DDQ-Promoted Benzylic/Allylic sp3 C-H Activation for the Stereoselective Intramolecular C-N Bond Formation: Applications to the Total Synthesis of (-)-Codonopsinine, (+)-5-epi-Codonopsinine, (+)-Radicamine B, and (-)-Codonopsinol

Article abstract of DOI:10.1021/acs.joc.5b02275

This is the first report on an intramolecular C-N bond formation of an amide-tethered benzylic/allylic system using DDQ under neutral conditions which has been successfully applied to the total synthesis of naturally occurring pyrolidine alkaloids. The key steps for the synthesis of corresponding precursors involve Julia-Kociensky olefination/cross-metathesis and dihydroxylation reactions, and this methodology is also extended to the ω-unsaturated N-sulfanilamide to furnish piperidines.

Full text of DOI:10.1021/acs.joc.5b02275

Subscriber access provided by NEW YORK UNIV
Article
DDQ-Promoted benzylic/allylic sp3 C-H activation for the stereoselective
intramolecular C-N bond formation: Applications to the total synthesis of (-)
codonopsinine, (+) 5-epi codonopsinine, (+) radicamine B and (-) codonopsinol
Macha Lingamurthy, Yerri Jagadeesh, Katakam Ramakrishna, and Batchu Venkateswara Rao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02275 • Publication Date (Web): 15 Jan 2016
Downloaded from http://pubs.acs.org on January 16, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 33
The Journal of Organic Chemistry
1
2
3
4
5
DDQ-Promoted benzylic / allylic sp3 C–H activation for the stereoselective intramolecu-
lar C–N bond formation: Applications to the total synthesis of (–) codonopsinine, (+) 5-
6
7
8
9
epi codonopsinine, (+) radicamine B and (–) codonopsinol
Macha Lingamurthy, Yerri Jagadeesh, Katakam Ramakrishna and Batchu Venkateswara Rao*
† Organic and Biomolecular Chemistry Division, CSIRꢀIndian Institute of Chemical Technology, Tarnaka,
Hyderabadꢀ500007, Telangana, India
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ABSTRACT: This is the first report on an intramolecular C–N bond formation of amide
tethered benzylic / allylic system using DDQ under neutral conditions which has been sucꢀ
cessfully applied to the total synthesis of naturally occurring pyrolidine alkaloids. The key
steps for the synthesis of corresponding precursors involve JuliaꢀKociensky olefination /
crossꢀmetathesis and dihydroxylation reactions and this methodology is also extended to the
ωꢀunsaturated Nꢀsulfanilamide to furnish piperidines.
INTRODUCTION
Presently, oxidative functionalisation of C–H bonds is an important strategy in organꢀ
ic synthesis. It provides excellent approach to make complex molecules from readily accessiꢀ
ble substrates.1 Direct conversion of C–H bond into C–N bond is a useful method for the synꢀ
thesis of valuable nitrogen containing compounds, which are prevalent in pharmaceuticals,
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 33
1
2
3
4
5
6
7
8
9
fine chemicals, and natural products. Several approaches have been developed for this purꢀ
pose using metal catalysts and HofmannꢀLofflerꢀFreytag reaction that involve activation of
benzylic / allylic sp3 C–H to form C–N bond.2 In general, the reaction on to nitrogen to give
C–N bond is more complicated, since it depends on the choice of protecting group, pH etc.,
than the analogues reactions with O and C ꢀ nucleophiles. Oxidation of benzylic and allylic
C–H bonds with DDQ (2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀbenzoquinone) giving rise to carbeniꢀ
um ions and their reaction with carbon nucleophiles intramolecularly to give functionalised
systems is a useful approach for making cyclic compounds.3 Conversion of benzylic / allylic
C–H to C–N bond in presence of DDQ has not been exploited and there are only couple of
reports are known for its intermolecular formation.4 To the best of our knowledge its intramoꢀ
lecular variant has not been studied. The development of such kind of strategy will provide an
excellent opportunity to create nitrogen heterocyclics under metal free conditions. Herein, we
report the DDQꢀmediated activation of benzylic / allylic sp3 C–H bond and its coupling with
amide to get C–N bond intramolecularly and application of this strategy for the synthesis of
pyrrolidine alkaloids such as (–) codonopsinine 15, (–) codonopsinol 36, (+) radicamine B 57
and (+) 5ꢀepi codonopsinine 6.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1: Pyrrolidine natural products
(–) Codonopsinine 1 and (–) codonopsine 2 (Figure 1) were isolated in 1969 from
Codonopsis clematidea. These two compounds have shown antibiotic and hypotensive activiꢀ
2
ACS Paragon Plus Environment

Page 3 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ties without interfering the central nervous system in animal tests.8 (–) Codonopsinol 3 was
isolated from the C. clematidea, whose aerial parts are useful for treating liver diseases.6a (–)
Codonopsinol 3 was found to have an inhibitary activity against αꢀglucosidase of yeast and
Bacillus stearothermophilus lymph.6c Radicamine A 4 and radicamine B 5 were isolated from
Lobelia chinenis Lour, a herb used in Chinese folk medicine.9a,b This herb is known for its
diuretic, antidote and hemostat activity. It also acts as a carcinostatic agent for stomach canꢀ
cer and was found to exhibit inhibitory activity on αꢀglucosidase.9c,d Recently interest in the
total synthesis of codonopsinine 1 and related structures originated because of their pharmaꢀ
cological activity and interesting structural features which constitute 1,2,3,4ꢀtetra substituted
pyrrolidine ring bearing four contiguous streogenic centres (2R,3R,4R&5R) in all trans arꢀ
rangement (Figure 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RESULTS AND DISCUSSION
Scheme 1: Retrosynthetic analysis of (–) codonopsinine and related natural products
The retrosynthetic plan was designed for the above natural products based on the enꢀ
visaged DDQꢀmediated C–N bond formation from 7 (Scheme 1).
Initially we planned to synthesise, (–) codonopsinine 1 starting from commercial
available alcohol 8. In the first step, compound 8 was converted to sulfone derivative 9 for
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 33
1
2
3
4
5
6
7
8
9
conducting JuliaꢀKocienski olefination. Alcohol 8 was converted to sulfide by using
Mitsunobu conditions in presence of TPP, DIAD and 1ꢀphenylꢀ1Hꢀtetrazoleꢀ5ꢀthiol followed
by oxidation with H2O2 and ammonium molybdate afforded the required sulfone 9. Juliaꢀ
Kocienski coupling10 of the compound 9 with aldehyde 10 (obtained from Dꢀalanine)5c in
presence of KHMDS at ꢀ78 °C afforded Eꢀolefin 11 (Scheme 2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2: Synthesis of the basic carbon skeleton of (–) codonopsinine
The next step was to construct the diol 12 from 11 using dihydroxylation under various
conditions (Table 1). For this purpose ADꢀmixꢀβ was choosen as a chiral reagent. When
compound 11 was subjected to dihydroxylation with ADꢀmixꢀβ gave the compounds 12 and
13 in 50% yield (dr = 53:47, mismatched).5c,11 To improve the yields and selectivity, the
compound 11 was subjected to modified SAD conditions (entries 2 and 3, Table 1), it gave
good yield of diols but without much improvement in diastereoselectivity. When dihydroxꢀ
ylation was carried with simple OsO4 afforded slightly better diastereoselectivity (dr = 70:30)
with 90% yield (entry 4, Table 1). Treatment of compound 11 with ADꢀmixꢀα under modiꢀ
fied SAD conditions afforded the diol 13 as a major product in 90% yield with good diastereꢀ
oselectivity (dr = 5:95, matched) (entry 5, Table 1).
4
ACS Paragon Plus Environment

Page 5 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Acetylation of compounds 12 and 13 was carried out separately to furnish the correꢀ
sponding diacetylated compounds 14 and 15 respectively (Scheme 2). After having the aceꢀ
tate derivatives in hand, we proceeded further to study the DDQ mediated amido cyclisation
on 14 to obtain the pyrrolidine core 16.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Asymmetric dihydroxylation studies on compound 11 under various reaction
conditions
Several explorations were carried out under various conditions in presence of DDQ to
get 16 from 14 and the results are summarized in Table 2. The conversion was examined in
presence of various solvents. Chlorinated solvents gave poor yields (entries 1–3, Table 2),
whereas in THF no reaction was observed (entry 4, Table 2). Dioxane and nitromethane gave
moderate yields (entries 5 and 6, Table 2). In dry acetonitrile, the reaction was sluggish at
room temperature, whereas at 85 °C for 4 h it gave the single diastereomer 16 in 90% yield.
Generally, DDQ oxidation is conducted in aprotic polar solvents such as nitromethane, dioxꢀ
ane, acetonitrile etc.. In the below conversion better yields were obtained in acetonitrile under
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 33
1
2
3
4
5
6
reflux condition (entry 8, Table 2). In fact, there are some studies reported earlier in support
of acetonitrile as a better choice for DDQ oxidation.3c,d
7
8
9
Table 2. Optimization of reaction conditionsa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3: Completion of total synthesis of (–) codonopsinine 1 and (+) 5-epi-
codonopsinine 6
Treatment of compound 16 with LiAlH4 in dry THF under reflux condition for 6 h
gave the (–) codonopsinine 1 in 80% yield (Scheme 3). The spectral (1H and 13C) and analytiꢀ
cal (optical rotation and melting point) data of synthetic (–) codonopsinine 1 were in excelꢀ
lent agreement with the reported values.5c Based on these results, we then proceeded to apply
this methodology for the synthesis of other target molecules. Similar reaction sequence was
6
ACS Paragon Plus Environment

Page 7 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
carried on 15 to complete the total synthesis of (+) 5ꢀepi codonopsinine 6 in 80% yield (for 2
steps) (Scheme 3). The stereochemistry of compound 6 was confirmed with 1D nuclear overꢀ
hauser enhancement (nOe) correlations (see in supporting information).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4: A plausible reaction pathway
The high stereoselectivity in this reaction can be explained as follows. The benzylic
carbocation formed by DDQ oxidation was further stabilized by the neighbouring acetoxy
group to give a transꢀdioxolane carbocation (acetoxonium ion) intermediate, thereby facilitatꢀ
ing the approach of the Nꢀnucleophile preferentially from the opposite face to yield the pyrꢀ
rolidine core 16 with Cꢀ2 aryl and Cꢀ3 hydroxy groups in transꢀposition (Scheme 4).
For the synthesis of (+) radicamine B 5, the alcohol 1712 was converted into sulfone
18 by following the same procedure as described for compound 11. 4ꢀBenzyloxyethyl sulfone
18 on JuliaꢀKociensky olefination with aldehyde 19 (prepared from Dꢀserine)13 in dry THF at
ꢀ78 °C gave the Eꢀolefin 20. Further, the compound 20 was subjected to dihydroxylation usꢀ
ing OsO4 in acetone and water at 0 °C for 8 h to afford the diol, which on treatment with
CuCl2.2H2O in CH3CN at 0 °C gave the triol. Subsequent acetylation afforded the separable
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 33
1
2
3
4
5
6
7
8
9
triacetates 21 and 22 in 70:30 ratio respectively. Treatment of triacetate 21 with DDQ affordꢀ
ed 23 in 82% yield. The cyclic compound 23 on deacetylation with K2CO3 in MeOH yielded
the carbamate 24 (84%). The spectral (1H and 13C) and analytical (optical rotation) data of 24
were in excellent agreement with the reported values (Scheme 5).7d Conversion of 24 to radiꢀ
camine B 5 was reported earlier by our group.7d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5: Total synthesis of (+) radicamine B 5
For the synthesis of (–) codonopsinol 3, we adopted crossꢀmetathesis approach for the
synthesis of olefine unit 27, since the starting material 3,4ꢀdimethoxy allylbenzene 26 was
commercially available. Crossꢀmetathesis between 26 and olefin 2513 was carried out in presꢀ
ence of Grubbs 2nd generation catalyst and CuI in dry CH2Cl2 at 45 oC to give exclusively the
Eꢀolefin 27 in 80% yield.14 The compound 27 was converted into separable triacetates 28 and
29 (70:30 ratio) in good yields using the procedure which was described for 20. Cyclisation
8
ACS Paragon Plus Environment

Page 9 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
of major triacetate 28 with DDQ in dry CH3CN under reflux for 4 h afforded the transꢀ
pyrrolidine compound 30 in 90% yield. Treatment of 30 with LiAH4 in dry THF under reflux
for 6 h afforded the (–) codonopsinol 3 in 80% yield. The spectral (1H and 13C) and analytical
(optical rotation and melting point) data of synthetic (–) codonopsinol 3 were in excellent
agreement with the reported values (Scheme 6).6b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6: Total synthesis of (–) codonopsinol 3
Next, we turned our attention to study the DDQ mediated intramolecular amido cyclisation
on allylic substrate. In 2012, Cossy et. al. reported2d an elegant approach for allylic activation
in presence of Rh metal catalyst. In their approach, (R)ꢀ(+)ꢀβꢀcitronellol 31 was converted to
Nꢀsulfonylamines 32. Intramolecular allylic amination of
32 in presence of
(MeCN)3RhCp*](SbF6)2/Cu(OAc)2.H2O in refluxing dichloro ethane for 16 h afforded the
diastereomeric mixture of cisꢀpiperidine 33 and transꢀpiperidine 34 in 9:1 ratio in 27% yield.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 33
1
2
3
4
Scheme 7: Synthesis of cyclic amines from ω-unsaturated N-sulfonylamines
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We have chosen 32 to study the DDQꢀmediated allylic amido cyclisation. When the comꢀ
o
pound 32 was treated with DDQ in dry CH3CN, interestingly the reaction proceeded at 0 C
to rt to afford the diastereomeric mixture of compounds 33 and 34 in just 30 min with 90%
yield. Here the transꢀpiperidine was formed as a major product (ratio 2:1). The spectral (1H
and 13C) data of piperidine compounds were in excellent agreements with the reported values
(Scheme 7).2d Thus the DDQ is able to give metal free condition to synthesise the above
compounds.
CONCLUSIONS
In summary, we have developed a novel reaction i.e DDQ mediated stereoselective
intramolecular dehydrogenative amido cyclisation, which was successfully demonstrated for
the synthesis of polyhydoxylated pyrrolidine alkaloids. We also extended this methodology to
prepare piperidines by allylic C(sp3) – H activation. In most of the earlier approaches C–N
bond formation requires prefunctionalisation of substrates, whereas our strategy does not reꢀ
quire any such kind of preactivation. Also this method offers significant advantages such as
mild reaction conditions, broad substrate scope, high conversions, metal free conditions and
excellent diastereoselectivity, thus making it a quite simple, more convenient and practical.
Further application of this methodology on different substrates is under progress.
10
ACS Paragon Plus Environment

Page 11 of 33
The Journal of Organic Chemistry
1
2
3
4
EXPERIMENTAL SECTION
5
6
7
8
9
General remarks: All solvents were dried according to standard literature procedures. The
reactions were performed in ovenꢀdried roundꢀbottom flasks, the flasks were fitted with rubꢀ
ber septa, and the reactions were conducted under a nitrogen atmosphere. Glass syringes were
used to transfer solvents. Crude products were purified by column chromatography on silica
gel of 60−120 or 100−200 mesh. Thinꢀlayer chromatography plates were visualized by expoꢀ
sure to ultraviolet light and/or by exposure to iodine vapors and/or by exposure to methanolic
acidic solution of pꢀanisaldehyde, followed by heating (<1 min) on a hot plate (∼250 °C).
Organic solutions were concentrated on a rotary evaporator at 35−40 °C. ADꢀmixꢀβ mixture
contains (DHQ)2PHAL (0.0016 mole), potassium carbonate (0.4988 mole), potassium ferriꢀ
cyanide (0.4988 mole) and potassium osmate dihydrate (0.0007 mole). ADꢀmixꢀα mixture
contains (DHQ)2PHAL (0.0016 mole), potassium carbonate (0.4988 mole), potassium ferriꢀ
cyanide (0.4988 mole) and potassium osmate dihydrate (0.0007 mole). IR spectra were recꢀ
orded on an FTꢀIR spectrometer.1H and 13C NMR (protonꢀ decoupled) spectra were recorded
in CDCl3 solvent on a 200, 300, 400, or 500 MHz NMR spectrometers. Chemical shifts (δ)
were reported in parts per million (ppm) with respect to TMS as an internal standard. Couꢀ
pling constants (J) are quoted in hertz (Hz). Mass spectra were recorded on a mass spectromꢀ
eter by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI)
technique and orbitrap mass analyser. Optical rotations were measured in digital polarmeter.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5ꢀ(4ꢀMethoxyphenethylsulfonyl)ꢀ1ꢀphenylꢀ1Hꢀtetrazole (9). To a solution of alcohol 8
(2.0 g, 13.1 mmol) in THF was added phenyltetrazole thiol (2.57 g, 14.4 mmol) and triꢀ
phenylphosphine (3.79 g, 14.4 mmol) and the mixture was cooled to 0 °C. To the mixture
was added dropwise a solution of DIAD (2.84 mL, 14.4 mmol). The cooling bath was reꢀ
moved and the mixture was allowed to warm to ambient temperature and was maintained for
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 33
1
2
3
4
5
6
7
8
9
1 h. The mixture was diluted with CH2Cl2 and silica gel was added. The mixture was concenꢀ
trated in vacuo and residue was purified by column chromatography (ethyl acetate/hexane
1:9) to furnish sulphide compound (3.69 g, 90%) as colourless and very viscous oil. The sulꢀ
fide compound (3.60 g, 1.5 mmol) was dissolved in EtOH (50 mL) and the solution was
cooled to 0 °C. In a separate flask, aqueous H2O2 (30%, 7.84 mL, 69.2 mmol) was added to
Mo7O24(NH4)6·4H2O (2.85 g, 2.30 mmol) and the mixture was stirred vigorously until comꢀ
plete dissolution of the Mo7O24(NH4)6·4H2O. The Mo7O24(NH4)6·4H2O/H2O2 solution was
then added dropwise to the sulfide solution and the cooling bath was removed. The mixture
was allowed to warm to ambient temperature and was maintained for 24 h. The mixture was
diluted with water and Et2O and the layers were separated. The organic phase was washed
twice with water and once with brine. The combined aqueous layers were extracted twice
with Et2O. The combined organic phases were dried with NaSO4, filtered, and concentrated
in vacuo. Purification by flash chromatography (ethyl acetate/hexane 1:9) furnished sulfone
compound 9 (3.57 g, 90%) as a colourless and very viscous oil. IR (neat): 2923, 2851, 1725,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1508, 1338, 1244, 1148, 1030 cmꢀ1; H NMR (500 MHz, CDCl3): δ 7.72ꢀ7.57 (m, 5H), 7.16
(AA’ part of AA’BB’ (m), 2H), 6.85 (BB’ part of AA’BB’ (m), 2H), 4.00ꢀ3.93 (m, 2H), 3.80
13
(s, 3H), 3.23ꢀ3.17 (m, 2H); C NMR (75 MHz, CDCl3): δ 158.7, 153.2, 132.8, 131.3, 129.6,
129.4, 128.0, 124.9, 114.2, 57.3, 55.2, 27.5; ESIMS (m/z): 367 [M+Na]+; HRMS (ESI)
[M+Na]+: Anal. Calcd for C16H16O3N4NaS 367.08353 found 367.08523.
(R,E)ꢀBenzyl 5ꢀ(4ꢀmethoxyphenyl)pentꢀ3ꢀenꢀ2ꢀylcarbamate (11). To a stirred solution of
oxalyl chloride (1.83 mL, 21.0 mmol) in dry DCM (20 mL) under nitrogen atmosphere, was
added DMSO (3.12 mL, 44.0 mmol) slowly at ꢀ78 °C and stirred further for 30 min at the
same temp. Then alcohol 10 (2.20 g, 10.5 mmol) in dry DCM (20 mL) was added slowly
over 10 min and stirred further for 2 h at ꢀ78 oC and then DIPEA (10.8 mL, 63.1 mmol) was
added at ꢀ78 oC. The temperature was slowly raised to room temperature over 20 min and the
12
ACS Paragon Plus Environment

Page 13 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
reaction mixture was diluted with DCM (50 mL). The organic layer was sequentially washed
with saturated aq. NH4Cl solution and brine, dried over anhydrous Na2SO4. The solvent was
removed on a rotary evaporator to give crude aldehyde which was chromatographed on silica
gel (ethyl acetate/hexane 1:9) to give aldehyde 10 (2.0 g, 90%) as a colourless oil.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To a stirred solution of sulfone 9 (3.0 g, 8.7 mmol) in THF (20 mL), KHMDS (32.8 mL of
0.5 M solution in toluene, 17.4 mmol) was added at −78 °C. After stirring for 1 h, aldehyde
10 (2.0 g, 9.6 mmol) was added (5 mL THF) at the same temperature and stirred for 1 h. The
mixture was allowed to warm to room temperature over 1 h by that time the reaction mixture
turned into white cloudy suspension and the TLC analysis indicated the complete consumpꢀ
tion of the starting material. Solvents were removed under reduced pressure to give the crude
product which was chromatographed over silica gel (ethyl acetate/hexane 1:9) to give olefin
20
11 (2.20 g, 80%) as a colourless oil. [α]D = +5.3 (c 0.47, CHCl3); IR (neat): 3314, 2923,
2851, 2365, 1705, 1510, 1238, 1032 cmꢀ1; 1H NMR (300 MHz, CDCl3): δ 7.38ꢀ7.28 (m, 5H),
7.06 (AA’ part of AA’BB’ (m), 2H), 6.83 (BB’ part of AA’BB’ (m), 2H), 5.72 (m, 1H), 5.46
(dd, J = 5.0, 15.4 Hz), 5.09 (ABq, J = 12.3 Hz, 2H), 4.67 (br, 1H), 4.29 (br, 1H), 3.78 (s,
3H), 3.30ꢀ3.26 (m, 2H), 1.22 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 157.9,
155.4, 136.5, 132.4, 131.9, 129.5, 129.3, 128.4, 127.9, 113.7, 66.5, 55.1, 48.0, 37.5, 21.0;
ESIMS (m/z): 326 [M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd for C20H24O3N 326.17507
found 326.17636.
Benzyl (2R,3R,4R)ꢀ3,4ꢀdihydroxyꢀ5ꢀ(4ꢀmethoxy phenyl) pentanꢀ2ꢀylcarbamate (12). To a
stirred solution of olefin compound 11 (2.0 g, 6.15 mmol) and Nꢀmethyl morpholineꢀNꢀoxide
(1.07 g, 9.23 mmol) in acetone and water at 0 °C was added a catalytic amount of OsO4 soluꢀ
tion in toluene (1.5 mL, 0.06 mmol). After stirring 8 h at room temperature, a saturated aqueꢀ
ous solution of Na2SO3 (4 mL) was added to the mixture and extracted with ethyl acetate (3 x
20 mL). The combined extracts were dried over Na2SO4 and solvent removed thoroughly unꢀ
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 33
1
2
3
4
5
6
der vacuum. The crude residue was chromatographed on silica gel (ethyl acetate/hexane 1:7)
to afford dihydroxylated compounds 12 (1.40 g) and 13 (0.58 g) in 90% yield (dr = 70:30).
7
8
Major diol compound 12. [α]D20 = ꢀ0.4 (c 0.36, CHCl3); IR (neat): 3393, 2922, 2852, 2364,
9
1
1693, 1513, 1459, 1247, 1036 cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.41ꢀ7.32 (m, 5H), 7.12
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(AA’ part of AA’BB’ (m), 2H), 6.84 (BB’ part of AA’BB’ (m), 2H), 5.10 (ABq, J = 12.0 Hz,
2H), 4.88 (d, J = 8.6 Hz), 3.84ꢀ3.66 (m, 2H), 3.79 (s, 3H), 3.29 (m, 1H, OH), 3.10 (m, 1H),
13
2.88ꢀ2.74 (m, 2H), 2.40 (d, J = 8.9 Hz, OH), 1.24 (d, J = 6.7 Hz, 3H); C NMR (75 MHz,
CDCl3): δ 158.2, 157.1, 136.1, 130.3, 130.1, 128.5, 128.3, 128.1, 113.9, 75.3, 71.1, 67.1,
55.2, 49.2, 38.4, 17.4; ESIMS (m/z): 360 [M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd for
C20H26O5N 360.18055 found 360.18242.
20
Benzyl(2R,3S,4S)ꢀ3,4ꢀdihydroxyꢀ5ꢀ(4ꢀmethoxyphenyl) pentanꢀ2ꢀylcarbamate (13). [α]D
= +11.5 (c 0.27, CHCl3); IR (neat): 3393, 2922, 2852, 2364, 1693, 1513, 1244, 1036 cmꢀ1; 1H
NMR (500 MHz, CDCl3): δ 7.40ꢀ7.30 (m, 5H), 7.10 (AA’ part of AA’BB’ (m), 2H), 6.84 (BB’
part of AA’BB’ (m), 2H), 5.12 (ABq, J = 11.9 Hz, 2H), 5.02 (d, J = 8.9 Hz, 1H), 3.97 (m,
1H), 3.79 (s, 3H), 3.70 (m, 1H), 3.35 (m, 1H), 2.96 (m, 1H), 2.61 (dd, J = 8.9, 13.4 Hz, 1H),
13
1.25 (d, J = 6.7 Hz, 3H); C NMR (75 MHz, CDCl3): δ 158.3, 156.5, 136.3, 130.4, 129.6,
128.5, 128.1, 128.0, 114.0, 76.3, 73.2, 66.8, 55.2, 48.2, 38.9, 18.8; ESIMS (m/z): 360
[M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd for C20H26O5N 360.18055 found 360.18238.
(2R,3R,4R)ꢀ4ꢀ(Benzyloxycarbonylamino)ꢀ1ꢀ(4ꢀmethoxyphenyl)pentaneꢀ2,3ꢀdiyl diacetate
(14). To a stirred solution of diol compound 12 (1.0 g, 2.78 mmol) in dichloromethane (10
mL) was added triethyl amine (1.36 mL, 9.74 mmol), acetic anhydride (0.78 mL, 8.3 mmol)
and 4ꢀdimethylamino pyridine (5 mg) at 0 °C under nitrogen atmosphere. After completion of
the addition, the reaction mixture was kept at room temperature and stirred for 2 h. The reacꢀ
tion mixture was diluted with chloroform (50 mL), washed with water and brine, dried over
Na2SO4 and concentrated under vacuum. The residue was chromatographed over silica gel
14
ACS Paragon Plus Environment

Page 15 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
(ethyl acetate/hexane 1:8) to afford the diacetate compound 14 (1.0 g, 85%) as a colourless
20
oil. [α]D = +6.7 (c 0.53, CHCl3); IR (neat): 2931, 2364, 2332, 1740, 1695, 1515, 1461,
7
8
1
1223, 1030 cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.40ꢀ7.28 (m, 5H), 7.08 (AA’ part of
9
AA’BB’ (m), 2H), 6.81 (BB’ part of AA’BB’ (m), 2H), 5.23 (m, 1H), 5.07 (brs, 2H), 4.89 (dd,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J =4.1, 5.2 Hz, 1H), 4.81 (d, J = 8.6 Hz, 1H), 4.08 (m, 1H), 3.77 (s, 3H), 2.89ꢀ2.67 (m, 2H),
13
2.14 (s, 3H), 2.01 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H); C NMR (125 MHz, CDCl3): δ 170.4,
170.0, 158.4, 155.4, 136.3, 130.2, 128.4, 128.0, 113.8, 74.6, 72.7, 66.7, 55.1, 46.9, 36.3, 20.9,
20.7, 16.6; ESIMS (m/z): 444 [M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd for C24H30O7N
444.19939 found 444.19920.
(2R,3R,4R,5R)ꢀ1ꢀ(Benzyloxycarbonyl)ꢀ2ꢀ(4ꢀmethoxy phenyl)ꢀ5ꢀmethylpyrrolidineꢀ
3,4ꢀdiyl diacetate (16). To a stirred solution of diacetate compound 14 (0.60 g, 1.35 mmol) in
CH3CN (2 mL) was added DDQ (0.33 g, 1.48 mmol). The resulting mixture was heated at 80
oC for 4 h under nitrogen atmosphere. After completion of the reaction as evidenced by TLC,
the reaction mixture was cooled to room temperature and quenched with Et3N, concentrated
under reduced pressure to give crude residue, which was purified on silica gel column (ethyl
20
acetate/hexane 1:8) to give cyclic compound 16 (0.53 g, 90%) as a colourless oil. [α]D
=
34
+19.1 (c 0.20, CHCl3){lit,5c [α]D = +20.2 (c 0.11, CHCl3)}; IR (neat): 2928, 2364, 1743,
1704, 1513, 1406, 1350, 1223, 1037 cmꢀ1; 1H NMR (300 MHz, CDCl3): δ 7.41ꢀ7.05 (m, 6H),
6.89ꢀ6.77 (m, 3H), 5.20ꢀ4.75 (m, 5H), 4.28 (qt, J = 6.4, 12.4 Hz, 1H), 3.79 (s, 3H), 2.15 (s,
3H), 1.83 (s, 3H), 1.54 (d, J = 6.7 Hz, 3H) (multiple peaks are due to rotameric mixture); 13C
NMR (75 MHz, CDCl3): δ 169.5, 169.4, 158.7, 154.2, 136.1, 131.6, 130.5, 128.4, 128.2,
128.0, 127.5, 127.4, 127.3, 127.1, 113.6, 113.4, 82.4, 81.4, 81.2, 80.3, 68.0, 67.6, 67.2, 66.7,
61.3, 60.7, 55.2, 20.9, 20.6, 18.3, 17.1(multiple peaks are due to rotameric mixture); ESIMS
(m/z): 442 [M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd for C24H28O7N 442.18338 found
442.18334.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 33
1
2
3
4
(2R,3R,4R,5R)ꢀ2ꢀ(4ꢀMethoxyphenyl)ꢀ1,5ꢀdimethylpyrrolidineꢀ3,4ꢀdiol
[(–)ꢀ
5
6
7
8
codonopsinine] (1). To a stirred suspension of LiAlH4 (0.103 g, 2.72 mmol) in THF (10 mL)
was added pyrrolidine derivative 16 (0.2 g, 0.45 mmol) in THF (5 mL) at 0 °C. After the
completion of addition the reaction mixture was refluxed for 5 h. The reaction mixture was
cooled to 0 °C, quenched with water (0.1 mL), 15% NaOH (0.1 mL) and water (0.3 mL) sucꢀ
cessively. After 15 min stirring at room temperature, the reaction mixture was filtered
through the celite pad, washed with chloroform (3 x 10 mL) and evaporated under vacuum.
The residue was purified through silica gel column (CHCl3/MeOH = 7:1) to afford the codoꢀ
nopsinine 1 (0.1 g, 80%) as a white powder. The spectral (1H and 13C) and analytical (optical
rotation and melting point) data of synthetic (–) codonopsinine 1 were in excellent agreement
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
with the reported values.5c mp 168ꢀ170 °C, [α]D = ꢀ8.9 (c 0.1, MeOH) {lit.5c mp 169ꢀ170
°C, [α]D34 = ꢀ8.8 (c 0.1, MeOH)}; IR (KBr) 3360, 2938, 2362, 1834, 1743, 1698, 1514, 1460,
1
1028 cmꢀ1; H NMR (300 MHz, pyridineꢀd5): δ 7.58 (AA’ part of AA’BB’ (m), 2H), 6.96
(BB’ part of AA’BB’ (m), 2H), 4.60 (dd, J = 4.5, 6.0 Hz, 1H), 4.36 (dd, J = 3.7, 4.3 Hz, 1H),
4.00 (d, J = 6.4 Hz, 1H), 3.66 ( m, 1H), 3.65 (s, 3H), 2.20 (s, 3H), 1.31 (d, J = 6.7 Hz, 3H);
13C NMR (75 MHz, pyridineꢀd5): δ 159.3, 135.0, 129.8, 114.1, 87.2, 85.0, 74.3, 65.0, 55.1,
34.7, 13.9; ESIMS m/z 238 (M+ +H); HRMS calcd for C13H20NO3 238.14377 found
238.14464.
(2S,3S,4R)ꢀ4ꢀ(Benzyloxycarbonylamino)ꢀ1ꢀ(4ꢀmethoxy phenyl)pentaneꢀ2,3ꢀdiyldiacetate
(15). To the stirred solution of diol compound 13 (0.5 g, 1.39 mmol) in dichloromethane (6
mL) was added triethyl amine (0.77 mL, 5.57 mmol), acetic anhydride (0.39 mL, 4.17 mmol)
and 4ꢀdimethylamino pyridine (5 mg) at 0 °C under nitrogen atmosphere. After completion of
the addition, the reaction mixture was kept at room temperature and stirred for 2 h. The reacꢀ
tion mixture was diluted with chloroform (50 mL), washed with water and brine, dried over
Na2SO4 and concentrated under vacuum. The residue was purified by column chromatogꢀ
16
ACS Paragon Plus Environment

Page 17 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
raphy (ethyl acetate/hexane 1:8) to afford the compound 15 (0.5 g, 85%) as a colourless oil.
[α]D20 = +38.2 (c 0.8, CHCl3); IR (neat): 2925, 2363, 1740, 1708, 1515, 1461, 1224, 1030 cmꢀ
1; 1H NMR (500 MHz, CDCl3): δ 7.40ꢀ7.30 (m, 5H), 7.05 (AA’ part of AA’BB’ (m), 2H), 6.79
(BB’ part of AA’BB’ (m), 2H), 5.23 (m, 1H), 5.12 (ABq, J = 12.1 Hz, 2H), 4.93ꢀ4.87 (m, 2H),
4.13 (m, 1H), 3.77 (s, 3H), 2.91 (dd, J = 4.4, 13.8 Hz, 1H), 2.75 (dd, J = 8.2, 13.8 Hz, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
2.05 (s, 3H), 1.95 (s, 3H), 1.11 (d, J = 6.6 Hz, 3H); C NMR (75 MHz, CDCl3): δ 170.4,
170.0, 158.3, 155.7, 136.3, 130.3, 128.5, 128.1, 128.0, 113.8, 75.5, 73.0, 66.8, 55.1, 47.1,
36.1, 20.7, 20.6, 18.5; ESIMS (m/z): 444 [M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd for
C24H30O7N 444.20168 found 444.20402.
(2R,3S,4S,5R)ꢀ1ꢀ(Benzyloxycarbonyl)ꢀ2ꢀ(4ꢀmethoxy phenyl)ꢀ5ꢀmethylpyrrolidineꢀ3,4ꢀdiyl
diacetate (S1). To a stirred solution of diacetate compound 15 (0.4 g, 0.90 mmol) in CH3CN
(2 mL) was added DDQ (0.23 g, 0.1 mmol). The resulting mixture was heated at 80 oC for 8
h under nitrogen atmosphere. After completion of the reaction as evidenced by TLC, the reacꢀ
tion mixture was cooled to room temperature and quenched with Et3N, concentrated under
reduced pressure to give crude residue, which was purified by column chromatography (ethyl
acetate/hexane 1:8) to give cyclic compound S1 (0.31 g, 80%) as colourless oil. [α]D20 = ꢀ16.1
1
(c 0.22, CHCl3); IR (neat): 2930, 2363, 1743, 1705, 1513, 1222, 1032 cmꢀ1; H NMR (300
MHz, CDCl3): δ 7.30ꢀ7.10 (m, 7H), 6.86 (BB’ part of AA’BB’ (m), 2H), 5.24ꢀ4.86 (m, 5H),
4.42 (m, 1H), 3.81 (s, 3H), 2.08 (s, 3H), 1.83 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H) (multiple
peaks are due to rotameric mixture); 13C NMR (75 MHz, CDCl3): δ 169.8, 169.7, 158.7,
155.4, 136.2, 131.0, 128.4, 128.3, 128.0, 127.8, 127.4, 127.0, 113.6, 80.2, 75.9, 74.1, 72.5,
66.9, 65.9, 55.5, 55.2, 20.9, 20.6, 20.4, 20.2, 14.8, 14.4 (multiple peaks are due to rotameric
mixture); ESIMS (m/z): 442 [M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd for C24H28O7N
442.18347 found 442.18341.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 33
1
2
3
4
5
6
7
8
9
(2S,3S,4S,5R)ꢀ2ꢀ(4ꢀMethoxyphenyl)ꢀ1,5ꢀdimethyl pyrrolidineꢀ3,4ꢀdiol [(+)ꢀ5ꢀepi codoꢀ
nopsinine] (6). To a stirred suspension of LiAlH4 (0.08 g, 2.26 mmol) in THF (3 mL) was
added pyrrolidine derivative S1 (0.2 g, 0.45 mmol) in THF (5 mL) at 0 °C. After the compleꢀ
tion of addition the reaction mixture was refluxed for 5 h. The reaction mixture was cooled to
0 °C, quenched with water (0.08 mL), 15% NaOH (0.08 mL) and water (0.24 mL) succesꢀ
sively. After 15 min stirring at room temperature, the reaction mixture was filtered through
the celite pad, washed with chloroform (3 x 10 mL) and evaporated under vacuum. The resiꢀ
due was purified by column chromatography (CHCl3/MeOH = 7:1) to afford the 5ꢀepi codoꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
nopsinine 6 (0.1 g, 80%) as a white powder: mp 168ꢀ170 °C, [α]D = +1.0 (c 0.18, MeOH;
IR (neat) 3360, 2938, 2362, 1743, 1698, 1514, 1028 cmꢀ1; 1H NMR (500 MHz, pyridineꢀd5):
δ 7.63 (AA’ part of AA’BB’ (m), 2H), 6.99 (BB’ part of AA’BB’ (m), 2H), 4.59 (dd, J = 3.5,
6.8 Hz, 1H), 4.53 (dd, J = 3.5, 6.8 Hz, 1H), 3.67 (s, 3H), 3.42 (d, J = 7.0 Hz, 1H), 2.87 (m,
1H), 2.21 (s, 3H), 1.49 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, pyridineꢀd5): δ 159.8, 135.2,
130.1, 114.6, 87.4, 79.8, 78.6, 65.3, 55.6, 39.6, 14.7; ESIMS m/z 238 [M+H]+; HRMS calcd
for C13H20NO3 238.14377 found 238.14454.
2ꢀ(4ꢀ(Benzyloxy)phenyl)ethanol (17). To a solution of (4ꢀhydroxyphenyl)acetic acid (3.0 g,
19.7 mmol) in acetone (80 mL) were added benzyl bromide (7.03 mL, 59.2 mmol) and anhyꢀ
drous K2CO3 (8.1 g, 59.2 mmol). The reaction mixture was refluxed for 10 h, and then filꢀ
tered over a celite pad of silica gel and concentrated. The residue was purified by column
chromatography (ethyl acetate/hexane 1:20) to give dibenzylated compound (5.8 g, 90%) as a
white solid. To a suspension of LiAlH4 (2.28 g, 60.2 mmol) in THF (45 mL) at 0 oC under N2
was added dropwise a solution of dibenzylated compound (4.98 g, 15 mmol) in THF. The
mixture was refluxed for 4 h, and the reaction mixture was cooled to 0 °C, quenched with waꢀ
ter (2.28 mL), 15% NaOH (2.28 mL) and water (6.84 mL) successively. After 30 min stirring
at room temperature, the reaction mixture was filtered through the celite pad, washed with
18
ACS Paragon Plus Environment

Page 19 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
EtOAc (3 x 50 mL) and evaporated under vacuum. The residue was purified by column
chromatography (ethyl acetate/hexane 1:7) to afford 17 (2.91 g, 85%) as a white solid. IR
7
8
1
(neat): 3271, 3032, 2924, 2862, 1610, 1511, 1246, 1217, 1013 cmꢀ1; H NMR (500 MHz,
9
CDCl3): δ 7.45ꢀ7.29 (m, 5H), 7.14 (AA’ part of AA’BB’ (m), 2H), 6.93 (BB’ part of AA’BB’
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(m), 2H), 5.04 (s, 2H), 3.81 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H); C NMR (125
MHz, CDCl3): δ 157.2, 136.9, 130.7, 129.7, 128.3, 127.7, 127.2, 114.7, 69.8, 63.4, 38.0;
ESIMS (m/z): 246 [M+NH4]+; HRMS (ESI) [M+NH4]+: Anal. Calcd for C15H20O2N
246.14886 found 246.14859.
5ꢀ(4ꢀ(Benzyloxy)phenethylsulfonyl)ꢀ1ꢀphenylꢀ1Hꢀtetrazole (18). To a solution of alcohol
17 (2.5 g, 6.4 mmol) in THF (20 mL) was added phenyltetrazole thiol (1.26 g, 7.0 mmol) and
triphenylphosphine (1.68 g, 7.0 mmol) and the mixture was cooled to 0 °C. To the mixture
was added dropwise a solution of DIAD (1.39 mL, 7.0 mmol). The cooling bath was removed
and the mixture was allowed to warm to ambient temperature and was maintained for 1 h.
The mixture was diluted with CH2Cl2 and silica gel was added. The mixture was concentrated
in vacuo and residue was purified by column chromatography (ethyl acetate/hexane 1:8) to
afford sulfide compound (3.82 g, 90%) as a colorless and viscous oil. The sulfide compound
(3.5 g, 9.0 mmol) was dissolved in EtOH (80 mL) and the solution was cooled to 0 °C. In a
separate flask, aqueous H2O2 (30%, 4.23 mL, 54.1 mmol) was added to Mo7O24(NH4)6·4H2O
(2.22 g, 1.80 mmol) and the mixture was stirred vigorously until complete dissolution of the
Mo7O24(NH4)6·4H2O. The Mo7O24(NH4)6·4H2O/H2O2 solution was then added dropwise to
the sulfide solution and the cooling bath was removed. The mixture was allowed to warm to
ambient temperature and was maintained for 24 h. The mixture was diluted with water and
Et2O and the layers were separated. The organic phase was washed twice with water and once
with brine. The combined aqueous layers were extracted twice with Et2O. The combined orꢀ
ganic phases were dried with Na2SO4, filtered, and concentrated in vacuo. Purification by
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 33
1
2
3
4
5
6
column chromatography (ethyl acetate/hexane 1:8) gave sulfone compound 18 (3.40 g, 90%)
1
as a colorless and very viscous oil. IR (neat): 3019, 1728, 1511, 1215, 1154, 1016 cmꢀ1; H
7
8
NMR (500 MHz, CDCl3): δ 7.71ꢀ7.58 (m, 5H), 7.45ꢀ7.29 (m, 5H), 7.16 (AA’ part of AA’BB’
9
13
(m), 2H), 6.93 (BB’ part of AA’BB’ (m), 2H), 5.06 (s, 2H), 3.96 (m, 2H), 3.21 (m, 2H); C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (125 MHz, CDCl3): δ 157.9, 153.2, 136.7, 132.8, 131.3, 129.5, 129.49, 128.47, 128.42,
127.8, 127.3, 124.9, 115.2, 69.9, 57.3, 27.5; ESIMS (m/z): 421 [M+H]+; HRMS (ESI)
[M+H]+: Anal. Calcd for C22H21O3N4S 421.13071 found 421.13064.
(S,E)ꢀBenzyl4ꢀ(3ꢀ(4ꢀ(benzyloxy)phenyl)propꢀ1ꢀenyl)ꢀ2,2ꢀdimethyloxazolidineꢀ3ꢀ
carboxylate (20). To a stirred solution of oxalyl chloride (1.58 mL, 18.1 mmol) in dry DCM
(20 mL) under nitrogen atmosphere, was added DMSO (2.57 mL, 36.2 mmol) slowly at ꢀ78
°C and stirred further for 30 min at the same temperature. Then Dꢀserine derived alcohol (2.4
g, 9.0 mmol) in dry DCM (20 mL) was added slowly over 10 min and stirred further for 2 h
o
o
at ꢀ78 C and then Et3N (7.57 mL, 54.3 mmol) was added at ꢀ78 C. The temperature was
slowly warmed to room temperature over 20 min and the reaction mixture was diluted with
DCM (50 mL). The organic layer was sequentially washed with saturated aq. NH4Cl solution
and brine, dried over anhydrous Na2SO4. The solvent was removed on a rotary evaporator to
give crude aldehyde which was purified by column chromatography (ethyl acetate/hexane
1:9) to give aldehyde 19 (2.38 g, 90%) as a colourless oil.
To a stirred solution of sulfone 18 (3.0 g, 7.14 mmol) in THF (20 mL), KHMDS (28.5 mL of
0.5 M solution in toluene, 14.2 mmol) was added at ꢀ78 °C. After stirring for 1 h, aldehyde 19
(2.3 g, 7.14 mmol) was added (5 mL THF) at the same temperature and stirred for 1 h. The
mixture was allowed to warm to room temperature over 3 h by which time the reaction mixꢀ
ture turned into white cloudy suspension and the TLC analysis indicated complete consumpꢀ
tion of the starting material. Solvents were removed under reduced pressure to give the crude
product which upon silica gel column chromatography (ethyl acetate/hexane 1:8) gave olefin
20
ACS Paragon Plus Environment

Page 21 of 33
The Journal of Organic Chemistry
1
2
3
4
5
24
20 (2.58 g, 78%) as a colourless oil. [α]D = ꢀ61.2 (c 0.65, CHCl3); IR (neat): 2984, 2932,
1700, 1509, 1404, 1347, 1220, 1091, 1024 cmꢀ1; H NMR (500 MHz, CDCl3): δ 7.47ꢀ7.23
1
6
7
8
9
(m, 10H), 7.12ꢀ6.82 (m, 4H), 5.65 (m, 1H), 5.50 (dd, J = 7.3, 15.4 Hz, 1H), 5.22ꢀ4.5.01 (m,
4H), 4.38 (m, 1H), 4.04 (dd, J = 5.9, 8.8 Hz, 1H), 3.77 (dd, J = 1.9, 8.8 Hz, 1H), 3.38ꢀ3.20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(m, 2H), 1.65 (s, 3H), 1.55 (s, 3H) (multiple peaks are due to rotameric mixture); C NMR
(75 MHz, CDCl3): δ 157.1, 157.0, 152.4, 137.0, 136.4, 132.4, 132.1, 132.0, 129.8, 129.6,
129.3, 129.0, 128.4, 128.3, 128.1, 127.9, 127.8, 127.3, 114.8, 94.2, 77.1, 69.9, 68.9, 68.6,
66.6, 66.4, 58.8, 54.8, 54.1, 37.5, 32.2, 27.3, 26.4, 23.7, 23.5 (multiple peaks are due to rotaꢀ
meric mixture); ESIMS (m/z): 480 [M+Na]+; HRMS (ESI) [M+Na]+: Anal. Calcd for
C29H31O4NNa 480.21453 found 480.21382.
(2R,3R,4R)ꢀ5ꢀ(4ꢀ(Benzyloxy)phenyl)ꢀ2ꢀ(benzyloxy carbonylamino)pentaneꢀ1,3,4ꢀtriyl triꢀ
acetate (21). To a stirred solution of olefin compound 20 (2.50 g, 5.47 mmol) and Nꢀmethyl
morpholineꢀNꢀoxide (1.0 g, 8.20 mmol) in acetone and water at 0 °C was added a catalytic
amount of OsO4 solution in toluene (1.3 mL, 0.054 mmol). After stirring 8 h at room temꢀ
perature, a saturated aqueous solution of Na2SO3 (4 mL) was added to the mixture and exꢀ
tracted with ethyl acetate (3 x 20 mL). The combined extracts were dried over Na2SO4 and
solvent removed thoroughly under vacuum. Purification by silica gel column chromatography
(ethyl acetate/hexane 1:6) afforded dihydroxylated compound (2.41 g, 90 %) as colourless
oil. The dihydroxylated compound (2.41 g, 4.90 mmol) in CH3CN (5 mL) was added
CuCl2.2H2O (0.97 g, 5.89 mmol) and quenched with saturated NaHCO3 and filtered through
celite pad of silica gel and solvents were removed under reduced pressure to give the crude
product. To the crude triol compound in dichloromethane (10 mL) was added triethyl amine
(2.73 mL, 19.6 mmol), acetic anhydride (1.38 mL, 14.7 mmol) and 4ꢀdimethylaminopyridine
(5 mg) at 0 °C under nitrogen atmosphere. After completion of the addition, the reaction mixꢀ
ture was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 33
1
2
3
4
5
6
7
8
chloroform (50 mL), washed with water and brine, dried over Na2SO4 and concentrated under
vacuum. Purification by silica gel column chromatography (ethyl acetate/hexane 1:8) affordꢀ
ed triacetate derivatives 21 (1.78 g) and 22 (0.76 g) in 90% yield (dr = 70:30).
9
Major triacetate compound 21. [α]D20 = ꢀ5.3 (c 0.25, CHCl3); IR (neat): 2925, 2854, 1740,
1512, 1372, 1216, 1027 cmꢀ1; 1H NMR (300 MHz, CDCl3): δ 7.47ꢀ7.25 (m, 10H), 7.10 (AA’
part of AA’BB’ (m), 2H), 6.88 (BB’ part of AA’BB’ (m), 2H), 5.36ꢀ4.96 (m, 7H), 4.28 (m,
1H), 4.16 (dd, J = 4.5, 11.7 Hz, 1H), 3.99 (dd, J = 3.3, 11.7 Hz, 1H), 2.88ꢀ2.66 (m, 2H), 2.15
(s, 3H), 2.05 (s, 3H), 1.98 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 170.6, 170.1, 170.0, 157.6,
155.5, 136.9, 136.0, 130.4, 130.2, 128.5, 128.2, 128.1, 127.9, 127.4, 114.7, 114.6, 72.4, 70.9,
69.8, 67.1, 63.0, 49.5, 36.1, 20.9, 20.7, 20.6; ESIMS (m/z): 578 [M+H]+; HRMS (ESI)
[M+H]+: Anal. Calcd for C32H36O9N 578.23555 found 578.23551.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2R,3S,4S)ꢀ5ꢀ(4ꢀ(Benzyloxy)phenyl)ꢀ2ꢀ(benzyloxy carbonylamino)pentaneꢀ1,3,4ꢀtriyl triꢀ
20
acetate (22). [α]D = +6.7 (c 0.26, CHCl3); IR (neat): 2924, 2853, 1742, 1512, 1371, 1219,
1
1027 cmꢀ1; H NMR (500 MHz, CDCl3): δ 7.47ꢀ7.30 (m, 10H), 7.05 (AA’ part of AA’BB’
(m), 2H), 6.87 (BB’ part of AA’BB’ (m), 2H), 5.29ꢀ5.01 (m, 7H), 4.30 (m, 1H), 4.07ꢀ3.98 (m,
2H), 2.89 (dd, J = 5.0, 13.9 Hz, 1H), 2.77 (dd, J = 8.0, 13.9 Hz, 1H), 2.04 (s, 3H), 1.96 (s,
13
3H), 1.95 (s, 3H); C NMR (75 MHz, CDCl3): δ 170.4, 170.0, 169.9, 157.6, 155.9, 136.9,
136.1, 131.1, 130.3, 128.5, 128.2, 128.1, 127.9, 127.4, 127.0, 114.7, 72.7, 71.4, 69.9, 67.1,
63.1, 50.1, 36.0, 20.7, 20.5; ESIMS (m/z): 578 [M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd
for C32H36O9N 578.23544 found 578.23516.
(2R,3R,4R,5R)ꢀ2ꢀ(Acetoxymethyl)ꢀ5ꢀ(4ꢀ(benzyloxy) phenyl)ꢀ1ꢀ(benzyloxycarbonyl) pyrꢀ
rolidineꢀ3,4ꢀdiyl diacetate (23). To a stirred solution of diacetate compound 21 (1.5 g, 2.5
mmol) in CH3CN (3 mL) was added DDQ (0.64 g, 2.85 mmol). The resulting mixture was
o
heated at 80 C for 4 h under nitrogen atmosphere. After completion of the reaction as eviꢀ
denced by TLC, the reaction mixture was cooled to room temperature and quenched with
22
ACS Paragon Plus Environment

Page 23 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Et3N, concentrated under reduced pressure to give crude residue, which was purified by colꢀ
umn chromatography (ethyl acetate/hexane 1:8) to give cyclic compound 23 (1.22 g, 82%) as
a colourless oil. [α]D20 = ꢀ1.3 (c 0.89, CHCl3) {lit,7d [α]D28 = ꢀ1.5 (c 2.83, CHCl3)}; IR (neat):
2923, 2853, 1744, 1706, 1511, 1404, 1217, 1041 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.49ꢀ
7.09 (m, 11H), 6.95ꢀ6.72 (m, 3H), 5.23ꢀ4.83 (m, 6H), 4.87 (d, J = 12.5 Hz, 1H), 4.61 (dd, J =
4.1, 10.6 Hz, 1H), 4.48 (dd, J = 4.1, 9.7 Hz, 1H), 4.32 (t, J = 10.2 Hz, 1H), 2.15 (s, 3H), 2.12
(s, 3H), 1.77 (s, 3H) (multiple peaks are due to rotameric mixture); 13C NMR (125 MHz,
CDCl3): δ 170.6, 170.4, 170.2, 169.5, 169.2, 157.9, 154.3, 153.6, 136.8, 135.9, 135.8, 135.7,
131.2, 130.1, 128.5, 128.4, 128.2, 128.1, 127.9, 127.7, 127.5, 127.3, 127.2, 126.9, 114.7,
82.1, 81.1, 76.4, 69.9, 68.1, 67.7, 67.6, 67.1, 63.6, 62.9, 61.7, 61.1, 20.9, 20.8, 20.6 (multiple
peaks are due to rotameric mixture); ESIMS (m/z): 598 [M+Na]+; HRMS (ESI) [M+Na]+:
Anal. Calcd for C32H33NO9Na 598.20475 found 598.20411.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5R,6R,7R,7αR)ꢀ5ꢀ(4ꢀ(Benzyloxy)phenyl)ꢀ6,7ꢀdihydroxytetrahydropyrꢀrolo[1,2ꢀc]oxꢀazolꢀ
3(1H)ꢀone (24). To a stirred solution of cyclic compound 23 (1.0 g, 1.73 mmol) in dry MeOH
(10 mL), was added K2CO3 (0.86 g, 6.26 mmol) under nitrogen atmosphere. After being
stirred for 60 min at rt, the MeOH was evaporated under reduced pressure and the residue
was extracted with chloroform (30 mL). The organic extract was washed with water (10 mL),
brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure and puriꢀ
fied by silica gel column chromatography using (ethyl acetate/hexane 1:3) as the eluant to
13
afford a bicyclic carbamate 24 (0.49 g, 84%) as white solid. The spectral (1H and C) and
analytical (optical rotation and melting point) data of synthetic compund 24 were in excellent
20
agreement with the reported values.7d mp 125ꢀ130 °C, [α]D = ꢀ4.6 (c 0.68, MeOH) {lit,7d
mp 129ꢀ131 oC, [α]D27 = ꢀ4.5 (c 1.4, MeOH)}; IR (neat): 3393, 3341, 2474, 2214, 2070, 1219,
1
1120, 1091 cmꢀ1; H NMR (300 MHz, CD3OD): δ 7.49ꢀ7.25 (m, 7H), 6.99 (d, J = 8.5 Hz,
2H), 5.09 (brs, 2H), 4.65 (dd, J = 8.3, 9.0 Hz, 1H), 4.49 (d, J = 6.3 Hz, 1H), 4.42 (dd, J =
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 33
1
2
3
4
5
6
7
8
9
13
4.1, 9.0 Hz, 1H), 4.08ꢀ3.97 (m, 2H), 3.85 (dd, J = 7.4, 15.1 Hz, 1H); C NMR (125 MHz,
CD3OD): δ 163.7, 159.6, 138.7, 134.0, 129.5, 128.8, 128.5, 128.1, 116.1, 86.7, 80.9, 71.0,
68.5, 67.7, 63.2; ESIMS (m/z): 364 [M+Na]+; HRMS (ESI) [M+Na]+: Anal. Calcd for
C19H19NO5Na 364.11554 found 364.11592.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)ꢀBenzyl 2,2ꢀdimethylꢀ4ꢀvinyloxazolidineꢀ3ꢀcarboxylate (25). To a solution of DMSO
(2.14 mL, 30.18 mmol) in DCM (20 mL) was added oxalyl chloride (1.31 mL, 15.09 mmol)
o
dropwise at ꢀ78 C. After stirring for 30 min, a solution of Dꢀserine derived alcohol (2.0 g,
7.54 mmol) in DCM (30 mL) was added over a period of 10 min. After stirring for 2 h at ꢀ78
oC, the reaction mixture was quenched with triethylamine (6.32 mL, 45.28 mmol). The temꢀ
perature was slowly raised to room temperature over 20 min and the reaction mixture was
diluted with chloroform (50 mL), washed with the water and brine, dried over Na2SO4 and
concentrated under vacuum. The crude residue was dissolved in THF (30 mL), a yellow soluꢀ
tion of Ph3P=CH2 (4.26 g, 10.5 mmol) in THF (40 mL) was added at ꢀ10 oC. After stirring for
o
3 h, the reaction mixture was quenched with saturated aq NH4Cl at 0 C, THF was removed
under reduced pressure and the residue was extracted with ethyl acetate (3 X 100 mL). The
combined organic extracts were washed with H2O (50 mL) brine (40 mL), dried over anhyꢀ
drous Na2SO4, concentrated under reduced pressure and purified by column chromatography
(ethyl acetate/hexane 1:7) to afford compound 25 (1.37 g, 70%) as a colourless oil. The specꢀ
13
tral (1H and C) and analytical (optical rotation) data of synthetic compound 25 were in exꢀ
20
24
cellent agreement with the reported values.13c [α]D = +19.1 (c 0.95, CHCl3) {lit,13c [α]D
=
+19.6 (c 1.6, CHCl3)}; IR (neat): 2984, 2937, 1696, 1413, 1403, 1345, 1251, 1208, 1089,
1
1058 cmꢀ1; H NMR (300 MHz, CDCl3): δ 7.43ꢀ7.23 (m, 5H), 5.84 (m, 1H), 5.32ꢀ5.06 (m,
4H), 4.40 (brs, 1H), 4.05 (dd, J = 6.0, 8.6 Hz, 1H), 3.79 (dd, J = 1.8, 8.6 Hz, 1H), 1.68ꢀ1.46
(3s, 6H) (multiple peaks are due to rotameric mixture); 13C NMR (125 MHz, CDCl3): δ
152.6, 152.3, 136.8, 136.4, 136.1, 128.4, 128.2, 127.9, 127.7, 127.6, 116.5, 116.1, 94.3, 93.7,
24
ACS Paragon Plus Environment

Page 25 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
68.2, 67.9, 67.0, 66.4, 60.0, 59.2, 27.1, 26.2, 24.8, 23.4 (multiple peaks are due to rotameric
mixture); ESIMS (m/z): 262 [M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd for C15H20NO3
262.14377, found 262.14347.
9
(S,E)ꢀBenzyl4ꢀ(3ꢀ(3,4ꢀdimethoxyphenyl)propꢀ1ꢀenyl)ꢀ2,2ꢀdimethyloxazolidineꢀ3ꢀ
carboxylate (27). To a solution of olefin compound 25 (1.2 g, 4.59 mmol) in dry DCM (10
mL) were added 4ꢀallylꢀ1,2ꢀdimethoxybenzene 26 (2.76 mL, 16.0 mmol) and the Grubbs seꢀ
cond generation catalyst (0.39 g, 0.459 mmol) and CuI (0.07 g, 0.367 mmol) in one portion at
room temperature and refluxed for 8 h, under a N2 atmosphere. Residue was concentrated unꢀ
der reduced pressure and purified by column chromatography (ethyl acetate/hexane 1:8) to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
afford the olefin compound 27 (1.51 g, 80%) as a syrupy liquid. [α]D = +5.0 (c 0.55,
CHCl3); IR (neat): 2984, 2936, 1701, 1590, 1514, 1406, 1348, 1260, 1236, 1140, 1092, 1028
1
cmꢀ1; H NMR (300 MHz, CDCl3): δ 7.45ꢀ7.23 (m, 5H), 6.83ꢀ6.61 (m, 3H), 5.67 (m, 1H),
5.52 (dd, J = 6.0, 15.1 Hz, 1H), 5.27ꢀ5.04 (m, 2H), 4.43 (m, 1H), 4.05 (dd, J = 6.0, 8.6 Hz,
1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.78 (dd, J = 1.8, 8.6 Hz, 1H), 3.41ꢀ3.19 (m, 2H), 1.57 (3s,
6H) (multiple peaks are due to rotameric mixture); 13C NMR (75 MHz, CDCl3): δ 152.3,
148.7, 147.2, 136.4, 132.3, 131.7, 129.6, 128.2, 127.7, 120.2, 111.7, 111.1, 94.1, 68.5, 66.9,
66.3, 59.4, 58.7, 55.8, 55.6, 37.8, 27.2, 26.3, 24.7, 23.4 (multiple peaks are due to rotameric
mixture); ESIMS (m/z): 412 [M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd for C24H30O5N
412.20982 found 412.20985.
(2R,3R,4R)ꢀ2ꢀ(Benzyloxycarbonylamino)ꢀ5ꢀ(3,4ꢀdimethoxyphenyl)pentaneꢀ1,3,4ꢀtriyl triꢀ
acetate (28). To a stirred solution of olefin compound 27 (1.0 g, 2.43 mmol) and Nꢀmethyl
morpholineꢀNꢀoxide (0.43 g, 3.64 mmol) in acetone and water at 0 °C was added a catalytic
amount of OsO4 solution in toluene (0.61 mL, 0.0243 mmol). After stirring for 8 h at room
temperature, a saturated aqueous solution of Na2SO3 (4 mL) was added to the mixture and
extracted with ethyl acetate (3 x 20 mL). The combined extracts were dried over Na2SO4 and
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 33
1
2
3
4
5
6
7
8
solvent removed thoroughly under vacuum. The crude residue was chromatographed on silica
gel (hexane/ethyl acetate = 2/1) to afford dihydroxylated compound (0.97 g, 90%) as a colꢀ
ourless oil.
9
To a stirred solution of dihydroxylated compound in CH3CN (5 mL) was added CuCl2.2H2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
(0.484 g, 2.91 mmol) at 0 C and the reaction mixture was warmed to room temperature unꢀ
der stirring for 2 h. The reaction mixture was quenched with saturated NaHCO3, filtered
through celite pad of silica gel and solvents were removed under reduced pressure to give the
crude product. To the crude triol compound in dry DCM (10 mL) was added triethyl amine
(2.03 mL, 14.59 mmol), acetic anhydride (0.92 mL, 9.73 mmol) and 4ꢀdimethylamino pyriꢀ
dine (5 mg) at 0 °C under nitrogen atmosphere. After completion of the addition, the reaction
mixture was kept at room temperature and stirred for 2 h. The reaction mixture was diluted
with chloroform (50 mL), washed with water and brine, dried over Na2SO4 and concentrated
under vacuum. Purification by column chromatography (ethyl acetate/hexane 1:8) afforded
triacetate derivatives 28 (0.81 g) and 29 (0.34 g) in 90% yield (dr = 70:30).
Major triacetate compound 28. [α]D20 = +2.2 (c 0.32, CHCl3); IR (neat): 3340, 2955, 2933,
1741, 1513, 1371, 1220, 1048, 1027 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.40ꢀ7.29 (m, 5H),
6.81ꢀ6.70 (m, 3H), 5.25 (m, 1H), 5.17ꢀ5.01 (m, 3H), 4.97 (d, J = 10.0 Hz, 1H), 4.28 (m, 1H),
4.16 (dd, J = 4.5, 11.7 Hz, 1H), 4.01 (dd, J = 3.4, 11.7 Hz, 1H), 3.85 (s, 6H), 2.81 (dd, J =
6.2, 13.6 Hz, 1H), 2.70 (dd, J = 7.3, 13.6 Hz, 1H), 2.17 (s, 3H), 2.07 (s, 3H), 1.98 (s, 3H); 13C
NMR (75 MHz, CDCl3): δ 170.4, 170.1, 169.9, 155.8, 148.6, 147.8, 136.0, 128.5, 128.2,
128.1, 121.4, 112.3, 111.0, 72.7, 71.2, 67.1, 63.0, 55.7, 50.2, 36.4, 20.7, 20.5, 20.4; ESIMS
(m/z): 554 [M+Na]+; HRMS (ESI) [M+Na]+: Anal. Calcd for C27H33O10NNa 554.19967
found 554.19876.
(2R,3S,4S)ꢀ2ꢀ(Benzyloxycarbonylamino)ꢀ5ꢀ(3,4ꢀdimethoxyphenyl)pentaneꢀ1,3,4ꢀtriyl triꢀ
20
acetate (29). [α]D = ꢀ0.6 (c 0.42, CHCl3); IR (neat): 3339, 2934, 1742, 1702, 1605, 1515,
26
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
1451, 1371, 1218, 1148, 1048, 1024 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.40ꢀ7.28 (m, 5H),
6.79ꢀ6.67 (m, 3H), 5.26 (m, 1H), 5.16ꢀ5.10 (m, 3H), 5.07 (d, J = 10.1 Hz, 1H), 4.29 (m, 1H),
4.05ꢀ3.99 (m, 2H), 3.85 (s, 6H), 2.89 (dd, J = 5.3, 14.0 Hz, 1H), 2.79 (dd, J = 7.8, 14.0 Hz,
9
13
1H), 2.05 (s, 3H), 1.97 (s, 3H), 1.95 (s, 3H); C NMR (75 MHz, CDCl3): δ 170.5, 170.1,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
169.9, 155.5, 148.6, 147.7, 136.0, 128.4, 128.19, 128.15, 127.9, 121.5, 121.2, 112.4, 111.0,
72.5, 70.8, 67.1, 63.0, 55.7, 49.5, 36.5, 21.0, 20.7, 20.6; ESIMS (m/z): 532 [M+H]+; HRMS
(ESI) [M+H]+: Anal. Calcd for C27H34O10N 532.21530 found 532.21527.
(2R,3R,4R,5S)ꢀ2ꢀ(Acetoxymethyl)ꢀ1ꢀ(benzyloxy carbonyl )ꢀ5ꢀ(3,4ꢀdimethoxyphenyl) pyrꢀ
rolidineꢀ3,4ꢀdiyl diacetate (30). To a stirred solution of triacetate compound 28 (0.6 g, 1.12
mmol) in CH3CN (3 mL) was added DDQ (0.28 g, 1.24 mmol). The resulting mixture was
o
heated at 80 C for 4 h under nitrogen atmosphere. After completion of the reaction as eviꢀ
denced by TLC, the reaction mixture was cooled to room temperature and quenched with
Et3N, concentrated under reduced pressure to give crude residue, which was purified by colꢀ
umn chromatography (ethyl acetate/hexane 1:8) to afford cyclic compound 30 (0.50 g, 85%)
20
as a colourless oil. [α]D = ꢀ9.8 (c 0.19, CHCl3); IR (neat): 2924, 2852, 1743, 1705, 1515,
1
1404, 1219, 1141, 1029 cmꢀ1; H NMR (300 MHz, CDCl3): δ 7.46ꢀ7.12 (m, 5H), 6.88ꢀ6.73
(m, 3H), 5.28ꢀ4.91 (m, 4H), 4.85 (d, J = 12.4 Hz, 1H), 4.61 (m, 1H), 4.50 (m, 1H), 4.32 (m,
1H), 3.89 (s, 3H), 3.76 (s, 3H), 2.17 (s, 3H), 2.12 (s, 3H), 1.85 (s, 3H) (multiple peaks are due
to rotameric mixture); 13C NMR (125 MHz, CDCl3): δ 170.6, 170.5, 169.6, 169.5, 169.2,
169.1, 154.3, 153.6, 148.77, 148.72, 148.1, 135.9, 135.6, 131.5, 130.3, 128.56, 128.51, 128.3,
128.1, 127.8, 127.7, 118.1, 117.9, 110.7, 110.6, 109.29, 109.24, 82.3, 81.2, 76.5, 68.3, 68.0,
67.6, 67.1, 63.6, 62.9, 61.7, 61.1, 55.9, 55.8, 55.6, 21.0, 20.8, 20.7 (multiple peaks are due to
rotameric mixture); ESIMS (m/z): 552 [M+Na]+; HRMS (ESI) [M+Na]+: Anal. Calcd for
C27H31O10NNa 552.18402 found 552.18300.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
5
6
7
8
9
(2R,3R,4R,5R)ꢀ2ꢀ(3,4ꢀDimethoxyphenyl)ꢀ5ꢀ(hydroxymethyl)ꢀ1ꢀmethylpyrrolidineꢀ3,4ꢀdiol
[(–)ꢀcodonopsinol] (3). To a stirred suspension of LiAlH4 (0.13 g, 183 mmol) in THF (3 mL)
was added pyrrolidine derivative 30 (0.3 g, 0.56 mmol) in THF (5 mL) at 0 °C. After the
completion of the addition the reaction mixture was refluxed for 5 h. The reaction mixture
was cooled to 0 °C, quenched with water (0.13 mL), 15% NaOH (0.13 mL) and water (0.4
mL) successively. After 15 min stirring at rt, the reaction mixture was filtered through the
celite pad, washed with ethyl acetate (3 x 10 mL) and the filtrate was evaporated under vacuꢀ
um. The residue was purified through silica gel column (CHCl3/MeOH = 7:1) to afford the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
codonopsinol 3 (0.12 g, 80%) as white solid. The spectral (1H and C) and analytical data
(optical rotation and melting point) of synthetic (–) codonopsinol 3 were in excellent agreeꢀ
20
ment with the reported values.6b mp 150ꢀ155 °C [α]D = ꢀ13.8 (c 0.63, MeOH) {lit,6b mp
150ꢀ152 °C [α]D25 = ꢀ13.0 (c 1.37, MeOH)}; IR (neat): 3329, 2944, 2832, 2506, 2071, 1449,
1
1414, 1219, 1119, 1020 cmꢀ1; H NMR (400 MHz, CD3OD): δ 7.03 (s, 1H), 6.90 (s, 2H),
4.03 (t, J = 4.4 Hz, 1H), 3.94 (dd, J = 5.0, 6.4 Hz, 1H), 3.78ꢀ3.87 (m, 8H), 3.66 (d,J = 6.6
13
Hz, 1H), 3.10 (m, 1H), 2.20 (s, 3H); C NMR (125 MHz, CD3OD): δ 150.5, 149.9, 134.7,
122.3, 112.6, 112.5, 85.8, 80.1, 75.8, 71.1, 60.8, 56.5, 56.4, 34.9; ESIMS (m/z): 284 [M+H]+;
HRMS (ESI) [M+H]+: Anal. Calcd for C14H22O5N 284.14776 found 284.14777.
(S)ꢀNꢀ(3,7ꢀDimethyloctꢀ6ꢀenꢀ1ꢀyl)ꢀ4ꢀmethylbenzene sulfonamide (32). To a solution of
(S)ꢀ3,7ꢀdimethyloctꢀ6ꢀenꢀ1ꢀol 31 (0.5 g, 3.20 mmol) and Et3N (1.34 mL, 9.61 mmol) in dry
DCM (8 mL) at 0 °C was added MsCl (0.26 mL, 3.36 mmol). After 15 min the reaction was
allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted
with chloroform (20 mL), washed with water and brine, dried over Na2SO4 and concentrated
under vacuum. The organic phase was washed with brine (20 mL), dried over NaSO4, filtratꢀ
ed and concentrated under vacuum to afford the compound as colourless oil. To the crude
compound (S)ꢀ3,7ꢀdimethyloctꢀ6ꢀenꢀ1ꢀyl methanesulfonate (0.75 g, 3.20 mmol) in CH3CN
28
ACS Paragon Plus Environment

Page 29 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(15 mL) were added K2CO3 (0.90 g, 6.41 mmol) and TsNH2 (1.10 g, 6.41 mmol) and the reꢀ
action was heated to reflux. After 5 h, the reaction mixture was filtered through celite pad and
evaporated under vacuum. Purification by silica gel column chromatography (ethyl aceꢀ
tate/hexane 1:9) afforded product 32 as a colourless oil (0.79 g, 80%). The spectral (1H and
13C) data of synthetic compound 32 was in excellent agreement with the reported values.2d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
[α]D = ꢀ5.6 (c 1.1, CHCl3); IR (KBr): 3283, 2925, 2871, 1712, 1598, 1453, 1327, 1158,
1092 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H),
5.02 (dd, J = 7.0 Hz, 1H), 4.50 (m, 1H), 3.02ꢀ2.88 (m, 2H), 2.43 (s, 3H), 1.98ꢀ1.80 (m, 2H),
1.67 (s, 3H), 1.57 (s, 3H), 1.51ꢀ1.36 (m, 2H), 1.31ꢀ1.03 (m, 3H), 0.81 (d, J = 6.6 Hz, 3H). 13C
NMR (CDCl3, 125 MHz): δ 143.0, 136.8, 131.1, 129.5, 126.9, 124.3, 41.1, 36.6, 36.3, 29.7,
25.5, 25.1, 21.3, 18.9, 17.4; ESIMS (m/z): 310 [M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd
for C17H28NO2S 310.18353 found 310.18295.
4ꢀMethylꢀ2ꢀ(2ꢀmethylpropꢀ1ꢀenꢀ1ꢀyl)ꢀ1ꢀtosylpiperidine (33). To a stirred solution of sulꢀ
phonamide compound 32 (0.2 g, 0.64 mmol) in CH3CN (2 mL) was added DDQ (0.16 g, 0.71
o
mmol) at 0 C. The resulting mixture was allowed to room temperature for 30 min under niꢀ
trogen atmosphere. After completion of the reaction as evidenced by TLC, the reaction mixꢀ
ture was cooled to room temperature and quenched with Et3N, concentrated under reduced
pressure to give crude residue, which was purified by silica gel column chromatography
(ethyl acetate/hexane 1:9) to give mixture of cyclic compounds 33 and 34 (0.39 g, 90%) as
colourless oils. The spectral (1H and 13C) data of synthetic compound 33 and 34 was in excelꢀ
lent agreement with the reported values.2d
Transꢀ(2R,4S)ꢀ4ꢀmethylꢀ2ꢀ(2ꢀmethylpropꢀ1ꢀenꢀ1ꢀyl)ꢀ1ꢀtosylpiperidine (33). IR (KBr):
2921, 2867, 1597, 1449, 1338, 1306, 1261, 1160, 1088 cmꢀ1. 1H NMR (CDCl3, 500 MHz): δ
7.56 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 5.29 (dqunit, J = 1.3, 9.3 Hz, 1H), 4.00 (dt,
J = 4.1, 12.0 Hz, 1H), 3.36 (ddd, J = 2.8, 10.0, 12.3 Hz, 1H), 2.63 (ddd, J = 2.8, 11.2, 12.0
29
ACS Paragon Plus Environment