Synthesis of resorcinol derived spironitronates

Article abstract of DOI:10.1021/ol0710257

Syntheses of several unique spironitronates are reported. The key transformation involves the first known example of an ipso oxidative cyclization of nitro functionality. Oxidation proceeds from both o- and p-phenols. Reductions of these compounds provide

Full text of DOI:10.1021/ol0710257

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3229-3232
Synthesis of Resorcinol Derived
Spironitronates
Maurice A. Marsini, Yaodong Huang, Ryan W. Van De Water, and
Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106-9510
pettus@chem.ucsb.edu
Received May 2, 2007
ABSTRACT
Syntheses of several unique spironitronates are reported. The key transformation involves the first known example of an ipso oxidative
cyclization of nitro functionality. Oxidation proceeds from both o- and p-phenols. Reductions of these compounds provide novel spiroisoxazoline
derivatives.
Natural products isolated from marine sponges come in a
variety of exotic forms. Secondary metabolites derived from
the oxidation of tyrosine, in particular, halogenated deriva-
tives, have a wide range of biological activity.1,2 The
biosynthesis of these compounds purportedly involves bro-
mination of tyrosine followed by oxidation of the amine to
an oxime and concludes by oxidative dearomatization to form
the spiroisoxazoline core.3 The latter scaffold is then further
processed by reduction and conversion of the ester moiety
into an amide (Figure 1). A number of syntheses of
spiroisoxazoline natural products have been reported; most
appear to resemble the reported biosynthesis.4
reaction proceeds by formation of a phenoxonium and
concomitant 5-exo-trig intramolecular nucleophilic attack of
the oxygen atom of the oxime to afford a spiroisoxazoline.
It occurs with a variety of substituents on the aromatic ring,
Hypervalent iodide reagents (diacetoxyiodo)benzene (PIDA)
and bis(trifluoroacetoxyiodo)benzene (PIFA) as well as other
chemical oxidants such as thallium(III) nitrate, manganese-
(III) acetate, and even electrochemical oxidations have all
been shown to mimic the postulated biosynthesis.4a-n The
(1) Berquist, P. R.; Wells, R. J. Chemotaxonomy of the Porifera: The
Development and Current Status of the Field. In Marine Natural Prod-
ucts: Chemical and Biological PerspectiVes; Scheuer, P. J., Ed.; Academic
Press: New York, 1993; Vol. 5, pp 1-50.
(2) Faulkner, D. J. Nat. Prod. Rep. 1998, 113 and previous reports in
this series.
(3) (a) Tymiak, A. A.; Rinehart, K. L., Jr. J. Am. Chem. Soc. 1981, 103,
6763. (b) De Rosa, M.; Minale, L.; Sodano, G. Comput. Biochem. Physiol.
1973, 45B, 883. (c) Carney, J. R.; Rinehart, K. L. J. Nat. Prod. 1995, 58,
971.
Figure 1. Biosynthesis of spiroisoxazoline derivatives.
10.1021/ol0710257 CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/24/2007

including halogen and methoxy substituents. Our interest was
sparked during studies with resorcinol derivatives (Scheme
1).5 When phenol 1 (0.05 M in CH3NO2) is subjected to
a spironitronate and as such deserved some additional
investigation.
We decided to probe the scope and generality of this
transformation as compared with the complementary oxime
oxidative cyclization. We began from the known bis-OBoc
benzaldehyde, 4, which undergoes addition of the sodium
salt of TIPS-protected nitroethanol (0.3 M in THF).8 The
intermediate product is reduced in situ with NaBH4. This
one-pot transformation proceeds by 1,4-reduction of an
o-quinone methide (o-QM) intermediate generated by an
anionic cascade to provide the phenol 5 in 49% yield
(Scheme 2).9 After failing to methylate the resulting phenol
Scheme 1. Unanticipated Spironitronate Formation
Scheme 2. General Synthesis of p-Quinol Spironitronates
PIFA, the expected lactone (Scheme 1, inset) is not observed.
Instead, the spironitronate 2, arising from nitro attack and
subsequent loss of a proton, is produced in 67% yield. In
addition, 13% of tricyclic lactone 3 is obtained displaying
1
four AB coupling patterns in the H NMR spectrum.
We speculate compound 3 arises from cyclization of the
amide carbonyl and after hydrolysis of the iminium inter-
mediate as expected (cf. Scheme 1, inset) undergoes an
intramolecular 1,4-addition to the vinylogous ester by an
oxygen atom belonging to the nitro group.6 The facile
addition of the electron-deficient nitro group to the phe-
noxonium as compared with the corresponding addition of
the supposedly more nucleophilic amide carbonyl was indeed
surprising. Subsequent studies have shown that placement
of a substituent between the oxygen atoms of the resorcinol
greatly facilitates cyclization of the oxygen atom of the amide
carbonyl.7 However, to the best of our knowledge, this is
the first example of an oxidative dearomatization affording
under a variety of conditions (AgOTf/MeI; DEAD/MeOH),
the necessary methylation of phenol 5 (1.4 M in Et2O) was
eventually accomplished with diazomethane to afford the
methyl ether 7 in an acceptable 55% yield. Deprotection of
the BOC residue in 7 (0.05 M in CH3NO2) with ZnBr2
affords the phenol 9 in 74% yield. This three-step sequence
was also carried out using methyl nitroacetate in place of
TIPS-protected nitroethanol and thereby provides the phenol
10 under similar conditions. A similar strategy of attachment
led to phenol 1, which prompted this initial study. Oxidative
dearomatization of 9 (0.05 M in CH3NO2) with PIFA
provides the p-quinol spironitronate 11 in 74% yield.
Similarly, oxidation of phenol 10 provides spironitronate 12
in 68% yield. The timing as to the loss of the nitro R-proton
remains unclear. With these results in hand, we set out to
probe the reactivity of these novel compounds with respect
to reduction and other functional group manipulations.
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Barbara, CA, 2003.
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15625. (b) Mejorado, L.; Hoarau, C.; Pettus, T. R. R. Org. Lett. 2004, 6,
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67, 6911. (b) Jones, R. M.; Van De Water, R. W.; Lindsey, C. C.; Hoarau,
C.; Ung, T.; Pettus, T. R. R. J. Org. Chem. 2001, 66, 3435. (c) Van De
Water, R. W.; Magdziak, D. J.; Chau, J. N.; Pettus, T. R. R. J. Am. Chem.
Soc. 2000, 122, 6502.
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Org. Lett., Vol. 9, No. 17, 2007

Attempts to reduce the spironitronate 11 were unsuccess-
ful. Exposure of 11 to metal catalysts and an H2 atmosphere
resulted in decomposition, presumably by single electron
transfer and rearomatization as is the case with cyclohexa-
dienone p-quinols.10 To circumvent this problem, 1,4-addition
of methanol to the enone moiety of 11 was examined
(Scheme 3). Treatment of 11 with catalytic sodium meth-
Scheme 4. Other Transformations of 11
Scheme 3. Stereoselective 1,4-Addition and Reduction of 11
addition of dimethyldioxirane (DMDO, 0.08 M in acetone)
to 11 cleanly affords the p-quinol 16 in >95% yield. Further
epoxidation of 16 (0.5 M in CH2Cl2) with m-CPBA at 0 °C
affords a single diastereomer of an epoxide of the vinylogous
ester. However, the decomposition of this product thwarted
rigorous identification. On the other hand, reduction of the
nitronate moiety of 11 with refluxing trimethylphosphite
(0.13 M) affords spiroisoxazoline 17 in quantitative yield.
Next, we set out to synthesize the corresponding o-quinol
spironitronates, which in principle enables access to spiro-
isoxazoline natural products. Boc-protection and subsequent
reduction of commercially available 2-hydroxy-4-methoxy-
benzaldehyde 18 affords the known benzyl alcohol 19 in 91%
yield over two steps (Scheme 5).13 Sodium tert-butoxide was
oxide (0.1 M in MeOH) at 0 °C affords a 5:1 mixture of
spironitronates 13 and 14 in a combined 68% yield. The
major diastereomer 13 reflects addition to the more congested
face of the enone 11. Monte Carlo conformational analysis
with Macromodel using MM3 parameters predicts a 0.5 kcal/
mol energy difference between diastereomers 13 and 14,
favoring the former isomer.11 Furthermore, after purification,
resubmission of the minor diastereomer 14, which arose from
addition to the least congested face of the cyclohexadienone
of the spironitronate 11, to the earlier conditions provides
the same 5:1 ratio of 13:14. With the cyclohexadienone
partially reduced, reduction of the spironitronate moiety was
reexamined. Hydrogenation of 13 (0.1 M in EtOH, 1 equiv
CHCl3) with platinum(II) oxide12 under an H2 atmosphere
affords the vinylogous amide 15 in 67% yield with 10:1 dr.
While the relative stereochemistry of the major diastereomer
could not be determined by NOE with absolute certainty, it
is likely that reduction occurs from the less congested Re
face of the spironitronate 13 as the Si face is blocked by the
vinyl methoxy residue. This result illustrates the steric and
electronic difference between the two faces of the nitronate
moiety and might suggest application of the reverse strat-
egy: use of a chiral R-carbon substituent to direct oxidative
dearomatization in a diastereoselective manner.
Scheme 5. General Synthesis of o-Quinol Spironitronates
Reductive rearomatization of 11 proceeds via single-
electron transfer with samarium diiodide (0.1 M in THF)
and affords the phenol 9 in 94% yield (Scheme 4). The
(10) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. ReV. 2004, 104,
1383.
(11) Since the nitro functionality is not tolerated in Macromodel, these
calculations were performed using the hemiaminals of 13 and 14.
(12) Denmark, S. E.; Schnute, M. E. J. Org. Chem. 1994, 59, 4576.
added to generate an o-QM intermediate, which is then
trapped by the anion of TIPS-protected nitroethanol to
(13) Lindsey, C. C.; Pettus, T. R. R. Tetrahedron Lett. 2006, 47, 201.
Org. Lett., Vol. 9, No. 17, 2007
3231

provide phenol 20 in 93% yield. Similarly, the addition of
methyl nitroacetate to the generated o-QM affords phenol
21 in 74% yield. Oxidative dearomatization of 20 (0.05 M
in CH2Cl2) with PIFA provides the TIPS-protected o-quinol
spironitronate 22 in 30% yield. Likewise, oxidation of 21
provides o-quinol spironitronate 23 in 35% yield. Reduction
of 23 with trimethylphosphite affords the desired spiro-
isoxazoline 20 in 95% yield. The lower yields for oxidation
as compared with the corresponding p-quinol derivatives
were disappointing. We speculate that the difference may
reflect the instability of the o-phenoxonium cation as
compared with the corresponding para cation. To further
probe the scope of this nitro cyclization with o-quinol
precursors, the dibromo analogues of 21 and 22 were
synthesized. Unfortunately, all attempts to cause formation
of the corresponding spironitronates from these materials
failed with a variety of oxidants. Instead of producing the
desired dibromospironitronates, small amounts of several
p-quinones and dihydrofuran products were isolated.
cyclization of the corresponding para derivatives, this
transformation provides access to spiroisoxazoline scaffolds
resembling natural products in short order. We speculate the
incorporation of a chiral ester or amide residue might enable
enantioselective access to these spironitronates as previously
seen for oxime substrates.14 Furthermore, nitronates are
known to be versatile partners in [3 + 2] cycloadditions and
therefore oxidative dearomatization may offer entry into a
variety of complex molecular architectures.15 Research into
this hypothesis is in progress and will be reported in due
course.
Acknowledgment. A substantial portion of this work was
performed in the period of 2001-2003 and can be found in
the thesis of R.W.V.D.W. We are grateful for past financial
support from the National Institutes of Health (NIH GM-
64831-06) for our oxidative dearomatization chemistry and
for past support by the National Science Foundation (NSF
CHE-9971211) for our o-quinone methide chemistry. We
also thank Daniel Haacke for technical assistance with
starting intermediates, as well as UCSB for current TA
support given the current funding climate.
In conclusion, the first synthesis of quinol spironitronates
has been illustrated and some of their reactivity examined.
Oxidative dearomatization of nitro phenols proceeds for both
o-quinol and p-quinol precursors. The p-quinol derivatives
are versatile intermediates that undergo a variety of high
yielding and stereoselective transformations. While the yields
for ortho cyclization are lower than desired compared to
Supporting Information Available: Full experimental
procedures for each reaction sequence, as well as select
spectroscopic data (1H NMR, 13C NMR, FT-IR, MS) for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Reference 4h.
(15) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137.
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