Efficient synthesis of (±)-, (+)-, and (-)-conduritol C via palladium(II)-catalyzed 1,4-diacetoxylation in combination with enzymatic hydrolysis

Article abstract of DOI:10.1021/jo981281k

Palladium-catalyzed diacetoxylation of 5,6-isopropylendioxy-1,3- cyclohexadiene (3) was stereoselective and gave the trans-diacetate 4 (> 94% trans), which after hydrolysis and deprotection, afforded (±)-conduritol. Enzymatic hydrolysis of diacetate 4 produced enantiomerically pure diol (-)- 5 (>99.5% ee) and enantiomerically pure (+)-4 (>99.5% ee). Compounds (-)-5 and (+)-4 were subsequently transformed to (-)- and (+)-conduritol C, respectively.

Full text of DOI:10.1021/jo981281k

J . Org. Chem. 1998, 63, 9339-9341
9339
Efficien t Syn th esis of (()-, (+)-, a n d (-)-Con d u r itol C via
P a lla d iu m (II)-Ca ta lyzed 1,4-Dia cetoxyla tion in Com bin a tion w ith
En zym a tic Hyd r olysis
Hiroki Yoshizaki and J an-E. B a¨ ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden
Received J une 30, 1998
Palladium-catalyzed diacetoxylation of 5,6-isopropylendioxy-1,3-cyclohexadiene (3) was stereose-
lective and gave the trans-diacetate 4 (>94% trans), which after hydrolysis and deprotection, afforded
(
(
()-conduritol. Enzymatic hydrolysis of diacetate 4 produced enantiomerically pure diol (-)-5
>99.5% ee) and enantiomerically pure (+)-4 (>99.5% ee). Compounds (-)-5 and (+)-4 were
subsequently transformed to (-)- and (+)-conduritol C, respectively.
In tr od u ction
Sch em e 1. Syn th esis of (()-Con d u r itol C
Conduritols constitute a class of 5-cyclohexene-1,2,3,4-
tetrols with interesting biological activity including
antibiotic, antileukemic, and tumor-inhibitory proper-
ties.1 Several of the conduritol isomers are inhibitors for
2
glycosidases. Various synthetic approaches toward the
3
different isomers of conduritols have been developed
including enantioselective versions.4,5
Conduritol C (1), one of the six possible diastereoiso-
mers of 5-cyclohexene-1,2,3,4-tetrols, has been synthe-
sized by several groups.3 In 1989, Vogel et al. success-
fully achieved the first total synthesis of optically pure
-5
4
5a-f
(
-)-conduritol C ((-)-1), and subsequently, others
have reported enantioselective syntheses. Their prime
synthetic strategies for introduction of the trans-dihy-
droxy groups were based on stereospecific reduction of
ketones or Mitsunobu displacement reactions after en-
zyme-catalyzed enantioselective reaction of the cis-di-
ester.
In this paper, we report on a different strategy involv-
ing a palladium-catalyzed trans-diacetoxylation of a
protected 3,5-cyclohexadiene-1,2-diol. Kinetic resolution
of the product afforded (+)- and (-)-1 in excellent
enantiomeric excess and yield.
(1) (a) K u¨ lber, K. Arch. Pharm. 1908, 346, 620. (b) Kern, W.; Fricke,
W. Pharm. Zentralhalle 1939, 80, 349-352. (c) Manni, P. E.; Sin-
sheimer, J . E. J . Pharm. Sci. 1965, 54, 1541. (d) Dominguez, X. A.;
Marroquin, J .; Olguin, L. M.; Morales, F.; Valdez, V. Phytochemistry
1
974, 13, 2617-2618.
(
2) (a) Legler, G.; Bause, E. Carbohydr. Res. 1973, 28. (b) Legler,
G.; Lotz, W. Physiol. Chem. 354, 1973, 243. (c) Umezawa, S. Adv.
Carbohydr. Chem. Biochem. 1974, 30, 111-225. (d) Atsumi, S.;
Umezawa, K.; Iinuma, H.; Nakamura, H.; Iitaka, Y. J . Antibiot. 1989,
4
3, 49-53.
3) For excellent reviews on preparation of conduritols, see: (a)
BalcI, M.; S u¨ tbeyaz, Y.; Se c¸ en, H. Tetrahedron 1990, 46, 3715-3742.
b) Hudlicky, T.; Reed, J . W. In Advances In Asymmetric Synthesis;
(
Resu lts a n d Discu ssion
(
J AI Press Inc.: London, 1995; Vol. 1, p 271-312. (c) BalcI, M. Pure
1. 1,4-Dia cetoxyla tion s of cis-5,6-(Isop r op ylid en e-
d ioxy)-1,3-cycloh exa d ien e. The diene 3 was prepared
from commercially available 1,2-dihydrocatechol 2 by
Appl. Chem. 1997, 69, 97-104.
(
4) Le Drian, C.; Vieira, E.; Vogel, P. Helv. Chim. Acta 1989, 72,
3
38-347.
(5) For more recent examples, see: (a) J ohnson, C. R.; Pl e´ , P. A.;
reaction with 2,2-dimethoxypropane under acidic condi-
Adams, J . P. J . Chem. Soc., Chem. Commun. 1991, 1006-1007. (b)
Dumortier, L.; Liu, P.; Dobbelaere, S.; Van der Eycken, J .; Vandewalle,
M. Synlett 1992, 243-245. (c) Patti, A.; Sanfilippo, C.; Piatteri, M.;
Nicolosi, G. Tetrahedron: Asymmetry 1996, 7, 2665-2670 (conduritol
C and D). (d) Carless, H. A. J .; Oak, O. Z. J . Chem. Soc., Chem.
Commun. 1991, 61-62. (e) McIntosh, M. C.; Weinreb, S. M. J . Org.
Chem. 1991, 56, 5010-5012. (f) Carless, H. A. J . J . Chem. Soc., Chem.
Commun. 1992, 234-235. (g) Innes, J . E.; Edwards, P. J .; Ley, S. V.
J . Chem. Soc., Perkin Trans. 1 1997, 795-796 ((+)-D-conduritol B).
tions in dichloromethane (Scheme 1).6 Using this diene
as a substrate, the palladium(II)-catalyzed 1,4-diacetox-
ylation was examined.7 First, trans-1,4-diacetoxylation
(6) (a) Yang, N. C.; Chen, M.-J .; Chen, P. J . J . Am. Chem. Soc. 1984,
106, 7310-7315. (b) Ramesh, K.; Wolfe, M. S.; Lee, Y.; Velde, D. V.;
Borchardt, R. T. J . Org. Chem. 1992, 57, 5861-5868.
1
0.1021/jo981281k CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/20/1998

9
340 J . Org. Chem., Vol. 63, No. 25, 1998
Yoshizaki
Ta ble 1. Exa m in a tion of tr a n s-1,4-Dia cetoxyla tion a
Sch em e 3. Syn th esis of Op tica lly P u r e (+)- a n d
a
yield (%)b
ratio (trans %)c
(-)-Con d u r itol C
run
oxidant
temp
1
2
3
MnO2
MnO2
Fe(Pc)/O2
rt
40 °C
rt
69
51
71
87
88
94
a
All reactions were carried out for 48 h. Isolated yield. c Ratio
b
1
was determined by H NMR spectrum.
Sch em e 2
a
Reagents and conditions: (a) lipase (from Candida rugosa),
phosphate buffer (pH 7.0), rt, 18 h ((-)-5: 49%). (b) Conc. HCl aq,
MeOH, 0 °C, 10 min (98%). (c) K2CO3, MeOH, rt, 10 min (99%).
2
. En a n tiom er ica lly P u r e (+)- a n d (-)-Con d u r itol
C. Enantioselective enzyme-catalyzed hydrolysis of trans-
diacetate 4 obtained from 1,4-diacetoxylation of 3 was
studied in an attempt to obtain enantiomerically pure
conduritol C.
In the planning of this synthesis, a significant question
was if the enzyme could recognize both of two acetates
simultaneously. If not, four compounds, one diacetate,
one diol, and two monoacetates, would be produced and
resolution would fail. However, according to the principle
was studied by employing 5 mol % of palladium diacetate
[
Pd(OAc)
lithium acetate dihydrate (LiOAc‚2H
of manganese(IV) oxide (MnO
2
], 10 mol % of p-benzoquinone, 1.2 equiv of
O), and 1.2 equiv
) in acetic acid at room
2
2
8,9
of enzymatic hydrolysis, it appeared to be possible in
this case.
temperature for 48 h (Table 1, run 1).7b The desired
product trans-1,4-diacetate 4 was obtained in 69% yield
in a trans/cis ratio of 87:13. When the temperature was
raised to 40 °C, the yield dropped to 51% (run 2). Using
The diacetate obtained from trans-1,4-diacetoxylation
of diene 3 having the acetonide function was hydrolyzed
9
by lipase from Candida rugosa, in a phosphate buffer
3
mol % of iron(II) phthalocyanine [Fe(Pc)] as a dioxygen
9
(
pH 7), according to Kazulauskas’ procedure. Fortu-
7
c
activating agent under an oxygen atmosphere afforded
nately, the acetonide function could be effectively distin-
guished by the enzyme, and the optical resolution pro-
ceeded smoothly and quantitatively. In this step, the
hydrolyzed trans-diol (-)-5 and trans-diacetate (+)-4
were obtained in 49% and 48% yields, respectively. The
enantiomeric excesses (ees) of the products were deter-
mined by chiral HPLC analysis after derivatization of
the trans-diols (+)- and (-)-5 into trans-dibenzoate. In
each case, the ees were >99.5%, showing that the
enzyme-catalyzed kinetic resolution was highly efficient
4
in 71% yield and with >94% trans selectivity (run 3).
The diacetate 4 obtained from 1,4-diacetoxylation of
diene 3 was hydrolyzed, and the purified trans-diol
obtained was subsequently deprotected to afford the (()-
conduritol ((()-1). The overall yield of (()-1 from com-
mercially available diol 2 was 54% (Scheme 1).
cis-1,4-Diacetoxylation of 3 was also studied by em-
ploying 5 mol % of Pd(OAc)
2
, 20 mol % of p-benzoquinone,
0 mol % of lithium chloride (LiCl), 30 mol % of LiOAc‚
O, and 1.2 equiv of MnO in acetic acid at room
The desired cis-diacetate was not ob-
2
2
H
2
2
(Scheme 3).
7
b
temperature.
The enantiomerically pure trans-diol (-)-5 was depro-
tained, and instead, the Diels-Alder adduct between
diene and quinone was produced.
In the diacetoxylation of 3, the reaction may proceed
via two different (π-allyl)palladium complexes (Scheme
tected to give (-)-1, and the diacetate (+)-4 was hydro-
lyzed-deprotected to give (+)-1. The overall yields of (+)-
and (-)-1 from 2 were 29% and 30%, respectively. The
1
13
H and C NMR spectra and optical rotations were in
2
). Palladium can coordinate either from the same or
good agreement with literature data.4
from the opposite side of the acetonide. Subsequent
nucleophilic attack by the first nucleophile would give
the (π-allyl)palladium intermediates 7 and 8. A cis
migration from the latter complexes would produce the
trans-diacetate. It is likely that 7 is the intermediate
π-allyl complex in this reaction. This was supported by
the fact that the cis-diacetate obtained as a minor isomer
In this manner, a short and efficient synthesis of
enantiomerically pure (+)- and (-)-conduritol C was
achieved. We have demonstrated the utility of pal-
ladium-catalyzed 1,4-trans-diacetoxylation for introduc-
tion of functional groups, as well as the enzyme-catalyzed
hydrolysis as a powerful tool for obtaining optically active
materials.
(diacetate of 6) was found to have the diacetoxy groups
cis to the oxygens in the acetonide (J 23 ) 3.3 Hz, see
Experimental Section). This diacetate would be formed
from external attack by acetate on intermediate 7.
Exp er im en ta l Section
(
1R*,4R*,5S*,6R*)-1,4-Dia cet oxy-5,6-(isop r op ylid en e-
d ioxy)-2-cycloh exen e (4). To a solution of palladium diac-
etate (161.2 mg, 0.718 mmol), p-benzoquinone (155.2 mg, 1.436
(7) (a) B a¨ ckvall, J . E. In Organometallic Reagents in Organic
Synthesis; Academic: London, 1994; p 81-97. (b) B a¨ ckvall, J . E.;
Bystr o¨ m, S. E.; Nordberg, R. E. J . Org. Chem. 1984, 49, 4619-4631.
(8) Prelog, V. Pure Appl. Chem. 1964, 9, 119-130.
(9) Kazlauskas, R. J .; Weissfloch, A. N. E.; Rappaport, A. V. T.;
Cuccia, L. A. J . Org. Chem. 1991, 56, 2656-2665.
(
c) B a¨ ckvall, J . E.; Hopkins, R. B.; Grennberg, H.; Mader, M.; Awasthi,
A. K. J . Am. Chem. Soc. 1990, 112, 5160.

Synthesis of (()-, (+)-, and (-)-Conduritol C
J . Org. Chem., Vol. 63, No. 25, 1998 9341
3
MHz, CDCl ): δ (ppm) 26.1, 28.1, 66.1, 71.3, 72.0, 75.9, 109.7,
mmol), iron phthalocyanine (272.1 mg, 0.431 mmol), and
LiOAc‚2H
C was added cis-5,6-(isopropylidenedioxy)-1,3-cyclohexadiene
3, 2.18 g, 14.36 mmol) during 3 h with a syringe pump.
2
O (1.81 g, 17.23 mmol) in acetic acid (45 mL) at 20
127.6, 130.1. (+)-4: [R]20
D
+154.7 (c 1.106, CHCl
).
3
). (-)-5:
°
(
[R]20
D
-157.2 (c 0.998, CHCl
3
Deter m in a tion of En a n tiom er ic P u r ity of Com p ou n d s
Stirring was continued for another 48 h at this temperature.
The reaction mixture was filtered through Celite under
reduced pressure and washed with 2 M aqueous sodium
hydroxide solution (5 × 50 mL), and the aqueous phase was
re-extracted with ethyl acetate. The combined organic phases
(
+)-4 a n d (-)-5. Diol (-)-5 was transformed to the dibenzoate
by reaction with benzoyl chloride and pyridine. Analysis of
the dibenzoate with chiral HPLC (Chiracel OD-H, hexane/2-
propanol ) 90:10) showed that the product was of >99.5% ee.
The diacetate (+)-4 was hydrolyzed, and the diol was diben-
zoylated. Chiral HPLC analysis as above showed that the ee
was >99.5%.
4
were washed with brine, dried (MgSO ), and concentrated in
vacuo to give the crude product. Purification of the crude
product by flash column chromatography (petroleum ether/
AcOEt, 5:1) afforded 2.63 g (71%) of trans-1,4-diacetate 4
(
1R,4R,5S,6R)-5-Cycloh exen e-1,2,3,4-tetr ol a n d (1S,4S,-
5
R,6S)-5-Cycloh exen e-1,2,3,4-tetr ol [(+)-1 a n d (-)-1]. To
(
(
3
3
>94% trans) as a colorless liquid. R
270 MHz, CDCl ): δ (ppm) 1.37 (s, 3H), 1.44 (s, 3H), 2.04 (s,
H), 2.07 (s, 3H), 4.42 (dd, J ) 6.2, 8.0 Hz, 1H), 4.71 (dd, J )
.7, 9.5 Hz, 1H), 5.18 (dd, J ) 3.7, 8.1 Hz, 1H), 5.49 (t, J ) 4.1
: 0.37 (AcOEt). 1H NMR
f
a methanol solution (20 mL) of trans-diol (-)-5 (1.0 g, 5.37
mmol), two drops of concentrated hydrochloric acid (37%) was
added dropwise, and the solution was stirred for 10 min at 0
3
°
C. The reaction mixture was neutralized with saturated
Hz, 1H), 5.93 (ddd, J ) 0.9, 4.0, 9.9 Hz, 1H), 6.07 (dd, J ) 3.7,
aqueous sodium bicarbonate. This suspension was evaporated
under reduced pressure, and the residue was suspended with
methanol. The filtrate was left overnight at -30 °C to yield
1
3
9
2
1
3
.9 Hz, 1H). C NMR (67.8 MHz, CDCl ): δ (ppm) 20.8, 20.9,
5.7, 27.6, 66.0, 71.0, 72.0, 72.8, 110.0, 126.6, 129.3, 170.1,
70.4.
7
76.1 mg (99%) of colorless crystals. Recrystallization from
(
1R*,4S*,5R*,6S*)-1,4-Dia cet oxy-5,6-(isop r op ylid en e-
methanol and ether gave 621.5 mg (80%) of colorless crystals,
mp 128-129 °C (lit. 129-130 °C). (-)-1: [R]
1
d ioxy)-2-cycloh exen e (Min or Isom er , Dia ceta te of 6).
4
20
D
-213° (c
20
1
R
f
: 0.37 (petroleum ether/AcOEt, 5:1). H NMR (270 MHz,
CDCl ): δ (ppm) 1.38 (s, 3H), 1.49 (s, 3H), 2.14 (s, 6H), 4.28
dd, J ) 1.4, 3.3 Hz, 2H), 5.29 (dd, J ) 1.1, 3.3 Hz, 2H), 5.73
4
25
.996, H
c 2.008, H
2
O) [lit. [R]
2
D
-209° (c 2, H
D
2
O)]. (+)-1: [R]
D
+215°
3
5d
25
1
(
O) [lit. [R]
+213° (c 0.4, H
2
O)]. H NMR (270
(
(
7
MHz, CD
3
OD): δ (ppm) 3.57 (dd, J ) 3.7, 6.6 Hz, 1H), 3.85
brt, J ) 3.1 Hz, 1H), 4.00 (t, J ) 6.2 Hz, 1H), 4.30 (dd, J )
1
3
s, 2H). C NMR (67.8 MHz, CDCl ): δ (ppm) 21.3, 25.3, 27.3,
1.8, 75.6, 109.9, 128.4, 170.4.
1R,4R,5S,6R)-1,4-Dih ydr oxy-5,6-(isopr opyliden edioxy)-
3
(
3
.3, 5.9 Hz, 1H), 5.45 (ddd, J ) 0.9, 3.6, 10.2 Hz, 1H), 5.54
(
13
(
(
dd, J ) 3.6, 10.2 Hz, 1H). C NMR (67.9 MHz, CD
3
OD): δ
2
1
-cycloh exen e ((-)-5). A suspension of racemate 4 (4.66 g,
8.04 mmol) and lipase in phosphate buffer (40 mL) at pH 7.0
ppm) 69.2, 72.3, 73.5, 77.6, 127.7, 132.3.
was vigorously stirred for 18 h at room temperature. After
addition of ethyl acetate (40 mL), this suspension was filtered
through Celite and the mixture was extracted 4 times with
ethyl acetate. The combined extracts were washed with
saturated aqueous sodium bicarbonate, water, and brine, dried
over magnesium sulfate, and concentrated. After purification
by flash column chromatography (petroleum ether/AcOEt,
Ackn owledgm en t. Financial support from the Swed-
ish Natural Science Research Council and the Swedish
Foundation for Strategic Research (Senior Individual
Grant) is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra of 4, 5, the diacetate of 6, and conduritol C (1) (10
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
1
:1-1:2), 2.23 g (48%) of trans-1,4-diacetate (+)-4 (>99.5% ee)
and 1.64 g (49%) of trans-diol (-)-5 (>99.5% ee) were obtained
Recrystallization of (-)-5 from n-hexane and ether gave 1.41
1
g (86%) of colorless crystals. H NMR (270 MHz, CDCl
3
): δ
(ppm) 1.38 (s, 3H), 1.44 (s, 3H), 2.98 (brs, 1H), 3.16 (brs, 1H),
3
4
.96-3.98 (m, 1H), 4.30 (brs, 1H), 4.37 (t, J ) 6.2 Hz, 1H),
.67 (brd, J ) 5.9 Hz, 1H), 5.92-5.94 (m, 2H). 13C NMR (67.9
J O981281K