Total synthesis of the akuammiline alkaloid picrinine

Article abstract of DOI:10.1021/ja501780w

We report the first total synthesis of the complex akuammiline alkaloid picrinine, which was first isolated nearly five decades ago. Our synthetic approach features a concise assembly of the [3.3.1]-azabicyclic core, a key Fischer indolization reaction to forge the natural product's carbon framework, and a series of delicate late-stage transformations to complete the synthesis. Our synthesis of picrinine also constitutes a formal synthesis of the related polycyclic alkaloid strictamine.

Full text of DOI:10.1021/ja501780w

Communication
pubs.acs.org/JACS
Total Synthesis of the Akuammiline Alkaloid Picrinine
Joel M. Smith, Jesus Moreno, Ben W. Boal, and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
acetal linkages within its polycyclic skeleton. In vitro studies
show that picrinine (5) exhibits anti-inflammatory activity
through inhibition of the 5-lipoxygenase enzyme.17 In this
Communication, we report the first total synthesis of picrinine
(5).
ABSTRACT: We report the first total synthesis of the
complex akuammiline alkaloid picrinine, which was first
isolated nearly five decades ago. Our synthetic approach
features a concise assembly of the [3.3.1]-azabicyclic core,
a key Fischer indolization reaction to forge the natural
product’s carbon framework, and a series of delicate late-
stage transformations to complete the synthesis. Our
synthesis of picrinine also constitutes a formal synthesis of
the related polycyclic alkaloid strictamine.
Our retrosynthetic analysis of picrinine (5) is highlighted in
Scheme 1.18 We envisioned that picrinine (5) could be accessed
Scheme 1
atural products belonging to the akuammiline family of
N
alkaloids have a rich history in the chemical literature.1
Representative akuammilines 1−6 are depicted in Figure 1,
by late-stage introduction of the bis(N,O-acetal) linkage via a
proximity-driven cyclization of aminolactol 7.19 This inter-
mediate would arise from pentacycle 8 through oxidative
cleavage of the cyclopentene and subsequent functional group
interconversions. Next, in a key step, it was thought that
pentacycle 8 could be constructed from a Fischer indolization
reaction20 between phenylhydrazine 9 and tricyclic cyclo-
pentene 10. If successful, this would allow for the introduction
of the C7 quaternary stereocenter and provide the complex
carbon framework of the natural product. Tricycle 10 would be
assembled from enal 11, which could be generated from
bridged [3.3.1]-azabicycle 12. Finally, it was hypothesized that
bicycle 12 would be accessible from readily available vinyl
iodide 13 using a Pd-catalyzed enolate cyclization.
Figure 1. Representative akuammiline alkaloids 1−6.
each of which possesses an indoline or indolenine core fused to
a daunting polycyclic framework.2−7 Since the initial isolation
report of echitamine (1) in 1875,2 more than 30 compounds in
this family have been isolated from plants predominantly in
Southeast Asia. The complex structures of these molecules,
along with their interesting biological properties,1 have recently
prompted a number of synthetic investigations. Notable
achievements in this arena include total syntheses of
aspidophylline A (2) by Zhu,8 Ma,9 and our group,10 vincorine
(3) by Qin,11 Ma,12 and MacMillan,13 and scholarisine A (4) by
Smith14 and Snyder.15,16
The present study focuses on picrinine (5), which has not
previously been prepared by total synthesis. First discovered in
1965 from the leaves of Alstonia scholaris,6 picrinine (5) is a
highly complex, cage-like molecule that contains a furoindoline
core fused to a densely functionalized cyclohexyl ring. In turn,
the central cyclohexyl ring is part of a bridged [3.3.1]-
azabicyclic framework. Picrinine (5) possesses six stereogenic
centers, five of which are contiguous, and contains two N,O-
Our synthesis commenced with the preparation of enal 11
(Scheme 2). Sulfonamide 14, which is available from
commercial sources or can be readily prepared,21 was identified
as a suitable starting material. Alkylation of 14 with tosylate
1522 afforded vinyl iodide 13 in excellent yield. Next, treatment
Received: February 19, 2014
Published: March 5, 2014
© 2014 American Chemical Society
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Scheme 2
Scheme 4
of 13 with PdCl2(dppf) and K2CO3 in MeOH at 70 °C
furnished bicycle 12 via a Pd-catalyzed enolate cyclization.23
Bicyclic ketone 12 was processed to enone 16 by IBX
oxidation.24 Subsequent epoxidation, using sodium perborate
as a mild oxidant,25 transformed 16 into epoxide 17 in 89%
yield with complete diastereoselectivity. To arrive at the desired
enal intermediate 11, epoxide 17 was subjected to Wittig
olefination using (methoxymethyl)triphenylphosphonium
chloride and potassium tert-butoxide.26 Fragmentation of the
presumed epoxy enol ether intermediate occurred sponta-
neously in situ to deliver 11 in 82% yield.
Thus, cyclopentene 10 was exposed to an oxidation31 and
protection32 sequence, providing carbonate 22 in 78% yield
over two steps. In the critical Fischer indolization, TFA-
promoted reaction of 22 with phenylhydrazine 9 afforded the
hexacyclic indolenine product 23 with complete diastereose-
lectivity. This transformation marks one of the most complex
examples of the Fischer indolization reaction20 and is testament
to the reliability of this venerable synthetic method.33 It should
be noted that indolenine 23 exists in equilibrium with its
hydrate,34 so careful purification and 2D NMR analysis were
necessary to facilitate structure elucidation. Nonetheless,
cleavage of the cyclic carbonate of 23,35 followed by oxidative
cleavage36 generated lactol 21 as an inconsequential mixture of
diastereomers.
As shown in Scheme 3, enal 11 could be elaborated to
tricyclic cyclopentene 10 through a five-step sequence.
Scheme 3
Having assembled the carbon scaffold of the natural product,
three transformations remained in order to access picrinine (5).
From late-stage intermediate 21, this would involve conversion
of the aldehyde to the corresponding methyl ester, cleavage of
the nosyl group, and cyclization to forge the second N,O-acetal
linkage. As shown in Scheme 5, the first of these challenges was
Scheme 5
Reduction of 11 proceeded smoothly upon exposure to
tributyltin hydride, catalytic Pd(PPh3)4, and zinc chloride27 to
furnish 18.28 Wittig olefination, followed by Dess−Martin
oxidation delivered vinyl ketone 19 in 80% yield over two steps.
Next, ketone 19 was treated with LHMDS and DMPU,
followed by allyl iodide. This step afforded allyl vinyl ketone 20,
which was subjected to the Hoveyda−Grubbs second-
generation catalyst in refluxing dichloromethane to give tricyclic
cyclopentene 10.29
With access to tricycle 10, we explored the critical Fischer
indolization and the ensuing furoindoline formation, as
summarized in Scheme 4. We were delighted to find that
treatment of 10 with phenylhydrazine (9) and trifluoroacetic
acid in dichloroethane at 40 °C furnished the desired
pentacycle 8 in 74% yield. However, exhaustive efforts to
oxidatively cleave the cyclopentene of 8 en route to lactol
aldehyde 21 were unsuccessful.30
Hypothesizing that access to the disubstituted olefin of
cyclopentene 8 was obstructed by the [3.3.1]-bicycle and the
C9 hydrogen, we pursued an alternate strategy, which involved
olefin oxidation prior to the Fischer indolization (Scheme 4).
addressed by implementing a two-step sequence involving
oxidation to the carboxylic acid,37 followed by esterification.
This generated ester 24 in 58% yield over the two steps without
disturbing the lactol. Next, our attempts to remove the nosyl
protecting group from 24 proved challenging. We ultimately
found, however, that denosylation could be achieved using a
solid-supported thiol resin.38,39 Much to our gratification,
proximity-driven cyclization of the presumed aminolactol
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Communication
K.-M.; Yoganathan, K. Phytochemistry 1997, 45, 1303−1305. (c) Cai,
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22.
intermediate 7 occurred under the reaction conditions to
provide the bis(N,O-acetal) linkage and furnish picrinine (5).
Synthetic picrinine (5) was found to be identical to a sample of
the natural material in all respects. It should be noted that our
total synthesis of 5 also constitutes a formal synthesis of
strictamine (6).40
In summary, we have completed the first total synthesis of
the akuammiline alkaloid picrinine (5, 18 steps from known
ketone 14), which was first isolated nearly 50 years ago. Our
synthetic approach features a concise assembly of the [3.3.1]-
azabicyclic core, a key Fischer indolization reaction to forge the
natural product’s carbon framework, and a series of delicate
late-stage transformations to complete the total synthesis. We
expect our approach to 5 will enable the syntheses of other
alkaloids in the akuammiline family of natural products.
(7) For the initial isolation of 6, see: Schnoes, H.; Biemann, K.;
Mokry, J.; Kompis, I.; Chatterjee, A.; Ganguli, G. J. Org. Chem. 1966,
31, 1641−1642.
(8) Ren, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2014, 53,
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(10) Zu, L.; Boal, B. W.; Garg, N. K. J. Am. Chem. Soc. 2011, 133,
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(11) (a) Zhang, M.; Huang, X.; Shen, L.; Qin, Y. J. Am. Chem. Soc.
2009, 131, 6013−6020. (b) Zhang, D.; Song, H.; Qin, Y. Acc. Chem.
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(12) Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 9126−
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(13) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013,
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(14) (a) Adams, G. L.; Carroll, P. J.; Smith, A. B., III. J. Am. Chem.
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(15) Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135,
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ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and compound character-
ization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(16) For other efforts toward these alkaloids, see: (a) Watanabe, T.;
Kato, N.; Umezawa, N.; Higuchi, T. Chem.Eur. J. 2013, 19, 4255−
4261. (b) Li, Q.; Li, G.; Ma, S.; Feng, P.; Shi, Y. Org. Lett. 2013, 15,
2601−2603.
(17) Shang, J.-H.; Cai, X.-H.; Feng, T.; Zhao, Y.-L.; Wang, J.-K.;
Zhang, L.-Y.; Yan, M.; Luo, X.-D. J. Ethnopharmacol. 2010, 129, 174−
181.
AUTHOR INFORMATION
Corresponding Author
neilgarg@chem.ucla.edu
Notes
■
The authors declare no competing financial interest.
(18) The 3D representation was prepared from the X-ray data of 5
using CYLview. For CYLview, see: (a) Legault, C. Y. CYLview, 1.0b;
Universite de Sherbrooke: Quebec, Montreal, Canada, 2009; http://
́ ́
www.cylview.org. For the X-ray structure of 5, see: (b) Ghosh, R.;
Roychowdhury, P.; Chattopadhyay, D.; Iitaka, Y. Acta Crystallogr.
1988, C44, 2151−2154.
(19) In a first-generation approach, we targeted 7 via intermediate i
shown below. Although we were able to access this compound,
exhaustive efforts to elaborate i to 5 were unsuccessful.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Science Foundation
(CHE-0955864), Boehringer Ingelheim, DuPont, Eli Lilly,
Amgen, AstraZeneca, Roche, Bristol-Myers Squibb, the A. P.
Sloan Foundation, the Dreyfus Foundation, the S.T. Li
Foundation, and the University of California, Los Angeles, for
financial support. J.M.S. acknowledges the National Science
Foundation for a GRFP (DGE-1144087), and we thank NIH-
NIGMS (R01 GM090007) for support of J.M. We thank the
Garcia-Garibay laboratory (UCLA) for access to instrumenta-
tion, Dr. John Greaves (UC Irvine) for mass spectra, Materia
Inc. for chemicals, and Joshua Demeo, Anish Nag, and Elias
Picazo for experimental assistance. We are grateful to
Professors Kam (University of Malaya) and Luo (Chinese
Academy of Sciences) for providing authentic samples of
picrinine. These studies were supported by shared instrumen-
tation grants from the NSF (CHE-1048804) and the National
Center for Research Resources (S10RR025631).
(20) For the classic Fischer indole synthesis, see: (a) Fischer, E.;
Jourdan, F. Ber. 1883, 16, 2241−2245. (b) Fischer, E.; Hess, O. Ber.
1884, 17, 559−568.
(21) Sulfonamide 14 is commercially available from Aurora Fine
Chemicals LLC (CAS No. 115462-23-0). For the preparation of 14
from trans-4-aminocyclohexanol, see the SI.
(22) Rawal, V. H.; Michoud, C. Tetrahedron Lett. 1991, 32, 1695−
1698.
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