A New Convergent Route to Conduritols A-F from a Common Chiral Building Block

Article abstract of DOI:10.1021/ol015963x

(matrix presented) A diastereocontrolled route to conduritols A-F has been developed starting from a common chiral building block containing an oxabicyclo-[3.2.1]octane framework.

Full text of DOI:10.1021/ol015963x

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1769-1772
A New Convergent Route to Conduritols
A−F from a Common Chiral Building
Block
Kohei Kadota, Miwako Takeuchi, Takahiko Taniguchi, and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
konol@mail.cc.tohoku.ac.jp
Received April 9, 2001
ABSTRACT
A diastereocontrolled route to conduritols A−F has been developed starting from a common chiral building block containing an oxabicyclo-
[3.2.1]octane framework.
We have recently developed an efficient preparation of chiral
building block 1, which contains a bicyclo[3.2.1]octane
framework, in both enantiomeric forms from furfural by
employing either chemical1 or enzymatic2 procedures. Owing
to its molecular bias, 1 exhibits inherent diastereoselectivity,
while the masked formyl and 1,2-glycol functionalities in
the molecule enforce its versatile applicability. The potential
of 1 as a chiral building block has so far been demonstrated
by a convergent synthesis of all eight of the aldohexoses1,3
as well as the diastereocontrolled syntheses of a variety of
natural products.4 In this report, we demonstrate an alterna-
tive utilization of the chiral building block 1 for the
diastereocontrolled construction of all six of the conduritol
diastereomers.5 Since there is only one precedent6 that is
capable of producing all six of the possible conduritols A-F
convergently from a common cyclohexenol building block,7
the present example constitutes the second convergent route
(Scheme 1).
The synthesis began with reduction of enantiopure enone
(-)-1 by sodium borohydride-ceriumIII) chloride8 to give
endo-allyl alcohol1 3 which was protected as methoxymethyl
(MOM) ether 4, [R]26 +34.8 (c 1.0, CHCl3). Dihydroxyl-
D
ation of 4 under catalytic conditions proceeded diastereo-
selectively from the convex face to give single exo-diol 5
which was transformed into tri-MOM ether 6a, [R]26D +65.4
(c 2.0, CHCl3), serving as the precursor of (+)-conduritol
B, (-)-conduritol E, and (-)-conduritol F. Moreover, endo-
alcohol 3 was treated under Mitsunobu conditions9 with
4-nitrobenzoic acid10 to give exo-benzoate 7 which furnished
diastereoselectively exo-diol 8 on catalytic dihydroxyl-
ation.1,11 On sequential debenzoylation and etherification, 8
(1) Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Synthesis 1999, 341.
(2) Taniguchi, T.; Takeuchi, M.; Kadota, K.; ElAzab, A. S.; Ogasawara,
K. Synthesis 1999, 1325.
afforded tri-MOM ether 6b, [R]26 +44.8 (c 0.9, CHCl3),
(3) Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Chirality 2000, 12, 338.
(4) (a) (+)-noviose: Takeuchi, M.; Taniguchi, T.; Ogasawara, K.
Tetrahedron Lett. 2000, 41, 2609. (b) FK-506 segment; Takeuchi, M.;
Taniguchi, T.; Ogasawara, K. Tetrahedron: Asymmetry 2000, 11, 1601.
(c) (-)-Shikimic acid: Takeuchi, M.; Taniguchi, T.; Ogasawara, K.
Synthesis 2000, 1375. (d) (-)-Physostigmine: ElAzab, A. S.; Taniguchi,
T.; Ogasawara, K. Org. Lett. 2000, 2, 2757. (e) (+)-Febrifugine: Taniguchi,
T.; Ogasawara, K. Org. Lett. 2000, 2, 3181. (f) Pseudomonic acid
segment: Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 3359.
(5) For pertinent reviews, see: (a) Balci, M.; Secen, H. Tetrahedron 1990,
46, 3715. (b) Vogel, P.; Fattori, F.; Gasparini, F.; Le Drian, C. Synlett 1990,
170. (c) Carless, H. A. J. Tetrahedron: Asymmetry 1992, 3, 795.
D
serving as the precursor of conduritol D.
(6) Honzumi, M.; Hiroya, K.; Taniguchi, T.; Ogasawara, K. Chem.
Commun. 1999, 1985.
(7) Ogasawara, K. J. Synth. Org. Chem. Jpn. 1999, 57, 957.
(8) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
(9) Mitsunobu, O. Synthesis 1981, 1.
(10) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(11) Matsumoto, K.; Ebata, T.; Koseki, K.; Kawakami, H. Heterocycles
1991, 32, 2225.
10.1021/ol015963x CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/09/2001

Scheme 1
On the other hand, enone (-)-1 was first converted to exo-
the conduritol diastereomers, their conversion into the 1,7-
diene substrates for the key ring-closing olefin metathesis
reaction13 was next examined. Thus, MOM ethers 6a-c were
transformed14 into the iodides 15a-c, via alcohols 14a-c,
which were further transformed into hemiacetals 16a-c on
exposure to zinc in methanol in the presence of acetic acid.1
epoxide 9 which was sequentially reduced to endo-alcohol
10 and benzoylated to give endo-benzoate 11, [R]25D +17.5
(c 1.4, CHCl3). Upon exposure to boron trifluoride etherate,
the benzoate-assisted regio- and diastereoselective epoxide
cleavage12 occurred to form oxonium intermediate 12 giving
rise to single triol 13, after alkaline methanolysis of the
monobenzoate mixture, which was transformed into tri-MOM
Of the hemiacetals 16a-c thus obtained, 16a was oxi-
dized15 to give δ-lactone 17 with R-axial alkoxy functionality.
When 17 was refluxed in benzene with 1,4-diazabicyclo-
[2.2.2]octane (DABCO),1 epimerization occurred to give
R-equatorial epimer 18 in 44% yield with unchanged 17 in
50% recovery yield, the latter of which was recycled. The
former lactone 18 was reduced with diisobutylaluminum
hydride (DIBAL) to yield the fourth hemiacetal 16d (Scheme
3).
ether 6c, [R]27 +15.2 (c 0.9, CHCl3), serving as the
D
precursor of conduritol A and (-)-conduritol C (Scheme 2).
Scheme 2a
Scheme 3a
a Reagents and conditions: (i) NaBH4-CeCl3, 0 °C (90% for 3;
75% for 11 from 1); (ii) MOM-Cl, Hu¨nig base, CH2Cl2 (94% for
4; 95% for 6a; 64% for 6b from 3; 99% for 6c); (iii) OsO4
(catalytic), NMO, 50% aqueous THF (95%); (iv) 4-nitrobenzoic
acid, PPh3, DIAD, THF; (v) NH4OH-MeOH; (vi) 30% H2O2,
aqueous NaOH-THF; (vii) benzoyl chloride, pyridine (68% from
1); (viii) BF3‚Et2O, toluene; (ix) NaOMe, MeOH (90% from 11).
a Reagents and conditions: (i) H2, 10% Pd-C, AcOEt (93% for
14a; 85% for 14b; 99% for 14c); (ii) I2, PPh3, imidazole, THF (90%
for 15a; 81% for 15b; 89% for 15c); (iii) Zn, AcOH-MeOH
(1:10), rt (96% for 16a and 16b; 98% for 16c); (iv) TPAP
(catalytic), NMO, CH2Cl2 (88%); (v) DABCO, benzene, reflux
(44% of 18 and 50% recovery of 17). DIBAL, CH2Cl2, -78 °C
(93%).
Having obtained the three intermediates 6a-c with the
stereochemistry requisite for the construction of all six of
(12) Prystas, M.; Gustafsson, H.; Sorm, F. Collect. Czech. Chem.
Commun. 1971, 36, 1487.
1770
Org. Lett., Vol. 3, No. 11, 2001

Transformation of hemiacetals 16a-d thus obtained into
the corresponding 1,7-dienes 20a-d was, however, found
to be unexpectedly difficult under standard Wittig olefination
conditions. Under these conditions, the yield did not exceed
20%. We, therefore, employed a two-step procedure involv-
ing the conversion of hemiacetals 16a-d first into 1,7-enyne
intermediates 19a-d on treatment with trimethylsilyldiazo-
methane16 in the presence of lithium diisopropylamide
(LDA). Enynes 19a-d were then hydrogenated over Lindlar
catalyst to obtain the desired dienes 20a-d in acceptable
overall yields. A ring-closing olefin metathesis reaction of
20a-d under standard conditions using Grubbs’ catalyst17
proceeded without difficulty to yield the corresponding
cyclohexenols 21a-d in satisfactory yields (Scheme 4).
-9.3 (c 0.7, CHCl3), and (+)-conduritol B, mp 174-175
°C, [R]24 +173.0 (c 0.3, MeOH) {lit.6 mp 174-175 °C,
D
[R]28 +153.5 (c 0.31, MeOH)}, from 21d, [R]24 +140.0
D
D
(c 0.9, CHCl3), were obtained in excellent yields under these
conditions, respectively.
The remaining two conduritols could also be obtained from
cyclohexenols 21a and 21c by inversion of the stereogenic
center of the hydroxy functionality of each compound. Thus,
the Mitsunobu reaction of 21a using 4-nitrobenzoic acid10
brought about inversion to give the fifth cyclohexenol 21e,
[R]27 +109.0 (c 0.9, CHCl3), via the benzoate 22, which
D
afforded (-)-conduritol E, mp 191 °C, [R]27D -314.0 (c 0.6,
H2O) {lit.6 mp 191-192 °C, [R]29D -330.3 (c 0.18, H2O)},
by sequential debenzoylation and de-MOM protection.
Meanwhile, the inversion of 21c was carried out by
sequential oxidation and reduction through the enone 23 to
give the sixth cyclohexenol 21f, [R]24D -68.3 (c 0.9, CHCl3),
Scheme 4a
which afforded (-)-conduritol C, mp 128-129 °C, [R]24
D
-213.0 (c 0.4, H2O){lit. for (+)-enantiomer,6 mp 129-130
°C, [R]28 +209.1 (c 0.62, H2O)}, by de-MOM protection
D
(Scheme 5).
Scheme 5a
a Reagents and conditions: (i) TMSCHN2, LDA, THF, -78 °C
to rt (61% for 19a; 62% for 19b; 60% for 19c; 61% for 19d); (ii)
H2, 5% Pd-BaSO4, quinoline (catalytic), AcOEt; (iii) Grubbs’
catalyst (10 mol %), benzene, reflux (two steps: 71% for 21a and
21b; 72% for 21c; 69% for 21d).
Transformation of the four cyclohexenols 21a-d to
conduritols was carried out by removal of the MOM-
protecting group just by stirring in hydrogen chloride-
saturated methanol at room temperature. Under these con-
ditions, the MOM-protecting group was removed by forming
volatile acetal byproducts, leaving conduritols virtually in
quantitative yield on evaporation under reduced pressure.
Thus, (-)-conduritol F, mp 128-129 °C, [R]25 -69.4 (c
D
1.0, MeOH) {lit.6 mp 129-130 °C, [R]28 -70.2 (c 0.15,
D
MeOH)}, from 21a, [R]25D +55.7 (c 0.4, CHCl3), conduritol
a Reagents and conditions: (i) saturated HCl-MeOH (∼100%);
(ii) 4-nitrobenzoic acid, PPh3, DIAD, THF; (iii) K2CO3, MeOH
(81% from 21a); (iv) PCC, NaOAc, CH2Cl2 (94%); (v) DIBAL,
CH2Cl2, -78 °C (97%).
D as an oil from 21b, [R]27D +1.0 (c 0.5, CHCl3), conduritol
A, mp 141-142 °C (lit.6 mp 141-142 °C) from 21c, [R]28
D
(13) Pertinent reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413. (b) Roy, R.; Das, S. K. Chem. Commun 2000, 519. (c)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(14) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980,
2866.
(15) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
In conclusion, a new convergent route to all six of the
conduritols has been developed, starting from a common
chiral building block, on the basis of its inherent diastereo-
(16) (a) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107. (b) Miwa,
K.; Aoyama, T.; Shioiri, T. Synlett 1994, 109.
(17) Bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichloride
was purchased from Strem Chemicals and used without further purification.
(18) Gigg, R.; Gigg, J. Synthesis of Glycosylphosphatidylinositol Anchors;
Large, D., Warren, C. D., Eds.; Glycolipids and related compounds; Marcel
Dekker: New York, 1997.
Org. Lett., Vol. 3, No. 11, 2001
1771

selectivity and high functionality. Although we have dem-
onstrated the synthesis of single enantiomeric products, the
present procedure constitutes formal production of their
alternative enantiomers since the enantiomer of the starting
material has also been prepared. Since the biological
importance of cyclitols has been well recognized recently,18
the present convergent method for the construction of all
conduritol diastereomers may be useful in the synthesis of a
variety of derivatives for biological evaluation.
Acknowledgment. This research was supported by the
Ministry of Science, Culture, and Sports, Japan.
OL015963X
1772
Org. Lett., Vol. 3, No. 11, 2001