Expeditious synthesis of aziridine-based cofactor mimics

Article abstract of DOI:10.1016/S0040-4020(02)00590-2

S-Adenosyl-L-methionine mimics were synthesized in a linear fashion highlighting methodology that bypasses the need for adenine base protection. These aziridine-based cofactor mimics are envisioned as useful biochemical tools and potential therapeutic agents whose mechanism of action hinges upon aberrant methyltransferase enzymes. Aziridination of the 5′ position of adenosine was effected by convergence of suitably protected 5′-aminoadenosine with various dibromopropionates. The economy and high yields for this route to said aziridine-based cofactors is highly amenable to large-scale chemistry which no doubt will be vital to their development as therapeutics and biochemical tools.

Full text of DOI:10.1016/S0040-4020(02)00590-2

TETRAHEDRON
Pergamon
Tetrahedron 58 92002) 6019±6026
Expeditious synthesis of aziridine-based cofactor mimics
Lindsay R. Comstock and Scott R. Rajskip
School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA
Received 3 May 2002; accepted 6 June 2002
AbstractÐS-Adenosyl-l-methionine mimics were synthesized in a linear fashion highlighting methodology that bypasses the need for
adenine base protection. These aziridine-based cofactor mimics are envisioned as usefulbiochemicaltools and potentialtherapeutic agents
whose mechanism of action hinges upon aberrant methyltransferase enzymes. Aziridination of the 50 position of adenosine was effected by
convergence of suitably protected 50-aminoadenosine with various dibromopropionates. The economy and high yields for this route to said
aziridine-based cofactors is highly amenable to large-scale chemistry which no doubt will be vital to their development as therapeutics and
biochemicaltoosl. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
regions, whereas their expressed counterparts are unmethyl-
ated. Genes differentially expressed in different tissues are
differentially methylated.6 Not surprisingly, aberrant DNA
methylation is inherent in a number of oncogenic processes
and is thought, in some cases, to be a leading contributor to
carcinogenesis.7 This suggests that agents capable of taking
part in or deterring Mtase-dependent transcriptionalerrors
would be of signi®cant clinical importance. For instance,
regions of the genome that might be improperly repressed
due to aberrant methylation of CpG units 9a signature of
numerous cancers) might be de-repressed by the replace-
ment of DNA bound methylgroups with non-natural
moieties. Indeed the concept of `cofactor mimicry' offers
abundant chemotherapeutic opportunity through alterations
of transcriptionally relevant molecular recognition
processes, as well as from the simple standpoint of sequence
speci®c DNA damaging moieties.
DNA interstrand cross-linking is one of the most potent and
usefulforms of DNA modi®cation used in chemotherapies.
Cross-linking selectivity often results due to drug activation
processes attributed to oxidizing or reducing environments
characteristic of diseased cells.1 Indeed, gene therapy has
been exploited as an effective means of attenuating drug
action based upon overexpression of certain enzymes asso-
2
ciated with these environmentalconditions. In addition,
many DNA sequence-selective targeting methods have
been developed resulting in impressive selectivities and
af®nities.3 Surprisingly, the exploitation of enzymatic
DNA modi®cation mechanisms has received considerably
less attention. Such an approach has advantages over
traditionalmethods. First, the sequence speci®city of
DNA alkylation results not from a small molecule:DNA
interaction, but rather a protein:DNA interaction. Second,
the association of drug with the DNA modifying enzyme
affords a drug traf®cking mechanism potentially capable of
shielding the drug from inactivating species such as
cytosolic nucleophiles or oxidants.
This rationale underscores the importance of recent work by
Weinhold and co-workers.8 The C50 aziridine 3 affords a
substitute for SAM in the M.TaqI catalyzed alkylation of
adenine within the recognition sequence 50TCGA30
9Scheme 1).8 Instead of generating the N6 methylated dA
residue, substrate adenylation is accomplished via ring-
opening of the aziridine. Importantly, the regiochemistry
of DNA substrate modi®cation is identicalto the S-adeno-
syl-l-methionine 9SAM, 2) dependent methylation.
Notably, a ¯uorescent analog of 3 has also been shown to
substitute for SAM in the C5 cytosine alkylation by M.HhaI
DNA methyltransferase.9
Perhaps the most well studied of the DNA modi®cation
enzymes are those involved in DNA methylation.4 Methyl-
ations at cytosine C5 and N4 and at adenosine N6 play an
integralreol in prokaryotic defense mechanisms. In
eukaryotes, a large body of data has revealed excellent
correlation between DNA methylation and gene repression.5
Silenced genes are generally methylated in their regulatory
The stability of the free base 3 suggests that such a cofactor
structure may be amenable to conjugation with other
DNA-reactive functionalities thus affording access to
synthetic agents which derive biological activity 9as a
function of DNA sequence selectivity) from selected
Keywords: S-adenosyl-l-methionine; aziridine-based cofactor mimics;
50-aminoadenosine; Gabriel±Cromwell.
Corresponding author. Tel.: 1608-262-7582; fax: 1608-262-5345;
e-mail: srrajski@pharmacy.wisc.edu
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020902)00590-2

6020
L. R. Comstock, S. R. Rajski / Tetrahedron 58 -2002) 6019±6026
Scheme 1.
methyltransferases. Our interest in the design and syn-
thesis of such agents necessitated the development of
a highly ef®cient route to `tetherable' analogs of 3.
Gabriel±Cromwell aziridination affords rapid access to the
desired agents.
congeners bearing suitable protection of the 20,30-diol.
Using a Mitsunobu variation of chemistry recently reported
by Austin and co-workers, we found that the desired
OH!NH2 interconversion coupled with silylation of both
the 20 and 30 alcohols could be most expeditiously effected
by treatment of commercially available 6 with diphenyl-
phosphorylazide 9DPPA), triphenpyhl osphine 9PPh
3),
diethylazodicarboxylate 9DEAD) as shown in Scheme
2.11,12 Azide installation in this manner proceeded in 73%
yield. The azide 7 was highly amenable to acetonide
cleavage with tri¯uoroacetic acid13 and subsequent 20,30
reprotection as the 20,30 bis9triethylsilyl ether).14 Disilyl-
ation permitted not only improved solubility traits through-
out the remainder of the synthesis, but also allowed for a
high degree of aziridine survivalupon ®naldioldeprotec-
tion. Staudinger reduction of the azide 8 ultimately afforded
the highly versatile 50 amine 9 in 74% yield over three steps
from azide 7.15
2. Results and discussion
There are few examples of ef®cient N-alkylation of
aziridines with alkyl halides and sulfonates; condensations
with yields .90% typically involve benzyl halides.10 This,
coupled with the anticipated limitations on possible
coupling components facilitated the development of alter-
native methodologies by which functionalized aziridines
could be appended to adenosine at the 50 position. Critical
to these other methodologies was an ef®cient means of
obtaining on large scale, 50-aminoadenosine or related
Scheme 2. 9a) DPPA, PPh3, DEAD, THF; 9b) 1. TFA/H2O, 2. chlorotriethylsilane, imidazole, DMF; 9c) PPh3, THF, H2O; 9d) 10 or 11, TEA, THF; 9e) nBu4NF,
dioxane.

L. R. Comstock, S. R. Rajski / Tetrahedron 58 -2002) 6019±6026
6021
Scheme 3. 9a) Dibromopropionylchol ride, CH 3CN; 9b) TEA, THF, 4; 9c) TEA, MeOH.
Although a host of chemistries have been used in our labora-
tories to prepare such compounds, by far the most ef®cient
hinges upon the reaction of 9 with a,b-unsaturated a-bromo
initialMichael-type addition to the transient bromoacryal te
that auxiliaries 16 and 17 might afford asymmetric induc-
tion at the brominated a carbonylcenter. Such rationael is
reminiscent of synthetic strategies applied to b-sheet
mimetic construction.16c This would presumably set aziri-
dine stereochemistry due to SN2 displacement of bromide
with concomitant aziridine ring closure. This, in fact was
found not to be the case. Rather, we determined that, regard-
less of dibromopropionate stereochemistry a 3:2 ratio of
aziridine stereoisomers was consistently obtained. That a
ratio of 1:1 is typically observed using non-chiral bromo-
propionates clearly indicates a stereochemical bias in the
auxiliary-based system yet a mechanistic rationale for
asymmetric induction regardless of auxiliary stereo-
chemistry is not yet apparent. It is clear that the asymmetric
environment of the adenosine ribose framework exerts
in¯uence upon the stereochemicaloutcome. However, this
in¯uence relies upon the ureadiyl moieties of 18 and 19.
Although efforts are still underway to explain this interest-
ing phenomenon, what was found was that the dibromo-
propionate auxiliaries ultimately afforded aziridines highly
amenable to separation by conventional chromatography.
Thus, although the ureadiyl moieties 18 and 19 serve partly
as chiralauxiilaries for aziridination 9in combination with
the adenosine ribose) they serve, most importantly in our
hands, as separatory auxiliaries.
16,17
carbonylcompounds.
Our particular interests rested on
the reaction of 9 with dibromopropionic methyland benzyl
esters 10 and 11. The reasons for this are twofold. First, we
envisioned that such aziridine carboxylates might serve as
more potent or effective cofactor mimics than the analogous
unsubstituted aziridines such as 3. Secondly, the anticipated
products would present two potential avenues by which to
conjugate DNA damaging moieties or perhaps drug delivery
tools.
Treatment of amine 9 with dibromopropionates 10 or 11 in
the presence of triethylamine in re¯uxing THF afforded dia-
stereomeric mixtures of 50 aziridines in good 980±87%)
yields. Perhaps most remarkable is that no protection of
the adenine base is necessary. Coupled with the potential
for introduction of molecular diversity via the use of
different dibromopropionates, this condensation represents
a powerfuladdition to the repertoire of nuceloside modi®-
cation chemistry. Following 50 aziridine construction,
simple cleavage of the silyl ethers with TBAF18 affords a
diastereomeric mixture of each SAM mimic.
In addition to the rapid construction of potentially diverse
nucleoside aziridines this chemistry holds promise for
generating stereodiverse populations of cofactor mimics.
Diastereomeric mixtures of aziridine-based cofactors were
initially envisioned to be readily separable by HPLC.
Although this was true in the case of the carbobenyloxy
aziridines this was not the case for diastereomeric mixture
14 or its precursor 12. Efforts to remedy this entailed the
exploitation of asymmetrically disposed dibromopropionate
18 and its antipode 19.
Having failed to assign stereochemical con®guration to
aziridines derived from Gabriel±Cromwell reactions with
9, we sought the independent synthesis of each stereoisomer
of hydroxymethylaziridines. Importantly, the conversion of
methylester 12 to the hydroxymethyl analog was desirable
for conjugation to other biologically relevant moieties. This,
coupled with the ability to separate auxiliary modi®ed
aziridine stereoisomers 20 and 21 on large scale led to an
important realization. As shown in Scheme 3, carboxy-
aziridines 20 and 21 are readily converted to methyl ester
12 upon exposure to methanolic triethylamine with 16 and
17 easily recovered intact.19 Exposure of each stereoisomer
of 12 to LiAlH4 at low temperature affords the correspond-
ing primary alcohol 2220 in 76% yield 9Scheme 4). Notably,
introduction of the hydroxymethylfunctionality at this point
allows for selective modi®cation of 22 with DNA modifying
Cardillo and co-workers successfully employed a related
system in their synthesis of chiralbenzylaziridine-2-
carboxylates.17a It must be noted, however, that an important
difference in the two systems exists. Unlike the Cardillo
system, the aziridines of interest here do not bear sub-
stituents at both aziridine carbons. We rationalized on the
basis of a chiral protonation step immediately following

6022
L. R. Comstock, S. R. Rajski / Tetrahedron 58 -2002) 6019±6026
Scheme 4. 9a) LiAlH4, THF, 2208C; 9b) nBu4NF, dioxane.
agents of choice, while leaving other potentially nucleo-
philic sites masked. Desilylation of 22 with TBAF affords
23 in 75% yield.
4. Experimental
4.1. General
Finally, with a facile means by which to derive `tetherable'
cofactor mimics in diastereomerically pure form, we
endeavored to assign aziridine stereochemistry. Very
simply, we synthesized each stereoisomer of 22 via
aminolysis of R-91) and S-92) O-benzyl glycidol, respec-
tively. Conversion of the resulting amino alcohols to their
respective stereoisomerically pure aziridines was accom-
plished using Mitsunobu conditions and 1H NMR chemical
shifts compared with those of previously obtained Gabriel±
Cromwell adducts.21 The synthesis of similarly substituted
aziridines had been noted to be very dif®cult and our efforts
substantiated this observation. Subjection of O-benzyl
glycidol-derived amino alcohols to triphenylphosphine,
and DEAD in re¯uxing THF afforded aziridines in ,40%
yield after very careful chromatographic separation.
All reactions were carried out under an inert atmosphere of
argon unless indicated otherwise. All reagents were
obtained from available commercial sources and used with-
out additionalpuri®cation. Anhydrous THF was from a J.T.
Baker Cycle-Tainer product number 9446-Q1. Melting
points were determined using a Mel-Temp apparatus and
are uncorrected. NMR spectra were recorded on Varian
ui400 and ui500 spectrometers using solvent as the internal
reference; the chemicalshifts are reported in ppm, in
d
units. Mass spectra were obtained from Colorado State
University on a Fisions VG Autospec spectrometer.
4.1.1. 50-Azido-50-deoxy-20,30-isopropylidene adenosine
7. To 450 mL, dry THF at 08C was added PPh3 921.5 g,
82.0 mmol). The solution was allowed to stir for 10 min
and DEAD 914.2 g, 81.3 mmol) was added and the resulting
mixture stirred for an additional10 min. The ice bath was
removed and to the warming solution was added DPPA
922.6 g, 82.1 mmol) over a period of 5 min, followed by
addition of 6 925.0 g, 81.5 mmol). The reaction was allowed
to stir for 36 h sheltered from light. The resulting white
precipitate was ®ltered and washed with petroleum ether.
The solvent was evaporated in vacuo to reveal a thick
orange oil. Column chromatography on silica gel 93:1:0.1
EtOAc/CH2Cl2/MeOH) afforded 7 as a gummy white solid
We had noted earlier, a remarkable difference in 1H
0
chemicalshifts of the C5
hydrogens based upon the
aziridine stereochemistry and this was again evident in the
O-benzyl-derived aziridines. Spectral analysis revealed
the R aziridine to possess chemicalshifts of 2.57 and
2.76 ppm for C50 Ha and Hb, respectively. Alternatively,
S aziridines demonstrate chemicalshifts of 2.42 and
2.96 ppm for Ha and Hb, respectively. Using these observa-
tions, we have thus assigned stereochemicalcon®guration to
all carboxy and hydroxymethyl-functionalized aziridines.
We also note that the 3:2 ratio of Cromwell adducts
obtained for compounds 20 and 21 indicates the preferred
formation in both cases of the S aziridine over the R isomer.
1
919.8 g, 73.1%). Mp 126±1308C. H NMR 9CDCl3) d 8.40
9s, 1H), 7.95 9s, 1H), 6.12 9d, Jˆ2.4 Hz, 1H), 5.62 9bs, 2H),
5.45 9dd, Jˆ6.4, 2.4 Hz, 1H), 5.05 9dd, Jˆ6.4, 3.6 Hz, 1H),
4.39 9m, 1H), 3.61 9dd, Jˆ12.8, 6.0 Hz, 1H), 3.56 9dd,
Jˆ13.2, 6.0 Hz, 1H), 1.61 9s, 3H), 1.42 9s, 3H); 13C NMR
9CDCl3) d 156.0, 153.8, 149.7, 140.0, 120.5, 114.8, 91.1,
86.1, 84.2, 82.0, 52.3, 27.6, 25.8. FAB-LRMS: calcd for
C13H16N8O3 9M1H1) 333.32; obsd 333.2.
3. Conclusions
Described herein is the highly ef®cient synthesis of SAM
mimics bearing differentially tetherable functionalities.
Synthesis of the 50 amine core, followed by Gabriel±
Cromwell aziridination affords carboxyaziridines capable
of facile reduction to the hydroxymethyl analogs. Silyl
ether cleavage from both 20 and 30 alcohols using TBAF
affords aziridine-based cofactor mimics of interest. Stereo-
chemicalassignment of the resulting SAM mimics has been
achieved through independent stereocontrolled synthesis of
each stereoisomer of O-benzyl 22. Cofactor mimics thus
obtained are currently being evaluated for compatibility
with a host of DNA and protein methyltransferases.
Progress on the application of these molecules as potential
chemotherapeutics and biochemical tools will be reported
shortly.
4.1.2. 50-Azido-50-deoxy-20,30-bis-)O-triethylsilyl)adeno-
sine 8. To 100 mL, 10:1 TFA/H2O at 08C was added 7
915.3 g, 45.9 mmol). After 5 min, the reaction was allowed
to warm to room temperature and stirred for an additional
20 min. The solution was evaporated in vacuo and
co-evaporated repetitively with ethanol to render a
gummy white foam. To the crude 50-azidoadenylate
920.7 g, 70.8 mmol) in 100 mL dry DMF at 08C, was
added imidazole 938.6 g, 566.8 mmol) and chlorotriethyl-
silane 919.8 g, 131.1 mol). The reaction was stirred for
2 h at room temperature. An aqueous workup was
performed 9NH4Cl, EtOAc, brine), the combined organic
layers dried over Na2SO4 and evaporated in vacuo. A
crude light yellow solid, 8, was obtained which was taken
directly forward.

L. R. Comstock, S. R. Rajski / Tetrahedron 58 -2002) 6019±6026
6023
4.1.3. 50-Amino-50-deoxy-20,30-bis-)O-triethylsilyl)adeno-
sine 9. To crude 8 925.0 g, 48.0 mmol) in 300 mL dry THF,
was added triphenylphosphine 918.9 g, 72.0 mmol) and the
solution was stirred for 15 min. Water 911.2 g, 624 mmol)
was added and the solution was heated at re¯ux for 1.5 h.
The solvent was removed in vacuo. Column chromato-
graphy on silica pre-treated with 1% TEA 94:2:1 EtOAc/
CH2Cl2/MeOH) gave 9 as white solid 916.8 g, 74.0%). Mp
164±1678C. 1H NMR 9CDCl3) d 8.35 9s, 1H), 7.95 9s, 1H),
6.48 9bs, 2H), 5.86 9d, Jˆ6.1 Hz, 1H), 5.15 9dd, Jˆ5.9,
4.6 Hz, 1H), 4.28 9dd, Jˆ4.4, 2.8 Hz, 1H), 4.09 9m, 1H),
3.08 9dd, Jˆ13.5, 3.6 Hz, 1H), 3.02 9dd, Jˆ13.3, 5.6 Hz,
1H), 2.25 9bs, 2H), 0.95 9t, Jˆ8.0 Hz, 9H), 0.78 9t,
Jˆ8.1 Hz, 9H), 0.64 9q, Jˆ8.0 Hz, 6H), 0.38 9qq, Jˆ16.0,
8.0 Hz, 6H); 13C NMR 9CDCl3) d 156.2, 153.6, 150.1,
141.1, 121.0, 90.0, 87.6, 74.0, 73.8, 44.0, 7.2, 6.9, 5.8,
5.5. FAB-LRMS: calcd for C22H42N6O3Si2 9M1H1)
495.78; obsd 495.2.
1.2 Hz, 1H), 1.74 9dd, Jˆ6.4, 1.2 Hz, 1H), 0.98 9t,
Jˆ8.0 Hz, 9H), 0.78 9t, Jˆ8.0 Hz, 9H), 0.65 9q, Jˆ8.0 Hz,
6H), 0.35 9qq, Jˆ16.0, 8.0 Hz, 6H); 13C 9CDCl3) d 170.21,
154.80, 151.77, 148.72, 119.47, 87.91, 83.81, 72.90, 72.87,
60.33, 51.25, 36.08, 33.61, 5.84, 5.53, 3.92, 3.50; FAB-
HRMS: calcd for C26H46N6O5Si2 9M1H1) 579.31; obsd
579.314.
A similar procedure was performed with 20b. The signals
due to 12b 9R aziridine) could be discerned: H NMR
1
9CDCl3) d 8.28 9s, 1H), 7.98 9s, 1H), 6.29 9s, 2H), 5.91 9d,
Jˆ5.6 Hz, 1H), 5.05 9dd, Jˆ5.2, 4.4 Hz, 1H), 4.41 9dd,
Jˆ4.4, 2.4 Hz, 1H), 4.25 9m, 1H), 3.67 9s, 3H), 2.96 9dd,
Jˆ12.8, 5.2 Hz, 1H), 2.51 9dd, Jˆ12.8, 6.0 Hz, 1H), 2.23
9dd, Jˆ6.4, 3.2 Hz, 1H), 2.18 9dd, Jˆ3.2, 1.2 Hz, 1H), 1.65
9dd, Jˆ6.4, 1.2 Hz, 1H), 1.00 9t, Jˆ8.0 Hz, 9H), 0.80 9t,
Jˆ8.0 Hz, 9H), 0.67 9q, Jˆ8.0 Hz, 6 H), 0.37 9qq,
Jˆ16.0, 8.0 Hz, 6H); 13C 9CDCl3) d 170.04, 154.81,
151.76, 148.62, 110.49, 88.21, 83.35, 72.68, 72.65, 60.18,
51.11, 36.05, 33.50, 5.82, 5.55, 3.89, 3.45; FAB-HRMS:
calcd for C26H46N6O5Si2 9M1H1) 579.31; obsd 579.314.
4.1.4. Methyl 2,3-dibromopropionate 10. Dibromopro-
pionylcholride 913.1 g, 52.3 mmo)l in 25 mL dry THF
was added to
a suspension of methanol93.35 g,
104.6 mmol) and potassium hydrogen carbonate 912.6 g,
125.5 mmol) in 25 mL dry THF at 08C over 10 min. The
reaction was warmed to room temperature and stirred for
2 h. The reaction was then chilled to 08C and ®ltered. An
aqueous workup was performed 9H2O, EtOAc, brine), dried
over Na2SO4 and evaporated in vacuo. Column chromato-
graphy on silica 91:1:1 Pet Et/EtOAc/MeOH) rendered 10 as
Note. 12 can be synthesized from 21a and 22b via the same
procedure.
4.1.7. 50-Aziridino-50-deoxy-)200-carboxylbenzyl)-20,30-
bis-)O-triethylsilyl)adenosine 13. To 11 91.835 g,
5.701 mmol) in 40 mL dry THF was stirred for 15 min at
room temperature. 9 92.848 g, 5.757 mmol) in 40 mL dry
THF was added to the dibromide solution, followed by TEA
91.730 g, 17.099 mmol). The solution was heated at re¯ux
for 16 h. The solution was cooled to 08C, ®ltered and the
residualEt 3N-HBr salts triturated with anhydrous Et2O. The
combination of organic layers was evaporated in vacuo
followed by column chromatography on silica 94:2:1
EtOAc/CH2Cl2/MeOH) to afford 13 as a mixture of dia-
1
a clear oil 910.23 g, 79.5%). H NMR 9CDCl3) d 4.46 9dd,
Jˆ11.2, 4.5 Hz, 1H), 3.94 9dd, Jˆ11.2, 9.9 Hz, 1H), 3.85 9s,
3H), 3.68 9dd, Jˆ9.9, 4.6 Hz, 1H); 13C NMR 9CDCl3) d
168.2, 53.6, 40.9, 29.8.
4.1.5. Benzyl 2,3-dibromopropionate 11. Dibromopro-
pionylcholride 98.72 g, 34.9 mmo)l in 18 mL dry THF
was added to a suspension of benzylaclohol93.15 g,
29.1 mmol) and potassium hydrogen carbonate 96.99 g,
69.8 mmol) in 22 mL dry THF at 08C over 10 min. The
reaction was warmed to room temperature and stirred for
2 h. The reaction was then chilled to 08C and ®ltered. An
aqueous workup was performed 9H2O, EtOAc, brine), dried
over Na2SO4 and evaporated in vacuo. Column chromato-
graphy on silica 92:1 Pet Et/EtOAc) gave 11 as a clear oil
96.89 g, 73.6%). 1H NMR 9CDCl3) d 7.35 9m, 5H), 5.25 9s,
2H), 4.47 9dd, Jˆ11.2, 3.6 Hz, 1H), 3.93 9dd, Jˆ10.8,
10.0 Hz, 1H), 3.66 9dd, Jˆ10.0, 4.8 Hz, 1H); 13C NMR
9CDCl3) d 167.6, 134.9, 128.88, 128.86, 128.53, 68.3,
41.3, 29.9.
1
stereomers 93.012 g, 80.7%). H NMR 9CDCl3) d 8.33 9s,
1H), 8.32 9s, 1H), 8.01 9s, 1H), 8.00 9s, 1H), 7.34 9m, 5H),
7.33 9m, 5H), 5.92 9d, Jˆ7.5 Hz, 1H), 5.90 9d, Jˆ7.5 Hz,
1H), 5.52 9bs, 2H), 5.51 9bs, 2H), 5.20 9d, Jˆ5.5 Hz, 2H),
5.14 9d, Jˆ5 Hz, 2H), 5.11 9dd, Jˆ7, 5.5 Hz, 1H), 5.06 9dd,
Jˆ7, 5.5 Hz, 1H), 4.42 9dd, Jˆ5.5, 4 Hz, 1H), 4.34 9dd,
Jˆ5, 3.5 Hz, 1H), 4.29 9m, 1H), 4.25 9m, 1H), 3.08 9dd,
Jˆ16, 5.5 Hz, 1H), 2.94 9dd, Jˆ15.5, 7.5 Hz, 1H), 2.53
9dd, Jˆ15.5, 3 Hz, 1H), 2.43 9dd, Jˆ16, 8 Hz, 1H), 2.29
9dd, Jˆ6.5, 3.5 Hz, 1H), 2.22 9dd, Jˆ3.5, 1.5 Hz, 1H),
2.20 9dd, Jˆ6.5, 3 Hz, 1H), 2.14 9dd, Jˆ3, 1.5 Hz, 1H),
1.74 9dd, Jˆ6.5, 1.5 Hz, 1H), 1.66 9dd, Jˆ6.5, 1.5 Hz,
1H), 1.00 9t, Jˆ8.0 Hz, 9H), 0.98 9t, Jˆ8.0 Hz, 9H), 0.80
9t, Jˆ8.0 Hz, 9H), 0.78 9t, Jˆ8.0 Hz, 9H), 0.67 9q,
Jˆ8.0 Hz, 6 H), 0.65 9q, Jˆ8.0 Hz, 6H), 0.37 9qq, Jˆ16.0,
8.0 Hz, 6H), 0.35 9qq, Jˆ16.0, 8.0 Hz, 6H); 13C 9CDCl3) d
170.83, 170.67, 156.03, 153.03, 149.98, 149.89, 140.92,
140.93, 135.74, 135.70, 128.73, 128.53, 128.52, 128.34,
120.73, 120.68, 89.44, 89.06, 84.93, 84.40, 74.24, 74.12,
74.03, 73.66, 67.14, 66.92, 61.48, 61.27, 37.41, 37.36,
35.01, 7.05, 6.76, 5.13, 4.76. FAB-HRMS: calcd for
C32H50N6O5Si2 9M1H1) 655.34; obsd 655.347.
4.1.6. 50-Aziridino-50-deoxy-)200-carboxylmethyl)-20,30-
bis-)O-triethylsilyl)adenosine 12. To 20a 90.600 g,
0.814 mmol) in 11 mL dry MeOH was added triethylamine
90.494 g, 4.885 mmol). The solution was heated at re¯ux for
2 h. The reaction was cooled and an aqueous workup was
performed 9EtOAc, H2O, brine), dried over Na2SO4 and
evaporated in vacuo. The crude was taken directly forward
due to co-migration of the auxiliary. The signals due to 12a
1
9S aziridine) could be discerned: H NMR 9CDCl3) d 8.26
4.2. General procedure for 20,30 desilylation of 50-
aziridino-50-deoxyadenosine analogs
9s, 1H), 7.97 9s, 1H), 6.29 9s, 2H), 5.91 9d, Jˆ5.6 Hz, 1H),
5.04 9dd, Jˆ5.6, 4.4 Hz, 1H), 4.30 9m, 2H), 3.73 9s, 3H),
3.04 9dd, Jˆ12.8, 3.6 Hz, 1H), 2.47 9dd, Jˆ12.8, 6.4 Hz,
1H), 2.16 9dd, Jˆ6.4, 3.2 Hz, 1H), 2.12 9dd, Jˆ3.2,
To the 20,30-bis-9O-triethylsilyl)adenosine 90.1085 mmol)

6024
L. R. Comstock, S. R. Rajski / Tetrahedron 58 -2002) 6019±6026
in 0.50 mL dry dioxane was added TBAF 90.2170 mmol) in
0.50 mL dry dioxane. The reaction was allowed to stir at
room temperature for 30 min and evaporated in vacuo to
reveal a yellow oil. Puri®cation by reverse-phase HPLC
4.2.3. )4R,5S)-1,5-Dimethyl-4-phenylimidazolidin-2-one-
3-)20,30-dibromopropionate) 18. To 16 90.250 g,
1.315 mmol) in 2.5 mL dry acetonitrile was added dibromo-
propionylchloride 90.395 g, 1.578 mmol) at room tempera-
ture. The solution was heated at re¯ux for 2 h. Upon cooling
to 08C, the reaction was diluted with 5% MeOH/CH2Cl2. An
aqueous workup was performed 9H2O, 5% MeOH/CH2Cl2,
brine), the resulting organic layer dried over Na2SO4 and
solvent removed in vacuo to yield a pink oil. Column
chromatography on silica gel 91:1 Pet Ether/EtOAc) yielded
18 as a mixture of diastereomers 90.436 g, 82.1%). Mp 112±
1148C. 1H NMR 9CDCl3) d 7.25 9m, 10H), 6.35 9dd,
Jˆ11.5, 4 Hz, 1H), 6.24 9dd, Jˆ11.5, 3.5 Hz, 1H), 5.39
9d, Jˆ9.0 Hz, 1H), 5.36 9d, Jˆ9.0 Hz, 1H), 4.00 9m, 4H),
3.66 9m, 2H), 2.89 9s, 6H), 0.83 9d, Jˆ6.5 Hz, 6H); 13C
9CDCl3) 166.70, 165.83, 154.73, 154.63, 135.74, 135.45,
128.77, 128.75, 128.73, 128.70, 128.60, 128.53, 60.14,
60.08, 54.00, 53.94, 40.04, 39.53, 29.84, 29.28, 28.52,
Ê
9C18-100A).
4.2.1. 50-Aziridino-50-deoxy-)200-carboxylmethyl) adeno-
sine 14. Puri®cation by reverse-phase HPLC on a linear
gradient 95±60% CH3CN over 20 min; retention time
15.0 min).
Compound 14a 9S aziridine). Yield: 34.9%. Mp 1308C
9dec). H NMR 9D2O) d 8.30 9s, 1H), 8.29 9s, 1H), 6.08
1
9d, Jˆ4.8 Hz, 1H), 4.59 9t, Jˆ5.6 Hz, 1H), 4.30 9m, 1H),
3.59 9s, 3H), 3.02 9dd, Jˆ13.6, 4.8 Hz, 1H), 2.61 9dd,
Jˆ13.6, 3.6 Hz, 1H), 2.33 9dd, Jˆ6.8, 3.2 Hz, 1H), 2.10
9d, Jˆ3.2 Hz, 1H), 1.88 9d, Jˆ6.8 Hz, 1H); 13C NMR
9D2O) d 172.79, 156.53, 152.22, 149.08, 140.23, 118.91,
87.76, 82.98, 73.38, 70.83, 58.55, 52.74, 37.91, 33.41.
FAB-HRMS: calcd for C14H18N6O5 9M1H1) 351.13; obsd
351.143.
28.48,
15.31,
15.17.
FAB-HRMS:
calcd
for
C14H16Br2N2O29M1H1) 404.96; obsd 404.962.
4.2.4. )4S,5R)-1,5-Dimethyl-4-phenylimidazolidin-2-one-
3-)20,30-dibromopropionate) 19. To 17 90.500 g,
2.639 mmol) in 5 mL dry acetonitrile was added dibromo-
propionylchloride 90.790 g, 3.156 mmol) at room tempera-
ture. The solution was heated at re¯ux for 2 h. Upon cooling
to 08C, the reaction was diluted with 5% MeOH/CH2Cl2. An
aqueous workup was performed 9H2O, 5% MeOH/CH2Cl2,
brine), dried over Na2SO4 and evaporated in vacuo to yield a
pink oil. Column chromatography on silica gel 91:1 Pet
Ether/EtOAc) gave 19 as a mixture of diastereomers
Compound 14b 9R aziridine). Yield: 43.3%. Mp 1328C
9dec). H NMR 9D2O) d 8.36 9s, 1H), 8.25 9s, 1H), 6.08
1
9d, Jˆ5.6 Hz, 1H), 4.87 9t, Jˆ5.2 Hz, 1H), 4.38 9t,
Jˆ5.2 Hz, 1H), 4.34 9m, 1H), 3.62 9s, 3H), 3.00 9dd,
Jˆ13.2, 4.0 Hz, 1H), 2.56 9dd, Jˆ13.2, 7.6 Hz, 1H), 2.38
9dd, Jˆ6.8, 3.2 Hz, 1H), 2.13 9d, Jˆ3.2 Hz, 1H), 1.89 9d,
Jˆ6.8 Hz, 1H); 13C NMR 9D2O) d 172.87, 155.07, 152.02,
149.01, 140.60, 119.06, 87.80, 83.54, 73.11, 71.44, 59.99,
52.77, 38.21, 33.05. FAB-HRMS: calcd for C14H18N6O5
9M1H1) 351.13; obsd 351.143.
1
90.690 g, 64.9%). Mp 113±1158C. H NMR 9CDCl3) d
7.25 9m, 10H), 6.34 9dd, Jˆ11.5, 4 Hz, 1H), 6.21 9dd,
Jˆ11.5, 3.5 Hz, 1H), 5.38 9d, Jˆ9.0 Hz, 1H), 5.35 9d,
Jˆ9.0 Hz, 1H), 4.00 9m, 4H), 3.65 9m, 2H), 2.89 9s, 6H),
0.83 9d, Jˆ6.5 Hz, 6H); 13C 9CDCl3) d 166.74, 165.86,
154.76, 154.74, 135.76, 135.46, 128.81, 128.74, 128.73,
128.64, 128.57, 127.26, 60.17, 59.59, 54.03, 53.97, 40.05,
39.54, 29.86, 29.30, 28.55, 28.51, 15.35, 15.20. FAB-
HRMS: calcd for C14H16Br2N2O29M1H1) 404.96; obsd
404.962.
4.2.2. 50-Aziridino-50-deoxy-)200-carboxylbenzyl) adeno-
sine 15. Puri®cation by reverse-phase HPLC on a linear
gradient of MeOH 90±50% over 4 min, 50±80% over
18 min; retention time 15.0, 16.2 min). Yield: 53.8%; mp
1458C 9dec).
1
Compound 15a 9R aziridine). H NMR 9DMSO) d 8.39 9s,
1H), 8.15 9s, 1H), 7.29 9m, 5H), 5.90 9d, Jˆ5.2 Hz, 1H),
5.47 9bs, 2H), 5.06 9ABq, Jˆ12.4 Hz, 2H), 4.60 9dd, Jˆ5.6,
4.8 Hz, 1H), 4.18 9ddˆt, Jˆ4.4 Hz, 1H), 4.03 9m, 1H), 2.73
9dd, Jˆ12.8, 3.6 Hz, 1H), 2.52 9dd, Jˆ12.8, 6.4 Hz, 1H),
2.34 9dd, Jˆ6.4, 3.2 Hz, 1H), 1.97 9dd, Jˆ3.2, 1.6 Hz, 1H),
1.70 9dd, Jˆ6.4, 1.6 Hz, 1H); 13C 9DMSO) d 170.94,
156.77, 153.32, 150.16, 140.39, 136.60, 129.12, 128.66,
128.40, 119.81, 88.07, 84.13, 73.81, 71.92, 66.41, 61.47.
FAB-HRMS: calcd for C20H22N6O5 9M1H1) 427.43; obsd
427.1733.
4.2.5.
)4000R,5000S)-50-Aziridino-50-deoxy-[200-carboxyl-
)1000,5000-dimethyl-4000-phenylimidazolidin-2000-one)]-20,30-
bis-)O-triethylsilyl)adenosine 20. To 18 90.125 g,
0.310 mmol) in 10 mL dry THF was added 9 90.155 g,
0.313 mmol) in 10 mL dry THF. The reaction was allowed
to stir for 15 min. Upon addition of TEA 90.094 g,
0.931 mmol), the solution was heated at re¯ux for 16 h.
The precipitate was triturated with anhydrous Et2O and
the organic removed in vacuo to yield a solid. Column chro-
matography on silica 95:2:1 EtOAc/CH2Cl2/MeOH) gave 20
as two diastereomers. Yield 90.091 g, 0.061 g, 66.5%). Mp
1848C 9dec).
1
Compound 15b 9S aziridine). H NMR 9DMSO) d 8.31 9s,
1H), 8.10 9s, 1H), 7.30 9m, 5H), 7.24 9s, 2H), 5.86 9d,
Jˆ5.2 Hz, 1H), 5.52 9d, Jˆ5.6 Hz, 1H), 5.29 9d,
Jˆ5.2 Hz, 1H), 5.05 9ABq, Jˆ12 Hz, 2H), 4.56 9dddˆq
9obsd), Jˆ5.2 Hz, 1H), 4.17 9dddˆq 9obsd), Jˆ5.2 Hz,
1H), 3.97 9m, 1H), 2.80 9dd, Jˆ12.8, 4.0 Hz, 1H), 2.38
9dd, Jˆ12.8, 3.2 Hz, 1H), 2.22 9dd, Jˆ6.4, 3.2 Hz, 1H),
1.93 9dd, Jˆ3.2, 1.2 Hz, 1H), 1.70 9dd, Jˆ6.4, 1.2 Hz,
1H); 13C 9DMSO) d 170.98, 156.72, 153.33, 150.14,
140.19, 136.49, 129.12, 128.79, 119.66, 87.83, 84.02,
73.82, 71.87, 66.62, 61.39, 36.92, 34.89. FAB-HRMS:
calcd for C20H22N6O5 9M1H1) 427.43; obsd 427.1733.
1
Compound 20a 9S aziridine). H NMR 9CDCl3) d 8.36 9s,
1H), 8.22 9s, 1H), 7.28 9m, 5H), 6.18 9s, 2H), 6.02 9d,
Jˆ6.4 Hz, 1H), 5.47 9d, Jˆ8.4 Hz, 1H), 4.99 9dd, Jˆ6,
4.4 Hz, 1H), 4.32 9dd, Jˆ4.4, 2.4 Hz, 1H), 4.25 9m, 1H),
3.89 9dq, Jˆ8.4, 6.8 Hz, 1H), 3.87 9dd, Jˆ6.4, 3.2 Hz, 1H),
3.31 9dd, Jˆ12.8, 3.6 Hz, 1H), 2.82 9s, 3H), 2.43 9dd,
Jˆ12.8, 5.6 Hz, 1H), 2.14 9dd, Jˆ2.8, 1.2 Hz, 1H), 1.71
9dd, Jˆ6.4, 1.2 Hz, 1H), 0.98 9t, Jˆ8.0 Hz, 9H), 0.78 9t,

L. R. Comstock, S. R. Rajski / Tetrahedron 58 -2002) 6019±6026
6025
Jˆ8.0 Hz, 9H), 0.75 9d, Jˆ6.8 Hz, 3H), 0.65 9q, Jˆ8.0 Hz,
6H), 0.35 9qq, Jˆ16.0, 8.0 Hz, 6H); 13C 9CDCl3) d 169.41,
156.17, 153.25, 150.29, 140.79, 136.63, 128.75, 128.34,
127.39, 120.15, 88.15, 85.62, 75.34, 74.19, 61.76, 59.40,
54.34, 36.89, 35.97, 28.38, 15.14, 7.13, 6.80, 5.17, 4.72.
FAB-HRMS: calcd for C36H56N8O5Si2 9M1H1) 737.40;
obsd 737.397.
120.68, 89.07, 85.38, 74.45, 74.26, 61.61, 59.75, 54.53,
36.97, 36.11, 28.32, 15.06, 7.05, 6.73, 5.14, 4.68. FAB-
HRMS: calcd for C36H56N8O5Si2 9M1H1) 737.40; obsd
737.397.
4.2.7. 50-Aziridino-50-deoxy-)200-hydroxymethyl)-20,30-
bis-)O-triethylsilyl)adenosine 22. To 12a 90.499 g,
0.862 mmol) in 10 mL dry THF at 2108C was added to a
1 M solution of LiAlH4 in THF 90.948 mL, 0.948 mmol)
dropwise. The reaction was warmed slowly and stirred for
an additional10 min. The reaction was quenched with
NaHCO3 and extracted into EtOAc. The organic layer was
washed with water and brine, dried over Na2SO4, and evapo-
rated in vacuo. Silica gel chromatography 95:2:1 EtOAc/
CH2Cl2/MeOH) afforded 22a 9R aziridine) 90.296 g,
1
Compound 20b 9R aziridine). H NMR 9CDCl3) d 8.35 9s,
1H), 8.25 9s, 1H), 7.24 9m, 5H), 6.10 9s, 2H), 6.01 9d,
Jˆ6.4 Hz, 1H), 5.35 9d, Jˆ8.8 Hz, 1H), 4.77 9dd, Jˆ6,
4.4 Hz, 1H), 4.41 9dd, Jˆ4.4, 2.4 Hz, 1H), 4.22 9m, 1H),
3.90 9dq, Jˆ8.4, 6.4 Hz, 1H), 3.84 9dd, Jˆ6.4, 3.2 Hz, 1H),
2.94 9dd, Jˆ12.8, 4.8 Hz, 1H), 2.82 9s, 3H), 2.63 9dd,
Jˆ12.8, 4.0 Hz, 1H), 2.17 9dd, Jˆ2.8, 1.2 Hz, 1H), 1.68
9dd, Jˆ6.4, 1.2 Hz, 1H), 1.00 9t, Jˆ8.0 Hz, 9H), 0.80 9t,
Jˆ8.0 Hz, 9H), 0.75 9d, Jˆ6.8 Hz, 3H), 0.67 9q,
Jˆ8.0 Hz, 6 H), 0.37 9qq, Jˆ16.0, 8.0 Hz, 6H); 13C
9CDCl3) d 169.33, 156.17, 153.34, 149.91, 140.26,
136.61, 128.61, 128.19, 127.38, 120.07, 89.01, 83.48,
75.71, 72.76, 60.39, 59.66, 54.51, 37.19, 37.01, 28.39,
15.15, 7.02, 6.81, 5.15, 4.90. FAB-HRMS: calcd for
C36H56N8O5Si2 9M1H1) 737.40; obsd 737.397.
1
66.0%). Mp 129±1328C. H NMR 9CDCl3) d 8.24 9s, 1H),
8.02 9s, 1H), 6.82 9s, 2H), 5.83 9d, Jˆ6.0 Hz, 1H), 5.06 9dd,
Jˆ5.5, 4.5 Hz, 1H), 4.51 9s, 1H), 4.28 9dd, Jˆ4.0, 3.5 Hz,
1H), 4.19 9m, 1H), 3.74 9dd, Jˆ11.5, 2.5 Hz, 1H), 3.34 9dd,
Jˆ11.5, 6.0 Hz, 1H), 2.85 9dd, Jˆ13.0, 3.5 Hz, 1H), 2.47
9dd, Jˆ13.0, 7.0 Hz, 1H), 1.72 9m, 1H), 1.67 9d, Jˆ3.5 Hz,
1H), 1.39 9d, Jˆ6.5 Hz, 1H), 0.92 9t, Jˆ8.0 Hz, 9H), 0.72 9t,
Jˆ8.0 Hz, 9H), 0.59 9q, Jˆ8.0 Hz, 6H), 0.34 9qq, Jˆ16.0,
8.0 Hz, 6H); 13C NMR 9CDCl3) d 156.25, 153.00, 149.77,
141.08, 120.58, 89.45, 85.29, 74.12, 74.06, 63.13, 62.11,
40.28, 32.04, 7.03, 6.74, 5.14, 4.74. FAB-HRMS: calcd
for C25H46N6O4Si2 9M1H1) 551.31; obsd 551.319.
4.2.6.
)4000S,5000R)-50-Aziridino-50-deoxy-[200-carboxyl-
)1000,5000-dimethyl-4000-phenylimidazolidin-2000-one)]-20,30-
bis-)O-triethylsilyl)adenosine 21. To 19 90.129 g,
0.320 mmol) in 10 mL dry THF was added 9 90.160 g,
0.323 mmol) in 10 mL dry THF. The reaction was allowed
to stir for 15 min. Upon addition of TEA 90.097 g,
0.961 mmol), the solution was heated at re¯ux for 16 h.
The precipitate was triturated with anhydrous Et2O and
the organic was evaporated in vacuo to yield a solid.
Column chromatography on silica 95:2:1 EtOAc/CH2Cl2/
MeOH) gave 21 as two diastereomers. Yield 90.061 g,
0.087 g, 62.8%); mp 2108C 9dec).
A similar procedure was performed with 12b to obtain 22b
9S aziridine). Yield: 0.231 g, 66.0%. Mp 130±1328C. H
1
NMR 9CDCl3) d 8.09 9s, 1H), 7.81 9s, 1H), 6.10 9s, 1H),
5.82 9d, Jˆ7.0 Hz, 1H), 5.62 9dd, Jˆ7.0, 4.0 Hz, 1H), 4.15
9d, Jˆ10.5 Hz, 1H), 4.08 9d, Jˆ4.0 Hz, 1H), 4.03 9t,
Jˆ11.0 Hz, 1H), 3.86 9d, Jˆ12.0 Hz, 1H), 3.17 9dd,
Jˆ12.5, 9.0 Hz, 1H), 1.92 9m, 1H), 1.81 9d, Jˆ12.5,
2.0 Hz, 1H), 1.69 9d, Jˆ3.5 Hz, 1H), 1.32 9d, Jˆ6.5 Hz,
1H), 1.02 9t, Jˆ8.0 Hz, 9H), 0.72 9t, Jˆ8.0 Hz, 9H), 0.68
9q, Jˆ8.0 Hz, 6H), 0.28 9qq, Jˆ16.0, 8.0 Hz, 6H); 13C NMR
9CDCl3) d 155.38, 152.46, 148.95, 141.39, 120.56, 90.28,
85.85, 75.18, 72.60, 53.38, 62.66, 41.91, 30.94, 7.08, 6.66,
5.17, 4.60. FAB-HRMS: calcd for C25H46N6O4Si2 9M1H1)
551.31; obsd 551.319.
1
Compound 21a 9R aziridine). H NMR 9CDCl3) d 8.34 9s,
1H), 8.11 9s, 1H), 7.29 9m, 5H), 6.18 9d, Jˆ5.2 Hz, 1H),
5.75 9s, 2H), 5.29 9d, Jˆ8.4 Hz, 1H), 4.93 9dd, Jˆ6, 4.4 Hz,
1H), 4.40 9dd, Jˆ4.4, 2.4 Hz, 1H), 4.25 9m, 1H), 3.88 9dq,
Jˆ8.4, 6.8 Hz, 1H), 3.82 9dd, Jˆ6.4, 3.2 Hz, 1H), 2.89 9dd,
Jˆ12.8, 5.2 Hz, 1H), 2.81 9s, 3H), 2.73 9dd, Jˆ12.8, 5.2 Hz,
1H), 2.23 9dd, Jˆ3.2, 1.2 Hz, 1H), 1.63 9dd, Jˆ6.4, 1.2 Hz,
1H), 0.98 9t, Jˆ8.0 Hz, 9H), 0.80 9t, Jˆ8.0 Hz, 9H), 0.79 9d,
Jˆ6.8 Hz, 3H), 0.66 9q, Jˆ8.0 Hz, 6H), 0.41 9qq, Jˆ16.0,
8.0 Hz, 6H); 13C 9CDCl3) d 168.99, 156.13, 153.11, 150.01,
140.48, 136.45, 128.70, 128.34, 127.30, 120.44, 89.02,
84.29, 74.88, 73.50, 61.56, 59.57, 54.31, 37.29, 35.83,
38.34, 15.15, 7.09, 6.82, 5.09, 4.81. FAB-HRMS: calcd
for C36H56N8O5Si2 9M1H1) 737.40; obsd 737.397.
4.2.8. 50-Aziridino-50-deoxy-)200-hydroxymethyl) adeno-
sine 23. Puri®cation by reverse-phase HPLC on a linear
gradient of CH3CN 95±100% over 11 min; retention time
5.7 min). Yield: 39.5%; mp 1408C 9dec).
Compound 23a 9R aziridine). 1H NMR 9D2O) d 8.23 9s, 1H),
8.07 9s, 1H), 5.98 9d, Jˆ4.8 Hz, 1H), 4.71 9ddˆt 9obsd),
Jˆ5.2 Hz, 1H), 4.32 9ddˆt 9obsd), Jˆ5.2 Hz, 1H), 4.28
9m, 1H), 3.58 9dd, Jˆ12.0, 4.8 Hz, 1H), 3.40 9dd, Jˆ12.0,
2.8 Hz, 1H), 2.77 9dd, Jˆ13.2, 4.0 Hz, 1H), 2.66 9dd,
Jˆ13.2, 7.2 Hz, 1H), 1.91 9m, 1H), 1.72 9d, Jˆ4.0 Hz,
1H), 1.61 9d, Jˆ6.4 Hz, 1H); 13C NMR 9D2O) d 155.53,
152.90, 148.81, 140.11, 118.82, 87.86, 83.72, 73.59,
71.52, 63.47, 60.89, 39.89, 31.82. FAB-HRMS: calcd for
C13H18N6O4 9M1H1) 323.14; obsd 323.147.
1
Compound 21b 9S aziridine). H NMR 9CDCl3) d 8.35 9s,
1H), 8.09 9s, 1H), 7.24 9m, 5H), 5.99 9s, 2H), 5.93 9d,
Jˆ6.4 Hz, 1H), 5.33 9d, Jˆ8.4 Hz, 1H), 4.99 9dd, Jˆ6,
4.4 Hz, 1H), 4.30 9m, 1H), 4.20 9dd, Jˆ4.4, 2.4 Hz, 1H),
3.94 9dq, Jˆ8.4, 6.4 Hz, 1H), 3.80 9dd, Jˆ6.4, 2.8 Hz, 1H),
3.38 9dd, Jˆ12.4, 4 Hz, 1H), 2.86 9s, 3H), 2.36 9dd, Jˆ12.4,
7.2 Hz, 1H), 2.10 9dd, Jˆ2.8, 1.2 Hz, 1H), 1.81 9dd, Jˆ6.4,
1.2 Hz, 1H), 0.97 9t, Jˆ8.0 Hz, 9H), 0.81 9d, Jˆ6.8 Hz, 3H),
0.76 9t, Jˆ8.0 Hz, 9H), 0.63 9q, Jˆ8.0 Hz, 6 H), 0.34
9qq, Jˆ16.0, 8.0 Hz, 6H); 13C 9CDCl3) d 169.29, 155.85,
153.05, 149.90, 141.14, 136.29, 128.60, 128.23, 127.25,
Compound 23b 9S aziridine). 1H NMR 9D2O) d 8.31 9s, 1H),
8.22 9s, 1H), 6.07 9d, Jˆ5.2 Hz, 1H), 4.40 9ddˆt 9obsd),
Jˆ5.2 Hz, 1H), 4.29 9m, 1H), 3.58 9dd, Jˆ12.0, 4.8 Hz,
1H), 3.39 9dd, Jˆ12.0, 6.8 Hz, 1H), 2.77 9dd, Jˆ13.2,

6026
L. R. Comstock, S. R. Rajski / Tetrahedron 58 -2002) 6019±6026
Ochiai, A.; Shimoyama, Y.; Sugimura, T.; Hirohashi, S. Proc.
Natl Acad. Sci. USA 1995, 92, 7416±7419.
3.6 Hz, 1H), 2.67 9dd, Jˆ13.2, 6.8 Hz, 1H), 1.93 9m, 1H),
1.69 9d, Jˆ4.0 Hz, 1H), 1.60 9d, Jˆ6.8 Hz, 1H); 13C NMR
9D2O) d 155.68, 152.99, 148.98, 140.13, 118.95, 87.80,
83.60, 73.61, 71.50, 63.49, 60.71, 40.65, 31.00. FAB-
HRMS: calcd for C13H18N6O4 9M1H1) 323.14; obsd
323.147.
8. Pignot, M.; Siethoff, C.; Linscheid, M.; Weinhold, E. Angew.
Chem. Int. Ed. 1998, 37, 2888±2891.
9. Pignot, M.; Siethoff, C.; Linscheid, M.; Weinhold, E. Patent
InternationalPub. No. WO 00/06587.
10. For recent examples see: 9a) Tanner, D.; Korno, H. T.;
Guijarro, D.; Andersson, P. G. Tetrahedron 1998, 54,
14213±14232. 9b) Aahman, J.; Somfai, P. Synth. Commun.
1994, 24, 1121±1127. 9c) Chamchaang, W.; Pinhas, A. R.
J. Org. Chem. 1990, 55, 2943±2950. 9d) Zablocki, J. A.;
Katzenellenbogen, J. A.; Carlson, K. E.; Norman, M. J.;
Katzenellenbogen, B. S. J. Med. Chem. 1987, 30, 829±838.
11. 9a) Liu, F.; Austin, D. J. J. Org. Chem. 2001, 66, 8643±8645
9and references therein). 9b) Lal, B.; Pramanik, B. N.; Manhas,
M. S.; Bose, A. K. Tetrahedron Lett. 1977, 18, 1977±1980.
12. For related applications of Mitsunobu chemistry to the 50
center of adenosine analogs see: 9a) Kolb, M.; Danzin, C.;
Barth, J.; Claverie, N. J. Med. Chem. 1982, 25, 550±556.
9b) Pignot, M.; Pljevaljcic, G.; Weinhold, E. Eur. J. Org.
Chem. 2000, 549±555. 9c) Miller, M. J.; Li, H. J. Org.
Chem. 1999, 64, 9289±9293.
Acknowledgements
The authors gratefully acknowledge ®nancial support
provided by American Association of Colleges of
Pharmacy, an NIH starter grant 9ES09090-04) administered
through University of Wisconsin EnvironmentalHeathl
Sciences Center for Developmental and Molecular Toxi-
cology and generous startup funds provided by University
of Wisconsin.
References
13. Fei, L.; Austin, D. J. Org. Lett. 2001, 3, 2273±2276.
14. Allerson, C. R.; Swaine, L.; Verdine, G. L. J. Am. Chem. Soc.
1997, 119, 7423±7433.
1. Rajski, S. R.; Williams, R. M. Chem. Rev. 1998, 98, 2723±
2796.
2. 9a) Patra, S. K.; Patra, A.; Dhiya, R. Biochem. Biophys. Res.
Commun. 2001, 287, 705±713. 9b) Nie, Y.; Yang, G. Y.; Song,
Y.; Zhao, X.; So, C.; Liao, J.; Wang, L.-D.; Yang, C. S.
Carcinogenesis 2001, 22, 1615±1623. 9c) Robertson, K. D.
Oncogene 2001, 20, 3139±3155.
15. Toyota, M.; Komori, C.; Ihara, M. J. Org. Chem. 2000, 65,
7110±7113.
16. For examples of Gabriel±Cromwell aziridinations see:
9a) DeShong, P.; Kell, D. A.; Sidler, D. R. J. Org. Chem.
1985, 50, 2309±2315. 9b) Stolberg, M. A.; O'Neill, J. J.;
Wagner-Jauregg, T. J. Am. Chem. Soc. 1953, 75, 5045±
5047. 9c) Filigheddu, S. N.; Taddei, M. Tetrahedron Lett.
1998, 39, 3857±3860. 9d) Eastwood, F. W.; Perimutter, P.;
Yang, Q. Tetrahedron Lett. 1994, 35, 2039±2042. 9e) Saint-
Fuscien, C.; Tarrade, A.; Dauben, P.; Dodd, R. H. Tetrahedron
Lett. 2000, 41, 6393±6397.
3. 9a) Wang, C. C.; Dervan, P. B. J. Am. Chem. Soc. 2000, 123,
8657±8661. 9b) Minehan, T. G.; Gottwald, K.; Dervan, P. B.
Helv. Chim. Acta 2000, 83, 2197±2213. 9c) Chang, A. Y.;
Dervan, P. B. J. Am. Chem. Soc. 2000, 122, 4856±4864.
4. 9a) Cheng, X.; Roberts, R. J. Nucleic Acids Res. 2001, 29,
3784±3795. 9b) Roberts, R. J.; Cheng, X. Annu. Rev. Biochem.
1998, 67, 181±198. 9c) Nelson, H. C. M.; Bestor, T. H. Chem.
Biol. 1996, 3, 419±423.
17. For asymmetric Gabriel±Cromwell entries see: 9a) Cardillo,
G.; Gentilucci, L.; Tomasini, C.; Pilar, V.; Castejon-Bordas,
M. Tetrahedron: Asymmetry 1996, 7, 755±762. 9b) Clark,
W. M.; Bender, C. J. Org. Chem. 1998, 63, 6732±6743.
5. 9a) Razin, A.; Riggs, A. D. Science 1980, 210, 604±610.
9b) Razin, A.; Szyf, M. Biochim. Biophys. Acta 1984, 782,
331±342. 9c) Yisraeli, J.; Szyf, M. In DNA Methylation and
its Biological Signi®cance, Razin, A., Cedar, H., Riggs, A. D.,
Eds.; Springer: Berlin, 1984; pp 353±378. 9d) Razin, A.;
Cedar, H. Microbiol. Rev. 1991, 55, 451±458.
Â
9c) Guillena, G.; Najera, C. J. Org. Chem. 2000, 65, 7310±
7322. 9d) Jahnisch, K.; Tittelbach, F.; Grundemann, E.;
Schneider, M. Eur. J. Org. Chem. 2000, 3957±3960.
18. Van der Wende, E. M.; Carnielli, M.; Roelen, H. C. P. F.;
Lorenzen, A.; von Frijtag Drabe, K.; Jacobien, K.; Ijzerman,
A. P. J. Med. Chem. 1998, 41, 102±108.
6. 9a) Siegfried, Z.; Eden, S.; Mendelsohn, M.; Feng, X.; Tsuberi,
B. Z.; Cedar, H. Nat. Genet. 1999, 22, 203±206. 9b) Colot, V.;
Rossignol, J. L. BioEssays 1999, 21, 402±411.
19. Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C.
Synlett 1999, 11, 1727±1730.
20. For related reductions of aziridines see: 9a) Ambrosi, H.-D.;
7. 9a) Robertson, K. D. Oncogene 2001, 20, 3139±3155.
9b) Johnstone, R. W. Nat. Rev. 2002, 1, 287±299. 9c) Laird,
P. W.; Jaenisch, R. Annu. Rev. Gen. 1996, 30, 441±464.
9d) Ahuja, N.; Mohan, A. L.; Li, Q.; Stolker, J. M.; Herman,
J. G.; Hamilton, S. R.; Baylin, S. B.; Issa, J. P. Cancer Res.
1997, 57, 3370±3374. 9e) Herman, J. G.; Graff, J. R.;
Myohanen, S.; Nelkin, B. D.; Baylin, S. B. Proc. Natl Acad.
Sci. USA 1996, 93, 9821±9826. 9f) Ohtani-Fujita, N.; Fujita,
T.; Aoike, A.; Osifchin, N. E.; Robbins, P. D.; Sakai, T.
Oncogene 1993, 8, 1063±1067. 9g) Yoshiura, K.; Kanai, Y.;
È
Duczek, W.; Ramm, M.; GrUndemann, E.; Schulz, B.;
È
Jahnisch, K. Liebigs Ann. Chem. 1994, 1013±1018.
9b) Davis, F. A.; Zhou, P. Tetrahedron Lett. 1994, 35,
7525±7528. 9c) Morimoto, Y.; Matsuda, F.; Shirahama, H.
Synlett 1991, 201±203.
È
21. For related work see: Lindstrom, U. M.; Somfai, P. Synthesis
1998, 109±117.