Synthesis of 2,2-disubstituted pyrrolidine-4-carboxylic acid derivatives and their incorporation into β-peptide oligomers

Article abstract of DOI:10.1021/jo048639z

(Chemical Equation Presented) We have recently shown that members of a new class of β-peptides, containing 2,2-disubstituted pyrrolidine-4-carboxylic acid residues, display discrete conformational preferences despite the impossibility of internal hydrogen bonding (Huck et al. J. Am. Chem. Soc. 2003, 125, 9035). Here we describe the synthesis of a variety of 2,2-disubstituted pyrrolidine-4-carboxylic derivatives that bear a diverse set of side chains and protecting groups suitable for oligomer synthesis. In addition, we discuss coupling methods for construction of oligomers in solution and on solid phase. Non-hydrogen bonded foldamers such as those generated from 2,2-disubstituted pyrrolidine-4-carboxylic acids may be useful in biomedical applications because the low intrinsic polarity of their backbones may promote bioavailability.

Full text of DOI:10.1021/jo048639z

Synthesis of 2,2-Disubstituted Pyrrolidine-4-carboxylic Acid
Derivatives and Their Incorporation into â-Peptide Oligomers
Bayard R. Huck and Samuel H. Gellman*
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706
gellman@chem.wisc.edu
Received August 5, 2004
We have recently shown that members of a new class of â-peptides, containing 2,2-disubstituted
pyrrolidine-4-carboxylic acid residues, display discrete conformational preferences despite the
impossibility of internal hydrogen bonding (Huck et al. J. Am. Chem. Soc. 2003, 125, 9035). Here
we describe the synthesis of a variety of 2,2-disubstituted pyrrolidine-4-carboxylic derivatives that
bear a diverse set of side chains and protecting groups suitable for oligomer synthesis. In addition,
we discuss coupling methods for construction of oligomers in solution and on solid phase. Non-
hydrogen bonded foldamers such as those generated from 2,2-disubstituted pyrrolidine-4-carboxylic
acids may be useful in biomedical applications because the low intrinsic polarity of their backbones
may promote bioavailability.
Introduction
â-Peptides displaying all three types of regular secondary
structure found among proteins, helix, sheet, and reverse
turn, have been characterized via high-resolution struc-
tural methods,4 and progress toward the development of
â-peptide tertiary structure has been described.5,6 In
addition, â-peptides have been shown to display a num-
ber of interesting activities,7 at least some of which
depend on the adoption of specific conformations.
The interesting functions reported for various â-pep-
tides, and the fundamental challenge of elucidating the
relationship between â-amino acid substitution pattern
and oligo-â-amino acid folding behavior, provide motiva-
tion for a continuing search for new â-peptide secondary
structures. Recently, we reported the first high-resolution
Complex molecular-level operations required for bio-
logical function, such as catalysis and signal trans-
duction, are governed by biopolymers. Proteins, the key
biopolymers in most such processes, are generated from
a relatively small set (ca. 20) of simple R-amino acid
building blocks. Proteins achieve the structural complex-
ity required for complex activity via folding. Nucleic acids,
too, can achieve a high level of operational complexity
by adopting diverse secondary and tertiary structures.
The substantial difference between the R-amino acid
residues that comprise proteins and the nucleotide
residues that comprise nucleic acids suggests that the
propensity to fold, rather than any specific composition,
provides the foundation for sophisticated molecular func-
tion. The rapidly expanding study of nonnatural “fold-
amers”, oligomers that adopt specific folding patterns,
emerges from these considerations.1-3
(3) Selected recent examples: (a) Gregar, T. Q.; Gervay-Hague, J.
J. Org. Chem. 2004, 69, 1001. (b) Smith, M. D.; Claridge, T. D. W.;
Sansom, M. S. P.; Fleet, G. W. J. Org. Biomol. Chem. 2003, 1, 3647.
(c) Doerksen, R. J.; Chen, B.; Yuan, J.; Winkler, J. D.; Klein, M. L.
Chem. Commun. 2003, 2534. (d) Yang, X. W.; Martinovic, S.; Smith,
R. D.; Gong, B. J. Am. Chem. Soc. 2003, 125, 9932. (e) Levins, C. G.;
Schafmeister, C. E. J. Am. Chem. Soc. 2003, 125, 4702. (f) Jiang, H.;
Leger, J.-M.; Huc, I. J. Am. Chem. Soc. 2003, 125, 3448.
(4) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001,
101, 3219-3232.
(5) Raguse, T. R.; Lai, J. R.; LePlae, P. R.; Gellman, S. H. Org. Lett.
2001, 3, 3963.
(6) Cheng, R. P.; DeGrado, W. F. J. Am. Chem. Soc. 2002, 124,
11564.
Oligo-â-amino acids (“â-peptides”) represent a major
feature in the current landscape of foldamer research.
* To whom correspondence should be addressed.
(1) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180.
(2) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. Rev. 2001, 101, 3893-4011.
10.1021/jo048639z CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/05/2005
J. Org. Chem. 2005, 70, 3353-3362
3353

Huck and Gellman
FIGURE 1. 2,2-DPCA building blocks prepared in this study.
structural evidence of folding by â-peptides that cannot
form internal hydrogen bonds because all backbone
linkages are tertiary amide groups.8 This development
is important at a fundamental level because internal
hydrogen bonding is prevalent among the most common
secondary structures found in proteins (R-helix, 310-helix,
â-sheet) and in â-peptides. The network of noncovalent
interactions that specifies the shape for internally hy-
drogen bonded structures must differ from the network
that controls folding when backbone hydrogen bonding
is precluded. The identification of tertiary amide fold-
amers is potentially important at a practical level because
the backbone in this case is intrinsically less polar than
a secondary amide backbone, which might ultimately
lead to favorable properties in biomedical contexts.
Here we describe the synthesis of a variety of 2,2-
disubstituted pyrrolidine-4-carboxylic acids (2,2-DPCAs;
Figure 1) and the construction of short â-peptides from
one of these â-imino acid building blocks. Placement of a
quaternary center adjacent to the ring nitrogen proved
to be necessary to limit the configuration of the inter-
residue tertiary amide linkages in 2,2-DPCA oligomers.8
The presence of multiple backbone rotamers ((E)- and
(Z)-amide configurations at some or all positions) has
been detected by NMR for other tertiary amide-based
oligomers, including those comprised of unsubstituted
PCA residues9 or 2-monosubstituted PCA residues,8 and
N-alkylglycine oligomers (“peptoids”).10 This local con-
formational heterogeneity ensures that oligomer second-
ary structure is heterogeneous as well. (In contrast,
proline oligomers and oligomers of modified proline-like
residues do not display tertiary amide rotamers;11 the
rotamer problem can also be eliminated by use of alkene
isosteres for the tertiary amide linkage.12) Achieving
conformational control via introduction of the quaternary
center in 2,2-DPCA residues carries the additional benefit
of providing two sites of side chain attachment, which
should facilitate our long-term goal of generating fold-
amers with useful functions. Access to 2,2-DPCA building
blocks carrying a range of side chain functional groups
(7) Selected examples of â-peptides with biological function:
(a) Werder, M.; Hauser, H.; Abele, S.; Seebach, D. Helv. Chim. Acta
1999, 82, 1774. (b) Hamuro, Y.; Schneider, J. P.; DeGrado, W. F. J.
Am. Chem. Soc. 1999, 121, 12200. (c) Porter, E. A.; Wang, X.; Lee,
H.-S.; Weisblum, B.; Gellman, S. H. Nature 2000, 404, 565.
(d) Gademann, K.; Kimmerlin, T.; Hoyer, D.; Seebach, D. J. Med. Chem.
2001, 44, 2461. (e) Liu, D.; DeGrado, W. F. J. Am. Chem. Soc. 2001,
123, 7553. (f) Porter, E. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem.
Soc. 2002, 124, 7324. (g) Raguse, T. L.; Porter, E. A.; Weisblum, B.;
Gellman, S. H. J. Am. Chem. Soc. 2002, 124, 12774. (h) Gelman, M.
A.; Richter, S.; Cao, H.; Umezawa, N.; Gellman, S. H.; Rana, T. M.
Org. Lett. 2003, 5, 3563.
(9) Abele, S.; Vogtli, K.; Seebach, D. Helv. Chim. Acta 1999, 82, 1539.
(10) Armand, P.; Kirshenbaum, K.; Goldsmith, R. A.; Farr-Jones,
S.; Barron, A. E.; Truong, K. T. V.; Dill, K. A.; Mierke, D. F.; Cohen,
F. E.; Zuckermann, R. N.; Bradley, E. K. Proc. Natl. Acad. Sci. U.S.A.
1998, 95, 4309.
(11) (a) Zhang, R.; Madalengoitia, J. S. Tetrahedron Lett. 1996, 37,
6235. (b) Zhang, R.; Brownewell, F.; Madalengoitia, J. S. J. Am. Chem.
Soc. 1998, 120, 3894. (c) Mamai, A.; Zhang, R.; Natarajan, A.;
Madalengoitia, J. S. J. Org. Chem. 2001, 66, 455.
(12) Wang, X. J.; Hart, S. A.; Xu, B.; Mason, M. D.; Goodell, J. R.;
Etzkorn, F. A. J. Org. Chem. 2003, 68, 2343.
(8) Huck, B. R.; Fisk, J. D.; Guzei, I. D.; Carlson, H. A.; Gellman, S.
H. J. Am. Chem. Soc. 2003, 125, 9035.
3354 J. Org. Chem., Vol. 70, No. 9, 2005

2,2-Disubstituted Pyrrolidine-4-carboxylic Acid Derivatives
FIGURE 3. Key NOE of 6a′ that helps confirm substituent
stereochemistry.
SCHEME 1. Conversion of 3a into Lactone 5a
FIGURE 2. Introduction of the first side chain.
has already proven to be useful from the perspective of
characterization, enabling the preparation of oligomers
with sufficient 1H NMR dispersion to allow high-resolu-
tion structural analysis.8
Results and Discussion
The synthesis of 2,2-DPCA residues begins with TBS-
protected 4-hydroxy-proline methyl ester, 2 (Figure 2).
The initial synthetic steps follow established prece-
dents.13,14 One side chain is introduced via alkylation of
the ester enolate derived from 2, and the second side
chain is then generated from the ester group itself. Each
ester enolate alkylation, performed with any of a variety
of alkyl, benzyl, and allyl halides, provided a pair of
products epimeric at the quaternary center, which is
consistent with a previous report.13 The diastereomers
could be separated chromatographically either at this
step or at a subsequent step; thus, each alkylating agent
shown in Figure 2 can lead to at least two functionalized
monomers for subsequent â-peptide synthesis. The dia-
stereomeric ratio of the alkylation product depends on
the nature of the electrophile. As noted in the original
report,13 benzyl halides afford a higher proportion of the
less polar methyl ester 3a-g, whereas alkyl and allyl
halides yield a majority of the more polar methyl ester
3a′-g′. The prime (′) designation introduced here, which
originates from the polarity of the alkylation products,
indicates the configuration at what will become the
quaternary center of the 2,2-DPCA units. The prime/no
prime distinction is retained in the designation of sub-
sequent synthetic products.
Stereochemical assignment of the epimeric products
was accomplished by following a literature procedure14
in three cases (3a-c/3a′-c′). For example, diastereomers
3a and 3a′ were separated from one another chromato-
graphically. Then, as shown in Scheme 1, pure isomer
3a was desilyated with tetrabutylammonium fluoride,
and the ester was hydrolyzed with sodium hydroxide to
provide 4a. Lactonization conditions led to formation of
5a. Similar sequences were carried out with resolved
stereoisomers from mixtures 3b/3b′ and 3c/3c′. In each
case, one of the two diastereomers formed a lactone, and
the other did not. The lactone-forming diastereomer was
assigned as having the carboxyl and hydroxyl groups cis.
In each case, the less polar constituent of the initial
alkylation product mixture (polarity judged to be in-
versely related to elution order upon silica chromatog-
raphy) led ultimately to lactone formation, and these less
polar epimers were assigned structures 3a-c. This
behavior matches previous reports on such systems,13,14
as does our observation that benzylic halides favor
formation of the less polar epimer, while alkyl and allylic
halides favor the more polar epimer. Stereochemical
assignments for pairs 3d/3d′, 3e/3e′, 3f/3f ′, and 3g/3g′
were made by analogy on the basis of their relative
chromatographic mobilities.
Our stereochemical assignment was supported by
NMR analysis of diamide 6a′ (Figure 3), which was
produced as described below from 3a′.8 A nuclear O¨ ver-
hauser effect (NOE) was observed between the proton at
the 4-position of the ring and the methyl group at the
2-position, which suggests that the 4-proton and 2-methyl
group are cis on the ring. In addition, no NOE was
detected between the 4-proton and the methylene protons
from the ether substituent at the 2-position, suggesting
a trans relationship. Further support for our stereochem-
ical assignments was obtained from the crystal structure
of a 2,2-DPCA dimer in which both residues were derived
from 3c.8
After the quaternary center had been generated via
alkylation, a series of additional steps produced the
2,2-DPCA building blocks shown in Figure 1. The prin-
cipal synthetic route we used is illustrated in Scheme 2,
which shows conversion of 3a′ to 1a′ and further reac-
tions to generate 6a′. Sodium borohydride reduction of
the methyl ester afforded primary alcohol 7a′ (Scheme
2). Two subsequent synthetic approaches were explored,
silver oxide-promoted alkylation (Scheme 2) and a Swern
(13) Nagumo, S.; Mizukami, M.; Akutsu, N.; Nishida, A.; Kawahara,
N. Tetrahedron Lett. 1999, 40, 3209-3212.
(14) Sato, T.; Kugo, Y.; Nakaumi, E.; Ishibashi, H.; Ikeda, M. J.
Chem. Soc., Perkin Trans. 1 1995, 1801.
J. Org. Chem, Vol. 70, No. 9, 2005 3355

Huck and Gellman
SCHEME 2. Conversion of Alkylation Product 3a′ to 2,2-DPCA Building Block 1a′ and Diamide Derivative
6a′
SCHEME 3. Alternative Manipulation of the Hydroxylmethyl Appendage
oxidation/Wittig sequence (Scheme 3; discussed below).
Silver oxide-promoted alkylation of the primary alcohol
group was performed with methyl iodide to generate 8a′
from 7a′ or with other alkyl and benzyl halides to provide
analogues. This approach has two limitations. First,
moderate yields (<60%) were obtained when a bulky
electrophile was used. Second, benzylic ethers are labile
under the highly acidic conditions employed for the
subsequent nitrile hydrolysis.
With the substituents at the quaternary center estab-
lished, the final synthetic steps were identical for each
2,2-DPCA building block, involving replacement of the
(15) Klein, S. I.; Czekaj, M.; Molino, B. F.; Chu, V. Biol. Med. Chem.
Lett. 1997, 7, 1773.
3356 J. Org. Chem., Vol. 70, No. 9, 2005

2,2-Disubstituted Pyrrolidine-4-carboxylic Acid Derivatives
SCHEME 4. Synthesis of 2,2-DPCA Monomer 1j′
OTBS group with a carboxylic acid group, with inversion
(Scheme 2). This portion of the route follows a previous
synthesis of the parent â-imino acid, pyrrolidine-3-
carboxylic acid.15 For the case shown in Scheme 2, silyl
ether deprotection followed by treatement with tosyl
chloride yielded 9a′. Potassium cyanide displacement
generated nitrile 10a′. Acidic hydrolysis of the nitrile
group yielded the corresponding carboxylic acid, with
concomitant cleavage of the tert-butyl carbamate protec-
tion group. The Boc group was replaced to afford the 2,2-
DPCA building block 1a′. Beginning with the commer-
cially available 4-hydroxy-proline, we were able to prepare
multigram quantities of this monomer and others shown
in Figure 1 in about a week.
The side chains in 2,2-DPCA building blocks 1a′-1i
in Figure 1 are relatively nonpolar. We sought an
analogue with a side chain that could be ionized, e.g.,
via protonation, for the long-term goal of generating
water-soluble 2,2-DPCA oligomers. Synthesis of a 2,2-
DPCA monomer bearing a protected amino group on a
side chain began by alkylating the ester enolate of 2 with
allyl bromide. Separation of the diastereomers and
conversion of the carboxyl group to a methoxymethyl
group generated intermediate 8g′. As shown in Scheme
4, the terminal alkene substituent was subjected to a
hydroboration/oxidation sequence to afford a primary
alcohol, and the hydroxyl group was converted to the
azide (16′) by way of a tosylate intermediate (15′). A one-
pot procedure for azide hydrogenation followed by Boc
protection delivered 17′. The carboxylic acid group was
then generated at the 4-position in the usual way (see
Scheme 2). Both Boc protecting groups were removed
during nitrile hydrolysis. The two amino groups of the
resulting diamino acid were sequentially reprotected in
Each 2,2-DPCA monomer was converted to a diamide
derivative, for example, 6a′ in Scheme 2, so that we could
determine whether the quaternary center enforced a
single tertiary amide rotamer for the group involving the
1
ring nitrogen. H and 13C NMR analysis revealed that
each diamide in this series displays a single detectable
rotameric state in solution.
The potential limitations associated with hydroxyl
group alkylation led us to pursue an alternative protocol
for elaborating the second side chain, a Swern oxidation
followed immediately by a Wittig reaction to give an
alkene (Scheme 3). Although this reaction sequence was
examined with only the ylide derived from methyl tri-
phenylphosphonium bromide, it should be possible to use
other ylides as well. Terminal alkenes 12a′, 12b/12b′, and
12c/12c′ (isomer separation was not carried out at this
stage in the latter two cases) were modified in two ways.
Hydrogenation afforded an ethyl side chain (13a′ and
13b/13b′). Alternatively, hydroboration/oxidation deliv-
ered primary alcohols that were then O-methylated to
provide 14/14′. The Swern/Wittig protocol appears to be
more general than hydroxyl alkylation for introduction
of diverse side chains into 2,2-DPCA monomers.
FIGURE 4. Location of the carbamate proton in 1j′. Chemical
shifts measured in CDCl3 at a solute concentration of 10 mM.
J. Org. Chem, Vol. 70, No. 9, 2005 3357

Huck and Gellman
FIGURE 5. Carbonyl region 13C NMR comparison of 2,2-DPCA tetramer 20 (lower) and the analogous unsubstituted PCA tetramer
(upper) in CDCl3 (25 °C).
a two-step process, the primary amine with a Boc group
and the secondary amine with a Cbz group.
NMR data for 1j′ and related compounds suggest that
the Boc and Cbz groups were introduced at the desired
positions (side chain and ring amino groups, respectively).
The NMR measurements were obtained for 10 mM
samples in CDCl3 (Figure 4); little or no intermolecular
hydrogen bonding is expected under these conditions.
Both 1j′ and nitrile precursor 10k′ display a carbamate
proton resonance at 4.6 ppm. The Cbz-protected analogue
of 10k′ was prepared as a reference compound, and in
this case the carbamate proton appears at 4.8 ppm. This
modest downfield shift relative to Boc-protected 10k′
suggests that the protecting group placement shown for
1j′ is correct.
of the 13C NMR spectrum, which is consistent with the
expectation that each of the four tertiary amide units
occurs in both E and Z conformations, which interchange
slowly on the NMR time scale. In contrast, 2,2-DPCA
tetramer 20 displays only five major 13C resonances in
this region, presumably arising from the five carbonyl
carbon atoms in a single rotameric form of this molecule
(or possibly from rapid rotation about the amide C-N
bonds).
Our long-term goal is to screen libraries of 2,2-DPCA
heterooligomers for specific biological activities. Solid-
phase synthesis is generally preferred relative to solu-
tion-phase methods for the preparation of libraries. We
undertook the solid-phase synthesis of a homotetramer
derived from 1a′ in order to explore this approach.
The availability of 2,2-DPCA monomers led us to
explore the synthesis of oligomers in solution. t-Boc-
protected monomer 1a′ was coupled to the N-deprotected
methyl ester derived from 1a′ through the use of BopCl16
to yield a dimer. Higher oligomers (trimer through
hexamer) were prepared analogously. These oligomers
were obtained with quite high purity, according to
reverse-phase HPLC of the crude products. We had been
concerned that the proximity of the quaternary center
to the secondary amino group might hinder the amide
bond-forming step; however, synthetic yields in the 2,2-
DPCA series were comparable to yields obtained for the
synthesis of unsubstituted PCA oligomers.17 Prior to
NMR analysis of the oligomers, we removed the N-
terminal Boc group, to avoid the presence of multiple
tertiary carbamate rotamers. Thus, 2,2-DPCA oligomers
were N-deprotected and an N-terminal isobutyryl amide
group was introduced, generating 18-22.
13C NMR comparison of 2,2-DPCA tetramer 20 and the
analogous tetramer containing unsubstituted PCA resi-
dues (Figure 5) suggests that disubstitution adjacent to
the ring nitrogen limits rotational isomerism of the
tertiary amide groups, as intended. The PCA tetramer
displays a large number of signals in the carbonyl region
Fmoc-protected monomer 23 was prepared from 1a′
and coupled to a modified TentaGel Rink amide resin
with PyBrOP (a standard coupling agent for the solid-
phase synthesis with hindered secondary amines18). The
(16) Tung, R. D.; Rich, D. H. J. Am. Chem. Soc. 1985, 107, 4342.
(17) Huck, B. R. Ph.D. Thesis, University of Wisconsin-Madison,
Madison, WI, 2002.
(18) Coste, J.; Dufour, M.-N.; Pantaloni, A.; Castro, B. Tetrahedron
Lett. 1990, 31, 669.
3358 J. Org. Chem., Vol. 70, No. 9, 2005

2,2-Disubstituted Pyrrolidine-4-carboxylic Acid Derivatives
SCHEME 5. Solid-Phase 2,2-DPCA Tetramer Synthesis
cal shifts are reported in ppm (δ) relative to the central line
of the CDCl3 triplet (δ 77.0). Mass spectra (MS) were obtained
using electrospray ionization. Benzene was distilled from Na/
benzophenone. Hexanes were distilled at atmospheric pres-
sure. Triethylamine (Et3N) was distilled from CaH2. Dichlo-
romethane (CH2Cl2) was distilled from CaH2. THF was dis-
tilled from sodium/benzophenone. All reagents and solvents
were purchased from commercial suppliers and used without
further purification. Analytical thin-layer chromatography
(TLC) was carried out on TLC plates pre-coated with silica
gel 60 (250 µM layer thickness). Visualization was accom-
plished using either a UV lamp or potassium permanganate
stain. Column chromatography was performed on silica gel 60
(230-400 mesh). Solvent mixtures used for TLC and column
chromatography are reported in v/v ratios.
protecting group was then removed, and the first coupling
was carried out with preactivated 23 (Scheme 5). The
coupling and deprotection sequence was repeated two
more times, followed by acylation of the N-terminus.
Tetramer 24 was then cleaved from the resin with TFA.
Workup of the cleavage reaction afforded the crude 2,2-
DPCA tetramer in quantitative yield; reverse-phase
HPLC analysis revealed that this material was 80% pure
on the basis of UV absorbance. The high yield and purity
of tetramer 24 led us to undertake synthesis of the
analogous hexamer and octamer. These â-peptides were
also synthesized in high yields (on the basis of crude
product mass) with moderate levels of purity (hexamer
25: 90% yield, 65% purity; octamer 26: 84% yield, 50%
purity). The only side products from each of these
syntheses were truncated â-peptides. It is possible that
these byproducts could be minimized by longer coupling
times or by double coupling. Even without such improve-
ments, solid-phase synthesis of these â-peptides is much
more efficient than solution-phase synthesis. For ex-
ample, the hexamer was prepared in 3 days via manual
solid-phase synthesis, but solution-phase synthesis re-
quired two weeks.
Compound 2. Di-tert-butyl dicarbonate (52.4 g, 0.24 mol)
was dissolved in dioxane (120 mL) and added to a stirred
solution of trans-4-hydroxy-L-proline (26.2 g, 0.2 mol) in 2 M
NaOH (120 mL, 0.24 mol). The resulting solution was stirred
for 2 h at room temperature. Dioxane was removed via rotary
evaporation. The resulting solution was washed with ether,
acidified to pH 2 with 1 M aqueous HCl, and extracted with
EtOAc. The organic layer was dried over MgSO4 and concen-
trated. The residue was dissolved in benzene/methanol
(440 mL, 10/1, v/v). (Trimethylsilyl)diazomethane (100 mL, 0.2
mol, 2.0 M solution in hexanes) was added dropwise, and the
resulting solution was stirred for 1 h at room temperature.
The reaction was quenched with acetic acid until a clear color
persisted, and the solution was then concentrated. The residue
was dissolved in DMF (200 mL). Imidazole (68.1 g, 1.0 mol)
and TBDMS-Cl (90.4 g, 0.6 mol) were added, and the resulting
solution was stirred overnight at room temperature. The DMF
was removed via rotary evaporation under vacuum. The
resulting residue was dissolved in EtOAc and washed with 1
M HCl. The organic layer was dried over MgSO4 and concen-
trated. The crude product was purifed by SiO2 column
chromatography eluting with hexane/EtOAc (4/1, v/v) (TLC Rf
) 0.28) to afford 54.5 g (76% overall yield) of 2 as a colorless
oil: 1H NMR (CDCl3, 300 MHz) δ 4.37-4.28 (m, 1H), 4.27-
4.21 (t, 7.7 Hz, 1H), 3.64 (s, 3H), 3.56-3.46 (dt, 11.0 Hz,
4.8 Hz, 1H), 3.35-3.20 (m, 1H), 2.14-2.03 (m, 1H), 1.98 - 1.87
(m, 1H), 1.41-1.30 (m, 9H), 0.79 (s, 9H), 0.01 (s, 6H); 13C NMR
(CDCl3, 75.4 MHz) mixture of rotamers δ 173.6, 173.4, 154.5,
153.7, 79.9, 77.4, 77.0, 76.6, 70.3, 69.6, 57.9, 57.5, 54.8, 54.4,
52.0, 51.8, 39.7, 38.8, 28.3, 28.1, 25.6, 17.8, -3.2, -5.0; ESI-
MS m/z (M + Na) calcd for C17H32NO5SiNa 382.5, obsd 382.1.
Compounds 3a and 3a′. Diisopropylamine (1.52 equiv) was
dissolved in THF (220 mL) and cooled to 0 °C. nBuLi (2.5 M
solution in hexanes, 1.50 equiv) was added dropwise. After the
addition, the solution was stirred for 10 min at 0 °C and then
cooled to -20 °C. HMPA (3.00 equiv) was added dropwise, and
the solution was stirred for 10 min at -20 °C. Methyl ester 2
(7.9 g, 0.022 mol) was dissolved in THF (220 mL) and added
to the stirred solution via cannula. The resulting solution was
Conclusion
We have developed an efficient synthetic route for the
synthesis of a diverse set of 2,2-DPCA monomers. In
addition, we have shown that such â-imino acids can be
coupled efficiently to generate oligomers, both in solution
and via solid-phase methods. These synthetic achieve-
ments lay the groundwork for investigation of biological
applications of 2,2-DPCA â-peptides. Such oligomers are
attractive because of their ability to adopt predictable
secondary structure despite the lack of intramolecular
hydrogen bonding.
Experimental Section
General Procedures. Proton nuclear magnetic resonance
(1H NMR) spectra were recorded in deuterated solvents on 300
MHz or 500 MHz spectrometers. Chemical shifts are reported
in parts per million (ppm, δ) relative to tetramethylsilane (δ
0.00). 1H NMR splitting patterns with observed first-order
coupling are designated as singlet (s), doublet (d), triplet (t),
or quartet (q). Splitting patterns that could not be interepreted
or easily visualized are designated as multiplet (m) or broad
(br). Carbon nuclear magnetic resonance (13C NMR) spectra
were recorded on 300 MHz or 500 MHz spectrometers. Chemi-
J. Org. Chem, Vol. 70, No. 9, 2005 3359

Huck and Gellman
stirred for 1 h while warming to 0 °C and then cooled to
-78 °C. Methyl iodide (1.50 equiv) was added dropwise, and
the reaction mixture was allowed to stir for 4 h. The reaction
was quenched with saturated aqueous NH4Cl, diluted with
H2O, and extracted with EtOAc. The organic layer was dried
over MgSO4 and concentrated. The crude product (7.96 g,
mixture of diastereomers) was separated by column chroma-
tography eluting with hexane/EtOAc (8/1; v/v) to afford 1.62 g
(20% yield) of 3a (Rf ) 0.42) and 6.34 g (77% yield) of 3a′ (Rf
) 0.34) as colorless oils. Characterization of 3a: 1H NMR
(CDCl3, 300 MHz) δ 4.33-4.22 (m, 1H), 3.68-3.55 (m, 4H),
3.31-3.18 (m, 1H), 2.17-1.90 (m, 2H), 1.50-1.43 (m, 3H),
1.38-1.28 (m, 9H), 0.78 (s, 9H), -0.03 (s, 6H); 13C NMR
(CDCl3, 75.4 MHz) mixture of rotamers δ 175.0, 174.9, 153.3,
79.8, 79.4, 69.8, 69.1, 64.9, 64.6, 55.9, 55.8, 51.9, 48.1, 47.2,
28.3, 28.2, 25.6, 23.3, 22.5, 17.8; ESI-MS m/z (M + Na) calcd
for C18H35NO5SiNa 396.5, obsd 396.2. Characterization of
3a′: 1H NMR (CDCl3, 300 MHz) δ 4.35-4.25 (m, 1H), 3.68-
3.52 (m, 4H), 3.37-3.20 (m, 1H), 2.26-2.12 (m, 1H), 1.83-
1.74 (m, 1H), 1.60-1.54 (m, 3H), 1.38-1.28 (m, 9H), 0.78
(s, 9H), -0.03 (s, 6H); 13C NMR (CDCl3, 75.4 MHz) mixture of
rotamers δ 175.0, 174.9, 153.8, 153.3, 79.8, 79.4, 69.8, 69.1,
64.9, 64.6, 55.9, 55.8, 51.9, 48.1, 47.2, 28.8, 28.2, 28.1, 26.0,
25.6, 23.3, 22.5, 17.8; electrospray ionization-MS m/z (M + Na)
calcd for C18H35NO5SiNa 396.5, obsd 396.2.
Compound 4a. Methyl ester 3a (78 mg, 0.21 mmol) was
dissolved in THF (2.1 mL). TBAF (0.23 mL, 0.23 mmol, 1.0 M
solution in THF) was added, and the solution was stirred 5 h
at room temperature. The reaction was quenched with satu-
rated aqueous NH4Cl, and the THF was removed via rotary
evaporation. The resulting solution was diluted with H2O and
extracted with EtOAc. The organic layer was dried over MgSO4
and concentrated.
The resulting residue was dissolved in MeOH (1 mL). To
this solution was added aqueous NaOH (1.05 mL, 2.1 mmol,
2.0 M solution in H2O). The reaction solution was stirred
overnight at room temperature, washed with ether, acidified
with 1 M aqueous HCl, and extracted with EtOAc. The organic
layer was dried over MgSO4 and concentrated to afford 41 mg
(80% yield) of 4a as a clear oil: 1H NMR (CDCl3, 300 MHz)
mixture of rotamers δ 6.95-6.30 (bs, 1H), 4.52-4.27 (m, 1H),
3.91-3.39 (m, 2H), 2.63-2.38 (m, 1H), 2.15-1.92 (m, 1H),
1.71-1.35 (m, 12H); 13C NMR (CDCl3, 75.4 MHz) mixture of
rotamers δ 177.3, 177.0, 155.5, 154.0, 81.6, 77.6, 69.3, 65.0,
64.1, 56.4, 55.3, 47.6, 47.4, 46.5, 28.4, 28.2, 23.8, 22.8; ESI-
MS m/z (M + Na) calcd for C11H18NO5Na 244.3, obsd 244.1.
Compound 5a. Compound 4a (0.041 g, 0.17 mmol) was
dissolved in toluene (1.7 mL). DMAP (0.002 g, 0.017 mmol)
and Et3N (0.12 mL, 0.84 mmol) were added, followed by a
solution of 2,4,6-trichlorobenzoyl chloride (0.13 mL, 0.84 mmol)
in toluene (3.4 mL). The reaction was stirred overnight at
reflux. The solution was cooled to room temperature and
washed with 1 M aqueous HCl and brine. The organic layer
was dried over MgSO4 and concentrated. The crude product
was purifed by column chromatography eluting with hexane/
EtOAc (2/1, v/v) to afford 0.021 g (50% yield) of 5a as a clear
oil: 1H NMR (CDCl3, 300 MHz) δ 4.91 (s, 1H), 3.64-2.97
(m, 2H), 2.14-2.02 (m, 2H), 1.80 (s, 3H), 1.46 (s, 9H); 13C NMR
(CDCl3, 75.4 MHz) δ 172.4, 128.2, 81.4, 75.0, 64.0, 53.1, 53.0,
46.4, 42.0, 28.3, 24.7, 14.0; ESI-MS m/z (M + Na) calcd for
C11H17NO4Na 250.3, obsd 250.1.
Compound 7a′. NaBH4 (3.3 g, 0.085 mol) was added to a
stirred solution of 3a′ (6.3 g, 0.017 mol) in THF (17 mL) and
stirred overnight at reflux. The reaction was quenched by
dropwise addition of MeOH (17 mL) and concentrated. The
resulting residue was dissolved in EtOAc and washed with
H2O. The organic layer was dried with MgSO4 and concen-
trated. The crude product was purifed by SiO2 column chro-
matography eluting with hexane/EtOAc (5/1; v/v) (TLC Rf )
0.15) to afford 4.74 g (81% yield) of 7a′ as a colorless oil: 1H
NMR (CDCl3, 300 MHz) δ 5.00-4.80 (bs, 1H), 4.27-4.14
(m, 1H), 3.55-3.27 (m, 4H), 1.78-1.58 (m, 2H), 1.46-1.30
(m, 12H), 0.78 (s, 9H), -0.02 (s, 6H); 13C NMR (CDCl3, 75.4
MHz) mixture of rotamers δ 155.5, 79.8, 70.2, 69.0, 68.2, 67.6,
64.7, 63.7, 57.3, 57.0, 46.1, 45.9, 28.4, 25.6, 22.7, 20.7, 17.8;
ESI-MS m/z (M + Na) calcd for C17H35NO4SiNa 368.5, obsed
368.2.
Compound 8a′. Methyl iodide (8.7 mL, 0.14 mol) and silver
oxide (9.7 g, 0.042 mol) were added to a stirred solution of 7a′
(4.7 g, 0.014 mol) in CH3CN (14 mL). The reaction mixture
was stirred overnight at reflux, filtered through Celite, and
concentrated. The crude product was purified by SiO2 column
chromatography eluting with hexane/EtOAc (9/1; v/v) (TLC Rf
) 0.33) to afford 3.61 g (73% yield) of 8a′ as a colorless oil: 1H
NMR (CDCl3, 300 MHz) δ 4.27-4.17 (m, 1H), 3.76-3.39 (m,
2H), 3.36-3.14 (m, 5H), 2.28-2.15 (m, 1H), 1.68-1.54 (m, 1H),
1.48-1.28 (m, 12H), 0.77 (s, 9H), -0.02 (s, 6H); 13C NMR
(CDCl3, 75.4 MHz) mixture of rotamers δ 154.6, 153.9, 119.6,
79.7, 79.0, 77.9, 77.6, 69.2, 68.6, 63.2, 62.5, 59.4, 57.1, 47.2,
46.2, 28.9, 26.1, 23.9, 22.9, 18.3; ESI-MS m/z (M + Na) calcd
for C18H37NO4SiNa 382.5, obsd 382.2.
Compound 9a′. TBAF (11 mL, 0.011 mol, 1 M solution in
THF) was added to a solution of 8a′ (3.61 g, 0.01 mol) in THF
(50 mL) and stirred 6 h at room temperature. The reaction
was quenched with saturated NH4Cl and diluted with H2O,
and the THF was removed via rotary evaporation. The aqueous
solution was washed with CH2Cl2. The organic layer was dried
over MgSO4 and concentrated. The crude product was dis-
solved in CH2Cl2 (50 mL) and cooled to 0 °C. DMAP (1.83 g,
0.015 mol) and triethylamine (4.18 mL, 0.03 mol) were added,
followed by TsCl (2.86 g, 0.015 mol). The solution was stirred
overnight at room temperature and washed with 1 M HCl and
brine. The organic layer was dried over MgSO4 and concen-
trated. The crude product was purified by SiO2 column
chromatography eluting with hexane/EtOAc (5/1; v/v) (TLC Rf
) 0.14) to afford 3.0 g (77% yield) of 9a′ as a colorless oil: 1H
NMR (CDCl3, 300 MHz) δ 7.82-7.75 (m, 2H), 7.40-7.33
(m, 2H), 5.00-4.92 (m, 1H), 3.90-3.50 (m, 3H), 3.35-3.11
(m, 4H), 2.52-2.33 (m, 4H), 2.05-1.80 (m, 1H), 1.50-1.32
(m, 12H); 13C NMR (CDCl3, 75.4 MHz) mixture of rotamers
δ 153.7, 153.0, 144.8, 133.9, 133.7, 129.8, 127.6, 79.8, 79.2, 78.5,
77.7, 76.6, 75.4, 62.6, 61.9, 58.9, 54.0, 53.9, 43.7, 42.4, 28.4,
28.3, 23.2, 22.2, 21.5; ESI-MS m/z (M + Na) calcd for C19H29-
NO6SNa 422.6, obsd 422.1.
Compound 10a′. NOTE: Extreme Caution Must Be
Used When Handling KCN. 18-Crown-6 (3.05 g, 11.55 mmol)
and finely ground KCN (0.75 g, 11.55 mol) were added to a
stirred solution of 9a′ (3.0 g, 7.70 mmol) in DMSO (7.7 mL).
The reaction mixture was stirred for 8 h at 80 °C. After the
reaction solution had cooled, H2O (1.0 M) was added and the
resulting solution was extracted with EtOAc. The organic layer
was dried over MgSO4 and concentrated. The crude product
was purified by SiO2 column chromatography eluting with
hexane/EtOAc (5/1; v/v) (TLC Rf ) 0.25) to afford 0.93 g (47%
yield) of 10a′ as a colorless oil: 1H NMR (CDCl3, 300 MHz)
δ 3.96-3.58 (m, 2H), 3.57-3.18 (m, 5H), 3.04-2.92 (m, 1H),
2.62-2.44 (m, 1H), 2.10-1.95 (m, 1H), 1.50-1.37 (m, 9H),
1.36-1.22 (m, 3H); 13C NMR (CDCl3, 75.4 MHz) mixture of
rotamers δ 152.6, 119.6, 80.2, 79.6, 76.0, 74.8, 62.7, 62.0, 58.8,
51.0, 41.0, 39.8, 28.2, 24.5, 24.1, 22.7, 21.7; ESI-MS m/z
(M + Na) calcd for C13H22N2O3Na 277.3, obsd 277.1.
Compound 1a′. Compound 10a′ (0.92 g, 3.6 mmol) was
dissolved in concentrated aqueous HCl (18 mL) and stirred at
60 °C for 6 h. The solution was then concentrated via rotary
evaporation and placed on the vacuum line. The residue was
dissolved in a CH2Cl2/MeOH solution (18 mL, 10/1, v/v).
Triethylamine (3.0 mL, 22.0 mmol) and di-tert-butyl dicarbon-
ate (0.83 g, 3.8 mmol) were added, and the solution was stirred
at reflux overnight. The solution was concentrated via rotary
evaporation. The residue was dissolved in saturated aqueous
NaHCO3 solution, washed with ether, and acidified to pH 2
with 0.5 M aqueous KHSO4. The aqueous solution was
extracted with EtOAc, and the organic layer was dried over
MgSO4 and concentrated to afford 0.71 g (71% yield) of 1a′ as
3360 J. Org. Chem., Vol. 70, No. 9, 2005

2,2-Disubstituted Pyrrolidine-4-carboxylic Acid Derivatives
a colorless oil with no further purfication: 1H NMR (CDCl3,
300 MHz) δ 10.7-10.2 (bs, 1H), 3.80-3.20 (m, 7H), 3.15-2.90
(m, 1H), 2.55-2.40 (m, 1H), 2.05-1.80 (m, 1H), 1.52-1.40
(m, 9H), 1.40-1.20 (m, 3H); 13C NMR (CDCl3, 75.4 MHz)
mixture of rotamers δ 178.3, 80.0, 79.3, 75.9, 63.2, 59.0, 50.2,
40.9, 40.8, 40.7, 39.7, 39.1, 28.5, 22.7, 21.7; ESI-MS m/z
(M - H) calcd for C13H22NO5 272.3, obsd 272.1.
3a′. The crude product (4.93 g, mixture of diastereomers) was
separated by column chromatography eluting with hexane/
EtOAc (8/1; v/v) to afford 3.65 g (57% yield) of 7b′ (TLC Rf )
0.19) as a colorless oil and 1.28 g (20% yield) of the diastereo-
mer 7b (epimer at the quaternary center) (TLC Rf ) 0.36) as
a colorless oil. Characterization of 7b′: 1H NMR (CDCl3,
300 MHz) δ 5.12-5.06 (dd, 1H), 4.27-4.16 (m, 1H), 3.96-3.27
(m, 4H), 2.28-1.72 (m, 3H), 1.65-1.33 (m, 11H), 1.28-1.14
(m, 1H), 1.11-0.81 (m, 16H), 0.12-0.01 (m, 6H); 13C NMR
(CDCl3, 75.4 MHz) mixture of rotamers δ 155.6, 79.9, 69.3,
68.7, 68.6, 68.1, 67.6, 66.5, 58.2, 57.2, 45.3, 44.0, 33.4, 33.0,
31.9, 31.1, 28.5, 28.3, 25.7, 22.8, 22.7, 22.6, 18.0, -4.8, -4.9,
-5.1; ESI-MS m/z (M + Na) calcd for C21H43NO4SiNa 424.6,
obsd 424.2. Characterization of 7b: 1H NMR (CDCl3, 300 MHz)
δ 5.04-4.98 (dd, 1H), 4.25-4.17 (m, 1H), 3.65-3.47 (m, 3H),
3.72-3.65 (dd, 1H), 2.02-1.83 (m, 3H), 1.65-1.30 (m, 12H),
0.92-0.82 (m, 16H), 0.06-0.02 (m, 6H); 13C NMR (CDCl3, 75.4
MHz) mixture of rotamers δ 155.8, 80.1, 69.1, 68.7, 67.9, 56.9,
42.4, 33.3, 30.3, 28.6, 28.5, 25.8, 22.8, 22.7, 18.0, -4.8, -4.9;
ESI-MS m/z (M + Na) calcd for C21H43NO4SiNa 424.6, obsd
424.2.
Compound 12a′. A solution of DMSO (1.2 mL) in CH2Cl2
(12.5 mL) was added to a stirred solution of oxalyl chloride
(0.72 mL) in CH2Cl2 (12.5 mL) at -78 °C and stirred for
10 min. 7b′ (2.0 g, 0.005 mol) in CH2Cl2 (2.5 mL) was added
via cannula and stirred 20 min at -78 °C. The reaction was
quenched with Et3N and stirred for 20 min at room temper-
ature. The reaction solution was diluted with H2O and then
extracted with ether. The organic extracts were washed with
0.5 M KHSO4 and brine. The resulting organic solution was
dried with MgSO4 and concentrated to give the desired
aldehyde. This material was carried on without purification
or characterization.
KHMDS (16.8 mL, 8.3 mmol, 0.5 M solution in toluene) was
added to a stirred solution of triphenylmethyl phosphonium
bromide (3.12 g, 8.7 mmol) in THF (77 mL) for 1 h. To this
solution was added the crude aldehyde (0.005 mol) in THF
(15 mL). The reaction solution was stirred 2 h at room
temperature. The reaction was quenched with MeOH and a
solution of potassium sodium tartrate/H2O (100 mL, 1/1, v/v).
The resulting solution was extracted with ether. The organic
extracts were dried over MgSO4 and concentrated. The crude
product was purifed by column chromatography eluting with
hexane/EtOAc (20/1; v/v) (TLC Rf ) 0.29) to afford 1.15 g (58%
yield) of 12a′ as a colorless oil: 1H NMR (CDCl3, 300 MHz)
mixture of rotamers δ 6.06-5.82 (m, 1H), 5.00-4.84 (m, 2H),
4.19 (p, 1H), 3.84-3.58 (m, 1H), 3.13-3.01 (m, 1H), 2.08-1.70
(m, 2H), 1.68-1.38 (m, 11H), 1.28-0.95 (m, 2H), 0.92-0.80
(m, 16H), 0.02 (s, 6H); 13C NMR (CDCl3, 75.4 MHz) mixture
of rotamers δ 142.8, 111.1, 110.9, 79.5, 78.6, 67.6, 67.0, 66.3,
65.6, 55.3, 55.1, 45.0, 43.8, 35.5, 34.7, 33.1, 32.6, 28.5, 28.3,
25.8, 22.8, 22.7, 18.1, -4.8; ESI-MS m/z (M + Na) calcd for
C22H43NO3SiNa 420.7, obsd 420.3.
Compound 7g′. The ester enolate alklyation was performed
with 2 (10.3 g, 0.029 mol) and allyl bromide using a protocol
similar to that used to prepare compound 3a/3a′. The crude
product was purifed by column chromatography eluting with
hexane/EtOAc (12/1, v/v) (TLC Rf ) 0.28) to afford 8.3 g (72%
yield) of diastereomeric mixture 3g/3g′ as a colorless oil: 1H
NMR (CDCl3, 300 MHz) mixture of diastereomers and rot-
amers δ 5.91-5.59 (m, 1H), 5.16-5.05 (m, 2H), 4.42-4.23
(m, 1H), 3.91-3.52 (m, 4H), 3.38-2.46 (m, 3H), 2.22-1.97
(m, 2H), 1.46-1.34 (m, 9H), 0.88-0.74 (m, 9H), 0.07-0.03
(m, 6H); 13C NMR (CDCl3, 75.4 MHz) mixture of diastereomers
and rotamers δ 174.6, 153.6, 153.3, 133.6, 133.5, 133.3, 133.2,
119.2, 119.0, 118.9, 80.3, 80.2, 79.8, 79.7, 68.5, 68.4, 68.1, 67.8,
66.8, 66.4, 55.6, 55.2, 54.8, 52.2, 52.1, 45.5, 44.2, 43.2, 40.0,
39.7, 38.9, 38.3, 28.3, 18.0, 17.9, -4.8, -4.9, -5.0; ESI-MS m/z
(M + Na) calcd for C20H37NO5SiNa 422.6, obsd 422.2.
Compound 11a′. Compound 1a′ (0.2 g, 0.73 mmol) was
dissolved in CH3CN (7.3 mL) and cooled to 0 °C. Dimethyl-
amine hydrochloride (0.077 g, 0.95 mmol), 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI*HCl)
(0.195 g, 1.02 mmol), 1-hydroxybenzotriazole hydrate (HOBt)
(0.137 g, 1.02 mmol), and N,N-diisopropylethylamine (DIEA)
(0.38 mL, 2.19 mmol) were added, and the solution was stirred
24 h at room temperature. The solution was concentrated via
rotary evaporation. The residue was dissolved in EtOAc and
washed with 1 M HCl and brine. The organic layer was dried
over MgSO4 and concentrated. The crude product was purified
by SiO2 column chromatography eluting with hexane/EtOAc
(1/2; v/v) (TLC Rf ) 0.23) to afford 0.20 g (90% yield) of 11a′
as a colorless oil: 1H NMR (CDCl3, 300 MHz) mixture of
rotamers δ 3.87-3.37 (m, 4H), 3.32 (s, 3H), 3.18-2.91 (m, 7H),
2.57-2.24 (m, 1H), 2.86-2.76 (m, 1H), 1.47-1.36 (m, 9H),
1.34-1.20 (m, 3H); 13C NMR (CDCl3, 75.4 MHz) mixture of
rotamers δ 171.7, 153.4, 79.6, 79.0, 62.9, 62.1, 59.1, 50.9, 50.7,
41.3, 40.4, 37.4, 37.2, 37.0, 35.7, 35.6, 28.5, 22.9, 21.8; ESI-
MS m/z (M + Na) calcd for C15H28N2O4Na 323.4, obsd 323.2.
Compound 6a′. Compound 11a′ (0.20 g, 0.66 mmol) was
dissolved in 4 N HCl/dioxane (2.1 mL) and stirred 2 h at room
temperature. The solution was concentrated under a stream
of nitrogen, and the residue was placed on the vacuum line.
The residue was dissolved in CH2Cl2 (3 mL) and cooled to
0 °C. DIEA (0.66 mL, 3.78 mmol) and isobutyryl chloride
(0.13 mL, 1.26 mmol) were added, and the solution was stirred
at room temperature for 24 h. The reaction solution was
washed with 1 M aqueous HCl and brine, and the organic layer
was dried over MgSO4 and concentrated. The crude product
was purified by SiO2 column chromatography eluting with
EtOAc (TLC Rf ) 0.26) to afford 0.052 g (34% yield) of 6a′ as
a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 3.92-3.66 (m,
4H), 3.36-3.17 (m, 4H), 3.12 (s, 3H), 2.97 (s, 3H), 2.66-2.52
(m, 1H), 2.39-2.28 (dd, 12.1 Hz, 1H), 1.86 (dd, 12.1 Hz, 6.6
Hz, 1H), 1.42 (s, 3H), 1.09 (dd, 6.6 Hz, 6H); 13C NMR (CDCl3,
75.4 MHz) δ 175.7, 171.2, 76.1, 64.9, 58.9, 51.0, 40.1, 37.9, 36.9,
35.6, 33.0, 21.4, 18.9, 18.7; ESI-MS m/z (M + Na) calcd for
C14H26N2O3Na 293.4, obsd 293.2.
Compound 7b′. The ester enolate alkylation was performed
with 2 (8.04 g, 0.022 mol) and 4-bromo-2-methyl-2-butene as
the alkylating agent using a protocol similar to that used to
prepare compounds 3a/3a′. The crude product was purifed by
column chromatography eluting with hexane/EtOAc (10/1, v/v)
(TLC Rf ) 0.40, 0.44) to afford 7.64 g (80% yield) of dia-
stereomer mixture 3b/3b′ as a colorless oil: 1H NMR (CDCl3,
300 MHz) mixture of diastereomers and rotamers δ 5.14-4.94
(m, 1H), 4.42-4.23 (m, 1H), 3.92-3.72 (m, 0.6H), 3.65 (s, 3H),
3.32-3.15 (m, 0.4H), 3.04-2.86 (m, 1H), 2.76-2.51 (m, 2H),
2.15-1.88 (m, 2H), 1.72-1.55 (m, 6H), 1.42-1.32 (m, 9H),
0.85-0.78 (m, 9H), 0.05 to -0.05 (m, 6H); 13C NMR (CDCl3,
75.4 MHz) mixture of diastereomers and rotamers δ 174.8,
153.7, 153.4, 148.8, 135.4, 135.1, 119.2, 119.0, 118.9, 118.6,
118.5, 80.2, 80.1, 79.6, 79.5, 68.7, 68.4, 68.0, 67.9, 67.6, 67.3,
66.9, 55.3, 55.0, 54.6, 52.2, 52.1, 45.5, 44.3, 43.3, 33.6, 33.4,
32.5, 32.2, 28.3, 28.2, 26.1, 25.7, 25.6, 18.2, 18.1, 18.0, 17.9,
-5.1; ESI-MS m/z (M + Na) calcd for C22H41NO5SiNa 450.7,
obsd 450.2.
The alkyation product (7.6 g, 0.018 mol) was dissolved in
MeOH (36 mL) and transferred to a hydrogenation apparatus.
Palladium (10%) on carbon (1.0 g) was added, and the reaction
mixture was charged with H2 (45 psi) and shaken overnight.
The mixture was filtered through Celite and concentrated. The
resulting intermediate was allowed to react with NaBH4 using
a protocol similar to that used to prepare compound 7a′ from
Diastereomeric mixture 3g/3g′ (8.3 g, 0.021 mol) was
allowed to react with NaBH4 via a protocol similar to that used
to prepare compound 7a′. The crude product (4.8 g, mixture
J. Org. Chem, Vol. 70, No. 9, 2005 3361

Huck and Gellman
of diastereomers) was purified by column chromatography
eluting with hexane/EtOAc (8/1; v/v) (TLC Rf ) 0.23) to afford
1.5 g (20% yield) of 7g (Rf ) 0.34) and 3.3 g (44% yield) of 7g′
(Rf ) 0.14) as colorless oils. Characterization of 7g: 1H NMR
(CDCl3, 300 MHz) mixture of rotamers δ 5.75-5.52 (m, 1H),
5.13-5.01 (m, 2H), 4.26-4.18 (m, 1H), 4.00-3.23 (m, 4H),
2.78-2.61 (m, 1H), 2.45-2.06 (m, 2H), 1.50-1.39 (m, 9H), 0.87
(s, 9H), 0.10-0.03 (m, 6H); 13C NMR (CDCl3, 75.4 MHz)
mixture of rotamers δ 133.7, 118.8, 80.1, 69.4, 68.4, 67.8, 67.2,
58.0, 57.1, 43.4, 39.8, 37.7, 28.4, 25.7, 18.0, -4.8, -4.9; ESI-
MS m/z (M + Na) calcd for C19H37NO4SiNa 394.6, obsd 394.1.
Characterization of 7g′: 1H NMR (CDCl3, 300 MHz) mixture
of rotamers δ 5.88-5.62 (m, 1H), 5.17-5.03 (m, 2H), 4.35-
4.15 (m, 1H), 3.88-3.19 (m, 3H), 4.02-3.37 (m, 2H), 2.02-
1.50 (m, 2H), 1.50-1.39 (m, 9H), 0.90-0.80 (m, 9H), 0.04
(s, 6H); 13C NMR (CDCl3, 75.4 MHz) mixture of rotamers
δ 155.9, 134.3, 118.7, 118.6, 80.3, 68.8, 68.7, 67.4, 57.2, 41.8,
36.9, 28.4, 25.8, 18.0, -4.8, -4.9; ESI-MS m/z (M + Na) calcd
for C19H37NO4SiNa 394.6, obsd 394.1.
product was purified by column chromatography eluting with
hexane/EtOAc (1/1; v/v) (TLC Rf ) 0.79) to afford 0.79 g (69%
yield) of 17′ as a colorless oil: 1H NMR (CDCl3, 300 MHz)
mixture of rotamers δ 4.72-4.38 (bd, 1H), 4.31 (m, 1H), 3.75-
3.49 (m, 2H), 3.27 (s, 3H), 3.23-2.98 (m, 4H), 2.23-1.65
(m, 2H), 1.65-1.30 (m, 21H), 0.85 (s, 9H), 0.03 (s, 6H); 13C
NMR (CDCl3, 75.4 MHz) mixture of rotamers δ 118.0, 79.1,
68.0, 67.4, 65.6, 64.8, 59.3, 59.2, 56.3, 43.4, 42.7, 40.6, 32.6,
31.4, 28.6, 28.5, 28.4, 28.2, 25.8, 24.2, 18.0, 14.1, -4.7, -4.8;
ESI-MS m/z (M + Na) calcd for C25H50N2O6SiNa 525.7, obsd
525.3.
Compound 9j′. Compound 9j′ was prepared from 17′
(0.79 g, 1.5 mmol) using a protocol similar to that used to
prepare compound 9a′. The crude product was purified by
column chromatography eluting with hexane/EtOAc (3/1; v/v)
(TLC Rf ) 0.28) to afford 0.62 g (76% yield) of 9j′ as a colorless
oil: 13C NMR (CDCl3, 75.4 MHz) mixture of rotamers δ 155.9,
153.2, 144.9, 133.7, 129.9, 127.8, 79.6, 65.6, 64.9, 59.1, 59.0,
53.9, 53.7, 41.1, 40.5, 39.6, 32.3, 31.2, 28.5, 28.4, 28.3, 24.1,
23.8, 21.6; ESI-MS m/z (M + Na) calcd for C26H42N2O8SNa
565.6, obsd 565.3.
Compound 10j′. Compound 10j′ was prepared from 9j′
(0.62 g, 1.10 mmol) using a protocol similar to that used to
prepare compound 10a′. The crude product was purified by
column chromatography eluting with hexane/EtOAc (2/1; v/v)
(TLC Rf ) 0.23) to afford 0.31 g (71% yield) of 10j′ as a colorless
oil: 1H NMR (CDCl3, 300 MHz) δ 4.65-4.45 (m, 1H), 3.82-
3.45 (m, 3H), 3.42-3.26 (m, 4H), 3.12-2.99 (m, 3H), 2.91
(m, 1H), 2.56-1.40 (m, 1H), 2.17-1.74 (m, 2H), 1.60-1.25
(m, 22H); 13C NMR (CDCl3, 75.4 MHz) mixture of rotamers
δ 155.9, 120.1, 80.1, 75.0, 65.7, 59.1, 59.0, 51.6, 40.6, 40.5, 37.0,
31.7, 28.6, 28.4, 28.2, 25.1, 24.5, 24.4; ESI-MS m/z (M + Na)
calcd for C20H35N3O5Na 420.5, obsd 420.3.
Compound 8g′. Compound 8g′ was prepared from 7g′
(3.3 g, 9.0 mmol) alkylating with methyl iodide using a protocol
similar to that used to prepare compound 8a′. The crude
product was purified by column chromatography eluting with
hexane/EtOAc (10/1; v/v) (TLC Rf ) 0.40) to afford 2.46 g (71%
yield) of 8g′ as a colorless oil: 1H NMR (CDCl3, 300 MHz)
mixture of rotamers δ 5.78-5.62 (m, 1H), 5.12-5.01 (m, 2H),
4.31 (m, 1H), 3.85-3.53 (m, 2H), 3.31-2.98 (m, 4H), 2.82-
2.57 (m, 1H), 2.47-2.28 (m, 1H), 2.17-2.06 (m, 1H), 1.95-
1.78 (m, 1H), 1.48-1.37 (m, 9H), 0.86 (s, 9H), 0.04 (s, 6H); 13
C
NMR (CDCl3, 75.4 MHz) mixture of rotamers δ 133.7, 133.6,
118.5, 78.9, 75.7, 68.2, 59.2, 56.2, 43.1, 42.0, 38.9, 28.6, 28.5,
25.8, 18.1, -4.7, -4.8; ESI-MS m/z (M + Na) calcd for C20H39-
NO4SiNa 408.6, obsd 408.3.
Compound 1j′. Compound 10j′ (0.3 g, 0.78 mmol) was
dissolved in concentrated HCl and stirred for 6 h at 60 °C.
The reaction solution was concentrated via rotary evaporation
and then placed on the vacuum line. The resulting intermedi-
ate was dissolved in a CH2Cl2/MeOH solution (2.2 mL, 10/1,
v/v). Di-tert-butyl dicarbonate (0.16 g, 0.74 mmol) and DIEA
(0.8 mL, 4.68 mmol) were added, and the reaction solution was
stirred overnight at room temperature. Benzyl chloroformate
(0.11 mL, 0.78 mmol) was added, and the reaction solution
was stirred overnight at room temperature. The reaction
solution was concentrated via rotary evaporation. The result-
ing intermediate was dissolved in EtOAc and washed with
1 M HCl and brine. The organic extracts were dried over
MgSO4 and concentrated. The crude product was purified by
SiO2 column chromatography eluting with hexane/EtOAc/
acetic acid (1/1/0.1; v/v/v) (TLC Rf ) 0.37) to afford 0.18 g (52%
yield) of 1j′ as a colorless oil: 1H NMR (CDCl3, 300 MHz)
mixture of rotamers δ 7.37-7.25 (m, 5H), 5.17-5.05 (m, 2H),
4.62-4.38 (m, 1H), 3.88-3.44 (m, 3H), 3.39-2.88 (m, 6H),
2.53-2.38 (m, 1H), 2.17-1.25 (m, 13H); 13C NMR (CDCl3, 75.4
MHz) mixture of rotamers δ 153.7, 136.9, 128.4, 128.2, 127.8,
127.6, 75.4, 66.4, 66.3, 59.0, 50.2, 40.2, 36.5, 31.7, 28.4, 24.5;
ESI-MS m/z (M + Na) calcd for C23H35N2O7 473.5, obsd 473.2.
Compound 15′. BH3 (12.8 mL, 12.8 mmol, 1 M solution in
THF) was added to a stirred solution of 8g′ (2.4 g, 6.4 mmol)
in THF (13 mL) at 0 °C. The solution was stirred for 45 min,
and the reaction was quenched with a solution of aqueous
NaOH (16 mL, 22.0 mmol, 2 M solution in H2O), H2O2
(3.3 mL, 22.0 mmol, 30% solution in H2O), and EtOH (13 mL).
The organic solvents were removed via rotary evaporation. The
resulting solution was diluted with H2O and extracted with
EtOAc. The organic layer was dried over MgSO4 and concen-
trated. The resulting intermediate was dissolved in CH2Cl2
and cooled to 0 °C. DMAP (1.17 g, 9.6 mmol), Et3N (2.7 mL,
19.2 mmol), and TsCl (1.83 g, 9.6 mmol) were added, and the
solution was stirred overnight at room temperature. The
reaction solution was washed with 1 M aqueous HCl and brine.
The organic layer was dried over MgSO4 and concentrated.
The crude product was purified by column chromatography
eluting with hexane/EtOAc (4/1; v/v) (TLC Rf ) 0.29) to afford
1.77 g (50% yield) of 15′ as a colorless oil.
Compound 16′. NaN3 (0.83 g, 12.8 mmol) was added to a
stirred solution of 15′ (1.7 g, 3.2 mmol) in DMF (6.4 mL) at 80
°C. The reaction mixture was stirred for 8 h, diluted with H2O,
and extracted with EtOAc. The organic layer was dried over
MgSO4 and concentrated. The crude product was purified by
column chromatography eluting with hexane/EtOAc (3/1; v/v)
(TLC Rf ) 0.78) to afford 1.01 g (74% yield) of 16′ as a colorless
oil: 1H NMR (CDCl3, 300 MHz) mixture of rotamers δ 4.36-
4.25 (m, 1H), 3.77-3.50 (m, 2H), 3.30-3.02 (m, 7H), 2.27-
2.13 (m, 1H), 2.10-1.38 (m, 14H), 0.87 (m, 9H), 0.03 (m, 6H);
13C NMR (CDCl3, 75.4 MHz) mixture of rotamers δ 153.4, 79.8,
79.1, 68.1, 67.5, 65.4, 64.7, 59.3, 59.2, 56.5, 52.0, 51.8, 44.0,
42.8, 32.8, 31.6, 28.6, 28.5, 25.8, 23.4, 18.0, 14.1, -4.8, -4.9;
ESI-MS m/z (M + Na) calcd for C20H40N4O4SiNa 451.6, obsd
451.3.
Acknowledgment. This research was supported by
the National Science Foundation (CHE-014062). Grants
from NSF and NIH supported the purchase of NMR
spectrometers.
Supporting Information Available: Synthetic proce-
dures available for 4b, 5b, 1b′, 6b′, 8b′-11b′, 1c, 4c, 6c, 10c,
11c, 1d′, 6d′, 8d′-11d′, 1e, 6e, 9e, 11e, 1e′, 6e′, 9e′-11e′, 1f,
6f, 10f, 11f, 1g′, 6g′, 9g′-11g′, 1h, 6h, 9h-11h, 1i, 6i, 10i,
11i, and 18-26 and 1H NMR and 13C NMR spectra of
compounds 2, 4a, 1a′, 3a′, 6a′-11a′, 4b, 5b, 1b′, 6b′-11b′,
1c, 5c, 6c, 10c, 11c, 6d′, 8d′, 1e, 6e, 9-11e, 1e′, 6e′, 9e′-
11e′, 1f, 6f, 10f, 11f, 1g′, 6g′-11g′, 1h, 6h, 9h, 10h, 6i, 10i,
11i, 1j′, 9j′, 15′, 16′, and 17′. This material is available free of
charge via the Internet at http://pubs.acs.org.
Compound 17′. Compound 16′ (1.0 g, 2.3 mmol) was
dissolved in MeOH (10 mL) and transferred to a hydrogenation
apparatus. Boc2O (1.0 g, 4.6 mmol) and 10% Pd/C (0.15 g) were
added; the mixture was charged with H2 (45 psi), and the
reaction solution was shaken overnight. The reaction mixture
was filtered through Celite and concentrated. The crude
JO048639Z
3362 J. Org. Chem., Vol. 70, No. 9, 2005