Facile One-Step Synthesis of β-Alkoxy Lactone via Sequential Lactonization and 1,4-Addition of Alkoxide Group: Total Synthesis of All Stereoisomers of Dihydrokawain-5-ol

Article abstract of DOI:10.1021/jo049858n

We describe here a divergent total synthesis of all of the four stereoisomers of dihydrokawain-5-ol starting from α-D-glucose. The approach involves the use of Ando's modification of Horner-Wadsworth-Emmons homologation to give a α,β-unsaturated ester. Subsequently, lactonization and 1,4-addition of OMe group in one step provided a γ-lactone, which was converted into the target compounds in two steps.

Full text of DOI:10.1021/jo049858n

F a cile On e-Step Syn th esis of â-Alk oxy La cton e via Sequ en tia l
La cton iza tion a n d 1,4-Ad d ition of Alk oxid e Gr ou p : Tota l
Syn th esis of All Ster eoisom er s of Dih yd r ok a w a in -5-ol†
Ravi P. Singh and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
vinodks@iitk.ac.in
Received J anuary 25, 2004
We describe here a divergent total synthesis of all of the four stereoisomers of dihydrokawain-5-ol
starting from R-D-glucose. The approach involves the use of Ando’s modification of Horner-
Wadsworth-Emmons homologation to give a R,â-unsaturated ester. Subsequently, lactonization
and 1,4-addition of OMe group in one step provided a δ-lactone, which was converted into the target
compounds in two steps.
In tr od u ction
(+)-Dihydrokawain-5-ol 1a , a unique 6-alkyl-5-hy-
droxy-5,6-dihydropyran-2-one, was isolated from the
methanol extracts of the kava plant (Piper mythisticum),
a Polynesian shrub of the Pepper family.1 The extract of
roots and stem of these plants are utilized in folk
medicine and in the preparation of a traditional ceremo-
nial beverage.2 The dihydropyran moiety is a frequently
encountered substructure in natural products (Figure 1).3
This and other kava constituents having an R-pyrone or
dihydropyrone skeleton such as (+)-kawain 2, methisticin
3, yangonin 4, and dihydrokawain 5 have attracted
considerable interest from the pharmaceutical industry
because of their sedative, anxiolytic, and analgesic prop-
erties.4
The absolute configuration (5R,6S) in (+)-dihydro-
kawain-5-ol 1a was suggested by its synthesis through
SeO2 allylic oxidation of (+)-dihydrokawain 5, derived
from kawain 2.5 The interesting structural properties,
especially the presence of oxygen substituents at both the
C5 and C6 positions on the pyranone scaffold and the
syn relationship between the oxygens at C5/C6, make
dihydrokawain-5-ol an attractive and challenging syn-
thetic target.6 The C5 hydroxyl group in 1a makes the
molecule susceptible to rearrangement to furanone under
basic condition.7 It is surprising to note that so far only
one asymmetric synthesis of (+)-dihydrokawain-5-ol 1a
has been reported8 in the literature, and there is no
F IGURE 1.
report for the synthesis of its other stereoisomers.9 As a
part of our continuing interest in the synthesis of natural
products having δ-lactone rings,10 we were interested in
the synthesis of all stereoisomers of dihydrokawain-5-
ol. In this article, we delineate our efforts on their total
synthesis from R-D-glucose, which is available in abun-
dance.11
† This paper is dedicated with respect to Professor H. Ila on her
60th birthday.
* To whom correspondence should be addressed. Fax: 91-512-259-
7436.
(7) Ha¨nsel, R.; Pelter, A.; Ayoub, M. T.; Reinhardt, R. Z. Naturforsch.
B: Anorg. Chem., Org. Chem. 1978, 33B, 1020; Chem. Abstr. 1978,
90, 22705u.
(8) Arai, Y.; Masuda, T.; Yoneda, S.; Masaki, Y.; Shiro, M. J . Org.
Chem. 2000, 65, 258.
(9) For a racemic synthesis of 1, see: Friesen, R. W.; Vanderwal, C.
J . Org. Chem. 1996, 61, 9103.
(10) (a) Raina, S.; Singh, V. K. Tetrahedron 1996, 52, 4479. (b)
Chandrasekhar, M.; Raina, S.; Singh, V. K. Tetrahedron Lett. 2000,
41, 4969. (c) Chandrasekhar, M.; Chandra, K. L.; Singh, V. K. J . Org.
Chem. 2003, 68, 4039. (d) Raina, S.; Prasad, B. A. B.; Singh, V. K.
Arkivoc 2003, vi, 16.
(1) Achenbach, H.; Wittman, G. Tetrahedron Lett. 1970, 37, 3259.
(2) Koppel, C.; Tenczer, J . J . Chromatogr. 1991, 562, 207.
(3) (a) Dickinson, J . M. Nat. Prod. Rep. 1993, 88. (b) Klohs, M. The
Chemistry of Kava; USPHS Publication 1645, USGPO: Washington,
DC, 1967; pp 126-140. (c) Achenbach, H.; Regel, W. Chem. Ber. 1973,
106, 2648.
(4) Spezialchemie, G.m.b. H. und Co. Patent DE 661220; Chem.
Abstr. 1969, 71, 3275v.
(5) Achenbach, H.; Huth, H. Tetrahedron Lett. 1974, 119.
(6) Ha¨nsel, R.; Schulz, J . Chem. Ber. 1973, 106, 570.
10.1021/jo049858n CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/20/2004
J . Org. Chem. 2004, 69, 3425-3430
3425

Singh and Singh
SCHEME 1
F IGURE 2.
Resu lts a n d Discu ssion
The retrosynthetic analysis of 1b is outlined in Figure
2. It was conceived that a â-methoxy δ-lactone type of
system could be built up from the 1,4-addition of methoxy
group on the unsaturated δ-hydroxy ester derivative 6.
Structural mapping of this subtarget was done with the
R-D-glucose derivative 7, keeping in mind the following
transformations: an addition of the side chain through
Wittig chemistry and the conversion of the acetonide to
an aldehyde for Horner-Emmons olefination reaction.
The above strategy was validated and executed success-
fully (vide infra).
The synthesis of (-)-dihydrokawainol 1b involved R-D-
pentodialdose 8, which was easily synthesized from
D-glucose using literature procedures.12 The aldehyde 8
was converted into 9b by performing Wittig olefination
with a ylid (Ph3PdCHPh) followed by hydrogenation of
the double bond. The acetonide of 9b was deprotected
with dilute sulfuric acid in dioxane to provide a hemi-
acetal 10b. Oxidative cleavage of the hemiacetal 10b with
NaIO4 led to an aldehyde 11b that was directly subjected
to Wittig olefination reaction with a stabilized ylid
(Ph3PdCHCO2Et). This gave an R,â-unsaturated ester
12 exclusively in the E-isomer (Scheme 1).
Now, what was left was to convert 12 into a δ-lactone
15b. At the outset, it appeared that it could be done in
one step by using K2CO3 in MeOH. This was based on a
proposition that under this condition methanol will add
to an R,â-unsaturated ester in a 1,4-fashion concomitant
with the formation of δ-lactone after hydrolysis of the
formate ester. There are some close precedents in the
literature where MeOH adds to alkynyl ester in a 1,4-
fashion.13,14 However, it was observed that the reaction
of 12 with K2CO3 in MeOH failed to give 15b. Instead,
transesterification of ethyl ester with MeOH along with
cleavage of the formyl ester to a hydroxy group took place
to give 13 in quantitative yield (Scheme 1). It was
expected that this trans-hydroxy ester 13 would not
lactonize because of geometrical constraint. Now, it
became logical to synthesize the (Z)-R,â-unsaturated ester
as cis-geometry would favor lactonization and then 1,4-
addition of MeOH to the R,â-unsaturated lactone is more
likely to happen. Thus, R,â-unsaturated ester 14b was
synthesized from the aldehyde 11b using Hornor-
Wadsworth-Emmons reaction under Ando’s condition.15
It was gratifying to note that a treatment of the Z-ester
14b with K2CO3 in MeOH gave the desired δ-lactone 15b
in quantitative yield. It was also observed that EtOH can
be added in this reaction if desired. However, other
higher alkoxides did not add on that pattern. On the basis
of the above results, it was postulated that 1,4-addition
of MeOH or EtOH took place after the lactonization.
The double bond in the lactonic ring of 15b was
introduced by doing phenylselenation16 with sodium
hexamethyldisilazide (NaHMDS) and trimethyl silyl
chloride (TMSCl) followed by oxidative syn elimantion.
The 16b thus obtained was treated with DDQ under
buffer condition17 to deprotect the p-methoxybenzyl (PMB)
ether group. This provided (-)-(5S,6R)-dihydrokawainol
1b in 91% yield (Scheme 2).
Once the total synthesis of 1b was achieved, we
realized that by manipulating the stereochemistry of
some of the sugar intermediates other stereoisomers of
dihydrokawainol could be synthesized. By looking at our
next target 1c, we realized that this could be done by
using the above strategy provided we can invert the
stereochemistry of OPMB ether in 9b. Thus, compound
17 was chosen as a suitable precursor for this purpose.
Hydrogenolysis of the benzyl ether in 17 gave alcohol 18,
which without any purification was oxidized under Swern
condition to give ketone 19. The reduction of ketone 19
with sodium borohydride, in which hydride will attack
(11) For use of D-glucose in synthesis, see: (a) Hanessian, S. The
Total Synthesis of Natural Products: The Chiron Approach; Pergamon
Press Ltd.: Oxford, 1983. (b) Bols, M. Carbohydrate Building Blocks;
J ohn Wiley & Sons Ltd.: New York, 1996.
(12) (a) Tronchet, J . M. J .; Grivet, C.; Grand, E.; Seman, M.; Dilda,
P. Carbohydr. Lett. 2000, 4, 5. (b) Sharma, G. V. M.; Vepachedu,
Sreenivasa Rao. Tetrahedron Lett. 1990, 31, 4931. (c) Oikawa, Y.;
Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885.
(13) (a) Carlson, R. M.; Oyler, A. R.; Tetrahedron Lett. 1974, 15,
2615. (b) Carlson, R. M.; Oyler, A. R.; Peterson, J . R. J . Org. Chem.
1975, 40, 1610.
(14) For intramolecular 1,4-addition of oxygen anion to an R,â-
unsaturated system, see: (a) Evans, D. A.; Gauchet-Prunet, J . A. J .
Org. Chem. 1993, 58, 2446. (b) O’Doherty, G. A.; Smith, C. M. Org.
Lett. 2003, 5, 1959. (c) Carreira, E. M.; Fettes, A. J . Org. Chem. 2003,
68, 9274.
(15) (a) Ando, K. J . Org. Chem. 1997, 62, 1934. (b) Ando, K. J . Org.
Chem. 1998, 63, 8411. (c) Ando, K. J . Org. Chem. 1999, 64, 8406. (d)
Ando, K.; Oishi, T.; Hirama, M.; Ibuka, T. J . Org. Chem. 2000, 65,
4745.
(16) (a) Imanishi, T.; Miyashita, K.; Ikejiri, M.; Kawasaki, H.;
Maemura, S. Chem. Com. 2002, 742. (b) Kitahara, T.; Tachihara, T.
Tetrahedron 2003, 59, 1773.
(17) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343.
3426 J . Org. Chem., Vol. 69, No. 10, 2004

Total Synthesis of of Dihydrokawain-5-ol
SCHEME 2
SCHEME 4
SCHEME 3
corresponding triflate. The reaction of the olefin with a
hindered boron reagent such as disiamylborane (Sia2BH)
followed by oxidation with basic hydrogen peroxide gave
alcohol 22 as an exclusive product. As expected, the
hydroboration took place from the top face of the ole-
fin.18,19 The hydroxyl group in 22 was protected as a PMB
ether to give 9d in which stereochemistry of the alkyl
side chain is opposite to that of 9b. Following the similar
sequence of reactions, synthesis of 1d was completed
(Scheme 3).
After successful synthesis of all the unnatural stereo-
isomers, we decided to complete the synthesis of natural
dihydrokawainol 1a by inverting the stereochemistry of
hydroxyl group in 22. This was achieved by reducing the
corresponding ketone 19a with sodium borohydride
where the hydride approached the ketone exclusively
from the top face. The alcohol, without any purification,
was converted into PMB ether 9a . Once 9a was in hand,
it was transformed into the natural 1a using the similar
sequence of reactions (Scheme 5).
In conclusion, we have completed total synthesis of all
stereoisomers of dihydrokawainol from R-D-glucose in an
efficient manner. The synthetic strategy focused on
lactonization followed by 1,4-addition of OMe group in
one step. The simplicity of the reactions with good yields
provided elegance to the synthesis.
the ketone from the top face, provided an alcohol as a
sole product, which was protected as PMB ether. Thus
9c was obtained in high yield in which the stereochem-
istry of the OPMB ether was opposite to that of 9b. Now,
using a similar sequence of reactions as described above,
we were able to synthesize 1c in an efficient manner
(Scheme 3). By looking at the stereochemistry of 1d , it
was obvious that this could be synthesized if the orienta-
tion of the alkyl side chain in 9b was changed. This was
done nicely by taking the alcohol 18 as a precursor. It
was converted into olefin 21 by elimination of the
(18) (a) Zweifel, G.; Brown, H. C. Org. Synth. 1972, 52, 59. (b) Brown,
H. C.; Desai, M. C.; J adhav, P. K. J . Org. Chem. 1982, 47, 5065.
(19) For hydroboration on a similar system, see: Kang, S.-K.; Cho,
H.-S.; Sim, H.-S.; Kim, B.-K. J . Carbohydr. Chem. 1992, 11, 807.
J . Org. Chem, Vol. 69, No. 10, 2004 3427

Singh and Singh
washed with water and brine, dried over Na2SO4, and con-
centrated. The crude reaction mixture was chromatographed
over silica gel to give 0.95 g (74% yield based on recovered
SCHEME 5
9b) of hemiacetal 10b as a white solid: mp 72 °C; [R]25 +12
D
(c 0.50, CHCl3); IR (KBr, cm-1) 3550, 2990, 1100; 1H NMR
(CDCl3, 400 MHz) δ 1.85-2.03 (m, 2H), 2.53-2.80 (m, 3H),
3.59 (m, 1H), 3.79 (s, 3H), 3.81-3.83 (m, 1H) 4.21-4.26 (m,
2H) 4.52 (ABq, J ) 11.48 Hz, ∆ν ) 73.48 Hz, 2H) 5.51 (m,
1H), 6.85-6.90 (m, 2H), 7.15-7.19 (m, 3H), 7.22-7.30 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ 30.6, 32.2, 55.3, 71.4, 75.7, 78.4,
83.3, 95.6, 113.8, 114.0, 125.8, 128.3, 128.4, 128.4, 129.4, 129.7,
141.8, 159.4; MS (FAB) 345 (M+ + 1). Anal. Calcd for
C
20H24O5: C, 69.75; H, 6.99. Found: C, 69.89; H, 6.92.
(2S,3R)-2-(4-Meth oxyben zyloxy)-3-for m yloxy-5-p h en -
yl-1-p en ta n a l (11b). A solution of 10b (0.69 g, 2 mmol) in
MeOH (40 mL) was treated with 0.6 N NaIO4 aqueous solution
(51 mL). The reaction mixture was stirred at room temperature
for 1 h and then concentrated on rotary evaparator. After the
reaction mixture was diluted with H2O (10 mL), it was
extracted with CH2Cl2 (few times). The organic layers were
combined, washed with brine, and dried with Na2SO4. The
solvent was removed in vacuo, and the residue was chromato-
graphed over silica gel to give aldehyde 11b as a yellow liquid
(0.68 g, 98% yield): [R]25-20 (c 0.65, CHCl3); IR (thin film,
D
cm-1) 3059, 2934, 2837,1723, 1174; 1H NMR (CDCl3, 400 MHz)
δ 1.97-2.10 (m, 2H), 2.44-2.52 (m, 1H), 2.58-2.66 (m, 1H),
3.67-3.86 (m, 4H), 4.60 (ABq, J ) 11.72 Hz, ∆ν ) 75.32 Hz,
2H), 5.21-5.30 (m, 1H), 6.83-6.90 (m, 2H), 7.10-7.30 (m, 7H),
8.05 (s, 1H), 9.60 (d, J ) 1.2 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 31.4, 31.6, 55.2, 71.9, 73.0, 82.3, 114.0, 126.2, 128.3,
128.4, 128.4, 128.5, 130.1, 140.3, 160.2, 201.0; MS (FAB) 343
(M+ + 1). Anal. Calcd for C20H22O5: C, 70.16; H, 6.43. Found:
C, 69.98; H, 6.56.
(4R,5R)-E t h yl,4-(4-m et h oxyb en zyloxy)-5-(for m id oh y-
d r oxy)-7-p h en yl-(2E)-h ep ten oa te (12). A solution of the
aldehyde 11b (342 mg, 1 mmol) and a stabilized Wittig reagent
(696 mg, 2 mmol) in anhydrous toluene (5 mL) was refluxed
for 6 h. The reaction mixture was diluted with water and
extracted with EtOAc. It was washed with brine, dried over
Na2SO4, and concentrated. The residue was chromatographed
over silica gel to give 0.36 g (88% yield) of an oily R,â-
Exp er im en ta l Section
5,6-Did eoxy-1,2-O-isop r op ylid en e-3-O-(4-m eth oxyben -
zyl)-6-C-(p h en yl)-r-D-glu cofu r a n ose (9b). n-BuLi (1.5 M
solution in n-hexane, 40 mL) was added dropwise to a solution
of triphenylphosphonium benzyl bromide (23.9 g, 55 mmol) in
anhydrous THF (200 mL) at 0 °C and allowed to stir for 15
min. Then, a solution of the aldehyde 8 (13.8 g, 50 mmol) in
anhydrous THF (50 mL) was added, and the mixture was
stirred at room temperature for 6 h. The reaction mixture was
quenched with water and filtered through Celite. The filtrate
was concentrated by evaporation and taken into ethyl acetate.
It was washed with water and brine and dried over Na2SO4.
After concentration on a rotary evaporator, the crude reaction
mixture was purified over silica gel to provide pure alkene (18
g), which was hydrogenated (10% Pd/C, 500 mg) in EtOH at 1
atm pressure for 6 h. It was filtered through Celite, and the
filtrate was concentrated to give pure saturated furanose 9b
unsaturated E-ester 12: [R]25 -32.3 (c 1.88, CHCl3); IR (thin
D
film, cm-1) 2934, 2359, 1723, 1175; 1H NMR (CDCl3, 400 MHz)
δ 1.30 (t, J ) 7.08 Hz, 3H), 1.84-2.00 (m, 2H), 2.48-2.55 (m,
1H), 2.60-2.68 (m, 1H), 3.80 (s, 3H), 4.05-4.08 (m, 1H), 4.21
(q, J ) 7.08 Hz, 2H), 4.44 (ABq, J ) 11.72 Hz, ∆ν ) 94.34 Hz,
2H), 5.07 (quintet, J ) 4.4 Hz, 1H), 6.08 (dd, J ) 15.88, 1.24
Hz, 1H), 6.78-6.88 (m, 3H), 7.11-7.29 (m, 7H), 8.10 (s, 1H);
13C NMR (CDCl3, 100 MHz) δ 14.2, 31.3, 31.5, 55.2, 60.7, 71.3,
73.8, 77.3, 113.9, 124.5, 126.1, 128.3, 128.4, 129.2, 129.6, 140.7,
143.1, 159.4, 160.6, 165.7; MS (FAB) 413 (M+ + 1). Anal. Calcd
for C24H28O6: C, 69.90; H, 6.79; Found: C, 69.98; H, 6.81.
(4R,5R)-Met h yl,4-(4-m et h oxyb en zyloxy)-5-(h yd r oxy)-
7-p h en yl-(2E)-h ep ten oa te (13). A solution of compound 12
(121 mg, 0.29 mmol) in MeOH (2 mL) was treated with K2-
CO3 (50 mg, 0.35 mmol) at 0 °C for 1 h. The reaction mixture
was quenched with 2 N HCl (3 mL) and concentrated on a
rotary evaporator. The crude residue was taken into EtOAc,
washed with water and brine, and dried with Na2SO4. The
solvent was removed in vacuo, and the crude reaction mixture
was chromatographed over silica gel to give 101 mg (yield 95%)
of R,â-unsaturated δ-hydroxy E-ester 13 as an oil: [R]25D -32.3
(c 1.88, CHCl3); IR (thin film, cm-1) 3488, 2947, 1722, 1513,
(17.9 g, 95% yield) as an oil: [R]25 -37.2 (c 4.53, CHCl3); IR
D
(thin film, cm-1) 2934, 2890, 1173; 1H NMR (CDCl3, 400 MHz)
δ 1.24 (s, 3H), 1.37 (s, 3H,), 1.77-1.86 (m, 1H), 1.98-2.06 (m,
1H), 2.45-2.52 (m, 1H), 2.59-2.66 (m, 1H) 3.66 (d, J ) 3.16
Hz, 1H), 3.71 (s, 3H), 4.02-4.07 (m, 1H), 4.41 (ABq, J ) 11.68
Hz, ∆ν ) 97.4 Hz, 2H) 4.53 (d, J ) 3.92 Hz, 1H), 5.84 (d, J )
3.92 Hz, 1H), 6.77-6.83 (m, 2H), 7.08-7.13 (m, 3H), 7.16-
7.21 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 26.3, 26.6, 29.5,
32.3, 55.3, 71.3, 79.5, 81.4, 82.3, 104.6, 111.2, 113.8, 125.8,
128.3, 128.4, 129.4, 129.6, 141.7, 159.4; MS (FAB) 385 (M+
1). Anal. Calcd for C23H28O5: C, 71.79; H, 7.29. Found: C,
71.75; H, 7.36.
5,6-Did eoxy-1,2-O-d ih yd r oxy3-O-(4-m eth oxyben zyl)-6-
C-(p h en yl)-r-D-glu cofu r a n ose (10b). A solution of the ac-
etonide 9b (1.54 g, 4.0 mmol) in dioxane (10 mL) was treated
with 0.4% H2SO4 (13 mL) at 50 °C for 2 h. The reaction mixture
was neutralized with solid Na2CO3 and then concentrated to
a residue, which was taken into EtOAc. The organic layer was
+
1
1249; H NMR (CDCl3, 400 MHz) δ 1.53 (bs, 1H), 1.62-1.68
(m, 2H), 2.52-2.59 (m, 1H), 2.72-2.79 (m, 1H), 3.49 (q, J )
6.36 Hz, 1H), 3.69 (s, 3H), 3.70-3.72 (m, 1H), 3.73 (s, 3H),
4.35 (ABq, J ) 11.00 Hz, ∆ν ) 115.08 Hz, 2H), 5.98 (d, J )
15.88 Hz, 1H), 6.74 (dd, J ) 15.88, 7.08 Hz, 1H), 6.80-6.82
(m, 2H), 7.08-7.21 (m, 7H); 13C NMR (CDCl3, 100 MHz) δ 31.7,
34.4, 51.8, 55.3, 71.1, 72.5, 81.5, 113.9, 124.3, 125.8, 128.3,
128.5, 129.3, 129.7, 141.7, 144.6, 159.5, 166.1; MS (FAB) 371
3428 J . Org. Chem., Vol. 69, No. 10, 2004

Total Synthesis of of Dihydrokawain-5-ol
(M+ + 1). Anal. Calcd for C22H26O5: C, 71.35; H, 7.03. Found:
(m, 1H), 2.62-2.69 (m, 1H), 2.74-2.81 (m, 1H), 3.69 (dd, J )
1.72, 0.72 Hz, 1H), 3.75 (s, 3H), 3.79 (s, 3H), 4.16-4.20 (m,
1H), 4.56 (Abq, J ) 11.44 Hz, ∆ν ) 75.7 Hz, 2H), 5.20 (s, 1H),
6.85-6.88 (m, 2H), 7.14-7.29 (m, 7H); 13CNMR (CDCl3, 100
MHz) δ 30.8, 31.2, 55.2, 56.0, 70.7, 72.0, 78.0, 92.3, 113.7,
126.0, 128.5, 129.2, 129.7, 140.8, 159.4, 166.1, 171.8; MS (FAB)
369 (M+ + 1). Anal. Calcd for C22H24O5: C, 71.74; H, 6.52.
Found: C, 71.66; H, 6.67.
C, 71.38; H, 7.00.
(4R,5R)-E t h yl,4-(4-m et h oxyb en zyloxy)-5-(for m id oh y-
d r oxy)-7-p h en yl-(2Z)-h ep ten oa te (14b). To a suspension of
NaH (65 mg, 60% dispersion in oil, 2.7 mmol) in anhydrous
THF (4.5 mL) was slowly added a solution of phosphonoacetate
(480 mg, 1 mmol) in anhydrous THF (1.5 mL) at -78 °C under
an argon atmosphere. The reaction mixture was stirred for
15 min at the same temperature. Then, a solution of the
aldehyde 11b (492 mg, 1.44 mmol) in THF (1.5 mL) was slowly
added, and the reaction mixture was stirred at -78 °C for 40
min. It was then brought to -35 °C and quenched with
aqueous NH4Cl solution. The reaction mixture was extracted
with CH2Cl2. The organic layer was washed with water and
brine. It was dried over Na2SO4 and concentrated. The crude
residue was chromatographed over silica gel to give R,â-
unsaturated Z-ester 14b as an oil (420 mg, 78% yield based
(-)-(5S,6R)-Dih yd r ok a w a in -5-ol (1b). A solution of 16b
(64.2 mg, 0.17 mmol) was treated with DDQ (59.4 mg, 0.26
mmol) in CH2Cl2-phosphate buffer (10:1, 8 mL) at room
temperature. The reaction mixture was stirred vigorously for
4 h and quenched with an aqueous saturated sodium hydrogen
carbonate (15 mL). The aqueous layer was extracted with CH2-
Cl2. The organic phase was washed with brine and dried over
anhydrous Na2SO4. The solvent was removed on a rotary
evaporator, and the crude mixture was chromatographed over
silica gel to give 39.2 mg (91% yield) of lactone 1b as a yellow
on recovered starting material): [R]25 -10.9 (c 0.66, CHCl3);
D
liquid: [R]25 -66.3 (c 1.02, CHCl3); IR (thin film, cm-1) 3387,
IR (thin film, cm-1) 2934, 2865, 1721, 1649; H NMR (CDCl3,
1
D
1
2943, 1696, 1633, 1230; H NMR (CDCl3, 400 MHz) δ 1.95-
400 MHz) δ 1.26 (t, J ) 7.08 Hz, 3H), 1.95-2.03 (m, 2H), 2.46-
2.53 (m, 1H), 2.60-2.68 (m, 1H), 3.77 (s, 3H), 4.15 (q, J ) 7.08
Hz, 2H), 4.43 (ABq, J ) 11.48 Hz, ∆ν ) 90.08 Hz, 2H), 5.12-
5.16 (m, 1H), 5.23 (dd, J ) 9.6, 4.12 Hz, 1H), 5.97 (d, J ) 11.96
Hz, 1H), 6.14 (m, 1H), 6.84 (d, J ) 8.04 Hz, 2H), 7.10-7.27
(m, 7H), 8.08 (s, 1H); 13C NMR (CDCl3, 400 MHz) δ 14.1, 31.4,
31.8, 55.1, 60.4, 71.2, 73.6, 75.0, 113.7, 123.5, 125.9, 128.3,
128.3, 129.6, 129.7, 141.0, 146.1, 159.3, 160.7, 165.4; MS (FAB)
413 (M+ + 1). Anal. Calcd for C24H28O6: C, 69.79; H, 6.79;
Found: C, 69.74; H, 6.86.
2.02 (m, 1H), 2.20-2.29 (m, 1H), 2.68-2.84 (m, 2H), 3.12 (bs,
1H), 3.68 (s, 3H), 3.86 (s, 1H), 4.12-4.15 (m, 1H), 5.07 (s, 1H)
7.10-7.23 (m, 5H); 13CNMR (CDCl3, 100 MHz) δ 30.8, 31.0,
56.3, 66.0, 78.2, 91.3, 126.1, 128.5, 128.5, 140.7, 166.6, 172.6;
MS (FAB) 249 (M+ + 1). Anal. Calcd for C14H16O4: C, 67.73;
H, 6.45. Found: C, 67.98; H, 6.40.
5,6-Did eoxy-1,2-O-isop r op ylid en e-5-C-(ben zyl)-r-D-glu -
cofu r a n ose (18). A solution of benzyl-protected glucofuranose
(384 mg, 1 mmol) was hydrogenated in the presence of Pd-
(OH)2/C (150 mg, 0.1 mmol) in anhydrous THF (5 mL) at 1
atm pressure for 12 h. The reaction mixture was filtered
through Celite and concentrated to give 277 mg (99% yield) of
18 as a white solid: mp 93-94 °C; [R]25D -2.9 (c 0.93, CHCl3);
(5R,6R)-4-Meth oxy-5-(4-m eth oxyben zyloxy)-6-(1-p h en -
yleth yl)-3,4,5,6-tetr a h yd r o-4H-p yr a n -2-on e (15b). A solu-
tion of 14b (20 mg, 0.05 mmol) in MeOH (1 mL) was treated
with K2CO3 (8 mg, 0.06 mmol) at 0 °C for 1 h. The reaction
mixture was quenched with 2 N HCl (500 µL) and concentrated
on a rotary evaporator. The crude residue was taken into
EtOAc and washed with water brine, and dried with Na2SO4.
The solvent was removed in vacuo, and the crude reaction
mixture was chromatographed over silica gel to give 17.6 mg
(99% yield) of an oily lactone 15b: [R]25D +30.3 (c 1.60, CHCl3);
1
IR (thin film, cm-1) 3557, 2988, 1453, 1265; H NMR (CDCl3,
400 MHz) δ 1.33 (s, 3H), 1.53 (s, 3H), 1.89-1.98 (m, 2H), 2.09-
2.18 (m, 1H), 2.66-2.73 (m, 1H), 2.82-2.89 (m, 1H), 3.91-
3.96 (m, 1H), 4.10 (s, 1H), 4.52 (d J ) 4.16 Hz, 1H), 5.92 (d, J
) 3.88 Hz, 1H), 7.16-7.30 (m, 5H); 13CNMR (CDCl3, 100 MHz)
δ 26.2, 26.5, 29.4, 32.2, 75.4, 79.5, 85.3, 104.1, 111.5, 126.1,
128.4, 128.4, 141.4; MS (FAB) 265 (M+ + 1). Anal. Calcd for
1
IR (thin film, cm-1) 2921, 1725, 1510, 1245; H NMR (CDCl3,
C
15H20O4: C, 68.18; H, 7.57. Found: C, 68.11; H, 7.71.
400 MHz) δ 1.78-1.87 (m, 1H), 2.18-2.27 (m, 1H), 2.57-2.65
(m, 2H), 2.78-2.87 (m, 2H), 3.31 (s, 3H), 3.50-3.52 (m, 1H),
3.68-3.71 (m, 1H), 3.80 (s, 3H), 4.45-4,50 (m, 1H), 4.57 (ABq,
J ) 11.48 Hz, ∆ν ) 40.76 Hz, 2H), 6.87 (d, J ) 8.28 Hz, 2H),
7.15-7.30 (m, 7H); 13C NMR (CDCl3, 100 MHz) δ 31.3, 31.9,
32.3, 55.3, 56.7, 72.0, 72.6, 73.8, 113.9, 126.0, 128.4, 129.2,
129.5, 141.1, 159.4, 169.6; MS (FAB) 371 (M+ + 1). Anal. Calcd
for C22H26O5: C, 71.35; H, 7.02; Found: C, 71.49; H, 6.96.
5,6-Did eoxy-1,2-O-isop r op ylid en e-3-ca r bon yl-5-C-(ben -
zyl)-r-D-a llofu r a n ose (19). A solution of oxalyl chloride (0.26
mL, 3.0 mmol) was cautiously treated with DMSO (0.43 mL,
6 mmol) in CH2Cl2 (20 mL) at -78 °C under a nitrogen
atmosphere. To this solution was added a solution of the
alcohol 18 (556 mg, 2 mmol) in CH2Cl2 (10 mL). After the
reaction mixture was stirred for 2 h at -78 °C, Et3N (500 µL)
was added, and the resulting reaction mixture was allowed to
come to 0 °C. The reaction mixture was diluted with phosphate
buffer (30 mL) and then extracted with Et2O. The organic layer
was washed with brine, dried over anhydrous Na2SO4, and
concentrated. The crude mixture was chromatographed over
silica gel to give 512 mg (93% yield) of ketofuranose 19 as a
(5S,6R)-4-Meth oxy-5-(4-m eth oxyben zyloxy)-6-(1-p h en -
yleth yl)-5,6-d ih yd r o-2H-p yr a n -2-on e (16b). NaHMDS (1.2
mL of 2 M solution in THF, 2.23 mmol) was slowly added to a
solution of the compound 15b (687 mg, 1.86 mmol) in THF
(10 mL) at -78 °C over 30 min, and stirring was continued
for 30 min at the same temperature. TMSCl (0.47 mL, 3.71
mmol) was then added over a period of 15 min, and the
reaction mixture was stirred for the next 1 h. PhSeBr
(prepared from 2 mmol of PhSeSePh and Br2) was slowly added
under an argon atmosphere, and the whole mixture was stirred
for 1.5 h. It was quenched with water and extracted with CH2-
Cl2. The organic layer was washed with water and brine and
dried. Solvent removal and quick filtration over silica gel
provided 670 mg of R-selenyl lactone, which was taken in THF/
EtOAc (1:1, 10 mL). This was treated with NaHCO3 (312 mg,
3.9 mmol) followed by slow addition of 30% H2O2 (730 µL, 3.12
mmol) at 0 °C. The reaction mixture was stirred at room
temperature for 1.5 h, diluted with some water, and extracted
with Et2O. The organic phase was washed with brine and dried
over anhydrous Na2SO4. The solvent was removed on a rotary
evaporator, and the crude mixture was chromatographed over
silica gel to give 432 mg (65% yield) of lactone 16b as an oil:
yellow solid: mp 60-61 °C; [R]25 +120.9 (c 1.21, CHCl3); IR
D
(thin film, cm-1) 3055, 2987, 2254, 1771, 1265; 1H NMR
(CDCl3, 400 MHz) δ 1.39 (s, 3H), 1.47 (s, 3H), 1.87-1.96 (m,
1H), 2.04-2.13 (m, 1H), 2.75 (t, J ) 7.56 Hz, 2H), 4.26 (d, J )
4.4 Hz, 1H), 4.34 (dd, J ) 7.32, 4.4 Hz, 1H), 6.05 (d, J ) 4.64
Hz, 1H), 7.18-7.21 (m, 3H), 7.26-7.30 (m, 2H); 13CNMR
(CDCl3, 100 MHz) δ 27.0, 27.1, 31.0, 32.2, 76.0, 76.8, 102.4,
113.8, 126.2, 128.4, 128.6, 140.5, 210.1; MS (FAB) 263 (M+
1). Anal. Calcd for C15H18O4: C, 68.78; H, 6.87. Found: C,
68.71; H, 6.84.
+
5,6-Did eoxy-1,2-O-isop r op ylid en e-3-O-(4-m eth oxyben -
zyloxy)-5-C-(ben zyl)-r-D-a llofu r a n ose (9c). A solution of 19
(442 mg, 1.6 mmol) in MeOH (180 mL) was treated with
NaBH4 (303 mg, 8 mmol) at 0 °C. The reaction mixture was
stirred for 12 h at room temperature. After the evaporation of
methanol, the crude material was diluted with water (60 mL)
and then extracted with CH2Cl2. The organic layer was dried
(Na2SO4), filtered, and concentrated. The residue was chro-
[R]25 -140.9 (c 3.27, CHCl3); IR (thin film, cm-1) 1707, 1635;
D
1H NMR (CDCl3, 400 MHz) δ 1.83-1.92 (m, 1H), 2.27-2.36
J . Org. Chem, Vol. 69, No. 10, 2004 3429

Singh and Singh
matographed over silica gel to give 440 mg of an alcohol, which
was added to a suspension of NaH (60 mg) in THF at 0 °C.
Then, p-methoxybenzylbromide (400 mg) and a catalytic
amount of tetra-butylammonium iodide was added and the
reaction mixture was stirred for 4 h (0 °C to rt) and quenched
with water. It was extracted with EtOAc, washed with water
and brine, and dried. Solvent removal and purification over
silica gel gave 9c as an oil in 528 mg (yield 96%).
mmol) in anhydrous THF (12 mL) was added 2-methyl-2-
butene (1.7 gm, 24.4 mmol) in anhydrous THF (10 mL) under
a nitrogen atmosphere at 0 °C. After the mixture was stirred
for 2 h at the same temperature, a solution of 21 (1.35 gm, 5.2
mmol) in THF (30 mL) was added dropwise. The reaction
mixture was stirred for 24 h again at room temperature. The
flask was cooled to 0 °C, and 3 N NaOH (2.6 mL) was added
to the reaction mixture. This was followed by a slow addition
of 30% H2O2 (3 mL). The reaction mixture was stirred for 1 h
at room temperature and filtered. The organic layer was
separated. The aqueous layer was extracted with ether. The
organic layers were mixed and dried (Na2SO4). Solvent removal
and chromatographic separation gave 0.63 g (65% yield based
3,5,6-Tr ideoxy-1,2-O-isopr opyliden e-r-D-er yth r o-2-ph en -
yleth -3-en ofu r a n ose (21). A solution of 18 (1.4 gm, 5 mmol)
in CH2Cl2 (70 mL) was treated with pyridine (1.5 mL) and
trifluoromethanesulfonic anhydride (1.65 mL, 10 mmol) at -10
°C. The reaction mixture was stirred at the same temperature
for 1 h and then diluted with ether (70 mL) to give a white
precipitate. It was filtered, and the filtrate was successively
washed with H2O, 5% HCl, aqueous NaHCO3 solution, and
saturated NH4Cl solution. The organic layer was dried over
Na2SO4, filtered, and concentrated to give 2.1 g of triflate,
which was taken in 50 mL of ether and then treated with DBU
(3.2 g, 21 mmol) at room temperature for 24 h. It was then
washed with water and brine and dried. The solvent was
removed, and the crude was chromatographed over silica gel
on recovered SM) of 22 as a white solid: mp 81-82 °C; [R]25
D
-42.8 (c 3.7, CHCl3); IR (thin film, cm-1) 3412, 2925, 1377; 1H
NMR (CDCl3, 400 MHz) δ 1.35 (s, 3H), 1.55 (s, 3H), 1.92-
2.01 (m, 1H), 2.11-2.21 (m, 1H), 2.68-2.76 (m, 1H), 2.84-
2.92 (m, 1H), 3.94-3.98 (m, 1H), 4.12 (d, J ) 1.48 Hz, 1H),
4.54 (d, J ) 4.16 Hz, 1H), 5.94 (d, J ) 3.92 Hz, 1H), 7.19-
7.32 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 26.1, 26.8, 32.2,
35.4, 78.8, 86.9, 87.2, 105.5, 112.5, 125.9, 128.4, 128.5, 141.4;
MS (FAB) 265 (M+ + 1). Anal. Calcd for C15H20O4: C, 68.18;
H, 7.57. Found: C, 68.41; H, 7.68.
to give 1.16 g (95% yield) of 21 as a slightly yellow oil: [R]25
D
-25.7 (c 7.0, CHCl3); IR (thin film, cm-1) 2929, 2254, 1454,
1
1245, 909; H NMR (CDCl3, 400 MHz) δ 1.42 (s, 6H), 2.43-
Ack n ow led gm en t. We thank CSIR for a research
grant and senior research fellowship to R.P.S.
2.50 (m, 2H), 2.79-2.87 (m, 2H), 4.91-4.92 (m, 1H), 5.22-
5.24 (m, 1H), 6.01 (d, J ) 5.12 Hz, 1H), 7.16-7.28 (m, 5H);
13CNMR (CDCl3, 100 MHz) δ 27.7, 28.0, 30.0, 32.0, 83.8, 97.6,
105.7, 111.7, 126.0, 128.3, 140.7, 161.7; MS (FAB) 247 (M+
1). Anal. Calcd for C15H18O3: C, 73.17; H, 7.31; Found: C,
73.01; H, 7.40.
+
Su p p or tin g In for m a tion Ava ila ble: General methods
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
5,6-Did eoxy-1,2-O-isop r op ylid en e-5-C-(ben zyl)-r-D-ga -
la ctofu r a n ose (22). To a solution of BH3‚DMS (925 µL, 12.2
J O049858N
3430 J . Org. Chem., Vol. 69, No. 10, 2004