Stereoselective synthesis of new modified conformationally constrained L-tyrosine analogue with potential applications to SH2 domain ligands

Article abstract of DOI:10.1016/j.tet.2005.03.042

This paper reports the stereoselective synthesis of a modified tricyclic tyrosine analogue 3, whose conformation is constrained by the covalent bonds and designed on the basis of X-ray and solution structures of SH2 domain and its natural peptide ligand.

Full text of DOI:10.1016/j.tet.2005.03.042

Tetrahedron 61 (2005) 4971–4981
Stereoselective synthesis of new modified conformationally
constrained L-tyrosine analogue with potential applications to SH2
domain ligands
*
Fa Liu, Tai-Shan Hu and Zhu-Jun Yao
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 23 December 2004; revised 7 March 2005; accepted 10 March 2005
Available online 7 April 2005
Abstract—This paper reports the stereoselective synthesis of a modified tricyclic tyrosine analogue 3, whose conformation is constrained by
the covalent bonds and designed on the basis of X-ray and solution structures of SH2 domain and its natural peptide ligand. A Michael
addition followed by an alkylation in high stereoselections, a Friedel–Crafts and a Mannich reaction-based cyclization served as the key steps
in the synthesis.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In recent years, developments of new ligands of the SH2
(Src homology 2) domains have drawn more and more
attention in drug design1 because of its tight relationships
with a variety of human cancers. As a general principle,
constrained conformation has often benefited the ligand’s
binding with the protein, such as alanine analogues2 and
tyrosine analogues.1,3 The previous X-ray and solution
structure of liganded SH2 domain have provided a clear
skeleton of the relevant ligands,4 which plays the key role in
the design of conformationally constrained tyrosine
analogues. Based on these knowledge and principles,
ligands or ligand platforms 1, 2, 3 and 4 were designed
(Fig. 1). Burke and colleagues firstly reported the design and
synthetic routes of racemic amino acid 15 and 2.6 In our
recent works, we reported the enantioselective syntheses of
both D-27 and L-2.8 However, these studies6 showed that
more modifications on the structure 2 are required to
enhance the binding affinity with SH2 domain. Therefore,
addition of one more carboxyl group on 2 (amino acid 3)
provides one practical possibility for such a purpose through
more hydrogen-bonding generation, because this provides a
site to introduce proper amino acid side chains. In this
paper, we report our recent achievement on the enantio-
soselective synthesis of amino acid 3.
Figure 1. Structures of conformation-constrained tyrosine analogues 1–4,
and representation of construction of the tricylclo-skeleton.
2. Synthesis
Keywords: Src homology 2; L-Tyrosine; Mannich reaction.
*
A method for the construction of the tricyclo-skeleton of
these ligands has been established during our previous
Corresponding author. Tel.: C86 21 54925133; fax: C86 21 64163300;
e-mail: yaoz@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.042

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F. Liu et al. / Tetrahedron 61 (2005) 4971–4981
synthesis of the analogue D-27 and L-2,8 which featured a
Friedel–Crafts reaction followed by a Mannich reaction
(Fig. 1). Accordingly, for the synthesis of L-tyrosine
analogue 3, our first task was to prepare the precursor of
the Friedel–Crafts reaction, compound 10.
was then treated with trifluoroacetic acid followed by
formaldehyde in hope of getting the Mannich product.
Unfortunately, 14 was provided as the only product. It was
believed that formation of the kinetically and thermo-
dynamically favored lactam retarded the expected Mannich
reaction. Attempt to reduce the diester in 13 to correspond-
ing diol was not successful due to the formation of a five-
membered lactol (Scheme 2). So we had to prepare an
alternative precursor for this Mannich reaction.
Our first synthetic strategy of the precursor acid 10 is based
on a Michael addition followed by an alkylation. Unsatu-
rated lactam 5 was prepared from L-Glu over six steps in
68% overall yield.9 The aryl group was introduced smoothly
in high yield using THF as the solvent and only one isomer
was obtained.10 However, if methyl sulfide was used as the
co-solvent (1:1 with tetrahydrofuran) in this step, a tandem-
Michael-addition product was detected as the major
product11 (Scheme 1).
Scheme 1. Reagents and conditions: (a) CuBr$Me2S, 4-MeOPhMgBr,
THF, K78 to 0 8C, 90%; (b) LiHMDS, BrCH2COOBn, THF, K78 to 0 8C,
98% (c) (1) LDA, THF, K78 8C, 30 min; (2) AcOH, K78 to 0 8C, 70%.
Scheme 2. Reagents and conditions: (a) (1) Jones reagent, acetone, 0 8C,
4 h; (2) CH2N2, Et2O, rt, 10 min, 55% for two steps; (b) 1 atm H2, Pd/C
(10%) (cat), EtOAc, rt, 3 h, 68%; (c) (1) (COCl)2, DMF (cat), CS2/CH2Cl2,
rt, 2 h; (2) AlCl3, CH2Cl2, rt, overnight, 74%; (d) (Boc)2O, DMAP (cat),
CH3CN, rt, 2 h, 81%; (e) K2CO3, MeOH, rt, 45 min, 100% (conv%: 60%);
(f) (1) TFA, CH2Cl2, rt, 60 min; (2) HCHO, ROH, reflux, 12 h, 75%.
Alkylation of the lactam 6 with benzyl bromoacetate gave
two isomers, 7 and 8 (ratio 1.5:1), in 98% total yield, and the
3,4-trans-isomer could be converted to the cis one
completely when being treated with LHMDS (sodium
bis(trimethylsilyl) amide) followed by acetic acid. Oxi-
dation and deprotection of compound 8 afforded the
precursor 1012 for the Friedel–Crafts reaction. Ketone 11
was obtained smoothly according to our reported method,7,8
and the tert-butoxoyl carbonyl group was cleaved at the
same time. The stereochemistry of 11 was confirmed by the
X-ray analysis (Fig. 2).13 Now it came to the expected
Mannich reaction. No Mannich product was deducted, when
ketone 11 was treated directly with formaldehyde. Re-
protection and ring opening of 11 gave diester 13, which
Synthesis of 23, the alternative Mannich reaction substrate,
commenced with acyclic unsaturated ester 15, which was
prepared form L-Garner’s alcohol through Swern oxidation
followed by a Wittig olefination (Scheme 3). It is
noteworthy that the Wittig reagent used in this step should
be free of sodium hydroxide, otherwise recemization would
happen.14 Michael addition of p-methoxylphenyl-
magnesium bromide to unsaturated ester 15 in the presence
of CuI gave ester 16 as the only isomer, whose
stereochemistry was confirmed by the X-ray of the
corresponding alcohol 25 (Fig. 3).13 Allylation of ester 16
also afforded one isomer 17 in nearly quantitative yield.
Reduction of ester 17 with lithium aluminum hydride,
protection of the resulting hydroxyl group as trimethyl
acetate and cleavage of the ketal with p-toluenesulphonic
acid gave alcohol 20, which was converted to oxazolidone
21 after being treated with sodium hydride in DMF.
Protection of the amide group with di-tert-butyl dicarbonate
and oxidation of the terminal double bond followed by
further oxidation with sodium chlorite afforded acid 23. The
subsequent Mannich reaction proceeded uneventfully and
ketone 24 was afforded in 74% yield under the previously
Figure 2. ORTEP drawing of ketone 11 based on the X-ray analysis.13

F. Liu et al. / Tetrahedron 61 (2005) 4971–4981
4973
reported conditions.8 Again, the N-tert-butoxyl carbonyl
group was cleaved in this step (Scheme 3).
Protection of the amide group of ketone 24 with di-tert-
butyl dicarbonate again and treatment with cesium carbon-
ate in methanol afforded diol 27, and the two hydroxyl
groups were both protected with trimethylacetyl chloride.
Cleavage of the tert-butoxoyl carbonyl followed by
refluxing with formaldehyde in ethanol, and reprotection
of the newly formed amino group with methyl chloro-
formate gave tricyclo ketone 29 in nearly quantitative yield
over three steps. Attempt to reduce the carbonyl of 29 to
methylene by dithioacetal/Raney-nickel was failed because
the prerequisite dithioacetal cannot be formed presumably
due to the steric hindrance; yet reduction with sodium
borohydride smoothly gave the corresponding alcohol,
which could be reduced further to compound 30 by
Barton–McCombie method. Reductive cleavage of the
trimethyl acetyl groups followed by oxidation gave diester
31 in total 63% yield over four steps. To get the correct
stereochemistry, diester 31 was treated with sodium
methoxide in methanol firstly, and 32 was separated in
quantitative yield; treatment with LDA followed by acetic
1
acid gave both 32 and 33 in about 1:1 ratio (based on H
NMR spectrum), but they cannot be separated by the
Scheme 3. Reagents and conditions: (a) (1) (COCl)2, DMSO, Et3N,
CH2Cl2, K78 8C, 2 h; (2) Ph3P]CHCOOEt, PhH, rt, overnight, 81%;
(b) p-methoxylphenylmagnesium bromide, CuI, THF, K78 to 0 8C, 100%;
(c) (1) LDA, HMPA, THF, K78 8C, 30 min; (2) allyl bromide, K78 8C–rt,
100%; (d) LAH, THF, 0 8C, 60 min, 95%; (e) PivCl, Et3N, DMAP (cat),
CH2Cl2, 0 8C—rt, overnight, 100%; (f) PTSA, MeOH, rt, overnight, 84%;
(g) NaH, DMF, 0 8C, 60 min, 76%; (h) (Boc)2O, Et3N, DMAP (cat),
CH2Cl2, 0 8C—rt, overnight, 93%; (i) (1) O3, CH2Cl2/MeOH, K78 8C, 1 h;
(2) Me2S, K78 to 0 8C; (3) NaClO2, KH2PO3, 2-methyl-2-butane,
tBuOH/H2O, 84%; (j) (1) (COCl)2, DMF (cat), CS2/CH2Cl2, rt, 2 h; (2)
AlCl3, CH2Cl2, 0 8C—rt, overnight, 74%.
Scheme 4. Reagents and conditions: (a) (Boc)2O, Et3N, DMAP (cat),
CH2Cl2, 0 8C–rt, 2 h, 95%; (b) Cs2CO3, MeOH, rt, overnight, 86%;
(c) PivCl, Et3N, DMAP (cat), CH2Cl2, 0 8C—rt, overnight, 76%; (d) (1)
TFA, CH2Cl2, rt, 2 h; (2) HCHO (36% aq), EtOH, refluxed, 2 h; (3)
ClCOOMe, NaHCO3, dioxane/H2O, rt, 60 min, 100%; (e) (1) NaBH4,
MeOH, rt, 20 min; (2) (i) NaH (60%), THF, 0 8C, 30 min; (ii) CS2, 0 8C—rt,
1.5 h; (iii) MeI, rt, 2 h, 86% for two steps; (3) n-Bu3SnH, AIBN, toluene,
refluxed, 3 h, 100%; (f) (1) DIBAL-H, CH2Cl2, K78 8C, 40 min; (2) DMP,
CH2Cl2, rt, 60 min; (3) NaClO2, KH2PO3, 2-methyl-2-butene, tBuOH/H2O,
rt; (4) CH2N2, Et2O, rt, 20 min, 63% for four steps; (g) NaOMe, MeOH,
0 8C, 20 min, 100%; (h) (1) LDA, HMPA, K78 8C, 30 min; (2) AcOH,
K78 8C, 10 min.
Figure 3. ORTEP drawing of alcohol 25 based on the X-ray analysis.13

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F. Liu et al. / Tetrahedron 61 (2005) 4971–4981
column chromatography (Scheme 4). The stereochemistry
of 32 was elucidated by chemical relation (see below).
Reductive cleavage of the trimethyl acetyl group of ketone
29 with DIBAL-H (the ketone carbonyl group was reduced
to the corresponding hydroxyl group) followed by oxidation
and etherification gave diester 34 (the hydroxyl group was
oxidized back to the carbonyl group), in 50% total yield
over four steps. Similar as diester 31, if 34 was treated with
sodium methoxide in methanol, only 36 was generated; and
treatment with LDA followed by acetic acid gave both 35
and 36 in about 1:1 ratio, fortunately both of them could be
easily separated by column chromatography (Scheme 5).
The stereochemistry of compound 34, 35 and 36 were all
confirmed by the NOESY studies (Fig. 4).
Scheme 6. Reagents and conditions: (a) 1,3-propanedithiol, BF3$Et2O,
CH2Cl2, rt, 48 h; (b) Raney-nickel, EtOH, rt, 30 min, 74% for two steps;
(c) 6 N HCl, reflux, 4 days, 85%.
3. Summary
In conclusion, an enantioselective synthetic route of new
tricyclic amino acid analogue 3 was developed efficiently,
utilizing Michael addition followed by allyllation, intra-
molecular Friedel–Crafts cyclization and intramolecular
Mannich cyclization as the key steps. All the stereo-
chemistries in this route were well controlled and the key
reactions were optimized and well repeated in good yields.
This would give a good starting point to develop the new
SH2 domain ligands based on the conformationconstrained
tyrosine analogue 3 as a scaffold. The chemical diversity
studies on 3 and related biochemical experiments are in
progress in this laboratory.
Scheme 5. Reagents and conditions: (a) (1) DIBAL-H, CH2Cl2, K78 8C,
40 min; (2) DMP, CH2Cl2, rt, 60 min; (3) NaClO2, KH2PO3, 2-methyl-2-
t
butene, BuOH/H2O, rt; 4. CH2N2, Et2O, rt, 20 min, 50% for four steps;
(b) NaOMe, MeOH, 0 8C, 20 min, 80% (for 36); (c) (1) LDA, HMPA,
K78 8C, 30 min; (2) AcOH, K78 8C, 10 min, 36% (for 35) and 36% (for
36).
4. Experimental
4.1. General methods
All reactions were carried out under argon or nitrogen in
oven-dried glassware using standard gastight syringes,
cannulas, and septa. Solvents and reagents were purified
and dried by standard methods prior to use; optical rotations
were measured at rt. IR spectra were recorded on an FT-IR
instrument. 1H NMR spectra were recorded at 300 MHz and
reported in parts per million (d) downfield relative to TMS
as internal standard, and 13C NMR spectra were recorded at
75 MHz and assigned in parts per million (d). Flash column
chromatography was performed on silica gel (10–40 mm)
using a mixture of petroleum ether and ethyl acetate as the
eluent.
4.1.1. (2S,3R)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-
3-(4-methoxy-phenyl)-5-oxo-pyrrolidine-1-carboxylic
acid tert-butyl ester (6). To a suspension of CuBr$Me2S
(12.6 g, 61.3 mmol) in dry THF (40 mL) at K40 8C, was
added fresh prepared p-anisolemagesium bromide (0.5 M in
THF, 122 mL, 61.0 mmol). After 30 min the mixture was
cooled to K78 8C. A mixture solution of unsaturated amide
5 (2.00 g, 6.10 mmol) and TMSCl (1.50 mL, 11.9 mmol) in
dry THF (30 mL) was added to the above suspension, the
reaction mixture was stirred at K78 8C for 30 min and
slowly warmed to rt. Satd NH4Cl was added and the mixture
was extracted with ether, the combined ether extracts were
Figure 4. NOESY studies of compounds 34, 35 and 36.
Protection of the ketone 35 with 1,3-propandithol followed
by reduction with Raney-nickel gave ester 32. Refluxing of
ester 32 with 6 N HCl for 4 days afforded amino acid 3 and
its isomer epi-3 (about 1:1 based on the 1H NMR spectrum)
(Scheme 6). Because the stereochemistry of a-carbon (in R
configuration) of epi-3 could be converted to the S one (3)
automatically under basic conditions or during amide
formation reactions,5,8 both 3 and epi-3 (as well as their
mixture) are good for use in the further application to
synthesis of new SH2 domain ligands.

F. Liu et al. / Tetrahedron 61 (2005) 4971–4981
4975
washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash column chroma-
tography to give 6 as a pale yellow solid (2.40 g) in 90%
yield. Mp: 58–59 8C. [a]2D0ZK29.5 (c 1.6, CHCl3). 1H
NMR (300 MHz, CDCl3): d 7.12 (d, JZ8.7 Hz, 2H), 6.87
(d, JZ8.7 Hz, 2H), 4.07–4.02 (m, 1H), 3.99 (dd, JZ10.2,
3.6 Hz, 1H), 3.84–3.78 (m, 1H), 3.80 (s, 3H), 3.43 (dt, JZ
9.6, 2.1 Hz, 1H), 3.15 (dd, JZ17.4, 9.6 Hz, 1H), 2.50 (dd,
JZ17.4, 2.7 Hz, 1H), 1.55 (s, 9H), 0.94 (s, 9H), 0.10 (s, 3H),
0.09 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d 174.3,
158.5, 149.8, 136.3, 127.3, 114.3, 82.9, 66.9, 63.5, 55.2,
40.1, 37.9, 28.0, 25.8, 18.1, K5.58 ppm. EIMS (m/z, %):
336 [(MHK100)C, 4.47], 322[(MH2K115)C, 59.3].
ESIMS (m/z, %): 474.3 (MCK)C, 458.3 (MCNa)C,
336.2 (MHK100)C. IR (KBr): 2956, 1774, 1290, 1164,
774, 538 cmK1. Anal. for C23H37NO5Si. Calcd: C, 63.41; H,
8.56; N, 3.22. Found: C, 63.67; H, 8.64; N 3.20. ee%Z
96.8% (measured by HPLC).
1254, 838, 699 cmK1. Anal. for C32H45NO7Si. Calcd: C,
65.84; H, 7.77; N, 2.40. Found: C, 66.22; H, 8.03; N, 2.30.
4.1.3. (3R,4R,5S)-3-Benzyloxycarbonylmethyl-5-(tert-
butyldimethyl-silanyloxymethyl)-4-(4-methoxy-phenyl)-
2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8).
To a solution of 7 (0.81 mg, 1.39 mmol) in dry THF
(30 mL) at K78 8C, was added fresh LHMDS (0.67 M in
THF, 6.3 mL, 4.22 mmol), the mixture was stirred at
K78 8C for 40 min and AcOH (0.27 mL, 4.29 mmol) was
added dropwise. Satd NH4Cl was added after additional
10 min, the mixture was warmed to rt and extracted with
Et2O. The combined Et2O extracts were washed with brine,
dried over Na2SO4 and concentrated in vacuo. The residue
was purified by flash column chromatography to give a pale
yellow oil (596 mg) in 73% yield. (The physical data has
been shown in the preparation of compound 7 and 8).
4.1.4. (2S,3R,4R)-4-Benzyloxycarbonylmethyl-3-(4-
methoxy-phenyl)-5-oxo-pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester 2-methyl ester (9). To a solution of
8 (1.46 g, 2.50 mmol) in acetone (40 mL) at 0 8C, was added
dropwise Jone’s reagent (2.67 M, 2.40 mL, 6.41 mmol); the
mixture was warmed to rt and stirred for 4 h. iso-propanol
(15 mL) was added, and the mixture was filtered through a
celite after being stirred for 30 min, the filtrate was basified
with sat. NaHCO3, and acetone was removed in vacuo; the
residue aqueous phase was extracted with ether two times,
then acidified to pH 3–4, and extracted with CH2Cl2. The
CH2Cl2 extracts were washed by brine, dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue
was dissolved in Et2O (20 mL) and treated with CH2N2 in
Et2O; after 10 min, excess CH2N2 was destroyed by AcOH
and the mixture was concentrated in vacuo, The residue was
purified by flash column chromatography to give a pale
yellow oil (664 mg) in 54% yield. [a]2D0ZK2.2 (c 1.3,
CHCl3). 1H NMR (300 MHz, CDCl3): d 7.40–7.32 (m, 3H),
7.28–7.22 (m, 2H), 6.90 (d, JZ8.7 Hz, 2H), 6.75 (d, JZ
4.1.2. (3S,4R,5S)-3-Benzyloxycarbonylmethyl-5-(tert-
butyldimethyl-silanyloxymethyl)-4-(4-methoxy-phenyl)-
2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester [7
(3S) and 8 (3R)]. To a solution of 6 (2.05 g, 4.71 mmol) in
dry THF (30 mL) at K78 8C, was added fresh LHMDS
(0.5 M in THF, 20 mL, 10. 0 mmol); the mixture was stirred
for 30 min and BrCH2COOBn (2.20 g, 9.61 mmol) was
added, then the mixture was slowly warmed to rt after
another 30 min. Sat. NH4Cl was added and the mixture was
extracted with ether. The combined ether extracts were
washed with brine, dried over Na2SO4 and concentrated in
vacuo, the residue was purified by flash column chroma-
tography to give 7 (1.50 g) and 8 (1.00 g) in 98% total yield,
both as pale yellow oil. Date for 7: [a]2D0ZK10.5 (c 2.7,
CHCl3). 1H NMR (300 MHz, CDCl3): d 7.30–7.26 (m, 3H),
7.21–7.17 (m, 2H), 7.10 (d, JZ8.6 Hz, 2H), 6.82 (d, JZ
8.6 Hz, 2H), 4.94 (AB, JABZ12.4 Hz, 1H), 4.83 (AB, JAB
Z
12.4 Hz, 1H), 4.13 (dd, JZ10.8, 3.1 Hz, 1H), 3.94 3.91 (m,
1H), 3.76 (s, 3H), 3.49 (dd, JZ10.8, 1.5 Hz, 1H), 3.17 3.11
(m, 2H), 2.83 (dd, JZ15.9, 5.9 Hz, 1H), 2.50 (dd, JZ15.9,
7.3 Hz, 1H), 1.52 (s, 9H), 0.85 (s, 9H), 0.01 (s, 3H), 0.00 (s,
6H) ppm. 13C NMR (75 MHz, CDCl3): d 173.6, 171.1,
158.9, 150.1, 135.6, 132.1, 128.8, 128.4, 128.1, 114.3, 83.1,
66.4, 64.9, 60.0, 55.2, 47.3, 43.9, 34.8, 29.6, 28.1, 25.8,
18.2, K5.5 ppm. EIMS (m/z, %): 483 [(MK100)C, 0.60].
ESIMS (m/z, %): 606.3 [(MCNa)C, 30.0], 584.3 [(MC
H)C, 8.0], 484.2 [(MHK100)C, 100]. IR(film): 2932, 1716,
1253, 837, 830 cmK1. Anal. for C32H45NO7Si. Calcd: C,
65.84; H, 7.77; N, 2.40. Found: C, 66.19; H, 7.77; N, 2.17.
8.7 Hz, 2H), 5.10 (AB, JABZ12.0 Hz, 1H), 4.99 (AB, JAB
Z
12.0 Hz, 1H), 4.67 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.67
(d, JZ9.0 Hz, 1H), 3.55–3.45 (m, 1H), 2.81 (dd, JZ18.0,
3.9 Hz, 1H), 1.92 (dd, JZ18.0, 10.8 Hz, 1H), 1.52 (s, 9H)
ppm. 13C NMR (75 MHz, CDCl3): d 173.1, 171.4, 170.6,
159.1, 149.1, 135.5, 130.0, 128.4, 128.3, 128.2, 114.4, 84.0,
66.5, 64.2, 55.2, 52.8, 43.4, 42.6, 30.9, 27.8 ppm. EIMS
(m/z, %): 497 (MC, 3.99), 397 [(MK100)C, 7.78]. IR
(film): 2981, 1794, 1751, 1255, 836, 531 cmK1. Anal. for
C27H31NO8. Calcd: C, 65.18; H, 6.28; N, 2.82. Found: C,
65.33; H, 6.15; N, 2.80.
Date for 8: [a]D20ZK31.0 (c 1.6, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.30–7.15 (m, 5H), 6.80 (dd, JZ
4.1.5.
(2S,3R,4R)-4-Carboxymethyl-3-(4-methoxy-
8.6 Hz, 2H), 6.65 (dd, JZ8.6 Hz, 2H), 5.03 (AB, JAB
Z
phenyl)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-
butyl ester 2-methyl ester (10). To a solution of 9
(250 mg, 0.50 mmol) in ethyl acetate (5 mL), was added
Pd/C (10%, 25 mg), and the mixture was stirred at rt for 3 h
under 1 atm hydrogen. Pd/C was filtered off and the filtrate
was concentrated in vacuo, the residue was purified by flash
column chromatography directly to give a pale yellow oil
12.3 Hz, 1H), 4.93 (AB, JABZ12.3 Hz, 1H), 4.13–4.10 (m,
1H), 3.95 (dd, JZ10.6, 4.1 Hz, 1H), 3.77 (dd, JZ10.6,
2.3 Hz, 1H), 3.70–3.60 (m, 4H), 3.52 (d, JZ9.0 Hz, 1H),
2.65 (dd, JZ17.7, 4.2 Hz, 1H), 1.81 (dd, JZ17.7, 10.3 Hz,
1H), 1.48 (s, 9H), 0.83 (s, 9H), 0.01 (s, 3H), 0.00 (s, 6H)
ppm. 13C NMR (75 MHz, CDCl3): d 174.7, 171.7, 158.8,
150.0, 135.8, 132.3, 128.5, 128.3, 128.2, 114.3, 83.2, 66.3,
64.9, 63.7, 55.2, 44.1, 42.9, 31.5, 28.1, 25.8, 18.2,
K5.50 ppm. EIMS (m/z, %): 483 [(MK100)C, 0.77], 468
[(MK115)C, 7.33]. ESIMS (m/z, %): 606.3 [(MCNa)C,
11.0], 484.2 [(MHK100)C, 100]. IR (film): 2932, 1741,
1
(140 mg) in 68% yield. [a]2D0ZK2.1 (c 0.7, CHCl3). H
NMR (300 MHz, CDCl3): d 7.00 (d, JZ8.4 Hz, 2H), 6.86
(d, JZ8.1 Hz, 2H), 4.70 (s, 1H), 3.85 (s, 3H), 3.84 (s, 3H),
3.67 (d, JZ8.7 Hz, 1H), 3.47 (m, 1H), 2.79 (dd, JZ12.3,
3.9 Hz, 1H), 1.98 (dd, JZ12.3, 9.9 Hz, 1H), 1.53 (s, 9H)

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F. Liu et al. / Tetrahedron 61 (2005) 4971–4981
ppm. EIMS (m/z, %): 307 [(MK100)C, 7.89]. IR (film):
3226, 2950, 1751, 1255, 838, 550 cmK1. HR-MALDI for
(C20H25NO8CNa)C. Calcd: 430.1478. Found 430.1472.
residue was purified by flash column chromatography to
give diester 13 as a colorless oil (32 mg) in 74% yield, and
recovered material as a colorless oil (15 mg). [a]2D0Z
C101.0 (c 0.9, CHCl3). 1H NMR (300 MHz, CDCl3): d 7.54
(s, 1H), 7.06 (s, 2H), 5.10 (d, JZ9.9 Hz, 1H), 4.56 (t, JZ
9.9 Hz, 1H), 3.85–3.75 (m, 7H), 3.47 (s, 3H), 3.36–3.10 (m,
2H), 2.95 (dd, JZ18.3, 3.0 Hz, 1H), 1.43 (s, 9H) ppm. 13C
NMR (75 MHz, CDCl3): d 195.5, 172.2, 159.5, 133.7,
133.1, 129.1, 121.5, 110.2, 80.6, 55.5, 52.2, 52.1, 43.3, 42.0,
35.5, 28.2, 14.2 ppm. ESIMS (m/z, %):460.3 [(MCK)C, 3.0],
444.3 [(MCNa)C, 100], 422.3 [(MH)C, 3.0]. IR (film): 3387,
2850, 1730, 1212, 828, 563 cmK1. HR-MALDI for
(C21H27NO8CNa)C. Calcd: 444.1634. Found: 444.1633.
4.1.6. 7-Methoxy-3,5-dioxo-2,3,3a,4,5,9b-hexahydro-1H-
benzo[e]isoindole-1S-carboxylic acid methyl ester (11).
To a solution of acid 10 (100 mg, 0.245 mmol) in dry
CH2Cl2 (4.0 mL) and CS2 (10.0 mL) at 0 8C, was added
(COCl)2 (87 mL, 1.02 mmol), followed by the slow addition
of dry DMF (6 mL, 0.077 mmol). The mixture was warmed
to rt and stirred for 2 h, the solvent was removed to give a
yellow oil. To the solution of this oil in dry CH2Cl2 (20 mL)
at 0 8C, was added AlCl3 (160 mg, 1.20 mmol) in one
portion. The reaction mixture was warmed to rt and stirred
overnight. Crashed ice was added and the reaction mixture
was extracted with CH2Cl2, the CH2Cl2 extracts were
washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash column chroma-
tography to give ketone 11 (54 mg) as a white solid in 76%
4.1.9. (1S,4R)-7-Methoxy-2-methoxymethyl-3,5-dioxo-
2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole-1-car-
boxylic acid methyl ester (14). To a solution of ester 13
(10 mg, 0.024 mmol) in DCM (3.0 mL) was added TFA
(3.0 mL), and the mixture was stirred at rt for 2 h. Solvent
was removed in vacuo, and the residue was redissolved in
methanol (10 mL), HCHO (30% aq, 0.30 mL, 3.00 mmol)
was added to the above solution. The mixture was refluxed
for 2 h and concentrated; the residue was purified by flash
column chromatography directly to give a colorless oil
(6.0 mg) in 75% yield. 1H NMR (300 MHz, CDCl3): d 7.49
(d, JZ3.0 Hz, 1H), 7.43 (d, JZ8.7 Hz, 1H), 7.21 (dd, JZ
8.7, 3.0 Hz, 1H), 4.81 (AB, JABZ11.1 Hz, 1H), 4.53 (AB,
JABZ11.4 Hz, 1H), 4.37 (s, 1H), 3.99 (d, JZ7.5 Hz, 1H),
3.89 (s, 3H), 3.85 (s, 3H), 3.42–3.36 (m, 1H), 3.26 (dd, JZ
17.1, 2.4 Hz, 1H), 2.80 (s, 3H), 2.75 (dd, JZ17.1, 6.9 Hz,
1H) ppm. EIMS (m/z, %): 333 (MC, 4.93), 302 [(MK31)C,
20.15]. ESIMS (m/z, %): 351.1 [(MCNH4)C, 25.0], 334.1
[(MCH)C, 38.0], 302.1 [(MKOMe)C, 100]. IR (film):
2927, 1716, 1283, 1228, 757, 496 cmK1. HR-EIMS for
C17H19NOC6 . Calcd: 333.1212. Found: 333.1232.
1
yield. Mp: 178–180 8C. [a]2D0ZK8.7 (c 1.0, CHCl3). H
NMR (300 MHz, CDCl3): d 7.44 (d, JZ2.9 Hz, 1H), 7.40
(d, JZ8.7 Hz, 1H), 7.18 (dd, JZ8.7, 2.9 Hz, 1H), 7.15 (br s,
1H), 4.25 (s, 1H), 4.02 (dd, JZ7.8, 1.8 Hz, 1H), 3.87 (s,
3H), 3.82 (s, 3H), 3.25–3.19 (m, 1H), 3.10 (dd, JZ16.9,
4.1 Hz, 1H), 2.72 (dd, JZ16.9, 7.1 Hz, 1H) ppm. 13C NMR
(75 MHz, CDCl3): d 194.0, 177.0, 171.5, 159.2, 133.8,
133.3, 130.0, 123.0, 108.7, 62.6, 55.6, 52.9, 40.5, 38.0,
34.7 ppm. EIMS (m/z, %): 289 (MC, 29.73). IR (KBr):
3396, 1693, 1198, 839, 548 cmK1
.
4.1.7. 7-Methoxy-3,5-dioxo-1,3,3a,4,5,9b-hexahydro-
benzo[e] isoindole-1S,2-dicarboxylic acid 2-tert-butyl
ester 1-methyl ester (12). To a solution of ketone 11
(53 mg, 0.183 mmol) in dry CH3CN (10 mL) at rt, was
added Boc2O (84 mg, 0.385 mmol) and DMAP (2 mg,
0.016 mmol) successively. After being stirred for 1.5 h, the
mixture was diluted with CH2Cl2, washed by water and
brine, dried over anhydrous Na2SO4, filtered and concen-
trated in vacuo, the residue was purified by flash column
chromatography to give ketone 12 (58 mg) as a colorless oil
in 81% yield. [a]D20ZC33.5 (c 1.6, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.49 (d, JZ2.7 Hz, 1H), 7.45 (d, JZ
8.7 Hz, 1H), 7.23 (dd, JZ8.7, 2.7 Hz, 1H), 4.75 (s, 1H),
3.90 (s, 3H), 3.85 (s, 3H), 3.83 (d, JZ6.9 Hz, 1H), 3.42 (dt,
JZ6.9, 3.0 Hz, 1H), 3.25 (dd, JZ17.1, 3.0 Hz, 1H), 2.73
(dd, JZ17.1, 6.9 Hz, 1H), 1.46 (s, 9H) ppm. 13C NMR
(75 MHz, CDCl3): d 193.4, 172.3, 170.9, 160.0, 150.0,
134.2, 132.6, 130.1, 123.7, 109.2, 84.6, 65.6, 56.0, 53.4,
40.5, 37.3, 34.7, 28.2 ppm. EIMS (m/z, %): 389 (MC, 24.0).
ESIMS (m/z, %): 428.2 [(MCK)C, 13.0], 412.2 [(MC
Na)C, 25.0]. IR (film): 2981, 1793, 1753, 1304, 732,
538 cmK1. HR-MALDI for (C20H23NO7CNa)C. Calcd:
412.1372. Found: 412.1361.
4.1.10. (4R)-4-(2-Ethoxycarbonyl-vinyl)-2,2-dimethyl-
oxazolidine-3-carboxylic acid tert-butyl ester (15). To a
solution of (COCl)2 (5.7 mL, 67.3 mmol) in dry DCM
(250 mL) at K78 8C, was added a solution of DMSO
(9.3 mL, 0.131 mol) in dry DCM (40 mL) during 15 min.
Garner’s alcohol (10.0 g, 43.2 mmol) in dry DCM (40 mL)
was added dropwise to the above solution. The mixture was
stirred at K78 8C for 2 h before Et3N (50.0 mL, 356 mmol)
was added, then warmed to rt. Satd NH4Cl was added and
the resulted mixture was extracted with DCM, the organic
layer was washed by brine, dried over anhydrous Na2SO4,
filtered and concentrated; the residue was redissolved in
ether (100 mL), filter through a celite to remove the
Et3N$HCl. Ether was removed in vacuo and the residue
was used directly for the next step. To a solution of the
above residue in benzene (150 mL) at 0 8C, was added
Ph3P]CHCOOEt (18.4 g, 52.5 mmol), and the mixture was
stirred at rt overnight. Most of the benzene was removed and
ether (150 mL) was added, filtered and concentrated, the
residue was purified by flash column chromatography
directly to give a pale yellow oil (10.7 g) in 83% yield.
[a]2D0ZK61.4 (c 0.95, CHCl3). 1H NMR (300 MHz,
CDCl3): d 6.95–6.78 (m, 1H), 6.02–5.85 (m, 1H), 4.62–
4.50 (m, 0.4H), 4.50–4.38 (m, 0.6H), 4.30–4.15 (m, 2H),
4.15–4.05 (m, 1H), 3.85–3.78 (m, 1H), 1.65–1.25 (m, 18H)
ppm. ee%Z97.3% (measured by HPLC).
4.1.8. (1R,2R)-1-(tert-Butoxycarbonylaminomethoxycar-
bonyl-methyl)-6-methoxy-4-oxo-1,2,3,4-tetrahydro-
naphthalene-2-carboxylic acid methyl ester (13). To a
solution of ketone 12 (58 mg, 0.149 mmol) in methanol
(5.0 mL), was added K2CO3 (31 mg, 0.225 mmol), and the
mixture was stirred at rt for 30 min. Water was added and
the resulted mixture was extracted with ethyl acetate
(50 mL!3); the organic layer was washed by brine, dried
over anhydrous Na2SO4, filtered and concentrated, the

F. Liu et al. / Tetrahedron 61 (2005) 4971–4981
4977
4.1.11. (1R,4R)-4-[2-Ethoxycarbonyl-1-(4-methoxy-
phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic
acid tert-butyl ester (16). To the suspension of CuI (16.0 g,
84.0 mmol) in dry THF (100 mL) at K78 8C, was added
fresh prepared p-methoxylphenylmagnesium bromide
(0.5 M, 0.34 L, 0.17 mol) dropwise, the mixture was slowly
warmed to K20 8C during 60 min. The mixture was cooled
back to K78 8C, then a solution of TMSCl (25.4 mL,
0.20 mol) and ester 15 (5.0 g, 16.7 mmol) in dry THF
(30 mL) was added. The mixture was stirred at K78 8C for
60 min and warmed to 0 8C during 2 h. Satd NH4Cl was
added and the resulted mixture was extracted with ether, the
organic layer was washed by Satd Na2S2O3 and brine, dried
over anhydrous Na2SO4, concentrated, the residue was
purified by flash column chromatography to give a colorless
oil (6.98 g) in 100% yield. [a]2D0ZC38.5 (c 2.0, CHCl3). 1H
NMR (300 MHz, CDCl3): d 7.26–7.10 (m, 2H), 6.88–6.80
(m, 2H), 4.10–3.65 (m, 9H), 2.85–2.70 (m, 2H), 1.60–1.30
(m, 15H), 1.25–1.05 (m, 3H) ppm. 13C NMR (75 MHz,
CDCl3): d 172.4, 158.3, 152.7/152.3(conformer), 132.1, 129.0,
128.6, 113.9, 113.6, 94.6/94.0, 80.1, 63.8/63.4, 61.8/61.5,
60.1, 55.0, 42.0, 33.7/32.5, 28.3, 26.6/25.9, 23.7/22.2,
13.9 ppm. EIMS (m/z, %): 407 (MC, 0.43). IR (film): 2980,
1700, 1252, 1178, 854, 541 cmK1. Anal. for C22H33NO6.
Calcd: C, 64.84; H, 8.16; N, 3.44. Found: C, 65.10; H, 8.29; N,
3.37. ee% O 96.4% (measured by HPLC).
was dried with anhydrous Na2SO4, filtered and concentrated;
the residue was purified by flash column chromatography to
give a colorless oil (17.3 g) in 93% yield. [a]2D0ZK70.1 (c
1
1.7, CHCl3). H NMR (300 MHz, CDCl3): d 7.09 (d, JZ
8.4 Hz, 2H), 6.79 (d, JZ8.4 Hz, 2H), 5.76–5.70 (m, 1H),
4.98–4.84 (m, 2H), 4.60–4.43 (m, 1H), 4.08 (m, 1H), 3.99–
3.90 (m, 1H), 3.80 (s, 3H), 3.80–3.72 (m, 1H), 3.60–3.50
(m, 1H), 3.40–3.28 (m, 1H), 2.86 (m, 1H), 2.28 (m, 1H),
2.05 (m, 1H), 1.68 (m, 1H), 1.50–1.30 (m, 12H), 0.90 (m,
3H) ppm. 13C NMR (75 MHz, CDCl3): d 158.2, 136.6,
131.9, 131.0, 116.4, 113.2, 94.4, 80.2, 68.9, 64.0, 58.3, 55.1,
42.8, 34.8, 28.3, 25.4, 24.5 ppm. EIMS (m/z, %): 407 (0.48),
308 (0.63). IR (film): 3462, 2978, 1694, 1513, 1249, 1178,
1040, 842, 563 cmK1. Anal. for C23H35NO5. Calcd: C,
68.12; H, 8.70; N, 3.45. Found: C, 68.07; H, 8.88; N, 3.33.
4.1.14. (1R,2S,4R)-4-[2-(2,2-Dimethyl-propionyloxy-
methyl)-1-(4-methoxy-phenyl)-pent-4-enyl]-2,2-di-
methyloxazolidine-3-carboxylic acid tert-butyl ester (19).
To a solution of alcohol 18 (6.50 g, 16.0 mmol) in dry DCM
(100 mL) at 0 8C was added Et3N (13.5 mL, 96.0 mmol),
DMAP (195 mg, 1.60 mmol) and PivCl (7.9 mL,
64.0 mmol), then the mixture was warmed to rt and stirred
overnight. The reaction mixture was diluted with DCM,
washed by water and brine, dried over anhydrous Na2SO4,
filtered and concentrated; the resulted residue was purified
by flash column chromatography to give a pale yellow oil
1
4.1.12. (1R,2S,4R)-4-[2-Ethoxycarbonyl-1-(4-methoxy-
phenyl)-pent-4-enyl]-2,2-dimethyl-oxazolidine-3-car-
boxylic acid tert-butyl ester (17). To a solution of
(i-Pr)2NH (7.6 mL, 54.3 mmol) in dry THF (250 mL) at
0 8C, was added n-BuLi (1.6 M in hexane, 30.0 mL,
48.0 mmol) dropwise, the mixture was stirred for 15 min
and cooled to K78 8C. HMPA (11.5 mL, 63.4 mmol) was
added to the above solution, and the mixture was stirred for
30 min before ester 16 (13.0 g, 31.9 mmol) in dry THF
(40 mL) was added. Allylic bromide (4.1 mL, 48.4 mmol)
was added after another 30 min. The mixture was stirred at
K78 8C for 30 min and warmed to rt during 60 min, satd
NH4Cl was added and the resulted mixture was extracted
with ether. The organic layer was washed by brine, dried
over Na2SO4, filtered and concentrated; the residue was
purified by flash column chromatography to give a pale
yellow oil (14.5 g) in 100% yield. [a]2D0ZK62.8 (c 1.3,
CHCl3). 1H NMR (300 MHz, CDCl3): d 7.10 (d, JZ8.4 Hz,
2H), 6.82 (d, JZ8.4 Hz, 2H), 5.68–5.52 (m, 1H), 4.92–4.79
(m, 2H), 4.25–4.10 (m, 3H), 4.03–3.90 (m, 2H), 3.80 (s,
3H), 3.40–3.10 (m, 2H), 2.17–1.95 (m, 2H), 1.60–1.45 (m,
15H), 0.80 (m, 3H) ppm. 13C NMR (75 MHz, CDCl3): d
158.4, 134.5, 131.0, 116.8, 113.3, 69.5, 60.3, 60.0, 55.2,
52.0, 48.5, 35.7, 28.3, 25.3, 24.4, 14.3 ppm. EIMS (m/z, %):
447 (MC, 0.35). IR (film): 2980, 1697, 1391, 1180, 1037,
840, 566 cmK1. Anal. for C25H37NO6. Calcd: C, 67.09; H,
8.33; N, 3.13. Found: C, 67.35; H, 8.35; N, 3.05.
(8.16 g) in 100% yield. [a]2D0ZK42.1 (c 2.2, CHCl3). H
NMR (300 MHz, CDCl3): d 7.08 (d, JZ8.7 Hz, 2H), 6.80
(d, JZ8.7 Hz, 2H), 5.70 (m, 1H), 5.00–4.90 (m, 2H), 4.45
(m, 1H), 4.30 (m, 1H), 4.05–3.84 (m, 3H), 3.80 (s, 3H), 2.98
(m, 1H), 2.38 (m, 1H), 2.17 (m, 1H), 1.73 (m, 1H), 1.60–
1.00 (m, 24H) ppm. 13C NMR (75 MHz, CDCl3): d 178.3,
158.3, 153.1, 136.1, 131.3/130.9, 130.7, 116.8, 113.0, 94.0,
79.7, 68.5, 64.0, 58.1, 55.1, 50.7, 40.0, 38.9, 33.5, 28.2,
27.2, 26.0, 24.6 ppm. EIMS (m/z, %): 491 (0.20), 490
(MHC, 0.61). IR (film): 2977, 1695, 1366, 1163, 838,
561 cmK1. HR-MALDI for (C28H43NO6CNa)C. Calcd:
512.2988. Found: 512.2957.
4.1.15. 2,2-Dimethyl-propionic acid 2S-[2R-tert-butoxy-
carbonylamino-3-hydroxy-1R-(4-methoxyphenyl)-pro-
pyl]-pent-4-enyl ester (20). To a solution of 19 (7.33 g,
15.0 mmol) in methanol (800 mL), was added PTSA$H2O
(86 mg, 0.45 mmol), and the mixture was stirred at rt
overnight. Satd NaHCO3 (20 mL) was added to the reaction
mixture, then methanol was removed in vacuo, and the
residue mixture was extracted with EtOAc; the organic
phase was washed by brine, dried over anhydrous Na2SO4,
filtered and concentrated, the residue was purified by flash
column chromatography to give a pale yellow oil (5.68 ) in
84% yield. [a]D20ZK51.8 (c 1.7, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.08 (d, JZ8.7 Hz, 2H), 6.80 (d,
JZ8.7 Hz, 2H), 5.72–5.58 (m, 1H), 5.00–4.82 (m, 2H),
4.40–4.25 (m, 1H), 4.20–4.00 (m, 2H), 3.80 (s, 3H), 3.48–
3.25 (m, 2H), 3.00 (m, 1H), 2.30–2.10 (m, 2H), 2.10–1.95
(m, 2H), 1.78 (m, 1H), 1.50–1.18 (m, 18H) ppm. 13C NMR
(75 MHz, CDCl3): d 178.3, 158.6, 156.2, 135.9, 130.2,
129.7, 117.0, 113.9, 79.6, 64.3, 63.4, 55.2, 52.0, 45.3, 38.9,
38.0, 32.8, 28.3, 27.2 ppm. EIMS (m/z, %): 350 (1.31). IR
4.1.13. (1R,2S,4R)-4-[2-Hydroxymethyl-1-(4-methoxy-
phenyl)-pent-4-enyl]-2,2-dimethyl-oxazolidine-3-car-
boxylic acid tert-butyl ester (18). To suspension of LiAlH4
(1.83 g, 46.0 mmol) in dry THF (250 mL) at 0 8C, was
added a solution of ester 17 (20.5 g, 46.0 mmol) in dry THF,
the mixture was stirred at 0 8C for 1.5 h. Water (5.0 mL) was
added dropwise to the reaction mixture, and the mixture
was stirred vigorously until becoming white. The mixture
(KBr film): 3437, 2978, 1725, 1168, 1036, 838, 539 cmK1
.
HR-MALDI for (C25H39NO6CNa)C. Calcd: 472.2675.
Found: 472.2697.

4978
F. Liu et al. / Tetrahedron 61 (2005) 4971–4981
4.1.16. 2,2-Dimethyl-propionic acid 2S-[R-(4-methoxy-
phenyl)-R-(2-oxo-oxazolidin-4-yl)-methyl]-pent-4-enyl
ester (21). To a suspension of NaH (60%, 1.10 g,
27.3 mmol) in dry DMF (50 ) at 0 8C, was added the
solution of alcohol 20 (4.9 g, 10.9 mmol) in dry DMF
(50 mL) dropwise, and the mixture was stirred for 30 min.
Satd NH4Cl (20 mL) was added to the reaction mixture, then
DMF was removed in vacuo, and the residue mixture was
extracted with EtOAc; the organic phase was washed by
brine, dried over anhydrous Na2SO4, filtered and concen-
trated, the residue was purified by flash column chroma-
tography to give a colorless oil (3.10 g) in 76% yield.
[a]2D0ZC3.91 (c 1.2, CHCl3). 1H NMR (300 MHz, CDCl3):
d 7.10 (d, JZ8.4 Hz, 2H), 6.90 (d, JZ8.4 Hz, 2H), 5.70–
5.60 (m, 2H), 5.10–4.90 (m, 2H), 4.50 (t, JZ8.4 Hz, 1H),
4.40–4.33 (m, 1H), 4.11–4.00 (m, 2H), 3.93 (dd, JZ12.0,
6.3 Hz, 1H), 3.80 (s, 3H), 2.80–2.76 (m, 1H), 2.15–2.00 (m,
2H), 1.77–1.70 (m, 1H), 1.25 (s, 9H) ppm. 13C NMR
(75 MHz, CDCl3): d 178.3, 159.0, 135.0, 130.1, 128.5, 117.7,
114.3, 68.8, 64.0, 55.2, 53.5, 49.9, 38.9, 32.8 27.2 ppm. EIMS
(m/z, %): 291 (3.33), 290 (17.04), 289 (8.13). IR (film): 3280,
anhydrous Na2SO4, filtered and concentrated, the residue
was purified by flash column chromatography to give a
white wax (1.30 g) in 84% yield. [a]2D0ZK80.3 (c 2.4,
CHCl3). 1H NMR (300 MHz, CDCl3): d 7.04 (m, 2H), 6.80
(m, 2H), 4.84 (d, JZ8.4 Hz, 1H), 4.63 (dd, JZ11.7, 4.5 Hz,
1H), 4.35 (t, JZ8.6 Hz, 1H), 4.27 (dd, JZ12.0, 3.0 Hz, 1H),
4.03 (dd, JZ12.0, 1.8 Hz, 1H), 3.78 (s, 3H), 2.84 (m, 1H),
2.74 (dd, JZ11.6, 2.0 Hz, 1H), 2.15 (m, 2H), 1.56 (s, 9H),
1.23 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3): d 178.4,
177.8, 159.4, 151.8, 150.2, 130.3, 126.6, 114.5, 84.5, 67.1,
63.8, 55.1, 54.2, 51.0, 39.0, 35.9, 34.5, 27.9, 27.2 ppm.
ESIMS (m/z, %): 516.3 [(MCNa)C, 10], 394.2 [(MHK
100)C, 50]. IR (film): 3224, 2979, 1813, 1726, 1156, 913,
734, 648 cmK1. Anal. for C25H35NO9. Calcd: C, 60.84; H,
7.15; N, 2.84. Found: C, 60.89; H, 7.22; N, 2.78.
4.1.19. 2,2-Dimethyl-propionic acid 6-methoxy-4-oxo-
1R-(2-oxo-oxazolidin-4R-yl)-1R,2R,3,4-tetrahydro-
naphthalen-2-ylmethyl ester (24). To a solution of acid 23
(1.25 g, 2.54 mmol) in DCM (5.0 mL) and CS2 (30 mL) at
rt, was added (COCl)2 (0.67 mL, 7.61 mmol) and DMF
(60 mL, 0.76 mmol), and the mixture was stirred at rt for 2 h.
The solvent was removed in vacuo and the residue was
redissovled in dry DCM (60 mL) and protected under N2 as
soon as possible, the solution was cooled to 0 8C before
AlCl3 (1.19 g, 8.89 mmol) was added, the reaction mixture
was warmed to rt and stirred overnight. The mixture was
poured into a mixture was ice and water and extracted with
DCM, the organic phase was washed by brine, dried over
anhydrous Na2SO4, filtered and concentrated, the residue
was purified by flash column chromatography to give a
white wax (0.70 g) in 74% yield. [a]2D0ZC62.4 (c 1.5,
CHCl3). 1H NMR (300 MHz, CDCl3): d 7.41 (d, JZ2.7 Hz,
1H), 7.15 (d, JZ8.4 Hz, 1H), 7.04 (dd, JZ8.4, 2.7 Hz, 1H),
5.85 (s, 1H), 4.52 (t, JZ8.4 Hz, 1H), 4.17 (dd, JZ9.0,
6.0 Hz, 1H), 4.00 (m, 1H), 3.89 (m, 2H), 3.75 (s, 3H), 2.87
(d, JZ9.0 Hz, 1H), 2.80 (dd, JZ19.2, 6.0 Hz, 1H), 2.55 (d,
JZ19.2 Hz, 1H), 2.42 (m, 1H), 1.06 (s, 9H) ppm. 13C NMR
(75 MHz, CDCl3): d 194.6, 178.0, 159.4, 158.9, 132.5,
131.7, 121.8, 110.2, 69.1, 65.7, 55.4, 55.3, 44.6, 38.6, 35.5,
34.0, 26.9 ppm. EIMS (m/z, %): 375 (MC, 0.62). IR (film):
3334, 2970, 1683, 1284, 1156, 1033, 769, 532 cmK1. Anal.
for C20H25NO6. Calcd: C, 63.99; H, 6.71; N, 3.73. Found: C,
64.43; H, 7.03; N, 3.58. ee%Z99.13% (measured by
HPLC).
2974, 1751, 1162, 1034, 769, 553 cmK1
.
4.1.17. 4R-[2S-(2,2-Dimethyl-propionyloxymethyl)-1R-
(4-methoxy-phenyl)-pent-4-enyl]-2-oxo-oxazolidine-3-
carboxylic acid tert-butyl ester (22). To a solution of 21
(6.3 g, 16.8 mmol) in dry DCM (300 mL) at 0 8C, was added
Et3N (8.2 mL, 58.5 mmol), DMAP (100 mg, 0.82 mmol)
and (Boc)2O (10.8 g, 49.5 mmol), the mixture was warmed
to rt and stirred overnight. The reaction mixture was washed
by water and brine, dried over anhydrous Na2SO4, filtered
and concentrated; the residue was purified by flash column
chromatography to give a colorless oil (7.40 g) in 93%
1
yield. [a]2D0ZK99.9 (c 2.4, CHCl3). H NMR (300 MHz,
CDCl3): d 7.01 (d, JZ8.4 Hz, 2H), 6.80 (d, JZ8.1 Hz, 2H),
5.60 (m, 1H), 5.00–4.75 (m, 3H), 4.54 (dd, JZ11.1, 3.9 Hz,
1H), 4.30 (m, 1H), 4.15 (m, 1H), 4.02 (m, 1H), 3.75 (s, 3H),
2.70 (dd, JZ10.8, 2.7 Hz, 1H), 2.30 (m, 1H), 1.94 (m, 1H),
1.75 (m, 1H), 1.52 (s, 9H), 1.20 (s, 9H) ppm. 13C NMR
(75 MHz, CDCl3): d 178.3, 159.0, 151.8, 150.2, 135.2,
130.3, 127.4, 117.4, 114.1, 84.1, 67.2, 62.9, 55.0, 54.6, 51.1,
38.9, 38.6, 33.7, 27.8, 27.2 ppm. ESIMS (m/z, %): 498.2
[(MCNa)C, 10], 376.2 [(MHK100)C, 40]. IR (KBr film):
2978, 1819, 1154, 1062, 776, 566 cmK1. Anal. for
C26H37NO7. Calcd: C, 65.66; H, 7.84; N, 2.95. Found: C,
65.69; H, 7.64; N, 2.88.
4.1.20. 4R-[2R-(2,2-Dimethyl-propionyloxymethyl)-6-
methoxy-4-oxo-1R,2R,3,4-tetrahydro-naphthalen-1-yl]-
2-oxooxazolidine-3-carboxylic acid tert-butyl ester (26).
To a solution of ketone 24 (1.00 g, 2.66 mmol) in dry DCM
(30 mL) at 0 8C, was added Et3N (1.2 mL, 8.56 mmol),
DMAP (5 mg, 0.041 mmol) and (Boc)2O (0.70 g,
3.21 mmol), the mixture was warmed to rt and stirred
overnight. The reaction mixture was washed by water and
brine, dried over anhydrous Na2SO4, filtered and concen-
trated; the residue was purified by flash column chroma-
tography to give a colorless oil (1.20 g) in 95% yield.
[a]2D0ZC27.2 (c 1.1, CHCl3). 1H NMR (300 MHz, CDCl3):
d 7.55 (d, JZ2.7 Hz, 1H), 7.18–7.10 (m, 2H), 4.59–4.53 (m,
1H), 4.39–4.33 (m, 1H), 4.16–4.10 (m, 1H), 4.05–3.90 (m,
2H), 3.84 (s, 3H), 3.23 (d, JZ8.7 Hz, 1H), 2.92 (dd, JZ
18.6, 5.7 Hz, 1H), 2.69 (d, JZ18.3 Hz, 1H), 2.58–2.51 (m,
1H), 1.24 (s, 9H), 1.11 (s, 9H) ppm. 13C NMR (75 MHz,
4.1.18. 4R-[3-Carboxy-2S-(2,2-dimethyl-propionyloxy-
methyl)-1R-(4-methoxy-phenyl)-propyl]-2-oxo-oxazoli-
dine-3-carboxylic acid tert-butyl ester (23). O3 was bulbed
through the solution of 22 (1.50 g, 3.15 mmol) in DCM
(40 mL) and methanol (10 mL) at K78 8C until pale blue
(about 2 h), then Me2S (10 mL) was added; the mixture was
warmed to rt during 2 h and concentrated to a colorless oil
which was used directly. To the solution of the above
t
residue in BuOH (50 mL) and H2O (10 mL) at 0 8C, was
added KH2PO4 (643 mg, 4.73 mmol) and 2-methyl-2-
butene (1.34 mL, 12.6 mmol), NaClO2 (860 mg,
9.46 mmol, in three portions); the mixture was warmed to
rt and stirred overnight. Satd Na2S2O3 (20 mL) was added to
the reaction mixture and tBuOH was removed in vacuo, the
residue aqueous was acidified to pH 3–4 and extracted by
DCM, the organic layer was washed by brine, dried over

F. Liu et al. / Tetrahedron 61 (2005) 4971–4981
4979
CDCl3): d 194.7, 178.1, 159.6, 151.8, 148.4, 133.2, 131.9,
131.0, 122.2, 110.0, 84.1, 66.6, 66.0, 56.9, 55.6, 41.9, 38.7,
35.9, 34.0, 27.5, 27.0 ppm. ESIMS (m/z, %): 498.2 [(MC
Na)C, 15], 476.2 [(MH)C, 100]. IR (film): 2978, 1816, 1728,
1284, 1156, 732, 550 cmK1. Anal. for C25H33NO8. Calcd: C,
63.14; H, 6.99; N, 2.95. Found: C, 63.23; H, 7.02; N, 2.88.
the residue was redissolved in dioxane (10 mL), water
(5.0 mL) and sat. NaHCO3 (5.0 mL), ClCOOMe (0.12 mL,
1.55 mmol) was added and the mixture was stirred at rt for
2 h. Dioxane was removed in vacuo and the residue was
extracted with EtOAc, the organic layer was washed by
water and brine, dried over anhydrous Na2SO4, filtered and
concentrated. The resulted residue was purified by flash
column chromatography to give a colorless oil (0.72 g) in
100% yield. [a]D20ZC51.2 (c 1.5, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.50 (d, JZ2.7 Hz, 1H), 7.19 (d,
JZ8.7 Hz, 1H), 7.14 (dd, JZ8.7, 2.7 Hz, 1H), 4.64–4.55
(m, 2H), 4.47 (dd, JZ12.0, 9.6 Hz, 1H), 3.96–3.80 (m, 5H),
3.70 (ddd, JZ9.6, 4.5, 1.5 Hz, 1H), 3.26 (s, 3H), 3.21 (m,
2H), 2.67 (m, 1H), 2.60 (m, 1H), 1.27 (s, 9H), 1.15 (s, 9H)
ppm. 13C NMR (75 MHz, CDCl3): d 197.7, 178.4, 178.3,
159.9, 155.8, 134.9, 132.0, 131.1, 122.6, 109.5, 64.8, 63.0,
62.1, 55.9, 52.7, 50.7, 45.4, 45.2, 39.2, 38.8, 31.9, 27.5,
27.3, 23.0 ppm. ESIMS (m/z, %): 526.4 (MCNa)C, 542.4
4.1.21. [2-Hydroxy-1R-(2R-hydroxymethyl-6-methoxy-
4-oxo-1R,2R,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-car-
bamic acid tert-butyl ester (27). To a solution of ketone 26
(1.10 g, 2.31 mmol) in methanol (50 mL), was added
Cs2CO3 (1.65 g, 5.05 mmol), the mixture was stirred at rt
overnight. Satd NaCl (30 mL) was added to the reaction
mixture, and methanol was removed in vacuo, the residue
was extracted with DCM; the organic layer was washed by
water and brine, dried over anhydrous Na2SO4, filtered and
concentrated, the residue was purified by flash column
chromatography to give a white wax (0.75 g) in 86% yield.
[a]2D0ZC54.1 (c 1.2, CHCl3). 1H NMR (300 MHz, CDCl3):
d 7.48 (d, JZ2.7 Hz, 1H), 7.20 (d, JZ8.4 Hz, 1H), 7.05 (dd,
JZ8.4, 2.7 Hz, 1H), 4.85 (d, JZ9.6 Hz, 1H), 4.00–3.60 (m,
7H), 3.55–3.30 (m, 3H), 3.05–2.80 (m, 2H), 2.50 (m, 2H),
1.26 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3): d 197.0,
158.9, 155.8, 133.4, 133.3, 132.4, 121.5, 109.4, 79.9, 64.8,
63.0, 55.5, 39.3, 38.6, 36.4, 29.6, 28.2 ppm. EIMS (m/z, %):
310 (1.10), 292 (3.39), 266 (1.09). ESIMS (m/z, %): 753
[(2MCNa)C, 25], 731.4 [(2MCH)C, 35], 310 [(MH2K
C4H9)C, 100], 266 [(MHK100)C, 8]. IR (film): 3360, 2927,
(MCK)C. IR (film): 2974, 1730, 1284, 1159, 764, 532 cmK1
.
HR-ESIMS for (C27H37NO8CNa)C. Calcd: 526.2417.
Found: 526.2412.
4.1.24. (1R,9S,12R,13S)-12,13-Bis-(2,2-dimethylpro-
pionyloxymethyl)-5-methoxy-11-azatricyclo[7.3.1.02,7]-
trideca-2(7),3,5-triene-11-carboxylic acid methyl ester
(30). To a solution of ketone 29 (0.70 g, 1.39 mmol) in
methanol (20 mL) at 0 8C, was added NaBH4 (53 mg,
1.39 mmol); satd NH4Cl was added after 10 min and the
mixture was extracted with EtOAc; the organic layer was
washed by brine, dried over anhydrous Na2SO4, filtered and
concentrated, the resulting residue was purified by flash
column chromatography to give a white wax (642 mg)
(contaminated by inseparable material). To a suspension of
NaH (60%, 253 mg, 6.33 mmol) in dry THF (15.0 mL) at
0 8C, was added the solution of the above white wax in dry
THF (5 mL), CS2 (0.77 mL, 12.7 mmol) was added after
30 min. The mixture was warmed to rt and stirred for 60 min
before MeI (0.79 mL, 12.7 mmol) was added, then stirred
for another 2 h. Satd NH4Cl was added and the mixture was
extracted with ether. The organic layer was washed by
brine, dried over anhydrous Na2SO4, filtered and concen-
trated, the residue was purified by flash column chroma-
tography to give white wax (553 mg) and ketone 29
(154 mg), in 86% modified yield for two steps, and 78%
conversion for the first step.
1683, 1035, 875, 533 cmK1
.
4.1.22. 2,2-Dimethyl-propionic acid 2R-tert-butoxy-
carbonylamino-2R-[2-(2,2-dimethylpropionyloxy-
methyl)-6-methoxy-4-oxo-1R,2R,3,4-tetrahydro-
naphthalen-1-yl]-ethyl ester (28). To a solution of diol 27
(0.66 g, 1.80 mmol) in dry DCM (30 mL) at 0 8C was added
Et3N (2.50 mL, 18.0 mmol), DMAP (5 mg, 0.041 mmol)
and PivCl (1.80 mL, 14.5 mmol), then the mixture was
warmed to rt and stirred overnight. The reaction mixture
was diluted with DCM, washed by water and brine, dried
over anhydrous Na2SO4, filtered and concentrated; the
resulted residue was purified by flash column chromato-
graphy to give a pale yellow oil (0.74 g) in 76% yield.
[a]2D0ZC21.3 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
d 7.45 (s, 1H), 7.01 (m, 2H), 4.32–4.00 (m, 2H), 4.15–3.95
(m, 2H), 3.83 (d, JZ6.9 Hz, 2H), 3.77 (s, 3H), 3.00–2.90
(m, 2H), 2.70–2.62 (m, 1H), 2.49 (m, 1H), 1.25 (s, 9H), 1.15
(s, 9H), 1.05 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3): d
195.0, 177.7, 177.5, 158.7, 154.6, 133.4, 131.1, 131.0,
121.1, 109.2, 79.4, 66.4, 63.8, 59.8, 54.9, 53.1, 40.4, 38.3,
38.1, 36.2, 35.6, 27.6, 26.6, 26.5, 20.5, 13.6 ppm. ESIMS
(m/z, %): 556.3 (MCNa)C. IR (film): 3363, 2977, 1731,
1284, 1154, 1035, 877, 771, 537 cmK1. HR-ESIMS for
(C29H43NO8CNa)C. Calcd: 556.2886. Found: 556.2878.
To the solution of the above product (553 mg) in dry toluene
(30 mL), was added AIBN (30 mg, 0.19 mmol) and
n-Bu3SnH (0.50 mL, 1.86 mmol) under N2, the mixture
was refluxed for 3 h. Solvent was removed in vacuo and the
residue was purified by flash column chromatography
directly to give a white wax (450 mg) in 100% yield.
[a]2D0ZK4.50 (c 1.2, CHCl3). 1H NMR (300 MHz, CDCl3):
d 6.93 (d, JZ8.7 Hz, 1H), 6.68 (dd, JZ8.7, 2.7 Hz, 1H),
6.60 (d, JZ2.4 Hz, 1H), 4.37 (dd, JZ11.4, 5.7 Hz, 1H),
4.29 (dd, JZ11.4, 9.0 Hz, 1H), 4.20 (dd, JZ13.5, 3.0 Hz,
1H), 3.90 (dd, JZ11.1, 7.2 Hz, 1H), 3.81 (dd, JZ11.1,
8.1 Hz, 1H), 3.75 (s, 3H), 3.62 (m, 1H), 3.30–3.22 (m, 4H),
3.00 (s, 1H), 2.90–2.80 (m, 2H), 2.30 (m, 1H), 2.17 (m, 1H),
1.23 (s. 9H), 1.18 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3):
d 140.0, 138.0, 133.3, 130.3, 128.9, 128.5, 128.3, 127.3,
72.3, 60.8, 56.6, 55.2, 26.0, 22.4, 22.1, 20.6 ppm. EIMS
(m/z, %): 489 (MC, 2.17). IR (film): 2974, 1729, 1160,
4.1.23. (1R, 9S,12R, 13R)-12,13-Bis-(2,2-dimethylpropio-
nyloxymethyl)-5-methoxy-8-oxo-11-azatricyclo[7.3.1.02,
7]trideca-2(7),3,5-triene-11-carboxylic acid methyl ester
(29). To a solution of 28 (0.66 g, 1.24 mmol) in DCM
(10 mL), was added TFA (10 mL); after 2 h at rt, the
mixture was concentrated to a pale yellow oil. To the
solution of the above yellow oil in ethanol (30 mL), was
added HCHO (36%, 0.50 mL, 6.00 mmol) and the mixture
was refluxed for 2 h. The solvent was removed in vacuo and

4980
F. Liu et al. / Tetrahedron 61 (2005) 4971–4981
1037, 733, 454 cmK1. HR-MALDI for (C27H39NO7C
(300 MHz, CDCl3): d 7.45 (d, JZ2.8 Hz, 1H), 7.26 (d,
JZ8.5 Hz, 1H), 7.05 (dd, JZ8.5, 2.8 Hz, 1H), 4.35 (dd, JZ
12.3, 2.6 Hz, 1H), 4.25 (d, JZ3.7 Hz, 1H), 4.00 (s, 1H),
3.80 (s, 3H), 3.55 (s, 3H), 3.52 (s, 3H), 3.50–3.38 (m, 4H),
3.20–3.09 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): d
196.1, 171.4, 169.0, 159.7, 157.2, 133.1, 131.7, 131.0,
122.0, 108.7, 61.9, 55.4, 53.1, 52.5, 51.9, 48.0, 47.6, 42.8,
38.3 ppm. EIMS (m/z, %): 392 (MHC, 2.81), 391 (MC,
11.19), 332 [(MK89)C, 100]. IR (film): 2955, 1713, 1234,
1037 cmK1. HR-MALDI for (C19H21NO8CNa)C. Calcd:
414.1159. Found: 414.1112.
Na)C. Calcd: 512.2624. Found: 512.2604.
4.1.25. (1R,9S,12R,13S)-5-Methoxy-11-azatricyclo-
[7.3.1.02,7]trideca-2(7),3,5-triene-11,12,13-tricarboxylic
acid trimethyl ester (31). The procedure was the same as
the preparation of compound 34. From material 30
(125 mg), 31 (61 mg) was obtained in 3% yield for four
steps. [a]2D0ZC72.6 (c 1.4, CHCl3). H NMR (300 MHz,
1
CDCl3): d 7.02 (d, JZ8.5 Hz, 1H), 6.65 (dd, JZ8.5, 2.6 Hz,
1H), 6.55 (d, JZ2.5 Hz, 1H), 4.50 (d, JZ6.2 Hz, 1H), 4.00
(br s, 1H), 3.87 (d, JZ6.0 Hz, 1H), 3.80 (s, 3H), 3.67–3.50
(m, 9H), 3.45 (m, 1H), 3.05 (dd, JZ17.5, 5.0 Hz, 1H), 2.87
(m, 1H), 2.80 (m, 1H), 2.67 (d, JZ17.6 Hz, 1H) ppm. 13C
NMR (75 MHz, CDCl3): d 172.2, 170.2, 158.9, 135.7,
131.4, 125.4, 113.6, 112.3, 62.2, 55.1, 52.9, 52.0, 51.6, 42.7,
35.6, 31.8, 29.7, 28.2 ppm. EIMS (m/z, %): 378 (MHC,
3.41), 3.77 (MC, 20.30), 318 [(MK59)C, 100]. IR (film):
4.1.28. (1R,9S,12S,13R)5-Methoxy-8-oxo-11-azatricyclo-
[7.3.1.02,7]trideca-2(7),3,5-triene-11,12,13-tricarboxylic
acid trimethyl ester (36). The procedure was similar to the
preparation of compound 33. From material 34 (25 mg), 36
was obtained (20 mg) in 80% yield. (The physical data are
shown in the preparation of 35 and 36).
2954, 1734, 1709, 1257, 1198, 778, 531 cmK1
.
4.1.29. (1R,9S,12S,13S/R)-5-Methoxy-8-oxo-11-azatri-
cyclo[7.3.1.02,7]trideca-2(7),3,5-triene-11,12,13-tri-
carboxylic acid trimethyl ester [35(13S) and 36(13R)]. To
a solution of LDA (2.0 M in THF, 1.05 mL, 2.10 mmol) in
dry THF (5.0 mL) at K78 8C, was added HMPA (0.6 mL,
3.31 mmol), after 30 min the solution of ketone 34 (55 mg,
0.14 mmol) in THF (5.0 mL) was added dropwise. The
mixture was stirred at K78 8C for additional 30 min before
acetic acid (0.14 mL, 2.10 mmol) was added, then warmed
to rt and quenched by satd NH4Cl. The reaction mixture was
extracted by ether, the organic layer was washed by brine,
dried over anhydrous Na2SO4, filtered and concentrated, the
residue was purified by flash column chromatography to
give 35 as a colorless oil (20 mg) in 36% yield, and 36 as a
pale yellow oil (20 mg) in 36% yield. Date for 35: [a]2D0Z
C48.4 (c 0.3, CHCl3). 1H NMR (300 MHz, CDCl3): d 7.45
(m, 1H), 7.35 (m, 1H), 7.12 (m, 1H), 4.60 (s, 0.6H), 4.50 (s,
0.4H), 4.30–4.05 (m, 2H), 3.90–3.70 (m, 10H), 3.60–3.45
(m, 3H), 3.25–3.10 (m, 2H) ppm. 13C NMR (75 MHz,
CDCl3): d 198.5, 170.8, 170.7, 159.5, 157.1/156.5, 137.0,
133.4/133.2, 129.1/128.8, 123.0/122.8, 109.5/109.4, 58.0,
57.2, 55.6, 53.2/53.1, 52.5/52.4, 42.7, 42.1, 41.9/41.6, 37.4/
37.3 ppm. EIMS (m/z, %): 391 (MC, 1.57), [332 (MK59)C,
100]. ESIMS (m/z, %): 392.2 (MHC). IR (film): 2957, 1740,
1710, 1447, 1234, 1025, 778, 531 cmK1. HR-MALDI for
(C19H21NO8CNa)C. Calcd: 414.1159. Found: 414.1153.
Date for 36: [a]D20ZC36.3 (c 0.7, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.45 (m, 1H), 7.30 (m, 1H), 7.10 (m,
1H), 4.86 (d, JZ2.0 Hz, 0.7H), 4.72 (d, JZ2.0 Hz, 0.3H),
4.45 (dd, JZ13.4, 2.0 Hz, 0.3H), 4.35 (dd, JZ13.4, 3.1 Hz,
0.7H), 4.12–4.04 (m, 1H), 3.85–3.55 (m, 6H), 3.55–3.45 (m,
7H), 3.13–3.00 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): d
196.7/196.1, 171.8/171.7, 170.3, 159.5/159.4, 156.9/156.3,
133.5/133.3, 133.1, 129.7/129.4, 122.8, 108.9/108.8, 60.5/
59.8, 55.5, 53.2/53.1, 52.9, 52.4, 45.4/45.1, 44.1/44.0, 42.8/
42.7, 38.1 ppm. EIMS (m/z, %): 392 (MHC, 2.15), 391
(MC, 9.47), [332 (MK59)C, 100]. IR (film): 1739, 1224,
4.1.26. (1R,9S,12S,13S)5-Methoxy-11-azatricyclo-
[7.3.1.02,7]trideca-2(7),3,5-triene-11,12,13-tricarboxylic
acid trimethyl ester (33). To a solution of diester 31 (5 mg)
in methanol (5.0 mL) at rt, was added NaOMe (3 mg); sat.
NH4Cl was added after 10 min. The mixture was extracted
with EtOAc, the organic layer was washed by brine, dried
over anhydrous Na2SO4, filtered and concentrated, the
residue was purified by flash column chromatography to
give a colorless oil (5 mg) in 100% yield. [a]2D0ZC14.1 (c
1
0.4, CHCl3). H NMR (300 MHz, CDCl3): d 7.10 (m, 1H),
6.68 (m, 1H), 6.53 (m, 1H), 4.75 (d, JZ3.0 Hz, 0.5H), 4.61
(d, JZ2.1 Hz, 0.5H), 4.25 (dd, JZ13.5, 1.5 Hz, 0.5H), 4.10
(dd, JZ13.5, 1.5 Hz, 0.5H), 3.90 (d, JZ1.2 Hz, 0.5H), 3.86
(d, JZ1.2 Hz, 0.5H), 3.80 (s, 3H), 3.75 (s, 3H), 3.64–3.35
(m, 7H), 3.20 (m, 1H), 2.78–2.55 (m, 3H) ppm.
4.1.27. (1R,9S,12R,13R)-5-Methoxy-8-oxo-11-azatricyclo-
[7.3.1.02,7]trideca-2(7),3,5-triene-11,12,13-tricarboxylic
acid trimethyl ester (34). To a solution of ketone 29
(250 mg, 0.50 mmol) in dry DCM (20 mL) at K78 8C, was
added DIBAL-H (1.0 in cyclohexane, 7.5 mL, 7.5 mmol),
1 N HCl (20 mL) was added after 60 min. The mixture was
extracted with DCM, washed by brine, dried over anhydrous
Na2SO4, filtered and concentrated, the residue was used
directly. To a solution of the above residue in DCM
(20 mL), was added Dess–Martin Periodinane (2.50 g,
5.91 mmol), and the mixture was stirred at rt for 30 min
before sat. Na2S2O3 and sat. NaHCO3 were added. The
reaction mixture was extracted with DCM, the organic layer
was washed by brine, dried over Na2SO4, filtered and
t
concentrated to a residue which was redissoved in BuOH
(5.0 mL) and H2O (1.0 mL); to this solution was added
KH2PO4 (408 mg, 3.00 mmol), 2-methyl-2-butane
(0.85 mL, 8.00 mmol) and NaClO2 (543 mg, 6.00 mmol),
the mixture was stirred at rt for 60 min before sat. Na2S2O3
was added. The solvent was removed in vacuo, the residue
was redissoved in CHCl3 and dried over Na2SO4, filtered
and concentrated. The residue was redissolved in Et2O
(30 mL) and excess CH2N2 (in ether) was added at 0 8C, the
mixture was stirred at rt for 30 min and concentrated. The
residue was purified by flash column chromatography
directly to give a colorless oil (100 mg) in 50% yield for
four steps. [a]D20ZC51.2 (c 1.3, CHCl3). 1H NMR
1031, 771, 530 cmK1
.
4.1.30. (1R,9S,12S,13R)-5-Methoxy-11-azatricyclo-
[7.3.1.02,7]trideca-2(7),3,5-triene-11,12,13-tricarboxylic
acid trimethyl ester (32). To a solution of 35 (20 mg,
0.051 mmol) in dry CH2Cl2 (5.0 mL) at 0 8C, was added
BF3$Et2O (20 mL, 0.16 mmol) and 1,3-propanedithiol

F. Liu et al. / Tetrahedron 61 (2005) 4971–4981
4981
Y.; Beaujouan, J. C.; Glowinski, J.; Chassaing, G. J. Med.
Chem. 1994, 37, 1586–1601.
(40 mL, 0.40 mmol). After stirring at rt for 48 h, the reaction
was quenched with sat. NaHCO3 and the mixture was
extracted with CH2Cl2. The combined CH2Cl2 extracts were
washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash column chroma-
tography to give the sulfer-ketal as a colorless oil (20 mg).
To a solution of sulfer-ketal (20 mg) in EtOH (15 mL), was
added Raney-nickel (about 0.5 g). After 40 min, Raney-
Nickel was filtered through a pad of celite and the filtrate
was concentrated. The residue was redissoved in EtOAc and
washed with water and brine. The organic extracts were
dried over Na2SO4 and concentrated in vacuo. The residue
was purified by flash column chromatography to give a
colorless oil (14 mg) in 73% yield for two steps. [a]2D0Z
C3.13 (c 0.4, CHCl3). 1H NMR (300 MHz, CDCl3): d 7.17–
7.12 (m, 1H), 6.74–6.70 (m, 1H), 6.61 (s, 1H), 4.56 (s,
0.5H), 4.43 (s, 0.5H), 4.10 (m, 0.5H), 3.95–3.90 (m, 2H),
3.80–3.70 (m, 9.5H), 3.60–3.40 (m, 3H), 3.20 (m, 1H),
2.98–2.82 (m, 1H), 2.80 (s, 1H), 2.68 (m, 1H) ppm. 13C
NMR (75 MHz, CDCl3): d 172.6, 171.2/171.1, 158.6, 156.8,
137.3/136.9, 130.5, 128.9/128.6, 113.0, 112.6/112.1, 59.4,
59.0, 55.2, 52.9/52.8, 52.2/52.0, 45.2/44.9, 41.2/41.1, 36.9/
36.7, 35.2/35.1, 27.8/27.7 ppm. EIMS (m/z, %): 378 (MHC,
1.12), 377 (MC, 5.36), 318 [(MK59)C, 100]. ESIMS (m/z,
%): 400.10 (MCNa)C, 378.10 (MCH)C, 318 (MK59)C.
3. (a) Jiao, D.; Russell, K. C.; Hruby, V. J. Tetrahedron 1993, 49,
3511–3520. (b) Mosberg, H. I.; Lomize, A. L.; Wang, C. G.;
Kroona, H.; Heyl, D. L.; Sobczykkojiro, K.; Ma, W. L.;
Mousigian, C.; Porreca, F. J. Med. Chem. 1994, 37, 4371–4383.
(c) Obrecht, D.; Lehmann, C.; Ruffieux, R.; Schonholzer, P.;
Muller, K. Helv. Chim. Acta 1995, 78, 1567–1587.
4. (a) Birge, R. B.; Hanafusa, H. Science 1993, 262, 522. (b)
Tong, L.; Warren, T. C.; King, J.; Betageri, R.; Jakes, S.
J. Mol. Biol. 1996, 256, 601.
5. Wang, X.-Z.; Yao, Z.-J.; Liu, H.; Zhang, M.; Yang, D.;
George, C.; Burke, R. T., Jr. Tetrahedron 2003, 59, 6087.
6. Ye, B.; Yao, Z.; Burke, T. R., Jr. J. Org. Chem. 1997, 62, 5428.
7. Liu, F.; Jiao, J.; Zha, H.; Yao, Z. Chin. J. Chem. 2004, 22,
1022–1028.
8. Liu, F.; Zha, H-Y. ; Yao, Z.-J. J. Org. Chem. 2003, 68, 6679.
9. (a) Otsuka, M.; Masuda, T.; Haupt, A.; Masaji, O. J. Am.
Chem. Soc. 1990, 112, 838–845. (b) Acevedo, C. M.; Kogut,
E. F.; Lipton, M. A. Tetrahedron 2001, 57, 6353–6359.
10. Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry 1994, 3,
351–354.
11. Formation of the two-time Michael addition product:
IR (KBr film): 2956, 1741, 1706, 1226, 1120, 776, 530 cmK1
.
4.1.31. (1R,9S,12S,13R)-5-hydroxy-11-azatricyclo-
[7.3.1.02,7]trideca-2(7),3,5-triene-12,13-dicarboxylic
acid hydrochloride salt (3). Compound 32 (14 mg,
0.037 mmol) was refluxed with HCl (6 N, 10 mL) for 4
days. The mixture was concentrated in vacuo to give 3 and
epi-3 as a white solid (10 mg) in 85% yield. [a]2D0ZC30.5
1
(c 0.3, H2O). H NMR (300 MHz, CDCl3): d 7.00 (d, JZ
7.8 Hz, 0.6H), 6.80 (d, JZ8.1 Hz, 0.4H), 6.60–6.43 (m,
2H), 4.10 (m, 1H), 3.95–3.68 (m, 1.4H), 3.45 (d, JZ
12.6 Hz, 0.6H), 3.23–3.00 (m, 2H), 2.95–2.50 (m, 3H) ppm.
13C NMR (75 MHz, CDCl3): d 177.9, 177.4, 172.9, 172.1,
158.2, 157.8, 143.0, 140.5, 139.2, 133.3, 133.1, 129.3,
127.5, 117.9, 117.6, 116.8, 63.7, 60.3, 51.0, 49.2, 44.4, 41.6,
37.7, 37.5, 36.4, 32.0, 29.3, 28.9 ppm. ESIMS (m/z, %):
278.1 (MCH)C. IR (KBr): 3375, 3131, 1720, 1403, 1214,
824 cmK1. HR-ESIMS for (C14H15NO5CH)C. Calcd:
278.1028. Found: 278.1021.
12. If 8 was treated with TBAF, Boc immigration occurred in high
conversion.
Acknowledgements
This project is financially supported by NSFC (20425205
and 20321202), MOST of China (G2000077502) and
Chinese Academy of Sciences.
13. CCDC 264692 & 264693 contain the supplementary crystal-
lographic data for compounds 25 and 11, respectively, in this
paper. These data can be obtained free of charge via www.
ccdc.cam.ac.uk/data_request/cif, by emailing data_request@
ccdc.cam.ac.uk, or by contacting The Cambridge Crystal-
lographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: C44 1223 336033.
References and notes
14. The Wittig reagent was prepared by treating the corresponding
phosphonium salt with aq. NaOH solution. If the excess NaOH
was not washed off completely, the olefin product of the
Witting reaction maybe partly racemize because of the base.
1. Burke, T. R., Jr.; Barchi, J. J., Jr.; George, C.; Wolf, G.;
Shoelson, S. E.; Yan, X. J. Med. Chem. 1995, 38, 1386–1396.
2. Josien, H.; Lavielle, S.; Brunissen, A.; Saffroy, M.; Torrens,