Enantioselective carbonyl allylation, crotylation, and tert- prenylation of furan methanols and furfurals via iridium-catalyzed transfer hydrogenation

Article abstract of DOI:10.1021/jo902697g

Chemical Equation Presentation 5-Substituted-2-furan methanols 1a-c are subject to enantioselective carbonyl allylation, crotylation and tertprenylation upon exposure to allyl acetate, a-methyl allyl acetate, or 1, 1-dimethylallene in the presence of an orthocyclometalated iridium catalyst modified by (R)-Cl,MeOBIPHEP, (R)-C3-TUNEPHOS, and (R)-C3-SEGPHOS, respectively. In the presence of 2-propanol, but under otherwise identical conditions, the corresponding substituted furfurals 2a-c are converted to identical products of allylation, crotylation, and tert-prenylation. Optically enriched products of carbonyl allylation, crotylation, and reverse prenylation 3b, 4b, and 5b were subjected to Achmatowicz rearrangement to furnish the corresponding γ-hydroxy-β-pyrones 6a-c, respectively, with negligible erosion of enantiomeric excess.

Full text of DOI:10.1021/jo902697g

pubs.acs.org/joc
acetate, and 1,1-dimethylallene to carbonyl electrophiles
Enantioselective Carbonyl Allylation, Crotylation,
and tert-Prenylation of Furan Methanols and
Furfurals via Iridium-Catalyzed Transfer
Hydrogenation
to furnish products of carbonyl allylation,2a,b,e-h croty-
lation,2c,f and tert-prenylation,2d,f respectively. For such
“C-C bond forming transfer hydrogenations”, 2-propanol
serves as the terminal reductant for additions to preformed
aldehyde electrophiles. Remarkably, primary alcohols serve
dually as hydrogen donors and aldehyde precursors, enab-
ling asymmetric carbonyl allylation, crotylation, and tert-
prenylation directly from the alcohol oxidation level. Here,
hydrogen exchange between an alcohol-unsaturate redox
pair enables generation of an electrophile-nucleophile pair.
In this way, nonstabilized carbanion equivalents are generated
in the absence of stoichiometric metallic reagents. This strategy
for carbonyl allylation differs significantly from conventional
carbonyl allylation protocols, which exploit stoichiometric
quantities of allylmetal reagents or metallic reductants.3-5
In connection with studies toward the syntheses of the
mitochondrial electron-transport inhibitors ajudazols A and
B,6 one of the present authors required a highly enantio-
selective method for the crotylation of a substituted furfural.
Although the enantioselective allylation of furfurals has been
achieved using stoichiometric allylmetal reagents,7 Denmark
reports the only catalytic methods for enantioselective croty-
lation and reverse prenylation of furfural.7f,o Given the
broad utility of furans as building blocks in organic synthe-
sis,8 we sought to further evaluate the scope of our emergent
Benjamin Bechem,†,‡ Ryan L. Patman,‡
A. Stephen K. Hashmi,*,† and Michael J. Krische*,‡
†Organisch-Chemisches Institut Ruprecht-Karls-Universita€t
Heidelberg, D-69120 Heidelberg, Germany, and ‡University
of Texas at Austin Department of Chemistry and
Biochemistry, Austin, Texas 78712
hashmi@hashmi.de; mkrische@mail.utexas.edu
Received December 22, 2009
(2) For enantioselective carbonyl allylation, crotylation, and reverse
prenylation via iridium-catalyzed C-C bond-forming-transfer hydrogena-
tion, see: (a) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 6340. (b) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 14891. (c) Kim, I. S.; Han, S.-B.; Krische, M. J. J. Am. Chem. Soc. 2009,
131, 2514. (d) Han, S. B.; Kim, I.-S.; Han, H.; Krische, M. J. J. Am. Chem.
Soc. 2009, 131, 6916. (e) Lu, Y.; Kim, I.-S.; Hassan, A.; Del Valle, D. J.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 5018. (f) Itoh, J.; Han, S. B.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 6316. (g) Lu, Y.; Krische, M.
J. Org. Lett. 2009, 11, 3108. (h) Hassan, A.; Lu, Y.; Krische, M. J. Org. Lett.
2009, 11, 3112. (i) For a recent application in natural product synthesis, see:
Harsh, P; O’Doherty, G. A. Tetrahedron 2009, 65, 5051.
(3) For selected reviews on enantioselective carbonyl allylation, see: (a)
Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207. (b) Ramachandran, P.
V. Aldrichim. Acta 2002, 35, 23. (c) Kennedy, J. W. J.; Hall, D. G. Angew.
Chem., Int. Ed. 2003, 42, 4732. (d) Denmark, S. E.; Fu, J. Chem. Rev. 2003,
103, 2763. (e) Yu, C.-M.; Youn, J.; Jung, H.-K. Bull. Korean Chem. Soc.
2006, 27, 463. (f) Marek, I.; Sklute, G. Chem. Commun. 2007, 1683. (g) Hall,
D. G. Synlett 2007, 1644.
(4) For selected reviews of carbonyl allylation based on the reductive
coupling of metallo-π-allyls derived from allylic alcohols, ethers, or carboxy-
lates, see: (a) Masuyama, Y. Palladium-Catalyzed Carbonyl Allylation via
π-Allylpalladium Complexes. In Advances in Metal-Organic Chemistry;
Liebeskind, L. S., Eds.; JAI Press: Greenwich, 1994; Vol. 3, pp 255-303. (b)
Tamaru, Y. Palladium-Catalyzed Reactions of Allyl and Related Derivatives with
Organoelectrophiles. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-i., de Meijere, A., Eds.; Wiley: New York, 2002; Vol. 2, pp
1917-1943. (c) Tamaru, Y. Novel Catalytic Reactions involving π-Allylpalla-
dium and -Nickel as the Key Intermediates: Umpolung and β-Decarbopalladation
of π-Allylpalladium and Nickel-Catalyzed Homoallylation of Carbonyl Com-
pounds with 1,3-Dienes. In Perspectives in Organopalladium Chemistry for the
XXI Century; Tsuji, J., Eds.; Elsevier: Amsterdam, 1999; pp 215-231. (d)
Kondo, T.; Mitsudo, T.-a. Curr. Org. Chem. 2002, 6, 1163. (e) Tamaru, Y. Eur. J.
Org. Chem. 2005, 13, 2647. (f) Zanoni, G.; Pontiroli, A.; Marchetti, A.; Vidari, G.
Eur. J. Org. Chem. 2007, 22, 3599.
5-Substituted-2-furan methanols 1a-c are subject to en-
antioselective carbonyl allylation, crotylation and tert-
prenylation upon exposure to allyl acetate, R-methyl allyl
acetate, or 1,1-dimethylallene in the presence of an ortho-
cyclometalated iridium catalyst modified by (R)-Cl,MeO-
BIPHEP, (R)-C3-TUNEPHOS, and (R)-C3-SEGPHOS,
respectively. In the presence of 2-propanol, but under
otherwise identical conditions, the corresponding substi-
tuted furfurals 2a-c are converted to identical products
of allylation, crotylation, and tert-prenylation. Optically
enriched products of carbonyl allylation, crotylation, and
reverse prenylation 3b, 4b, and 5b were subjected to
Achmatowicz rearrangement to furnish the correspond-
ing γ-hydroxy-β-pyrones 6a-c, respectively, with negli-
gible erosion of enantiomeric excess.
In the course of studies on C-C bond-forming hydro-
genations and transfer hydrogenations,1 we found that
cyclometalated iridium C,O-benzoates modified by chiral
phosphine ligands are effective catalysts for the enantio-
selective reductive coupling of allyl acetate, R-methyl allyl
(1) For selected reviews on C-C bond-forming hydrogenation and
transfer hydrogenation, see: (a) Ngai, M.-Y.; Kong, J. R.; Krische,
M. J. J. Org. Chem. 2007, 72, 1063. (b) Skucas, E.; Ngai, M.-Y.; Komanduri,
V.; Krische, M. J. Acc. Chem. Res. 2007, 40, 1394. (c) Shibahara, F.; Krische,
M. J. Chem. Lett. 2008, 37, 1102. (d) Bower, J. F.; Kim, I. S.; Patman, R. L.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34. (e) Han, S. B.; Kim, I. S.;
Krische, M. J. Chem. Commun. 2009, 7278.
(5) For selected examples of carbonyl allylation via catalytic Nozaki-
€
Hiyama-Kishi coupling of allylic halides, see: (a) Furstner, A.; Shi, N.
J. Am. Chem. Soc. 1996, 118, 2533. (b) Bandini, M.; Cozzi, P. G.; Umani-
Ronchi, A. Polyhedron 2000, 19, 537. (c) McManus, H. A.; Cozzi, P. G.;
€
Guiry, P. J. Adv. Synth. Catal. 2006, 348, 551. (d) Hargaden, G. C.; Muller-
Bunz, H.; Guiry, P. J. Eur. J. Org. Chem. 2007, 4235. (e) Hargaden, G. C.;
O’Sullivan, T. P.; Guiry, P. J. Org. Biomol. Chem. 2008, 6, 562.
DOI: 10.1021/jo902697g
r
Published on Web 02/04/2010
J. Org. Chem. 2010, 75, 1795–1798 1795
2010 American Chemical Society

Bechem et al.
JOCNote
allylation methodology in a systematic study of allylation,
crotylation and reverse prenylation of substituted furfurals
from both the alcohol and aldehyde oxidation levels. Here,
we disclose that 5-substituted-2-furan methanols 1a-c are
subject to highly enantioselective carbonyl allylation, croty-
lation, and reverse prenylation upon exposure to allyl ace-
tate, R-methyl allyl acetate, or 1,1,-dimethylallene, respec-
tively, in the presence of an ortho-cyclometalated iridium
catalyst modified by (R)-Cl,MeO-BIPHEP, (R)-C3-TUNE-
PHOS, and (R)-C3-SEGPHOS, respectively. Under nearly
identical conditions, but in the presence of 2-propanol, the
corresponding substituted furfurals are converted to identi-
cal products of allylation, crotylation, and reverse prenyl-
ation. Achmatowicz rearrangement of the 5-methyl-2-furan
methanol adducts 3b, 4b, and 5b is described.9
TABLE 1. Enantioselective Carbonyl Allylation of Furan Methanols
via Iridium-Catalyzed Transfer Hydrogenationa
entry
furan methanol
product
isolated yield (%)
ee (%)
1
2
3
R = H, 1a
R = Me, 1b
R = Ar, 1c
3a
3b
3c
69
75
79
92 (R)
95 (R)
94 (R)
aYields are of material isolated by silica gel chromatography.
Enantiomeric excess was determined by chiral stationary-phase HPLC
analysis. For compound 1c, Ar = 3-chloro-4-methoxyphenyl. See the
Supporting Information for additional details.
In an initial set of experiments, 5-substituted-2-furan
methanols 1a-c were subjected to conditions for enantio-
selective iridium-catalyzed carbonyl allylation employing an
ortho-cyclometalated catalyst generated in situ from
[Ir(cod)Cl]2, (R)-Cl,MeO-BIPEHP, and 4-chloro-3-nitro-
benzoic acid.2a,b,e-h Use of the preformed complex provided
comparable yields and selectivities. The products of carbonyl
allylation 3a-c are formed in good isolated yield with
uniformly high levels of optical purity using only 2 equiv of
allyl acetate as the allyl donor (Table 1). Under the same
conditions, but in the presence of 2-propanol, the corre-
sponding 5-substituted 2-furfurals 2a-c are converted to an
identical set of carbonyl allylation products 3a-c in good to
excellent isolated yields with uniformly high levels of enantio-
selectivity. Notably, the parent furans 1a and 2a provide
slightly lower yields of the homoallylic alcohol 3a, presumably
due to volatility or sensitivity of the furan nucleus with respect
to acid-promoted degradation during isolation by silica gel
chromatography (Table 2).
TABLE 2. Enantioselective Carbonyl Allylation of Furfurals via
Iridium-Catalyzed Transfer Hydrogenationa
entry
furan methanol
product
isolated yield (%)
ee (%)
1
2
3
R = H, 1a
R = Me, 1b
R = Ar, 1c
3a
3b
3c
70
82
94
97 (R)
95 (R)
97 (R)
aAs described for Table 1.
TABLE 3. Enantioselective Carbonyl Crotylation of Furan Methanols
via Iridium-Catalyzed Transfer Hydrogenationa
Enantioselective crotylation of 5-substituted 2-furan
methanols 1a-c was explored next.2c,f Here, the preformed
ortho-cyclometalated complex generated from [Ir(cod)Cl]2,
(6) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot. 2004,
57, 151.
(7) For selected examples of enantioselective furfural allylation employ-
ing preformed allylmetal reagents, see: (a) Racherla, U. S.; Liao, Y.; Brown,
H. C. J. Org. Chem. 1992, 57, 6614. (b) Keck, G. E.; Geraci, L. S. Tetrahedron
Lett. 1993, 34, 7827. (c) Yanagisawa, A.; Nakashima, H.; Ishiba, A.;
Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 4723. (d) Loh, T.-P.; Zhou,
J. R. Tetrahedron Lett. 2000, 41, 5261. (e) Denmark, S. E.; Wynn, T. J. Am.
Chem. Soc. 2001, 123, 6199. (f) Denmark, S. E.; Fu, J. J. Am. Chem. Soc.
2001, 123, 6199. (g) Kii, S.; Maruoka, K. Tetrahedron Lett. 2001, 42, 1935. (h)
Yanagisawa, A.; Nakashima, H.; Nakatsuka, Y.; Ishiba, A.; Yamamoto, H.
Bull. Chem. Soc. Jpn. 2001, 74, 1129. (i) Hanawa, H.; Uraguchi, D.; Konishi,
S.; Hashimoto, T.; Maruoka, K. Chem.;Eur. J. 2003, 9, 4405. (j) Hanawa,
H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708. (k) Xia,
G.; Shibatomi, K.; Yamamoto, H. Synlett 2004, 2437. (l) Kwiatkowski, P.;
Jurczak, J. Synlett 2005, 227. (m) Kwiatkowski, P.; Chazadaj, W.; Jurczak, J.
Synlett 2005, 2301. (n) Kwiatkowski, P.; Chazadaj, W.; Jurczak, J. Tetra-
hedron 2006, 62, 5116. (o) Denmark, S. E.; Fu, J.; Lawler, M. J. J. Org. Chem.
2006, 71, 1523.
(8) For selected review articles on the chemistry of furans, see: (a)
Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Maier, M. E. Nachr. Chem.
1993, 41, 696. (c) Raczko, J.; Jurczak, J. Stud. Nat. Prod. Chem. 1995, 16, 639.
(d) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53, 14179. (e)
Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem. Soc. Rev. 2000, 29,
109. (f) D’Auria, M.; Emanuele, L.; Racioppi, R.; Romaniello, G. Curr. Org.
Chem. 2003, 7, 1443. (g) Wright, D. L. Prog. Heterocycl. Chem. 2005, 17, 1.
(h) Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Acc. Chem. Res. 2008,
41, 1001.
entry furan methanol product isolated yield (%), dr
ee (%)
1
2
3
R = H, 1a
R = Me, 1b
R = Ar, 1c
4a
4b
4c
77, 10:1
76, 7:1
95, 10:1
92 (R,R)
91 (R,R)
95 (R,R)
aAs described for Table 1.
(R)-C3-TUNEPHOS, and 4-cyano-3-nitrobenzoic acid pro-
vided enhanced yields and selectivities. A further increase in
isolated yield resulted from the use of tribasic potassium
phosphate as base in the presence of water. Under these
conditions, the 5-substituted 2-furan methanols 1a-c were
converted to the products of crotylation 4a-c in good to
excellent isolated yield with high levels of anti-diastereo-
selectivity and uniformly high levels of enantioselectivity, as
determined by HPLC analysis (Table 3). Under the same
conditions, but in the presence of 2-propanol, the corre-
sponding 5-substituted 2-furfurals 2a-c are converted to an
identical set of carbonyl crotylation products 4a-c with
(9) (a) Achmatowicz, O. Jr; Bukowski, P.; Szechner, B.; Zwierzchowska,
Z.; Zamojski, A. Tetrahedron 1971, 27, 1973. (b) For a review, see: Harris,
J. M.; Li, M.; Scott, J. G.; O’Doherty, G. A. Strategies Tactics Org. Synth.
2004, 5, 221.
1796 J. Org. Chem. Vol. 75, No. 5, 2010

Bechem et al.
JOCNote
TABLE 4. Enantioselective Carbonyl Crotylation of Furfurals via
Iridium-Catalyzed Transfer Hydrogenationa
TABLE 6. Enantioselective Carbonyl tert-Prenylation of Furfurals via
Iridium Catalyzed Transfer Hydrogenationa
entry
furan methanol
product
isolated yield (%)
ee (%)
entry furan methanol product isolated yield (%), dr
ee (%)
1
2
3
R = H, 1a
R = Me, 1b
R = Ar, 1c
5a
5b
5c
82
89
94
88 (R)
89 (R)
93 (R)
1
2
3
R = H, 1a
R = Me, 1b
R = Ar, 1c
4a
4b
4c
72, >20:1
79, >20:1
94, >20:1
97 (R,R)
94 (R,R)
99 (R,R)
aAs described for Table 1.
aAs described for Table 1.
SCHEME 1. Achmatowicz Rearrangement of Optically
TABLE 5. Enantioselective Carbonyl tert-Prenylation Furan
Enriched Adducts 3b, 4b, and 5ba
Methanols via Iridium Catalyzed Transfer Hydrogenationa
entry
furan methanol
product
isolated yield (%)
ee (%)
1
2
3
R = H, 1a
R = Me, 1b
R = Ar, 1c
5a
5b
5c
82
84
91
87 (R)
84 (R)
85 (R)
aAs described for Table 1.
notably enhanced levels of anti-diastereo- and enantioselec-
tivity (Table 4).
Finally, the enantioselective tert-prenylation of 5-substi-
tuted-2-furan methanols 1a-c was explored using the iso-
lated the ortho-cyclometalated catalyst generated from
[Ir(cod)Cl]2, (R)-SEGPHOS, and 4-cyano-3-nitrobenzoic
acid.2d,f Under remarkably mild conditions, good to excel-
lent isolated yields of 5a-c were attended by good levels of
asymmetric induction (Table 5). Slightly improved isolated
yields and enantioselectivities were observed when the tert-
prenylated adducts 5a-c were generated from the corre-
sponding aldehydes 2a-c (Table 6). Thus, allylation, anti-
crotylation, and tert-prenylation are achieved from either the
alcohol or aldehyde oxidation level with roughly equal
facility using 5-substituted 2-furan methanols 1a-c or
5-substituted-2-furfurals 2a-c, respectively.
The Achmatowicz rearrangement of substituted furan
methanols is frequently employed in the total synthesis of
natural products.9b Accordingly, the optically enriched
products of allylation, crotylation, and tert-prenylation
3b, 4b, and 5b, respectively, were subjected to conditions
for Achmatowicz rearrangement employing N-bromosucci-
nimide as the oxidant. The corresponding γ-hydroxy-
β-pyrones 6a-c were formed as diastereomeric mix-
tures at the lactol center. However, negligible erosion of
aYields are of material isolated by silica gel chromatography. Enantio-
meric excess was determined by chiral stationary-phase HPLC analysis.
enantiomeric excess was observed at preexisting stereocen-
ters, as determined by chiral stationary-phase HPLC ana-
lysis (Scheme 1).
In summary, we report that 5-substituted-2-furan methanols
1a-c are subject to enantioselective carbonyl allylation,
crotylation, and tert-prenylation upon exposure to allyl
acetate, R-methyl allyl acetate, or 1,1,-dimethylallene in the
presence of an ortho-cyclometalated iridium catalyst modi-
fied by (R)-Cl,MeO-BIPHEP, (R)-C3-TUNEPHOS, and
(R)-SEGPHOS, respectively. In the presence of 2-propanol,
but under otherwise identical conditions, the corresponding
substituted furfurals 2a-c are converted to identical pro-
ducts of allylation, crotylation, and tert-prenylation. Opti-
cally enriched products of carbonyl allylation, crotylation
and reverse prenylation 3b, 4b, and 5b engage in Achmatowicz
rearrangement to furnish the corresponding γ-hydroxy-β-pyrones
in good yield and with negligible erosion of enantiomeric excess
at the preexisting stereocenters.
J. Org. Chem. Vol. 75, No. 5, 2010 1797

Bechem et al.
JOCNote
Experimental Section
noted, to furnish the corresponding products of crotyl-
ation 4a-c.
General Procedure for the Preparation of Adducts 3a-c from
Furan Methanols 1a-c. To a flame-dried resealable reaction
tube purged with argon and containing a magnetic stirrer were
added [Ir(cod)Cl]2 (6.7 mg, 0.010 mmol, 2.5 mol %), (R)-Cl,
MeO-BIPHEP (13.0 mg, 0.020 mmol, 5 mol %), 3-nitro-
4-chlorobenzoic acid (8.1 mg, 0.040 mmol 10 mol %), Cs2CO3
(26.1 mg, 0.080 mmol, 20 mol %), and the furan methanol
(0.40 mmol, 100 mol %). THF (2.0 mL, 0.2 M concentration
with respect to the furan methanol) and allyl acetate (86 μL,
0.80 mmol, 200 mol %) were added, and the reaction mixture
was allowed to stir at 100 °C for 24 h. The reaction mixture was
concentrated in vacuo and purified by flash column chromato-
graphy (SiO2) to furnish the corresponding products of allyla-
tion 3a-c.
General Procedure for the Preparation of Adducts 3a-c from
Furfurals 2a-c. To a flame-dried resealable reaction tube
purged with argon and containing a magnetic stirrer were added
[Ir(cod)Cl]2 (6.7 mg, 0.010 mmol, 2.5 mol %), (R)-Cl,MeO-
BIPHEP (13.0 mg, 0.020 mmol, 5 mol %), 3-nitro-4-chloroben-
zoic acid (8.1 mg, 0.040 mmol 10 mol %), Cs2CO3 (26.1 mg,
0.080 mmol, 20 mol %), and the furfural (0.40 mmol, 100 mol
%). THF (2.0 mL, 0.2 M concentration with respect to the
furfural), i-PrOH (61 μL, 0.80 mmol, 200 mol %), and allyl
acetate (86 μL, 0.80 mmol, 200 mol %) were added, and the
reaction mixture was allowed to stir at 100 °C for 24 h. The
reaction mixture was concentrated in vacuo and purified by
flash column chromatography (SiO2) to furnish the correspond-
ing products of allylation 3a-c.
General Procedure for the Preparation of Adducts 4a-c from
Furan Methanols 1a-c. To a flame-dried resealable reaction
tube purged with argon and containing a magnetic stirrer were
added (R)-Ir-complex I (20.4 mg, 0.020 mmol, 5 mol %), K3PO4
(84.9 mg, 0.40 mmol, 100 mol %), and the corresponding furan
methanol (0.40 mmol, 100 mol %). THF (0.2 mL, 2 M con-
centration with respect to the alcohol), H2O (36 μL, 2.0 mmol,
500 mol %), and R-methyl allyl acetate (86 μL, 0.80 mmol, 200
mol %) were added, and the reaction mixture was allowed to stir
at 70 °C for 48 h. The reaction mixture was concentrated in
vacuo and purified by flash column chromatography (SiO2) to
furnish the corresponding products of crotylation 4a-c.
General Procedure for the Preparation of Adducts 4a-c from
Furfurals 2a-c. To a flame-dried resealable reaction tube
purged with argon and containing a magnetic stirrer were added
(R)-Ir-complex I (20.4 mg, 0.020 mmol, 5 mol %), K3PO4 (84.9
mg, 0.400 mmol, 100 mol %), and the corresponding furfural
(0.40 mmol, 100 mol %). THF (0.2 mL, 2 M concentration with
respect to the aldehyde), H2O (36 μL, 2.0 mmol, 500 mol %),
i-PrOH (61 μL, 0.80 mmol, 200 mol %), and R-methyl allyl
acetate (86 μL, 0.80 mmol, 200 mol %) were added, and the
reaction mixture was allowed to stir at 70 °C for 48 h. The
reaction mixture was concentrated in vacuo and purified by
flash column chromatography (SiO2), under the conditions
General Procedure for the Preparation of Adducts 5a-c from
Furan Methanols 1a-c. To a flame-dried resealable reaction
tube purged with nitrogen and containing a magnetic stirrer
were added (R)-Ir-complex II (5 mol %) and the corresponding
furan methanol (100 mol %). Toluene (1 M concentration with
respect to the alcohol), 1,1-dimethylallene (200 mol %), and
propionaldehyde (5 mol %) were added, and the reaction
mixture was allowed to stir at 40 °C for 72 h. The reaction
mixture was concentrated in vacuo and purified by flash column
chromatography (SiO2) to furnish the corresponding products
of tert-prenylation 5a-c.
General Procedure for the Preparation of Adducts 5a-c from
Furfurals 2a-c. To a flame-dried resealable reaction tube
purged with nitrogen and containing a magnetic stirrer were
added (R)-Ir-complex II (5 mol %) and the corresponding
furfural (100 mol %). Toluene (1 M concentration with respect
to the aldehyde), 1,1-dimethylallene (200 mol %), and i-PrOH
(200 mol %) were added, and the reaction mixture was allowed
to stir at 40 °C for 72 h. The reaction mixture was concentrated
in vacuo and purified by flash column chromatography (SiO2)
to furnish the corresponding products of tert-prenylation 5a-c.
General Procedure for the Achmatowicz Rearrangement of
Adducts 3b, 4b, and 5b. Alcohol 3b, 4b, or 5b (100 mol %) was
dissolved in aqueous THF (THF/H2O, 4:1, 0.1 M), and the
solution was cooled to 0 °C. N-Bromosuccinimide (100 mol %)
was added portionwise while a temperature of 0 °C was main-
tained. After the reaction had gone to completion as determined
by TLC analysis, the reaction mixture was diluted with dichloro-
methane and washed with KI (10% aqueous solution), Na2S2O4
(15% aqueous solution), NaHCO3 (10% aqueous solution), and
brine. The organic layer was dried (MgSO4), filtered, and
concentrated in vacuo. The crude residue was purified by flash
column chromatography (SiO2) to furnish the corresponding
pyrones 6a, 6b, or 6c, respectively.
Acknowledgment. Acknowledgment is made to the Robert
A. Welch Foundation, the ACS-GCI Pharmaceutical
Roundtable, and the NIH-NIGMS (RO1-GM069445) for
partial support of this research. Dr. Oliver Briel of Umicore
is thanked for the generous donation of [Ir(cod)Cl]2. The
€
Landesgraduiertenforderung and the Deutscher Akademischer
Austausch Dienst are acknowledged for generous support of
Benjamin Bechem.
Supporting Information Available: Spectral data for all new
compounds, including scanned images of 1H and 13C NMR
spectra. Scanned images of chiral stationary-phase HPLC data.
Single-crystal X-ray diffraction data for the Ir(BIPHEP)-
(η-C3H5)(C,O-O2C6H3NO2). This material is available free of
charge via the Internet at http://pubs.acs.org.
1798 J. Org. Chem. Vol. 75, No. 5, 2010