Formal syntheses of (-)- and (+)-aphanorphine from (2S,4R)-4-hydroxyproline

Article abstract of DOI:10.1016/j.tet.2007.05.059

We describe the efficient formal syntheses of both natural (-)-aphanorphine and unnatural (+)-aphanorphine from the same commercially available amino acid, (2S,4R)-4-hydroxyproline. The tricyclic framework was constructed by intramolecular Friedel-Crafts

Full text of DOI:10.1016/j.tet.2007.05.059

Tetrahedron 63 (2007) 7523–7531
Formal syntheses of (L)- and (D)-aphanorphine
from (2S,4R)-4-hydroxyproline
Zhiqiang Ma,a Hanwei Hu,a Wanting Xionga and Hongbin Zhaia,b,
*
aThe Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
bThe State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences,
Peking University, 38 College Road, Beijing 100083, China
Received 19 March 2007; revised 30 April 2007; accepted 17 May 2007
Available online 21 May 2007
Abstract—We describe the efficient formal syntheses of both natural (ꢀ)-aphanorphine and unnatural (+)-aphanorphine from the same com-
mercially available amino acid, (2S,4R)-4-hydroxyproline. The tricyclic framework was constructed by intramolecular Friedel–Crafts reac-
tion. (1R,4S)-1-Methyl-8-methoxy-3-(4-toluenesulfonyl)-2,3,4,5-tetrahydro-1,4-methano-3-benzazepine (8) was synthesized in six steps
from sulfonamide 3; (ꢀ)-aphanorphine methyl ether 24 was obtained in seven steps from lactone 10. Intramolecular etherification of 18 pro-
ceeded with excellent stereoselectivity in the presence of BF3$OEt2, which has paved an efficient synthetic route to a series of medicinally
attractive heterocycles.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
enantiomers of aphanorphine, which would lead to novel,
formal syntheses of (ꢀ)-aphanorphine and (+)-aphanorphine
based on the ‘chiral pool’ strategy. Although we were not the
first to ‘extract’ the chiron from 2 in the synthesis of aphanor-
phine, the previous approach2m made use of an initial enolate
benzylation of a derivative of 2 and decarboxylation at a later
stage, which adversely affected the overall synthetic effi-
ciency in terms of atom economy and stereoselectivity.
Moreover, our present research should be of great signifi-
cance in terms of diversity-oriented synthesis. Some prelim-
inary results along this line have been reported by our
laboratory.2s,y Herein, we wish to describe the full account
of our findings regarding the syntheses of natural (ꢀ)-apha-
norphine and unnatural (+)-aphanorphine from (2S,4R)-4-
hydroxyproline (2).
(ꢀ)-Aphanorphine [(ꢀ)-1, Scheme 1], a novel alkaloid iso-
lated by Shimizu and Clardy from the freshwater blue-green
alga Aphanizomenon flos-aquae nearly two decades ago,1 has
stimulated tremendous synthetic attention2 owing to its po-
tential biological activity and unique structure containing
tricyclic 3-benzazepine framework that resembles benzo-
morphane analgesics3,4 such as pentazocine. Although a
number of synthetic strategies have been reported for natural
(ꢀ)-aphanorphine, unnatural (+)-aphanorphine, and (ꢁ)-
aphanorphine in the literature,2 currently there still exists
strong demand for developing simpler and more efficient
synthetic approaches for these molecules for the purpose
of biological studies. Our previous synthesis of (ꢀ)-apha-
norphine2r featured the formation of ring B at the final stage
by Friedel–Crafts alkylative cyclization, while in most other
strategies ring B was constructed prior to ring C. Moreover,
carbohydrates,5a terpenes,5b and especially amino acids,5c
have been widely used in the total synthesis of natural prod-
ucts. As shown in Scheme 1, (2S,4R)-4-hydroxyproline (2)
was considered as an excellent starting point to secure
the advanced tricyclic intermediates for constructing both
H
HO2C
N
OH
2
H
H
3
3
A
B
N Me
12
C
A
8
B
1
N Me
12
C
8
HO
HO
1
Me
(+)-1: (+)-aphanorphine
Keywords: Alkaloid; Aphanorphine; Asymmetric synthesis; Configuration
inversion; Intramolecular Friedel–Crafts reaction.
* Corresponding author. Tel.: +86 21 54925163; fax: +86 21 64166128;
e-mail: zhaih@mail.sioc.ac.cn
Me
(-)-1: (-)-aphanorphine
Scheme 1. Proposed synthesis of (ꢀ)- and (+)-aphanorphine.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.059

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Z. Ma et al. / Tetrahedron 63 (2007) 7523–7531
2. Results and discussion
2.2. (B) Formal synthesis of (D)-aphanorphine:
synthesis of 24 from 2
2.1. (A) Formal synthesis of (L)-aphanorphine:
synthesis of 8 from 2
The synthesis of unnatural (+)-aphanorphine from (2S,4R)-
4-hydroxyproline (2) featured configuration inversion at
C-2 of the amino acid. Chemoselective N-benzoylation
(BzCl, NaOH, Et2O, 0 ꢃC and then room temperature,
24 h, 76%) of 2 produced amide 9 (Scheme 3).11a Agitation
of 9 in acetic anhydride heated at 90 ꢃC for 5 h effected the
requisite lactonization and configuration inversion at C-2 in
the same step to provide bicycle 10 in 90% yield, by taking
advantage of an efficient protocol developed recently by
Rosa and Croce.11b Interestingly, treatment of sulfonamide
1112 (prepared in 83% yield by selective N-tosylation of 2
with TsCl in the presence of Na2CO3) with acetic anhydride
at 90 ꢃC for 8 h resulted only in the acylation of the second-
ary hydroxyl and the acetate 12 was obtained in 95% yield as
a colorless solid. The desirable lactonization with configura-
tion inversion at C-2 failed to take place just because the sub-
stituent on the nitrogen atom was switched from Bz (in 9) to
Ts (in 11).
As outlined in Scheme 2, the synthesis of (ꢀ)-aphanorphine
((ꢀ)-1) commenced from alcohol 3, an intermediate6 ob-
tainable from 2 in 72% yield by a four-step process. Swern
oxidation7a of 3 gave a crude aldehyde, which in turn was
arylated8 with 4-methoxyphenylmagnesium bromide to fur-
nish 4 in 91% yield as a single pure compound. Exposure9
of alcohol 4 to triethylsilane in the presence of BF3$OEt2 in
dichloromethane produced 5 in high yield (95%), as a result
of benzylic reductive dehydroxylation with concomitant
O-desilylation. Oxidation7b with IBX (i.e., o-iodoxybenzoic
acid) of 5 afforded ketone 6 in 98% yield. Nucleophilic
methylation of 6 with methylmagnesium iodide10 produced
the tertiary alcohols 7a/7b (equally utilizable, 78%). The
1
diastereomeric ratio was measured by H NMR integral
analysis to be 4:1, presumably favoring 7a based on steric
consideration. By following the previously published proto-
col from this laboratory,2r AlCl3-promoted Friedel–Crafts
alkylative cyclization of alcohols 7a/7b was effected to
furnish the desired intermediate 8 as colorless needles
(64%). The sample of 8 was in high enantiopurity (99.8%
ee), as determined by HPLC analysis [Chiralpak AD
column: 250ꢂ4.6 mm, UV detector: 254 nm, eluant: hex-
anes/2-propanol (4:1), flow rate: 0.7 mL/min], indicating
that essentially no epimerization ever took place. The
[a]2D0 of 8 was found to be ꢀ14.2 (c 0.93, CHCl3) {lit.2r
[a]2D0 ꢀ13.4 (c 0.969, CHCl3)}. Other spectroscopic data
of 8 were also in agreement with those disclosed in the
literature.2r Thus a new formal synthesis of alkaloid
(ꢀ)-aphanorphine ((ꢀ)-1) has been completed, since 8
could further be manipulated to give (ꢀ)-1 in three addi-
tional steps (desulfurization, N-methylation, and 8-O-
demethylation).
Bz
BzCl
O
O
Bz
HO2C
Ac2O
NaOH
N
N
76%
90%
H
N
Ref. 11b
Ref. 11a
HO2C
OH
9
10
Na2CO3
TsCl
Ts
Ts
Ac2O
95%
OH
HO2C
HO2C
N
2
N
83%
Ref. 12
OH
11
OAc
12
Bz = benzoyl
Scheme 3. Cyclization of 9.
Treating13 a mixture of lactone 10 and Me(MeO)NH$HCl
(120 mol %) in tetrahydrofuran with p-methoxyphenylmag-
nesium bromide (370 mol %) at ꢀ10 ꢃC furnished g-hy-
droxy-a-amido ketone 14 (27%) along with diamide 13
(55%) and diol 15 (17%) (Scheme 4; Table 1, entry 1).
The yield of 14 was increased to 41% when the reaction
was run at ꢀ78 ꢃC (entry 2). Since additional 14 could be
formed from the Weinreb amide 13 in moderate yield
(64%) by reacting with excess p-methoxyphenylmagnesium
bromide (at ꢀ35 ꢃC and then room temperature), phenyl ke-
tone 14 could be obtained from lactone 10 in 76% overall
yield. For comparison, direct addition of p-methoxyphenyl-
magnesium bromide (130 mol %) to lactone 10 at ꢀ78 ꢃC
(i.e., without the involvement of Me(MeO)NH$HCl) gave
14 in only 44% yield.
Ts
N
H
N
i) Swern
HO2C
4 steps
ii) PMPMgBr
HO
72%
Ref. 6
H
91%
OH
OTBS
2
3
Et3SiH
OH
Ts
N
Ts
N
F3B.OEt2
95%
IBX
98%
PMP
PMP
PMP
PMP
H
H
OTBS
OH
Ts
4
5
Ts
N
AlCl3
64%
MeMgI
78%
N
Ketone deoxygenation of 14 was then vigorously pursued
(Scheme 5). Initially, a stepwise reduction strategy (i.e.,
via the benzylic alcohol intermediate) was explored. For in-
stance, reduction of 14 with NaBH414 in MeOH at 0 ꢃC for
1 h smoothly formed the diol 18 (88%) essentially as a single
diastereomer (dr¼70:1). The configuration of the newly gen-
erated stereocenter of this diol was assigned based on the
Cram rule. To our surprise, exposure of 18 to triethylsilane
in the presence of BF3$OEt2 in dichloromethane (at 0 ꢃC
and then room temperature) effected intramolecular etherifi-
cation rather than benzylic reductive dehydroxylation. In
H
H
R1
R2
O
7a: R1 = Me, R2 = OH
7b: R1 = OH, R2 = Me
6
H
PMP = p-methoxyphenyl,
IBX = o-iodoxybenzoic acid
N
Ts
MeO
Me
8
Scheme 2. Synthesis of 8.

Z. Ma et al. / Tetrahedron 63 (2007) 7523–7531
7525
Bz
Bz
Bz
HO
PMP
O
O
H
H
H
O
O
.
Bz
Me
Me(MeO)NH HCl
N
N
N
N
N
PMP
+
PMPMgBr
+
PMP
OMe
OH
OH
OH
14
13
10
15
PMPMgBr
64%
Scheme 4. Ring opening of 10.
Table 1. Comparison of the results obtained under different temperatures
Entry Me(MeO)NH$HCl PMPMgBr Temperature Isolated yield (%)
TFA and Et3SiH. This method even proved to be successful
in the case of ketone 14 itself acting as the substrate. Subject-
ing 14 to Et3SiH15 in the presence of TFA produced 17
directly in one step (17: 62% and 14: 13%; the yield of 17
was amounted to be 71% based on the recovered starting
material). The remarkable difference between BF3$OEt2/
Et3SiH and TFA/Et3SiH as reducing agent combinations
should be noted.
(equiv)
(equiv)
(ꢃC)
13
14
15
1
2
1.2
1.2
3.7
3.7
ꢀ10
ꢀ78
55
55
27
41
17
4
contrast, dehydroxylation of 4 took place smoothly under the
same condition, as mentioned above (Scheme 2). The hy-
droxyl at the C-4 of 18, situating cis to the a-hydroxy
PMB moiety on the pyrrolidine ring, rapidly captured the
benzylic cation generated in the system before it was re-
duced by Et3SiH. Bicyclic heterocycle 19 was produced
(82%) as a pair of rotamers (1.3:1, deduced from the line
integrals of 1H NMR spectrum). Note that the benzylamine
derivative 20, obtained in 76% yield by reducing 19 with
LiAlH4 in refluxing THF, proved to be a single pure com-
pound. The PMP substituents of 19 and 20 should occupy
the exo position according to the NOESYexperiments on 20.
In addition, alcohol 17 could be obtained from ketone 14
via 1,3-dithiolane formation (HSCH2CH2SH, BF3$OEt2,
CH2Cl2, reflux, 80%),16 followed by desulfurization via
a free-radical reaction (n-Bu3SnH, AIBN, MePh, 90 ꢃC;
17: 73% and 14: 15%; the yield of 17 was amounted to be
86% based on the recovered starting material).17
After alcohol 17 became easily accessible, we focused
on completing the formal synthesis of (+)-aphanorphine
(Scheme 6). Under the typical Swern condition, secondary
alcohol 17 was oxidized to afford pyrrolidinone 21 in excel-
lent yield (98%). Nucleophilic addition of methyllithium18
to ketone 21 (from the less hindered face) in tetrahydrofuran
at ꢀ78 ꢃC produced tertiary alcohol 22 in 39% yield (or 80%
yield based on the recovered starting material) and in excel-
lent stereoselectivity along with the recovered 21 (52%). The
1H NMR of 22 showed two sets of peaks for some protons as
a result of the presence of two rotamers in a ratio of 5:1. Re-
duction of 22 with lithium aluminum hydride in refluxing
tetrahydrofuran gave the corresponding benzylamine, which
displayed only one set of resonance signals in the 1H NMR
spectrum. Aluminum chloride2r promoted intramolecular
Obviously, BF3$OEt2 alone was responsible for the intramo-
lecular etherification of 18 and Et3SiH did not play any role
here. Actually, trifluoroacetic acid (TFA) could also bring
about the same intramolecular etherification of 18 although
ether 19 was obtained in only 34% yield in this case. Next,
we were pleased to reveal that exposure of 18 to triethylsi-
lane in the presence of TFA (instead of BF3$OEt2) afforded
17 in 75% yield. Furthermore, bicycle 19, inert to the
BF3$OEt2/Et3SiH system, could be converted to 17 in 61%
yield through reductive ring opening upon treatment with
TFA
34%
.
Bz
O
OH
Bz BF3 OEt2
H
H
Et3SiH
N
NaBH4
88%
N
PMP
H
Bz
PMP
PMP
*
N
82%
O
dr = 70:1
OH
OH
14
19
18
TFA,
Et3SiH
61%
(CH2SH)2
TFA,
Et3SiH
75%
TFA,
Et3SiH
71%
LAH
76%
.
BF3 OEt2
80%
H H
H
N
Ph
H2
Bz
Bz
n
Bu 3SnH
AIBN
S
H
S
MeO
N
N
PMP
PMP
H
H
O
H
86%
H
OH
OH
: NOESY
20
16
17
Scheme 5. Synthesis of 17 and Cyclization of 18. PMP¼p-methoxyphenyl, Bz¼benzoyl.

7526
Z. Ma et al. / Tetrahedron 63 (2007) 7523–7531
Bz
Bz
H
Bz
H
H
N
N
MeLi
80%
N
Swern
98%
PMP
PMP
MeO
OH
Me
OH
O
22
17
21
H
NaOH;
CH2O
NaBH3CN
H
N
Bz
(+)-1
N Me
AlCl3
76%
Ref. 2a
MeO
MeO
71%
Me
Me
24
(2 steps)
23
Scheme 6. Synthesis of 24. PMP¼p-methoxyphenyl, Bz¼benzoyl.
Friedel–Crafts reaction of alcohol 22 took place at room
temperature to generate the desired alkylative cyclization
product 23 as a colorless oil (76%). Thus the tricyclic frame-
work of aphanorphine was rapidly constructed from lactone
10. Hydrolysis19 of 23 with 50% aqueous sodium hydroxide
solution in refluxing ethanol, followed by N-methylation
with formalin and sodium cyanoborohydride in methanol
at room temperature, afforded (ꢀ)-aphanorphine methyl
ether 24 in 71% overall yield for the two steps from 23.
The [a]2D8 of 24 was found to be ꢀ10.38 (c 1.36, CHCl3)
{lit.2a [a]2D7 ꢀ7.40 (c 0.35, CHCl3), lit.2v [a]D30 ꢀ9.72
(c 0.67, CHCl3), lit.2i ent-24 [a]D21 +10.4 (c 1.24, CHCl3)}.
Other spectroscopic data of 24 were in accord with those
reported previously.2i
obtained by chromatography on silica gel. Anhydrous sol-
vents and reagents were obtained as follows: dichlorome-
thane was distilled over calcium hydride under N2; THF,
ether, and toluene were distilled over sodium benzophenone
ketyl under N2.
4.1.1. Compound 4. To a solution of (COCl)2 (2.60 mL,
30.3 mmol) in anhydrous CH2Cl2 (60 mL) was added drop-
wise a solution of DMSO (3.50 mL, 49.3 mmol) in CH2Cl2
(20 mL) at ꢀ78 ꢃC under Ar. The mixture was stirred for
10 min and then a solution of 3 (7.47 g, 19.4 mmol) in anhy-
drous CH2Cl2 (20 mL) was introduced slowly. After the ad-
dition, the mixture was stirred for 0.5 h at ꢀ78 ꢃC and Et3N
(15.0 mL, 108 mmol) was added. The dry-ice bath was re-
moved and the mixture was allowed to warm up to room
temperature over 10 min. After evaporation of the solvent,
the mixture was dissolved in anhydrous THF (50 mL) under
Ar. The THF solution was transferred to an addition funnel
fitted to a three-necked flask charged with a solution of
p-methoxyphenylmagnesium bromide in THF (50 mL)
[prepared from p-methoxyphenyl bromide (12.0 mL,
95.9 mmol)]. The flask was cooled in a dry-ice/acetone
bath. The solution of the aldehyde in THF (50 mL) was
slowly added while the mixture in the reaction flask was vig-
orously stirred. After the addition, the reaction mixture was
stirred at 0 ꢃC for 3 h, quenched with saturated aqueous
NH4Cl solution, concentrated, and extracted with CH2Cl2.
The combined organic layers were dried (MgSO4), filtered,
and concentrated to give a residue, which was chromato-
graphed (hexanes/EtOAc, 4:1) to afford adduct 4 (8.67 g,
91%) as a pale yellow syrup: 1H NMR (300 MHz,
CD3COCD3) d 0.00 (s, 3H), 0.05 (s, 3H), 0.82 (s, 9H),
1.25–1.29 (m, 1H), 2.25–2.33 (m, 1H), 2.54 (s, 3H), 3.22
(dd, J¼10.8, 4.2 Hz, 1H), 3.74 (ddd, J¼10.8, 4.8, 1.8 Hz,
1H), 3.90 (s, 3H), 3.94–3.99 (m, 1H), 4.60–4.63 (m, 1H),
4.76 (dd, J¼3.9, 2.1 Hz, 1H), 5.47 (br s, 1H), 7.04 (dd,
J¼8.7, 2.1 Hz, 2H), 7.46 (dd, J¼8.7, 1.2 Hz, 2H), 7.55
(dd, J¼7.8, 1.2 Hz, 2H), 7.94 (dd, J¼7.8, 1.8 Hz, 2H); 13C
NMR (75 MHz, CD3COCD3) d ꢀ4.9, ꢀ4.8, 18.5, 21.4,
26.1, 34.6, 55.4, 58.2, 66.4, 71.1, 74.0, 114.3, 127.5,
128.6, 130.5, 135.0, 135.7, 144.2, 159.6; EIMS: m/z
(%)¼354 (100), 137 (41), 91 (35), 200 (27), 355 (26), 155
(21), 476 (1) [MꢀCH3]+; Anal. Calcd for C25H37NO5SSi:
C 61.07, H 7.58, N 2.85; found C 61.10, H 7.69; N 2.77.
3. Conclusion
In summary, we have accomplished efficient syntheses of
(1R,4S)-1-methyl-8-methoxy-3-(4-toluenesulfonyl)-2,3,4,5-
tetrahydro-1,4-methano-3-benzazepine (8) in six steps from
sulfonamide 3, and of (ꢀ)-aphanorphine methyl ether 24 in
seven steps from lactone 10, both featuring an intramolecu-
lar Friedel–Crafts reaction for the construction of ring B.
Both 3 and 10 were derived from the same commercially
available amino acid, (2S,4R)-4-hydroxyproline (2). The
present work constitutes efficient formal syntheses of both
natural (ꢀ)-aphanorphine and unnatural (+)-aphanorphine.
In addition, it is noteworthy that under similar conditions
(BF3$OEt2/Et3SiH and TFA/Et3SiH) diol 18 underwent dif-
ferent reactions (intramolecular etherification and reduction,
respectively), which would find applications in total synthe-
sis of natural products. Especially, intramolecular etherifica-
tion of 18 proceeded with excellent stereoselectivity in the
presence of BF3$OEt2, which has paved an efficient syn-
thetic route to a series of medicinally attractive heterocycles.
4. Experimental
4.1. General
Melting points were uncorrected. All solvents and reagents
were obtained from commercial sources and used without
further purification unless otherwise stated. NMR spectra
were recorded in CDCl3, D2O, CD3COCD3, and DMSO-d6
(1H at 300 MHz and 13C at 75, 100, and 125 MHz) using
TMS as the internal standard. Analytical samples were
4.1.2. Compound 5. A mixture of 4 (8.04 g, 16.4 mmol) and
Et3SiH (9.0 mL, 56 mmol) in CH2Cl2 (80 mL) was cooled to

Z. Ma et al. / Tetrahedron 63 (2007) 7523–7531
7527
0 ꢃC by an ice/salt bath. To this cooled solution was added
slowly a solution of BF3$OEt2 (9.0 mL, 71 mmol) in
CH2Cl2 (30 mL). The reaction was monitored by TLC. After
3 h, the reaction was quenched with saturated aqueous
NaHCO3 solution and extracted with CH2Cl2. The combined
organic layers were washed with H2O and brine succes-
sively, dried (MgSO4), filtered, and concentrated. The resi-
due was chromatographed (EtOAc) to afford 5 (5.63 g,
95%) as a pale yellow syrup: [a]2D0 ꢀ78.5 (c 0.95, CHCl3);
1H NMR (300 MHz, CDCl3) d 1.68–1.78 (m, 2H), 2.43 (s,
3H), 2.87 (dd, J¼13.2, 8.4 Hz, 1H), 3.17 (dd, J¼13.5,
3.3 Hz, 1H), 3.26 (dd, J¼10.5, 1.5 Hz, 1H), 3.40 (dd,
J¼10.2, 4.2 Hz, 1H), 3.80 (s, 3H), 3.93–3.97 (m, 1H),
4.02–4.08 (m, 1H), 6.83 (dd, J¼8.7, 1.2 Hz, 2H), 7.16 (dd,
J¼8.7, 1.2 Hz, 2H), 7.33 (d, J¼8.1 Hz, 2H), 7.78 (d,
J¼8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 21.5, 39.2,
41.0, 55.1, 56.8, 60.0, 69.3, 113.7, 127.7, 128.3, 129.6,
130.7, 134.3, 143.6, 158.2; EIMS: m/z (%)¼240 (100), 91
(38), 155 (36), 121 (19), 68 (7), 361 (1) [M]+; Anal. Calcd
for C19H23NO4S: C 63.13, H 6.41, N 3.88; found C 63.25,
H, 6.41, N 4.00.
for C20H25NO4S: C 63.97, H 6.71, N 3.73; found C 64.08,
H 6.97, N 3.50.
4.1.5. Compound 8. Compound 7 (532 mg, 1.42 mmol) and
pulverized AlCl3 (3.20 g, 24.0 mmol) were mixed in anhy-
drous CH2Cl2 (35 mL). The mixture was stirred at room
temperature for 8 h and then quenched with saturated aque-
ous NaHCO3 solution. The organic phase was washed with
distilled H2O and brine successively, dried (MgSO4), filtered
and concentrated. The residue was purified by column
chromatography (hexanes/EtOAc, 10:1) to afford 8 as a col-
orless solid. Recrystallization from petroleum ether/EtOAc
afforded pure 8 (327 mg, 64%) as colorless needles: mp
161–162 ꢃC. [a]D20 ꢀ14.3 (c 0.93, CHCl3); 1H NMR
(300 MHz, CDCl3) d 1.42 (s, 3H), 1.45–1.49 (m, 1H), 1.80
(d, J¼11.1 Hz, 1H), 2.43 (s, 3H), 2.94 (d, J¼16.8 Hz, 1H),
3.02 (dd, J¼9.0, 2.4 Hz, 1H), 3.13 (d, J¼16.2 Hz, 1H),
3.41 (dd, J¼9.0, 1.2 Hz, 1H), 3.79 (s, 3H), 4.37–4.41 (m,
1H), 6.71–6.80 (m, 2H), 6.99 (d, J¼8.4 Hz, 1H), 7.27 (d,
J¼8.4 Hz, 2H), 7.71 (d, J¼8.4 Hz, 2H); EIMS: m/z
(%)¼173 (100), 174 (56), 357 (30) [M]+, 91 (25), 159 (25).
4.1.3. Compound 6. A mixture of 5 (105 mg, 0.290 mmol)
and IBX (o-iodoxybenzoic acid) (656 mg, 2.34 mmol) in
EtOAc (20 mL) was refluxed for 9 h and the solid mass
was filtered off. The filtrate was concentrated to give a resi-
due, which was chromatographed (petroleum ether/EtOAc,
3:1) to afford 6 (102 mg, 98%) as a colorless solid: mp 98–
4.1.6. Compound 9. To a solution of (2S,4R)-4-hydroxypro-
line (2, 10 g, 0.076 mol) in cold aqueous NaOH solution
(1.0 M, 200 mL, 0.20 mol) was added freshly distilled
BzCl (12 mL, 0.10 mol) in Et2O (200 mL). The mixture
was stirred for 24 h and the ether layer was then separated
off. The aqueous layer was washed with Et2O, cooled in
an ice-bath, and acidified with hydrochloric acid. The solid
was collected by filtration, washed with several portions of
Et2O to remove residual benzoic acid, and dried to provide
9 (13.55 g, 76%) as a colorless solid: mp 192–194 ꢃC;
1
99 ꢃC; [a]D20 +61.1 (c 0.94, CHCl3); H NMR (300 MHz,
CDCl3) d 2.25 (d, J¼7.8 Hz, 2H), 2.44 (s, 3H), 2.87 (AB
part of ABX, JAB¼13.2, JAx¼8.1, JBx¼3.3 Hz, 2H), 3.55
(AB, JAB¼18.6 Hz, 2H), 3.79 (s, 3H), 4.44–4.49 (m, 1H),
6.81 (d, J¼8.1 Hz, 2H), 7.09 (d, J¼8.1 Hz, 2H), 7.33 (d,
J¼8.1 Hz, 2H), 7.73 (d, J¼8.1 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 21.5, 40.9, 41.5, 53.1, 55.1, 58.5,
114.0, 127.1, 127.7, 130.0, 130.7, 134.8, 144.1, 158.6,
209.2; EIMS: m/z (%)¼182 (100), 181 (61), 155 (32), 91
(31), 238 (24), 359 (3) [M]+; Anal. Calcd for C19H21NO4S:
C 63.49, H 5.89, N 3.90; found C 63.48, H 5.90, N 3.74.
1
[a]2D6 ꢀ135.8 (c 1.38, EtOH); H NMR (300 MHz, D2O)
d 2.10–2.21 (m, 1H), 2.41 (dd, J¼13.8, 7.8 Hz, 1H), 3.43
(d, J¼12.3 Hz, 1H), 3.80 (dd, J¼12.0, 3.0 Hz, 1H), 4.40–
4.46 (m, 1H), 4.66 (dd, J¼9.6, 8.4 Hz, 1H), 7.38–7.53 (m,
5H).
4.1.7. Compound 10. A mixture of 9 (3.00 g, 12.8 mmol)
and acetic anhydride (22 mL) was heated at 90 ꢃC under
nitrogen for 5 h, cooled to room temperature, concentrated,
and taken up in dichloromethane. The organic phase was
washed with cold water, dried (Na2SO4), and concentrated.
The residue was chromatographed (petroleum ether/EtOAc,
2:5) to yield 10 (2.5 g, 90%) as a colorless solid: mp 128–
4.1.4. Compound 7. To a solution of methylmagnesium
iodide [prepared from methyl iodide (0.80 mL, 13 mmol)]
in anhydrous Et2O (20 mL) was added dropwise a solution
of 6 (655 mg, 1.82 mmol) in anhydrous THF (10 mL). The
reaction mixture was refluxed for 24 h and then quenched
with saturated aqueous NH4Cl solution. After removal of
organic solvents, the residue was extracted with CH2Cl2.
The combined extracts were washed with distilled H2O
and brine successively, dried (MgSO4), filtered, and concen-
trated. The residue was chromatographed (hexanes/EtOAc,
1:1) to afford 7 (532 mg, 78%) as a syrup: 1H NMR
(300 MHz, CDCl3) d 1.07 (s, 2.4H), 1.18 (s, 0.6H), 1.52–
1.84 (m, 2H), 1.79 (s, 1H), 2.41 (s, 0.6H), 2.43 (s, 2.4H),
3.07 (d, J¼10.5 Hz, 1H), 3.18–3.27 (m, 2H), 3.33 (d,
J¼10.2 Hz, 1H), 3.74–3.78 (m, 1H), 3.75 (s, 3H), 6.85 (d,
J¼8.1 Hz, 2H), 7.19 (d, J¼8.1 Hz, 2H), 7.34 (d, J¼8.1 Hz,
2H), 7.76 (d, J¼8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d (for the major epimer) 21.5, 25.4, 41.1, 43.0, 55.2, 61.5,
61.6, 75.9, 113.9, 127.6, 129.7, 130.0, 130.9, 133.7, 143.7,
158.2; d (for the minor epimer) 21.5, 24.1, 40.9, 45.4,
55.2, 61.0, 61.6, 75.9, 113.7, 127.7, 129.6, 130.0, 130.6,
133.7, 143.7, 158.2; EIMS: m/z (%)¼254 (100), 91 (46),
155 (27), 121 (23), 255 (16), 375 (0.4) [M]+; Anal. Calcd
1
130 ꢃC; [a]2D5 ꢀ93.0 (c 1.14, EtOH); H NMR (300 MHz,
CDCl3) d 2.11 (dd, J¼10.8, 1.2 Hz, 1H), 2.29 (d,
J¼10.5 Hz, 1H), 3.60–3.80 (m, 1H), 3.80 (d, J¼10.2 Hz,
1H), 4.60 (br s, 1H), 5.24 (br s, 1H), 7.40–7.55 (m, 3H),
7.63 (d, J¼7.2 Hz, 2H).
4.1.8. Compound 11. To a solution of (2S,4R)-4-hydroxy-
proline (2, 5.0 g, 38 mmol) in water (40 mL) were added
Na2CO3 (8.5 g, 80 mmol) at 0 ꢃC. Then p-toluenesulfonyl
chloride (8.73 g, 45.8 mmol) was added in several portions
over a period of 20 min. The slurry was then warmed to
room temperature and allowed to stir for 48 h. The reaction
mixture was acidified with concentrated HCl solution to pH
2 and the crude product was isolated via filtration. The filter
cake was washed with 0.01 M HCl solution and dried
in vacuum oven at 60 ꢃC for 12 h to yield 11 (9.01 g, 83%)
1
as a colorless solid: mp 149–151 ꢃC; H NMR (300 MHz,
DMSO-d6) d 1.90–2.00 (m, 2H), 2.39 (s, 3H), 3.08 (d,

7528
Z. Ma et al. / Tetrahedron 63 (2007) 7523–7531
J¼10.8 Hz, 1H), 3.45 (dd, J¼9.9, 3.3 Hz, 1H), 4.04 (t, J¼
8.1 Hz, 1H), 4.15–4.30 (m, 1H), 4.84 (s, 1H), 7.40 (d,
J¼7.5 Hz, 2H), 7.69 (d, J¼7.8 Hz, 2H), 12.71 (s, 1H).
198.0; ESI-MS: m/z (%)¼326 (100) [M+H]+, 348 (64)
[M+Na]+, 673 (34) [2M+Na]+; Anal. Calcd for
C19H19NO4: C 70.14, H 5.89, N 4.31; found C 70.00, H
5.89, N 4.14.
4.1.9. Compound 12. A mixture of 11 (350 mg, 1.23 mmol)
and acetic anhydride (2 mL) was heated at 90 ꢃC under ni-
trogen for 8 h, cooled to room temperature, concentrated,
and the residual acetic anhydride was neutralized with satu-
rated aqueous NaHCO3 solution. The mixture was acidified
with HCl solution to pH 2 and extracted with CH2Cl2/IPA
(3:1). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated. The residue was chromatographed
(EtOAc/MeOH, 4:1) to yield 12 (382 mg, 95%) as a colorless
solid: mp 55–57 ꢃC; [a]D25 ꢀ76.4 (c 1.38, CHCl3); 1H NMR
(300 MHz, DMSO-d6) d 1.50 (s, 3H), 2.06–2.16 (m, 1H),
2.24 (dd, J¼14.4, 7.5 Hz, 1H), 2.40 (s, 3H), 3.36 (d,
J¼12.9 Hz, 1H), 3.64 (dd, J¼12.9, 3.9 Hz, 1H), 4.06 (dd,
J¼9.6, 7.2 Hz, 1H), 5.02 (s, 1H), 7.46 (d, J¼7.8 Hz, 2H),
7.71 (d, J¼7.8 Hz, 2H), 12.94 (br s, 1H); 13C NMR
(75 MHz, DMSO-d6) d 19.7, 20.5, 35.7, 53.5, 59.5, 72.2,
127.1, 129.3, 133.6, 143.2, 169.1, 172.5; ESI-MS: m/z
(%)¼328 (100) [M+H]+, 345 (15) [M+NH4]+, 350 (28)
[M+Na]+. HRMS (MALDI): calcd for C14H18NO6S
[M+H]+ 328.0855; found 328.0849.
4.1.11. Compound 14 (from 13). A solution of 4-methoxy-
phenylmagnesium bromide (0.275 M, (7.5+12) mL,
5.36 mmol), prepared from 4-bromoanisole and Mg in
THF, was added to a solution of 13 (212 mg, 0.762 mmol)
in THF (7 mL) at ꢀ35 ꢃC. The mixture was warmed gradu-
ally to room temperature, stirred at that temperature for 4 h,
quenched with saturated aqueous NH4Cl solution, concen-
trated, and extracted with EtOAc. The combined organic
layers were washed with brine, dried (MgSO4), filtered,
and concentrated to give a residue, which was chromato-
graphed (petroleum ether/EtOAc, 1:2) to afford 14
(159 mg, 64%) as a colorless solid.
4.1.12. Compound 16. A mixture of 14 (4.20 g, 12.9 mmol),
1,2-ethanedithiol (4.4 mL, 52 mmol), and BF3$OEt2
(0.66 mL, 5.2 mmol) in dry CH2Cl2 (110 mL) was refluxed
for 4 days. The reaction mixture was quenched with satu-
rated aqueous NaHCO3 solution and extracted with
CH2Cl2. The combined organic layers were washed with
brine, dried (MgSO4), filtered, and concentrated. The resi-
due was chromatographed (petroleum ether/EtOAc, 3:2) to
yield 16 (4.17 g, 80%) as a colorless solid: mp 168–
4.1.10. Compounds 13, 14 and 15 (from 10). A solution of
4-methoxyphenylmagnesium bromide (0.278 M, 19.0 mL,
5.28 mmol), prepared from 4-bromoanisole and Mg in
THF, was added to a mixture of 10 (300 mg, 1.38 mmol)
and Me(MeO)NH$HCl (162 mg, 1.66 mmol) in THF
(18 mL) under nitrogen at ꢀ78 ꢃC. The mixture was stirred
at ꢀ78 ꢃC for 10 h, quenched with saturated aqueous
NH4Cl solution, and extracted with EtOAc. The combined
organic layers were dried (MgSO4), filtered, and concen-
trated. The residue was chromatographed (petroleum ether/
EtOAc, 1:1, 1:2 then 0:1) to afford sequentially 15 (26 mg,
4%), 14 (187 mg, 41%), and 13 (212 mg, 55%) as colorless
solids. Compound 15: mp 146–148 ꢃC; [a]D23 ꢀ71.8 (c
0.97, CHCl3); 1H NMR (300 MHz, CDCl3) d 1.84–1.93 (m,
1H), 2.30–2.41 (m, 1H), 3.10–3.30 (m, 2H), 3.55–3.67 (m,
1H), 3.71 (s, 3H), 3.83 (s, 3H), 4.15–4.30 (m, 1H), 5.15–
5.25 (m, 1H), 5.44–5.55 (m, 1H), 6.76 (d, J¼6.6 Hz, 2H),
6.92 (d, J¼9.0 Hz, 2H), 7.22–7.50 (m, 9H). ESI-MS: m/z
(%)¼416 (100) [MꢀOH]+, 456 (39) [M+Na]+; Anal. Calcd
for C26H27NO5: C 72.04, H 6.28, N 3.23; found C 71.84, H
6.26, N 3.11. Compound 13: mp 126–128 ꢃC; [a]D24 ꢀ150.3
1
170 ꢃC; [a]D25 +68.0 (c 0.92, CHCl3); H NMR (300 MHz,
CDCl3) d 1.75–1.85 (m, 1H), 2.36–2.50 (m, 1H), 2.61 (d,
J¼6.6 Hz, 1H), 3.02–3.10 (m, 3H), 3.26–3.34 (m, 2H),
3.55–3.65 (m, 1H), 3.79 (s, 3H), 3.95–4.08 (m, 1H),
5.30 (t, J¼7.5 Hz, 1H), 6.84 (d, J¼8.4 Hz, 2H), 7.33–
7.45 (m, 3H), 7.49 (d, J¼6.6 Hz, 2H), 7.78 (d, J¼8.4 Hz,
2H); 13C NMR (75 MHz, CDCl3) d 38.2, 38.3, 38.5,
55.2, 57.7, 62.5, 69.2, 80.1, 112.8, 128.1, 128.2, 130.0,
130.8, 134.5, 135.5, 158.8, 171.7; ESI-MS m/z (%)¼402
(100) [M+H]+, 424 (16) [M+Na]+. HRMS (MALDI):
calcd for C21H23NO3S2Na [M+Na]+ 424.1017; found
424.1012.
4.1.13. Compound 17 from 16. To a stirred solution of
16 (4.03 g, 10.0 mmol) in dry toluene (100 mL) maintained
at 90 ꢃC under argon was added a solution of tributyltin
hydride (11.0 mL, 40.9 mmol) and AIBN (660 mg,
4.02 mmol) in toluene (25 mL). The reaction mixture was
stirred for 2.5 h, cooled to room temperature, quenched
with saturated aqueous NaHCO3 solution, and extracted
with EtOAc. The combined organic layers were washed
with brine, dried (MgSO4), filtered, and concentrated. The
residue was chromatographed (petroleum ether/EtOAc, 3:2
then 1:2) to provide recovered 16 (617 mg, 15%) and 17
(2.26 g, 73%; or 86% brsm). Compound 17, a colorless
solid: mp 70–72 ꢃC; [a]D26 +95.7 (c 0.91, CHCl3); 1H NMR
(300 MHz, CDCl3) d 1.70–2.20 (m, 2H), 2.55–3.05 (m,
1.5H), 3.08–3.24 (m, 1.5H), 3.50–3.60 (m, 1H), 3.78 (s,
3H), 4.00–4.30 (m, 1H), 4.40–4.60 (m, 1H), 6.55–6.70 (m,
1H), 6.87 (d, J¼8.1 Hz, 1.5H), 7.20 (d, J¼7.8 Hz, 1.5H),
7.35–7.50 (m, 5H); 13C NMR (100 MHz, CDCl3) d 37.0,
37.8, 55.1, 57.0, 57.6, 69.2, 113.6, 126.2, 127.1, 128.1,
130.1, 130.6, 136.4, 158.0, 170.0; ESI-MS m/z (%)¼312
(100) [M+H]+, 333 (73) [M+NaꢀH], 366 (15)
[M+MeOH+Na]+, 645 (21) [2M+Na]+; HRMS (EI): calcd
for C19H21NO3 311.1521; found 311.1518.
1
(c 1.23, CHCl3); H NMR (300 MHz, CDCl3) d 2.02 (d,
J¼10.8 Hz, 1H), 2.34–2.44 (m, 1H), 3.30 (s, 3H), 3.71 (s,
2H), 3.94 (s, 3H), 4.32 (d, J¼10.5 Hz, 1H), 5.18 (s, 1H),
5.24 (d, J¼10.2 Hz, 1H), 7.36–7.45 (m, 3H), 7.51–7.54 (m,
2H); 13C NMR (100 MHz, CDCl3) d 32.2, 36.7, 55.0, 59.0,
61.2, 71.3, 127.0, 128.2, 130.1, 135.8, 169.9, 173.6; ESI-
MS: m/z (%)¼218 (100) [MꢀN(MeO)Me]+, 279 (20)
[M+H]+, 301 (93) [M+Na]+; HRMS (MALDI): calcd for
C14H18N2O4Na [M+Na]+ 301.1164; found 301.1159. Com-
pound 14: mp 152–154 ꢃC; [a]D28 ꢀ162.9 (c 0.87, CHCl3);
1H NMR (300 MHz, CDCl3) d 2.0 (d, J¼13.8 Hz, 1H),
2.38–2.48 (m, 1H), 3.76 (s, 2H), 3.87 (s, 3H), 4.30–4.40
(m, 1H), 4.46 (d, J¼10.5 Hz, 1H), 5.70 (d, J¼9.6 Hz, 1H),
6.97 (d, J¼8.4 Hz, 2H), 7.38–7.45 (m, 3H), 7.53 (d,
J¼6.3 Hz, 2H), 8.12 (d, J¼7.8 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 36.8, 55.5, 57.9, 59.4, 70.8, 113.9,
127.3, 128.0, 128.2, 130.3, 131.1, 135.4, 164.0, 169.3,

Z. Ma et al. / Tetrahedron 63 (2007) 7523–7531
7529
4.1.14. Compound 17 from 14. To a stirred solution of 14
(150 mg, 0.461 mmol) in trifluoroacetic acid (3 mL) at
0 ꢃC was added Et3SiH (0.60 mL, 3.8 mmol). The mixture
was stirred at room temperature for 36 h. After removal of
most of the solvent, the residue was quenched with saturated
aqueous NaHCO3 solution and extracted with EtOAc. The
combined organic layers were washed with brine, dried
(MgSO4), filtered, and concentrated. The residue was chro-
matographed (petroleum ether/EtOAc, 1.5:1 then 1:2) to
give sequentially 17 (89 mg, 62% or 71% brsm) as a color-
less solid, 14 (19 mg, 13%).
layers were washed with brine, dried (MgSO4), filtered,
and concentrated. The residue was chromatographed (petro-
leum ether/EtOAc, 1:1) to give 19 (88 mg, 82%) as a color-
less oil, rotamers (1.3:1): [a]2D6 ꢀ157.9 (c 1.37, CHCl3).
Major rotamer: 1H NMR (300 MHz, CDCl3) d 1.61 (d,
J¼10.2 Hz, 1H), 1.82 (d, J¼10.2 Hz, 1H), 3.66 (s, 2H),
3.72 (s, 3H), 4.22 (s, 1H), 4.84 (s, 1H), 5.12 (s, 1H), 6.81
(d, J¼8.7 Hz, 2H), 7.02 (d, J¼8.4 Hz, 2H), 7.40–7.53 (m,
3H), 7.53–7.62 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 33.1, 55.1 (probably corresponding to two types of car-
bon), 65.2, 76.1, 84.6, 113.7, 126.0, 126.9, 128.5, 130.2,
131.5, 136.2, 158.9, 169.0. Minor rotamer: 1H NMR
(300 MHz, CDCl3) d 1.67 (d, J¼10.5 Hz, 1H), 1.93 (d,
J¼9.9 Hz, 1H), 3.47 (s, 2H), 3.76 (s, 3H), 4.71 (s, 1H),
4.87 (s, 1H), 5.16 (s, 1H), 6.88 (d, J¼8.4 Hz, 2H), 7.29 (d,
J¼8.7 Hz, 2H), 7.40–7.53 (m, 3H), 7.53–7.62 (m, 2H); 13C
NMR (75 MHz, CDCl3) d 31.5, 53.5, 57.3, 61.6, 76.3,
84.0, 113.6, 126.4, 127.2, 128.2, 130.3, 132.1, 135.7,
158.8, 170.1; ESI-MS m/z (%)¼310 (100) [M+H]+, 332
(17) [M+Na]+, 350 (12) [M+NH4+Na]+, 364 (43)
[M+MeOH+Na]+, 641 (35) [2M+Na]+; Anal. Calcd for
C19H19NO3: C 73.77, H 6.19, N 4.53; found C 73.63, H
6.30, N 4.47.
4.1.15. Compound 17 from 18. To a stirred solution of 18
(150 mg, 0.458 mmol) in trifluoroacetic acid (3 mL) at
0 ꢃC was added Et3SiH (0.60 mL, 3.8 mmol). The mixture
was stirred at room temperature for 3 h. Standard work-up
and chromatography by the procedure described for the
conversion of 14 to 17 gave 17 (107 mg, 75%).
4.1.16. Compound 17 from 19. To a stirred solution of 19
(41 mg, 0.13 mmol) in trifluoroacetic acid (1 mL) at 0 ꢃC
was added Et3SiH (0.17 mL, 1.1 mmol). The mixture was
stirred at room temperature for 18.5 h. Standard work-up
and chromatography by the procedure described for the
conversion of 14 to 17 gave 17 (25 mg, 61%).
(b) From 18 in the presence of TFA: a stirred solution of 18
(100 mg, 0.305 mmol) in trifluoroacetic acid (3 mL) was
stirred at room temperature for 6.5 h. Standard work-up
and chromatography by the procedure described above
gave 19 (32 mg, 34%).
4.1.17. Compound 18. To a solution of 14 (240 mg,
0.738 mmol) in MeOH (5 mL) at 0 ꢃC was added NaBH4
(110 mg, 2.91 mmol). The reaction mixture was stirred at
this temperature for 1 h, and then acetone was added to
quench the excess NaBH4. The mixture was concentrated,
diluted with saturated aqueous NH4Cl solution, and ex-
tracted with EtOAc. The combined organic layers were
washed with brine, dried (MgSO4), filtered, and concen-
trated. The residue was chromatographed (petroleum ether/
EtOAc, 1:2) to give 18 (212 mg, 88%) as a colorless solid:
4.1.19. Compound 20. To a suspension of LiAlH4 (29 mg,
0.763 mmol) in THF (4 mL) at room temperature was added
a solution of 19 (59 mg, 0.19 mmol) in THF (6 mL). The
mixture was refluxed for 30 min and then cooled to room
temperature. A small quantity of Na2SO4 solid and several
drops of H2O were added to the reaction mixture. The solid
mass was filtered off and the filtrate was concentrated to give
a residue, which was chromatographed (petroleum ether/
EtOAc, 2:1) to give 20 (43 mg, 76%) as a pale yellow oil:
[a]2D6 ꢀ104.9 (c 0.87, CHCl3); 1H NMR (300 MHz,
CDCl3) d 1.66 (dd, J¼10.2, 2.1 Hz, 1H), 1.75 (d,
J¼9.9 Hz, 1H), 2.69 (d, J¼9.9 Hz, 1H), 2.98 (dd, J¼9.6,
1.2 Hz, 1H), 3.35 (s, 1H), 3.79 (s, 3H), 3.94 (dd, J¼20.7,
12.3 Hz, 2H), 4.60 (s, 1H), 5.24 (s, 1H), 6.86 (d,
J¼8.7 Hz, 2H), 7.15 (d, J¼8.7 Hz, 2H), 7.25–7.50 (m,
5H); 13C NMR (75 MHz, CDCl3) d 31.6, 55.1, 57.3, 59.8,
66.9, 77.5, 78.9, 113.4, 126.2, 127.0, 128.3, 128.5, 133.8,
139.3, 158.3; ESI-MS m/z (%)¼296 (100) [M+H]+; HRMS
(MALDI): calcd for C19H22NO2 [M+H]+ 296.1651; found
296.1645.
1
mp 70–72 ꢃC; H NMR (300 MHz, CDCl3) d 1.51–1.59
(m, 1H), 1.81–1.90 (m, 1H), 3.23–3.36 (m, 2H), 3.56 (dd,
J¼11.4, 6.0 Hz, 1H), 3.77 (s, 3H), 4.08 (dd, J¼11.1,
5.4 Hz, 1H), 4.62 (dd, J¼13.8, 7.5 Hz, 1H), 4.89 (d,
J¼7.5 Hz, 1H), 5.67 (s, 1H), 6.85 (d, J¼8.4 Hz, 2H), 7.30
(d, J¼8.4 Hz, 2H), 7.36–7.46 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 36.2, 55.1, 57.9, 63.3, 68.7, 77.7,
113.6, 126.9, 128.2, 130.3, 133.7, 135.7, 159.0, 173.0,
229.5; ESI-MS m/z (%)¼310 (93) [MꢀOH]+, 350 (100)
[M+Na]+, 382 (29) [M+MeOH+Na]+, 677 (80) [2M+Na]+;
HRMS (EI): calcd for C19H19NO3 [MꢀH2O] 309.1365;
found 309.1373. A small amount of the epimer of 18 (as
the minor product) was also isolated. epi-18: 1H NMR
(300 MHz, CDCl3) d 1.97–2.10 (m, 2H), 3.50–3.58 (m,
2H), 3.82 (s, 3H), 4.20–4.27 (m, 1H), 4.60–4.67 (m, 1H),
5.52–5.58 (m, 1H), 6.91 (d, J¼8.1 Hz, 2H), 7.33–7.52 (m,
7H); ESI-MS m/z (%)¼310 (100) [MꢀOH]+, 328 (41)
[M+H]+.
4.1.20. Compound 21. To a solution of (COCl)2 (78 mL,
0.91 mmol) in CH2Cl2 (5 mL) was added dropwise a solution
of DMSO (0.13 mL, 1.8 mmol) in CH2Cl2 (3 mL) at
ꢀ78 ꢃC. The mixture was stirred at ꢀ78 ꢃC for 10 min and
a solution of 17 (70 mg, 0.22 mmol) in CH2Cl2 (3 mL)
was added. The mixture was stirred at ꢀ78 ꢃC for 30 min
and Et3N (0.38 mL, 2.7 mmol) was added. The reaction mix-
ture was allowed to warm to room temperature. Standard
work-up and evaporation gave a residue, which was chroma-
tographed (petroleum ether/EtOAc, 2:1) to afford 21 (68 mg,
98%) as a pale yellow solid: mp 98–100 ꢃC; [a]D27 +8.2 (c
4.1.18. Compound 19. (a) From 18 in the presence of
BF3$OEt2 and Et3SiH:
a mixture of 18 (113 mg,
0.345 mmol) and Et3SiH (0.44 mL, 2.76 mmol) in CH2Cl2
(18 mL) was cooled in an ice/salt bath to 0 ꢃC. To this cooled
solution was added slowly BF3$OEt2 (0.32 mL, 2.5 mmol).
When the reaction reached completion as judged by TLC,
the mixture was quenched with saturated aqueous NaHCO3
solution and extracted with CH2Cl2. The combined organic
1
1.14, CHCl3); H NMR (300 MHz, CDCl3) d 2.40–3.10

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Z. Ma et al. / Tetrahedron 63 (2007) 7523–7531
(m, 4H), 3.40–3.80 (m, 2H), 3.78 (s, 3H), 4.10–5.35 (m, 1H),
6.71–7.22 (m, 4H), 7.37–7.52 (m, 5H); ESI-MS m/z
(%)¼310 (85) [M+H]+, 332 (56) [M+Na]+, 364 (100)
[M+MeOH+Na]+; Anal. Calcd for C19H19NO3: C 73.77, H
6.19, N 4.53; found C 73.93, H 6.24, N 4.32.
chromatographed (CH2Cl2/MeOH/Et3N, 100:10:1) to give
the hydrolysis product.
A mixture of the above hydrolysis product, formalin (con-
taining 37% CH2O, 1.4 mL, 18 mmol), and NaCNBH3
(95%, 990 mg, 15.0 mmol) in MeOH (18 mL) was stirred
overnight at room temperature. After evaporation of the
volatiles, the residue was partitioned between 5% HCl and
ether, and the two layers were separated. The aqueous layer
was washed one more time with ether and the organic layer
was discarded. The aqueous layer was made basic with con-
centrated NH4OH solution and extracted with CH2Cl2/IPA
(3:1). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated. The residue was chromatographed
(CH2Cl2/MeOH/Et3N, 100:2:1) to give (ꢀ)-aphanorphine
methyl ether 24 (230 mg, 71% for two steps from 23) as
4.1.21. Compound 22. A solution of MeLi (1.0 M, 1.20 mL,
1.20 mmol) was added dropwise to a solution of 21 (277 mg,
0.895 mmol) in anhydrous THF (15 mL) at ꢀ78 ꢃC. After
2 h, the mixture was quenched with saturated aqueous
NH4Cl solution, concentrated, and extracted with EtOAc.
The combined organic layers were washed with brine, dried
(MgSO4), filtered, and concentrated. The residue was chro-
matographed (petroleum ether/EtOAc, 5:2 then 3:2) to af-
ford recovered 21 (143 mg, 52%) and 22 (113 mg, 39%; or
80% brsm). Compound 22, a colorless solid: mp 121–
123 ꢃC; [a]2D7 +107.9 (c 0.85, CHCl3); 1H NMR
(300 MHz, CDCl3) d 1.21 (s, 2.5H), 1.44 (s, 0.5H), 1.91
(d, J¼7.2 Hz, 2H), 2.26 (s, 1H), 2.96–3.10 (m, 1H), 3.13–
3.35 (m, 2.5H), 3.70–3.82 (m, 0.5H), 3.79 (s, 3H), 4.00–
4.15 (m, 0.17H), 4.40–4.50 (m, 0.83H), 6.56–6.77 (m,
0.66H), 6.85 (d, J¼7.2 Hz, 1.67H), 7.18 (d, J¼7.8 Hz,
1.67H), 7.38–7.45 (m, 3H), 7.45–7.55 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 26.2, 37.7, 42.8, 55.1, 58.1, 62.2,
75.1, 113.7, 126.3, 127.2, 128.2, 130.1, 130.7, 136.5,
158.1, 170.2; ESI-MS m/z (%)¼326 (100) [M+H]+, 348
(39) [M+Na]+, 380 (8) [M+MeOH+Na]+; Anal. Calcd for
C20H23NO3: C 73.82, H 7.12, N 4.30; found C 73.95, H
7.11, N 4.17.
1
a colorless oil: [a]D28 ꢀ10.38 (c 1.36, CHCl3); H NMR
(300 MHz, CDCl3) d 1.46 (s, 3H, CH3), 1.83 (d,
J¼11.1 Hz, 1H, 0.5CH2), 2.01 (dd, J¼11.1, 6.0 Hz, 1H,
0.5CH2), 2.46 (s, 3H, NCH3), 2.74 (d, J¼6.0 Hz, 1H,
0.5CH2), 2.81 (s, 1H, 0.5CH2), 2.84 (s, 1H, 0.5CH2), 3.02
(d, J¼16.8 Hz, 1H, 0.5CH2), 3.37–3.40 (m, 1H, NCH),
3.75 (s, 3H, OCH3), 6.67 (dd, J¼8.4, 2.1 Hz, 1H, CH),
6.77 (s, 1H, CH), 7.00 (d, J¼8.4 Hz, 1H, CH); 13C NMR
(100 MHz, CDCl3) d 21.2, 35.3, 41.3, 41.4, 42.9, 54.9,
61.1, 71.0, 109.1, 110.8, 125.6, 129.9, 147.6, 157.5; EIMS
m/z (%)¼218 (18) [M+H]+, 217 (48) [M]+, 202 (100), 159
(64), 144 (28), 115 (38); HRMS (EI): calcd for C14H19NO
217.1467; found 217.1460.
4.1.22. Compound 23. AlCl3 (4.14 g, 31.0 mmol) was
added to a solution of 22 (0.718 g, 2.21 mmol) in dry
CH2Cl2 (45 mL). The mixture was stirred at room tempera-
ture for 27 h and poured into saturated aqueous NaHCO3 so-
lution. The solid mass was filtered off and the two layers of
the filtrate were separated. The aqueous layer was extracted
with CH2Cl2. The combined organic layers were washed
successively with water and brine, dried (MgSO4), filtered,
and concentrated. The residue was chromatographed (petro-
leum ether/EtOAc, 3:1) to give 23 (513 mg, 76%) as a color-
Acknowledgements
The financial support was provided by the grants from NSFC
(20625204; 20632030), STCSM (‘Post-Venus’ Program,
05QMH1416), and GCCP of ECNU.
References and notes
1
less oil: [a]2D8 +76.2 (c 1.53, CHCl3); H NMR (300 MHz,
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2.81 (s, 0.67H), 2.98 (dd, J¼17.1, 2.4 Hz, 0.67H), 3.30–
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