Asymmetric syntheses of protected (2S,3S,4S)-3-hydroxy-4-methylproline and 4′-tert-butoxyamido-2′-deoxythymidine

Article abstract of DOI:10.1016/j.tetasy.2004.10.030

Described herein is a versatile approach to (i) (2S,3S,4S)-3-hydroxy-4- methylproline 3, a constituent of echinocandins and related oligopeptide antibiotics; (ii) (2S,3S)-3-hydroxyproline 1; (iii) (2R,3S)-3-hydroxyprolinol 5, and (iv) 4′-tert-butoxyamido-

Full text of DOI:10.1016/j.tetasy.2004.10.030

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3899–3910
Asymmetric syntheses of protected (2S,3S,4S)-3-hydroxy-4-
methylproline and 40-tert-butoxyamido-20-deoxythymidine
Wei-Hua Meng, Tian-Jun Wu, Hong-Kui Zhang and Pei-Qiang Huang*
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry
and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, PR China
Received 22 September 2004; accepted 20 October 2004
Abstract—Described herein is a versatile approach to (i) (2S,3S,4S)-3-hydroxy-4-methylproline 3, a constituent of echinocandins
and related oligopeptide antibiotics; (ii) (2S,3S)-3-hydroxyproline 1; (iii) (2R,3S)-3-hydroxyprolinol 5, and (iv) 40-tert-butoxyam-
ido-20-deoxythymidine 6b. The method features a stepwise regio- and diastereoselective reductive furylation of the protected
(3S,4S)-4-methylmalimide 10, (S)-malimide 9, and a chemoselective oxidative transformation of the furyl group to the carboxyl
group as the key steps.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
roxy-L-prolinol, 5), the reduced form of trans-3-
hydroxy-L-proline, is also a natural product isolated
from the seeds of the legume Castarospermum australe.10
Moreover, azanucleosides,11 such as 6a,12 have been
shown to stabilize antisense oligonucleotides toward
30-exonucleases.12a
3-Hydroxyproline and 3-hydroxyprolinol are found as
integrality or as sub-unities in a number of bioactive
natural products. For example, (2S,3S)-3-hydroxypro-
line 1 (trans-3-hydroxy-L-proline) is a nonproteinogenic
amino acid isolated both from hydrolyzates of Mediter-
ranean sponge1 and the seeds of Delonix regia.2,3 It is
also a component found in a number of bioactive natu-
ral peptides, such as mucrorin-D,4 tetomycin,5 and cyc-
lic peptide alkaloids;6 the dimethylated derivative of
3-hydroxyproline, namely 3-hydroxyproline betaines
(L-trans-3-hydroxystachydrine 27) was isolated from
Courbonia virgata;7a (2S,3S,4S)-3-hydroxy-4-methylpro-
line 3 (Hmp), another nonproteinogenic amino acid, is
present as a common structural moiety in a class of nat-
ural oligopeptide antibiotic (e.g., echinocandins 4) and
the pharmaceutically interesting analogues8 such as
LY303366 and FK-463. The latters are currently being
investigated in phase II/III clinical studies against Can-
dida and Aspergillums species. Hmp 3 is also a constitu-
ent found in nostopeptins,9 which are elastase inhibitors
isolated from the cultured freshwater Cyanobacterium
Nostoc minutum (CNIES-26); (2R,3S)-2-hydroxy-
methyl-3-hydroxypyrrolidine (CYB-3 or trans-3-hyd-
HO
OH
HO
Me R1
O
H
N
H
HO2C
N
HO
N
OH
O
(2S,3S)-1
H
O
HN
O
O
HO
HN
R2
H
N
O
R2
N
H
O2C
N
H3C
OH
CH
3
O
NH
Me
OH
(2S,3S)-2
HO
H
CH3
Echinocandins
B 4a, R1=R2=OH
C 4b, R1=H, R2=OH
D 4c, R1=R2=H
N
H
HO2C
(2S,3S,4S)-Hmp 3
HO
COR
N
Base
HO
H
N
OH
HO
6
H
*
(a. R = CH3, Base=thymine)
Corresponding author. Tel.: +86 592 218 0992; fax: +86 592 218
6400; e-mail: pqhuang@xmu.edu.cn
(2R,3S)-5
(b. R = t-BuO, Base=thymine)
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.10.030

3900
W.-H. Meng et al. / Tetrahedron: Asymmetry 15 (2004) 3899–3910
Different strategies have been developed for the synthe-
ses of (2S,3S)-3-hydroxyproline 1,13 (2S,3S,4S)-3-hyd-
verted (a: 7equiv AcCl, ꢀ47ꢁC, 1h; b: 1.5equiv
PMBNH2, ꢀ47ꢁC, 2h; c: 5equiv AcCl, ꢀ47ꢁC, 1h), in
one-pot23 and in an overall yield of 61%, to 14 as an
inseparable 9:1 (cis/trans) diastereomeric mixture as
indicated by its 1H NMR spectrum. Higher reaction
temperatures and prolonged reaction times led to epime-
rization at the C-4 stereogenic center. De-acetylation
(AcCl, EtOH, 0–rt, 30h, yield 95%) followed by recrys-
roxy-4-methylproline
3
(Hmp),14 (2R,3S)-3-hydro-
xyprolinol 5,13b,g,15 and azanucleosides 6.11,12,16 How-
ever, none of them has been used to synthesize different
kinds of above-mentioned 3-hydroxyprolines and 3-
hydroxyprolinols. We report herein a versatile approach
for the asymmetric syntheses of protected (2S,3S,4S)-3-
hydroxy-4-methylprolines 20 and 21,17 protected
(2S,3S)-3-hydroxyproline 23, protected (2R,3S)-3-hyd-
roxyprolinol 25, and azathymidine 6b.
tallization gave cis-15. O-Benzylation of cis-15 afforded
28
D
the desired imide 10 {½aŠ ¼ þ59:6 (c 1.0, CHCl3)} in
82% yield.
RO
CH3
O
1) AcCl
2) PMBNH2, CH2Cl2
HO
CH3
2. Results and discussion
RO2C
CO2R
O
N
3) AcCl
61%
We have long been interested in developing a synthetic
methodology based on the stepwise asymmetric reduc-
tive alkylation of the cyclic imides.18 An extension of this
strategy to the asymmetric synthesis of (2S,3S)-3-
hydroxyproline 1, (2S,3S,4S)-3-hydroxy-4-methylpro-
line 3 (Hmp), (2R,3S)-3-hydroxyprolinol 5, and azanu-
cleosides 6, would require a reductive carboxylation or
reductive hydroxymethylation of an appropriate mali-
mide. As 2-lithiofuran is a useful synthetic equivalent
to an unpoled carboxyl group,19 a simple retrosynthetic
analysis (Scheme 1) shows that 1, 3, and 5 could be de-
rived from 5-(fur-2-yl)-pyrrolidin-2-one 7 or 8, which
could in turn be prepared from the protected malimide
9 or 10 via a stepwise reductive furylation. 2-Pyrrolidi-
none 11, useful intermediate for the syntheses of prolinol
5 and azathymidine 6 could be derived either from 5-(fur-
2-yl)-pyrrolidin-2-one 7, or from the protected malimide
9 via a stepwise reductive hydroxymethylation. The key
questions resided on the feasibility of both the chemose-
lective oxidation of the 2-furyl group to the carboxyl
group with strong oxidative agent RuO4, while keeping
the easily oxidizable p-methoxybenzyl group (PMB)20 in-
tact, and the regioselective furylation or hydroxymethy-
lation at the C-2 carbonyl of the malimide 9 or 10.
PMB
12. R = Me
13. R = H
LiOH
MeOH/H2O
14. R = Ac
AcCl, EtOH (ds 9:1, mixture)
15. R = H
95%
BnO
CH3
O
(ds 9:1, mixture)
(only the major
diastereomer
was shown)
BnBr, Ag2O
O
N
Et2O
82%
PMB
10
Scheme 2.
For the addition of 2-lithiofuran to imide 10, the regio-
selectivity was the major concern.24–27 The regioselectiv-
ities in the addition of carbon nucleophiles to protected
(S)-N,O-diprotected malimides, such as 9,18a–f,h have
been shown to be dependent on the organonmetallic rea-
gents used: high regioselectivity at the C-2 carbonyl with
Grignard reagents,18a–g or lithium enolates,18h while
modest to high C-5 regioselectivities was obtained with
alkyllithiums,18g,27a organocerium reagents27a or
organotitanium reagents.27b It was envisioned that 2-
lithiofuran, being less active than alkyllithiums, would
behave like Grignard reagents and react with imide 10
with C-2 regioselectivity. In this event, treatment of
the imide 10 with 2-lithiofuran, which was generated
in situ from furan and n-BuLi at ꢁ78ꢁC, yielded the de-
sired diastereomeric C-2 adduct 16 in 79% yield. The
yield was improved to 90% by using an inverse addition
procedure. Attribution of the C-2 addition instead of the
C-5 addition during the transformation of 10 to 16 was
made based on the observed H-3 resonance appearing at
2.92ppm of the 1H NMR spectrum of 8, which was later
confirmed by conversion of 8 to the known compound
21. The diastereomeric mixture 16 was then treated with
boron trifluoride etherate and triethylsilane28 (ꢁ78ꢁC,
8h, then rt, 8h) (Scheme 3) to give, via a presumed N-
acyliminium intermediate,29 diastereomers 8 and 8a in
3:1 ratio and in a combined yield of 91%. The stereo-
chemistries of the lactams 8 and 8a were assigned based
on the observed characteristic vicinal coupling con-
BnO
H
R
HO
HO2C
R
O
N
N
H
O
PMB
BnO
O
R
7. R=H
1. R=H
8. R=Me
3. R=Me
O
N
HO
PMB
BnO
9. R=H
H
N
R
10. R=Me
H
HO
O
N
H
P
HO
5. R = H, P = H
11
6. R = Base, P = COR'
Scheme 1.
stants18,30 (J4,5 = 2.0Hz for trans-isomer
8
and
Our first target was (2S,3S,4S)-3-hydroxy-4-methylpro-
line 3. The synthesis started with (2S,3S)-3-methylmalic
acid 13,21 easily available from the known (2S,3S)-3-
methylmalate 1222 (as a 10:1 diastereomeric mixture)
by saponification (Scheme 2). Compound 13 was con-
J4,5 = 6.3Hz for cis-diastereomer 8a), and were further
confirmed by converting 8 to the known 21.
Compared with previous results where the reductive
alkylation of 9 led to at least 94:6 trans/cis diastereo-

W.-H. Meng et al. / Tetrahedron: Asymmetry 15 (2004) 3899–3910
3901
BnO
CH3
O
BnO
H
CH3
O
BnO
H
CH3
BnO
O
CH3
O
furan, n-BuLi
THF, -78 oC
H3B SMe2
O
N
N
N
THF, rt~60oC
65%
N
H3CO2C
H3CO2C
HO
PMB
PMB
PMB
PMB
10
18
19
16
BnO
CH3
O
PO
CH3
BnO
CH3
O
Pd(OH)2/C, H2
EtOH, (Boc)2O
Et3SiH, F3B·OEt2
H
H
N
CH2Cl2, -78 o
91%
C
+
12 h. 85% (to 20)
36 h. 85% (to 21)
O
N
N
H3CO2C
H
PMB
Boc-t
PMB
O
(trans:cis = 3:1)
20. P = Bn
8a
8
21. P = H
Scheme 3.
Scheme 6.
selectivities,18a–f,h lower diastereoselectivity during the
reductive deoxygenation of 16 may be due to the
presence of the cis-methyl group in 16.18a–f,h To confirm
this assumption, reductive n-pentanylation of 10 was
performed, and indeed, only a 6:1 trans/cis diastereo-
selectivity was observed (Scheme 4). Further evidence
was gained by performing the reductive furylation
of 9 (vide infra).
alyst and (Boc)2O [Pd(OH)2, H2, 1atm, (Boc)2O, EtOH,
rt, 12h] afforded the protected Hmp 20 in 85% yield
(Scheme 4). If the catalytic hydrogenolysis was per-
formed under prolonged reaction time (36h), the known
25
D
(2S,3S,4S)-N-Boc-Hmp-OMe 21: {½aŠ ¼ ꢁ23:4 (c 0.8,
25
CHCl3); lit.14a ½aŠ ¼ ꢁ24:2 (c 1.1, CHCl3)}, a com-
D
pound which has been used in the total synthesis of
echinocandin D,14a was obtained in 85% yield.
Next, we addressed the synthesis of protected 3-hydroxy-
proline13 23. Thus, the known imide 918a,f,h was treated,
at ꢁ78ꢁC, with a 0.25M THF solution of 2-lithiofuran,
which was generated from furan and n-BuLi, and the
reaction was quenched after stirring for 20min at
ꢁ78ꢁC. In this way, the desired adduct was obtained
in 78% yield alongside 5% of the C-5 regioisomer. It is
noteworthy that a higher concentration of 2-lithiofuran
and higher reaction temperature should be avoided to
prevent the ring opening side reaction. The diastereo-
meric adducts were then treated with boron trifluoride
etherate and triethylsilane (ꢁ78ꢁC, 8h, then rt, 8h) to
give trans-lactam 7 (J4,5 = 2.1Hz) as the only isolable
diastereomer (70% overall yield from 9) (Scheme 7). This
result implicates that the diastereoselectivity during the
reductive deoxygenation is at least 95%. The high
diastereoselectivity observed in the reductive furylation
of 9 further confirms the assumption (vide supra) that
the methyl groups present in 10 (and thus 16) are
BnO
H
CH3
O
1) n-C5H11MgBr, THF
10
2) Et3SiH, F3B OEt2
N
CH2Cl2, -78 o
C
n-C5H11
PMB
trans : cis = 6 : 1
90%
Scheme 4.
With compound 8 in hand, the chemoselective unmask-
ing of the 2-furyl group to the carboxyl group was
undertaken. Treatment of 8 with RuO4, in situ gener-
ated from a RuCl3ÆxH2O–NaIO4 system in a mixed sol-
vent system (H2O–MeCN–CCl4, 3:3:2)19 at rt led, after
esterification (CH2N2, Et2O–THF, 0ꢁC) of the crude
acid, to the desired methyl ester 18 in 56% yield over
two steps (Scheme 5). To improve the yield of the chemo-
selective oxidation of 8, the oxidation of 8 was con-
ducted at 0–5ꢁC, and the overall yield from 8 to 18
was improved to 70–78%. Thus remarkable chemoselec-
tivity was achieved during the oxidative cleavage of the
furan ring.
BnO
H
BnO
O
furan, n-BuLi
THF, -78 oC;
BnO
H
CH3
O
BnO
H
CH3
O
Et3SiH, F3B OEt2
O
O
NaIO4, RuCl3· xH2O
CH3CN-H2O-CCl4
CH2N2, Et2O, rt
75%
N
PMB
7
N
PMB
CH2Cl2, -78 oC
N
RO2C
N
O
70%
PMB
PMB
9
O
17. R = H
18. R = CH3
BnO
8
1) NaIO4, RuCl3 xH2O
CH3CN-H2O-CCl4
H
O
N
PMB
22
Scheme 5.
H3CO2C
2) CH2N2
70-78%
BnO
Chemoselective reduction of the amide carbonyl to
methylene in the presence of an ester group31 was
achieved by treatment of 18 with BH3ÆSMe2, which pro-
vided the desired fully protected Hmp 19 in 65% yield
(Scheme 6). Finally, chemoselective N-de-(p-meth-
oxybenzylation) in the presence of both Pearlmanꢀs cat-
H
H3B SMe2
N
PMB
23
H3CO2C
THF, rt
65%
Scheme 7.

3902
W.-H. Meng et al. / Tetrahedron: Asymmetry 15 (2004) 3899–3910
responsible for the lower diastereoselectivity in the
reductive deoxygenation of 16.
CH2Cl2, rt) gave acetate 29 as a 1:1 diastereomeric mix-
ture in a combined yield of 90%. It is noteworthy that
diastereomeric acetates 29 were unstable and decom-
posed to the starting material during routine flash chro-
matography purification. However, when the flash
chromatography was performed on a short pad of silica
gel and pre-cooled eluent was used, the desired acetates
29 can be obtained in high yield.
Oxidation of 7 (RuCl3ÆxH2O–NaIO4, 0 –5ꢁC) followed
by esterification (CH2N2, Et2O, 0ꢁC) gave the desired
methyl ester 22 in yields ranging from 70% to 78%. Sub-
sequent chemoselective reduction of the amide carbonyl
group in 22 with borane dimethyl sulfide at rt furnished
the desired protected (2S,3S)-3-hydroxyproline 23 in
65% yield.
Installation of the thyminyl group was achieved using
the Hilbert–Johnson protocol.12a,34 Thus, treatment of
29 with SnCl4 in the presence of freshly prepared
(TMS)2–thymine at ꢁ25ꢁC for 1h gave a separable mix-
ture of diastereomers 30/31 in 1:1.8 ratio and in a com-
bined yield of 87% (Scheme 10). The two diastereomers
were separated by careful flash chromatography on sil-
ica gel. The identities of 30 and 31 were determined by
means of COSY and NOESY. We observed strong
NOEs between H-10 and H-20a in 30, while no NOEs
between H-10 and H-20b clearly indicate that the thymi-
nyl group is disposed in the b-face, and thus is in cis rela-
tionship with the C-40 benzyloxymethyl group. This was
confirmed by the observed strong NOEs between H-10
and H-20b of the diastereomer 31, and small NOEs
between H-10 and H-20a. Thus, in 31, the C-10 thyminyl
group and C-40 substituent are in a trans disposition.
For the synthesis of protected (2R,3S)-3-hydroxyproli-
nol 25 and azanucleoside 6b, because the attempted
direct reductive benzyloxymethylation (BnOCH2MgCl,
HgCl2 (cat.);32 Et3SiH, F3BÆOEt2) of 9 gave a disap-
pointing 1:1 regioisomeric ratio and 20–25% overall
yield, we then turned attention to their synthesis from
22. Thus, treatment of 22 with an excess of sodium
borohydride in the presence of anhydrous calcium chlo-
ride33 in EtOH–THF system gave the desired partially
reduced product 11 in 94% yield (Scheme 8). Protection
of the hydroxyl group (NaH, BnBr, THF, ꢁ20ꢁC, 28h)
afforded 24 in 84% yield. Treatment of 24 with an excess
of borane dimethyl sulfide in THF gave the protected
(2R,3S)-3-hydroxyprolinol 25 in 88% yield.
BnO
BnO
O
NaBH4, CaCl2
H
H
NH
O
N
PMB
22
O
H3CO2C
EtOH-THF
94%
N
PMB
11
Boc-t
N
RO
1) (TMS)2-thymine
N
O
OH
SnCl4, CH3CN
-25 oC; rt, 1 h
87%
H
BnO
BnO
29
OR
30. R = Bn
6b. R = H
H3B ·SMe2
+
2) H2, 10%Pd/C
NaH, THF H
H
O
THF, 60 oC
88%
EtOH, rt, 9 h
RO
Boc-t
N
N
PMB
N
PMB
BnBr, rt
84%
85%
H
OBn
OBn
25
24
N
O
OR
NH
Scheme 8.
31. R = Bn
6c. R = H
O
Scheme 10.
In pursuing the synthesis of azathymidine, 24 was first
converted to 27 by N-deprotection (CAN, rt, yield:
84%) and N-activation [(t-Boc)2O, DMAP, MeCN,
yield: 95%] (Scheme 9). Partial reduction of the C-2 car-
bonyl of 27 (DIBAL-H, CH2Cl2, ꢁ78ꢁC, 30min, yield:
99%) followed by acetylation (AcCl, Et3N, DMAP,
Finally, a controlled catalytic hydrogenation (H2, 10 %
Pd/C, EtOH, rt, 9h) of 30 furnished 6b in 85% yield.
Similarly, chemoselective catalytic hydrogenation of 31
furnished 6c in 85% yield.
BnO
H
BnO
H
3. Conclusion
CAN
(Boc)2O
O
O
In summary, a versatile approach to the protected
(2S,3S)-3-hydroxyproline 23, (2S,3S,4S)-3-hydroxy-4-
methylproline 21 (Hmp), (2R,3S)-3-hydroxyprolinol
25, and azathymidines 6b was developed via a stepwise
regio- and diastereoselective reductive furylation of the
protected (3S,4S)-4-methylmalimide 10 and (S)-mal-
imide 9. The choice of the furyl group as the masked
carboxyl group allowed the successful chemoselective
unmasking of the former in the presence of the N-(p-
methoxybenzyl) group, which constituted as the second
key step of the synthesis.
N
PMB
N
H
CH3CN-H2O
84%
CH3CN
95%
OBn
OBn
24
26
BnO
H
BnO
H
DIBAL-H
CH2Cl2, -78oC
99%
OR
N
Boc-t
Ac2O, DMAP
CH2Cl2, Et3N
O
N
Boc-t
OBn
OBn
27
28. R = H
29. R = Ac
Scheme 9.

W.-H. Meng et al. / Tetrahedron: Asymmetry 15 (2004) 3899–3910
3903
4. Experimental
4.3. (3S,4S)-3-Benzyloxy-1-(4-methoxybenzyl)-4-methyl-
pyrrolidin-2,5-dione 10
The general information is described in Ref. 18f.
To a solution of diastereomeric 15 (ratio 9:1) (2.37g,
9.54mmol) in 50mL of diethyl ether were added benzyl
bromide (3.4mL, 28.60mmol) and silver oxide (6.64g,
28.60mmol). After being stirred in the dark for 7days
at rt, the mixture was filtered through Celite and concen-
trated in vacuo. Flash chromatography (EtOAc–
4.1. Acetic acid (3S,4S)-1-(4-methoxybenzyl)-4-methyl-
2,5-dioxo-pyrrolidin-3-yl ester 14
A mixture of (2S,3S)-3-methylmalic acid 1322 (7.50g,
50.67mmol) and acetyl chloride (26.0mL, 0.36mol)
was refluxed for 1.5h and then concentrated in vacuo.
The crude anhydride was dissolved in CH2Cl2 (30mL),
to which was added a solution of 4-methoxybenzyl-
amine (10.6mL, 76.01mmol) in CH2Cl2 (24.0mL). The
resultant mixture was stirred at 47ꢁC for 2h, and then
concentrated in vacuo. The residue was dissolved in
acetyl chloride (18mL, 0.25mol) and refluxed for 1.5h.
After concentration of the reaction mixture in vacuo,
the residue was purified by flash chromatography
(EtOAc–PE = 1:3) to give cis-14 and its diastereomer
as an inseparable diastereomeric mixture (ratio 9:1)
(8.99g, combined yield 61%). A sample of pure cis-14
PE = 1:4) of the residue afforded 10 (2.65g, 82% yield)
28
D
as a colorless oil. ½aŠ ¼ þ59:6 (c 1.0, CHCl3). IR (film):
m = 2937, 1708, 1611, 1520, 1389, 1341, 1301, 1249, 1179,
1030cmꢁ1 1H NMR (500MHz, CDCl3): d = 1.27 (d,
.
J = 7.7Hz, 3H, CH3), 2.77 (dq, J = 7.8, 7.7Hz, 1H, H-
4), 3.77 (s, 3H, OCH3), 4.26 (d, J = 7.8Hz, 1H, H-3),
4.57 (d, J = 14.5Hz, 1H, NCH2Ar), 4.60(d,
J = 14.5Hz, 1H, NCH2Ar), 4.78 (d, J = 12.0Hz, 1H,
OCH2Ph), 4.98 (d, J = 12.0Hz, 1H, OCH2Ph), 6.82 (d,
J = 8.5Hz, 2H, Ar), 7.32–7.38 (m, 7H, Ar) ppm. 13C
NMR (125MHz, CDCl3): d = 10.0, 39.6, 41.5, 55.1,
73.0, 73.7, 114.0, 127.7, 127.8, 128.0, 128.4, 130.1,
136.9, 159.2, 175.6, 178.1ppm. ESI-MS: m/z (%) = 340
(7) (M+Na+), 300 (100). Elementary analysis calcd for
C20H21NO4: C, 70.79; H, 6.19; N, 4.13. Found: C,
70.63; H, 6.26; N, 4.40.
was obtained by deacetylation of diastereomeric pure
28
D
cis-15 (vide infra). cis-14: colorless oil. ½aŠ ¼ ꢁ2:0 (c
1.0, CHCl3). IR (NaCl): m = 2925, 1749, 1711, 1651,
1612, 1512, 1432, 1399, 1244, 1220, 1174, 1097,
1025cmꢁ1 1H NMR (500MHz, CDCl3): d = 1.16 [d,
.
J = 7.7Hz, 3H, C(4)–CH3], 2.18 (s, 3H, CO2CH3), 3.13
4.4. (3S,4S,5S)-4-Benzyloxy-5-(fur-2-yl)-1-(4-methoxy
benzyl)-3-methylpyrrolidin-2-one 8
[dq, J = 8.2, 7.7Hz, 1H, C(4)–H], 3.80(s, 3H, OCH ),
3
5.6 [d, J = 8.2Hz, 1H, C(3)–H], 4.61 (d, J = 14.2Hz,
1H, NCH2Ar), 4.62 (d, J = 14.2Hz, 1H, NCH2Ar),
6.82 (d, J = 8.5Hz, 2H, Ar), 7.35 (d, J = 8.5Hz, 2H,
Ar) ppm. 13C NMR (125MHz, CDCl3): d = 10.6, 20.3,
38.9, 42.0, 55.2, 69.0, 114.0, 127.4, 130.3, 159.4, 169.8,
173.0, 177.2ppm. ESI-MS: m/z (%) = 274 (100), 314
(49) (M+Na+). Elemental analysis calcd for
C15H17NO5: C, 61.86; H, 5.84; N, 4.81. Found: C,
62.06; H, 6.03; N, 5.04.
To a well-stirred cooled solution (ꢁ78ꢁC) of furan
(0.64g, 9.48mmol) in anhydrous THF (13mL), was
added, under argon, n-butyllithium (1.9mL, 4.74mmol,
2.5M solution in hexane). The solution was stirred at
0ꢁC for 2h. To a cooled (ꢁ78ꢁC) solution of 10
(1.07g, 3.16mmol) in anhydrous THF (43mL) was
added dropwise 2-lithiofuran (15mL, 4.47mmol, 0.3M
solution in THF). After being stirred for 20min at the
same temperature, the reaction was quenched with a sat-
urated aqueous solution of NH4Cl (14mL). The mixture
was warmed to rt and diluted with Et2O (14mL). The
organic layer was separated and the aqueous layer
extracted with Et2O three times. The combined organic
extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The crude was puri-
fied by column chromatography using ethyl acetate–
petroleum ether (1:3) as an eluent to yield a diastereo-
meric mixture of 16 (1.22g, yield 95%), which was used
in the next step without separation.
4.2. (3S,4S)-3-Hydroxy-1-(4-methoxybenzyl)-4-methyl-
pyrrolidin-2,5-dione 15
To a solution of diastereomeric 14 (3.08g, 10.58mmol)
in 65mL of absolute ethanol was added dropwise AcCl
(2.3mL, 31.5mmol) at 0ꢁC. The mixture was stirred at
rt for 30h and concentrated in vacuo. Flash chromato-
graphy (EtOAc–PE = 1:2) of the residue afforded cis-
15 and its diastereomer (ratio 9:1) as an inseparable
diastereomeric mixture (white crystals, 2.50g, combined
yield 95%). A sample of the pure cis-diastereomer 15
was obtained after recrystallization. cis-Diastereomer
To a cooled (ꢁ78ꢁC) solution of the diastereomeric mix-
ture of 16 (1.22g, 3.00mmol) in dry CH2Cl2 (30mL) was
added successively triethylsilane (4.74mL, 30.0mmol)
and boron trifluoride etherate (1.3mL, 10.51mmol)
under argon. After being stirred at ꢁ78ꢁC for 8h, the
reaction was allowed to warm up and the stirring contin-
ued at rt for 8h. The reaction was quenched by saturated
aqueous NaHCO3 (4mL) and extracted with CH2Cl2
for three times. The combined extracts were dried over
Na2SO4, filtered, and concentrated in vacuo. The crude
was flash chromatographed (EtOAc–PE = 1:4–1:2) to
give trans-diastereomer 8 (0.80g, 68%, colorless oil)
28
D
15: Mp 56ꢁC (EtOAc/PE). ½aŠ ¼ ꢁ45:5 (c 1.0, CHCl3).
IR (KBr): m = 3450, 2980, 2920, 1610, 1612, 1513, 1434,
1344, 1248, 1178, 1142cmꢁ1 1H NMR (500MHz,
.
CDCl3): d = 1.25 [d, J = 7.7Hz, 3H, C(4)–CH3], 1.80
(s, 1H, OH), 3.03 [dq, J = 8.3, 7.7Hz, 1H, C(4)–H],
3.80(s, 3H, OCH ), 4.57 [d, J = 8.3Hz, 1H, C(3)–H],
3
4.58 (s, 2H, NCH2 Ar), 6.82 (d, J = 8.5Hz, 2H, Ar),
7.35 (d, J = 8.5Hz, 2H, Ar) ppm. 13C NMR
(125MHz, CDCl3): d = 10.3, 40.9, 41.7, 55.2, 68.5,
114.0, 127.6, 130.1, 159.3, 178.1, 178.3ppm. ESI-MS:
m/z (%) = 250 (100) (M+H+). Elemental analysis calcd
for C13H15NO4: C, 62.65; H, 6.02; N, 5.62. Found: C,
62.93; H, 6.04; N, 5.85.
and cis-diastereomer 8a (0.27g, 23%, white crys-
28
D
tals). trans-Diastereomer 8: ½aŠ ¼ þ31:3 (c 1.2, CHCl3).

3904
W.-H. Meng et al. / Tetrahedron: Asymmetry 15 (2004) 3899–3910
IR (film): m = 2933, 1694, 1611, 15121 1451, 1415, 1246,
(6mL). The solvent was evaporated under reduced pres-
sure. To the resulting residue were added successively
EtOAc (8mL) and H2O (6mL). The resulting solution
was stirred at 60ꢁC for 2h before being extracted with
Et2O (5mL). The combined extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated in
vacuo. Flash chromatography of the residue using ethyl
1
1069, 1031cmꢁ1. H NMR (500MHz, CDCl3): d = 1.27
[d, J = 7.3Hz, 3H, C(3)–CH3], 2.92 [qd, J = 7.3, 6.1Hz,
1H, C(3)–H], 3.61 (d, J = 15.0Hz, 1H, NCH2Ar), 3.78
(s, 3H, OCH3), 4.10[dd, J = 6.1, 2.0Hz, 1H, C(4)–H],
4.41 [d, J = 2.0Hz, 1H, C(5)–H], 4.45 (d, J = 12.0Hz,
1H, OCH2Ph), 4.51 (d, J = 12.0Hz, 1H, OCH2Ph), 5.07
(d, J = 15.0Hz, 1H, NCH2Ar), 6.14 [d, J = 3.2Hz, 1H,
C(30)–H], 6.33 [dd, J = 3.2, 1.8Hz, 1H, C(40)–H], 6.82
(d, J = 8.8Hz, 2H, Ar), 7.11 (d, J = 8.4Hz, 2H, Ar),
7.19 [d, 1H, J = 1.8Hz, C(50)–H], 7.26–7.38 (m, 5H, Ar)
ppm. 13C NMR (125MHz, CDCl3): d = 9.0, 40.0, 43.7,
55.2, 71.8, 75.4, 79.0, 108.3, 110.4, 113.9, 127.4, 127.7,
128.1, 128.3, 129.3, 137.6, 142.9, 150.6, 159.0ppm. ESI-
MS: m/z (%) = 392 (100) (M+H+), 414 (4) (M+Na+). Ele-
mental analysis calcd for C24H25NO4: C, 73.66; H, 6.39;
N, 3.58. Found: C, 73.68; H, 6.30; N, 3.56.
acetate–petroleum ether (1:3.5) as an eluent afforded 19
23
D
(55mg, 65%) as a colorless oil. ½aŠ ¼ ꢁ54:9 (c 0.9,
CHCl3). IR (film): m = 2960, 2921, 1737, 1613, 1510,
1455, 1259, 1093, 1028cmꢁ1 1H NMR (500MHz,
.
CDCl3): d = 1.09 [d, J = 6.6Hz, 3H, C(4)–CH3], 2.35–
2.41 [m, 1H, C(4)–H], 2.45 [dd, J = 11.0, 8.0Hz, 1H,
C(5)–H], 3.11 [dd, J = 11.0, 6.0Hz, 1H, C(5)–H], 3.45
[d, J = 2.3Hz, 1H, C(2)–H], 3.67 (s, 3H, CH3O), 3.69
(d, J = 12.6Hz, 1H, NCH2Ar), 3.82 (d, J = 12.6Hz,
1H, NCH2Ar), 3.83 (s, 3H, CO2CH3), 3.96 [dd,
J = 5.8, 2.3Hz, 1H, C(3)–H], 4.51 (d, J = 11.9Hz, 1H,
OCH2Ph), 4.69 (d, J = 11.9Hz, 1H, OCH2Ph), 6.82
(d, J = 8.5Hz, 2H, Ar), 7.20–7.39 (m, 7H, Ar) ppm.
13C NMR (125MHz, CDCl3): d = 11.2, 37.2, 44.8,
52.0, 55.2, 59.0, 59.1, 71.2, 72.5, 84.2, 113.5, 127.6,
128.3, 130.2, 130.4, 138.2, 158.7, 173.5ppm. ESI-MS:
m/z (%) = 370 (100) (M+H+). ESI-HRMS: calcd for
[C22H27NO4+H+]: 370.2013; found: 370.2013.
4.5. (3S,4S,5S)-4-Benzyloxy-1-(4-methoxybenzyl)-3-
methyl-2-oxo-proline methyl ester 18
To a solution of NaIO4 (4.31g, 20.16mmol) in a mixed
solvent system H2O–CH3CN–CCl4 (3:3:2, v/v/v, 73mL)
was added an aqueous solution of RuCl3ÆxH2O
(2.24mL, 0.11mmol, 0.05M). After being stirred for
20min at 0 ꢁC, a solution of furanoid derivative 8
(0.95g, 2.24mmol) in CH3CN (24.2mL) was added.
The color of the solution turned instantaneously from
light yellow-green to black. After 10min, the mixture
was diluted with water (40mL) and extracted with
EtOAc (5 · 20mL). The combined organic extracts were
washed successively with saturated aqueous NaHSO3
and brine, dried over Na2SO4, filtered, and concentrated
in vacuo. The crude acid was dissolved in Et2O–THF
(2:1 v/v) and treated with an ethereal solution of diazo-
methane (0.56M, 24mL) at 0ꢁC. Flash chromatography
(EtOAc/PE = 1:2.5) of the residue afforded ester 18
4.7. (2S,3S,4S)-3-Benzyloxy-1-(tert-butoxycarbonyl)-4-
methylproline methyl ester 20
A suspension of 19 (44mg, 0.12mmol), 20% Pd(OH)2/C
(13mg), and (Boc)2O (0.1mL, 0.9mmol) in 4mL of 95%
ethanol was stirred under an atmosphere of hydrogen
for 12h. The mixture was filtered through Celite and
the filtrate evaporated in vacuo. Flash chromatography
(EtOAc–PE = 1:4.5) of the residue afforded 20 (26mg,
17
D
85%) as a colorless oil. ½aŠ ¼ ꢁ26:7 (c 0.9, CHCl3).
IR (film): m = 2967, 1746, 1711, 1612, 1511, 1452, 1357,
1
(0.64g, 75%) as a white solid. Mp 87ꢁC (EtOAc–PE).
1250cmꢁ1. H NMR (500MHz, CDCl3, two rotamers):
28
½aŠ ¼ þ17:1 (c 1.0, CHCl3). IR (film): m = 2934, 1711,
d = 1.11, 1.12 [two rotamers, each d, J = 6.8, 6.9Hz, 3H,
C(4)–CH3], 1.44, 1.49 (each s, 9H, Boc), 2.35–2.45
[m, 1H, C(4)–H], 3.18, 3.22 [each dd, J = 10.1, 9.8Hz,
1H, C(5)–H], 3.70[dd, J = 8.2, 10.1Hz, 0.5H, C(5)–H,
rotamer 1], 3.74 [dd, J = 10.1, 8.2Hz, 0.5H, overlapped
with CO2CH3, C(5)–H, rotamer 2], 3.75, 3.76 [each s,
3H, overlapped with H–5, CO2CH3], 3.88, 3.91 [each
dd, J = 1.1, 4.5Hz, 1H, C(3)–H], 4.38 [d, J = 1.1Hz,
0.5H, C(2)–H, rotamer 1], 4.51 [s, 0.5H, C(2)–H, rota-
mer 2], 4.54, 4.56 (each d, J = 11.4Hz, 1H, OCH2Ph),
4.76, 4.78 (each d, J = 11.4Hz, 1H, OCH2Ph), 7.28–
7.40(m, 5H, Ph) ppm. 13C NMR (125MHz, CDCl3,
two rotamers): d = 11.0, 11.1, 28.2, 28.4, 29.7, 35.8,
36.7, 50.9, 51.4, 52.1, 52.3, 64.2, 64.7, 71.2, 71.3, 79.9,
82.6, 83.3, 127.5, 127.7, 127.8, 128.4, 137.6, 154.6,
153.7, 171.6, 171.3ppm. ESI-MS: m/z (%) = 274
D
1696, 1611, 1512, 1450, 1413, 1360, 1247, 1177, 1069,
1032cmꢁ1 1H NMR (500MHz, CDCl3): d = 1.26 [d,
.
J = 7.3Hz, 3H, C(3)–CH3], 2.70[qd, J = 7.3, 5.8Hz,
1H, C(3)–H], 3.68 (s, 3H, CO2CH3), 3.78 (s, 3H,
OCH3), 3.98 (d, J = 15.0Hz, 1H, NCH2Ar), 4.00 [s,
1H, C(5)–H], 4.09 [d, J = 5.8Hz, 1H, C(4)–H], 4.43 (d,
J = 11.9Hz, 1H, OCH2Ph), 4.54 (d, J = 11.9Hz, 1H,
OCH2Ar), 5.02 (d, J = 15.0Hz, 1H, NCH2Ar), 6.82 (d,
J = 8.4Hz, 2H, Ar), 7.11 (d, J = 8.4Hz, 2H, Ar), 7.20–
7.38 (m, 5H, Ar) ppm. 13C NMR (125MHz, CDCl3):
d = 8.6, 40.3, 44.8, 52.4, 55.1, 62.7, 71.1, 73.7, 114.0,
127.7, 127.8, 128.4, 130.1, 136.9, 159.0, 170.2,
175.5ppm. ESI-MS: m/z (%) = 384 (100) (M+H+), 404
(5) (M+Na+). ESI-HRMS: calcd for [C22H25NO5+H+]:
384.1805; found: 384.1810.
(100)
(M–But–H2O+).
ESI-HRMS:
calcd
for
4.6. (2S,3S,4S)-3-Benzyloxy-1-(4-methoxybenzyl)-4-
methylproline methyl ester 19
[C12H21NO5+H+]: 350.1967; found: 350.1964.
4.8. (2S,3S,4S)-1-(tert-Butoxycarbonyl)-3-hydroxy-4-
methylproline methyl ester 21
To a solution of 18 (90mg, 0.23mmol) in anhydrous
THF (4.6mL) was added BH3ÆSMe2 (0.2mL, 2.1mmol)
at 0ꢁC. The resulting mixture was stirred at 15ꢁC for
1.5days. The solution was re-cooled to ꢁ10ꢁC, diluted
with EtOAc (8mL), and then quenched by MeOH
A suspension of 19 (44mg, 0.12mmol), 20% Pd(OH)2/C
(13mg), and (Boc)2O (0.09mL, 0.9mmol) in 4mL of
95% ethanol was stirred under an atmosphere of hydro-

W.-H. Meng et al. / Tetrahedron: Asymmetry 15 (2004) 3899–3910
3905
gen for 36h. The mixture was filtered through Celite and
the filtrate evaporated in vacuo. Flash chromatography
(EtOAc–PE = 1:3) of the residue afforded 21 (26mg,
7.19 [d, J = 1.8Hz, 1H, C(50)–H], 7.23–7.35 (m, 5H,
Ar) ppm. 13C NMR (125MHz, CDCl3): d = 37.5, 43.5,
55.2, 60.8, 71.1, 76.4, 108.6, 110.3, 113.9, 127.5, 127.8,
127.9, 128.4, 129.3, 137.2, 143.0, 150.6, 159.0,
172.3ppm. ESI-MS: m/z = 378 (100) (M+H+). Elemen-
tal analysis calcd for C23H23NO4: C, 73.21; H, 6.10;
N, 3.71. Found: C, 73.52; H, 6.06; N 3.90.
15
85%) as a colorless oil. ½aŠ ¼ ꢁ23:4 (c 0.8, CHCl3).
D
IR (film): m = 3420, 2970, 1750, 1710, 1690, 1680cmꢁ1
.
1H NMR (500MHz, CDCl3, two rotamers): d = 1.07
[each d, J = 6.9Hz, 3H, C(4)–CH3], 1.40, 1.44 (each s,
9H, Boc), 1.78 (s, 1H, OH), 2.32–3.28 [m, 1H, C(4)–
H], 3.13, 3.16 [each d, J = 10.3Hz, 1H, C(5)–H], 3.68
[dd, J = 10.3, 8.2Hz, 0.5H, C(5)–H, rotamer 1], 3.74
[m, 0.5H, C(5)–H, rotamer 2, overlapped with
CO2CH3], 3.74, 3.75 (each s, 3H, CO2CH3), 4.20, 4.21
[each dd, J = 4.5Hz, 1H, C(3)–H], 4.22, 4.33 [each br
s, 1H, C(2)–H] ppm. 13C NMR (125MHz, CDCl3):
13C NMR (125MHz, CDCl3, 20ꢁC): d = 10.8, 28.2,
28.4, 36.1, 36.8, 50.2, 50.8, 52.2, 52.4, 68.0, 68.2, 76.1,
80.1, 153.8, 154.6, 171.2, 171.6ppm. ESI-MS: m/z
(%) = 260 (100) (M+H+). ESI-HRMS: calcd for
[C12H21NO5+H+]: 260.1492; found: 260.1488.
4.10. [(4S,5S)-4-Benzyloxy-1-(4-methoxybenzyl)-2-oxo-
proline methyl ester 22
To a stirred solution of NaIO4 (8.34g, 38.97mmol) in
H2O–CH3CN–CCl4 3:3:2 (195mL) was added an aque-
ous solution of RuCl3–xH2O (4.33mL, 0.22mmol,
0.05M). After being stirred for 20min at 0ꢁC, 2-furyl
derivative 7 (1.63g, 4.33mmol) in CH3CN (27mL) was
added. The color of the solution changed instantane-
ously from light yellow-green to black. After 5min, the
mixture was diluted with water (40mL) and extracted
with EtOAc (3 · 60mL). The combined organic extracts
were washed successively with saturated aqueous NaH-
SO3 (until the solution become colorless) and brine,
dried over Na2SO4, filtered, and concentrated in vacuo.
The crude acid was dissolved in Et2O–THF (2:1 v/v) and
treated with an ethereal solution of diazomethane
(0.56M, 62mL) at 0ꢁC. Flash chromatography
(EtOAc–PE = 1:2) of the residue afforded ester 22
4.9. (4S,5S)-4-Benzyloxy-5-(fur-2-yl)-1-(4-methoxy-
benzyl)pyrrolidin-2-one 7
To a cooled (ꢁ78ꢁC) solution of furan (1.25g,
18.45mmol) in anhydrous THF (26mL) was added n-
butyllithium (3.69mL, 9.23mmol, 2.5M solution in hex-
ane) under argon and the resulting solution stirred at
0ꢁC for 2h. To a cooled (ꢁ78ꢁC) solution of 9 (2.00g,
6.15mmol) in anhydrous THF (70mL) was added drop-
wise a diluted 2-lithiofuran (37mL, 9.23mmol, 0.25M
solution in THF). After being stirred for an additional
20min at the same temperature, the reaction was
quenched by saturated aqueous NH4Cl solution. The
organic layer was separated and the aqueous layer
extracted with Et2O (3 · 20mL). The combined organic
extracts were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Flash chro-
matography on silica gel using ethyl acetate–petroleum
ether (1:3) as an eluent yielded the furylated product
as a mixture of two diastereomers.
(1.24g, 78%) as a white solid. Mp 65ꢁC (EtOAc/PE).
14
½aŠ ¼ þ29:8 (c 1.0, CHCl3). IR (KBr): m = 2934, 1713,
D
1689, 1607, 1512, 1448, 1251, 1219, 1078, 1031cmꢁ1
.
1H NMR (500MHz, CDCl3): d = 2.53 [dd, J = 17.5,
1.1Hz, 1H, C(3)–H], 2.76 [dd, J = 17.5, 6.4Hz, 1H,
C(3)–H], 3.68 (s, 3H, CO2CH3), 3.80(s, 3H, OCH ),
3
4.00 (d, J = 14.9Hz, 1H, NCH2Ar), 4.09 [s, 1H, C(5)–
H], 4.14 [dd, J = 6.4, 1.1Hz, 1H, C(4)–H], 4.46 (d,
J = 11.8Hz, 1H, OCH2Ph), 4.50(d, J = 11.8Hz, 1H,
OCH2Ph), 4.99 (d, J = 14.9Hz, 1H, NCH2Ar), 6.81 (d,
J = 8.4Hz, 2H, Ar), 7.15 (d, J = 8.4Hz, 2H, Ar), 7.20–
7.38 (m, 5H, Ar) ppm. 13C NMR (125MHz, CDCl3):
d = 37.5, 44.7, 55.2, 64.9, 70.8, 74.5, 113.9, 127.2,
127.6, 127.9, 128.4, 129.5, 136.8, 159.0, 170.2,
172.9ppm. ESI-MS: m/z (%) = 370 (100) (M+H+). Ele-
mental analysis calcd for C21H23NO5: C, 68.29; H,
6.23; N, 3.79. Found: C, 68.73; H, 6.42; N, 3.94.
To a cooled (ꢁ78ꢁC) solution of the diastereomeric mix-
ture the furylated product in dry CH2Cl2 (51mL) were
added triethylsilane (8.1mL, 50.87mmol) and boron tri-
fluoride etherate (1.9mL, 15.22mmol). After being stir-
red at ꢁ78ꢁC for 8h, the reaction was allowed to
warm up and stirred for an additional 8h at rt. The reac-
tion was quenched by a saturated aqueous NaHCO3
(4mL) and extracted with CH2Cl2. The combined ex-
tracts were dried (Na2SO4), filtered, and concentrated
in vacuo. The crude was flash chromatographed
(EtOAc–PE = 1:4–1:2) to give 7 (1.63g, 70%, over two
4.11. (2S,3S)-3-Benzyloxy-1-(4-methoxybenzyl)proline
methyl ester 23
To a solution of 22 (46mg, 0.12mmol) in anhydrous
THF (1.3mL) was added BH3ÆSMe2 (0.1mL, 1.12mmol)
at 0ꢁC. The resulting mixture was stirred at 25ꢁC over-
night. The solution was re-cooled to ꢁ10ꢁC, diluted
with EtOAc (8mL), and quenched with MeOH
(0.5mL). The solvent was evaporated under reduced
pressure. To the residue were added successively EtOAc
(2mL) and H2O (2mL). The resulting solution was stir-
red at 60ꢁC for 2h before being extracted with Et2O
(3 · 5mL). The combined extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated in
vacuo. Flash chromatography (EtOAc–PE = 1:3.5) of
steps) as colorless crystals. Mp 55ꢁC (EtOAc/
14
PE). ½aŠ ¼ þ50:2 (c 1.1, CHCl3). IR (KBr): m = 2926,
D
1683, 1511, 1427, 1245, 1031cmꢁ1
.
1H NMR
(500MHz, CDCl3): d = 2.59 [dd, J = 17.3, 2.7Hz, 1H,
C(3)–H], 2.92 [dd, J = 17.3, 6.7Hz, 1H, C(3)–H], 3.57
[d, J = 14.9Hz, 1H, NCH2Ar], 3.80(s, 3H, OCH 3),
4.20[ddd, J = 6.7, 2.7, 2.1Hz, 1H, C(4)–H], 4.46 (s,
2H, OCH2Ph), 4.50[d, J = 2.1Hz, 1H, C(5)–H], 5.03
(d, J = 14.9Hz, 1H, NCH2Ar), 6.14 [d, J = 3.1Hz, 1H,
C(30)–H], 6.35 [dd, J = 3.1, 1.8Hz, 1H, C(40)–H], 6.81
(d, J = 8.5Hz, 2H, Ar), 7.11 (d, J = 8.4Hz, 2H, Ar),
the residue afforded 23 (29mg, 65%) as a colorless oil.
25
D
½aŠ ¼ ꢁ13:3 (c 0.6, CHCl3). IR (film): m = 2960, 2921,
1737, 1613, 1510, 1455, 1259, 1093, 1028cmꢁ1
.
1H

3906
W.-H. Meng et al. / Tetrahedron: Asymmetry 15 (2004) 3899–3910
NMR (500MHz, CDCl3): d = 1.86–1.91 [m, 1H, C(4)–
H], 2.06–2.11 [m, 1H, C(4)–H], 2.67 [ddd, J = 16.0 , 6.5,
2.0Hz, 1H, C(5)–H], 3.03 [ddd, J = 16.0, 9.0, 2.0Hz,
1H, C(5)–H], 3.36 [d, J = 3.5Hz, 1H, C(2)–H], 3.63
(d, J = 13.0Hz, 1H, NCH2Ar), 3.65 (s, 3H, CO2CH3),
3.80(s, 3H, OCH 3), 3.83 (d, J = 13.0Hz, 1H, NCH2Ar),
4.15–4.18 [m, 1H, C(3)–H], 4.51 (d, J = 11.9Hz, 1H,
OCH2Ph), 4.69 (d, J = 11.9Hz, 1H, OCH2Ph), 6.82
(d, J = 8.5Hz, 2H, Ar), 7.22–7.39 (m, 7H, Ar) ppm.
13C NMR (125MHz, CDCl3): d = 31.4, 51.7, 51.9,
55.2, 58.2, 71.0, 72.2, 82.7, 113.5, 127.6, 128.3, 130.0,
130.4, 137.9, 158.9, 173.3ppm. ESI-HRMS: calcd for
[C21H25NO4+H+]: 356.1865; found: 356.1876. Calcd
for [C21H25NO4+Na+]: 378.1681; found: 378.1690.
with brine, dried over Na2SO4, filtered, and concen-
trated in vacuo. Flash chromatography (EtOAc–
PE = 1:3) of the residue afforded 24 (0.30g, 84%) as an
20
oil. ½aŠ ¼ ꢁ31:7 (c 0.8, CHCl3). IR (film): m = 2922,
D
1686, 1611, 1512, 1453, 1246cmꢁ1
.
1H NMR
(500MHz, CDCl3): d = 2.51 [dd, J = 17.3, 1.9Hz, 1H,
C(3)–H], 2.81 [dd, J = 17.3, 6.6Hz, 1H, C(3)–H], 3.43
[dd, J = 10.0, 3.5Hz, 1H, C(6)–H], 3.45 [dd, J = 10.0,
4.1Hz, 1H, C(6)–H, overlapped with other C(6)–H],
3.61 [ddd, J = 4.1, 3.5, 3.5Hz, 1H, C(5)–H], 3.80(s,
3H, OCH3), 4.00 (d, J = 15.1Hz, 1H, NCH2Ar), 4.08
[ddd, J = 6.6, 3.5, 1.9Hz, 1H, C(4)–H], 4.38 (d,
J = 11.9Hz, 1H, OCH2Ph), 4.41 (d, J = 11.7Hz, 1H,
OCH2Ph), 4.42 (d, J = 11.7Hz, 1H, OCH2Ph), 4.48 (d,
J = 11.9Hz, 1H, OCH2Ph), 4.89 (d, J = 15.1Hz, 1H,
NCH2Ar), 6.81 (d, J = 8.5Hz, 2H, Ar), 7.16 (d,
J = 8.5Hz, 2H, Ar), 7.22–7.39 (m, 10H, Ar) ppm. 13C
NMR (125MHz, CDCl3): d = 37.8, 43.8, 55.2, 63.2,
67.2, 70.6, 74.5, 113.9, 127.5, 127.7, 127.8, 128.3,
128.4, 129.1, 137.5, 158.9, 173.2ppm. ESI-MS: m/z
(%) = 342 (100) (M+H+). ESI-HRMS: calcd for
(C27H29NO4+H+): 432.2169; found: 432.2155. Calcd
for (C27H29NO4+Na+): 454.1994; found: 454.1981.
4.12. (4S,5R)-4-Benzyloxy-5-hydroxymethyl-1-(4-meth-
oxybenzyl)pyrrolidin-2-one 11
To a suspension of 22 (0.30g, 0.81mmol) and CaCl2
(0.38g, 3.4mmol) in EtOH–THF (1:2) (3.24mL) was
added NaBH4 (0.25mg, 6.48mmol). The mixture was
stirred for 3h at rt, then cooled to 0ꢁC and diluted with
EtOAc (10mL). To the resultant mixture was added
Na2SO4Æ10H2O until the evolution of gas ceased. The
mixture was filtered through Celite. The aqueous layer
was extracted with EtOAc (2 · 10mL). The combined
organic phases were washed with aqueous NH4Cl, dried
over Na2SO4, filtered, and evaporated in vacuo. The
residue was chromatographed (EtOAc–PE = 3: 1) to
4.14. (2R,3S)-3-Benzyloxy-2-benzyloxymethyl-1-(4-
methoxybenzyl)prolinol 25
To a solution of 24 (37mg, 0.09mmol) in anhydrous
THF (0.9mL) was added BH3ÆSMe2 (0.07mL, 0.8mmol)
at 0ꢁC. The resulting mixture was stirred at 25ꢁC over-
night and quenched by the addition of MeOH (0.5mL)
and H2O (2mL). The resulting mixture was stirred at
60ꢁC for 3h before being extracted with Et2O
(3 · 5mL). The combined extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated in
vacuo. Flash chromatography (EtOAc–PE = 1:4.5) of
give 11 (0.26g, 95%) as a white solid. Mp 101ꢁC
14
(EtOAc/PE). ½aŠ ¼ þ74:6 (c 1.1, CHCl3). IR (KBr):
D
m = 3322, 2904, 1678, 1652, 1511, 1250, 1091cmꢁ1
.
1H NMR (500MHz, CDCl3): d = 2.49 [dd, J = 17.4,
2.0Hz, 1H, C(3)–H], 2.62 (br s, 1H, OH), 2.78 [dd,
J = 17.4, 6.7Hz, 1H, C(3)–H], 3.53 [dd, J = 3.7, 2.4Hz,
1H, C(5)–H], 3.57 [ddd, J = 11.2, 4.1, 2.4Hz, 1H,
C(6)–H], 3.72 [ddd, J = 11.2, 4.0, 3.7Hz, 1H, C(6)–H],
3.80(s, 3H, OCH 3), 4.13 [dd, J = 6.7, 2.0Hz, 1H,
C(4)–H, overlapped with one of N–CH2], 4.17 (d,
J = 14.9Hz, 1H, NCH2Ar), 4.42 (d, J = 11.7Hz, 1H,
OCH2Ph), 4.49 (d, J = 11.7Hz, 1H, OCH2Ph), 4.83 (d,
J = 14.9Hz, 1H, NCH2Ar), 6.81 (d, J = 8.5Hz, 2H,
Ar), 7.21 (d, J = 8.5Hz, 2H, Ar), 7.23–7.35 (m,
5H, Ar) ppm. 13C NMR (125MHz, CDCl3): d = 38.1,
43.8, 55.2, 60.4, 65.2, 70.6, 74.4, 114.1, 127.6, 127.8,
128.3, 128.4, 129.0, 137.5, 159.0, 173.9ppm. ESI-MS:
m/z (%) = 342 (100) (M+H+). Elemental analysis calcd
for C20H23NO4: C, 70.38; H, 4.10; N, 6.74. Found: C,
70.11; H, 4.25; N, 6.67.
the residue afforded 25 (32mg, 88%) as a colorless oil.
25
D
½aŠ ¼ ꢁ21:6 (c 0.7, CHCl3). IR (film): m = 2922, 1611,
1512, 1453, 1246cmꢁ1
.
1H NMR (500MHz, CDCl3):
d = 1.85–1.91 [m, 2H, C(4)–H], 2.57 [ddd, J = 7.0, 4.5,
2.0Hz, 1H, C(2)–H], 2.87–2.93 [m, 2H, C(5)–H], 3.36
[dd, J = 9.5, 7.0Hz, 1H, C(6)–H], 3.47 [dd, J = 9.5,
4.5Hz, 1H, C(6)–H], 3.53 (d, J = 13.0Hz, 1H,
NCH2Ar), 3.81 (s, 3H, OCH3), 3.94–3.97 [m, 1H,
C(3)–H], 3.98 (d, J = 13.0Hz, 1H, NCH2Ar), 4.51 (d,
J = 12.0Hz, 2H, OCH2Ph), 4.54 (d, J = 12.0Hz, 2H,
OCH2Ph), 6.83 (d, J = 8.5Hz, 2H, Ph), 7.22–7.38 (m,
12H, Ph) ppm. 13C NMR (125MHz, CDCl3): d = 30.5,
52.2, 55.2, 59.1, 69.2, 70.5, 71.4, 73.2, 82.0, 113.5,
127.4, 127.5, 127.6, 127.6, 128.3, 130.1, 131.4, 138.4,
138.7,
158.6ppm.
ESI-HRMS:
calcd
for
4.13. (4S,5S,5R)-4-Benzyloxy-5-benzyloxymethyl-1-(4-
methoxybenzyl)pyrrolidin-2-one 24
(C27H31NO3++H+): 418.2382; found: 418.2394. Calcd
for (C27H31NO3+Na+): 440.2236; found: 440.2216.
To a suspension of NaH (40mg, 60% in mineral oil,
1.00mmol) in dry THF (4.3mL) was added dropwise a
solution of 11 (0.29g, 0.84mmol) in THF (4.5mL) at
ꢁ20ꢁC. The reaction was stirred for 30min at ꢁ20ꢁC,
then to the mixture was added BnBr (0.15mL,
1.26mmol) and the stirring continued for 40h at the
same temperature before being quenched with NH4Cl.
The aqueous layer was extracted with Et2O
(3 · 10mL). The combined organic phases were washed
4.15. (4S,5R)-4-Benzyloxy-5-benzyloxymethylpyrrol-
idin-2-one 26
To a solution of 24 (0.35g, 0.81mmol) in CH3CN–H2O
(9:1, 41mL) was added cerium(IV) ammonium nitrate
(2.22g, 4.05mmol). The mixture was stirred for 3h at
rt and then diluted with water (5mL). The aqueous layer
was extracted with ethyl acetate (3 · 10mL). The com-
bined organic layers were washed successively with sat-

W.-H. Meng et al. / Tetrahedron: Asymmetry 15 (2004) 3899–3910
3907
urated sodium bicarbonate and brine, dried over
Na2SO4, filtered, and concentrated in vacuo. Flash chro-
matography (EtOAc–PE = 1.5:1) of the residue afforded
1392, 1366, 1169, 1096cmꢁ1
.
1H NMR (500MHz,
CDCl3): d = 1.45 (2s, 9H, t-Boc), 1.95 [ddd, J = 15.4,
5.0, 2.5Hz, 1H, C(3)–H], 2.26 [ddd, J = 15.4, 6.4,
1.9Hz, 1H, C(3)–H], 3.42–3.50(m, 1H, C(6)–H), 3.60
[dd, J = 9.5, 2.8Hz, 1H, C(5)–H], 3.90–3.97 [m, 1H,
C(6)–H], 4.14 [dd, J = 6.4, 2.5Hz, 1H, C(4)–H], 4.48
(d, J = 12.2Hz, 1H, OCH2Ph), 4.50(d, J = 12.2Hz,
1H, OCH2Ph), 4.54 (d, J = 12.0Hz, 1H, OCH2Ph),
4.57 (d, 1H, J = 12.0Hz, OCH2Ph), 5.48 [dd, J = 11.4,
5.0Hz, 1H, C(2)–H], 7.28–7.39 (m, 10H, Ph) ppm. 13C
NMR (125MHz, CDCl3): d = 28.3, 28.4, 29.7, 40.1,
37.9, 36.8, 62.8, 62.5, 69.5, 69.1, 70.8, 73.2, 73.4, 78.9,
79.2, 80.5, 81.7, 82.1, 127.4, 127.7, 127.7, 127.8, 128.4,
137.7, 137.9, 153.4, 154.6ppm. ESI-MS: m/z (%) = 296
(100) (M+H+ꢁH2OꢁBoc), 396 (72) (M+H+ꢁH2O),
18
26 (0.14g, 84%) as a colorless oil. ½aŠ ¼ þ51:7 (c 1.1,
D
CHCl3). IR (film): 3238, 3030, 2861, 1697, 1497, 1453,
1092, 1068, 1027cmꢁ1 1H NMR (500MHz, CDCl3):
.
m = 2.44 [dd, J = 17.4, 3.5Hz, 1H, C(3)–H], 2.66 [dd,
J = 17.4, 7.0Hz, 1H, C(3)–H], 3.39 [dd, J = 9.5, 6.7Hz,
1H, C(6)–H], 3.51 [dd, J = 9.5, 4.5Hz, 1H, C(6)–H],
3.85 [ddd, J = 6.7, 4.5, 3.5Hz, 1H, C(5)–H], 4.03 [ddd,
J = 7.0, 3.5, 3.5Hz, 1H, C(4)–H], 4.50 (d, J = 11.8Hz,
1H, OCH2Ph), 4.51 (d, J = 11.6Hz, 1H, OCH2Ph),
4.53 (d, J = 11.6Hz, 1H, OCH2Ph), 4.55 (d, 1H,
J = 11.8Hz, OCH2Ph), 6.28 (s, 1H, NH), 7.25–7.38 (m,
10H, Ph) ppm. 13C NMR (125MHz, CDCl3): d = 37.1,
60.2, 71.1, 71.3, 73.4, 75.9, 127.6, 127.7, 127.8, 128.4,
137.3, 137.5, 175.4ppm. ESI-MS: m/z (%) = 288 (100),
436
(10)
(M+Na+).
ESI-HRMS:
calcd
for
(C24H31N3O5+Na+): 436.2099; found: 436.2091.
312
(63)
(M+H+).
ESI-HRMS:
calcd
for
(C19H21NO3+H+): 312.1593; found: 312.1609. Calcd
for (C19H21NO3+Na+): 334.1419; found: 334.1435.
4.18. Acetic acid (2RS,4S,5R)-4-benzyloxy-5-benzylox-
ymethyl-1-(tert-butoxycarbonyl)pyrrolidin-2-yl ester 29
4.16. (4S,5R)-4-Benzyloxy-5-benzyloxymethyl-1-(tert-
butoxycarbonyl)pyrrolidin-2-one 27
To a solution of 28 (0.12g, 0.28mmol) and Ac2O
(0.16mL, 1.68mmol) and DMAP (cat.) in dichlorometh-
ane was added Et3N (1.68mmol, 0.23mL) at 0ꢁC. The
mixture was stirred at 23ꢁC overnight and then cooled
to ꢁ15ꢁC. Saturated aqueous NaHCO3 was added
and the aqueous layer extracted with dichloromethane.
The combined organic layers were dried over Na2SO4,
filtered, and evaporated in vacuo. Short column chro-
matography purification of the residue on SiO2 using
pre-cooled eluent (EtOAc–PE = 1:5) afforded 29 as a
diastereomeric mixture, that was immediately used in
the next step.
A solution of 26 (0.11g, 0.35mmol), di-tert-butyl dicar-
bonate (0.2mL, 0.83mmol), and DMAP (cat.) in
CH3CN (1.2mL) was stirred for 1h under N2. The res-
idue obtained after removal of the solvent was purified
by column chromatography (EtOAc–PE = 1:4) to afford
14
D
27 (0.14g, 95%) as a colorless oil ½aŠ ¼ ꢁ37:4 (c 0.3,
CHCl3). IR (film): m = 2977, 2924, 2860, 1785, 1748,
1715, 1671, 1604, 1454, 1367cmꢁ1
.
1H NMR
(500MHz, CDCl3): d = 1.50(s, 9H, t-Boc), 2.44 [d,
J = 18.0Hz, 1H, C(3)–H], 2.91 [dd, J = 18.0, 6.1Hz,
1H, C(3)–H], 3.64 [d, J = 3.7Hz, 2H, C(6)–H], 4.08 [d,
J = 6.1Hz, 1H, C(4)–H], 4.30[t, J = 3.7Hz, 1H, C(5)–
H], 4.48 (d, J = 12.0Hz, 1H, OCH2Ph), 4.52 (d,
J = 12.2Hz, 2H, OCH2Ph), 4.55 (d, J = 12.0Hz, 1H,
OCH2Ph), 7.25–7.38 (m, 10H, Ph) ppm. 13C NMR
(125MHz, CDCl3): d = 27.8, 29.7, 39.3, 63.8, 68.9,
70.5, 73.4, 73.6, 83.0, 127.5, 127.7, 127.8, 127.9, 128.4,
137.3, 137.5, 149.7, 172.8ppm. ESI-MS: m/z (%) = 312
(100) (M+H+ꢁBoc), 434 (32) (M+Na+). Elementary
analysis calcd for C24H29NO5: C, 70.07; H, 7.05; N
3.40. Found: C, 69.96; H,7.11; N, 3.25.
4.19. (10S,30S,40R)-40-(tert-Butoxyamido)-30,50-dibenzyl-
0
oxy-20-deoxythymidine 30and (1 R,30S,40R)-40-(tert-
butoxyamido)-30,50-dibenzyloxy-20-deoxythymidine 31
A mixture of thymine (44mg, 0.35mmol), (NH4)2SO4
(15mg, 0.12mmol), and hexamethydisilazane (2mL)
was refluxed at 125ꢁC for 5h. The excess HMDS was re-
moved by co-distillation with xylene (3 · 1mL) under
reduced pressure. To the residue was added MeCN
(2mL), the resultant solution was transferred to com-
pound 29 (45mg, 0.1mmol). To the resultant mixture
was added dropwise a solution of SnCl4 (0.1mL,
0.15mmol) in MeCN (0.6mL) at ꢁ25ꢁC under argon.
The resultant mixture was stirred for 1h at the same
temperature. Saturated NaHCO3 aqueous was added
and the resultant mixture warmed to rt, and filtered
through Celite. The aqueous layer was extracted with
CH2Cl2 (3 · 3mL). The combined organic layers were
dried over Na2SO4, filtered, and evaporated in vacuo.
Flash chromatography (Et2O–PE = 2:1) of the residue
gave b-anomer 30 (colorless oil, 16mg, 31%) and a-ano-
4.17. (2R/S,4S,5R)-4-Benzyloxy-5-benzyloxymethyl-1-
(tert-butoxycarbonyl)-2-hydroxypyrrolidine 28
A solution of DIBAL-H (0.85M in toluene, 0.68mmol,
0.8mL) was added dropwise under argon to a stirred
solution of 27 (0.14g, 0.34mmol) in dry THF (1.7mL)
at ꢁ78ꢁC. After being stirred for 30min at ꢁ78ꢁC, a
saturated aqueous NH4Cl solution was added dropwise.
The resultant mixture was warmed to rt and filtered
through Celite. The aqueous layer was extracted with
dichloromethane, and the combined organic phases
dried over Na2SO4, filtered, and evaporated in vacuo.
The residue was purified by column chromatography
(EtOAc–PE = 1:4) to give 28 as a diastereomeric mix-
mer 31 (colorless oil, 29mg, yield 56%). b-Anomer 30:
15
D
½aŠ ¼ ꢁ77:5 (c 0.4, CHCl3). IR (film): m = 3186, 2976,
2927, 2863, 1711, 1694, 1681, 1472, 1454, 1367cmꢁ1
.
1H NMR (500MHz, CDCl3): d = 1.45 (br s, 9H,
t-Boc), 1.50, 1.65 (2s, 3H, CH3–Thy.), 2.24 [ddd,
J = 13.5, 8.0, 5.0Hz, 1H, C(20)–H], 2.54 [dd, J = 13.5,
7.0Hz, 1H, C(2 0)–H], 3.65 [dd, J = 5.0, 2.5Hz, 1H,
C(50)–H], 3.25 [m, 0.3H, C(50)–H, C(40)–H, C(30)–H,
ture (0.14g, diastereomeric ratio 1:1, combined yield
14
D
99%). ½aŠ ¼ ꢁ14:8 (c 0.8 CHCl3, diastereomeric mix-
ture). IR (film): m = 3465, 2973, 2925, 2856, 1693, 1454,

3908
W.-H. Meng et al. / Tetrahedron: Asymmetry 15 (2004) 3899–3910
min.], 4.08 [d, J = 5.0Hz, 0.9H, C(3 )–H, maj.], 4.03,
4.17 [2br s, 1.8H, C(60)–H, C(40)–H, maj.], 4.52
(d, J = 11.0Hz, 1H, OCH2Ph), 4.54 (d, J = 11.0Hz,
1H, OCH2Ph), 4.56 (d, J = 12.0Hz, 1H, OCH2Ph), 4.60
(d, J = 12.0Hz, 1H, OCH2Ph), 6.35 [dd, J = 7.0,
8.0Hz, 1H, C(1 0)–H], 7.25, 7.39 (m, 10H, Ph), 8.48 [br
s, 0.8H, C(6)–H, maj.], 8.56 [d, J = 4.5Hz, 0.2H, C(6)–
H, min.] ppm. 13C NMR (125MHz, CDCl3): d = 11.9,
28.1, 29.6, 37.7, 64.4, 68.5, 70.8, 70.4, 73.5, 78.7, 81.5,
110.6, 127.4, 127.5, 127.6, 127.9, 128.0, 128.6, 136.1,
137.3, 137.4, 150.3, 154.2, 163.6ppm. ESI-MS: m/z
(%) = 423 (100), 445 (76), 544 (43) (M+Na+). ESI-
HRMS: calcd for [C29H35N3O6+H+]: 522.2597; found:
522.2592.
(100) (M+Na+). ESI-HRMS: calcd for [C15H23N3O6+
H+]: 342.1658; found: 342.1659.
0
4.21. (10R,30S,40R)-40-tert-Butoxyamido-20-deoxythymi-
dine 6c
To 13mg of 20% Pd/C (13mg) was added a solution of
31 (18mg, 0.034mmol) in 3mL of 95% ethanol. The
mixture was hydrogenated under 1atm hydrogen pres-
sure and stirred at room temperature for 78h. The mix-
ture was filtered through Celite and the filtrate was
evaporated in vacuo. Flash chromatography of the res-
idue using ethyl acetate as an eluent afforded 6c (10mg,
20
D
85%) as a colorless oil. ½aŠ ¼ þ6:6 (c 0.9, MeOH). IR
(film): m = 3390, 2924, 1684, 1473, 1392, 1369, 1267,
1
1162, 1038cmꢁ1. H NMR (500MHz, CD3OD): 1.38
15
a-Anomer 31: ½aŠ ¼ ꢁ1:3 (c 0.4, CHCl3). IR (film):
D
(br s, 9H, t-Boc), 1.87 [m, 3.5H, C(20)–H, CH3–Thy.,
maj.], 1.91 [m, 0.5H, C(20)–H, CH3–Thy., min.], 2.71
[ddd, J = 14.0, 8.5, 5.0Hz, 0.3H, C(20)–H, min.], 2.76
[ddd, J = 14.0, 8.5, 5.0Hz, 0.7H, C(20)–H, maj.], 3.58–
3.71 [m, 2H, C(50)–H], 3.95 [m, 0.3H, C(40)–H, min.],
4.01 [t, J = 3.5Hz, 0.7H, C(40)–H, maj.], 4.35 [d,
m = 3186, 2976, 2927, 2863, 1711, 1694, 1681, 1472,
1454, 1367cmꢁ1
.
1H NMR (500MHz, CDCl3):
d = 1.45 (br s, 9H, t-Boc), 1.50, 1.65 (2s, 3H, CH3–
Thy.), 2.10[2d, J = 15.0Hz, 1H, C(2 0)–H], 2.66 [ddd,
J = 15.0, 8.5, 5.5Hz, 0.3H, C(20)–H, min.], 2.76 [ddd,
J = 15.0, 8.5, 5.5Hz, 0.7H, C(20)–H, maj.], 3.48 [m,
0.2H, C(50)–H, C(40)–H, min.], 3.58–3.66 [m, 1.8H,
C(50)–H, C(40)–H, maj.], 3.69 [dd, J = 5.5, 5.5Hz,
0.8H, C(50)–H, maj.], 4.13 [d, J = 5.5Hz, 0.8H, C(30)–
H, maj.], 4.17 [d, J = 5.5Hz, 0.2H, C(30)–H, min.],
4.21 [d, J = 5.5Hz, 0.2H, C(50)–H, maj.], 4.45 (d,
J = 11.0Hz, 1H, OCH2Ph), 4.47 (d, J = 11.0Hz, 1H,
OCH2Ph), 4.50(d, J = 12.0Hz, 1H, OCH2Ph), 4.54 (d,
J = 12.0Hz, 1H, OCH2Ph), 6.25 [d, J = 8.5Hz, 1H,
C(10)–H], 7.22–7.38 (m, 10H, Ph), 8.60 [br s, 0.2H,
C(6)–H, min.], 8.72 [s, 0.8H, C(6)–H, maj.] ppm. 13C
NMR (125MHz, CDCl3): d = 12.1, 29.6, 28.1, 38.0,
64.5, 68.0, 68.5, 70.9, 73.4, 79.4, 81.6, 109.7, 127.4,
127.5, 127.7, 127.8, 128.0, 128.5, 136.9, 137.1, 137.8,
150.6, 152.7, 163.7ppm. ESI-MS: m/z (%) = 423 (100),
445 (76), 544 (43) (M+Na+). ESI-HRMS: calcd for
[C29H35N3O6+H+]: 522.2597; found: 522.2598.
0
J = 5.0Hz, 0.7H, C(3 )–H], 4.37 [d, J = 5.0Hz, 0.3H,
C(30)–H], 6.13 [d, J = 8.5Hz, 0.3H, C(10)–H], 6.18 [d,
J = 8.5Hz, 0.7H, C(10)–H], 7.63 [s, 0.3H, C(6)–H,
min.], 7.82 [s, 0.7H, C(6)–H, maj.] ppm. 13C NMR
(125MHz, CD3OD): d = 12.6, 28.5, 28.6, 40.6, 41.4,
61.1, 62.0, 70.6, 71.1, 72.8, 73.8, 82.6, 82.7, 110.2,
110.7, 138.9, 139.4, 152.9, 154.6, 166.6ppm. ESI-MS:
m/z (%) = 364 (100) (M+Na+). ESI-HRMS: calcd for
[C15H23N3O6+H+]: 342.1659; found: 342.1658.
Acknowledgements
The authors are grateful to the National Science Fund
for Distinguished Young Investigators, the NSF of
China (20272048; 203900505) and the Ministry of
Education (Key Project 104201) for financial support.
4.20. (10S,30S,40R)-40-tert-Butoxyamido-20-deoxythymi-
dine 6b
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and stirred at room temperature for 9h. The mixture
was filtered through Celite and the filtrate evaporated
in vacuo. Flash chromatography of the residue using
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D
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¨