Stereoselective synthesis of (Z)-alkene-containing proline dipeptide mimetics

Article abstract of DOI:10.1021/jo0606002

In peptides and proteins, the peptide bond between an amino acid and proline exists as an equilibrium mixture of the cis-imide and trans-imide due to the low energy barrier in their interconversion. This feature greatly influences the structure and function of the proline-containing peptides and proteins. Therefore, restricting the amide bond with an (E)- or (Z)-alkene should provide a promising method for elucidating the structure-activity relationships of the peptide and the proteins. In this report, the regio-and stereoselective synthesis of cis-alanylproline (Ala-Pro) type (Z)-alkene dipeptide mimetic is described. The key steps of this synthesis are to introduce a C3 unit onto a γ-phosphoryloxy-α,β-unsaturated-(3-lactam with an organocopper-mediated anti-S_N2′ reaction and subsequently construct a five-membered proline-like cyclic structure with an intramolecular Suzuki coupling reaction. Hydrolysis of the amide bond in the resulting bicyclic lactam yields the desired cis-Ala-Pro type (Z)-alkene dipeptide isostere. The presented synthetic methodology should be applicable to the general syntheses of other cis-aminoacylproline type (Z)-alkene dipeptide mimetics.

Full text of DOI:10.1021/jo0606002

Stereoselective Synthesis of (Z)-Alkene-Containing Proline Dipeptide
Mimetics
Yoshikazu Sasaki,†,‡ Ayumu Niida,† Takashi Tsuji,‡ Akira Shigenaga,‡ Nobutaka Fujii,† and
Akira Otaka*,†,‡
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Sakyo-ku, Kyoto 606-8501, Japan, and
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokushima, Tokushima 770-8505, Japan
aotaka@ph.tokushima-u.ac.jp
ReceiVed March 20, 2006
In peptides and proteins, the peptide bond between an amino acid and proline exists as an equilibrium
mixture of the cis-imide and trans-imide due to the low energy barrier in their interconversion. This
feature greatly influences the structure and function of the proline-containing peptides and proteins.
Therefore, restricting the amide bond with an (E)- or (Z)-alkene should provide a promising method for
elucidating the structure-activity relationships of the peptide and the proteins. In this report, the regio-
and stereoselective synthesis of cis-alanylproline (Ala-Pro) type (Z)-alkene dipeptide mimetic is described.
The key steps of this synthesis are to introduce a C3 unit onto a γ-phosphoryloxy-R,â-unsaturated-δ-
lactam with an organocopper-mediated anti-SN2′ reaction and subsequently construct a five-membered
proline-like cyclic structure with an intramolecular Suzuki coupling reaction. Hydrolysis of the amide
bond in the resulting bicyclic lactam yields the desired cis-Ala-Pro type (Z)-alkene dipeptide isostere.
The presented synthetic methodology should be applicable to the general syntheses of other cis-
aminoacylproline type (Z)-alkene dipeptide mimetics.
Introduction
which conformer contributes to a biological function is an
important task in peptide/protein chemistry. One potential
method for this purpose is structural analysis of Pro-peptides
with NMR or X-ray diffraction, but precise profiling of the
conformer is difficult due to the facile interconversion between
the cis and trans forms. Thus, use of synthetic equivalents which
possess the fixed conformation for functional analysis of Pro-
peptides represents a promising alternative to spectroscopic
methods.3,7 These include alkene-type dipeptide isosteres with
Proline (Pro) can form a cis- or trans-peptide bond through
the acylation of the secondary amine with amino acids.1 Low
energy barriers in the cis/trans interconversion allow proline-
containing peptides to exist in a trans or cis form, depending
on the surrounding environments (Figure 1). These isomeric
peptides (or proteins) show distinct biological functions, which
differ from each other.2-6 The genome sequence cannot deduce
this kind of dynamic conformational change or the subsequent
involvement in biological functions. Therefore, determining
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Scheraga, H. A. Biochemistry 2002, 41, 14637-14644. (c) Andreotti, A.
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† Kyoto University.
‡ The University of Tokushima.
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10.1021/jo0606002 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/18/2006
J. Org. Chem. 2006, 71, 4969-4979
4969

Sasaki et al.
SCHEME 1. Regio- and Stereoselective Synthesis of
trans-(E)-Alkene Pro Dipeptide Isosteres, Using
Organocopper Reagents
SCHEME 2. Regio- and Stereoselective anti-SN2′ Alkylation
of γ-Phosphoryloxy-r,â-unsaturated Lactam 1 with
Organocopper Reagents
FIGURE 1. Cis/trans interconversion of peptide bond in proline
dipeptide and cis-(Z)-alkene or trans-(E)-alkene dipeptide isosteres,
which correspond to the cis- or trans-dipeptides.
an (E)- or (Z)-olefin unit, which corresponds to the aminoacyl-
proline bonds.
Therefore, many research groups, including ours, have been
extensively engaged in the synthetic study on (E)- or (Z)-alkene-
containing Pro dipeptide mimetics.8-10 In terms of this issue,
the efforts of Etzkorn’s group have provided a practical route
to alkene-containing Pro mimetics,9 using Still-Wittig [2,3]-
sigmatropic9a,b,11 and Ireland-Claisen [3,3]-sigmatropic9c,12 rear-
rangements as key transformations to prepare cis-Pro and trans-
Pro mimetics, respectively. Alternatively, we have investigated
using an organocopper-mediated anti-SN2′ reaction to synthesize
alkene-type Pro mimetics, in which introduction of a “CO2H”
synthon using organocopper reagent into vinyl oxazolidinone
derivatives led to the success in the development of a facile
synthetic route to (E)-alkene-containing Pro dipeptide isosteres,
which correspond to the trans-Pro dipeptides (Scheme 1).10 In
this synthetic protocol, the organocopper reagents derived from
CuCN and (i-PrO)Me2SiCH2MgCl were utilized for “CO2H”
introduction, and the incorporated (i-PrO)Me2SiCH2 unit was
oxidatively converted to “CO2H”.
However, attempts to prepare the cis-Pro mimetics with this
protocol were unsuccessful since the “CO2H” synthon was
exclusively introduced into a preferable reactive conformer
accessible to trans-(E)-alkene mimetics. Generally, only a few
practical and efficient synthetic methods are available to
synthesize (Z)-alkene-type dipeptide isosteres.11b,13 Recently, we
devised an efficient synthetic method for diketopiperazine
mimetics, which possess one (Z)-alkene moiety per molecule,
using organocopper reagents (Scheme 2).14 These diketopip-
erazine mimetics13,15,16 have potential as synthetic precursors
for (Z)-alkene-type dipeptide isosteres. A careful examination
of reaction conditions suitable to synthesize diketopiperazine
mimetics indicated that utilizing highly stereo- and regioselective
anti-SN2′ alkylation of a γ-phosphoryloxy-R,â-unsaturated lac-
tam with organocopper reagents is crucial.17 This result prompted
(5) (a) Mallis, R. J.; Brazin, K. N.; Fulton, D. B.; Andreotti, A. H. Nat.
Struct. Biol. 2002, 9, 900-905. (b) Brazin, K. N.; Mallis, R. J.; Fulton, D.
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Chem. Soc. 2003, 125, 15706-15707. (d) Colgan, J.; Asmal, M.; Neagu,
M.; Yu, B.; Schneidkraut, J.; Lee, Y.; Sokolskaja, E.; Andreotti, A.; Luban,
J. Immunol. 2004, 21, 189-201.
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(b) Yaffe, M. B.; Schutkowski, M.; Shen, M.; Zhou, X. Z.; Stukenberg, P.
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L. C.; Lu, K. P. Science 1997, 278, 1957-1960. (c) Yeh, E.; Cunningham,
M.; Arnold, H.; Chasse, D.; Monteith, T.; Ivaldi, G.; Hahn, W. C.;
Stukenberg, P. T.; Shenoliokar, S.; Uchida, T.; Counter, C. M.; Nevins, J.
R.; Means, A. R.; Sear, R. Nat. Cell Biol. 2004, 6, 308-317. (d) Shen,
Z.-J.; Esnault, S.; Malter, J. S. Nat. Immunol. 2005, 6, 1280-1286. (e)
Wulf, G.; Finn, G.; Suizu, F.; Lu, K. P. Nat. Cell Biol. 2005, 7, 435-441.
(7) (a) Delaney, D. G.; Madison, V. J. Am. Chem. Soc. 1982, 104, 6635-
6641. (b) Magaard, V. W.; Sanchez, R. M.; Bean, J. W.; Moore, M. L.
Tetrahedron Lett. 1993, 34, 381-384. (c) Beausoleil, E.; Lubell, W. D.
Biopolymers 2000, 53, 249-256. (d) Beausoleil, E.; Lubell, W. D. J. Am.
Chem. Soc. 1996, 118, 12902-12908. (e) Brandsch, M.; Thuneche, F.;
Ku¨llertz, G.; Schutkowski, M.; Fisher, G.; Neubert, K. J. Biol. Chem. 1998,
273, 3861-3864. (f) Keller, M.; Boissard, C.; Patiny, L.; Chung, N. N.;
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7580-7581. (b) Hart, S. A.; Trindle, C. O.; Etzkorn, F. A. Org. Lett. 2001,
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J. R.; Etzkorn, F. A. J. Org. Chem. 2003, 68, 2343-2349. (d) Wang, X. J.;
Xu, B.; Mullins, A. B.; Neiler, F. K.; Etzkorn, F. A. J. Am. Chem. Soc.
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(13) Boucard, V.; S.-Dorizon, H.; Guibe´, F. Tetrahedron 2002, 58, 7275-
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N.; Otaka, A. Tetrahedron Lett. 2005, 46, 4183-4186.
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(15) For the effective formation of diketopiperazine mimetics, which have
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4970 J. Org. Chem., Vol. 71, No. 13, 2006

(Z)-Alkene-Containing Proline Dipeptide Mimetics
SCHEME 3. Synthetic Strategy for cis-Xaa-Pro Type
(Z)-Alkene Dipeptide Isostere 8
SCHEME 4. Synthesis of
â-Iodo-γ-phosphoryloxy-r,â-unsaturated-δ-lactam 4aa
a Reagents and conditions: (i) DIBAL-H, toluene, CH2Cl2, then
CH2dCHMgCl, ZnCl2, LiCl, THF; (ii) TBSOTf, 2,6-lutidine, CH2Cl2; (iii)
O3, EtOAc, then Me2S; (iv) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH,
H2O; (v) SOCl2, EtOH; (vi) HSCH2CO2H, LiOH‚H2O, DMF; (vii) Pd(OH)2,
H2, EtOH; (viii) 2,4-dimethoxybenzaldehyde, NaBH(OAc)3, 1,2-dichloro-
ethane; (ix) EtOCOCH2COCl, diisopropylethylamine (DIPEA), CH2Cl2; (x)
NaOEt, EtOH; (xi) H2O, MeCN; (xii) Tf2NPh, Et3N, CH2Cl2; (xiii)
(Me3Sn)2, PdCl2[P(o-Tol)3]2, LiCl, THF; (xiv) I2, CH2Cl2; (xv) TBAF, THF;
(xvi) (PhO)2P(O)Cl, pyridine.
us to explore synthetic protocols using organocopper reagents
for (Z)-alkene-containing Pro dipeptide mimetics. Herein, we
report the stereoselective synthesis of the (Z)-alkene mimetic,
which corresponds to a cis-Pro dipeptide, using an organocop-
per-mediated anti-SN2′ reaction.
Scheme 4 shows the preparation of key intermediate 4a (R
) Me, X ) 2,4-dimethoxybenzyl; DMB), which is a prerequisite
for the synthesis of the Ala-Pro type isostere. Activation of the
γ-hydroxy group by formation of a γ-phosporyloxy compound
is critical for the anti-SN2′ alkylation reactions14,17 by organo-
copper reagents. The alkenyl iodide unit on lactam 4a provides
a scaffold for an intramolecular cross-coupling reaction, which
is used to construct the proline cyclic structure.
Reduction of N-2-nitrobenzensulfonyl-N-benzyl-protected L-
alanine derivative 9 (2-nitrobenzensulfonyl ) Ns) with DIBAL-H
in CH2Cl2-toluene at -78 °C, and subsequent addition of vinyl
Grignard reagent-ZnCl2-LiCl in THF at -78 °C exclusively
gave anti-1,2-amino alcohol 10, which was purified by recrys-
tallization from EtOAc-hexane. The resulting amino alcohol
10 was converted to protected allyl alcohol derivative 11 by
O-tert-butyldimethylsilyl protection (tert-butyldimethylsilyl )
TBS).18 The Felkin-Anh model can explain the observed anti-
diastereoselectivity.19 Ozonolysis of the alkene moiety in
compound 11 and subsequent oxidation with a NaClO2-mediated
reaction afforded R-hydroxy-â-amino acid derivative 12 where
Results and Discussion
Scheme 3 depicts the envisioned synthetic outline to prepare
(Z)-alkene-containing amino acid-proline (Xaa-Pro) dipeptide
isosteres. On the basis of our previous synthetic study on
diketopiperazine mimetics,14 we selected â-iodo-γ-phosphoryl-
oxy-R,â-unsaturated lactam 4, which is derived from an amino
acid, as a key synthetic intermediate. The planned transforma-
tions are as follows: (1) organocopper-mediated reaction to
introduce a C3 unit (4 to 5); (2) conversion of the C3 unit to an
alkyl-metal moiety (5 to 6); (3) an intramolecular cross-
coupling reaction between the alkyl-metal and the vinyl iodide
to construct a Pro cyclic structure (6 to 7); and (4) ring-opening
of the resulting bicyclic lactam (7 to 8). The synthetic feasibility
of this envisioned route was evaluated by synthesizing an Ala-
Pro type (Z)-alkene isostere.
(17) (a) Calaza, M. I.; Hupe, E.; Knochel, P. Org. Lett. 2003, 5, 1059-
1061. (b) Soorukram, D.; Knochel, P. Org. Lett. 2004, 6, 2409-2411.
J. Org. Chem, Vol. 71, No. 13, 2006 4971

Sasaki et al.
SCHEME 5. Conversion of Allyl Alcohol 10 to
Oxazolidinones 22 for NOE Analysesa
the O-TBS protection on the hydroxy group was removed under
acidic conditions in this oxidative treatment. Esterification of
resulting carboxlic acid 12 with SOCl2-EtOH yielded ester 13.
Treating 13 with tert-butyldimethylsilyl trifluoromethane-
sulfonate (TBSOTf)-2,6-lutidine in CH2Cl2 gave O-TBS-â-
amino acid derivative 14 in 80% yield from 11. After consecu-
tive removal of the N-Ns20 and N-benzyl groups on 14 with
mercaptoacetic acid-LiOH‚H2O-DMF and hydrogenolysis
with H2/Pd(OH)2, respectively, reductive alkylation of the
resulting amino group with 2,4-dimethoxybenzaldehyde in the
presence of NaBH(OAc)3 afforded secondary amine derivative
15. The secondary amino function of 15 was acylated with ethyl
malonyl chloride to give malonylate 16 in 81% yield. Dieck-
mann condensation of the malonylate 16 with NaOEt-EtOH
proceeded smoothly to give the corresponding cyclized tricar-
bonyl compound, which was then efficiently converted to the
â-keto lactam 17 by a sequence of reactions including hydrolysis
of the ethyl carboxylate and subsequent decarboxylation in
H2O-CH3CN. Then, enol-trapping of â-keto lactam 17 was
achieved by trifluoromethanesulfonylation with N-phenylbis-
(trifluoromethanesulfonimide) (Tf2NPh)21-Et3N in CH2Cl2 to
give alkenyl triflate 18 in 78% yield from 16. Palladium (0)-
catalyzed stannylation of resulting triflate 18 with hexameth-
ylditin afforded alkenyl tin compound 19 in 97% yield.22
Exposing tin compound 19 to iodine in CH2Cl2 converted the
alkenyl tin moiety on 19 to corresponding alkenyl iodide 20,
which is amenable to the intramolecular cross-coupling reactions
to construct the proline cyclic side chain structure. After
deprotection of the γ-O-TBS group on lactam 20 with tetrabu-
tylammonium fluoride (TBAF) in THF, the resulting γ-hydroxy
moiety was activated by (PhO)2P(O)Cl in pyridine to form key
intermediate 4a in 88% yield. This activation is suitable for
organocopper-mediated anti-SN2′ alkylation reactions and allows
the acyclic C3 unit corresponding to the proline moiety to be
incorporated into the lactam.
a Reagents and conditions: (i) HSCH2CO2H, LiOH‚H2O, DMF, then
Boc2O, Et3N, THF; (ii) NaH, THF; (iii) PPh3, diethyl azodicarboxylate,
toluene, THF.
phoryloxy-R,â-unsaturated-δ-lactams, 4a and 4b24 were sub-
jected to reactions with several organocopper reagents as shown
in Table 1. Here, we planned to transform the incorporated C3
unit into the corresponding C3 alkylborane moiety, which could
be used in an intramolecular Suzuki coupling reaction with the
alkenyl iodide. The C3 alkylborane unit could be formed by
incorporating the allyl group and subsequent hydroboration of
the terminal alkene. To introduce the allyl group by organo-
copper-mediated anti-SN2′-alkylation, γ-phosphate 4a was
subjected to the treatment with an allyl copper reagent. However,
the reaction with ClMgCu(CN)allyl‚2LiCl gave a complex
mixture including R-allyl product 23 and reductive product 24
(Table 1, entry 1). Thus, R-allylation with a stepwise transfor-
mation was conducted. Acyclic C3 units such as “CH2CH2CO2-
Me” or “CH2CH2CH2OR” (R ) Ac or TBS) were introduced
by organocopper-mediated reactions. For alkylation with re-
agents that possess an ester function, organozinc-derived copper
reagents were utilized.25,26 Reaction of 4a or 4b with “lower
order” cyanocuprates derived from zinc reagents, IZnCu(CN)-
(CH2)2CO2Me‚2LiCl and IZnCu(CN)(CH2)3OAc‚2LiCl, in THF
at 0 °C failed to complete the anti-SN2′ alkylation reactions
due to the insufficient reactivity of these reagents (entries 2 and
4). On the other hand, applying a “higher order” counterpart,
(IZn)2Cu(CN)[(CH2)2CO2Me]2‚2LiCl or (IZn)2Cu(CN)[(CH2)3-
OAc]2‚2LiCl,27 to the phosphates allowed the reactions to
To determine the relative configurations of the amino alcohol
derivative with use of comparative NOE measurements, alcohol
derivative 10 was converted to oxazolidinones 22 (Scheme 5).
N-Boc amino alcohol 21, which was derived from amino alcohol
10, was converted to oxazolidinone 22a by NaH in THF, while
retaining the relative configuration. On the other hand, treatment
of 21 under Mitsunobu condition afforded 22b with inverted
stereochemistry.23 The comparative NOE measurements of
oxazolidinones 22a and 22b support the anti-relative configu-
ration of alcohol 10 (3R,4S).
To examine the synthetic feasibility of introducing an acyclic
C3 unit, which corresponds to the Pro side chain moiety by
organocopper-mediated anti-SN2′ alkylation of â-iodo-γ-phos-
(18) Amino alcohol 10, which was gradually decomposed at room
temperature, was converted to more stable derivative 11 by O-TBS
protection.
(24) Phosphate 4b, which was easily obtainable by synthetic manipula-
tions similar to those of 4a, was also used as a substrate in Table 1 to
explore the suitable synthetic route to the desired isostere.
(25) (a) Knochel, P.; Singer, R. Chem. ReV. 1993, 93, 2117-2188. (b)
Knochel, P.; Millot, N.; Rodriguez, A. L. Org. React. 2001, 58, 417-731.
(26) For review of organocopper reagents, see: (a) Lipshutz, B. H.;
Wilhelm, R. S.; Kozlowski, J. A. Tetrahedron, 1984, 40, 5005-5038. (b)
Wipf, P. Synthesis 1993, 6, 537-557. (c) Nakamura, E.; Mori, S. Angew.
Chem., Int. Ed. 2000, 39, 3750-3771.
(27) The reactive structure of copper reagents prepared from CuCN and
2 equiv of organometallic reagents (RLi etc.) has been under discussion
(R2Cu(CN)Li2 or R2CuLi‚LiCN). In this paper, the copper reagents derived
from CuCN and 1 or 2 equiv of RZnX are referred to as “lower order” or
“higher order” cyanocuprate (RCu(CN)ZnX or R2Cu(CN)(ZnX)2), respec-
tively, as a matter of convenience. For the discussion about the structure of
the copper reagents, see: (a) Bertz, S. H. J. Am. Chem. Soc. 1990, 112,
4031-4032. (b) Lipshutz, B. H.; Sharma, S.; Ellsworth, E. L. J. Am. Chem.
(19) (a) Che´rest, M.; Felkin, H. Tetrahedron Lett. 1968, 18, 2205-2208.
(b) Anh, N. T. Top. Curr. Chem. 1980, 88, 145-162.
(20) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373. (b) Kurosawa, W.; Kan, T.; Fukuyama, T. Org. Synth. 2002, 79,
186-191.
(21) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 46, 4607-
4610.
(22) (a) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron,
K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J.
Org. Chem. 1986, 51, 277-279. (b) Scott, W. J.; Stille, J. K. J. Am. Chem.
Soc. 1986, 108, 3033-3040.
(23) Hamdach, A.; Hadrami, E. M. E.; Testa, M. L.; Gil, S.; Zaballos-
Garc´ıa, E.; Sepu´lveda-Arques, J.; Arroyo, P.; Domingo, L. R. Tetrahedron
2004, 60, 12067-12073.
4972 J. Org. Chem., Vol. 71, No. 13, 2006

(Z)-Alkene-Containing Proline Dipeptide Mimetics
TABLE 1. r-Alkylation of γ-Phosphoryloxy-r,â-unsaturated Lactam by Organocopper-Mediated anti-SN2′ Reactions
entry
substrate
reagent
conditions
products (isolated yield %)
1
2
3
4
5
6
4a
4b
4b
4a
4a
4a
ClMgCu(CN)allyl‚2LiCl
-78 °C/30 min
23 (9), 24 (12)
25 (79)b
25 (92)
26 (85)
26 (96)
IZnCu(CN)(CH2)2CO2Me‚2LiCla
(IZn)2Cu(CN)[(CH2)2CO2Me]2‚2LiCla
IZnCu(CN)(CH2)3OAc‚2LiCl
(IZn)2Cu(CN)[(CH2)3OAc]2‚2LiCl
LiCu(CN)(CH2)3OTBS‚2LiCl‚LiI
0 °C/2 h
0 °C/2 h
-78 °C/30 min then 0 °C/30 min
-78 °C/30 min then 0 °C/30 min
-78 °C/30 min
27 (93)
a Reagent was added at -78 °C. b Substrate 4b (12%) was recovered.
SCHEME 6. Conversion of r-Alkylated Products 26, 27 to
cis-Ala-Pro Type (Z)-Alkene Dipeptide Isostere 8aa
proceed smoothly and produced the desired anti-SN2′ alkylated
products in excellent yields (entries 3 and 5). Contrary to the
organozinc-derived reagents, an organolithium28-derived “lower
order” cyanocuprate, LiCu(CN)(CH2)3OTBS‚2LiCl‚LiI, ef-
ficiently reacted with 4a even at -78 °C with a high stereose-
lectivity to afford R-alkylated product 27 in good yield (entry
6). Organocopper reagents are known to react with â-iodo-R,â-
unsaturated carbonyl compounds to give the corresponding
â-substituted products.29 On the other hand, in the case of
substrates 4a and 4b (entries 2-6), the anti-SN2′ reactions
preferentially proceeded without accompanying the â-substituted
products.
Next, we attempted to convert the incorporated R-alkyl
moieties in the resulting anti-SN2′ reaction products to alkyl-
borane moieties, which are amenable to an intramolecular
Suzuki coupling reaction, in order to construct the proline cyclic
side chain unit. To this end, the resulting R-alkylated products
were transformed to olefin 23, which was subjected to
9-borabicyclo[3.3.1]nonane (9-BBN-H)-mediated hydroboration
through the sequence of reactions shown in Scheme 6. First,
we planned to convert methyl ester 25 to alcohol 28b by
reduction with NaBH4 in MeOH-THF,30 but the reduction of
25 gave a trace amount of the desired alcohol. Thus, we
examined the conversion of other R-alkylated products to the
alcohol. Therefore, acetate 26 was subjected to acid-catalyzed
alcoholysis mediated by Ti(Oi-Pr)4 in EtOH to give alcohol 28a
in 81% yield. Furthermore, treatment of O-TBS protected
product 27 with H2SiF6 in H2O-MeOH-MeCN afforded
deprotected product 28a in excellent yield.
Treatment of alcohol 28a with 2-nitrophenylselenocyanate
in pyridine at room temperature in the presence of tributylphos-
Soc. 1990, 112, 4032-4034. (c) Krause, N. Angew. Chem., Int. Ed. 1999,
38, 79-81. (d) Nakamura, E.; Yoshikai, N. Bull. Chem. Soc. Jpn. 2004,
77, 1-12. (e) Henze, W.; Vyater, A.; Krause, N.; Gschwind, R. M. J. Am.
Chem. Soc. 2005, 127, 17335-17342.
(28) (a) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404-
5406. (b) Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990,
55, 5406-5409.
(29) (a) Piers, E.; Nagakura, I. J. Org. Chem. 1975, 40, 2694-2696. (b)
Yeh, M. C. P.; Knochel, P.; Butler, W. M.; Berk, S. C. Tetrahedron Lett.
1988, 29, 6693-6696. (c) Otaka, A.; Mitsuyama, E.; Kinoshita, T.;
Tamamura, H.; Fujii, N. J. Org. Chem. 2000, 65, 4888-4899. (d) Dieter,
R. K.; Oba, G.; Chandupatla, K. R.; Topping, C. M.; Lu, K.; Watson, R. T.
J. Org. Chem. 2004, 69, 3076-3086.
a Reagents and conditions: (i) NaBH4, MeOH, THF; (ii) Ti(Oi-Pr)4,
EtOH; (iii) H2SiF6, H2O, CH3CN, MeOH; (iv) 2-nitrophenylselenocyanate,
PBu3, pyridine; (v) H2O2, H2O, THF; (vi) 9-BBN-H, THF; (vii) CsF,
PdCl2(dppf), DMF; (viii) H2O, TFA; (ix) Me3O‚BF4, 2,6-di-tert-butylpy-
ridine, CH2Cl2; (x) HCl, H2O, THF, then Boc2O, Et3N.
(30) Prugh, J. D.; Deana, A. A. Tetrahedron Lett. 1999, 29, 37-40.
J. Org. Chem, Vol. 71, No. 13, 2006 4973

Sasaki et al.
phine formed alkyl selenide 29 in 94% isolated yield.31 This
air-sensitive selenide 29 was immediately converted to the
corresponding selenoxide, which underwent a facile elimination
to form olefin 23 in quantitative yield. The resulting alkene 23
was hydroborated with 9-BBN-H in THF at room temperature
to afford an alkylborane compound, which is a potential
precursor for the intramolecular Suzuki coupling reaction to
construct the proline cyclic side chain moiety. A survey of
suitable conditions for intramolecular Suzuki coupling reac-
tions32 on this substrate revealed that treating the alkylborane
with CsF in the presence of PdCl2(dppf) (dppf ) 1,1′-bis-
(diphenylphosphino)ferrocene) as a catalyst in THF-DMF at
50 °C formed the desired bicyclic lactam 30 in 85% yield from
23. Use of K3PO4 or NaOH as a base, which is common in
Suzuki coupling conditions, was also examined. However, the
reaction with NaOH did not afford the desired lactam because
the strong basicity formed the corresponding isomerized R,â-
unsaturated bicyclic lactam and an R-epimerized product. The
K3PO4 counterpart formed a complex mixture with little of the
desired coupling product. Taken together, the use of CsF33 was
superior to that of K3PO4 or NaOH in this reaction. The
superiority is probably due to the weak basic character of CsF
and the facile formation of the borate complex caused by the
high B-F affinity.
The stereochemistry of the obtained byproduct L,D-8a was
tentatively assigned by comparative NMR measurements of 8a
and L,D-8a.
In conclusion, we have achieved a regio- and stereoselective
synthesis of cis-Ala-Pro type (Z)-alkene dipeptide isostere. In
this synthetic route, a five-membered proline cyclic structure
was successfully constructed by incorporating the C3 unit, which
corresponds to the proline cyclic side chain moiety onto
γ-phosphoryloxy-R,â-unsaturated-δ-lactam with organocopper-
mediated anti-SN2′ reactions and subsequent cyclization with
palladium-catalyzed intramolecular cross-coupling reactions.
This synthetic methodology may be applicable to the syntheses
of other cis-proline type (Z)-alkene dipeptide isosteres. In
addition to our previous synthetic study of trans-proline type
(E)-alkene dipeptide isostere, our result should provide a useful
method to probe the bioactivity-conformation relationships of
proline-containing peptides and proteins.
Experimental Section
(2S)-2-[Benzyl-(2-nitrobenzenesulfonyl)amino]propionic Acid
Methyl Ester (9) from L-Alanine. To methanol (120 mL) at -78
°C was added dropwise thionyl chloride (15.9 mL, 219 mmol), and
the mixture was warmed to room temperature with stirring. To the
mixture was added L-alanine (15.0 g, 168.4 mmol), and the reaction
mixture was refluxed for 2 h. The recooled mixture was concen-
trated under reduced pressure to give oily residues. To a solution
of the residues in 400 mL of CH2Cl2 were successively added nosyl
chloride (39.2 g, 177 mmol) and DIPEA (64.5 mL, 371 mmol) at
0 °C. After additional stirring at room temperature for 2 h, the
reaction mixture was quenched with 1 N HCl and extracted with
EtOAc. The extract was washed with 1 N HCl and brine, dried
over MgSO4, and concentrated in vacuo to give solid materials.
To a solution of the materials in DMF (300 mL) at 0 °C were added
K2CO3 (116 g, 842 mmol) and benzylbromide (21.0 mL, 177 mmol)
with additional stirring at room temperature for 12 h. After removal
of residual salts by centrifuge separation, 1 N HCl and EtOAc were
added to the solution at 0 °C with stirring. The mixture was
extracted with EtOAc, and the extract was washed with 1 N HCl
and brine, dried over MgSO4, and concentrated under reduced
pressure to give solid products. Recrystallization of the products
from EtOAc-n-hexane gave 56.3 g (88.4% yield) of the titled
compound 9 as a colorless crystal: mp 84-85 °C; [R]20D -50.8 (c
1.18, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.47 (d, J ) 7.2 Hz,
3H), 3.61 (s, 3H), 4.41 (d, J ) 16.2 Hz, 1H), 4.79 (d, J ) 16.2 Hz,
1H), 7.17-7.20 (m, 3H), 7.30 (m, 2H), 7.44 (m, 1H), 7.59 (m,
2H), 7.70 (d, J ) 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
171.5, 147.3, 136.2, 133.7, 133.1, 131.3, 130.9, 128.2, 127.5, 123.8,
56.1, 52.3, 49.5, 16.8. Anal. Calcd for C17H18N2O6S: C, 53.96; H,
4.79; N, 7.40. Found: C, 53.87; H, 4.72; N, 7.40.
(3R,4S)-4-[Benzyl-(2-nitrobenzenesulfonyl)amino]pent-1-en-
3-ol (10) from 9. To a solution of dried ZnCl2 (2.17 g, 15.9 mmol)-
LiCl (672 mg, 15.9 mmol) in THF (30 mL) at -78 °C under argon
was added vinylmagnesium chloride in THF (1.55 M, 10.2 mL,
15.9 mmol) with additional stirring for 30 min at 0 °C. To a solution
of 2.00 g (5.29 mmol) of 9 in CH2CH2 (12 mL) was added dropwise
6.28 mL (6.34 mmol) of 1.01 M DIBAL-H in toluene at -78 °C
under argon. After being stirred at -78 °C until disappearance of
the starting material (ca 30 min), the solution of vinyl zinc reagent
prepared above was added at -78 °C under argon with additional
stirring for 2 h at 0 °C. The reaction was quenched with saturated
citric acid solution at -78 °C and was allowed to warm to 0 °C.
The mixture was extracted with EtOAc, and the extract was
successively washed with saturated citric acid solution, water,
saturated NaHCO3, and brine, dried over MgSO4, and concentrated
under reduced pressure to leave residues. Addition of n-hexane to
the residues gave solid materials. Recrystallization of the solid from
Removing the N-dimethoxybenzyl group on bicyclic lactam
30 by TFA-H2O afforded deprotected lactam 31 in 94%
isolated yield. X-ray analysis of the recrystallized material
indicated that lactam 31 represented a precursor of the L-L type
Ala-Pro isostere, which demonstrates that organocopper-medi-
ated introduction of the C3 unit unequivocally proceeds in an
anti-SN2′ manner (X-ray analysis data are shown in the
Supporting Information). Cleavage of the amide bond of 31 was
34
achieved by formation of the lactim ether 32 with Me3O‚BF4
-
2,6-di-tert-butylpyridine35 in CH2Cl2 and subsequent HCl-
mediated acid hydrolysis13 in H2O-THF. The addition of 2,6-
di-tert-butylpyridine was critical to form the lactim ether
smoothly. Without being isolated, the resulting methyl ester was
treated with Boc2O-Et3N to furnish cis-Ala-Pro type (Z)-alkene
isostere 8a. The relative configuration of 8a was established
by X-ray analysis of the crystallized product (X-ray analysis
data are shown in the Supporting Information). In this sequence
of reactions, desired L-L type 8a was obtained in 61% isolated
yield, whereas corresponding epimerized product (L,D-8a) was
co-generated in 21% yield. The observed epimerization likely
occurs during the lactim ether formation step.36 Although we
extensively examined the reaction conditions for the ring-
opening (O-alkylation reagents, reaction temperatures, and
reaction solvents), the conditions have yet to be fully optimized.
(31) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485-1486.
(32) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-321. (b) Miyaura, N.;
Ishikawa, M.; Suzuki, A. Tetrahedron Lett. 1999, 29, 37-40. (c) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (d) Chemler, S. R.;
Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544-
4568.
(33) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem.
1994, 59, 6095-6097.
(34) Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed. Engl.
1981, 20, 798-799.
(35) Flann, C. J.; Overman, L. E. J. Am. Chem. Soc. 1987, 109, 6115-
6118.
(36) Exposure of 8a to the N-Boc protection reaction conditions induced
no epimerization at the 4-position on the isostere.
4974 J. Org. Chem., Vol. 71, No. 13, 2006

(Z)-Alkene-Containing Proline Dipeptide Mimetics
EtOAc-n-hexane gave 1.76 g (88% yield) of the titled compound
28.4 mmol) at 0 °C under argon. After being stirred at room
temperature for 12 h, the reaction mixture was quenched by addition
of saturated NaHCO3 solution at 0 °C. The mixture was extracted
with EtOAc, and the extract was washed with saturated citric acid,
brine, saturated NaHCO3, and brine, dried over MgSO4, and
concentrated under reduced pressure to give solid materials.
Recrystallization of the solid from EtOAc-n-hexane gave 8.29 g
(87.1% yield) of the title compound 14 as a white crystal: mp 127-
128 °C; [R]24D -112 (c 0.994, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 0.01 (s, 3H), 0.07 (s, 3H), 0.92 (s, 9H), 1.29 (d, J ) 6.4 Hz, 3H),
1.30 (t, J ) 7.0 Hz, 3H), 4.15 (q, J ) 7.0 Hz, 2H), 4.32 (d, J ) 4.8
Hz, 1H), 4.49 (m, 1H), 4.70 (s, 2H), 7.14 (m, 3H), 7.23 (m, 2H),
7.36 (m, 1H), 7.56 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3
147.3, 136.8, 134.5 132.9, 131.5, 131.2, 128.2, 128.2, 127.3, 123.8,
75.8, 61.2, 56.9, 48.9, 25.8, 18.2, 14.5, 14.2, -4.9, -5.0. Anal.
Calcd for C26H40N2O7SSi: C, 55.95; H, 6.76; N, 5.22. Found: C,
55.77; H, 6.72; N, 5.17.
10 as a colorless crystal: mp 90-92 °C; [R]24 -19.7 (c 1.27,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.21 (d, J ) 7.2 Hz, 3H),
4.13 (m, 1H), 4.30 (m, 1H), 4.61 (d, J ) 16.0 Hz, 1H), 4.73 (d, J
) 16.0 Hz, 1H), 5.13 (d, J ) 10.4 Hz, 1H), 5.18 (d, J ) 17.2 Hz,
1H), 5.85 (ddd, J ) 17.2, 10.4, 5.6 Hz, 1H), 7.19 (m, 3H), 7.31
(m, 2H), 7.42 (m, 1H), 7.57 (m, 2H), 7.67 (d, J ) 7.6 Hz, 1H); 13
C
NMR (75 MHz, CDCl3) δ 137.9, 137.3 134.4, 133.1, 131.4, 131.3,
128.6, 128.5, 128.2, 127.5, 124.0, 116.2, 75.9, 58.1, 48.7, 12.4.
Anal. Calcd for C18H20N2O5S: C, 57.43; H, 5.36; N, 7.44. Found:
C, 57.19; H, 5.22; N, 7.36.
(3R,4S)-4-[Benzyl-(2-nitrobenzenesulfonyl)amino]-3-(tert-bu-
tyldimethylsilanyloxy)pent-1-en (11) from 10. To a solution of
11.0 g (29.2 mmol) of 10 in CH2Cl2 (50 mL) were added 2,6-
lutidine (8.85 mL, 76.0 mmol) and TBSOTf (8.72 mL, 38.0 mmol)
at 0 °C under argon. After being stirred at room temperature for
12 h, the reaction mixture was quenched by addition of saturated
NaHCO3 solution at 0 °C. The mixture was extracted with EtOAc,
and the extract was washed with saturated citric acid, brine,
saturated NaHCO3, and brine, dried over MgSO4, and concentrated
under reduced pressure to give an oily product. Flash chromato-
graphic purification of the crude material over silica gel with
EtOAc-n-hexane (1:9) gave 14.3 g (100% yield) of the title
compound 11 as a colorless oil: [R]24D 81.6 (c 0.686, CHCl3); 1H
NMR (400 MHz, CDCl3) δ -0.03 (s, 3H), 0.04 (s, 3H), 0.88 (s,
9H), 1.29 (d, J ) 4.8 Hz, 3H), 4.63 (m, 1H), 4.15 (m, 1H), 4.60
(d, J ) 16.0 Hz, 1H), 4.66 (d, J ) 16.0 Hz, 1H), 5.05 (d, J ) 17.6
Hz, 1H), 5.06 (d, J ) 10.4 Hz, 1H), 5.75 (ddd, J ) 17.6, 10.4, 7.0
Hz, 1H), 7.14 (m, 3H), 7.23 (m, 2H), 7.34 (m, 1H), 7.55 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 138.8, 136.9 134.8, 132.7, 131.2,
131.1, 128.4, 128.1, 127.3, 123.7, 116.7, 77.4, 59.4, 48.6, 25.9,
18.1, 14.4, -3.8, -4.7; HRMS (FAB) m/z calcd for C24H35N2O5-
SSi (MH+) 491.2036, found 491.2029.
(2S,3S)-3-[Benzyl-(2-nitrobenzenesulfonyl)amino]-2-hydroxy-
butyric Acid Ethyl Ester (13) from 11. Ozone gas was bubbled
through a stirring solution of 13 (14.5 g, 29.6 mmol) in EtOAc
(200 mL) at -78 °C for 80 min. After removal of residual ozone
by bubbling of N2 gas for 10 min, Me2S (2.18 mL, 296 mmol) was
added to the solution with stirring at -78 °C for 15 min. The
mixture was additionally stirred at 0 °C for 10 min, dried over
MgSO4, and concentrated in vacuo to give the crude aldehyde,
which was subjected to the following reactions without further
purification. To a stirring solution of the above crude material in
t-BuOH (200 mL) and 2-methyl-2-butene (30 mL) were added an
aqueous solution (45 mL) consisting of NaH2PO4‚2H2O (6.93 g,
44.4 mmol) and NaClO2 (80%, 6.70 g, 59.3 mmol) at 0 °C. After
being stirred at room temperature for 15 h, the reaction mixture
was concentrated under reduced pressure to give residues. To the
residues in EtOAc was added 1 N HCl (10 mL). The organic layer
was washed with brine, dried over MgSO4, and concentrated in
vacuo to give the crude carboxylic acid 12. After addition of SOCl2
(2.49 mL, 34.1 mmol) to EtOH at -78 °C followed by warming
the solution to room temperature, the crude 12 was added to the
solution. The solution mixture was refluxed for 1 h and concentrated
under reduced pressure. After flash chromatography over silica gel
(2S,3S)-2-(tert-Butyldimethylsilanyloxy)-3-(2,4-dimethoxyben-
zylamino)butyric Acid Ethyl Ester (15) from 14. To a solution
of 14 (6.64 g, 12.4 mmol) in DMF (90 mL) were added LiOH‚
2H2O (5.19 g, 123 mmol) and mercaptoacetic acid (4.30 mL, 61.8
mmol) at 0 °C with stirring. The reaction mixture was stirred for
4 h followed by quenching with addition of H2O. The mixture was
extracted with EtOAc, and the extract was washed with saturated
NaHCO3 and brine, dried over MgSO4, and concentrated under
reduced pressure to give oily crude. After removal of the residual
thiol reagent from the crude with silica pad filtration, the crude
was used for the following reactions. To a solution of the crude in
EtOH (100 mL) was added a drop of AcOH and 20% palladium
hydroxide on carbon (2.00 g), and the suspension was stirred for 2
h under H2 at room temperature. The mixture was filtrated through
Celite pad and the filtrate was concentrated under reduced pressure
to give an oily material. To a solution of the material in
1,2-dichloroethane (400 mL) were added 2,4-dimethoxybenzylal-
dehyde (2.00 g, 12.0 mmol) and NaBH(OAc)3 (2.70 g, 12.0 mmol)
at room temperature. The reaction mixture was stirred for 10 h,
quenched with saturated NaHCO3, and extracted with EtOAc. The
extract was washed with saturated NaHCO3 and brine, dried with
MgSO4, and concentrated in vacuo to give oily residues. Purification
of the residues with silica gel chromatography gave 4.43 g (87.0%
yield) of the title compound 15 as a colorless oil: [R]24D -4.25 (c
1
0.638, CHCl3); H NMR (400 MHz, CDCl3) δ 0.05 (s, 3H), 0.09
(s, 3H), 0.91 (s, 9H), 1.06 (d, J ) 6.4 Hz, 3H), 1.28 (t, J ) 7.6 Hz,
3H), 1.99 (br, 1H), 3.02 (m, 1H), 3.73 (s, 2H), 3.80 (s, 6H), 4.18
(m, 2H), 4.31 (d, J ) 4.0 Hz, 1H), 6.44 (m, 2H), 7.18 (d, J ) 8.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.9 159.7, 158.3, 129.8,
121.1, 103.6, 98.4, 74.3, 60.6, 55.9, 55.4, 55.2, 45.7, 25.8, 18.3,
15.8, 14.3, -4.8, -5.2; HRMS (FAB) m/z calcd for C21H38NO5Si
(MH+) 412.2519, found 412.2515.
(2S,3S)-2-(tert-Butyldimethylsilanyloxy)-3-[(2,4-dimethoxy-
benzyl)ethoxycarbonylacetylamino]butyric Acid Ethyl Ester (16)
from 15. To a solution of 15 (545 mg, 1.32 mmol) in CH2Cl2 (15
mL) were added ethyl malonyl chloride (217 µL, 1.66 mmol) and
DIPEA (300 µL, 1.72 mmol) at 0 °C under argon. After being
stirred at room temperature for 10 h, the reaction mixture was
quenched by addition of 1 N HCl at 0 °C. The mixture was extracted
with EtOAc, and the extract was washed with 1 N HCl, brine,
saturated NaHCO3, and brine, dried over MgSO4, and concentrated
under reduced pressure to give the residues. Chromatograhy of the
oil over silica gel EtOAc-n-hexane (1:4) gave 561 mg (80.1%
yield) of the title compound 16 as a colorless oil: [R]24D -10.5 (c
with EtOAc-n-hexane (1:4), the title compound 13 (87.9% yield)
1
as a colorless oil was obtained: [R]24 37.9 (c 0.870, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 1.18 (d, J ) 7.2 Hz, 3H), 1.34 (t, J )
7.2 Hz, 3H), 2,99 (br, 1H), 4.28 (q, J ) 7.2 Hz, 2H), 4.41 (d, J )
2.8 Hz, 1H), 4.62 (m, 1H), 4.73 (d, J ) 16.0 Hz, 1H), 4.82 (d, J
) 16.0 Hz, 1H), 7.15 (m, 3H), 7.28 (m, 2H), 7.36 (m, 1H), 7.57
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 172.7, 137.2, 134.3 133.0,
131.3, 131.2, 128.1, 127.2, 123.9, 74.5, 62.6, 55.8, 48.8, 14.1, 13.3;
HRMS (FAB) m/z calcd for C19H23N2O7S (MH+) 423.1226, found
423.1224.
1
0.300, CHCl3); H NMR (400 MHz, CDCl3) δ 0.06 (s, 6H), 0.95
(s, 9H), 1.07 (d, J ) 7.2 Hz, 3H), 1.23-1.33 (m, 6H), 3.33 (d, J
) 15.2 Hz, 1H), 3.41 (d, J ) 15.2 Hz, 1H), 3.80 (s, 6), 4.11-4.27
(m, 4H), 4.31 (d, J ) 18 Hz, 1H), 4.64 (d, J ) 18 Hz, 1H), 4.65
(m, 1H), 6.45 (m, 2H), 7.02 (d, J ) 8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 171.8, 167.6, 167.5, 160.1, 157.3, 127.3, 117.8,
103.6, 98.4, 73.7, 61.2, 60.9, 55.4, 55.1, 41.8, 25.7, 25.7, 18.1, 14.3,
(2S,3S)-3-[Benzyl-(2-nitrobenzenesulfonyl)amino]-2-(tert-bu-
tyldimethylsilanyloxy)butyric Acid Ethyl Ester (14) from 13.
To a solution of 13 (7.50 g, 17.8 mmol) in CH2Cl2 (50 mL) were
added 2,6-lutidine (3.31 mL, 28.4 mmol) and TBSOTf (6.52 mL,
J. Org. Chem, Vol. 71, No. 13, 2006 4975

Sasaki et al.
14.2, 14.1, -5.0, -5.2; HRMS (FAB) m/z calcd for C26H44NO8Si
(MH+) 526.2836, found 526.2844.
MHz, CDCl3) δ 160.1, 159.8, 158.3, 136.5, 130.8, 117.1, 111.1,
104.5, 98.3, 77.9, 57.9, 55.4, 41.1, 25.6, 18.0 16.9, -4.4, -4.6;
HRMS (ESI-TOF) m/z calcd for C21H33INO4Si (MH+) 518.1224,
found 518.1225.
(5S,6S)-5-(tert-Butyldimethylsilanyloxy)-1-(2,4-dimethoxyben-
zyl)-6-methyl-4-trifluoromethanesulfonyloxy-5,6-dihydro-1H-
pyridin-2-one (18) from 16. To a solution of 16 (560 mg, 1.07
mmol) in EtOH (2 mL) was added 6 mL (1.28 mmol) of freshly
prepared NaOEt in EtOH (0.213 M) at 0 °C under argon, and the
mixture was stirred for 30 min. After additional stirring at room
temperature for 2 h, the reaction mixture was quenched with 1 N
HCl at 0 °C. The mixture was washed with brine, dried over
MgSO4, and concentrated in vacuo to give an oil material, which
was used for following reactions without further purification. A
mixture of the oil in 150 µL of H2O and 30 mL of CH3CN was
refluxed for 2 h and concentrated under reduced pressure to give
solid crude materials. To a solution of the crude materials in CH2-
Cl2 (10 mL) were added N-phenylbis(trifluoromethanesulfonimide)
(571 mg, 1.60 mmol) and Et3N (443 µL, 3.20 mmol) at 0 °C, and
the mixture was stirred at room temperature for 12 h. The reaction
mixture was quenched by the addition of 0.1 N HCl and extracted
with Et2O. The mixture was washed with 0.1 N HCl, brine, saturated
NaHCO3, and brine, dried over MgSO4, and concentrated under
reduced pressure to give crude materials. Chromatographic purifica-
tion of the crude materials over silica gel with EtOAc-n-hexane
(1:9) gave the title compound 18 (448 mg, 78.0% yield) as a white
crystal: mp 136-138 °C; [R]24D -103 (c 0.640, CHCl3); 1H NMR
(400 MHz, CDCl3) δ -0.06 (s, 3H), 0.06 (s, 3H), 0.75 (s, 9H),
1.20 (d, J ) 6.8 Hz, 3H), 3.54 (q, J ) 6.8 Hz, 1H), 3.78 (s, 3H),
3.80 (s, 3H), 4.04 (s, 1H), 4.11 (d, J ) 15.0 Hz, 1H), 5.10 (d, J )
15.0 Hz, 1H), 6.13 (s, 1H), 6.40-6.43 (m, 2H), 7.22 (d, J ) 8.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.2, 160.1, 158.2, 156.4,
130.4, 129.1, 116.5, 115.6, 104.4, 98.2, 70.1, 57.9, 55.2, 41.1, 25.3,
17.7, 16.5, -5.2, -5.3. Anal. Calcd for C22H32F3NO7SSi: C, 48.97;
H, 5.98; N, 2.60. Found: C, 48.67; H, 5.78; N, 2.62.
(5S,6S)1-(2,4-Dimethoxybenzyl)-5-diphenylphosphoryloxy-4-
iodo-6-methyl-5,6-dihydro-1H-pyridin-2-one (4a) from 20. To
a solution of 20 (64.0 mg, 0.115 mmol) in THF (0.5 mL) was added
1 M TBAF in THF (121 µL, 0.121 mmol) at 0 °C. After being
stirred at 0 °C for 1 h, the reaction mixture was quenched with 1
N HCl followed by extraction with EtOAc. The extract was washed
with brine, dried over MgSO4, and concentrated under reduced
pressure to give crude materials, which were used in the following
reaction without further purification. To a solution of the above
materials in pyridine (2 mL) was added diphenylphosphoryl chloride
(47.9 mg, 0.231 mmol) at 0 °C under argon with additional stirring
at room temperature for 12 h. The reaction mixture was quenched
with 1 N HCl and extracted with EtOAc. The extract was washed
with 1 N HCl and brine, dried over MgSO4, and concentrated under
reduced pressure to give oily residues. After chromatographic
purification of the residues over silica gel with EtOAc-n-hexane
(1:9), the title compound 4a (64.8 mg, 88.3% yield) was obtained
1
as a colorless oil: [R]24 -204 (c 0.333, CHCl3); H NMR (400
D
MHz, CDCl3) δ 1.19 (d, J ) 6.8 Hz, 3H), 3.66 (s, 3H), 3.75 (s,
3H), 3.83 (qd, J ) 6.8, 1.6 Hz, 1H), 4.25 (d, J ) 14.8 Hz, 1H),
4.74 (d, J ) 14.8 Hz, 1H), 4.98 (dd, J ) 8.4, 1.6 Hz, 1H), 6.31
(dd, J ) 8.4, 2.4 Hz, 1H), 6.35 (d, J ) 2.4 Hz, 1H), 6.93 (s, 1H),
6.99 (d, J ) 8.4 Hz, 1H), 7.00 (m, 1H), 7.14-7.35 (m, 10H); 13C
NMR (100 MHz, CDCl3) δ 160.3, 159.3, 158.3, 150.2 (d, J ) 7.1
Hz), 150.0 (d, J ) 7.5 Hz), 130.9, 129.7 (d, J ) 5.7 Hz), 125.4 (d,
J ) 7.4 Hz), 125.4, 120.1 (d, J ) 5.0 Hz), 119.9 (d, J ) 4.9 Hz),
116.5, 104.2, 102.7, 100.5, 98.2, 82.3 (d, J ) 5.0 Hz), 60.3, 56.4
(d, J ) 2.5 Hz), 55.3, 55.2, 42.2, 21.1, 17.0, 14.2; HRMS (FAB)
m/z calcd for C27H28INO7P (MH+) 636.0648, found 636.0656.
(5S,6S)1-Benzyl-5-diphenylphosphoryloxy-4-iodo-6-methyl-
5,6-dihydro-1H-pyridin-2-one (4b). By use of synthetic manipula-
tions similar to those described for the preparation of 4a from 14,
4b was obtained from 14 as a colorless oil: [R]20D -75.1 (c 1.13,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.13 (d, J ) 6.8 Hz, 3H),
3.64 (qd, J ) 6.8, 1.2 Hz, 1H), 4.15 (d, J ) 15.2 Hz, 1H), 4.79 (d,
J ) 15.2 Hz, 1H), 4.98 (dd, J ) 8.4, 1.2 Hz, 1H), 6.96 (d, J ) 8.4
Hz, 2H), 6.97 (s, 1H), 7.15-7.35 (m, 13H); 13C NMR (100 MHz,
CDCl3) δ 159.2, 150.1 (d, J ) 7.4 Hz), 149.7 (d, J ) 6.6 Hz),
139.3, 136.0, 129.6, 128.4, 127.9, 127.5, 125.4 (d, J ) 7.4 Hz),
120.0 (d, J ) 5.0 Hz), 119.8 (d, J ) 4.2 Hz), 103.2 (d, J ) 6.6
Hz), 81.9 (d, J ) 5.0 Hz), 56.5 (d, J ) 3.3 Hz), 48.0, 16.9; HRMS
(ESI-TOF) m/z calcd for C25H24INO5P (MH+) 576.0437, found
576.0439.
(5S,6S)-5-(tert-Butyldimethylsilanyloxy)-1-(2,4-dimethoxyben-
zyl)-6-methyl-4-(trimethylstannanyl)-5,6-dihydro-1H-pyridin-2-
one (19) from 18. To a suspension of dried LiCl (141 mg, 3.32
mmol) and PdCl2[P(o-Tol)3]2 (65.3 mg, 0.0830 mmol) in THF (20
mL) was added a solution of 18 (448 mg, 0.830 mmol) in THF (5
mL) at 0 °C under argon, and the mixture was stirred at 50 °C for
20 min. The reaction mixture was quenched and extracted with
saturated NaHCO3 at 0 °C and extracted with Et2O. The extract
was washed with saturated NaHCO3 and brine, dried over MgSO4,
and concentrated under reduced pressure to leave solid residues.
After chromatographic purification of the residues over silica gel
with EtOAc-n-hexane (1:9), the title compound 19 (450 mg, 97.8%
yield) was obtained as a white crystal: mp 143-145 °C; [R]24
D
-95.2 (c 0.039, CHCl3); 1H NMR (400 MHz, CDCl3) δ -0.16 (s,
3H), 0.24 (s, 3H), 0.75 (s, 9H), 1.07 (d, J ) 6.8 Hz, 3H), 3.50 (m,
1H), 3.78 (s, 3H), 3.80 (s, 3H), 4.03 (s, 1H), 4.24 (d, J ) 14.8 Hz,
1H), 4.94 (d, J ) 14.8 Hz, 1H), 6.27 (s, 1H), 6.42 (m, 2H), 7.30
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 160.6, 160.0, 158.3, 154.2,
135.7, 130.8, 117.8, 104.4, 98.1, 70.8, 57.5, 55.3, 55.2, 41.4, 25.6,
17.6, 16.7, -4.2, -4.9, -9.5. Anal. Calcd for C24H41NO4SiSn: C,
52.00; H, 7.45; N, 2.53. Found: C, 51.70; H, 7.44; N, 2.51.
(5S,6S)-5-(tert-Butyldimethylsilanyloxy)-1-(2,4-dimethoxyben-
zyl)-4-iodo-6-methyl-5,6-dihydro-1H-pyridin-2-one (20) from 19.
To a solution of 19 (198 mg, 0.357 mmol) in CH2Cl2 (6 mL) was
added iodine (136 mg, 0.536 mmol) at 0 °C under argon, and the
reaction mixture was stirred at room temperature for 12 h. The
reaction mixture was quenched with a few drops of 28% NH4OH
and extracted with Et2O. The extract was washed with brine, dried
over MgSO4, and concentrated in vacuo to give solid residues.
Chromatography of the residues over silica gel with EtOAc-n-
hexane (1:9) gave the title compound 21 (154 mg, 83.4%) as an
amorphous powder: [R]24D -115 (c 0.686, CHCl3); 1H NMR (400
MHz, CDCl3) δ -0.11 (s, 3H), 0.13 (s, 3H), 0.77 (s, 9H), 1.18 (d,
J ) 6.8 Hz, 3H), 3.44 (m, 1H), 3.78 (s, 3H), 3.79 (s, 3H), 4.07 (s,
1H), 4.11 (d, J ) 15.0 Hz, 1H), 5.01 (d, J ) 15.0 Hz, 1H), 6.41
(m, 2H), 6.75 (s, 1H), 7.24 (d, J ) 8.8 Hz, 1H); 13C NMR (100
(3R,4S)-4-[Benzyl(tert-butoxycarbonyl)amino]pent-1-en-3-
ol (21) from 10. To a solution of 10 (3.48 g, 9.25 mmol) in DMF
(20 mL) were added mercaptacetic acid (1.29 mL, 18.5 mmol) and
LiOH‚H2O (1.55 g, 37.0 mmol) at 0 °C, with additional stirring at
room temperature for 14 h. The reaction mixture was quenched
with saturated NaHCO3 at 0 °C, followed by extraction with EtOAc.
The extract was washed with saturated NaHCO3 and brine, dried
over MgSO4, and concentrated under reduced pressure to give oily
crude. To a solution of the crude in THF (30 mL) were added Boc2O
(2.42 g, 11.1 mmol) and Et3N (1.55 mL, 11.1 mmol) at 0 °C. The
reaction mixture was stirred at room temperature for 14 h, quenched
with saturated citric acid, and extracted with EtOAc. The extract
was washed with saturated citric acid, saturated NaHCO3, and brine,
dried over MgSO4, and concentrated in vacuo to give residues. The
residues were purified by column chromatography over silica gel
with EtOAc-n-hexane (1:9) to give the title compound 21 (1.98
g, 73.6% yield) as a colorless oil: [R]24 4.22 (c 0.946, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 1.18 (d, J ) 7.2 Hz, 3H), 1.43 (br,
9H), 3.46 (d, J ) 7.2 Hz, 1H), 3.50 (d, J ) 7.2 Hz, 1H), 3.61 (br,
1H), 4.20-4.53 (m, 4H), 5.10 (d, J ) 10.0 Hz, 1H), 5.20 (dt, J )
17.0, 1.6 Hz, 1H), 5.76 (ddd, J ) 17.0, 10.0, 5.8 Hz, 1H), 7.20-
7.35 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 156.6, 139.0, 138.5,
4976 J. Org. Chem., Vol. 71, No. 13, 2006

(Z)-Alkene-Containing Proline Dipeptide Mimetics
128.3, 126.9, 115.5, 80.4, 75.9, 58.8, 51.3, 28.3, 11.7; HRMS (FAB)
44.4, 40.6, 20.3; HRMS (ESI-TOF) m/z calcd for C15H19INO3
(MH+) 388.0410, found 388.0405.
m/z calcd for C17H26NO3 (MH+) 292.1913, found 292.1914.
(3S,6S)-3-(1-Benzyl-4-iodo-6-methyl-2-oxo-1,2,3,6-tetrahydro-
pyridin-3-yl)propionic Acid Methyl Ester (25) from 4b. To a
suspension of activated zinc dust25 (341 mg, 5.21 mmol) in THF
(2 mL) was added 3-iodopropionic acid methyl ester (781 mg, 3.65
mmol) in THF (3 mL) at room temperature with additional stirring
for 2 h. After further addition of THF (5 mL) to a solution of the
zinc reagent, 2 mL of the reagent solution in THF was added to a
solution of anhydrous Lick (58.8 mg, 1.39 mmol) and CuCN (62.3
mg, 0.695 mmol) in THF (4 mL) at -78 °C under argon, and the
mixture was allowed to warm to 0 °C and was stirred at this
temperature for 10 min. To recooled solution of organocopper
reagent to -78 °C was added 4b (200 mg, 0.348 mmol) in THF (4
mL) at this temperature. The reaction mixture was stirred at 0 °C
for 2 h, quenched with saturated NH4Cl and 28% NH4OH solution
at 0 °C, followed by additional stirring at this temperature. The
mixture was extracted with Et2O, and the extract was washed with
saturated NH4Cl and brine, dried over MgSO4, and concentrated
under reduced pressure to give residues. Column chromatography
purification of the residues over silica gel with EtOAc-n-hexane
(4S,5R)-3-Benzyl-4-methyl-5-vinyloxazolidin-2-one (22a) from
21. To a solution of 21 (200 mg, 0.686 mmol) in THF (10 mL)
was added 55% NaH (110 mg, 2.75 mmol) at -78 °C under argon.
The reaction mixture was stirred at room temperature for 5 h,
quenched with 1 N HCl at 0 °C, and extracted with EtOAc. The
extract was washed with brine to give oily materials. After
purification of the materials by chromatography over silica gel with
EtOAc-n-hexane (1:9), the title compound 22a (130 mg, 87.2%
yield) was obtained as a colorless oil: [R]24 -5.90 (c 0.870,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.07 (d, J ) 6.8 Hz, 3H),
3.73 (td, J ) 6.8, 6.8 Hz, 1H), 4.04 (d, J ) 15.2 Hz, 1H), 4.83 (d,
J ) 15.2 Hz, 1H), 4.88 (t, J ) 6.8 Hz, 1H), 5.37 (d, J ) 10.6 Hz,
1H), 5.44 (d, J ) 17.4 Hz, 1H), 5.83 (ddd, J ) 17.4, 10.6, 6.8 Hz,
1H), 7.28-7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 157.3,
135.6, 130.8, 128.4, 127.6, 127.5, 119.6, 77.7, 52.9, 45.4, 13.5;
HRMS (FAB) m/z calcd for C13H16NO2 (MH+) 218.1181, found
218.1177.
(4S,5S)-3-Benzyl-4-methyl-5-vinyloxazolidin-2-one (22b) from
21. To a solution of 117 mg (0.446 mmol) of Ph3P in THF (1 mL)
were successively added a solution of 21 in THF (1 mL) and 40%
azodicarboxylic acid diethyl ester solution in toluene (203 µL, 0.446
mmol) at 0 °C under argon. After being stirred at room temperature
for 1 h, the reaction solvent was evaporated under reduced pressure
to give oily residues. Purification of the residues by chromatography
over silica gel with EtOAc-n-hexane (1:9) gave the title compound
(1:4) gave the title compound 25 (113 mg, 78.4% yield) as a
1
colorless oil: [R]20 -85.5 (c 1.30, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 1.28 (d, J ) 6.4 Hz, 3H), 2.02 (m, 1H), 2.43 (m, 2H),
2.52 (m, 1H), 3.28 (m, 1H), 3.69 (s, 3H), 3.80 (m, 1H), 3.98 (d, J
) 14.8 Hz, 1H), 5.38 (d, J ) 14.8 Hz, 1H), 6.32 (d, J ) 4.4 Hz,
1H), 7.21-7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 173.0,
166.7, 137.8, 136.3, 128.6, 127.9, 127.5, 94.9, 86.5, 54.5, 51.7,
51.4, 46.6, 20.7; HRMS (ESI-TOF) m/z calcd for C17H21INNaO3
(Man+) 436.0386, found 436.0381.
22b (53.0 mg, 71.1% yield) as a colorless oil: [R]24 -50.6 (c
D
1
0.209, CHCl3); H NMR (400 MHz, CDCl3) δ 1.21 (d, J ) 6.1
Hz, 3H), 3.32 (qd, J ) 7.3, 6.1 Hz, 1H), 4.12 (d, J ) 15.2 Hz,
1H), 4.38 (t, 7.3 Hz, 1H), 4.76 (d, J ) 15.2 Hz, 1H), 5.29 (d, J )
10.4 Hz, 1H), 5.40 (d, J ) 17.0 Hz, 1H), 5.79 (ddd, J ) 17.0,
10.4, 7.0 Hz, 1H), 7.26-7.36 (m, 5 H); 13C NMR (100 MHz,
CDCl3) δ 157.7, 135.8, 133.5, 128.7, 128.0, 127.8, 119.5, 81.8,
55.8, 45.8, 16.9; HRMS (FAB) m/z calcd for C13H16NO2 (MH+)
218.1181, found 218.1186.
“Higher-Order” Cyanocuprate Complex (Table 1, entry 3)
(25) from 4b. To a solution of anhydrous LiCl (58.8 mg, 1.39
mmol) and CuCN (62.3 mg, 0.695 mmol) in THF (4 mL) was added
4 mL of the zinc reagent prepared in the above Experimental Section
at -78 °C under argon, and the mixture was allowed to warm to
0 °C and was stirred at this temperature for 10 min. A procedure
identical with those described above gave the tile compound 25
(132 mg, 91.6% yield).
(3S,6S)-3-Allyl-1-(2,4-dimethoxybenzyl)-4-iodo-6-methyl-3,6-
dihydro-1H-pyridin-2-one (23) from 4. To a solution of anhydrous
LiCl (13.3 mg, 0.315 mmol) and CuCN (14.1 mg, 0.157 mmol) in
THF (200 µL) was added 78.4 µL (0.157 mmol) of 2.0 M
allylmagnesium chloride in THF at -78 °C under argon with
stirring for 10 min. The mixture was allowed to warm to 0 °C and
then stirred for 5 min at this temperature. To recooled solution of
organocopper reagent to -78 °C was added a solution of 4a (50
mg, 0.0786 mmol) in THF (1 mL). After being stirred at -78 °C
for 30 min, the reaction mixture was quenched at 0 °C by addition
of saturated NH4Cl and 28% NH4OH solution with additional
stirring at room temperature. The mixture was extracted with Et2O,
and the extract was washed with saturated NH4Cl and brine, dried
over MgSO4, and concentrated under reduced pressure to give a
crude mixture of 23 and 24. Column chromatography purification
of the crude materials over silica gel with EtOAc-n-hexane (1:9)
Acetic Acid {3-[(3S,6S)-1-(2,4-Dimethoxybenzyl)-4-iodo-6-
methyl-2-oxo-1,2,3,6-tetrahydropyridin-3-yl]propyl} Ester (26)
from 4a. To a suspension of activated zinc dust25 (154 mg, 2.36
mmol) in THF (1 mL) was added acetic acid 3-iodopropyl ester
(337 mg, 1.57 mmol) in THF (2 mL) at room temperature with
stirring for 2 h. After further addition of THF (2 mL) to the solution
of zinc reagent, 0.5 mL of the reagent solution in THF was added
to a solution of anhydrous LiCl (13.3 mg, 0.315 mmol) and CuCN
(14.1 mg, 0.157 mmol) in THF (0.2 mL) at -78 °C under argon,
and the mixture was allowed to warm to 0 °C and was stirred at
this temperature for 5 min. To recooled solution of organocopper
reagent to -78 °C was added 4a (50 mg, 0.0786 mmol) in THF (1
mL) at this temperature. The reaction mixture was stirred at -78
°C for 30 min and at 0 °C for 30 min, quenched with saturated
NH4Cl and 28% NH4OH solution at this temperature, followed by
additional stirring at this temperature. The mixture was extracted
with Et2O, and the extract was washed with saturated NH4Cl and
brine, dried over MgSO4, and concentrated under reduced pressure
to give oily materials. Column chromatographic purification of the
materials over silica gel with EtOAc-n-hexane (1:4) gave the title
gave 23 (4.0 mg, 9.5% yield) and 24 (3.7 mg, 12.2% yield) as
1
colorless oily materials. 23: [R]24 -63.1 (c 0.224, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 1.26 (d, J ) 6.4 Hz, 3H), 2.62 (m,
1H), 2.83 (m, 1H), 3.31 (m, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 3.84
(m, 1H), 4.19 (d, J ) 15.0 Hz, 1H), 5.08 (d, J ) 15.0 Hz, 1H),
5.12 (d, J ) 11.0 Hz, 1H), 5.20 (d, J ) 16.8 Hz, 1H), 5.70 (m,
1H), 6.31 (d, J ) 4.4 Hz, 1H), 6.44 (m, 2H), 7.19 (d, J ) 9.2 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 166.3, 159.9, 158.1, 137.7,
133.1, 130.3, 118.1, 117.1, 104.1, 98.1, 94.8, 55.2, 55.2, 54.8, 51.7,
40.5, 36.3, 21.1; HRMS (FAB) m/z calcd for C18H23INO3 (MH+)
compound 26 (32.4 mg, 84.6% yield) as a colorless oil: [R]24
D
-91.1 (c 1.580, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.29 (d, J
) 5.6 Hz, 3H), 1.61 (m, 1H), 1.72 (m, 1H), 1.82 (m, 1H), 2.07 (s,
3H), 2.14 (m, 1H), 3.25 (m, 1H), 3.79 (d, J ) 1.2 Mz, 3H), 3.80
(d, J ) 1.2 Mz, 3H), 3.88 (m, 1H), 4.12 (m, 1H), 4.17 (d, J ) 14.8
Hz, 1H), 5.12 (d, J ) 14.8 Hz, 1H), 6.32 (d, J ) 4.4 Hz, 1H),
6.43-6.46 (m, 2H), 7.18 (d, J ) 7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 171.0, 166.8, 160.2, 158.4, 138.0, 130.6, 117.1, 104.4,
98.3, 95.5, 64.0, 55.4, 55.4, 54.8, 51.4, 40.6, 29.2, 25.0, 21.1, 21.0;
HRMS (ESI-TOF) m/z calcd for C20H27INO5 (MH+) 488.0934,
found 488.0950.
428.0723, found 428.0727. 24: [R]20 -98.3 (c 0.204, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 1.27 (d, J ) 6.8 Hz, 3H), 3.43 (m,
2H), 3.79 (s, 3H), 3.80 (s, 3H), 3.89 (m, 1H), 4.15 (d, J ) 15.2
Hz, 1H), 5.15 (d, J ) 15.2 Hz, 1H), 6.28 (m, 1H), 6.44 (m, 2H),
7.14 (d, J ) 9.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 165.6,
160.3, 158.5, 137.1, 130.4, 117.1, 104.3, 98.4, 86.5, 55.4, 54.9,
J. Org. Chem, Vol. 71, No. 13, 2006 4977

Sasaki et al.
“Higher-Order” Cyanocuprate Complex (Table 1, entry 5)
(26) from 4a. To a suspension of activated zinc dust25 (1.02 g,
15.6 mmol) in THF (6 mL) was added acetic acid 3-iodopropyl
ester (2.22 g, 10.4 mmol) in THF (5 mL) at room temperature with
stirring for 2 h. After further addition of THF (10 mL) to the
solution of zinc reagent, 14 mL of the reagent solution in THF
was added to a solution of anhydrous LiCl (310 mg, 3.46 mmol)
and CuCN (293 mg, 6.92 mmol) in THF (5 mL) at -78 °C under
argon, and the mixture was allowed to warm to 0 °C and was stirred
at this temperature for 10 min. To recooled solution of organocopper
reagent to -78 °C was added 4 (1.10 g, 1.73 mmol) in THF (5
mL) at this temperature. The reaction mixture was stirred at -78
°C for 30 min and at 0 °C for 30 min, quenched with saturated
NH4Cl and 28% NH4OH solution at this temperature, followed by
additional stirring at this temperature. The mixture was extracted
with Et2O, and the extract was washed with saturated NH4Cl and
brine, dried over MgSO4, and concentrated under reduced pressure
to give oily materials. Column chromatography purification of the
materials over silica gel with EtOAc-n-hexane (1:4) gave the title
compound 26 (806 mg, 95.5% yield) as a colorless oil.
(3S,6S)-3-[3-(tert-Butyldimethylsilanyloxy)propyl]-1-(2,4-di-
methoxybenzyl)-4-iodo-6-methyl-3,6-dihydro-1H-pyridin-2-
one (27) from 4a. To a solution of tert-butyl-(3-iodopropoxy)-
dimethylsilane (142 mg, 0.472 mmol) in Et2O (1.5 mL) was added
621 µL (0.968 mmol) of 1.56 M tert-butyllithium in pentane at
-78 °C under argon, with additional stirring for 30 min. In another
flask CuCN (42.3 mg, 0.472 mmol) and anhydrous LiCl (40.0 mg,
0.944 mmol) were suspended in THF (3.5 mL) under argon. To
the above solution of lithium reagent was added the recooled
suspension of CuCN‚2LiCl in THF to -78 °C at this temperature
through cannular, followed by stirring at -78 °C for 45 min. To a
cool solution of 4a (150 mg, 0.235 mmol) in THF (10 mL) at -78
°C was added the organocopper reagent solution prepared above
at -78 °C through cannular. After being stirred at this temperature
for 30 min and at 0 °C for 15 min, the reaction mixture was
quenched with saturated NH4Cl and 28% NH4OH solution at 0 °C
followed by additional stirring at this temperature. The mixture was
extracted with Et2O, and the extract was washed with saturated
NH4Cl and brine, dried over MgSO4, and concentrated under
reduced pressure to give oily materials. Column chromatography
purification of the materials over silica gel with EtOAc-n-hexane
(1:9) gave the title compound 27 (123 mg, 93.1% yield) as a
colorless oil: [R]24D -59.0 (c 0.130, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 0.06 (s, 6H), 0.90 (s, 9H), 1.28 (d, J ) 6.4 Hz, 3H), 1.45
(m, 1H), 1.62 (m, 1H), 1.81 (m, 1H), 2.08 (m, 1H), 3.24 (m, 1H),
3.65 (m, 2H), 3.79 (s, 3H), 3.80 (s, 3H), 3.85 (m, 1H), 4.18 (d, J
) 15.2 Hz, 1H), 5.10 (d, J ) 15.2 Hz, 1H), 6.29 (d, J ) 4.4 Hz,
1H), 6.43-6.46 (m, 2H), 7.18 (d, J ) 8.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 167.1, 160.1, 158.3, 137.5, 130.5, 117.2, 104.2,
98.2, 96.0, 62.7, 55.3, 54.8, 51.7, 40.5, 29.1, 29.0, 26.0, 20.8, 18.3,
-5.2; HRMS (FAB) m/z calcd for C24H38INO4Si (MH+) 560.1693,
found 560.1696.
CDCl3) δ 167.4, 160.1, 158.2, 137.5, 130.4, 116.8, 104.3, 98.2,
95.7, 62.1, 55.3, 55.3, 54.7, 51.3, 40.6, 29.6, 28.9, 20.8; HRMS
(FAB) m/z calcd for C18H25INO4 (MH+) 446.0828, found 446.0821.
28a from 27. To a solution of 27 (452 mg, 0.808 mmol) in CH3-
CN (15 mL) was added 300 µL of 40% hexafluorosilicic acid at
room temperature with additional stirring at this temperature for
40 min. The reaction mixture was quenched with saturated NaHCO3
and extracted with EtOAc. The extract was washed with saturated
NaHCO3 and brine, dried over MgSO4, and concentrated under
reduced pressure to give oily materials. The materials were purified
by column chromatography over silica gel with EtOAc-n-hexane
(1:1) to give the title compound 28a (355 mg, 98.6% yield).
(3S,6S)-1-(2,4-Dimethoxybenzyl)-4-iodo-6-methyl-3-[3-(2-ni-
trophenylselanyl)propyl]-3,6-dihydro-1H-pyridin-2-one (29) from
28a. To a solution of 2-nitorphenylselenocyanate (202 mg, 0.862
mmol) in pyridine were successively added 28a (192 mg, 0.432
mmol) and tributylphosphine (214 µL, 0.862 mmol) at room
temperature under argon. After being stirred at this temperature
for 1.5 h, the reaction mixture was quenched by addition of 1 N
HCl at 0 °C and extracted with EtOAc. The extract was washed
with 1 N HCl and brine, dried over MgSO4, and concentrated under
reduced pressure to give oily products. Column chromatographic
purification of the residues over silica gel with EtOAc-n-hexane
(1:4) gave 29 (416 mg, 83.1% yield) as a yellow oil: 1H NMR
(400 MHz, CDCl3) δ 1.24 (d, J ) 6.4 Hz, 3H), 1.77 (m, 1H), 1.85
(m, 1H), 1.98 (m, 1H), 2.24 (m, 1H), 2.93 (m, 1H), 3.02 (m, 1H),
3.27 (m, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 3.86 (m, 1H), 4.16 (d, J
) 15.0 Hz, 1H), 5.10 (d, J ) 15.0 Hz, 1H), 6.30 (d, J ) 4.4 Hz,
1H), 6.44 (m, 2H), 7.16 (d, J ) 8.8 Hz, 1H), 7.32 (m, 1H), 7.55
(m, 2H), 8.29 (d, J ) 8.0 Hz, 1H). Compound 29 was used for the
next reaction without further analytical identification due to the
air sensitivity.
23 from 29. To a solution of 29 (279 mg, 0.443 mmol) in THF
(8 mL) was added 240 µL of 30% H2O2 at room temperature with
additional stirring for 3 h. The reaction mixture was quenched with
1 N HCl at 0 °C and extracted with EtOAc. The extract was washed
with 1 N HCl and brine, dried over MgSO4, and concentrated in
vacuo to give residues. After purification of the residues by column
chromatography over silica gel with EtOAc-n-hexane (1:9), the
title compound 23 (189 mg, 99.9% yield) was obtained as a
colorless oil.
(6S,3aR)-5-(2,4-Dimethoxybenzyl)-6-methyl-2,3,5,6,3a-pen-
tahydro-5-azainden-4-one (30) from 23. The oily substrate 23 (280
mg, 0.655 mmol) was dried in vacuo with stirring at room
temperature for 5 h. To the crude oil was added 4.91 mL (1.97
mmol) of 0.4 M 9-BBN-H in THF at room temperature under argon
with additional stirring at this temperature for 7 h. To a suspension
of dried CsF (299 mg, 1.97 mmol) and PdCl2(dppf) (16.1 mg,
0.0197 mmol) in DMF (19.2 mL) was added the above alkyl borane
solution at room temperature under argon. After being stirred at
50 °C for 3.5 h, the reaction mixture was quenched with addition
of saturated NaHCO3 at 0 °C and extracted with Et2O. The extract
was washed with saturated NaHCO3 and brine, dried over MgSO4,
and concentrated under reduced pressure to give oily materials.
Column chromatographic purification of the materials over silica
gel with EtOAc-n-hexane (15:85) gave the title compound 30 (170
mg, 86.1% yield) as a colorless oil: [R]24D -62.5 (c 0.204, CHCl3);
1H NMR (400 MHz, CDCl3) δ 1.25 (d, J ) 6.8 Hz, 3H), 1.75 (m,
3H), 2.31 (m, 1H), 2.37 (m, 2H), 3.00 (m, 1H), 3.78 (s, 3H), 3.80
(s, 3H), 4.04 (m, 1H), 4.35 (d, J ) 15.4 Hz, 1H), 5.08 (d, J ) 15.4
Hz, 1H), 5.30 (m, 1H), 6.40-6.44 (m, 2H), 7.06 (d, J ) 8.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 171.3, 159.4, 157.6, 140.1,
129.3, 118.3, 118.0, 103.9, 97.9, 55.1, 55.1, 52.8, 44.9, 40.2, 29.6,
29.1, 22.9, 21.2; HRMS (FAB) m/z calcd for C18H23NO3 (MH+)
302.1756, found 302.1753.
(3S,6S)-1-(2,4-Dimethoxybenzyl)-3-(3-hydroxypropyl)-4-iodo-
6-methyl-3,6-dihydro-1H-pyridin-2-one (28a) from 26. To a
solution of 26 (50 mg, 0.103 mmol) in EtOH (1 mL) was added
titanium isopropoxide (60.1 µL, 0.205 mmol) at room temperature,
and the mixture was refluxed 1 h. The reaction mixture was diluted
with EtOAc at 0 °C, quenched with saturated NaHCO3, and stirred
at this temperature. After extraction of the mixture with EtOAc,
the extract was washed with brine, dried over MgSO4, and
concentrated in vacuo to give residues. After column chromato-
graphic purification of the residues over silica gel with EtOAc-
n-hexane (1:1), the title compound 28a (36.9 mg, 80.8% yield) was
obtained as a colorless oil: [R]24D -25.1 (c 0.084, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 1.29 (d, J ) 7.6 Hz, 3H), 1.62 (m, 1H), 1.71
(m, 1H), 1.83 (m, 1H), 2.12 (m, 1H), 3.31 (m, 1H), 3.71 (t, J )
6.4 Hz, 2H), 3.79 (s, 3H), 3.80 (s, 3H), 3.87 (m, 1H), 4.17 (d, J )
14.8 Hz, 1H), 5.11 (d, J ) 14.8 Hz, 1H), 6.30 (d, J ) 5.2 Hz, 1H),
6.43-6.46 (m, 2H), 7.17 (d, J ) 8.0 Hz, 1H); 13C NMR (100 MHz,
(6S,3aR)-6-Methyl-2,3,5,6,3a-pentahydro-5-azainden-4-one (31)
from 30. TFA (2.85 mL) and H2O (150 µL) were added to 30 (90
mg, 0.299 mmol) at 0 °C with additional stirring at room
temperature for 12 h. After residual TFA was blown away by N2
4978 J. Org. Chem., Vol. 71, No. 13, 2006

(Z)-Alkene-Containing Proline Dipeptide Mimetics
gas, the reaction mixture was quenched by saturated NaHCO3 at 0
°C and extracted with EtOAc. The extract was washed with
saturated NaHCO3 and brine, dried over MgSO4, and concentrated
under reduced pressure to give solid materials. After purification
of the materials by column chromatography over silica gel with
EtOAc-n-hexane (1:1), the title compound 31 (42.6 mg, 94.4%
yield) as colorless oily materials. Keeping the oily material 8a at
-20 °C gave the crystal, which was brought to X-ray analysis. 8a:
mp 40-42 °C; [R]20D -74.9 (c 0.588, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 1.20 (d, J ) 6.4 Hz, 3H), 1.43 (s, 9H), 1.59 (m, 1H),
1.84 (m, 1H), 1.99 (m, 2H), 2.28 (m, 1H), 2.43 (m, 1H), 3.50 (m,
1H), 3.69 (s, 3H), 4.26 (m, 1H), 4.46 (br, 1H), 5.33 (dd, J ) 8.8,
2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 175.2, 154.9, 143.3,
125.6, 77.2, 52.1, 46.2, 45.6, 34.0, 31.6, 28.4, 24.6, 22.2; HRMS
yield) was obtained as a colorless crystal: mp 138-140 °C; [R]24
D
2.29 (c 0.250, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.27 (d, J )
6.8 Hz, 3H), 1.70 (m, 1H), 1.78 (m, 2H), 2.21 (m, 1H), 2.38 (m,
(ESI-TOF) m/z calcd for C15H25NNaO4 (MNa+) 306.1681, found
2H), 2.95 (m, 1H), 4.17 (m, 1H), 5.41 (m, 1H), 5.52 (m, 1H); 13
C
306.1671. L,D-8a: [R]20 94.2 (c 0.234, CHCl3); H NMR (400
1
D
NMR (100 MHz, CDCl3) δ 173.2, 142.3, 118.5, 48.9, 44.6, 30.0,
28.0, 23.8, 22.1. Anal. Calcd for C18H20N2O5S: C, 71.49; H, 8.67;
N, 9.26. Found: C, 71.17; H, 8.83; N, 9.08.
MHz, CDCl3) δ 1.13 (d, J ) 6.0 Hz, 3 H), 1.43 (s, 9 H), 1.59 (m,
1 H), 1.84 (m, 1 H), 1.99 (m, 2 H), 2.28 (m, 1 H), 2.38 (m, 1 H),
3.67 (s, 3 H), 4.28-4.44 (m, 2 H), 5.23 (d, J ) 8.0 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) δ 77.2, 55.5, 51.9, 45.5, 33.7, 31.1, 28.4,
24.8, 21.1; HRMS (FAB) m/z calcd for C15H25NO4 (MH+)
284.1862, found 284.1852.
(1R)-2-[(2S)-2-tert-Butoxycarbonylaminopropylidene]cyclo-
pentanecarboxylic Acid Methyl Ester (Boc-L-Ala-Ψ[(Z)-CHd
C]-L-Pro-OMe) (8a) from 31. To a solution of 31 (10 mg, 0.0661
mmol) and Me3O‚BF4 (29.4 mg, 0.199 mmol) in CH2Cl2 (500 µL)
was added 2,6-tert-butylpyridine (17.6 µL, 0.0798 mmol) at room
temperature under argon with additional stirring for 30 min at this
temperature. To the recooled reaction mixture to 0 °C were
successively added THF (0.5 mL), 0.6 N HCl (120 µL), and MeOH
(200 µL). The homogeneous mixture was stirred at this temperature
for 2 h and at room temperature for 5 h. To the solution were added
Boc2O (36.0 mg, 0.165 mmol) in THF (0.5 mL) and Et3N (41.6
µL, 0.30 mmol) at 0 °C, and the reaction was continued at room
temperature for 5 h. The reaction was quenched with addition of
saturated NaHCO3 and extracted with EtOAc. The extract was
washed with saturated NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo to give a crude mixture of 8a and its epimer
L,D-8a. Purification of the mixture by column chromatography over
silica gel with EtOAc-n-hexane (1:9) gave the title compounds
8a (11.6 mg, 61.9% yield) and its epimer L,D-8a (3.9 mg, 20.8%
Acknowledgment. We thank Mr. K. Miyamoto, The Uni-
versity of Tokushima, for his support in X-ray analysis. This
research was supported in part by the 21st Century COE
Program “Knowledge Information Infrastructure for Genome
Science”, a Grand-in-Aid for Scientific Research (KAKENHI).
Y.S. and A.N. are grateful for Research Fellowships from the
JSPS for Young Scientists.
Supporting Information Available: ORTEP diagrams for 31
1
and 8a and their CIF files; copies of H and 13C NMR spectra of
4a, 4b, 9, 8a, L,D-8a, 10, 11, 13, 14, 15, 16, 18, 19, 20, 21, 22a,
22b, 23, 24, 25, 26, 27, 28, 29, 30, 31. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0606002
J. Org. Chem, Vol. 71, No. 13, 2006 4979