Highly stereoselective synthesis of 2,6- cis -substituted tetrahydropyrans using a one-pot sequential catalysis

Article abstract of DOI:10.1021/ol400900h

A catalytic highly diastereo- and enantioselective synthesis of 2,6-cis-substituted tetrahydropyrans was realized using a one-pot sequential catalysis involving Henry and oxa-Michael reactions. The nitroaldol products obtained in a highly enantioselective copper(II)-catalyzed Henry reaction between nitromethane and 7-oxo-hept-5-enals were subsequently treated with a catalytic amount of camphorsulfonic acid (CSA) to give the desired tetrahydropyran derivatives in excellent yields, diastereoselectivities (dr >99:1), and enantioselectivities (ee = 98-99%). The reaction can also be used for the high stereoselective synthesis of a cis-2,6-disubstituted morpholine.

Full text of DOI:10.1021/ol400900h

ORGANIC
LETTERS
2013
Vol. 15, No. 12
2922–2925
Highly Stereoselective Synthesis of
2,6-cis-Substituted Tetrahydropyrans
Using a One-Pot Sequential Catalysis
Qipu Dai,† Nirmal K. Rana, and John Cong-Gui Zhao*
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle,
San Antonio, Texas 78249-0698, United States
cong.zhao@utsa.edu
Received April 2, 2013; Revised Manuscript Received June 6, 2013
ABSTRACT
A catalytic highly diastereo- and enantioselective synthesis of 2,6-cis-substituted tetrahydropyrans was realized using a one-pot sequential
catalysis involving Henry and oxa-Michael reactions. The nitroaldol products obtained in a highly enantioselective copper(II)-catalyzed Henry
reaction between nitromethane and 7-oxo-hept-5-enals were subsequently treated with a catalytic amount of camphorsulfonic acid (CSA) to give
the desired tetrahydropyran derivatives in excellent yields, diastereoselectivities (dr >99:1), and enantioselectivities (ee = 98À99%). The reaction
can also be used for the high stereoselective synthesis of a cis-2,6-disubstituted morpholine.
One-pot sequential catalysis, also referred to as tandem
catalysis,1 is a very efficient method for assembling com-
plex molecular structures from relatively simple starting
materials since this synthetic strategy involves a modular
combination of several catalytic reactions into one synthetic
operation with minimum workup or change in reaction
conditions. Because this method can significantly improve
the synthetic efficiency, recently there has been a lot of
attention in developing novel one-pot sequential catalytic
methods.1,2
Tetrahydropyran is an important structural motif that
may be found in many natural products that often show
diverse and potent biological activities.3 Due to their
importance in organic synthesis, many synthetic strategies
have been developed in order to obtain these derivatives in
highly diastereo- and/or enantioselectivities.4,5 Among these
reported methods, catalytic intramolecular oxa-Michael5
† Current address: Department of Chemistry, University of Alabama at
Birmingham.
(1) For reviews, see: (a) Zhou, J. Chem.;Asian J. 2010, 5, 422–434.
(b) Ambrosini, L. M.; Lambert, T. H. ChemCatChem 2010, 2, 1373–
1380. (c) Wende, R. C.; Schreiner, P. R. Green Chem. 2012, 14, 1821–
1849. (d) Patil, N. T.; Shinde, V. S.; Gajula, B. Org. Biomol. Chem. 2012,
10, 211–224.
(3) (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2010, 27, 165–237. (b) Molinski, T. F.;
Dalisay, D. S.; Lievens, S. L.; Saludes, J. P. Nat. Rev. Drug Discov. 2009,
8, 69–85.
(4) For reviews, see: (a) Larrosa, I.; Romea, P.; Urpı, F. Tetrahedron
´
2008, 64, 2683–2723. (b) Clarke, P. A.; Santos, S. Eur. J. Org. Chem.
2006, 2045–2053. (c) Smith, A. B., III; Fox, R. J.; Razler, T. M. Acc.
Chem. Res. 2008, 41, 675–687.
(5) For reviews, see: (a) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2008,
37, 1218–1228. (b) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2012, 41, 988–
999.
(2) For some selected recent examples, see: (a) Li, F.; Sun, L.; Teng,
Y.; Yu, P.; Zhao, J. C.-G.; Ma, J.-A. Chem.;Eur. J. 2012, 18, 14255–
14260. (b) Dai, Q.; Arman, H.; Zhao, J. C.-G. Chem.;Eur. J. 2013, 19,
~
ꢀ
1666–1671. (c) Pena, J.; Anton, A. B.; Moro, R. F.; Marcos, I. S.;
Garrido, N. M.; Dıez, D. Tetrahedron 2011, 67, 8331–8337. (d) Liu, L.;
Wei, L.; Lu, Y.; Zhang, J. Chem.;Asian J. 2010, 16, 11813–11817. (e)
´
(4) For reviews, see: (a) Larrosa, I.; Romea, P.; Urpı, F. Tetrahedron
´
ꢁ
€
Kolarovic, A.; Schnurch, M.; Mihovilovic, M. D. J. Org. Chem. 2011,
ꢀ
76, 2613–2618. (f) Fructos, M. R.; Alvarez, E.; Dıaz-Requejo, M. M.;
´
2008, 64, 2683–2723. (b) Clarke, P. A.; Santos, S. Eur. J. Org. Chem.
2006, 2045–2053. (c) Smith, A. B., III; Fox, R. J.; Razler, T. M. Acc.
Chem. Res. 2008, 41, 675–687.
(5) For reviews, see: (a) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2008,
37, 1218–1228. (b) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2012, 41, 988–
999.
ꢀ
Perez, P. J. J. Am. Chem. Soc. 2010, 132, 4600–4607. (g) Fuwa, H.;
Noguchi, T.; Noto, K.; Sasaki, M. Org. Biomol. Chem. 2012, 10, 8108–
8112. (h) Cai, Q.; Liang, X.-W.; Wang, S.-G.; You, S.-L. Org. Biomol.
Chem. 2013, 11, 1602–1605. (i) Cai, Q.; Zhao, Z.-A.; You, S.-L. Angew.
Chem., Int. Ed. 2009, 48, 7428–7431.
r
10.1021/ol400900h
Published on Web 06/11/2013
2013 American Chemical Society

reactions have been shown to be a highly efficient ap-
proach for obtaining tetrahydropyran derivatives.6,7 For
example, both cis- and trans-2,6-disubstituted tetrahydro-
pyran derivatives, which are among the most abundant
motifs in natural products, have been synthesized this way.6,7
these catalysts led to the formation of the carba-Michael
product 2 only.2b,8 No formation of the desired oxa-
Michael product was observed probably because in com-
pound 1a the CÀH bond is more acidic than the OÀH
bond. Most recently Fuwa and co-workers have reported
that camphorsulfonic acid (CSA) (Figure 1) is a highly syn-
selective catalyst for oxa-Michael reactions of 7-oxo-hept-
5-enol derivatives.7 We then evaluated CSA as a catalyst
for cyclizing compound 1a. Indeed, with CSA as the
catalyst, the intramolecular oxa-Michael reaction gave
the expected 2,6-disubstituted 3a (R = Ph) (Scheme 1) as
a single diastereomer in a high yield. The relative stereo-
chemistry of this product was determined to be cis by NOE
experiments, which is also in agreement with the reported
syn-selectivity.7 Unfortunately, 3a was obtained as a race-
mic product using this protocol (data not shown). None-
theless, according to the reported mechanism,7 if an
optically enriched 1a is used as the substrate, then product
3a should be obtained in optically enriched form. Thus, we
screened several catalysts to obtain compound 1a in high
optical purity from enal 6a and nitromethane. Again many
basic catalysts reported for Henry reactions failed to
produce 1a as the reactions went further to form com-
pound 2 directly (data not shown). Gratifyingly, both
Ooi’s precatalyst 4 (Figure 1) in the presence of t-BuOK10
and Cu(OAc)2 in the presence of Wan’s ligands (5 and ent-5)
(Figure 1)11 gave 1a in good yields under their respective
optimized conditions.10,11 The (S)-enantiomer of compound
1a was obtained in 55% ee with 4/t-BuOK (Scheme 2, eq 3).
In contrast, with Wan’s catalytic system, both the (R)- and
(S)-enantiomers were obtained in a high ee value of 98%
using the enantiomeric ligands 5 and ent-5, respectively
(Scheme 2, eqs 4 and 5). With the optically enriched 1a in
hand, the CSA-catalyzed oxa-Michael reaction was con-
ducted again, and product 3a was obtained as a single
diastereomer in 90% yield with complete retention of the
optical purity (Scheme 2, eq 6). The enantiomer of 3a may be
similarly obtained by using (S)-1a as the starting material.
Scheme 1. Henry Product 1 May Be Used As an Ambident
Nucleophile in Intramolecular Michael Reactions
Using a one-pot sequential catalysis, we recently devel-
oped a highly stereoselective synthesis of trisubstituted
cyclohexane derivatives 2 from nitromethane and 7-oxo-
hept-5-enals involving the Henry product 1 as the inter-
mediate (Scheme 1).2b A base-catalyzed intramolecular
carba-Michael reaction leads to the formation of the
cyclohexane derivatives 2 (Scheme 1, eq 1).2b,8 During this
study, we envisioned that compound 1 may be used as an
ambident nucleophile in catalysis: An intramolecular oxa-
Michael reaction using the hydoxy group in compound 1
as a nucleophile should lead to the formation of 2,6-
disubstituted tetrahydropyrans 3 (Scheme 1, eq 2). Devel-
oping stereoselective synthesis of pyran derivatives has
been our ongoing research interest,9 and therefore, we
sought methods to conduct a stereoselective oxa-Michael
reaction on compound 1. Herein we wish to report a highly
diastereo- and enantioselective synthesis of cis-2,6-disubsti-
tuted tetrahydropyrans using a one-pot sequential catalysis.
Using the racemic Henry product 1a (R = Ph)
(Scheme 1) as the model substrate, we first attempted the
oxa-Michael using different base catalysts; however, all
(6) For some selected recent examples, see: (a) Lee, K.; Kim, H.;
Hong, J. Eur. J. Org. Chem. 2012, 1025–1032. (b) Byeon, S. R.; Park, H.;
ꢀ~
´
ez, D.; Nunez,
Kim, H.; Hong, J. Org. Lett. 2011, 13, 5816–5819. (c) Dı
ꢀ
M. G.; Beneitez, A.; Moro, R. F.; Marcos, I. S.; Basabe, P.; Broughton,
H. B.; Urones, J. G. Synlett 2009, 390. (d) Farmer, R. L.; Biddle, M. M.;
Nibbs, A. E.; Huang, X.; Bergan, R. C.; Scheidt, K. A. ACS Med. Chem.
Lett. 2010, 1, 400–405. (e) Hong, B.-C.; Kotame, P.; Tsai, C.-W.; Liao,
J.-H. Org. Lett. 2010, 12, 776–779. (f) Massi, A.; Nuzzi, A.; Dondoni, A.
€
J. Org. Chem. 2007, 72, 10279–10282. (g) Pellicena, M.; Kramer, K.;
Romea, P.; Urpı, F. Org. Lett. 2011, 13, 5350–5353. (h) Wang, L.; Li, P.;
´
Menche, D. Angew. Chem., Int. Ed. 2010, 49, 9270–9273. (i) Fuwa, H.;
Saito, A.; Sasaki, M. Angew. Chem., Int. Ed. 2010, 49, 3041–3044. (j)
Hajare, A. K.; Ravikumar, V.; Khaleel, S.; Bhuniya, D.; Reddy, D. S.
J. Org. Chem. 2010, 76, 963–966. (k) Xie, J.-H.; Guo, L.-C.; Yang, X.-H.;
Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2012, 14, 4758–4761. (l) McGarraugh,
P. G.;Brenner-Moyer, S. E.Org. Lett. 2011, 13, 6460–6463. (m) Lee, K.; Kim,
H.; Hong, J. Org. Lett. 2011, 13, 2722–2725.
(7) (a) Fuwa, H.; Ichinokawa, N.; Noto, K.; Sasaki, M. J. Org. Chem.
2011, 77, 2588–2607. (b) Fuwa, H.; Noto, K.; Sasaki, M. Org. Lett. 2011,
13, 1820–1823.
(8) Dai, Q.;Huang, H.;Zhao, J. C.-G. J. Org. Chem. 2013, 78, 4153–4157.
(9) (a) Ding, D.; Zhao, C.-G. Tetrahedron Lett. 2010, 51, 1322–1325.
(b) Gogoi, S.; Zhao, C.-G. Tetrahedron Lett. 2009, 50, 2252–2255. (c)
Muramulla, S.; Zhao, C.-G. Tetrahedron Lett. 2011, 52, 3905–3908. (d)
Ramireddy, N.; Abbaraju, S.; Zhao, C.-G. Tetrahedron Lett. 2011, 52,
6792–6795.
Figure 1. Structure of the catalyst and ligands used in this study
(Ar = p-CF3C6H4-).
(10) Uraguchi, D.; Sakaki, S.; Ooi, T. J. Am. Chem. Soc. 2007, 129,
12392–12393.
Org. Lett., Vol. 15, No. 12, 2013
2923

Table 1. Synthesis of 2,6-cis-Disubstituted Tetrahydrofurans
Using a One-Pot Sequential Catalysisa
Scheme 2. Synthesis of the Oxa-Michael Product Using Step-
wise and Sequential Catalyses
time (h)
yield
(%)b
ee
(%)d
entry
R
t1
t2
6/3
drc
1
C6H5
60
48
48
48
48
48
48
48
48
48
48
60
60
48
12
6
a
b
c
d
e
f
86
89
84
89
90
94
94
96
91
94
91
90
95
93
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
98
98
99
98
98
98
98
99
98
98
98
98
98
98
2
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
3-BrC6H4
Me
3
6
4
6
5
6
6
6
7
6
g
h
i
8
6
9
6
10
11
12
13
14
6
j
6
k
l
12
12
6
t-Bu
m
n
c-C3H5
a The Henry reaction was carried out with enal 6 (0.10 mmol) and
nitromethane (0.10 mL) in EtOH (0.4 mL) at room temperature with
copper(II) acetate monohydrate (0.0050 mmol, 5.0 mol %) and ligand 5
(0.0050 mmol, 5.0 mol %) as the catalyst for the indicated reaction time
(monitored by TLC). Once the Henry reaction was complete, CSA
(0.010 mmol, 10.0 mol %) was added to reaction mixture and the
reaction was continued for the indicated times (monitored by TLC) to
give the desired oxa-Michael product 3. b Yield of isolated product 3.
c Determined by 1HNMR analysis of the crude oxa-Michael reaction
product. d Determined by HPLC analysis using chiral HPLC columns.
Although the synthesis of the tetrahydropyran 3a may
be achieved in excellent results using the above stepwise
protocol, we thought a one-pot sequential catalysis using
enal 6a and nitromethane directly would be more conve-
nient and efficient. Thus, enal 6a and nitromethane were
first treated with Cu(OAc)2/5 for 60 h at rt and then with
CSA for 12 h under their respective optimized conditions,
and 3a was obtained as a single diastereomer in 86% yield
and 98% ee (Scheme 2, eq 7). These results are comparable
with those of the stepwise protocol.
The scope of this one-pot sequential catalysis was then
investigated with different enal derivatives 6, and the
results are summarized in Table 1. As the data in Table 1
show, all 7-aryl-substituted 7-oxo-hept-5-enals gave the
desired tetrahydropyran products 3 in similarly high yields
and excellent dr and ee values (Table 1, entries 1À11). The
electronic nature of the substituent and its position on the
phenyl ring have almost no influence at all on the reactiv-
ity, diastereoselectivity, or enantioselectivity of this reac-
tion. Similarly, 7-alkyl-substituted 7-oxo-hept-5-enals also
gave the desired tetrahydropyrans in excellent yields, dr,
and enantioselectivities (Table 1, entries 12À14). It should
be pointed out that the high dr and high ee value achieved in
this reaction are of different origins: The high ee values of oxa-
Michael product 3 originated in the first step of this reaction
via Wan’s catalytic system while the high diastereoselectivities
were achieved in the second step via the CSA-catalysis.
Using a nitrogen-containing substrate 7, the above
reaction may also be used for the synthesis of the optically
enriched cis-2,6-disubstituted morpholine derivative 8 in
high diastereoselectivity (dr > 99:1) and ee value (ee =
96%) (Scheme 3, eq 8).
Scheme 3. Some Further Applications of the One-Pot Sequen-
tial Catalysis
(11) Jin, W.; Li, X.; Huang, Y.; Wu, F.; Wan, B. Chem.;Eur. J. 2010,
16, 8259–8261.
2924
Org. Lett., Vol. 15, No. 12, 2013

As a potential application of this one-pot sequential
Henry-oxa-Michael reaction, product 3a was reduced by
hydrogenation. It was found that both the nitro and keto
groups in 3awere reducedtogivea diastereomeric mixture.
The mixture was then in situ protected with Boc anhydride
and oxidized with PCC to give compound 9 in 76% overall
yield with complete retention of the stereochemistry of the
starting material (Scheme 3, eq 9).
and enantioselectivities (ee = 98À99%) in a one-pot sequen-
tial catalysis. Using an appropriate substrate, the reaction
may also be used for the stereoselective synthesis of a cis-2,6-
disubstituted morpholine.
Acknowledgment. We thank the Welch Foundation
(Grant No. AX-1593) for the financial support of this
project.
Insummary, we have shown thatthe nitroaldol products
of 7-oxo-hept-5-enals and nitromethane may be used as
good substrates in the intramolecular oxa-Michael reac-
tion. Through combining a highly enantioselective copper-
(II)-catalyzed Henry reaction between 7-oxo-hept-5-enals
and nitromethane withthe camphorsulfonic acid catalyzed
highly diastereoselective intramolecular oxa-Michael reac-
tion, the corresponding tetrahydrofuran derivatives were
obtained in excellent yields, diastereoselectivities (dr > 99:1),
Supporting Information Available. General experimen-
tal procedure, characterization data of all new com-
1
pounds, and copies of H and 13C NMR spectra and
HPLC chromatograms of the oxa-Michael products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 12, 2013
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