New and Efficient Synthesis of Azabicyclo[4.4.0]alkane Amino Acids by Rh-Catalyzed Cyclohydrocarbonylation

Article abstract of DOI:10.1021/ol026782d

(Matrix Presented) Highly efficient syntheses of azabicyclo[4.4.0]alkane amino acids were achieved by Rh-catalyzed cyclohydrocarbonylation of dipeptides bearing a terminal olefin moiety and a heteroatom nucleophile.

Full text of DOI:10.1021/ol026782d

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4575-4578
New and Efficient Synthesis of
Azabicyclo[4.4.0]alkane Amino Acids by
Rh-Catalyzed Cyclohydrocarbonylation
Nobuhiro Mizutani,† Wen-Hua Chiou, and Iwao Ojima*
Department of Chemistry, State UniVersity of New York at Stony Brook,
Stony Brook, New York 11794-3400
iojima@notes.cc.sunysb.edu
Received August 24, 2002
ABSTRACT
Highly efficient syntheses of azabicyclo[4.4.0]alkane amino acids were achieved by Rh-catalyzed cyclohydrocarbonylation of dipeptides bearing
a terminal olefin moiety and a heteroatom nucleophile.
Recently, the importance of azabicyclo[X.Y.0]alkane amino
acids as conformationally restricted dipeptide surrogates has
been recognized among medicinal and peptide chemists in
the design of peptides and peptidomimetics for enzyme
inhibitors and receptor antagonists or agonists.1-9
Azabicyclo[X.Y.0]alkane amino acids also serve as peptide
â-turn mimetics for controlling peptide secondary struc-
tures.10,11 These scaffolds can also serve as excellent units
for making combinatorial libraries. Accordingly, efficient and
versatile methods for the syntheses of this class of com-
pounds are currently in strong demand. Various approaches
have been studied to develop relevant synthetic methods
toward this goal.1-3 However, to the best of our knowledge,
no synthetic route has been developed based on a catalytic
cyclization process.
We describe here the first and efficient catalytic method
for the syntheses of enantiomerically pure azabicyclo[4.4.0]-
alkane amino acids using highly regioselective cyclohydro-
carbonylation catalyzed by a Rh-diphosphite complex.
We have reported12 that the cyclohydrocarbonylation of
N-acylallylglycinate catalyzed by Rh-BIPHEPHOS proceeds
via extremely regioselective hydroformylation, followed by
cyclization to form the corresponding hemiamidal. This
hemiamidal readily generates N-acyliminium ion, which may
accept the addition of an alcohol (in alcohol solvent) or
isomerize to N-acylenamine (in aprotic solvent).11 Accord-
ingly, if a nucleophile is located within the substrate, a second
cyclization should occur via the N-acyliminium intermediate
as shown in Scheme 1.13
† Present address: Tokyo Research Laboratory, Yuki Gosei Kogyo Co.
Ltd., 3-37-1 Sakashita, Itabashi, Tokyo 174-0043, Japan.
(1) Polyak, F.; Lubell, W. D. J. Org. Chem. 1998, 63, 5937-5949.
(2) Lombart, H.-G.; Lubell, W. D. J. Org. Chem. 1994, 59, 6147-6149.
(3) Lombart, H.-G.; Lubell, W. D. J. Org. Chem. 1996, 61, 9437-9446.
(4) Gosselin, F.; Lubell, W. D. J. Org. Chem. 2000, 65, 2163-2171.
(5) Siddiqui, M. A.; Pre´ville, P.; Tarazi, M.; Warder, S. E.; Eby, P.;
Gorseth, E.; Puumala, K.; DiMaio, J. Tetrahedron Lett. 1997, 38, 8807-
8810.
(6) Kim, H.-O.; Kahn, M. Tetrahedron Lett. 1997, 38, 6483-6484.
(7) Robl, J. A.; Sun, C.-Q.; Srevenson, J.; Ryono, D. E.; Simpkins, L.
M.; Cimarusti, M. P.; Dejneka, T.; Slusarchyk, W. A.; Chao, S.; Stratton,
L.; Misra, R. N.; Bednarz, M. S.; Asaad, M. M.; Cheung, H. S.; Abboa-
Offei, B. E.; Smith, P. L.; Mathers, P. D.; Fox, M.; Schaeffer, T. R.;
Seymour, A. A.; Trippodo, N. C. J. Med. Chem. 1997, 40, 1570-1577.
(8) Tran, T.-A.; Mattern, R.-H.; Goodman, M. Bioorg. Med. Chem. Lett.
1997, 7, 997-1002.
(11) Colombo, L.; Giacomo, M. D.; Brusotti, G.; Sardone, N.; Angiolini,
M.; Belvisi, L.; Maffioli, S.; Manzoni, L.; Scolastico, C. Tetrahedron 1998,
54, 5325-5336.
(12) Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J. Org. Chem. 1995, 60,
7078-7079.
(9) Baures, P. W.; Ojala, W. H.; Costain, W. J.; Ott, M. C.; Pradhan,
A.; Gleason, W. B.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1997,
40, 3594-3600.
(10) Kim, H.-O.; Lee, M. S. Tetrahedron Lett. 1997, 38, 4935-4938.
10.1021/ol026782d CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/02/2002

did not occur, but gave aldehyde 2a in 94% yield. The
cyclization also did not take place in the presence of a small
amount of 4-(dimethylamino)pyridine (DMAP) even when
toluene was used as the solvent. On the contrary, addition
of a catalytic amount of p-toluenesulfonic acid (PTSA)
accelerated the cyclization to give (S,S,S)-5a in 96% yield.
In the same manner, the reaction of (S,R)-1a in toluene in
the presence of PTSA gave (S,R,R)-5a as the single product
in 90% yield (Scheme 2). The stereochemistry of the newly
formed bridgehead position C-6 of (S,S,S)-5a as well as
(S,R,R)-5a was determined by NOESY analyses.
Scheme 1
In the reaction of dipeptide (S,S)-1b bearing a â-ami-
noalanine (BAA)15 moiety, the cyclization did not occur in
the absence of PTSA as shown in Scheme 3. The reaction
As Scheme 2 illustrates, the cyclohydrocarbonylation of
Boc-(S)-Ser-(S)-(allyl)Gly-OMe [(S,S)-1a] catalyzed by
Scheme 3a
Scheme 2a
a Reagents and conditions: (i) Rh(acac)(CO)2 (2 mol %),
BIPHEPHOS (4 mol %), H2 (2 atm), CO (2 atm), PTSA (10 mol
%), toluene, 65 °C, 20 h; (ii) same as (i), but without PTSA.
afforded linear aldehyde 2b (52%) and N-acylenamine 6
(48%). The latter product 6 was formed by dehydration of a
hemiamidal intermediate 3 via N-acyliminium intermediate
4. This indicates that the nucleophilic addition of the Boc-
amino group to the iminium bond does not compete with
isomerization of 4, resulting in the formation of acylinamine
6 under neutral conditions. In fact the reaction proceeded
efficiently in the presence of PTSA to give (S,S,S)-5b as the
single product in 95% yield (Scheme 3). The (3S,6S,10S)
stereochemistry of 5b was determined by X-ray crystal-
lographic analysis (Figure 1). It should be noted that no
1-azabicyclo[4.3.0] product was formed although either Boc-
amino group in the BAA residue could react with the
acyliminium intermediate 4 (R ) Boc, X ) BocN).
a Reagents and conditions: Rh(acac)(CO)2 (2 mol %), BIPHEP-
HOS (4 mol %), H2 (2 atm), CO (2 atm), 65 °C, 20 h; (i) toluene;
(ii) toluene, PTSA (10 mol %); (iii) toluene, DMAP (10 mol %);
(iv) THF.
Rh(acac)(CO)2-BIPHEPHOS proceeded smoothly in toluene
under mild conditions (CO/H2 1/1, 4 atm, 60 °C). The
generated aldehyde cyclized spontaneously in situ to afford
the bicyclic dipeptide (S,S,S)-5a as the single product in 93%
yield.14 When the reaction was run in THF the cyclization
In the case of a dipeptide substrate bearing a cysteine
moiety, an S-trityl derivative was used to avoid undesirable
(13) Jackson et al. reported a facile bicyclization of an alkenyldiamine
under classical hydroformylation conditions. This reaction is likely to
proceed thorough an iminium ion intermediate. See: Campi, E. M.; Jackson,
W. R.; McCubbin, Q. J.; Trnacek, A. E. Aust. J. Chem. 1994, 47, 1061-
1070.
(14) Typical procedure: In a 10-mL round-bottomed flask was placed
dipeptide 1 (0.100 mmol) in 2 mL of toluene under N2. In a 25-mL reaction
vessel were placed Rh(acac)(CO)2 (0.5 mg, 2.0 µmol) and BIPHEPHOS
(3 mg, 4 µmmol), and toluene (1 mL) was added by syringe under N2. The
catalyst mixture was stirred until it became a homogeneous solution. Then,
the substrate solution was transferred to the catalyst solution via syringe.
The reaction vessel was placed in a 300-mL stainless steel autoclave. The
autoclave was flushed with CO several times then filled with 2 atm of CO
and 2 atm of H2. The autoclave was immersed into an oil bath that was
maintained at 60-65 °C and kept for 20 h with magnetic stirring. Then,
the autoclave was cooled to room temperature and pressure was slowly
released. Solvent was evaporated to give a viscous oil, which was purified
by flash chromatography on silica gel to give 5.
(15) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Ohno, M. Chem.
Pharm. Bull. 1985, 33, 509.
4576
Org. Lett., Vol. 4, No. 26, 2002

Scheme 5
useful insight into the mechanism of cyclization in this
process.
Figure 1. Single-crystal X-ray structure of (S,S,S)-5b.
S-S bond formation as well as possible deactivation of an
active catalyst species during the reaction (Scheme 4). Since
the thiol group is protected, a spontaneous cyclization cannot
take place, which is likely to lead the reaction to undesirable
N-acylenamine formation (see 6 in Scheme 3). Accordingly,
the reaction of S-Tr-N-Cbz-(S)-Cys-(S)-(allyl)Gly-OMe [(S,S)-
1c] was carried out in MeOH to trap the resulting aldehyde
moiety by converting it in situ to the corresponding acetal
(Scheme 4). The reaction of (S,S)-1c in MeOH was run under
the standard conditions to give acetal 7 in high yield. The
subsequent deprotection-cyclization with a catalytic amount
of trifluoroacetic acid (TFA) afforded bicyclic dipeptide
(S,S,S)-5c in 89% isolated yield (Scheme 4).
Figure 2. Single-crystal X-ray structure of (R,R,S)-8.
As Scheme 6 illustrates, the extremely diastereoselective
cyclization of (S,S)-2a and (S,R)-2a, generating a new chiral
Scheme 6
Scheme 4a
a Reagents and conditions: (i) Rh(acac)(CO)2 (2 mol %),
BIPHEPHOS (4 mol %), H2 (2 atm), CO (2 atm), MeOH, 65 °C,
20 h; (ii) TFA (cat.), CH2Cl2, rt, 30 min.
In the same manner, the reaction of S-Tr-N-phthalyl-(S)-
Cys-(S)-(allyl)Gly-OMe [(S,S)-1d] was carried out under the
same conditions to afford the corresponding bicyclic dipep-
tide 8 (60% isolated yield for 2 steps) (Scheme 5).
To our surprise, however, the X-ray crystallographic
analysis revealed that the product 8 possesses (3R,6R,10S)
stereochemistry as shown in Figure 2, i.e., epimerization of
the N-phthalylserine moiety took place. This result provides
Org. Lett., Vol. 4, No. 26, 2002
4577

center at the bridgehead C-6 position in (S,S,S)-5a and
(S,R,R)-5a, can be nicely explained by taking into account
the A1,3-strain in the N-acyliminium intermediate 4 at the
cyclization step. It is very clear that the C-2 position of the
pipecolate moiety serves as the stereogenic center, which
takes an axial position to avoid the A1,3-strain, in the
transition state of the cyclization. Thus, the S and R
configurations are exclusively induced at the C-6 position
of 5a from S-pipecolate (pro-6S-4) and R-pipecolate (pro-
6R-4), respectively. Naturally, the formations of (S,S,S)-5b
and (S,S,S)-5c should have followed the pro-6S-4 pathway.
As Figure 1 implies, flipping of the quasi-chair-chair
bicyclic framework of 5 takes place to accommodate the most
favorable conformation during or after the cyclization.
Scheme 7
In the case of the formation of bicyclic dipeptide 8, it is
reasonable to assume that the rigid and bulky phthalimido
group blocks the pro-1S-4 approach of the N-phthalimido-
cystein moiety, leading to the formation of S configuration
at the C-6 position, i.e., pro-6R-4-(S)-Cys approach (Scheme
7). At this stage, it is obvious that the axial phthalimido group
is sterically very unfavorable. Thus, epimerization at the C-3
position, which has an acidic hydrogen, takes place to make
the phthalimido group equatorial, yielding (R,R,S)-8 as the
sole product. Another possibility is that the stereochemistry
of the N-phthalyl-cystein moiety is flexible due to rapid
epimerization or enol formation under the reaction conditions
and only the (R)-Cys-isomer undergoes cyclization via the
pro-6R-4-(R)-Cys pathway (Scheme 7).
through extremely diastereoselective cyclization of N-
acyliminium intermediates 4 wherein the C-2 position of the
pipecolate moiety in 4 serves as the stereogenic center.
Plausible mechanisms for the extremely stereoselective
cyclization step are proposed. Further studies on the scope
and applications of this method are actively underway in
these laboratories.
Acknowledgment. This work was supported by a grant
from the National Institutes of Heath (NIGMS). The authors
would like to thank Prof. Joseph W. Lauher for the X-ray
crystallographic analyses.
Supporting Information Available: The characterization
data of compounds 5 and 8, as well as the X-ray crystal-
lographic analysis data for (S,S,S)-5b and (R,R,S)-8. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, a new and highly efficient catalytic method
for the syntheses of azabicyclo[4.4.0]alkane amino acids 5
has been developed by means of Rh-catalyzed cyclohydro-
carbonylation of dipeptides 1 bearing a terminal olefin
moiety. This method provides enantiomerically pure product
OL026782D
4578
Org. Lett., Vol. 4, No. 26, 2002