Highly efficient synthesis of azabicyclo[x.y.0]alkane amino acids and congeners by means of Rh-catalyzed cyclohydrocarbonylation

Article abstract of DOI:10.1021/jo061692y

A highly efficient method for the synthesis of 1-azabicyclo[x.y.0]alkane amino acid derivatives and their congeners by means of extremely regioselective cyclohydrocarbonylation (CHC) is described. The CHC reactions are catalyzed by Rh-BIPHEPHOS complex un

Full text of DOI:10.1021/jo061692y

VOLUME 72, NUMBER 6
MARCH 16, 2007
© Copyright 2007 by the American Chemical Society
Highly Efficient Synthesis of Azabicyclo[x.y.0]alkane Amino Acids
and Congeners by Means of Rh-Catalyzed Cyclohydrocarbonylation
Wen-Hua Chiou, Nobihiro Mizutani, 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 14, 2006
A highly efficient method for the synthesis of 1-azabicyclo[x.y.0]alkane amino acid derivatives and their
congeners by means of extremely regioselective cyclohydrocarbonylation (CHC) is described. The CHC
reactions are catalyzed by Rh-BIPHEPHOS complex under mild conditions. These CHC reaction processes
involve (i) an extremely linear-selective hydroformylation of the terminal alkene moiety of a
dehydrodipeptide substrate, (ii) intramolecular condensation to form cyclic N-acyliminium key intermediate,
and (iii) the second cyclization through intramolecular nucleophilic addition of a heteoatom nucleophile
to the cyclic N-acyliminium moiety to afford the corresponding 1-azabicyclo[x.y.0] system. This
consecutive double cyclization process proceeds with extremely high diastereoselectivity in most cases.
This method has been successfully applied to the syntheses of 1-azabicyclo[4.4.0], -[5.4.0], and -[4.3.0]
systems. The mechanisms of the reactions and the rationale for the observed extremely high
diastereoselectivity are presented. This Rh-catalyzed CHC process would serve as a highly efficient and
versatile method for the syntheses of a variety of conformationally restrained dipeptides, peptidomimetics,
alkaloids, and other biologically active natural or unnatural products.
Introduction
be used to restrain the backbone geometry and side-chain
conformations of the native peptide to investigate the structure-
activity relationships.6,7 As these restrained dipeptide scaffolds
possess spatially defined substituents at both N and C terminal
positions, azabicyclo[x.y.0]alkane amino acids provide versatile
templates for generating combinatorial libraries for drug dis-
covery.8,9 Furthermore, it has been shown that these â-turn
Azabicyclo[x.y.0]alkane amino acids1,2 are highly useful
synthetic building blocks in the rational design and synthesis
of peptidomimetics because these dipeptide surrogates serve as
a conformationally fixed scaffold of â-turn (type II) secondary
structures of peptides,3-5 which are commonly found in biologi-
cally active peptides. These unique heterocyclic frameworks can
(1) Cluzeau, J.; Lubell, W. D. Pept. Sci. 2005, 80, 98-150.
(6) Sato, K.; Nagai, U. J. Chem. Soc., Perkin Trans. 1 1986, 1231-
1234.
(2) Maison, W.; Prenzel, A. H. G. P. Synthesis 2005, 1031-1048.
(3) Hanessian, S.; Laoui, B. R. Bioorg. Med. Chem. Lett. 1994, 4, 1397-
(7) Haubner, R.; Schmitt, W.; Ho¨lzemann, G.; Goodman, S. L.; Jonczyk,
A.; Kessler, H. J. Am. Chem. Soc. 1996, 118, 7881-7891.
(8) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W.
D. Tetrahedron 1997, 53, 12789-12854.
(9) Falorni, M.; Giacomelli, G.; Nieddu, F.; Taddei, M. Tetrahedron Lett.
1997, 38, 4663-4666.
1400.
(4) Genin, M. J.; Johnson, R. L. J. Am. Chem. Soc. 1992, 114, 8778-
8783.
(5) Gramberg, D.; Robinson, J. A. Tetrahedron Lett. 1994, 35, 861-
864.
10.1021/jo061692y CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/17/2006
J. Org. Chem. 2007, 72, 1871-1882
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Chiou et al.
SCHEME 1. Representative Routes to Azabicyclo[x.y.0]alkane Amino Acids
mimics are very useful for the development of efficient enzyme
inhibitors and receptor agonists or receptor antagonists. For
example, 1-azabicyclo[5.4.0]- and 1-azabicyclo[5.3.0]alkane
amino acid derivatives have been successfully developed as
potent inhibitors of angiotensin-converting enzyme, neutral
endopeptidase, atrial natriuretic peptide, and enkephalinase.10-13
To obtain a variety of azabicyclo[x.y.0]alkane amino acids
for drug design, discovery, and development, it is essential to
secure efficient methods for the syntheses of these compounds.
Accordingly, various approaches have been investigated. These
synthetic routes to 1-azabicyclo[x.y.0]alkane amino acids bearing
a heteroatom in addition to the bridgehead nitrogen can be
categorized as follows: (1) cyclic amine formation through an
imine intermediate followed by lactam formation,14-20 (2) cyclic
acyliminium formation followed by a second cyclization,11,21-23
and (3) electrochemical cyclization by anodic oxidation of the
prolinyl dipeptides (Scheme 1).24-26 An aldehyde or acetal group
at the terminus of the side chain of an amino acid or amino
acid residue is necessary in Routes 1 and 2 for construction of
the bridging carbon-nitrogen bond. Route 1 only affords the
azabicycles in which the heteroatom is located at the C-terminus.
Route 2 is a versatile way to azabicyclic compounds. The
heteroatom can be either at the N-terminus or at the C-terminus.
The critical issue for this route is the introduction of the aldehyde
group. Route 3 is confined to the azabicyclo[x.3.0] system.
Consequently, Route 2 appears to be the most flexible and
versatile synthetic strategy.
For Route 2 synthesis, the preparation of dipeptide derivatives
bearing an aldehyde group in one of the amino acid residues
and a free heteroatom nucleophile in the other amino acid
residue is essential, but challenging. However, if we can use a
masked aldehyde and generate the reactive aldehyde functional-
ity in situ, it would solve this challenging problem associated
with Route 2. To this end, a terminal olefin would serve as the
masked aldehyde since it can be converted to the terminal
aldehyde through linear selective Rh-catalyzed hydroformylation
under neutral conditions. In fact, we reported that the Rh-
catalyzed cyclohydrocarbonylation (CHC)23,27-32 of N-acylal-
lylglycinate proceeded via extremely regioselective hydroformy-
lation, followed by cyclization to form the corresponding
hemiamidal.28 This hemiamidal readily generated N-acyliminium
ion that accepted the addition of an alcohol (in alcohol solvent)
or isomerized to N-acylenamine (in aprotic solvent).28 Accord-
ingly, if a nucleophile is located within the substrate, the second
cyclization should occur via N-acyliminium intermediate.33 We
explored this idea and indeed succeeded in the rapid construction
of 1-azabicyclo[4.4.0]decane amino acids with perfect stereo-
chemical control at the bridgehead position through the ex-
tremely regioselective Rh-catalyzed CHC process and commu-
nicated the first examples of the catalytic cyclization approach
to this class of compounds.23 We describe here a full account
(10) Robl, J. A.; Cimarusti, M. P.; Simpkins, L. M.; Brown, B.; Ryono,
D. E.; Bird, J. E.; Asaad, M. M.; Schaeffer, T. R.; Trippodo, N. C. J. Med.
Chem. 1996, 39, 494-502.
(11) Robl, J. A.; Sun, C.-Q.; Stevenson, 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.
(12) Fink, C. A.; Carlson, J. E.; McTaggart, P. A.; Qiao, Y.; Webb, R.;
Chatelain, R.; Jeng, A. Y.; Trapani, A. J. J. Med. Chem. 1996, 39, 3158-
3168.
(13) Flynn, G. A. PCT Int. Appl. WO 9410193 A1, 1994.
(14) Tamura, S. Y.; Goldman, E. A.; Brunck, T. K.; Ripka, W. C.;
Semple, J. E. Bioorg. Med. Chem. Lett. 1997, 7, 331-336.
(15) Wagner, J.; Kallen, J.; Ehrhardt, C.; Evenou, J.-P.; Wagner, D. J.
Med. Chem. 1998, 41, 3664-3674.
(16) Nagai, U.; Sato, K. Tetrahedron Lett. 1985, 26, 647-650.
(17) Nagai, U.; Sato, K.; Nakamura, R.; Kato, R. Tetrahedron 1993, 49,
3577-3592.
(18) 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.
(26) Slomczynska, U.; Chalmers, D. K.; Cornille, F.; Smythe, M. L.;
Beusen, D. D.; Moeller, K. D.; Marshall, G. R. J. Org. Chem. 1996, 61,
1198-1204.
(27) Ojima, I.; Korda, A.; Shay, W. R. J. Org. Chem. 1991, 56, 2024-
2030.
(19) Akasaka, K.; Komatsu, Y.; Tagami, K.; Shimizu, T.; Shimomura,
N.; Naka, H.; Hayashi, K.; Negi, S. Chem. Pharm. Bull. 1999, 47, 1532-
1537.
(20) Estiarte, M. A.; Rubiralta, M.; Diez, A. J. Org. Chem. 2000, 65,
6992-6999.
(28) Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J. Org. Chem. 1995, 60,
7078-7079.
(21) Robl, J. A. Tetrahedron Lett. 1994, 35, 393-396.
(22) Baldwin, J. E.; Hulme, C.; Schofield, C. J.; Edwards, A. J. J. Chem.
Soc., Chem. Commun. 1993, 11, 935-936.
(29) Ojima, I.; Vidal, E. S. J. Org. Chem. 1998, 63, 7999-8003.
(30) Ojima, I.; Iula, D. M.; Tzamarioudaki, M. Tetrahedron Lett. 1998,
39, 4599-4602.
(23) Mizutani, N.; Chiou, W.-H.; Ojima, I. Org. Lett. 2002, 4, 4575-
4578.
(24) Cornille, F.; Fobian, Y. M.; Slomczynska, U.; Beusen, D. D.;
Marshall, G. R.; Moeller, K. D. Tetrahedron Lett. 1994, 35, 6989-6992.
(25) Cornille, F.; Slomczynska, U.; Smythe, M. L.; Beusen, D. D.;
Moeller, K. D.; Marshall, G. R. J. Am. Chem. Soc. 1995, 117, 909-917.
(31) Ojima, I. Pure Appl. Chem. 2002, 74, 159-166.
(32) Ojima, I.; Bonafoux, D.; Lee, S.-Y. In Encyclopedia of Catalysis;
Horvath, I. T., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2003; Vol. 2,
pp 706-766.
(33) Campi, E. M.; Jackson, W. R.; McCubbin, Q. J.; Trnacek, A. E.
Aust. J. Chem. 1994, 47, 1061-1071.
1872 J. Org. Chem., Vol. 72, No. 6, 2007

Synthesis of Azabicyclo[x.y.0]alkane Amino Acids
SCHEME 2. One-Step Synthesis of 1-Azabicyclo[x.y.0]alkane Amino Acids through Rh-Catalyzed Cyclohydrocarbonylation
(CHC)
SCHEME 3. CHC of (S,S)-1a and (S,R)-1aa
of our work on the scope of this highly efficient catalytic
bicyclization process as well as the stereochemical issues of
the process.
Results and Discussion
1-Azabicyclo[x.y.0] systems can be constructed in one step
through Rh-catalyzed cyclohydrocarbonylation (CHC) that
induces a cascade double cyclization process as shown in
Scheme 2. Extremely regioselective hydroformylation of de-
hydrodipeptide derivative 1 catalyzed by a Rh-BIPHEPHOS34
complex gives linear aldehyde 2 exclusively, which is followed
by the first cyclization to yield the corresponding hemiamidal
3. After the conversion of hemiamidal 3 to N-acyliminium ion
4, the second cyclization through addition of an intramolecular
nucleophile to 4 takes place to furnish azabicyclic product 5.
The substrates of this process, dipeptide derivatives 1a-j,
were readily synthesized from the corresponding enantiopure
N-protected amino acids (i.e., serine, cysteine, homoserine,
a Reagents and conditions: Rh(acac)(CO)2 (2 mol %), BIPHEPHOS (4
mol %), H2 (2 atm), CO (2 atm), 65 °C, 20 h; (i) toluene; (ii) toluene,
â-aminoalanine,35 homocysteine, threonine, and allo-threonine)
and enantiopure amino acids or amines (methyl allylglycinate,
allylglycinol benzyl ether, methyl vinylglycine, vinylglycinol
benzyl ether,36 and 3-aminobutene) under the standard peptide
coupling conditions, i.e., EDC, HOBt, and Et3N (only when
hydrochloride was used) in CH2Cl2.
PTSA (10 mol %); (iii) toluene, DMAP (10 mol %); (iv) THF.
of PTSA as additive was considered to be optimal based on
these results. Thus, the standard reaction conditions for the
cyclohydrocarbonylation of 1a-j were set to be the use of Rh-
(acac)(CO)2-BIPHEPHOS catalyst at 60 °C and 4 atm of H2
and CO (1:1) in toluene and a catalytic amount (10%) of PTSA.
The CHC reactions of 1a-j were carried out with the Rh-
(acac)(CO)2-BIPHEPHOS catalyst under mild conditions (H2:
CO ) 1:1, 4 atm, 60 °C). To find the optimal reaction
conditions, solvents and additives were examined in the reactions
of Boc-(S)-Ser-(S)-(allyl)Gly-OMe [(S,S)-1a] (Scheme 3). The
reaction of (S,S)-1a proceeded in toluene smoothly to afford
the bicyclic dipeptide (3S,6S,10S)-5a as the single product in
96% yield. When the reaction was run in THF the cyclization
did not occur, but gave aldehyde (S,S)-2a in 94% yield, which
confirms that the first step in this process is indeed the extremely
linear-selective hydroformylation of the olefin moiety of (S,S)-
1a. 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 (3S,6S,10S)-5a in 96% yield. Conse-
quently, the use of toluene as the solvent and a catalytic amount
The reaction of (S,R)-1a in toluene in the presence of PTSA
gave (3S,6R,10R)-5a as single product in 90% yield (Scheme
3). Stereochemistry of the newly formed bridgehead position
C-6 of (S,S,S)-5a as well as (S,R,R)-5a was determined by
ROESY analyses. The results indicate that the chiral center in
the C-terminus, i.e., the C-10 position, is the stereogenic center
for the second cyclization that determines the stereochemistry
at the bridgehead carbon (C-6).
In the same manner, the reaction of Boc-(S)-Ser-(S)-O-benzyl-
(allyl)glycinol (S,S)-1b, bearing a CH2OBn group in place of a
CO2Me group at C-10, was carried out to give azabicyclic
product (S,R,S)-5b in 82% yield, while the reaction of the other
diastereomer (R,S)-1b gave (3R,6R,10S)-5b in 80% yield
(Scheme 4). Stereochemistry of the products was unambiguously
assigned on the basis of NOESY analysis. In both cases, the
formation of a small amount of noncyclized acylenamine, (S,S)-
6b or (R,S)-6b, was observed. These side products are formed
by deprotonation-isomerization of the acyliminium intermediate
4 (see Scheme 2) prior to the second cyclization via a
nucleophilic addition of the hydroxyl moiety to 4.
(34) Billig, E.; Abatjoglou, A. G.; Bryant, D. Union Carbide, US 476498,
1988.
(35) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.;
Ohno, M. Chem. Pharm. Bull. 1985, 33, 509.
(36) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N. Synthesis
1994, 1, 31-33.
J. Org. Chem, Vol. 72, No. 6, 2007 1873

Chiou et al.
SCHEME 4. CHC of (S,S)-1b and (R,S)-1ba
SCHEME 6. CHC of 1da
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.
SCHEME 7. CHC of 1ea
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.
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.
SCHEME 5. CHC of 1ca
of active catalyst species during the reaction (Schemes 7 and
8). 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 Schemes 4 and
6). To circumvent this problem, we designed to carry out the
reaction in MeOH to trap the resulting aldehyde moiety by
converting it in situ to the corresponding acetal. Moreover, the
Boc protection is not stable under the acidic conditions required
to remove the trityl (Tr) group. Thus, the N-Boc group should
be replaced with a carbobenzoxy (Cbz) group. Consequently,
we prepared N-Cbz-S-Tr dipeptides (R,S)-1e and (S,S)-1f as
substrates for the two-step bicyclization process.
The reaction of S-Tr-N-Cbz-(R)-Cys-(S)-(allyl)Gly-OMe [(R,S)-
1e] was carried out in MeOH under the standard conditions,
which was supposed to give the dimethylacetal of 2e. However,
to our surprise, the reaction gave 2e in 86% yield (Scheme 7).
The subsequent deprotection-cyclization with a catalytic
amount of trifluoroacetic acid (TFA) afforded azabicyclic
product (3R,6S,10S)-5e in 89% isolated yield (Scheme 7). The
(3R,6S,10S) stereochemistry of 5e was determined by NOESY
analysis, which is consistent with the case of (3S,6S,10S)-5a
from (S,S)-1a (Scheme 2).
1-Aza-6-thiabicyclo[5.4.0]undecane amino acid derivative
(3S,7S,11S)-5f was also synthesized from N-Cbz-S-Tr-(S)-homo-
Cys-(S)-(allyl)Gly-OMe [(S,S)-1f] in the same manner in 84%
yield for two steps (Scheme 8). It may be worthy of note that
this azabicyclo[5.4.0] framework is the core part of Omapat-
rilat,11 an efficacious ACE inhibitor developed by the Bristol-
Myers Squibb company. The stereochemistry of (3S,7S,11S)-
5f was determined by NOESY and NOE difference analyses.
We also examined the effect of another chiral center at the
side chain of an amino acid residue of unsaturated dipeptide
substrates on the stereochemistry of the second cyclization by
introducing threonine isomers at the N-terminus. The reaction
of Boc-(L)-Thr-(S)-(allyl)Gly-OMe (S,R,S)-1g under the standard
conditions afforded a single azabicyclic product (3S,4R,6S,10S)-
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.
These results confirm that the C-10 position in the C-terminus
is the stereogenic center. However, the results also have revealed
that the stereochemistry induced at the bridgehead (C-6) position
in 1b is opposite to that in 1a, which indicates that the nature
of the substituent at the C-10 position exerts a critical effect on
the direction of the second cyclization, generating the bridgehead
carbon in the azabicyclic product 5.
This process is readily applicable for the construction of the
1-azabicyclo[5.4.0] system. Thus, the reaction of Boc-(S)-homo-
Ser-(S)-(allyl)Gly-OMe [(S,S)-1c] under the standard conditions
afforded (3S,7S,11S)-5c in 87% yield (Scheme 5).
Next, we examined a carbamate group as internal nucleophile
to trap the N-acyliminium intermediate 4. Thus, the reaction of
unsaturated dipeptide (S,S)-1d, bearing a â-aminoalanine35
moiety, proceeded efficiently under the standard conditions to
give (3S,6S,10S)-5d as the single product in 95% yield (Scheme
6). The (3S,6S,10S) stereochemistry of 5d was determined by
X-ray crystallographic analysis (see Figure S1, Supporting
Information), which is consistent with the case of (3S,6S,10S)-
5a from (S,S)-1a (Scheme 2). It should be noted that no
1-azabicyclo[4.3.0] product was formed in spite of the fact that
either of the Boc-amino groups in the â-aminoalanine residue
could have reacted with the acyliminium intermediate 4d (R )
Boc, X ) BocN).
In the case of unsaturated dipeptide substrates bearing a
cysteine moiety, an S-trityl derivative was used to avoid
undesirable S-S bond formation as well as possible deactivation
1874 J. Org. Chem., Vol. 72, No. 6, 2007

Synthesis of Azabicyclo[x.y.0]alkane Amino Acids
SCHEME 8. CHC of 1fa
the threonine side chain are very close to the reacting hydroxyl
group in the second cyclization. This also means that the three
chiral centers at the allylglycine residue and the (L)-threonine
side chain both happen to be inducing S configuration at the
bridgehead carbon in the reaction of (S,R,S)-1g. The predominant
effect of the stereogenic centers at the threonine side chain is
also observed in the reactions of Boc-(L)-allo-Thr-(S)-(allyl)-
Gly-OMe (S,S,S)-1g and Boc-(DL)-Thr-(S)-(allyl)Gly-OMe (R,S,S)-
1g. The reaction of (S,S,S)-1g gave a mixture of two azabicyclic
products, (3S,4S,6S,10S)-5g (major, 69% yield) and (3S,4S,6R,-
10S)-5g (minor, 17% yield), while the reaction of (R,S,S)-1g
afforded two diastereomeric products, (3R,4S,6R,10S)-5g (major,
78% yield) and (3R,4S,6S,10S)-5g (minor, 10% yield) (Scheme
9).
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) MeSO3H
(1%), Ch2Cl2, 30 °C, 1 h and then Et3SiH (2 equiv) in TFA.
In these cases, the three stereogenic centers at the threonie
side chain and the allylglycine residue have a conflicting effect
on the direction of the second cyclization, but the stereogenic
centers at the threonine side chain exert a predominant role.
These results also indicate that the Boc-NH group at the C-3
position has a critical effect on the direction of the second
cyclization (vide infra).
SCHEME 9. CHC Reaction of 1ga
The CHC of unsaturated dipeptides, bearing a vinlyglycine
residue in place of an allylglycine residue, was challenging due
to the inherent instability of the vinylglycine residue, which is
prone to isomerize to the corresponding conjugated ethylene-
glycine residue. In fact, the reaction of Boc-(S)-Ser-(S)-(vinyl)-
Gly-OMe [(S,S)-1h] under the standard conditions afforded a
mixture of azabicyclic products, (3S,6S,9S)-5h (major, 48%
yield) and (3S,6S,9R)-5h (minor, 21% yield), accompanied by
noncyclized dipeptide (S)-7h, in 21% yield (Scheme 10). The
reaction of (R,S)-1h also gave a mixture of (3R,6R,9S)-5h
(major, 42% yield) and (3R,6R,9R)-5h (minor, 16% yield),
accompanied by (R)-7h in 23% yield (Scheme 10). Then it was
found, unexpectedly, these four distereomeric azabicyclic
products 5h were comprised of two pairs of enantiomers on
the basis of the facts that a pair of 5h showed the identical NMR
spectra and the same [R]D value but with opposite signs. The
structures of one pair of enantiomers, (3S,6S,9R)-5h and
(3R,6R,9S)-5h, were confirmed by X-ray crystallography (see
Figures S2 and S3, Supporting Information). Thus, the other
pair of enantiomers, (3S,6S,9S)-5h and (3R,6R,9R)-5h, were also
unambiguously assigned.
The results clearly show that partial epimerization took place
at the C-9 position of the product during the reaction. Since it
is highly unlikely that the epimerization occurs after the
formation of the azabicyclic skeleton 5h, the epimerization
should have happened during the hydroformylation step or at
the N-acyliminium intermediate stage. For the formation of
noncyclized dipeptides 7h, there are two possible pathways, i.e.,
(a) via hydroformylation of the vinylglycinate residue as a result
of low regioselectivity and (b) via hydroformylation of the
ethylideneglycinate residue generated in situ by double bond
migration. Judging from the fact that no branched aldehyde
formation was observed when the electron-withdrawing ester
group was replaced with a benzyloxymethyl or a methyl group
(substrate 1i or 1j, vide infra), the possible pathway (b) is most
likely to be the case.
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, 10
h.
5g in 85% yield (Scheme 9). This result alone appears to imply
that the additional chiral center does not have any influence on
the second cyclization and the stereogenic center is still the one
at the C-10 position in the same manner as that observed for
1a (Scheme 2). However, the reaction of Boc-(D)-allo-Thr-(S)-
(allyl)Gly-OMe (R,R,S)-1g gave (3R,4R,6R,10S)-5g as the
exclusive product in 94% yield (Scheme 9). This result clearly
indicates that the chiral centers at the side chain of the D-allo-
threonine residue serve as the stereogenic centers in the second
cyclization. This result makes sense since the chiral centers at
As described above, the use of a vinylglycine residue in
unsaturated dipeptide substrates causes complications. Accord-
ingly, we replaced the vinylglycine residue with O-protected
vinylglycinol residue to circumvent the problem. In fact, the
reaction of Boc-(S)-Ser-(R)-(O-benzyl)Glycinol [(S,R)-1i] under
J. Org. Chem, Vol. 72, No. 6, 2007 1875

Chiou et al.
SCHEME 10. CHC to of 1ha
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.
SCHEME 11. CHC of 1ia
SCHEME 12. CHC of 1ja
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
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.
h.
the standard conditions afforded the corresponding azabicyclo-
[4.3.0] product (3S,6S,9R)-5i exclusively in 87% isolated yield
(Scheme 11). However, reaction of the other diasteromer
substrate (R,R)-1i gave a nearly 1:1 mixture of (3R,6R,9R)-5i
and (3R,6S,9R)-5i in 83% combined yield although no formation
of other side products was observed (Scheme 11). The results
indicate that the chiral centers at the N-terminus as well as at
the C-terminus are stereogenic centers in these reactions, and
(S,R)-1i is a matching pair while (R,R)-1i is a mismatching pair.
As already observed in the reactions of 1b (Scheme 4), the
directing effect of the PhCH2OCH2 group in 1i on the second
cyclization to generate the bridgehead carbon (C-6) is opposite
to that of the CO2Me group in 1a (Scheme 3).
SCHEME 13. CHC of 1ka
a Reagents and conditions: (i) Rh(acac)(CO)2 (2 mol %), BIPHEPHOS
In the same manner, the reactions of N-(S)-3-buten-1-ylamides
of (S)- and (R)-N-Boc-serine [(S,S)-1j and (R,S)-1j] were carried
out under the standard conditions. The results were very similar
to those for 1i described above, i.e., the reaction of (S,S)-1j
afforded (3S,6S,9S)-5j exclusively in 94% yield, while that of
(R,S)-1j gave a mixture of (3R,6R,9S)-5j (45% yield) and
(3R,6S,9S)-5j (34% yield) (Scheme 12). The structure of
(3S,6S,9S)-5j was confirmed by X-ray crystallographic analysis
(see Figure S4, Supporting Information). The directing effect
of the methyl group in 1j is the same as that of the PhCH2-
OCH2 group in 1i (although the S, R designation is different,
the stereochemical sense of the substituents is the same). In
this case, however, it appears that the stereogenic center of the
N-Boc-serine residue has a stronger directing effect than the
N-but-1-en-3-yl moiety.
(4 mol %), H2 (2 atm), CO (2 atm), PTSA (10 mol %), toluene, 65 °C, 20
h.
N-allylamide of Boc-(S)-serine (S)-1k under the standard
conditions, which gave (3S,6S)-5k (major, 70% yield) and
(3S,6R)-5k (minor, 6% yield) (Scheme 13). This result confirms
the anticipated and substantial directing effect of the stereogenic
center in the Boc-serine residue.
Mechanisms of the Second Cyclization. As described above,
extremely high diastereoselectivity was observed in most of the
syntheses of 1-azabicyclo[x.y.0]alkane amino acids and their
derivatives by means of the Rh-BIPHEPHOS-catalyzed cyclo-
hydrocarbonylation (CHC). One might guess that the second
cyclization step is thermodynamic control, yielding the ther-
modynamically most stable products. However, this possibility
is easily eliminated by molecular mechanics calculation of the
energies of a pair of diastereomers in each case (see the
To confirm the directing effect of the N-Boc-serine residue
on the second cyclization, we carried out the reaction of the
1876 J. Org. Chem., Vol. 72, No. 6, 2007

Synthesis of Azabicyclo[x.y.0]alkane Amino Acids
SCHEME 14. Mechanism of the Extremely Diastereoselective Cyclization of 4a
Supporting Information). Thus, the extremely diastereoselective
second cyclization step should be a kinetically controlled
process.
As mentioned above, the CH2OBn group at C-6 of the
intermediate (S,S)-4b and (S,R)-4b should occupy the equatorial
position (Conformer B). Thus, it is anticipated that the intramo-
lecular addition of the hydroxyl group to the iminium bond of
(S,S)-4b takes place from the re face (bottom face) to afford
(3S,6R,10S)-5b, while that of (S,R)-4b proceeds through the si
face (top face) to give (3S,6S,10R)-5b (Scheme 15). The
experimental results are consistent with the anticipated outcomes
(Scheme 4). The proposed mechanism (Scheme 15) is certainly
applicable to other nucleophiles, i.e., nitrogen (4d) and sulfur
(4e), as well as homologues (4c and 4f). Thus, the reactions of
(S,S)-1c (Scheme 5), (S,S)-1d (Scheme 6), (R,S)-1e (Scheme
7), and (S,S)-1f (Scheme 8) indeed gave the corresponding 5c-
f, respectively, in accordance with the proposed mechanism.
For the reactions of Boc-(D/L)-Thr-(S)-(allyl)Gly-OMe and
Boc-(D/L)-allo-Thr-(S)-(allyl)Gly-OMe diastereomers (1g), the
chiral center in the threonine or allo-threonine residue serves
as an additional stereogenic center in addition to the stereogenic
center in the C-terminus residue (Scheme 9). As described
above, the reactions of (S,R,S)-1g and (R,R,S)-1g led to the
exclusive formation of the corresponding (3S,4R,6S,10S)-5g
(85% yield) and (3R,4R,6R,10S)-1g (94% yield), respectively.
In the case of the (S,R,S)-1g to (3S,4R,6S,10S)-5g conversion,
it appears that the R configuration at the chiral centers in the
L-threonine and D-allo-threonine forms a matching pair with
the S configuration at the C-terminus residue that fixes 4g as
Conformer A (Scheme 14). Inspection of the approach of the
hydroxyl group to the iminium carbon of 4g (si-face attack)
has revealed that the methyl group at the side chain is exo to
the second cycle being formed (“exo-Methyl” approach, Figure
1). Thus, the induction of the 6S configuration at the bridgehead
is directed by the S configuration at the C-terminus residue in
the same manner as that for (S,S)-4a (Scheme 14).
Deslongchamps has reported that a nucleophilic addition to
a conformationally rigid didehydropiperidinium ion is controlled
by stereoelectronic effects, wherein an axial attack is favored
to avoid the unfavorable boat transition state.37 Accordingly,
the conformation of N-acyldidehydropiperidinium ion 4 should
play a key role in the second cyclization. To determine the
favorable conformation of intermediate 4, two conflicting strains,
i.e., 1,3-diaxial strain and 1,3-allylic strain,38 should play critical
roles, i.e., the relative significance of these two strains would
determine the conformation. In other words, the predominance
of allylic strain (i.e., allylic strain >1,3-diaxial strain) would
render the substituent at C-6 to the axial position, favoring
Conformer A (Scheme 14), whereas the C-6 substituent would
take the equatorial position when the 1,3-diaxial strain over-
whelms the 1,3-allylic strain, favoring Conformer B (Scheme
14).
The estimated equatorial preference is 1.2 kcal/mol for CO2-
Me and 1.8 kcal/mol for methyl group.39-41 This indicates the
sp3-hybridized methyl group at the axial position of C-6 would
suffer more from the 1,3-diaxial strain than the sp2-hybridized
CO2Me. Accordingly, the sp3-hybridized CH2OBn group should
occupy the equatorial position of C-6 to avoid critical 1,3-diaxial
strain, while the sp2-hybridized CO2Me group should take the
axial position of C-6 because of the predominant 1,3-allylic
strain. Therefore, it is anticipated that the intramolecular
nucleophilic addition of the hydroxyl group to the iminium bond
of (S,S)-4a (Conformer A) takes place from the si face (i.e.,
the top face), leading to the formation of (3S,6S,10S)-5a
(Scheme 14). In the same manner, the addition to (S,R)-4a
(Conformer A) should occur from the re face (i.e., the bottom
face) to give (3S,6R,10R)-5a (Scheme 14). The experimental
results (Scheme 3) are consistent with these anticipations.
However, when D-allo-threonine, L-allo-threonine, and D-
threonine are used as N-terminus residues, the situation becomes
more complicated. In the case of the (R,R,S)-1g to (3R,4R,6R,-
10S)-5g conversion, 6R configuration was introduced at the
bridgehead position exclusively (94% isolated yield)! This
means that the chiral center at the C2 position of D-allo-threonine
residue emerges as the stereogenic center, which directs
exclusive re-face attack (pro-6R approach) on the iminium
carbon of (R,R,S)-4g. The inspection of the possible transition
state structures has disclosed an additional critical factor that
(37) Deslongchamps, P. In Stereoelectronic Effects in Organic Chemistry;
Pergamon: New York, 1983, Chapter 6.
(38) Johnson, F. Chem. ReV. 1968, 68, 375-413.
(39) Booth, H.; Everett, J. R. J. Chem. Soc., Chem. Commun. 1976, 8,
278-279.
(40) Booth, H. E.; Jeremy R. J. Chem. Soc., Perkin Trans. 2 1980, 2,
255-259.
(41) Carroll, F. A. PerspectiVes on Structure and Mechanism in Organic
Chemistry; Thomson Publishing Inc.: 1998, p 138.
J. Org. Chem, Vol. 72, No. 6, 2007 1877

Chiou et al.
SCHEME 15. Mechanism of the Extremely Diastereoselective Cyclization of 4b
between the “endo-Methyl” group of the D-allo-threonine residue
and the iminium moiety of (R,R,S)-4g. The steric conflict can
be avoided when the hydroxyl group undergoes re-face attack
through the “exo-Methyl” approach although it should cause
1,3-allylic strain (Figure 1). A very similar analysis is applicable
to the (R,S,S)-4g case, which favors the re-attack (pro-6R
approach) of the hydroxyl group of the D-threonine residue to
give (3R,4S,6R,10S)-5g as the predominant product (78%
isolated yield). In the case of (S,S,S)-4g bearing an L-allo-
threonine residue, the si-attack is favored, although minor steric
conflict exists between the “endo-Methyl” and the iminium
moiety, to give (3S,4S,6S,10S)-5g as the major product (69%
isolated yield). When the same analysis is applied to the most
straightforward case, i.e., an apparent “matching pair” case
(S,R,S)-4g, the intramolecular hydrogen bonding indeed fixes
the “exo-Methyl” conformation and favors the si-attack (pro-
6S approach) of the hydroxyl group of L-threonine residue to
give (3S,4R,6S,10S)-5g exclusively (Figure 1).
As described above, the reactions of Boc-(S/R)-Ser-(S)-
(vinyl)Gly-OMe (1h) gave a mixture of two diastereomeric
1-aza-5-oxabicyclo[4.3.0]nonane products (5h) and noncyclized
dipeptide (7h) (Scheme 10). It is indicated that epimerization
of the vinylglycine residue as well as isomerization of the double
bond to ethyleneglycine residue took place during the hydro-
formylation step. The occurrence of the epimerization and the
double bond isomerization can be accommodated by assuming
the intermediacy of π-allyl-[Rh]H complex 8h in competition
with hydroformylation, as illustrated in Scheme 16 (only the
(S,S)-1h case is shown: the mechanism is essentially identical
for (R,S)-1h).
A key olefin-Rh complex intermediate, (S,S)-1h-Rh, in the
Rh-catalyzed hydroformylation reacts with CO and H2 to give
(3S,6S,9S)-5h as a single diastereomer. As a competitive process
with the hydroformylation, (S,S)-1h-Rh forms π-allyl-[Rh]H
complex (S)-8h, which is in equilibrium with olefin-Rh complex
intermediates (S,S)-1h-Rh, (S,R)-1h-Rh, and (S)-iso-1h-Rh. Each
olefin-Rh complex reacts with CO and H2 to give the corre-
sponding product, (3S,6S,9S)-5h, (S,S,R)-5h, or (S)-7h. It should
be noted that the absolute configuration of the bridgehead carbon
(C6) is S, regardless of the configuration of the vinylglycine
residue. The result clearly indicates that the stereogenic center
in the 1-aza-5-oxabicyclo[4.3.0] system is the chiral center of
FIGURE 1. Rationale for the diastereoselective cyclization of 4g.
determines the conformation of the threonine and allo-threonine
residues. This critical factor is the intramolecular hydrogen
bonding of the hydroxyl group to the BocNH group in nonpolar
aprotic solvent (toluene). Because of this hydrogen bonding,
the si-attack becomes impossible due to the severe steric conflict
1878 J. Org. Chem., Vol. 72, No. 6, 2007

Synthesis of Azabicyclo[x.y.0]alkane Amino Acids
SCHEME 16. Product Distribution of the CHC of the Vinylglycyl Dipeptide 1h
the Boc-(S)-serine residue, which makes a sharp contrast with
the cases of the 1-azabicyclo[4.4.0] as well as 1-azabicyclo-
[5.4.0] system formation (Schemes 3, 5-8, and 13). This is
partly due to the fact that the 1,3-allylic strain is substantially
weakened in the pyrrolidinium ions as compared with the
piperidinium ions. The strong directing effect of the Boc-(S)-
serine residue on the second cyclization via dehydropyrroli-
dinium ion intermediate 4h-j for the formation of the 1-aza-
bicylco[4.3.0] system was further confirmed in the reaction of
FIGURE 2.
simple N-allylamide of Boc-(S)-serine, (S)-1k, which gave
(3S,6S)-5k and (3S,6R)-5k in 92:8 ratio (Scheme 13).42
lectivity in most cases. The mechanism of the reactions, the
The observed strong directing effect of the N-Boc-(S)-serine
residue is rationalized by taking into account the intramolecular
hydrogen bonding between the NH-Boc moiety and the hydroxyl
group of the serine residue (see Figure 1 and discussions) as
well as the steric conflict associated with si-face and re-face
attacks of the hydroxyl group at the iminium moiety of 4k. As
Figure 2 clearly illustrates, the si-face attack (pro-6S approach)
does not have appreciable steric conflict other than a minor 1,3-
allylic strain, while the re-face attack (pro-6R approach) suffers
from severe steric conflict between the NH-Boc group and the
hydrogen of the iminium moiety although there is no 1,3-allylic
strain. Thus, the 6S-product, (3S,6S)-5k, is formed as the
predominant product.
In conclusion, we have developed a highly efficient method
for the synthesis of 1-azabicyclo[x.y.0]alkane amino acid
derivatives and their congeners by means of extremely regio-
selective cyclohydrocarbonylation (CHC) catalyzed by Rh-
BIPHEPHOS complex under mild conditions. The reaction
involves two consecutive cyclization steps, i.e., the first cy-
clization to form the cyclic N-acyliminium key intermediate 4
via CHC and the second cyclization to yield the corresponding
1-azabicyclo[x.y.0] system 5 with extremely high diastereose-
rationale for the extremely high diastereoselectivity, and the key
factors governing the stereochemistry of the second cyclization
are discussed in detail. We believe this catalytic synthetic
method is applicable to the syntheses of a variety of restrained
dipeptide units, peptidomimetics, alkaloids, and other biologi-
cally active natural or unnatural products.
Experimental Section
General Methods and Materials. See the Supporting Informa-
tion.
General Procedure for the Preparation of Unsaturated
Dipeptide Derivatives 1. Unsaturated dipeptide or amide substrates
1 were prepared according to the standard peptide coupling method
with 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) and 1-hy-
droxybenzotriazol (HOBt). One equivalent of Et3N was used in
the case of hydrochlorides. A typical procedure is described for
the preparation of N-(tert-butoxycarbonyl)-(S)-seryl-(S)-allylglycine
methyl ester,23 (S,S)-1a: To a mixture of N-t-Boc-L-serine (103
mg, 0.50 mmol, 1.0 equiv), methyl allylglycinate hydrochloride (83
mg, 0.50 mmol, 1.0 equiv), EDC (106 mg, 0.55 mmol, 1.1 equiv),
and HOBt (102 mg, 0.75 mmol, 1.5 equiv) in CH2Cl2 (1.0 mL)
was added Et3N (70 µL, 0.5 mmol, 1.0 equiv) in an ice bath under
nitrogen. After the addition was complete, the ice bath was removed.
The reaction mixture was allowed to warm up to room temperature
and stirred overnight (∼16 h) under nitrogen. The reaction mixture
was partitioned with EtOAc (15 mL) and aqueous NaHCO3 (0.5
N, 25 mL). The resulting aqueous solution was extracted with
EtOAc (2 × 15 mL). The combined organic layers were washed
with saturated NH4Cl (25 mL) and brine (15 mL), dried over
MgSO4, and then concentrated under reduced pressure to give crude
residue. The residue was purified by flash chromatography on silica
gel, using EtOAc/n-hexane as eluant to afford (S,S)-1a (120 mg,
76% yield) as a colorless liquid. Characterization data for all
substrates 1a-k are summarized in the Supporting Information.
(42) Baldwin reported the strong directing effect of the Boc-(S)-serine
residue on the selective formation of the 6S bridgehead configuration in
his tandem ozonolysis-cyclization of Boc-(S)-Ser-(S/R)-(homoallyl)Gly-
OBn substrates, which gave the corresponding (6S)-1-aza-5-oxobicyclo-
[4.3.0] product in 72-77% yield with high diastereoselectivity (6S:6R )
>7:1) regardless of the absolute configuration of the homoallylglycine
residue (see ref 22). Marshall also reported a similar directing effect of
Boc-(S)-homoserine residue in his electrochemical (i.e., anodic electrolysis)
cyclization of Boc-(S)-homo-Ser-(S/R)-Pro-OMe, which gave (7S)-1-aza-
6-oxabicyclo[5.3.0] product exclusively, regardless of the absolute config-
uration of the proline residue although the chemical yields were only
moderate (48-52%) (see ref 26).
J. Org. Chem, Vol. 72, No. 6, 2007 1879

Chiou et al.
General Procedure of Cyclohydrocarbonylation. A typical
procedure is described for the synthesis of (3S,6S,10S)-1-aza-3-
tert-butoxycarbonylamino-10-methoxycarbonyl-5-oxa-2-oxobicyclo-
[4.4.0]decane, (3S,6S,10S)-5a: Into a 10 mL round-bottomed
reaction flask were placed Rh(acac)(CO)2 (1.9 mg, 0.0073 mmol,
2 mol %) and BIPHEPHOS (11.6 mg, 0.0148 mmol, 4 mol %).
The atmosphere of the reaction flask was replaced with nitrogen,
followed by the addition of degassed toluene (1.0 mL). The resulting
solution was allowed to stir until it became homogeneous. The
dipeptide substrate (S,S)-1a (120 mg, 0.363 mmol) and PTSA (7
mg, 0.036 mmol) were placed in a 25 mL reaction flask. The
catalyst solution was transferred to the reaction flask via syringe,
and the total volume was adjusted to 6.0 mL (0.06 M). The reaction
flask was placed in a 300 mL stainless steel autoclave, and the
autoclave was flushed with CO several times. Then the autoclave
was filled with 2 atm of CO, followed by 2 atm of H2. The autoclave
was heated at 65 °C with stirring for 20-24 h. Then, the autoclave
was cooled to room temperature and gases were slowly and
carefully released. The reaction mixture was then concentrated under
reduced pressure to give viscous oil. The crude oily product was
purified by flash column chromatography on silica gel, using
EtOAc/n-hexane as eluant, to give (3S,6S,10S)-5a (120 mg, 96%
yield) as a colorless oil: 1H NMR (400 MHz, 25 °C, CDCl3) δ
1.38 (s, 9H), 1.47-1.57 (m, 1H), 1.65-1.79 (m, 2H), 1.84-2.01
(m, 3H), 3.68 (s, 3H), 3.75 (dd, J ) 10.2, 7.0 Hz, 1H), 4.16 (dd,
J ) 10.2, 6.2 Hz, 1H), 4.39-4.44 (m, 2H), 4.93 (dd, J ) 8.4, 4.4
Hz, 1H), 5.36 (d, J ) 6.0 Hz, 1H); 13C NMR (100 MHz, 25 °C,
CDCl3) δ 16.5, 24.5, 28.0, 28.2, 49.8, 52.4, 54.0, 67.0, 80.0, 82.7,
155.4, 168.4, 171.5. HRMS-FAB (m/z): [M + H]+ calcd for
C15H24N2O6‚H+, 329.1713; found, 329.1713 (∆ ) 0.0 ppm).
138.2, 155.7, 165.7. HRMS-FAB (m/z): [M + H]+ calcd for
C21H30N2O5‚H+, 391.2234; found, 391.2242 (∆ ) 2.0 ppm).
(3S,7S,11S)-1-Aza-3-tert-butoxycarbonylamino-11-methoxy-
carbonyl-2-oxo-6-oxabicyclo[5.4.0]undecane, (3S,7S,11S)-5c. Col-
1
orless oil; 87% yield; H NMR (500 MHz, 25 °C, C6D6) δ 0.95
(ddddd, J ) 13.2, 9.6, 4.8, 4.8, 4.8 Hz, 1H), 1.06 (dddd, J ) 12.5,
12.5, 4.5, 4.5 Hz, 1H), 1.17 (dddd, J ) 15.0, 13.0, 7.0, 4.0 Hz,
1H), 1.35-1.45 (m, 1H), 1.45-1.55 (m, 1H), 1.46 (s, 9H), 1.80
(dd, J ) 14.0, 2.0 Hz, 1H), 2.09-2.17 (m, 2H), 3.27 (s, 3H), 3.50
(ddd, J ) 12.0, 12.0, 1.5 Hz, 1H), 3.77 (ddd, J ) 12.0, 7.0, 3.5
Hz, 1H), 4.36 (br s, 1H), 4.73 (ddd, J ) 11.5, 6.3, 2.0 Hz, 1H),
5.15 (dd, J ) 7.5, 2.0 Hz, 1H), 6.20 (d, J ) 5.5 Hz, 1H); 13C NMR
(100 MHz, 25 °C, C6D6) δ 15.9, 25.6, 28.8, 30.9, 33.8, 52.0, 52.8,
53.5, 70.4, 79.4, 82.9, 155.7, 171.9, 175.1. HRMS-FAB (m/z): [M
+ H]+ calcd for C16H26N2O6‚H+, 343.1869; found, 343.1869 (∆
) 0.0 ppm).
(3S,6S,10S)-1,5-Diaza-3-tert-butoxycarbonylamino-5-tert-bu-
toxycarbonyl-10-methoxycarbonyl-2-oxobicyclo[4.4.0]decane,
(3S,6S,10S)-5d. Colorless oil; 95% yield: 1H NMR (400 MHz, 25
°C, CDCl3) δ 1.41 (s, 9H), 1.49 (s, 9H), 1.65-2.02 (m, 6H), 3.03
(t, J ) 12.0 Hz, 1H), 3.71 (s, 3H), 3.74 (m, 1H), 4.01 (ddd, J )
10.8, 4.8, 4.8 Hz, 1H), 4.60 (br s, 1H), 5.30 (br s, 1H), 5.47 (br s,
1H); 13C NMR (100 MHz, 25 °C, CDCl3) δ 21.5, 24.5, 28.3, 29.6,
41.7, 50.3, 52.2, 59.8, 68.5, 79.8 (2C), 81.8, 153.2, 155.4, 167.8,
169.5. HRMS-FAB (m/z): [M + H]+ calcd for C20H33N3O7‚H+,
428.2397; found, 428.2398. (∆ ) 0.2 ppm).
(3R,6S,10S)-1-Aza-3-benzyloxycarbonylamino-10-methoxy-
carbonyl-2-oxo-6-thiabicyclo[4.4.0]decane, (3R,6S,10S)-5e. The
reaction of (R,S)-1e (195 mg, 0.32 mmol) was carried out in MeOH
in place of toluene and in the absence of PTSA, but otherwise under
the same conditions as the standard procedure described above, to
give N-benzyloxycarbonyl-S-trityl-(R)-cysteinyl-(S)-6-oxonorleucine
methyl ester [(R,S)-2e] (180 mg, 86% yield) as a colorless oil; 1H
NMR (400 MHz, 25 °C, CDCl3) δ 1.52-1.68 (m, 3H), 1.75-1.86
(m, 1H), 2.34-2.39 (m, 2H), 2.53 (dd, J ) 13.2, 5.6 Hz, 1H), 2.79
(dd, J ) 13.2, 7.2 Hz, 1H), 3.67 (s, 3H), 3.85 (br s, 1H), 4.48-
4.54 (m, 1H), 5.03 (d, J ) 13.2 Hz, 1H), 5.07 (d, J ) 13.2 Hz,
1H), 5.28 (d, J ) 6.8 Hz, 1H), 6.58 (d, J ) 6.8 Hz, 1H), 7.17-
7.41 (m, 20H), 9.63 (t, J ) 1.2 Hz, 1H); 13C NMR (100 MHz, 25
°C, CDCl3) δ 17.5, 31.3, 33.7, 42.8, 51.7, 52.3, 53.8, 66.9, 67.1,
126.8, 127.9, 127.9, 128.0, 128.3, 129.4, 136.0, 144.2, 155.7, 169.9,
171.7, 201.4.
(R,S)-2e (139 mg, 0.216 mmol) was dissolved in dichloromethane
(1.0 mL). To this solution was added trifluoracetic acid (TFA) (1
mL) at room temperature. The reaction mixture was poured into
saturated NaHCO3 (3 mL) and extracted with EtOAc (3 × 5 mL).
The combined extracts were washed with brine, dried over MgSO4,
filtered, and evaporated. The crude product was purified by flash
chromatography on silica gel with EtOAc/n-hexane as eluant to
afford (3R,6S,10S)-5e (72 mg, 87%) as a colorless oil: 1H NMR
(400 MHz, 25 °C, CDCl3) δ 1.50-1.60 (m, 1H), 1.62-1.82 (m,
1H), 1.70-1.80 (m, 1H), 1.84-1.90 (m, 1H), 1.94-2.04 (m, 1H),
2.16-2.26 (m, 1H), 2.69 (dd, J ) 12.0, 10.5 Hz, 1H), 3.55 (dd, J
) 10.5, 6.0 Hz, 1H), 3.70 (s, 3H), 4.69 (ddd, J ) 12.0, 6.0, 6.0
Hz, 1H), 4.88 (dd, J ) 7.2, 3.6 Hz, 1H), 5.04-5.14 (m, 1H), 5.09
(s, 2H), 6.13 (d, J ) 6.0 Hz, 1H), 7.25-7.35 (m, 5H); 13C NMR
(100 MHz, 25 °C, CDCl3) δ 17.2, 24.6, 27.8, 29.0, 51.5, 52.4, 53.1,
53.5, 66.9, 127.9, 128.0, 128.4, 136.2, 155.5, 170.9, 171.5. HRMS-
FAB (m/z): [M + H]+ calcd for C18H22N2O5S‚H+, 379.1327; found,
379.1328 (∆ ) 0.2 ppm).
(3S,7S,11S)-1-Aza-3-benzyloxycarbonylamino-11-methoxy-
carbonyl-2-oxo-6-thiabicyclo[5.4.0]undecane, (3S,7S,11S)-5f. The
reaction of (S,S)-1f was carried out in the same manner as that for
(R,S)-1e. Thus, the hydroformylation of (S,S)-1f in MeOH gave
(S,S)-2f (520 mg, 93%) as a colorless oil: 1H NMR (400 MHz, 25
°C, CDCl3) δ 1.57 (m, 4H), 1.77 (m, 2H), 2.29 (m, 2H), 2.39 (m,
2H), 3.71 (s, 3H), 4.12 (m, 1H), 4.49 (dd, J ) 7.6, 13.2 Hz, 1H),
5.05 (d, J ) 12.4 Hz, 1H), 5.09 (d, J ) 12.4 Hz, 1H), 5.15 (d, J )
8.0 Hz, 1H), 5.59 (d, J ) 7.6 Hz, 1H), 7.16-7.40 (m, 20H), 9.68
In the same manner, other reactions were carried out to give the
corresponding 1-azabicyclic products 5. The characterization data
for 5a-k are shown below:
(3S,6R,10R)-1-Aza-3-tert-butoxycarbonylamino-10-methoxy-
carbonyl-5-oxa-2-oxobicyclo[4.4.0]decane, (3S,6R,10R)-5a. Col-
orless oil; 90% yield: 1H NMR (400 MHz, 25 °C, CDCl3) δ 1.31-
1.41 (m, 1H), 1.39-1.49 (m, 1H), 1.40 (s, 9H), 1.57-1.67 (m,
1H), 1.71-1.77 (m, 1H), 1.92-1.99 (m, 1H), 2.16-2.23 (m, 1H),
3.69 (s, 3H), 3.98-4.02 (m, 2H), 4.25 (br s, 1H), 4.90 (dd, J )
10.2, 3.4 Hz, 1H), 5.23 (d, J ) 7.2 Hz, 1H), 5.33 (d, J ) 5.2 Hz,
1H); 13C NMR (100 MHz, 25 °C, CDCl3) δ 19.0, 26.1, 28.3, 31.4,
50.9, 52.2, 52.5, 68.2, 80.1, 85.1, 155.2, 166.5, 171.1. HRMS-FAB
(m/z): [M + H]+ calcd for C15H24N2O6‚H+, 329.1713; found,
329.1713 (∆ ) 0.0 ppm).
(3S,6R,10S)-1-Aza-10-benzyloxymethyl-3-tert-butoxycarbony-
lamino-5-oxa-2-oxobicyclo[4.4.0]decane, (3S,6R,10S)-5b. Color-
1
less oil; 82% yield; H NMR (600 MHz, 25 °C, CDCl3) δ 1.39-
1.45 (m, 1H), 1.42 (s, 9H), 1.54-1.60 (m, 1H), 1.66-1.68 (m,
2H), 1.84 (d, J ) 13.8 Hz, 1H), 1.93 (ddd, J ) 12.6, 1.8, 1.8 Hz
1H), 3.45-3.46 (m, 1H), 3.48-3.51 (m, 1H), 3.55 (t, J ) 7.8 Hz
1H), 4.14 (quintet, J ) 6.0 Hz, 1H), 4.37-4.43 (m, 1H), 4.50 (m,
2H), 4.80 (dd, J ) 10.8, 3.0 Hz, 1H), 4.86 (quartet, J ) 6.0 Hz,
1H), 5.24 (br s, 1H), 7.25-7.34 (m, 5H); 13C NMR (100 MHz, 25
°C, CDCl3) δ 18.3, 25.4, 28.5, 32.5, 48.9, 50.5, 67.0, 69.2, 73.2,
80.0, 85.7, 127.8, 127.9, 128.6, 138.4, 156.1, 167.1. HRMS-FAB
(m/z): [M + H]+ calcd for C21H30N2O5‚H+, 391.2234; found,
391.2244 (∆ ) 2.5 ppm).
(3R,6R,10S)-1-Aza-10-benzyloxymethyl-3-tert-butoxycarbony-
lamino-5-oxa-2-oxobicyclo[4.4.0]decane, (3R,6R,10S)-5b. Color-
less oil; 80% yield; 1H NMR (600 MHz, 25 °C, CDCl3) δ 1.42 (s,
9H), 1.42-1.49 (m, 1H), 1.54-1.60 (m, 1H), 1.66-1.72 (m, 2H),
1.80 (d, J ) 13.8 Hz, 1H), 1.92 (dd, J ) 12.6, 3.0 Hz, 1H), 3.48-
3.51 (m, 1H), 3.55 (t, J ) 7.8 Hz, 1H), 3.86 (dd, J ) 12.6, 3.6 Hz,
1H), 3.95 (d, J ) 12.0 Hz, 1H), 4.18 (br s, 1H), 4.46 (d, J ) 12.0
Hz, 1H), 4.48 (d, J ) 12.0 Hz, 1H), 4.79 (dd, J ) 10.8, 3.0 Hz,
1H), 4.98 (quartet, J ) 6.0 Hz, 1H), 5.27 (br s, 1H), 7.25-7.33
(m, 5H); 13C NMR (100 MHz, 25 °C, CDCl3) δ 18.5, 25.5, 28.5,
32.1, 48.4, 51.2, 67.5, 69.6, 73.2, 80.2, 84.7, 127.8, 127.9, 128.6,
1880 J. Org. Chem., Vol. 72, No. 6, 2007

Synthesis of Azabicyclo[x.y.0]alkane Amino Acids
(t, J ) 1.2 Hz, 1H); 13C NMR (100 MHz, 25 °C, CDCl3) δ 17.9,
28.2, 31.7, 31.8, 43.2, 52.1, 52.7, 54.3, 67.2, 67.3, 126.9, 128.2,
128.3, 128.4, 128.8, 129.8, 136.4, 144.9, 156.3, 171.3, 172.3, 201.8.
Then, (S,S)-2f (53 mg, 0.07 mmol) was dissolved in benzene
(0.5 mL) containing 1% (v/v) methanesulfonic acid (MsOH) at room
temperature. To this solution was added trifluoracetic acid (TFA)
(0.4 mL) followed by Et3SiH (10 µL) in an ice bath. The reaction
immediately gave a precipitate of triphenylmethane. Fitration of
the precipitate and concentration gave a crude product, which was
purified by flash chromatography on silica gel with EtOAc/n-hexane
as eluant to afford (3S,7S,11S)-5f (27 mg) in 90% yield as a
colorless oil: 1H NMR (400 MHz, 50 °C, CDCl3) δ 1.14-1.22
(m, 1H), 1.50-1.60 (m, 1H), 1.55-1.65 (m, 1H), 1.76-1.84 (m,
1H), 2.05-2.25 (m, 1H), 2.05-2.25 (m, 1H), 2.05-2.25 (m, 1H),
2.38-2.46 (m, 1H), 2.50-2.58 (m, 1H), 2.61-2.70 (m, 1H), 3.77
(s, 3H), 4.37 (t, J ) 5.0 Hz, 1H), 5.02 (d, J ) 6.5 Hz, 1H), 5.10-
5.20 (m, 1H), 5.11-5.32 (m, 3H), 7.25-7.35 (m, 5H); 13C NMR
(100 MHz, 25 °C, CDCl3) δ 19.4, 20.3, 26.5, 32.8, 36.8, 51.4, 52.9,
58.1, 67.9, 69.8, 128.4, 128.7, 128.9, 135.9, 154.7, 168.2, 170.6.
HRMS-FAB (m/z): [M + H]+ calcd for C19H24N2O5S‚H+, 393.1484;
found, 393.1482 (∆ ) 0.5 ppm).
(3R,4S,6R,10S)-1-Aza-3-tert-butoxycarbonylamino-10-meth-
oxycarbonyl-4-methyl-5-oxa-2-oxo-bicyclo[4.4.0]decane,(3R,4S,6R,-
10S)-5g. Colorless oil; 78% yield; H NMR (500 MHz, 25 °C,
1
CDCl3) δ 1.15 (d, J ) 6.0 Hz, 3H), 1.27-1.33 (m, 1H), 1.32-
1.40 (m, 1H), 1.36 (s, 9H), 1.54-1.60 (m, 1H), 1.66-1.72 (m,
1H), 1.88-1.94 (m, 1H), 2.14-2.18 (m, 1H), 3.64 (s, 3H), 3.96-
4.02 (m, 1H), 4.21 (d, J ) 10.0 Hz, 1H), 4.87 (d, J ) 6.0 Hz, 1H),
4.97 (d, J ) 10.0 Hz, 1H), 5.24 (d, J ) 5.0 Hz, 1H); 13C NMR
(100 MHz, 25 °C, CDCl3) δ 15.8, 19.4, 26.3, 28.4, 31.8, 52.1, 52.6,
54.3, 73.6, 80., 85.1, 155.8, 167.2, 171.3. HRMS-FAB (m/z): [M
+ H]+ calcd for C16H26N2O6‚H+, 343.1870; found, 343.1868 (∆
) 0.6 ppm).
(3R,4S,6S,10S)-1-Aza-3-tert-butoxycarbonylamino-10-meth-
oxycarbonyl-4-methyl-5-oxa-2-oxo-bicyclo[4.4.0]decane,(3R,4S,6S,-
1
10S)-5g. Colorless oil; 10% yield; H NMR (500 MHz, 25 °C,
CDCl3) δ 1.18 (d, J ) 7.0 Hz, 3H), 1.40 (s, 9H), 1.46-1.55 (m,
1H), 1.67-1.77 (m, 2H), 1.83-1.91 (m, 2H), 1.90-1.97 (m, 1H),
3.72 (s, 3H), 4.46 (br s, 1H), 4.71-4.78 (m, 1H), 4.72 (dd, J )
11.0, 3.0 Hz, 1H), 5.34 (dd, J ) 11.0, 4.0 Hz, 1H), 5.45 (br s, 1H);
13C NMR (100 MHz, 25 °C, CDCl3) δ 12.9, 20.0, 27.5, 28.5, 30.5,
52.5, 54.2, 56.7, 70.5, 80.1, 81.3, 155.8, 169.3, 171.5. HRMS-FAB
(m/z): [M + H]+ calcd for C16H26N2O6‚H+, 343.1870; found,
343.1869 (∆ ) 0.3 ppm).
(3S,4R,6S,10S)-1-Aza-3-tert-butoxycarbonylamino-10-meth-
oxycarbonyl-4-methyl-5-oxa-2-oxo-bicyclo[4.4.0]decane,(3S,4R,6S,-
1
10S)-5g. Colorless oil; 85% yield; H NMR (400 MHz, 25 °C,
(3S,6S,9R)-1-Aza-3-tert-butoxycarbonylamino-9-methoxycar-
bonyl-5-oxa-2-oxobicyclo[4.3.0]nonane, (3S,6S,9R)-5h. Colorless
CDCl3) δ 1.21 (d, J ) 6.0 Hz, 3H), 1.44 (s, 9H), 1.52-1.58 (m,
1H), 1.66-1.72 (m, 1H), 1.74-1.81 (m, 1H), 1.95-2.00 (m, 2H),
1.97-2.03 (m, 1H), 3.72 (s, 3H), 4.27 (dq, J ) 6.0, 5.0 Hz, 1H),
4.41 (t, J ) 7.0 Hz, 1H), 4.45 (dd, J ) 8.0, 5.0 Hz, 1H), 4.92 (dd,
J ) 10.0, 4.5 Hz, 1H), 5.25 (d, J ) 8.0 Hz, 1H); 13C NMR (100
MHz, 25 °C, CDCl3) δ 16.5, 17.0, 24.7, 28.3, 28.4, 52.4, 53.4,
53.8, 72.6, 80.0, 82.7, 155.6, 168.1, 171.7. HRMS-FAB (m/z): [M
+ H]+ calcd for C16H26N2O6‚H+, 343.1870; found, 343.1868 (∆
) 0.6 ppm).
1
needles (from n-heptane); 21% yield; mp 139-141 °C; H NMR
(500 MHz, 25 °C, CDCl3) δ 1.41 (s, 9H), 1.88-1.98 (m, 2H), 2.23-
2.33 (m, 2H), 3.64 (dd, J ) 10.0, 7.0 Hz, 1H), 3.70 (s, 3H), 4.36
(t, J ) 10.0 Hz, 1H), 4.41-4.46 (m, 1H), 4.72 (dd, J ) 8.0, 5.0
Hz, 1H), 5.21 (dd, J ) 5.5, 4.5 Hz, 1H), 5.49 (br s, 1H); 13C NMR
(100 MHz, 25 °C, CDCl3) δ 26.3, 28.5, 31.7, 49.3, 52.8, 58.2, 68.9,
80.4, 87.6, 155.9, 166.8, 171.6. HRMS-FAB (m/z): [M + Na]+
calcd for C14H22N2O6‚Na+, 315.1556; found, 315.1545 (∆ ) 3.5
ppm).
(3R,4R,6R,10S)-1-Aza-3-tert-butoxycarbonylamino-10-meth-
oxycarbonyl-4-methyl-5-oxa-2-oxo-bicyclo[4.4.0]decane,(3R,4R,6R,-
(3S,6S,9S)-1-Aza-3-tert-butoxycarbonylamino-9-methoxycar-
1
bonyl-5-oxa-2-oxobicyclo[4.3.0]nonane, (3S,6S,9S)-5h. Colorless
10S)-5g. Colorless oil; 94% yield; H NMR (500 MHz, 25 °C,
1
oil; 48% yield; [R]21 -22 (c 0.37, CHCl3); H NMR (500 MHz,
CDCl3) δ 1.43 (d, J ) 7.0 Hz, 3H), 1.43-1.50 (m, 1H), 1.46 (s,
9H), 1.59 (dq, J ) 13.0, 3.0 Hz, 1H), 1.66 (dddd, J ) 14.0, 14.0,
6.0, 4.0 Hz, 1H), 1.82-1.86 (m, 1H), 1.90-1.94 (m, 1H), 2.23-
2.26 (m, 1H), 3.75 (s, 3H), 4.01-4.08 (m, 1H), 4.12 (quintet, J )
6.0 Hz, 1H), 5.08 (dd, J ) 10.5, 3.0 Hz, 1H), 5.17 (d, J ) 7.0 Hz,
1H), 5.43 (d, J ) 6.0 Hz, 1H); 13C NMR (100 MHz, 25 °C, CDCl3)
δ 17.1, 19.7, 26.2, 28.4, 31.3, 52.6 (2 C), 55.6, 71.4, 80.1, 80.7,
155.8, 167.0, 171.3. HRMS-FAB (m/z): [M + H]+ calcd for
C16H26N2O6‚H+, 343.1870; found, 343.1884 (∆ ) 4.1 ppm).
(3S,4S,6S,10S)-1-Aza-3-tert-butoxycarbonylamino-10-meth-
oxycarbonyl-4-methyl-5-oxa-2-oxo-bicyclo[4.4.0]decane, (3S,4S,6S,-
10S)-5g. Colorless oil; 69% yield: 1H NMR (500 MHz, 25 °C,
CDCl3) δ 1.34 (d, J ) 5.5 Hz, 3H), 1.41 (s, 9H), 1.46-1.53 (m,
1H), 1.67-1.78 (m, 2H), 1.85-1.94 (m, 2H), 1.99-2.06 (m, 1H),
3.70 (s, 3H), 3.78 (dq, J ) 10.0, 6.0 Hz, 1H), 4.31 (t, J ) 8.5 Hz,
1H), 4.48 (t, J ) 6.0 Hz, 1H), 5.12 (dd, J ) 7.0, 5.5 Hz, 1H), 5.15
(d, J ) 6.5 Hz, 1H); 13C NMR (100 MHz, 25 °C, CDCl3) δ 16.7,
19.2, 24.7, 28.3 (C-7 and t-Bu), 52.48, 53.96, 55.1, 72.5, 79.1, 80.1,
156.2, 170.2, 171.8. HRMS-FAB (m/z): [M + H]+ calcd for
C16H26N2O6‚H+, 343.1870; found, 343.1878 (∆ ) 2.3 ppm).
(3S,4S,6R,10S)-1-Aza-3-tert-butoxycarbonylamino-10-meth-
oxycarbonyl-4-methyl-5-oxa-2-oxo-bicyclo[4.4.0]decane,(3S,4S,6R,-
D
25 °C, CDCl3) δ 1.39 (s, 9H), 1.93-2.01 (m, 1H), 2.04-2.12 (m,
1H), 2.06-2.17 (m, 1H), 2.23-2.28 (m, 1H), 3.70 (s, 3H), 3.81
(dd, J ) 9.0, 6.5 Hz, 1H), 4.29 (dd, J ) 9.0, 8.0 Hz, 1H), 4.32-
4.37 (m, 1H), 4.40 (dd, J ) 8.0, 1.0 Hz, 1H), 5.17 (dd, J ) 7.0,
6.0 Hz, 1H), 5.49 (br s, 1H); 13C NMR (100 MHz, 25 °C, CDCl3)
δ 26.5, 28.4, 30.9, 49.4, 52.7, 57.9, 69.3, 80.3, 88.0, 156.0, 166.8,
171.3. HRMS-FAB (m/z): [M + Na]+ calcd for C14H22N2O6‚Na+,
315.1556; found, 315.1551 (∆ ) 1.6 ppm).
(3R,6R,9S)-1-Aza-3-tert-butoxycarbonylamino-9-methoxycar-
bonyl-5-oxa-2-oxobicyclo[4.3.0]nonane, (3R,6R,9S)-5h. White
1
needle (from n-heptane); 42% yield; mp 141-142 °C; H NMR
(400 MHz, 25 °C, CDCl3) δ 1.41 (s, 9H), 1.88-1.98 (m, 2H), 2.23-
2.33 (m, 2H), 3.64 (dd, J ) 10.0, 7.0 Hz, 1H), 3.70 (s, 3H), 4.36
(t, J ) 10 Hz, 1H), 4.41-4.46 (m, 1H), 4.72 (dd, J ) 8.0, 5.0 Hz,
1H), 5.21 (dd, J ) 5.5, 4.5 Hz, 1H), 5.49 (br s, 1H); 13C NMR
(100 MHz, 25 °C, CDCl3) δ 26.3, 28.5, 31.7, 49.3, 52.8, 58.2, 68.9,
80.4, 87.6, 155.9, 166.8, 171.6. HRMS-FAB (m/z): [M + Na]+
calcd for C14H22N2O6‚Na+, 315.1556; found, 315.1545 (∆ ) 3.5
ppm).
(3R,6R,9R)-1-Aza-3-tert-butoxycarbonylamino-9-methoxycar-
bonyl-5-oxa-2-oxobicyclo[4.3.0]nonane, (3R,6R,9R)-5h. Colorless
1
oil; 16% yield; [R]21 +22 (c 0.27, CHCl3); H NMR (400 MHz,
1
10S)-5g. Colorless oil; 17% yield; H NMR (500 MHz, 25 °C,
D
25 °C, CDCl3) δ 1.39 (s, 9H), 1.93-2.01 (m, 1H), 2.04-2.12 (m,
1H), 2.06-2.17 (m, 1H), 2.23-2.28 (m, 1H), 3.70 (s, 3H), 3.81
(dd, J ) 9.0, 6.5 Hz, 1H), 4.29 (dd, J ) 9.0, 8.0 Hz, 1H), 4.32-
4.37 (m, 1H), 4.40 (dd, J ) 8.0, 1.0 Hz, 1H), 5.17 (dd, J ) 7.0,
6.0 Hz, 1H), 5.49 (br s, 1H); 13C NMR (100 MHz, 25 °C, CDCl3)
δ 26.5, 28.4, 30.9, 49.4, 52.7, 57.9, 69.3, 80.3, 88.0, 156.0, 166.8,
171.3. HRMS-FAB (m/z): [M + Na]+ calcd for C14H22N2O6‚Na+,
315.1556; found, 315.1551 (∆ ) 1.6 ppm).
CDCl3) δ 1.30-1.36 (m, 1H), 1.33 (d, J ) 6.0 Hz, 3H), 1.39-
1.47 (m, 1H), 1.42 (s, 9H), 1.65 (dddd, J ) 13.5, 13.5, 6.5, 4.0 Hz,
1H), 1.75 (dq, J ) 13.0, 3.0 Hz, 1H), 1.94 (dddd, J ) 13.0, 10.0,
3.5, 1.5 Hz, 1H), 2.19 (dq, J ) 14.0, 1.5 Hz, 1H), 3.70 (s, 3H),
3.77 (dddd, J ) 10.0, 6.0, 6.0, 6.0 Hz, 1H), 4.04-4.11 (m, 1H),
4.87 (br s, 1H), 4.98 (dd, J ) 11.0, 3.0 Hz, 1H), 5.18 (d, J ) 6.0
Hz, 1H); 13C NMR (100 MHz, 25 °C, CDCl3) δ 19.1, 19.5, 26.3,
28.5, 31.8, 52.6, 53.1, 56.1, 74.7, 80.1, 85.4, 156.6, 169.1, 171.6.
HRMS-FAB (m/z): [M + H]+ calcd for C16H26N2O6‚H+, 343.1870;
found, 343.1883 (∆ ) 3.8 ppm).
(3S,6S,9R)-1-Aza-9-benzyloxymethyl-3-tert-butoxycarbony-
lamino-5-oxa-2-oxobicyclo[4.3.0]nonane, (3S,6S,9R)-5i. Colorless
J. Org. Chem, Vol. 72, No. 6, 2007 1881

Chiou et al.
oil; 87% yield; 1H NMR (500 MHz, 25 °C, CDCl3) δ 1.43 (s, 9H),
1.79-1.85 (m, 1H), 1.83-1.91 (m, 1H), 2.02-2.10 (m, 1H), 2.27-
2.34 (m, 1H), 3.52 (dd, J ) 9.5, 3.0 Hz, 1H), 3.56 (dd, J ) 9.5,
5.0 Hz, 1H), 3.61 (dd, J ) 9.5, 6.0 Hz, 1H), 4.30 (t, J ) 8.0 Hz,
1H), 4.31-4.38 (m, 1H), 4.38-4.43 (m, 1H), 4.46 (d, J ) 12.0
Hz, 1H), 4.49 (d, J ) 12.0 Hz, 1H), 5.06 (dd, J ) 6.0, 3.5 Hz,
1H), 5.45 (br s, 1H), 7.24-7.34 (m, 5H); 13C NMR (100 MHz, 25
°C, CDCl3) δ 24.6, 28.5, 31.8, 49.5, 57.3, 68.7, 71.0, 73.5, 80.4,
87.9, 127.8, 127.9, 128.6, 138.4, 156.1, 166.8. HRMS-FAB (m/z):
[M + Na]+ calcd for C20H28N2O5‚Na+, 399.1896; found, 399.1908
(∆ ) 3.0 ppm).
(3R,6R,9R)-1-Aza-9-benzyloxymethyl-3-tert-butoxycarbony-
lamino-5-oxa-2-oxobicyclo[4.3.0]nonane, (3R,6R,9R)-5i. Colorless
oil; 42% yield; 1H NMR (500 MHz, 25 °C, CDCl3) δ 1.43 (s, 9H),
1.94 (dddd, J ) 12.0, 12.0, 7.0, 7.0 Hz, 1H), 1.98-2.07 (m, 1H),
2.13 (dd, J ) 12.0, 1.5 Hz, 1H), 2.21 (quintet, J ) 6.0 Hz, 1H),
3.52 (dd, J ) 9.5, 3.0 Hz, 1H), 3.56 (dd, J ) 9.5, 5.0 Hz, 1H),
3.58 (t, J ) 8.5 Hz, 1H), 4.36-4.44 (m, 3H), 4.46 (d, J ) 12.0
Hz, 1H), 4.49 (d, J ) 12.0 Hz, 1H), 5.16 (t, J ) 6.5 Hz, 1H), 5.45
(br s, 1H). 7.24-7.36 (m, 5H); 13C NMR (100 MHz, 25 °C, CDCl3)
δ 25.5, 28.5, 30.6, 49.4, 56.7, 68.4, 68.6, 73.5, 80.3, 87.2, 127.7,
127.8, 128.6, 138.4, 156.0, 166.6. HRMS-FAB (m/z): [M + Na]+
calcd for C20H28N2O5‚Na+, 399.1896; found, 399.1909 (∆ ) 3.3
ppm).
(3R,6S,9S)-1-Aza-3-tert-butoxycarbonylamino-9-methyl-5-
oxa-2-oxobicyclo[4.3.0]nonane, (3R,6S,9S)-5j. Colorless oil; 34%
yield; H NMR (600 MHz, 25 °C, CDCl3) δ 1.28 (d, J ) 6.4 Hz,
1
3H), 1.39-1.45 (m, 1H), 1.41 (s, 9H), 1.69-1.76 (m, 1H), 2.16-
2.21 (m, 2H), 3.67 (t, J ) 10.8 Hz, 1H), 4.02 (br s, 1H), 4.15 (sextet,
J ) 7.0 Hz, 1H), 4.45 (br s, 1H), 5.03 (dd, J ) 8.8, 5.2 Hz, 1H),
5.49 (br s, 1H); 13C NMR (100 MHz, 25 °C, CDCl3) δ 21.7 (2 C),
28.5, 31.4, 50.0, 52.6, 69.3, 80.3, 89.2, 156.2, 165.7. HRMS-FAB
(m/z): [M + Na]+ calcd for C13H22N2O4‚Na+, 293.1477; found,
293.1495 (∆ ) 6.0 ppm).
(3S,6S)-1-Aza-3-tert-butoxycarbonylamino-5-oxa-2-oxobicyclo-
[4.3.0]nonane, (S,S)-5k. White solid; 70% yield; mp 104-106 °C;
1H NMR (500 MHz, 25 °C, CDCl3) δ 1.41 (s, 9H), 1.70-1.77 (m,
1H), 1.82-1.88 (m, 1H), 1.89-1.96 (m, 1H), 2.15 (ddd, J ) 12.0,
6.0, 6.0, 6.0 Hz, 1H), 3.26 (ddd, J ) 12.0, 7.5, 5.5 Hz, 1H), 3.55
(dd, J ) 9.0, 6.0 Hz, 1H), 3.73 (ddd, J ) 11.5, 7.0, 7.0 Hz, 1H),
4.22-4.34 (m, 2H), 5.01 (t, J ) 5.5 Hz, 1H), 5.54 (d, J ) 4.5 Hz,
1H); 13C NMR (100 MHz, 25 °C, CDCl3) δ 21.4, 28.2, 32.4, 44.8,
49.4, 68.5, 79.3, 86.4, 156.0, 166.2. HRMS-FAB (m/z): [M + H]+
calcd for C12H20N2O4‚H+, 257.1501; found, 257.1490 (∆ ) 4.3
ppm).
(3S,6R)-1-Aza-3-tert-butoxycarbonylamino-5-oxa-2-oxobicyclo-
[4.3.0]nonane, (S,R)-5k. White solid; 6% yield; mp 140-142 °C;
1H NMR (500 MHz, 25 °C, CDCl3) δ 1.41 (s, 9H), 1.73-1.85 (m,
2H), 1.94-2.00 (m, 1H), 2.16-2.23 (m, 1H), 3.41-3.46 (m, 1H),
3.68 (ddd, J ) 12.0, 8.5, 8.5 Hz, 1H), 3.74 (t, J ) 11.0 Hz, 1H),
3.93-4.01 (m, 1H), 4.38-4.48 (m, 1H), 5.00-5.05 (m, 1H), 5.14
(br s, 1H); 13C NMR (100 MHz, 25 °C, CDCl3) δ 19.7, 28.5, 31.8,
43.6, 49.8, 69.3, 80.5, 90.0, 156.1, 166.0. HRMS-FAB (m/z): [M
+ H]+ calcd for C12H20N2O4‚H+, 257.1501; found, 257.1498 (∆
) 1.2 ppm).
(3R,6S,9R)-1-Aza-9-benzyloxymethyl-3-tert-butoxycarbony-
lamino-5-oxa-2-oxobicyclo[4.3.0]nonane, (3R,6S,9R)-5i. Colorless
oil; 41% yield; 1H NMR (600 MHz, 25 °C, CDCl3) δ 1.41 (s, 9H),
1.66-1.73 (m, 1H), 1.84-1.90 (m, 1H), 1.99-2.04 (m, 1H), 2.17-
2.21 (m, 1H), 3.53 (dd, J ) 9.6, 2.4 Hz, 1H), 3.64 (t, J ) 10.8 Hz,
1H), 3.74 (dd, J ) 9.6, 4.2 Hz, 1H), 4.04 (br s, 1H), 4.27 (br s,
1H), 4.43 (br s, 1H), 4.46 (d, J ) 12.0 Hz, 1H), 4.49 (d, J ) 12.6
Hz, 1H), 5.03 (dd, J ) 8.4, 6.5 Hz, 1H), 5.11 (d, J ) 6.0 Hz, 1H),
7.24-7.36 (m, 5H); 13C NMR (100 MHz, 25 °C, CDCl3) δ 22.7,
28.5, 31.4, 49.9, 56.0, 69.2, 70.7, 73.4, 80.2, 90.1, 127.7, 127.8,
128.6, 138.5, 156.1, 166.7. HRMS-FAB (m/z): [M + Na]+ calcd
for C20H28N2O5‚Na+, 399.1896; found, 399.1909 (∆ ) 3.3 ppm).
(3S,6S,9S)-1-Aza-3-tert-butoxycarbonylamino-9-methyl-5-oxa-
2-oxobicyclo[4.3.0]nonane, (3S,6S,9S)-5j. Colorless needles (from
Single-Crystal X-ray Analyses for (3S,6S,10S)-5d (Figure S1),
(3S,6S,9R)-5h (Figure S2), (3R,6R,9S)-5h (Figure S3), and
(3S,6S,9S)-5j (Figure S4). See the Supporting Information.
Acknowledgment. This research was supported by grants
form the National Institutes of Health (NIGMS) and the National
Science Foundation. The authors would like to thank Professor
Joseph W. Lauher for X-ray crystallographic analyses and Dr.
James Marecek as well as Mr. Francis Picart for their technical
support in 2D and 1D difference NMR analyses at the
Department of Chemistry, State University of New York at
Stony Brook. The authors would like to extend their special
thanks to Mr. Gary Y. H. Teng for providing us with an
imaginative cover art for this article.
1
n-heptane); 94% yield; mp 121-122 °C; H NMR (500 MHz, 25
°C, CDCl3) δ 1.21 (d, J ) 6.0 Hz, 3H), 1.40 (s, 9H), 1.44 (m, 1H),
1.80 (dddd, J ) 15.0, 7.5, 7.5, 4.5 Hz, 1H), 2.10 (dddd, J ) 14.0,
7.5, 7.5, 7.5 Hz, 1H), 2.22 (dddd, J ) 13.5, 7.0, 7.0, 6.5 Hz, 1H),
3.61 (dd, J ) 9.0, 6.0 Hz, 1H), 4.23 (sextet, J ) 6.5 Hz, 1H), 4.30
(m, 2H), 5.05 (dd, J ) 5.5, 5.0 Hz, 1H), 5.50 (br s, 1H); 13C NMR
(100 MHz, 25 °C, CDCl3) δ 20.7, 28.5, 29.4, 31.2, 49.5, 53.7, 68.9,
80.2, 87.4, 156.1, 166.6. HRMS-FAB (m/z): [M + Na]+ calcd for
C13H22N2O4‚Na+, 293.1477; found, 293.1499 (∆ ) 7.5 ppm).
(3R,6R,9S)-1-Aza-3-tert-butoxycarbonylamino-9-methyl-5-
oxa-2-oxobicyclo[4.3.0]nonane, (3R,6R,9S)-5j. Colorless oil; 45%
Supporting Information Available: Characterization data for
1a-k, (S,S)-2a, (S,S)-2d, (R,S)-2e, (S,S)-2f, (S,S)-6b, (R,S)-6b,
(S,S)-6d, (S)-7h, and (R)-7h, full assignments of NMR spectra and
stereochemistry determination for 5a-k, and single-crystal X-ray
analysis data for (3S,6S,9R)-5h, (3R,6R,9S)-5h, and (3S,6S,9S)-5j.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
yield; H NMR (600 MHz, 25 °C, CDCl3) δ 1.31 (d, J ) 6.6 Hz,
3H), 1.41 (s, 9H), 1.65-1.70 (m, 1H), 1.92-2.01 (m, 2H), 2.19-
2.22 (m, 1H), 3.54 (t, J ) 9.0 Hz, 1H), 4.09 (quintet, J ) 6.6 Hz,
1H), 4.32 (q, J ) 7.8 Hz, 1H), 4.40 (t, J ) 9.0 Hz, 1H), 5.10 (t, J
) 6.3 Hz, 1H), 5.49 (br s, 1H); 13C NMR (100 MHz, 25 °C, CDCl3)
δ 19.2, 28.5, 29.6, 30.3, 49.3, 53.2, 68.5, 80.3, 87.2, 156.1, 166.2.
HRMS-FAB (m/z): [M + Na]+ calcd for C13H22N2O4‚Na+,
293.1477; found, 293.1494 (∆ ) 5.8 ppm).
JO061692Y
1882 J. Org. Chem., Vol. 72, No. 6, 2007