Mimics of peptide turn backbone and side-chain geometry by a general approach for modifying azabicyclo[5.3.0]alkanone amino acids

Article abstract of DOI:10.1021/jo2006363

Peptide mimics with constrained backbone and side-chain geometry are important tools for studying structure activity relationships of biologically active candidates. A general method for creating β-turn mimics possessing side-chain diversity has been deve

Full text of DOI:10.1021/jo2006363

NOTE
pubs.acs.org/joc
Mimics of Peptide Turn Backbone and Side-Chain Geometry
by a General Approach for Modifying Azabicyclo[5.3.0]alkanone
Amino Acids
Tanya A. Godina and William D. Lubell*
Dꢀepartement de Chimie, Universitꢀe de Montrꢀeal, C. P. 6128, Succursale Centre Ville, Montrꢀeal, Quꢀebec, Canada H3C 3J7
S Supporting Information
b
ABSTRACT: Peptide mimics with constrained backbone and side-
chain geometry are important tools for studying structure activity
relationships of biologically active candidates. A general method for
creating β-turn mimics possessing side-chain diversity has been devel-
oped featuring diastereoselective SN1 displacements of an iodide
precursor. In particular, 6-iodo-pyrroloazepin-2-one amino ester 10 has served as a common precursor in reactions with a variety
of alcohol, phenol, nitrate, and azide nucleophiles to provide an array of constrained peptide mimics.
urn motifs reversethe overall direction of a polypeptide chain1
and play important roles in peptide folding, recognition, and
improved yields (54ꢀ71%) by using excess sodium bicarbonate
in acetonitrile to neutralize HI formed during the reaction. The
(6R)-iodide stereochemistry of both Boc- and Fmoc-10 was
previously established by X-ray analysis.12
At first, attempts were made to react (6R)-iodides 10a and 10b
with nucleophiles under SN2 displacement conditions; however,
either startingmaterialwas recoveredor elimination products were
observed. For example, starting material was recovered after
treatment of 10 with sodium azide under mild conditions. After
heating under more vigorous conditions, LCꢀMS analysis of
crude material indicated no alkyl azide formation; instead, a
molecular ion was detected corresponding to product from
elimination. Moreover, a vinyl proton signal at 5.23 ppm was
observed in the NMR spectrum of the crude product.
Without success in the SN2 displacement, silver salts were used
next to assist the ionization of the iodide14 and facilitate
nucleophilic attack, by way of a secondary carbocation. Under
such conditions, elimination was avoided; moreover, diastereo-
selective nucleophilic attack on the least hindered face of the
bicycle gave a product with a net retention of configuration.
Initially, a series of silver salts were tested in methanol to
determine optimal activity with iodide 10a. After 1 h of stirring at
room temperature, the products were analyzed by LCꢀMS, which
indicated that silver salts of tosylate, trifluoroacetate, and nitrate
gave thedesired methyl ether 11contaminated with products from
substitution by the anions of the respective salt. Silver iodide gave
100% recovery of starting material. On the other hand, silver
triflate consumed the starting material and delivered the bicyclic
methyl ether 11. Silver triflate became the initial salt of choice
for substitution with alcohols and water (Table 1).
T
biology. Mimics of peptide turns have thus served as useful tools
for studying conformationꢀactivity relationships.2 In particular,
azabicyclo[X.Y.0]alkanone dipeptide surrogates have been com-
monly employed as β- and γ-turn mimics.3 For example, the 7,5-
fused pyrroloazepinone, as well as analogues possessing an aryl,
alkyl, or heteroalkyl ring substituent, have been employed as
components of proapoptotic protein second mitochondria-de-
rived activator of caspases (SMAC) mimics (14 and 25), bradyki-
nin B2 receptor antagonists (36), and Rvβ3/Rvβ5 integrin receptor
antagonists7 (4, Figure 1).
The importance of side-chain functionality at the turn sites of
bioactive peptides has evoked many syntheses of azabicycloalk-
anone mimics possessing various functional groups at different
ring positions.8 The methods for generating such scaffolds with
side-chain attachments have, however, required multistep pro-
cesses and often provided stereoisomeric mixtures.9 Toward a
strategy for adding side-chain groups to a common heterocycle
scaffold with stereocontrol, an efficient method has now been
achieved featuring displacement of an iodide precursor, as illu-
strated by the stereoselective functionalization of the 6-position of
the pyrroloazepinone skeleton.
Several routes exist for synthesizing bicyclic lactams of various
ring sizes, stereochemistry, functionality, and substitution
pattern.10,11 Among these methods, a particularly effective entry
into substituted azabicyclo[X.3.0]alkanones has involved the
stereoselective electrophilic transannular cyclization of their
corresponding 9- and 10-membered macrocyclic dipeptides
(Scheme 1).12 Following the procedure for the synthesis of
6-iodo-pyrroloazepin-2-one amino ester 10, dipeptide 7 was
readily assembled by coupling homoallylglycines 5 and 6 using
TBTU and HOBt and subjected to ring-closing metathesis using
the first generation of Grubbs' catalyst 8 to give the macrocycle
9.13 Electrophilic transannular cyclization was optimized to avoid
loss of the Boc group, such that bicycle 10 was obtained in
By using silver triflate to assist in iodide displacement, alcohols
and phenol were used as oxygen nucleophiles to give methyl,
ethyl, isopropyl, and phenyl ethers 11ꢀ14 in 91%, 87%, 77%, and
Received: March 25, 2011
Published: June 03, 2011
r
2011 American Chemical Society
5846
dx.doi.org/10.1021/jo2006363 J. Org. Chem. 2011, 76, 5846–5849
|

The Journal of Organic Chemistry
NOTE
Scheme 2. SN1 Substitution of 10b with Silver Salts of the
Desired Nucleophiles
Figure 1. Examples of biologically active substituted pyrroloazepinones.
Scheme 1. Synthesis of 6-Iodo-azabicyclo[5.3.0]alkanone
Methyl Ester 10a (N-Fmoc) and 10b (N-Boc)
Figure 2. NOESY correlations observed for 16.
Attempts to use nitrogen nucleophiles such as Et2NH and
BnNH2 caused amine-induced Fmoc-deprotection of 10a; how-
ever, trace amounts of amine were observed by LCꢀMS, but not
isolated using Boc-protected 10b. Other nucleophiles [PrSH,
AcSH, KSCN, KCN, CuCN, NaN3, HP(O)(OMe)2, and
P(OMe)3] failed to provide product in acetonitrile, dioxane,
and DMSO. On the other hand, application of the silver salt of
certain nucleophiles proved successful (Scheme 2). For example,
silver nitrate was soluble in acetonitrile and reacted with iodide
10b to give alkyl nitrate 17 in 89% yield. Azide 18 was prepared in
45% and 76% yields using silver azide at 40 and 60 °C, respec-
tively. Despite applications of increasing temperature, sonication,
microwave irradiation, and the addition of sodium thiosulfate,
attempts were unsuccessful using silver salts of cyanide and
thiocyanate, likely because of their low dissociation constants
(Ksp).15 The displacement reaction is driven to completion by
precipitation of the biproduct, silver iodide, which has a Ksp of
Table 1. Substitution of 10 with AgOTf and Oxygen
Nucleophiles
8.3 ꢁ 10
.
ꢀ18 15 The reactions were inhibited as the dissociation
constants of the silver salts approached that of silver iodide.
Only one stereoisomer was detected in the crude product
from each displacement reaction. The relative stereochemistry of
the new center was assigned to be the same as that of the starting
iodide and presumed to arise from attack of the carbocation from
the convex face of the bicycle. Assignment of the stereochemistry
is based on that for alcohol 16 (Figure 2). In the spectrum of 16,
most of the ring protons appeared at distinct chemical shifts, and
their sequential order was assigned using a COSY experiment.
For example, the downfield carbamate proton coupled with the
proton of the adjacent 3-position carbon, which was used as the
starting point for tracing the through-bond connectivities of the
various protons around the bicycle. Moreover, the 3-position
proton exhibited magnetization transfer with the C4 R-proton at
2.38 ppm in the NOESY spectrum, as well as the proton on the
alcohol-bearing 6-position carbon. The latter NOE, as well as the
magnetization transfer between the 6- and 10-position protons
established the alcohol to have the R-stereochemistry. The ring
fusion stereochemistry was assigned the S-configuration because
of the observed NOE between the 4β- and 7-position protons
(1.71 and 3.66 ppm, respectively; the β-protons are considered
to be on the same face as that on which the amine is located).
A novel approach has been developed for installing side chains
onto peptide mimics by way of a common iodide intermediate.
product
P
ROH
solvent
T (°C)
yield (%)
11
12
13
14
15
16
Fmoc
Fmoc
Boc
MeOH
EtOH
i-PrOH
PhOH
H2O
rt
rt
91
87
77
53
67
66
rt
Fmoc
Fmoc
Boc
50
rt
CH3CN
CH3CN
H2O
rt
53% yields, respectively. The steric bulk of the nucleophile appears
to have influenced the yields of the methyl, ethyl, and isopropyl
ethers, which were prepared using their respective alcohols as
solvent under homogeneous conditions at room temperature.
For the formation of the phenyl ether, the iodide and silver salt
were reacted with phenol in the absence of a co-solvent at 50 °C.
Both the Fmoc- and the Boc-protected 6-iodoazabicyclo[5.3.0]-
alkanones 10a and 10b were reacted with water in acetonitrile
to obtain alcohols 15 and 16 in 67% and 66% yield, respectively.
Acetonitrile was added as co-solvent to help solubilize the starting
material, which could not be dissolved in water.
5847
dx.doi.org/10.1021/jo2006363 |J. Org. Chem. 2011, 76, 5846–5849

The Journal of Organic Chemistry
NOTE
Eight azabicyclo[5.3.0]alkanone dipeptide mimics were prepared
possessing different 6-position ring substituents using silver-
assisted iodide displacements. Considering the diversity of
alcohols amenable for use in this method as well as the potential
for modification of azide 18 by way of chemistry such as
Staudinger16 and 1,3-dipolar cycloaddition reactions,17,18 this
method may find general use for creating libraries of turn mimics
for studying the structureꢀactivity relationships of various side
chains in biologically active peptides.
Evaporation of the collected fractions gave 11 (38.1 mg, 91% yield) as
white foam; Rf 0.33 (60% EtOAc in hexanes as eluant); [R]20D ꢀ22.3
(c 0.01 g/ml, CHCl3); 1H NMR δ 7.76 (d, J = 7.5 Hz, 2H), 7.60 (dd, J =
4.5, 6.7 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 5.83
(broad s, 1H), 4.35ꢀ4.33 (m, 2H), 4.20ꢀ4.18 (m, 2H), 3.93ꢀ3.91 (m,
1H), 3.74 (s, 3H), 3.43ꢀ3.42 (m, 1H), 3.36 (s, 3H), 3.25ꢀ3.24 (m, 1H),
2.47ꢀ2.45 (m, 1H), 2.19ꢀ2.08 (m, 3H), 1.88ꢀ1.86 (m, 1H), 1.72
(s, 2H), 1.51ꢀ1.48 (m, 1H); 13C NMR δ 170.6, 170.3, 156.1, 143.9,
143.8, 141.2, 127.6, 127.0, 125.2, 119.9, 66.9, 59.5, 57.9, 56.7, 52.3, 51.7,
47.0, 26.2, 24.6, 23.0, 22.5; HRMS calcd for C27H31N2O6 [M þ H]þ
479.2177, found 479.2178.
’ EXPERIMENTAL SECTION
(3S,6R,7S,10S)-Methyl 2-Oxo-3-N-(Fmoc)amino-6-ethoxy-
1-azabicyclo[5.3.0]decane-10-carboxylate (12). As described
for 11, after reaction of iodide 10a (30.0 mg, 0.05 mmol), silver
trifluoromethanesulfonate (20.1 mg, 0.08 mmol), and EtOH (1.1 mL)
and workup, the residue was purified by flash column chromatography
using 25% to 75% EtOAc in hexanes as eluant to furnish 12 (22.4 mg,
87% yield) as white foam; Rf 0.51 (60% EtOAc in hexanes as eluant);
[R]20D ꢀ21.6 (c 0.007 g/mL, CHCl3); 1H NMR δ 7.76 (d, J = 7.5 Hz,
2H), 7.60 (d, J = 7.3 Hz, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.4,
2H), 5.80 (broad s, 1H), 4.35 (d, J = 6.5 Hz, 2H), 4.25ꢀ4.10 (m, 2H),
3.94 (dd, J = 3.8, 8.4 Hz, 1H), 3.74 (s, 3H), 3.71ꢀ3.59 (m, 1H),
3.48ꢀ3.26 (m, 2H), 2.47 (broad s, 1H), 2.25ꢀ2.05 (m, 3H), 1.88 (q, J =
9.3 Hz, 1H), 1.71 (broad s, 1H), 1.51 (q, J = 9.1 Hz, 2H), 1.20 (t, J = 7.0
Hz, 3H); 13C NMR δ 170.6, 170.3, 144.0, 143.9, 141.3, 127.7, 127.0,
125.2, 119.9, 106.0, 75.7, 64.6, 57.8, 52.3, 51.8, 47.1, 27.0, 24.7, 23.2,
22.7, 15.5; HRMS calcd for C28H33N2O6 [M þ H]þ 493.2331, found
493.2394.
(3S,6R,7S,10S)-Methyl 2-Oxo-3-N-(Boc)amino-6-isopropoxy-
1-azabicyclo[5.3.0]decane-10-carboxylate (13). As described
for 11, after reaction of iodide 10b (25.0 mg, 0.06 mmol), silver tri-
fluoromethanesulfonate (17.1 mg, 0.07 mmol), and i-PrOH (0.6 mL)
and workup, the residue was purified by flash column chromatography
using 0 to 45% EtOAc in hexanes as eluant to provide 13 (16.3 mg,
77% yield) as yellow oil; Rf 0.45 (60% EtOAc in hexanes as eluant);
[R]20D ꢀ45.4 (c 0.014 g/mL, CHCl3); 1H NMR δ 5.46 (broad s, 1H),
4.10 (quintet, J = 5.6 Hz, 1H), 3.85 (dd, J = 3.9, 8.8 Hz, 1H), 3.72
(s, 3H), 3.71ꢀ3.59 (m, 1H), 3.39ꢀ3.29 (m, 2H), 2.47ꢀ2.34 (m, 1H),
2.19ꢀ2.04 (m, 3H), 1.93ꢀ1.59 (m, 3H), 1.54ꢀ1.43 (m, 1H), 1.42
(s, 9H), 1.13 (overlapping doublets, J = 6.3, 6.3 Hz, 6H); 13C NMR δ
170.7, 170.6, 155.8, 79.7, 73.6, 70.5, 60.4, 58.3, 52.3, 51.7, 28.8, 28.5,
25.1, 23.7, 23.5, 22.4, 22.2; HRMS calcd for C19H33N2O6 [M þ H]þ
385.2333 Found: 385.2341.
General Experimental. Unless otherwise stated, all reactions were
performed under argon atmosphere, in oven-dried glassware, using
distilled solvents, which were transferred by syringe. Anhydrous CH3CN
and MeOH were obtained from a solvent filtration system and further
dried overnight over activated 4 Å molecular sieves; EtOH and i-PrOH
were distilled from CaH2. Phenol was recrystallized from petroleum ether,
and the crystals were dried by coevaporation with toluene (3ꢁ) and
stored under vacuum in a desiccator over P2O5. Silver trifluoromethane-
sulfonate was flame-dried under argon atmosphere prior to use. Silver
azide, cyanide, and thiocyanate were precipitated from reactions of
stoichiometric aqueous silver nitrate with sodium azide, potassium
cyanide, and potassium thiocyanate, respectively, collected by filtration,
washed with water and ether, coevaporated with toluene, and stored
under vacuum in a desiccator over P2O5. 1H (300 MHz) and 13C NMR
(75 MHz) spectra were recorded in CDCl3. Chemical shifts are reported
in ppm (δ units) downfield from residual CHCl3 (δ 7.26 and 77.0 ppm).
Two dimensional NMR experiments (i.e., COSY, NOESY, and HSQC)
for 16 were performed at 500 and 125 MHz. Analytical thin-layer
chromatography (TLC) was performed by using glass-backed silica gel
plates coated with a 0.25 mm thickness of silica gel, and visualization was
achievedbyceriumammonium molybdate (CAM) staining. Flashcolumn
chromatography was performed on silica gel of 40ꢀ63 μm particle size.19
(3S,6R,7S,10S)-Methyl 2-Oxo-3-N-(Fmoc)amino-6-iodo-1-
azabicyclo[5.3.0]decane-10-carboxylate (10a). A solution of
macrocycle 9a (134 mg, 0.3 mmol, prepared according to ref 13) in
acetonitrile (3 mL) was treated with NaHCO3 (75 mg, 0.9 mmol),
followed by iodine (228 mg, 0.9 mmol) in three portions, stirred for
20 min at rt, and treated with 1 M Na2S2O3 until the purple solution
became clear. The product was extracted with EtOAc. The organic phase
was washed with brine, dried over MgSO4, and concentrated under
reduced pressure. Purification by flash chromatography (0 to 35%
EtOAc in hexanes as eluant) afforded iodide 10a as yellow oil (114 mg,
67% yield); spectroscopic data was in accordance with ref 12.
(3S,6R,7S,10S)-Methyl 2-Oxo-3-N-(Boc)amino-6-iodo-1-
azabicyclo[5.3.0]decane-10-carboxylate (10b). As described
for the synthesis of Fmoc-counterpart 10a, the Boc-protected bicycle
10b was prepared from 9b (954 mg, 2.9 mmol, prepared according to
ref 13) in acetonitrile (30 mL), using NaHCO3 (737 mg, 8.8 mmol) and
iodine (2.2 g, 8.8 mmol). Purification by flash chromatography (0 to
35% EtOAc in hexanes as eluant) afforded iodide 10b as pale yellow oil
(810 mg, 62% yield); spectroscopic data was in accordance with ref 12.
(3S,6R,7S,10S)-Methyl 2-Oxo-3-N-(Fmoc)amino-6-methoxy-
1-azabicyclo[5.3.0]decane-10-carboxylate (11). Silver trifluor-
omethanesulfonate (33.6 mg, 0.13 mmol) was flame-dried in a round-
bottom flask under argon flow, allowed to cool to room temperature,
treated with a solution of iodide 10a (50.0 mg, 0.09 mmol) in methanol
(2.20 mL), stirred at rt overnight, and concentrated to dryness.
The mixture was taken up in EtOAc and filtered through a plug of
Celite. The filtrate was transferred to a separatory funnel and washed
with water and brine, and the organic phase was dried over MgSO4,
filtered, and concentrated to a residue, which was purified by flash
column chromatography using 25% EtOAc in hexanes as eluant.
(3S,6R,7S,10S)-Methyl 2-Oxo-3-N-(Fmoc)amino-6-phenoxy-
1-azabicyclo[5.3.0]decane-10-carboxylate (14). As described
for 11, after reaction of iodide 10a (30.0 mg, 0.05 mmol), silver tri-
fluoromethanesulfonate (20.2 mg, 0.08 mmol), and phenol (1.10 mL) at
50 °C and workup, the residue was purified by flash column chroma-
tography using 0 to 40% EtOAc in hexanes as eluant to yield 14
(14.9 mg, 53%) as beige foam; Rf 0.72 (60% EtOAc in hexanes as
eluant); [R]20D ꢀ24.8 (c 0.004, CHCl3); 1H NMR δ 7.76 (d, J = 7.4 Hz,
2H), 7.60 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.4, 2H), 7.29 (m, 4H), 6.99
(t, J = 7.3, 1H), 6.88 (d, J = 8.6, 2H), 5.78 (broad s, 1H), 4.40ꢀ4.28
(m, 3H), 4.21 (t, J = 7.0, 2H), 4.12ꢀ4.05 (m, 1H), 3.77 (s, 3H), 3.73
(broad s, 1H), 2.43 (broad s, 1H), 2.28ꢀ2.12 (m, 4H), 2.05ꢀ1.89
(m, 1H), 1.79ꢀ1.61 (m, 2H); 13C NMR δ 170.6, 170.4, 156.9, 143.9,
143.8, 141.3, 129.8, 127.7, 127.0, 125.2, 121.7, 119.9, 115.8, 91.6, 73.7,
66.9, 58.5, 57.7, 52.4, 51.8, 47.1, 26.7, 24.6, 22.7; HRMS calcd for
C32H33N2O6 [M þ H]þ 541.2333, found 541.2337.
(3S,6R,7S,10S)-Methyl 2-Oxo-3-N-(Fmoc)amino-6-hydroxy-
1-azabicyclo[5.3.0]decane-10-carboxylate (15). Silver trifluor-
omethanesulfonate (67.1 mg, 0.261 mmol) was flame-dried in a round-
bottom flask under argon flow, allowed to cool to room temperature,
and treated with a solution of iodide 10a (50.0 mg, 0.0871 mmol) in
5848
dx.doi.org/10.1021/jo2006363 |J. Org. Chem. 2011, 76, 5846–5849

The Journal of Organic Chemistry
NOTE
acetonitrile (4.00 mL), followed by distilled H2O (1.00 mL). The
mixture was stirred at room temperature for 2 h, concentrated to
dryness, taken up in EtOAc, and filtered through a plug of Celite. The
filtrate was transferred to a separatory funnel and washed with water
and brine, and the organic phase was dried over MgSO4, filtered, and
concentrated to a residue, which was purified by flash column chroma-
tography using a gradient of 50% to 100% EtOAc in hexanes as eluant
and gave 15 (27.1 mg, 67% yield) as white foam; Rf 0.15 (60% EtOAc
in hexanes as eluant); [R]20D ꢀ27 (c 0.009 g/mL, CHCl3); 1H NMR
(400 MHz, CDCl3): δ 7.76 (d, J = 7.4 Hz, 2H), 7.59 (d, J = 7.4 Hz, 2H);
7.39 (t, J = 7.2 Hz, 2H); 7.31 (dt, J = 7.4, 1.1 Hz, 2H); 5.81 (broad s, 1H);
4.43ꢀ4.30 (m, 2H); 4.24ꢀ4.08 (m, 2H); 3.85ꢀ3.77 (m, 1H); 3.73
(s, 3H); 3.71ꢀ3.62 (m, 1H); 3.33 (bs, 1H); 2.43 (bs, 1H); 2.27ꢀ2.08
(m, 4H); 2.01ꢀ1.68 (m, 3H); 1.63ꢀ1.45 (m, 1H); 13C NMR
((CD3)2CO) δ; 170.2, 143.9, 141.3, 127.7, 127.0, 125.1, 119.9, 77.2,
68.7, 61.9, 58.4, 52.3, 59.9, 47.1, 31.6, 24.5, 23.9, 22.1; HRMS calcd for
C26H29N2O6 [M þ H]þ 465.20201, found 465.20236.
NMR spectra for compounds 11ꢀ18; copies of COSY and
NOESY for compound 16. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: lubell@chimie.umontreal.ca.
’ ACKNOWLEDGMENT
We gratefully acknowledge the financial support of Universitꢀe
de Montrꢀeal. This work was supported by the grants from Fonds
Quꢀebecois de la Recherche sur la Nature et les Technologies
(FQRNT) and the Natural Science and Engineering Research
Council of Canada (NSERC). We thank Dr. Alexandra F€urt€os
from the Regional Laboratory for Mass Spectrometry and Minh
Tan Phan Viet and Sylvie Bilodeau from the Regional Laboratory
for NMR Spectroscopy, at the Universitꢀe de Montrꢀeal, for their
assistance in compound analysis.
(3S,6R,7S,10S)-Methyl 2-Oxo-3-N-(Boc)amino-6-hydroxy-
1-azabicyclo[5.3.0]decane-10-carboxylate (16). As described
for 15, iodide 10b (55.0 mg, 0.12 mmol) in acetonitrile (1.00 mL) was
treated with silver trifluoromethanesulfonate (46.9 mg, 0.18 mmol) and
distilled H2O (25.0 μL, 1.22 mmol), and the residue after workup was
purified by flash column chromatography using 50% to 100% EtOAc in
hexanes as eluant gave 16 (41.6 mg, 66% yield) as white foam; Rf 0.32
(100% EtOAc); [R]20D ꢀ37 (c 0.0056 g/ml, CHCl3); 1H NMR δ 5.47
(broad s, 1H), 4.10 (quin, J = 4.2, 1H), 3.80 (dd, J = 7.1 Hz, 2.8 Hz, 1H),
3.72 (s, 3H), 3.70ꢀ3.61 (m, 1H), 3.31 (quin, J = 4.6 Hz, 1H), 2.43ꢀ2.33
(m, 1H), 2.21ꢀ2.07 (m, 4H), 2.02 (broad s, 1H), 1.97ꢀ1.85 (m, 1H),
1.77ꢀ1.64 (m, 1H), 1.59ꢀ1.46 (m, 1H), 1.42 (s, 9H); 13C NMR δ 170.5,
170.4, 155.9, 79.8, 68.9, 62.0, 58.5, 52.4, 51.7, 31.6, 28.5, 24.9, 24.1, 22.3;
HRMS calcd for C16H26N2NaO6 [M þ Na]þ 365.16831, found 365.16911.
(3S,6R,7S,10S)-Methyl 2-Oxo-3-N-(Boc)amino-6-nitrooxy-
1-azabicyclo[5.3.0]decane-10-carboxylate (17). To a solution
of 10b (25.0 mg, 0.06 mmol) in acetonitrile (0.60 mL), silver nitrate
(11.3 mg, 0.0663 mmol) was added and the mixture was stirred at room
temperature for 2 h and concentrated to dryness. The residue was
purified by flash column chromatography using 0 to 40% EtOAc in
hexanes as eluant and gave 17 (19.1 mg, 89% yield) as colorless oil;
Rf 0.30 (50% EtOAc in hexanes as eluant); [R]20D ꢀ43.9 (c 0.014 g/ml,
’ REFERENCES
(1) Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico, C.
Eur. J. Org. Chem. 1999, 389.
(2) Rao, M. H. V. R.; Pinyol, E.; Lubell, W. D. J. Org. Chem. 2007,
72, 736.
(3) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(4) Zhang, B.; Nikolovska-Coleska, Z.; Zhang, Y.; Bai, L.; Qiu, S.;
Yang, C.-Y.; Sun, H.; Wang, S.; Wu, Y. J. Med. Chem. 2008, 51, 7352.
(5) Mastrangelo, E.; Cossu, F.; Milani, M.; Sorrentino, G.; Lecis, D.;
Delia, D.; Manzoni, L.; Drago, C.; Seneci, P.; Scolastico, C.; Rizzo, V.;
Bolognesi, M. J. Mol. Biol. 2008, 384, 673.
(6) Alcaro, M.; Vinci, V.; D’Ursi, A. M.; Scrima, M.; Chelli, M.;
Giuliani, S.; Meini, S.; Di Giacomo, M.; Colombo, L.; Papini, A. M.
Bioorg. Med. Chem. Lett. 2006, 16, 2387.
(7) Belvisi, L.; Bernardi, A.; Colombo, M.; Manzoni, L.; Potenza, D.;
Scolastico, C.; Giannini, G.; Marcellini, M.; Riccioni, T.; Castorina, M.;
LoGiudice, P.; Pisano, C. Bioorg. Med. Chem. 2006, 14, 169.
(8) Boeglin, D.; Hamdan, F. F.; Melendez, R. E.; Cluzeau, J.;
Laperriere, A.; Hꢀeroux, M.; Bouvier, M.; Lubell, W. D. J. Med. Chem.
2007, 50, 1401.
(9) Vagner, J.; Qu, H.; Hruby, V. Curr. Opin. Chem. Biol. 2008, 12, 1.
(10) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789.
CHCl3); IR (CDCl3) 3407, 2931, 1632, 1550, 1436, 1270, 1165 cmꢀ1
;
1H NMR δ 5.41 (broad s, 1H), 5.06 (dt, J = 4.8, 7.7, 1H), 4.20ꢀ4.07 (m,
2H), 3.74 (s, 3H), 3.66 (dt, J = 5.7, 7.8, 1H), 2.47ꢀ2.38 (m, 1H),
2.31ꢀ1.95 (m, 5H), 1.87ꢀ1.60 (m, 2H), 1.43 (s, 9H); 13C NMR δ 171.2,
170.5, 155.7, 80.0, 78.7, 57.0, 56.0, 52.6, 51.4, 28.5, 25.4, 24.8, 23.3, 22.4;
HRMS calcd for C16H25N3NaO8 [M þ Na]þ 410.1534, found 410.1538.
(3S,6R,7S,10S)-Methyl 2-Oxo-3-N-(Boc)amino-6-azido-1-
azabicyclo[5.3.0]decane-10-carboxylate (18). Similar to the
procedure for 17, iodide 10b (25.0 mg, 0.06 mmol) was reacted with
silver azide (9.9 mg, 0.07 mmol) and acetonitrile (0.6 mL) at 60 °C. After
workup, the residue was purified by flash column chromatography using
0 to 40% EtOAc in hexanes as eluant and gave 18 (15.4 mg, 76% yield) as
(11) Cluzeau, J.; Lubell, W. D. Biopolymers (Peptide Sci.) 2005, 80,
98.
(12) Surprenant, S.; Lubell, W. D. Org. Lett. 2006, 8, 2851.
(13) Kaul, R.; Surprenant, S.; Lubell, W. D. J. Org. Chem. 2005, 70,
3838.
(14) Winstein, S.; Ingraham, L. L. J. Am. Chem. Soc. 1955, 77, 1738.
(15) Lide, D. R. CRC Handbook of Chemistry and Physics, 87th ed.;
CRC Press, Taylor & Francis Group: Boca Raton, 2006; pp 8ꢀ120.
(16) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635–646.
(17) Huisgen, R. Angew. Chem. 1963, 75, 604.
a clear oil; Rf 0.35 (50% EtOAc in hexanes as eluant); [R]20 ꢀ55.7
D
(c 0.013 g/ml, CHCl3); IR (CDCl3) 3414, 2953, 2102, 1672, 1165 cmꢀ1
;
1H NMR δ 5.40 (broad s, 1H), 4.09 (q, J = 5.7, 1H), 3.78 (dd, J = 3.9, 9.5,
1H), 3.73 (s, 3H), 3.52ꢀ3.41 (m, 1H), 3.35ꢀ3.27 (m, 1H), 2.48ꢀ2.36
(m, 1H), 2.36ꢀ2.25 (m, 1H), 2.24ꢀ2.09 (m, 3H), 2.03ꢀ1.86 (m, 1H),
1.79ꢀ1.61 (m, 2H), 1.43 (s, 9H); 13C NMR δ 170.5, 170.0, 155.8, 79.9,
60.2, 59.5, 58.5, 52.5, 51.8, 28.5, 28.1, 24.8, 24.1, 23.1; HRMS calcd for
C16H25N5NaO5 [M þ Na]þ 390.1748, found 390.1753.
(18) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952–3015.
(19) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–
2925.
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental methods
b
and spectral data for compounds 11ꢀ18; copies of 1H and 13
C
5849
dx.doi.org/10.1021/jo2006363 |J. Org. Chem. 2011, 76, 5846–5849