Stereoselective synthesis of dihydropyran-4-ones via a formal hetero diels-alder reaction and ceric ammonium nitrate dehydrogenation

Full text of DOI:10.1021/jo961325u

7600
J . Org. Chem. 1996, 61, 7600-7602
Sch em e 1
Ster eoselective Syn th esis of
Dih yd r op yr a n -4-on es via a F or m a l Heter o
Diels-Ald er Rea ction a n d Cer ic
Am m on iu m Nitr a te Deh yd r ogen a tion
P. Andrew Evans* and J ade D. Nelson
Lammot du Pont Laboratory, Department of Chemistry and
Biochemistry, University of Delaware,
Newark, Delaware 19716
propylsilyl)oxy enol ethers 2.12-14 The (triisopropylsilyl)-
oxy diene 1 is a practical synthetic intermediate, owing
to its resistance to acid-catalyzed hydrolysis, compared
to the trimethylsilyl derivative, and generally affords the
2,3-disubstituted dihydropyran with improved diastereo-
control.5,6 This increased stability of triisopropylsilyl
derivatives has been attributed to steric hindrance at
silicon created by the isopropyl groups which makes them
more stable to proto-desilylation.12-14
Received J uly 12, 1996
The synthesis of pyranoid rings continues to be a
topical area of interest owing to the number of biologically
important molecules that contain this important moi-
ety.1,2 Several methods have been developed for dihy-
dropyran-4-one ring construction.3 However, the hetero
Diels-Alder4 reaction with Danishefsky’s diene5-7 pro-
vides one of the most convenient entries into this class
of compounds, and has provided the basis for a number
of synthetic strategies. Furthermore, the application of
asymmetric catalysis to this protocol has made it a very
powerful synthetic tool.8
In this note, we describe a new approach to the
dihydropyran-4-ones 4a -f based on a novel ceric am-
monium nitrate-induced dehydrogenation of 4-[(triiso-
propylsilyl)oxy]dihydropyrans 2a -f,9 which were pre-
pared by a formal hetero Diels-Alder of the monoacti-
vated (triisopropylsilyl)oxy diene 110,11 with an array of
aldehydes (Scheme 1). The advantage of this strategy is
the ability to isolate and directly functionalize the (triso-
Table 1 summarizes the results for the optimization
study using the (triisopropylsilyl)oxy diene 1 and ben-
zaldehyde. The reactions were all carried out by initially
precomplexing the aldehyde with the relevant Lewis acid
followed by the addition of the diene 1. Treatment of the
aldehyde with stoichiometric zinc chloride followed by the
diene 1 furnished the 2,3-disubstituted dihydropyrans 2a /
3a in modest yield favoring the cis-diastereoisomer (entry
1). The modest yield was attributed to hydrolysis of the
diene 1 over the extended reaction time. Treatment of
benzaldehyde with stoichiometric boron trifluoride ether-
ate at -78 °C followed by addition of the diene 1
furnished the dihydropyrans 2a /3a in excellent yield in
a slightly improved 8.5:1 mixture of stereoisomers (entry
2). The diastereoselectivity was further improved using
catalytic boron trifluoride etherate to afford the dihydro-
pyrans 2a /3a in 94% yield with a 28:1 preference for the
cis-diastereoisomer (entry 3). Two aluminum-based Lewis
acids were also examined. Treatment of benzaldehyde
and the diene 1 under analogous conditions with a
catalytic amount of trimethylaluminum led to recovered
starting materials (entry 4). However, the same reaction
with catalytic dimethylaluminum chloride at -78 °C
furnished the dihydropyrans 2a /3a in 93% yield as a 30:1
mixture of diastereoisomers (entry 5). Interestingly, the
stereochemical outcome may be completely reversed by
employing a stoichiometric amount of dimethylaluminum
chloride at higher temperature (entry 6). The ability to
alter the stereochemical outcome in this manner has been
attributed to a Mukaiyama aldol (stepwise) rather than
a formal hetero Diels-Alder (concerted) mechanistic
pathway.5,6
(1) (a) Doblem, M. Ionophores and Their Structures; Wiley-
Interscience: New York, 1981. (b) Westley, J . W., Ed. Polyether
Antibiotics; Marcel Dekker: New York, 1982; Vols. I and II. (c) Boivin,
T. L. B. Tetrahedron 1987, 43, 3309. (d) Alvarez, E.; Candenas, M.
-L.; Perez, R.; Ravelo, J . L.; Martin, J . D. Chem. Rev. 1995, 95, 1953.
(2) For recent reviews on the glycosides, see: (a) Danishefsky, S.;
DeNinno, M. P. Angew. Chem., Int. Ed. Engl. 1987, 26, 15. (b) Postema,
M. H. D. Tetrahedron 1992, 48, 8545. (c) Ager, D. J .; East, M. B.
Tetrahedron 1993, 49, 5683.
(3) (a) Paterson, I.; Osborne, S. Tetrahedron Lett. 1990, 31, 2213.
(b) Obrecht, D. Helv. Chim. Acta 1991, 74, 27. (c) Coleman, R. S.;
Fraser, J . R. J . Org. Chem. 1993, 58, 385. (d) Nangia, A.; Rao, P.-B.
Tetrahedron Lett. 1993, 34, 2681 and pertinent references cited therein.
(4) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in
Organic Synthesis; Academic Press: San Diego, CA, 1987.
(5) For reviews on the hetero Diels-Alder reaction, see: (a) Dan-
ishefsky, S. Aldrichim. Acta 1986, 19, 59. (b) Schmidt, R. R. Acc. Chem.
Res. 1986, 19, 250. (c) Danishefsky, S. J . Chemtracts 1989, 273. (d)
Bednarski, M. D.; Lyssikatos, J . P. In Comprehensive Organic Syn-
thesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 2, p 661.
(6) (a) Danishefsky, S. J .; Larson, E.; Askin, D.; Kato, N. J . Am.
Chem. Soc. 1985, 107, 1246. (b) Danishefsky, S.; Chao, K.-H.; Schulte,
G. J . Org. Chem. 1985, 50, 4650. (c) Danishefsky, S. J .; Maring, C. J .
J . Am. Chem. Soc. 1985, 107, 1269. (d) Danishefsky, S. J .; Myles, D.
C.; Harvey, D. F. J . Am. Chem. Soc. 1987, 109, 862. (e) Danishefsky,
S. J .; DeNinno, S.; Lartey, P. J . Am. Chem. Soc. 1987, 109, 2082 and
pertinent references cited therein.
(7) (a) Gould, S. J .; Eisenburg, R. L.; Hillis, L. R. Tetrahedron 1991,
47, 7209. (b) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G.;
Raimondi, L. J . Org. Chem. 1992, 57, 3605. (c) Reetz, M. T.; Gansa¨uer,
G. Tetrahedron 1993, 49, 6025. (d) Yang, G.; Myles, D. C. Tetrahedron
Lett. 1994, 35, 2503. (e) Burger, M. T.; Still, W. C. J . Org. Chem. 1996,
61, 775 and pertinent references cited therein.
(10) For examples of monoactivated dienes in the hetero Diels-Alder
reaction, see: (a) Danishefsky, S. J .; Pearson, W. H. J . Org. Chem.
1983, 48, 3865. (b) Danishefsky, S.; Harvey, D. F.; Quallich, G.; Uang,
B.-J . J . Org. Chem. 1984, 49, 392. (c) Danishefsky, S. J .; Pearson, W.
H.; Harvey, D. F.; Maring, C. J .; Springer, J . P. J . Am. Chem. Soc.
1985, 107, 1256. (d) Danishefsky, S. J .; Uang, B.-J .; Quallich, G. J .
Am. Chem. Soc. 1985, 107, 1285. (e) Mujica, M. T.; Afonso, M. M.;
Galindo, A.; Palenzuela, J . A. Tetrahedron 1996, 52, 2167 and pertinent
references cited therein.
(8) (a) Bednarski, M.; Maring, C.; Danishefsky, S. Tetrahedron Lett.
1983, 24, 3451. (b) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto,
H. J . Am. Chem. Soc. 1988, 110, 310. (c) Gao, Q.; Maruyama, T.; Mouri,
M.; Yamamoto, H. J . Org. Chem. 1992, 57, 1951. (d) Corey, E. J .;
Cywin, C. L. Roper, T. D. Tetrahedron Lett. 1992, 33, 6907. (e) Gao,
Q.; Ishihara, K.; Maruyama, T.; Mouri, M.; Yamamoto, H. Tetrahedron
1994, 50, 979. (f) Mikami, K.; Kotera, O.; Motoyama, Y.; Sakaguchi,
H. Synlett 1995, 975. (g) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J .
Org. Chem. 1995, 60, 5998 and pertinent references cited therein.
(9) Evans, P. A.; Longmire, J . M.; Modi, D. P. Tetrahedron Lett.
1995, 36, 3985.
(11) The (triisopropylsilyl)oxy diene 1 can be stored at -20 °C for
months without decomposition.
(12) For a review on the triisopropylsilyl enol ethers, see: Ru¨cker,
C. Chem. Rev. 1995, 95, 1009.
(13) (a) Magnus, P.; Roe, M. B.; Hulme, C. J . Chem. Soc., Chem.
Commun. 1995, 263. (b) Magnus, P.; Lacour, J .; Evans, P. A.; Roe, M.
B.; Hulme, C. J . Am. Chem. Soc. 1996, 118, 3406 and pertinent
references cited therein.
(14) (a) Evans, P. A.; Longmire, J . M. Tetrahedron Lett. 1994, 35,
8345. (b) Evans, P. A.; Modi, D. P. J . Org. Chem. 1995, 60, 6662.
S0022-3263(96)01325-4 CCC: $12.00 © 1996 American Chemical Society

Notes
Ta ble 1. Op tim iza tion of th e Lew is Acid Ca ta lyzed
J . Org. Chem., Vol. 61, No. 21, 1996 7601
methyl and methine ) o (odd). GC analysis was carried out
using an HP 5890 GC Series 2 using an Rtx-5 high performance
capillary column (flow rate: 1 mL/min). The GC temperature
program was 150 °C for 1 min, 150-200 °C at 10 °C/min, and
then 200-250 °C at 3 °C/min. All compounds were purified as
specified and gave spectroscopic data consistent with being
g95% of the assigned structure. Analytical TLC was carried
out on precoated 0.2 mm thick Merck 60 F254 silica plates. Flash
chromatography was carried out using Merck Silica Gel 60 (230-
400 mesh).
Heter o Diels-Ald er of th e Tr iisop r op ylsilyloxy Dien e 1
w ith Ben za ld eh yd e
ratio of yield
entry lewis acida (equiv)b temp, °C time (h) 2a /3a c (%)d
1
2
3
4
5
6
ZnCl2
(1.1)
(1.1)
(0.15)
(0.15)
(0.15)
(1.1)
rt
-78
-78
-78
-78
-20
62
1.5
1.5
24
3
1
5:1
63
93
94
0
93
80
BF3‚Et2O
BF3‚Et2O
Me3Al
Me2AlCl
Me2AlCl
8.5:1
28:1
NA
30:1
1:17
(Z)-3-[(Tr iisopr opylsilyl)oxy]-1,3-pen tadien e (1). Freshly-
distilled ethyl vinyl ketone (1.632 g, 20.0 mmol) was dissolved
in anhydrous THF (150 mL) and cooled with stirring to ca. -78
°C under an atmosphere of dry nitrogen. Triisopropylsilyl
trifluoromethanesulfonate (6.6 mL, 24.0 mmol) was then added
via syringe, followed by the dropwise addition of potassium bis-
(trimethylsilyl)amide (5.04 g, 24.0 mmol) in THF (50 mL) over
a period of ca. 45 min. The resulting cloudy white slurry was
stirred at -78 °C for 30 min and then was allowed to warm to
room temperature and stirred for an additional 1 h. The reaction
mixture was then poured into saturated aqueous sodium bicar-
bonate and extracted with diethyl ether. The organic layers
were combined, washed with saturated NaCl solution, dried over
anhydrous Na2SO4, and filtered, and the solvent was removed
in vacuo to afford a colorless crude oil. Purification by flash
chromatography on silica gel (eluting with n-pentane), followed
by Kugelro¨hr distillation under reduced pressure (oven temper-
ature 100-110 °C at 2.0 mmHg) afforded the diene 1 (4.038 g,
84%) as a colorless oil. The Z:E ratio was determined by 1H-
NMR to be g19:1: IR (CDCl3) 2946 (s), 2893 (s), 2868 (s), 1645
a
Reactions carried out on a 1 mmol reaction scale in anhydrous
b
toluene. The Lewis acid was precomplexed with the aldehyde
prior to the addition of the TIPS diene 1. c Ratios determined by
d
capillary GLC analysis of the mixture. Isolated yields.
Table 2 summarizes the results of the application of
this protocol to various aldehydes. The reactions were
all carried out with catalytic boron trifluoride etherate
and dimethylaluminum chloride, to allow a direct com-
parison of the Lewis acids in terms of their efficiency and
influence on the diastereoselectivity.5,6 The alkyl and
R,â-unsaturated aldehydes proved to be particularly
sensitive under these reaction conditions. In order to
circumvent this problem an alternative protocol was
developed. The alkyl and R,â-unsaturated aldehydes
were premixed (with the diene 1) at the desired temper-
ature, and a catalytic amount of Lewis acid was added
to furnish the dihydropyrans 2/3c-f in 75-95% yield
with good to excellent diastereoselectivity (entries 3-6).
This protocol presumably reduces competitive self-
condensation of the aldehydes. The reduced diastereo-
selectivity for the 2-furaldehyde and 2-[(tert-butyldime-
thylsilyl)oxy]acetaldehyde is presumably due to
competitive exo-addition under chelation control condi-
tions, which is the direct result of the â-alkoxy substitu-
ent present in both aldehydes (entries 2 and 4).5,6
The triisopropylsilyl enol ether provides an ambiphilic
synthon that may be transformed into a wide array of
complementary functionality.12-14 In this particular
study the triisopropylsilyl enol ethers were converted
directly to the dihydropyran-4-ones via a novel ceric
ammonium nitrate-induced dehydrogenation to allow a
direct comparison with related synthetic strategies.9
Treatment of the cis-4-[(triisopropylsilyl)oxy]dihydro-
pyrans 2a -f with ceric ammonium nitrate at 0 °C
furnished the cis-2,3-disubstituted dihydropyran-4-ones
4a -f in excellent yield (entries 1-6). Furthermore, the
3-methyl substituent did not equilibrate to the thermo-
dynamically more stable trans-2,3-disubstituted dihy-
dropyran-4-ones under the reaction conditions.
1
(m), 1596 (m) cm-1; H NMR (400 MHz, C6D6) δ 6.13 (dd, J )
17.1, 10.8 Hz, 1H), 5.43 (dd, J ) 17.1, J ) 0.6 Hz, 1H), 4.90 (dd,
J ) 10.5, 0.6 Hz, 1H), 4.69 (q, J ) 7.0 Hz, 1H), 1.63 (d, J ) 7.0
Hz, 3H), 1.25-1.12 (m, 3H), 1.14 (d, J ) 4.9 Hz, 18H); 13C NMR
(62.5 MHz, CDCl3) δ 150.54 (e), 136.16 (o), 111.40 (e), 108.19
(o), 18.03 (o), 13.83 (o), 11.46 (o); HRMS (EI) calcd for C14H28
OSi 240.1909, found 240.1904.
-
Gen er a l Exp er im en ta l P r oced u r es for th e Heter o Di-
els-Ald er Rea ction s. (2R*,3R*)-3-Meth yl-2-p h en yl-4-[(tr i-
isop r op ylsilyl)oxy]-2,3-d ih yd r op yr a n (2a ). Method A: Pre-
complexation Protocol. Benzaldehyde (0.107 g, 1.01 mmol) was
dissolved in anhydrous toluene (5 mL, freshly distilled from
CaH2) and cooled with stirring to -78 °C under an atmosphere
of argon. Dimethylaluminum chloride (150 µL, 0.15 mmol, 1.0
M in hexanes) was added and the colorless solution stirred for
15 min. The (triisopropylsilyl)oxy diene 1 (0.266 g, 1.11 mmol)
was then added, resulting in a pale yellow solution. The reaction
mixture was then stirred for an additional ca. 3 h (TLC control).
The reaction was then quenched by the addition of saturated
NaHCO3 solution (1 mL) and allowed to warm to ambient
temperature. The reaction mixture was poured into saturated
NaHCO3 solution and extracted with diethyl ether. The com-
bined organic phases were then washed with saturated NaCl
solution and dried over anhydrous Na2SO4, and the solvent was
removed in vacuo to afford a colorless oil. Purification by flash
chromatography on silica gel (eluting with 1-4% ethyl acetate
in hexane gradient) furnished the dihydropyrans 2a /3a (0.324
g, 93%) in an 30:1 ratio of diastereoisomers as a colorless oil.
The stereoisomers were easily separable at this stage to afford
the cis- and trans-diastereoisomers 2a and 3a respectively: IR
(CDCl3) 3032 (w), 2946 (s), 2894 (m), 2868 (s), 1713 (m), 1683
(m) cm-1; 1H NMR (250 MHz, CDCl3) δ 7.36-7.19 (m, 5H), 4.79-
4.77 (m, 1H), 4.73 (d, J ) 3.1 Hz, 1H), 4.39-4.25 (m, 2H), 2.30-
2.21 (m, 1H), 1.36-1.02 (m, 3H), 1.10 (d, J ) 5.8 Hz, 18H), 0.80
(d, J ) 6.9 Hz, 3H); 13C NMR (62.5 MHz, CDCl3) δ 153.34 (e),
140.72 (e), 128.03 (o), 126.74 (o), 125.58 (o), 99.07 (o), 78.64 (o),
65.25 (e), 40.00 (o), 18.06 (o), 12.68 (o), 12.39 (o); HRMS calcd
for C21H34O2Si 346.2328, found 346.2306.
In conclusion, we have applied the novel ceric am-
monium nitrate dehydrogenation of triisopropylsilyl enol
ethers to a hetero Diels-Alder/dehydrogenation sequence
for the conversion of (triisopropylsilyl)oxy dienes, via
triisopropylsilyl enol ethers, to the corresponding cis-2,3-
disubstituted dihydropyran-4-ones with improved dias-
tereocontrol. The advantage of this approach is the
ability to isolate and further functionalize the triisopro-
pylsilyl enol ethers 2, making this method for dihydro-
pyran ring construction particularly attractive for target
directed synthesis.12-14
(2R*,3R*)-3-Met h yl]-2-[(E)-2-p h en ylet h en yl]-4-[(t r iiso-
p r op ylsilyl)oxy]-2,3-d ih yd r op yr a n (2e). Method B: Internal
Quench Protocol. trans-Cinnamaldehyde (0.134 g, 1.01 mmol)
and the (triisopropylsilyl)oxy diene 1 (0.266 g, 1.11 mmol) were
dissolved in anhydrous toluene (5 mL, freshly distilled from
CaH2) and cooled with stirring to -40 °C under an atmosphere
of argon. Dimethylaluminum chloride (150 µL, 0.15 mmol) was
added to the colorless solution and the resulting pale yellow
solution stirred for an additional ca. 3.5 h (TLC control). The
reaction was quenched, worked-up, and purified as above to
Exp er im en ta l Section
Gen er a l. The chemical shifts of the 1H-NMR and 13C-NMR
spectra were all recorded relative to chloroform or benzene.
Multiplicities were determined with the aid of an APT sequence,
separating methylene and quaternary carbons ) e (even), from

7602 J . Org. Chem., Vol. 61, No. 21, 1996
Notes
Ta ble 2. Syn th esis of 4-[(Tr iisop r op ylsilyl)oxy]d ih yd r op yr a n s 2a -f a n d Th eir Con ver sion to 2,3-Disu bstitu ted
Dih yd r op yr a n -4-on es 4a -f
afford the dihydropyran 2e (0.358 g, 93%) as a colorless oil: IR
(CDCl3) 2946 (s), 2893 (m), 2868 (s), 1670 (m) cm-1 1H NMR
(250 MHz, CDCl3) δ 7.41-7.18 (m, 5H), 6.63 (A of AB, J AB
16.1 Hz, 1H), 6.21 (ABX, J AB ) 16.1, J BX ) 5.6 Hz, 1H), 4.73 (t,
J ) 2.7 Hz, 1H), 4.30-4.24 (m, 3H), 2.15-2.11 (m, 1H), 1.22-
0.98 (m, 24H); 13C NMR (62.5 MHz, CDCl3) δ 153.02 (e), 137.12
(e), 130.43 (o), 128.52 (o), 128.28 (o), 127.44 (o), 126.42 (o), 99.09
(o), 77.68 (o), 64.87 (e), 39.20 (o), 18.04 (o), 12.67 (o); HRMS (EI)
for C23H36O2Si, calcd 372.2485, found 372.2485.
Gen er a l P r oced u r e for th e Deh yd r ogen a tion of Tr iiso-
p r op ylsilyl E n ol E t h er s t o Dih yd r op yr a n -4-on es. (2R*,
3R*)-3-Meth yl-2-((E)-2-p h en yleth en yl)-2,3-d ih yd r o-4H-p y-
r a n -4-on e8e (4e). The triisopropylsilyl enol ether 2e (0.379 g,
1.02 mmol) was dissolved in anhydrous dimethylformamide (10
mL) and cooled with stirring to 0 °C under a nitrogen atmo-
sphere. Ceric ammonium nitrate (2.183 g, 3.98 mmol) was then
added portionwise over ca. 30 min. The resulting bright orange
solution was then stirred for an additional 3 h (TLC control).
The reaction mixture was then poured into water and extracted
with diethyl ether. The combined organic phases were washed
with saturated NaHCO3 solution, saturated NaCl solution, dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo to
afford a pale yellow oil. Purification by flash chromatography
;
on silica gel (eluting with 10% and then 30% ethyl acetate in
hexane) furnished the cis-2,3-disubstituted dihydropyran-4-one
4e (0.199 g, 91%) as a colorless oil.
)
Ack n ow led gm en t. We thank the University of
Delaware Research Foundation and the Donors of the
Petroleum Research Foundation, administered by the
American Chemical Society, for generous financial sup-
port. Dr. Keith Russell is also thanked for stimulating
discussions.
Su p p or tin g In for m a tion Ava ila ble: Full characteriza-
tion for compounds 2b,c, 2/3d , 2f, 3a /b, and 4a -f, in addition
to the 1H-NMR spectra for compounds 1, 2a -f, 3a /b, and 4a -f
(19 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O961325U