Divergent reaction pathways in amine additions to β-lactone electrophiles. An application to β-peptide synthesis

Article abstract of DOI:10.1016/S0040-4020(02)00722-6

β-Lactone electrophiles are subject to regioselective addition-elimination (AE) or S_N2 ring opening with various nitrogen-based nucleophiles. Primary and secondary amines promote AE ring opening to deliver products that are the functional equiv

Full text of DOI:10.1016/S0040-4020(02)00722-6

Tetrahedron 58 (2002) 7081–7091
Divergent reaction pathways in amine additions to b-lactone
electrophiles. An application to b-peptide synthesis
*
Scott G. Nelson, Keith L. Spencer, Wing S. Cheung and Steven J. Mamie
Department of Chemistry, University of Pittsburgh, 1401 Chevron Science Center, Pittsburgh, PA 15260, USA
Received 13 May 2002; accepted 22 May 2002
Abstract—b-Lactone electrophiles are subject to regioselective addition–elimination (AE) or SN2 ring opening with various nitrogen-based
nucleophiles. Primary and secondary amines promote AE ring opening to deliver products that are the functional equivalent of amide aldol
adducts. Azide and sulfonamide anion nucleophiles engender SN2 lactone ring opening to deliver N-protected b-amino acid derivatives.
These nucleophile-dependent ring opening pathways, coupled with the convenient access to highly enantoenriched b-lactones afforded by
acyl halide–aldehyde cyclocondensations, constitute versatile methodologies for asymmetric organic synthesis. The application of this
reaction technology to a new method for b-peptide synthesis based on the optically active b-azido acids emerging from the AAC-ring
opening sequence is also described. q 2002 Elsevier Science Ltd. All rights reserved.
1. Background
addition–elimination (AE) ring opening pathway reveals
b-lactones as convenient surrogates for prototypical aldol
adducts.2 However, ring strain within the b-lactone nucleus
can elicit electrophilic character reminiscent of that
expressed by epoxides. Appropriate tuning of nucleophile
reactivity can lead to scission of the Calkyl–O bond in an
SN2 reaction pathway. As a result, b-lactones also afford
access to b-disubstituted carboxylate derivatives including
b-amino, b-thio, and b,b-dialkyl carboxylic acids.3,4
b-Lactones offer considerable versatility as intermediates
for organic synthesis.1 This utility is derived primarily from
the reactivity b-lactones express as electrophiles toward a
variety of carbon or heteroatom nucleophiles. Ring opening
via nucleophilic addition at the carbonyl residue affords
access to a variety of b-hydroxy ester or amide adducts
depending on the choice of nucleophile (Fig. 1). The
On the basis of the bifunctional electrophilic character
expressed by b-lactones, we have been interested in
developing optically active 4-substituted 2-oxetanones as
generally useful platforms for asymmetric organic
synthesis. Catalytic asymmetric acyl halide–aldehyde
Figure 1. Nucleophile-dependent b-lactone ring opening pathways.
Figure 2. Alternative AAC-amine-mediated ring opening sequences.
Keywords: amino acids; asymmetric catalysis; lactones; nucleophilic additions; peptides.
*
Corresponding author. Fax: þ1-412-624-8611; e-mail: sgnelson@pitt.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00722-6

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S. G. Nelson et al. / Tetrahedron 58 (2002) 7081–7091
cyclocondensation (AAC) reactions have been developed as
an operationally simple approach to highly enantiomerically
enriched b-lactones 1 (Fig. 2).2 This reaction technology
provides convenient and economical access to the optically
active b-lactones required for applications in asymmetric
synthesis. In order to reveal b-lactones as versatile aldol
surrogates, we envisioned that amine-promoted lactone
opening via the addition–elimination pathway would afford
enantioenriched b-hydroxy amides 2 constituting formal
aldol adducts of amide enolates. However, we were also
cognizant of the facile access to enantioenriched b-amino
acids derivatives 3 afforded by b-lactones provided suitable
conditions existed for securing amine-mediated SN2 ring
opening. Herein we outline the structural and electronic
requirements for engaging enantioenriched b-lactones in
regioselective addition–elimination or SN2 ring opening
with amine-based nucleophiles and the versatility the
derived ring opened products provide in various synthesis
activities.5
3. Nucleophilic b-lactone ring opening
3.1. Amine-mediated addition–elimination
Primary and secondary amines are considered to be
relatively non-polarizable, hard nucleophiles.9 As a result,
amine nucleophiles were expected to engage b-lactone
electrophiles in facile AE ring opening owing to the
activation of the carbonyl function engendered by the ring
strain associated with the b-lactone. In examining these
reactions, we were aware of one other example of an amine
addition to an a-methylene b-lactone reported by Calter that
adhered to this predicition.11 Owing to the versatility of
N-methoxy-N-methyl amides as conduits to other functional
groups, we were especially interested in the potential for
eliciting b-lactone ring opening using N,O-dimethyl-
hydroxyl amine as the nucleophile.12 The aluminum
amide derived from N,O-dimethylhydroxylamine has
proven to be the most generally effective reagent for
converting various carbonyl functionalities to the corre-
sponding Weinreb amides.13 We had hoped that the
enhanced electrophilicity of b-lactones relative to acylic
ester derivatives would lead to nucleophilic ring opening
using N,O-dimethylhydroxylamine without resorting to the
more nucleophilic aluminum amide reagent (Eq. (1)).
Indeed, reacting b-lactone 4 with N,O-dimethylhydroxyl-
amine (Procedure A: MeO(Me)NH·HCl, Et3N) delivered
the desired Weinreb amide 5 in high yield (Eq. (2)).2c
However, reactions utilizing the MeO(Me)NH·HCl/Et3N
reaction conditions did not afford uniformly high reaction
yields for all of the b-lactones examined. For example, the
b-lactone 6a provides the derived amide 7a in only 43%
yield using Procedure A (Eq. (3)). For those b-lactone
substrates that do not deliver high yields under the free-base
(Procedure A) reaction conditions (cf. 6a and b), application
of the prototypical aluminum N,O-dimethylhydroxylamide
reagent (Procedure B: MeO(Me)NH·HCl, Me2AlCl) con-
sistently delivered the derived amides (cf. 7a and b) in high
yields.
2. Reactivity of b-lactones
Techniques and procedures for achieving nucleophile-
dependent regioselectivity in additions to a,b-unsaturated
carbonyl electrophiles are widely recognized and exploited
in organic synthesis.6 The widespread utility of these
addition reactions has resulted in extensive investigations
of the factors affecting regiochemical preferences expressed
by various nucleophiles.7 However, similar analyses of the
factors dictating regioselection in nucleophile additions to
b-lactones have been less extensive, undoubtedly due to the
relative obscurity of b-lactone electrophiles as compared to
conjugated enones.1 Indeed, the hard–soft nucleophile–
electrophile matching arguments often used to rationalize
preferences for 1,2- or 1,4-addition to enones correlate well
with the nucleophile-dependent partioning of b-lactone ring
opening (Fig. 3).8 As expected, hard nucleophiles express a
strong preference for addition to the lactone carbonyl,
eliciting ring opening via an addition–elimination path-
way.9 Soft nucleophiles achieve better electronic matching
with the electrophilic b-carbon, thereby promoting SN2
displacement of the carboxylate residue.10 While these
considerations do not provide a comprehensive model for
nucleophile-b-lactone additions, they are useful as a
guideline for selecting the correct nucleophilic reaction
partners required to elicit the desired mode of ring opening.
ð1Þ
ð2Þ
ð3Þ
Figure 3. HSAB model for nucleophile additions to b-lactones.

S. G. Nelson et al. / Tetrahedron 58 (2002) 7081–7091
7083
Table 1. Azide-mediated ring opening reaction of b-lactones 1
optically active b-lactone electrophiles.21 Catalytic asym-
metric acyl halide–aldehyde cyclocondensation reactions
coupled with appropriate reaction conditions for achieving
regioselective SN2 ring opening of enantiomerically
enriched b-lactones was considered as an economical and
efficient asymmetric synthesis of b-amino acids derivatives.
Entry
Lactone 1
(R)
% ee 1a
% Yield 11b
(configuration)
% ee 11
a
b
c
d
e
f
BnOCH2– (1a)
91
97
95
96
97
94
99e
97
94 (R-11a)
95 (S-11b)
95 (S-11c)
78 (S-11d)
83 (S-11e)
87 (S-11f)
93 (R-11g)
83 (S-11h)
92c
93c
97d
PhCH2CH2– (1b)
Me2CHCH2– (1c)
CH3CH2CH2– (1d)
CH3(CH2)3– (1e)
CH2CH(CH2)8– (1f)
cC6H11– (1g)
ð5Þ
g
h
pNO2C6H4– (ent-1h)f
a
Pioneering observations by Vederas and Seebach had
previously established azide nucleophiles to have the
correct chemical potential to engage b-lactone electrophiles
in the desired SN2 ring openings.19a–c Indeed, this
observation is consistent with hard–soft matching of
nucleophile and electrophile, where the relatively polariz-
able azide anion would be expected to interact most strongly
with the softer carboxylate carbon electrophile.9,10 Based on
this information, azide anion was initially evaluated as a
suitable nucleophile for effecting the desired SN2-mode of
2-oxetanone ring opening (Eq. (6)). Among the various
solvent and azide salt combinations examined during
reaction optimization, the optically active b-lactones
1a–h were found to undergo SN2 lactone ring opening
most efficiently using sodium azide (2.0 equiv.) in DMSO
(508C) to directly afford the b-azido acids 11a–h in
78–95% yield (Table 1). Highly polar reaction solvents
are essential for achieving consistently high yields of the
b-azido acids, with DMSO proving to be superior even to
DMF in terms of reaction reproducibility. Under the
optimized NaN3–DMSO reaction conditions, azide-
induced ring opening was insensitive to the structure
of the lactone alkyl substituent, with lactones bearing
aliphatic unbranched, alkoxy-substituted, a-branched,22 and
b-branched alkyl substituents being subject to efficient
lactone ring opening with the anticipated inversion of
stereochemistry.23
Lactones 1 were prepared and assayed using the procedures in Ref. 2a
(except lactone 1g).
Lactone 1g was obtained by the resolution procedure described in Ref.
22a.
Reported yields are for materials obtained from the acid–base extractive
work-up of the azide ring opening reactions.
Enantiomer ratio determined by chiral HPLC (Chiralcel OD-H column)
of the corresponding methyl ester.
b
c
d
e
f
Enantiomer ratio determined by chiral HPLC (Chiralcel OD-H column)
of the corresponding benzyl ester.
(R)-4-(p-nitrophenyl)-2-oxetanone was used in this reaction.
Primary and dialkyl amines are also efficient nucleophiles
for promoting AE b-lactone ring opening (Eq. (4)).
Preliminary investigations evaluating morpholine as a
suitable nucleophile for addition–elimination b-lactone
ring opening were inspired by the versatility the resulting
amides would afford in accessing other functionalities.14
Indeed, the optically active b-lactone 8 was subject to facile
ring opening with morpholine at ambient temperatures to
deliver the corresponding morpholine amide 9 in good yield
(95%). Primary amine nucleophiles appear to function
similarly to morpholine; reacting the enantioenriched
b-lactone with benzyl amine afforded the corresponding
benzyl amide 10 (88%).
ð4Þ
ð6Þ
Precedent indicated that each of these SN2 ring opening
reactions would proceed with rigorous inversion of the
2-oxetanone stereocenter.3,4 The absolute configuration of
b-azido acids 11b–d was established by conversion to the
corresponding N-Boc amino esters 12b–d ((i) CH2N2; (ii)
H2, Boc2O, Pd–C) and correlation of their optical rotation
to those of authentic samples of known configuration
(Eq. (7)). The configuration of azido acid 11e was
established similarly by conversion to the corresponding
N-Boc amino acid 12e ((i) H2, 10% Pd–C; (ii) Boc2O,
Et3N); the configuration of the remaining b-azido acids
(11a,f,g) was assigned by analogy to these determinations.24
This stereochemical outcome was assumed to arise from a
kinetic preference for azide addition at the b-lactone C4
position (pathway a, Eq. (8)). However, a reaction
mechanism involving competing addition–elimination can-
not be discounted since the emergent acyl azide would be
expected to revert to the b-lactone with concomitant
ejection of the azide nucleophile (pathway b, Eq. (8)).25
While no reaction by-products that would suggest the
3.2. SN2 ring opening
3.2.1. Azide nucleophiles. Optically active b-amino acids
have become increasingly prevalent features in small-
molecule chemotherapeutic agents15 and are integral
components of peptidic materials that exhibit unique
structural properties.16 As a result, efficient and economical
preparation of enantiomerically enriched b-amino acids has
become the focus of numerous synthesis studies.17,18 We
recognized that amine-mediated SN2 ring opening of
b-lactones would provide an especially attractive and
straightforward entry to b-amino carbonyl relationships
(Eq. (5)).19,20 However, the evolution of this strategy as a
general asymmetric synthesis of b-amino acids had
previously been limited by the availability of the requisite

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S. G. Nelson et al. / Tetrahedron 58 (2002) 7081–7091
Figure 4. Purification of b-azido acids by extractive work-up.
intermediacy of the acyl azide were observed during these
reactions, the participation of reversible carbonyl addition
cannot be excluded.
to N-protected b-amino acids incorporating ubiquitous
t-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz)
amine protecting groups. Sulfonamide anions were
expected to exhibited attenuated basicity relative to the
carbamate-derived nucleophiles, thereby offering an
alternative for identifying amide anions possessing the
correct electronic properties (‘softness’) to elicit SN2
b-lactone ring opening.
ð7Þ
ð9Þ
Recognizing the utility of N-Boc and N-Cbz functionalities
in peptide synthesis, preliminary investigations of carba-
mate anion-mediated b-lactone ring openings utilized
nucleophles derived from t-butyl- or benzyl carbamate.
However, reacting lactone 1b with a variety of carbamate
salts (M¼Li, Na, K, MgBr) afforded imide 13 derived from
addition–elimination ring opening as the major product
(Eq. (10));27 only minor amounts of the desired b-amino
acid derivative 14 could be isolated using carbamate-based
nucleophiles. No salient reaction parameter (solvent,
temperature, etc.) could be identified that rendered SN2
ring opening as the predominant reaction mode for
carbamate nucleophiles.
ð8Þ
In addition to the high yields and enantioselectivities
achieved in the AAC-based b-azido acid synthesis, the
asymmetric AAC-azide ring opening sequence provides an
operationally simple method for product isolation and
purification. The carboxylic acid function that emerges
from the ring opening reaction can be exploited in acid–
base partitioning of the b-azido acid reaction products
(Fig. 4). Typical product purification involved extracting the
b-azido acid from an acidic aqueous wash to remove
inorganic salts and excess DMSO.26 Any remaining organic
impurities were removed by extracting a basic aqueous
solution of the carboxylate salt then reacidification to obtain
the b-azido acid products. The b-azido acids 11 typically
emerge from the extractive work-up in .95% purity.
ð10Þ
3.2.2. Sulfonamide anion nucleophiles. In anticipation of
the demands that multistep synthesis applications might
place on the b-amino acid derivatives emerging from this
procedure, we were interested in developing methods for
directly installing the protected b-amine function in the
correct oxidation state. Ring-opening of optically active
b-lactones with stabilized amine anions would afford an
asymmetric synthesis of b-amino acids in which the
nitrogen function would incorporate an electron-withdraw-
ing protecting group. Based on the HSAB model for
nucleophilic b-lactone ring opening, resonance stabilized
amide anions were expected to exhibit the correct electronic
properties for achieving SN2 ring opening (Eq. (9)).
Thus, carbamate nucleophiles would afford direct access
Inadequate attenuation of amide anion basicity by the
carboalkoxy function, leading to a harder nitrogen nucleo-
phile, was considered responsible for the predominant
carbonyl addition by carbamate nucleophiles. Believing that
further attenuation of nitrogen basicity would lead to
enhanced selectivity for the SN2 ring opening mode, the
anion derived from o-nitrobenzenesulfonamide was next
examined as a suitable nucleophile based on the sulfonyl
function’s ability to stabilize the amide anion. Furthermore,
these sulfonamide anions would successfully install the
nitrogen functionality in protected form as nosylate (oNs)
groups had previously been developed as nitrogen protecting

S. G. Nelson et al. / Tetrahedron 58 (2002) 7081–7091
Table 2. Sulfonamide anion-mediated b-lactone ring opening
7085
structure and function.16 The b-peptide materials pioneered
by Seebach29 and Gellman30 exhibit a considerably greater
propensity for adopting well-defined secondary structures
than the corresponding materials derived from natural
a-amino acids. Moreover, direct biomedical applications
of these b-peptidic materials have also been discovered;
helical b-peptide oligomers exhibit potent antibacterial
activity, reminiscent of the ubiquitous a-peptide antibac-
terial agents such as cephalosporin.31,32 However, diversity
within these b-peptide materials has been somewhat limited
by the availability of the requisite enantioenriched b-amino
acid building blocks. The b-azido acids emerging from the
AAC-azide ring opening sequence were considered to be
ideal building blocks for constructing structurally diverse
b-peptide units (Fig. 5). Specifically, b-peptide construction
would proceed by formatting a b-azido acid unit as the
peptide C terminus using a two step esterification-azide
reduction sequence. The active ester coupling partner
required for peptide elongation would be derived from a
similar b-azido acid; significantly, coupling can be
accomplished by direct activation of the carboxylate
function as the amine function would already exist in
protected form. The resulting azide-terminated peptide
chain would then be ready for iterative application of the
azide reduction–peptide coupling sequence with the next
b-azido acid unit.
Entry
Lactone 1
(R)
% Yield 15a
(configuration)
% ee 15b
(% ee lactone 1)
a
b
c
d
e
1a (BnOCH2–)
64 (R-15a)
72 (S-15b)
74 (S-15c)
83 (S-15d)
43 (R-15e)c
1b (PhCH2CH2–)
1c (Me2CHCH2–)
1f (CH2CH(CH2)8–)
1g (cC6H11–)
$95 (97)
93 (95)
$95 (99)
a
Reported values are for chromatographically purified materials.
Enantiomer ratios determined by 1H NMR analysis of corresponding (S)-
a-methoxyphenylacetamides; see Section 6.
b
c
38% of regioisomer isolated.
groups (Eq. (11)).28 Thus, reacting the enantiomerically
enriched b-lactones 1a–c,f,g with the sodium salt of
o-nitrobenzenesulfonamide in DMSO (508C) afforded the
N-protected b-amino acids 15a–e in good yields (64–83%)
accompanied by little (#10%) to none of the imide product
arising from carbonyl addition (Table 2). Steric bulk
adjacent to the electrophilic carbon atom, however, alters
the regioselectivity of nucleophilic addition to the b-lac-
tones; sulfonamide anion addition to the cyclohexyl-
substituted lactone 1g suffers from significant competition
between the SN2 and carbonyl addition reaction pathways
(Table 2, entry e). In this regard, the azide-mediated ring
opening reactions that do not exhibit substrate-dependent
regioselectivity represent attractive complements to sul-
fonamide anion addition reactions. Since o-nitrobenzene-
sulfonyl-protected nitrogen functionalities are conveniently
unmasked with thiolate ion, this procedure constitutes a
convenient two-step synthesis of versatile N-protected
b-amino acids.
Assemblying the enantioenriched b-azido acids into peptide
units was initiated by first esterifying the amino acid unit
that would become the peptide C terminus, rendering
methyl ester 16 as the starting point for peptide elongation
(Scheme 1). To format the resulting azido ester 16 for
peptide coupling, the azide function was reduced to the
corresponding primary amine 17 (H2, Pd–C). The activated
coupling partner required for amide bond construction is
available by directly activating b-azido acid 18 as the
corresponding b-azido acyl halide 19 (oxalyl chloride,
DMF, CH2Cl2). Peptide coupling then involved simple
acylation of the primary amine 16 with the acid chloride 19
(Et3N, CH2Cl2) to afford the dipeptides 20a–d (74–83%).
Further elongation of the peptide chain could be accom-
plished by reiteration of the azide reduction–amine
acylation sequence (Eq. (12)). Thus, azide reduction of
the dipeptide 20a and acylation with acid chloride 19
(R¼CH2CHMe2) afforded the tri-b-peptide 21 (74%).
ð11Þ
4. b-Azido acids in peptide synthesis
b-Peptides have emerged recently as important tools for
deconvoluting structural imperatives for protein secondary
Figure 5. b-Azido acid-based peptide synthesis.

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S. G. Nelson et al. / Tetrahedron 58 (2002) 7081–7091
Scheme 1.
6.1.1. N-Methoxy-N-methyl-2-(R)-methyl-3-(R)-hydroxy-
5-trimethylsilyl-4-pentynamide (5). To a solution of
180 mg of lactone 4 (1.0 mmol) and 250 mL of diisopropyl-
ethylamine (1.5 mmol, 1.5 equiv.) in 2 mL of CH2Cl2
was added 150 mg of N,O-dimethylhydroxyamine·HCl salt
(1.5 mmol, 1.5 equiv.) and the reaction was stirred 10 h
at ambient temperature. A saturated aqueous solution of
NH4Cl was added and the resulting mixture was extracted
with ether (3£15 mL). The combined organic portions were
washed with brine and dried (MgSO4). The volatiles were
evaporated in vacuo and the crude product mixture was
subjected to silica gel chromatography (10% ethyl acetate in
hexane) to afford 235 mg of amide 5 (97%) as a colorless
oil. [a]D¼216 (c 2.8, CHCl3). 1H NMR (300 MHz, CDCl3)
d 4.68 (d, J¼3.0 Hz, 1H), 3.72 (s, 3H), 3.18 (s, 3H), 3.02 (b,
1H), 3.03 (dq, J¼7.5, 3.0 Hz, 1H), 1.32–1.34 (d, J¼7.5 Hz,
3H), 0.15 (s, 9H). 13C NMR (75 MHz, CDCl3) d 176.6,
104.3, 89.8, 63.8, 61.8, 40.7, 32.0, 11.6, 20.02. IR (NaCl)
3404, 2248, 2175, 1640, 1251, 845 cm21. MS (EI, 70 eV):
m/z 244 (Mþ1)þ, 228 (M2Me)þ, 226 (M2OH)þ. HRMS
m/z calcd for C10H18NO3Si (M2Me)þ: 228.1056; found
228.1057.
ð12Þ
5. Conclusion
Uniting asymmetric AAC reaction methodology with
regioselective amine-mediated b-lactone ring opening
provides an operationally simple and economical enantio-
selective synthesis of amide aldol and b-amino acid
derivatives. Amine nucleophiles afford addition–elimi-
nation lactone ring opening to deliver optically active
b-hydroxy amides. Alternatively, azide and sulfonamide
anion nucleophiles elicit SN2 ring opening to deliver
enantioenriched b-amino acid derivatives in which the
amine function is introduced directly in protected from. The
availability of either enantiomer of the cyclocondensation
catalyst affords convenient access to b-amino acids in either
enantiomeric series. This methodology has been exploited
in developing an efficient synthesis of b-peptide fragments
based on b-azido acid building blocks.
6.1.2. 4-(tert-Butyldiphenylsilanyloxy)-(3S )-hydroxy-N-
methoxy-N-methylbutyramide (7b). To a 08C solution
containing 1.36 g of methoxymethylamine hydrochloride
(14 mmols) in 30 mL methylene chloride was added 14 mL
of dimethylaluminum chloride (14 mmols) as a 1 M solu-
tion in hexanes. The solution was allowed to warm to room
temperature and stir for 1 h. A 5 mL methylene chloride
solution containing 2.39 g of lactone 6b (7.0 mmol) was
transferred via cannula to the amine solution at room
temperature. After stirring the reaction mixture for 12 h at
room temperature, 42 mL of pH¼8 hydrogen phosphate
buffer was added to the reaction. The reaction was filtered
through a pad of celite to remove the solid aluminum salts.
The resulting biphasic solution was separated, and the
aqueous layer was washed with methylene chloride
(2£10 mL). The combined organics were dried over
MgSO4, filtered, and concentrated in vacuo. The crude oil
was purified by silica gel chromatography (30:70 EtOAc/
hexanes) to provide 2.64 g of amide 7b (94%) as a white
6. Experimental
6.1. General
Lactones 1a–f, 1h, 6a, 6b,2a 1g,22a and 42c were prepared
according to the published procedures. The (R,R )- and
(S,S )-catalyst complexes (Fig. 2) were prepared according
to the published procedure.2a
solid. [a ] ¼216 (91% ee, c 1.1, CHCl3). 1H NMR
23
546

S. G. Nelson et al. / Tetrahedron 58 (2002) 7081–7091
7087
(CDCl3) d 7.72 (dd, J¼5.0, 1.8 Hz, 4H), 7.44–7.36 (m, 6H),
4.24 (m, 1H), 3.85 (d, J¼3.2 Hz, 1H), 3.80 (dd, J¼10.1,
4.7 Hz, 1H), 3.72 (dd, J¼10.0, 5.0 Hz, 1H), 3.64 (s, 3H),
3.16 (s, 3H), 2.78 (d, J¼15.6 Hz, 1H), 2.67 (dd, J¼8.3,
15.2 Hz, 1H), 1.11 (s, 9H). 13C NMR (CDCl3) d 173.1,
135.4, 133.2, 129.7, 127.7, 68.6, 67.0, 61.1, 53.4, 34.9, 31.7,
26.8, 19.2. IR (NaCl) 3441, 3069, 3046, 2954, 2931, 2891,
2855, 1640, 1465, 1426, 1386, 1184, 1109, 998, 828, 741,
705, 610. EI-MS (70 eV) 344 (M2tBu)þ, 266, 241, 223,
199, 181, 163, 153, 135, 123. HRMS m/z calcd for
C10H18NO3Si (M2Me)þ: 344.1322; found 344.1318.
H, 5.99. Conversion of 11b to the corresponding methyl
ester (CH2N2, Et2O) and separation of the enantiomers by
chiral HPLC (Diacel Chiracele OD-H column, flow rate
1.0 mL/min, 10% i-PrOH, 90% hexane, Tr 7.05 (S ) and 8.44
(R ) min) provided the enantiomer ratio: 4(S)/4(R)¼
96.5:3.5 (93%ee).
6.2.3. (S)-3-Azido-5-methylhexanoic acid (11c). General
procedure A was followed employing 100 mg of b-lactone
1c (0.78 mmol). Extractive work-up gave 126 mg (95%) of
the title compound. [a ]2D5¼þ4.2 (c 4.8, CH2Cl2). 1H NMR
(CDCl3, 300 MHz) d 3.86 (m, 1H), 2.56 (d, J¼7.0 Hz, 2H),
1.81 (m, 1H), 1.55 (ddd, J¼14.1, 9.5, 5.4 Hz, 1H), 1.33
(ddd, J¼13.7, 8.7, 4.8 Hz, 1H), 0.98 (d, J¼6.6 Hz, 3H), 0.97
(d, J¼6.7 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d 177.2,
57.0, 43.3, 40.0, 25.0, 23.0, 21.8; IR (NaCl) 3029, 2954,
2925, 2880, 2870, 2666, 2108, 1710, 1431, 1262 cm21. MS
(CI, methane): m/z 172 (MþH)þ. HRMS m/z cacld for
C6H10N1O2 (M2CH3, N2): 128.0711; found: 128.0713.
Conversion of 11c to the corresponding benzyl ester
(BnOH, DCC, DMAP, CH2Cl2) and separation of the
enantiomers by chiral HPLC (Diacel Chiracele OD-H
column, flow rate 1.0 mL/min, 3% i-PrOH, 97% hexane, Tr
5.45 (R ) and 5.99 (S) min) provided the enantiomer ratio:
4(S)/4(R )¼98.5:1.5 (97%ee).
6.2. General procedure A: SN2 addition of NaN3 to
b-lactone 1
To a 508C solution of 72 mg of NaN3 (2.0 mmols,
2.0 equiv.) in 3.4 mL of anhydrous DMSO (0.3 M in
lactone) was added 176 mg of b-lactone 1 (1.0 mmol) via
syringe. The resulting homogeneous solution was stirred
until all the lactone had been consumed as monitored by
TLC (,6 h). After cooling the reaction mixture to ambient
temperature, 3 mL of saturated aqueous NaHCO3 was
added. The resulting heterogeneous mixture was triturated
with water until all the precipitated salts dissolved. The
resulting mixture was extracted with ethyl acetate (2£5 mL)
and the aqueous layer was separated and acidified with 1 M
HCl. The acidic aqueous layer was extracted with ethyl
acetate (3£5 mL) and the combined organic portions were
washed with water (2£5 mL) and brine (2£5 mL). The
organic portion was dried (Na2SO4) and evaporated in
vacuo to afford the b-azido acid 11.
6.2.4. (S )-3-Azidohexanoic acid (11d). General procedure
A was followed employing 250 mg of b-lactone 1d (2.19
mmol). Extractive work-up gave 269 mg (78%) of the title
1
compound. [a ]D25¼þ21 (c 4.3, CH2Cl2). H NMR (CDCl3,
300 MHz) d 8.80 (br s, 1H), 3.82 (m, 1H), 2.59 (dd, J¼16.7,
5.9 Hz, 1H), 2.53 (dd, J¼16.4, 8.1 Hz, 1H), 1.65–1.37 (m,
4H), 0.98 (t, J¼7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d
177.4, 58.5, 39.2, 36.3, 19.0, 13.5. IR (NaCl) 3049, 2962,
2935, 2875, 2665, 2123, 1715, 1434, 1263 cm21. MS (CI,
isobutane): m/z 158 (MþH)þ. Anal. calcd for C6H11N3O2:
C, 45.85; H, 7.05; found: C, 46.19; H, 7.11.
6.2.1. (R )-3-Azido-4-benzyloxybutanoic acid (11a).
General procedure A was followed employing 192 mg of
b-lactone 1a (1.0 mmol). Extractive work-up gave 221 mg
(94%) of the title compound. [a ]2D5¼þ27 (c 5.5, CH2Cl2).
1H NMR (CDCl3, 300 MHz) d 7.40–7.24 (m, 5H), 4.59 (s,
2H), 4.04 (m, 1H), 3.60 (d, J¼5.5 Hz, 2H), 2.67 (dd,
J¼16.6, 5.0 Hz, 1H), 2.54 (dd, J¼16.6, 8.4 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) d 176.8, 137.7, 128.7 (2C), 128.1,
127.8 (2C), 73.5, 71.8, 57.7, 36.1. IR (NaCl) 3089, 3065,
3034, 2927, 2863, 2673, 2127, 2095, 1711, 1414, 1267,
1093, 741, 701 cm21. MS (EI, 70 eV): m/z 207 (M2N2)þ,
130, 91. MS (FAB, Na-ethylene glycol): m/z 258 (MþNa)þ.
Conversion of 11a to the corresponding methyl ester
(CH2N2, Et2O) and separation of the enantiomers by
chiral HPLC (Diacel Chiracele OD-H column, flow rate
1.0 mL/min, 10% i-PrOH, 90% hexane, Tr 7.51 (R ) and 8.35
(S) min) provided the enantiomer ratio: 4(R)/4(S )¼96:4
(92%ee).
6.2.5. (S )-3-Azidoheptanoic acid (11e). General procedure
A was followed employing 350 mg of b-lactone 1e (2.73
mmol). Extractive work-up gave 387 mg (83%) of the title
1
compound. [a ]D25¼þ20 (c 4.6, CH2Cl2). H NMR (CDCl3,
300 MHz) d 9.10 (br s, 1H), 3.80 (m, 1H), 2.59 (dd, J¼16.3,
5.5 Hz, 1H), 2.53 (dd, J¼16.4, 7.9 Hz, 1H), 1.57 (m, 2H),
1.49–1.30 (m, 4H), 0.94 (t, J¼7.0 Hz, 3H). 13C NMR
(CDCl3, 75 MHz) d 177.4, 58.7, 39.3, 33.9, 27.9, 22.2, 13.8.
IR (NaCl) 3041, 2958, 2935, 2863, 2669, 2127, 2103, 1715,
1434, 1255 cm21. MS (CI, isobutane): m/z 172 (MþH)þ.
HRMS m/z cacld for C6H10N1O2 (M2CH3, N2)þ:
128.0711; found: 128.0716.
6.2.2. (S)-3-Azido-5-phenylpentanoic acid (11b). General
procedure A was followed employing 176 mg of b-lactone
1b (1.0 mmol). Extractive work-up gave 208 mg (95%) of
the title compound. [a]2D5¼23.0 (c 3.9, CH2Cl2). 1H NMR
(CDCl3, 300 MHz) d 7.35–7.29 (m, 2H), 7.25–7.20 (m,
3H), 3.81 (m, 1H), 2.84 (m, 1H), 2.72 (m, 1H), 2.60
(d, J¼6.7 Hz, 1H), 1.89 (m, 2H). 13C NMR (CDCl3,
75 MHz) d 177.1, 140.4, 128.5 (2C), 128.3 (2C), 126.2,
58.0, 39.3, 36.0, 32.0. IR (NaCl) 3084, 3059, 3029, 2929,
6.2.6. (S )-3-Azido-12-tridecenoic acid (11f). General
procedure A was followed employing 50 mg of b-lactone
1f (0.24 mmol). Extractive work-up gave 52 mg (87%) of
1
the title compound. [a]2D5¼þ15 (c 4.1, CH2Cl2). H NMR
(CDCl3, 300 MHz) d 10.60 (br s, 1H), 5.82 (dddd, J¼17.0,
10.2, 6.6, 6.6 Hz, 1H), 5.00 (ddd, J¼17.0, 3.3, 1.6 Hz, 1H),
4.94 (ddd, J¼8.9, 2.1, 1.0 Hz, 1H), 3.80 (m, 1H), 2.58 (dd,
J¼16.7, 5.8 Hz, 1H), 2.52 (dd, J¼16.4, 8.1 Hz, 1H), 2.05
(dt, J¼8.2, 6.8 Hz, 2H), 1.57 (m, 2H), 1.48–1.25 (m, 12H).
13C NMR (CDCl3, 75 MHz) d 177.2, 139.2, 114.2, 58.9,
39.4, 34.4, 33.8, 29.4 (2C), 29.2, 29.1, 28.9, 25.9. IR (NaCl)
2855, 2661, 2128, 2098, 1710, 1431, 1257, 749, 699 cm21
.
MS (FAB, Na-ethylene glycol): m/z 242 (MþNa)þ. Anal.
calcd for C11H13N3O2: C, 60.26; H, 5.98; found: C, 60.35;
3074, 2925, 2855, 2666, 2103, 1715, 1426, 1262, 908 cm21
.

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S. G. Nelson et al. / Tetrahedron 58 (2002) 7081–7091
MS (CI, methane): m/z 254 (MþH)þ. Anal. calcd for
filtration. The filtrate was concentrated in vacuo to afford
the crude b-sulfonamido acid. The crude acid was dissolved
in ethyl acetate and an ethereal solution of CH2N2 was
added until a yellow color persisted. Glacial acetic acid was
added to decolorize the reaction mixture and the volatiles
were evaporated in vacuo to afford the b-sulfonamido ester
15 as a yellow oil that was purified by silica gel chroma-
tography (hexanes/ethyl acetate).
C13H23N3O2: C, 61.63; H, 9.15; found: C, 62.12; H, 9.30.
6.2.7. (R )-3-Azido-3-cyclohexylpropanoic acid (11g).
General procedure A was followed employing 200 mg of
b-lactone 1g (1.30 mmol). Extractive work-up gave 238 mg
(93%) of the title compound. [a]2D5¼þ44 (c 4.9, CH2Cl2).
1H NMR (CDCl3, 300 MHz) d 10.08 (br s, 1H), 3.65 (m,
1H), 2.58 (dd, J¼16.3, 3.8 Hz, 1H), 2.45 (dd, J¼16.4,
9.8 Hz, 1H), 1.79–1.67 (m, 4H), 1.48 (m, 1H), 1.29–1.00
(m, 6H, Cyclohexyl). 13C NMR (CDCl3, 75 MHz) d 176.0,
64.2, 42.0, 39.4, 36.7, 29.4, 28.2, 26.0, 25.8. IR (NaCl)
3007, 2929, 2853, 2617, 2121, 2085, 1716, 1450, 1271,
999 cm21. MS (CI, isobutane): m/z 198 (MþH)þ. HRMS
calcd for C9H15N1O2 (M2N2)þ: 169.1103; found:
169.1107.
6.3.1. (S )-4-Benzyloxy-3-(o-nitrobenzenesulfonamido)-
butanoic acid, methy ester (15a). General procedure B
was followed employing 200 mg of b-lactone 1a (1.04
mmol). Extractive work-up gave 272 mg (64%) of the title
1
compound. [a ]2D5¼þ72 (c 4.5, CHCl3). H NMR (CDCl3,
300 MHz) d 8.13 (m, 1H), 7.79 (m, 1H), 7.67 (m, 2H),
7.34–7.28 (m, 3H), 7.16 (m, 2H), 6.10 (d, J¼8.0 Hz, 1H),
4.33 (s, 2H), 4.02 (m, 1H), 3.60 (s, 3H), 3.50 (dd, J¼9.8,
5.4 Hz, 1H), 3.42 (dd, J¼9.5, 5.0 Hz, 1H), 2.71 (dd, J¼16.4,
5.6 Hz, 1H), 2.64 (dd, J¼16.5, 6.6 Hz, 1H). 13C NMR
(CDCl3, 75 MHz) d 171.0, 147.4, 137.1, 134.4, 133.3,
132.7, 130.5, 128.2 (2C), 127.7 (2C), 127.6, 125.2, 73.0,
70.7, 51.7, 51.2, 36.6. IR (NaCl) 3335, 3089, 3061, 3030,
2950, 2867, 1735, 1541, 1366, 1164, 1121, 851, 784, 741,
697, 653 cm21. MS (EI, 70 eV): m/z 287 (M2CH2OBn)þ,
222 [M2SO2(C6H4NO2)]þ. HRMS m/z calcd for
6.2.8. (S)-3-Azido-3-(4-nitrophenyl)propanoic acid (11h).
General procedure A was followed employing 153 mg of
b-lactone 1h (0.79 mmol). Extractive work-up gave 155 mg
(83%) of the title compound. [a ]D¼2139 (c 1.5, CHCl3).
1H NMR (300 MHz, CDCl3) d 8.28 (dt, J¼1.9, 8.8 Hz, 2H),
7.56 (dt, J¼2.0, 8.8 Hz, 2H), 5.11 (dd, J¼5.5, 8.8 Hz, 1H),
2.9 (dd, J¼8.7, 16.7 Hz, 1H), 2.78 (dd, J¼5.6, 16.7 Hz, 1H).
13C NMR (75 MHz, CDCl3) d 175.7, 147.9, 145.2, 127.7,
124.2, 60.9, 40.9. HRMS m/z calcd for C9H8N2O4
(M2N2)þ: 208.484; found: 208.490.
C10H11N2O6S
287.0331.
[M2CH2OBn]þ:
287.0338;
found:
6.2.9. Stereochemical proofs for b-azido acids. The
absolute configuration of b-azido acids 11b–d was
established by conversion to the corresponding N-Boc
amino esters 12b–d ((i) CH2N2; (ii) H2, Boc2O, Pd–C) and
correlation of their optical rotation to those of authentic
samples of known configuration: 12b [a ]2D5¼25.8 (c 1.8,
CHCl3) [lit. [a]D25¼þ7.2 (R) (c 1.8, CHCl3)];24a 12c [a ]2D5¼
225.8 (c 1.47, CH3OH) [lit. [a]2D5¼222.8 (c 1.47,
CH3OH)];24b 12d [a ]D25¼221 (c 1.9, CHCl3) [lit. [a ]2D5¼
þ20.9 (R) (c 1.9, CHCl3)].24a The configuration of azido
acid 11e was established similarly by conversion to the
corresponding N-Boc amino acid 12e ((i) H2, Pd–C;
(ii) Boc2O, Et3N): [a ]2D5¼21.0 (c 0.5, DMF) [lit. [a ]2D5¼
21.2 (c 0.5, DMF)].24c The configuration of the remaining
b-azido acids (11a,f,g) was assigned by analogy to these
determinations.
6.3.2. (S)-3-(o-Nitrobenzenesulfonamido)-5-phenylpenta-
noic acid, methy ester (15b). General procedure B was
followed employing 200 mg of b-lactone 1b (1.14 mmol).
Extractive work-up gave 322 mg (72%) of the title
1
compound. [a ]2D5¼24.6 (c 8.2, CHCl3). H NMR (CDCl3,
300 MHz) d 8.11 (m, 1H), 7.88 (m, 1H), 7.74 (m, 2H),
7.29–7.11 (m, 3H), 7.08 (m, 2H), 5.93 (d, J¼8.6 Hz, 1H),
3.85 (m, 1H), 3.61 (s, 3H), 2.73–2.47 (m, 2H), 2.57 (dd,
J¼16.3, 5.0 Hz, 1H), 2.51 (dd, J¼16.3, 5.5 Hz, 1H), 1.94–
1.85 (m, 2H). 13C NMR (CDCl3, 75 MHz) d 171.0, 147.4,
140.5, 134.4, 133.5, 132.8, 130.3, 128.2 (2C), 128.1 (2C),
125.9, 125.0, 51.6, 51.2, 38.9, 36.2, 31.7. IR (NaCl) 3335,
3089, 3061, 3026, 2946, 2859, 1727, 1541, 1358, 1168, 848,
784, 741, 695, 653 cm21. MS (EI, 70 eV): m/z 287 (M2
CH2Bn)þ, 206 [M2SO2(C6H4NO2)]þ. Anal. calcd for
C18H20N2O6S: C, 55.09; H, 5.14; found: C, 55.07; H,
5.34. The enantiomeric purity of the b-sufonamido ester
15b was determined by the integration of the methyl ester
portion (CO2Me ) of the crude (S)-a-methoxyphenyl-
acetamides which provided the diastereomer ratio:
3(S )/3(R).96.5:3.5. (93% de). 1H NMR (CDCl3,
500 MHz) [–CO2Me ] d 3.70 (major), 3.59 (minor). The
diastereomeric (S)-a-methoxyphenylacetamides were pre-
pared from 15b by sulfonamide deprotection (PhSH,
K2CO3, DMF) followed by coupling the derived b-amino
ester with (S )-a-methoxyphenylacetic acid (DCC, 5 mol%
DMAP).
6.3. General procedure B: SN2 addition of o-nitro-
benzenesulfonamide, mono sodium salt to b-lactone 1
To a 508C suspension of 700 mg of o-nitrobenzenesul-
fonamide, mono sodium salt (3.13 mmols, 2.0 equiv.) and
˚
200 mg of activated powdered 4 A molecular seives in
5.2 mL of anhydrous DMSO (0.3 M in lactone) was added
200 mg of b-lactone 1 (1.56 mmols) via syringe. The
resulting suspension was stirred until all the lactone had
been consumed as monitored by TLC (,5 h). After cooling
the reaction mixture to ambient temperature, 5 mL of 1 M
aqueous HCl was added and the resulting mixture was
extracted with ethyl acetate (3£5 mL). The combined
organic extracts were washed with water (2£5 mL) and
brine (2£5 mL). The organic layer was separated, dried
(Na2SO4), and concentrated in vacuo to afford a yellow
solid. The solid was triturated with chloroform and the
insoluble material (o-nitrobenzenesulfonamide) removed by
6.3.3. (S)-5-Methyl-3-(o-nitrobenzenesulfonamido)hexa-
noic acid, methy ester (15c). General procedure B was
followed employing 200 mg of b-lactone 1c (1.56 mmol).
Extractive work-up gave 381 mg (74%) of the title
1
compound. [a]2D5¼215 (c 8.4, CHCl3). H NMR (CDCl3,
300 MHz) d 8.18 (m, 1H), 7.89 (m, 1H), 7.75 (m, 2H), 5.78
(d, J¼8.4 Hz, 1H), 3.89 (m, 1H), 3.62 (s, 3H), 2.55 (dd,

S. G. Nelson et al. / Tetrahedron 58 (2002) 7081–7091
7089
J¼16.2, 4.9 Hz, 1H), 2.48 (dd, J¼16.2, 5.6 Hz, 1H), 1.58
(m, 1H), 1.50 (m, 1H), 1.30 (m, 1H), 0.85 (d, J¼6.5 Hz,
3H), 0.77 (d, J¼6.4 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d
171.2, 147.5, 134.7, 133.5, 132.9, 130.3, 125.2, 51.6, 49.9,
43.8, 39.4, 24.3, 22.6, 21.4. IR (NaCl) 3331, 3093, 2958,
deprotection (PhSH, K2CO3, DMF) followed by coupling
the derived b-amino ester with (S)-a-methoxyphenylacetic
acid (DCC, 5 mol% DMAP).
6.3.6. Stereochemical proofs for b-sulfonamido acids.
The absolute configuration of b-sulfonamido acids 15b and
15c was established by conversion to the corresponding
N-Boc amino methyl esters 12b and 12c ((i) CH2N2;
(ii) PhSH, K2CO3, DMF; (iii) Boc2O, Et3N), respectively,
and correlation of their optical rotation to those of authentic
samples of known configuration: 12b [a ]2D5¼26.4 (c 1.8,
CHCl3) [lit. [a]D25¼þ7.2 (R ) (c 1.8, CHCl3)];24a 12c
[a ]D25¼228.7 (c 1.47, CH3OH) [lit. [a]2D5¼222.8 (c 1.47,
CH3OH)];24b The configuration of the remaining b-sul-
fonamido acids (15a,d,e) was assigned by analogy to these
determinations.
2867, 1735, 1537, 1362, 1160, 851, 780, 741, 653 cm21
.
MS (EI, 70 eV): m/z 344 (M)þ, 287 (M2CH2CHMe2)þ, 186
[SO2(C6H4NO2)]þ. HRMS m/z calcd for C14H20N2O6S
(M2CH2OBn)þ: 344.1042; found: 344.1037. The enantio-
meric purity of the b-sufonamido ester 15c was determined
by the integration of the methyl ester portion (CO2Me ) of
the crude (S )-a-methoxyphenylacetamides which provided
1
the diastereomer ratio: 3(S)/3(R ).97.5:2.5. (95% de). H
NMR (CDCl3, 500 MHz) [–CO2Me ] d 3.70 (major),
3.57 (minor). The diastereomeric (S)-a-methoxyphenyl-
acetamides were prepared from 15c by sulfonamide
deprotection (PhSH, K2CO3, DMF) followed by coupling
the derived b-amino ester with (S)-a-methoxyphenylacetic
acid (DCC, 5 mol% DMAP).
6.4. General procedure C: b-peptide coupling reactions
To 0.2 M solution of azido acid 11 (4.9 mmol) in CH2Cl2
was added oxalyl chloride (1.2 equiv., 5.9 mmol) and DMF
(0.03 equiv., 0.15 mmol). The resulting solution was stirred
2 h at ambient temperature whereupon the volatile reaction
components were evaporated in vacuo to afford the acid
chloride 17 as a yellow oil.
6.3.4. (S )-3-(o-Nitrobenzenesulfonamido)-12-tridecenoic
acid, methy ester (15d). General procedure B was followed
employing 200 mg of b-lactone 1f (0.95 mmol). Extractive
work-up gave 337 mg (83%) of the title compound.
[a]2D5¼þ4.4 (c 3.9, CHCl3). H NMR (CDCl3, 300 MHz)
1
d 8.17 (m, 1H), 7.88 (m, 1H), 7.75 (m, 2H), 5.81 (dddd,
J¼16.9, 10.3, 6.7, 6.7 Hz, 1H), 5.78 (d, J¼8.2 Hz, 1H), 5.00
(m, 1H,), 4.94 (m, 1H), 3.80 (m, 1H), 3.61 (s, 3H), 2.57 (dd,
J¼16.2, 5.2 Hz, 1H), 2.49 (dd, J¼16.3, 6.1 Hz, 1H), 2.03
(m, 2H), 1.54 (m, 2H), 1.37–1.15 (m, 12H). 13C NMR
(CDCl3, 75 MHz) d 171.2, 147.5, 138.9, 134.7, 133.4,
132.8, 130.3, 125.1, 114.0, 51.7, 51.6, 39.2, 34.6, 33.8, 29.1
(2C), 28.8, 28.7, 28.6, 25.5. IR (NaCl) 3331, 3073, 2927,
2855, 1735, 1541, 1358, 1168, 784, 741 cm21. MS (EI,
70 eV): m/z 353 (M2MeO2CCH2)þ, 287 (M2(CH2)8-
CHCH2)þ, 186 [SO2(C6H4NO2)]þ. HRMS m/z cacld for
C10H11N2O6S (M2(CH2)8CHCH2)þ: 287.0338; found:
287.0330.
In a separate flask, a suspension of 10% Pd–C (0.49 mmol)
and ethyl acetate (0.3 M in 16) was stirred under hydrogen
gas (1 atm via balloon) for 1 h. A 1.2 M solution of azido
ester 16 (4.9 mmol) in ethyl acetate was then added and the
reaction stirred 2 h under 1 atm of H2. The reaction mixture
was filtered through celite and the filtrate was evaporated to
afford the amino ester 17 as a yellow oil. This oil was
dissolved into CH2Cl2 (14 mL) containing diisopropylethyl-
amine (1.2 equiv., 5.9 mmol) and a 1 M CH2Cl2 solution
of the acid chloride (prepared above) was added and
the resulting solution was stirred 15 min at ambient
temperature. The reaction was quenched by adding 1N
aqueous NaHCO3 and the resulting mixture was extracted
with diethyl ether (2£). The combined organic portions
were washed with brine and dried (MgSO4), and the
crude product mixture was purified by silica gel chroma-
tography (hexanes/ethyl acetate) to provide the coupling
product.
6.3.5. (R )-3-Cyclohexyl-3-(o-nitrobenzenesulfonamido)-
propionic acid, methy ester (15e). General procedure B
was followed employing 308 mg of b-lactone 1g
(2.0 mmol). Extractive work-up gave 309 mg (43%) of the
title compound. [a ]2D5¼233 (c 1.9, CHCl3). 1H NMR
(CDCl3, 300 MHz) d 8.15 (m, 1H), 7.87 (m, 1H), 7.74 (m,
2H), 5.77 (d, J¼8.8 Hz, 1H), 3.66 (m, 1H), 3.56 (s, 3H),
2.54 (dd, J¼16.2, 6.0 Hz, 1H), 2.54 (dd, J¼16.1, 5.4 Hz,
1H), 1.84–1.48 (m, 6H), 1.27–1.03 (m, 3H), 0.99–0.84 (m,
2H). 13C NMR (CDCl3, 75 MHz) d 171.5, 147.5, 134.9,
133.3, 132.8, 130.4, 125.1, 60.3, 56.6, 51.7, 41.4, 36.6, 29.2,
28.8, 25.9, 25.8. IR (NaCl) 3331, 3097, 2927, 2852, 1731,
1541, 1442, 1358, 1164, 852, 784, 733, 657 cm21. MS (EI,
70 eV): m/z 297 (M2MeO2CCH2)þ, 287 (M2C6H11)þ, 186
[SO2(C6H4NO2)]þ. HRMS m/z cacld for C10H11N2O6S
(M2C6H11): 287.0338; found: 287.0326. Anal. calcd for
C16H22N2O6S: C, 51.88; H, 5.99; found: C, 51.86; H, 6.05.
The enantiomeric purity of the b-sulfonamido ester 15e was
determined by the integration of the methyl ester portion
(CO2Me ) of the crude (S )-a-methoxyphenylacetamides
which provided the diastereomer ratio: 3(R)/3(S).98:2
(.95% de). 1H NMR (CDCl3, 500 MHz) [–CO2Me ] d 3.70
(major), 3.52 (minor). The diastereomeric (S)-a-methoxy-
phenylacetamides were prepared from 15e by sulfonamide
6.4.1. (3R )-3-((3R)-3-Azido-5-methylhexanoylamino)-5-
phenylpentanoic acid, methyl ester (20a). General
procedure C was followed using 861 mg of azido acid ent-
11c (5.0 mmol) and 1.173 g of azido ester ent-16b (from
ent-11b, 5.0 mmol) to afford 1.341 g of dipeptide 20a (74%)
1
as a colorless oil. [a]D¼þ16 (c 2.7, CHCl3). H NMR
(300 MHz, CDCl3) d 7.44–7.39 (m, 2H), 7.34–7.29 (m,
3H), 6.48 (d, J¼9.0, 1H), 4.52–4.41 (m, 1H), 4.10–4.01 (m,
1H), 3.81 (s, 3H), 2.85–2.76 (m, 2H), 2.71 (t, J¼5.2 Hz,
2H), 2.50 (dd, J¼4.6, 11.5 Hz, 1H), 2.40 (dd, J¼8.7,
14.6 Hz, 1H), 2.06–1.88 (m, 3H), 1.69–1.61 (m, 1H),
1.49–1.37 (m, 1H), 1.10 (d, J¼3.5 Hz, 3H), 1.08 (d, J¼
3.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 172.5, 169.6,
141.5, 128.8, 128.6, 126.4, 58.3, 53.7, 52.0, 46.3, 43.8,
42.6, 38.5, 35.9, 33.0, 32.0, 25.3, 23.3, 22.1. IR
(NaCl) 3291, 2951, 2107, 1747, 1644, 1549, 1259, 1200,
697 cm21. HRMS calcd for C19H28N4O3: 360.2161; found
360.2150.

7090
S. G. Nelson et al. / Tetrahedron 58 (2002) 7081–7091
6.4.2. (3R )-3-((3S )-3-Azido-5-phenylpentanoylamino)-3-
cyclohexylpropionic acid, methyl ester (20b). General
procedure C was followed using 1.1 g of azido acid 11b
(4.9 mmol) and 1.0 g of azido ester 16g (from 11g,
4.9 mmol) to afford 1.6 g of dipeptide 20a (83%) as a
colorless solid. [a ]D¼227 (c 1.8, CHCl3). 1H NMR
(300 MHz, CDCl3) d 7.38–7.26 (m, 5H), 6.33 (d, J¼
9.4 Hz, 1H), 4.20–4.11 (m, 1H), 4.01–3.93 (m, 1H), 3.77
(s, 3H), 2.94–2.39 (m, 6H), 2.00–1.56 (m, 8H), 1.34–0.98
(m, 5H). 13C NMR (75 MHz, CDCl3) d 172.5, 168.9, 140.7,
128.5, 128.3, 126.1, 59.2, 51.7, 50.6, 42.0, 40.7, 36.3, 35.8,
32.2, 29.6, 29.2, 26.1, 25.8. HRMS calcd for C21H30N4O3:
386.2318; found 386.2327.
Acknowledgments
The authors thank Dr Zhonghui Wan and Dr Mark
A. Hilfiker for valuable contributions. The National
Science Foundation (CHE-9875735), the Clorox Services
Company, and the Bristol-Myers Squibb Foundation are
gratefully acknowledged for their generous support.
References
1. Pommier, A.; Pons, J.-M. Synthesis 1993, 441.
2. For a discussion of b-lactones as surrogates for prototypical
aldol adducts, see: (a) Nelson, S. G.; Peelen, T. J.; Wan, Z.
J. Am. Chem. Soc. 1999, 121, 9742. (b) Nelson, S. G.; Wan, Z.;
Peelen, T. J.; Spencer, K. L. Tetrahedron Lett. 1999, 40,
6535–6540. (c) Nelson, S. G.; Wan, Z. Org. Lett. 2000, 2,
1883.
6.4.3. (3S)-3-[(3S)-3-Azido-3-(4-nitrophenyl)propionyl-
amino]-5-phenylpentanoic acid, methyl ester (20c).
General procedure C was followed using 153 mg of azido
acid 11h (0.65 mmol) and 151 mg of azido ester 16b (from
11b, 0.65 mmol) to afford 226 mg of dipeptide 20c (82%) as
a colorless solid. [a ]D¼295 (c 3.0, CHCl3). 1H NMR
(300 MHz, CDCl3) d 8.28 (d, J¼8.7 Hz, 2H), 7.60 (d,
J¼8.7 Hz, 2H), 7.37–7.32 (m, 2H), 7.27–7.23 (m, 3H),
6.54 (d, J¼9.0 Hz, 1H), 5.29 (dd, J¼5.5, 8.6 Hz, 1H), 4.37
(m, 1H), 3.69 (s, 3H), 2.78–2.55 (m, 6H), 2.00–1.89 (m,
2H). 13C NMR (75 MHz, CDCl3) d 171.9, 167.8, 147.5,
146.1, 140.9, 128.3, 128.1, 127.5, 125.9, 123.9, 61.5, 51.5,
45.9, 43.4, 38.0, 35.4, 32.3. HRMS calcd for C21H23N5O5:
425.1699; found: 425.1704.
3. The SN2 ring opening pathway provides entry to a variety of
versatile synthesis building blocks including b-amino acids
and b-thiocarboxylic acids. Nitrogen nucleophiles: (a) Arnold,
L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985,
107, 7105. (b) Griesbeck, A.; Seebach, D. Helv. Chim. Acta
1987, 70, 1326. (c) Arnold, L. D.; May, R. G.; Vederas, J. C.
J. Am. Chem. Soc. 1988, 110, 2237. (d) Castagnani, R.; De
Angelis, F.; De Fusco, E.; Giannessi, F.; Misiti, D.; Meloni,
D.; Tinti, M. O. J. Org. Chem. 1995, 60, 8318. (e) Bernabei, I.;
Castagnani, R.; De Angelis, F.; De Fusco, E.; Giannessi, F.;
Misiti, D.; Muck, S.; Scafetta, N.; Tinti, M. O. Chem. Eur. J.
1996, 2, 826. Sulfur nucleophiles: (f) Griesbeck, A.; Seebach,
D. Helv. Chim. Acta 1987, 70, 1326. (g) Tempkin, O.;
Blacklock, T. J.; Burke, J. A.; Anastasia, M. Tetrahedron:
Asymmetry 1996, 7, 2721.
6.4.4. (3S )-3-((3S )-3-Azido-4-benzyloxybutyrylamino)-
5-phenylpentanoic acid, methyl ester (20d). General
procedure C was followed using 282 mg of azido acid ent-
11a (1.3 mmol) and 303 mg of azido ester 16b (from 11b,
1.3 mmol) to afford 410 mg of dipeptide 20d (74%) as a
colorless oil after column chromatography. [a ]D¼29.1
4. For the ring opening of b-lactones with carbon nucleophiles,
see: (a) Sato, T.; Kawara, T.; Kawashima, M.; Fujisawa, T.
Chem. Lett. 1980, 571. (b) Sato, T.; Kawara, T.; Nishizawa,
A.; Fujisawa, T. Tetrahedron Lett. 1980, 21, 3377.
(c) Fujisawa, T.; Sato, T.; Kawara, T.; Ohashi, K. Tetrahedron
Lett. 1981, 22, 4823. (d) Sato, T.; Naruse, K.; Fujisawa, T.
Tetrahedron Lett. 1982, 23, 3587. (e) Sato, T.; Itoh, T.;
Hattori, C.; Fujisawa, T. Chem. Lett. 1983, 1391.
(f) Kawashima, M.; Sato, T.; Fujisawa, T. Tetrahedron
1989, 45, 403.
1
(c 2.2, CHCl3). H NMR (300 MHz, CDCl3) d 7.43–7.27
(m, 9H), 6.33 (d, J¼8.9 Hz, 1H), 4.66 (s, 2H), 4.42–4.38
(m, 1H), 4.19–4.14 (m, 1H), 3.76 (s, 3H), 3.73–3.62
(m, 2H), 2.81–2.68 (m, 2H), 2.63 (t, J¼4.2 Hz, 2H), 2.50
(dd, J¼4.9, 18.2 Hz, 1H), 2.38 (dd, J¼8.6, 14.7 Hz, 1H),
2.07–1.85 (m, 2H). 13C NMR (75 MHz, CDCl3) d 172.3,
169.0, 141.3, 137.7, 128.6, 128.5, 128.0, 127.7, 126.2, 73.5,
72.1, 58.4, 51.9, 46.1, 38.5, 38.4, 35.9, 32.7. IR (thin film)
3299, 3063, 2950, 2861, 2127, 1736, 1549, 1496, 1268,
1202, 750, 699 cm21. HRMS calcd for C23H28N4O4:
424.2111; found: 424.2121.
5. For a preliminary account of this work, see: Nelson, S. G.;
Spencer, K. L. Angew. Chem., Int. Ed. Engl. 2000, 39, 1323.
6. For reviews of conjugate enone additions, see: (a) Rossiter,
B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771. (b) Sibi,
M. P.; Manyem, S. Tetrahedron 2000, 56, 8033. (c) Krause,
6.4.5. (3R )-3-[(3R )-3-((3R )-3-Azido-5-methylhexanoyl-
amino)-5-methylhexanoylamino]-5-phenyl-pentanoic
acid, methyl ester (21). General procedure C was followed
using 494 mg of azido acid ent-11c (2.9 mmol) and 1.04 g
of dipeptide 20a (2.9 mmol) to afford 1.1 g of tripeptide 21
(74%) as a colorless solid after column chromatography.
¨
N.; Hoffman-Roder, A. Synthesis 2001, 171.
7. For selected recent examples: (a) Sikorski, W. H.; Reich, H. J.
J. Am. Chem. Soc. 2001, 123, 6527. (b) Lee, P. H.; Ahn, H.;
Lee, K.; Sung, S.-Y.; Kim, S. Tetrahedron Lett. 2001, 42, 37.
(c) Reich, H. J.; Sikorski, W. H. J. Org. Chem. 1999, 64, 14.
(d) Strzalko, T.; Seyden-Penne, J.; Wartski, L.; Corset, J.;
Castella-Ventura, M.; Froment, F. J. Org. Chem. 1998, 63,
3295.
1
[a ]D¼þ33 (c 2.4, CHCl3). H NMR (300 MHz, CDCl3) d
7.38–7.22 (m, 5H), 7.02 (d, J¼8.9 Hz, 1H), 6.38 (d, J¼
9.0 Hz, 1H), 4.41–4.35 (m, 2H), 4.11–4.08 (m, 1H), 3.76
(s, 3H), 2.77–2.35 (m, 8H), 1.95–1.70 (m, 4H), 1.62–1.53
(m, 2H), 1.44–1.35 (m, 2H); 1.03–0.98 (m, 12H). 13C NMR
(75 MHz, CDCl3) d 172.2, 171.0, 169.3, 141.2, 128.6,
128.4, 126.2, 58.03, 51.9, 46.2, 44.9, 43.6, 43.0, 42.5,
40.3, 38.6, 35.7, 32.7, 25.3, 25.1, 23.2, 22.9, 22.3,
21.9. HRMS calcd for C26H41N5O4: 487.3159; found:
487.3168.
8. For reviews: (a) Pearson, R. G. Chemical Hardness; Wiley–
VCH: New York, 1997. (b) Pearson, R. G. J. Chem. Ed. 1987,
64, 561. (c) Ho, T. Tetrahedron 1985, 41, 1.
9. For the ‘hard/soft’ classification of specific Lewis bases, see:
(a) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533.
(b) Pearson, R. G. Science 1966, 151, 172. (c) Pearson, R. G.;

S. G. Nelson et al. / Tetrahedron 58 (2002) 7081–7091
7091
Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827. (d) Pearson,
R. G. J. Am. Chem. Soc. 1988, 110, 7684 and references
therein.
Fusco, E.; Giannessi, F.; Misiti, D.; Muck, S.; Scafetta, N.;
Tinti, M. O. Chem. Eur. J. 1996, 2, 826.
20. For an alternative approach to b-amino acid derivatives
derived from b-lactones, see: Yang, H. W.; Romo, D. J. Org.
Chem. 1999, 64, 7657.
10. Chattaraj, P. K.; Lee, H.; Parr, R. G. J. Am. Chem. Soc. 1991,
113, 1855.
11. Calter, M. A.; Guo, X. J. Org. Chem. 1998, 63, 5308.
12. For a review: Weinreb, S. M.; Folmer, J. J. Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. E., Ed.; Wiley:
New York, 1995; Vol. 3, p 2083.
21. For recent developments in asymmetric b-lactone synthesis,
see: Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403.
22. b-Lactones possessing a-branched substituents are not
obtained in sufficiently high enantioselectivities from the
catalyzed AAC reactions to be generally useful. Lactone 1g
was readily prepared from the enzyme-mediated resolution of
the racemic b-lactone derived from the achiral AAC reaction,
see: (a) Nelson, S. G.; Spencer, K. L. J. Org. Chem. 2000, 65,
1227. (b) Koichi, Y.; Suginaka, K.; Yamamoto, Y. J. Chem.
Soc., Perkin Trans. 1 1995, 1645.
13. Garigipati, S. G.; Tschaen, D. M.; Weinreb, S. M. J. Am.
Chem. Soc. 1985, 107, 7790.
14. For the conversion of morpholine amides to ketones, see:
´ ´
Martın, R.; Romea, P.; Tey, C.; Urpı, F.; Vilarrasa, J. Synlett
1997, 1414.
15. Juaristi, E. Enantioselective Synthesis of b-Amino Acids;
Wiley–VCH: New York, 1997.
23. To verify that lactone ring opening was proceeding with
rigorous inversion of stereochemistry, the enantiomeric
purities of azides 11a–c were determined by chiral HPLC
(Chiralcel OD-H column) of the methyl esters derived from
11a and 11b, and the benzyl ester derived from 11c. See
Section 6 for full procedural details.
16. For reviews of b-peptide synthesis and structure, see:
(a) Hintermann, T.; Seebach, D. Chimia 1997, 50, 244.
(b) Seebach, D.; Matthews, J. L. J. Chem. Soc., Chem.
Commun. 2015, 1997. (c) Koert, U. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1836. (d) Gellman, S. H. Acc. Chem. Res.
1998, 31, 173.
´
24. (a) Compounds 12b and 12d: Alcon, M.; Canas, M.; Poch, M.;
´
Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron Lett. 1994,
17. Asymmetric b-amino acid synthesis employing optically
active starting materials or chiral auxiliaries: (a) Ref. 15.
(b) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichim. Acta
1994, 27, 3. (c) Cole, D. C. Tetrahedron 1994, 50, 9517.
(d) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 117. See
also: (e) Enders, D.; Bettray, W.; Raabe, G.; Runsink, J.
Synthesis 1994, 1322. (f) Enders, D.; Wahl, H.; Bettray, W.
Angew. Chem., Int. Ed. Engl. 1995, 34, 455–457. (g) Podlech,
J.; Seebach, D. Liebigs Ann. 1995, 1217. (h) Guibourdenche,
C.; Podlech, J.; Seebach, D. Liebigs Ann. 1996, 1121. and
references therein. (i) Farras, J.; Ginesta, X.; Sutton, P. W.;
Taltavull, J.; Egeler, F.; Romea, P.; Urpi, F.; Vilarrasa, J.
Tetrahedron 2001, 57, 7665.
35, 1589. (b) Compound 12c: Gordon, E. M.; Godfrey, J. D.;
Delaney, N. G.; Asaad, M. M.; Von Langen, D.; Cushman,
D. W. J. Med. Chem. 1988, 31, 2199. (c) Compound 12e:
Mendre, C.; Rodriguez, M.; Laur, J.; Aumelas, A.; Martinez, J.
Tetrahedron 1988, 44, 4415.
25. For the synthesis of b-lactones via lactonization of b-hydroxy
carboxylate derivatives, see Ref. 21 and references therein.
26. Acidic work-up of the dimethylsulfoxide reaction solutions
should remove any remaining azide reagent by conversion to
the sulfoximine, see: Johnson, C. R.; Rogers, P. E. J. Org.
Chem. 1973, 38, 1793.
27. The potassium and magnesium halide carbamate salts were
unstable toward decomposition during the course of the
reaction.
18. Recent catalytic asymmetric synthesis of b-amino acid
derivatives: (a) Falborg, L.; Jørgensen, K. A. J. Chem. Soc.,
Perkin Trans. 1 1996, 2823. (b) Kobayashi, S.; Ishitani, H.;
Ueno, M. J. Am. Chem. Soc. 1998, 120, 431. (c) Sibi, M. P.;
Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998,
120, 6615. (d) Zhou, F.; Detty, M. R.; Lachicotte, R. J.
Tetrahedron Lett. 1999, 40, 585. (e) Meyers, J. K.; Jacobsen,
E. N. J. Am. Chem. Soc. 1999, 121, 8959. (f) Guerin, D. J.;
Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134.
28. (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373. (b) Wipf, P.; Henninger, T. C. J. Org. Chem.
1997, 62, 1586. (c) Miller, S. C.; Scanlan, T. S. J. Am. Chem.
Soc. 1997, 119, 2301.
29. Seebach, D.; Abele, S.; Gademann, K.; Jaun, B. Angew.
Chem., Int. Ed. Engl. 1999, 38, 1595. and references therein.
30. Barchi, Jr. J. J.; Huang, X.; Appella, D. H.; Christianson, L. A.;
Durell, S. R.; Gellman, S. H. J. Am. Chem. Soc. 2000, 122,
2711. and references therein.
19. (a) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem.
Soc. 1985, 107, 7105. (b) Griesbeck, A.; Seebach, D. Helv.
Chim. Acta 1987, 70, 1326. (c) Arnold, L. D.; May, R. G.;
Vederas, J. C. J. Am. Chem. Soc. 1988, 110, 2237.
(d) Castagnani, R.; De Angelis, F.; De Fusco, E.; Giannessi,
F.; Misiti, D.; Meloni, D.; Tinti, M. O. J. Org. Chem. 1995, 60,
8318. (e) Bernabei, I.; Castagnani, R.; De Angelis, F.; De
31. (a) Hamura, Y.; Schneider, J. P.; Degrado, W. F. J. Am. Chem.
Soc. 1999, 121, 12200. (b) Porter, E. A.; Wang, X.; Lee, H.-S.;
Weisblum, B.; Gellman, S. H. Nature 2000, 404, 565.
32. Grademann, K.; Ernst, M.; Hoyer, D.; Seebach, D. Angew.
Chem. Int. Ed. Engl. 1999, 38, 1223.