Asymmetric synthesis of the tricyclic core of calyciphylline A-type alkaloids via intramolecular [3 + 2] cycloaddition

Article abstract of DOI:10.1021/ol403609c

Asymmetric synthesis of the [5-6-7] tricyclic system common to the Calyciphylline A-type alkaloids is reported, featuring Overman rearrangement, Heck cyclization, intramolecular [3 + 2] cycloaddition, diastereoselective hydrogenation, and Claisen rearrangement as strategic events. The approach is capable of installing the crucial carbonyl functionality as well as multiple stereogenic centers within a congested polycyclic ring skeleton.

Full text of DOI:10.1021/ol403609c

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of the Tricyclic Core of Calyciphylline A‑Type
Alkaloids via Intramolecular [3 + 2] Cycloaddition
Lu Wang,† Chen Xu,†,§ Li Chen,† Xiaojiang Hao,*,‡ and David Zhigang Wang*,†
†Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University,
Shenzhen 518055, China
‡Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China
S
* Supporting Information
ABSTRACT: Asymmetric synthesis of the [5−6−7] tricyclic system common to the Calyciphylline A-type alkaloids is reported,
featuring Overman rearrangement, Heck cyclization, intramolecular [3 + 2] cycloaddition, diastereoselective hydrogenation, and
Claisen rearrangement as strategic events. The approach is capable of installing the crucial carbonyl functionality as well as
multiple stereogenic centers within a congested polycyclic ring skeleton.
substances are the shared [5−6−7] tricyclic framework
tructurally complex natural products continuously serve as
Sa powerful vehicle for the invention of novel synthetic possessing a carbonyl group as well as four contiguous
stereogenic centers (two of which being quaternary) embedded
in a highly congested ring system (in red). In our previous
reports, we had described our developed strategies toward the
tri- and tetracyclic skeletons of daphnilongeranin B (1),
featuring sequentially Mannich condensation, [2 + 2] photo-
chemical cycloaddition, and Grob fragmentation for the
construction of A−C−D and A−B−C−D ring systems.3f,k
The previous lesson subsequently teaches a revised retro-
synthetic analysis outlined herein. With daphnilongeranin B as
the exemplary target, as illustrated in Scheme 1A, a sequence
involving Pauson−Khand annulation followed by base-medi-
ated enone isomerization3j,s and intramolecular SN2 displace-
ment3k would efficiently degrade the target into the tricyclic
intermediate 9, to which we have already established a facile
access.3f,k Thus, our attention was next focused on installing the
requisite carbonyl group on ring A and introducing the all-
carbon quaternary functionalities at C4.
strategies, and in such activities the desired stereochemical
controls are frequently achieved through substrate-directed
strategies enabled by structural characteristics of a synthetic
target of interest. Among the numerous natural products
uncovered in recent years, the Daphniphyllum alkaloids
constitute a fascinating family due to their unusual polycyclic
ring skeletons, stereochemical complexities,1 and demonstrated
bioactivities.2
Intrigued by their unprecedented structures as well as their
scarce natural supply, we are particularly interested in chemical
syntheses of the Calyciphylline A-type alkaloids within this
family.3 As highlighted in Figure 1, structural hallmarks of these
It is notable that while our synthetic explorations are in
progress,3s Dixon and co-workers described their syntheses of
A−C−D and D−E−F tricyclic cores of Calyciphylline A-type
alkaloids.3i,j As shown in Scheme 1B, the Claisen rearrange-
ment3i as well as Michael addition3j used for installation of the
critical functionalities at C4 position are particularly inspiring
for our investigation. Their work demonstrated that the
carbonyl groups on ring A and ring D played important roles
in construction of the E−F ring system through the intended
Pauson−Khand event.
Figure 1. Calyciphylline A-class alkaloids featuring a common [5−6−7]
tricyclic core and embedded carbonyl functionality.
Received: December 13, 2013
Published: February 7, 2014
© 2014 American Chemical Society
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Scheme 1
Scheme 2. Retrosynthetic Analysis of the New Strategy
trisubstituted double bond in 14 that should facilitate the
intended INOC event.8
As summarized in Scheme 3, (S)-carvone was converted into
carbamate 19 with a series of known procedures involving an
Overman rearrangement,3f thus establishing the original
chirality in the target, in a combined yield of 68% over the
four-step sequence. LiAlH4 reduction of 19 then gave allylic
amine 16 in nearly quantitative yield. Condensation of amine
16 with unsaturated acid 17 afforded amide 20, the precursor
for the key Heck cyclization, in 84% isolated yield. The initial
reaction condition screenings involving the use of 10 mol % of
Pd(OAc)2 as precatalyst, 20 mol % of BINAP as ligand, and 5
equiv of Et3N as base and revealed a significant solvent effect:
while the use of MeOH, EtOH, toluene, or THF led to low
product yields (0−37%), the use of CH3CN and DMF
promoted a remarkable improvement (78% and 83% yield,
respectively). The use of simpler PPh3 in place of bidentate
BINAP enhanced further the yield of 21 to 91% when the Heck
cyclization was performed at 100 °C in DMF. The C5-Me and
C7-H were confirmed to adopt spatially a syn-orientation
(NOESY). Compound 21 was next transformed into oxime 22
in very high yield by sequential oxidative removal of the PMB
group, oxidation of the alcohol, and condensation with
hydroxylamine. Delightfully, upon exposure to the oxidant
NaOCl, 22 underwent smoothly intramolecular 1,3-dipolar
cycloaddition via the nitrile oxide intermediate 14 to afford the
tetracyclic isoxazoline 13 as a single diastereomer12 and in
excellent isolated yield (90%). The facile formation of 13 laid
the foundation for not only constructing the seven-membered
D ring but also site-specific functionalization on the C3-carbon
in the six-membered A ring. With 13 in hand, an appropriate
reaction condition for effecting the N−O bond cleavage was
then investigated. The use of activated zinc,7a molybdenum
hexacarbonyl,9a Fe/NH4Cl,9b and samarium diiodide9c all failed
to produce the desired product. A notable improvement while
After numerous unsuccessful attempts to construct the C4
quaternary center as well as exploring carbonyl-directed C−H
oxidations at C3,4 we elected to proceed through a revised new
scenario for simultaneous entries to both of the ring skeleton and
the embedded carbonyl functionality. For this purpose, a tricyclic
diketone 10 and its simplified analogue 11 thus constituted an
ideal platform for examining the feasibility of the proposed
strategies. We envisioned that the terminal alkene could be
transformed into the requisite alkyne5,3j,p and the carbonyl
group on ring D could be selectively converted to an olefin,6
which would set the stage for Pauson−Khand annulation to
furnish the E−F ring system (Scheme 1A).
As shown in Scheme 2, we envisioned that the stereogenicity
at C4 could be installed via a substrate-directed Claisen
rearrangement.5,3i The seven-membered ring D and both of the
carbonyl groups in 11 could be accessed with an intramolecular
nitrile oxide cycloaddition (INOC)7 followed by reductive
cleavage of the N−O bond and oxidation of the resulting
secondary alcohol. With C7 chirality as a critical stereochemical
control element, the five-membered C ring as well as the C5 all-
carbon quaternary center could be established by a stereo-
selective Heck reaction of bromide 15, from which the released
double bond moiety would provide the needed alkenyl partner
to engage on the subsequent INOC process. The precursor 15
would next be assembled by an amide formation event between
enantiopure allylic amine 16 and unsaturated carboxylic acid
17. Finally, the key C7-chirality in 16 could be introduced by an
Overman rearrangement established in our previous synthetic
routes and, through a series of substrate-directed stereo-
chemical controls, it would serve as the foundation for securing
all of the rest stereogenicities present in the target compound
1.3f,k Notably, within this scenario, a (Z)-conjugated carboxylic
acid 17 must be employed for the delivery of (E)-exo-
10
using Raney nickel/H3BO3 in place of Pd/C9d was next
observed, leading to the hydroxy ketone 23 in 92% yield upon
hydrogenolysis at 45 °C for 8 h in an optimal solvent mixture of
MeOH and H2O (in 5:1 volume ratio). Compound 23 was
readily oxidized by Dess−Martin periodinane via a 1,3-diketone
intermediate 24 to exclusively generate enol 25, whose
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Scheme 3. Synthesis of the [5−6−7] Tricyclic Skeleton 25
Scheme 4. Synthesis of the Tricyclic Skeleton 11
study and their nuclear Overhauser effect (NOE) correla-
tions.12
In summary, a concise and fully stereochemically controlled
synthetic route to the [5−6−7] tricyclic framework of the
Daphniphyllum subclass Calyciphylline A-type alkaloids has been
demonstrated. Success hinged on such key events as Heck
cyclization to install a congested quaternary stereogenic center,
an intramolecular nitrile oxide [3 + 2] cycloaddition to deliver
both seven-membered ring and the crucial carbonyl function-
alities, diastereoselective hydrogenation to furnish a cis-[5−7]
ring junction, and a late-stage Claisen rearrangement to yield
allyl-substituted 1,3-diketone amendable for further structural
editing toward Pauson−Khand annulation. Further studies
directed toward enantioselective total synthesis of certain
members of these alkaloids are currently underway in our
laboratories.
ASSOCIATED CONTENT
* Supporting Information
■
S
structure and stereochemistry were established by X-ray
crystallographic analysis.11
The above success prompted us to progress further to the
synthesis of the tricyclic system 11 (Scheme 4).
Experimental procedures, X-ray crystallographic analysis, and
1H and 13C NMR spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org
Considering both reactivity and stereoselectivity in the bowl-
shaped architecture disclosed in our previous work,3k we
believed that the tetracyclic core 13 (see the 3D structure of
13a in Scheme 4) was the appropriate substrate for installing
the correct chiral center at C6. To our delight, upon exposure to
simple Pd/C hydrogenation conditions, 26 was obtained in
89% yield as a single isomer.12 Treatment of 26 with Raney
nickel protocol followed by oxidation with TPAP exclusively
afforded enol 12. The enolic double bond was determined to
reside within the six-membered ring A on the basis of 2D NMR
spectroscopic analysis, which was consistent with the structure
of 25.12 The resulting enol 12 was subjected to allylation with t-
BuOK, [18]crown-6,13 and allyl iodide to give the correspond-
ing allyl enol ether 27 (83%), which in turn underwent Claisen
rearrangement at 180 °C in xylene to afford ketone 11 in
excellent selectivity and yield (dr >20:1, 92%). The stereo-
chemistry of compound 11 was clearly manifested via 2D-NMR
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: haoxj@mail.kib.ac.cn.
*E-mail: dzw@pkusz.edu.cn.
Present Address
§Division of Chemistry and Chemical Engineering, California
Institute of Technology, Mail Code 101-20, 1200 E California
Blvd, Pasadena, CA 91125.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation of China (Grant
Nos. 21290183, 21272014, and 20972008 to D.Z.W. and
20672160 to X.J.H.), the national “973 Project” of the State
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Letter
(10) (a) Curran, D. P. J. Am. Chem. Soc. 1982, 104, 4024. (b) Curran,
D. P. J. Am. Chem. Soc. 1983, 105, 5826.
(11) The crystal structure of 25 was deposited at the Cambridge
Crystallographic Data Centre (tracking no. 951031).
(12) For detailed NMR spectroscopic analysis, see the Supporting
Information.
Ministry of Science and Technology (Grant Nos.
2012CB722602 and 2010CB833200), and the Shenzhen
Bureau of Science and Technology for financial support. We
also thank Mr. Bo Zhang (Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai) for helpful
discussions.
(13) 18-Crown-6 was obtained from Adamas-beta Chemical
Company (Switzerland).
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