Serine-cis-proline and serine-trans-proline isosteres: Stereoselective synthesis of (Z)- and (E)-alkene mimics by Still-Wittig and Ireland-Claisen rearrangements

Article abstract of DOI:10.1021/jo026663b

Two new amide isosteres of Ser-cis-Pro and Ser-trans-Pro dipeptides were designed and stereo-selectively synthesized to be incorporated into potential inhibitors of the phosphorylation-dependent peptidylprolyl isomerase Pin1, an essential regulator of the

Full text of DOI:10.1021/jo026663b

Ser in e-cis-p r olin e a n d Ser in e-tr a n s-p r olin e Isoster es:
Ster eoselective Syn th esis of (Z)- a n d (E)-Alk en e Mim ics by
Still-Wittig a n d Ir ela n d -Cla isen Rea r r a n gem en ts
Xiaodong J . Wang,† Scott A. Hart,‡ Bailing Xu,† Matthew D. Mason,† J ohn R. Goodell,‡ and
Felicia A. Etzkorn*,†
Department of Chemistry, MC 0212, Virginia Tech, Blacksburg, Virginia 24061, and
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904
fetzkorn@vt.edu
Received November 5, 2002
Two new amide isosteres of Ser-cis-Pro and Ser-trans-Pro dipeptides were designed and stereo-
selectively synthesized to be incorporated into potential inhibitors of the phosphorylation-dependent
peptidylprolyl isomerase Pin1, an essential regulator of the cell cycle. The cis mimic, the (Z)-alkene
isomer, was formed through the use of a Still-Wittig [2,3]-sigmatropic rearrangement, while the
trans mimic, the (E)-alkene, was synthesized through the use of an Ireland-Claisen [3,3]-
sigmatropic rearrangement. Starting from N-Boc-Ser(OBn)-N(OMe)Me, both mimics were synthe-
sized in Boc-protected form suitable for peptide synthesis with an overall yield of 20% in 10 steps
for the cis mimic and 13% in eight steps for the trans mimic.
Because proline is the only proteinogenic amino acid
in which the R-amino group is dialkylated, there are
lower energy differences for the resulting tertiary Xaa-
Pro cis- and trans-amide bonds (∆G° ) 0.5 kcal/mol) than
for typical secondary amide bonds in proteins (∆G° ) 2.6
kcal/mol).1 The resulting propensity of proline for cis-
trans isomerization2 imparts unique structural and func-
tional features to proteins.3 Cis-trans isomerization of
proline-containing peptides has been implicated in a
number of biologically important processes. The phos-
phorylation-dependent peptidylprolyl isomerase (PPIase)
Pin14 is suggested to regulate mitosis via cis-trans
isomerization of phospho-Ser-Pro amide bonds in a
variety of cell cycle proteins,5 particularly Cdc25 phos-
phatase,6,7 a key regulator of the Cdc2/cyclinB complex
in mitosis.8 The central role Pin1 plays in the cell cycle
makes it an interesting target for inhibition, both for
potential anticancer activity and for elucidation of the
mechanism of mitosis.
uents attached to either of these functional groups.9 We
have reviewed peptidomimetics of cis- and trans-pro-
lines.9 We have stereoselectively synthesized an Ala-cis-
Pro (Z)-alkene isostere that inhibited the PPIase activity
of cyclophilin (IC50 ) 6.5 µM).10,11 The alkene isostere was
indeed an amide bond surrogate, and the alkene was not
a substrate for the peptidylprolyl isomerase. Fluoro-
alkene isosteres of Ala-trans-Pro12 have been incorpo-
rated into potent inhibitors of dipeptidyl protease IV.12,13
An (E)-alkene trans-Pro mimic was shown to inhibit the
PPIase activity of FKBP.14 Organocuprate routes to (E)-
alkene Xaa-trans-Pro dipeptide mimics were published
recently.15 Relatively fewer (Z)-alkenes16 have been made
due to the difficulty of (Z)-alkene formation and the
possibility of isomerization of the â,γ-unsaturated car-
bonyl to the more stable R,â-unsaturated carbonyl com-
pounds.17
Our previous success in Ala-cis-Pro (Z)-alkene isostere
synthesis10 and the various synthetic methods available
for (E)-alkene formation led us to design analogous
inhibitors based on the best substrate for Pin1, WFYpSPR-
One of the ideal peptide bond surrogates is the alkene
because of the similar geometrical disposition of substit-
* To whom correspondence should be addressed.
† Virginia Tech.
(9) Etzkorn, F. A.; Travins, J . M.; Hart, S. A. In Advances in Amino
Acid Mimetics and Peptidomimetics; Abell, A., Ed.; J AI Press Inc.:
Greenwich, CT, 1999; Vol. 2, pp 125-163.
‡ University of Virginia.
(1) Stewart, D. E.; Sarkar, A.; Wampler, J . E. J . Mol. Biol. 1990,
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P. T.; Rahfeld, J .-U.; Xu, J .; Kuang, J .; Kirschner, M. W.; Fischer, G.;
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Chem. Soc., Perkin Trans. 1 1982, 307-314.
10.1021/jo026663b CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/26/2003
J . Org. Chem. 2003, 68, 2343-2349
2343

Wang et al.
SCHEME 1. Syn th esis of
Boc-Ser -Ψ[(Z)CHdC]-P r o-OH by Still-Wittig
Rea r r a n gem en t
F IGURE 1. Phospho-Ser-cis/trans-Pro equilibrium and (Z)-
and (E)-alkene conformationally locked Ser-Pro mimics. Ar-
rows indicate alkene isostere bond vectors that superimpose
on amide vectors.
pNA (kcat/Km) 2 × 107 M-1s-1).5 We now report the
stereoselective synthesis of a Ser-cis-Pro alkene mimic,
1, and the corresponding Ser-trans-Pro alkene mimic, 2
(Figure 1). These mimics will be used for Pin1 inhibition
and elucidation of the role of this essential regulator in
the cell cycle. Preliminary reports of the (Z)-alkene mimic
have been published.18,19 The (Z)- and (E)-alkenes serve
as conformationally locked surrogates for cis- and trans-
proline amide bonds without incorporating additional
functional groups or steric bulk.
Resu lts a n d Discu ssion
Optically active amino acids are versatile synthons for
stereoselective synthesis. Starting with the optically pure
amino acid N-terminal to Pro not only provides the source
for stereoselective synthesis, but also imparts generality
to the synthesis of any Xaa-Pro alkene mimic. In this
case, N-Boc-O-benzyl-L-serine, used in Merrifield peptide
synthesis,20 was chosen as the starting material for the
syntheses of both Ser-cis-Pro and Ser-trans-Pro mimics.
Because Ser is so highly functionalized, significant chal-
lenges and side reactions were encountered during the
synthesis of these particular Pro mimics.19 A Still-Wittig
[2,3]-sigmatropic rearrangement21 could be used to form
both the (Z)- and (E)-alkene stereoisomers, but the (E)-
alkene was synthesized more efficiently by an Ireland-
Claisen [3,3]-sigmatropic rearrangement.
Still-Wittig Rou te to th e Ser -cis-P r o Mim ic. The
key steps in the synthesis of Boc-Ser-Ψ[(Z)CHdC]-Pro-
OH were stereoselective reduction of ketone 5 to the
(S,S)-alcohol 6, and Still-Wittig rearrangement to (Z)-
alkene 8 (Scheme 1). Starting with the Weinreb amide22
of Boc-Ser(OBn)-OH,23 ketone 5 was formed by condensa-
tion with cyclopentenyllithium derived from iodide 4. The
reagent 1-iodo-cyclopentene24 (4) was prepared most
easily by the method of Barton25 in two steps with 50%
overall yield from cyclopentanone. Reduction of ketone
5 with LiAlH4 proceeded with Felkin-Ahn stereoselec-
tivity26,27 to give (S,S)-alcohol 6. A single diastereomer
was observed in the crude 1H NMR spectrum. The
relative stereochemistry was established by derivatiza-
tion of a mixture of diastereomers as the oxazolidinones
(Supporting Information).28 The iodomethyltributyltin
reagent was prepared by the method of Steitz et al.29
Fractional distillation is recommended. After the inter-
mediate tributylstannylmethyl ether 7 was formed, Still-
Wittig rearrangement21 gave a 53% (Z)-8a to 28% (E)-
8b ratio of alkenes.19 The ratio varies and appears to be
temperature and scale sensitive. The diastereomers were
separated by column chromatography. The E/Z stereo-
chemistry of these alkenes was determined by 1D NOE.19
With (Z)-alkene 8a in hand, it was necessary to remove
the benzyl protection and reprotect the amine for peptide
synthesis. (Alternative amine protection, such as trityl
or Boc, gave poor stereoselectivity and/or yields in some
of the previous reactions.) Monodebenzylation of amine
8a was accomplished by catalytic transfer hydrogenation
with formic acid on Pearlman’s catalyst30 selectively in
the presence of the benzyl ether and the alkene. A side
product in this reaction was avoided by keeping the
reaction time short. Interestingly, the (E)-alkene 8b
cannot be deprotected in this reduction.
(18) Hart, S. A.; Etzkorn, F. A. Pept. New Millenium: Proc. 16th
Am. Pept. Symp. 2000, 478-480.
(19) Hart, S. A.; Trindle, C. O.; Etzkorn, F. A. Org. Lett. 2001, 3,
1789-1791.
(20) Merrifield, R. B. J . Am. Chem. Soc. 1963, 85, 2149-2154.
(21) Still, W. C.; Mitra, A. J . Am. Chem. Soc. 1978, 100, 1927-1928.
(22) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818.
(23) Niel, G.; Roux, F.; Maisonnasse, Y.; Maugras, I.; Poncet, J .;
J ouin, P. J . Chem. Soc., Perkin Trans. 1 1994, 10, 1275-1280.
(24) MacDougall, J . M.; Santora, V. J .; Verma, S. K.; Turnbull, P.;
Hernandez, C. R.; Moore, H. W. J . Org. Chem. 1998, 63, 6905-6913.
(25) Barton, D. H. R.; Bashiardes, G.; Fourrey, J .-L. Tetrahedron
Lett. 1983, 24, 1605-1608.
(26) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204.
(27) Ahn, N. T. Top. Curr. Chem. 1980, 88, 145-162.
(28) Williams, T. M.; Crumbie, R.; Mosher, H. S. J . Org. Chem. 1985,
50, 91-97.
(29) Seitz, D. E.; Carroll, J . J .; Cartaya M., C. P.; Lee, S.-H.; Zapata,
A. Synth. Commun. 1983, 13, 129-134.
(30) Hiskey, R. G.; Northrop, R. C. J . Am. Chem. Soc. 1961, 83,
4798-4800.
2344 J . Org. Chem., Vol. 68, No. 6, 2003

(Z)- and (E)-Alkene Dipeptide Mimics of Ser-Pro
SCHEME 2. Keton e Sid e P r od u ct fr om J on es
Oxid a tion of 9 a n d 17
SCHEME 3. Still-Wittig Rea r r a n gem en t of
Sta n n a n e 11a
Carbamate protection (Boc) to give 9 was required to
remove the second benzyl. At this stage, it was possible
to remove the second benzyl from 9 by Na/NH3 reduction;
however, J ones oxidation31 of the resulting alcohol, with
the Boc-protected amine, did not afford the corresponding
acid. In contrast, J ones oxidation of the doubly protected
Boc-benzylamine 9 produced acid 10 in 95% yield.
Initially, we observed a ketone as a major side product
from the J ones oxidation of 9, probably resulting from
allylic oxidation and C-C bond cleavage (Scheme 2). This
side product was minimized by adding an excess of the
J ones reagent to the alcohol and keeping the reaction at
0 °C. Final benzyl deprotection by Na/NH3 reduction
yielded Boc-Ser-Ψ[(Z)CHdC]-Pro-OH (1). Again, a large
excess of sodium was required to minimize the cyclization
of the side chain oxyanion onto the Boc carbonyl to
produce a cyclic carbamate. Presumably benzyl ether
deprotection is slightly more rapid than benzylamine
deprotection, and the large excess of sodium increases
the rate for both to improve the yield of the desired
product.
a
Yields in THF at 66 °C and toluene at 50 °C are averages of
multiple reactions.
SCHEME 4. Syn th esis of
Boc-Ser -Ψ[(E)CHdC]-P r o-OH by Ir ela n d -Cla isen
Rea r r a n gem en t
St ill-Wit t ig R ou t e t o t h e (E)-Alk en e Ser -tr a n s-
P r o Mim ic. Recently we reported syntheses of (E)-8b,
precursor to the L-Ser-trans-D-Pro mimic, and (Z)-8a ,
precursor to the L-Ser-cis-L-Pro mimic, and a computa-
tional analysis explaining solvent-dependent E- or Z-
selectivity of the Still-Wittig rearrangement.19 The
preference for the formation of (E)-8b in toluene (3:1 E:Z)
was particularly interesting since our work necessitates
comparisons between cis- and trans-Pro analogues. How-
ever (E)-8b bears the wrong stereochemistry (S) in the
cyclopentyl ring necessary to mimic L-Pro. To mimic the
structure of naturally occurring amino acids, the (R,E,R)-
12b mimic of L-Ser-trans-L-Pro was required (Scheme 3).
We synthesized stannane 11 (Scheme 3 and Supporting
Information) expecting the Still-Wittig rearrangement
to yield (E)-12b with solvent selectivity similar to that
observed for the rearrangement of 7.19 Stereochemical
control in the synthesis of stannane 11 could be ac-
complished via Luche 1,2-reduction32 of the Boc-protected
cyclopentenyl ketone 14 (Scheme 4). Unfortunately,
favorable E-selectivity was not observed in the Still-
Wittig rearrangement of 11 in toluene, and the highest
yield of (E)-12b was 33% in refluxing THF, although the
average was 26% (Scheme 3). In either THF or toluene
at various temperatures, (E)-12b was not obtained
selectively or in reasonable yield. Although the Still-
Wittig rearrangement allows stereocontrolled access to
eight isomeric compounds of interest in our work (the
enantiomers of 7 and 11 provide access to the D-Ser
analogues), a more efficient route to the (E)-alkene was
desired.
Ir ela n d -Cla isen Rou te to th e (E)-Alk en e Ser -
tr a n s-P r o Mim ic. The Ireland-Claisen rearrangement
was more successful at producing the desired (E)-alkene,
both in stereoselectivity and in yield (Scheme 4). Weinreb
amide 13 was prepared easily from N-Boc-O-benzyl-L-
serine.23 The reaction of 13 with cyclopentenyllithium
gave the desired ketone 14 in 86% yield. The reaction
was difficult to bring to completion, even with excess
cyclopentenyllithium, probably due to deprotonation of
the carbamate. The yield was increased to 86% by adding
3 equiv of cyclopentenyllithium in portions.
The chelation-controlled Luche reduction32 of ketone
14 gave a 4:1 mixture of diastereomers in good yield
(92%). The minor diastereomer was removed by precipi-
tation. The major diastereomer of 15 proved to be the
desired (S,R) by derivatization as the oxazolidinones
(Supporting Information).28 Alcohol 15 was readily trans-
formed to the Ireland-Claisen precursor ester 1633 by
reaction with tert-butyldimethylsilyloxyacetyl chloride,
prepared according to the published procedure.34 The
(31) Bowden, K.; Heilbron, I. M.; J ones, E. R. H.; Weedon, B. C. L.
J . Chem. Soc., Perkin Trans. 1 1946, 39-45.
(32) Luche, J .-L.; Gemal, A. L. J . Am. Chem. Soc. 1979, 101, 5848-
5849.
J . Org. Chem, Vol. 68, No. 6, 2003 2345

Wang et al.
Ireland-Claisen rearrangement of ester 16 was the key
step in our synthesis of the Ser-trans-Pro mimic (Scheme
4). The standard Ireland-Claisen procedure33,35 was not
successful, and only starting material was recovered.
Activation of TMSCl by pyridine was necessary.36 The
intermediate TBS-protected alcohol was unstable toward
silica gel, but subsequent removal of the TBS protecting
group by tert-butylammonium fluoride (TBAF) in THF
gave the R-hydroxy acid 17 as a stable product. The crude
1H NMR of 17 showed three minor diastereomers in
addition to the major isomer, but the stereochemistry at
the alcohol center is eliminated by oxidation in the next
step. After oxidation, the major diastereomer of 18 was
isolated readily by chromatography. The NOESY spec-
trum of 18 showed the (E)-alkene as the major product
of the rearrangement (Supporting Information).
Initial attempts using the J ones reagent to oxidatively
decarboxylate R-hydroxy acid 17 and oxidize the resulting
aldehyde in one step afforded little of the desired acid
18 (10% yield). The major product identified was the R,â-
unsaturated ketone directly analogous to the ketone side
product from J ones oxidation of the (Z)-alkene (Scheme
2). For decarboxylation of R-hydroxy acid 17, several
types of oxidizing reagents failed, including sodium
periodate37 and tetrabutylammonium periodate.38 Lead-
(IV) tetraacetate39 was the only reagent that cleanly gave
high yields of the â,γ-unsaturated aldehyde.
The â,γ-unsaturated aldehyde was oxidized further
without purification. Isomerization of the â,γ-unsaturated
aldehyde to the more stable R,â-unsaturated aldehyde
occurred readily during basic workup (aqueous NaHCO3)
or silica gel purification, so the aldehyde was handled
as little as possible. J ones oxidation of the aldehyde
yielded the corresponding â,γ-unsaturated carboxylic acid
18, without loss of the acid-sensitive Boc group. As an
alternative to the J ones oxidation, sodium chlorite led
only to decomposition of the aldehyde.40 The ketone side
product from allylic oxidation was not observed in this
oxidation of the aldehyde. The â,γ-unsaturated acid 18
was stable toward isomerization under aqueous acidic or
basic conditions. A single diastereomer of 18 was ob-
tained after chromatography. The (E)-alkene stereochem-
istry of 18 was demonstrated by NOESY (Supporting
Information). The benzyl protection on oxygen was suc-
cessfully removed with Na/NH3 to give the desired Boc-
Ser-Ψ[(E)CHdC]-Pro-OH (2).
stereoselectivity. The Ser-cis-Pro mimic 1 was synthe-
sized in 10 steps and 20% overall yield from Weinreb
amide N-Boc-Ser(OBn)-N(OMe)Me. The Ser-trans-Pro
mimic 2 was synthesized in eight steps and 13% overall
yield from the Weinreb amide. Both mimics 1 and 2 can
be used in peptide synthesis without protection of the
side chain alcohol, or they may be reprotected as the
Fmoc-amine, TBS ether for Fmoc-based peptide synthesis
(S. A. Hart, X. J . Wang, and F. A. Etzkorn, unpublished
results). The Ser-Pro mimics will be incorporated into
Pin1 substrate analogues for inhibition and mechanistic
studies of Pin1 enzymology and cancer biology.
Exp er im en ta l Section
Gen er a l In for m a tion . Unless otherwise indicated, all
reactions were carried out under N2 in flame-dried glassware.
THF, toluene, and CH2Cl2 were dried by passage through
alumina. Anhydrous (99.8%) DMF was available commercially
and used directly from SureSeal bottles. Dimethyl sulfoxide
(DMSO) was anhydrous and dried with 4 Å molecular sieves.
Triethylamine (TEA) was distilled from CaH2, and (COCl)2 was
distilled before use each time. Diisopropylethylamine (DIEA)
was distilled from CaH2 under a N2 atmosphere. Brine (NaCl),
NaHCO3, and NH4Cl refer to saturated aqueous solutions
unless otherwise noted. Flash chromatography was performed
on 32-63 µm or 230-400 mesh, ASTM silica gel with reagent
grade solvents. Melting points were uncorrected. NMR spectra
were obtained at ambient temperature in CDCl3 unless
otherwise noted. Proton (300 MHz) NMR spectra were ob-
tained for compounds 1, 3, 6, and 8-12, and carbon-13 (75
MHz) NMR spectra for compounds 1-6 and 8-12. Proton (500
MHz) NMR spectra were obtained for compounds 2, 4, 5, 7-9,
and 13-18, and carbon-13 (125 MHz) NMR spectra for
compounds 7 and 13-18. Coupling constants J are given in
hertz.
N,N,O-Tr iben zyl Ser in e Wein r eb Am id e (3). N-Boc-O-
benzyl serine Weinreb amide23 (24.1 g, 71.2 mmol) was
dissolved in CH2Cl2 (400 mL), TFA (125 mL) was added, and
the solution was stirred for 30 min. The mixture was concen-
trated and then quenched with NaHCO3 until gas evolution
ceased. The aqueous mixture was extracted with CH2Cl2 (8 ×
300 mL), dried on MgSO4, and concentrated. Chromatography
on silica with 50% EtOAc in petroleum ether to remove
impurities, followed by product elution with 10% MeOH in
EtOAc yielded 13.1 g (83%) of the amine as a clear oil: 1H
NMR δ 7.40-7.20 (m, 5H), 4.57 (d, J ) 12.1, 1H), 4.52 (d, J )
12.1, 1H), 4.06 (m, 1H), 3.67 (s, 3H), 3.66-3.45 (m, 2H), 3.20
(s, 3H), 1.88 (br s, 2H). The amine (13 g, 58 mmol) was
dissolved in CH2Cl2 (50 mL), and then benzyl bromide (24.8
g, 145 mmol) and DIEA (37.4 g, 290 mmol) were added. After
4 d at rt, the reaction was diluted with EtOAc (600 mL),
washed with NH4Cl (4 × 200 mL) and brine (200 mL), dried
on MgSO4, and concentrated. Chromatography on silica with
10% EtOAc in petroleum ether to remove benzyl bromide and
then 50% EtOAc in petroleum ether to elute the product
yielded 21.4 g (91%) of dibenzylamine 3 as a clear oil: 1H NMR
δ 7.40-7.17 (m, 15H), 4.56 (d, J ) 11.9, 1H), 4.48 (d, J ) 11.9,
1H), 4.13 (m, 1H), 3.98-3.84 (m, 4H), 3.76 (d, J ) 14.1, 2H),
3.28 (br s, 3H), 3.20 (br s, 3H); 13C NMR δ 171.5, 140.0, 138.2,
128.7, 128.1, 127.9, 127.3, 126.6, 73.0, 68.6, 60.8, 56.4, 55.0,
30.9. Anal. Calcd for C26H30N2O3: C, 74.61; H, 7.22; N, 6.69.
Found: C, 74.31; H, 7.32; N, 6.40.
Con clu sion s
We have synthesized new (Z)- and (E)-alkene isosteres
1 and 2 of Ser-cis-Pro and Ser-trans-Pro with high
(33) Gould, T. J .; Balestra, M.; Wittman, M. D.; Gary, J . A.; Rossano,
L. T.; Kallmerten, J . J . Org. Chem. 1987, 52, 3889-3901.
(34) Bischofberger, N.; Waldmann, H.; Saito, T.; Simon, E. S.; Lees,
W.; Bednarski, M. D.; Whitesides, G. M. J . Org. Chem. 1988, 53, 3457-
3465.
(35) Ireland, R. E.; Mueller, R. H. J . Am. Chem. Soc. 1972, 94, 5897-
5898.
(36) Barrish, J . C.; Lee, H. L.; Mitt, T.; Pizzolato, G.; Baggiolini, E.
G.; Uskokovic, M. R. J . Org. Chem. 1988, 53, 4282-4295.
(37) Yanuka, Y.; Katz, R.; Sarel, S. Tetrahedron Lett. 1968, 1725-
1728.
(38) Santaniello, E.; Manzocchi, A.; Farachi, C. Synthesis 1980, 563-
565.
1-Iod ocyclop en ten e24 (4). This compound was prepared
by the method of Barton et al.25 Cyclopentanone (44 mL, 0.50
mol) and hydrazine monohydrate (115 mL, 2.37 mol) were
combined at rt and heated at reflux for 16 h. The reaction was
poured into water (500 mL), extracted with CH2Cl2 (4 × 200
mL), washed with brine (200 mL), dried over Na2SO4, and
concentrated to give 40 g (80%) of the hydrazone as a colorless
liquid: 1H NMR δ 4.80 (s, 2H), 2.33-2.30 (t, 2H), 2.16-2.12
(39) Sheldon, R. A.; Kochi, J . K. Org. React. 1972, 19, 279-421.
(40) Bal, B. S.; Childers, W. E., J r.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096.
2346 J . Org. Chem., Vol. 68, No. 6, 2003

(Z)- and (E)-Alkene Dipeptide Mimics of Ser-Pro
(m, 2H), 1.85-1.67 (m, 4H). To a solution of I2 (97.5 g, 384
mmol) in Et2O (600 mL) was added a solution of tetrameth-
ylguanidine (265 mL, 2.09 mol) in Et2O (400 mL) slowly
(caution! exothermic), and the resulting solution was stirred
for 2.5 h. A solution of cyclopentanone hydrazone (17.3 g, 174
mmol) in Et2O (200 mL) was added dropwise over 2.5 h
(caution! exothermic), and the resulting solution was stirred
for 16 h and then heated at reflux for 2 h. The reaction was
cooled to rt, filtered to remove the solids, and concentrated to
remove Et2O. The solution was reheated at 80-90 °C for 3 h.
The reaction was cooled to rt, diluted with Et2O (500 mL),
washed with 2 N HCl (3 × 150 mL), Na2S2O3 (3 × 100 mL),
NaHCO3 (100 mL), and brine (100 mL), dried over MgSO4, and
concentrated to give 21.1 g (62%) of 4 as a pale yellow liquid
that was stored under N2 at -20 °C and used without further
purification, usually within a week of synthesis (the product
may be purified, if necessary, by chromatography with petro-
leum ether on silica): 1H NMR δ 6.12-6.10 (m, 1H), 2.64-
2.58 (m, 2H), 2.36-2.30 (m, 2H), 1.98-1.90 (m, 2H).
Keton e 5. Cyclopentenyllithium was generated by adding
fresh s-BuLi (1.3 M in cyclohexane, 50 mL, 65 mmol) to a
solution of freshly prepared 4 (10.0 g, 51.5 mmol) in THF (100
mL) at -40 °C. The solution was maintained at -40 °C for 70
min, and Weinreb amide 3 (7.40 g, 17.7 mmol) in THF (30 mL)
was cooled to -40 °C and added slowly via cannula. The
mixture was stirred for 1 h at -40 °C. The reaction was
quenched with NH4Cl (20 mL), diluted with EtOAc (600 mL),
washed with NH4Cl (3 × 100 mL) and brine (100 mL), dried
over Na2SO4, and concentrated. Chromatography on silica with
5% EtOAc in hexanes yielded 7.1 g (94%) of the ketone 5: 1H
NMR δ 7.39-7.20 (m, 15H), 6.11 (m, 1H), 4.55 (d, J ) 12.3,
1H), 4.48 (d, J ) 12.3, 1H), 4.24 (app t, J ) 6.6, 1H), 3.90 (d,
J ) 6.6, 2H), 3.79 (d, J ) 13.6, 2H), 3.71 (d, J ) 14.1, 2H),
2.59-2.39 (m, 4H), 1.98-1.84 (m, 2H); 13C NMR δ 197.8, 145.5,
144.7, 139.7, 138.2, 128.8, 128.2, 128.1, 127.5, 126.9, 73.3, 67.6,
60.6, 54.8, 33.9, 30.5, 22.6. Anal. Calcd for C29H31NO2: C,
81.85; H, 7.34; N, 3.29. Found: C, 81.51; H, 7.42; N, 3.52.
(S,S)-Alcoh ol 6. Ketone 5 (6.8 g, 16 mmol) was dissolved
in THF (250 mL), and LiAlH4 (6.0 g, 160 mmol) was added.
After 1 h, the reaction was quenched with MeOH (50 mL) and
then NH4Cl (50 mL), diluted with EtOAc (500 mL), and
washed with NH4Cl (150 mL) and 1 M sodium potassium
tartrate (2 × 150 mL). The aqueous layers were extracted with
CH2Cl2 (3 × 200 mL). The combined organic layers were dried
over MgSO4 and concentrated to yield 6.68 g (98%) of alcohol
6 as a colorless oil: 1H NMR δ 7.49-7.24 (m, 15H), 5.65 (m,
1H), 4.62 (d, J ) 11.9, 1H), 4.53 (d, J ) 11.9, 1H), 4.48 (s,
1H), 4.26 (d, J ) 10.1, 1H), 4.02 (d, J ) 13.2, 2H), 3.80-3.70
(m, 3H), 3.58 (dd, J ) 10.6, 3.1, 1H), 3.07 (m, 1H), 2.43-2.17
(m, 3H), 2.00-1.75 (m, 3H); 13C NMR δ 144.1, 139.0, 138.2,
129.2, 129.0, 128.3, 127.5, 127.4, 127.1, 73.2, 67.5, 66.4, 59.7,
54.3, 32.0, 29.5, 23.0. Anal. Calcd for C29H33NO2: C, 81.46; H,
7.78; N, 3.28. Found: C, 81.25; H, 7.66; N, 3.11.
Sta n n a n e 7. To a solution of alcohol 6 (2.20 g, 5.15 mmol)
in THF (40 mL) were added 18-crown-6 (4.09 g, 15.5 mmol) in
THF (10 mL), KH (1.03 g, 7.73 mmol, 35% suspension in
mineral oil) in THF (10 mL), and Bu3SnCH2I,29 purified by
fractional distillation at reduced pressure (3.33 g, 7.73 mmol),
in THF (10 mL), and the resulting solution was stirred for 30
min at rt. The reaction was quenched with MeOH, diluted with
EtOAc (400 mL), washed with NH4Cl (2 × 100 mL) and brine
(100 mL), dried on MgSO4, and concentrated. Purification by
chromatography on silica with 3% EtOAc in hexanes yielded
3.51 g (94%) of stannane 7 as a clear liquid: 1H NMR δ 7.40-
7.26 (m, 15H), 5.60 (br s, 1H), 4.45 (d, J ) 12.0, 1H), 4.37 (d,
J ) 12.0, 1H), 4.05 (d, J ) 7.8, 1H), 3.99 (d, J ) 13.7, 2H),
3.83 (d, J ) 13.7, 2H), 3.74 (dm, J ) 9.9, 1H), 3.60 (dd, J )
9.6, 5.7, 1H), 3.53 (dd, J ) 9.6, 4.6, 1H), 3.41 (dm, J ) 9.6,
1H), 2.99 (m, 1H), 2.40-2.28 (m, 2H), 1.99 (br s, 2H), 1.82 (m,
2H), 1.54 (m, 6H), 1.33 (m, 6H), 0.91 (m, 15H); 13C NMR (125
MHz) δ 143.0, 141.6, 138.9, 129.1, 128.6, 128.4, 128.0, 127.6,
126.5, 85.4 (s), 85.4 (d, J C-Sn ) 51), 73.2, 70.6, 59.2, 58.6, 55.8,
32.3, 31.1, 29.4 (s), 29.4 (d, J C-Sn ) 20), 27.6 (s), 27.6 (d, J C-Sn
) 54), 23.5, 13.9, 9.0 (s), 9.0 (dd, J C-Sn ) 316, 7.6).
(Z)-Alk en e 8a a n d (E)-Alk en e 8b. Stannane 7 (9.60 g, 13.1
mmol) was dissolved in THF (150 mL) and cooled to -78 °C.
n-BuLi (2.5 M in hexane, 15 mL, 39 mmol) was cooled to -78
°C, added slowly via cannula, and stirred for 1.5 h at -78 °C.
The reaction was quenched with MeOH and concentrated. The
residue was diluted with EtOAc (700 mL), washed with NH4-
Cl (2 × 150 mL) and brine (150 mL), dried on Na2SO4, and
concentrated. Chromatography on silica with 15% EtOAc in
hexanes yielded 3.0 g (53%) of (Z)-8a and 1.57 g (28%) of (E)-
8b as clear oils. (NOE spectra are included in the Supporting
Information of the preliminary communication.19) Data for (E)-
8b: 1H NMR δ 7.38-7.27 (m, 15H), 5.43 (br d, J ) 9.4, 1H),
4.51 (d, J ) 12.1, 1H), 4.47 (d, J ) 12.1, 1H), 3.84 (d, J ) 13.9,
2H), 3.73 (m, 1H), 3.64-3.47 (m, 6H), 2.65 (m, 1H), 2.05 (m,
2H), 1.85 (m, 1H), 1.69 (m, 1H), 1.56 (m, 2H); 13C NMR δ 148.6,
140.3, 138.5, 129.4, 128.5, 128.2, 128.0, 127.5, 127.3, 126.6,
117.6, 72.6, 71.7, 65.4, 57.3, 54.7, 47.0, 29.6, 29.2, 24.1. Data
for (Z)-8a : 1H NMR δ 7.38-7.26 (m, 15H), 5.55 (br d, J ) 8.7,
1H), 4.57 (d, J ) 12.2, 1H), 4.53 (d, J ) 12.2, 1H), 4.12 (br s,
1H), 3.89 (d, J ) 13.3, 2H), 3.79 (m, 1H), 3.67 (m, 4H), 3.33
(m, 1H), 3.27 (m, 1H), 2.53 (m, 1H), 2.31-2.18 (m, 2H), 1.71-
1.47 (m, 4H); 13C NMR δ 149.0, 139.2, 138.4, 129.4, 128.3,
128.0, 127.5, 126.8, 120.9, 73.2, 69.7, 64.8, 57.3, 55.0, 43.5, 33.1,
29.4, 23.1. Anal. Calcd for C30H35NO2: C, 81.59; H, 7.99; N,
3.17. Found: C, 81.42; H, 8.27; N, 3.25.
Boc-ben zyla m in e 9. (Z)-Alkene 8 (1.44 g, 3.26 mmol) and
20% Pd(OH)2/C (150 mg) were blanketed with Ar, and MeOH
(100 mL) was added, followed by 96% HCOOH (20 mL). After
being stirred for exactly 20 min, the reaction was filtered
immediately through Celite, concentrated, neutralized with
solid NaHCO3 until gas evolution ceased, extracted with CH2-
Cl2 (5 × 100 mL), dried over Na2SO4, and concentrated to yield
1.1 g (98%) of the monobenzylamine without further purifica-
tion: 1H NMR (500 MHz) δ 7.36-7.30 (m, 10H), 5.50 (br d, J
) 8.3, 1H), 4.56 (br d, J ) 1.6, 2H), 3.72 (d, J ) 11.2, 1H),
3.66-3.60 (m, 3H), 3.55-3.50 (m, 1H), 3.48-3.45 (dd, J ) 10.8,
4.3, 1H), 3.41-3.37 (m, 1H), 2.83 (m, 1H), 2.37-2.22 (m, 2H),
1.89-1.85 (m, 1H), 1.64 (m, 1H), 1.54-1.38 (m, 2H); HRMS
(FAB+) m/z calcd for C23H30NO2 (M + 1)+ 352.2276, found
352.2278. The monobenzylamine (1.10 g, 3.12 mmol) was
dissolved in CH2Cl2 (60 mL), di-tert-butyl dicarbonate (1.70 g,
7.79 mmol) was added, and the resulting solution was stirred
for 17 h. The mixture was concentrated, and purification by
chromatography on silica with 20% EtOAc in hexanes yielded
1.3 g (95%) of the Boc-benzylamine 9 as a pale yellow oil: 1H
NMR (500 MHz) δ 7.36-7.16 (m, 10H), 5.36 (br d, J ) 8.9,
1H), 5.18 (br s, 1H), 4.47-4.37 (m, 4H), 3.48-3.46 (m, 5H),
2.87 (br s, 1H), 2.20 (m, 2H), 1.75 (m, 1H), 1.65 (m, 2H), 1.54
(m, 1H), 1.34 (br s, 9H); 13C NMR δ 155.7, 149.2, 139.9, 138.1,
127.9, 127.8, 127.2, 126.7, 126.3, 117.8, 79.8, 72.3, 71.1, 64.3,
54.1, 47.3, 43.9, 33.2, 29.1, 28.0, 23.0; HRMS m/z calcd for
C
28H37NO4 (MH+) 452.2801, found 452.2813.
Boc-ben zyla m in o Acid 10. Boc-benzylamine 9 (2.2 g, 4.9
mmol) was dissolved in acetone (220 mL) and cooled to 0 °C.
J ones reagent (2.7 M H2SO4, 2.7 M CrO3; 4.5 mL, 12 mmol)
was added, and the resulting solution was stirred for 30 min
at 0 °C. The reaction was quenched with 2-propanol (50 mL)
and stirred for 5 min. The mixture was diluted with water
(400 mL), extracted with CH2Cl2 (10 × 50 mL), dried on
MgSO4, and concentrated. Chromatography on silica with 20%
EtOAc in petroleum ether yielded 2.1 g (95%) of the acid 10
as a pale yellow oil: 1H NMR δ 7.34-7.16 (m, 10H), 5.53 (br
d, J ) 9.2, 1H), 4.92 (br s, 1H), 4.47-4.27 (m, 4H), 3.69-3.24
(m, 3H), 2.46 (m, 1H), 2.28 (m, 1H), 2.11 (m, 1H), 1.89 (m,
2H), 1.62 (m, 1H), 1.38 (br s, 9H); 13C NMR (CDCl3) δ 179.1,
155.6, 145.7, 139.8, 138.3, 128.2, 128.1, 127.4, 127.1, 126.6,
120.9, 80.0, 72.6, 72.0, 55.6, 49.0, 45.9, 33.5, 31.0, 28.3, 23.8;
HRMS m/z calcd for
C
28H36NO5 (MH+) 466.2593, found
466.2601.
J . Org. Chem, Vol. 68, No. 6, 2003 2347

Wang et al.
Boc-Ser -Ψ[(Z)CHdC]-P r o-OH (1). NH3 (ca. 160 mL) was
distilled into 40 mL of THF at -78 °C and allowed to warm to
reflux (-33 °C). Na (ca. 2.0 g, 87 mmol) was added until a
deep blue solution was sustained. A solution of acid 10 (2.0 g,
4.3 mmol) in THF (10 mL) was added directly to the Na/NH3
solution slowly via cannula over ca. 5 min. After being stirred
for 45 min at reflux, the reaction was quenched with NH4Cl
(10 mL) and then allowed to warm to rt with concentration to
ca. 30 mL (caution! NH3 evolved). The mixture was diluted
with NH4Cl (50 mL), acidified with 1 N HCl to pH 7, and
extracted with CHCl3 (10 × 50 mL), dried on MgSO4, and
concentrated to give 810 mg (66%) of the alcohol 1 as a pale
yellow oil (further purification can be achieved by chromatog-
raphy on silica with 3% MeOH in CHCl3 if desired): 1H NMR
(DMSO-d6) δ 6.48 (br d, J ) 6.2, 1H), 5.20 (d, J ) 8.4, 1H),
4.08 (m, 1H), 3.36 (m, 1H), 3.28 (dd, J ) 10.6, 5.7, 1H), 3.13
(dd, J ) 10.6, 6.6, 1H), 2.20 (m, 2H), 1.81 (m, 2H), 1.67 (m,
1H), 1.47 (m, 1H), 1.31 (s, 9H); 13C NMR (DMSO-d6) δ 175.4,
154.8, 142.7, 122.5, 77.4, 64.0, 51.9, 45.5, 33.5, 31.2, 28.3, 24.1;
Anal. Calcd for C20H29O4N: C, 69.14; H, 8.41; N, 4.03. Found:
C, 69.42; H, 8.54; N, 4.12.
Ester 16. To a solution of alcohol 15 (3.26 g, 9.38 mmol)
and pyridine (2.28 mL, 28.2 mmol) in THF (4 mL) was added
a solution of tert-butyldimethylsilyloxyacetyl chloride34 (2.05
g, 9.40 mmol) in THF (4 mL) dropwise at 0 °C. The reaction
was stirred for 3 h at rt, then diluted with 30 mL of Et2O,
washed with 0.5 N HCl (2 × 20 mL), NaHCO3 (10 mL), and
brine (10 mL), dried on MgSO4, and concentrated. Chroma-
tography with 4% EtOAc in hexanes on silica gave 3.48 g (70%)
of ester 16 as a yellow oil: 1H NMR δ 7.35-7.28 (m, 5H), 5.67
(s, 1H), 5.58 (d, J ) 8.0, 1H), 4.83 (d, J ) 9.4, 1H), 4.51 (d, J
) 11.9, 1H), 4.42 (d, J ) 11.9, 1H), 4.16 (s, 2H), 4.04 (m, 1H),
3.55 (dd, J ) 3.5, 9.4, 1H), 3.48 (dd, J ) 3.3, 9.5, 1H), 2.41 (m,
1H), 2.33-2.21 (m, 3H), 1.83 (m, 2H), 1.40 (s, 9H), 0.90 (s, 9H),
0.07 (s, 6H); 13C NMR δ 170.6, 155.3, 139.9, 138.0, 130.2, 128.5,
127.8, 127.7, 79.5, 73.3, 72.6, 68.5, 61.8, 51.0, 32.4, 31.6, 28.4,
25.8, 23.2, 18.4, -5.4. Anal. Calcd for C28H45NO4Si: C, 64.70;
H, 8.73; N, 2.69. Found: C, 64.58; H, 8.89; N, 2.69.
HRMS m/z calcd for
C
14H23NO5 (MH+) 286.1654, found
r-Hyd r oxy Acid 17. To a solution of diisopropylamine (3.3
mL, 24 mmol) in THF (40 mL) was added n-butyllithium (2.5
M in hexane, 8.6 mL, 22 mmol) at 0 °C. The mixture was
stirred for 15 min to generate LDA. Then a mixture of
chlorotrimethylsilane (7.52 mL, 59.2 mmol) and pyridine (5.22
mL, 64.6 mmol) in THF (15 mL) was added dropwise to the
LDA solution at -100 °C. After 5 min, a solution of ester 16
(2.83 g, 5.38 mmol) in THF (18 mL) was added dropwise, and
the reaction was stirred at -100 °C for 25 min, then warmed
slowly to rt over 1.5 h, and stirred at rt for 1.5 h. The reaction
was quenched with 1 N HCl (70 mL), and the aqueous layer
was extracted with Et2O (2 × 150 mL). The organic layer was
dried on MgSO4 and concentrated to give 1.98 g (crude yield
70%) of colorless glassy oil. Without further purification, the
product was dissolved in 10 mL of THF. Tetrabutylammonium
fluoride (2.8 g, 11 mmol) in THF (10 mL) was added at 0 °C,
and the resulting solution was stirred at 0 °C for 5 min and
then at rt for 1 h. The reaction was quenched with 0.5 N HCl
(50 mL), extracted with EtOAc (100 mL), dried on MgSO4, and
concentrated. Chromatography with 50% EtOAc in hexane on
silica gave 1.16 g (52%) of R-hydroxy acid 17 as a colorless
foam: 1H NMR (DMSO-d6) δ 7.36-7.24 (m, 5H), 6.84 (d, J )
7.35, 1H), 5.28 (d, J ) 7.80, 1H), 4.50 (d, J ) 11.9, 1H), 4.44
(d, J ) 12.2, 1H), 4.31 (br s, 1H), 3.84 (d, J ) 6.0, 1H), 3.40-
3.32 (m, 2H), 3.27 (dd, J ) 5.1, 10.1, 1H), 2.70-2.61 (m, 1H),
2.41-2.37 (m, 1H), 2.17-2.10 (m, 1H), 1.74-1.67 (m, 2H),
1.55-1.42 (m, 2H), 1.37 (s, 9H); 13C NMR (DMSO-d6) δ 175.3,
155.7, 145.4, 139.2, 128.7, 127.9, 127.8, 121.6, 78.0, 74.0, 72.5,
286.1653.
Boc-Ser (OBn ) Wein r eb Am id e (13).23 N-Boc-Ser(OBn)-
OH (2.95 g, 10.0 mmol), N,O-dimethylhydroxylamine hydro-
chloride (1.85 g, 20.0 mmol), and DIEA (5.2 g, 40 mmol) were
dissolved in 1:1 CH2Cl2/DMF (100 mL) and cooled to 0 °C.
1-Hydroxy-1H-benzotriazole (HOBt, 1.84 g, 12.0 mmol), DCC
(2.48 g, 12.0 mmol), and DMAP (ca. 30 mg) were added, and
the reaction was stirred for 24 h. The reaction was filtered to
remove dicyclohexylurea and concentrated. The resulting
slurry was diluted with 150 mL of ethyl acetate and washed
with NH4Cl (2 × 50 mL), NaHCO3 (2 × 50 mL), and brine (50
mL). The organic layer was dried on MgSO4 and concentrated.
Chromatography on silica with 30% EtOAc in hexane gave 3.04
g (90%) of 13 as a colorless syrup: 1H NMR δ 7.35-7.23 (m,
5H), 5.42 (d, J ) 8.5, 1H), 4.87 (br s, 1H), 4.56 (d, J ) 12.5,
1H), 4.49 (d, J ) 12.5, 1H), 3.71 (s, 3H), 3.66 (m, 2H), 3.17 (s,
3H), 1.43 (s, 9H).
Keton e 14. To a solution of 4 (7.59 g, 39.1 mmol) in 100
mL of THF at -40 °C was added s-BuLi (1.3 M in cyclohexane,
60 mL, 78 mmol). The reaction was stirred at -40 °C for 3 h
to generate cyclopentenyllithium. Then the mixture was added
via syringe in three portions to a solution of Weinreb amide
13 (4.41 g, 13.0 mmol) in THF (50 mL), dried over 3 Å
molecular sieves for 3 h, at -78 °C. The mixture was stirred
for 3 h at -78 °C, quenched with NH4Cl (20 mL), diluted with
EtOAc (200 mL), washed with NH4Cl (2 × 50 mL), NaHCO3
(50 mL), and brine (50 mL), dried over MgSO4, and concen-
trated. Chromatography on silica with 8% EtOAc in hexane
and then 12% EtOAc in hexane gave 3.88 g (86%) of ketone
14 as a yellow oil: 1H NMR δ 7.34-7.22 (m, 5H), 6.79 (m, 1H),
5.57 (d, J ) 10.5, 1H), 5.00 (m, 1H), 4.54 (d, J ) 12.4, 1H),
4.43 (d, J ) 12.0, 1H), 3.71 (d, J ) 4.4, 2H), 2.62 (m, 1H), 2.54
(m, 3H), 2.00-1.82 (m, 2H), 1.44 (s, 9H); 13C NMR δ 195.0,
155.5, 145.5, 143.3, 137.7, 128.4, 127.8, 127.6, 79.8, 73.2, 71.1,
56.4, 34.3, 31.0, 28.4, 22.5. Anal. Calcd for C20H27O4N: C,
69.54; H, 7.88; N, 4.05. Found: C, 69.54; H, 7.74; N, 4.01.
Alcoh ol 15. Ketone 14 (3.78 g, 11.0 mmol) was dissolved
in 2.5:1 THF/MeOH (125 mL) and cooled to 0 °C. CeCl3 (4.91
g, 13.2 mmol) was added, followed by NaBH4 (0.84 g, 22 mmol).
After being stirred for 2 h at 0 °C, the reaction was quenched
with NH4Cl (50 mL), diluted with EtOAc (200 mL), washed
with NH4Cl (2 × 100 mL) and brine (100 mL), dried on MgSO4,
and concentrated. Chromatography on silica with 15% EtOAc
in hexane yielded 3.49 g (92%) of a white solid as a 4:1 mixture
of diastereomers, mp 67-68 °C. The major diastereomer was
isolated by precipitation from EtOAc/n-hexane: 1H NMR δ
7.36-7.28 (m, 5H), 5.65 (m, 1H), 5.35 (d, J ) 8.4, 1H), 4.51 (d,
J ) 11.6, 1H), 4.42 (d, J ) 12.0, 1H), 4.33 (br s, 1H), 3.84 (br
s, 1H), 3.71-3.68 (dd, J ) 3.4, 13.4, 1H), 3.60-3.55 (dd, J )
2.6, 9.4, 1H), 3.18 (d, J ) 8.4, 1H), 2.35-2.20 (m, 4H), 1.87
(m, 2H), 1.44 (s, 9H); 13C NMR δ 155.9, 144.7, 137.6, 128.7,
128.2, 128.1, 126.7, 79.7, 74.1, 74.0, 70.6, 52.1, 32.4, 28.6, 23.9.
72.3, 50.5, 47.6, 30.0, 29.6, 28.8, 24.6. Anal. Calcd for C22H31
-
NO6: C, 65.17; H, 7.71; N, 3.45. Found: C, 65.03; H, 7.80; N,
3.47.
Acid 18. Lead tetraacetate (2.69 g, 6.06 mmol) in CHCl3
(13.5 mL) was added dropwise to a solution of acid 17 (2.28 g,
5.51 mmol) in EtOAc (81 mL) at 0 °C. The reaction was stirred
for 10 min, then quenched with ethylene glycol (8 mL), diluted
with EtOAc (150 mL), washed with H2O (4 × 15 mL) and brine
(15 mL), dried on Na2SO4, and concentrated to give 2.02 g
(100% crude yield) of aldehyde as yellow oil: 1H NMR (CHCl3)
δ 9.38 (d, J ) 2.8, 1H), 7.36-7.27 (m, 5H), 5.39 (dd, J ) 2.2,
8.6, 1H), 4.95 (d, J ) 7.1, 1H), 4.55 (d, J ) 12.2, 1H), 4.47 (d,
J ) 12.2, 1H), 4.41 (br s, 1H), 3.50 (dd, J ) 4.3, 9.3, 1H), 3.43
(dd, J ) 5.0, 9.4, 1H), 3.25 (m, 1H), 2.55 (m, 1H), 2.24 (m, 1H),
1.99 (m, 1H), 1.86 (m, 1H), 1.72 (m, 2H), 1.43 (s, 9H). The
product was dissolved in acetone (140 mL) and cooled to 0 °C.
J ones reagent (2.7 M H2SO4, 2.7 M CrO3; 4 mL, 11 mmol) was
added dropwise. The reaction was stirred at 0 °C for 0.5 h,
quenched with isopropyl alcohol (12 mL), and stirred for 10
min. The precipitate was filtered out, and the solvent was
evaporated. The residue was extracted with EtOAc (3 × 200
mL), washed H2O (50 mL) and brine (50 mL), dried on Na2-
SO4, and concentrated. Chromatography on silica with 30%
EtOAc in hexane gave 1.65 g (78%) of acid 18 as a colorless
oil: 1H NMR (CHCl3) δ 7.30 (m, 5H), 5.55 (d, J ) 6.7, 1H),
2348 J . Org. Chem., Vol. 68, No. 6, 2003

(Z)- and (E)-Alkene Dipeptide Mimics of Ser-Pro
4.93 (br s, 1H), 4.53 (d, J ) 12.1, 1H), 4.51 (d, J ) 12.1, 1H),
4.39 (br s, 1H), 3.47 (dd, J ) 3.5, 9.2, 1H), 3.41 (dd, J ) 5.3,
9.6, 1H), 3.36 (t, J ) 7.0, 1H), 2.54 (m, 1H), 2.29 (m, 1H), 2.04-
1.84 (m, 3H), 1.66 (m, 1H), 1.43 (s, 9H); 13C NMR (CHCl3) δ
179.9, 155.6, 143.8, 138.2, 128.5, 127.7, 127.6, 122.6, 79.4, 73.1,
72.1, 50.4, 49.5, 30.1, 29.4, 28.5, 25.1; IR (cm-1) 3000-2800
(br), 1701 (s), 1162, 731, 697; HRMS m/z calcd for C21H29NO5
(MH+) 376.2124, found 376.2133.
Boc-Ser -Ψ[(E)CHdC]-P r o-OH (2). NH3 (35 mL) was
distilled and allowed to warm to reflux (-33 °C), and Na (ca.
330 mg, 14 mmol) was added until a deep blue solution was
sustained. Acid 18 (575 mg, 1.50 mmol) in THF (13 mL) was
added directly to the Na/NH3 solution via syringe. After being
stirred for 15 min at reflux, the reaction was quenched with
NH4Cl (20 mL) and then allowed to warm to rt. NH4Cl (40
mL) was added, and the mixture was extracted with CHCl3 (5
× 30 mL). The aqueous layer was acidified with 1 N HCl and
extracted with CHCl3 (6 × 50 mL). The CHCl3 layer was dried
on MgSO4 and concentrated to give 280 mg (64%) of the acid
as a yellow oil: 1H NMR (DMSO-d6) δ 6.66 (d, J ) 7.4, 1H),
5.31 (dd, J ) 2.1, 8.7, 1H), 4.61 (br s, 1H), 4.06 (s, 1H), 3.27
(dd, J ) 7.1, 10.8, 1H), 3.20 (dd, J ) 5.7, 10.5, 1H), 3.16 (m,
1H), 2.39 (m, 1H), 2.22 (m, 1H), 1.80 (m, 3H), 1.52 (m, 1H),
1.36 (s, 9H); 13C NMR δ 175.4, 155.7, 143.6, 122.5, 78.0, 64.0,
52.9, 49.6, 30.1, 29.5, 28.8, 25.0; HRMS m/z calcd for C14H23
-
NO5 (MH+) 286.1654, found 286.1661.
Ack n ow led gm en t. This work was supported by
NIH Grant No. R01 GM63271-01. We thank Dr. J eremy
Travins (3D Pharmaceuticals) and Professor Richard
Sundberg (University of Virginia) for helpful discus-
sions.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for 11, 12, 19, and 20 and NMR spectra for compounds
1, 2, 9-12, and 18-20. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O026663B
J . Org. Chem, Vol. 68, No. 6, 2003 2349