Synthesis and conformational analysis of bicyclic extended dipeptide surrogates

Article abstract of DOI:10.1021/jo1008433

(Figure presented) Regio- and diastereoselective reactions of a homoproline enolate enable the synthesis of novel extended dipeptide surrogates. Bicyclic carbamate 9 and fused β-lactam scaffold 11 were prepared from l-pyroglutamic acid via substrate-controlled electrophilic azidation. Synthesis of orthogonally protected hexahydropyrrolizine, hexahydropyrrolizinone, and hexahydropyrroloazepinone dipeptide surrogates relied on allylation of proline derivative 5, followed by Curtius rearrangement to introduce the N-terminal carbamate group. A total of six azabicycloalkane derivatives were evaluated for conformational mimicry of extended dipeptides by a combination of X-ray diffraction and molecular modeling. Analysis of putative backbone dihedral angles and N- to C-terminal dipeptide distances indicate that compounds (α′S)-14b and 21 approximate the conformation of dipeptides found in β-sheets, while tripeptide mimic 28 is also highly extended in the solid state. Structural data suggest that ring size and relative stereochemistry have a profound effect on the ability of these scaffolds to act as β-strand mimetics and should inform the design of related conformational probes.

Full text of DOI:10.1021/jo1008433

pubs.acs.org/joc
Synthesis and Conformational Analysis of Bicyclic Extended Dipeptide
Surrogates
Sujeewa Ranatunga,† Wathsala Liyanage,† and Juan R. Del Valle*,‡
†Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico 88003,
and Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa,
Florida 33612
‡
juan.delvalle@moffitt.org
Received April 30, 2010
Regio- and diastereoselective reactions of a homoproline enolate enable the synthesis of novel
extended dipeptide surrogates. Bicyclic carbamate 9 and fused β-lactam scaffold 11 were prepared
from L-pyroglutamic acid via substrate-controlled electrophilic azidation. Synthesis of orthogonally
protected hexahydropyrrolizine, hexahydropyrrolizinone, and hexahydropyrroloazepinone dipep-
tide surrogates relied on allylation of proline derivative 5, followed by Curtius rearrangement to
introduce the N-terminal carbamate group. A total of six azabicycloalkane derivatives were
evaluated for conformational mimicry of extended dipeptides by a combination of X-ray diffraction
and molecular modeling. Analysis of putative backbone dihedral angles and N- to C-terminal
dipeptide distances indicate that compounds (R0S)-14b and 21 approximate the conformation of
dipeptides found in β-sheets, while tripeptide mimic 28 is also highly extended in the solid state.
Structural data suggest that ring size and relative stereochemistry have a profound effect on the
ability of these scaffolds to act as β-strand mimetics and should inform the design of related
conformational probes.
Introduction
the design and synthesis of various peptidomimetic β-strand
inducers. Nucleation of β-strand conformations in model sys-
tems has generally relied on β-hairpin templates that facilitate
intramolecular backbone contacts between peptide appen-
dages and extended peptide surrogates that replace short
sections of the peptide backbone.2
While conformationally extended peptidomimetics have
often been employed to study the dynamics of β-sheet
formation,3 a number of important enzymatic and protein
surface binding events involve interactions with the side-
chain pharmacophores of isolated β-strand substrates.2,4
The β-strand consists of a highly extended or “sawtooth”
amino acid arrangement and is the simplest peptide secondary
structure motif. β-Strands lack intramolecular hydrogen
bonds between backbone residues and typically interact with
complementary peptide chains to form β-sheets. These super-
secondary structures are key recognition elements in protein-
protein and protein-DNA interactions relevant to cell pro-
liferation, infectious diseases, and neurological disorders.1
The biological relevance of such interactions has prompted
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DOI: 10.1021/jo1008433
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Published on Web 07/01/2010
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FIGURE 2. Design of azabicycloalkane-based dipeptide surrogates.
In efforts toward β-strand peptidomimetics targeting cell
signaling pathways, our laboratory is pursuing the synthesis
of constrained scaffolds to mimic the conformational and
electronic properties of extended peptides. Although rigid
dipeptide mimics have been extensively studied with respect
to turn nucleation, extended dipeptide surrogates are less
common.9 Peptidomimetics based on azabicycloalkane scaf-
folds, for example, have been widely employed as peptide
turn inducers, and their synthesis has been the subject of
comprehensive reviews.10 Conceptually, these scaffolds arise
from a 3-amino (Freidinger-type) lactam constraint,11 fol-
lowed by additional covalent tethering to afford structures of
type A (Figure 2). We envisioned that a 4-, 5-, or 6-amino
lactam constraint (transposition of the carbonyl group)
could be introduced in conjunction with a second backbone
tether to provide scaffolds of type B. The unique azabicy-
cloalkane substitution pattern and highly constrained ψ, φ,
and ω dihedral angles are designed to maintain a sawtooth
peptide backbone arrangement.
FIGURE 1. Selected examples of β-strand peptidomimetics.
For example, farnesyl transferases and Akt (PKB), both of
which are implicated in oncogenesis, are notable examples of
proteins that recognize single β-strand peptides5 as well as
constrained isosteres.6 Previously reported scaffolds often
feature substituted aromatic motifs to impart backbone
rigidity (Figure 1).2b,3g,6a,7 Artificial β-strands composed
entirely of nonpeptidic subunits have also been developed
as potential disruptors of protein-protein interactions.8
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Here, we report our efforts toward novel dipeptide surro-
gates based on structure B. The synthesis of these scaffolds
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SCHEME 1. Diastereoselective Azidation of Homoproline De-
rivative 3
tion of 1,3-allylic strain and reaction with the electrophile on
the less hindered face of the enolate.14
Although derivative 4 served as a useful precursor to the
carbapyochelins (which also harbor an N-Me group), failed
attempts at demethylation15 severely limited the synthetic
utility of the azidation product. We then evaluated the N-
benzyl group as a more convenient protecting group alter-
native. As shown in Scheme 2, acidolysis of the Boc group of 2a
was followed by benzylation to give derivative 5 in 67% yield.
Electrophilic azidation of 5 under the same conditions used for
3
12 resulted in low conversion, indicating that the benzyl group
has a deleterious effect on the reaction. After some optimizi-
taion it was found that the addition of HMPA in the presence
of 2.2 equiv of KHMDS and 2.0 equiv of 2,4,6-triisopropyl-
benezensulfonyl azide gave 84% yield of the desired product (6a)
after acetic acid quenching. We later confirmed that HMPA
was essential to ensure good conversions in the reactions of 5
with other electrophiles. Similar conditions in the presence of
methylbromoacetate afforded 45% isolated yield of 6b,whilethe
use of allyl bromide resulted in 95% yield of 6c. As with proline
3, only one diastereomer was observed in reactions with the
enolate derived from 5. Single-crystal X-ray diffraction carried
out on 6a confirmed the expected stereochemistry at the newly
formed R0 chiral center.
Intermediate 6a was elaborated into novel bicyclic scaffolds
as depicted in Scheme 2. Azide reduction and Boc protection
gave rise to the orthogonally protected bis-amino acid 7. Ethyl
ester reduction with lithium borohydride then afforded amino
alcohol 8 in high yield. Finally, carbamate scaffold 9 was
obtained after hydrogenolysis and treatment of the crude amine
with 1,10-carbonyldiimidazole. A 1-azabicyclo[3.2.0]heptan-7-
one scaffold (11) was also efficiently prepared from intermedi-
ate 7 by way of protecting group removal and treatment with
Mukaiyama’s condensation reagent. Although β-lactam 11
shares its core structure with the carbapencillins and is remini-
scent of β-turn-inducing azabicycloalkanes, its evaluation in
the context of dipeptide mimicry has not been previously
investigated. Unfortunately, although 11 was stable to flash
chromatography over silica gel, we found that an unsoluble gel
formed during attempted acidolysis of the N-Boc group (TFA/
DCM) and even upon prolonged exposure to CHCl3.
relies on regio- and diastereoselective reactions of a homo-
proline enolate and subsequent elaboration into bicyclic core
structures. The current work highlights the synthetic versa-
tility of key chimeric proline intermediates and explores the
ability of our scaffolds to mimic the conformation of ex-
tended dipeptides. Although structures such as B are devoid
of amino acid side chain functionality, the established role of
the extended peptide conformation in molecular recognition
suggests that these surrogates could serve as useful β-strand
inducers and conformational probes.
Results and Discussion
Synthesis. We recently reported the diastereoselective elec-
trophilic azidation of a homoproline en route to analogues of
the Pseudomonas siderophore pyochelin (Scheme 1).12 In our
studies, it became apparent that the ability to react enolates of
2 with alkylating reagents could lead to synthetically useful
and diversely substituted proline derivatives. Although simi-
lar alkylations of urethane-protected homoprolines have been
reported to proceed uneventfully,13 we found that the enolates
formed from 2 failed to give satisfactory yields of R0-substi-
tuted products. In most cases, we recovered unreacted starting
material along with ring-opened enoates resulting from re-
verse-Michael addition. In contrast, when the urethane pro-
tecting group was replaced with a methyl substituent (3),
azidation in the presence of LiHMDS and 2,4,6-triisopropyl-
benezensulfonyl azide afforded 4 in 71% isolated yield.
Analysis of the crude product mixture by 1H NMR revealed
the presence of only one diastereomer, later identified as the
anti isomer by X-ray diffraction of an advanced intermediate.
The stereochemical outcome can be rationalized by minimiza-
We next turned our attention to the synthesis of larger
bicyclic lactams starting from 6b and 6c (Scheme 3).
Although we previously observed modest conversion of 5
into triester 6b, the introduction of a methoxycarbonyl-
methyl group allowed rapid access to a hexahydropyrrolizi-
none scaffold. Hydrogenolysis of the N-benzyl group,
followed by heating in toluene, resulted in selective lactami-
zation to afford 12 in 89% yield. Somewhat surprisingly, we
found that treatment of diester 12 with 1 M aqueous LiOH in
MeOH resulted in isolation of the diacid as the major
product. The unusual lability of the tert-butyl ester required
the use of 1.5 equiv of LiOH and close monitoring to effect
selective saponification.16 Although near-quantitave yield of
1
13 was obtained, the H and 13C NMR spectra revealed
(14) Similar stereochemical outcomes were observed in the examples from
ref 13.
(12) Liyanage, W.; Weerasinghe, L.; Strong, R. K.; Del Valle, J. R. J. Org.
Chem. 2008, 73, 7420–7423.
(13) (a) Knight, D. W.; Share, A. C.; Gallagher, P. T. J. Chem. Soc.,
Perkin Trans. 1 1997, 2089–2098. (b) Hanessian, S.; Sharma, R. Heterocycles
2000, 52, 1231–1239. (c) Yi, J. J.; Hua, Z. M.; Rong, T. G. Synth. Commun.
2003, 33, 3913–3917.
(15) (a) Olofson, R. A.; Martz, J. T.; Senet, J. P.; Piteau, M.; Malfroot, T.
J. Org. Chem. 1984, 49, 2081–2082. (b) Olofson, R. A.; Schnur, R. C.
Tetrahedron Lett. 1977, 18, 1571–1574.
(16) Use of excess trimethyltin hydroxide as a mild ester deprotection reagent
gave only trace amounts of the desired acid. See: Nicolaou, K. C.; Estrada, A. A.;
Zak, M.; Lee, S. H.; Safina, B. S. Angew. Chem., Int. Ed. 2005, 44, 1378–1382.
J. Org. Chem. Vol. 75, No. 15, 2010 5115

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SCHEME 2. Synthesis of Scaffolds 9 and 11a
a(brsm = based on recovered starting material).
SCHEME 3. Epimerization en Route to Bicyclic Lactams 14
and 17
ethyl ester resulted in two diastereomeric lactam products.
However, in this case the tert-butyl ester group remained
intact in the presence of 1 M aqueous NaOH. The mixture of
diastereomers were then subjected to Curtius rearrangement to
give compounds 17, which were separable by careful column
chromatography over silica gel. 1D NOE studies revealed a
correlation between the carbamate N-H proton and Hδ in
only one of the two diastereomers of 17. These results con-
firmed that epimerization occurs at the R0 rather than R center
and allowed stereochemical assignment of each product.
To circumvent the configurational lability of 12 and 16, we
opted to change the order of operations in our synthetic
strategy. As shown in Scheme 4, the ethyl ester of 6c was
efficiently hydrolyzed without epimerization in the presence
of 2 M aqueous NaOH and catalytic tetrabutylammonium
hydroxide at 50 °C.17 Curtius rearrangement in the presence
of 2,2,2-trichloroethanol then afforded orthogonally pro-
tected diamino acid 19 in good yield. Hexahydropyrrolizi-
none 21 was formed via oxidative olefin cleavage, followed
by aldehyde oxidation, hydrogenolysis, and lactamization in
the presence of HBTU. To access the hexahydropyrroloaze-
pinone variant (23), intermediate 19 was subjected to cross
metathesis prior to hydrogenation and condensation. We
found the hydrogenation steps particularly challenging as a
result of the lability of the chlorine atoms of the trichlor-
oethoxycarbonyl (Troc) protecting groups. The use of Pearl-
man’s catalyst was required for efficient removal of the
N-benzyl group, but the des-chloro ethyl carbamate analogues
of 21 and 23 were also isolated as side products. Optimized
hydrogenation conditions and careful monitoring of reaction
progress did, however, provide 21 and 23 as single diastereo-
mers suitable for incorporation into peptide host sequences.
The synthesis of a [5,7]-fused carbamate from N-trimethyl-
silylethoxycarbonyl derivative 24 was also investigated
(Scheme 5). In this case, dihydroxylation and cleavage of
olefin 24 was followed by aldehyde reduction and debenzyla-
tion. Treatment of the resulting amine with 1,10-carbonyldii-
midazole (CDI) resulted in the formation of hexahydro-
pyrrolizine 26 instead of the desired seven-membered cyclic
significant epimerization despite the mild hydrolysis condi-
tions. The inseparable acids were then subjected to Curtius
rearrangement in the presence of various alcohols to give
carbamates 14a-c as diastereomeric mixtures.
In order to prepare a homologous hexahydropyrroloaze-
pinone core, allyl derivative 6c was subjected to cross-
metathesis with benzyl acrylate to give 15. Removal of both
benzyl groups and concomitant reduction of the alkene
was followed by lactamization in the presence of HBTU
(O-benzotriazole-N,N,N0,N0-tetramethyl-uronium-hexafluoro-
phosphate) to give 16. As with 12, alkaline hydrolysis of the
(17) The configurational instability of 12 and 16 versus 6c is likely due to
steric interactions of the endo R0 substituent in the convex bicyclic frame-
works. On the basis of the X-ray structure of 23, the ethylcarboxy substituent
in 16 presumably also occupies an axial position.
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SCHEME 4. Diastereoselective Synthesis of 21 and 23
SCHEME 6. C-Terminal Coupling of Scaffolds 9, 21, and 23
toward hydrolysis prompted us to investigate aqueous
base as a selective deprotection alternative. We found that
2 M aqueous NaOH at room temperature was effective for
providing the carboxylic acid in high yield. Coupling to
phenylalanine methyl ester proceeded uneventfully to give
tripeptide mimic 28 in diastereomerically pure form, indicat-
ing negligible epimerization during hydrolysis and C-term-
inal condensation. In the case of lactams 21 and 23, tert-butyl
ester cleavage with TFA was followed by condensation with
phenylalanine tert-butyl ester to give 29 and 30, which were
also diastereomerically pure by RP-HPLC and NMR.
Finally, we sought to demonstrate the ability to introduce
lactam constraints following incorporation into a short
peptide (Scheme 7). We utilized the configurationally stable
N-benzyl derivative 19 as a starting material for dipetide
formation. Cross-metathesis, hydrogenation, and lactamiza-
tion, as described above, afforded tripeptide mimic 30 in an
slightly higher overall yield relative to the route in Scheme 6.
Analysis by RP-HPLC and NMR revealed a single diaster-
eomer. Compound 31 was also transformed into lactam 29 in
reasonable yield and high diastereomeric purity. This strat-
egy represents a potentially useful alternative in cases where
peptide coupling to preformed bicyclic scaffolds may present
a challenge.
SCHEME 5. UnexpectedFormationof Hexahydropyrrolizine 26
Configurational and Conformational Analysis. The ability
of the above-described azabicycloalkanes to act as structu-
rally defined dipeptide surrogates was evaluated by a com-
bination of X-ray crystallography and molecular modeling.
With respect to β-strand mimicry, we have targeted scaffolds
that severely restrict the ψ and φ dihedral angles of sequential
amino acid residues (in addition to the ω torsion defined
by the central trans amide bond). In β-sheet peptides, ψ and φ
torsions are generally of similar magnitude (in the range of
113° to 139°) but of opposite sign.9,19 This alternation is
critical for maintaining an extended conformation over
longer sections of a peptide. Because of the transposition
of the carbonyl group in our scaffolds, we have labeled the
dihedral angles in relation to the backbone torsions they are
meant to replace, as shown in Figure 3.
carbamate, likely through 5-exo-tet displacement.18 Attempts
to carry out the same transformation with triphosgene
and nitrophenylchloroformate also failed to provide carba-
mate 27.
We next carried out the coupling of our scaffolds in order
to demonstrate their suitability for incorporation into pep-
tides (Scheme 6). Various attempts to selectively remove the
N-Boc group in 9 under mildly acidic conditions resulted in
concomitant tert-butyl ester cleavage. The previously ob-
served sensitivity of the tert-butyl ester in compound 12
The X-ray structure of (R0S)-14b, the major isomer of which
crystallized out of EtOAc/hexanes, is shown in Figure 4A. In
the solid state, (R0S)-14b exhibits an “up-down” relationship
between the N-H andC-terminalcarbonyl groupreminiscent
of a sawtooth extended dipeptide. Moreover, the distance
˚
between the terminalnitrogen and carbonylcarbonis 5.7 A, as
˚
compared to ∼5.9 A typically found across the dipeptide of a
(18) For a study on similar reaction pathways with 1,10-carbonyldiimi-
€
dazole, see: de Figueiredo, R. M.; Frohlich, R.; Christmann, M. J. Org.
Chem. 2006, 71, 4147–4154.
(19) Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem. Rev.
2001, 101, 3131–3152.
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SCHEME 7. Introduction of Lactam Constraint after Incorporation
pattern (both the hydrogen bond donor and acceptor are
oriented in the same direction, linking the two molecules in a
macrocyclic motif). In addition to crystal packing forces, this
conformation is assumed to be largely dependent on the
stereochemical relationship between the chiral centers of the
bicyclic scaffold. As opposed to compounds (R0S)-14b and
23, the terminal acyloxyamine in 28 resides on the exo face of
the ring system. This difference is clearly manifested in the ψ1
dihedral angle of þ171.4°,21 which is not only higher magni-
tude but of the same sign as the φ1 torsion. As with (R0S)-14b,
the distance between the terminal nitrogen and the scaffold
carbonyl carbon in 28 was near that observed in an ideal
FIGURE 3. Backbone torsions and N-to-C dipeptide distance for
β-strands and synthetic dipeptide surrogates.
˚
extended dipeptide (5.9 A for each molecule in the dimer).
Azabicycloalkanes 11, (R0R)-17, and 26 represent addi-
tional scaffolds that were synthetically accessible but not
initially targeted as β-strand mimics. Still, we sought to
evaluate their conformational properties by molecular mod-
eling after attempts to obtain diffraction quality crystals
were unsuccessful. We performed a conformational search
using Macromodel with the MM3* force field.22 In each case
the 50 lowest energy conformers exhibited only slight differ-
ences in the constrained dihedral angles. Calculated torsions
and distances from molecular mechanics (given for the low-
est energy conformer) are shown in Table 1.
As expected, azabicyclo[3.2.0]heptan-7-one scaffold 11
exhibits ψ1 and φ2 angles that are of the same sign (as in
the case of 28), owing to the exo carbamate substituent. The
low energy conformer of compound (R0R)-17 features a
similar relationship, in addition to a putative ω torsion that
deviates significantly from planarity. Energy minimization
of hexahydropyrrolizine 26, which lacks a carbonyl group,
resulted in an opening of the ψ1 torsion relative to the bicyclic
lactam. However, the calculated ω dihedral angle closes as
the result of a change in nitrogen bond order. Although
scaffold 26 is not isoelectronic with a native peptide back-
bone, its structure and conformation suggest potential utility
as an extended dipeptide scaffold. We further note that
compound 26 was also synthesized in a more direct manner
from 24 by oxidation followed by hydrogenolysis (75%
overall yield).23
β-strand. Examination of the putative ψ1 and φ2 dihedral
angles in (R0S)-14b reveals values of -112.8° and þ102.4°,
respectively. These values correspond well to the torsions
found in a typical parallel β-sheet peptide.20 In addition, the
ω surrogate dihedral angle is þ156.8°, which deviates only
slightly from the ideal 180° despite the tetrahedral geometry at
C5. Bicyclic lactam 21, which differs only in N-terminal
protection, is expected to exhibit the same conformational
characteristics as (R0S)-14b. Since 21 is readily accessible in
diastereomerically pure form, it should serve as a useful
building block for the introduction of a β-strand dipeptide
mimic into host structures.
Hexahydropyrroloazepinone 23 yielded diffraction qual-
ity crystals by slow evaporation from diethyl ether/hexanes
(Figure 4B). Although the putative φ2 angle in compound 23
is close to that found in hexahydropyrrolizinone (R0S)-14b,
the ψ1 torsion deviates significantly as the result of the axial
disposition of the Troc-carbamate substituent. Moreover,
the putative ω angle is more acute relative to that in the
hexahydropyrrolizinone scaffold. Taken together, these con-
straints result in an N- to C-terminal distance much shorter
˚
(4.8 A) than that expected for an extended dipeptide.
Although we did not obtain diffraction quality crystals of
carbamate scaffold 9, we did obtain an X-ray structure of
phenylalanyl derivative 28 (Figure 4C). Interestingly, this
compound features two intermolecular H-bonds at either
end of the bicyclic scaffold and exists as a head-to-tail dimer
in the solid state. Since the rigid core is intended to replace a
sawtooth dipeptide, the observed conformation for the N-H
and carbonyl groups deviates from the expected alternating
Finally, the X-ray structures in Figure 4 serve to establish
the relative configuration of each bicyclic scaffold. The anti
relationship resulting from functionalization of 5 is thus
(20) It should be noted that these values are of roughly equal and opposite
sign, which is the principle requirement for our surrogates. However,
mimicry of a natural L,L-dipeptide strand would require the synthesis of
the enantiomer scaffold starting from D-pyroglutamic acid.
(21) Measured torsions and distances for 28 are given as the average
between the two molecules in the dimer.
(22) See Supporting Information for details.
(23) See Experimental Section for details.
5118 J. Org. Chem. Vol. 75, No. 15, 2010

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FIGURE 4. X-ray structures and calculated torsions in degrees for compounds (R0S)-14b, 23, and 28 (most hydrogens omitted for clarity).
0
˚
TABLE 1. Calculated Torsions (deg) and Distances (A) for 11, (R R)-
analysis (single spot/two solvent systems) using a UV lamp, CAM
(ceric ammonium molybdate), ninhydrin, or basic KMnO4 stain-
(s) for detection purposes. NMR spectra were recorded on a 400
MHz spectrometer. 1H and 13C NMR chemical shifts are reported
as δ using residual solvent as an internal standard. Analytical high
performance liquid chromatography (HPLC) was performed on a
C18 reverse phase analytical column. HPLC elution was carried
out with a 20 min linear gradient of MeCN in water (each
containing 0.1% formic acid buffer).
17, and 26 from MM3* Conformational Searches22
scaffold
ψ1
φ2
ω
N
CO distance
3 3 3
11
(R0R)-17
26
þ116.0
þ160.3
-147.3
þ115.6
þ105.0
þ147.1
þ148.0
þ111.6
þ121.2
5.4
5.9
6.0
confirmed, supporting the proposed A1,3-minimized stereo-
chemical model for the N-benzyl series. The structure of 23
also provides confirmation of the proposed stereochemistry
of 21 and 26, both of which are derived from allylated
intermediate 6c.
(2S,5S)-tert-Butyl 1-Benzyl-5-(2-ethoxycarbonylmethyl)pyr-
rolidine-2-carboxylate (5). A solution of 2a (9.50 g, 26.6 mmol)
in 10% TFA/DCM was stirred at rt for 5 h. The reaction
solution was diluted with EtOAc and evaporated under reduced
pressure (dilution and evaporation was repeated two times). The
resulting sticky foam was dissolved in 150 mL of acetone,
treated with benzyl bromide (7.90 mL, 66.5 mmol) and K2CO3
(36.7 g, 266 μmol), and stirred for 1 d. The resulting white
suspension was filtered through a Celite pad and rinsed with
excess acetone. The filtrate was evaporated to afford a white
slurry, which was then dissolved in water and extracted with
EtOAc. The combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure. Purification
by flash chromatography over silica gel (3% to 20% EtOAc/
hexanes as eluent) afforded 5 as a colorless oil (6.15 g, 67% over
2 steps, 72% based on recovered starting material). [R]25D -74.5
Conclusion
We have prepared a series of novel azabicycloalkanes
as potential extended dipeptide surrogates via regio- and
stereoselective reactions of a chimeric homoproline enolate.
Orthogonally protected bicyclic scaffolds are obtained in
reasonable overall yields and high diastereomeric purities.
Conformational analysis by X-ray diffraction and molecular
modeling indicate that relative stereochemistry and ring size
have a profound effect on key dihedral angles. Hexahydro-
pyrrolizinones (R0S)-14b and 21 share a number of confor-
mational characteristics with extended dipeptides found
in parallel β-sheets. Scaffold 9 may also serve as a useful
extended dipeptide surrogate based on X-ray structure data
obtained for tripeptide mimic 28. The synthetic routes
described here highlight the versatility of proline derivative
5 and should allow access to additional probes of local
peptide conformation. We are currently pursuing the synth-
esis of functionalized derivatives to mimic a wider array of
extended dipeptides. Studies on the incorporation of selected
scaffolds into β-strand peptides involved in oncogenic sig-
naling are also underway in our laboratory.
1
(c 3.6, CHCl3); H NMR (400 MHz, CDCl3) δ 7.38-7.16 (m,
5H), 4.11 (q, J = 7.1, 2H), 3.94 (d, J = 13.6, 1H), 3.80 (d, J =
13.6, 1H), 3.43 (m, 1H), 3.43 (dd, J = 8.1, 1.3, 1H), 2.58 (dd, J =
14.5, 3.9, 1H), 2.26 (ddd, J = 17.2, 13.4, 8.8, 2H), 2.06 (ddd, J =
18.4, 12.9, 9.7, 1H), 1.75 (m, 2H), 1.44 (s, 9H), 1.24 (t, J = 7.1,
3H); 13C NMR (101 MHz, CDCl3) δ 173.9, 172.5, 139.8, 128.8,
128.4, 127.1, 80.7, 63.9, 60.4, 58.9, 52.9, 40.3, 29.7, 28.4, 27.9,
14.5; HRMS (ESI-TOF) (m/z) [MH]þ calcd for C20H29NO4
348.21693, found 348.21646.
(2S,5S)-tert-Butyl 5-((S)-1-Azido-2-ethoxycarbonylmethyl)-
1-benzylpyrrolidine-2-carboxylate (6a). A solution of 5 (1.00 g,
2.88 mmol) in 20 mL of THF under argon at -78 °C was treated
with KHMDS (0.5 M in toluene, 12.7 mL, 6.34 mmol) and
stirred for 45 min. HMPA (1.10 mL, 6.34 mmol) was added, and
the reaction was stirred another 15 min at the same temperature.
A solution of 2,4,6-triisopropylbenzenesulfonyl azide (1.78 mL,
5.76 mmol) in 2.0 mL of THF was cannulated into the reaction
mixture. After 2-3 min the reaction was quenched with glacial
acetic acid (830 μL, 14.4 mmol) and stirred for 16 h with gradual
warming to rt. The reaction solution was evaporated, taken up
in 10% aq NaHCO3, and extracted with EtOAc. The combined
organic layers were dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. Purification by flash chroma-
tography over silica gel (5% EtOAc/hexanes as eluent) afforded
Experimental Section
General. Unless stated otherwise, reactions were performed
in flame-dried glassware under a positive pressure of argon or
nitrogen gas using dry solvents. Commercial grade reagents
and solvents were used without further purification except
where noted. Diethyl ether, toluene, dimethylformamide dichlor-
omethane, and tetrahydrofuran were purified by solvent purifica-
tion system. Other anhydrous solvents were purchased directly
from chemical suppliers. Thin-layer chromatography (TLC) was
performed using silica gel 60 F254 precoated plates (0.25 mm).
Flash chromatography was performed using silica gel (60 μm
particle size). The purity of all compounds was judged by TLC
6a as a white solid (930 mg, 84%). Mp 82-84°; [R]25 -80.0
D
1
(c 0.8, CHCl3); H NMR (400 MHz, CDCl3) δ 7.35-7.21 (m,
J. Org. Chem. Vol. 75, No. 15, 2010 5119

Ranatunga et al.
JOCArticle
5H), 4.20 (qd, J = 7.2, 2.7, 2H), 4.08 (d, J = 2.6, 1H), 4.03 (d,
J = 13.3, 1H), 3.94 (d, J = 13.3, 1H), 3.77 (m, 1H), 3.59 (d, J =
7.1, 1H), 2.12 (m, 2H), 1.81 (m, 2H), 1.43 (s, 9H), 1.27 (t, J = 7.1,
3H); 13C NMR (101 MHz, CDCl3) δ 173.6, 169.1, 138.9, 129.1,
128.6, 127.5, 81.0, 64.7, 64.6, 64.5, 61.9, 53.6, 28.9, 28.3, 25.5,
14.4; HRMS (ESI-TOF) (m/z) [MH]þ calcd for C20H28N4O4,
389.21833, found 389.22139, [M þ Na]þ calcd 411.20028, found
411.20342.
(2S,5S)-tert-Butyl 1-Benzyl-5-((S)-1-(tert-butoxycarbonyla-
mino)-2-hydroxyethyl)pyrrolidine-2-carboxylate (8). A solution
of 7 (870 mg, 1.88 mmol) in Et2O under argon atmosphere at rt
was treated with LiBH4 (2 M in THF, 1.60 mL, 3.20 mmol) and
stirred for 6.5 h. The reaction was quenched with 1 M aq NaOH
(4 mL) and stirred for 10 min. After dilution with water, the
mixture was stirred vigorously for 30 m. The aqueous layer was
extracted with EtOAc, and the combined organic layers were
dried over anhydrous Na2SO4 and evaporated. Purification by
flash chromatography over silica gel (50% EtOAc/hexanes as
eluent) afforded 8 as a white solid (730 mg, 92%). Mp 113-115°;
[R]25D -47.3. (c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.27
(m, 5H), 5.43 (bs, 1H), 5.01 (bs, 1H), 3.94 (d, J = 13.2, 1H), 3.78
(m, 2H), 3.60 (m, 3H), 3.45 (d, J = 7.4, 1H), 1.99 (m, 2H), 1.76
(dd, J = 12.4, 9.9, 1H), 1.63 (m, 1H), 1.46 (s, 9H), 1.45 (s, 9H);
13C NMR (101 MHz, CDCl3) δ 173.3, 158.4, 138.8, 129.1, 128.6,
127.5, 81.2, 80.3, 65.8, 63.4, 62.7, 54.6, 52.8, 28.6, 28.4, 28.2, 24.8;
HRMS (ESI-TOF) (m/z) [MH]þ calcd for C23H36N2O5 421.26970,
found 421.27058, [M þ Na]þ calcd 443.25164, found 443.25554.
(4S,4aS,7S)-tert-Butyl 4-(tert-butoxycarbonylamino)-1-oxoh-
exahydro-1H-pyrrolo[1,2-c][1,3]oxazine-7-carboxylate (9). A so-
lution of 8 (715 mg, 1.70 mmol) in 7 mL of MeOH was treated
with 250 mg of 20% Pd(OH)2/C and stirred under H2 (balloon)
at rt for 2.5 h. The reaction solution was filtered through a Celite
pad and rinsed with excess MeOH. The filtrate was evaporated
under reduced pressure to afford a thick colorless oil (562 mg,
quantitative yield).
The above amino alcohol (360 mg, 1.09 mmol) was dissolved in
10 mL of THF and treated with triethylamine (230 μL, 1.64
mmol), 4-dimethylaminopyridine (130 mg, 1.09 mmol), and 1,10-
carbonyldiimidazole (880 mg, 5.45 mmol), respectively. After
stirring for 3.5 h at rt, the reaction mixture was evaporated, taken
up in EtOAc, and washed with 1 M aq HCl. The aqueous layer
was dried over anhydrous Na2SO4, filtered, and evaporated. The
crude residue was adsorbed onto silica gel and purified by flash
chromatography over silica (60% to 80% EtOAc/hexanes as
eluent) to afford 9 as a white solid (357 mg, 92%). Mp 208-210°-
(dec); [R]25D -43.1 (c 0.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ
4.76 (d, J = 8.8, 1H), 4.37 (t, J = 8.3, 1H), 4.29 (dd, J = 10.5, 4.6,
1H), 3.98 (t, J = 10.7, 1H), 3.79 (m, 1H), 3.52 (td, J = 9.4, 5.0,
1H), 2.36 (m, 1H), 2.24(m, 1H), 1.71 (m, 2H), 1.46 (s, 9H), 1.42 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 171.6, 155.1, 151.7, 82.2,
80.8, 68.5, 61.6, 60.8, 48.2, 31.5, 28.5, 28.2, 28.0; HRMS (ESI-TOF)
(m/z) [MH]þ calcd for C17H28N2O6 357.20201, found 357.20442,
[M þ Na]þ calcd 379.18396, found 379.18658.
(S)-1-Ethyl 4-Methyl 2-((2S,5S)-1-benzyl-5-(tert-butoxycarbonyl)-
pyrrolidin-2-yl)succinate (6b). A solution of 5 (1.00 g, 2.88 mmol) in
12 mL of THF under argon at -78 °C was treated dropwise with
KHMDS (0.5 M in toluene, 7.49 mL, 3.75 mmol) and stirred for
30 min. HMPA (1.10 mL, 6.34 mmol) was added and stirred
another 10 min at the same temperature. Methyl bromoacetate
(580 μL, 6.34 mmol) was then added dropwise into the mixture,
and the reaction was stirred for 40 min. The reaction was
quenched with sat. aq NH4Cl, and the aqueous layer was extra-
cted with EtOAc. The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
Purification by flash chromatography over silica gel (5% to 10%
EtOAc/hexanes as eluent) afforded 6b as a colorless oil (540 mg,
45%, 79% borsm). [R]25D -39.9 (c 0.8, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.33-7.18 (m, 5H), 4.15 (m, 2H), 3.96 (d, J =
13.3, 1H), 3.80 (m, 2H), 3.67 (s, 3H), 3.44 (d, J = 7.5, 1H), 3.24
(dt, J = 10.4, 3.8, 1H), 2.76 (dd, J = 16.8, 3.6, 1H), 2.67 (dd, J =
16.7, 10.4, 1H), 2.04 (m, 1H), 1.87 (m, 1H), 1.66 (m, 2H), 1.43 (s,
9H), 1.26 (t, J = 7.1, 3H); 13C NMR (101 MHz, CDCl3) δ 173.9,
173.8, 173.6, 139.2, 128.9, 128.5, 127.3, 80.9, 63.8, 62.0, 60.9, 52.8,
51.9, 43.7, 29.6, 28.6, 28.4, 25.2, 14.4; HRMS (ESI-TOF) (m/z)
[MH]þ calcd for C23H33NO6 420.23806, found 420.23877, [M þ
Na]þ calcd 442.22001, found 442.2197.
(2S,5S)-tert-Butyl 1-Benzyl-5-((S)-1-ethoxy-1-oxopent-4-en-
2-yl)pyrrolidine-2-carboxylate (6c). Triester 6c was prepared
from 5 following the same procedure described for 6b, with
methyl bromoacetate in place of allyl bromide. Purification of
the crude rmaterial by flash chromatography over silica gel (5%
EtOAc/hexanes as eluent) afforded 6c as a colorless oil (3.20 g,
95%). [R]25D -55.8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.27 (m, 5H), 5.74 (ddt, J = 17.0, 10.1, 6.8, 1H), 5.04 (ddd, J =
17.1, 3.2, 1.5, 2H), 4.96 (m, 1H), 4.11 (m, 2H), 3.96 (d, J = 13.7,
1H), 3.83 (d, J = 13.6, 1H), 3.64 (dt, J = 9.3, 3.7, 1H), 3.49 (d,
J = 7.0, 1H), 2.63 (m, 1H), 2.47 (m, 1H), 2.37 (m, 1H), 1.93
(m, 3H), 1.73 (dd, J = 11.3, 8.6, 1H), 1.44 (s, 9H), 1.24 (t, J =
7.1, 3H); 13C NMR (101 MHz, CDCl3) δ 174.4, 173.8, 139.8,
137.0, 128.8, 128.5, 127.1, 116.1, 80.8, 64.1, 63.2, 60.5, 53.1, 48.4,
29.5, 28.8, 28.4, 25.5, 14.5; HRMS (ESI-TOF) (m/z) [MH]þ
calcd for C23H33NO4 388.24901, found 388.24665.
(2S,5S)-tert-Butyl 1-Benzyl-5-((S)-1-(tert-butoxycarbonylamino)-
2-ethoxycarbonylmethyl)pyrrolidine-2-carboxylate (7). A solution
of 6a (810 mg, 2.10 mmol) and triphenylphosphine (1.21 g, 4.62
mmol) in 12 mL of THF was refluxed for 2 h, and 500 μL of water
was added. After another24h ofrefluxing, triethylamine(880 μL,
6.30 mmol) was added followed by di-tert-butyl dicarbonate
(590 mg, 2.73 mmol), and the reaction was stirred for an additional
24 h at rt. The reaction was quenched with sat. aq NH4Cl and the
aqueous layer was extracted with EtOAc. The combined organic
layers were dried over anhydrous Na2SO4 and evaporated under
reduced pressure. Purification by flash chromatography over
silica gel (5% to 10% EtOAc/hexanes as eluent) afforded 7 as a
thick colorless oil (920 mg, 94%). [R]25D -26.9 (c 0.9, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.24 (m, 5H), 5.16 (m, 1H), 4.49 (m,
1H), 4.20 (q, J = 7.1, 2H), 4.02 (d, J = 12.6, 1H), 3.77 (d, J =
12.8, 2H), 3.40 (d, J = 7.0, 1H), 1.97 (m, 2H), 1.75 (m, 2H), 1.45
(m, 18H), 1.27 (t, J = 7.1, 3H); 13C NMR (101 MHz, CDCl3) δ
173.6, 171.9, 156.1, 139.0, 129.2, 128.4, 127.3, 80.9, 79.9, 63.4, 62.5,
61.4, 54.7, 52.3, 28.6, 28.3, 28.1, 25.0, 14.4, 1.3; HRMS (ESI-TOF)
(m/z) [MH]þ calcd for C25H38N2O6 463.28026, found 463.28064,
[M þ Na]þ calcd 485.26221, found 485.26586.
(S)-2-((2S,5S)-5-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-2-(tert-
butoxycarbonylamino)acetic Acid (10). A solution of 7 (280 mg,
605 μmol) in 6 mL of THF/H2O (1:1) at rt was treated with LiOH
(78.8 mg, 1.88 mmol) and stirred for 7 h. The reaction solution
was evaporated under reduced pressure. The aqueous layer was
washed with Et2O, acidified with 1 M aq HCl, and extracted with
EtOAc. The combined organic layers were dried over anhydrous
Na2SO4 and evaporated to afford a white solid (250 mg, 96%).
[R]25D -15.5 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28
(m, 5H), 5.45 (bs, 1H), 4.45 (bs, 1H), 4.13 (m, 1H), 3.97 (m, 2H),
3.52 (d, J = 7.6, 1H), 2.18 (m, 1H), 2.03 (m, 1H), 1.83 (m, 2H),
1.45 (m, 18H); 13C NMR (101 MHz, CDCl3) δ 174.3, 172.1,
157.0, 137.1, 129.4, 128.7, 127.9, 81.8, 80.6, 63.9, 63.5, 54.9, 52.8,
28.6, 28.3, 28.2, 25.2.
The above acid (200 mg, 460 μmol) was dissolved in 2 mL of
MeOH and treated with 69 mg of 20% Pd(OH)2/C and stirred
under H2 (balloon) for 1.25 h. The reaction solution was filtered
through a Celite pad and rinsed with excess MeOH. The filtrate
was evaporated in vacuo to afford 10 as a white solid (160 mg,
1
quantitative yield). Mp 163-165° (dec); H NMR (400 MHz,
CDCl3) δ 7.26 (m, 2H), 5.96 (d, J = 6.4, 1H), 4.23 (m, 1H), 4.15
(t, J = 7.2, 1H), 3.94 (dd, J = 13.3, 6.7, 1H), 2.45 (m, 1H), 2.17
(m, 1H), 2.05 (m, 2H), 1.47 (s, 9H), 1.41 (s, 9H); 13C NMR (101
5120 J. Org. Chem. Vol. 75, No. 15, 2010

Ranatunga et al.
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MHz, CDCl3) δ 173.1, 168.6, 157.0, 84.0, 80.0, 62.7, 59.5, 54.6,
28.6, 28.5, 28.1, 26.9; HRMS (ESI-TOF) (m/z) [MH]þ calcd
for C17H28N2O6 345.20201, found 345.20310, [M þ Na]þ calcd
367.18396, found 367.18288.
was stirred at 110 °C for 20 h. The reaction solution was
evaporated under reduced pressure and adsorbed onto silica gel.
Purification by flash chromatography over silica gel (5% to 10%
EtOAc/hexanes as eluent) afforded 14a as a ∼3:1 mixture of
diastereomers(118 mg, 60%). 1H NMR(400 MHz, CDCl3) δ 7.35
(m, 5H), 5.36 (d, J = 8.0, 1H), 5.11 (m, 2H), 4.41 (m, 1H), 4.27
(dd, J = 13.5, 6.1, 1.5H), 4.09 (m, 0.25H), 3.86 (dt, J = 13.1, 6.5,
0.25H), 3.13 (dd, J = 17.0, 7.2, 1H), 2.81 (dd, J = 16.3, 8.6,
0.25H), 2.64 (dt, J = 8.8, 7.3, 0.25H), 2.39 (m, 1H), 2.24 (d, J =
17.1, 1H), 2.05 (m, 1H), 1.89 (m, 1H), 1.61 (m, 1H), 1.45 (s, 9H);
13C NMR (101 MHz, CDCl3) δ 171.8, 170.8, 156.2, 136.4, 128.8,
128.8, 128.6, 128.5, 128.4, 128.3, 82.2, 67.2, 66.0, 55.7, 49.4,
42.0, 32.5, 28.2, 24.6; HRMS (ESI-TOF) (m/z) [MH]þ calcd
for C20H26N2O5 375.19217, found 375.19207, [M þ Na]þ calcd
397.17339, found 397.17330.
(3S,7aS)-tert-Butyl 7-(tert-Butoxycarbonylamino)-5-oxohexa-
hydro-1H-pyrrolizine-3-carboxylate (14b). N-Boc derivative 14b
was prepared from 13 following the same procedure described for
14a, with tert-butyl alcohol in place of benzyl alcohol. Purifica-
tion by flash chromatography over silica gel (5% to 10% EtOAc/
hexanes as eluent) afforded 14b as a ∼3:1 mixture of diastereo-
mers (26%). 1H NMR (400 MHz, CDCl3) δ 4.95 (dd, J = 21.2,
6.8, 1H), 4.29 (m, 3H), 4.00 (m, 0.25 H), 3.82 (m, 0.25), 3.12 (dd,
J = 17.0, 7.2, 1H), 2.79 (m, 1H), 2.61 (m, 0.25H), 2.43(m, 1.25H),
2.22 (d, J = 17.0, 1H), 2.05 (m, 1H), 1.88 (bs, 1H), 1.60 (m, 1H),
1.43 (m, 18H); 13C NMR (101 MHz, CDCl3) δ 171.8, 171.1,
170.9, 155.5, 82.1, 82.0, 80.2, 66.2, 56.0, 55.6, 48.7, 41.9, 32.4,
32.0, 30.9, 28.6, 28.5, 28.2, 24.7; HRMS (ESI-TOF) (m/z) [MH]þ
calcd for C17H28N2O5 341.20710, found 341.20804, [M þ Na]þ
calcd 363.18904, found 363.18941.
(3S,7aS)-tert-Butyl 5-Oxo-7-((2-(trimethylsilyl)ethoxy)carbony-
lamino)hexahydro-1H-pyrrolizine-3-carboxylate (14c). N-Teoc de-
rivative 14c was prepared from 13 following the same procedure
described for 14a, with 2-trimethylsilylethanol in place of benzyl
alcohol. Purification by flash chromatography over silica gel (5%
to 10% EtOAc/hexanes as eluent) afforded 14c as a ∼3:1 mixture
of diastereomers (57%); 1H NMR (400 MHz, CDCl3) δ 5.25 (d,
J = 8.1, 1H), 4.38 (m, 1H), 4.24 (m, 2H), 4.11 (m, 2H), 3.12 (dd,
J = 17.0, 7.2, 1H), 2.37 (m, 1H), 2.21 (d, J = 17.0, 1H), 2.04 (m,
1H), 1.86 (m, 1H), 1.62(m, 1H), 1.43 (s, 9H), 0.93 (m, 2H), 0.00 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 173.2, 172.2, 157.8, 83.4,
67.3, 65.0, 57.2, 56.9, 50.5, 43.3, 33.7, 33.2, 32.1, 29.5, 25.8, 19.2,
0.00; HRMS (ESI-TOF) (m/z) [MH]þ calcd for C18H32N2O5Si
385.21533, found 385.21625, [M þ Na]þ calcd 407.19727, found
407.19812.
(2S,5S,6S)-tert-Butyl 6-(tert-Butoxycarbonylamino)-7-oxo-1-
azabicyclo[3.2.0]heptane-2-carboxylate (11). A solution of Mu-
kaiyama’s reagent (210 mg, 810 μmol) in 15 mL of acetonitrile
was treated with triethylamine (240 μL, 1.70 mmol) and heated to
70 °C. A solution of 10 (70.0 mg, 203 μmol) in 15 mL of
acetonitrile was cannulated into the mixture, and the reaction
was allowed to cool to rt gradually and stirred for 2 days. The
reaction solution was evaporated, taken up in EtOAc, and washed
with water. The organic layer was dried over anhydrous Na2SO4,
filtered, and evaporated under reduced pressure. Purification by
flash chromatography over silica gel (30% EtOAc/hexanes as
eluent) afforded 11 as a sticky colorless oil (57.0 mg, 86%). [R]25
D
-58.1(c 0.4, DMSO); 1H NMR (400 MHz, CDCl3) δ 5.36 (d, J =
8.5, 1H), 4.57 (d, J = 8.4, 1H), 4.34 (dd, J = 7.8, 5.8, 1H), 3.78 (t,
J = 5.8, 1H), 2.39 (m, 1H), 2.24 (dt, J = 11.4, 6.4, 1H), 2.13 (dt,
J = 14.1, 7.4, 1H), 1.70 (m, 1H), 1.42 (d, J = 2.3, 18H). 1H NMR
(400 MHz, DMSO-d6) δ 7.81 (d, J = 8.6, 1H), 4.35 (d, J = 8.6,
1H), 4.19 (dd, J = 7.7, 5.7, 1H), 3.68 (m, 1H), 2.33 (m, 1H), 2.03
(m, 2H), 1.71 (m, 1H), 1.39 (s, 9H), 1.37 (s, 9H); 13C NMR (101
MHz, DMSO-d6) δ 174.7, 170.7, 155.3, 81.7, 79.3, 63.1, 63.0, 59.9,
34.8, 28.8, 28.5, 28.2; HRMS (ESI-TOF) (m/z) [MH]þ calcd
for C16H26N2O5 327.19217, found 327.19028, [M þ Na]þ calcd
349.17339, found 349.17259.
(1S,5S,7aS)-5-tert-Butyl 1-Ethyl 3-oxohexahydro-1H-pyrro-
lizine-1,5-dicarboxylate (12). A solution of 6b (295 mg, 703 μmol)
in 4 mL of MeOH was treated with 100 mg of 20% Pd/C and
stirred for 3 h under H2 (balloon) atmosphere. The reaction
solution was filtered through a Celite pad and rinsed with excess
MeOH. The filtrate was evaporated invacuo to afford a yellowish
oil, which was then dissolved in 5 mL of toluene and stirred at
90 °C for 20 h. The solvent was evaporated under reduced
pressure, and the residue was purified by flash chromatography
over silica gel (50% EtOAc/hexanes as eluent) to furnish 12 as a
pale yellow solid (186 mg, 89% over 2 steps). Mp 64-66°; [R]25
D
-140.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.39 (dd,
J = 8.7, 6.6, 1H), 4.29 (m, 1H), 4.17 (m, 2H), 3.45 (m, 1H), 2.82
(dd, J = 7.4, 2.4, 2H), 2.41 (m, 1H), 1.94 (m, 2H), 1.71 (s, 1H),
1.45 (s, 9H), 1.26 (t, J = 7.1, 3H); 13C NMR (101 MHz, CDCl3) δ
174.7, 171.8, 171.3, 82.1, 62.6, 61.4, 56.4, 39.7, 35.2, 31.4, 28.2,
27.7, 14.5; HRMS (ESI-TOF) (m/z) [MH]þ calcd for C15H23NO5
298.16490, found 298.16433, [M þ Na]þ calcd 320.14684, found
320.14613.
(S)-1-Benzyl 6-Ethyl 5-((2S,5S)-1-benzyl-5-(tert-butoxycarbonyl)-
pyrrolidin-2-yl)hex-2-enedioate (15). A solution of 6c (100 mg, 258
μmol) in 1.70 mL of 1,2-dichloroethane was treated with methyl
acrylate (418 μL, 2.58 mmol) and Grubbs’ second generation
catalyst (21.0 mg, 24.7 μmol) and stirred for 1d at 65 °C. The
reaction solution was evaporated under reduced pressure and
adsorbed onto silica gel. Purification by flash chromatography
over silica gel (5% to 10% EtOAc/hexanes as eluent) afforded 15
as a 14:1 mixture of E:Z isomers (72.0 mg, 53%, 66% based on
(5S,7aS)-5-(tert-Butoxycarbonyl)-3-oxohexahydro-1H-pyrro-
lizine-1-carboxylic Acid (13). A solution of 12 (218 mg, 734
μmol) in 5 mL of THF/H2O (1:1) at rt was treated with LiOH
(45.0 mg, 1.07 mmol) and stirred for 15 min. The reaction was
diluted with 1 M aq HCl, and the aqueous layer was extracted
with EtOAc. The combined organic layers were dried over
anhydrous Na2SO4, filtered, and evaporated to afford 13 as a
1
∼3:1 mixture of diastereomers (196 mg, 99%). H NMR (400
1
MHz, CDCl3) δ 6.70 (bs, 1H), 4.36 (m, 2H), 3.48 (td, J = 8.0,
6.2, 1H), 2.87 (m, 2H), 2.48 (m, 1.5H), 2.27 (s, 0.5H), 2.04 (m,
2H), 1.46 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 175.7, 175.5,
174.8, 172.7, 171.1, 170.8, 82.5, 82.3, 63.9, 62.7, 56.4, 55.7, 45.8,
39.9, 37.8, 35.7, 32.3, 31.8, 31.6, 28.2, 27.8.; HRMS (ESI-TOF)
(m/z) [MH]þ calcd for C13H19NO5 270.13360, found 270.13479,
[M þ Na]þ calcd 292.11554, found 292.11663.
recovered starting material). Data given for the E isomer: H
NMR (400 MHz, CDCl3) δ 7.40-7.17 (m, 10H), 6.89 (dt, J =
15.5, 7.1, 1H), 5.84 (d, J =15.7, 1H), 5.16(s, 1H), 4.11 (q, J =7.1,
2H), 3.89 (q, J = 13.5, 2H), 3.70 (dt, J = 9.6, 3.5, 1H), 3.53 (d,
J = 7.4, 1H), 2.63 (m, 2H), 2.50 (ddd, J = 14.7, 10.5, 7.5, 1H),
2.05 (ddd, J = 21.2, 10.6, 6.4, 1H), 1.91 (m, 1H), 1.76 (m, 2H),
1.44 (s, 9H), 1.23 (t, J = 7.1, 3H); 13C NMR (101 MHz, CDCl3) δ
173.7, 173.7, 166.5, 148.5, 139.5, 136.3, 128.8, 128.8, 128.6, 128.4,
128.4, 127.3, 122.2, 80.9, 66.2, 64.5, 63.2, 60.8, 53.3, 47.2, 28.7,
28.4, 27.7, 25.3, 14.5; HRMS (ESI-TOF) (m/z) [MH]þ calcd
for C31H39NO6 522.280501, found 522.28167, [M þ Na]þ calcd
544.26696, found 544.26345.
(3S,7aS)-tert-Butyl 7-(Benzyloxycarbonylamino)-5-oxohexa-
hydro-1H-pyrrolizine-3-carboxylate (14a). A solution 13 (140
mg, 520 mmol) in toluene at 50 °C was treated with triethyla-
mine (181 μL, 1.30 mmol) followed by diphenylphosphoryl
azide (DPPA) (281 mL, 1.30 mmol), dropwise. The reaction
was stirred from 50 to 110 °C over 1 h and at 110 °C for 4.5 h.
Benzyl alcohol (107 μL, 1.04 mmol) was added, and the reaction
(3S,9S,9aS)-3-tert-Butyl 9-Ethyl 5-oxooctahydro-1H-pyrrolo-
[1,2-a]azepine-3,9-dicarboxylate (16). A solution of 15 (165 mg,
J. Org. Chem. Vol. 75, No. 15, 2010 5121

Ranatunga et al.
JOCArticle
317 μmol) in 3 mL of MeOH was treated with 80 mg of Pd(OH)2/
C, and the reaction was stirred under H2 (balloon) for 1.25 h. The
reaction solution was filtered through a Celitepadand rinsedwith
excess MeOH/EtOAc. The filtrate was evaporated under reduced
pressure to afford a thick oil, which was then dissolved in
DMF and treated with triethylamine (86.0 μL, 620 μmol), HBTU
(140 mg, 370 μmol), and hydroxybenzotriazole (HOBt) (8.50 mg,
62.9 μmol). The reaction was stirred for 24 h. The reaction
solution was evaporated at 60 °C under reduced pressure, and
the residuewas dissolvedinEtOAc. The organiclayerwas washed
with 1 M aq HCl and 10% aq Na2CO3. The organic layer was
dried over anhydrous Na2SO4 and evaporated under reduced
pressure. Purification by flash chromatography over silica gel
(50% EtOAc/hexanes as eluent) afforded 16 as a colorless oil
(75.0 mg, 73%, 2 steps). [R]25D -57.8 (c 0.5, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 4.36 (dd, J = 9.1, 2.3, 1H), 4.23 (dt, J = 9.5,
1.9, 1H), 4.10 (m, 2H), 2.70 (bs, 1H), 2.55 (m, 2H), 2.42 (m, 1H),
2.16 (m, 2H), 1.98 (m, 2H), 1.75 (m, 3H), 1.42 (s, 9H), 1.24 (t, J =
7.1, 3H);13C NMR (101 MHz, CDCl3) δ 173.9, 172.6, 172.1, 81.3,
61.9, 60.9, 60.0, 47.3, 38.1, 32.7, 31.3, 28.2, 27.4, 19.9, 14.4; HRMS
(ESI-TOF) (m/z) [MH]þ C17H27NO5 326.19690, found 326.19382.
(3S,9aS)-tert-Butyl 9-(Benzyloxycarbonylamino)-5-oxoocta-
hydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate (17). A solution
of 16 (41.0 mg, 138 μmol) in 2 mL of THF/MeOH (2:1) was
treated with 1 mL of 1 M aq NaOH and stirred at 40 °C for 4.5 h.
The reaction was diluted with water and the solution mixture
was washed with Et2O. After acidification to pH < 3 with 1 M
aq HCl, the aqueous layer was extracted with EtOAc. The
combined organic layers were dried over anhydrous Na2SO4
and evaporated under reduced pressure to afford the carboxylic
dried over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure to afford 18 as a white solid (870 mg, 94%); mp
76-78°; [R]25 -104.2 (c 1.0, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 7.31 (m, 5H), 5.80 (ddt, J = 16.9, 10.1, 6.8, 1H), 5.08
(m, 2H), 4.11 (d, J = 13.2, 1H), 3.97 (d, J = 13.2, 1H), 3.75 (dt,
J = 10.0, 3.2, 1H), 3.52 (d, J = 7.6, 1H), 2.65 (ddd, J = 8.8, 6.4,
2.7, 1H), 2.53 (m, 2H), 2.28 (m, 1H), 2.03 (m, 1H), 1.78 (m, 2H),
1.44 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 177.9, 172.4, 137.7,
136.0, 129.1, 128.9, 127.90, 117.3, 81.5, 64.2, 62.5, 53.9, 49.1,
33.2, 28.3, 28.2, 28.1; HRMS (ESI-TOF) (m/z) [MH]þ calcd for
C21H29NO4 360.21766, found 360.21856.
(2S,5S)-tert-Butyl 1-Benzyl-5-((S)-1-((2,2,2-trichloroethoxy)-
carbonylamino)but-3-enyl)pyrrolidine-2-carboxylate (19). N-Troc
derivative 19 was prepared from 18 following the same procedure
described for 14a, with 2,2,2-tricloroethanol in place of benzyl
alcohol. Purification by flash chromatography over silica gel
(50% EtOAc/hexanes as eluent) afforded 19 as a colorless oil
(75%); [R]25D -48.7 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.27 (m, 5H), 5.75 (ddt, J = 16.8, 10.2, 6.9, 1H), 5.08 (m, 3H),
4.72 (q, J = 12.1, 2H), 4.04 (d, J = 13.9, 1H), 3.91 (d, J = 13.9,
1H), 3.78 (tdd, J = 9.7, 4.5, 2.9, 1H), 3.56 (m, 2H), 2.56 (dt, J =
14.2, 5.3, 1H), 2.24 (m, 1H), 2.12 (m, 1H), 1.95 (tt, J = 12.0, 8.3,
1H), 1.74 (dd, J = 12.7, 8.3, 1H), 1.62 (m, 1H), 1.44 (s, 9H); 13
C
NMR (101 MHz, CDCl3) δ 173.9, 154.7, 139.7, 135.3, 128.7,
128.6, 127.3, 117.6, 96.1, 80.9, 74.6, 65.1, 64.1, 54.7, 54.5,
35.8, 29.1, 28.4, 27.1; HRMS (ESI-TOF) (m/z) [MH]þ calcd for
C23H31Cl3N2O4 505.14222, found 505.14626, [M þ Na]þ calcd
527.12416, found 527.12359.
(S)-3-((2S,5S)-1-Benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)-
3-((2,2,2-trichloroethoxy)carbonylamino)propanoic Acid (20). A so-
lution of 19 (100 mg, 197 μmol) in 2.5 mL of THF/H2O (3:1) was
treated with 4-methylmorpholine N-oxide (51.0 mg, 435 μmol) and
osmium tetroxide (2.5% solution in 2-methyl-2-propanol, 220 μL,
20.0 μmol). After 2 h of stirring at rt, the resulting diol inter-
mediate was treated with sodium periodate (93.0 mg, 435 μmol),
and the reaction was stirred for another 15 h. The reaction was
quenched with 5% aq Na2S2O3 and diluted with brine. The
aqueous layer was extracted with EtOAc, and the combined
organic layers were dried over anhydrous Na2SO4, filtered, and
evaporated. Purification by flash chromatography over silica gel
(50% EtOAc/hexanes as eluent) afforded the aldehyde as a
colorless thick oil (95.0 mg, 95%). 1H NMR (400 MHz, CDCl3)
δ 9.58 (t, J = 2.5, 1H), 7.28 (ddd, J = 12.0, 10.8, 7.6, 5H), 5.14 (d,
J = 8.8, 1H) 4.72 (m, 2H), 4.35 (m, 1H), 3.98 (m, 2H), 3.57 (dt,
J = 9.8, 2.9, 1H), 3.51 (d, J = 7.5, 1H), 2.72 (ddd, J = 15.6, 6.0,
2.4, 1H), 2.47 (ddd, J = 15.6, 8.1, 2.7, 1H), 2.23 (m, 1H), 1.91 (tt,
J = 12.0, 8.4, 1H), 1.77 (dd, J = 12.9, 8.4, 1H), 1.61 (m, 2H), 1.42
(s, 9H); 13C NMR (101 MHz, CDCl3) δ 199.7, 173.2, 154.3,
138.8, 128.9, 128.7, 127.6, 95.7, 81.2, 74.8, 64.9, 64.5, 54.4, 49.3,
44.9, 28.8, 28.3, 25.7; HRMS (ESI-TOF) (m/z) [MH]þ calcd for
C22H29Cl3N2O5 507.12220, found 507.11920.
1
acid as a ∼2:1 mixture of diastereomers. (36.0 mg, 96%). H
NMR (400 MHz, CDCl3) δ 7.88 (bs, 1H), 4.41 (m, 1H), 4.21 (m,
1H), 2.77 (s, 0.5H), 2.60 (m, 2H), 2.46 (m, 1H), 2.33 (m, 1.5H),
2.11 (m, 2H), 2.01-1.70 (m, 4H), 1.57 (m, 1H), 1.44 (s, 9H); 13
C
NMR (101 MHz, CDCl3) δ 178.1, 177.1, 174.9, 174.7, 172.0,
171.3, 81.8, 81.6, 62.3, 61.3, 60.1, 59.6, 50.0, 46.8, 37.8, 36.9,
33.2, 32.7, 31.5, 30.5, 28.2, 27.6, 27.3, 21.7, 19.7.
The above distereomeric mixture of carboxylic acids was
subjected to the same Curtius rearrangement conditions de-
scribed for 14a. Purification by flash chromatography over silica
gel (50% EtOAc/hexanes as eluent) afforded (R0S)-17 (22%
isolated yield, 2 steps) as a colorless oil and (R0R)-17 (38%
isolated yield, 2 steps) as a white solid.
1
Data for (R0S)-17a: [R]25 -60.9 (c 0.8, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 7.35 (m, 5H), 5.09 (s, 2H), 4.97 (d, J = 10.0,
1H), 4.43 (d, J = 8.6, 1H), 4.16 (d, J = 8.6, 1H), 4.05 (m, 1H),
2.59 (dd, J = 14.4, 6.7, 1H), 2.48 (m, 1H), 2.32 (m, 1H), 2.02 (m,
3H), 1.85-1.54 (m, 4H), 1.44 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 174.9, 171.5, 156.3, 136.4, 128.8, 128.5, 128.4, 81.7,
67.3, 62.1, 61.4, 52.4, 38.1, 35.5, 30.6, 28.2, 27.9, 18.2; HRMS
(ESI-TOF) (m/z) [MH]þ calcd for C22H30N2O5 403.22347,
found 403.22247, [M þ Na]þ calcd 435.20469, found 425.20439.
A solution of the above aldehyde (65.0 mg, 128 μmol) in
0.7 mL of t-BuOH was treated with amylene (160 μL, 1.52
mmol) and cooled to 0 °C. A solution of NaH2PO4 (158 mg, 1.15
mmol) and NaClO2 (87.0 μL, 767 μmol) was added dropwise,
and the reaction was stirred from 0 to 10 °C over 1 h. The
reaction was quenched with 5% aq Na2S2O3 and diluted with
brine. The pH of the aqueous layer was adjusted to 3 with 1 M aq
HCl and extracted with EtOAc. The combined organic layers
were dried over anhydrous Na2SO4, filtered, and evaporated.
Purification by flash chromatography over silica gel (from 70%
to 100% EtOAc/hexanes as eluent) afforded carboxylic acid 20
Data for (R0R)-17a: mp 121-123°; [R]25 -57.9 (c 1.5,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32 (m, 5H), 5.09 (d,
J = 1.9, 2H), 4.74 (d, J = 9.4, 1H), 4.39 (d, J = 8.1, 1H), 3.82 (t,
J = 8.6, 1H), 3.52 (m, 1H), 2.49 (m, 2H), 2.27 (m, 1H), 2.09 (m,
3H), 1.68 (m, 5H), 1.45 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
174.0, 171.7, 156.2, 136.4, 129.7, 128.8, 128.5, 128.4, 81.5, 67.3,
63.7, 61.4, 52.6, 37.4, 37.0, 28.2, 27.8, 27.1, 22.1; HRMS (ESI-TOF)
(m/z) [MH]þ calcd for C22H30N2O5 403.22347, found 403.22207,
[M þ Na]þ calcd 435.20469, found 425.20409.
(S)-2-((2S,5S)-1-Benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)-
pent-4-enoic Acid (18). A solution of 6c (1.00 g, 2.58 mmol) in 17
mL of MeOH was treated with 13 mL of 2 M aq NaOH and
tetrabutylammonium hydroxide (134 μL, 516 μmol) as a phase
transfer catalyst and stirred at 50 °C for 24 h. The reaction
solution was concentrated, acidified to pH = 3 with 1 M aq HCl,
and extracted with EtOAc. The combined organic layers were
as a thick colorless oil (67.0 mg, 90%). [R]25 -43.6 (c 0.4,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.29 (m, 5H), 5.45 (d,
J = 8.7, 1H), 4.77 (m, 2H), 4.36 (m, 1H), 4.11 (dd, J = 31.3,
10.1, 1H), 3.96 (m, 1H), 3.67 (d, J = 9.8, 1H), 3.49 (dd, J = 14.8,
7.3, 1H), 2.86 (dd, J = 15.9, 6.6, 1H), 2.51 (ddd, J = 23.8, 15.5,
7.4, 1H), 2.24 (m, 1H), 1.95 (m, 1H), 1.77 (m, 2H), 1.43 (s, 9H);
5122 J. Org. Chem. Vol. 75, No. 15, 2010

Ranatunga et al.
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13C NMR (101 MHz, CDCl3) δ 175.8, 172.6, 154.3, 137.7, 129.2,
128.8, 127.8, 95.8, 81.5, 74.8, 64.4, 64.1, 54.1, 50.3, 36.1, 28.9,
28.3, 25.6; HRMS (ESI-TOF) (m/z) [M - H]- calcd for C22H29-
Cl3N2O6 521.10184, found 521.10280.
4.83 (d, J = 12.1, 1H), 4.64 (d, J = 12.0, 1H), 4.51 (dd, J = 8.7,
1.5, 1H), 4.19 (d, J = 8.1, 1H), 4.07 (dt, J = 9.7, 3.3, 1H), 2.63 (dd,
J = 14.5, 6.9, 1H), 2.50 (m, 1H), 2.36 (tt, J = 12.5, 8.3, 1H), 2.15
(ddd, J = 12.6, 10.6, 6.3, 1H), 2.05 (m, 1H), 186 (m, 4H), 1.63
(m, 1H), 1.44 (s, 9H);13C NMR (101 MHz, CDCl3) δ175.0, 171.5,
154.6, 121.6, 81.8, 74.7, 62.2, 61.2, 52.9, 38.1, 35.4, 30.6, 28.2,
27.9, 18.2; HRMS (ESI-TOF) (m/z) [MH]þ calcd for C17H25-
Cl3N2O5 443.09090, found 443.09069, [M þ Na]þ 465.07212,
found 465.07230.
(2S,5S)-tert-Butyl 1-Benzyl-5-((S)-1-((2-(trimethylsilyl)ethoxy)-
carbonylamino)but-3-enyl)pyrrolidine-2-carboxylate (24). N-Teoc
derivative 24 was prepared from 18 following the same procedure
described for 14a, with 2-trimethylsilylethanol in place of benzyl
alcohol. Purification by flash chromatography over silica gel (5%
to 10% EtOAc/hexanes as eluent) afforded 24 as a colorless oil
(58%). [R]25D -58.9 (c 2.3, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.24 (m, 5H), 5.72 (m, 1H), 5.01 (m, 2H), 4.75 (d, J = 9.0, 1H),
4.10 (m, 2H), 4.02 (d, J = 14.1, 1H), 3.86 (d, J = 14.0, 1H), 3.72
(m, 1H), 3.48 (dd, J = 12.8, 4.8, 2H), 2.49 (m, 1H), 2.18 (m, 1H),
2.05 (m, 1H), 1.90 (tt, J = 12.5, 8.6, 1H), 1.69 (d, J = 12.7, 8.4,
1H), 1.58 (m, 1H), 1.40(s, 9H), 0.95 (dd, J = 16.9, 8.5, 2H), 0.00 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 174.9, 158.0, 141.1, 136.9,
129.9, 129.8, 128.4, 118.5, 82.1, 66.3, 65.3, 64.3, 55.6, 55.3, 37.2,
30.4, 29.6, 28.2, 19.2, 0.00; HRMS (ESI-TOF) (m/z) [MH]þ calcd
for C26H42N2O4Si 475.29866, found 475.29934.
(3S,7S,7aS)-tert-Butyl 5-Oxo-7-((2,2,2-trichloroethoxy)car-
bonylamino)hexahydro-1H-pyrrolizine-3-carboxylate (21). A so-
lution of 20 (60.0 mg, 116 μmol) in 2 mL of THF was treated
with 25 mg of Pd(OH)2/C, purged with H2 and stirred under H2
(balloon) for 7.5 h. The reaction solution was filtered through a
Celite pad and rinsed with excess MeOH/EtOAc. The filtrate
was evaporated under reduced pressure to afford a thick oil,
which was then dissolved in 3 mL of acetonitrile, treated with
triethylamine (53.0 μL, 378 μmol), HBTU (62.0 mg, 164 μmol),
and HOBt (3.00 mg, 25.0 μmol), and stirred at rt for 20 h. The
reaction mixture was evaporated under reduced pressure. The
residue was dissolved in EtOAc and washed with 1 M aq HCl
followed by 10% aq Na2CO3. The organic layer was dried over
anhydrous Na2SO4, filtered, and evaporated. Purification by
flash chromatography over silica gel (50% to 100% EtOAc/
hexanes as eluent) afforded 21 as a white solid (20.0 mg, 42%,
2 steps) inaddition to10 mg of the corresponding ethyl carbamate.
1
Data for 21: mp 147-149°; [R]25 -120.3 (c 1.0, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 5.93 (d, J = 8.3, 1H), 4.78 (d, J =
12.0, 1H), 4.68 (d, J = 12.0, 1H), 4.49 (dd, J = 12.9, 7.4, 1H), 4.32
(dd, J = 13.5, 6.4, 2H), 3.19 (dd, J = 16.9, 7.1, 1H), 2.45 (dtd, J =
12.7, 8.3, 4.2, 1H), 2.30 (d, J = 17.0, 1H), 2.09 (m, 1H), 1.92 (m,
1H), 1.71 (m, 2H), 1.46 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
171.7, 170.7, 154.5, 95.7, 82.3, 74.7, 65.9, 55.7, 49.8, 42.1, 32.5,
28.2, 24.5; HRMS (ESI-TOF) (m/z) [MH]þ calcd for C15H21Cl3-
N2O5 415.05888, found 415.05815, [M þ Na]þ calcd 437.04083,
found 437.03907.
(2S,5S)-tert-Butyl 1-Benzyl-5-((S)-3-hydroxy-1-((2-(trimethyl-
silyl)ethoxy)carbonylamino)propyl)pyrrolidine-2-carboxylate (25).
A solution of 24 (90.0 mg, 190 μmol) in 2.5 mL of THF/H2O (3:1)
was treated with 4-methyl morpholine N-oxide (54.0 mg, 464
μmol) and osmium tetroxide (2.5% solution in 2-methyl 2-pro-
panol, 231 μL, 22.7 μmol). After stirring at rt for 2 h, the resulting
diol intermediate was treated with sodium periodate (99.0 mg,
464 μmol) and stirred for another 15 h. The reaction was quenched
with 5% aq Na2S2O3 and diluted with brine. The aqueous layer
was extracted with EtOAc. The combined organic layers were
dried over anhydrous Na2SO4, filtered, and evaporated. Purifica-
tion by flashchromatography over silica gel (50% EtOAc/hexanes
as eluent) afforded the desired aldehyde as a colorless thick oil
(60.0 mg, 66%). [R]25D -55.3 (c 0.6, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 9.54 (s, 1H), 7.24 (m, 5H), 4.69 (d, J = 8.3, 1H), 4.32 (m,
1H), 4.10 (m, 2H), 3.94 (dd, J = 41.0, 13.5, 2H), 3.50 (dt, J = 9.9,
3.0, 1H), 3.45 (d, J = 7.5, 1H), 2.63 (ddd, J = 15.4, 6.1, 2.7, 1H),
2.37 (dd, J = 13.8, 9.1, 1H), 2.17 (tt, J = 12.0, 9.6, 1H), 1.86 (tt,
J = 12.0, 8.4, 1H), 1.71 (dd, J = 12.8, 8.5, 1H), 1.56 (m, 1H), 1.39
(s, 9H), 0.93 (dd, J = 11.8, 5.3, 2H), 0.00 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 201.5, 174.5, 157.6, 140.2, 130.2, 129.9, 128.7,
82.3, 66.0, 65.9, 64.9, 55.6, 50.1, 46.6, 30.1, 29.6, 26.9, 19.2, 0.0.
A solution of above aldehyde (50.0 mg, 105 μmol) in 2 mL of
THF was treated with NaBH4 (6.00 mg, 157 μmol) and stirred
for 30 min at rt. The reaction was quenched with sat. aq NH4Cl
and extracted with EtOAc. The combined organic layers were
dried over anhydrous Na2SO4 and evaporated under reduced
pressure to afford 25 as a sticky foam (50.0 mg, quantitative
yield). 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 5H), 5.02 (d, J =
9.0, 1H), 4.12 (m, 2H), 3.99 (d, J = 13.7, 1H), 3.84 (d, J = 13.6,
2H), 3.59 (m, 3H), 3.46 (m, 2H), 2.24 (m, 1H), 1.89 (m, 3H), 1.69
(dd, J = 12.8, 8.4, 1H), 1.58 (m, 1H), 1.47 (m, 1H), 1.39 (s, 9H),
0.95 (m, 2H), 0.00 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 174.7,
159.2, 140.4, 130.0, 129.9, 128.6, 82.2, 66.2, 66.1, 64.9, 60.7, 55.9,
52.8, 37.2, 30.2, 29.6, 29.1, 19.2, 0.0; HRMS (ESI-TOF) (m/z)
[MH]þ calcd for C25H42N2O5Si 479.29358, found 479.29459,
[M þ Na]þ 501.27552, found 501.27650.
(2S,5S)-tert-Butyl 1-Benzyl-5-((S)-5-(benzyloxy)-5-oxo-1-((2,2,2-
trichloroethoxy)carbonylamino)pent-3-enyl)pyrrolidine-2-carboxy-
late (22). A solution of 19 (265 mg, 520 μmol) in 750 μL of
dichloroethane was treated with benzyl acrylate (850 mg, 5.23
mmol) and Grubbs’ second generation catalyst (40.0 mg, 47.1
μmol) and stirred at 65 °C for 1 d (catalyst was added in 3 por-
tions). The reaction solution was evaporated and adsorbed onto
silica gel. Purification by flash chromatography over silica gel
(0% to 20% EtOAc/hexanes as eluent) afforded 22 as a 7.4:1
mixture of E:Z isomers (210 mg, 62%, 87%, borsm). Data given
for the Eisomer:[R]25D -26.4 (c0.5, CHCl3);1H NMR (400 MHz,
CDCl3) δ 7.30 (m, 10H), 6.92 (dt, J = 14.6, 7.1, 1H), 5.87 (d, J =
15.6, 1H), 5.16 (d, J = 5.3, 1H), 5.12 (m, 2H), 4.73 (m, 2H), 3.90
(m, 3H), 3.55 (m, 2H), 2.69 (dt, J = 13.4, 4.8, 1H), 2.24 (m, 2H),
1.94 (tt, J = 12.0, 8.4, 1H), 1.77 (dd, J = 12.7, 8.5, 1H), 1.65 (m,
1H), 1.44 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 173.5, 166.1,
154.5, 146.2, 139.5, 136.2, 128.8, 128.7, 128.6, 128.4, 127.5, 123.4,
96.0, 81.1, 74.6, 66.4, 65.3, 64.4, 54.5, 53.7, 33.7, 29.0, 28.4,
26.6; HRMS (ESI-TOF) (m/z) [MH]þ calcd for C31H37Cl3N2O6
639.17900, found 639.17605.
(3S,9S,9aS)-tert-Butyl 5-Oxo-9-((2,2,2-trichloroethoxy)carbo-
nylamino)octahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate (23).
A solution of 22 (82.0mg, 128μmol)in2.5 mLofTHFwas treated
with 30.0 mg of 20% Pd(OH)2/C and stirred for 6 h at rt under H2
(balloon) atmosphere. The reaction was filtered through a Celite
pad, rinsed with EtOAc, and evaporated under reduced pressure.
The resulting amino acid was dissolved in acetonitrile and treated
with triethylamine (54.0 μL, 384 μmol), HBTU (63.0 mg, 166
μmol), and HOBt (3.50 mg, 25.9 μmol). After 24 h of stirring at rt,
the reaction was evaporated and dissolved in EtOAc. The organic
layer was washed with 1 M aq HCl and 10% aq Na2CO3, dried
over anhydrous Na2SO4, filtered, and evaporated. The residue
was purified by flash chromatography over silica gel (60% to 80%
EtOAc/hexanes as eluent) to afford 23 as a white solid (30.0 mg,
53%, over 2 steps) along with 10 mg of the corresponsing ethyl
(3S,7S,7aS)-tert-Butyl 7-((2-(trimethylsilyl)ethoxy)carbony-
lamino)hexahydro-1H-pyrrolizine-3-carboxylate (26). Method A.
A solution of 25 (48.0 mg, 100 μmol) in 2 mL of MeOH was
treated with 20 mg of 20% Pd(OH)2/C and stirred for 1.5 h at rt
under H2 (balloon) atmosphere. The reaction was filtered
through a Celite pad, rinsed with MeOH/EtOAc, and evaporated
carbamate. Data for 23: mp 198-200°; [R]25 -51.8 (c 0.8,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.21 (d, J = 10.2, 1H),
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Ranatunga et al.
JOCArticle
under reduced pressure. The resulting colorless oil was dis-
solved in 2 mL of THF and treated with triethylamine (41.8 μL,
300 μmol), 4-dimethylaminopyridine (12.2 mg, 100 μmol), and
1,10-carbonyldiimidazole (81.0 mg, 500 μmol). The reaction was
stirred under argon atmosphere at rt for 20 h. The mixture was
concentrated under reduced pressure, diluted with EtOAc, and
washed with sat. aq NH4Cl. The combined organic layers were
dried over anhydrous Na2SO4 and evaporated. Purification by
flash chromatography over silica gel (70% to 100% EtOAc/
hexanes as eluent) afforded 26 as a colorless oil (30.0 mg, 82%).
Method B. Bicyclic amine 26 was also prepared from 24 via
alkene oxidation as described above, followed by treatment of
the intermediate aldehyde (40.0 mg, 84.0 μmol) with 20.0 mg of
20% Pd(OH)2/C in 2 mL of MeOH. After stirring for 20 h at
rt under H2 (balloon) atmosphere, the reaction was filtered
through a Celite pad, rinsed with MeOH/EtOAc, and evapo-
rated under reduced pressure. Purification by flash chromatog-
raphy over silica gel (70% to 100% EtOAc/hexanes and then
5% MeOH/EtOAc as eluents) afforded 26 as a colorless oil
(29.0 mg, 93% for the last step). [R]25D -30.0 (c 0.5, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 4.44 (d, J = 7.5, 1H), 4.13 (m, 3H),
3.82 (dd, J = 14.1, 7.0, 1H), 3.20 (m, 2H), 2.58 (dt, J = 11.0, 7.1,
1H), 2.16 (m, 2H), 1.99 (dt, J = 21.9, 9.3, 1H), 1.83 (m, 1H), 1.70
(m, 1H), 1.51 (m, 1H), 1.44 (s, 9H), 0.96 (m, 2H), 0.00 (s, 9H);
13C NMR (101 MHz, CDCl3) δ 174.4, 157.8, 82.2, 71.4, 69.1,
64.7, 54.4, 53.5, 34.3, 33.3, 29.6, 27.1, 19.2, 0.0; HRMS (ESI-TOF)
(m/z) [MH]þ calcd for C18H34N2O4Si 371.23606, found 371.23664.
Boc-[5,6-carbamate]-Phe-OMe (28). A solution of 9 (164 mg,
440 μmol) in 4 mL of MeOH was treated with 5 mL of 2 M aq
NaOH at rt and stirred for 24 h. The reaction was evaporated
under reduced pressure, and the aqueous layer was washed with
Et2O. The pH of the aqueous layer was adjusted to 3, and the
mixture was extracted with EtOAc. The combined organic
layers were dried over anhydrous Na2SO4 and evaporated under
reduced pressure to afford the desired carboxylic acid as a white
solid (120 mg, 87%).
diluted with EtOAc. The organic layer was washed with 1 M aq
HCl followedby 10%aqNa2CO3, driedoveranhydrousNa2SO4,
and evaporated. Purification by flash chromatography over silica
gel (60% EtOAc/hexanes as eluent) afforded 29 as a thick oil
(15.0 mg, 74%, 2 steps). [R]25D -83.8 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.44 (d, J = 7.7, 1H), 7.23 (m, 3H), 7.12 (dd,
J = 11.4, 4.9, 2H), 5.97 (d, J = 8.4, 1H), 4.69 (m, 3H), 4.45 (dd,
J = 13.3, 7.5, 1H), 4.31 (t, J = 7.9, 1H), 4.04 (dt, J = 9.1, 6.0,
1H), 3.12 (ddd, J = 24.4, 15.6, 6.8, 2H), 2.98 (dd, J = 13.9, 6.9,
1H), 2.34 (m, 3H), 1.83 (dtd, J = 9.0, 6.7, 2.6, 1H), 1.62 (m, 1H),
1.41 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 173.3, 170.6, 170.0,
154.4, 136.6, 129.7, 128.4, 127.1, 95.6, 82.5, 74.7, 66.4, 56.9,
54.1, 49.4, 42.1, 38.1, 30.5, 28.2, 24.6; HRMS (ESI-TOF) (m/z)
[MH]þ calcd for C24H30Cl3N3O6 562.12730, found 562.12662,
[M þ Na]þ 584.10924, found 584.10870.
Compound 29 was also obtained from 33 as follows: A
solution of 33 (50.0 mg, 74.5 μmol) in 1.5 mL of MeOH at rt
was treated with 18 mg of 20% Pd(OH)2/C and stirred for 2 h
under H2 (balloon). The reaction was filtered through a Celite
pad, rinsed with MeOH/EtOAc, and evaporated under reduced
pressure to afford a white solid, which was then dissolved in
2 mL of DMF and treated with triethylamine (20.8 μL, 149
μmol), HBTU (37.0 mg, 96.8 μmol), and HOBt (2.00 mg, 14.9
μmol), respectively. After 20 h of stirring at rt, the reaction
was evaporated under reduced pressure and diluted with
EtOAc. The organic layer was washed with 1 M aq HCl followed
by 10% aq Na2CO3, dried over anhydrous Na2SO4, and evapo-
rated. Purification by flash chromatography over silica gel
(60% EtOAc/hexanes as eluent) afforded 29 as a colorless oil
(23.0 mg, 54%, 2 steps).
Troc-[5,7-lactam]-Phe-OtBu (30). Tripeptide mimic 30 was
prepared from 23 using the same two-step procedure described
for 29. Purification of the crude material by flash chromatog-
raphy over silica gel (60% EtOAc/hexanes as eluent) afforded 30
as a white solid (42.0 mg, 77%, 2 steps). Mp 97-99°; [R]25
D
-9.62 (c 1.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.24 (m,
5H), 6.62 (d, J = 7.7, 1H), 5.36 (d, J = 10.1, 1H), 4.81 (d, J =
12.1, 1H), 4.66 (m, 3H), 4.08 (m, 2H), 3.09 (dd, J = 5.9, 3.6, 2H),
2.60 (dd, J = 14.1, 6.8, 1H), 2.40 (m, 2H), 2.03 (m, 3H), 1.82 (m,
3H), 1.61 (m, 1H), 1.40 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
175.3, 171.1, 170.7, 154.6, 136.4, 129.9, 128.5, 127.1, 95.7, 82.6, 74.7,
62.3, 61.5, 53.8, 53.1, 38.3, 38.0, 35.4, 31.3, 28.2, 27.5, 18.0; HRMS
(ESI-TOF) (m/z) [MH]þ calcd for C26H34Cl3N3O6 590.15860,
found 590.15828, [M þ Na]þ 612.14054, found 612.14093.
The above carboxylic acid (24.0 mg, 79.9 μmol) was dissolved
in 2 mL of MeCN and treated with triethylamine (33.5 μL,
240 μmol), HBTU (40.0 mg, 105 μmol), and HOBt (2.00 mg,
16.0 μmol) and stirred for 5 min before adding phenylalanine
methyl ester (20.0 mg, 100 μmol). After stirring at rt for 20 h, the
reaction was evaporated under reduced pressure and diluted
with EtOAc. The organic layer was washed with 1 M aq HCl
followed by 10% aq Na2CO3, dried over anhydrous Na2SO4,
and evaporated. Purification by flash chromatography over
silica gel (70% to 80% EtOAc/hexanes as eluent) afforded 28
Compound 30 was also obtained from 32 following the same
procedure use to convert 33 to 29. Purification by flash chro-
matography over silica gel (60% to 100% EtOAc/hexanes as
eluent) afforded 30 as a colorless oil (32.0 mg, 53% 2 steps).
Dipeptide 31. Compound 31 was prepared from 19 using the
same two-step procedure described for 29. Purification by flash
chromatography over silica gel (30% EtOAc/hexanes as eluent)
as a white solid (23.0 mg, 60%, 2 steps). Mp 140-142°; [R]25
D
-26.5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25 (m,
5H), 7.05 (d, J = 8.2, 1H), 4.85 (td, J = 8.0, 5.5, 1H), 4.63 (d,
J = 8.7, 1H), 4.38 (t, J = 8.1, 1H), 4.26 (dd, J = 10.4, 4.4, 1H),
3.90 (dd, J = 13.4, 7.5, 1H), 3.72 (m, 3H), 3.29 (td, J = 9.8, 5.7,
1H), 3.20 (dd, J = 13.9, 5.4, 1H), 3.04 (dd, J = 13.9, 7.9, 1H),
2.17 (m, 1H), 2.10 (ddd, J = 11.2, 6.6, 4.1, 1H), 1.98 (m, 1H),
1.60 (m, 1H), 1.45 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 172.1,
170.8, 155.0, 153.3, 136.3, 129.6, 129.4, 128.7, 127.1, 68.2, 61.7,
61.6, 53.5, 52.7, 48.1, 37.8, 31.3, 28.6, 28.5, 26.1; HRMS (ESI-TOF)
(m/z) [MH]þ calcd for C23H31N3O7 462.22420, found 462.22620,
[M þ Na]þ 484.20542, found 484.20800.
afforded 31 as a white solid (100 mg, 77% 2 steps). Mp
1
116-118°; [R]25 -21.1 (c 0.8, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 7.24 (m, 8H), 7.09 (dd, J = 7.5, 1.5, 2H), 6.35 (d, J =
8.0, 1H), 5.73 (ddt, J = 14.0, 10.2, 7.0, 1H), 5.08 (dd, J = 13.3,
5.4, 2H), 4.94 (d, J = 9.3, 1H), 4.71 (m, 3H), 3.84 (m, 3H), 3.45
(dd, J = 8.1, 1.5, 1H), 3.26 (m, 1H), 3.05 (m, 2H), 2.46 (dt, J =
14.3, 5.2, 1H), 2.08 (m, 3H), 1.82 (m, 1H), 1.61 (m, 1H), 1.36
(s, 9H); 13C NMR (101 MHz, CDCl3) δ 173.5, 170.7, 154.5,
139.3, 136.5, 134.5, 129.6, 128.7, 128.7, 128.6, 128.5, 127.3,
127.2, 118.0, 96.0, 82.5, 74.7, 65.4, 64.6, 53.5, 53.4, 52.9, 38.3,
36.7, 28.6, 28.2, 28.1, 27.2; HRMS (ESI-TOF) (m/z) [MH]þ
calcdfor C32H40Cl3N3O5 652.21064, found 652.21560, [M þ Na]þ
674.19258, found 674.20121.
Troc-[5,5-lactam]-Phe-OtBu (29). A solution of 21 (15.0 mg,
36.0 μmol) in 1.5 mL of 75% THF/DCM was stirred at rt for
6.5 h. The reaction was diluted with EtOAc and evaporated
under reduced pressure (dilution and evaporation was repeated
three more times). The resulting colorless oil was dissolved in
1.5 mL of acetonitrile, treated with triethylamine (30.0 μL,
216 μmol), HBTU (17.7 mg, 46.8 μmol), and HOBt (972 μg,
7.20 μmol), and stirred for 5 min before the addition of phenyl-
alanine tert-butyl ester (12.0 mg, 47.0 μmol). After stirring at rt
for 20 h, the reaction was evaporated under reduced pressure and
Dipeptide 32. A solution of 31 (105 mg, 160 μmol) in 1 mL
of 1,2-dichloroethane was treated with Grubbs’ second genera-
tion catalyst (13.0 mg, 18.0 μmol) and benzyl acrylate (296 mg,
1.83 mmol) and stirred for 24 h at 65 °C. The reaction was
5124 J. Org. Chem. Vol. 75, No. 15, 2010

Ranatunga et al.
JOCArticle
evaporated, adsorbed onto silica gel, and purified by flash
chromatography over silica gel (20% to 40% EtOAc/hexanes
as eluent) to afford 32 as a thick colorless oil (102 mg, 80%, 97%
borsm). Data for the E isomer: [R]25D -15.8 (c 1.3, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.30 (m, 13H), 7.07 (dd, J = 7.3, 1.8,
2H), 6.92 (m, 1H), 6.15 (d, J = 8.1, 1H), 5.88 (d, J = 15.6, 1H),
5.16 (s, 2H), 4.96 (dd, J = 16.6, 9.5, 1H), 4.70 (m, 3H), 3.90 (m,
3H), 3.46 (d, J = 6.9, 1H), 3.35 (dt, J = 8.9, 4.4, 1H), 3.05 (m,
2H), 2.61 (m, 1H), 2.22 (m, 2H), 2.01 (m, 1H), 1.85 (m, 1H), 1.62
(m, 2H), 1.37 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 173.3,
170.8, 166.0, 154.4, 145.5, 139.2, 136.4, 136.2, 129.6, 128.8, 128.8,
128.7, 128.5, 128.4, 128.4, 127.4, 127.3, 123.7, 95.8, 82.6, 74.6,
66.4, 65.4, 64.7, 53.7, 53.1, 52.9, 38.3, 34.8, 28.8, 28.1, 27.1; HRMS
(ESI-TOF) (m/z) [MH]þ calcd for C40H46Cl3N3O7 786.24741,
found 786.25238, [M þ Na]þ 808.22936, found 808.23375.
Dipeptide 33. A solution of 31 (180 mg, 276 μmol) in 6 mL of
THF/H2O (4:2) at rt was treated with 4-methylmopholine N-
oxide (71.1 mg, 607 μmol) and osmium tetroxide (2.5% solution
in 2-methyl 2-propanol, 308 μL, 30.0 μmol) and stirred for 4.5 h.
Sodium periodate (130 mg, 607 μmol) was then added into the
diol intermediate, and the reaction was stirred for 14 h. The
reaction was quenched with 5% aq Na2S2O3 and diluted with
brine. The aqueous layer was extracted with EtOAc, and the
combined organic layers were dried over anhydrous Na2SO4 and
evaporated. Purification by flash chromatography over silica gel
(20% to 40% EtOAc/hexanes as eluent) afforded the desired
[MH]þ calcd for C31H38Cl3N3O6 654.18990, found 654.18966,
[M þ Na]þ 676.17184, found 676.17397.
A solution of the above aldehyde (56.0 mg, 85.5 μmol) in 500
μL of t-BuOH was treated with amylene (108 μL, 1.02 mmol)
and cooled to 0 °C. A solution of NaH2PO4 (105 mg, 765 μmol)
and NaClO2 (58.0 μL, 510 μmol) in water (1.00 mL) was added
dropwise, and the reaction was stirred at 0-10 °C over 1 h. The
reaction was quenched with 5% aq Na2S2O3 and diluted with
brine. The pH of the aqueous layer was adjusted to 5, and the
mixture was extracted with EtOAc. The combined organic
layers were dried over anhydrous Na2SO4 and evaporated.
Purification by flash chromatography over silica gel (60% to
100% EtOAc/hexanes and 10% MeOH/EtOAc as eluent) af-
forded 33 as a thick colorless oil (51.0 mg, 89%). 1H NMR (400
MHz, CDCl3) δ 7.25 (m, 8H), 7.07 (d, J = 6.3, 2H), 6.45 (m,
1H), 5.53 (bs, 1H), 4.71 (dt, J = 20.3, 8.3, 3H), 4.28 (m, 1H), 4.00
(m, 2H), 3.79-3.46 (m, 2H), 3.02 (m, 2H), 2.75 (dd, J = 16.3,
7.2, 1H), 2.55 (dd, J = 16.2, 6.1, 1H), 2.29 (m, 1H), 2.05-1.82
(m, 2H), 1.72 (m, 1H), 1.36 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 175.4, 171.8, 170.6, 154.3, 136.4, 129.5, 129.4, 129.1,
128.9, 128.7, 128.1, 127.3, 95.7, 82.6, 74.8, 65.3, 64.5, 53.8, 53.4,
49.7, 38.1, 36.9, 29.0, 28.1, 25.8; HRMS (ESI-TOF) (m/z)
[MH]þ calcd for C31H38Cl3N3O7 670.18481, found 670.18508,
[M þ Na]þ 692.16675, found 692.16718.
Acknowledgment. This research was supported by the
Moffitt Cancer Center and a grant from National Institutes
of Health (U54 CA132383). We thank Dr. Eileen Duesler
(Universityof New Mexico) for carrying out X-ray diffraction
studies and Drs. Wayne Guida and Kenyon Daniel (Moffitt
Cancer Center) for assistance with molecular modeling.
aldehyde as a colorless oil (110 mg, 61%). [R]25 -39.7 (c 2.3,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.62(t, J = 2.5, 1H), 7.24
(m, 8H), 7.00 (dd, J = 6.5, 2.8, 2H), 5.87 (d, J = 8.1, 1H), 5.13 (d,
J = 8.7, 1H), 4.72 (m, 3H), 4.35 (m, 1H), 3.88 (m, 2H), 3.54 (m,
1H), 3.42 (d, J = 7.6, 1H), 3.05 (dd, J = 14.0, 6.0, 1H), 2.94 (dd,
J = 14.0, 6.3, 1H), 2.67 (ddd, J = 15.6, 6.2, 2.6, 1H), 2.49 (ddd,
J = 15.7, 7.7, 2.5, 1H), 2.27 (m, 1H), 1.92 (m, 1H), 1.81 (m, 1H),
1.61 (ddt, J = 12.3, 6.6, 3.6, 1H), 1.36 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 199.5, 172.9, 170.7, 154.2, 138.8, 136.2, 129.5,
128.8, 128.7, 128.6, 127.5, 127.3, 95.6, 82.6, 74.8, 65.0, 64.7, 53.9,
52.9, 49.1, 45.4, 38.4, 29.0, 28.1, 26.0; HRMS (ESI-TOF) (m/z)
Supporting Information Available: NMR spectra for all new
compounds and crystal structure data in CIF format for com-
pounds 6a, (R0S)-14, 23, and 28. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5125