Formation of γ-lactones through CAN-mediated oxidative cleavage of hemiketals

Article abstract of DOI:10.1021/jo801258h

(Chemical Equation Presented) The generation of substituted γ-lactones can be accomplished through application of a tandem chain extension-aldol reaction, followed by CAN-mediated oxidative cleavage of the aldol product. The oxidative cleavage requires the intermediacy of a hemiketal and the presence of an α-heteroatom. Formation of the γ-lactone through the oxidative cleavage is used to assign stereochemistry of the aldol reaction and as the final step in a short synthesis of members of the phaseolinic acid family of natural products.

Full text of DOI:10.1021/jo801258h

SCHEME 1. γ-Lactone Formation through CAN Oxidation
Formation of γ-Lactones through CAN-Mediated
Oxidative Cleavage of Hemiketals
Alexander M. Jacobine, Weimin Lin, Bethany Walls, and
Charles K. Zercher*
Department of Chemistry, UniVersity of New Hampshire,
Durham, New Hampshire 30824
ckz@cisunix.unh.edu
ReceiVed June 11, 2008
cleavage and its utility for the establishment of stereochemistry
in a select group of tandem chain extension-aldol reactions. We
also report on the utility of the CAN-mediated oxidation for
the rapid and stereocontrolled access to substituted γ-lactones
and, in particular, a member of the phaseolinic acid family of
natural products.5
The generation of substituted γ-lactones can be accomplished
through application of a tandem chain extension-aldol
reaction, followed by CAN-mediated oxidative cleavage of
the aldol product. The oxidative cleavage requires the
intermediacy of a hemiketal and the presence of an R-het-
eroatom. Formation of the γ-lactone through the oxidative
cleavage is used to assign stereochemistry of the aldol
reaction and as the final step in a short synthesis of members
of the phaseolinic acid family of natural products.
The general strategy for γ-lactone formation is illustrated in
Scheme 1. Treatment of methyl 4-methoxyacetoacetate 1 with
the Furukawa reagent,6 derived from diethylzinc and di-
iodomethane, results in the formation of a chain-extended
organometallic 2, which can act as a latent enolate and trap a
variety of electrophiles. When the latent enolate was used to
capture acetone, the tandem chain extension-aldol product 3 was
present as a mixture of open and closed (hemiketal) forms.
Treatment of the aldol product 3 with aqueous ceric ammonium
nitrate (CAN) provided the corresponding γ-lactone 4.7 Simi-
larly, a mixture of aldol products (5 and 6) was produced
through capture of benzaldehyde with the same enolate. The
ratio and identity of diastereomers produced in this tandem chain
extension-aldol reaction was difficult to estimate from NMR
analysis of the crude reaction material due to the appearance of
hemiketal isomers and/or the open chain form for each diaste-
reomer. Separation of the major isomer of the aldol reaction
and comparison to the NMR spectra of the crude reaction
material revealed a diastereomeric ratio of 3:1. While the
stereochemical assignment of the major diastereomer (5) as
either the syn or the anti aldol product was not possible at this
stage, it was apparent that the presence of the methoxy group
diminished the syn-selectivity in the aldol reaction, since the
3:1 diastereomeric ratio was significantly poorer than the average
Our interest in a zinc carbenoid-mediated chain extension
reaction1 has led to the development of a number of tandem
reaction variants. One of these variations is a tandem chain
extension-aldol reaction2 that produces an R-substituted-γ-keto
ester (amide) from ꢀ-keto ester (amide) in one reaction flask.
In many cases this tandem chain extension-aldol reaction
exhibits good diastereoselection, with an average syn:anti
selectivity of 10:1 when simple ꢀ-keto esters are used as starting
materials. Studies by our group have established that the aldol
reaction is kinetically controlled, which suggests that the
diastereoselectivity of the zinc-enolate reaction might be
understood on the basis of enolate geometry applied to a closed
transition state.3 The assessment of the diastereoselectivity of
these aldol reactions is complicated by the appearance of closed
hemiketal forms, which are prevalent in both the syn and anti
aldol stereoisomers. The determination of absolute stereochem-
istry of the aldol products has also been a challenge and, in
general, has relied upon the availability of crystalline products.
During our efforts to apply the zinc-mediated chain extension-
aldol reaction to the generation of peptide isosteres, we observed
a ceric ammonium nitrate (CAN)-initiated oxidative cleavage
that resulted in the preparation of substituted γ-lactones.4 We
report herein an investigation of this CAN-mediated oxidative
(4) Other methods for the formation of γ-lactones: (a) Blanc, D.; Madec, J.;
Popowyck, F.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V.; Genet, J.-
P. AdV. Synth. Catal. 2007, 349, 943–950. (b) Berti, F.; Felluga, F.; Forzato, C.;
Furlan, G.; Nitti, P.; Pitacco, G.; Valentin, E.; Barros, M. T. Tetrahedron:
Asymmetry 2006, 17, 2344–2353. (c) Maycock, C. D.; Ventura, M. R. Org. Lett.
2003, 5, 4097–4099.
(5) Mahato, S. B.; Siddiqui, K. A. I.; Bhattacharya, G.; Ghosal, T.; Miyahara,
K.; Sholichin, M.; Kawasaki, T. J. Nat. Prod. 1987, 50, 245.
(6) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53.
(7) (a) Shono, T.; Hamaguchi, H.; Nishiguchi, I.; Sasaki, M.; Miyamoto, T.;
Miyamoto, M.; Fujita, S. Chem. Lett. 1981, 1217–1220. (b) Majeti, S. J. Org.
Chem. 1972, 37, 2914–2916.
(1) Brogan, J. B.; Zercher, C. K. J. Org. Chem. 1997, 62, 6444.
(2) Lai, S.-J.; Zercher, C. K.; Jasinski, J. P.; Reid, S. N.; Staples, R. J. Org.
Lett. 2001, 3, 4169.
(3) Dewar, M. J. S.; Metz, K. M., Jr J. Am. Chem. Soc. 1987, 109, 6553.
10.1021/jo801258h CCC: $40.75
Published on Web 08/12/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7409–7412 7409

SCHEME 2. CAN Oxidation of Alanine Derivative
(10:1 syn:anti) diastereoselectivity observed in the reactions of
unsubstituted acetoacetate starting materials.2 The reason for
this poorer diastereoselection is not clear, although zinc-
complexation with the methoxy group and disruption of selective
(Z)-enolate formation may play a role. The major aldol
stereoisomer 5 was reacted with CAN to provide the known
γ-lactone 7,8 which indicated that the major stereoisomer of
the aldol reaction was, in fact, the syn aldol product. When the
crude aldol reaction mixture (3:1, syn:anti) was treated with
CAN, a similar mixture of diastereomeric lactones8 was
produced, which indicates that little epimerization was taking
place in the oxidative cyclization.
A proposed mechanism for the oxidation involves single
electron-mediated cleavage of a cerium complexed hemiketal
9. Oxidative cleavage of monomethylated 1,2-diols by CAN
has been reported previously.9 The appearance of hemiketal
forms in the aldol products (i.e. 3) presents a similar 1,2-
dioxygenated functionality for the cleavage. The necessity of
the R-heteroatom for the oxidative cleavage was confirmed by
the preparation of aldol products 10 and 11, which were
unreactive and returned starting material upon exposure to CAN.
Furthermore, no oxidative cleavage was observed with substrates
lacking the R-hydroxymethyl (aldol-derived) substituents.
SCHEME 3. Unsuccessful Lactone Formation of TBDPS
Ether
Substrates for the chain extension-aldol reaction that contained
nitrogen atoms R to the ketone were also studied. Our interest
in developing a stereocontrolled approach to ketomethylene-
containing peptide isosteres provided additional motivation for
the study of these compounds.10 Reductive alkylation of alanine
with anisaldehyde provided compound 12,11 which was further
protected with a Cbz group. The use of two nitrogen-protecting
groups was necessary to prevent quenching of the intermediate
enolate in the tandem chain extension-aldol reaction. Formation
of the ꢀ-keto imide 15 was accomplished through a mixed
Claisen reaction utilizing an acyl imidazole (Scheme 2). The
chain extension-aldol reaction took place with high diastereo-
selectivity; however, the stereochemistry of the product 16 could
not be assigned. Oxidative cleavage of the aldol product with
CAN proceeded cleanly to provide the γ-lactone 17, which
demonstrated that an R-nitrogen can facilitate the oxidative
cleavage. Removal of the oxazolidinone with lithium hydrogen
peroxide provided the known (S)-γ-lactone 18,12 which allowed
the assignment of the stereoselectivity of the aldol reaction.
Compound 19 was also generated from the alanine derivative
13 by application of the Masamune acylation procedure13
(Scheme 3). A tandem chain extension-aldol reaction of allyl
ester 19 provided two inseparable aldol products 20 in a 1:1
ratio, which were subsequently protected with a TBDPS group.
Exposure of the silyl ether 21 to CAN resulted in the removal
of the Pmb group, but did not result in oxidative cleavage and
formation of a γ-lactone. This result lends strong support to
the assertion that hemiketal formation is essential for the
oxidative cleavage. Even though a small concentration of the
ketone hydrate might be expected under the aqueous reaction
conditions, no oxidative cleavage of 21 was observed over the
course of 8 h.
We recently reported a variation on the chain extension
reaction in which substituted diiodomethanes are used to
generate the carbenoid.14 Use of this substituted carbenoid
results in the formation of ꢀ-substituted γ-keto esters in one
step from ꢀ-keto ester starting materials. The use of substituted
diiodomethanes as reagents in a tandem chain extension-aldol
reaction had not been explored; however, we anticipated that
oxidative cleavage of the proposed aldol products with CAN
would provide rapid access to the phaseolinic acid family of
natural products.5
(8) Fristad, W. E.; Peterson, J. R. J. Org. Chem. 1985, 50, 10–18.
(9) (a) Littler, J.; Waters, W. A. J. Chem. Soc. 1960, 2767. (b) Young, L. B.;
Trahanovsky, W. S. J. Am. Chem. Soc. 1969, 91, 5060.
(10) Lin, W.; Tryder, N.; Su, F.; Zercher, C. K.; Jasinski, J. P.; Butcher,
R. J. J. Org. Chem. 2006, 71, 8140–8145.
(11) Santiago, B.; Dalton, C. R.; Huber, E. W.; Kane, J. M. J. Org. Chem.
1995, 67, 4947.
(12) Comini, A.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin, E. Tetrahedron:
Asymmetry 2004, 15, 617–625.
(13) Brooks, D. W.; Lu, L. D.-D.; Masamune, S. Angew. Chem., Int. Ed.
Engl. 1979, 18, 72.
As expected, treatment of methyl 4-methoxyacetoacetate (1)
with a carbenoid derived from 1,1-diiodoethane15 provided a
(14) Lin, W.; McGinness, R. J.; Wilson, E.; Zercher, C. K. Synthesis 2007,
2404–2408.
7410 J. Org. Chem. Vol. 73, No. 18, 2008

SCHEME 4. Formation of 3,4,5-Trisubsituted-γ-lactone
substituents, was accomplished through application of these
sequential transformations.
Experimental Section
Representative experimental details are given below.
Methyl 5-Hydroxy-5-(methoxymethyl)-2,2-dimethyltetrahy-
drofuran-3-carboxylate (3). An oven-dried, one-necked, 100-mL
round-bottomed flask was equipped with a magnetic stir bar, and
rubber septum, charged with dichloromethane (20 mL) via syringe,
and flushed with nitrogen. The flask was put in an ice bath and
diethylzinc (1 M solution in hexanes) (3.0 mmol, 3.0 mL) was added
via syringe followed by slow addition of diiodomethane (3.3 mmol,
0.26 mL) via syringe over 5 min. The resulting solution was allowed
to stir for approximately 10 min. Methyl 4-methoxyacetoacetate
(1.0 mmol, 0.13 mL) was added via syringe over 5 min and the
mixture was allowed to stir for an additional 30 min. Acetone (2.0
mmol, 0.15 mL) was added via syringe over 1 min and the reaction
mixture was monitored by TLC (15:2, hexanes:ethyl acetate) until
starting material was consumed. The reaction mixture was quenched
with saturated ammonium chloride (10 mL) and extracted with
dichloromethane (3 × 15 mL). The combined organic layers were
dried over anhydrous sodium sulfate, gravity filtered, and concen-
trated on a rotary evaporator (35 °C, 30 mmHg) to give a yellowish
liquid. The crude reaction product was purified by flash chroma-
tography (15:2, hexanes:ethyl acetate) to yield 0.14 g (63% yield)
of product as a mixture of hemiketal anomers. IR (neat) 3437, 2979,
2829, 2250, 1721, 1445, 1366, 1105, 978, 916, 818, 732, 647, 533
chain-extended organometallic 23 that could be trapped with
hexanal (Scheme 4). A complex mixture of products, due to
the appearance of hemiketal forms, was observed. Chromato-
graphic separation provided the aldol product (24), as a mixture
of open chain and hemiketal forms, in 51% yield. Upon exposure
of the aldol product to aqueous CAN, the cis,cis-stereoisomer
25 was produced in 77% yield. Structural assignment was
confirmed by comparison to previously published spectral data
of the phaseolinic acids.16 The cis relationship between the
methyl substituent and the carboxyester group can be rational-
ized due to facial bias on a zinc-complexed (Z)-enolate (26);
however, the preference for the anti-aldol product, which leads
to a cis relationship in the hemiketal and lactone systems, was
unanticipated. Whether the change in selectivity to favor
formation of the aldol product (24) is due to a decreased bias
for Z-enolate intermediacy, due to a reversal in aldehyde facial
selectivity, or due to the operation of an alternate (open)
transition state is unclear, although the substituent at the
ꢀ-position of the intermediate enolate is clearly playing a role.
The role that the ꢀ-substituent plays in stereocontrolled tandem
chain extension-aldol reactions is under investigation in our
group.
1
cm-1. H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H, minor isomer),
3.71 (s, 3H, major isomer), 3.52-3.38 (m, major (2H) and minor
(2H) isomers), 3.45 (s, 3H, minor isomer), 3.43 (s, 3H, major
isomer), 3.29 (dd, 1H, J ) 11.8, 7.2 Hz, major isomer), 2.93 (dd,
1H, J ) 8.5, 4.2 Hz, minor isomer), 2.54-2.07 (m, major (2H)
and minor (2H) isomers), 2.32 (m, 1H), 2.12 (dd, 1H, J ) 12.9,
7.2 Hz), 1.54 (s, 3H, major isomer), 1.35 (m, 3H, minor isomer),
1.32 (s, 3H, minor isomer), 1.09 (s, 3H, major isomer). 13C NMR
(400 MHz, CDCl3) δ 175.5, 172.4, 105.2, 103.5, 84.3, 83.8, 77.5,
59.8, 53.4, 52.4, 52.1, 37.6, 37.3, 30.7, 29.6, 25.5, 24.6. HRMS
(FAB+) m/z calcd for C10H17O4 [M - OH] 218.1127, found [M
- OH] 201.1134.
Methyl 2,2-Dimethyl-5-oxotetrahydrofuran-3-carboxylate (4).
An oven-dried, one-necked, 25-mL round-bottomed flask equipped
with a magnetic stir bar was charged with acetonitrile (8 mL), water
(2 mL), and the acetone aldol product (0.84 mmol, 0.18 g). Ceric
ammonium nitrate (CAN) (3.37 mmol, 1.85 g) was added and the
solution was allowed to stir at room temperature. The reaction
progress was monitored by TLC (5:1, hexanes:ethyl acetate) until
starting material was consumed (approximately 1 h). Water (5 mL)
was added and the solution was extracted with diethyl ether (3 ×
10 mL). The combined organic layers were dried over anhydrous
sodium sulfate, gravity filtered, and concentrated on a rotary
evaporator (35 °C, 40 mmHg) to give 0.12 g (83% yield) of a
slightly colored liquid. Purification of the crude reaction mixture
was not necessary. IR (neat) 3110, 2939, 2677, 1741, 1671, 1576,
In conclusion, a rapid method for the assembly of substituted
γ-lactones has been developed. The reaction sequence relies
upon a zinc carbenoid-mediated tandem chain extension-aldol
reaction and a CAN-mediated oxidative cleavage. While the
oxidative cleavage is only applicable to aldol products that have
heteroatoms R to the ketone and are capable of forming
γ-lactols, the CAN-mediated reaction was shown to be useful
in the identification of syn- or anti-aldol stereochemistry through
conversion to the corresponding γ-lactones. The assignment of
stereochemistry in a diastereoselective tandem chain extension-
aldol reaction was made possible through the application of the
CAN-mediated cleavage reaction. Lastly, the rapid assembly
of naturally occurring γ-lactones, even those with R-alkyl
1
1427, 1371, 1293, 1124, 997, 937, 844, 773 cm-1. H NMR (400
MHz, CDCl3) δ 3.78 (s, 3H), 3.26 (dd, 1H, J ) 9.3, 8.7 Hz), 3.15
(dd, 1H, J ) 18.0, 9.3 Hz), 2.80 (dd, 1H, J ) 18.0, 8.6 Hz), 1.62
(s, 3H), 1.36 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 176.6, 170.6,
86.3, 52.9, 50.5, 32.3, 28.5, 23.4. HRMS (FAB+) m/z calcd for
C8H13O4 [M + H] 173.0814, found [M + H] 173.0827.
Methyl 5-Hydroxy-5-(methoxymethyl)-4-methyl-2-pentyltet-
rahydrofuran-3-carboxylate (24). An oven-dried, one-necked,
100-mL round-bottomed flask was equipped with a magnetic stir
bar and rubber septum, charged with dichloromethane (20 mL) via
syringe, and flushed with nitrogen. The flask was put in an ice bath
and methyl 4-methoxyacetoacetate (1) (1.0 mmol, 0.13 mL) was
added via syringe followed by the slow addition of diethylzinc (1
M solution in hexanes) (5.0 mmol, 5.0 mL) via syringe and the
mixture was allowed to stir for 10 min. 1,1-Diiodoethane (5.0 mmol,
(15) (a) Letsinger, R. L.; Kammeyer, C. W. J. Am. Chem. Soc. 1951, 73,
4476. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett. 1968,
3495. (c) Charette, A. B.; Lemay, J. Angew. Chem., Int. Ed. Engl. 1997, 36,
1090.
(16) Amador, M.; Ariza, X.; Garcia, J. Heterocycles 2006, 67, 705–720.
J. Org. Chem. Vol. 73, No. 18, 2008 7411

0.39 mL) was added via syringe over 5 min. The resulting solution
was allowed to stir for approximately 2 h. Hexanal (2.0 mmol, 0.25
mL) was added via syringe over 1 min and the reaction mixture
was monitored by TLC (15:2, hexanes:ethyl acetate) until starting
material was almost completely gone (about 45 min). The reaction
mixture was quenched with saturated ammonium chloride (10 mL)
and extracted with dichloromethane (3 × 15 mL). The combined
organic layers were dried over anhydrous sodium sulfate, gravity
filtered, and concentrated on a rotary evaporator (35 °C, 30 mmHg)
to give a pale-yellowish liquid. The crude reaction product was
purified by flash chromatography (15:2, hexanes:ethyl acetate) to
yield 0.14 g (51% yield) of aldol product 24. IR 3434, 2937, 2353,
material was almost completely gone (about 6 h.). Water (2 mL)
was added and the solution was extracted with diethyl ether (3 ×
10 mL). The combined organic layers were dried over anhydrous
sodium sulfate, gravity filtered, and concentrated on a rotary
evaporator (35 °C, 40 mmHg) to give 0.03 g (77% yield) of a
slightly colored liquid. IR 2951, 2867, 1779, 1736, 1634, 1559,
1444, 1378, 1345, 1275, 1180, 1131, 995, 876, 797, 769, 631, 594,
1
475, 453, 434 cm-1. H NMR (400 MHz, CDCl3) δ 4.41 (dt, 1H,
J ) 8.5, 5.1 Hz), 3.74 (s, 3H), 3.33 (dd, 1H, J ) 7.5, 5.1 Hz), 2.92
(pentet, 1H, J ) 7.2), 1.75 (m, 1H), 1.62-1.49 (m, 3H), 1.35-1.28
(m, 4H), 1.24 (d, 3H, J ) 7.1 Hz), 0.88 (br t, 3H, J ) 6.8 Hz). 13
C
NMR (400 MHz, CDCl3) δ 177.7, 170.3, 79.4, 52.0, 50.9, 39.4,
31.6, 31.1, 25.7, 22.6, 14.1, 10.6. HRMS (FAB+) m/z calcd for
C12H21O4 [M + H] 229.1440, found [M + H] 229.1441.
1
1714, 1449, 1386, 1200, 1124, 1006 cm-1. H NMR (400 MHz,
CDCl3) δ 5.53 (s, 1H), 4.02 (dt, 1H, J ) 7.3, 5.9 Hz), 3.75 (s, 3H),
3.45-3.39 (m, 2H), 3.42 (s, 3H), 3.08 (dd, 2H, J ) 6.8, 6.8 Hz),
2.76 (pentet, 1H, J ) 7.1 Hz), 1.23-1.71 (m, 8H), 1.06 (d, 3H, J
) 7.2 Hz), 0.88 (br t, 3H, J ) 6.8 Hz). 13C NMR (400 MHz, CDCl3)
δ 175.2, 105.3, 80.7, 74.4 59.9, 52.7, 52.3, 40.3, 32.5, 32.0, 26.1,
22.7, 14.2, 10.3. HRMS (FAB+) m/z calcd for C14H25O4 [M -
OH] 257.1753, found [M - OH] 257.1749.
cis,cis-Methyl 4-Methyl-5-oxo-2-pentyltetrahydrofuran-3-car-
boxylate (25). An oven-dried, one-necked, 25-mL round-bottomed
flask was equipped with a magnetic stir bar and charged with
acetonitrile (4 mL), water (1 mL), and compound 24 (0.19 mmol,
0.05 g). Ceric ammonium nitrate (CAN) (0.77 mmol, 0.42 g) was
added and the mixture was allowed to stir. The reaction progress
was monitored by TLC (4:1, hexanes:ethyl acetate) until starting
Acknowledgment. We thank the National Institutes of Health
(R15 GM060967-02) and the University of New Hampshire for
their financial support.
Supporting Information Available: Experimental proce-
dures for the preparation of 5, 6, 7, 8, 10, 11, 13, 15, 16, 17,
18, 19, 20, 21, and 22 and 1H and 13C NMR spectra for 3, 4, 5,
6, 7, 8, 10, 11, 13, 15, 16, 17, 18, 19, 20, 21, 22, 24, and 25.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801258H
7412 J. Org. Chem. Vol. 73, No. 18, 2008