Synthesis of tetrasubstituted ozonides by the Griesbaum coozonolysis reaction: Diastereoselectivity and functional group transformations by post-ozonolysis reactions

Article abstract of DOI:10.1021/jo040171c

The diastereoselectivity of the Griesbaum coozonolysis reaction with O-methyl 2-adamantanone oxime and 4-substituted cyclohexanones reveals that the major tetrasubstituted ozonide isomers possess cis configurations, suggesting a preferred axial attack of

Full text of DOI:10.1021/jo040171c

SCHEME 1. Gr iesba u m Coozon olysis
Syn th esis of Tetr a su bstitu ted Ozon id es by
th e Gr iesba u m Coozon olysis Rea ction :
Dia ster eoselectivity a n d F u n ction a l Gr ou p
Tr a n sfor m a tion s by P ost-Ozon olysis
Rea ction s
TABLE 1. Gr iesba u m Coozon olysis Dia ster eoselectivity
Yuanqing Tang,† Yuxiang Dong,† J ean M. Karle,‡
Charles A. DiTusa,‡ and J onathan L. Vennerstrom*,†
Department of Pharmaceutical Sciences, College of
Pharmacy, University of Nebraska Medical Center,
Omaha, Nebraska 68198-6025, and Division of
Experimental Therapeutics, Walter Reed Army Institute of
Research, Silver Spring, Maryland 20910-7500
group
I
R
cis (3):trans (4)
C(CH3)3
C6H5
3a :4a >20:1
3b:4b >20:1
3c:4c >20:1
3d :4d >20:1
3e:4e 4.7:1
3f:4f 4.5:1
3g:4g 4.9:1
3h :4h 4.7:1
3i:4i 2.5:1
3j:4j 4:1
p-C6H4OAc
phthalimido
CH2OAc
jvenners@unmc.edu
Received April 9, 2004
II
CH2COOEt
CH2SO2C6H5
phthalimidomethyl
COOEt
COOCH2C(CH3) 3
CON(CH2CH3) 2
Ab st r a ct : The diastereoselectivity of the Griesbaum co-
ozonolysis reaction with O-methyl 2-adamantanone oxime
and 4-substituted cyclohexanones reveals that the major
tetrasubstituted ozonide isomers possess cis configurations,
suggesting a preferred axial attack of the carbonyl oxide on
the cyclohexanone dipolarophiles. It is evident that these
tetrasubstituted ozonides are quite stable to triphenylphos-
phine, borohydrides, hydrazine, alkyllithiums, Grignard
reagents, mercaptides, and aqueous KOH as illustrated by
the synthesis of amine, alcohol, acid, ester, ether, sulfide,
sulfone, and heterocycle-functionalized ozonides by a wide
range of post-ozonolysis transformations.
III
3k :4k 5:1
synthesis of parent tetrasubstituted olefins or enol ethers
and instead requires only the straightforward synthesis
of oxime ethers. The large number of commercially
available ketones as both dipolarophile coupling partners
and oxime ether precursors adds to the flexibility of this
reaction.
Although the detailed mechanism6 for this cross-
ozonolysis has not been well defined, the reaction out-
come is consistent with the general pathway of the
Criegee mechanism7 for ozonolysis of olefins, especially
involving the key carbonyl oxide intermediate. This is
evidenced by formation of 1,2,4,5-tetraoxanes8 in the
absence of a ketone coupling partner and substantiated
further by trapping experiments.1,2 In this paper, we
report the diastereoselectivity of cycloadditions between
the carbonyl oxide derived from the O-methyl 2-adaman-
tanone oxime (1) and 4-substituted cyclohexanones (2)
and functional group transformations of the tetrasubsti-
tuted ozonide products by post-ozonolysis reactions.
Dia st er eoselect ivit y of t h e Gr iesb a u m Coozon -
olysis Rea ction . Because use of the symmetrical oxime
ether avoids syn-anti isomerism of the resulting 2-ada-
mantanone oxide, the stereochemistry of the cycloaddi-
tion products is only a function of the starting material
cyclohexanones. For 4-substituted cyclohexanones, only
two achiral diastereomers (cis and trans) are possible
(Table 1). Preferably, the coozonolyses of 1 and 2 were
carried out in pentane or cyclohexane at 0 °C, the
conditions mostly suitable for ozonide formation as
prescribed by Griesbaum.1,2 For more polar cyclohex-
anones, a mixed solvent system (hydrocarbon and dichlo-
Gr iesba u m Coozon olysis. In 1995, Griesbaum et al.1
reported a new type of cross-ozonolysis reaction (Scheme
1) in which an O-alkyl ketone oxime was ozonized in the
presence of added carbonyl compounds such as acyl
cyanides and activated esters to give cross-ozonides.
Subsequently, they2 found that this novel method could
be efficiently applied to a number of unactivated ketones
as exemplified by acetone or cyclohexanone. This pro-
vided for the first time a widely applicable synthesis of
both symmetrical and unsymmetrical tetrasubstituted
ozonides that are otherwise generally inaccessible by
ozonolysis of a parent alkene3 or cross-ozonolysis of an
alkene4 or enol ether5 in the presence of carbonyl
compounds in solution. Another useful feature of the
Griesbaum coozonolysis reaction is that it obviates the
* To whom correspondence should be addressed. Tel: 402-559-5362.
Fax: 402-559-9543.
† University of Nebraska Medical Center.
‡ Walter Reed Army Institute of Research.
(1) Griesbaum, K.; O¨ vez, B.; Huh, T. S.; Dong, Y. Liebigs Ann. 1995,
1571-1574.
(2) (a) Griesbaum, K.; Liu, X.; Kassiaris, A.; Scherer, M. Liebigs
Ann./ Recl. 1997, 1381-1390. (b) Griesbaum, K.; Liu, X.; Dong, Y.
Tetrahedron 1997, 5463-5470. (c) Dong, Y.; Griesbaum, K.; Mc-
Cullough, K. J . J . Chem. Soc., Perkin Trans. 1 1997, 1601-1604. (d)
Griesbaum, K. Trends Org. Chem. 1997, 6, 145-168.
(3) (a) Griesbaum, K.; Krieger-Beck, P.; Beck, J . Chem. Ber. 1991,
124, 391-396. (b) Bunnelle, W. H. Chem. Rev. 1991, 91, 335-362.
(4) (a) Criegee, R.; Blust, G.; Zinke, H. Chem. Ber. 1954, 87, 766-
768. (b) Keul, H. Chem. Ber. 1975, 108, 1207-1217.
(5) (a) Keul, H.; Choi, H. S.; Kuczkowski, R. L. J . Org. Chem. 1985,
50, 3365-3371. (b) Griesbaum, K.; Kim, W. S.; Nakamura, N.; Mori,
M.; Nojima, M.; Kusabayashi, S. J . Org. Chem. 1990, 55, 6153-6161.
(c) Tabuchi, T.; Nojima, M. J . Org. Chem. 1991, 56, 6591-6595. (d)
Kuwabara, H.; Ushigoe, Y.; Nojima, M. J . Chem. Soc., Perkin Trans.
1 1996, 871-874.
(6) Bailey, P. S. Ozonation in Organic Chemistry; Academic Press:
New York, 1982; Vol. II, pp 231-235.
(7) Criegee, R. Mechanism of Ozonolysis. Angew. Chem. 1975, 87,
765-771.
(8) (a) Ito, Y.; Konishi, M.; Matsuura, T. Photochem. Photobiol. 1979,
30, 53-57. (b) Ito, Y.; Yokoya, H.; Umehara, Y.; Matsuura, T. Bull.
Chem. Soc. J pn. 1980, 53, 2407-2408. (c) Dong, Y.; Vennerstrom, J .
L. J . Org. Chem. 1998, 63, 8582-8585.
10.1021/jo040171c CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/19/2004
6470
J . Org. Chem. 2004, 69, 6470-6473

SCHEME 2. Ozon id e Decom p osition
romethane) was employed, with the proportion of dichlo-
romethane minimized as less polar solvents favor ozonide
formation. The oxime ether-to-ketone ratio varied be-
tween 1.5:1 and 1:2. Reaction yields of ozonides 3 + 4
ranged from 20% to 70%.
SCHEME 3. Red u ctive Rea ction s of Ozon id es 3i
a n d 7
Product ratios were determined by integration of
uniquely characteristic signals in the H NMR spectra
1
of unpurified reaction mixtures. In most cases, only the
major isomers (3) were separated by flash chromatogra-
phy or crystallization and individually characterized. The
stereochemical assignments (cis or trans) are based on
X-ray analyses and on the assumption that the stereo-
chemical outcomes were consistent for all cycloaddition
products (3 and 4) studied. No clear confirmation of
stereochemistry could be derived from examination of
chemical shifts and coupling constants or from elution
rates on silica gel.
forming reactions, including allylation with allylzinc
bromide or allylsilanes and allylstannanes in the pres-
ence of TiCl4 or SnCl4 and Mukaiyama-type aldol con-
densations.
Acetoxy ozonide 3c, a representative example from
group I, was assigned a cis configuration on the basis of
the X-ray crystallographic analysis of its phenol hydroly-
sis product 5 (Supporting Information). The data revealed
a chair cyclohexane with the 4-hydroxyphenyl and peroxo
groups at the equatorial and axial positions, respectively.
In group II, structures (Supporting Information) for the
major (3h ) and minor (4h ) isomers were confirmed to be
cis and trans, respectively, again by X-ray crystal-
lographic analysis. In trans isomer 4h , the 4-phthalimi-
domethyl and peroxo groups were both equatorial. The
cis configuration of the major isomer 3i in group III was
established by successfully transforming 3i into 3h (vide
infra). These results also lend support to the conjecture
that the major cycloaddition products share the same cis
configuration and that the stereochemistry of the cy-
cloaddition remains unchanged for 4-substituted cyclo-
hexanones.
Ozonide ketones in which the ketone functional group
was at the R-position (R-oxo ozonides) are transformed
to R-diozonides by Greisbaum coozonolysis2c and con-
verted to ozonide O-methyl oximes and epoxides with
O-methylhydroxylamine and diazomethane, respectively.15
R-Chloro ozonides, with16 or without13 AgBF4 and R-ac-
13,17
etoxy ozonides in the presence of NaHCO3
undergo
displacement reactions with various alcohols to form
ozonide ethers. Various post-ozonolysis chemistries have
also been applied to unsaturated ozonides. Griesbaum
and Zwick18 described the bromination of several vinyl
and vinylidene ozonides to form ozonide dibromides.
Several unsaturated bicyclic unsaturated ozonides were
reduced by diimide to give saturated ozonides.19 Ozo-
nolysis of a vinyl chloride ozonide in methanol afforded
the corresponding methyl ester ozonide.20 Successive
treatment of another vinyl chloride ozonide with m-CPBA
and AgBF4 afforded an enone ozonide via an epoxy
ozonide.20
In post-ozonolysis transformations of these tetrasub-
stituted ozonides, we observed that reaction tempera-
tures are best maintained below 60 °C3 to avoid decom-
position of the ozonide heterocycle into adamantane
lactone and the starting material cyclohexanones in
Hock-type fragmentations (Scheme 2). As expected, these
ozonides were quite stable to basic conditions as a result
The results are compiled in Table 1. We found that
diastereoselectivity is a function of the nature and size
of the substituents at the 4-position of the cyclohexanone
dipolarophile. Specifically, large groups (group I) such as
tert-butyl, phenyl, and phthalimido gave exclusively one
diastereomer with estimated cis/trans ratios greater than
20:1. 4-Substituted cyclohexanones with functional groups
linked by a single methylene (group II) provided cis/trans
ratios of approximately 5:1. The distal substituents
attached to the methylene group apparently have no
discernible directive effect on the cycloaddition reaction.
Cyclohexanones with ester and amide groups at the
4-position (Group III) provided cis/trans ratios ranging
from 2.5:1 to 5:1.
(9) McCullough, K. J .; Nojima, M. Peroxides from Ozonization. In
Organic Peroxides; Ando, W., Ed.; Wiley: Chichester, 1992; pp 661-
728.
P ost-Ozon olysis Rea ction s. With these ozonides in
hand, we then turned our attention to ozonide-compatible
synthetic transformations. Despite the utility of the
Griesbaum coozonolysis reaction, the synthesis of func-
tionalized tetrasubstituted ozonides is largely untested;2d,9
however, a limited number of post-ozonolysis reactions
have been successfully employed for di-, tri-, and tetra-
substituted ozonides. For example, ozonide ketones10 and
aldehydes11,12 have been reduced to ozonide alcohols with
lithium and sodium borohydride. An ozonide alcohol was
oxidized to the corresponding ozonide aldehyde by a
Swern oxidation.13 Ozonide aldehydes were converted to
their dimethyl and 1,3-dioxolane acetals11,12,14 and were
successfully employed in several carbon-carbon bond-
(10) Bunnelle, W. H.; Meyer, L. A.; Schlemper, E. O. J . Am. Chem.
Soc. 1989, 111, 7612-7613.
(11) Hon, Y.-S.; Yan, S.-L. Tetrahedron Lett. 1993, 34, 6591-6594.
(12) Hon, Y.-S.; Yan, J .-L. Tetrahedron 1997, 53, 5217-5232.
(13) Griesbaum, K.; Quinkert, R. O. Liebigs Ann./ Recl. 1997, 2581-
2585.
(14) Hon, Y.-S.; Yan, J .-L. Tetrahedron Lett. 1994, 35, 1743-1746.
(15) Griesbaum, K.; Dong, Y.; McCullough, K. J . J . Org. Chem. 1997,
62, 6129-6136.
(16) Griesbaum, K.; Schlindwein, K. J . Org. Chem. 1995, 60, 8062-
8066.
(17) Griesbaum, K.; Volpp, W.; Huh, T.-S. Tetrahedron Lett. 1989,
30, 1511-1512
(18) Griesbaum, K.; Zwick, G. Chem. Ber. 1985, 118, 3041-57.
(19) Adam, W.; Eggelte, H. J .; Rodriguez, A. Synthesis 1979, 383-
384.
(20) Griesbaum, K.; Bandyopadhyay, A. R.; Meister, M. Can. J .
Chem. 1986, 64, 1553-1559.
J . Org. Chem, Vol. 69, No. 19, 2004 6471

SCHEME 4. Red u ctive Am in a tion Rea ction s of Ozon id e Ald eh yd e 9
of their lack of R-hydrogen atoms that precluded Korn-
SCHEME 5. Rea ction of Ozon id e Keton e 7 w ith
Or ga n olith iu m a n d Gr ign a r d Rea gen ts
blum-DeLaMare fragmentation.11,21 The ozonides were
also stable to mild acid treatment such as that required
for Boc deprotection.
X-ray data for 3h and 5 permit us to assign the
stereochemistry of ozonides 3c, 32, and 33 as cis.
Although 3h is customarily synthesized directly via the
coozonolysis reaction, it was also synthesized in a Mit-
sunobu reaction between ozonide alcohol 6 and phthal-
imide (vide infra), establishing the stereochemistry of 6
as cis. Ozonide ester 3i, the precursor of 6, and the
aldehyde (9) and mesylate (25) ozonides derived from 6
also share its cis stereochemistry. Ozonide acid 20,
derived from 3i, is similarly cis. With the exception of
ozonide carbinols 8, 18, and 19, these data permit us to
assign the stereochemistry of the remaining ozonides
reported herein as cis.
Reductive reactions with borohydride reagents are
depicted in Scheme 3. Treatment of ozonide ester 3i with
a combination of lithium borohydride and 10 mol % of
lithium triethylborohydride22 afforded ozonide alcohol 6
in nearly quantitative yield. Reduction of ozonide ketone
723 with sodium borohydride gave ozonide alcohol 8 as a
1:1 mixture of cis and trans diasteromers in high yield.
Reductive amination reactions are depicted in Scheme
4. Ozonide aldehyde 9 was prepared in quantitative yield
by Swern oxidation of ozonide alcohol 6. Reductive
amination of 9 with primary, secondary, and aromatic
amines using NaBH(OAc)3/AcOH/DCE afforded the cor-
responding ozonide amines 10-17 in poor to good yields
along with various proportions of ozonide alcohol 6.
Reductive amination of 9 with cyclopropylamine gave, in
addition to 12, the corresponding diozonide tertiary
amine in 37% yield. Although anilines worked well in this
reaction (15), less nucleophilic heterocyclic aromatic
amines were not as efficient (11 and 17). Because
glycineamide hydrochloride was only sparingly soluble
in DCE, it was used in large excess in a reductive
amination reaction with NaBH3CN in MeOH to afford
10.
Reactions with carbon nucleophiles are depicted in
Scheme 5. Treatment of ozonide ketone 7 with methyl-
lithium in ether at -78 °C formed ozonide carbinol 18
as a 1.4:1 mixture of diastereomers along with 2-methyl-
2-adamantanol (6%), the methyllithium addition product
of 2-adamantanone, produced in turn from decomposition
of ozonide ketone 7. Treatment of 7 with either phenyl-
lithium or phenylmagnesium bromide followed a parallel
course with formation of ozonide carbinol 19 as a 1:1
mixture of cis and trans diastereomers. For the latter
reactions, no 2-phenyl-2-adamantanol was detected. These
results demonstrate that the 1,2,4-trioxolane heterocycle
in ozonide ketone 7 is quite stable to Grignard reagents
at low temperatures and fairly stable to aryl- and
alkyllithium reagents.
Mitsunobu reactions using diisopropyl azodicarboxy-
late/triphenylphosphine as coupling reagents are depicted
in Scheme 6. Ozonide acid 20, prepared by aqueous KOH
hydrolysis of its corresponding ester 3i, reacted with 1-(2-
hydroxyethyl)imidazole to form ozonide imidazole ester
21. Similarly, ozonide phenyl ethers 22 and 23 were
prepared by Mitsunobu reactions of ozonide phenol 5 and
ozonide alcohol 6, respectively. In the preparation of 22,
addition of triethylamine improved the yield from 20%
to 80%. Ozonide phenol 5 was obtained by aqueous KOH
hydrolysis of the corresponding ozonide acetate 3c.
Phthalimide and hydantoin ozonides 3h and 24 were
synthesized by Mitsunobu reactions of ozonide alcohol 6
with phthalimide and hydantoin, respectively.
The syntheses of azoles, sulfides, and sulfones are
depicted in Scheme 7. Ozonide imidazole 26 and ozonide
triazole 27 were synthesized by nucleophilic displacement
reactions of ozonide mesylate 25 with the NaH-generated
anions of imidazole and triazole, respectively. Reaction
of ozonide mesylate 25 with 2-mercaptopyridine-N-oxide
sodium salt hydrate and 1-methyl-5-mercaptotetrazole
sodium salt dihydrate afforded the respective ozonide
(21) Kornblum, N.; DeLaMare, H. E. J . Am. Chem. Soc. 1951, 73,
880-881.
(22) Brown, H. C.; Narasimhan, S. J . Org. Chem. 1982, 47, 1604-
1606.
(23) Vennerstrom, J . L.; Dong, Y.; Chollet, J .; Matile, H. Spiro and
Dispiro 1,2,4-Trioxolane Antimalarials. U.S. Patent 6,486,199, No-
vember 2002.
6472 J . Org. Chem., Vol. 69, No. 19, 2004

SCHEME 6. Ozon id e Mitsu n obu Rea ction s
SCHEME 7. Syn th esis of Ozon id e Azoles, Su lfid es, a n d Su lfon es fr om Ozon id e Mesyla te 25
SCHEME 8. Hyd r a zin e Dep r otection of Ozon id e
P h th a lim id es 3h a n d 22
Su m m a r y. The diastereoselectivity of the Griesbaum
coozonolysis reaction reveals that attack of the carbonyl
oxide from the axial side24 is strongly favored. The
product ratio is mainly a reflection of the conformational
rigidity of the cyclohexanones, although electronic con-
tributions by the 4-substituent cannot be ruled out. These
findings suggest that the stereochemistry of cycloaddition
(preferred axial attack) is controlled mainly by kinetic
(transition-state hyperconjugation) factors. This work has
also expanded the range of ozonide-compatible synthetic
transformations to include ester to alcohol reductions,
reductive aminations, various Mitsunobu reactions, dis-
placement reactions with mercaptides and imidazole/
triazole anions, addition reactions with organolithium
and Grignard reagents, and phthalimide deprotections
with hydrazine. Although it is unknown whether di-, tri-,
or other tetrasubstituted ozonides are similarly unaltered
by these chemical transformations, the wide range of
applicable post-ozonolysis chemistry for these tetrasub-
stituted ozonides parallels that seen in the preparation
of the many semisynthetic artemisinin derivatives.25,26
sulfides 28 and 30, which were further oxidized to the
corresponding ozonide sulfones 29 and 31.
Phthalimide deprotection using hydrazine is depicted
in Scheme 8. When ozonide phthalimides 3h and 22 were
treated with hydrazine in CHCl3/EtOH (7:3) at 60 °C,
ozonide primary amines 32 and 33 were formed in high
yields and isolated as their mesylate salts. The depro-
tection reactions were completed without effect on the
trioxolane ring. An array of reaction conditions for the
deprotection of ozonide phthalimide 3h was investigated,
and it was found that the optimal reaction was 5-6 equiv
of hydrazine in CHCl3/EtOH at 60 °C for 12 h.
Ack n ow led gm en t. We thank the Medicines for
Malaria Venture (MMV) for generous support of this
research.
Su p p or tin g In for m a tion Ava ila ble: Synthesis and char-
acterization data for 2a -k , 3a -k , 4h , 4i, and 5-33 and X-ray
structural data for 3h , 4h , and 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
(24) Gung, B. W. Chem. Rev. 1999, 99, 1377-1386.
(25) Vroman, J . A.; Alvim-Gaston, M.; Avery, M. A. Curr. Pharm.
Des. 1999, 5, 101-138.
(26) G. Bez,; Kalita, B.; Sarmah, P.; Barua, N. C.; Dutta, D. K. Curr.
Org. Chem. 2003, 7, 1231-1255.
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