A new synthesis of 2-azabicyclo[2.1.1]hexanes

Article abstract of DOI:10.1021/jo001790y

An efficient synthesis of the 2-azabicyclo[2.1.1]hexane ring system has been accomplished starting from cis-cyclobut-3-ene-1,2-dicarboxylic anhydride 7, which was prepared using a photochemical method. The key step of this new strategy involved a stereoselective electrophilic addition of phenylselenyl bromide to the double bond of cyclobutene dicarbamate 16 derived from 7. The subsequent ring closure of 17a in the presence of sodium hydride afforded the 2-azabicyclohexane compound 18 with a satisfying overall yield. Reductive removal of the phenylselenyl group and subsequent deprotection led rapidly to the amino derivative 4a functionalized on the carbon ring. Syntheses of the hydroxy and carboxylic derivatives 4b,c were then achieved from the intermediary disulfonamide 23. Displacement of the activated amino group by potassium acetate yielded hydroxy derivative 4b after three additional steps. Finally, oxidation of the alcohol function of 4b under Jones conditions followed by hydrogenolysis afforded the carboxylic derivative 4c, which is the first reported β-isomer of 2,4-methanoproline 1.

Full text of DOI:10.1021/jo001790y

J . Org. Chem. 2001, 66, 4187-4193
4187
A New Syn th esis of 2-Aza bicyclo[2.1.1]h exa n es
Cyrille Lescop, Laurence Me´vellec, and Franc¸ois Huet*
Laboratoire de Synthe`se Organique, UMR CNRS 6011, Faculte´ des Sciences, Universite´ du Maine,
Avenue Olivier Messiaen, F-72085 Le Mans Cedex 9, France
fhuet@univ-lemans.fr
Received December 26, 2000
An efficient synthesis of the 2-azabicyclo[2.1.1]hexane ring system has been accomplished starting
from cis-cyclobut-3-ene-1,2-dicarboxylic anhydride 7, which was prepared using a photochemical
method. The key step of this new strategy involved a stereoselective electrophilic addition of
phenylselenyl bromide to the double bond of cyclobutene dicarbamate 16 derived from 7. The
subsequent ring closure of 17a in the presence of sodium hydride afforded the 2-azabicyclohexane
compound 18 with a satisfying overall yield. Reductive removal of the phenylselenyl group and
subsequent deprotection led rapidly to the amino derivative 4a functionalized on the carbon ring.
Syntheses of the hydroxy and carboxylic derivatives 4b,c were then achieved from the intermediary
disulfonamide 23. Displacement of the activated amino group by potassium acetate yielded hydroxy
derivative 4b after three additional steps. Finally, oxidation of the alcohol function of 4b under
J ones conditions followed by hydrogenolysis afforded the carboxylic derivative 4c, which is the
first reported â-isomer of 2,4-methanoproline 1.
In tr od u ction
2,4-methanoproline 1 is a natural non-protein amino
acid that was isolated in 1980 from the seeds of Ateleia
herbert smithii Pittier, a legume growing on the coast of
Costa Rica (Figure 1).1 It is well-known for its strong
antifeedant activity and protects the seeds of this plant
against at least 100 predators in this habitat. This
compound drew our attention not only for its biological
activity, which makes it of potential use in agrochemistry,
but also for its unusual bicyclic structure. Indeed, this
amino acid contains the 2-azabicyclo[2.1.1]hexane skel-
eton. Since its discovery, 2,4-methanoproline has been
used in the field of peptidomimetics as a constrained
equivalent of L-proline to study its conformational prop-
erties in peptides.2 Replacement of L-proline in small
peptides with this new bicyclic compound resulted in a
selective stabilization of the trans tertiary peptide bond
conformation, which suggests that 2,4-methanoproline
may be a useful L-proline analogue for polypeptide
molecular design. More recently, Piotrowski synthesized
a novel class of rigid nicotine analogues from this
2-azabicyclohexane ring system with the aim to obtain
less toxic biologically active molecules.3
F igu r e 1.
tion of N-vinyl-N-allylamines derived from amino acids,
and the second5 uses an intramolecular cyclization of a
substituted cyclobutylamine.6 Nevertheless, neither of
these routes are readily amenable to synthesis of ana-
logues. Up to now, little work has been devoted to the
preparation of derivatives of 2,4-methanoproline. De
Kimpe and co-worker have reported an interesting 10-
step synthesis of the 2-azabicyclo[2.1.1]hexane system 2,
unsubstituted on the ring carbons, which is based upon
the final ring closure of 1-(N-alkylamino)-3-(chlorometh-
yl)cyclobutane.7 Unfortunately the overall yield is quite
low (1.0-4.0%). Recently, the first synthesis of 5-hydroxy-
2-azabicyclo[2.1.1]hexane 3 has been described by Krow
et al.8 This approach involves an original rearrangement
of a bromohydrin. Access to the bicylic skeleton 3 is short
and requires only four steps; however, the yield of the
key reaction is only 17% and the major compound is an
unrearranged bromohydrin (53%).8a
Two main approaches have been described to prepare
the 1-substituted 2-azabicyclo[2.1.1]hexane skeleton. The
first4 involves an intramolecular [2 + 2] photocycloaddi-
(5) Gaoni, Y. Org. Prep. Proced. Int. 1995, 27, 185.
(6) For more substituted 2-azabicyclo[2.1.1]hexanes, see ref 3 and
(a) 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. (b) Ikeda, M.; Uchino, T.; Takahashi, M.; Ishibashi,
H.; Tamura, Y.; Kido, M. Chem. Pharm. Bull. 1985, 33, 3279. (c)
Swindel, C. S.; Patel, B. P.; deSolms, S. J .; Springer, J . P. J . Org. Chem.
1987, 52, 2346.
(7) Stevens, C.; De Kimpe, N. J . Org. Chem. 1996, 61, 2174.
(8) (a) Krow, G. R.; Lee, Y. B.; Lester, W. S.; Christian, H.; Shaw,
D. A.; Yuan, J . J . Org. Chem. 1998, 63, 8558. (b) Lee, Y. B. Diss. Abstr.
Int. B 1987, 48, 1051. (c) In the course of the refereeing process of this
paper an improvement of synthesis of 2-azabicyclo[2.1.1]hexanols has
been published: 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.
* Tel: 33 2 43 83 33 38. Fax: 33 2 43 83 39 02.
(1) Bell, E. A.; Qureshi, M. Y.; Pryce, R. J .; J anzen, D. H.; Lemke,
P.; Clardy, J . J . Am. Chem. Soc. 1980, 102, 1409.
(2) (a) Talluri, S.; Montelione, G. T.; Van Duyne, G.; Clardy, J .;
Scheraga, H. A. J . Am. Chem. Soc. 1987, 109, 4473. (b) Montelione,
G. T.; Hughes, P.; Clardy, J .; Scheraga, H. A. J . Am. Chem. Soc. 1986,
108, 6765. (c) Mapelli, C.; Van Halbeek, H.; Stammer, C. H. Biopoly-
mers 1990, 29, 407.
(3) Piotrowski, D. W. Synlett 1999, 1091.
(4) (a)Hughes, P.; Clardy, J . J . Org. Chem. 1988, 53, 4793. (b)
Pirrung, M. C. Tetrahedron Lett. 1980, 21, 4577. (c) Hughes, P.; Martin,
M.; Clardy, J . Tetrahedron Lett. 1980, 21, 4579. (d) Tamura, Y.;
Ishibashi, H.; Hirai, M.; Kita, Y.; Ikeda, M. J . Org. Chem. 1975, 40,
2702.
10.1021/jo001790y CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/17/2001

4188 J . Org. Chem., Vol. 66, No. 12, 2001
Lescop et al.
Sch em e 1
of the azide functions with lithium aluminum hydride.
As purification of this crude polar diamine was tricky,
we used it as such in the next step. When it was subjected
to reaction with di-tert-butyl dicarbonate in methanol,14
the expected dicarbamate 16 was easily obtained.
We had noticed that haloselenylation reactions of
cyclobutenes with oxygen substituents proceeded with
excellent stereoselectivities,12 and thus we have antici-
pated that cyclobutene dicarbamate 16 would lead to
similar results. We were pleased to observe that, in this
case, reaction also worked with a good selectivity in favor
of the electrophilic attack syn to the nitrogen substitu-
ents. The expected compound 17 was obtained in 86%
isolated yield as a mixture of two diastereomers, 17a :
17b ) 85:15. The isomers could be separated by column
chromatography. On the other hand, attempts to halo-
selenylate the non protected diamine 15 failed. No
selectivity was observed, and the reaction did not go
quickly to completion (35% conversion in 24 h). The high
preference of 16 for syn-attack is likely to be due to
stabilization of the intermediary selenonium ion by the
lone pair of nitrogen atoms.15 Configurations of 17a and
17b were assigned by several NMR experiments (Figure
2). Carbon atoms linked to the phenylselenyl group were
assessed on the basis of coupling with 77Se: J C-1/Se ) 89.1
Hz for 17a and J C-1/Se ) 91.0 Hz for 17b. The subsequent
1H/13C HETCOR correlations led to assignments of the
corresponding cyclobutane proton H-1, then to the other
In this paper, we report a new route to the synthesis
of 5-substituted 2-azabicyclo[2.1.1]hexane 4 with different
substituents R′ (Scheme 1). From our experience with
cyclobutene chemistry, we envisaged using cis-cyclobut-
3-ene-1,2-dicarboxylic anhydride 7 as the precursor.9 It
is one of the most useful cyclobutene starting materials
because it can give rise to a wide range of compounds.
For instance, anhydride 7 is the source of various
carbocyclic nucleosides10 and dienes.11 Our approach
consisted of the use of the suitable cyclobutene 6, derived
from 7, bearing nitrogen substituents. A stereoselective
electrophilic addition to the double bond of 6 followed by
an intramolecular nucleophilic substitution involving
cyclobutane 5 could afford the expected bicyclic structure.
This new procedure would be an extension to the nitrogen
series of our previous results on synthesis of the
2-oxabicyclo[2.1.1]hexane system 9 from the intramo-
lecular cyclization of the dihydroxymethyl cyclobutane
8.12
1
ones by successive H/1H spin decoupling experiments.
At last, the stereochemistry of compounds 17a and 17b
were unequivocally established on the basis of 1H/1H
correlations observed in the phase-sensitive NOESY
spectra. The major isomer 17a corresponds to the cis-cis
relative relationships between protons H-1, H-3, and H-4.
The bromine atom, in an anti relationship to the car-
bamate groups, is then in the suitable position to gener-
ate the bicyclic system by an intramolecular substitution.
Resu lts a n d Discu ssion
Syn th esis of th e Am in o Der iva tive 4a . The starting
anhydride 7 has been synthesized in two steps from the
commercially available trans-dichloroethene 10 and ma-
leic anhydride 11 using a photochemical method already
described in a previous work (Scheme 2).9a As shown in
Scheme 2, reduction of cyclobutene anhydride 7 with
lithium aluminum hydride in THF at reflux provided diol
12 in excellent yield.11c The latter was converted to
diamine 15 under standard conditions.13 Treatment of
diol 12 with methanesulfonyl chloride and triethyl-
amine,12 followed by nucleophilic substitution with so-
dium azide at 70 °C in DMF afforded diazide 14 in 75%
isolated yield. The latter compound is quite unstable even
at low temperatures (-18 °C) and must be used quickly
for the next step after purification by column chroma-
tography. Diamine 15 was then prepared by reduction
Further treatment of compound 17a with sodium
hydride in DMF led to the expected ring closure, thus
providing the 2-azabicyclo[2.1.1]hexane structure 18
(Scheme 3). This reaction has to be carried out in a dilute
medium (0.02 M) to minimize the intermolecular nucleo-
philic substitution, and a reasonable yield (71%) was
obtained. When we increased the scale slightly (0.07 M
1
concentration) the yield diminished (54%). Both H and
13C NMR spectra are quite complex because, at room
temperature, two conformations are in equilibrium due
to the slow inversion of the nitrogen atom of the bicyclic
skeleton or to the carbamate resonance. The structure
of 18 was assigned by 1H NMR. Indeed, protons H-1 at δ
4.41 and 4.32 and H-4 at δ 2.84 and 2.80 show a four
bond coupling, J 1/4 ) 6.7 Hz. This value is in agreement
with a 2-azabicyclo[2.1.1]hexane system since it is typical
for the coupling of bridgehead protons. Similar coupling
constants (6.3-6.9 Hz) were measured for compounds 27
and 3.8a Subsequent reductive removal of the phenyl-
selenyl group from bicyclic compound 18 with tributyltin
hydride in the presence of AIBN afforded the protected
amino derivative 19 in excellent yield.16 Deprotection of
(9) (a) Gauvry, N.; Comoy, C.; Lescop, C.; Huet, F. Synthesis 1999,
574. (b) Bloomfield, J . J .; Owsley D. C. Org. Photochem. Synth. 1976,
2, 36. (c) Brauman, J . I.; Archie, W. C., J r. J . Am. Chem. Soc. 1972,
94, 4262. (c) Koltzenburg, G.; Fuss, P. G.; Leitich J . Tetrahedron Lett.
1966, 7, 3409.
(10) (a) Gourdel-Martin, M.-E.; Huet, F. J . Org. Chem. 1997, 62,
2166. (b) Me´vellec, L.; Huet, F. Tetrahedron 1997, 53, 5797. (c) J ung,
M. E.; Sledeski, A. W. J . Chem. Soc., Chem. Commun. 1993, 589. (d)
Gauvry, N.; Huet, F. Tetrahedron 1999, 55, 1321. (e) Lescop, C.;
Nguyen-Kim, P.-P.; Huet, F. Tetrahedron Lett. 2000, 41, 3047.
(11) (a) Gourdel-Martin, M.-E.; Huet, F. Tetrahedron Lett. 1996, 37,
7745. (b) Binns, F.; Hayes, R.; Hodgetts, K. J .; Saengchantara, S. T.;
Wallace, T. W.; Wallis, C. J . Tetrahedron 1996, 52, 3631. (c) Binns, F.;
Hayes, R.; Ingham, S.; Saengchantara, S. T.; Turner, R. W.; Wallace,
T. W. Tetrahedron 1992, 48, 515. (d) Trost, B. M.; McDougal, P. G. J .
Org. Chem. 1984, 49, 458.
(14) Ponnusamy, E.; Fotadar, U.; Spisni, A.; Fiat, D. Synthesis 1986,
48.
(15) (a) Cooper, M. A.; Ward, A. D. Tetrahedron Lett. 1995, 36, 2327.
(b) Black, K. A.; Vogel, P. J . Org. Chem. 1986, 51, 5341. (c) Liotta, D.;
Zima, G.; Saindane, M. J . Org. Chem. 1982, 47, 1258.
(16) Nicolaou, K. C.; Seitz, S. P.; Sipio, W. J .; Blount, J . F. J . Am.
Chem. Soc. 1979, 101, 3884.
(12) Me´vellec, L.; Evers, M.; Huet, F. Tetrahedron 1996, 52, 15103.
(13) Fleischer, E. B.; Gebala, A. E.; Levey, A.; Tasker, P. A. J . Org.
Chem. 1971, 36, 3042.

New Synthesis of 2-Azabicyclo[2.1.1]hexanes
J . Org. Chem., Vol. 66, No. 12, 2001 4189
Sch em e 2a
a
Reagents and conditions: (a) hν, EtOAc; (b) Zn, Ac2O, toluene, 80 °C; (c) LiAlH4, THF, reflux; (d) MsCl, Et3N, CH2Cl2; (e) NaN3,
DMF, 75 °C; (f) LiAlH4, THF, reflux; (g) Boc2O, Et3N, DMAP, MeOH; (h) PhSeBr, CH2Cl2.
or carboxylic acid group, as those molecules could exhibit
interesting biological properties (Scheme 4). To achieve
the conversion of the amine function of compound 19 or
4a into a hydroxymethyl group, we used an intermediary
disulfonamide leaving group. We encountered difficulties
when trying to regenerate the amine functions of 19 upon
treatment with trifluoroacetic acid in dichloromethane.
This problem was overcome by the use of the seleno
compound 18, which led under the same experimental
F igu r e 2. Significant phase-sensitive NOESY correlations.
Sch em e 3
conditions to a less polar diamine 20. This crude diamine
was thus obtained quantitatively, and the subsequent
synthesis of the disulfonamide 23 was then achieved in
two steps using tosyl chloride. For the first stage, the
reaction was performed in dichloromethane instead of
DMF. Although the latter is known to be the suitable
solvent for this kind of reaction,17 in our case DMF
induced a partial formylation of sulfonamide 21 into 22.
Moreover, the reaction with the secondary amine function
could not be avoided because it already takes place in
the first step even when using 1 equiv of tosyl chloride.
This is the reason we used an excess of reagent to
transform 20 into sulfonamide 21 alone. The latter was
isolated in 66% yield after column chromatography.
Further treatment of 21 with sodium hydride and tosyl
chloride in DMF afforded the disulfonamide 23 in excel-
lent yield and without formylation. Displacement of the
activated amino group was then achieved with potassium
acetate in the presence of potassium iodide in HMPA
according to the method of Andersen et al.17 The expected
acetate 24 was obtained in high yield together with a
small amount of compound 21 (13%) resulting from a
N-S bond cleavage. Such a side reaction is well-known
in this kind of substitution.18 However, sulfonamide 21
could be recycled. Tributyltin hydride mediated removal
of the phenylselenyl group from 24 then afforded the
desired compound 25 in 77% yield.
the carbamate groups was achieved by treatment with
gaseous hydrogen chloride in methanol to provide quan-
titatively dihydrochloride of 5-methylamino-2-azabicyclo-
[2.1.1]hexane 4a . Thus, this new strategy, which gives a
better yield (30%) than the previous ones, allowed us to
prepare easily the 2-azabicyclo[2.1.1]hexane 18 in a
multigram scale. Furthermore, this key intermediate 18
led to the amino derivative 4a , functionalized on the
carbon ring, which was then obtained in nine steps from
cyclobutene anhydride 7 with a satisfying 27% overall
yield.
Subsequently, we envisioned that the tosyl group could
be removed from the nitrogen atom in a final step to
generate the â-amino acid 4c. The N-toluenesulfonyl
group has been reported to be cleaved with 32% hydro-
bromic acid in acetic acid.19 Unfortunately, this standard
Syn th esis of th e Hyd r oxy a n d Ca r boxylic Der iva -
tives 4b,c. This good result encouraged us to synthesize
bicyclic compounds 4b,c substituted by a hydroxylmethyl
(17) Andersen, N. H.; Uh, H.-S. Synth. Commun. 1972, 2, 297.
(18) Mu¨ller, P.; Nguyen Thi, M. P. Helv. Chim. Acta 1979, 62, 1485.

4190 J . Org. Chem., Vol. 66, No. 12, 2001
Lescop et al.
Sch em e 4a
a
Reagents and conditions: (a) CF3CO2H/CH2Cl2 1:1; (b) TsCl, Et3N, CH2Cl2; (c) TsCl, NaH, DMF; (d) KOAc, KI, HMPA, 120 °C; (e)
n-Bu3SnH, AIBN, toluene, reflux; (f) 32% HBr/AcOH, EtOAc; (g) CbzCl, 1 M NaOH, dioxane; (h) CrO3, H2SO4, acetone, -5 °C; (i) H2,
Pd/C, MeOH.
1
tometer. All melting points are uncorrected. H and 13C NMR
method failed to provide the expected amino acid hydro-
spectra were recorded at 400 and 100.6 MHz, respectively.
bromide. Alternative deprotection procedures involving
Chemical shifts are reported in ppm downfield from TMS,
48% aqueous hydrobromic acid,20 sodium in liquid am-
which was used as the internal reference. In D2O solution,
monia,18 or sodium naphthalenide21 in THF were also
TMS was replaced by DSS. Multiplicities in the 13C spectra
unfruitful and gave only decomposition products, and no
were determined by DEPT experiments, and numerous as-
reaction occurred with magnesium in methanol.22 We
then examined the deprotection in an earlier step.
Exposure of acetate 25 to 32% HBr in acetic acid in a
sealed tube resulted in the formation of the corresponding
amino alcohol hydrobromide after detosylation and si-
multaneous hydrolysis of the ester function. The latter
was purified via its benzyloxycarbonyl derivative 4b,
which was prepared in moderate yield by treatment with
benzyl chloroformate. Further oxidation of the hydroxy
compound 4b under J ones conditions gave the corre-
sponding carboxylic acid 26 in 82% yield. Finally, hydro-
genolysis of 26 afforded quantitatively the free â-amino
acid 4c which is an isomer of 2,4-methanoproline 1.
In conclusion, we have described a new efficient
strategy for the synthesis of the 2-azabicyclo[2.1.1]hexane
system using the ring closure of a cyclobutane intermedi-
ate. This method is convenient for the multigram-scale
preparation of a compound with skeleton 18 and has the
potential to provide several functionalized derivatives.
Biological evaluations of the new 5-substituted 2-azabi-
cyclo[2.1.1]hexanes 4a -c in crop protection have shown
no significant activity. To the best of our knowledge, it
is the first time that a â-isomer of 2,4-methanoproline
has been prepared. In the field of peptidomimetics, it may
be interesting to incorporate the latter into peptides as
a proline constrained analogue and to study the resulting
conformational effects.
signments were obtained by 13C/1H HETCOR and HMBC
experiments. Ratios in mixtures of diastereomers were calcu-
lated from 1H NMR. Elemental analyses were obtained from
the Service de Microanalyse, CNRS ICSN, Gif-sur-Yvette.
High-resolution mass measurements were performed at the
CRMPO, Rennes.
cis-3,4-Bis(a zid om eth yl)cyclobu t-1-en e (14). To a solu-
tion of dimesylate 1312 (18.64 g, 68.95 mmol) in anhydrous
DMF (190 mL) was added sodium azide (9.43 g, 145.05 mmol)
portionwise. The reaction mixture was then stirred at 75 °C
for 3 h. After cooling to room temperature, the mixture was
poured into ice-cold water (350 mL). The aqueous layer was
then extracted with Et2O (5 × 220 mL). The combined organic
layers were dried over MgSO4 and concentrated under reduced
pressure. Purification of the crude product by column chro-
matography (silica gel, cyclohexane/EtOAc; 1/0 f 94/6) af-
forded diazide 14 (9.45 g, 83%) as a colorless oil: IR (neat)
2094, 1263 cm-1; 1H NMR (CDCl3) δ 6.20 (s, 2H, H-1 and H-2),
3.49-3.44 (m, 4H, H-5 and H-6), 3.23 (m, 2H, H-3 and H-4);
13C NMR (CDCl3) δ 138.5 (C-1 and C-2), 51.3 (C-5 and C-6),
45.04 (C-3 and C-4); HRMS calcd for [(C6H8N6) - 2N2]+
108.0687, found 108.0691.
cis-3,4-Bis(a m in om eth yl)cyclobu t-1-en e (15). A solution
of diazide 14 (8.85 g, 53.90 mmol) in anhydrous THF (60 mL)
was added to a suspension of LiAlH4 (6.46 g, 161.71 mmol) in
anhydrous THF (90 mL) at 0 °C under N2 atmosphere. When
the addition was complete, the mixture was heated at reflux
for 18 h. After cooling to 0 °C, the reaction mixture was diluted
with CH2Cl2 (50 mL) and then hydrolyzed with water (12.5
mL). The granular white solid was filtered off and washed
several times with CH2Cl2 (100 mL). The latter was then
extracted for 12 h in a Soxhlet thimble with THF. Both organic
layers were combined and concentrated under reduced pres-
sure to afford the crude diamine 15 (6.78 g) as a pale yellow
oil which was used as such for the next step: IR (neat) 3317,
Exp er im en ta l Section
Gen er a l. All moisture-sensitive reactions were carried out
in oven-dried glassware (110 °C) under nitrogen atmosphere.
Commercially available reagents and solvents were purified
and dried, when necessary, by standard methods just prior to
use. IR spectra were scanned on a FT infrared spectropho-
3045, 1590, 1481 cm-1 1H NMR (CDCl3) δ 6.08 (s, 2H, H-1
;
and H-2), 5.68 (br s, 4H, NH2), 3.34 (m, 2H, H-3 and H-4, J )
10.1, 3.5 Hz), 3.24 (dd, 2H, H-5 and H-6, J ) 12.8, 3.5 Hz),
2.82 (dd, 2H, H-5′ and H-6′, J ) 12.8, 10.1 Hz); 13C NMR
(CDCl3) δ 137.8 (C-1 and C-2), 45.4 (C-3 and C-4), 39.9 (C-5
and C-6); HRMS calcd for C6H12N2 112.1000, found 112.1001.
cis-3,4-Bis(ter t-bu toxyca r bon yla m in om eth yl)cyclobu t-
1-en e (16). Triethylamine (16.70 mL, 0.12 mol) and DMAP
(14.70 g, 0.12 mol) were added to a solution of crude diamine
(19) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1988, 53, 2367.
(20) Maurer, P. J .; Takahata, H.; Rapoport, H. J . Am. Chem. Soc.
1984, 106, 1095.
(21) Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett. 1999, 40, 6181.
(22) Alonso, D. A.; Andersson, P. G. J . Org. Chem. 1998, 63, 9455.

New Synthesis of 2-Azabicyclo[2.1.1]hexanes
J . Org. Chem., Vol. 66, No. 12, 2001 4191
15 (6.78 g) in anhydrous MeOH (120 mL). The mixture was
cooled to 0 °C, and Boc2O (52.80 g, 0.24 mol) was added
portionwise. The reaction mixture was then stirred at room
temperature for 2 h. After evaporation of the solvent the yellow
residue was dissolved in CH2Cl2 (500 mL) and washed suc-
cessively with 0.3 M KHSO4 (350 mL), H2O (100 mL), and
brine (100 mL). Drying of the organic layer over MgSO4 and
evaporation of the solvent gave the crude compound, which
was chromatographed (silica gel, cyclohexane/EtOAc; 9/1 f
4/1) to lead to dicarbamate 16 (13.24 g, 79% from diazide 14)
as white crystals: mp 131-132 °C (petroleum ether/CH2Cl2);
IR (KBr) 3370, 1687, 1525, 1172 cm-1; 1H NMR (CDCl3) δ 6.12
(s, 2H, H-1 and H-2), 4.80 (br s, 2H, NH), 3.28 (m, 4H, H-5
and H-6), 3.06 (m, 2H, H-3 and H-4), 1.44 (s, 18H, (CH3)3C);
13C NMR (CDCl3) δ 156.0 (CdO), 138.5 (C-1 and C-2), 79.3
((CH3)3C), 46.0 (C-3 and C-4), 40.4 (C-5 and C-6), 28.4
((CH3)3C). Anal. Calcd for C16H28N2O4: C, 61.51; H, 9.03; N,
8.97. Found: C, 61.56; H, 8.88; N, 8.72.
H-7′), 2.84 (m, 0.5H, H-4), 2.80 (m, 0.5H, H-4), 2.71 (m, 0.5H,
H-7′), 2.22 (m, 0.5H, H-6), 2.15 (m, 0.5H, H-6), 1.51 (s, 4.5H,
(CH3)3C), 1.46 (s, 4.5H, (CH3)3C), 1.43 (s, 4.5H, (CH3)3C), 1.42
(s, 4.5H, (CH3)3C); 13C NMR (CDCl3) δ 157.1 (CdO), 156.9 (Cd
O), 155.9 (CdO), 155.8 (CdO), 133.8 (CH, arom), 133.0 (CH,
arom), 129.4 (quat C, arom), 129.1 (CH, arom), 129.0 (CH,
arom), 127.3 (CH, arom), 127.1 (CH, arom), 80.1 ((CH3)3C), 79.7
((CH3)3C), 79.5 ((CH3)3C), 79.4 ((CH3)3C), 64.6 (CH), 63.7 (CH),
47.9 (CH), 47.8 (CH), 45.9 (CH); 45.4 (CH), 44.7 (CH2), 44.1
(CH), 44.0 (CH2), 43.9 (CH), 36.9 (CH2), 28.4 ((CH3)3C), 28.3
((CH3)3C). Anal. Calcd for C22H32N2O4Se: C, 56.53; H, 6.90;
N, 5.99; Se, 16.89. Found: C, 56.23; H, 6.64; N, 6.04; Se, 16.60.
(1R*,4S*,5R*)-2-N-ter t-Bu toxycar bon yl-5-N-ter t-bu toxy-
ca r bon yla m in om eth yl-2-a za bicyclo[2.1.1]h exa n e (19). To
a solution of seleno compound 18 (1.60 g, 3.42 mmol) in freshly
distilled toluene (18.5 mL) were added n-Bu3SnH (2.76 mL,
10.26 mmol) and a solution of AIBN (0.02M) in toluene (5.13
mL, 0.10 mmol). The mixture was degassed with a steam of
N2 for 15 min, and heated to reflux for 12 h. The reaction
mixture was then cooled to room temperature, and the solvent
was removed in vacuo. The residue was purified by column
chromatography (silica gel, cyclohexane/EtOAc: 98/2 f 7/3)
followed by a recrystallization (iPr2O) to afford compound 19
(984 mg, 92%) as white crystals: mp 86-87 °C; IR (KBr) 3384,
(1S*,2S*,3S*,4R*)-2-Br om o-3,4-b is(N-ter t-b u t oxyca r -
bon yla m in om et h yl)-1-p h en ylselen ylcyclob u t a n e (17a )
a n d (1S*,2S*,3R*,4S*)-2-Br om o-3,4-bis(N-ter t-bu toxyca r -
bon yla m in om eth yl)-1-p h en ylselen ylcyclobu ta n e (17b). A
solution of phenylselenyl bromide (10.31 g, 42.82 mmol) in
anhydrous CH2Cl2 (190 mL) was added dropwise to a solution
of cyclobutene dicarbamate 16 (13.11 g, 41.96 mmol) in
anhydrous CH2Cl2 (130 mL) at 0 °C under N2 atmosphere. The
reaction mixture was then stirred at room temperature
overnight, and the solvent was evaporated in vacuo. The ratio
of isomers, 17a :17b ) 85:15, was measured by 1H NMR of the
residue. Purification by column chromatography (silica gel,
cyclohexane/EtOAc; 1/0 f 5/1) afforded seleno compounds 17a
(16.78 g, 73%) and 17b (3.02 g, 13%) both as white crystals.
Major isomer 17a : mp 165-166 °C (petroleum ether/CH2Cl2);
IR (KBr) 3361, 1681, 1519, 1170 cm-1; 1H NMR (CDCl3) δ 7.54
(m, 2H, H arom), 7.28 (m, 3H, H arom), 5.21 (br s, 1H, NH),
4.73 (br s, 1H, NH), 4.11 (m, 1H, H-2), 4.06 (m, 1H, H-1), 3.39
(m, 2H, H-5), 3.32 (m, 1H, H-6), 3.25 (m, 1H, H-6′), 2.99 (m,
1H, H-4), 2.86 (m, 1H, H-3), 1.44 (s, 9H, (CH3)3C), 1.42 (s, 9H,
(CH3)3C); 13C NMR (CDCl3) δ 155.9 (CdO), 155.7 (CdO), 133.4
(CH, arom), 129.3 (CH, arom), 129.0 (quat C, arom), 127.7 (CH,
arom), 79.7 ((CH3)3C), 79.5 ((CH3)3C), 48.5 (C-1), 47.4 (C-2),
47.3 (C-3), 41.2 (C-4), 39.3 (C-6), 38.9 (C-5), 28.4 ((CH3)3C),
28.3 ((CH3)3C), J (13C/77Se) ) 89 Hz. Anal. Calcd for C22H33N2O4-
BrSe: C, 48.19; H, 6.06; N, 5.11; Br, 14.57; Se, 14.40. Found:
C, 48.03; H, 6.06; N, 5.16; Br, 14.53; Se, 14.37. Minor isomer
17b: mp 154-155 °C (petroleum ether/CH2Cl2); IR (KBr) 3365,
1720, 1687, 1520, 1182 cm-1 1H NMR (CDCl3) δ 4.60 (br s,
;
0.5H, NH), 4.49 (br s, 0.5H, NH), 4.30 (d, 0.5H, H-1, J ) 5.6
Hz), 4.21 (d, 0.5H, H-1, J ) 5.6 Hz), 3.22 (m, 2H, H-3), 3.09
(m, 0.5H, H-7), 2.95 (m, 0.5H, H-7), 2.70 (m, 1.5H, H-7′ and
H-4), 2.53 (m, 0.5H, H-7′), 2.17 (m, 1H, H-5); 1.69 (m, 1H, H-6),
1.47 (s, 9H, (CH3)3C), 1.43 (s, 9H, (CH3)3C), 1.32 (m, 1H, H-6′);
13C NMR (CDCl3) δ 156.7 (CdO), 156.5 (CdO), 156.0 (CdO),
155.8 (CdO), 79.5 ((CH3)3C), 79.4 ((CH3)3C), 79.2 ((CH3)3C),
61.3 (CH), 60.2 (CH), 47.7 (CH), 47.6 (CH), 46.3 (CH2), 45.5
(CH2), 39.4 (CH), 39.1 (CH), 37.8 (CH2), 37.6 (CH2), 36.6 (CH2),
28.4 ((CH3)3C), 28.3 ((CH3)3C). Anal. Calcd for C16H28N2O4: C,
61.51; H, 9.03; N, 8.97. Found: C, 61.63; H, 9.02; N, 8.91.
(1R*,4S*,5R*)-5-Am in om et h yl-2-a za bicyclo[2.1.1]h ex-
a n e Dih yd r och lor id e (4a ). A saturated solution of HCl in
MeOH (16.0 mL) was added with stirring to a solution of
bicyclo dicarbamate 19 (250 mg, 0.80 mmol) in MeOH (1.0 mL)
at -5 °C. The mixture was stirred at room temperature for 3
h, and then N2 was bubbled for 2 h to remove the excess of
gaseous HCl. The solvent was evaporated under reduced
pressure, and the yellow residue was stirred at reflux in a
solution of Et2O/MeOH (1/1) to provide, after filtration, the
amino dihydrochloride 4a (146 mg, 99%) as a white solid: dec
246 °C; IR (KBr) 3300-2400, 1610, 1525 cm-1; 1H NMR (D2O)
δ 4.28 (m, 1H, H-1, J ) 6.1, 1.0 Hz), 3.41 (d, 1H, H-3, J ) 11.0
Hz), 3.39 (d, 1H, H-3′, J ) 11.0 Hz), 3.04 (m, 1H, H-4, J ) 6.1
Hz), 2.93 (dd, 1H, H-7, J ) 13.9, 7.1 Hz), 2.88 (dd, 1H, H-7′,
J ) 13.9, 7.8 Hz), 2.57 (m, 1H, H-5, J ) 7.8, 7.1 Hz), 2.02 (m,
1H, H-6, J ) 9.5, 1.0 Hz), 1.43 (d, 1H, H-6′, J ) 9.5 Hz); 13C
NMR (D2O) δ 62.0 (CH), 45.3 (CH2), 44.2 (CH), 40.6 (CH), 36.3
(CH2), 35.7 (CH2). Anal. Calcd for C6H14N2Cl2: C, 38.93; H,
7.62; N, 15.13; Cl, 38.31. Found: C, 38.73; H, 7.47; N, 15.12;
Cl, 38.16; HRMS calcd for [(C6H14N2Cl2) - H - 2(HCl)]+
111.0922, found 111.0922.
1681, 1519, 1168 cm-1 1H NMR (CDCl3) δ 7.61 (m, 2H, H
;
arom), 7.33 (m, 3H, H arom), 5.16 (br s, 1H, NH), 4.83 (br s,
1H, NH), 4.20 (m, 1H, H-2), 3.65 (m, 1H, H-1), 3.43 (m, 2H,
H-6), 3.32 (m, 2H, H-5), 2.72 (m, 1H, H-3), 2.33 (m, 1H, H-4),
1.45 (s, 9H, (CH3)3C), 1.41 (s, 9H, (CH3)3C); 13C NMR (CDCl3)
δ 155.8 (CdO), 155.6 (CdO), 136.4 (CH, arom), 129.2 (CH,
arom), 128.6 (CH, arom), 126.3 (quat C, arom), 79.5 ((CH3)3C),
48.2 (C-2), 47.9 (C-1), 41.6 (C-3), 41.3 (C-4), 39.8 (CH2), 39.0
(CH2), 28.4 ((CH3)3C), 28.3 ((CH3)3C), J (13C/77Se) ) 91 Hz.
Anal. Calcd for C22H33N2O4BrSe: C, 48.19; H, 6.06; N, 5.11;
Br, 14.57; Se, 14.40. Found: C, 47.98; H, 6.04; N, 4.92; Br,
14.71; Se, 14.22.
(1S*,4S*,5R*,6R*)-6-Am in om et h yl-5-p h en ylselen yl-2-
a za bicyclo[2.1.1]h exa n e (20). Trifluoroacetic acid (14.5 mL)
was added to a solution of compound 18 (2.37 g, 5.07 mmol)
in CH2Cl2 (14.5 mL) at 0 °C. The mixture was stirred at room
temperature for 2 h and then cooled to 0 °C. A 20% NaOH
solution was carefully added until pH 10, and the mixture was
extracted with CH2Cl2 (10 × 80 mL). The combined organic
layers were washed with brine (60 mL), dried over K2CO3, and
concentrated under reduced pressure to yield crude diamine
20 (1.33 g, 98%) as a pale yellow oil: IR (neat) 3500-3200,
(1S*,4S*,5R*,6R*)-2-N-ter t-Bu t oxyca r b on yl-6-N-ter t-
b u t oxyca r b on yla m in om et h yl-5-p h en ylselen yl-2-a za b i-
cyclo[2.1.1]h exa n e (18). Sodium hydride (60% dispersion in
mineral oil, 1.40 g, 35.00 mmol) was added portionwise to a
solution of compound 17a (6.39 g, 11.65 mmol) in anhydrous
DMF (610 mL) at 0 °C. The mixture was then stirred at room
temperature for 2 days. Water (0.4 mL) was added, and solvent
was removed under reduced pressure. Purification of the
residue by column chromatography (silica gel, cyclohexane/
EtOAc; 5/1 f 5/2) provided bicyclic compound 18 (3.87 g, 71%)
as a white solid: mp 135-137 °C; IR (KBr) 3365, 2975, 1687,
1
2985, 1577, 1477, 735, 690 cm-1; H NMR (CDCl3) δ 7.46 (m,
2H, arom), 7.24 (m, 3H, arom), 3.59 (m, 1H, H-1, J ) 6.0 Hz),
3.36 (m, 1H, H-5), 2.89 (d, 1H, H-3, J ) 9.7 Hz), 2.81 (m, 1H,
H-4, J ) 6.0 Hz), 2.75 (d, 1H, H-3′, J ) 9.7 Hz), 2.68 (dd, 1H,
H-7, J ) 12.8, 7.8 Hz), 2.58 (dd, 1H, H-7′, J ) 12.8, 6.2 Hz),
1.80 (m, 1H, H-6, J ) 7.8, 6.2 Hz), 1.63 (br s, 3H, NH and
NH2); 13C NMR (CDCl3) δ 132.8 (CH, arom), 129.6 (quat C,
arom), 129.0 (CH, arom), 126.9 (CH, arom), 61.6 (CH), 48.6
1388, 1172 cm-1 1H NMR (CDCl3) δ 7.51 (m, 1H, H arom),
;
7.47 (m, 1H, H arom), 7.25 (m, 3H, H arom), 4.63 (br s, 0.5H,
NH), 4.56 (br s, 0.5H, NH), 4.41 (m, 0.5H, H-1, J ) 6.7 Hz),
4.32 (m, 0.5H, H-1, J ) 6.7 Hz), 3.51 (d, 0.5H, H-3, J ) 9.7
Hz), 3.44 (m, 1.5H, H-5 and H-3), 3.25 (d, 1H, H-3′, J ) 9.7
Hz), 3.19 (m, 0.5H, H-7), 3.06 (m, 0.5H, H-7), 2.90 (m, 0.5H,

4192 J . Org. Chem., Vol. 66, No. 12, 2001
Lescop et al.
(CH), 46.9 (CH), 44.6 (CH), 42.1 (CH2), 38.0 (CH2); HRMS calcd
for C12H16N2Se 268.0479, found 268.0491.
7.74 (m, 4H, arom), 7.36 (m, 2H, arom), 7.30 (m, 6H, arom),
7.25 (m, 3H, arom), 4.37 (m, 1H, H-1, J ) 6.8 Hz), 3.66 (d, 1H,
H-3, J ) 8.6 Hz), 3.60 (d, 2H, H-7, J ) 5.6 Hz), 3.47 (d, 1H,
H-3′, J ) 8.6 Hz), 3.39 (m, 1H, H-5), 2.90 (m, 1H, H-4, J ) 6.8
Hz), 2.45 (s, 6H, 2 × CH3), 2.42 (s, 3H, CH3), 2.41 (m, 1H, H-6,
J ) 5.6 Hz); 13C NMR (CDCl3) δ 145.1 (quat C, arom), 143.2
(quat C, arom), 138.1 (quat C, arom), 136.1 (quat C, arom),
133.3 (CH, arom), 129.7 (CH, arom), 129.5 (CH, arom), 129.2
(CH, arom), 129.1 (quat C, arom), 128.2 (CH, arom), 127.4 (CH,
arom), 127.0 (CH, arom), 67.9 (CH), 47.9 (CH), 46.4 (CH), 45.8
(CH), 45.6 (CH2), 45.1 (CH2), 21.6 (CH3), 21.5 (CH3). Anal.
Calcd for C33H34N2O6S3Se: C, 54.31; H, 4.70; N, 3.84; S, 13.18;
Se, 10.83. Found: C, 54.21; H, 4.61; N, 3.88; S, 13.18; Se, 10.50.
(1S*,4S*,5R*,6S*)-6-Acetoxym eth yl-5-p h en ylselen yl-2-
N-p-tolu en esu lfon yl-2-a za -bicyclo[2.1.1]h exa n e (24). Di-
tosylamine 23 (1.15 g, 1.57 mmol) in anhydrous HMPA (7.8
mL) was treated with anhydrous potassium iodide (785 mg,
4.73 mmol) and anhydrous potassium acetate (465 mg, 4.73
mmol) at 120-130 °C for 5 days under N2 atmosphere. After
cooling to 0 °C, the reaction mixture was diluted with CH2-
Cl2. The organic layer was then washed with H2O (90 mL),
dried over MgSO4, and concentrated under reduced pressure.
The orange residue was purified by column chromatography
(silica gel, cyclohexane/EtOAc; 95/5 f 7/3) to yield acetate 24
(591 mg, 81%) as white crystals: mp 110-112 °C (Et2O/CH2-
(1S*,4S*,5R*,6R*)-5-P h en ylselen yl-2-N-p-tolu en esu lfo-
n yl-6-N-(p-t olu en esu lfon yl)-a m in om et h yl-2-a za bicyclo-
[2.1.1]h exa n e (21). To a solution of diamine 20 (0.64 g, 2.39
mmol) in anhydrous CH2Cl2 (6.6 mL) at 0 °C were added
triethylamine (1.33 mL, 9.57 mmol) and tosyl chloride (1.60
g, 8.39 mmol) portionwise under N2 atmosphere. The mixture
was then stirred at room temperature for 16 h. After cooling
to 0 °C, the reaction mixture was diluted with CH2Cl2 (100
mL) and washed with 10% HCl (100 mL). The aqueous layer
was extracted twice with CH2Cl2 (2 × 100 mL). The combined
organic layers were then dried over MgSO4 and concentrated
in vacuo. The orange residue was purified by column chroma-
tography (silica gel, cyclohexane/EtOAc; 9/1 f 7/3) to afford
compound 21 (0.91 g, 66%) as white crystals: mp 150-151 °C
(Et2O/CH2Cl2); IR (KBr): 3269, 1340, 1155 cm-1 1H NMR
;
(CDCl3) δ 7.79 (m, 2H, arom), 7.73 (m, 2H, arom), 7.31 (m,
6H, arom), 7.27-7.18 (m, 3H, arom), 5.04 (dd, 1H, NH, J )
8.8, 4.7 Hz), 4.22 (ddd, 1H, H-1, J ) 6.6, 1.6, 1.2 Hz), 3.51 (d,
1H, H-3, J ) 8.6 Hz), 3.47 (d, 1H, H-3′, J ) 8.6 Hz), 3.44 (dd,
1H, H-5, J ) 2.7, 1.6 Hz), 3.00 (ddd, 1H, H-7, J ) 14.1, 8.8,
6.2 Hz), 2.88 (ddd, 1H, H-4, J ) 6.6, 2.8, 2.7 Hz), 2.78 (ddd,
1H, H-7′, J ) 14.1, 9.1, 4.7 Hz), 2.43 (s, 3H, CH3), 2.42 (s, 3H,
CH3), 2.34 (m, 1H, H-6, J ) 9.1, 6.2, 2.8, 1.2 Hz); 13C NMR
(CDCl3) δ 143.5 (quat C, arom), 143.4 (quat C, arom), 138.2
(quat C, arom), 136.9 (quat C, arom), 133.2 (CH, arom), 129.7
(CH, arom), 129.6 (CH, arom), 129.2 (CH, arom), 128.9 (quat
C, arom), 127.4 (CH, arom), 127.0 (CH, arom), 126.8 (CH,
arom), 66.9 (CH), 48.2 (CH), 45.8 (CH), 45.6 (CH2), 44.2 (CH),
39.5 (CH2), 21.6 (CH3), 21.5 (CH3). Anal. Calcd for C26H28N2O4S2-
Se: C, 54.25; H, 4.90; N, 4.87; S, 11.14. Found: C, 54.03; H,
4.83; N, 4.74; S, 11.18.
1
Cl2); IR (KBr) 1736, 1336, 1248, 1153 cm-1; H NMR (CDCl3)
δ 7.80 (m, 2H, arom), 7.41 (m, 2H, arom), 7.30 (m, 2H, arom),
7.27-7.19 (m, 3H, arom), 4.41 (m, 1H, H-1, J ) 6.8 Hz), 3.95
(dd, 1H, H-7, J ) 11.7, 7.2 Hz), 3.86 (dd, 1H, H-7′, J ) 11.7,
6.8 Hz), 3.57 (d, 1H, H-3, J ) 8.3 Hz), 3.48 (m, 1H, H-5), 3.45
(d, 1H, H-3′, J ) 8.3 Hz), 2.93 (m, 1H, H-4, J ) 6.8 Hz), 2.43
(s, 3H, CH3), 2.30 (m, 1H, H-6, J ) 7.2, 6.8 Hz), 2.00 (s, 3H,
CH3); 13C NMR (CDCl3) δ 170.7 (CdO), 143.2 (quat C, arom),
138.3 (quat C, arom), 133.4 (CH, arom), 129.5 (CH, arom),
129.1 (CH, arom), 127.4 (CH, arom), 126.8 (CH, arom), 67.3
(CH), 60.3 (CH2), 48.4 (CH), 45.1 (CH2), 44.8 (2 × CH), 21.5
(CH3), 20.7 (CH3); HRMS calcd for C21H23NO4SSe 465.0513,
found 465.0532.
(1S*,4S*,5R*,6R*)-5-P h en ylselen yl-2-N-p-tolu en esu lfo-
n yl-6-N-(p -t olu en esu lfon yl)-for m a m id om et h yl-2-a za b i-
cyclo[2.1.1]h exa n e (22). If DMF was used as solvent for the
preparation of 21, the byproduct 22, resulting from formylation
reaction of 21, was isolated. The quantity of 22 increased
proportionally to the reaction time; after 48 h of stirring a
mixture 21/22 in a 1.9:1 ratio was then obtained (overall yield
) 58%): mp 148-150 °C (Et2O/CH2Cl2); IR (KBr) 3448, 1693,
(1R*,4S*,5S*)-5-Acetoxym eth yl-2-N-p-tolu en esu lfon yl-
2-a za b icyclo[2.1.1]h exa n e (25). The reaction was run in
the same experimental conditions as for 19 (except reaction
time ) 72 h) and starting from seleno compound 24 (583 mg,
1.25 mmol) in toluene (6.8 mL), n-Bu3SnH (1.05 mL, 3.61
mmol), and a 0.02 M AIBN toluene solution (1.90 mL; 0.04
mmol). Bicyclo compound 25 (299 mg, 77%) was thus obtained
as white crystals: mp 126-127 °C (Et2O/CH2Cl2); IR (KBr)
1
1358, 1346, 1192, 1163 cm-1; H NMR (CDCl3) δ 9.04 (s, 1H,
CHO), 7.81 (m, 2H, arom), 7.73 (m, 2H, arom), 7.36 (m, 4H,
arom), 7.31-7.19 (m, 5H, arom), 4.39 (ddd, 1H, H-1, J ) 6.8,
1.5, 1.4 Hz), 3.76 (d, 1H, H-3, J ) 8.5 Hz), 3.48 (d, 1H, H-3′,
J ) 8.5 Hz), 3.46 (dd, 1H, H-7, J ) 14.9, 8.8 Hz), 3.41 (dd, 1H,
H-5, J ) 2.6, 1.5 Hz), 3.30 (dd, 1H, H-7′, J ) 14.9, 3.5 Hz),
2.92 (ddd, 1H, H-4, J ) 6.8, 2.7, 2.6 Hz), 2.47 (s, 3H, CH3),
2.41 (s, 3H, CH3), 2.31 (m, 1H, H-6, J ) 8.8, 3.5, 2.7, 1.4 Hz);
13C NMR (CDCl3) δ 161.4 (CdO), 145.8 (quat C, arom), 143.2
(quat C, arom), 138.1 (quat C, arom), 134.1 (quat C, arom),
133.3 (CH, arom), 130.4 (CH, arom), 129.5 (CH, arom), 129.1
(CH, arom), 129.0 (quat C, arom), 127.5 (CH, arom), 127.4 (CH,
arom), 127.0 (CH, arom), 67.8 (CH), 48.0 (CH), 45.7 (CH), 45.2
(CH2), 45.1 (CH), 39.5 (CH2), 21.7 (CH3), 21.5 (CH3). Anal.
Calcd for C27H28N2O5S2Se‚0.2H2O: C, 53.41; H, 4.71; N, 4.61;
S, 10.56; Se, 13.00. Found: C, 53.21; H, 4.66; N, 4.51; S, 10.72;
Se, 12.86.
1
1737, 1340, 1246, 1155 cm-1; H NMR (CDCl3) δ 7.73 (d, 2H,
arom, J ) 8.2 Hz), 7.31 (d, 2H, arom, J ) 8.2 Hz), 4.21 (ddd,
1H, H-1, J ) 6.8, 1.9, 1.1 Hz), 3.98 (dd, 1H, H-7, J ) 11.6, 7.0
Hz), 3.94 (dd, 1H, H-7′, J ) 11.6, 6.8 Hz), 3.32 (d, 1H, H-3,
J ) 8.8 Hz), 3.15 (d, 1H, H-3′, J ) 8.8 Hz), 2.69 (ddd, 1H, H-4,
J ) 6.8, 3.0, 2.8 Hz), 2.43 (s, 3H, CH3), 2.28 (m, 1H, H-5, J )
7.0, 6.8, 3.0, 1.9 Hz), 2.02 (s, 3H, CH3), 1.42 (ddd, 1H, H-6,
J ) 8.1, 2.8, 1.1 Hz), 0.68 (d, 1H, H-6′, J ) 8.1 Hz); 13C NMR
(CDCl3) δ 171.0 (CdO), 143.6 (quat C, arom), 135.6 (quat C,
arom), 129.8 (CH, arom), 127.7 (CH, arom), 63.6 (CH), 60.0
(CH2), 47.1 (CH2), 46.8 (CH), 39.6 (CH), 35.3 (CH2), 21.5 (CH3),
20.8 (CH3). Anal. Calcd for C15H19NO4S‚0.2H2O: C, 57.56; H,
6.25; N, 4.47; S, 10.24. Found: C, 57.63; H, 6.21; N, 4.35; S,
10.15.
(1S*,4S*,5R*,6R*)-5-P h en ylselen yl-2-N-p-tolu en esu lfo-
n yl-6-N,N-d i-(p -t olu en esu lfon yl)-a m in om et h yl-2-a za b i-
cyclo[2.1.1]h exa n e (23). Sodium hydride (60% dispersion in
mineral oil, 201 mg, 5.02 mmol) was added portionwise to a
solution of compound 21 (0.95 g, 1.65 mmol) in anhydrous
DMF (53 mL) at 0 °C. The mixture was then stirred at room
temperature for 15 min under N2 atmosphere and cooled again
to 0 °C. Tosyl chloride (635 mg, 3.33 mmol) was added
portionwise, and the reaction mixture was stirred at room
temperture overnight. Water (15 mL) was then added, and the
aqueous solution was extracted with CH2Cl2 (2 × 30 mL). The
combined organic layers were dried over MgSO4 and concen-
trated under reduced pressure. Purification of the orange
residue by column chromatography (silica gel, cyclohexane/
EtOAc; 95/5 f 3/1) afforded ditosylamine 23 (1.13 g, 94%) as
white crystals: 171-172 °C (Et2O/CH2Cl2); IR (KBr) 1373,
1167, 1153, 815 cm-1; 1H NMR (CDCl3) δ 7.82 (m, 2H, arom),
(1R*,4S*,5S*)-5-Hyd r oxym eth yl-2-N-ben zyloxyca r bon -
yl-2-a za bicyclo[2.1.1]h exa n e (4b). A solution of 25 (75 mg,
0.24 mmol) in EtOAc (2 mL) was added in four portions over
2 h to a 32% solution of HBr in AcOH (3 mL) at 0 °C. Then
the flask was sealed. After an additionnal 60 h of stirring at
room temperature, the reaction mixture was cooled to 0 °C,
and H2O (6 mL) was added. The aqueous phase was washed
with CH2Cl2 (2 × 3 mL) before being evaporated to dryness in
vacuo to yield the corresponding crude amino alcohol hydro-
bromide (31 mg, 66%), which was purified via its benzyloxy-
carbonyl derivative 4b. Amino alcohol hydrobromide (25 mg,
0.13 mmol) was added to a 1 M aqueous NaOH solution (260
µL, 0.26 mmol). After cooling to 0 °C, seven equal portions of
(benzyloxy)carbonyl chloride (26 µL, 0.15 mmol) in dioxane
(280 µL) were added to this solution, alternatively with seven

New Synthesis of 2-Azabicyclo[2.1.1]hexanes
J . Org. Chem., Vol. 66, No. 12, 2001 4193
portions of 1 M aqueous NaOH (7 × 15 µL) over a 1 h period.
The mixture was allowed to warm to room temperature over
3 h, stirred for an additional 16 h, and basified to pH 12 with
NaOH. The mixture was stirred for 1 h and extracted with
CH2Cl2 (3 × 4 mL). The combined organic layers were dried
over MgSO4 and evaporated under reduced pressure. Purifica-
tion by column chromatography (silica gel, cyclohexane/EtOAc;
1/2) afforded hydroxy derivative 4b (21 mg, 66% (44% from
5.15 (m, 2H, CH2 benzylic), 4.68 (m, 1H, H-1), 3.67 (m, 1H,
H-3, J ) 8.9 Hz), 3.36 (d, 1H, H-3′, J ) 8.9 Hz), 3.09 (m, 1H,
H-4), 2.84 (m, 1H, H-5), 1.82 (m, 1H, H-6, J ) 7.8 Hz), 1.35 (d,
1H, H-6′, J ) 7.8 Hz); 13C NMR (CDCl3) δ 172.9 (CdO), 156.6
(CdO), 136.7 (quat C, arom), 128.4 (CH, arom), 127.9 (CH,
arom), 127.8 (CH, arom), 66.9 (CH2), 62.2 (CH), 50.0 (CH), 46.7
(CH2), 41.0 (CH), 37.9 (CH2); HRMS calcd for C14H15NO4
261.1001, found 261.0998.
25)) as a colorless oil: IR (neat) 3406, 1693, 1425 cm-1
;
1H
(1R*,4S*,5S*)-2-Aza bicyclo[2.1.1]h exa n e-5-ca r boxylic
Acid (4c). A suspension of compound 26 (12 mg, 0.05 mmol)
and 10% Pd/C (12 mg) in MeOH (7 mL) was stirred for 12 h
under H2 (1 atm) at room temperature. The palladium carbon
catalyst was then filtered off, washed with H2O (2 mL), and
the solution was concentrated in vacuo to give â-amino acid
4c (6 mg, 100%) as a pale yellow oil: IR (neat) 3452, 1578,
NMR (CDCl3) δ 7.35 (m, 5H, arom), 5.16 (m, 2H, CH2 benzylic),
4.42 (m, 1H, H-1), 3.28 (m, 4H, H-3 and H-7), 2.77 (m, 1H,
H-4), 2.24 (m, 1H, H-5), 2.10 (br s, 1H, OH), 1.75 (m, 1H, H-6,
J ) 7.4 Hz), 1.35 (d, 1H, H-6′, J ) 7.4 Hz); 13C NMR (CDCl3)
δ 156.7 (CdO), 136.8 (quat C, arom), 128.5 (CH, arom), 128.0
(CH, arom), 127.9 (CH, arom), 66.8 (CH2), 61.1 and 60.7 (CH),
58.4 and 58.2 (CH2), 50.0 and 49.6 (CH), 46.2 and 46.0 (CH2),
39.2 and 38.9 (CH), 38.3 and 38.0 (CH2); HRMS calcd for
C14H17NO3 247.1208, found 247.1210.
(1R*,4S*,5S*)-2-N-Ben zyloxycar bon yl-2-azabicyclo[2.1.1]-
h exa n e-5-ca r boxylic Acid (26). Alcohol 4b (21 mg, 0.08
mmol) dissolved in acetone (0.6 mL) was added dropwise to a
solution of freshly prepared J ones reagent (76 µL) in acetone
(0.6 mL) at -5 °C over a period of 2 h. The reaction mixture
was stirred at room temperature for 4 h, and then iPrOH
(10 µL) was added at 0 °C. The mixture was filtered through
Celite and washed with acetone (2 mL). The solvent was
evaporated in vacuo, and the residue was dissolved in CH2Cl2
and extracted with a 1 M aqueous NaOH (3 mL). The basic
aqueous layer was then acidified with concentrated H2SO4 (pH
1-2) and extracted with CH2Cl2 (3 × 3 mL). The combined
organic layers were dried over MgSO4, and evaporation of the
solvent provided carboxylic acid 26 (18 mg, 82%) as white
crystals. It was pure enough to be used as such in the next
step: mp 97-99 °C; IR (KBr) 3442, 1705, 1674, 1436 cm-1; 1H
NMR (CDCl3) δ 8.10 (br s, 1H, CO2H), 7.30 (m, 5H, arom),
1
1419 cm-1; H NMR (D2O) δ 4.15 (m, 1H, H-1, J ) 5.9 Hz),
3.27 (d, 1H, H-3, J ) 10.3 Hz), 3.21 (d, 1H, H-3′, J ) 10.3 Hz),
3.03 (m, 1H, H-4, J ) 5.9 Hz), 2.89 (m, 1H, H-5), 1.87 (m, 1H,
H-6, J ) 9.0 Hz), 1.24 (d, 1H, H-6′, J ) 9.0 Hz); 13C NMR (D2O)
δ 176.2 (CdO), 61.0 (CH), 50.9 (CH), 46.4 (CH2), 41.4 (CH),
33.8 (CH2); HRMS calcd for [(C6H9NO2) + H]+ 128.0712, found
128.0709.
Ack n ow led gm en t. We thank Novartis for the bio-
logical tests, Dr. Mike Waring (University of Texas at
Austin) for his assistance with the English language,
and CNRS and Re´gion des Pays de la Loire for a
fellowship to C.L.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
4a , 4b, 4c, 14, 15, 20, 24, 26 and phase-sensitive NOESY
spectra of 17a and 17b. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O001790Y