Carbocyclic ribosylamines: Synthesis of 5-substituted carbocyclic β-ribofuranosylamines

Article abstract of DOI:10.1021/jo060920l

(Chemical Equation Presented) A synthesis of 5-substituted cyclopentylamine precursors for 5′-substituted carbocyclic nucleoside analogues was developed. We show that the stereochemistry of the OsO₄-catalyzed hydroxylation of an apically bromin

Full text of DOI:10.1021/jo060920l

also related to the synthetic precursors of the anti-retroviral drugs
carbovir and abacavir.8
Carbocyclic Ribosylamines: Synthesis of
5-Substituted Carbocyclic â-Ribofuranosylamines
James T. Slama,*,† Nimish Mehta,†,‡ and
Ewa Skrzypczak-Jankun§,||
Department of Medicinal & Biological Chemistry, College of
Pharmacy, and Department Chemistry, UniVersity of Toledo,
Toledo, Ohio 43606
james.slama@utoledo.edu
Numerous synthetic methods have been reported for these
important compounds.9-13 Relatively few of the available
methods allow facile introduction of a substituent into the
5-position of the cyclopentane ring, and those available are either
excessively long or utilize an achiral starting material and
therefore require a resolution. We have developed a method to
produce a 5-substituted carbocyclic amine 2 starting from
2-azabicyclo[2.2.1]hept-5-ene-3-one (3).14,15 Bicyclic lactam 3
has been used previously as the precursor of the carbocyclic
ribosylamine.3,4 It is an attractive starting material, since it is
commercially available both as the racemate and as either of
the pure enantiomers and can be hydroxylated stereoselectively.
The ready availability of inexpensive enantiomerically pure 3
is the result of efficient enzymatic resolution of the racemate.16-18
Our synthetic strategy is based on the observation that N-benzyl-
protected 3 can be converted into an apically substituted lactam
in two steps involving bromination and dehydrobromination.19
The apical position of bicyclic 3 corresponds to the C-5 position
of the cyclopentylamine 2. Osmium tetraoxide catalyzed cis-
hydroxylation of N-benzyl-protected olefin 6, however, exclu-
sively produced the diastereomeric endo-hydroxylation product,
resulting in carbocyclic analogues of lyxofuranosides. We now
report that the stereochemistry of hydroxylation of brominated
lactam 6 can be controlled through the appropriate selection of
the nitrogen protecting group to yield exo-hydroxylation
products exclusively.
ReceiVed May 3, 2006
A synthesis of 5-substituted cyclopentylamine precursors for
5′-substituted carbocyclic nucleoside analogues was devel-
oped. We show that the stereochemistry of the OsO4-
catalyzed hydroxylation of an apically brominated lactam,
7-bromo-2-azabicyclo[2.2.1]hept-5-en-3-one, can be con-
trolled through the appropriate selection of the lactam N-H
protecting group. Sterically large groups direct the hydroxyl-
ation to the exo-face of the olefin, yielding hydroxylation
products that can be converted into analogues of carbocyclic
ribosides. Conversely, a sterically small protecting group
permits OsO4 approach from the endo-face, yielding hy-
droxylation products analogous to carbocyclic lyxosides. A
key intermediate for carbocyclic sugar production, (1S,2S,3R,
4R,5S)-1-(tert-butyloxycarbonyl)amino-5-bromo-2,3-(dimeth-
ylmethylene)dioxy-4-hydroxymethylcyclopentane, was syn-
thesized starting from a commercially available enantiomer-
ically pure lactam, (1S)-(+)-2-azabicyclo[2.2.1]hept-5-en-
3-one, in seven steps in an overall yield of 21%.
Carbocyclic ribofuranosylamine (1),1-5 in which a cyclopen-
tane replaces the ribofuranose ring of the parent sugar, is a
synthetic precursor for biologically active carbocyclic nucleo-
sides, such as aristeromycin,1-5 and for carbocyclic analogues
of phosphosugar intermediates in purine biosynthesis.6,7 It is
Lactam 3 can be converted into apically substituted lactam 6
in a three-step process of protection, bromination, and dehy-
(7) Antle, V. D.; Donat, N.; Hua, M.; Liao, P. L.; Vince, R.; Carperelli,
C. A. Arch. Biochem. Biophys. 1999, 370, 231-5.
* Corresponding author. Telephone: (419) 530-1925. Fax: (419) 530-7946.
† Department of Medicinal & Biological Chemistry.
‡ Current address: Precept Educational Sciences, Four Connell Drive, Building
IV, Suite 602, Berkeley Heights, NJ.
(8) Daluge, S. M.; Martin, M. T.; Sickles, B. R.; Livingston, D. A.
Nucleosides, Nucleotides, Nucleic Acids 2000, 19, 297-327.
(9) Marquez, V. E.; Lim, M.-I. Med. Res. ReV. 1986, 6, 1-40.
(10) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571-623.
(11) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611-10670.
(12) Crimmins, M. T. Tetrahedron 1998, 54, 9229-9272.
(13) Zhu, X. F. Nucleosides, Nucleotides, Nucleic Acids 2000, 19, 651-
690.
§ Department Chemistry.
| Current address: Urology Research Center, Medical College of Ohio, 3065
Arlington Ave. Toledo, OH 43614.
(1) Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1969, 91, 3075-
3083.
(2) Arita, M.; Adachi, K.; Ito, Y.; Sawai, H.; Ohno, M. J. Am. Chem.
Soc. 1983, 105, 4049-4055.
(3) Kam, B. L.; Oppenheimer, N. J. J. Org. Chem. 1981, 46, 3268-
3272.
(14) Jagt, J. C.; van Leusen, A. M. J. Org. Chem. 1974, 39, 564-566.
(15) Griffiths, G. J.; Previdoli, F. E. J. Org. Chem. 1993, 58, 6129-
6131.
(16) Taylor, S. J. C.; Sutherland, A. G.; Lee, C.; Wisdom, R.; Thomas,
S.; Roberts, S. M.; Evans, C. J. Chem. Soc., Chem. Commun. 1990, 1120-
1121.
(4) Cermak, R. C.; Vince, R. Tetrahedron Lett. 1981, 22, 2331-2332.
(5) Katagiri, N.; Muto, M.; Nomura, M.; Higashikawa, T.; Kaneko, C.
Chem. Pharm. Bull. 1991, 39, 1112-1122.
(6) Liu, D. S.; Caperelli, C. A. J. Biol. Chem. 1991, 266, 16699-702.
10.1021/jo060920l CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/31/2006
J. Org. Chem. 2006, 71, 7877-7880
7877

SCHEME 1
lected for evaluation because it was reported to cleave under
mild acidic conditions, similar to that for a trityl group.23
Protection of the amide nitrogen was achieved with dimethoxy-
diphenylmethyl chloride in CH2Cl2 under phase-transfer ca-
talysis, using powdered sodium hydroxide and potassium
carbonate as the base, to give 4c in 66% yield. Bromination of
4c in CH2Cl2 at room temperature afforded the desired rear-
ranged dibromide 5c in 50% yield. Elimination by heating with
DBU, at 120 °C gave a clean dehydrohalogenation to generate
the olefin 6c in 89% yield. Finally, protection of the pure
enantiomer lactam (3) with monomethoxytrityl chloride (MMT-
Cl) in CH2Cl2 under phase-transfer catalysis afforded the MMT-
protected lactam (4d) in 63% yield. Bromination under the
previously successful conditions i.e., in CH2Cl2 at ambient
temperature, gave the rearranged dibromide (5d) in a very low
yield (14%). The yield could be improved to 50% by using
carbon tetrachloride as the solvent and further improved to 70%
by including magnesium oxide as the base. This dibromide (5d)
was cleanly dehydrobrominated by heating in DBU at 120 °C
for 12 h to produce the olefin (6d) in 85% yield.
drohalogenation (Scheme 1). Previous studies of this reaction
established that bromination proceeds via a carbonium ion
rearrangement involving migration of the nitrogen and results
in stereospecific production of the enantiomeric lactam in high
yield.19,20 The second step, dehydrohalogenation of the dibro-
mide 5 resulting in the apically brominated 6, was reportedly
successful only if the amide N-H was protected. We therefore
began our investigation by producing several N-protected
lactams (4a-4d) and subjecting them to the conditions of
bromination and dehydrohalogenation.
Hydroxylation of olefin 6 with osmium tetraoxide produces
the cis-glycol 7 or 8, with the stereoselectivity governed by
approach of the reagent from the least sterically hindered face.
Osmium tetroxide-catalyzed cis-hydroxylation of the N-benzyl-
protected olefin (6b) led exclusively to the undesired endo-diol
(7b). This was due to the fact that the bulky bromide moiety
blocks the exo-face of the olefin, while the endo-face is easily
accessible to the bulky catalyst. This was in contrast with the
results obtained with the 7-unsubstituted bicyclic lactam 3, in
which the catalytic oxidation of the double bond gave the exo-
diol (8, R ) H) exclusively.3,4 Catalytic cis-hydroxylation of
N-diphenylmethyl-protected 6c, on the other hand, gave a
mixture of endo- and exo-cis-diols (7c, 8c, respectively) in a
ratio of 65% endo to, 35% exo with an overall yield of 100%.
The increased steric bulk of the protecting group was beginning
to shield the endo-face of the olefin and alter the stereoselectivity
of the hydroxylation. The assignment of structures for the exo-
Carbamate nitrogen protecting groups were first evaluated
and found to be unuseable. Bromination of the carbobenzyloxy
(Cbz)-protected lactam 4a resulted in a mixture of the two
isomeric and unrearranged dibromides in low yield, in which
there was no detectable 5. Bromination of the tert-butyloxy-
carbonyl (t-Boc)-protected lactam 4 resulted in a small amount
of the rearranged dibromide (5a, approximately 25%), ac-
companied by three unrearranged diastereomeric dibromides
1
(approximately 25% each), as determined from the H NMR.
Direct bromination21 of the unprotected lactam (3) produced
the rearranged dibromide (5, R ) H) in high yield, which was
then protected by treatment with di-tert-butyl dicarbonate and
DMAP to give the t-Boc-protected lactam dibromide (5a) in
80% yield. This compound was identical to the minor product
obtained by direct bromination of the t-Boc lactam (4a),
confirming our assignment of its structure. All attempts to
dehydrobrominate t-Boc-protected 5a to produce the corre-
sponding olefin 6a, under several basic conditions gave only
tars. Electron-withdrawing substituents on the lactam nitrogen
have been known to facilitate ring opening,22 and perhaps the
electron-withdrawing carbamate facilitates the cleavage of the
amide bond and decomposition. It has also been reported that
the unprotected lactam dibromide cannot be dehydrobrominated,
probably due to the formation of the amide anion leading to
decomposition.19
1
and endo-isomers was made by comparison of H NMR with
compound (7b). The compound exhibiting resonances and
couplings similar to that of 7b was assigned structure 7c, while
the other isomer was assigned structure 8c.
Since the exo-isomer was desired for our target compounds,
we sought to improve the yield of this isomer by using a bulkier
protecting group that would prevent OsO4 approach from the
endo-face of the olefin and favor production of the exo-diol.
Monomethoxytrityl protection was selected, since it would also
afford easy deprotection after hydroxylation, without opening
the bicyclic ring. Catalytic cis-hydroxylation by refluxing with
OsO4 and N-methylmorpholine N-oxide (NMO) in H2O/acetone/
tert-butyl alcohol for 36 h gave complete conversion of 6d to
a single product 8d in 90% yield, identified as the exo-diol by
NMR. Confirmation of this stereochemistry was sought by X-ray
crystallography, but suitable crystals of 8d could not be obtained.
However, another intermediate at a later stage in the synthesis
(10) was identified by X-ray crystallography as the exo-diol
(see the following text). We believe that even though the apical
bromide hindered approach of the osmium reagent to the exo-
face of the olefin (6d), the presence of the even larger MMT-
group on the nitrogen blocks access of the reagent to the endo-
face even more. A three-dimensional model (not shown) shows
Next, we turned to N-alkyl derivatives for amide protection.
The N-benzyl derivative 4b was produced by treating 3 with
benzyl bromide and KOH. Olefin 4b was quantitatively bro-
minated to rearranged dibromide 5b and dehydrohalogenated
at 120 °C in 1,8-diazabicycloundecene (DBU) in 70% yield as
reported.19 The 4,4′-dimethoxydiphenylmethyl group was se-
(17) Taylor, S. J. C.; McCague, R.; Wisdom, R.; Lee, C.; Dickson, K.;
Ruecroft, G.; Obrien, F.; Littlechild, J.; Bevan, J.; Roberts, S. M.; Evans,
C. T. Tetrahedron-Asymmetry 1993, 4, 1117-1128.
(18) Mahmoudian, M.; Lowdon, A.; Jones, M.; Dawson, M.; Wallis, C.
Tetrahedron: Asymmetry 1999, 10, 1201-1206.
(19) Faith, W. C.; Booth, C. A.; Foxman, B. M.; Snider, B. B. J. Org.
Chem. 1985, 50, 1983-1985.
(20) Evans, C.; McCague, R.; Roberts, S. M.; Sutherland, A. G. J. Chem.
Soc. Perkin Trans. 1 1991, 656-657.
(21) Hutchinson, E. J.; Taylor, B. F.; Blackburn, G. M. Chem. Commun.
1996, 2765-2766.
(22) Katagiri, N.; Muto, M.; Kaneko, C. Tettrahedron Lett. 1989, 30,
1645-1448.
(23) Hanson, J. C.; Law, H. D. J. Chem. Soc. 1965, 7285-7297.
7878 J. Org. Chem., Vol. 71, No. 20, 2006

SCHEME 2
temperature for 18 h The mixture was then filtered to remove the
solids and the filtrate evaporated. The residue was purified by flash
column chromatography on silica gel using hexanes-ethyl acetate
as the eluent to give a white solid (21 g, 70.5%): mp 95.8-96.5
°C; TLC Rf 0.52 (silica gel, hexanes-ethyl acetate, 70:30); 1H NMR
(CDCl3) δ 2.63 (m, 2H), 2.95 (s, 1H), 3.81 (s, 3H), 3.87 (d, J )
7.5 Hz, 1H), 4.25 (s, 1H), 4.46 (s, 1H), 6.85 (d, J ) 9 Hz, 2H),
7.20 (m, 12H); 13C NMR (CDCl3) δ 33.3, 41.9, 48.4, 54.7, 55.3,
69.1, 113.4, 127.4, 128.1, 128.9, 130.5, 134.3, 142.5, 142.6, 158.8,
171.6; MS m/z 539, 541, 543 (M+, Br2 isotope pattern, EI), 562,
564, 566 (MNa+, Br2 isotope pattern, MALDI). Anal. Calcd for
C26H23Br2NO2: C, 57.69; H, 4.28; N, 2.59. Found: C, 57.72; H,
4.45; N, 2.37.
that the propeller shape of the three aromatic groups positions
one of the aromatic rings of the trityl protecting group right
below the endo-face of the olefin, thus shielding that face to
approach of the OsO4 from that direction. This interpretation is
supported by the fact that the hydroxylation of 6d requires more
drastic conditions, e.g. higher temperature and longer reaction
time as compared to the hydroxylation in case of benzyl-
protected compound (6b).
Treatment of the diol 8d with trifluoroacetic acid (TFA) in
methylene chloride at room temperature for 2 h produced the
deprotected lactam (Scheme 2), which was converted to the
acetonide 9 (trifluoroacetic acid in acetone) in quantitative yield.
Lactam 9 was reprotected as the t-Boc lactam (10) in 82% yield.
To verify stereochemistry, the structure of 10 was established
by X-ray crystallography (see Figure 1, Supporting Information).
Sodium borohydride reduction and cleavage of the lactam in
methanol at room temperature yielded the ring-opened alcohol
2.
(1S,7S)-N-(p-Anisyldiphenylmethyl)-2-azabicyclo[2.2.1]hept-
7-bromo-5-en-3-one (6d). A mixture of N-(p-anisyldiphenylm-
ethyl)-2-azabicyclo[2.2.1]heptan-6,7-dibromo-3-one (21 g, 38.8
mmol) and DBU (30 mL) was heated at 125 °C in an oil bath for
18 h. Upon cooling, the reaction mixture was diluted with methylene
chloride (300 mL) and extracted with dilute HCl solution. The
organic layer was evaporated in vacuo and purified by flash column
chromatography on silica gel using hexanes-ethyl acetate as the
eluent to give the pure product as a white solid (15 g, 84%): mp
81.5-82.2 °C; TLC Rf 0.52 (silica gel, hexanes-ethyl acetate, 70:
1
30); H NMR (CDCl3) δ 3.42 (s, 1H), 3.80 (s, 3H), 4.51 (s, 1H),
4.74 (s, 1H), 6.18 (dd, J ) 5.0 Hz, 1.65 Hz, 1H), 6.26 (m, 1H),
6.80 (d, J ) 9 Hz, 2H), 7.30 (m, 12H); 13C NMR (CDCl3) δ 55.2,
61.6, 65.9, 68.9, 74.3, 113.2, 126.9, 127.9, 128.5, 130.2, 132.9,
134.1, 137.3, 142.6, 158.5, 172.4; MS m/z 459, 461 (M+, Br isotope
pattern, EI), 482, 484 (MNa+, Br isotope pattern, MALDI). Anal.
Calcd for C26H22BrNO2: C, 67.83; H, 4.82; N, 3.04. Found: C,
67.97; H, 5.07; N, 3.00.
Compound 2 has all its carbons functionalized with groups
in the appropriate stereochemical relationship for synthesis of
C-5 substituted carbocyclic ribofuranoside analogues. The bromo
group at the C-5 position can work as an excellent nucleofuge
for substitution with a number of nucleophilic substituents, thus
making this compound a versatile and key intermediate.
(1S,4S,5R,6S,7S)-N-(p-Anisyldiphenylmethyl)-2-azabicyclo-
[2.2.1]heptan-7-bromo-5,6-diol-3-one (8d). To a solution of N-(p-
anisyldiphenylmethyl)-2-azabicyclo[2.2.1]hept-7-bromo-5-en-3-
one (500 mg, 1.09 mmol) in acetone (15 mL) was added water (10
mL) followed by tert-butyl alcohol (5 mL) to give a clear solution.
N-Methylmorpholine N-oxide (495 mg, 3.6 mmol) was then added
with stirring followed by a solution of OsO4 (50 mg, 0.20 mmol)
in tert-butyl alcohol (2.5 mL), and the mixture was heated at reflux
for 24 h. Solvents were evaporated in vacuo, and the residue was
purified by flash column chromatography on silica gel using
hexanes-ethyl acetate as the eluent to give a white solid (480 mg,
90%): mp 194.1-194.3 °C; TLC Rf 0.09 (silica gel, hexanes-
ethyl acetate, 70:30), Rf 0.51 (silica gel, hexanes-ethyl acetate,
50:50); 1H NMR (CDCl3) δ 2.81 (d, J ) 7.5 Hz, 1H), 2.88 (d, J )
7.5 Hz, 1H), 3.13 (s, 1H), 3.80 (s, 3H), 4.22 (m, 2H), 4.37 (m,
1H), 4.53 (t, J ) 6.8 Hz, 1H), 6.84 (d, J ) 9 Hz, 2H), 7.20 (m,
12H); 13C NMR (CDCl3) δ 47.3, 55.2, 59.2, 67.7, 70.1, 73.4, 113.3,
127.4, 128.0, 128.9, 128.9, 130.6, 134.2, 142.3, 158.7, 170.0; MS
m/z 493, 495 (M+, Br isotope pattern, EI), 516, 518 (MNa+, Br
isotope pattern, MALDI). Anal. Calcd for C26H24BrNO4: C, 63.17;
H, 4.89; N, 2.83. Found: C, 63.15; H, 5.07; N, 2.67.
Experimental Section
(1S)-N-(p-Anisyldiphenylmethyl)-2-azabicyclo[2.2.1]hept-5-en-
3-one (4d). To a solution of the lactam (1S)-(+)-2-azabicyclo[2.2.1]-
hept-5en-3-one (10 g, 91.74 mmol) in CH2Cl2 (400 mL) were added
finely powdered sodium hydroxide (13 g) and potassium carbonate
(10 g) followed by benzyl tributylammonium bromide (1 g). The
mixture was stirred with a magnetic stirring bar and p-anisylchlo-
rodiphenylmethane (56 g, 183.48 mmol) was added dropwise as a
solution in methylene chloride (200 mL). The mixture was then
stirred at room temperature for 22 h. The mixture was filtered
through a short column of silica gel and the filtrate concentrated
and purified by flash column chromatography on silica gel using
hexanes-ethyl acetate as the eluent to give a white solid (22 g,
63%). An analytically pure sample was obtained by HPLC
purification on a silica gel column: mp 63.2-63.8 °C; TLC Rf
0.27 (silica gel, hexanes-ethyl acetate, 70:30), Rf 0.56 (silica gel,
1
hexanes-ethyl acetate, 50:50); H NMR (CDCl3) δ 2.04 (d, J )
7.6 Hz, 1H), 2.50 (d, J ) 7.6 Hz, 1H), 3.28 (s, 1H), 3.78 (s, 3H),
4.41 (s, 1H), 5.93 (dd, J ) 5 Hz, 2 Hz, 1H), 6.17 (dd, J ) 5 Hz,
3.5 Hz, 1H), 6.80 (d, J ) 9 Hz, 2H), 7.30 (m, 12H); 13C NMR
(CDCl3) δ 55.2, 55.6, 57.0, 64.0, 73.6, 112.9, 126.5, 126.5, 127.6,
128.0, 128.6, 128.7, 130.3, 134.6, 134.7, 139.0, 143.2, 158.2, 177.1;
MS m/z 381 (M+, EI), 404 (MNa+, MALDI). Anal. Calcd for
C26H23NO2: C, 81.86; H, 6.08; N, 3.67. Found: C, 81.73; H, 6.41;
N, 3.48.
(1S,6R,7S)-N-(p-Anisyldiphenylmethyl)-2-azabicyclo[2.2.1]-
heptan-6,7-dibromo-3-one (5d). To a solution of N-(p-anisyl-
diphenylmethyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (21 g, 55 mmol)
in carbon tetrachloride (300 mL) was added magnesium oxide (10
g) and the slurry was stirred well. A solution of bromine (8.80 g,
55 mmol) in carbon tetrachloride (200 mL), which had been stirred
with magnesium oxide and filtered, was added dropwise over a
period of 2 h, and the mixture was allowed to stir at room
(1S,4S,5R,6S,7S)-2-Azabicyclo[2.2.1]heptan-7-bromo-5,6-(di-
methylmethylene)dioxy-3-one (9). Trifluoroacetic acid (1 mL) was
added to a solution of the diol (8d) (250 mg, 0.5 mmol) in
methylene chloride (15 mL) and the mixture was stirred at room
temperature for 2 h. The solvent was evaporated in vacuo, acetone
was added, and the mixture was stirred for 30 min at room
temperature. The solvent was then evaporated and methanol (2 mL)
added to give white solids. The mixture was filtered, yielding a
pure product as white solid (65 mg, 49%). The filtrate was
evaporated and the residue purified by flash column chromatography
on silica gel using hexanes-ethyl acetate to give an additional
quantity of pure product (55 mg, 41.5%), resulting in isolation of
a total of 120 mg (90.5%): mp (dec) 170.2-170.5 °C; TLC Rf
0.21 (silica gel, hexanes-ethyl acetate, 50:50), Rf 0.40 (silica gel,
1
hexane-ethyl acetate, 30:70); H NMR (CDCl3) δ 1.38 (s, 3H),
1.67 (s, 3H), 3.19 (s, 1H), 4.15 (s, 1H), 4.39 (s, 1H), 4.79 (dd, J )
J. Org. Chem, Vol. 71, No. 20, 2006 7879

14.8 Hz, 3.8 Hz, 2H), 6.24 (s, 1H). 13C NMR (CDCl3) δ 23.7, 24.2,
44.8, 53.0, 59.7, 78.4, 82.5, 115.4, 173.3; MS m/z 246, 248 (M+ -
Me, Br isotope pattern, EI). Anal. Calcd for C9H12BrNO: C, 41.24;
H, 4.61; N, 5.34. Found: C, 41.08; H, 4.54; N, 5.22.
mmol) was added all at once. Stirring was continued for 1 h at
room temperature, at which point TLC indicated completion of the
reaction. The mixture was neutralized with a glacial acetic acid-
methanol mixture, the solvents were evaporated, the residue was
stirred with chloroform and filtered. The filtrate was purified by
flash column chromatography on silica gel using hexanes-ethyl
acetate as the eluent to give a white solid (700 mg, 77%): mp
116.6-117.1 °C; TLC Rf 0.11 (silica gel, hexanes-ethyl acetate,
70:30), Rf 0.44 (silica gel, hexanes-ethyl acetate, 50:50); 1H NMR
(CDCl3) δ 1.31 (s, 3H), 1.45 (s, 9H), 1.53 (s, 3H), 1.69 (br, 1H),
2.34 (m, 1H), 3.85 (m, 3H), 4.30 (m, 1H), 4.58 (m, 2H), 5.02 (s,
1H); 13C NMR (CDCl3) δ 25.1, 27.3, 28.3, 48,9, 54.3, 60.3, 66.1,
78.1, 80.2, 81.0, 113.3, 155.1; MS m/z 365, 367 (M+, Br isotope
pattern, EI), 388, 390 (MNa+, Br isotope pattern, MALDI). Anal.
Calcd for C14H24BrNO5: C, 45.91; H, 6.60; N, 3.82. Found: C,
45.88; H, 6.64; N, 3.78.
(1S,4S,5R,6S,7S)-N-tert-Butyloxycarbonyl-2-azabicyclo[2.2.1]-
heptan-7-bromo-5,6-(dimethylmethylene)dioxy-3-one (10). DMAP
(800 mg, 6.68 mmol) followed by di-tert-butyl dicarbonate (3.65
g, 16.70 mmol) was added to a solution of the acetonide bromo-
lactam (9) (1.75 g, 6.68 mmol) in methylene chloride (30 mL) and
the mixture was stirred at room temperature overnight. The solvent
was evaporated and the residue purified by flash column chroma-
tography on silica gel using hexanes-ethyl acetate (90:10) as the
eluent to give white crystalline solid (2.0 g, 82.7%): mp 163.1-
163.6 °C; TLC Rf 0.46 (silica gel, hexanes-ethyl acetate, 70:30);
1H NMR (CDCl3) δ 1.38 (s, 3H), 1.52 (s, 9H), 1.67 (s, 3H), 3.32
(s, 1H), 4.33 (t, J ) 1.3 Hz, 1H), 4.67 (d, J ) 5.7 Hz, 1H), 4.75
(s, 1H), 4.77 (d, J ) 5.7 Hz, 1H); 13C NMR (CDCl3) δ 23.7, 24.2,
27.9, 42.0, 55.2, 62.8, 78.2, 81.1, 84.6, 115.1, 147.6, 167.9; MS
m/z 362, 364 (MH+, Br isotope pattern, EI), 384, 386 (MNa+, Br
isotope pattern, MALDI). Anal. Calcd for C14H20BrNO5: C, 46.42;
H, 5.56; N, 3.87. Found: C, 46.37; H, 5.58; N, 3.83.
(1S,2S,3R,4R,5S)-1-(tert-Butyloxycarbonyl)amino-5-bromo-
2,3-(dimethylmethylene)-dioxy-4-hydroxymethylcyclopentane (2).
Methanol (20 mL) was added to N-tert-butyloxycarbonyl-2-
azabicyclo[2.2.1]hept-7-bromo-5,6-diol-3-one-5,6-acetonide (900
mg, 2.49 mmol) and the mixture was warmed at 35 °C on a water
bath for 5 min for complete dissolution. The solution was allowed
to cool to room temperature and sodium borohydride (188 mg, 4.98
Acknowledgment. This work was supported in part by the
Ohio Division, American Cancer Society.
Supporting Information Available: Experimental details in-
cludes the following: (1) experimental procedures for synthesis of
4a, bromination of 4a, synthesis of 4c, 5c, 6c, 7c, 8c, and (2)
crystallographic information and data files (CIF) for compound 10.
This material is available free of change via the Internet at
http://pubs.acs.org.
JO060920L
7880 J. Org. Chem., Vol. 71, No. 20, 2006