Catalytic Asymmetric Vinylogous Prins Cyclization: A Highly Diastereo- and Enantioselective Entry to Tetrahydrofurans

Article abstract of DOI:10.1021/jacs.6b09129

We describe the design and development of the first catalytic asymmetric vinylogous Prins cyclization. This reaction constitutes an efficient approach for highly diastereo- and enantioselective synthesis of tetrahydrofurans (THFs) and is catalyzed by a confined chiral imidodiphosphoric acid (IDP). Aromatic and heteroaromatic aldehydes react with various 3,5-dien-1-ols to afford 2,3-disubstituted THFs in excellent selectivity (d.r. > 20:1, e.r. up to 99:1). Aliphatic aldehydes react with similarly excellent results when a highly acidic imidodiphosphorimidate (IDPi) catalyst is used. With a racemic dienyl alcohol, the reaction proceeds via a kinetic resolution. DFT calculations suggest an explanation for unusually high stereoselectivity.

Full text of DOI:10.1021/jacs.6b09129

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Vinylogous Prins Cyclization: A Highly
Diastereo- and Enantioselective Entry to Tetrahydrofurans
Youwei Xie, Gui-Juan Cheng, Sunggi Lee, Philip S. J. Kaib, Walter Thiel, and Benjamin List*
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mulheim an der Ruhr, Germany
̈
̈
S
* Supporting Information
diastereomeric forms of similar energy.8a,9 We speculated that
the confined chiral pocket provided by our recently developed
imidodiphosphates could further enhance the energetic differ-
ence of the two diastereomeric TSs and lead to highly
enantioenriched THF products.10
We started by reacting anisaldehyde (1a) with dienyl alcohol
2a in the presence of various chiral Brønsted acids (eq 2),
including phosphoric acids,11 disulfonimides,12 and imidodi-
phosphates:10
ABSTRACT: We describe the design and development of
the first catalytic asymmetric vinylogous Prins cyclization.
This reaction constitutes an efficient approach for highly
diastereo- and enantioselective synthesis of tetrahydrofur-
ans (THFs) and is catalyzed by a confined chiral
imidodiphosphoric acid (IDP). Aromatic and heteroar-
omatic aldehydes react with various 3,5-dien-1-ols to afford
2,3-disubstituted THFs in excellent selectivity (d.r. > 20:1,
e.r. up to 99:1). Aliphatic aldehydes react with similarly
excellent results when a highly acidic imidodiphosphor-
imidate (IDPi) catalyst is used. With a racemic dienyl
alcohol, the reaction proceeds via a kinetic resolution.
DFT calculations suggest an explanation for unusually high
stereoselectivity.
nitially reported by Hanschke in 1955,1 the Prins cyclization
has evolved into an important approach to biologically
I
relevant tetrahydropyrans (THPs).2−6 Catalytic asymmetric
variants of this transformation have emerged only recently,7
including an organocatalytic approach by our group.7a,b Despite
the maturity of the Prins cyclization, it almost invariably leads to
THPs rather than to the equally important and biologically active
tetrahydrofurans (THFs).8 We show that by using a confined
chiral imidodiphosphoric acid catalyst a previously unknown
vinylogous Prins cyclization can be realized that leads to THFs in
excellent regio-, diastereo-, and enantioselectivity.
Most imidodiphosphoric acids tested showed significantly
improved diastereoselectivity (>20:1) compared to those of
achiral Brønsted acids (4−5:1) and to chiral phosphoric acids
and disulfonimides (3−6:1), although yields and enantioselec-
tivity varied dramatically (a full list of catalysts and reaction
conditions investigated is in Table S3). Extensive experimenta-
tion with chiral Brønsted acids revealed two lead catalysts, (S,S)-
4a and (S,S)-4b, which both catalyze the reaction in toluene with
promising enantioselectivity (e.r. 85:15). Further optimization of
the reaction conditions with these two catalysts showed that
when used at room temperature in cyclohexane in the presence
of 5 Å molecular sieves as dehydrant, catalyst (S,S)-4b catalyzed
the reaction with good diastereo- and enantioselectivity;
corresponding 2,3-trans THF product 3a was obtained as sole
product in 80% isolated yield with e.r. of 94:6.
These reaction conditions were then used to explore the scope
of the catalytic asymmetric vinylogous Prins cyclization (Table
1). Various commercially available aldehydes bearing different
substituents were submitted to the reaction conditions using 4b.
Electron-rich (1a), -neutral (1b), and -deficient (1c) aldehydes
were all suitable substrates; corresponding THF products were
obtained in good yields and excellent diastereo- and
enantioselectivity. Other common substituents, e.g., alkynyl
(3d), vinyl (3e), and alkyl (3f), were also tolerated. Disubstituted
3g was also obtained in good yield and excellent selectivity.
Tested heteroaromatic aldehydes showed even better reactivity
In the Prins cyclization, acid-catalyzed condensation of an
aldehyde with a homoallylic alcohol leads to the formation of an
oxocarbenium ion, undergoing a 6-endo-trig cyclization to
deliver THP product selectively.2−5 We hypothesized that with a
dienyl homoallylic alcohol a vinylogous Prins cyclization to the
corresponding THF product via 5-endo-trig pathway should be
preferred as it would proceed via an allylic cation:
A challenge in developing such a THF synthesis is to achieve
high stereoselectivity: Unlike 6-membered cyclic TS of the
normal Prins cyclization, adopting a well-defined chair
conformation to deliver THP products with high diastereose-
lectivity,3e 5-membered TS of THF formation can exist in two
Received: August 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b09129
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Scope of the Asymmetric Vinylogous Prins Cyclization
a
Reaction conditions: r.t. in cyclohexane (0.1 M), 4b (5 mol %), 1.05 equiv of 1, 1.0 equiv of 2, and 5 Å molecular sieves (0.3 g mmol−1) for the
b
c
specified period of time. Isolated yields are reported. Only one disastereomer was obtained. Starting dienyl alcohol was enantiomerically pure;
absolute configuration of the stereogenic center is indicated in corresponding product. No THP formation was detected. For more examples, see the
SI.
compared to that of common aromatic aldehydes and gave
corresponding products 3h and 3i with slightly improved e.r.
Piperonal (1j) and 2-naphthaldehyde (1k) were also viable
substrates. Aliphatic α,β-unsaturated aldehydes could not be
used in this transformation due to an oxa-Michael side reation,
but cinnamaldehyde reacted smoothly to give 3l in good yield
and selectivity. The absolute configuration of 3b was determined
by derivatization to a known compound; those of the others were
assigned by analogy (Supporting Information (SI))
observed for these substrates depending on the absolute
configuration of the chiral dienyl alcohol. In the match case, 3s
and 3t were formed in excellent diastereoselectivity; in the
mismatch case, the reaction was much slower and an inseparable
mixture of diastereomers was obtained (SI). This observation
encouraged us to explore the possibility of a kinetic resolution:
We also explored some dienyl alcohols with varied substitution
patterns (Table 1, entries 13−18). Alkyl substituents at different
positions of diene moieties were all well-tolerated (3m−3r). Of
note is 3q, in which a quaternary center has been formed with
excellent diastereoselectivity but slightly diminished enantiose-
lectivity. The double bond of the diene can also be part of a ring
to deliver corresponding product 3r in excellent yield and
selectivity. 2,3,4- or 2,3,5-Trisubstituted THFs can be accessed
when enantiomerically enriched chiral dienyl alcohols are used
(Table 1, entries 19 and 20). A “match”/“mismatch” effect was
Indeed, (rac)-2s reacted selectively with 1m to give 3s in
excellent selectivity in the presence of 4b. This methodology
bears some promise for the syntheses of biologically active
B
DOI: 10.1021/jacs.6b09129
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Journal of the American Chemical Society
Communication
natural products and therapeutic agents that contain highly
substituted THFs. For example, the stereochemical arrangement
around the THF ring in 3s matches that of the lignan natural
products Sesaminone and Tanegool.15,16
tally. Figure 1 shows 3D structures of the most stable
conformations of TStrans and TScis, respectively. Several non-
Simple aliphatic aldehydes could not be used in this
transformation when 4b was used due to exclusive formation
of acetals, which do not react further, even at elevated
temperature. To solve this problem, catalysts with enhanced
acidity were evaluated, including nitrated imidodiphosphates
(nIDP),13 iminoimidodiphosphates (iIDP),7b and imidodiphos-
phorimidates (IDPi).14 To our delight, by using extremely
reactive IDPi catalysts recently introduced by our group, aliphatic
aldehydes became viable substrates. With optimized 5a, linear
(1u−1v), β-branched (1w), and α-branched (1x−1y) aldehydes
all reacted smoothly to give corresponding cis-products in good
yields and good to excellent diastereo- and enantioselectivity
(Table 2; see the SI for catalyst and reaction condition
optimization).
Figure 1. 3D structures and relative activation free energies (relative
activation energies) of TStrans and TScis for the reaction catalyzed by
chiral confined acid (S, S)-4a. Distances are given in Å.
Table 2. Vinylogous Prins Cyclization of Aliphatic Aldehydes
classical C−H···O H-bonds between substrate and catalyst direct
the substrate into the confined pocket of (S,S)-4a.8k,19 The C−
H···O H-bond between the C−H bond of the oxocarbenium
moiety and catalyst which stabilizes TStrans does not exist in TScis
because that C−H bond is oriented away from catalyst due to the
bulky methyl group of the substrate. Further stabilization of
TStrans originates from π−π stacking interactions between the
phenyl group of the substrate and the phenyl ring of the catalyst
which are well-oriented to achieve a parallel-displaced geometry
at a distance of 3.3 Å and with a displacement of 2.1 Å.8k,20 The
interaction energy between substrate and catalyst decreases by
5.0 kcal/mol when replacing the phenyl ring of the catalyst by H,
suggesting π−π stacking interaction (Table S1). In TScis, the two
phenyl groups are not parallel to each other; the terminal methyl
group of substrate suffers steric repulsion with catalyst.
Therefore, C−H···O H-bonding, π−π stacking, and steric
interactions between substrate and imidodiphosphoric acid
assist in the discrimination of the two TSs, leading to very high
diastereoselectivity.
We have developed an organocatalytic asymmetric vinylogous
Prins cyclization for the synthesis of 2,3-disubstituted THFs.
Various aldehydes and dienyl alcohols react to give products with
excellent diastereo- and enantioselectivities. 2,3,4- and 2,3,5-
Trisubstituted THFs are also available from chiral dienyl
alcohols. We have also introduced confined 4b and 5a as
powerful catalysts. These catalysts not only control reactivity and
enantioselectivity but also help enlarge the energetic difference
between two diastereomeric TSs in THF formation, leading to
very high diastereoselectivity. Further exploration of this
methodology, particularly toward applying it in the total
synthesis of biologically and pharmaceutically relevant mole-
cules, is currently in progress in our group.
a
Reactions were performed at −20 °C in methylcyclohexane (0.1 M)
with catalyst 5a (3 mol %), 1.05 equiv of 1, 1.0 equiv of 2, and 5 Å
molecular sieves (0.3 g mmol−1) for the specified period of time.
b
c
d
Reaction was performed at 0 °C. Isolated yield. NMR yield with an
e
internal standard. No tetrahydropyran formation was detected. d.r. =
10:1.
DFT calculations were performed to elucidate the origin of
diastereoselectivity of chiral imidodiphosphoric acid catalyzed
Prins cyclization reaction.17,18 The calculated potential energy
profile (Figure S1) suggests that C−C bond formation is the
stereoselectivity-determining step. TStrans is more stable than
TScis by 4.0 kcal/mol when using (S,S)-4a as catalyst, in
agreement with high diastereoselectivity observed experimen-
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b09129.
■
S
Screening data; synthetic procedures; spectra and HPLC
traces; computational methods and results (PDF)
C
DOI: 10.1021/jacs.6b09129
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(d) Overman, L. E.; Castaneda, A.; Blumenkopf, T. A. J. Am. Chem.
̃
AUTHOR INFORMATION
Corresponding Author
*list@kofo.mpg.de
Notes
■
Soc. 1986, 108, 1303. Prins cyclizations of homopropargyl alcohols
leading to THFs: (e) Gogoi, P.; Das, V. K.; Saikia, A. K. J. Org. Chem.
2014, 79, 8592. (f) Gharpure, S. J.; Prasath, V. J. Chem. Sci. 2011, 123,
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Marsden, S. P.; Leatherbarrow, R. J.; Coates, W. J. Chem. Commun.
2004, 40, 2292. (i) Sarkar, T. K.; Haque, Sk. A.; Basak, A. Angew. Chem.,
Int. Ed. 2004, 43, 1417. (j) Chen, C.; Mariano, P. S. J. Org. Chem. 2000,
65, 3252. Prins-like cyclizations with enol ethers leading to THFs:
(k) Kanomata, Ky.; Toda, Y.; Shibata, Y.; Yamanaka, M.; Tsuzuki, S.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous support by the Max-Planck-Society and the European
Research Council (Advanced Grant “High Performance Lewis
Acid Organocatalysis, HIPOCAT”) is gratefully acknowledged.
Y.X. thanks the Alexander von Humboldt Foundation for a
postdoctoral fellowship. We also thank our technicians and the
members of our NMR, MS, GC, and HPLC departments for
their excellent service.
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Gridnev, I. D.; Terada, M. Chem. Sci. 2014, 5, 3515. (l) Unaldi, S.;
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DOI: 10.1021/jacs.6b09129
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX