One-pot catalytic asymmetric synthesis of pyranones

Article abstract of DOI:10.1021/ol900905r

Enantioenriched pyranones are important intermediates in the synthesis of natural products and the generation of compound libraries. A one-pot method for their synthesis is outlined. Catalytic asymmetric alkylation of 2-furfurals in the presence of catalytic (-)-MIB generates enantioenriched furyl zinc alkoxides. Addition of water/THF followed by NBS results in formation of pyranones with ee's > 90% and yields between 46-77%.

Full text of DOI:10.1021/ol900905r

ORGANIC
LETTERS
2
009
Vol. 11, No. 12
703-2706
One-Pot Catalytic Asymmetric Synthesis
of Pyranones
2
Kevin Cheng, Ann Rowley Kelly, Rachel A. Kohn, Jessica F. Dweck, and
Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, UniVersity of PennsylVania, Department of
Chemistry, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323
pwalsh@sas.upenn.edu
Received April 25, 2009
ABSTRACT
Enantioenriched pyranones are important intermediates in the synthesis of natural products and the generation of compound libraries. A
one-pot method for their synthesis is outlined. Catalytic asymmetric alkylation of 2-furfurals in the presence of catalytic (-)-MIB generates
enantioenriched furyl zinc alkoxides. Addition of water/THF followed by NBS results in formation of pyranones with ee’s >90% and yields
between 46-77%.
7
Advances in organic synthesis enable chemists to prepare
most natural product targets. Even with state of the art
methods, however, syntheses often require many synthetic
manipulations and purifications, resulting in low overall
yields and generation of large amounts of chemical waste.
To address these issues, increasing synthetic efficiency and
reducing E-factors (defined as the ratio of the mass of waste
produced to the mass of product) are becoming more
matowicz reaction. Key intermediates in the Achmatowicz
reaction are illustrated in Scheme 1. An example of the
7
Scheme 1. Key Intermediates in the Achmatowicz Reaction
1
important in designing synthetic routes. One approach to
streamline organic synthesis is through tandem and sequential
reactions that accomplish multiple steps in a single flask and
minimize isolations, purifications, and solvent use.
Herein, we present a one-pot method to prepare enan-
tioenriched pyranones from 2-furfurals. Pyranones are valu-
able building blocks that have been extensively used in
2
-5
6
natural product
-Hydroxy-(2H)-pyran-3-ones are typically prepared by
the oxidative rearrangement of furyl alcohols in the Ach-
and diversity oriented syntheses.
6
Achmatowicz reaction in the synthesis of (-)-8a-epi-
2
swainsonine by O’Doherty is shown in Scheme 2.
The most popular approach to enantioenriched pyranones
has relied on kinetic resolution (KR) of racemic furyl
(
(
1) Sheldon, R. A. Green Chem. 2007, 9, 1273–1283.
2) Abrams, J. N.; Babu, R. S.; Guo, H.; Le, D.; Le, J.; Osbourn, J. M.;
O’Doherty, G. A. J. Org. Chem. 2008, 73, 1935–1940
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Zhou, M. Q.; O’Doherty, G. A. J. Org. Chem. 2007, 72, 2485–2493. (c)
Guo, H. B.; O’Doherty, G. A. J. Org. Chem. 2008, 73, 5211–5220
.
8
alcohols, as illustrated in F u¨ rstner’s elegant synthesis of
(
9
ipomoeassian E (Scheme 3). Upon treatment of the racemic
.
furyl alcohol under KR conditions with the Sharpless-Katsuki
catalyst and TBHP, the matched enantiomer underwent the
Achmatowicz reaction to generate the optically active
(
4) (a) Leverett, C. A.; Cassidy, M. P.; Padwa, A. J. Org. Chem. 2006,
1, 8591–8601. (b) Harris, J. M.; Padwa, A. J. Org. Chem. 2003, 68, 4371–
381
7
4
.
10.1021/ol900905r CCC: $40.75
Published on Web 05/20/2009
 2009 American Chemical Society

KR selectivity factor () kfast/kslow) is very large, it is always
the enantioenriched starting material that is carried forward.
Our approach to enantioenriched pyranones is based on
our enantioselective carbonyl addition/epoxidation (Scheme
Scheme 2. O’Doherty Synthesis of (-)-8a-epi-Swainsonine
10
Featuring a Ketone Reduction with Noyori’s Catalyst and the
Achmatowicz Reaction
12
4). These one-pot transformations generate epoxy alcohols
1
2
Scheme 4. Our One-Pot Transformations
pyranone. The unreacted enantiomerically enriched furyl
alcohol was then isolated in 47% yield (>99% ee) and
9
subjected to a second Achmatowicz reaction.
9
Scheme 3. F u¨ rstner’s KR in the Synthesis of Ipomoeassin E
with three contiguous stereogenic centers with high enantio-
and diastereoselectivity. In applying this approach to the
synthesis of enantioenriched pyranones, we focused on
2
-furfurals as substrates.
Employing Nugent’s enantioenriched amino alcohol (-)-
1
3,14
MIB (Scheme 5, 4 mol %),
we first examined the
Scheme 5. Asymmetric Addition with MIB
In a KR, the product ee decreases with rising conversion
1
1
while the starting material ee increases. Thus, unless the
(
5) (a) Um, J. M.; Houk, K. N.; Phillips, A. J. Org. Lett. 2008, 10, 3679–
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Henderson, J. A.; Jackson, K. L.; Phillips, A. J. Org. Lett. 2007, 9, 5299.
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77. (e) Peng, X.; Li, A.; Lu, J.; Wang, Q.; Pan, X.; Chan, A. S. C.
asymmetric addition of diethylzinc to 2-furfural in hexanes
at 0 °C. We were pleased to observe that the addition
furnished the furyl alcohol in 97% enantioselectivity and 98%
yield. With suitable conditions for the asymmetric addition,
attention was then focused on the second half of the tandem
process, the Achmatowicz reaction.
3
(
1
Tetrahedron 2002, 58, 6799–6804. (f) Yang, Z. C.; Jiang, X. B.; Wang,
Z. M.; Zhou, W. S. J. Chem. Soc., Perkin Trans. 1 1997, 317–321. (g)
Wender, P. A.; Bi, F. C.; Buschmann, N.; Gosselin, F.; Kan, C.; Kee, J. M.;
Ohmura, H. Org. Lett. 2006, 8, 5373–5376. (h) Jackson, K. L.; Henderson,
J. A.; Morris, J. C.; Motoyoshi, H.; Phillips, A. J. Tetrahedron Lett. 2008,
We initially employed reagents and conditions for the
Achmatowicz reaction that were similar to those used in our
4
9, 2939–2941. (i) Couladouros, E. A.; Strongilos, A. T. Angew. Chem.,
Int. Ed. 2002, 41, 3677–3680. (j) Zhou, X.; Wu, W.; Liu, X.; Lee, C. S.
Org. Lett. 2008, 10, 5525–5528. (k) Babu, R. S.; O’Doherty, G. A. J. Am.
Chem. Soc. 2003, 125, 12406–12407. (l) Harris, J. M.; O’Doherty, G. A.
Org. Lett. 2000, 2, 2983–2986. (m) DeShong, P.; Waltermire, R. E.;
Ammon, H. L. J. Am. Chem. Soc. 1988, 110, 1901–1910. (n) Martin, S. F.;
Zinke, P. W. J. Am. Chem. Soc. 1989, 6, 2311–2313. (o) Yu, X.; O’Doherty,
G. A. Org. Lett. 2008, 10, 4529–4532.
(6) Burke, M. D.; Berger, E. M.; Schreiber, S. L. J. Am. Chem. Soc.
2004, 126, 14095–14104.
(7) (a) Achmatowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165–
176. (b) Georgiadis, M. P.; Couladouros, E. A. J. Org. Chem. 1986, 51,
2725–2727.
2704
Org. Lett., Vol. 11, No. 12, 2009

asymmetric addition/diastereoselective epoxidation chemistry
Scheme 4, B and C). Thus, after completion of the
asymmetric addition, TBHP (up to 5 equiv) and Ti(Oi-Pr)
20 mol %) were added at 0 °C and the oxidation was stirred
quench alkyl organozinc species, followed by slow addition
of OV(acac) . With the vanadium catalyst, our best results
were obtained with 15 mol % catalyst loading and 3 equiv
TBHP under slow addition conditions (70% yield, entry 6).
(
2
4
(
for 12-15 h (Table 1, entry 1). Under these, and related
2
In general, OV(acac) /TBHP systems require significantly
lower catalyst loadings, but these conditions were unsuc-
cessful in this oxidation.
Employing more traditional Achmatowicz oxidation con-
Table 1. Optimization of Oxidation Conditions
ditions, we found that addition of THF/H
zinc alkoxide product followed by N-bromosuccinimide
NBS) in three equal portions at rt resulted in complete
2
O (4:1) to the furyl
(
consumption of the furyl alcohol in about 4 h. The pyranone
was isolated in 73% yield after purification as a 2.6:1 ratio
of diastereomers about the anomeric carbon (Table 1, entry
7
). Due to the low cost and ease of the NBS oxidation, these
a
entry
1
additive
TBHP
oxidant
yield (%)
50
conditions were used to determine the substrate scope of the
one-pot pyranone synthesis in Table 2.
Ti(Oi-Pr)
4
(
5 equiv)
TBHP
2 equiv)
TBHP
3 equiv)
TBHP
3 equiv)
TBHP
3 equiv)
TBHP
3 equiv)
THF/H
(20 mol %)
OV(acac)
(10 mol %)
OV(acac)
(40 mol %)
OV(acac)
(30 mol %)
OV(acac)
(30 mol %)
OV(acac)
2
3
2
0
50
50
70
70
73
(
2
Table 2. Substrate Scope for One-Pot Synthesis of Pyranones
(
b
4
2
(
5
6
2
(
2
(
(15 mol %)
NBS
,
b c
7
2
O
a
Oxidants were slowly added as a solution by syringe pump unless
b
otherwise noted. See Supporting Information for additional details. Oxidant
was added neat. NBS was added in three portions over 30 min at rt.
c
conditions, the oxidation stalled at or below 50% conversion
in all cases. Longer reaction times and addition of a second
dose of Ti(Oi-Pr) were unsuccessful at increasing conver-
4
sions. Despite extensive experimentation, we were unable
to satisfactorily optimize this process.
We next examined the OV(acac)
Achmatowicz oxidation (Table 1, entries 2-6). Direct
addition of OV(acac) and TBHP to the asymmetric addition
2
/TBHP system for the
2
reaction mixture after the aldehyde was consumed resulted
in reduction of the vanadium by the residual alkylzinc species
(entry 2). We therefore added the TBHP (2-3 equiv) to first
(
8) (a) Kametani, T.; Tsubuki, M.; Tatsuzaki, Y.; Honda, T. J. Chem.
Soc., Perkin Trans. 1 1990, 639–646. (b) Kusakabe, M.; Kitano, Y.;
Kobayashi, Y.; Sato, F. J. Org. Chem. 1989, 54, 2085–2091. (c) Honda,
T.; Sano, N.; Kanai, K. Heterocycles 1995, 41, 425–429. (d) Yang, Z. C.;
Jiang, X. B.; Wang, Z. M.; Zhou, W. S. J. Chem. Soc., Chem. Commun.
a
1
995, 2389–2390.
Enantiomeric excess was determined after the dialkylzinc addition to
(
(
9) F u¨ rstner, A.; Nagano, T. J. Am. Chem. Soc. 2007, 129, 1906–1907.
the furfurals.
10) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 2521–2522. (b) Coral, J. A. ; Guo, H.; Shan,
M.; O’Doherty, G. A. Heterocycles 2009, 79, 521–529.
(
11) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric
A series of 2-furfurals were examined in combination with
dialkylzinc reagents in the one-pot pyranone synthesis (Table
Catalysis; University Science Books: Sausalito, CA, 2008; Chapter 7, p
2
31.
(
12) (a) Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc.
2). It is noteworthy that enantioselectivities were >90% with
2
005, 127, 14668–14674. (b) Jeon, S. J.; Li, H. M.; Walsh, P. J. J. Am.
all substrates examined. Isolated yields for the one-pot
procedure ranged from 46 to 77%. Of note, the pyranone in
entry 2 is an intermediate in O’Doherty’s syntheses of
Chem. Soc. 2005, 127, 16416–16425. (c) Wooten, A.; Kim, J. G.; Walsh,
P. J. Org. Lett. 2007, 9, 381–384. (d) Kim, J. G.; Waltz, K. M.; Garcia,
I. F.; Kwiatkowski, D.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 12580–
1
8
2585. (e) Hussain, M. M.; Walsh, P. J. Acc. Chem. Res. 2008, 41, 883–
93.
3
daumone, digitoxin, and anthrax.
Org. Lett., Vol. 11, No. 12, 2009
2705

2
-Furfural derivatives substituted at the 5 or disubstituted
Subsequent oxidation with NBS promotes the Achmatowicz
reaction to furnish the pyranone products. This method
enables the one-pot synthesis of a variety of pyranones
simply by varying the structure of the 2-furfural derivative
and organozinc reagents employed. Our protocol represents
an improvement over the kinetic resolution approach to
pyranones by circumventing the need for additional purifica-
tions and leading to an increase in overall yield. Enantioen-
riched pyranones such as these have been used in several
natural product syntheses. Given the utility of enantioen-
riched pyranones in synthesis, we believe that this one-pot
method will be useful in the assembly of natural products.
at the 4 and 5 positions participated in the reaction to yield
pyranone products (entries 3-8). Functionalized organozinc
reagents generated by Knochel’s procedure were also
employed to provide pyranone products (entry 3) in com-
parable yields to reactions utilizing commercially available
dialkylzinc reagents. As shown in entry 4, the TBS protected
alcohol was tolerated. A decrease in the yield was noted for
,5-disubstituted 2-furfural (entries 8-9). It is possible that
the cyclization onto the R-substituted enone intermediate
Scheme 1, R * H) is more difficult than when R ) H for
steric reasons.
1
5
4
2
2
(
In summary, we have developed a one-pot protocol to
prepare enantioenriched pyranones with enantioselectivities
Acknowledgment. We are grateful to the National Science
Foundation (CHE-0615210) and National Institutes of Health,
National Institute of General Medical Sciences (GM58101)
for financial support of this work.
>
90%. The procedure involves initial asymmetric alkylation
of 2-furfurals to generate zinc furyl alkoxide intermediates.
(
13) (a) Nugent, W. A. Chem. Commun. 1999, 1369–1370. (b) Chen,
Y. K.; Jeon, S. J.; Walsh, P. J. Org. Synth. 2005, 82, 87–92. (c) Kim, J. G.;
Walsh, P. J. Angew. Chem., Int. Ed. 2006, 45, 4175–4178.
Supporting Information Available: Procedures and full
characterization are available. This material is available free
of charge via the Internet at http://pubs.acs.org.
(
14) Rowley Kelly, A.; Kerrigan, M. H.; Walsh, P. J. J. Am. Chem.
Soc. 2008, 130, 4097–4104.
15) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P. Y.;
Knochel, P. J. Org. Chem. 1996, 61, 8229–8243.
(
OL900905R
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Org. Lett., Vol. 11, No. 12, 2009