Regio- and stereoselective synthesis of (E)-alkene trans-Xaa-Pro dipeptide mimetics utilizing organocopper-mediated anti-S(N)2' reactions.

Article abstract of DOI:10.1021/jo025922u

Proline dipeptides (Xaa-Pro) exist as an equilibrium mixture of cis- and trans-rotamers, which depends on the energy barriers for imide isomerization. This conformation mixture contributes to both structure and function of proline-containing peptides and proteins. Structural motifs resembling these cis- or trans-conformers have served as useful tools for elucidating contributions of proline residues in the physicochemical and biological profiles of structures which contain them. Among such motifs are alkene dipeptide isosteres which mimic cis- or trans-imide using (Z)- or (E)-alkene, respectively. In this report, the first regio- and stereoselective syntheses of (E)-alkene dipeptide isosteres (20, 31, and 35) corresponding to trans-proline dipeptides are described. Key to the synthesis of these mimetics is the anti-S(N)2' reaction of vinyl aziridines such as 15 or vinyl oxazolidinones such as 28 and 32 with organocopper reagents "RCu" (R = CH(2)SiMe(2)(Oi-Pr)). Reaction of cis-vinylaziridine 15 derived from L-serine with organocopper reagent gave a precursor of the trans-L-Ser-D-Pro type alkene isosteres 20, accompanied by an S(N)2 side product. One limitation with the use of such aziridine-mediated methodology is formation of the corresponding trans-aziridine 22, which leads to L-L type isosteres, that is unstable and obtainable only in low yield. On the other hand, both isomers of oxazolidinone derivatives can be easily obtained from N-Boc-protected amino alcohols. The reaction of trans- 28 or cis-oxazolidinone derivative 32 with organocopper reagents proceeds quantitatively with high regio- and diastereoselectivities in anti-S(N)2' fashion. Subsequent oxidative treatment of the newly introduced isopropoxydimethylsilylmethyl group yields trans-L-Ser-L-Pro 31 or trans-L-Ser-D-Pro type isosteres 35, respectively. Of note, synthesized isostere 31 can also be converted to trans-phosphoSer-Pro 42 and trans-Cys-Pro mimetics 44. The present synthetic methodology affords trans-Xaa-Pro alkene-type dipeptide isosteres in high yield with relatively simple manipulation.

Full text of DOI:10.1021/jo025922u

Regio- a n d Ster eoselective Syn th esis of (E)-Alk en e tr a n s-Xa a -P r o
Dip ep tid e Mim etics Utilizin g Or ga n ocop p er -Med ia ted An ti-SN2′
Rea ction s
Akira Otaka,*,† Fumihiko Katagiri,† Takayoshi Kinoshita,‡ Yoshihiko Odagaki,§
Shinya Oishi,† Hirokazu Tamamura,† Nobuyuki Hamanaka,§ and Nobutaka Fujii*,†
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, J apan,
Fujisawa Pharmaceutical Co., Ltd., Kashima, Yodogawa-ku, Osaka 532-8514, J apan, and Minase
Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka 618-8585, J apan
nfujii@pharm.kyoto-u.ac.jp
Received May 9, 2002
Proline dipeptides (Xaa-Pro) exist as an equilibrium mixture of cis- and trans-rotamers, which
depends on the energy barriers for imide isomerization. This conformation mixture contributes to
both structure and function of proline-containing peptides and proteins. Structural motifs resembling
these cis- or trans-conformers have served as useful tools for elucidating contributions of proline
residues in the physicochemical and biological profiles of structures which contain them. Among
such motifs are alkene dipeptide isosteres which mimic cis- or trans-imide using (Z)- or (E)-alkene,
respectively. In this report, the first regio- and stereoselective syntheses of (E)-alkene dipeptide
isosteres (20, 31, and 35) corresponding to trans-proline dipeptides are described. Key to the
synthesis of these mimetics is the anti-SN2′ reaction of vinyl aziridines such as 15 or vinyl
oxazolidinones such as 28 and 32 with organocopper reagents “RCu” (R ) CH2SiMe2(Oi-Pr)).
Reaction of cis-vinylaziridine 15 derived from L-serine with organocopper reagent gave a precursor
of the trans-L-Ser-D-Pro type alkene isosteres 20, accompanied by an SN2 side product. One limitation
with the use of such aziridine-mediated methodology is formation of the corresponding trans-
aziridine 22, which leads to L-L type isosteres, that is unstable and obtainable only in low yield.
On the other hand, both isomers of oxazolidinone derivatives can be easily obtained from N-Boc-
protected amino alcohols. The reaction of trans- 28 or cis-oxazolidinone derivative 32 with
organocopper reagents proceeds quantitatively with high regio- and diastereoselectivities in anti-
SN2′ fashion. Subsequent oxidative treatment of the newly introduced isopropoxydimethylsilylmethyl
group yields trans-L-Ser-L-Pro 31 or trans-L-Ser-D-Pro type isosteres 35, respectively. Of note,
synthesized isostere 31 can also be converted to trans-phosphoSer-Pro 42 and trans-Cys-Pro
mimetics 44. The present synthetic methodology affords trans-Xaa-Pro alkene-type dipeptide
isosteres in high yield with relatively simple manipulation.
In tr od u ction
Proline (Pro) exerts great influence on both the struc-
ture and function of peptides and proteins through cis-/
trans-equilibrium of its associated peptide bonds (Xaa-
Pro) (Figure 1).1,2 Proline is the sole imino acid in
naturally occurring mammalian proteins and forms imide
bonds with amino acids N-terminal to the imino acid.
F IGURE 1. Cis- and trans-conformers of Xaa-Pro imides and
their equilibrium.
* To whom correspondence should be addressed. Tel.: +81-75-753-
4551. Fax: +81-75-753-4570.
† Kyoto University.
Consequently, Xaa-Pro bonds exist in cis-/trans-equilibria
having similar energy barriers1 for imide isomerization.2
Alternatively, other peptide bonds3 favor trans-conforma-
tions with ca. 5.0 kcal/mol lower energy barriers for
amide bond isomerization in trans- as compared to cis-
conformations. Energetic similarity between cis- and
trans-isomers of Xaa-Pro bonds may create multiple low
‡ Fujisawa Pharmaceutical Co., Ltd.
§ Ono Pharmaceutical Co., Ltd.
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10.1021/jo025922u CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/01/2002
6152
J . Org. Chem. 2002, 67, 6152-6161

(E)-Alkene trans-Xaa-Pro Dipeptide Mimetics
proline mimetics (L-Ala-ψ[(Z)-CHdC]-L-Pro) correspond-
ing to an L-Ala-L-Pro sequence.9c In this synthesis, a
Still-Wittig [2,3]-sigmatoropic rearrangement10 in THF
was used for selective formation of trisubstituted (Z)-
alkenes.11 Subsequently, in the synthesis of Ser-Pro
dipeptide alkene isosteres they found that a Still-Wittig
reaction afforded opposite selectivities for (Z: E)-alkenes
in THF (3:1) vs toluene (1:3).9e Extensive synthetic efforts
toward (E)-alkene dipeptide isosteres 6 have been made
by several groups, including us.12-16 Organocopper-medi-
ated reactions previously employed by us have converted
either γ-mesyloxy-R,â-enoates 3,13 â-aziridinyl-R,â-enoates
4,12f-g,14 or â-(1,3-oxazolidin-2-on-5-yl)-R,â-enoates 515 to
R-substituted â,γ-enoates corresponding to 6 in highly
regio- and stereoselective manners (Scheme 1).
Using our protocol, R-substituents corresponding to
side chain functionality can be introduced into dipeptide
mimetic backbones. However, in the case of Xaa-Pro
dipeptides, which have cyclic structures that include
peptide backbone, use of R,â-enoates as substrates (3-
5) cannot be applied to the synthesis of corresponding
mimetics. This fact prompted us to examine the feasibil-
ity of introducing “CO2H” functionality included in the
backbone in regio- and stereoselective fashion using
organocopper-mediated reactions which would yield Xaa-
Pro type alkene dipeptide isosteres. Regarding this point,
Etzkorn et al. also utilized a strategy based on Still-
Wittig [2,3]-rearrangements to introduce “CO2H” units.9c
Since hydroxyl functionality in serine residues can be
converted to other functional groups, we selected Ser-
Pro mimetics as synthetic targets. For introduction of the
“CO2H” moiety, we envisioned using isopropoxydimeth-
ylsilylmethyl groups,17 which would be incorporated by
F IGURE 2. (Z)- or (E)-Alkene dipeptide isosteres correspond-
ing to cis- or trans-proline peptide bonds, respectively.
energy conformers in Pro-containing proteins/peptides,
which complicate understanding the relationship be-
tween Xaa-Pro geometry and biological activity. Although
investigations of Xaa-Pro geometries of bioactive peptides
using techniques such as X-ray and NMR spectroscopy
have been extensively undertaken, it is difficult for such
studies to define whether cis- or trans-geometries are
involved with particular bioactive conformations.4
Restriction of Xaa-Pro imide conformations provides
one promising means for studying relationships between
imide bond geometry and biological activity of peptides.
To control geometry, alkylproline analogues possessing
substituents at the 2- or 5-positions of proline have been
used to induce preference for trans- or cis-isomer popula-
tions, respectively.5,6 Additionally, syntheses of dipeptide
isosteres7 corresponding to Xaa-Pro having cis- or trans-
imide geometries have been made.8,9 For example, cyclo-
cystine,8b dipeptide lactams,8c and tetrazole derivatives8e
have been incorporated as the cis-Pro mimetics into
somatostatin, resulting in potent peptide mimetics.
Replacement of Xaa-Pro imide bonds with (Z)- or (E)-
alkene units (1 or 2 in Figure 2) represents a more
straightforward method for mimicking proline imide
backbone geometry. Dipeptide isosteres, including fluo-
roalkenes with trans-Pro geometry, have been non-
stereoselectively synthesized by a strategy which relied
on construction of alkene units using Peterson or Hor-
ner-Emmons olefination reactions of 2-substituted cyclo-
pentanones, followed by derivatization of terminal func-
tional groups.9a,b Etzkorn et al. have reported the first
enantio- and regioselective synthesis of (Z)-alkene cis-
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J . Org. Chem, Vol. 67, No. 17, 2002 6153

Otaka et al.
SCHEME 2. Syn th etic P la n for Alk en e-typ e
SCHEME 1. Syn th esis of Non p r olin e Typ e
(E)-Alk en e Dip ep tid e Isoster es (6) via An ti-SN2′
Rea ction of γ-Mesyoxy-r,â-en oa tes (3),
â-Azir id in yl-r,â-en oa tes (4), or
â-(1,3-Oxa zolid in -2-on -5-yl)-r,â-en oa tes (5) w ith
Or ga n ocop p er Rea gen ts
Ser -P r o Dip ep tid e Isoster es
organocopper-mediated reactions and subsequently trans-
formed to “CO2H” groups by oxidative treatment. Accord-
ingly, we report herein the regio- and stereoselective
synthesis of (E)-alkene Ser-Pro dipeptide isosteres with
trans-Xaa-Pro geometry using organocopper reagents.
Additionally, conversion of Ser units to other amino acid
residues is also investigated.
Resu lts a n d Discu ssion
Our synthetic plan to Ser-Pro type alkene isosteres 12
is conceptually outlined in Scheme 2: (1) addition of
metalated cyclopentenyl reagents 818 to serinal deriva-
tives 7; (2) transformation of the resulting hydroxy group
of 9 to a leaving group susceptible to organocopper
reagents in an SN2′ manner; (3) incorporation of silyl-
methyl groups into 10 using organocopper-mediated SN2′
reactions; (4) conversion of the introduced silylmethyl
group of 11 to a “CO2H” moiety by oxidative treatment.
As shown in Scheme 3, we first selected aziridine
moieties as the activating functionality for SN2′ reactions
since our previous studies indicated that treatment of
â-(N-activated-aziridinyl)-R,â-enoates 4 with organocop-
per reagents proceeded with high regio- and stereoselec-
tivity to afford R-alkylated nonproline-type alkene dipep-
tide isosteres 6. Herein N-benzenesulfonyl-type protecting
groups (Mts, etc.) were preferably employed as N-activat-
ing groups since the use of these groups in the synthesis
of alkene isosteres affords less undesired γ-alkylated
product as compared with Boc groups.12f,14 Additionally,
requisite aziridines could be easily obtained by mild
Mitsunobu reaction19 of N-Mts-protected 1,2-amino al-
cohols. Reduction of the N-Mts-protected L-serine deriva-
tive (Mts-L-Ser(Ot-Bu)-OMe 13) with DIBAL in CH2Cl2-
toluene at -78 °C, followed by addition of cyclopentenyl-
lithium-ZnCl2-LiCl in THF at -78 °C, exclusively
afforded syn-1,2-amino alcohol 14. The syn diastereo-
selectivity observed with NHMts aldehyde could be
explained using a chelation-controlled Cram cyclic
model.20,21 Treatment of 14 with Ph3P-DEAD in THF-
toluene gave cis-aziridine 15. Relative configurations of
aziridines (15 and 22), including trans-isomers later
discussed, were determined by comparative NOE mea-
surements (Scheme 3). Organocopper-mediated reaction22
of resulting 15 with “lower-order” cyanocuprate, (i-PrO)-
Me2SiCH2Cu(CN)MgCl‚2LiCl prepared from Grignard
reagents17 in THF at -78 °C for 2 h with additional
stirring overnight at 0 °C, gave a mixture of anti-SN2′
product 16 and SN2 product 17 in 83% combined yield
(16:17 ) 3:1). Following flash chromatographic purifica-
tion, the desired anti-SN2′ product 16 was subjected to
oxidation in DMF using KF and 30% H2O2 to yield alcohol
derivative 18 in 80% yield without affecting the alkene
moiety. Following flash chromatographic purification, 18
was crystallized from Et2O. X-ray analysis of 18 showed
that it possessed (E)-alkene geometry and (S)-configu-
ration of the introduced hydroxymethyl group. This
indicated that the organocopper-mediated reaction pro-
ceeded in an anti-SN2′ manner with the resultant 18
(20) (a) Cram, D. J .; Wilson, D. R. J . Am. Chem. Soc. 1963, 85, 1245.
(b) Reetz, M. T.; Drewes, M. W.; Schimitz, A. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1141.
(21) Tohdo, K.; Hamada, Y.; Shoiri, T. Tetrahedron Lett. 1992, 33,
2031.
(22) For recent reviews, see: (a) Lipshutz, B. H.; Sengupta, S. Org.
React. 1992, 41, 135. (b) Organocopper Reagents, A Practical Approach;
Taylor, R. J . K., Eds.; Oxford University Press: Oxford, 1994. (c)
Nakamura, E.; Mori, S. Angew. Chem., Int. Ed. 2000, 39, 3750 and
references cited threrein.
(18) Lee, K.; Wiemer, D. F. Tetrahedron Lett. 1993, 34, 2433.
(19) Mitsunobu, O. Synthesis 1981, 1.
6154 J . Org. Chem., Vol. 67, No. 17, 2002

(E)-Alkene trans-Xaa-Pro Dipeptide Mimetics
SCHEME 3. Syn th esis of Ser -P r o Alk en e Isoster es
via Azir id in esa
65% yield. During oxidative manipulations of 16 to 20,
no significant side reactions were observed.
Since application of organocopper reagents to cis-vinyl
aziridine compound such as 15 constitutes a synthetic
strategy for trans-L-Ser-D-Pro-type isosteres, we specu-
lated that reaction of trans-vinyl aziridine derivative 22
with organocopper reagents would give trans-L-Ser-L-Pro-
type alkene isosteres. To confirm this, we attempted the
synthesis of trans-aziridine 22 from 14 by a sequence of
reactions including oxidation/rereduction (inversion of
hydroxy-configuration) followed by Mitsunobu reaction
(aziridine formation). Oxidation of 14 with Dess-Martin
periodinane followed by reduction with Zn(BH4)2 gave
inverse anti-amino alcohol 21. Subsequent Mitsunobu
reaction of 21 with Ph3P-DEAD proceeded quantita-
tively; however, flash chromatography over silica gel,
even over Et3N-pretreated gel, gave only a trace amount
of desired trans-aziridine 22. This may be attributed to
the fact that trans-aziridine 22 was much less stable than
cis-isomer 15.26 Additionally, attempted activation of 14
to 23 with MsCl as an approach toward L-L type
isosteres also met with failure. Consequently, it was
found that a synthetic strategy consisting of organocopper
reagents and aziridine moieties as the activation devices
could be applicable to the synthesis of trans-L-Ser-D-Pro
(or trans-D-Ser-L-Pro) type alkene isosteres but not to that
of trans-L-L (or trans-D-D) type. In addition to the
limited use of aziridine-mediated techniques, removal of
the N-Mts group requires harsher acidic conditions, such
as 1 M TMSBr-thioanisole in TFA,27 as compared to Boc-
deprotection. When considering the use of the isosteres
in peptide synthesis, more acid labile protecting groups
such as Boc would be preferable for the N-protection.
Therefore, we examined the susceptibility of N-Boc
protected compounds to organocopper reagents for the
synthesis of the isosteres, in which mesyloxy or 1,3-
oxazolidin-2-on-5-yl moieties would be used as shown in
Scheme 4. Reduction of starting N-Boc protected serine
derivative 24 with DIBAL in CH2Cl2-toluene at -78 °C
gave the corresponding aldehyde. Without isolation, the
aldehyde was subsequently carried forward in a one-pot
reaction using cyclopentenyllithium-ZnCl2-LiCl in THF
to yield a mixture of syn-25 and anti-amino alcohols 26
(25:26 ) 87:13) in 48% combined yield. As described
below, relative configurations of the amino alcohols were
determined by comparative NOE measurements of cor-
responding oxazolidinone derivatives (28 and 32 in
Scheme 4). Attempted activation of the hydroxy group
in 25 with MsCl-pyridine-DMAP in CH2Cl2 failed to
give any corresponding activated product 27.
a
Key: (i) DIBAL, CH2Cl2-toluene, and then cyclopentenyl-
lithium, ZnCl2, LiCl, THF; (ii) DEAD, Ph3P, THF; (iii) (i-
PrO)Me2SiCH2Cu(CN)MgCl‚2LiCl, THF; (iv) 30% H2O2, KF, DMF;
(v) Dess-Martin periodinane, CHCl3; (vi) NaClO2, 2-methyl-2-
butene, NaH2PO4, t-BuOH, H2O; (vii) Zn(BH4)2, Et2O; (viii) MsCl,
pyridine, CHCl3.
representing a precursor of trans-L-Ser-D-Pro type alkene
isosteres. Formation of this anti-SN2′ product can be
explained in a fashion similar to the reported mechanism
for the organocopper-mediated synthesis of 6 from 4.14,23
The structure of SN2 product 17 was also ascertained by
X-ray analysis of the corresponding alcohol derivative 19.
Alcohol derivative 18 was oxidized to carboxylic acid
derivative 20 by a sequence of reactions, which included
Dess-Martin periodinane24 followed by NaClO2-mediated
reaction.25 Flash chromatographic purification of crude
material gave desired N-Mts-protected L-Ser-ψ[(E)-CHd
C]-D-Pro 20 possessing trans-L-Ser-D-Pro configuration in
Consequently, we planned to activate the hydroxy
group by formation of 1,3-oxazolidin-2-one rings, where
the hydroxy group would be protected and activated as
a cyclic carbamate. Reaction of 5-vinyl-1,3-oxazolidin-2-
one with organometallic reagents gave products resulting
(26) (a) Ibuka, T.; Mimura, N.; Ohno, H.; Nakai, K.; Akaji, M.;
Habashita, H.; Tamamura, H.; Miwa, Y.; Taga, T.; Fujii, N. J . Org.
Chem. 1997, 62, 2982. (b) Aoyama, H.; Mimura, N.; Ohno, H.; Ishii,
K.; Toda, A.; Tamamura, H.; Otaka, A.; Fujii, N.; Ibuka, T. Tetrahedron
Lett. 1997, 38, 7383.
(27) (a) Fujii, N.; Otaka, A.; Sugiyama, N.; Hatano, M.; Yajima, H.
Chem. Pharm. Bull. 1987, 35, 3880. (b) Yajima, H.; Fujii, N.; Funa-
koshi, S.; Watanabe, T.; Murayama, E.; Otaka, A. Tetrahedron 1988,
44, 805.
(23) Corey, E. J .; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063.
(24) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(25) Bal, B. S.; Childers, W. E., J r.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
J . Org. Chem, Vol. 67, No. 17, 2002 6155

Otaka et al.
SCHEME 4. Syn th esis of Ser -P r o Alk en e Isoster es
via Oxa zolid in on esa
by (Boc)2O in THF gave trans-oxazolidinone derivative
28 in 54% yield. Organocopper-mediated reaction of the
resulting oxazolidinone 28 with a “lower order complex”
(i-PrO)Me2SiCH2Cu(CN)MgCl‚2LiCl in THF at -78 °C
for 30 min, with additional stirring for 3 h at 0 °C,
proceeded quantitatively with ring-opening and decar-
boxylation to give anti-SN2′ product 29 as the sole
product.29 Flash chromatographic purification gave pure
29 in 98% isolated yield. Note should be taken that
retention of 29 in silica gel flash chromatography columns
overnight can result in decomposition of the desired
material to some extent. Oxidation of 29 with KF (4
equiv) and 30% H2O2 (12 equiv) in DMF gave alcohol
derivative 30. Use of 4-fold amounts of oxidants as
compared to condition mentioned above allowed oxidation
of unpurified 29 to 30, thereby obviating the need for
problematic purification of intermediate 29 over silica gel.
Stepwise oxidation of purified 30 with Dess-Martin
periodinane followed by NaClO2 yielded desired N-Boc
protected L-Ser-ψ[(E)-CHdC]-L-Pro 31. Following flash
chromatographic purification, the corresponding dicyclo-
hexylamine (DCHA) salt of 31 was crystallized from
Et2O. X-ray analysis of the DCHA salt showed that it
possessed a configuration corresponding to a trans-L-Ser-
L-Pro type-alkene isostere. From this analysis, “lower
order complexes” are likely to react with 28 in anti-SN2′
fashion. Next, to obtain trans-L-Ser-D-Pro-type alkene
isosteres, cis-oxazolidinone derivative 32 was subjected
to the “lower order complex” reagent. Requisite 32 was
prepared from anti-amino alcohol 26 in a manner identi-
cal to protocols employed in the synthesis of 28. Reaction
of 32 with (i-PrO)Me2SiCH2Cu(CN)MgCl‚2LiCl in THF
proceeded quantitatively to afford alkylated product 33.
Without flash chromatographic purification, crude 33 was
oxidized to alcohol 34 with KF (16 equiv) and 30% H2O2
(48 equiv). Subsequent flash chromatographic purifica-
tion provided pure 34 in 66% yield as calculated from
32. Successive oxidation of 34 with Dess-Martin perio-
dinane and NaClO2 afforded desired L-Ser-ψ[(E)-CHdC]-
D-Pro derivative 35, corresponding to a trans-L-Ser-D-Pro
dipeptide. The structure of 35 was assigned on the basis
of conversion of precursor 34 to 18, whose structure had
been established already. This was acquired as follows:
(1) selective removal of the Boc group of 34 using
TMSOTf-2,6-lutidine in CH2Cl230; (2) N-protection of Boc-
deprotected product using MtsCl-Et3N; (3) compounds
obtained following reactions 1 and 2, showed identical
NMR data and the same signs of optical rotation as
compared to the established authentic compound 18. On
the basis of this, we concluded that reaction of cis-
oxazolidinone 32 with the organocopper reagent pro-
ceeded in a fashion similar to the reaction of trans-
oxazolidinone 28 (anti-SN2′ path) to give a precursor of
trans-L-Ser-D-Pro alkene isostere 35. These anti-SN2′
reactions were confirmed to proceed with high selectivity
by comparison of NMR data of 30 and 34. Additionally
no Z-isomer contamination was observed by judging from
a comparison of NMR data of 30 and 37 (discussed later).
Next, to examine the synthetic feasibility of cis-Ser-
Pro isosteres, oxazolidinone 28 was subjected to reaction
a
Key: (i) DIBAL, CH2Cl2-toluene, and then cyclopentenyl-
lithium, ZnCl2, LiCl, THF; (ii) MsCl, pyridine, CHCl3; (iii) NaH,
THF; (iv) (Boc)2O, THF; (v) (i-PrO)Me2SiCH2Cu(CN)MgCl‚2LiCl,
THF; (vi) 30% H2O2, KF, DMF; (vii) Dess-Martin periodinane,
CHCl3; (viii) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH, H2O.
from ring-opening and decarboxylation.28 Previously, we
reported regio- and enantioselective synthesis of vinyl-
glycine derivatives by alkylation of 5-vinyl-1,3-oxazolidin-
2-ones with organocopper reagents.28a Additionally, we
recently found that â-(N-Boc-1,3-oxazolidin-2-on-5-yl)-R,â-
enoates are potential synthetic intermediates for the
synthesis of alkene dipeptide isosteres using organocop-
per reagents (from 5 to 6 in Scheme 1).15 Cyclization and
N-Boc reprotection of 25 by treatment with NaH followed
(28) (a) Ibuka, T.; Suzuki, K.; Habashita, H.; Otaka, A.; Tamamura,
H.; Mimura, N.; Miwa, Y.; Taga, T.; Fujii, N. J . Chem. Soc. Chem.
Commun. 1994, 2151. (b) Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji,
M.; Ohno, H.; Miwa, Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N.;
Yamamoto, Y. J . Org. Chem. 1997, 62, 999. (c) Xin, T.; Okamoto, S.;
Sato, F. Tetrahedron Lett. 1998, 39, 6927. (d) Knight, J . G.; Ainge, S.
W.; Harm, A. M.; Harwood: S. J .; Maughan, H. I.; Armour, D. R.;
Hollinshead, D. M.; J axa-Chamiec, A. A. J . Am. Chem. Soc. 2000, 122,
2944.
(29) No contamination of syn-SN2′ product, which corresponded to
L-Ser-ψ[(E)-CHdC]-D-Pro, was confirmed by NMR analyses of 30 and
34. The (Z)-iosomer 37 was easily separated over both TLC and flash
chromatography from 30.
6156 J . Org. Chem., Vol. 67, No. 17, 2002

(E)-Alkene trans-Xaa-Pro Dipeptide Mimetics
TABLE 1. Tr ea tm en t of Oxa zolid in on e 28 w ith Sever a l Or ga n ocop p er Rea gen ts
run
reagenta,b
products (isolated yields %)
1
2
3
4
(i-PrO)Me2SiCH2Cu(CN)MgCl‚2LiCl
29 (98)
29 (95)
(i-PrO)Me2SiCH2Cu(CN)MgCl‚BF3‚2LiCl
((i-PrO)Me2SiCH2)2Cu(CN)(MgCl)2‚2LiCl
((i-PrO)Me2SiCH2)2Cu(CN)(MgCl)2‚BF3‚2LiCl
29 (98)
30c (60), 37c (33)
a
b
4 equiv of reagents was used. Reaction at -78 °C for 30 min and then 0 °C for 3 h. c Obtained products were racemates.
F IGURE 3. Plausible explanation for stereoselectivity in anti-SN2′ reaction using “lower-order” cyanocuprates.
cyanocuprates was deduced based on analogy with γ-me-
with several organocopper reagents as shown in Table
1. Alkylation of 28 with either “lower-order” cyanocu-
prate-BF3 complex,31 (i-PrO)Me2SiCH2Cu(CN)MgCl‚BF3‚
2LiCl (run 2) or “higher-order” cyanocuprate complex, ((i-
PrO)Me2SiCH2)2Cu(CN)(MgCl)2‚2LiCl (run 3) proceeded
at -78 °C for 30 min then 0 °C for 3 h to give anti-SN2′
product 29 in quantitative yield. This was similar to what
was observed using “lower-order” cyanocuprate, (i-PrO)-
Me2SiCH2Cu(CN)MgCl‚2LiCl (run 1). In the case of run
1-3, treatment at 0 °C was necessary for complete
consumption of starting material. In contrast, reaction
of 28 with “higher-order” cyanocuprate-BF3 complex, ((i-
PrO)Me2SiCH2)2Cu(CN)(MgCl)2‚BF3‚ 2LiCl (run 4), pro-
ceeded with near complete disappearance of 28 even at
-78 °C to yield a mixture of trans- and cis-isomers (29
and 36). Since separation of each isomer using silica gel
flash chromatography with prolonged times would cause
decomposition, the mixture was oxidized and then sub-
jected to flash chromatographic separation, to yield trans-
alcohol 30 and cis-alcohol 37 (30:37 ) 1.8:1). Surprisingly,
measurements of optical rotations of flash chromato-
graphically purified samples showed that both alcohols
were racemates. X-ray analysis of crystalline 37 sup-
ported that isolated material consisted of cocrystals
possessing configurations corresponding to cis-L-Ser-D-
Pro and its enantiomer.
syloxy-R,â-enoates13 or â-aziridinyl-R,â-enoates.14 Copper-
mediated substitution of acyclic allylic carbamates has
been well documented to give syn-SN2′ products.32 This
is in contrast to the fact that other allylic derivatives
typically undergo substitution anti to the leaving group.23
Herein complexation of copper with the nitrogen in
carbamates is likely to be responsible for syn-selectivity.
In our cyclic carbamate system, a corresponding nitrogen
lacks the ability to undergo complexation due to the
presence of an N-Boc group. Therefore, reactive inter-
mediates accounting for the organocopper-mediated anti-
SN2′ reactions, conformer 38A or 38B for trans-oxazoli-
dinone derivative 28 and conformer 39A or 39B for cis-
oxazolidinone derivative 32, could be envisioned. Therein,
1,3-allylic strain33 may result in the preference for
conformers 38B and 39B. Organocopper attack on pre-
ferred conformer 38B or 39B in anti-SN2′ manner should
give 29 or 33 with the trans-proline geometry, respec-
tively. This may be the case for both “lower-order”
cyanocuprate-BF3 complexes and “higher-order” cyano-
cuprates. Formation of enantiomerically pure cis-Xaa-
Pro isosteres could be explained by the reaction of
organocopper reagents via a path involved with un-
favourable conformer 38A. However, alkylation using
“higher-order” cyanocuprate-BF3 complexes afforded an
As shown in Figure 3, a plausible mechanism for the
regio- and stereoselective reaction with “lower-order”
(32) (a) Gallina, C.; Ciattini, P. G. J . Am. Chem. Soc. 1979, 101,
1035. (b) Goering, H. L.; Kantner, S. S.; Tseng, C. C. J . Org. Chem.
1983, 48, 715. (c) Denmark, S. E.; Marble, L. K. J . Org. Chem. 1990,
55, 1984. (d) Smitrovich, J . H.; Woerpel, K. A. J . Am. Chem. Soc. 1998,
120, 12998.
(30) Sakaitani, M.; Ohfune, Y. J . Org. Chem. 1990, 55. 870.
(31) (a) Maruyama, K.; Yamamoto, Y. J . Am. Chem. Soc. 1977, 99,
8068. (b) Ibuka, T.; Yamamoto, Y. In ref 22b, p 143.
(33) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
J . Org. Chem, Vol. 67, No. 17, 2002 6157

Otaka et al.
SCHEME 5. Syn th esis of p Ser -P r o a n d Cys-P r o
Alk en e Isoster esa
followed by flash chromatographic purification, gave
S-protected trans-L-Cys-L-Pro type alkene isostere 44.
In conclusion, we have achieved the first regio- and
stereoselective synthesis of trans-Ser-Pro alkene dipep-
tide mimetics using an organocopper-mediated anti-SN2′
reaction onto key intermediate vinyl aziridines or vinyl
oxazolidinones. Of note, the use of either trans- or cis-
isomers of oxazolidinones in the anti-SN2′ reaction pro-
vides facile and efficient stereoselective access to trans-
L-L (or D-D)- or trans-L-D (or D-L)-type proline dipeptide
isosteres, respectively. Together with studies on cis-Xaa-
Pro mimetics by Etzkorn et al., our results are of value
in elucidating relationships between Xaa-Pro geometry
in peptides and their biological activity. We are now
examining the extension of combined oxazolidinone and
organocopper chemistry to the synthesis of cis-proline
alkene isosteres.
Exp er im en ta l Section
a
Key: (i) BnBr, DCHA, DMF; (ii) TFA, CH2Cl2 then (Boc)2O,
Et3N, THF; (iii) dimethyl N,N-diisopropylphosphoramidite, tetra-
zole, MeCN then H2O2; (iv) TsCl, pyridine, CHCl3; (v) NaI, acetone;
(vi) triphenylmethanethiol, Et3N, DMF.
(1S,2S)-{1-[(ter t-Bu toxy)m eth yl]-2-cyclop en t-1-en yl-2-
h ydr oxyeth yl}[(2,4,6-tr im eth ylph en yl)su lfon yl]am in e (14)
fr om 13. To a solution of 16.3 g (83.9 mmol) of 1-iodocyclo-
pentene in THF (50 mL) at -78 °C under argon was added
53.8 mL (83.9 mmol) of 1.56 M n-BuLi in hexane with
additional stirring for 30 min at this temperature. In another
flask 11.4 g (83.9 mmol) of anhydrous ZnCl2 and 3.6 g (83.9
mmol) of anhydrous LiCl were suspended in THF (80 mL)
under argon. To the cooled suspension of ZnCl2 and LiCl to
-78 °C was added the above solution of cyclopentenyllithium
in THF with additional stirring for 30 min at -78 °C. To a
solution of 15.0 g (42 mmol) of 13 in CH2Cl2 (40 mL) was added
dropwise 83.9 mL (83.9 mmol) of 1 M DIBAL in toluene at
-78 °C under argon. After stirring the reaction at -78 °C until
disappearance of the starting material (ca 1 h), the solution
of metalated cyclopentenyl reagents prepared above was added
at -78 °C under argon with additional stirring for 1 h at -78
°C. After being stirred at 0 °C for 4 h, 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 satu-
rated citric acid 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 EtOAc-n-hexane gave 9.7 g (58.0% yield) of the
unprecedented racemic mixture of 29 and 36 (Table 1).
Reaction mechanisms depicted in Figure 3 cannot provide
an explanation for the formation of the racemic mixture.
At this stage, reasons for the racemate formation still
remains as a matter to be discussed further.
As shown in Scheme 5, we next examined the trans-
formation of the hydroxy group corresponding to the Ser
moiety. Amino acid sequences containing a Ser-Pro
arrangement serve as kinase phosphorylation sites. Ad-
ditionally, Pin 1, a phosphorylation-dependent peptidyl
prolyl isomerase (PPIase), was recently found to regulate
several intracellular signaling events involved in mito-
sis.34 Synthesis of (Z)-alkene phosphoSer(pSer)-Pro isos-
teres has already been achieved by Etzkorn et al.35 In
conjunction with our recent studies on phosphopeptides,36
we also carried out the synthesis of trans-L-pSer-L-Pro
according to their protocol. Protection of carboxylic
functionality in 31 gave benzyl ester 40. Treatment of
40 with TFA followed by reprotection with (Boc)2O
afforded alcohol derivative 41. Phosphorylation of the
resulting 41 with dimethyl phosphoramidite and tetra-
zole in acetonitrile,37 followed by addition of 30% H2O2,
gave protected L-pSer-ψ[(E)-CHdC]-L-Pro derivative 42
possessing trans-L-pSer-L-Pro geometry in 44% yield.
titled compound 14 as colorless crystals: mp 104-106 °C;
1
[R]27 +54.6 (c ) 1.01, CHCl3); H NMR (270 MHz, CDCl3) δ
D
6.93 (s, 2H), 5.60 (m, 1H), 5.30 (d, J ) 7.9 Hz, 1H), 4.39 (s,
1H), 3.64 (s, 1H), 3.63 (dd, J ) 9.2, 3.3 Hz, 1H), 3.51 (dd, J )
9.2, 2.3 Hz, 1H), 3.31 (m, 1H), 2.62 (s, 6H), 1.15 (s, 9H); Anal.
Calcd for C21H33NO4S: C, 63.77; H, 8.41; N, 3.54. Found: C,
63.48; H, 8.70; N, 3.47.
Conversion of Ser to Cys was also attempted. Com-
pound 41 was activated as iodide 43 by a sequence of
reactions consisting of tosylation with TsCl-pyridine in
CHCl3 followed by replacement with NaI in acetone.
Reaction of 43 with triphenylmethanethiol in DMF,
(2S,3R)-2-[(ter t-Bu t oxy)m et h yl]-3-cyclop en t -1-en yl-1-
[(2,4,6-tr im eth ylp h en yl)su lfon yl]a zir id in e (15) fr om 14.
To a solution of 2.0 g (7.6 mmol) of Ph3P in THF (7 mL) were
successively added 40% DEAD solution in toluene (3.4 mL,
7.6 mmol) and a solution of 14 (2.0 g, 5.1 mmol) in THF (5
mL) at 0 °C under argon. After being stirred at 0 °C for 1 h,
the reaction mixture was purified by flash chromatography
over silica gel with EtOAc-n-hexane (1:19) to give 1.6 g (84.0%
yield) of the title compound 15 as a pale yellow oil: [R]26D -47.0
(34) (a) Yaffe, M. B.; Schutkowski, M.; Shen, M.; Zhou, X. Z.;
Stukenberg, P. T.; Rahfeld, J . U.; Xu, J .; Kuang, J .; Kirschner, M. W.;
Fischer. G.; Cantley, L. C.; Lu, K. P. Science 1997, 278, 1957. (b) Liou,
Y. C.; Ryo, A.; Huang, H. K.; Lu, P. J .; Bronson, R.; Fujimori, F.;
Uchida, T.; Hunter, T.; Lu, K. P. Proc. Natl. Acad. Sci. U. S. A. 2002,
99, 1335.
(35) Hart, S. A.; Etzkorn, F. A. Peptides for the New Millenium:
Proc. 16th American Peptide Symp. 2000, 478.
(36) (a) Otaka, A.; Miyoshi, K.; Kaneko, M.; Tamamura, H.; Fujii,
N.; Nomizu, M.; Burke, T. R. J r.; Roller, P. P. J . Org. Chem. 1995, 60,
3967. (b) Otaka, A.; Mitsuyama, E.; Kinoshita, T.; Tamamura, H.; Fujii,
N. J . Org. Chem. 2000, 65, 4888.
1
(c ) 0.91, CHCl3); H NMR (300 MHz, CDCl3) δ 6.95 (d, J )
0.5 Hz, 2H), 5.61 (dd, J ) 3.5, 2.0 Hz, 1H), 3.43 (dd, J ) 7.0,
1.3 Hz, 1H), 3.33 (dd, J ) 9.7, 5.6 Hz, 1H), 3.18 (dd, J ) 9.7,
6.8 Hz, 1H), 3.05 (dt, J ) 6.9, 5.7 Hz, 1H), 2.70 (s, 6H), 2.35-
2.24 (m, 7H), 1.92-1.81 (m, 2H), 1.02 (s, 9H); Anal. Calcd for
C
21H31NO3S: C, 66.81; H, 8.28; N, 3.71. Found: C, 66.55; H,
8.28; N, 3.54.
(1R,2′S,E)-(1-[(ter t-Bu t oxy)m et h yl]-2-{2′-[2-m et h yl-2-
(m et h ylet h oxy)-2-sila p r op yl]cyclop en t ylid en e}et h yl)-
(37) Bannwarth, W.; Trzeciak, A. Helv.Chim. Acta 1987, 70, 175.
6158 J . Org. Chem., Vol. 67, No. 17, 2002

(E)-Alkene trans-Xaa-Pro Dipeptide Mimetics
[(2,4,6-tr im eth ylp h en yl)su lfon yl]a m in e (16) fr om 15. To
a solution of LiCl (898 mg, 21.2 mmol) and CuCN (949 mg,
10.6 mmol) in THF (20 mL) was added 13.2 mL (10.6 mmol)
of 0.8 M (i-PrO)Me2SiCH2MgCl in THF at -78 °C under argon
with additional stirring for 5 min. The mixture was allowed
to warm to 0 °C and then stirred for 10 min at this temper-
ature. To recooled solution of the organocopper reagent to -78
°C was added a solution of 1.0 g (2.7 mmol) of 15 in THF (3
mL) at -78 °C under argon. The reaction was continued for 2
h at -78 °C and then overnight at 0 °C. The reaction was
quenched at 0 °C by addition of saturated NH4Cl-28% NH4-
OH solution (1:1, 20 mL) with additional stirring at room
temperature. The mixture was extracted with Et2O, and the
extract was washed with brine, dried over MgSO4, and
concentrated in vacuo to give an oily product. Flash chromato-
graphic purification of the crude material over silica gel with
EtOAc-n-hexane (1:19) give 844 mg (62% yield) of the title
compound 16 and 278 mg (21% yield) of SN2-product 17 as
(1S,2′R,E)-2-(3′-(ter t-Bu toxy)-2′-{[(2,4,6-tr im eth ylph en yl)-
su lfon yl]am in o}pr opyliden e)cyclopen tan ecar boxylic acid
(L-Ser -ψ[(E)-CH dC]-D-P r o d er iva t ive 20) fr om 18. To a
suspension of 621 mg (1.5 mmol) of Dess-Martin periodinane
in CHCl3 (2 mL) was added a solution of 300 mg (0.7 mmol) of
18 in CHCl3 (1 mL) at 0 °C under argon. The reaction was
continued for 1 h at room temperature and then quenched with
25% Na2S2O3-saturated NaHCO3 solution (1:1, 10 mL) at 0
°C. After being stirred at room temperature for 15 min, the
mixture was extracted with Et2O. The extract was successively
washed with saturated NaHCO3 solution and H2O, dried over
MgSO4, and concentrated under reduced pressure to leave
residues. The residues were redissolved with t-BuOH (2 mL).
To the solution were successively added 2-methyl-2-butene (1.6
mL, 14.7 mmol) and an aqueous solution (1.5 mL) consisting
of NaClO2 (132 mg, 1.5 mmol) and NaH2PO4 (132 mg, 1.5
mmol) at room temperature. After being stirred for 15 h at
room temperature, the reaction was concentrated under
reduced pressure to give residues. To the residues was added
1 N HCl (2 mL), followed by extraction with EtOAc. The
extract was successively washed with 1 M Na2S2O3 and brine,
dried over MgSO4, and concentrated to leave an oil. Flash
chromatography of the oil over silica gel with EtOAc-n-hexane
(1:2) gave 202 mg (65% yield) of the title compound 20 as a
colorless oils. 16: [R]27 -0.8 (c ) 1.26, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 6.90 (d, J ) 0.5 Hz, 2H), 5.20 (d, J ) 3.5 Hz,
1H), 4.86 (ddd, J ) 9.1, 4.9, 2.5 Hz, 1H), 3.95 (m, 1H), 3.89-
3.81 (m, 1H), 3.27 (dd, J ) 8.9, 4.0 Hz, 1H), 3.15 (dd, J ) 8.9,
7.6 Hz, 1H), 2.60 (s, 6H), 2.28 (s, 3H), 2.11-1.97 (m, 3H), 1.91-
1.82 (m, 1H), 1.69-1.59 (m, 1H), 1.50-1.34 (m, 1H), 1.57 (s,
9H), 1.15 (d, J ) 1.8 Hz, 3H), 1.13 (d, J ) 1.8 Hz, 3H), 0.93
(dd, J ) 11.6, 7.0 Hz, 1H), 0.67 (dd, J ) 14.9, 3.7 Hz, 1H),
colorless oil: [R]26 -13.5 (c ) 0.96, CHCl3); 1H NMR (270
D
MHz, CDCl3) δ 6.93 (s, 2H), 5.49 (m, 1H), 5.31 (d, J ) 4.3 Hz,
1H), 3.69 (m, 1H), 3.25 (m, 3H), 2.60 (s, 6H), 2.29 (s, 3H), 2.09-
1.67 (m, 5H), 1.60-1.50 (m, 1H), 1.13 (s, 9H); HRMS (FAB)
m/z calcd for C22H34NO5S (MH+) 424.2158, found 424.2173.
0.84 (s, 3H), 0.76 (s, 3H); HRMS (FAB) m/z calcd for C27H46
-
NO4SSi (MH-) 508.2917, found 508.2908.
17: [R]21 +3.1 (c ) 0.33, CHCl3); 1H NMR (300 MHz,
D
(1S,2R)-{1-[(ter t-Bu toxy)m eth yl]-2-cyclop en t-1-en yl-2-
h ydr oxyeth yl}[(2,4,6-tr im eth ylph en yl)su lfon yl]am in e (21)
fr om 14. To a solution of 12.9 g (30.3 mmol) of Dess-Martin
periodinane in CHCl3 (10 mL) was added 6.0 g (15.2 mmol) of
14 in CHCl3 (10 mL) at 0 °C with additional stirring for 1 h at
room temperature. The reaction was quenched with saturated
Na2S2O3 and extracted with Et2O. The extract was successively
washed with saturated NaHCO3 and H2O, dried over MgSO4,
and concentrated to leave residue. The residue was dissolved
with Et2O (10 mL). To the solution was added 0.5 M Zn(BH4)2
in Et2O (30 mL, 15.0 mmol) under argon at -78 °C. The
reaction was continued at -78 °C for 30 min and then at 0 °C
overnight and quenched with 1 N HCl at -78 °C. The mixture
was allowed to warm to room temperature with stirring and
extracted with Et2O. The extract was washed with H2O, dried
over MgSO4, and concentrated to give crude materials. Flash
chromatographic purification of the crude materials over silica
gel with EtOAc-n-hexane (1:9) gave 2.9 g (49% yield) of the
CDCl3) δ 6.92 (d, J ) 0.3 Hz, 2H), 5.38 (m, 1H), 5.17 (d, J )
9.2 Hz, 1H), 3.91 (m, 1H), 3.14-3.05 (m, 1H), 2.92 (dd, J )
8.4, 3.9 Hz, 1H), 2.72-2.67 (m, 1H), 2.65 (s, 6H), 2.27 (s, 3H),
2.22-2.12 (m, 3H), 2.03-1.93 (m, 1H), 1.80-1.69 (m, 2H), 1.13
(d, J ) 1.7 Hz, 3H), 1.11 (d, J ) 1.7 Hz, 3H), 1.02 (s, 9H), 0.46
(dd, J ) 11.9, 14.9 Hz, 1H), 0.05-0.00 (m, 8H).
Con ver sion of SN2 P r od u ct 17 to Cor r esp on d in g Al-
coh ol Der iva tive 19. By a procedure identical with that
described for synthesis of 18 from 16 (next section), 178 mg
(0.4 mmol) of 17 was oxidized to alcohol derivative 19 (130
mg, 91% yield). Recrystallization of 19 from Et2O gave colorless
crystals: mp 121-123 °C; [R]25 +6.9 (c ) 1.01, CHCl3); 1H
D
NMR (300 MHz, CDCl3) δ 6.95 (s, 2H), 5.43 (m, 1H), 5.37 (d,
J ) 9.9 Hz, 1H), 3.96-3.88 (m, 1H), 3.69-3.61 (m, 1H), 3.45-
3.38 (m, 1H), 3.13 (dd, J ) 8.7, 1.6 Hz, 1H), 2.83 (dd, J ) 8.8,
3.7 Hz, 1H), 2.77-2.72 (m, 1H), 2.65 (s, 6H), 2.30 (s, 3H), 2.27-
2.10 (m, 2H), 1.81-1.71 (m, 2H), 1.55 (s, 9H); HRMS (FAB)
m/z calcd for C22H36NO4S (MH+) 410.2365, found 410.2370. An
X-ray structural analysis of 19 showed that the side reaction
of 15 with the organocopper reagent proceeded via SN2 path.
title compound 21 as a colorless oil: [R]23 -24.8 (c ) 0.12,
D
CHCl3); 1H NMR (270 MHz, CDCl3) δ 6.95 (s, 2H), 5.66 (m,
1H), 5.52 (d, J ) 8.6 Hz, 1H), 4.06 (s, 1H), 3.58 (d, J ) 8.9 Hz,
1H), 3.51 (dd, J ) 8.9, 2.6 Hz, 1H), 3.43-3.36 (m, 1H), 3.34-
3.30 (m, 1 H), 2.67 (s, 6H), 2.29-2.26 (m, 5H), 2.09-2.01 (m,
2H), 1.88-1.77 (m, 2H), 1.08 (s, 9H); HRMS (FAB) m/z calcd
for C21H34NO4S (MH+) 396.2208; found 396.2219. Attempted
conversion of 21 to anti-aziridine derivative 22 by a procedure
identical with that described for the synthesis of 15 from 14,
followed by flash chromatography, gave trace amount of
corresponding aziridine 22 limited for NMR analysis. 22: 1H
NMR (300 MHz, CDCl3) δ 6.92 (d, J ) 0.5 Hz, 2H), 5.73 (m,
1H), 3.88 (dd, J ) 10.3, 5.0 Hz, 1H), 3.69 (dd, J ) 10.3, 7.0
Hz, 1H), 3.46 (d, J ) 3.9 Hz, 1H), 3.04-2.98 (m, 1H), 2.68 (s,
6H), 2.33-2.27 (m, 5H), 2.19-2.10 (m, 2H), 1.86-1.75 (m, 2H),
1.16 (s, 9H).
(1R,2′S,E)-{1-[(ter t-Bu toxy)m eth yl]-2-[2′-(h yd r oxym e-
th yl)cyclop en tylid en e]eth yl}[(2,4,6-tr im eth ylp h en yl)su l-
fon yl]a m in e (18) fr om 16. To a solution of 500 mg (1.0 mmol)
of 16 in DMF (5 mL) were successively added solid KF (228
mg, 3.9 mmol) and 30% H2O2 aqueous solution (1.3 g, 11.8
mmol) at room temperature. After being stirred at room
temperature for 10 h, the reaction was diluted with H2O, and
extracted with Et2O. The extract was successively washed with
1 M Na2S2O3 solution and H2O and dried over MgSO4. The
solvent was removed by evaporation, followed by flash chro-
matography over silica gel with EtOAc-n-hexane (1:4), to give
332 mg (80% yield) of the title compound 18. Recrystallization
of 18 from Et2O gave colorless crystals: mp 111-112 °C; [R]26
D
-62.0 (c ) 1.26, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.96 (d,
J ) 0.5 Hz, 2H), 5.35 (d, J ) 1.8 Hz, 1H), 5.24 (ddd, J ) 9.0,
4.5, 2.4 Hz, 1H), 3.65-3.58 (m, 1H), 3.63 (dd, J ) 11.4, 5.2
Hz, 1H), 3.42 (dd, J ) 11.4, 6.3 Hz, 1H), 3.27-3.16 (m, 2H),
2.61 (s, 6H), 2.49 (m, 1H), 2.31 (s, 3H), 2.02-1.90 (m, 2H),
1.79-1.48 (m, 4H), 1.16 (s, 9H); Anal. Calcd for C22H35NO4S:
C, 64.51; H, 8.61; N, 3.42. Found: C, 64.24; H, 8.51; N, 3.33.
An X-ray structural analysis of the crystals indicated that 18
possesses trans-L-Ser-D-Pro configuration.
(1S,2S)-(ter t-Bu toxy)-N-{1-[(ter t-bu toxy)m eth yl]-2-cy-
clop en t -1-en yl-2-h yd r oxyet h yl}ca r b oxa m id e (25) fr om
24. To a solution of 13.3 g (49.2 mmol) of 24 in CH2Cl2 (50
mL) was added dropwise 95.4 mL (96.3 mmol) of 1.01 M
DIBAL in toluene at -78 °C under argon with additional
stirring at -78 °C until disappearance of the starting material
(ca. 1 h). To this solution was added cyclopentenyllithium-
ZnCl2-LiCl (96.3 mmol) in THF-hexane (1.7:1, 165 mL),
prepared by a procedure identical with that described for the
J . Org. Chem, Vol. 67, No. 17, 2002 6159

Otaka et al.
synthesis of 14, at -78 °C under argon. After being stirred
for 2 h at -78 °C, followed by additional stirring at room-
temperature overnight. The recooled reaction mixture to -78
°C was quenched with saturated citric acid, allowed to warm
to 0 °C, and extracted with EtOAc. The extract was succes-
sively washed with saturated citric acid and brine, dried over
MgSO4, and concentrated to leave residues. Flash chromato-
graphic purification of the residues over silica gel with EtOAc-
n-hexane (1:9) gave 6.3 g of the title compound 25 and 0.9 g of
6.0 Hz, 1H), 3.41-3.30 (m, 2H), 2.64-2.45 (m, 2H), 2.27-2.21
(m, 2H), 1.88-1.52 (m, 4H), 1.44 (s, 9H), 1.16 (s, 9H); HRMS
(FAB) m/z calcd for C18H34NO4 (MH+) 328.2488, found 328.2490.
Compound 30 (273 mg, 0.8 mmol) was converted to 248 mg
(87% yield) of the title compound 31 by a procedure identical
with that described for the synthesis of 20 from 18. 31:
colorless oil; [R]26D -32.8 (c ) 1.10, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 5.55 (d, J ) 7.2 Hz, 1H), 4.97 (s, 1H), 4.27 (s, 1H),
3.40-3.34 (m, 2H), 3.30 (dd, J ) 8.6, 4.6 Hz, 1H), 2.56 (t, J )
8.4, 1H), 2.34 (q, J ) 7.6 Hz, 1H), 2.04-1.97 (m, 1H), 1.96-
1.86 (m, 2H), 1.70-1.63 (m, 1H), 1.44 (s, 9H), 1.14 (s, 9H);
HRMS (FAB) m/z calcd for C18H30NO5 (MH-) 340.2123, found
340.2112.
DCHA Sa lt of 31. Treatment of a solution of 55 mg (0.2
mmol) of 31 in Et2O (0.5 mL) with dicyclohexylamine (32 µL,
0.2 mmol), followed by standing at room temperature, afforded
84 mg (99% yield) of corresponding DCHA salt as colorless
crystals: mp 141-144 °C; Anal. Calcd for C30H54N2O5: C,
68.93; H, 10.41; N, 5.36. Found: C, 68.63; H, 10.50; N, 5.14.
An X-ray structural analysis of the crystals indicated that 31
possesses trans-L-Ser-L-Pro configuration.
anti-isomer 26 in 48% combined yield as colorless oils. 25:
1
[R]27 +15.3 (c ) 1.90, CHCl3); H NMR (270 MHz, CDCl3) δ
D
5.68 (d, J ) 2.0 Hz, 1H), 5.23 (d, J ) 8.3 Hz, 1H), 4.51 (s, 1H),
3.78 (s, 1H), 3.69 (dd, J ) 9.2, 3.0 Hz, 1H), 3.60 (dd, J ) 9.2,
2.6 Hz, 1H), 2.40-2.17 (m, 4H), 1.87 (m, 2H), 1.43 (s, 9H), 1.20
(s, 9H); HRMS (FAB) m/z calcd for C17H32NO4 (MH+) 314.2331,
1
found 314.2323. 26: [R]28 +5.4 (c ) 1.47, CHCl3); H NMR
D
(270 MHz, CDCl3) δ 5.73 (d, J ) 1.7 Hz, 1H), 5.44 (d, J ) 7.8
Hz, 1H), 4.30 (s, 1H), 3.84-3.72 (m, 2H), 3.60 (dd, J ) 9.1, 2.5
Hz, 1H), 3.51 (dd, J ) 9.2, 2.5 Hz, 1H), 2.39-2.23 (m, 4H),
1.92 (m, 2H), 1.46 (s, 9H), 1.16 (s, 9H); HRMS (FAB) m/z calcd
for C17H32NO4 (MH+) 314.2331, found 314.2337.
(4S,5S)-ter t-Bu tyl 5-[(ter t-Bu toxy)m eth yl]-4-cycop en t-
1-en yl-2-oxo-3,1-oxa zolid in eca r boxyla te (tr a n s-oxa zoli-
d in on e d er iva tive 28) fr om 25. To a suspension of 777 mg
(19.4 mmol) of 60% NaH in THF (20 mL) was added 1.5 g (4.9
mmol) of 25 in THF (5 mL) at room temperature under argon.
The reaction was refluxed for 30 min and then cooled to 0 °C.
To the reaction mixture was added (Boc)2O (2.1 g, 9.2 mmol).
The reaction was stirred for 3 h at room temperature,
quenched with saturated NH4Cl solution, and extracted with
EtOAc. The extract was washed with brine, dried over MgSO4,
and concentrated to give residues. The residues were purified
by flash chromatography over silica gel with EtOAc-n-hexane
“Low er -Or d er ” Cya n ocu p r a te-BF 3 Com p lex (Ta ble 1,
r u n 2). To a solution of “lower-order” cyanocuprate (0.6 mmol)
in THF (2.4 mL) at -78 °C, which prepared by a procedure
identical with that described for the synthesis of 16 from 15,
was added BF3‚Et2O (72 µL, 0.6 mmol). After additional
stirring for 5 min at -78 °C, 50 mg (0.14 mmol) of 28 was
added at this temperature. The reaction was continued at -78
°C for 30 min and then at 0 °C for 3 h. Procedures identical to
those described above gave 60 mg (95% yield) of 29.
“High er -Or d er ” Cya n ocu p r a te Com p lex (Ta ble 1, r u n
3). To a solution of LiCl (50 mg, 1.2 mmol) and CuCN (53 mg,
0.6 mmol) in THF (1.5 mL) was added 1.7 mL (1.2 mmol) of
0.7 M (i-PrO)Me2SiCH2MgCl in THF at -78 °C under argon
with additional stirring for 5 min. The mixture was allowed
to warm to 0 °C and then stirred for 10 min at this temper-
ature. To recooled solution of the organocopper reagent to -78
°C was added 50 mg (0.14 mmol) of 28 at this temperature.
The reaction was continued at -78 °C for 30 min and then at
0 °C for 3 h. Procedures identical to those described above gave
62 mg (98% yield) of 29.
(1:19) to yield 884 mg (54% yield) of the title compound 28 as
1
a colorless oil: [R]26 -12.6 (c ) 1.03, CHCl3); H NMR (600
D
MHz, CDCl3) δ 5.80 (s, 1H), 4.96 (d, J ) 2.3 Hz, 1H), 4.02 (m,
1H), 3.64 (dd, J ) 9.2, 5.9 Hz, 1H), 3.52 (dd, J ) 9.4, 2.8 Hz,
1H), 2.39-2.35 (m, 3H), 2.32-2.27 (m, 1H), 1.87 (m, 1H), 1.55
(s, 9H), 1.18 (s, 9H); Anal. Calcd for C18H29NO5: C, 63.69; H,
8.61; N, 4.13. Found: C, 63.48; H, 8.74; N, 4.02.
(1R,2′R,E)-(ter t-Bu toxy)-N-(1-[(ter t-bu toxy)m eth yl]-2-
{2′-[2-m eth yl-2-(m eth yleth oxy)-2-sila p r op yl]cyclop en tyl-
id en e}et h yl)ca r boxa m id e (29) fr om 28. To a solution of
organocopper reagent (5.9 mmol) in THF (16 mL), prepared
by a procedure identical with that described for the synthesis
of 16, was added 0.5 g (1.5 mmol) of 28 in THF (2 mL) at -78
°C under argon. The reaction was stirred at -78 °C for 30 min
and then at 0 °C for 3 h, quenched with saturated NH4Cl-
28% NH4OH (1:1, 10 mL) at 0 °C, and stirred at room
temperature for 30 min. The mixture was extracted with Et2O.
The extract was washed with H2O, dried over MgSO4, and
concentrated to give an oil. The oily material was purified by
flash chromatography over silica gel with EtOAc-n-hexane
(1:7) to yield 617 mg (98% yield) of the title compound 29 as a
colorless oil: [R]27D -8.6 (c ) 1.05, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 5.20 (dd, J ) 8.6, 2.4 Hz, 1H), 4.78 (s, 1H), 4.24 (m,
1H), 3.99 (dt, J ) 12.2, 6.1 Hz, 1H), 3.39 (dd, J ) 9.0, 4.2 Hz,
1H), 3.27 (dd, J ) 8.9, 4.8 Hz, 1H), 2.51 (q, J ) 8.6 Hz, 1H),
2.37 (br, 1H), 2.16-2.07 (m, 1H), 1.96-1.88 (m, 1H), 1.80-
1.71 (m, 1H), 1.64-1.46 (m, 1H), 1.43 (s, 9H), 1.16 (s, 9H), 1.15
(d, J ) 6.7 Hz, 6H), 0.99 (dd, J ) 14.8, 3.8 Hz, 1H), 0.53 (dd,
J ) 14.8, 10.7 Hz, 1H), 0.16-0.02 (m, 6H); HRMS (FAB) m/z
calcd for C23H46NO4Si (MH+) 428.3196, found 428.3182.
“High er -Or d er ” Cya n ocu p r a te-BF 3 Com p lex (Ta ble 1,
r u n 4). To a solution of “higher-order” reagent (0.6 mmol)
described above at -78 °C was added BF3‚Et2O (72 µL, 0.6
mmol). After additional stirring for 5 min at -78 °C, 50 mg
(0.14 mmol) of 28 was added at this temperature. The reaction
was continued at -78 °C for 30 min and then at 0 °C for 3 h.
Procedures identical to those described above gave a crude
mixture of 29 and 36. The mixture was subjected to the
oxidation identical with that described for the synthesis of 18
from 16 to yield 37 mg (60% yield) of 30 and 21 mg (33% yield)
of 37 as racemates. Recrystallization of 37 from EtOAc-
hexane gave colorless cocrystals of the racemate: mp 104-
107 °C; [R]28 0 (c ) 0.30, CHCl3); 1H NMR (600 MHz, CDCl3)
D
δ 5.21 (d, J ) 7.9 Hz, 1H), 4.47 (s, 1H), 3.56-3.53 (m, 1H),
3.52-3.47 (m, 1H), 3.40-3.37 (m, 1H), 3.18 (t, J ) 7.8 Hz, 1H),
2.98 (s, 1H), 2.37-2.31 (m, 1H), 2.27-2.21 (m, 1H), 1.90-1.83
(m, 1H), 1.70-1.63 (m, 1H), 1.57-1.47 (m, 2H), 1.44 (s, 9H),
1.18 (s, 9H); HRMS (FAB) m/z calcd for C18H34NO4 (MH+)
328.2488, found 328.2503. An X-ray structural analysis of the
crystals indicated that 37 consists of racemate possessing
relative configuration corresponding to cis-L-Ser-D-Pro.
Ben zyl (1R,2′R,E)-2-{3′-(ter t-Bu toxy)-2′-[(ter t-bu toxy)-
ca r b on yla m in o]p r op ylid en e}cyclop en t a n eca r b oxyla t e
(40) fr om 31. To a solution of 231 mg (0.7 mmol) of 31 in DMF
(1 mL) were successively added DCHA (97 µL, 0.7 mmol) and
BnBr (97 µL, 0.8 mmol) at 0 °C. The reaction was stirred
overnight at room temperature, diluted with H2O, and ex-
tracted with EtOAc. The extract was washed with brine, dried
over MgSO4, and concentrated to leave residues. Flash chro-
matographic purification of the residues over silica gel with
EtOAc-n-hexane (1:7) gave 203 mg (70% yield) of the title
(1R,2′R,E)-2-{3′-(ter t-Bu toxy)-2′-[(ter t-bu toxy)ca r bon yl-
a m in o]p r op ylid en e}cyclop en ta n eca r boxylic a cid (L-Ser -
ψ[(E)-CHdC]-L-P r o d er iva tive 31) fr om 29. By a procedure
identical with that described for the synthesis of 18 from 16,
538 mg (1.3 mmol) of 29 was converted to 325 mg (79% yield)
of the corresponding alcohol derivative 30 as a colorless oil:
1
[R]26 -27.4 (c ) 1.42, CHCl3); H NMR (270 MHz, CDCl3) δ
D
5.27 (dd, J ) 8.6, 2.0 Hz, 1H), 4.85 (d, J ) 7.3 Hz, 1H), 4.29
(br, 1H), 3.57 (dd, J ) 10.9, 6.6 Hz, 1H), 3.47 (dd, J ) 10.9,
6160 J . Org. Chem., Vol. 67, No. 17, 2002

(E)-Alkene trans-Xaa-Pro Dipeptide Mimetics
compound 40 as a colorless oil: [R]19D -30.8 (c ) 0.07, CHCl3);
1H NMR (270 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 5.47 (dd, J
) 8.7, 2.1 Hz, 1H), 5.11 (s, 2H), 4.84 (s, 1H), 4.24 (m, 1H),
3.43-3.29 (m, 2H), 3.19 (dd, J ) 9.1, 4.8 Hz, 1H), 2.63-2.50
(m, 1H), 2.40-2.24 (m, 1H), 2.09-1.82 (m, 3H), 1.43 (s, 9H),
1.12 (s, 9H); HRMS (FAB) m/z calcd for C25H38NO5 (MH+)
432.2750, found 432.2737.
-22.3 (c ) 0.36, CHCl3); 1H NMR (270 MHz, CDCl3) δ 7.75 (d,
J ) 8.6 Hz, 2H), 7.39-7.29 (m, 7H), 5.35 (d, J ) 6.6 Hz, 1H),
5.12 (dd, J ) 15.0, 12.4 Hz, 2H), 4.61 (s, 1H), 4.39 (s, 1H),
3.97 (dd, J ) 9.6, 3.6 Hz, 1H), 3.86 (dd, J ) 9.9, 5.3 Hz, 1H),
3.45 (t, J ) 7.3 Hz, 1H), 2.49-2.34 (m, 4H), 2.49-2.13 (m, 1H),
1.82-2.09 (m, 3H), 1.72-1.51 (m, 1H), 1.40 (s, 9H). Without
further chracterization, the tosylated material (143 mg, 0.3
mmol) was converted to the title compound by the reaction
with NaI (81 mg, 0.5 mmol) in acetone (1.5 mL) at room
temperature. The reaction was stirred for 30 h at room
temperature, diluted with H2O, and extracted with EtOAc. The
extract was washed with brine, dried over MgSO4, and
concentrated to leave residues. Flash chromatographic puri-
fication of the residues over silica gel with EtOAc-n-hexane
(1:9) gave 61 mg (67% yield) of the title compound 43 as a
Ben zyl (1R,2′R,E)-2-{2′-[(ter t-Bu toxy)ca r bon yla m in o]-
3′-h yd r oxyp r op ylid en e}cyclop en t a n eca r b oxyla t e (41)
fr om 40. To a solution of 191 mg (0.4 mmol) of 40 in CH2Cl2
(0.5 mL) was added TFA (0.5 mL) at 0 °C with additional
stirring for 1 h at this temperature. After removal of TFA by
N2-stream, the residues were dissolved with THF (1 mL). The
mixture was neutralized by Et3N, followed by successive
addition of Et3N (56 µL, 0.4 mmol) and (Boc)2O (193 mg, 0.9
mmol). The reaction was stirred overnight at room tempera-
ture, extracted with EtOAc. The extract was washed with
brine, dried over MgSO4, and concentrated to give oily materi-
als. Flash chromatographic purification of the oil over silica
gel with EtOAc-n-hexane (1:4) yielded 152 mg (91% yield) of
colorless oil: [R]27 -30.8 (c ) 0.07, CHCl3); 1H NMR (270
D
MHz, CDCl3) δ 7.39-7.32 (m, 5H), 5.35 (dd, J ) 8.3, 2.3 Hz,
1H), 5.14 (dd, J ) 17.5, 12.2 Hz, 2H), 4.62 (s, 1H), 4.18 (m,
1H), 3.37 (t, J ) 7.1 Hz, 1H), 3.31-3.11 (m, 2H), 2.45-2.32
(m, 2H), 2.13-1.92 (m, 3H), 1.90-1.60 (m, 1H), 1.44 (s, 9H);
HRMS (FAB) m/z calcd for C21H29NO4I (MH+) 486.1143, found
486.1161.
the title compound 41 as a colorless solid: [R]19 -44.9 (c )
D
0.09, CHCl3); 1H NMR (270 MHz, CDCl3) δ 7.40-7.30 (m, 5H),
5.26 (ddd, J ) 8.9, 4.6, 2.7 Hz, 1H), 5.13 (dd, J ) 26.1, 12.2
Hz, 2H), 4.65 (m, 1H), 4.27 (m, 1H), 3.46 (dd, J ) 5.6 Hz, 2H),
3.42-3.34 (m, 1H), 2.58-2.46 (m, 1H), 2.42-2.25 (m, 1H),
2.11-1.82 (m, 3H), 1.54 (s, 9H); HRMS (FAB) m/z calcd for
Ben zyl (1R,2′R,E)-2-{2′-[(ter t-Bu toxy)ca r bon yla m in o]-
3′-(t r ip h e n ylm e t h ylt h io)p r op ylid e n e }cyclop e n t a n e -
ca r boxyla te (L-Cys-ψ[(E)-CH dC]-L-P r o d er iva tive 44)
fr om 43. To a solution of 5 mg (0.02 mmol) of triphenyl-
methanethiol in DMF (0.5 mL) was successively added 43 (8
mg, 0.02 mmol) in DMF (0.5 mL) and Et3N (3 µL, 0.02 mL) at
0 °C. The reaction was continued for 10 h at room temperature,
quenched with saturated NH4Cl (1 mL), and extracted with
EtOAc. The extract was washed with brine, dried over MgSO4,
and concentrated. Flash chromatographic purification (EtOAc-
n-hexane ) 1:9) of the crude materials gave 5 mg (51% yield)
C
21H30NO5 (MH+) 376.2124, found 376.2135.
Ben zyl (1R,2′R,E)-2-{(3′-Bis(m eth oxy)p h osp h a r yloxy)-
2′-[(ter t-bu toxy)ca r bon yla m in o]p r op ylid en e}cyclop en t-
a n eca r boxyla te (L-p Ser -ψ[(E)-CHdC]-L-P r o Der iva tive
42) fr om 41. To a solution containing tetrazole (19 mg, 0.3
mmol) and 41 (50 mg, 0.1 mmol) in MeCN (0.5 mL) was added
dimethyl N,N-diisopropylphosphramidite (19 mg, 0.2 mmol)
in MeCN (0.5 mL) at 0 °C under argon. After the reaction was
stirred at 0 °C for 1 h, 30% H2O2 solution (23 mg, 0.2 mmol)
was added at 0 °C with additional stirring for 1 h. Then the
mixture was diluted with H2O and extracted with Et2O. The
extract was successively washed with 1 M Na2S2O3, saturated
NaHCO3, and H2O, dried over MgSO4, and concentrated. After
flash chromatography over silica gel with EtOAc-n-hexane
(1:4), the title compound 42 (28 mg, 44% yield) as a colorless
of the title compound 44 as a colorless oil: [R]26 -43.9 (c )
D
0.11, CHCl3); 1H NMR (270 MHz, CDCl3) δ 7.43-7.17 (m, 20H),
5.29 (dd, J ) 8.6, 2.3 Hz, 1H), 5.02-5.14 (m, 2H), 4.42 (s, 1H),
4.16 (s, 1H), 3.32 (t, J ) 7.3 Hz, 1H), 2.35-2.17 (m, 4H), 2.05-
1.86 (m, 3H), 1.56 (m, 1H), 1.10 (s, 9H); HRMS (FAB) m/z calcd
for C40H42NO4S (MH-) 632.2834, found 632.2852.
Ackn owledgm en t. We thank Dr. Terrence R. Burke,
J r., NCI, NIH, Frederick, MD 21702-1201, for proofing
the manuscript and providing useful comments. This
research was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, J apan, the
J apan Society for the Promotion of Science, and the
J apan Health Science Foundation.
oil was obtained. 42: [R]18 -17.5 (c ) 0.11, CHCl3); 1H NMR
D
(270 MHz, CDCl3) δ 7.40-7.31 (m, 5H), 5.37 (dd, J ) 8.6, 2.3
Hz, 1H), 5.12 (dd, J ) 13.9, 12.5 Hz, 2H), 4.86 (s, 1H), 4.44 (s,
1H), 4.00-3.82 (m, 2H), 3.74 (dd, J ) 11.0, 1.5 Hz, 6H), 3.38
(t, J ) 7.3, 1H), 2.61-2.46 (m, 1H), 2.41-2.26 (m, 1H), 2.08-
1.84 (m, 3H), 1.74-1.58 (m, 1H), 1.43 (s, 9H); HRMS (FAB)
m/z calcd for C23H35NO8P (MH+) 484.2100, found 484.2096.
Ben zyl (1R,2′R,E)-2-{2′-[(ter t-Bu toxy)ca r bon yla m in o]-
3′-iod op r op ylid en e}cyclop en ta n eca r boxyla te (43) fr om
41. To a solution of 65 mg (0.2 mmol) of 41 in CHCl3 (0.5 mL)
were successively added pyridine (140 µL, 1.7 mmol) and TsCl
(165 mg, 0.9 mmol) at 0 °C. The reaction was stirred for 30
min at 0 °C, diluted with H2O, and extracted with EtOAc. The
extract was successively washed with saturated citric acid and
brine, dried over MgSO4, and concentrated to give oily materi-
als. After flash chromatography over silica gel with EtOAc-
n-hexane (1:9), tosylated compound (65 mg, 71% yield) as a
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of 35 from 26. ORTEP diagrams for
18, 19, 31, and 37 and their CIF files. Copies of 1H NMR
spectra of compounds 15, 22, 28, 31, 32, and 35 including NOE
1
spectra for 15, 22, 28, and 32. Copies of H NMR spectra in
comparison between 30 and 34 or 30 and 37. This material is
available free of charge via the Internet at http://pubs.acs.org.
colorless oil was obtained. The tosylated compound: [R]24
J O025922U
D
J . Org. Chem, Vol. 67, No. 17, 2002 6161