A versatile strategy for the synthesis of 2,6-disubstituted dihydropyranones

Article abstract of DOI:10.1021/jo070346t

(Chemical Equation Presented) A concise synthesis of 2,6-disubstituted dihydropyranones was developed. This sequence is based on the Smith three-component dithiane linchpin coupling strategy. By simply switching the order of epoxide addition in the linchp

Full text of DOI:10.1021/jo070346t

SCHEME 1
A Versatile Strategy for the Synthesis of
2,6-Disubstituted Dihydropyranones
Hua Wang, Brian J. Shuhler, and Ming Xian*
Department of Chemistry, Washington State UniVersity,
Pullman, Washington 99164
mxian@wsu.edu
ReceiVed February 19, 2007
(2a and 2b, Scheme 1).7 The location of the silyl protecting
group on the coupling product can be simply orchestrated
by the order of the epoxide additions. Therefore, two 1,5-diol
derivatives (3a and 3b) can be readily prepared from the
same starting materials. Next, we expected the removal of the
dithiane group and the oxidation of the unprotected hydroxyl
to be achieved in a single step, or stepwise, to provide the
diketones 4a and 4b. Finally, deprotection of the TBS ether
and cyclization were expected to proceed in a single operation
to furnish the structurally related dihydropyranones 5a
and 5b.
A concise synthesis of 2,6-disubstituted dihydropyranones
was developed. This sequence is based on the Smith three-
component dithiane linchpin coupling strategy. By simply
switching the order of epoxide addition in the linchpin
coupling step, two analogous dihydropyranones were pre-
pared in good yield from the same starting materials. This
sequence allows for considerable flexibility in the nature of
R1 and R2 groups, which facilitates the preparation of a
diverse array of 2,6-disubstituted dihydropyranones.
To explore this sequence, we first examined the linchpin
coupling reactions (Scheme 2). When the procedure developed
by Tietze et al.8 was employed for pseudo-symmetric com-
pounds (R1 ) R2, entries 1-3), only 70-80% yields of the
products were formed, because of the incomplete silyl migration
under such conditions. This problem was solved by the addition
of 0.4 equiv of HMPA into the reaction mixture because polar
solvents such as HMPA can significantly increase the rate of
silyl migration.7 In this manner, compounds 3a-c were obtained
in almost quantitative yields. When two different epoxides were
involved in the linchpin coupling (entries 4-7), the procedure
developed by Smith7 was followed. Upon changing the order
of epoxide addition, two pairs of 1,5-diol derivatives (3d and
3e, 3f and 3g) were obtained in good yields.
2,6-Disubstituted dihydropyranones have seemingly ubiqui-
tous functionalities in many natural products. They are also
important synthetic intermediates in the synthesis of biologically
interesting molecules.1 The syntheses of dihydropyranones have
been well documented in literature. For example, hetero Diels-
Alder reactions have been used to prepare this type of
compounds in the last two decades.2 New strategies that have
been recently developed include the tandem aldol reaction/
conjugate addition3 and the oxidative cyclization of â-hydroxy-
enones with palladium(II).4 The addition of a variety of
nucleophiles to unsaturated lactones that result from the reaction
of Brassard’s diene with aldehydes has also been employed to
synthesize 2,6-disubstituted dihydropyranones.5
To synthesize diospongin B, a novel anti-osteoporotic agent,6
as well as structurally modified analogues, we outline in this
paper a versatile synthetic route to assemble 2,6-disubstituted
dihydropyranones from readily available chiral epoxides. This
route is based on the Smith protocol, that is, the three-component
linchpin coupling of silyl dithiane (1) with two epoxides
With these 1,5-diol derivatives in hand, we then turned to
investigate the stepwise preparation of diketones from these
compounds (Scheme 3). Various dithiane group removal condi-
tions were applied to compounds 3a-g.9 We were pleased to
find that HgCl2/CaCO3 in CH3CN/water was the most efficient
method to remove dithiane groups on these substrates, which
provided the desired product in excellent yield (see Supporting
Information). The resulting â-hydroxyl ketones were then
successfully converted to diketones upon treatment with Dess-
Martin periodinane (DMP). This two-step sequence provided
(1) (a) Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100, 2407. Fleming,
I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063. (b) Danishefsky, S.
J.; Biolodeau, M. T. Angew. Chem. Int. Ed. Engl. 1996, 35, 1380.
(2) (a) Jorgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 3558. Jorgensen,
K. A. Eur. J. Org. Chem. 2004, 2093. (b) Evens, P. A.; Nelson, J. D. J.
Org. Chem. 1996, 61, 7600.
(3) Gao, B.; Yu, Z. P.; Fu, Z. Y.; Feng, X. M. Tetrahedron Lett. 2006,
47, 1537.
(4) Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91.
(5) Winkler, J. D.; Oh, K. Org. Lett. 2005, 7, 2421.
(6) Yin, J.; Kouda, K.; Tezuka, Y.; Tran, Q.; Miyahara, T.; Chen, Y.;
Kadota, S. Planta Med. 2004, 70, 54.
(7) Smith, A. B., III; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.;
Sfouggatakis, C.; Moser, M. H. J. Am. Chem. Soc. 2003, 125, 14435.
(8) Tietze, L. F.; Geissler, H.; Gewert, J. A.; Jakobi, U. Synlett 1994,
511.
(9) Burghardt, T. E. J. Sulfur Chem. 2005, 26, 411.
10.1021/jo070346t CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/21/2007
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J. Org. Chem. 2007, 72, 4280-4283

SCHEME 2
SCHEME 3
the desired diketones 4a-g in good yield (72-90%, Scheme
3, method A).
to the reaction mixture to achieve the conditions reported by
Panek et al.10 However, the desired diketone 4b was obtained
only in very small amounts (10% yield) after 48 h. Most of the
ketone intermediate 5b (60%) was recovered from this reaction.
2-Iodoxybenzoic acid (IBX)11 was also used in an attempt to
achieve the one-step transformation. Again, only the ketone
intermediate was obtained. We were unable to find suitable
conditions for the removal of dithiane groups on these substrates
using DMP or IBX. Surprisingly, when 3b was treated with
excess NBS, the desired diketone 4b was obtained in 68% yield
(Scheme 4, entry 2). Unfortunately, when this protocol was
applied to other substrates, none of them gave the desired
product.
With the diketones 4a-g in hand, we turned to the last step
in the sequence. Treatment of the diketones with protic acids,
either a stoichiometric amount of TFA or catalytic amount of
p-toluenesulfonic acid (p-TsOH), resulted in deprotection of the
TBS ether, and ring cyclization took place smoothly in one step
to furnish the dihydropyranones 6a-g in outstanding yield
(Scheme 5). In general, the reaction with TFA was completed
within 2 h, while the reaction with p-TsOH required 2 or 3
days to complete, but the yields were similar.
Alternatively, diketones could also be prepared from diol
derivatives via a hydroxyl oxidation followed by removal of
the dithiane group (Scheme 3, method B). It was previously
suggested that DMP is not effective in the oxidation of hydroxyls
on dithiane-containing substrates.10 However, when our sub-
strates (3a-g) were treated with a stoichiometric amount (1.0
equiv) of freshly prepared DMP for 15 min, the corresponding
ketone products were obtained in good yield. If excess DMP
(>2.0 equiv) was added or the reaction time was prolonged
(>30 min), the yield dropped dramatically with the formation
of a significant amount of unidentified byproducts. The ketone
intermediates were then subjected to various conditions to
remove the dithiane group. Again, HgCl2/CaCO3 turned out to
be the best choice, albeit the yield was moderate (60-80%). In
general, this two-step sequence provided diketone products in
lower overall yield than the yield obtained from the dithiane
group removal/oxidation sequence (method A).
Because DMP was reported to be an efficient reagent to
remove the dithiane group10 and has the ability to oxidize the
hydroxyl groups in our substrates, we then sought conditions
that would achieve diketone formation from 1,5-diol derivatives
in one step using DMP. As shown in Scheme 4 (entry 1), after
3b was completely converted to the ketone intermediate 5b by
treatment with DMP (1.0 equiv) in pure CH3CN (reaction
monitored by TLC), CH2Cl2/H2O and more DMP were added
In summary, we have developed a concise synthetic sequence
to form 2,6-disubstituted dihydropyranones. The Smith dithiane
linchpin coupling strategy was utilized to construct 1,5-diol
derivatives as key intermediates, which provide a flexible way
(11) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem.
Soc. 2004, 126, 5192.
(10) Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 575.
J. Org. Chem, Vol. 72, No. 11, 2007 4281

SCHEME 4
was stirred and warmed to rt over 1.5 h, and the reaction was
quenched with saturated aqueous NH4Cl (1 mL). After dilution of
the mixture with Et2O, the organic layer was separated. The aqueous
phase was extracted with Et2O (3 × 10 mL), and the combined
organic layers were dried over Na2SO4, filtered, and concentrated
in vacuo. Flash chromatography (hexanes/ethyl acetate, 30:1)
provided (-)-3a (171.5 mg, 96%). [R]2D3 ) -40.8 (c 1.1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 4.36-4.26 (m, 1H), 4.21-4.13 (m,
1H), 3.92 (d, J ) 3.6 Hz, 1H), 2.87-2.73 (m, 4H), 2.44-2.22 (m,
2H), 2.14-1.94 (m, 4H), 1.25 (d, J ) 6.0 Hz, 3H), 1.19 (d, J )
6.6 Hz, 3H), 0.92 (s, 9H), 0.16 (s, 3H), 0.14 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 66.9, 64.1, 51.4, 47.1, 46.9, 26.2, 25.7, 25.1, 24.7,
18.0, -3.6, -4.2; MS (ESI) m/z 389.5, [M + K]+; HRMS (ES+)
m/z 373.1676 [(M + Na)+; calcd for C16H34O2S2SiNa: 373.1667].
General Procedure for the Conversion of Compounds 3a-g
to Compounds 4a-g (Method A). To a well-stirred solution of
(-)-3a (31 mg, 0.09 mmol) in CH3CN/H2O (4 mL/1 mL), HgCl2/
CaCO3 (72 mg, 0.26 mmol; 36 mg, 0.35 mmol) was added in one
portion. The reaction mixture was heated to 65 °C and was stirred
for 2 h. After the starting material completely disappeared
(monitored by TLC), the reaction mixture was cooled to rt. Et2O
(20 mL) was then added to the mixture, and the mixture was filtered
through celite. The filtrate was washed with water and brine and
was dried over Na2SO4. The solution was then filtered and
concentrated in vacuo. Flash chromatography (hexanes/ethyl acetate,
15:1) gave the corresponding ketone intermediate as a colorless
oil (17.5 mg, 77%). [R]D23 ) -89.7 (c 0.8, CHCl3); 1H NMR (300
MHz, CDCl3) δ 4.33-4.19 (m, 2H), 3.14 (d, J)3.0 Hz, 1H), 2.70-
2.36 (m, 4H), 1.18 (s, 3H), 1.16 (s, 3H), 0.86 (s, 9H), 0.07 (s, 3H),
0.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 212.3, 66.7, 64.6, 53.8,
53.5, 26.7, 25.1, 23.1, 18.9, -3.5, -4.0; MS (ESI) m/z 283.5, [M
+ Na]+.
SCHEME 5
The ketone intermediate (28 mg, 0.11mmol) was dissolved in
CH2Cl2 (2 mL). To this solution, DMP (50 mg, 0.12 mmol) and
NaHCO3 (84 mg, 1mmol) were added at rt. The mixture was stirred
for 15 min, and the reaction was quenched with saturated aqueous
Na2S2O3 (1 mL). The layers were separated. The aqueous phase
was extracted with Et2O (3 × 10 mL), and the combined organic
layers were dried over Na2SO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 50:1) gave (-)-4a as a
colorless oil (26 mg, 94%). [R]2D3 -99.0 (c 0.5, CHCl3); H NMR
1
(300 MHz, CDCl3) δ 5.53 (s, 1H), 4.27-4.21 (m, 1H), 2.43-2.24
(m, 2H), 2.07 (s, 3H), 1.20 (d, J ) 6.0 Hz, 3H), 0.87 (s, 10H),
0.06 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 192.6,
190.4, 101.6, 66.3, 48.3, 25.7, 25.3, 24.2, 18.0, -4.6, -5.1; MS
(ESI) m/z 281.5, [M + Na]+.
General Procedure for the Conversion of Compounds 3a-g
to Compounds 4a-g (Method B). To a well-stirred solution of
(-)-3a (30 mg, 0.09mmol) in CH2Cl2 (2 mL), DMP (40 mg, 0.09
mmol) and NaHCO3 (84 mg, 1 mmol) were added at rt. The mixture
was stirred for 10 min, and the reaction was quenched with saturated
aqueous Na2S2O3 (1 mL). The layers were separated. The aqueous
phase was extracted with Et2O (3 × 10 mL), and the combined
organic layers were dried over Na2SO4, filtered, and concentrated.
Flash chromatography (hexanes/ethyl acetate, 93:7) gave the
corresponding ketone intermediate as a colorless oil (28 mg, 93%).
to switch two groups on the C2 and the C6 positions. The
transformation from 1,5-diol intermediates to dihydropyranones
was studied in detail. This short sequence allows for consider-
able flexibility in the nature of the C2 and the C6 substitutents,
which facilitates the preparation of a diverse array of 2,6-
disubstituted dihydropyranones.
[R]2D3 -28.8 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 4.25
1
(m, 1H), 3.34 (d, J ) 15.6 Hz, 1H), 3.10 (d, J)15.6 Hz, 1H), 2.82-
2.79 (m, 4H), 2.47 (dd, J ) 7.5, 15.0 Hz, 1H), 2.23 (s, 3H), 2.16
(dd, J ) 3.3, 15.0 Hz, 1H), 2.00-1.90 (m, 2H), 1.23 (d, J ) 6.3
Hz, 3H), 0.88 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 204.6, 66.4, 51.2, 49.0, 47.1, 32.1, 26.5, 26.4, 26.0,
25.7, 24.8, 18.0, -3.9, -4.0; MS (ESI) m/z 371.5, [M + Na]+.
The ketone intermediate (28 mg, 0.08 mmol) was dissolved in
CH3CN/H2O (6 mL/2 mL). To this solution, HgCl2 (109 mg, 0.4
mmol) and CaCO3 (80 mg, 0.8 mmol) were added. The mixture
was then stirred at rt for 4 h. Et2O (20 mL) was then added to the
mixture, and the mixture was filtered through celite. The aqueous
Experimental Section
Modified Procedure for the Coupling of TBS-Dithiane with
an Excess of Epoxides. To a well-stirred solution of TBS-dithiane
1 (120 mg, 0.51 mmol) in THF (1 mL), n-BuLi was added (1.6 M
in hexane, 0.35 mL) via syringe at rt. The reaction mixture was
stirred for 10 min. Then a solution of (R)-(+)-propylene oxide (120
mg, 0.51 mmol) in THF/HMPA (35.8 mg HMPA in 0.5 mL of
THF) was added to the reaction mixture at -78 °C. The mixture
4282 J. Org. Chem., Vol. 72, No. 11, 2007

phase was extracted with Et2O (3 × 5 mL), and the combined
organic layers were dried over Na2SO4, filtered, and concentrated
in vacuo. Flash chromatography (hexanes/ethyl acetate, 50:1) gave
(-)-4a as a colorless oil (12.4 mg, 60%).
TFA was added. The mixture was stirred overnight, and the reaction
was quenched with saturated aqueous NaHCO3 (3 mL). The solution
was diluted with Et2O (10 mL), and the layers were separated. The
aqueous phase was extracted with Et2O (3 × 5 mL), and the
combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography (hexanes/ethyl acetate, 10:1)
provided (+)-6b (31 mg, 93%) as a solid. mp. 90-91.5 °C;
[R]2D3 +111.1 (c 1.0, MeOH); 1H NMR (300 MHz, CDCl3) δ 7.62
(m, 2H), 7.30 (m, 8H), 5.95 (s, 1H), 5.42 (dd, J ) 3.3, 13.8 Hz,
1H), 2.79 (dd, J ) 14.1, 17.1 Hz, 1H), 2.58 (dd, J ) 3.6, 16.8 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 192.9, 170.2, 138.2, 132.5,
131.7, 128.8, 128.7, 128.6, 126.6, 102.2, 80.9, 42.9; MS (ESI) m/z
251.4, [M + H]+, HRMS (ES+) m/z 273.0899 [(M + Na)+; calcd
for C17H14O2Na: 273.0891].
One-Step Procedure for the Preparation of (-)-4b from (-)-
3b. To a well-stirred solution of NBS (310 mg, 1.74 mmol) in 10
mL of acetone/water (97/3), a solution of (-)-3b (47.2 mg, 0.1
mmol) in acetone (1 mL) was slowly added via syringe in 20 min
at 0 °C. The mixture was stirred for 2 h at 0 °C. The reaction was
then quenched with saturated aqueous NaHSO3 (3 mL), and the
layers were separated. The aqueous phase was extracted with Et2O
(3 × 5 mL), and the organic layers were dried over Na2SO4, filtered,
and concentrated. Flash chromatography provided (-)-4b as a
colorless oil (26 mg, 68%). [R]2D3 -78.2 (c 1.0, CHCl3); H NMR
1
(300 MHz, CDCl3) δ 8.14 (m, 2H), 7.73-7.60 (m, 8H), 6.45 (s,
1H), 5.46 (dd, J ) 3.9, 9.0 Hz, 1H), 3.04 (dd, J ) 9.0, 13.5 Hz,
1H), 2.90 (dd, J ) 3.9, 13.5 Hz, 1H), 1.08 (s, 10H), 0.24 (s, 3H),
0.11 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 192.8, 184.1, 144.5,
135.0, 132.3, 128.6, 128.3, 127.0, 125.6, 98.2, 72.5, 50.8, 25.7,
18.1, -4.8, -5.3; MS (ESI) m/z 405.5, [M + Na]+; HRMS (ES+)
m/z 405.1877 [(M + Na)+; calcd for C23H30O3SiNa: 405.1862].
General Procedure for the Preparation of Dihydropyranones
6a-g from 4a-g. To a well-stirred solution of (-)-4b (50 mg,
0.13 mmol) in CH2Cl2 (4 mL), 10 µL (14.8 mg, 0.13 mmol) of
Acknowledgment. This work has been supported by the
Washington State University.
Supporting Information Available: Synthetic procedures,
characterization data of all new compounds, and 1H and 13C NMR
spectra. This material is available free of charge on the Internet at
http://pubs.acs.org.
JO070346T
J. Org. Chem, Vol. 72, No. 11, 2007 4283