Asymmetric synthesis of highly functionalized tetrahydropyrans via a one-pot organocatalytic Michael/Henry/Ketalization sequence

Article abstract of DOI:10.1021/ol501236a

A diastereo- and enantioselective Michael/Henry/ketalization sequence to functionalized tetrahydropyrans is described. The multicomponent cascade reaction uses acetylacetone or β-keto esters, β-nitrostyrenes, and alkynyl aldehydes as substrates affording

Full text of DOI:10.1021/ol501236a

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of Highly Functionalized Tetrahydropyrans via
a One-Pot Organocatalytic Michael/Henry/Ketalization Sequence
Robert Hahn, Gerhard Raabe, and Dieter Enders*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: A diastereo- and enantioselective Michael/
Henry/ketalization sequence to functionalized tetrahydropyr-
ans is described. The multicomponent cascade reaction uses
acetylacetone or β-keto esters, β-nitrostyrenes, and alkynyl
aldehydes as substrates affording tetrahydropyrans with five
contiguous stereocenters. Employing a bifunctional quinine-
based squaramide organocatalyst, the title compounds are
obtained in moderate to good yields (27−80%), excellent
enantiomeric excesses (93−99% ee), and high diastereomeric
ratios (dr > 20:1) after one crystallization.
ver the past years, we have witnessed a strong increase in
the number of publications on organocatalysis as the main
To build up the motif of the tetrahydropyran we planned the
addition of a γ-nitro carbonyl compound to an aldehyde.17
Achiral γ-nitro carbonyl compounds were extensively tested, but
no good asymmetric inductions could be achieved. After
intensive literature research, a method provided by Rawal et
al.18 was tested. They developed the synthesis of several Michael
adducts between 1,3-diketones with β-nitrostyrenes with a novel
squaramide organocatalyst based on cinchonine in excellent
yields and enantiomeric excesses. Because of the pseudoenantio-
meric nature of the cinchona alkaloids, we decided to employ a
quinine-based organocatalyst to prove the diversity of this
method by synthesizing the corresponding enantiomer.
According to the protocol of the Rawal group, acetylacetone
1a and β-nitrostyrene 2a reacted smoothly with catalyst A to the
Michael adduct 3a, and in the following new step of the one-pot
sequence the aldehyde 4a was added to form the hemiketal 5a
(Scheme 1). The product was obtained in an excellent
enantiomeric excess of 99%, but in a low yield of 30% after
column chromatography. To investigate this outcome, we stirred
the intermediate Michael product 5a over silica gel and found out
that a retro-aldol reaction between C2/C3 occurred. Addition of
a small amount of base during chromatography to neutralize the
acidity of silica resulted in a noncharacterizable product. To
create a stable compound, we investigated several hydroxyl
protecting groups, which all had to react under almost neutral or
mild conditions. The best result was obtained with the
combination of pTSA and HC(OMe)3 in a quantitative yield
and with no loss of enantioselectivity. With this knowledge in
hand, we added the protecting reagents to the reaction mixture,
and thus, we were able to get the desired product in a good yield.
Knowing how to overcome the stability problems, we screened
for the best reaction conditions. A short temperature screening
O
topic because of their wide applications for the synthesis of
valuable chiral entities.1 Today, numerous groups of organo-
catalysts are known, with the classes of primary2 and secondary
amines,3 hydrogen-bonding organocatalysts,4 chiral phosphoric
acids,5 as well as N-heterocyclic carbenes6 being used
preferentially. The catalytic asymmetric synthesis with these
small organic molecules under metal-free conditions now
constitutes a rapidly growing research area at the frontier of
green chemistry.7 Furthermore, the construction of contiguous
stereocenters via cascade reactions from easily available starting
materials is one of the main reasons for its exponential increase
over the past years.8 Hayashi and co-workers9 reported a cross-
aldol reaction of alkynyl aldehydes 4 with other simple aliphatic
aldehydes to obtain synthetically useful β-alkynyl-β-hydroxy
aldehydes. Similar to the cross-aldol reactions, Henry reactions
with α-acidic nitro compounds are possible as well.10 We wanted
to combine these methods by incorporating the resulting alcohol
functionality in an intramolecular fashion to generate six-
membered rings. We envisaged the use of alkynyl aldehydes 4
to facilitate the 1,2-addition to be followed up by a ketalization
key step to afford 2-hydroxytetrahydropyrans.11 To the best of
our knowledge, an organocascade Michael/Henry/ketalization12
sequence to generate densely functionalized tetrahydropyrans
bearing five stereogenic centers including one tetrasubstituted
carbon is not known. Moreover, the reported organocatalytic
asymmetric Michael/Henry/acetalization sequences require
additional base to facilitate the formation of tetrahydropyr-
ans.12b,c The triple bond is a versatile structural element that can
be used for several transformations, e.g., cycloadditions or
selective reductions to alkenes and as a precursor of ketones. The
2-hydroxy (or rather alkoxy) tetrahydropyran unit is a character-
istic structural feature of a huge number of natural products,
besides carbohydrates for instance of spiroketals,13 in soraphen
A14 and pederin15 as well as in the class of the bryostatins.16
Received: April 30, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501236a | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Initial Outcome of the Envisaged Domino
Sequence
Figure 1. Determination of the relative configuration by NOE for
compound 6c.
for the synthesis of the tetrahydropyrans. Following the protocol
of the Rawal group, we started with the addition of acetylacetone
(1a) and β-nitrostyrene (2a) with 4 mol % of catalyst in DCM at
room temperature (Table 2, entry 1). As opposed to the 2 equiv
of acetylacetone of the Rawal group, we used a 1:1 ratio because
excess acetylacetone would react with aldehyde 4a in an aldol
condensation and thus increase the complexity of the final
mixture. Reducing the amount of catalyst was not successful.
Although the first step occurred quantitatively, we could obtain
only 53% yield at 2 mol % catalyst loading, respectively, 11% yield
at 0.7 mol % (entries 2 and 3). For the next set of modifications,
we changed the amount of aldehyde 4a (Table 2, entry 4−7).
With 10 equiv a lower yield as compared to 4 or 2 equiv was
obtained, indicating a concentration issue. Further reduction of
the amount of the aldehyde led to a small decrease in yield
(entries 6 and 7). Extending the reaction time resulted in no
increase in yield (entries 8−10). The amount of solvent was
reduced to a concentration of 0.5 M, which resulted in an
increase of yield (Table 2, entry 11). Having the proper
conditions in hand, an extension of the scope was investigated
(Table 3). Several different substituents R3 on the aryl moiety of
2 (entries b−d and f) were introduced, giving moderate to good
yields of 27−65% and very good enantioselectivities (93−97%
ee). Even a heterocyclic group, like the protected N-Boc-indolyl,
could be used (Table 3, entry e).
Table 1. Optimizing the Reaction Temperature for the
Henry/Ketalization Sequence
a
b
c
entry
temp (°C)
yield (%)
dr
1
2
3
rt
0
50
61
80
3:1
8:1
−20
>20:1
a
b
The reaction was performed on a 0.2 mmol scale. Combined yield of
isolated product as a mixture of diastereomers after flash
c
chromatography. Diastereomeric ratio; major-(2S,3S,4S,5R,6R) vs
1
minor-(2S,3S,4S,5S,6S) diastereomer determined by H NMR.
Table 2. Screening for the Optimal Conditions
The aromatic part R4 of the aldehyde 4 was substituted with
electron-donating and electron-withdrawing groups to yield the
cascade product in modest to good yields (61−80%) and in very
good enantioselectivities of 94−97% ee (Table 3, entries g−i).
Switching to a cyclopentyl moiety (entry j) led to the same range
of yield (68%) and enantioselectivity (96% ee). No product was
obtained with benzaldehyde or propanal. Desymmetrization of
the acetylacetone to the corresponding methyl ester gave 60%
yield and 97% ee (Table 3, entry k). Increasing the bulkiness to a
tert-butoxy group (entry m) resulted in a drop of obtained
product (34% yield) but still impressive 98% ee.
A further domino product was obtained in 69% yield and 96%
ee after extending the side chain to an ethyl group (Table 3, entry
l). The relative configuration was determined by NOE
measurements for compound 6c (Figure 1) as well as the
absolute configuration by single-crystal X-ray analysis of
compound 6a (Figure 2).19
In summary, we have developed an organocatalytic Michael/
Henry/ketalization cascade sequence to access highly funtion-
alized tetrahydropyrans. A hydrogen-bonding organocatalyst on
a squaramide basis was used to merge acetylacetone or different
β-keto esters with nitroalkenes and ynals. In this manner,
tetrahydropyrans bearing five contiguous stereocenters were
obtained in moderate to good yields (27−80%), after one
a
b
c
d
entry
mol %
4a (equiv)
time (d)
yield (%)
dr
1
2
3
4
5
6
7
8
9
10
4
4
4
4
62
53
11
46
61
52
50
59
57
59
79
>20:1
>20:1
2
5
e
0.7
4
4
5
n.d.
10
2
5
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
4
5
4
1.5
1.1
2
5
4
5
4
6
4
2
7
4
2
9
f
11
4
2
5.5
a
The reaction was performed on a 0.2 mmol scale (0.2 M in DCM).
Sum of reaction time. Combined yield of isolated product as a
mixture of diastereomers after flash chromatography. Diastereomeric
ratio: major-(2S,3S,4S,5R,6R) vs minor-(2S,3S,4S,5S,6S) diastereomer
determined by H NMR. Not determined. Conducted in 0.4 mL of
solvent (0.5 M).
b
c
d
e
f
1
was conducted with Michael adduct 3a and aldehyde 4a (Table
1). Reducing the reaction temperature from room temperature
to −20 °C (entries 1−3) was followed by an increase in yield and
diastereoselectivity. Now we focused on the one-pot procedure
B
dx.doi.org/10.1021/ol501236a | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Scope of the Michael/Henry/Ketalization Sequence To Form Tetrahydropyrans
a
b
c
d
e
6
R1
R2
R3
R4
time (d)
yield (%)
dr
ee (%)
a
b
c
d
e
f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5.5
5.5
6.5
5
79
65
45
27
38
46
67
61
80
68
60
69
34
>20:1
13:1
6:1
2:1
8:1
2:1
5:1
7:1
3:1
4:1
4:1
3:1
2:1
>99
93 (99)
97 (99)
95 (99)
95
Me
2-BrC6H4
Me
3-MeOC6H4
Me
3,4−OCHH2OC6H3
3-(N-Boc-indolyl)
Me
6
Me
4-NO2C6H4
9
93
g
h
i
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3-FC6H4
4-MeC6H4
2-MeOC6H4
cyclopentyl
Ph
5.5
5.5
5.5
5.5
5.5
5
94 (99)
97
Me
Me
95 (99)
96
j
Me
k
l
OMe
OMe
OtBu
97 (99)
96 (99)
98
Ph
m
Me
Ph
9
a
b
c
The reaction was performed on a 0.4 mmol scale (0.5 M in DCM). Sum of reaction time. Combined yield of isolated product as a mixture of
d
diastereomers after flash chromatography. Diastereomeric ratio: major-(2S,3S,4S,5R,6R) vs minor-(2S,3S,4S,5S,6S) diastereomer determined by 1H
NMR; after one recrystallization dr > 20:1. Determined by HPLC analysis on a chiral stationary phase for the major diastereomer; value in
e
parentheses after one recrystallization.
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: enders@rwth-aachen.de. Fax: (+49)-241-809-2127.
Notes
The authors declare no competing financial interest.
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