Diastereo- and enantioselective synthesis of trans-2,3-disubstituted 2,3-dihydropyran-4-one derivatives

Article abstract of DOI:10.1002/adsc.200606159

trans-Diastereoselective hetero-Diels-Alder reactions took place in the presence of SiCl₄/ activator systems. The reactions of aldehydes with a derivative of Danishefsky's diene afforded the corresponding pyrones with high yields and diastereos

Full text of DOI:10.1002/adsc.200606159

FULL PAPERS
DOI: 10.1002/adsc.200606159
Diastereo- and Enantioselective Synthesis of trans-2,3-Disubstitut-
ed 2,3-Dihydropyran-4-one Derivatives
Arrigo Scettri,a,* Maria R. Acocella,a Laura Palombi,a Chiara Scalera,a
Rosaria Villano,a and Antonio Massaa
a
Dipartimento di Chimica, Universitàdi Salerno, Via S. Allende, 84081 Baronissi (Salerno), Italy
Fax : (+39)-089-965-296; e-mail: scettri@unisa.it
Received: April 4, 2006; Accepted: August 8, 2006
Abstract: trans-Diastereoselective hetero-Diels– cases. The employment of a chiral activator allowed
Alder reactions took place in the presence of SiCl4/ us to convert Danishefskyꢀs diene (or its disubstitut-
activator systems. The reactions of aldehydes with a ed derivative) into both aldols and pyrones in good
derivative of Danishefskyꢀs diene afforded the corre- to high enantiomeric excesses.
sponding pyrones with high yields and diastereose-
lectivity upon activating SiCl4 with suitable neutral Keywords: aldol reaction; asymmetric synthesis; dia-
Lewis bases. Aldol intermediates deriving from a stereoselectivity; enantioselectivity; pyrones; silicon
Mukaiyama-type pathway were isolated in many tetrachloride
Introduction
The hetero-Diels–Alder (HDA) reaction represents
one of the most powerful tools for the synthesis of
racemic or enantiopure pyran derivatives,[1,2] well-
known as key intermediates in the preparation of
many bio-active compounds.[3] In particular, the HDA
reaction of Danishefskyꢀs diene 1 with carbonyl com-
Scheme 1.
pounds has allowed an easy access to a broad variety
of 2,3-dihydro-4H-pyran-4-one derivatives of type 3
A two-step sequence (pathway a) involving an ini-
tial Mukaiyama aldol reaction, followed by acid-cata-
(Scheme 1).
The sequence depicted in Scheme 1 usually requires lyzed cyclization, is typical of B
(III),[4] Ti(IV)[5] and
A
in the first step the presence of a Lewis acid as cata- Zr(IV)[6] catalysts, while a concerted Diels–Alder re-
lyst and, accordingly, depending on the used catalytic action has been pointed out in processes promoted by
system, two different mechanistic pathways have been Zn(II),[7] Cr
A
N
detected (Scheme 2).
b).
Scheme 2.
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In the course of an investigation on the reactivity
of masked forms of 1,3-dicarbonyl compounds, Dani-
shefskyꢀs diene 1 confirmed its relevant nucleophilic
properties, and its vinylogous addition[10] to aldehydes
was found to proceed in moderate yields in the pres-
ence of a very mild Lewis acid such as SiCl4.[11] In
fact, for example, benzaldehyde (2a) was converted
into the corresponding pyrone derivative 3a in 56%
yield under the conditions depicted in Scheme 3.
It is noteworthy that a significant enhancement of
efficiency (up to 85% yield) in more reduced reaction
times was obtained by activating SiCl4 with suitable
additives such as sulfoxides, hexamethylphosphora-
Scheme 4.
mide (HMPA), dimethylformamide (DMF) and pyri- Table 1. HDA reaction of diene 5 with benzaldehyde (2a).
dine N-oxide (PyN+Oꢀ). Rather interestingly from a
mechanistic point of view, appropriate quenching,
Entry Activator [0.1 equiv.] Yield [%][a] 6a trans/cis dr[b]
work-up and purification procedures allowed us to
obtain several intermediates of type 4 in a rather sat-
isfactory way (57–85% yield) confirming the involve-
ment of a Mukaiyama-type pathway.
In order to expand the synthetic utility of the
above protocol, especially as regards the preparative
and stereochemical aspects, the reactivity of the Dani-
shefskyꢀs diene derivative 5 was examined. Further-
more, the possibility of achieving an enantioselective
version of the vinylogous reaction of dienes 1 and 5
was explored.
1
2
3
4
5
-
16
95
95
64
32
>95/5
>95/5
>95/5
94/6
p-TolSOMe
DMF
Py-N+Oꢀ
HMPA
95/5
[a]
All the yields refer to isolated chromatographically pure
compound and are based on the starting 2a
[b]
trans/cis diastereoisomeric ratios were determined by
1H NMR analysis (400 MHz) on the crude products 6.
reoisomer. The activation of SiCl4 by suitable neutral
Lewis bases such as methyl p-tolyl sulfoxide (entry 2),
and DMF (entry 3) proved to be particularly fruitful,
while much less satisfactory results were obtained by
Results and Discussion
In the preliminary phase benzaldehyde (2a) was using HMPA and PyN+Oꢀ, respectively, entries 4 and
chosen as a representative substrate and was submit- 5. However, in all entries 6a was attained as the by
ted to treatment with diene 5 under the typical condi- far predominant trans-stereoisomer.
tions, as reported in Scheme 4 and Table 1.
It is notable that in Danishefskyꢀs pioneering
A control experiment was performed in the ab- work[7] the BF3·Et2O-catalyzed reaction of diene 5 on
sence of any activator (entry 1) and after the acidic benzaldehyde afforded the corresponding pyrone 6a
treatment the corresponding pyrone 6a was obtained in 90% overall yield as a 76/24 trans/cis mixture.
in not negligible way (16% yield) in spite of the more
In order to gain further information on the reaction
enhanced steric hindrance on the reaction site with pathway leading to 6a, benzaldehyde was reacted
respect to Danishefskyꢀs diene 1. More interestingly with diene 5 under the usual conditions (activator
from a stereochemical point of view, 6a was isolated methyl p-tolyl sulfoxide) and the following acidic
almost exclusively as the trans-2,3-disubstituted ste- treatment was omitted (Scheme 5).
Scheme 3.
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Synthesis of trans-2,3-Disubstituted 2,3-Dihydropyran-4-one Derivatives
FULL PAPERS
Scheme 5.
After quenching with MeOH/Et3N mixture, the re- both SiCl4/HMPA and SiCl4/PyN+Oꢀ catalytic systems
1
sulting crude product was submitted to H NMR anal- led directly to the free aldol 8a contaminated by a sig-
ysis (400 MHz), which revealed the almost complete nificant amount of the cyclization product 6a. Particu-
disappearance of the starting materials and the pres- larly, after a fast filtration of the crude reaction mix-
ence of the O-protected vinylogous aldol 7a as only ture on a short pad of silica gel, a 1/1 6a/8a mixture
product. In the course of the attempted purification was obtained by using PyN+Oꢀ as activator. However
of 7a by silica gel column chromatography cleavage the production of 6a as exclusive trans-diastereoiso-
of the (MeO)3Si- group took place[12] and the anti- mer in both the above experiments could be reasona-
aldol 8a was isolated, as a diastereoisomerically pure bly explained through a Mukaiyama-type pathway in-
compound, in satisfactory yield (65%). anti-Diaste- volving the not negligible occurrence of a direct cycli-
reoselectivity has been already observed in the SiCl4- zation process of 8a to pyrone 6a under the conditions
catalyzed vinylogous aldol condensation of a Chanꢀs used for the vinylogous aldol reaction.
diene derivative of type 9 (Figure 1) and was reasona-
In order to assess the level of general validity of
the procedure, several aldehydes were submitted to
the usual treatment (Scheme 6) and rac-methyl p-tolyl
sulfoxide was chosen as activator.
Figure 1.
bly attributed to a steric interaction between the
methyl group and the Lewis acid coordinated to the
carbonyl oxygen in an open transition state.[10]
The conversion 7a!8a proved to be a reversible
process since 7a could be quantitatively obtained by a
serial treatment of 8a with SiCl4/DIPEA and MeOH/
Et3N mixtures in CH2Cl2 solution. In every case, both
7a and 8a underwent an acid-catalyzed process of cyc-
lization to afford the trans-2,3-disubstituted pyrone 6a
in very high yields (>95%).
Scheme 6.
As reported in Table 2, both the preparative and
It is notable that the choice of the activator proved stereochemical results were found to depend on the
to be critical for an efficient and highly selective pro- aldehyde used: in fact, in entries 1–3 silica gel chro-
duction of the aldol 8a: in fact, in the presence of matography on the resulting crude O-trimethoxysilyl
DMF the aldol reaction proceeded very satisfactorily derivatives 7a–c afforded the corresponding free
so that pure anti-8a could be obtained in 71% yield, aldols 8a–c, exclusively as anti-diastereoisomers, in ac-
as exclusive product. Conversely, the employment of ceptable yields in spite of a significant tendency to de-
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Table 2. SiCl4/rac-pTolSOMe-catalyzed HDA reaction of diene 5 with different RCHO 2.
Entry
R
Aldol
Yield [%][a]
Pyrone
Yield [%][b]
trans/cis dr[c]
1
2
3
4
5
6
7
Ph
8a
8b
8c
8d
8e
8f
8g
65
54
70
-
-
-
6a
6b
6c
6d
6e
6f
6g
95
95
80
80
87
85
-
>95/5
>95/5
>95/5
86/14
89/11
83/17
-
p-Cl-C6H4
PhCH=CH
p-Me-C6H4
p-MeO-C6H4
p-CN-C6H4
PhCH2CH2
-
[a]
All the yields refer to isolated chromatographically pure products 8a–c (exclusively anti diastereoisomers) and are based
on the starting RCHO 2.
[b]
[c]
The reported values refer to the yields of the overall sequence 2!7!6 and are based on the starting RCHO 2.
1
trans/cis diastereoisomeric ratios were determined by H NMR analysis (400 MHz) on the crude products 6.
compose in the course of the purification procedure.
However, in all the above entries the vinylogous aldol
reaction of the diene 5 proved to take place with very
satisfactory efficiency since the usual acidic treatment
converted the crude intermediates 7a–c into the trans-
pyrones 6a–c in rather good yields (up to 95%) and
complete diastereoselectivity.[6,13] Very interestingly, in
entries 4–6 the standard procedure (SiCl4/DIPEA/rac-
pTolSOMe) and quenching (MeOH/Et3N) directly led
to the pyrones 6d–f, as by far the predominant trans-
diastereoisomers in 80–87% yields.
On the ground of the stereochemical outcome,
these latter results can be reasonably explained
through a very efficient domino process [anti-diaste-
reoselective Mukaiyama reaction of diene 5, desilyla-
tion of (MeO)3Si-derivatives 7, cyclization to trans-py-
Scheme 7.
rones 6] occurring directly in the reaction medium, as Taking advantage of the easy commercial availability
previously observed. Furthermore, aliphatic aldehydes of the chiral ligand (R,R)-10, the catalytic properties
proved to be completely unreactive, so that, for exam- of the SiCl /
A
ple, 3-phenylpropionaldehyde was recovered un- ined in several vinylogous aldol reactions of dienes 1
changed after the usual treatment.
and 5.
The easy and, in some cases, satisfactory accessibili-
ty of aldol intermediates of type 4 and 8, containing
several functionalities susceptible of further manipu-
lation, suggested an investigation devoted to the ach-
ievement of an enantioselective version of the vinylo-
gous aldol reaction of the dienes 1 and 5.
Therefore, a set of experiments was performed on
different aldehydes by using (R)-methyl p-tolyl sulf-
oxide as chiral activator (Scheme 7). Although all the
vinylogous aldols of type 4 and 8 could be obtained in
acceptable yields (54–64%), unfortunately rather low
Figure 2.
As reported in Table 3, in the presence of a very re-
ees were always observed. For example, the usual duced chiral ligand (0.01 equiv. with respect to SiCl4)
treatment afforded respectively (R)-4a in 64% yield the conversion of Danishefskyꢀs diene 1 into the
(33% ee) and (2S,3R)-8a in 65% yield (17% ee).
chiral aldols 4 was found to take place in comparable
However, as widely reported in these last years, the yields and remarkably improved ees (entries 1–6), in
activation of SiCl4 by chiral phosphoramides proved spite of the competing non-asymmetrical background
to be particularly successful and allowed the realiza- reaction (see Introduction). In the case of the disub-
tion of an impressive series of related processes for stituted diene 5 (entries 7–9) the anti-aldols 8 were
[14–20]
ꢀ
the highly enantioselective C C bond formation.
obtained with complete diastereoselectivity and a
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Adv. Synth. Catal. 2006, 348, 2229 – 2236

Synthesis of trans-2,3-Disubstituted 2,3-Dihydropyran-4-one Derivatives
Table 3. Asymmetric aldol reaction of dienes 1 and 5 promoted by SiCl4/(R,R)-10 system.
FULL PAPERS
A
Entry
R
Reaction time [h]
Product
Yield [%][a]
ee [%][b,c]
1
2
3
4
5
6
7
8
9
Ph
0.15
1.5
1.0
1.5
3.0
2.0
4.0
4.0
4.0
4a
4c
4d
4e
4f
4g
8a
8b
8d
50
65
51
60
54
60
42
22
52
86
53
87
77
78
84
81
78
91
PhCH=CH
o-MeO-C6H4
p-CF3-C6H4
p-Br-C6H4
p-Me-C6H4
Ph
p-Cl-C6H4
p-Me-C6H4
[a]
All the yields refer to isolated chromatographically pure aldols 4 or 8 and are based on the starting RCHO 2. Aldols 8a,
b and d were obtained as exclusive anti-diastereoisomers.
The ee values were determined by HPLC analysis.
The 2(R) configuration was assigned to the products 4a, c–f by comparing the sign of the optical rotation of the corre-
sponding pyrones 3a, c–f (obtained through acidic treatment)[4a] with the ones reported in the literature.[21] The (2R,3S)
configuration was assigned to product 8a by comparing the sign of the optical rotation of the corresponding pyrone 6a
([a]D: ꢀ25.5, c 0.7, CHCl3)(obtained by acidic treatment) with the one reported in the literature[22] ([a]D: ꢀ27.3, c 0.7,
CHCl3 for 52% ee).The absolute configuration of compounds 8b and d was not assigned.
[b]
[c]
good to high level of enantioselectivity: the lower effi- methyl-substituted Danishefskyꢀs diene 5 comparable
ciency could be again attributed to the lability of in- levels of enantioselectivity and complete anti-diaste-
termediates 7 (or the aldols 8) in the course of the pu- reoselectivity could be observed for the corresponding
rification by silica gel chromatography. In fact, the aldols 8 whose acid-catalyzed conversion into the
usual acidic treatment of the crude product of type 7, chiral trans-pyrones 6 took place very efficiently and
deriving from the vinylogous aldol reaction, afforded no significant modification of optical purity.
the corresponding pyrones 6, as exclusive trans-diaste-
reoisomers, in good yield and almost unchanged ees
[6a (78% yield, 80% ee); 6b (60% yield, 77% ee), 6d
(76% yield, 86% ee).
Experimental Section
The result obtained in entry 9 pointed out the de-
termining role exerted by the chiral activator in the
reaction pathway: in fact, when the same experiment
was performed in the presence of SiCl4/(R)-methyl p-
General Remarks
All reactions were performed in oven-dried (1408C) or
flame-dried glassware under an atmosphere of dry nitrogen.
tolyl sulfoxide system, the formation of the pyrone 6d All the solvents for the reactions were of reagent grade and
were dried and distilled immediately before use (dichloro-
methane from calcium hydride). Column chromatographic
purification of products was carried out using silica gel 60
(70–230 mesh, Merck). The chiral phosphoramide R,R-10,
commercially available from Obiter Research, LLC, and the
other reagents (Aldrich and Fluka) were used without fur-
ther purification. The NMR spectra were recorded on a
Bruker DRX 400 (400 MHz, 1H; 100 MHz, 13C). Spectra
were referenced to residual chloroform (7.26 ppm, 1H,
77.23 ppm, 13C). Chemical shifts are reported in ppm, multi-
(84/16 trans/cis ratio, 23% ee of the predominant dia-
stereoisomer) was found to occur directly under the
conditions used for the vinylogous aldol reaction.
Conclusions
In conclusion, trans-2,3-disubstituted pyrone deriva-
tives proved to be easily accessible with a high level
of diastereoselectivity by a new procedure based on plicities are indicated by s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet) and br (broad). Coupling constants,
J, are reported in Hz. Yields are given for isolated products
showing one spot on a TLC plate and no impurities detecta-
ble in the NMR spectrum. HPLC analyses were performed
with Waters Associates equipment (Waters 2487 Dual l ab-
sorbance Detector) and using a CHIRALPAK AD or a
CHIRALCEL OD column with hexane/isopropyl alcohol
mixtures and flow rates as indicated. The HPLC methods
were calibrated with the corresponding racemic mixtures.
Optical rotations were measured with a JASCO DIP-1000
the vinylogous aldol reaction of a Danishefskyꢀs diene
derivative, promoted by SiCl4/neutral Lewis base sys-
tems. The corresponding anti-aldol intermediates
could be isolated in a satisfactory way in several
cases, confirming the involvement of a Mukaiyama-
type pathway. The employment of a chiral SiCl4/bis-
phosphoramide catalyst proved to be successful, usu-
ally allowing the production of the intermediate vinyl-
ogous aldols of type 4 in a satisfactory way and good
to high enantiomeric excesses. In the case of the di- polarimeter. Mass spectrometry analysis was carried out
Adv. Synth. Catal. 2006, 348, 2229 – 2236
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Arrigo Scettri et al.
FULL PAPERS
using an electrospray spectrometer Waters 4 micro quadru-
pole.
Aldol (2R)-4c: [a]2D5: +108 (c 1.0, CHCl3). Enantiomeric
excess of 4c was determined to be 53% by HPLC with a
Diacel Chiralpak AD column (9/1 hexane/i-PrOH,
0.5 mLminꢀ1): tR =67.3 min for major enantiomer; tR =
73.6 min for minor enantiomer. Absolute configuration was
assigned as R by comparison of the sign of the optical rota-
tion of the corresponding g-pyrone, obtained by acidic treat-
ment according to ref.[4] with the one reported in the litera-
ture.[20]
General Procedure for the Enantioselective
Vinylogous Addition of Danishefskyꢀs Diene 1 (or
Diene 5)
In a flame-dried, 2-necked, round-bottom flask, diisopropyl-
ethylamine (1.34 mmol), SiCl4 (1.34 mmol) and the aldehyde
(1.34 mmol) were successively added at ꢀ788C under argon
to a solution of chiral activator (0.013 mmol) in dry CH2Cl2
(6 mL). Then, Danishefskyꢀs diene 1 (or 5) (1.48 mmol) was
slowly added over a period of 5 min. The reaction was stir-
red at ꢀ788C for the time reported in Scheme 6. At the end
of the reaction, a mixture of MeOH/Et3N=0.2/0.3 mL was
added at ꢀ788C and the resulting mixture was allowed to
stir at 08C until the formation of a precipitate. Then 5 mL
of petroleum ether/AcOEt (8/2) solution were added and
the mixture was filtered and washed with petroleum ether/
AcOEt (8/2) (5 mL). The solvent was evaporated under re-
duced pressure and the residue was purified by flash chro-
matography on silica gel with a petroleum ether-AcOEt
mixture (from 95/5 to 8/2) to afford the pure aldols 4 (or 8).
The same procedure was used for non-asymmetric vinylo-
gous reactions by omitting the employment of the chiral ac-
tivator.
Aldol 4d: [a]2D5: +778 (c 1.0, CHCl3). Enantiomeric excess
of 4d was determined to be 87% by HPLC with a Diacel
Chiralpak AD column (9/1 hexane/i-PrOH, 0.6 mLminꢀ1):
tR =59.0 min for major enantiomer; tR =72.1 min for minor
enantiomer. The absolute configuration of 4d was not as-
signed.
Aldol 4e: IR (KBr): n=3376, 1718, 1676, 1617, 1588,
1
833 cmꢀ1; H NMR (CDCl3): d=2.83 (m, 2H), 3.71 (s, 3H),
5.15 (m, 1H), 5.57 (d, J=12.8 Hz, 1H), 7.48 (d, J=8.1 Hz,
2H), 7.59 (m, 3H); 13C NMR (CDC13): d=48.8, 57.7, 69.6,
105.6, 120.1, 125.5 (2C), 127.6 (2C), 129.9, 147.0, 163.9,
198.9. [a]2D5: +448 (c 1.0, CHCl3). Enantiomeric excess of 4e
was determined to be 77% by HPLC with a Diacel Chiral-
pak AD column (95/5 hexane/i-PrOH, 0.6 mLminꢀ1): tR =
42.4 min for major enantiomer; tR =37.8 min for minor en-
antiomer. The absolute configuration of 4e was not as-
signed.
Aldol 4f: IR (KBr): n=3421, 1718, 1676, 1619, 1590, 821,
1
701 cmꢀ1; H NMR (CDCl3): d=2.85 (m, 2H), 3.70 (s, 3H),
General Procedure for the Conversion of Aldols 4 (or
8) to Pyrones 3(or 6)
5.15 (m, 1H), 5.57 (d, J=12.6 Hz, 1H), 7.26–7.36 (m, 4H),
7.60 (d, J=12.6 Hz, 1H); 13C NMR (CDC13): d=49.0, 57.7,
70.2, 105.9, 126.5 (2C), 128.5, 130.0 (2C), 143.0, 163.8, 199.4;
anal. calcd. for C13H13BrO3: C 50.55, H 4.60; found: C 50.60,
H 4.55. [a]2D5: +348 (c 1.0, CHCl3). Enantiomeric excess of 4f
was determined to be 76% by HPLC with a Diacel Chiral-
pak AD column (95/5 hexane/i-PrOH, 0.6 mLminꢀ1): tR =
64.7 min for major enantiomer; tR =61.6 min for minor en-
antiomer. The absolute configuration of 4f was not assigned.
The crude product obtained from the vinylogous addition
(or the purified aldol) was dissolved in 10 mL of CH2Cl2 at
08C and a solution of trifluoroacetic acid (0.15 mL) in
CH2Cl2 (1 mL) was added and the mixture was allowed to
stir for 3 h at this temperature. Then saturated aqueous
NaHCO3 (20 mL) was added and the mixture was extracted
with CH2Cl2 (25 mL”2). The organic layers were combined
and dried over anhydrous Na2SO4. After filtration and evap-
oration of the solvent under reduced pressure, the crude
product was purified by flash chromatography (petroleum
ether-AcOEt mixtures, from 95/5 to 8/2) to afford the de-
sired product.
Aldol 4g: IR (KBr): n=3421, 1675, 1617, 1590, 817 cmꢀ1
;
1H NMR (CDCl3): d=2.34 (s,3H), 2.85 (m, 2H), 3.70 (s,
3H), 5.14 (m, 1H), 5.58 (d, J=12.7 Hz, 1H), 7.15 (d, J=
7.8 Hz, 2H), 7.25 (d, J=7.8 Hz, 2H), 7.62 (d, J=12.7 Hz,
1H); 13C NMR (CDC13): d=21.1, 49.0, 57.6, 70.1, 105.9,
125.6, 129.1, 137.2, 140.1, 163.7, 199.4; anal. calcd. for
C13H16O3: C 70.89, H 7.32; found: C 70.95, H 7.30. [a]2D5:
+938 (c 1.0, CHCl3). Enantiomeric excess of 4g was deter-
mined to be 84% by HPLC with a Diacel Chiralpak AD
column (95/5 hexane/i-PrOH, 0.6 mLminꢀ1): tR =61.5 min
for major enantiomer; tR =66.8 min for minor enantiomer
The absolute configuration of 4g was not assigned.
The spectroscopic (IR, 1H NMR and 13C NMR) data of
aldols 4a–d matched the ones reported in the literature.[10]
Aldol (2R)-4a: [a]25: +578 (c 1.0, CHCl3). Enantiomeric
excess of 4a was detDermined to be 86% by HPLC with a
Diacel Chiralpak AD column (95/5 hexane/i-PrOH,
0.6 mLminꢀ1): tR =46.2 min for major enantiomer; tR =
51.0 min for minor enantiomer. Absolute configuration was
assigned as R by comparison of the sign of the optical rota-
tion of the corresponding g-pyrone, obtained by acidic treat-
ment according to ref.[4a] with the one reported in the litera-
ture.[20]
Aldol (2R,3S)-8a: anti isomer: IR (KBr): n=3418, 1720,
1635, 1599, 1098, 871, 705 cmꢀ1; H NMR (CDCl3): d=1.06
1
(d, J=7.1 Hz, 3H), 1.68 (s, 3H), 3.24 (m, 1H), 3.83 (s, 3H),
4.85 (d, J=6.9 Hz, 1H), 7.16 (s, 1H), 7.3–7.5 (m, 5H);
13C NMR (CDCl3): d=8.1, 16.5, 29.6, 46.7, 61.4, 117.2, 126.3,
127.5, 128.2, 142.7, 160.7, 204.1; MS-ES: m/z=257 [M+
Na]+; [a]D22: +83.0 (c 0.5, CHCl3). Enantiomeric excess of 8a
was determined to be 81% by HPLC with a Diacel Chiral-
pak AD column (95/5 hexane/i-PrOH, 0.6 mLminꢀ1): tR =
29.3 min for minor enantiomer; tR =36.1 min for major en-
antiomer. The absolute configuration of 8a was assigned as
reported in Table 3, footnote [c].
Aldol (2R)-4b: [a]2D5: +18 (c 1.0, CHCl3). Enantiomeric
excess of 4b was determined to be 21% by HPLC with a
Diacel Chiralpak AD column (95/5 hexane/i-PrOH,
0.6 mLminꢀ1): tR =56.9 min for major enantiomer; tR =
60.5 min for minor enantiomer. Absolute configuration was
assigned as R by comparison of the sign of the optical rota-
tion of the corresponding g-pyrone, obtained by acidic treat-
ment according to ref.[4a] with the one reported in the litera-
ture.[20]
2234
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Adv. Synth. Catal. 2006, 348, 2229 – 2236

Synthesis of trans-2,3-Disubstituted 2,3-Dihydropyran-4-one Derivatives
FULL PAPERS
Aldol 8b: anti isomer: IR (KBr): n=3420, 1718, 1670,
[2] For some recent examples of the enantioselective
hetero-Diels–Alder reaction of aldehydes with the
diene 1, see: a) Y. Yuan, J. Long, J. Sun, K. Ding,
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[3] For reviews see: a) S. J. Danishefsky, M. P. De Ninno,
Angew. Chem. Int. Ed. Engl. 1987, 16, 15–23; b) K. A.
Jorgensen, Angew. Chem. Int. Ed. Engl. 2000, 39,
3555–3588; c) K. Maruoka, in: Catalytic Asymmetric
Synthesis, 2nd edn.; Wiley-VCH, New York, 2000,
Chapter 8A.
[4] a) E. J. Corey, C. L. Cywin, T. D. Ropez, Tetrahedron
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52, 2167–2176.
1
1633, 1595, 860, 700 cmꢀ1; H NMR (CDCl3): d=1.06 (d, J=
7.1 Hz, 3H), 1.66 (s, 3H), 3.18 (m, 1H), 3.84 (s, 3H), 4.81
(bd, 1H), 7.15 (s, 1H), 7.26 (m, 4H); 13C NMR (CDCl3): d=
8.1, 16.5, 29.5, 46.5, 61.5, 117.1, 127.6, 128.3, 133.1, 141.3,
160.8, 203.9; MS-ES: m/z=291 [M+Na]+. [a]D24: +7.4 (c 0.4,
CHCl3). Enantiomeric excess of 8b was determined to be
78% by HPLC with a Diacel Chiralpak AD column (95/5
hexane/i-PrOH, 0.6 mLminꢀ1): tR =23.9 min for minor enan-
tiomer; tR =30.6 min for major enantiomer. The absolute
configuration of 8b was not assigned.
Aldol 8d: anti isomer: IR (KBr): n=3421, 1718, 1671,
1
1635, 1595, 862, 701 cmꢀ1. H NMR (CDCl3): d=1.03 (d, J=
7.0 Hz, 3H), 1.69 (s, 3H), 2.33 (s,3H), 3.22 (m, 1H), 3.84 (s,
3H), 4.82 (d, J=7.1 Hz, 1H), 7.14 (d, J=7.9 Hz, 2H), 7.18
(s, 1H), 7.22 (d, J=7.9 Hz, 2H); 13C NMR (CDCl3): d=8.2,
16.5, 21.0, 29.6, 46.7, 61.4, 117.2, 126.2, 128.9, 137.1, 139.6,
160.6, 204.1; MS-ES: m/z=271 [M+Na]+; [a]D24: +93.0 (c
0.25, CHCl3). Enantiomeric excess of 8d was determined to
be 91% by HPLC with a Diacel Chiralpak AD column (95/
5 hexane/i-PrOH, 0.6 mLminꢀ1): tR =25.0 min for minor en-
antiomer; tR =31.4 min for major enantiomer. The absolute
configuration of 8d was not assigned.
1
The spectroscopic (IR, H NMR and 13C NMR) and ana-
lytical data of trans-pyrones 6a–d matched the ones reported
in the literature.[6,13,21]
Pyrone 6e: trans isomer: 1H NMR (CDCl3): d=0.91 (d,
J=7.0 Hz, 3H), 1.72 (s, 3H), 2.78 (dq, J=13.5; 7.0 Hz, 1H),
3.82 (s, 3H), 4.87 (d, J=13.5 Hz, 1H), 6.92 (d, J=6.5 Hz,
2H), 7.29 (s, 1H), 7.30 (d, J=6.5 Hz, 2H); 13C NMR
(CDCl3): d=11.3, 11.7, 45.6, 56.2, 87.5, 114.0, 115.0, 129.7,
130.7, 159.8, 161.0, 196.2; MS-ES: m/z=255 [M+Na]+.
Pyrone 6f: 1H NMR (CDCl3): trans isomer: d=0.93 (d,
J=6.9 Hz, 3H), 1.72 (s, 3H), 2.72 (dq, J=13.2; 6.9 Hz, 1H),
4.96 (d, J=13.2 Hz, 1H), 7.30 (s, 1H), 7.51 (d, J=8.1 Hz,
2H), 7.61 (d, J=8.1 Hz, 2H); cis isomer: d=0.86 (d, J=
7.2 Hz, 3H), 1.75 (s, 3H), 2.61 (dq, J=7.2; 3.1 Hz, 1H), 5.50
(d, J=3.1 Hz, 1H), 7.38 (s, 1H), 7.46 (d, J=8.3 Hz, 2H),
7.71 (d, J=8.3 Hz, 2H); 13C NMR (CDCl3); trans isomer:
d=11.2, 11.6, 45.7, 86.8, 113.9, 114.6, 119.2, 129.0, 133.5
143.6, 159.1, 194.8; cis isomer: d=10.2, 10.5, 44.6, 85.7,
112.7, 113.5, 118.2, 127.4, 132.3 142.5, 158.1, 193.7; MS-ES:
m/z=250 [M+Na]+.
[5] G. E. Keck, X. Y. Li, D. Krishnamurty, J. Org. Chem.
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Acknowledgements
We are grateful to MIUR (Ministero dell’Istruzione, Universi-
tà e della Ricerca Scientifica) for financial support.
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Adv. Synth. Catal. 2006, 348, 2229 – 2236