The rearrangement route to 3-carboxy- and 3-hydroxymethyl-2-azabicyclo[2.1. 1]hexanes: 3,5-Methanoprolines

Article abstract of DOI:10.1021/jo0484171

(Chemical Equation Presented) Improved stereocontrolled syntheses of 5-anti-hydroxy-3-exo-methoxycarbonyl-2-azabicyclo[2.1.1]-hexanes have been effected from pyridine. The key step in the electrophilic addition-rearrangement of 2-azabicyclo[2.2.0]hex-5-en

Full text of DOI:10.1021/jo0484171

The Rearrangement Route to 3-Carboxy- and
3-Hydroxymethyl-2-azabicyclo[2.1.1]hexanes: 3,5-Methanoprolines
Grant R. Krow,* Guoliang Lin, and Fang Yu
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
grantkrow@aol.com
Received September 8, 2004
Improved stereocontrolled syntheses of 5-anti-hydroxy-3-exo-methoxycarbonyl-2-azabicyclo[2.1.1]-
hexanes have been effected from pyridine. The key step in the electrophilic addition-rearrangement
of 2-azabicyclo[2.2.0]hex-5-ene precursors incorporates either a 3-endo-phenyl group, as an acid
precursor, or a 3-endo-phenyldimethylsilylmethyl group, as a potential hydroxymethyl and acid
precursor.
One strategy in the search for bioactive molecules is
to incorporate key pharmacophoric units into inflexible
structures, such as fused or bridged small rings.1 Hy-
droxyprolines are representative of such units that have
proven to be valuable scaffolds for drug discovery.2-12
Among cis hydroxyprolines, the allo-4-hydroxy-L-proline
1 is found in the lipopeptide component of the cytotoxic13
majusculamide D and the immunosuppressive antileu-
kemic14 microcolin A, which also has protein kinase C
inhibitory properties.15 The enantiomeric allo-4-hydroxy-
D-proline 2 has been isolated from the hydrolysate of
(1) 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) Piotroski,
D. W. Synlett 1999, 1091. (d) 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. 1988, 8, 3101. (e) 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. (f)
Mapelli, C.; van Halbeek, H.; Stammer, C. H. Biopolymers 1990, 29,
407. (g) Bell, E. A.; Qureshi, M. Y.; Pryce, R. J.; Janzen, D. H.; Lemke,
P.; Clardy, J. J. Am. Chem. Soc. 1980, 102, 1409. (h) Han, W.; Pelletier,
J. C.; Mersinger, L.; Ketner, C. A.; Hodge, C. N. Org. Lett. 1999, 1,
1875. (i) Park, T. H.; Ha, Y. H.; Jeong, D. Y. Patent Application WO
98-KR246 19989898; Chem. Abstr. 1999, 130, 182388.
etamycin, a broad-spectrum antibiotic.16 We require
methanobridged proline structures related to 3 and its
enantiomer as building blocks for projects designed to
prepare conformationally constrained analogues of sub-
stituted prolines and pyrrolidines.17 There is a potential
for both the 5-hydroxy and 3-methoxycarbonyl groups of
3 to serve as useful functional groups for preparation of
(2) For a review of naturally occurring proline analogues, see:
Mauger, A. B. J. Nat. Prod. 1996, 59, 1205.
(6) For peptide nucleic acids from 4-hydroxyproline, 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.
(3) For a review of 4-hydroxy-L-proline as a building block, see:
Remuzon, P. Tetrahedron 1996, 52, 13803.
(4) For generation of nonproteinogenic amino acids from 4-hydroxy-
proline, see: (a) Cheng, W.-C.; Liu, Y.; Wong, M.; Olmstead, M. M.;
Lam, K. S.; Kurth, M. J. J. Org. Chem. 2002, 67, 5673. (b) Webb, T.
R.; Eigenbrot, C. J. Org. Chem. 1991, 56, 3009. (c) Tamaki, M.; Han,
G.; Hruby, V. J. J. Org. Chem. 2001, 66, 1038.
(5) For aminonucleotides based on 4-hydroxyprolinol, see: (a) Reed,
M. W.; Lukhtanov, E. A.; Gorn, V. V.; Lucas, D. D.; Zhou, J. H.; Pai, S.
B.; Cheng, Y.; Meyer, R. B., Jr. J. Med. Chem. 1995, 38, 4587. (b)
Peterson, M. L.; Vince, R. J. Med. Chem. 1991, 34, 2787.
(7) For azasugars from 4-hydroxyprolinal, see: Zhu, Y.-H.; Vogel,
P. J. Org. Chem. 1999, 64, 666.
10.1021/jo0484171 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/29/2004
590
J. Org. Chem. 2005, 70, 590-595

3-Carboxy- and 3-Hydroxymethyl-2-azabicyclo[2.1.1]hexanes
SCHEME 1. The Rearrangement Route
other 3- and 5-substituted methanopyrrolidines and such
methanoproline analogues might be incorporated into
native protein sequences.18
Recently, we showed that N-acetyl-3-methoxycarbonyl-
5-hydroxy-2-azabicyclo[2.1.1]hexane 4, in which the pyr-
rolidine ring of the allo-4-hydroxyproline is constrained
into a unique envelope conformation, can provide insights
into the factors that stabilize collagens.19a The synthetic
route to 4 required 14 steps from pyridine. Key interme-
diates in the sequence include the 1,2-dihydropyridines
5, the photoproduct 6, and the rearranged bromohydrin
7. Contributing to the length of the synthesis are five
steps associated with introduction and removal of the
p-nitrobenzenesulfonate (ONs) group and protection of
the 5-hydroxyl group of 7 during subsequent oxidation
steps leading to ester 4.19a,20 Thus, we desired a more
efficient route to this type of compound.
SCHEME 2. A Nonselective Oxidationa
a Reagents and conditions: (a) NBS, HOAc, NaOAc, Ac2O, 25
°C, 1 h; (b) RuCl3, NaIO4, CCl4, CH3CN, H2O, 25 °C, 24 h; then
Me3SiCHN2, hexane, i-PrOH.
9.19 This is followed by a regioselective attack of water
on ion 9 to give a 2-azabicyclo[2.1.1]hexane system 7. The
O-nosylate protecting group is necessary to minimize
intramolecular trapping of bromonium ion 8 by oxygen
to give the unwanted tricycle 10.
A shorter alternative that avoids the problem of
neighboring group participation by the 3-endo substituent
of a 1,2-dihydropyridine photoadduct is desirable. Two
superior alternative routes to structures related to
methanoproline 4 are now described. In one approach a
phenyl group was chosen as a latent carboxylic acid. In
a second approach the dimethylphenylsilylmethyl group
was chosen as the precursor of a hydroxymethyl group.
Results and Discussion
Our previous rearrangement approach to the metha-
noproline 4 shown in Scheme 1 takes advantage of the
finding that the bromonium ion 8, formed by addition of
Br+ to photoproduct 6, rearranges to the aziridinium ion
The 2-Phenyl-1,2-dihydropyridine Route. Pyridine
previously has been converted to 2-phenyl-1,2-dihydro-
pyridine and then by irradiation to 3-endo-phenyl-2-
azabicyclo[2.2.0]hex-5-ene 11 in 15% yield.21 Attempted
selected use of the phenyl group as a latent ester is shown
in Scheme 2. Reaction of 11 with NBS/Ac2O/AcOH affords
the rearranged bromoacetate 12 (86%) that shows char-
acteristic doublets, J1,4 ) 7.2 Hz and J5,6 ) 7.5 Hz, for
this 2-azabicyclo[2.1.1]hexane ring system.22 Selective
oxidation of the 3-phenyl group of 12 with ruthenium
tetroxide was not successful;23 following esterification
with trimethylsilyldiazomethane24 an 8:1 mixture (63%)
(8) For incorporation of 4-hydroxyproline derivatives into antibiotics,
see: (a) Kamal, A. J. Org. Chem. 1991, 56, 2237. (b) Kamal, A.; Reddy,
G. S. K.; Reffy, K. L.; Raghavan, S. Tetrahedron Lett. 2002, 43, 2103.
(c) Azami, H.; Barrett, D.; Tanaka, A.; Sasaki, H.; Matsuda, K.; Chiba,
T.; Matsumoto, Y.; Matsumoto, S.; Moringa, C.; Ishiguro, K.; Tawara,
S.; Sakane, K.; Takasugi, H. Bioorg. Med. Chem. Lett. 1995, 5, 2199.
(9) For use of 4-hydroxyproline in the synthesis of antihypertensives,
see: 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.
(10) For generation of polyamines from 4-hydroxyproline, see:
Nagamani, D.; Ganesh, K. N. Org. Lett. 2001, 3, 103.
(11) For incorporation of 4-hydroxyproline derivatives into macro-
cycles, see: (a) Arasappan, A.; Chen, K. X.; Njoroge, F. G.; Parekh, T.
N.; Girijavallabhan, V. J. Org. Chem. 2002, 67, 3923. (b) Goldberg,
M.; Smith, L., II; Tamayo, N.; Kiselyov, A. S. Tetrahedron 1999, 55,
13887.
(18) Kim, W.; George, A.; Evans, M.; Conticello, V. P. ChemBioChem
2004, 5, 928.
(12) For recent synthetic efforts related to the synthesis of 4-sub-
stituted-prolines and 2-hydroxymethylpyrrolidines, see: (a) Del Valle,
J. R.; Goodman, M. J. Org. Chem. 2003, 68, 3923. (b) Tamaki, M.; Han,
G.; Hruby, V. J. J. Org. Chem. 2001, 66, 3593.
(19) (a) Jenkins, C. L.; Lin, G.; Duo, J.; Rapolu, D.; Guzei, I. A.;
Raines, R. T.; Krow, G. R. J. Org. Chem. 2004, 69, 8565. (b) Krow, G.
R.; Yuan, J.; Lin, G.; Sonnet, P. E. Org. Lett. 2002, 4, 1259.
(20) Krow, G. R.; Yuan, J.; Fang, Y.; Meyer, M. D.; Anderson, D. J.;
Campbell, J. E.; Carroll, R. J. Tetrahedron 2000, 56, 9227.
(21) (a) Kurita, J.; Iwata, K.; Sakai, H.; Tsuchiya, T. Chem. Pharm.
Bull. 1985, 33, 4572. (b) The low yield in the photocyclization step can
be attributed to competitive aromatization and/or electrocyclic ring
opening of the 1,2-dihydropyridine. Kumagai, T.; Saito, S.; Ehara, T.
Tetrahedron Lett. 1991, 32, 6895.
(13) Moore, R. E.; Entzeroth, M. Phytochemistry 1988, 27, 3101.
(14) Koehn, F. E.; Longley, R. E.; Reed, J. K. J. Nat. Prod. 1992,
55, 613.
(15) (a) Koehn, F. E.; McConnell, O. J.; Longley, R. E.; Sennett, S.
H.; Reed, J. K. J. Med. Chem. 1994, 37, 3181. (b) Dicicco, C. P.; Grover,
P. J. Org. Chem. 1996, 61, 3534.
(16) Sheehan, J. C.; Zachau, H. G.; Lawson, W. B. J. Am. Chem.
Soc. 1958, 80, 3349.
(17) For a library based upon 4-hydroxyproline, see: Goldberg, M.;
Smith, L., II; Tamayo, N.; Kiselyov, A. S. Tetrahedron 1999, 55, 13887.
For a library based upon amide diols, see: Lee, C. E.; Kick, E. K.;
Ellman, J. A. J. Am. Chem. Soc. 1998, 120, 9735.
(22) Krow, G. R.; Lin, G.; Rapolu, D.; Fang, Y.; Lester, W. S.; Herzon,
S. B.; Sonnet, P. E. J. Org. Chem. 2003, 68, 5292.
(23) Carlsen, H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
(24) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 5, 1475.
J. Org. Chem, Vol. 70, No. 2, 2005 591

Krow et al.
SCHEME 3. An allo-Hydroxymethanoproline
alternative route shown in Scheme 4, pyridine was
reacted with the Grignard reagent prepared from chlo-
romethyldimethylphenylsilane in the presence of ben-
zylchloroformate.28 The resulting crude 1,2-dihydropyri-
dine 20 was directly subjected to irradiation at 300 nm
in acetone for 2-5 days to give 3-endo-dimethylphenyl-
silylmethyl-2-azabicyclo[2.2.0]hex-5-ene 21 in 30% overall
yield.21 Reaction of alkene 21 with NBS/THF/water25 gave
Synthesisa
1
an unstable yellow oil with an H NMR spectrum that
showed characteristic doublet patterns J1,4 ) 7.5 Hz and
J5,6 ) 7.5 Hz consistent with the rearranged bromo
alcohol 22; however, the color changed to blue in the
NMR tube. Chromatography of this new material re-
sulted in isolation of a cyclopentenone 23 (65%). The
methyl group of 23 was assigned adjacent to the carbonyl
group on the basis of NOESY correlations between the
vinyl proton and the two adjacent allylic protons. This
surprising molecular rearrangement 21 f 23 can be
suppressed by protection of the alcohol,29 since alkene
21, when it was reacted with NBS/AcOH/Ac2O,22 affords
the stable bromoacetate 24 (89% yield). Oxidation of the
alkylsilane of bromoacetate 24 with bromine/peracetic
acid/acetic acid gives the 3-hydroxymethyl bromoacetate
25 (80%).30 Oxidation of the 3-hydroxymethyl group with
NaOCl/TEMPO31 and esterification with trimethylsilyl-
diazomethane24 gives the desired 3-ester 14 (80%). This
is converted to the known hydroxymethanoproline ana-
logue 4 in several steps. The N-benzyloxycarbonyl group
is removed with H2/Pd/C/MeOH to give the amine 26
(85%) and acylation gives amide 27 (93%). Debromination
of 27 with tributyltin hydride in benzene affords diester
19 (93%), which was earlier converted to 4 as described
in Scheme 3. The overall yield of 4 as described in Scheme
2 from silyl photoproduct 21 is 42%; from pyridine the
yield is 13%. The four-step yield from pyridine to the
selectively protected multifunctional 3-hydroxymethyl-
bromoacetate 25 is 21%. This route is a 5-fold improve-
ment over the previous nine-step (4.4% yield) route19a
from pyridine to the TBDMS-protected alcohol 28.
a Reagents and conditions: (a) H2/Pd/C, MeOH, 25 °C, 1 h; (b)
Bu3SnH, AIBN, benzene, reflux, 3 h; (c) B-bromocatecholborane,
CH2Cl2, 25 °C, 2 h; then AcCl, DMAP, CH2Cl2, 25 °C, 2 h; (d)
RuCl3, NaIO4, CCl4, CH3CN, H2O, 25 °C, 24 h; then Me3SiCHN2,
hexane, i-PrOH; (e) Et3N, MeOH, 25 °C, 6 h.
of an undesired 3-phenyl isomer 13, in which the benzyl
protecting group was preferentially oxidized, and the
desired 3-ester 14 was obtained.
To avoid oxidation of the nitrogen protecting group, we
attempted selective removal of the N-benzyloxycarbonyl
group of bromoacetate 12 by catalytic hydrogenation
(Scheme 3). Although reduction of 12 with Pd(OH)2/H2/
MeOH removed the benzyloxycarbonyl group, it also
broke the benzylic N-C3 bond to give the bromocyclobu-
tylamine 15. To relieve strain the 5-bromo substituent
of 12 was removed with tributyltin hydride (94%) to give
acetate 16.25 Nevertheless, reductive removal of the
N-benzyloxycarbonyl group of 16 with Pd/C/MeOH again
resulted in ring cleavage at the benzylic position to give
cyclobutylamine 17. Finally, the N-benzyloxycarbonyl
group was selectively removed with B-bromocatecholbo-
rane26 in CH2Cl2 and the resulting amine was directly
acylated with AcCl/pyridine/DMAP to give the amide 18
in 43% yield. The phenyl group of 18 was oxidized with
RuO4 and the resulting acid was immediately esterified
with trimethylsilyldiazomethane to give the diester 19
(52%). Selective hydrolysis of the acetate of 19 with Et3N/
MeOH27 quantitatively afforded the known hydroxyester
4 in seven steps (16%) from the dihydropyridine photo-
product 11 and nine steps (2.4%) from pyridine. While
the result is an improvement over the previously de-
scribed route to ester 4, an alternative route remained
desirable.
Experimental Section
Preparation of N-(Benzyloxycarbonyl)-5-anti-bromo-
6-anti-acetoxy-3-endo-phenyl-2-azabicyclo[2.1.1]-
hexane (12). Alkene 11 (292 mg, 1 mmol)21 and NBS (445
mg, 2.5 mmol) in a solution of acetic acid (8 mL), sodium
acetate (205 mg, 2.5 mmol), and acetic anhydride (0.2 mL, 2
The 2-Dimethylphenylsilylmethyl-1,2-dihydropy-
ridine Route. An alternative to synthon 11 was sought
that would avoid the problems inherent in deprotecting
a benzylic amine protected as a benzyl carbamate. In the
(28) Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org.
Chem. 1999, 64, 2184.
(29) The rearrangement of alcohol 22 might be envisioned as
occurring through a series of steps shown in Scheme 5. An alcohol
proton catalyzed ring opening could give a â-silyl cation i. A subsequent
1,2-alkyl shift gives a ring-enlarged cation ii. Proton loss generates
an allylic silane iii. Desilylation accompanied by bromide elimination
gives diene iv and a series of acid-catalyzed proton transfers affords
ketone 23.
(25) (a) Krow, G. R.; Lee, Y. B.; Lester, W. S.; Christian, H.; Shaw,
D. A.; Yuan, J. J. Org. Chem. 1998, 63, 8558. (b) 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.
(26) Boeckman, R. K., Jr.; Potenza, J. C. Tetrahedron Lett. 1985,
26, 1411.
(27) Tsuzuki, K.; Nakajima, Y.; Watanabe, T.; Yanagiya, M.; Mat-
sumoto, T. Tetrahedron Lett. 1978, 19, 989.
(30) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 317.
(31) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559.
592 J. Org. Chem., Vol. 70, No. 2, 2005

3-Carboxy- and 3-Hydroxymethyl-2-azabicyclo[2.1.1]hexanes
SCHEME 4. An Improved Route to allo-Hydroxymethanoprolinea
a Reagents and conditions: (a) hν, 300 nm, Rayonet reactor, acetone, 25 °C, 2-5 d; (b) NBS, THF, H2O, 25 °C, 2.5 h; (c) NBS, HOAc,
NaOAc, Ac2O, 25 °C, 1 h; (d) Br2, PAA, HOAc, 25 °C, 5 h; (e) NaOCl, TEMPO, KBr, Bu4NCl, CH2Cl2, NaHCO3, H2O, 0 °C, 45 min; then
TMSCHN2, hexane, i-PrOH; (f) H2/Pd/C, MeOH, 25 °C, 2 h; (g) AcCl, DMAP, CH2Cl2, 25 °C, 2 h; (h) Bu3SnH, AIBN, benzene, reflux, 3
h; (i) Et3N, MeOH, 25 °C, 6 h.
(1:2 ether/hexane) to afford 322 mg (56%) of N-COOCH2-
COOMe product 13 at Rf 0.29 (2:1 hexane/ether): 1H NMR δ
7.29 (m, 5H), 5.21 (br, 1H), 4.81 (d, J ) 8.0 Hz, 1H), 4.60 (m,
3H), 4.11 (d, J ) 7.2 Hz, 1H), 3.67 (br, 3H), 3.20 (d, J ) 7.2
Hz, 1H), 2.06 (s, 3H); 13C NMR δ 170.4, 168.4, 155.5, 137.2,
SCHEME 5. A Proposed Ring-Cleavage
Mechanism
130.0, 128.6, 127.7, 126.2, 83.5, 65.1, 62.8, 61.6, 54.0, 52.5, 46.3,
79
21.1; HRMS m/z 434.0209 and 436.0185, calcd for C17H18NO6
-
BrNa (MNa+) 434.0215 and C17H18NO681BrNa (MNa+) 436.0195.
Also obtained was 31.3 mg (7%) of N-COOBn product 14 at Rf
0.31 (2:1 hexane/ether): 1H NMR δ 7.39 (br, 5H), 5.22 (s, 2H),
4.66 (d, J ) 7.2 Hz, 1H), 4.55 (m, 2H), 3.82 (br, 3H), 3.33 (d,
J ) 7.2 Hz, 1H), 2.18 (s, 3H); 13C NMR δ 170.2, 169.0, 154.3,
153.3, 135.7, 128.4, 128.2, 127.9, 83.6, 67.7, 64.3, 59.3, 52.7,
51.7, 46.2, 21.0; HRMS m/z 434.0213 and 436.0197, calcd for
C17H18NO679BrNa (MNa+) 434.0215 and C17H18NO681BrNa
(MNa+) 436.0195.
Hydrogenative Cleavage of Acetate 12: c-3-Acetoxy-
t-2-amino-1-r-bromo-t-4-benzylcyclobutane (15). To a so-
lution of acetate 12 (415 mg, 0.97 mmol) in methanol (40 mL)
was added 10% Pd(OH)2/C (150 mg). The solution was stirred
at 25 °C under a hydrogen balloon for 2 h and filtered through
Celite, and solvent was removed in vacuo to give an oil.
Purification by flash chromatography (EtOAc) afforded 241 mg
(84%) of amine 15 at Rf 0.20 (ethyl acetate): 1H NMR δ 7.2-
7.1 (m, 5H), 4.31 (t, J ) 7.1 Hz, 1H), 3.44 (t, J ) 7.1 Hz, 1H),
3.23 (t, J ) 7.7 Hz, 1H), 2.92 (m, 2H), 2.56 (m, 1H), 1.99 (s,
3H), 1.73 (br, 2H); 13C NMR δ 171.3, 138.2, 130.0, 129.2, 127.2,
76.4, 64.3, 48.8, 45.3, 36.7, 21.4; HRMS m/z 298.0443 and
300.0422, calcd for C13H17NO279Br (MH) 298.0443. and C13H17-
NO281Br (MH) 300.0422.
mmol) were stirred at 25 °C for 1 h.22 The solution was diluted
with CH2Cl2 (20 mL), washed with 10% NaHCO3 (3 × 10 mL)
and brine (10 mL), dried over MgSO4, and filtered and solvent
was removed in vacuo to provide an oil that was chromato-
graphed on silica gel (1:2 ether/hexane) to afford 432 mg (86%)
of rearranged bromoacetate 12 at Rf 0.36 (2:1 hexane/ether):
1H NMR δ 7.34 (m, 10H), 5.23 (s and br, 3H), 4.81 (d, J ) 7.5
Hz, 1H), 4.74 (d, J ) 7.5 Hz, 1H), 4.26 (d, J ) 7.2 Hz, 1H),
3.30 (d, J ) 7.2 Hz, 1H), 2.21 (s, 3H); 13C NMR δ 170.5, 156.0,
137.6, 136.0, 128.8, 128.5, 127.7, 127.4, 127.0, 126.3, 83.6, 67.6,
65.3, 62.8, 53.8, 46.5, 21.1; HRMS m/z 452.0468 and 454.0451,
81
calcd for C21H21NO479BrNa (MNa+) 452.0473 and C21H21NO4
-
BrNa (MNa+) 454.0452.
Debromination of Acetate 12: Preparation of N-(Ben-
zyloxycarbonyl)-5-anti-acetoxy-3-exo-phenyl-2-azabicyclo-
[2.1.1]hexane (16). To a solution of acetate 12 (415 mg, 0.97
mmol) in benzene (50 mL) was added tributyltin hydride (0.59
g, 2.05 mmol) and AIBN (22 mg, 0.13 mmol).25 The resulting
mixture was refluxed for 3 h. The solvent was removed in
vacuo and the crude product was purified by column chroma-
tography to give 220 mg (94%) of halide free acetate 16 as a
colorless oil at Rf 0.53 (1:1 ether:/hexane): 1H NMR (400 MHz)
δ 7.40 (m, 10H), 5.20 (d, J ) 10.3 Hz, 2H), 5.12 (s,1H), 4.75
(d, J ) 7.0 Hz, 1H), 4.59 (m, 1H), 3.00 (br, 1H), 2.53 (br, 1H),
2.17 (s, 3H), 1.87 (m, 1H); 13C NMR δ 170.6, 156.6, 138.9, 136.4,
128.3, 127.7, 127.4, 127.1, 126.4, 82.6, 66.9, 62.2, 61.3, 49.3
and 48.7, 32.5 and 31.7, 13.6; HRMS m/z 374.1382, calcd for
C21H21NO4Na (MNa) 374.1368.
Oxidation of Bromoacetate 12: Preparation of N-[(Car-
bomethoxymethyl)methoxycarbonyl]-5-anti-bromo-6-
anti-acetoxy-3-endo-phenyl-2-azabicyclo[2.1.1]hexane (13)
and N-(Benzyloxycarbonyl)-5-anti-bromo-6-anti-acetoxy-
3-endo-methoxycarbonyl-2-azabicyclo[2.1.1]hexane (14).
To a solution of bromoacetate 12 (600 mg, 1.45 mmol) in carbon
tetrachloride (3 mL), acetonitrile (3 mL), and water (5 mL)
was added sodium metaperiodate (4.64 g, 5.95 mmol). To this
biphasic solution was added 8.43 mg (2.2 mol %) of ruthenium
trichloride and the entire mixture was stirred for 24 h at room
temperature. Then CH2Cl2 (15 mL) was added and the phases
were separated. The aqueous phase was extracted with CH2-
Cl2 (3 × 10 mL). The combined organic extracts were dried
over MgSO4 and concentrated. Hexane (15 mL) and 2-propanol
(15 mL) were added followed by a 2 M solution of trimethyl-
silyldiazomethane in hexane (700 µL).24 The resulting mixture
was stirred under argon for 0.5 h. The solvent was removed
in vacuo to give an oil that was chromatographed on silica gel
Hydrogenative Cleavage of Acetate 16: r-1-Acetoxy-
t-2-amino-t-4-benzylcyclobutane (17). To a solution of
acetate 16 (168 mg, 0.48 mmol) in methanol (20 mL) was added
J. Org. Chem, Vol. 70, No. 2, 2005 593

Krow et al.
Pd/C (100 mg). The solution was stirred at 25 °C under a
hydrogen balloon for 2 h and filtered through Celite, and
solvent was removed in vacuo to give an oil. Purification by
flash chromatography (EtOAc) afforded 82 mg (78%) of amine
17 at Rf 0.18 (ethyl acetate): 1H NMR δ 7.13 (m, 5H), 4.50 (t,
J ) 7.20 Hz, 1H), 3.82 (br, 2H), 3.20 (m, 1H), 2.87 (dd, J )
14.0, 7.3 Hz, 1H), 2.66 (dd, J ) 14.0, 8.0 Hz, 1H), 2.22 (m,
2H), 1.94 (s, 3H), 1.19 (m, 1H); 13C NMR δ 171.3, 139.5, 128.6,
128.3, 126.1, 80.0, 51.9, 39.5, 36.8, 28.5, 20.9; HRMS m/z
220.1334, calcd for C13H18NO2 (MH) 220.1334.
(CDCl3, 100 MHz) δ 170.1 and 168.5, 81.9 and 81.4, 65.4 and
62.6, 60.0 and 58.0, 52.4, 48.5 and 47.9, 34.2 and 32.9, 21.7
and 21.4; HRMS m/z 222.0747, calcd for C9H13NO4Na (MNa)
222.0742.
N-Benzyloxycarbonyl-2-(phenyldimethylsilylmethyl)-
1,2-dihydropyridine (20). A few milliliters of a solution of
chloromethyldimethylphenylsilane (18.47 g, 100 mmol) in dry
THF (120 mL) was added to a flask containing Mg turnings
(2.43 g, 100 mmol) under argon, a small crystal of iodine was
added, and the mixture was heated until an exothermic
reaction occurred.28 The remaining THF solution of chloride
was added over 20 min so that gentle reflux was maintained.
The tan-gray mixture was then heated to reflux for 0.5 h and
cooled to 0 to -5 °C, and a solution of dry pyridine (6.33 g, 80
mmol) was added dropwise with stirring over 20 min. After
an additional 20 min, a solution of benzyl chloroformate (13.70
g, 80 mmol) in THF (100 mL) was added dropwise at such a
rate as to maintain the temperature below -5 °C. After an
additional 2 h, the mixture was allowed to stir at room
temperature for 1 h and water (50 mL) was added. The organic
layer was separated; if there was too much undissolved solid,
dilute HCl was added to dissolve the residue while keeping
the pH no less than 7. The aqueous layer was extracted with
diethyl ether (4 × 50 mL) and the combined organic layers
were washed with brine (50 mL), dried over sodium sulfate,
and filtered and solvent was removed in vacuo to give 28.60 g
(95%, crude) of 1,2-dihydropyridine 20 as a light yellow oil.
The crude product is pure enough for the next reaction. A
portion (200 mg) of crude 20 was purified by flash chroma-
tography (10:1 hexane/ether) to give 110 mg (56%) of pure 20
at Rf 0.58 (6:1 hexane/ether): 1H NMR δ 7.31 (m, 10H), 6.74
and 6.58 (two d, J ) 7.5 Hz, 1H), 5.79 (m, 1H), 5.51-4.95 (m,
5H), 1.46-1.20 (m, 2H), 0.35 (m, 6H); 13C NMR δ 154.2 and
153.3, 139.2, 136.4, 129.4, 129.0, 128.2, 127.7, 127.5, 133.9,
124.4 and 124.3, 121.3 and 120.7, 106.3, 68.0, 50.67 and 50.22,
23.2 and 22.2, 0.2 and 0.0; HRMS m/z 364.1736, calcd for
C22H26NO2Si (MH) 364.1733.
N-Benzyloxycarbonyl-3-(phenyldimethylsilylmethyl)-
2-azabicyclo[2.2.0]hex-5-ene (21). Photoirradiation of the
crude 2-silylmethyl-1,2-dihydropyridine 20 (28.6 g) in acetone
(5wt %) at 300 nm with a Rayonet photoreactor for 2-5 days
and removal of solvent gave a crude oil, which was purified
by silica gel column chromatography (1:9 ether/hexane) to give
8.7 g (30%) of photoproduct 21 as a yellow oil at Rf 0.33 (6:1
hexane/ether): 1H NMR δ 7.41 (m, 10H), 6.55, 6.48, 6.08, 5.98
(four s, 2H), 5.12 (br, 2H), 4.73 (br, 1H), 4.28 (br, 1H), 3.36
(m, 1H), 1.85 and 1.65 (two br, 1H), 1.16 br, 1H), 0.40 (m, 6H);
13C NMR δ 155.1 and 153.4, 142.4 and 140.7, 138.3 and 137.1,
133.4 and 133.0, 129.2, 128.4, 127.9, 127.7, 66.0, 62.9 and 62.2,
58.3, 43.8, 19.2 and 18.2, -0.0 and -2.7; HRMS m/z 386.1557,
calcd for C22H25NO2NaSi (MNa) 386.1552.
Attempted Preparation of Bromohydrin 22: N-Ben-
zyloxycarbonyl-2-amino-5-methyl-2-cyclopentenone (23).
To silane 21 (0.55 g, 1.51 mmol) in THF (10 mL) and H2O (5
mL) at 0 °C was added N-bromosuccinimide (0.67 g, 3.76
mmol) in small portions so that the temperature never
exceeded 0 °C.25 Upon completion of addition the solution was
warmed to room temperature and stirred for 2.5 h, then diluted
with water (5 mL) and extracted with chloroform (5 × 10 mL).
The combined organic layers were washed with brine (10 mL)
and dried over Na2SO4, and the solvent was removed to give
a yellow oil that changed to blue. Purification by flash
chromatography (1:3 ether/ hexane) provided 0.32 g (65%) of
rearranged product 23 at Rf 0.60 (1:1 ether/ hexane): 1H NMR
δ 7.41 (m, 6H), 6.98 (br, 1H), 5.23 (s, 2H), 2.91 (ddd, J ) 18.6,
6.4, 3.0 Hz, 1H), 2.46 (m, 1H), 2.23 (d, J ) 18.6 Hz, 1H), 1.23
(d, J ) 8.4 Hz, 3H); 13C NMR δ 206.2, 153.8, 136.6, 136.1,
129.1, 128.8, 128.6, 67.7, 38.6, 34.3, 16.6; HRMS m/z 268.0957,
calcd for C14H15NO3Na (MNa) 268.0950. The protons at δ 2.91
and 2.23 have NOESY correlation with the vinyl proton at δ
7.41.
Preparation of N-Acetyl-5-anti-acetoxy-3-exo-phenyl-
2-azabicyclo[2.1.1]hexane (18). To a solution of acetate 16
(200 mg, 0.57 mmol) in dry CH2Cl2 (4 mL) was added
B-bromocatecholborane (240 mg, 1.20 mmol) dropwise at room
temperature. The solution was stirred at 25 °C for 2 h, treated
with water (3 mL), and stirred for 20 min, then diluted with
additional CH2Cl2 (30 mL) and washed with 10% NaOH
solution (2 × 10 mL) and brine (5 mL). The organic phase was
dried over MgSO4 and the solvent was removed in vacuo to
give an oil (143 mg). To the crude amine in dry CH2Cl2 (10
mL) at 0 °C was added (dimethylamino)pyridine (244 mg, 2.0
mmol); acetyl chloride (124 mg, 1.2 mmol) was added dropwise
and the mixture was stirred another 30 min at 0 °C, then
slowly warmed to 25 °C and stirred for another 2 h. Water (5
mL) was added to form two layers. The water layer was
extracted with EtOAc (3 × 10 mL). The combined organic
layers were dried over sodium sulfate and filtered, solvent was
removed in vacuo, and the residue was purified by flash
chromatography to afford 59 mg (43%) of amide 18 at Rf 0.15
(1:1 hexane/ethyl acetate): 1H NMR δ 7.23 (m, 5H), 5.23 and
4.95 (two s, 1H), 4.85 and 4.33 (two d, J ) 7.3, 7.2 Hz, 1H),
4.58 and 4.54 (two d, J ) 7.5, 7.4 Hz, 1H), 2.86 (dd, J ) 7.5,
2.0 Hz, 1H), 2.07 (m, 1H), 2.04-1.99 (m, 7H); 13C NMR δ 171.2
and 170.7, 138.4, 128.7, 128.3, 127.8, 127.1, 82.4, 64.0 and 62.1,
60.9 and 60.6, 50.2 and 48.1, 33.1 and 30.7, 22.2 and 20.92;
HRMS m/z 264.0847, calcd for C11H15NO5Na (MNa) 264.0848.
Preparation from Acetate 18 of N-Acetyl-5-anti-
acetoxy-3-exo-methoxycarbonyl-2-azabicyclo[2.1.1]-
hexane (19). To a solution of acetate 18 (120 mg, 0.46 mmol)
in carbon tetrachloride (2 mL), acetonitrile (2 mL), and water
(4 mL) was added sodium metaperiodate (1.9 g, 2.0 mmol). To
this biphasic solution ruthenium trichloride (2.8 mg, 2.2 mol
%) was added and the entire mixture was stirred for 24 h at
room temperature. Then CH2Cl2 (10 mL) was added and the
phases were separated. The aqueous phase was extracted with
CH2Cl2 (3 × 10 mL). The combined organic extracts were dried
over MgSO4 and concentrated to afford crude acid. To the
solution of the crude acid in hexane (10 mL) and 2-propanol
(10 mL) was added a 2 M solution of trimethylsilyldiaz-
omethane in hexane (233 µL).24 The resulting mixture was
stirred under argon for 0.5 h. The solvent was removed in
vacuo to give an oil that was chromatographed on silica gel
(1:2 ether/hexane) to afford 58 mg (52%) of amide 19 at Rf 0.40
(ethyl acetate): 1H NMR (CD3COCD3, 400 MHz) δ 4.63 and
4.30 (two s, 1H), 4.57 and 4.36 (two d, J ) 7.2, 7.2 Hz, 1H),
4.43 (d, J ) 7.2, 1H), 3.70 and 3.60 (two s, 3H), 3.00 and 2.90
(two d, J ) 7.2, 7.2 Hz, 1H), 2.59 (m, 1H, H6), 2.04∼1.66 (m,
7H and acetone); 13C NMR (CD3COCD3, 100 MHz) δ 205.2
(solvent), 170.0, 169.6, 168.7, 167.4, 82.4 and 81.7, 63.4 and
60.0, 58.9 and 57.2, 52.1 and 51.5, 47.1, 46.0, 35.7 and 32.6,
20.9, 20.5 and 19.9; HRMS m/z 281.1095, calcd for C15H17-
NO3Na (MNa) 282.1106.
Preparation of N-Acetyl-5-anti-hydroxy-3-exo-meth-
oxycarbonyl-2-azabicyclo[2.1.1]hexane (4). To a solution
of acetate 19 (241 mg, 1.0 mmol) in methanol (10 mL) was
added triethylamine (505 mg, 5.0 mmol).27 The resulting
mixture was stirred at room temperature for 6 h. The solvent
was removed in vacuo and the resulting mixture was purified
by flash chromatography to provide 199 mg (100%) of alcohol
4 as a colorless liquid at Rf 0.30 (1:15 MeOH/ethyl acetate):
1H NMR (CDCl3, 400 MHz) δ 4.35-3.79 (m, 4H), 3.56 and 3.51
(two s, 3H), 2.69-2.61 (m, 2H), 1.93-1.63 (m, 4H); 13C NMR
594 J. Org. Chem., Vol. 70, No. 2, 2005

3-Carboxy- and 3-Hydroxymethyl-2-azabicyclo[2.1.1]hexanes
N-Benzyloxycarbonyl-5-anti-bromo-6-anti-acetoxy-3-
endo-(phenyldimethylsilylmethyl)-2-azabicyclo[2.1.1]-
hexane (24). Alkene 21 (363 mg, 1 mmol) and NBS (445 mg,
2.5 mmol) in a solution of acetic acid (8 mL), sodium acetate
(205 mg, 2.5 mmol), and acetic anhydride (0.2 mL, 2 mmol)
were stirred at 25 °C for 1 h,22 diluted with CH2Cl2 (20 mL),
washed with 10% NaHCO3 (3 × 10 mL) and brine (10 mL),
dried over MgSO4, and filtered and solvent was removed in
vacuo to provide an oil, which was chromatographed on silica
gel (1:2 ether/hexane) to afford 432 mg (89%) of bromoacetate
24 at Rf 0.50 (1:1 hexane/ether): 1H NMR δ 7.40 (m, 10H),
5.18 (s, 2H), 4.60 (d, J ) 7.4 Hz, 1H), 4.56 (d, J ) 7.2 Hz, 1H),
4.33 (d, J ) 7.4 Hz, 1H), 4.04 (br, 1H), 2.73 (d, J ) 7.2 Hz,
1H), 2.14 (s, 3H), 1.95 and 1.04 (m, 2H), 0.42 (m, 6H); 13C NMR
δ 170.3, 154.9, 136.1, 133.3, 128.5, 128.3, 128.2, 128.0, 127.7,
83.7, 67.1, 65.0, 58.1, 52.7, 47.9, 21.1, 20.0, -2.4, -2.8; HRMS
m/z 524.0856 and 526.0848, calcd for C24H28NO4NaSi79Br
(MNa) 524.0869 and C24H28NO4NaSi81Br (MNa) 526.0839.
N-Benzyloxycarbonyl-5-anti-bromo-6-anti-acetoxy-3-
endo-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane (25). Bro-
mine (80.0 mg, 0.50 mmol) was added dropwise to a stirred
solution of bromoacetate 24 (502 mg, 1.0 mmol) in peracetic
acid (1 mL) and acetic acid (1.5 mL) at 0 °C.30 The disappear-
ance of the starting material was monitored by TLC, and more
bromine (160 mg, 1.0 mmol) was added until none remained.
The resulting mixture was stirred for 5 h at room temperature.
Ether (10 mL) was added to the solution that was then washed
with aqueous sodium thiosulfate solution (5 mL), aqueous
sodium bicarbonate (3 × 5 mL), and brine (5 mL), dried over
MgSO4, and evaporated under reduced pressure. The residue
was chromatographed to give 342 mg (80%) of alcohol 25 at
Rf 0.24 (2:1 ether/hexane): 1H NMR δ 7.41 (m, 5H), 5.22 (s,
2H), 4.68 (d, J ) 7.2 Hz, 1H), 4.63 (d, J ) 7.2 Hz, 1H), 4.13 (d,
J ) 7.2 Hz, 1H), 3.87 (br, 3H), 3.14 (d, J ) 7.2 Hz, 1H), 2.18
(s, 3H); 13C NMR δ 170.4, 156.4, 135.6, 128.4, 128.4, 128.1,
84.0, 68.0, 64.9, 64.1, 62.8, 50.7, 47.4, 21.1; HRMS m/z
406.0252 and 408.0241, calcd for C16H18NO5Na 79Br (MNa)
406.0266 and C16H18NO5Na 81Br (MNa) 408.0246.
N-Benzyloxycarbonyl-5-anti-bromo-6-anti-acetoxy-3-
endo-(methoxycarbonyl)-2-azabicyclo[2.1.1]hexane (14).
To a solution of alcohol 25 (384 mg, 1.0 mmol) in dichlo-
romethane (6.0 mL) containing TEMPO (1.2 mg) was added
saturated NaHCO3 (aq) (3 mL) containing KBr (11 mg) and
tetrabutylammonium chloride (14.2 mg). The mixture was
cooled to 0 °C and a solution of NaOCl (2.5 mL), saturated
NaHCO3 (aq) (2.0 mL), and brine (2.2 mL) was added dropwise
over 45 min. The two layers were separated and the organic
layer was extracted with water (4 × 5 mL). The aqueous layers
were combined and acidified with 10% HCl. The resulting
solution was extracted with EtOAc (4 × 15 mL). The combined
organic solution was dried over Na2SO4. The solvent was
removed to give a crude acid to which was added hexane (15
mL) and 2-propanol (15 mL). A 2 M solution of trimethylsi-
lyldiazomethane in hexane (465 µL) was added and the
resulting mixture was stirred under argon for 0.5 h.24 The
solvent was removed in vacuo to give 330 mg (80% from
alcohol) of ester 14 (see above).
N-H-5-anti-Bromo-6-anti-acetoxy-3-endo-(methoxycar-
bonyl)-2-azabicyclo[2.1.1hexane (26). To a solution of ester
14 (814 mg, 2.0 mmol) in methanol (40 mL) was added 10%
Pd/C (200 mg). The solution was stirred at 25 °C under a
hydrogen balloon for 2 h and filtered through Celite, and
solvent was removed in vacuo to give an oil. Purification by
flash chromatography (1:1 hexane/EtOAc) afforded 487 mg
(85%) of amine 26 at Rf 0.19 (ethyl acetate): 1H NMR (400
MHz) δ 4.71 (d, J ) 7.2 Hz, 1H), 4.00 (d, J ) 7.3 Hz, 1H), 3.98
(br, 1H), 3.81 (d, J ) 7.3 Hz), 3.72 (s, 3H), 3.20 (d, J ) 7.2 Hz,
1H), 3.09 (br, 1H), 2.04 (s, 3H); 13C NMR δ 172.4, 171.0, 84.1,
63.9, 57.7, 53.4, 52.6, 48.6, 21.6; HRMS m/z 278.0027 and
280.0009, calcd for C9H13NO479Br (MH) 278.0028 and C9H13-
NO481Br (MH) 280.0007.
N-Acetyl-5-anti-bromo-6-anti-acetoxy-3-endo-(meth-
oxycarbonyl)-2-azabicyclo[2.1.1-hexane (27). To a solution
of the amine 26 (487 mg, 1.6 mmol) in dry methylene chloride
(20 mL) at 0 °C was added (dimethylamino)pyridine (0.66 g,
4.8 mmol); CH3COCl (373 mg, 4.8 mmol) was added dropwise
and the mixture was stirred another 30 min at 0 °C, then
slowly warmed to 25 °C and stirred for another 2 h. Water (5
mL) was added to form two layers. The water layer was
extracted with EtOAc (3 × 10 mL). The combined organic
layers were dried over sodium sulfate and filtered, solvent was
removed in vacuo, and the residue was purified by flash
chromatography to afford 488 mg (93%) of amide 27 at Rf 0.20
(1:1 hexane/EtOAc): 1H NMR (400 MHz) δ 4.50 (d, J ) 7.5
Hz, 1H), 4.46 (d, J ) 7.2 Hz, 1H), 4.43 (d, J ) 7.5 Hz, 1H),
4.42 (s, 1H), 3.74 (m, 3H), 3.23 (d, J ) 7.2 Hz, 1H), 1.97 (m,
6H); 13C NMR δ 171.1, 170.4, 168.9, 168.2, 83.7 and 83.2, 65.7
and 62.8, 60.9 and 60.5, 53.2 and 52.9, 52.3 and 51.0, 46.1,
21.3 and 21.1; HRMS m/z 341.9951 and 343.9937, calcd for
C11H14NO5 Na 79Br (MNa) 341.9953 and C11H14NO5 Na 81Br
(MNa) 343.9933.
Preparation from Acetate 27 of N-Acetyl-5-anti-acet-
oxy-3-exo-methoxycarbonyl-2-azabicyclo[2.1.1]hexane
(19). To a solution of acetate 27 (412 mg, 1.3 mmol) in benzene
(50 mL) was added tributyltin hydride (0.59 g, 2.05 mmol) and
AIBN (22 mg, 0.13 mmol).25 The resulting mixture was
refluxed for 3 h. Then the solvent was removed in vacuo and
the crude product was purified by chromatography to give 220
mg (93%) of halide free acetate 19 (see above).
Acknowledgment is made to the donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, and the National Science Foun-
dation (CHE 0111208). We thank Professor Hans Reich
for helpful insights.
Supporting Information Available: All experimental
1
procedures, spectroscopic data, as well as copies of H NMR
and 13C NMR for compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO0484171
J. Org. Chem, Vol. 70, No. 2, 2005 595