Chirospecific synthesis of conformationally constrained 7-azabicycloheptane amino acids by transannular alkylation

Article abstract of DOI:10.1021/jo960759m

A new method is reported for the chirospecific preparation of optically pure 1-carboxy-7-azabicycloheptane amino acids for the generation of peptidomimetics as conformational probes. The method allows for the multigram preparation of these amino acid analogues through use of a thiolactam sulfide contraction and a transannular alkylation sequence as the key C-C bond-forming steps, starting from L-glutamic acid. The route provides access to two common intermediates, 7-(benzyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptane and (1S,4R)-7-(benzyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptanon e tert-butyl ester, for elaboration to symmetrical and chiral amino acid homologues, respectively. Decarboxylation of the C-1 carboxy unit of the latter intermediate also demonstrated the applicability of the method for a short, chirospecific preparation of a (+)-epibatidine intermediate, (1S,4R)-7-(tert-butyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]3-hepta none.

Full text of DOI:10.1021/jo960759m

J . Org. Chem. 1996, 61, 6313-6325
6313
Ch ir osp ecific Syn th eses of Con for m a tion a lly Con str a in ed
7-Aza bicycloh ep ta n e Am in o Acid s by Tr a n sa n n u la r Alk yla tion
J effrey A. Campbell and Henry Rapoport*
Department of Chemistry, University of California, Berkeley, California 94720
Received April 25, 1996X
A new method is reported for the chirospecific preparation of optically pure 1-carboxy-7-
azabicycloheptane amino acids for the generation of peptidomimetics as conformational probes.
The method allows for the multigram preparation of these amino acid analogues through use of a
thiolactam sulfide contraction and a transannular alkylation sequence as the key C-C bond-forming
steps, starting from L-glutamic acid. The route provides access to two common intermediates,
7-(benzyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptane and (1S,4R)-7-(benzyloxycarbonyl)-
1-carboxy-7-azabicyclo[2.2.1]-3-heptanone tert-butyl ester, for elaboration to symmetrical and chiral
amino acid homologues, respectively. Decarboxylation of the C-1 carboxy unit of the latter
intermediate also demonstrated the applicability of the method for a short, chirospecific preparation
of a (+)-epibatidine intermediate, (1S,4R)-7-(tert-butyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-
3-heptanone.
In tr od u ction
One tactic successful in overcoming some limitations
of peptides as drugs has been the use of conformationally
constrained peptidomimetics that mimic the receptor-
bound conformation of the bioactive peptide. Studies
have shown these analogues to be more protease-
resistant as well as to have increased selectivity toward
the receptor and thus fewer side effects.1 Even if the
receptor-bound conformation of the parent peptide is not
known, substitution of conformationally constrained
amino acids for the natural amino acids in the parent
peptide can generate structurally defined peptides, pos-
sibly serving a dual role as conformational probes and
bioactive peptidomimetics. Incorporation of conforma-
tionally constrained amino acid analogues, such as 1-car-
boxy-7-azabicyclo[2.2.1]heptane amino acids, containing
the pendant side chain of the parent amino acid, into the
backbone of a peptide in order to mimic the presumed
bioactive conformation, might produce such an effective
peptidomimetic.
F igu r e 1. Proposed route to conformationally constrained
7-azabicyclo[2.2.1]heptane amino acids.
with the known sequence involving a two-carbon homolo-
gation of thiopyroglutamate A via a sulfide contraction
sequence using methyl bromoacetate, followed by func-
tional group manipulation involving two reductions to
prepare (2S)-cis-1-benzyl-5-(2-hydroxyethyl)proline tert-
butyl ester, a key precursor of B. Elaboration of this side
chain to an unsubstituted or substituted bromoethyl unit
of B, sets the stage for a key transannular alkylation to
install the second and final C-C bond at C1-C2 of C,
completing the formation of the bicyclic ring system.
Substitution of the side chain of B with an H or OR
moiety should allow the preparation of symmetrical or
chiral amino acid analogues D via elaboration of the OR
moiety of C to the appropriate amino acid D with side
chain R′. Thus, the transannular cyclization of B allows
the preparation of a symmetrical analogue D (where R′
) H), and also serves for the preparation of D where R′
) OR, the proposed precursor of the C-3 functionalized
amino acid analogues. As examples, conversion of the
3-substituent (OR moiety) of C into a phenyl, meth-
ylguanidinyl, and 2-aminoethyl moieties, respectively,
allows the preparation of conformationally constrained
homophenylalanine, arginine, and lysine analogues.
Present paths to the 1-carboxy-7-azabicyclo[2.2.1]-
heptane system include a Diels-Alder approach2 involv-
ing simultaneous formation of C1-C4 bonds and free
radical cyclization of a C-1 radical, generated from 1,5-
hydrogen abstraction of an o-bromobenzoyl-protected
4-allyl-1-carboxyproline, forming the C1-C4 bond.3 Both
of these approaches, however, suffer from low generality
for the incorporation of substituents and poor overall
yields. The latter approach, although brief, demonstrates
poor regiochemical control in formation of the 7-azabicyclo-
[2.2.1]heptane system over the competing 8-azabicyclo-
[3.2.1]octane system.
We now report a chirospecific route to conformationally
constrained 1-carboxy-7-azabicyclo[2.2.1]heptane amino
acids. The projected synthesis, shown in Figure 1, begins
X Abstract published in Advance ACS Abstracts, August 15, 1996.
(1) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32,
1244.
(2) Avenoza, A.; Cativiela, C.; Busto, J . H.; Peregrina, J . M.
Tetrahedron Lett. 1995, 36, 7123.
(3) (a) Sato, T.; Kugo, Y.; Nakaumi, E.; Hiroyuki, I.; Masazumi, I.
J . Chem. Soc., Perkin Trans. 1 1995, 1801. (b) Sato, T.; Mori, T.;
Tadakatsu, S.; Hiroyuki, I.; Masazumi, I. Heterocycles 1994, 37, 245.
S0022-3263(96)00759-1 CCC: $12.00 © 1996 American Chemical Society

6314 J . Org. Chem., Vol. 61, No. 18, 1996
Campbell and Rapoport
Sch em e 1. Syn th esis of th e 7-Aza bicyclo[2.2.1]h ep ta n e System by Tr a n sa n n u la r Alk yla tion
Resu lts a n d Discu ssion
cis-4 in 82% yield then gave 7. Although the reaction of
N-BOC alcohol 6 with CBr4/PPh3 gave N-BOC bromide
8 in only 68% yield, similar treatment of N-CBZ alcohol
7 gave N-CBZ bromide 9 in 90% yield.5 The principal
byproduct in the preparation of 8 is the 6-membered
cyclic carbamate, resulting from displacement of the
bromide by the carbamate carbonyl oxygen. Presumably,
the increased formation of this intermediate via the
closure of N-BOC bromide 8 results from the easy and
irreversible loss of isobutylene.
The transannular alkylation with N-BOC bromide 8
or N-CBZ bromide 9 then was at hand. Cyclization of
the potassium enolate of 8 in THF gave the desired
N-BOC bicycle 10 in 93% yield.6 Treatment of 10 in
refluxing 2 M aqueous HCl for 24 h gave the fully
unprotected crystalline symmetrical bicycle 11 in six
steps and 47% overall from thiolactam 5. Alternatively,
selective removal of the N-BOC moiety was achieved
using TBDMSOTf and 2,6-lutidine, followed by fluoride-
mediated deprotection of the resulting silyl carbamate,
gave amino tert-butyl ester 12 in 60% yield.7 Although
this selective procedure in a more highly functionalized
example might not prove as satisfactory, the transannu-
lar alkylation of N-CBZ bromide 9 provided an answer,
affording the orthogonally protected N-CBZ bicyclic tert-
butyl ester 13 in 90% yield.
P r ep a r a tion of Key P r ecu r sor (2S)-cis-1-Ben zyl-
5-(2-h yd r oxyeth yl)p r olin e ter t-Bu tyl Ester (5). Cen-
tral to the proposed synthesis is the efficacious prepa-
ration of (2S)-cis-1-benzyl-5-(2-hydroxyethyl)proline tert-
butyl ester (5), a key precursor for incorporation of the
functionalized ethyl side chain required for the transan-
nular alkylation sequence. In an early synthesis of (-)-
anatoxin, alcohol 5 was prepared in high enantiomeric
purity (er g 99/1) in three steps and 81% overall yield
from N-benzylthiopyroglutamate 1.4 Some modifications
of the synthesis, however, were necessary to allow
reproducibility on a larger scale and resulted in an 83%
yield of 2 after crystallization. This crystallization
removed trace sulfur impurities and allowed hydrogena-
tion essentially quantitatively to 3. Removal of ap-
proximately 1% of trans-3 and selective reduction of the
resulting methyl ester of cis-3 provided the key precursor
5 in 94% yield.
F or m a tion of Bicycles 10 a n d 13 via Tr a n sa n n u -
la r Cycliza tion of Br om id es 8 a n d 9 (Sch em e 1).
Attempts to convert N-benzyl alcohol 5 into the corre-
sponding bromide failed. Thus, treatment of 5 with CBr4/
PPh3 formed the labile N-benzyl bromide analogue and
HBr was produced upon concentration.5 Presumably this
was due to azetidine formation through intramolecular
alkylation and N-debenzylation. Alternative alcohol
substrates for use in the bromination reaction, the
N-BOC and N-CBZ analogues 6 and 7, were prepared in
yields of 99% and 98%, respectively, from 5, in a
straightforward manner.
To further investigate the functionalization of the C1-
carboxy unit of N-BOC and N-CBZ bicycles 10 and 13,
various analogues were prepared according to Scheme
2. Subjection of 11 to a benzyl esterification and N-BOC
protection sequence afforded N-BOC benzyl ester 14 in
96% overall yield. To prepare an aldehyde analogue from
14, a DibalH reduction of ester 14 was first attempted,
affording aldehyde 15 and alcohol 16 in yields of 83% and
15%, respectively, after chromatography.8 To avoid the
necessity of chromatographic purification of aldehyde 15
A simpler path to 7 was found in hydrogenation of the
olefinic moiety of 2 with concomitant hydrogenolysis of
the N-Bn group using 10% Pd/C in MeOH. Treatment
with CBZCl then gave the corresponding N-CBZ ester
cis-4 in 93% yield, and reduction of the methyl ester of
(6) Campbell, J . A.; Lee, W. K.; Rapoport H. J . Org. Chem. 1995,
60, 4602.
(7) Sakaitani, M.; Ohfune, Y. Tetrahedron Lett. 1985, 26, 5543.
(8) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361.
(4) Petersen, J . S.; Fels, G.; Rapoport, H. J . Am. Chem. Soc. 1984,
106, 4539.
(5) Falorni, M.; Lardicci, L. J . Org. Chem. 1986, 51, 5291.

Syntheses of 7-Azabicycloheptane Amino Acids
J . Org. Chem., Vol. 61, No. 18, 1996 6315
Sch em e 2. Am in o Acid a n d Am in o Ald eh yd e
An a logu es in th e 7-Aza bicyclo[2.2.1]h ep ta n e
System
bromohydrin diastereomers of 23, following the favorable
cyclization results observed with bromides 8 and 9.
Thus, ring opening of either epoxide diastereomer of 23
with dibromotriphenylphosphorane,13 followed by treat-
ment of the resulting bromohydrin with Et3SiCl/imida-
zole,14 gave the TES ether of the corresponding bromo-
hydrin 24 in 84-92% yield. Transannular cyclization of
the potassium enolate of 24â in THF, followed by desi-
lylation using TBAF, gave the desired bicycle 25â in 92%
yield.
The corresponding minor diastereomer 24R cyclized
completely upon warming to room temperature only after
25-30 min, in contrast to 24â, which cyclized within 5
min at room temperature. This prolonged warming at
room temperature lowered the yield of the minor alcohol
25R to only 68%. Alternatively, transannular cyclization
of the potassium enolate mixture of TES ether diaster-
eomers of 24 (-60 °C f rt), stirring for 20 min, followed
by desilylation using TBAF, gave 25 in 84% yield as a
3/1 mixture of â/R alcohol diastereomers.6 It was fortu-
nate that 24R, the isomer derived from the minor epoxide
diastereomer 23R, could be prepared exclusively from this
mixture through use of an oxidation-reduction sequence.
Thus, oxidation of the mixture of alcohols, 25â/25R,
followed by DibalH reduction of the resulting ketone 26,
afforded alcohol 25R in 81% overall yield.15 In this
manner, differentially protected homoserine amino acid
analogues 25â and 25R were both prepared in overall
yields of 40% from N-benzylthiopyroglutamate 1 using
either epoxide diastereomer 23â or the 23â/23R mixture
of diastereomers.
Initial assignment of the C-3 stereochemistry of bicyclic
alcohols 25â and 25R was simply made on the basis of
the multiplicity and magnitude of the coupling constant
of H-4, observed as a doublet (J H4,H6exo ) 5.4 Hz) and
triplet (J H4,H3exo,H6exo ) 4.4 Hz), respectively. The lack of
coupling between H-4, H-3endo, and H-6endo was clearly
consistent with the 90° dihedral relationship of H-4 to
H-3endo and H-6endo. In addition, the magnitude of the
coupling constant between H-4 and H-6exo was consis-
tent with a 30° relationship. For the endo alcohol 25R,
the 30° dihedral relationship of H-4 to H-3exo and H-6exo
was consistent with the observed multiplicity and cou-
pling data. A more rigorous proof of the assignment of
stereochemistry was provided by the X-ray data for
alcohol 25â, as shown in Figure 2, definitively demon-
strating the exo configuration of the alcohol moiety at
C-3.16
from closely eluting alcohol 16, the benzyl ester 14 was
first reduced to primary alcohol 16 using Ca(BH4)2, then
oxidized to aldehyde 15 in 99% overall yield.9
As an example of coupling of the C1-carboxy unit with
a hindered amine, tert-butyl amide 19 was prepared from
either hydrochloride salt 11 or N-CBZ tert-butyl ester 13.
Protection of 11 using CBZCl under modified Schotten-
Baumann conditions gave the CBZ carbamate 17 in 93%
yield.10 Alternatively, TFA-mediated cleavage of the tert-
butyl group of 13 gave 17 in quantitative yield. Surpris-
ingly, preparation of the N-BOC analogue of 17 from
amino acid 11 using (BOC)2O gave yields consistantly
under 50%. Conversion of acid 17 to the acid chloride
18 using oxalyl chloride, followed by treatment with tert-
butylamine in the presence of Et3N/4-DMAP provided the
desired hindered amide 19 in 97% yield.
P r ep a r a tion of Hom oser in e a n d C-3 F lu or in a ted
Am in o Acid An a logu es. The route allowing access to
C-3 functionalized analogues is shown in Scheme 3 and
uses N-CBZ alcohol 7 as the starting point. Conversion
of the alcohol 7 to mesylate 20 using MsCl/Et3N followed
by displacement of the mesylate with sodium phenylse-
lenide (prepared from diphenyl diselenide and NaBH4/
EtOH),11 afforded selenide 21 cleanly in 95% yield.
Although attempts to effect an oxidation-elimination
sequence on selenide 20 when separately using NaIO4
or 30% H2O2 at 55 °C only gave olefin 22 in 50-64% yield,
these conditions used in combination provided the desired
olefin 22 in 98% yield. Epoxidation of olefin 20 using
m-CPBA12 in CH2Cl2 at -10 f 0 °C gave the desired
transannular cyclization precursor 23 as a 2.3/1 mixture
of easily separable diastereomers, providing 23â and 23R
in 61% and 27% isolated yields, respectively.
Attempted DAST-mediated fluorine substitution with
inversion of 25R produced approximately a 1/1 mixture
of easily separable exo and endo fluoro substituted
bicycles, 26â and 26r, respectively.6 Presumably, the exo
fluoro analogue 26â originates from the normal inversion
pathway, whereas the endo fluoro compound 26R is
formed via anchimeric assistance involving the nitrogen
moiety.17 Thus, both fluoro-substituted bicycles were
prepared from a single alcohol 25R. Alternatively, treat-
All attempts, however, to promote transannular cy-
clization of the potassium enolate of either the minor or
major diastereomer of epoxide 23 failed, even in the
presence of Lewis acid catalysis. Attention was then
turned to preparation of the TES(triethylsilyl)-protected
(13) Palumbo, G.; Ferreri, C.; Caputo, R. Tetrahedron Lett. 1983,
24, 1307.
(14) Clive, D. L. J .; Zhang, C. J . Org. Chem. 1995, 60, 1413.
(15) Fletcher, S. R.; Baker, R.; Chambers, M. S.; Herbert, R. H.;
Hobbs, S. C.; Thomas, S. R.; Verrier, H. M.; Watt, A. P.; Ball, R. G. J .
Org. Chem. 1994, 59, 1771.
(9) Konradi, A. W.; Kemp, S. J .; Pedersen, S. F. J . Am. Chem. Soc.
1994, 116, 1316.
(10) Bodansky, M.; Bodansky, A. The Practice of Peptide Synthesis;
Reactivity and Structural Concepts in Organic Chemistry;
Springer-Verlag: New York, 1984; Vol. 21, p 12.
(11) Raederstorff, D.; Shu, A. Y. L.; Thompson, J . E.; Djerassi, C. J .
Org. Chem. 1987, 52, 2337.
(12) Shaw, K. J .; Luly, J . R.; Rapoport, H. J . Org. Chem. 1985, 50,
4515.
(16) The authors have deposited atomic coordinates for this struc-
ture with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.
(17) Mazzocchi, P. H.; Ammon, H. L.; Liu, L.; Colicelli, E.; Ravi, P.;
Burrows, E. J . Org. Chem. 1981, 46, 4530.

6316 J . Org. Chem., Vol. 61, No. 18, 1996
Campbell and Rapoport
Sch em e 3. P r ep a r a tion of 1-Ca r boxy-2-flu or o- a n d -2,2-d iflu or o-7-a za bicyclo[2.2.1]h ep ta n e Am in o Acid
An a logu es
subjection of 29R and 29â to a hydrolysis-Curtius
rearrangement sequence involving trapping of the inter-
mediate isocyanate with 2-(trimethylsilyl)ethanol pro-
vided ornithine homologues 30R and 30â in overall yields
of 93% and 81%, respectively.19 Deprotection of the
N-TEOC [[(trimethylsilylethyl)oxy]carbonyl] moiety of
30R and 30â using TBAF in THF, followed by capture of
the resulting primary amine using N,N′-bis(tert-butoxy-
carbonyl)-S-methylisothiourea20 in buffer solution af-
forded arginine analogues 31R and 31â in overall yields
of 89% and 72%, respectively.
The route to several differentially protected lysine
analogues also starts from ester 29, except that only the
major isomer 29R was taken through the sequence.
Chemoselective reduction of the methyl ester of 29R using
LiBH4 in Et2O gave primary alcohol 32 in 74% yield.4
Treatment of alcohol 32 with tert-butyl [[(2-trimethylsi-
lyl)ethyl]sulfonyl]carbamate (SES-NHBOC) under Mit-
sunobu conditions afforded N-acylsulfonamide 33 in 95%
yield.21 Removal of the N-BOC and tert-butyl ester
moieties was accomplished in a single operation using
TFA, and CH2N2 treatment of the resulting acid 34 gave
F igu r e 2. Structure of (1S,3S,4R)-N-(benzyloxycarbonyl)-1-
carboxy-3-hydroxy-7-azabicyclo[2.2.1]heptane tert-butyl ester
(25â) as determined by X-ray crystallography.
35 in 78% yield.
To prepare the homophenylalanine analogues, ketone
26 was used as the starting point. The addition of PhLi
to ketone 26 afforded alcohols 36 in 90% yield as a
mixture of â/R diastereomers.15 Dehydration of 36 using
Ts2O/pyridine afforded styrene analogue 37 in 82% yield
and reduction of the double bond of 37 proceeded un-
eventfully, providing homophenylalanine analogues 38R
and 38â in yields of 74% and 20%, respectively. It is
notable that treatment of 36 with SOCl2/pyridine22 and
hydrogenolysis of the resulting mixture containing chloro-
olefin only afforded 38, suggesting that anchimeric
assistance by the nitrogen moiety during the chlorination
step might be playing a role.17
ment of ketone 26 with DAST afforded the difluoro
analogue 28 in 26% yield (49% based on unconverted 26).
P r ep a r a tion of Or n ith in e, Ar gin in e, Hom op h e-
n yla la n in e, a n d Lysin e An a logu es. Ketone 26 proved
to be a most versatile intermediate, allowing the prepa-
ration of differentially protected ornithine, arginine,
homophenylalanine and lysine analogues, as shown in
Scheme 4. Key to the strategy for the preparation of the
ornithine, arginine, and lysine analogues was the elabo-
ration of the methyl ester moiety of saturated ester 29.
This ester could be prepared from ketone 26 in either
diastereomeric form at C-3, via two-carbon homologa-
tion-hydrogenation. Thus, reaction of 26 with trimethyl
phosphonoacetate provided the corresponding unsatur-
ated ester, which, upon reduction, afforded esters 29R
and 29â in yields of 77% and 21%, respectively.18 Each
isomer of 29 was converted to the corresponding ornithine
and arginine isomer, 30 and 31, respectively. Thus,
(18) Ornstein, P. L.; Augenstein, N. K.; Arnold, M. B. J . Org. Chem.
1994, 59, 7862.
(19) Corey, E. J .; Loh, T.-P.; AchyuthaRao, S.; Daley, D. C.; Sarshar,
S. J . Org. Chem. 1993, 58, 5600.
(20) Bergeron, R. J .; McManis, J . S. J . Org. Chem. 1987, 52, 1700.
(21) (a) Campbell, J . A.; Hart, D. J . J . Org. Chem. 1993, 58, 2900.
(b) Campbell, J . A.; Hart, D. J . Tetrahedron Lett. 1992, 6247.
(22) Yoshifuji, S.; Kaname, M. Chem. Pharm. Bull. 1995, 43, 1302.

Syntheses of 7-Azabicycloheptane Amino Acids
J . Org. Chem., Vol. 61, No. 18, 1996 6317
Sch em e 4. P r ep a r a tion of Or n ith in e, Ar gin in e, Hom op h en yla la n in e, a n d Lysin e An a logu es of th e
1-Ca r boxy-7-a za bicyclo[2.2.1]h ep ta n e Rin g System
P r ep a r a tion of (1S4R)-7-(ter t-Bu tyloxyca r bon yl)-
1-ca r boxy-7-a za bicyclo[2.2.1]-3-h ep ta n on e (39), a n
(+)-Ep iba tid in e P r ecu r sor . A variation in the route
to the bicyclic amino acids also makes the method
amenable to the chirospecific synthesis of epibatidine
precursor, 39.15 This sequence uses reductive radical
decarboxylation of the C-1 carboxy group and the result-
ing ketone 26 as the starting point. Cleavage of the tert-
butyl ester (TFA) of 26 afforded acid 40 in essentially
quantitative yield. Coupling of the acid chloride of 40
(prepared by treatment of 40 with oxalyl chloride) with
N-hydroxy-2-thiopyridone in the presence of Et3N af-
forded the corresponding O-acyl thiohydroxamate, which
was photolyzed with tert-butyl thiol using two 100 W
tungsten lamps to afford 41 in 81% overall yield.23
Hydrogenolysis (10% Pd/C) of 41 in MeOH containing
(BOC)2O afforded 39 in 98% yield (eq 1). This method,
sion homologation sequence demonstrated in this study,
should provide access to natural products containing the
8-azabicyclo[3.2.1]octane and 9-azibicyclo[4.2.1]nonane
framework.24
Con clu sion
We report a new method for the chirospecific prepara-
tion of enantiomerically pure 1-carboxy-7-azabicyclohep-
tanes, amino acids for the generation of peptidomimetics
as conformational probes and bioactive agents. The
method allows for the multigram preparation of these
conformationally constrained amino acid analogues
through a sulfide contraction and transannular alkyla-
tion sequence as the key C-C bond-forming steps,
starting from L-glutamic acid. The route provides access
to two common intermediates, 7-(benzyloxycarbonyl)-1-
carboxy-7-azabicyclo[2.2.1]-3-heptane and (1S,4R)-7-(ben-
zylocarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-hepta-
none tert-butyl ester, for elaboration to symmetrical and
chiral amino acid analogues. Decarboxylation of the C-1
carboxy unit of the latter intermediate also demonstrated
the potential applicability of the method for natural
product synthesis, with the short chirospecific prepara-
tion of (1S,4R)-7-(tert-butyloxycarbonyl)-1-carboxy-7-
azabicyclo[2.2.1]-3-heptanone, an (+)-epibatidine precur-
sor.
Exp er im en ta l Section
Gen er a l P r oced u r es. All melting points are uncorrected.
NMR spectra were taken in CDCl3 and are referenced to
internal TMS unless otherwise noted; 13C NMR chemical shifts
constituting a formal synthesis of epibatidine, may also
be amenable to the synthesis of other natural products.
Thus, use of a three- and four-carbon sulfur extrusion
homologation sequence, instead of the two-carbon extru-
are followed by multiplicity as determined from DEPT.
J
values are given in Hs. Solvents were dried and purified prior
(23) Herna´ndez, A.; Marcos, M.; Rapoport, H. J . Org. Chem. 1995,
60, 2683.
(24) Herna´ndez, A.; Thaler, A.; Castells, J .; Rapoport, H. J . Org.
Chem. 1996, 61, 314.

6318 J . Org. Chem., Vol. 61, No. 18, 1996
Campbell and Rapoport
to use: THF and NMP were distilled from sodium metal; CH2-
Cl2, DMF, hexane, and pyridine were distilled from CaH2; CH3-
CN was distilled from P2O5 and then CaH2. Reactions were
conducted under Ar or N2. For isolation, the organic phase
was dried over MgSO4 unless otherwise noted and evaporated
under reduced pressure using a Berkeley rotary evaporator.
TLC analysis was performed on aluminum-backed silica gel
60 F254, 0.2 mm plates (MCB Reagents), visualized with UV
light (254 nm), followed by heating with ethanolic phospho-
molybdic acid. Chromatography was carried out using 230-
400 mesh silica gel. The diameter of the column corresponded
to the amount of of silica gel used in the separation: (a) 1.6
cm width, 0-20 g silica, (b) 3 cm width, 20-90 g, (c) 5-cm
width, 90-360 g, (d) 8-cm width; 360-500 g. Elemental
analyses were determined by Microanalytical Laboratories,
University of California at Berkeley.
(2S)-1-Ben zyl-(E)-5-[(m eth oxyca r bon yl)m eth ylid en e]-
p r olin e ter t-Bu tyl Ester (2). A solution of thiolactam 11 (40
g, 137 mmol) and methyl bromoacetate (26 g, 170 mmol) in
CH3CN (80 mL) was stirred for 42 h and then cooled to -5
°C, and a solution of PPh3 (43.2 g, 165 mmol) in CH2Cl2 (640
mL) was added over 20 min, followed by 18.4 mL (151 mmol)
of NMP. The mixture was stirred for 30 h and then poured
into 1 M aqueous KHSO4 (300 mL), and the aqueous layer was
washed with additional CH2Cl2 (3 × 80 mL). The combined
organic extracts were washed with 1 M aqueous KH2PO4 (200
mL) and then H2O (100 mL), dried, and evaporated. This solid
residue was triturated with 550 mL of 25% EtOAc/hexane for
10 min and then cooled for 24 h at 0 °C. The resulting slurry
was filtered to remove Ph3PS, the filtrate was evaporated, and
the residue was chromatographed twice (450 g of silica gel,
eluted with 8% then 15% EtOAc/hexane) to afford the nearly
pure vinylogous ester. This material was recrystallized from
the minimum amount of hexane (∼1 mL of hexane/gram of
ester) at 0 °C to afford a total (three crops) of 37.7 g (83%) of
pure vinylogous carbamate 2. The analytical data were
identical to those reported.4
gel, eluted with 50% EtOAc/hexane) to afford 8.20 g (94%) of
alcohol 5 as a colorless oil with properties identical to those
reported.1
(2S)-cis-1-(ter t-Bu tyloxyca r bon yl)-5-(2-h yd r oxyeth yl)-
p r olin e ter t-Bu tyl Ester (6). A solution of 2.21 g (7.2 mmol)
of N-benzylamine 5 and 3.64 g (16.7 mmol) of BOC2O in 80
mL of MeOH was degassed (Ar), and 0.64 g of 10% Pd/C was
added. The resulting slurry was hydrogenated (55 psig) over
14 h and filtered through Celite, and the Celite pad was
washed with 250 mL of CH2Cl2. The filtrate was evaporated
and chromatographed (100 g of silica gel, eluted with 40%
EtOAc/hexane) to afford 2.26 g (99%) of carbamate 6: IR (CH2-
Cl2) 3290-3540 (br), 1740, 1675 cm-1; 1H NMR δ 1.43 (s, 9H),
1.45 (s, 9H), 1.50-1.74 (m, 3H), 1.85-2.05 (m, 2H), 2.25-2.34
(m, 1H), 3.60-3.68 (m, 1H), 3.72-3.80 (m, 1H), 4.13 (dd, J )
9.2, 8.0, 1H), 4.27 (ddd, J ) 11.2, 7.2, 3.4, 1H), 4.34 (dd, J )
9.9, 4.5, 1H); 13C NMR δ 27.9 (q), 28.1 (q), 28.9 (t), 30.3 (t),
37.5 (t), 54.6 (d), 58.8 (t), 60.7 (d), 80.5 (s), 80.88 (s), 155.4 (s),
172.1 (s).
(2S)-cis-1-(Ben zyloxyca r bon yl)-5-(2-h yd r oxyeth yl)p r o-
lin e ter t-Bu tyl Ester (7). A solution of 2.38 g (7.8 mmol) of
N-benzylamine 5 in 30 mL of MeOH was degassed (Ar), and
0.18 g of 10% Pd-C was added. The resulting slurry was
degassed once more and then hydrogenated (60 psig) over 12
h. The slurry was degassed (N2) and filtered through Celite,
and the Celite pad washed with 250 mL of CH2Cl2. The filtrate
was carefully evaporated at ambient temperature to afford 1.68
g of the crude secondary amine. This mixture was im-
mediately dissolved in 40 mL of 50% EtOAc/H2O and 3.23 g
(23.3 mmol) of calcined K2CO3 added, followed by 1.28 mL (9
mmol) of CBZCl dropwise over 5 min. The mixture was stirred
1.5 h, the aqueous layer was extracted with EtOAc (4 × 40
mL), and the combined EtOAc layers were washed with 40
mL of 2 M aqueous HCl, dried, and evaporated. The residue
was chromatographed (40 g silica gel, eluted with 50% EtOAc/
hexane) to afford 2.67 g (98%) of carbamate 7 as a colorless
oil: [R]20 -56.7° (c 1.6, CHCl3); IR (CH2Cl2) 3210-3690 (br),
D
1733, 1682 cm-1; H NMR δ 1.33 (s, 9H), 1.61-1.79 (m, 3H),
1
(2S)-cis-1-Be n zyl-5-[(m e t h oxyca r b on yl)m e t h yl]p r o-
lin e ter t-Bu tyl Ester (3). A solution of 12.2 g (36.6 mmol)
of vinylogous carbamate 2 in 120 mL of EtOAc was degassed
(Ar), and 3.5 g of 5% Pt/C was added. The resulting slurry
was degassed once more and then hydrogenated (60 psig) over
16 h. The slurry was filtered through Celite, the Celite pad
was washed with 500 mL of CH2Cl2, the filtrate was evapo-
rated, and the residue was chromatographed (450 g of silica
gel, eluted with 5% then 12% EtOAc/hexane) to afford 45 mg
(0.4%) of trans-3, 200 mg (1.6%) of a mixture of trans-3 and
cis-3, followed by 12.0 g (98%) of cis-3. The analytical data
were identical to those reported.4
1.93-2.08 (m, 2H), 2.28-2.34 (m, 1H), 3 62-3.70 (m, 1H),
3.73-3.81 (tm, J ) 11.5, 1H), 4.04 (dd, J ) 9.4, 4.3, 1H), 4.22-
4.25 (m, 1H), 4.31-4.37 (m, 1H), 5.07 (d, J ) 12.4, 1H), 5.18
(d, J ) 12.5, 1H), 7.25-7.40 (m, 5H); 13C NMR δ 27.7 (q), 29.0
(t), 30.4 (t), 37.4 (t), 55.5 (d), 58.9 (t), 60.5 (d), 67.4 (t), 81.3 (s),
127.7 (d), 128.0 (d), 128.35 (d), 136.1 (s), 155.9 (s), 171.88 (s).
Anal. Calcd for C19H27NO5: C, 65.3; H, 7.8; N, 4.0. Found:
C, 65.2; H, 8.0; N, 4.1.
P r ep a r a tion of N-CBZ Alcoh ol 7 fr om N-CBZ Ester 4.
Applying the procedure for preparing N-benzyl alcohol 5 from
N-benzyl ester 3, 300 mg (0.79 mmol) of N-CBZ ester 4 was
converted to 226 mg (82%) of N-CBZ alcohol 7.
(2S)-cis-1-(Ben zyloxyca r bon yl)-5-[(m eth oxyca r bon yl)-
m eth yl]p r olin e ter t-Bu tyl Ester (4). To a solution of 0.95
g (2.85 mmol) of 2 in 25 mL of degassed (Ar) MeOH was added
550 mg of 10% Pd/C, and the mixture was hydrogenated at
60 psi for 36 h. The slurry was filtered through Celite, and
the Celite pad was washed with 50 mL of MeOH and then
200 mL of CH2Cl2. The filtrate was evaporated, the residue
was immediately dissolved in 14 mL of 50% EtOAc/H2O, and
560 mg (4 mmol) of calcined K2CO3 was added, followed by
422 mL (9 mmol) of CBZCl, added dropwise over 5 min. The
mixture was stirred for 1 h, and the aqueous layer was
extracted with EtOAc (4 × 40 mL). The combined EtOAc
layers were washed with 40 mL of 2 M aqueous HCl, dried,
and evaporated. The residue was chromatographed (40 g silica
gel, eluted with 10% EtOAc/hexane) to afford 954 mg (94%) of
(2S)-cis-1-(ter t-Bu t yloxyca r b on yl)-5-(2-b r om oet h yl)-
p r olin e ter t-Bu tyl Ester (8). To a solution of 1.18 g (3.74
mmol) of primary alcohol 6 and 1.74 g (5.24 mmol) of CBr4 in
17 mL of CH2Cl2 at -5 °C was added a solution of PPh3 (1.18
g, 4.5 mmol) in 9 mL of CH2Cl2 dropwise over a 5 min period.
The mixture was warmed to 0 °C over 5 min, warmed to rt
over 10 min and then stirred for 20 min. The solution was
evaporated at rt, and the resulting residue was chromato-
graphed (60 g of silica gel, eluted with 25% EtOAc/hexane) to
afford 0.97 g (68%) of bromide 8 as a colorless oil that was
used directly in the next reaction. Selected data for 8: IR
(CH2Cl2) 1735, 1640 cm-1; 1H NMR (60/40 rotomers) δ 1.43 (s,
9H), 1.46 (s, minor rotomer, 3.6 H), 1.48 (s, major rotomer,
5.4 H), 1.66-1.75 (m, 1H), 1.87-2.05 (m, 3H), 2.20-2.30 (m,
1H), 2.32-2.46 (m, 1H), 3.38-3.55 (m, 2H), 3.98-4.08 (m, 1H),
4.13 (t, major rotomer, J ) 7.8, 0.6H), 4.23 (t, J ) 7.6, minor
rotomer, 0.4 H); 13C NMR δ (1H decoupled only, rotomers) 27.9,
28.0, 28.3, 28.4, 28.9, 29.6, 29.7, 30.2, 30.5, 38.0, 38.4, 57.0,
57.4, 60.5, 60.6, 79.9, 80.1, 80.9, 153.9, 172.15, 172.23.
(2S)-cis-1-(Ben zyloxyca r b on yl)-5-(2-b r om oet h yl)p r o-
lin e ter t-Bu tyl Ester (9). To a solution of 1.50 g (4.3 mmol)
of primary alcohol 7 and 1.99 g (6.0 mmol) of CBr4 in 17 mL
of CH2Cl2 at -5 °C was added a solution of 1.99 g (6.0 mmol)
of PPh3 in 11 mL of CH2Cl2 dropwise over 18 min. The mixture
was warmed to 4 °C over 1.75 h, to rt over 2 h and then stirred
2 h. The solution was evaporated at rt and the residue
chromatographed (40 g of silica gel, eluted with hexane then
carbamate 4: mp 43-44 °C; [R]20 -20.5° (c 1.1, CHCl3); IR
D
(CH2Cl2) 1747, 1703 cm-1
;
13C NMR (C6D6, 339 K) δ 27.9 (q),
28.7 (t), 39.1 (t), 50.8 (q), 56.0 (t), 61.1 (d), 67.0 (t), 80.8 (s),
127.8 (d), 128.0 (d), 128.25 (d), 132.9 (d), 137.5 (s), 154.1 (s),
171.5 (s), 171.9 (s). Anal. Calcd for C20H27NO6: C, 63.7; H,
7.2; N, 3.7. Found: C, 64.0; H, 7.4; N, 3.6.
(2S)-cis-1-Ben zyl-5-(2-h yd r oxyeth yl)p r olin e ter t-Bu tyl
Ester (5). A solution of LiBH4 in Et2O (1 M, 38 mL, 38.0
mmol) was added to a solution of 9.57 g (28.5 mmol) of cis-3
in 68 mL of Et2O. The mixture was stirred for 4.5 h, poured
into 100 mL of 1 M aqueous K2CO3, and extracted with Et2O
(5 × 100 mL). The combined organic layers were dried and
evaporated. The residue was chromatographed (400 g of silica

Syntheses of 7-Azabicycloheptane Amino Acids
J . Org. Chem., Vol. 61, No. 18, 1996 6319
15% EtOAc/hexane) to afford 1.60 g (90%) of bromide 9 as a
colorless oil: [R]20D -24° (c 1.5, CHCl3); IR (CH2Cl2) 1735, 1650
mixture was then warmed to rt and stirred for 10 min more.
The solution was concentrated to ∼0.5 mL and then chromato-
graphed (15 g of silica gel, eluted with 9% EtOAc/hexane) to
afford 140 mg (84%) of the resulting TBDMS carbamate, which
was used immediately in the next reaction.
To a solution of 140 mg (0.39 mmol) of the TBDMS
carbamate in 7 mL of CH3CN was added 360 mg (2.37 mmol)
of dry CsF. The mixture was heated to reflux for 20 h, cooled
to rt, and then partitioned between 100 mL of CH2Cl2 and 10
mL of H2O. The aqueous layer was extracted with two 20 mL
portions of CH2Cl2. The combined organic layers were dried
and evaporated to afford 54 mg (60% from 10) of amine 12 as
an amber oil that was unstable upon prolonged heating under
vaccum.
Selected data for TBDMS carbamate: 1H NMR δ 0.24 (s,
6H), 0.92 (s, 9H), 1.43-1.53 (m with s at d 1.48, 11H), 1.72
(m, 2H), 1.90 (m, 2H), 2.16 (m, 2H), 4.24 (t, J ) 4.0, 1H); 13C
NMR δ -4.8, -3.0, 17.2, 25.7, 28.0, 29.7, 32.9, 60.1, 69.1, 81.0,
155.7, 170.2.
Selected data for secondary amine 12: 1H NMR δ 1.42-
1.48 (m with s at d 1.45, 5H), 1.91 (br s, 1H), 3.62 (t, J ) 4.0,
1H); 13C NMR δ 27.96 (q), 31.0 (t), 33.7 (t), 56.8 (d), 69.1 (s),
80.7 (s), 173.2 (s).
1
cm-1; H NMR (65/35 rotomers) δ 1.30-1.52 (m, 2H), 1.35 (s,
5.85H), 1.45 (s, 3.15H), 1.70-1.78 (m, 1H), 1.90-2.05 (m, 3H),
2.21-2.28 (m, 1H), 2.33-2.43 (m, 0.35H), 2.44-2.53 (m, 65H),
2.34-2.57 (m, 2H), 4.08-4.18 (m, 1H), 4.24 (t, J ) 7.4, 0.65H),
4.29 (t, J ) 7.6, 0.35 H), 5.10 (dd, J ) 12.5, 1.30H), 5.10-5.18
(m, 0.7H), 7.22-7.40 (m, 5H); 1H NMR (C6D6, 298 K, 60/40
rotomers) δ 0.99-1.11 (m, 1H), 1.21 (s, 5.4H), 1.33 (s, 3.6H),
1.12-1.35 (m, 1H), 1.43-1.65 (m, 1.8H), 1.63-1.84 (m, 1.2H),
2.13-2.23 (m, 0.40H), 2.35-2.45 (m, 0.6H), 3.03-3.13 (m,
0.8H), 3.27-3.41 (m, 1.2H), 3.65-3.73 (m, 0.4H), 3.82-3.90
(m, 0.6H), 4.03 (t, J ) 7.8, 0.6H), 4.25 (t, J ) 7.9, 0.4 H), 4.93-
5.08 (m, 2H), 7.00 (t, J ) 7.3, 1 H), 7.05-7.12 (m, 2H), 7.20
(d, J ) 6.7, 2H); 13C NMR (C6D6, 298 K, rotomers) δ 27.8 (q),
27.9 (q), 28.0 (t), 28.03 (t), 29.04 (t), 29.6 (t), 30.1 (t), 30.5 (t),
38.4 (t), 38.7 (t), 57.2 (t), 58.3 (t), 60.6 (t), 61.2 (t), 67.0, 67.2
(t), 80.7 (s), 128.01 (d), 128.05 (d), 128.23 (d), 128.56 (d), 128.66
1
(d), 137.17 (s), 137.29 (s), 154.35 (s), 154.54 (s), 172.0 (s); H
NMR (C6D6, 339 K) δ 1.19-1.43 (m, 2H), 1.27 (s, 9H), 1.54-
1.72 (m, 2H), 1.79-1.92 (m, 1H), 2.37 (br mc, 1H), 3.26 (br mc,
1H), 3.85 (br mc, 1H), 4.14 (br mc, 1H), 4.98 (d, J ) 12.5, 1H),
5.03 (d, J ) 12.5, 1H), 7.01 (t, J ) 7.3, 1H), 7.05-7.12 (m,
2H), 7.20 (d, J ) 7.3, 2H); 13C NMR (C6D6, 339 K) δ 28.0 (q),
28.8 (t), 30.06 (t), 30.24 (t), 38.8 (t), 58.2 (d), 61.0 (d), 67.1 (t),
80.8 (s), 128.07 (d), 128.30 (d), 128.58 (d), 137.4 (s), 154.6 (s),
171.9 (s). Anal. Calcd for C19H26NO4Br: C, 55.4; H, 6.4; N,
3.4. Found: C, 55.2; H, 6.6; N, 3.4.
7-(Ben zyloxyca r bon yl)-1-ca r boxy-7-a za bicyclo[2.2.1]-
h ep ta n e ter t-Bu tyl Ester (13). Applying the procedure for
preparing N-BOC bicycle 10, 1.45 g (3.52 mmol) of N-CBZ
bromide 9 was converted to 1.05 g (90%) of N-CBZ bicycle 13:
1
mp 74-75 °C; IR (CH2Cl2) 1722, 1705 cm-1; H NMR δ 1.47
7-(ter t-Bu tyloxycar bon yl)-1-car boxy-7-azabicyclo[2.2.1]-
h ep t a n e ter t-Bu t yl E st er (10). To a solution of KHMDS
(5.65 mL of a 0.92 M solution in THF, 5.2 mmol) in 84 mL of
THF cooled to -60 °C was added a solution of 960 mg (2.54
mmol) of bromide 8 in 37 mL of THF dropwise, maintaining
an internal temperature of -50 °C during the addition (15-
20 min). The solution was warmed to -40 °C gradually over
15 min, stirred 60 min, warmed to 0 °C over 30 min, and then
warmed to rt over 20 min. The mixture was stirred for an
additional 10 min, and then 0.15 mL (2.8 mmol) of glacial
AcOH was added. The mixture was evaporated to 15 mL,
diluted with 50 mL of 1 M aqueous KH2PO4, and extracted
with EtOAc (4 × 50 mL). The organic layers were combined,
washed with 50 mL of saturated aqueous NaHCO3, dried, and
evaporated. The residue was chromatographed (45 g of silica
gel, eluted with 15% EtOAc/hexane) to afford 700 mg (93%) of
the bicyclic carbamate 10: mp 63.0-64.3 °C; IR (CH2Cl2) 1730,
1703 cm-1; 1H NMR δ 1.43 (s, 9H), 1.45-1.50 (m, 2H), 1.49 (s,
9H), 1.68 (tm, J ) 13.0, 2H), 1.88 (tm, J ) 13.0, 2H), 2.14 (tm,
J ) 13.0, 2H), 4.25 (t, J ) 4.8, 1H); 13C NMR δ 27.97 (q), 28.03
(q), 29.5 (t), 32.9 (t), 60.1 (d), 69.2 (s), 80.1 (s), 80.7 (s), 156.5
(s), 170.4 (s). Anal. Calcd for C16H27NO4: C, 64.6; H, 9.2; N,
4.7. Found: C, 64.6; H, 9.5; N, 4.7.
(s, 9H), 1.43-1.52 (m, 2H), 1.72 (tm, J ) 10.3, 2H), 1.83-1.93
(m, 2H), 2.16 (tm, J ) 13.1, 2H), 4.38 (t, J ) 4.8, 1H), 5.12 (s,
2H), 7.27-7.37 (m, 5H); 13C NMR δ 27.8 (q), 29.4 (t), 33.2 (t),
59.7 (d), 67.0 (s), 69.6 (s), 81.1 (s), 127.85 (d), 127.94 (d), 128.4
(d), 136.4 (s), 156.8 (s), 169.9 (s). Anal. Calcd for C19H25NO4:
C, 68.9; H, 7.6; N, 4.2. Found: C, 69.1; H, 7.7; N, 4.2.
7-(ter t-Bu tyloxycar bon yl)-1-car boxy-7-azabicyclo[2.2.1]-
h ep ta n e Ben zyl Ester (14). A mixture of 732 mg (4.12
mmol) of HCl salt 11, 980 mg (5.15 mmol) of p-TsOH‚H2O,
3.0 mL (28.8 mmol) of BnOH, and 12 mL of benzene was
heated at reflux with a Dean-Stark trap for 25 h. The
reaction mixture was cooled to rt and evaporated, after which
time the residue was dissolved in 40 mL of MeOH containing
2.75 g (12.6 mmol) of (BOC)2O and 6.0 mL (34.4 mmol) of
DIEA. The mixture was stirred for 21 h and evaporated and
the residue chromatographed (60 g of silica gel, eluted with
5% then 10% EtOAc/hexane) to afford 1.34 g (96%) of the
benzyl ester 14: mp 58.5-59.5 °C; IR (CH2Cl2) 1733, 1695
1
cm-1; H NMR δ 1.42 (s, 9H), 1.45-1.53 (m, 2H), 1.76 (tm, J
) 10.3, 2H), 1.86-1.96 (m, 2H), 2.21(tt, J ) 13.1, 3.3, 2H),
4.32 (t, J ) 4.7, 1H), 5.24 (s, 2H), 7.30-7.41 (m, 5H); 13C NMR
δ 28.0 (q), 29.3 (t), 33.3 (t), 59.7 (d), 66.5 (s), 68.7 (s), 80.6 (s),
127.97 (d), 128.00 (d), 128.4 (d), 136.0 (s), 156.5 (s), 171.2 (s).
Anal. Calcd for C19H25NO4: C, 68.9; H, 7.6; N, 4.2. Found:
C, 68.6; H, 7.8; N, 4.2.
7-(ter t-Bu tyloxycar bon yl)-1-car boxy-7-azabicyclo[2.2.1]-
h ep ta n e Hyd r och lor id e (11). A slurry of 1.00 g (3.36 mmol)
of N-BOC ester 10 in 38 mL of 2 M aqueous HCl was heated
at 85 °C for 25 h, and then the resulting solution was cooled
to rt and evaporated. The residue was dissolved in 3.5 mL of
MeOH, diluted with 25 mL of Et2O to form a white flocculent
precipitate, and cooled to 0 °C over 12 h. The slurry was
filtered and the solid washed with 5 mL of Et2O and then dried
under vacuum (24 h, 55 °C/0.2 Torr then 24 h, 65 °C/0.2 Torr)
to afford 590 mg (99%) of HCl salt 11: mp >210 °C dec; IR
7-(ter t-Bu tyloxyca r bon yl)-1-for m yl-7-a za bicyclo[2.2.1]-
h ep ta n e (15). To a solution of 100 mg (0.30 mmoL) of ester
14 in 0.6 mL of toluene at -78 °C was added dropwise a
solution of 0.34 mL (0.51 mmoL) of 1.5 M DibalH in toluene.
The mixture was stirred for 2 h, and 0.2 mL (2.9 mmol) of
MeOH precooled to -78 °C was added. The solution was
stirred for 5 min, warmed to rt, and then diluted with 1 mL of
1 M aqueous HCl solution. The solution was then partitioned
between 70 mL of CH2Cl2 and 20 mL of 1 N aqueous HCl
solution. The CH2Cl2 layer was dried and evaporated and the
residue chromatographed (15 g of silica gel, eluted with 8%
EtOAc/hexane) to afford 57 mg (83%) of the aldehyde 15
(existing presumably as a 83/17 mixture of the aldehyde/
hydrate), followed by 10 mg (15%) of alcohol 16. The aldehyde
could be reduced using Ca(BH4)2 to a single compound 16.
Heating (340 K) did not change the ratio. Selected data for
the hydrate form of 15: 1H NMR δ 1.44 (s, 1.53H), 2.01 (t, J
) 10 Hz, 0.34H), 4.24 (t, J ) 4.4 Hz, 0.17H).
(Nujol) 1743 cm-1 1H NMR (CD3OD) δ 1.86-1.97 (m, 2H),
;
2.04-2.18 (m, 6H), 4.19 (t, J ) 3.7, 1H); 13C NMR δ 28.80 (t),
31.82 (t), 60.00 (d), 73.33 (s), 171.09 (s). Anal. Calcd for
C7H12NO2Cl: C, 47.3; H, 6.8; N, 7.9. Found: C, 47.3; H, 7.1;
N, 7.5.
1-Ca r boxy-7-a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester
(12). To a solution of 140 mg (0.471 mmol) of N-BOC ester
10 in 2 mL of CH2Cl2 at 0 °C was added 0.12 mL (0.53 mmol)
of TBDMSOTf and 0.42 mL of 2,6-lutidine. The mixture was
stirred 5 min, warmed to rt, stirred 30 min, and then cooled
to 0 °C. To this solution was added 0.42 mL (0.18 mmol) of
TBDMSOTf, followed by warming of the mixture to rt over 5
min, and stirring 10 min. An additional 0.20 mL (0.17 mmol)
portion of 2,6-lutidine was then added and the mixture stirred
an additional 10 min. The mixture was cooled to 0 °C and a
final 0.42 mL (0.18 mmol) portion of TBDMSOTf added. The
P r ep a r a tion of Ald eh yd e 15 fr om Alcoh ol 16. To a
solution of 0.49 mL (5.63 mmol) of oxalyl chloride in 10 mL of
CH2Cl2 at -78 °C was added dropwise a solution of 0.8 mL
(11.3 mmol) of DMSO. The pale yellow solution was stirred
for 30 min at -78 °C and a solution of 640 mg (2.8 mmol) of
alcohol 16 in 7 mL of CH2Cl2 added over a 10 min period. The

6320 J . Org. Chem., Vol. 61, No. 18, 1996
Campbell and Rapoport
mixture was stirred for an additional 1 h to produce a white
slurry, and then 3.14 mL (22.5 mmol) of Et3N was added over
5 min and the mixture warmed to rt over 20 min. The mixture
was stirred for an additional 30 min and then partitioned
between 150 mL of CH2Cl2 and 20 mL of water. The organic
layer was washed with 2 M aqueous H3PO4 (2 × 20 mL)and
20 mL of brine, dried, and evaporated. The residue was
chromatographed (60 g of silica gel, eluted with 10% EtOAc/
hexane) to afford 628 mg (99%) of aldehyde 15 (containing <5%
of the hydrate) as a colorless oil. For analysis this material
was passed through a 2 g plug of anhydrous MgSO4 on top of
5 g of silica gel (eluted with 10% EtOAc/hexane): IR (CH2Cl2)
δ 1.32 (s, 9H), 1.42-1.51 (m, 2H), 1.78-1.91 (m, 4H), 1.97-
2.07 (m, 2H), 4.39 (t, J ) 4.5, 1H), 5.11 (s, 2H), 5.84 (s, 1H),
7.27-7.38 (m, 5H) 13C NMR δ 28.5 (q), 29.1 (t), 34.1 (t), 50.9
(s), 60.7 (d), 67.2 (t), 71.3 (s), 128.05 (s), 128.11 (d), 128.42 (d),
136.2 (s), 157.5 (s), 170.4 (s). Anal. Calcd for C19H26N2O3: C,
69.1; H, 7.9; N, 8.5. Found: C, 68.9; H, 8.1; N, 8.4.
(2S)-cis-1-(Ben zyloxyca r bon yl)-5-[2-[(m eth a n esu lfon -
yl)oxy]eth yl]p r olin e ter t-Bu tyl Ester (20). To a solution
of 8.87 g (25.4 mmol) of alcohol 7 in 140 mL of CH2Cl2 at 0 °C
was added 8.8 mL (63.5 mmol) of Et3N, followed by 2.50 mL
(31.8 mmol) of MsCl. The reaction mixture was stirred for 5
min, warmed to rt over 5 min, washed with 20 mL of 1 M
aqueous H3PO4 and 30 mL of 50% (v/v) aqueous 2 M NaOH/
NaHCO3 (saturated), dried, and evaporated to afford the crude
mesylate 20. The oil was dried at 0.3 Torr, and the residual
pale yellow oil, 10.85 g (100%), was used in the next reaction
without further purification.
1
1723, 1683 cm-1; H NMR δ 1.43 (s, 9H), 1.53 (tm, J ) 10.0
Hz, 1H), 1.62 (tm, J ) 10.0, 2H), 1.88-2.06 (m, 4H), 4.30 (bm,
1H), 9.94 (s, 1H); 13C NMR δ 27.9 (q), 29.3 (t), 30.3 (t), 58.9
(d), 73.4 (s), 81.3 (s), 156.5 (s, very low intensity), 197.3 (s).
Anal. Calcd for C12H19NO3: C, 64.0; H, 8.5; N, 6.2. Found:
C, 64.0; H, 8.8; N, 6.2.
(2S)-cis-1-(Ben zyloxyca r b on yl)-5-[2-(p h en ylselen yl)-
eth yl]p r olin e ter t-Bu tyl Ester (21). To a stirred solution
of 20.6 g (66.0 mmol) of (PhSe)2 in 90 mL of absolute EtOH at
0 °C was added 2.50 g (66.0 mmol) of NaBH4 slowly over 8
min, followed by stirring of the mixture for an additional 5
min and then heating to reflux for 1 h and cooling to 0 °C. To
this orange slurry was added a solution of 10.85 g (25.4 mmol)
of mesylate 20 in 44 mL of EtOH over a 5 min period. The
mixture was gradually heated to reflux over 10 min, stirred
20 min, and then allowed to cool to rt over 35 min. It was
diluted with 750 mL of EtOAc and washed with 75 mL of
saturated aqueous NaHCO3. The aqueous layer was back-
extracted with EtOAc (3 × 75 mL), and the combined organic
layers were dried, evaporated, and chromatographed (300 g
of silica gel, eluted with 5% CH2Cl2/hexane to remove selenide
byproducts then 15% EtOAc/hexane) to afford 11.79 g (95%
7-(t er t -B u t y lo x y c a r b o n y l)-1-(h y d r o x y m e t h y l)-7-
a za bicyclo[2.2.1]h ep ta n e (16). To a slurry of 1.00 g (3.0
mmol) of ester 14 and 670 mg (6.0 mmol) of CaCl2 in 10 mL of
60% EtOH/THF at 0 °C was added 457 mg (12.1 mmol) of
NaBH4 in one portion. The slurry was stirred for 25 min,
warmed to rt over 10 min, stirred 1.5 h, and then poured into
30 mL of 1 M aqueous K2CO3. The aqueous layer was
extracted with Et2O (3 × 50 mL), and the combined organic
layers were washed with 20 mL of 2 M aqueous HCl and 20
mL of brine, dried, and evaporated. The residue was chro-
matographed (60 g of silica gel, eluted with 8% EtOAc/hexane)
to afford 680 mg (100%) of alcohol 16 as a colorless oil: IR
(CH2Cl2) 3180-3520 (br), 1648 cm-1; 1H NMR δ 1.17-1.38 (m,
4H), 1.54-1.75 (m, 4H), 3.70 (d, J ) 6.6, 2H), 4.30 (bt, J )
3.8, 1H), 4.71 (bs, 1H); 13C NMR δ 27.9 (q), 28.8 (t), 31.4(t),
57.9 (d), 61.6 (t), 68.6 (s), 79.5 (s), 154.7 (s). Anal. Calcd for
C12H21NO3: C, 63.4; H, 9.3; N, 6.2. Found: C, 63.3; H, 9.4; N,
6.4.
overall from alcohol 7) of selenide 21: [R]20 -8.7° (c 1.3,
D
CHCl3); IR (CH2Cl2) 1738, 1700 cm-1; 1H NMR (rotomers, C6D6,
298 K) δ 1.15-1.21 (m, 1H), 1.31 (s, 6.13H), 1.44 (s, 3.87H),
1.63-1.77 (m, 2H), 1.78-1.92 (m, 1H), 2.22-2.32 (m, 0.43H),
2.41-2.51 (m, 0.57H), 2.80-2.90 (m, 0.86H), 3 02-3.17 (m,
1.14H), 3.79-3.84 (m, 0.43H), 4.07-4.13 (m, 0.57H), 4.17 (t,
J ) 7.8, 0.57H), 4.39 (t, J ) 7.9, 0.43H), 5.02-5.35 (m, 2H),
7.00-7.12 (m, 4H), 7.17 (t, J ) 7.4, 2H), 7.31 (m, 2H), 7.50 (d,
J ) 6.5, 0.86H), 7.59 (d, J ) 7.2, 1.14H); 13C NMR (rotomers,
C6D6, 298 K, three obscured signals between δ 127.75-128.24)
δ 24.3, 24.4, 27.79, 27.95, 28.1, 29.1, 29.6, 30.1, 35.6, 58.4, 59.3,
60.6, 61.2, 66.9, 67.1, 77.7, 80.6, 126.6, 128.53, 128.60, 128.92,
129.06, 131.29, 131.46, 132.51, 132.58, 137.34, 137.42, 154.44,
7-(Ben zyloxyca r bon yl)-1-ca r boxy-7-a za bicyclo[2.2.1]-
h ep ta n e (17). To a solution of 400 mg (2.25 mmol) of 11‚-
HCl in 4.5 mL of 1 M aqueous NaOH cooled to 5 °C was added
seven equal portions of 0.06 mL (0.4 mmol) of CBZCl in 0.7
mL of dioxane, alternatively with seven portions of 0.32 mL
of (0.32 mmol) of 1 M aqueous NaOH over a 1 h period. The
mixture was allowed to warm to rt over 3 h, stirred for an
additional 15 h, and then basified to pH 12 with NaOH. The
mixture was stirred for 1.5 h and extracted with 67% Et2O/
hexane (2 × 25 mL) and the aqueous layer acidified to pH 2
with hydrochloric acid and extracted with CH2Cl2 (7 × 25 mL).
The combined CH2Cl2 layers were dried and evaporated to
afford 580 mg (93%) of acid 17: mp 102-103 °C; IR (CH2Cl2)
1
154.73, 172.1; H NMR (C6D6, 339 K) δ 1.15-1.40 (m, 11H),
1.57-1.71 (m, 2H), 1.77-1.87 (m, 1H), 2.22-2.43 (bm, 1H),
2.77-3.00 (bm, 1H), 3.83-4.00 (bm, 1H), 4.06-4.23 (bm, 1H),
4.99 (d, J ) 12.5, 1H), 5.07 (d, J ) 12.5, 1H), 6.90-7.02 (m,
4H), 7.03-7.10 (m, 2H), 7.20 (d, J ) 7.4, 2H), 7.45 (bd, J )
6.6, 2H); 13C NMR (C6D6, 339 K) δ 24.6 (t), 28.0 (q), 28.7 (t),
30.0 (t), 35.8 (t), 59.2 (d), 61.1 (d), 67.1 (t), 80.6 (s), 126.7 (d),
127.98 (d), 128.29 (d), 128.56 (d), 129.2 (d), 131.5 (s), 132.9
(d), 137.6 (s), 154.7 (s), 171.9 (s). Anal. Calcd for C25H31NO4-
Se: C, 61.5; H, 6.4; N, 2.9. Found: C, 61.4; H, 6.4; N, 3.0.
3000-2200 (br), 1753, 1709 cm-1 1H NMR δ 1.49-1.58 (m,
;
2H), 1.80-2.00 (m, 4H), 2.17-2.30 (m, 2H), 4.44 (bt, J ) 4.4,
1H), 5.13 (s, 2H), 7.26-7.40 (m, 5H), 9.63 (s, 1H); 13C NMR δ
29.2 (t), 33.6 (t), 59.7 (d), 67.7 (t), 69.1 (s), 127.97 (s), 128.11
(d), 128.43 (d), 135.8 (s), 157.0 (s), 175.3 (s). Anal. Calcd for
C15H17NO4: C, 65.4; H, 6.2; N, 5.1. Found: C, 65.2; H, 6.2; N,
5.1.
7-(Ben zyloxycar bon yl)-1-(ch lor ocar bon yl)-7-azabicyclo-
[2.2.1]h ep ta n e (18). To a solution of 578 mg (2.09 mmol) of
acid 17 and 0.02 mL (0.22 mmol) of DMF in 4.5 mL of 1,2-
DCE was added 0.38 mL (4.4 mmol) of oxalyl chloride. The
mixture was stirred 24 h and was concentrated in vacuo until
the theoretical mass (616.5 mg) was achieved. This material
was taken directly into the next reaction without further
(2S)-cis-1-(Ben zyloxyca r bon yl)-5-vin ylp r olin e ter t-Bu -
tyl Ester (22). To a solution of 11.68 g (23.9 mmol) of selenide
21 in 176 mL of THF was added a solution of NaIO4 (15.34,
71.7 mmol) in 176 mL of water. The mixture was stirred for
45 min, heated to 55 °C, and stirred for 2.5 h more. To this
mixture was added 6.6 mL of 30% H2O2, the mixture was
stirred 30 min, and then three portions of 6.6 mL of 30% H2O2
at 1 h intervals were added. During the second 1 h, a single
portion of 1.33 mL (12.1 mmol) of NMM was also added. The
mixture was heated for an addition 3 h, cooled to rt over 1 h,
and diluted with 750 mL of EtOAc, which was washed with
saturated aqueous NaHCO3 (2 × 200 mL), 200 mL of 1 M
aqueous H3PO4, dried, and evaporated. The residue was
chromatographed (400 g of silica gel, eluted with 25% EtOAc/
purification: IR (CH2Cl2) 1777, 1708 cm-1
.
7-(Ben zyloxyca r bon yl)-1-(ter t-bu tyla m in oca r bon yl)-7-
a za bicyclo[2.2.1]h ep ta n e (19). To a solution of 616 mg (2.1
mmol) of acid chloride 18 and 25 mg (0.20 mmol) of 4-DMAP
in 8 mL of 1,2-DCE at 0 °C was added 2.2 mL (20.9 mmol) of
tert-BuNH2 dropwise over a 5 min period. The reaction
mixture was stirred for 30 min and 0.58 mL (4.2 mmol) of Et3N
added. The mixture was warmed to rt, stirred for 24 h, heated
to reflux for 15 min, and then diluted with 125 mL of CH2Cl2.
The organic layer was washed with 2 M aqueous HCl (2 × 25
mL) and 30 mL of 1 M aqueous K2CO3, dried, and evaporated.
The residue was chromatographed (60 g of silica gel, eluted
with 15% EtOAc/hexane) to afford 671 mg (97%) of amide 19:
mp 115-116 °C; IR (CH2Cl2) 3425, 1709, 1678 cm-1; 1H NMR
hexane) to afford 7.85 g (99%) of olefin 22 as a pale yellow oil:
1
[R]20 -51.7° (c 1.5, CHCl3); IR (CH2Cl2) 1740, 1706 cm-1; H
D
NMR (rotomers, C6D6, 298 K) δ 1.21 (s, 4.3H), 1.34 (s, 4.7H)
1.26-1.43 (m, 2H), 1.57-1.73 (m, 2H), 4.03-4.11 (m, 1H),
4.24-4.31 (m, 0.52H), 4.33-4.42 (m, 0.48H), 4.93-5.12 (m,
3H), 5.34 (d, J ) 7.0, 0.52H), 5.49 (d, J ) 7.1, 0.48H), 5.78-
5.96 (m, 1H), 7.00 (d, J ) 7.3, 1H), 7.03-7.12 (m, 2H), 7.17-

Syntheses of 7-Azabicycloheptane Amino Acids
J . Org. Chem., Vol. 61, No. 18, 1996 6321
7.23 (m, 2H); 13C NMR (rotomers, C6D6, 298 K) δ 27.85 (q),
27.96 (q), 28.13 (t), 29.2 (t), 30.6 (t), 31.6 (t), 60.6 (d), 60.9 (d),
61.2 (d), 61.6 (d), 66.87 (t), 66.89 (t), 80.6 (s), 114.9 (t), 115.3
(t), 127.9 (d), 129.2 (d), 132.5 (d), 137.5 (s), 138.7 (d), 139.4
(d), 153.9 (s), 154.8 (s), 171.7 (s), 171.8 (s); 1H NMR (C6D6, 339
K) δ 1.29 (s, 9H), 1.40-1.56 (m, 2H), 1.65-1.78 (m, 2H), 4.12-
4.32 (m, 2H), 4.98 (d, J ) 10.2, 1H), 5.02 (d, J ) 13.2, 1H),
5.06 (d, J ) 12.6, 1H), 5.32 (d, J ) 16.7, 1H), 5.89 (ddd, J )
17.0, 10.4, 6.4, 1H), 6.99-7.03 (m, 1H), 7.06-7.11 (m, 2H), 7.20
(d, J ) 7.3, 2H); 13C NMR (C6D6, 339 K) δ 28.0 (q), 28.8 (t),
31.3 (t), 61.0 (d), 61.4 (d), 67.0 (t), 80.6 (s), 115.8 (t), 127.3 (d),
129.2 (d), 132.9 (d), 137.7 (s), 139.4 (d), 154.47 (s), 154.79 (s),
171.7 (s). Anal. Calcd for C19H25NO4: C, 68.9; H, 7.3; N, 4.0.
Found: C, 68.6; H, 7.6; N, 4.1.
(2S)-cis-1-(Ben zyloxyca r bon yl)-5-[(1′S)-2′-br om o-1′-[(tr i-
eth ylsilyl)oxy]eth yl]p r olin e ter t-Bu tyl Ester (24r). To a
solution of 670 mg (2.55 mmol) of PPh3 in 4 mL of CH2Cl2 was
added 0.97 mL (2.55 mmol) of freshly prepared 2.63 M Br2 in
CH2Cl2 to form a slurry that was stirred for 10 min. To this
mixture was added a solution of 785 mg (2.25 mmol) of epoxide
23, as a 2.2/1 mixture of â/R epoxide diastereomers, in 7 mL
of CH2Cl2 over a 5 min period. The mixture was stirred for
50 min, transferred into 25 mL of rapidly stirring ice-cold
saturated aqueous NaHCO3, stirred for 3 min, and diluted with
25 mL of CH2Cl2. The aqueous layer was extracted with 25
mL of CH2Cl2, and the combined organic extract was dried,
evaporated at rt, and chromatographed (15 g of silica gel,
eluted with 13% EtOAc/hexane) to afford 895 mg (92%) of the
mixed bromohydrins. To a solution of the mixture of bromo-
hydrins in 20 mL of CH2Cl2 at 0 °C was added 786 mg (11.5
mmol) of imidazole, followed by 780 mL (4.65 mmol) of TESCl
dropwise over 3 min. The mixture was warmed to rt after 10
min, stirred for 35 min, and evaporated. The residue was
chromatographed (15 g of silica gel, eluted with 10% EtOAc/
hexane) to afford a mixture of the silyl ethers (24â/24R) and
unreacted TESCl. Heating at 60 °C/0.1 Torr for 15 min and
then for 36 h at rt afforded 1.10 g (98%, 90% overall from
epoxides 23â/23R) of pure silyl ethers 24 as a colorless oil,
existing as a 2/1 mixture of diastereomers (24â/24R). The yield
range of this two-step procedure, 87-92%, was identical when
using the R- or â-epoxide diastereomer of 23 to afford,
respectively, the individual bromo silyl ether diastereomers
of 24.
(2S)-cis-1-(Ben zyloxyca r b on yl)-5-(S)-oxir a n ylp r olin e
ter t-Bu tyl Ester (23â) a n d (2S)-cis-1-(Ben zyloxyca r bo-
n yl)-5-(R)-oxir a n ylp r olin e ter t-Bu t yl E st er (23r). To a
solution of 15.74 g (63.8 mmol) of m-CPBA (prewashed with
pH 8 aqueous 0.1 M K2HPO4 (2 × 70 mL) in 295 mL of CH2-
Cl2 at -10 °C) was added a solution of 7.60 g (22.9 mmol) of
olefin 22 in 35 mL of CH2Cl2 over 5 min. The mixture was
allowed to warm to 4 °C over 6 h and then was stirred for an
additional 41 h at 4 °C. The resulting slurry was filtered at 0
°C, and the filtrate was added over 5 min to a rapidly stirred
ice-cold solution of 700 mL of 10% aqueous Na2SO3. The
aqueous layer was back-extracted with CH2Cl2 (3 × 100 mL).
The combined organic extracts were washed with 10% aqueous
Na2SO3 (2 × 200 mL), pH 8 aqueous 0.1 M K2HPO4 (2 × 200
mL), and saturated aqueous NaHCO3 (200 mL), dried, evapo-
rated, and chromatographed (200 g of silica gel, eluted with
15% EtOAc/hexane) to afford 230 mg (3%) of recovered olefin
22, followed by 7.06 g (89%) of epoxide 23 as a 2.2/1 mixture
of easily separable 23â/23R epoxide diastereomers. Chroma-
tography of 3.19 g of this mixture (300 g of silica gel, eluted
with 13% and then 25% EtOAc/hexane) gave 2.19 g of 23â,
followed by 1.00 g of 23R.
24â: [R]20D -4.6° (c 1.6, CHCl3); IR (CH2Cl2) 1740, 1703 cm-1
;
1H NMR (rotomers, C6D6, 298 K) δ 0.50-0.76 (br m, 6H), 0.80-
1.07 (br m, 9H), 1.24 (s, 5.6H), 1.10-1.27 (m, 1H), 1.34 (s,
4.4H), 1.76 (t, J ) 8.1, 2H) 1.80-1.93 (m, 1H), 3.47-3.60 (m,
0.76H), 3.62-3.80 (m, 1.24 H) 3.93-4.32 (m, 3H) 4.97 (d, J )
12.5, 1H) 4.98-5.16 (bm, 1H), 7.01 (t, J ) 7.2, 1H), 7.03-7.14
(m, 2H), 7.15-7.30 (bm, 2H); 13C NMR (rotomers, C6D6, 298
K, two dCH obscured) δ 5.7, 7.2, 26.3, 26.7, 27.9, 29.1, 37.4,
37.7, 60.9, 61.5, 61.7, 63.0, 67.3, 73.2, 74.1, 80.7, 128.6, 129.0,
137.1, 155.1, 171.7; 1H NMR (C6D6, 339 K) δ 0.66 (q, J ) 7.9,
6H), 0.96 (t, J ) 8.0, 9H), 1.29 (s, 9H), 1.26-1.37 (m, 2H) 1.76-
1.82 (m, 2H), 1.87-1.97 (bm, 1H), 3.50-3.57 (bm, 1H), 3.58-
3.67 (bm, 1H) 4.08 (t, J ) 6.6, 1H), 4.12-4.22 (bm, 2H), 5.03
(d, J ) 12.4, 1H) 5.06 (d, J ) 12.4, 1H), 7.02 (t, J ) 7.3, 2H),
7.08 (t, J ) 7.6, 2H), 7.22 (d, J ) 7.3, 2H); 13C NMR (C6D6,
339 K) δ 5.9 (t), 7.1 (q), 26.6 (t), 28.0 (q), 28.8 (t), 37.4 (t), 61.4
(d), 62.9 (d), 67.4 (t), 74.0 (d), 80.8 (s), 128.15 (d), 128.50 (d),
128.58 (d), 137.2 (s), 155.2 (s), 171.6 (s). Anal. Calcd for
C25H40NO5SiBr: C, 55.3; H, 7.4; N, 2.6. Found: C, 55.6; H,
7.6; N, 2.3.
23â: [R]20 -45.5° (c 1.9, CHCl3) IR (CH2Cl2) 1740, 1705
D
cm-1; H NMR (rotomers, C6D6, 298 K) δ 1.21 (s, 5.1H), 1.33
1
(s, 4.9H), 1.33-1.49 (m, 1H), 1.58-1.82 (m, 3H), 2.32-2.42
(m, 0.86 H), 2.57 (t, J ) 4.6, 0.57H) 2.75 (dd J ) 4.8, 2.1, 0.57H)
3.03-3.10 (m, 0.43H), 3.11-3.18 (m, 0.57H), 3.26 (t, J ) 7.1,
0.43H), 3.56 (td, J ) 5.6, 2.2 Hz, 0.57H), 4.04 (t, J ) 7.2,
0.57H), 4.23-4.30 (m, 0.43H), 4.90-5.13 (m, 2H), 7.00-7.32
(m, 5H); 13C NMR (rotomers, C6D6, 298 K, two dCH obscured)
δ 27.23, 27.75, 27.9, 28.24, 28.48, 29.3, 47.66, 47.86, 52.64,
52.99, 60.15, 60.62, 61.06, 61.38, 67.00, 67.26, 80.73, 80.79,
126.92, 127.20, 128.55, 128.57, 137.05, 137.20, 154.23, 154.52,
171.9; 1H NMR (C6D6, 339 K) δ 1.27 (s, 9H), 1.42-1.58 (m,
1H), 1.65-1.83 (m, 3H), 2.38-2.68 (bm, 2H), 3.04-3.14 (bm,
1H) 3.38-3.58 (bm, 1H), 4.08-4.24 (bm, 1H) 4.92-5.08 (m,
2H), 6.97-7.15 (m, 3H), 7.17 (d, J ) 7.3, 2H); 13C NMR (C6D6,
339 K) δ 27.56 (t), 27.96 (q), 29.0 (t), 47.6 (t), 52.9 (d), 60.9 (d),
61.2 (d), 67.2 (t), 80.8 (s), 126.97 (d), 127.76 (d), 128.6 (d), 137.4
(s), 154.5 (s), 171.8 (s). Anal. Calcd for C19H25NO5: C, 65.7;
H, 7.3; N, 4.0. Found: C, 65.6; H, 7.3; N, 3.8.
24r: mp 90-91.5 °C; [R]20 -18.8° (c 1.1, CHCl3); IR (CH2-
D
Cl2) 1736, 1703 cm-1; 1H NMR (rotomers, C6D6, 298 K) δ 0.48-
0.67 (m, 2.88H), 0.73-0.83 (m, 3H), 1.19 (s, 4.32H), 1.36 (s,
4.68H), 1.20-1.48 (m, 2H), 1.53-1.62 (m, 1H), 1.64-1.77 (m,
1H), 3.10 (t, J ) 10.0, 0.48H), 3.10 (t, J ) 10.0, 0.48H), 3.21
(t, J ) 9.9, 0.52H), 3.63-3.68 (m, 0.48H), 3.87-3.97 (m, 1.04H),
4.13 (t, J ) 8.5, 0.52H), 4.27 (t, J ) 10.1, 0.52H), 4.36 (t, J )
10.1, 0.48H), 4.46-4.51 (m, 0.48H), 4.83-5.05 (m, 2H), 6.99-
7.18 (m, 5H); 13C NMR (rotomers, C6D6, 298 K, one dCH
obscured) δ 5.3, 5.5, 7.2, 23.9, 24.7, 27.78, 27.96, 28.9, 30.0,
35.7, 61.6, 62.5, 62.8, 64.1, 67.3, 67.8, 73.4, 74.2, 81.03, 81.11,
128.58, 128.65, 129.1, 136.6, 136.9, 154.8, 171.6; 1H NMR
(C6D6, 339 K) δ 0.57-0.80 (bm, 6H), 0.93-1.08 (bm, 9H), 1.28
(s, 9H), 1.31-1.45 (m, 1H), 1.50-1.58 (m, 1H), 1.60-1.71 (m,
1H) 1.77-1.85 (bm, 1H), 3.21 (t, J ) 9.6, 1H), 3.77-3.95 (bm,
1H), 4.00-4.12 (bm, 1H) 4.21 (dd, J ) 10.3, 1.3, 1H) 4.58-
4.85 (bm, 1H) 4.95 (d, J ) 12.3, 1H) 5.00 (d, J ) 12.3, 1H)
7.01 (t, J ) 7.3, 1H), 7.08 (t, J ) 7.6, 2H), 7.17 (d, J ) 7.2,
2H); 13C NMR (C6D6, 339 K) δ 5.7 (t), 7.0 (q), 24.5 (t), 28.0 (q),
29.5 (t), 35.5 (t), 62.2 (d), 63.8 (d), 67.6 (t) 73.8 (d), 81.1 (s),
128.2 (d), 128.6 (d), 137.0 (s), 155.0 (s), 171.5 (s). Anal. Calcd
for C25H40NO5SiBr: C, 55.3; H, 7.4; N, 2.6. Found: C, 55.6;
H, 7.7; N, 2.3.
23r: [R]20D -9.0° (c 1.1, CHCl3); IR (CH2Cl2) 1737, 1702 cm-1
;
1H NMR (rotomers, C6D6, 298 K) δ 1.22 (s, 5.04H), 1.32 (s,
3.96H), 1.32-1.59 (m, 2H), 1.63-2.03 (m, three overlapping
signals, 2H), 2.27-2.36 (m, 0.44H), 2.36-2.45 (m, 0.56H) 2.48-
2.58 (m, 0.44H), 2.76-2.82 (m, 0.56H) 2.87-3.03 (m, two
overlapping signals, 1H), 3.66-3.75 (m, 0.44H), 3.99 (t, J )
7.5, 0.56H) 4.07-4.16 (m, 0.56H) 4.17-4.27 (m, 0.44H) 4.95-
5.18 (m, 2H) 6.98-7.18 (m, 3H), 7.18-7.30 (m, 2H); 13C NMR
(rotomers, C6D6, 298 K, two dCH obscured) δ 27.1, 27.82,
27.90, 28.64, 29.7, 44.0, 44.3, 53.5, 53.9, 58.15, 58.22, 60.6, 61.3,
67.1, 80.6, 128.5, 137.23, 137.38, 154.7, 171.15, 171.27; 1H
NMR (C6D6, 339 K) δ 1.28 (s, 9H), 1.20-1.48 (m, 1H), 1.48-
1.58 (m, 1H), 1.67-1.77 (m, 1H) 1.80-1.92 (bm, 1H), 2.36 (t,
J ) 4.3, 1H), 2.62 (bm, 1H), 2.97-3.03 (bm, 1H), 3.83-4.08
(bm, 1H), 4.09-4.22 (bm, 1H), 5.00-5.14 (m, 2H) 7.02 (t, J )
7.2, 1H) 7.09 (t J ) 7.6, 2H) 7.24 (d, J ) 7.3, 2H); 13C NMR
(C6D6, 339 K) δ 27.4 (t), 28.0 (q), 29.3 (t), 44.2 (t), 53.6 (d),
58.5 (d), 61.2 (d), 67.2 (t), 80.6 (s), 128.0 (d), 128.2 (d), 128.5
(d), 137.5 (s), 154.8 (s), 171.2 (s). Anal. Calcd for C19H25NO5:
C, 65.7; H, 7.3; N, 4.0. Found: C, 65.5; H, 7.2; N, 4.1.
(1S,3S,4R)-7-(Ben zyloxycar bon yl)-1-car boxy-3-h ydr oxy-
7-a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester (25â) a n d
(1S,3R,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-h yd r oxy-
7-a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester (25r). Cy-
cliza tion of a Dia ster eom er ic Mixtu r e of 24r/24â or 24r.
(2S)-cis-1-(Ben zyloxycar bon yl)-5-[(1′R)-2′-br om o-1′-[(tr i-
eth ylsilyl)oxy]eth yl]p r olin e ter t-Bu tyl Ester (24â) a n d

6322 J . Org. Chem., Vol. 61, No. 18, 1996
Campbell and Rapoport
P r oced u r e A. To a solution of 8.5 mL (7.83 mmol) of KHMDS
in 150 mL of THF at -70 °C was added a solution of 3.08 g
(5.68 mmol) of silyl ether 24, existing as a 2/1 mixture 24â/
24R, over a 10 min period via cannula. The mixture was
stirred for 10 min, warmed to -40 °C, stirred for 1 h, warmed
to -10 °C, stirred for 30 min, warmed to 0 °C, and stirred for
20 min. The mixture was warmed to rt over 10 min and
stirred 20 min, and 0.3 mL of AcOH (5.68 mmol) was added.
The mixture was concentrated at ambient temperature to 10
mL and diluted with 400 mL of EtOAc, the EtOAc layer was
washed with 1 M H3PO4 (2 × 100 mL) and saturated aqueous
NaHCO3 (2 × 50 mL), dried, and evaporated, and the residue
was immediately dissolved in 50 mL of THF. The aqueous
washes from the extraction were then combined. To the
organic residue was added 6.9 mL of 1 M TBAF in THF, the
mixture was stirred for 20 min, and then 0.42 mL (7.41 mmol)
of AcOH was added. The solution was evaporated at rt, and
the residue was chromatographed (100 g of silica gel, eluted
with 25% EtOAc/hexane then 1% MeOH/35% EtOAc/hexane)
to afford 1.65 g (84%) of alcohol 25, existing as 3/1 mixture of
â/R stereoisomers that was used immediately in the prepara-
tion of ketone 26. The â/R stereoisomers were completely
separated (the R-stereoisomer eluted first) during the chro-
matography but were recombined for the preparation of ketone
26. Alcohol 25â was labile to mild heating under reduced
pressure but could be stored indefinitely at 0 °C.
5 mL) and 25 mL of saturated aqueous NaHCO3, dried, and
evaporated. The residue was chromatographed (125 g of silica
gel, eluted with 10% EtOAc/hexane) to afford 1.38 g (93%) of
ketone 26: mp 68-69 °C; [R]20D -40.7° (c 1.3, CHCl3); IR (CH2-
Cl2) 3630-3400, 1733, 1713 cm-1; 1H NMR δ 1.49 (s, 9H), 1.64
(ddd, J ) 13.2, 9.0, 4.5, 1H) 1.85 (ddd, J ) 12.5, 9.0, 4.4, 1H)
2.11 (ddd, J ) 15.3, 12.8, 5.3, 1H), 2.28 (d, J ) 17.7, 1H), 2.36
(ddd, J ) 12.2, 4.3, 3.4, 1H), 2.84 (dd, J ) 17.7, 2.6H), 4.41 (d,
J ) 5.6, 1H) 5.10 (d, J ) 12.3, 1H) 5.14 (d, J ) 12.3, 1H), 7.27-
7.37 (m, 5H); 13C NMR δ 23.9 (t), 27.7 (q), 31.5 (t), 47.3 (t),
66.9 (d), 67.7 (t), 69.4 (s), 82.3 (s), 127.9 (d), 128.25 (d), 128.45
(d), 135.6 (s), 155.9 (s), 167.2 (s), 207.0 (s). Anal. Calcd for
C19H23NO5: C, 66.1; H, 6.7; N, 4.1. Found: C, 65.9; H, 6.9; N,
3.7.
(1S,3R,4R)-7-(Ben zyloxycar bon yl)-1-car boxy-3-h ydr oxy-
7-a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester (25r). To a
solution of 66 mg (0.19 mmol) of ketone 26 in 3 mL of THF
cooled to -55 °C was added dropwise 0.22 mL of a 1 M
L-Selectride (Aldrich) solution in THF. The mixture was
allowed to warm to -40 °C over 15 min, stirred for 30 min,
warmed to rt, stirred for 20 min, and then quenched with 1
mL of 50% (v/v) EtOH/saturated aqueous NH4Cl and parti-
tioned between 70 mL of CH2Cl2 and 10 mL of water. The
organic layer was washed with 20 mL of 2 M NaOH containing
1 mL of 30% H2O2, dried, evaporated, and chromatographed
(15 g of silica gel, eluted with 40% EtOAc/hexane) to afford
57 mg (87%) of alcohol 25R, identical spectroscopically to that
isolated from the transannular alkylation sequence.
(1S,3S,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-[(tr ieth -
ylsilyl)oxy]-7-a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester ,
TES Eth er of 25â. Cycliza tion of 24â. P r oced u r e B.
Following the procedure described for the preparation of 10
and 13, except that the mixture, rather than being stirred for
30 min at 0 °C, was stirred for 30 min at -10 °C and then 20
min at 0 °C, 131 mg of 24â was converted to 104 mg (93%) of
the triethylsilyl ether of 25â. Following the TBAF treatment
described in procedure A, 150 mg (0.325 mmol) of the TES
ether of 24â was converted to 112 mg (99%) of alcohol 25â.
(1S,3R,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-flu or o-
7-a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester (27r) a n d
(1S,3S,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-flu or o-7-
a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester (27â). To a
solution of 0.11 mL (0.86 mmol) of DAST in 1.38 mL of pyridine
at 0 °C was added a solution of 300 mg (0.86 mmol) of alcohol
25R in 5 mL of CH2Cl2. The mixture was warmed to rt over
5 min, stirred for 6 h, cooled to 0 °C, and quenched by the
dropwise addition of 1 mL of H2O and then partitioned
between 75 mL of CH2Cl2 and 20 mL of aqueous NaHCO3. The
aqueous layer was washed with CH2Cl2 (2 × 40 mL), and the
combined organic extracts were washed with 10 mL of 2 M
aqueous HCl and 10 mL of brine, dried, and evaporated. The
residue was chromatographed (70 g of silica gel, eluted with
15% EtOAc/hexane) to afford 44 mg (18%) of fluoro analogue
27R, 35 mg (14%) of 27â, and 50 mg (17%) of recovered 25R.
1
TES eth er of 25â: IR (CH2Cl2) 1728, 1703 cm-1; H NMR
δ 0.53 (q, J ) 8.1, 6H), 0.89 (t, J ) 8.0, 9H), 1.22-1.30 (m,
1H), 1.40-1.54 (m, 1H), 1.45 (s, 9H), 1.78-1.88 (m, 1H), 1.98-
2.12 (m, 3H), 3.93 (dd, J ) 5.6, 3.3, 1H), 4.19 (d, J ) 5.4, 1H),
4.93 (d, J ) 12.5, 1H), 5.18 (d, J ) 12.5, 1H), 7.23-7.35 (m,
5H); 13C NMR δ 4.6 (t), 6.6 (q), 23.9 (t), 27.8 (q), 33.2 (t), 44.4
(t), 66.63 (d), 66.84 (t), 68.5 (s), 74.9 (d), 81.2 (s), 127.73 (d),
127.78 (d), 128.2 (d), 136.5 (s), 157.2 (s), 169.2 (s).
25â: mp 101-102 °C; [R]20 -38.4° (c 1.4, CHCl3); IR (CH2-
27r: [R]20D -5.8° (c 1.2, CHCl3); IR (CH2Cl2) 1725, 1715 cm-1
;
D
Cl2) 3600-3300, 1733, 1710 cm-1; H NMR δ 1.27-1.37 (m,
1H NMR δ 1.47 (s, 9H), 1.62-1.73 (m, 1H), 1.75-1.86 (m, 2H),
2.08-2.17 (m, 1H), 2.18-2.27 (m, 1H), 2.52-2.65 (m, 1H), 4.50
1
1H) 1.46 (s, 9H), 1.50-1.58 (m, 1H), 1.76-1.87 (m, 1H), 1.96-
2.06 (m, 1H), 2.11 (dd, J ) 12.9, 6.8, 1H) 2.48 (bs, 1H), 3.92
(dm, J ) 6.3, 1H), 4.26 (d, J ) 5.5, 1H) 5.08 (d, J ) 12.4, 1H),
5.12 (d, J ) 12.3, 1H) 7.26-7.35 (m, 5H); 13C NMR δ 24.0 (t),
27.8 (q), 31.2 (t), 45.7 (t), 66.3 (d), 67.2 (t), 68.8 (s), 73.5 (d),
81.5 (s), 127.92 (d), 127.98 (d), 128.3 (d), 136.2 (s), 157.4 (s),
169.0 (s). Anal. Calcd for C19H25NO5: C, 65.7; H, 7.3; N, 4.0.
Found: C, 65.8; H, 7.3; N, 3.8.
(t, J ) 4.1, 1H), 5.07 (dm, J
) 53, 1H), 5.11 (s, 2H), 7.26-
HF
7.38 (m, 5H); 19F NMR δ -42.55 (ddd, J FH ) 53.4, 34.8, 18.7,
1F); 13C NMR δ 20.2 (t, J
) 7.0), 27.8 (q), 32.0 (t), 40.8 (t,
CF
J CF ) 23.1), 61.5 (d, J CF ) 23.3), 67.4 (t), 69.9 (s), 81.6 (s), 89.1
(d, J CF ) 190.7), 127.96 (d), 128.18 (d), 128.46 (d), 136.0 (s),
156.2 (s), 168.5 (s). Anal. Calcd for C19H24NO4F: C, 65.3; H,
6.9; N, 4.0. Found: C, 65.5; H, 7.1; N, 3.9.
25r: mp 94-96 °C; [R]20 -10.5° (c 1.1, CHCl3); IR (CH2-
27â: [R]20 -20.7° (c 1.5, CHCl3); IR (CH2Cl2) 1740, 1715
D
D
Cl2) 3630-3400, 1733, 1713 cm-1
;
1H NMR δ 1.38 (dd, J )
cm-1; H NMR δ 1.24-1.33 (m, 2H), 1.49 (s, 9H), 1.45-1.62
1
12.8, 3.2, 1H) 1.45 (s, 9H), 1.68-1.83 (m, 1H), 2.13-2.24 (m,
1H) 2.55 (t, J ) 10.1, 1H), 4.28 (t, J ) 4.4, 1H), 4.33-4.38 (m,
1H), 5.10 (s, 1H), 7.30-7.40 (m, 5H); 13C NMR δ 20.9 (t), 27.8
(q), 32.9 (t), 42.6 (t), 63.2 (d), 67.2 (t), 69.6 (s), 70.3 (d), 81.4
(s), 127.9 (d), 128.07 (d), 128.43 (d), 136.2 (s), 156.6 (s), 169.3
(s). Anal. Calcd for C19H25NO5: C, 65.7; H, 7.3; N, 4.0.
Found: C, 66.0; H, 7.6; N, 3.9.
(m, 1H), 1.85-1.97 (m, 1H), 2.03-2.20 (m, 2H), 2.35 (dd, J )
38.8, 14.5, 1H), 4.53 (dd, J ) 7.8, 6.4, 1H), 4.80 (dd, J HF
)
54.5, 5.5, 1H), 5.09 (d, J ) 12.3, 1H), 5.14 (d, J ) 12.3, 1H),
7.26-7.40 (m, 5H); 19F NMR δ -17.93 (ddm, J FH ) 54.5, 38.8,
1F); 13C NMR δ 22.3 (t, J CF ) 7.3), 27.8 (q), 32.3 (t), 41.9 (t,
J CF ) 22.7), 63.9 (d, J CF ) 20.0), 67.2 (t), 68.4 (s), 81.7 (s), 93.8
(d, J CF ) 188.5), 127.9 (d), 128.3 (d), 136.1 (s), 156.7 (s), 168.8
(s). Anal. Calcd for C19H24NO4F: C, 65.3; H, 6.9; N, 4.0.
Found: C, 65.4; H, 7.0; N, 3.9.
(1S,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3,3-d iflu or o-
7-a za bicyclo[2.2.1]-h ep t a n e ter t-Bu t yl E st er (28). To a
solution of 180 mg (0.52 mmol) of ketone 26 in 5 mL of CH2-
Cl2 at -78 °C was added 0.35 mL (2.61 mmol) of DAST. The
mixture warmed to rt over 5 min, stirred for 38 h, and cooled
to 0 °C, and an additional 0.14 mL (1.04 mmol) of DAST was
added. The mixture was then warmed to rt, stirred for 17 h,
cooled to 0 °C, and quenched by the dropwise addition of 1
mL of H2O. The solution was partitioned between 70 mL of
CH2Cl2 and 20 mL of aqueous NaHCO3, the aqueous layer was
washed with CH2Cl2 (2 × 40 mL), and the combined organic
extracts were washed with 20 mL of brine, dried, and
(1S,4R)-7-(Ben zyloxycar bon yl)-1-car boxy-7-azabicyclo-
[2.2.1]-3-h ep ta n on e ter t-Bu tyl Ester (26). To a solution of
0.79 mL (9.04 mmol) of oxalyl chloride in 17 mL of CH2Cl2 at
-78 °C was added dropwise 1.28 mL (18.1 mmol) of DMSO.
The pale yellow solution was stirred for 45 min at -78 °C,
and a solution of 1.495 g (4.30 mmol) of a mixture of alcohols
25â/25R, prepared according to cyclization procedure A, was
added in 35 mL of CH2Cl2 added over a 10 min period. The
mixture was stirred for an additional 1 h to produce a white
slurry, and then 4.8 mL (34.4 mmol) of Et3N was added over
5 min and the mixture stirred for 30 min and then warmed to
rt. The mixture was stirred for an additional 1 h and then
partitioned between 250 mL of CH2Cl2 and 30 mL of water.
The organic layer was washed with 1 M aqueous H3PO4 (2 ×

Syntheses of 7-Azabicycloheptane Amino Acids
J . Org. Chem., Vol. 61, No. 18, 1996 6323
evaporated. The residue was chromatographed (90 g of silica
gel, eluted with 10% EtOAc/hexanes) to afford 50 mg (26%) of
difluoro analogue 28 and 81 mg (45%) of recovered 26: IR
To a solution of 373 mg (0.96 mmol) of this acid in 5 mL of
dry toluene containing 4 Å molecular sieves was added 0.16
mL (1.15 mmol) of Et3N, followed by 0.24 mL (1.11 mmol) of
DPPA. The mixture was heated at 85 °C for 2 h and cooled to
rt, 0.16 mL (1.15 mmol) of 2-(trimethylsilyl)ethanol added, and
the mixture heated to 85 °C for an additional 12 h. The
mixture was cooled to rt, concentrated to 1/4 volume, and
filtered, washing with 120 mL of EtOAc. The filtrate was
evaporated and the residue chromatographed (100 g of silica
gel, eluted with 17% EtOAc/hexane then 25% EtOAc/hexane)
to afford 450 mg (93%) of N-TEOC carbamate 30R as a
(CH2Cl2) 1710 cm-1 1H NMR δ 1.50 (s, 9H), 1.77-1.83 (m,
;
1H), 1.92-1.98 (m, 1H), 2.10 (td, J ) 9.1, 13.9, 1H), 2.20-
2.28 (m, 1H), 2.67-2.79 (m, 1H), 4.42-4.45 (m, 1H), 5.11 (d,
J ) 12.2, 1H), 5.15 (d, J ) 12.2, 1H), 7.26-7.42 (m, 5H); 19F
NMR δ 53.52 (dd, J FF/FH ) 26.1, 6.1, 1F), 54.11 (dd, J FF/FH
)
26.1, 7.3, 1F); 13C NMR δ 27.5 (t, J CF ) 4.3), 27.8 (q), 32.0 (t),
44.7 (t, J CF ) 25.2), 64.5 (d, J CF ) 25.2), 67.6 (s, J CF ) 4.6,
1.5), 82.2 (s), 126.9 (s, m from J CF), 127.9 (d), 128.47 (d), 128.51
colorless oil: [R]20 -12.1° (c 1.2, CHCl3); IR (CH2Cl2) 3450,
(d), 135.8 (s), 155.9 (s), 167.4 (s); HRMS (FAB) calcd for C19H24
-
D
NO4F2 (M+ + 1) 368.1673, found 368.1675.
1710 cm-1; 1H NMR δ 0.04 (s, 9H), 0.96 (t, J ) 8.4, 2H), 1.18-
1.28 (m, 1H), 1.45 (s, 9H), 1.60-1.70 (m, 2H), 1.73-1.84 (m,
1H), 2.10-2.20 (m, 1H), 2.33-2.43 (m, 2H), 3.08-3.20 (m, 1H),
3.22-3.31 (m, 1H), 4.14 (t, J ) 8.4, 2H), 4.30 (m, 1H), 4.53-
4.60 (bm, 1H), 5.09 (d, J ) 12.4, 1H), 5.13 (d, J ) 12.4, 1H),
7.26-7.38 (m, 5H); 13C NMR δ -1.5 (q), 17.7 (t), 23.2 (t), 27.8
(q), 33.3 (t), 38.2 (t), 40.8 (d), 42.2 (t), 61.6 (d), 63.1 (t), 67.2
(t), 70.0 (s), 81.3 (s), 127.9 (d), 128.0 (d), 128.4 (s), 136.2 (s),
156.5 (s), 169.3 (s). Anal. Calcd for C26H40SiN2O6: C, 61.9;
H, 8.0; N, 5.6. Found: C, 62.0; H, 8.1; N, 5.7.
(1S,3R,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-[(m eth -
oxyca r b on yl)m et h yl]-7-a za b icyclo[2.2.1]-h ep t a n e ter t-
Bu tyl Ester (29â) a n d (1S,3S,4R)-7-(Ben zyloxyca r bon yl)-
1 -c a r b o x y -3 -[ ( m e t h o x y c a r b o n y l ) m e t h y l ] -7 -a z a -
bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester (29r). To a solution
of 0.63 mL (3.91 mmol) of trimethyl phosphonoacetate in 18
mL of THF at 0 °C was added 4.20 mL (3.86 mmol) of 0.92 M
KHMDS in THF. The mixture was stirred for 10 min, warmed
to rt, and stirred for an additional 15 min, producing a white
slurry. The mixture was cooled to 4 °C, a solution of 900 mg
(2.61 mmol) of ketone 26 was added in 18 mL of THF, and the
mixture was stirred for 15 h and then for 2 h at rt. A solution
of 0.22 mL (3.90 mmol) of AcOH was added, the mixture was
stirred for 5 min, and then the slurry was chromatographed
(15 g of silica gel, eluted with 20% EtOAc/hexane) to afford
1.05 g of the R,â-unsaturated ester. Applying the procedure
for preparing N-CBZ alcohol 7, except that 110 mL of MeOH
and 350 mg of 10% Pd/C were used, 966 mg (2.41 mmol) of
the N-CBZ unsaturated ester was converted to 963 mg (99%)
of N-CBZ bicycle 29 as a 3.7/1 mixture of 29â and 29R.
Chromatography (150 g of silica gel, eluted with 10% EtOAc/
hexane and then 20% EtOAc/hexane) afforded 208 mg (21%)
of 29â, 16 mg (1.6%) of mixed fractions, and 749 mg (77%) of
29R.
(1S,3R,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-[[N-[[[2-
(t r im e t h ylsilyl)e t h yl]oxy]ca r b on yl]a m in o]m e t h yl]-7-
a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester (30â). Applying
the hydrolysis procedure used in the preparation of carbamate
30R from ester 29R, 279 mg (0.69 mmol) of ester 29â was
converted to 270 mg (100%) of the resulting carboxylic acid
30â, which was used without further purification: IR (CH2-
Cl2) 3300-2800 (br), 1730, 1710 cm-1; 1H NMR δ 1.46 (s, 9H),
1.48-1.58 (m, 1H), 1.65-1.79 (m, 2H), 1.80-1.90 (m, 1H), 2.02
(d, J ) 12.3, 8.5, 1H), 2.07-2.23 (m, 2H), 2.35 (dd, J ) 16.9,
7.1, 1H), 2.52 (dd, J ) 16.9, 8.0, 1H), 4.20 (d, J ) 4.9, 1H),
5.09 (d, J ) 12.4, 1H), 5.14 (d, J ) 12.4, 1H), 7.26-7.38 (m,
5H); 13C NMR δ 27.8 (q), 29.3 (t), 31.2 (t), 38.3 (d), 39.2 (t),
41.8 (t), 63.4 (d), 67.1 (t), 69.7 (s), 81.4 (s), 127.98 (d), 128.05
(d), 128.4 (d), 136.2 (s), 156.8 (s), 169.2 (s), 177.9 (s).
29â: [R]20 -27.2° (c 1.2, CHCl3); IR (CH2Cl2) 1732, 1710
D
Applying the rearrangement procedure used in the prepara-
tion of 30R from 29R, 260 mg (0.67 mmol) of the above acid
was converted to 273 mg (81% yield from 29â) of carbamate
cm-1; H NMR δ 1.45 (s, 9H), 1.46-1.57 (m, 1H), 1.64-1.77
1
(m, 2H), 1.79-1.89 (m, 1H), 1.99 (dd, J ) 12.2, 8.4, 1H), 2.06-
2.16 (m, 1H), 2.17-2.26 (m, 1H), 2.28 (dd, J ) 16.3, 7.0, 1H),
2.46 (dd, J ) 16.3, 7.9, 1H), 3.63 (s, 3H), 4.16 (d, J ) 4.2, 1H),
5.08 (d, J ) 12.5, 1H), 5.12 (d, J ) 12.4, 1H), 7.26-7.38 (m,
5H); 13C NMR δ 27.8 (q), 29.3 (t), 31.3 (t), 38.6 (d), 39.2 (t),
41.6 (t), 51.5 (q), 63.4 (d), 67.0 (t), 69.7 (s), 81.2 (s), 127.89 (d),
127.96 (d), 128.3 (d), 136.2 (s), 156.7 (s), 169.2 (s), 172.6 (s).
Anal. Calcd for C22H29NO6: C, 65.5; H, 7.2; N, 3.5. Found:
C, 65.4; H, 7.3; N, 3.6.
30â as a colorless oil: [R]20 -36.4° (c 1.1, CHCl3); IR (CH2-
D
Cl2) 3445, 1710 cm-1; 1H NMR δ 0.03 (s, 9H), 0.96 (t, J ) 8.4,
2H), 1.40-1.53 (m, 2H), 1.45 (s, 9H), 1.63-1.73 (m, 1H), 1.80-
1.89 (m, 1H), 2.05-2.18 (m, 1H), 2.87-2.95 (m, 2H), 2.98-
3.07 (m, 1H), 4.12 (t, J ) 8.4, 2H), 4.18 (d, J ) 4.7, 1H), 4.85-
4.93 (bm, 1H), 5.08-5.13 (m, 2H), 7.28-7.37 (m, 5H); 13C NMR
δ -1.5 (q), 17.7 (t), 27.8 (q), 29.2 (t), 31.8 (t), 39.0 (t), 42.2 (d),
44.4 (t), 61.6 (d), 62.9 (t), 67.1 (t), 69.6 (s), 81.3 (s), 128.03 (d),
128.13 (d), 128.5 (s), 136.2 (s), 156.7 (s), 169.2 (s). Anal. Calcd
for C26H40SiN2O6: C, 61.9; H, 8.0; N, 5.6. Found: C, 61.9; H,
8.2; N, 5.6.
29r: [R]20 -11.8° (c 1.7, CHCl3); IR (CH2Cl2) 1732, 1712
D
cm-1; 1H NMR δ 1.20 (dd, J ) 12.1, 5.1, 1H), 1.42 (s, 9H), 1.55-
1.83 (m, 3H), 2.08-2.18 (m, 1H), 2.31 (dd, J ) 15.8, 7.5, 1H),
2.37 (dd, J ) 15.8, 8.1, 1H), 2.47 (dd, J ) 11.7, 3.2, 1H), 3.63
(s, 3H), 4.31 (t, J ) 4.2, 1H), 5.05-5.15 (m, 2H), 7.25-7.40
(m, 5H); 13C NMR δ 23.1 (t), 27.6 (q), 33.1 (t), 36.02 (t), 36.21
(d), 39.9 (t), 51.5 (q), 62.3 (d), 66.9 (t), 69.9 (s), 81.0 (s), 127.73
(d), 127.85 (d), 128.25 (d), 136.1 (s), 156.4 (s), 169.2 (s), 172.1
(s). Anal. Calcd for C22H29NO6: C, 65.5; H, 7.2; N, 3.5.
Found: C, 65.6; H, 7.4; N, 3.3.
(1S,3S,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-[[N′,N′′-
b i s (t e r t -b u t y l o x y c a r b o n y l )g u a n i d i n o ]m e t h y l ]-7 -
a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester (31r). To a
solution of 92 mg (0.18 mmol) of N-TEOC carbamate 30R in 1
mL of THF was added 0.2 mL (0.2 mmol) of 1 M TBAF in THF.
The mixture was heated at 50 °C for 24 h and cooled to rt and
then 12.4 µL (0.22 mmol) of glacial AcOH added. The mixture
was stirred for 10 min, 100 µL of water at pH 7 and 76 mg of
N,N′-bis(tert-butyloxycarbonyl)-S-methylisothiourea were added,
the mixture was heated to 50 °C for 24 h and then cooled to rt
and evaporated. The residue was chromatographed (15 g of
silica gel, eluted with 15% EtOAc/hexane) to afford 98 mg
(1S,3S,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-[[N-[[[2-
(t r im e t h ylsilyl)e t h yl]oxy]ca r b on yl]a m in o]m e t h yl]-7-
a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester (30r). To a
solution of 400 mg (0.991 mmol) of ester 29R in 4.89 mL of
50% THF/MeOH was added a solution of 250 mg (5.95 mmol)
of LiOH‚H2O in 0.96 mL of H2O. The mixture was stirred for
24 h, acidified to pH 3 using 1 M H3PO4, and extracted with
EtOAc (4 × 45 mL). The EtOAc layers were combined, dried,
and evaporated to afford 386 mg (100%) of the corresponding
carboxylic acid, which was used without further purification:
IR (CH2Cl2) 3300-2700 (br), 1732, 1718 cm-1; 1H NMR δ 1.25
(dd, J ) 11.9, 5.1, 1H), 1.45 (s, 9H), 1.60-1.85 (m, 3H), 2.18
(tt, J ) 12.1, 3.6, 1H), 2.38 (dd, J ) 16.1, 7.6, 1H), 2.45 (dd, J
) 16.2, 7.9, 1H), 2.50-2.58 (m, 1H), 2.59-2.69 (m, 1H), 4.37
(t, J ) 4.3, 1H), 5.09-5.16 (m, 2H), 7.26-7.38 (m, 5H); 13C
NMR δ 23.2 (t), 27.8 (q), 33.3 (t), 36.1 (t), 39.99 (d), 39.89 (t),
62.4 (d), 67.2 (t), 70.1 (s), 81.4 (s), 127.9 (d), 128.0 (d), 128.4
(d), 136.2 (s), 156.6 (s), 169.4 (s), 177.5 (s); FABMS calcd for
C21H28NO6 (M + H)+ 390.1919, found 390.1917.
(89%) of arginine analogue 31R as a foam: [R]20 -10.7° (c
D
1.0, CHCl3); IR (CH2Cl2) 3321, 3270, 1721,1636, 1616 cm-1
;
1H NMR δ 1.27 (dd, J ) 10.1, 3.0, 1H), 1.46 (s, 9H), 1.50 (s,
9H), 1.51 (s, 9H), 1.57-1.68 (m, 1H), 1.80-1.87 (m, 2H), 2.12-
2.20 (m, 1H), 2.38-2.48 (m, 2H), 3.34-3.40 (m, 1H), 3.42-
3.48 (m, 1H), 4.33-4.35 (m, 1H), 4.30 (m, 1H), 5.13 (s, 2H),
7.26-7.39 (m, 5H), 8.34 (t, J ) 3.5, 1H), 11.46 (s, 1H); 13C NMR
δ 23.3 (t), 27.8 (q), 28.02 (q), 28.22 (q), 33.4 (t), 38.2 (t), 39.8
(d), 42.1 (t), 61.6 (d), 67.2 (t), 70.0 (s), 79.3 (s), 81.3 (s), 83.3
(s), 127.88 (d), 128.03 (d), 128.4 (s), 136.3 (s), 153.2 (s), 156.1
(s), 156.5 (s), 163.4 (s), 169.3 (s). Anal. Calcd for
C31H46N4O8: C, 61.8; H, 7.7; N, 9.3. Found: C, 61.5; H, 7.7;
N, 9.2.

6324 J . Org. Chem., Vol. 61, No. 18, 1996
Campbell and Rapoport
(1S,3R,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-[[N′,N′′-
b is(t er t -b u t yloxyca r b on yl)gu a n id in o]m e t h yl]-7-a za -
bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester (31â). Applying the
procedure used for the preparation of 31R, 200 mg (0.40 mmol)
of 30â was converted to 173 mg (73%) of arginine analogue
31â as a foam: [R]20D -26.7° (c 1.4, CHCl3); IR (CH2Cl2) 3320,
until a yellow color persisted and bubbling had ceased. The
mixture was stirred 30 min, 0.2 mL of AcOH was added, and
the mixture was stirred overnight. The solution was dissolved
in 100 mL of CH2Cl2, washed with 20 mL of saturated aqueous
NaHCO3, dried, and evaporated, and the residue was chro-
matographed (15 g of silica gel, eluted with 25% EtOAc/
hexane) to afford 128 mg (77%) of the methyl ester 35 as a
1
3280, 1720, 1638, 1620 cm-1; H NMR δ 1.46 (s, 9H), 1.49 (s,
18H), 1.61-1.73 (m, 1H), 1.77-1.95 (m, 2H), 2.04-2.20 (m,
2H), 3.21-3.28 (m, 1H), 3.33-3.40 (m, 1H), 4.22 (d, J ) 4.7,
1H), 5.09 (d, J ) 12.4, 1H), 5.13 (d, J ) 12.3, 1H), 7.26-7.40
(m, 5H), 8.52 (t, J ) 3.5, 1H), 11.47 (s, 1H); 13C NMR δ 27.8
(q), 28.04 (q), 28.26 (q), 29.3 (t), 31.5 (t), 39.4 (t), 41.6 (t), 44.3
(t), 61.6 (d), 67.1 (t), 69.6 (s), 79.2 (s), 81.3 (s), 83.0 (s), 128.0
(d), (d), 128.4 (d), 153.1 (s), 156.27 (s), 156.51 (s), 163.5 (s),
169.1 (s). Anal. Calcd for C31H46N4O8: C, 61.8; H, 7.7; N, 9.3.
Found: C, 61.4; H, 7.6; N, 9.1.
colorless oil: [R]20 -12.3° (c 1.0, CHCl3); IR (CH2Cl2) 410,
D
1
1753, 1718 cm-1; H NMR δ 0.05 (s, 9H), 0.93-1.02 (m, 2H),
1.16-1.30 (m, 1H), 1.55-1.72 (m, 4H), 1.75-1.88 (m, 2H),
2.13-2.29 (m, 2H), 2.44 (td, J ) 11.8, 2.3, 1H), 2.85-2.93 (m,
2H), 2.95-3.08 (m, 2H), 3.61 (br s, 3H), 4.27 (m, 1H), 4.68 (t,
J ) 4.2, 1H), 5.00-5.10 (m, 2H), 7.28-7.37 (m, 5H); 13C NMR
δ -2.1 (q), 10.5 (t), 23.1 (t), 33.0 (t), 33.3 (t), 37.7 (d), 40.0 (t),
42.2 (t), 52.1 (t), 62.2 (d), 67.5 (t), 69.2 (s), 128.1 (d), 128.2 (d),
128.5 (d), 135.8 (s), 156.4 (s), 170.9 (s). Anal. Calcd for
C23H36N2O6SiS: C, 55.6; H, 7.3; N, 5.6. Found: C, 55.8; H,
7.5; N, 5.3.
(1S,3S,4R)-7-(Ben zyloxyca r b on yl)-1-ca r b oxy-3-(2-h y-
d r oxyeth yl)-7-a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester
(32). Applying the procedure used for the preparation of
alcohol 5 from ester 3, 480 mg (1.19 mmol) of ester 29R was
(1S,3R/S,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-p h en -
yl-3-h yd r oxy-7-a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester
(36r/36â). To 4 mL of Et2O at -85 °C was added 0.41 mL
(0.69 mmol) of 1.67 M PhLi in Et2O/pentane, followed by 207
mg (0.60 mmol) of ketone 26 in 4 mL of THF over 30 min. The
mixture was warmed to -78 °C and stirred 45 min and 0.40
mL (0.69 mmol) of glacial AcOH added. After partitioning
between 75 mL of CH2Cl2 and 20 mL of aqueous NaHCO3, the
aqueous layer was washed with CH2Cl2 (2 × 40 mL), and the
combined organic extracts were washed with 20 mL of brine,
dried, and evaporated. The residue was chromatographed (90
g of silica gel, eluted with 8% EtOAc/hexane) to afford 98 mg
(47%) of recovered ketone 26, as well as 120 mg (47%) of the
carbinol as a 8/1 mixture of 36â/36R, respectively, 90% yield,
based on recovered ketone 26. This mixture was used without
further purification as a 1/8, 36R/36â mixture: IR (CH2Cl2)
converted to 332 mg (74%) of alcohol 32 as a colorless oil: [R]20
D
-17.8° (c 1.2, CHCl3); IR (CH2Cl2) 3618, 1728, 1708 cm-1; H
1
NMR δ 1.21 (dd, J ) 11.9, 5.3, 1H), 1.44 (s, 9H), 1.56-1.66
(m, 3H), 1.68-1.80 (m, 2H), 2.06 (bs, 1H), 2.10-2.18 (m, 1H),
2.22-2.32 (m, 1H), 2.41 (td, J ) 11.8, 3.4, 1H), 3.52-3.63 (m,
2H), 4.24 (t, J ) 3.8, 1H), 5.08 (d, J ) 12.4, 1H), 5.12 (d, J )
12.5, 1H), 7.25-7.37 (m, 5H); 13C NMR δ 23.1 (t), 27.8 (q), 33.4
(t), 34.6 (t), 37.1 (d), 40.3 (t), 61.5 (t), 62.9 (d), 67.0 (t), 70.0 (s),
81.1 (s), 127.8 (d), 127.96 (d), 128.35 (d), 136.3 (s), 156.7 (s),
169.7 (s). Anal. Calcd for C21H29NO5: C, 67.2; H, 7.8; N, 3.7.
Found: C, 67.2; H, 8.0; N, 3.6.
(1S,3S,4R)-7-(Ben zyloxyca r b on yl)-1-ca r b oxy-3-[2-[N-
(ter t-bu t yloxyca r b on yl)-N-[[2-(t r im et h ylsilyl)et h yl]su l-
fon yl]a m in o]eth yl]-7-a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl
Ester (33). To a solution of 627 mg (2.39 mmol) of PPh3, 448
mg (1.59 mmol) of tert-butyl N-[2-(trimethylsilylethyl)sulfonyl]-
carbamate, and 299 mg (0.96 mmol) of alcohol 32 in 9 mL of
THF at 0 °C was added 0.30 mL (1.91 mmol) of DEAD over a
5 min period. The solution was stirred for 4 h and concen-
trated in vacuo, and 500 mg of the Ph3PO and diethyl
hydrazinedicarboxylate was removed by recrystallization from
7.5 mL of 20% EtOAc/hexane at 0 °C. The residue was
chromatographed (100 g of activity grade II basic alumina,
eluted with 10% EtOAc/hexane) to afford 485 mg (95%) of
lysine analogue 33 as a colorless oil: [R]20D -8.8° (c 1.2, CHCl3);
IR (CH2Cl2) 1725 cm-1; 1H NMR δ 0.06 (s, 9H), 0.90-0.96 (m,
2H), 1.24 (dd, J ) 11.9, 5.0, 1H), 1.44 (s, 9H), 1.52 (s, 9H),
1.57-1.87 (m, 5H), 2.10-2.20 (m, 2H), 2.42 (td, J ) 11.8, 2.8,
1H), 3.33-3.39 (m, 1H), 3.47-3.60 (m, 2H), 4.24 (t, J ) 4.2,
1H), 5.07 (d, J ) 12.4, 1H), 5.13 (d, J ) 12.4, 1H), 7.26-7.37
(m, 5H); 13C NMR δ -2.1 (q), 10.4 (t), 23.1 (t), 27.81 (q), 27.97
(q), 32.7 (t), 33.3 (t), 37.7 (d), 40.2 (t), 45.9 (t), 50.8 (t), 62.5
(d), 67.1 (t), 70.0 (s), 81.1 (s), 84.4 (s), 127.9 (d), 127.99 (d),
128.39 (d), 136.3 (s), 151.4 (s), 156.6 (s), 169.5 (s). Anal. Calcd
for C31H50N2O8SiS: C, 58.3; H, 7.9; N, 4.4. Found: C, 58.0;
H, 8.1; N, 4.3.
(1S,3S,4R)-7-(Ben zyloxyca r b on yl)-1-ca r b oxy-3-[2-[N-
[[2-(t r im e t h ylsilyl)e t h yl]su lfon yl]a m in o]e t h yl]-7-a za -
bicyclo[2.2.1]h ep ta n e (34). To a solution of 213 mg (0.334
mmol) of tert-butyl ester 33 in 1.3 mL of CH2Cl2 was added
2.60 mL (33.8 mmol) of TFA. The mixture was stirred for 42
h and evaporated to afford 161 mg of slightly impure crude
acid 34 as a brownish oil that was used without further
purification: IR (CH2Cl2) 2100-3400 cm-1; selected data for
1H NMR (rotomers) δ 0.06 (s, 9H), 0.89-0.99 (m, 2H), 1.35-
3.15 (several br m, 17H), 4.43 (m, 1H), 5.12 (m, 2H), 7.25-
7.43 (m, 5H); 13C NMR (rotomers) δ -2.2, 10.2, 10.3, 14.0, 17.5,
21.7, 22.5, 23.0, 29.6, 31.1, 31.5, 32.5, 33.7, 35.8, 36.8, 37.6,
40.2, 41.4, 42.0, 48.6, 48.8, 53.4, 62.7, 68.0, 69.5, 127.9, 128.3,
128.5, 128.8, 129.2, 130.3, 133.2, 135.4, 157.1, 161.3, 174.5;
HRMS (FAB) calcd for C22H35N2O6SiS (M+ + 1) 483.1985,
found 483.1989.
1
3580-3570, 1733, 1711 cm-1; major isomer 36â only H NMR
δ 1.49 (s, 9H), 1.68-1.78 (m, 1H), 1.84-2.00 (m, 2H), 1.17-
2.27 (m, 1H), 2.33-2.57 (m, 2H), 2.96 (dd J ) 12.7, 2.7, 1H),
4.32 (d, J ) 4.5, 1H), 4.80-4.96 (br m, 1H), 5.02 (d, J ) 12.4,
1H), 7.08-7.20 (m, 2H), 7.22-7.43 (m, 6H), 7.63 (d, J ) 7.5,
1H); 13C NMR δ 23.4 (t), 27.8 (q), 31.0 (t), 51.1 (t), 66.9 (t),
68.8 (d), 78.7 (s), 81.4 (s), 125.6 (d), 127.3 (d), 127.5 (d), 127.9
(d), 128.24 (d), 128.29 (d), 136.2 (s), 146.7 (s), 156.0 (s), 169.0
(s). Anal. Calcd for C25H29NO5: C, 70.9; H, 6.9; N, 3.3.
Found: C, 70.8; H, 7.2; N, 3.2.
(1S,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-p h en yl-7-
a za b icyclo[2.2.1]-2-h ep t en e
ter t-Bu t yl E st er
(37),
(1S,3S,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-p h en yl-7-
a za b icyclo[2.2.1]h ep t a n e ter t-Bu t yl E st er (38r), a n d
(1S,3R,4R)-7-(Ben zyloxyca r bon yl)-1-ca r boxy-3-p h en yl-7-
a za bicyclo[2.2.1]h ep ta n e ter t-Bu tyl Ester (38â). To a
solution of 120 mg (0.28 mmol) of the carbinol mixture 36R/
36â in 2.5 mL of pyridine at 0 °C was added 231 mg (0.71
mmol) of Ts2O. The mixture was warmed to rt over 1 h, stirred
for 21 h, heated for 3 h at 95 °C, stirred for 12 h at rt, and
partitioned between 75 mL of CH2Cl2 and 40 mL of aqueous 2
M HCl solution. The aqueous layer was washed with CH2Cl2
(2 × 40 mL), and the combined organic extracts were washed
with 20 mL of brine, dried, and evaporated. The residue was
chromatographed (15 g of silica gel, eluted with 15% EtOAc-
hexane) to afford 94 mg (82%) of pure styrene 37 as an oil
that crystallized upon standing. Applying the hydrogenation-
CBZ acylation procedure described for the preparation of 4
from 2, 131.5 mg (0.32 mmol) of styrene 37 gave 97 mg (74%)
of 38R and 27 mg (20%) of 38â as colorless oils. Selected data
for styrene 37: mp 103-104 °C; IR (CH2Cl2) 1743, 1750 cm-1
;
1H NMR δ 1.35 (ddd, J ) 11.8, 9.3, 3.4, 1H), 1.54 (s, 9H), 1.67
(ddd, J ) 11.8, 8.5, 3.6, 1H), 2.13-2.23 (m, 1H), 2.41 (ddd, J
) 11.8, 9.3, 3.4, 1H), 5.06 (d, J ) 12.5, 1H), 5.12 (d, J ) 12.5,
1H), 5.27 (d, J ) 4.2, 1H), 6.71 (s, 1H), 7.26-7.42 (m, 10H);
13C NMR δ 25.2 (t), 27.9 (q), 29.6 (t), 31.7 (t), 63.9 (d), 67.2 (t),
74.8 (s), 81.8 (s), 125.4 (d), 127.7 (d), 127.9 (d), 128.09 (d),
128.18 (d), 128.32 (d), 128.66 (d), 132.4 (s), 136.1 (s), 147.5 (s),
156.7 (s), 16.4 (s); HRMS (FAB) calcd for C25H28NO4 (M+ + 1)
406.2018, found 406.2015.
(1S,3S,4R)-7-(Ben zyloxyca r b on yl)-1-ca r b oxy-3-[2-[N-
[[2-(t r im e t h ylsilyl)e t h yl]su lfon yl]a m in o]e t h yl]-7-a za -
bicyclo[2.2.1]h ep ta n e Meth yl Ester (35). To a solution of
crude acid 34 (161 mg, 0.334 mmol) in 12 mL of 30% THF/
Et2O was added an ethereal solution of 1.2 M CH2N2 dropwise
38r: [R]20D +8.0° (c 1.0, CHCl3); IR (CH2Cl2) 1737, 1718 cm-1
;
1H NMR δ 1.45-1.58 (m, 1H), 1.52 (s, 9H), 1.63-1.78 (m, 2H),
2.02 (dd, J ) 12.6, 5.8, 1H), 2.18-2.27 (m, 1H), 2.64 (td, J )

Syntheses of 7-Azabicycloheptane Amino Acids
J . Org. Chem., Vol. 61, No. 18, 1996 6325
12.2, 3.1, 1H), 3.61 (td, J ) 5.6, 3.8, 1H), 4.52 (t, J ) 4.5, 1H),
5.19 (s, 2H), 7.17-7.40 (m, 10H); 13C NMR δ 23.3 (t), 27.8 (q),
33.8 (t), 37.3 (t), 46.0 (d), 64.2 (d), 67.2 (t), 70.5 (s), 81.3 (s),
126.3 (d), 127.82 (d), 127.93 (d), 128.04 (d), 128.42 (d), 128.45
(d), 136.3 (s), 139.3 (s), 156.7 (s), 169.6 (s). Anal. Calcd for
C25H29NO4: C, 73.7; H, 7.2; N, 3.4. Found: C, 73.5; H, 7.3; N,
3.3.
ridone and 0.31 mL (2.20 mmol) of Et3N in 5 mL of THF added
over 5 min. The mixture was warmed to rt over 10 min, stirred
for 1 h, and filtered, washing the filter cake with 5 mL of THF
and diluting the filtrate with 0.7 mL of tert-butyl thiol. The
filtrate solution was irradiated for 2 h using two tungsten
lamps (100 W each), with external cooling to maintain the
reaction mixture at rt. Addition of 90 mg (0.34 mmol) of PPh3
was followed by partition between 75 mL of CH2Cl2 and 40
mL of saturated aqueous NaHCO3. The aqueous layer was
washed with CH2Cl2 (2 × 40 mL), and the combined organic
extracts were washed with 40 mL of aqueous 1 M H3PO4 and
20 mL of brine, dried, and evaporated. The residue was
chromatographed (15 g of silica gel, eluted with 12% EtOAc/
hexane) to afford 206 mg (81%) of bicyclic ketone 41 as a
1
38â: IR (CH2Cl2) 1730, 1710 cm-1; H NMR δ 1.51 (s, 9H),
1.65-1.70 (m, 1H), 1.78-1.93 (m, 2H), 2.17-2.25 (m, 1H), 2.27
(dd, J ) 12.4, 9.2, 1H), 2.42 (td, J ) 12.4, 4.1, 1H), 2.97 (dd, J
) 9.1, 4.9, 1H), 4.32 (d, J ) 4.5, 1H), 5.02 (bd, J ) 12.0, 1H),
5.10 (d, J ) 12.4, 1H), 7.20-7.38.(m, 10H); 13C NMR δ 27.9
(q), 30.2 (t), 30.9 (t), 47.6 (d), 65.9 (d), 67.0 (t), 69.6 (s), 81.3
(s), 126.5 (d), 127.36 (d), 127.80 (d), 127.93 (d), 128.36 (d),
128.43 (d), 136.4 (s), 144.8 (s), 156.6 (s), 169.4 (s); HRMS (FAB)
calcd for C25H30NO4 (M+ + 1) 408.2175, found 408.2169.
(1S,4R)-7-(Ben zyloxycar bon yl)-1-car boxy-7-azabicyclo-
[2.2.1]-3-h ep ta n on e (40) a n d (1R,4S)-7-(Ben zyloxyca r bo-
n yl)-7-a za bicyclo[2.2.1]-2-h ep ta n on e (41). To a solution of
350 mg (1.01 mmol) of ketone 26 in 1.50 mL of CH2Cl2 was
added 1.82 mL (23.6 mmol) of TFA. The mixture was stirred
for 48 h and then evaporated to afford 305.3 mg (100%) of the
acid 40 as a brown oil that was used without further purifica-
colorless oil: [R]20 -64.6° (c 1.9, CHCl3); IR (CH2Cl2) 3630-
D
3400, 1763, 1708 cm-1; H NMR δ 1.57-1.67 (m, 2H), 1.94-
1
2.03 (m, 2H), 2.01 (d, J ) 17.5, 1H), 2.47 (dd, J ) 17.4, 5.2,
1H), 4.35 (d, J ) 5.2, 1H), 4.64 (t, J ) 4.6, 1H), 5.11 (d, J )
12.3, 1H), 5.14 (d, J ) 12.3, 1H), 7.25-7.37 (m, 5H); 13C NMR
δ 24.4 (t), 27.5 (t), 45.1 (t), 56.0 (d), 63.6 (d), 67.2 (t), 127.8 (d),
128.13 (d), 128.44 (d), 136.0 (s), 155.1 (s), 208.6 (s). Anal. Calcd
for C14H15NO3: C, 68.6; H, 6.2; N, 5.7. Found: C, 68.8; H,
6.2; N, 5.8.
1
tion: IR (CH2Cl2) 3300-2800 (br), 1725, 1770 cm-1; H NMR
(1R,4S)-7-(ter t-Bu tyloxyca r bon yl)-7-a za bicyclo[2.2.1]-
2-h ep ta n on e (39). To a solution of 115 mg (0.45 mmol) of
ketone 41 in 10 mL of degassed MeOH under Ar was added 1
drop of DIEA, 293 mg (1.34 mmol) of BOC2O, and 40 mg of
10% Pd/C. The resulting slurry was degassed and stirred
under a balloon of H2 for 5 h and then filtered through Celite,
and the Celite pad was washed with 15 mL of CH2Cl2. The
filtrate was evaporated and the residue chromatographed (15
g of silica gel, eluted with 10% EtOAc/hexane then 25% EtOAc/
δ 1.68-1.74 (m, 1H), 1.92-1.98 (m, 1H), 2.11-2.20 (m, 1H),
2.38 (d, J ) 17.7, 1H), 2.37-2.45 (m, 1H), 2.91 (dd, J ) 17.7,
2.6, 1H), 4.48 (d, J ) 5.5, 1H), 5.11 (d, J ) 12.2, 1H), 5.16 (d,
J ) 12.2, 1H), 7.27-7.37 (m, 5H), 10.14 (br s, 1H); 13C NMR
δ 24.0 (t), 31.6 (t), 47.2 (t), 66.8 (d), 68.3 (t), 68.6 (s), 128.1 (d),
128.46 (d), 128.58 (d), 135.2 (s), 156.2 (s), 173.2 (s), 206.3 (s);
HRMS (FAB) calcd for C15H15NO5 (M+ + 1) 290.1036, found
290.1036.
To a solution of 300 mg (1.0 mmol) of acid 40 in 6 mL of
1,2-DCE was added 0.01 mL (0.129 mmol) of DMF, followed
by 0.22 mL (2.50 mmol) of oxalyl chloride. The mixture was
stirred for 3 h and evaporated, and proceeding in the dark,
the residue was dissolved in 1 mL of THF and cooled to 0 °C,
and a solution of 268 mg (2.10 mmol) of N-hydroxy-2-thiopy-
hexane) to afford 97.5 mg (98%) of the N-BOC ketone 39: [R]20
D
-75.5° (c 1.0, CHCl3) [lit.23 [R]20 -73.6° (c 1.1, CHCl3)];
D
spectral data were identical to those reported.23
J O960759M