Asymmetric synthesis of 2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazoles

Article abstract of DOI:10.1021/jo961630f

A method for preparing the eight stereoisomers of the biologically active compound (1R,2S,3R)-2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole (THI, 1) is reported. This method employs a palladium(0)-catalyzed coupling of 1-(ethoxymethyl)-4-iodoimidazole (7) to functionalized vinylstannanes (R)- or (S)-12a,b or 13a,b or 1-alkynylstannanes (R)- or (S)-6a,b to introduce the C-4 imidazole four-carbon side chain. The 1,2-dihydroxy functionality of the butyl side chain was introduced by Sharpless catalytic asymmetric dihydroxylation reactions.

Full text of DOI:10.1021/jo961630f

J . Org. Chem. 1997, 62, 1023-1032
1023
Asym m etr ic Syn th esis of
2-Acetyl-4(5)-(1,2,3,4-tetr a h yd r oxybu tyl)im id a zoles
Matthew D. Cliff and Stephen G. Pyne*
Department of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
Received August 21, 1996X
A method for preparing the eight stereoisomers of the biologically active compound (1R,2S,3R)-2-
acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole (THI, 1) is reported. This method employs a
palladium(0)-catalyzed coupling of 1-(ethoxymethyl)-4-iodoimidazole (7) to functionalized vinyl-
stannanes (R)- or (S)-12a ,b or 13a ,b or 1-alkynylstannanes (R)- or (S)-6a ,b to introduce the C-4
imidazole four-carbon side chain. The 1,2-dihydroxy functionality of the butyl side chain was
introduced by Sharpless catalytic asymmetric dihydroxylation reactions.
Sch em e 1
In tr od u ction
(1R,2S,3R)-2-Acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)-
imidazole (THI, 1), a constituent of Caramel Color III,
has been found to depress blood lymphocyte counts in
both mice and rats.1 THI produces lymphopenia, appar-
ently without toxic effects, in rats and mice and is able
to affect the immune competence in the rat in quite small
quantities (e.g., 1-50 ppm in drinking water).2 THI has
also been reported to prevent spontaneous and cyclo-
phosphamide-induced diabetes in non-obese diabetic
mice.3 To investigate the structure-activity relation-
([R]28D +76.3° (c 1.06, toluene), lit.8 [R]28D +80.1° (c 0.166,
toluene) and 4b ([R]23D -74.8° (c 1.18, toluene), lit.8 [R]28
D
-79.4° (c 1.18, toluene)) were converted to their respec-
tive alkynes 5a and 5b in good overall yields, using the
procedure of Corey and Fuchs (Scheme 2).9 Treatment
of these individual alkynes with n-BuLi, followed by
quenching of the resulting 1-lithioalkyne derivative with
chlorotrimethylstannane gave the 1-(trimethylstannyl)-
alkynes 6a and 6b, respectively. Attempted palladium-
(0) catalyzed couplings of 5b with 1-(ethoxymethyl)-4-
iodoimidazole (7)10 using PdCl2(PPh3)2 in the presence of
copper(I) iodide and triethylamine in acetonitrile at
reflux10 for 4 h gave poor yields (23%) of the desired
alkyne 8b. The major product (69%) was the undesired
dialkyne 9 that was difficult to separate from the desired
imidazole product. However, treatment of 7 with either
6a or 6b under Stille-type coupling conditions,10-12 using
Pd(PPh3)4 as catalyst in DMF at 80 °C for 24 h gave
enhanced yields (53-59%) of the desired alkynes 8a and
8b, respectively. Deprotonation of 8a and 8b with
n-BuLi in THF at -78 °C followed by quenching of the
resulting 2-lithioimidazole derivative with N-methoxy-
N-methylacetamide10,13 gave the 2-acetyl derivatives 10a
and 10b, respectively, in 67-69% yields. Catalytic
hydrogenation of 10a and 10b over Lindlar’s catalyst,14
ships of this structurally simple but biologically intrigu-
ing molecule, we desired a general and flexible synthesis
of THI analogues. Three earlier syntheses of THI have
been reported, and these all rely on the use of glucose
derivatives to prepare the 1,2,3,4-tetrahydroxybutyl side
chain.4-6 These syntheses are not sufficiently flexible for
the synthesis of the stereoisomers of THI. In a recent
communication,7 we reported a new synthetic protocol for
the synthesis of THI. We now report the full details of
this synthesis and the synthesis of the other seven
tetrahydroxybutyl side-chain stereoisomers of THI. The
general synthetic strategy involved the conversion of
1-protected-4-iodoimidazole 3 to the (E)- or (Z)-alkenes
2, followed by a Sharpless catalytic asymmetric dihy-
droxylation (AD) to introduce the 1,2-dihydroxy func-
tionality into the butyl side chain (Scheme 1).
Resu lts a n d Discu ssion
Syn th esis of 4-[(1Z)-Bu ten yl]im id a zole Der iva -
tives. The protected (2R)- and (2S)-glyceraldehydes 4a
X Abstract published in Advance ACS Abstracts, J anuary 1, 1997.
(1) Iscaro, A.; Mackay, I. R.; O’Brien, C. Immunol. Cell. Biol. 1988,
66, 395.
(2) Golin, S. J . P.; Phillips, J . A. Clin. Exp. Immunol. 1991, 85, 335.
(3) Mandel, T. E.; Koulmanda, M.; Mackay, I. R. Clin. Exp. Immu-
mol. 1992, 88, 414.
(8) Schmid, C. R.; Bradley, D. A. Synthesis 1992, 587.
(9) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(10) Cliff, M. D.; Pyne, S. G. J . Org. Chem. 1995, 60, 2378.
(11) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(4) Kroplien, U.; Rosdorfer, J .; Vander Geef, J .; Long, R. C., J r.;
Goldstein, J . H. J . Org. Chem. 1985, 50, 1131.
(5) Sweeny, J . G.; Ricks, E.; Estrada-Valdes, M. C.; Iacobucci, G.
A.; Long, R. C., J r. J . Org. Chem. 1985, 50, 1133.
(6) Halweg, K. M.; Buchi, G. J . Org. Chem. 1985, 50, 1134.
(7) Cliff, M. D.; Pyne, S. G. Tetrahedron Lett. 1995, 36, 5969.
(12) For a recent review on the palladium-catalyzed coupling
reactions of heterocyclic compounds, see: Kalinin, V. N. Synthesis
1992, 413.
(13) Prepared according to the general method described in the
following: Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(14) Marvell, E. N.; Thomas, L. Synthesis 1973, 457.
S0022-3263(96)01630-1 CCC: $14.00 © 1997 American Chemical Society

1024 J . Org. Chem., Vol. 62, No. 4, 1997
Cliff and Pyne
Sch em e 2a
Sch em e 3a
a
Key: (a) From (S)-5b: Bu3SnH, AlBN (cat.), 130 °C, 2.5 h,
85% of 12b. (b) From 4a ,b: CrCl2, Br2CHSnMe3, LiI, THF, DMF,
16 h, rt, 80-85% of 13a ,b. (c) 12, 5% Pd(PPh3)4, DMF, 80 °C, 24
h, 26-31% (see Experimental Section for details). (d) 12, Pd2(dba)3,
AsPh3, CuI, DMF, 80 °C, 24 h, 45%. (e) 13a or 13b, 5% Pd(PPh3)4,
DMF, 80 °C, 24 h, 46-83%. (f) n-BuLi, THF, -78 °C; MeCON-
Me(OMe), -78 °C to rt, 65-72%.
DMF, THF, or MeCN as solvent gave the desired (E)-
alkene 14b in yields of 26-31% (Scheme 3). A better
yield (45%) of 14b was achieved using 5 mol % of Pd2-
(dba)3, 10 mol % of AsPh3, and 10 mol % of CuI in DMF
and at 80 °C for 24 h.17
a
Key: (a) Ph3P, CBr4, Zn, 77-87%. (b) n-BuLi/THF, -78 °C to
Alternatively compounds 14a and 14b could more
readily and reliably be obtained via Stille-type coupling
reactions of 7 and the vinyl-trimethylstannanes 13a ,b
using 5 mol % of Pd(PPh3)4 in DMF at 80 °C for 24 h.
These conditions gave the pure (E)-alkenes 14a ,b in
yields ranging from 45 to 83%. The (Z)-geometric isomers
of vinylstannes 13a and 13b underwent coupling at a
much slower rate than their (E) counterparts, and none
of the (Z)-isomer of 14a or 14b could be isolated from
these reactions after purification by column chromatog-
raphy on silica gel. The alkenes 14a or 14b were
converted to their corresponding 2-acetylimidazole de-
rivatives 15a and 15b in yields of 65-72% using the
previously described acylation method (Scheme 3).
Asym m etr ic Dih yd r oxyla tion s of 4-[(1Z)-Bu ten yl]-
im id a zole Der iva t ives. Catalytic dihydroxylation of
11b, in the absence of chiral ligand (K2OsO4‚H2O (3 mol
%)/K3Fe(CN)6 (3 equiv)/K2CO3 (3 equiv)/MeSO2NH2 (3
equiv)/t-BuOH, H2O at 0 °C, 16 h), gave a mixture of 16
and its diastereomeric anti-(1S,2R)-diol 17 in a ratio of
2.1:1, respectively. The major diastereoisomer (16) was
that expected on the basis of Kishi’s18 (A in Scheme 4) or
rt, 69-76%. (c) n-BuLi/THF, -78 to 0 °C; Me3SnCl, 0 °C to rt,
59-60%. (d) From 5b:5% PdCl2(Ph3P)2, Et3N, CuI, MeCN, reflux,
4 h, 23% of 8b, 69% of 9. From 6a ,b: 5% Pd(PPh3)4, DMF, 80 °C,
24 h, 53-58% of 8a ,b. (e) n-BuLi, THF, -78 °C, 1 h; MeCON-
Me(OMe), -78 °C to rt, 67-69%. (f) 10% Pd on CaCO3, quinoline,
H2, 2 h, rt, 79-80%.
in the presence of quinoline, gave the pure (Z)-alkenes
11a and 11b, respectively, in yields of 79-80% after
purification by column chromatography to remove small
quantities of the corresponding (E)-alkene (5-6%) and
over-reduced material (4-7%).
Syn th esis of 4-[(1E)-Bu ten yl]im id a zole Der iva -
tives. Hydrostannylation15 of 5b at 130 °C gave an
inseparable 81:19 mixture of the (E)- and (Z)-vinyltri-n-
butylstannanes 12b in 85% yield (Scheme 3). The related
trimethylstannanes 13a and 13b were directly prepared
from their respective aldehydes, 4a and 4b, in good yields
(80-85%) and high stereoselectivity ((E):(Z) ca. 90:10)
using trimethyl(dibromomethyl)stannane (Me3SnCHBr2),
lithium iodide, and chromium(II) chloride.16
Treatment of iodoimidazole 7 with 12b ((E):(Z) ) 81:
19)) at 80 °C in the presence of Pd(PPh3)4 (5 mol %) in
(15) Tolstikov, G. A.; Miftakhov, M. S.; Danilova, N. A.; Vel’der, Ya.
L. Synthesis 1986, 496.
(16) Cliff, M. D.; Pyne, S. G. Tetrahedron Lett. 1995, 36, 763.
(17) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585.
(18) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron 1984, 40, 2247.

Synthesis of (Tetrahydroxybutyl)imidazoles
J . Org. Chem., Vol. 62, No. 4, 1997 1025
Sch em e 4
Sch em e 5
dihydroxylations were similarly poor. Both AD mix-R
and AD mix-â gave 20 as the major diastereoisomer,
albeit in low diastereomeric excess (Scheme 5). The
failure of the pseudoenantiomeric DHQ and DHQD
ligands to provide opposite diastereoisomers from the AD
of chiral alkenes has been noted previously.24 Unfortu-
nately these diastereomeric diols could not be separated
by column chromatography on silica gel, but they could
be separated as their tetraacetate esters (see later).
While the AD of (Z)-alkenes is known to give 1,2-diols in
lower enantiomeric purities than their isomeric (E)-
alkenes,22 it has been reported that higher enantiomeric
purities can be realized from (Z)-allylic alcohols and (Z)-
homoallylic alcohols.25 It has been suggested that hy-
drogen bonding between the hydroxy group and an oxo
group on the osmium is responsible for the higher
enantiotopic π-face selectivity in these substrates. How-
ever, the AD of the diol formed from hydrolysis of 11b
with PdCl2(MeCN)2 in aqueous MeCN26 gave a mixture
of diastereomeric 1,2,3,4-tetrols in a similar diastereo-
meric ratio to that obtained from the AD of 11b with the
various chiral ligands. Acid-catalyzed hydrolysis of the
diastereomeric mixtures of 16 and 17 or 20 and 21 with
aqueous 10% hydrochloric acid/ethanol (2:1) at 80 °C for
90 min gave mixtures of the diastereomeric imidazole
hydrochloride salts 18 and 19 or 22 and 23, respectively,
in yields of 85-90%.
Vedejs’s19 transition state models for the osmylation
reaction. Catalytic asymmetric dihydroxylation (AD) of
11b at 0 °C for 2 days using commercially available AD
mix-â or AD mix-R20,21 gave mixtures of the same dia-
stereomeric anti-diols 16 and 17 with poor diastereofacial
selection. Using AD mix-â, the ratio of 16 to 17 (2:1,
Scheme 4) was essentially the same as that obtained from
the catalytic dihydroxylation of 11b in the absence of a
chiral ligand, while AD mix-R resulted in a reversal in
the diastereoselectivity (16:17 ) 1:3.4). Little improve-
ment in the diastereoselectivity of these reactions was
observed using Sharpless’s indoline (IND)22 or pyrimidine
(PYR)23 based DHQ or DHQD chiral ligands, the former
have been successfully employed in the AD of cis-alkenes
(Scheme 4). In the case of 11a , the enantiomer of 11b,
the diastereoselectivities of the catalytic asymmetric
(19) Vedejs, E.; McClure, C. K. J . Am. Chem. Soc. 1986, 108, 1094.
(20) AD mix-R and AD mix-â were purchased from the Aldrich
Chemical Co.
(21) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Harting, J .; J eong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.;
Xu, D.; Zhang, X. L. J . Org. Chem. 1992, 57, 2768.
(22) Wang, L.; Sharpless, K. B. J . Am. Chem. Soc. 1992, 114, 7568.
(23) Crispino, G. A.; J eong, K. S.; Kolb, H. C.; Wang, Z. M.; Xu, D.;
Sharpless, K. B. J . Org. Chem. 1993, 58, 3785.
(24) Iwashima, M.; Kinsho, T.; Smith III, A. B. Tetrahedron Lett.
1995, 36, 2199; Carreira, E. M.; Du Bois, J . J . Am. Chem. Soc. 1994,
116, 10825.
(25) Sharpless, K. B.; Van Nieuwenhze, M. S; Tetrahedron Lett.
1994, 35, 843.
(26) Lipshutz, B. H.; Pollart, D.; Monforte, J .; Kotsuki, H. Tetrahe-
dron Lett. 1985, 26, 705.

1026 J . Org. Chem., Vol. 62, No. 4, 1997
Cliff and Pyne
Sch em e 6
Sch em e 7
AD mix-R was also highly diastereoselective and gave the
syn-(1S,2R)-diol 25 in 96% de and in 67% yield after
purification by column chromatography (Scheme 6). The
AD reactions of 15a with AD mix-â or AD mix-R were
also highly diastereoselective and gave the diols 28 (de
90%) and 29 (de 94%), respectively, in good to excellent
yields (Scheme 7). Hydrolysis of 24 with aqueous 10%
hydrochloric acid/ethanol (2:1) at 80 °C for 90 min gave
the imidazole hydrochloride salt 26, which was identical
in all respects to authentic THI‚HCl. Neutralization of
this mixture with aqueous potassium carbonate solution
and then cooling to 5 °C and collection of the precipitate
gave THI (1) in 24% yield from 24. The physical
properties of our synthetic 1 (mp 240-244 °C (lit.6 mp
234-236 °C), [R]23 -14.9° (c 1.4, HCl/H2O) (lit.5 [R]25
Asym m etr ic Dih yd r oxyla tion s of 4-[(1E)-Bu ten yl]-
im id a zole Der iva tives. In contrast to the (Z)-alkenes
11a ,b, catalytic asymmetric dihydroxylation of 15b at 0
°C for 3 days using AD mix-â and additional chiral ligand
((DHQD)2-PHAL (4 mol %) and methanesulfonamide (2
equiv)) in t-BuOH/H2O gave the syn (1R,2S)-diol 24, in
good yield (80%) and high diastereoselectivity (de 98%)
D
D
-12° (c 1.17, 1 N HCl), 1H NMR (DCl/D2O)) were in
agreement with those of 1 that was prepared according
to the method of Buchi.6 In a similar fashion the diols
25, 28, and 29 were converted to their corresponding
imidazole hydrochloride salts 27, 30, and 31, respectively,
in high yields (Schemes 6 and 7). Attempts to isolate
the free imidazole derivatives of 27, 30, or 31, as was
successfully achieved above with THI, by neutralization
of an aqueous solution of these hydrochloride salts with
aqueous potassium carbonate solution and then cooling
to 5 °C failed to provide a precipitated product. Conse-
quently, these tetrols were characterized as their hydro-
chloride salts. The hydrochloride salt 30 had identical
1H and 13C NMR spectral data to those of THI‚HCl (26)
1
as determined by H NMR analysis (Scheme 6).27 Cata-
lytic dihydroxylation of 15b in the absence of chiral
ligand (K2OsO4‚H2O (5 mol %)/K3Fe(CN)6 (3 equiv)/ K2-
CO3 (3 equiv)/ MeSO2NH2 (2 equiv)/t-BuOH, H2O at 0
°C, 3 days) gave a mixture of 24 and its diastereomeric
syn-(1S,2R)-diol 25 in a ratio of 3.5:1 respectively. The
major diastereoisomer (24) was that expected on the basis
of Kishi’s18 (B in Scheme 5) or Vedejs’s19 transition state
models for the osmylation reaction. The AD of 15b using
(27) (a) For the AD of chiral (E)-alkenes, see: Morikawa, K.;
Sharpless, K. B. Tetrahedron Lett. 1993, 34, 5575. Wade, P. A.; Cole,
D. T.; D’Ambrosio, S. G. Tetrahedron Lett. 1994, 35, 53. (b) For the
AD of chiral (E)-alkenes, see: Honda, T.; Horiuchi, S.; Mizutani, H.;
Kanai, K. J . Org. Chem. 1996, 61, 4944.
and an equal and opposite specific rotation ([R]23 +14.9
D
(c 0.7, H2O)). While the salts 27 and 31 had identical
NMR spectra. The stereochemical outcomes of the AD

Synthesis of (Tetrahydroxybutyl)imidazoles
J . Org. Chem., Vol. 62, No. 4, 1997 1027
Sch em e 8
Sch em e 9
reactions of 15a ,b were consistent with Sharpless’s
mnemonic21,28,29 (Scheme 8) in which the imidazole group
occupies the southwest corner, which is believed to be
attractive to flat aromatic groups, and the dioxolane ring
occupies the NE corner. Both the matched and mis-
matched cases were highly diastereoselective (Schemes
6 and 7).
0.06, MeCN)) from the acetylation of 30 was identical
spectroscopically to 32 ([R]24 -22.6° (c 0.58, MeCN))
D
which was obtained from 1, while the major tetraacetate
36 from the acetylation of 31 was identical spectroscopi-
cally to 33. The minor diastereomeric tetraacetates (35
P r oof of Ster eoch em istr y. While the stereochem-
istry of the syn-1,2-diols 26, 27, 30, and 31 was clear,
from the chemical correlations of 26 and 30 with THI
(1) and the known cis dihydroxylations of alkenes, the
stereochemistry of the anti-1,2-diols 18, 19, 22, and 23
was not. To assist in these stereochemical assignments,
and in the separation of diastereoisomers, the tetrols
were converted to their corresponding tetraacetates by
acetylation with acetic anhydride/acetic acid/perchloric
acid (cat.) at 60 °C. Acetylation of THI (1) or 27 at 60 °C
for 1 h gave the tetraacetates 32 and 33, respectively, as
single diastereoisomeric compounds in moderate to poor
yields (47 and 23%, respectively, eqs 1 and 2). The poor
yield of acetylated product 33 was thought to be due to
the poor solubility of the hydrochloride salt 27 in the
reaction medium. Acetylation of 30 or 31 under similar
and 37) were clearly anti-1,2-acetates that were the
result of epimerization at C-1. Likewise, acetylation of
mixtures of the diastereomeric imidazole hydrochloride
salts 18 and 19 or 22 and 23 at 60 °C for 6 h gave
mixtures of four (two syn-1,2-diacetates and two anti-
1,2-diacetates) diastereomeric acetates. For example,
acetylation of a 3.4:1 mixture of 19 and 18, respectively,
gave, in 65% yield, a 4:2.7:1.1:1 mixture of the tetraac-
etates 38, 33, 39, and 32, respectively (eq 5). The
diastereoisomeric tetraacetates could be separated by
preparative HPLC. Exposure of diastereomerically pure
39 to the acetylation conditions also gave a mixture (ca.
2:1) of 39 and 32. A proposed stabilized cationic inter-
mediate for this latter epimerization reaction is shown
in Scheme 9. Thus the formation of the C-1 epimeric
acetates in these acetylation reactions allowed us to
reaction conditions also gave poor yields of acetylated
products. Extended reaction times (6 h) gave good to
excellent yields of acetylated products; however mixtures
of two diastereomeric acetates resulted in each case (eqs
3 and 4). The major tetraacetate 34 ([R]24 + 19.4° (c
D
(28) J ohnson, R. A.; Sharpless, K. B. in Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, 1993; Chapter 4.4, pp 243-
245.
(29) For examples of anomalous face selectivity in the AD reaction,
see: Hale, K. J .; Manaviazar, S.; Peak, S. A. Tetrahedron Lett. 1994,
35, 425. Boger, D. L.; McKie, J . A.; Nishi, T.; Ogiku, T. J . Am. Chem.
Soc. 1996, 118, 2301. Salvadori, P.; Superchi, S.; Minutolo, F. J . Org.
Chem. 1996, 61, 4190.

1028 J . Org. Chem., Vol. 62, No. 4, 1997
Cliff and Pyne
92.4; 76.3; 68.2; 29.59; 29.35; 8.07; 7.96. MS (CI positive): m/ z
315 (M + H+, 6); 285 (70); 229 (20); 215 (31); 160 (100); 119
(100); 107 (100). IR (neat): 2971; 2938; 2880; 1718; 1616; 1458;
1172; 1078; 915; 808; 665 cm-1. HRMS: calcd for C9H1579Br2O2
312.9440, found 312.9446.
unequivocally assign the stereochemistry to the 1,2-anti-
tetraacetates 35, 37, 38, and 39.
(4R)-Dieth yl-4-(2′,2′-dibr om oeth en yl)-1,3-dioxolan e (41).
Using the procedure described above for the synthesis of 40,
the title compound was obtained as a light yellow oil (77%),
[R]25 -6.4° (c 1.05, CHCl3). Spectral data are identical to
D
those of 40.
(4S)-2,2-Dieth yl-4-eth yn yl-1,3-d ioxola n e (5b). To a so-
lution of alkene 40 (6.88 g, 22.1 mmol) in anhydrous THF (50
mL) at -78 °C under N2 was added n-BuLi in hexanes (48.7
mmol). The solution was stirred for 1 h at -78 °C and then
for 1 h at ambient temperature. Water (15 mL) and hexane
(60 mL) were added, and the phases were separated. The
aqueous phase was extracted with hexane (15 mL), and the
combined extracts were washed with H2O (10 mL) and dried
(MgSO4). The solvent was removed to leave an orange oil
which was purified by bulb-to-bulb distillation (61 °C/6 mmHg)
to give the title dioxolane as a clear oil (2.36 g, 69%), [R]27
D
+44.1° (c 0.75, CHCl3). 1H NMR (400 MHz, CDCl3) δ 4.70 (1H,
ddd, J ) 2.0, 6.4, 8.0 Hz); 4.18 (1H, dd, J ) 6.4, 8.0 Hz); 3.89
(1H, dd, J ) 6.8, 8.0 Hz); 2.49 (1H, d, J ) 2.0 Hz); 1.74; 1.63
(2 × 2H, 2 × q, J ) 7.6 Hz); 0.94; 0.89 (2 × 3H, 2 × t, J ) 7.6
Hz). 13C NMR (22.5 MHz, CDCl3) δ 114.5; 81.3; 73.8; 70.3;
65.5; 29.6; 29.3; 8.1; 7.8. MS (CI positive): m/ z 155 (M + H+,
26); 125 (100); 87 (96). IR (neat): 3300 (HCtC); 2972; 2940;
Con clu sion
In summary, we have developed a new method for the
synthesis of THI and its syn 1,2-dihydroxy analogues in
high diastereomeric and enantiomeric purities. The
synthesis of the anti 1,2-dihydroxy analogues of THI have
proven more difficult due to the poor diastereofacial
control in the AD reaction of the (Z)-alkenes 11a ,b. The
biological activities of these tetrols are currently under
investigation and will be reported elsewhere.
2883; 1464; 1355; 1172; 1079; 912; 665 cm-1
for C9H15O2 155.1072, found 155.1070.
. HRMS: calcd
(4R)-2,2-Dieth yl-4-eth yn yl-1,3-d ioxola n e (5a ). Using
the procedure described above for 5b, the title compound was
obtained as a clear oil (76%) after bulb-to-bulb distillation (85
°C/10 mmHg), [R]26D -38.3° (c 1.75, CHCl3). Spectral data are
identical to those of 5b.
Exp er im en ta l Section
(4S)-2,2-Diet h yl-4-((t r im et h ylst a n n yl)et h yn yl)-1,3-d i-
oxola n e (6b). To a solution of alkyne 5b (1.0 g, 6.5 mmol) in
anhydrous THF (5 mL) at -78 °C under N2 was added n-BuLi
in hexanes (7.15 mmol). The reaction was stirred for 10 min
at -78 °C and 20 min at 0 °C. A solution of trimethyltin
chloride (1.60 g, 7.80 mmol) in THF (5 mL) was then added
dropwise. The solution was stirred for 35 min at 0 °C and
then warmed to rt and left to stir for 16 h. The mixture was
diluted with CH2Cl2 (20 mL), washed consecutively with H2O
(10 mL) and saturated aqueous NaCl (10 mL), and then dried
(MgSO4). The solvent was removed to leave a thick black oil.
Bulb-to-bulb distillation (104 °C/0.5 mmHg) gave the title
stannane as a fluorescent green oil (1.23 g, 60%), [R]27D +24.4°
(c 1.3, CHCl3). 1H NMR (400 MHz, CDCl3) δ 4.70 (1H, dd, J
) 6.4, 7.6 Hz); 4.16 (1H, dd, J ) 6.4, 8.0 Hz); 3.83 (1H, t, J )
8.0 Hz); 1.74; 1.62 (2 × 2H, 2 × q, J ) 7.6 Hz); 0.94; 0.89 (2 ×
3H, 2 × t, J ) 7.6 Hz); 0.289 (9H, s, 2J (117Sn,H) ) 58.0 Hz,
General procedures were as previously described.10 Pre-
parative HPLC was carried out using a Waters pump Model
510 and a Waters µ-Porasil column (particle size 10 mm, pore
size 125, dimensions 25 mm × 100 mm). The UV detector was
a Waters Series 450 variable wavelength detector operating
at 254 nm.
(4S )-2,2-Die t h yl-4-(2′,2′-d ib r om oe t h e n yl)-1,3-d ioxo-
la n e (40). A mixture of triphenylphosphine (26.56 g, 101.3
mmol), carbon tetrabromide (33.58 g, 101.3 mmol), and zinc
dust (6.62 g, 101.3 mmol) were suspended in anhydrous CH2-
Cl2 (200 mL), and the mixure was stirred for 24 h under N2.
2J (119Sn,H) ) 60.4 Hz). MS (EI positive): m/ z 289* (M - Et+,
+
51); 217* (31); 165* (SnMe3
, 100). HRMS: calcd for
C10H17O2120Sn 289.0250, found 289.0241. *identifies 120Sn
isotope peak.
The aldehyde 4b8 (5.16 g, 32.7 mmol) was then added, and
the mixture was stirred for a further 24 h. The mixture was
diluted with hexane (800 mL) and filtered, and the insoluble
residue was taken into CH2Cl2 (100 mL). The CH2Cl2 solution
was then diluted with hexane (400 mL) and filtered. The
combined filtrates were washed with saturated aqueous NH4-
Cl (400 mL) and H2O (300 mL) and dried (MgSO4). The
solvent was removed to give a light yellow oil of essentially
pure olefin (8.90g, 87%), [R]28D +6.8° (c 1.18, CHCl3). 1H NMR
(400 MHz, CDCl3) δ 6.52 (1H, d, J ) 7.2 Hz); 4.72 (1H, dd, J
) 6.4, 7.6 Hz); 4.21 (1H, dd, J ) 6.4, 8.4 Hz); 3.63 (1H, t, J )
7.6 Hz); 1.65 (2 × 2H, p, J ) 7.6 Hz); 0.93; 0.89 (2 × 3H, 2 ×
t, J ) 7.6 Hz). 13C NMR (100 MHz, CDCl3) δ 136.9; 113.4;
(4R)-2,2-Dieth yl-4-((tr im eth ylsta n n yl)eth yn yl)-1,3-d i-
oxola n e (6a ). Using the procedure described above for the
synthesis of 6b, the title compound was obtained as a bright
green oil (59%) after bulb-to-bulb distillation, [R]26 -23.4° (c
D
0.97, CHCl3). Spectral data are identical to those of 6b.
(3′S)-4-[3′,4′-O-(3′-P en t ylid en e)-3′,4′-d ih yd r oxyb u t -1′-
yn yl]-1-(eth oxym eth yl)im id a zole (8b). A solution of tri-
methylstannane 6b (0.80 g, 2.53 mmol), iodoimidazole 7 (0.76
g, 3.03 mmol), and Pd(Ph3P)4 (290 mg, 0.25 mmol) in anhy-
drous DMF (10 mL) in a thick-walled reaction vessel was
degassed with a stream of argon. The vessel was sealed, and
the solution was stirred at 80 °C for 24 h in the dark. The

Synthesis of (Tetrahydroxybutyl)imidazoles
J . Org. Chem., Vol. 62, No. 4, 1997 1029
resulting dark solution was then cooled to rt, diluted with ethyl
acetate (50 mL), and filtered. The filtrate was washed with a
half-saturated aqueous solution of NaCl (2 × 20 mL), dried
(MgSO4), and concentrated to give a dark oil. Purification by
column chromatography (50% ethyl acetate/hexane) gave the
title compound as a tan oil (405 mg, 58%), [R]29D +18.0° (c 5.0,
CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.55 (1H, d, J ) 1.2
Hz); 7.24 (1H, d, J ) 1.6 Hz); 5.26 (2H, s); 4.92 (1H, t, J ) 6.8
Hz); 4.22 (1H, dd, J ) 6.4, 8.0 Hz); 3.97 (1H, t, J ) 7.6 Hz);
3.44 (2H, q, J ) 6.8 Hz); 1.76; 1.65 (2 × 2H, 2 × q, J ) 7.6
Hz); 1.18 (3H, t, J ) 6.8 Hz); 0.95; 0.91 (2 × 3H, 2 × t, J ) 7.6
Hz). 13C NMR (22.5 MHz, CDCl3) δ 137.1; 124.2; 122.9; 114.1;
86.2; 77.2; 76.3; 70.1; 66.1; 64.4; 29.5; 29.2; 14.5; 8.0; 7.7. MS
(ES positive): m/ z 279 (M + H+, 100); 193 (14); 59 (8); 42 (63).
IR (neat): 2973; 2937; 2881; 2238; 1493; 1355; 1107; 1078; 913;
a tan oil (69%), with the starting alkyne (11%) also isolated
after column chromatography (20% ethyl acetate/hexane),
[R]23 -32.4° (c 1.0, CHCl3). Spectral data are identical to
D
those of 10b.
(3′S)-(Z)-2-Acetyl-4-[3′,4′-O-(3′-p en tylid en e)-3′,4′-d ih y-
d r oxybu t-1′-en yl]-1-(eth oxym eth yl)im id a zole (11b). To
a solution of alkyne 10b (740 mg, 2.31 mmol) and quinoline
(300 mg, 2.31 mmol) in hexane (10 mL) was added 10% Pd on
CaCO3 (70 mg). The mixture was stirred for 2 h under a H2
atmosphere until the hydrogenation was complete by 1H NMR
analysis. The mixture was vacuum filtered through a bed of
Celite and the plug washed thoroughly with ethyl acetate. The
filtrate was then concentrated in vacuo to give a tan oil which
was purified by column chromatography (15% ethyl acetate/
hexane) to give the title (Z)-alkene as a tan oil (595 mg, 80%),
[R]21D +18.7° (c 0.87, CHCl3). A small amount of the (E)-alkene
(35 mg, 5%) and over-reduced alkane (30 mg, 4%) were also
separately isolated from the column, both as tan oils. 1H NMR
(400 MHz, CDCl3): δ 7.27 (1H, s); 6.39 (1H, dd, J ) 1.2, 7.6
Hz); 5.79-5.73 (3H, m,); 5.69-5.64 (1H, m); 4.43 (1H, dd, J )
6.4, 8.0 Hz); 3.63 (1H, t, J ) 8.0 Hz); 3.54 (2H, q, J ) 7.2 Hz);
2.66 (3H, s); 1.72; 1.71 (2 × 2H, 2 × q, J ) 7.2 Hz); 1.20 (3H,
t, J ) 7.2 Hz); 0.97; 0.96 (2 × 3H, 2 × t, J ) 7.2 Hz). 13C
NMR (22.5 MHz, CDCl3) δ 190.8; 142.4; 130.4; 139.0; 124.0;
122.1; 113.1; 77.1; 73.9; 70.2; 65.0; 30.04; 29.85; 27.2; 14.8; 8.11;
7.92. MS (ES positive): m/ z 323 (M + H+, 100); 237 (56).
HRMS: calcd for C17H26N2O4 322.1892, found 322.1901.
(3′R)-(Z)-2-Acetyl-4-[3′,4′-O-(3′-p en tylid en e)-3′,4′-d ih y-
d r oxybu t-1′-en yl]-1-(eth oxym eth yl)im id a zole (11a ). Us-
ing the procedure described above for the synthesis of 11b,
the title compound was obtained pure as a tan oil (79%), with
the (E)-alkene (6%) and over-reduced alkane (7%) also isolated
after purification by column chromatography (15% ethyl
752 cm-1
278.1626.
. HRMS: calcd for C15H22N2O3 278.1630, found
(3′R)-4-[3′,4′-O-(3′-P en t ylid en e)-3′,4′-d ih yd r oxyb u t -1′-
yn yl]-1-(eth oxym eth yl)im id a zole (8a ). Using the proce-
dure described above for the synthesis of imidazole 8b, the
title compound was obtained as a tan oil (53%) after purifica-
tion by column chromatography (40% ethyl acetate/hexane),
[R]23 -25.9° (c 1.03, CHCl3). Spectral data are identical to
D
those of 8b.
Syn th esis of Im id a zole 8b a n d (2S,7S)-1,2:7,8-O-d i(3-
p en tylid en e)-1,2,7,8-tetr a h yd r oxy-3,5-octa d iyn e (9) via
P a lla d iu m (0)/Alk yn e Cou p lin g. A solution of alkyne 5b
(1.83 g, 11.88 mmol), iodoimidazole 7 (3.59 g, 14.26 mmol),
CuI (230 mg, 1.21 mmol), PdCl2(Ph3P)2 (420 mg, 0.60 mmol),
and triethylamine (12.0 g, 0.119 mmol) in anhydrous CH3CN
(20 mL) was degassed using a stream of argon, and the
solution was heated to reflux for 4 h under N2. The mixture
was then cooled to rt, poured into H2O (100 mL), and extracted
with CH2Cl2 (4 × 80 mL). The combined extracts were dried
(MgSO4), and the solvent was removed to leave a thick black
oil. Purification by column chromatography (50% ethyl acetate/
hexane) gave the target imidazole 8b (0.76 g, 23%) plus the
dialkyne 9 (1.26 g, 69%). Da ta for 9. 1H NMR (400 MHz,
CDCl3) δ 4.77 (2H, t, J ) 6.0 Hz); 4.17 (2H, dd, J ) 6.4, 8.0
Hz); 3.92 (2H, dd, J ) 6.4, 8.0 Hz); 1.73; 1.63 (2 × 4H, 2 × q,
J ) 7.6 Hz); 0.94; 0.88 (2 × 6H, 2 × t, J ) 7.6 Hz). 13C NMR
(22.5 MHz, CDCl3) δ 114.8; 77.2; 69.9; 69.5; 65.9; 29.5; 29.2;
8.1; 7.8. MS (EI positive): m/ z 277 (M - Et+, 44); 217 (10);
191 (15); 135 (23); 87 (31); 57 (100). IR (neat): 2972; 2938;
2881; 2150; 1463; 1336; 1171; 1082; 910; 762 cm-1. HRMS:
calcd for C16H21O4 277.1440, found 277.1446.
(3′S )-2-Ace t yl-4-[3′,4′-O-(3′-p e n t ylid e n e )-3′,4′-d ih y-
d r oxybu t-1′-yn yl]-1-(eth oxym eth yl)im id a zole (10b). To
a solution of alkyne 8b (550 mg, 1.98 mmol) in anhydrous THF
(5 mL) at -78 °C under N2 was added n-BuLi in hexanes (2.37
mmol), and the solution was stirred for 90 min at -78 °C.
Freshly distilled N-methoxy-N-methylacetamide (0.29 g, 2.77
mmol) in THF (5 mL) was then added dropwise, and the
reaction mixture was stirred for 1 h at -78 °C and then was
slowly warmed to rt and stirred for a further 1 h. The mixture
was diluted with CH2Cl2 (15 mL), washed with a 5% aqueous
solution of NaHCO3 (5 mL), and dried (MgSO4), and the solvent
was removed to leave a black oil. Purification by column
chromatography (40% ethyl acetate/hexane) gave the title
compound as a tan oil (10b, 67% corrected for recovered
starting alkyne), [R]29D +23.3° (c 2.40, CHCl3) plus the starting
alkyne 8b (150 mg). Da ta for 10b. 1H NMR (400 MHz,
CDCl3) δ 7.45 (1H, s); 5.75 (2H, s); 4.93 (1H, t, J ) 7.2 Hz);
4.24 (1H, t, J ) 7.2 Hz); 4.00 (1H, t, J ) 7.2 Hz); 3.54 (2H, q,
J ) 7.2 Hz); 2.67 (3H, s); 1.77; 1.66 (2 × 2H, 2 × q, J ) 7.2
Hz); 1.20 (3H, t, J ) 7.2 Hz); 0.96; 0.92 (2 × 3H, 2 × t, J ) 7.2
Hz). 13C NMR (100 MHz, CDCl3) δ 190.6; 142.3; 128.1; 123.8;
114.4; 86.9; 78.4; 77.6; 70.1; 66.2; 65.3; 29.6; 29.3; 27.5; 14.8;
8.2; 7.9. MS (ES positive): m/ z 321 (M + H+, 100). IR
(neat): 2973; 2937; 2881; 2201; 1685; 1457; 1352; 1170; 1108;
1079; 913; 764 cm-1. HRMS: calcd for C17H24N2O4 320.1736,
found 320.1749.
acetate/hexane), [R]27 -16.5° (c 0.62, CHCl3). Spectral data
D
are identical to those of 11b.
(4S)-(E)-2,2-Dieth yl-4-(2′-(tr ibu tylsta n n yl)eth en yl)-1,3-
d ioxola n e a n d (4S)-(Z)-2,2-Diet h yl-4-(2′-(t r ib u t ylst a n -
n yl)eth en yl)-1,3-d ioxola n e (12). A mixture of freshly dis-
tilled alkyne 5b (1.2 g, 7.79 mmol), Bu3SnH (2.50 g, 8.57
mmol), and a catalytic amount of AIBN under argon was
sealed in a thick-walled reaction vessel and set to react at 130
°C for 2.5 h. The solution was then cooled to rt and the
solution evaporated in vacuo. Purification by bulb-to-bulb
distillation (125 °C/0.01 mmHg) gave a mixture of the title
stannanes as a clear oil (2.94 g, 85%, E:Z ) 81:19). (E)-
Isom er . 1H NMR (400 MHz, CDCl3): δ 6.31 (1H, dd, J ) 0.8,
19.2 Hz); 5.94 (1H, dd, J ) 6.4, 18.8 Hz); 4.49-4.43 (1H, m);
4.10 (1H, dd, J ) 6.0, 8.0 Hz); 3.56 (1H, t, J ) 8.0 Hz); 1.71-
1.62 (4H, m); 1.52-1.25 (18H, m); 0.98-0.87 (15H, m). (Z)-
Isom er . 1H NMR (400 MHz, CDCl3): δ 6.44 (1H, dd, J ) 8.4,
12.4 Hz); 6.19 (1H, d, J ) 12.4 Hz); 4.28-4.23 (1H, m); 4.04
(1H, dd, J ) 6.0, 7.6 Hz); 3.58 (1H, t, J ) 8.0 Hz); 1.71-1.62
(4H, m); 1.52-1.25 (18H, m); 0.98-0.87 (15H, m).
(4S)-(E)-2,2-Diet h yl-4-(2′-(t r im et h ylst a n n yl)et h en yl)-
1,3-d ioxola n e (13b). To a stirred slurry of chromium(II)
chloride (1.46 g, 11.8 mmol) in anhydrous THF (16 mL) under
N2 was added anhydrous DMF (0.70 g, 11.8 mmol), and the
reaction was stirred for 15 min at rt. Aldehyde 4b (190 mg,
1.18 mmol) and (dibromomethyl)trimethylstannane (700 mg,
2.07 mmol) in anhydrous THF (4 mL) were then added, and
the reaction vessel was wrapped in aluminum foil to exclude
light. Lithium iodide (0.63 g, 4.72 mmol) in anhydrous THF
(4 mL) was added and the reaction left to stir for 16 h. The
mixture was then poured into H2O (30 mL) and extracted with
40-60 °C petroleum ether (3 × 30 mL). The combined extracts
were washed with H2O (20 mL) and saturated aqueous NaCl
(20 mL) and then dried (MgSO4) and concentrated to leave a
light yellow oil. Purification by bulb-to-bulb distillation (78
°C/0.01 mmHg) gave the vinylstannane as a clear oil (300 mg,
80%, ratio E:Z ) 88:12). 1H NMR (400 MHz, CDCl3) δ 6.38
2
2
(1H, dd, J ) 0.8, 18.8 Hz, J (117Sn,H) ) 76 Hz, J (119Sn,H) )
78 Hz); 5.95 (1H, dd, J ) 7.2, 18.8 Hz, J (117Sn,H) ) 66.4 Hz,
2
(3′R )-2-Ace t yl-4-[3′,4′-O-(3′-p e n t ylid e n e )-3′,4′-d ih y-
d r oxybu t-1′-yn yl]-1-(eth oxym eth yl)im id a zole (10a ). Us-
ing the procedure described above for the synthesis of the
methyl ketone 10b, the title compound was obtained pure as
2J (119Sn,H) ) 70.4 Hz); 4.49-4.43 (1H, m); 4.10 (1H, dd, J )
6.4, 8.0 Hz); 3.57 (1H, t, J ) 8.0 Hz); 1.71-1.59 (4H, m); 1.00-
0.88 (6H, m); 0.14 (9H, s, 2J (117Sn,H) ) 53.6 Hz, 2J (119Sn,H) )
56.0 Hz). 13C NMR (75.6 MHz, CDCl3) δ 144.5; 134.2; 113.2;

1030 J . Org. Chem., Vol. 62, No. 4, 1997
Cliff and Pyne
80.2; 67.7; 29.96; 29.76; 8.12; 8.05; -9.8. HRMS: calcd for
C12H25O2120Sn 321.0876, found 321.0871.
the title compound was obtained pure as a light tan oil (72%)
after purification by column chromatography (15% ethyl
acetate/hexane) with the starting alkene (19%) also recovered,
[R]26D -39.0° (c 0.92, CHCl3). Spectral data of 15a are identical
to those of 15b.
(1′S ,2′S ,3′R )-2-Ac e t y l-4-[3′,4′-O -(3′-p e n t y li d e n e )-
1′,2′,3′,4′ -tetr a h yd r oxy-1′-bu tyl]-1-(eth oxym eth yl)im id a -
zole (16). Gen er a l AD P r oced u r e for Alk en es Usin g AD
m ix-â. Into a 25 mL round bottom flask were added AD mix-
(4R)-(E)-2,2-Diet h yl-4-(2′-(t r im et h ylst a n n yl)et h en yl)-
1,3-d ioxola n e (13a ). Using the general procedure described
above for the synthesis of 13b, the title compound was obtained
as a pale oil (85%, E:Z ) 94:6) after bulb-to-bulb distillation
(51 °C/0.1 mmHg). Spectral data are identical to those of 13a .
Ta ble 1
â
20 (1.09 g), (DHQD)2PHAL (24 mg, 3.09 × 10-5 mol), K2OsO4‚-
run
solventa
DMF
THF
acetonitrile
DMF
catalyst
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
yield of 14b, %
2H2O (2.8 mg, 9.75 × 10-6 mol), and methanesulfonamide (147
mg, 1.55 mmol). The reagents were dissolved in H2O (4 mL)
and t-BuOH (2 mL) and the solution cooled to 0 °C. The (Z)-
alkene 11b (250 mg, 7.76 × 10-4 mol) in t-BuOH (2 mL) was
added in a single addition, and the reaction was allowed to
stir for 48 h at 0 °C until complete by TLC. Sodium sulfite
(1.2 g) was then added, and the reaction was warmed to rt
and stirred for 1 h. The mixture was extracted with CH2Cl2
(4 × 5 mL) and ethyl acetate (5 mL), and the combined extracts
were washed with a 2 M aqueous solution of KOH (7 mL),
dried (MgSO4), and concentrated. Purification by column
chromatography (40% ethyl acetate/hexane) gave the title
compounds as a pale yellow oil (200 mg, 72%). The ratio of
16:17 was 2.0:1 from 1H NMR analysis.
1
2
3
4
26
28
31
45
Pd2(dba)3, AsPh3, CuI
a
All reactions were carried out in sealed reaction vessels at 80
°C under argon.
(3′S)-(E)-4-[3′,4′-O-(3′-P en tylid en e)-3′,4′-d ih yd r oxybu t-
1′-en yl]-1-(eth oxym eth yl)im id a zole (14b). See Ta ble 1.
Rep r esen ta tive P r oced u r e. A solution of iodoimidazole 7
(560 mg, 2.22 mmol), stannane 12 (900 mg, 2.02 mmol, (E):
(Z) ) 81:19), and Pd(PPh3)4 (230 mg, 2.0 × 10-4 mol) in
anhydrous DMF (10 mL) in a thick-walled tube was flushed
with argon, sealed, and stirred at 80 °C for 24 h. The reaction
was then cooled to rt, diluted with CH2Cl2 (60 mL), washed
with H2O (30 mL), dried (MgSO4), and concentrated. Purifica-
tion by column chromatography (45% ethyl acetate/hexane)
16. 1H NMR (400 MHz, CDCl3) δ 7.38 (1H, s); 5.77 (2H, d,
J ) 2.4 Hz); 4.82 (1H, dd, J ) 4.0, 6.4 Hz); 4.56 (1H, d, J )
4.0 Hz); 4.23-4.18 (1H, m); 4.04-3.98 (1H, m); 3.85-3.73 (2H,
m); 3.66 (1H, d, J ) 3.6 Hz); 3.561 (2H, q, J ) 7.2 Hz); 2.62
(3H, s); 1.74-1.59 (4H, m); 1.207 (3H, t, J ) 7.2 Hz); 0.926;
0.881 (2 × 3H, 2 × t, J ) 7.2 Hz). 13C NMR (75.6 MHz,
CDCl3): δ 190.3; 142.8; 141.7; 122.4; 113.8; 77.8; 77.4; 75.5;
69.4; 68.2; 65.2; 29.6; 29.0; 27.3; 14.8; 8.13; 8.05. MS (ES
positive): m/ z 357 (M + H+, 100). HRMS: calcd for C15H23N2O6
327.1556, found 327.1556.
(1′R,2′R,3′R)-2-Acet yl-4-[3′,4′-O-(3′-p en t ylid en e)-1′,2′,
3′, 4′-tetr a h yd r oxy-1′-bu tyl]-1-(eth oxym eth yl)im id a zole
(17). Gen er a l AD P r oced u r e for Alk en es Usin g AD Mix-
r. Into a 25 mL round bottom flask were added AD mix-R20
(1.09 g), (DHQ)2PHAL (24 mg, 3.09 × 10-5 mol), K2OsO4‚2H2O
(2.8 mg, 9.75 × 10-6 mol), and methanesulfonamide (147 mg,
1.55 mmol). The reagents were dissolved in H2O (4 mL) and
t-BuOH (2 mL), and the solution was then cooled to 0 °C. The
(Z)-alkene 11b (250 mg, 7.76 × 10-4 mol) in t-BuOH (2 mL)
was added in a single addition, and the reaction was allowed
to stir for 48 h at 0 °C until complete by TLC analysis. Sodium
sulfite (1.2 g) was then added, and the reaction was warmed
to rt and stirred for 1 h. The mixture was extracted with CH2-
Cl2 (4 × 5 mL) and ethyl acetate (5 mL), and the combined
extracts were washed with a 2 M aqueous solution of KOH (7
mL), dried (MgSO4), and concentrated. Purification by column
chromatography (40% ethyl acetate/hexane) gave the final
product as a pale yellow oil (200 mg, 72%). The ratio of 17:16
was 3.4:1 from 1H NMR analysis.
gave the title compound as a tan oil (120 mg, 26%), [R]25
D
+18.8° (c 3.0, MeOH). 1H NMR (400 MHz, CDCl3): δ 7.54 (1H,
d, J ) 1.2 Hz); 6.95 (1H, d, J ) 1.6 Hz); 6.58 (1H, d, J ) 15.6
Hz); 6.31 (1H, dd, J ) 8.0, 16.0 Hz); 5.24 (2H, s); 4.67-4.61
(1H, m); 4.14 (1H, dd, J ) 6.0, 8.0 Hz); 3.65 (1H, t, J ) 8.0
Hz); 3.44 (2H, q, J ) 7.2 Hz); 1.73-1.65 (4H, m); 1.18 (3H, t,
J ) 7.2 Hz); 0.944; 0.935 (2 × 3H, 2 × t, J ) 7.2 Hz). 13C
NMR (75.6 MHz, CDCl3): δ 140.0); 137.3; 125.2; 124.4; 116.6;
112.9; 77.3; 76.0; 69.8; 64.1; 29.8; 29.6; 14.4; 7.9; 7.8. MS (ES
positive): m/ z 281 (M + H+, 100). HRMS: calcd for C15H24O3N2
280.1787, found 280.1793.
Syn th esis of 14b via th e Tr im eth ylvin ylsta n n a n e 13b.
A solution of trimethylvinylstannane 13b (100 mg, 0.314
mmol), iodoimidazole 7 (87 mg, 3.45 × 10-4 mol), and Pd(Ph3P)4
(20 mg, 1.73 × 10-5 mol) in anhydrous DMF (2.5 mL) in a
thick-walled reaction vessel was flushed with argon and then
sealed and left to stir at 80 °C in the dark for 24 h. The
solution was then cooled to rt, diluted with CH2Cl2 (10 mL),
washed with a half-saturated aqueous solution of NaCl (2 × 5
mL), dried (MgSO4), and concentrated. Purification by column
chromatography (40% ethyl acetate/hexane) gave the title
alkene as a tan oil (64 mg, 83%).
(3′R)-(E)-4-[3′,4′-O-(3′-P en tylid en e)-3′,4′-d ih yd r oxybu t-
1′-en yl]-1-(eth oxym eth yl)im id a zole (14a ). Using the pro-
cedure described above for the synthesis of 14b, the title
compound was obtained as a dark tan oil (46%) after purifica-
tion by column chromatography (35% ethyl acetate/hexane),
17. 1H NMR (400 MHz, CDCl3) δ 7.35 (1H, s); 5.76 (2H, d,
J ) 7.2 Hz); 4.76 (1H, t, J ) 6.0 Hz); 4.32-4.27 (1H, m); 4.04-
3.98 (1H, m); 3.85-3.73 (2H, m); 3.547 (2H, q, J ) 7.2 Hz);
3.28 (1H, d, J ) 6.8 Hz); 3.21 (1H, d, J ) 6.4 Hz); 2.643 (3H,
s); 1.74-1.60 (4H, m); 1.200 (3H, t, J ) 7.2 Hz); 0.929; 0.880
(2 × 3H, 2 × t, J ) 7.2 Hz). 13C NMR (75.6 MHz, CDCl3): δ
190.6; 142.7; 142.0; 122.1; 113.1; 77.3; 76.0; 73.5; 69.8; 66.5;
65.2; 29.6; 27.0; 27.3; 14.8; 8.13; 8.05. MS (ES positive): m/ z
357 (M + H+, 100). HRMS: calcd for C15H23N2O6 327.1556,
found 327.1546.
(1′R,2′R,3′S)-2-Acet yl-4-[3′,4′-O-(3′-p en t ylid en e)-1′,2′,
3′,4′ -tetr a h yd r oxy-1′-bu tyl]-1-(eth oxym eth yl)im id a zole
(20). Using the general procedure described above for the
synthesis of 17 except that the (Z)-alkene 11a (225 mg, 6.98
× 10-4 mol) was used, the title compound was obtained as a
pale yellow oil (235 mg, 95%) after purification by column
chromatography (40% ethyl acetate/hexane). The ratio of 20:
21 was 1.9:1 from 1H NMR analysis. Spectral data of 20 and
21 are identical to those of 16 and 17, respectively.
[R]25 -18.3° (c 0.82, MeOH). Spectral data are identical to
D
those of 14b.
(3′S)-(E)-2-Acetyl-4-[3′,4′-O-(3′-p en tylid en e)-3′,4′-d ih y-
d r oxybu t-1′-en yl]-1-(eth oxym eth yl)im id a zole (15b). The
title compound was prepared from the alkene 14b (345 mg,
1.23 mmol) using the method descibed above for the synthesis
of 10b. Purification by column chromatography (15% ethyl
acetate/hexane) gave the title methyl ketone as a tan oil (255
mg, 65%). 1H NMR (300 MHz, CDCl3) δ 7.26 (1H, s); 6.61 (1H,
d, J ) 15.6 Hz); 6.37 (1H, dd, J ) 7.2, 15.6 Hz); 5.75 (2H, s);
4.69-4.62 (1H, m); 4.16 (1H, dd, J ) 6.0, 8.1 Hz); 3.66 (1H, t,
J ) 8.1 Hz); 3.53 (2H, q, J ) 6.9 Hz); 2.68 (3H, s); 1.75-1.65
(4H, m); 1.19 (3H, t, J ) 6.9 Hz); 0.96; 0.94 (2 × 3H, 2 × t, J
) 7.5 Hz). 13C NMR (75.6 MHz, CDCl3) δ 190.9; 142.6; 139.5;
127.2; 124.0; 122.2; 113.3; 77.14; 77.10; 69.9; 64.9; 29.94; 29.67;
27.3; 14.8; 8.1. MS (CI positive): m/ z 332 (M+, 21); 293 (24);
277 (16); 265 (11); 236 (30); 177 (68); 161 (100). HRMS: calcd
for C17H26N2O4 322.1892, found 322.1891.
(1′S,2′S,3′S)-2-Acetyl-4-[3′,4′-O-(3′-pen tyliden e)-1′,2′,3′,4′-
tetr a h yd r oxy-1′-bu tyl]-1-(eth oxym eth yl)im id a zole (21).
Using the general procedure described above for the synthesis
of 16 except that (Z)-alkene 11a (225 mg, 6.98 × 10-4 mol)
(3′R)-(E)-2-Acetyl-4-[3′,4′-O-(3′-p en tylid en e)-3′,4′-d ih y-
d r oxybu t-1′-en yl]-1-(eth oxym eth yl)im id a zole (15a ). Us-
ing the procedure described above for the synthesis of 15b,

Synthesis of (Tetrahydroxybutyl)imidazoles
J . Org. Chem., Vol. 62, No. 4, 1997 1031
was used, the title compound was obtained as a pale yellow
oil (225 mg, 91%) after purification by column chromatography
(40% ethyl acetate/hexane). The ratio of 20:21 was 1:1.1 from
1H NMR analysis. Spectral data of 20 and 21 are identical to
those of 16 and 17, respectively.
the title compound was obtained as a pale oil (155 mg, 93%,
de ) 90%) after purification by column chromatography (45%
ethyl acetate/hexane), [R]23 -5.3° (c 1.55, MeOH). Spectral
D
data are identical to those of 25.
(1′R,2′S,3′R)-2-Acet yl-4-(1′,2′,3′,4′-t et r a h yd r oxy-1′-b u -
tyl)im id a zoliu m Ch lor id e (26). To a solution of imidazole
24 (120 mg, 3.37 × 10-4 mol) in ethanol/H2O (1:1, 8 mL) was
added concd aqueous HCl (4 mL), and the reaction was stirred
at 80 °C for 90 min. The solution was then cooled to rt,
filtered, and concentrated by freeze drying to give the title
compound as a tan solid (90 mg, 100%). 1H NMR (300 MHz,
D2O): δ 7.60 (1H, s); 5.21 (1H, s); 3.83-3.60 (4H, m); 2.66 (3H,
s). This coumpound was identical to the hydrochloride salt of
THI (1) that was prepared by an independent route.6
Dih yd r oxyla tion of th e (E)-Alk en e 15b in th e Absen ce
of a Ch ir a l Liga n d : (1′R,2′S,3′R)-2-Acetyl-4-[3′,4′-O-(3′-
p en tylid en e)-1′,2′,3′,4′ -tetr a h yd r oxy-1′-bu tyl]-1-(eth oxy-
m eth yl)im id a zole (24) a n d (1′S,2′R,3′R)-2-Acetyl-4-[3′,4′-
O-(3′-p e n t ylid e n e )-1′,2′,3′,4′-t e t r a h yd r oxy-1′-b u t yl]-1-
(et h oxym et h yl)im id a zole (25). To a solution of the (E)-
alkene 15b (20 mg, 6.21 × 10-5 mol) in t-BuOH/H2O (1:1, 2
mL) were added K3Fe(CN)6 (62 mg, 1.86 × 10-4 mol), K2CO3
(26 mg, 1.86 × 10-4 mol), methanesulfonamide (12 mg, 1.2 ×
-6
10-4 mol), and K2OsO4‚2H2O (1 mg, 3.48 ×
mol), and the
(1′S,2′R,3′R)-2-Acetyl-4-(1′,2′,3′,4′-tetr a h yd r oxy-1′-bu tyl-
)im id a zoliu m Ch lor id e (27). Using the general procedure
described above for the synthesis of 26, compound 27 was
obtained from the hydrolysis of 25 as a tan solid in quantitative
yield (100%). 1H NMR (300 MHz, D2O): δ 7.61 (1H, s); 5.04
(1H, d, J ) 4.8 Hz); 3.83-3.57 (4H, m); 2.64 (3H, s). 13C NMR
(75.6 MHz, D2O): δ 184.7; 139.4; 136.6; 119.5; 72.7; 71.3; 66.1;
62.5; 26.4. MS (LSIMS positive): m/ z 231 (M + H+, 100).
HRMS: calcd for C9H15N2O5 231.0981, found 231.0975.
(1′S,2′R,3′S)-2-Acetyl-4-(1′,2′,3′,4′-tetr a h yd r oxy-1′-bu tyl-
)im id a zoliu m Ch lor id e (30). Using the general procedure
described above for the synthesis of 26, compound 30 was
obtained as a glassy yellow solid (100%), mp 174-178 °C dec,
solution was cooled to 0 °C and stirred vigorously for 3 days
until complete by TLC analysis. Sodium sulfite (200 mg) was
added, and the reaction was warmed to rt and stirred for 1 h.
The mixture was diluted with H2O (2 mL) and extracted with
CH2Cl2 (4 × 5 mL), and the combined extracts were washed
with a 2 M aqueous solution of KOH (6 mL), dried (MgSO4),
and concentrated. The residue was purified by preparative
layer chromatography (50% ethyl acetate/hexane) and the
diastereomeric mixture taken into deuterated acetone for 1H
NMR analysis. The ratio of 24:25 was 3.5:1 from 1H NMR
analysis. Spectral data for 24 and 25 are given below.
(1′R,2′S,3′R)-2-Acet yl-4-[3′,4′-O-(3′-p en t ylid en e)-1′,2′,
3′,4′ -tetr a h yd r oxy-1′-bu tyl]-1-(eth oxym eth yl)im id a zole
(24). Using the general procedure described above for the
synthesis of 16 except that the (E)-alkene 15b (70 mg, 2.17 ×
10-4 mol) was used and additional osmium catalyst excluded,
the title compound was obtained as a thick pale oil (62 mg,
80%, de > 99%) after purification by column chromatography
[R]27 +14.9° (c 0.70, H2O). 1H NMR (300 MHz, D2O): δ 7.60
D
(1H, s); 5.21 (1H, s); 3.82-3.61 (4H, m); 2.66 (3H, s). 13C NMR
(100 MHz, D2O): δ 187.2; 141.7; 140.2; 121.6; 75.2; 73.1; 67.3;
65.4; 28.9. MS (ES positive): m/ z 231 (M + H+, 100); 213(64);
200 (23).
(1′R,2′S,3′S)-2-Acetyl-4-(1′,2′,3′,4′-tetr a h yd r oxy-1′-bu tyl-
)im id a zoliu m Ch lor id e (31). Using the general procedure
described above for the synthesis of 26, the title compound
was obtained as a light tan solid after concentration by freeze
(50% ethyl acetate/hexane), [R]23 +3.7° (c 2.10, MeOH). 1H
D
NMR (400 MHz, acetone-d6): δ 7.48 (1H, d, J ) 0.4 Hz); 5.77
(1H, d, J AB ) 10.4 Hz); 5.74 (1H, d, J AB ) 10.4 Hz); 4.84 (1H,
d, J ) 2.0 Hz; 4.23 (1H, dd, J ) 6.4, 13.2 Hz); 4.08 (1H, dd, J
) 6.0, 8.0 Hz); 3.91 (1H, dd, J ) 6.4, 8.0 Hz); 3.85 (1H, dd, J
) 2.4, 7.6 Hz); 3.53 (2H, q, J ) 6.8 Hz); 2.53; 1.66-1.56 (4H,
m); 1.12 (3H, t, J ) 6.8 Hz; 0.89; 0.86 (2 × 3H, 2 × t, J ) 7.6
Hz). 13C NMR (75.6 MHz, acetone-d6): δ 190.6; 145.1; 142.6;
124.0; 113.2; 77.5; 76.4; 75.6; 68.7; 68.2; 65.1; 29.4; 29.0; 27.2;
15.1; 8.5; 8.3. MS (ES positive): m/ z 379 (M + Na+, 100).
HRMS: calcd for C17H28N2O6 356.1947, found 356.1942.
(1′S,2′R,3′R)-2-Acet yl-4-[3′,4′-O-(3′-p en t ylid en e)-1′,2′,
3′,4′ -tetr a h yd r oxy-1′-bu tyl]-1-(eth oxym eth yl)im id a zole
(25). Using the general procedure described above for the
synthesis of 17 except that the (E)-alkene 15b (70 mg, 2.17 ×
10-4 mol) was used and additional osmium catalyst excluded,
the title compound was obtained as a thick pale oil (52 mg,
67%, de ) 96%) after purification by column chromatography
drying (95%), [R]26 -11.3° (c 0.70, H2O). Spectral data are
D
identical to those of 27.
(1′S,2′S,3′R)-2-Acetyl-4-(1′,2′,3,′4′-tetr a h yd r oxy-1′-bu tyl-
)im id a zoliu m Ch lor id e (18). Using the general procedure
described above for the synthesis of 26, the title compound
was obtained as a mixture of 18 and 19 (ca. 2:1) from the
hydrolysis of a 2:1 mixture of 16 and 17. Concentration by
freeze drying gave a light tan solid (85%), mp 161-168 °C dec.
1H NMR (300 MHz, D2O): δ 7.61 (1H, s); 5.12 (1H, d, J ) 4.8
Hz); 3.95-3.56 (4H, m); 2.65 (3H, s). 13C NMR (75.6 MHz,
D2O): δ 184.6; 139.1; 135.6; 119.7; 72.9; 71.8; 65.9; 62.5; 26.4.
MS (ES positive): m/ z 231 (M + H+, 100); 213 (24). HRMS:
calcd for C9H15N2O5 231.0981, found 231.0976.
(1′R,2′R,3′R)-2-Acetyl-4-(1′,2′,3′,4′-tetr ah ydr oxy-1′-bu tyl)-
im id a zoliu m Ch lor id e (19). Using the general procedure
described above for the synthesis of 26, the title compound
was obtained as a mixture of 19 and 18 (ca. 3:1) from
hydrolysis of a mixture (3.4:1) of 17 and 16 as a light tan solid
(90%) after concentration by freeze drying, mp 168-174 °C
dec. 1H NMR (300 MHz, D2O): δ 7.60 (1H, s); 4.89 (1H, d, J )
8.4 Hz); 3.92-3.60 (4H, m); 2.64 (3H). 13C NMR (75.6 MHz,
D2O): δ 184.6; 139.1; 137.4; 119.5; 72.2; 69.9; 65.0; 62.8; 26.4.
MS (ES negative): m/ z 229 (M - H-, 100). HRMS: calcd for
C9H15N2O5 231.0981, found 231.0970.
(1′R,2′R,3′S)-2-Acetyl-4-(1′,2′,3′,4′-tetr a h yd r oxy-1′-bu tyl-
)im id a zoliu m Ch lor id e (22) a n d (1′S,2′S,3′S)-2-Acetyl-4-
(1′,2′,3′,4′-tetr ah ydr oxy-1′-bu tyl)im idazoliu m Ch lor ide (23).
Using the general procedure described above for the synthesis
of 26, the title compounds were obtained as a mixture (22:23
ca. 2:1) from hydrolysis of a mixture (1.9:1) of 20 and 21 as a
light tan solid after concentration by freeze drying (85%), mp
177-182 °C dec. Spectral data of 22 and 23 are identical to
those of 18 and 19, respectively.
(1′R,2′S,3′R)-2-Acetyl-4(5)-(1′,2′,3′,4′-tetr a h yd r oxy-1′-bu -
tyl)im id a zole (THI, 1). To a solution of the imidazolium salt
26 (155 mg, 0.59 mmol) in H2O (3 mL) was added solid K2CO3
(82 mg, 0.59 mmol). The solution was then cooled to near
freezing for 3 days and the precipitated THI collected after
centrifuging the solution. The precipitate was washed with
H2O to remove salts and then dried under high vacuum to give
(50% ethyl acetate/hexane), [R]23 +4.4° (c 2.40, MeOH). 1H
D
NMR (400 MHz, acetone-d6): δ 7.47 (1H, s); 5.73; (2H, ABq, J
) 10.4 Hz); 4.72 (1H, d, J ) 4.4 Hz); 4.25 (1H, s(b)); 4.21 (1H,
ddd, J ) 5.2, 6.8, 11.2 Hz); 3.97 (1H, dd, J ) 6.4, 8.0 Hz); 3.96-
3.92 (1H, s(b)); 3.84-3.77 (2H, m); 3.52 (2H, q, J ) 7.2 Hz);
2.54 (3H, s); 1.66-1.54 (4H, m); 1.15 (3H, t, J ) 7.2 Hz); 0.88;
0.84 (2 × 3H, 2 × t, J ) 7.2 Hz). 13C NMR (100 MHz, acetone-
d6): δ 190.6; 144.2; 142.7; 124.2; 113.0 77.9; 77.5; 74.5; 70.4;
67.0; 65.0; 30.4; 30.0; 27.2; 15.1; 8.3. MS (ES positive): m/ z
379 (M + Na+, 100). HRMS: calcd for C17H28N2O6 356.1947,
found 356.1942.
(1′S,2′R,3′S)-2-Acet yl-4-[3′,4′-O-(3′-p en t ylid en e)-1′,2′,
3′,4′ -tetr a h yd r oxy-1′-bu tyl]-1-(eth oxym eth yl)im id a zole
(28). Using the general procedure described above for the
synthesis of 17 except that the (E)-alkene 15a (150 mg, 4.66
× 10-4 mol) was used and additional osmium catalyst excluded,
the title compound was obtained as a thick pale oil (130 mg,
78%, de ) 94%) after purification by column chromatography
(45% ethyl acetate/hexane), [R]23 -3.3° (c 1.3, MeOH). Spec-
D
tral data are identical to those of 24.
(1′R,2′S,3′S)-2-Acet yl-4-[3′,4′-O-(3′-p en t ylid en e)-1′,2′,
3′,4′ -tetr a h yd r oxy-1′-bu tyl]-1-(eth oxym eth yl)im id a zole
(29). Using the general procedure described above for the
synthesis of 16 except that the (E)-alkene 15a (150 mg, 4.66
× 10-4 mol) was used and additional osmium catalyst excluded,

1032 J . Org. Chem., Vol. 62, No. 4, 1997
Cliff and Pyne
the title compound as a light yellow solid (33 mg, 24%), mp
34 and 35 was obtained as a tan solid (71%, ratio 34:35 ) 5.3:
1) after purification by preparative layer chromatography (60%
ethyl acetate/hexane). Separation of the diastereomers by
preparative HPLC (30% ethyl acetate/hexane) gave the title
compounds as single diastereomers, 34. [R]24D +19.4° (c 0.06,
CH3CN), spectral data of 34 are identical to those of 32. Da ta
for 35. 1H NMR (300 MHz, CD3CN) δ 7.31 (1H, s); 6.01 (1H,
d, J ) 5.1 Hz); 5.61 (1H, dd, J ) 5.1, 6.3 Hz); 5.12 (1H, ddd,
J ) 3.0, 6.0, 9.3 Hz); 4.34 (1H, dd, J ) 3.3, 12.3 Hz); 4.13 (1H,
dd, J ) 6.0, 12.3 Hz); 2.49 (3H, s); 2.05; 2.01; 2.00; 1.99 (4 ×
3H, 4 × s). 13C NMR (75.6 MHz, CD3CN): δ 188.7; 170.37;
169.62; 169.61; 169.60; 144.7; 138.6; 119.7; 70.4; 69.5; 68.9;
61.6; 24.6; 20.09; 20.06; 19.88. MS (ES positive): m/ z 399 (M
+ H+, 78); 339 (100). HRMS: calcd for C17H23N2O9 399.1402,
found 399.1389.
(1′R,2′S,3′S)-2-Acetyl-4(5)-(1′,2′,3′,4′-tetr a a cetoxy-1′-bu -
tyl)im idazole (36) an d (1′S,2′S,3′S)-2-Acetyl-4(5)-(1′,2′,3′,4′-
t et r a a cet oxy-1′-b u t yl)im id a zole (37). Using the general
procedure described above for the synthesis of 32 and a
reaction time of 6 h at 60 °C, a mixture of the tetraacetates
36 and 37 was obtained as a cream solid (93%, ratio 36:37 )
1.3:1) after purification by preparative layer chromatography
(60% ethyl acetate/hexane). HPLC separation of the diaster-
eomers (30% ethyl acetate/hexane) gave the title compounds
as single diastereomers. Spectral data of 36 were identical to
those of 33. Da ta for 37. 1H NMR (300 MHz, CD3CN) δ 7.29
(1H, s); 5.89 (1H, d, J ) 7.8 Hz); 5.62 (1H, dd, J ) 3.9, 7.8
Hz); 5.42 (1H, ddd, J ) 4.8, 6.9, 8.4 Hz); 4.20 (1H, dd, J ) 4.5,
12.0 Hz); 4.11 (1H, dd, J ) 6.6, 11.7 Hz); 2.50 (3H, s); 2.03;
2.01; 1.99; 1.94 (4 × 3H, 4 × s). 13C NMR (75.6 MHz, CD3-
CN): δ 188.7; 170.3; 169.9, 169.6; 169.5; 144.8; 139.1; 119.9;
70.9; 68.5; 67.4; 62.2; 24.6; 20.1; 19.9; 19.8. MS (ES positive):
m/ z 399 (M + H+, 57%); 339 (100). HRMS: calcd for
C17H23N2O9 399.1402, found 399.1407.
240-244 °C (lit.6 mp 234-236 °C), [R]23 -14.9° (c 0.09, H2O)
D
(lit.6 [R]25 -12°, c 1.17, 1 N HCl). 1H NMR (300 MHz, D2O/
D
DCl): δ 7.30 (1H, s); 4.91 (1H, s); 3.51-3.32 (4H, m); 2.35 (3H,
s). Spectral data are identical to those of an authentic sample
of THI (1).6
(1′R,2′S,3′R)-2-Acetyl-4(5)-(1′,2′,3′,4′-tetr a a cetoxy-1′-bu -
tyl)im id a zole (32). Gen er a l P r oced u r e. F r om Au th en tic
THI.6 To a stirred solution of acetic anhydride (3.0 mL) and
glacial acetic acid (5.0 mL) was added THI (1) (200 mg, 0.87
mol). A perchloric acid/acetic anhydride catalyst was added
(4 drops, prepared by addition of 1.0 g of 70% HClO4 to 2.3 g
of acetic anhydride at 0 °C), and the reaction was stirred for
1 h at 60 °C. The mixture was poured into H2O/ice (30 mL)
and extracted with ethyl acetate (3 × 20 mL). The combined
extracts were dried (MgSO4) and concentrated to give a thick
tan oil. Recrystallization from ethyl acetate gave the title
compound as a white powder (190 mg, 55%), mp 153-154 °C,
[R]24 -22.6° (c 0.58, CH3CN).
D
F r om THI Syn th esized in Th is P r oject. Using the
general procedure descibed above, THI synthesized in this
study was converted to the tetraacetate. Purification by
preparative layer chromatography (60% ethyl acetate/hexane)
gave the title compound as a white solid (47%), [R]24 -20.0°
D
(c 0.09, CH3CN). Spectral data are identical to those of the
tetraacetate synthesized from authentic THI above. 1H NMR
(400 MHz, CD3CN): δ 7.27 (1H, s); 6.05 (1H, d, J ) 4.8 Hz);
5.56 (1H, dd, J ) 5.2, 7.2 Hz); 5.18 (1H, ddd, J ) 2.8, 5.6, 8.8
Hz); 4.25 (1H, dd, J ) 3.2, 12.4 Hz); 4.11 (1H, dd, J ) 6.0,
12.4 Hz); 2.51 (3H, s); 2.04; 2.02; 2.00; 1.98 (4 × 3H, 4 × s).
13C NMR (100 MHz, CD3CN): δ 188.7; 170.3; 169.7; 169.6;
169.5; 145.0; 138.5; 120.2; 70.8; 68.7; 67.5; 61.5; 24.7; 20.00;
19.93; 19.88; 19.86. MS (ES positive): m/ z 399 (M + H+, 100);
339 (71). HRMS: calcd for C17H23N2O9 399.1402, found
399.1398. Anal. Calcd for C17H22N2O9: C, 51.26; H, 5.57; N,
7.03. Found: C, 51.09; H, 5.66; N, 6.65.
Ack n ow led gm en t. We thank Don Dougan and
David Atkins, J ohnson & J ohnson Research Pty. Lim-
ited (J J RPL), for valuable discussions and encourage-
ment, Prof. K. B. Sharpless for the exchange of infor-
mation concerning the AD reaction, and Dr. Alison Ung
for a sample of 1 that was prepared using the method
of Buchi.6 M.D.C. thanks the Australian Research
Council and J J RPL for an Australian Postgraduate
Research Award (Industry).
(1′S,2′R,3′R)-2-Acetyl-4(5)-(1′,2′,3′,4′-tetr a a cetoxy-1′-bu -
tyl)im id a zole (33). Using the general procedure described
above for the synthesis of 32, the title compound was obtained
as a glassy solid (23%) after purification by preparative layer
chromatography (60% ethyl acetate/hexane). 1H NMR (400
MHz, CD3CN): δ 7.29 (1H, s); 5.98 (1H, d, J ) 8.4 Hz); 5.70
(1H, dd, J ) 3.6, 8.0 Hz); 5.01 (1H, ddd, J ) 3.6, 5.2, 8.8 Hz);
4.18 (1H, dd, J ) 5.2, 11.6 Hz); 4.00 (1H, dd, J ) 6.4, 11.6
Hz); 2.52 (3H, s); 2.08; 2.05; 2.00; 1.96 (4 × 3H, 4 × s). 13C
NMR in part (100 MHz, CD3CN): δ 181.7; 170.2; 169.8; 169.7;
145.1; 71.2; 68.7; 68.2; 61.6; 24.7; 20.1; 20.0; 19.9; 19.8. MS
(ES positive): m/ z 399 (M + H+, 100); 339 (82). HRMS: calcd
for C17H23N2O9 399.1402, found 399.1409.
1
Su p p or tin g In for m a tion Ava ila ble: H NMR of com-
pounds 1, 8b, 10b, 11a , 13b, 15b, 16-19, 24-26, and 31-40
(18 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, can be ordered from the ACS; see any current
masthead page for ordering information.
(1′S,2′R,3′S)-2-Acetyl-4(5)-(1′,2′,3′,4′-tetr a a cetoxy-1′-bu -
tyl)im id a zole (34) a n d (1′R,2′R3′S)-2-Acetyl-4(5)-(1′,2′,3′,4′-
tetr a a cetoxy-1′-bu tyl)im id a zole (35) fr om 30. Using the
general procedure described above for the synthesis of 32 and
a reaction time of 6 h at 60 °C, a mixture of the tetraacetates
J O961630F