A Concise Total Synthesis of (-)-Mesembrine

Article abstract of DOI:10.1021/acs.joc.6b01908

A concise total synthesis of mesembrine (four steps from known compound) was achieved both racemically and asymmetrically. Two key reactions were used here. One is the Rh(I)-catalyzed [5 + 1] cycloaddition of vinylcyclopropane 3c and CO. The other one is Buchwald's Pd-catalyzed coupling reaction that coupled β,γ-cyclohexenone 2c with aryl bromide 5 (using dppe ligand for racemic or (S)-Antphos ligand for asymmetric synthesis) to give γ,γ-disubstituted α,β-cyclohexenone 1c. Finally, aza-Michael addition converted 1c to mesembrine.

Full text of DOI:10.1021/acs.joc.6b01908

Subscriber access provided by University of Illinois at Urbana-Champaign Library
Brief Communication
A concise total synthesis of (-)-Mesembrine
Lu-Ning Wang, Qi Cui, and Zhi-Xiang Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01908 • Publication Date (Web): 10 Oct 2016
Downloaded from http://pubs.acs.org on October 12, 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 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A Concise Total Synthesis of (–)-Mesembrine
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
LuꢀNing Wang, Qi Cui, and ZhiꢀXiang Yu*
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking
University, Beijing 100871, China
ABSTRACT: A concise total synthesis of mesembrine (four steps from known compound) was achieved
both racemically and asymmetrically. Two key reactions were used here. One is the Rh(I)ꢀ catalyzed [5 + 1]
cycloaddition of vinylcyclopropane 3c and CO. The other one is Buchwald’s Pdꢀcatalyzed coupling reaction
that coupled β,γꢀcyclohexenone 2c with aryl bromide 5 (using dppe ligand for racemic or (S)ꢀAntphos ligand
for asymmetric synthesis) to give γ,γꢀdisubstituted α,βꢀcyclohexenone 1c. Finally, azaꢀMichael addition
converted 1c to mesembrine.
(–)ꢀMesembrine, a natural product extracted from a South African plant Sceletium Tortuosum(Figure 1),1 has
shown an excellent effect of antiꢀanxiety and antiꢀaddiction.2 This molecule is a family member of
benzylphenethylamineꢀtype alkaloids,3 which contain a synthetically challenging bridgehead quaternary
carbon with one aryl substituent (Figure 1). Since its discovery in 1957, this molecule has been an intensely
pursued target for total synthesis. Until now, more than 40 routes toward its total and formal syntheses have
been reported.4 Despite these, the appealing structure with the challenging bridgehead quaternary carbon,
and significant biological activity of mesembrine have been stimulating chemists to design new strategy to
synthesize this molecule and its analogs under the consideration of step economy.5
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 14
1
2
3
4
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
Figure 1. (–)ꢀMesembrine and representative benzylphenethylamineꢀtype alkaloids.
We report here our concise synthesis of mesembrine, both racemic and asymmetric. Our approach to the total
synthesis of mesembrine was inspired by both Buchwald’s work and our own [5 + 1] reaction (Scheme 1). In
2008, Hyde and Buchwald developed a palladiumꢀcatalyzed crossꢀcoupling reaction of β,γꢀcyclohexenones
with aryl bromides to γ,γꢀdisubstituted α,βꢀcyclohexenones.6 One salient feature of this reaction is that a
quaternary carbon can be built. The authors also demonstrated that its asymmetric version can be realized by
using chiral phosphine ligand (R)ꢀDTBMꢀSegphos.6 Furthermore, the Buchwald group tandemed this
coupling reaction with azaꢀMichael addition of amine to build indoline skeleton when orthoꢀbromoaniline
was used as the coupling partner.
The starting material, β,γꢀcyclohexenones in Buchwald’s chemistry was prepared by Birch reduction of aryl
compounds.7 Recently we developed a Rh(I)ꢀcatalyzed [5 + 1] cycloaddition of vinylcyclopropanes (VCPs)
and CO (Scheme 1).8a The [5 + 1] cycloaddition can be used to construct either β,γꢀcyclohexenones or
α,βꢀcyclohexenones, depending on whether DBU base was used or not in the reaction. Considering that our
[5 + 1] reaction has broad scope, preparation of VCPs are easy, and the reaction conditions are mild, we
envisioned that a combination of our [5 + 1] reaction to the synthesis of β,γꢀcyclohexenones, with
Buchwald’s coupling chemistry may provide an efficient route to γ,γꢀdisubstituted α,βꢀcyclohexenones, in
both racemic and asymmetric fashions.
Scheme 1. Pd(0)ꢀcatalyzed coupling reaction and Rh(I)ꢀcatalyzed [5 + 1] cycloaddition
2
ACS Paragon Plus Environment

Page 3 of 14
The Journal of Organic Chemistry
1
2
3
Buchwald's work: coupling reaction of cyclohexenones with aryl bromides
4
5
6
7
8
9
Pd(OAc)2 (2.0 mol%)
dppe (4.0 mol%)
1.5 eq. Cs2CO3
O
O
+
+
ArBr
toluene/ 100 o
C
Ar
R
O
R
NH2
Me
R2
O
[Pd2(dba)3] (1 mol%)
Br
R1
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
N
H
R)-DTBM-Segphos (4 mol%)
2.5 eq. K3PO4
H
R1
Me
R2
toluene, 100 oC, 8h
(S)-DTBM-Segphos
O
t-Bu
OMe
t-Bu
O
O
PR2
PR2
R=
O
Our work: [5 + 1] cycloaddition of VCPs with CO
O
O
[Rh(dppp)]OTf (10 mol%)
4 Å MS, DCE, 85 °C
R4
R3
R4
+
R1
R1
R3
Conditions A
R2
R2
major
R2 R3
+
CO
R1
1) [Rh(dppp)]SbF6 (10 mol%)
4 Å MS, DCE, 85 °C
2) DBU, rt
minor
O
0.2 atm
R4
R3
R4
Conditions B
R1
R2
The total synthesis of mesembrine provides a chance to show the power of this combination for the synthesis
of γ,γꢀdisubstituted α,βꢀcyclohexenones. Scheme 2 shows the retrosynthetic analysis of mesembrine. We
proposed that the pyrrolidine skeleton could be synthesized by an intramolecular azaꢀMichael addition from
Nꢀprotected γ,γꢀdisubstituted α,βꢀcyclohexenone 1.9 The cyclohexenone 1 could be accessed by Buchwald
coupling reaction using β,γꢀcyclohexenone 2 and aryl bromide 5. The cyclohexenone 2 could be prepared by
our Rh(I)ꢀcatalyzed [5 + 1] cycloaddition of corresponding VCP 3 with CO. VCP 3 was expected to be
synthesized from the known compound 4,10 with a protected methylamine via a SN2 reaction. This strategy
could also be advanced to its asymmetric version, if Buchwald’s chiral DTBMꢀSegphos ligand or other
chiral ligands was used.
Scheme 2. Synthetic strategy for (±)ꢀmesembrine
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 14
1
2
3
4
5
6
7
8
9
Because Ts group (tosyl) is stable under both acidic and basic conditions and it often acts as a good
protecting group on nitrogen atom,11 we firstly synthesized TsꢀVCP 3a as the substrate to test whether the [5
+ 1] cycloaddition, coupling reaction and the deprotection reaction can all work (Scheme 3). The known
compound 4 reacted with TsNHMe to give corresponding 3a in 80% yield. Then we tried the key
Rhꢀcatalyzed [5 + 1] cycloaddition of 3a with CO by using the previous reported reaction conditions.8a
Fortunately, under a balloon pressured mixed gas of CO and N2 (the ratio of CO / N2 is 1 / 4 and this is
usually labeled as 0.2 atm CO), using 10 mol% Rh(dppp)OTf, we obtained the target molecule 2a in 43 %
yield. When the loading of catalyst was increased to 15 mol%, the yield of 2a was improved to 52 %. The
low yield of this [5 + 1] reaction is due to the presence of a side reaction: side product 2a', which was
generated from the βꢀH elimination of sixꢀmembered rhodacycle intermediate A (Scheme 4), was obtained in
37 % yield.12 We speculated that, increasing the pressure of CO and its concentration in the reaction system
could inhibit the βꢀH elimination reaction and, consequently improve the yield of [5 + 1] reaction. To our
delight, under balloon pressure of CO atmosphere (1 atm), we obtained the [5 + 1] cycloadduct 2a in 56 %
isolated yield, together with the remaining starting material (Scheme 3). No side product 2a' was observed.
The [5 + 1] reaction yield in this case was 90 % based on recovered starting material (brsm).
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. Synthesis of Ts protected cyclohexenone 1a
O
Pd(OAc)2 (10 mol%)
dppe (20 mol%)
1.5 eq. Cs2CO3
[Rh(dppp)]OTf (15 mol%)
x atm CO
O
Ts
DCE/4 Å MS
TsNHMe, NaH
NMe
Ts
toluene/100 oC
Br
90 o
C
Ts
0 oC/THF
80 %
I
NMe
NMe
2a
x=1.0, 56 %
4
3a
(90 %, brsm)
MeO
OMe
2a
MeO
OMe
5
1a
(
)-
x=0.2, 52 % 2a
together with 37 %
(see Scheme 4)
2a'
46 %
Scheme 4. Proposed mechanisms for the [5 + 1] reaction and the formation of βꢀH elimination product
Then we tested the coupling reaction of cyclohexenone 2a with 4ꢀbromoveratrole 5 under the reaction
conditions reported by the Buchwald group.6 When we used
mol% Pd(OAc)2, mol%
2
4
1,2ꢀbis(diphenylphosphino)ethane (dppe), 1.0 eq of compound 2a, 1.1 eq of 4ꢀbromoveratrole and 1.5 eq of
o
Cs2CO3 (heating in toluene at 100 C), to our disappointment, we got a complex mixture. Considering that
some side reactions (such as dehydrogenation) may occur if the aryl bromide was excess,13 we reduced the
amount of 5 from 1.1 eq to 0.8 eq. Unfortunately, still a complex mixture was observed. Finally we were
pleased to find that, increasing loadings of both preꢀcatalyst and ligand (10 mol% Pd(OAc)2 and 20 mol%
4
ACS Paragon Plus Environment

Page 5 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
dppe), the target coupling reaction underwent smoothly and the desired compound (
46 % yield (Scheme 3).
±)ꢀ1a was obtained in
With the compound (±)ꢀ1a in hand, we tried to remove the tosyl group to achieve an intramolecular
7
8
9
azaꢀMichael addition to accomplish the total synthesis of (±)ꢀmesembrine. We tried several conditions such
as using TMSI,14 Mg/MeOH15 and Na/naphthalene16 to finish the synthesis. Only Na/naphthalene could give
the target product (±)ꢀmesembrine in a low yield. We did not try other conditions to remove the Ts group.
Instead, we planned to use other protecting groups for the accomplishment of the total synthesis of
mesembrine.
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
Considering oꢀNs group (oꢀnitrobenzenesulfonyl) is also a sulfamideꢀtype protecting group and it can be
easy to be removed with thiols,11 we prepared oꢀNsꢀVCP 3b. The yield of [5 + 1] cycloaddition was 61 %.
But under optimized conditions, the coupling reaction didn’t work, giving a complex mixture (Scheme 5).
The reason for this is not known at this moment.
Scheme 5. Synthesis of cyclohexenone 2b
Because Boc group (tꢀbutoxycarbonyl) is stable under basic ambient conditions and easy to be removed
under acidic ambient conditions,11 we tried to synthesize BocꢀVCP 3c to accomplish the synthesis of
mesembrine (Scheme 6). Compound 4 was use to react with BocNHMe, giving BocꢀVCP 3c in 47 % yield.
Under the optimized conditions of [5 + 1] cycloaddition, target cyclohexenone 2c was obtained in 73 %
isolated yield. Using higher pressure of CO did not improve the reaction yield of [5 + 1] reaction (when the
pressure of CO was increased to 5 atm, the yield of [5 + 1] reaction was only 52ꢀ56 %). Then 0.7 eq 5 was
used to carry out the coupling reaction with 1.0 eq. 2c, and we found that (±)ꢀ1c was obtained in 68 % yield
in this case (we want to mentioned that, in all the coupling reactions, excess 2 could not be recovered). After
1
removing the Boc group using TFA, the final product (±)ꢀmesembrine was obtained in 76% yield. H
NMR,13C NMR, IR and HRMS data of the synthesized mesembrine are in agreement with those reported in
the literature.4h
Scheme 6. Concise total synthesis of (±)ꢀmesembrine.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
1
2
3
4
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
Then we tried to use chiral phosphine ligands to test the asymmetric coupling reaction so that an asymmetric
total synthesis of mesembrine could be realized. Firstly, we used chiral ligand (S)ꢀDTBMꢀSegphos, which
was used by Hyde and Buchwald,6 to do the coupling reaction. Fortunately, the expected reaction happened
and gave product 1c in 40 % yield. Removing Boc group in 1c gave the product mesembrine, which was
found to be racemic, as determined by chiral HPLC.
We noticed that, Tang and coworkers developed several chiral monophosphine ligands that can facilitate
Pdꢀcatalyzed coupling reaction to form congested C–C bonds,17 including the dearomatization of
bromineꢀsubstituted phenol (Scheme 7).17b, 17c We envisioned that, this reaction occurs via similar mechanism
with that of the Buchwald reaction in Scheme 1, and could be a choice for our asymmetric synthesis.
Therefore, we tested the Pd catalyzed coupling reaction using Tang’s (S)ꢀAntphos ligand.17b, 17c Using 10 mol%
Pd(OAc)2 and 10 mol% (S)ꢀAntphos, the target compound (R)ꢀ1c was obtained in 30 % yield (0.7 eq. 5, 1 eq.
2c were used). After removing the Boc group, we got the product (–)ꢀmesembrine in 73 % yield and 86 % ee.
Then we increased the loading of catalyst to 20 mol% and decreased the amount of aryl bromide to 0.5 eq
(2c was 1 eq.), the yield of coupling reaction was 63 % (Scheme 8). Removal of Boc group from (R)ꢀ1c gave
the (–)ꢀmesembrine in 73 % yield with 86 % ee.
Scheme 7. Asymmetric intramolecular phenol/aryl bromide coupling reaction by Tang
Scheme 8. Total synthesis of (–)ꢀmesembrine
6
ACS Paragon Plus Environment

Page 7 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
In summary, we have accomplished both racemic and asymmetric total synthesis of mesembrine, each in
four steps from known compound via Rh(I)ꢀcatalyzed [5 + 1] cycloaddition of VCP with CO; and the
Pd(0)ꢀcatalyzed coupling reaction of β,γꢀcyclohexenone with aryl bromide. This strategy could be used to
synthesize other benzylphenethylamineꢀtype alkaloids with quaternary bridgehead carbon center. Further
application of the strategy in synthesis is ongoing in our laboratory.
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
EXPERIMENTAL SECTION
General information. Airꢀ and moistureꢀsensitive reactions were carried out in ovenꢀdried glassware sealed
with rubber septa under a positive pressure of dry argon or nitrogen. Similarly, sensitive liquids and
solutions were transferred via syringe. Reactions were stirred using Teflon coated magnetic stir bars.
Elevated temperatures were maintained using thermostatꢀcontrolled silicone oil baths. Organic solutions
were concentrated using a rotary evaporator with a desktop vacuum pump. Tetrahydrofuran (THF) and
toluene were distilled from sodium and benzophenone prior to use. Dichloromethane (DCM) was distilled
from CaH2 prior to use. N,Nꢀdimethylformamide (DMF) and methanol were dried by molecular sieves
prior to use. Dichloroethane (DCE) was superꢀdry level. Synthetic reagents were purchased and used without
further purification unless otherwise indicated. Analytical TLC was performed with 0.25 mm silica gel G
plates. The TLC plates were visualized by ultraviolet light and treatment with phosphomolybdic acid stain
followed by gentle heating. Purification of products was accomplished by flash chromatography on silica gel,
and the purified compounds showed a single spot by analytical TLC. The diastereomeric ratio was
determined by 1H NMR of crude reaction mixtures. NMR spectra were recorded at 400 MHz for 1H and 100
MHz for 13C using TMS (1H, 0.00 ppm) and CDCl3 (13C, 77.0 ppm) as internal standard. The following
abbreviations were used to explain the multiplicities: s = singlet, brs = broad singlet, d = doublet, t = triplet,
q = quartet, dd = doublet of doublets, ddd = doublet of doublet of doublets, m = multiplet, coupling constant
(Hz), and integration. IR spectra were recorded on fourier transform infrared spectrometer and reported in
wavenumbers (cm−1). HRMS were recorded on FTMS mass spectrometer (ESI). Optical rotations were
measured on a spectrometer. Enantiomer excess (ee) values were determined by analytical liquid
chromatography (HPLC) analysis on a chromatograph (Daicel chiral columns Chiralpak ASꢀH (4.6 × 250
mm). PE refers to petroleum ether and EA refers to ethyl acetate.
N,4ꢀDimethylꢀNꢀ(2ꢀ(1ꢀvinylcyclopropyl)ethyl)benzenesulfonamide (3a)
To NaH (167 mg, 60% in mineral oil, 4.18 mmol) was added solution of TsNHMe (709.9 mg, 3.83 mmol in
15 mL THF) at 0oC. After stirring at room temperature for 5 min, a solution of 49 (773.9 mg, 3.48 mmol) in
DMF (5 mL) was added. Then the reaction solution was stirred for anothor 15 h and quenched with dropwise
addition of water. The aqueous mixture was extracted with diethyl ether. The combined organic phase was
dried with anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue through column
chromatography on silica gel (eluted with PE/EA 5:1) afforded the product 3a as a colorless oil (771.9 mg,
80 % yield).
1
3a: Colorless oil. TLC Rf (PE/EA 5:1) = 0.45. H NMR (400 MHz, CDCl3): δ 0.55ꢀ0.63 (m, 4H), 1.65ꢀ1.72
(m, 2H), 2.43 (s, 3H), 2.74 (s, 3H), 3.04ꢀ3.11 (m, 2H), 4.92 (dd, J = 10.6, 0.8 Hz, 1H), 4.94 (dd, J = 17.6, 0.8
Hz, 1H), 5.49 (dd, J = 17.6, 10.6 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H) 7.66 (d, J = 8.2 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ 143.2, 142.7, 134.8, 129.6, 127.3, 111.3, 48.4, 35.2, 34.4, 21.5, 20.3, 14.0. IR (neat): v 3081,
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 14
1
2
3
4
5
2998, 2927, 2866, 1638, 1598, 1460, 1341, 1161, 1090, 970, 816 cm−1. HRMS (ESI): calcd for C15H22NO2S+
(M+H+): 280.1366. Found: 280.1358.
6
7
N,4ꢀDimethylꢀNꢀ(2ꢀ(4ꢀoxocyclohexꢀ1ꢀenꢀ1ꢀyl)ethyl)benzenesulfonamide (2a)
8
9
A solution of [Rh(CO)2Cl]2 (27.8 mg, 0.072 mmol) and AgOTf (37.0 mg, 0.144 mmol) in anhydrous DCE
(9.5 mL) was stirred for 15 min at room temperature. After precipitating it for 5 min, add the supernate(4.5
mL, the used Rh(CO)2OTf was estimated as 0.068 mmol) from the above solution to a reaction tube with
dppp (28.0 mg, 0.068 mmol) and 4A MS (300 mg). After stirring for 5 min, a solution of substrate 3a (127.2
mg, 0.46 mmol) in DCE (4.5 mL) was added to the tube. Then the reaction solution was degassed by
bubbling 1.0 atm CO for 5 min. The reaction mixture was placed in a 90 °C oil bath and stirred under the
balloon pressure gas of CO for 22 h. The reaction mixture was cooled to room temperature and concentrated
in vacuo. Purification of the residue through column chromatography on silica gel (eluted with PE/EA 2:1)
afforded the starting material 3a (50.6 mg ) and product 2a as a colorless oil (77.7 mg, 56 % yield, 90 %
brsm).
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
2a: Colorless oil. TLC Rf (PE/EA 5:1) = 0.1. 1H NMR (400 MHz, CDCl3): δ 2.31 (t, J = 7.1 Hz, 2H), 2.43 (s,
3H), 2.42ꢀ2.47 (m, 2H), 2.49ꢀ2.54 (m, 2H) 2.73 (s, 3H), 2.84ꢀ2.88 (m, 2H), 3.13 (t, J = 7.1 Hz, 2H), 5.52 (m,
1H), 7.32 (d, J = 8.0, 2H), 7.67 (d, J = 8.0, 2H). 13C NMR (100 MHz, CDCl3): δ 210.3, 143.4, 135.2, 134.6,
129.7, 127.3, 120.6, 48.4, 39.6, 38.5, 35.2, 34.6, 28.2, 21.5. IR (neat): v 2959, 2925, 2872, 2361, 2342, 1713,
1686, 1598, 1459, 1338, 1160, 1090, 817, 721 cm−1. HRMS (ESI): calcd for C16H22NO3S+ (M+H+):
308.1315. Found: 308.1308.
NꢀMethylꢀNꢀ(tosylmethyl)ꢀ3ꢀvinylpentꢀ3ꢀenꢀ1ꢀamine (2a')
A solution of [Rh(CO)2Cl]2 (27.8 mg, 0.072 mmol) and AgOTf (37.0 mg, 0.144 mmol) in anhydrous DCE
(9.5 mL) was stirred for 15 min at room temperature. After precipitating it for 5 min, add the supernate (5.0
mL, the used Rh(CO)2OTf was estimated to be 0.076 mmol) from the above solution to a reaction tube with
dppp (31.0 mg, 0.075 mmol) and 4A MS (330 mg). After stirring for 5 min, a solution of substrate 3a (139.5
mg, 0.50 mmol) in DCE (5.0 mL) was added to the tube. Then the reaction solution was degassed by
bubbling 0.2 atm CO (this is a mixed gas of N2 and CO with ratio of 4:1) for 5 min. The reaction mixture
was placed in a 90 °C oil bath and stirred under 0.2 atm CO for 22 h. The reaction mixture was cooled to
room temperature and concentrated in vacuo. Purification of the residue through column chromatography on
silica gel (eluted with PE/EA 2:1) afforded product 2a' as a colorless oil (51.3 mg, 37 % yield) and 2a as a
oil mixture of Z/E isomers ( 80.4 mg, 52 % yield).
2a': Colorless oil. TLC Rf (PE/EA 5:1) = 0.48. Major one: 1H NMR (400 MHz, CDCl3): δ 1.72 (d, J = 6.8 Hz,
3H), 2.40ꢀ2.47 (m, 5H), 2.77 (s, 3H), 3.05ꢀ3.11 (m, 2H), 5.11 (d, J = 11.2 Hz, 1H), 5.24 (d, J = 17.6 Hz, 1H),
5.51 (qm, J = 7.0 Hz, 1H), 6.64 (dd, 17.6, 11.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H) 13
C
NMR (100 MHz, CDCl3):δ 143.2, 135.0, 133.8, 131.9, 129.6, 127.3, 127.1, 113.4, 50.0, 35.1, 32.5, 21.5,
13.2. Minor one: selected peaks of 1H NMR (400 MHz, CDCl3), 1.75 (d, J = 7.6 Hz,0.45 H), 2.82 (s, 0.45H),
2.98ꢀ3.04 (m, 0.3H), 4.93 (d, J = 11.2 Hz, 0.15H), 5.64 (q, J = 7.0 Hz, 0.15H), 6.25 (dd, J = 17.6, 10.8 Hz,
0.15H). IR (neat): v 3016, 2925, 2865, 1598, 1459, 1340, 1305, 1161, 1459, 1090, 944, 816 cm−1. HRMS
(ESI): calcd for C15H22NO2S+ (M+H+): 280.1366. Found: 280.1358.
8
ACS Paragon Plus Environment

Page 9 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
(±)ꢀNꢀ(2ꢀ(3',4'ꢀDimethoxyꢀ4ꢀoxoꢀ3,4ꢀdihydroꢀ[1,1'ꢀbiphenyl]ꢀ1(2H)ꢀyl)ethyl)ꢀN,4ꢀdimethylbenzenesulfonam
ide [(±)ꢀ1a]
7
8
9
A suspension of Pd(OAc)2 (2.5 mg, 0.011 mmol), dppe (8.8 mg, 0.022mmol) and Cs2CO3 (53.7 mg, 0.16
o
mmol) in toluene (1.0 mL) was stirred in 100 C oil bath for 10 min. Then a solution of 5 (19.2 mg. 0.089
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
mmol) and 2a (33.1 mg, 0.11 mmol) in toluene (1.3 mL) was added. The reaction mixture was heating at 100
oC for 4 h. Then the reaction mixture was cooled to room temperature and concentrated in vacuo.
Purification of the residue through column chromatography on silica gel (eluted with PE/EA 2:1) afforded
product (±)ꢀ1a as a yellow oil (18.0 mg, 46 % yield. This was calculated based on the amount of 5). This
reaction gave also some unidentified side products, judged from TLC.
(±)-1a: Yellow oil. TLC Rf (PE/EA 1:1) = 0.50. 1H NMR (400 MHz, CDCl3): δ 2.06ꢀ2.16 (m, 1H),
2.17ꢀ2.24(m, 3H), 2.24ꢀ2.37 (m, 2H), 2.41 (s, 3H), 2.70 (s, 3H), 2.83ꢀ3.00 (m, 2H), 3.88 (s, 3H), 3.90 (s,3H),
6.18 (d, J = 10.2 Hz, 1H), 6.77ꢀ6.81 (m, 1H), 6.82ꢀ6.85 (m, 2H), 7.05 (d, J = 10.2 Hz, 1H), 7.27 (d, J = 7.4
Hz, 2H), 7.56 (d, J = 7.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 199.0, 153.9, 149.3, 148.1, 143.4, 134.6,
134.5, 129.8, 129.7, 127.3, 119.1, 111.1, 109.8, 56.0, 55.9, 46.5, 42.7, 39.4, 36.5, 35.3, 34.4, 21.4. IR (neat):
v 2954, 2931, 2871, 2861, 1685, 1678, 1518, 1460, 1339, 1257, 1160, 1026, 815, 807 cm−1. HRMS (ESI):
calcd for C24H30NO5S+ (M+H+): 444.1839. Found: 444.1846.
NꢀMethylꢀ2ꢀnitroꢀNꢀ(2ꢀ(1ꢀvinylcyclopropyl)ethyl)benzenesulfonamide (3b)
A suspension of 4 (234.9.1 mg, 1.06 mmol), oꢀNsNHMe (457.0 mg, 2.11 mmol) and K2CO3 (586 mg, 4.24
mmol) in anhydrous acetone (10.0 mL) was heated in a 60 oC oil bath for 12 h and quenched with water. The
aqueous mixture was extracted with diethyl ether. The combined organic phase was dried with anhyous
sodium sulfate and concentrated in vacuo. Purification of the residue through column chromatography on
silica gel (eluted with PE/EA) afforded the product 3b as a yellow oil (256.8 mg, 78 % yield).
3b: yellow oil. TLC Rf (PE/EA 2:1) = 0.53 1H NMR (400 MHz, CDCl3): δ 0.57ꢀ0.64 (m, 4H), 1.71ꢀ1.77 (m,
2H), 2.92 (s, 3H), 3.28ꢀ3.33 (m, 2H), 4.94 (dd, J = 10.8, 0.8 Hz, 1H), 4.96 (dd, J = 17.3, 0.8Hz, 1H), 5.48
(dd, J = 17.3, 10.8 Hz, 1H), 7.59ꢀ7.64 (m, 1H), 7.66ꢀ7.73 (m, 2H), 7.94ꢀ7.99 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 148.1, 142.5, 133.4, 132.5, 131.5, 130.6, 124.0, 111.4, 48.2, 34.8, 34.2, 20.2, 14.0. IR (neat): v
3584, 3083, 2932, 1635, 1544, 1461, 1348, 1163, 1058, 974, 774, 695, 580 cm−1. HRMS (ESI): calcd for
C14H19N2O4S+ (M+H+): 311.1060. Found: 311.1062.
NꢀMethylꢀ2ꢀnitroꢀNꢀ(2ꢀ(4ꢀoxocyclohexꢀ1ꢀenꢀ1ꢀyl)ethyl)benzenesulfonamide (2b)
A solution of [Rh(CO)2Cl]2 (2.8 mg, 0.0072 mmol) and AgOTf (4.5 mg, 0.0175 mmol) in anhydrous DCE
(1.5 mL) was stirred for 15 min at room temperature. After precipitating it for 5 min, add all the supernate to
a reaction tube with dppp (6.0 mg, 0.0145 mmol) and 4A MS (65 mg). After stirring for 5 min, a solution of
substrate 3b (30.2 mg, 0.0973 mmol) in DCE (1.5 mL) was added to the tube. Then the reaction solution was
degassed by bubbling 1.0 atm CO for 5 min. The reaction mixture was moved to a 90 °C oil bath and stirred
under the balloon pressure gas of CO for 24 h. The reaction mixture was then cooled to room temperature
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 14
1
2
3
and concentrated in vacuo. Purification of the residue through column chromatography on silica gel (eluted
4
5
with PE/EA 3:1) afforded product 2b as a colorless oil (20.0 mg, 61 % yield).
6
7
8
9
1
2b: colorless oil. TLC Rf (PE/EA 2:1) = 0.30 H NMR (400 MHz, CDCl3): δ 2.37 (t, J = 7.1 Hz, 2H),
2.42ꢀ2.48 (m, 2H), 2.49ꢀ2.54 (m, 2H), 2.85ꢀ2.88 (m, 2H), 2.90 (s, 3H), 3.38 (t, J = 7.1 Hz, 2H), 5.53ꢀ5.57 (m,
1H), 7.60ꢀ7.64 (m, 1H), 7.66ꢀ7.74 (m, 2H), 7.95ꢀ8.04 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 210.2, 148.1,
134.8, 133.5, 132.4, 131.5, 130.9, 124.1, 121.1, 48.6, 39.6, 38.4, 35.3, 34.2, 28.2. IR (neat): v 3584, 2925,
1712, 1544, 1440, 1346, 1267, 1163, 1057, 953 cm−1. HRMS (ESI): calcd for C15H19N2O5S+ (M+H+):
339.1009. Found: 339.1017.
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
Tertꢀbutyl methyl(2ꢀ(1ꢀvinylcyclopropyl)ethyl)carbamate (3c)
To a suspension of NaH (361 mg, 60 % in mineral oil, 9.02 mmol) in anhydrous DMF (7 mL) was added
solution of BocNHMe (1.1812 g, 9.00 mmol in 7 mL DMF) at 0oC. After stirring at room temperature for 45
min, a solution of 4 (502.1 mg, 2.26 mmol) in DMF (8.0 mL) was added. Then the reaction solution was
stirred for anothor 16 h and quenched with dropwise addition of water. The aqueous mixture was extracted
with diethyl ether The combined organic phase was dried with anhydrous sodium sulfate and concentrated in
vacuo. Purification of the residue through column chromatography on silica gel (eluted with PE/EA 5:1)
afforded product 3c as a colorless oil (239.4 mg, 47 % yield).
3c: Colorless oil. TLC Rf (PE/EA 5:1) = 0.70 1H NMR (400 MHz, CDCl3): δ 0.55ꢀ0.63 (m, 4H), 1.46 (s, 9H),
1.60ꢀ1.65 (m, 2H), 2.84 (s, 3H), 3.24ꢀ3.30 (m, 2H), 4.93 (dd, J = 10.6, 1.0 Hz, 1H), 5.00 (d, J = 17.5 Hz, 1H),
5.52 (dd, J = 17.5, 10.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 155.6, 143.2, 110.9, 79.1, 47.1, 34.4 &
33.9, 28.5, 20.3, 14.0. The redundant peaks of 34.4 & 33.9 are due to the existence of carbamate rotamers.
IR (neat): v 3081, 2976, 2931, 1698, 1637, 1482, 1395, 1212, 1053, 955, 772 cm−1. HRMS (ESI): calcd for
C13H24NO2+ (M+H+): 226.1802. Found: 226.1792.
Tertꢀbutyl methyl(2ꢀ(4ꢀoxocyclohexꢀ1ꢀenꢀ1ꢀyl)ethyl)carbamate (2c)
A solution of [Rh(CO)2Cl]2 (27.6 mg, 0.071 mmol) and AgOTf (44.0 mg, 0.171 mmol) in anhydrous DCE
(9.5 mL) was stirred for 15 min at room temperature. After precipitating it for 5 min, add all the supernate to
a reaction tube with dppp (58.8 mg, 0.143 mmol) and 4A MS (600 mg). After stirring for 5 min, a solution
of substrate 3c (213 mg, 0.95 mmol) in DCE (9.5 mL) was added to the tube. Then the reaction solution was
degassed by bubbling 1.0 atm CO for 5 min. The reaction mixture was moved in a 90 °C oil bath and stirred
under the balloon pressure gas of CO for 24 h. The reaction mixture was cooled to room temperature and
concentrated in vacuo. Purification of the residue through column chromatography on silica gel (eluted with
PE/EA 3:1) afforded product 2c as a colorless oil mixture of amide rotamers (175.8 mg, 73 % yield).
1
2c: Colorless oil. TLC Rf (PE/EA 5:1) = 0.25. H NMR (400 MHz, CDCl3): δ 1.45 (s, 8H) & 1.46 (s, 1H),
2.26 (t, J = 7.0 Hz, 2H) 2.44ꢀ2.53 (m, 4H), 2.82ꢀ2.91 (m, 2H), 2.85 (s, 3H) 3.34 (t, J = 6.2 Hz, 2H), 5.48 (brs,
1H). The redundant peaks of 1.45 & 1.46 and 2.85 & 2.90 are due to the existence of carbamate rotamers.
13C NMR (100 MHz, CDCl3):δ 211.1, 210.4, 198.6, 155.7, 136.2, 135.8, 120.1, 119.8, 80.2, 79.4, 47.6, 46.5,
39.6, 38.6, 35.6, 34.9, 34.0, 29.5, 28.5, 28.4, 28.2, 28.0. The redundant peaks are due to the rotation of the
10
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
1
2
3
C–N bond in the molecule. IR (neat): v 2975, 2931, 1692, 1482, 1396, 1366, 1158, 1052, 882, 771 cm−1.
HRMS (ESI): calcd for C14H23NO3Na+ (M+Na+): 276.1570. Found: 276.1565.
4
5
6
7
8
9
When this [5+1] reaction was carried out under 5 atm CO, the reaction yields were 52 % and 56 % (two
times tests)( 3c: 22.4 mg, 15 mmol % Rh(dppp)OTf, 48h, get 2c: 13.1 mg, 52 % yield; 3c:31.8 mg, 15 mmol %
Rh(dppp)OTf, 48h, get 2c: 20.0mg, 56 % yield)
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
(±)ꢀTertꢀbutylꢀ(2ꢀ(3',4'ꢀdimethoxyꢀ4ꢀoxoꢀ3,4ꢀdihydroꢀ[1,1'ꢀbiphenyl]ꢀ1(2H)ꢀyl)ethyl)(methyl)carꢀbamate
[(±)ꢀ1c]
A suspension of Pd(OAc)2 (3.0 mg, 0.0134 mmol), dppe (10.7 mg, 0.0269 mmol) and Cs2CO3 (65.5 mg,
o
0.20 mmol) in toluene (1.0 mL) was stirred in 100 C oil bath for 10 min. Then a solution of 5 (20.3 mg,
0.0935 mmol) in toluene (1.0 mL) was added. After stirring for 5 min, a solution of 2c (33.9 mg, 0.134
mmol) in toluene (1.0 mL) was added. The reaction mixture was heating at 100 oC for 4 h. Then the reaction
mixture was cooled to room temperature and concentrated in vacuo. Purification of the residue through
column chromatography on silica gel (eluted with PE/EA 3:1) afforded product (±)ꢀ1c as a colorless oil
(25.3 mg, 68 % yield. This was calculated based on the amount of 5). This reaction gave also some
unidentified side products, judged from TLC.
(±)-1c: Colorless oil. TLC Rf (PE/EA 2:1) = 0.26. 1H NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 1.96ꢀ2.06 (m,
1H), 2.06ꢀ2.16 (m, 1H), 2.20ꢀ2.31 (m, 3H), 2.31ꢀ2.42 (m, 1H), 2.78 (s, 3H), 3.03 (brs, 1H), 3.13ꢀ3.25 (m,
1H), 3.87 (s, 3H), .3.88 (s, 3H), 6.18 (d, J = 10.0 Hz, 1H), 6.84 (brs, 3H), 7.11 (d, J = 10.0 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 199.2, 155.4, 154.6, 149.1, 147.9, 135.0, 129.6, 119.0, 111.1, 109.8, 79.5, 55.8,
44.9, 42.5, 38.9 & 38.5, 36.1, 34.4, 28.4. The redundant peaks of 38.9 & 38.5 are due to the existence of
carbamate rotamers. IR (neat): v 2972, 2935, 2868, 2837, 1688, 1518, 1395, 1366, 1259, 1174, 1149, 1027,
881, 770 cm−1. HRMS (ESI): calcd for C22H31NO5Na+ (M+Na+): 412.2094. Found: 412.2086.
Tertꢀbutyl(R)ꢀ(2ꢀ(3',4'ꢀdimethoxyꢀ4ꢀoxoꢀ3,4ꢀdihydroꢀ[1,1'ꢀbiphenyl]ꢀ1(2H)ꢀyl)ethyl)(methyl)carbamate
[(R)ꢀ1c]
A suspension of Pd(OAc)2 (5.7 mg, 0.0254 mmol), (S)ꢀAntphos (9.4 mg, 0.0254 mmol) and Cs2CO3 (62.1
o
mg, 0.191 mmol) in toluene (1.0 mL) was stirred in 100 C oil bath for 10 min. Then a solution of 5 (13.2
mg, 0.061 mmol) in toluene (1.0 mL) was added. After stirring for 5 min, a solution of 2c (32.1 mg, 0.127
mmol) in toluene (1.0 mL) was added. The reaction mixture was heating at 100 oC for 4 h. Then the reaction
mixture was cooled to room temperature and concentrated in vacuo. Purification of the residue through
column chromatography on silica gel (eluted with PE/EA 3:1) afforded product (R)ꢀ1c as a colorless oil
(15.9 mg, 63 % yield. This was calculated based on the amount of 5). This reaction gave also some
unidentified side products, judged from TLC.
(ꢀ)ꢀMesembrine4h,4l
To a solution of (R)-1c (15.9 mg, 0.0397 mmol) in DCM (3.0 mL) was added TFA (46.0 mg, 0.400 mmol).
After stirring at room temperature for 12 h, the reaction mixture was quenched with saturated NaHCO3
aqueous solution and extracted with DCM. The combined organic phase was dried with anhydrous sodium
sulfate and concentrated in vacuo. Purification of the residue through column chromatography on silica gel
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 14
1
2
3
4
5
(eluted with DCM/EtOH 20:1) afforded product (ꢀ)ꢀmesembrine as a colorless oil (8.4 mg, 73 % yield) in 86 %
ee.
6
7
8
9
(-)-Mesembrine: Colorless oil. TLC Rf (DCM/MeOH 10:1) = 0.55. [α]D20 = ꢀ60.5 (c = 0.42, CHCl3); (lit.4h
[α]D20 = ꢀ61.6, c = 0.25, MeOH;) 1H NMR (400 MHz, CDCl3): δ 2.07ꢀ2.26 (m, 5H), 2.29ꢀ2.48 (m, 2H), 2.33
(s, 3H), 2.61 (d, J = 3.6 Hz, 2H), 2.97 (t, J = 3.6 Hz, 1H), 3.12ꢀ3.19 (m, 1H), 3.88 (s, 3H), 3.90 (s, 3H), 6.84
(d, J = 8.4 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.93 (dd, J = 8.4, 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
211.4, 149.0, 147.5, 140.0, 117.9, 111.0, 109.9, 70.3, 56.0, 55.9, 54.8, 47.5, 40.5, 40.1, 38.8, 36.2, 35.2. IR
(neat): v 2926, 2847, 2783, 1717, 1645, 1592, 1517, 1457, 1413, 1327, 1258, 1180, 1147, 1028, 809, 765
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
+
cm−1. HRMS (ESI): calcd for C17H24NO3 (M+H+): 290.1751. Found: 290.1744. The enantiomeric excess
was determined by chiral HPLC analysis (DAICEL CHIRALPAK ASꢀH, 4.6 × 250 mm, eluent = nꢀhexane:
isopropanol = 80:20, 1.00 mL·min−1, λ = 220 nm) tR (major) = 10.6 min, tR (minor) = 8.9 min.
(±)ꢀMesembrine
To a solution of (±)-1c (31.4 mg, 0.081 mmol) in DCM (2.5 mL) was added TFA (89.0 mg, 0.78 mmol).
After stirring at room temperature for 22 h, the reaction mixture was quenched with saturated NaHCO3
aqueous solution and extracted with DCM. The combined organic phase was dried with anhydrous sodium
sulfate and concentrated in vacuo. Purification of the residue through column chromatography on silica gel
(eluted with DCM/EtOH 20:1) afforded product (±)ꢀmesembrine as a colorless oil (17.8 mg, 76 % yield).
ASSOCIATED CONTENT
Supporting Information
NMR spectra for all new compounds and HPLC chromatograms data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: yuzx@pku.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the Natural Science Foundation of China (21472005) for financial support. We thank Prof.
WenꢀJun Tang (Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences) for providing us
ligand (S)ꢀAntphos. Mr. Jun Yang (Peking University) is highly appreciated for repeating some experiments.
Prof. Yuxin Cui (Peking University, School of Pharmaceutical Sciences) is highly appreciated for discussion
of NMR spectra of two compounds.
REFERENCES
(1) Bodendorf, K.; Krieger, W. Arch. Pharm. 1957, 290, 441.
12
ACS Paragon Plus Environment

Page 13 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
(2) (a) Pelletier, S. W. Alkaloids: Chemical and Biological Perspectives,Vol. 15, Elsevier Science Ltd.,
Oxford, 2001, pp. 34ꢀ564.(b) Smith, M. T.; Crouch, N.; Gericke, N.; Hirst, M. J. Ethnopharmacol. 1996, 50,
119. (c) Jeffs, P. W.; Archie, W. C.; Hawks, R. L.; Farrier, D. S. J. Am. Chem. Soc. 1971, 93, 3752.
7
8
9
(3) (a) Wang, F.ꢀP. Alkaloid Chemistry, Chemical Industry Press, Beijing, 2008, pp. 230ꢀ239 (in Chinese).
(b) Jeffs, P. W.; Archie, W. C.; Hawks, R. L.; Farrier, D. S. J. Am. Chem. Soc. 1971, 93, 3752.
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
(4) For a review on synthesis of mesembrine, see: (a) Zhao, Y.; Zhou, Y.; Du, F.; Liang, L.; Zhang, H. Chin.
J. Org. Chem. 2010, 30, 47. For recent syntheses of mesembrine: (b) Wu, X.ꢀS.; Chen, Z.ꢀW.; Bai, Y.ꢀB.;
Dong, V. M. J. Am. Chem. Soc. 2016, 138, 12013. (c) Spittler, M.; Lutsenko, K.; Czekelius, C. J. Org. Chem.
2016, 81, 6100. (d) Gan, P.; Smith, M. W.; Braffman, N. R.; Snyder, S. A. Angew. Chem., Int. Ed. 2016, 55,
3625−3630. (e) Nunokawa, S.; Minamisawa, M.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Synlett. 2015,
2301−2305. (f) Ozaki, T.; Kobayashi, Y. Org. Chem. Front. 2015, 2, 328−335. (g) Geoghegan, K.; Evans, P.
Tetrahedron Lett. 2014, 55, 1431−1433. (h) Geoghegan, K.; Evans, P. J. Org. Chem. 2013, 78, 3410−3415.
(i) Zhang, Q.ꢀQ.; Xie, J.ꢀH.; Yang, X.ꢀH.; Xie, J.ꢀB.; Zhou, Q.ꢀL. Org. Lett. 2012, 14, 6158−6161. (j) Honda,
T.; Arai, H.; Yamamoto, N.; Takahashi, K. Heterocycles. 2012, 84, 327−331. (k) Gu, Q.; You, S.ꢀL. Chem.
Sci. 2011, 2, 1519−1522. (l) Zhao, Y.ꢀH.; Zhou, Y.ꢀY.; Liang, L.ꢀL.; Yang, X.ꢀD.; Du, F.ꢀX.; Li, L.; Zhang,
H.ꢀB. Org. Lett. 2009, 11, 555.
(5) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40.
(6) Hyde, A. M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 177.
(7) (a) Birch, A. J. J. Chem. Soc. 1946, 596. (b) Corey, E. J.; Watt, D. S. J. Am. Chem. Soc. 1973, 95, 2303.
(8) (a) Jiang, G.ꢀJ.; Fu, X.ꢀF.; Li, Q.; Yu, Z.ꢀX.; Org. Lett. 2012, 14, 692. For selected recent development of
[5 + 1] reaction of cyclopropanes and their anologs with CO: (b) Liu, C.ꢀH.; Yu, Z.ꢀX. Org. Biomol. Chem.
2016, 14, 5945ꢀ5950. (c) Liu, Cꢀ.H.; Zhuang, Z.; Bose S.; Yu, Z.ꢀX. Tetrahedron. 2016, 72, 2752. (d)
Zhang .M.; Tang, W.ꢀP.; Org. Lett. 2012, 14, 3756. (e) Shu, D.; Li, X.; Zhang, M.; Robichaux, P. J.; Guzei I.
A.; Tang, W.ꢀP.; J. Org. Chem. 2012, 77, 6463. (f) Taber, D, F,; Guo, P.; Guo, N. J. Am. Chem. Soc., 2010,
132, 11179. For a review of transition metalꢀcatalyzed or ꢀmediated [5 + 1] cycloadditions, see: (g)
Khusnutdinov, R. I.; Dzhemilev, U. M. J. Organomet. Chem. 1994, 471, 1; For reviews of [5+1] reactions,
see: (h) Fu, X.ꢀF.; Yu, Z.ꢀX. In Methods and Applications of Cycloaddition Reactions in Organic Syntheses;
Nishiwaki, N., Ed.; WileyꢀVCH: Weinheim, Germany, 2014, pp 551ꢀ564; (i) Gao, Y.; Fu, X.ꢀF.; Yu, Z.ꢀX.
Top. Curr. Chem. 2014, 346, 195.
(9) (a) Shamma, M.; Rodriguez, H. Tetrahedron Lett. 1965, 6, 4847. (b) Yamada, S.; Otani, G. Tetrahedron
Lett. 1971, 12, 1133. (c) Martin, S. F.; Puckette, T. A.; Colapret, J. A. J. Org. Chem. 1979, 19, 3391. (d)
Dalko, P. I.; Brun, V.; Langlois, Y. Tetrahedron Lett. 1998, 39, 8979.
(10) Jiao, L.; Lin, M.; Zhuo, L.ꢀG.; Yu, Z.ꢀX. Org. Lett. 2010, 12, 2528.
(11) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed., Wiley Interscience,
New York, 1999. (b) Kocienski, P. J.; Protecting Groups, 3rd ed., Georg Thieme, New York, 2005.
(12) We obtained a mixture of dienes with different conformations. Theoretically only one isomer should be
obtained by the reductive elimination from intermediate C. But this isomer could isomerize to its other
isomer under the catalysis of Rh species.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 14
1
2
3
(13) Imahori, T.; Tokuda, T.; Taguchi, T.; Takahata, H. Org. Lett. 2012, 14, 1172.
4
5
(14) Sabitha, G.; Reddy, B. V. S.; Abraham, S.; Yadav, J. S. Tetrahedron Lett. 1999, 40, 1569.
6
7
8
9
(15) (a) Sridhar, M.; Kumar, B. A.; Narender, R. Tetrahedron Lett. 1998, 39, 2847. (b) Nyasse, B.;
Ragnarsson, U. Chem. Commun. 1997, 1017.
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
(16) Ji, S.; Gortler, L. B.; Waring, A.; Battisti, A. J.; Bank, S.; Closson, W. D.; Wriede, P. A. J. Am. Chem.
Soc. 1967, 89, 5311.
(17) (a) For a review on chiral monophosphorus ligands for asymmetric catalytic reactions by Tang, see: Fu,
W.ꢀZ.; Tang, W.ꢀJ. ACS Catal. 2016, 6, 4814. (b) Du, K.; Guo, P.; Chen, Y.; Cao, Z.; Wang, Z.; Tang, W.ꢀJ.
Angew. Chem., Int. Ed. 2015, 54, 3033. (c) Cao, Z.; Du, K.; Liu, J.ꢀH.; Tang, W.ꢀJ. Tetrahedron. 2016, 72,
1782.
14
ACS Paragon Plus Environment