Synthetic studies directed toward kaitocephalin: A highly stereocontrolled route to the right-hand pyrrolidine core

Article abstract of DOI:10.1055/s-2008-1042801

A highly stereocontrolled method for the construction of the right-hand segment of kaitocephalin, an antagonist of AMPA/KA and NMDA glutamate receptors, has been developed employing palladium-catalyzed cyclization of an oxiranylacrylate at the quaternary

Full text of DOI:10.1055/s-2008-1042801

LETTER
671
Synthetic Studies Directed toward Kaitocephalin: A Highly Stereocontrolled
Route to the Right-Hand Pyrrolidine Core
Synthetic Studies
D
irected tow
i
a
rd
K
s
aitocephal
u
in ke Takahashi, Natsumi Haraguchi, Jun Ishihara, Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Fax +81(95)8192426; E-mail: susumi@nagasaki-u.ac.jp
Received 14 December 2007
Dedicated to the memory of the late Professor Yoshihiro Matsumura
O
Abstract: A highly stereocontrolled method for the construction of
the right-hand segment of kaitocephalin, an antagonist of AMPA/
KA and NMDA glutamate receptors, has been developed employ-
ing palladium-catalyzed cyclization of an oxiranylacrylate at the
quaternary center as the key step.
Cl
Cl
O
HN
Ar
H2N
CO2H
OH
HO
ZnI
NH
MeO2C
2
HO2C
N
CO2H
H
Key words: kaitocephalin, natural products, pyrrolidines, Tsuji–
1
Trost reaction, ring closure
"N"
PHN
CO2R
OP
OH
O
OP
CO2R
Kaitocephalin (1), isolated from Eupenicillium shearii
PF1191 by Seto and Shin-ya et al.,1 is known to exhibit
potent inhibitory activity against neuronal cell death by
the antagonistic action on AMPA [(S)-a-amino-3-hy-
droxy-5-methyl-4-isoxazolepropionic acid]/KA (kainic
acid) as well as NMDA (N-methyl-D-asparatic acid)
glutamate receptors.1 This natural product has, therefore,
considerable potential as a promising lead compound for
developing therapeutic agents against neuronal diseases
such as stroke and epilepsy.2 However, detailed neurobio-
logical studies have become very difficult at present be-
cause the fungus has not produced kaitocephalin anymore.
Due to such extremely low availability from natural
sources as well as the intriguing biological activity and
synthetically challenging molecular architecture, kaito-
cephalin has attracted much attention in the chemical and
biological communities. Thus, there have been a number
of synthetic studies3 including two total syntheses4 of kai-
tocephalin. However, the reported syntheses are not effi-
cient enough to obtain sufficient quantities of this natural
product.5 The most difficult aspect of its synthesis resides
in the stereoselective assembly of the right-hand segment
consisting of an a-substituted proline connected to serine
with a C–C bond.
N
O
N
N
P
P
OP
OP
4
5
3
Pd
CO2R
CO2R
Pd(0)
O
NH
O
PHN
7
P
6
Scheme 1 Retrosynthesis.
CHO
e
X
OH
8: X = OH
9: X = N3
N3
10
a–d
f
g, h
k, l
OH
N3
OH
11
OH
O
O
CbzHN
BocHN
12a 98% ee
12b 99% ee
m, n
i, j
Scheme 1 illustrates our retrosynthetic analysis of kaito-
cephalin which starts from the disconnection relying on
coupling of nitrone 3, a right-hand segment, with orga-
nozinc reagent 2, a left-hand segment, tactically devised
by Kitahara et al.3c,4a It is assumed that nitrone 3 would be
accessible from ester 5 via stereo- and regioselective in-
troduction of an amino group to epoxide 4 by taking ad-
vantage of the epoxy alcohol functionality. For the
construction of the pyrrolidine skeleton with a quaternary
CO2Et
CO2Me
O
O
BocHN
CbzHN
13a
13b E/Z = 4:1
Scheme 2 Reagents and conditions: (a) DHP, PPTS, CH2Cl2; (b) p-
TsCl, Et3N, DMAP, CH2Cl2; (c) NaN3, DMF; (d) PPTS, MeOH, 56%
(4 steps); (e) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C, then N,N-di-
methylmethyleneammonium iodide, Et3N, CH2Cl2, 77%; (f) NaBH4,
CeCl3·7H2O, MeOH, –78 °C, 78%; (g) Ph3P, H2O, THF then Boc2O,
NaHCO3, 89% (h) (–)-DIPT, Ti(i-PrO)4, TBHP, 4 Å MS, CH2Cl2,
–40 °C, 61%; (i) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C; (j)
Ph3P=CHCO2Et, CH2Cl2, 97% (2 steps); (k) Ph3P, H2O, THF then
CbzCl, Na2CO3, 89%, (l) (–)-DIPT, Ti(i-PrO)4, TBHP, 4 Å MS,
CH2Cl2, –40 °C, 100%; (m) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C;
(n) (MeO)2POCH2CO2Me, NaH, THF, 69% (2 steps).
SYNLETT 2008, No. 5, pp 0671–0674
x
x.
x
x.
2
0
0
8
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1042801; Art ID: U12407ST
© Georg Thieme Verlag Stuttgart · New York

672
K. Takahashi et al.
LETTER
center, we envisioned stereoselective cyclization of oxira-
nylacrylate 7 through p-allylpalladium complex 6 under
Tsuji–Trost reaction conditions.6 Since, to our knowl-
edge, such a pyrrolidine formation is unprecedented,7 it is
of great interest to probe whether the cyclization takes
place via double inversion of stereochemistry even at the
quaternary center without significant loss of the enantio-
meric purity.
Table 1 Palladium-Catalyzed Cyclization of 13a and 13b
CO2R2
CO2R2
Pd(PPh3)4 (5 mol%)
O
R1HN
N
OH
R1
13a: R1 = Boc, R2 = Et (E only), 98%ee
13b: R1 = Cbz, R2 = Me (E/Z = 4:1), 99% ee
14a: R1 = Boc, R2 = Et
14b: R1 = Cbz, R2 = Me
Entry Epoxide Conditions
Yield (%)a ee (%)
To examine the key pyrrolidine formation, oxiranylacry-
late 13a and 13b were synthesized in over 98% ee
(Scheme 2). Thus, 1,5-pentanediol (8) was first converted
into azido alcohol 9 by a four-step sequence involving
monotetrahydropyranylation, tosylation, azidation, and
removal of the tetrahydropyranyl ether protecting group.
Swern oxidation of 9 followed by in situ methylenation8
using Eschenmoser’s salt gave aldehyde 10 which was
subjected to Luche reduction9 to afford allyl alcohol 11.
Compound 11 was then converted into epoxy alcohol 12a
and 12b via Staudinger reaction,10 N-protection with ei-
ther tert-butoxycarbonyl or benzyloxycarbonyl group,
and Katsuki–Sharpless catalytic asymmetric epoxida-
tion.11 Swern oxidation followed by Wittig reaction con-
verted 12a into 13a exclusively. On the other hand, 13b
was obtained as a 4:1 E/Z-mixture from 12b by Swern ox-
idation followed by Horner–Emmons reaction.12
1
2
Toluene, reflux, 10 min
THF, reflux, 1 h
16
68
40
46
52
12
23
60
ND
76b
72c
83c
83c
ND
61b
77d
80b
78d
91b
3
13a
DMF, 60 °C, 4.5 h
4
DMF, r.t., 35 h.
5
MeCN, 70 °C, 45 min
THF, reflux, 45 min
THF, Et3N, reflux, 30 min
MeCN, 70 °C, 30 min
6
7
8
13b
9
MeCN, Et3N, 70 °C, 20 min 72
10
11
DMF, 70 °C, 20 min
54
86
DMF, Et3N, 70 °C, 30 min
Palladium-catalyzed cyclizations of 13a and 13b were ex-
amined under various conditions using a catalytic amount
(5 mol%) of (Ph3P)4Pd (Table 1).13 When the reaction of
13a was conducted in boiling toluene, the cyclization be-
came competitive with decomposition to give 14a in poor
yield (entry 1). In the reaction in boiling THF, 14a was
formed in 76% ee and in 68% yield (entry 2).14 This ee
value showed that appreciable racemization occurred dur-
ing the cyclization. Similarly, in DMF and MeCN, the cy-
clization was also accompanied by racemization to
produce 14a in 73 to 83% ee in moderate yield (entries 3–
5). On the other hand, in the reactions using 13b, better
yields were observed in MeCN and DMF than in THF (en-
tries 6–11). It is important to note that E-isomer 14b was
produced exclusively in spite of the use of a 4:1 E/Z-mix-
ture as a substrate. To our delight, addition of 1 equivalent
of triethylamine brought about remarkable improvement
in both yield and enantiomeric purity (entries 8–11).
a Isolated yields.
b Determined by HPLC analysis using a chiral column (see ref. 12).
c Calculated by the [a]D based on that of the sample of entry 2.
d Calculated by the [a]D based on that of the sample of entry 9.
nor Katsuki–Sharpless asymmetric epoxidation condi-
tions turned out to be effective. The stereoselective out-
come thus observed can be rationalized by assuming a
preferred approach of MCPBA from the less-hindered
bottom face of Felkin–Ahn model 16.4b
Reaction of 17 with benzoyl isocyanate followed by treat-
ment of the resulting N-benzoyl carbamate 18 with K2CO3
allowed stereoselective cyclization accompanied by mi-
gration of the N-benzoyl group to afford cyclic carbamate
19.17 Upon desilylation followed by Jones oxidation, 19
afforded tricyclic lactam 2018 almost quantitatively. After
methanolysis of 20 with Cs2CO3 in methanol,19 the result-
ing diol was protected as its tert-butyldimethylsilyl ether
to give 21. tert-Butoxycarbonylation and hydrogenolytic
removal of the benzyloxycarbonyl group converted 21
into amine 22.20 According to the procedure employed by
Kitahara et al.,3c,4a,21 22 was cleanly oxidized to nitrone
23,22 a right-hand segment, in good yield. The stereostruc-
ture of 23 was established by its NOESY spectrum. Con-
sequently, it was unambiguously confirmed that the
above-mentioned epoxidation of 15 proceeded with the
desired stereoselectivity as depicted in 16.
When the reaction was carried out under the conditions
listed in entry 11,15 14b was obtained in 91% ee and in
86% yield. The absolute configurations of 14a and 14b
were determined to be S by their correlation to an authen-
tic sample.16 This result clearly showed that the palladi-
um-catalyzed cyclization took place via double inversion
of stereochemistry at the quaternary center.
Having obtained key pyrrolidine 14b in high enantiomeric
purity, we then examined the stereoselective assembly of
the right-hand segment from 14b as shown in Scheme 3.
Upon silylation and DIBAL-H reduction, 14b gave allyl
alcohol 15, which was epoxidized with MCPBA at low
temperature to give epoxide 17 as the sole product. In this
particular case, neither VO(acac)2-catalyzed epoxidation
Furthermore, it was gratifyingly found that, upon hydro-
genolysis of 20 in MeOH, methanolysis of the lactam ring
also simultaneously took place to afford amino ester 2423
in excellent yield. Oxidation of 24 in the same manner as
Synlett 2008, No. 5, 671–674 © Thieme Stuttgart · New York

LETTER
Synthetic Studies Directed toward Kaitocephalin
673
References and Notes
NCbz
OH
H
c
OTBS
OH
H
a, b
(1) (a) Shin-ya, K.; Kim, J.-S.; Furihata, K.; Hayakawa, Y.;
14b
Seto, H. Tetrahedron Lett. 1997, 38, 7079. (b) Kobayashi,
H.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 2001, 42, 4021. (c) Shin-ya, K. Biosci.
Biotechnol. Biochem. 2005, 69, 867.
N
OTBS
16
MCPBA
BzO
Cbz
15
O
OR
O
(2) (a) Sheardown, M. J.; Nielsen, E. P.; Hansen, A. J.;
Jacobsen, P.; Honore, T. Science 1990, 247, 571.
(b) Bleakman, D.; Lodge, D. Neuropharmacology 1998, 37,
1187; and references therein.
(3) (a) Loh, T.-P.; Chok, Y.-K.; Yin, Z. Tetrahedron Lett. 2001,
42, 7893. (b) The synthesis of the 2S-isomer of
kaitocephalin: Ma, D.; Yang, J. J. Am. Chem. Soc. 2001,
123, 9706. (c) The structure revision of kaitocephalin: Okue,
M.; Kobayashi, H.; Shin-ya, K.; Furiata, K.; Hayakawa, Y.;
Seto, H.; Watanabe, H.; Kitahara, T. Tetrahedron Lett. 2002,
43, 857.
O
O
HN
e
f, g
N
N
O
N
OTBS
Cbz
Cbz
20
OBz
O
17: R = H
18: R = CONHBz
N
d
OTBS
Cbz
19
TBSO
TBSO
OTBS
OTBS
j, k
h, i
NH
NBoc
N
N
H
Cbz
O
O
(4) (a) Watanabe, H.; Okue, M.; Kobayashi, H.; Kitahara, T.
Tetrahedron Lett. 2002, 43, 861. (b) Kawasaki, M.;
Shinada, T.; Hamada, M.; Ohfune, Y. Org Lett. 2005, 7,
4165.
(5) Very recently, Watanabe et al. presented an efficient
synthesis of kaitocephalin. See: Doi, F.; Watanabe, H. In
49th Symposium on the Chemistry of Natural Products,
Symposium Papers; Sapporo: Japan, 2007, 533.
(6) For a representative review, see: Tsuji, J. In Handbook of
Organopalladium Chemistry for Organic Synthesis, Vol. 2;
Negishi, E., Ed.; Wiley and Sons: New York, 2002, 1669–
1687.
(7) For a similar palladium-catalyzed cyclization forming a
pyrrolidine, see: Noguchi, Y.; Uchiro, H.; Yamada, T.;
Kobayashi, S. Tetrahedron Lett. 2001, 42, 5253.
(8) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Chem. Soc.,
Chem. Commun. 1988, 1294.
(9) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
(10) For a leading review, see: Gololobov, Y. G.; Kasukhin, L. F.
Tetrahedron 1992, 48, 1353.
(11) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765.
(12) Since the aldehyde derived from 12b existed as the
corresponding aminal, Wittig reaction using
Ph3P=CHCO2Et did not give 13b.
(13) The ee values of 14a (entry 2) and 14b (entries 7, 9, 11) were
determined by HPLC analysis [Daicel Chiralcell OJ-H,
hexane–i-PrOH (20:1)] of 26 and 27, respectively
(Scheme 4).
21
22
TBSO
H
H
OTBS
OTBS
NBoc
H
H
l
OTBS
H
+
N
O–
+
N
O–
N
H
O
Boc
O
NOE
23
BzO
BzO
O
O
m
n
20
HN
HN
CO2Me
O
N
H
O
CO2Me
N
O
24
25
Scheme 3 Reagents and conditions: (a) t-BuMe2SiOTf, 2,6-lutidi-
ne, CH2Cl2, 88%; (b) DIBAL-H, THF, –78 °C, 96%; (c) MCPBA,
CH2Cl2, –40 °C, 99%; (d) PhCON=C=O, THF; (e) K2CO3, Bu4NCl,
MeCN, 55% (2 steps); (f) TBAF, AcOH, THF; (g) H2CrO4, H2SO4,
acetone, 0 °C, 99% (2 steps); (h) Cs2CO3, MeOH, 96%; (i) t-
BuMe2SiOTf, 2,6-lutidine, CH2Cl2, 98%; (j) Boc2O, Et3N, MeCN,
81%; (k) H2, 10% Pd/C, MeOH, 76%; (l) urea·H2O2, MeReO3 (20
mol%), MeOH, SiO2, 81%; (m) H2, 10% Pd/C, MeOH, 95%; (n)
urea·H2O2, MeReO3 (11 mol%), MeOH, SiO2, 64%.
employed for 22 furnished nitrone 25,24 another right-
hand segment.
In conclusion, we have developed a highly enantio- and
stereoselective route to the right-hand segment of kaito-
cephalin. The key palladium-catalyzed cyclization was
proved to occur with double inversion of configuration
even at the quaternary center. The present work provides
a new methodology for the enantioselective construction
of gem-substituted pyrrolidines. The synthetic effort to-
ward achieving a total synthesis of kaitocephalin via cou-
pling of 2 with 23 or 25 is currently ongoing.25
CO2Et
1. (R) or (S)-MTPACl, Et3N
DMAP, CH2Cl2
O
14a
2. TFA, CH2Cl2
OMe
Ph
*
N
O
H
CF3
26
OBz
1. H2, Pd-C, MeOH
14b
N
2. PhCOCl, Et3N
DMAP, CH2Cl2
27
O
Acknowledgment
Scheme 4
We thank Professor Hidenori Watanabe (The University of Tokyo)
for informing us of the detailed coupling reaction conditions. This
work is supported by Grant-in-Aid for Scientific Research of Japan
Society for the Promotion of Science (JSPS).
(14) Reaction of 13a Giving 14a (Entry 2)
To a solution of 13a (51 mg, 0.17 mmol) in THF (3.3 mL)
was added (Ph3P)4Pd (10 mg, 0.0583 mmol) under an argon
atmosphere, and the mixture was refluxed for 1 h. The
reaction mixture was diluted with EtOAc, washed with H2O
Synlett 2008, No. 5, 671–674 © Thieme Stuttgart · New York

674
K. Takahashi et al.
LETTER
and brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by flash column chromatography
twice [SiO2 5 g, hexane–EtOAc (3:1); SiO2 5 g, PhH–EtOAc
(10:1)] to give 14a as a colorless oil (35 mg, 68%, 76% ee):
[a]D24 +56.5 (c 0.66, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 7.00 (d, J = 15.9 Hz, 1 H), 5.73 (d, J = 15.9 Hz, 1 H),
5.43 (d, J = 10.2 Hz, 1 H), 4.20 (q, J = 7.0 Hz, 2 H), 3.89 (t,
J = 10.5 H, 1 H), 3.76 (d, J = 10.5 Hz, 1 H), 3.56 (br s, 1 H),
3.41 (br s, 1 H), 1.75 (m, 4 H), 1.58 (s, 9 H), 1.29 (t, J = 7.0
Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 166.1, 155.8,
148.3, 121.0, 80.8, 69.6, 68.8, 60.5, 48.9, 36.0, 28.3, 20.9,
14.2. FT-IR (neat): 3400, 1702, 1545, 1395, 1170 cm–1.
HRMS (EI): m/z calcd for C11H25NO5 [M+]: 299.1733;
found: 299.1717.
H), 3.75 (dd, J = 10.4, 2.0 Hz, 1 H), 3.68 (br s, 1 H), 3.22–
3.16 (m, 1 H), 2.93–2.89 (m, 1 H), 2.22–2.17 (m, 1 H), 1.90–
1.74 (m, 3 H), 1.53 (s, 9 H) 0.92–0.83 (m, 18 H), 0.07–0.01
(m, 12 H). 13C NMR (75 MHz, CDCl3): d = 176.8, 150.2,
83.1, 73.1, 72.1, 64.7, 59.8, 47.0, 29.3, 28.0, 25.7, 25.6, 17.9,
–4.8, –5.4; FT-IR (film): 1754, 1719, 1489 cm–1. HRMS
(EI): m/z calcd for C25H50N2O5Si2 [M+]: 514.3260; found:
528.3258.
(21) (a) Murray, R. W.; Iyanar, K. J. Org. Chem. 1996, 61, 8099.
(b) Goti, A.; Nannelli, L. Tetrahedron Lett. 1996, 37, 6025.
(22) Oxidation of 22 to 23
To a solution of urea·H2O2 (1.54 g, 16.4 mmol) in MeOH (5
mL) was added MeReO3 (47 mg, 0.16 mmol) under an argon
atmosphere, and the mixture was stirred at r.t. for 10 min. A
solution of 22 (449 mg, 0.82 mmol) in MeOH (8 mL) and
SiO2 (1.35 g) were added and the mixture was stirred at r.t.
for 1.5 h. The reaction was quenched with sat. Na2S2O3 and
the reaction mixture was extracted with EtOAc. The extract
was washed with H2O and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography [SiO2 20 g, hexane–EtOAc (3:2)] to give 23
(350 mg, 81%) as a colorless viscous oil. [a]D23 +39.2 (c
1.01, CHCl3). 1H NMR (500 MHz, CDCl3): d = 7.17 (s, 1 H),
5.33 (d, J = 7.0 Hz, 1 H), 4.37 (d, J = 10.5 Hz, 1 H), 3.74 (d,
J = 10.5 Hz, 1 H), 3.61 (m, 1 H), 2.87 (m, 1 H), 2.76–2.71
(m, 1 H), 2.64–2.59 (m, 1 H) 2.08 (t, J = 10.5 Hz, 1 H), 1.52
(s, 9 H), 0.84 (s, 18 H), 0.16–0.14 (m, 12 H). 13C NMR (75
MHz, CDCl3): d = 168.5, 149.6, 136.0, 84.7, 83.9, 65.4,
63.3, 59.6, 28.2, 26.0, 25.7, 22.8, 17.4, 17.1, 4.0, –5.6. FT-
IR (neat): 1764, 1725, 1304, 1254 cm–1. HRMS (EI): m/z
calcd for C25H48N2O6Si2 [M+]: 528.3035; found: 528.3051.
(23) Compound 24: [a]D23 +19.2 (c 1.05, CHCl3). 1H NMR (300
MHz, CDCl3): d = 8.03 (d, J = 7.2 Hz, 2 H), 7.60 (t, J = 7.3
Hz, 1 H), 7.47 (t, J = 7.5 Hz, 2 H), 6.37 (br s, 1 H), 5.24 (d,
J = 5.7 Hz, 1 H), 4.53 (dd, J = 11.6, 3.6 Hz, 1 H), 4.26 (dd,
J = 12.0, 8.1 Hz, 1 H), 3.81 (m, 1 H), 3.79 (s, 3 H), 3.29–2.15
(m, 1 H), 3.10–2.92 (m, 1 H), 2.38–2.31 (m, 1 H), 1.92–1.79
(m, 3 H). 13C NMR (75 MHz, CDCl3): d = 179.4, 165.6,
155.4, 133.6, 129.7, 129.1, 128.6, 77.6, 69.6, 68.1, 56.0,
55.1, 47.7, 29.9, 26.5. FT-IR (neat): 3240, 2262, 2875, 1720,
1448 cm–1. HRMS (EI): m/z calcd for C17H20N2O6 [M+]:
348.1306; found: 348.1321.
(15) Reaction of 13b Giving 14b (Entry 11)
To a solution of 13b (8.8 g, 27.6 mmol) and Et3N (3.87 ml,
27.6 mmol) in DMF (276 mL) was added (Ph3P)4Pd (1.6 g,
1.38 mmol) under an argon atmosphere, and the mixture was
stirred for 0.5 h at 70 °C. The reaction mixture was diluted
with Et2O, washed with H2O and brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash
column chromatography [SiO2 600 g, hexane–EtOAc (2:1)]
26
to give 14b as a colorless oil (7.6 g, 86%, 91% ee): [a]D
+47.2 (c 0.96, CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.32
(s, 5 H), 7.02 (d, J = 15.9 Hz, 1 H), 5.76 (d, J = 15.9 Hz, 1
H), 5.20 (s, 2 H), 4.96 (d, J = 10.8 Hz, 1 H), 3.98–3.77 (m, 2
H), 3.74 (s, 3 H), 3.67–3.44 (m, 2 H), 1.87–1.78 (m, 4 H). 13
NMR (75 MHz, CDCl3): d = 166.3, 155.9, 148.1,136.2,
128.8, 128.7, 128.5, 128.1, 127.8, 120.8, 70.5, 68.2, 67.4,
51.6, 48.7, 35.6, 20.9. FT-IR (neat): 3419, 1691, 1412,
C
1350,1309 cm–1. HRMS (EI): m/z calcd for C17H21NO5 [M+]:
319.1421; found: 319.1420.
(16) The authentic samples were prepared from the known
aldehyde (Scheme 5), see: Bittermann, H.; Gmeiner, P. J.
Org. Chem. 2006, 71, 97.
1. (MeO)2P(O)CH2CO2Me
NaH, THF, 0 °C
CHO
O
or
14a
14b
N
2. NaOMe, MeOH
or NaOEt, EtOH
O
Cl3C
then AcCl, reflux
3. NaBH4, MeOH or EtOH
then CbzCl or Boc2O
aq NaHCO3
(24) Oxidation of 24 to 25
Compound 24 (139 mg, 0.40 mmol) was oxidized using
urea·H2O2 (827 mg, 8.80 mmol), MeReO3 (11 mg, 0.044
mmol), and SiO2 (580 mg) in MeOH (5 mL) in the same
manner as described in ref. 22. Purification of crude product
by column chromatography [SiO2 7 g, MeOH–EtOAc (0:1 to
Scheme 5
(17) (a) Hirai, Y.; Watanabe, J.; Nozaki, T.; Yokoyama, T.;
Yamaguchi, S. J. Org. Chem. 1997, 62, 776. (b) Masaki,
H.; Maeyama, J.; Kameda, K.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. J. Am. Chem. Soc. 2000, 122, 5216.
23
1:10)] gave 25 (92 mg, 64%) as a colorless viscous oil: [a]D
(18) Compound 20: [a]D27 +103.6 (c 0.87, CHCl3). 1H NMR (500
MHz, CDCl3, ca 2:3 mixture of rotamers): d = 7.99 (d,
J = 7.0 Hz, 2 H), 7.92 (d, J = 7.0 Hz, 2 H), 7.65 (m, 1 H),
7.38 (m, 5 H), 5.65 (d, J = 7.0 Hz, 0.6 H), 5.24 (d, J = 7.5 Hz,
0.4 H), 5.14 (s, 1 H), 5.14 (d, J = 11.0 Hz, 0.4 H), 4.96 (d,
J = 11.0 Hz, 0.6 H), 4.81 (dd, J = 8.0 Hz, 0.6 H), 4.73 (dd,
J = 8.0 Hz, 0.6 H), 4.46 (dd, J = 8.0 Hz, 0.4 H), 4.43 (m, 0.6
H), 4.30 (m, 0.4 H), 4.10 (m, 0.4 H), 3.73 (m, 1 H), 3.67 (m,
1 H), 2.75 (m, 1 H), 2.17 (m, 3 H). 13C NMR (75 MHz,
CDCl3): d = 180.0, 167.2, 154.4, 148.8, 135.8, 134.2, 131.2,
129.6, 129.1, 129.0, 128.9, 128.8, 128.5, 128.2, 128.0, 78.1,
71.3, 68.7, 67.6, 58.6, 47.7, 31.1, 24.5. FT-IR (film): 1835,
1738, 1565 cm–1. HRMS (EI): m/z calcd for C24H22N2O7
[M+]: 450.1425; found: 450.1427.
+65.9 (c 0.83, CHCl3). 1H NMR (300 MHz, CDCl3): d = 8.04
(d, J = 7.2 Hz, 2 H), 7.64 (t, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.2
Hz, 2 H), 7.07 (s, 1 H), 6.95 (br s, 1 H), 5.99 (d, J = 3.9 Hz,
1 H), 4.79 (dd, J = 11.1, 4.8 Hz, 1 H), 4.48 (dd, J = 11.1, 4.8
Hz, 1 H), 4.04–3.96 (m, 1 H), 3.78 (s, 3 H), 2.97, 2.91 (m, 1
H), 2.69–2.61 (m, 1 H), 2.56–2.51 (m, 2 H). 13C NMR (75
MHz, CDCl3): d = 170.4, 165.1, 155.2, 133.9, 129.8, 128.7,
128.5, 128.3, 82.8, 72.0, 68.4, 57.0, 55.1, 26.9, 23.7. FT-IR
(neat): 3230, 2922, 1724, 1373, 1277,1176, 1109 cm–1.
HRMS (EI): m/z calcd for C17H18N2O7 [M+]: 362.1104;
found: 362.1114.
(25) Coupling reactions of 2 (Ar = 4-benzyloxy-3,5-dichloro-
phenyl) with 23 and 25 were preliminarily examined
following the procedure reported by Kitahara et al.,3c,4a but
the desired coupling products were obtained in <10% yield,
respectively. To improve the yield, these coupling reactions
are now being examined under various conditions.
(19) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185.
(20) Compound 22: [a]D23 +32.0 (c 1.14, CHCl3). 1H NMR (400
MHz, CDCl3): d = 4.18–4.12 (m, 1 H), 4.06 (d, J = 3.9 Hz, 1
Synlett 2008, No. 5, 671–674 © Thieme Stuttgart · New York

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