Rhodium-catalyzed reductive cyclization of 1,6-enynes and stereoselective synthesis of the putative structure of lucentamycin A and its stereoisomers

Article abstract of DOI:10.1016/j.tet.2011.12.075

A Rh-catalyzed diastereoselective reductive cyclization, mediated by hydrogen, of optically active 1,6-enynes using chiral BINAP was successfully applied to the total synthesis of four stereoisomers of the proposed structure of lucentamycin A. In order to

Full text of DOI:10.1016/j.tet.2011.12.075

Tetrahedron 68 (2012) 1918e1925
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Tetrahedron
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Rhodium-catalyzed reductive cyclization of 1,6-enynes and stereoselective
synthesis of the putative structure of lucentamycin A and its stereoisomers
Young Jin Ham a, Hana Yu a, Nam Doo Kim b, Jung-Mi Hah a, Khalid B. Selim a, Hwan Geun Choi a,
,
Taebo Sim a
*
a Future Convergence Research Division, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, Republic of Korea
b Department of Biotechnology, Yonsei University, 262 Seongsanno, Seodaemun-Gu, Seoul 120-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A Rh-catalyzed diastereoselective reductive cyclization, mediated by hydrogen, of optically active 1,6-
enynes using chiral BINAP was successfully applied to the total synthesis of four stereoisomers of the
proposed structure of lucentamycin A. In order to synthesize two of these four stereoisomers, we suc-
cessfully constructed chiral proline derivatives bearing cis-carbon substituents at C2 and C3 positions
based on Krische’s methodology, which has very rarely been reported. Anti-proliferative activities on
HCT-116 cell line and NMR data of these four stereoisomers were compared with those of naturally
occurring lucentamycine A. The results show that the proposed structure of lucentamycin A needs
revision.
Received 11 November 2011
Received in revised form 28 December 2011
Accepted 28 December 2011
Available online 2 January 2012
Keywords:
Lucentamycin A
Structure revision
1,6-Enynes
Ó 2012 Elsevier Ltd. All rights reserved.
Reductive cyclization
Natural product
1. Introduction
Lindsley and co-workers2 have recently synthesized the puta-
tive 8-epi-lucentamycin A (1d) instead of the natural product owing
Lucentamycin A was isolated by Fenical and co-workers1 from
the culture extract of an actinomycete Nocardiopsis lucentensis. This
natural product has aroused much interest since it displays good
anti-proliferative activity against HCT-116 (human colon cancer cell
to the failure of a planned epimerization step. Based on an as-
sessment of anti-proliferative activity of putative 8-epi-lucenta-
mycin A (1d), Lindsley suggested that the C8 stereochemistry of
lucentamycin A is essential for its anti-proliferative properties. In
the interim period, Valle and co-workers3 have accomplished the
synthesis of the proposed structure of lucentamycin A (1a) by using
a glycine enolate-Claisen rearrangement based strategy but found
that the NMR spectrum of the synthetic material is not identical
with that of the naturally occurring substance. This discrepancy led
Valle to suggest that the absolute stereochemistry of the proline
residue in the putative structure of lucentamycin A (1a) should be
revised. Since we were approaching completion of the synthesis of
putative lucentamycin A at the time, this suggestion prompted us to
initiate a program to prepare all four possible stereoisomers cor-
responding to the two contiguous C2 and C3 stereocenters in the
proline core of this substance. The goal was to elucidate the correct
structure/stereochemistry of the natural product with the hope
that either of the two stereoisomers 1b and 1c (Scheme 1) would
have identical spectroscopic and biological properties with natu-
rally occurring lucentamycin A. For construction of the four ste-
reoisomers of the proline core of lucentamycin A, we selected
a strategy that employs Rh-catalyzed reductive cyclization, in the
presence of hydrogen, using chiral BINAP ligands and two different
optically active 1,6-enyne substrates, one of 2-(but-2-ynylamino)
line) with an IC50 value of 0.20
mM. The chemical structure of
lucentamycin A was proposed to be 1a, a tripeptide composed of
N-acyl homoarginine, 3-methyl-4-ethylideneproline, and leucine
(Fig. 1).
Fig. 1. Proposed structure of putative lucentamycin A.
* Corresponding author. Tel.: þ82 2 958 6347; fax: þ82 2 958 5189; e-mail
address: tbsim@kist.re.kr (T. Sim).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.075

Y.J. Ham et al. / Tetrahedron 68 (2012) 1918e1925
1919
but-3-en-1-ol (4), which serves as an ‘open’ substrate and the other
3-(but-2-ynyl)-4-vinyloxazolidin-2-one (3), that is, a ‘closed’ sub-
strate. The Rh-catalyzed reductive cyclization methodology we
adopted was elegantly developed by Krische and co-workers.4
configuration at C2 in each case originates from the chirality of the
starting oxazolidinone.
Table 1
Diastereoselective Rh-catalyzed reductive cyclization of 1,6-enynea
Entry
Substrate
BINAP
Product
trans/cisb
1c
2c
3
4
5
6
7
8
3a
3b
4a
4b
R
S
S
R
R
S
rac
PPh3
5b
5d
2b/2a
2d/2c
MOM-2b/MOM-2a
MOM-2b/MOM-2a
2b/2a
d
d
d
3:1
3:1
1:4
4:1
1:1
d
4a*d
4a*d
4a
4a
a
Reaction condition: [Rh(cod)2]BF4 (6 mol %), (R)- or (S)-BINAP (9 mol %), H2
Scheme 1. Retrosynthetic analysis of putative lucentamycin A (1a) and its stereoiso-
mers 1bed.
(1 atm), DCE (substrate, 0.04 M), rt, 2 h.
b
Ratio estimated by HPLC analysis after replacement of Boc group on 2 with Fmoc
group.
c
Only a trace amount of the desired product was formed and the substrate was
Cyclization reactions of 1,6-enynes,5 using various transition
metals, such as Ti,2,6 Pd,7 Co,8 Rh,9 Au,10 Fe,11 Pt,12 Y,13 and Ru14 have
been applied to the construction of several kinds of five-membered
ring frameworks over the past two decades. For example, pyrroli-
dine or tetrahydrofuran derivatives, bearing substituents at C2 and/
or C3, have been generated by employing a metal-catalyzed re-
ductive cyclization process.15 However, it is very rare that cis-di-
astereomers can be produced predominantly when constructing
pyrrolidine derivatives possessing two contiguous stereocenters at
C2 and C3 by using this approach.15a,b It is also worth emphasizing
that Lindsley and co-workers planned to obtain the cis-proline core
of putative lucentamycin A by epimerization of a trans-proline
precursor, which was constructed via a titanium-mediated cyclo-
isomerization reaction but modified their plan and finally synthe-
recovered.
d
4a*: MOM-protected version of 4a: (S)-tert-butyl but-2-ynyl(1-(methox-
ymethoxy)but-3-en-2-yl)carbamate.
sized 8-epi-lucentamycin
A owing to failure of the desired
epimerization.2
We envisaged that the relative stereochemical relationship be-
tween C2 and C3 in pyrrolidine products could be controlled in the
reductive cyclization process by employing chiral RheBINAP cata-
lysts and two types (open or closed) of starting chiral 1,6-enynes.
The results of the investigation described below validate this pro-
posal and show that the proline core possessing the cis C2eC3
relative stereorelationship can be generated directly. This stereo-
selective Rh-catalyzed reductive cyclization procedure enabled the
synthesis of the four possible stereoisomers (1aed, Scheme 1) of
the pyrrolidine core present in the putative lucentamycin A and led
to the elucidation that the proposed structure of the natural
product needs revision.
2. Results and discussion
The synthesis of the four stereoisomers of (Z)-(4-ethylidene-3-
methylpyrrolidin-2-yl)methanol [2a: (2S,3R), 2b: (2S,3S), 2c:
(2R,3S), 2d: (2R,3R)] began with 3-(but-2-ynyl)-4-vinyloxazolidin-
2-one8a (3a or 3b), prepared from -vinyl glycine16 and tert-
L- or D
butyl but-2-ynyl(1-hydroxybut-3-en-2-yl)carbamate (4a or 4b),
generated by hydrolysis and Boc-protection of 3a or 3b. According
to earlier suggestions,4 reductive cyclization reactions were con-
ducted by using [Rh(cod)2]BF4 (6 mol %) and (R)- or (S)-BINAP
(9 mol %) in 1,2-dichloroethane (0.04 M substrate) under hydrogen
atmosphere at room temperature for 2 h. The diastereoselectivities
of the processes, depending on the substrate (closed 3 or open 4),
and the chirality (R or S) of BINAP used in these processes,
are recorded in Table 1 and Scheme 2. The C3 absolute configura-
tions of the products are easily determined by assessing the
C2eC3 relative stereochemistry by using Nuclear Overhauser
Effect Spectroscopy (NOESY) experiments since the absolute
Scheme 2. Synthesis of pyrrolidine derivatives 2aed.
The diastereoselectivities in products of reactions of the closed
system 3a or 3b were assessed by 1H NMR analyses of both 5b and
5d and pyrrolidines 2b and 2d, derived from 5b or 5d through se-
quential hydrolysis and Boc-protection (Scheme 2). In the case of

1920
Y.J. Ham et al. / Tetrahedron 68 (2012) 1918e1925
‘open’ systems 4a and 4b, the diastereomer ratios of reductive cy-
clization products were determined by HPLC investigation of the
crude mixture containing the pyrrolidine products 2aed (Scheme 2
and entries 3e7 in Table 1, after conversion of Boc to Fmoc). Boc
group of 2 was converted to Fmoc group, that is, a suitable chro-
mophore for UV-triggered HPLC analysis.
In the ‘closed’ system, reductive cyclizations of the (2S)-sub-
strate 3a/(S)-BINAP and (2R)-substrate 3b/(R)-BINAP produce al-
most quantitatively the trans-(7aS,7S)-isomer 5b in 76% yield and
the trans-(7aR,7R)-isomer 5d in 73% yield, respectively (Scheme 2).
Steric hindrance generated by the rigid oxazolidinone ring in the
closed system might force the BINAP-ligated rhodium to be posi-
tioned on the unhindered convex face, a result that would lead to
predominant formation of the trans-isomer. In contrast, it turned
out that the combinations of the (2S)-substrate 3a/(R)-BINAP and
its enantiomeric pair (Table 1, entries 1 and 2, respectively) are
resistant to this reductive cyclization reaction.
In the case of the ‘open’ system, reductive cyclization of (2S)-
substrate 4a with (R)-BINAP leads to production of the cis-(2S,3R)-
isomer 2a preferentially (5:1 dr, Scheme 2) in 76% yield (from 4a to
5a). However, the diastereoselectivity of the reaction promoted by
the (S)-BINAP catalyst is 3:1 in favor of the trans-(2S,3S)-isomer 2b
(entry 3). As for (2R)-substrate 4b, reaction with the (R)-BINAP
catalyst results in a 3:1 mixture of stereoisomers favoring the trans-
(2R,3R)-isomer 2d (entry 4) and the cis-(2R,3S)-isomer 2c is ob-
tained as a major product when (S)-BINAP is employed (5:1 dr,
Scheme 2).
the proline derivatives 6aed with HATU/DIEA and H-Leu-OMe
leads to the formation of the leucine methyl esters 7aed in 37e87%
yield. Following HCl-mediated N-Boc deprotection, amide coupling
reactions to arginine derivative 8 are carried out using HATU/DIEA
to yield 33e58% of the respective tripeptides 9aed. Saponification
of methyl ester groups in 9aed, followed by N-Boc deprotection
using 25% TFA provides the four stereoisomers of putative lucen-
tamycin A, which are purified by reverse-phase HPLC and lyophi-
lized to afford desired substances as white solids in 40e88% yield.
The (8S,9R)-isomer 1a: ½a D25
ꢁ34.8 (c 0.175 in MeOH) has an iden-
ꢀ
tical 1H NMR spectrum and almost the same optical rotation as the
substance synthesized by Valle and co-workers, ½a D25
ꢁ35.2 (c 0.500
ꢀ
in MeOH). As mentioned above, Valle suggested that the absolute
stereochemistry of proline core in the putative structure of lucen-
tamycin A proposed by Fenical and co-workers should be revised.
Our anticipation that either 1b or 1c would be identical with nat-
ural lucentamycin A turned out to be incorrect. The assessment of
the NMR data demonstrates that none of the four final compounds
1aed is naturally occurring lucentamycin A.
In reactions of the ‘open’ substrates 4, the configuration of the
newly created C3 center depends on the chirality of BINAP. When
BINAP having the same configuration as that of C2 in 4 is employed,
the trans-isomer is generated as the major product with modest
diastereoselectivities (entries 3 and 4). However, BINAP bearing the
opposite configuration relative to that of C2 in 4 promotes pro-
cesses that yield the cis-isomer preferentially (Scheme 2). As
mentioned above, reductive cyclization reactions that afford C2eC3
cis-proline derivatives have rarely been described; Krische reported
that acetylenic aldehydes were predominantly transformed to the
corresponding C2 (methyl)-C3 (hydroxyl) cis-pyrrolidine de-
rivatives by Rh-catalyzed reductive cyclization.15a,b Therefore, the
results of our effort would be significant since we successfully
constructed chiral proline derivatives bearing cis-carbon sub-
stituents at C2 and C3 positions. In order to investigate whether the
free hydroxyl group in 4a affects the diastereoselectivity, MOM-
protected version of 4a was subjected to this reductive cyclization
reaction (entries 5 and 6). It turned out that the hydroxyl group in
4a exerts modest effects on control of the diastereoselectivity. It
should be noted that the employment of (rac)-BINAP resulted in
complete loss of diastereoselectivity (entry 7) and no desired
product was observed when BINAP was replaced with triphenyl-
phosphine (entry 8).4a
Scheme 3. Synthesis of putative lucentamycin A (1a) and its stereoisomers 1bed.
Reagent and conditions: a. DMP, DCM, rt, 1 h; b. NaClO2, NaH2PO4, 2-methyl-2-butene,
t-BuOH/H2O, rt, 1 h, 84e95% (two steps); c. H-Leu-OMe, HATU, DIEA, THF, rt, 5 h,
37e87%; d. HCl, rt, 15 h; e. 8, HATU, DIEA, THF, rt, 5 h, 33e58% (two steps); f. LiOH, THF/
H2O, 0 ꢂC, 3 h; g. 25% TFA, DCM, rt, 15 h, 40e88% (two steps).
The two cis pyrrolidines 2a and 2c, generated by reaction of the
open system, are transformed to the corresponding bicycles 5a
and 5c through Boc-deprotection followed by oxazolidinone cy-
clization (Scheme 2) as a result of the fact that the latter substances
can be more readily separable by silica column chromatography as
pure isomers. (Z)-(4-ethylidene-3-methylpyrrolidin-2-yl)methanol
compounds (2aed), which serve as precursors of the putative
lucentamycin A proline core, are prepared using the reaction con-
ditions displayed in Scheme 2. With the four stereoisomers of (Z)-
(4-ethylidene-3-methylpyrrolidin-2-yl)methanol (2aed) in hand,
the stage was set for the straightforward synthesis of the four
stereoisomers of putative lucentamycin A utilizing the routes out-
lined in Scheme 3. The primary alcohol groups of 2aed were oxi-
dized to afford the corresponding carboxylic acids 6aed in 84e95%
yield through a two steps procedure involving DesseMartin peri-
odinane oxidation followed by oxidation with NaClO2. Treatment of
In addition, all four substances 1aed display exceptionally low
(IC50 values of over 50
trast to natural lucentamycin A, which is reported to have a signif-
icant anti-proliferative activity (IC50 of 0.2 M) on HCT-116. Taken
mM) cytotoxicities against HCT-116 in con-
m
together, the observations made in this effort show that natural
lucentamycin A does not have the structures/stereochemistries of
the four final compounds 1aed.
3. Conclusion
On the basis of Krische’s methodology, this study described
above has led to an efficient, Rh-catalyzed reductive cyclization
based, one-potstereoselectivesynthesisof fourstereoisomers of(Z)-
4-ethylidene-2-hydroxymethyl-3-methylpyrrolidine. Especially an
important finding is that the two cis-isomers, (2S,3R) and (2R,3S),

Y.J. Ham et al. / Tetrahedron 68 (2012) 1918e1925
1921
can be prepared in this fashion. As mentioned above, Rh-catalyzed
reductive cyclization reactions that afford chiral proline de-
rivatives bearing cis-carbon substituents at C2 and C3 positions
have very rarely been described. Thus, this process might serve as
the basis for an efficient and stereocontrolled methodology for
121.8, 80.7, 72.1, 67.2, 58.2, 32.2, 3.4 ppm; MS (ESI): m/z¼166
[MþH]þ.
4.1.3. (S)-tert-Butyl but-2-ynyl(1-hydroxybut-3-en-2-yl)carbamate
(4a). Compound 3a (500 mg, 3.02 mmol) was treated with 1.25 M
NaOH solution (15.0 mL, 18.8 mmol) in ethanol/H2O (3:1) and the
reaction mixture was heated at 80 ꢂC for 3 h. After cooling to room
temperature, the reaction mixture was diluted with Et2O, dried
over MgSO4, filtered, and concentrated. The residue was dissolved
in dichloromethane (6.0 mL), and di-tert-butyl dicarbonate
(1.40 mL, 6.04 mmol) and triethylamine (0.63 mL, 4.53 mmol) were
added. After stirring at room temperature for 2 h, the volatiles were
removed under reduced pressure to give crude oil. The crude
product was purified by column chromatography (SiO2, hexane/
EtOAc¼4:1) to afford compound 4a (620 mg, 85%) as colorless oil. Rf
construction
of
(Z)-4-alkylidene-2-hydroxymethyl-3-
alkylpyrrolidine and tetrahydrofuran frameworks. Finally, the
Rh-catalyzed reductive cyclization reaction, using chiral BINAP
ligand and optically active 1,6-enyne substrates, has been used to
synthesize the four possible stereoisomers of the proposed
structure of lucentamycin A. The fact that the properties of these
substances do not match those of the natural product suggests the
putative structure of lucentamycin A, proposed by Fenical and co-
workers, needs to be revised. We are currently attempting to iso-
late natural lucentamycin A in order to elucidate its actual
structure.
0.20 (hexane/EtOAc¼4:1); IR (neat)
n
¼3467, 2970, 1737, 1688, 1366,
1265, 1166, 735 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
d
¼5.69 (m, 1H),
4. Experimental section
4.1. General
5.06 (d, J¼9.1 Hz, 1H), 5.02 (d, J¼15.1 Hz, 1H), 4.38 (br s, 1H), 3.94
(br, 1H), 3.67 (br s, 1H), 3.64 (m, 2H), 3.00 (br s, 1H), 1.63 (s, 3H),
1.31 ppm (s, 9H); 13C NMR (100 MHz, CDCl3):
d
¼155.4, 133.7, 117.2,
80.3, 78.4, 75.9, 62.6, 60.1, 34.0, 28.2, 3.2 ppm; MS (ESI): m/z¼262
[MþNa]þ; HRMS (MALDI): m/z: calcd for C13H21NO3Na: 262.1419;
found: 262.1418 [MþNa]þ.
Thin-layer chromatography (TLC) was performed using silica gel
60 F254 pre-coated plates (0.25 mm). Flash chromatography was
performed using silica gel (230e400 mesh). Reaction progress was
monitored by TLC analysis using a UV lamp, ninhydrin, or p-ani-
saldehyde stain(s) for detection purposes. NMR spectra were
recorded on 400 MHz spectrometer. 1H and 13C NMR chemical
shifts are reported as using residual solvent as an internal standard
and J-values are reported in hertz. NOESY experiment was con-
ducted by 900 MHz NMR. Infra red (IR) spectra were recorded in
wave numbers (cmꢁ1). Low resolution mass spectra (LRMS) were
obtained on an analytical LC/MS with electrospray ionization. High
resolution mass spectra (HRMS) were recorded on a 4.7 T ESI-FTMS,
a ESI-TOF or a MALDI-TOF mass spectrometer. Preparative (Prep
4.1.4. (R)-tert-Butyl but-2-ynyl(1-hydroxybut-3-en-2-yl)carbamate
(4b). Compound 4b was prepared in 74% yield from compound 3b
according to the procedures for the preparation of compound 4a as
colorless oil. Rf 0.20 (hexane/EtOAc¼2:1); 1H NMR (400 MHz,
CDCl3):
d
¼5.69 (m, 1H), 5.06 (d, J¼9.1 Hz, 1H), 5.02 (d, J¼14.9 Hz,
1H), 4.38 (br s, 1H), 3.94 (br s, 1H), 3.67 (br s, 1H), 3.64 (m, 2H), 3.00
(br s, 1H), 1.63 (s, 3H), 1.31 ppm (s, 9H); 13C NMR (100 MHz, CDCl3):
d
¼155.2, 133.9, 117.0, 80.1, 78.2, 75.9, 62.4, 59.8, 33.9, 28.1, 3.1 ppm;
MS (ESI) m/z¼262 [MþNa]þ; HRMS (MALDI): m/z: calcd for
C13H21NO3Na: 262.1419; found: 262.1409 [MþNa]þ.
C18, 5
m
m, 19ꢃ50 mm column) and analytical (C18, 5
mm,
4.8ꢃ50 mm column) RP-HPLC was performed with 5e95% aq
acetonitrile for 5 min or 45e95% aq methanol for 5 min (with
0.035% trifluoroacetic acid) as eluent.
4.1.5. (7R,7aS,Z)-6-Ethylidene-7-methyltetrahydropyrrolo[1,2-c]ox-
azol-3(1H)-one (5a). Compound 4a (113 mg, 0.472 mmol),
Rh(cod)2BF4 (11.3 mg, 0.028 mmol), and (R)-BINAP (26.4 mg,
0.042 mmol) were dissolved in 1,2-dichloroethane (11 mL, 0.04 M).
The reaction mixture was stirred under hydrogen atmosphere
(1 atm) at room temperature for 2 h. The volatiles were removed
under reduced pressure to give crude product. The crude product
was dissolved in EtOAc and filtered through silica pad, then con-
centrated. The residue was dissolved in Et2O (1.0 mL) and then
slowly treated with 4 N HCl solution in dioxane (1.0 mL, 4.0 mmol)
at 0 ꢂC. After stirring at room temperature for 15 h, the reaction
mixture was concentrated under reduced pressure. The resulting
residue was dissolved in dichloromethane (2.0 mL) and treated
4.1.1. (S)-3-(But-2-ynyl)-4-vinyloxazolidin-2-one (3a).8a (S)-4-Vinyl-
oxazolidin-2-one (1.0 g, 8.84 mmol) was dissolved in THF
(30.0 mL). Sodium hydride (60% dispersion in oil, 530 mg,
13.3 mmol) was added portionwise at 0 ꢂC. After stirring for 30 min,
the reaction mixture was treated with 1-bromo-2-butyne
(0.850 mL, 9.70 mmol) and TBAI (1.60 g, 4.42 mmol) at 0 ꢂC. After
stirring at room temperature for 3 h, the reaction mixture was di-
luted with EtOAc and washed with water. The organic layer was
dried over MgSO4, filtered, and concentrated. The product was pu-
rified by column chromatography (SiO2, hexane/EtOAc¼4:1) to af-
ford compound 3a (1.30 g, 89%) as colorless oil. Rf 0.38 (hexane/
with triethylamine (100
mL, 0.615 mmol) and 1,1-
carbonyldiimidazole (73 mg, 0.451 mmol). After stirring at room
temperature for 1 h, the reaction mixture was diluted with
dichloromethane and washed with water and brine. The organic
layer was dried over MgSO4, filtered, and concentrated under re-
duced pressure. The crude product was purified by column chro-
matography (SiO2, hexane/EtOAc¼4:1) to afford compound 5a
(60 mg, 76%) as colorless oil. Rf 0.40 (hexane/EtOAc¼2:1); IR (neat)
EtOAc¼2:1); IR (neat)
n
¼3377, 2977, 1678, 1407, 1167, 1025,
775 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
d
¼5.38 (m, 1H), 5.07 (d,
J¼17.1 Hz, 1H), 5.04 (d, J¼10.2 Hz, 1H), 4.10 (t, J¼8.4 Hz, 1H), 4.04 (t,
J¼7.7 Hz,1H), 3.81 (dd, J¼17.3, 2.4 Hz,1H), 3.58 (t, J¼8.1 Hz,1H), 3.24
(dd, J¼17.3, 2.2 Hz,1H),1.44 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼157.1, 133.9, 121.1, 80.1, 72.1, 66.8, 57.8, 31.7, 3.2 ppm; MS (ESI): m/
z¼166 [MþH]þ.
n
¼2970,1750, 1689, 1396, 1209, 1002, 734 cmꢁ1; 1H NMR (400 MHz,
CDCl3):
d
¼5.47 (m, 1H), 4.46 (dd, J¼9.2, 8.2 Hz, 1H), 4.26 (dd, J¼9.2,
4.1.2. (R)-3-(But-2-ynyl)-4-vinyloxazolidin-2-one (3b).2 Compound
3b was prepared in 82% yield from (R)-4-vinyloxazolidin-2-one
according to the procedures for the preparation of compound 3a
as colorless oil. Rf 0.33 (hexane/EtOAc¼2:1); 1H NMR (400 MHz,
2.4 Hz, 1H), 4.15 (d, J¼14.9 Hz, 1H), 4.04 (m, 1H), 3.67 (d, J¼14.9 Hz,
1H), 2.59 (m, 1H), 1.56 (d, J¼6.8 Hz, 3H), 0.95 ppm (d, J¼7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3):
d¼161.3, 142.9, 118.3, 63.9, 61.8, 46.2,
40.4, 15.6, 14.3 ppm; MS (ESI): m/z: 168 [MþH]þ; HRMS (MALDI):
m/z: calcd for C9H13NO2Na: 190.0838; found: 190.0834 [MþNa]þ.
CDCl3):
d
¼5.71e5.62 (m, 1H), 5.42 (d, J¼17.1 Hz, 1H), 5.37 (d,
J¼9.9 Hz, 1H), 4.45 (t, J¼8.4 Hz, 1H), 4.38 (t, J¼7.6 Hz, 1H), 4.25 (dq,
J¼13.8, 2.3 Hz, 1H), 3.95 (t, J¼8.1 Hz, 1H), 3.57 (dd, J¼13.8, 2.2 Hz,
4.1.6. (7S,7aS,Z)-6-Ethylidene-7-methyltetrahydropyrrolo[1,2-c]ox-
azol-3(1H)-one (5b). Compound 3a (314 mg, 1.81 mmol),
1H), 1.79 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼157.6, 133.9,

1922
Y.J. Ham et al. / Tetrahedron 68 (2012) 1918e1925
Rh(cod)2BF4 (44.0 mg, 0.10 mmol), and (S)-BINAP (101 mg,
0.16 mmol) were dissolved in 1,2-dichloroethane (35.0 mL, 0.04 M).
The reaction mixture was stirred under hydrogen atmosphere
(1 atm) at room temperature for 2 h. The volatiles were removed
under reduced pressure to give the crude product. The crude
product was purified by column chromatography (SiO2, hexane/
EtOAc¼10:1 to 4:1) to afford compound 5b (230 mg, 76%) as col-
CHCl3); Rf 0.20 (hexane/EtOAc¼4:1); IR (neat)
n
¼3413, 2929, 1686,
¼5.22 (m, 1H),
1392, 1162, 736 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
d
4.76 (m, 1H), 3.98 (d, J¼14.1 Hz, 1H), 3.81 (d, J¼15.1 Hz, 1H), 3.52 (m,
2H), 3.45 (m, 1H), 2.26 (br s, 1H), 1.49 (d, J¼11.9 Hz, 3H), 1.40 (s, 9H),
1.04 ppm (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
¼156.6,
d
140.0, 115.8, 80.2, 67.2, 65.9, 48.4, 40.1, 28.3, 17.9, 14.2 ppm; MS
(ESI): m/z¼264 [MþNa]þ; HRMS (ESI): m/z: calcd for C13H23NO3Na:
264.1576; found: 264.1575 [MþNa]þ.
orless oil. Rf 0.40 (hexane/EtOAc¼2:1); IR (neat)
n
¼2968, 2917, 1751,
1395, 1203, 1070, 775 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
d
¼5.24e5.18 (m, 1H), 4.37 (dd, J¼8.9, 7.6 Hz, 1H), 4.10 (dd, J¼8.9,
4.1.11. (2R,3S,Z)-tert-Butyl 4-ethylidene-2-(hydroxymethyl)-3-
methylpyrrolidine-1-carboxylate (2c). Compound 2c was prepared
in 96% yield from compound 5c according to the procedures for the
2.4 Hz, 1H), 4.05 (m, 1H), 3.67 (d, J¼15.5 Hz, 1H), 3.34 (ddd, J¼10.0,
7.5, 2.4 Hz, 1H), 2.16 (m, 1H), 1.50 (d, J¼5.5 Hz, 3H), 0.97 ppm (d,
J¼6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
¼161.3, 141.3, 116.6,
preparation of compound 2a as colorless oil. ½a D23:4
ꢁ27.0 (c 0.2 in
ꢀ
66.4, 65.4, 48.6, 42.3, 13.2, 12.9 ppm; MS (ESI): m/z¼168 [MþH]þ;
HRMS (MALDI): m/z: calcd for C9H13NO2Na: 190.0838; found:
190.0840 [MþNa]þ.
CHCl3); Rf 0.29 (hexane/EtOAc¼4:1); 1H NMR (400 MHz, CDCl3):
d
¼5.21 (m, 1H), 4.09 (m, 1H), 3.95 (m, 2H), 3.69 (d, J¼7.3 Hz, 1H),
3.58 (s, 1H), 3.41 (m, 1H), 2.79 (s, 1H), 1.59 (d, J¼5.7 Hz, 3H), 1.43 (s,
9H), 1.01 ppm (d, J¼6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3):
4.1.7. (7S,7aR,Z)-6-Ethylidene-7-methyltetrahydropyrrolo[1,2-c]ox-
azol-3(1H)-one (5c). Compound 5c was prepared in 61% yield from
compound 4b and (S)-BINAP according to the procedures for the
preparation of compound 5a as colorless oil. Rf 0.32 (hexane/
d
¼156.6, 140.3, 114.5, 80.2, 63.4, 61.9, 47.7, 38.7, 28.4, 14.1, 11.7 ppm;
MS (ESI): m/z¼264 [MþNa]þ; HRMS (ESI): m/z: calcd for
C13H23NO3Na: 264.1576; found: 264.1578 [MþNa]þ.
EtOAc¼2:1); 1H NMR (400 MHz, CDCl3):
d
¼5.33 (m, 1H), 4.30 (dd,
4.1.12. (2R,3R,Z)-tert-Butyl 4-ethylidene-2-(hydroxymethyl)-3-
methylpyrrolidine-1-carboxylate (2d).2 Compound 2d was pre-
pared in 89% yield from compound 5d according to the procedures
J¼8.2, 7.3 Hz, 1H), 4.14 (d, J¼8.2 Hz, 1H), 3.99 (d, J¼14.2 Hz, 1H), 3.93
(m, 1H), 3.54 (d, J¼15.1 Hz, 1H), 2.48 (m, 1H), 1.44 (d, J¼6.8 Hz, 3H),
0.81 ppm (d, J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d¼161.3,
for the preparation of compound 2a as colorless oil. ½a D23:8
þ27.5 (c
ꢀ
142.9, 137.6, 118.3, 63.9, 61.8, 46.2, 40.4, 15.6, 14.3 ppm; MS (ESI): m/
z¼168 [MþH]þ; HRMS (MALDI): m/z: calcd for C9H13NO2Na:
190.0838; found: 190.0842 [MþNa]þ.
0.2 in CHCl3); Rf 0.34 (hexane/EtOAc¼2:1); 1H NMR (400 MHz,
CDCl3):
d
¼5.18 (m, 1H), 3.97 (m, 1H), 3.69 (m, 1H), 3.46 (m, 2H), 3.39
(m, 1H), 2.22 (br s, 1H), 1.46 (d, J¼6.5 Hz, 3H), 1.35 (s, 9H), 0.99 ppm
(d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
¼156.4, 140.0, 115.7,
d
4.1.8. (7R,7aR,Z)-6-Ethylidene-7-methyltetrahydropyrrolo[1,2-c]ox-
azol-3(1H)-one (5d).2 Compound 5d was prepared in 73% yield
from compound 3b and (R)-BINAP according to the procedures for
the preparation of compound 5b as colorless oil. Rf 0.40 (hexane/
80.1, 67.1, 65.5, 48.3, 40.1, 28.3, 18.0, 14.2 ppm; MS (ESI): m/z¼264
[MþNa]þ; HRMS (ESI): m/z: calcd for C13H23NO3Na: 264.1576;
found: 264.1579 [MþNa]þ.
EtOAc¼2:1); 1H NMR (400 MHz, CDCl3):
d¼5.18e5.14 (m, 1H), 4.31
4.1.13. (2S,3R,Z)-1-(tert-Butoxycarbonyl)-4-ethylidene-3-
methylpyrrolidine-2-carboxylic acid (6a). Compound 2a (50.0 mg,
0.20 mmol) dissolved in dichloromethane (5.0 mL) was treated
with DesseMartin periodinane (352 mg, 0.82 mmol) solution in
dichloromethane (5.0 mL) at 0 ꢂC. The reaction mixture was
allowed to warm to room temperature over 1 h and stirred for
additional 2 h at room temperature. The reaction mixture was di-
luted with Et2O and washed with satd Na2S2O3 solution, satd
Na2S2O3/NaHCO3 (1:1) solution and brine. The organic layer was
dried over MgSO4, filtered, and concentrated to afford crude oil. The
resulting crude product was dissolved in tert-butanol/H2O (2:1,
12 mL) and then treated with 2-methyl-2-butene (8.0 mL) and
NaH2PO4 (131 mg, 0.84 mmol) successively at room temperature.
After stirring at room temperature for 0.5 h, the reaction mixture
was treated with NaClO2 (108 mg, 1.20 mmol) and stirred at room
temperature for additional 1 h. The mixture was diluted with EtOAc
and washed with water and brine. The organic layer was dried over
MgSO4, filtered, and concentrated to afford compound 6a (49 mg,
95%) as colorless oil. Rf 0.34 (dichloromethane/methanol¼10:1); IR
(d, J¼9.1 Hz, 1H), 4.05 (dd, J¼9.1, 2.2 Hz, 1H), 4.00 (d, J¼14.9 Hz, 1H),
3.61 (d, J¼14.9 Hz, 1H), 3.29 (ddd, J¼10.0, 7.5, 2.4 Hz, 1H), 2.10 (m,
1H), 1.44 (d, J¼5.6 Hz, 3H), 0.91 ppm (d, J¼6.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3):
d
¼161.4, 141.4, 116.8, 66.5, 65.5, 48.8, 42.4, 14.1,
13.3 ppm; MS (ESI): m/z¼168[MþH]þ.
4.1.9. (2S,3R,Z)-tert-Butyl 4-ethylidene-2-(hydroxymethyl)-3-
methylpyrrolidine-1-carboxylate (2a). Compound 5a (100 mg,
0.60 mmol) was treated with 1.25 M NaOH solution (3 mL,
3.75 mmol) in ethanol/H2O (3:1) and the reaction mixture was
heated at 80 ꢂC for 3 h. After cooling to room temperature, the
reaction mixture was diluted with Et2O, dried over MgSO4, filtered,
and concentrated. The residue was dissolved in dichloromethane
(2.0 mL) and then treated with di-tert-butyl dicarbonate (0.2 mL,
0.90 mmol) and triethylamine (0.12 mL, 0.90 mmol). After stirring
at room temperature for 2 h, the volatiles were removed under
reduced pressure to give crude oil. The crude product was purified
by column chromatography (SiO2, hexane/EtOAc¼4:1) to afford
compound 2a (140 mg, 97%) as colorless oil. ½a D23
ꢀ
þ25.0 (c 0.2 in
¼3413, 2929, 1676,
¼5.23 (m, 1H),
(neat)
CDCl3):
n
¼3344, 2943, 2831, 1677, 1412 cmꢁ1
;
1H NMR (400 MHz,
¼5.21 (m, 1H), 4.42e3.95 (m, 3H), 3.02e2.96 (m, 1H), 1.58
CHCl3); Rf 0.20 (hexane/EtOAc¼4:1); IR (neat)
n
d
1394, 1160, 773 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
(d, J¼6.7 Hz, 3H), 1.39 (m, 9H), 1.08 ppm (d, J¼6.8 Hz, 3H); 13C NMR
4.13 (m, 1H), 3.97 (m, 2H), 3.69 (d, J¼7.3 Hz, 1H), 3.58 (s, 1H), 3.41
(100 MHz, CDCl3):
d¼176.4, 154.2, 138.6, 115.7, 80.3, 67.9, 48.5, 39.5,
(m, 1H), 2.79 (s, 1H), 1.61 (d, J¼5.7 Hz, 3H), 1.43 (s, 9H), 1.03 ppm (d,
28.4, 14.4, 12.5 ppm; MS (ESI): m/z¼278 [MþNa]þ; HRMS (MALDI):
m/z: calcd for C13H21NO4Na: 278.1368; found: 278.1360 [MþNa]þ.
J¼6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3):
¼156.7, 140.2, 114.6,
d
80.2, 63.5, 61.9, 47.7, 38.7, 28.4, 14.1, 11.7 ppm; MS (ESI): m/z¼264
[MþNa]þ; HRMS (ESI): m/z: calcd for C13H23NO3Na: 264.1576;
found: 264.1574 [MþNa]þ.
4.1.14. (2S,3S,Z)-1-(tert-Butoxycarbonyl)-4-ethylidene-3-
methylpyrrolidine-2-carboxylic acid (6b). Compound 6b was pre-
pared in 84% yield from compound 2b according to the procedures
for the preparation of compound 6a as colorless oil. Rf 0.34
4.1.10. (2S,3S,Z)-tert-Butyl 4-ethylidene-2-(hydroxymethyl)-3-
methylpyrrolidine-1-carboxylate (2b). Compound 2b was prepared
in 85% yield from compound 5b according to the procedures for the
(dichloromethane/methanol¼10:1); IR (neat)
1706, 1368, 1169 cmꢁ1; 1H NMR (400 MHz, CDCl3):
4.12e3.85 (m, 3H), 2.86 (m, 1H), 1.58 (dd, J¼6.8, 1.4 Hz, 3H), 1.44 (m,
n
¼3396, 2926, 2858,
d
¼5.31 (m, 1H),
preparation of compound 2a as colorless oil. ½a D23
ꢁ24.5 (c 0.2 in
ꢀ

Y.J. Ham et al. / Tetrahedron 68 (2012) 1918e1925
1923
9H), 1.20 ppm (d, J¼6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 5.28 (m, 1H), 4.60 (m, 1H), 4.26 (m, 1H), 4.19 (m, 1H), 4.01 (m, 1H),
d¼178.3, 154.2, 138.8, 116.8, 80.7, 66.1, 47.8, 43.2, 28.4, 19.0,
3.69 (s, 3H), 2.94 (br s, 1H), 1.65e1.46 (m, 5H), 1.44 (s, 9H), 1.07 (d,
14.4 ppm; MS (ESI): m/z¼278 [MþNa]þ; HRMS (MALDI): m/z: calcd
for C13H21NO4Na: 278.1368; found: 278.1367 [MþNa]þ.
3H, J¼6.7 Hz), 0.87 (d, 3H, J¼6.7 Hz), 0.86 (d, 3H, J¼6.7 Hz); 13C NMR
(100 MHz, CDCl3)
d 173.0, 170.3, 156.0, 154.2, 117.0, 80.5, 64.9, 52.2,
50.2, 48.0, 41.6, 40.1, 28.3, 24.6, 22.8, 21.8,14.4,12.1; MS m/z [MþNa]
calcd 405.25, found 404.98; HRMS (MALDI) m/z: [MþNa]þ calcd for
C20H34N2O5Na, 405.2361; found 405.2356.
4.1.15. (2R,3S,Z)-1-(tert-Butoxycarbonyl)-4-ethylidene-3-
methylpyrrolidine-2-carboxylic acid (6c). Compound 6c was pre-
pared in 95% yield from compound 2c according to the procedures
for the preparation of compound 6a as colorless oil. Rf 0.39
4.1.20. (2R,3R,Z)-tert-Butyl 4-ethylidene-2-((S)-1-methoxy-4-
methyl-1-oxopentan-2-ylcarbamoyl)-3-methylpyrrolidine-1-
carboxylate (7d). Compound 7d was prepared in 37% yield from
compound 6d according to the procedures for the preparation of
compound 7a as white solid. Rf 0.47 (hexane/EtOAc¼2:1); 1H NMR
(dichloromethane/methanol¼10:1); IR (neat)
n
¼3397, 2976, 2931,
1700, 1393, 1153 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
¼5.26 (m, 1H),
4.47e3.98 (m, 3H), 2.96 (m, 1H), 1.58 (d, J¼6.7 Hz, 3H), 1.39 (m, 9H),
1.08 ppm (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
¼176.9,
d
154.1, 139.5, 115.8, 80.4, 63.7, 48.6, 39.6, 28.4, 14.4, 12.5 ppm; MS
(ESI): m/z¼278 [MþNa]þ; HRMS (MALDI): m/z: calcd for
C13H21NO4Na: 278.1368; found: 278.1356 [MþNa]þ.
(400 MHz, CDCl3):
d
¼5.30 (m, 1H), 4.60 (m, 1H), 4.20 (m, 1H), 3.98
(d, J¼11.1 Hz, 1H), 3.85e3.78 (m, 1H), 3.67 (s, 3H), 3.0e2.98 (br s,
1H), 1.66 (m, 1H), 1.58 (m, 4H), 1.44 (m, 9H), 1.17 (d, J¼6.6 Hz, 3H),
0.93 (d, J¼6.9 Hz, 3H), 0.91 ppm (d, J¼6.7 Hz, 3H); 13C NMR
4.1.16. (2R,3R,Z)-1-(tert-Butoxycarbonyl)-4-ethylidene-3-
methylpyrrolidine-2-carboxylic acid (6d). Compound 6d was pre-
pared in 95% yield from compound 2d according to the procedures
for the preparation of compound 6a as colorless oil. Rf 0.39
(dichloromethane/methanol¼10:1); 1H NMR (400 MHz, CDCl3):
(100 MHz, CDCl3):
d
¼173.1, 171.0, 116.8, 80.7, 68.3, 52.1, 50.3, 47.8,
41.7, 28.2, 24.6, 22.8, 21.7, 19.4, 14.4 ppm; MS (ESI): m/z¼405
[MþNa]þ; HRMS (MALDI): m/z: calcd for C20H34N2O5Na: 405.2361;
found: 405.2374 [MþNa]þ.
d
¼5.31 (m, 1H), 4.12e3.87 (m, 3H), 3.08e2.80 (m, 1H), 1.57 (d,
4.1.21. (S)-Methyl 2-((2S,3R,Z)-1-((S)-2-benzamido-6-((Z)-2,3-
bis(tert-butoxycarbonyl)guanidino)hexanoyl)-4-ethylidene-3-
methylpyrrolidine-2-carboxamido)-4-methylpentanoate (9a). To
a stirred solution of compound 7a (60.0 mg, 0.15 mmol) in Et2O
J¼6.7 Hz, 3H), 1.45 (m, 9H), 1.23 ppm (d, J¼6.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3):
d¼177.0, 154.3, 138.9, 116.6, 80.5, 66.2, 47.8, 43.2,
28.4, 28.2, 14.4 ppm; MS (ESI): m/z¼278 [MþNa]þ; HRMS (MALDI):
m/z: calcd for C13H21NO4Na: 278.1368; found: 278.1353 [MþNa]þ.
(3.0 mL) was added dropwise
4 N HCl solution (3.0 mL,
4.50 mmol) in dioxane at 0 ꢂC. After stirring at room temperature
overnight, the reaction mixture was concentrated under reduced
pressure. The resulting residue was dissolved in THF (2.0 mL) and
4.1.17. (2S,3R,Z)-tert-Butyl 4-ethylidene-2-((S)-1-methoxy-4-methyl-
1-oxopentan-2-ylcarbamoyl)-3-methylpyrrolidine-1-carboxylate
(7a). To a solution of compound 6a (50.0 mg, 0.19 mmol) and
L-
treated with DIEA (73.0 m
L, 0.42 mmol). After cooling to 0 ꢂC, the
Leucine methyl ester hydrochloride (44.0 mg, 0.24 mmol) in THF
(2.0 mL) were added DIEA (0.12 mL, 0.58 mmol) and HATU (148 mg,
0.39 mmol) successively at room temperature. After stirring at
room temperature for 2 h, the mixture was diluted with EtOAc and
washed with water and brine. The organic layer was dried over
MgSO4, filtered, and concentrated. The residue was purified by
column chromatography (SiO2, hexane/EtOAc¼4:1) to afford com-
pound 7a (65.0 mg, 87%) as white solid. Rf 0.42 (hexane/
reaction mixture was treated with compound 8 (70.2 mg,
0.14 mmol) and HATU (106 mg, 0.28 mmol) successively at 0 ꢂC
and then stirred at room temperature for 4 h. The reaction mix-
ture was diluted with EtOAc and washed with water and brine.
The organic layer was dried over MgSO4, filtered, and concen-
trated. The residue was purified by column chromatography
(SiO2, hexane/EtOAc¼2:1 to 1:1) to afford compound 9a (53.0 mg,
0.07 mmol, 50%) as white solid. Rf 0.37 (hexane/EtOAc¼1:1); IR
EtOAc¼2:1); 1H NMR (400 MHz, CDCl3):
d¼5.28 (m, 1H), 4.60 (m,
(neat)
n
¼2969, 1739, 1639, 1365, 1216 cmꢁ1
;
1H NMR (400 MHz,
1H), 4.26 (d, J¼8.7 Hz, 1H), 4.19 (m, 1H), 4.01 (m, 1H), 3.69 (s, 3H),
2.94 (m, 1H), 1.77e1.47 (m, 5H), 1.44 (s, 9H), 1.07 (d, J¼6.7 Hz, 3H),
0.89 (d, J¼6.7 Hz, 3H), 0.88 ppm (d, J¼6.7 Hz, 3H); 13C NMR
CDCl3):
d
¼11.45 (s, 1H), 8.30 (br s, 1H), 7.80 (d, J¼7.3 Hz, 2H),
7.47e7.37 (m, 3H), 7.10 (d, J¼8.3 Hz, 1H), 6.57 (d, J¼8.3 Hz, 1H),
5.30 (m, 1H), 5.01 (m, 1H), 4.65 (d, J¼8.7 Hz, 1H), 4.55 (m, 1H),
4.49e4.40 (m, 2H), 3.67 (s, 3H), 3.37 (m, 2H), 2.85 (m, 1H), 1.90
(m, 1H), 1.75 (m, 1H), 1.66 (d, J¼6.6 Hz, 3H), 1.65e1.53 (m, 7H),
1.46 (s, 9H), 1.44 (s, 9H), 1.05 (d, J¼6.8 Hz, 3H), 0.88 (d, J¼5.2 Hz,
3H), 0.87 ppm (d, J¼5.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
(100 MHz, CDCl3):
d
¼171.2, 170.1, 148.8, 145.5, 116.0, 80.5, 64.7, 52.1,
50.2, 48.8, 41.6, 40.6, 28.2, 24.6, 22.8, 14.3 ppm; MS (ESI): m/z¼405
[MþNa]þ; HRMS (MALDI): m/z: calcd for C20H34N2O5Na: 405.2361;
found: 405.2358 [MþNa]þ.
d
¼173.4, 171.2, 169.2, 167.1, 163.5, 156.0, 153.2, 138.6, 133.7, 131.6,
4.1.18. (2S,3S,Z)-tert-Butyl 4-ethylidene-2-((S)-1-methoxy-4-methyl-
1-oxopentan-2-ylcarbamoyl)-3-methylpyrrolidine-1-carboxylate
(7b). Compound 7b was prepared in 74% yield from compound 6b
according to the procedures for the preparation of compound 7a as
white solid. Rf 0.42 (hexane/EtOAc¼2:1); 1H NMR (400 MHz,
128.4, 127.1, 116.1, 82.9, 79.1, 63.7, 52.2, 50.4, 50.4, 49.2, 41.4, 40.5,
38.4, 32.1, 31.5, 28.8, 28.2, 28.0, 24.7, 22.7, 22.7, 21.9, 14.5, 14.1,
12.0 ppm; MS (ESI): m/z¼757 [MþH]þ; HRMS (MALDI): m/z:
calcd for C39H60N6O9Na: 779.4320; found: 779.4344 [MþNa]þ.
CDCl3):
d
¼5.28 (m, 1H), 4.60 (m, 1H), 4.26 (m, 1H), 4.19 (m, 1H), 4.01
4.1.22. (S)-Methyl 2-((2S,3S,Z)-1-((S)-2-benzamido-6-((Z)-2,3-
bis(tert-butoxycarbonyl)guanidino)hexanoyl)-4-ethylidene-3-
(m, 1H), 3.69 (s, 3H), 2.94 (br s, 1H), 1.65e1.46 (m, 5H), 1.44 (s, 9H),
1.07 (d, J¼6.7 Hz, 3H), 0.87 (d, J¼6.7 Hz, 3H), 0.86 ppm (d, J¼6.7 Hz,
methylpyrrolidine-2-carboxamido)-4-methyl
pentanoate
(9b).
3H); 13C NMR (100 MHz, CDCl3):
d
¼173.0, 170.3, 156.0, 154.2, 117.0,
Compound 9b was prepared in 58% yield from compound 7b
according to the procedures for the preparation of compound 9a as
80.5, 64.9, 52.2, 50.2, 48.0, 41.6, 40.1, 28.3, 24.6, 22.8, 21.8, 14.4,
12.1 ppm; MS (ESI): m/z¼405 [MþNa]þ; HRMS (MALDI): m/z: calcd
for C20H34N2O5Na: 405.2361; found: 405.2356 [MþNa]þ.
white solid. Rf 0.37 (hexane/EtOAc¼1:1); IR (neat)
n
¼2969, 1738,
1435, 1365, 1264, 1216, 1022 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
d
¼11.48 (br s, 1H), 8.46 (br s, 1H), 7.80 (d, J¼7.2 Hz, 2H), 7.50e7.37
4.1.19. (2R,3S,Z)-tert-Butyl 4-ethylidene-2-((S)-1-methoxy-4-methyl-
1-oxopentan-2-ylcarbamoyl)-3-methylpyrrolidine-1-carboxylate
(7c). Compound 7c was prepared in 37% yield from compound 6c
according to the procedures for the preparation of compound 7a as
white solid. Rf 0.47 (hexane/EtOAc¼2:1); 1H NMR (400 MHz, CDCl3)
(m, 3H), 7.06 (d, J¼8.1 Hz, 1H), 6.68 (d, J¼7.9 Hz, 1H), 5.39 (m, 1H),
5.01 (m, 1H), 4.65e4.52 (m, 2H), 4.24e4.04 (m, 2H), 3.70 (s, 3H),
3.45 (m, 2H), 2.97 (m, 1H), 1.90 (m, 1H), 1.75 (m, 1H), 1.65 (d,
J¼6.6 Hz, 3H), 1.65e1.50 (m, 7H), 1.47 (s, 9H), 1.45 (s, 9H), 1.14 (d,
J¼7.0 Hz, 3H), 0.89 (d, J¼6.0 Hz, 3H), 0.88 ppm (d, J¼6.0 Hz, 3H); 13C

1924
Y.J. Ham et al. / Tetrahedron 68 (2012) 1918e1925
NMR (100 MHz, CDCl3):
d
¼173.4, 172.0, 170.4, 167.1, 155.7, 153.1,
compound 1a as white solid (19.9 mg, 88%), mp 188e189 ꢂC. ½a D22
ꢀ
139.0, 133.7, 131.7, 128.5, 127.1, 117.5, 83.4, 80.0, 67.0, 52.2, 50.8, 50.7,
48.4, 41.4, 40.8, 40.6, 32.3, 28.7, 28.2, 28.0, 24.7, 22.9, 22.8, 22.6,
22.0, 21.3, 19.4, 14.7, 14.1 ppm; MS (ESI): m/z¼757 [MþH]þ; HRMS
(MALDI) m/z: calcd for C39H60N6O9: 757.4500; found: 757.4509
[MþH]þ.
ꢁ34.8 (c 0.175 in MeOH); IR (neat)
n
¼3287, 1629, 1181, 693 cmꢁ1; 1H
NMR (400 MHz, DMSO-d6):
d
¼10.41 (br s, 1H), 8.55 (d, J¼7.1 Hz, 1H),
7.88 (d, J¼7.1 Hz, 2H), 7.52 (t, J¼7.2 Hz,1H), 7.45 (t, J¼7.7 Hz, 2H), 6.95
(br s, 2H), 6.66 (br s, 1H), 5.29 (m, 1H), 4.80 (m, 1H), 4.58 (d,
J¼14.0 Hz, 1H), 4.44 (d, J¼14.0 Hz, 1H), 4.36 (d, J¼9.2 Hz, 1H), 3.89
(m, 1H), 3.18 (m,1H), 3.02 (m,1H), 2.83 (m, 1H), 2.00 (m, 1H), 1.66 (d,
J¼5.7 Hz, 3H), 1.58e1.32 (m, 9H), 1.00 (d, J¼6.8 Hz, 3H), 0.82 (d,
J¼2.1 Hz, 3H), 0.80 (d, J¼2.1 Hz, 3H); 1H NMR (400 MHz, MeOD):
4.1.23. (S)-Methyl 2-((2R,3S,Z)-1-((S)-2-benzamido-6-((Z)-2,3-
bis(tert-butoxycarbonyl)guanidino)hexanoyl)-4-ethylidene-3-
methylpyrrolidine-2-carboxamido)-4-methylpentanoate
(9c). Compound 9c was prepared in 45% yield from compound 7c
according to the procedures for the preparation of compound 9a as
white solid, mp 108e109 ꢂC. Rf 0.51 (hexane/EtOAc¼1:2); IR (neat)
d
¼7.84 (d, J¼5.7 Hz, 2H), 7.54 (m,1H), 7.46 (m, 2H), 5.40 (m,1H), 4.93
(q, J¼7.1 Hz, 1H), 4.69e4.48 (m, 3H), 4.30 (m, 1H), 3.19 (m, 2H), 2.99
(m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.74e1.44 (m, 10H), 1.14 (d,
J¼6.4 Hz, 3H), 0.92 ppm (d, J¼6.2 Hz, 6H); 13C NMR (100 MHz,
n
¼2948, 1721, 1638, 1365, 1227, 1027 cmꢁ1
;
1H NMR (400 MHz,
MeOD):
d¼171.5, 169.6, 168.4, 157.3, 138.7, 133.5, 131.5, 128.1, 127.1,
CDCl3):
d
¼11.45 (s, 1H), 8.32 (br s, 1H), 7.79 (m, 2H), 7.48e7.38 (m,
116.1, 64.7, 53.0, 51.2, 42.1, 40.9, 38.1, 30.7, 28.3, 24.5, 22.6, 22.2, 21.2,
13.1, 10.9 ppm; MS (ESI): m/z¼543 [MþH]þ; HRMS (MALDI): m/z:
calcd for C28H42N6O5Na: 565.3114; found: 565.3118 [MþNa]þ.
3H), 7.05 (d, J¼7.0 Hz, 1H), 6.60 (d, J¼8.1 Hz, 1H), 5.38e5.36 (m, 1H),
4.84 (m, 1H), 4.72 (d, J¼13.0 Hz, 1H), 4.56 (d, J¼8.9 Hz, 1H), 4.44 (m,
1H), 4.20 (m, 1H), 3.63 (s, 3H), 3.39 (q, J¼6.2 Hz, 2H), 2.95 (m, 1H),
1.90 (m, 1H), 1.84e1.77 (m, 1H), 1.69 (d, J¼5.9 Hz, 3H), 1.64e1.47 (m,
7H), 1.47 (s, 9H), 1.46 (s, 9H), 1.15 (d, J¼6.8 Hz, 3H), 0.79 (d, J¼5.7 Hz,
3H), 0.70 ppm (d, J¼5.7 Hz, 3H); 13C NMR (100 MHz, CDCl3):
4.1.26. (S)-2-((2S,3S,Z)-1-((S)-2-Benzamido-6-guanidinohexanoyl)-
4-ethylidene-3-methylpyrrolidine-2-carboxamido)-4-
methylpentanoic acid (1b). To a stirred solution of compound 9b
(37.0 mg, 0.048 mmol) in THF (1.0 mL) was added 1 N LiOH solution
d
¼173.0, 171.0, 169.0, 167.0, 156.1, 153.3, 138.0, 132.0, 128.6, 127.3,
116.6, 83.1, 79.4, 63.9, 52.1, 51.3, 50.5, 49.0, 40.5, 38.7, 31.7, 28.8,
28.2, 28.0, 24.6, 22.7, 21.6, 14.5, 14.1, 11.8 ppm; MS (ESI): m/z¼757
[MþH]þ; HRMS (MALDI): m/z: calcd for C39H60N6O9Na: 779.4320;
found: 779.4324 [MþNa]þ.
(97.0 m
L, 0.097 mmol) at 0 ꢂC. The reaction mixture was allowed to
warm to room temperature for 3 h. After cooling to 0 ꢂC, the re-
action mixture was treated with H2O (1.0 mL) and 1 N HCl solution
(60
mL, 0.060 mmol) for neutralization. The aqueous layer was
separated and extracted with EtOAc. The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure to afford the corresponding saponified compound. To
a stirred solution of the saponified compound (20.0 mg, 0.027
mmol) in dichloromethane (1.0 mL) was added TFA (25% v/v,
0.20 mL) at 0 ꢂC. After stirring at room temperature for 15 h, the
reaction mixture was concentrated under reduced pressure. The
resulting residue was purified by reverse-phase HPLC chromatog-
raphy eluting with 20e60% acetonitrile for 10 min at a flow rate of
25 mL/min with detection at 254 nm by a UV spectrometer
(tR¼3.67 min) and lyophilized to give compound 1b as white solid
4.1.24. (S)-Methyl 2-((2R,3R,Z)-1-((S)-2-benzamido-6-((Z)-2,3-
bis(tert-butoxycarbonyl)guanidino)hexanoyl)-4-ethylidene-3-
methylpyrrolidine-2-carboxamido)-4-methylpentanoate
(9d). Compound 9d was prepared in 33% yield from compound 7d
according to the procedures for the preparation of compound 9a as
white solid. Rf 0.52 (hexane/EtOAc¼1:2); IR (neat)
n
¼2925, 1721,
1638, 1365, 1228, 1027 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
¼11.47 (s,
1H), 8.32 (t, J¼4.8 Hz, 1H), 7.83 (m, 2H), 7.50 (t, J¼7.3 Hz, 1H), 7.41 (t,
J¼7.8 Hz, 2H), 7.21 (d, J¼8.7 Hz, 1H), 6.94 (d, J¼6.8 Hz, 1H),
5.45e5.38 (m, 1H), 4.81 (q, J¼6.9 Hz, 1H), 4.56e4.52 (m, 1H), 4.46
(d, J¼14.0 Hz, 1H), 4.40 (d, J¼1.6 Hz, 1H), 4.29 (d, J¼14.0 Hz, 1H),
3.59 (s, 3H), 3.44e3.40 (m, 2H), 3.15e3.11 (m, 1H), 1.94e1.91 (m,
1H),1.87e1.86 (m,1H),1.62 (d, J¼6.8 Hz, 3H),1.62e1.51 (m, 7H),1.47
(s, 9H), 1.46 (s, 9H), 1.15 (d, J¼7.1 Hz, 3H), 0.81 (d, J¼5.8 Hz, 3H),
(13.0 mg, 60%), mp 176e177 ꢂC. ½a D21:2
ꢁ41.1 (c 0.175 in MeOH); IR
ꢀ
(neat)
n
¼3301,1631, 1180, 692 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d
¼10.45 (br,1H), 8.57 (d, J¼6.8 Hz,1H), 7.87 (d, J¼7.2 Hz, 2H), 7.53 (t,
J¼7.3 Hz,1H), 7.45 (t, J¼7.7 Hz, 2H), 6.96 (br s, 3H), 5.36 (m,1H), 4.78
(m, 1H), 4.76 (m, 2H), 4.30 (d, J¼14.0 Hz, 1H), 3.84 (m, 1H), 3.17 (m,
1H), 3.03 (m, 1H), 2.72 (m, 1H), 1.99 (m, 1H), 1.66e1.32 (m, 9H), 1.59
(d, J¼6.7 Hz, 3H), 1.09 (d, J¼6.9 Hz, 3H), 0.82 (d, J¼6.5 Hz, 3H),
0.68 ppm (d, J¼5.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
¼173.4,
d
171.7, 170.3, 167.6, 163.5, 156.1, 153.3, 131.9, 128.5, 127.3, 118.1, 83.1,
79.3, 66.4, 52.1, 51.7, 50.6, 47.7, 40.7, 40.5, 31.6, 28.9, 28.2, 28.0, 24.6,
22.9, 22.6, 21.5, 21.1, 14.6, 14.2 ppm; MS (ESI): m/z¼757 [MþH]þ;
HRMS (MALDI): m/z: calcd for C39H60N6O9Na: 779.4320; found:
779.4294 [MþNa]þ.
0.80 ppm (d, J¼6.5 Hz, 3H); 1H NMR (400 MHz, MeOD):
¼7.82 (m,
d
2H), 7.54 (m, 1H), 7.45 (m, 2H), 5.46 (m, 1H), 4.92 (q, J¼4.3 Hz, 1H),
4.78 (m, 1H), 4.48 (d, J¼14.0 Hz, 1H), 4.25 (q, J¼4.9 Hz, 1H), 4.17 (d,
J¼4.0 Hz, 1H), 3.23 (m, 2H), 2.84 (m, 1H), 2.04 (m, 1H), 1.90 (m, 1H),
1.68 (d, J¼6.7 Hz, 3H), 1.66e1.52 (m, 7H), 1.23 (d, J¼6.9 Hz, 3H), 0.93
(d, J¼6.2 Hz, 3H), 0.91 ppm (d, J¼6.2 Hz, 3H); 13C NMR (100 MHz,
4.1.25. (S)-2-((2S,3R,Z)-1-((S)-2-Benzamido-6-guanidinohexanoyl)-
4-ethylidene-3-methylpyrrolidine-2-carboxamido)-4-
methylpentanoic acid (1a).1,3 To a stirred solution of compound 9a
(37.0 mg, 0.048 mmol) in THF (1.0 mL) was added 1 N LiOH solution
MeOD):
d
¼172.2, 171.2, 168.6, 157.3, 139.2, 133.6, 131.5, 128.1, 127.1,
117.3, 67.7, 53.3, 51.4, 42.8, 41.9, 40.8, 30.7, 28.2, 24.6, 22.3, 22.3, 21.3,
18.6, 13.1 ppm; MS (ESI): m/z¼543 [MþH]þ; HRMS (ESI): m/z: calcd
for C28H42N6O5: 543.3295; found: 543.3298 [MþH]þ.
(97.0
warm to room temperature for 3 h. After cooling to 0 ꢂC, the reaction
mixture was treated with H2O (1.0 mL) and 1 N HCl solution (60 L,
m
L, 0.097 mmol) at 0 ꢂC. The reaction mixture was allowed to
m
0.060 mmol) for neutralization. The aqueous layer was separated
and extracted with EtOAc. The combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pressure to
afford the corresponding saponified compound. To a stirred solution
of the saponified compound (30.0 mg, 0.04 mmol) in dichloro-
methane (1.52 mL) was added TFA (25% v/v, 0.48 mL) at 0 ꢂC. After
stirring at room temperature for 15 h, the reaction mixture was
concentrated under reduced pressure. The residue was purified by
reverse-phase HPLC chromatography eluting with 20e60% aq ace-
tonitrile for 10 min at a flow rate of 25 mL/min with detection at
254 nm by a UV spectrometer (tR¼3.46 min) and lyophilized to give
4.1.27. (S)-2-((2R,3S,Z)-1-((S)-2-Benzamido-6-guanidinohexanoyl)-
4-ethylidene-3-methylpyrrolidine-2-carboxamido)-4-
methylpentanoic acid (1c). Compound 1c was prepared in 66% yield
from compound 9c according to the procedures for the preparation
of compound 1a as white solid, mp 164e165 ꢂC. ½a D22
þ28.0 (c 0.175
ꢀ
in MeOH); IR (neat)
(400 MHz, DMSO-d6):
n
¼3279, 1634, 1201, 720 cmꢁ1
;
1H NMR
d
¼10.29 (br s, 1H), 8.58 (d, J¼7.1 Hz, 1H), 8.23
(d, J¼8.7 Hz, 1H), 7.91 (d, J¼7.6 Hz, 2H), 7.53 (t, J¼7.3 Hz, 1H), 7.45 (t,
J¼7.7 Hz, 2H), 6.91 (br s, 2H), 5.16 (m, 1H), 5.11 (d, J¼9.6 Hz, 1H),
4.60 (m,1H), 4.07 (d, J¼14.0 Hz,1H), 4.02 (m,1H), 3.97 (d, J¼15.9 Hz,
1H), 3.07 (m, 1H), 3.00 (m, 1H), 2.80 (m, 1H), 1.70e1.54 (m, 5H), 1.57

Y.J. Ham et al. / Tetrahedron 68 (2012) 1918e1925
1925
(d, J¼6.2 Hz, 3H), 1.45e1.32 (m, 4H), 1.03 (d, J¼6.7 Hz, 3H), 0.86 (d,
J¼6.4 Hz, 3H), 0.80 ppm (d, J¼6.4 Hz, 3H); 1H NMR (400 MHz,
EtOAc. The combined organic layer was dried over MgSO4, filtered,
and concentrated under reduced pressure to afford compound 8
(950 mg, 98%) as white solid. Rf 0.35 (dichloromethane/meth-
MeOD):
d
¼7.84 (m, 2H), 7.56e7.44 (m, 3H), 5.32e5.30 (m, 1H), 5.27
(d, J¼8.6 Hz, 1H), 4.71 (t, J¼6.7 Hz, 1H), 4.62 (m, 1H), 4.31 (m, 1H),
3.20e3.10 (m, 3H), 1.75e1.69 (m, 3H), 1.65 (d, J¼5.5 Hz, 3H),
1.63e1.39 (m, 6H), 1.16 (d, J¼6.7 Hz, 3H), 0.97 (d, J¼6.5 Hz, 3H),
anol¼10:1); 1H NMR (400 MHz, DMSO-d6):
¼11.47 (s, 1H), 8.30 (br
d
s, 1H), 8.26 (br s, 1H), 7.85 (d, J¼7.5 Hz, 2H), 7.51 (t, J¼7.1 Hz, 1H),
7.44 (t, J¼7.1 Hz, 2H), 4.28 (m, 1H), 3.24 (m, 2H), 1.79 (m, 3H), 1.45
(m, 3H), 1.44 (s, 9H), 1.37 ppm (s, 9H); 13C NMR (100 MHz, DMSO-
0.93 ppm (d, J¼6.5 Hz, 3H); 13C NMR (100 MHz, MeOD):
¼171.9,
d
169.8, 168.9, 157.4, 138.3, 133.6, 131.4, 128.1, 127.1, 114.5, 64.8, 51.9,
48.9, 41.5, 40.4, 40.2, 30.7, 28.0, 24.7, 22.5, 22.2, 20.5, 13.0, 11.3 ppm;
MS (ESI): m/z¼543 [MþH]þ; HRMS (ESI): m/z: calcd for
C28H42N6O5: 543.3295; found: 543.3285 [MþH]þ.
d6):
d
¼163.5, 155.6, 134.9, 131.5, 128.6, 127.7, 83.2, 78.5, 28.8, 28.4,
28.0, 23.5 ppm.
Acknowledgements
4.1.28. (S)-2-((2R,3R,Z)-1-((S)-2-Benzamido-6-guanidinohexanoyl)-
4-ethylidene-3-methylpyrrolidine-2-carboxamido)-4-
methylpentanoic acid (1d).2 Compound 1d was prepared in 40%
yield from compound 9d according to the procedures for the
This research was supported by Korea Institute of Science and
Technology (Grant: 2E22250) and a grant (2011-0028676) from the
creative/challenging research program of National Research Foun-
dation of Korea funded by the Ministry of Education, Science and
Technology, Republic of Korea.
preparation of compound 1a as white solid. ½a D26
þ21.7 (c 0.175 in
ꢀ
MeOH); IR (neat)
n
¼3285,1628,1201, 692 cmꢁ1; 1H NMR (400 MHz,
DMSO-d6):
d
¼10.24 (br s, 1H), 8.64 (d, J¼6.9 Hz, 1H), 8.23 (d,
References and notes
J¼9.0 Hz, 1H), 7.90 (d, J¼7.9 Hz, 2H), 7.51 (t, J¼6.3 Hz, 1H), 7.45 (t,
J¼7.1 Hz, 2H), 6.90 (m, 2H), 5.31 (m, 1H), 4.69 (s, 1H), 4.47 (m, 1H),
4.16 (d, J¼15.9 Hz,1H), 3.99 (m, 1H), 3.88 (d, J¼15.1 Hz, 1H), 3.05 (m,
1H), 2.94 (m, 1H), 2.63 (m, 1H), 1.65e1.54 (m, 5H), 1.54 (d, J¼6.3 Hz,
3H), 1.42e1.32 (m, 4H), 1.17 (d, J¼6.9 Hz, 3H), 0.87 (d, J¼5.9 Hz, 3H),
1. Cho, J. Y.; Williams, P. G.; Kwon, H. C.; Jensen, P. R.; Fenical, W. J. Nat. Prod. 2007,
70, 1321e1328.
2. Daniels, R. N.; Melancon, B. J.; Wang, E. A.; Crews, B. C.; Marnett, L. J.; Suli-
kowski, G. A.; Lindsley, C. W. J. Org. Chem. 2009, 74, 8852e8855.
3. Pal, U.; Ranatunga, S.; Ariyarathna, Y.; Valle, J. R. D. Org. Lett. 2009, 11,
5298e5301.
4. (a) Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 7875e7880; (b) Jang,
H.-Y.; Hughes, F. W.; Gong, H.; Zhang, J.; Brodbelt, J. S.; Krische, M. J. J. Am. Chem.
Soc. 2005, 127, 6174e6175; (c) Krische, M. J.; Jang, H.-Y. In Metal-Catalyzed Re-
ductive Carbocyclization (C]C, C^C, C]O Bonds), Comprehensive Organometallic
Chemistry III; Crabtree, R. H., Mingos, D. M. P., Eds.; Elsevier: Oxford, 2006; Vol.
10, pp 493e536.
5. For selected reviews on metal-catalyzed enyne cycloisomerization, see: (a)
Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813e834; (b) Lloyd-
Jones, G. C. Org. Biomol. Chem. 2003, 1, 215e236; (c) Diver, S. T.; Giessert, A. J.
0.80 ppm (d, J¼5.8 Hz, 3H); 1H NMR (400 MHz, MeOD):
¼7.83 (d,
d
J¼8.0 Hz, 2H), 7.53 (t, J¼7.4 Hz, 1H), 7.45 (t, J¼7.7 Hz, 2H), 5.40 (m,
1H), 4.59 (t, J¼7.0 Hz, 1H), 4.33 (m, 1H), 4.30 (d, J¼14.1 Hz, 1H), 4.13
(d, J¼15.8 Hz, 1H), 3.23e3.12 (m, 2H), 2.83 (q, J¼7.0 Hz, 1H), 2.66 (s,
1H), 1.76 (m, 2H), 1.69e1.67 (m, 3H), 1.62 (d, J¼6.0 Hz, 3H),
1.58e1.52 (m, 4H), 1.29 (d, J¼6.9 Hz, 3H), 0.95 ppm (dd, J¼18.9,
5.9 Hz, 6H); 13C NMR (100 MHz, MeOD):
d
¼172.7, 171.7, 169.0, 157.4,
138.8, 131.4, 128.1, 127.1, 116.5, 67.4, 53.4, 51.7, 45.9, 41.4, 40.6, 30.3,
27.9, 25.1, 22.8, 22.3, 20.4, 20.0, 13.2 ppm; MS (ESI): m/z¼543
[MþH]þ; HRMS (ESI): m/z: calcd for C28H42N6O5Na: 565.3114;
found: 565.3132 [MþNa]þ.
Chem. Rev. 2004, 104, 1317e1382; (d) Bruneau, C. Aˇ ngew. Chem., Int. Ed. 2005,
44, 2328e2334; (e) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed.
ꢀ~
2008, 47, 4268e4315; (f) Nunez, E. J.; Echavarren, A. M. Chem. Rev. 2008, 108,
3326e3350; (g) Lee, S. I.; Chatani, N. Chem. Commun. 2009, 371e384.
6. Zhang, Z.; Shi, M. Eur. J. Org. Chem. 2011, 14, 2610e2614.
7. (a) Hatano, M.; Terada, M.; Mikami, K. Angew. Chem., Int. Ed. 2001, 40, 249e253;
(b) Yin, G.; Liu, G. Angew. Chem., Int. Ed. 2008, 47, 5442e5445.
8. (a) Yoo, S.-e.; Lee, S. H. J. Org. Chem. 1994, 59, 6968e6972; (b) Ajamian, A.;
4.1.29. (S,Z)-Methyl 2-benzamido-6-(2,3-bis(tert-butoxycarbonyl)gua-
nidino)hexanoate (8b).2 To a stirred solution of 1-H-pyrazole-1-
[N,N0-bis(tert-butoxycarbonyl)]carboxamidine (1.20 g, 3.89 mmol)
Gleason, J. L. Org. Lett. 2003, 5, 2409e2411.
9. (a) Schmid, T. M.; Consiglio, G. Chem. Commun. 2004, 2318e2319; (b) Evans, P.
A.; Baum, E. W.; Fazal, A. N.; Pink, M. Chem. Commun. 2005, 63e65; (c) Ota, K.;
Lee, S. I.; Tang, J.-M.; Takachi, M.; Nakai, H.; Morimoto, T.; Sakurai, H.; Kataoka,
K.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 15203e15211; (d) Lei, A.; He, M.;
Zhang, X. J. Am. Chem. Soc. 2003, 125, 11472e11473; (e) Denmark, S. E.; Liu, JH.-
and DIEA (2.23 mL, 12.8 mmol) in THF (20 mL) was added L-lysine
methyl ester hydrochloride (1.0 g, 4.28 mmol) at room temperature.
After stirring at room temperature for 1 h, the reaction mixture was
treated with DIEA (1.40 mL, 7.78 mmol) and benzoyl chloride
(0.67 mL, 5.83 mmol) successively at room temperature. After stir-
ring at room temperature for 1 h, the reaction mixture was diluted
with EtOAc and washed with water. The organic layer was dried over
MgSO4, filtered, and concentrated. The residue was purified by col-
umn chromatography (SiO2, hexane/EtOAc¼2:1) to afford compound
8b (1.50 g, 70%) as white solid. Rf 0.34 (hexane/EtOAc¼1:1); 1H NMR
C.; Muhuhi, J. M. J. Org. Chem. 2011, 76, 201e21ˇ 5.
10. (a) Chao, C.-M.; Vitale, M. R.; Toullec, P. Y.; Genet, J.-P.; Michelet, V. Chem.dEur.
J. 2009, 15, 1319e1323; (b) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108,
3239e3265; (c) Matsumoto, Y.; Selim, K. B.; Nakanishi, H.; Yamada, K.; Yama-
moto, Y.; Tomioka, K. Tetrahedron Lett. 2010, 51, 404e406.
11. Furstner, A.; Majima, K.; Martin, R.; Krause, H.; Kattnig, E.; Goddard, R.; Leh-
mann, C. W. J. Am. Chem. Soc. 2008, 130, 1992e2004.
12. (a) Brissy, D.; Skander, M.; Jullien, H.; Retailleau, P.; Marinetti, A. Org. Lett. 2009,
ꢁ
11, 2137e2139; (b) Munoz, M. P.; Adrio, J.; Carretero, J. C.; Echavarren, A. M.
(400 MHz, CDCl3):
d
¼11.37 (br s, 1H), 8.16 (s, 1H), 7.66 (m, 2H),
Organometallics 2005, 24, 1293e1300.
13. Molander, G. A.; Corrette, C. P. J. Org. Chem. 1999, 64, 9697e9703.
14. (a) Trost, B. M.; Shen, H. C.; Schulz, T.; Koradin, C.; Schirok, H. Org. Lett. 2003, 5,
4149e4151; (b) Trost, B. M.; Surivet, J.-P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,
15592e15602.
7.30e7.14 (m, 3H), 4.58 (m, 1H), 3.56 (s, 3H), 3.21 (m, 2H), 1.94 (m,
1H), 1.75 (m, 1H), 1.65 (m, 1H), 1.40 (m, 3H), 1.31 ppm (s, 18H); 13C
NMR (100 MHz, CDCl3):
131.4, 128.2, 127.1, 82.8, 78.9, 52.4, 52.1, 40.3, 31.6, 30.6, 28.4, 28.1,
27.8, 22.7, 14.0 ppm.
d
¼172.8, 167.2, 163.3, 156.0, 153.1, 133.6,
15. For metal-catalyzed reductive cyclization of substrates with stereogenic cen-
ters; using hydrogen: (a) Rhee, J. U.; Krische, M. J. J. Am. Chem. Soc. 2006, 128,
10674e10675; (b) Rhee, J. U.; Jones, R. A.; Krische, M. J. Synthesis 2007,
3427e3430 For metal-catalyzed reductive cyclization of substrates without
stereogenic centers; using hydrogen: (c) Jung, I. G.; Seo, J.; Lee, S. I.; Choi, S. Y.;
Chung, Y. K. Organometallics 2006, 25, 4240e4242; (d) Sylvester, K. T.; Chirik, P.
J. J. Am. Chem. Soc. 2009, 131, 8772e8774 Using organosilanes: (e) Chakrapani,
H.; Liu, C.; Widenhoefer, R. A. Org. Lett. 2003, 5, 157e159; (f) Fan, B.-M.; Xie, J.-
H.; Li, S.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2007, 46, 1275e1277 see
also Ref. 13. Using organozincs: (g) Chen, M.; Weng, Y.; Guo, M.; Zhang, H.; Lei,
A. Angew. Chem., Int. Ed. 2008, 47, 2279e2282 Using organoboranes: (h) Kinder,
R. E.; Widenhoefer, R. A. Org. Lett. 2006, 8, 1967e1969.
4.1.30. (S,Z)-2-Benzamido-6-(2,3-bis(tert-butoxycarbonyl)guani-
dino)hexanoic acid (8).2 To a stirred solution of compound 8b (1.0 g,
1.97 mmol) in THF (20 mL) was added 1 N LiOH solution (3.94 mL,
3.94 mmol) at room temperature. After stirring at room tempera-
ture for 3 h, the reaction mixture was cooled to 0 ꢂC and then
treated with water (20 mL) and 1 N HCl solution (3.0 mL) for
neutralization. The aqueous layer was separated and extracted with
16. Afzali-Ardakani, A.; Rapoport, H. J. Org. Chem. 1980, 45, 4817e4820.