Enantioselective Synthesis of (+)-Peganumine A

Article abstract of DOI:10.1021/jacs.6b07846

A gram-scale enantioselective total synthesis of (+)-peganumine A was accomplished in 7 steps from commercially available 6-methoxytryptamine. Key steps included (a) a Liebeskind-Srogl cross-coupling; (b) a one-pot construction of the tetracyclic skeleton from an ω-isocyano-γ-oxo-aldehyde via a sequence of an unprecedented C-C bond forming lactamization and a transannular condensation; (c) a one-pot organocatalytic process merging two achiral building blocks into an octacyclic structure via a sequence of enantioselective Pictet-Spengler reaction followed by a transannular cyclization. This last reaction created two spirocycles and a 2,7-diazabicyclo[2.2.1]heptan-3-one unit with excellent control of both the absolute and relative stereochemistry of the two newly created quaternary stereocenters.

Full text of DOI:10.1021/jacs.6b07846

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Communication
Enantioselective Synthesis of (+)-Peganumine A
Cyril Piemontesi, Qian Wang, and Jieping Zhu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07846 • Publication Date (Web): 25 Aug 2016
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Enantioselective Synthesis of (+)-Peganumine A
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Cyril Piemontesi, Qian Wang, and Jieping Zhu*
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Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique
Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, BCH5304, CH-1015 Lausanne, Switzerland
Supporting Information Placeholder
Scheme 1. Peganumine A and Its Biosynthetic Hy-
pothesis
ABSTRACT: A gram-scale enantioselective total synthesis of
(+)-peganumine A was accomplished in 7 steps from com-
mercially available 6-methoxytryptamine. Key steps included
a) A Liebeskind-Srogl cross coupling; b) A one-pot construc-
tion of the tetracyclic skeleton from an ω-isocyano-γ-oxo-
aldehyde via a sequence of an unprecedented C-C bond
forming lactamization and a transannular condensation; c) A
one-pot organocatalytic process merging two achiral building
blocks into an octacyclic structure via a sequence of enanti-
oselective Pictet-Spengler reaction followed by a transannu-
lar cyclization. This last reaction created two spirocycles and
NH2
MeO
O
N
N
2a
N
N
H
H
HN
1 Peganumine A
OMe
MeO
MeO
N
N
OMe
A
H
HN
a
2,7-diazabicyclo[2.2.1]heptan-3-one unit with excellent
HN
NH
N
HOOC
control of both the absolute and relative stereochemistry of
the two newly created quaternary stereocenters.
O–
N
MeO
H
HN
HO
B
C
Scheme 2. Strategic Bond Disconnections of the Core
Structure of Peganumine A
Peganumine A (1), a dimeric tetrahydro-β-carboline alka-
loid, was isolated by Li, Hua and co-workers in 2014 from the
seeds of Peganum harmala L.1 Its structure including the
absolute configuration was determined by spectroscopic
data, X-ray crystallography, ECD calculation, and CD exciton
chirality method. Its octacyclic architecture with a unique
O
O
*
a
O
N
N
N
D
N
NH
N
*
*
a
Nu
b
E
F
H2N
O
3,9-diazatetracyclo-[6.5.2.01,9.03,8]pentadec-2-one
scaffold
OH
O
a
b
O
was unprecedented. It displayed significant cytotoxic activity
against MCF-7, PC-3, HepG2 cells and selective effect on HL-
60 cells with an IC50 value of 5.8 µM. Biosynthetically, it was
postulated that heteroannulation of the two C1-substituted β-
carbolines A and B, both derived from tryptamine (2a), could
afford spirocycle C with concurrent generation of two qua-
ternary stereocenters. Lactamization of the latter would then
provide the natural product 1 (Scheme 1).1
a
O
O
NH2
N
J
NH
I
b
O
+
O
Nu
O
N
O
O
G
H
K
F would reveal an amine G containing a tethered nucleophile
and a cyclic α-ketoamide H. In a forward sense, it was ex-
pected to obtain compound D in a one-pot manner from G
and H. Since the absolute configuration of Ca generated in
the Pictet-Spengler (PS) reaction will be completely translat-
ed into that of Cb, a catalytic enantioselective PS reaction2
would allow us to convert achiral building blocks G and H to
enantio-enriched final product D. Compound H could be
obtained by transannular cyclization of δ-oxo-α-ketolactam
I. Instead of the classic macrolactamization of an appropri-
ately functionalized linear ω-amino-δ-oxo-α-ketoacid J (dis-
connection a) for the access to I, we envisaged to build the
macrolactam via the formation of a C-C bond with concur-
rent formation of the α-hydroxylamide or α-ketoamide func-
tion and planned to use either the intramolecular Passerini
reaction3 or the Ugi reaction4 of ω−isocyano-γ-oxoaldehyde K
for this purpose (disconnection b). This last transformation
was unknown in the forward sense, presenting therefore a
The intriguing molecular architecture in conjunction with
its significant bioactivity and extremely low isolation yield
(3.5 mg from 15.4 kg of the seeds of P. harmala L.) prompted
us to undertake the total synthesis of peganumine A (1).
While the proposed biosynthesis is appealing, achieving the
same [3+2] heteroannulation in the laboratory setting would
be difficult if not impossible. Therefore, we set out to devel-
op a disparate approach involving different strategic bond
disconnections. The characteristic structural feature of 1 is
the presence of a central 2,7-diazabicyclo[2.2.1]heptan-3-one
unit that connects the two tetrahydro-β-carbolines via spiro-
cyclizations (Scheme 2). Retro-synthetically, cleavage of one
of the two C-N bonds of the aminal function in D, which was
used to represent the generic structure of peganumine A,
would generate an N-acyliminium salt E that would be in
equilibrium with enamide F. Further bond disconnection of
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new opportunity to explore the synthetic potential of the
isocyanide chemistry.
transannular cyclization to provide tetracycle 12a. Hydrolysis
1
2
3
4
5
6
7
8
of the latter furnished then the product 10a. Attempts to
detect the presence of intermediate 11a or its hydrolyzed
product in the crude reaction mixture were unsuccessful due
probably to the fast transannular cyclization process. Corey-
Kim oxidation11 of 10a afforded α-ketolactam 13a in 94%
yield. Swern oxidation12 of 10a provided 13a in a slightly low-
er yield (87%). Following the same synthetic sequence de-
tailed in Schemes 3 and 4, 6-methoxytryptamine (2b) was
converted to 13b in 48% overall yield.
Our synthesis began with the preparation of C2 acylated
tryptamine
8
(Scheme 3). Thioesterification of 3,3-
5
dimethylpent-4-enoic acid (3) afforded 4 (TFAA, PhSH,
CH2Cl2, reflux, 85%) which, upon ozonolysis, was converted
to S-phenyl 3,3-dimethyl-4-oxobutanethioate (5) in 83%
yield. In parallel, chemoselective N-formylation of the prima-
ry aliphatic amine of tryptamine (2a, HCOOEt, 55 °C) fol-
lowed by N-Boc protection of the indolic nitrogen (Boc2O,
DMAP, DMF, rt) afforded 6a in 72% overall yield. C2-
Lithiation followed by interception of the resulting vinyllith-
ium with tributyltin chloride provided 7a in 80% yield.6 The
Liebeskind-Srogl cross coupling7 between 7a and 5 turned
out to be challenging. Under standard conditions [copper(I)
thiophene-2-carboxylate (CuTC, Pd2dba3, PPh3 or TFP, THF),
9
Scheme 4. Passerini 3-Center-2-Component Reaction
of ω-Isocyano-γ-oxoaldehyde with Carboxylic Acid:
Synthesis of Tetracyclic α-Ketoamide 13
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11
12
13
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CN
OHCHN
POCl3, Et3N
O
8
O
the major product isolated was 6a. The competitive
O
O
CH2Cl2, -78 °C
N
Boc
transmetallation of tin to copper is presumably responsible
for the rapid protodestannylation of 7a to 6a.9 A systematic
survey of reaction parameters was subsequently carried out
that allowed us to obtain the desired coupling product 8a in
94% yield under optimized conditions [Pd2dba3 (0.1 equiv),
AsPh3 (0.1 equiv), copper(I) diphenylphosphinate (CuDPP, 1.2
equiv), hexane/THF = 3/1, c 0.067 M, rt]. We note that the
effective concentration of Cu ion in the above solvent system
is significantly reduced due to the low solubility of CuDPP in
hexane, avoiding therefore the protodestannylation process.
It is worthy noting that coupling of 2-indolylboronic acid
with thioester 5 failed to produce the desired coupling prod-
uct.
N
Boc
R
R
8a R = H,
9a R = H, 89%
8b R = OMe
9b R = OMe, 92%
O
NH
TFA, Py
O
O
O
F3C
CH2Cl2, rt
BocN
R
11a R = H,
11b R = OMe
O
N
O
N
O
HO
F3C
BocN
BocN
R
R
O
12a R = H
12b R = OMe
10a R = H, 85%
10b R = OMe, 85%
O
NCS, Me2S
N
Scheme 3. Synthesis of C2 Acylated Tryptamine De-
rivatives
13a R = H, 95%
13b R = OMe, 96%
O
then Et3N, CH2Cl2
-78 °C
BocN
R
TFAA
CH2Cl2, rt
O3, CH2Cl2
-78 °C
O
O
O
Scheme 5. One-pot Conversion of ω-Isocyano-γ-
oxoaldehyde 9 to Tetracyclic α-Ketoamide 13 by an
Internal Redox Process
O
SPh
SPh
OH
then PhSH
reflux, 85%
then PPh3, rt
83%
3
4
5
H2N
OHCHN
a) HCOOEt, 55 °C
CN
O
TMPLi, THF, -78°C
then Bu3SnCl
R
MeNHOH•HCl
NaHCO3
4 Å MS
N
O
b) Boc2O, DMAP
DMF, rt
O
+
N
H
N
Boc
R
O
BocN
AcOH
MeOH, rt
N
Boc
R
R
2a R = H
6a R = H, 72%
9a R = H
9b R = OMe
13a R = H, 75%
13b R = OMe, 75%
2b R = OMe
6b R = OMe, 87%
OHCHN
Bu3Sn
O
OHCHN
O
SPh
5
O
O
O
O
O
NH
N
Boc
O
R
Pd2dba3, CuDPP, AsPh3
hexane/THF = 3/1, rt
NH
N
Boc
R
O
N
O
MeN
BocN
7a R = H, 80%
7b R = OMe,78%
8a R = H, 94%
8b R = OMe, 95%
BocN
15
R
R
14
Dehydration of N-formamide 8a (POCl3, Et3N, CH2Cl2, -78
°C) provided ω-isocyano-γ-oxoaldehyde 9a in 89% yield
(Scheme 4). Compound 9a has to be purified by FCC on
aluminum support as partial decomposition occurred on
silica gel. Gratefully, Passerini 3-center-2-component reac-
tion of 9a with acetic acid in dichloromethane (c 0.01 M, 1.5
days) at rt followed by saponification of the resulting acetate
afforded directly tetracycle 10a in 83% overall yield (cf SI).
Using TFA as acid input, the same reaction afforded directly
10a (TFA, Py, CH2Cl2, rt, 5 days) after simple aqueous work-
up in 85% yield, albeit with a longer reaction time.10 It is
reasonable to assume that the reaction went through the 10-
membered macrolactam 11a, which underwent spontaneous
A one-pot synthesis of tetracycle 13 from 9 involving a
formal intramolecular oxidative coupling of the ω-isocyano-
γ-oxoaldehyde is shown in Scheme 5. Reaction of 9a with N-
methylhydroxylamine and acetic acid in MeOH (c 0.01 M) in
the presence of 4 Å molecular sieves and NaHCO3 afforded
13a in 75% yield.13 Compound 9b (R = OMe) was converted to
13b in a similar yield. In accordance with the previous mech-
anistic studies, we assumed that the initial Ugi 4-center-3-
component reaction occurred smoothly to afford the adduct
14 which underwent β-elimination to afford the α-
iminolactam 15. Hydrolysis of the latter furnished then the
observed product 13. We stress that, against the common
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wisdom, the formation of 7-membered lactam resulting from
between 2b and 13a in the presence of chiral phosphoric acid
1
2
3
4
5
6
7
8
the attack of the isocyano group onto the internal oxo func-
tion, a generally much faster process than that of 10-
membered ring, was not observed. Note that the terminal
aldehyde function is of neopentyl type and is therefore steri-
cally hindered. To the best of our knowledge, ω-isocyano
carbonyl compounds have never been used as bifunctional
inputs neither in Passerini nor in Ugi type reactions.14 We
believe that these reactions might be useful additions to
synthetic arsenal in light of the frequent occurrence of the α-
ketoamide unit in bioactive macrocycles and drugs.15
(TRIP) indeed afforded 9'-demethoxy-peganumine A (17),
albeit with low yield (7%) and enantioselectivity (er
64.5/35.5).17 Using Jacobsen's chiral thiourea catalyst (S)-18
was found to be more rewarding.18 Since the thiourea of type
18 has not been applied to the Pictet-Spengler reaction of
ketone, (S)-18 was chosen arbitrarily as no empirical model
could be followed to predict the stereochemical outcome.
After survey of reaction parameters, the optimized condi-
tions consisted of refluxing a toluene solution of 2b and 13a
in the presence of 4 Å MS (24 h) followed by adding a solu-
tion of thiourea (S)-18 (0.2 equiv) and PhCOOH (0.2 equiv)
in CH2Cl2 (10% by volume). After being heated at 35 °C for 4
days, TFA (0.2 equiv) was added and the reaction mixture
was refluxed for an additional 2 days to afford (+)-9'-
demethoxy-peganumine A (17) in 67% yield with er of 96/4
(Scheme 7). Using PhCOOH as co-catalyst is of utmost im-
portance for the enantioselectivity of the reaction since using
AcOH instead of PhCOOH under otherwise identical condi-
tions provided compound 17 (75% yield) with significantly
reduced enantioselectivity (er 72/28). To our delight, con-
densation of 2b with 13b proceeded equally well to afford
(+)-peganumine A (1) (69%, er 96/4) whose spectroscopic
data are identical in all respects to those reported for the
natural product.19 Comparison of the sign and value of the
[α]D [synthetic: +6.2 (c 0.1, MeOH); [Lit]1: +5.6 (c 0.15,
MeOH)] allowed us to conclude that the natural enantiomer
was produced using (S)-18 as catalyst. Performing the reac-
tion in a gram scale afforded the natural product with similar
yield and enantioselectivity.
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With a reliable, multigram synthesis of tetracycle 13a in
hand, its condensation with 6-methoxytryptamine (2b) was
next attempted.16 Although the ketone carbonyl is electroni-
cally activated by the neighboring amide function, it is steri-
cally hindered due to its neopentylic position. After extensive
screening of reaction conditions, it was found that heating to
reflux a toluene solution of 2b and 13a in the presence of 4 Å
molecular sieves afforded cleanly imine 16. Addition of a
catalytic amount of TFA (0.2 equiv) to the reaction mixture
(reflux, 5 days) provoked a sequence of domino cyclization
and N-Boc deprotection (vide supra) to afford (±)-9'-
demethoxy-peganumine A (rac-17) in 91% yield (Scheme 6).
It is worthy noting that increasing the amount of TFA re-
duced significantly the yield of the final product. Gratefully,
condensation of 2b with 13b under the identical conditions,
afforded (±)-peganumine A (rac-1) in 72% isolated yield.
Scheme 6. Synthesis of (±)-Peganumine A
O
NH2
N
toluene, 4 Å MS, reflux
Scheme 8. Merging Two Achiral Building Blocks to
(+)-Peganumine A: Reaction Pathway
O
+
N
H
MeO
then TFA (0.2 equiv), reflux
BocN
R
13a R = H,
13b R = OMe
2b
O
(S)-18
PhCO2H
N
Δ
MeO
2b
+
13b
N
MeO
4 Å MS
MeO
BocN
O
OMe
N
O
H
HN
N
N
16b
N
HN
N
MeO
MeO
HN
O
BocN
R
O
HN
N
TFA
HN
N
NH
rac-17 (±)-9'-Demethoxy-peganumine A
R = H, 91%
rac-1 (±)-Peganumine A, R = OMe, 72%
NH
16
R
BocN
BocN
19
20
OMe
OMe
MeO
MeO
Scheme 7. Thiourea-catalyzed Enantioselective Syn-
thesis of (+)-Peganumine A
O
O
HN
N
N
HN
N
N
toluene, 4 Å MS, reflux, 24 h
then CH2Cl2 (10% by volume)
(S)-18 (0.2 equiv)
PhCOOH (0.2 equiv)
O
NH2
HN
1 (+)-Peganumine A
BocN
N
OMe
O
+
21
OMe
N
H
MeO
MeO
BocN
35 °C, 4 days
then TFA (0.2 equiv)
reflux, 2 days
R
13a R = H,
13b R = OMe
2b
The reaction pathway leading to (+)-peganumine A (1) is
depicted in Scheme 8. Condensation of amine 2b with α-
ketoamide 13b afforded imine 16b, which underwent the
enantioselective aza-Friedel-Crafts addition under the influ-
ence of the thiourea (S)-18 and PhCOOH to provide the
enantioenriched 19. Upon addition of a catalytic amount of
strong acid (TFA), enamine-imine tautomerization occurred
to provide 20, which, upon stereospecific transannular addi-
tion of the secondary amine to iminium, furnished octacycle
21. Removal of N-Boc furnished then the natural product 1.
Monitoring the reaction progress using 1H NMR spectroscopy
O
H
N
H
N
O
CF3
HN
N
N
N
S
HN
(S)-18
CF3
R
17 (+)-9'-Demethoxy-peganumine A, R = H, 67%, er 96/4
1 (+)-Peganumine A, R = OMe, 69%, er 96/4
The feasibility of our synthetic approach being approved,
we next searched for conditions to accomplish a catalytic
enantioselective synthesis of (+)-peganumine A. The reaction
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see: Prokopcová, H.; Kappe, C. O. Angew. Chem., Int. Ed. 2009, 48,
2276.
(8) (a) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org.
Lett. 2003, 5, 3033. (b) Li, H.; He, A.; Falck, J. R.; Liebeskind, L. S.
Org. Lett. 2011, 13, 3682.
(9) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L.
S. J. Org. Chem. 1994, 59, 5905.
(10) (a) Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985.
(b) Semple, J. E:, Owens, T. D.; Nguyen, K.; Levy, O. E. Org. Lett.
2000, 2, 2769.
indicated that the N-Boc deprotection is the slowest step of
1
2
3
4
5
6
7
8
the sequence. In this domino process, three chemical bonds
were formed leading to the formation of two spirocycles and
a diazabicyclo[2.2.1]heptan-3-one unit. Two quaternary ste-
reocenters were created from two achiral building blocks
with excellent control of both enantio- and diastereo-
selectivities.
In summary, the first asymmetric total synthesis of (+)-
peganumine A (1) has been achieved featuring two novel
multiple bond forming processes: a) A hydroxylamine-
mediated intramolecular oxidative coupling of ω-isocyano
aldehydes for the direct access to tetracycles with an α-
ketoamide function. This lactamization process via C-C ra-
ther than C-N bond formation is unprecedented; b) A one-
pot chiral thiourea/PhCOOH-catalyzed domino process
merging two achiral building blocks into an octacyclic struc-
ture via a sequence of enantioselective Pictet-Spengler reac-
tion followed by a TFA-catalyzed transannular cyclization.
Overall (+)-peganumine A (1) was synthesized in 7 steps with
33% overall yield (er 96/4) from the commercially available
6-methoxytryptamine. The synthetic route, scalable and
amenable for the analogues synthesis, paved the way for the
SAR studies of this structurally novel natural product.
(11) Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586.
(12) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
9
10
11
12
13
14
15
16
17
18
19
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(13) (a) Grassot, J.-M.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed.
2008, 47, 947. (b) Bouma, M.; Masson, G.; Zhu, J. J. Org. Chem. 2010,
75, 2748.
(14) For reviews on multicomponent synthesis of macrocycles, see:
(a) Wessjohann, L. A.; Rivera, D. G.; Vercillo, O. E. Chem. Rev. 2009,
109, 796. (b) Masson, G.; Neuville, L.; Bughin, C.; Fayol, A.; Zhu, J. in
"Synthesis of Heterocycles via Multicomponent Reactions II" (Eds. R.
V. A. Orru, E. Ruijter), 2010, Springe, Heidelberg. (c) C. J. White, A.
K. Yudin, Nat. Chem. 2011, 3, 509.
(15) For examples, see: (a) FK-506: Tanaka, H.; Kuroda, A.;
Marusawa, H.; Hatanaka, H.; Kino, T.; Goto, T.; Hashimoto, M.;
Taga, T. J. Am. Chem. Soc. 1987, 109, 5031. (b) Cyclotheonamide:
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S. P.; Lee, J.; Terrett, N. K. Nat. Rev. 2008, 7, 208.
(16) Although commercially available, this compound is easily
prepared in multiple gram scale in two steps, see: (a) Jia, Y.; Zhu, J.
Synlett 2005, 2469. (b) Jia, Y.; Zhu, J. J. Org. Chem. 2006, 71, 7826. (c)
Hu, C.; Qin, H.; Cui, Y.; Jia, Y. Tetrahedron 2009, 65, 9075.
(17) Chiral phosphoric acid catalyzed enantioselective Pictet-
Spengler reaction, see: (a) Seayad, J.; Seayad, A. M.; List, B., J. Am.
Chem. Soc. 2006, 128, 1086. (b) Wanner, M. J.; van der Haas, R. N. S.;
de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem.,
Int. Ed. 2007, 46, 7485. (c) Sewgobind, N. V.; Wanner, M. J.; Inge-
mann, S.; De Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. J. Org.
Chem. 2008, 73, 6405. (d) Muratore, M. E.; Holloway, C. A.; Pilling,
A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009,
131, 10796. (e) Holloway, C. A.; Muratore, M. E.; Storer, R. I.; Dixon,
D. J. Org. Lett. 2010, 12, 4720. (f) Badillo, J. J.; Silva-Garcia, A.; Shupe,
B. H.; Fettinger, J. C.; Franz, A. K. Tetrahedron Lett. 2011, 52, 5550. (g)
Duce, A.; Pesciaioli, F.; Gramigna, L.; Bernardi, L.; Mazzanti, A.;
Ricci, A.; Bartoli, G.; Bencivenni, G. Adv. Synth. Catal. 2011, 353, 860.
(h) Huang, D.; Xu, F. X.; Lin, X. F.; Wang, Y. G. Chem. Eur. J. 2012, 18,
3148. (i) Toda, Y.; Terada, M. Synlett 2013, 24, 752. Chiral
chlorosilane-promoted enantioselective Pictet-Spengler reaction,
see: (j) Bou-Hamdan, F. R.; Leighton, J. L. Angew. Chem., Int. Ed.
2009, 48, 2403. (k) Schönherr, H.; Leighton, J. L. Org. Lett. 2012, 14,
2610.
ASSOCIATED CONTENT
Supporting Information
Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
Experimental procedures and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
*jieping.zhu@epfl.ch
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank EPFL (Switzerland), Swiss National Science Foun-
dation (SNSF) for financial supports. We thank Mr. B. Budai
for having participated in this work during his internship.
(18) Chiral thiourea-catalyzed enantioselective Pictet-Spengler
reaction, see: (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 10558. (b) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404. (c) Klausen, R. S.;
Jacobsen, E. N. Org. Lett. 2009, 11, 887. (d) Mittal, N.; Sun, D. X.;
Seidel, D. Org. Lett. 2014, 16, 1012.
REFERENCES
(1) Wang, K.-B.; Di, Y.-T.; Bao, Y.; Yuan, C.-M.; Chen, G.; Li, D.-
H.; Bai, J.; He, H.-P.; Hao, X.-J.; Pei, Y.-H.; Jing, Y.-K.; Li, Z.-L.; Hua,
H.-M. Org. Lett. 2014, 16, 4028.
(2) For a recent review, see: Stöckigt, J.; Antonchick, A. P.; Wu, F.;
Waldmann, H. Angew. Chem., Int. Ed. 2011, 50, 8538.
(3) Banfi, L.; Riva, R. Org. React. 2005, 65, 1.
(4) a) Zhu, J. Eur. J. Org. 2003, 1133. b) Dömling, A., Chem. Rev.
2006, 106, 17.
(5) Although this acid is commercially available, it can be easily
synthesized in multigram scale from prenol via a two-step sequence
involving Johnson-Claisen rearrangement and saponification (cf
Supporting Information).
(6) Qi, X.; Bao, H.; Tambar, U. K. J. Am. Chem. Soc. 2011, 133,
10050.
(7) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.
(b) Yang, H.; Li, H.; Wittenberg, R.; Egi, M.; Huang, W.; Liebeskind,
L. S. J. Am. Chem. Soc. 2007, 129, 1132. (c) Villalobos, J. M.; Srogl, J.;
Liebeskind, L. S. J. Am. Chem. Soc. 2007, 129, 15734. (d) For a review,
(19) We found that (+)-peganumine A (1) is poorly soluble in most
of the common organic solvents including methanol and DMSO.
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MeO
MeO
H
O
6
7
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Longest linear
sequence: 7 steps
EtO
O
HN
H2N
HN
N
N
+
H2N
9
HN
O
HN
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OMe
OH
1 (+)-Peganumine A
OMe
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