Synthesis of (Z)-alkene-containing cis-proline dipeptide mimetics using samarium(II) diiodide (SmI2)-mediated reductive alkylation reaction

Article abstract of DOI:10.1016/j.tet.2006.12.055

The amide bond between an amino acid and proline can take the trans- or cis-conformation. The conformation influences both the structure and function of peptides and proteins. Therefore, constrained mimetic, which corresponds to Pro-dipeptides whose amide

Full text of DOI:10.1016/j.tet.2006.12.055

Tetrahedron 63 (2007) 2000–2008
Synthesis of (Z)-alkene-containing cis-proline dipeptide mimetics
using samarium(II) diiodide (SmI2)-mediated reductive
alkylation reaction
Yoshikazu Sasaki,a,b Akira Shigenaga,b Nobutaka Fujiia and Akira Otakab,
*
aGraduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
bGraduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima 770-8505, Japan
Received 20 November 2006; revised 15 December 2006; accepted 18 December 2006
Available online 20 December 2006
Abstract—The amide bond between an amino acid and proline can take the trans- or cis-conformation. The conformation influences both the
structure and function of peptides and proteins. Therefore, constrained mimetic, which corresponds to Pro-dipeptides whose amide bond is
replaced with an (E)- or (Z)-alkene, is a useful bioprobe for elucidating the structure–function relationship of peptides and proteins. Herein, we
report the synthesis of cis-(Z)-alkene-containing Pro-dipeptide mimetics via a samarium(II) diiodide (SmI2)-mediated reductive alkylation
reaction.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
(Z)-Pro mimetics using Still–Wittig [2,3]-sigmatropic and
Ireland–Claisen [3,3]-sigmatropic rearrangements, respec-
tively, as key transformations.5 Alternatively, we have ap-
plied organocopper-mediated anti-SN20 reactions to the
stereoselective synthesis of trans-mimetics.4a Our synthesis
of the trans derivative uses the anti-SN20 reaction of a vinyl
oxazolidinone derivative.
Dipeptide mimetics represent attractive compounds for de-
veloping peptide-based drugs or bioprobes to analyze pep-
tide and protein functions. Amino acyl prolines (Xaa–Pro),
which are important dipeptide units, should be mimicked by
a structural scaffold because the Xaa–Pro bonds can take
either the trans- or cis-conformation (1 or 2 in Fig. 1), and
the conformation should influence the functions of a Pro-
containing protein.1 Therefore, constrained Pro-dipeptide
mimetics, which correspond to trans- or cis-imides, have
received increasing attention in the fields of organic, me-
dicinal, and peptide/protein chemistry.2 Much effort has
focused on preparing constrained analogs, including alkene
dipeptide mimetics that possess a replacement for the trans-
or cis-imide with an (E)- or a (Z)-alkene, respectively (3 or 4
in Fig. 1).3–5
On the other hand, we envisioned that the construction of the
five-membered ring corresponding to Pro moiety on an
O
NH
NH
N
R
N
R
O
O
O
trans-amino acyl
proline unit 1
cis-amino acyl
proline unit 2
In addition to other research groups, we have been engaged
in preparing (E)- or (Z)-Xaa–Pro alkene mimetics.4 Etzkorn
et al. have reported the stereoselective syntheses of (E)- and
O
NH
Keywords: Samarium diiodide; Reductive alkylation reaction; Dipeptide
mimetic; Proline.
NH
R
X
Abbreviations: Ns, 2-nitrobenzenesulfonyl; Bn, benzyl; TBS, tert-butyldi-
methylsilyl; DIBAL-H, diisobutylaluminumhydride; Tf2NPh, N-phenyl-
bis(trifluoromethanesulfonimide); TBAF, tetrabutylammonium fluoride;
DMAP, 4-dimethylaminopyridine; TsCl, p-toluenesulfonylchloride; o-Tol,
o-tolyl; TBSCl, tert-butyldimethylsilylchloride; HMPA, hexamethylphos-
phoramide; DMPU, N,N0-dimethylpropyleneurea; THP, tetrahydropyran.
* Corresponding author. Tel.: +81 88 633 7283; fax: +81 88 633 9505;
e-mail: aotaka@ph.tokushima-u.ac.jp
R
O
(E)-alkene-containing
trans-proline mimetic 3
(Z)-alkene-containing
cis-proline mimetic 4
Figure 1. Amino acyl proline bonds can take a trans- or cis-conformation
and the corresponding alkene-containing mimetics.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.055

Y. Sasaki et al. / Tetrahedron 63 (2007) 2000–2008
2001
organocopper-
mediated
R1
R2
X
Y
cross-coupling
anti-SN2' reaction
N
O
C-3 alkylated
Intermediate 5
R1
route A
lactam opening
(Z)-alkene-containing
cis-Pro mimetics 4
Amino Acids
N
R2
route B
R1
R2
O
Bicyclo Lactam 7
N
X
O
Y
dienolate formation
by reduction
C-4 alkylated electrophilic trapping
Intermediate 6
of dienolate
Scheme 1. Rational synthetic routes to (Z)-alkene-containing cis-Pro mimetic 4.
unsaturated lactam as a (Z)-alkene precursor was a rational
way for the preparation of the (Z)-alkene-containing Pro
mimetics as shown in Scheme 1. This five-membered ring
formation involves the use of C-3 alkylated intermediate 5
(route A) or C-4 alkylated intermediate 6 (route B). In the
route A synthesis, an organocopper-mediated anti-SN20
action of SmI2 to give the corresponding Sm-dienolate,
which intramolecularly reacted with an alkyl halide or alde-
hyde unit in a one-pot manner.
Scheme 2 shows the synthetic route to the key intermediates.
Starting from b-amino acid derivative 10,4b a well-estab-
lished sequence of reactions was applied to prepare a,b-un-
saturated lactam 13. A similar reaction sequence was also
reaction yields the requisite intermediate
5
(X¼I,
Y¼B(alkyl)2), which then can be subjected to an intramolec-
ular Suzuki coupling reaction to give bicyclo lactam 7 as a
crucial precursor of the (Z)-Pro mimetic.4b In route B, intra-
molecular alkylation of a dienolate relevant to the intermedi-
ate 6 (X¼metal, Y¼halide or carbonyl) is likely to afford
bicyclo lactam 7. In terms of forming dienolates followed
by a-substitution, we recently reported that reduction of
g-activated a,b-unsaturated enoates in a successive single
electron transfer (SET) manner affords the corresponding di-
enolate, which then reacts with an appropriate electrophile at
the a-position.6 This reaction sequence has been success-
fully applied to the synthesis of (E)-alkene dipeptide
Bn
O
OTBS
CO2Et
N
iii, iv
i, ii
Ns
OTBS
Bn CO2Et
10
N
CO2Et
11
Bn
OTBS
OTf
vi
90%
N
Bn
O
OTBS
v
N
75%
from 10
O
O
13
12
mimetics, including fluoroalkene mimetics where organo-
copper6a,b or SmI2
the basis of these findings, we realized that route B synthesis
would be possible using a reaction sequence that consists
of reduction and subsequent a-alkylation of the resulting
dienolate.
6c,d
is the reducing agent of choice. On
Bn
OTBS
Bn
OTBS
vii
99%
N
N
O
CO2Me
O
CH2OH
15
14
viii, ix, x,
viii, xi
71%
xii
In this paper, we examined the feasibility of reductive alkyl-
ation with SmI27,8 in the presence of alkyl halides to prepare
(Z)-alkene-containing Pro mimetics, which correspond to
the cis-Xaa–Pro conformation.
Bn
O
OAc
Bn
O
OTBS
N
N
OTs
CHO
16
17
2. Results and discussion
xiii, xiv
88% from 15
As shown in Figure 2, we selected g-acetoxy-b-substituted-
a,b-unsaturated-d-lactams (8 and 9) as requisite synthetic
intermediates in the route B cyclization. The g-acetoxy-
a,b-unsaturated-d-lactam moiety could be reduced by the
Bn
OAc
I
N
O
18
OAc
Scheme 2. Synthetic route to key intermediates 16 and 18. Reagents: (i)
HSCH2CO2H, LiOH$H2O, DMF; (ii) EtOCOCH2COCl, diisopropylethyl-
amine (DIPEA), CH2Cl2; (iii) NaOEt, EtOH; (iv) H2O, CH3CN, reflux;
(v) Tf2NPh, Et3N, CH2Cl2; (vi) IZn(CH2)2CO2Me, Pd[P(o-Tol)3]2Cl2;
(vii) NaBH4, MeOH, THF; (viii) TBAF, THF; (ix) TBSCl, imidazole,
DMF; (x) Ac2O, pyridine, DMAP, CH2Cl2; (xi) (COCl)2, DMSO, DIPEA,
CH2Cl2; (xii) TsCl, pyridine, CH2Cl2; (xiii) H2SiF6, MeOH, H2O,
CH3CN, then Ac2O, pyridine, DMAP, CHCl3; (xiv) NaI, acetone.
R
8 (X: =O)
9 (X: -halogen)
N
P
X
P = protection
O
Reduced to Sm-dienolate
Figure 2. Requisite synthetic intermediates in route B.

2002
Y. Sasaki et al. / Tetrahedron 63 (2007) 2000–2008
utilized to synthesize the corresponding N-dimethoxybenzyl
derivative in the route A cyclization.4b The alkenyl triflate
moiety in 13 was subjected to a palladium(0)-catalyzed
cross-coupling reaction with a C3 unit. An organozinc re-
agent derived from methyl iodopropionate was utilized as
the C3 unit. Among the examined Pd catalysts, Pd[P(o-
Tol)3]2Cl2 (20 mol %) afforded the best result as it yielded
cross-coupling product 14 in 90% isolated yield. The ester
function of the resulting coupling product 14 was reduced
to give primary alcohol derivative 15.9 Selective O-TBS
protection of the primary alcohol unit was achieved by the
re-protection of TBAF-treated sample of 15 with TBSCl–
imidazole in DMF to afford a secondary alcohol derivative,
which was then subjected to O-acetylation followed by suc-
cessive reactions, which consisted of O-TBS deprotection
and Swern oxidation of the resulting primary alcohol to
give potential precursor 16 for the route B cyclization. Alter-
natively, compound 15 also led to O-Ts derivative 17. After
converting the O-TBS to the O-Ac function, iodo derivative
18, which is another key intermediate, was obtained by treat-
ing 17 with NaI in acetone. Having the precursors for the
route B cyclization, we examined the bicyclo lactam forma-
tion by SmI2.
which would improve the cyclization yield. Although the
chemical yield improved (43%), the reaction remained at
an unsatisfactory level (Table 1, entries 3 and 4). In these
attempted reactions, we were curious about the formation
of reduction product 21 in the absence of a proton source
such as an alcohol. In the case of SmI2-mediated reduction
of g-activated-a,b-enoates, the presence of an alcohol as a
proton source is crucial for a clean conversion.6c Because
one possible origin of the proton in the reduction appears
to be derived from the quenching procedure of the reaction,
we attempted to quench the reaction with CD3CO2D (Table
1, entry 2). However, deuterated reduction product 21-D was
not observed.
These observations indicate that the hydrogen atom is likely
incorporated at the a-position from THF in a radical mech-
anism (Fig. 3).10–12 Compared to a,b-enoates, a,b-enamides
(or unsaturated lactams) are less electrophilic due to the
presence of the amide function. Successive SETs are in-
volved in the formation of the anionic Sm-dienolate (e.g.,
24) from the enoates or enamides. Radical intermediates
(22 or 23) produced through the first SET step are less elec-
trophilic than the starting material. Therefore, the first SET
step proceeds more rapidly than the second step. In conjunc-
tion with these considerations, we speculated that the SmI2-
mediated reduction of unsaturated lactam 18 would give
a mixture that contains dienolates 24 and radicals 22 or 23
as reaction intermediates, whereas the enoates were suscep-
tible to the successive SETs to form the dienolate intermedi-
ate. In the reduction of 18 with SmI2 in THF, formed
dienolate 24 and the radical intermediate 23 were likely to
be involved in the reaction with the intramolecular electro-
philic part and the hydrogen atom abstraction from THF,
respectively. Therefore, we attempted to investigate the
reaction conditions without the formation of 21 through
the abstraction of hydrogen atom from THF.
The reaction of g-acetoxy- or g,g-difluoro-a,b-enoates with
SmI2 in THF in the presence of an aldehyde as an electro-
phile proceeds efficiently to yield a-aldol compounds.6c,d
On the basis of these findings, we speculated that treating
16 with SmI2 in THF should give bicyclo lactams. To easily
evaluate the reaction, the crude products were converted to
dehydrated product 19. However, the attempted cyclization
proceeded with a low efficiency and yielded 19 in 9% iso-
lated yield (Table 1, entry 1). Next, we investigated the
synthetic utility of compound 18, which possesses an alkyl
halide moiety that serves the electrophilic part in SmI2-
mediated cyclization reactions. The reaction of 18 with
SmI2 (3 equiv) in THF at 0 ꢀC for 30 min gave reductive
alkylation product 20 and reduction product 21 in 35% and
The emphasis of our first attempt was to enhance the reduc-
tion potential of the Sm(II) reagent when the starting mate-
rial should be reduced to the corresponding dienolate
without accumulating radical intermediates. However, the
reaction using SmBr2 in THF,13 which is known to have a
superior reduction potential to SmI2 in THF, did not afford
1
22% yields, respectively. H NMR analysis indicated that
the alkylation reaction probably proceeds in a diastereoselec-
tive manner. The addition of HMPA or DMPU into the reac-
tion mixture after 15 min treatment with SmI2 was expected
to enhance the nucleophilicity of the resulting dienolate,
Table 1. Cyclization utilizing reductive-aldol or -alkylation reaction by SmI2 in THF
Bn
O
Bn
O
Bn
O
Bn
O
N
N
Bn
O
OAc
N
N
SmI2 in THF
N
D
R
I
21
I
21-D
16: R = CHO
18: R = CH2I
19
20
Entry
Substrate
Reagentsa in THF
Conditions
Productsf (isolated yield %)
b
1
2
3
4
16
18
18
18
SmI2c
SmI2
rt, 1 h
19 (9)
0 ꢀC, 30 min
0 ꢀC, 15 mine
0 ꢀC, 15 mine
20 (35), 21 (22), 21-D (0)
20 (43), 21 (42)
20 (43), 21 (39)
SmI2, then HMPAd (12 equiv)
SmI2, then DMPUd (12 equiv)
a
Three equivalents of SmI2 were used.
Subsequent treatment with methanesulfonyl chloride (1.2 equiv) and Et3N (5 equiv) in CH2Cl2.
The reaction was quenched by the addition of CD3CO2D.
b
c
d
e
f
After 15 min reaction with SmI2 at 0 ꢀC, HMPA or DMPU was added.
After addition of HMPA or DMPU, the reaction mixture was stirred for 15 min at 0 ꢀC and subsequently stirred for 18 h at room temperature.
Compound 20 was obtained as a single diastereomer.

Y. Sasaki et al. / Tetrahedron 63 (2007) 2000–2008
2003
Bn
O
Bn
OAc
Bn
N
N
N
dienolate
alkylation
I
I
(III)SmO
(III)SmO
24
22
Second SET
step
SmI2
20
Bn
O
OAc
SmI2
N
First SET
step
AcOSm(III)
I
18
Bn
O
Bn
O
H
O
N
N
H abstraction
from THF
I
I
21
23
H
Figure 3. Plausible mechanism of the reaction with SmI2 in THF.
satisfactory results (Table 2, entry 1). Furthermore, dehalo-
genation was observed in the reduction using SmI2–HMPA
in THF.14,15 Replacing THF as the reaction solvent with
THP11 or CH3CN12 has been reported to effectively suppress
the radical-mediated side reaction involved in the SmI2-
mediated reduction. Unfortunately, using THP as the reac-
tion solvent was unsatisfactory (Table 2, entry 2). Reduction
with SmI2 in CH3CN did not yield reduced products, proba-
bly due to its low reduction potential (Table 2, entry 4). Ad-
ditionally, the instability of SmI2 in CH3CN might be partly
responsible for the result. DMPU as an additive to SmI2 in
the CH3CN system is known to enhance both the stability and
reduction potential of the reagent.16 After surveying suitable
reaction conditions, we found that the reaction of 18 with
SmI2–DMPU in CH3CN at ꢁ18 ꢀC for 3 min yielded the de-
sired cyclized product 20 as a single diastereomer in 70%
isolated yield without reduction product 21 (Table 2, entry
8). In this system, a long reaction time or an elevated temper-
ature induced the isomerization of 20 to thermodynamically
more stable a,b-enamide 25.
is more stable than complex 26 (Fig. 4). The interaction be-
tween the cation (Li) and halide (alkyl halide) in the more
stable complex 27 allows the alkyl halide to be located at
the face opposite to the methyl group, which leads to the for-
mation of the 3,6-trans product. Although other factors in the
reaction cannot be excluded, this type of oxa-p-allylmetal
complex may be the case for the Sm-dienolates and the
more stable complex is probably the main contributor in
the alkylation of the enolate.
Ph
Li
O
Me
Ph
O
Me
N
N
Li
26
27
Figure 4. Plausible oxa-p-allyllithium complexes and their relative stability
calculated by DFT.
Conversion of lactam 20 to the corresponding Ala–Pro type
(Z)-alkene dipeptide mimetic 29 was achieved by the reac-
tion sequence shown in Scheme 3.18 The reaction of 20
with MeOTf in dichloroethane effected the formation of
the lactim ether. Without isolating the lactim ether, the ob-
tained crude reaction mixture was subjected to hydrolysis
in the presence of trifluoromethanesulfonic acid followed
by N-Boc protection of the resulting secondary amino func-
tion to afford N-Boc-N-Bn-methyl ester 28 in 48% yield with
The obtained cyclized product has a 3,6-trans relationship.
This diastereoselectivity may be explained based on previ-
ous DFT calculations on the plausible oxa-p-allyllithium
complex involved in the intermolecular alkylation of Li-di-
enolate with alkyl halides.17 In this system, two oxa-p-allyl-
lithium complexes 26 and 27 are possible where complex 27
Table 2. Examination of reductive cyclization of 18 with Sm(II)
Bn
Bn
N
Bn
N
N
Bn
O
OAc
Sm(II)
N
O
O
O
I
I
21
18
20
25
Entry
Reagent(s)
Conditions
Productsa (isolated yield %)
1
2
3
4
5
6
7
8
SmBr2 (3 equiv), THF
SmI2 (3 equiv), THP
SmI2 (3 equiv), HMPA (36 equiv), THP
SmI2 (3 equiv), CH3CN
SmI2 (3 equiv), DMPU (30 equiv), CH3CN
SmI2 (8 equiv), DMPU (80 equiv), CH3CN
SmI2 (8 equiv), DMPU (80 equiv), CH3CN
SmI2 (8 equiv), DMPU (80 equiv), CH3CN
0 ꢀC, 30 min
0 ꢀC, 30 min
0 ꢀC, 30 min
0 ꢀC, 30 min
0 ꢀC, 3 h
20 (23), 21 (44)
20 (10)
20 (23), 21 (33)b
b
—
20 (41), 21 (5), 25 (6)b
20 (9), 25 (85)
20 (50)
0 ꢀC, 3 h
ꢁ18 ꢀC, 1 min
ꢁ18 ꢀC, 3 min
20 (70)
a
Compound 20 was obtained as a single isomer.
Starting material was recovered.
b

2004
Y. Sasaki et al. / Tetrahedron 63 (2007) 2000–2008
Bn
Bn
O
ii, iii
i
N
iv, v
NHBoc
CO2H
29
N
• OTf
NBoc
CO2Me
48%
from 20*
86%
Bn
MeO
Ala-Pro type
(Z)-Alkene
20
28
Dipeptide Mimetic
Scheme 3. Conversion of lactam 20 to the corresponding Ala–Pro type (Z)-alkene dipeptide mimetic 29. Reagents: (i) MeOTf, ClCH2CH2Cl; (ii) TfOH aq, THF;
(iii) Boc2O, DIPEA, DMF; (iv) 1 M KOH aq, THF; (v) Na-NH3, THF. *Starting material 20 was partly recovered.
recovery of starting material 20 (24%). Saponification of the
resulting ester followed by a Birch reduction to remove the
N-Bn group yielded dipeptide mimetic 29 in 86% isolated
yield. The stereochemistry of the obtained compound was
unambiguously established as the L–D mimetic by compar-
ing to the literature.5a Formation of the L–D type is likely
due to the preferential cyclization, which leads to the 3,6-
trans bicyclo lactam as mentioned in the previous section.
with 1 N HCl, brine, saturated NaHCO3 and brine, dried
over MgSO4, and concentrated under reduced pressure to
give residues. Column chromatography of the residues over
silica gel with EtOAc–n-hexane (1:9) gave 2.87 g (85.6%
yield) of the title compound 11 as colorless oil: [a]2D6 ꢁ32.4
(c 1.24, CHCl3); 1H NMR (400 MHz, CDCl3) (mixture of ro-
tamers, data for one isomer) d 0.06 (s, 6H), 0.94 (s, 9H), 1.13
(d, J¼7.2 Hz, 3H), 1.23–1.33 (m, 6H), 3.27 (d, J¼15.2 Hz,
1H), 3.36 (d, J¼15.2 Hz, 1H), 4.12–4.28 (m, 4H), 4.53 (d,
J¼18.4 Hz, 1H), 4.61 (d, J¼4.8 Hz, 1H), 4.75 (d,
J¼18.4 Hz, 1H), 4.78 (br, 1H), 7.16–7.41 (m, 3H), 7.36 (t,
J¼7.6 Hz, 3H); HRMS (ESI-TOF) m/z calcd for
C24H40NO6Si (MH+) 466.2625; found 466.2646.
In this work, we successfully synthesized (Z)-alkene-con-
taining cis-proline dipeptide mimetics using a SmI2-medi-
ated reductive alkylation reaction. The reaction outcome is
determined by the reaction solvent used in the reduction of
the key intermediate such as 18 with SmI2. The reductive
alkylation in THF affords the desired cyclized product with
concomitant formation of the reduction product where the
hydrogen atom derived from THF is incorporated into the
substrate via a radical mechanism. On the other hand, for
the (Z)-alkene-containing cis-Pro mimetic, CH3CN in the
presence of DMPU is the solvent of choice for SmI2-
mediated reductive alkylation. The incorporation of the syn-
thesized mimetics into peptides for biological evaluation is
underway.
3.1.2. (5S,6S)-1-Benzyl-5-(tert-butyldimethylsilanyloxy)-
6-methyl-4-trifluoromethanesulfonyloxy-5,6-dihydro-
1H-pyridin-2-one (13) from 11. To a solution of 11 (2.70 g,
5.80 mmol) in EtOH (14 mL) was added 14 mL (6.38 mmol)
of freshly prepared NaOEt in EtOH (0.456 M) at 0 ꢀC under
argon, and the reaction mixture was stirred for 45 min and
quenched with saturated citric acid solution. The mixture
was extracted with EtOAc, and the extract was washed
with brine, dried over MgSO4, and concentrated in vacuo
to give an oily material, which was used for following reac-
tions without further purification. The mixture of the oil in
800 mL of H2O and 160 mL of CH3CN was refluxed for
2 h and concentrated under reduced pressure to give solid
crude materials containing 12. To a solution of the crude
materials in CH2Cl2 (80 mL) were added N-phenylbis(tri-
fluoromethanesulfonimide) (2.90 g, 8.12 mmol) and Et3N
(1.13 mL, 8.12 mmol) at 0 ꢀC, and the mixture was stirred
at room temperature for 10 h. The reaction mixture was
quenched by the addition of H2O and extracted with Et2O.
The organic phase was washed with H2O and brine, dried
over MgSO4, and concentrated under reduced pressure to
give crude materials. Chromatographic purification of the
crude materials over silica gel with EtOAc–n-hexane
(5:95) gave the title compound 13 (2.41 g, 86.7% yield)
as a white crystal: mp 70–72 ꢀC; [a]D27 ꢁ89.7 (c 0.61,
CHCl3); 1H NMR (400 MHz, CDCl3) d ꢁ0.10 (s, 3H),
0.05 (s, 3H), 0.75 (s, 9H), 1.20 (d, J¼6.8 Hz, 3H), 3.48 (q,
J¼6.8 Hz, 1H), 3.89 (d, J¼15.1 Hz, 1H), 4.07 (s, 1H),
5.38 (d, J¼15.1 Hz, 1H), 6.16 (s, 1H), 7.22–7.34 (m, 5H);
13C NMR (100 MHz, CDCl3) d ꢁ5.2, ꢁ5.0, 16.4, 17.9,
25.4, 47.3, 58.0, 70.2, 115.6, 127.5, 128.0, 128.6, 136.1,
156.6, 160.3. Anal. Calcd for C20H28F3NO5SSi: C, 50.09;
H, 5.88; N, 2.92. Found: C, 49.82; H, 5.82; N, 3.02.
3. Experimental
3.1. General
1H NMR spectra were recorded using JEOL-GSX-400 spec-
trometer at 400 MHz and 13C NMR spectra were recorded
using JEOL-GSX-400 spectrometer at 100 MHz or JEOL-
JNM-AL300 spectrometer at 75 MHz. Tetrahydrofuran
(THF) in every reaction conducted under argon was freshly
distilled from sodium-benzophenone ketyl radical under
argon. Melting points are uncorrected.
3.1.1. (2S,3S)-3-(Benzylethoxycarbonylacetylamino)-2-
(tert-butyldimethylsilanyloxy)butyric acid ethyl ester
(11) from 10. To a solution of 10 (4.00 g, 7.45 mmol) in
CH3CN were added Cs2CO3 (2.91 g, 8.94 mmol) and thio-
phenol (918 mL, 8.94 mmol) at 0 ꢀC with stirring. After being
stirred at room temperature for 12 h, the reaction mixturewas
filtered and the filtrate was diluted with EtOAc. Resulting
organic layer was washed with saturated NaHCO3 and brine,
dried over Na2SO4, and concentrated under reduced pressure
to give oily crude. To the crude in CH2Cl2 (70 mL) were
added ethyl malonyl chloride (1.21 mL, 9.61 mmol) and
DIPEA (1.67 mL, 9.61 mmol) at 0 ꢀC under argon. After be-
ing stirred at room temperature for 10 h, the reaction mixture
was quenched by addition of 1 M HCl at 0 ꢀC. The mixture
was extracted with EtOAc, and the extract was washed
3.1.3. (2S,3S)-3-[1-Benzyl-3-(tert-butyldimethylsilanyl-
oxy)-2-methyl-6-oxo-1,2,3,6-tetrahydropyridin-4-yl]pro-
pionic acid methyl ester (14) from 13. To a solution of
13 (2.41 g, 5.03 mmol) and Pd[P(o-Tol)3]2Cl2 (198 mg,

Y. Sasaki et al. / Tetrahedron 63 (2007) 2000–2008
2005
0.251 mmol) in THF (30 mL) was added IZnCH2CH2-
CO2Me19 in THF (100 mL, 20.1 mmol) at 0 ꢀC under argon.
The reaction mixture was stirred at room temperature for 1 h
and quenched with saturated NaHCO3 solution. The mixture
was extracted with Et2O and the extract was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure to give residues. The residues were purified by
silica gel column chromatography to give 1.90 g of the title
compound 14 (4.56 mmol, 90.7% yield) as a white crystal:
mp 78–80 ꢀC; [a]D27 ꢁ96.0 (c 0.18, CHCl3); 1H NMR
(400 MHz, CDCl3) d ꢁ0.20 (s, 3H), 0.02 (s, 3H), 0.75 (s,
9H), 1.08 (d, J¼6.8 Hz, 3H), 2.40–2.66 (m, 4H), 3.40 (q,
J¼6.8 Hz, 1H), 3.69 (s, 3H), 3.75 (s, 1H), 3.89 (d,
J¼15.2 Hz, 1H), 5.34 (d, J¼15.2 Hz, 1H), 5.84 (s, 1H),
7.20–7.32 (m, 5H); 13C NMR (100 MHz, CDCl3) d ꢁ5.5,
ꢁ4.4, 16.3, 17.8, 25.5, 28.7, 31.2, 47.2, 51.7, 57.3, 70.5,
121.0, 127.0, 128.0, 128.3, 137.0, 148.8, 162.1, 172.3;
LRMS (FAB) m/z 418 (MH+), 360, 321 (base peak), 132,
91, 73; HRMS (FAB) m/z calcd for C23H36O4NSi (MH+)
418.2414; found 418.2418.
at room temperature for 2 h, the reaction mixture was
quenched with saturated NH4Cl and extracted with EtOAc.
The extract was dried over MgSO4 and concentrated under
reduced pressure to give oily crude. To a solution containing
the crude in THF (10 mL) was added 1 M TBAF (1.98 mL,
1.98 mmol) at 0 ꢀC. After being stirred at room temperature
for 3 h, the mixturewas quenched with 1 N HCl and extracted
with EtOAc. The extract was washed with brine, dried over
MgSO4, and concentrated in vacuo to give oily materials.
To a solution of oxalylchloride (291 mL, 3.34 mmol) in
CH2Cl2 (10 mL) was added DMSO (355 mL, 5.01 mmol) at
ꢁ78 ꢀC under argon. The mixture was stirred for 15 min at
this temperature, followed by addition of the above oily
materials in CH2Cl2 (10 mL) at ꢁ78 ꢀC. After being stirred
for 15 min at this temperature, the mixture was stirred for
1 h at ꢁ45 ꢀC followed by addition of 2.18 mL of DIPEA
(12.5 mmol) and 20 min stirring at 0 ꢀC. The reaction mix-
ture was quenched with 1 N HCl and extracted with EtOAc.
The extract was washed with brine, dried over MgSO4, and
concentrated under reduced pressure to give oily materials.
After purification by column chromatography over silica
gel with EtOAc–n-hexane (1:4), the title compound 16 was
obtained as colorless oil (104 mg, 90.6% yield): [a]D26
ꢁ84.9 (c 0.26, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.19
(d, J¼7.0 Hz, 3H), 1.79 (s, 3H), 2.45–2.60 (m, 2H), 2.64–
2.79 (m, 2H), 3.50 (qd, J¼7.0 Hz, 1.6 Hz, 1H), 3.73 (d,
J¼15.2 Hz, 1H), 4.93 (d, J¼1.6 Hz, 1H), 5.47 (d,
J¼15.2 Hz, 1H), 6.01 (s, 1H), 7.22–7.34 (m, 5H), 9.81 (s,
1H); 13C NMR (100 MHz, CDCl3) d 16.0, 20.7, 26.5, 40.6,
46.8, 53.7, 70.2, 124.6, 127.4, 128.0, 128.4, 136.9, 144.6,
161.7, 170.2; HRMS (ESI-TOF) m/z calcd for C18H22NO4
(MH+) 316.1549; found 316.1534.
3.1.4. (5S,6S)-1-Benzyl-5-(tert-butyldimethylsilanyloxy)-
4-(3-hydroxypropyl)-6-methyl-5,6-dihydro-1H-pyridin-
2-one (15) from 14. To a solution of 14 (4.19 g, 10.0 mmol)
in MeOH (40 mL) and THF (40 mL) was added NaBH4
(4.55 g, 121 mmol) in small portions over 12 h at 0 ꢀC.
After being stirred for 8 h at this temperature, the reaction
mixture was quenched with 1 N HCl and extracted with
EtOAc. The extract was washed with brine, dried over
MgSO4, and concentrated under reduced pressure to give
crude materials. Column chromatography purification of
the crude over silica gel with EtOAc–n-hexane (2:1) gave
15 (3.85 g, 98.7% yield) as a white crystal: mp 85–87 ꢀC;
[a]2D6 ꢁ80.1 (c 0.84, CHCl3); H NMR (400 MHz, CDCl3)
3.1.6. (2S,3S)-Acetic acid 1-benzyl-4-(3-iodo-propyl)-2-
methyl-6-oxo-1,2,3,6-tetrahydropyridin-3-yl ester (18)
from 15. A solution containing 15 (1.00 g, 2.57 mmol),
DMAP (31.4 mg, 0.257 mmol), TsCl (735 mg, 3.85 mmol),
and pyridine (620 mL, 7.71 mmol) in CH2Cl2 (5 mL) was
stirred at room temperature for 12 h. The reaction mixture
was quenched with 1 N HCl and extracted with EtOAc.
The extract was washed with 1 N HCl and brine, dried over
MgSO4, and concentrated under reduced pressure to give
crude materials containing 17. To a stirred solution of the
materials in CH3CN (15 mL) and MeOH (1 mL) was added
3.9 mL of hexafluorosilicic acid solution (ca. 40%, ca.
11 mmol) at room temperature. The reaction mixture was
heated to 40 ꢀC and stirred for 3 h. After being cooled at
0 ꢀC, the mixture was quenched with saturated NaHCO3
and extracted with EtOAc. The extract was washed with
saturated NaHCO3 and brine, dried over MgSO4, and con-
centrated under reduced pressure to give oily residues. After
column chromatography purification over silica gel with
EtOAc–n-hexane (15:85), 884 mg of the title compound 18
(2.07 mmol, 88.4% yield) was obtained as colorless oil:
1
d ꢁ0.21 (s, 3H), 0.02 (s, 3H), 0.75 (s, 9H), 1.08 (d,
J¼7.2 Hz, 3H), 1.38 (t, J¼4.8 Hz, 3H), 1.69–1.88 (m, 2H),
2.21–2.41 (m, 2H), 3.41 (qd, J¼7.2 Hz, 1.2 Hz, 1H), 3.71
(m, 2H), 3.74 (d, J¼1.2 Hz, 1H), 3.89 (d, J¼15.4 Hz, 1H),
5.34 (d, J¼15.4 Hz, 1H), 5.87 (s, 1H), 7.20–7.32 (m, 5H);
13C NMR (100 MHz, CDCl3) d ꢁ5.0, ꢁ4.4, 16.3, 17.8,
25.6, 29.8, 30.1, 47.3, 57.3, 61.5, 70.1, 120.6, 127.0, 128.0,
128.3, 137.0, 150.7, 162.7. Anal. Calcd for C22H35NO3Si:
C, 67.82; H, 9.05; N, 3.60. Found: C, 67.58; H, 9.02;
N, 3.58.
3.1.5. (2S,3S)-Acetic acid 1-benzyl-2-methyl-6-oxo-4-(3-
oxopropyl)-1,2,3,6-tetrahydropyridin-3-yl ester (16)
from 15. To a solution containing 15 (700 mg, 1.80 mmol)
in THF (7 mL) was added 1 M TBAF in THF (1.98 mL,
1.98 mmol) at 0 ꢀC. After being stirred for 4 h at room tem-
perature, the mixture was quenched with 1 N HCl and
extracted with EtOAc. The extract was washed with brine,
dried over MgSO4, and concentrated in vacuo to give color-
less oil. The solution of the above oil in 10 mL of DMF was
mixed with TBSCl (325 mg, 2.16 mmol) and imidazole
(281 mg, 4.13 mmol) at 0 ꢀC, and stirred at this temperature
for 2 h. The reaction mixture was quenched with saturated
NaHCO3 followed by extraction with EtOAc. The extract
was washed with saturated NaHCO3 and brine, dried over
MgSO4 followed by evaporation of solvent to give crude ma-
terial. The crude in 10 mL of CHCl3 was treated with Ac2O
(850 mL, 8.99 mmol), pyridine (722 mL, 8.99 mmol), and
DMAP (22.0 mg, 0.180 mmol) at 0 ꢀC. After being stirred
1
[a]2D6 ꢁ87.8 (c 0.98, CHCl3); H NMR (400 MHz, CDCl3)
d 1.19 (d, J¼6.8 Hz, 3H), 1.80 (s, 3H), 1.93–2.08 (m, 2H),
2.30–2.37 (m, 2H), 3.14–3.26 (m, 2H), 3.49 (qd, J¼6.8 Hz,
1.6 Hz, 1H), 3.73 (d, J¼15.0 Hz, 1H), 4.91 (d, J¼1.6 Hz,
1H), 3.48 (d, J¼15.0 Hz, 1H), 6.07 (s, 1H), 7.20–7.32 (m,
5H); 13C NMR (100 MHz, CDCl3) d 4.8, 16.0, 20.7, 30.1,
35.0, 46.7, 53.7, 70.0, 124.9, 127.3, 128.0, 128.3, 136.8,
144.4, 161.7, 170.1; HRMS (ESI-TOF) m/z calcd for
C18H23NO3I (MH+) 428.0723; found 428.0717.

2006
Y. Sasaki et al. / Tetrahedron 63 (2007) 2000–2008
3.1.7. Preparation of SmI2 in THF solution. To a suspen-
sion of samarium (Kojundo Chemical Lab. Co., Ltd: 850 mm
powder, 240 mg, 1.60 mmol) in THF (4 mL) was added
CH2I2 (64.0 mL, 0.800 mmol) in THF (4 mL) at room tem-
perature under argon. After 1 h stirring, 0.1 M of SmI2 in
THF solution (8 mL) was obtained.
1H), 7.22–7.34 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 5.7, 20.7, 30.3, 35.1, 36.0, 46.5, 52.6, 122.6, 127.2,
127.6, 128.5, 131.3, 137.0, 167.7; HRMS (ESI-TOF) m/z
calcd for C16H20INONa (MNa+) 392.0498; found 392.0487.
3.1.10. Reductive alkylation with SmI2 and additive
(HMPA or DMPU) in THF (Table 1, entries 3 and 4). To
a solution of 18 (50.0 mg, 0.118 mmol) in THF (1.5 mL)
was added SmI2 in THF (0.100 M, 3.54 mL, 0.354 mmol)
at 0 ꢀC under argon. After 15 min, 4.24 mmol of HMPA or
DMPU was added to the mixture, which was stirred for
18 h at room temperature. After addition of silica gel
(300 mg) and n-hexane (3 mL), the mixture was filtrated
and the filtrate was diluted with EtOAc followed by washing
with saturated NH4Cl and brine, and dried over MgSO4.
Concentration in vacuo gave crude materials. Column chro-
matography purification over silica gel with EtOAc–n-hex-
ane (15:85) gave 20 (12.2 mg, 0.0506 mmol, 43.6% or
12.4 mg, 0.0514 mmol, 44.3% yield).
3.1.8. (3S)-2-Benzyl-3-methyl-2,3,5,6-tetrahydro-[2]pyr-
indine-1-one (19) from 16 (Table 1, entry 1). To a solution
containing 16 (75.0 mg, 0.238 mmol) in THF (3 mL) was
added SmI2 in THF (0.1 M, 7.13 mL, 0.713 mmol) at 0 ꢀC
under argon. After 1 h reaction, silica gel (300 mg) and
n-hexane (3 mL) were added to the reaction mixture. The
mixture was stirred for 5 min and filtrated. The resulting fil-
trate was diluted with EtOAc and washed with saturated
NH4Cl and brine, dried over MgSO4, and concentrated
in vacuo to give crude materials. To a solution of the mate-
rials in CH2Cl2 (6 mL) was added MsCl (46.1 mL,
0.595 mmol) and Et3N (247 mL, 1.78 mmol) at 0 ꢀC. After
being stirred for 3 h at room temperature, the reaction mix-
ture was quenched with 1 N HCl and extracted with EtOAc.
The extract was washed with brine, dried over MgSO4, and
concentrated in vacuo to give an oily crude. After purifica-
tion of the crude over silica gel with EtOAc–n-hexane
(5:95), the title compound 19 (5.10 mg, 8.96% yield) was
obtained as a colorless oil: [a]2D6 ꢁ59.5 (c 0.19, CHCl3);
1H NMR (400 MHz, CDCl3) d 1.26 (m, 3H), 2.65 (m, 4H),
4.06 (m, 1H), 4.12 (d, J¼15.3 Hz, 2H), 5.30 (s, 1H), 5.48
(d, J¼15.3 Hz, 2H), 6.83 (s, 1H), 7.23–7.32 (m, 5H);
LRMS (FAB) m/z 240 (MH+), 240, 149, 91, 57 (base
peak); HRMS (FAB) m/z calcd for C16H18ON (MH+)
240.1388; found 240.1392.
3.1.11. Preparation of SmI2–DMPU in CH3CN. Samar-
ium powder (450 mg, 2.99 mmol: Aldrich—40 mesh,
99.9%) in a flask was dried in vacuo with stirring and heating
for 30 min. Solid ICH2CH2I (423 mg, 1.50 mmol) was
added to the above flask charged with argon. The mixture
was dissolved in CH3CN (13.2 mL: freshly distilled from
CaH2) at room temperature and stirred for 2 h at this temper-
ature followed by addition of DMPU (1.81 mL, 15.0 mmol)
to give purple solution of SmI2–DMPU in CH3CN.
3.1.12. Reductive alkylation with SmI2–DMPU in
CH3CN. Compound 18 (50.0 mg, 0.117 mmol) in freshly
distilled CH3CN (500 mL) was treated with freshly prepared
SmI2–DMPU in CH3CN (9.37 mL, 0.937 mmol) at ꢁ18 ꢀC
under argon followed by 3 min stirring. To the reaction mix-
ture were added 200 mg of silica gel and 3 mL of n-hexane.
After filtration of the mixture, the filtrate was diluted with
EtOAc, washed with saturated NH4Cl and brine, and dried
over MgSO4. Concentration under reduced pressure fol-
lowed by column chromatography over silica gel with
EtOAc–n-hexane (15:85) gave 19.8 mg of 20 (70.1% yield).
3.1.9. (3S,6S)-2-Benzyl-3-methyl-2,3,5,6,7,7a-hexahydro-
[2]pyrindine-1-one (20) and (6S)-1-benzyl-4-(3-iodo-
propyl)-6-methyl-3,6-dihydro-1H-pyridin-2-one (21)
from 18 (Table 1, entry 2). To a solution of 30.0 mg of 18
(0.0702 mmol) in THF (1 mL) was added SmI2 in THF
(0.1 M, 2.11 mL, 0.211 mmol) at 0 ꢀC under argon. After be-
ing stirred for 30 min, acetic acid-d4 (39.6 mL, 0.702 mmol)
at this temperature was added to the reaction mixture. After
being stirred for 30 min, the mixture was quenched by satu-
rated NH4Cl and extracted with EtOAc. The extract was
washed with brine, dried over MgSO4, and concentrated in
vacuo to give crude materials. After column chromatography
purification over silica gel with EtOAc–n-hexane (from
15:85 to 1:4), the title compounds 20 (5.9 mg, 34.8% yield)
and byproduct 21 (5.8 mg, 22.4% yield) were obtained as
colorless oily materials. Compound 20: [a]2D6 ꢁ41.1 (c
0.88, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.21 (d,
J¼6.6 Hz, 3H), 1.92–1.76 (m, 2H), 2.48–2.26 (m, 4H),
3.12–3.05 (m, 1H), 3.84–3.75 (m, 1H), 4.02 (d, J¼14.9 Hz,
2H), 5.31 (d, J¼15.2 Hz, 2H), 5.58–5.55 (m, 1H), 7.32–
7.18 (m, 5H); 13C NMR (100 MHz, CDCl3) d 19.1, 24.3,
29.0, 30.2, 45.1, 46.9, 53.8, 118.4, 127.1, 127.6, 128.4,
137.5, 142.0, 171.5; LRMS (FAB) m/z 242 (MH+), 149, 91,
57 (base peak); HRMS (FAB) m/z calcd for C16H20ON
(MH+) 242.1545; found 242.1552. Compound 21: [a]2D6
ꢁ25.7 (c 0.89, CHCl3); 1H NMR (400 MHz, CDCl3)
d 1.22 (d, J¼6.8 Hz, 3H), 1.95 (m, 2H), 2.15 (t, J¼7.6 Hz,
2H), 2.91 (dd, J¼20.8 Hz, 2.8 Hz, 1H), 3.01 (d, J¼
20.8 Hz, 1H), 3.17 (t, J¼6.8 Hz, 2H), 3.85 (m, 1H), 4.06
(d, J¼15.4 Hz, 1H), 5.39 (d, J¼15.4 Hz, 1H), 5.47 (m,
3.1.13. Physical data of (3S)-2-benzyl-3-methyl-2,3,4,5,6,
7-hexahydro-[2]pyrindine-1-one (25). [a]2D6 ꢁ16.9 (c 0.24,
1
CHCl3); H NMR (400 MHz, CDCl3) d 1.17 (d, J¼6.6 Hz,
3H), 1.90–2.08 (m, 3H), 2.45–2.76 (m, 5H), 3.60 (m, 1H),
3.88 (d, J¼15.3 Hz, 2H), 5.39 (d, J¼15.3 Hz, 2H), 7.22–
7.34 (m, 5H); 13C NMR (75 MHz, CDCl3) d 18.2, 22.2,
30.3, 31.7, 36.7, 46.8, 50.7, 127.1, 127.8, 128.5, 131.5,
138.7, 150.0, 164.0; LRMS (FAB) m/z 242 (MH+), 91
(base peak); HRMS (FAB) m/z calcd for C16H20ON (MH+)
242.1545; found 242.1548.
3.1.14. (1S)-2-[(2S)-2-(Benzyl-tert-butoxycarbonyl-
amino)propylidene]cyclopentanecarboxylic acid methyl
ester (28) from 20. Compound 20 (58.0 mg, 0.240 mmol)
in 1,2-dichloroethane (1 mL) was treated with MeOTf
(79.1 mL, 0.721 mmol) at 0 ꢀC under argon. After being
stirred for 3 h at room temperature, the reaction mixture
was concentrated under vacuo to give an oily crude. To a so-
lution containing the crude in THF (1.8 mL) was added 0.1%
(w/w) TfOH aqueous solution (100 mL) and H2O (100 mL) at
room temperature. After 3 h, the mixture was dried with

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MgSO4 and filtrated. To a solution containing evaporated
filtrate in DMF (2 mL) were added Boc2O (105 mg,
0.481 mmol) and DIPEA (62.8 mL, 0.361 mmol) at room
temperature. The reaction mixture was stirred for 2 h,
quenched by 0.1 N HCl, and extracted with EtOAc. The ex-
tract was washed with brine, dried over MgSO4, and concen-
trated in vacuo to give crude materials. The materials were
purified by column chromatography over silica gel with
EtOAc–n-hexane (from 5:95 to 15:85) to give 28 (42.8 mg,
47.7% yield) as colorless oil and recovered 20 (13.8 mg,
23.8% yield): [a]D26 91.3 (c 1.29, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.14 (d, J¼6.8 Hz, 3H), 1.44 (br, 9H),
1.72–1.86 (m, 2H), 1.90–2.02 (m, 2H), 2.03–2.18 (m, 1H),
2.23–2.39 (m, 1H), 3.65 (s, 9H), 4.70 (br, 1H), 4.37 (d,
J¼12.8 Hz, 1H), 4.41 (d, J¼12.8 Hz, 1H), 5.47 (dd,
J¼1.6 Hz, 9.6 Hz, 1H), 7.15–7.34 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 20.6, 24.6, 28.5, 30.9, 33.5, 39.3,
45.4, 47.6, 51.9, 79.6, 124.6, 126.5, 126.8, 128.0, 128.9,
140.0, 142.4, 174.8; HRMS (ESI-TOF) m/z calcd for
C22H32NO4 (MH+) 374.2331; found 374.2324.
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3.1.15. (1S)-2-[(2S)-2-tert-Butoxycarbonylaminopropyl-
idene]cyclopentanecarboxylic acid 29 (Boc-L-Ala-J[(Z)-
CH]C]-D-Pro-OH) from 28. A solution containing 28
(12.0 mg, 0.0321 mmol) and 1 N KOH aqueous solution
(32.0 mL, 0.0320 mmol) in THF (350 mL), H2O (350 mL),
and MeOH (100 mL) was stirred for 14 h at room tempera-
ture. The reaction mixture was quenched by 1 N HCl and ex-
tracted with EtOAc. The extract was dried over MgSO4 and
concentrated under reduced pressure to give an oily crude. To
a flask containing THF (0.5 mL) and liquid NH3 (1 mL) was
added Na (10.0 mg, 0.412 mmol) at ꢁ78 ꢀC. After 3 min, the
crude was added with additional stirring for 20 min at
ꢁ78 ꢀC. The reaction mixture was quenched with solid
NH4Cl. After evaporation of NH3 at room temperature, satu-
rated NH4Cl solution was added to the mixture, which was
extracted with EtOAc. The extract was washed with 1 N
HCl and brine, dried over MgSO4, and concentrated to give
oily materials. After purification by column chromatography
over silica gel with EtOAc–n-hexane–AcOH (160:40:1), the
title compound 29 was obtained (7.40 mg, 85.5% yield) as
colorless oil: [a]2D8 37.7 (c 0.11, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.16 (d, J¼6.6 Hz, 3H), 1.43 (s, 9H),
1.96–2.50 (m, 6H), 3.76 (br, 1H), 4.47 (br, 1H), 5.26 (dd,
J¼9.4 Hz, 1.4 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 20.9, 24.7, 28.4, 31.0, 33.6, 45.5, 46.2, 79.3, 127.0,
141.4, 155.2, 180.1; LRMS (FAB) m/z 292 (MNa+), 270
(MH+), 214, 153, 152, 107 (base peak), 57; HRMS (FAB)
m/z calcd for C14H24O4N (MH+) 270.1705; found 270.1712.
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This research was supported in part by the 21st Century
COE Program ‘Knowledge Information Infrastructure for
Genome Science’, a Grant-in-Aid for Scientific Research
(KAKENHI). Y.S. is grateful for Research Fellowships of
the JSPS for Young Scientists.
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