Pyran annulation: asymmetric synthesis of 2,6-disubstituted-4-methylene tetrahydropyrans.

Article abstract of DOI:10.1021/ol025645d

[reaction: see text] A reaction process for the asymmetric construction of a variety of cis or trans disubstituted pyrans is described. This sequences allows for the asymmetric convergent union of two aldehydes with silyl-stannane reagent 1 in a two-step

Full text of DOI:10.1021/ol025645d

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1189-1192
Pyran Annulation: Asymmetric
Synthesis of
2,6-Disubstituted-4-methylene
Tetrahydropyrans
Gary E. Keck,* Jonathan A. Covel, Tobias Schiff, and Tao Yu
Department of Chemistry, UniVersity of Utah, Salt Lake City, Utah 84112
keck@chemistry.utah.edu
Received January 30, 2002
ABSTRACT
A reaction process for the asymmetric construction of a variety of cis or trans disubstituted pyrans is described. This sequences allows for
the asymmetric convergent union of two aldehydes with silyl-stannane reagent 1 in a two-step process: catalytic asymmetric allylation of the
first aldehyde using 1 with a BITIP catalyst, followed by reaction of the alcohol so obtained with a second aldehyde and TMSOTf.
An ever increasing number of biologically significant natural
products, especially those of marine origin, possess func-
tionalized tetrahydropyran rings as critical substructural
motifs. Prominent examples of considerable current interest
would include bryostatin 1 and phorboxazole (Figure 1).1-2
Our interest in these structures, particularly bryostatin 1 and
other potential therapeutic agents based upon this structural
platform,3 has led us to investigate new methods for the
asymmetric synthesis of pyrans bearing the substitution
patterns commonly encountered in these natural products.
The occurrence of such pyran motifs in a number of
biologically active natural products has inspired the develop-
ment of many clever methods for obtaining these oxacycles.
The intramolecular attack of an olefin on an oxocarbenium
ion, or intramolecular Prins reaction, although one of the
established methods, has been underutilized in this capacity.
This is in part due to the paucity of methods for obtaining
suitable substrates to provide appropriately functionalized
nonracemic tetrahydropyrans.
There exists extensive precedent for the construction of
oxygen-containing heterocycles, including tetrahydropyrans,
by approaches based upon intramolecular versions of the
basic Prins reaction.4 Previous work has also documented
the utility and enhanced reactivity of allylsilanes as intra-
molecular traps for oxocarbenium ions generated in various
(1) For total syntheses of bryostatin and leading references to other work,
see: (a) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.; Somfai,
P.; Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7407.
(b) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J.
A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540. (c) Ohmori, K.; Ogawa,
Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.; Yamamura, S. Angew. Chem.,
Int. Ed. 2000, 39, 2290.
(2) For total syntheses of phorboxazole and leading references to other
work, see: (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am.
Chem. Soc. 1998, 120, 5597. (b) Evans, D. A.; Fitch, D. M.; Smith, T. E.;
Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033. (c) Smith, A. B., III;
Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M. J. Am. Chem. Soc. 2001,
123, 4834.
(3) (a) Wender, P. A.; De Brabander, J.; Harran, P. G.; Jimenez, J.-M.;
Koehler, M. F. T.; Lippa, B.; Park, C.-M.; Shiozaki, S. J. Am. Chem. Soc.
1998, 120, 4534. (b) Wender, P. A.; De Brabander, J.; Harran, P. G.;
Jimenez, J. M.; Koehler, M. F.; Lippa, B.; Park, C. M.; Siedenbiedel, C.;
Pettit, G. R. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 6624. (c) Wender, P.
A.; Blaise, L. Tetrahedron Lett. 2000, 41, 1007. (d) Wender, P. A.; Hinkle,
K. W.; Koehler, M. F. T.; Lippa, B. Med. Res. ReV. 1999, 19, 388.
10.1021/ol025645d CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/03/2002

Scheme 1. Related Racemic Pyran Syntheses
Figure 1. Structures of bryostatin 1 and phorboxazole.
differentially substituted pyrans as shown in Scheme 1 below
(eq 3).10
ways.5 Kang has described reactions of racemic hydroxy
allylsilanes of general structure 2 with vinyl ethers and R-halo
acetals to give acetals that were subsequently cyclized to
afford pyrans.6 Marko has developed an efficient pyran
synthesis that combines the Noyori method7 for generation
of oxocarbenium ions with intramolecular allylsilane trapping
and has coined the term ISMS (intramolecular silyl modified
Sakurai) to describe this reaction (eq 1, Scheme 1).8 Studies
by Marko have also documented the use of racemic hydroxy
allylsilanes in sequences leading to pyrans via an initial ene
reaction; Marko has suggested the term “IMSC” (intra-
molecular Sakurai cyclization) to refer to the cyclization step
of the process (eq 2, Scheme 1).9 Very recently, during the
preparation of our manuscript, Leroy and Marko reported
on the use of a functionalized allylstannane in BF3‚OEt2-
promoted reactions with aldehydes, followed by Bi(OTf)3-
promoted cyclocondensation with a second aldehyde, to yield
Rychnovsky has also developed a process termed “segment
coupling Prins cyclization”11 and applied it to an extremely
concise construction of the C20-C27 pyran subunit of
phorboxazole.12 Rychnovsky and Kopecky have also recently
reported a tandem Mukaiyama aldol-Prins sequence utilizing
allylsilanes, which bears similarity to the process described
herein.13 Both of these methods access nonracemic pyrans.
Smith has utilized the Petasis-Ferrier rearrangement in
efficient syntheses of nonracemic tetrahydropyrans, and
Panek has employed nonracemic allylsilanes to access
dihydropyrans.14
Herein we report an exceptionally facile enantioselective
synthesis of 2,6-cis-disubstituted-4-methylenetetrahydropyran
systems. These are obtained in a very brief three steps from
commercially available starting materials. As indicated in
Scheme 2, the overall two-step reaction process results in
the convergent union of two aldehyde components with a
four-carbon unit derived from the known 2-(trimethylsilyl-
methyl)allyltri-n-butylstannane reagent 1.15 For purposes of
(4) (a) Adams, D. R.; Bhaynagar, S. D. Synthesis 1977, 661. (b) Snider,
B. B. ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: Oxford, U.K., 1991; Vol. 2, p 527. (c) Cloninger, M. J.; Overman,
L. E. J. Am. Chem. Soc. 1999, 121, 1092. (d) Kozmin, S. A. Org. Lett.
2001, 3, 755.
(5) (a) Mohr, P. Tetrahedron Lett. 1993, 34, 6251. (b) Paquette, L. A.;
Tae, J. J. Org. Chem. 1996, 61, 7860. (c) Sano, T.; Oriyama, T. Synlett
1997, 716. (d) Suginome, M.; Iwanami, T.; Ito, Y. J. Org. Chem. 1998, 63,
6096. (e) Chen, C.; Mariano, P. S. J. Org. Chem. 2000, 65, 3252.
(6) Sung, T. M.; Kwak, W. Y.; Kang, K.-T. Bull. Korean Chem. Soc.
1998, 19, 862.
(7) Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 44, 4259.
(8) (a) Mekhalfia, A.; Marko, I. E. Tetrahedron Lett. 1991, 32, 4779.
(b) Mekhalfia, A.; Marko, I. E.; Adams, H. Tetrahedron Lett. 1991, 32,
4783.
(9) (a) Marko, I. E.; Bayston, D. J. Tetrahedron Lett. 1993, 34, 6595.
(b) Marko, I. E.; Bayston, D. J. Tetrahedron 1994, 50, 7141. (c) Marko, I.
E.; Mekhalfia, A.; Murphy, F.; Bayston, D. J.; Bailey, M.; Janousek, Z.;
Dolan, S. Pure Appl. Chem. 1997, 69, 565. (d) Marko, I. E.; Plancher, J.-
M.; Tetrahedron Lett. 1999, 40, 5259.
(10) Leroy, B.; Marko, I. E. Tetrahedron Lett. 2001, 41, 8685.
(11) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem. 2001, 66,
4679.
(12) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217.
(13) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123,
8420.
(14) For other recent asymmetric approaches to pyrans, see: (a) Petasis,
N. A.; Lu, S.-P. Tetrahedron Lett. 1996, 36, 141. (b) Smith, A. B., III;
Verhoest, P. R.; Minbiole, K. P.; Lim, J. J. Org. Lett. 1999, 1, 909. (c)
Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Beauchamp, T. J. Org.
Lett. 1999, 1, 913. (d) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000,
122, 9836.
(15) (a) Kang, K.-T.; Hwang, S. S.; Kwak, W. Y.; Yoon, U. C. Bull.
Korean Chem. Soc. 1999, 20, 801. (b) Clive, D. L. J.; Paul, C. C.; Wang,
Z. J. Org. Chem. 1997, 62, 7028. (c) The 2-(chloromethyl)allylsilane
precursor to 1 is commercially available (Aldrich).
1190
Org. Lett., Vol. 4, No. 7, 2002

detected. The stereochemical outcome is in accord with
previous observations and with the expectation that cycliza-
tion should occur via a chairlike transition state with R1 and
R2 equatorially disposed. The results for several examples
are provided in Table 2.
Scheme 2. Overall Pyran Annulation Process
Table 2. Isolated Yields for TMSOTf-Promoted Annulations
discussion, it is convenient to refer to these as the first
aldehyde, R1CHO, and the second aldehyde, R2CHO.
The first step in the overall process is the preparation of
the requisite hydroxy allylsilanes in nonracemic form. This
was achieved for the present examples by catalytic asym-
metric allylation of the first aldehyde R1CHO with stannane
1.16 These reactions were found to proceed well using our
previously described BINOL titanium tetraisopropoxide
(BITIP) catalyst;17 in general, the hydroxy allylsilanes were
obtained in high yields and with high levels of enantio-
selectivity. (Table 1).
We have noticed an interesting combination of solvent
effects and substrate dependence with respect to this annu-
lation reaction. The reaction generally proceeded well in CH2-
Cl2, but in all cases at least a trace amount of an endocyclic
olefin that was inseparable from the desired product was
obtained. In the cases where the cyclization substrate is 2c,
this problem was greatly magnified. Previous attempts by
Marko to cyclize similar preformed TMS ethers also resulted
in mixtures of endo and exo olefins, which were very difficult
to separate.8a,18 However, noting that the substrates that
performed best in this reaction contained R- or â-alkoxy
substituents, diethyl ether was also examined as solvent. A
dramatic improvement was found with this oxygenated
solvent as no endocyclic olefins were obtained regardless
of the substrate employed.
Table 1. Isolated Yields and Enantiomeric Excesses for the
Reaction of 1 with Aldehydes
Another problem observed in these reactions is related to
the use of substrates 2d and 2e (Table 1). In CH2Cl2, these
substrates decomposed immediately upon exposure to TM-
SOTf. In ether at -78 °C no decomposition was observed;
however, no cyclized product was obtained either. Under
these conditions the alcohol is rapidly converted to the TMS
ether, but the reaction stalls at this juncture.19 We are
currently still examining this issue.
The second step of the process, the TMSOTf-promoted
annulation of such silanes with the second aldehyde R2CHO,
was found to occur rapidly (generally within 15 min at -78
°C) to provide the 2,6-cis-tetrahydropyran containing an exo-
methylene in the 4-position. The trans diastereomer was not
It is also possible to use this pyran annulation to obtain
access to 2,6-trans-disubstituted pyrans. As shown in eq 4,
(16) For an alternative preparation of such hydroxy silanes, by Noyori
reduction of â-ketoesters followed by application of the Brunelle allylsilane
synthesis, see ref 13.
(17) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467. The “method B” catalyst preparation was found to be the most
suitable for the reaction of stannane 1 with aldehydes. Experimental
procedures may be found in Supporting Information.
the annulation reaction works very well when an ortho ester
is used as the electrophile.20 Thus, the reaction of 2a with
Org. Lett., Vol. 4, No. 7, 2002
1191

trimethylorthoformate smoothly provides methylacetal 4 in
excellent yield (eq 4). Although 4 is obtained as an epimeric
mixture, this is of little consequence. Reaction of a storable
nucleophile (allylsilane, allylstannane, or enol silane) with
the oxocarbenium ion generated upon treatment of such
acetals with a Lewis acid is well-known to afford the 2,6-
trans isomer with high selectivity as a consequence of
stereoelectronically preferred axial addition to the intermedi-
ate oxocarbenium ion.21
Scheme 3. Iterative Pyran Annulation
This annulation process also lends itself to iterative
applications that allow for the rapid assembly of structures
containing multiple pyran rings, such as the bis pyran subunit
of phorboxazole. Thus, if a pyran constructed using this
process contains a latent or protected aldehyde, exposure of
the aldehyde function and reaction with an appropriate
hydroxy allylsilane in a second annulation affords a bis pyran.
An example of this iterative annulation is shown in Scheme
3. In this case, bis pyran 6 is assembled from stannane 1,
R-benzyloxyacetaldehyde, and â-OTBDPS propionaldehyde
in five linear steps. The compatibility of both R- and â-alkoxy
aldehydes in these reactions thus easily provides pyrans
containing three differentiated and highly malleable func-
tional groups on the THP ring. Finally, this pyran synthesis
is quite flexible since the annulation can be approached from
two different directions for any given pyran. This should
increase its utility and help to promote its application.
(18) Marko subsequently reported a solution to this problem through the
use of trimethylsilyl ethers of simple alcohols as an additive: Marko, I. E.;
Bayston, D. J.; Mekhalfia, A.; Adams, H. Bull. Soc. Chim. Belg. 1993,
102, 655.
(19) Both Kang and Marko have also noticed greatly diminished yields
using certain aromatic or heteroaromatic materials in their acetal cyclizations
and ene reactions. Note refs 6 and 9a.
(20) For previous uses of acetals, ketals, and ortho esters in this context,
note: (a) Marko, I. E.; Mekhalfia, A. Tetrahedron Lett. 1992, 33, 1799.
(b) Marko, I. E.; Mekhalfia, A.; Bayston, D. J.; Adams, H. J. Org. Chem.
1992, 57, 2211. Note also ref 8b.
Acknowledgment. Financial support from the National
Institutes of Health (through GM-28961) and by Pfizer, Inc.
is gratefully acknowledged.
Supporting Information Available: Spectral and ana-
lytical data and experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
(21) For two recent examples, see refs 2b and 14b.
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