Pyrones to pyrans: Enantioselective radical additions to acyloxy pyrones

Article abstract of DOI:10.1021/ja0648108

This paper describes a highly site-, diastereo-, and enantioselective intermolecular radical addition/hydrogen atom transfer to hydroxypyrone pyromeconic and kojic acids. The methodology can be extended to the formation of chiral quaternary centers. The p

Full text of DOI:10.1021/ja0648108

Published on Web 09/26/2006
Pyrones to Pyrans: Enantioselective Radical Additions to Acyloxy Pyrones
Mukund P. Sibi* and Jake Zimmerman
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105
Received July 6, 2006; E-mail: mukund.sibi@ndsu.edu
Table 1. Lewis Acid Screening with Pyromeconic Acid
Enantioselective Lewis acid-mediated free radical reactions
continue to attract interest.1 Detachable achiral auxiliaries play a
pivotal role in most of the enantioselective radical chemistry
reported in the literature to date.2 These auxiliaries provide an extra
donor atom that enables Lewis acid chelation. Another significant
structural feature is that, in general, R,â-unsaturated carbonyl
compounds that have undergone enantioselective radical additions
have reacted via s-cis conformers.
Derivativesa
We have been interested in developing enantioselective radical
additions onto substrates that will not require an achiral template3
and react via an s-trans geometry. Stereocontrolled functionalization
of readily available hydroxypyrones4 is important since they provide
access to pyrans, a structural unit present in compounds with
significant biological activity. For example, marine natural products
apicularen, phorboxazole, and spongistatin all contain pyran rings
with various substitution patterns.5 Recently, Hoveyda has dem-
onstrated enantioselective conjugate additions to chromones.4e This
communication addresses several challenging issues for Lewis acid-
catalyzed conjugate radical additions to hydroxypyrones (Scheme
1): (1) How reactive are they toward conjugate radical additions?
Lewis
acid
yield
(%)b
dr (5)c
ee of 5d
entry
R
ligand
syn/anti
5:6
(%)
1
2
3
4
5
6
7
8
9
Bn
Ac
Ac
Piv
Piv
Piv
Piv
Piv
Piv
Ac
Piv
Sc(OTf)3
Mg(NTf2)2
Sc(OTf)3
Mg(NTf2)2
Sc(OTf)3
Mg(NTf2)2
Mg(ClO4)2
Sc(OTf)3
8
trace
22
78
60
76
40
33
80
71
60
80
95:5
86:14
99:1
91:9
91:9
99:1
88:12
99:1
99:1
99:1
3.3:1
1.9:1
5.3:1
2.6:1
1.1:1
4.0:1
4.5:1
13:1
Scheme 1
7
7
7
8
9
9
62
16
3
30
49
70
10
11
9
9
4.0:1
10:1
a For reaction conditions, see Supporting Information. b Isolated yield.
c Diastereomeric ratio and site selectivity (5:6) were determined by 1H NMR
(400 MHz). d Determined by chiral HPLC.
(2) What is the C-2 versus C-6 site selectivity (2 vs 3) and will
electronic or steric factors act as control elements? (3) What will
be the optimal chiral Lewis acid system for stereoselectivity?
Our initial studies began using pyromeconic acid derivatives 4
(Table 1). It was found early on that the enol hydroxyl group needed
to be functionalized with an electron-withdrawing group in order
to achieve good reactivity (entry 1). No reaction took place (<5%)
for substrates 4a-c without a Lewis acid. More interesting was
the effect of the Lewis acid in these reactions. Initial racemic
reactions showed that magnesium and scandium salts yielded a
mixture of isomers (entries 2-5).6 Traditional bisoxazoline ligands
were screened with magnesium and scandium Lewis acids, but only
low to moderate enantioselectivities were achieved (entries 6-8).
Promising results were obtained using chiral aluminum salen
derived catalysts (entries 9-11).7 The commercially available 9
gave 5c in excellent yield and diastereoselectivity with the major
isomer possessing syn stereochemistry.8 The C-2 isomer was
preferentially formed (g10:1) in the Al-salen catalyzed reactions
with moderate enantioselectivities (entry 11).9
Table 2. Radical Additions to Pyromeconic Acid Pivalate
yield
(%)a
ee (%) of
entry
R
5:6
drb
5 (6)c
1
2
3
i-propyl 5c
c-pentyl 5d
c-hexyl 5e
tert-butyl 5f
tert-butyl 5f
(CH3)2C(CH2)3Cl 5g
91:9
93:7
92:8
90:10
93:7
92:8
80
74
55
76
60
45
99:1
99:1
99:1
99:1
99:1
99:1
70
76 (36)
70
92
92
4
5d
6
95 (39)
a Isolated yield. b Diastereomeric ratio and site selectivity (5:6) were
1
determined by H NMR (400 MHz). c Determined by chiral HPLC. d 100
mol % of 9.
to be much less selective with enantiomeric excesses <40% (entries
2 and 5). In contrast, reactions with bulky tertiary radicals yielded
the major C-2 adducts with excellent diastereo- and enantioselec-
tivities (>90%) (entries 4-6). Another important point of note is
that lowering the catalytic loading to 30 mol % showed no erosion
of enantioselectivity (compare entry 4 with 5).
We next investigated the addition of various radicals to substrate
4c under the optimized conditions (Table 2). Addition of secondary
radicals gave good yields, excellent diastereoselectivity, and moder-
ate enantioselectivity for the major C-2 product (5) (entries 1-3).
The minor C-6 products (6) were analyzed in two cases and found
9
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J. AM. CHEM. SOC. 2006, 128, 13346-13347
10.1021/ja0648108 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Radical Addition to Kojic Acid Derivatives
Figure 1. Stereochemical model.
yield
(%)a
ee
(%)c
entry
R
R1
R2
drb
The absolute stereochemistry for product 5e was determined by
conversion to a known compound.13 Figure 1 shows a proposed
chiral Lewis acid substrate model which accounts for the observed
stereochemistry in pyromeconic acid radical conjugate additions.
We propose that the substrate binds through the ketone carbonyl
to the Al-salen catalyst.14 The electron-withdrawing acyloxy
substituent may facilitate addition at C-2, even though C-6 is more
sterically accessible. Captodative effects may also impact regiose-
lectivity. The bulky -OR group orients away from the axial
hydrogen atoms on the cyclohexane ring, leaving the si face more
open for nucleophilic radical addition. Subsequent hydrogen transfer
to the R-carbon is apparently controlled not by the chiral ligand
but by the newly formed â-stereocenter, with the radical R group
shielding the top face.
1
2
3
4
5
6
7
8d
9
i-propyl 12a
c-pentyl 12b
tert-butyl 12c
(CH3)2C(CH2)3Cl 12d
i-propyl 12e
H
H
H
H
Piv
Piv
Piv
Piv
Piv
Piv
Piv
Piv
Piv
Piv
Piv
Piv
Piv
Piv
85
67
91
35
92
74
96
98
77
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
74
76
92
92
72
76
93
92
90
c-pentyl 12f
tert-butyl 12g
tert-butyl 12g
(CH3)2C(CH2)3Cl 12h
a Isolated yield. b Diastereomeric ratio was determined by 1H NMR (400
MHz). c Determined by chiral HPLC. d 10 mol % of 9.
Table 4. Quaternary Center Formation
Acknowledgment. This work was supported by the National
Institutes of Health (NIH-GM-54656).
Supporting Information Available: Characterization data for
compounds 4-13 and experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
yield
(%)a
ee
entry
R
drb
(%)c
1
2
i-propyl 13a
c-pentyl 13b
77
90
99:1
99:1
70
69
References
a Isolated yield. b Diastereomeric ratio was determined by 1H NMR (400
MHz). c Determined by chiral HPLC.
(1) (a) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. ReV. 2003, 103, 3263.
(b) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 33, 163. (c) Sibi, M.
P.; Manyem, S. Tetrahedron 2000, 56, 8033.
(2) (a) Sibi, M. P.; Sausker, J. B. J. Am. Chem. Soc. 2002, 124, 984. (b) Sibi,
M. P.; Prabagaran, N. Synlett 2004, 2421. (c) Sibi, M. P.; Shay, J. J.; Ji,
J. Tetrahedron Lett. 1997, 38, 5955.
(3) (a) Sibi, M. P.; Patil, K. Angew. Chem., Int. Ed. 2004, 43, 1235. (b) Sibi,
M. P.; Patil, K. Org. Lett. 2005, 6, 1543. (c) Sibi, M. P.; Asano, Y.;
Sausker, J. B. Angew. Chem., Int. Ed. 2001, 40, 1293.
(4) For selected examples on the use of pyrones in synthesis, see: (a)
Woodard, B. T.; Posner, G. H. AdV. Cycloaddit. 1999, 5, 47. (b) Marko,
I. E.; Evans, G. R.; Seres, P.; Chelle, I.; Janousek, Z. Pure Appl. Chem.
1996, 68, 113. (c) Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc.
1990, 112, 4956. (d) Rodriguez, J. R.; Rumbo, A.; Castedo, L.;
Mascarenas, J. L. J. Org. Chem. 1999, 64, 4560. (e) Brown, M. K.;
Degrado, S. J.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2005, 44, 5306.
(f) Okamura, H.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 1995, 36,
5939.
(5) (a) Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365. (b)
Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425. (c) Haustedt, L.
O.; Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2003, 42,
2711.
(6) For the synthesis of starting materials, reaction conditions for radical
reactions, ee determination, and product stereochemical analysis, see
Supporting Information.
(7) (a) For a review on salen catalysts in synthesis, see: Cozzi, P. G. Chem.
Soc. ReV. 2004, 33, 410. For selected examples on the use of salens in
conjugate additions, see: (b) Myers, J. K.; Jacobsen, E. N. J. Am. Chem.
Soc. 1999, 121, 8959. (c) Taylor, M. S.; Zalatan, D. B.; Lerchner, A. M.;
Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313.
(8) The relative stereochemistry was assigned by analogy of a very similar
series of compounds. See: Yamashita, Y.; Saito, S.; Ishitani, H.;
Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793.
(9) For site selectivity in radical addition to 2-methoxybenzoquinone, see:
Ling, T.; Poupon, E.; Rueden, E. J.; Kim, S. H.; Theodorakis, E. A. J.
Am. Chem. Soc. 2002, 124, 12261.
We next focused our attention on kojic acid, which is an
inexpensive, commercially available starting pyrone. In this case,
the C-6 position is functionalized with a hydroxymethyl moiety,
which could provide a handle for further synthetic manipulations
but also deactivates the C-6 position toward conjugate radical
addition. Kojic acid is relatively insoluble in nonpolar solvents and
thus was converted to 10 and 11 to increase solubility. Again, no
reaction took place without Lewis acid for substrates 10 and 11
(Table 3). As was expected, radical addition occurs exclusively at
the less substituted C-2 position. Addition of secondary radicals to
10 proceeded smoothly to yield 12a,b in good yields, excellent
diastereoselectivity, and moderate enantiomeric excesses (entries
1 and 2). More bulky tertiary radicals again proved to give enantio-
selectivities >90% (entries 3 and 4). We also examined the bis-
pivalyl substrate 11. Again, excellent yields and diastereoselectiv-
ities were obtained when secondary nucleophilic radicals were
added, while tertiary radicals gave excellent enantiomeric excesses
(entries 5-9).
We were also interested in forming two carbon-carbon bonds
via conjugate addition of a nucleophilic radical followed by trapping
of the electrophilic R-radical with an allyltin reagent.10 This process
establishes two new adjacent stereocenters with one being a
quaternary carbon. Initial attempts using catalyst 9 were unsuc-
cessful, but by utilizing a more reactive chiral Lewis acid (Cl
exchanged to NTf2, 9a),11 we were able to obtain good to excellent
yields of the addition/trapping products 13a,b (Table 4).12 The
enantioselectivities are modest and similar to what was observed
under reductive tin hydride conditions for isopropyl radical addition
(Table 3).
(10) Rosenstein, I. J. In Radicals in Organic Synthesis; Renaud, P., Sibi, M.
P., Eds.; Wiley-VCH: New York, 2001; Vol. 1, pp 50-71.
(11) This catalyst was prepared in situ by adding 1 equiv of AgNTf2 to the
commercially available chloride catalyst.
(12) Tetraallyltin was found to be much more efficient than allyltributyltin.
(13) Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem.
Soc. 2005, 127, 1336.
(14) For a similar model, see: Huang, Y.; Iwama, T.; Rawal, V. H. Org. Lett.
2002, 4, 1163.
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