B-Alkyl Suzuki couplings for the stereoselective synthesis of substituted pyrans

Article abstract of DOI:10.1039/b806898d

Unprotected homoallylic alcohols can be directly converted to cis-2,6-disubstituted pyrans by palladium catalyzed B-alkyl Suzuki coupling and subsequent Michael addition. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806898d

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B-Alkyl Suzuki couplings for the stereoselective synthesis of substituted
pyransw
Gregory W. O’Neil and Alois Furstner*
¨
Received (in Cambridge, UK) 23rd April 2008, Accepted 4th June 2008
First published as an Advance Article on the web 16th July 2008
DOI: 10.1039/b806898d
Unprotected homoallylic alcohols can be directly converted to
cis-2,6-disubstituted pyrans by palladium catalyzed B-alkyl
Suzuki coupling and subsequent Michael addition.
Substituted pyrans represent a structural motif common to a
wide range of natural products. Given their highly varying
degrees of functionalization, they remain a significant syn-
thetic challenge. Hence, a number of methods have been
Fig. 1 Pyran retrosynthesis.
as a 410 : 1 (NMR) diastereomeric mixture in favor of the cis-
2,6-disubstituted pyran 7.6
developed for their selective preparation.1 Our own synthetic
efforts toward a synthesis of the tetrahydropyran containing
natural product spirastrellolide
In order to investigate the generality of this method for the
stereoselective construction of 2,6-substituted pyrans, readily
available homoallylic alcohol 87 was first treated with 2
equivalents of 9-BBN. The alkyl borane thus obtained was
exposed to aqueous sodium hydroxide before stirring with
iodide 5 in the presence of (dppf)PdCl2 at ambient tempera-
ture. To our delight, upon acidic hydrolysis, cis-2,6 pyran 9
was obtained in good yield and again with excellent levels of
diastereocontrol. (Scheme 3).8 As a demonstration of this
methodology in the context of natural product synthesis, 9
was converted to the olfactory (+)-(S,S)-(cis-6-methyltetra-
hydropyran-2-yl)acetic acid 10,9 a glandular secretion from
the civet cat (Viverra civetta), using the conditions previously
described by Ley and co-workers.10
A (1) made use of a
thermodynamically controlled 6-exo-trig cyclization of an
intermediate a,b-unsaturated hydroxyketone 2, affording the
cis-2,6-disubstituted pyran 3 (Scheme 1).2
We questioned whether this same compound could be
obtained by Suzuki reaction3 of an in situ prepared alkyl
boronate of type 4 and iodobutenone 54 (Fig. 1).
It was anticipated that the use of two equivalents of 9-BBN
would allow for the reaction to be carried out without prior
hydroxyl group protection. To test this hypothesis, Brown
allylation adduct 65 was treated with two equivalents of
9-BBN and subsequently exposed to sodium hydroxide and
(dppf)PdCl2 in the presence of iodide 5 in THF at room
temperature (Scheme 2). Gratifyingly, upon aqueous acidic
workup, the cyclized product itself was obtained in good yield
To further explore the scope of this reaction, 1-allylcyclo-
hexanol (11)11 was subjected to the optimized tandem Suzuki-
coupling/oxy-Michael conditions in the presence of iodide 5,
affording the structurally unique spiro-pyran 12 in 70%
isolated yield (Scheme 4).
This reaction is not limited to the preparation of
2,6-substituted pyrans. For instance, known crotylation
adduct 1312 also underwent
a productive alkyl-Suzuki
coupling with iodide 5 to generate selectively the anti-2,3-cis-
2,6 trisubstituted pyran 14 (Scheme 5).13
An extension of this method would be toward the synthesis
of five-membered substituted heterocycles. To that end, allylic
Scheme 1 Acid-catalyzed 6-exo-trig cyclization.
Max-Planck-Institut fur Kohlenforschung, D-45470 Mulheim/Ruhr,
¨
¨
Germany. E-mail: fuerstner@mpi-muelheim.mpg.de;
Fax: +49 208 306 2994; Tel: +49 208 306 2342
w Electronic supplementary information (ESI) available: Experimental
part including spectroscopic data of all new compounds. See DOI:
10.1039/b806898d
Scheme 2 Reagents and conditions: (a) 9-BBN (2 eq.), aq. NaOH,
(dppf)PdCl2 (10 mol%), AsPh3 (10 mol%), THF, then HCl (1 M),
62%.
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Scheme 7 Reagents and conditions: (a) THF, 88%; (b) TMSI, CH2Cl2
then i-Pr2NEt, 96%; (c) 9-BBN then aq. NaOH, (dppf)PdCl2
(10 mol%), AsPh3 (10 mol%), THF, then HCl (1 M), 63% (d.r. = 6.5 : 1).
Scheme 3 Reagents and conditions: (a) 9-BBN (2 eq.), THF; (b) aq.
NaOH then 5, (dppf)PdCl2 (10 mol%), AsPh3 (10 mol%), THF, then
HCl (1 M), 73% (d.r. 4 10 : 1) (c) NaOBr (aq), dioxane, 65%.
This method may prove highly useful in the context of
fragment couplings. As a demonstration, a more complex
iodide 20 was chosen as a suitable Suzuki coupling partner,
available in two steps from known Weinreb amide 1816 via an
intermediate alkynone 19 (Scheme 7). As expected, 20 under-
went a smooth Suzuki reaction with a homoallylic alcohol 8
derived alkyl borane in the presence of (dppf)PdCl2 and
sodium hydroxide in THF at room temperature. The corres-
ponding 2,6-substituted pyran 21 was obtained under the
described reaction conditions as a separable 6.5 : 1 cis : trans
mixture of diastereomers in 64% overall yield.17
Scheme 4 Reagents and conditions: (a) 9-BBN (2 eq.), aq. NaOH, 5,
(dppf)PdCl2 (10 mol%), AsPh3 (10 mol%), THF, then HCl (1 M),
70%.
In conclusion, Suzuki couplings of homoallylic alcohols with
a,b-unsaturated iodoketones afford upon aqueous acidic work-
up the corresponding cis-2,6-disubstituted pyrans in good yield
and with high levels of diastereoselectivity. The reaction has
been extended to include the synthesis of substituted tetrahy-
drofurans and pyrrolidines from the corresponding allylic
alcohols and allylcarbamates, respectively. Given the plethora
of conditions available for the preparation of both coupling
partners and the avoidance of protecting groups, we hope this
reaction will find further application to the synthesis of complex
substituted heterocycle containing natural products.
Generous financial support from the MPG and the
Alexander-von-Humboldt Foundation is gratefully acknow-
ledged. We thank Ms Phillips and Dr R. Mynott for expert
NMR support.
Scheme 5 Reagents and conditions: (a) 9-BBN (2 eq.), aq. NaOH, 5,
(dppf)PdCl2 (10 mol%), AsPh3 (10 mol%), THF, then HCl (1 M),
64% (d.r 4 10 : 1).
alcohol 1514 was first transformed to the corresponding alkyl
borane in the presence of 9-BBN, and subsequently exposed to
Suzuki coupling conditions in the presence of iodide 5
(Scheme 6). Indeed, the desired 2,5-disubstituted tetrahydro-
furan 16 was obtained in good yield, albeit as a 1.7 : 1 mixture
of diastereomers. This same sequence can also be applied to
the synthesis of nitrogen-containing heterocycles exemplified
by the conversion of N-allylcarbamate to the corresponding
2-substituted pyrrolidine 17.15
Notes and references
1 For a recent review on pyran synthesis, see: I. Larrosa, P. Romea
and F. Urpı, Tetrahedron, 2008, 64, 2683.
´
2 (a) A. Furstner, M. D. B. Fenster, B. Fasching, C. Godbout and K.
¨
Radkowski, Angew. Chem., Int. Ed., 2006, 45, 5506; (b) A.
Furstner, M. D. B. Fenster, B. Fasching, C. Godbout and K.
¨
Radkowski, Angew. Chem., Int. Ed., 2006, 45, 5510; (c) A.
Furstner, B. Fasching, G. W. O’Neil, M. D. B. Fenster, C.
¨
Godbout and J. Ceccon, Chem. Commun., 2007, 3045; (d) for a
completed total synthesis, see: I. Paterson, E. A. Anderson, S. M.
Dalby, J. H. Lim, J. Genovino, P. Maltas and C. Moessner, Angew.
Chem., Int. Ed., 2008, 47, 3021.
3 (a) A. Suzuki, J. Organomet. Chem., 1999, 576, 147; (b) for a review
on alkyl-Suzuki reactions, see: S. R. Chemler, D. Trauner and S. J.
Danishefsky, Angew. Chem., Int. Ed., 2001, 40, 4544.
4 M. R. Rivero and S. L. Buchwald, Org. Lett., 2007, 9, 973.
5 (a) H. C. Brown and P. K. Jadhav, J. Am. Chem. Soc., 1983, 105,
2092; (b) J. Zhang, Y. Li, W. Wang, X. She and X. Pan, J. Org.
Chem., 2006, 71, 2918.
6 The stereochemistry was later confirmed after bisecting other
spirastrellolide intermediates, see ref. 2.
7 P. Kumar, P. Gupta and S. V. Naidu, Chem.–Eur. J., 2006, 12, 1397.
8 The stereochemistry was determined by comparison to literature,
see: (a) P. A. Evans and W. J. Andrews, Tetrahedron Lett., 2005,
Scheme 6 Reagents and conditions: (a) 9-BBN (2 eq.), aq. NaOH, 5,
(dppf)PdCl2 (10 mol%), AsPh3 (10 mol%), THF, then HCl (1 M),
61% (d.r. = 1.7 : 1); (b) 9-BBN then aq. NaOH, 5, (dppf)PdCl2 (10
mol%), AsPh3 (10 mol%), THF, then aq. NH4Cl, 55%.
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46, 5625; (b) H. H. Jung and P. E. Floreancig, Org. Lett., 2006, 8,
1949.
9 B. Maurer, A. Grieder and W. Thommen, Helv. Chim. Acta, 1979,
62, 44.
10 D. J. Dixon, S. V. Ley and E. W. Tate, J. Chem. Soc., Perkin
Trans. 1, 2000, 2385.
13 For detailed NMR analysis see the ESIw.
14 R. Zibuck and J. M. Streiber, J. Org. Chem., 1989, 54,
4717.
15 For an alternative synthesis of 16, see: M. Mori, Y. Washioka, T.
Urayama, K. Yoshiura, K. Chiba and Y. Ban, J. Org. Chem., 1983,
48, 4058.
11 G. J. Sormunen and D. E. Lewis, Synth. Commun., 2004, 34, 3473.
12 P. R. Blakemore, C. C. Browder, J. Hong, C. M. Lincoln, P. A.
Nagornyy, A. L. Robarge, D. J. Wardrope and J. D. White, J. Org.
Chem., 2005, 70, 5449.
16 C.-M. Wong and T.-P. Loh, Tetrahedron Lett., 2006, 47,
4485.
17 The stereochemistry has been tentatively assigned by inference and
spectral comparison to the preceding results.
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4296 | Chem. Commun., 2008, 4294–4296