Organocatalytic approach to polysubstituted piperidines and tetrahydropyrans

Article abstract of DOI:10.1021/ol200004s

Polysubstituted piperidines and tetrahydropyrans are synthesized from aldehydes and two classes of trisubstituted nitroolefins via an O-TMS protected diphenylprolinol catalyzed domino Michael addition/aminalization (or acetalization) process. This approac

Full text of DOI:10.1021/ol200004s

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1602–1605
Organocatalytic Approach to
Polysubstituted Piperidines and
Tetrahydropyrans
You Wang,† Shaolin Zhu,‡ and Dawei Ma*,‡
Department of Chemistry, Fudan University, Shanghai 200433, China, and State Key
Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Madw@mail.sioc.ac.cn
Received January 3, 2011
ABSTRACT
Polysubstituted piperidines and tetrahydropyrans are synthesized from aldehydes and two classes of trisubstituted nitroolefins via an O-TMS
protected diphenylprolinol catalyzed domino Michael addition/aminalization (or acetalization) process. This approach allows formation of four
contiguous stereocenters in the piperidine or tetrahydropyran ring in one step with excellent enantioselectivity.
In recent years, organocatalytic Michael addition of
aldehydes to nitroolefins has received great attention.1,2,4a,4b
However, attempts to extend the reaction scope to trisub-
stituted nitroolefins are rare.3 Until now only two such
substrates, 1-nitrocyclohexene and 1-nitrocyclopentene,
were reported to be suitable Michael acceptors for
this reaction.3 This problem might result from these
trisubstituted olefins being less reactive owing to their
steric hindrance and electronic nature.
By employing functionalized electron-deficient olefins,
we have explored the scope of organocatalytic Michael
addition and found some synthetically useful reactions.4
Recently, we discovered that Cbz-protected 1-amino-
methyl nitroolefins 3 could react with aldehydes under
the catalysis of O-TMS protected diphenylprolinol to give
adducts 4 (Scheme 1), which spontaneously underwent
aminalization to provide polysubstituted piperidines 5.5,6
Additionally, 1-hydroxymethyl nitroolefins were found to
undergo a similar process to afford polysubstituted tetra-
hydropyrans. Herein, we wish to disclose our results.
† Fudan University.
‡ Chinese Academy of Sciences.
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r
10.1021/ol200004s
Published on Web 03/01/2011
2011 American Chemical Society

Table 2. Assembly of Polysubstituted Piperidines via Organo-
catalytic Reaction of Aldehydes and Functionalized
Nitroolefinsa
Scheme 1. Organocatalytic Michael Addition of Aldehydes to
Cbz-Protected 1-Aminomethyl Nitroolefins 3 and Subsequent
Aminalization
Table 1. Condition Screening for Formation of 5a from
n-Butanal and Nitroolefin 3aa
BzOH
t
yield
(%)b
ee
(%)d
entry
solvent
(mol %)
(h)
drc
1
2
3
4
5
H2O
50
4
4
82
85
24
54
60
6:1
6:1
5:1
5:1
6:1
98
98
99
-
H2O
30
CHCl3
MeOH
H2O
60e
30
24
24
4
30f
-
a Reaction conditions: 3a (0.15 mmol), n-butanal (0.30 mmol),
10 mol % 1, 30 mol % BzOH, water (0.3 mL), rt. b Isolated yield.
c Determined by 1H NMR of the crude product. d Determined by chiral-
phase HPLC analysis of 5a. e 20 mol % 1 was used. f HOAc was used to
replace benzoic acid.
As indicated in Table 1, we chose the reaction of
n-butanal with nitroolefin 3a (prepared via condensation of
Cbz protected 2-amino-1-nitroethane with n-butanal and
subsequent elimination) as a model to explore optimized
reaction conditions. It was found that this reaction worked
under our previous conditions (10 mol % of 1and 50 mol %
a Reaction conditions: nitroolefin (0.15 mmol), aldehyde (0.30
mmol), 10 mol % 1, 30 mol % BzOH, water (0.3 mL), rt. b Isolated
yield. c Determined by 1H NMR of the crude products. d Determined by
chiral-phase HPLC analysis of piperidines 5-7. e Determined by chiral-
phase HPLC analysis of reduced products (with Et3SiH/BF3•OEt2) of 5.
f 20 mol % 1 was used. g The data in parentheses is for the minor isomer.
h The reaction was catalyzed by O-TMS protected dinaphthylprolinol in
the absence of BzOH. i 15 mol % 1 was used.
(6) For recent examples on the synthesis of polysubstituted piper-
idines, see: (a) Wang, Y.; Yu, D.-F.; Liu, Y.-Z.; Wei, H.; Luo, Y.-C.;
Dixon, D. J.; Xu, P.-F. Chem.;Eur. J. 2010, 16, 3922. (b) Urushima, T.;
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Chem. Soc. 2007, 129, 9300. (g) Wu, T. R.; Chong, J. M. J. Am. Chem.
Soc. 2006, 128, 9646. (h) Reggelin, M.; Junker, B.; Heinrich, T.; Slavik,
of benzoic acid, in water) to afford hemiaminal 5a in 82%
yield (entry 1). Reducing the amount of benzoic acid gave a
similar result (entry 2), and therefore this ratio was used in
later studies. Using organic solvents (entries 3 and 4) or
switching the additive to acetic acid (entry 5) reduced the
€
S.; Buhle, P. J. Am. Chem. Soc. 2006, 128, 4023. (i) Zhang, Y.;
Liebeskind, L. S. J. Am. Chem. Soc. 2006, 128, 465. (j) Smith, A. B.;
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Org. Lett., Vol. 13, No. 7, 2011
1603

reaction yields. Thus, it seemed that a combination of
benzoic acid and water is essential for this transformation.
We next examined the reaction scope by varying alde-
hydes and functionalized nitroolefins. As summarized in
Table 2, two other simple aldehydes and three functionalized
aldehydes worked well, affording substituted piperidines
5b-5f with good to excellent yields and diastereoselectivity
(entries 1-5). In these transformations greater than 99% ee
were observed for major isomers. However, the reaction
became sluggish when bulky isobutyraldehyde was em-
ployed. In this case only a moderate yield and diastereoselec-
tivity were observed, although the enantioselectivity did not
drop significantly (entry 6). We were pleased that acetalde-
hyde could be used successfully, delivering 3-unsubstituented
piperidines with a good yield and satisfactory stereochemical
outcome (entry 7). A better result was obtained by changing
reaction conditions (entry 8, using O-TMS protected di-
naphthylprolinol as a catalyst and without the addition of
PhCO2H).
For functionalized nitroolefins, it was found that both
alkyl substituted (entries 1-8) and aryl substituted olefins
(entries10-12) were compatible with this reaction. Addition-
ally, an olefin without any substituents at the 2-position could
be applied in this reaction, although both the yield and enan-
tioselectivity were only moderate (entry 13). Furthermore,
changing the N-protecting group to Boc was found possible,
as evident from the fact substituted piperidines 6a and 6b
could be elaborated from the corresponding olefins. In this
case improved diastereoselectivity was obtained (compare
entry 14 with entry 2 of Table 1). While an Ac-protected
substrate was utilized, the resulting product was found not
stable during column purification, and therefore these piper-
idines were converted into tetrahydropyridine 7 by treatment
with TFA in order to obtain the pure product (entry 16).
Obviously, the present cyclic hemiaminals are valuable
building blocks for elaborating other substituted piperidines.
For example, the reduction of 5a with Et3SiH in the presence
Scheme 2. Transformation of Cyclic Hemiaminals into Other
Substituted Piperidines
Scheme 3. Formation of Tetrahydropyrans via Reaction of
Hydroxymethyl Substituted Nitroolefins with n-Pentanal
of BF3 OEt2 produced 1,3,4,5-tetrasubstituted piperidine 8
(Scheme 2) and the dehydration of 5i with TFA afforded
tetrahydropyridine 9, while BF3 OEt2 mediated allylation of
3
Figure 1. Structures of some trisubstituted nitroolefins.
3
In view of the above encouraging results, we next checked
other trisubstituted nitroolefins. As outlined in Scheme 3, the
reaction of hydroxymethyl substituted nitroolefins 11 and
n-pentanal proceeded smoothly under the catalysis of 1 and
benzoic acid, giving hemiacetals 12 with good yields and
excellent enantioselectivity. However, nitroolefins 13-16
(Figure 1) were found inert under our typical reaction
conditions. These results clearly demonstrated that a free
NH or OH group at the 1-methylene position is essential for
Michael addition of these two classes of trisubstituted ni-
troolefins. We speculated that two factors might be respon-
sible for their special reactivity. One is that the intramolecular
hydrogen bond might lead to a more active nitro group.9
Another one is subsequent cyclization might facilitate the
first Michael reaction. Noteworthy is that compounds 12
4l with allyl trimethylsilane delivered piperidine 10 as a single
product. This fact, together with the knowledge that a wide
range of cyclic hemiaminals could be assembled via the
domino process, demonstrated that our approach provides
a useful method for the diverse synthesis of substituted
piperidines.5,6 It is notable that nitro group-containing piper-
idines have been used as valuable intermediates for the
synthesis of novel farnesyltransferase inhibitors7 and selective
dipeptidyl peptidase IV inhibitors that are promising for
treatment of type 2 diabetes.8
(7) (a) Nara, S.; Tanaka, R.; Eishima, J.; Hara, M.; Takahashi, Y.;
Otaki, S.; Foglesong, R. J.; Hughes, P. F.; Turkington, S.; Kanda, Y. J.
Med. Chem. 2003, 46, 2467. (b) Tanaka, R.; Rubio, A.; Harn, N. K.;
Gernert, D.; Grese, T. A.; Eishima, J.; Hara, M.; Yoda, N.; Ohashi, R.;
Kuwabara, T.; Soga, S.; Akinaga, S.; Naraa, S.; Kanda, Y. Bioorg. Med.
Chem. 2007, 15, 1363.
(8) Pei, Z.; Li, X.; von Geldern, T. W.; Longenecker, K.; Pireh, D.;
Stewart, K. D.; Backes, B. J.; Lai, C.; Lubben, T. H.; Ballaron, S. J.;
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(9) During the preparation of this manuscript, an example about the
activation of a nitro group via an intramolecular hydrogen bond was
reported; see: Zhang, F.; Wei, M.; Dong, J.; Zhou, Y.; Lu, D.; Gong, Y.;
Yang, X. Adv. Synth. Catal. 2010, 352, 2875.
1604
Org. Lett., Vol. 13, No. 7, 2011

substituted nitroolefins 11 were compatible with this process,
while related alkyl substituted nitroolefins were found in-
active. Further studies are required in order to solve this
problem.
The structures of the present products were initially
established by NMR analysis. Their stereochemistry was
further confirmed by X-ray analysis of 6b and 12b as
depicted in Figure 2. It is notable that in our case the
stereochemistry of the nitro group was controlled excel-
lently through enantioselective protonation (presumably
in a thermodynamic manner).11
In conclusion, we have developed a highly efficient
domino process for the assembly of polysubstituted
piperidines and tetrahydropyrans. This process allows
for the formation of four contiguous stereocenters in
the piperidine or tetrahydropyran ring in one step with
excellent enantioselectivity. The diverse functional
groups in the products will permit further manipulation
for synthesizing bioactive compounds. More impor-
tantly, our results demonstrated that some trisubsti-
tuted nitroolefins are suitable Michael acceptors for
organocatalytic reactions, in which the intramolecular
hydrogen bond might play an important role for acti-
vating the nitro group. Further investigations for ex-
tending the scope of Michael addition by using this
concept are actively pursued in our laboratory, and the
results will be reported in due course.
Acknowledgment. The authors are grateful to the Min-
istry of Science and Technology (Grant 2009ZX09501-00),
Chinese Academy of Sciences, and National Natural
Science Foundation of China (Grants 20632050 and
20921091) for their financial support.
Figure 2. X-ray structures of 6b and 12b.
could be transformed into substituted glutamate derivatives
that are useful building blocks for assembling biologi-
cally important compounds.10 Unfortunately, only aryl
Supporting Information Available. Experimental pro-
1
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