Cu(II)-Catalyzed Olefin Migration and Prins Cyclization: Highly Diastereoselective Synthesis of Substituted Tetrahydropyrans

Article abstract of DOI:10.1021/ol2016675

Metal-ligand complexes of Cu(OTf)₂ with an appropriate bisphosphine ligand have been shown to effectively catalyze the formation of substituted tetrahydropyrans via a sequential olefin migration and Prins-type cyclization. This methodology provides convenient access to a variety of functionalized tetrahydropyrans in excellent diastereoselectivities and good to excellent yields.

Full text of DOI:10.1021/ol2016675

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4328–4331
Cu(II)-Catalyzed Olefin Migration and
Prins Cyclization: Highly
Diastereoselective Synthesis of
Substituted Tetrahydropyrans
Arun K. Ghosh* and Daniel R. Nicponski
Departments of Chemistry and Medicinal Chemistry, Purdue University,
560 Oval Drive, West Lafayette, Indiana 47907, United States
akghosh@purdue.edu
Received June 21, 2011
ABSTRACT
Metalꢀligand complexes of Cu(OTf)2 with an appropriate bisphosphine ligand have been shown to effectively catalyze the formation of
substituted tetrahydropyrans via a sequential olefin migration and Prins-type cyclization. This methodology provides convenient access to a
variety of functionalized tetrahydropyrans in excellent diastereoselectivities and good to excellent yields.
Substituted tetrahydropyran rings are important struc-
tural motifs in a variety of bioactive natural products.1,2
These heterocycles are also frequently utilized in medicinal
chemistry.3 As a result, numerous new strategies for the
synthesis of tetrahydropyran units have been developed
and utilized in the synthesis of bioactive compounds.4
Methods such as hetero-DielsꢀAlder reactions,5a Prins
reactions,5b oxy-Michael reactions,5c PetasisꢀFerrier
rearrangement,5d and MaitlandꢀJapp reactions5e have
been widely used for the synthesis of highly functionalized
tetrahydropyrans.5,6 In our continuing studies to probe the
active sites of various aspartic acid proteases with ste-
reochemically defined, cyclic ether-derived ligands, we
required a range of 2,3-disubstituted tetrahydropyran
derivatives.7 Hosomi and co-workers have reported access
to these functionalized tetrahydropyrans by a platinum-
(II)-catalyzed condensation of 5-methyl-5-hexen-l-ol with
aldehydes.8 This methodology appeared attractive because
of the ready availability of the starting alkenols and
aldehydes. However, the reported platinum(II)-catalyzed
condensation reaction required an elevated reaction tem-
perature (100 °C).8 In an effort to carry out this transfor-
mation under more ambient conditions, we have
investigated a variety of ligandꢀmetal complexes under
mild conditions. Herein, we report a Cu(OTf)2-bispho-
sphine catalyzed sequential olefin migration and Prins
cyclization of alkenols with a variety of aldehydes to
provide 2,3-disubstituted and 2,3,6-trisubstituted tetrahy-
dropyrans in a highly diastereoselective manner.
(1) (a) Tan, L. T. Phytochemistry 2007, 68, 954–979. (b) Sanz, M. A.;
Voigt, T.; Waldmann, H. Adv. Synth. Catal. 2006, 348, 1511–1515.
(c) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301–2323.
(2) (a) Nakata, T. Chem. Rev. 2005, 105, 4314–4347. (b) Gademann,
K.; Portmann, C. Curr. Org. Chem. 2008, 12, 326–341.
(3) (a) Carrillo, R.; Leon, L. G.; Martın, T.; Martın, V. S.; Padron,
J. M. Bioorg. Med. Chem. Lett. 2006, 16, 6135–6138. (b) Singh, P.;
Bhardwaj, A. J. Med. Chem. 2010, 53, 3707–3717.
(4) Tietze, L. F.; Kettschau, G.; Gewer, J. A.; Schuffenhauer, A.
Curr. Org. Chem. 1998, 2, 19–62.
As shown in Scheme 1, we initially surveyed the reaction
of 5-methyl-5-hexen-1-ol (1) with benzyloxyacetaldehyde
(5) (a) Pellissier, H. Tetrahedron 2009, 65, 2839–2877. (b) Crane,
E. A.; Scheidt, K. A. Angew. Chem., Int. Ed. 2010, 49, 8316–8326.
(c) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2008, 1218–1228. (d) Smith,
A. B., III; Fox, R. J.; Razler, T. M. Acc. Chem. Res. 2008, 41, 675–687.
(e) Clarke, P. A.; Martin, W. H. C.; Hargreaves, J. M.; Wilson, C.; Blake,
A. J. Org. Biomol. Chem. 2005, 3, 3551–3563.
(6) (a) Katritzsky, A. R. Ed. Comp. Heterocycl. Chem. 2008, 7,
419ꢀ700. (b) Santos, S.; Clarke, P. A. Eur. J. Org. Chem. 2006, 2045.
(7) (a) Ghosh, A. K. J. Med. Chem. 2009, 52, 2163–2176. (b) Ghosh,
A. K. J. Org. Chem. 2010,75, 7967–7989. (c) Ghosh, A. K.; Kumaragurubaran,
N.; Hong, L.; Koelsh, G.; Tang., J. Curr. Alz. Res. 2008, 5, 121–131.
(8) Miura, K.; Horiike, M.; Inoue, G.; Ichikawa, J.; Hosomi, A.
Chem. Lett. 2008, 37, 270–271.
r
10.1021/ol2016675
Published on Web 07/28/2011
2011 American Chemical Society

(entry 8). Of particular note, the corresponding reaction
with Cu(OTf)2 in CH2Cl2 at 25 °C for 24 h provided no
product formation. The reaction with Cu(BINAP)(OTf)2
in CH2Cl2 at 25 °C afforded 80% yield of 3a and 3b (entry
10) The corresponding reaction with Pt(BINAP)(OTf)2
required 100 °C to provide 3a and 3b in 55% yield
(entry 11). We then examined Cu(OTf)2 and a number of
bisphosphine complexes (entries 12ꢀ18). Among them,
metalꢀligand complexes of Cu(OTf)2ꢀcis-1,2-bis-
(diphenylphosphino)ethylene (L1) or Cu(OTf)2ꢀ1,2-bis-
(diphenylphosphino)benzene (L2) provided the best
results at 40 °C (entries 17 and 18). Catalyst loading
was found to be optimal at 15 mol %. Also, we found
that 1.25 equiv of alkenol, 1 equiv of aldehyde in 0.1 M
solution of CH2Cl2, provided best results. The Cu(II)-
catalyzed reaction with 2,20-bis(diphenylphosphino)-
1,10-binaphthyl also provided good conversion and
yield. However, this reaction did not exhibit any enan-
tioselectivity with the atropisomerically chiral BINAP.
We therefore decided to use achiral ligands 4 (L1) and 5
(L2) and planned to investigate the scope and utility of
this catalytic system using a range of aldehydes.
Scheme 1. Catalytic Diastereoselective Synthesis of Substituted
Tetrahydropyrans
(2) in the presence of a number of metalꢀligand complexes
typically utilized in Prins-type cyclization reactions.9 As
can be seen in Table 1, various metal triflate-catalyzed
reactions (10 mol %, entries 1ꢀ4, and 11) at 100 °C
provided only moderate yields of diastereomeric mixtures
(dr >20:1) of products 3a and 3b. In addition to the triflate
in entry 4, we studied counterion effects at 100 °C in PhMe
for 24 h. Both BF4ꢀ (18% yield of 3a) and ClO4ꢀ (0% yield
of 3a) showed poor results. The Cu(OTf)2-catalyzed reac-
tion in dichloroethane at 65 °C provided 26% yield of 3a as
the major product (entry 5). Interestingly, the addition of
water or the attempted elimination of water (CaCl2,
Table 2. Substrate Scope and Product Structure of Substituted
Tetrahydropyrans
Table 1. Survey of Metals and Ligands for the Formation of
Substituted Tetrahydropyrans
entry catalyst (10 mol %) solvent temp (°C) (time (h)) yield (%)
1
2
3
4
5
6
7
8
9
Pd(OTf)2
PhMe
PhMe
PhMe
PhMe
DCE
111 (12)
100 (12)
100 (12)
100 (15)
65 (12)
65 (12)
25 (120)
25 (168)
25 (144)
25 (12)
100 (5)
25 (120)
25 (12)
25 (14)
25 (72)
25 (168)
40 (40)
40 (40)
29
24
31
52
26
37
38
52
0
Ni(OTf)2 6H2O
3
Ni(PPh3)2(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(dppe)(OTf)2
Cu(L1)(OTf)2
Cu(L2)(OTf)2
DCE
DCM
DCM
Cu(t-BuBOX)(OTf)2 DCM
10 Cu(BINAP)(OTf)2
11 Pt(BINAP)(OTf)2
12 Cu(MeCN)2(OTf)2
13 Cu(dppm)(OTf)2
14 Cu(dppe)(OTf)2
15 Cu(DIOP)(OTf)2
DCM
PhMe
DCM
DCM
DCM
DCM
80
55
58
15
43
24
33
64
51
16 Cu(TRIPhos)(OTf)2 DCM
17 Cu(L1)(OTf)2
18 Cu(L2)(OTf)2
DCM
DCM
MgSO4, and 4 A MS) resulted in the cessation of this
reaction.10 The reaction with Cu(dppe)(OTf)2 in dichlor-
oethane at 65 °C resulted in 37% yield after 24 h (entry 6).
The Cu(OTf)2-catalyzedreactionwithligandL2 inCH2Cl2
at 25 °C provided a slight improvement in the yield
a Conditions: 1 (1.25 equiv), aldehyde (1 equiv), Cu(OTf)2 (0.15
equiv), ligand (0.15 equiv), 0.1 M in CH2Cl2, 40 °C, 12ꢀ40 h. b Values
shown in parentheses are brsm. c Determined by NMR. d GCꢀMS
analysis.
(9) Clarke, M. L.; France, M. B. Tetrahedron 2008, 64, 9003–9031.
(10) Tadpetch, K.; Rychnovsky, S. D. Org. Lett. 2008, 10, 4839–
4842.
Org. Lett., Vol. 13, No. 16, 2011
4329

As can be seen from Table 2, a wide range of function-
ality istolerated in this reaction. Inthe caseofreactionwith
benzyloxyacetaldehyde (2), good yield and excellent dia-
stereoselectivity were observed (entries 1 and 2). The
corresponding reaction with tosyloxyacetaldehyde
(entries 3 and 4) also provided good yield; however, the
observed diastereomeric ratio was 16:1 with L1 and 13:1
with L2. Both benzaldehyde (8) and electron-poor 4-ni-
trobenzaldehyde (10) provided respective products 9 and
11 in good yield and excellent diastereoselectivity (entries
5ꢀ8). In the case of anthracene-9-carboxaldehyde (12),
good yield and good diastereoselectivity were observed
(entries 9 and 10). Thiophene-2-carboxaldehyde (14) is
also a suitable substrate for this reaction, providing ex-
cellent yield and diastereoselectivity (entries 11 and 12).
Conjugated aldehyde 16 (entries 13 and 14) or saturated
arylalkyl aldehydes 18 and 20 (entries 15ꢀ18) also gave
good results. Branched chain aliphatic aldehydes afforded
good yields and excellent diastereoselectivity (entries
19ꢀ22). The reaction with n-butyraldehyde provided only
moderate yield but excellent diastereoselectivity (entry 23).
Attempted reaction with electron-rich p-anisaldehyde re-
sulted in no appreciable cyclization product.
For determination of the X-ray crystal structure, the
major product 3 (entry 1) was subjected to hydrogenation
under a hydrogen atmosphere in the presence of 10%
Pearlman’s catalyst in ethanol. This resulted in the satura-
tion of the double bond as well as the removal of the benzyl
protecting group.
The resulting alcohol was treated with p-nitrobenzoyl
chloride and triethylamine to provide nitrobenzoate deri-
vative 28. This was later recrystallized from hexanes and
CH2Cl2 (ꢀ20 °C, 14 days). Subsequent single crystal X-ray
crystallographic analysis (Figure 2) further supported the
assignment of the trans-stereochemistry.11,12
Figure 1. 1H NOESY analysis of 7a (trans-isomer) and 7b (cis-
isomer).
Figure 2. Synthesis and ORTEP drawing of 28.
We have also carried out olefin migration and Prins
cyclization using enantioenriched alcohol 29, which was
prepared by CoreyꢀBakshiꢀShibata reduction13 of the
corresponding ketone. Alcohol 29 was obtained in 89% ee.
As shown in Scheme 2, reaction of alcohol 29 with
benzyloxyacetaldehyde 2 provided 30a diastereoselectively
(dr >20:1). The trans-isomer 30a was obtained in 89% ee
which indicated that the cyclization resulted in no loss of
optical activity. Rychnovski and co-workers have shown
that the condensation of alcohols with aldehydes in at-
tempted 6-(2,5)-Prins reactions undergoes partial or com-
plete racemization via an oxonia-Cope processes.14 This
As shown, the trans isomer was the major product.
Typically, only a single isomer was observed by NMR or
GCꢀMS analysis. The reaction of 5-methyl-5-hexen-1-ol
(1) with tosyloxyacetaldehyde (6) (entries 3 and 4) was
found to provide chromatographically separable diaster-
eoisomers 7a (trans-major) and 7b (cis-minor). The stereo-
chemical assignment of these compounds was carried out
1
by H NMR NOESY experiments (Figure 1). The ob-
served NOESY between HaꢀHd, HbꢀHc, HcꢀHf, and
HdꢀHe for compound 7a is consistent with the assigned
trans-stereochemistry. Similarly, the observed NOESY
between HbꢀHc, HcꢀHd, HcꢀHf, and HdꢀHf supported
the assigned cis-stereochemistry for compound 7b.
(14) Rychnovski, S. D.; Jasti, R. J. Am. Chem. Soc. 2006, 128, 13640–
13648.
(15) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920–1923.
(16) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021–1050.
(17) Kocovsky, P.; Ahmed, G.; Srogl, J.; Malkov, A. V.; Steele, J.
J. Org. Chem. 1999, 64, 2765–2775.
(11) Single-crystal X-ray analysis was performed in-house. Dr. Phil
Fanwick, X-Ray Crystallography Laboratory, Department of Chemis-
try, Purdue University, West Lafayette, IN, 47907.
(12) CCDC 830732 contains the supplementary crystallographic
data for Compound 28. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(13) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551–5553.
(18) Gesinski, M. R.; Van Orden, L. J.; Rychnovsky, S. D. Synlett
2008, 3, 363–366.
4330
Org. Lett., Vol. 13, No. 16, 2011

Scheme 2. Synthesis of Optically Active Tetrahydropyran
indicates that the present cyclization pathway does not
involve a [3,3]-sigmatropic rearrangement.
The stereochemical outcome of the olefin migration and
Prins cylization reactions which lead to trans-2,3-disubsti-
tuted tetrahydropyran derivatives can be rationalized
based upon the ZimmermanꢀTraxler15 transition-state
models shown in Figure 3. The Cu(OTf)2-based Lewis acid
catalyzed reaction could lead to the formation of an
oxycarbenium ion.16 Subsequentolefinmigration followed
by cyclization may proceed through either favored transi-
tion state 32 or disfavored transition state 33. The proton
abstraction beta to the carbocation would give rise to
trans-2,3- and cis-2,3-tetrahydropyrans 34 and 35,
respectively.17,18 The transition state 32 is favored due to
the lack of developing pseudo-1,3-diaxial interactions, as is
seen in 33. Consistent with the primary alkenol cycliza-
tions, the secondary alkenol cyclization (29) also provided
a 2,3,6-trans,trans-tetrahydropyran (30a) as the only de-
tectable isomer.
Figure 3. Stereochemical model for trans-selectivity.
good yields and excellent trans-diastereoselectivity. The
combination of Cu(OTf)2 and bisphophine ligands 4 and 5
has not been previously used in the synthesis of such
substituted tetrahydropyran derivatives. Further applica-
tion of these substituted tetrahydropyran derivatives are
currently underway in our laboratory.
Acknowledgment. Financial support by the National
Institutes of Health is gratefully acknowledged. We thank
Professor Ei-ichi Negishi (Purdue University) for helpful
discussions. We also thank Dr. Bruno D. Chapsal (Purdue
University) for his help and David D. Anderson (Purdue
University) for assistance with HPLC work.
In summary, we have developed a mild Cu(OTf)2-bi-
sphosphine-catalyzed reaction for the synthesis of substi-
tuted tetrahydropyran derivatives using 5-methyl-5-hexen-
1-ol and an appropriate aldehyde. The reaction proceeded
with an olefin migration followed by a Prins cyclization
to provide a range of tetrahydropyran derivatives in
Supporting Information Available. Experimental pro-
cedures and 1H and 13C NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
4331