Confinement-Controlled, Eithersyn- oranti-Selective Catalytic Asymmetric Mukaiyama Aldolizations of Propionaldehyde Enolsilanes

Article abstract of DOI:10.1021/jacs.1c07447

Protected aldols (i.e., true aldols derived from aldehydes) with eithersyn- oranti- stereochemistry are versatile intermediates in many oligopropionate syntheses. Traditional stereoselective approaches to such aldols typically require several nonstrategic

Full text of DOI:10.1021/jacs.1c07447

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Confinement-Controlled, Either syn- or anti-Selective Catalytic
Asymmetric Mukaiyama Aldolizations of Propionaldehyde
Enolsilanes
Tynchtyk Amatov, Nobuya Tsuji, Rajat Maji, Lucas Schreyer, Hui Zhou, Markus Leutzsch,
and Benjamin List*
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ABSTRACT: Protected aldols (i.e., true aldols derived from aldehydes) with either syn- or anti- stereochemistry are versatile
intermediates in many oligopropionate syntheses. Traditional stereoselective approaches to such aldols typically require several
nonstrategic operations. Here we report two highly enantioselective and diastereoselective catalytic Mukaiyama aldol reactions of the
TBS- or TES- enolsilanes of propionaldehyde with aromatic aldehydes. Our reactions directly deliver valuable silyl protected
propionaldehyde aldols in a catalyst controlled manner, either as syn- or anti- isomer. We have identified a privileged IDPi catalyst
motif that is tailored for controlling these aldolizations with exceptional selectivities. We demonstrate how a single atom modification
in the inner core of the IDPi catalyst, replacing a CF3-group with a CF2H-group, leads to a dramatic switch in enantiofacial
differentiation of the aldehyde. The origin of this remarkable effect was attributed to tightening of the catalytic cavity via
unconventional C−H hydrogen bonding of the CF2H group.
olyketides are pharmaceutically important secondary
1
Pmetabolites.
Erythromycin is a prototypical example,
which as a synthetic target was declared by Woodward as
“hopelessly complex ...in view of its plethora of asymmetric
centers”.2 This statement encouraged the beginning of several
decades of intense and highly innovative method development
in acyclic stereocontrol. Generations of chemists have
contributed approaches to overcoming the synthetic challenges
posed by oligopropionates, typically bearing linear stereo-
polyads with alternating methyl and hydroxyl groups.3
Nonetheless, only few truly reliable methods have found
general utility in numerous syntheses of complex oligopropi-
onates.4 Widely used approaches, based on chiral auxiliaries,
rely on diastereoselective asymmetric propionate aldolizations
or crotylation reactions (Figure 1).5,6 Very often, both
approaches converge after several steps: following the critical
diastereoselective C−C bond-formation, protecting group
installation and redox manipulations lead to stable protected
aldol intermediates of a general structure I, which are ideal for
downstream functionalization to construct various polyketide
motifs. Catalytic asymmetric crotylation methods developed
more recently by Krische et al. provide an attractive alternative
Figure 1. Complex bioactive polyketides. Established approaches to
but feature a moderate step-economy when protected aldols of
protected aldols I vs our single-step, stereodivergent method.
type I are needed.7 Direct stereoselective cross-aldol reactions
of aldehydes have also been described, but an additional
protection step is often unavoidable.8 A truly practical
approach, from a total synthesis chemist’s perspective, would
Received: July 19, 2021
directly deliver the protected aldols in a predictable catalytic
manner, with full control over diastereoselectivity and
enantioselectivity. In this regard, arguably the most useful
variant of the Mukaiyama aldol reaction,9 the aldolization of
propionaldehyde-derived enolsilanes with aldehydes, has
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remained elusive. In addition to directly delivering the
protected aldols, such a reaction would favorably meet all of
the metrics used to evaluate synthetic methods, such as
atom-,10 redox-,11 and especially step-economy.12
Table 1. Reaction Development
Yamamoto reported nonenantioselective examples using the
bulky tris(trimethylsilyl)silyl (TTMSS, supersilyl) group to
control selectivity toward single addition of aldehyde-derived
enolsilanes.13 The first diastereo- and enantioselective
examples by Denmark utilized trichlorosilyl enolsilanes under
Lewis base catalysis.14 This approach is poorly atom-economic,
as the silyl group is not retained in the final product and several
steps are required to obtain aldols suitable for chain
elongations. Kanai and Matsunaga reported an asymmetric
Cu-catalyzed aldolization using in situ generated boron
enolates of propionaldehyde, which gives mainly syn-aldols.15
Although up to quadruple aldolizations were achieved, the
existence of unprotected oligoaldols in various cyclic hemi-
acetal forms limits their selective elaboration to useful
oligopropionate motifs. Recently we reported the first, highly
enantioselective Mukaiyama cross-aldol reaction with simple
triethylsilyl (TES) and tert-butyldimethylsilyl (TBS) enolsi-
lanes of acetaldehyde and aliphatic and aromatic aldehydes
using confined and strongly acidic imidodiphosphorimidate
(IDPi) catalysts developed here.16 Enzyme-like discrimination
of the small substrate aldehyde over the larger product
aldehyde is believed to be the origin of single aldolization
without oligomerization.17 From such a vantage point,
exploitation of the unique reactivity of IDPi catalysts in the
Mukaiyama cross-aldol reaction with propionaldehyde-derived
enolsilanes would be even more valuable as it generates two
(vicinal) stereogenic centers simultaneously, which are present
in many bioactive polyketides (Figure 1).18 We envisioned
developing a fully stereodivergent method giving access to all
four stereoisomers.19 Herein, we report that the IDPi family of
catalysts provides a powerful solution to this long-standing
goal.20
Our investigations commenced with an exploration of
different IDPi catalysts in the aldolization of benzaldehyde 1
with (E)-enolsilanes 2a−b or (Z)-enolsilanes 4a−c (Table 1).
At the onset we found that the diastereoselectivity was
dependent on the nucleophile geometry, with (E)-enolsilanes
providing syn-aldols and (Z)-enolsilanes giving anti-aldols, with
varying degrees of diastereoselectivity, depending on the silyl
group and the catalyst. IDPi 6, which was a preferred catalyst
in our acetaldehyde-derived enolsilane additions, was tested in
the reaction of (E)-enolsilane 2a with benzaldehyde at −20 °C.
Single aldolization product 3 was indeed formed in high yield,
excellent diastereoselectivity (d.r. 97.5:2.5) in favor of the syn-
aldol 3a ([Si] = TES), and with a promising enantiomeric ratio
(e.r.) of 10.5:89.5 (Table 1A, entry 1). Given that fluorene-
substituted IDPi catalysts were especially privileged in our
recent silylium-ion asymmetric counteranion-directed catalysis
(Si-ACDC)21 methodologies,22a−d we turned our attention to
catalysts 7a−d (and S8a−c in the Supporting Information).
Indeed, these IDPis emerged as preferred catalysts for our
reactions. Spirocyclobutane-substituted IDPi 7a markedly
stood out in terms of enantioselectivity, providing aldol 3a
with a 95.5:4.5 e.r. (Table 1A, entry 2). Modification of the
inner core of the IDPi from the Tf-group to a Nf-group further
increased diastereoselectivity and enantioselectivity. Lowering
the temperature to −40 °C led to a d.r. of 99:1 and a 98:2 e.r.
(Table 1A, entry 5). Variation of the silyl group was well-
tolerated when the TBS-enolsilane 2b was used instead of the
a
Reactions were conducted with benzaldehyde 1 (0.1 mmol),
enolsilanes 2a−b or 4a−c (1.2 equiv), and IDPi (2 mol %) for
b
1
16−24 h at the indicated temperature. Determined by H NMR
c
d
spectroscopy. Determined by crude 1H NMR analysis. The e.r. was
e
determined by HPLC. At −78 °C using a 5:4 CHCl3/n-hexane
mixture. TES, triethylsilyl; TIPS, triisopropylsilyl; TBS, tert-
butyldimethylsilyl. See the Supporting Information for determination
of the absolute configuration.
TES-enolsilane 2a (Table 1A, entry 6). An opposite trend was
observed in the anti-selective Mukaiyama aldol addition of
(Z)-enolsilanes (Table 1B). Both the size of the perfluorinated
sulfonamide in the inner core of IDPi and the silyl group had
tremendous effects on the selectivity. Longer perfluorinated
groups gave poorer d.r. and e.r. At −60 °C, the addition of
B
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a
Table 2. Substrate Scope for the syn- and anti-Mukaiyama Aldol Additions
a
Reaction scale: 0.2−5 mmol. See the Supporting Information for full reaction conditions and the determination of e.r.
(Z)-enolsilane 4a ([Si] = TES) to benzaldehyde proceeded
with modest d.r. and e.r. using catalysts 7b and 7c, which
performed exceptionally well previously in the syn-aldolization
(Table 1B, entries 4−5). In contrast, IDPi 7a with the shortest
trifluoromethylsulfonamide core performed far better, but to
our surprise, with inverted benzaldehyde enantiofacial prefer-
ence. Among (Z)-enolsilanes 4a−4c with different silyl-groups
(Table 1B, entries 1−3), enolsilane 4b with the TBS-group
performed best, albeit only in 89:11 e.r. Hypothesizing that
replacing one of the F atoms in the CF3-group to an H atom
may help in positively influencing the selectivity without
introducing significant steric changes,23 IDPi 7d containing a
CF2H-group was designed and synthesized. Specifically, we
envisioned that CF2H···heteroatom interactions could lead to a
modulation of the active site of the IDPi catalyst.24 Strikingly,
the single-atom modification of the inner core of the catalyst,
replacing the CF3-groups with CF2H-groups, indeed resulted
in a spectacular enhancement of both the d.r. (99:1) and e.r.
(98:2) in the addition of enolsilane 4b (Table 1B, entries 7 and
8).
provided products 3k−3m, which contain substructures of
complex polyketides.25,26 The catalyst loading could be
reduced to 0.5 mol % without compromising the reaction
time and stereoselectivity as shown with the gram scale
synthesis of aldols 3h and 3k. A diastereoselective and
enantioselective single aldolization of a dialdehyde substrate
gave product 3m.
Essentially the same set of aromatic aldehydes performed
equally well in our anti-aldolization process furnishing products
5b−k and 5m (Table 2B). Electron-rich aromatic aldehydes
also delivered anti-aldols 5l and 5n with good diastereose-
lectivity and enantioselectivity. Only furfural gave somewhat
lower yield of product 5i.
Furthermore, butyraldehyde-derived enolsilanes 8 and 9 also
readily reacted to either syn- or anti-products 10 and 11
(Scheme 1A). Moreover, both enantiomers of our IDPi
catalysts enabled access to all four possible stereoisomers of
aldols as shown in Scheme 1B.
Our stereodivergent aldolization method is especially
valuable in the context of the rapid generation of complex
polyketide motifs (Scheme 1C). For example, when syn-aldol
3h was subjected to a follow-up propionate aldolization using
in situ generated chiral boron enolates 12,27 either the all-syn-
stereotetrad 13 or its syn, anti, syn stereoisomer 14 were
obtained as single diastereomers. The structure of the
polyketide-like molecule 13 was unambiguously confirmed by
With these results in hand, the scope of our syn-selective
Mukaiyama aldol reaction with various aromatic aldehydes was
explored, using catalyst 7c (Table 2A). Aromatic aldehydes
with o-, m-, and p-substituents and heteroaromatic aldehydes
(3a−3j) gave the corresponding products in excellent yields
and stereoselectivity. Multisubstituted aromatic aldehydes
C
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Scheme 1. Further Applications of the Diastereoselective and Enantioselective Aldol Reactions
Figure 2. Mechanistic studies. (A−C) Control experiments. (D) Computed transition-state structures of major enantiomer of 3a (syn-selective
addition) with 7a (left) and 5b (anti-selective addition) with 7d (right) at B3LYP-D3(BJ)/def2TZVP+CPCM(Chloroform)//ONIOM(PBE-D3/
6-31G(d):PBE-D3/3-21G) level of theory. Distances between centroids of the two inner spirocyclobutyl-2-fluorenyl groups are shown. *Energies
in kcal/mol (see the Supporting Information for details). (E) Effect of C−H hydrogen bondings on the cavity size. Angles represent centroids of
the two inner spirocyclobutyl-2-fluorenyl groups and the central nitrogen.
D
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X-ray crystallography. Alternatively, iterative aldolization using
the proline-catalyzed cross-aldol addition with propionalde-
hyde delivered the syn, syn, anti-stereotetrad 15 with excellent
diastereoselectivity. Further, anti-aldol 5d was converted to a
fully protected double aldol adduct 16, containing the key anti,
syn-stereotriad of antarlide A,28 when our method was coupled
with Yamamoto’s supersilyl enolate technology. Stereotriad 16
is fully suited for further aldol addition toward antarlides. 1,3-
Dienyl-6-oxy polyketide motif 17, an intermediate from a
reported total synthesis of nannocystin Ax, was also obtained
in only two steps starting from benzaldehyde (via ent-3b). The
previous synthesis of 17 involved five steps, including an
Evans-aldolization.29 It is noteworthy that all of the polyketide
motives 13−17 were obtained in just two steps from
commercially available aldehydes such as furfural, m-
anisaldehyde, and benzaldehyde.
To gain insight into the mechanism of our stereoselective
aldol additions, experimental and computational studies were
performed. Experiments were directed at probing aspects of
our aldol reactions such as the origin of single aldolization and
the unexpected change of facial selectivity during anti-
aldolization using IDPi 7d. Initially, we confirmed that our
IDPi catalysts were indeed unique in promoting the single
aldolization of propionaldehyde enolsilanes: the well-estab-
lished Mukaiyama aldol addition catalyst triflimide did not give
even a trace of the desired single aldolization products because
of complete enolsilane oligomerization (Figure 2A, see the
Supporting Information, Figure S2 for details). syn-Aldol 3c,
which was obtained using IDPi (S,S)-7c at −40 °C, underwent
less than 10% conversion under the same conditions using the
opposite enantiomer of the catalyst (R,R)-7c, excluding a
potential matched−mismatched scenario (Figure 2B). The
change in facial selectivity of aldehyde attack upon switching
from the n-C4F9- and CF3-groups to the CF2H-group was also
manifested when simple acetaldehyde-derived enolsilanes 19a-
b were used (Figure 2C). With catalysts 7a and 7c,
acetaldehyde-derived enolsilane additions to benzaldehyde
proceeded with re-selectivity, giving ent-20 irrespective of the
silyl groups. In contrast, IDPi 7d, having a difluoromethane-
sulfonyl group in the core, reacted with si-selectivity.
Additionally, our study has identified the involvement of
CH/π interactions, indicated in Figure 2D,31 between the
spirocyclic methylene groups of the catalyst counteranion and
the aromatic ring of the aldehyde substrate, which contribute
to the high enantioselectivities in both transition states.32 This
is in agreement with our experimental observations, showing a
strong effect of the spirocycle on the enantioselectivity (Figure
S1).
Our highly stereoselective Mukaiyama aldol additions of
propionaldehyde enolsilanes give access to all stereoisomers of
the stable and versatile protected aldols in a predictable
manner and can be used in rapid syntheses of complex
polyketide motifs. Ultimately, our approach could aid in
streamlining the synthesis of complex oligopropionates. We
also uncovered an unusual enantioreversal effect by modifying
a CF3-group to a CF2H-group. The origin of stereoselectivities
and enantiofacial switch was rationalized through computa-
tional studies, revealing the cooperation of C−H hydrogen
bonds and CH/π interactions to govern catalyst structure and
transition states.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c07447.
■
sı
Experimental details and analytical data for all new
compounds (PDF)
Accession Codes
CCDC 2097850−2097853 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Benjamin List − Max-Planck-Institut fu
̈
r Kohlenforschung, D-
45470 Mulheim an der Ruhr, Germany; Institute for
̈
In order to probe the origin of stereoselectivity and the
switch of enantiofacial selectivity, an extensive DFT study was
conducted for both syn- and anti-selective additions with IDPis
7a and 7d. Computed e.r.s and d.r.s were in good agreement
with experimental observations in both cases (Figure 2D; see
the Supporting Information, Figures S6−S10 for more details).
When the optimized major transition-state structures of syn-
and anti-selective aldolizations are compared, one of the most
prominent differences appears to be the catalyst pocket size.30
While catalyst 7a with CF3-cores has a relatively open cavity,
the CF2H-groups in catalyst 7d engage in intramolecular
hydrogen bonding interactions resulting in a more compact
catalytic pocket (Figure 2D and 2E). Accordingly, for the syn-
selective addition with 7a, the bulky (E)-enolsilane 2a bearing
a smaller TES group would approach from the less hindered re-
face (Figure 2B, left). In contrast, for the case of anti-selective
addition with 7d, the sterically less hindered (Z)-enolsilane 4b,
with a slightly bulkier TBS group, provides a perfect fit into the
narrower cavity, resulting in the complete switch of the facial
selectivity (Figure 2D, right). The outcome of the
acetaldehyde-derived enolsilane additions using catalysts 7a
and 7d is also in good agreement with this model (Figures 2C,
S12, and S13).
Chemical Reaction Design and Discovery (WPI-ICReDD),
Hokkaido University, Sapporo 001-0021, Japan;
orcid.org/0000-0002-9804-599X; Email: list@
kofo.mpg.de
Authors
Tynchtyk Amatov − Max-Planck-Institut fu
Kohlenforschung, D-45470 Mulheim an der Ruhr, Germany;
̈
r
̈
orcid.org/0000-0002-6404-1253
Nobuya Tsuji − Institute for Chemical Reaction Design and
Discovery (WPI-ICReDD), Hokkaido University, Sapporo
001-0021, Japan
Rajat Maji − Max-Planck-Institut fu
45470 Mulheim an der Ruhr, Germany; orcid.org/0000-
0003-2614-1795
Lucas Schreyer − Max-Planck-Institut fu
D-45470 Mulheim an der Ruhr, Germany
Hui Zhou − Max-Planck-Institut fur Kohlenforschung, D-
45470 Mulheim an der Ruhr, Germany
Markus Leutzsch − Max-Planck-Institut fu
D-45470 Mulheim an der Ruhr, Germany; orcid.org/
̈
r Kohlenforschung, D-
̈
̈
r Kohlenforschung,
̈
̈
̈
̈
r Kohlenforschung,
̈
0000-0001-8171-9399
Complete contact information is available at:
E
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Communication
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https://pubs.acs.org/10.1021/jacs.1c07447
Funding
Open access funded by Max Planck Society.
Notes
The authors declare the following competing financial
interest(s): A patent on the general catalyst class and its
asymmetric catalysis has been filed.
ACKNOWLEDGMENTS
■
The authors acknowledge generous support from the Deutsche
Forschungsgemeinschaft (DFG, German Research Foundation
Leibniz Award to B.L.) and under Germany’s Excellence
Strategy (EXC 2033-390677874-RESOLV), the European
Research Council (ERC, European Union’s Horizon 2020
research and innovation program “C−H Acids for Organic
Synthesis, CHAOS” Advanced Grant Agreement No. 694228),
and the Horizon 2020 Marie Sklodowska-Curie Postdoctoral
Fellowship (to R.M., Grant Agreement No. 897130). The
authors thank Benjamin Mitschke for his help with figures and
several members of the group for our internal crowd reviewing.
We also thank the technicians of our group and the members
of our NMR, MS, X-ray, and chromatography groups for their
excellent service. This work was also financially supported by
the Institute for Chemical Reaction Design and Discovery
(ICReDD), which was established by the World Premier
International Research Initiative (WPI), MEXT, Japan, and by
JSPS KAKENHI Grants 21H01925 and 20K22515.
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