Synthesis of azabicycloalkane amino acid scaffolds as reverse-turn inducer dipeptide mimics

Article abstract of DOI:10.1002/1099-0690(200007)2000:14<2571::aid-ejoc2571>3.0.co;2-d

In an effort to design dipeptide structural mimics of protein and peptide reverse-turns, a series of 5,5-, 6,5-, and 7,5-fused 2-oxo-1- azabicycloalkane amino acids has been synthesized. A new and convenient synthetic route utilizing a Horner-Emmons react

Full text of DOI:10.1002/1099-0690(200007)2000:14<2571::aid-ejoc2571>3.0.co;2-d

FULL PAPER
Synthesis of Azabicycloalkane Amino Acid Scaffolds as Reverse-Turn Inducer
Dipeptide Mimics
Mauro Angiolini,[a] Silvia Araneo,[c] Laura Belvisi,[a] Edoardo Cesarotti,[c] Anna Checchia,[a]
Luca Crippa,[a] Leonardo Manzoni,[a] and Carlo Scolastico*[a,b]
Keywords: Peptidomimetics / Amino acids / Enamides / Wittig reactions
In an effort to design dipeptide structural mimics of protein
and peptide reverse-turns, a series of 5,5-, 6,5-, and 7,5-fused
Horner−Emmons reaction followed by double-bond reduc-
tion has been used to prepare the bicyclic lactams in high
2-oxo-1-azabicycloalkane amino acids has been synthesized. yields.
new and convenient synthetic route utilizing
A
a
Introduction
In the course of our studies on peptide secondary struc-
ture mimics, we have synthesized several 6,5- and 7,5-fused
2-oxo-1-azabicyclo[X.3.0]alkane amino acids using rad-
ical[5a,5b] or ionic reactions.[5c] These structures can be re-
garded as conformationally restricted substitutes for Ala-
Pro and Phe-Pro dipeptide units, and, if their conforma-
tions meet certain criteria, they can be used to replace the
central (i ϩ 1 and i ϩ 2) residues of β-turns.[6] All possible
diastereomeric 2-oxo-1-azabicyclo[X.3.0]alkane amino ac-
ids that include a natural [Cα(S)] Pro unit and differ in the
configuration at the bridgehead atom and at the N-bearing
C3 are depicted in Figure 2. According to the relative con-
figuration of Pro-Cα and of the bridgehead, they have been
classified as cis-fused (1Ϫ3, 7Ϫ9) or trans-fused (4Ϫ6,
10Ϫ12) lactams. Their conformational properties have been
investigated by computational and spectroscopic means,
and the results are reported in the preceding paper in this
issue.[6a]
The synthesis of so-called peptidomimetic molecules has
been a very active and productive field of research in drug
design.[1] The rationale for the development of peptide ana-
logues is that these molecules will have the same biological
effects as natural peptides, but at the same time will be
metabolically more stable. Of particular interest has been
the replacement of reverse-turn dipeptide motifs with con-
strained molecules that reproduce their conformational fea-
tures.[1,2] This goal has been frequently achieved using the
oxoazabicyclo[X.Y.0]alkane skeleton (Figure 1) and/or het-
eroatom analogues thereof.[3] This has created a demand for
efficient synthetic approaches toward such molecules; many
methods have been introduced, which have recently been
reviewed.[3] One particularly effective and versatile route,
developed by Lubell et al., has been employed for the pre-
paration of enantiopure indolizidinone-type 6,5-fused bi-
cyclic lactams (Figure 1, m ϭ 1, n ϭ 1).[4] Several proced-
ures are also available for the synthesis of 7,5-fused bicyclic
lactams (Figure 1, m ϭ 1, n ϭ 2),[3] the majority of which
require relatively long synthetic sequences. On the contrary,
there are not many published protocols that allow the syn-
thesis of 5,5-fused bicyclic lactams (Figure 1, n ϭ 0).[3]
With the aim of obtaining an improved reaction se-
quence, amenable to large-scale preparation and suitable for
the synthesis of many different bicyclic lactams from com-
mon intermediates, a new convenient general scheme has
now been developed (Scheme 1).
Starting from prolines 13Ϫ17,
a
(Z)-selective
HornerϪEmmons olefination followed by double-bond re-
duction has been used to build the second ring. The starting
aldehydes were stereoselectively synthesized by modifica-
tions of known procedures (vide infra). Stereorandom
double-bond reduction was performed using H2/Pd to yield,
after cyclization, mixtures of easily separable epimers. Ster-
eoselective hydrogenation was studied for the synthesis of
6,5-fused lactams, and was achieved with 80% de using
(chiral phosphane)Rh catalysts. Our new strategy offers
structural diversity, in terms of ring size and stereochem-
istry of the azabicycloalkane fragment, as well as access to
the less common 5,5-fused bicyclic scaffold.
Figure 1. Azabicyclo[X.Y.0]alkane amino acids
[a]
`
Dipartimento di Chimica Organica e Industriale, Universita
degli Studi di Milano,
via G. Venezian 21, 20133 Milano, Italy
Centro CNR per lo Studio delle Sostanze Organiche Naturali,
via G. Venezian 21, 20133 Milano, Italy
[b]
[c]
Dipartimento di Chimica Inorganica, Organometallica
e
`
Analitica, Universita degli Studi di Milano,
Following the above procedure, all the cis-fused lactams
1Ϫ3 and 7Ϫ9, as well as the 6,5- and 7,5-trans-fused lac-
tams 5, 6, 11, and 12 have been synthesized.
via G. Venezian 21, 20133 Milano, Italy
Fax: (internat.) ϩ 39-2/236-4369
E-mail: scola@iumchx.chimorg.unimi.it
Eur. J. Org. Chem. 2000, 2571Ϫ2581
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0714Ϫ2571 $ 17.50ϩ.50/0
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C. Scolastico et al.
FULL PAPER
In all cases where stereoisomeric mixtures of lactams
were formed, they could easily be separated by flash chro-
matography. Their configurations were assigned with the
aid of NOE experiments.
The synthetic scheme is best illustrated by the synthesis
of the 6,5-fused ‘‘cis’’-lactams 2 and 8 (Scheme 2). The re-
quisite cis-aldehyde 14 was obtained from the known cis-5-
allylproline derivative 23[8] and treated with the commer-
cially available phosphonate 24[7] to give 19 in 98% yield
with a 7:1 (Z)/(E) ratio.
Hydrogenation of 19 occurred initially at the enamino
Cbz group, and thus resulted in a complex mixture of prod-
ucts. To circumvent this problem, the substrate was treated
with Boc2O to give 25 (98%). Reduction of 25 with H2/
Pd(OH)2 followed by reflux in MeOH gave a 1.4:1 mixture
of 8 and 2, which could easily be separated by flash chroma-
tography. Starting from 14, the whole sequence requires
only two chromatographic separations (purification of 19
and separation of 8 from 2) and can easily be carried out
on a multigram scale.
The stereoselective preparation of the two C3 epimers 8
and 2 (Scheme 3) was attempted by means of (chiral phos-
phane)Rh-catalyzed hydrogenation of the enamino acid 26.
The (chiral phosphane)Rh-catalyzed hydrogenation is a
powerful and well-established means of access to both nat-
urally occurring and non-natural amino acids and the cata-
lytic asymmetric hydrogenation of dehydropeptides repres-
ents a logical extension of this methodology to the prepara-
tion of biologically active chiral oligo- and polypeptides.[9]
In asymmetric catalytic hydrogenations using (chiral phos-
phane)Rh catalysts, the highest de values are usually ob-
tained starting from (Z)-olefins. However, the key require-
ment for the substrate remains the presence of an acetamido
group, or an equivalent thereof, at the double bond.[10] The
amide-type carbonyl group is needed in order to allow two-
point coordination of the substrate to the metal centre, as
has been fully elucidated experimentally.[11] For applications
in peptide synthesis, protecting groups such as Boc or Cbz
are preferable to the acetamido function, since they allow
easy and specific deprotection. However, there have been
very few examples of asymmetric catalytic hydrogenation
where these protecting groups are found on the enamino
nitrogen atom.[12,13] More frequently, Boc or Cbz protecting
groups are present in different positions of the dehydropep-
tides, which are hydrogenated at their N-termini.[14,15]
For the catalytic asymmetric hydrogenation of 26,
[Rh(phosphane)(COD)]ClO4 catalysts were used. The cata-
lysts were prepared by displacing one cyclooctadiene ligand
Figure 2. Bicyclic dipeptide mimics 1-12
Scheme 1
Results and Discussion
The syntheses of lactams 1Ϫ3, 5Ϫ9, 11, and 12 were ac- of [Rh(COD)2]ClO4 with the appropriate phosphane. The
complished following the common steps outlined in ligands investigated were (R)-Prophos 27, (ϩ)-BitianP 28,
Scheme 1. Starting from the cis- or trans-proline aldehydes and (Ϫ)-BitianP 29. BitianP is a chiral atropisomeric chelat-
13Ϫ17, a HornerϪEmmons olefination with the potassium ing phosphane belonging to a new class of ligands based
enolate of (Ϯ)-(Z)-α-phosphonoglycine trimethyl ester[7] on a biheteroaromatic framework, which has been shown
was used to set up the requisite carbon chain. Following to give very high ee values in asymmetric hydrogenations of
protecting group manipulation (vide infra), reduction of the olefins and ketones.[16,17]
enamino acrylic acids and treatment with condensing
The results of the present asymmetric hydrogenations are
agents gave the lactams of both the ‘‘cis’’ and ‘‘trans’’ series reported in Table 1. The conversion was invariably quantit-
in good yields.
2572
ative and the highest stereodifferentiation was obtained
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Azabicycloalkane Amino Acid Scaffolds as Reverse-Turn Inducer Dipeptide Mimics
FULL PAPER
Scheme 2. a) O3, Me2S, 75%; b) (Ϯ)-(Z)-α-phosphonoglycine trimethyl ester, tBuOK, CH2Cl2, Ϫ78 °C, 98%; c) Boc2O, 4-DMAP, THF,
98%; d) H2, Pd/C, MeOH; MeOH, reflux, 48 h, 70%
starting material for these compounds was the trans-substi-
tuted proline 17 (Scheme 4). Aldehyde 17 was best obtained
from ester 33, which was prepared in one step from N-Cbz-
5-hydroxyproline tert-butyl ester (32)[8] as a 4:1 trans/cis
mixture according to
a
published procedure.[18] The
HornerϪEmmons reaction with the potassium enolate of
24 proceeded with 99% yield. Treatment with Boc2O, sep-
aration of the cis/trans isomers, and subsequent unselective
hydrogenation (H2, Pd/C) of the crude intermediate fol-
lowed by refluxing in MeOH gave a 1.4:1 mixture of easily
separable 5 and 11.
Scheme 3. a) NaOH, MeOH, 85%; b) H2, Rh-BitianP, MeOH; c)
CH2N2, MeOH; H2, Pd/C, MeOH; MeOH, reflux, 48 h, 85%
Table 1. Asymmetric hydrogenation of 26, the reactions were car-
ried out at room temperature for 24 h under 10 atm of H2
Entry
Catalyst
30/31
de %
1
2
2
Rh-27
Rh-28
Rh-29
96:14
13:87
90:10
72
74
80
Scheme 4. a) Triethyl phosphonoacetate, KH, DMF, 75%; b)
LiBH4, Et2O, Ϫ10 °C, 94%; DessϪMartin periodinane, CH2Cl2,
92%; c) (Ϯ)-(Z)-α-phosphonoglycine trimethyl ester, tBuOK,
CH2Cl2, Ϫ78 °C, 99%; Boc2O, 4-DMAP, THF, 92% (73% trans
isomer); d) H2, Pd(OH)2/C, MeOH; MeOH, reflux 70%
with [Rh/(Ϫ)-BitianP] (Entry 3). The results suggest that
the configuration at the newly created stereocentre is mainly
determined by the catalyst, which overrules the effect of the
stereocentre in the substrate (Entries 2 and 3). The results
also indicate that the Boc protecting group on the enamino
nitrogen atom is a good replacement for the acetamido
group and allows chelation of the catalyst by the olefin.
All the remaining lactams 1, 3, 6, 7, 9, and 12 were syn-
thesized following essentially the same sequence as de-
scribed above. The main variations in the synthetic scheme
arose as a result of the different conditions required for the
Treatment of crude 30 and 31 with CH2N2, followed by formation of lactam rings of different sizes.
hydrogenation and cyclization under the usual conditions
Thus, the 7,5-fused lactams 3 and 9 (Scheme 5) were pre-
(H2, Pd/C, followed by reflux in MeOH) allowed a stereose- pared starting from the cis-aldehyde 15, which was easily
lective access to lactams 8 and 2.
obtained from the cis-5-allylproline 23.[8] HornerϪEmmons
The same synthetic scheme was successfully adopted for reaction of 15 with 24 gave a 6:1 (Z)/(E) mixture of 2-ami-
the synthesis of the 6,5-fused ‘‘trans’’-lactams 5 and 11. The noacrylates. After N-protection, these were reduced with
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C. Scolastico et al.
FULL PAPER
Scheme 6. a) 9-BBN, H2O2, 98%; (COCl)2, DMSO, Et3N, CH2Cl2,
Ϫ60 °C, 82%; b) (Ϯ)-(Z)-α-phosphonoglycine trimethyl ester,
tBuOK, CH2Cl2, Ϫ78 °C, 90%; Boc2O, 4-DMAP, THF, 98%; c)
NaOH, MeOH; H2, Pd/C, 40% over 2 steps
Scheme 5. a) 9-BBN, H2O2, 95%; (COCl)2, DMSO, Et3N, CH2Cl2,
Ϫ60 °C, 89%; b) (Ϯ)-(Z)-α-phosphonoglycine trimethyl ester,
tBuOK, CH2Cl2, Ϫ78 °C, 95%; c) Boc2O, 4-DMAP, THF, 95%;
H2, Pd/C, MeOH, 83%; d) NaOH, MeOH, 84%; e) EDC, DMAP,
HOBt, Et3N, CH2Cl2, 72%, over 2 steps
Finally, the starting material for the synthesis of the 5,5-
fused ‘‘cis’’-lactams 1 and 7 (Scheme 7) was the alcohol
39.[5b] Oxidation and HornerϪEmmons reaction with 24
H2, Pd/C resulting in a 1:1 diastereomeric mixture. The followed by N-Boc protection gave 40 as a 5:1 (Z)/(E) mix-
thermal cyclization of methyl ester 35 could be achieved ture in 57% yield. Hydrogenation of 40 [H2/Pd(OH)2] re-
in refluxing xylene, albeit in low yields. Better results were sulted in a complex mixture of products, from which the
obtained by ester hydrolysis and subsequent EDC/HOBT- 1,2-diamino ester 41 could be isolated in 40% yield. Some
promoted lactam formation to give 3 and 9, which were 42 was also formed, which may be attributed to initial N-
easily separated by flash chromatography (51% overall yield debenzylation of 41 followed by intramolecular Michael ad-
from 23).
dition to the enamino ester double bond and hydrogenolysis
The synthesis of the 7,5-fused ‘‘trans’’-lactams 6 and 12 of the resulting aziridine. The problem could be partly cir-
was achieved starting from the ‘‘trans’’-allylproline 37 cumvented by carrying out the hydrogenation starting from
(Scheme 6).[8] Hydroboration and Swern oxidation (80% the acid 42. Treatment of 42 with H2, Pd/C followed by
over 2 steps) gave the aldehyde 17, which was treated with reflux in MeOH gave an easily separable 1:1 mixture of 1
24 to give, after nitrogen protection, 38 as a 6:1 (Z)/(E) and 7 in 40% yield.
mixture. The usual sequence (NaOH; H2, Pd/C; lactam ring
An alternative synthesis of these lactams was also devised
closure) allowed the isolation of 6 and 12 in 40% overall starting from the trifluoroacetamido aldehyde 13
yield. However, the catalytic hydrogenation step in this case (Scheme 8). Aldehyde 13 was synthesized from 39 through a
proved to be capricious, as it was often accompanied by series of five high-yielding steps. HornerϪEmmons reaction
variable quantities of by-products resulting from Michael and nitrogen protection gave 43 (46% over 7 steps), which
addition of the proline nitrogen atom to the 2-aminoacryl- could be directly reduced to give a 1:1 diastereomeric mix-
ate. Thus, -Selectride reduction of 38 was also attempted, ture of the fully protected ester 44 (77%). Removal of the
which yielded the diastereoisomeric methyl esters in an trifluoroacetamido protecting group (NaBH4 in MeOH,
85:15 ratio, with the (R) isomer predominating. After 84%) followed by treatment in refluxing xylene gave the lac-
NaOH hydrolysis, hydrogenolytic removal of the Cbz pro- tams 1 and 7 in 78% yield.
tecting groups followed by thermally induced lactam ring
formation yielded 6 and 12 in 40% overall yield in a 15:85 synthesis of the 5,5-, 6,5-, and 7,5-fused bicyclic lactams
ratio. 1Ϫ3, 5Ϫ9, 11, and 12 using a HornerϪEmmons olefination
In conclusion, we have devised a practical route for the
Scheme 7. a) (COCl)2, DMSO, Et3N, CH2Cl2, Ϫ60 °C, 81%; (Ϯ)-(Z)-α-phosphonoglycine trimethyl ester, tBuOK, CH2Cl2, Ϫ78 °C, 98%;
Boc2O, 4-DMAP, THF, 98%; b) H2, Pd/C, MeOH; c) NaOH, MeOH; d) H2, Pd/C, MeOH; xylene, reflux, 40% over 2 steps
2574
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Azabicycloalkane Amino Acid Scaffolds as Reverse-Turn Inducer Dipeptide Mimics
FULL PAPER
The residue was purified by flash chromatography (hexane/ethyl
acetate) to afford the acrylic ester as a (Z)/(E) diastereoisomeric
mixture.
General Procedure B: Preparation of the N-Boc-Protected Acrylic
Esters: A solution of the acrylic ester (11.0 mmol), (Boc)2O
(22.0 mmol), and a catalytic amount of DMAP in dry THF
(40 mL) was stirred for 30 min under nitrogen. The solution was
then quenched with water (40 mL) and extracted with ethyl acetate.
The combined organic extracts were dried with Na2SO4 and the
solvent was evaporated under reduced pressure. The residue was
purified by flash chromatography (hexane/ethyl acetate) to yield the
Boc-protected acrylic ester.
General Procedure C: Preparation of the Alcohols through Hydro-
boration: To a solution of allylproline (2.34 mmol) in dry THF
(4.2 mL) was added a 0.5  solution of 9-BBN in THF (2.52 mL,
1.26 mmol). The reaction mixture was stirred for 12 h, then cooled
to 0 °C, whereupon water (0.6 mL), a 3  solution of NaOH
(0.5 mL), and 30% H2O2 (0.44 mL) were added. The resulting mix-
ture was stirred for 1 h at room temperature and then refluxed for
a further 2 h. After cooling, the aqueous phase was extracted with
AcOEt and the combined organic phases were dried with Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
Scheme 8. a) TBDMSCl, Et3N, 94%; H2, Pd(OH)2/C, MeOH, 94%;
trifluoroacetic anhydride, pyridine, 89%; Bu4NF, THF, 98%;
(COCl)2, DMSO, Et3N, CH2Cl2, Ϫ60 °C, 93%; b) (Ϯ)-(Z)-α-phos-
phonoglycine trimethyl ester, tBuOK, CH2Cl2, Ϫ78 °C, 68%;
Boc2O, 4-DMAP, THF, 95%; c) H2, Pd(OH)2/C, MeOH, 77%; d)
NaBH4, MeOH, 84%; e) xylene, reflux
as the key step. After hydrogenation, the lactams were usu-
ally obtained as easily separable stereoisomeric mixtures at
the N-bearing carbon atom, but stereoselective syntheses purified by flash chromatography (hexane/ethyl acetate) to yield the
alcohol as a yellow oil.
(80% de) could also be achieved by means of (chiral phos-
phane)Rh-catalyzed hydrogenation.
General Procedure D: Preparation of the Aldehydes by Swern Oxida-
tion: To a stirred solution of oxalyl chloride (16.9 mmol) in CH2Cl2
(35 mL), DMSO (23.1 mmol), a solution of the appropriate alcohol
(5.66 mmol) in CH2Cl2 (21 mL), and TEA (28.2 mmol) were added
at Ϫ60 °C. The reaction mixture was allowed to warm to room
temperature and after 1 h it was washed with water (50 mL) and
the aqueous phase was extracted with CH2Cl2. The combined or-
ganic layers were dried with Na2SO4. The solvent was evaporated
under reduced pressure and the crude product was purified by flash
chromatography (hexane/ethyl acetate) to yield the aldehyde.
These amino acid motifs may be used as scaffolds on
which pharmacologically relevant groups can be appended.
Alternatively, the motifs may be utilized as conforma-
tionally constrained entities that mimic segments of natural
peptide substrates. Initial applications of these compounds
as reverse-turn inducers have been reported.[6b,6c]
Experimental Section
Synthesis of the 6,5-Fused ‘‘cis’’-Lactams 2 and 8 (Scheme 2)
General: 1H- and 13C-NMR spectra were recorded in CDCl3 or
C6D6 solution as indicated, at 200 (or 300) and 50.3 MHz, respect-
ively. The chemical shift values are given in ppm and the coupling
constants in Hz. Ϫ Optical rotation data were obtained with a
PerkinϪElmer model 241 polarimeter. Ϫ Thin-layer chromato-
graphy (TLC) was carried out using Merck precoated silica gel F-
254 plates. Flash chromatography was carried out using Merck sil-
ica gel 60, 200Ϫ400 mesh. Ϫ Solvents were dried according to
standard procedures, and reactions requiring anhydrous conditions
were performed under nitrogen. Solutions containing the final
products were dried with Na2SO4, filtered, and concentrated under
reduced pressure using a Büchi rotary evaporator. Ϫ Elemental
analyses were performed by the staff of the microanalytical laborat-
ory of our department. Ϫ Compounds 23,[8] 39,[5b] 37,[8] and 32[8]
have been described previously.
Aldehyde 14: A stirred solution of 23[8] (6.0 g, 17.4 mmol) in
CH2Cl2 (84 mL) was cooled to Ϫ60 °C, whereupon O3 was bubbled
through it (flow rate ϭ 30 L/h). After 1.5 h, the solution was al-
lowed to warm to room temperature, and then N2 was bubbled
through it in order to eliminate the excess O3. The solution was
then cooled to 0 °C by means of an ice bath and Me2S
(101.8 mmol, 38 mL) was added. After stirring for 5 d at room
temperature, the solvent was evaporated under reduced pressure
and the crude product was purified by flash chromatography (hex-
ane/ethyl acetate, 8:2) to yield 4.53 g of 14 (75%) as a yellow oil. Ϫ
1
[α]2D2 ϭ Ϫ22.0 (c ϭ 1.27, CHCl3). Ϫ H NMR (200 MHz, CDCl3)
(signals are split due to amidic isomerism): δ ϭ 1.4Ϫ1.5 [2 s, 9 H,
C(CH3)3], 1.6Ϫ2.4 (m, 4 H, CH2CH2), 2.4Ϫ3.2 (2 m, 2 H,
CH2CHO), 4.3Ϫ4.5 (m, 2 H, CH2CHN, NCHCOOtBu), 5.15 (s, 2
H, CH2Ph), 7.30 (m, 5 H, arom.), 9.8 (2 s, 1 H, CHO). Ϫ 13C NMR
(50.3 MHz, CDCl3) (signals are split due to amidic isomerism): δ ϭ
200.8, 171.7, 154.0, 136.2, 128.3, 128.0, 127.8, 127.6, 81.4, 67.0,
66.9, 60.8, 60.3, 54.0, 53.2, 49.0, 48.3, 31.0, 30.2, 29.5, 28.9, 28.0,
27.7. Ϫ FABϩMS: calcd. for C19H25NO5 347.4; found 348.
General Procedure A: Preparation of Acrylic Esters 18؊22 by
Horner؊Emmons Reaction (Scheme 1): To a stirred solution of
tBuOK (7.36 mmol) in dry CH2Cl2 (40 mL) under nitrogen, a solu-
tion of (Z)-α-phosphonoglycine trimethyl ester 24[7] (7.36 mmol) in
dry CH2Cl2 (5.0 mL) was added at Ϫ78 °C. The resulting mixture
was stirred for 30 min at this temperature and then a solution of
Acrylic Ester 19: According to General Procedure A, 14 was sub-
the appropriate aldehyde (6.13 mmol) in dry CH2Cl2 (25 mL) was jected to the HornerϪEmmons reaction. The crude product was
added. After 5 h, the solution was allowed to warm to room tem-
perature and neutralized with phosphate buffer. The aqueous phase
was extracted with CH2Cl2, the combined extracts were dried with
Na2SO4, and the solvent was evaporated under reduced pressure.
purified by flash chromatography (hexane/ethyl acetate, 65:35) to
afford 19 (98%) in a 7:1 (Z)/(E) ratio as separable colourless oils.
Ϫ (Z) isomer: [α]2D2 ϭ ϩ38.8 (c ϭ 1.26, CHCl3). Ϫ 1H NMR
(200 MHz, CDCl3) (signals are split due to amidic isomerism): δ ϭ
Eur. J. Org. Chem. 2000, 2571Ϫ2581
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C. Scolastico et al.
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1.3Ϫ1.5 [2 s, 9 H, C(CH3)3], 1.5Ϫ2.3 (m, 4 H, CH2CH2), 2.4Ϫ2.7
J ϭ 11.2 Hz, J ϭ 4.2 Hz, 1 H, CHϪN), 3.90 (m, 1 H, CHϪNBoc),
(2 m, 2 H, ϭCHϪCH2), 3.7 (2 s, 3 H, COOCH3), 4.2 (2 m, 2 H, 4.32 (d, J ϭ 9.2 Hz, 1 H, NCHCOOtBu), 5.59 (br., 1 H, NH). Ϫ
CH2CHN, NCHCOOtBu), 5.10 (m, 4 H, CH2Ph), 6.15 (m, 1 H, ϭ 13C NMR (50.3 MHz, CDCl3): δ ϭ 170.6, 167.9, 155.7, 81.2, 79.4,
CH), 7.30 (m, 10 H, arom.). Ϫ 13C NMR (50.3 MHz, CDCl3) (sig-
77.5, 60.4, 59.0, 52.2, 31.4, 28.5, 28.3, 28.2, 27.8, 27.6. Ϫ FABϩMS:
nals are split due to amidic isomerism): δ ϭ 172.4, 164.9, 154.5, calcd. for C18H30N2O5 354.46; found 354.
136.2, 132.5, 128.3, 128.2, 127.8, 127.7, 127.6, 81.8, 67.2, 66.9, 60.8,
Stereoselective Synthesis of 2 and 8 by Rh-Catalyzed Hydrogenation
of 26 (Scheme 3)
60.3, 57.9, 57.2, 52.1, 33.8, 33.2, 30.7, 29.8, 29.5, 29.0, 28.0, 27.7,
27.6. Ϫ FABϩMS: calcd. for C30H36N2O8 552.6; found 553. Ϫ (E)
1
isomer: [α]2D2 ϭ Ϫ4.1 (c ϭ 1.17, CHCl3). Ϫ H NMR (200 MHz,
Acid 26: To a solution of 25 (0.640 g, 0.980 mmol) in MeOH
(4.9 mL) was added 1  NaOH (4.9 mL, 4.9 mmol). After stirring
for 18 h at room temperature, the solvents were evaporated under
reduced pressure. The solid residue was redissolved in water (5 mL),
2  aq. HCl was added until pH ϭ 3 was reached, and then the
aqueous solution was extracted with CH2Cl2. The combined or-
ganic phases were dried with Na2SO4, the solvent was evaporated
under reduced pressure, and the residue was purified by flash chro-
matography (CH2Cl2/MeOH, 95:5) to yield 0.420 g of 26 (85%) as
a white solid. Ϫ (Z) isomer: [α]2D2 ϭ Ϫ57.0 (c ϭ 1.99, CHCl3). Ϫ
1H NMR (200 MHz, CDCl3) (signals are split due to amidic iso-
merism): δ ϭ 1.30Ϫ1.50 [2 s, 18 H, C(CH3)3], 1.7Ϫ2.7 (m, 6 H,
CDCl3) (signals are split due to amidic isomerism): δ ϭ 1.25Ϫ1.50
[3 s, 9 H, C(CH3)3], 1.5Ϫ2.3 (m, 4 H, CH2CH2), 2.8Ϫ3.3 (2 m, 2
H, ϭCHϪCH2), 3.8 (2 s, 3 H, COOCH3), 4.1 (m, 1 H, CH2CHN),
4.25 (m, 1 H, NCHCOOtBu), 5.15 (2 s, 4 H, CH2Ph), 6.30 (m, 1
H, ϭCH), 7.30 (m, 10 H, arom.). Ϫ 13C NMR (50.3 MHz, CDCl3)
(signals are split due to amidic isomerism): δ ϭ 171.8, 164.4, 154.1,
153.6, 136.4, 135.9, 128.7, 128.4, 128.2, 128.1, 128.0, 127.8, 127.7,
127.6, 126.5, 125.9, 81.2, 80.9, 66.7, 61.0, 60.6, 60.2, 58.8, 58.1,
52.2, 32.7, 32.0, 31.8, 29.9, 29.5, 29.2, 28.8, 27.8, 27.7, 22.5, 14.0.
Acrylic Ester 25: According to General Procedure B, 19 was N-Boc-
protected. The crude product was purified by flash chromatography
(hexane/ethyl acetate, 7:3) to yield 25 (98%) as a yellow oil. Ϫ (Z)
CH2CH2, ϭCHϪCH2), 4.2Ϫ4.3 (m,
2 H, ϭCHϪCH2CHN,
NCHCOOtBu), 5.1 (m, 2 H, CH2Ph), 6.6 (m, 1 H, ϭCH), 7.30 (m,
6 H, arom., NHBoc). Ϫ 13C NMR (50.3 MHz, CDCl3) (signals are
split due to amidic isomerism): δ ϭ 171.5, 168.3, 154.8, 154.5,
140.6, 136.4, 136.1, 133.9, 133.5, 128.3, 128.2, 128.1, 127.8, 127.4,
126.9, 81.3, 80.9, 67.1, 66.9, 65.0, 66.9, 65.0, 57.5, 56.8, 33.4, 32.4,
29.5, 28.5, 28.5, 28.0, 27.8, 27.7, 27.4. Ϫ (E) isomer: [α]2D2 ϭ Ϫ41.63
(c ϭ 1.87, CHCl3). Ϫ 1H NMR (200 MHz, CDCl3) (signals are
split due to amidic isomerism): δ ϭ 1.35Ϫ1.50 [3 s, 18 H, C(CH3)3],
1.7Ϫ2.4 (m, 4 H, CH2CH2), 2.7Ϫ3.2 (m, 2 H, ϭCHϪCH2),
4.2Ϫ4.3 (m, 2 H, ϭCHϪCH2CHN, NCHCOOtBu), 5.1 (m, 2 H,
CH2Ph), 6.7Ϫ6.9 (m, 2 H, ϭCH, NHBoc), 7.30 (m, 5 H, arom.).
1
isomer: [α]2D2 ϭ ϩ16.9 (c ϭ 1.86, CHCl3). Ϫ H NMR (200 MHz,
CDCl3) (signals are split due to amidic isomerism): δ ϭ 1.3Ϫ1.5 [2
s, 18 H, C(CH3)3], 1.6Ϫ2.2 (m, 4 H, CH2CH2), 2.3Ϫ2.8 (2 m, 2
H, ϭCHϪCH2), 3.7 (s, 3 H, COOCH3), 4.1Ϫ4.2 (2 m, 2 H, ϭ
CHϪCH2CHN, NCHCOOtBu), 5.15 (m, 4 H, CH2Ph), 6.95 (dd,
J ϭ 8.5, J ϭ 6.4 Hz, 1 H, ϭCH), 7.30 (m, 10 H, arom.). Ϫ 13C
NMR (50.3 MHz, CDCl3) (signals are split due to amidic isomer-
ism): δ ϭ 171.4, 163.8, 154.6, 154.3, 152.1, 150.4, 139.0, 138.8,
136.2, 135.1, 129.7, 128.3, 128.2, 128.1, 127.8, 127.6, 83.3, 81.2,
77.1, 68.2, 66.8, 60.9, 60.4, 57.5, 56.7, 52.1, 32.8, 32.1, 29.9, 29.1,
1
28.8, 27.7. Ϫ (E) isomer: [α]2D2 ϭ ϩ7.34 (c ϭ 1.33, CHCl3). Ϫ H
Ϫ
13C NMR (50.3 MHz, CDCl3) (signals are split due to amidic
NMR (200 MHz, CDCl3) (signals are split due to amidic isomer-
ism): δ ϭ 1.3Ϫ1.5 [2 s, 18 H, C(CH3)3], 1.6Ϫ2.2 (m, 4 H, CH2CH2),
3.0Ϫ3.3 (m, 2 H, ϭCHϪCH2), 3.75 (2 s, 3 H, COOCH3), 4.1Ϫ4.2
(2 m, 2 H, ϭCHϪCH2CHN, NCHCOOtBu), 5.1Ϫ5.2 (m, 4 H,
CH2Ph), 6.3 (m, 1 H, ϭCH), 7.30 (m, 10 H, arom.). Ϫ 13C NMR
(50.3 MHz, CDCl3) (signals are split due to amidic isomerism): δ ϭ
171.6, 163.8, 154.5, 154.3, 152.1, 150.4, 142.8, 142.5, 136.3, 135.2,
128.7, 128.3, 128.2, 128.1, 127.9, 127.8, 127.6, 83.2, 81.1, 68.2, 66.8,
61.1, 60.6, 58.1, 57.4, 51.7, 32.7, 32.0, 29.5, 29.4, 28.9, 28.7, 27.7.
isomerism): δ ϭ 171.7, 167.2, 154.9, 154.5, 154.3, 136.5, 136.2,
128.3, 128.2, 127.7, 127.5, 126.9, 126.3, 126.1, 81.2, 80.4, 66.9, 65.0,
60.7, 60.4, 58.3, 57.7, 32.9, 32.0, 29.5, 28.4, 28.1, 27.8, 27.7, 27.4,
27.1, 14.0.
Acids 30 and 31: To [Rh-(Ϫ)-BitianP] catalyst, prepared as de-
scribed in the literature,[16,17] 26 (0.16 mmol) and MeOH (30 mL)
were added and the resulting solution was stirred for 30 min. A
200-mL stainless steel autoclave, equipped with a magnetic stirrer
and a thermostatted bath, was pressurized with hydrogen and
vented three times. The solution was then transferred to the auto-
clave by means of a syringe, the autoclave was pressurized to 10
KPa with hydrogen, and stirring was maintained for 24 h at 30
°C. The hydrogen pressure was then released and the solvent was
evaporated. The crude product was used for the next reaction with-
out further purification.
6,5-Fused Bicyclic Lactams 2, 8: A solution of 25 (0.320 g,
0.49 mmol) in MeOH (5 mL) containing a catalytic amount of 10%
Pd/C was stirred for about 12 h under H2. The catalyst was then
removed by filtration through Celite and the collected solid was
washed with MeOH. The combined filtrate and washings were then
concentrated under reduced pressure, the residue was redissolved
in MeOH, and this solution was refluxed for 48 h. The solvent was
then removed and the two diastereoisomers thus obtained were sep-
arated by flash chromatography (hexane/ethyl acetate, 7:3) to yield
0.122 g of 8 and 2 (70%) in a 1.4:1 diastereoisomeric ratio as a
6,5-Fused Bicyclic Lactam 2: To a solution of crude 30 and 31
(0.15 mmol), as obtained from [Rh-(Ϫ)-BitianP]-catalyzed hydro-
genation of 26 in MeOH (1.5 mL) as described above, a solution
white foam. Ϫ 2: [α]2D2 ϭ Ϫ10.7 (c ϭ 1.29, CHCl3). Ϫ 1H NMR of CH2N2 in Et2O was added until TLC analysis showed that the
(200 MHz, CDCl3): δ ϭ 1.43Ϫ1.45 [2 s, 18 H, C(CH3)3], 1.5Ϫ2.5 reaction had reached completion. The solution was then concen-
(m, 8 H, CH2CH2, BocNϪCHCH2CH2), 3.69 (m, 1 H, CHϪN),
4.1 (m, 1 H, CHϪNBoc), 4.38 (dd, J ϭ 7.7 Hz, J ϭ 1.8 Hz, 1 and a catalytic amount of Pd/C was added. The resulting mixture
H, NCHCOOtBu), 5.59 (d, J ϭ 5.4 Hz, 1 H, NH). Ϫ 13C NMR
was stirred under H2 for 12 h. The catalyst was then removed by
trated to dryness, the residue was redissolved in MeOH (2 mL),
(50.3 MHz, CDCl3): δ ϭ 170.7, 165.8, 155.8, 147.1, 81.4, 79.3, 59.0, filtration through a Celite pad and washed with MeOH. The com-
56.2, 49.9, 32.0, 29.5, 29.1, 28.2, 27.8, 27.0, 26.5. Ϫ FABϩMS: bined filtrate and washings were concentrated under reduced pres-
calcd. for C18H30N2O5 354.46; found 354. Ϫ 8: [α]2D2 ϭ Ϫ45.07 (c ϭ
1.69, CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ 1.44Ϫ1.46 [2 in MeOH for 48 h. The solvent was subsequently evaporated under
s, 18 H, C(CH3)3], 1.55Ϫ2.2 (m, 7 H, CH2CH2, reduced pressure and the residue was purified by flash chromato-
BocNϪCHCHHCH2), 2.5 (m, 1 H, BocNϪCHCHH), 3.75 (m, graphy (hexane/ethyl acetate, 7:3) to afford 2 (85%) as a white solid.
sure and the crude product, obtained as a white foam, was refluxed
1
2576
Eur. J. Org. Chem. 2000, 2571Ϫ2581

Azabicycloalkane Amino Acid Scaffolds as Reverse-Turn Inducer Dipeptide Mimics
FULL PAPER
6,5-Fused Bicyclic Lactam 8: This bicyclic lactam was prepared ac-
cording to the same synthetic sequence as followed for the lactam
2, using the [Rh-(ϩ)-BitianP] catalyst for the asymmetric hydro-
genation.
ism): δ ϭ 1.35Ϫ1.45 [2 s, 9 H, C(CH3)3], 1.6Ϫ2.6 (m, 4 H,
CH2CH2), 2.8Ϫ3.1 (2 m, H, CH2CHO), 4.3 (m, H,
2
1
CHOϪCH2CHN), 4.6 (m, 1 H, NCHCOOR), 5.15 (m, 2 H,
CH2Ph), 7.30 (m, 5 H, arom.), 9.1, 9.3 (2 m, 1 H, CHO). Ϫ 13C
NMR (50.3 MHz, CDCl3) (signals are split due to amidic isomer-
ism): δ ϭ 200.3, 171.4, 154.1, 136.2, 128.4, 128.2, 128.0, 127.8,
127.7, 81.3, 67.1, 66.9, 60.5, 60.1, 53.4, 52.5, 49.0, 48.4, 29.5, 28.6,
28.3, 27.8, 27.7, 27.3.
Synthesis of the 6,5-Fused ‘‘trans’’-Lactams 5 and 11 (Scheme 4)
Ester 33: To a stirred suspension of KH (0.777 g, 19.4 mmol) in
anhydrous DMF (80 mL), triethyl phosphonoacetate (19.4 mmol,
3.9 mL) was added. The mixture was stirred at room temperature
for 1 h and then a solution of hemiaminal 32[8] (5.2 g, 16.2 mmol)
in DMF (80 mL) was added. The reaction mixture was stirred for
about 12 h at room temperature, then quenched with saturated
aqueous NH4Cl solution, and extracted with AcOEt. The com-
bined organic extracts were dried with Na2SO4, concentrated to
dryness, and the residue was purified by flash chromatography to
yield 4.8 g of 33 (75%) in a 4:1 trans/cis diastereoisomeric ratio.
N-Boc-Protected Acrylic Ester 34: The 4:1 mixture of aldehydes 14
and 17 obtained as described above was subjected to the
HornerϪEmmons reaction according to General Procedure A. The
crude product was purified by flash chromatography (hexane/ethyl
acetate, 7:3) to afford the enamide in 99% yield as a trans/cis, (Z)/
(E) mixture. Ϫ trans-(Z) isomer: [α]2D2 ϭ Ϫ61.8 (c ϭ 1.01, CHCl3).
Ϫ
1H NMR (200 MHz, CDCl3) (signals are split due to amidic
isomerism): δ ϭ 1.35Ϫ1.50 [2 s, 9 H, C(CH3)3], 1.6Ϫ2.3 (m, 4 H,
CH2CH2), 2.3Ϫ2.8 (2 m, 2 H, ϭCHϪCH2), 3.75 (s, 3 H, CO-
OCH3), 4.15Ϫ4.25 (2 m, 2 H, CH2CHN and NCHCOOtBu), 5.15
(m, 4 H, CH2Ph), 6.55 (t, J ϭ 8.5 Hz, 1 H, ϭCH), 7.35 (m, 10 H,
arom.). Ϫ 13C NMR (50.3 MHz, CDCl3) (signals are split due to
amidic isomerism): δ ϭ 171.4, 164.8, 164.6, 154.4, 153.9, 153.7,
136.4, 136.2, 135.9, 135.7, 133.0, 132.0, 128.4, 128.3, 128.2, 128.1,
128.0, 127.9, 127.8, 127.6, 126.7, 81.2, 67.3, 67.2, 67.0, 66.8, 60.6,
60.2, 57.6, 56.7, 52.3, 33.5, 32.5, 28.5, 27.7, 27.4. Ϫ FABϩMS:
calcd. for C30H36N2O8 552.6; found 552. Ϫ trans-(E) isomer:
Ϫ
1H NMR (200 MHz, CDCl3) (signals are split due to amidic
isomerism): δ ϭ 1.2Ϫ1.35 (m, 3 H, CH3CH2O), 1.35, 1.40, 1.45,
1.50 [4 s, 9 H, C(CH3)3], 1.60Ϫ2.60 (m, 5 H, CH2CH2, CHCO2Et),
2.70Ϫ3.1 (2 dd, J1 ϭ 4 Hz, J2 ϭ 15 Hz, 1 H, CHCO2Et, trans
isomer), 3.2Ϫ3.5 (2 dd, J1 ϭ 4 Hz, J2 ϭ 15 Hz, 1 H, CHCO2Et,
cis isomer), 4.13 (dq, J1 ϭ J2 ϭ 7 Hz, 2 H, CH3CH2O) 4.27 (m, 1
H, CHCO2tBu), 4.45 (m, 1 H, CH2CHN), 5.15Ϫ5.35 (m, 2 H,
CH2Ph), 7.3Ϫ7.4 (m, 5 H, arom.). Ϫ 13C NMR (50.3 MHz, CDCl3)
(signals are split due to amidic isomerism): δ ϭ 171.4, 171.3, 171.1,
171.0, 154.4, 154.1, 153.8, 136.5, 136.3, 128.3, 128.2, 127.7, 127.6,
81.2, 66.9, 66.8, 60.8, 60.5, 60.3, 60.2, 55.5, 55.2, 54.5, 39.1, 38.0,
30.4, 29.7, 28.9, 28.7, 28.2, 28.0, 27.8, 27.7, 27.1, 14.1. Ϫ FABϩMS:
calcd. for C21H29NO6 391.2; found 392.
1
[α]2D2 ϭ Ϫ50.2 (c ϭ 1.48, CHCl3). Ϫ H NMR (200 MHz, CDCl3)
(signals are split due to amidic isomerism): δ ϭ 1.35Ϫ1.45 [2 s, 9
H, C(CH3)3], 1.6Ϫ2.4 (m, 4 H, CH2CH2), 2.7Ϫ3.1 (2 m, 2 H, ϭ
CHϪCH2), 3.8 (2 s, 3 H, COOCH3), 4.1Ϫ4.3 (2 m, 2 H, CH2CHN,
NCHCOOtBu), 5.10 (m, 4 H, CH2Ph), 6.50 (m, 1 H, ϭCH), 7.25
(m, 10 H, arom.). Ϫ 13C NMR (50.3 MHz, CDCl3) (signals are
split due to amidic isomerism): δ ϭ 171.7, 171.5, 164.2, 164.0,
154.7, 154.3, 153.5, 136.6, 136.4, 135.8, 128.4, 128.3, 128.2, 128.1,
127.7, 126.2, 125.9, 125.8, 81.0, 87.1, 66.8, 66.6, 60.8, 60.4, 58.2,
57.3, 52.2, 32.8, 31.9, 28.5, 28.1, 27.8, 27.7, 27.4, 27.1. Ϫ The mix-
ture of acrylic esters (0.394 g, 0.71 mmol) was directly subjected to
N-Boc protection according to General Procedure B. Flash chro-
matography of the crude product (hexane/ethyl acetate, 75:25) af-
forded 0.287 g (73%) of the pure trans isomer 34. Ϫ trans-(Z) iso-
mer: [α]2D2 ϭ Ϫ50.9 (c ϭ 1.56, CHCl3). Ϫ 1H NMR (200 MHz,
CDCl3) (signals are split due to amidic isomerism): δ ϭ 1.3Ϫ1.5 [4
s, 18 H, C(CH3)3], 1.7Ϫ2.6 (m, 6 H, CH2CH2 and ϭCHϪCH2),
Aldehyde 17: To a stirred solution of 33 (1.205 g, 3.08 mmol) in dry
diethyl ether (31 mL), 2  LiBH4 in THF (1.5 mL, 3.08 mmol) was
added at Ϫ10 °C. After 24 h, a saturated solution of NaHCO3
(40 mL) was added and the resulting mixture was extracted with
AcOEt. The combined organic phases were dried with Na2SO4 and
concentrated to dryness. The crude product was purified by flash
chromatography (hexane/ethyl acetate, 1:1) to yield 1.01 g of the
alcohol (94%) as a yellow oil. Ϫ trans isomer: [α]2D2 ϭ Ϫ32.3 (c ϭ
1.02, CHCl3). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.35 [s, 9 H,
C(CH3)3], 1.5Ϫ2.4 (m, 6 H, CH2CH2, CH2CH2O), 3.5Ϫ3.7 (m, 2
H, CH2OH), 3.82 (br. s, 1 H, OH), 4.22 (dd, J ϭ 7.5 Hz, J ഠ 0 Hz,
1 H, CHCO2tBu), 4.38 (m, 1 H, CH2CHN), 5.15 (m, 2 H, CH2Ph),
7.32 (s, 5 H, arom.). Ϫ 13C NMR (50.3 MHz, CDCl3) (signals are
split due to amidic isomerism): δ ϭ 171.4, 156.1, 136.0, 128.4,
128.3, 127.9, 127.8, 127.7, 81.2, 81.1, 67.2, 67.0, 60.4, 59.9, 59.0,
3.7 (s,
3 H, COOCH3), 4.1Ϫ4.3 (m, 2 H, CH2CHN and
NCHCOOtBu), 5.15 (m, 4 H, CH2Ph), 6.8 (m, 1 H, ϭCH), 7.30
(m, 10 H, arom.). Ϫ 13C NMR (50.3 MHz, CDCl3) (signals are
split due to amidic isomerism): δ ϭ 171.4, 163.9, 154.6, 154.5,
150.0, 146.2, 138.5, 138.0, 136.2, 129.9, 128.3, 128.2, 128.1, 127.8,
83.4, 81.2, 68.3, 67.0, 66.8, 60.6, 60.2, 56.9, 56.2, 52.2, 32.9, 32.0,
28.3, 27.8, 27.7, 27.3. Ϫ FABϩMS: calcd. for C35H44N2O10 652.7;
55.2, 55.1, 38.6, 37.7, 28.9, 28.7, 27.8, 27.7. Ϫ cis isomer: [α]2D2
ϭ
Ϫ54.0 (c ϭ 1.51, CHCl3). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ
1.33 [s, 9 H, C(CH3)3], 1.4Ϫ1.24 (m, 6 H, CH2CH2, CH2CH2O),
3.6Ϫ3.9 (m, 2 H, CH2OH), 4.08 (dd, J ϭ 9.5 Hz, J ϭ 4 Hz, 1 H,
OH), 4.25 (dd, J1 ϭ J2 ϭ 8.5 Hz, 1 H, CHCO2tBu), 4.40 (m, 1 H,
CH2CHN), 5.15 (m, 2 H, CH2Ph), 7.35 (s, 5 H, arom.). Ϫ 13C
NMR (50.3 MHz, CDCl3): δ ϭ 27.7, 28.9, 30.4, 37.4, 55.4, 58.8,
60.5, 67.4, 81.3, 127.7, 127.9, 128.3, 136.1, 155.9, 171.8. Ϫ A solu-
tion of the alcohol (0.304 g, 0.87 mmol) in dry CH2Cl2 (2.5 mL)
was added to a suspension of DessϪMartin periodinane (0.408 g,
1.13 mmol) in dry CH2Cl2 (2.5 mL) at room temperature. After 1 h,
Et2O and 1  NaOH were added until a clear solution was ob-
tained. The aqueous phase was then extracted twice with Et2O, and
the combined organic layers were washed with H2O, dried with
Na2SO4, and concentrated to dryness. The crude product was puri-
1
found 652. Ϫ trans-(E) isomer: H NMR (200 MHz, CDCl3): δ ϭ
1.3Ϫ1.4 [2 s, 18 H, C(CH3)3], 1.5Ϫ2.3 (m, 4 H, CH2CH2), 3.0 (2
m, 2 H, ϭCHϪCH2), 3.65 (2 s, 3 H, COOCH3), 4.2 (m, 2 H,
CH2CHN and NCHCOOtBu), 5.15 (m, 4 H, CH2Ph), 6.1 (2 t, J ϭ
8.5 Hz, 1 H, ϭCH), 7.30 (m, 10 H, arom.). Ϫ 13C NMR (50.3
MHz, CDCl3): δ ϭ 171.5, 163.7, 154.6, 154.3, 152.2, 150.4, 142.7,
142.2, 136.3, 135.1, 128.9, 128.3, 128.2, 128.0, 127.8, 127.7, 83.4,
83.3, 81.1, 77.1, 68.3, 66.9, 66.7, 60.7, 60.3, 57.6, 56.8, 51.7, 32.9,
32.0, 28.4, 28.0, 27.7, 27.3, 27.0.
fied by flash chromatography (hexane/ethyl acetate, 7:3) to afford 6,5-Fused Bicyclic Lactams 5 and 11: A solution of 34 (0.489 g,
0.277 g of a 4:1 stereoisomeric mixture of aldehydes 17 and 14
0.75 mmol) in MeOH (7.5 mL) containing 20% Pd(OH)2/C (cata-
lytic amount) was stirred for about 12 h under H2. The catalyst was
then filtered off and the filtrate was refluxed for 24 h. The solvent
1
(92%). Ϫ trans isomer 17: [α]2D2 ϭ Ϫ48.6 (c ϭ 1.01, CHCl3). Ϫ H
NMR (200 MHz, CDCl3) (signals are split due to amidic isomer-
Eur. J. Org. Chem. 2000, 2571Ϫ2581
2577

C. Scolastico et al.
FULL PAPER
was then removed and the two diastereoisomeric products were sep-
arated by flash chromatography (hexane/ethyl acetate, 6:4) to yield
0.186 g of 5 and 11 (70%) in a 1.4:1 diastereoisomeric ratio. Ϫ 5:
added sequentially. After 15 min, EDC (0.180 g, 0.937 mmol) was
added and the mixture was stirred for 24 h. Thereafter, H2O
(40 mL) was added, the aqueous phase was extracted with CH2Cl2,
and the combined organic layers were dried with Na2SO4, filtered,
1
[α]2D2 ϭ Ϫ36.5 (c ϭ 0.97, CHCl3). Ϫ H NMR (200 mhz, CDCl3):
δ ϭ 1.45Ϫ1.50 [2 s, 18 H, C(CH3)3], 1.55Ϫ2.60 (m, 8 H, CH2CH2 and concentrated under reduced pressure to afford 0.191 g of 3 and
and BocNϪCHCH2CH2), 3.68 (tt, J ϭ 14.9 Hz and 4.2 Hz, 1 H, 9 in a 1:1 diastereoisomeric ratio (72% yield over the 2 steps). Ϫ 3:
CHϪN), 4.05 (m, 1 H, CHϪNBoc), 4.35 (t, J ϭ 8.5 Hz, 1 H, [α]2D2 ϭ Ϫ34.6 (c ϭ 1, CHCl3). Ϫ 1H NMR (200 MHz, CDCl3):
NCHCOOtBu), 5.28 (br., 1 H, NH). Ϫ 13C NMR (50.3 MHz,
δ ϭ 1.41, 1.42 [2 s, 18 H, C(CH3)3], 1.5Ϫ2.5 (m, 10 H, CH2CH2),
CDCl3): δ ϭ 59.0, 58.4, 51.3, 32.7, 28.6, 28.2, 27.8, 27.7, 27.6, 27.3. 3.80 (m, 1 H, CHϪN), 4.2 (m, 1 H, CHϪNBoc), 4.51 (dd, J ϭ
Ϫ FABϩMS: calcd. for C18H30N2O5 354.46; found 354. Ϫ 11: [α]D22 4.8 Hz, 1 H, NCHCOOtBu), 5.54 (br. d, 1 H, NH). Ϫ13C NMR
1
ϭ Ϫ107.9 (c ϭ 1.7, CHCl3). Ϫ H NMR (200 mhz, CDCl3): δ ϭ
1.45Ϫ1.50 [2 s, 18 H, C(CH3)3], 1.75Ϫ2.50 (m, 8 H, CH2CH2 and
BocNϪCHCH2CH2), 3.70 (m, 1 H, CHϪN), 4.15 (m, 1 H,
(50.3 MHz, CDCl3): δ ϭ 61.2, 59.0, 54.2, 34.2, 32.8, 31.7, 28.3,
27.6, 27.7, 27.9. Ϫ FABϩMS: calcd. for C19H32N2O5 368.6; found
1
391 [M ϩ Naϩ]. Ϫ 9: [α]2D2 ϭ Ϫ53.2 (c ϭ 1, CHCl3). Ϫ H NMR
CHϪNBoc), 4.50 (t, J ϭ 7.0 Hz, 1 H, NCHCOOtBu), 5.55 (br., 1 (200 MHz, CDCl3): δ ϭ 1.42, 1.43 [2 s, 18 H, C(CH3)3], 1.50Ϫ2.2
H, NH). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 170.6, 168.5, 155.5, (m, 10 H, CH2CH2), 3.8 (m, 1 H, CHϪN), 4.25 (dd, J ϭ 4.6 Hz,
81.4, 79.3, 59.0, 56.2, 49.9, 32.3, 28.1, 27.8, 26.5, 25.9. Ϫ FABϩMS:
calcd. for C18H30N2O5 354.46; found 354.
J ϭ 9.6 Hz, 1 H, CHϪNBoc), 4.42 (dd, J ϭ 2.3 Hz, J ϭ 7.2 Hz, 1
H, NCHCOOtBu), 5.30 (br. s, 1 H, NH). Ϫ13C NMR (50.3 MHz,
CDCl3): δ ϭ 62.1, 58.5, 34.2, 32.9, 32.8, 28.3, 27.9, 27.5, 27.3, 22.6.
Ϫ FABϩMS: calcd. for C19H32N2O5 368.6; found 391 [M ϩ Naϩ].
Synthesis of 7,5-Fused ‘‘cis’’-Lactams 3 and 9 (Scheme 5)
Aldehyde 15: Hydroboration of 23[8] according to General Proced-
ure C gave the primary alcohol, which was obtained as a yellow oil
(95%) following purification by flash chromatography (hexane/
ethyl acetate, 7:3). Ϫ 1H NMR (200 MHz, CDCl3) δ ϭ 1.4 [s, 9 H,
C(CH3)3], 1.6Ϫ2.4 (m, 8 H, CH2CH2), 3.5Ϫ3.8 (2 m, 2 H,
CH2OH), 4.1 (m, 1 H, CH2CHN), 4.25 (m, 1 H, NCHCOOtBu),
5.15 (s, 2 H, CH2Ph), 7.30 (m, 5 H, arom.). Ϫ The alcohol was
oxidized according to General Procedure D and the crude product
was purified by flash chromatography (hexane/ethyl acetate, 7:3) to
Synthesis of 7,5-Fused ‘‘trans’’-Lactams 6 and 12 (Scheme 6)
Aldehyde 17: According to General Procedure C, 37[8] was sub-
jected to hydroboration. The crude product was purified by flash
chromatography to afford the alcohol in 98% yield. Ϫ 1H NMR
(200 MHz, CDCl3) δ ϭ 1.32 [s, 9 H, C(CH3)3], 1.4Ϫ2.4 (m, 8 H,
CH2CH2), 3.5Ϫ3.7 (m, 2 H, CH2OH), 4.1 (m, 1 H, CH2CHN),
4.24 (m, 1 H, NCHCOOtBu), 5.05 (s, 2 H, CH2Ph), 7.25 (m, 5
H, arom.). Ϫ The alcohol was then oxidized according to General
Procedure D. The crude product was purified by flash chromato-
1
yield 15 (89%) as an oil. Ϫ H NMR (200 MHz, CDCl3) (signals
1
are split due to amidic isomerism): δ ϭ 1.4Ϫ1.5 [2 s, 9 H, C(CH3)3],
1.6Ϫ2.8 (m, 4 H, CH2CH2), 4.05 (m, 1 H, CH2CHN), 4.25 (m, 1
H, NCHCOOtBu), 5.15 (s, 2 H, CH2Ph), 7.30 (m, 5 H, arom.),
9.6Ϫ9.8 (2 s, 1 H, CHO).
graphy (hexane/ethyl acetate, 6:4) to afford 17 in 82% yield. Ϫ H
NMR (200 MHz, CDCl3) (signals are split due to amidic isomer-
ism): δ ϭ 1.32, 1.45 [2 s, 9 H, C(CH3)3], 1.5Ϫ2.7 (m, 8 H,
CH2CH2), 4.1 (m, 1 H, CH2CHN), 4.25 (m, 1 H, NCHCOOtBu),
5.15 (s, 2 H, CH2Ph), 7.20Ϫ7.40 (m, 5 H, arom.), 9.6Ϫ9.8 (2 m, 1
H, CHO).
Acrylic Ester 20: According to General Procedure A, 15 was sub-
jected to the HornerϪEmmons reaction. The resulting residue was
purified by flash chromatography to yield the acrylic ester (95%)
as a yellow oil. Ϫ 1H NMR (200 MHz, CDCl3) (signals are split
due to amidic isomerism): δ ϭ 1.36, 1.41 [2 s, 18 H, C(CH3)3],
1.6Ϫ2.5 (m, 8 H, CH2CH2), 3.8 (s, 6 H, COOMe), 4.01 (m, 2 H,
CH2CHN), 4.4 (m, 2 H, NCHCOOtBu), 5.1 (s, 4 H, CH2Ph), 6.58
(m, 2 H, HCϭ), 6.9 (br. s, 2 H, NH), 7.30 (m, 5 H, arom.).
Acrylic Ester 38: According to General procedure A, 17 was sub-
jected to the HornerϪEmmons reaction. The crude product was
purified by flash chromatography (hexane/ethyl acetate, 6:4) to af-
ford the acrylic ester in 90% yield [diastereomeric ratio (Z)/(E) ϭ
7:1]. Ϫ 1H NMR (200 MHz, CDCl3) (signals are split due to amidic
isomerism): δ ϭ 1.32, 1.42 [s, 9 H, C(CH3)3], 1.5Ϫ2.7 (m, 8 H,
CH2CH2), 3.71 (s, 1 H, COOCH3), 4.1 (m, 1 H, CH2CHN), 4.22
(m, 1 H, NCHCOOtBu), 5.0Ϫ5.20 (m, 4 H, CH2Ph), 6.6 (m, 1
H, ϭCH), 7.20Ϫ7.45 (m, 10 H, arom.). Ϫ According to General
Procedure B, the acrylic ester was N-Boc-protected. The crude
product was purified by flash chromatography to yield 38 (98%).
Acrylic Ester 35: Compound 20 was N-Boc-protected according
to General Procedure B. The crude product was purified by flash
chromatography to yield the N-Boc-protected compound (95%) as
a white solid. A solution of this compound (0.96 mmol) in MeOH
(1 mL) containing a catalytic amount of Pd/C was stirred under
hydrogen for 12 h. The catalyst was then removed by filtration
through a Celite pad. The filtrate was concentrated to dryness un-
der reduced pressure to yield 0.320 g of 35 (83%) as a white solid
(mixture of two diastereoisomers). Ϫ 1H NMR (200 MHz, CDCl3):
δ ϭ 1.47, 1.48 [2 s, 18 H, C(CH3)3], 1.40Ϫ2.1 (m, 10 H, CH2CH2,
BocNϪCHCHHCH2), 3.00 (m, 1 H, CHϪN), 3.6 (m, 1 H,
NCHCOOtBu), 4.3 (m, 1 H, CHϪNBoc), 5.05 (br. d, 1 H, NH).
Ϫ
1H NMR (200 MHz, CDCl3) (signals are split due to amidic
isomerism): δ ϭ 1.32, 1.42 [2 s, 18 H, C(CH3)3], 1.5Ϫ2.2 (m, 8 H,
CH2CH2), 3.71 (s, 1 H, COOCH3), 3.9 (m, 1 H, CH2CHN), 4.22
(m, 1 H, NCHCOOtBu), 5.0Ϫ5.20 (m, 4 H, CH2Ph), 6.9 (m, 1
H, ϭCH), 7.20Ϫ7.45 (m, 10 H, arom.). Ϫ 13C NMR (50.3 MHz,
CDCl3) (signals are split due to amidic isomerism): δ ϭ 141.6,
128.4, 128.2, 128.1, 127.8, 127.7, 68.2, 66.8, 60.5, 58.1, 52.1, 31.3,
29.5, 27.1, 27.3, 24.6.
Amino Acid 36: To a solution of 35 (0.288 g, 0.720 mmol) in MeOH
was added 1  NaOH. After 1.5 h, the solution was acidified to
pH ϭ 3 with 1  HCl, and then the solvents were evaporated. The
crude residue was used for the next reaction without further puri-
fication.
trans-7,5-Fused Bicyclic Lactams 6 and 12: To a solution of 38
(0.093 g, 0.141 mmol) in MeOH (2 mL) was added 1  NaOH
(0.705 mmol, 0.705 mL) and the resulting mixture was stirred for
1.5 h. The solution was then acidified to pH ϭ 3 with 1  aq. HCl
and the solvents were evaporated. The crude residue was used in
the next reaction without further purification. Ϫ 1H NMR
(200 MHz, CDCl3) (signals are split due to amidic isomerism): δ ϭ
7,5-Fused Bicyclic Lactams 3 and 9: To a solution of the crude 36
(0.720 mmol) in CH2Cl2 (80 mL), Et3N (0.720 mmol, 0.220 mL),
HOBt (0.166 g, 1.22 mmol), and a catalytic amount of DMAP were 1.25, 1.48 [2 s, 18 H, C(CH3)3], 1.5Ϫ2.4 (m, 8 H, CH2CH2), 4.1
2578 Eur. J. Org. Chem. 2000, 2571Ϫ2581

Azabicycloalkane Amino Acid Scaffolds as Reverse-Turn Inducer Dipeptide Mimics
(m, 1 H, CH2CHN), 4.3 (m, 1 H, NCHCOOtBu), 5.12 (s, 2 H, 1 H, CH2CHN), 3.7 (s, 1 H, COOCH3), 3.7 (d, J ϭ 12 Hz, 1 H,
FULL PAPER
CH2Ph), 6.65 (m, 1 H, ϭCH), 7.1Ϫ7.4 (m, 5 H, arom.), 9.00 (br.
s, 1 H, COOH). Ϫ A solution of the aforementioned crude product
in xylene was refluxed for 48 h. The solvent was then evaporated
and the residue was purified by flash chromatography to yield 6
and 12 in 40% yield. Ϫ 6: 1H NMR (200 MHz, CDCl3) (signals are
split due to amidic isomerism): δ ϭ 1.43, 1.45 [2 s, 18 H, C(CH3)3],
1.51Ϫ2.40 (m, 10 H, CH2CH2), 3.75 (m, 1 H, CHϪN), 4.22 (m, 1
H, CHϪNBoc), 4.48 (t, J ϭ 17 Hz, 1 H, NCHCOOtBu), 5.7 (br.,
1 H, NH). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 61.7, 59.3, 53.2,
HCHPh), 3.9 (d, J ϭ 12 Hz, 1 H, HCHPh), 5.20 (d, J ϭ 12 Hz,
1 H, HCHPh), 7.0 (d, J ϭ 8.6 Hz, 1 H, ϭCH), 7.1Ϫ7.4 (m, 10
H, arom.).
Amino Acid 42: To a solution of 40 (0.424 g, 0.713 mmol) in MeOH
(4 mL) was added 1  NaOH (4 mmol, 4 mL) and the resulting
mixture was stirred for 1.5 h. It was then acidified to pH ϭ 3 with
1  HCl and the solvents were evaporated. The crude product was
1
used in the next reaction without further purification. Ϫ H NMR
(200 MHz, CDCl3) (signals are split due to amidic isomerism): δ ϭ
1.35, 1.5 [2 s, 18 H, C(CH3)3], 1.7Ϫ2.3 (m, 4 H, CH2CH2), 3.3 (m,
1 H, NCHCOOtBu), 3.65 (m, 1 H, CH2CHN), 3.7 (d, J ϭ 12.8 Hz,
1 H, HCHPh), 3.9 (d, J ϭ 12.8 Hz, 1 H, HCHPh), 6.5 (d, J ϭ
7.6 Hz, 1 H, ϭCH), 7.1Ϫ7.4 (m, 10 H, arom.), 9.00 (br. s, 1 H,
COOH).
34.0, 28.4, 28.2, 27.9, 26.4, 22.9.
Ϫ
FABϩMS: calcd. for
C19H32N2O5 368.6; found 391 [M ϩ Naϩ]. Ϫ 12: 1H NMR
(200 MHz, CDCl3) (signals are split due to amidic isomerism): δ ϭ
1.47, 1.48 [2 s, 18 H, C(CH3)3], 1.55Ϫ2.50 (m, 8 H, CH2CH2), 4.0
(m, 1 H, CHϪN), 4.30 (m, 1 H, CHϪNBoc), 4.50 (dd, J ϭ 5.4 Hz,
J ϭ 17 Hz, 1 H, NCHCOOtBu), 6.0 (br. d, 1 H, NH). Ϫ FABϩMS:
calcd. for C19H32N2O5 368.6; found 369 [M ϩ 1].
5,5-Fused Bicyclic Lactams 1 and 7: A solution of 42 (0.713 mmol)
in MeOH (7 mL), containing a catalytic amount of 20% Pd(OH)2/
C, was stirred under hydrogen for 12 h. The catalyst was then re-
moved by filtration through a Celite pad and the filtrate was con-
centrated to dryness under reduced pressure. The residue was redis-
solved in MeOH and this solution was refluxed for 48 h. Thereafter,
the solvent was evaporated under reduced pressure and the crude
product was purified by flash chromatography (hexane/ethyl acet-
ate, 6:4) to afford 0.097 g of a 1:1 diastereomeric mixture of 1 and
7 as a white solid in 40% yield (over 2 steps). Ϫ 1: [α]2D2 ϭ Ϫ4.8
(c ϭ 1.20, CHCl3). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.50, 1.51
[2 s, 18 H, C(CH3)3], 1.6Ϫ2.4 (m, 5 H, CH2CH2, BocNϪCHCHH),
2.95 (m, 1 H, BocNϪCHCHH), 3.85 (m, 1 H, CHϪN), 4.15 (d,
J ϭ 8.8 Hz, 1 H, NCHCOOtBu), 4.60 (m, 1 H, CHϪNBoc), 5.25
(br., 1 H, NH). Ϫ 13C NMR (50.3 MHz, CDCl3) (signals are split
due to amidic isomerism): δ ϭ 171.7, 169.7, 155.6, 81.8, 79.5, 58.8,
56.5, 56.0, 55.8, 39.5, 33.4, 29.5, 28.2, 27.8. Ϫ FABϩMS: calcd. for
C17H28N2O5 340.41; found 341. Ϫ 7: [α]2D2 ϭ Ϫ4.8 (c ϭ 1.20,
CHCl3). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.45 [2 s, 18 H,
C(CH3)3], 1.5Ϫ2.5 (m, 6 H, CH2CH2, BocNϪCHCH2), 4.05 (d,
J ϭ 8.8 Hz, 1 H, NCHCOOtBu), 4.12 (m, 1 H, CHϪN), 4.25 (m,
1 H, CHϪNBoc), 5.05 (br., 1 H, NH). Ϫ 13C NMR (50.3 MHz,
CDCl3) (signals are split due to amidic isomerism): δ ϭ 170.9,
169.8, 155.2, 82.2, 81.8, 79.9, 77.1, 61.2, 58.8, 57.6, 56.0, 55.8, 34.4,
33.8, 33.4, 29.9, 29.5, 29.2, 28.5, 28.1, 27.7. Ϫ FABϩMS: calcd. for
C17H28N2O5 340.41; found 341.
l
-Selectride Reduction of 38: To a solution of 38 (0.8385 g,
1.258 mmol) in THF, a 1  solution of -Selectride in THF
(3.2 mL, 3.145 mmol) was added at Ϫ78 °C. After 30 min, a satur-
ated solution of NH4Cl was added and the resulting mixture was
extracted with AcOEt. The combined organic phases were dried
with Na2SO4 and concentrated to dryness. The crude product was
purified by flash chromatography (hexane/ethyl acetate, 7:3) to
yield 0.7224 g of the reduced compound (86%). Ϫ 1H NMR
(200 MHz, CDCl3) (signals are split due to amidic isomerism): δ ϭ
1.30, 1.40 [2 s, 9 H, C(CH3)3], 1.75Ϫ2.20 (m, 10 H, CH2CH2), 3.65
(s, 1 H, COOCH3), 4 (m, 1 H, CH2CHN), 4.20 (m, 1 H,
NCHCOOtBu), 4.90 (m, 1 H, CHCOOMe), 5.10Ϫ5.30 (m, 4 H,
CH2Ph), 7.20Ϫ7.45 (m, 10 H, arom.). Ϫ 13C NMR (50.3 MHz,
CDCl3) (signals are split due to amidic isomerism): δ ϭ 128.4,
128.3, 128.2, 128.1, 127.7, 127.6, 68.7, 66.6, 60.1, 58.5, 52.1, 33.0,
29.9, 29.6, 28.6, 27.8, 27.7, 26.9.
Ϫ
FABϩMS: calcd. for
C35H48N2O8 668.7; found 691 [M ϩ Naϩ].
Synthesis of the 5,5-Fused ‘‘cis’’-Lactams 1a and 7a (Scheme 7)
Acrylic Ester 40: According to General Procedure D, compound
39[5b] was oxidized. The crude product was purified by flash chro-
matography (hexane/ethyl acetate, 7:3) to yield the aldehyde (81%)
1
as an oil. Ϫ H NMR (200 MHz, CDCl3) (signals are split due to
amidic isomerism): δ ϭ 1.48 [s, 9 H, C(CH3)3], 1.8Ϫ2.2 (m, 4 H,
CH2CH2), 3.21 (m, 1 H, CH2CHN), 3.45 (m, 1 H, NCHCOOtBu),
3.70 (d, J ϭ 12 Hz, 1 H, HCHPh), 4.10 (d, J ϭ 12 Hz, 1 H,
HCHPh), 7.30 (m, 5 H, arom.), 9.12 (d, 1 H, CHO). Ϫ According
to General Procedure A, the aforementioned aldehyde was sub-
Alternative Synthesis of the 5,5-Fused ‘‘cis’’-Lactams 1 and 7
(Scheme 8)
jected to the HornerϪEmmons reaction. The crude product was Aldehyde 13: To a stirred solution of 39[5b] (1.5 g, 5.14 mmol) in
purified by flash chromatography (hexane/ethyl acetate, 65:35) to
dry CH2Cl2 (39 mL) under nitrogen, TBDMSCl (0.931 g,
6.17 mmol), TEA (6.17 mmol, 0.94 mL), and DMAP (0.063 g,
afford the acrylic ester (98%) in a 9:1 (Z)/(E) ratio as separable
1
colourless oils. Ϫ (Z) isomer Ϫ H NMR (200 MHz, CDCl3): δ ϭ 0.51 mmol) were added sequentially. After 12 h, the solvent was
1.31 [s, 9 H, C(CH3)3], 1.7Ϫ2.2 (m, 4 H, CH2CH2), 3.3 (m, 1 H,
NCHCOOtBu), 3.5 (s, 1 H, CH2CHN), 3.66 (d, J ϭ 13.2 Hz,
evaporated under reduced pressure and the residue was purified by
flash chromatography (hexane/ethyl acetate, 9:1) to yield 1.910 g of
HCHPh), 3.73 (s, 1 H, COOCH3), 3.79 (d, 1 H, HCHPh), 5.11 (d, the silyl ether (94%) as a colourless oil. Ϫ [α]2D2 ϭ Ϫ3.6 (c ϭ 2.52,
J ϭ 12.5 Hz, 1 H, OHCHPh), 5.15 (d, J ϭ 12.5 Hz, 1 H,
OHCHPh), 6.07 (d, J ϭ 7.4 Hz, 1 H, ϭCH), 7.10Ϫ7.6 (m, 10 H, 0.85 [s, 9 H, (CH3)3CϪSi], 1.4 [s, 9 H, C(CH3)3], 1.5Ϫ2.1 (m, 4 H,
CHCl3). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ Ϫ0.5 (s, 6 H, CH3Si),
arom.), 8.15 (br. s, 1 H, NH). Ϫ 13C NMR (50.3 MHz, CDCl3):
δ ϭ 173.7, 165.1, 154.1, 137.4, 136.1, 129.5, 128.5, 128.3, 128.0,
127.8, 127.7, 127.1, 80.5, 66.9, 65.3, 62.3, 57.5, 52.0, 30.1, 28.9,
27.7. Ϫ According to General Procedure B, the acrylic ester synthe-
sized as described above was N-Boc-protected. The crude product
was purified by flash chromatography (hexane/ethyl acetate, 7:3) to
yield 40 (98%). Ϫ 1H NMR (200 MHz, CDCl3) (signals are split
CH2CH2), 2.9 (m, 1 H, SiOϪCH2CHN), 3.3Ϫ3.4 (m, 3 H,
NCHCOOtBu, SiOϪCH2), 3.9 (s, 2 H, CH2Ph), 7.3 (m, 5 H,
arom.). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 173.6, 139.3, 129.1,
127.9, 126.7, 19.9, 67.5, 66.8, 65.8, 58.8, 28.4, 28.0, 27.8, 25.8, 18.1,
Ϫ3.6.
Ϫ A solution of the silyl-protected alcohol (1.850 g,
4.55 mmol) in MeOH (45 mL), containing 20% Pd(OH)2 (0.250 g,
0.45 mmol), was stirred under hydrogen for 4 h. The catalyst was
due to amidic isomerism): δ ϭ 1.3Ϫ1.5 [2 s, 18 H, C(CH3)3], then removed by filtration through a Celite pad and washed with
1.6Ϫ2.2 (m, 4 H, CH2CH2), 3.1 (m, 1 H, NCHCOOtBu), 3.5 (m, MeOH. The combined filtrate and washings were concentrated un-
Eur. J. Org. Chem. 2000, 2571Ϫ2581
2579

C. Scolastico et al.
FULL PAPER
der reduced pressure to yield 1.34 g of the N-deprotected com-
through a Celite pad and washed with MeOH. The combined fil-
trate and washings were concentrated to dryness under reduced
pound (94%) as a colourless oil. Ϫ [α]2D2 ϭ Ϫ5.8 (c ϭ 1.99, CHCl3).
1
Ϫ H NMR (200 MHz, CDCl3): δ ϭ 0.4 (s, 6 H, CH3Si), 0.92 [s, pressure and the residue was purified by flash chromatography
9 H, (CH3)3CϪSi], 1.49 [s, 9 H, C(CH3)3], 1.5Ϫ2.1 (m, 4 H, (toluene/Et2O, 85:15) to yield 0.365 g of 44 (77%) as a yellow oil.
CH2CH2), 2.35 (br., 1 H, NH), 3.2 (m, 1 H, SiOϪCH2CHN), 3.65
(m, 3 H, NCHCOOtBu, SiOϪCH2). Ϫ To a stirred solution of the isomerism and refer to the mixture of two diastereoisomers): δ ϭ
Ϫ
1H NMR (200 MHz, CDCl3) (signals are split due to amidic
aforementioned compound (1.2 g, 3.79 mmol) in CH2Cl2 (38 mL)
were added pyridine (11.39 mmol, 0.92 mL) and (CF3CO)2O
(8.35 mmol, 1.16 mL). After 1.5 h, the solvent was evaporated un-
der reduced pressure and the residue was purified by flash chroma-
tography (hexane/ethyl acetate, 9:1) to yield 1.4 g of the trifluo-
1.45 [s, 18 H, C(CH3)3], 1.6Ϫ2.7 (m,
6
H, CH2CH2,
BocNϪCHCH2), 3.75 (2 s, 3 H, COOCH3), 4.25Ϫ4.4 (2 m, 2 H,
BocNϪCH, BocNϪCHCH2CH), 4.55 (m, 1 H, NCHCOOtBu),
5.30 (d, J ϭ 8.5 Hz, 1 H, NH). Ϫ 13C NMR (50.3 MHz, CDCl3)
(signals are split due to amidic isomerism and refer to the mixture
roacetamide-protected pyrrolidine (89%) as a colourless oil. Ϫ [α]D22 of two diastereoisomers): δ ϭ 172.4, 170.0, 155.8, 128.9, 128.0,
1
ϭ Ϫ8.6 (c ϭ 2.11, CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ
0.4 (s, 6 H, CH3Si), 0.9 [s, 9 H, (CH3)3CϪSi], 1.47 [s, 9 H,
82.7, 82.0, 79.7, 61.4, 60.6, 58.0, 56.5, 52.2, 51.5, 37.7, 36.4, 35.5,
30.2, 29.7, 29.0, 28.4, 28.1, 27.6, 25.5. Ϫ FABϩMS: calcd. for
C(CH3)3], 1.7Ϫ2.4 (m, 4 H, CH2CH2), 3.5 (m, 1 H, SiOϪCHH), C20H31F3N2O7 468.47; found 468.
3.75 (dd, J ϭ 10.6 Hz, J ϭ 4.2 Hz, 1 H, SiOϪCHH), 4.2 (m, 1 H,
Amino Acid 45: A solution of 44 (0.184 g, 0.393 mmol) and NaBH4
SiOϪCH2CHN), 4.35 (t, J ϭ 8.5 Hz, 1 H, NCHCOOtBu). Ϫ O-
Desilylation was achieved by treating a stirred solution of the N-
protected pyrrolidine (1.2 g, 2.91 mmol) in THF (29 mL) at Ϫ40 °C
with a 1  solution of TBAF in THF (3.20 mmol, 3.2 mL). The
mixture was allowed to warm at room temp. over a period of 2.5
h, and then brine (30 mL) was added and the resulting mixture
was extracted with ethyl acetate. The organic phase was dried with
Na2SO4 and the solvent was evaporated under reduced pressure.
The residue was purified by flash chromatography (hexane/ethyl
acetate, 6:4) to yield 0.850 g of the O-deprotected compound (98%)
as a colourless oil. Ϫ [α]2D2 ϭ Ϫ6.4 (c ϭ 1.45, CHCl3). Ϫ 1H NMR
(200 MHz, CDCl3): δ ϭ 1.5 [s, 9 H, C(CH3)3], 2.0Ϫ2.4 (m, 4 H,
CH2CH2), 3.4Ϫ3.7 (m, 2 H, HOϪCH2), 4.2Ϫ4.6 (m, 3 H,
NCHCOOtBu, HOϪCH2CHN). Ϫ According to General Proced-
ure D, the aforementioned alcohol was oxidized. The crude product
was purified by flash chromatography (hexane/ethyl acetate, 6:4) to
yield the aldehyde 13 (93%) as a white solid. Ϫ [α]2D2 ϭ ϩ22.5 (c ϭ
1.53, CHCl3). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.5 [s, 9 H,
(0.0298 g, 0.781 mmol) in MeOH (8 mL) was stirred for 1 h at room
temperature. It was then concentrated and the residue was taken
up in water (10 mL). The aqueous solution thus obtained was ex-
tracted with ethyl acetate, the combined organic phases were dried
with Na2SO4, and the solvent was evaporated under reduced pres-
sure. The two diastereoisomers formed in the previous reactions
were separated at this stage by flash chromatography (ethyl acetate/
hexane, 6:4) to afford 0.123 g of 45 (3R) and 45 (3S) (84%) in a
2.6:1 diastereoisomeric ratio as a colourless oil. Ϫ 45 (3R): 1H
NMR (200 MHz, C6D6) (signals are split due to amidic isomerism):
δ ϭ 1.30, 1.45 [2 s, 18 H, C(CH3)3], 1.5Ϫ1.9 (m, 6 H, CH2CH2,
BocNϪCHCH2), 2.85 (m, 1 H, BocNϪCHCH2CH), 3.2Ϫ3.4 (m,
4 H, COOCH3, NCHCOOtBu), 4.65 (m, 1 H, BocNϪCH), 6.6
(br., 1 H, NHBoc). Ϫ 13C NMR (50.3 MHz, C6D6) (signals are
split due to amidic isomerism): δ ϭ 174.1, 173.2, 155.8, 81.4, 81.3,
79.5, 60.6, 60.4, 56.5, 56.3, 52.5, 52.0, 37.7, 31.9, 30.0, 29.8, 28.2,
28.0, 27.9. Ϫ FABϩMS: calcd. for C18H32N2O6 372.46; found 373.
Ϫ 45 (3S): 1H NMR (200 MHz, C6D6) (signals are split due to
amidic isomerism): δ ϭ 1.30, 1.50 [2 s, 18 H, C(CH3)3], 1.50Ϫ1.80
C(CH3)3], 1.8Ϫ2.5 (m,
4 H, CH2CH2), 4.5Ϫ4.7 (m, 2 H,
CHOϪCHN, NCHCOOtBu), 9.7 (s, 1 H, CHO).
(m,
6
H, CH2CH2, BocNϪCHCH2), 2.8 (m,
1
H,
BocNϪCHCH2CH), 3.3 (s, 3 H, COOCH3), 3.4 (dd, J ϭ 9.1 Hz,
J ϭ 5.9 Hz, 1 H, NCHCOOtBu), 4.45 (m, 1 H, BocNϪCH), 5.3
(br., 1 H, NHBoc). Ϫ 13C NMR (50.3 MHz, C6D6) (signals are
split due to amidic isomerism): δ ϭ 171.7, 171.5, 164.2, 164.0,
154.7, 154.3, 153.5, 136.6, 136.4, 135.8, 128.4, 128.3, 128.2, 128.1,
127.7, 126.2, 125.9, 125.8, 81.0, 87.1, 66.8, 66.6, 60.8, 60.4, 58.2,
57.5, 52.3, 52.2, 32.8, 31.9, 28.5, 28.1, 27.8, 27.7, 27.4, 27.1. Ϫ
FABϩMS: calcd. for C18H32N2O6 372.46; found 373.
Acrylic Ester 43: According to General Procedure A, compound
13 was subjected to the HornerϪEmmons reaction. The crude
product was purified by flash chromatography to afford the en-
amide (68%) as a colourless oil [diastereoisomeric ratio (Z)/(E) ϭ
1:1]. Ϫ 1H NMR (200 MHz, CDCl3) (signals are split due to amidic
isomerism and refer to the mixture of two diastereoisomers): δ ϭ
1.5 [s, 9 H, C(CH3)3], 1.6Ϫ2.45 (m, 4 H, CH2CH2), 3.75 (s, 3 H,
COOCH3), 4.6 (m, 1 H, NCHCOOtBu), 4.8 (dd, J ϭ 18 Hz, J ϭ
10 Hz, 1 H, ϭCHϪCHN), 5.12 (s, 2 H, CH2Ph), 6.3, 6.8 [2 d, J ϭ
10 Hz, 1 H, ϭCH of (Z) isomer, (E) isomer], 7.35 (m, 5 H, arom.).
Ϫ According to General Procedure B, the acrylic ester was N-Boc-
protected. The crude product was purified by flash chromatography
to afford 43 in 95% yield as a colourless oil. Ϫ 1H NMR (200 MHz,
C6D6) (signals are split due to amidic isomerism and refer to the
mixture of two diastereoisomers): δ ϭ 1.3, 1.5 [2 s, 18 H, C(CH3)3],
1.6Ϫ2.35 (m, 4 H, CH2CH2), 3.7 (s, 3 H, COOCH3), 4.6Ϫ4.8 (m,
2 H, NCHCOOtBu, ϭCHϪCHN), 5.25 (m, 2 H, CH2Ph), 7.0 (m,
1 H, ϭCH), 7.35 (m, 5 H, arom.). Ϫ 13C NMR (50.3 MHz, C6D6)
(signals are split due to amidic isomerism and refer to the mixture
of two diastereoisomers): δ ϭ 169.1, 163.9, 141.2, 136.1, 129.9,
128.4, 128.2, 127.4, 119.4, 113.7, 83.6, 82.5, 82.0, 68.8, 68.5, 68.2,
62.5, 60.9, 60.8, 58.5, 57.6, 56.8, 53.2, 51.9, 51.7, 51.6, 33.7, 31.8,
30.2, 27.7, 27.5, 26.9.
5,5-Fused Bicyclic Lactam 1: A stirred solution of 45 (3S) (0.028 g,
0.075 mmol) in p-xylene (1.5 mL) was heated to 130 °C for 24 h.
The solvent was then evaporated under reduced pressure and the
residue was purified by flash chromatography (hexane/ethyl acetate,
7:3) to yield 19 mg of 1 (74%) as a white foam. Ϫ [α]2D2 ϭ Ϫ4.8
(c ϭ 1.20, CHCl3). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.50, 1.51
[2 s, 18 H, C(CH3)3], 1.6Ϫ2.4 (m, 5 H, CH2CH2, BocNϪCHCHH),
2.95 (m, 1 H, BocNϪCHCHH), 3.85 (m, 1 H, CHϪN), 4.15 (d,
J ϭ 8.8 Hz, 1 H, NCHCOOtBu), 4.60 (m, 1 H, CHϪNBoc), 5.25
(br., 1 H, NH). Ϫ 13C NMR (50.3 MHz, CDCl3) (signals are split
due to amidic isomerism): δ ϭ 171.7, 169.7, 155.6, 81.8, 79.5, 58.8,
56.5, 56.0, 55.8, 39.5, 33.4, 29.5, 28.2, 27.8. Ϫ FABϩMS: calcd. for
C17H28N2O5 340.41; found 341.
5,5-Fused Bicyclic Lactam 7: Compound 7 was obtained from com-
pound 45 (3R) according to the same procedure as described for
the synthesis of 1. It was obtained in 65% yield as a white foam.
Ϫ [α]2D2 ϭ Ϫ4.8 (c ϭ 1.20, CHCl3). Ϫ 1H NMR (200 MHz, CDCl3):
δ ϭ 1.45 [2 s, 18 H, C(CH3)3], 1.5Ϫ2.5 (m, 6 H, CH2CH2,
Amino Ester 44: A (Z)/(E) mixture of 43 (0.609 g, 1.01 mmol) and
20% Pd(OH)2/C (0.054 g) in MeOH (10 mL) was stirred under hy-
drogen for 18 h. The catalyst was then removed by filtration
2580
Eur. J. Org. Chem. 2000, 2571Ϫ2581

Azabicycloalkane Amino Acid Scaffolds as Reverse-Turn Inducer Dipeptide Mimics
FULL PAPER
[5]
[5a]L. Colombo, M. Di Giacomo, C. Scolastico, L. Manzoni,
L. Belvisi, V. Molteni, Tetrahedron Lett. 1995, 36, 625Ϫ628. Ϫ
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Scolastico, Tetrahedron 1998, 54, 5325Ϫ5336.
BocNϪCHCH2), 4.05 (d, J ϭ 8.8 Hz, 1 H, NCHCOOtBu), 4.12
(m, 1 H, CHϪN), 4.25 (m, 1 H, CHϪNBoc), 5.05 (br., 1 H, NH).
Ϫ
13C NMR (50.3 MHz, CDCl3) (signals are split due to amidic
isomerism): δ ϭ 170.9, 169.8, 155.2, 82.2, 81.8, 79.9, 77.1, 61.2,
58.8, 57.6, 56.0, 55.8, 34.4, 33.8, 33.4, 29.9, 29.5, 29.2, 28.5, 28.1,
27.7. Ϫ FABϩMS: calcd. for C17H28N2O5 340.41; found 341.
[6]
[6a]L. Belvisi, A. Bernardi, L. Manzoni, D. Potenza, C. Scolas-
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Acknowledgments
This work was supported by the C.N.R., Progetto Strategico
‘‘Modellistica Computazionale di Sistemi Molecolari Complessi’’,
and MURST COFIN 1998Ϫ99 ‘‘Nuove Metodologie e Strategie di
Sintesi di Composti di Interesse Biologico’’.
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[11]
[12]
[13]
[14]
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M. Kahn (Ed.), ‘‘Peptide Secondary Structure Mimetics’’, Tet-
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references therein.
[3]
For a review, see: S. Hanessian, G. McNaughton-Smith, H.-G.
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[4]
[4a]H.-G. Lombart, W. D. Lubell, J. Org. Chem. 1996, 61,
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63, 5937Ϫ5949 and references therein for syntheses of azabicy-
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publication of ref.[3] See also: F. Gosselin, W. D. Lubell, J. Org.
Chem. 1998, 63, 7463Ϫ7471.
Received December 17, 1999
[O99680]
Eur. J. Org. Chem. 2000, 2571Ϫ2581
2581