Tandem Oxidative Dearomatizing Spirocyclizations of Propargyl Guanidines and Ureas

Article abstract of DOI:10.1021/acs.orglett.7b01898

Treatment of propargyl ureas or guanidines with iodosobenzene diacetate results in an oxidative tandem amination/etherification dearomatizing spirocyclization. This transformation leads directly to the complete framework of the Leucetta alkaloids, spiroca

Full text of DOI:10.1021/acs.orglett.7b01898

Letter
pubs.acs.org/OrgLett
Tandem Oxidative Dearomatizing Spirocyclizations of Propargyl
Guanidines and Ureas
Ravi P. Singh, Jayanta Das, Muhammed Yousufuddin,† Delphine Gout, and Carl J. Lovely*
Department of Chemistry and Biochemistry, University of TexasArlingon, Arlington, Texas 76019-0065, United States
S
* Supporting Information
ABSTRACT: Treatment of propargyl ureas or guanidines with iodoso-
benzene diacetate results in an oxidative tandem amination/etherification
dearomatizing spirocyclization. This transformation leads directly to the
complete framework of the Leucetta alkaloids, spirocalcaridine A and B.
n a project directed toward the total synthesis1 of two
I
members of the Leucetta alkaloids,2 spirocalcaridine A (3) and
B (4),3 we have reported high-yielding approaches to the
spirocyclic system4 based on a Larock-type electrophile-induced
dearomatizing spirocyclization (i.e., Figure 1a, E = I)5 through
Figure 2. General approach to spirocyclic Leucetta alkaloids.
workers involving trapping of alkynes with phenoxonium ions
was especially encouraging (Figure 1b).12 The requisite substrate
12 was assembled via chemistry described by Looper13 and van
der Eycken14 through a Mannich-like reaction between aldehyde
6, allylic amine 7, and the copper acetylide derived from anisyl
acetylene 8 and copper bromide (Scheme 1). Deallylation with
Pd(PPh3)4 and N,N′-dimethylbarbituric acid (DMBA) provided
secondary amine 10 which upon treatment with the bis BOC-
protected isothiourea 11 and mercury oxide delivered the
protected guanidine 12. Fluoride-induced desilylation then
afforded the required phenol substrate 13 for oxidation. The
phenol was reacted with IBDA (iodosobenzene diacetate) to
initiate reaction via the formation of the phenoxonium ion. A
complex mixture of products was formed from which two
cyclohexadienones were isolated in poor yield (Scheme 1). It was
clear from the characterization data that they were indeed
tricyclic products. The 13C NMR spectra were particularly
Figure 1. Modes of dearomatizing spirocyclizations.
formation of bond b (Figure 2).6 Attempts to elaborate these
intermediates through annulation of the imidazole, resulting
from the formation of bond a (Figure 2), have not been
successful in our hands to date. However, the facility of the
dearomatizing spirocyclization7 to construct the BC rings
encouraged us to explore this chemistry further. Specifically,
we wished to establish whether there was a possibility of
configuring the system such that both the spirocyclization (bond
b formation) and the imidazole formation (bond a formation)
would occur in one synthetic operation. As indicated in Figure 2,
oxidation of either the phenol (phenoxonium, 5 site b)8 or
guanidine (nitrenium, 5 site a)9 could trigger the reaction with
the only (nominal) difference being the direction of the
sequence.10
Given the large number of examples of phenolic oxidations
(route b) reported in the literature,7b,c,11 we chose to evaluate
this approach first. In particular, chemistry by Canesi and co-
Received: June 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01898
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Organic Letters
Letter
Scheme 1. Preliminary Scouting Experiments and X-ray Structures of Compounds 14 (Methyl Groups on t-BOC Groups Removed
for Clarity) and 16
diagnostic in which signals consistent with the quaternary
spirocyclic carbon (δC = 45.7) and the conjugated ketone (δC =
185.5) were observed. Thus, on the basis of these data, the
structures were assigned tentatively as the initial cyclization
product 14 and a product 15 where olefin migration had
occurred. Subsequently, X-ray crystal structures were obtained
on both of the isolated compounds from this transformation. The
minor product 14 was shown to be the expected cyclization
product derived from a 5-endo-dig pathway, whereas the major
product 16 contained a vinylidene cyclobutane framework
arising from a 4-exo-dig pathway. It had been expected that the
five-membered ring would be formed preferentially, but on closer
analysis of the putative intermediates 18 and 19 (Scheme 2), the
formation of vinylic carbocation 18 would appear to be more
stabilized through a resonance interaction than the correspond-
ing cyclopentenyl cation 19.
delivered a single product in good yield; NMR data showed
clearly that dearomatization had taken place. However, it was not
immediately clear whether cyclization had occurred through the
urea nitrogen as desired for total synthesis applications or
through oxygen. Gratifyingly, the material was sufficiently
crystalline to obtain an X-ray crystal structure of the product
which clearly revealed that the reaction had occurred via oxygen
to produce the 2-iminooxazole 31. On the basis of this initial
result, optimization of the reaction was undertaken and is
reported in Table 1. Addition of base improved the yield and
conversion of the process (Table 1, entries 2−7), Cs2CO3 being
particularly effective (Table 1, entry 2), although KOH was
equally effective. Organic bases (entries 6 and 7), although
effective, did not lead to significant improvements. HFIP proved
to be the only solvent evaluated (entries 2, 8−10) in which the
reaction proceeded in delivering the spirocyclic product.
Interestingly, in TFE, a different product was observed,
specifically a dihydronaphthoxazole (Table 1, entry 8).15,16
Two other iodosobenzene oxidants were examined (entries 13
and 14) but these resulted in no improvement, and thus, the
conditions identified in entry 2 were used in subsequent
reactions.
Scheme 2. Mechanistic Overview of the Dearomatizing
Spirocyclization Reaction
With conditions identified for the tandem dearomatizing
spirocyclization, the substrate scope and limitations were
investigated. Accordingly, exposure of amine 22 to other
isocyanates, including aryl-, benzoyl- and benzyl-substituted
congeners, delivered the corresponding ureas 26−30. Oxidation
with IBDA provided the 2-iminooxazoles 32−36 in good overall
yields. Reaction with the chiral isocyanate (R = CHMePh)
delivered a 1:1 inseparable mixture of diastereomeric ureas 30
which underwent spirocyclization to produce the corresponding
oxazoles 36 also as an inseparable mixture (Scheme 3).
The success of this chemistry with ureas encouraged us to
evaluate the corresponding guanidines. These substrates 37−39
were simple to prepare by reaction of secondary amine 22 with
the corresponding isothiourea 11, 23, 24, and HgO (Scheme 3).
Exposure of the BOC-protected guanidine 37 to IBDA and 1.5
equiv of Cs2CO3 resulted in the smooth conversion of the
propargylguanidine into the previously synthesized spirocyclic
derivative 14 in excellent yield. Similarly, the CBZ- and TEOC-
protected guanidines 38 and 39 underwent dearomatizing
spirocyclization to deliver the corresponding cyclohexadienones
40 and 41 in good yields.
Given these initial observations with the phenoxonium
pathway, the corresponding system which would proceed via
the putative intermediacy of the nitrenium ion was evaluated.
Preparation of the substrate was accomplished in a largely
analogous fashion from the methoxy-substituted aldehyde 20
through a three-component coupling reaction (Scheme 3).
Deallylation of 21 provided the secondary amine 22 in good
yield. In an initial experiment, it was decided to prepare and
evaluate ureas as this would facilitate scouting experiments. Thus,
upon treatment of 22 with phenyl isocyanate the N-phenyl urea
25 was obtained. Subjection of 25 to oxidation with IBDA in
hexafluoroisopropanol (HFIP) (Scheme 3, Table 1, entry 1)
Mechanistically, we envision that the process begins by the
IBDA activation of the urea oxygen or the guanidine nitrogen
B
DOI: 10.1021/acs.orglett.7b01898
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Organic Letters
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Scheme 3. Oxidative Etherification and Oxidative Amination Dearomatization Spirocyclization
a
Table 1. Initial Reaction Screening Using Propargyl Urea 25
Scheme 4. Putative Mechanism of the Tandem Oxidative
Dearomatizing Spirocyclization
b
entry
oxidant
base
solvent
time (h)
yield (%)
1
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(TFA)2
PhI(OPiv)2
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
TFE
1.5
1.5
1.5
1.5
1.5
1.5
1.5
16
75
2
Cs2CO3
K2CO3
KOH
90 (60)
87
3
4
90
5
NaOH
Et3N
80
6
80
7
DBU
75
c
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
72 (54)
9
MeCN
CH2Cl2
16
NR
NR
85
10
11
12
13
14
16
d
HFIP
1.5
1.5
1.5
2
e
HFIP
74
HFIP
HFIP
78 (55)
72
a
Oxidant was added in one portion to a stirred solution of 25 (1
b
mmol/30 mL) and base (1.2 equiv) at room temperature. Yield of 31
based on integration data obtained by H NMR spectroscopy using
CH2Br2 as an internal standard; isolated yields in parentheses. The
dihydronaphthoxazole was isolated after 2.5 h on a 0.24 mmol scale. c
1
c
d
Scheme 5. Initial Experiments toward the Spirocalcaridines
(X-ray Structure of Rearrangement Product 47)
e
= 1 mmol/20 mL. c = 1 mmol/10 mL.
forming the electrophilic species 43 (Scheme 4).17 Intra-
molecular addition of the electrophilic heteroatom delivers the
vinylic cation 44, which is then perfectly poised for ipso addition
to the pendant electron-rich aromatic ring and dearomatization.
Demethylation, presumably by acetate anion, then delivers the
tricyclic product 45.
The guanidine products 14, 40, and 41 contain the complete
skeleton of the spirocalcaridines requiring migration of the C4/
C8 double bond to C4/C5, oxidation, and deprotection to
complete a synthesis of the natural products (14 → 46 → 3 or 4,
Scheme 5). An initial attempt to elaborate one of the guanidine
derivatives by deprotection of the carbonates was informative of
potential challenges to be faced in this approach to the
spirocalcaridines. Specifically, treatment of 14 with TFA resulted
in the removal of one of the BOC groups but was coupled with
rearrangement of the cyclohexadienone into the corresponding
hydroxydihydronaphthimidazole 47 (Scheme 5), the structure of
which was confirmed through X-ray crystallography.6a Intrigu-
ingly, this material upon standing in DMSO-d6 for a few days
underwent air oxidation to produce a mixture of the
corresponding naphthalene 48 and the dihydronaphthalene 47.
C
DOI: 10.1021/acs.orglett.7b01898
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Organic Letters
Letter
Sivappa, R.; Yousufuddin, M.; Lovely, C. J. J. Org. Chem. 2014, 79, 2481.
(m) Koswatta, P. B.; Kasiri, S.; Das, J. K.; Bhan, A.; Lima, H. M.; Garcia-
Barboza, B. J.; Khatibi, N. N.; Yousufuddin, M.; Mandal, S. S.; Lovely, C.
J. Bioorg. Med. Chem. 2017, 25, 1608.
(2) (a) Koswatta, P. B.; Lovely, C. J. Nat. Prod. Rep. 2011, 28, 511.
(b) Lovely, C. J. Strategies and Tactics in Organic Synthesis; Academic
Press, 2012; Vol. 8, pp 199−224. (c) Sullivan, J. D.; Giles, R. L.; Looper,
R. E. Curr. Bioact. Compd. 2009, 5, 39. (d) Roue, M.; Quevrain, E.;
Domart-Coulon, I.; Bourguet-Kondracki, M. L. Nat. Prod. Rep. 2012, 29,
739.
(3) Edrada, R. A.; Stessman, C. C.; Crews, P. J. Nat. Prod. 2003, 66, 939.
(4) (a) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50,
4068. (b) Sannigrahi, M. Tetrahedron 1999, 55, 9007. (c) Sun, W.; Li,
G.; Hong, L.; Wang, R. Org. Biomol. Chem. 2016, 14, 2164.
(5) (a) Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 12230.
(b) Zhang, X.; Sarkar, S.; Larock, R. C. J. Org. Chem. 2006, 71, 236.
(c) Tang, B.; Tang, D.; Tang, S.; Yu, Q.; Zhang, Y.; Liang, Y.; Zhong, P.;
Li, J. Org. Lett. 2008, 10, 1063. (d) Clarke, A. K.; James, M. J.; O’Brien,
P.; Taylor, R. J. K.; Unsworth, W. P. Angew. Chem., Int. Ed. 2016, 55,
13798. (e) James, M. J.; Cuthbertson, J. D.; O’Brien, P.; Taylor, R. J. K.;
Unsworth, W. P. Angew. Chem., Int. Ed. 2015, 54, 7640.
(6) (a) Koswatta, P. B.; Das, J.; Yousufuddin, M.; Lovely, C. J. Eur. J.
Org. Chem. 2015, 2015, 2603. (b) Singh, R. P.; Spears, J. A.; Dalipe, A.;
Yousufuddin, M.; Lovely, C. J. Tetrahedron Lett. 2016, 57, 3096.
(7) (a) Reddy, C. R.; Prajapti, S. K.; Warudikar, K.; Ranjan, R.; Rao, B.
B. Org. Biomol. Chem. 2017, 15, 3130. (b) Quideau, S.; Pouysegu, L.;
Deffieux, D. Synlett 2008, 2008, 467. (c) Ding, Q.; Ye, Y.; Fan, R.
Synthesis 2013, 45, 1.
While not definitive, these results are suggestive of a possible
biosynthetic link between the spirocalcaridines and the
kealiinines (e.g., kealiinine A (50), Scheme 5)1i,6a,13b,15,18 and
it is thought that the kealiinines serve as biosynthetic precursors
to kealiiquinone/2-deoxy-2-aminokealiiquinone.1k,18 Treatment
of this mixture with TFA led to removal of the BOC group and
complete oxidation to deliver naphthimidazole 49. The
deprotection−oxidation sequence could be performed more
efficiently through the reaction of 14 with TFA in air over a
longer period, which resulted in the direct formation of 49 in a
few hours (Scheme 5).
In summary, we have developed a tandem alkyne amination−
dearomatization strategy for the rapid construction of complex
spiro heterocyclic frameworks. These derivatives may serve as
precursors to a variety of natural products belonging to the
Leucetta family of alkaloids including the spirocalcaridines, the
kealiinines, and the kealiiquinones. Efforts toward these ends are
underway and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01898.
Experimental procedures and characterization data for all
new compounds (1H and 13C NMR) (PDF)
X-ray data for compound 14 (CIF)
X-ray data for compound 16 (CIF)
X-ray data for compound 31 (CIF)
X-ray data for compound 47 (CIF)
FID files (ZIP)
(8) Harned, A. M. Tetrahedron Lett. 2014, 55, 4681.
(9) Wardrop, D. J.; Bowen, E. G. Synthetic Applications of Nitrenium
Ions. In Nitrenes and Nitrenium Ions; Falvey, D. E., Gudmundsdottir, A.
D., Eds.; John Wiley and Sons, Inc., 2013; Chapter 10, pp 347−449.
(10) (a) Huang, J.; He, Y.; Wang, Y.-G.; Zhu, Q. Chem. - Eur. J. 2012,
18, 13964. (b) Saito, A.; Matsumoto, A.; Hanzawa, Y. Tetrahedron Lett.
2010, 51, 2247.
(11) (a) Pelter, A.; Ward, R. S. Tetrahedron 2001, 57, 273.
(b) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66,
2235. (c) Silva, L. F., Jr.; Olofsson, B. Nat. Prod. Rep. 2011, 28, 1722.
(12) Andrez, J.-C.; Giroux, M.-A.; Lucien, J.; Canesi, S. Org. Lett. 2010,
12, 4368.
(13) (a) Gainer, M. J.; Bennett, N. R.; Takahashi, Y.; Looper, R. E.
Angew. Chem., Int. Ed. 2011, 50, 684. (b) Gibbons, J. B.; Gligorich, K. M.;
Welm, B. E.; Looper, R. E. Org. Lett. 2012, 14, 4734. (c) Gibbons, J. B.;
Salvant, J. M.; Vaden, R. M.; Kwon, K.-H.; Welm, B. E.; Looper, R. E. J.
Org. Chem. 2015, 80, 10076.
(14) Ermolat’ev, D. S.; Bariwal, J. B.; Steenackers, H. P. L.; De
Keersmaecker, S. C. J.; Van der Eycken, E. V. Angew. Chem., Int. Ed.
2010, 49, 9465.
(15) Tian, G.; Fedoseev, P.; Van der Eycken, E. V. Chem. - Eur. J. 2017,
23, 5224. This paper appeared while this manuscript was in review.
(16) The dihydronaphthoxazole was isolated, which suggests that
either spirocyclization is disfavored in this solvent or spirocyclization
and rearrangement occur prior to demethylation.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lovely@uta.edu.
ORCID
Carl J. Lovely: 0000-0001-7012-2001
Present Address
†(M. Y.) Department of Chemistry, University of North Texas at
Dallas, Dallas, TX 75241.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported through the Robert A. Welch
Foundation (Y-1362) and instrument grants from the NSF
(CHE-0234811 and CHE-0840509).
REFERENCES
■
(1) (a) Koswatta, P. B.; Sivappa, R.; Dias, H. V. R.; Lovely, C. J. Org.
Lett. 2008, 10, 5055. (b) Bhandari, M. R.; Sivappa, R.; Lovely, C. J. Org.
Lett. 2009, 11, 1535. (c) Koswatta, P. B.; Lovely, C. J. Tetrahedron Lett.
2009, 50, 4998. (d) Koswatta, P. B.; Sivappa, R.; Dias, H. V. R.; Lovely,
C. J. Synthesis 2009, 2009, 2970. (e) Koswatta, P. B.; Lovely, C. J. Chem.
Commun. 2010, 46, 2148. (f) Koswatta, P. B.; Lovely, C. J. Tetrahedron
Lett. 2010, 51, 164. (g) Mukherjee, S.; Sivappa, R.; Yousufuddin, M.;
Lovely, C. J. Org. Lett. 2010, 12, 4940. (h) Lima, H. M.; Garcia-Barboza,
B. J.; Khatibi, N. N.; Lovely, C. J. Tetrahedron Lett. 2011, 52, 5725.
(i) Das, J.; Koswatta, P. B.; Yousufuddin, M.; Jones, J. D.; Lovely, C. J.
Org. Lett. 2012, 14, 6210. (j) Lima, H. M.; Sivappa, R.; Yousufuddin, M.;
Lovely, C. J. Org. Lett. 2012, 14, 2274. (k) Das, J.; Bhan, A.; Mandal, S.;
Lovely, C. J. Bioorg. Med. Chem. Lett. 2013, 23, 6183. (l) Lima, H. M.;
(17) The intermediacy of a discrete guanidine or urea nitrenium ion
cannot be ruled out.
(18) Hassan, W.; Edrada, R.; Ebel, R.; Wray, V.; Berg, A.; Van Soest, R.;
Wiryowidagdo, S.; Proksch, P. J. Nat. Prod. 2004, 67, 817.
D
DOI: 10.1021/acs.orglett.7b01898
Org. Lett. XXXX, XXX, XXX−XXX