Chemo- and Diastereoselective N-Heterocyclic Carbene-Catalyzed Cross-Benzoin Reactions Using N-Boc-α-amino Aldehydes

Article abstract of DOI:10.1021/acs.orglett.6b02123

N-Boc-α-amino aldehydes are shown to be excellent partners in cross-benzoin reactions with aliphatic or heteroaromatic aldehydes. The chemoselectivity of the reaction and the facial selectivity on the amino aldehyde allow cross-benzoin products to be obtained in good yields and good diastereomeric ratios. The developed method is utilized as the key step in a concise total synthesis of d-arabino-phytosphingosine.

Full text of DOI:10.1021/acs.orglett.6b02123

Letter
pubs.acs.org/OrgLett
Chemo- and Diastereoselective N‑Heterocyclic Carbene-Catalyzed
Cross-Benzoin Reactions Using N‑Boc-α-amino Aldehydes
Pouyan Haghshenas and Michel Gravel*
Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada
S
* Supporting Information
ABSTRACT: N-Boc-α-amino aldehydes are shown to be
excellent partners in cross-benzoin reactions with aliphatic or
heteroaromatic aldehydes. The chemoselectivity of the reaction
and the facial selectivity on the amino aldehyde allow cross-
benzoin products to be obtained in good yields and good
diastereomeric ratios. The developed method is utilized as the
key step in a concise total synthesis of D-arabino-phytosphin-
gosine.
nantioenriched α-hydroxy ketones are convenient building
Scheme 1. Products of NHC-Catalyzed Benzoin Reaction
E
blocks for a variety of synthetic transformations as well as
important structural features present in a wide array of natural
products.1 A typical synthetic approach toward this motif relies
on preformation of a ketone’s C−C bond followed by α-
hydroxylation.2 However, achieving desirable enantio- and/or
diastereoselectivities in such reactions has remained a challenge.
In addition, controlling the regioselectivity of hydroxylation in
the case of aliphatic ketones is particularly problematic.
of studies have addressed the chemoselectivity of NHC-catalyzed
cross-benzoin reactions, most of which rely on substrate
modifications to control the selectivity. One strategy consists
of utilizing highly reactive ketones as they can only enter the
catalytic cycle in the C−C bond-forming step.7 Another
approach makes use of a stoichiometric amount of preformed
silylated Breslow intermediate which could only participate as the
nucleophile in the C−C bond-forming step.8 However, when
two aldehydes are used as coupling partners, the product ratio is
often difficult to control and even to predict.
In contrast to the α-hydroxylation of ketones, disconnection at
the central carbon−carbon bond represents a more efficient
strategic approach to α-hydroxy ketones as it introduces the
stereogenic center while assembling the carbon chain (Figure
1).3 N-Heterocyclic carbene (NHC)-catalyzed cross-benzoin
In 1977, Stetter and co-workers demonstrated that ortho-
chloro aromatic aldehydes or sterically hindered aliphatic
aldehydes can be coupled chemoselectively in some cases.9
Figure 1. Retrosynthetic strategies toward α-hydroxy ketones.
Muller and co-workers later showed the coupling of ortho-
̈
substituted aromatic aldehydes with other aromatic aldehydes
bearing an electron-withdrawing group using thiamine-depend-
ent enzymes.10 Later, in 2011, Glorius and co-workers showed
that similar results could be obtained by using thiazolium-derived
NHC precatalysts.11 The same group reported on the use of
paraformaldehyde as a formaldehyde equivalent in the synthesis
of hydroxymethyl ketones.12 Han, Ryu, and Yang showed the
catalyst-dependent chemoselectivity in the coupling of aromatic
aldehydes with a large excess of acetaldehyde.13 Glorius and co-
workers showed that electron-deficient benzaldehyde derivatives
can be used as electrophiles toward the Breslow intermediate
formed between an NHC and isobutyraldehyde or benzalde-
hyde.11 Connon and Zeitler have discovered that N-C6F5
triazolium salts could be used to selectively couple aliphatic
aldehydes with aromatic aldehydes, particularly ortho-halogen-
reactions are potentially useful for such purposes. These types of
reactions directly couple two aldehydes in an umpolung fashion
to produce α-hydroxy ketones in a single step. The generally
accepted mechanism4 involves the formation of a “Breslow
intermediate” between the NHC and an aldehyde.5 This
intermediate then attacks another molecule of aldehyde (C−C
bond formation step) followed by ejection of the catalyst to form
the desired α-hydroxy ketone product.
In order to devise a viable synthetic strategy toward these
motifs, it is crucial to control the chemoselectivity of the reaction,
i.e., control of the aldehyde being attacked by the NHC and by
the Breslow intermediate, respectively. Without such control, a
mixture of all four possible products (two homobenzoin and two
cross-benzoin6 products) will be obtained (Scheme 1).
Controlling the chemoselectivity in the NHC-catalyzed cross-
benzoin reaction remains the most important challenge despite
significant efforts to address the issue in recent years. A number
Received: July 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02123
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Organic Letters
Letter
ated ones.14 Recent kinetic studies have shed light on the origins
of the observed chemoselectivity of this system.15 We have
shown that a slightly more hindered triazolium salt could be used
to couple a wider variety of aromatic and aliphatic aldehydes.16
The factors affecting chemoselectivity in cross-benzoin
reactions are quite complex. In addition to the structure of the
catalyst and that of the substrates, the potential reversibility of the
reaction can play an important role in the product distribution.
Connon, Zeitler, and co-workers have demonstrated that the
interplay between steric bulk and the electronic nature of the
substrates is critical to the chemoselectivity in cross-acyloin
reactions catalyzed by C6F5-triazolylidenes.
g
Scheme 2. Scope of the Cross-Benzoin Reaction
Despite the recent body of work in this area, the synthetically
useful cross-benzoin reaction between two aliphatic aldehydes
remains a challenge. We wondered whether installing a bulky
electron-withdrawing group close to the reaction center could
lead to chemoselectivity in such cases. N-Boc-protected α-amino
aldehydes were chosen as suitable substrates due to the tunability
of both their steric and electronic properties. The use of these
readily available chiral pool-derived substrates can also lead to
diastereofacial selectivity during C−C bond formation. It is
worth noting that very few examples of diastereoselective
benzoin reactions have been reported.17
a
b
Isolated yield of major diastereomer. Overall yield of diastereomers
1
determined by H NMR analysis using dimethyl terephthalate as the
c
internal standard. Isolated yield of a 2:1 mixture of diastereomers.
d
e
The choice of catalyst, base,18 and solvent was determined
through an optimization study (see the Supporting Information).
We were gratified to find that by using catalyst 1 the
corresponding α-hydroxy-β-amino ketone was obtained as the
major product with good diastereoselectivity with the undesired
cross-benzoin and N-Boc-L-valinal homobenzoin reaction path-
ways suppressed. Although good yields of cross-benzoin
products are obtained using 1.5 equiv of the achiral aldehyde
partner, the use of 3 equiv leads to an increase in yield by ca. 10%,
and this stoichiometry was used throughout the rest of our study.
Having established optimized conditions, the scope of the
reaction was explored using a variety of N-Boc-protected amino
aldehydes19 and heteroaromatic or aliphatic aldehydes (Scheme
2). N-Boc-amino aldehydes bearing unbranched substituents
such as N-Boc-alaninal, N-Boc-phenylalaninal, and N,N′-bis-
Boc-L-lysinal furnished the desired product with good yields and
moderate diastereomeric ratios (2−4).20 Increased bulk on the
α-substituent of the amino aldehyde improved the diastereose-
lectivity, as shown in the case of L-valine, L-tert-leucine, and L-
isoleucine derivatives (5−7).21 Importantly, good yields were
obtained by using aliphatic aldehydes as coupling partners,
including one bearing an ester functionality (8−10). Interest-
ingly, higher diastereoselectivities were observed when using
aliphatic aldehydes compared to heteroaromatic aldehydes.22 β-
Branching in the donor aldehyde is well tolerated (11). However,
and as expected, the presence of α-branching in both aldehyde
partners resulted in lower yields (12). Benzaldehyde and its
derivatives are not suitable for this reaction, as their use results in
the formation of a complex mixture of homo- and cross-benzoin
products (not shown). Other heteroaromatic aldehydes such as
2-pyridine carboxaldehyde afforded good yields and diastereo-
meric ratios under the reaction conditions (13). It should be
noted that separation of diastereomers is often difficult by
chromatography, highlighting the importance of diastereoselec-
tivity in this process. This problem can be circumvented through
the diastereoselective reduction of the product, giving rise to
easily separable aminodiols (vide infra).
Isolated yield of a 3:1 mixture diastereomers. Isolated yield of a 13:1
f
g
mixture of the two diastereomers. Product is air sensitive. Reaction
conditions: 1 equiv of N-Boc-amino aldehyde, 3 equiv of aliphatic or
heteroaromatic or aromatic aldehyde.
natural product (vide infra). The diastereoselectivity of the
reaction can be predicted using a Cram-chelate model involving a
hydrogen bond between the carbamate and the aldehyde (Figure
2).23
Figure 2. Rationale for diastereoselectivity.
All α-amino aldehyde substrates used in this study were
enantiomerically enriched and derived from naturally occurring
amino acids. The racemization of these reactants under the basic
reaction conditions was a matter of concern.24 Gratifyingly,
comparison of a representative cross-benzoin product (8) with a
racemic sample showed no erosion of the enantiomeric ratio
(>98:2 er) following the reaction (see the SI).
To gain mechanistic insight into the reaction, two experiments
were carried out using a 1:1 ratio of the two aldehydes and
monitored by H NMR spectroscopy. In the NHC-catalyzed
cross-benzoin reaction between hydrocinnamaldehyde (14) and
valine derivative 15, the rate of formation of the desired cross-
benzoin product (8) is comparable to the rate of consumption of
both starting materials (Figure 3a and SI). The formation of the
undesired homobenzoin dimer of hydrocinnamaldehyde (16) is
much slower than formation of 8. This suggests that the observed
major product is kinetically favored. Subjecting 8 to reaction
conditions did not lead to the formation of the minor
diastereomer, homobenzoin products, or the starting aldehydes.
Therefore, the cross-benzoin product is formed irreversibly
under the reaction conditions. Although the exact factors
1
The relative configuration of the cross-benzoin products was
initially established as depicted via computational methods (see
the SI) and later confirmed through the synthesis of a known
B
DOI: 10.1021/acs.orglett.6b02123
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Letter
Scheme 3. Concise Total Synthesis of D-arabino-
Phytosphingosine
Figure 3. (a) 1H NMR monitoring experiment for the reaction between
14 and 15; (b) 1H NMR monitoring experiment for the reaction
between 17 and 15.
dictating chemoselectivity in this case remain unclear, it can be
concluded that the reaction is under kinetic control. When N-
Boc-L-valinal was subjected to standard reaction conditions
without the partner aldehyde, the homobenzoin product was
obtained in 49% NMR yield. To determine the importance of
this homobenzoin pathway, the crude mixtures from the
stereocenters. Finally, simultaneous removal of BOM- and Boc-
protecting groups using MeOH/HCl led to the formation of D-
arabino-phytosphingosine (23). Spectroscopic data, optical
rotation, and the melting point of the product match the
previously reported values for the title compound (see the SI).
Despite the moderate yield of the key cross-benzoin step, this
strategic bond formation enables the shortest synthesis of this
natural product to date.27b,28 To our knowledge, no other total
synthesis has utilized a cross-benzoin reaction between aliphatic
aldehydes.
In summary, the use of α-amino aldehydes in NHC-catalyzed
cross-benzoin reactions provides chemoselectivity through a
combination of steric hindrance and electronic activation. The
method affords the desired products diastereoselectively and in
good yield for a variety of aldehydes. This method is the first
example of both chemoselective cross-benzoin reaction between
aliphatic aldehydes and of diastereoselectivity in intermolecular
NHC-catalyzed benzoin reactions. NMR studies and a crossover
experiment highlight the subtle interplay between reversibility
and kinetic control and inform on the origin of chemoselectivity
using different aldehydes. However, in order to firmly establish
the origins of diastereo- and chemoselectivity, more thorough
mechanistic studies are required. Finally, the value of the
developed method is demonstrated through a concise synthesis
of D-arabino-phytosphingosine.
1
reactions depicted in Scheme 2 were carefully analyzed by H
NMR spectroscopy. Only trace quantities (3−8% NMR yield) of
this product were present, suggesting that either the formation of
the Breslow intermediate with the amino aldehydes is possible
but not preferred in the presence of aliphatic or heteroaromatic
aldehydes or that a subsequent step is rate-limiting and
responsible for the observed chemoselectivity.15,16b
A similar experiment was performed for the cross-benzoin
reaction involving furfural and 15 (Figure 3b and SI). This
experiment suggests a different rationale for the formation of the
major product. The rate of formation of 18 is faster than the
formation of the desired cross-benzoin product (5). However,
after partial formation of 18, a retro-benzoin reaction leads to the
steady production of the cross-benzoin product (5). These
results highlight an important point: chemoselectivity at every
step of the mechanism is not necessary to obtain high yields of
cross-benzoin product. In this case, a presumably unfavorable
formation of the Breslow intermediate with the amino aldehyde
combined with reversibility of the homobenzoin reaction of
furfural leads to formation of the desired cross-benzoin product
over time. Furthermore, the reversibility of the cross-benzoin
reaction pathway was verified through a crossover experiment by
subjecting 4 and trans-chalcone to reaction conditions, and the
expected Stetter product was observed (see the SI).
The absence of a method to address chemoselectivity in the
NHC-catalyzed cross-benzoin reaction between aliphatic
aldehydes has limited its use in total synthesis. Having developed
a viable method, we set out to demonstrate its application in a
concise synthesis of the sphingoid base D-arabino-phytosphingo-
sine (Scheme 3). Sphingoid bases are key building blocks of
sphingolipids, which play crucial structural and signaling
functions.25 The biological importance of phytosphingosines26
and their difficult isolation have spurred wide interest in their
chemical synthesis.27
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02123.
■
S
Experimental procedures and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Initial efforts toward the NHC-catalyzed cross-benzoin
reaction of 19 and 20 under previously optimized conditions
proved disappointing. Reaction optimization revealed that
moderate yield and diastereoselectivity can be achieved using
conditions depicted in Scheme 3. The resulting diastereomeric
mixture (21) was subjected to stereoselective hydroxyl-directed
reduction using ZnCl2/NaBH4. The reaction proceeded
smoothly with a >20:1 diastereomeric ratio to afford 22 in 35%
yield over two steps. This two-step process provides rapid and
stereocontrolled access to amino diols bearing three contiguous
*E-mail: michel.gravel@usask.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council of Canada, the Canada Foundation for Innovation, and
the University of Saskatchewan for financial support. This
research was enabled in part by support provided by WestGrid
C
DOI: 10.1021/acs.orglett.6b02123
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Letter
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