A Short, Enantioselective Synthesis of the AB-Ring Substructure of the Brevetoxins via endo-Selective Alkynol Cycloisomerization

Full text of DOI:10.1021/jo970597+

6432
J . Org. Chem. 1997, 62, 6432-6435
Sch em e 1. En a n tioselective Syn th esis of Alk yn yl
Diols 16 a n d 17a
A Sh or t, En a n tioselective Syn th esis of th e
AB-Rin g Su bstr u ctu r e of th e Br evetoxin s
via en d o-Selective Alk yn ol
Cycloisom er iza tion
Mark M. Gleason and Frank E. McDonald*
Department of Chemistry, Northwestern University,
2145 Sheridan Road, Evanston, Illinois 60208-3113
Received April 2, 1997
In tr od u ction
The brevetoxin family of marine natural products is
of considerable interest due to their biological activities
as potent neurotoxins, as well as the relatively complex
polycyclic ether skeletons of these compounds.1 The
brevetoxin-type structures generally possess a trans-
syn-trans arrangement of fused cyclic ethers, except for
ring A in which the terminal alkyl substituent is anti,
as represented in the simplest member of this family,
hemibrevetoxin B (1).2 We have considered a unique
synthetic approach to hemibrevetoxin which features
cyclization of an alkynyl alcohol B to the isomeric enol
ether A (Figure 1), but this strategy requires regioselec-
tive formation of endocyclic products rather than the
kinetically favored exocyclic isomers.
a
Reagents and conditions: (a) 7, Et2O, -78 °C; then 6, -5 °C
(45%). (b) i-Pr2NEt, TMSOTf, CH2Cl2, -78 to 20 °C (70%). (c)
CeCl3‚7H2O, NaBH4, EtOH, -78 °C. (d) i-Pr2NEt, Ac2O, CH2Cl2
(82%, two steps). (e) CH2dCHOSi(t-Bu)(CH3)2, Cl2Ti(O-i-Pr)2, -40
°C (79%). (f) PPh3, Zn0, CBr4, CH2Cl2; then 12 (74%). (g) n-BuLi
(2.1 equiv), THF, -78 to 20 °C; then H2O (97%). (h) n-BuLi (2.1
equiv), THF, -78 to 20 °C; then CH3I (95%). (i) Cat. RuCl3‚3H2O,
NaIO4, EtOAc:CH3CN:H2O (3:3:1), 0 °C, 5 min (47-54%).
tions to endocyclic enol ethers 5 via vinylidene carbene
intermediates (eq 2).4 In this paper we present an
F igu r e 1. Retrosynthetic analysis of brevetoxins via alkynol
cyclization.
Riediker and Schwartz have shown that the alkynyl
alcohol 2 undergoes endocycloisomerization to give bicy-
clic dihydropyran 3 under mercury(II)-, or palladium(II)-
promoted reaction conditions (eq 1), but endocyclic regio-
selectivity is observed only when the alcohol and alkyne-
containing chains are placed in a trans-relationship on
the cyclic ring.3 We have developed mechanistically
unique group(VI)-metal-promoted procedures in which
terminal alkyne-containing alcohols 4 undergo cycliza-
enantioselective synthesis of the AB-ring substructure
of the brevetoxin natural products via the application of
alkynol cycloisomerization methodology.
Resu lts a n d Discu ssion
En a n tioselective Syn th esis of A-Rin g Alk yn yl
Diol Su bstr a tes. Compounds 16 and 17 represented
projected substrates for the AB-ring substructure of
hemibrevetoxin B and were prepared in relatively straight-
forward fashion, as shown in Scheme 1. The asymmetric
aldol reaction of aldehyde 65 and dienol borinate 76 gave
the secondary alcohol 8, which underwent cyclization/
dehydrohalogenation to afford dihydropyranone 9. The
enantiomeric excess was determined to be approximately
(1) (a) Catterall, W. A. Science 1988, 242, 50. (b) Trainer, V. L.;
Edwards, R. A.; Szmant, A. M.; Stuart, A. M.; Mende, T. J .; Baden, D.
G. In Marine Toxins: Origin, Structure, and Molecular Pharmacology;
Hall, S., Strichartz, G., Eds.; ACS Symposium Series 418; American
Chemical Society: Washington, DC, 1990; pp 166-175. (c) Shimizu,
Y. Chem. Rev. 1993, 93, 1685. (d) Garson, M. Chem. Rev. 1993, 93,
1699. (e) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897.
(2) (a) Alvarez, E.; Candenas, M.-L.; Pe´rez, R.; Ravelo, J . L.; Mart´ın,
J . D. Chem. Rev. 1995, 95, 1953. (b) Nicolaou, K. C. Angew. Chem.
Int. Ed. 1996, 35, 588. For syntheses of hemibrevetoxin B, see: (c)
Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X.-Y.;
Hwang, C.-K. J . Am. Chem. Soc. 1993, 115, 3558. (d) Kadota, I.; J ung-
Youl, P.; Koumura, N.; Pollaud, G.; Matsukawa, Y.; Yamamoto, Y.
Tetrahedron Lett. 1995, 36, 5777. (e) Morimoto, M.; Matsukura, H.;
Nakata, T. Tetrahedron Lett. 1996, 37, 6365. (f) Mori, Y.; Yaegashi,
Y.; Furukawa, H. J . Am. Chem. Soc. 1997, 119, 4557.
(4) McDonald, F. E.; Bowman, J . L. Tetrahedron Lett. 1996, 37, 4675.
(5) (a) Kanao, M.; Hashimuze, T.; Ichikawa, Y.; Irie, K.; Isoda, S. J .
Med. Chem. 1982, 25, 1358. (b) Baudouy, R.; Prince, P. Tetrahedron
1989, 45, 2067.
(6) (a) Price, C. C.; Pappalardo, J . A. J . Am. Chem. Soc. 1950, 72,
2613. (b) Paterson, I.; Smith, J . D.; Ward, R. A. Tetrahedron 1995, 51,
9413.
(3) Riediker, M.; Schwartz, J . J . Am. Chem. Soc. 1982, 104, 5842.
S0022-3263(97)00597-5 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 18, 1997 6433
Sch em e 2. En d ocycliza tion of Alk yn yl Diol 17
90% ee by NMR analyses of both diastereomeric Mosher
esters obtained from the aldol product 8. The two-carbon
side chain of the aldehyde 12 was introduced with
excellent diastereoselectivity by Cl2Ti(O-i-Pr)2-promoted
carba-Ferrier reaction7 of (tert-butyldimethylsilyloxy-
)ethene8 with the allylic acetate 11 (generated by selec-
tive 1,2-reduction9 of enone 9 and acylation). We could
not detect the minor diastereomeric allylic acetates or
1
diastereomeric aldehydes by H NMR.
Most other routes reported for synthesis of this substruc-
ture begin with the carbohydrate starting material
D-mannose2b-d and thus require considerable functional
group manipulation sequences including deoxygenation
reactions. In contrast, our approach sets one stereocenter
in an asymmetric aldol reaction, with the remaining
chiral centers arising from substrate-induced stereocon-
trol. We are currently studying reiterative applications
of metal-catalyzed alkynol endo-cyclizations to the syn-
thesis of brevetoxin-type polycyclic ether structures.
Application of the Corey-Fuchs alkynylation proce-
dure10 to aldehyde 12 afforded the alkyne products 14
and 15. Alkene dihydroxylation of 14 or 15 with osmium
tetraoxide catalysis (N-methylmorpholine N-oxide cooxi-
dant) was sluggish and provided a low yield (<20%) of
diols 16 and 17. However, the ruthenium-catalyzed
procedure developed by Shing11 was much more effective
for chemo- and stereoselective dihydroxylation of the
alkene, affording product 16 in 54% yield (69% based on
recovered 14) as a 4:1 mixture of diastereomers in only
5 min at 0 °C. Similar results were obtained with the
terminal alkyne substrate 15.
Exp er im en ta l Section
Cycliza tion Stu d ies. Reaction of the terminal alkyn-
yl diol 16 with (THF)W(CO)5 at room temperature failed
to produce the expected bicyclic oxacarbene product, and
little of the substrate 16 was recovered.12 However,
Lewis acidic reagents permitted cyclization under ther-
modynamic conditions. Reaction of the alkynyl diol 17
with mercuric trifluoroacetate provided the desired bi-
cyclic enol ether 18, albeit in only 16% yield. Treatment
of 17 with palladium(II) acetate gave a better yield of
product 18 (42%), which could be isolated in pure form
after silica gel chromatography. This reaction was
optimized by addition of acetic acid and molecular sieves
(3 Å), which exhibited rate acceleration (reaction was
complete after approximately 1 h by thin layer chroma-
tography) and an increase in the isolated yield of enol
ether 18 to 52%. Acylation of the secondary alcohol of
18 confirmed the structure of this bicyclic product
(Scheme 2).
(E,5R)-8-(Ben zyloxy)-1-ch lor o-5-h yd r oxyoct-1-en -3-on e
(8). (+)-Ipc2BCl (4.698 g, 14.65 mmol) was dissolved in dry Et2O
(29 mL) and chilled to 0 °C under N2. N,N-Diisopropylethyl-
amine (2.55 mL, 14.64 mmol) was added followed by â-chlorovi-
nyl ketone 7 (1.544 g, 14.77 mmol) via cannula in dry Et2O (5
mL). After 1.5 h at 0 °C, the mixture was chilled to -78 °C.
Aldehyde 6 (2.40 g, 13.5 mmol) was added via cannula in Et2O
(5 mL). After 1.5 h at -78 °C, the mixture was transferred to
a freezer (-5 °C) for 18 h. The mixture was warmed to 0 °C for
30 min, diluted with Et2O, and washed with 3 N HCl and
saturated NaHCO3. The aqueous layers were extracted with
Et2O and the combined organic layers were added to MeOH (17
mL) and pH 7 buffer (28 mL) at 0 °C. Hydrogen peroxide (30
wt %, 15 mL) was added and the biphasic mixture was stirred
at 0 °C for 30 min. The layers were separated, and the organic
layer was washed with 10% Na2S2O5. The aqueous layers were
extracted with Et2O, and the combined organic layers were
washed with brine, dried over Na2SO4, and concentrated. The
residue was purified by silica gel chromatography (pentane:Et2O
) 2:1) to give alcohol 8 (1.75 g, 45%). This compound is an
unstable colorless solid which appears to eliminate water upon
standing: [R]23 ) -21.8 (CHCl3, c ) 1.56); IR (thin film) 3390
D
Con clu sion
(br), 3064, 1659, 1594 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.38-
7.28 (6 H, m), 6.53 (1 H, d, J ) 13.5 Hz), 4.51 (2 H, s), 4.15-
4.07 (1 H, m), 3.52 (2 H, t, J ) 6.0 Hz), 2.67 (2 H, d J ) 6.0 Hz),
1.84-1.52 (4 H, m); 13C NMR (75 MHz, CDCl3) δ 197.1, 138.1,
137.4, 132.5, 128.2, 127.5, 127.5, 72.8, 70.0, 67.2, 47.7, 33.7, 25.8;
HRMS (EI) calcd for C15H20O3Cl [(M + H)+] 283.1101, found
283.1102.
We have accomplished a short and highly stereoselec-
tive synthesis of the AB-fused bispyran system corre-
sponding to many of the brevetoxin natural products.
(7) Mukaiyama, T. Angew. Chem. Int. Ed. Engl. 1977, 16, 817.
(8) J ung, M. E.; Blum, R. B. Tetrahedron Lett. 1977, 18, 3791.
(9) Luche, J .-L.; Gemal, A. L. J . Am. Chem. Soc. 1979, 101, 5848.
(10) (a) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3796.
(b) Romo, D.; J ohnson, D. D.; Plamondon, L.; Miwa, T.; Schreiber, S.
L. J . Org. Chem. 1992, 57, 5060.
(11) (a) Shing, T. K. M.; Tai, V. W.-F.; Tam. E. K. W. Angew. Chem.
Int. Ed. Engl. 1994, 33, 2312. (b) Shing, T. K. M.; Tam, E. K. W.; Tai,
V. W.-F.; Chung, I. H. F.; J iang, Q. Chem. Eur. J . 1996, 2, 50.
(12) We attribute the failure of this relatively general cyclization
reaction to an unfavorable conformational equilibrium in compounds
16 and 17. Although conformation i
(2R)-2-[3-(Ben zyloxy)-1-p r op yl]-2,3-d ih yd r o-4H-p yr a n -4-
on e (9). Alcohol 8 (505.9 mg, 1.789 mmol) was dissolved in dry
CH2Cl2 (3 mL) and chilled to -78 °C under N2. Addition of N,N-
diisopropylethylamine (0.25 mL, 1.4 mmol) was followed by
dropwise addition of TMSOTf (0.38 mL, 2.0 mmol). After 5 min,
the mixture was allowed to warm to 20 °C and was stirred for
1 h. The mixture was diluted with CH2Cl2 and was quenched
with saturated aqueous NaHCO3. The aqueous layer was
extracted with CH2Cl2, and the combined organic layers were
dried over Na2SO4 and concentrated. The residue was purified
by silica gel chromatography (pentane:EtOAc ) 3:1) to give 9
(318.6 mg, 70%) as a colorless oil; [R]23 ) +94.7 (CHCl3, c )
D
0.530); IR (thin film) 1675, 1596 cm-1
;
1H NMR (300 MHz,
CDCl3) δ 7.38-7.27 (6 H, m), 5.40 (1 H, d, J ) 6.9 Hz), 4.51 (2
H, s), 4.46-4.37 (1 H, m), 3.52 (2 H, t, J ) 5.4 Hz), 2.53 (1 H,
dd, J ) 17, 13 Hz), 4.42 (1 H, dd, J ) 16.7, 3.3 Hz), 1.92-1.69
(4 H, m); 13C NMR (75 MHz, CDCl3) δ 192.6, 163.1, 138.3, 128.4,
127.6, 107.0, 79.3, 73.0, 69.5, 41.9, 31.3, 25.1; HRMS (EI) calcd
for C15H18O3 (M+) 246.1256, found 246.1262. Anal. Calcd for
C15H18O3: C, 73.15; H, 7.37. Found: C, 72.57; H, 7.43.
has the trans-diequatorial relationship of propargyl and hydroxyl
substituents required for cyclization, a cis-1,3-diaxial interaction is
present between the C4-hydroxyl group and the C6-side chain. This
interaction is avoided in conformation ii, but now the C2-propargyl
and C3-hydroxyl substituents are in a trans-diaxial configuration. The
vinylidene carbene arising from 16 apparently decomposes (possibly
by an intermolecular reaction leading to polymerization) at a faster
rate than the conformational interconversion required for cyclization.
(2R,4S)-4-Acetoxy-2-(3-(ben zyloxy)-1-pr opyl)-3,4-dih ydr o-
2H-p yr a n (11). Pyrone 9 (674 mg, 2.74 mmol) was dissolved
in anhydrous EtOH (57 mL), and CeCl3‚7H2O (1.2692 g, 3.41

6434 J . Org. Chem., Vol. 62, No. 18, 1997
Notes
mmol) was added. The mixture was stirred until the CeCl3‚7H2O
was dissolved, and the resulting solution was chilled to -78 °C.
A solution of NaBH4 (250 mg, 6.56 mmol) in EtOH (20 mL) was
added dropwise over 15 min. After stirring for 1 h at -78 °C,
the reaction was quenched by addition of acetone (4 mL). After
warming to 20 °C, the mixture was concentrated and the residue
was dissolved in H2O and Et2O. The aqueous layer was
extracted with Et2O. The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated to give crude
alcohol 10 as a yellow oil (430 mg). Typically, the crude alcohol
10 was acetylated without prior purification, as this compound
was highly unstable, extremely acid-sensitive, and rapidly
decomposed even in a freezer. An analytical sample was purified
by silica gel chromatography (Et2O:Et2NH ) 99:1) and charac-
decanted. This process was repeated four times. The solvents
were evaporated and the residue was purified by silica gel
chromatography (pentane:Et2O ) 5:1) to give dibromoolefin 13
(546.8 mg, 74%): colorless oil; [R]23D ) -42.9 (CH2Cl2, c ) 0.750);
IR (thin film) 3029, 2914, 2855, 1093 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.36-7.27 (5 H, m), 6.52 (1 H, t, J ) 6.9 Hz), 5.90-
5.83 (1 H, m), 5.70-5.64 (1 H, m), 4.52 (2 H, s), 4.30-4.22 (1 H,
m), 3.70-3.61 (1 H, m), 3.57-3.45 (2 H, m), 2.48-2.38 (1 H, ddd,
J ) 15.3, 9.2, 6.9, Hz), 2.32-2.23 (1 H, ddd, J ) 15.4, 7.2, 4.7
Hz), 13C NMR (75 MHz, CDCl3) δ 138.6, 135.4, 128.3, 128.3,
127.6, 127.5, 125.3, 89.8, 72.8, 70.7, 70.2, 67.7, 37.7, 32.0, 30.5,
25.9; HRMS (EI) calcd for
431.0044, found 431.0020.
C
18H22O279Br81BrH [(M + H)+]
(2R,6R)-6-[3-(Ben zyloxy)-1-p r op yl]-5,6-d ih yd r o-2-(2-p r o-
p yn yl)-2H-p yr a n (14). Dibromoolefin 13 (358 mg, 0.832 mmol)
was dissolved in dry THF (6 mL) and chilled to -78 °C under
N2. n-Butyllithium (2.5 M in hexanes, 0.70 mL, 1.8 mmol) was
added dropwise. After 1.5 h, the mixture was warmed to 20 °C.
After an additional hour, the reaction was quenched by addition
of H2O (4 mL). The aqueous layer was extracted with Et2O. The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated. Purification by silica gel chroma-
tography (pentane:Et2O ) 8:1) gave alkyne 14 (220 mg, 97%):
colorless oil; [R]23D ) -87 (CH2Cl2, c ) 0.576); IR (thin film) 3307,
terized as follows: yellow oil; [R]23 ) +55 (CH2Cl2, c ) 0.456);
D
IR (thin film) 3369 (br), 1642 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.38-7.27 (5 H, m), 6.36 (1 H, dd, J ) 6.2, 1.1 Hz), 4.72 (1 H,
dt, J ) 6.2, 1.9 Hz), 4.51 (2 H, s), 4.47-4.37 (1 H, m), 3.96-3.88
(1 H, m), 3.53-3.45 (2 H, m), 2.14 (1 H, ddt, J ) 13, 6.5, 1.6 Hz)
1.83-1.54 (6 H, m); 13C NMR (75 MHz, CDCl3) δ 145.1, 138.4,
128.3, 127.6, 105.4, 74.5, 72.9, 69.9, 63.2, 38.1, 31.7, 25.3; HRMS
(EI) calcd for C15H20O3 (M)+ 248.1412, found 248.1423.
The crude alcohol 10 (ca. 2.7 mmol), dried by azeotropic
evaporations from toluene (3×), was dissolved in dry CH2Cl2 (14
mL) under N2. Addition of N,N-diisopropylethylamine (2.9 mL,
17 mmol) was followed by addition of DMAP (2-3 mg) and Ac2O
(0.78 mL, 11 mmol) at 20 °C. After 16 h, the mixture was diluted
with CH2Cl2 and washed with saturated NaHCO3. The aqueous
layer was extracted with CH2Cl2. The organic layers were dried
over Na2SO4 and concentrated. Purification by silica gel chro-
matography (pentane:Et2O ) 2:1, 1% Et2NH) gave acetate ester
11 (685 mg, 82%): colorless oil; [R]23D ) +23 (CH2Cl2, c ) 0.526);
2119 cm-1 1H NMR (300 MHz, CDCl3) δ 7.38-7.25 (5 H, m),
;
5.93-5.82 (2 H, m), 4.51 (2 H, s), 4.37-4.32 (1 H, m), 3.72-3.64
(1 H, m), 3.57-3.45 (2 H, m), 2.50 (1 H, ddd, J ) 16.5, 7.0, 2.7
Hz), 2.40 (1 H, ddd, J ) 16.6, 7.0, 2.7 Hz), 2.08-1.57 (6 H, m),
2.02 (1 H, t, J ) 2.7 Hz); 13C NMR (100 MHz, CDCl3) δ 138.6,
128.3, 127.8, 127.6, 127.4, 125.3, 81.0, 72.8, 70.8, 70.2, 70.0, 68.1,
31.7, 30.4, 25.8, 24.3; HRMS (EI) calcd for C18H22O2 (M+)
270.1620, found 270.1633.
IR (thin film) 1734, 1646 cm-1 1H NMR (300 MHz, CDCl3) δ
;
(2R,6R)-6-[3-(Ben zyloxy)-1-p r op yl]-2-(2-bu tyn yl)-5,6-d i-
h yd r o-2H-p yr a n (15). Dibromoolefin 13 (547 mg, 1.27 mmol)
was dissolved in dry THF (8.5 mL) and chilled to -78 °C under
N2. n-BuLi (1.1 mL, 2.8 mmol, 2.5 M in hexanes) was added
dropwise. After 1.5 h, the mixture was warmed to 20 °C for an
additional 1.5 h. The mixture was chilled to -78 °C and methyl
iodide (0.158 mL, 2.54 mmol) was added. After 1 h at -78 °C,
the mixture was warmed to 20 °C for 2 h and quenched with
H2O. The aqueous layer was extracted with Et2O, and the
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated. Purification by silica gel chroma-
tography (pentane:Et2O ) 4:1) gave alkyne 15 (455 mg, 95%):
7.38-7.28 (5 H, m), 6.43 (1 H, d, J ) 6.2 Hz), 5.38 (1 H, dddd,
J ) 8.7, 6.7, 1.9, 1.7 Hz), 4.72 (1 H, dt, J ) 6.3, 1.9 Hz), 4.50 (2
H, s), 4.02-3.94 (1 H, m), 3.53-3.44 (2 H, m), 2.23 (1 H, ddt, J
) 13, 6.6, 1.8 Hz), 2.04 (3 H, s), 1.83-1.62 (5 H, m); 13C NMR
(75 MHz, CDCl3) δ 170.8, 146.6, 138.4, 128.3, 127.6, 100.8, 74.1,
72.8, 69.7, 65.6, 33.3, 31.3, 25.3, 21.2; HRMS (EI) calcd for
C
H
17H22O4 (M+) 290.1518, found 290.1546. Anal. Calcd for C17
22O4: C, 70.32; H, 7.64. Found: C, 70.36; H, 7.58.
-
(2R,6R)-6-[3-(Ben zyloxy)-1-pr opyl]-5,6-dih ydr o-2-(for m yl-
m eth yl)-2H-p yr a n (12). Acetate 11 (801 mg, 2.76 mmol), dried
by azeotropic evaporation from toluene (3×), was dissolved in
dry toluene (25 mL) and chilled to -40 °C under N2. Addition
of (tert-butyldimethylsiloxy)ethene (603.3 mg, 3.81 mmol) via
cannula in toluene (5 mL) was followed by dropwise addition of
Cl2Ti(Oi-Pr)2 (3.0 mL, 2 M solution in CH2Cl2, 6.1 mmol,
prepared by adding an equimolar amount of TiCl4 to a solution
of Ti(Oi-Pr)4 in CH2Cl2 at 0 °C, followed by warming to 20 °C).
After 1 h at -40 °C, the reaction was quenched by addition of
saturated NaHCO3 (5 mL). After warming to 20 °C, the aqueous
layer was extracted with CH2Cl2. The organic layers were
washed with brine, dried over Na2SO4, and concentrated. The
residue was purified by silica gel chromatography (pentane:
EtOAc ) 3:1) to give aldehyde 12 (598.4 mg, 79%, single isomer
by 1H NMR after chromatography). This compound is a colorless
oil which slowly decomposed upon freezer storage after ca. 2
colorless oil; [R]23 ) -89.8 (CH2Cl2, c ) 0.668); IR (thin film)
D
3031, 2918, 2856, 1090 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.36-
7.24 (5 H, m), 5.87-5.85 (2 H, s), 4.29-4.25 (1 H, m), 3.71-3.62
(1 H, m), 3.52 (2 H, ddd, J ) 9.3, 6.3, 3.0 Hz), 2.49-2.29 (2 H,
m), 2.05-1.55 (6 H, m), 1.79 (3 H, dd, J ) 5.2, 2.6 Hz); 13C NMR
(75 MHz, CDCl3) δ 138.6, 128.4, 128.3, 127.6, 127.5, 124.9, 77.3,
75.6, 72.8, 71.3, 70.2, 68.0, 31.8, 30.5, 25.9, 24.7; HRMS (EI)
calcd for C15H19O2 [(M - C4H5)+] 231.1385, found 231.1402. Anal.
Calcd for C19H24O2: C, 80.24; H, 8.51. Found: C, 80.04; H, 8.47.
(2R,6R)-6-[3-(Ben zyloxy)-1-p r op yl]-3,4-d ih yd r oxy-2-(2-
p r op yn yl)-3,4,5,6-tetr a h yd r o-2H-p yr a n (16). Alkene 14 (67.7
mg, 0.25 mmol) was dissolved in EtOAc (1.5 mL) and MeCN (1.5
mL) and chilled to 0 °C. RuCl3‚3H2O (6.9 mg, 0.026 mmol) and
NaIO4 (91.4 mg, 0.43 mmol) were combined, dissolved in H2O
(0.5 mL), and added to the alkene solution. After 5 min, the
reaction was quenched by addition of saturated Na2S2O5 (3 mL).
After stirring for 10 min at 20 °C, the aqueous layer was
extracted with EtOAc. The organic layers were washed with
brine, dried over Na2SO4, and concentrated. The residue was
purified by silica gel chromatography (EtOAc) to give starting
material (12 mg) and diol 16 as a 3:1 mixture of isomers (35.9
mg, 47% combined). This mixture was characterized as fol-
weeks: [R]23 ) -59.9 (CHCl3, c ) 1.15); IR (thin film) 2858,
D
2734, 1725 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.80 (1 H, d, J )
3.3 Hz), 7.37-7.27 (5 H, m), 5.91-5.84 (1 H, m), 5.68 (1 H, br d,
J ) 10.2 Hz), 4.82-4.73 (1 H, m), 4.50 (2 H, s), 3.66-3.60 (1 H,
m), 3.52-3.42 (2 H, m), 2.72 (1 H, ddd, J ) 16, 9.0, 3.3 Hz), 2.50
(1 H, dd, J ) 16, 4.5 Hz), 2.07-1.55 (6 H, m); 13C NMR (75 MHz,
CDCl3) δ 201.0, 138.5, 128.3, 127.8, 127.6, 127.4, 125.4, 77.2,
72.8, 70.0, 67.8, 47.8, 31.7, 30.3, 25.8; HRMS (EI) calcd for
17H22O3 (M+) 274.1569, found 274.1562.
lows: colorless oil; [R]23 ) +12 (CH2Cl2, c ) 0.492); IR (thin
C
D
film) 3660-3140 (br), 2120 cm-1
;
1H NMR (300 MHz, CDCl3,
(2R,6R)-6-[3-(Ben zyloxy)-1-p r op yl]-2-(3,3-d ibr om o-2-p r o-
major isomer) δ 7.33-7.28 (5 H, m), 4.49 (2 H, s), 4.06 (1 H,
ddd, J ) 7.3, 7.2, 3.6 Hz), 3.92-3.83 (1 H, m), 3.77 (1 H, dt, J )
6.6, 3.3 Hz), 3.60-3.46 (3 H, m), 2.84 (1 H, br d, J ) 6.3 Hz),
2.70 (1 H, br d, J ) 6.7 Hz), 2.46 (2 H, dd, J ) 7.4, 2.5 Hz), 2.05
(1 H, t, J ) 2.6 Hz), 1.84-1.53 (6 H, m); 13C NMR (75 MHz,
CDCl3, major isomer) δ 138.4, 128.3, 127.7, 127.5, 79.9, 74.0,
72.8, 70.9, 69.9, 69.7, 69.1, 66.0, 34.8, 31.6, 25.9, 20.2; HRMS
(EI) calcd for C18H24O4 (M+) 304.1674, found 304.1695.
p en yl)-5,6-d ih yd r o-2H-p yr a n (13). Dry CH2Cl2 (11 mL) was
added to triphenylphosphine (1.410 g, 5.38 mmol) and zinc dust
(349.5 mg, 5.35 mmol) under N2, and the suspension was chilled
to 0 °C. Carbon tetrabromide (1.832 g, 5.44 mmol) was added
and the mixture was stirred at 20 °C for 66 h. Aldehyde 12
(467 mg, 1.70 mmol), dried by evaporation from toluene (3×),
was added via cannula in dry CH2Cl2 (8 mL). After 40 h, the
mixture was poured into pentane (30 mL), and the solvents were
decanted from the resulting residue. The residue was dissolved
in CH2Cl2 (5 mL), poured into pentane (30 mL) again, and
(2R,6R)-6-[3-(Ben zyloxy)-1-p r op yl]-2-(2-bu tyn yl)-3,4-d i-
h yd r oxy-3,4,5,6-tetr a h yd r o-2H-p yr a n (17). Alkene 15 (143

Notes
J . Org. Chem., Vol. 62, No. 18, 1997 6435
mg, 0.503 mmol) was dissolved in EtOAc (3.0 mL) and MeCN
(3.0 mL) and chilled to 0 °C. RuCl3‚H2O (7 mg, 0.03 mmol) and
NaIO4 (199 mg, 0.930 mmol) were dissolved in H2O (1 mL) and
added to the alkene solution. After 5 min, the reaction was
quenched by addition of saturated aqueous Na2S2O5 (5 mL).
After stirring for 10 min, the aqueous layer was extracted with
EtOAc. The organic layers were washed with brine, dried over
Na2SO4, and concentrated. The residue was purified by chro-
matography (100% EtOAc) to give starting material (31.5 mg)
and diol 17 (87 mg, 54%, 69% based on recovered starting
material) as a 4:1 mixture of diastereomers. This mixture was
128.3, 127.6, 127.4, 94.1, 76.4, 72.8, 72.2, 70.2, 65.3, 59.8, 33.3,
29.2, 27.4, 27.1, 19.4; HRMS (EI) calcd for C19H26O4 (M+)
318.1831, found 318.1851.
Bicyclic En ol Eth er Aceta te Ester (19). Alcohol 18 (12.2
mg, 0.0383 mmol) was dissolved in Et3N (1.0 mL) under N2.
DMAP (1 mg), followed by Ac2O (0.015 mL, 0.16 mmol), was
added and the mixture stirred at 20 °C for 16 h. The volatiles
were evaporated under reduced pressure and the residue was
purified by silica gel chromatography (pentane:Et2O ) 2:1, 1%
Et2NH) to give acetate 19 (13.5 mg, 97%): colorless oil; [R]23
)
D
+51° (CH2Cl2, c ) 0.314); IR (thin film) 1740, 1683 cm-1 1H
;
characterized as follows: colorless oil; [R]23 ) +33.1° (CH2Cl2,
D
NMR (300 MHz, CDCl3) δ 7.37-7.27 (5 H, m), 5.35 (1 H, dt, J
) 3.3, 3.2 Hz), 4.50 (2 H, s), 4.41 (1 H, d, J ) 4.8 Hz), 3.98 (1 H,
ddd, J ) 9.8, 9.5, 6.2 Hz), 3.93-3.86 (1 H, m), 3.58 (1 H, dd, J
) 9.9, 3.3 Hz), 3.53-3.44 (2 H, m), 2.21-1.92 (4 H, m), 2.07 (3
H, s), 1.76-1.55 (4 H, m), 1.70 (3 H, s); 13C NMR (75 MHz,
CDCl3) δ 170.4, 150.6, 138.5, 128.3, 127.6, 127.5, 93.1, 74.3, 72.9,
71.9, 69.9, 67.2, 60.8, 32.1, 28.9, 27.5, 27.0, 21.4, 19.4; HRMS
(EI) calcd for C21H28O5 360.1937, found 360.1928.
c ) 3.50); IR (thin film) 3640-3130 (br), 2931, 2858, 2244 cm-1
;
1H NMR (300 MHz, CDCl3, major diastereomer) δ 7.32-7.27 (5
H, m), 4.49 (2 H, s), 4.01 (1 H, ddd, J ) 7.5, 7.2, 3.3 Hz), 3.87-
3.79 (2 H, m), 3.55-3.45 (3 H, m), 2.84 (1 H, br d, J ) 6.2 Hz),
2.72 (1 H, br d, J ) 6.8 Hz), 2.42-2.39 (2 H, m), 1.80-1.47 (6 H,
m), 1.76 (3 H, t, J ) 2.2 Hz); 13C NMR (75 MHz, CDCl3, major
diastereomer) δ 138.4, 128.3, 127.6, 127.5, 78.3, 74.8, 74.4, 72.8,
69.9, 69.5, 69.2, 65.9, 34.8, 31.7, 25.9, 20.4, 3.5; HRMS (EI) calcd
for C19H26O5 (M+) 318.1831, found 318.1821.
Ack n ow led gm en t. This research was supported by
the National Science Foundation Early Career Develop-
ment Program (CHE-9501608). F.E.M. also acknowl-
edges support from the Alfred P. Sloan Foundation and
Lilly Research Laboratories. M.M.G. was an American
Chemical Society Organic Division Graduate Fellow,
sponsored by Glaxo Research Laboratories.
Bicyclic En ol Eth er (18). Alkynyl diol 17 (34.9 mg, 0.110
mmol) was dried by evaporation from toluene (3×), dissolved in
dry CH2Cl2 (1.5 mL), and added to 3 Å molecular sieves (43 mg,
flame dried) via cannula. Acetic acid (0.013 mL, 0.23 mmol),
followed by Pd(OAc)2 (15.9 mg, 0.071 mmol), was added and the
mixture was stirred under N2 at 20 °C for 2.5 h (reaction was
complete by thin layer chromatography (pentane:Et2O ) 2:1)
after ca. 1 h). The mixture was filtered through silica gel (1
cm) eluting with EtOAc. The solvents were concentrated and
the residue was purified by silica gel chromatography (pentane:
Et2O ) 2:1, 1% Et2NH) to give enol ether 18 as a colorless oil
(18.4 mg, 52%). [R]23D ) +7.5 (CH2Cl2, c ) 0.348); IR (thin film)
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
new compounds 8-19 (12 pages). This material is contained
in libraries on microfiche, 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.
3459 (br), 1682 cm-1 1H NMR (300 MHz, CDCl3) δ 7.34-7.24
;
(5 H, m), 4.50 (2 H, s), 4.44 (1 H, d, J ) 5.7 Hz), 4.22-4.19 (1 H,
m), 3.96 (1 H, ddd, J ) 9.9, 9.8, 6.3 Hz), 3.90-3.83 (1 H, m),
3.53-3.44 (3 H, m), 2.40-1.90 (6 H, m), 1.78-1.58 (3 H, m), 1.74
(3 H, t, J ) 1.1 Hz); 13C NMR (75 MHz, CDCl3) δ 150.2, 138.6,
J O970597+