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Stereochemistry of mono-tetrahydrofuranyl moiety in cytotoxic polyketides. Part A: Synthesis of model compounds
Tetahedrontiters. Vol. 34. No. 37. pp. 5847-5850.1993
0040-4039/93 $6.00 + .oO Pergamonpress Ltd
Priiti in Great Britain
STEREOCHEMISTRY
OF
MONO-TETRAHYDROFURANYL
CYTOTOXIC PART
A: SYNTHESIS
MOIETY
IN
POLYKETIDES. OF
MODEL
COMPOUNDS
Jonathan 8. Gale, Jing-Guang Yu, Xiufeng E. Hu, Anakshi Khare, David K. Ho andJohn M. Cassady’ Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy The Ohio State University, Columbus, Ohio 43210, U. S. A.
Dimesitoate
Abstract.
esters
of a.a-dibutyL2,!Xetrahydrofurandimethanols
stereochemistry were prepared. They serve as model compounds for a the mono-tetrahydmfuranyl
different
relative analysis Of
moiety of cylotoxic polyketides.
Recently, pattern recognition approaches based on t H-NM in assigning the retativete.tb
of
1H-NMR-basedstereochemical
and the absolutelc
chemical shift differences had been devised
stereochemistry of the his-tetrahydrofuranyl
polyketides such as uvarfcin,2a asimicin,% rolliniastatin, 2c bullatacin and bullatacinone.2d
moiety of cytotoxic
However, no systematic
study has been carried out to address the assignment of those polyketides containing a mono-tetrahydrofuran (mono-THF)
ring adjoined to hydroxyalkyl
groups at the 2,5-positions. 3 Therefore, a novel lH-NMR-based
method is devised to assign the relative stereochemistry of the mono_THF moiety of cylotoxic polyketides. synthesis of the model compounds 1
The
- 6 is described in this letter.4
2 (my-&-efy)
trans,trans-Diene 9 was prepared by reduction of diyne 7 with Na/NHs5
c&c&Diene
10 is commercially
available.6
trans,cis-Diene
11 was prepared from diyne 7 by reduction with NaINH3 to give trans-enyne 8 and
subsequent
reduction with Pd/BaSOq. 7a The symmetrical cis diols 12 (thr-cis-thr) and 13 (cry-cis-cry)
5841
were
5848
prepared from dienes 9 (tfans, frans) and 10 (c&c&).
respectively, by the general methods according to Klein et
al.% and Walba and Co-workem7c*d which stereo@ecifically gke diols with a cis ring. The unsymmetrical cis diil 14 (thr-cis-efy)
11 as shown in Scheme 1. The corresponding
was prepared by using the trens,cisdiene
dimesitoates 1,2 and 3 were prepared in Cl-Q
from mesltoyi chbride (2,4,6-Me3CsH2COCl).
e
Nanh_ 63%
8
3 I !2?
I
9
HP, 5% PdlSaSQ 77%
1 O(cOmnerdally available) KMnQ,5-ldk 23%
acetone/H 20
33%
I
5%
MawN** i HIO;
“O
12
g
OH
Ha
OH
HO
14
13
(i-Pr)#Et, CHCls. 2,4,6-Me sCsH&lCI 70%
1
76%
(Me&l)
1 (thr-cis-thr)
OH 86%
2 (eryds-ety)
3 (rhr-cis-wy)
Scheme 1
Symmetrical trans dimesitoates 4 and 6 and unsymmetrical Pans dimssitoates 5 were prepared from the diepoxide 15 (Scheme 2). A 50:50 mixture of substituted tetrahydrofurans
16 (rrans) and 17 @is) was prepared
based on a literature procedures followed by the separation of the isomers on silka gel.9110 Swem oxidationl1 of 18 gave a crude mixture containing approximately butylmagnesium
bromide to give compounds
were protected
using mesitoyl
hydrogenation
45% of the corresponding
18 (three) and 19 (erythro), respectively.12-15
chloride to give the mesitoates
to afford the alcohols
aldehyde which was treated with
22 and 23. Compounds
respective aldehydes which were used without further purification.
These alcohols
20 and 21, which were debenzylated 22 and 23 were in turn oxidized
by
to their
Addition of butylmagnesium bromide at -29 “c
did not give any significant stereoselectivity except in the reaction involving the atdehyde from 23. in which thrso and erythrv analogs 26 and 27 were isolated in yields of 9% and 320/o, respectively.12-rs 27 were reduced to diols 28, 29, 29, and 30, respectively
Alcohols 24,25,26,
(alcohols 25 and 26 both gave diol 29). which were
subsequently converted to the dimesitoate esters 4 (thr-tramthr),
5 (thr-tram-my) and 6 (ev-trans-erv).
The application of the ‘H-NMR study of l-6 will be discussed in the next letter.
5849
Benzyl alcohol Na, 150°C (16 h) 1. Swem oxidation
(53% distilled 16/lp
2,4,6-hW&GOCI
(MesCf),
I
2 Qww HP, Pd/C, EtOl-UEtOAc
p$$ib!k7+ 2 6(960/o)
1 (i-Pr)2NEt, Ct-K&, Me&l 4 ( thr-tram-tbf) (71%)
2
from 2
W%from I 9(65% 5 ( thr-tram-cry) (66%)
Scheme 2
26$
3 W=) 1 6 ( my-tram-cry) wm
5850
Acknowledgments The supportof this work by Grant CA 33326 (to JMC)fromthe NationalCancerInstituteis appreciated. References and Notes 1
(a) Hoye, T. R.; Suhadolnik, J. C. J. Am. Chem. Sot. 1967, fO9,4402. (b) Hoye, T. R.; Zhuang, 2. J. Org. Chem. 1969, 53, 5576. (c) Rieser, M. J.: Hui, Y.-H.; Rupprecht, J. K.; Kozlowski, J. F.; Wood, K. V.; McLaughlin, J. L.; Hanson, P. R.; Zhuang, 2.; Hoye, T. R. J. Am. Chem. Sot. 1992, 114, 10203.
2
(a) Jolad, S. D.; Hoffmann, J. J.; Schram, K. H.; Cole, J. R. J. 0~. Chem. 1962, 47,3152. (b) Rupprecht, J. K.; Chang, C.-J.; Cassady, J. M.; McLaughlin, J. L.; Mikolajczak, K. L.; Weisleder, D. /feterocyc/es 1966, 24, 1197. (c) Pettit, G. R.; Cragg, G. M.; Polonsky, J.; Herald, D. L.; Goswami, A.; Smith, C. R.; Morettf, C.; Schmidt, J. M.; Weisfeder, D. Can. J. Chem. 1967, 65, 1433. (d) Hui, Y. H.; Rupprecht, J. K.; Uu, Y. M.; Anderson, J. E.; Smith, D. L.; Chang, C.-J.; McLaughlin, J. L. J. Nat. Pd. 1969, 52,463.
3
(a) McCloud, T. G.; Smith, D. L.; Chang, C.-j.; Cassady, J. M. Experienria 1967, 43,947. (b) Alkofahi, A.; Rupprecht. J. K.; Chang, C.-j.; McLaughlin, J. L. Experfenfia 1966, 44.63. (c) Xu, I_.; Chang, C.-j.; Yu; J.G.; Cassady, J. M. J. Org. Chem. 1969,54, 5416.
4
While 1 and 2 are meso, 4 and 6 both have rotational symmetry and were prepared Unsymmetrical 3 and 5 were also orepared as racemates.
as racemates.
Gamood, R. F.; Naser-ud-Din; Scott, C. J.; Weedon, B. C. L. J. Chem. Sot. Perkin /, 1973,2714. K&K Laboratories. a division of ICN Biomedicals specializing in rare chemicals. (a) Tashner, M. J.; Tosen, T.; Heathcock, C. Ii. Org. Synth. 1965, 64, 106. (b) Klein, E.; Rojahn, W. Tetrahedron 1965, 27, 2353. (c) Walba. D. M.; Wand, M. D.; Wilkes, M. C. J. Am. Chem. Sot. 1979, 107.4396. (d) Walba, D. M.; Edwards, P. D. Tefr. Leff. 1960, 21, 3531. 6
Hauck, F. P.; Jacobs, G. A. (E. R. Squibb & Sons, Inc., Princeton, N. J.) U.S.Patent 1961.
9
Alcohols 16 and 17 were reductively debenzylated (Hp, Pd/C) to transtetrahydrofurandimethanol, respectively, which are diols of known stereochemistries.
10
(a) Gagnaire,
D.; Monzeglio,
P. Bull. Sot.
Chim. Fr. 1965,
474.
4.279,902, July 21,
and cis-2,5-
(b) Moore, J. A.; Kelly, J. E.
Macromolecules 1976, 11, 566. 11
Omura. K.; Sharma, A. K.; Swern, D. J. Org. Chem. 1976,41, 957.
12
It is long known that for a given isomeric pair of a-substituted P-tetrahydm- furanmethanols the carbinol methine protons give chemical shifts that are considerably upfield for the three analogs compared with the erythro counterparfs.13 Thus, alcohols 16 (&foH 3.40), 24 (GCHoH 3.36) and 26 (GCHDH 3.37) were assigned three relationships while the counterparts 19 (GCHOH 3.65), 25 (SCHOH 3.76) and 27 (&OH 3.79) were assigned erythru relationships.
13
(a) Descotes, G.; Lailly, A. Bull. Sot. Chim. Fr. 1967, 2969. (b) Amouroux, R.; Chastrette, F.; Chastrette, M. J. Heterocyc/ic Chem. 1961, 16, 565. (c) Mulholland. Jr., R. L.:Chamberlain, A. R. J. Org. Chem. 1966, 53, 1062.
14
Although the reaction of organometallics with 2-monosubstituted-2-formyltetrahydro-furans might be expected to give stereoselectivity following Cram’s rule, l5 little or no stereoselectivity appears to result.13o15 In our hands, reaction of the akfehydes from either 16 or 22 with rrBuMgBr ocurred with little or no stereoselectivity (analysis of the crude confirmed this) while reaction of the aldehyde from 23 with * BuMgBr ocurred with anti-Cram stereoselectivity (analysis of the crude verified this).
15
Amouroux, R.; Chastrette, F.; Chastrette, M. Bull. Sot. Chim. Fr. 1961, 2, 293.
(Received in USA 15 April 1993; accepted 15 July 1993)
0040-4039/93 $6.00 + .oO Pergamonpress Ltd
Priiti in Great Britain
STEREOCHEMISTRY
OF
MONO-TETRAHYDROFURANYL
CYTOTOXIC PART
A: SYNTHESIS
MOIETY
IN
POLYKETIDES. OF
MODEL
COMPOUNDS
Jonathan 8. Gale, Jing-Guang Yu, Xiufeng E. Hu, Anakshi Khare, David K. Ho andJohn M. Cassady’ Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy The Ohio State University, Columbus, Ohio 43210, U. S. A.
Dimesitoate
Abstract.
esters
of a.a-dibutyL2,!Xetrahydrofurandimethanols
stereochemistry were prepared. They serve as model compounds for a the mono-tetrahydmfuranyl
different
relative analysis Of
moiety of cylotoxic polyketides.
Recently, pattern recognition approaches based on t H-NM in assigning the retativete.tb
of
1H-NMR-basedstereochemical
and the absolutelc
chemical shift differences had been devised
stereochemistry of the his-tetrahydrofuranyl
polyketides such as uvarfcin,2a asimicin,% rolliniastatin, 2c bullatacin and bullatacinone.2d
moiety of cytotoxic
However, no systematic
study has been carried out to address the assignment of those polyketides containing a mono-tetrahydrofuran (mono-THF)
ring adjoined to hydroxyalkyl
groups at the 2,5-positions. 3 Therefore, a novel lH-NMR-based
method is devised to assign the relative stereochemistry of the mono_THF moiety of cylotoxic polyketides. synthesis of the model compounds 1
The
- 6 is described in this letter.4
2 (my-&-efy)
trans,trans-Diene 9 was prepared by reduction of diyne 7 with Na/NHs5
c&c&Diene
10 is commercially
available.6
trans,cis-Diene
11 was prepared from diyne 7 by reduction with NaINH3 to give trans-enyne 8 and
subsequent
reduction with Pd/BaSOq. 7a The symmetrical cis diols 12 (thr-cis-thr) and 13 (cry-cis-cry)
5841
were
5848
prepared from dienes 9 (tfans, frans) and 10 (c&c&).
respectively, by the general methods according to Klein et
al.% and Walba and Co-workem7c*d which stereo@ecifically gke diols with a cis ring. The unsymmetrical cis diil 14 (thr-cis-efy)
11 as shown in Scheme 1. The corresponding
was prepared by using the trens,cisdiene
dimesitoates 1,2 and 3 were prepared in Cl-Q
from mesltoyi chbride (2,4,6-Me3CsH2COCl).
e
Nanh_ 63%
8
3 I !2?
I
9
HP, 5% PdlSaSQ 77%
1 O(cOmnerdally available) KMnQ,5-ldk 23%
acetone/H 20
33%
I
5%
MawN** i HIO;
“O
12
g
OH
Ha
OH
HO
14
13
(i-Pr)#Et, CHCls. 2,4,6-Me sCsH&lCI 70%
1
76%
(Me&l)
1 (thr-cis-thr)
OH 86%
2 (eryds-ety)
3 (rhr-cis-wy)
Scheme 1
Symmetrical trans dimesitoates 4 and 6 and unsymmetrical Pans dimssitoates 5 were prepared from the diepoxide 15 (Scheme 2). A 50:50 mixture of substituted tetrahydrofurans
16 (rrans) and 17 @is) was prepared
based on a literature procedures followed by the separation of the isomers on silka gel.9110 Swem oxidationl1 of 18 gave a crude mixture containing approximately butylmagnesium
bromide to give compounds
were protected
using mesitoyl
hydrogenation
45% of the corresponding
18 (three) and 19 (erythro), respectively.12-15
chloride to give the mesitoates
to afford the alcohols
aldehyde which was treated with
22 and 23. Compounds
respective aldehydes which were used without further purification.
These alcohols
20 and 21, which were debenzylated 22 and 23 were in turn oxidized
by
to their
Addition of butylmagnesium bromide at -29 “c
did not give any significant stereoselectivity except in the reaction involving the atdehyde from 23. in which thrso and erythrv analogs 26 and 27 were isolated in yields of 9% and 320/o, respectively.12-rs 27 were reduced to diols 28, 29, 29, and 30, respectively
Alcohols 24,25,26,
(alcohols 25 and 26 both gave diol 29). which were
subsequently converted to the dimesitoate esters 4 (thr-tramthr),
5 (thr-tram-my) and 6 (ev-trans-erv).
The application of the ‘H-NMR study of l-6 will be discussed in the next letter.
5849
Benzyl alcohol Na, 150°C (16 h) 1. Swem oxidation
(53% distilled 16/lp
2,4,6-hW&GOCI
(MesCf),
I
2 Qww HP, Pd/C, EtOl-UEtOAc
p$$ib!k7+ 2 6(960/o)
1 (i-Pr)2NEt, Ct-K&, Me&l 4 ( thr-tram-tbf) (71%)
2
from 2
W%from I 9(65% 5 ( thr-tram-cry) (66%)
Scheme 2
26$
3 W=) 1 6 ( my-tram-cry) wm
5850
Acknowledgments The supportof this work by Grant CA 33326 (to JMC)fromthe NationalCancerInstituteis appreciated. References and Notes 1
(a) Hoye, T. R.; Suhadolnik, J. C. J. Am. Chem. Sot. 1967, fO9,4402. (b) Hoye, T. R.; Zhuang, 2. J. Org. Chem. 1969, 53, 5576. (c) Rieser, M. J.: Hui, Y.-H.; Rupprecht, J. K.; Kozlowski, J. F.; Wood, K. V.; McLaughlin, J. L.; Hanson, P. R.; Zhuang, 2.; Hoye, T. R. J. Am. Chem. Sot. 1992, 114, 10203.
2
(a) Jolad, S. D.; Hoffmann, J. J.; Schram, K. H.; Cole, J. R. J. 0~. Chem. 1962, 47,3152. (b) Rupprecht, J. K.; Chang, C.-J.; Cassady, J. M.; McLaughlin, J. L.; Mikolajczak, K. L.; Weisleder, D. /feterocyc/es 1966, 24, 1197. (c) Pettit, G. R.; Cragg, G. M.; Polonsky, J.; Herald, D. L.; Goswami, A.; Smith, C. R.; Morettf, C.; Schmidt, J. M.; Weisfeder, D. Can. J. Chem. 1967, 65, 1433. (d) Hui, Y. H.; Rupprecht, J. K.; Uu, Y. M.; Anderson, J. E.; Smith, D. L.; Chang, C.-J.; McLaughlin, J. L. J. Nat. Pd. 1969, 52,463.
3
(a) McCloud, T. G.; Smith, D. L.; Chang, C.-j.; Cassady, J. M. Experienria 1967, 43,947. (b) Alkofahi, A.; Rupprecht. J. K.; Chang, C.-j.; McLaughlin, J. L. Experfenfia 1966, 44.63. (c) Xu, I_.; Chang, C.-j.; Yu; J.G.; Cassady, J. M. J. Org. Chem. 1969,54, 5416.
4
While 1 and 2 are meso, 4 and 6 both have rotational symmetry and were prepared Unsymmetrical 3 and 5 were also orepared as racemates.
as racemates.
Gamood, R. F.; Naser-ud-Din; Scott, C. J.; Weedon, B. C. L. J. Chem. Sot. Perkin /, 1973,2714. K&K Laboratories. a division of ICN Biomedicals specializing in rare chemicals. (a) Tashner, M. J.; Tosen, T.; Heathcock, C. Ii. Org. Synth. 1965, 64, 106. (b) Klein, E.; Rojahn, W. Tetrahedron 1965, 27, 2353. (c) Walba. D. M.; Wand, M. D.; Wilkes, M. C. J. Am. Chem. Sot. 1979, 107.4396. (d) Walba, D. M.; Edwards, P. D. Tefr. Leff. 1960, 21, 3531. 6
Hauck, F. P.; Jacobs, G. A. (E. R. Squibb & Sons, Inc., Princeton, N. J.) U.S.Patent 1961.
9
Alcohols 16 and 17 were reductively debenzylated (Hp, Pd/C) to transtetrahydrofurandimethanol, respectively, which are diols of known stereochemistries.
10
(a) Gagnaire,
D.; Monzeglio,
P. Bull. Sot.
Chim. Fr. 1965,
474.
4.279,902, July 21,
and cis-2,5-
(b) Moore, J. A.; Kelly, J. E.
Macromolecules 1976, 11, 566. 11
Omura. K.; Sharma, A. K.; Swern, D. J. Org. Chem. 1976,41, 957.
12
It is long known that for a given isomeric pair of a-substituted P-tetrahydm- furanmethanols the carbinol methine protons give chemical shifts that are considerably upfield for the three analogs compared with the erythro counterparfs.13 Thus, alcohols 16 (&foH 3.40), 24 (GCHoH 3.36) and 26 (GCHDH 3.37) were assigned three relationships while the counterparts 19 (GCHOH 3.65), 25 (SCHOH 3.76) and 27 (&OH 3.79) were assigned erythru relationships.
13
(a) Descotes, G.; Lailly, A. Bull. Sot. Chim. Fr. 1967, 2969. (b) Amouroux, R.; Chastrette, F.; Chastrette, M. J. Heterocyc/ic Chem. 1961, 16, 565. (c) Mulholland. Jr., R. L.:Chamberlain, A. R. J. Org. Chem. 1966, 53, 1062.
14
Although the reaction of organometallics with 2-monosubstituted-2-formyltetrahydro-furans might be expected to give stereoselectivity following Cram’s rule, l5 little or no stereoselectivity appears to result.13o15 In our hands, reaction of the akfehydes from either 16 or 22 with rrBuMgBr ocurred with little or no stereoselectivity (analysis of the crude confirmed this) while reaction of the aldehyde from 23 with * BuMgBr ocurred with anti-Cram stereoselectivity (analysis of the crude verified this).
15
Amouroux, R.; Chastrette, F.; Chastrette, M. Bull. Sot. Chim. Fr. 1961, 2, 293.
(Received in USA 15 April 1993; accepted 15 July 1993)