Stereocontrolled [4+2]-annulation accessing dihydropyrans: Synthesis of the C1a-C10 fragment of kendomycin

Article abstract of DOI:10.1021/ol0501875

(Chemical Equation Presented) Development of new organosilane reagents bearing C-centered chirality where the stereocenter is fully substituted, and their use in the stereocontrolled synthesis of cis- and trans-dihydropyrans containing a trisubstituted ol

Full text of DOI:10.1021/ol0501875

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1529-1532
Stereocontrolled [4+2]-Annulation
Accessing Dihydropyrans: Synthesis of
the C1a-C10 Fragment of Kendomycin
Jason T. Lowe and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, 590 Commonwealth
AVenue, Boston UniVersity, Boston, Massachusetts 02215
panek@chem.bu.edu
Received January 28, 2005
ABSTRACT
Development of new organosilane reagents bearing C-centered chirality where the stereocenter is fully substituted, and their use in the
stereocontrolled synthesis of cis- and trans-dihydropyrans containing a trisubstituted olefin is described. The reagents participate in Lewis
acid promoted [4+2]-annulations providing useful levels of selectivity with both aliphatic and aromatic aldehydes. A stereoselective synthesis
of the C1a-C10 fragment of kendomycin (1) is also described.
Functionalized pyrans are important subunits of biologically
active compounds, serving as common structural motifs of
natural products and precursors to chemically diverse C-
glycosides.1 Much of their chemistry has been extensively
reviewed.2 Examples of complex natural products bearing
pyran subunits include the phorboxazoles,3 lasonolide A,4
callipeltoside,5 and spongistatin 1.6 Accessing anomeric-
linked aliphatic and aromatic pyran systems in a stereocon-
trolled manner would be a useful contribution to the field of
synthesis. Approaches previously documented for the con-
struction of dihydropyran ring systems include palladium
mediated reactions,7 ring closing metathesis (RCM),8 radical
cyclization,9 cationic cyclization,10 Prins cyclization,11 hetero-
Michael additions,12 and hetero-Diels-Alder reaction path-
(1) (a) Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100, 2407. (b) Shimizu,
Y. Chem. ReV. 1993, 93, 1685.
(7) (a) Ramnauth, J.; Poulin, O.; Rakhit, S.; Maddaford, S. Org. Lett.
2001, 3, 2013. (b) Kim, C. R.; Dobler, W.; Meier, M.; Semmelhack, M. F.
Tetrahedron. Lett. 1989, 30, 4925.
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A.; Alberti, M. J.; Burke, S. D. J. Org. Chem. 1998, 63, 3160.
(9) (a) Kumar, V. S.; Floreancig, P. E. J. Am. Chem. Soc. 2001, 123,
3842. (b) Rancourt, J.; Burke, S. D. J. Am. Chem. Soc. 1991, 113, 2335.
(10) (a) Betancort, J. M.; Martin, T.; Palazon, J. M.; Martin, V. S. J.
Org. Chem. 2003, 68, 3216. (b) Semeyn, C.; Blaauw, R. H.; Hiemstra, H.;
Speckamp, W. N. J. Org. Chem. 1997, 62, 3426.
(2) (a) Somsak, L. Chem. ReV. 2001, 101, 81. (b) Du, Y.; Linhardt, R.;
Valhov, I. R. Tetrahedron 1998, 54, 9913. (c) Jaramillo, C.; Knapp, S.
Synthesis 1994, 1. (d) Postema, M. H. D. Tetrahedron 1992, 48, 8545. (e)
Hosomi, A.; Sakata, Y.; Sakurai, H. Carbhydr. Res. 1987, 171, 223. (f)
Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Pergamon Press:
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Amsterdam, The Netherlands, 1996; p 319.
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10.1021/ol0501875 CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/22/2005

ways.13 Several of these methods constitute efficient path-
ways and high levels of selectivity for the formation of 2,6-
cis-dihydropyrans. However, access to the complimentary
2,6-trans-dihydropyrans remains underdeveloped.14
Scheme 2. New Chiral Crotyl Silanes in [4+2]-Annulation15
We have described the use of chiral silanes 2a-d in
[4+2]-annulations leading to the preparation of functional-
ized dihydropyrans.15 These reagents access pyrans of the
general structure 3a-e illustrated in Scheme 1.
Scheme 1. Chiral Crotyl and Allyl Silanes in
[4+2]-Annulations
diethyl zinc, and a catalytic amount of copper(I) cyanide to
give 7a in 90% yield as a single stereoisomer.19
Scheme 3. Synthesis of (E) and (Z)-Vinyl Silanes
The complementary Z-vinyl silane 7b was synthesized in
3 steps from 6. A regioselective hydroalumination with Red-
Al followed by an iodine trap provided an enantiomerically
pure vinyl iodide.20 The alcohol was then protected as the
dimethylphenylsilyl ether and subjected to a retro-Brook
rearrangement21 to give 7b in 3 steps (65% yield).22 Both
the Z- and E-vinyl silanes can be prepared on a 20 g scale
with greater than 99% enantiomeric excess as determined
by chiral HPLC.23
With both vinyl silanes in hand the remaining steps in the
formation of the desired crotyl silanes parallel each other
with few variations in yield and procedure for [3,3]-
sigmatropic rearrangement (Scheme 4). Substrates for the
Claisen rearrangements were prepared through a DCC
coupling of (4-methoxybenzyloxy)acetic acid24 with vinyl
silanes depicted in Scheme 2 to give 8a and 8b. Treatment
with LiHMDS and trapping of the intermediate lithium
enolate at -78 °C with TMSCl and warming to room
temperature afforded the desired R-alkoxy acids 9a and
9b.25,26 The rearrangement of 8a gave only one detectable
diastereoisomer of the hexanoic acid by NMR. The comple-
Herein, we describe the synthesis of dihydropyrans with
high diastereo- and enantioselectivity from silanes 4a and
4b bearing a quaternary center at the carbon bearing the silyl
group.16 The described methodology will then be utilized in
the synthesis of the C1a-C10 fragment of kendomycin 1.
The synthesis of silanes 4a and 4b began with the
preparation of vinyl silanes 7a and 7b (Scheme 3). The
synthesis of E-vinyl silane used a silyl-zincation of (R)-3-
pentyn-2-ol 617 employing lithium dimethylphenyl silane,18
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(b) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem., Int.
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J. Am. Chem. Soc. 2004, 126, 2425. (d) Su, Q.; Panek, J. S. Angew. Chem.,
Int. Ed. 2005, 44, 1223.
(16) Prior methods required several additional steps to install a methyl
group in the 3-position with use of 2a or 2b. A more efficient approach
would be to introduce the second methyl group prior to annulation as
depicted in Scheme 2, transforming 4 into 5. Representative examples of
3,5-substituted glycosides: (a) Wang, L.; Floreancig, P. E. Org. Lett. 2004,
6, 569. (b) Wender, P. A.; Jankowski, O. D.; Tabet, E. A.; Seto, H. Org.
Lett. 2003, 5, 2299. (c) Czuba, I. R.; Zammit, S.; Rizzacasa, M. A. Org.
Biomol. Chem. 2003, 1, 2044 and references therein.
(19) (a) Wakamatsu, K.; Nonaka, T.; Okuda, Y.; Tuckmantel, W.;
Oshima, K.; Utimoto, K.; Nozaki, H. Tetrahedron 1986, 42, 4427. (b)
Okuda, Y.; Wakamatsu, K.; Tuckmantel, W.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1985, 26, 4629.
(20) Marshall, J. A.; Shearer, B.; Crooks, S. J. Org. Chem. 1987, 52,
1236.
(21) For recent examples of retro-Brook rearrangement see: Gandon,
V.; Bertus, P.; Szymoniak, J. Tetrahedron Lett. 2000, 41, 3053 and
references therein.
(22) (a) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2001, 123, 5841. (b) Kim, L.; Margiotis, P. Tetrahedron Lett.
1990, 31, 6137.
(23) See the Supporting Information.
(17) (a) Shimizu, A.; Ogawa, O.; Shiozaki, S.; Kodama, K. Japanese
Patent 11235195, 1999. (b) Ogawa, J.; Xie, S.-X.; Shimizu, S. Appl.
Microbiol. Biotechnol. 1999, 51, 53.
(24) Abraham, D. J.; Kennedy, P. E.; Mehanna, A. S.; Patwa, D. C.;
Williams, F. L. J. Med. Chem. 1984, 27, 967.
(25) Sparks, M. A.; Panek, J. S. J. Org. Chem. 1991, 56, 3431.
(26) Clark, T.; Panek, J. S. J. Org. Chem. 1992, 57, 4323.
(18) Trost, B.; Tour, J. J. Org. Chem. 1989, 54, 484.
1530
Org. Lett., Vol. 7, No. 8, 2005

Scheme 4. Preparation of Chiral Crotyl Silanes
Table 1. Application of 4a/4b in the [4+2]-Annulation
Reaction
mentary 9b was unfortunately obtained as a 5:1 to 8:1
mixture of anti:syn diastereomers, which may be separated
at a later stage. Esterification with the phase transfer catalyst
Adogen27 in the presence of iodomethane followed by the
deprotection of the PMB group gave a free R-hydroxy ester.
The alcohol may then be protected as a TMS ether to
complete the synthesis of both the syn- and anti-crotyl silanes
(5 steps, 60% 4a; 56% 4b, respectively) from 7a and 7b.
Once a practical method was developed for the preparation
of 4a and 4b, we turned our attention toward exploring their
utility in [4+2]-annulations with a number of different
aldehydes (Table 1). On exposure to TMSOTf (0.05 M CH2-
Cl2 at -50 °C) the desired dihydropyrans 2,6-cis 11a (from
4a) and 2,6-trans 11b (from 4b) were obtained respectfully.
a Typical experiment was run in CH2Cl2 (0.05M), using 1 to 1.3 equiv
of aldehyde in the presence of TMSOTf (0.3 equiv). b All yields are based
on isolated product after chromatography. c Relative stereochemical as-
signments were determined by nOe experiments. d The ratio of products is
1
determined by H NMR. e See the Supporting Information.
Aromatic and conjugated aldehydes (entries 1-5 and 6)
gave the corresponding pyrans with useful yields and high
levels of diastereoselectivity. The lower yield observed for
entry 5 was a result of competitive deprotection of a single
acetonide group on the aromatic aldehyde. Aldehydes
containing multiple heteroatoms (chelatable centers) also
performed well under the described conditions (entries 2 and
5).
screening program to detect new metabolites from actino-
mycetes.30 The highly substituted tetrahydropyran core of 1
makes for an attractive target for this methodology. Presently
there is one reported total synthesis31 and multiple reports
of synthetic approaches.32
Use of silane ent-4a in the [4+2]-annulation with the
highly substituted aromatic aldehyde 12b gave the desired
2,5-syn-dihydropyran 13 in 85% isolated yield (dr >30:1).
The epoxidation of the resulting trisubstituted double bond
with 1,1,1-trifluoro dimethyl dioxirane in acetonitrile at -20
°C gave epoxide 14 with an R:â > 12:1 and 93% yield.
Oxirane ring opening occurred with elimination of the
intermediate â-methoxy ester in the presence of potassium
carbonate in methanol and gave the secondary alcohol 15.
Aliphatic aldehydes (entries 7 and 8) showed slightly lower
levels of diastereoselectivities with 4a.28 Interestingly the
[4+2]-annulation utilizing 4b with aliphatic aldehydes
(entries 7 and 8) gave a 2,6-cis 5,6-cis relationship (11b)
suggesting a mechanistic crossover in the stereochemical
course of the annulation.
The utility of these crotyl silanes in complex molecule
synthesis is documented in the synthesis of the C1a-C10
fragment of kendomycin 1 (Scheme 5).
(29) (a) Funahashi, Y.; Kawamura, N.; Ishimaru, T. Japanese Patent
08231551, 1996; Chem. Abstr. 1997, 126, 6553. (b) Funahashi, Y.;
Kawamura, N.; Ishimaru, T. Japanese Patent 08231553, 1996; Chem. Abstr.
1997, 125, 326518. (c) Su, M.; Hosken, M. I.; Hotovec, B. J.; Johnston, T.
L. U.S. Patent 5728727, 1998; Chem. Abstr. 1998, 128, 239489.
(30) Bode, H.; Zeeck, A. J. Chem. Soc., Perkin. Trans. 1 2000, 323.
(31) Yaun, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720.
(32) (a) Smits, H.; White, J. D. Org. Lett. 2005, 7, 235. (b) Mulzer, J.;
Pichlmair, S.; Green, M. P.; Marques, M. M. B.; Martin, H. J. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 11980. (c) Sengoku, T.; Arimoto, H.; Uemura,
D. J. Chem. Soc., Chem. Commun. 2004, 1220. (d) Pichlmair, S.; Marques,
M. M. B.; Green, M. P.; Martin, H. J.; Mulzer, J. Org. Lett. 2003, 5, 4657.
(e) Marques, M. M. B.; Pichlmair, S.; Martin, H. J.; Mulzer, J. Synthesis
2002, 2766. (f) Martin, H.; Drescher, M.; Ka¨hlig, H.; Schneider, S.; Mulzer,
J. Angew. Chem., Int. Ed. 2001, 40, 3186.
Compound 1 was isolated from two different Streptomyces
species as described in the patent literature.29 More recently
this substance was re-isolated from Streptomyces Violace-
oruber (strain 3844-33C) in connection with a chemical
(27) Bocchi, V.; Casnati, G.; Dossena, A.; Marchelli, R. Synthesis 1979,
957.
(28) One notable exception involves the use of trimethylacetaldehyde,
as only the product from Peterson elimination was observed to give the
conjugated diene of 4. This result was consistent with that observed for
crotyl silanes 2a and 2b with this particular aldehyde.14a
Org. Lett., Vol. 7, No. 8, 2005
1531

Scheme 5. Synthesis for the C1a-C10 Fragment of Kendomycin
Catalytic hydrogenation of the R,â-unsaturated ester com-
annulations with structurally diverse aldehydes to produce
both 2,6-cis- and trans-dihydropyrans with useful levels of
diastereoselectivity. Application in the synthesis of the C1a-
C10 fragment of kendomycin has also been described.
Further studies on the application of this reagent for complex
molecule synthesis will be reported in due course.
pleted the installation of the final two stereocenters. The
stereochemical course of the reduction is consistent with a
sterically controlled approach in a 69% 2 step yield and
>20:1 selectivity for 16. The undesired diastereoisomer 14â
could be recycled to give the correct C7 stereochemistry.
This was realized with the oxirane ring opening, Swern
oxidation of the resulting secondary alcohol, followed by
selective Luche reduction33 to give compound 15 in a 15:1
and 3 step 55% overall yield. Completion of the synthesis
required the protection of secondary alcohol in 16 as a TBS
ether, followed by DIBAl-H reduction of the methyl ester
to give aldehyde 17.
Acknowledgment. The authors are grateful to Dr. Hong-
bing Huang, Qibin Su, and Dr. Gwilherm Evano for useful
suggestions and discussions. Financial support for this
research is obtained from NIH CA56304. J.S.P. is grateful
to Johnson & Johnson, Merck Co., Novartis, Pfizer, and GSK
for financial support.
In conclusion, we have developed a reliable route for the
preparation of two new organosilanes bearing a quaternary
center on the carbon containing the silicon moiety. The route
provides the silanes 4a and 4b in multigram quantities (>10
g) in high enantiopurity. These reagents were used in [4+2]-
Supporting Information Available: General experimen-
tal procedures, including spectroscopic and analytical data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(33) Luche, J. L.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101, 5848.
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