5-Carboxy-2-azabicyclo[2.1.1]hexanes as precursors of 5-halo, amino, phenyl, and 2-methoxycarbonylethyl methanopyrrolidines

Article abstract of DOI:10.1021/jo052506b

Novel 5-X-substituted-2-azabicyclo[2.1.1]hexanes (X = 5-syn-Cl, -Br, -I, -Ph, -NHCOOR (R = Me, Bn, t-Bu), -CH₂CH₂COOMe and X = 5-anti-Br, -I, -Ph) were synthesized from the X = 5-syn-carboxy derivative. New 5-anti-X-2-azabicyclo[2.1.

Full text of DOI:10.1021/jo052506b

5-Carboxy-2-azabicyclo[2.1.1]hexanes as Precursors of 5-Halo,
Amino, Phenyl, and 2-Methoxycarbonylethyl Methanopyrrolidines
Grant R. Krow,*,† Qiuli Huang,‡ Guoliang Lin,† Ryan A. Centafont,† Andrew M. Thomas,†
Deepa Gandla,† Charles DeBrosse,† and Patrick J. Carroll§
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122, Bionumerik
Pharmaceuticals, San Antonio, Texas 78229, and Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
grantkrow@aol.com
ReceiVed December 5, 2005
Novel 5-X-substituted-2-azabicyclo[2.1.1]hexanes (X ) 5-syn-Cl, -Br, -I, -Ph, -NHCOOR (R ) Me, Bn,
t-Bu), -CH2CH2COOMe and X ) 5-anti-Br, -I, -Ph) were synthesized from the X ) 5-syn-carboxy
derivative. New 5-anti-X-2-azabicyclo[2.1.1]hexanes, X ) NHCOOR (R ) Me, Bn), were prepared
stereoselectively from the X ) 5-anti-carboxy substrate.
Introduction
The rigid 2-azabicyclo[2.1.1]hexanes 2 can be viewed as
pyrrolidines in which conformation is constrained by a 2,4-
Pyrrolidines 1 with amino,1-6 aryl,7 alkyl,8,9 fluoro,10 or
thio6,9,11 substituents at the 3-position, â to the nitrogen atom,
are found in a number of biologically significant molecules.
(6) For incorporation of 4-aminoproline derivatives into macrocycles,
see: Arasappan, A.; Chen, K. X.; Njoroge, F. G.; Parekh, T. N.;
Girijavallabhan, V. J. Org. Chem. 2002, 67, 3923.
(7) For 3-arylpyrrolidines, see: (a) Sonesson, C.; Wikstrom, H.; Smith,
M. W.; Svennson, K.; Carlsson, A.; Waters, N. Bioorg. Med. Chem. Lett.
1997, 7, 241. (b) Ahn, K. H.; Lee, S. J.; Lee, C.-H.; Hong, C. Y.; Park, T.
K. Bioorg. Med. Chem. Lett. 1999, 9, 1379.
† Temple University.
‡ Bionumerik Pharmaceuticals.
§ University of Pennsylvania.
(1) For recent utility of 3-aminopyrrolidines, see: (a) Tsuzuki, Y.; Tomita,
K.; Shibamori, K.-i.; Sato, Y.; Kashimoto, S.; Chiba, K. J. Med. Chem.
2004, 47, 2097. (b) Kuramoto, Y.; Ohshita, Y.; Yoshida, J.; Yazaki, A.;
Shiro, M.; Koike, T. J. Med. Chem. 2003, 46, 1905. (c) For library
generation: Lavrador, K.; Murphy, B.; Saunders, J.; Struthers, S.; Wang,
X.; Williams, J. J. Med. Chem. 2004, 47, 6864. (d) Chen, C.; Yu, J.; Fleck,
B. A.; Hoare, S. R. J.; Saunders, J.; Foster, A. C. J. Med. Chem. 2004, 47,
4083. (e) Alexopoulos, K.; Fatseas, P.; Melissari, E.; Vlahakos, D.;
Roumelioti, P.; Mavromoustakos, T.; Mihailescu, S.; Paredes-Carbajal, M.
C.; Mascher, D.; Matsoukas, J. J. Med. Chem. 2004, 47, 3338.
(2) For 4-amino- and 4-aminomethylprolines, see: (a) Webb, T. R.;
Eigenbrot, C. J. Org. Chem. 1991, 56, 3009. (b) Tamaki, M.; Han, G.;
Hruby, V. J. J. Org. Chem. 2001, 66, 1038.
(8) For a review of nonproteinogenic amino acids from 4-hydroxyproline,
see: Remuzon, P. Tetrahedron 1996, 52, 13803.
(9) For recent synthetic efforts related to the synthesis of other 4-alkyl,
alkylester, or benzyl-substituted prolines and 2-hydroxymethylpyrrolidines,
see: (a) Del Valle, J. R.; Goodman, M. J. Org. Chem. 2003, 68, 3923. For
4-phenyl- or 4-cyclohexylprolines, see: (b) Tamaki, M.; Han, G.; Hruby,
V. J. J. Org. Chem. 2001, 66, 3593. (c) Krapcho, J.; Turk, C.; Cushman,
D. W.; Powell, J. R.; DeForrest, J. M.; Spitzmiller, E. R.; Karanewsky, D.
S.; Duggan, M.; Rovnyak, G.; Schwartz, J.; Natarajan, S.; Godfrey, J. D.;
Ryono, D. E.; Neubeck, R.; Atwal, K. S.; Petrillo, E. W., Jr. J. Med. Chem.
1988, 31, 1148.
(3) For peptide nucleic acids from 4-aminoprolines, see: (a) Lowe, G.;
Vilaivan, T. J. Chem. Soc., Perkin Trans. 1 1997, 547. (b) Lowe, G.;
Vilaivan, T. J. Chem. Soc., Perkin Trans. 1 1997, 555. (c) Westwood, N.
B.; Walker, R. T. Tetrahedron 1998, 54, 13391. (d) Lowe, G.; Vilaivan, T.
J. Chem. Soc., Perkin Trans. 1 1997, 539. (e) Jordan, S.; Schwemler, C.;
Kosch, W.; Kretschmer, A.; Schwenner, E.; Stropp, U.; Mielke, B. Bioorg.
Med. Chem. Lett. 1997, 7, 681. (f) Jordan, S.; Schwemler, C.; Kosch, W.;
Kretschmer, A.; Stropp, U.; Schwenner, E.; Mielke, B. Bioorg. Med. Chem.
Lett. 1997, 7, 687. (g) Puschl, A.; Tedeschi, T.; Nielsen, P. E. Org. Lett.
2000, 2, 4161.
(4) For aminonucleotides based on 4-hydroxyprolinol, see: (b) Peterson,
M. L.; Vince, R. J. Med. Chem. 1991, 34, 2787.
(5) For generation of polyamines based upon 4-aminoproline, see:
Nagamani, D.; Ganesh, K. N. Org. Lett. 2001, 3, 103.
(10) For fluoropyrrolidines, see: (a) Giardina, G.; Dondio, G.; Grugni,
M. Synlett 1995, 43, 55. (b) For leading references to 4-fluoroprolines and
5-fluoromethanoproline, see: Jenkins, C. L.; Lin, G.; Duo, J.; Rapolu, D.;
Guzei, I. A.; Raines, R. T.; Krow, G. R. J. Org. Chem. 2004, 69, 8565.
(11) For other references to 4-thioprolines, see: (a) Williams, J. M.;
Brands, K. M. J.; Skerlj, R. T.; Jobson, R. B.; Marchesini, G.; Conrad, K.
M.; Pipik, B.; Savary, K. A.; Tsay, F.-R.; Houghton, P. G.; Sidler, D. R.;
Dolling, U.-H.; DiMichele, L. M.; Novak, T. J. J. Org. Chem. 2005, 70,
7479. (b) Azami, H.; Barrett, D.; Tanaka, A.; Sasaki, H.; Matsuda, K.; Chiba,
T.; Matsumoto, Y.; Matsumoto, S.; Morinaga, C.; Ishiguro, K.; Tawara,
S.; Sakane, K.; Takasugi, H. Bioorg. Med. Chem. Lett. 1995, 5, 2199. (c)
Kemp. D. S.; Curran, T. P.; Davis, W. M.; Boyd, J. G.; Muendel, C. J.
Org. Chem. 1991, 56, 6672. For a 4-thiopyrrolidine, see: (d) Shibata, T.;
Iono, K.; Sugimura, Y. Heterocycles 1986, 24, 1331.
10.1021/jo052506b CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/09/2006
2090
J. Org. Chem. 2006, 71, 2090-2098

5-Carboxy-2-azabicyclo[2.1.1]hexanes
methylene bridge. As part of a strategy of incorporation of key
pharmacophoric units into inflexible structures,12-14 azabicycles
such as 2, which display functionality in defined spatial
orientations, are of interest. Such molecules may prove to be
valuable scaffolds for incorporation into proteins15 or for drug
discovery. However, there is a need for practical methods to
introduce a diverse array of substituents onto the 2-azabicyclo-
[2.1.1]hexanes. Our focus in this contribution is upon the C5
methylene bridge position and the substituent X.
(X/H ) difluoride).18 Aryl X ) syn-Ph has been introduced
via a rearrangement route.17e For alkyl groups there are
rearrangement (X ) syn- or anti-methyl),17e ring closure (X )
syn-CH2NH2, CH2OH),13a and photochemical cycloaddition
routes (X/H ) Me2 or X ) syn- or anti-oriented cyclohexane
rings fused from C5 to C4 or cyclohexanone rings fused from
C5 to C1).19 For 5-syn/anti-carbonyl substitution several pho-
tochemical syntheses are reported,20 but except for one case of
a 5-acetyl group,20a these examples are for 1,5-fused cyclohex-
anone ring systems. Two routes to 5-carboxy azabicycles have
been described. One somewhat lengthy route to a 5-syn acid
involves ring closure13a and subsequent modification of sub-
stituents. Recently, we described21 a shorter approach to the
preparation of 5-syn- and 5-anti-carboxy-2-azabicyclo[2.1.1]-
hexanes in multigram quantities from readily prepared and
separable 5-acetyl-2-azabicyclo[2.1.1]hexanes first described by
Winkler.20a
There is a paucity of examples that describe the synthesis of
N-protected C5-monosubstituted 2-azabicyclo[2.1.1]hexanes. The
reported examples with various N-alkoxycarbonyl groups are
5-anti-hydroxy 3a,17c,d 5-anti-acetyl 4c,20a,21 5-anti-carboxy 5c,21
5-anti-2-pyridylthioether 6c,21 5-syn-hydroxylmethyl 7b and
5-syn-aminomethyl 8b,13a 5-syn-acetyl20a,21 9c, 5-syn-carboxylic
acid13a,21 10c, and 5-syn-2-pyridylthioether 11c.21 In this paper
we describe replacements of 5-carboxy substituents of 5c or 9c
for the preparation of 5-substituted 2-azabicyclo[2.1.1]hexanes
with halo, amino, phenyl, and 2-carboxyethyl substituents X.
Since preparation of 5-acids with compatible substituents at other
ring positions is feasible, the functional group modifications
described for these acids should prove useful in the preparation
of more highly functionalized 5-substituted 2-azabicyclo[2.1.1]-
hexanes.22
Functional groups at C5 on 2-azabicyclo[2.1.1]hexanes 2 are
known.16 Heteroatoms at C5 have been introduced by rearrange-
ment routes (X ) halogen, hydroxyl),17 nucleophilic ring closure
of cyclobutanes (X ) SePh),13a or a thermal 2+2 cycloaddition
(12) For leading references with bridged pyrrolidines, see: (a) Bunch,
L.; Liljefors, T.; Greenwood, J. R.; Frydenvang, K.; Brauner-Osborne, H.;
Krogsgaard-Larsen, P.; Madsen U. J. Org. Chem. 2003, 68, 1489. (b) Hart,
B. P.; Rapoport, H. J. Org. Chem. 1999, 64, 2050. (c) Han, W.; Pelletier,
J. C.; Mersinger, L.; Ketner, C. A.; Hodge, C. N. Org. Lett. 1999, 1, 1875.
(13) For biologically interesting 2-azabicyclo[2.1.1]hexanes, see: (a)
Lescop, C.; Mevellec, L.; Huet, F. J. Org. Chem. 2001, 66, 4187. (b)
Piotroski, D. W. Synlett 1999, 1091. (c) Esslinger, C. S.; Koch, H. P.;
Kavanaugh, M. P.; Philips, D. P.; Chamberlin, A. R.; Thompson, C. M.;
Bridges, R. J. Bioorg. Med. Chem. Lett. 1998, 8, 3101. (d) Koch, H. P.;
Kavanaugh, M. P.; Esslinger, C. S.; Zerangue, N.; Humphrey, J. M.; Amara,
S. G.; Chamberlain, A. R.; Bridges, R. J. Mol. Pharmacol. 1999, 56, 1095.
(e) Mapelli, C.; van Halbeek, H.; Stammer, C. H. Biopolymers 1990, 29,
407. (f) Bell, E. A.; Qureshi, M. Y.; Pryce, R. J.; Janzen, D. H.; Lemke, P.;
Clardy, J. J. Am. Chem. Soc. 1980, 102, 1409. (g) Park, T. H.; Ha, Y. H.;
Jeong, D. Y. Patent Application WO 98-KR246 19989898; Chem. Abstr.
1999, 130, 182388. (h) Pirrung, M. C. Tetrahedron Lett. 1980, 21, 4577.
(i) Hughes, P.; Martin, M.; Clardy, J. Tetrahedron Lett. 1980, 21, 4579. (j)
Kite, G. C.; Ireland, H. Phytochemistry 2002, 59, 163. (k) Juvvadi, P.;
Dooley, D. J.; Humblet, C. C.; Lu, G. H.; Lunney, E. A.; Panek, R. L.;
Skeean, R.; Marshall, G. R. Int. J. Peptide Protein Res. 1992, 40, 163. (l)
Piela, L.; Nemethy, G.; Scheraga, H. A. J. Am. Chem. Soc. 1987, 109, 4477.
(m) Montelione, G. T.; Hughes, P.; Clardy, J.; Scheraga, H. A. J. Am. Chem.
Soc. 1986, 108, 6765. (n) Talluri, S.; Montelione, B. T.; van Duyne, G.;
Piola, L.; Clardy, J.; Scheraga, H. A. J. Am. Chem. Soc. 1987, 109, 4473.
(o) Gaoni, Y. Org. Prep. Proced. Int. 1995, 27, 185. (p) Gaoni, Y.;
Chapman, A. G.; Parvez, N.; Pook, P. C.-K.; Jane, D. E. J. Med. Chem.
1994, 37, 4288. (q) Rammelooo, T.; Stevens, C. V.; De Kimpe, N. J. Org.
Chem. 2002, 67, 6509. (r) Rammeloo, T.; Stevens, C. V.; De Kimpe, N. J.
Chem. Soc., Chem. Commun. 2002, 250. (s) Malpass, J. R.; Patal, A. B.;
Davies, J. W.; Fulford, S. Y. J. Org. Chem. 2003, 68, 9348.
Results and Discussion
Baeyer-Villiger Attempts with Ketone 9c. We attempted
to convert the 5-syn-ketone20a,21 9c to the 5-syn-acetate 12 under
Baeyer-Villiger conditions using MCPBA, buffered MCPBA,
(18) Amii, H.; Ichihara, Y.; Nakagawa, T.; Kobayashi, T.; Uneyama,
K. J. Chem. Soc., Chem. Commun. 2003, 2902.
(19) (a) Ikeda, M.; Uchno, T.; Takahashi, M.; Ishibashi, H.; Tamura,
Y.; Kido, M. Chem. Pharm. Bull. 1985, 33, 3279. (b) Ikeda, M.; Takahashi,
M.; Ohno, K.; Tamura, Y.; Kido, M. Chem. Pharm. Bull. 1982, 30, 2269.
(c) Toda, F.; Miyamoto, H.; Takeda, K.; Matsugawa, R.; Maruyama, N. J.
Org. Chem. 1993, 58, 6208.
(14) For 5(6)-substituted methanoprolines, see ref 10b and: (a) Krow,
G. R.; Lin, G.; Fang, Y. J. Org. Chem. 2005, 70, 590. (b) Krow, G. R.;
Lin, G.; Rapolu, D.; Fang, Y.; Lester, W. S.; Herzon, S. B.; Sonnet, P. E.
J. Org. Chem. 2003, 68, 5292.
(15) Kim, W.; George, A.; Evans, M.; Conticello, V. P. ChemBioChem.
2004, 5, 928.
(16) For a review of synthetic approaches to 2-azabicyclo[2.1.1]hexanes,
see: Krow, G. R.; Cannon, K. C. Heterocycles 2004, 62, 877.
(20) (a) Kwak, Y.-S.; Winkler, J. D. J. Am. Chem. Soc. 2001, 123, 7429.
(b) Schell, F. M.; Cook, P. M.; Hawkinson, S. W.; Cassady, R. E.; Thiessen,
W. E. J. Org. Chem. 1979, 44, 1380. (c) Tamura, Y.; Ishibashi, H.; Hirai,
M.; Kita, Y.; Ikeda, M. J. Org. Chem. 1975, 40, 2702. (d) Swindel, C. S.;
Patel, B. P.; deSolms, S. J.; Springer, J. P. J. Org. Chem. 1987, 52, 2346.
(e) Tamura, Y.; Kita, Y.; Ishibashi, H.; Ikeda, M. J. Chem. Soc., Chem.
Commun. 1971, 1167. (f) Tamura, Y.; Kita, Y.; Ishibashi, H.; Ikeda, M.
Tetrahedron Lett. 1972, 13, 1977.
(21) Krow, G. R.; Lin, G.; Herzon, S. B.; Thomas, A. M.; Moore, K. P.;
Huang, Q.; Carroll, P. J. J. Org. Chem. 2003, 68, 7562.
(22) For C3 substitution by R-functionalization reactions, see: Krow,
G. R.; Herzon, S. B.; Lin, G.; Qiu, F.; Sonnet, P. E. Org. Lett. 2002, 4,
3151.
(17) For 3-alkyl(aryl), 5(6)-heteroatom-substituted methanopyrrolidines,
see: (a) Krow, G. R.; Yuan, J.; Lin, G.; Sonnet, P. E. Org. Lett. 2002, 4,
1259. (b) Krow, G. R.; Lee, Y. B.; Lester, W. S.; Liu, N.; Yuan, J.; Duo,
J.; Herzon, S. B.; Nguyen, Y.; Zacharias, D. J. Org. Chem. 2001, 66, 1805.
(c) Krow, G. R.; Lester, W. S.; Liu, N.; Yuan, J.; Hiller, A.; Duo, J.; Herzon,
S. B.; Nguyen, Y.; Cannon, K. J. Org. Chem. 2001, 66, 1811. For other
5(6)-heteroatom-substituted methanopyrrolidines, see: (d) Krow, G. R.; Lee,
Y. B.; Lester, W. S.; Christian, H.; Shaw, D. A.; Yuan, J. J. Org. Chem.
1998, 63, 8558. (e) Krow, G. R.; Lin, G.; Moore, K. P.; Thomas, A. M. C.;
DeBrosse, C.; Ross, C. W., III; Ramjit, H. G. Org. Lett. 2004, 6, 1669. (f)
Krow, G. R.; Lin, G.; Yu, F.; Sonnet, P. E. Org. Lett. 2003, 5, 2739.
J. Org. Chem, Vol. 71, No. 5, 2006 2091

Krow et al.
SCHEME 1. Synthesis and Peracid Ring Cleavage of
Ketone 9c
coupling with H6s. The preference for the syn isomers can be
contrasted with the stereoselective formation of anti-bromo
isomers in a rearrangement route to 5,6-disubstituted 2-azabicyclo-
[2.1.1]hexanes.17b-d
It also was possible to trap the bridge radical derived from
Barton ester 16 with methyl acrylate to form a mixture of
separable diastereomeric 5-syn-alkylthioethers 23a/23b and a
mixture of four diastereomeric diester products in principle,
represented by 24, derived from the addition of two molecules
of methyl acrylate.24 Raney nickel reduction of the diastereo-
meric thioethers 23 afforded the 5-syn-2-methoxycarbonylethyl
azabicycle 25.24a As expected for the syn isomer, decoupling
experiments indicate the H6s proton at δ 1.28 does not couple
long range with H5a.
Reaction of the 5-syn-Acid 10c with Oxidants. Substitutions
of other groups for carboxy without the intermediacy of the
Barton ester 16 are shown in Table 2. The 5-acid 10c with lead
tetraacetate/LiCl in refluxing toluene affords only the 5-syn-
chloride 18 (entry 1).25 With mercuric oxide in the presence of
bromine,26 acid 10c affords a mixture of bromides in which the
syn isomer 19 was favored over the anti-bromide 20 if
irradiation was performed at ambient temperature (entry 2), but
the anti isomer 20 was formed if the irradiation was performed
with a refluxing solution of reactants (entry 3). The yields of
chloride and bromides in these reactions are lower than those
for preparations from the Barton ester 14 (Table 1).
Irradiation of acid 10c in the presence of phenyliodonium
diacetate/iodine affords more useful yields of iodides 21/22.27
This reaction was run numerous times with variation of
temperature (ambient temperature or reflux), equivalents of
reagents (1.1 to 2.2 equiv), time of reaction, and scale.
Representative examples from 15 separate trials are shown in
Table 2 (entries 4-10). We were unable to optimize the reaction
conditions, since seemingly identical experimental conditions
led to different outcomes (entries 4/6, 7/9, 8/10). It was shown
that a 28:72 mixture of iodides 21 and 22 remains unchanged
after 4 h in CCl4 at 60 °C, or for 2 weeks at ambient temperature
while exposed to visible light. Recovery of both iodides from
chromatography columns is >90%.
or buffered PAA (Scheme 1). Only ketolactam 15 was isolated.
Significant in the 13C NMR spectrum of ketone 15 are its three
methylene groups at δ 38.9, 47.4 and 51.6 and the single upfield
methine group at δ 30.2, not adjacent to carbonyl or nitrogen.
The formation of 15 is rationalized by acid-catalyzed fragmenta-
tion of the ketone to give iminium ion 13, addition of peracid
to give 14, and acid elimination.
Reactions of the Barton Esters of the 5-Acids.Despite their
sensitivity to acid, we were successful in oxidizing both the
anti-4c and syn-9c ketones to the corresponding carboxylic acids
5c/10c with basic sodium hypochlorite. The acid 10c was earlier
converted to its Barton ester 16 and this was reduced to the
parent azabicycle 17 by means of radical reducing agents.21
During the trapping of the bridge radical formed upon irradiation
of the Barton ester with tris(trimethylsilyl)silane a mixture of
aryl thioethers 6c (4%) and 11c (11%) was formed in minor
amounts (Table 1, entry 1).21 These products were also formed
as a 3:9 mixture (12%) if the Barton ester 16 was allowed to
sit at room temperature in toluene for 48 h. Irradiation with a
250-W tungsten lamp for 1 h or microwave irradiation did not
improve this process. In light of the ability of radicals formed
from the Barton ester to be trapped by heteroatoms, we decided
to first explore using the Barton ester 16 as a precursor of other
5-substituents.23 The results are shown in Table 1.
It has been found that irradiation of the Barton ester 16 in
halogenated solvents (entries 2 and 3), or mixed solvents (entries
4 and 5), affords azabicycles with halogen substituents.23 The
syn halides were formed exclusively (entries 2 and 4 for Cl
and Br) or preferentially over the anti isomers (entries 3 and 5
for Br and I). The stereochemistry of these products was readily
The most reliable route to obtain a mixture of syn and anti
iodides is to carry out the reaction with 1.1 equiv of reagents.
At ambient temperature upon irradiation for 2 h, two trials
(entries 4 and 5) gave mixtures containing 24-50% syn iodide
1
assigned by using H NMR couplings. The 5-syn isomers are
(24) (a) Garner, P.; Anderson, J. T.; Cox, P. B.; Klippenstein, S. J.; Leslie,
R.; Scardovi, N. J. Org. Chem. 2002, 67, 6195. (b) Barton, D. H. R.; Chern,
C. Y.; Jaszberenyi, J. C. Tetrahedron 1995, 51, 1867.
characterized by a singlet peak for H5a, adjacent to the
heteroatom substituent. In the 5-anti isomers the H5s hydrogen
appears as a doublet (J ) 8-9 Hz) by virtue of long-range
(25) Kochi, J. K. J. Org. Chem. 1965, 30, 3265.
(26) (a) Meyers, A. I.; Fleming, M. P. J. Org. Chem. 1979, 44, 3405.
(b) Meek, J. S.; Osuga, D. T. Organic Synthesis; Wiley: New York, 1973;
Collect. Vol. V, p 126.
(27) Concepcion, J. I.; Francisco, C. G.; Freire, R.; Hernandez, R.;
Salazar, J. A.; Suarez, E. J. Org. Chem. 1986, 51, 402.
(23) (a) Avenoza, A.; Busto, J. H.; Cativiela, C.; Peregrina, J. M.
Tetrahedron, 2002, 58, 1193. (b) Barton, D. H. R.; Crich, D.; Motherwell,
W. B. Tetrahedron 1985, 41, 3901.
2092 J. Org. Chem., Vol. 71, No. 5, 2006

5-Carboxy-2-azabicyclo[2.1.1]hexanes
TABLE 1. Functional Group Replacements with Use of the 5-syn-Barton Ester 16
products (yield, %)
syn
entry
1
conditions
lighta
reactant/solvent
X
anti
TTMSS/cyclohexaneb
S-2-pyridyl
11c (11)
6c (4)
and H
Cl
Br
17 (31)
2
3
4
5
6
lighta
lighta
lighta
lighta
lightc
CCl4
BrCCl3
BrCCl3/cyclohexane
CHI3/cyclohexane
CH2Cl2/methyl acrylate
18 (77)
19 (33)
19 (45)
21 (45)
23 (58)
24 (15)
20 (4)
22 (5)
Br
I
CH2Xd
CH2Ye
a 600-W tungsten lamp, AIBN, 30 min. b See ref 21. c 250-W tungsten lamp, reflux, 4 h. d Two diastereomers, X ) CH(S-2-pyridyl)COOMe. e Four
diastereomers,Y ) CH(COOMe)CH2CH(S-2-pyridyl)COOMe.
TABLE 2. Reactions of 5-syn-Acid 10c with Oxidizing Agents
products (yield, %)a
entry
conditions
85 °C, 6 h
reactants/solvent
X
syn
anti
1
2
3
4
5
6
7
8
9
Pb(OAc)4/LiCl/PhCH3
HgO/bromine/CCl4
Cl
Br
Br
I
18 (15)b
19 (16)
-
21 (50)
21 (24)
-
21 (23)
-
-
hν,c 25 °C, 1 h
hν,c 0.5 h, heat
hν,c 25 °C, 2 he
hν,c 25 °C, 1.5 he
hν,c 25 °C, 2 he,g
hν,c reflux,10 mine
hν,c reflux, 2 hi
hν,c reflux, 20 minj
hν,c reflux, 1.5 hk
reflux, 16h
20 (2)
d
HgO/bromine/CCl4
PhI(OAc)2/I2/CCl4
20 (11)
22 (23)
22 (17)
22 (26)
22 (44)
22 (33)
22 (26)
22 (32)
f
h
PhI(OAc)2/I2/CCl4
I
-
10
11
12
21 (27)
17 (59)l
26 (35)
Pb(OAc)4/pyridine/cyclohexane
Pb(OAc)4/pyridine/PhH
H
Ph
reflux, 3 h
27 (6)
a Isolated yields. b Corrected for 50% recovered acid. c 50-W tungsten lamp. d Bromine added at reflux temperature. e 1.1 equiv of reagents. f Reactions
were run on 0.5-4.5 mmol scale. g 85:15 syn/anti acid mixture. h Reactions were run on 0.5-7.4 mmol scale. i 1.4 equiv of reagents. j 85:15 syn/anti acid
mixture, 2 equiv of reagents. k 2.2 equiv of reagents. l Corrected for 33% recovery of starting acid.
SCHEME 2. Reactions of Acid 10c with LTA in
Nonhalogenated Solvents
21 and 17-23% anti iodide 22; two apparently identical trials
represented by entry 6 resulted in only anti iodide 22 (26%).
With heating during the irradiation for from 10 min to 2 h three
experiments (entries 7-10) gave mixtures ranging from 6% to
23% syn iodide 21 and 18-44% anti iodide 22; the highest
yield for these attempts is shown by entry 7. After seven trials
with 2.2 equiv of reagents and heating for 20 min to 2.5 h, for
which entries 8-10 are examples, only one trial, 27% syn iodide
21 and 32% anti iodide 22 (entry 10), gave the syn isomer.
The remaining trials gave only anti iodide 22 in 12-40% yields.
In a unsuccessful effort to prepare the 5-acetate 12 the 5-syn-
acid 10c was reacted with lead tetraacetate/pyridine in refluxing
cyclohexane (Scheme 2).28 Only the parent 2-azabicyclo[2.1.1]-
which is reported to facilitate cation formation.29 Instead the
radical 28 either abstracts a hydrogen atom in cyclohexane to
give parent 17 or in benzene solvent it adds to the aryl ring and
then loses a hydrogen atom to give phenyl isomers 26/27.
Arylation reactions have previously been observed for LTA
reactions of acids at tertiary bridgehead positions of structures
that have unstable bridgehead cations,28 but arylation at a
secondary position is a novel result.
Replacement Reactions of the 5-Iodide. We next attempted
to explore further synthetic utility of the iodides 21/22. Examples
of radical and ionic reactions to replace iodide are shown in
Scheme 3. The parent azabicycle 17 was obtained in 37% overall
yield from the 5-syn-acid 10c when a mixture of iodides was
reduced with tris(trimethylsilyl)silane/AIBN in refluxing THF
while irradiating with a 250-W tungsten lamp for 30 min. This
hexane 17 was obtained (entry 11). When the same reaction
was attempted in benzene as solvent, an 85:15 mixture largely
favoring the 5-syn-phenyl 26 over the 5-anti-phenyl isomer 27
was obtained (entry 12).28 The 5-syn isomer 26 could be
obtained pure, but the minor 5-anti isomer 27 retained a minor
amount of the 5-syn isomer even after extensive chromatogra-
phy. The 5-syn-phenyl isomer 26 was identified by a singlet at
δ 3.28 for H5a, while the 5-anti-phenyl isomer 27 was identified
by the doublet pattern for H5s (J ) 8.1 Hz) at δ 3.17.
As shown in Scheme 2, the products in entries 11 and 12
can be obtained from an initially formed radical 28. Because
of the ring strain in this system, it does not lose an electron to
afford a planar 5-cation, even in the presence of copper acetate,
(28) (a) Moriarty, R. M.; Khosrowshahi, J. S.; Miller, R. S.; Flippen-
Andersen, J.; Gilardi, R. J. Am. Chem. Soc. 1989, 111, 8943. (b) Davies,
D. I.; Waring, C. J. Chem. Soc., Chem. Commun. 1965, 263. (c) Sheldon,
R. A.; Kochi, J. K. Org. React. 1972, 19, 279.
(29) Ogibin, Y. N.; Katzin, M. I.; Nikishin, G. I. Synthesis 1974, 12,
889.
J. Org. Chem, Vol. 71, No. 5, 2006 2093

Krow et al.
SCHEME 3. Replacement Reactions with Iodides 21/22
SCHEME 4. Curtius Rearrangement of Acid 10c
method for the parent from the acid avoids formation of
the Barton ester 16 (Table 1, entry 1) and is comparable in yield
to the reaction of the acid 10c with lead tetraacetate (Table 2,
entry 11).
Initial attempts to prepare 5-propanoate ester 25 by irradiation
of the 5-anti-iodide 22 with a 250-W tungsten lamp in refluxing
CCl4 in the presence of methyl acrylate were unsuccessful and
lead to destruction of starting material. However, by adding
excess methyl acrylate and the iodide in 1:2 ethanol/water
solution to a suspension of zinc powder and copper(I) iodide
in water, and then sonicating with an ultrasonic cleaning bath
for 1.25 h, the ester 25 was obtained (35%).30
The 5-anti-iodide 22 fails to react with silver fluoride in
nitromethane after 24 h at 60 °C; however, after 4 h at 80 °C
the 5-anti-fluoride 29 is obtained in 19% yield.17f The anti
stereochemistry is assigned by the dd pattern for H5 (J ) 62,
7.9 Hz); only the 5-syn proton shows long-range coupling with
yield. The same reactions with the 5-anti-acid 5c afforded the
5-anti-methoxycarbonylamine 39a (75%) and 5-anti-benzy-
loxycarbonylamine 39b (80%). These differentially protected
1,2-amines should be of interest for preparation of quinolone
antibiotics.13g
H6syn. The stereochemical retention in this nucleophilic substitu-
tion reaction is consistent with neighboring group participation
by the nitrogen bridge.10b
Nonradical Reactions of the 5-Acids 5c/10c: The Curtius
Rearrangement. The Curtius rearrangement is a valuable
method for replacing a carboxylic acid with an amino group,31
but could such a rearrangement succeed with azabicyclic acid
10c? As shown in Scheme 4, when anti acid 10c was reacted
with diphenylphosphoryl azide (DPPA) and triethylamine in
refluxing tert-butyl alcohol followed by addition of water, only
a small amount (8%) of the desired BOC-protected carbamate
33a was obtained. The other products were the acyl azide 34
(30%), an inseparable mixture of diastereomeric ureas 36/37
(26%), and the ester 38 (2%). The stereochemistry of these
compounds could be assigned as 5-syn on the basis of the
absence of couplings between H5anti and H6syn. The acyl azide
34 was prepared independently in 37% yield by stirring a neat
mixture of acid 10c, DPPA, and triethylamine at room temper-
ature under argon for 3 d; its structure was confirmed by X-ray
structural analysis.
Conclusions. In summary, we have described totally stereo-
selective functional group replacement strategies using readily
available 5-carboxy-2-azabicyclo[2.1.1]hexanes 5c/10c to afford
new 5-syn-chloro, and 5-syn-(2-carboxyethyl) derivatives and
partially stereoselective syntheses of syn/anti mixtures of mainly
5-syn-bromo and 5-syn-phenyl isomers. Conditions favoring
either 5-syn- or 5-anti-iodides have been noted. Although there
are reproducibility issues for isomer ratios, both of these
separable iodides have utility as synthetic intermediates. Con-
version of 5-syn- and 5-anti-carboxylic acids under Curtius
rearrangement conditions is stereospecific with retention and
affords novel differentially protected conformationally con-
strained diamines. A simplified route to the parent azabicycle
involves decarboxylation of the 5-acid with lead tetraacetate in
cyclohexane.
To obtain desired protected 5-amines the 5-syn-acid 10c was
refluxed in carbon tetrachloride with DPPA and triethylamine
for 1.5 h and different alcohols were added. Addition of
methanol after 12 h afforded the desired methoxycarbonylamine
33b in 65% yield. When benzyl alcohol was added in place of
methanol, the benzyloxycarbonylamine 33c was obtained in 82%
Experimental Section
(30) Sarandeses, L. A.; Mourino, A.; Luche, J. L. J. Chem. Soc., Chem.
Commun. 1992, 798.
(31) (a) Ninomiya, K.; Shiori, T.; Yamada, S. Tetrahedron 1974, 30,
2151. (b) Burgess, K.; Li, S.; Rebenspies, J. Tetrahedron Lett. 1997, 38,
1681.
Preparation of N-tert-Butoxycarbonyl-4-(2-oxopropyl)pyrro-
lidin-2-one (15). A solution of 5-syn-acetyl 9c (226 mg, 1.0 mmol),
MCPBA (77% purity, 300 mg, 1.34 mmol), and p-toluenesulfonic
acid monohydrate (56 mg, 0.29 mmol) in CH2Cl2 (20 mL) was
2094 J. Org. Chem., Vol. 71, No. 5, 2006

5-Carboxy-2-azabicyclo[2.1.1]hexanes
stirred in an ice bath for 4 h. Saturated sodium sulfite solution was
added to scavenge the unreacted MCPBA. The CH2Cl2 layer was
separated and washed with saturated NaHCO3 solution, dried with
Na2SO4, and concentrated. The crude product was purified through
a short flash column (cyclohexanes-EtOAc 2:1) to give 140 mg
(58%) of pyrrolidinone 15 at Rf 0.38 (cyclohexane/EtOAc 1:2); 1H
NMR (CDCl3, 300 MHz) δ 1.49 (s, 9H, tert-butyl), 2.14 (s, 3H,
COCH3), 2.16 (m, 1H, H3), 2.65 (m, 4H, H3, H4, 5-CH2Ac), 3.27
(m, 1H, H5), 3.95 (m, 1H, H5); 13C NMR (CDCl3, 75 MHz) δ 25.9,
28.0, 30.2, 38.9, 47.4, 51.6, 83.0, 149.9, 173.2, 206.3; HRMS m/z
264.1209, calcd for C12H19NO4Na (M + Na) 264.1212. Buffered
peracids: (a) Ketone 9c (115 mg, 0.5 mmol), MCPBA (133 mg,
0.77 mmol), and NaHCO3 (75 mg, 0.89 mmol) in CH2Cl2 (10 mL)
after 72 h at 25 °C afforded after workup 54 mg (44%) of
pyrrolidinone 15. (b) Ketone 9c (225 mg, 1.0 mmol) and peracetic
acid (25%, 1.2 mL) in acetic acid (2.1 mL) containing sodium
acetate (120 mg) after 18 h at 25 °C was treated with 10% sodium
sulfite until a negative test resulted for peracid with starch-KI paper.
Extraction with CH2Cl2 (4 × 10 mL), washing of the extracts with
water (6 mL) and brine (6 mL), drying over MgSO4 and chroma-
tography afforded 164 mg (68%) of pyrrolidinone 15.
Preparations of N-tert-Butoxycarbonyl-5-syn-iodo-2-azabicyclo-
[2.1.1]hexane (21) and N-tert-Butoxycarbonyl-5-anti-iodo-2-
azabicyclo[2.1.1]hexane (22) by the Barton Protocol. To a 25
mL reaction flask equipped with a cold water condenser was added
Barton ester 16 (109 mg, 0.32 mmol), AIBN (18 mg), iodoform
(374 mg, 0.95 mmol), and cyclohexane (10 mL). Reaction according
to the general procedure after chromatography with a short flash
column in darkness, eluting with cyclohexane/EtOAc gradiently,
gave 45 mg of 5-syn-iodide 21 (45% yield) and 5 mg of 5-anti-
iodide 22 (5% yield). 5-syn-Iodide 21: Rf 0.46 (cyclohexane/EtOAc
5:1), mp 44 °C (cyclohexane/EtOAc); 1H NMR (CDCl3, 300 MHz)
δ 1.47 and 1.51 (m, 9H), 2.04 (m, 2H, H6), 2.94 (m, 1H, H4), 3.38
(m, 1H, H3), 3.43 and 3.50 (d and d, J ) 9.3 Hz, 1H, H3), 4.21 (s,
1H, H5), 4.38 and 4.50 (d and d, J ) 6.9 Hz, 1H, H1); 13C NMR
(CDCl3, 75 MHz) δ 27.7, 28.5, 36.0 and 36.5, 43.9, 48.3 and 49.0,
64.3 and 65.1, 79.6 and 80.0, 156.1; HRMS m/z 332.0117, calcd
for C10H16INO2Na (M + Na) 332.0123. 5-anti-Iodide 22: Rf 0.71
(cyclohexane/EtOAc 5:1), mp 62 °C (cyclohexane/EtOAc); 1H
NMR (CDCl3, 300 MHz) δ 1.47 (s, 9H), 1.63 (t, J ) 9.0 Hz, 1H,
H6s), 2.90 (dd, J ) 6.9, 3.0 Hz, 1H, H4), 3.00 (m, 1H, H6a), 3.37
(d, J ) 8.7 Hz, 1H, H3), 3.47 (d, J ) 8.7 Hz, 1H, H3), 3.65 (d, J
) 9.0 Hz, 1H, H5), 4.34 (br, 1H, H1); 13C NMR (CDCl3, 75 MHz)
δ 28.5, 29.5, 40.3, 46.5, 48.4, 65.6, 80.1, 155.2; HRMS m/z
332.0126, calcd for C10H16INO2Na (M + Na) 332.0123. Chroma-
tography resulted in isolation of 93% of syn-iodide 21 and 98%
recovery of anti-iodide 22 based upon NMR analysis of a crude
reaction mixture.
Preparations of 5-syn-[2-Methoxycarbonyl-2-(pyridin-2-yl-
sulfanyl)ethyl]-2-azabicyclo[2.1.1]hexane-2-carboxylic Acid tert-
Butyl Ester Diastereomers (23a and 23b) and 2-(tert-Butoxy-
carbonyl-2-azabicyclo[2.1.1]hex-5-syn-ylmethyl)-4-(pyridin-2-
sulfanyl)pentanedioic Acid Dimethyl Ester (24). Barton ester 16
in CH2Cl2 solution was prepared in situ from 5-syn-acid 10c (114
mg, 0.50 mmol) following the general preparation procedure.
Without filtration or concentration, methyl acrylate (0.25 mL, 2.8
mmol) and AIBN (10 mg) were added. The reaction mixture was
irradiated with a 250 W tungsten lamp while being refluxed for 4
h. The solvent was removed in vacuo. The crude products were
purified through a short flash column, eluting with cyclohexane/
EtOAc 10:1, then 5:1, to give 110 mg of a mixture of diastereomers
23a and 23b (58% yield) and 35 mg of diaddition product 24 (15%
yield). The mixture of 23a and 23b could be separated by
semipreparative HPLC, eluting with 50% acetonitrile aqueous
solution to give equal amounts of 23a and 23b with the retention
time of 21.5 and 23.5 min, respectively. The diastereomers have
very similar NMR spectra. The configuration of each diastereomer
was not determined. Isomer 23a: Rf 0.53 (cyclohexane/EtOAc 1:1);
1H NMR (CDCl3, 300 MHz) δ 1.28 (d, J ) 6.3 Hz, 1H), 1.45 (s,
9H), 1.65 (m, 1H), 1.75 (m, 2H), 2.14 (m, 1H), 2.65 (m, 1H), 3.19
(d, J ) 10.8 Hz, 2H), 3.72 (s, 3H), 4.21 and 4.28 (d and d, J ) 6.6
Hz, 1H), 4.51 (t, J ) 7.2 Hz, 1H), 6.99 (ddd, J ) 7.8, 4.8, 0.9 Hz,
1H), 7.17 (d, J ) 7.8 Hz, 1H), 7.48 (td, J ) 7.8, 1.8 Hz, 1H), 8.39
(m, 1H); 13C NMR (CDCl3, 75 MHz) δ 27.7 and 27.9, 28.5, 38.0
and 38.1, 40.2, 44.9, 45.3 and 46.1, 46.2 and 46.6, 52.6, 61.6 and
62.7, 79.2 and 79.3, 120.0, 122.3, 136.2, 149.4, 156.2 and 156.5,
157.0, 172.8; HRMS m/z 401.1531, calcd for C19H26N2O4SNa (M
+ Na) 401.1511. 23b: Rf 0.53 (cyclohexane/EtOAc 1:1); 1H NMR
(CDCl3, 300 MHz) δ 1.28 (d, J ) 7.5 Hz, 1H), 1.46 (s, 9H), 1.64
(m, 2H), 1.80 (m, 1H), 2.16 (m, 1H), 2.71 (m, 1H), 3.26 (m, 2H),
3.72 (s, 3H), 4.17 and 4.26 (d and d, J ) 7.2 Hz, 1H), 4.53 (m,
1H), 7.01 (m, 1H), 7.18 (d, J ) 8.1 Hz, 1H), 7.50 (td, J ) 7.8, 1.8
Hz, 1H), 8.40 (d, J ) 4.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
27.9 and 28.1, 28.5, 38.0 and 38.1, 40.1, 44.7, 45.4 and 46.2, 46.2
and 46.4, 52.6, 61.5 and 62.5, 79.2 and 79.3, 120.0, 122.3, 136.3,
149.4, 156.3 and 156.5, 156.9, 172.7; HRMS m/z 401.1511, calcd
for C19H26N2O4SNa (M + Na) 401.1511. The diester 24 of
undetermined stereochemistry: Rf 0.43 (cyclohexane/EtOAc 1:1);
1H NMR (CDCl3, 300 MHz) δ 1.25 (m, 1H), 1.45 (s, 9H), 1.32
(m, 1H), 1.60 (m, 1H), 1.92 (m, 2H), 2.16 (m, 1H), 2.36-2.65 (m,
Preparation of N-tert-Butoxycarbonyl-5-syn-chloro-2-azabi-
cyclo[2.1.1]hexane (18) from Barton Ester 16:21 General Pro-
cedure. To a 50 mL flask equipped with cold water condenser was
added Barton ester 16 (91 mg crude, 0.27 mmol), AIBN (5 mg),
and carbon tetrachloride (2 mL). The reaction solution was irradiated
with a 600 W tungsten lamp and refluxed for 30 min. The solvent
was removed in vacuo. The residue was extracted with diethyl ether.
The ether solution was concentrated and the crude product was
purified by a short flash column, eluting with cyclohexanes-EtOAc
30:1 and then CH2Cl2-CH3OH 10:1 to give 41 mg of 18 as a white
solid, mp 43 °C (cyclohexane/EtOAc), and 6 mg of 5-syn-acid 10c.
The corrected yield from 10c to 18 was 77%. Chloride 18: Rf 0.32
1
(cyclohexane/EtOAc 10:1); H NMR (CDCl3, 300 MHz) δ 1.45
and 1.47 (s and s, 9H), 1.63 (m, 2H, H6), 2.87 (m, 1H, H4), 3.24
(d, J ) 9.0 Hz, 1H, H3), 3.43 and 3.50 (d and d, J ) 9.0 Hz, 1H,
H3), 3.99 (s, 1H, H5), 4.32 and 4.43 (d and d, J ) 6.3 Hz, 1H, H1);
13C NMR (CDCl3, 75 MHz) δ 28.5, 33.0 and 33.4, 40.0, 45.5 and
46.2, 57.1 and 57.3, 63.7 and 64.7, 79.7 and 79.9, 156.7 and 156.9;
HRMS m/z 240.0760, calcd for C10H16ClNO2Na (M + Na)
240.0767.
Preparations of N-tert-Butoxycarbonyl-5-syn-bromo-2-aza-
bicyclo[2.1.1]hexane (19) and N-tert-Butyoxycarbonyl-5-anti-
bromo-2-azabicyclo[2.1.1]hexane (20) from Barton Ester 16. To
a 25 mL reaction flask equipped with a cold water condenser was
added Barton ester 16 (91 mg, 0.27 mmol), AIBN (10 mg), and
bromotrichloromethane (2 mL). Reaction according to the general
procedure gave after chromatography (cyclohexane/EtOAc 40:1)
23 mg of bromide 19 (33% yield) and 3 mg of bromide 20 (4%
yield). 5-syn-Bromide 19: Rf 0.46 (cyclohexane/EtOAc 5:1), mp
1
56 °C (cyclohexane/EtOAc); H NMR (CDCl3, 300 MHz) δ 1.47
and 1.48 (s and s, 9H), 1.76-1.88 (m, 2H, H6), 2.92 (m, 1H, H4),
3.31 (dd, J ) 9.0, 3.6 Hz, 1H, H3), 3.46 and 3.53 (d and d, J ) 9.0
Hz, 1H, H3), 4.13 (s, 1H, H5), 4.36 and 4.47 (d and d, J ) 6.6 Hz,
1H, H1); 13C NMR (CDCl3, 75 MHz) δ 28.5, 34.3 and 34.8, 40.0,
46.5 and 47.2, 59.1 and 59.3, 63.8 and 64.7, 79.6 and 79.9, 156.6;
HRMS m/z 284.0246, calcd for C10H16NO2Na (M + Na) 284.0262.
1
5-anti-Bromide 20: Rf 0.74 (cyclohexane/EtOAc 10:1); H NMR
(CDCl3, 300 MHz) δ 1.48 (s, 9H), 1.64 (t, J ) 8.4 Hz, 1H, H6s),
2.90 (dd, J ) 7.2, 3.0 Hz, 1H, H4), 3.00 (m, 1H, H6a), 3.43 (s, 2H,
H3), 3.82 (d, J ) 8.4 Hz, 1H, H5), 4.33 (m, 1H, H1); 13C NMR
(CDCl3, 75 MHz) δ 28.6, 38.9, 46.1, 49.0, 55.3, 65.2, 80.2, 155.4;
HRMS m/z 284.0268, calcd for C10H16NO2Na (M + Na) 284.0262.
Preparation of 5-syn-Bromide 19 from Barton Ester 16. To
a 25 mL reaction flask equipped with a cold water condenser was
added Barton ester 16 (130 mg, 0.39 mmol), AIBN (10 mg),
bromotrichloromethane (1 mL), and cyclohexane (2 mL). Reaction
according to the general procedure after chromatography (cyclo-
hexane/EtOAc 50:1) gave 46 mg of syn-bromide 19 (45% yield).
J. Org. Chem, Vol. 71, No. 5, 2006 2095

Krow et al.
3H), 3.15 (m, 2H), 3.64 and 3.69 (s and s, 3H), 3.71 (s, 3H), 4.14
(m, 1H), 4.61 (m, 1H), 6.99 (m, 1H), 7.16 (d, J ) 7.8 Hz, 1H),
7.48 (td, J ) 7.8, 1.8 Hz, 1H), 8.37 (m, 1H); 13C NMR (CDCl3, 75
MHz) δ 28.0 and 28.2, 28.5, 33.9 (multiple peaks), 37.9 and 38.1,
40.0 and 40.1, 41.1 (multiple peaks), 44.0 and 44.4, 45.3 and 46.1,
46.4 and 46.8, 51.8, 52.6, 61.4 and 62.5, 79.1 and 79.3, 120.1, 122.3,
136.3, 149.3 and 149.4, 156.5 and 156.6, 172.4 and 172.6, 175.2;
HRMS m/z 487.1867, calcd for C23H32N2O6SNa (M + Na)
487.1879.
Direct Preparations of 5-syn-Iodide 21 and 5-anti-Iodide 22
from 5-syn-Acid 10c (Table 2, entry 4). In a three-necked jacketed
reaction flask circulated with running water, the reaction mixture
of 5-syn-acid 10c (121 mg, 0.53 mmol), iodobenzene diacetate
(IBDA, 189 mg, 0.59 mmol), and iodine (148 mg, 0.59 mmol) in
carbon tetrachloride (20 mL) was irradiated with a 250 W tungsten
lamp at ambient temperature under argon for 2 h. The reaction
solution was concentrated in vacuo and the crude products were
purified on a short flash column in darkness, eluting with cyclo-
hexane and then cyclohexane/EtOAc 30:1 to give 83 mg of iodide
21 (50% yield) and 38 mg of iodide 22 (23% yield). For other
attempts see the Supporting Information.
Preparation of Parent N-tert-Butoxycarbonyl-2-azabicyclo-
[2.1.1]hexane (17) Directly from 5-syn-Acid 10c. The reaction
mixture of acid 10c (0.356 g, 1.57 mmol), lead tetraacetate (1.17
g, 2.64 mmol), and pyridine (0.278 g, 3.52 mmol) in cyclohexane
(15 mL) was refluxed under argon for 16 h. The solid in the reaction
mixture was removed by filtration. The filtrate was concentrated
and purified by a short silica gel column, eluting with cyclohexane/
EtOAc 10:1, then 1:1, to give 78 mg of recovered 10c and 118 mg
of parent 17 (51% yield corrected for recovered acid).21
Preparation of 5-syn-(2-Methoxycarbonyl)ethyl-2-azabicyclo-
[2.1.1]hexane Carboxylic Acid tert-Butyl Ester (25). Raney nickel
was prepared according to Garner’s procedure.24a Nickel-aluminum
alloy (50/50 by wt %, 1.0 g) in three portions was added to an
aqueous NaOH solution (6.0 N, 10 mL) over 30 min with vigorous
stirring at 0 °C under argon. The ice bath was removed and the
reaction mixture was stirred at room temperature for 3 h. The basic
supernatant was decanted. The black solid was washed with water
(4 × 50 mL) and MeOH (3 × 20 mL). The resulting Raney nickel
was suspended in MeOH (30 mL) under argon. The mixture of
thioethers 23a and 23b (43 mg, 0.11 mmol) was added. The reaction
mixture was stirred under argon at room temperature overnight.
TLC indicated the complete consumption of the starting material.
The solid in the reaction mixture was removed by filtration. The
filtrate was concentrated and purified through a short flash column,
eluting with cyclohexane/EtOAc 10:1 to give 25 mg of ester 25
(82% yield): Rf 0.60 (cyclohexane/EtOAc 2:1); 1H NMR (CDCl3,
300 MHz) δ 1.29 (d, J ) 7.2 Hz, 1H, H6s, no long-range coupling
with H5), 1.38 (m, 2H), 1.46 (s, 9H), 1.64 (m, 1H, H6a), 1.94 (m,
1H), 2.21 (m, 2H), 2.62 (m, 1H), 3.19 (s, 2H), 3.66 (s, 3H), 4.20
(d, J ) 6.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 20.8, 28.5,
31.7, 37.8, 39.7, 45.6, 48.1, 50.6, 61.4, 79.2, 156.5, 173.7; HRMS
m/z 292.1519, calcd for C14H23NO4Na (M + Na) 292.1525.
One-Step Preparation of 5-syn-Chloride 18 from 5-syn-Acid
10c. The reaction mixture of 5-syn-acid 10c (60 mg, 0.26 mmol),
lead tetraacetate (300 mg, 0.68 mmol), and lithium chloride (80
mg, 1.67 mmol) was dried under high vacuum overnight. Anhydrous
toluene (10 mL) was added and the reaction mixture was stirred at
85 °C under argon for 6 h. The solid was removed by filtration.
The filtrate was concentrated and purified by a short flash column,
eluting with cyclohexanes-EtOAc 30:1 and then CH2Cl2-CH3-
OH 10:1 to give 5 mg of chloride 18 and 30 mg of 5-syn-acid 10c
(corrected yield 17%).
Preparations of N-tert-Butoxycarbonyl-5-syn-phenyl-2-aza-
bicyclo[2.1.1]hexane (26) and N-tert-butoxycarbonyl-5-anti-
phenyl-2-azabicyclo[2.1.1]hexane (27). The 5-syn acid 10c (81
mg, 0.36 mmol) in benzene (3 mL) was added to an oven-dried
flask purged with argon. Lead tetraacetate (208 mg, 0.47 mmol)
was added in one portion followed by the dropwise addition of
pyridine (43 mg, 0.57 mmol, 43 µL). The yellow/orange reaction
was then heated to 80 °C for 3 h. The reaction was then cooled to
room temperature and the crude oil was filtered through Celite,
which was washed with ethyl acetate (25 mL). The combined
solutions were washed with saturated sodium bicarbonate (3 × 10
mL). The combined organic layers were washed with brine, dried
over Na2SO4, and filtered, and solvent was removed in vacuo. The
residue was chromatographed on silica gel, eluting with 30%
EtOAc/hexanes to afford 38 mg (41% yield) of an 85:15 mixture
of syn and anti phenyl isomers 26/27 by comparative NMR
integrations of H6 for each isomer. Separation of isomers: See
the Supporting Information. When the mixture was analyzed by
1H NMR, the ratio was 87:13 from the integrations of the H6a
protons, or 89:11 from the integrations of the H3 protons. The 5-syn
1
isomer 26: Rf 0.60 (cyclohexane/EtOAc 2:1); H NMR (CDCl3,
300 MHz) δ 1.30 and 1.47 (s and s, 9H), 1.50 (m, 1H, H6), 1.89
(m, 1H, H6), 2.87 and 2.95 (d and d, J ) 9.0 Hz, 1H, H3), 3.10 (m,
1H, H4), 3.14 and 3.19 (d and d, J ) 9.0 Hz, 1H, H3), 3.28 (br,
1H, H5), 4.66 and 4.77 (d and d, J ) 6.9 Hz, 1H, H1), 7.05-7.29
(m, 5H); 13C NMR (CDCl3, 75 MHz) δ 28.5 and 28.7, 37.1 and
37.5, 41.0 and 41.4, 45.2 and 46.2, 52.1, 60.8 and 61.9, 79.0 and
79.2, 116.3 and 116.5, 127.2 and 127.4, 128.4 and 128.5, 138.1,
155.5 and 155.9; HRMS m/z 282.1464, calcd for C16H21NO2Na
(M + Na) 282.1470. The 5-anti isomer 27: Rf 0.60 (cyclohexane/
EtOAc 2:1); 1H NMR (CDCl3, 300 MHz) δ 1.52 (s, 9H), 1.58 (m,
1H, H6s), 2.27 (m, 1H, H6a), 3.09 (dd, J ) 7.2, 3.0 Hz, 1H, H4),
3.17 (d, J ) 8.1 Hz, 1H, H5), 3.52 (m, 2H, 2H3), 4.54 (br, 1H, H1),
7.25-7.38 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 28.7, 38.5, 42.0,
50.7, 57.3, 62.9 and 64.0, 79.5, 116.5, 128.2, 128.6, 138.5, 155.9;
HRMS m/z 282.1473 calcd for C16H21NO2Na (M + Na) 282.1470.
Preparation of Parent 17 from 5-Iodides 21 and 22. The
reaction mixture of 5-syn-acid 10c (0.490 g, 2.16 mmol), IBDA
(1.40 g, 4.3 mmol), and iodine (1.09 g, 4.3 mmol) in CCl4 (70
mL) was irradiated and refluxed under argon for 30 min. The
solvent was removed in vacuo. The crude products were passed
through a short flash column, rinsed with cyclohexane to removed
excessive iodine and reaction byproducts, then eluted with cyclo-
hexane/EtOAc 5:1 solution to give 515 mg of a mixture of iodides
21 and 22. To this mixture of iodides there was added AIBN (89
mg) and TTMSS (2.0 mL, 6.5 mmol) in THF (15 mL). The reaction
mixture was irradiated with a 250 W tungsten lamp while being
One-Step Preparation of 5-syn-Bromide 19 and 5-anti-
Bromide 20 from 5-syn-Acid 10c (Table 2, entry 2). In a three-
neck jacketed reaction flask circulated with running water, the
reaction mixture of 5-syn-acid 10c (116 mg, 0.51 mmol), HgO (171
mg, 0.79 mmol), and bromine (0.045 mL, 0.87 mmol) in CCl4 (20
mL) was irradiated at ambient temperature for 1 h. After the solid
had precipitated and settled in the bottom of the reaction flask, the
supernatant was decanted to another flask, concentrated, and purified
by a short flash column, eluting with cyclohexanes-EtOAc 30:1
to give 21 mg of 19 (16% yield), 2.0 mg of 20 (1.5% yield), and
1.0 mg of unreacted acid 10c (Table 2, entry 3). The reaction
mixture of 5-syn-acid 10c (116 mg, 0.51 mmol) and mercury oxide
(171 mg, 0.79 mmol) in carbon tetrachloride (10 mL) was irradiated
with a 250-W tungsten lamp. Bromine (0.045 mL, 0.87 mmol) was
added by syringe once the reaction mixture started to reflux. The
color of the reaction mixture changed from brown to colorless
immediately. The mixture was irradiated and refluxed for an
additional 15 min. The insoluble solid was removed by filtration.
The filtrate was concentrated and purified by a short flash column,
eluting with cyclohexanes-EtOAc 30:1 to give 15 mg of 5-anti-
bromide 20 (11% yield). No 5-syn-bromide 19 or starting 5-syn-
acid 10c were isolated. Other experiments performed by mixing
all reactants before irradiating and refluxing for 30 min, or by
irradiating and refluxing the mixture of 10c and HgO in CCl4 for
20 min before adding bromine and then irradiating for 30 min, led
to the total decomposition of starting material.
2096 J. Org. Chem., Vol. 71, No. 5, 2006

5-Carboxy-2-azabicyclo[2.1.1]hexanes
refluxed for 4 h under argon. The reaction solution was concentrated
and purified by a silica gel short flash column, eluting with
cyclohexane/EtOAc 30:1 to give 145 mg of parent compound 17
(37% overall yield).
33.0, 41.8, 45.3, 52.7, 62.4, 80.3, 156.0, 156.7; HRMS m/z
290.1225, calcd for C11H17N5O3Na (M + Na) 290.1229; see also,
X-ray data. The mixture of ureas 36/37: Rf 0.25 (CH2Cl2/EtOAc
5:1), mp 214 °C (EtOAc); 1H NMR (CDCl3, 300 MHz) δ 1.12 (d,
J ) 8.1 Hz, 2H, H6), 1.44 (s, 18H), 1.52 (m, 2H, H6), 2.76 (m, 2H,
H4), 3.09 (d, J ) 9.0 Hz, 2H, H3), 3.22 (d, J ) 9.0 Hz, 2H, H3),
3.94 (br, 2H, H5), 4.20 (d, J ) 6.6 Hz, 2H, H1), 5.52 (br, 2H, NH);
13C NMR (CDCl3, 75 MHz) δ 28.6, 33.0, 41.8, 45.6, 52.4, 63.3,
79.9, 156.8, 157.2; HRMS m/z 445.2387, calcd for C21H34N4O5Na
(M + Na) 445.2427. The ester 38: Rf 0.43 (cyclohexane/EtOAc
5:1); 1H NMR (CDCl3, 300 MHz) δ 1.28 (d, J ) 7.5 Hz, 1H, H6),
1.42 (s, 9H), 1.47 (s, 9H), 1.72 (m, 1H, H6), 2.70 (s, 1H, H5), 2.99
(m, 1H, H4), 3.22 (d, J ) 8.7 Hz, 1H, H3), 3.53 (d, J ) 8.7 Hz,
1H, H3), 4.53 (br, 1H, H1); 13C NMR (CDCl3, 75 MHz) δ 28.0 and
28.5 and 29.5, 37.4, 40.7, 46.0 and 46.7, 50.2 and 51.2, 61.6 and
62.5, 79.3 and 80.8, 155.3 and 155.4, 168.7 and 168.9; HRMS m/z
306.1671, calcd for C15H25NO4Na (M + Na) 306.1681.
Preparation of 5-syn-Azidocarbonylamine 34 from 5-syn-Acid
10c (Neat DPPA and Triethylamine). Triethylamine (0.15 mL)
was added to 5-syn-acid 10c (107 mg, 0.47 mmol). Over 30 min
DPPA (0.25 mL) was added and the neat reaction solution was
stirred under argon for 3 d. All volatile components were removed
under high vacuum. The crude product was purified by a short flash
column, eluting with cyclohexane/EtOAc 10:1, to give 46 mg of
azide 34 (37% yield). No other product was detected by 1H NMR
or isolated.
Preparation of N-tert-Butoxycarbonyl-5-syn-methoxycarbo-
nylamino-2-azabicyclo[2.1.1]hexane (33b). The reaction mixture
of acid 10c (122 mg, 0.54 mmol) and triethylamine (TEA, 60 mg,
0.085 mL, 0.60 mmol) in carbon tetrachloride (6.0 mL) was heated
to reflux. Diphenylphosphoryl azide (DPPA, 163 mg, 0.13 mL, 0.59
mmol) was added with a syringe. The reaction solution was refluxed
under argon for 1.5 h. Methanol (0.8 mL) was added and the oil
bath was removed. The reaction solution was cooled to room
temperature and stirred under argon overnight. It was then
concentrated and purified by a short flash column (cyclohexane/
EtOAc 10:1) to give 89 mg of protected amine 33b (65% yield):
Rf 0.30 (cyclohexane/EtOAc 2:1), mp 84 °C (cyclohexane/EtOAc);
1H NMR (CDCl3, 300 MHz) δ 1.18 (d, J ) 8.1 Hz, 1H, H6), 1.46
(s, 9H), 1.54 (m, 1H, H6), 2.83 (m, 1H, H4), 3.13 (d, J ) 9.3 Hz,
1H, H3), 3.25 (d, J ) 9.3 Hz, 1H, H3), 3.64 (s, 3H), 3.81 (m, 1H,
H5), 4.26 (m, 1H, H1), 4.90 (m, 1H, NH); 13C NMR (CDCl3, 75
MHz) δ 28.4, 32.8, 41.7, 45.3, 52.2, 53.0, 62.2, 79.9, 156.2, 156.7;
HRMS m/z 279.1312, calcd for C12H20N2O4Na (M + Na) 279.1321.
See the Supporting Information for X-ray data.
Preparation of 5-Propanoate 25 from 5-anti-Iodide 22. A
suspension of zinc powder (65 mg, 1.0 mmol) and copper(I) iodide
(63 mg, 0.33 mmol) in water (0.2 mL) was sonicated in an
Ultrasonic cleaning bath (Fisher14 Model) for 15 min. Methyl
acrylate (0.12 mL, 1.34 mmol), 5-anti-iodide 22 (107 mg, 0.35
mmol) in ethanol (0.2 mL) solution, and ethanol in water solution
(33%, 3 mL) were introduced. Additional amounts of zinc powder
(33 mg) and copper(I) iodide (32 mg) were added. The reaction
mixture was sonicated for 1 h. Upon monitoring the reaction at
this stage, besides the formation of product 25, no more iodide 22
remained, but the epimerized stereoisomer 5-syn-iodide 21 was
detected. Additional methyl acrylate (0.12 mL), zinc powder (65
mg), and copper(I) iodide (61 mg) were added and sonication of
the reaction mixture was continued for an additional 1 h. The solid
precipitate in the reaction mixture was removed by filtration and
washed several times with EtOAc. After removal of solvent in
vacuo, the crude products were purified with a short flash column,
eluting with cyclohexane/EtOAc 10:1 to give 33 mg of 25 (35%
yield) and 6 mg of 5-syn-iodide 21 (6%).
Preparation of N-tert-Butoxycarbonyl-5-anti-fluoro-2-azabi-
cyclo[2.1.1]hexane (29). To a solution of anti-iodide 22 (22.6 mg,
0.073 mmol) in nitromethane (0.5 mL) there was added silver
fluoride (23.2 mg, 0.18 mmol). After heating 1 d at 60 °C showed
no reaction by TLC, the solution was stirred at 80 °C for an
additional 4 h. The reaction mixture was then diluted with ether (6
mL) and washed with water (2 × 3 mL). The ether layer was dried
over MgSO4 and filtered. Solvent was removed in vacuo to give
2.8 mg (19%) of fluoride 29 at Rf 0.39 (1:1 hexane/ether); 1H NMR
δ 1.45 (s, 9H), 1.70 (ddd, J ) 7.9, 7.3, 2.7 Hz, H6s), 2.83 (m, 2H,
H4/H6a), 3.35 (d, J ) 9.7 Hz, 1H, H3), 3.38 (d, J ) 9.7 Hz, 1H,
H3), 4.30 (br, 1H, H1), 4.80 (dd, J ) 62, 7.9 Hz, 1H, H5); 13C
NMR δ 155.4, 98.5 (d, J ) 210 Hz), 79.9, 62.2, 47.2, 43.4 and
43.2, 36.7, 28.4; HRMS m/z 224.1052, calcd for C10H16FNO2Na
(M + Na) 224.1063.
Preparations of 5-syn-tert-Butoxycarbonylamino-2-azabicyclo-
[2.1.1]hexane-2-carboxylic Acid tert-Butyl Ester (33a), 5-syn-
Azidocarbonylamino-2-azabicyclo[2.1.1]hexane-2-carboxylic Acid
tert-Butyl Ester (34), 1,3-Bis(2-tert-butoxycarbonyl-2-azabicyclo-
[2.1.1]hex-5-syn-yl)ureas (36/37), and 2-Azabicyclo[2.1.1]hexane-
2,5-syn-dicarboxylic Acid Di-tert-butyl Ester (38). Triethylamine
(84 mg, 0.12 mL, 0.83 mmol) was added to the solution of 5-syn-
acid 10c (105 mg, 0.46 mmol) in tert-butyl alcohol (5 mL).
Diphenylphosphoryl azide (DPPA, 190 mg, 0.15 mL, 0.69 mmol)
was added to the reaction solution after it was heated to reflux
under argon. After an additional 4 h at reflux temperature, the
reaction solution was concentrated in vacuo. EtOAc (20 mL) was
added to the concentrated residue and the EtOAc solution was
washed with water, concentrated, and purified by flash column,
eluting with gradient cyclohexane/EtOAc, then EtOAc/MeOH 20:1
to give 11 mg of carbamate 33a (8% yield), 37 mg of azide 34
(30% yield), 50 mg of ureas 36/37 (26% yield), and 3 mg of ester
38 (2% yield). The 5-syn-amino derivative 33a: Rf 0.33 (cyclo-
Preparation of 5-syn-Benzyloxycarbonylamino-N-tert-butoxy-
carbonyl-2-azabicyclo[2.1.1]hexane (33c). The reaction mixture
of acid 10c (122 mg, 0.54 mmol) and triethylamine (60 mg, 0.085
mL, 0.60 mmol) in carbon tetrachloride (6.0 mL) was heated to
reflux. Diphenylphosphoryl azide (DPPA, 163 mg, 0.13 mL, 0.59
mmol) was added with a syringe. The reaction solution was refluxed
under argon for 1.5 h. Benzyl alcohol (0.8 mL) was added and the
reaction solution was cooled to room temperature and stirred under
argon overnight. The excessive benzyl alcohol was removed by
Kugelrohr distillation and the remaining residue was purified on a
short flash column (cyclohexane/Et2O 5:1) to give 146 mg of
protected amine 33c (82% yield): Rf 0.33 (cyclohexane/Et2O 1:1),
1
hexane/EtOAc 5:1), mp 105 °C (EtOAc); H NMR (CDCl3, 300
1
mp 121 °C (EtOAc); H NMR (CDCl3, 300 MHz) δ 1.18 (d, J )
MHz) δ 1.17 (d, J ) 8.1 Hz, 1H, H6), 1.43 (s, 9H), 1.48 (s, 9H,
tert-butyl), 1.53 (m, 1H, H6), 2.83 (m, 1H, H4), 3.14 (d, J ) 9.3
Hz, 1H, H3), 3.25 (d, J ) 9.3 Hz, 1H, H3), 3.79 (d, J ) 7.8 Hz,
1H, H5), 4.25 (d, J ) 6.3 Hz, 1H, H1), 4.70 (br, 1H, NH); 13C
NMR (CDCl3, 75 MHz) δ 28.3, 28.5, 32.8, 41.7, 45.3, 52.7, 62.6,
79.9, 155.0, 156.8; HRMS m/z 321.1790, calcd for C15H26N2O4Na
(M + Na) 321.1785. The acyl azide 34: Rf 0.50 (CH2Cl2/EtOAc
5:1), mp 107 °C (ethyl ether); 1H NMR (CDCl3, 300 MHz) δ 1.22
(d, J ) 8.4 Hz, 1H, H6), 1.46 (s, 9H), 1.58 (m, 1H, H6), 2.88 (m,
1H, H4), 3.11 (d, J ) 9.3 Hz, 1H, H3), 3.27 (d, J ) 9.3 Hz, 1H,
H3), 3.88 (dt, J ) 7.8, 2.4 Hz, 1H, H5), 4.28 (dt, J ) 6.6, 1.5 Hz,
1H, H1), 5.25 (br, 1H, NH); 13C NMR (CDCl3, 75 MHz) δ 28.4,
8.4 Hz, 1H, H6), 1.45 (s, 9H), 1.54 (m, 1H, H6), 2.83 (m, 1H, H4),
3.13 (d, J ) 9.3 Hz, 1H, H3), 3.25 (d, J ) 9.3 Hz, 1H, H3), 3.84
(m, 1H, H5), 4.27 (m, 1H, H1), 4.99 (m, 1H, NH), 5.07 (s, 2H),
7.29-7.40 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 28.4, 32.8, 41.7,
45.3, 53.1, 62.2, 66.9, 79.9, 128.1, 128.2, 128.5, 136.4, 155.4, 156.6;
HRMS m/z 355.1633, calcd for C18H24N2O4Na (M + Na) 355.1634.
See the Supporting Information for an X-ray structure.
Preparation of N-tert-Butoxycarbonyl-5-anti-methoxycarbo-
nylamino-2-azabicyclo[2.1.1]hexane (39a). The reaction mixture
of anti-acid 5c (122 mg, 0.54 mmol) and triethylamine (TEA, 60
mg, 0.085 mL, 0.60 mmol) in carbon tetrachloride (6.0 mL) was
J. Org. Chem, Vol. 71, No. 5, 2006 2097

Krow et al.
heated to reflux. Diphenylphosphoryl azide (DPPA, 163 mg, 0.13
mL, 0.59 mmol) was added with a syringe. The reaction solution
was refluxed under argon for 1.5 h. Methanol (0.8 mL) was added
and the oil bath removed. The reaction solution was cooled to room
temperature and stirred under argon overnight. It was then
concentrated and purified on a short flash column, eluted with
cyclohexane/EtOAc 5:1 to give 104 mg of protected amine 39a
(75% yield): Rf 0.23 (cyclohexane/EtOAc 2:1), mp 105 °C (CHCl3);
1H NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.56 (m, 1H, H6s),
2.51 (m, 1H, H6a), 2.82 (m, 1H, H4), 3.37 (m, 2H, H3), 3.52 (m,
1H, H5), 3.68 (s, 3H), 4.28 (d, J ) 6.3 Hz, 1H, H1), 5.32 (m, 1H,
NH); 13C NMR (CDCl3, 75 MHz) δ 28.4, 37.2, 42.3, 48.7, 52.2,
62.4, 62.6, 79.6, 155.7, 157.0; HRMS m/z 279.1310, calcd for
C12H20N2O4Na (M + Na) 279.1321.
33c, eluting with cyclohexane/Et2O 5:1, then 2:1, gave 82 mg of
39b (80% yield): Rf 0.27 (cyclohexane/Et2O 1:1), mp 84 °C
(CHCl3); H NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.56 (m,
1H, H6s), 2.51 (m, 1H, H6a), 2.83 (m, 1H, H4), 3.41 (d, J ) 9 Hz,
1H, H3), 3.63 (d, J ) 9 Hz, 1H, H3), 3.57 (m, 1H, H5), 4.30 (d, J
) 6.9 Hz, 1H, H1), 5.11 (s, 2H), 5.27 (m, 1H, NH), 7.30-7.41 (m,
5H); 13C NMR (CDCl3, 75 MHz) δ 28.5, 37.2, 42.4, 48.7, 62.6,
66.9, 79.6, 128.1, 128.2, 128.5, 136.3, 155.7, 156.3; HRMS m/z
355.1624, calcd for C18H24N2O4Na (M + Na) 355.1634.
1
Acknowledgment is made to the donors of the Petroleum
Research Fund, administered by the American Chemical Society,
and the National Science Foundation (CHE 0111208 and CHE
0515635).
Preparation of 5-anti-Benzyloxycarbonylamino-N-tert-bu-
toxycarbonyl-2-azabicyclo[2.1.1]hexane (39b). According to the
general procedure, anti-acid 5c (70 mg, 0.31 mmol) and triethy-
lamine (TEA, 35 mg, 0.050 mL, 0.35 mmol) in carbon tetrachloride
(6.0 mL) were heated to reflux. Diphenylphosphoryl azide (DPPA,
94 mg, 0.075 mL, 0.34 mmol) was added with a syringe. The
reaction solution was refluxed under argon for 1.5 h, benzyl alcohol
(0.5 mL) was added, and the oil bath was removed to allow cooling
to room temperature. After 12 h under argon and workup as for
Supporting Information Available: General experimental,
procedures for iodide 21/22 (entries 5-10 in Table 2), parent 17
from iodide 21, copies of 1H NMR and 13C NMR for new
compounds, and X-ray data for amine derivatives 33b and 34. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO052506B
2098 J. Org. Chem., Vol. 71, No. 5, 2006