Control of selectivity in the generation and reactions of oxonium ylides

Article abstract of DOI:10.1039/c1cc12443a

Dirhodium catalyzed reactions of aryl-substituted tetrahydropyranone diazoacetoacetates produce ylide intermediates that unexpectedly yield two oxabicyclo[4.2.1]-nonane diastereoisomers, but a single diastereoisomer is formed by increasing the steric bulk of the aryl substituent.

Full text of DOI:10.1039/c1cc12443a

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Control of selectivity in the generation and reactions of oxonium ylidesw
Deana M. Jaber, Ryan N. Burgin, Matthew Hepler, Peter Zavalij and Michael P. Doyle*
Received 26th April 2011, Accepted 23rd May 2011
DOI: 10.1039/c1cc12443a
Dirhodium catalyzed reactions of aryl-substituted tetrahydro-
pyranone diazoacetoacetates produce ylide intermediates that
unexpectedly yield two oxabicyclo[4.2.1]-nonane diastereoisomers,
but a single diastereoisomer is formed by increasing the steric bulk
Scheme 2 Stereoretentive [1,2] rearrangement and C–H insertion.
of the aryl substituent.
The synthesis and controlled reactions of oxonium ylides formed
through catalytic reactions of diazocarbonyl compounds with
ethers1 have high potential for the construction of diverse
natural products.2 In our search for viable substrates that could
take advantage of oxonium ylide chemistry, we considered the
tetrahydro-4-pyranone framework 3 which is accessible in a two
step synthetic process from synthetically available reactants
(Scheme 1). The hetero-Diels–Alder reaction has numerous
variants,3 including those that are highly enantioselective.4 The
subsequent Mukaiyama-Michael reaction has recently been
reported to occur in high yield5 and exceptional diastereocontrol
is well known in Lewis acid catalyzed reactions of 1 with silyl
enol ethers.6 We anticipated then that transition metal catalyzed
reaction of 3 would form oxonium ylide 4 and from this reaction
intermediate the resultant [1,2]-rearrangement product 5 would
be obtained with high selectivity.7 Consistent with this expecta-
tion, West and coworkers have reported that a similar six-
membered ring diazoketone underwent [1,2]-rearrangement with
complete stereoretention, which occurred in competition with
C–H insertion and elimination (Scheme 2).8b The structural
oxabicyclo[4.2.1]nonane framework is found in a number of
Scheme 3 Coupled hetero-Diels–Alder and highly diastereoselective
Mukaiyama–Michael reactions.
natural products,9 and a limited number of approaches have
been used for their synthesis.10
Phenyldihydropyranone 6a was prepared by BF3ꢀEt2O-
mediated hetero-Diels–Alder reaction between benzaldehyde
and Danishefsky’s diene.11 This process was followed by the
Mukaiyama–Michael reaction of 6a with methyl 3-(tert-butyl-
dimethylsilanoxy)-2-diazo-3-butenoate 2 catalyzed by Zn(OTf)2
(1.0 mol%) in refluxing dichloromethane.5 After hydrolysis and
purification, 7a was isolated in 99% yield (Scheme 3) and was
determined to be solely the trans isomer by NOE analysis
(see supporting informationw). This high stereocontrol is general
for reactions of 2 with all 6-substituted 5,6-dihydro-4-pyranones.
Dinitrogen extrusion catalyzed by 1.0 mol% of dirhodium
(perfluorobutyrate) [Rh2(pfb)4] in refluxing dichloromethane
produced, after chromatography, a white solid that was the
oxabicyclo[4.2.1]nonan-4,8-dione product 8 in 77% isolated yield
(Scheme 4). No evidence was obtained for the product from C–H
insertion into the C–H bond adjacent to the phenyl substituent
of 7a. Because the trans isomer 7a was the reactant, and analogous
to the process described in Scheme 2, we expected that the final
product would also have that same stereochemistry. However, the
reaction resulted in a mixture of two stereoisomers in a 71 : 29
Scheme 1 Strategy for the synthesis of the oxabicyclo[4.2.1]-nonane.
Department of Chemistry and Biochemistry, University of Maryland,
College Park, Maryland 20742, USA. E-mail: mdoyle3@umd.edu
w Electronic supplementary information (ESI) available: General
procedure for compounds 6a–e, 7a–e and 8a–e. Characterization data
and 1H and 13C NMR for all oxabicyclo[4.2.1]nonanes. CCDC 826314
and 826315. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc12443a
Scheme 4 Products from Rh(II) catalyzed dinitrogen extrusion with
diazo substituted tetrahydropyranones.
c
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Fig. 2 Elimination products from reactions of 7d (Z = Me) and 7e
(Z = OMe) with Rh2(pfb)4.
retention is a stepwise mechanism involving radical or ion pairs
in the formation of 8 from the ylide precursor.8,14 The lack of
product dependence on catalyst suggests that the catalyst is not
bound to the ylide during the product forming step. In the case
of diazoacetoacetate 7 the stepwise mechanism would involve
ylide formation followed by homolytic or heterolytic cleavage
of the benzyl-oxygen bond, then bond rotation at the benzyl
carbon and ring closure to form the observed anti-8 and syn-8
products. However, the absence of a substituent effect on the
isomer ratio and the production of a single ylide-derived isomer
from a comparable diazoketone (Scheme 2) suggests that other
factors may be operating, one of which could be conforma-
tional (e.g., one conformational isomer of 7 forming syn-8 while
a second conformer of 7 forms anti-8).
Fig. 1 Views of (a) syn-8a and (b) anti-8a showing the anisotropic atomic
displacement ellipsoids for the non-hydrogen atoms at the 30% probability
level. Hydrogen atoms are displayed with an arbitrarily small radius.
molar ratio that were chromatographically and spectrally distin-
guishable. The isomer ratio was invariant with common ligands on
dirhodium (tfa = trifluoroacetate, OAc, cap = caprolactamate)
that cover a broad range of electronic influences.12 Solvent and
temperature influences were also minor.13 1H NMR spectroscopic
evaluation showed that the two compounds were constitutionally
identical and had the same connectivity. Spectral analysis provided
their identification as the anti and syn stereoisomers of 1-carbo-
methoxy-2-phenyl-9-oxabicyclo[4.2.1]nonan-4,8-dione 8a, but
only through the crystal structures of the major isomer (71% of
the total) and the minor isomer (29% of total) could their identities
as the major and minor isomers be established (Fig. 1). Note that
the original trans-stereochemistry of the reactant 7a (positions 2
and 6) is formally inverted in forming anti-8a.
To evaluate the influence of conformational factors several
bulky aryl groups of 7 were examined for their suitability in
ylide formation and [1,2]-rearrangement. The mesityl (10) and
the 9-anthranyl (12) derivatives were screened in the
dirhodium(II) catalyzed dinitrogen extrusion reaction. Single
ylide-derived isomers [syn-11 from 10 (eqn (1)) and syn-13
from 12 (eqn (2))15] were observed without evidence for the
We investigated the influence of substituents at the para-
position on the benzene ring in 7 on the ratio of syn-8a to anti-
8a. The results from this investigation are reported in Table 1.
The catalytic dinitrogen extrusion/metal carbene-derived reac-
tions of 7 with the strongly electron-withdrawing p-NO2 7b and
p-CF3 7c substituents were remarkably clean, and isolation of
anti-8 and syn-8 from both substrates was achieved in very high
yield. Compounds 7d and 7e, which have electron-donating para
substituents, produced elimination products trans-9d and cis-9e
(Fig. 2) in competition with [1,2]-rearrangement products anti-8
and syn-8. The ratios of syn-8(d or e) to anti-8(d or e) from 7d or
7e were the same, within experimental error, as those from 7a
with the same catalyst. Also, the trans-9(d and e) to cis-9(d and e)
ratios were remarkably similar to those of the corresponding
ratios of syn-8a to anti-8a, suggesting that the diastereoselection
established in the formation of 8 and 9 could both be determined
in the ylide formation step.
1
anti-isomer, as determined by H NMR data, but they were
formed in less than 50% yield as mixtures with other reaction
products. However, dirhodium(II)-catalyzed reaction of the
2,6-dimethyl-4-nitrophenyl derivative (14) proved to be rela-
tively free of competing reactions, and dinitrogen extrusion of
14, catalyzed by Rh2(pfb)4, formed syn-15 in 77% isolated
yield without a measurable contribution (1H NMR) from the
potential anti-15 diastereomer (eqn (3)).
ð1Þ
ð2Þ
ð3Þ
How did this apparent ‘‘isomerism’’ arise? The most common
explanation is that the cause of this erosion of stereochemical
Table 1 Influence of phenyl substituents on product ratioa
Entry Z = Yield 8, %b syn-8 : anti-8c Yield 9, %d trans-9 : cis-9c
1
2
3
4
5
H
77
71 : 29
74 : 26
74 : 26
69 : 31
69 : 31
Trace
Trace
Trace
14
—
—
—
64 : 36
58 : 42
NO2 94
CF3 92
Me 55
OMe 22
16
a
Reactions were performed in refluxing CH2Cl2 for 2 h using 1.0 mol%
of Rh2(pfb)4. Results reported are averages of two or more reactions.
b
Weight yield of isolated anti-8 and syn-8 products following chromato-
c
In conclusion, dirhodium carboxylate catalyzed ylide generation
with aryl-substituted tetrahydropyranone diazo-acetoacetates
and their subsequent [1,2]-rearrangement forms two dia-
stereoisomers with the oxabicyclo[4.2.1]nonane framework.
graphic separation. Product ratio determined by 1H NMR analysis with
d
variance of ꢁ4%. NMR yield of trans-9 and cis-9 products determined
by the use of benzaldehyde as an internal standard.
c
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para-Substituents on the 2-substituted aromatic ring were
expected to influence the stability of intermediates for this
reaction if formed from the ylide by homolytic or heterolytic
cleavage, but the ratio of these two diastereoisomers was
independent of para-substituents. However, using the same
catalysts and conditions with aryl-substituted tetrahydro-
pyranone diazoacetoacetates in which the steric bulk of the
2-aryl group is substantially increased produced a single
diastereoisomer. The importance of the size of the aryl group,
coupled with the absence of a substituent effect on the ratio
of oxabicyclo[4.2.1]-nonane diastereomers suggests that
conformational influences may be responsible for the apparent
isomerism; in this case each reacting conformer forms a
different ylide-derived intermediate by reaction of the rhodium
carbene with either the axial or equatorial lone pair of
electrons on oxygen. Rearrangement of each of these two
non-equilibrating ylides would then form a distinct diastereo-
isomeric product. However, our results do not rule out the
long held dissociation–rearrangement–recombination pathway,8
and further investigations are underway to delineate the
mechanism of this and related transformations.
H. Yamamoto and V. H. Rawal, J. Am. Chem. Soc., 2005, 127,
1336–1337; (g) D. E. Chavez and E. N. Jacobsen, Org. Synth.,
2005, 82, 34–42; (h) X. Li, X. Meng, H. Su, X. Wu and D. Xu,
Synlett, 2008, 6, 857–860; (i) H. Du, X. Zhang, Z. Wang, H. Bao,
T. You and K. Ding, Eur. J. Org. Chem., 2008, 13, 2248–2254;
(j) Y. Watanabe, T. Washio, N. Shimada, M. Anada and
S. Hashimoto, Chem. Commun., 2009, 7294–7296; (k) H. Pellissier,
Tetrahedron, 2009, 65, 2839–2877.
5 Y. Liu, Yu. Zhang, N. Jee and M. P. Doyle, Org. Lett., 2008, 10,
1605–1608.
6 (a) M. Anada, T. Washio, Y. Watanabe, K. Takeda and
S. Hashimoto, Eur. J. Org. Chem., 2010, 6850–6854;
(b) J. C. Jewett and V. H. Rawal, Angew. Chem., Int. Ed., 2007,
46, 6502–6504; (c) A. B. Smith III, T. M. Razler, J. P. Ciavarri,
T. Hirose and T. Ishikawa, Org. Lett., 2005, 7, 4399–4402;
(d) Y. Yamashita, S. Saito, H. Ishitani and S. Kobayashi, J. Am.
Chem. Soc., 2003, 125, 3783–3798.
7 Representative examples for [1,2]-rearrangements of oxonium
ylides: (a) M. P. Doyle, D. G. Ene, D. C. Forbes and
J. S. Tedrow, Tetrahedron Lett., 1997, 38, 4367–4370; (b) A. Oku
and M. Numata, J. Org. Chem., 2000, 65, 1899–1906;
(c) N. P. Karche, S. M. Jachak and D. D. Dhavale, J. Org. Chem.,
2001, 66, 6323–6332; (d) S. J. Clark, G. Whitlock, S. Jiang and
N. Onvia, Chem. Commun., 2003, 2578–2579; (e) F. P. Marmsater,
G. K. Murphy and F. G. West, J. Am. Chem. Soc., 2003, 125,
14724–14725; (f) Y. Sawada, T. Mori and A. Oku, J. Org. Chem.,
2003, 68, 10040–10045; (g) M. P. Doyle, K. Kundu and A. Russell,
Org. Lett., 2005, 7, 5171–5174; (h) J. S. Clark, S. B. Walls,
C. Wilson, S. P. East and M. J. Drysdale, Eur. J. Org. Chem.,
2006, 323–327.
8 (a) W. Kirmse, P. V. Chiem and V. Schurig, Tetrahedron Lett.,
1985, 26, 197–200; (b) F. G. West, T. H. Eberlein and R. W. Tester,
J. Chem. Soc., Perkin Trans. 1, 1993, 2857–2859; (c) F. G. West
and B. N. Naidu, J. Am. Chem. Soc., 1994, 116, 8420–8421;
(d) F. P. Marmsater, J. A. Vanecko and F. G. West, Org. Lett.,
2004, 6, 1657–1660; (e) A. Oku, Y. Sawada, M. Schroeder,
I. Higashikubo, T. Yoshida and S. Ohki, J. Org. Chem., 2004,
69, 1331–1336; (f) G. K. Murphy and F. G. West, Org. Lett., 2005,
7, 1801–1804.
9 (a) P. Cai, A. T. McPhail, E. Krainer, B. Katz, C. Pearce, C. Boros,
B. Caceres, D. Smith and D. R. Houck, Tetrahedron Lett., 1999,
40, 1479–1482; (b) K.-I. Takao, G. Watanabe, H. Yasui and
K.-I. Tadano, Org. Lett., 2002, 4, 2941–2943; (c) W.-L. Xiao,
Y.-Q. Gong, R. R. Wang, Z.-Y. Weng, X. Luo, X.-N. Li,
G.-Y. Yang, F. He, J.-X. Pu, L.-M. Yang, Y.-T. Zheng, Y. Lu
and H.-D. Sun, J. Nat. Prod., 2009, 72, 1678–1681.
10 (a) R. Benhaddou, S. Czernecki and G. Ville, J. Org. Chem., 1992,
57, 4612–4616; (b) J. Ramnauth, O. Poulin, S. S. Bratovanov,
S. Rakhit and S. P. Maddaford, Org. Lett., 2001, 3, 2571–2573;
(c) F. P. Marmsater, G. K. Murphy and F. G. West, J. Am. Chem.
Soc., 2003, 125, 14724–14725; (d) K.-I. Takao, H. Yasui,
S. Yamamoto, D. Sasaki, S. Kawasaki, G. Watanabe and
K.-I. Tadano, J. Org. Chem., 2004, 69, 8789–8795;
(e) G. Kumaraswamy, G. Ramakrishna, P. Naresh, B. Jagadeesh
and B. Sridhar, J. Org. Chem., 2009, 74, 8468–8471.
11 (a) S. J. Danishefsky, J. F. Kerwin Jr and S. Kobayashi, J. Am.
Chem. Soc., 1982, 104, 358–360; (b) S. J. Danishefsky, E. Larson,
D. Askin and N. Kato, J. Am. Chem. Soc., 1985, 107, 1246–1255.
12 (a) A. Padwa, D. J. Austin, S. F. Hornbuckle, M. A. Semones,
M. P. Doyle and M. N. Protopopova, J. Am. Chem. Soc., 1992,
114, 1874–1896; (b) A. Padwa and D. J. Austin, Angew. Chem.,
Int. Ed. Engl., 1994, 33, 1797–1815.
13 Reactions were performed in CH2Cl2 at room temperature, at
40 1C in toluene and in refluxing DCE all at the same reaction time.
14 (a) R. W. Jemison and D. G. Morris, Chem. Commun., 1969,
1226–1227; (b) M. J. S. Dewar and C. Ramsden, J. Chem. Soc.,
Perkin Trans. 1, 1974, 1839–1844; (c) W. D. Ollis, M. Rey and
I. O. Sutherland, J. Chem. Soc., Chem. Commun., 1975, 543–545;
(d) W. D. Ollis, M. Rey and I. O. Sutherland, J. Chem. Soc., Perkin
Trans. 1, 1983, 1009–1027; (e) I. G. Stara, M. Tichy, J. Zavada and
V. Hanus, J. Am. Chem. Soc., 1994, 116, 5084–5088.
We are grateful to the National Institutes of Health (GM
465030) for their support of this research.
Notes and references
1 (a) A.-H. Li, L.-X. Dai and V. K. Aggarwal, Chem. Rev., 1997, 97,
2341–2372; (b) M. P. Doyle, M. A. McKervey and T. Ye, Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds, Wiley,
New York, 1998; (c) L. Yet, Chem. Rev., 2000, 100, 2963–3008;
(d) Nitrogen, Oxygen and Sulfur Ylide Chemistry. A Practical Approach
in Chemistry, ed. J. S. Clark, Oxford University Press, Oxford, 2002;
(e) F. G. West, Modern Rhodium-Catalyzed Organic Reactions,
ed. P. A. Evans, Wiley-VCH, New York, 2005, ch. 18;
(f) G. Desimoni, G. Faita and K. A. Jørgensen, Chem. Rev., 2006,
106, 3561–3651; (g) H. Wee and G. H. Andrew, Curr. Org. Synth., 2006,
3, 499–555; (h) J. B. Sweeney, Chem. Soc. Rev., 2009, 38, 1027–1038.
2 (a) F. P. Marmsater and F. G. West, J. Am. Chem. Soc., 2001, 123,
5144–5145; (b) J. S. Clark, T. C. Fessard and C. Wilson, Org. Lett.,
2004, 6, 1773–1776; (c) J. S. Clark, C. A. Baxter and J. L. Castro,
Synthesis, 2005, 3398–3404; (d) J. S. Clark, T. C. Fessard and
G. A. Whitlock, Tetrahedron, 2005, 62, 73–78; (e) T. Yakura,
W. Muramatsu and J. Uenishi, Chem. Pharm. Bull., 2005, 53,
989–994; (f) J. S. Clark, S. T. Hayes, C. Wilson and L. Gobbi,
Angew. Chem., Int. Ed., 2007, 46, 437–440; (g) J. S. Clark,
C. A. Baxter, A. G. Dossetter and W. G. Poigny, J. Org. Chem.,
2008, 73, 1040–1055; (h) D. M. Hodgson, D. Angrish,
S. P. Erickson, J. Kloesges and C. H. Lee, Org. Lett., 2008, 10,
5553–5556.
3 (a) L. F. Tietze and G. Kettschau, in Stereoselective Heterocyclic
Synthesis, ed. I. P. Metz, Springer-Verlag, Berlin, 1997;
(b) K. C. Nicolaou and E. J. Sorensen, in Classics in Total
Synthesis: Targets, Strategies, Methods, ed. H. Waldmann, VCH,
New York, 1996; (c) D. L. Boger and S. H. Weinreb, in Hetero-
Diels–Alder Methodology in Organic Synthesis, ed. H. H. Wasserman,
Academic Press, San Diego, 1996; (d) K. A. Jørgensen, Angew.
Chem., Int. Ed., 2000, 39, 3558–3588; (e) K. Maruoka, in Catalytic
Asymmetric Synthesis, ed. I. Ojima, VCH, New York, 2000;
(f) S. Reymond and J. Cossy, Chem. Rev., 2008, 108, 5359–5406.
4 (a) E. N. Jacobsen, T. F. Jamison and A. G. Dossetter, Angew.
Chem., Int. Ed., 1999, 38, 2398–2400; (b) M. P. Doyle,
I. M. Phillips and W. Hu, J. Am. Chem. Soc., 2001, 123,
5366–5367; (c) K. Ding, J. Long, J. Hu, S. Xiaoqiang and B. Ji,
J. Am. Chem. Soc., 2002, 124, 10–11; (d) M. Anada, T. Washio,
N. Shimada, S. Kitagaki, M. Nakajima, M. Shiro and
S. Hashimoto, Angew. Chem., Int. Ed., 2004, 43, 2665–2668;
(e) M. P. Doyle, M. Valenzuela and P. Huang, Proc. Natl. Acad.
Sci. U. S. A., 2004, 101, 5391–5395; (f) A. K. Unni, N. Takenaka,
15 In this case, the yield was lower with Rh2(pfb)4 (31%).
c
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