Synthesis of 2,2-disubstituted furanoid natural products: Total synthesis of sphydrofuran

Full text of DOI:10.1021/jo9813336

J . Org. Chem. 1998, 63, 8595-8598
8595
Sch em e 1
Syn th esis of 2,2-Disu bstitu ted F u r a n oid
Na tu r a l P r od u cts: Tota l Syn th esis of
Sp h yd r ofu r a n
Romina Di Florio and Mark A. Rizzacasa*
School of Chemistry, The University of Melbourne,
Parkville, Victoria 3052, Australia
Received J uly 9, 1998
In tr od u ction
Tetrahydrofuran and γ-lactone rings are present in a
large number of natural products, which include impor-
tant biologically active compounds such as carbohydrates
and polyether antibiotics.1 Other examples of furanoid
natural products include the microbial metabolite sphy-
drofuran (1)2-4 and the γ-lactone-containing cinatrins A
(2) and C1 (3), which are inhibitors of phospholipase A2
(PLA2).5,6 PLA2 is a lipolytic enzyme that plays a crucial
role in the rate-limiting step in the biosynthesis of
proinflammatory eicosanoids such as prostaglandins, and
inhibition of this enzyme may therefore result in a
reduction of inflammatory processes. Compound 1 exists
as a complex mixture of two hemiacetals 1 and the open
chain form 1a . Although 1 possesses no significant
biological activity itself, the furan derivative (2),2,4 ob-
tained by acid treatment of 1, exhibits growth promotion
for some bacteria and viruses.
acid derivatives II that might not be accessible by simple
routes such as alkylation. The detail of this rearrange-
ment sequence is shown in Scheme 1 and is based on
work conducted by us in similar systems during our
synthetic studies on the zaragozic acids/squalestatins.8-10
Treatment of an ester such as I with base in the
presence of TMSCl with HMPA as cosolvent generates
the enolate III, which can undergo either unwanted
â-elimination to give a glycal IV or silylation to give the
silyl ketene acetal V. Intermediate V can then undergo
a facile [3.3]-sigmatropic rearrangement to form the new
carbon-carbon bond and asymmetric center. The ster-
eochemistry at the newly formed stereocenter can be
controlled to a degree by the configuration â-stereocenter
(rearrangement occurs from the â-face in the case shown
in Scheme 1), and it has already been demonstrated that
â-elimination can be avoided by careful choice of reaction
conditions and substrate.10 To test this proposal, we
selected the microbial metabolite sphydrofuran 1 as a
target. Compound 1 has been synthesized on two other
occasions, one involving a chemoenzymatic protocol11
while the route reported by Wong utilized a furan
oxidation/Michael addition sequence.12
It is envisaged that a general route to compounds such
as 1, 3, and 4 could be developed from simple ester
precursors derived from carbohydrates. The stereogenic
centers marked by an asterisk in the tetrahydrofuran
rings of each of these molecules could be set by an
Ireland-Claisen rearrangement7 of an appropriate allylic
ester I obtained from a furanose derived acid (Scheme
1). This rearrangement would generate a new asym-
metric center in each and provide access to a number of
Resu lts a n d Discu ssion
Our synthesis of 1 began with the alcohol 5, which is
readily synthesized in three steps from commercially
available 2,3,5-tri-O-benzyl-â-D-arabinofuranose (Scheme
2).13 Two-step oxidation of 5 provided the acid 6 in
excellent yield, which upon treatment with allyl alcohol
and DCC/DMAP produced ester 7. Rearrangement of 7
(1) Polyether Antiobiotics: Naturally Occurring Acid Ionophores,
Westley, J . W., Ed.; Marcel Dekker, Inc.: New York, 1982; Vols. 1 and
2.
(2) Umezawa, S.; Usui, T.; Umezawa, H.; Tsuchiya, T.; Takeuchi,
T.; Hamada, M. J . Antibiot. 1971, 24, 85.
(3) Usui, T.; Umezawa, S.; Tsuchiya, T.; Naganawa, H.; Takeuchi,
T.; Umezawa, H. J . Antibiot. 1971, 24, 93.
(4) Bindseil, K. U.; Henkel, T.; Zeeck, A.; Bur, D.; Niederer, D.;
Se´quin, U. Helv. Chim. Acta 1991, 74, 1281.
(5) Itazaki, H.; Nagashima, K.; Kawamura, Y.; Matsumoto, K.;
Nakai, H.; Terui, Y. J . Antibiot. 1992, 45, 38.
(6) Tanaka, K.; Itazaki, H.; Yoshida, T. J . Antibiot. 1992, 45, 50.
(7) Ireland, R. E.; Mueller, R. H. J . Am. Chem. Soc. 1972, 94, 5897.
Review: Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 17.
(8) McVinish, L. M.; Rizzacasa, M. A. Tetrahedron Lett. 1994, 35,
923.
(9) Gable, R. W.; McVinish, L. M.; Rizzacasa, M. A. Aust. J . Chem.
1994, 47, 1537.
(10) Mann, R. K.; Parsons, J . G.; Rizzacasa, M. A. J . Chem. Soc.,
Perkin Trans 1 1998, 1283.
(11) Maliakel, B. P.; Schmid, W. Tetrahedron Lett. 1992, 33, 3297.
Maliakel, B. P.; Schmid, W. J . Carbohydr. Chem. 1993, 12, 415.
(12) Yu, P.; Yang, Y.; Zhang, Z. Y.; Mak, T. C. W.; Wong, H. N. C.
J . Org. Chem. 1997, 62, 6359.
(13) Nicotra, F.; Panza, L.; Russo, G.; Zucchelli, L. J . Org. Chem.
1992, 57, 2154.
10.1021/jo9813336 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998

8596 J . Org. Chem., Vol. 63, No. 23, 1998
Notes
Sch em e 2
Sch em e 3
was effected with LDA in the presence of HMPA and
TMSCl at -100 °C to give the ester 8 as a 9:1 mixture of
diastereoisomers in good yield. Critical to the success
of this reaction was the use of the supernatant from a
centrifuged mixture (∼1:1 v/v) of TMSCl/NEt3.14 Also
important to the success of this reaction was the fact that
the relative stereochemistry between H2 and the C3
benzyloxy group was cis, which retards â-elimination by
an E2 type process. In an earlier study, we observed
substantial â-elimination upon attempted rearrangement
of a similar substrate that possessed a trans relationship
between H2 and a C3 benzyloxy group.10 The stereo-
chemistry of ester 8 was ultimately confirmed by its
conversion to known11 sphydrofuran intermediate 12.
Reductive debenzylation of the alcohol 9 derived from
ester 8 proved troublesome; however, debenzylation
proceeded smoothly when conducted on the corresponding
TIPS ether 10. Desilylation of 11 followed by acetylation
of the resulting triol gave the triacetate 12, which was
identical in all respects to the intermediate obtained by
Maliakel and Schmid11 in their synthesis of 1, thus
confirming the outcome of the rearrangement. In addi-
tion, a NOE interaction between the allylic methylene
protons and H3 was observed in the NOESY spectrum
of triacetate 12. Wacker oxidation15 of 12 to provide
sphydrofuran triacetate 14 was achieved using a catalytic
amount palladium(II) chloride in the presence of CuCl
and oxygen. In the previous synthesis of 14, a stoichio-
metric amount of palladium(II) chloride was employed,
which also gave a substantial amount of the aldehyde
13 (ratio of 14/13 is 2.7:1).11 Using a catalytic amount
of Pd(II), the ratio of 14 to 13 was increased to 5.5:1.
Treatment of 14 with a catalytic amount (0.5 mol %) of
NaOMe in methanol as described previously3,11 provided
sphydrofuran as a complex mixture of anomers and the
open chain compound 1a .
structure was assigned as the spiro epimer of 1, which
we have named “isosphydrofuran” (15). Isosphydrofuran
(15) was more stable than sphydrofuran16 and exists only
in the hemiketal forms with no open chain form detected
by NMR. Furthermore, sphydrofuran (1) isomerizes
quantitatively to spiroisomer 15 on exposure to NaOMe.
Compound 15 was further characterized by conversion
into its triacetate 16, which was different from triacetoxy
sphydrofuran (14).
The formation of 15 under basic conditions can be
explained by the sequence shown in Scheme 3 where
equilibration of sphydrofuran (1) to the thermodynami-
cally more stable isosphydrofuran (15) is achieved by a
retro-Michael/Michael addition sequence. It is notewor-
thy that the base-mediated isomerization of 1 has not
been observed previously. In the original account, which
describes the isolation of 1, the presence of an impurity
of higher Rf during isolation was noted.2 However, the
amount of this impurity increases when the solution
becomes acidic during the purification steps, and this
material was later identified as the furan 2.2,4
Initially, we employed larger amounts of NaOMe (1-2
equiv) for the deacetylation of 14, which resulted in the
rapid formation of a new compound with a higher Rf than
sphydrofuran (1). The combustion analysis and mass
spectrum of this compound revealed that it was isomeric
1
with 1, while the H and 13C NMR spectra displayed a
mixture of only two components in a ratio of ∼5:1. The
(14) For examples of the use of this silylating mixture in the
Ireland-Claisen rearrangement, see: Ireland, R. E.; Norbeck, D. W.
J . Am. Chem. Soc. 1985, 107, 3279. Paterson, I.; Hulme, A. N. J . Org.
Chem. 1995, 60, 3288. Burke, S. D.; Ng, R. A.; Morrison, J . A.; Alberti,
M. J . J . Org. Chem. 1998, 63, 3160.
(16) Sphydrofuran (1) is unstable on silica gel but could be purified
by rapid chromatography on neutral alumina. Isosphydrofuran (15)
was stable to silica gel chromatography.
(15) Tsuji, J . Synthesis 1984, 369.

Notes
In conclusion, we have achieved a synthesis of sphy-
drofuran 1 using a highly stereoselective ester-enolate
Claisen rearrangement in the presence of a â-leaving
group. The application of this methodology to the
synthesis of the more complex cinatrins is underway.
J . Org. Chem., Vol. 63, No. 23, 1998 8597
freshly distilled TMSCl (3.75 mL, 29.15 mmol) and dry NEt3
(4.02 mL, 28.84 mmol) in dry THF (49 mL) at -100 °C (liquid
N2/MeOH bath). The resulting mixture was stirred at -100 °C
for 10 min and then allowed to warm to room temperature and
left to stir overnight. The solution was cooled to 0 °C, and
aqueous NaOH (1 M, 57 mL) was added followed by ether and
water. The aqueous phase was then acidified with concentrated
HCl at 0 °C and extracted with ether. The combined organic
fractions were washed with water and brine, dried, and then
concentrated. A solution of the crude acid in ether (25 mL) was
treated with excess CH2N2, and the crude product was purified
by flash chromatography using 20% ethyl acetate/petroleum
ether as the eluent to yield 8 (2.57 g, 81%) as a pale-yellow oil
(9:1 mixture of diastereoisomers): [R]19D ) +10.3 (c 0.80, CHCl3);
Exp er im en ta l Section
1
Gen er a l. Unless otherwise stated, H NMR (300 MHz) and
proton decoupled 13C NMR spectra (75.5 MHz) were recorded
for deuteriochloroform solutions, with residual chloroform as an
internal standard. Microanalyses were carried out at the
University of Otago, Dunedin, New Zealand. Optical rotations
1
IR (film) 2947, 2870, 1737 cm-1; H NMR δ 2.73 (m, 2H), 3.72
were recorded in
a 10 cm microcell. HRMS (electrospray
ionization) (ESI) mass spectra were run on a Bruker 4.7T
BiOAPEX FTMS mass spectrometer at Monash University,
Clayton, Victoria. Flash chromatography was carried out on
Merck silica gel 60. Anhydrous THF was distilled from potas-
sium metal under a nitrogen atmosphere. All other anhydrous
solvents were purified according to standard methods. Petro-
leum ether refers to the fraction boiling between 40 and 60 °C.
2,5-An h yd r o-3,4-d i-O-ben zyl-D-lyxon ic a cid (6). To a
solution of the alcohol 513 (2.95 g, 9.40 mmol) in dry CH2Cl2 (31
mL) was added Dess-Martin periodinane (5.98 g, 14.10 mmol),
and the reaction mixture was stirred at room temperature for 3
h. Ether, saturated aqueous NaHCO3, and 1.5 M Na2S2O3 were
added, and stirring was continued until two clear layers resulted.
The aqueous layer was then extracted with ether, and the
combined organic fractions were washed with brine and dried
(MgSO4) and the solvent removed under reduced pressure. The
resulting oil was dissolved in ethanol (47 mL), and a solution of
AgNO3 (3.66 g) in H2O (5 mL) was added followed by the
dropwise addition of a solution of KOH (3.33 g) in H2O (47 mL).
The suspension was stirred for 12 h at room temperature and
then filtered through Celite, and the filter cake was washed with
aqueous 6% KOH. Most of the ethanol was removed under
reduced pressure, and the remaining aqueous solution washed
with ether, then acidified with concentrated HCl, and extracted
with ether. The combined organic fractions were washed with
saturated NaCl and dried, and the solvent was removed under
reduced pressure to give the carboxylic acid 6 (2.91 g, 97%) as a
(s, 3H), 4.00-4.08 (m, 3H), 4.29 (dd, J ) 9.6, 4.5 Hz, 1H), 4.45
(s, 2H), 4.56 (ABq, J ) 12.0 Hz, 2H), 5.07-5.13 (m, 2H), 5.82
(m, 1H), 7.26-7.35 (m, 10H); 13C NMR δ 40.3, 51.9, 71.4, 72.1,
72.8, 82.6, 87.3, 89.7, 118.5, 127.5, 127.6, 127.8, 127.9, 128.3,
128.4, 132.5, 137.3, 137.5, 171.4; MS (CI) m/z 383 (M+ + 1, 73%).
Anal. Calcd for C23H26O5: C, 72.23; H, 6.85. Found C, 72.44;
H, 6.55.
1,4-An h yd r o-2,3-d i-O-ben zyl-4-C-(p r op -2-en yl)-L-xylitol
(9). To a suspension of LiAlH4 (893 mg, 23.52 mmol) in dry ether
(70 mL) at 0 °C under an argon atmosphere was added the
methyl ester 8 (2.57 g, 6.72 mmol) in dry ether (33 mL) via
cannula. The reaction was stirred at 0 °C for 10 min then
allowed to warm to room temperature overnight, cooled to 0 °C,
and treated with aqueous NaOH (5 M) until a white precipitate
had formed. The mixture was filtered through a pad of Celite,
and the filtrate was concentrated under reduced pressure. The
residue was purified by flash chromatography with 40% ethyl
acetate/petroleum spirits as the eluent to give alcohol 9 (2.00 g,
84%) as an oil: [R]18 ) +16.1 (c 0.50, CHCl3); IR (film) 3448,
D
1
2925, 2867 cm-1; H NMR δ 2.27 (br s, 1H), 2.40 (br d, J ) 7.5
Hz, 2H), 3.68 (ABq, J ) 12.0 Hz, 2H), 3.81 (dd, J ) 9.3, 4.8 Hz,
1H), 4.06 (d, J ) 3.9 Hz, 1H), 4.13 (dd, J ) 9.3, 5.4 Hz, 1H),
4.23 (m, 1H), 4.53 (s, 2H), 4.62 (ABq, J ) 11.7 Hz, 2H), 5.03-
5.11 (m, 2H), 5.81 (m, 1H), 7.20-7.40 (m, 10H); 13C NMR δ 39.9,
65.1, 69.8, 72.0, 72.7, 84.0, 84.8, 87.6, 118.5, 127.7, 127.8, 127.9,
128.0, 128.5, 128.6, 133.2, 137.5, 137.8; MS (CI) m/z 355 (M+
1, 66%). Anal. Calcd for C22H26O4: C, 74.55; H, 7.39. Found:
C, 74.38; H, 7.31.
+
1
clear, viscous oil, which was homogeneous as determined by H
NMR spectroscopy: [R]18D ) -2.6 (c 1.28, CHCl3); IR (film) 3850,
3032, 2924, 1738 cm-1; 1H NMR δ 4.01 (d, J ) 3.3 Hz, 1H), 4.10
(dd, J ) 9.8, 3.3 Hz, 1H), 4.19 (d, J ) 9.8 Hz, 1H), 4.24 (s, 1H),
4.58 (s, 1H), 4.46 (ABq, J ) 11.7 Hz, 2H), 4.64 (ABq, J ) 11.7
Hz, 2H), 7.22-7.37 (m, 10H); 13C NMR δ 71.2, 71.9, 73.1, 80.8,
81.3, 84.8, 127.7, 127.8, 128.0, 128.1, 128.4, 128.5, 130.2, 136.9,
172.8; MS (CI) m/z 329 (M+ + 1, 22%); HRMS (ESI) calcd for
C19H20O5Na (M + Na+) 351.1209, found 351.1195.
1,4-An h yd r o-2,3-d i-O-b en zyl-4-C-(p r op -2-en yl)-5-O-t r i-
isop r op ylsilyl-L-xylitol (10). To a solution of the alcohol 9 (875
mg, 2.47 mmol) and 2,6-lutidine (489 µL, 4.20 mmol) in dry CH2-
Cl2 (37 mL) was added triisopropylsilyl trifluoromethane-
sulfonate (863 µL, 3.21 mmol) at 0 °C under argon, and the
reaction was stirred at 0 °C for 1.5 h and then quenched with
saturated aqueous NaHCO3. The mixture was extracted with
ether, and the combined organic fractions were washed with cold
5% aqueous HCl (10 mL), water, saturated NaHCO3, and
saturated NaCl and dried (MgSO4), and the solvent removed
under reduced pressure. Purification by flash chromatography
using 5% ethyl acetate/petroleum ether as the eluent afforded
the ether 10 (1.23 g, 98%) as a pale-yellow oil: [R]19D ) -10.8 (c
P r op -2-en yl 2,5-An h yd r o-3,4-d i-O-ben zyl-D-lyxon a te (7).
To a stirred solution of the acid 6 (3.23 g, 9.85 mmol) in dry
CH2Cl2 (26 mL) at 0 °C was added allyl alcohol (775 µL, 11.82
mmol), DMAP (120 mg, 0.98 mmol) and DCC (2.24 g, 10.86
mmol). The resulting white suspension was stirred for 1 h, then
diluted with petroleum ether, and filtered through a pad of
Celite. The filtrate was washed with 10% aqueous HCl,
saturated NaHCO3, and brine, dried, and concentrated. Puri-
fication of the crude product by flash chromatography using 30%
ethyl acetate/petroleum ether as the eluent gave the allyl ester
0.4, CHCl3); IR (film) 3029, 1462 cm-1 1H NMR δ 1.03-1.08
;
(m, 21H), 2.41 (m, 2H), 3.75 (dd, J ) 9.3, 4.5 Hz, 1H), 3.76 (ABq,
J ) 10.2 Hz, 2H), 3.96 (d, J ) 3.9 Hz, 1H), 4.17 (dd, J ) 9.3, 6.3
Hz, 1H), 4.32 (m, 1H), 4.46 (s, 2H), 4.62 (ABq, J ) 12.0 Hz, 2H),
5.00-5.08 (m, 2H), 5.84 (m, 1H), 7.29-7.35 (m, 10H); 13C NMR
δ 12.0, 18.0, 38.8, 64.9, 70.4, 71.9, 72.4, 84.0, 85.6, 86.1, 117.9,
127.5, 127.6, 127.7, 128.2, 128.4, 133.9, 138.1, 138.4; MS (CI)
m/z 511 (M+ + 1, 6%). Anal. Calcd for C31H46O4Si: C, 72.90;
H, 9.08. Found C, 72.60; H, 8.66.
1,4-An h yd r o-4-C-(p r op -2-en yl)-5-O-t r iisop r op ylsilyl-L-
xylitol (11). To a blue solution of Li metal (65 mg, 9.32 mmol)
in anhydrous liquid NH3 (∼10 mL) at -78 °C was added a
solution of the dibenzyl ether 10 (476 mg, 0.93 mmol) in dry
THF (6.5 mL) via a cannula. The reaction mixture was stirred
at -78 °C for 10 min, then ether was added, and the reaction
was quenched by the slow addition of solid NH4Cl until the blue
color had dissipated. The NH3 was allowed to evaporate, and
the salts were removed by filtration through Celite. Concentra-
tion of the filtrate gave the crude product, which was purified
by silica gel chromatography with 40% ethyl acetate/petroleum
ether as the eluent to give diol 11 (282 mg, 92%) as a viscous
7 (3.04, 83%) as a clear oil: [R]21 ) +7.5 (c 1.78, CHCl3); IR
D
(film) 2874, 1754 cm-1;1H NMR δ 4.08-4.14 (m, 3H), 4.38 (t, J
) 1.8 Hz, 1H), 4.46 (s, 2H), 4.58-4.63 (m, 3H), 4.64 (ABq, J )
12.0 Hz, 2H), 5.20-5.32 (m, 2H), 5.86 (m, 1H), 7.26-7.37 (m,
10H); 13C NMR δ 65.8, 71.2, 71.8, 72.4, 81.3, 81.7, 85.7, 118.7,
127.6, 127.76, 127.82, 128.0, 128.4, 128.5, 131.6, 137.2, 137.4,
170.3; MS (CI) m/z 369 (M+ + 1, 4%). Anal. Calcd for
C22H24O5: C, 71.72; H, 6.57. Found C, 71.51; H, 6.31.
Meth yl 2,5-An h yd r o-3,4-d i-O-ben zyl-2-C-(p r op -2-en yl)-D-
xylon a te (8). A solution of n-BuLi in hexanes (2.2 M, 7.49 mL,
16.48 mmol) was added dropwise to a solution of i-Pr2NH (2.16
mL, 16.48 mmol) in dry THF (36 mL) at 0 °C under an argon
atmosphere. The resultant base solution was stirred at 0 °C
for 5 min; then it was cooled to -78 °C and added dropwise via
cannula to a solution of the ester 7 (3.04 g, 8.25 mmol), HMPA
(9.12 mL), and the supernatant from a centrifuged mixture of

8598 J . Org. Chem., Vol. 63, No. 23, 1998
Notes
oil: [R]18 ) +3.4 (c 0.26, CHCl3); IR (film) 3420, 2940 cm-1; 1H
residue was chromatographed on neutral alumina (activity I)
with 6:1:1 methanol/acetone/water as the eluent to give sphy-
drofuran (1) (58 mg, 98%). The spectroscopic data of this
D
NMR δ 1.07-1.12 (m, 21H), 2.37 (m, 2H), 3.65 (dd, J ) 9.3, 5.1
Hz, 1H), 3.80 (ABq, J ) 10.5 Hz, 2H), 4.02 (d, J ) 4.2 Hz, 1H),
4.11 (dd, J ) 9.3, 5.7 Hz, 1H), 4.32 (m, 1H), 5.10-5.17 (m, 2H),
5.87 (m, 1H); 13C NMR δ 11.8, 17.8, 40.5, 67.4, 71.3, 79.0, 84.1,
84.8, 118.8, 132.9; MS (CI) m/z 331 (M+ + 1, 24%). Anal. Calcd
for C17H34O4Si: C, 61.77; H, 10.37. Found C, 61.46; H, 10.51.
1,4-An h yd r o-2,3,5-t r i-O-a cet yl-4-C-(p r op -2-en yl)-L-xyli-
tol (12). To a solution of the diol 11 (500 mg, 1.51 mmol) in dry
THF (54 mL) was added TBAF‚3H2O (955 mg, 3.03 mmol) at 0
°C. After the mixture was stirred at 0 °C for 45 min, the solvent
was evaporated under reduced pressure and the crude product
was flash filtered through a plug of TLC grade silica with 1:8
MeOH/CH2Cl2 as the eluent. The triol was then dissolved in a
mixture of dry pyridine (15.1 mL) and acetic anhydride (7.6 mL),
and DMAP (38 mg) was added. The mixture was stirred at room
temperature overnight, and the solvents were removed under
reduced pressure to give a brown residue, which was purified
by silica gel chromatography using 40% ethyl acetate/petroleum
ether as the eluent to provide the triacetate 12 (434 mg, 93%)
compound were identical to that reported previously:3 [R]20
)
D
D
+15.9 (c 0.66, H2O), lit.2 [R]22 ) +18.0 (c 1.0, H2O), lit.4 [R]20
D
) +16.0 (c 0.5, H2O); 1H NMR (300 MHz, DMSO-d6, DMSO
internal standard) δ 1.28 (s, 3H, R- or â-anomer), 1.33 (s, 3H, R-
or â-anomer), 1.94 (br s, 1H), 1.95 (ABq, J ) 13.2 Hz, 2H, R- or
â-anomer), 2.07 (s, 3H, open chain form), 2.72 (ABq, J ) 14.4
Hz, 2H, open chain form), 3.38-4.10 (m, 6H); HRMS (ESI) calcd
for C8H14O5Na (M+Na+) 213.0739, found 213.0728.
(3R,4S,5R)-8-Meth yl-1,7-d ioxosp ir o[4,4]n on a n e-3,4,8-tr i-
ol, Isosp h yd r ofu r a n (15). To a solution of the ketone 14 (96
mg, 0.303 mmol) in dry methanol (9.6 mL) under argon was
added a solution of NaOCH3 in MeOH (25 wt %, 139 µL, 0.607
mmol). The solution stirred at room temperature for 1.5 h, the
solvent was removed under reduced pressure, and the residue
was purified by flash chromatography with 1:4 MeOH/CH2Cl2
as the eluent to afford compound 15 (45 mg, 78%) as a solid,
which was recrystallized from acetone to give needles: mp 136-
as an oil: [R]20 ) -24.0 (c 0.36, CHCl3); IR (film) 2980, 1750,
137 °C; [R]18 ) -22.6 (c 0.26, H2O); IR (KBr disk) 3346, 2974
D
D
1436 cm-1
;
1H NMR δ 2.06 (s, 3H), 2.08 (s, 6H), 2.45 (m, 2H),
cm-1; H NMR (D2O, HDO set to δ 4.80, 5:1 mixture of R- and
1
3.77 (dd, J ) 10.5, 3.9 Hz, 1H), 4.08 (ABq, J ) 11.7 Hz, 2H),
4.28 (dd, J ) 10.5, 6.0 Hz, 1H), 5.14-5.22 (m, 3H), 5.33 (d, J )
3.3 Hz, 1H), 5.79 (m, 1H); 13C NMR δ 20.7, 20.8, 20.9, 39.1, 64.0,
70.3, 78.4, 79.3, 83.7, 119.7, 131.7, 169.5, 170.2, 170.3; MS (EI)
m/z 300 (M+, 89%). Anal. Calcd for C14H20O7: C, 55.99; H, 6.71.
Found C, 55.75; H, 6.83.
â-anomers) δ 1.49 (s, 3H, R- or â-anomer), 1.53 (s, 3H, R- or
â-anomer), 2.18 (ABq, J ) 14.4 Hz, R- or â-anomer), 2.21 (ABq,
J ) 14.7 Hz, R- or â-anomer), 3.71 (s, 2H), 3.81 (s, 2H), 3.88 (m,
2H), 3.93 (d, J ) 10.5 Hz), 3.98 (dd, J ) 10.5, 2.7 Hz), 4.23 (d,
J ) 2.7 Hz), 4.33-4.40 (m, 2H), 4.36 (br s, 1H); 13C NMR (100
MHz, D2O, 1,4-dioxane external standard) δ 26.1, 27.5, 47.2,
65.0, 65.3, 73.6, 74.8, 75.5, 77.1, 88.9, 90.8, 95.1, 95.2, 107.5,
108.0; MS (EI) m/z 172 (M+ - H2O, 80%), 140 (47%), 95 (100%).
Anal. Calcd for C8H14O5: C, 50.52; H, 7.42. Found C, 50.64;
H, 7.67.
1,4-An h yd r o-2,3,5-tr i-O-a cetyl-4-C-(2-oxop r op -1-yl)-L-xy-
litol, Sp h yd r ofu r a n Tr ia ceta te (14). A mixture of palladium
chloride (20 mg, 0.11 mmol), copper chloride (75 mg, 0.76 mmol)
in DMF (2.1 mL), and water (314 µL) was stirred under an
oxygen atmosphere (balloon) for 1 h (black suspension turned
green-brown), after which time a solution of the alkene (229 mg,
0.76 mmol) in DMF (2.2 mL) and water (306 µL) was added.
The reaction was left to stir at room temperature overnight and
then heated to 45 °C for 4 h, cooled, diluted with ether, and
filtered through a pad of Celite. The solvents were evaporated
under reduced pressure to give the crude product (1H NMR
showed the presence of aldehyde 13; ratio of ketone to aldehyde,
5.5:1), which was purified by flash chromatography using 30%
acetone/petroleum ether as the eluent to provide 14 (198 mg,
82%) as a yellow oil. The spectroscopic data of this compound
1,4-An h yd r o-2,3,5-t r i-O-a cet yl-4-C-(2-oxo-p r op -1-yl)-D-
a r a bin itol, Isosp h yd r ofu r a n Tr ia ceta te (16). To isosphy-
drofuran (15) (69 mg, 0.363 mmol) was added dry pyridine (3.63
mL), acetic anhydride (1.82 mL), and DMAP (9.0 mg), and the
resultant solution was stirred at room temperature for 2 days
then quenched with saturated aqueous NaHCO3. The aqueous
phase was extracted with ethyl acetate, and the combined
organic fractions were washed with 10% aqueous HCl, saturated
aqueous NaHCO3, and brine. Removal of the solvent afforded
the crude triacetate, which was purified by flash chromatography
with 40% ethyl acetate/petroleum ether as the eluent to give
the triacetate 16 (60 mg, 53%) as a pale-yellow oil: [R]18D ) -8.6
were identical to that reported previously:3,11 [R]19 ) -29.8 (c
D
0.29, CHCl3), lit.3 [R]20 ) -30 (c 1.0, MeOH); IR (film) 1745
(c 1.45, CHCl3); IR (film) 1746 cm-1 1H NMR δ 2.03 (s, 3H),
;
D
cm-1
;
1H NMR δ 2.05 (s, 6H), 2.07 (s, 3H), 2.17 (s, 3H), 2.88
2.08 (s, 3H), 2.10 (s, 3H), 2.17 (s, 3H), 2.88 (ABq, J ) 17.1 Hz,
2H), 3.80 (dd, J ) 10.8, 3.6 Hz, 1H), 4.22 (dd, J ) 10.8, 5.7 Hz,
1H), 4.34 (ABq, J ) 11.7 Hz, 2H), 5.10 (m, 1H), 5.29 (d, J ) 1.5
Hz, 1H); 13C NMR δ 20.5, 20.8, 20.8, 30.9, 44.4, 64.0, 70.6, 78.01,
78.04, 83.6, 168.8, 169.9, 170.4, 205.2; MS (EI) m/z 316 (M+,
11.3%); HRMS (ESI) calcd for C14H20O8Na (M + Na+) 339.1056,
found 339.1033.
(ABq, J ) 16.5 Hz, 2H), 3.80 (dd, J ) 10.2, 3.3 Hz, 1H), 4.20
(ABq, J ) 12.0 Hz, 2H), 4.21 (dd, J ) 10.5, 5.7 Hz, 1H), 5.16 (m,
1H), 5.48 (d, J ) 3.0 Hz, 1H); 13C NMR δ 20.6, 20.7, 31.5, 47.2,
63.7, 70.1, 78.0, 79.5, 82.3, 169.5, 169.9, 170.1, 205.2; MS (EI)
m/z 316 (M+, 34%); HRMS (ESI) calcd for C14H20O8Na (M+Na+)
339.1056, found 339.1029.
(3R,4S,5S)-8-Meth yl-1,7-d ioxosp ir o[4,4]n on a n e-3,4,8-tr i-
ol, Sp h yd r ofu r a n (1). To a solution of the ketone 14 (98 mg,
0.310 mmol) in dry methanol (10 mL) under argon was added a
solution of NaOMe in methanol (0.05 M, 31.0 µL, 1.55 µmol).
After the solution was stirred at room temperature for 30 min,
the methanol was removed under reduced pressure and the
Ack n ow led gm en t. We thank Mr. Steven Zammit
for preliminary experiments and the Australian Re-
search Council for financial support.
J O9813336