A new synthesis of valienamine

Full text of DOI:10.1021/jo010202t

7184
J . Org. Chem. 2001, 66, 7184-7190
A New Syn th esis of Va lien a m in e1
Stanton H.-L. Kok, C. C. Lee, and Tony K. M. Shing*
Department of Chemistry, The Chinese University of Hong
Kong, Shatin, Hong Kong, China
tonyshing@cuhk.edu.hk
F igu r e 1.
Received February 21, 2001
stereospecific opening of a cyclic sulfite as the key step
to generate a 2-epi-valienamine derivative that was
followed by inversion at C2 to provide the target molecule.
In this note, valienamine was produced directly from a
cyclohexene precursor bearing an allylic acetate moiety.
A regio- and stereospecific palladium-catalyzed reaction
was proven to effectively install the amino function.
In tr od u ction
Valienamine (Figure 1)2 [(1S,2S,3S,4R)-1-amino-5-
hydroxymethylcyclohex-5-en-2,3,4-triol] is an R-glucosi-
dase inhibitor3 that was isolated from the microbial
degradation of validoxylamine A4 with Pseudomonas
denitrificans5 or Flavobacterium saccharophilum6 or from
the NBS cleavage of validoxylamine A.7,8 Since the
isolation of valienamine in 1972, twelve enantiospecific
syntheses have been described.1a,9-19 The first synthesis
was reported by Paulsen et al.9 using the cyclitol que-
brachitol as the chiral starting material. Seven syntheses
constructed the carbocyclic framework from D-glucose
involving either a Ferrier rearrangement,10-12 an aldol-
type cyclization of a nitrofuranose,13 an intramolecular
Horner-Emmons reaction,14 a ring-closing alkene meta-
thesis,15 or an aldol condensation of a sulfone as the key
step.16 Three other constructions employed the Diels-
Alder reaction to generate the cyclohexene skeleton.17-19
The last one was asymmetric and involved two consecu-
tive palladium-catalyzed asymmetric alkylations as the
key steps.19 In our previous endeavor,1a we described the
synthesis of valienamine (1) on the basis of a regio- and
Resu lts a n d Discu ssion
Synthesis of a dibenzyl ether with a cyclohexylidene
blocking group similar to 8 from (-)-quinic acid (2) was
known, and the procedure was developed by one of us.20
We were tempted to employ the ethylpropylidene protect-
ing group instead because it would provide simpler 1H
NMR spectra and would not, in particular, obscure the
high-field methylene protons of the cyclohexane skeleton.
Thus, the modified Stoodley21 procedure was applied to
the construction of ethylpropylidene quinic acid lactone
3. In this method, (-)-quinic acid 2 was heated in boiling
3-pentanone with a catalytic amount of H3PO4 and with
azeotropic removal of water, affording the crystalline
lactone 3 in a 94% yield (Scheme 1). Using a Dean and
Stark apparatus provided better yields because the
continuous removal of water forced the equilibrium
toward the target lactone 3. It is noteworthy that
3-pentanone seems to be a better azeotropic agent than
cyclohexanone; hence, the removal of water was speedy.
In the presence of sodium methoxide in methanol, the
lactone ring was opened to give a 98% yield of the diol 4.
The secondary alcohol in 4 was oxidized into the corre-
sponding ketone 5 as white needles in an 86% yield and
was followed by elimination of the tertiary alcohol with
phosphorus oxychloride in pyridine, giving an excellent
yield of enone 6. Due to the presence of the bulky
ethylpropylidene ring at the R-face of enone 6, DIBALH
attacked the ketone exclusively from the â-face. The diol
7 was isolated as the sole product in a 93% yield. Since
both hydroxy groups remain untouched most of time
during the route, a protecting group that is stable in
different manipulation conditions is required and would
be deprotected easily. Silyl ether had been used but was
prone to migration under basic conditions in the presence
of an adjacent free hydroxy group.22 The benzyl group
was thus chosen for this task and could be removed
readily via hydrogenolysis or dissolving-metal reduction.
Therefore, the diol 7 was treated with sodium hydride
and benzyl bromide in the presence of a catalytic amount
of tetra-n-butylammonium iodide in THF to give dibenzyl
* To whom correspondence should be addressed. Fax: (852)-2603
5057. E-mail: tonyshing@cuhk.edu.hk.
(1) (-)-Quinic acid in organic synthesis. 10. Part 9: (a) Shing, T. K.
M.; Li, T. Y.; Kok, S. H. L. J . Org. Chem. 1999, 64, 1941. Part 8: (b)
Shing, T. K. M.; Tam, E. K. W. J . Org. Chem. 1998, 63, 1547. Part 7:
(c) Shing, T. K. M.; Wan, L. H. J . Org. Chem. 1996, 61, 8468. (d) Shing,
T. K. M.; Wan, L. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1643.
(2) Horii, S.; Iwasa, T.; Mizuta, E.; Kameda, Y. J . Antibiot. 1971,
24, 59.
(3) Kameda, Y.; Asano, N.; Yoshikawa, M.; Matsui, K. J . Antibiot.
1982, 35, 1624.
(4) Iwasa, I.; Yamamoto, H.; Shibata, M. J . Antibiot. 1970, 23, 595.
(5) Kameda, Y.; Horii, S. J . Chem. Soc., Chem. Commun. 1972, 746.
(6) Kameda, Y.; Asano, N.; Teranishi, M.; Matsui, K. J . Antibiot.
1980, 33, 1573.
(7) Ogawa, S.; Miyamotom, Y.; Nakjima, A. Chem. Lett. 1989, 725.
(8) Ogawa, S.; Nakjima, A.; Miyamotom, Y. J . Chem. Soc., Perkin
Trans. 1 1991, 3287.
(9) (a) Paulsen, H.; Heiker, F. R. Angew. Chem., Int. Ed. Engl. 1980,
19, 904; (b) Liebigs Ann. Chem. 1981, 2180.
(10) Schmidt, D. D.; Ko¨hn, A. Angew. Chem., Int. Ed. Engl. 1987,
26, 482.
(11) Nicotra, F.; Panza, L.; Ronchetti, F.; Russo, G. Gazz. Chim. Ital.
1989, 119, 577.
(12) Park, T. K.; Danishefsky, S. J . Tetrahedron Lett. 1994, 35, 2667.
(13) Yoshikawa, M.; Cha, B. C.; Okaichi, Y.; Takinami, Y.; Yokoka-
wa, Y.; Kitagawa, I. Chem. Pharm. Bull. 1988, 36, 4236.
(14) Fukase, H.; Horii, S. J . Org. Chem. 1992, 57, 3651.
(15) Vasella, A.; Kapferer, P.; Sarabia, F. Helv. Chim. Acta 1999,
82, 645.
(16) Tatsuta, K.; Mukai, H.; Takahashi, M. J . Antibiot. 2000, 53,
430.
(17) Ogawa, S.; Shibata, Y.; Nose, T.; Suami, T. Bull. Chem. Soc.
J pn. 1985, 58, 3387.
(18) Knapp, S.; Naughton, A. B. J .; Dhar, T. G. M. Tetrahedron Lett.
1992, 33, 1025.
(19) Trost, B. M.; Chupak, L. S.; Lu¨bbers, T. J . Am. Chem. Soc. 1998,
120, 1732.
(20) Shing, T. K. M.; Cui, Y.-X.; Tang, Y. Tetrahdedron 1992, 48,
2349.
(21) Elliott, J . D.; Kelson, A. B.; Purcell, N.; Stoodley, R. J . J . Chem.
Soc., Perkin Trans. 1 1983, 2441.
(22) Shing, T. K. M.; Tang, Y. Tetrahedron 1990, 46, 6575.
10.1021/jo010202t CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/18/2001

Notes
J . Org. Chem., Vol. 66, No. 21, 2001 7185
Sch em e 1
Sch em e 2
using a catalytic amount of K2CO3 in methanol to give a
ether 8 in six steps with an overall yield of 63% from
(-)-quinic acid.
triol that was converted into the diacetate 16 with acetic
1
anhydride and pyridine in CH2Cl2. The H NMR data of
cis-Dihydroxylation of alkene 8 was performed using
a catalytic amount of osmium tetraoxide to diastereo-
selectively give diol 9 (Scheme 2). Since the R-face was
more sterically hindered as a result of the bulky ethyl-
propylidene group, dihydroxylation occurred preferen-
tially at the â-face (see Figure 2). The inferior reactivity
of the tertiary hydroxyl group allowed success in the
regioselective benzylation of the secondary hydroxyl
group. Thus, tribenzyl ether 10 was obtained in an
overall yield of 90% from alkene 8. The tertiary hydroxy
group in tribenzyl ether 10 was acylated as acetate 11.
Then, hydrolysis of the acetal group in 11 with aqueous
TFA in CH2Cl2 gave the R-diol 12. The configuration of
the diol moiety in 12 had to be inverted into the
corresponding â-diol. The R-diol was first deoxygenated
via the Corey-Winter reaction.23 Reaction of the diol 12
with 1,1′-thiocarbonyldiimidazole in toluene afforded the
intermediate thiocarbonate 13. This intermediate was
then treated with trimethyl phosphite under reflux to
give the alkene 14 in an 87% overall yield from the diol
12. Dihydroxylation of the alkene 14 could be realized
using the new ruthenium-catalyzed dihydroxylation pro-
tocol developed by our group.24 This dihydroxylation gave
exclusively the â-diol product 15. The stereoselectivity
of the ruthenium tetraoxide attack was apparently
controlled by the benzyl ether adjacent to the alkene
moiety. Deacetylation of acetate 15 was accomplished
diacetate 16 clearly indicate the stereochemistries at C1
and C2. The coupling constants of 10.2 Hz between H2
and H3 and 9.3 Hz between H3 and H4 show that H2, H3,
and H4 are axial protons. Furthermore, the coupling
constant of 3.4 Hz between H1 and H2 shows that H1 and
H2 are syn-disposed (see Figure 3). These data supported
the assignment of â-OH groups at C1 and C2 in diol 15.
Attempts to convert alcohol 16 into alkene 17 were
carried out with thionyl chloride and pyridine in CH2-
Cl2. It was found that the elimination reaction was very
F igu r e 2.
(23) Corey, E. J .; Winter, R. A.-E. J . Am. Chem. Soc. 1980, 102, 3641.
(24) (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, 142.
F igu r e 3.

7186 J . Org. Chem., Vol. 66, No. 21, 2001
Notes
slow and that the selectivity of the elimination was poor,
giving two alkene products 17 and 18 in a 1:1 ratio (eq
1).
F igu r e 4.
apparently hindered by the juxtaposed R-substituent in
acetal 19 and in diacetate 22 (see Figure 4). Proton
abstraction therefore occurred at the less hindered exo-
cyclic methylene to give exo-alkenes 20 and 23 from 19
and 22, respectively. For the dehydration of tertiary
alcohol 16, the ring methylene proton is more acidic than
the exocyclic methylene proton (attached to a carbon
bearing an oxygen functionality) and therefore under-
went elimination preferentially to give the desired alkene
17.
There was no improvement in selectivity when triethyl-
amine was used instead of pyridine. In contrast to our
previous findings,1a no dimer was found when the thionyl
chloride was added dropwise to the solution of 16. Due
to the nonselectivity of the elimination of 16, Martin
sulfurane dehydrating agent was employed in dry ben-
zene25 under reflux to give the single product 17 in a 90%
yield. According to our previous work,1a elimination of
the tertiary hydroxy group in acetal 19 furnished the
undesired exocyclic enol ether 20 (eq 2).
The diacetate 17 obtained would act as a precursor for
the syntheses of various kinds of N-alkylated valienamine
derivatives via palladium-catalyzed allylic amination.27
Initially, diacetate 17 was allowed to react with benzyl-
amine in the presence of a catalytic amount of tetrakis-
(triphenylphosphine) palladium [Pd(PPh3)4] and with
triphenylphosphine (PPh3) in THF under reflux but failed
to give any product. Conducting the reaction in a sealed
tube at 140 °C caused the decomposition of Pd(PPh3)4,
and metallic palladium was deposited on the wall of the
tube. When acetonitrile was used as the solvent instead
of THF,28 the amination took place with benzylamine to
yield the desired amine 24. The palladium-catalyzed
allylic amination of diacetate 17 with propylamine was
also successful, affording the allylic amine 25. Allylic
amines 24 and 25 could not be fractionated to purity by
chromatography. Fortunately, their deacetylated prod-
ucts could be isolated cleanly and characterized. Thus,
treatment of acetate 24 or 25 with a catalytic amount of
NaOMe in MeOH provided the valienamine derivative
26 or 27 in a 60 or 58% overall yield, respectively, from
allylic acetate 17 (Scheme 4). The catalytic cycle of the
Pd(0)-mediated allylic amination is shown in Figure 1.
The stereochemistry at C1 in 26 and in 27 was confirmed
by proton NMR two-dimensional (NOESY and COSY)
experiments, indicating that H1 and H2 were syn-
disposed.
This elimination preference might be attributable to the
bulky cyclohexylidene ring blocking the R-face. To ex-
amine if the steric effect was the dominant effect for the
undesired reaction, we decided to make R-diacetate 22
for use in a direct comparison. Thus, hydrolysis of the
ethylpropylidene blocking group in 10 using aqueous
trifluoroacetic acid in CH2Cl2 gave the triol 21 in an 87%
yield (Scheme 3). The secondary hydroxy groups in 21
were acetylated to give the R-diacetate 22 in a 98% yield.
The elimination reaction of 22 with Martin sulfurane
dehydrating agent afforded the undesired enol ether 23
as the sole product in a moderate yield of 60%. These
findings supported the assignment of the E2 mechanism26
to the elimination pathway via Martin sulfurane. The
axial R-proton trans-periplanar to the tertiary alcohol was
The presence of the alkene moiety in 26 precluded the
use of catalytic hydrogenolysis; therefore, debenzylation
of benzyl ether 26 was carried out using sodium in liquid
ammonia at -78 °C to give valienamine 1. Acetylation
of 1 then afforded pentaacetate 28 for isolation and
characterization.
Sch em e 3
The spectral and physical data of the pentaacetate 28
derived from 26 were completely identical to the data of
(25) (a) Martin, J . C.; Arhart, R. J . J . Am. Chem. Soc. 1971, 93,
4327. (b) Paquette, L. A.; Zhao, M. J . Am. Chem. Soc. 1993, 115, 354.
(26) Arhart, R. J .; Martin, J . C. J . Am. Chem. Soc. 1972, 94, 5003.
(27) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173.
For reviews see: (b) Tsuji, J . Palladium Reagents and Catalysts-
Innovations in Organic Synthesis, 2nd ed.; Wiley: Chichester, 1995.
(c) Trost, B. M.; Verhoeven, T. R. In Organopalladium Compounds
Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon
Press: New York, 1982.
(28) Mungall, W. S.; Greene, G. L.; Heavnerm, G. A.; Letsinger, R.
L. J . Org. Chem. 1975, 40, 1659.

Notes
J . Org. Chem., Vol. 66, No. 21, 2001 7187
) 14.4, 7.2, and 3.0 Hz), 1.80 (1H, dd, J ) 13.5 and 11.1 Hz),
2.01 (1H, ddd, J ) 13.8, 4.2, and 1.2 Hz), 2.12-2.24 (2H, m),
3.11 (1H, brd, J ) 3.0 Hz), 3.49 (3H, brs), 3.77 (3H, s), 3.97 (1H,
t, J ) 6.6 Hz), 4.07-4.14 (1H, m), 4.43 (1H, m); 13C NMR δ 8.2,
8.6, 28.3, 29.7, 34.9, 38.9, 53.0, 68.2, 72.9, 79.6, 113.2, 175.6;
MS (FAB) m/z (relative intensity) 275 ([M + H]+, 59); HRMS
[M + H]+ calcd for C13H23O6 275.1489, found 275.1491. Anal.
Calcd for C13H22O6: C, 56.92; H, 8.08. Found: C, 56.61; H, 8.39.
Met h yl 3,4-O-E t h ylp r op ylid en e-5-d eh yd r oq u in a t e (5).
To a mixture of 3 Å molecular sieves (ca. 25 g) and pyridium
dichromate (19.6 g, 52 mmol) in dry CH2Cl2 (150 mL) was added
a solution of alcohol 4 (9.5 g, 35 mmol) in CH2Cl2 (70 mL) in
one portion under a N2 atmosphere, followed by an addition of
glacial acetic acid (0.5 mL). The mixture was stirred for 24 h at
room temperature. The mixture was then filtered through a pad
of silica gel, and the residue was washed with ethyl acetate.
Concentration of the filtrate followed by flash chromatography
(4:1 hexanes/ethyl acetate) produced the ketone 5 (8.18 g, 86%)
as a white solid: mp 92 °C; Rf ) 0.44 (2:1 hexanes/ethyl acetate);
Sch em e 4
[R]21 -7.6 (c ) 0.5, CHCl3); IR (KBr) 3338, 2973, 2964, 2937,
D
2881, 1726, 1127, 1068 cm-1
;
1H NMR δ 0.92 (3H, t, J ) 7.5
an authentic sample from our previous work.1a The
palladium-catalyzed allylic amination was therefore proved
to occur with an overall retention of configuration. The
synthesis of N,O,O,O,O-pentacetylvalienamine 28 from
(-)-quinic acid was achieved in 20 steps with an overall
yield of 11%.
Hz), 0.93 (3H, t, J ) 7.5 Hz), 1.63-1.76 (4H, m), 2.56 (2H, brd,
J ) 3.6 Hz), 2.78 and 2.90 (2H, ABq, J ) 14.7 Hz), 3.64 (1H, s),
3.84 (3H, s), 4.42 (1H, d, J ) 6 Hz), 4.77 (1H, dt, J ) 6.0 and 3.6
Hz); 13C NMR δ 8.1, 8.3, 28.4, 29.3, 34.8, 48.6, 53.1, 75.6, 76.2,
77.9, 114.7, 173.0, 204.2; MS (FAB) m/z (relative intensity) 273
([M + H]+, 100). Anal. Calcd for C13H20O6: C, 57.34; H, 7.40.
Found: C, 57.18; H, 7.48.
Meth yl 4,5-O-Eth ylp r op ylid en e-3-d eh yd r o-4-epi-sh ik i-
m a te (6). Phosphorus oxychloride (3.0 mL, 32.2 mmol) was
slowly added to a solution of tertiary alcohol 5 (4.25 g, 15.6 mmol)
in pyridine (30 mL) at 0 °C. The reaction mixture was allowed
to warm to room temperature and was stirred for 12 h. The
solution was washed successively with saturated NH4Cl (20 mL),
extracted with CH2Cl2 (2 × 30 mL), dried with MgSO4, and
filtered. Concentration of the filtrate followed by flash chroma-
tography (5:1 hexanes/ethyl acetate) gave the enone 6 (3.92 g,
99%) as a yellow solid: mp 63 °C; Rf ) 0.41 (2:1 hexanes/ethyl
In summary, the present studies demonstrate the high
efficiency of the palladium-catalyzed coupling strategy
for the synthesis of valienamine 1. Application of this new
strategy to the synthesis of pseudoaminodisaccharides
or oligosaccharides is in progress.
Exp er im en ta l Section
For general experimental procedures, see ref 1a. All 1H and
13C NMR spectra were recorded at 300 and 75 MHz, respectively,
and in CDCl3 unless otherwise stated.
acetate); [R]21D -41.3 (c ) 0.6, CHCl3); IR (KBr) 2948, 1723 cm-1
;
1H NMR δ 0.79 (3H, t, J ) 7.4 Hz), 0.91 (3H, t, J ) 7.4 Hz), 1.52
(2H, dq, J ) 7.5 and 2.2 Hz), 1.66 (2H, q, J ) 7.6 Hz), 2.82 (1H,
ddd, J ) 20.2, 5.0, and 2.8 Hz), 3.24 (1H, d, J ) 20 Hz), 3.85
(3H, s), 4.30 (1H, d, J ) 5.4 Hz), 4.73 (1H, dt, J ) 5.2 and 1.7
Hz), 6.84 (1H, dd, J ) 3.0 and 0.8 Hz); 13C NMR δ 7.8, 8.3, 26.6,
29.0, 29.7, 52.7, 72.3, 74.7, 113.4, 131.3, 144.3, 166.1, 196.0; MS
(FAB) m/z (relative intensity) 255 ([M + H]+, 83); HRMS [M +
H]+ calcd for C13H19O5 255.1227, found 255.1232.
3,4-O-Eth ylp r op ylid en equ in ic Acid -1,5-la cton e (3). A
mixture of (-)-quinic acid (2) (100 g, 0.52 mol), pentan-3-one
(550 mL, 1.54 mol), and concentrated phosphoric acid (1 mL)
was refluxed with a Dean and Stark apparatus for 12 h at 180
°C. The excess of pentan-3-one was recovered by simple distil-
lation. The mixture was cooled to room temperature, and ethyl
acetate (200 mL), potassium hydrogen carbonate (ca. 10 g), and
anhydrous sodium sulfate (ca. 10 g) were added. The mixture
was stirred until neutralization was completed, and the mixture
was then filtered. The filtrate was concentrated to give lactone
3 (118 g, 94%) as a solid residue that was recrystallized from
ethyl acetate/hexane as colorless needles: mp 68 °C; Rf ) 0.41
(1:2 hexane/diethyl ether); [R]21D -25.6 (c ) 0.6, CHCl3); IR (KBr)
2971, 2941, 2880, 1783, 1460, 1166, 1077 cm-1; 1H NMR δ 0.86
(3H, t, J ) 7.5 Hz), 0.93 (3H, t, J ) 7.5 Hz), 1.55 (2H, q, J ) 7.5
Hz), 1.72 (2H, q, J ) 7.5 Hz), 2.12 (1H, dd, J ) 14.4 and 3.3
Hz), 2.28-2.42 (2H, m), 2.56 (1H, d, J ) 11.7 Hz), 3.72 (1H, brs),
4.27 (1H, ddd, J ) 6.9, 2.7, and 1.2 Hz), 4.42-4.48 (1H, m), 4.74
(1H, dd, J ) 6.3 and 2.7 Hz); 13C NMR δ 7.9, 8.5, 27.5, 28.6,
34.5, 38.5, 71.0, 71.4, 71.7, 75.7, 77.2, 113.8, 179.0; MS (FAB)
m/z (relative intensity) 243 ([M + H]+, 4); HRMS [M + H]+
calcd for C12H19O5 243.1227, found 243.1229. Anal. Calcd for
C12H18O5: C, 59.49; H, 7.49. Found: C, 59.21; H, 7.52.
Meth yl 3,4-O-Eth ylp r op ylid en equ in a te (4). To a solution
of lactone 3 (2.0 g, 8.3 mmol) in methanol (30 mL) was added
dropwise a solution of sodium methoxide (580 mg, 10.7 mmol)
in methanol (60 mL) over 30 min at 0 °C. The mixture was
stirred for 2 h, and then the pH of the solution was adjusted to
4 with glacial acetic acid. The mixture was diluted with CH2Cl2
(60 mL), washed with water (2 × 20 mL) and brine (2 × 20 mL),
dried over MgSO4, and filtered. Concentration of the filtrate
followed by flash chromatography (2:1 hexanes/ethyl acetate)
gave the tertiary alcohol 4 [1.96 g, 98% (based on recovery of
12% lactone)] as a clear yellowish oil: Rf ) 0.16 (1:4 hexane/
diethyl ether); [R]21D -37.5 (c ) 0.8, CHCl3); IR (film) 3418, 2972,
2943, 2883, 1732 cm-1; 1H NMR δ 0.85 (3H, t, J ) 7.5 Hz), 0.92
(3H, t, J ) 7.5 Hz), 1.60 (2H, brq, J ) 7.8 Hz), 1.72 (2H, ddd, J
(1R,2S,3S)-1,2-O-Eth ylp r op ylid en e-5-(h yd r oxym eth yl)-
4-cycloh exen e-1,2,3-tr iol (7). To a solution of the enone 6 (267
mg, 1.1 mmol) in dry toluene (5 mL) was added dropwise a
solution of DIBALH (4 mL, 4.0 mmol) over 30 min at -40 °C.
The mixture was stirred for 30 min at 0 °C, quenched with
saturated NH4Cl, and filtered through a pad of Celite. The
filtrate was extracted with ethyl acetate (3 × 15 mL). The
combined extracts were washed with brine (2 × 5 mL), dried
over MgSO4, and filtered. Concentration of the filtrate followed
by flash chromatography (1:2 hexanes/ethyl acetate) gave the
diol 7 (233 mg, 93%) as a yellowish syrup: Rf ) 0.12 (1:1
hexanes/ethyl acetate); [R]21 -4.8 (c ) 0.6, CHCl3); IR (film)
D
3393, 2972, 2935, 1075, 985 cm-1
;
1H NMR δ 0.80-0.91 (6H,
m), 1.54-1.67 (5H, m), 1.98 (1H, d, J ) 15.9 Hz), 2.42 (1H, dd,
J ) 16.2 and 2.4 Hz), 2.62 (1H, s), 4.07 (3H, brd, J ) 3.9 Hz),
4.50 (1H, ddd, J ) 7.8, 4.5, and 1.2 Hz), 4.57 (1H, ddd, J ) 7.5,
3.9, and 2.7 Hz); 13C NMR δ 7.3, 8.3, 27.8, 28.3, 28.4, 65.3, 67.1,
72.3, 76.2, 77.0, 112.1, 124.8, 136.8; MS (FAB) m/z (relative
intensity) 229 ([M + H]+, 4); HRMS [M + H]+ calcd for C12H21O4
229.1434, found 229.1433.
(1R,2S,3S)-3-O-Ben zyl-5-(ben zyloxym eth yl)-1,2-O-eth yl-
p r op ylid en e-4-cycloh exen e-1,2,3-tr iol (8). Sodium hydride
(60%, 945 mg, 23.6 mmol) was washed with dry hexane (3 × 5
mL) and suspended in dry THF (20 mL) under nitrogen at 0 °C.
A solution of the diol 7 (1.29 g, 5.66 mmol) in THF (30 mL) was
added dropwise over 20 min, and the mixture was stirred for
0.5 h at 0 °C. Benzyl bromide (2.7 mL, 22.6 mmol) was added
dropwise over 20 min at 0 °C followed by the addition of a
catalytic amount of tetra-n-butylammonium iodide. The mixture
was refluxed for 12 h. Methanol (3 mL) was added slowly

7188 J . Org. Chem., Vol. 66, No. 21, 2001
Notes
followed by the addition of water (10 mL). Concentration of the
mixture was followed by dilution with ethyl acetate (30 mL),
and the aqueous layer was extracted with ethyl acetate (2 × 30
mL). The combined organic extracts were washed with brine (20
mL), dried over MgSO4, and filtered. Concentration of the filtrate
followed by flash chromatography (8:1 hexane/diethyl ether) gave
dibenzyl ether 8 (2.26 g, 98%) as a colorless oil: Rf ) 0.27 (8:1
chromatography (6:1 hexane/diethyl ether) gave acetate 11 (419
mg, 83%) as a colorless oil: Rf ) 0.45 (3:1 hexanes/ethyl acetate);
[R]21 -1.3 (c ) 0.36, CHCl3); IR (film) 3088, 3064, 3030, 2974,
D
2936, 1738, 1094, 735, 697 cm-1; 1H NMR δ 0.88-0.99 (6H, m),
1.61-1.71 (3H, m), 1.87-2.04 (2H, m), 1.97 (3H, s), 1.99-2.04
(1H, m), 2.88 (1H, dd, J ) 14.1 and 6.3 Hz), 3.84 (1H, d, J ) 7.1
Hz), 4.02-4.15 (4H, m), 4.37 (1H, t, J ) 4.5 Hz), 4.65 and 4.49
(2H, ABq, J ) 11.8 Hz), 4.65 and 4.94 (2H, ABq, J ) 10.8 Hz),
4.74 and 4.83 (2H, ABq, J ) 11.7 Hz), 7.22-7.42 (15H, m); 13C
NMR δ 8.7, 8.8, 21.8, 28.4, 30.4, 32.4, 69.7, 72.0, 73.0, 73.3, 74.3,
75.7, 77.7, 78.0, 84.5, 113.3, 127.3, 127.4, 127.5, 127.7, 127.9,
128.0, 128.2, 128.3, 137.9, 138.5, 138.9, 170.0; HRMS (L-SIMS)
[M + H]+ calcd for C35H42O7 575.3003, found 575.3006.
hexane/diethyl ether); [R]21 +33.9 (c ) 0.8, CHCl3); IR (film)
D
3086, 3062, 3028, 2970, 2934, 2879, 1071, 736, 697 cm-1
;
1H
NMR δ 0.81 (3H, t, J ) 7.4 Hz), 0.89 (3H, t, J ) 7.4 Hz), 1.55-
1.70 (4H, m), 1.85 (1H, d, J ) 16.0 Hz), 2.22 (1H, d, J ) 17 Hz),
3.81 (1H, t, J ) 1.7 Hz), 3.97 (2H, brs), 4.46-4.59 (4H, m), 4.69
and 4.81 (2H, ABq, J ) 12.8 Hz), 5.90 (1H, brs), 7.25-7.41 (10H,
m); 13C NMR δ 7.5, 8.8, 28.1, 28.6, 29.7, 70.9, 72.3, 73.1, 73.5,
74.1, 75.4, 112.4, 125.1, 127.5, 127.7, 127.9, 128.3, 134.7, 138.1,
138.2; MS (FAB) m/z (relative intensity) 408 ([M]+, 4); HRMS
[M + H]+ calcd for C26H33O4 409.2373, found 409.2370.
(1R,2S,3S,4S,5S)-5-O-Acet yl-3,4-d i-O-b en zyl-5-(b en zyl-
oxym eth yl)cycloh exa n e-1,2,3,4,5-p en tol (12). To a solution
of the acetate 11 (266 mg, 0.46 mmol) in CH2Cl2 (10 mL) were
added TFA (5 drops) and water (2 drops) at room temperature.
The mixture was stirred for 24 h and poured into saturated
NaHCO3 (5 mL). The aqueous layer was extracted with CH2Cl2
(2 × 10 mL). The combined organic extracts were washed with
brine (10 mL), dried over MgSO4, and filtered. Concentration of
the filtrate followed by flash chromatography (3:2 hexanes/ethyl
acetate) gave the diol 12 (233 mg, 100%) as a colorless oil: Rf )
(1R,2S,3S,4R,5S)-3-O-Ben zyl-5-(ben zyloxym eth yl)-1,2-O-
eth ylp r op ylid en e-cycloh exa n e-1,2,3,4,5-p en tol (9). To a
solution of dibenzyl ether 8 (3.0 g, 7.4 mmol) in acetone/water
(20 mL:5 mL) was added NMO (1.72 g, 14.7 mmol) with a
catalytic amount of osmium tetraoxide (ca. 5 mg) at room
temperature. The mixture was stirred for 48 h and quenched
with saturated Na2S2O3 (30 mL). The solution was washed with
brine (2 × 20 mL), dried over MgSO4, and filtered. Concentration
of the filtrate followed by flash chromatography (2:1 hexanes/
ethyl acetate) gave diol 9 (3.0 g, 92%) as a white solid: mp 77-
0.22 (1:1 hexanes/ethyl acetate); [R]21 -0.5 (c ) 0.9, CHCl3);
D
IR (film) 3441, 1732 cm-1; H NMR δ 2.0 (3H, s), 2.19 (1H, dd,
1
J ) 13.7 and 12.5 Hz), 2.45 (1H, brd, J ) 8.2 Hz), 2.75-2.82
(2H, m), 3.67 (1H, m), 3.82 (1H, dd, J ) 9.7 and 2.9 Hz), 3.84
(1H, d, J ) 8.2 Hz), 4.07 (1H, d, J ) 9.8 Hz), 4.18-4.21 (2H, m),
4.42 and 4.51 (2H, ABq, J ) 11.8 Hz), 4.63 and 4.86 (2H, ABq,
J ) 11 Hz), 4.67 and 4.73 (2H, ABq, J ) 11.3 Hz), 7.18-7.35
(15H, m); MS (L-SIMS) m/z (relative intensity) 507 ([M + H]+,
0.35); HRMS (EI) [M]+ calcd for C30H34O7 506.2305, found
506.2349.
78 °C; Rf ) 0.21 (2:1 hexanes/ethyl acetate); [R]21 -29.5 (c )
D
0.6, CHCl3); IR (KBr) 3331, 2969, 2939, 2854, 1098, 1077, 743,
696 cm-1; 1H NMR δ 0.87-0.96 (6H, m), 1.54-1.87 (4H, m), 2.02
(1H, dd, J ) 14.5 and 6.6 Hz), 2.63 (1H, brs), 2.75 (1H, s), 3.34
(1H, brs), 3.79 (1H, dd, J ) 9.5 and 3.9 Hz), 4.00 (1H, dd, J )
9.5 and 1.6 Hz), 4.28-4.39 (2H, m), 4.53 (2H, s), 4.68 and 4.77
(2H, ABq, J ) 12 Hz), 7.24-7.41 (10H, m); 13C NMR δ 8.7, 8.8,
28.1, 30.3, 35.3, 70.7, 72.1, 72.2, 73.3, 73.4, 73.6, 75.6, 113.3,
127.5, 127.7, 127.9, 128.1, 128.4, 128.5, 137.8, 137.8, 138.2; MS
(FAB) m/z (relative intensity) 443 ([M + H]+, 100). Anal. Calcd
for C26H34O6: C, 70.56; H, 7.74. Found: C, 70.37; H, 7.45.
(1R,2R,3R,4S,5S)-3,4-Di-O-ben zyl-5-(ben zyloxym eth yl)-
1,2-O-eth ylp r op ylid en e-cycloh exa n e-1,2,3,4,5-p en tol (10).
Sodium hydride (60%, 118 mg, 3.1 mmol) was washed with dry
hexane (2 × 5 mL) and suspended in dry THF (50 mL) under
nitrogen at 0 °C. A solution of the diol 9 (791 mg, 1.8 mmol) in
THF (10 mL) was added dropwise for 15 min at 0 °C, and the
mixture was stirred for 45 min at 0 °C. Benzyl bromide (0.35
mL, 2.9 mmol) was added dropwise for 20 min at 0 °C followed
by the addition of a catalytic amount of tetra-n-butylammonium
iodide. The mixture was stirred for 3 h at room temperature.
Methanol (5 mL) was added slowly and followed by the addition
of water (20 mL). Concentration of the mixture was followed by
dilution with ethyl acetate (20 mL), and the aqueous layer was
extracted with ethyl acetate (2 × 10 mL). The combined organic
extracts were washed with brine (10 mL), dried over MgSO4,
and filtered. Concentration of the filtrate followed by flash
chromatography (5:1 hexane/diethyl ether) afforded the tribenzyl
ether 10 (785 mg, 98%) as a yellowish clear oil: Rf ) 0.58 (4:1
(3R ,4R ,5S )-5-O-Ace t yl-3,4-d i-O-b e n zyl-5-(b e n zyloxy-
m eth yl)-1-cycloh exen e-3,4,5-tr iol (14). To a solution of the
diol 12 (1.82 g, 3.6 mmol) in toluene (100 mL) was added 1,1′-
thiocarbonyldiimidazole (0.96 g, 5.4 mmol) at room temperature.
The reaction mixture was refluxed for 4 h. Concentration of the
cooled mixture followed by flash chromatography (4:1 hexanes/
ethyl acetate) gave the thiocarbonate 13 as a colorless oil. The
thiocarbonate was then dissolved in trimethyl phosphite (50 mL)
at room temperature, and the mixture was gently refluxed for
24 h. The excess of trimethyl phosphite was removed under
reduced pressure. The residue was purified by flash chroma-
tography (8:1 hexane/diethyl ether) to give alkene 14 (1.48 g,
87%) as a colorless oil: Rf ) 0.80 (1:1 hexanes/ethyl acetate);
[R]21D -39.0 (c ) 0.5, CHCl3); IR (film) 3030, 1731 cm-1; 1H NMR
δ 1.99 (3H, s), 2.67 (1H, dd, J ) 18.7 and 2.6 Hz), 2.98 (1H, dd,
J ) 15.0 and 3.8 Hz), 3.73 (1H, d, J ) 13.4 Hz), 3.99 and 4.17
(2H, ABq, J ) 8.9 Hz), 4.14 (1H, d, J ) 6.3 Hz), 4.25-4.33 (1H,
m), 4.44 and 4.50 (2H, ABq, J ) 11.9 Hz), 4.58 and 4.65 (2H,
ABq, J ) 11.5 Hz), 4.71 and 4.83 (2H, ABq, J ) 11.3 Hz), 5.63
(1H, brd, J ) 10.3 Hz), 5.75 (1H, brd, J ) 10.2 Hz), 7.19-7.31
(15H, m); 13C NMR δ 22.1, 30.0, 68.9, 71.7, 73.2, 74.7, 78.2, 78.8,
84.5, 125.6, 125.6, 127.4, 127.6, 127.8, 128.2, 138.0, 138.5, 138.7,
170.5; MS (FAB) m/z (relative intensity) 472 ([M]+, 2); HRMS
(EI) [M]+ calcd for C30H32O5 472.2249, found 472.2251.
hexanes/ethyl acetate); [R]21 +6.7 (c ) 0.6, CHCl3); IR (film)
D
3440, 2971, 2938, 2876, 1353, 1172 cm-1; 1H NMR δ 0.91-0.99
(6H, m), 1.57-1.99 (5H, m), 3.97 (2H, brd, J ) 1.2 Hz), 4.28-
4.34 (2H, m), 4.51 and 4.46 (2H, ABq, J ) 12.0 Hz), 4.79 and
4.74 (2H, ABq, J ) 12.3 Hz), 4.93 and 4.54 (2H, ABq, J ) 10.8
Hz), 7.23-7.42 (15H, m); 13C NMR δ 8.6, 8.7, 28.2, 30.2, 35.6,
72.0, 72.6, 73.1, 74.3, 74.5, 75.3, 77.6, 77.8, 113.0, 127.4, 127.5,
127.7, 128.0, 128.2, 137.9, 138.3; MS (FAB) m/z (relative
intensity) 532 ([M]+, 9); HRMS [M + H]+ calcd for C33H41O6
533.2897, found 533.2877.
(1S,2S,3R,4S,5S)-5-O-Acet yl-3,4-d i-O-b en zyl-5-(b en zyl-
oxym eth yl)cycloh exa n e-1,2,3,4,5-p en tol (15). To a solution
of the alkene 14 (288 mg, 0.61 mmol) in ethyl acetate (6 mL)
and CH3CN (6 mL) was added a solution of NaIO4 (200 mg, 0.94
mmol) and ruthenium trichloride (9 mg, 0.04 mmol) in H2O (2
mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 min
and quenched with a saturated, aqueous sodium thiosulfate
solution (10 mL). The aqueous layer was extracted with ethyl
acetate (3 × 15 mL). The combined organic extracts were washed
with brine (10 mL), dried over MgSO4, and filtered. Concentra-
tion of the filtrate followed by flash chromatography (1:1
hexanes/ethyl acetate) gave the diol 15 (245 mg, 81%) as a
(1R,2S,3S,4S,5S)-5-O-Acet yl-3,4-d i-O-b en zyl-5-(b en zyl-
oxym eth yl)-1,2-O-eth ylp r op ylid en e-cycloh exa n e-1,2,3,4,5-
p en tol (11). To a solution of the tertiary alcohol 10 (467 mg,
0.88 mmol) in dry pyridine (5 mL) were added acetic anhydride
(6 mL, 64 mmol) and a catalytic amount of DMAP (ca. 5 mg) at
room temperature. The reaction mixture was stirred for 24 h.
The mixture was diluted with CH2Cl2 (30 mL) and washed with
saturated NaHCO3 solution (15 mL). The aqueous layer was
extracted with CH2Cl2 (2 × 15 mL). The combined organic
extracts were washed with brine (15 mL), dried over MgSO4,
and filtered. Concentration of the filtrate followed by flash
colorless oil: Rf ) 0.33 (1:1 hexanes/ethyl acetate); [R]21 +34.9
D
(c ) 2.3, CHCl3); IR (film) 3452, 1730 cm-1; 1H NMR δ 1.80 (1H,
dd, J ) 15.5 and 3.1 Hz), 1.95 (3H, s), 2.14 (1H, brs), 2.20 (1H,
brs), 2.93 (1H, brd, J ) 10.6 Hz), 3.50-3.53 (1H, m), 3.74 (2H,
d, J ) 8.4 Hz), 3.93-4.03 (2H, m), 4.10 (1H, d, J ) 8.6 Hz), 4.34
and 4.43 (2H, ABq, J ) 11.7 Hz), 4.68 and 4.63 (2H, ABq, J )
4 Hz), 4.76 (1H, d, J ) 11.2 Hz), 4.86 (1H, d, J ) 11.4 Hz), 7.18-

Notes
J . Org. Chem., Vol. 66, No. 21, 2001 7189
7.31 (15H, m); MS (FAB) m/z (relative intensity) 507 ([M + H]+,
1). Anal. Calcd for C30H34O7: C, 71.13; H, 6.76. Found: C, 71.20;
H, 6.68.
Method B. To a solution of the tertiary alcohol 16 (30 mg,
0.05 mmol) in dry benzene (4 mL) was added Martin sulfurane
dehydrating agent25 (60 mg, 0.09 mmol) at room temperature.
The reaction mixture was refluxed for 1 h under nitrogen.
Concentration of the mixture was followed by dilution with CH2-
Cl2 (15 mL) and washing with brine (10 mL). The aqueous layer
was extracted with CH2Cl2 (2 × 10 mL). The combined organic
extracts were dried over MgSO4 and filtered. Concentration of
the filtrate followed by flash chromatography (1:1 hexane/diethyl
ether) gave the alkene 17 (24 mg, 90%).
(1S,2S,3R,4S,5S)-1,2-Di-O-a cetyl-3,4-d i-O-ben zyl-5-(ben -
zyloxym eth yl)cycloh exa n e-1,2,3,4,5-p en tol (16). To a solu-
tion of the diol 15 (31 mg, 0.061 mmol) in MeOH (2 mL) was
added a catalytic amount of potassium carbonate at room
temperature, and the mixture was stirred for 3 h at room
temperature. The mixture was diluted with CH2Cl2 (10 mL) and
washed with a saturated, aqueous ammonium chloride solution.
The aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The
combined organic extracts were washed with brine (10 mL),
dried over MgSO4, and filtered. Concentration of the filtrate
followed by flash chromatography (1:1 hexanes/ethyl acetate)
gave a triol (26 mg, 92%) as a white solid: mp 81-83 °C; Rf )
(1R,2R,3R,4S,5S)-3,4-Di-O-ben zyl-5-(ben zyloxym eth yl)-
cycloh exa n e-1,2,3,4,5-p en tol (21). To a solution of the acetal
10 (169 mg, 0.32 mmol) in CH2Cl2 (15 mL) were added TFA (0.25
mL) and water (5 drops) at room temperature. The mixture was
stirred for 3 h. Concentration of the mixture followed by flash
chromatography (1:1 hexanes/ethyl acetate) gave the triol 21
(129 mg, 87%) as a colorless oil: Rf ) 0.16 (2:1 hexanes/ethyl
acetate); [R]21D -1.2 (c ) 1.5, CHCl3); IR (film) 3428, 3087, 3062,
0.36 (1:1 hexanes/ethyl acetate); [R]20 +34.3 (c ) 1.1, CHCl3);
D
IR (film) 3418 cm-1; H NMR δ 1.91 (1H, dd, J ) 15.3 and 2.7
1
Hz), 2.06 (1H, dd, J ) 15.3 and 3.1 Hz), 2.68 (1H, d, J ) 6.4
Hz), 3.20 and 3.47 (2H, ABq, J ) 8.7 Hz), 3.27 (1H, brs), 3.53-
3.56 (2H, m), 3.90 (1H, t, J ) 9.4 Hz), 4.02-4.06 (1H, m), 4.41
and 4.48 (2H, ABq, J ) 11.8 Hz), 4.54 (1H, d, J ) 10.8 Hz),
4.84-4.93 (3H, m), 7.19-7.39 (15H, m); 13C NMR δ 34.2, 70.2,
72.9, 73.1, 75.1, 75.4, 76.2, 80.8, 81.4, 127.5, 127.6, 127.7, 128.0,
128.3, 137.6, 138.0, 138.6; MS (FAB) m/z (relative intensity) 465
([M + H]+, 100); HRMS (L-SIMS) [M + H]+ calcd for C28H33O6
465.2277, found 465.2256.
1
3029, 2918, 2864, 1027 cm-1; H NMR δ 1.86 (1H, dd, J ) 13.2
and 4.8 Hz), 1.89-2.15 (4H, m), 3.20 and 3.41 (2H, ABq, J )
8.7 Hz), 3.77 (1H, dd, J ) 9.3 and 2.7 Hz), 3.90 (1H, d, J ) 9.3
Hz), 3.99 (1H, ddd, J ) 11.7, 4.8, and 2.7 Hz), 4.19 (1H, brs),
4.44 and 4.52 (2H, ABq, J ) 12.0 Hz), 4.51 and 4.88 (2H, ABq,
J ) 10.8 Hz), 4.69 (2H, brs), 7.19-7.35 (15H, m); 13C NMR δ
35.1, 66.5, 70.5, 72.3, 73.2, 73.4, 74.0, 75.5, 77.6, 80.3, 127.7,
127.8, 128.1, 128.3, 128.3, 128.4, 137.8, 138.0, 138.2; MS (EI)
m/z (relative intensity) 466 ([M + 2H]+, 9); HRMS (L-SIMS) [M
+ H]+ calcd for C28H32O6 465.2272, found 465.2251.
To a solution of the triol (26 mg, 0.056 mmol) in CH2Cl2 (10
mL) were added acetic anhydride (1 mL, 10.6 mmol), pyridine
(1 mL, 11 mmol), and a catalytic amount DMAP at room
temperature. The reaction mixture was stirred for 12 h at room
temperature. The mixture was diluted with CH2Cl2 (15 mL) and
washed with aqueous, saturated Na2CO3. The aqueous layer was
extracted with CH2Cl2 (2 × 10 mL). The combined organic
extracts were washed with brine (10 mL), dried over MgSO4,
and filtered. Concentration of the filtrate followed by flash
chromatography (1:1 hexane/diethyl ether) afforded the tertiary
alcohol 16 (30 mg, 96%) as a white solid: mp 62-65 °C; Rf )
(1R,2R,3R,4S,5S)-1,2-Di-O-a cetyl-3,4-d i-O-ben zyl-5-(ben -
zyloxym eth yl)cycloh exa n e-1,2,3,4,5-p en tol (22). To a solu-
tion of the diol 21 (69 mg, 0.15 mmol) in dry pyridine (10 mL)
were added acetic anhydride (1 mL, 11 mmol) and a catalytic
amount of DMAP (ca. 3 mg) at room temperature. The reaction
mixture was stirred for 2 h. Concentration of the reaction
mixture followed by flash chromatography (1:1 hexanes/ethyl
acetate) gave diacetate 22 (81 mg, 98%) as a white solid: mp
100-101 °C; Rf ) 0.16 (2:1 hexanes/ethyl acetate); [R]21 -8.7
D
(c ) 0.8, CHCl3); IR (film) 3463, 3092, 3064, 3031, 2937, 2865,
0.65 (1:1 hexanes/ethyl acetate); [R]21 +23 (c ) 0.9, CHCl3); IR
1744, 1243, 1228, 1047, 1029, 739, 698 cm-1 1H NMR δ 1.86
;
D
(film) 3478, 1738 cm-1; H NMR δ 1.97 (3H, s), 2.04 (2H, dd, J
1
(1H, dd, J ) 13.5 and 4.8 Hz), 2.01 (3H, s), 2.17 (3H, s), 2.26
(1H, t, J ) 13.2 Hz), 2.49 (1H, brs), 3.21 and 3.47 (2H, ABq, J
) 8.7 Hz), 3.85-3.94 (2H, m), 4.42-4.55 (4H, m), 4.72 (1H, d, J
) 11.7 Hz), 4.90 (1H, d, J ) 11.4 Hz), 5.20 (1H, ddd, J ) 12.3,
4.8, and 2.4 Hz), 5.80 (1H, brs), 7.17-7.36 (15H, m); 13C NMR δ
20.9, 21.0, 32.4, 67.5, 68.8, 72.0, 73.2, 73.2, 73.8, 75.6, 77.4, 78.1,
127.5, 127.7, 127.7, 127.8, 128.0, 128.1, 128.3, 128.3, 128.3, 128.4,
137.7, 138.0, 138.2, 170.1, 170.5; MS (EI) m/z (relative intensity)
549 ([M + H]+, 4); HRMS (L-SIMS) [M + H]+ calcd for C35H42O7
549.2483, found 549.2448.
) 5.7 and 3.5 Hz), 2.09 (3H, s), 2.68 (1H, brs), 3.14 and 3.45
(2H, ABq, J ) 8.7 Hz), 3.78 (1H, d, J ) 9.4 Hz), 4.19 (1H, t, J )
9.9 Hz), 4.39 and 4.45 (2H, ABq, J ) 11.9 Hz), 4.52 and 4.90
(2H, ABq, J ) 10.9 Hz), 4.75 and 4.83 (2H, ABq, J ) 11.2 Hz),
4.96 (1H, dd, J ) 10.2 and 3.3 Hz), 5.37 (1H, q, J ) 3.2 Hz),
7.19-7.38 (15H, m); 13C NMR δ 20.8, 21.2, 32.9, 69.4, 73.0, 73.2,
73.6, 74.3, 75.6, 75.7, 78.2, 80.5, 127.5, 127.6, 127.8, 128.0, 128.3,
128.4, 137.6, 138.1, 138.5, 170.2, 170.3; HRMS (EI) [M - H]+
calcd for C32H36O8 547.2332, found 547.2359.
(1S,2S,3S,4R)-1,2-Di-O-a cetyl-3,4-d i-O-ben zyl-5-(ben zyl-
oxym eth yl)-5-cycloh exen e-1,2,3,4-tetr a ol (17). Method A. To
a solution of thionyl chloride (0.01 mL, 0.14 mmol) in dry CH2-
Cl2 (5 mL) at 0 °C was added dropwise a solution of the tertiary
alcohol 16 (50 mg, 0.09 mmol) in dry CH2Cl2 (5 mL) and pyridine
(0.08 mL, 0.99 mmol) for 30 min at 0 °C, and the resultant
mixture was stirred overnight at 0 °C. The reaction mixture was
diluted with CH2Cl2 (10 mL) and washed with saturated
NaHCO3 (10 mL). The aqueous layer was extracted with CH2-
Cl2 (2 × 10 mL). The combined organic extracts were washed
with brine (10 mL), dried over MgSO4, and filtered. Concentra-
tion of the filtrate followed by flash chromatography (2:1 hexane/
diethyl ether) gave alkene 17 (20 mg, 40%) and alkene 18 (21
mg, 42%) as colorless oils. Compound 17: Rf ) 0.34 (2:1 hexane/
(1S,2S,3R,4S)-1,2-Di-O-a cetyl-3,4-d i-O-ben zyl-5-(ben zyl-
oxym eth ylen e)-5-cycloh exen e-1,2,3,4-tetr a ol (23). To a solu-
tion of the tertiary alcohol 22 (34 mg, 0.06 mmol) in dry benzene
(10 mL) was added Martin sulfurane dehydrating agent (60 mg,
0.09 mmol) at room temperature. The reaction mixture was
refluxed for 1 h under nitrogen. Concentration of the mixture
was followed by dilution with CH2Cl2 (15 mL) and washing with
brine (10 mL). The aqueous layer was extracted with CH2Cl2 (2
× 10 mL). The combined organic extracts were dried over MgSO4
and filtered. Concentration of the filtrate followed by flash
chromatography (1:1 hexane/diethyl ether) gave the alkene 23
(19 mg, 60%) as a colorless oil: Rf ) 0.29 (2:1 hexane/diethyl
ether); [R]21 -36.5 (c ) 1.5, CHCl3); IR (film) 1744, 1684 cm-1
;
D
1H NMR δ 2.01 (3H, s), 2.12 (3H, s), 2.32 (1H, t, J ) 10.5 Hz),
2.87 (1H, dd, J ) 13.5 and 5.1 Hz), 3.51 (1H, dd, J ) 8.2 and 3.0
Hz), 4.10 (1H, brd, J ) 8.2 Hz), 4.54 and 4.68 (2H, ABq, J )
11.6 Hz), 4.55 and 4.65 (2H, ABq, J ) 11.4 Hz), 4.80-4.86 (3H,
m), 5.65 (1H, m), 6.37 (1H, s), 7.22-7.41 (15H, m); HRMS (EI)
[M]+ calcd for C32H34O7 530.2304, found 530.2297.
diethyl ether); [R]21D +48.5 (c ) 0.9, CHCl3); IR (film) 1746 cm-1
;
1H NMR δ 1.97 (3H, s), 2.07 (3H, s), 3.98 (1H, d, J ) 6.4 Hz),
4.13-4.54 (3H, m), 4.44 and 4.52 (2H, ABq, J ) 11.8 Hz), 4.68
(1H, d, J ) 10.9 Hz), 4.74-4.84 (3H, m), 5.13 (1H, dd, J ) 9.6
and 3.8 Hz), 5.58 (1H, t, J ) 4.5 Hz), 5.85 (1H, d, J ) 5.3 Hz),
7.24-7.37 (15H, m); HRMS (L-SIMS) [M]+ calcd for C32H34O7
530.2304, found 530.2306. Compound 18: Rf ) 0.37 (2:1 hexane/
(1S,2S,3S,4R)-3,4-Di-O-ben zyl-1-ben zyla m in o-5-(ben zyl-
oxym eth yl)-5-cycloh exen e-2,3,4-tr iol (26). To a solution of
the allylic acetate 17 (100 mg, 0.19 mmol) in CH3CN (15 mL)
were added PPh3 (10 mg, 0.04 mmol) and Pd(PPh3)4 (22 mg, 0.02
mmol) at room temperature. The mixture was stirred for 30 min
at room temperature. Benzylamine (0.06 mL, 0.55 mmol) was
added at room temperature, and the reaction mixture was then
heated under reflux overnight. The solvent was removed under
reduced pressure. The residue was purified by flash chroma-
diethyl ether); [R]21D +23.1 (c ) 0.8, CHCl3); IR (film) 1744 cm-1
;
1H NMR δ 2.04 (3H, s), 2.06 (3H, s), 2.40-2.62 (2H, m), 4.08
(1H, d, J ) 11.5 Hz), 4.16-4.22 (2H, m), 4.35 and 4.40 (2H, ABq,
J ) 11.9 Hz), 4.63 (3H, d, J ) 11.4 Hz), 4.82 (1H, d, J ) 11.4
Hz), 5.34-5.41 (1H, m), 5.46 (1H, dd, J ) 3.6 and 2.3 Hz), 7.25-
7.41 (15H, m); HRMS (L-SIMS) [M]+ calcd for C32H34O7 530.2304,
found 530.2309.

7190 J . Org. Chem., Vol. 66, No. 21, 2001
Notes
tography (1:1 hexanes/EtOAc) to give the crude coupled product
24 (70 mg, 65%) as a colorless oil. To a solution of compound 24
in MeOH (10 mL) was added a catalytic amount of NaOMe, and
the mixture was refluxed overnight. The solvent was removed
under reduced pressure. The residue was purified by flash
chromatography (2:1 hexanes/EtOAc) to give benzylamine 26 (61
(1S,2S,3S,4R)-1-Acet a m id o-5-(a cet oxym et h yl)-2,3,4-t r i-
O-a cetyl-5-cycloh exen e-2,3,4-tr iol (28). To a solution of the
amine 26 (78.4 mg, 0.15 mmol) in dry THF (3 mL) and liquid
NH3 (15 mL) was added sodium (76 mg, 3.3 mmol) at -78 °C.
The reaction mixture was stirred for 2 h at -78 °C. Solid NH4-
Cl (100 mg) was added to the mixture at -78 °C. After the
disappearance of the blue color of the mixture, NH3 and solvent
were removed under reduced pressure to give crude valienamine
(1). The crude product 1 was dissolved in pyridine (10 mL) and
acetic anhydride (3 mL) containing a catalytic amount of DMAP.
The mixture was stirred overnight at room temperature. The
reaction mixture was diluted with EtOAc (10 mL) and washed
with saturated NaHCO3 (10 mL). The aqueous layer was
extracted with EtOAc (2 × 20 mL). The combined organic
extracts were washed with brine (10 mL), dried over MgSO4,
and filtered. Concentration of the filtrate followed by flash
chromatography (1:4 hexanes/EtOAc) gave pentaacetate 28 (38.3
mg, 69%) as a white solid, identical to an authentic sample from
our previous work: mp 93-94 °C (lit.1a mp 92-94 °C); Rf ) 0.29
mg, 60%) as a colorless oil: Rf ) 0.37 (2:1 hexanes/EtOAc); [R]21
D
+39.4 (c ) 1.0, CHCl3); IR (film) 3418 cm-1; 1H NMR δ 2.11 (2H,
brs), 3.40 (1H, t, J ) 4.3 Hz), 3.81 (1H, dd, J ) 7.7 and 5.1 Hz),
3.88-3.49 (4H, m), 4.06 (1H, d, J ) 5.1 Hz), 4.19 (1H, d, J )
12.2 Hz), 4.40 and 4.49 (2H, ABq, J ) 11.8 Hz), 4.57 and 4.73
(2H, ABq, J ) 11.1 Hz), 4.68 and 4.82 (2H, ABq, J ) 11.5 Hz),
5.90 (1H, d, J ) 2.8 Hz), 7.22-7.36 (20H, m); MS (EI) m/z
(relative intensity) 534 ([M - H]+, 0.7); HRMS (EI) [M]+ calcd
for C35H37NO4 535.2723, found 535.2722.
(1S,2S,3S,4R)-3,4-Di-O-ben zyl-5-(ben zyloxym eth yl)-1-pr o-
p yla m in o-5-cycloh exen e-2,3,4-tr iol (27). To a solution of the
allylic acetate 17 (116 mg, 0.22 mmol) in CH3CN (15 mL) were
added PPh3 (10 mg, 0.04 mmol) and Pd(PPh3)4 (25 mg, 0.02
mmol) at room temperature. The mixture was stirred for 30 min
at room temperature. Propylamine (0.07 mL, 0.85 mmol) was
added, and the reaction mixture was refluxed overnight. The
solvent was removed under reduced pressure. The residue was
purified by flash chromatography (1:1 hexanes/EtOAc) to give
the crude compound 25 (74 mg) as a colorless oil. To a solution
of amine 25 in MeOH (10 mL) was added a catalytic amount of
NaOMe, and the mixture was refluxed overnight. The solvent
was removed under reduced pressure, and the residue was
purified by flash chromatography (EtOAc) to give the propy-
lamine 27 (60 mg, 58%) as a colorless oil: Rf ) 0.37 (EtOAc);
(1:4 hexanes/EtOAc); [R]20 +20.1 (c ) 0.8, CHCl3); IR (film)
D
3366, 3281, 1746, 1658 cm-1 1H NMR δ 2.00-2.05 (15H, m),
;
4.37 and 4.63 (2H, ABq, J ) 13.2 Hz), 4.98-5.09 (2H, m), 5.36
(1H, brd, J ) 6.3 Hz), 5.43 (1H, dd, J ) 9.3 and 6.3 Hz), 5.80
(1H, brd, J ) 8.6 Hz), 5.87 (1H, dd, J ) 5 and 1.1 Hz); 13C NMR
δ 20.6, 23.2, 44.9, 62.9, 68.5, 69.2, 71.2, 126.2, 134.3, 169.8, 170.0,
170.1, 170.2.
Ack n ow led gm en t. Financial support from Hong
Kong RGC Earmarked Grant (Ref No. CUHK 308/96P)
is gratefully acknowledged.
[R]21 +31.7 (c ) 0.8, CHCl3); IR (film) 3417 cm-1 1H NMR δ
;
D
0.92 (3H, t, J ) 7.4 Hz), 1.53 (2H, q, J ) 7.3 Hz), 2.19 (2H, brs),
2.57-2.82 (2H, m), 3.33 (1H, m), 3.75 (1H, dd, J ) 7.8 and 5.3
Hz), 3.88-3.94 (2H, m), 4.07 (1H, d, J ) 5.4 Hz), 4.20 (1H, d, J
) 12.3 Hz), 4.41 and 4.50 (2H, ABq, J ) 11.9 Hz), 4.57 and 4.74
(2H, ABq, J ) 11.1 Hz), 4.70 and 4.86 (2H, ABq, J ) 11.3 Hz),
5.96 (1H, d, J ) 3.1 Hz), 7.22-7.35 (15H, m); MS (EI) m/z
(relative intensity) 488 (MH+, 7.7); HRMS (EI) [M]+ calcd for
Su p p or tin g In for m a tion Ava ila ble: 1H spectra of 6-8,
10-12, 14, 16-18, 21-23, 26, and 27. This material is
available free of charge via the Internet at http://pubs.acs.org.
C
31H37NO4 487.2722, found 487.2694.
J O010202T