, 6-H ] ppm. The indicated H), 5.77 (dqd, J
protons were distinguished in a DQF-COSY spectrum [“H,H- H, 3Ј-H) ppm. The indicated protons were distinguished in a
5.42 (ddq, J2Ј,3Ј = 15.2 Hz, J2Ј,1Ј = 7.9 Hz, J2Ј,4Ј = 1.7 Hz, 1 H, 2Ј-
4
2
A
4
3
A
Ј,2Ј
3Ј,1Ј
= 15.2 Hz, J3Ј,4Ј = 6.5 Hz, J = 1.0 Hz, 1
COSY spectrum” (400.13 MHz, CDCl
3
)] by their crosspeaks with
DQF-COSY spectrum [“H,H-COSY spectrum” (400.13 MHz,
1
protons that previously had been assigned unequivocally [δ
H
( H)
( H)]: δ = 3.67 (1Ј-H) ↔ δ = 1.77–1.88 (4-H , 5-H , 2Ј-H); δ
CDCl )] by their crosspeaks with protons that previously had been
3
1
2
1
1
1
↔
δ
H
assigned unequivocally [δ ( H) ↔ δ ( H)]: δ = 5.42 (2Ј-H) ↔ δ =
4.22 (1Ј-H); δ = 4.26 (6-H ) ↔ δ = 1.83 (5-H ) and δ = 4.38 (6-H )
H
1
H
1
2
1
1
2
=
4.24 (6-H ) ↔ δ = 1.77–1.88 (4-H , 5-H , 2Ј-H) and δ = 4.41 (6-
2
2
1
1
1
1
2
H ) ↔ δ = 1.77–1.88 (4-H , 5-H , 2Ј-H); δ = 4.24 (6-H ) ↔ δ =
↔ δ = 1.83 (5-H ); δ = 4.26 (6-H ) ↔ δ = 1.95 (5-H ) and δ = 4.38
2 2 1 1
2
2
2
1
1
2
1
.93–2.05 (5-H ) and δ = 4.41 (6-H ) ↔ δ = 1.93–2.05 (5-H ); δ =
(6-H ) ↔ δ = 1.95 (5-H ); δ = 1.83 (5-H ) ↔ δ = 1.49 (4-H ) and
2 1 1
2
1
1
.77–1.88 (4-H , 5-H , 2Ј-H) ↔ δ = 1.66–1.74 (4-H ) and δ = 1.93–
δ = 1.95 (5-H ) ↔ δ = 1.49 (4-H ); δ = 1.83 (5-H ) ↔ δ = 2.10
2 2 2 13
2
1
2
.05 (5-H ) ↔ δ = 1.66–1.74 (4-H ); δ = 1.93–2.05 (5-H ) ↔ δ =
(4-H ) and δ = 1.95 (5-H ) ↔ δ = 2.10 (4-H ) ppm. C NMR
A A
2
1
1
.77–1.88 (4-H , 5-H , 2Ј-H) and δ = 1.66–1.74 (4-H ) ↔ 1.77–1.88
3
(100.62 MHz, CDCl ): δ = 17.97 (C-4Ј) , 20.74 (C-5) , 24.16 (C-
2
1
13
A
A
A
A
A
(
3
4-H , 5-H , 2Ј-H) ppm. C NMR (100.62 MHz, CDCl ): δ = 3-Me) , 27.99 (C-4) , 47.32 (C-3) , 70.25 (C-6) , 78.54 (C-1Ј) ,
A
A
A
A
A
A
A
1
2
1
8.39 (C-3Ј) , 20.23 (C-5) , 21.71 (C-2Ј-Me) , 23.27 (C-3-Me) , 128.46 (C-2Ј) , 130.79 (C-3Ј) , 176.80 (C-2) ppm. The indicated
A A A A
8.20 (C-4) , 30.33 (C-2Ј) , 46.29 (C-3) , 70.30 (C-6) , 79.66 (C- nuclei – they are non-quaternary – were identified in an edHSQC
A
A
Ј) , 176.85 (C-2) ppm. The indicated nuclei – they are non-qua-
spectrum [“short-range C,H-COSY spectrum” (100.62/
ternary – were identified in an edHSQC spectrum [“short-range
400.13 MHz, CDCl )] by their crosspeaks with directly bonded pro-
3
1
3
C,H-COSY spectrum” (100.62/400.13 MHz, CDCl
3
)] by their tons (these had previously been assigned unequivocally) [δ ( C)
C
1
crosspeaks with directly bonded protons (these had previously been
↔ δ ( H)]: δ = 17.97 (C-4Ј) ↔ δ = 1.73 (4Ј-H ); δ = 20.74 (C-5)
H
3
1
3
1
1
2
assigned unequivocally) [δ
0.99 (3Ј-H ); δ = 20.23 (C-5) ↔ δ = 1.77–1.88 (4-H , 5-H , 2Ј- (3-Me); δ = 27.99 (C-4) ↔ δ = 1.49 (4-H ) and 2.10 (4-H ); δ =
2
1 2
C
( C) ↔ δ
H
( H)]: δ = 18.39 (C-3Ј) ↔ δ
↔ δ = 1.83 (5-H ) and 1.95 (5-H ); δ = 24.16 (C-3-Me) ↔ δ = 1.26
2
1
1 2
=
3
H) and 1.93–2.05 (5-H ); δ = 21.71 (C-2Ј-Me) ↔ δ = 0.92 (2Ј-Me);
δ = 23.27 (C-3-Me) ↔ δ = 1.36 (3-Me); δ = 28.20 (C-4) ↔ δ =
70.25 (C-6) ↔ δ = 4.26 (6-H ) and 4.38 (6-H ); δ = 78.54 (C-1Ј) ↔
δ = 4.22 (1Ј-H); δ = 128.46 (C-2Ј) ↔ δ = 5.42 (2Ј-H); δ = 130.79
1
2
1
1
2
(
.66–1.74 (4-H ) and 1.77–1.88 (4-H , 5-H , 2Ј-H); δ = 30.33 (C- (C-3Ј) ↔ δ = 5.77 (3Ј-H). IR (film): ν = 3445, 2965, 2940, 2360,
˜
2 1
Ј) ↔ δ = 1.77–1.88 (4-H , 5-H , 2Ј-H); δ = 70.30 (C-6) ↔ δ = 4.24
2340, 1710, 1450, 1400, 1375, 1270, 1150, 1110, 1070, 1020, 970,
1
2
–1
6-H ) and 4.41 (6-H ); δ = 79.66 (C-1Ј) ↔ δ = 3.67 (1Ј-H). IR 930, 770, 650 cm . HRMS (pos. APCI, MeOH): calcd. for
C H O [M + H]+ 185.11777; found 185.11760 (Δ = 0.9 ppm).
film): ν˜ = 3450, 2965, 2880, 2360, 1710, 1465, 1400, 1265, 1215,
(
1
0
17
3
1
6
165, 1140, 1115, 1075, 1040, 1015, 1000, 950, 770, 755, 720, 675,
10 16 3
C H O (184.23): calcd. C 65.19, H 8.75; found C 64.92, H 8.93.
–1
50 cm . HRMS (pos. APCI, MeOH): calcd. for C
9
H
O
19
O
3
[M +
rel-(S)-3-[(S,trans)-1-Hydroxybut-2-enyl]-3-methyl-3,4,5,6-tetra-
hydro-2H-pyran-2-one (anti-34)
+
H] 187.13342; found 187.13370 (+1.5 ppm). C
calcd. C 64.49, H 9.74; found C 64.24, H 9.53.
9 18
H
3
(174.24):
rel-(S)-3-[(R,trans)-1-Hydroxybut-2-enyl]-3-methyl-3,4,5,6-tetra-
hydro-2H-pyran-2-one (syn-34)
Following the General Procedure B the title compound was pre-
pared from α-methyl-δ-lactone (18, 114 g, 1.00 mmol) and croton-
aldehyde (23, 140 mg, 2.00 mmol, 2.0 equiv.). Purification by flash
chromatography[ (2.0ϫ15 cm, 15 mL, pentane/Et
25]
O 1:3, 7–13)
Following the General Procedure A the title compound was pre-
pared from α-methyl-δ-lactone (18, 150 mg, 1.32 mmol) and
crotonaldehyde (23, 0.30 mL, 256 mg, 3.65 mmol, 2.8 equiv.). Puri-
2
rendered the product as a colorless oil (83 mg, 45%). syn/anti 7:93
[determined by integration of the signals at δ = 1.26 (3-Me, syn-34)
7904
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7892–7918

Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
1
2 A
vs. δ = 1.32 (3-Me, anti-34) in the 400.13 MHz H NMR spectrum 11.8 Hz, J4-H(2),5-H(1) = 3.4 Hz, 1 H, 4-H ] , 1.92 [ddddd, Jgem
=
1
of the crude product]. H NMR (400.13 MHz, CDCl
H, 3-Me), 1.57–1.63 (m, 1 H, 4-H ) , 1.73 (ddd, J4Ј,3Ј = 6.5 Hz,
), 1.78–1.87 (m, 2 H, 4-
H , 5-H ) , 1.91–2.03 (m, 1 H, 5-H ) , 3.48 (d, JOH,1Ј = 2.2 Hz, 1
3
): δ = 1.31 (s,
13.8 Hz, J5-H(2),4-H(2) = 11.7 Hz, J5-H(2),6-H(1) = 10.5 Hz, J5-H(2),6-H(2)
1
A
2 A
3
J
= 4.9 Hz, J5-H(2),4-H(1) = 3.3 Hz, 1 H, 5-H ] , 4.17 [ddd, Jgem
=
4
5
1
4Ј,2Ј = 1.7 Hz, J4Ј,1Ј = 0.7 Hz, 3 H, 4Ј-H
3
J
J
J
6-H(1),5-H(2) = 10.9 Hz, J6-H(1),5-H(1) = 3.8 Hz, 1 H, 6-H ], 4.29 (d,
2
1 A
2 A
OH,1Ј-H = 1.7 Hz, 1 H, OH), 4.40 [dddd, Jgem = 11.2 Hz,
4
5
4
H, OH), 4.21 (ddq, J1Ј,2Ј = 7.3 Hz, J1Ј,OH = 2.1 Hz, J1Ј,3Ј = J1Ј,4Ј
6-H(2),5-H(2) = 5.0 Hz, J6-H(2),5-H(1) = 3.4 Hz
,
J
6-H(2),4-H(1) = 1.9 Hz,
A
2
=
=
0.7 Hz, 1 H, 1Ј-H) , 4.28 [m
10.8 Hz, J6-H(1),5 = 10.8 and 3.4 Hz
c
, possibly interpretable as ddd, Jgem
1 H, 6-H ], 4.94 (d, J1Ј-H,OH = 1.7 Hz, 1 H, 1Ј-H) 7.28 (m
c
, 2ϫor-
, 2ϫmeta-H) ppm. AThe indicated protons were
distinguished in a DQF-COSY spectrum [“H,H-COSY spectrum”
1
,
1 H, 6-H ], 4.42 [m
c
, possibly
tho-H), 7.46 (m
c
interpretable as dddd, Jgem = 11.1 Hz, J6-H(1),5 = 4.8 and 3.7 Hz,
6-H(1),4-H = 1.9 Hz, 1 H, 6-H ], 5.53 (ddq, J2Ј,3Ј = 15.3 Hz, J2Ј,1Ј
4
2
J
(400.13 MHz, CDCl
3
)] by their crosspeaks with protons that pre-
4
1
1
=
J
7.3 Hz, J2Ј,4Ј = 1.7 Hz, 1 H, 2Ј-H), 5.80 (dqd, J3Ј,2Ј = 15.3 Hz, viously had been assigned unequivocally [δ
H
( H) ↔ δ
H
( H)]: δ =
3Ј,4Ј = 6.5 Hz, 4
J
3Ј,1Ј = 1.0 Hz, 1 H, 3Ј-H) ppm. AThe indicated
4.17 (6-H ) ↔ δ = 1.70 (5-H ) and δ = 4.40 (6-H ) ↔ δ = 1.70 (5-
1
1
2
1
1
2
2
protons were distinguished in a DQF-COSY spectrum [“H,H- H ); δ = 4.17 (6-H ) ↔ δ = 1.92 (5-H ) and δ = 4.40 (6-H ) ↔ δ =
)] by their crosspeaks with
protons that previously had been assigned unequivocally [δ
2
1
1
COSY spectrum” (400.13 MHz, CDCl
3
1.92 (5-H ); δ = 1.70 (5-H ) ↔ δ = 1. 28 (4-H ) and δ = 1.92 (5-
2 1 1 2
1
H
1
( H)
H ) ↔ δ = 1.28 (4-H ); δ = 1.70 (5-H ) ↔ δ = 1.80 (4-H ) and δ =
2 2 13
1
↔
δ
H
( H)]: δ = 5.53 (2Ј-H) ↔ δ = 4.21 (1Ј-H); δ = 4.28 (6-H ) ↔
1.92 (5-H ) ↔ δ = 1.80 (4-H ) ppm. C NMR (100.62 MHz,
A A A
2
1
2
3
δ = 1.78–1.87 (4-H , 5-H ) and δ = 4.42 (6-H ) ↔ δ = 1.78–1.87 CDCl ): δ = 20.02 (C-5, C-3-Me) , 29.92 (C-4) , 46.43 (C-3) ,
2
1
1
2
A
A
(
(
1
4-H , 5-H ); δ = 4.28 (6-H ) ↔ δ = 1.91–2.03 (5-H ) and δ = 4.42
6-H ) ↔ δ = 1.91–2.03 (5-H ); δ = 1.78–1.87 (4-H , 5-H ) ↔ δ =
.57–1.63 (4-H ) and δ = 1.91–2.03 (5-H ) ↔ δ = 1.57–1.63 (4-H );
δ = 1.91–2.03 (5-H ) ↔ δ = 1.78–1.87 (4-H , 5-H ) and δ = 1.57– trum [“short-range C,H-COSY spectrum” (100.62/400.13 MHz,
.63 (4-H ) ↔ δ = 1.78–1.87 (4-H , 5-H ) ppm. C NMR
): δ = 17.96 (C-4Ј) , 20.48 (C-5) , 20.78 (C- had previously been assigned unequivocally) [δ
-Me) , 30.36 (C-4) , 45.96 (C-3) , 70.48 (C-6) , 77.41 (C-1Ј) ,
27.89 (C-2Ј) , 130.65 (C-3Ј) , 177.25 (C-2) ppm. The indicated
nuclei – they are non-quaternary – were identified in an edHSQC
spectrum [“short-range C,H-COSY spectrum” (100.62/
70.67 (C-6) , 77.27 (C-1Ј) , 122.13 (C-para), 129.81 (2ϫC-ortho),
131.15 (2ϫC-meta), 137.73 (C-ipso), 177.44 (C-2) ppm. The indi-
cated nuclei – they are non-quaternary – were identified in a spec-
2
2
2
1
A
1
2
1
2
2
1
1
2
1
13
1
(
3
1
CDCl
3
)] by their crosspeaks with directly bonded protons (these
A
A
13
1
100.62 MHz, CDCl
3
A
C
( C) ↔ δ
H
( H)]: δ
A
A
A
A
1
2
= 20.02 (C-5) ↔ δ = 1.70 (5-H ) and 1.92 (5-H ); δ = 20.02 (C-3-
Me) ↔ δ = 1.37 (3-Me); δ = 29.92 (C-4) ↔ δ = 1.28 (4-H ) and
1.80 (4-H ); δ = 70.67 (C-6) ↔ δ = 4.17 (6-H ) and 4.40 (6-H ); δ
= 77.27 (C-1Ј) ↔ δ = 4.94 (1Ј-H). IR (film): ν˜ = 3840, 3430, 2960,
A
A
A
1
2
1
2
4
00.13 MHz, CDCl
3
)] by their crosspeaks with directly bonded pro- 2360, 1700, 1490, 1400, 1265, 1220, 1165, 1135, 1075, 1010, 945,
1
3
–1
tons (these had previously been assigned unequivocally) [δ
C
( C)
); δ = 20.48 (C-5)
840, 770, 645 cm . HRMS (pos. APCI, MeOH): calcd. for
1
Br [M + H]+ 299.02828; found 299.02800 (Δ = 0.9 ppm).
15BrO (299.16): calcd. C 52.19, H 5.05; found C 52.56, H
↔
↔
δ
H
( H)]: δ = 17.96 (C-4Ј) ↔ δ = 1.73 (4Ј-H
3
C
C
13
H
H
16 3
O
2
1
2
δ = 1.78–1.87 (4-H , 5-H ) and 1.91–2.03 (5-H ); δ = 20.78 (C-
13
3
2
3
5
4
-Me) ↔ δ = 1.31 (3-Me); δ = 30.36 (C-4) ↔ δ = 1.78–1.87 (4-H ,
-H ) and 1.57–1.63 (4-H ); δ = 70.48 (C-6) ↔ δ = 4.28 (6-H ) and
5.21.
1
1
1
rel-(S)-3-[(S)-(4-Bromophenyl)(hydroxy)methyl]-3-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (anti-35)
1
.42 (6-H ); δ = 77.41 (C-1Ј) ↔ δ = 4.21 (1Ј-H); δ = 127.89 (C-2Ј)
↔
δ = 5.53 (2Ј-H); δ = 130.65 (C-3Ј) ↔ δ = 5.80 (3Ј-H). IR (film):
ν˜ = 3450, 2965, 2940, 2880, 2360, 1710, 1480, 1455, 1400, 1375,
1
9
345, 1305, 1265, 1215, 1165, 1135, 1110, 1190, 1170, 1020, 970,
–
1
50, 840, 800, 745, 705, 675, 647 cm . HRMS (pos. APCI,
+
MeOH): calcd. for C10
+2.8 ppm). C10
4.92, H 8.93.
H
17
O
3
[M + H] 185.11777; found 185.11800
(
6
16 3
H O (184.23): calcd. C 65.19, H 8.75; found C
Following the General Procedure B the title compound was pre-
pared from α-methyl-δ-lactone (18, 1.18 mg, 10.3 mmol) and 4-
bromobenzaldehyde (24, 2.27 g, 12.3 mmol, 1.2 equiv.). Purifica-
rel-(S)-3-[(R)-(4-Bromophenyl)(hydroxy)methyl]-3-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (syn-35)
[25]
tion by flash chromatography
Et
2.34 g, 78%). syn/anti 8:92 [determined by integration of the sig-
nals at δ = 4.94 (1Ј-H, syn-35) vs. δ = 4.99 (1Ј-H, anti-35) in the
(5.0ϫ 20 cm, 50 mL, pentane/
2
O 10:1 to 2:1, 27–33) rendered the product as a colorless solid
(
1
1
4
00 MHz H NMR spectrum of the crude product], m.p. 76 °C. H
NMR (400.13 MHz, CDCl ): δ = 1. 23 [dddd, Jgem = 13.4 Hz,
3
4
Following the General Procedure A the title compound was pre-
pared from α-methyl-δ-lactone (18, 114 mg, 1.00 mmol) and 4-
bromobenzaldehyde (24, 410 mg, 2.00 mmol, 2.2 equiv.). Purifica-
tion by flash chromatography[ (3.0ϫ 20 cm, 20 mL, pentane/
J4-H(1),5-H(1) = 4.9 Hz, J4-H(1),5-H(2) = 3.5 Hz, J4-H(1),6-H(2) = 2.1 Hz,
1 H, 4-H ] superimposed by 1.25 (s, 3 H, 3-Me), 1.75 [ddddd, Jgem
1
A
= 14.5 Hz, J5-H(1),4-H(1) = 4.5 Hz, J5-H(1),4-H(2) = J5-H(1),6-H(1)
=
25]
1 A
J5-H(1),6-H(2) = 3.7 Hz, 1 H, 5-H ] , 1.89 [ddddd, Jgem = 14.4 Hz,
Et
2
O 2:1 to 1:2, 45–73) rendered the product as a colorless solid
J
5-H(2),4-H(2) = 12.2 Hz, J5-H(2),6-H(1) = 11.0 Hz, J5-H(2),6-H(2)
=
=
2
A
(132 mg, 44%). Additionally, a fraction containing anti-35 (33–43,
4.6 Hz, J5-H(2),4-H(1) = 3.5 Hz, 1 H, 5-H ] , 2.17 [ddd, Jgem
9
5
5 mg, 32%) was collected (overall yield: 227 mg, 76%). syn/anti 13.1 Hz, J4-H(2),5-H(2) = 12.4 Hz, J4-H(2),5-H(1) = 4.0 Hz, 1 H,
2
A
0:50 [determined by integration of the signals at δ = 4.94 (1Ј-H,
4-H ] , 3.10 (d, JOH,1Ј-H = 5.6 Hz, 1 H, OH), 4.22 [ddd, Jgem =
J6-H(1),5-H(2) = 11.0 Hz, J6-H(1),5-H(1) = 3.5 Hz, 1 H, 6-H ], 4.39
1
1
syn-35) vs. δ = 4.99 (1Ј-H, anti-35) in the 400 MHz H NMR spec-
trum of the crude product], m.p. 69 °C. 1H NMR (400.13 MHz,
[dddd, Jgem = 11.0 Hz, J6-H(2),5-H(2) = 4.6 Hz, J6-H(2),5-H(1) = 3.3 Hz,
2
CDCl
3
): δ = 1.28 [dddd, Jgem = 13.4 Hz, J4-H(1),5-H(1) = 5.2 Hz,
J
6-H(2),4-H(1) = 2.1 Hz, 1 H, 6-H ], 5.00 (d, J1Ј-H,OH = 5.5 Hz,
4
1 A
J
J
4-H(1),5-H(2) = 3.3 Hz, J4-H(1),6-H(2) = 2.0 Hz, 1 H, 4-H ] , 1.37 [d, 1 H, 1Ј-H), 7.22 (m
c
, 2 H, 2ϫortho-H), 7.48 (m
H) ppm. The indicated protons were distinguished in a DQF-
COSY spectrum [“H,H-COSY spectrum” (400.13 MHz, CDCl )]
by their crosspeaks with protons that previously had been assigned
c
, 2 H, 2ϫmeta-
4
A
3-Me,4-H(1) = 0.4 Hz, 3 H, 3-Me], 1.70 [ddddd, Jgem = 13.7 Hz,
J5-H(1),4-H(1) = 5.0 Hz, J5-H(1),4-H(2) = J5-H(1),6-H(1) = J5-H(1),6-H(2)
=
=
3
1
A
3
.6 Hz, 1 H, 5-H ] , 1.80 [ddd, Jgem = 13.4 Hz, J4-H(2),5-H(2)
Eur. J. Org. Chem. 2015, 7892–7918
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7905

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
1
1
1
A
A
A
A
unequivocally [δ
H
( H) ↔ δ
H
( H)]: δ = 4.22 (6-H ) ↔ δ = 1.75 (5-
= 18.44 (C-3Ј) , 20.15 (C-2Ј-Me) , 21.71 (C-4-Me) , 26.88 (C-4) ,
1
2
1
1
A
A
A
A
H ) and δ = 4.39 (6-H ) ↔ δ = 1.75 (5-H ); δ = 4.22 (6-H ) ↔ δ =
30.78 (C-2Ј) , 31.62 (C-5) , 51.60 (C-3) , 67.69 (C-6) , 77.98 (C-
.89 (5-H ) and δ = 4.39 (6-H ) ↔ δ = 1.89 (5-H ); δ = 1.75 (5-H ) 1Ј) , 174.76 (C-2) ppm. The indicated nuclei – they are non-qua-
2
2
2
1
A
A
1
1
2
1
↔
δ = 1. 23 (4-H ) and δ = 1.89 (5-H ) ↔ δ = 1. 23 (4-H ); δ =
ternary – were identified in an edHSQC spectrum [“short-range
C,H-COSY spectrum” (100.62/400.13 MHz, CDCl )] by their
crosspeaks with directly bonded protons (these had previously been
1
2
2
1
.75 (5-H ) ↔ δ = 2.17 (4-H ) and δ = 1.89 (5-H ) ↔ δ = 2.17 (4-
3
2
13
A
3
H ) ppm. C NMR (100.62 MHz, CDCl ): δ = 20.37 (C-5) , 24.60
A
A
A
A
13
1
(
(
C-3-Me) , 27.22 (C-4) , 48.16 (C-3) , 70.49 (C-6) , 78.61
C-1Ј) , 122.09, (C-para), 129.49 (2 ϫ C-ortho), 131.24 (2 ϫ C-
assigned unequivocally) [δ
= 0.99 (3Ј-H ); δ = 20.15 (C-2Ј-Me) ↔ δ = 0.97 (2Ј-Me); δ = 21.71
(C-4-Me) ↔ δ = 1.13 (4-H ); δ = 26.88 (C-4) ↔ δ = 2.24 (4-H); δ
= 30.78 (C-2Ј) ↔ δ = 1.86 (2Ј-H); δ = 31.62 (C-5) ↔ δ = 1.58 (5-
C
( C) ↔ δ
H
( H)]: δ = 18.44 (C-3Ј) ↔ δ
A
3
A
meta), 138.62 (C-ipso), 176.56 (C-2) ppm. The indicated nuclei –
they are non-quaternary – were identified in an edHSQC spectrum
3
1
2
[“short-range C,H-COSY spectrum” (100.62/400.13 MHz, CDCl
3
)]
H ) and 1.97 (5-H ); δ = 51.60 (C-3) ↔ δ = 2.52 (3-H); = 67.69
(C-6) ↔ δ = 4.33–4.38 (6-H ); δ = 77.98 (C-1Ј) ↔ δ = 3.82 (1Ј-H).
by their crosspeaks with directly bonded protons (these had pre-
2
13
1
viously been assigned unequivocally) [δ
C
2
( C) ↔ δ
H
( H)]: δ = 20.37
IR (film): ν˜ = 3440, 2960, 1715, 1475, 1400, 1315, 1265, 1230, 1195,
1
–1
(
C-5) ↔ δ = 1.75 (5-H ) and 1.89 (5-H ); δ = 24.60 (C-3-Me) ↔ δ
1085, 1055, 1000, 915, 745, 655 cm . HRMS (pos. ESI): calcd. for
1
2
[M + H]+ 187.13287; found 187.13301 (+0.7 ppm).
3
O (186.25): calcd. C 64.49, H 9.74; found C 64.48,
=
1.25 (3-Me); δ = 27.22 (C-4) ↔ δ = 1.23 (4-H ) and 2.17 (4-H );
C
C
10
H
H
19
O
3
1
2
δ = 70.49 (C-6) ↔ δ = 4.22 (6-H ) and 4.39 (6-H ); δ = 78.61 (C-
10
18
1
2
Ј) ↔ δ = 5.00 (1Ј-H). IR (film): ν˜ = 3840, 3735, 2990, 2870, 2360,
H 9.91.
–1
340, 1700, 1395, 1220, 1140, 1075, 775, 675 cm . HRMS (pos.
rel-(3S,4S)-3-[(S)-1-Hydroxy-2-methylpropyl]-4-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (anti,trans-36)
+
APCI, MeOH): calcd. for C13
2
5
H
16
O
3
Br [M + H] 299.02828; found
99.02870 (+1.4 ppm). C13
H
15BrO (299.16): calcd. C 52.19, H
3
.05; found C 52.24, H 5.08.
rel-(3S,4S)-3-[(R)-1-Hydroxy-2-methylpropyl]-4-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (syn,trans-36)
Following the General Procedure B the title compound was pre-
pared from β-methyl-δ-lactone (19, 114 mg, 1.00 mmol) and iso-
butyraldehyde (22, 144 mg, 2.00 mmol, 2.0 equiv.). Purification by
flash chromatography[ (2.0ϫ15 cm, 15 mL, c-C
25]
H12/EtOAc 3:1
6
Following the General Procedure A the title compound was pre-
pared from β-methyl-δ-lactone (19, 114 mg, 1.00 mmol) and iso-
butyraldehyde (22, 144 mg, 2.00 mmol, 2.0 equiv.). Purification by
to 1:1, 15–20) rendered the product as a colorless solid (147 mg,
79 %). syn,trans/syn,cis/anti,trans/anti,cis 2:0:98:0; syn/anti 2:98;
syn,trans/syn,cis Ͼ95:5, anti,trans/anti,cis Ͼ95:5 [determined by in-
tegration of the signals at δ = 3.82 (1Ј-H, syn,trans-36) vs. δ = 4.15–
[
25]
flash chromatography
to 1:1, 12–19) rendered the product as a colorless oil (142 mg,
6%). syn,trans/syn,cis/anti,trans/anti,cis 96:0:4:0; syn/anti 96:4;
6
(2.0ϫ15 cm, 15 mL, c-C H12/EtOAc 3:1
2
4.45 (6-H , syn,trans-36 and anti,trans-36) in the 400 MHz
1
7
H NMR spectrum of the crude product; the NMR contained no
syn,trans/syn,cis Ͼ95:5, anti,trans/anti,cis Ͼ95:5. [The 300 MHz
H NMR spectrum of the crude product was too contaminated by
byproducts to integrate any signals. A short column chromato-
signal clearly attributable to syn,cis-36 or anti,cis-36], m.p. 41 °C.
1
1
H NMR (400.13 MHz, CDCl
3
): δ = 0.91 (d, J2Ј-Me,2Ј = 6.7 Hz, 3
)A, 1.11 (d, J4-Me,4
, possibly interpretable as dddd, Jgem
A
H, 2Ј-Me) , 1.03 (d, J3Ј,2Ј = 6.6 Hz, 3 H, 3Ј-H
3
graphic separation (2.0ϫ10 cm, 15 mL, c-C
6
H12/EtOAc 3:1 to 1:1, = 6.6 Hz, 3 H, 4-Me), 1.58 [m
c
8
–20) was conducted to get rid of most byproducts and a 400 MHz
= 14.3 Hz, J5-H(1),4 = 6.9 Hz, J5-H(1),6 = 5.6 and 5.0 Hz, 1 H,
1
1 A
H NMR spectrum of the product thus obtained was recorded. In-
tegration of the signals at δ = 1.02 (3Ј-H , anti,trans-36) vs. δ =
.12 (4-Me, syn,trans-36) as well as δ = 2.50 (3-H, syn,trans-36) vs.
c
5-H ] , 2.01 [m , possibly interpretable as dddd, Jgem = 14.3 Hz,
2
A
3
J
J
5-H(2),4 = 6.2 Hz, J5-H(2),6 = 6.2 and 5.7 Hz, 1 H, 5-H ] , 2.18 (dqq,
A
1
2Ј,1Ј = 8.8 Hz, J2Ј,2Ј-Me = J2Ј,3Ј = 6.7 Hz, 1 H, 2Ј-H) superimposed
δ = 3.22 (1Ј-H, anti,trans-36) resulted in syn/anti 96:04. The NMR
contained no signal clearly attributable to syn,cis-36 or anti,cis-36.]
by 2.21 [dddq, J4,3 = 8.8 Hz, J4,5-H(1) = J4,5-H(2) = J4,4-Me = 6.6 Hz,
A
A
1 H, 4-H] , 2.32 (dd, J3,4 = 9.0 Hz, J3,1Ј = 2.0 Hz, 1 H, 3-H) , 2.49
1
A
H NMR (400.13 MHz, CDCl
3
): δ = 0.97 (d, J3Ј,2Ј = 5.4 Hz, 3 H, (br. d, JOH,1Ј = 7.8 Hz, 1 H, OH), 3.22 (br. m
c
, 1 H, 1Ј-H) , 4.27–
) ppm. AThe indicated protons were distin-
guished in a DQF-COSY spectrum [“H,H-COSY spectrum”
(400.13 MHz, CDCl )] by their crosspeaks with protons that pre-
viously had been assigned unequivocally [δ
0.91 (2Ј-Me) ↔ δ = 2.18 (2Ј-H) and δ = 1.03 (3Ј-H
5-H(2),4 = 5.0 Hz, J5-H(2),6 = 5.0 and 3.4 Hz, 1 H, 5-H ] , 2.24 (2Ј-H); δ = 1.11 (4-Me) ↔ δ = 2.21 (4-H); δ = 2.21 (4-H) ↔ δ =
2.32 (3-H); δ = 2.32 (3-H) ↔ δ = 3.22 (1Ј-H); δ = 4.27–4.35 (6-H
3
6
=
5
2
J
Ј-H
3
), 0.99 (d, J2Ј-Me,2Ј = 5.3 Hz, 3 H, 2Ј-Me), 1.13 (d, J4-Me,4
=
4.35 (m, 2 H, 6-H
2
A
.7 Hz, 3 H, 4-Me) , 1.58 [m
c
, possibly interpretable as dddd, Jgem
14.1 Hz, J5-H(1),4 = 9.2 Hz, J5-H(1),6 = 8.7 and 4.9 Hz, 1 H,
3
1
A
1
1
-H ] , 1.86 (dqq, J2Ј,1Ј = 7.7 Hz, J2Ј,3Ј = J2Ј,2Ј-Me = 6.7 Hz, 1 H,
H
( H) ↔ δ
H
( H)]: δ =
Ј-H), 1.97 [m , possibly interpretable as dddd, Jgem = 14.2 Hz,
c
3
) ↔ δ = 2.18
2
A
[dqdd, J4,5-H(1) = 9.1 Hz, J4,4-Me = J4,3 = 7.0 Hz, J4,5-H(2) = 5.0 Hz,
2
)
A
A
1
2
1
(
J
6
H, 4-H] , 2.52 (dd, J3,4 = 7.4 Hz, J3,1Ј = 3.4 Hz, 1 H, 3-H) , 2.86 ↔ δ = 1.58 (5-H ); δ = 4.27–4.35 (6-H ) ↔ δ = 2.01 (5-H ) ppm.
A
2
1
3
d, J1Ј-OH,1Ј = 6.7 Hz, 1 H, 1Ј-OH), 3.82 (ddd, J1Ј,2Ј = 7.6 Hz,
3
C NMR (100.62 MHz, CDCl ): δ = 19.43 (C-3Ј) , 19.98 (C-2Ј-
A
A
A
A
A
A
1Ј,1Ј-OH = 6.5 Hz, J1Ј,3 = 3.3 Hz, 1 H, 1Ј-H) , 4.33–4.38 (m, 2 H, Me) , 20.87 (C-4-Me) , 29.30 (C-4) , 31.27 (C-5) , 32.25 (C-2Ј) ,
) ppm. AThe indicated protons were distinguished in a DQF-
)]
49.79 (C-3) , 67.04 (C-6) , 77.72 (C-1Ј) , 173.45 (C-2) ppm. The
indicated nuclei – they are non-quaternary – were identified in an
edHSQC spectrum [“short-range C,H-COSY spectrum” (100.62/
A
A
A
A
-H
2
COSY spectrum [“H,H-COSY spectrum” (400.13 MHz, CDCl
3
by their crosspeaks with protons that previously had been assigned
1
1
unequivocally [δ
(
H
( H) ↔ δ
H
( H)]: δ = 4.33–4.38 (6-H
2
3
) ↔ δ = 1.58 400.13 MHz, CDCl )] by their crosspeaks with directly bonded pro-
1
2
1
13
5-H ); δ = 4.33–4.38 (6-H
δ = 2.24 (4-H) and δ = 1.97 (5-H ) ↔ δ = 2.24 (4-H); δ = 2.24 (4-
H) ↔ δ = 1.13 (4-Me); δ = 2.24 (4-H) ↔ δ = 2.52 (3-H); δ = 2.52
2
) ↔ δ = 1.97 (5-H ); δ = 1.58 (5-H ) ↔
tons (these had previously been assigned unequivocally) [δ
C
( C)
2
1
↔ δ
H
( H)]: δ = 19.43 (C-3Ј) ↔ δ = 1.03 (3Ј-H
3
); δ = 19.98 (C-2Ј-
Me) ↔ δ = 0.91 (2Ј-Me); δ = 20.87 (C-4-Me) ↔ δ = 1.11 (4-Me);
δ = 29.30 (C-4) ↔ δ = 2.21 (4-H); δ = 31.27 (C-5) ↔ δ = 1.59 (5-
13
(
3-H) ↔ δ = 3.82 (1Ј-H) ppm. C NMR (100.62 MHz, CDCl
3
): δ
7906
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7892–7918

Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
1
2
H ) and δ = 2.01 (5-H ); δ = 32.25 (C-2Ј) ↔ δ = 2.18 (2Ј-H); δ = rel-(3S,4S)-3-[(S,trans)-1-Hydroxybut-2-enyl]-4-methyl-3,4,5,6-tetra-
4
H
2
7
9.79 (C-3) ↔ δ = 2.32 (3-H); δ = 67.04 (C-6) ↔ δ = 4.27–4.35 (6-
); δ = 77.72 (C-1Ј) ↔ δ = 3.22 (1Ј-H). IR (film): ν˜ = 3300, 2955,
870, 2360, 1720, 1460, 1400, 1255, 1145, 1090, 1055, 945, 915,
hydro-2H-pyran-2-one (anti,trans-37)
2
–1
45 cm . HRMS (pos. APCI, MeOH): calcd. for C10
H
O
19
O
3
[M +
+
H] 187.13342; found 187.13360 (+1.4 ppm). C10
calcd. C 64.49, H 9.74; found C 64.27, H 10.06.
H
18
3
(186.25):
Following the General Procedure B the title compound was pre-
pared from β-methyl-δ-lactone (19, 114 mg, 1.00 mmol) and cro-
rel-(3S,4S)-3-[(R,trans)-1-Hydroxybut-2-enyl]-4-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (syn,trans-37)
tonaldehyde (23, 140 mg, 2.00 mmol, 2.0 equiv.). Purification by
flash chromatography[ (2.0ϫ15 cm, 15 mL, c-C
25]
H12/EtOAc 3:1
6
to 1:1, 16–22) rendered the product as a colorless oil (139 mg,
5 %). syn,trans/syn,cis/anti,trans/anti,cis 6:0:94:0; syn/anti 6:94;
7
syn,trans/syn,cis Ͼ95:5, anti,trans/anti,cis Ͼ95:5 [determined by in-
tegration of the signals at δ = 2.25 (3-H, anti,trans-37) vs. δ = 2.48
1
(
3-H, syn,trans-37) in the 400 MHz H NMR spectrum of the crude
Following the General Procedure A the title compound was pre-
pared from β-methyl-δ-lactone (19, 114 mg, 1.00 mmol) and cro-
tonaldehyde (23, 140 mg, 2.00 mmol, 2.0 equiv.). Purification by
product; the NMR contained no signal clearly attributable to
syn,cis-37 or anti,cis-37]. H NMR (400.13 MHz, CDCl ): δ = 1.14
3
(d, J4-Me,4 = 6.6 Hz, 3 H, 4-Me), 1.57 [m , possibly interpretable as
dddd, Jgem = 14.4 Hz, J5-H(1),4 = 6.5 Hz, J5-H(1),6 = 6.5 and 3.8 Hz,
1
flash chromatography[
25]
(2.0ϫ15 cm, 15 mL, c-C
6
H12/EtOAc 3:1
c
to 1:1, 13–17) rendered the product as a colorless oil (138 mg,
5 %). syn,trans/syn,cis/anti,trans/anti,cis 97:0:3:0; syn/anti 97:3;
1
1
H, 5-H ], 1.74 (m
c
, 3 H, 4Ј-H
3
), 1.99 [m
c
, possibly interpretable as
7
dddd, Jgem = 14.2 Hz, J5-H(2),4 = 6.6 Hz, J5-H(2),6 = 7.7 and 4.2 Hz, 1
H, 5-H ], 2.14 [dqdd, J4,3 = 8.2 Hz, J4,4-Me = J4,5-H(1) = J4,5-H(2)
, possibly interpretable as dd, J3,4
8.2 Hz, J3,1Ј = 4.4 Hz, 1 H, 3-H), 2.98 (m , possibly interpretable
as d, JOH,1Ј = 6.1 Hz, 1 H, OH), 4.22–4.40 (m, 3 H, 6-H , 1Ј-H) ,
.68–5.80 (m, 2 H, 2Ј-H, 3Ј-H) ppm. The indicated protons were
syn,trans/syn,cis Ͼ95:5, anti,trans/anti,cis Ͼ95:5 [determined by in-
tegration of the signals at δ = 5.53 (2Ј-H, syn,trans-37) vs. δ = 5.68–
2
=
=
A
6
.6 Hz, 1 H, 4-H] , 2.25 (m
c
5
4
.80 (3Ј-H, syn,trans-37; 2Ј-H and 3Ј-H, anti,trans-37) in the
1
00 MHz H NMR spectrum of the crude product; the NMR con-
c
A
1
tained no signal clearly attributable to syn,cis-37 or anti,cis-37]. H
2
A
5
NMR (400.13 MHz, CDCl
3
): δ = 1.07 (d, J4-Me,4 = 6.3 Hz, 3 H, 4-
distinguished in a DQF-COSY spectrum [“H,H-COSY spectrum”
400.13 MHz, CDCl )] by their crosspeaks with protons that pre-
viously had been assigned unequivocally [δ ( H) ↔ δ ( H)]: δ =
Me), 1.60 [m , possibly interpretable as dddd, Jgem = 15.2 Hz,
c
(
3
J
5-H(1),4 = J5-H(1),6-H(A) = 10.9 Hz, J5-H(1),6-H(B) = 4.2 Hz, 1 H, 5-
1
1
1
A
4
H ] , 1.73 (m
=
H ) , 2.43 (m
3
c
, possibly interpretable as ddd, J4Ј,3Ј = 6.5 Hz, J4Ј,2Ј
1.5 Hz, J4Ј,1Ј = 0.5 Hz, 3 H, 4Ј-H ), 1.81–1.91 (m, 2 H, 4-H, 5-
, possibly interpretable as dd, J3,4 = 9.4 Hz, J3,1Ј
.7 Hz, 1 H, 3-H), 3.93 (d, JOH,1Ј = 9.7 Hz, 1 H, OH), AB-signal;
= 4.23, δ = 4.33 ppm, A part additionally split by J6-H(A),5-H(1)
10.9 Hz, J6-H(A),5-H(2) = 3.0 Hz, B part additionally split by
H
H
5
5.68–5.80 (2Ј-H, 3Ј-H) ↔ δ = 4.22–4.40 (6-H , 1Ј-H); δ = 1.14 (4-
13
2
3
2
A
Me) ↔ δ = 2.14 (4-H) ppm. C NMR (100.62 MHz, CDCl ): δ =
A A A A
=
3
c
1
7.74 (C-4Ј) , 21.45 (C-4-Me) , 28.17 (C-4) , 31.10 (C-5) , 53.46
A
A
A
(
C-3) , 66.86 (C-6) , 73.07 (C-1Ј) , 128.76, 131.77 (C-2Ј, C-3Ј),
δ
A
B
A
1
73.68 (C-2) ppm. The indicated nuclei – they are non-quater-
nary – were identified in an edHSQC spectrum [“short-range C,H-
COSY spectrum” (100.62/400.13 MHz, CDCl )] by their cross-
peaks with directly bonded protons (these had previously been as-
=
2
J6-H(B),5-H(1) = J6-H(B),5-H(2) = 4.1 Hz, JAB = 11.0 Hz, 2 H, 6-H )
c
superimposed by 4.27 (m , possibly interpretable as ddd, J1Ј,OH =
3
J
J
1
1Ј,2Ј = 8.7 Hz, J1Ј,3 = 3.4 Hz, 1 H, 1Ј-H), 5.49 (ddq, J2Ј,3Ј = 15.2 Hz,
1
3
1
4
signed unequivocally) [δ ( C) ↔ δ ( H)]: δ = 17.74 (C-4Ј) ↔ δ =
2Ј,1Ј = 7.7 Hz, J2Ј,4Ј = 1.6 Hz, 1 H, 2Ј-H), 5.73 (dqd, J3Ј,2Ј
=
C
H
5.1 Hz, J3Ј,4Ј = 6.5 Hz, 4
3Ј,1Ј = 0.9 Hz, 1 H, 3Ј-H) ppm. AThe
1.74 (4Ј-H ); δ = 21.45 (C-4-Me) ↔ δ = 1.14 (4-Me); δ = 28.17 (C-
J
3
1
4
(
4
) ↔ δ = 2.14 (4-H); δ = 31.10 (C-5) ↔ δ = 1.57 (5-H ) and 1.99
indicated protons were distinguished in a DQF-COSY spectrum
“H,H-COSY spectrum” (400.13 MHz, CDCl )] by their cros-
speaks with protons that previously had been assigned unequivo-
2
5-H ); δ = 53.46 (C-3) ↔ δ = 2.25 (3-H); δ = 66.86 (C-6) ↔ δ =
.22–4.40 (6-H , 1Ј-H, CH part); δ = 73.07 (C-1Ј) ↔ δ = 4.22–
4.40 (6-H , 1Ј-H, CH part). IR (film): ν = 3450, 2960, 2875, 2360,
[
3
2
2
1
1
cally [δ
H
( H) ↔ δ
H
( H)]: δ = 1.07 (4-Me) ↔ δ = 1.81–1.91 (4-H, 5-
2
2
˜
–
1
2
A
1
B
2255, 1920, 1455, 1400, 1265, 1090, 910, 735, 650 cm . HRMS
H ); δ = 4.23 (6-H ) ↔ δ = 1.60 (5-H ) and δ = 4.33 (6-H ) ↔
(pos. APCI, MeOH): calcd. for C H O [M + H]+ 185.11722;
1
A
2
1
4
.60 (5-H ); δ = 4.23 (6-H ) ↔ δ = 1.81–1.91 (4-H, 5-H ) and δ =
10 17
3
B
2
1 3
10 16 3
found 185.11725 (+0.1 ppm). C H O (184.23): calcd. C 65.19, H
.33 (6-H ) ↔ 1. 81–1.91 (4-H, 5-H ) pp m. C N MR
100.62 MHz, CDCl
C-4) , 31.09 (C-5) , 53.67 (C-3) , 68.34 (C-6) , 72.34 (C-1Ј) ,
29.69 (C-2Ј, C-3Ј) , 173.93 (C-2) ppm. The indicated nuclei –
A
A
8.75; found C 64.93, H 8.93.
rel-(3S,4S)-3-[(S)-(4-Bromophenyl)(hydroxy)methyl]-4-methyl-
,4,5,6-tetrahydro-2H-pyran-2-one (syn,trans-38)
(
(
3
A
): δ = 17.78 (C-4Ј) , 20.45 (C-4-Me) , 28.25
A
A
A
A
A
A
1
3
they are non-quaternary – were identified in an edHSQC spectrum
“short-range C,H-COSY spectrum” (100.62/400.13 MHz, CDCl )]
by their crosspeaks with directly bonded protons (these had pre-
[
3
1
3
1
viously been assigned unequivocally) [δ
C-4Ј) ↔ δ = 1.73 (4Ј-H ); δ = 20.45 (C-4-Me) ↔ δ = 1.07 (4-Me);
δ = 28.25 (C-4) ↔ δ = 1.81–1.91 (4-H, 5-H ); δ = 31.09 (C-5)↔ δ =
C
( C) ↔ δ
H
( H)]: δ = 17.78
(
3
2
Following the General Procedure A the title compound was pre-
.60 (5-H ) and 1.81–1.91 (4-H, 5-H ); δ = 53.67 (C-3) ↔ δ = 2.43 pared from β-methyl-δ-lactone (19, 114 mg, 1.00 mmol) and 4-
3-H); δ = 68.34 (C-6) ↔ δ = AB-Signal (δ = 4.23, δ = 4.33, 6- bromobenzaldehyde (24, 370 mg, 2.00 mmol, 2.0 equiv.). Purifica-
); δ = 72.34 (C-1Ј) ↔ δ = 4.27 (1Ј-H); δ = 129.69 (C-2Ј, C-3Ј) ↔ tion by flash chromatography[ (2.0ϫ 15 cm, 15 mL, c-C
1
2
1
(
A
B
25]
H
2
6 12
H /
δ = 5.49 (2Ј-H) and 5.73 (3Ј-H). IR (film): ν˜ = 3445, 2960, EtOAc 3:1 to 1:1, 11–15) rendered the product as a colorless solid
2
920, 2360, 2345, 1710, 1475, 1450, 1405, 1315, 1270, 1220, 1190,
(238 mg, 80%). syn,trans/syn,cis/anti,trans/anti,cis 95:0:5:0; syn/anti
): 95:5; syn,trans/syn,cis Ͼ95:5, anti,trans/anti,cis Ͼ95:5 [determined
by integration of the signals at δ = 2.64 (3-H syn,trans-38) vs. δ =
–1
1160, 1090, 1065, 1030, 1005, 970, 770, 650 cm . HRMS (CI, NH
3
+
calcd. for C10
+0.7 ppm).
H
17
O
3
[M + H] 185.11777; found 185.11790
1
(
2.50 (3-H, anti,trans-38) in the 400 MHz H NMR spectrum of the
Eur. J. Org. Chem. 2015, 7892–7918
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7907

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
crude product; the NMR contained no signal clearly attributable
rectly bonded protons (these had previously been assigned unequiv-
to syn,cis-38 or anti,cis-38], m.p. 87 °C. 1H NMR (400.13 MHz, ocally) [δ
( C) ↔ δ ( H)]: δ = 21.37 (C-4-Me) ↔ δ = 0.88 (4-Me);
13
1
C
H
CDCl
3
): δ = 0.81 (d, J4-Me,4 = 6.6 Hz, 3 H, 4-Me), 1.55 [dddd, Jgem
δ = 27.80 (C-4) ↔ δ = 1.99 (4-H); δ = 30.90 (C-5) ↔ δ = 1.51 (5-
1 2
=
1
14.0 Hz, J5-H(1),4 = J5-H(1),6-H(1) = 10.0 Hz, J5-H(1),6-H(2) = 4.0 Hz, H ) and 1.89 (5-H ); δ = 54.41 (C-3) ↔ δ = 2.48 (3-H); δ = 66.78
H, 5-H ], 1.83 [dddd, Jgem = 14.3 Hz, J5-H(2),4 = J5-H(2),6-H(2)
1
1
2
=
=
(C-6) ↔ δ = 4.13 (6-H ) and 4.27 (6-H ); δ = 73.51 (C-1Ј) ↔ δ =
4.92 (1Ј-H); δ = 128.34 (2ϫC-ortho) ↔ δ = 7.25 (2ϫortho-H); δ =
2
4
9
.9 Hz, J5-H(2),6-H(1) = 2.8 Hz, 1 H, 5-H ], 1.98 [ddqd, J4,5-H(1)
.8 Hz, J4,3 = 8.4 Hz, J4,4-Me = 6.6 Hz, J4,5-H(2) = 5.0 Hz, 1 H, 4-
131.51 (2ϫC-meta) ↔ δ = 7.47 (2ϫmeta-H). IR (CHCl
3
): ν˜ =
H], 2.64 (dd, J3,4 = 8.5 Hz, J3,1Ј = 3.7 Hz, 1 H, 3-H), 3.93 (d, JOH,1Ј
3430, 2960, 2920, 2850, 1715, 1485, 1400, 1265, 1225, 1160,
–
1
=
7.2 Hz, 1 H, OH), 4.10 [ddd, Jgem = 11.1 Hz, J6-H(1), 5-H(1)
=
=
1130, 1090, 1070, 1010, 825 cm . HRMS (pos. APCI, MeOH):
calcd. for C13
Br [M + H]+ 299.02828; found 299.02860
1
1
1
5
2
0.2 Hz, J6-H(1),5-H(2) = 2.8 Hz, 1 H, 6-H ], 4.30 [ddd, Jgem
16 3
H O
2
1.1 Hz, J6-H(2),5-H(2) = 4.7 Hz, J6-H(2),5-H(1) = 3.8 Hz, 1 H, 6-H ], (+1.1 ppm).
.23 (dd, J1Ј,OH = 7.2 Hz, J1Ј,3 = 3.6 Hz, 1 H, 1Ј-H), 7.23 (m , 2 H,
, 2 H, 2 ϫ meta-H) ppm. C NMR
c
rel-(3S,5R)-3-[(R)-1-Hydroxy-2-methylpropyl]-5-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (syn,trans-39)
1
3
ϫ ortho-H), 7.47 (m
): δ = 21.20 (C-4-Me) , 27.06 (C-4) , 31.44
c
A
A
(
(
100.62 MHz, CDCl
3
A
A
A
A
C-5) , 54.96 (C-3) , 68.11 (C-6) , 72.93 (C-1Ј) , 121.81, 128.14,
1
31.70, and 140.28 (6ϫAr-C), 173.75 (C-2) ppm. AThe indicated
nuclei – they are non-quaternary – were identified in an edHSQC
spectrum [“short-range C,H-COSY spectrum” (100.62/
4
00.13 MHz, CDCl
3
)] by their crosspeaks with directly bonded pro-
1
3
tons (these had previously been assigned unequivocally) [δ
↔
4
C
( C)
H
δ ( H)]: δ = 21.20 (C-4-Me) ↔ δ = 0.81 (4-Me); δ = 27.06 (C-
1
Following the General Procedure A the title compound was pre-
pared from γ-methyl-δ-lactone (20, 114 mg, 1.00 mmol) and iso-
butyraldehyde (22, 144 mg, 2.00 mmol, 2.0 equiv.). Purification by
flash chromatography[ (2.0ϫ15 cm, 15 mL, c-C H /EtOAc 3:1
1
) ↔ δ = 1.98 (4-H); δ = 31.44 (C-5) ↔ δ = 1.55 (5-H ) and 1.83
2
(5-H ); δ = 54.96 (C-3) ↔ δ = 2.64 (3-H); δ = 68.11 (C-6) ↔ δ =
25]
1
2
4
.10 (6-H ) and 4.30 (6-H ); δ = 72.93 (C-1Ј) ↔ δ = 5.23 (1Ј-H).
6
12
to 1:1, 16–24) rendered the product as a colorless oil (112 mg,
60%). syn,trans/syn,cis/anti,trans/anti,cis 72:28:0:0; syn/anti Ͼ95:5;
syn,trans/syn,cis 72:28, anti,trans/anti,cis Ͼ95:05. [The 300.06 MHz
H NMR spectrum of the crude product was too contaminated by
byproducts to integrate any signals. A short column chromato-
IR (film): ν˜ = 3420, 2990, 2955, 2870, 1705, 1485, 130, 1380, 1360,
–1
1
350, 1265, 1220, 1145, 1085, 1070, 770 cm . HRMS (pos. APCI,
+
MeOH): calcd. for C13
99.02790 (–1.3 ppm).
16 3
H O Br [M + H] 299.02828; found
1
2
rel-(3S,4S)-3-[(R)-(4-Bromophenyl)(hydroxy)methyl]-4-methyl-
,4,5,6-tetrahydro-2H-pyran-2-one (anti,trans-38)
6
graphic separation (2.0ϫ10 cm, 15 mL, c-C H12/EtOAc 3:1 to 1:1,
3
8
4
–16) was conducted to get rid of most byproducts and a
1
00.13 MHz H NMR spectrum of the product thus obtained was
2
recorded. Integration of the signals at δ = 4.22 (6-H , syn,trans-39)
vs. δ = 4.31–4.33 (left half of 6-H , syn,cis-39) resulted in syn/iso-
2
syn 72:28. The NMR contained no signal clearly attributable to
1
anti,trans-39 or anti,cis-39.] H NMR (400.13 MHz, CDCl
3
): δ =
A
Following the General Procedure B the title compound was pre-
pared from β-methyl-δ-lactone (19, 114 mg, 1.00 mmol) and 4-
0.86 (d, J2Ј-Me,2Ј = 6Hz, 3 H, 2Ј-Me) , 1.04 (d, J5-Me,5 = 6.7 Hz, 3
A
A
3
H, 5-Me) superimposed by 1.05 (d, J3Ј,2Ј = 6.6 Hz, 3 H, 3Ј-H ) ,
1
A
bromobenzaldehyde (24, 370 mg, 2.00 mmol, 2.0 equiv.). Purifica-
1.47–1.59 (m
c
, 1 H, 4-H ) , 1.68 (dqq, J2Ј,1Ј = 9.7 Hz, J2Ј,3Ј
=
tion by flash chromatography[ (2.0ϫ 15 cm, 15 mL, c-C
25]
H
/
J
2Ј,2Ј-Me = 6.6 Hz, 1 H, 2Ј-H), 2.10–2.21 (m, 4-H , 5-H) , 2.54
2
A
6
12
EtOAc 3:1 to 1:1, 12–18) rendered the product as a colorless solid (br. s, 1 H, OH), 2.74 [ddd, possibly interpretable as, J3,4-H(1)
=
(
3
244 mg, 82%). syn,trans/syn,cis/anti,trans/anti,cis 3:0:88:9; syn/anti
:97; syn,trans/syn,cis Ͼ95:5, anti,trans/anti,cis 91:9 [determined by
integration of the signals at δ = 4.91 (1Ј-H, anti,cis-38) vs. δ = 4.95
1Ј-H, anti,trans-38) vs. δ = 5.24 (1Ј-H, syn,trans-38) in the
J
J
J
3,4-H(2) = 9.3 Hz, J3,1Ј = 2.3 Hz, 1 H, 3-H], 3.84 (dd, J1Ј,2Ј = 9.7 Hz,
1Ј,3 = 2.3 Hz, 1 H, 1Ј-H), 3.92 [m , possibly interpretable as dd,
gem = 10.8 Hz, J6-H(1),5 = 9.7 Hz, 1 H, 6-H ], 4.23 (m
c
1
c
, 1 H, 6-
2
A
(
4
H ) ppm. The indicated protons were distinguished in a DQF-
COSY spectrum [“H,H-COSY spectrum” (400.13 MHz, CDCl )]
by their crosspeaks with protons that previously had been assigned
1
00 MHz H NMR spectrum of the crude product; the NMR con-
3
1
tained no signal clearly attributable to syn,cis-38], m.p. 72 °C. H
NMR (400.13 MHz, CDCl ): δ = 0.88 (d, J4-Me,4 = 6.7 Hz, 3 H, 4- unequivocally [δ
Me), 1.51 [dddd, Jgem = 14.3 Hz, J5-H(1),4 = J5-H(1),6-H(1) = 6.5 Hz,
J
J
5
H, 4-H], 2.48 (dd, J3,4 = 7.5 Hz, J3,1Ј = 5.7 Hz, 1 H, 3-H), 3.94 (br.
s, 1 H, OH), 4.13 [dddd, Jgem = 11.2 Hz, J6-H(1),5-H(1) = 6.7 Hz,
J
1
1
3
H
( H) ↔ δ
H
( H)]: δ = 1.68 (2Ј-H) ↔ δ = 0.86 (2Ј-
); δ = 2.74 (3-H) ↔ δ =
Me); δ = 1.68 (2Ј-H) ↔ δ = 1.05 (3Ј-H
1.47–1.59 (4-H ) and 2.10–2.21 (4-H , 5-H); δ = 3.92 (6-H ) and
3
1
1
2
1
5-H(1),6-H(2) = 3.2 Hz, 1 H, 5-H ], 1.89 [dddd, Jgem = 14.4 Hz,
2
2
13
5-H(2),6-H(2) = 8.1 Hz, J5-H(2),4 = 6.3 Hz, J5-H(2),6-H(1) = 3.6 Hz, 1 H, 4.23 (6-H ) ↔ δ = 2.10–2.21 (4-H , 5-H) ppm. C NMR
2
A
A
-H ], 1.99 [qddd, J4,3 = J4,4-Me = J4,5-H(1) = J4,5-H(2) = 6.8 Hz, 1
3
(100.62 MHz, CDCl ): δ = 17.16 (C-5-Me) , 18.87 (C-2Ј-Me) ,
19.77 (C-3Ј) , 24.96 (C-4) , 27.94 (C-5) , 29.78 (C-2Ј) , 40.34 (C-
3) , 73.10 (C-6) , 75.51 (C-1Ј) , 175.69 (C-2) ppm. The indicated
nuclei – they are non-quaternary – were identified in an edHSQC
A
A
A
A
A
A
A
A
1
6-H(1),5-H(2) = 3.7 Hz, J6-H(1),4-H = 0.4 Hz, 1 H, 6-H ], 4.27 [ddd,
J
gem = 11.3 Hz, J6-H(2),5-H(2) = 8.1 Hz, J6-H(2),5-H(1) = 3.2 Hz, 1 H, spectrum [“short-range C,H-COSY spectrum” (100.62/
2
6-H ], 4.92 (d, J1Ј,3 = 5.7 Hz, 1 H, 1Ј-H), 7.25 (m
c
, 2 H, 2ϫortho-
3
400.13 MHz, CDCl )] by their crosspeaks with directly bonded pro-
1
3
13
H), 7.47 (m
CDCl
5
c
, 2 H, 2 ϫ meta-H) ppm. C NMR (100.62 MHz, tons (these had previously been assigned unequivocally) [δ
C
( C)
( H)]: δ = 17.16 (C-5-Me) ↔ δ = 1.04 (5-Me); δ = 18.87 (C-
4.41 (C-3) , 66.87(C-6), 73.51 (C-1Ј) , 121.76 (C-para), 128.34 2Ј-Me) ↔ δ = 0.86 (2Ј-Me); δ = 19.77 (C-3Ј) ↔ δ = 1.05 (3Ј-H );
A
A
A
1
3
): δ = 21.37 (C-4-Me) , 27.80 (C-4) , 30.90 (C-5) , ↔ δ
H
A
A
3
A
A
1
2
(2ϫC-ortho) , 131.51 (2ϫC-meta) , 140.56 (C-ipso), 173.72 (C-
δ = 24.96 (C-4) ↔ δ = 1.47–1.59 (4-H ) and 2.10–2.21 (4-H , 5-H);
δ = 27.94 (C-5) ↔ δ = 2.10–2.21 (4-H , 5-H); δ = 29.78 (C-2Ј) ↔
A
2
1
) ppm. The indicated nuclei – they are non-quaternary – were
identified in an edHSQC spectrum [“short-range C,H-COSY spec-
trum” (100.62/400.13 MHz, CDCl )] by their crosspeaks with di-
δ = 1.68 (2Ј-H); δ = 40.34 (C-3) ↔ δ = 2.74 (3-H); δ = 73.10 (C-6)
1
2
3
↔ δ = 3.92 (6-H ) and 4.23 (6-H ); δ = 75.51 (C-1Ј) ↔ δ = 3.84
7908
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7892–7918

Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
(
1
1Ј-H). IR (film): ν˜ = 3460, 2960, 2875, 1730, 1460, 1385, 1345, rel-(3S,5R)-3-[(R,trans)-1-Hydroxybut-2-enyl]-5-methyl-3,4,5,6-
–1
250, 1210, 1185, 1160, 1095, 1050, 1020 cm . HRMS (CI, NH
3
):
tetrahydro-2H-pyran-2-one (syn,trans-40)
+
calcd. for C10
–1.0 ppm).
H O [M – H O] 168.11503; found 168.11520
16 2 2
(
rel-(3S,5R)-3-[(S)-1-Hydroxy-2-methylpropyl]-5-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (anti,trans-39)
Following the General Procedure A the title compound was pre-
pared from γ-methyl-δ-lactone (20, 114 mg, 1.00 mmol) and
crotonaldehyde (23, 140 mg, 2.00 mmol, 2.0 equiv.). Purification by
flash chromatography[ (2.0ϫ15 cm, 15 mL, c-C
25]
H12/EtOAc 3:1
6
to 1:1, 13–17) rendered the product as a colorless oil (109 mg, 59%,
syn,trans-40:syn,cis-40 = 66:33). syn,trans/syn,cis/anti,trans/anti,cis
Following the General Procedure B the title compound was pre-
pared from γ-methyl-δ-lactone (20, 114 mg, 1.00 mmol) and iso-
6
2
8:25:2:5; syn/anti 93:7; syn,trans/syn,cis 73:27, anti,trans/anti,cis
3:77 [determined by integration of δ = 0.98 (right peak of 5-Me,
butyraldehyde (22, 144 mg, 2.00 mmol, 2.0 equiv.). Purification by
flash chromatography[ (2.0ϫ15 cm, 15 mL, c-C
25]
H12/EtOAc 3:1
6
syn,cis-40) vs. δ = 0.99 (right peak of 5-Me, anti,cis-40) vs. δ = 1.01
right peak of 5-Me, anti,trans-40) vs. δ = 1.02 (right peak of 5-Me,
to 1:1, 19–24) rendered the product as a colorless oil (130 mg, 70%,
syn,trans-39/syn,cis-39 = 95:5). syn,trans/syn,cis/anti,trans/anti,cis
(
syn,trans-40) as well as of δ = 1.00 (left peak of 5-Me, syn,cis-40)
vs. δ = 1.01 (left peak of 5-Me, anti,cis-40) vs. δ = 1.03 (left peak
of 5-Me, anti,trans-40) vs. δ = 1.04 ppm (left peak of 5-Me, syn,-
5
≈
:0:72:24; syn/anti ≈ 5:95; syn,trans/syn,cis Ͼ95:5, anti,trans/anti,cis
75:25. [The 300.06 MHz H NMR spectrum of the crude product
1
was too contaminated by byproducts to integrate any signals. A
short column chromatographic separation (2.0ϫ10 cm, 15 mL, c-
1
trans-40) in the 400.13 MHz H NMR spectrum of the crude prod-
1
uct]. H NMR (400.13 MHz, CDCl
3
, 66:33 mixture of dia-
6
C H12/EtOAc 3:1 to 1:1, 11–21) was conducted to get rid of most
stereomers): δ = 0.98 [d, J5-Me,5 = 6.8 Hz, 3 H, 5-Me (syn,cis-40)],
.01 [d, J5-Me,5 = 6.8 Hz, 3 H, 5-Me (syn,trans-40)], 1.45 [ddd, Jgem
1
byproducts and a 400.13 MHz H NMR spectrum of the product
1
=
thus obtained was recorded. Integration of the signals at δ = 4.21
1
13.3 Hz, J4-H(1),3 = 12.4 Hz, J4-H(1),5 = 11.4 Hz, 1 H, 4-H
2
2
(
3
6-H , anti,trans-39) vs. δ = 4.28–4.30 (right half of 6-H , syn,trans-
(
=
=
syn,cis-40)], 1.56 [ddd, Jgem = 13.6 Hz, J4-H(1),3 = 9.3 Hz, J4-H(1),5
2
2
9) vs. δ = 4.30–4.35 (left half of 6-H , syn,trans-39 + 6-H , anti,cis-
1
4
7.6 Hz, 1 H, 4-H (syn,trans-40)], 1.73 [ddd, J4Ј,3Ј = 6.5 Hz, J4Ј,2Ј
3
9) resulted in syn/anti:iso-anti 05:71:24. The NMR contained no
5
3
1.7 Hz, J4Ј,1Ј = 1.0 Hz, 3 H, 4Ј-H (both diastereomers)], 1.88
1
signal clearly attributable to syn,cis-39.] H NMR (400.13 MHz,
[
dddd, Jgem = 13.4 Hz, J4-H(2),3 = 6.9 Hz, J4-H(2),5 = 4.2 Hz,
CDCl
3
, 95:5 mixture of diastereomers): δ = 0.92 (d, J2Ј-Me,2Ј =
4
2
J
4-H(2),6-H(2) = 2.5 Hz, 1 H, 4-H (syn,cis-40)], 1.97 [dddd, Jgem
=
A
A
6.8 Hz, 3 H, 2Ј-Me) , 1.03 (d, J3Ј,2Ј = 7.0 Hz, 3 H, 3Ј-H
3
) , 1.04
4
1
1
2
J
4
J
J
3.6 Hz, J4-H(2),3 = 9.3 Hz, J4-H(2),5 = 7.4 Hz, J4-H(2),6-H(2) = 1.2 Hz,
A
(
d, J5-Me,5 = 6.9 Hz, 3 H, 5-Me) , 1.59 [ddd, Jgem = 13.6 Hz,
2
H, 4-H (syn,trans-40)], 2.03–2.18 {m, possibly interpretable as
1
A
J
4-H(1),3 = 9.1 Hz, J4-H(1),5 = 7.1 Hz, 1 H, 4-H ] , 1.80 [ddd, Jgem =
.03–2.15 [m, 1 H, 5-H (syn,cis-40)] superimposed by 2.11 [dddqd,
2
A
13.7 Hz, J4-H(2),3 = 11.0 Hz, J4-H(2),5 = 8.4 Hz, 1 H, 4-H ] , 1.85
5,6-H(1) = 9.8 Hz, J5,4-H(1) = J5,4-H(2) = J5,5-Me = 7.1 Hz, J5,6-H(2)
=
A
(qqd, J2Ј,3Ј = J2Ј,2Ј-Me = 6.8 Hz, J2Ј,1Ј = 3.7 Hz, 1 H, 2Ј-H) , 2.15
.5 Hz, 1 H, 5-H (syn,trans-40)]}, 2.69 [ddd, J3,4-H(1) = 12.1 Hz,
3,4-H(2) = 6.9 Hz, J3,1Ј = 3.4 Hz, 1 H, 3-H (syn,cis-40)], 2.73 [ddd,
3,4-H(1) = J3,4-H(2) = 9.3 Hz, J3,1Ј = 3.2 Hz, 1 H, 3-H (syn,trans-40)],
A
(m
c
, 1 H, 5-H) , 2.61 [ddd, J3,4-H(2) = 10.8 Hz, J3,4-H(1) = J3,1Ј
=
8.4 Hz, 1 H, 3-H], 3.56 (dd, J1Ј,3 = 7.6 Hz, J1Ј,2Ј = 3.7 Hz, 1 H, 1Ј-
H), 3.62 (br. s, 1 H, OH), 3.93 [dd, Jgem = J6-H(1),5 = 10.8 Hz, 1 H,
1
2
A
3.02 [br. d, JOH,1Ј = 5.9 Hz, 1 H, OH (syn,trans-40)], 3.09 [br. d,
6
-H ], 4.21 [dd, Jgem = 11.1 Hz, J6-H(2),5 = 4.8 Hz, 1 H, 6-H ]. The
indicated protons were distinguished in a DQF-COSY spectrum
“H,H-COSY spectrum” (400.13 MHz, CDCl )] by their
crosspeaks with protons that previously had been assigned
J
J
J
OH,1Ј = 6.6 Hz, 1 H, OH (syn,cis-40)], 3.85 [dd, Jgem = 10.8 Hz,
1
6-H(1),5 = 10.6 Hz, 1 H, 6-H (syn,cis-40)], 3.91 [dd, Jgem = 11.0 Hz,
[
3
1
6-H(1),5 = 9.5 Hz, 1 H, 6-H (syn,trans-40)], 4.21 [ddd, Jgem
=
2
1
1
11.0 Hz, J6-H(2),5 = 4.4 Hz, J6-H(2),4-H(2) = 1.2 Hz, 1 H, 6-H
syn,trans-40)], 4.26 [ddd, Jgem = 11.0 Hz, J6-H(2),5 = 4.6 Hz,
unequivocally [δ
H); δ = 1.85 (2Ј-H) ↔ δ = 0.92 (2Ј-Me) and 1.03 (3Ј-H
3-H) ↔ δ = 1.59 (4-H ) and 1.80 (4-H ); δ = 3.93 (6-H ) ↔ δ
2.15 (5-H); δ = 4.21 (6-H )↔ δ = 2.15 (5-H) ppm. C NMR
100.62 MHz, CDCl
0.22 (C-3Ј) , 27.53 (C-5) , 29.18 (C-2Ј) , 29.28 (C-4) , 40.84 (C-
) , 72.63 (C-6) , 75.60 (C-1Ј) , 176.33 (C-2) ppm. The indicated
H
( H) ↔ δ
H
( H)]: δ = 3.56 (1Ј-H) ↔ δ = 1.85 (2Ј-
); δ = 2.61
(
3
2
1
2
1
J6-H(2),4-H(2) = 2.4 Hz, 1 H, 6-H (syn,cis-40)], 4.47 [br. m
c
, 1 H, 1Ј-
(
=
(
2
2
13
H (syn,cis-40)] superimposed by 4.50 [br. m , 1 H, 1Ј-H (syn,trans-
c
A
A
40)], 5.44–5.52 {m, possibly interpretable as 5.48 [ddq, J
15.3 Hz, J2Ј,1Ј = 6.9 Hz, J2Ј,4Ј = 1.7 Hz, 1 H, 2Ј-H (syn,cis-40)]
superimposed by 5.49 [ddq, J2Ј,3Ј = 15.3 Hz, J2Ј,1Ј = 6.8 Hz, J
2Ј,4Ј
2Ј,3Ј
=
3
): δ = 15.00 (C-2Ј-Me) , 17.16 (C-5-Me) ,
4
A
A
A
A
4
A
A
A
A
3
=
1.7 Hz, 1 H, 2Ј-H (syn,trans-40)]}, 5.70–5.80 {m, possibly inter-
nuclei – they are non-quaternary – were identified in an edHSQC
spectrum [“short-range C,H-COSY spectrum” (100.62/
4
pretable as 5.75 [dqd, J3Ј,2Ј = 15.5 Hz, J3Ј,4Ј = 6.4 Hz, J3Ј,1Ј
=
=
4
00.13 MHz, CDCl
)] by their crosspeaks with directly bonded pro- 1.2 Hz, 1 H, 3Ј-H (syn,cis-40)] superimposed by 5.76 [dqd, J3Ј,2Ј
3
4
1
3
tons (these had previously been assigned unequivocally) [δ
↔
5
=
C
( C)
( H)]: δ = 15.00 (C-2Ј-Me) ↔ δ = 0.92 (2Ј-Me); δ = 17.16 (C-
-Me) ↔ δ = 1.04 (5-Me); δ = 20.22 (C-3Ј) ↔ δ = 1.03 (3Ј-H ); δ
27.53 (C-5) ↔ δ = 2.15 (5-H); δ = 29.18 (C-2Ј) ↔ δ = 1.85
15.4 Hz, J3Ј,4Ј = 6.5 Hz, J3Ј,1Ј = 1.3 Hz, 1 H, 3Ј-H (syn,trans-40)]}.
1
13
δ
H
C NMR (100.63 MHz, CDCl
3
, 76:24 mixture of diastereomers):
A
A
δ = 16.80 [C-5-Me (syn,trans-40)] , 16.97 [C-5-Me (syn,cis-40)] ,
17.80 [C-4Ј (both diastereomers)] , 27.04 [C-4 (syn,trans-40)] ,
27.52 [C-5 (syn,trans-40)] , 28.37 [C-5 (syn,cis-40)] , 29.19 [C-4
(syn,cis-40)] , 42.93 [C-3 (syn,trans-40)] , 46.50 [C-3 (syn,cis-40)] ,
3
A
A
1
2
A
A
(2Ј-H); δ = 29.28 (C-4) ↔ δ = 1.59 (4-H ) and 1.80 (4-H ); δ =
A
A
A
4
(
0.84 (C-3) ↔ δ = 2.61 (3-H); δ = 72.63 (C-6) ↔ δ = 3.93
1
2
A
A
6-H ) and 4.21 (6-H ); δ = 75.60 (C-1Ј) ↔ δ = 3.56 (1Ј-H). IR 71.99 [C-1Ј (syn,trans-40)] , 72.51 [C-1Ј (syn,cis-40)] , 73.50 [C-6
film): ν˜ = 3530, 2960, 2360, 1725, 1460, 1400, 12.45, 1205, (syn,trans-40)] , 75.01 [C-6 (syn,cis-40)] , 128.74 [C-3Ј (syn,trans-
A A
(
1
160, 1090, 1050, 1000, 745 cm– . HRMS (pos. APCI, MeOH):
1
40)] , 128.89 [C-3Ј (syn,cis-40)] , 129.61 [C-2Ј (syn,trans-40)] ,
129.80 [C-2Ј (syn,cis-40)] , 173.21 [C-2 (syn,cis-40)], 174.57 [C-2
(syn,trans-40)]. The indicated nuclei – they are non-quaternary –
A
A
A
+
A
calcd. for C10
+0.3 ppm).
H
19
O
3
[M + H] 187.13287; found 187.13293
A
(
Eur. J. Org. Chem. 2015, 7892–7918
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7909

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
were identified in an edHSQC spectrum [“short-range C,H-COSY
0.9 Hz, 1 H, 6-H2 (anti,trans-40)], 4.31 [ddd, Jgem = 11.1 Hz,
2
spectrum” (100.6/400.1 MHz, CDCl
3
)] by their crosspeaks with di-
J
6-H(2),5 = 4.8 Hz, J6-H(2),4-H(2) = 2.1 Hz, 1 H, 6-H (anti,cis-40)],
4
rectly bonded protons (these had previously been assigned unequiv-
5.44 [ddq, J2Ј,3Ј = 15.3 Hz, J2Ј,1Ј = 7.7 Hz, J2Ј,4Ј = 1.5 Hz, 1 H, 2Ј-
H (anti,cis-40)] superimposed by 5.45 [ddq, J2Ј,3Ј = 15.3 Hz, J2Ј,1Ј
= 7.7 Hz, J2Ј,4Ј = 1.6 Hz, 1 H, 2Ј-H (anti,trans-40)], 5.75 [dqd, J3Ј,2Ј
= 15.4 Hz, J3Ј,4Ј = 6.4 Hz, J3Ј,1Ј = 0.7 Hz, 1 H, 3Ј-H (anti,cis-40)]
superimposed by 5.76 [dqd, J3Ј,2Ј = 15.3 Hz, J3Ј,4Ј = 6.5 Hz, J3Ј,1Ј
13
1
ocally) [δ
C
( C) ↔ δ ( H)]: δ = 16.80 [C-5-Me (syn,trans-40)] ↔ δ
H
4
=
=
1.01 [5-Me (syn,trans-40)]; δ = 16.97 [C-5-Me (syn,cis-40)] ↔ δ
0.98 [5-Me (syn,cis-40)]; δ = 17.80 [C-4Ј (both diastereomers)] ↔
4
4
δ = 1.73 [4Ј-H
δ = 1.56 [4-H (syn,trans-40)] and 1.97 [4-H (syn,trans-40)]; δ =
7.52 [C-5 (syn,trans-40)] ↔ δ = 2.11 [5-H (syn,trans-40)]; δ = 28.37
C-5 (syn,cis-40)] ↔ δ = 2.03–2.15 [5-H (syn,cis-40)]; δ = 29.19 [C-
3
(both diastereomers)]; δ = 27.04 [C-4 (syn,trans-40)]
1
2
13
↔
2
= 0.8 Hz, 1 H, 3Ј-H (anti,trans-40)]. C NMR (100.62 MHz,
CDCl
3
, 75:25 mixture of diastereomers): δ = 16.95 [C-5-Me (anti,-
A
A
[
4
4
trans-40)] , 17.43 [C-5-Me (anti,cis-40)] , 17.75 [C-4Ј (anti,cis-
1
2
A
A
A
(syn,cis-40)] ↔ δ = 1.45 [4-H (syn,cis-40)] and 1.88 [4-H (syn,cis- 40)] , 17.78 [C-4Ј (anti,trans-40)] , 27.30 [C-5 (anti,trans-40)] ,
A A
0)]; δ = 42.93 [C-3 (syn,trans-40)] ↔ δ = 2.73 [3-H (syn,trans-40)];
28.17 [C-5 (anti,cis-40)] , 29.26 [C-4 (anti,trans-40)] , 30.99 [C-4
A
A
δ = 46.50 [C-3 (syn,cis-40)] ↔ δ = 2.69 [3-H (syn,cis-40)]; δ = 71.99
C-1Ј (syn,trans-40)] ↔ δ = 4.50 [1Ј-H (syn,trans-40)]; δ = 72.51 [C-
Ј (syn,cis-40)] ↔ δ = 4.47 [1Ј-H (syn,cis-40)]; δ = 73.50 [C-6 (syn,-
(anti,cis-40)] , 43.02 [C-3 (anti,trans-40)] , 45.81 [C-3 (anti,cis-
A
A
A
[
40)] , 72.96 [C-6 (anti,trans-40)] , 73.30 [C-1Ј (anti,trans-40)] ,
73.70 [C-1Ј (anti,cis-40)] , 74.84 [C-6 (anti,cis-40)] , 129.80 [C-2Ј
A
A
1
1
2
B
B
trans-40)] ↔ δ = 3.91 [6-H (syn,trans-40)] and 4.21 [6-H (syn,-
trans-40)]; δ = 75.01 [C-6 (syn,cis-40)] ↔ δ = 3.85 [6-H (syn,cis-
(anti,trans-40)] , 129.88 [C-3Ј (anti,trans-40)] , 129.92 [C-2Ј
1
B
B
(anti,cis-40)] , 129.97 [C-3Ј (anti,cis-40)] , 174.45 [C-2 (anti,cis-40)],
2
A
40)] and 4.26 [6-H (syn,cis-40)]; δ = 128.74 [C-3Ј (syn,trans-40)] ↔
175.61 [C-2 (anti,trans-40)]. The indicated nuclei – they are non-
δ = 5.76 [3Ј-H (syn,trans-40)]; δ = 128.89 [C-3Ј (syn,cis-40)] ↔ δ =
.75 [3Ј-H (syn,cis-40)]; δ = 129.61 [C-2Ј (syn,trans-40)] ↔ δ = 5.49
2Ј-H (syn,trans-40)]; δ = 129.80 [C-2Ј (syn,cis-40)] ↔ δ = 5.48 [2Ј- crosspeaks with directly bonded protons (these had previously been
quaternary – were identified in an edHSQC spectrum [“short-range
5
3
C,H-COSY spectrum” (100.62/400.13 MHz, CDCl )] by their
[
1
3
1
H (syn,cis-40)]. IR (film): ν˜ = 3550, 2965, 1726, 1460, 1400, 1165,
1
for C10H O [M + H] 185.11722; found 185.11717 (–0.3 ppm).
17 3
assigned unequivocally) [δ
C
(
H
C) ↔ δ ( H)]: δ = 16.95 [C-5-Me
–1
095, 1045, 970, 915, 745 cm . HRMS (pos. APCI, MeOH): calcd.
(anti,trans-40)] ↔ δ = 1.00 [5-Me (anti,trans-40)]; δ = 17.43 [C-5-
Me (anti,cis-40)] ↔ δ = 0.99 [5-Me (anti,cis-40)]; δ = 17.75 [C-4Ј
+
(
4
2
anti,cis-40)] ↔ δ = 1.71 [4Ј-H
3
(both diastereomers)]; δ = 17.78 [C-
Ј (anti,trans-40)] ↔ δ = 1.71 [4Ј-H (both diastereomers)]; δ =
7.30 [C-5 (anti,trans-40)] ↔ δ = 2.03–2.18 [5-H (both dia-
rel-(3S,5R)-3-[(S,trans)-1-Hydroxybut-2-enyl]-5-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (anti,trans-40)
3
stereomers)]; δ = 28.17 [C-5 (anti,cis-40)] ↔ δ = 2.03–2.18 [5-H
both diastereomers)]; δ = 29.26 [C-4 (anti,trans-40)] ↔ δ = 1.55
(
1
2
[4-H (anti,trans-40)] and 1.72 [4-H (anti,trans-40)]; δ = 30.99 [C-
1
2
4
(anti,cis-40)] ↔ δ = 1.15 [4-H (anti,cis-40)] and 1.97 [4-H
(
(
(
(
(
anti,cis-40)]; δ = 43.02 [C-3 (anti,trans-40)] ↔ δ = 2.55 [3-H
anti,trans-40)]; δ = 45.81 [C-3 (anti,cis-40)] ↔ δ = 2.49 [3-H
Following the General Procedure A the title compound was pre-
pared from γ-methyl-δ-lactone (20, 114 mg, 1.00 mmol) and
crotonaldehyde (23, 144 mg, 2.00 mmol, 2.0 equiv.). Purification by
1
anti,cis-40)]; δ = 72.96 [C-6 (anti,trans-40)] ↔ δ = 3.90 [6-H
2
anti,trans-40)] and 4.20 [6-H (anti,trans-40)]; δ = 73.30 [C-1Ј
[
25]
flash chromatography
6
(2.0ϫ15 cm, 15 mL, c-C H12/EtOAc 3:1
anti,trans-40)] ↔ δ = 4.19–4.26 [1Ј-H (both diastereomers)]; δ =
to 1:1, 12–20) rendered the product as a colorless oil (137 mg, 74%,
anti,trans-40/anti,cis-40 = 75:25). syn,trans/syn,cis/anti,trans/anti,cis
7
3.70 [C-1Ј (anti,cis-40)] ↔ δ = 4.19–4.26 [1Ј-H (both dia-
1
stereomers)]; δ = 74.84 [C-6 (anti,cis-40)] ↔ δ = 3.84 [6-H (anti,cis-
4
changeable. IR (film): ν˜ = 3450, 2965, 2935, 2920, 2880, 1725, 1460,
1
7
7
4
:0:73:20; syn/anti 7:93; syn,trans/syn,cis Ͼ95:5, anti,trans/anti,cis
8:22. [Integration of the signals at δ = 2.46–2.60 (3-H, anti,trans-
0 + anti,cis-40) vs. δ = 2.75 (3-H, syn,trans-40) in the 400 MHz
2
B
0)] and 4.31 [6-H (anti,cis-40)]; Assignments pairwise inter-
–1
400, 1250, 1220, 1165, 1120, 1095, 1045, 970 cm . HRMS (pos.
1
H NMR spectrum of the crude product resulted in (overall-)
[M + H]+ 185.11722; found
APCI, MeOH): calcd. for C10
85.11725 (+0.1 ppm).
17 3
H O
syn/anti 07:93. Integration of the signals at δ = 2.46–2.60 (3-H,
1
2
anti,trans-40 + anti,cis-40) vs. δ = 4.32 (6-H , anti,cis-40) resulted
rel-(3S,5R)-3-[(S)-(4-Bromophenyl)(hydroxy)methyl]-5-methyl-
3,4,5,6-tetrahydro-2H-pyran-2-one (syn,trans-41)
in anti:iso-anti 78:22. The NMR contained no signal clearly attrib-
1
utable to syn,cis-40.] H NMR (400.13 MHz, CDCl
3
, 75:25 mixture
of diastereomers): δ = 0.99 [d, J5-Me,5 = 6.7 Hz, 3 H, 5-Me (anti,cis-
4
0)], 1.00 [d, J5-Me,5 = 6.9 Hz, 3 H, 5-Me (anti,trans-40)], 1.15 [ddd,
1
Jgem = 13.5 Hz, J4-H(1),3 = 12.7 Hz, J4-H(1),5 = 10.4 Hz, 1 H, 4-H
(
=
J
anti,cis-40)], 1.55 [ddd, Jgem = 13.8 Hz, J4-H(1),3 = 9.0 Hz, J4-H(1),5
7.3 Hz, 1 H, 4-H1 (anti,trans-40)], 1.72 [dddd, Jgem = 13.8 Hz,
4-H(2),3 = 10.4 Hz, J4-H(2),5 = 8.2 Hz, J4-H(2),6-H(2) = 0.9 Hz, 1 H, 4-
Following the General Procedure A the title compound was pre-
pared from γ-methyl-δ-lactone (20, 114 mg, 1.00 mmol) and 4-
2
4
H (anti,trans-40)] superimposed by 1.71 [dd, J4Ј,3Ј = 6.3 Hz, J4Ј,2Ј
1.4 Hz, 3 H, 4Ј-H (both diastereomers)], 1.97 [dddd, Jgem
=
1
1
3
=
bromobenzaldehyde (24, 370 mg, 2.00 mmol, 2.0 equiv.). Purifica-
4
[25]
3.6 Hz J4-H(2),3 = 6.8 Hz, J4-H(2),5 = 4.8 Hz, J4-H(2),6-H(2) = 2.1 Hz,
tion by flash chromatography
6 12
(2.0ϫ 15 cm, 15 mL, c-C H /
H, 4-H2 (anti,cis-40)], 2.03–2.18 [m, 1 H, 5-H (both dia- EtOAc 3:1 to 1:1, 17–25) rendered the product as a colorless
stereomers)], 2.49 [ddd, J3,4-H(1) = 12.6 Hz, J3,1Ј = 8.0 Hz, J3,4-H(2)
6.9 Hz, 1 H, 3-H (anti,cis-40)], 2.55 [ddd, J3,4-H(2) = 10.4 Hz,
solid (225 mg, 75 %, syn,trans-41:syn,cis-41 = 66:33).
syn,trans/syn,cis/anti,trans/anti,cis 66:31:2:1; syn/anti 97:3;
syn,trans/syn,cis 68:32, anti,trans/anti,cis 70:30 [determined by inte-
gration of the signals at δ = 4.77 (1Ј-H anti,trans-41) vs. δ = 4.80
(1Ј-H, anti,cis-41) vs. δ = 5.44 (1Ј-H, syn,trans-41) vs. δ = 5.48 (1Ј-
=
J
3,4-H(1) = 9.0 Hz, J3,1Ј = 8.0 Hz, 1 H, 3-H (anti,trans-40)], 3.84 [dd,
1
J
gem = J6-H(1),5 = 9.9 Hz, 1 H, 6-H (anti,cis-40)], 3.87 [br. s, 1 H,
OH (anti,trans-40)] superimposed by 3.90 [dd, Jgem = J6-H(1),5
=
1
1
10.7 Hz, 1 H, 6-H (anti,trans-40)], 4.14 [br. s, 1 H, OH (anti,cis-
H, syn,cis-41) in the 400 MHz H NMR spectrum of the crude
1
4
0)], 4.19–4.26 [m, 1 H, 1Ј-H (both diastereomers)] superimposed
product], m.p. 66 °C. H NMR (400.13 MHz, CDCl
3
, 66:33 mix-
4
by 4.20 [ddd, Jgem = 11.1 Hz, J6-H(2),5 = 4.9 Hz, J6-H(2),4-H(2)
=
ture of diastereomers): δ = 0.91 [d, J5-Me,5 = 6.8 Hz, 3 H, 5-Me
7910
www.eurjoc.org © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7892–7918

Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
(syn,trans-41)] superimposed by 0.92 [d, J5-Me,5 = 6.7 Hz, 3 H, 5-
were assigned in analogy to syn-41. IR (film): ν˜ = 3440, 2960, 1725,
Me (syn,cis-41)], 1.14 [m , possibly interpretable as ddd, Jgem
c
=
1490, 1460, 1400, 1345, 1220, 1175, 1165, 1095, 1070, 1050, 1030,
1010 cm . HRMS (pos. APCI, MeOH): calcd. for C13H O Br [M
16 3
1
–1
1
3.4 Hz, J4-H(1),3 = 9.3 Hz, J4(1),5 = 7.4 Hz, 1 H, 4-H (syn,trans-
1)] , 1.47–1.53 [m, 2 H, 4-H
2
A
(syn,cis-41)] , 1.92–2.16 [m, 5-H + H]+ 299.02773; found 299.02786 (+0.4 ppm).
, possibly inter-
pretable as dddd, Jgem = 13.4 Hz, J4-H(2),3 = 9.4 Hz, J4-H(2),5
A
4
(
both diastereomers)]A superimposed by 2.00 [m
c
rel-(3S,5R)-3-[(R)-(4-Bromophenyl)(hydroxy)methyl]-5-methyl-
,4,5,6-tetrahydro-2H-pyran-2-one (anti,trans-41)
=
c
,
3
4
2
A
7
.9 Hz, J4-H(2),6-H(2) = 1.3 Hz, 1 H, 4-H (syn,trans-41)] , 2.77 [m
possibly interpretable as ddd, J3,4 = 11.0 and 8.2 Hz, J3,1Ј = 2.8 Hz,
1
=
H, 3-H (syn,cis-41)], 2.84 [ddd, J3.4-H(1) = J3,4-H(2) = 9.4 Hz, J3,1Ј
2.7 Hz, 1 H, 3-H (syn,trans-41)], 3.17 [br. s, 1 H, OH (syn,cis-
41)] superimposed by 3.22 [br. s, 1 H, OH (syn,trans-41)], 3.85 [m
c
,
possibly interpretable as dd, Jgem = 11.1 Hz, J6-H(!),5 = 10.1 Hz, 1
1
Following the General Procedure B the title compound was pre-
pared from γ-methyl-δ-lactone (20, 114 mg, 1.00 mmol) and 4-
H, 6-H (syn,cis-41)] superimposed by 3.88 [m
able as dd Jgem = 11.2 Hz, J6-H(!),5 = 9.5 Hz, 1 H, 6-H (syn,trans-
c
, possibly interpret-
1
bromobenzaldehyde (24, 370 mg, 2.00 mmol, 2.0 equiv.). Purifica-
4
J
4
4
1)], 4.19 [m
c
, possibly interpretable as ddd, Jgem = 11.0 Hz,
tion by flash chromatography[ (2.0ϫ 15 cm, 15 mL, c-C
25]
6-H(2),5 = 4.3 Hz, 4J6-H(2),4-H(2) = 1.2 Hz, 1 H, 6-H (syn,trans-41)],
2
6 12
H /
EtOAc 3:1 to 1:1, 19–27) rendered the product as a colorless solid
( 2 4 5 m g , 8 2 % , a n t i , t r a n s - 4 1 / a n t i , c i s - 4 1 = 7 5 : 2 5 ) .
syn,trans/syn,cis/anti,trans/anti,cis 3:4:68:25; syn/anti 7:93;
syn,trans/syn,cis 41:59, anti,trans/anti,cis 73:27 [determined by inte-
gration of the signals at δ = 4.77 (1Ј-H anti,trans-41) vs. δ = 4.80
.25 [m , possibly interpretable as ddd, Jgem = 11.0 Hz, J6-H(2),5 =
c
4
2
.6 Hz, J6-H(2),4-H(2) = 1.9 Hz, 1 H, 6-H (syn,cis-41)], 5.42 [d, J1Ј,3
2.4 Hz, 1 H, 1Ј-H (syn,trans-41)], 5.48 [d, J1Ј,3 = 2.5 Hz, 1 H, 1Ј-
H (syn,cis-41)], 7.23 [m , 2 H, 2ϫortho-H (both diastereomers)],
, 2 H, 2ϫmeta-H (both diastereomers)]. AThe indicated
.47 [m
protons were distinguished in a DQF-COSY spectrum [“H,H-
COSY spectrum” (400.13 MHz, CDCl )] by their crosspeaks with
protons that previously had been assigned unequivocally [δ
=
c
7
c
(
1Ј-H, anti,cis-41) vs. δ = 5.43 (1Ј-H, syn,trans-41) vs. δ = 5.48 (1Ј-
1
H, syn,cis-41) in the 400 MHz H NMR spectrum of the crude
product], m.p. 60 °C. H NMR (400.13 MHz, CDCl , 75:25 mix-
3
3
1
1
H
( H)
1
ture of diastereomers): δ = 0.90 [d, J5-Me,5 = 6.8 Hz, 3 H, 5-Me
(anti,trans-41)] superimposed by 0.91 [d, J5-Me,5 = 6.7 Hz, 3 H, 5-
↔
δ
H
( H)]: δ = 2.77 [3-H (syn,cis-41)] ↔ δ = 1.47–1.53 [4-H
2
1
(
(
(
syn,cis-41)]; δ = 2.84 [3-H (syn,trans-41)] ↔ δ = 1.14 [4-H
syn,trans-41)] and 2.00 [4-H2 (syn,trans-41)]; δ = 3.85 [6-H
1
Me (anti,cis-41)], 1.05 [m
4-H(1),3 = 13.2 Hz, J4(1),5 = 10.5 Hz, 1 H, 4-H (anti,cis-41)] , 1.11
, possibly interpretable as ddd, Jgem = 13.8 Hz, J4-H(1),3 = 9.0 Hz,
c
, possibly interpretable as ddd, Jgem =
1
A
J
syn,cis-41)] ↔ δ = 1.92–2.16 [5-H (both diastereomers)]; δ = 3.88
[
J
m
c
1
[6-H (syn,trans-41)] ↔ δ = 1.92–2.16 [5-H (both diastereomers)];
1
A
c
4(1),5 = 7.2 Hz, 1 H, 4-H (anti,trans-41)] , 1.44 [m , possibly inter-
2
δ = 4.19 [6-H (syn,trans-41)] ↔ δ = 1.92–2.16 [5-H (both dia-
stereomers)]; δ = 4.25 [6-H (syn,cis-41)] ↔ δ = 1.92–2.16 [5-H
pretable as dddd, Jgem = 13.5 Hz, J4-H(2),3 = 6.7 Hz, J4-H(2),5
=
c
,
2
4
2
A
4.7 Hz, J4-H(2),6-H(2) = 2.0 Hz, 1 H, 4-H (anti,cis-41)] , 1.59 [m
13
(both diastereomers)]. C NMR (100.62 MHz, CDCl
3
, 66:33 mix-
possibly interpretable as dddd, Jgem = 13.8 Hz, J4-H(2),3 = 10.8 Hz,
A
ture of diastereomers): δ = 16.76 [C-5-Me (syn,trans-41)] , 17.04
4
2
A
J
1
4-H(2),5 = 8.4 Hz, J4-H(2),6-H(2) = 0.8 Hz, 1 H, 4-H (anti,trans-41)] ,
A
A
[
C-5-Me (syn,cis-41)] , 25.25 [C-4 (syn,trans-41)] , 27.16 [C-4
A
.97–2.14 [m, 1 H, 5-H (both diastereomers)] , 2.66 [m
c
, possibly
A
A
A
(syn,cis-41)] , 27.70 [C-5 (syn,trans-41)] , 28.32 [C-5 (syn,cis-41)] ,
interpretable as ddd, J3,4-H(1) = 12.8 Hz, J3,1Ј = 8.7 Hz, J3,4-H(2)
=
A
A
44.37 [C-3 (syn,trans-41)] , 48.00 [C-3 (syn,cis-41)] , 71.03 [C-1Ј
6
.7 Hz, 1 H, 3-H (anti,cis-41)], 2.75 [ddd, J3.4-H(2) = 10.7 Hz,
A
A
(
syn,trans-41)] , 71.67 [C-1Ј (syn,cis-41)] , 73.47 [C-6 (syn,trans-
J
3,4-H(1) = J3,1Ј = 8.8 Hz, 1 H, 3-H (anti,trans-41)], 3.86 [m , possibly
c
A
A
4
1
1
1
1
1)] , 75.05 [C-6 (syn,cis-41)] , 121.26 [C-para (syn,trans-41)],
1
interpretable as dd, Jgem = 11.2 Hz, J6-H(1),5 = 9.3 Hz, 1 H, 6-H
anti,cis-41)] superimposed by 3.91 [m , possibly interpretable as dd
gem = J6-H(1),5 = 10.7 Hz, 1 H, 6-H (anti,trans-41)], 4.21 [m , poss-
ibly interpretable as ddd, Jgem = 11.1 Hz, J6-H(2),5 = 4.8 Hz,
A
21.28 [C-para (syn,cis-41)], 127.52 [2 ϫC-ortho (syn,trans-41)] ,
(
J
c
B
B
27.60 [2ϫC-ortho (syn,cis-41)] , 131.52 [2ϫC-meta (syn,cis-41)] ,
31.54 [2ϫC-meta (syn,trans-41)] , 139.83 [C-ipso (syn,trans-41)],
40.16 [C-ipso (syn,cis-41)], 172.93 [C-2 (syn,cis-41)], 174.69 [C-2
1
A
c
4
2
J
6-H(2),4-H(2) = 0.9 Hz, 1 H, 6-H (anti,trans-41)], 4.32 [m
c
, possibly
A
(syn,trans-41)]. The indicated nuclei – they are non-quaternary –
interpretable as ddd, Jgem = 11.2 Hz, J6 -H (2 ), 5 = 4.8 Hz,
were identified in an edHSQC spectrum [“short-range C,H-COSY
spectrum” (100.62/400.13 MHz, CDCl )] by their crosspeaks with
directly bonded protons (these had previously been assigned
4
2
J
6-H(2),4-H(2) = 2.0 Hz, 1 H, 6-H (anti,cis-41)], 4.41 [br. s, 1 H, OH
anti,trans-41)], 4.77 [d, J1Ј,3 = 8.7 Hz, 1 H, 1Ј-H (anti,trans-41)],
.80 [d, J1Ј,3 = 8.5 Hz, 1 H, 1Ј-H (anti,cis-41)], 4.38 [br. s, 1 H, OH
anti,cis-41)], 7.24 [m , 2 H, 2ϫortho-H (both diastereomers)], 7.50
, 2 H, 2ϫmeta-H (both diastereomers)]. The indicated protons
were distinguished in a DQF-COSY spectrum [“H,H-COSY spec-
trum” (400.13 MHz, CDCl )] by their crosspeaks with protons that
previously had been assigned unequivocally [δ
3
(
4
(
13
1
unequivocally) [δ
C
H
( C) ↔ δ ( H)]: δ = 16.76 [C-5-Me (syn,trans-
c
41)] ↔ δ = 0.91 [5-Me (syn,trans-41)]; δ = 17.04 [C-5-Me (syn,cis-
A
[m
c
4
1)] ↔ δ = 0.92 [5-Me (syn,cis-41)]; δ = 25.25 [C-4 (syn,trans-41)]
1
2
↔
δ = 1.14 [4-H (syn,trans-41)] and 2.00 [4-H (syn,trans-41)]; δ =
(syn,cis-41)]; δ =
7.70 [C-5 (syn,trans-41)] ↔ δ = 1.92–2.16 [5-H (both dia-
3
27.16 [C-4 (syn,cis-41)] ↔ δ = 1.47–1.53 [4-H
2
1
1
H
H
( H) ↔ δ ( H)]: δ
2
1
=
2.66 [3-H (anti,cis-41)] ↔ δ = 1.05 [4-H (anti,cis-41)] and 1.44
stereomers)]; δ = 28.32 [C-5 (syn,cis-41)] ↔ δ = 1.92–2.16 [5-H
both diastereomers)]; δ = 44.37 [C-3 (syn,trans-41)] ↔ δ = 2.84 [3-
H (syn,trans-41)]; δ = 48.00 [C-3 (syn,cis-41)] ↔ δ = 2.77 [3-H
2
1
1
[4-H (anti,cis-41)]; δ = 2.75 [3-H (anti,trans-41)] ↔ δ = 1.11 [4-H
(
2
(
(
(
anti,trans-41)] and 1.59 [4-H (anti,trans-41)]; δ = 3.86 [6-H
2
anti,cis-41)] and 4.32 [6-H (anti,cis-41)] ↔ δ = 1.97–2.14 [5-H
both diastereomers)]; δ = 3.91 [6-H (anti,trans-41)] and 4.21 [6-
(
(
(
(
(
syn,cis-41)]; δ = 71.03 [C-1Ј (syn,trans-41)] ↔ δ = 5.42 [1Ј-H
syn,trans-41)]; δ = 71.67 [C-1Ј (syn,cis-41)] ↔ δ = 5.48 [1Ј-H
1
2
13
H (anti,trans-41)] ↔ δ = 1.97–2.14 [5-H (both diastereomers)].
NMR (100.62 MHz, CDCl , 75:25 mixture of diastereomers): δ =
1
2
C
1
syn,cis-41)]; δ = 73.47 [C-6 (syn,trans-41)] ↔ δ = 3.88 [6-H
3
2
syn,trans-41)] and 4.19 [6-H (syn,trans-41)]; δ = 75.05 [C-6
A
A
6.83 [C-5-Me (anti,trans-41)] , 17.33 [C-5-Me (anti,cis-41)] ,
1
2
syn,cis-41)] ↔ δ = 3.85 [6-H (syn,cis-41)] and 4.25 [6-H (syn,cis-
1)]; δ = 127.52 [2ϫC-ortho (syn,trans-41)] ↔ δ = 7.23 [2ϫortho-
A
A
7.29 [C-5 (anti,trans-41)] , 28.18 [C-5 (anti,cis-41)] , 29.22 [C-4
4
A
A
(
anti,trans-41)] , 31.08 [C-4 (anti,cis-41)] , 44.36 [C-3 (anti,trans-
H (both diastereomers)]; δ = 131.54 [2ϫC-meta (syn,trans-41)] ↔
A
A
A
4
1)] , 47.13 [C-3 (anti,cis-41)] , 72.93 [C-6 (anti,trans-41)] , 74.28
B
δ = 7.47 [2ϫmeta-H (both diastereomers)]; the indicated nuclei
A
A
[C-1Ј (anti,trans-41)] , 74.70 [C-1Ј (anti,cis-41)] , 75.00 [C-6 (an-
Eur. J. Org. Chem. 2015, 7892–7918
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7911

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
ti,cis-41)] , 122.23 [C-para (anti,cis-41)], 122.26 [C-para (anti,trans-
A
= 1.68 (2Ј-H) and δ = 1.05 (3Ј-H ) ↔ δ = 1.68 (2Ј-H); δ = 1.68 (2Ј-
3
A
4
1)], 128.80 [2 ϫ C-ortho (anti,trans-41)] , 128.85 [2 ϫ C-ortho H) ↔ δ = 3.83 (1Ј-H); δ = 3.83 (1Ј-H) ↔ δ = 2.63–2.71 (3-H); δ =
B
B
2
(
anti,cis-41)] , 131.76 [2ϫC-meta (anti,cis-41)] , 131.80 [2 ϫ C-
2.63–2.71 (3-H) ↔ δ = 1.85–2.03 (m, 4-H , 5-H ); δ = 1.37 (6-Me)
2
A
1
meta (anti,trans-41)] , 139.16 139.83 [C-ipso (anti,trans-41)], 139.34 ↔ δ = 4.46 (6-H); δ = 4.46 (6-H) ↔ δ = 1.57–1.68 (5-H ); δ = 4.46
2
1 3
[
C-ipso (anti,cis-41)], 174.62 [C-2 (anti,cis-41)], 175.72 [C-2 (anti,- (6-H) ↔ δ = 1.85–2.03 (m, 4-H , 5-H ) ppm. C NMR
2
A
A A
trans-41)]. The indicated nuclei – they are non-quaternary – were
3
(100.62 MHz, CDCl ): δ = 15.39 (C-4) , 18.83 (C-2Ј-Me) , 19.85
A
A
A
A
identified in an edHSQC spectrum [“short-range C,H-COSY spec-
(C-3Ј) , 20.89 (C-6-Me) , 28.98 (C-5) , 29.72 (C-2Ј) , 41.06
A
A
A
A
trum” (100.62/400.13 MHz, CDCl
rectly bonded protons (these had previously been assigned unequiv-
3
)] by their crosspeaks with di-
(C-3) , 74.75 (C-6) , 75.02 (C-1Ј) , 176.18 (C-2) ppm. The indi-
cated nuclei – they are non-quaternary – were identified in an
edHSQC spectrum [“short-range C,H-COSY spectrum” (100.62/
13
1
ocally) [δ
C
( C) ↔ δ ( H)]: δ = 16.83 [C-5-Me (anti,trans-41)] ↔ δ
H
=
=
0.90 [5-Me (anti,trans-41)]; δ = 17.33 [C-5-Me (anti,cis-41)] ↔ δ
0.91 [5-Me (anti,cis-41)]; δ = 27.29 [C-5 (anti,trans-41)] ↔ δ =
400.13 MHz, CDCl )] by their crosspeaks with directly bonded pro-
3
1
3
tons (these had previously been assigned unequivocally) [δ ( C)
C
1
2
1.97–2.14 [5-H (both diastereomers)]; δ = 28.18 [C-5 (anti,cis-41)]
↔ δ ( H)]: δ = 15.39 (C-4) ↔ δ = 1.85–2.03 (4-H , 5-H ); δ = 18.83
H
2
↔
δ = 1.97–2.14 [5-H (both diastereomers)]; δ = 29.22 [C-4
(C-2Ј-Me) ↔ δ = 0.86 (2Ј-Me); δ = 19.85 (C-3Ј) ↔ δ = 1.05 (3Ј-
1
2
(
(
anti,trans-41)] ↔ δ = 1.11 [4-H (anti,trans-41)] and 1.59 [4-H
1
H
=
3
); δ = 20.89 (C-6-Me) ↔ δ = 1.37 (6-Me); δ = 28.98 (C-5) ↔ δ
anti,trans-41)]; δ = 31.08 [C-4 (anti,cis-41)] ↔ δ = 1.05 [4-H (an-
1
2
1.57–1.68 (5-H ) and 1.85–2.03 (4-H , 5-H ); δ = 29.72 (C-2Ј) ↔
2
2
ti,cis-41)] and 1.44 [4-H (anti,cis-41)]; δ = 44.36 [C-3 (anti,trans-
δ = 1.68 (2Ј-H); δ = 41.06 (C-3) ↔ δ = 2.63–2.71 (3-H); δ = 74.75
4
↔
1)] ↔ δ = 2.75 [3-H (anti,trans-41)]; δ = 47.13 [C-3 (anti,cis-41)]
(
C-6) ↔ δ = 4.46 (6-H); δ = 75.02 (C-1Ј) ↔ δ = 3.83 (1Ј-H). IR
δ = 2.66 [3-H (anti,cis-41)]; δ = 72.93 [C-6 (anti,trans-41)] ↔ δ
(
1
film): ν˜ = 3480, 2980, 2875, 2360, 2250, 1720, 1470, 1385, 1200,
130, 1075, 910, 735, 650 cm . HRMS (pos. APCI, MeOH): calcd.
=
3.91 [6-H1 (anti,trans-41)] and 4.21 [6-H2 (anti,trans-41)]; δ =
–1
74.28 [C-1Ј (anti,trans-41)] ↔ δ = 4.77 [1Ј-H (anti,trans-41)]; δ =
[M + H]+ 187.13287; found 187.13292 (+0.3 ppm).
10 18 3
C H O (186.25): calcd. C 64.49, H 9.74; found C 64.26, H 9.78.
19 3
for C10H O
7
[
4.70 [C-1Ј (anti,cis-41)] ↔ δ = 4.80 [1Ј-H (anti,cis-41)]; δ = 75.00
C-6 (anti,cis-41)] ↔ δ = 3.86 [6-H1 (anti,cis-41)] and 4.32 [6-H
2
rel-(3S,6S)-3-[(S)-1-Hydroxy-2-methylpropyl]-6-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (anti,cis-42)
(
[
(
(
1
anti,cis-41)]; δ = 128.80 [2ϫC-ortho (anti,trans-41)] ↔ δ = 7.24
2 ϫ ortho-H (both diastereomers)]; δ = 131.80 [2 ϫ C-meta
anti,trans-41)] ↔ δ = 7.50 [2ϫmeta-H (both diastereomers)]. IR
film): ν˜ = 3450, 2960, 1720, 1485, 1460, 1400, 1345, 1165, 1095,
–1
070, 1045, 1010, 915, 835, 745 cm . HRMS (pos. APCI, MeOH):
+
calcd. for C13
Ϯ0.0 ppm).
16 3
H O Br [M + H] 299.02773; found 299.02774
(
Following the General Procedure B the title compound was pre-
pared from δ-methyl-δ-lactone (21, 114 mg, 1.00 mmol) and iso-
rel-(3S,6S)-3-[(R)-1-Hydroxy-2-methylpropyl]-6-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (syn,cis-42)
butyraldehyde (22, 144 mg, 2.00 mmol, 2.0 equiv.). Purification by
flash chromatography[ (2.0ϫ15 cm, 15 mL, c-C
25]
H12/EtOAc 3:1
6
to 1:1, 18–24) rendered the main diastereomer as a colorless oil
115 mg, 62 %). syn,trans/syn,cis/anti,trans/anti,cis 0:6:23:71;
(
syn/anti 6:94; syn,trans/syn,cis Ͻ5:95, anti,trans/anti,cis 24:76 [de-
termined by integration of the signals at δ = 2.44 (3-H, anti,trans-
42) vs. δ = 2.51–2.61 (3-H, anti,cis-42) vs. δ = 2.63–2.71 (3-H,
Following the General Procedure A the title compound was pre-
pared from δ-methyl-δ-lactone (21, 114 mg, 1.00 mmol) and iso-
butyraldehyde (22, 144 mg, 2.00 mmol, 2.0 equiv.). Purification by
1
syn,cis-42) in the 400 MHz H NMR spectrum of the crude prod-
uct; the NMR contained no signal clearly attributable to syn,trans-
[
25]
1
flash chromatography
to 1:1, 20–26) rendered the main diastereomer as a colorless oil
140 mg, 75 %). syn,trans/syn,cis/anti,trans/anti,cis 14:85:0:1;
syn/anti 99:1; syn,trans/syn,cis 14:86, anti,trans/anti,cis Ͻ5:95. [The
00 MHz 1H NMR spectrum of the crude product was too con-
taminated by byproducts to integrate any signals. A short column
chromatographic separation (2.0ϫ10 cm, 15 mL, c-C 12/EtOAc
:1 to 1:1, 11–24) was conducted to get rid of most byproducts and
(2.0ϫ15 cm, 15 mL, c-C
6
H12/EtOAc 3:1
42]. H NMR (400.13 MHz, CDCl
3
): δ = 0.92 (d, J2Ј-Me,2Ј = 6.8 Hz,
A
A
3 H, 2Ј-Me) , 1.03 (d, J3Ј,2Ј = 7.3 Hz, 3 H, 3Ј-H
= 6.2 Hz, 3 H, 6-Me), 1.52–1.69 (m, 2 H, 4-H , 5-H ) , 1.85 (qqd,
3
) , 1.37 (d, J6-Me,6
1
1 A
(
J
2Ј,3Ј = J2Ј,2-Me = 6.8 Hz, J2Ј,1Ј = 3.8 Hz, 1 H, 2Ј-H), 1.94–2.06 (m,
2
2 A
A
3
2 H, 4-H , 5-H ) , 2.51–2.61 (m, 1 H, 3-H) , 3.56 (m
interpretable as dd, J1Ј,3 = 7.6 Hz, J1Ј,2Ј = 3.7 Hz, 1 H, 1Ј-H) , 3.66
(br. s, 1 H, OH), 4.43–4.53 (m, 1 H, 6-H) . The indicated protons
were distinguished in a DQF-COSY spectrum [“H,H-COSY spec-
c
, possibly
A
A
A
6
H
3
1
a 400 MHz H NMR spectrum of the product thus obtained was
recorded. Integration of the signals at δ = 3.54 (1Ј-H , anti,cis-42)
trum” (400.13 MHz, CDCl
previously had been assigned unequivocally [δ
= 1.86 (2Ј-H) ↔ δ = 0.92 (2Ј-Me); δ = 1.85 (2Ј-H) ↔ δ = 1.03 (3Ј-
); δ = 1.85 (2Ј-H) ↔ δ = 3.56 (1Ј-H); δ = 3.56 (1Ј-H) ↔ δ =
3
)] by their crosspeaks with protons that
1
1
3
H
H
( H) ↔ δ ( H)]: δ
vs. δ = 3.83 (1Ј-H, syn,cis-42) vs. δ = 3.96 (1Ј-H, syn,trans-42) re-
sulted in syn/anti 99:01 and syn/iso-syn 86:13. The NMR contained
no signal clearly attributable to anti,trans-42.] 1H NMR
H
3
1
1
2.51–2.61 (3-H); δ = 2.51–2.61 (3-H) ↔ δ = 1.52–1.69 (4-H , 5-H );
2
2
(
400.13 MHz, CDCl
3
): δ = 0.86 (d, J2Ј-Me,2Ј = 6.8 Hz, 3 H, 2Ј-Me), δ = 2.51–2.61 (3-H) ↔ δ = 1.94–2.06 (4-H , 5-H ); δ = 1.37 (6-Me)
1
6
=
.05 (d, J3Ј,2Ј = 6.5 Hz, 3 H, 3Ј-H ), 1.37 (d, J6-Me,6 = 6.2 Hz, 3 H, ↔ δ = 4.43–4.53 (6-H); δ = 4.43–4.53 (6-H) ↔ δ = 1.52–1.69 (4-
3
1
A
1
1
2
2
-Me), 1.57–1.68 (m, 1 H, 5-H ) superimposed by 1.68 (dqq, J2Ј,1Ј
H , 5-H ); δ = 4.43–4.53 (6-H) ↔ δ = 1.94–2.06 (4-H , 5-H ) ppm.
A
A
13
9.7 Hz, J2Ј,2Ј-Me = J2Ј,3Ј = 6.6 Hz, 1 H, 2Ј-H) , 1.85–2.03 (m, 3
3
C NMR (100.62 MHz, CDCl ): δ = 15.02 (C-2Ј-Me) , 20.00 (C-
2
A
A
B
A
A
B
A
2 c
H, 4-H , 5-H ) , 2.63–2.71 (m, 2 H, 3-H, OH) , 3.83 (m , possibly 4) , 20.20 (C-3Ј) , 20.73 (C-6-Me) , 28.61 (C-5) , 29.19 (C-2Ј) ,
A
A
A
A
A
interpretable as dd, J1Ј,2Ј = 9.8 Hz, J1Ј,3 = 2.0 Hz, 1 H, 1Ј-H) , 4.46
, possibly interpretable as dqd, J6,5 = 10.6 and 2.6 Hz, J6,6-Me
41.60 (C-3) , 74.28 (C-6) , 75.52 (C-1Ј) , 176.66 (C-2) ppm. The
indicated nuclei – they are non-quaternary – were identified in an
edHSQC spectrum [“short-range C,H-COSY spectrum” (100.62/
(m
c
A
A
=
6.3 Hz, 1 H, 6-H) . The indicated protons were distinguished
in a DQF-COSY spectrum [“H,H-COSY spectrum” (400.13 MHz,
CDCl )] by their crosspeaks with protons that previously had been
assigned unequivocally [δ
400.13 MHz, CDCl
3
)] by their crosspeaks with directly bonded pro-
1
3
3
tons (these had previously been assigned unequivocally) [δ
C
( C)
( H)]: δ = 15.02 (C-2Ј-Me) ↔ δ = 0.92 (2Ј-Me); δ = 20.20 (C-
1
1
1
H
( H) ↔ δ
H
( H)]: δ = 0.86 (2Ј-Me) ↔ δ
↔ δ
H
7912
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7892–7918

Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
Ј) ↔ δ = 1.03 (3Ј-H ); δ = 20.73 (C-6-Me) ↔ δ = 1.37 (6-Me); δ
3
3
75.08 (C-6) ↔ δ = 4.28 (6-H); δ = 128.57 (C-3Ј) ↔ δ = 5.74 (3Ј-
=
29.19 (C-2Ј) ↔ δ = 1.86 (2Ј-H); δ = 41.60 (C-3) ↔ δ = 2.51–2.61 H); δ = 129.65 (C-2Ј) ↔ δ = 5.49 (2Ј-H); BThe indicated nuclei
(
3-H); δ = 74.28 (C-6) ↔ δ = 4.43–4.53 (6-H); δ = 75.52 (C-1Ј) ↔
belong to syn,trans-43 and were assigned in analogy with the corre-
sponding nuclei in syn,cis-43. IR (film): ν˜ = 3450, 2935, 1720, 1450,
B
δ = 1.56 (1Ј-H); these nuclei produce identical crosspeaks in the
C,H-COSY spectrum, because their respective protons have iden- 1385, 1245, 1200, 1080, 970, 770, 700, 640 cm . HRMS (CI, NH
tical chemical shifts. They were assigned by their chemical shifts.
IR (film): ν˜ = 3530, 2980, 2875, 2360, 2245, 1720, 1465, 1390, 1130,
1
C
C
–
1
3
):
+
calcd. for C
–1.1 ppm).
9 16 2 2
H O [M – H O] 166.09938; found 166.09920 (δ =
170, 915, 735 cm– . HRMS (pos. APCI, MeOH): calcd. for
1
rel-(3S,6S)-3-[(R,trans)-1-Hydroxybut-2-enyl]-6-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (anti,cis-43)
[M + H]+ 187.13287; found 187.13290 (+0.2 ppm).
(186.25): calcd. C 64.49, H 9.74; found C 64.32, H 9.73.
10
H
19
O
3
10
H
18
O
3
rel-(3S,6S)-3-[(R,trans)-1-Hydroxybut-2-enyl]-6-methyl-3,4,5,6-
tetrahydro-2H-pyran-2-one (syn,cis-43)
Following the General Procedure B the title compound was pre-
pared from δ-methyl-δ-lactone (21, 114 mg, 1.00 mmol) and cro-
tonaldehyde (23, 140 mg, 2.00 mmol, 2.0 equiv.). Purification by
flash chromatography[ (2.0ϫ15 cm, 15 mL, c-C H /EtOAc 3:1
25]
Following the General Procedure A the title compound was pre-
pared from δ-methyl-δ-lactone (21, 114 mg, 1.00 mmol) and
6
12
to 1:1, 18–24) rendered the product as a colorless oil (134 mg, 73%,
anti,cis-43/anti,trans-43 77:23). syn,trans/syn,cis/anti,trans/anti,cis
0:6:24:71; syn/anti 6:94; syn,trans/syn,cis Ͻ5:95, anti,trans/anti,cis
25:75 [determined by integration of the signals at δ = 4.20 (1Ј-H,
anti,cis-43) vs. δ = 4.27 (1Ј-H, anti,trans-43) vs. δ = 4.52 (1Ј-H,
crotonaldehyde (23, 140 mg, 2.00 mmol, 2.0 equiv.). Purification by
flash chromatography[ (2.0ϫ15 cm, 15 mL, c-C
25]
H12/EtOAc 3:1
6
to 1:1, 17–22) rendered the product as a colorless oil (131 mg, 71%,
syn,cis-43:syn,trans-43 = 90:10). syn,trans/syn,cis/anti,trans/anti,cis
1
2
7:73:0:0; syn/anti Ͼ95:5; syn,trans/syn,cis 27:73, anti,trans/anti,cis
Ͻ5:95 [integration of the signals at δ = 4.53 (1Ј-H, syn,cis-43) vs. δ
5.46–5.56 (2Ј-H, syn,cis-43 + syn,trans-43) as well as δ = 3.04
syn,cis-43) in the 400 MHz H NMR spectrum of the crude prod-
uct; the NMR contained no signal clearly attributable to syn,trans-
1
=
43]. H NMR (400.13 MHz, CDCl , 77:23 mixture of dia-
3
(
OH, syn,cis-43) vs. δ = 3.16 (OH, syn,trans-43) in the 400 MHz stereomers): δ = 1.37 [d, J6-Me,6 = 6.2 Hz, 3 H, 6-Me (anti,cis-43)]
1
H NMR spectrum of the crude product resulted in syn/iso-syn
superimposed by 1.39 [d, J6
-Me,6
= 6.3 Hz, 3 H, 6-Me (anti,trans-
1
1
7
4
3:27; the NMR contained no signal clearly attributable to anti,cis-
43)], 1.45–1.64 [m, 2 H, 4-H (both diastereomers), 5-H (both dia-
1
A
3
3
3 or anti,trans-43]. H NMR (400.13 MHz, CDCl , contains 10% stereomers)] , 1.71–1.74 [m, 3 H, 4Ј-H (both diastereomers)],
2
2
syn,trans-43 with signals at δ = 1.34 and 3.20): δ = 1.34 (d, J6-Me,6
=
interpretable as ddd, J4Ј.3Ј = 6.5 Hz, J4Ј,2Ј = 1.5 Hz, J4Ј,1Ј = 0.9 Hz,
1.89–2.02 [m, 2 H, 4-H (both diastereomers), 5-H (both dia-
1
A
A
6.2 Hz, 3 H, 6-Me), 1.54–1.65 (m, 1 H, 5-H ) , 1.69 (m
c
, possibly stereomers)] , 2.38–2.53 {m, possibly interpretable as δ = 2.42 [ddd,
4
5
J3,4 = 12.0 und 6.6 Hz, J3,1Ј = 8.2 Hz, 1 H, 3-H(anti,trans-43)], δ =
2.49 [ddd, J3,4 = 11.0 und 8.2 Hz, J3,1Ј = 8.2 Hz, 1 H, 3-H (anti,cis-
43)]}, 3.95 [br. s, 1 H, OH (anti,cis-43)] , 4.20 [br. dd, J
2
A
3
H, 4Ј-H
interpretable as ddd, J3.4 = 10.3 and 8.5 Hz, J3,1Ј = 2.9 Hz, 1 H, 3-
H), 3.06 (d, JOH,1Ј = 5.8 Hz, 1 H, OH) 4.28 (m , possibly interpret-
able as dqd, J6,5 = 9.6 and 3.2 Hz, J6,6-Me = 6.4 Hz, 1 H, 6-H), 4.50
br. m , possibly interpretable as br. dd, J1Ј,2Ј = 7.7 Hz, J1Ј,OH
3
), 1.76–1.97 (m, 3 H, 4-H
2
, 5-H ) , 2.64 (m
c
, possibly
A
1
Ј,3
= J1Ј,2Ј
c
= 7.9 Hz, 1 H, 1Ј-H (anti,cis-43)], 4.27 [br. dd, J1Ј,2Ј = J1Ј,3Ј =
8.1 Hz, 1 H, 1Ј-H (anti,trans-43)], 4.32 [br. s, 1 H, OH (anti,trans-
43)], 4.39–4.50 [m, 1 H, 6-H (both diastereomers)], 5.41–5.52 {m,
(
6
c
=
4
.0 Hz, 1 H, 1Ј-H), 5.49 (ddq, J2Ј,3Ј = 15.1 Hz, J2Ј.1Ј = 6.9 Hz, J2Ј,4Ј
possibly interpretable as δ = 5.45 [ddq, J
Ј,3Ј
= 15.1 Hz, J2Ј,1Ј =
2
4
=
1.6 Hz, 1 H, 2Ј-H), 5.74 (dqd, J3Ј,2Ј = 15.2 Hz, J3Ј,4Ј = 6.5 Hz,
7.7 Hz, J
Ј,4Ј
= 1.6 Hz, 1 H, 2Ј-H (anti,trans-43)], δ = 5.48 [ddq,
2
4
3Ј,1Ј = 1.2 Hz, 1 H, 3Ј-H) ppm. AThe indicated protons were dis-
4
J
J2Ј,3Ј = 15.3 Hz, J2Ј,1Ј = 7.8 Hz, J
2Ј,4Ј
= 1.6 Hz, 2Ј-H (anti,cis-
A
tinguished in a DQF-COSY spectrum [“H,H-COSY spectrum”
400.13 MHz, CDCl )] by their crosspeaks with protons that pre-
viously had been assigned unequivocally [δ
43)] }, 5.72–5.83 {m, possibly interpretable as δ = 5.77 [dqd, J
3Ј,2Ј
4
(
3
= 15.2 Hz, J3Ј,4Ј = 6.5 Hz, J
3Ј,1Ј
= 0.8 Hz, 1 H, 3Ј-H (anti,trans-
1
1
4
H
( H) ↔ δ
H
( H)]: δ =
43)], δ = 5.78 [dqd, J3Ј,2Ј = 15.3 Hz, J
1 H, 3Ј-H (anti,cis-43)]}. The indicated protons – they all belong
to anti,cis-43 – were distinguished in a DQF-COSY spectrum
3Ј,4Ј
= 6.5 Hz, J
3Ј,1Ј
= 0.9 Hz,
1
A
4
1
.28 (6-H) ↔ δ = 1.54–1.65 (5-H ); δ = 4.28 (6-H) ↔ δ = 1.76–
2
2
.97 (4-H
2
, 5-H ); δ = 2.64 (3-H) ↔ δ = 1.76–1.97 (4-H
2
, 5-H ).
1
3
C NMR (100.62 MHz, CDCl , 90:10 mixture of diastereomers):
3
[“H,H-COSY spectrum” (400.13 MHz, CDCl )] by their
3
A
A,B
δ = 17.51 [C-4 (syn,cis-43)] , 17.77 [C-4Ј (both diastereomers)]
2
6
trans-43)] , 43.80 [C-3 (syn,cis-43)] , 46.47 [C-3 (syn,trans-43)] , 2.53 (3-H); δ = 2.38–2.53 (3-H) ↔ δ = 1.45–1.64 (4-H , 5-H ); δ =
7
(
4
1
,
crosspeaks with protons that previously had been assigned une-
A
B
1
1
0.93 [C-6-Me (syn,cis-43)] , 21.10 [C-4 (syn,trans-43)] , 21.93 [C-
quivocally [δ ( H) ↔ δ ( H)]: δ = 4.20 (1Ј-H) ↔ δ = 5.41–5.52 (2Ј-
H
H
B
A
-Me (syn,trans-43)] , 28.65 [C-5 (syn,cis-43)] , 30.37 [C-5 (syn,-
H); δ = 4.20 (1Ј-H) ↔ δ = 3.95 (OH); δ = 4.20 (1Ј-H) ↔ δ = 2.38–
1 1
B
A
B
A
B
2
2
1.50 [C-1Ј (syn,cis-43)] , 72.92 [C-6 (syn,trans-43)] , 75.08 [C-6 2.38–2.53 (3-H) ↔ δ = 1.89–2.02 (4-H , 5-H ); δ = 4.39–4.60 (6-H)
A B
1 1
syn,cis-43)] , 78.01 [C-1Ј (syn,trans-43)] , 128.57 [C-3Ј (syn,cis-
3)] , 128.91 [C-3Ј (syn,trans-43)] , 129.65 [C-2Ј (syn,cis-43)] ,
29.94 [C-2Ј (syn,trans-43)] , 173.34 [C-2 (syn,trans-43)] , 175.07
↔ δ = 1.45–1.64 (4-H , 5-H ); δ = 4.39–4.60 (6-H) ↔ δ = 1.89–
2.02 (4-H , 5-H ). C NMR (100.62 MHz, CDCl , 77:23 mixture
of diastereomers): δ = 17.80 [C-4Ј (anti,trans-43)] , 17.83 [C-4Ј
(anti,cis-43)] , 20.30 [C-4* (anti,cis-43)] , 20.85 [C-6-Me (anti,cis-
A
B
A
2
2
13
3
B
B
A
A
A
A
[
C-2 (syn,cis-43)]. The indicated nuclei – they are non-quater-
nary – belong to syn,cis-43 and were identified in an edHSQC spec-
trum [“short-range C,H-COSY spectrum” (100.62/400.13 MHz, 43)**] , 28.47 [C-5* (anti,cis-43)] , 30.41 [C-5 (anti,trans-43)**] ,
A
A
43)] , 22.06 [C-6-Me (anti,trans-43)] , 23.12 [C-4 (anti,trans-
A
A
A
A
A
CDCl
3
)] by their crosspeaks with directly bonded protons (these
43.94 [C-3 (anti,cis-43)] , 46.05 [C-3 (anti,trans-43)] , 73.33 [C-1Ј
13
1
A
A
had previously been assigned unequivocally) [δ
=
=
C
( C) ↔ δ
, 5-H ); δ = 17.77 (C-4Ј) ↔ δ
); δ = 20.93 (C-6-Me) ↔ δ = 1.34 (6-Me); δ = 28.65 ti,cis-43)] , 129.99, 130.18 [C-2Ј, C-3Ј (anti,trans-43)] , 174.42 [C-2
H
( H)]: δ
(anti,cis-43)] , 74.04 [C-1Ј (anti,trans-43)] , 74.69 [C-6 (anti,cis-
2
A
A
17.51 (C-4) ↔ δ = 1.76–1.97 (4-H
1.69 (4Ј-H
2
43)] , 78.57 [C-6 (anti,trans-43)] , 129.87, 129.89 [C-2Ј, C-3Ј (an-
B
B
3
1
2
A
(C-5) ↔ δ = 1.54–1.65 (5-H ) and 1.76–1.97 (4-H
2
, 5-H ); δ = 43.80
(anti,trans-43)], 176.17 [C-2 (anti,cis-43)]. the indicated nuclei –
(C-3) ↔ δ = 2.64 (3-H); δ = 71.50 (C-1Ј) ↔ δ = 4.50 (1Ј-H); δ = they are non-quaternary – were identified in an edHSQC spectrum
Eur. J. Org. Chem. 2015, 7892–7918
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7913

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
A
B
[“short-range C,H-COSY spectrum” (100.62/400.13 MHz, CDCl
3
)]
3
NMR (100.62 MHz, CDCl ): δ = 15.84 (C-4) , 20.86 (C-6-Me) ,
A
B
B
B
by their crosspeaks with directly bonded protons (these had pre-
28.70 (C-5) , 45.21 (C-3) , 70.45 (C-1Ј) , 75.07 (C-6) , 121.26 (C-
1
3
1
B
B
viously been assigned unequivocally) [δ
C-4Ј(anti,trans-43)] ↔ δ = 1.71–1.74 [4Ј-H
δ = 17.83 [C-4Ј (anti,cis-43)] ↔ δ = 1.71–1.74 [4Ј-H
stereomers)]; δ = 20.30 [C-4* (anti,cis-43)] ↔ δ = 1.45–1.64 [4-H
C
( C) ↔ δ
H
( H)]: δ = 17.80
para), 127.53 (2ϫC-ortho) , 131.53 (2ϫC-meta) , 139.78 (C-ipso),
A
[
3
(both diastereomers)]; 175.24 (C-1) ppm. Assignments interchangeable. BThe indicated
3
(both dia-
nuclei – they are non-quaternary – were identified in an edHSQC
spectrum [“short-range C,H-COSY spectrum” (100.63/
1
1
(
both diastereomers), 5-H (both diastereomers)] and 1.89–2.02 [4-
400.13 MHz, CDCl )] by their crosspeaks with directly bonded pro-
3
2
2
13
C
H (both diastereomers), 5-H (both diastereomers)]; δ = 20.85 [C-
tons (these had previously been assigned unequivocally) [δ ( C)
-Me (anti,cis-43)] ↔ δ = 1.37 [6-Me (anti,cis-43)]; δ = 22.06 [C-6- ↔ δ ( H)]: δ = 20.86 (C-6-Me) ↔ δ = 1.34 (6-Me); δ = 45.21 (C-
1
6
H
Me (anti,trans-43)] ↔ δ = 1.39 [6-Me (anti,trans-43)]; δ = 23.12 [C-
3) ↔ δ = 2.76 (3-H); δ = 70.45 (C-1Ј) ↔ δ = 5.43 (1Ј-H); δ =
(anti,trans-43)**] ↔ δ = 1.45–1.64 [4-H (both diastereomers), 5- 75.07 (C-6) ↔ δ = 4.42 (6-H); δ = 127.53 (2ϫC-ortho) ↔ δ = 7.23
1
4
1
2
H (both diastereomers)] and 1.89–2.02 [4-H (both diastereomers),
(2ϫortho-H); δ = 131.53 (2ϫC-meta) ↔ δ = 7.48 (2ϫmeta-H).
2
5
1
-H (both diastereomers)]; δ = 28.47 [C-5* (anti,cis-43)] ↔ δ =
IR (film): ν = 3450, 2975, 2935, 1720, 1490, 1390, 1365, 1295, 1205,
˜
1
1
–1
.45–1.64 [4-H (both diastereomers), 5-H (both diastereomers)]
1185, 1115, 1095, 1070, 1050, 1010, 960, 835, 820, 770 cm . HRMS
pos. APCI, MeOH): calcd. for C13
and 1.89–2.02 [4-H (both diastereomers), 5-H2 (both dia-
2
Br [M + H]+ 299.02773;
16 3
H O
(
stereomers)]; δ = 30.41 [C-5 (anti,trans-43)**] ↔ δ = 1.45–1.64 [4-
found 299.02777 (+0.1 ppm).
1
1
H (both diastereomers), 5-H (both diastereomers)] and 1.89–2.02
1
2
2
Analytical Data for syn,trans-44: H NMR (400.13 MHz, CDCl
3
,
[
[
4-H (both diastereomers), 5-H (both diastereomers)]; δ = 43.94
C-3 (anti,cis-43)] ↔ δ = 2.38–2.53 [3-H (both diastereomers)]; δ =
contains 6% syn,cis-44): δ = 1.35 (d, J6-Me,6 = 6.3 Hz, 3 H, 6-Me),
1
1 A
2
2 A
1
2
=
.40–1.54 (m, 2 H, 4-H , 5-H ) , 1.73–1.92 (m, 2 H, 4-H , 5-H ) ,
.72 (m , possibly interpretable as ddd, J3,4 = 12.1 and 6.7 Hz, J3,1Ј
3.0 Hz, 1 H, 3-H), 2.97 (d, JOH,1Ј = 5.6 Hz, 1 H, OH), 4.38 (m
possibly interpretable as dqd, J6,5 = 11.2 and 3.0 Hz, J6,6-Me
.3 Hz, 1 H, 6-H), 5.49 (br. dd, J1Ј,OH = 5.4 Hz, J1Ј,3 = 3.0 Hz, 1
4
6.05 [C-3 (anti,trans-43)] ↔ δ = 2.38–2.53 [3-H (both dia-
stereomers)]; δ = 73.33 [C-1Ј (anti,cis-43)] ↔ δ = 4.20 [1Ј-H
anti,cis-43)]; δ = 74.04 [C-1Ј (anti,trans-43)] ↔ δ = 4.27 [1Ј-H (anti-
trans-43)]; δ = 74.69 [C-6 (anti,cis-43)] ↔ δ = 4.39–4.50 [6-H (both
c
c
,
=
(
,
6
diastereomers)]; δ = 78.57 [C-6 (anti,trans-43)] ↔ δ = 4.39–4.50 [6-
H (both diastereomers)]. Designation pairwise interchangeable.
B
H, 1Ј-H), 7.23 (m, 2 H, 2 ϫ ortho-H), 7.43 (m, 2 H, 2 ϫ meta-
A
H) ppm. The indicated protons were distinguished in a DQF-
IR (film): ν˜ = 3450, 2935, 1720, 1450, 1385, 1245, 1200, 1080, 970,
–
1
COSY spectrum [“H,H-COSY spectrum” (400.13 MHz, CDCl
3
)]
7
70, 700, 640 cm . HRMS (CI, NH
3
): calcd. for C10
17 3
H O [M +
+
by their crosspeaks with protons that previously had been assigned
H] 185.11777; found 185.11820 (+2.3 ppm).
1
1
unequivocally [δ
H
( H) ↔ δ
H
( H)]: δ = 2.72 (3-H) ↔ δ = 1.40–1.54
2 2
rel-(3S,6S)-3-[(S)-(4-Bromophenyl)(hydroxy)methyl]-6-methyl-
,4,5,6-tetrahydro-2H-pyran-2-one (syn,cis-44)
1
1
(
1
(
(
1
(
4-H , 5-H ) and 1.73–1.92 (4-H , 5-H ); δ = 4.38 (6-H) ↔ δ =
.40–1.54 (4-H , 5-H ) and 1.73–1.92 (4-H , 5-H ) ppm. C NMR
100.62 MHz, CDCl ): δ = 19.45 (C-4) , 22.00 (C-6-Me) , 30.46
3
C-5) , 48.17 (C-3) , 72.25 (C-1Ј) , 78.33 (C-6) , 121.41 (C-para),
3
1
1
2
2
13
A
B
A
B
B
B
B
B
27.70 (2ϫC-ortho) , 131.59 (2ϫC-meta) , 140.24 (C-ipso), 172.80
C-1) ppm. Assignments interchangeable. BThe indicated nuclei –
A
they are non-quaternary – were identified in an edHSQC spectrum
[“short-range C,H-COSY spectrum” (100.62/400.13 MHz, CDCl )]
pared from δ-methyl-δ-lactone (21, 114 mg, 1.00 mmol) and 4- by their crosspeaks with directly bonded protons (these had pre-
Following the General Procedure A the title compound was pre-
3
1
3
1
bromobenzaldehyde (24, 370 mg, 2.00 mmol, 2.0 equiv.). Purifica-
viously been assigned unequivocally) [δ
(C-6-Me) ↔ δ = 1.35 (6-Me); δ = 48.17 (C-3) ↔ δ = 2.72 (3-H); δ
EtOAc 3:1 to 1:1, 10–14) rendered the product as a colorless solid = 72.25 (C-1Ј) ↔ δ = 5.49 (1Ј-H); δ = 78.33 (C-6) ↔ δ = 4.38 (6-
C
( C) ↔ δ
H
( H)]: δ = 22.00
tion by flash chromatography[ (2.0ϫ 15 cm, 15 mL, c-C
25]
H /
6 12
(
155 mg, 52%). Two further fractions were collected, containing a
H); δ = 127.70 (2ϫC-ortho) ↔ δ = 7.23 (2ϫortho-H); δ = 131.59
(2ϫC-meta) ↔ δ = 7.43 (2ϫmeta-H). IR (film): ν˜ = 3425, 2975,
2935, 2920, 1710, 1485, 1390, 1365, 1265, 1240, 1215, 1185, 1140,
mixture of both diastereomers (15–16, 36.2 mg, 12 %) and
syn,trans-44 (17–22, 52.1 mg, 17 %; overall yield: 81 %).
syn,trans/syn,cis/anti,trans/anti,cis 26:72:1:1; syn/anti 98:2;
syn,trans/syn,cis 27:73, anti,trans/anti,cis 37:63 [determined by inte-
gration of the signals at δ = 4.79 (1Ј-H anti,cis-44) vs. δ = 4.82 (1Ј-
H, anti,trans-44) vs. δ = 5.44 (1Ј-H, syn,cis-44) vs. δ = 5.49 (1Ј-
–
1
1090, 1070, 1010, 945, 915, 840, 740 cm . HRMS (pos. APCI,
15 3
H O
BrNa [M + Na]+ 321.00968; found
MeOH): calcd. for C13
321.00983 (+0.5 ppm).
rel-(3S,6S)-3-[(R)-(4-Bromophenyl)(hydroxy)methyl]-6-methyl-
,4,5,6-tetrahydro-2H-pyran-2-one (anti,cis-44)
1
H, syn,trans-44) in the 400 MHz H NMR spectrum of the crude
product].
3
1
Analytical Data for syn,cis-44: M.p. 84 °C. H NMR (400.13 MHz,
CDCl
3
, contains 6% syn,trans-44): δ = 1.34 (d, J6-Me,6 = 6.2 Hz, 3
1
1 A
H, 6-Me), 1.47–1.64 (m, 2 H, 4-H , 5-H ) , 1.80–1.92 (m, 2 H, 4-
2
2 A
H 5-H ) , 2.76 (m
c
, possibly interpretable as ddd, J3,4 = 10.7 and
8.4 Hz, J3,1Ј = 2.5 Hz, 1 H, 3-H), 3.18 (d, JOH,1Ј = 4.0 Hz, 1 H, Following the General Procedure B the title compound was pre-
OH), 4.42 (m
c
, possibly interpretable as dqd, J6,5 = 9.8 and 3.3 Hz,
pared from δ-methyl-δ-lactone (21, 114 mg, 1.00 mmol) and 4-
J
3
2
6,6-Me = 6.5 Hz, 1 H, 6-H), 5.43 (br. dd, J1Ј,OH = 3.5 Hz, J1Ј,3
=
bromobenzaldehyde (24, 370 mg, 2.00 mmol, 2.0 equiv.). Purifica-
tion by flash chromatography[
25]
.1 Hz, 1 H, 1Ј-H), 7.23 (m, 2 H, 2 ϫ ortho-H), 7.48 (m, 2 H,
6 12
(2.0ϫ15 cm, 15 mL, c-C H /
A
ϫmeta-H) ppm. The indicated protons were distinguished in a
EtOAc 3:1 to 1:1, 8–13) rendered the product as a colorless oil
(248 mg, 83%, anti,cis-44/anti,trans-44 77:23). syn,trans/syn,cis/
anti,trans/anti,cis 0:6:23:71; syn/anti 6:94; syn,trans/syn,cis Ͼ5:95,
anti,trans/anti,cis 24:76 [determined by integration of the signals at
δ = 2.68 (3-H, anti,cis-44) vs. δ = 2.77 (3-H, syn,cis-44) vs. δ = 2.57
DQF-COSY spectrum [“H,H-COSY spectrum” (400.13 MHz,
CDCl )] by their crosspeaks with protons that previously had been
assigned unequivocally [δ
1
↔
3
1
1
H
( H) ↔ δ
H
( H)]: δ = 2.76 (3-H) ↔ δ =
1
1
2
2
.47–1.64 (4-H , 5-H ) and 1.80–1.92 (4-H 5-H ); δ = 4.42 (6-H)
δ = 1.47–1.64 (4-H , 5-H ) and 1.80–1.92 (4-H 5-H ) ppm.
1
1
2
2
13
1
C
(3-H, anti,trans-44) in the 400 MHz H NMR spectrum of the
7914
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7892–7918

Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
crude product; the spectrum contained no signal clearly attribut-
1
able to syn,trans-44]. H NMR (400.13 MHz, CDCl
3
, 77:23 mixture
, 5-H1 (both dia-
2
[1] Recent reviews: a) M. Kalesse, M. Cordes, G. Symkenberg, H.-
H. Lu, Nat. Prod. Rep. 2014, 31, 563–594; b) J. Mlynarski, S.
Bas, Chem. Soc. Rev. 2014, 43, 577–587; c) I. Shiina, Chem.
Rec. 2014, 14, 144–183; d) R. Mahrwald (Ed.), Modern Meth-
ods in Stereoselective Aldol Reactions, Wiley-VCH, Weinheim,
Germany, 2013; e) T. Kitanosono, S. Kobayashi, Adv. Synth.
Catal. 2013, 355, 3095–3118; f) R. L. Sutar, N. N. Joshi, Tetra-
hedron: Asymmetry 2013, 24, 1345–1363; g) M. M. Heravi, V.
Zadsirjan, Tetrahedron: Asymmetry 2013, 24, 1149–1188; h)
S. B. J. Kan, K. K. H. Ng, I. Paterson, Angew. Chem. Int. Ed.
2013, 52, 9097–9108; Angew. Chem. 2013, 125, 9267–9279; i)
G. L. Beutner, S. E. Denmark, Angew. Chem. Int. Ed. 2013, 52,
9086–9096; Angew. Chem. 2013, 125, 9256–9266; j) S. Kotani,
M. Sugiura, M. Nakajima, Chem. Rec. 2013, 13, 362–370; The
Mukaiyama Aldol Reaction: 40 Years of Continuous Develop-
ment: k) J.-i. Matsuo, M. Murakami, Angew. Chem. Int. Ed.
of diastereomers): δ = 1.33–1.60 [m, 3 H, 4-H
stereomers)] superimposed by 1.35 [d, J6-Me,6 = 6.2 Hz, 3 H, 6-
Me (anti,cis-44)] superimposed by 1.36 [d, J6-Me,6 = 5.8 Hz, 3 H, 6-
A
2
A
Me (anti,trans-44)], 1.79–1.91 [m, 1 H, 5-H (both diastereomers)] ,
.56 [m , possibly interpretable as ddd, J3,4 = 11.3 and 7.6 Hz, J3,1Ј
8.8 Hz, 1 H, 3-H (anti,trans-44)], 2.67 [m , possibly interpretable
as ddd, J3,4 = 11.3 and 8.6 Hz, J3,1Ј = 8.6 Hz, 1 H, 3-H (anti,cis-
4)], 4.35–4.49 [m, 2 H, 6-H (both diastereomers), OH (anti,cis-
4)], 4.75 [d, J1Ј,3 = 8.7 Hz, 1 H, 1Ј-H (anti,cis-44)], 4.82 [d, J1Ј,3
.8 Hz, 1 H, 1Ј-H (anti,trans-44)], 5.03 [br. s, 1 H, OH, (anti,trans-
4)], 7.24 [m , 2 H, 2ϫortho-H (both diastereomers)], 7.45–7.50
m, 2 H, 2ϫmeta-H (both diastereomers)]. The indicated protons
were distinguished in a DQF-COSY spectrum [“H,H-COSY spec-
trum” (400.13 MHz, CDCl
previously had been assigned unequivocally [δ
2
c
=
c
4
4
8
4
=
c
A
[
3
)] by their crosspeaks with protons that
2
013, 52, 9109–9118; Angew. Chem. 2013, 125, 9280–9289; l) V.
1
1
H
( H) ↔ δ
H
( H)]: δ
Bisai, A. Bisai, V. K. Singh, Tetrahedron 2012, 68, 4541–4580;
m) L. C. Dias, E. C. de Lucca Jr., M. A. B. Ferreira, E. C. Polo,
J. Braz. Chem. Soc. 2012, 23, 2137–2158.
1
=
2.56 [3-H (anti,trans-44)] ↔ δ = 1.33–1.60 [4-H
stereomers)]; δ = 2.67 [3-H (anti,cis-44)] ↔ δ = 1.33–1.60 [4-H , 5-
2
H (both diastereomers)]; δ = 4.35–4.49 [6-H (both diastereomers),
OH (anti,cis-44)] ↔ δ = 1.79–1.91 [5-H (both diastereomers)].
2
, 5-H (both dia-
1
[2]
Examples of aldol additions of lithium enolates of δ-lactones
that proceeded without stereocontrol (c, d, e, g, h, i, j) or were
not characterized stereochemically (a, b, f): a) K. Narasaka, T.
Sakakura, T. Uchimaru, D. Guédin-Vuong, J. Am. Chem. Soc.
1986, 106, 2954–2961 (stereoselectivity not specified); b) H.
Niwa, Y. Miyachi, Y. Uosaki, K. Yamada, Tetrahedron Lett.
2
13
C
A
NMR (100.62 MHz, CDCl
3
): δ = 20.25 [C-4 (anti,cis-44)] , 20.75
A
A
[
(
4
7
(
C-6-Me (anti,cis-44)] , 22.00 [C-6-Me (anti,trans-44)] , 23.20 [C-4
A
A
anti,trans-44)] , 28.24 [C-5 (anti,cis-44)] , 30.47 [C-5 (anti,trans-
4)] , 45.37 [C-3 (anti,cis-44)] , 47.37 [C-3 (anti,trans-44)] ,
4.28 [C-1Ј (anti,cis-44)] , 74.67 [C-6 (anti,cis-44)] , 74.85 [C-1Ј
anti,trans-44)] , 78.89 [C-6 (anti,trans-44)] , 122.18 [C-para (both
A
A
A
1
986, 27, 4601–4604 (stereoselectivity not specified); c) M.
Shiozaki, Y. Kobayashi, T. Hata, Y. Furukawa, Tetrahedron
991, 47, 2785–2800 (mixture of four diastereomers); d) J. D.
A
A
A
A
1
A
diastereomers)], 128.77 [2ϫC-ortho (anti,cis-44)] , 128.85 [2ϫC-
White, J. C. Amedio Jr., S. Gut, S. Ohira, L. R. Jayasinghe, J.
Org. Chem. 1992, 57, 2270–2284 (mixture of unspecified
number of diastereomers); e) R. Schneider, P. Gérardin, B.
Loubinoux, J. Org. Chem. 1995, 60, 6397–6401 (syn/anti 54:46);
f) A. Padwa, C. K. Eidell, J. D. Ginn, M. S. McClure, J. Org.
Chem. 2002, 67, 1595–1606 (stereoselectivity not specified); g)
S. V. Ley, D. J. Dixon, R. T. Guy, F. Rodríguez, T. D. Sheppard,
Org. Biomol. Chem. 2005, 3, 4095–4107 (syn/anti 71:29 to
A
A
ortho (anti,trans-44)] , 131.72 [2ϫC-meta (both diastereomers)] ,
39.31 [C-ipso (anti,cis-44)], 139.56 [C-ipso (anti,trans-44)], 174.43
1
[
A
C-2 (anti,trans-44)], 176.10 [C-2 (anti,cis-44)]. The indicated
nuclei they are non-quaternary were identified in an
edHSQC spectrum [“short-range C,H-COSY spectrum” (100.62/
00.13 MHz, CDCl )] by their crosspeaks with directly bonded pro-
tons (these had previously been assigned unequivocally) [δ
–
–
4
3
1
3
C
( C)
( H)]: δ = 20.25 [C-4 (anti,cis-44)] ↔ δ = 1.33–1.60 [4-H , 5-
H (both diastereomers)]; δ = 20.75 [C-6-Me (anti,cis-44)] ↔ δ =
7
(
6:24); h) P. Tang, B. Yu, Eur. J. Org. Chem. 2009, 259–269
diastereomeric mixture); i) A. M. Stewart, K. Meier, B. Schulz,
M. Steinert, B. B. Snider, J. Org. Chem. 2010, 75, 6057–6060
syn/anti ≈ 66:34); j) D. Petrovi c´ , R. Brückner, Org. Lett. 2011,
1
↔
δ
H
2
1
1
1
1
.35 [6-Me (anti,cis-44)]; δ = 22.00 [C-6-Me (anti,trans-44)] ↔ δ =
(
.36 [6-Me (anti,trans-44)]; δ = 23.20 [C-4 (anti,trans-44)] ↔ δ =
13, 6524–6527 (syn/anti ≈ 50:50).
.33–1.60 [4-H
2
, 5-H1 (both diastereomers)]; δ = 28.24 [C-5 (an- [3] For an aldol addition of the lithium enolate of a cyclononene-
1
ti,cis-44)] ↔ δ = 1.33–1.60 [4-H
.79–1.91 [5-H (both diastereomers)]; δ = 30.47 [C-5 (anti,trans-
2
, 5-H (both diastereomers)] and
fused δ-lactone that proceeded with 100% syn selectivity, see:
C. Hamel, E. V. Prusov, J. Gertsch, W. B. Schweizer, K.-H.
Altmann, Angew. Chem. Int. Ed. 2008, 47, 10081–10085; An-
gew. Chem. 2008, 120, 10235–10239.
2
1
4
1
1
4)] ↔ δ = 1.33–1.60 [4-H
2
, 5-H (both diastereomers)] and 1.79–
.91 [5-H (both diastereomers)]; δ = 45.37 [C-3 (anti,cis-44)] ↔ δ
2.67 [3-H (anti,cis-44)]; δ = 47.37 [C-3 (anti,trans-44)] ↔ δ = 2.56
3-H (anti,trans-44)]; δ = 74.28 [C-1Ј (anti,cis-44)] ↔ δ = 4.75 [1Ј-
H (anti,cis-44)]; δ = 74.67 [C-6 (anti,cis-44)] ↔ δ = 4.35–4.49 [6-H
both diastereomers), OH (anti,cis-44)]; δ = 74.85 [C-1Ј (anti,trans-
2
[
4] Aldol additions of dibutylboron enolates of δ-lactones: The
aldol addition described in ref.[ was effected based on prior
experience in our group with a closely related anti-selective re-
action: a) S. Anklam, Dissertation, University of Freiburg, Ger-
many, 2003, 17–19, 65; b) H. Ito, T. Momose, M. Konishi, E.
Yamada, K. Watanabe, K. Iguchi, Tetrahedron 2006, 62,
10425–10433 (highly anti-selective); c) S. P. Cakir, S. Stokes, A.
Sygula, K. T. Mead, J. Org. Chem. 2009, 74, 7529–7532 (only
anti isomer); d) S. B. Kamptmann, R. Brückner, Eur. J. Org.
Chem. 2013, 6584–6600 (perfectly anti-selective).
=
[
4d]
(
4
4
4)] ↔ δ = 4.82 [1Ј-H (anti,trans-44)]; δ = 78.89 [C-6 (anti,trans-
4)] ↔ δ = 4.35–4.49 [6-H (both diastereomers), OH (anti,cis-44)];
δ = 128.77 [2ϫC-ortho (anti,cis-44)] ↔ δ = 7.24 [2ϫortho-H (both
diastereomers)]; δ = 128.85 [2ϫC-ortho (anti,trans-44)] ↔ δ = 7.24
2ϫortho-H (both diastereomers)]; δ = 131.72 [2ϫC-meta (both
diastereomers)] ↔ δ = 7.45–7.50 [2ϫmeta-H (both diastereomers)].
IR (CHCl ): ν˜ = 3450, 2975, 2935, 1715, 1490, 1390, 1210, 1190,
120, 1090, 1070, 1010, 945, 835, 740 cm . HRMS (pos. APCI,
16 3
MeOH): calcd. for C13H O Br [M + H] 299.02773; found
99.02777 (+0.1 ppm).
[
[
[
[
5] An aldol addition of the dibutylzinc enolate of a trisubstituted
δ-lactone to benzaldehyde delivered a single yet unassigned dia-
stereomer: F. Marion, S. Calvet, J.-C. Marié, C. Courillon, M.
Malacria, Eur. J. Org. Chem. 2006, 453–462.
3
–1
1
+
6] For aldol additions of the trichlorotitanium(IV) enolate
of a δ-lactone, which proceeded with ds = 50:50 to 67:33,
see: Q. Su, J. L. Wood, Tetrahedron Lett. 2010, 51, 4237–
2
4239.
Acknowledgments
The authors thank the Studienstiftung des Deutschen Volkes for a
Ph.D. fellowship to F. W. They also thank Rita M. DaSilva-Freitas
for tireless technical assistance.
7] For aldol additions of an (R)-MeO-BIPHEP-complexed sil-
ver(I) enolate of the α-methylsulfanylated δ-lactone, which pro-
ceeded with Ͼ95:5 anti selectivity (in the nomenclature of the
sulfur-free analogue) and with 99% ee, see: S. Takechi, S. Ya-
Eur. J. Org. Chem. 2015, 7892–7918
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7915

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
suda, N. Kumagai, M. Shibasaki, Angew. Chem. Int. Ed. 2012,
the addition of the dibutylboron enolate of cyclohexanone to
benzaldehyde and Ͼ96:4 for the addition of the cyclopent-
yl(tert-hexyl)boron enolate]; b) M. T. Reetz, R. Peter, Tetrahe-
dron Lett. 1981, 22, 4691–4694 [up to syn/anti 97:3 for ad-
ditions of the tris(diethylamino)titanium(IV) enolate of cyclo-
hexanone]; c) R. W. Hoffmann, K. Ditrich, S. Froech, D.
Cremer, Tetrahedron 1985, 41, 5517–5524 (syn/anti 92:8 for the
addition of the dimethoxyboron enolate of cyclohexanone to
benzaldehyde); d) M. Hirama, T. Noda, S. Îto, J. Org. Chem.
1988, 53, 706–708 [anti/syn 100:0 for the addition of the lithium
enolate of cyclohexanone to (Z)-5-(p-methoxybenzyloxy)-2-
methylpent-2-enal]; e) M. Hirama, T. Noda, S. Takeishi, S. Îto,
Bull. Chem. Soc. Jpn. 1988, 61, 2645–2646 (anti/syn up to 84:16
for the addition of the lithium enolate of cyclohexanone to
benzaldehyde and up to 97:3 for the addition to isobutanal).
51, 4218–4222; Angew. Chem. 2012, 124, 4294–4298.
[
8] For aldol additions of copper(I)-containing magnesium enol-
ates of monosubstituted δ-lactones, which proceeded with up
to a 85:15 syn/anti preference, see: J. Csizmadiová, M. Me cˇ ia-
ˇ
rová, A. Almássy, B. Horváth, R. Sebesta, J. Organomet. Chem.
013, 737, 47–52.
2
[9b]
[
9] a) The aldol addition described in ref. was effected based on
prior experience in our group with a closely related reaction:
S. Müller, Dissertation, University of Freiburg, 2008, 65. 78–87,
98–101; b) The aldol addition of a dichloro(cyclopentadienyl)-
titanium(IV) enolate of a disubstituted δ-lactone proceeded
completely syn-selectively, see: P. Walleser, R. Brückner, Eur. J.
Org. Chem. 2014, 3210–3224.
[
10] For aldol additions of dialkylboron enolates of α-unsubstituted
β-oxa-δ-lactones (i.e., of 3-unsubstituted 1,4-dioxan-2-ones),
see: a) M. B. Andrus, B. B. V. S. Sekhar, E. L. Meredith, N. K.
Dalley, Org. Lett. 2000, 2, 3035–3037 (anti-selective; ratio of
the anti diastereomers: 4:1 to Ͼ20:1); b) M. B. Andrus, E. L.
Meredith, B. B. V. S. Sekhar, Org. Lett. 2001, 3, 259–262 (anti-
selective; ratio of the anti diastereomers: 15:1); c) M. B.
Andrus, K. G. Mendenhall, E. L. Meredith, B. B. V. S. Sekhar,
Tetrahedron Lett. 2002, 43, 1789–1792 (anti-selective; ratio of
the anti diastereomers: 2:1 to 12:1); d) M. B. Andrus, E. L.
Meredith, B. L. Simmons, B. B. V. S. Sekhar, E. J. Hicken, Org.
Lett. 2002, 4, 3549–3552(anti-selective; ratio of the anti dia-
stereomers: 10:1); e) M. B. Andrus, E. L. Meredith, E. J.
Hicken, B. L. Simmons, R. R. Glancey, W. Ma, J. Org. Chem.
[16]
For aldol additions of the “thermodynamic” dibutylboron
(
Ǟanti/syn up to 99.5:0.5) and triisopropoxytitanium(IV) enol-
ates of α-methylcyclohexanone (Ǟanti/syn 95:5), see: S. Yam-
ago, D. Machii, E. Nakamura, J. Org. Chem. 1991, 56, 2098–
2
106.
[
[
[
17] There seem to be no aldol additions of metal enolates of γ-
oxacyclohexanones (i.e., of 4-pyranones) even if organocata-
lytic aldol additions of γ-oxacyclohexanone abound.
18] For aldol additions of the lithium enolate of a γ-azacyclohex-
anone (i.e., of 4-piperidone), see: M. Majewski, D. M. Gleave,
Tetrahedron Lett. 1989, 30, 5681–5684 (anti/syn 84:16).
19] For aldol additions of various metal enolates of γ-thiacyclohex-
anones (i.e., of 4-thianones), see: a) T. Hayashi, Tetrahedron
Lett. 1991, 32, 5369–5372 [lithium enolates generated with
LDA: anti/syn 70:30 to 98:2; 1,3-dioxa-2-borolan enolate:
anti/syn 95:5 triisopropoxytitanium(IV) enolate: anti/syn 99:1];
b) D. E. Ward, C. C. Man, C. Guo, Tetrahedron Lett. 1997, 38,
2
003, 68, 8162–8169 (anti-selective; ratio of the anti dia-
stereomers: 10:1); f) M. Kapur, A. Khartulyari, M. E. Maier,
Org. Lett. 2006, 8, 1629–1632 (anti-selective; ratio of the anti
diastereomers: 9:1 to 10:1); g) X.-T. Zhou, L. Lu, D. P. Furkert,
C. E. Wells, R. G. Carter, Angew. Chem. Int. Ed. 2006, 45,
2
7
201–2202 (lithium enolate generated with LDA: anti/syn
1:29; amine-free lithium enolate: anti/syn 88:12); c) D. E.
7622–7626; Angew. Chem. 2006, 118, 7784–7788 (anti-selective;
ratio of the anti diastereomers: Ͼ10:1); h) A. S. Khartulyari,
M. Kapur, M. E. Maier, Org. Lett. 2006, 8, 5833–5836 (anti-
selective; ratio of the anti diastereomers: 9:1); i) C. M. Burnett,
R. M. Williams, Tetrahedron Lett. 2009, 50, 5449–5451
Ward, C. Guo, P. K. Sasmal, C. C. Man, M. Sales, Org. Lett.
000, 2, 1325–1328 [various chiral titanium(IV) enolates were
2
combined with chiral aldehydes; syn/anti selectivity was deter-
mined by the substrates]; d) D. E. Ward, M. Sales, C. C. Man,
J. Shen, P. K. Sasmal, C. Guo, J. Org. Chem. 2002, 67, 1618–
(
syn/anti 1:1); j) M. B. Andrus, Y. Wong, J. Liu, K. Beebe,
L. M. Neckers, Tetrahedron Lett. 2009, 50, 6705–6708 (anti-
selective; ratio of the anti diastereomers: 8:1 to 9:1).
1
629 (dialkylboron enolatesǞanti/syn up to 94:6; trichloro-
titanium(IV) enolatesǞsyn/anti 78:22); e) D. E. Ward, G. E.
Beye, M. Sales, I. Q. Alarcon, H. M. Gillis, V. Jheengut, J. Org.
Chem. 2007, 72, 1667–1674 [various chiral titanium(IV) enol-
ates were combined with chral aldehydes; syn/anti selectivity
was determined by the substrates]; f) V. Jheengut, D. E. Ward,
J. Org. Chem. 2007, 72, 7805–7808 [chiral titanium(IV) enolate
combined with a chral aldehyde: syn/anti 41:59]; g) G. E. Beye,
J. M. Goodman, D. E. Ward, Org. Lett. 2009, 11, 1373–1376
[
11] Astonishingly, the most selective aldol additions of the lithium
enolate of an α-unsubstituted β-oxa-δ-lactone (i.e., of a 3-un-
substituted 1,4-dioxan-2-one) gave the anti product exclusively,
see: a) S. V. Ley, D. J. Dixon, R. T. Guy, M. A. Palomero, A.
Polara, F. Rodríguez, T. D. Sheppard, Org. Biomol. Chem.
2
004, 2, 3618–3627; b) For analogous diastereoselective aldol
additions to ketones, see: D. J. Dixon, A. Guarna, S. V. Ley, A.
Polara, F. Rodríguez, Synthesis 2002, 1973–1978.
(
chiral aldehydes were combined with chiral enolates: dicyclo-
[12] Aldol additions of the potassium enolates of α-substituted ana-
logues (i.e., of 3-substituted 1,4-dioxan-2-ones) of the β-oxa-δ-
hexylboron enolates: anti/syn 90:10 to 100:0); h) D. E. Ward,
F. Becerril-Jimenez, M. M. Zahedi, J. Org. Chem. 2009, 74,
lactone mentioned in ref.[
11a]
exhibited perfect anti selectivities.
4
447–4454 [dialkylboron enolates: anti/syn 83:17 to 95:5; tri-
[
13] For aldol additions of boron enolates of β-aza-δ-lactones (i.e.,
of morpholin-2-ones), see: a) D. S. Reno, B. T. Lotz, M. J.
Miller, Tetrahedron Lett. 1990, 31, 827–830 (predominantly
anti-selective; ratio of diastereomers: 5:1 and 17:3:1; the minor
diastereomers were not identified); b) R. M. Williams, M. N.
Im, J. Cao, J. Am. Chem. Soc. 1991, 113, 6976–6981 (anti-selec-
tive; ratio of the anti diastereomers: 15:1 to 25:1); c) R. M.
Williams, C. Yuan, J. Org. Chem. 1992, 57, 6519–6527 (anti-
selective; ratio of the anti diastereomers not given, but “excel-
lent” selectivity); d) J. D. Scott, T. N. Tippie, R. M. Williams,
Tetrahedron Lett. 1998, 39, 3659–3662 (anti-selective). e) D. E.
DeMong, R. M. Williams, Tetrahedron Lett. 2001, 42, 183–185
chlorotitanium(IV) enolates: syn/anti 50:50 to Ͼ95:5]; i) G. E.
Beye, D. E. Ward, J. Am. Chem. Soc. 2010, 132, 7210–7215
[a chiral aldehyde was combined with a chiral trichloro-
titanium(IV) enolate: syn/anti 95:5]; j) D. E. Ward, A. Kazeme-
ini, J. Org. Chem. 2012, 77, 10789–10803 [chiral aldehydes were
combined with chiral enolates: dicyclohexylboron enolates:
anti/syn 90:10 to Ͼ95:5; triisopropoxytitanium(IV) enolates:
syn/anti 25:75 to 93:7].
[
20] For aldol additions of various metal enolates of dihydroxy-
acetone acetonide and substituted dihydroxyacetone aceton-
ides, see: a) M. Hirama, T. Noda, S. Ito, C. Kabuto, J. Org.
Chem. 1988, 53, 706–708 (an achiral aldehyde was combined
with a “kinetic”, chiral lithium enolate; selectivity was pre-
dominantly anti, but not specified further); b) D. Enders, O. F.
Prokopenko, G. Raabe, J. Runsink, Synthesis 1996, 1095–1100
(achiral aldehydes were combined with “kinetic”, chiral dicy-
clohexylboron enolates: anti/syn 98:2 to Ͼ99:1); c) M. Majew-
ski, P. Nowak, Synlett 1999, 1447–1449 (dicyclohexylboron
(predominantly anti-selective; ratio of diastereomers 8:1; the
minor diastereomers were not identified).
[
14] We are unaware of aldol additions of dialkylboron enolates of
β-thia-δ-lactones (i.e., of 1,4-oxathian-2-ones).
[
15] Early aldol additions of metal enolates of unsubstituted cyclo-
hexanone: a) D. A. Evans, J. V. Nelson, E. Vogel, T. R. Taber,
J. Am. Chem. Soc. 1981, 103, 3099–3111 [anti/syn 67:33 for
7916
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Eur. J. Org. Chem. 2015, 7892–7918

Aldol Additions of Achiral and Chiral Titanium and Boron Enolates
enolate: anti/syn 96:4; lithium enolates: anti/syn 65:35 to 100:0);
d) M. Majewski, P. Nowak, J. Org. Chem. 2000, 65, 5152–5160
Weber, R. Brückner, Eur. J. Org. Chem. 2015, 2428–2449). Here
we needed a second equivalent of PhI(OAc) combined with a
catalytic amount of TEMPO for obtaining the lactone and not
ending one oxidation level lower (i.e., at the lactol).
2
(
diakylboron enolates: anti/syn 53:47 to 96:4, depending on the
alkyl groups and the workup; lithium enolate: anti/syn 65:35);
e) D. Enders, S. J. Ince, Synthesis 2002, 619–624 (achiral alde-
hydes were combined with “kinetic”, chiral dicyclohexylboron
enolates: anti/syn 98:2); f) D. Enders, S. J. Ince, M. Bonnekes-
sel, J. Runsink, G. Raabe, Synlett 2002, 962–966 (achiral alde-
hydes were combined with “kinetic”, chiral dicyclohexylboron
enolates anti-selectively); g) D. Enders, J. Barbion, Chem. Eur.
J. 2008, 14, 2842–2849 (an achiral aldehyde was combined with
a “kinetic”, chiral dicyclohexylboron enolate: anti/syn Ն99:1);
h) I. Niewczas, M. Majewski, Eur. J. Org. Chem. 2009, 33–37
[30] The conversion of lactone 19 was calculated after determining
1
the integrals over the H NMR signals at δ = 2.62–2.73 (two
α-protons of 19) versus δ = 7.64–7.77 (four aromatic protons
of aldehyde 24).
[31] a) For detailed compilation see Table SI-1 in the Supporting
Information; b) cf. also footnote 39.
[32] A highly anti-selective (anti/syn 95:5) aldol addition of the tri-
isopropoxytitanium(IV) enolate of α-methylcyclohexanone was
described in ref.[ (cf. also the bottom line of Scheme 2). This
is the same sense of simple diastereocontrol as in analogous
aldol additions of the dibutylboron enolate of the same α-
methylcyclohexanone (Ǟanti/syn up to 99.5:0.5; cf. the bottom
line of Scheme 2 again).[
16]
(
achiral aldehyde + “kinetic”, chiral dicyclohexylboron enolate:
anti/syn 99:1; achiral aldehydes + chiral and achiral lithium
enolates: anti/syn 91:9 to 100:0); i) N. Palyam, I. Niewczas, M.
Majewski, Synlett 2012, 23, 2367–2370 [an achiral aldehyde
16]
was combined with a chiral lithium enolate anti-selectively (two [33] We obtained pure specimens of the aldol adducts syn-33–35
by flash chromatography (on silica gel):[ aldol adduct syn-33
eluted slightly faster than anti-33 and resulted pure from the
early fractions. Aldol adduct syn-34 eluted slightly before anti-
34. The 50:50 mixture of the aldol adducts syn- and anti-35
furnished pure anti-35 in 32% yield followed by pure syn-35 in
25]
anti diastereomers)]; j) S. D. Halperin, R. Britton, Org. Biomol.
Chem. 2013, 11, 1702–1705 (a chiral aldehyde was combined
with an achiral lithium enolate. Selectivity was predominantly
anti and “excellent”, but not specified further).
IV
[
[
21] Such CpCl Ti enolates – albeit cyclic – have a certain resem-
2
1
blance to (acyclic) ester enolates that contain the Cp(diacetone-
44% yield. The 400 MHz H NMR spectra of these syn-aldols
IV
glucofuranosyl)Ti group (diacetoneglucofuranosyl = 1:2,5:6-
(syn-34: 300 MHz) supplemented the previously obtained
1
di-O-isopropylidene-d-α-glucofuranos-3-yl). The latter is the
Duthaler–Hafner auxiliary (R. O. Duthaler, A. Hafner, M.
Riedike, Pure Appl. Chem. 1990, 62, 631–642).
400 MHz H NMR spectroscopic data of the isomeric anti-
aldols such that an independent indication for the configura-
tional homologies, which we assume, emerged.
[
25]
22] This methylation has been reported repeatedly, by, for example:
a) J. L. Herrmann, R. H. Schlessinger, J. Chem. Soc., Chem.
Commun. 1973, 711–712; b) M. Kuehne, US Patent 4841045 A
[34] Isolation, through purification by flash chromatography, of
binary mixtures of the major cis and the major trans aldol ad-
duct from these seven aldol additions was not self-evident. This
is because the corresponding crude aldol mixtures were binary
only in one case (Ǟ43, boron route) but contained a small
amount of a third diastereomer in four instances (Ǟ40, 43, 44,
boron route; Ǟ43, titanium route) and small amounts both of
a third and a fourth diastereomer in two cases (Ǟ41, boron
and titanium route) ppm. Accordingly, six of these seven purifi-
cations by flash chromatography[ depleted the third and
fourth diastereomer sufficiently for being no longer recogniz-
1
989; c) J. J. Wolff, G. Frenking, K. Harms, Chem. Ber. 1991,
1
24, 551–561; d) M. Oikawa, H. Oikawa, A. Ichihara, Tetrahe-
dron 1995, 51, 6237–6254; e) B. W. Boal, A. W. Schammel,
N. K. Garg, Org. Lett. 2009, 11, 3458–3461; f) A. W. Scham-
mel, B. W. Boal, L. Zu, T. Mesganaw, N. K. Garg, Tetrahedron
2
010, 66, 4687–4695.
25]
23] Usually (see ref. 22a,22c–22f]) this methylation has seemed to re-
[
[
quire the addition of HMPA. However, this additive might
complicate workup procedures and leave trace amounts of resi-
1
able H-NMR-spectroscopically.
[22c]
[35] The 1Ј-H resonances in CDCl of anti,trans-38 (δ = 4.95 ppm,
due in the product (ref. ). Therefore we opted for a pro-
cedure without HMPA (ref.[ ) even if this lowers the yield.
24] D. J. Phillips, A. E. Graham, Synlett 2008, 649–652.
3
22b]
d, J = 5.7; 88 mol-%) and syn,trans-38 (δ = 5.24 ppm, mc,
3
c
mol-%) were accompanied by another m at δ = 4.91 ppm
[
[
(
9 mol-%). We attributed it to the aldol anti,cis-38 rather than
25] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–
syn,cis-38 because of its chemical shift.
2925.
[
36] The aldol syn,trans-41 was the major constituent in a 67:33
[
26] a) For a review on TEMPO oxidations, see: A. E. J. de Nooy,
A. C. Besemer, H. van Bekkum, Synthesis 1996, 1153–1174; b)
for TEMPO oxidations of lactols furnishing lactones, see: C. U.
Grünanger, B. Breit, Angew. Chem. Int. Ed. 2010, 49, 967–970;
Angew. Chem. 2010, 122, 979–982; c) for a TEMPO oxidation
of pentane-1,5-diol giving δ-valerolactone in 61% yield, see: T.
Miyazawa, T. Endo, J. Org. Chem. 1985, 50, 3930–3931.
27] J. M. Aurrecoechea, B. López, A. Fernández, A. Arrieta, F. P.
Cossío, J. Org. Chem. 1997, 62, 1125–1135.
28] These conditions resemble those of Sharpless’ asymmetric di-
hydroxylations with AD-mix α (K. B. Sharpless, W. Amberg,
Y. L. Bennani, G. A. Crispino, J. Hartung, K.-S. Jeong, H.-L.
Kwong, K. Morikawa, Z.-M. Wang, D. Xu, X.-L. Zhang, J.
Org. Chem. 1992, 57, 2768–2771). Unusually, stereocontrol –
potentially comprising both enantio- and diastereocontrol –
was of no interest in our work. We simply made recourse to
this procedure after attempted racemic dihydroxylations in the
presence of citric acid (“second cycle dihydroxylation”; P. Du-
pau, R. Epple, T. A. Allen, V. V. Fokin, K. B. Sharpless, Adv.
Synth. Catal. 2002, 344, 421–433) of the unsaturated alcohol
mixture with the isomer syn,cis-41. This mixture was obtained
[25]
by flash chromatography
from a 66:31:2:1 mixture of syn,
trans-41, syn,cis-41, anti,trans-41, and anti,cis-41, which had re-
sulted from the titanium-mediated addition of γ-methyl-δ-lact-
one (20) to para-bromobenzaldehyde (24; Table 2, Entry 6, at
right). For (re)crystallizing the mentioned 67:33 mixture of
2
syn,trans-41 and syn,cis-41 from Et O, almost all solvent had to
[
[
have evaporated (over the course of two weeks) before crystals
appeared. As a consequence we obtained two different crops
of crystals. They had different habiti: what appeared more
abundant and would be identified as syn,trans-41 by X-ray
analysis (cf. Figure 2, line 4, right) occurred as long, thin, flat-
tened needles. What appeared less abundant was in essence a
single platelet-like crystal. We performed X-ray diffraction on
this particular crystal and interpreted the result as the scat-
tering of a single crystal, which was composed of the dia-
stereomers syn,trans-41 and syn,cis-41 in a 1:2 ratio. The dissec-
tion of this analysis’ original crystal structure (cf. Supporting
Information) into superimposing scatterings from the dia-
stereomers syn,trans-41 and syn,cis-41 is shown in Figure 3.
2
7 had failed (to the extent that 27 had been recovered quanti-
[37] At the time of the single-crystal structure analyses of syn,trans-
41 and anti,trans-41 we had assumed, but not verified, that the
crystals represented the respective major diastereomer of the
respective aldol adduct mixture. In order to make sure in retro-
spect, we sampled one spatula tip of representative small crys-
tatively).
[
29] When trying to oxidize a secondary hydroxy group that was
part of a vicinal diol we found that one equivalent of
PhI(OAc) was enough to effect quantitative glycol cleavage (F.
2
Eur. J. Org. Chem. 2015, 7892–7918
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7917

F. Weber, F. Becker, M. Keller, H. Hillebrecht, R. Brückner
FULL PAPER
tals from each of the two final crops of solids, from which, at
the time, we had gathered the X-ray single-crystal specimens
of syn,trans-41 and anti,trans-41, respectively. These “final
crops of solids” had each been obtained by a series of consecu-
sight led us to our search for extensive crystallographic infor-
mation (Figure 2) as a basis for our structural assignments.
[41] The crystallographic data of the aldol adduct syn-32 are con-
tained in CCDC-1061978.
tive crystallizations; the X-rayed syn,trans-41 stemmed from [42] The crystallographic data of the aldol adduct anti-32 are con-
what had originally been a 67:33 mixture of syn,trans-41 and
syn,cis-41, whereas the X-rayed anti,trans-41 originated from
what had originally been a 75:25 mixture of anti,trans-41 and
anti,cis-41. After grinding of these samples XRD diffracto-
grams of the resulting powders were recorded. They showed
nothing but reflections from syn,trans-41 and anti,trans-41,
respectively (details: Supporting Information). These findings,
tained in CCDC-1061979.
[43] The crystallographic data of the aldol adduct anti-35 are con-
tained in CCDC-1061980.
[44] The crystallographic data of the aldol adduct syn,trans-38 are
contained in CCDC-1061981.
[45] The crystallographic data of the aldol adduct syn,trans-41 are
contained in CCDC-1400059.
1
in conjunction with the corresponding H NMR spectra, con-
[46] The crystallographic data of the aldol adduct anti,trans-41 are
contained in CCDC-1400060.
firmed that our corresponding single-crystal structure analyses
had affected the major diastereomer produced by the men-
tioned serial crystallizations of the mentioned aldol adduct
mixtures.
[47] The crystallographic data of the aldol adduct syn,cis-44 are
contained in CCDC-1061983.
[48] The crystallographic data of the aldol adduct anti,trans-36 are
contained in CCDC-1061982.
[
38] The aldol anti,trans-41 was the major constituent in a 75:25
[
[
[
[
49] The crystallographic data of the aldol adduct anti,cis-45 are
mixture with the isomer anti,cis-41. This mixture was obtained
by flash chromatography[25] from a 68:25:4:3 mixture of anti,-
contained in CCDC-1061984.
50] The crystallographic data of a co-crystal of the aldol adducts
syn,cis-41 and syn,trans-41 are contained in CCDC-1400061.
51] H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 78,
trans-41, anti,cis-41, syn,cis-41, and syn,trans-41, which had re-
sulted from the titanium-mediated addition of γ-methyl-δ-lact-
one (20) to para-bromobenzaldehyde (24; Table 2, Entry 6, at
left). For recrystallizing the mentioned 75:25 mixture from
1920–1923.
52] The weakness of this interpretation is the absence of an expla-
nation for why boat-like Zimmerman–Traxler analogous tran-
sition states should be favored over chair-like transition states.
Accordingly, different ways of interpreting our respective re-
sults should not be excluded. For instance, chlorotitanium(IV)-
containing enolates are known to be able to – or at least sus-
pected of being able to – aldol-add via acyclic (i.e., non-Zim-
merman–Traxler) transition states. The best-known examples
2
Et O, the solvent was slowly evaporated (over 7 days) until the
product crystallized. Care was taken to stop this procedure
when the first crystals appeared, such that the major compo-
nent anti,trans-41 exclusively would crystallize.
[
[
39] Altogether, Table 2 documents the identification of nine
syn,anti-isomeric trans-aldols (compounds 36–44) and six
syn,anti-isomeric cis-aldols (compounds 39–44). In each syn,
1
anti pair the 400 MHz H NMR resonance of 3-H is deshielded
are Heathcock’s TiCl
aldols from dibutylboron enolates of acyloxazolidinones,
TiCl , and aldehydes. It was suggested that they proceed via an
4
-mediated formations of non-Evans syn-
3
in the syn isomer (in CDCl ); for a detailed compilation see
Table SI-1 in the Supporting Information. The identical de-
4
shielding of 3-H was noticed in the syn versus anti isomers of
the aldols 30–32 (Table 1).[31a]
acyclic transition state: M. A. Walker, C. H. Heathcock, J. Org.
Chem. 1991, 56, 5747–5750. Cyclic transition states, yet of bi-
metallic enolates – specifically with 2ϫTi – were suggested
for aldol additions, see: J. Zambrana, F. Urpí, C. Luján, J. Org.
Chem. 2011, 76, 8575–8587.
40] In order to establish the configurations of our products we first
IV
1
envisioned a purely H NMR-based assignment. Its foundation
1
1
would have been the analysis of vicinal H, H coupling con-
stants: interpreted with the aid of the Karplus equation, they
1
[53] The meaning of a “half-chair” conformation in the present
context is defined in footnote [a] of Figure 5.
[54] The meaning of a “half-boat” conformation in the present con-
text is defined in footnote [b] of Figure 5.
might have allowed the dihedral angle of the respective H-C-
1
C- H moieties to be assessed. Analyzing the dihedral angles
1
1
in all endocyclic H-C-C- H moieties might have revealed the
conformation and configuration of the lactone ring itself. Ana-
lyzing the dihedral angle in the hemicyclic 1H-C -C(OH)- H
α
1
[55] “Half-chair” conformations of α,β-substituted δ-lactone enol-
ates were drawn in K. Tomioka, H. Kawasaki, K. Yasuda, K.
Koga, J. Am. Chem. Soc. 1988, 110, 3597–3601 for rationalizing
the diastereoselectivity of α-alkylations.
56] B. E. Love, E. G. Jones, J. Org. Chem. 1999, 64, 3755–3756.
57] The melting points are neither corrected nor uncorrected, be-
cause these terms refer to total immersion thermometers. In
our laboratory, like in most modern laboratories, only partial
immersion thermometers are used, which per definition need
no correction for immersion depth, as they are intended to be
only partially immersed, see: G. V. D. Tiers, J. Chem. Educ.
moiety might have established the syn or anti correlation [this
might have been less straightforward than it appears at first
sight, because the mentioned moiety might have a different
conformation in the adducts 36–38 of β-methyl-δ-lactone (19)
than in the adducts 39–44 of γ-methyl- (20) and δ-methyl-δ-
lactone (21)]. However, this approach failed. As a consequence
we performed a computational conformational analysis of di-
methylated δ-lactones to model our aldol adducts (F. Weber,
R. Brückner, Chem. Eur. J. 2013, 19, 1288–1302). The hope
was that that would deliver clearly preferred conformations of
our possible products. In that case we just would have had to
[
[
1990, 67, 258–259.
1
[58] The supplementary crystallographic data for this paper can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: August 31, 2015
fit the dihedral angles of our H NMR analysis to the lactone
structures obtained by our calculations. It turned out, however,
that δ-lactones in general are conformationally insufficiently
biased towards representing a single stereostructure. This in-
Published Online: November 13, 2015
7918
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7892–7918