Photoassisted access to enantiopure conformationally locked ribofuranosylamines spiro-linked to oxazolidino-diketopiperazines

Article abstract of DOI:10.1021/co3001296

N-Furoylated l-threonine-, serine-, or cysteine-based aminoacetals are coupled with o-aminoketones or aldehydes to offer rapid access to diverse enantiopure polyheterocycles possessing conformationally locked aminoglycoside-containing molecular scaffolds.

Full text of DOI:10.1021/co3001296

Research Article
pubs.acs.org/acscombsci
Photoassisted Access to Enantiopure Conformationally Locked
Ribofuranosylamines Spiro-Linked to Oxazolidino-Diketopiperazines.
Nitin S. Nandurkar, N. N. Bhuvan Kumar, Olga A. Mukhina, and Andrei G. Kutateladze*
Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, United States
S
* Supporting Information
ABSTRACT: N-Furoylated L-threonine-, serine-, or cysteine-based
aminoacetals are coupled with o-aminoketones or aldehydes to offer
rapid access to diverse enantiopure polyheterocycles possessing
conformationally locked aminoglycoside-containing molecular scaf-
folds. The key step involves photogeneration of azaxylylenes which
undergo [4 + 4] or [4 + 2] cycloadditions to the tethered furoyl
pendants.
KEYWORDS: conformationally locked ribofuranosylamines, enantiopure polyheterocycles, molecular scaffolds,
photogeneration of azaxylylenes, [4 + 2] and [4 + 4] photocycloadditions
Earlier we found that short-lived azaxylylenes, generated via
the excited state intramolecular proton transfer (ESIPT6) in
aromatic o-aminoketones and aldehydes, undergo intramolec-
ular cycloaddition reactions with the appropriately tethered
unsaturated pendants, including alkenes, thiophenes, and
furans.7
In this paper we report on a new photoassisted synthesis of
enantiopure conformationally locked ribofuranosylamines
possessing a spiro-diketopiperazine moiety which are derived
from a straightforward modular preassembly of N-furoylated L-
threonine, serine, or cysteine-based aminoacetals 1a−f8 with
photoactive o-aminoketones and aldehydes.
INTRODUCTION
■
Conformational flexibility of potential therapeutic agents has
always been one of the critical properties in drug design and
discovery. The relationship between the promiscuity of binding
due to a large number of rotatable bonds and the associated
entropic penalty attenuating the relevant KD’s is generally well
understood and taken into consideration when modeling
molecular recognition events.1 Even the properties such as
oral bioavailability of drug candidates, which normally are not
associated with conformational flexibility, in fact correlate
strongly with the number of rotatable bonds.2 Smythe and
coauthors of a review3 prominently referenced on the NCI’s
Screening Services Web site Selection guidelines for small
molecule structures for screening4 believe that “bicyclic and
tricyclic scaffolds are ... an ideal size for library synthesis”
because “they provide molecular rigidity allowing less entropic
energy to be lost upon binding and also provide better
bioavailability”.
Thus, synthetic methods to access new relatively rigid and
diverse poly(hetero)cyclic core scaffolds decorated with
biorelevant functional groups are always sought after. We
have been developing5 such methods for diversity-oriented
synthesis based on a synthetic paradigm which involves
modular synthesis of photochemical precursors and their
subsequent photoassisted transformations, for example, intra-
molecular [4 + 4] or [4 + 2] cycloadditions. Modular assembly
of photoprecursors renders this methodology suitable for
combinatorial chemistry, while the photochemical step allows
for a dramatic increase in molecular complexity, generally not
available for chemical transformations in the ground state.
RESULTS AND DISCUSSION
■
As shown in Figure 1 such preassembly of the furan-bearing
azadienophiles requires three components, the β−OH or SH
amino acid, an aldehyde, and furoyl chloride, which in the
combinatorial context constitute three diversity inputs. The
acetal formation is stereospecific. X-ray structure of oxaproline
1c, based on threonine and pivalic aldehyde, reveals that the
tert-butyl group is cis to the carboxylate (and trans to the
methyl).
These furan-containing azadienophile modules, outfitted
with the carboxylate handle, are readily coupled with the
photoactive o-aminoketone pendants via the well-developed
amide bond-forming chemistry as shown in Figure 2.
Received: October 27, 2012
Revised: November 6, 2012
Published: November 19, 2012
© 2012 American Chemical Society
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Research Article
Figure 1. Preassembly of the azadienophile furoyl pendant with oxa-
or thioproline tether from three components (i) β-XH aminoacid, (ii)
aldehyde R′CHO, and (iii) 2-furoyl chloride.
Figure 3. Stereochemistry of the OH group in photoproducts 5−11
depends on whether the initial carbonyl is rotatable.
The benzaldehyde-based precursors yielded [4 + 4] cyclo-
adducts as major products, whereas the indanone- and
tetralone-based precursors 3−4 predominantly gave the [4 +
2] products, with the exception of the tetralone-based
thiaproline 4f which did not require addition of HMPA and
gave 11:1 ratio of [4 + 4] to [4 + 2] products. These results
show that the variations in the structure of the starting materials
and the presence of HMPA additive affect the regiochemistry,
that is, the [4 + 4] to [4 + 2] ratio, of this photoinduced
transformation.
One aspect of the stereochemical outcome is the stereo-
chemistry of the OH group, which can be either syn or anti to
dihydrofuran’s oxygen. In the presence of HMPA the
benzaldehyde-based anti-[4 + 4] cycloadducts 5 were formed
with high selectivitythe syn stereoisomers were not detected
at all in the NMR of reaction mixture. The minor [4 + 2]
dihydroquinolinoles 6 (anti) and 7 (syn) were both observed in
the reaction, albeit in low amounts, 5−10%. In contrast,
photoprecursors 3 and 4 based on cyclic ketones produced only
anti-[4 + 2] and syn-[4 + 4] adducts. The OH-epimers, syn-[4 +
2] or anti-[4 + 4] were not observed.
Our rationale is that in all cases the endo transition state is
involved, with the furan’s π-system hovering over the aromatic
moiety of azaxylylene (biased by the secondary π-overlap).
Figure 3 illustrates that the resulting stereochemistry of the
hydroxy group thus depends on whether it is “out” or “in” in the
photogenerated azaxylylene. The addition of HMPA is
expected to increase the lifetime of azaxylylenes because of
hydrogen bonding,9 preventing wasteful back proton transfer.
In azaxylylenes derived from benzaldehydes, the bulky HMPA
ensures the out configuration of the rotatable OH, which yields
the anti-[4 + 4] adducts. Such rotation is not possible in
indanone or tetralone and precursors 3,4 yield only the syn-[4 +
4] products.
Figure 2. Coupling of furoyl azadienophiles with the photoactive
aminoketone moiety.
o-Aminobenzaldehyde was protected as a cyclic acetal before
coupling.
Table 1 gives the matrix of photoprecursors which were
synthesized to probe the generality of photoinduced cyclization
reactions of azaxylylenes tethered to the furan moiety via a
substituted thia- or oxaproline linker, Table 2.
Table 1. Matrix of Photoprecursors Assembled in This Study
with o-Aminobenzaldehyde and o-Amino Ketones,
Indanone, and Tetralone
The second stereochemical aspect of these reactions is the
folding of the chiral oxa/thiaproline tether which, depending on
the furoyl approach from “above” or from “under”, can produce
two diastereomeric cores. We classify the two by their epimeric
aminoacetal carbons. In most of the cases studied this aminal
carbon has the S configuration for the [4 + 4] and R
configuration for the [4 + 2] products, as shown in Table 2.
However, in the case of indanones 3 the diastereomers
possessing the S configuration of the aminal carbon in [4 + 2]
cycloadducts 8a and 8b were the major products. In fact,
diastereomer 8b with an “inverted” tether fold was the sole
product isolated from 3b. Its structure was proven by X-ray
crystallographic analysis, and the structures of 8a and 9a were
inferred based on the analysis of their NMR spectra relative to
8b.
serine (XO,
R′H)
threonine (XO,
R′Me)
cysteine (XS,
R′H)
benzaldehyde
2a, RH
2d, RPh
3a, RH
4a, RH
2b, RH
2c, Rt-Bu
3b, RH
4b, RH
2e, Rt-Bu
indanone
tetralone
4f, RH
Precursors 2−4 were all found to be photoactive. Upon
irradiation with an in-house built UV LED illuminator (five 365
nm Nichia LEDs @ 250mW each) in acetonitrile in the
presence of HMPA, they underwent photoinduced cyclo-
addition yielding enantiopure polyheterocycles 5−11.
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Table 2. Enantiopure [4 + 4] and [4 + 2] Products Resulting from the Intramolecular Cycloadditions of Photogenerated
a
Azaxylylenes
a
b
c
Isolated yields, after column chromatography. The minor syn-[4 + 2] was detected in the reaction mixture but not isolated. The major product in
the reaction mixture (>80% by NMR), mostly degraded during chromatographic purification, although enough was collected to crystallize and obtain
d
e
X-ray structure. Stereoisomers are tentatively assigned by NMR. Observed as a minor product in the reaction mixture, not isolated.
Figure 4. exo-cis-Dihydroxylation of double bonds in 5c and 5b; shown at left is the ORTEP drawing of X-ray structure of 5c illustrating the exo
approach.
The [4 + 4] cycloadducts possess a 2,5-dihydrofuran moiety,
which lends itself to dihydroxylation from the exo-face.
Inspection of the X-ray structure of the benzaldehyde-based
anti-[4 + 4] cycloadduct 5c indicates that the exo-approach is
less sterically hindered. We proceeded to dihydroxylate it using
OsO4 and N-methylmorpholine oxide (NMO) as shown in
Figure 4.
Dihydroxylation was carried out at ambient temperature in
wet 1:1 t-butanol/acetone and required extended time (48 h)
for completion. Under these conditions dihydrofuran 5b
undergoes further oxidation of its benzylic hydroxy group to
yield ketone 13. In both cases the reaction yielded a single
stereoisomer for which we assigned the exo-configuration of the
two hydroxy groups based on their NMR spectra. The
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3401. (c) Valiulin, R. A.; Kutateladze, A. G. First Example of
Intramolecular [2π+2π] Alkene-Arene Photocyclization in the
Chromone Series and its Synthetic Utility. Tetrahedron Lett. 2010,
51, 3803−3806. (d) Valiulin, R. A.; Kutateladze, A. G. Harvesting the
experimental data were augmented with density functional
theory (DFT) NMR calculations: the Fermi contact terms were
computed and scaled by 0.9155 as described by Bally and
Rablen,10 (see Supporting Information).
The characteristic spin−spin coupling constant between the
bridgehead proton and the adjacent CH−OH of the newly
introduced exo-hydroxy group is calculated to be 0.3 Hz in 12
(Jexp < 0.5 Hz). For the endo-isomer (not observed) this
constant is predicted to be much larger, 6.7 Hz. The same
criterion is used for the stereochemical assignment of ketone
13, where the calculated bridgehead to CH−OH coupling
follows similar trend (0.4 Hz for the bridgehead proton’s
coupling with CH-exo-OH, and much larger, 8.0 Hz for the
CH-endo-OH).
̀
Strain Installed by a Paterno-Buchi Step in a Synthetically Useful Way:
̈
High Yielding Photo-Protolytic Oxametathesis in Polycyclic Systems.
Org. Lett. 2009, 11, 3886−3889.
(6) See Schmidtke, S.; Underwood, D. F.; Blank, D. A. Probing
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Phys. Chem. A 2005, 109, 7033−7045 , and references therein.
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Polyheterocycles with Benzoazocine and Hydroquinoline Cores via
Intramolecular Cycloadditions of Photogenerated Azaxylylenes. Angew.
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(8) Aminoacetals 1a-e were synthesized using a modified procedure
from: Conti, S.; Cossu, S.; Giacomelli, G.; Falorni, M. Chiral ligands
containing heteroatoms:13. Optically active 4-(2′-pyridyl)-1,3-oxazo-
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(9) By analogy to the reported effect of HMPA on lifetimes of all-
carbon xylylenes: Haag, R.; Wirz, J.; Wagner, P. J. The Photo-
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Chim. Acta 1977, 60, 2595−2607.
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cules. J. Org. Chem. 2011, 76, 4818−4830.
CONCLUSION
■
In conclusion, azaxylylenes photogenerated from modular
photoprecursors 2−4 undergo intramolecular [4 + 4] or [4 +
2] cycloadditions with considerable selectivity, both in the
folding of the chiral tether (to produce a single stereoisomer of
the polyheterocyclic core) and in the diastereoselectivity of the
resulting benzylic alcohol. The [4 + 4] photoadducts,
possessing benzoazacane core, can be further cis-dihydroxylated
with OsO4/NMO to give novel enantiopure conformationally
locked ribofuranosylamines spiro-connected to diketopiper-
azines.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, NMR spectra, and computational
details (76 pages). This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Phone: 1-303-871-2995. Fax: 1-303-871-2254. E-mail:
akutatel@du.edu.
■
Funding
Support of this research by the NIH (GM-093930) is gratefully
acknowledged.
Notes
The authors declare no competing financial interest.
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