Kinetic Resolution of Racemic Aldehydes through Asymmetric Allenoate γ-Addition: Synthesis of (+)-Xylogiblactone A

Article abstract of DOI:10.1021/acs.orglett.9b02982

A synthesis of (+)-xylogiblactone A has been achieved from t-butyl 2-methylbuta-2,3-dienoate in a linear three-step sequence. The key elements of the synthesis include a kinetic resolution of racemic 2-silyoxyaldehyde through the allenoate γ-addition to y

Full text of DOI:10.1021/acs.orglett.9b02982

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Kinetic Resolution of Racemic Aldehydes through Asymmetric
Allenoate γ‑Addition: Synthesis of (+)-Xylogiblactone A
Saehansaem Park,‡ Gyungah Pak,‡ Changhwa Oh,‡ Jieun Lee,† Jimin Kim,*,‡ and Chan-Mo Yu*,†
†Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea
‡Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
S
* Supporting Information
ABSTRACT: A synthesis of (+)-xylogiblactone A has been
achieved from t-butyl 2-methylbuta-2,3-dienoate in a linear
three-step sequence. The key elements of the synthesis include
a kinetic resolution of racemic 2-silyoxyaldehyde through the
allenoate γ-addition to yield the γ-adduct as a single isomer
and the subsequent gold catalysis to form the butenolide core.
For a general method, the kinetic resolution of several racemic
2-silyloxyaldehydes is also performed to provide products in
high levels of stereoselectivity with unusual anti-Felkin−Anh
addition fashion.
Scheme 1. General Strategy
he reliable design of chemical transformations to access
Tuseful structures for target substances is an important task
of current organic chemistry.1 In this regard, control of the
regio- and stereochemical pathways is one of the most essential
elements of their synthetic values.2 Accordingly, monumental
discoveries of new methods with important concepts have been
made in the chemical community.3
In the course of our research program aimed at finding new
synthetic methods, we disclosed our investigations on the
unprecedented γ-addition of 2-alkylallenoates to normal
aldehydes to construct a unique structure with axial and
central chirality.4 The reaction usually produced a γ-adduct as
a single isomer in regio- and stereochemically pure form.5 With
these observations in hand, we became quite interested in
designing a synthetic route for the synthesis of naturally
occurring bioactive butenolides6 including (+)-xylogiblactone
A (1a),7 as shown in Scheme 1. It was envisaged that the
enantioselective synthesis of 1a can be achieved from 2-methyl
allenoate 5a within an only three-step sequence through an
allenoate aldol γ-addition and gold catalysis, as depicted in
Scheme 1.
The utilization of readily available racemic ( )-3a instead of
inaccessible chiral 3a can be more ideal to produce the key
intermediate 2a through a kinetic resolution in the allenoate γ-
addition (Scheme 1). Although there are extensive studies of
the relationship of chiral aldehydes in asymmetric aldol-type
additions in terms of matching or mismatching cases,8 the lack
of data in the literature concerning the direct addition of a
chiral enolate to racemic carbonyl units via kinetic resolution
surprised us. Known methods for the kinetic resolution of
racemic aldehydes in carbonyl additions are limited to specific
substrates9 despite the expected similarities of the well-
established kinetic-resolution processes.10 To achieve correct
stereochemical relationships appearing in the structure of
(+)-xylogiblactone A, it is required to obtain an addition
product through an anti-Felkin−Anh fashion (Scheme 1).11
On the basis of the reasonable speculation that the
stereochemical model for this regio- and stereochemically
specific transformation of the allenoate γ-addition is highly
organized, the investigation of such an organization like a
Received: August 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02982
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Preliminary Investigations of Kinetic Resolution
b
c
d
entry
R
5
dr (7:8)
product
ee (%)
yield (%)
1
2
3
4
5
6
7
Me (6a)
Me (6a)
Ph (6b)
PhCH2CH2 (6c)
PhCH2CH2 (6c)
Me2CH (6d)
Me2CH (6d)
5a
5b
5a
5a
5b
5a
5b
20:01
9:01
5:01
>50:1
>50:1
>99:1
>99:1
7a
7b
7c
7d
7e
7f
>99
>99
>99
>99
>99
>99
>99
68
71
54
61
58
63
61
7g
a
b
See the Supporting Information (SI) for the experimental details and the analysis of data. Diastereomeric ratio (dr) values were determined by
c
the analysis of 1H NMR. Enantiomeric excess (ee, %) values were determined by the analysis of the 1H NMR of (R)-MTPA esters in comparison
with authentic samples prepared from (S,S)-4. Yields (%) are those of products isolated after purification by chromatography.
d
kinetic-resolution process assumes another importance. On a
positive note, we envisaged that an anti-Felkin−Anh adduct
could be a major product after the extensive analysis of cyclic
stereochemical models to regulate stereoselectivity based on
our previous observation.4
Scheme 2. Allenoate γ-Additions of Chiral (S)-6a
We describe herein our discovery of a conversion of 2-alkyl-
allenoates 5 with racemic 2-silyoxyaldehydes ( )-6 to afford γ-
adducts with high levels of diastereoselectivity with a single
enantiomer through anti-Felkin−Anh carbonyl π-facial selec-
tivity. Synthetic applications to (+)-xylogiblactone A are
achieved in three steps with the correction of the stereo-
chemical relationship, which proves that chemical synthesis has
an important role to play in the process of solving the
molecular structure.12 The concise synthesis of bioactive
butenolides could demonstrate the utility of this synthetic tool.
With this issue in mind, our investigations began with 5a
and( )-6a to judge and prove the efficiency of the kinetic
resolution. The initial attempts of a γ-addition reaction of 5a
(R1 = Me) with (R,R)-4 in the presence of i-Pr2NEt, followed
by the addition of ( )-6a (R = Me, 3 equiv) at −78 °C
indicated that the conversion to the desired 7 or 8 could not be
satisfied mainly due to a lack of reactivity at low temperature.
After surveying numerous conditions, the following observa-
tions emerged (entry 1, Table 1): (1) The reaction performed
at −50 °C for 1 h in CH2Cl2 turned out to be most efficient in
terms of chemical yield (68%). (2) The diastereoselectivity
(dr) was confirmed to be a 20:1 (7/8) ratio, as judged by the
analysis of 500 MHz 1H NMR. (3) The enantiomeric excesses
of products 7a and 8a were proved to be >99% ee, determined
by the analysis of the H NMR of corresponding (+)-MTPA
esters in comparison with an authentic sample prepared from
(S,S)-4.
To verify the stereochemistry of products 7a and 8a, the
reactions of chiral (S)-6a carried out with (R,R)-4 and (S,S)-4
under similar conditions are shown in Scheme 2. The reaction
of (S,S)-4 with (S)-6a at −50 °C under the same procedure
resulted in the formation of ent-7a in 64% yield. The formation
of ent-7a was proved by a comparison of 1H NMR with 7a and
corresponding (R)-MTPA esters. On the contrary, the reaction
with (R,R)-4 tuned out to be extremely slow. Product 8a was
only obtained at −20 °C in 22% yield, whereas the reaction did
not take place at −50 °C. These experiments clearly
demonstrated that the kinetic resolution of ( )-6a in the
allenoate γ-addition provided the anti-Felkin−Anh addition
product as a predominant reaction route.
With the notion that this approach might lead to a general
and efficient method for the kinetic resolution of racemic
( )-6 to extend the reaction scope, we set out to explore
different aldehydes, as shown in Table 1. Indeed, the method
turned out to be successful with structurally diverse racemic 2-
silyoxyaldehydes ( )-6 in forming exclusively γ-addition
products 7 in moderate to good yield with high levels of
diastereoselectivity (except for the R = phenyl case of 5:1 dr,
entry 3). It is worth noting that the reaction produced 7 as a
single enantiomer of >99% ee for all cases in Table 1.
Fortunately, the X-ray structure of 7f was obtained to prove
the stereochemistry unambiguously (Figure 1). To the best of
our knowledge, the kinetic-resolution process of the allenoate
γ-addition described herein represents the first instance of a
highly diastereo- and enantioselective carbonyl addition
reaction.
1
From the mechanistic perspective, two major functions for
the stereoselectivity are immediately discernible in a kinetic
resolution of the allenoate γ-addition. Although the exact
mechanistic aspects of this transformation have not been
B
DOI: 10.1021/acs.orglett.9b02982
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On the basis of this argument, conformations A and B
summarize the preferred stereochemical models for two
possible γ-additions along with a well-established trajectory
of an approaching nucleophile under an optimum electronic
effect.11 In general, less steric demand in B caused by the
interaction between Ha and Hb (Felkin−Anh addition) is
favored over model A due to the more severe interaction
between R and Ha (anti-Felkin−Anh). However, our stereo-
chemical models have another steric demand between R1 and
Hb in A versus R1 and R in B (Scheme 3).
Stereochemical models A′ and B′ with different angles more
clearly illustrate the stereochemical routes for the anti-Felkin−
Anh adduct 7 and the Felkin−Anh adduct 8, providing major
factors. The formation of the anti-Felkin−Anh adduct 7 via
models A and A′ can be explained by the steric interactions
between R1 ↔ Hb and R ↔ Ha in model A/A′ being favored
over the steric repulsion between R1 ↔ R and Ha ↔ Hb in
model B/B′ for a kinetic resolution of ( )-6. Thus the origin
of the stereochemical outcomes for 7 might be a subtle
geometrical preference and an electronic characteristic in the
anti-Felkin−Anh model A.
Figure 1. X-ray structure of 7f (R = i-Pr).
rigorously elucidated, Scheme 3 illustrates possible stereo-
chemical routes for anti-Felkin−Anh adduct 7 and Felkin−Anh
Scheme 3. Origin of Stereochemical Outcomes
In light of the above results for the kinetic resolution of 2-
silyloxyaldehydes ( )-6 via the allenoate γ-addition, we next
turned our attention to the application of this approach for the
synthesis of naturally occurring (+)-xylogiblactone A (1a).
Structurally unique xylogiblactone A along with B and C was
isolated from the ethyl acetate extracts of the fermented broth
of Xylotumulus gibbisporus YMJ863, which exhibits antifungal
activities.4 Structurally related butenolide (+)-hypoxylactone
was isolated from a different source, the fermentation broth of
the facultative marine Hypoxylon croceum together with a new
sordarin derivative.13
To begin, we undertook the synthesis of (+)-xylogiblactone
A (1a) starting from the aldehyde ( )-3a, readily prepared in
quantity from methyl crotonate in four steps.14 The treatment
of (R,R)-4 with 5a at −50 °C for 30 min, followed by the
addition of ( )-3a (3 equiv) at a somewhat higher
temperature −20 °C, presumably due to a steric factor,
afforded 2a as a single stereochemical adduct in 61% yield. The
stereochemistry of 2a was confirmed by X-ray crystallography.
The regiospecific cyclization of 2a by gold catalysis15 using
Ph3PAuNTf2 (10 mol %) clearly provided the γ-butenolide
core 9a in 83% yield. The known desilylation methods for the
tert-butyldimethylsilyl (TBS) group encountered unexpected
problems such as the decomposition of the product and the
partial epimerization of the γ-butenolide core.16 Fortunately,
under acidic conditions (aq. HCl in MeOH) (+)-xylogi-
blactone A (1a) was afforded in 88% yield.17 However, H
1
NMR, 13C NMR, and specific rotation values obtained from
synthetic 1a were not consistent with the literature values.7
We speculated that 1a must be an epimer at the C*−Cl
position of the natural product after the analysis of several
related structures of butenolides.9 In this regard, ( )-3b was
prepared from methyl crotonate in five steps.18 Reactions were
performed again with ( )-3b, as described in Scheme 4, and
we obtained 1b as a single product (40.7% overall yield in a
three-step sequence). Finally, all physical data, including the
specific rotation for 1b, were exactly consistent with the
literature values. Consequently, the structure of naturally
occurring (+)-xylogiblactone A was verified unambiguously to
be 1b.
adduct 8 stereoisomers on the basis of our previous
observations4 and the well-defined π-facial selectivity of
racemic aldehydes toward various nucleophiles.8 To explain
the preference of the π-facial selectivity of racemic 2-
silyloxyaldehydes ( )-6 through a kinetic resolution in the
allenoate γ-addition, we started to analyze two possible
stereochemical models A and B to provide 7 and 8,
respectively, as shown in Scheme 3. Geometrical preference
depicted as Newman projections in A and B can be explained
by a stereoelectronic effect: The interaction of the π*CO
orbital with an adjacent perpendicular σC−O orbital lowers the
energy of the lowest unoccupied molecular orbital (LUMO).
In summary, we describe a highly efficient kinetic resolution
of racemic 2-silyloxyaldehydes via the allenoate γ-addition
C
DOI: 10.1021/acs.orglett.9b02982
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Letter
Scheme 4. Synthesis and Correction of (+)-Xylogiblactone
A
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jiminkim@chonnam.ac.kr (J.K.).
*E-mail: cmyu@skku.edu (C.-M.Y.).
ORCID
Jimin Kim: 0000-0003-3223-9983
Chan-Mo Yu: 0000-0002-5213-2529
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Research Foundation (NRF),
K o r e a f o r s u p p o r t i n g t h i s w o r k ( C . - M . Y . ,
2015R1D1A1A01060430; J.K., 2018R1D1A1B07044008 and
2015R1A4A1041036)
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
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supplementary crystallographic data for this paper. These
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