Histidine-catalyzed asymmetric aldol addition of enolizable aldehydes: Insights into its mechanism

Article abstract of DOI:10.1021/jo202558f

Extensive studies of asymmetric cross-aldol addition between enolizable aldehydes are described and provide a deeper insight into histidine-catalyzed aldol additions. In particular, aspects of enantio- as well as diastereoselectivity of these reactions are discussed. Rules and predictions of configurative outcome are explained by using different transition-state models. These discussions are confirmed by extensive computations.

Full text of DOI:10.1021/jo202558f

Article
pubs.acs.org/joc
Histidine-Catalyzed Asymmetric Aldol Addition of Enolizable
Aldehydes: Insights into its Mechanism
Ulf Scheffler and Rainer Mahrwald*
Institute of Chemistry, Humboldt University, Brook-Taylor Strasse 2, 12489 Berlin, Germany
S
* Supporting Information
ABSTRACT: Extensive studies of asymmetric cross-aldol
addition between enolizable aldehydes are described and
provide a deeper insight into histidine-catalyzed aldol additions.
In particular, aspects of enantio- as well as diastereoselectivity of
these reactions are discussed. Rules and predictions of
configurative outcome are explained by using different
transition-state models. These discussions are confirmed by
extensive computations.
as nucleophiles, whereas electron-deficient aldehydes react as
carbonyl compounds (eq 2). Thus, when used with α-branched
INTRODUCTION
■
Over the past decade, extremely valuable results and progress
have been realized in organocatalyzed asymmetric aldol
additions. In particular, studies by MacMillan have outlined
the first examples of direct and enantioselective cross-aldol
reactions of enolizable aldehydes in the presence of catalytic
amounts of proline.1 This new aldol methodology allows the
direct and asymmetric coupling of different enolizable
aldehydes. After the first reports of proline-catalyzed cross-
aldol additions between enolizable aldehydes,2 protocols on
catalytic transformation in the presence of proline derivatives,3
chiral imidazolinones,4 chiral 1,2-diamines,5 and chiral sulfona-
mides6 were published. Though these transformations are
extremely high enantioselective coupling processes, there are
several problems that could not be solved by these reactions.
Because of the instability of the intermediate enamines,7
α-branched enolizable aldehydes exclusively react as carbonyl
components in these transformations. In contrast, α-unbranched
enolizable aldehydes can react as carbonyl components as well
as enol components. This problem can be overcome by
utilization of a syringe pump technique. A highlight of this
development is shown in eq 1. Both aldehydes, propionaldehyde
electron-rich aldehydes this reaction gives access to α-quaternary
carbon atoms. Artificial reaction conditions such as syringe
pump techniques are not necessary because of this strict
differentiation.
Herein, we describe experiments that provide a general
extension of this transformation. In addition, we offer a deeper
insight into the mechanism and configuration of this reaction.
RESULTS AND DISCUSSION
■
Reactions of Achiral Aldehydes. In order to explore the
scope and limitations of this histidine-catalyzed aldol addition,
several series of different substrates have been examined. The
results will be discussed in this paper to provide a more general
insight into the configurative events of this histidine-catalyzed
aldol addition. In a first set, isobutyraldehyde 1 was reacted as
the enol component with several different aldehydes 2−11 as
electrophiles. During these reactions, a differing ratio of aldol
adducts 13e−j and the corresponding isobutyracetals 12a−h
was detected (Scheme 1). The degree of acetalization can be
influenced only to a very small degree by the stoichiometry
of reactants (on that basis, the amount of isobutyraldehyde 1
was adjusted (1−2 equiv 1 relative to the electrophile)).
In order to avoid troublesome separation and identification of
as well as isovaleraldehyde, bear two α-methylene protons, but
only one regioisomer could be detected by 1H NMR analysis in
this reaction.1
We have recently described preliminary results of asymmetric
histidine-catalyzed cross-aldol addition of enolizable aldehydes.8
Histidine is able to discriminate deployed aldehydes based on
their electronic nature. Electron-rich aldehydes react exclusively
Received: December 20, 2011
Published: February 6, 2012
© 2012 American Chemical Society
2310
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
a
Scheme 1. Histidine-Catalyzed Aldol Additions of Isobutyraldehyde
a
Reaction conditions: 10 mol % of histidine in 0.2 mL of water, 5.5 respectively, 10 mmol of 1 and 5 mmol of 2−11, rt. 13a−d: yields after
transformation into corresponding dioxolanes. 13e−j: combined yields of acetals and aldol adducts.
stereoisomers, acetals 12a−d were converted and purified as
their corresponding 1,3-dioxolanes 13a−d. In contrast, the
corresponding hydroxy aldehydes 13e−j were isolated in good
to high yields when used with the more reactive aldehydes 6−
11 as carbonyl components. The formation of acetals 12a−h is
mainly dictated by the electronic nature of the electrophile.
Also, the formation of acetals correlates with reaction time. The
longer the reaction time, the greater the degree of acetalization.
(For detailed information about the degree of acetalization, see
the Supporting Information.) A similar trend is observed in
stereoselectivity. When used with relative electron-rich
aldehydes 2−5, moderate enantioselectivities were detected in
aldol adducts 13a−d. The more reactive carbonyl components
6−11 yield aldol adducts 13e−j with good to high levels of
enantioselectivity. Even in reactions of electron-rich aldehydes,
a strong preference for the formation of quaternary centers was
detected. Products 13a−c were isolated without relevant
amounts of homoaldol adducts of α-unbranched aldehydes
2−5. Instead of that, the homo aldol adduct of isobutyr-
aldehyde 1 was detected as the major byproduct.
Table 1. Influence of Solvent on Histidine-Catalyzed Aldol
Addition
a
entry
solvent
toluene
yield (%)
ee (%)
time (h)
1
2
3
4
5
6
7
8
−
7
−
<10
41
120
36
60
36
24
20
20
DMSO
MeCN
22
31
34
74
23
65
Cl3CCN
HO(CH)3−OH
HO(CH)2−OH
H2O
28
67
77
60
b
H2O
65
16
a
Reaction conditions: 10 mol % of histidine in 1.0 mL of solvent,
b
5 mmol of isobutyraldehyde, and ethyl glyoxylate, rt. 10 mol % of
histidine in 0.2 mL of water, 5 mmol of isobutyraldehyde, and ethyl
glyoxylate, rt.
An inadequate reproducibility was observed in reactions of
ethyl glyoxylate 11 (toluenic solution) with isobutyraldehyde 1.
Ethyl glyoxylate 11 is known as a very reactive aldehyde, but
toluene turned out to be the wrong solvent in these reactions.
For that reason, several additional solvents were tested in this
model reaction (Table 1). These interesting results represent
an excerpt of more detailed investigation which is found in the
Experimental Section. No reaction occurs when used with
ethyl glyoxylate 11 in toluene and isobutyraldehyde 1 (entry 1,
Table 1). A reaction is observed at varying levels by addition of
different solvents.
The highest yields as well as enantioselectivities were observed
by adding ethylene glycol. Also, water is accelerating this reaction
as well. However, there is an optimum for the use of water as can
be seen by comparing entries 7 and 8 in Table 1. Large amounts
of water sharply decrease yields, whereas equimolar amounts
of water relative to the reactants strongly increase yields.
Interestingly, a very low influence on enantioselectivity was
observed in both cases (compare entries 7 and 8, Table 1). By
deployment of aqueous buffer systems or solutions of different
salts as solvents a clear decrease in yield and selectivity was
observed. A neutral pH value turned out to be essential. On the
2311
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
a
Scheme 2. Histidine-Catalyzed Aldol Additions of Ethyl Glyoxylate and Enolizable Aldehydes
a
Reaction conditions: 10 mol % of histidine in 1.0 mL of solvent, 5 mmol of isobutyraldehyde and ethyl glyoxylate, rt. Numbering: for clarity and
ease of comparison between results the aldehyde functionality of the aldol adducts was set as 1-position for all examples in this paper. In order to
define syn- or anti-configuration of aldol products, the substituents of the aldol chain are specified by priority rules (CIP rules).
Scheme 3. Histidine-Catalyzed Diastereoselective Aldol Addition of Chiral Oxygen-Containing Aldehydes to Isobutyraldehyde
a
(Matched Situation)
a
bD-Histidine.
c
Reaction conditions: 10 mol % of histidine in 0.2 mL of water, 5.5 mmol of 1, and 5 mmol of 21−27, rt.
L-Histidine, R′ = R′′ = CMe2.
Absolute and relative configuration as well as enantiomeric excess were determined for products 13k−m to exclude a potential racemization of the
electrophile. To exclude epimerization in aldol adducts 13n−q simple determination of the relative configuration is necessary.
basis of these findings, ethylene glycol was used as standard
solvent in further reactions of ethyl glyoxylate 11 with different
aldehydes as enol components (Scheme 2).
NaBH4 and subsequent acidic treatment in good to excellent
yields. Determination of simple diastereoselectivity was deter-
mined at the stage of the corresponding γ-lactones. Absolute
configuration was determined for aldehydes 20a−c at the stage
of the corresponding γ-lactones and directly for the aldehydes
20d−h (see the Supporting Informations).
Reactions of Chiral Carbonyl Components. Inspired
by these results, chiral oxygen-substituted aldehydes were tested
in a next series of transformations. In order to explore the
stereochemical direction, several different chiral aldehydes were
reacted with isobutyraldehyde in the presence of catalytic
amounts of L- and D-histidine.
In contrast to the well-known anti-selective proline catalysis,
the aldol adducts in this series were detected in moderate 2,3-
syn-diastereoselectivity. When used with α-branched aldehydes
an increasing of enantiomeric excess is observed. The formation
of aldol adduct 20h represents an exception with regard to
enantioselectivity (44% ee). This is suspected to be attributable
to the formation of conjugated enamine of hydratropaldehyde
19. Similar results relating to yields and selectivities were
obtained when used with dimethoxyacetaldehyde 10 as carbonyl
component.8a β-Hydroxy aldehydes 20a−h were transformed
into the corresponding 2-hydroxy-α-lactones by reduction with
A matched situation is observed when used with L-histidine
and (R)-configured α-chiral aldehydes or D-histidine and
2312
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
Scheme 4. Histidine-Catalyzed Aldol Addition of Chiral Oxygen-Containing Aldehydes to Isobutyraldehyde (Mismatched
a
Situation)
a
bL-Histidine. cD-Histidine. R′ =
Reaction conditions: 10 mol % of histidine in 0.2 mL of water, 5.5 mmol of 1, and 5 mmol of 21−27, rt.
R′′ = CMe2. Absolute and relative configuration as well as enantiomeric excess were determined for products 13k−m to exclude a potential
racemization of the electrophile. To exclude epimerization in aldol adducts 13n−q simple determination of the relative configuration is
necessary.
(S)-configured aldehydes 21−27 (Scheme 3). The aldol
adducts 13k−q were isolated with extremely high degrees of
diastereoselectivity. The formation of acetals was not detected.
Racemization or epimerization of starting aldehydes were not
observed under these reaction conditions. Thus, enantiopure
products were isolated. Exclusively 3,4-syn-configured aldol
adducts were detected. Both the configurational stability of
chiral aldehydes 21−27 as well as the exceptionally high internal
syn-diastereoselectivity dictate the configurative installation of
the β-hydroxy group in aldol adducts 13k−q.
Scheme 5. Histidine-Catalyzed Aldol Addition of α-Chiral
Oxygen-Containing Aldehydes to 2-Methylbutyraldehyde
a
When used with L-histidine and (S)-configured α-chiral
aldehydes respectively D-histidine and (R)-configured α-chiral
aldehydes the mismatched situation is observed (Scheme 4).
Aldol adducts 13k−q were observed with slightly lower yields
(approximately 10%; compare the results of Scheme 3 with
those of Scheme 4). The most outstanding feature of these
transformations is the complete breakdown of diastereoselec-
tivity compared with the matched series (Scheme 3). Both
diastereoisomers, the anti- as well as the syn-configured aldol
adducts, were isolated in a ratio of nearly 1:1 (13k−m). A slight
increase of syn-diastereoselectivity is observed when used
with aldehydes bearing large substituents (13n−q). It is
assumed that only the α-chiral center of the aldehydes has a
noticeable influence on the reaction. Comparison of the results
of 13n and 13o indicates no influence of the β-stereocenter
of the reactants on diastereoselectivity. Syn- as well as anti-
configured diastereoisomers 13k−q were detected in enantio-
pure form.
a
Reaction conditions: 10 mol % of histidine in 0.2 mL of water,
5.5 mmol of 17, and 5 mmol of 22−23, rt.
In order to gain a deeper insight into diastereocontrol of
histidine-catalyzed aldol reactions, we also tested the combina-
tion of chiral electrophiles and differently substituted α-
branched nucleophiles. To this end, racemic 2-methylbutyr-
aldehyde 17 was reacted with α-chiral aldehydes 22 and 23 in
the presence of D- or L-histidine (Scheme 5). Remarkable
differences in 2,3-selectivity could not be detected by comparing
these results with those of Scheme 2 (compare 20f in Scheme 2
bL-Histidine.
cD-Histidine. Racemization of the carbonyl component was not observed.
with 28 and 29 in Scheme 5). In addition, the internal 3,4-
diastereoselectivity is comparable to the corresponding reactions
of isobutyraldehyde 1. In the mismatched case, an enhancement
of the formation of 3,4-anti-configured product is detected
2313
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
(compare 13l and 13m, Schemes 3 and 4). These results
indicate that the α-chiral center of the electrophile has a very
low influence on the 2,3-diastereoselectivity.
anti-selective (compare results of Scheme 6 with those of
Scheme 2). Structures in brackets were not detected. The actual
acetal structure has been omitted for a clear illustration of the
configurative outcome.
Homodimerization Reactions of Chiral Aldehydes. In a
further series of experiments, we tested chiral oxygen-containing
aldehydes in homoaldol additions (Scheme 6). Once again,
matched/mismatched situations were observed in these trans-
formations but not to the extent as discussed previously (compare
the results of Schemes 3 and 4 with those of Schemes 6 and 7).
Similar yields, diastereoselectivities, and enantioselectivities
were detected in both series. Thus, even the mismatched case
becomes a valuable tool for stereoselective synthesis. Again,
the matched situation is dictated by the α-chiral center of
the carbonyl compound. In the matched series, only one
stereoisomer was detected (Scheme 6). The internal 3,4-syn-
configuration is observed exclusively as an outstanding feature
of matched histidine-catalyzed aldol additions. In contrast
to previous results bond formation proceeds quantitatively
In the following series, we have realized the mismatched
situation (Scheme 7). When used with (S)-configured aldehyde
21 in the presence of L-histidine two diastereoisomers 33 and 30
were detected in a ratio of approximately 1:1. Furthermore, aldol
adducts 30 and 33 were isolated with lower yields (53%
compared to 62% compound 30 in Scheme 6). When used
with aldehydes 22 and 23, aldol adducts 34 and 35 were
isolated with slightly lower yields though with nearly the same
high stereoselectivities as observed in the matched series
(compare 31 and 32, Scheme 6, with 34 and 35, Scheme 7).
Again the bond formation proceeds quantitatively anti-selective,
but the outstanding feature of mismatched homodimeriza-
tion reactions is a moderate to excellent internal 3,4-anti-
configuration.
a
Scheme 6. Matched Homoaldol Additions of α-Chiral Aldehydes
a
Reaction conditions: 3.3 mol % of histidine in 0.1 mL of water, 6 mmol of 21−23, rt. The aldol adducts form acetals quantitatively, though these acetals
can be very labile. Racemization of the carbonyl component was not observed. Products 30−32 were isolated in enantio- and diastereopure form.
a
Scheme 7. Mismatched Homoaldol Additions of α-Chiral Aldehydes
a
Reaction conditions: 3.3 mol % of histidine in 0.1 mL of water, 6 mmol of 21−23, rt. Racemization of the carbonyl component was not observed.
Products 30 and 33−35 were isolated in enantiopure form.
2314
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
The existence of a matched/mismatched situation was
demonstrated conclusively by following experiments. Homo-
dimerization of protected glyceraldehyde 23 was accomplished
with catalytic amounts of racemic histidine. On the other hand
racemic aldehyde 23 was reacted with L-histidine (Scheme 8).
Scheme 9. Histidine-Catalyzed Homodimerization of α,β-
Chiral Aldehydes
a
Scheme 8. Matched and Mismatched Homodimerization of
Isopropylideneglyceraldehyde under Competitive
a
Conditions
a
Reaction conditions: 3.3 mol % of histidine in 0.1 mL of water,
6 mmol of 24−25, rt. R′ = R′′ = CMe2. Epimerization of the carbonyl
component was not observed. Products 38 and 39 were isolated in
enantio- and diastereopure form.
This general statement has been proven by several experimental
series.
a
Reaction conditions: (i) 3.3 mol % of histidine in 0.1 mL of water,
6 mmol of 21−23, rt; (ii) NaBH4, i-PrOH, rt.
Reaction Mechanism. We have described the reaction
pathway in histidine catalysis in a previous paper in cooperation
with Ken Houk et al. In particular, aspects of enantioselectivity as
well as simple diastereoselectivity were discussed and confirmed
by extensive computations.9 The reaction proceeds via an
enamine mechanism and the attraction of carbonyl aldehyde by
hydrogen bonds. The enamine is formed by the primary amine
of the amino acid permitting the deployment of α-branched
aldehydes.
Both reactions were quenched before full conversion was
observed (reaction time 30 h). For reasons of simplicity
regarding the isolation as well as identification the reduction
products of these reactions were analyzed. On the basis of the
conditions, the matched reaction competes with the mismatched
reaction. Thus, the faster reaction provides higher yield.
Unambiguously, product 36 was identified as the matched
product (respectively identically configured compound 32,
Scheme 6).
In summary, matched homodimerizations of oxygen-
containing α-chiral aldehydes result in 2,3-anti-3,4-syn-config-
ured aldol adducts with excellent stereoselectivities. The
mismatched situation gives access to 2,3-anti-3,4-anti-config-
ured products (with the restriction for 30, Scheme 7). 2,3-Syn-
configured diastereoisomers were not detected.
In contrast to proline, histidine contains two possible hydrogen
bond donators. Thus, the two most favorable transition states lead
to opposite chirality of the products (Scheme 10). The energy
Scheme 10. General Transition States for L-Histidine in
Reactions of Isobutyraldehyde
In contrast to homodimerization of α-chiral aldehydes
(Schemes 6 and 7), homodimerizations of α,β-chiral aldehydes
proceed with excellent diastereoselectivities by deployment of
L- as well as D-histidine. To this end, we tested aldehydes 24
and 25 (Scheme 9). The (S)-configured β-chiral center of the
nucleophiles alone dictates the diastereoselective outcome of
these reactions. The products were isolated with an extremely
high degree of 2,3-anti-configuration. Furthermore, the instal-
lation of the chiral center in 3-position proceeds completely
(R)-selective independent of the deployed catalyst. Thus,
neither the configuration of histidine nor the configuration of
the carbonyl aldehyde have a relevant influence on the config-
uration during the C−C bond formation process (compare the
results of 38 and 39, Scheme 9). In addition, an optional access
to 3,4-syn- or 3,4-anti-configured aldol adducts as observed by
deployment of L- or D-histidine in the α-chiral aldehyde series is
not possible (compare results of Scheme 6 and 7 with those of
Scheme 9).
difference between these two transition states determines the
obtained selectivity.
The preferred zwitterionic transition state A results in the
Re-attack using L-histidine. Attraction of the electrophile is
realized by the imidazolium group. This situation explains the
configuration of products discussed in Schemes 1 and 2. The
uncharged transition state B is very important to understand
the complex situation of diastereoselectivity in histidine
catalysis. It opens another reaction pathway if A is disfavored
because of the configuration of chiral aldehydes (mismatched
Note that other enantiomers of aldol products described in
Schemes 1 and 2 are available with same yields and stereo-
selectivities by deployment of D-histidine. Access to both
enantiomers of Schemes 3−9 is given by optional deployment
of L- or D-histidine and (R)- or (S)-configured chiral aldehydes.
2315
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
case). In transition state B, the attraction of the electrophile is
realized by the carboxylic group.
act as additional hydrogen bond acceptors for the imidazolium-
as well as for the carboxylic-proton. The excellent diastereo-
selectivity in the matched situation is the result of the constructive
influence of the catalyst. The mentioned hydrogen bond can
be formed effectively if (R)-configured carbonyl aldehydes and
L-histidine are deployed. As a consequence of that, the electro-
philes are attacked at their Re-site. These findings match the
preferred attraction of the carbonyl compound by the
imidazolium group as illustrated in Scheme 11 (matched case,
Schemes 3 and 6) (models C and E).
In contrast, when used with D-histidine, the imidazolium group
directs the electrophile to a Si-site attack in the mismatched case
(Scheme 4, 21 in Scheme 7). On the basis of these considera-
tions, 3,4-anti-configured products should be favored. However,
instead, a mixture of 3,4-syn- and 3,4-anti-configured products
was detected (3/1 to 1/1). An explanation for this apparent
contradiction is given by the following assumption. Because
of steric interactions (demonstrated in transitions state models D
or F), the reaction switches partially to transition state B, which
is still an option to proceed with formation of the additional
hydrogen bond. Following this pathway, the same syn-configured
products as in the matched case are achieved even though the
catalyst of opposite chirality is applied.
The diastereoselective outcome of the reactions described
above is determined by the structure of the particular enamine
and the orientation of the carbonyl compound. Aldol reac-
tions of aldehydes 17 and (R)-22 were selected as examples
(Schemes 11 and 12). These considerations can easily be
transferred to aldol reactions with other aldehydes. The moiety
of the carbonyl aldehyde occupies a pseudoaxial position as
illustrated in transition states A and B for reactions with
isobutyraldehyde. Thus, reactions of the E-enamine of aldehydes
17 or (R)-22 gives access to 2,3-syn-configured aldol adducts
and the Z-enamine to 2,3-anti-configured products, respectively.
When used with unfunctionalized enol components, E-enamine
will be formed predominantly resulting in a moderate syn-
selectivity of the products (transition-state model C and D in
Scheme 11). These considerations are related to the results of
20a−c, f−h in Scheme 2 and 28 and 29 in Scheme 5.
When used with functionalized, chiral aldehydes the
formation of the relative 3,4-configuration is dictated by a
Re- or Si-site attack at the carbonyl component (Scheme 3−9).
The configurative findings are in agreement with those obtained
in Cram-chelate-selective reactions. α-Oxygen atoms are able to
Scheme 11. Schematic Models for Reactions of 2-Methylbutyraldehyde and (R)-Benzyloxypropionaldehyde with Internal and
a
External Diastereodifferentiation
a
These models are related to reactions of Schemes 2−5. For reactions in Scheme 2, no matched/mismatched situation can occur. Thus models can
be simplified to E- and Z-enamine formation. For reactions of Schemes 3 and 4, configuration of the enamine is irrelevant. Thus models can be
simplified considering no 2,3-selectivity. C: L-histidine; E-enamine; (R)-22 (matched); E: L-histidine; Z-enamine; (R)-22 (matched); D: D-histidine;
E-enamine; (R)-22 (mismatched); F: D-histidine; Z-enamine; (R)-22 (mismatched); models for attraction of the carbonyl component by the
carboxylic group (transition state B) are not depicted because they relate to C−F except for the directing group.
Scheme 12. Transition State Models for Homodimerization Reactions of (R)-Benzyloxypropionaldehyde with Internal and
a
External Diastereodifferentiation
a
These models are related to reactions in Schemes 6−8; G: L-histidine; Z-enamine; (R)-22 (matched); H: D-histidine; Z-enamine; (R)-22
(mismatched).
2316
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
a
Scheme 13. Transition State Models for Homodimerization of Aldehydes 24 and 25
a
R′ = R′′ = CMe2; these models are related to reactions in Scheme 9; I: D-histidine; Z-enamine; (R.S)-24; K: D-histidine; Z-enamine; (S.S)-25;
models for L-histidine are not depicted because they relate to I and K except for the directing group.
When used with α-chiral oxygen-containing enol compo-
nents in homoaldol additions, Z-enamine is formed exclusively
due to another additional hydrogen bond with the enamine
proton (G and H, Scheme 12).10 As a result of that, the C−C
bond formation process proceeds with an extremely high
degree of 2,3-anti-diastereoselectivity. This is observed in
matched as well as in mismatched series (Schemes 6 and 7).
Again, the matched reaction yields 3,4-syn-configured products.
In contrast to reactions of unfunctionalized nucleophiles, the
mismatched reaction also proceeds with excellent diastereocon-
trol. Compared to the matched situation, the aldol adducts
were isolated with a high degree of 3,4-anti-diastereoselectivity
(Scheme 7). Because of the enamine hydrogen bond, it is
assumed that steric interactions are very low between the
enamine and electrophile moiety in these reactions, compared
to aldol additions of isobutyraldehyde 1 or 2-methylbutyr-
aldehyde 17 with chiral oxygen-containing aldehydes (tran-
sition-state model H, Scheme 12). Thus, a switch to transition
state B is unfavored.
These considerations are impressively supported by results of
homodimerizations of both diastereoisomers of α,β-chiral
aldehydes 24 and 25 (Scheme 9). The β-chiral centers of the
nucleophiles dictate the stereochemical outcome of these
reactions. Because of the cyclic structure of the chiral enamine,
the γ-methyl substituent prevents the attack at the carbonyl
aldehyde by the (Si)-site of the enamine (Scheme 13). The
formation of Z-enamine is strongly supported by experimental
data. In reactions of E-enamine, different diastereoisomers would
have to be obtained. Also, by deployment of both D- or L-
histidine the same configured aldol adducts 38 or 39 are isolated.
These results support the existence of the two reaction pathways
A and B since L- as well as D-catalyst must have the possibility to
assist the Si-attack at the electrophile to give the same products.
Again, yields are slightly higher if the carbonyl attraction can be
accomplished by the imidazolium group (Scheme 9).
which is the carbohydrate moiety of Trachycladines A and B.13
2-Hydroxypropanoates 20a−h were transformed into the
corresponding 2-hydroxy-γ-lactones.14 This implies the total
synthesis of pantolactone15 (derivative of 13j) and 3-hydroxy-4-
ethyl-4-methyldihydrofuran-2-one (derivative of anti-20f).16
EXPERIMENTAL SECTION
■
General Methods. Commercially available aldehydes 1−4 and
14−19 were freshly distilled before use. tert-Butyldimethylsilyloxyace-
taldehyde 6 and benzyloxyacetaldehyde 7, chloroacetaldehyde 9 (50%
aqueous solution), 2,2-dimethoxyacetaldehyde 10 (60% aqueous
solution), and ethyl glyoxylate 11 (50% in toluene) were used as
purchased. Additional aldehydes were prepared according to published
protocols: 5,17 8,18 21,19 R-22,20 S-22,21 23,22 24,23 25,24 26,25 and 27.26
1H NMR and 13C NMR spectra were recorded at 300, 400, or 500
and 75, 100, or 125 MHz, respectively. Chemical shifts are given in
ppm and coupling constants in Hz. Purification of products was
accomplished by flash chromatography (silica gel 60, particle size
0.04−0.063 mm). Yields were determined after column chromatog-
raphy. Thin-layer chromatography was performed with silica gel 60
F254 TLC plates. Development was performed either with cer(IV)-
sulfate/phosphomolybdic acid or KMnO4 solutions. The structures
were refined with SHELX97 (Sheldrick, G. M. Program for Crystal
Structure Refinement, Universitat Gottingen).
̈
̈
General Reaction Procedures. General Aldol Procedure A
(Synthesis of Compounds 13a−d). In these experiments, relevant
amounts of the corresponding hemiacetals 12 were detected.
In a typical experiment, 78 mg of L-histidine (0.5 mmol) was
added to a mixture of isobutyraldehyde 1 (10 mmol) and
5 mmol of corresponding aldehydes 2−5 and 200 mg of water.
The reaction mixture was stirred vigorously at room temper-
ature and monitored by TLC. After completion of the reaction
(5−7 days), the mixture was quenched with acetone, dried
(MgSO4), and filtrated. The filtrate was evaporated in vacuo.
The remaining residue was dissolved in 1.0 mL of glycol and
5 mL of THF, and then 0.5 mmol of toluenesulfonic acid was
added. The reaction was monitored by TLC. After completion
(∼12 h, rt) the reaction mixture was neutralized, filtrated,
absorbed to Celite, and purified by column chromatography
(hexane/acetone 19/1−4/1).
General Aldol Procedure B (Synthesis of Compounds 13e−j). In
these experiments, the corresponding hemiacetals 12 were detected
only in minority. In a typical experiment, 78 mg of L-histidine (0.5 mmol)
was added to a mixture of isobutyraldehyde 1 (5.5−6 mmol) and 5 mmol
of corresponding aldehydes 6−11 and 200 mg of water (note: since
aldehydes 9 and 10 are already applied as aqueous solutions no water
needs to be added). The reaction mixture was stirred vigorously at
room temperature and monitored by TLC. After completion of the
reaction (16 h to 4 days), the mixture was quenched with acetone,
dried (MgSO4), and filtrated. The filtrate was absorbed to Celite and
evaporated in vacuo, and the remaining residue was purified by column
chromatography (hexane/acetone 19/1−3/1).
CONCLUSION
■
In summary, we have given a comprehensive overview of the
possibilities in histidine-catalyzed direct aldol additions between
enolizable aldehydes. Rules and tendencies for the application
as well as prediction of the stereochemical outcome were
explained and supported by different transition state models.
This insight into histidine catalysis is especially important for
synthetic prediction of new compounds. These transformations
are characterized by operationally simple and very mild
conditions, high stereoselectivities and yields. We are convinced
that histidine catalysis will prove of much value as a key tool in
total synthesis. This is already demonstrated by contemplating
structures in this paper. In particular this has been demonstrated
by the first organocatalytic synthesis of D-hamamelose 3511 and
the first total synthesis of 2-C-methyl-D-5-deoxyribose 34,12
General Aldol Procedure C (Synthesis of Compounds 20a−h).
L-Histidine (155 mg) was added to a mixture of ethyl glyoxylate 11
(10 mmol, 50% in toluene), 11 mmol of corresponding aldehydes 14,
3, 4, and 15−19, and 1 mL of glycol. The reaction mixture was stirred
2317
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
vigorously at room temperature and monitored by TLC. After
completion of the reaction (12 h to 2 days), the mixture was quenched
with acetone, dried (MgSO4), and filtrated. The filtrate was evaporated
in vacuo with toluene (three times) and absorbed to Celite, and the
remaining residue was purified by column chromatography (hexane/
acetone 19/1−3/1).
General Aldol Procedure D (Synthesis of Compounds 13k−q).
L- or D-histidine (78 mg) was added to a mixture of isobutyraldehyde 1
(5.5 mmol), 5 mmol of corresponding aldehydes 21−27, and 200 mg
of water. The reaction mixture was stirred vigorously at room temp-
erature and monitored by TLC. After completion of the reaction (12 h
to 2 days), the mixture was quenched with acetone, dried (MgSO4),
and filtrated. The filtrate was absorbed to Celite and evaporated in
vacuo, and the remaining residue was purified by column
chromatography (hexane/acetone 19/1−5/1).
General Aldol Procedure E (Synthesis of Compounds 28 and 29).
L- or D-histidine (78 mg) was added to a mixture of rac-2-methy-
lbutyraldehyde 17 (5.5 mmol), 5 mmol of corresponding aldehydes
22−23, and 200 mg of water. The reaction mixture was stirred
vigorously at room temperature and monitored by TLC. After comple-
tion of the reaction (12 h to 2 days), the mixture was quenched with
acetone, dried (MgSO4) and filtrated. The filtrate was absorbed to
Celite and evaporated in vacuo, and the remaining residue was purified
by column chromatography (hexane/acetone 19/1).
5H); 13C NMR (75 MHz) δ = 16.9, 19.1, 33.8, 35.9, 41.0, 64.9, 65.1,
73.7, 108.6, 127.0, 128.4, 129.0, 138.2; HRMS (CI) m/z calcd for
C15H22O3S + H+ 283.1362, found 283.1363.
(R)-4-tert-Butyldimethylsilyloxy-3-hydroxy-2,2-dimethylbutanal
1
(13e). Colorless oil: [α] = −8.5 (c = 1, CHCl3) (74% ee); H NMR
(CDCl3, 300 MHz) δ = 0.87 (s, 3H), 0.88 (s, 9H), 0.90 (s, 3H), 1.08
(s, 3H), 1.10 (s, 3H), 3.57 (dd, 1H, J = 6.8, 10.0), 3.68 (dd, 1H, J = 3.6,
10.0), 3.73 (dd, 1H, J = 3.6, 6.8), 9.60 (s, 1H); 13C NMR (75 MHz)
δ = −5.5, −5.5, −3.6, 17.9, 19.0, 25.8, 48.5, 63.2, 75.8, 205.4; HRMS
(CI) m/z calcd for C12H26O3Si + H+ 247.1724, found 247.1726.
(R)-4-Benzyloxy-3-hydroxy-2,2-dimethylbutanal (13f). Colorless
oil: [α] = −8.7 (c = 1, CHCl3) (93% ee); 1H NMR (CDCl3, 300 MHz)
δ = 1.11 (s, 3H), 1.12 (s, 3H), 3.49 (dd, 1H, J = 7.4, 9.6 Hz), 3.59 (dd,
1H, J = 3.4, 9.6), 3.94 (dd, 1H, J = 3.3, 7.4), 4.6 (s, 2H), 7.2−7.5 (m,
5H), 9.60 (s, 1H). 13C NMR (75 MHz) δ = 17.7, 19.0, 48.7, 70.6, 73.5,
74.3, 127.8, 127.9, 128.5, 137.6, 206.5; HRMS (CI) m/z calcd for
C13H18O3 + H+ 223.1329, found 223.1328
(R)-4-(1,3-Dioxoisoindolin-2-yl)-3-hydroxy-2,2-dimethylbutanal
(13g). Colorless oil: [α] = −19.6 (c = 1, CHCl3) (77% ee); 1H NMR
(CDCl3, 300 MHz) δ = 1.18 (s, 3H), 1.20 (s, 3H), 3.75 (dd, 1H, J =
9.2, 14.2), 3.82 (dd, 1H, J = 2.7, 14.2), 4.03 (dd, 1H, J = 2.7, 9.2), 7.70
(m, 2H), 7.82 (m, 2H), 9.53 (s, 1H); 13C NMR (75 MHz) δ = 16.5,
18.9, 40.5, 49.6, 73.6, 123.4, 134.1,168.7, 205.1; HRMS (CI) m/z calcd
for C14H15O4N + Na+ 284.0893, found 284.0889.
General Aldol Procedure F (Synthesis of Compounds 30−35 and
38−39). L- or D-histidine (31 mg) was added to a mixture of 6 mmol
of corresponding aldehydes 21−25 and 100 mg of water. The reaction
mixture was stirred vigorously at room temperature and monitored
by TLC. After completion of the reaction (2−4 days), the mixture was
quenched with acetone, dried (MgSO4), and filtrated. The filtrate was
absorbed to Celite and evaporated in vacuo, and the remaining residue
was purified by column chromatography (hexane/acetone 19/1−4/1).
General Procedure for Reduction of Hemiacetals and Crude
Reaction Products. In a typical experiment, 3 mmol of the cor-
responding hemiacetals was dissolved in i-PrOH, and 60 mg of NaBH4
was added. The reaction mixture was stirred vigorously at room
temperature and monitored by TLC. After completion of the reaction
(10 min to 2 h), the mixture was slowly quenched with acetone and
after 10 min with saturated aqueous NH4Cl solution, dried (MgSO4),
and filtrated. The filtrate was absorbed to Celite and evaporated in
vacuo, and the remaining residue was purified by column
chromatography (hexane/acetone 9/1−3/1).
(R)-4-Chloro-3-hydroxy-2,2-dimethylbutanal (13h). Colorless oil:
[α] = −12.2 (c = 1, CHCl3) (90% ee); H NMR (CDCl3, 300 MHz)
δ = 1.15 (s, 3H), 1.16 (s, 3H), 3.49 (dd, 1H, J = 9.6, 11.4), 3.71 (dd,
1H, J = 2.4, 11.4), 3.97 (dd, 1H, J = 2.2, 9.6), 9.57 (s, 1H); 13C NMR
(75 MHz) δ = 17.1, 19.1, 46.9, 49.6, 75.3, 204.7; HRMS (CI) m/z
calcd for C12H22Cl2O4 + Na+ 323.0787, found 323.0787.
1
(R)-3-Hydroxy-4,4-dimethoxy-2,2-dimethylbutanal (13i). Color-
1
less oil: [α] = +5.3 (c = 1, CHCl3) (84% ee); H NMR (CDCl3,
300 MHz) δ = 1.05 (s, 3H), 1.08 (s, 3H), 3.33 (s, 3H), 3.41 (s, 3H),
3.68 (1H, d, J = 6.2), 4.18 (1H, d, J = 6.2), 9.42 (s, 1H); 13C NMR
(75 MHz) δ = 16.6, 19.5, 48.4, 54.9, 55.8, 74.2, 104.8, 203.1; HRMS
(CI) m/z calcd for C14H28O8 + H+ 325.1857, found 325.1863 2 [M −
CH2] + H+
2(R)-Hydroxy-3,3-dimethyl-4-oxobutyric Acid Ethyl Ester (13j).
Colorless oil: 1H NMR (CDCl3, 300 MHz) δ = 1.06 (s, 3H), 1.14 (s,
3H), 1.27 (t, 3H, J = 7.2), 4.25 (m, 2H), 4.32 (s, 1H), 9.57 (s, 1H);
13C NMR (75 MHz) δ = 14.1, 16.9, 18.2, 50.4, 62.3, 73.5, 172.8, 202.5;
(S)-2-(1,3-Dioxolan-2-yl)-2-methylhexan-3-ol (13a). Colorless oil:
HRMS (CI) m/z calcd for C8H14O4 + H+ 175.0965, found 175.0963.
(S)-3-Hydroxy-2,2-dimethyl-3(S)-tetrahydrofuran-2-yl)propanal
(syn-13k). Colorless oil: [α] = −1.3 (c = 1, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ = 1.10 (s, 3H), 1.13(s, 3H), 1.74−2.00 (m, 4H),
3.54 (d, 1H, J = 2.7), 3.70−3.86 (m, 2H), 3.95 (dpst, 1H, J = 2.6, 6.7),
9.61 (s, 1H); 13C NMR (75 MHz) δ = 18.4, 19.6, 26.1, 29.3, 49.8,
1
[α] = −21.8 (c = 1, CHCl3) (57% ee); H NMR (CDCl3, 300 MHz)
δ = 0.87 (s, 3H), 0.92 (s, 3H), 0.92 (t, 3H, J = 7.2), 1.28−1.66
(m, 4H), 3.56 (dd, 1H, J = 2.3, 9.8), 3.81−3.89 (m, 2H), 3.94−4.00
(m, 2H), 4.65 (s, 1H); 13C NMR (75 MHz) δ = 14.1, 16.5, 19.8,
20.3, 33.2, 40.7, 64.8, 65.1, 75.3, 110.0; HRMS (CI) m/z calcd for
C10H20O3 + Na+ 11.1305, found 211.1299.
+
68.9, 77.2, 77.3, 206.2; HRMS (CI) m/z calcd for C9H16O3
(S)-2-(1,3-Dioxolan-2-yl)-2-methyl-5-phenylpentan-3-ol (13b).
Colorless oil: [α] = −6.2 (c = 1, CHCl3) (54% ee); 1H NMR
(CDCl3, 300 MHz) δ = 0.91 (s, 3H), 0.97 (s, 3H), 1.66−1.83 (m,
2H), 2.64 (ddd, 1H, J = 6.4, 10.2, 13.6), 3.00 (ddd, 1H, J = 5.0, 10.6,
13.6), 3.64 (dd, 1H, J = 1.9, 10.7), 3.85−4.04 (m, 4H), 4.67 (s, 1H),
7.19−7.33 (m, 5H); 13C NMR (75 MHz) δ = 16.5, 20.4, 33.0, 33.2,
40.7, 64.8, 65.1, 75.1, 110.0, 125.6, 128.3, 128.5, 142.7; HRMS (CI)
m/z calcd for C15H22O3 + H+ 251.1642, found 251.1641.
172.10999, found 172.1099.
(S)-2-(1,3-Dioxolan-2-yl)-2,5-dimethylhexan-3-ol (13c). Colorless
oil: [α] = −31.6 (c = 1, CHCl3) (56% ee); 1H NMR (CDCl3,
300 MHz) δ = 0.85 (s, 3H), 0.88 (d, 3H, J = 6.6), 0.91 (s, 3H), 0.92
(d, 3H, J = 6.5), 1.11 (ddd, 1H, J = 1.8, 10.3, 13.7), 1.35 (ddd, 1H,
J = 3.6, 10.9, 13.6), 1.84 (ddspt, 1H, J = 3.5, 6.6, 10.2), 3.63 (dd, 1H,
J = 1.9, 10.8), 3.81−3.99 (m, 4H), 4.65 (s, 1H); 13C NMR (75 MHz)
δ = 16.5, 20.2, 21.2, 24.2, 24.4, 40.1, 40.6, 64.8, 65.1, 73.3, 110.0;
HRMS (CI) m/z calcd for C11H22O3 + H+ 203.1642, found 203.1642.
(R)-1-Benzylthio-3-(1,3-dioxolan-2-yl)-3-methylbutan-2-ol (13d).
Colorless oil: [α] = −45.9 (c = 1, CHCl3) (71% ee); 1H NMR
(CDCl3, 300 MHz) δ = 0.84 (s, 3H), 0.92 (s, 3H), 2.43 (dd, 1H, J =
8.8, 13.6), 2.60 (dd, 1H, J = 1.2, 13.7), 3.71 (dd, 1H, J = 1.3, 8.7),
3.72−3.79 (m, 2H), 3.81−3.98 (m, 4H), 4.69 (s, 1H), 7.23−7.36 (m,
(R)-3-Hydroxy-2,2-dimethyl-3(S)-tetrahydrofuran-2-yl)propanal
(anti-13k). Colorless oil: [α] = −12.1 (c = 1, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ = 1.09 (s, 3H), 1.16 (s, 3H), 1.81−1.96 (m,
4H), 3.66−3.89 (m, 3H), 3.74 (d, 1H, J = 6.2), 9.54 (s, 1H); 13C
NMR (75 MHz) δ = 17.6, 19.0, 25.8, 27.7, 49.1, 67.8, 76.9, 79.2, 205.1.
(3R,4R)-4-Benzyloxy-3-hydroxy-2,2-dimethylpentanal (syn-13l).
1
Colorless oil: [α] = −34.0 (c = 1, CHCl3); H NMR (CDCl3, 300
MHz) δ = 1.05 (s, 3H), 1.15 (s, 3H), 1.28 (d, 3H, J = 6.2), 3.39 (d,
1H, J = 2.0), 3.69 (dq, 1H, J = 2.0, 6.2), 4.33 (d, 1H, J = 11.1), 4.56 (d,
1H, J = 11.1), 7.27 - 7.37 (m, 5H), 9.62 (s, 1H); 13C NMR (75 MHz)
δ = 16.4, 18.9, 20.3, 49.2, 70.4, 72.5, 81.1, 127.9, 128.2, 128.4, 137.4,
2318
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
205.3; HRMS (CI) m/z calcd for C14H20O3 + H+ 237.1485, found
237.1486.
[α] = −23.3 (c = 1, CHCl3); 1H NMR (CDCl3, 300 MHz) δ =
1.08 (s, 3H), 1.13(s, 3H), 1.40 (s, 3H),1.41 (s, 3H), 3.58 (dd, 1H, J =
5.0, 10.2), 3.63 (d, 1H, J = 0.6), 3.66 (dd, 1H, J = 4.9, 10.2), 3.97 (dd,
1H, J = 0.6, 8.4), 4.21 (dpst, 1H, J = 4.9, 8.5), 4.58 (s, 2H), 7.27−7.38
(m, 5H), 9.57 (s, 1H); 13C NMR (75 MHz) δ = 18.2, 19.3, 26.7, 27.2,
50.2, 69.8, 72.7, 73.6, 76.5, 76.8, 110.0, 127.7, 127.7, 128.9, 137.7,
205.7; HRMS (CI) m/z calcd for C18H26O5 + H+ 323.1853, found
323.1853.
(3S,4R)-4-Benzyloxy-3-hydroxy-2,2-dimethylpentanal (anti-13l).
1
Colorless oil: [α] = −12.2 (c = 1, CHCl3); H NMR (CDCl3, 300
MHz) δ = 1.06 (s, 3H), 1.08 (s, 3H), 1.26 (d, 3H, J = 6.1), 3.45 (dq, 1H,
J = 6.1, 7.2), 3.70 (d, 1H, J = 7.2), 4.36 (d, 1H, J = 11.3), 4.49 (d, 1H,
J = 11.4), 7.25−7.38 (m, 5H), 9.48 (s, 1H); 13C NMR (75 MHz) δ =
16.1, 16.4, 19.9, 49.1, 70.5, 75.0, 78.1, 127.7, 128.1, 128.3, 137.6, 203.3.
(R)-3-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-hydroxy-2,2-dime-
thylpropanal (syn-13m).8a Colorless oil: [α] = +0.5 (c = 1, CHCl3);
1H NMR (CDCl3, 300 MHz) δ = 1.09 (s, 3H), 1.11(s, 3H), 1.32 (s,
(S)-3-((4S,5S)-5-Benzyloxymethyl-2,2-dimethyl-1,3-dioxolan-4-
yl)-3-hydroxy-2,2-dimethylpropanal (3,4-anti-13p). Colorless oil:
1
[α] = +10.1 (c = 1, CHCl3); H NMR (CDCl3, 300 MHz) δ = 1.12
(s, 3H), 1.13 (s, 3H),1.32 (s, 3H),1.32 (s, 3H), 3.51 (dd, 1H, J = 7.9,
9.0), 3.67 (dd, 1H, J = 7.4, 9.0), 3.77 (dd, 1H, J = 4.5, 9.0), 3.78 (d, 1H,
J = 8.9), 4.06 (dpst, 1H, J = 4.5, 7.8), 4.60 (s, 2H), 7.28−7.39 (m, 5H),
9.48 (s, 1H); 13C NMR (75 MHz) δ = 15.9, 19.1, 26.5, 26.7, 50.1, 70.4,
73.9, 75.6, 79.2, 80.7, 109.6, 128.0, 128.2, 128.6, 136.6, 204.2.
(S)-3-Hydroxy-2,2-dimethyl-3-((4R,4′R,5R)-2,2,2′,2′-tetramethyl-
4,4′-bi(1,3-dioxolan)-5-yl)propanal (3,4-syn-13q). Colorless prisms:
mp 65.7 °C: [α] = +12.5 (c = 1, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ = 1.12 (s, 3H), 1.16 (s, 3H),1.32 (s, 3H),1.35 (s, 3H), 1.38 (s, 3H),
1.41 (s, 3H), 3.79 (d, 1H, J = 9.8), 3.89−3.95 (m, 2H), 4.00−4.07 (m,
2H), 4.13 (dd, 1H, J = 6.0, 8.4), 9.61 (s, 1H); 13C NMR (75 MHz) δ =
18.2, 19.6, 25.2, 26.7, 26.7, 27.2, 50.2, 67.9, 73.4, 77.3, 77.8, 78.5, 109.8,
110.1, 205.9; HRMS (CI) m/z calcd for C15H26O6 + H+ 303.1802,
found 303.1801.
3H), 1.38 (s, 3H), 2.62 (d, 1H, J = 7.6, OH), 3.54 (dd, 1H, J = 2.6,
7.6), 3.81 (dd, 1H, J = 7.0, 8.1), 4.01 (dd, 1H, J = 7.0, 8.1), 4.19 (dpst,
1H, J = 2.6, 7.0), 9.59 (s, 1H); 13C NMR (75 MHz) δ = 18.2, 19.5,
25.3, 26.1, 49.6, 66.8, 74.3, 74.8, 109.6, 205.6; HRMS (CI) m/z calcd
+
for C10H18O4 + NH4 220.1543, found: 220.1543.
(S)-3-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-hydroxy-2,2-dime-
thylpropanal (anti-13m). Colorless oil: [α] = +13.1 (c = 1, CHCl3);
1H NMR (CDCl3, 300 MHz) δ = 1.10 (s, 3H), 1.14 (s, 3H), 1.32 (s,
3H), 1.38 (s, 3H), 3.84 (dd, 1H, J = 7.1, 8.1), 3.89−3.96 (m, 1H), 4.05
(d, 1H, J = 7.4), 4.06 (dd, 1H, J = 3.3, 8.1), 9.50 (s, 1H); 13C NMR (75
MHz) δ = 17.8, 18.1, 25.2, 26.4, 49.3, 66.5, 75.4, 75.7, 109.1, 204.8.
(S)-3-Hydroxy-2,2-dimethyl-3-((4R,5S)-2,2,5-trimethyl-1,3-dioxo-
lan-4-yl)propanal (3,4-syn-13n). Colorless oil: [α] = +23.5 (c = 1,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ = 1.11 (m, 6H), 1.33 (s, 3H),
1.39 (d, 3H, J = 6.5), 1.47 (s, 3H), 3.62 (s, 1H), 4.14 (d, 1H, J = 6.9),
4.40 (psqin, 1H, J = 6.6), 9.65 (s, 1H); 13C NMR (125 MHz) δ = 15.3,
18.5, 19.5, 24.6, 26.7, 50.1, 73.6, 74.0, 75.2, 107.9, 205.8.
(R)-3-Hydroxy-2,2-dimethyl-3-((4R,4′R,5R)-2,2,2′,2′-tetramethyl-
1
4,4′-bi(1,3-dioxolan)-5-yl)propanal (3,4-anti-13q). Colorless oil: H
NMR (CDCl3, 300 MHz) δ = 1.12 (s, 3H), 1.14 (s, 3H),1.31 (m,
6H),1.36 (s, 3H),1.46 (s, 3H), 3.71−4.21 (m, 6H), 9.49 (s, 1H); 13C
NMR (75 MHz) δ = 15.5, 19.5, 25.0, 26.3, 26.4, 26.6, 50.1, 68.0, 75.2,
76.3, 80.9, 82.1, 109.8, 110.5, 203.8.
2(R)-Hydroxy-3(R)-methyl-4-oxobutyric Acid Ethyl Ester (syn-
20a). syn- and anti-20a were obtained as inseparable mixture of aldol
adducts and different anomers of n-propylidene hemiacetals. Thus,
exact characterization by NMR experiments was accomplished for the cor-
responding lactone derivatives: HRMS (CI) m/z calcd for C7H12O4 + H+
161.0808, found 161.0806 (see the Supporting Information).
(R)-3-Hydroxy-2,2-dimethyl-3-((4R,5S)-2,2,5-trimethyl-1,3-dioxo-
lan-4-yl)propanal (3,4-anti-13n). Colorless oil: [α] = −8.5 (c = 1,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ = 1.12 (s, 3H), 1.15 (s, 3H),
1.27 (s, 3H), 1.30 (d, 3H, J = 6.5), 1.37 (s, 3H), 3.83 (d, 1H, J = 9.7),
3.93 (dd, 1H, J = 6.0, 9.7), 4.39 (psqin, 1H, J = 6.4), 9.43 (s, 1H); 13C
NMR (75 MHz) δ = 15.7, 16.1, 19.2, 25.2, 27.8, 50.0, 72.4, 73.7, 76.9,
108.2, 204.5.
2(R)-Hydroxy-3(R)-benzyl-4-oxobutyric Acid Ethyl Ester (syn-
1
20b). Colorless oil: H NMR (CDCl3, 300 MHz) δ = 1.27 (t, 3H,
J = 7.1), 2.99 (dd, 1H, J = 9.0, 12.8), 3.07−3.15 (m, 1H), 3.21 (dd, 1H,
J = 7.3, 12.7), 4.17 (d, 1H, J = 3.1), 4.23 (q, 2H, J = 7.1), 7.18−7.36
(m, 5H), 9.67 (s, 1H); 13C NMR (75 MHz) δ = 14.1, 31.4, 56.1, 62.2,
68.5, 126.7, 128.7, 129.1, 137.9, 173.5, 201.5; HRMS (CI) m/z calcd
for C13H16O4 + Na+ 259.0941, found 259.0939.
(S)-3-Hydroxy-2,2-dimethyl-3-((4R,5R)-2,2,5-trimethyl-1,3-dioxo-
lan-4-yl)propanal (3,4-syn-13o). Colorless oil: [α] = +11.0 (c = 1,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ = 1.09 (s, 3H), 1.14 (s, 3H),
1.27 (d, 3H, J = 6.0), 1.37 (s, 3H), 1.39 (s, 3H), 3.49 (d, 1H, J = 0.4),
3.57 (dd, 1H, J = 0.4, 8.5), 4.08 (dq, 1H, J = 6.0, 8.6), 9.59 (s, 1H);
13C NMR (75 MHz) δ = 16.8, 18.3, 19.1, 26.6, 27.6, 50.2, 71.8, 73.6,
2(R)-Hydroxy-3(S)-benzyl-4-oxobutxyric Acid Ethyl Ester (anti-
1
20b). Colorless oil: H NMR (CDCl3, 300 MHz) δ = 1.18 (t, 3H,
J = 7.1), 2.82 (dd, 1H, J = 7.0, 13.7), 3.07−3.15 (m, 1H), 3.20 (dd, 1H,
J = 8.4, 13.8), 4.26 (q, 2H, J = 7.2), 4.65 (d, 1H, J = 3.8), 7.18−7.36
(m, 5H), 9.76 (d, 1H, J = 0.9); 13C NMR (75 MHz) δ = 13.9, 29.6,
56.3, 62.2, 68.5, 126.6, 128.5, 129.2, 138.0, 173.2, 201.2.
+
80.3, 109.1, 205.7; HRMS (CI) m/z calcd for C11H20O4 + NH4
2(R)-Hydroxy-3(R)-isopropyl-4-oxobutyric Acid Ethyl Ester (syn-
20c). Colorless oil: 1H NMR (CDCl3, 300 MHz) δ = 1.01 (d, 3H, J =
6.9), 1.02 (d, 3H, J = 7.0), 1.29 (t, 3H, J = 7.1), 2.33 (m, 1H), 2.48
(ddd, 1H, J = 2.2, 3.0, 8.6), 4.25 (q, 2H, J = 7.1), 4.38 (d, 1H, J = 2.9),
9.72 (d, 1H, J = 2.2); 13C NMR (75 MHz) δ = 14.1, 20.5, 20.8, 26.2,
60.3, 62.2, 69.2, 174.0, 204.1; HRMS (CI) m/z calcd for C9H16O4 +
Na+ 211.0941, found 211.0939.
234.1700, found 234.1698.
(R)-3-Hydroxy-2,2-dimethyl-3-((4R,5R)-2,2,5-trimethyl-1,3-dioxo-
lan-4-yl)propanal (3,4-anti-13o). Colorless oil: 1H NMR (CDCl3,
300 MHz) δ = 1.11 (s, 3H), 1.14 (s, 3H), 1.30 (s, 3H), 1.35 (s, 3H),
1.36 (d, 3H, J = 6.0), 3.48 (dd, 1H, J = 7.5, 8.6), 3.76 (d, 1H, J = 8.7),
4.07 (dq, 1H, J = 6.1, 7.4), 9.45 (s, 1H); 13C NMR (75 MHz) δ = 16.9,
18.7, 19.5, 26.6, 27.3, 50.2, 76.8, 77.3, 81.4, 108.6, 205.1.
(R)-3-((4S,5S)-5-Benzyloxymethyl-2,2-dimethyl-1,3-dioxolan-4-
yl)-3-hydroxy-2,2-dimethylpropanal (3,4-syn-13p). Colorless oil:
2(R)-Hydroxy-3(S)-isopropyl-4-oxobutyric Acid Ethyl Ester (anti-
1
20c). Colorless oil: H NMR (CDCl3, 300 MHz) δ = 1.05 (d, 3H,
2319
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
J = 6.5), 1.07 (d, 3H, J = 6.5), 1.29 (t, 3H, J = 7.2), 2.33 (m, 1H), 2.54
(ddd, 1H, J = 2.8, 5.2, 8.0), 4.28 (q, 2H, J = 7.2), 4.55 (d, 1H, J = 5.2),
9.78 (d, 1H, J = 2.8); 13C NMR (75 MHz) δ = 14.0, 19.8, 21.1, 26.2,
60.6, 62.2, 68.8, 174.0, 203.1.
δ = 0.85 (pst, 3H, J = 7.6), 1.02 (s, 3H), 1.30 (d, 3H, J = 6.0), 1.54 (m,
1H), 1.76 (m, 1H), (3.45 (dq, 1H, J = 6.0, 8.1), 3.76 (d, 1H, J = 8.1),
4.34 (d, 1H, J = 11.2), 4.47 (d, 1H, J = 11.2), 7.27 - 7.41 (m, 5H), 9.44
(s, 1H); 13C NMR (75 MHz) δ = 8.0, 11.9, 16.6, 26.9, 52.5, 70.4, 74.8,
77.9, 127.6, 128.3, 128.3, 137.4, 202.9.
2(R)-Hydroxy-3,3-diethyl-4-oxobutyric Acid Ethyl Ester (20d).
1
Colorless oil: H NMR (CDCl3, 300 MHz) δ = 0.87 (t, 3H, J =
(2S,3S,4R)-4-Benzyloxy-2-ethyl-3-hydroxy-2-methylpentanal
(2,3-anti-3,4-anti-28). Colorless oil: 1H NMR (CDCl3, 300 MHz) δ =
0.84 (pst, 3H, J = 7.5), 1.00 (s, 3H), 1.19 (d, 3H, J = 6.2), 1.61 (dq,
1H, J = 7.5, 14.0), 1.78 (dq, 1H, J = 7.5, 14.0), (3.59 (dq, 1H, J = 4.9,
6.2), 3.86 (d, 1H, J = 4.8), 4.44 (d, 1H, J = 11.6), 4.57 (d, 1H, J =
11.6), 7.25−7.37 (m, 5H), 9.61 (s, 1H); 13C NMR (75 MHz) δ = 8.2,
14.8, 15.7, 25.4, 51.9, 70.5, 75.1, 77.3, 127.7, 128.3, 128.4, 137.9, 206.1.
(R)-2-((R)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)-
2-methylbutanal (2,3-syn-3,4-syn-29). Colorless oil: 2,3-syn-3,4-syn-
29, 2,3-anti-3,4-syn-29, 2,3-syn-3,4-anti-29 and 2,3-anti-3,4-anti-29 →
7.6), 0.88 (t, 3H, J = 7.6), 1.29 (t, 3H, J = 7.1), 1.59−1.78 (m, 4H),
4.25 (m, 2H, J = 7.2), 4.41 (s, 1H), 9.60 (s, 1H); 13C NMR (75 MHz)
δ = 7.9, 8.0, 14.0, 21.7, 22.6, 55.8, 62.2, 72.6, 173.6, 204.1; HRMS (CI)
m/z calcd for C10H18O4 + H+ 203.1278, found 203.1276.
(R)-Ethyl 2-(1-Formylcyclohexyl)-2-hydroxyacetate (20e). Color-
less oil: 1H NMR (CDCl3, 300 MHz) δ = 1.27 (t, 3H, J = 7.1), 1.37−
1.66 (m, 8H), 1.74−1.80 (m, 1H), 1.91−1.96 (m, 1H), 4.13 (s, 1H),
4.23 (m, 2H, J = 7.1), 9.57 (s, 1H); 13C NMR (75 MHz) δ = 14.1,
22.0, 22.2, 25.1, 25.9, 27.8, 53.5, 62.2, 73.8, 172.8, 204.5; HRMS (CI)
+
1
m/z calcd for C11H18O4 + NH4 232.1543, found 232.1543.
inseparable mixture; H NMR (CDCl3, 300 MHz) δ = 0.85 (pst, 3H,
2(R)-Hydroxy-3(R)-ethyl-3-methyl-4-oxobutyric Acid Ethyl Ester
(syn-20f). Colorless oil: 1H NMR (CDCl3, 300 MHz) δ = 0.84 (t, 3H,
J = 7.6), 0.96 (s, 3H), 1.25 (t, 3H, J = 7.1), 1.63−1.83 (m, 2H), 4.22
(m, 2H, J = 7.2), 4.40 (s, 1H), 9.58 (s, 1H); 13C NMR (75 MHz) δ =
8.1, 12.7, 14.1, 26.0, 53.8, 62.4, 72.8, 173.2, 203.0; HRMS (CI) m/z
calcd for C9H16O4 + Na+ 211.0941, found 211.0939.
J = 7.6), 1.10 (s, 3H), 1.34 (s, 3H), 1.39 (s, 3H), 1.57 (dq, 1H, J = 7.6,
15.0), 1.86 (dq, 1H, J = 7.5, 15.0), 3.60 (d, 1H, J = 2.2), 3.81 (dd, 1H,
J = 7.4, 8.0), 4.03 (dd, 1H, J = 6.6, 8.0), 4.19 (ddd, 1H, J = 2.2, 6.6,
7.3), 9.59 (s, 1H); 13C NMR (75 MHz) δ = 8.3, 15.5, 25.4, 25.7, 26.1,
53.2, 67.0, 73.1, 74.6, 109.7, 206.6; HRMS (CI) m/z calcd for
+
C11H20O4+ NH4 234.1700, found 234.1699.
2(R)-Hydroxy-3(S)-ethyl-3-methyl-4-oxobutyric Acid Ethyl Ester
(anti-20f). Colorless oil: 1H NMR (CDCl3, 300 MHz) δ = 0.86 (t, 3H,
J = 7.5), 1.06 (s, 3H), 1.29 (t, 3H, J = 7.2), 1.61−1.76 (m, 2H), 4.26
(m, 2H, J = 7.2), 4.34 (s, 1H), 9.54 (s, 1H); 13C NMR (75 MHz) δ =
8.2, 12.7, 14.0, 24.9, 53.4,62.1, 73.3, 172.9, 203.4.
2(R)-Hydroxy-3(R)-methyl-3-propyl-4-oxobutyric Acid Ethyl Ester
(syn-20g). Colorless oil: 1H NMR (CDCl3, 300 MHz) δ = 0.88 (t, 3H,
J = 7.3), 0.96 (s, 3H), 1.23 (t, 3H, J = 7.1), 1.18−1.34 (m, 2H), 1.55−
1.73 (m, 2H), 4.21 (m, 2H, J = 7.4), 4.38 (s, 1H), 9.58 (s, 1H); 13C
NMR (75 MHz) δ = 13.2, 14.0, 14.6, 16.9, 35.5, 53.7, 62.3, 73.0, 173.1,
203.1; HRMS (CI) m/z calcd for C10H19O4 + H+ 203.1278, found
203.1276.
(S)-2-((R)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)-
2-methylbutanal (2,3-anti-3,4-syn-29). Colorless oil: 1H NMR
(CDCl3, 300 MHz) δ = 0.84 (pst, 3H, J = 7.5), 1.08 (s, 3H), 1.34
(s, 3H), 1.40 (s, 3H), 1.60 (dq, 1H, J = 7.5, 14.3), 1.73 (dq, 1H, J = 7.5,
14.6), 3.59 (d, 1H, J = 2.2), 3.87 (dd, 1H, J = 6.9, 8.1), 4.04 (dd, 1H, J =
6.6, 8.1), 4.19 (dpst, 1H, J = 2.6, 6.7), 9.62 (s, 1H); 13C NMR (75
MHz) δ = 8.0, 14.5, 25.2, 26.1, 26.1, 52.8, 66.8, 74.2, 75.2, 109.7, 206.3.
(S)-2-((S)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)-
2-methylbutanal (2,3-syn-3,4-anti-29). Colorless oil: 1H NMR
(CDCl3, 300 MHz) δ = 0.84 (pst, 3H, J = 7.6), 1.08 (s, 3H), 1.29
(s, 3H), 1.36 (s, 3H), 1.59 (dq, 1H, J = 7.6, 14.1), 1.73 (dq, 1H, J = 7.6,
14.1), 3.84 (d, 1H, J = 4.9), 3.88−3.96 (m, 1H), 4.00−4.07 (m, 2H),
9.48 (s, 1H); 13C NMR (75 MHz) δ = 8.1, 13.3, 25.0, 26.2, 26.3, 52.6,
66.7, 75.3, 75.7, 109.2, 204.7.
(R)-2-((S)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)-
2-methylbutanal (2,3-anti-3,4-anti-29). Colorless oil: 1H NMR
(CDCl3, 300 MHz) δ = 0.85 (pst, 3H, J = 7.5), 1.05 (s, 3H), 1.32
(s, 3H), 1.38 (s, 3H), 1.65 (dq, 1H, J = 7.6, 14.1), 1.81 (dq, 1H, J = 7.5,
14.2), 3.86 (dd, 1H, J = 7.2, 8.3), 3.95 (m, 1H), 3.98 (d, 1H, J = 6.2),
4.12 (m, 1H), 9.52 (s, 1H); 13C NMR (75 MHz) δ = 8.2, 14.3, 25.5,
25.8, 26.3, 52.5, 65.9, 73.1, 75.6, 109.8, 206.4.
Compounds 30 and 33 were obtained by NaBH4 reduction of the
crude reaction products containing a mixture of acetals and aldol
adducts. 30 and 33 are inseparable mixtures of diasteromers.
1(R)-(Tetrahydro-2(S)-(hydroxymethyl)furan-2-yl)(2(S)-tetrahy-
drofuran-2-yl)methanol (30). Colorless oil: 1H NMR (CDCl3,
300 MHz) δ = 1.79−2.01 (m, 8H), 3.45 (d, 1H, J = 11.6), 3.53 (d,
1H, J = 2.1), 3.63 (d, 1H, J = 11.6), 3.78−3.91 (m, 4H), 3.98 (dpst,
1H, J = 2.1, 7.2); 13C NMR (75 MHz) δ = 25.8, 26.2, 29.2, 29.4, 64.6,
68.3, 69.2, 75.5, 77.2, 86.4; HRMS (CI) m/z calcd for C10H18O4 + H+
203.1278, found 203.1278.
1(S)-(Tetrahydro-2(R)-(hydroxymethyl)furan-2-yl)(2(S)-tetrahy-
drofuran-2-yl)methanol (33). Colorless oil: 1H NMR (CDCl3,
300 MHz) δ = 1.76−2.07 (m, 8H), 3.44 (d, 1H, J = 7.7), 3.59 (m,
1H), 3.72−3.94 (m, 6H); 13C NMR (75 MHz) δ = 25.4, 26.1, 29.4,
31.2, 64.6, 68.4, 68.9, 76.5, 78.9, 86.0.
2(R)-Hydroxy-3(S)-methyl-3-propyl-4-oxobutyric Acid Ethyl Ester
1
(anti-20g). Colorless oil: H NMR (CDCl3, 300 MHz) δ = 0.88 (t,
3H, J = 7.2), 1.06 (s, 3H), 1.29 (t, 3H, J = 7.2), 1.15−1.29 (m, 2H),
1.51−1.70 (m, 2H), 4.26 (m, 2H, J = 7.2), 4.34 (s, 1H), 9.54 (s, 1H);
13C NMR (75 MHz) δ = 13.2, 14.1, 14.6, 17.1, 34.5, 53.3, 62.1, 73.4,
172.8, 203.4.
2(R)-Hydroxy-3(R)-methyl-3-phenyl-4-oxobutyric Acid Ethyl Ester
(syn-20h). Colorless oil: 1H NMR (CDCl3, 300 MHz) δ = 1.22 (t, 3H,
J = 7.2), 1.53 (s, 3H), 4.19 (m, 2H), 4.92 (s, 1H), 7.27−7.41 (m, 5H),
9.71 (s, 1H); 13C NMR (75 MHz) δ = 14.0, 15.2, 58.0, 62.3, 73.5,
127.6, 127.8, 128.8, 136.1, 172.4, 198.9; HRMS (CI) m/z calcd for
C13H16O4 + H+ 237.1121, found 237.1117.
2(R)-Hydroxy-3(S)-methyl-3-phenyl-4-oxobutyric Acid Ethyl Ester
1
(anti-20h). Colorless oil: H NMR (CDCl3, 300 MHz) δ = 0.93 (t,
3H, J = 7.2), 1.58 (s, 3H), 3.95 (q, 2H, J = 7.2), 4.91 (s, 1H), 7.27−
7.41 (m, 5H), 9.64 (s, 1H); 13C NMR (75 MHz) δ = 13.6, 13.8, 57.7,
61.6, 73.8, 127.6, 127.9, 128.7, 135.7, 172.3, 199.4.
(2R,3R,4R)-4-Benzyloxy-2-ethyl-3-hydroxy-2-methylpentanal
1
(2,3-syn-3,4-syn-28). Colorless oil: [α] = −11.8 (c = 1, CHCl3); H
NMR (CDCl3, 300 MHz) δ = 0.84 (pst, 3H, J = 7.5), 0.98 (s, 3H),
1.31 (d, 3H, J = 6.3), 1.67 (dq, 1H, J = 7.5, 13.9), 1.79 (dq, 1H, J = 7.6,
13.9), 3.43 (d, 1H, J = 1.2), 3.70 (dq, 1H, J = 1.5, 6.3), 4.31 (d, 1H, J =
11.1), 4.53 (d, 1H, J = 11.1), 7.27−7.38 (m, 5H), 9.62 (s, 1H); 13C
NMR (75 MHz) δ = 7.9, 15.0, 16.4, 26.2, 52.4, 70.4, 72.2, 80.3, 127.9,
128.3, 128.4, 137.3, 205.7; HRMS (CI) m/z calcd for C15H22O3 + H+
251.1642, found 251.1644.
Compounds 31 and 34 were obtained as their unprotected methy-
lglycosides as follows: The intermediate and instable acetal was
subjected to reductive deprotection. The crude product was dissolved
in MeOH under hydrogen atmosphere (1 atm) and a spatula of
palladium on charcoal was added. The deprotection was completed
within 12 h at rt. The mixture was filtrated and acidic ion-exchanger
(DOWEX-50WX2) was added to the filtrate. After 12 h at rt the mixure
was filtrated (and, if needed, neutralized). The filtrate was adsorbed to
Celite and evaporated in vacuo The remaining residue was purified by
column chromatography (hexane/acetone 4/1).
(2S,3R,4R)-4-Benzyloxy-2-ethyl-3-hydroxy-2-methylpentanal
1
(2,3-anti-3,4-syn-28). Colorless oil: [α] = −20.2 (c = 1, CHCl3); H
NMR (CDCl3, 300 MHz) δ = 0.84 (pst, 3H, J = 7.6), 1.13 (s, 3H),
1.27 (d, 3H, J = 6.3), 1.49 (dq, 1H, J = 7.6, 14.2), 1.76 (dq, 1H, J = 7.6,
14.2), 3.49 (d, 1H, J = 2.3), 3.68 (dq, 1H, J = 2.3, 6.2), 4.35 (d, 1H, J =
11.2), 4.58 (d, 1H, J = 11.2), 7.27−7.37 (m, 5H), 9.60 (s, 1H); 13C
NMR (75 MHz) δ = 8.1, 15.7, 16.4, 25.8, 52.4, 70.4, 72.9, 79.3, 127.8,
128.0, 128.4, 137.5, 206.2.
(2R,3S,4R)-4-Benzyloxy-2-ethyl-3-hydroxy-2-methylpentanal
(2,3-syn-3,4-anti-28). Colorless oil: 2,3-syn-3,4-anti-28 and 2,3-anti-
3,4-anti-28 → inseparable mixture; 1H NMR (CDCl3, 300 MHz)
Both anomers of compound 31 and 34 are easily separable by
column chromatography (31: α/β 2.2:1; 34: α/β 1:3.5).
2320
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
(2R,3R,4R,5S)-Tetrahydro-2-methoxy-3,5-dimethylfuran-3,4-diol
(α-31). Colorless oil: [α] = −58.9 (c = 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz) δ = 1.27 (d, 3H, J = 6.6), 1.29 (s, 3H), 3.40 (s, 3H), 3.55
(d, 1H, J = 4.6), 4.27 (dq, 1H, J = 4.6, 6.6), 4.40 (1H, s); 13C NMR
(75 MHz) δ = 16.3, 22.3, 55.4, 77.0, 77.5, 77.7, 106.8; HRMS (CI)
m/z calcd for C7H14O4 + Na+ 185.0784, found 185.0783.
107.6, 108.9; HRMS (CI) m/z calcd for C14H26O6 + H+ 291.1802,
found 291.1802.
(2S,3R,4R,5S)-Tetrahydro-2-methoxy-3,5-dimethylfuran-3,4-diol
(β-31). Colorless oil: [α]= +104.6 (c = 1.0, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ = 1.23 (d, 3H, J = 7.1), 1.31 (s, 3H), 3.35 (s,
3H), 3.89 (d, 1H, J = 6.1), 4.23 (dq, 1H, J = 6.1, 7.1), 4.64 (s, 1H); 13C
NMR (75 MHz) δ = 15.3, 19.9, 55.2, 75.3, 76.5, 79.5, 108.1.
(2R,3R,4R,5R)-Tetrahydro-2-methoxy-3,5-dimethylfuran-3,4-diol
(β-34).12 Colorless oil: [α] = −76.8 (c = 1.0, CHCl3) 1H NMR
(CDCl3, 300 MHz) δ = 1.28 (s, 3H), 1.23 (d, 3H, J = 6.4), 3.36 (s,
3H), 3.61 (d, 1H, J = 7.0), 3.91 (psquin, 1H, J = 6.7), 4.58 (s, 1H); 13C
NMR (75 MHz) δ = 19.2, 20.5, 55.0, 79.0, 79.2, 81.0, 108.7.
(2S,3R,4R,5R)-Tetrahydro-2-methoxy-3,5-dimethylfuran-3,4-diol
(α-34). Colorless oil: [α] = −29.4 (c = 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz) δ = 1.22 (d, 3H, J = 6.6), 1.33 (s, 3H), 3.36 (s, 3H), 3.92
(d, 1H, J = 6.2), 4.24 (psquin, 1H, J = 6.4), 4.65 (s, 1H); 13C NMR
(75 MHz) δ = 15.4, 19.8, 55.2, 75.3, 76.4, 79.6, 108.0.
Compounds 32 and 35 were achieved by acidic treatment of the
crude reaction product (acetal) with ion-exchanger (DOWEX-50WX2)
in aq dioxane (5%) for 12 h. Upon completion of deprotection the
mixture was filtrated, the filtrate absorbed to Celite and evaporated in
vacuo The remaining residue was purified by column chromatography
(CH2Cl2/MeOH/H2O 13/6/1).
1(R)-((4R,5S)-4-(Hydroxymethyl)-2,2,5-trimethyl-1,3-dioxolan-4-
yl)((4R,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl)methanol (39). Color-
1
less oil: [α] = +35.0 (c = 1.0, CHCl3); H NMR (CDCl3, 500 MHz)
δ = 1.25 (d, 3H, J = 6.5), 1.33 (d, 3H, J = 6.1), 1.36 (s, 3H), 1.39 (s,
3H), 1.45 (s, 3H), 1.49 (s, 3H), 3.62 (d, 1H, J = 11.2), 3.78 (m, 1H),
3.92 (dd, 1H, J = 1.6, 7.0), 4.34−4.43 (m, 2H), 4.4.49 (q, 1H, J = 6.5);
13C NMR (125 MHz) δ = 13.9, 16.0, 24.8, 26.3, 27.0, 28.7, 61.7, 68.1,
73.9, 74.0, 74.6, 83.7, 107.6, 107.7.
Degree of Acetalization. The ratio between aldol products and
corresponding acetals 12 depends on the deployed aldehydes. A
tendency to less formation of acetals for electron-poor carbonyl com-
ponents was observed. This is demonstrated in Table 2.
(3S,4S,5R)-Tetrahydro-3-(hydroxymethyl)-2H-pyran-2,3,4,5-tetrol
or -2-(hydroxymethyl)-D-lyxose (32).27 Colorless oil: [α] = −1.4 (c =
0.05, CHCl3); 1H NMR (D2O, 300 MHz) δ = [mixture of two
anomers] 3.34−3.88 (m, 6H), 4.94 (s, 1H); 13C NMR (75 MHz) δ =
[mixture of two anomers] major anomer: 61.9, 64.1, 67.7, 71.9, 76.1,
94.9; minor anomer: 60.8, 65.5, 67.8, 72.6, 75.5, 95.3; HRMS (CI)
m/z calcd for C6H12O6 − H+ 179.0561, found 179.0555.
(3R,4R,5R)-Tetrahydro-3-(hydroxymethyl)-2H-pyran-2,3,4,5-tet-
raol (Hamamelose, 35).28 Analytical data of this compound are in full
agreement, especially with the complete NMR assignment of all anomers
of furanoic and pyranoic forms in literature.
Compounds 36 and 37 were obtained by general procedure for
NaBH4 reduction of the crude reaction mixture of homodimerization
of (R)-23 (Scheme 8).
1(S)-(4(R)-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)(4(R)-
2,2-dimethyl-1,3-dioxolan-4-yl)methanol (36).8a Colorless oil: 1H
NMR (CDCl3, 300 MHz) δ = 1.35 (s, 3H), 1.38 (s, 3H), 1.40 (s, 3H),
1.42 (s, 3H), 3.68−4.10 (m, 7H), 4.26 (dpst, 1H, J = 6.8, 3.0 Hz); 13C
NMR (CDCl3, 75 MHz) δ = 25.3, 26.3, 26.5, 27.1, 65.0, 67.3, 67.4,
71.6, 74.1, 83.9, 109.6, 110.3.
Table 2. Degree of Acetalization of Different Aldol Adducts
reaction
time
degree of acetalization
(%)
isobutyraldehyde
(equiv)
product
13a
13b
13c
13d
13e
13f
13g
13h
13i
7 d
>90
>90
>90
90
2
7 d
2
7 d
2
5 d
2
40 h
24 h
16 h
16 h
16 h
16 h
85
2
36
1.2
1.2
1.1
1.1
1.1
23
<10
<5
13j
<5
The acetals 12 contain two additional stereocenters, hence four
corresponding diastereomers exist. In solution most of these acetals are
quite labile and tend to epimerize (Table 3); thus, no analytical data for
compounds 12 is given in this paper with one exception: in the crude
product mixture of the reaction leading to product 13b crystals of one
diastereomer of the corresponding racemic hemiactal 12b were found.
rac-(S,S,S)-2-Isopropyl-5,5-dimethyl-6-phenethyl-1,3-dioxan-4-ol
(12b).
1(R)-(4(S)-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)(4R)-
2,2-dimethyl-1,3-dioxolan-4-yl)methanol (37). Colorless oil: 1H
NMR (CDCl3, 300 MHz) δ = 1.34 (s, 3H), 1.41 (s, 3H), 1.43 (s,
3H), 1.44 (s, 3H), 3.61 (d, 1H, J = 8.2), 3.69 (d, 1H, J = 11.5), 3.78 (d,
1H, J = 11.7), 3.94−4.11 (m, 4H), 4.17 (dd, 1H, J = 6.1, 8.1); 13C
NMR (75 MHz) δ = 25.2, 26.4, 26.7, 27.0, 63.2, 68.1, 68.7, 74.2, 75.1,
84.0, 109.7, 110.0.
Enantiomeric excess of acetals 12 is according to ee detected in
aldol adducts 13. This was confirmed by separated determi-
nation of the enantiomeric excess. The isolated acetals of
suitable examples were transferred into their corresponding
aldol adducts 13 by acidic treatment. The ee for these aldol
Compounds 38 and 39 were obtained by NaBH4 reduction of the
crude reaction mixture of homodimerization of 24 and 25 (Scheme 9).
1(R)-((4R,5S)-4-(Hydroxymethyl)-2,2,5-trimethyl-1,3-dioxolan-4-
yl)((4S,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl)methanol (38). Color-
less oil: [α] = −11.2 (c = 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz) δ
= 1.37−1.44 (m, 18H), 3.55−3.62 (m, 3H), 3.78 (d, 1H, J = 12.3),
4.16 (dq, 1H, J = 1.9, 5.8), 4.33 (q, 1H, J = 6.5); 13C NMR (125 MHz)
δ = 13.6, 19.5, 26.4, 26.7, 27.3, 28.5, 61.5, 72.6, 74.7, 77.6, 80.6, 84.6,
products was separately determined.
General Procedure for the Formation of Lactone Derivatives of
Compounds 20a−h. In a typical experiment 3 mmol of the cor-
responding aldehydes 20a−h were solved in Et2O and 40 mg NaBH4
2321
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
(dd, 1H, J = 9.3, 10.1), 4.19 (d, 1H, J = 10.1), 4.25 (dd, 1H, J = 7.5,
9.3), 7.16−7.35 (m, 5H); 13C NMR (75 MHz) δ = 36.2, 45.0, 69.2,
71.9, 126.9, 128.7, 128.8, 137.3, 177.6.
Table 3. Influence of Solvent in Histidine-Catalyzed Aldol
Addition: Yields and Selectivity of a Model Reaction with
Different Solvents (Isobutyraldehyde and Ethyl Glyoxylate)
a
3(R)-Hydroxy-4(S)-isopropyldihydrofuran-2-one (:actone of syn-
20c). Colorless oil: 1H NMR (CDCl3, 300 MHz) δ = 0.86 (d, 3H, J =
6.8), 0.99 (d, 3H, J = 6.8), 2.08 (psok, 1H, J = 6.9), 2.27 (psqin, 1H,
J = 6.9), 4.22 (dd, 1H, J = 6.3, 9.2), 4.33 (dd, 1H, J = 7.0, 9.2), 4.38 (d,
1H, J = 7.0)M; 13C NMR (75 MHz) δ = 18.8, 20.9, 24.7, 46.6, 68.3,
entry
solvent
yield (%) ee (%) reaction time
b
1
2
DMSO
7
10
12
10
12
22
31
5
<10
<10
30
46
0
3 d
b
DMF
3 d
b
3
THF
3 d
+
69.6, 178.3; HRMS (CI) m/z calcd for C7H12O3 + NH4 162.1125,
b
4
4-methyl-1,3-dioxolan-2-one
2 d
found 162.1122.
b
5
1-methylpyrrolidin-2-one
3 d
3(R)-Hydroxy-4(R)-isopropyldihydrofuran-2-one (Lactone of anti-
20c). Colorless oil: 1H NMR (CDCl3, 300 MHz) δ = 0.92 (d, 3H, J =
6.7), 1.08 (d, 3H, J = 6.7), 1.77 (dpssep, 1H, J = 5.0, 6.7), 2.16−2.32
(m, 1H), 3.88 (dd, 1H, J = 9.2, 10.6), 4.18 (d, 1H, J = 10.4), 4.38 (dd,
1H, J = 6.9, 9.2); 13C NMR (75 MHz) δ = 10.0, 20.5, 30.5, 49.7, 68.8,
71.5, 178.5.
6
acetonitrile
41
28
<20
37
36
65
67
61
60
77
60
65
5 d
7
trichloracetonitrile
propyloxyethanol
hexafluoro-2-propanol
2-propanol
3 d
8
2 d
9
10
9
2 d
10
11
12
13
14
15
16
17
2 d
3(R)-Hydroxy-4,4-dimethyldihydrofuran-2-one (Lactone of
13j).30 Colorless oil: 1H NMR (CDCl3, 300 MHz) δ = 1.08 (s,
3H), 1.23 (s, 3H), 3.94 (d, 1H, J = 8.9), 4.02 (d, 1H, J = 8.9), 4.11 (s,
1H); 13C NMR (75 MHz) δ = 18.8, 22.9, 40.9, 75.7, 76.4, 177.6;
HRMS (CI) m/z calcd for C6H10O3 + Na+ 153.0522, found 153.0522
3(R)-Hydroxy-4,4-diethyldihydrofuran-2-one (Lactone of 20d).31
Colorless oil: [α] = −13.2 (c = 1, CHCl3) (59% ee); 1H NMR
(CDCl3, 300 MHz) δ = 0.86 (t, 3H, J = 7.5), 0.93 (t, 3H, J = 7.6),
1.37−1.64 (m, 4H), 3.85 (d, 1H, J = 9.3), 4.10 (d, 1H, J = 9.3), 4.22 (s,
1H); 13C NMR (75 MHz) δ = 8.0, 8.3, 21.5, 27.9, 46.3, 73.1, 74.4,
methanol
25
34
24
52
74
23
65
20 h
24 h
24 h
20 h
20 h
20 h
16 h
1,3-propanediol
1,4-butanediol
glycerol
glycol
water
c
water
a
Reaction conditions: 10 mol % of histidine in 1.0 mL of solvent,
5 mmol of isobutyraldehyde and ethyl glyoxylate (50% in toluene).
Reaction does not proceed unless 0.2 mL water is added. 10 mol %
b
c
+
178.8; HRMS (CI) m/z calcd for C8H14O3 + NH4 176.1281, found
176.1282.
histidine in 0.2 mL water, 5 mmol of isobutyraldehyde, and ethyl
glyoxylate (50% in toluene).
4(R)-Hydroxy-2-oxaspiro[4.5]decan-3-one (Lactone of 20e).31
Colorless oil: [α] = +19.4 (c = 1, CHCl3) (71% ee); 1H NMR
(CDCl3, 300 MHz) δ = 1.14−1.78 (m, 10H), 3.87 (d, 1H, J = 9.2),
4.07 (s, 1H), 4.33 (d, 1H, J = 9.2); 13C NMR (75 MHz) δ = 21.7, 22.9,
25.3, 25.8, 33.6, 44.0, 73.7, 75.6, 178.0; HRMS (CI) m/z calcd for
C9H14O3 170.09429, found 170.09429.
3(R)-Hydroxy-4(S)-ethyl-4-methyldihydrofuran-2-one (Lactone of
syn-20f).32 Colorless oil: 1H NMR (CDCl3, 300 MHz) δ = 0.97
(t, 3H, J = 7.6), 1.07 (s, 3H), 1.38−1.60 (m, 2H), 3.96 (d, 1H, J = 9.2),
4.01 (d, 1H, J = 9.1), 4.17 (s, 1H); 13C NMR (75 MHz) δ = 8.3, 15.9,
24.1, 44.1, 75.0, 75.6, 178.0; HRMS (CI) m/z calcd for C7H12O3 + H+
145.0859, found 145.0859.
was added. The reaction mixture was stirred vigorously at room
temperature and monitored by TLC. After completion of the reaction
(10 min to 2 h), the mixture was slowly quenched with saturated
aqueous NH4Cl solution, dried (MgSO4) and filtrated. The filtrate was
acidified with toluenesulfonic acid, stirred at room temperature, and
monitored by TLC. After completion of the reaction (1−12 h), the
mixture was neutralized, absorbed to Celite, evaporated in vacuo and
the remaining residue was purified by column chromatography
(hexane/acetone or pentane/diethylether).
No remarkable change in diastereomeric ratio was observed (with
the exception of 20h). Yields of transformations are given in Table 4.
3(R)-Hydroxy-4(S)-methyldihydrofuran-2-one (Lactone of syn-
3(R)-Hydroxy-4(R)-ethyl-4-methyldihydrofuran-2-one (Lactone
of anti-20f).32 Colorless oil: H NMR (CDCl3, 300 MHz) δ = 0.91
1
20a).29 Colorless oil: H NMR (CDCl3, 300 MHz) δ = 1.21 (d, 3H,
1
(t, 3H, J = 7.5), 1.18 (s, 3H), 1.48−1.72 (m, 2H), 3.86 (d, 1H, J = 9.1),
4.15 (s, 1H), 4.19 (d, 1H, J = 9.2); 13C NMR (75 MHz) δ = 8.6, 20.9,
30.1, 43.5, 73.7, 75.8, 178.0.
J = 6.6), 2.51 (m, 1H), 3.78 (dd, 1H, J = 9.1, 10.6), 4.03 (d, 1H, J =
10.5), 4.39 (dd, 1H, J = 7.9, 9.0); 13C NMR (75 MHz) δ = 14.2, 38.7,
70.7, 73.6, 178.0; HRMS (CI) m/z calcd for C5H8O3 + Na+ 139.0366,
found 139.0360.
3(R)-Hydroxy-4(S)-methyl-4-propyldihydrofuran-2-one (Lactone
1
of syn-20g). Colorless oil: H NMR (CDCl3, 300 MHz) δ = 0.92
(t, 3H, J = 7.0), 1.06 (s, 3H), 1.26−1.61 (m, 4H), 3.95 (d, 1H, J = 9.0),
3.99 (d, 1H, J = 8.9), 4.18 (s, 1H); 13C NMR (75 MHz) δ = 14.6, 16.4,
17.5, 39.8, 43.9, 75.2, 75.8, 178.2; HRMS (CI) m/z calcd for for
3(R)-Hydroxy-4(R)-methyldihydrofuran-2-one (lactone of anti-
20a).29 Colorless oil: H NMR (CDCl3, 300 MHz) δ = 1.09 (d, 3H,
1
J = 7.1), 2.73 (dddq, 1H, J = 2.0, 5.2, 7.1, 7.3), 4.03 (dd, 1H, J = 2.0,
9.3), 4.33 (dd, 1H, J = 5.3, 9.3), 4.51 (d, 1H, J = 7.3); 13C NMR (75
MHz) δ = 11.5, 34.9, 69.9, 71.8, 177.8.
+
C8H14O3 + NH4 176.1281, found: 176.1278.
3(R)-Hydroxy-4(R)-methyl-4-propyldihydrofuran-2-one (Lactone
of anti-20g). Colorless oil: 1H NMR (CDCl3, 300 MHz) δ = 0.91 (t,
3H, J = 6.9), 1.17 (s, 3H), 1.20−1.52 (m, 4H), 3.85 (d, 1H, J = 9.2),
4.14 (s, 1H), 4.18 (d, 1H, J = 9.2); 13C NMR (75 MHz) δ = 14.6, 17.2,
21.4, 33.8, 43.3, 74.2, 75.8, 178.3.
3(R)-Hydroxy-4(S)-benzyldihydrofuran-2-one (Lactone of syn-
1
20b). Colorless oil: H NMR (CDCl3, 300 MHz) δ = 2.41 (dd, 1H,
J = 11.1, 14.1), 2.80−2.92 (m, 1H), 3.15 (dd, 1H, J = 4.6, 14.1), 4.14
(m, 2H, J = 5.6, 9.6), 4.57 (d, 1H, J = 7.1), 7.15−7.33 (m, 5H); 13C
NMR (75 MHz) δ = 31.1, 42.1, 68.7, 69.6, 126.6, 128.7, 129.0, 138.5,
3(R)-Hydroxy-4(S)-methyl-4-phenyldihydrofuran-2-one (Lactone
1
+
of syn-20h). Colorless oil: H NMR (CDCl3, 300 MHz) δ = 1.42 (s,
177.5; HRMS (CI) m/z calcd for for C11H12O3 + NH4 210.1125,
3H), 4.33 (d, 1H, J = 8.9), 4.44 (d, 1H, J = 8.9), 4.70 (s, 1H), 7.27−
7.40 (m, 5H); 13C NMR (75 MHz) δ = 21.1, 48.0, 74.2, 74.7, 125.2,
127.3, 128.9, 143.1, 177.0; HRMS (CI) m/z calcd for for C11H12O3 +
H+ 193.0859, found 193.0859.
found 210.1122.
3(R)-Hydroxy-4(R)-benzyldihydrofuran-2-one (Lactone of anti-
20b). Colorless oil: H NMR (CDCl3, 300 MHz) δ = 2.72 (dd, 1H,
J = 9.3, 13.2), 2.73−2.82 (m, 1H), 3.18 (dd, 1H, J = 3.7, 13.2), 3.90
Table 4. Yields of γ-Lactone Synthesis
1
entry
1
2
3
4
5
6
7
8
9
starting compd
yield (%)
20a
50
20b
79
20c
59
20d
92
20e
90
20f
96
20g
93
20h
13j
95
a
60
a
Cyclization of anti-20h does not take place under these reaction conditions. Thus, the product was achieved in lower yield but diastereopure.
2322
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
For single-crystal X-ray structure analysis 3(S)-hydroxy-4(R)-
methyl-4-phenyldihydrofuran-2-one was synthesized by using catalytic
amounts of D-histidine.
(R)-Mosher ester of 13b: 1H NMR (CDCl3, 500 MHz) δ = 0.89 (s,
3H), 0.90 (s, 3H), 1.82−1.91 (m, 1H), 1.99−2.06 (m, 1H), 2.56 (pst,
2H, J = 8.3), 3.61 (m, 3H), 3.75 (m, 2H), 3.85 (m, 2H), 4.48 (s, 1H),
5.31 (dd, 1H, J = 2.0, 10.0), 7.11−7.66 (m, 10H).
Determination of Absolute Configuration and Enantiomeric
Excess. The determination of the absolute configuration and the
enantiomeric excess of products 20, 13a−m, 31, and 34 was performed
using the Mosher ester technique. In some cases, derivatives of the
products had to be used, usually since chemical shifts of the diastereomeric
MTPA esters were too similar for a definite determination.
(S)-Mosher ester of 13c: 1H NMR (CDCl3, 500 MHz) δ = 0.81 (d,
3H, J = 6.3), 0.89 (s, 3H), 0.93 (s, 3H), 0.94 (d, 3H, J = 6.7), 1.13
(ddd, 1H, J = 1.8, 10.4, 13.6), 1.52 (m, 1H), 1.86 (m, 1H), 3.52 (m,
3H), 3.74−3.99 (m, 4H), 4.51 (s, 1H), 5.30 (dd, 1H, J = 1.6, 10.6),
7.31−7.71 (m, 5H).
Determination of Enantiomeric Excess. The aldol adducts were
converted into the corresponding (S)-MTPA esters as follows:
A 1.5 mL (0.01 mmol) portion of a CH2Cl2 solution of (R)-MTPA-
Cl (0.015 mol/L) was added to a solution of the corresponding aldol
adduct (0.01 mmol) and catalytic amounts of DMAP in 1.0 mL of
abs CH2Cl2. After 10 h at rt, the reaction mixture was diluted with
diethyle ther and extracted with aq NH4Cl solution. The organic layer
was separated, dried (Na2SO4), and filtrated, and the filtrate was
(R)-Mosher ester of 13c: 1H NMR (CDCl3, 500 MHz) δ = 0.87 (s,
3H), 0.87 (s, 3H), 0.90 (d, 3H, J = 6.4), 0.94 (d, 3H, J = 6.3), 1.13
(ddd, 1H, J = 1.8, 10.1, 13.6), 1.58 (m, 1H), 1.86 (m, 1H), 3.57 (m,
3H), 3.74−4.01 (m, 4H), 4.44 (s, 1H), 5.31 (dd, 1H, J = 1.5, 10.3),
7.34−7.73 (m, 5H).
1
evaporated in vacuo The remaining crude residue was used for H
NMR experiments.
The enantiomeric excess of the reactants was determined by integra-
1
tion of corresponding signals in the H NMR spectra.
Proof of Absolute Configuration. The calculated differences of
1
chemical shifts in the H NMR spectra of the corresponding Mosher
esters indicate the assigned configuration of aldol products.33
The indicated chemical shift differences (Δδ(S−R), ppb)
established the absolute stereochemistry at the C3 for aldol adducts
(stereogenic center formed by aldol addition).
(S)-Mosher ester of 13d: 1H NMR (CDCl3, 500 MHz) δ = 0.90 (s,
3H), 0.93 (s, 3H), 2.48 (dd, 1H, J = 10.6, 14.6), 2.78 (dd, 1H, J = 2.4,
14.6), 3.53 (m, 3H), 3.73 (m, 2H), 3.74−3.94 (m, 4H), 4.55 (s, 1H),
5.41 (dd, 1H, J = 2.4, 10.5), 7.23−7.71 (m, 10H).
(R)-Mosher ester of 13d: 1H NMR (CDCl3, 500 MHz) δ = 0.81 (s,
3H), 0.82 (s, 3H), 2.50 (dd, 1H, J = 10.6, 14.6), 2.81 (dd, 1H, J = 2.3,
14.6), 3.63 (m, 3H), 3.77 (m, 2H), 3.78−3.95 (m, 4H), 4.36 (s, 1H),
5.39 (dd, 1H, J = 2.3, 10.5), 7.23−7.71 (m, 10H).
For compounds 30 and 39, the absolute configuration was also
determined by single-crystal X-ray analysis of derivatives.
(R)-4-tert-Butyl-dimethylsilyloxy-2,2-dimethylbutane-1,3-diol was
obtained by the general procedure for NaBH4 reduction of the
crude reaction product 13e containing a mixture of acetals and aldol
adducts: 1H NMR (CDCl3, 300 MHz) δ = 0.08 (m, 6H), 0.89 (s, 3H),
0.90 (s, 9H), 0.91 (s, 3H), 3.45 (m, 2H), 3.56 (m, 2H), 3.70 (d, 1H,
J = 6.4); 13C NMR (75 MHz) δ = −5.4, −5.4, 18.2, 19.3, 22.4, 25.8,
37.3, 63.4, 71.7, 78.4. In this case, the Mosher ester can be used for
determination of the enantiomeric excess only. It is assumed that the
absolute configuration is in analogy to other reaction products.
Compounds 13a−k (Scheme 1). (S)-Mosher ester of 13a: 1H
NMR (CDCl3, 500 MHz) δ = 0.86 (t, 3H, J = 7.3), 0.89 (s,
3H), 0.90 (s, 3H), 1.15−1.28 (m, 2H), 1.51−1.61 (m, 2H),
3.53 (m, 3H), 3.78−3.81 (m, 2H), 3.89−3.92 (m, 2H), 4.52 (s,
1H), 5.24 (dd, 1H, J = 3.4, 9.2), 7.38−7.41 (m, 3H), 7.58−7.59
(m, 2H).
(R)-Mosher ester of 13a: 1H NMR (CDCl3, 500 MHz) δ = 0.88 (s,
3H), 0.88 (s, 3H), 0.90 (t, 3H, J = 7.3), 1.25−1.37 (m, 2H), 1.52−1.67
(m, 2H), 3.57 (m, 3H), 3.72−3.76 (m, 2H), 3.84−3.90 (m, 2H),
4.44 (s, 1H), 5.23 (dd, 1H, J = 2.4, 9.6), 7.37−7.41 (m, 3H), 7.58−
7.61 (m, 2H).
1
(S)-Mosher ester: H NMR (CDCl3, 500 MHz) δ = 0.04 (s, 3H),
0.05 (s, 3H), 0.89 (s, 9H), 0.91 (s, 3H), 0.94 (s, 3H), 3.42 (dd, 1H, J =
3.1, 8.7), 3.49 (dd, 1H, J = 8.7, 9.8), 3.54 (m, 3H), 3.62 (dd, 1H, J = 3.2,
9.8), 4.05 (d, 1H, J = 10.7), 4.33 (d, 1H, J = 10.7), 7.39−7.56 (m, 5H).
1
(R)-Mosher ester: H NMR (CDCl3, 500 MHz) δ = 0.05 (s, 3H),
0.05 (s, 3H), 0.89 (s, 9H), 0.92 (m, 6H), 3.48 (m, 2H), 3.54 (m, 3H),
3.65 (d, 1H, J = 6.5), 4.12 (d, 1H, J = 10.7), 4.24 (d, 1H, J = 10.7),
7.39−7.56 (m, 5H).
Compound 13f was transferred into its corresponding dimethylacetal
by acidic treatment of the crude reaction product with ion-exchanger
(S)-Mosher ester of 13b: 1H NMR (CDCl3, 500 MHz) δ = 0.89 (s,
3H), 0.91 (s, 3H), 1.77−1.85 (m, 1H), 1.93−2.00 (m, 1H), 2.50 (pst,
2H, J = 8.4), 3.58 (m, 3H), 3.78 (m, 2H), 3.88 (m, 2H), 4.51 (s, 1H),
5.31 (dd, 1H, J = 2.2, 10.0), 7.08−7.65 (m, 10H).
2323
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
(DOWEX-50WX2) in methanol for 12 h. Upon completion of
deprotection the mixture was filtrated and the filtrate absorbed to Celite
and evaporated in vacuo The remaining residue was purified by column
chromatography (hexane/acetone 9/1).
(d, 1H, J = 6.8), 5.42 (d, 1H, J = 6.8), 7.44−7.39 (m, 3H), 7.54−7.59
(m, 2H), 9.44 (s, 1H).
(R)-Mosher ester of 13i: 1H NMR (CDCl3, 300 MHz) δ = 0.97 (s,
3H), 1.02 (s, 3H), 3.32 (s, 3H), 3.36 (s, 3H), 3.59 (m, 3H), 4.40 (d,
1H, J = 6.8), 5.46 (d, 1H, J = 6.8), 7.44−7.39 (m, 3H), 7.54−7.59 (m,
2H), 9.41 (s, 1H).
1
(S)-Mosher ester of 13f (dimethyl acetal): H NMR (CDCl3, 300
MHz) δ = 0.95 (s, 3H), 0.98 (s, 3H), 3.44 (m, 3H), 3.44 (s, 3H), 3.45
(s, 3H), 3.60 (dd, 1H, J = 8.5, 11.1), 3.73 (dd, 1H, J = 2.8, 11.1), 3.91
(s, 1H), 4.40 (d, 1H, J = 11.9), 4.53 (d, 1H, J = 11.9), 5.52 (dd, 1H, J =
2.8, 8.5), 7.22−7.70 (m, 10H).
(S)-Mosher ester of 13j: 1H NMR (CDCl3, 300 MHz) δ = 1.14 (s,
3H), 1.17 (s, 3H), 1.27 (t, 3H, J = 7.2), 3.51 (q, 3H, J = 1.0), 4.20−
4.29 (m, 2H), 5.33 (s, 1H), 7.38−7.66 (m, 5H), 9.51 (s, 1H).
(R)-Mosher ester of 13j: 1H NMR (CDCl3, 300 MHz) δ = 1.09 (s,
3H), 1.11 (s, 3H), 1.28 (t, 3H, J = 7.2), 3.62 (q, 3H, J = 1.2), 4.20−
4.29 (m, 2H), 5.31 (s, 1H), 7.38−7.66 (m, 5H), 9.58 (s, 1H).
1
(R)-Mosher ester of 13f (dimethyl acetal): H NMR (CDCl3, 300
MHz) δ = 0.90 (s, 3H), 0.91 (s, 3H), 3.40 (s, 3H), 3.43 (s, 3H), 3.56
(m, 3H), 3.65 (dd, 1H, J = 8.5, 11.1), 3.80 (dd, 1H, J = 2.7, 11.1), 3.83
(s, 1H), 4.46 (d, 1H, J = 11.7), 4.60 (d, 1H, J = 11.7), 5.51 (dd, 1H, J =
2.7, 8.5), 7.15−7.70 (m, 10H).
(S)-Mosher ester of (R)-pantolactone: 1H NMR (CDCl3, 300
MHz) δ = 1.26 (s, 6H), 3.54 (q, 3H, J = 1.0), 4.09 (s, 2H), 5.55 (s,
1H), 7.32−7.63 (m, 5H).
(R)-Mosher ester of (R)-pantolactone: 1H NMR (CDCl3, 300
MHz) δ = 0.95 (s, 3H), 1.17 (s, 3H), 3.63 (q, 3H, J = 1.1), 4.05 (s,
2H), 5.59 (s, 1H), 7.40−7.80 (m, 5H).
Compounds 20a−h (Scheme 2). Absolute configuration and
enantiomeric excess for compounds 20a−c was determined using the
corresponding lactone derivatives to avoid undesired elimination
reactions.
(S)-Mosher ester of 13g: 1H NMR (CDCl3, 500 MHz) δ = 1.24 (s,
3H), 1.26 (s, 3H), 3.37 (m, 3H), 3.74 (dd, 1H, J = 2.3, 14.6), 4.07 (dd,
1H, J = 9.8, 14.6), 5.78 (dd, 1H, J = 2.4, 9.8), 7.16−7.32 (m, 5H), 7.74
(m, 2H), 7.80 (m, 2H), 9.55 (s, 1H).
(R)-Mosher ester of 13g: 1H NMR (CDCl3, 500 MHz) δ = 1.16 (s,
3H), 1.17 (s, 3H), 3.50 (m, 3H), 3.76 (dd, 1H, J = 2.3, 14.7), 4.11 (dd,
1H, J = 9.6, 14.7), 5.73 (dd, 1H, J = 2.1, 9.6), 7.27−7.41 (m, 5H), 7.72
(m, 2H), 7.84 (m, 2H), 9.44 (s, 1H).
Compound 13h was transferred into its corresponding dimethyl
acetal by acidic treatment of the crude reaction product with ion-
exchanger (DOWEX-50WX2) in methanol for 12 h. Upon completion
of deprotection, the mixture was filtrated and the filtrate absorbed to
Celite and evaporated in vacuo The remaining residue was purified by
column chromatography (hexane/acetone 9/1).
1
(S)-Mosher ester of lactone of syn-20a: H NMR (CDCl3, 300
MHz) δ = 1.24 (d, 3H, J = 6.7), 2.81−2.98 (m, 1H), 3.56 (q, 3H, J =
1.5), 3.92 (dd, 1H, J = 9.2, 10.4), 4.51 (dd, 1H, J = 8.2, 9.0), 5.35 (d,
1H, J = 10.6), 7.37−7.64 (m, 5H).
(R)-Mosher ester: 1H NMR (CDCl3, 300 MHz) δ = 1.16 (d, 3H, J =
6.6), 2.63−2.75 (m, 1H), 3.64 (q, 3H, J = 1.2), 3.91 (dd, 1H, J = 9.2,
10.4), 4.46 (dd, 1H, J = 8.0, 9.0), 5.48 (d, 1H, J = 10.7), 7.36−7.65 (m,
5H).
(S)-Mosher ester of 13h (dimethyl acetal): 1H NMR (CDCl3, 300
MHz) δ = 0.94 (s, 3H), 0.97 (s, 3H), 3.51 (m, 3H), 3.52 (s, 3H), 3.53
(s, 3H), 3.59 (dd, 1H, J = 9.8, 12.3), 3.88 (s, 1H), 3.93 (dd, 1H, J =
2.3, 12.3), 5.46 (dd, 1H, J = 2.3, 9.8), 7.38−7.71 (m, 5H).
1
(S)-Mosher ester of lactone of anti-20a: H NMR (CDCl3, 300
(R)-Mosher ester of 13h (dimethyl acetal): 1H NMR (CDCl3, 300
MHz) δ = 0.87 (s, 3H), 0.87 (s, 3H), 3.40 (s, 3H), 3.41 (s, 3H), 3.62
(dd, 1H, J = 9.4, 12.3), 3.63 (m, 3H), 3.77 (s, 1H), 3.96 (dd, 1H, J =
2.1, 12.3), 5.44 (dd, 1H, J = 2.1, 9.4), 7.39−7.71 (m, 5H).
MHz) δ = 0.93 (d, 3H, J = 7.1), 2.85−2.95 (m, 1H), 3.63 (q, 3H, J =
1.3), 4.06 (dd, 1H, J = 2.5, 9.3), 4.43 (dd, 1H, J = 5.0, 9.3), 5.81 (d,
1H, J = 7.5), 7.39−7.63 (m, 5H).
(R)-Mosher ester: 1H NMR (CDCl3, 300 MHz) δ = 1.13 (d, 3H, J =
7.1), 2.64−2.75 (m, 1H), 3.45 (q, 3H, J = 1.0), 4.11 (dd, 1H, J = 2.6, 9.3),
4.43 (dd, 1H, J = 5.0, 9.3), 5.76 (d, 1H, J = 7.5), 7.39−7.63 (m, 5H).
1
1
(S)-Mosher ester of 13i: H NMR (CDCl3, 300 MHz) δ = 1.04
(S)-Mosher ester of lactone of syn-20b: H NMR (CDCl3, 300
(s, 3H), 1.10 (s, 3H), 3.27 (s, 3H), 3.33 (s, 3H), 3.51 (m, 3H), 4.32
MHz) δ = 2.50 (dd, 1H, J = 11.4, 14.3), 2.95 (dd, 1H, J = 4.4, 14.1),
2324
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
3.02−3.12 (m, 1H), 3.55 (q, 3H, J = 0.9), 4.18 (dd, 1H, J = 3.0, 12.4),
4.21 (dd, 1H, J = 5.4, 11.9), 5.88 (d, 1H, J = 7.4), 7.03−7.68 (m, 10H).
1
(R)-Mosher ester: H NMR (CDCl3, 300 MHz) δ = 2.31 (dd, 1H,
J = 11.8, 14.2), 2.66 (dd, 1H, J = 4.2, 14.2), 2.94−3.01 (m, 1H), 3.67
(q, 3H, J = 1.1), 4.15 (dd, 1H, J = 2.9, 9.8), 4.21 (dd, 1H, J = 5.2, 9.6),
5.93 (d, 1H, J = 7.4), 7.03−7.70 (m, 10H).
1
(S)-Mosher ester of lactone of 20e: H NMR (CDCl3, 300 MHz)
δ = 1.14−1.68 (m, 8H), 1.26 (t, 3H, J = 7.1), 1.93 (m, 2H), 3.51 (q,
3H, J = 1.0), 4.23 (q, 2H, J = 7.1), 5.13 (s, 1H), 7.38−7.67 (m, 5H),
9.59 (s, 1H).
(R)-Mosher ester: 1H NMR (CDCl3, 300 MHz) δ = 1.14−1.68 (m,
8H), 1.28 (t, 3H, J = 7.1), 1.83 (m, 2H), 3.62 (q, 3H, J = 1.2), 4.26 (q,
2H, J = 7.1), 5.10 (s, 1H), 7.38−7.67 (m, 5H), 9.55 (s, 1H).
(S)-Mosher ester of lactone of anti-20b: 1H NMR (CDCl3,
300 MHz) δ = 2.81 (dd, 1H, J = 8.6, 13.9), 3.01 (dd, 1H, J = 5.6,
13.7), 3.01−3.11 (m, 1H), 3.44 (q, 3H, J = 0.9), 4.03 (pst, 1H, J =
9.6), 4.39 (dd, 1H, J = 8.2, 9.2), 5.53 (d, 1H, J = 10.2), 7.03−7.68 (m,
10H).
1
(R)-Mosher ester: H NMR (CDCl3, 300 MHz) δ = 2.72 (dd, 1H,
J = 10.2, 15.0), 2.95 (dd, 1H, J = 4.7, 15.0), 2.96−3.04 (m, 1H), 3.61
(q, 3H, J = 1.1), 4.15 (pst, 1H, J = 9.4), 4.31 (dd, 1H, J = 7.6, 9.2), 5.64
(d, 1H, J = 10.2), 7.03−7.70 (m, 10H).
1
(S)-Mosher ester of lactone of syn-20f: H NMR (CDCl3, 300
MHz) δ = 0.84 (t, 3H, J = 7.5), 1.10 (s, 3H), 1.25 (t, 3H, J = 7.2),
1.57−1.74 (m, 2H), 3.52 (q, 3H, J = 0.9), 4.22 (q, 2H, J = 7.2), 5.45 (s,
1H), 7.38−7.58 (m, 5H), 9.61 (s, 1H).
1
(S)-Mosher ester of lactone of syn-20c: H NMR (CDCl3, 300
(R)-Mosher ester: 1H NMR (CDCl3, 300 MHz) δ = 0.76 (t, 3H, J =
7.6), 1.05 (s, 3H), 1.26 (t, 3H, J = 7.1), 1.42−1.63 (m, 2H), 3.65 (q,
3H, J = 1.1), 4.25 (q, 2H, J = 7.2), 5.43 (s, 1H), 7.40−7.67 (m, 5H),
9.57 (s, 1H).
MHz) δ = 0.88 (d, 3H, J = 6.9), 0.96 (d, 3H, J = 6.7), 1.86 (psokt, 1H,
J = 6.8), 2.53 (m, 1H), 3.52 (q, 3H, J = 1.0), 4.23 (dd, 1H, J = 6.2,
9.4), 4.24 (dd, 1H, J = 7.0, 9.3), 5.73 (d, 1H, J = 7.6), 7.40−7.65 (m,
5H).
(R)-Mosher ester: 1H NMR (CDCl3, 300 MHz) δ = 0.77 (d, 3H, J =
6.8), 0.88 (d, 3H, J = 6.7), 1.61 (psokt, 1H, J = 6.8), 2.48 (m, 1H),
3.59 (q, 3H, J = 1.2), 4.19 (dd, 1H, J = 5.9, 9.4), 4.40 (dd, 1H, J = 7.0,
9.4), 5.81 (d, 1H, J = 7.5), 7.40−7.65 (m, 5H).
1
(S)-Mosher ester of lactone of anti-20f: H NMR (CDCl3, 300
MHz) δ = 0.89 (t, 3H, J = 7.5), 1.15 (s, 3H), 1.28 (t, 3H, J = 7.1),
1.60−1.72 (m, 2H), 3.51 (q, 3H, J = 1.1), 4.25 (q, 2H, J = 7.2), 5.33 (s,
1H), 7.38−7.58 (m, 5H), 9.45 (s, 1H).
1
(S)-Mosher ester of lactone of anti-20c: H NMR (CDCl3, 300
MHz) δ = 0.94 (d, 3H, J = 6.4), 0.96 (d, 3H, J = 6.7), 1.81 (m,
1H), 2.61 (m, 1H), 3.55 (q, 3H, J = 1.0), 4.01 (dd, 1H, J = 9.8,
9.6), 4.54 (dd, 1H, J = 8.9, 9.2), 5.42 (d, 1H, J = 10.1), 7.40−7.65 (m,
5H).
(R)-Mosher ester: 1H NMR (CDCl3, 300 MHz) δ = 0.84 (t, 3H, J =
7.6), 1.11 (s, 3H), 1.30 (t, 3H, J = 7.1), 1.54−1.72 (m, 2H), 3.61 (q,
3H, J = 1.2), 4.24 (q, 2H, J = 7.1), 5.29 (s, 1H), 7.40−7.67 (m, 5H),
9.42 (s, 1H).
(R)-Mosher ester: 1H NMR (CDCl3, 300 MHz) δ = 0.81 (d, 3H, J =
6.9), 0.87 (d, 3H, J = 6.7), 1.75 (m, 1H), 2.50 (m, 1H), 3.64 (q, 3H,
J = 1.3), 3.99 (dd, 1H, J = 9.7, 9.4), 4.48 (dd, 1H, J = 8.9, 9.1), 5.63 (d,
1H, J = 10.3), 7.40−7.65 (m, 5H).
1
(S)-Mosher ester of lactone of syn-20g: H NMR (CDCl3, 300
(S)-Mosher ester of lactone of 20d: 1H NMR (CDCl3, 300 MHz)
δ = 0.83 (t, 3H, J = 7.5), 0.85 (t, 3H, J = 7.5), 1.26 (t, 3H, J = 7.2),
1.61−1.82 (m, 4H), 3.52 (q, 3H, J = 1.1), 4.23 (q, 2H, J = 7.2), 5.41 (s,
1H), 7.40−7.65 (m, 5H), 9.53 (s, 1H).
MHz) δ = 0.85 (t, 3H, J = 7.2), 1.10 (s, 3H), 1.18−1.53 (m, 4H), 1.25
(t, 3H, J = 7.1), 3.52 (q, 3H, J = 1.1), 4.22 (q, 2H, J = 7.1), 5.46 (s,
1H), 7.40−7.67 (m, 5H), 9.62 (s, 1H).
(R)-Mosher ester: 1H NMR (CDCl3, 300 MHz) δ = 0.74 (t, 3H, J =
7.1), 1.05 (s, 3H), 1.12−1.53 (m, 4H), 1.26 (t, 3H, J = 7.2), 3.67 (q,
3H, J = 1.2), 4.25 (q, 2H, J = 7.2), 5.43 (s, 1H), 7.39−7.67 (m, 5H),
9.59 (s, 1H).
(R)-Mosher ester: 1H NMR (CDCl3, 300 MHz) δ = 0.77 (t, 3H, J =
7.5), 0.80 (t, 3H, J = 7.5), 1.28 (t, 3H, J = 7.1), 1.47−1.67 (m, 4H),
3.63 (q, 3H, J = 1.3), 4.27 (q, 2H, J = 7.2), 5.38 (s, 1H), 7.40−7.65 (m,
5H), 9.52 (s, 1H).
2325
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
1
(S)-Mosher ester of syn-13k: H NMR (CDCl3, 300 MHz) δ =
1.04 (s, 3H), 1.15 (s, 3H), 1.68−2.00 (m, 4H), 3.53 (q, 3H, J = 1.3),
3.60−3.72 (m, 2H), 4.15 (dpst, 1H, J = 3.5, 7.5), 5.25 (d, 1H, J = 3.5),
7.39−7.64 (m, 5H), 9.59 (s, 1H).
1
(S)-Mosher ester of lactone of anti-20g: H NMR (CDCl3, 300
MHz) δ = 0.84 (t, 3H, J = 7.2), 1.12 (s, 3H), 1.21−1.59 (m, 4H), 1.30
(t, 3H, J = 7.1), 3.61 (q, 3H, J = 1.2), 4.23 (q, 2H, J = 7.1), 5.28 (s,
1H), 7.39−7.67 (m, 5H), 9.43 (s, 1H).
1
(R)-Mosher ester of syn-13k: H NMR (CDCl3, 300 MHz) δ =
1.04 (s, 3H), 1.12 (s, 3H), 1.64−1.98 (m, 4H), 3.54 (q, 3H, J = 1.3),
3.56−3.68 (m, 2H), 4.18 (dpst, 1H, J = 2.9, 7.4), 5.20 (d, 1H, J = 2.9),
7.39−7.61 (m, 5H), 9.60 (s, 1H).
(R)-Mosher ester: 1H NMR (CDCl3, 300 MHz) δ = 0.89 (t, 3H, J =
7.3), 1.15 (s, 3H), 1.21−1.60 (m, 4H), 1.28 (t, 3H, J = 7.1), 3.51 (q,
3H, J = 1.1), 4.25 (q, 2H, J = 7.2), 5.33 (s, 1H), 7.40−7.67 (m, 5H),
9.45 (s, 1H).
1
(S)-Mosher ester of anti-13k: H NMR (CDCl3, 300 MHz) δ =
0.95 (s, 3H), 1.15 (s, 3H), 1.61−1.91 (m, 4H), 3.51 (q, 3H, J = 1.2), 3.61−
3.96 (m, 3H), 5.33 (d, 1H, J = 7.9), 7.39−7.56 (m, 5H), 9.46 (s, 1H).
1
(R)-Mosher ester of anti-13k: H NMR (CDCl3, 300 MHz) δ =
1
(S)-Mosher ester of lactone of anti-20h: H NMR (CDCl3, 300
0.93 (s, 3H), 1.17 (s, 3H), 1.79−1.97 (m, 4H), 3.53 (q, 3H, J = 1.2),
3.66−4.09 (m, 3H), 5.37 (d, 1H, J = 7.6), 7.38−7.58 (m, 5H), 9.46 (s,
1H).
MHz) δ = 1.20 (t, 3H, J = 7.2), 1.62 (s, 3H), 3.34 (q, 3H, J = 1.2), 3.94
(m, 2H), 6.06 (s, 1H), 7.18−7.64 (m, 10H), 9.74 (s, 1H).
(R)-Mosher ester: 1H NMR (CDCl3, 300 MHz) δ = 0.83 (t, 3H, J =
7.1), 1.64 (s, 3H), 3.53 (q, 3H, J = 1.1), 3.83 (m, 2H), 5.75 (s, 1H),
7.18−7.64 (m, 10H), 9.38 (s, 1H).
1
Since the calculated differences of chemical shifts in the H NMR
spectra of the corresponding Mosher esters of 20h do not explicitly
indicate the configuration of aldol product, the cyclic lactone of syn-
20h was used to confirm the configuration.
(S)-Mosher ester of syn-13l: 1H NMR (CDCl3, 300 MHz) δ = 0.96
(s, 3H), 1.05 (s, 3H), 1.07 (d, 3H, J = 6.4), 3.49 (m, 3H), 3.80 (dq,
1H, J = 2.1, 6.4), 4.29 (d, 1H, J = 11.7), 4.46 (d, 1H, J = 11.7), 5.15 (d,
1H, 2.1), 7.20−7.68 (m, 10H), 9.57 (s, 1H).
(R)-Mosher ester of syn-13l: 1H NMR (CDCl3, 300 MHz) δ = 0.94
(s, 3H), 1.06 (s, 3H), 1.11 (d, 3H, J = 6.4), 3.60 (m, 3H), 3.82 (dq,
1H, J = 2.0, 6.4), 4.32 (d, 1H, J = 11.5), 4.49 (d, 1H, 11.5), 5.15 (d,
1H, 2.0), 7.23−7.68 (m, 10H), 9.59 (s, 1H).
1
(S)-Mosher ester: H NMR (CDCl3, 300 MHz) δ = 1.54 (s, 3H),
3.53 (q, 3H, J = 1.0), 4.47 (m, 2H), 6.15 (s, 1H), 7.16−7.62 (m, 10H).
1
(R)-Mosher ester: H NMR (CDCl3, 300 MHz) δ = 1.38 (s, 3H),
3.68 (q, 3H, J = 1.0), 4.45 (m, 2H), 6.12 (s, 1H), 7.16−7.62 (m, 10H).
1
(S)-Mosher ester of anti-13l: H NMR (CDCl3, 300 MHz) δ =
0.97 (s, 3H), 1.04 (s, 3H), 1.09 (d, 3H, J = 6.2), 3.52 (m, 3H), 4.17 (d,
1H, J = 17.0), 4.46 (d, 1H, J = 17.3), 4.51 (dq, 1H, J = 6.2, 7.0), 5.45
(d, 1H, 6.8), 7.23−7.59 (m, 10H), 9.43 (s, 1H).
1
(S)-Mosher ester of anti-20h: H NMR (CDCl3, 300 MHz) δ =
1
0.84 (t, 3H, J = 7.1), 1.66 (s, 3H), 3.62 (q, 3H, J = 1.1), 3.89 (m, 2H),
(R)-Mosher ester of anti-13l: H NMR (CDCl3, 300 MHz) δ =
0.96 (s, 3H), 1.04 (s, 3H), 1.07 (d, 3H, J = 6.2), 3.47 (q, 3H, J = 1.5),
4.36 (d, 1H, J = 11.1), 4.41 (dq, 1H, J = 6.4, 7.1), 4.51 (d, 1H, 11.2),
5.40 (d, 1H, 7.0), 7.25−7.63 (m, 10H), 9.45 (s, 1H).
5.80 (s, 1H), 7.18−7.64 (m, 10H), 9.33 (s, 1H).
(R)-Mosher ester of anti-20h: H NMR (CDCl3, 300 MHz) δ =
1.20 (t, 3H, J = 7.2), 1.60 (s, 3H), 3.40 (q, 3H, J = 1.2), 3.80 (m, 2H),
1
5.99 (s, 1H), 7.18−7.64 (m, 10H), 9.65 (s, 1H).
Compounds 13k−m (Schemes 3 and 4). Absolute and relative
configuration as well as enantiomeric excess were determined for
products 13l−n to exclude a potential racemization of the electrophile.
In order to exclude potential epimerization in aldol adducts 13o−r
only simple determination of the relative configuration is necessary
(see Determination of Relative Configuration).
2326
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
1
(S)-Mosher ester of syn-13m: H NMR (CDCl3, 300 MHz) δ =
aldol adducts and reasonable analogy. In some cases, the aldol adducts
could be transferred into derivatives known from literature.
1.06 (s, 3H), 1.19 (s, 3H), 1.26 (s, 3H), 1.27 (s, 3H), 3.50 (m, 3H),
3.54 (dd, 1H, J = 6.8, 8.5), 3.94 (dd, 1H, J = 6.8, 8.5), 4.34 (dpst, 1H,
J = 3.6, 6.8), 5.27 (d, 1H, J = 3.4), 7.37−7.45 (m, 3H), 7.53−7.60 (m,
2H), 9.57 (s, 1H).
Compounds of Scheme 2. Relative configuration of new compounds
20b,g was determined by NO experiments of the corresponding lactone
derivatives (see the Supporting Informations). Since these experiments
do not explicitly indicate the relative configuration of compound 20c, we
assumed the configuration in analogy to the other reaction products.
Compounds of Scheme 3−5. The relative 3,4-configuration of
products of diastereoselective reactions in Scheme 3 and 4 can be
1
(R)-Mosher ester of syn-13m: H NMR (CDCl3, 300 MHz) δ =
1.02 (s, 3H), 1.15 (s, 3H), 1.30 (s, 3H), 1.34 (s, 3H), 3.58 (m, 3H),
3.61 (dd, 1H, J = 6.6, 8.7), 3.99 (dd, 1H, J = 6.6, 8.7), 4.37 (dpst, 1H,
J = 4.0, 6.6), 5.32 (d, 1H, J = 4.0), 7.36−7.47 (m, 3H), 7.61−7.68 (m,
2H), 9.54 (s, 1H).
1
determined by the H-coupling constants of aldol adducts. Generally,
the 3,4-anti-configured products show higher values of coupling
constants. To support this principle, single-crystal X-ray analysis and
NO experiments of many products were additionally performed. In
some cases, derivatives of the aldol adducts were used. For examples
13k−m the absolute configuration of the new generated stereocenter
was determined by Mosher-ester technique to demonstrate that no
racemization of the deployed chiral reactant takes place. Since no
racemization or epimerization of the reactants were observed, Mosher
ester technique is also effective for determination of the relative
configuration of the reaction products (compounds syn-13o and anti-
13p). Table 5 shows the 1H-coupling constants of compounds in
1
(S)-Mosher ester of anti-13m: H NMR (CDCl3, 300 MHz) δ =
0.97 (s, 3H), 1.15 (s, 3H), 1.29 (s, 3H), 1.37 (s, 3H), 3.52 (q, 3H, J =
1.3), 3.70 (dd, 1H, J = 6.1, 8.6), 3.88 (dd, 1H, J = 6.3, 8.5), 4.13 (dpst,
1H, J = 6.2, 7.7), 5.42 (d, 1H, J = 7.7), 7.41−7.56 (m, 3H), 7.53−7.60
(m, 2H), 9.48 (s, 1H).
Table 5. 3,4-Coupling Constants of Compounds in Schemes
3 and 4 (1H NMR) (M: Mosher Ester Technique)
1
(R)-Mosher ester of anti-13m: H NMR (CDCl3, 300 MHz) δ =
3,4-
J3,4
0.98 (s, 3H), 1.14 (s, 3H), 1.28 (s, 3H), 1.35 (s, 3H), 3.50 (q, 3H, J =
1.2), 3.65 (dd, 1H, J = 6.1, 8.7), 3.84 (dd, 1H, J = 6.3, 8.7), 4.08 (dpst,
1H, J = 6.2, 8.1), 5.37 (d, 1H, J = 8.0), 7.41−7.55 (m, 5H) 9.48
(s, 1H).
Compounds 28 to 39 (Schemes 5−9). Possible racemization of the
carbonyle compound could be excluded for compounds 28−39 (see
the results of Schemes 3 and 4). Thus, determination of the absolute
configuraton is not necessary. Nevertheless, the absolute configuration
for compounds 31 and 34 was exemplified.
entry
compd
13k
config
(Hz)
config confirmed by
crystal structure/M
1
2
3
4
5
6
7
syn
2.7
6.2
2.0
7.2
2.6
7.4
0.0
13k
13l
anti
syn
M
M
M
13l
anti
syn
a
13m
13m
13n
crystal structure /M
crystal structure/M
anti
syn
crystal structure/NOE of
derivative
8
9
13n
anti
syn
9.7
0.4
8.7
0.6
8.9
1.2
4.8
2.3
8.1
2.2
4.9
2.2
6.2
NOE of derivative
M
13o
10
11
12
13
14
15
16
17
18
19
20
13o
anti
syn
13p
13p
anti
syn
M
2,3-syn-28
2,3-syn-28
2,3-anti-28
2,3-anti-28
2,3-syn-29
2,3-syn-29
2,3-anti-29
2,3-anti-29
1
(S)-Mosher ester of β-31: H NMR (CDCl3, 400 MHz) δ = 1.14
anti
syn
(d, 3H, J = 6.6), 1.40 (s, 3H), 3.35 (s, 3H), 3.55 (q, 3H, J = 1.1), 4.42
(s, 1H), 4.43 (dq, 1H, J = 5.1, 6.6), 5.11 (d, 1H, J = 5.1), 7.39−7.45
(m, 3H), 7.58−7.64 (m, 2H).
NOE of derivative/M
anti
syn
crystal structure of derivative
crystal structure of derivative
1
(R)-Mosher ester of β-31: H NMR (CDCl3, 400 MHz) δ = 1.21
anti
syn
(d, 3H, J = 6.6), 1.40 (s, 3H), 3.33 (s, 3H), 3.56 (q, 3H, J = 1.1), 4.40
(s, 1H), 4.44 (dq, 1H, J = 5.1, 6.6), 5.13 (d, 1H, J = 5.1), 7.38−7.44
(m, 3H), 7.56−7.61 (m, 2H).
anti
a
Crystal structure was reported in ref 8a.
Schemes 3−5, and additional methods that were used to determine the
relative configuration.
Compounds 13n were transferred into the corresponding unpro-
tected methylglycosides as follows: To a mixture of 1 mmol of 13n in
5 mL of methanol and 0.5 mL of water was added 0.1 mmol of
toluenesulfonic acid. The reaction mixture was stirred vigorously at
room temperature and monitored by TLC. After completion of the
reaction (∼12 h), the mixture was neutralized with Na2CO3, dried
(MgSO4), and filtrated. The remaining residue was absorbed to Celite
and purified by column chromatography (hexane/acetone/methanol
6/3/1). The reaction products were used in NO experiments for
determination of the relative configuration (see the Supporting
Informations).
(S)-Mosher ester of β-34: 1H NMR (CDCl3, 300 MHz) δ = 1.22 (s,
3H), 1.41 (d, 3H, J = 6.4), 3.39 (s, 3H), 3.55 (q, 3H, J = 1.2), 4.19
(psquin, 1H, J = 6.5), 4.58 (s, 1H), 5.07 (d, 1H, J = 6.9), 7.40−7.54
(m, 5H).
(R)-Mosher ester of β-34: 1H NMR (CDCl3, 300 MHz) δ = 1.31 (s,
3H), 1.37 (d, 3H, J = 6.4), 3.40 (s, 3H), 3.55 (q, 3H, J = 1.1), 4.08
(psquin, 1H, J = 6.5), 4.58 (s, 1H), 5.06 (d, 1H, J = 6.6), 7.41−7.55
(m, 5H).
Determination of Relative Configuration. The relative
configuration was determined by a combination of single-crystal
(2S,3R,4S,6R)-Tetrahydro-6-methoxy-2,2,5-trimethyl-2H-pyran-
1
3,4-diol. Colorless oil (derivative of syn-13n): H NMR (CDCl3, 500
1
MHz) δ = 0.97 (s, 3H), 1.00 (s, 3H),1.29 (d, 3H, J = 6.2), 3.26 (pst,
1H, J = 9.4), 3.31 (s, 3H), 3.58 (d, 1H, J = 9.3), 3.61 (dq, 1H, J = 6.2,
X-ray structure analysis, analysis of the vicinal H-coupling constants
(1H NMR), by NO experiments of corresponding cyclic derivatives of
2327
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
9.5), 4.16 (s, 1H); 13C NMR (125 MHz) δ = 18.0, 19.0, 22.4, 40.8,
55.0, 67.8, 74.4, 76.1, 106.1.
NaBH4 reduction. The crude product was dissolved in methanol under
a hydrogen atmosphere, and a spatula of palladium on charcoal was
added. The deprotection was completed within 12 h at rt. The mixture
was filtrated, and 5 mL of 2,2-dimethoxypropane and 0.2 mmol of
toluenesulfonic acid were added. The reaction mixture was stirred
vigorously at room temperature and monitored by TLC. After
completion of the reaction (∼24 h), the mixture was diluted with
acetone, neutralized with Na2CO3, dried (MgSO4), and filtrated. The
remaining residue was absorbed to Celite and purified by column
chromatography (hexane/acetone 9/1).
(R)-2-Methyl-2-((4R,5R)-2,2,5-trimethyl-1,3-dioxolan-4-yl)butan-
1-ol. Colorless oil (derivative of 2,3-anti-3,4-syn-28): 1H NMR
(CDCl3, 500 MHz) δ = 0.85 (s, 3H), 0.90 (t, 3H, J = 7.5), 1.31 (d,
3H, J = 6.0), 1.38 (s, 3H), 1.38 (s, 3H), 1.54 (m, 1H), 1.67 (m, 1H),
3.43 (d, 1H, J = 11.2), 3.54 (d, 1H, J = 11.2), 3.58 (d, 1H, J = 8.1),
4.05 (dq, 1H, J = 6.0, 7.9); 13C NMR (125 MHz) δ = 7.7, 18.4, 20.3,
23.8, 27.0, 27.2, 38.6, 68.9, 72.7, 90.0, 107.5.
Compounds 29 were transferred into the corresponding unpro-
tected glycosides as follows:to a mixture of 1 mmol 29 in 5 mL
dioxane and 2 mL water 0.1 mmol toluenesulfonic acid was added.
The reaction mixture was stirred vigorously at room temperature and
monitored by TLC. After completion of the reaction (∼12 h), the
mixture was diluted with dioxane, neutralized with Na2CO3, dried
(MgSO4), and filtrated. The remaining residue was absorbed to Celite
and purified by column chromatography (hexane/acetone/methanol
2/2/1).
(2S,3R,4S,6S)-Tetrahydro-6-methoxy-2,2,5-trimethyl-2H-pyran-
3,4-diol. Colorless oil: 1H NMR (CDCl3, 500 MHz) δ = 0.89 (s, 3H),
1.00 (s, 3H),1.34 (d, 3H, J = 6.0), 3.11 (d, 1H, J = 8.9), 3.20 (pst, 1H,
J = 9.0), 3.26 (dq, 1H, J = 5.9, 9.1), 3.47 (s, 3H), 3.96 (s, 1H); 13C
NMR (125 MHz) δ = 12.7, 17.9, 22.1, 41.7, 57.4, 72.1, 74.1, 79.6,
107.3.
(2S,3R,5S)-Tetrahydro-2-((S)-1-hydroxyethyl)-5-methoxy-4,4-di-
methylfuran-3-ol. Colorless oil (derivative of anti-13n): 1H NMR
(CDCl3, 500 MHz) δ = 1.02 (s, 3H), 1.03 (s, 3H), 1.23 (d, 3H, J =
6.5), 3.35 (s, 3H), 3.68 (dd, 1H, J = 4.8, 7.2), 3.87 (dq, 1H, J = 4.8,
6.5), 4.11 (d, 1H, J = 7.2), 4.39 (s, 1H); 13C NMR (125 MHz) δ =
18.6, 19.3, 19.7, 46.1, 55.6, 68.8, 76.9, 86.4, 111.4.
(2S,3R,5R)-Tetrahydro-2-((S)-1-hydroxyethyl)-5-methoxy-4,4-di-
1
methylfuran-3-ol. Colorless oil: (derivative of anti-13n): H NMR
(CDCl3, 500 MHz) δ = 1.00 (s, 3H), 1.04 (s, 3H), 1.27 (d, 3H, J =
6.5), 3.34 (s, 3H), 3.64 (pst, 1H, J = 4.8), 3.68 (d, 1H, J = 4.4), 3.93
(dq, 1H, J = 5.3, 6.5), 4.45 (s, 1H); 13C NMR (125 MHz) δ = 16.4,
19.3, 25.4, 45.7, 55.0, 67.8, 78.1, 89.4, 111.0.
Absolute and relative configuration as well as enantiomeric excess
were determined for products 13k−m to exclude a potential racemiza-
tion of the electrophile. In order to exclude potential epimerization
in aldol adducts 13n−q, only simple determination of the relative
configuration is necessary.
(3R,4R,5R)-3-Ethyl-3-methyltetrahydro-2H-pyran-2,4,5-triol (De-
1
rivative of 2,3-syn-3,4-syn-29). Colorless oil: H NMR (OC(CD3)2,
500 MHz) δ = (mixture of four anomers) 0.85−1.07 (m, 6H), 1.27−
1.67 (m, 2H), 3.04−4.16 (m, 4H), (4.53 (d, J = 5.1 Hz), 4.76 (d, J =
3.7 Hz), 4.85 (d, J = 4.1 Hz), 5.02 (d, J = 3.8 Hz) 1H); 13C NMR (125
MHz) δ = (mixture of four anomers) 8.8, 9.0, 9.9, 10.3, 14.1, 14.6,
16.5, 17.3, 28.6, 29.2, 30.4, 30.6, 44.5, 45.1, 51.0, 52.2, 63.8, 63.9, 68.0,
69.9, 70.0, 70.0, 77.0, 77.8, 78.6, 79.8, 80.6, 83.6, 98.8, 98.8, 100.2,
1
+
(S)-Mosher ester of syn-13o: H NMR (CDCl3, 300 MHz) δ =
104.9; HRMS (CI) m/z calcd for C8H20O4 + NH4 194.1387, found
1.05 (s, 3H), 1.19 (s, 3H), 1.21 (s, 3H), 1.27 (d, 3H, J = 5.9), 1.33 (s,
3H), 3.51 (q, 3H, J = 1.1), 3.61 (dq, 1H, J = 5.9, 8.6), 3.75 (dd, 1H, J =
1.6, 8.6), 5.25 (d, 1H, J = 1.6), 7.41−7.59 (m, 3H), 9.59 (s, 1H).
194.1385.
1
(R)-Mosher ester of syn-13o: H NMR (CDCl3, 300 MHz) δ =
1.03 (s, 3H), 1.12 (s, 3H), 1.19 (s, 3H), 1.24 (d, 3H, J = 5.9), 1.30 (s,
3H), 3.52 (q, 3H, J = 1.4), 3.57 (m, 1H), 3.70 (dd, 1H, J = 1.6, 8.7),
5.20 (d, 1H, J = 1.6), 7.40−7.57 (m, 5H), 9.59 (s, 1H).
(3S,4S,5R)-3-Ethyl-5-(hydroxymethyl)-3-methyltetrahydrofuran-
1
2,4-diol (Derivative of 2,3-syn-3,4-anti-29): H NMR (OC(CD3)2,
500 MHz) δ = (mixture of two anomers) major anomer: 0.87 (t, 3H,
J = 7.5), 0.93 (s, 3H), 1.45 (dq, 1H, J = 7.5, 13.6), 1.56 (dq, 1H, J =
7.5, 13.5), 3.53−3.56 (m, 1H), 3.64 (dd, 1H, J = 3.0, 11.6), 3.81 (ddd,
1H, J = 3.0, 4.4, 7.4), 3.96 (d, 1H, J = 7.4), 4.87 (s, 1H). minor
anomer: 0.86 (t, 3H, J = 7.5), 0.91 (s, 3H), 1.31−1.41 (m, 2H), 3.53−
3.56 (m, 1H), 3.66 (m, 1H), 3.69 (d, 1H, J = 7.2), 3.84 (ddd, 1H, J =
3.3, 5.1, 7.2), 4.96 (s, 1H); 13C NMR (125 MHz) δ = (mixture of two
anomers) major anomer: 9.9, 16.5, 28.7, 50.9, 63.9, 78.0, 85.7, 104.8;
minor anomer: 9.7, 13.2, 32.2, 49.6, 64.2, 78.0, 84.5, 104.7.
1
(S)-Mosher ester of anti-13o: H NMR (CDCl3, 400 MHz) δ =
1.03 (s, 3H), 1.18 (s, 3H), 1.36 (s, 3H), 1.38 (s, 3H), 3.13 (dd, 1H, J =
5.1, 10.7), 3.31 (dd, 1H, J = 2.2, 10.7), 3.46 (q, 3H, J = 1.1), 3.99 (m,
1H), 4.00 (m, 1H), 4.34 (d, 1H, J = 12.2), 4.47 (d, 1H, J = 12.2), 5.44
(d, 1H, J = 8.2), 7.24−7.51 (m, 10H), 9.51 (s, 1H).
1
(R)-Mosher ester of anti-13o: H NMR (CDCl3, 400 MHz) δ =
0.97 (s, 3H), 1.14 (s, 3H), 1.37 (s, 3H), 1.39 (s, 3H), 3.29 (dd, 1H, J =
5.3, 10.8), 3.43 (q, 3H, J = 1.0), 3.44 (dd, 1H, J = 2.7, 10.8), 4.05 (dd,
1H, J = 7.7, 8.0), 4.13 (ddd, 1H, J = 2.6, 5.2, 7.9), 4.43 (d, 1H, J =
12.2), 4.53 (d, 1H, J = 12.2), 5.46 (d, 1H, J = 8.0), 7.27−7.52 (m,
10H), 9.50 (s, 1H).
(S)-Mosher ester of 2,3-syn-3,4-syn-28: 1H NMR (CDCl3, 400
MHz) δ = 0.73 (t, 3H, J = 7.5), 0.97 (s, 3H), 1.09 (d, 3H, J = 6.4),
1.20−1.36 (m, 2H), 3.48 (q, 3H, J = 1.0), 3.77 (dq, 1H, J = 1.9, 6.5),
4.28 (d, 1H, J = 11.1), 4.45 (d, 1H, J = 11.1), 5.17 (d, 1H, J = 1.9),
7.20 - 7.62 (m, 10H), 9.49 (s, 1H).
Compound 2,3-anti-3,4-syn-28 was transferred into the correspond-
ing isopropylidene-derivative as follows: 2 mmol of 2,3-anti-3,4-syn-28
was reduced to the corresponding alcohol by the general procedure for
2328
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
Compounds of Scheme 6−8. Compounds 30 and 33 were
transferred into the corresponding p-bromophenyl acetals as follows:
to a mixture of 2 mmol of diol in 5 mL of DCM and 2.5 mmol of
p-bromobenzaldehyde was added 0.1 mmol of toluenesulfonic acid.
The reaction mixture was stirred vigorously at room temperature and
monitored by TLC. After completion of the reaction (∼24 h), the
mixture was diluted with DCM, neutralized with Na2CO3, dried
(MgSO4), and filtrated. The remaining residue was absorbed to Celite
and purified by column chromatography (hexane/acetone 19/1).
ASSOCIATED CONTENT
* Supporting Information
■
S
Optimization works, structure elucidations, proof of config-
uration, corresponding lactones, diols, and acetonides, spectral
data of Mosher esters, results of X-ray structure analyses, and
1
copies of H NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
Bromophenyl acetal of 30: H NMR (CDCl3, 500 MHz) δ =
AUTHOR INFORMATION
Corresponding Author
*E-mail: rainer.mahrwald@rz.hu-berlin.de.
Notes
■
1.79−2.08 (m, 7H), 2.52 (ddpst, 1H J = 1.2, 8.1, 12.7), 3.59 (d, 1H,
J = 10.7), 3.66 (d, 1H, J = 4.2), 3.81 (d, 1H, J = 10.7), 3.76−3.90 (m,
4H), 4.13 (dpst, 1H, J = 4.2, 7.0), 5.49 (s, 1H), 7.36 (m, 2H), 7.47 (m,
2H); 13C NMR (125 MHz) δ = 25.7, 25.8, 28.8, 29.3, 68.6, 68.7, 75.5,
76.3, 78.0, 84.5, 100.9, 122.8, 128.0, 131.2, 136.9.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Deutsche Forschungsgemeinschaft (Priority
Program Organocatalysis), Bayer-Schering Pharma AG, Chem-
tura Organometallics GmbH Bergkamen, Bayer Services
GmbH, BASF AG, and Sasol GmbH for financial support.
REFERENCES
1
■
Bromophenyl acetal of 33. Colorless oil: H NMR (CDCl3, 500
(1) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 6798−6799.
MHz) δ = 1.83−2.06 (m, 7H), 2.09−2.17 (m, 1H), 3.64 (d, 1H, J =
10.8), 3.71 (psq, 1H, J = 7.2), 3.81 (d, 1H, J = 10.8), 3.84 (d, 1H, J =
5.2), 3.87−3.92 (m, 3H), 4.03 (dpst, 1H, J = 5.2, 6.8), 5.49 (s, 1H),
7.32−7.35 (m, 2H), 7.47−7.50 (m, 2H); 13C NMR (125 MHz) δ =
25.6, 25.8, 28.1, 29.2, 68.1, 68.6, 75.2, 76.9, 77.4, 84.4, 100.3, 122.8,
127.9, 131.3, 137.0.
(2) (a) Gijsen, H. J. M.; Wong, C.-H. J. Am. Chem. Soc. 1995, 17,
7585−7591. (b) Chowdari, N. S.; Ramachary, D. B.; Cordova, A.;
Barbas, C. F. III. Tetrahedron Lett. 2002, 43, 9591−9595. (c) Pihko, P.
M.; Erkkila, A. Tetrahedron Lett. 2003, 44, 7607−7609. (d) Northrup,
A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem.
Int. Ed. 2004, 43, 2152−2154. (e) Kofoed, J.; Machuqueiro, M.;
Reymond, J.-L.; Darbre, T. Chem. Commun. 2004, 1540−1541.
(f) Thayumanavan, R.; Tanaka, F.; Barbas, C. F. III. Org. Lett.
2004, 6, 3541−3544. (g) Northrup, A. B.; MacMillan, D. W. C. Science
2004, 305, 1752−1755. (h) Storer, R. I.; MacMillan, D. W. C.
Tetrahedron 2004, 60, 7705−7714. (i) Cordova, A. Tetrahedron Lett.
2004, 45, 3949−3952. (j) Mangion, I. K.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 3696−3697. (k) Casas, J.; Engqvist, M.;
Ibrahem, I.; Kaynak, B.; Cordova, A. Angew. Chem. Int. Ed. 2005, 44,
1343−1345. (l) Reyes, E.; Cordova, A. Tetrahedron Lett. 2005, 46,
6605−6609. (m) Cordova, A.; Engqvist, M.; Ibrahem, I.; Casas, J.;
Sunden, H. Chem. Commun. 2005, 2047−2049. (n) Cordova, A.;
Ibrahem, I.; Casas, J.; Sunden, H.; Engqvist, M.; Reyes, E. Chem.Eur.
J. 2005, 11, 4772−4784. (o) Kofoed, J.; Reymond, J.-L.; Darbre, T.
Org. Biomol. Chem. 2005, 3, 1850−1855. (p) Zhao, G.-L.; Liao, W.-W.;
Cordova, A. Tetrahedron Lett. 2006, 47, 4929−4932. (q) Smith, A. B.
III; Tomioka, T.; Risatti, C. A.; Sperry, J. B.; Sfouggatakis, C. Org. Lett.
2008, 10, 4359−4362.
1
(S)-Mosher ester of 33: H NMR (CDCl3, 400 MHz) δ = 1.65
(ddd, 1H, J = 6.5, 8.2, 12.9), 1.78−1.91 (m, 6H), 2.10 (ddd, 1H, J =
6.9, 8.4, 12.9), 3.44 (m, 1H), 3.55 (m, 3H), 3.76−3.87 (m, 4H), 3.89−
3.93 (m, 1H), 4.33 (d, 1H, J = 11.3), 4.46 (d, 1H, J = 11.3), 7.38−7.41
(m, 3H), 7.54−7.56 (m, 2H).
1
(S)-Mosher ester of 37: H NMR (CDCl3, 300 MHz) δ = 1.28 (s,
3H), 1.29 (s, 3H), 1.38 (m, 6H), 3.60 (d, 1H, J = 7.3), 3.86 (m, 3H),
3.86 (d, 1H, J = 9.5), 3.91 (dd, 1H, J = 5.6, 7.8), 3.98 (dpst, 1H, J =
5.7, 7.4), 4.08 (dd, 1H, J = 5.7, 7.8), 4.10 (d, 1H, J = 9.5), 4.38 (d, 1H,
J = 11.6), 4.47 (d, 1H, J = 11.6), 7.38−7.54 (m, 5H).
Compound 39 was transformed into the corresponding dimethyl-
silyl ether as follows: to a solution of 2 mmol of 39 in 10 mL of
DCM was added 1 mmol of imidazole, 5 mmol of triethylamine, and
1.2 mmol of dimethyldichlorosilane. The reaction mixture was stirred
vigorously at room temperature and monitored by TLC. After
completion of the reaction (∼6 h), the mixture was diluted with DCM
and filtrated. The remaining residue was absorbed to Celite and
purified by column chromatography (hexane/acetone 19/1).
1
Dimethylsilyl ether of 39: H NMR (CDCl3, 500 MHz) δ = 0.18
(3) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.;
Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 5527−3529.
(4) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2004, 43, 6722−6724.
(5) Li, J.; Fu, N.; Li, X.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2010, 75,
4501−4507.
(6) Kano, T.; Sugimoto, H.; Maruoka, K. J. Am. Chem. Soc. 2011, 133,
18130−18133.
(s, 3H), 0.21 (s, 3H), 1.34 (s, 3H), 1.34 (d, 3H, J = 6.2), 1.37 (s, 3H),
1.37 (s, 3H), 1.42 (d, 3H, J = 6.4), 1.47 (s, 3H), 3.57 (dd, 1H, J = 1.3,
11.4), 3.99 (s, 1H), 4.15 (d, 1H, J = 11.4), 4.36 (d, 1H, J = 6.8), 4.39
(dq, 1H, J = 6.2, 6.8), 4.88 (dq, 1H, J = 1.2, 6.4); 13C NMR (125
MHz) δ = −3.8, −2.2, 14.5, 15.0, 25.9, 26.0, 26.4, 28.7, 67.0, 73.6, 73.9,
73.9, 74.8, 79.4, 106.5, 108.2.
(7) (a) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. J. Org. Chem.
2011, 76, 3005−3015. (b) Schmid, M. B.; Zeitler, K.; Gschwind, R. M.
J. Am. Chem. Soc. 2011, 133, 7065−7074. (c) Schmid, M. B.; Zeitler,
K.; Gschwind, R. M. Chem. Science 2011, 2, 1793−1803. (d) Guillena,
G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249−
2293.
(8) (a) Markert, M.; Scheffler, U.; Mahrwald, R. J. Am. Chem. Soc.
2009, 131, 16642−16643. (b) Scheffler, U.; Mahrwald, R. Synlett
2011, 1660−1667.
(9) (a) Y.-h. Lam, Houk, K. N.; Scheffler, U.; Mahrwald, R.
Manuscript in preparation (b) Lam, Y.-h.; Houk, K. N. Abstracts 241st
ACS Natl. Meeting, Anaheim, CA, 2011, 27−31.
2329
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330

The Journal of Organic Chemistry
Article
(10) For a similar discussion in threonine-catalysis, see: Ramasastry,
S. S. V.; Albertshofer, K.; Utsumi, N.; Tanaka, F.; Barbas, C. F. III.
Angew. Chem. Int. Ed. 2007, 46, 5572−5575.
(11) Hricoviniova, Z.; Lamba, D.; Hricovini, M. Carb. Res. 2005, 340,
455−458.
(12) Searle, P. A.; Molinski, T. F. J. Org. Chem. 1995, 60, 4296−4298.
(13) For a synthesis of epi-trachycladine A and B, see: Enders, D.;
Breuer, I.; Drosdow, E. Synthesis 2005, 3239−3244.
(14) For an overview of classical approaches to chiral pantolactones,
see: Camps, P.; Munoz-Torrero, D. Curr. Org. Chem. 2004, 8, 1339−
1380.
(15) Shinkre, B. A.; Deshmukh, A. R. A. S. Tetrahedron: Asymmetry
2004, 15, 1081−1084.
(16) Tadano, K.; Kanazawa, S.; Ogawa, S. J. Org. Chem. 1988, 53,
3868−3870.
(17) Zhdanko, A. G.; Gulevich, A. V.; Nenajdenko, V. G. Tetrahedron
2009, 65, 4692−4702.
(18) Falck, J. R.; He, A.; Fuki, H.; Tsutsui, H.; Radha, A. Angew.
Chem., Int. Ed. 2007, 24, 4527−4529.
(19) Carley, S.; Brimble, M. A. Org. Lett. 2009, 11, 563−566.
(20) Fernandes, R. A.; Chavan, V. P. Eur. J. Org. Chem. 2010, 4306−
4311.
(21) Hoppe, D.; Tarara, G.; Wilckens, M. Synthesis 1989, 83−88.
(22) Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Philips, J. L.;
Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J. Org. Chem.
1991, 56, 4056−4058.
(23) Bianchi, P.; Roda, G.; Riva, S.; Danieli, B.; Zabelinskaja-
Mackova, A.; Griengl, H. Tetrahedron 2001, 57, 2213−2220.
(24) Palik, M.; Karlubikova, O.; Lasikova, A.; Kozisek, J.; Gracza, T.
Eur. J. Org. Chem. 2009, 709−715.
(25) Huang, H.-L.; Liu, R.-S. J. Org. Chem. 2003, 68, 805−810.
(26) (a) Wiggins, L. F. J. Chem. Soc 1946, 13−14. (b) Bourne, E. J.;
McSweeney, G. P.; Wiggins, L. F. J. Chem. Soc. 1952, 3113−3114.
(27) Woods, R. J.; Neish, A. C. Can. J. Chem. 1954, 32, 404−414.
(28) Hricoviniova-Bilikova, Z.; Hricovini, M.; Petrusova, M.;
Serianni, A. S.; Petrus, L. Carb. Res. 1999, 319, 38−46.
(29) Akita, H.; Matsukura, H.; Oishi, T. Chem. Pharm. Bull. 1986, 34,
2656−2659.
(30) Upadhya, T. T.; Gurunath, S.; Sudalai, A. Tetrahedron:
Asymmetry 1999, 10, 2899−2904.
(31) Evans, D. A.; Jimmy, W.; Masse, C. E.; MacMillan, D. W. C.
Org. Lett. 2002, 4, 3379−3382.
(32) Pansare, S. V.; Bhattacharyya, A. Tetrahedron 2003, 59, 3275−
3282.
(33) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092−4096. (b) Seco, J. M.; Qinoa, E.; Giguera,
R. Chem. Rev. 2004, 104, 17−118. (c) Freire, F.; Seco, J. M.; Quinoa,
E.; Riguera, R. J. Org. Chem. 2005, 70, 3778−3790.
2330
dx.doi.org/10.1021/jo202558f | J. Org. Chem. 2012, 77, 2310−2330