New access to unsaturated keto carba sugars (gabosines) using an intramolecular nozaki-kishi reaction as the key step

Full text of DOI:10.1021/jo980309p

5668
J . Org. Chem. 1998, 63, 5668-5671
Sch em e 1
New Access to Un sa tu r a ted Keto Ca r ba
Su ga r s (Ga bosin es) Usin g a n
In tr a m olecu la r Noza k i-Kish i Rea ction a s
th e Key Step
Andre´ Lubineau* and Isabelle Billault
Laboratoire de Chimie Organique Multifonctionnelle (URA
CNRS 462), Institut de Chimie Mole´culaire, Universite´
Paris-Sud, Bt 420, F-91405 Orsay Cedex, France
Received February 19, 1998
We report here the first synthesis of gabosine I 1 in
nine steps from tetra-O-benzyl-D-glucose 2 (Scheme 1).
The gabosines, the majority of which are trihydroxylated
cyclohexenone derivatives, have been isolated from Strep-
tomyces strains.1 These unsaturated keto carbasugars
present a great structural diversity due to variations at
three asymmetric centers and differing substitutions at
C-2 or C-3 such as for example in 3 or 4. Isolation of 10
skeleton and have focused on the preparation of gabosine
I 1,9 which could serve as a precursor of various glucosi-
dase inhibitors. A key step in our synthesis was a
Nozaki-Kishi mediated cyclization10 which provides a
new and efficient access to functionalized cyclohexene
derivatives.11
Resu lts a n d Discu ssion
gabosines has been reported, and to these may be added
the glyoxylase I inhibitor (COTC)2 5 and the antibiotic
KD16-U13 6 (gabosine C). Several methods for the
synthesis of 5 and 6 have been developed.4,5 Moreover,
gabosine-related derivatives have been used as interme-
diates for the synthesis of biological active compounds
(i.e., a L-fucosyl-transferase inhibitor,6 valienamine and
derivatives,7 and a “pseudo sugar C-disaccharide” 8).
Considering their versatily as synthons, we are interested
in developing a new general access to the gabosines
Starting from tetra-O-benzyl-D-glucose 2, the silylated
D-glucitol 8 was prepared, upon sodium borohydride
reduction12 followed by silylation (Scheme 1). Oxidation
of 8 with either PCC in the presence of AcONa13 or with
the Dess-Martin periodinane14 (DMP) gave the L-sorbose
derivative 9 (90%). This ketone reacted with chloro-
methylenetriphenylphosphorane15 at -70 °C in THF to
give 10a /10b in 92% yield, while the bromo analogue 11
was obtained in 74% yield by reaction of 9 with bromo-
(1) Bach, G.; Breiding-mack, S.; Grabley, S.; Hammann, P.; Hu¨tter,
K.; Thiericke, R.; Uhr, H.; Wink, J .; Zeeck, A. Liebig Ann. Chem. 1993,
241-250.
(9) In ref 1, only the relative configuration of gabosine I has been
determined, giving the possibility of either an ido or gluco configura-
tion.
(2) Takeuchi, T.; Chimura, H.; Hamada, M.; Umezawa, H. J .
Antibiot. 1975, 28, 737-742.
(10) CrCl2 in the presence of catalytic amounts of NiCl2. (a) Takai,
K.; Taghashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H.
J . Am. Chem. Soc. 1986, 108, 6048-6050. (b) J in, H.; Uenishi, J .-I.;
Christ, W. J .; Kishi, Y. J . Am. Chem. Soc. 1986, 108, 5644-5646.
(11) For a review on the conversion of carbohydrate derivatives into
functionalized cyclohexanes and cyclopentanes, see: Ferrier R. J .;
Middleton S. Chem. Rev. 1993, 93, 2779-2831. For an alternative
synthesis of cyclohexene derivatives, see: McIntosh M. C.; Weinreb
S. M. J . Org. Chem. 1991, 56, 5010-5012.
(12) Rao, V. S.; Perlin, A. S. Can. J . Chem. 1995, 59, 333-338.
(13) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 31, 2647-
2650.
(14) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4156-
4158. (b) Meyer, S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549-
7552.
(3) Tatsuta, K.; Tsuchiya, T.; Mikami, N.; Umezawa, S.; Umezawa,
H.; Naganawa, H. J . Antibiot. 1974, 27, 579-586.
(4) (a) Mirza, S.; Molleyres, L.-P.; Vasella, A. Helv. Chim. Acta 1985,
988-996. (b) Takayama, H.; Hayashi, K.; Koizumi, T. Tetrahedron Lett.
1986, 27, 5509-5512. (c) Shing, T. K. M.; Tang, Y.; Tetrahedron 1990,
46, 6575-6584. (d) Yamakoshi, Y. N.; Ge, W.-Y.; Sugita, J .; Okayama,
K.; Takahashi, T.; Koizumi, T. Heterocyles 1996, 42, 129-133.
(5) Lygo, B.; Swiatyj, M.; Trabsa, H.; Voyle, M. Tetrahedron Lett.
1994, 35, 4197-4200.
(6) Cai, S.; Stroud, M. R.; Hakomori, S.; Toyokuni, T. J . Org. Chem.
1992, 57, 6693-6696.
(7) (a) Horii, S.; Fukase, H. European Patent EP 0240175B1, 1987.
(b) Horii, S.; Kameda, Y.; Fukase, H. European Patent EP 0089812A1,
1983.
(8) Barbaud, C.; Bols, M.; Lundt, I.; Sierks, M. R. Tetrahedron 1995,
51, 9063-9078.
(15) Miyano, S.; Izumi, Y.; Hashimoto, H. J . Chem. Soc., Chem.
Commun. 1978, 446-447.
S0022-3263(98)00309-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/21/1998

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5669
by hydrogenolysis could not be envisaged, and we there-
27
fore used BCl3 at -78 °C and obtained gabosine I 1 in
74% yield. In this latter step neither epimerization at
C-6 or â-elimination were observed. Compound 1 was
obtained as a hygroscopic brown solid compound which
prevented us from getting a reliable melting point, but
it was fully characterized through a high-resolution mass
spectrum and 1H and 13C NMR spectra which confirm
its homogeneity and which were found to be identical to
those already described.1 Finally, the negative value of
the specific rotation, although smaller than the reported
one, gave indication that the natural compound1 has the
gluco configuration.
In conclusion, we have prepared gabosine I 1 in nine
steps from tetra-O-benzyl-D-glucose via a Nozaki-Kishi
reaction. The cyclization of vinyl bromide 15 using this
reaction provides a novel and efficient access to func-
tionalized cyclohexene derivatives. Moreover, this method
could be extended in principle to other sugars and should
allow the preparation of a large number of gabosine type
compounds.
F igu r e 1.
methylenetriphenylphosphorane.16,17 The Wittig reaction
turned out to be very stereoselective,14,18 yielding exclu-
sively the Z-isomer for the vinyl bromide 11 and a 98:2
Z/E mixture for the vinyl chlorides 10a /10b. The pres-
ence of 10b (E-isomer) in the mixture has been evidenced
by a second vinylic proton NMR signal at δ 6.22. The
configurations of 10a and 11 were assigned on the basis
of NOE data. The NOESY spectra of 10a /10b and 11
show a NOE between the vinylic proton H-1 and the
allylic proton H-7 and H-7′ but not between H-1 and H-3,
suggesting a Z configuration (Figure 1). The vinyl
halogenides 10a and 11 were then desilylated with
tetrabutylammonium fluoride19 to afford the alcohols 12
(90%) and 13 (80%), respectively. Oxidation of 12, with
DMP,12 and of 13, under Swern conditions,20 yielded the
aldehydes 1421 (70%) and 15 (89%). We failed to cyclize
14 under Barbier conditions,22 using magnesium as the
metal. Turning to the more reactive bromide 15, with
lithium activation, the problem was not solved, and at
room temperature no reaction was detected, while at 40
°C, a â-elimination occurred. The Nozaki-Kishi reac-
tion10 is known to promote the addition of vinyl halo-
genides or triflate to aldehydes. Examples of macrocy-
clizations using this reagent have been reported,23 but
to the best of our knowledge it has never been applied to
the synthesis of cyclohexenes. Very pleasingly, the Cr/
Ni catalysis smoothly promoted the cyclization of the
vinyl bromide 15 and gave 16a /16b24 in 61% yield.
Exp er im en ta l Section
Gen er a l. Chemical shifts are reported in δ vs Me4Si for 1H
NMR spectra and relative to the CDCl3 resonance at 77.00 ppm
for 13C NMR spectra. Solvents were distilled just before use:
THF from sodium/benzophenone, CH2Cl2 and DMF from CaH2.
Oxygen free DMF was obtained by passing argon under ultra-
sound. Elemental analyses were performed at the service
central de microanalyses du CNRS at Gif-sur-Yvette.
1-O-ter t-Bu tyld im eth ylsilyl-2,3,4,6-tetr a -O-ben zyl-D-glu -
citol (8). Pyridine (90 mL) was added to a mixture of 710 (4.90
g, 9.04 mmol) and t-Bu(Me)2SiCl (1.93 g, 10.8 mmol) at 0 °C.
The reaction mixture was then slowly warmed to room temper-
ature and stirred overnight. The mixture was then concentrated
and the residue dissolved in CH2Cl2 (100 mL). The organic
phase was washed with water (100 mL), filtered on phase
separator filter, and then concentrated. Flash chromatography
(hexane/AcOEt 9:1) of the residue (6.20 g) gave 5.72 g (97%) of
8 as colorless syrup. 1H NMR (CDCl3): δ 0.00 (s, 6H, (CH3)2-
Si); 0.87 (s, 9H, (CH3)3C); 3.10 (br d, 1H, J ) 4.5 Hz, OH); 3.61
(br d, 2H, J ) 4.5 Hz, H-1, H1′); 3.66-3.90 (m, 5H, H-6, H-6′,
H-2, H-3, H-4); 3.98 (m, 1H, H-5); 4.47 (d, 1H, J ) 12.0 Hz,
PhCH); 4.53 (d, J ) 12.0 Hz, 1H, PhCH); 4.55 (s, 2H, PhCH2);
4.61 (d, J ) 11.5 Hz, 1H, PhCH); 4.64 (s, 2H, PhCH2); 4.73 (d,
J ) 11.5 Hz, 1H, PhCH); 7.15-7.40 (m, 20 H aromatic). 13C
NMR (CDCl3): δ -5.5, 18.1, 25.8, 62.8, 70.9, 71.1, 73.1, 73.3, 74.1,
77.41, 78.08, 79.60, 127.5-128.4, 138.0, 138.1, 138.2, 138.4. IR
25
Oxidation of the allylic alcohols 16a /16b with MnO2 or
the DMP12 gave the enone 1726 in only moderate yields
(ca. 50%). Better yields (76%) were obtained by using
PCC in the presence of AcONa.11 Debenzylation of 17
(16) Matsumoto, M.; Kuroda, K. Tetrahedron Lett. 1980, 21, 4021-
4024.
(17) While chloromethylenetriphenylphosphorane could be prepared
at room temperature, the bromomethylenetriphenylphosphorane had
to be prepared at much lower temperature (-5 °C) and had to be used
immediately.
(neat): 3500 cm-1 (OH). [R]24 ) +20 (c 1.75, CH2Cl2). Anal.
D
Calcd for C40H52O6Si (656.94): C, 73.13; H, 7.98. Found: C,
72.99; H, 7.97.
1,3,4,5-Tetr a -O-ben zyl-6-O-ter t-bu tyld im eth ylsilyl-L-sor -
bose (9). A suspension of AcONa (2.25 g, 27.4 mmol), PCC (2.95
g, 13.6 mmol), and 4 Å molecular sieves (5.30 g) in CH2Cl2 (30
mL) was stirred for 1 h at room temperature; then a solution of
8 (3.00 g, 4.56 mmol) in CH2Cl2 (15 mL) was added. After 2 h,
the mixture was diluted with Et2O (90 mL) and hexane (45 mL)
and the mixture was stirred for a further 15 min. The suspen-
sion was filtered through a silica gel (70-200 µm) column which
was further eluted with Et2O (400 mL). The organic phase was
concentrated to 100 mL, washed with water (100 mL), and then
dried (MgSO4). After evaporation, flash chromatography (hex-
ane/AcOEt 9:1 with Et3N 0.2%) of the residue (3.10 g) gave 2.55
g of 9 (89%) as colorless syrup. 1H NMR (CDCl3): δ 0.00 (s, 6H,
(CH3)2Si); 0.85 (s, 9H, (CH3)3C); 3.60 (dd, 1H, J ) 7.5, 12.0 Hz,
H-6); 3.74 (m, 2H, H-6′, H-5); 3.97 (t, 1H, J ) 4.0 Hz, H-4); 4.18
(d, 1H, J ) 17.5 Hz, H-1); 4.19 (d, 1H, J ) 4.0 Hz, H-3); 4.26 (d,
1H, J ) 17.5 Hz, H-1′); 4.39 (s, 2H, PhCH2); 4,44 (d, 1H, J )
12.0 Hz, PhCH); 4.49 (d, 1H,J ) 12.0 Hz, PhCH); 4.56 (d, 1H, J
(18) (a) J ust, G.; O’Connor, B. Tetrahedron Lett. 1988, 29, 753-756.
(b) O’Donnell, M. J .; Arasappan, A.; Hornback, W. J .; Huffman, J . C.
Tetrahedron Lett. 1990, 31, 157-160.
(19) Corey, E. J .; Venkasteswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190-6191.
(20) Mancuso, A. J .; Huang, S. L.; Swern, D.J . Org. Chem. 1978,
43, 2480-2483.
(21) Degradation of aldehyde 14 may be observed, even after two
purifications by flash chromatography. It was rapidely used in the
following cyclization step.
(22) (a) Barbier, P. C.R. Acad. Sci. Paris 1899, 110-111. (b)
Blomberg, C.; Hartog, F. A. Synthesis 1977, 18-31. For cyclization
using this reaction, see: Leroux, Y. Bull. Soc. Chim. Fr. 1968, 359-
364.
(23) (a) Schreiber, S. L.; Meyers, H. V. J . Am. Chem. Soc. 1988, 110,
5180-5200. (b) MacMillan, D. W. C.; Overman L. E. J . Am. Chem.
Soc. 1995, 117, 10391-10392.
(24) The (1R) diastereoisomer 16b has been described: Schmidt, R.
R.; Laesecke, K. CH 648 326 A5, 1981.
(25) Hoeger, C. A.; J ohnston, A. D.; Okamura , W. H. J . Am. Chem.
Soc. 1987, 109, 4690-4698.
(26) For an other access to 17, or of 17 with other protecting groups,
see ref 7a and Paulsen, H.; VonDey, W. Liebig Ann. Chem. 1987, 125-
131.
(27) Williams, D. R.; Brown, D. L.; Benbow, J . W. J . Am. Chem.
Soc. 1989, 111, 1923-1925.

5670 J . Org. Chem., Vol. 63, No. 16, 1998
Notes
) 18.0 Hz, PhCH); 4.59 (s, 2H, PhCH2); 4.60 (d, 1H, J ) 18.0
Hz, PhCH); 7.17-7.39 (m, 20H, H aromatic). 13C NMR
(CDCl3): δ -5.4, 18.1, 25.8, 62.4, 73.1, 73.3, 73.4, 74.2, 74.3, 79.1,
79.3, 81.7, 127.5-128.4, 137.0, 137.4, 137.6, 138.4, 207.00. IR
16 h, the mixture was concentrated and flash chromatography
(hexane/AcOEt 8:2) of the crude residue (1.2 g) gave 0.64 g of
pure 12 as colorless syrup (90%) with no trace of the E-isomer.
1H NMR (CDCl3): δ 3.42 (m, 1H, H-6); 3.60 (m, 1H, H-6′); 3.67
(q,1H, J ) 7.5 Hz, H-5); 3.86 (t, 1H, J ) 7.5 Hz, H-4); 4.09 (dd,
1H, J ) 1.5, 16.5 Hz, H-7); 4.25 (dd, 1H, J ) 1.5, 16.5 Hz, H-7′);
4.33 (d, 1H,J ) 13.5 Hz, PhCH); 4.44 (s, 2H, PhCH2); 4.51 (d,
1H, J ) 13.5 Hz, PhCH); 4.54 (d, 1H, J ) 13.5 Hz, PhCH); 4.63
(d, 1H, J ) 13.5 Hz, PhCH); 4.67 (d, 1H, J ) 13.5 Hz, PhCH);
4.71 (d, 1H, J ) 13.5 Hz, PhCH); 4.88 (d, 1H, J ) 7.5 Hz, H-3);
6.43 (br s, 1H, H-1); 7.20-7.40 (m, 20H, H aromatic). 13C NMR
(CDCl3): δ 61.5, 68.8, 71.7, 72.9, 75.2, 76.1, 79.3, 80.4, 118.8,
127.59-128.46, 137.3, 137.5, 137.8, 137.9, 138.3. IR (neat): 3434
(neat): 1731 cm-1 (CO). [R]24 ) -2.9 (c 1.35, CH2Cl2). Anal.
D
Calcd for C40H50O6Si (654.94): C, 73.36; H, 7.70. Found: C,
73.58; H, 7.64.
1-Ch lor o-2-[(p h en ylm eth oxy)m eth yl]-3,4,5-tr is(p h en yl-
m eth oxy)-6-O-ter t-bu tyld im eth ylsilylh ex-1-en e (10a /10b).
A chloromethylenetriphenylphosphorane solution (0.3 M) was
prepared just before its use as follows: A solution of potassium
tert-butylate (411 mg, 3.66 mmol) in THF was added at 0 °C to
a stirred suspension of chloromethylenetriphenylphosphonium
chloride (1.06 g, 3.06 mmol) in THF (6.5 mL). After 1 h at 0 °C,
the mixture was warmed to room temperature and kept under
stirring for a further 1 h. The resulting solution of phosphorane
was then added to a cooled (-70 °C) solution of 9 (1.00 g, 1.53
mmol) in THF (4.5 mL). After 2 h at -70 °C, the mixture was
warmed to -30 °C (30 min) and pentane (75 mL) was added.
The resulting suspension was filtered, and the filtrate was
washed with H2O (75 mL). The aqueous phase was extracted
twice with pentane (2 × 75 mL). The combined organic phases
were then dried (MgSO4), filtered, and concentrated. Flash
chromatography (hexane/AcOEt 95:5) of the residue (1.2 g) gave
0.973 g of 10a /10b (Z/E 98:2) as a colorless syrup (92%). The
ratio Z/E was determined by integration of both vinylic H-1
signals (E-isomer δ 6.22 ppm). 1H NMR (CDCl3): δ 0.00 (s, 6H,
(CH3)2Si); 0.90 (s, 9H, (CH3)3C); 3.54 (dd, J ) 5.0, 10.0 Hz, H-6);
3.63 (q, J ) 5.0 Hz, H-5); 3.73 (dd, J ) 5.0, 10.0 Hz, H-6′); 3.90
(dd, J ) 5.0, 6.0 Hz, H-4); 4.16 (dd, J ) 1.5, 14.0 Hz, H-7); 4.26
(dd, J ) 1.5, 14.0 Hz, H-7′); 4.40 (d, J ) 12.5 Hz, 1H, PhCH);
4.50 (s, 2H, PhCH2); 4.55 (d, J ) 12.5 Hz, 1H, PhCH); 4.66 (s,
2H, PhCH2); 4.70 (s, 2H, PhCH2); 4.99 (d, J ) 6.0 Hz, H-3); 6.50
(br s, H-1); 7.20-7.40 (m, 20H, H aromatic). 13C NMR (CDCl3):
δ -5.4, 18.2, 25.9, 62.5, 68.8, 71.6, 72.9, 73.2, 75.4, 77.0, 79.8,
80.6, 118.85, 127.3-128.4, 137.4, 137.8, 138.5, 139.0. IR (neat):
2856, 2957, 3030, 3064, 3088 cm-1 (CH aromatic and CH double
bond). Anal. Calcd for C41H51O5SiCl (687.39): C, 71.64; H, 7.48;
Cl, 5.16. Found: C, 71.90; H, 7.58; Cl, 5.27.
cm-1 (OH). [R]23 ) -17 (c 1, CH2Cl2). Anal. Calcd for
D
C35H37O5Cl (572.50): C, 73.35; H, 6.51; Cl, 6,19. Found: C, 72.56;
H, 6.51, Cl, 6,91.
1-Br om o-2-[(p h en ylm eth oxy)m eth yl]-3,4,5-tr is(p h en yl-
m eth oxy)-6-h yd r oxyh ex-1-en e (13). A solution (1 M) of TBAF
in THF (1 M, 2.36 mL) was added to a stirred solution of 11
(1.55 g, 2.14 mmol) in THF (21 mL) at 0 °C. The solution was
warmed slowly to room temperature and stirred overnight. Et2O
(75 mL) was added, and the organic phase was washed with
water (100 mL), dried (MgSO4), and concentrated. Flash chro-
matography (hexane/AcOEt 95:5 to 85:15) of the residue (1.59
g) gave 1.06 g of 13 as colorless syrup (80%). 1H NMR (CDCl3):
δ 2.10 (br s, 1H, OH); 3.42 (m, 1H, H-6); 3.60 (m, 1H, H-6′); 3.68
(q, 1H, J ) 5.0 Hz, H-5); 3.87 (dd, 1H, J ) 4.0, 5.0 Hz, H-4);
4.07 (dd, 1H, J ) 2.0, 14.0 Hz, H-7); 4.25 (dd, 1H, J ) 2.0, 14.0
Hz, H-7′); 4.30 (d, 1H, J ) 11.0 Hz, PhCH); 4.42 (s, 2H, PhCH2);
4.50 (d, 1H, J ) 11.0 Hz, PhCH); 4.53 (d, 1H, J ) 11.0 Hz,
PhCH); 4.58 (d, 1H, J ) 11.0 Hz, PhCH); 4.70 (d, 1H,J ) 11.0
Hz, PhCH); 4.71 (d, 1H, J ) 11.0 Hz, PhCH); 4.79 (d, 1H, J )
4.0 Hz, H-3); 6.56 (br s, 1H, H-1); 7.18-7.40 (m, 20H, H
aromatic). 13C NMR (CDCl3): δ 61.5, 69.9, 71.6, 72.8, 72.90,
75.17, 78.0, 79.5, 80.3, 107.5, 127.5-128.3, 137.1, 137.8, 138.2,
140.3. IR (neat): 3500 cm-1 (OH). [R]23 ) -25.9 (c 1.35, CH2-
D
Cl2). Anal. Calcd for C35H37O5Br (617.58): C, 68.07; H, 6.04.
Found: C, 67.98; H, 6.19.
6-Ch lor o-2,3,4-tr is(p h en ylm eth oxy)-5-[(p h en ylm eth oxy)-
m eth yl]h ex-5-en a l (14). A solution of 12 (0.66 g, 1.15 mmol)
in CH2Cl2 (3.5 mL) was added to a cooled (0 °C) solution of Dess-
Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-
3(1H)-one) (0.98 g, 2.30 mmol) in CH2Cl2 (4 mL). The mixture
was then brought to 10 °C, and wet CH2Cl2 (55 mL containing
1.15 mmol (1 equiv) of water) was added dropwise over 1 h. The
mixture was then concentrated. Then, Et2O (50 mL) was added,
followed by a 1:1 mixture (50 mL) of saturated NaHCO3 solution
and sodium thiosulfate solution (20%). The mixture was then
stirred for 20 min further. The two phases were separated, and
the aqueous phase extracted twice with Et2O (2 × 50 mL). The
combined organic phases were washed with H2O (100 mL), dried
(MgSO4), filtered, and then concentrated. Flash chromatography
(hexane/AcOEt 9:1) of the crude residue (0.70 g) gave 0.47 g of
14 as a colorless syrup (70%) which was shown to be relatively
unstable at room temperature. 1H NMR (CDCl3): δ 3.86 (d, 1H,
J ) 4.5 Hz, H-2); 4.02 (dd, 1H, J ) 1.5, 13.0 Hz, H-7); 4.05 (t,
1H, J ) 4.5 Hz, H-3); 4.25 (dd, 1H, J ) 1.5, 13.0 Hz, H-7′); 4.33
(d, 1H, J ) 14.5 Hz, PhCH); 4.41 (d, 1H, J ) 14.5 Hz, PhCH);
4.45 (s, 2H, PhCH2); 4,48-4.68 (4d, 4H, J ) 14.5 Hz, 4 PhCH);
5.01 (d, 1H, J ) 4.5 Hz, H-4); 6.40 (m, 1H, H-6); 7.15-7.40 (m,
20H, H aromatic); 9.54 (br s, 1H, H-1). 13C NMR (CDCl3): δ
68.8, 72.1, 72.9, 73.2, 74.5, 76.0, 80.8, 81.5, 118.8, 127.6-128.3,
136.9, 137.2, 137.3, 139.7, 201.05. IR (neat): 1701 cm-1 (CO).
6-Br om o-2,3,4-tr is(p h en ylm eth oxy)-5-[(p h en ylm eth oxy)-
m eth yl]h ex-5-en a l (15). To a stirred solution of oxalyl chloride
(86 µL, 1.10 mmol) in CH2Cl2 (3.5 mL) was added DMSO (0.38
mL) at -78 °C. After 15 min, a solution of 13 (334 mg, 0.54
mmol) in CH2Cl2 (1.25 mL) was added dropwise and the stirring
was continued at the same temperature for 15 min before
addition of NEt3 (7.56 × 10-1 mL, 5.40 mmol). The mixture was
then slowly warmed to room temperature, diluted with Et2O (20
mL), washed with 0.1 M HCl (20 mL), water (20 mL), and brine
(20 mL), and finally dried (MgSO4). Flash chromatography
(hexane/AcOEt 98:02 to 9:1) of the residue (0.34 g) gave 0.30 g
of 15 as a colorless syrup (89%). 1H NMR (CDCl3): δ 3.85 (d,
1H, J ) 4.5 Hz, H-2); 4.01 (dd, 1H, J ) 2.0, 14.0 Hz, H-7); 4.07
(t, 1H, J ) 4.5 Hz, H-3); 4.23 (dd, 1H, J ) 2.0, 14 Hz, H-7′); 4.33
1-Br om o-2-[(p h en ylm eth oxy)m eth yl]-3,4,5-tr is(p h en yl-
m eth oxy)-6-O-ter t-bu tyld im eth ylsilylh ex-1-en e (11). A Bro-
momethylenetriphenylphosphorane solution (3 M) was prepared
just before its use as follows: To a suspension of bromomethyl-
enephosphonium bromide (2.66 g, 6.10 mmol) in THF (14 mL)
was added dropwise at -5 °C a 1 M potassium tert-butylate
solution in 2-methylpropanol (6.1 mL). The resulting orange
solution was then immediately added to a solution of 9 (2.00 g,
3.05 mmol) in THF (20 mL) at -70 °C. The reaction went to
completion after adding two times more of the orange bromo-
methylenetriphenylphosphorane solution prepared in the same
conditions. After the third addition, the mixture was slowly
warmed to room temperature (2 h) and diluted with hexane (100
mL). The resulting suspension was filtered through a silica gel
(70-200 µm) column which was further eluted with Et2O (600
mL). The organic phase was concentrated and the residue
triturated with hexane (3 × 150 mL). The resulting suspension
was then filtered and concentrated. Flash chromatography
(hexane/Et2O 98:2 and then hexane/AcOEt 95:5) of the residue
(2.21 g) gave 1.62 g of 11 (Z-isomer) as colorless syrup (74%).
1H NMR (CDCl3): δ 0.00 (s, 3H, (CH3)Si); 0.05 (s, 3H, (CH3)Si);
0.90 (s, 9H, (CH3)3C); 3.56 (dd, J ) 4.5, 10.5 Hz, H-6); 3.65 (q, J
) 4.5 Hz, H-5); 3.75 (dd, J ) 4.5, 10.5 Hz, H-6′); 3.91 (t, J ) 4.5
Hz, H-4); 4.16 (dd, J ) 1.5,12.0 Hz, H-7); 4.26 (dd, J ) 12.0, 1.5
Hz, H-7′); 4.40 (d, J ) 10.5 Hz, 1H, PhCH); 4.50 (s, 2H, PhCH2);
4.55 (d, J ) 10.5 Hz, 1H, PhCH); 4.66 (d, J ) 10.5 Hz, 1H,
PhCH); 4.70 (s, 2H, PhCH2); 4.73 (d, J ) 10.5 Hz, 1H, PhCH);
4.92 (d, J ) 4.5 Hz, H-3); 6.65 (br s, H-1); 7.25-7.45 (m, 20H, H
aromatic). 13C NMR (CDCl3): δ -5.4, 18.2, 25.9, 62.5, 69.8, 71.6,
72.9, 73.3, 75.4, 78.9, 79.8, 80.6, 107.4, 127.3-128.4, 137.6, 137.9,
138.4, 138.9, 140.2. IR (neat): 2856, 2927, 2953, 3031, 3064,
3088 cm-1 (CH aromatic and CH double bond). [R]29 ) -11.3
D
(c 1.5, CH2Cl2). Anal. Calcd for C41H51O5SiBr (731.85): C, 67.29;
H, 7.02. Found: C, 67.84; H, 6.99.
1-Ch lor o-2-[(p h en ylm eth oxy)m eth yl]-3,4,5-tr is(p h en yl-
m eth oxy)-6-h yd r oxyh ex-1-en e (12). A solution of TBAF in
THF (1 M, 1.23 mL) was added at room temperature to a stirred
solution of 10a /10b (0.842 g, 1.23 mmol) in THF (11 mL). After

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5671
(d, 1H, J ) 11.0 Hz, PhCH); 4.41 (d, 1H, J ) 11.0 Hz, PhCH);
4.45 (s, 2H, PhCH2); 4,50 (d, 1H, J ) 11.0 Hz, PhCH); 4.58 (d,
1H, J ) 11.0 Hz, PhCH); 4.59 (d, 1H,J ) 11.0 Hz, PhCH); 4,67
(d, 1H, J ) 11.0 Hz, PhCH); 4.93 (d, 1H, J ) 4.5 Hz, H-4); 6.52
(br s, 1H, H-6); 7.10-7.40 (m, 20H, H aromatic); 9.60 (br s, 1H,
H-1). 13C NMR (CDCl3): δ 69.9, 72.2, 72.9, 73.1, 74.5,77.9, 80.7,
81.3, 107.5, 127.5-128.4, 137.0, 137.2, 137.3, 139.8, 200.6. IR
sieves (1.80 g) in CH2Cl2 (5 mL) was stirred for 30 min at room
temperature; then a solution of 16a /16b (0.40 g, 0.75 mmol) in
CH2Cl2 (45 mL) was added. After 2 h, Et2O (15 mL) and hexane
(7.5 mL) were added and the reaction mixture was stirred for
15 min. The resulting suspension was filtered through a silica
gel (70-200 µm) column which was further eluted with Et2O
(150 mL). The organic phase was then concentrated to 50 mL,
washed with water (50 mL), dried (MgSO4), and finally concen-
trated. Flash chromatography (hexane/AcOEt 93:3 to 95:5 with
Et3N 0.3%) of the residue (0.31 g) gave 305 mg of 17 as a colorless
syrup (76%). 1H NMR (CDCl3): δ 4.05 (dd, 1H, J ) 7.0, 11.0
Hz, H-5); 4.04 (d, 1H, J ) 10.0 Hz, H-6); 4.08 (br d, 1H, J )
16.0 Hz, H-7); 4.27 (br d, 1H, J ) 16.0 Hz, H-7′); 4.38 (br d, 1H,
J ) 7.0 Hz, H-4); 4.51 (s, 2H, PhCH2); 4.65-4.80 (3d, 3H, J )
11.0 Hz, 3 PhCH); 3.88-5.15 (3d, 3H, J ) 11.0 Hz, 3 PhCH);
6.23 (q, 1H, J ) 1.5 Hz, H-2); 7.20-7.47 (m, 20H, H aromatic).
13C NMR (CDCl3): δ 68.9, 73.1, 74.4, 75.6, 75.7, 79.1, 83.9, 84.9,
123.88, 127.7-128.5, 137.4, 137.6, 137.7, 138.0, 159.1, 196.7.
[R]28 ) -9 (c 1, CHCl3) (lit. [R]23 ) -12 (c 1, CHCl3)). Anal.
(neat): 1726 cm-1 (CO). [R]23 ) -18.7 (c 1.55, CH2Cl2). Anal.
D
Calcd for
Found: C, 67.86; H, 5.82.
C35H35O5Br‚0.5H2O (624.77): C, 67.31; H, 5.81.
(1RS,4R,5S,6S)-4,5,6-Tr is(p h en ylm et h oxy)-3-[(p h en yl-
m eth oxy)m eth yl]cycloh ex-2-en ol (16a /16b). A stirred mix-
ture of CrCl2 (617 mg, 5 mmol) and NiCl2 (0.1%) was dried under
reduce pressure (≈30 mmHg) at 160 °C. After 1 h, the gray
powder was cooled to room temperature and DMF (oxygene free,
5 mL) was added under argon. The resulting green suspension
was stirred at room temperature for a further 30 min, before a
solution of 15 (124 mg, 0.20 mmol) in DMF (oxygene free, 5 mL)
was added. After 22 h of stirring at 40 °C, cold water (30 mL)
was added, and the mixture was extracted with Et2O (4 × 30
mL). The combined organic phases were dried and concentrated.
Flash chromatography (hexane/AcOEt 9:1) of the residue (118
mg) gave 65 mg of 16a /16b (1/1 mixture) as a colorless syrup
(61%). 1H NMR (CDCl3), data of (1S) 16a : δ 2.60 (br d, 1H,
OH); 3.60 (dd, 1H, J ) 4.2, 9.2 Hz, H-6); 3.94 (d, 1H, J ) 12.0
Hz, H-7); 4.06 (dd, 1H, J ) 7.0, 12.0 Hz, H-5); 4.16 (br d, 1H, J
) 7.0 Hz, H-4); 4.24 (br d, 1H, J ) 12.0 Hz, H-7′); 4.30 (m, 1H,
H-2); 4.50 (d, 1H, J ) 11.0 Hz, PhCH); 4.53 (d, 1H, J ) 11.0 Hz,
PhCH); 4.62-5.93 (6d, 6H, J ) 11.0 Hz, 6 PhCH); 5.91 (br d,
1H, J ) 4.7 Hz, H-2); 7.20-7.40 (m, 20H, H aromatic). 1H NMR
(CDCl3), data of (1R) 16b: δ 2.12 (br d, 1H, OH); 3.57 (dd, 1H,
J ) 7.0, 10.0 Hz, H-6); 3.85 (dd, 1H, J ) 7.0, 10.0 Hz, H-5); 3.91
(br d, 1H, J ) 10 Hz, H-7); 4.25 (br d, 1H, J ) 10.0 Hz, H-7′);
4.29 (br d, 1H, J ) 10.0 Hz, H-4); 4.29-4.36 (m, 1H, H-2); 4.44
(d, 1H, J ) 11.0 Hz, PhCH); 4.52 (d, 1H, J ) 11.0 Hz, PhCH);
4.67-5.02 (6d, 6H, J ) 11.0 Hz, 6 PhCH); 5.73 (br s, 1H, H-1);
7.18-7.40 (m, 20H, H aromatic). 13C NMR (CDCl3), (1R and
1S): δ 65.0, 71.2, 69.9, 70.9, 72.2, 72.5, 72.8, 74.0, 74.6, 74.7,
74.9, 75.1, 78.7, 78.7, 79.0, 79.6, 83.5, 83.7, 124.6, 127.1, 127.7-
128.6, 137.9, 138.0, 138.3, 138.5, 139.9, 139.7, 200.6. IR (neat):
3500 cm-1 (OH). Anal. Calcd for C35H36O5‚0.25 H2O (541.17):
C, 77.68; H, 6.80; O, 15.52. Found: C, 77.52; H, 6.89; O, 15.49.
(4R,5S,6R)-4,5,6-Tris(phenylmethoxy)-3-[(phenylmethoxy)-
m eth yl]cycloh ex-2-en on e (17). A suspension of AcONa (245
mg, 3.0 mmol), PCC (323 mg, 1.5 mmol), and 4 Å molecular
D
D
Calcd for C35H34O5: C, 78.63; H, 6.41; O, 14.96. Found: C, 77.93;
H, 6.52; O, 15.18.
(4R,5S,6R)-4,5,6-Tr ih ydr oxy-3-(h ydr oxym eth yl)cycloh ex-
2-en on e (1). A solution (1 M) of BCl3 in CH2Cl2 (2.25 mL) was
added to a cooled solution (-70 °C) of 17 (0.30 g, 0.56 mmol) in
CH2Cl2 (30 mL). The reaction mixture was then warmed slowly
to 0 °C (2 h) and then cooled to -70 °C before addition of pyridine
(1.45 mL, 18 mmol) and MeOH (0.730 mL, 18 mmol). The
mixture was then warmed to room temperature and concen-
trated. Water (1 mL) was added to the residue, and the solution
-
was passed first through a column of Dowex resin (1 × 8) (HCO3
form) and then through a column of Dowex resin (1 × 50) (H+
form). The aqueous phase was reduced to 10 mL, washed with
Et2O (10 mL), and then concentrated. Flash chromatography
(AcOEt/2-propanol/H2O 8:2:1) of the residue followed by filtration
through a polyacrylamide gel column gave 72 mg of 1 as a
hygroscopic brown solid (74%). 1H NMR (CD3OD): δ 3.59 (dd,
1H, J ) 8.4, 10.9 Hz, H-5); 4.01 (d, 1H, J ) 10.9 Hz, H-6); 4.32-
4.50 (2d, 2H, 2H-7); 4.36 (m, 1H, H-4); 6.16 (q, 1H, J ) 2.0 Hz,
H-2). 13C NMR (CDCl3): δ 62.0, 73.7, 78.1, 79.4, 121.3, 167.9,
199.4. [R]27 ) -40 (c 1, MeOH) (lit.1 [R]20 ) -61.4 (c 1,
D
D
MeOH)). EI-MS: M+ calcd ) 174.0528; found 174.0524 (0.25),
156 (1.2), 138 (18.0), 126 (19.5), 114 (68.11), 96 (100), 68 (85.98).
J O980309P