Total synthesis of (±)-kopsihainanine A

Article abstract of DOI:10.1002/chem.201200867

Going all the way: The first total synthesis of (±)-kopsihainanine A has been achieved in ten steps with a 12 % overall yield from commercially available 1,2,3,4-tetrahydrocarbazol-4-one (see scheme). This synthesis features an intramolecular conjugate addition of the iminium ion formed in situ with the amide and a substrate-controlled diastereoselective α-hydroxylation. Furthermore, ring D is formed by a late-stage transannular S_N2 reaction. Copyright

Full text of DOI:10.1002/chem.201200867

COMMUNICATION
DOI: 10.1002/chem.201200867
Total Synthesis of (Æ)-Kopsihainanine A
Peng Jing,[a] Zhen Yang,[a] Changgui Zhao,[a] Huaiji Zheng,[a] Bowen Fang,[a]
Xingang Xie,*[a] and Xuegong She*[a, b]
Kopsihainanine A (Figure 1) is an indole alkaloid that was
isolated from the leaves and stems of a Chinese medicinal
plant, Kopsia hainanensis, together with a biogenetically re-
lated compound, kopsihainanine B, by Gao and co-workers
Figure 1. Structures of kopsihainanine A and B.
in 2011.[1] In Hainan Province, China, Kopsia hainanensis
Scheme 1. Retrosynthetic analysis of (Æ)-kopsihainanine A (1).
has historically been used in folk medicine for the treatment
of dropsy, pharyngitis, tonsillitis, and rheumatoid arthritis.[2]
Pharmacological investigations on the crude and purified al-
kaloids from some Kopsia plants have shown promising anti-
leishmanial, antitumor, antimitotic, and antitussive activi-
ties.[3] The structure of kopsihainanine A has an unprece-
dented strained pentacyclic skeleton of 6-, 5-, 6-, 6-, 6-mem-
bered rings, which is possibly formed by a rearrangement of
kopsihainanine B.[1,4] Due to its biological profile and intri-
guing structure, kopsihainanine A represents an attractive
target for the synthetic community. In this communication,
the first total synthesis of (Æ)-kopsihainanine A (1) is de-
scribed.
stereoselective a-hydroxylation of the amide. Amide 2 could
be easily prepared from intermediate 3 through an N-alkyla-
tion to construct ring D. The key transformation in our syn-
thetic plan was the formation of tetracyclic lactam 3. In this
pivotal conversion, ketoamide 5 was expected to be trans-
formed into iminium ion intermediate 4, which we thought
would be trapped by the amide to form the tetracyclic
lactam 3. Ketoamide 5 could be derived from commercially
available ketone 6 by several chemical transformations.
Our synthesis of (Æ)-kopsihainanine A (1) started with
commercially available ketone 6, which was easily trans-
formed into its N-benzyl derivative 7 in 95% isolated yield
by following a literature protocol (Scheme 2).[5] Alkylation
of ketone 7 with allyl bromide followed by a conjugate addi-
tion with acrylonitrile in the presence of tBuOK afforded ni-
trile 9 in 67% yield over two steps. It is worth mentioning
that all atoms of the pentacyclic skeleton of the natural
product have been provided in these two steps.
Our retrosynthetic analysis for (Æ)-kopsihainanine A (1)
is outlined in Scheme 1. We envisaged that it would be pos-
sible to access 1 from 2 through a substrate-controlled dia-
[a] P. Jing, Z. Yang, C. Zhao, H. Zheng, B. Fang, Dr. X. Xie,
Prof. Dr. X. She
State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University, Lanzhou, Gansu, 730000 (P.R. China)
Fax : (+86)931-8912582
À
The remaining work was to form the two C N bonds to
construct rings D and E. Our initial attempt at the forma-
tion of tetracyclic lactam 3 involved use of the Ritter reac-
tion (Scheme 2).[6] To this end, selective reduction of the car-
bonyl group in 9 to the corresponding alcohol 10 was neces-
sary. However, the reduction was unsuccessful under several
different sets of mild reaction conditions, such as NaBH4
and the Luche reagent, probably due to the steric hindrance
of the a-quaternary center and the electron-donating effect
E-mail: shexg@lzu.edu.cn
xiexg@lzu.edu.cn
[b] Prof. Dr. X. She
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences, Lanzhou, Gansu, 730000 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200867.
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sure of nitrile 9 to anhydrous formic acid smoothly generat-
ed ketoamide 5 in quantitative yield.[8] Then, formation of
tetracyclic lactam 3 in a one-pot reaction was attempted. To
our delight, the desired product 3 was obtained in excellent
yield as a single diastereomer through selective reduction of
ketoamide 5 with LiAlH4 at À208C followed by treatment
with aqueous hydrochloric acid directly.[9] The good diaste-
reoselectivity observed for this reaction can be explained by
the conformation of the newly formed six-membered ring,
which makes the conjugate addition tend to take place on
the b face. It should be noted that the relative stereochemis-
try of the hydroxyl group in 11 was deemed insignificant be-
cause it would be destroyed during the subsequent acid-pro-
moted elimination reaction to generate iminium ion 4.
With key tetracyclic lactam 3 in hand, we turned our at-
tention to the construction of ring D to complete the total
synthesis of kopsihainanine A (Scheme 4). Lactam 3 was
Scheme 2. Synthesis of nitrile 9 and attempts to construct ring E by use
of the Ritter reaction.
of the protective benzyl group.[7] This persuaded us to give
up the attempts to construct ring E from nitrile 9 by using
the Ritter reaction although it seemed to be one of the
more direct potential routes.
As an alternative, we proposed that ring E could be con-
structed by a one-pot process involving a carbonyl reduc-
tion/iminium formation/intramolecular conjugate-addition
reaction starting from ketoamide 5 (Scheme 3). Thus, expo-
Scheme 4. Total synthesis of (Æ)-kopsihainanine A. CCDC-853071 (13)
contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallograph-
ic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
converted into alcohol 12 in 73% yield through a hydrobora-
tion–oxidation reaction. Mesylation of 12, followed by
a transannular N-alkylation reaction, afforded pentacyclic
intermediate 2 in 58% yield over the two steps. At this
point, the key pentacyclic core of kopsihainanine A has
been established. The remaining steps were the introduction
of a hydroxyl group a to the carbonyl group and removing
the protective benzyl group. In preliminary studies, the sub-
Scheme 3. Synthesis of tetracyclic intermediate 3.
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(Æ)-Kopsihainanine A
COMMUNICATION
trated to dryness in vacuo to give pure lactam 3 (940 mg, 98% yield) as
a white solid. M.p. 173–1748C; H NMR (400 MHz, CDCl3,): d=1.60 (m,
strate-controlled a-hydroxylation of pentacyclic compound 2
was then examined by using a variety of oxidants, such as
the Davisꢁ reagent,[10] meta-chloroperbenzoic acid (m-
CPBA)[11] and (TMSO)2 (TMSO=trimethylsilyloxyl;
(TMSO)2 =BTMSPO=bis(trimethylsilyl)peroxide).[12]
However, in all cases the N-oxide of indole was the major
product. This may be attributed to two factors: 1) as shown
in Figure 2, the rigid structure of the compound makes the
1
1H), 1.85 (m, 1H), 1.94 (m, 1H), 2.02 (m, 1H), 2.09 (m, 1H), 2.23 (m,
1H), 2.42 (m, 2H), 2.66 (m, 2H), 4.51 (s, 1H), 4.97 (m, 1H), 5.08 (m,
1H), 5.27 (m, 2H), 5.84 (m, 1H), 5.90 (s, 1H), 6.94 (d, J=6.8 Hz, 2H),
7.14 (m, 2H), 7.26 (m, 4H), 7.51 ppm (dd, J=6.8, 2.0 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): d=18.7, 25.4, 27.8, 30.3, 34.4, 40.2, 46.4, 53.2, 108.7,
109.6, 116.9, 118.7, 119.9, 121.7, 125.9, 127.4, 128.8, 133.3, 135.5, 137.1,
137.3, 170.8 ppm; IR (KBr): n˜max =3391, 3212, 3058, 2928, 2857, 1657,
1462, 1429, 1358, 1302, 1210, 1188, 919, 737, 697 cmÀ1; HRMS (ESI) calcd
for C25H26N2O: 393.1943 [M+Na]+; found: 393.1949.
Compound 13: Anhydrous Na2SO3 (470 mg, 3.73 mmol, 5.0 equiv) was
added to a solution of lactam 2 (276 mg, 0.746 mmol) in anhydrous THF
(1 mL) under an oxygen balloon. LDA (2n in THF, 1.9 mL, 3.73 mmol,
5.0 equiv) was slowly added to the reaction mixture over 2 min. The re-
sulting solution was stirred at 08C for 30 min and at room temperature
overnight. The reaction mixture was quenched by addition of aqueous
HCl (1n, 8 mL). The combined organic extracts were washed with water
and brine (10 mL) and then dried over anhydrous Na2SO4. The solution
was concentrated to dryness in vacuo. The residue was purified by
column chromatography (silica gel, hexane/EtOAc 4:1) to give alcohol 13
(244 mg, 85% yield, d.r.=6:1) as a white solid. M.p. 1958C; 1H NMR
(CDCl3, 400 MHz): d=1.24 (m, 1H), 1.60 (m, 1H), 1.68 (m, 2H), 1.77
(m, 1H), 1.93 (m, 2H), 2.32 (dd, J=8.4, 13.6 Hz, 1H), 2.69 (dd, J=6.0,
17.2 Hz, 1H), 2.90 (m, 1H), 3.25 (td, J=3.2, 12.8 Hz, 1H), 3.61 (s, 1H),
4.01 (t, J=8.8 Hz, 1H), 4.43 (m, 2H), 5.26 (s, 2H), 6.97 (d, J=7.2 Hz,
2H), 7.04 (t, J=7.6 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.20 (d, J=8.0 Hz,
1H), 7.26 (m, 3H), 7.68 ppm (d, J=8.0 Hz, 1H); 13C NMR (CDCl3,
100 MHz): d=18.7, 21.8, 34.3, 37.3, 37.4, 39.3, 46.4, 53.8, 63.9, 68.7, 109.2,
109.4, 119.6, 119.9, 121.7, 124.3, 125.9, 127.5, 128.9, 134.5, 137.3, 137.4,
185.8 ppm; IR (KBr): n˜max =3442, 3054, 3032, 2926, 2854, 1721, 1668,
1611, 1461, 1434, 1340, 1320, 1220, 1147, 1092, 1027, 901, 842, 738,
698 cmÀ1; HRMS (ESIMS) calcd for C25H26N2O2: 387.2073 [M+H]+;
found: 387.2065.
Figure 2. Chem 3D images of amide 2 and the deprotonation of 2.
a position of the carbonyl group difficult to deprotonate[13]
and functionalize and 2) the N-benzyl indole was sufficiently
active to be oxidized to the N-oxide when stronger oxidants
were used. Thus, milder reaction conditions were needed to
install the required hydroxyl group. With this idea in mind,
we chose O2 as the oxidant. To our delight, deprotonation of
2 with an excess of lithium diisopropylamide (LDA) and
subsequent treatment with O2 in the presence of anhydrous
sodium sulfite smoothly provided 13 in 85% yield as two
separable diastereomers (d.r.>6:1).[14] Single-crystal X-ray
analysis of the major isomer of 13 allowed us to determine
its relative configuration to be the desired one. Removal of
the benzyl group with AlCl3 in anisole at 1008C furnished
(Æ)-kopsihainanine A (1) in 64% yield.[15] The spectroscopic
data of our synthetic compound 1 matched those reported
for naturally derived kopsihainanine A.[16]
Acknowledgements
We are grateful for generous financial support by the MOST
(2010CB833200), the NSFC (21125207, 21072086, 21102062) and Pro-
gram 111.
In summary, the first total synthesis of (Æ)-kopsihainani-
ne A (1) has been achieved in ten steps with a 12% overall
yield. The synthesis started from an inexpensive and com-
mercially available material, and all of the reaction condi-
tions were practically convenient. The developed synthetic
strategy may also be suitable for the total synthesis of aspi-
dospermidine and its analogues,[17] which is currently in
progress in our laboratory and will be reported in due
course.
Keywords: alkaloids · indoles · intramolecular conjugate
addition · kopsihainanine A · oxidation · total synthesis
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Experimental Section
Compound 3: Lithium aluminum hydride (LAH; 197 mg, 5.18 mmol,
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Received: March 15, 2012
Published online: && &&, 2012
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(Æ)-Kopsihainanine A
COMMUNICATION
Natural Products
P. Jing, Z. Yang, C. Zhao, H. Zheng,
B. Fang, X. Xie,* X. She* ... &&&& — &&&&
Total Synthesis of (Æ)-Kopsihaina-
nine A
Going all the way: The first total syn-
thesis of (Æ)-kopsihainanine A has
been achieved in ten steps with a 12%
overall yield from commercially avail-
able 1,2,3,4-tetrahydrocarbazol-4-one
(see scheme). This synthesis features
an intramolecular conjugate addition
of the iminium ion formed in situ with
the amide and a substrate-controlled
diastereoselective a-hydroxylation.
Furthermore, ring D is formed by
a late-stage transannular SN2 reaction.
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!