Stereoselective trans- and cis-dihydroxylations of 2H-pyranyl and dihydropyridinyl heterocycles synthesized from formal [3 + 3]-cycloaddition reactions of alpha,beta-unsaturated iminium ions with 1,3-dicarbonyl equivalents.

Article abstract of DOI:10.1021/ol010034r

[reaction: see text]We describe here an inherent problem in direct epoxidation of the endocyclic olefin in 2H-pyrans fused to 2-pyrones. Such difficulties led to the development of highly stereoselective trans- and cis-dihydroxylations of these olefinic s

Full text of DOI:10.1021/ol010034r

ORGANIC
LETTERS
2001
Vol. 3, No. 14
2141-2144
Stereoselective trans- and
cis-Dihydroxylations of 2H-Pyranyl and
Dihydropyridinyl Heterocycles
Synthesized from Formal [3 +
3]-Cycloaddition Reactions of
r,â-Unsaturated Iminium Ions with
1,3-Dicarbonyl Equivalents†
,1
Luke R. Zehnder, Lin-Li Wei, Richard P. Hsung,* Kevin P. Cole,
Michael J. McLaughlin, Hong C. Shen, Heather M. Sklenicka, Jiashi Wang, and
Craig A. Zificsak
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received February 23, 2001
ABSTRACT
We describe here an inherent problem in direct epoxidation of the endocyclic olefin in 2H-pyrans fused to 2-pyrones. Such difficulties led to
the development of highly stereoselective trans- and cis-dihydroxylations of these olefinic systems in both 2H-pyrans and dihydropyridines
fused to a 2-pyrones or a 2-cyclohexenone. Protocols for the removal of the activated allylic hydroxyl group are also reported.
Reactions of R,â-unsaturated iminiums with 1,3-dicarbonyl
equivalents constitute a stepwise formal [3 + 3]-cyclo-
addition2-4 useful for the synthesis of complex 2H-pyranyl
and dihydropyridinyl heterocycles [Figure 1].5-7 These
reactions involve a sequence that consists of a Knoevenagel
condensation followed by a 6π-electron electrocyclic ring
closure8 and, thus, can be classified as a sequential anionic-
pericyclic strategy highly useful for natural product synthe-
sis.9 The net result of this process is formation of two σ-bonds
and a new stereocenter adjacent to the heteroatom. Our work
has demonstrated synthetic efficacy of this formal cyclo-
addition reaction.5,6 More recently, we have also succeeded
† With the deepest appreciation and respect, this paper is dedicated to
Professor Gilbert Stork on the occassion of his 80th birthday.
(1) After the corresponding author, all author names are listed alphabeti-
cally.
(2) There are a limited number of examples of metal-mediated [3 +
3]-cycloaddition reactions. For recent reviews, see: (a) Fru¨hauf, H.-W.
Chem. ReV. 1997, 97, 523. (b) Lautens, M.; Klute, W.; Tam, W. Chem.
ReV. 1996, 96, 49.
(5) (a) McLaughlin, M. J.; Shen, H. C.; Hsung, R. P. Tetrahedron Lett.
2001, 42, 609. (b) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C.
D.; Degen, S. J.; Yao, L. J. J. Org. Chem. 1999, 64, 690.
(3) For recent reviews on stepwise [3 + 3] formal cycloaddition, see:
(a) Filippini, M.-H.; Rodriguez, J. Chem. ReV. 1999, 99, 27-76. (b)
Rappoport, Z. The Chemistry of Enamines. In The Chemistry of Functional
Groups; John Wiley and Sons: New York, 1994.
(4) Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Shen, H. C.; McLaughlin,
M. J.; Zehnder, L. R. Submitted.
(6) (a) Wei, L.-L.; Sklenicka, H. M.; Gerasyuto, A. I.; Hsung, R. P.
Angew. Chem., Int. Ed. 2001, 40, 1516. (b) Sklenicka, H. M.; Hsung, R.
P.; Wei, L.-L.; McLaughlin, M. J.; Gerasyuto, A. I.; Degen, S. J.; Mulder,
J. A. Org. Lett. 2000, 2, 1161. (c) Hsung, R. P.; Wei, L.-L.; Sklenicka, H.
M.; Douglas, C. J.; McLaughlin, M. J.; Mulder, J. A.; Yao, L. J. Org. Lett.
1999, 1, 509.
10.1021/ol010034r CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/13/2001

oxidative transformations involving the endocyclic olefin in
2H-pyrans or dihydropyridines such as 3 have been much
less explored.17 We report here our initial success in
stereoselective oxidation of this ubiquitous endocyclic olefin.
The unique position of hydroxyl groups in the C-rings of
arisugacin A [4] and H [5] and the B-ring of lepadin A [6]
prompted us to investigate two approaches [Figure 2]. The
Figure 1.
Figure 2.
in designing both stereoselective5a,6b and intramolecular
variants of this formal cycloaddition.6a
first one involved the epoxidation of the 2H-pyran 8 at C4-
C5, followed by a hydride reduction of epoxide 9, leading
to monohydroxylated compound 10. We had suspected that
the hydride would selectively approach toward C4 owing to
the activation from the pyranyl oxygen. The second approach
involved dihydroxylation of 8 at C4-C5 followed by a
selective removal of the C4 hydroxyl group in 10, which is
not well-explored.
Having demonstrated its synthetic feasibility, we have been
pursuing applications of this formal [3 + 3]-cycloaddition
in the total syntheses of arisugacin A [4] and H [5],10-12
lepadin A [6],13 and orevactaene [7]14 [Figure 1]. However,
to render this formal cycloaddition approach useful in natural
product synthesis, an ensuing key transformation would
involve oxidation of the endocyclic olefin in the heterocycle
3 to provide the desired hydroxyl functionalities present in
4-7. Despite well-known oxidation chemistry involving
analogous endocyclic olefinic systems such as chromenes,15,16
As shown in Scheme 1, epoxidation of 2H-pyrans 12 and
13 using m-CPBA at room temperature in CH2Cl2 led to
(7) For some recent notable studies in this area, see: (a) Cravotto, G.;
Nano, G. M.; Tagliapietra, S. Synthesis 2001, 49. (b) Hua, D. H.; Chen,
Y.; Sin, H.-S.; Robinson, P. D.; Meyers, C. Y.; Perchellet, E. M.; Perchellet,
J.-P.; Chiang, P. K.; Biellmann, J.-P. Acta Crystallogr. 1999, C55, 1698.
(c) P. Benovsky, G. A. Stephenson, J. R. Stille, J. Am. Chem. Soc. 1998,
120, 2493.
Scheme 1
(8) (a) Shishido, K.; Ito, M.; Shimada, S.-I.; Fukumoto, K.; Kametani,
T. Chem. Lett. 1984, 1943. (b) Maynard, D. F.; Okamura, W. H. J. Org.
Chem. 1995, 60, 1763.
(9) (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131. (b) Tietze, L. F. J. Heterocycl. Chem. 1990, 27, 47.
(10) For a leading reference, see: Otoguro, K.; Shiomi, K.; Yamaguchi,
Y.; Arai, N.; Sunazuka, T.; Masuma, R.; Iwai, Y.; O˜ mura, S. J. Antibiot.
2000, 53, 50.
(11) Zehnder, L. R.; Hsung, R. P.; Wang, J.-S.; Golding, G. M. Angew.
Chem., Int. Ed. 2000, 39, 3876.
(12) For our other approaches related to the synthesis of arisugacin,
see: (a) Zehnder, L. R.; Dahl, J. W.; Hsung, R. P. Tetrahedron Lett. 2000,
41, 1901. (b) Granum, K. G.; Merkel, G.; Mulder, J. A.; Debbins, S. A.;
Hsung, R. P. Tetrahedron Lett. 1998, 39, 9597. (c) Hsung, R. P. J. Org.
Chem. 1997, 62, 7904.
(13) (a) Steffan, B. Tetrahedron 1991, 41, 8729. (b) Kubanek, J.;
Williams, D. E.; de silva, E. D.; Allen, T.; Andersen, R. J. Tetrahedron
Lett. 1995, 36, 6189. (c) Ozawa, T.; Aoyagi, S.; Kibayashi, C. Org. Lett.
2000, 2, 2955. (d) Toyooka, N.; Okumura, M.; Takahata, H. J. Org. Chem.
1999, 64, 2182.
(14) (a) Shu, Y.-Z.; Ye, Q.; Li, H.; Kadow, K. F.; Hussain, R. A.; Huang,
S.; Gustavson, D. R.; Lowe, S. E.; Chang, L. P.; Pirnik, D. M.; Kodukula,
K. Bioorg. Med. Chem. Lett. 1997, 17, 22295. (b) Organ, M. G.; Bratovanov,
S. Tetrahedron Lett. 2000, 41, 6945.
2142
Org. Lett., Vol. 3, No. 14, 2001

exclusive formation of hydroxyesters 14 and 1518 in 50%
and 71% yields, respectively, as a 1:1 mixture of trans and
cis isomers. A variety of other conditions [buffered or
biphasic conditions] were explored but failed to diminish
the addition of the Bz*O [m-chlorobenzoyloxy] anion to the
initially formed epoxide 16 and/or oxocarbenium intermedi-
ate 17 [Scheme 1]. In our hands, epoxide 16 is unstable and
undergoes rapid ring opening, especially under acidic condi-
tions, leading to oxocarbenium species 17. Oxocarbenium
species 17 presents minimum stereochemical discrimination
toward the incoming Bz*O anion, and thus, both the trans
and cis isomers of 14 or 15 were isolated. It should be noted
that the addition of Bz*O anion did occur regioselectively
at C4 and not C2. The hydroxyester 14 was unambiguously
assigned via a HETCOR experiment where the C4 protons
of trans and cis isomers correlate to 13C chemical shifts with
δ values of 65.3 and 68.4 ppm.
On the other hand, cis-dihydroxylation of these endocyclic
olefins was quite successful. As shown in Table 1, a range
Table 1
Subsequent attempts using reagents such as dimethyl-
dioxirane, in situ reductive trapping of 16 or 17 using
NaCNBH3, or attempts to reduce the Bz*O group in 14 or
15 using hydrides such as NaBH4 and NaCNBH3 in the
presence of CeCl3 or AcOH were unsuccessful.19,20 The
earlier assertion regarding the activation of C4 in 16 due to
the pyranyl oxygen atom appears to be very real as well as
extremely problematic in the epoxidation of these particular
endocyclic olefins, thereby rendering them very different
from those that have been explored in epoxidation studies.15,16
We then turned to dihydroxylation protocols to construct
the monohydroxylated product 10. As shown in Scheme 2,
Scheme 2
a Cis or trans is designated for the C4-C5 relative stereochemistry. Anti
or syn is designated for C5-C6 relative stereochemistry. No trans products
were observed in these reactions due to epimerizations. b All yields are
isolated yields. c All ratios were determined by 1H NMR and/or 13C NMR.
Relative stereochemistry was assigned by NOE experiments. d NMO was
used and the reaction was carried out in acteone/H2O. e K3FeCN6 gave a
74% yield withan anti:syn ratio of 92:8.
MMPP [magnesium monoperoxyphthalate] epoxidation of
12 and 18, a more basic protocol, did lead to diols 19 and
20 in 50% and 61% yields, respectively. The relative
stereochemistry favored the trans isomers with ratios of 90:
10 and 91:9 for 19 and 20, respectively, and trans and cis
isomers are readily separable. The improved stereoselectivity
favoring the trans isomer may be due to the large excess of
H2O [as a cosolvent] that could efficiently trap out epoxide
intermediate 16.
of different substrates [18, 21-25] could be cis-dihydroxy-
lated in high yields using OsO4 and K3FeCN6 or NMO
[entries 4 and 6],22 and more significantly, diastereoselec-
tivities were very high for reactions of 21-25 [entries 2-6].
Given the relatively flat nature of these ring systems [the R2
substituent actually assumes the pseudoequatorial position
for the starting 2H-pyrans 21-25], the observed high
diastereoselectivity was quite remarkable. The assigned
relative stereochemistry of cis-diols 20 and 26-30 indicates
that the approach of OsO4 still preferred the slightly less
hindered face of the olefin.
Given the above success in the cis-dihydroxylation, we
examined Sharpless’ asymmetric dihydroxylation23 of 2H-
pyran 12 using [DHQD]2PYR [two dihydroquinidine ligands
linked with pyrimidine] and obtained diol 19-cis in 66% yield
(Scheme 3). Formation of the bis-(+)-MTPA ester indicated
Attempts to generate an epoxide from trans diol 19 via
mesylation of either the C4 or C5 hydroxyl group led to
epimerization, even in the presence of reducing agents such
21
as NaCNBH3/ZnI2 and NaBH4.20 However, the ability to
stereoselectively construct trans diol 19 solidifies an attrac-
tive entry for synthesis of orevactaene 714 via the formal [3
+ 3]-cycloaddition approach [see Figure 1].
Org. Lett., Vol. 3, No. 14, 2001
2143

Scheme 3
Scheme 4a
a (a) 5% Pd-C, H2, Ac2O [as solvent], rt, 4 h; (b) CF3COOH,
Et3SiH, CH2Cl2, rt, 2 h; (c) AIBN [cat.], n-Bu3SnH [as solvent],
130 °C, sealed tube.
64% ee, which is quite comparable to those reported by
Sharpless for asymmetric cis-dihydroxylation of chromenes.23
Likewise, the use of [DHQ]2PHAL [two dihydroquinine
ligands linked with phthalazine] led to ent-19-cis in 50%
yield with 54% ee. In addition, we found that optically pure
dihydropyridine 31 could also undergo cis-dihydroxylation,
although slower, using OsO4 and K3FeCN622 to provide cis-
diol 32 as a single diastereomer in 50% yield. The relative
stereochemistry between C4, C5, and C6 was unambiguously
assigned using NOE experiments. This stereoselective cis-
dihydroxylation protocol provides ocataquinolenone system
31 and offers a potential approach to the AB-ring system of
lepadin A [6].
With these cis-diols in hand, the remaining challenging
issue is the ability to selectively remove the C4 hydroxyl
group which is not very well-known. This stands as a key
transformation for potential total synthesis of relevant natural
products 4-6 using the formal [3 + 3]-cycloaddition
approach.
hydroxylated compound 33 in 74% yield by using a
hydrogenation protocol in which Ac2O is used as solvent.25
The use of alcohol solvents such as MeOH led to isolation
of products with the MeO group substituted at C4. While
TMSH reduction in TFAA was also feasible,26 the most
reliable protocol that provided 33 in 78% yield has been the
two-step sequence consisting of the formation of thiolcar-
bonate 34 followed by a Barton-type deoxygenation of the
more activated allylic hydroxyl group at C4 [Scheme 4].27
We have described here highly stereoselective trans- and
cis-dihydroxylations of these olefinic systems in both 2H-
pyrans and dihydropyridines. This methodology represents
a key transformation in constructing various natural products
using the formal [3 + 3]-cycloaddition approach. Efforts
related to these natural product syntheses are currently
underway.
Acknowledgment. R.P.H. thanks the National Institutes
of Health [NS38049] and the donors of the Petroleum
Research Fund [Type-G].
As shown in Scheme 4, after exploring a variety of
different conditions,24 the C4 hydroxyl group in cis-diol 30
was successfully removed to provide the desired mono-
Supporting Information Available: Experimental pro-
1
cedures as well as H NMR spectral and characterization
(15) For some examples, see: (a) Jacobsen, E. N.; Zhang, W.; Muci, A.
R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113, 7063. (b) Yorozu,
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5380.
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL010034R
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G. J. Nat. Prod. 1999, 62, 490. (b) David, M.; Boustie, J.; Peilloux, A.;
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(23) The absolute stereochemistry of 19-cis and ent-19-cis were assigned
on the basis of Sharpless’ mnemonics, see: Wang, Z.-M.; Kakiuchi, K.;
Sharpless, K. B. J. Org. Chem. 1994, 59, 6895.
(24) Reductive conditions such as ZnI2 with NaCNBH3, Ph3P with
NaCNBH3, and SOCl2 followed by DIBAL-H did not provide the desired
monohydroxylated products.
(25) (a) Burns, C. J.; Gill, M.; Saubern, S. Aust. J. Chem. 1991, 44,
1427. (b) Rodriguez-Hahn, L.; Esquivel, B.; Sanchez, C.; Estebanes, L.;
Cardenas, J. Phytochemistry 1989, 28, 567.
(18) All new compounds are characterized by 1H NMR, 13C NMR, FTIR,
and mass spectroscopy.
(19) cis/trans-Isomers of diol 14 or 15 were isolated under some of
these conditions.
(20) Appendino, G.; Cravotto, G.; Nano, G. M.; Palmisano, G.; Annun-
zata, R. HelV. Chim. Acta 1993, 76, 1194.
(26) Carey, F. A.; Tremper, H. S. J. Org. Chem. 1971, 36, 758.
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Fukukawa, K.; Ueda, T.; Hirano, T. Chem. Pharm. Bull. 1983, 31, 1842.
Many side products such as 25 [from elimination of both hydroxyl groups]
were observed when n-Bu3SnH was not used as solvent or in large excess.
(21) Lau, C. K.; Defresne, C.; Belanger, P. C.; Pietre, S.; Scheigetz, J.
J. Org. Chem. 1986, 51, 3038.
(22) Vedejs, E.; Kruger, A. W. J. Org. Chem. 1999, 64, 4790.
2144
Org. Lett., Vol. 3, No. 14, 2001