Remodeling of fumagillol: Discovery of an oxygen-directed oxidative mannich reaction

Article abstract of DOI:10.1021/ol4035269

An efficient, two-step construction of highly complex alkaloid-like compounds from the natural product fumagillol is described. This approach, which mimics a biosynthetic cyclase/oxidase sequence, allows for rapid and efficient structure elaboration of th

Full text of DOI:10.1021/ol4035269

Letter
pubs.acs.org/OrgLett
Remodeling of Fumagillol: Discovery of an Oxygen-Directed
Oxidative Mannich Reaction
Alexander J. Grenning, John K. Snyder,* and John A. Porco, Jr.*
Center for Chemical Methodology and Library Development, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts
02215, United States
S
* Supporting Information
ABSTRACT: An efficient, two-step construction of highly
complex alkaloid-like compounds from the natural product
fumagillol is described. This approach, which mimics a
biosynthetic cyclase/oxidase sequence, allows for rapid and
efficient structure elaboration of the basic fumagillol scaffold
with a variety of readily available coupling partners.
Mechanistic experiments leading to the discovery of an
oxygen-directed oxidative Mannich reaction are also described.
reactions,4 reminiscent of natural product biosynthesis5
he use of abundant natural products as synthetic
Tlaunching points for diversity-oriented synthesis (DOS) (“cyclase” followed by “oxidase” as coined by Baran6), yielding
alkaloid-like structures 4 with high levels of complexity
(Scheme 1). Mechanistic experiments leading to the discovery
of an oxygen-directed Mannich reaction are also outlined.
Following our previously reported preparation of fumagillol−
anisidine adducts 2a,2a,7 we began oxidative coupling studies on
this scaffold. An oxidation screen led to the discovery of a rapid
(<1 min, 100% conversion as monitored by UPLC analysis7)
amine-to-iminium oxidation of scaffold 2a when 1 equiv of
DDQ was added in THF (Scheme 2).8,9 The site of oxidation
was confirmed by a quench with sodium borodeuteride,
stereoselectively yielding α-deutero-2a as the sole product in
83% isolated yield.
has garnered significant attention recently, as highly complex
compounds can be rapidly prepared for biological evaluation.1
Importantly, this approach utilizes the inherent complexity of
the natural product which may be “structurally remodeled”2a
into a new architecture with unique biological activity in
comparison to the parent natural product. Exemplary natural
products include semisynthetic steroids,2b bryonolic acid,2c
adrenosterone,2d cinchonine,2d gibberelic acid,2d and steviol.2e
We recently reported that the natural product fumagillol 1
can undergo controlled 5-exo- or 6-endo-bis-epoxide opening/
cyclization, depending on the metal-catalyst additive, leading to
highly complex alkaloidal perhydroisoindoles 2 and perhydro-
isoquinolines 3 (Scheme 1).2a Due to the efficiency of these
reactions, we considered further processing of this scaffold to
increase diversity and complexity for biological evaluation.
Herein we report a two-step diversity-oriented synthesis3
strategy using cascade cyclizations and oxidative Mannich
Scheme 2. Discovery of a Chemoselective Oxidation
Scheme 1. Fumagillol Bis-Epoxide Opening and Oxidative
Mannich Strategy
The scope of the oxidative coupling of fumagillol−aniline
adducts 2 with various nucleophiles was next examined (Figure
1). Substrates 2a−2c underwent clean oxidation and
subsequent nucleophilic addition with N-methylindole to afford
adducts 4a−4c, respectively, in good yields.9 Similarly,
substrates substituted with a meta-electron withdrawing group
on the aniline subunit underwent chemoselective oxidation
adjacent to nitrogen and were found to be suitable for the
methodology (2d → 4d, 81% yield). In general, substrates
Received: December 5, 2013
Published: January 10, 2014
© 2014 American Chemical Society
792
dx.doi.org/10.1021/ol4035269 | Org. Lett. 2014, 16, 792−795

Organic Letters
Letter
Figure 2. Oxidative Povarov cyclization.
additional structural complexity to be achieved by constructing
multiple bonds in a single transformation. Simple styrenic
nucleophiles including styrene and p-methoxystyrene under-
went Povarov cycloaddition with the in situ generated iminum
ion. Adducts 10a−c were isolated in good to excellent yields
with the electronically differentiated fumagillol scaffolds 2b and
2c containing p-methoxy and p-fluoro groups, respectively. In
all cases, the diastereoselectivity of the newly formed benzylic
stereocenter was modest (dr = 2.5−3:1). However, in the case
of 10b−c, the products could be diastereomerically enriched
(to >20:1 dr) by recrystallization, allowing for stereochemistry
determination by NOE analysis.7 By utilizing indene, the highly
complex adduct 10d was prepared as a single diastereomer.
Unfortunately, the trans-styrene derivative anethole did not
react with the in situ generated iminium (Figure 2, note b).
Having defined a wide scope for our oxidative coupling
methodology, the possibility for an “oxygen”-directed oxidation
mechanism for the initial DDQ conversion of the aniline to an
iminium intermediate was next examined. Two possible
mechanisms by which the hydroxy group could influence the
oxidation were envisioned (Scheme 3): the hydroxyl group
could function (1) as a general acid catalyst for DDQ activation
and direction (pathway A) or (2) as a neighboring nucleophile
(pathway B via anchimeric assistance) to facilitate formal
hydride delivery to the DDQ oxidant. Since the α′-position of
the fumagillol substrate is fully substituted and therefore cannot
undergo oxidation, it was not clear whether there was also a
hydroxy-directing, regioselectivity effect14 in addition to the
diastereocontrol in nucleophilic addition to the iminium ion
intermediate.
As shown in Scheme 4, if there is an intrinsic hydroxyl-
directing effect, one would expect products of type 12 to arise
from either the simplified hydroxy (11a) and/or ether (11b)
substrates thus allowing for development of a general
methodology toward vicinally chiral pyrrolidinols. However, if
there is no directing effect, a sterically driven oxidation would
be expected, likely resulting in the formation of pyrrole 13.8e
Thus, the directed oxidation would produce compounds of
increased complexity containing vicinal stereocenters whereas
the steric oxidation would result in a loss of complexity, likely
leading to N-arylpyrrole 13 via enamine formation and
dehydration.15
Figure 1. Scope of the oxidative coupling. aMultiple runs, 50−750 mg
b
c
scale. Nucleophile = N-methylindole (1.1 equiv). Initial oxidation
required heating at 60 °C for 1−3 h to complete. Once complete,
indole (1.1 equiv) was added and the reaction was stirred until
coupling was complete as monitored by UPLC. dNucleophile = indole
(1.1 equiv). eNucleophile = N-methylpyrrole (1.1 equiv). f Nucleophile
g
= diethylphosphite (10 equiv). Nucleophile = cyclohexane silylenol
ether (1.5 equiv); the α-stereocenter could not be unambiguously
h
assigned. Nucleophile = phenylacetylene (1.5 equiv) + Cul (10 mol
I
%) and Et3N (1.1 qeuiv). Nucleophile = exomethylenecyclopentene
(10 equiv). [DDQ = 2,3-dichloro-5,6-dicyano-p-benzoquinone, Ar =
aryl, PMP = p-methoxyphenyl].
containing electron-withdrawing groups required heating (60
°C) to enable oxidation in a timely fashion (3 h). In addition to
N-methylindole as the nucleophilic partner, simple indole was
also compatible with the methodology and could be oxidatively
coupled to scaffold 2a to afford adduct 4e. To illustrate the
practicality of the couplings, product 4a could be prepared on
reaction scales from 50 to 750 mg. Thus, both the bis-epoxide
opening and the oxidative coupling steps are applicable to near
gram scale synthesis.
Highly efficient oxidative couplings of remodeled scaffold 2a
with other nucleophiles were also found to be successful
(Figure 1, products 5−9). Under the optimized conditions,
oxidative couplings with N-methylpyrrole, diethyl phosphite,10
cyclohexanone silyl enol ether,11 phenylacetylene,12 and
methylenecyclopentane11 produced products 5a−9a, respec-
tively.
The use of styrenes as nucleophilic partners in the oxidative
couplings yielded Povarov products 10 (Figure 2).13
Importantly, this oxidative Povarov reaction allowed for
793
dx.doi.org/10.1021/ol4035269 | Org. Lett. 2014, 16, 792−795

Organic Letters
Letter
The nature of the oxygen-directed oxidative Mannich
reaction was further explored using a deuterium labeling
experiment.16 Stereoselective oxidation was observed on the
deuterated-fumagillol scaffold deutero-2a wherein complete
deuterium transfer to the DDQ oxidant was observed and
deuterium-free product 4a was isolated in high yield following
nucleophilic quench with N-methylindole (Scheme 6). This
result is in line with the hypothesis that the oxygen atom
activates its anti-hydrogen toward transfer via anchimeric, σ*-
orbital overlap (Pathway B, Scheme 3).14a
Scheme 3. Possible Pathways for Oxygen-Directed Oxidation
Scheme 6. Deuterium Labeling Study
Scheme 4. Possible Outcomes for Oxidative Mannich
Reaction of 11
In conclusion, we have outlined a rapid approach for the
construction of highly complex alkaloid-like “unnatural
products” from the natural product scaffold fumagillol utilizing
a cascade of bis-epoxide opening (“structure remodeling”)
followed by a diversifying chemo- and stereoselective oxidative
Mannich/coupling protocol. Mechanistic experiments including
a deuterium labeling study as well as oxidations with simpler
pyrrolidine substrates were used to define the nature of the
oxygen-directed oxidative Mannich reaction and support an
“anchimeric-assisted” mechanism. Further studies including
additional applications and biological evaluation of alkaloid-like
products are currently in progress and will be reported in due
course.
We were pleased to find that the simplified substrate 11a
indeed underwent the oxidative Mannich reaction with N-
methylindole in the direction of the hydroxy group affording
adduct 12a in 91% yield as a single diastereomer (Scheme 5).
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, compound characterization, and
1H/13C NMR reprints. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
a
Scheme 5. A Simplified Variant
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: porco@bu.edu.
*E-mail: snyder@bu.edu.
Notes
The authors declare no competing financial interest.
a
Standard conditions: 1 equiv DDQ, THF (0.5M), 5 equiv, indole
ACKNOWLEDGMENTS
■
derivative, 12 h, rt.
Financial support from the National Institutes of Health (P50
GM067041) is gratefully acknowledged. We thank Professors
Scott Schaus (Boston University) and Corey Stephenson
(University of Michigan) for helpful discussions. We thank
Madeline Weber (CMLD-BU) for assistance with preparative
HPLC purification and Gina Kim for full spectroscopic analysis
of fumagillol.
This result confirmed that there is an oxygen-directing effect;
however it does not distinguish between the H-bonding and
anchimeric-assisted mechanisms (Paths A and B, Scheme 3).
Interestingly, ether substrate 11b also underwent directed
oxidative Mannich reaction with N-methylindole in good yield
producing 12b as the sole product, suggesting that preorganiza-
tion of the DDQ and the substrate through a hydrogen bond is
not required, thus supporting the anchimeric-assisted mecha-
nism (Pathway B).
REFERENCES
■
14.
(1) Morrison, K. C.; Hergenrother, P. J. Nat. Prod. Rep. 2014, 31, 6−
794
dx.doi.org/10.1021/ol4035269 | Org. Lett. 2014, 16, 792−795

Organic Letters
Letter
(2) (a) Balthaser, B. R.; Maloney, M. C.; Beeler, A. B.; Porco, J. A.,
Jr.; Snyder, J. K. Nat. Chem. 2011, 3, 969−973. (b) Kumar, N.; Kiuchi,
M.; Tallarico, J. A.; Schreiber, S. L. Org. Lett. 2005, 7, 2535−2538.
(c) Ignatenko, V. A.; Han, Y.; Tochtrop, G. P. J. Org. Chem. 2012, 78,
410−418. (d) Huigens, R. W.; Morrison, K. C.; Hicklin, R. W.; Flood,
T. A.; Richter, M. F.; Hergenrother, P. J. Nat. Chem. 2013, 5, 195−
202. (e) Hutt, O. E.; Doan, T. L.; Georg, G. I. Org. Lett. 2013, 15,
1602−1605. (f) Schwarz, O.; Jakupovic, S.; Ambrosi, H.-D.; Haustedt,
(16) For deuterium-labeling studies of DDQ-mediated oxidative
Prins cyclizations, see: Jung, H. H.; Floreancig, P. E. Tetrahedron 2009,
65, 10830−10836.
L. O.; Mang, C.; Muller-Kuhrt, L. J. Comb. Chem. 2007, 9, 1104−1113.
̈
(g) Sumskaya, Y. G.; Whitney, P. S., III; Bergmeier, S. C.; McMills, M.
C.; Priestley, N. D.; Wright, D. L. ARKIVOC 2011, 144−166.
(h) Kesavan, S.; Marcaurelle, L. A. Nat. Chem. Biol. 2013, 9, 210−213.
(i) Li, J.; Cisar, J. S.; Zhou, C.-Y.; Vera, B.; Williams, H.; Rodríguez, A.
D.; Cravatt, B. F.; Romo, D. Nat. Chem. 2013, 5, 510−517.
(3) (a) O’Connor, C. J.; Beckmann, H. S. G.; Spring, D. R. Chem. Soc.
Rev. 2012, 41, 4444−4456. (b) Ganem, B. Acc. Chem. Res. 2009, 42,
463−472. (c) Tan, D. S. Nat. Chem. Biol. 2005, 1, 74−84. (d) Spring,
D. R. Org. Bio. Mol. Chem. 2003, 1, 3867−3870. (e) Schreiber, S. L.
Science 2000, 287, 1964−1969.
(4) (a) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215−1292.
(b) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780−
1824. (c) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2010, 111, 1293−
1314. (d) Li, C.-J. Acc. Chem. Res. 2009, 42, 335−344. (e) Murahashi,
S.-I.; Zhang, D. Chem. Soc. Rev. 2008, 37, 1490−1501.
(5) (a) Ames, B. D.; Haynes, S. W.; Gao, X.; Evans, B. S.; Kelleher,
N. L.; Tang, Y.; Walsh, C. T. Biochemistry 2011, 50, 8756−8769.
(b) Ames, B. D.; Liu, X.; Walsh, C. T. Biochemistry 2010, 49, 8564−
8576.
(6) (a) Ishihara, Y.; Baran, P. S. Synlett 2010, 1733−1745. (b) Chen,
K.; Baran, P. S. Nature 2009, 459, 824−828. (c) Foo, K.; Usui, I.;
Gotz, D. C. G.; Werner, E. W.; Holte, D.; Baran, P. S. Angew. Chem.,
̈
Int. Ed. 2012, 51, 11491−11495.
(7) See the Supporting Information for complete details.
(8) DDQ is a common oxidant in various cross-dehydrogenative
coupling (CDC) reactions; see: (a) Zhang, Y.; Li, C.-J. Angew. Chem.,
Int. Ed. 2006, 45, 1949−1952. (b) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc.
2006, 128, 4242−4243. (c) Tu, W.; Liu, L.; Floreancig, P. E. Angew.
Chem., Int. Ed. 2008, 47, 4184−4187. (d) Zhai, L.; Shukla, R.; Rathore,
R. Org. Lett. 2009, 11, 3474−3477. (e) Liu, L.; Floreancig, P. E. Org.
Lett. 2010, 12, 4686−4689. (f) Brizgys, G. J.; Jung, H. H.; Floreancig,
P. E. Chem. Sci. 2012, 3, 438−442. (g) Clausen, D. J.; Floreancig, P. E.
J. Org. Chem. 2012, 77, 6574−6582.
(9) For select examples of oxidative Mannich reactions, see:
(a) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am.
Chem. Soc. 2006, 128, 5648−5649. (b) Yang, F.; Li, J.; Xie, J.; Huang,
Z.-Z. Org. Lett. 2010, 12, 5214−5217. (c) Condie, A. G.; Gonzal
́
ez-
Gomez, J. C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2010, 132, 1464−
́
1465. (d) Freeman, D. B.; Furst, L.; Condie, A. G.; Stephenson, C. R.
J. Org. Lett. 2011, 14, 94−97. (e) Allen, J. M.; Lambert, T. H. J. Am.
Chem. Soc. 2011, 133, 1260−1262.
(10) Alagiri, K.; Devadig, P.; Prabhu, K. R. Chem.Eur. J. 2012, 18,
5160−5164.
(11) Huang, L.; Zhang, X.; Zhang, Y. Org. Lett. 2009, 11, 3730−3733.
(12) (a) Su, W.-K.; Yu, J.-B.; Li, Z.-H.; Jiang, Z.-J. J. Org. Chem. 2011,
76, 9144−9150. (b) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47,
7075−7078.
(13) (a) Richter, H.; García Mancheno, O. Org. Lett. 2011, 13,
̃
6066−6069. (b) Rohlmann, R.; Stopka, T.; Richter, H.; García
Mancheno, O. J. Org. Chem. 2013, 78, 6050−6064. (c) Jia, X.; Wang,
̃
Y.; Peng, F.; Huo, C.; Yu, L.; Liu, J.; Wang, X. J. Org. Chem. 2013, 78,
9450−9456.
(14) (a) Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem. 1995, 60, 4743−
4748. (b) Goti, A.; Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi, A. J. Org.
Chem. 1997, 62, 3119−3125. (c) Archibald, G.; Lin, C.-P.; Boyd, P.;
Barker, D.; Caprio, V. J. Org. Chem. 2012, 77, 7968−7980.
(15) Takasu, N.; Oisaki, K.; Kanai, M. Org. Lett. 2013, 15, 1918−
1921.
795
dx.doi.org/10.1021/ol4035269 | Org. Lett. 2014, 16, 792−795