Convergent One-Pot Oxidative [n + 1] Approaches to Spiroacetal Synthesis

Article abstract of DOI:10.1021/acs.orglett.5b01736

Two one-pot oxidative annulative approaches to spiroacetal synthesis are described. One approach uses a Lewis acid mediated Ferrier reaction in the fragment-coupling stage followed by DDQ-promoted oxidative carbon-hydrogen bond cleavage and cyclization. An alternative approach employs a Heck reaction for fragment coupling followed by DDQ-mediated enone formation and cyclization. These strategies provide convergent routes to common subunits in natural products, medicinal agents, and chemical libraries under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.5b01736

Letter
pubs.acs.org/OrgLett
Convergent One-Pot Oxidative [n + 1] Approaches to Spiroacetal
Synthesis
GuangRong Peh and Paul E. Floreancig*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: Two one-pot oxidative annulative approaches to
spiroacetal synthesis are described. One approach uses a Lewis acid
mediated Ferrier reaction in the fragment-coupling stage followed by
DDQ-promoted oxidative carbon−hydrogen bond cleavage and
cyclization. An alternative approach employs a Heck reaction for
fragment coupling followed by DDQ-mediated enone formation and
cyclization. These strategies provide convergent routes to common
subunits in natural products, medicinal agents, and chemical libraries
under mild reaction conditions.
piroacetals are integral components in numerous biologically
active natural products of marine origin1 as represented by
Alder reactions for fragment coupling (Scheme 1).10 The
intermediate silyloxy dihydropyrans are excellent substrates for
S
alotaketal A (1, Figure 1),2 a potent activator of the cAMP cell-
Scheme 1. Convergent, Oxidative Approaches to Spiroacetals
Figure 1. Representative biologically active spiroacetals.
signaling pathway. Spiroacetal subunits are also present in non-
natural biologically active compounds such as the selective
sodium glucose cotransporter 2 inhibitor toflogliflozin (2),3
which has recently been approved for the treatment of type 2
diabetes. The structural rigidity and capacity to orient functional
groups in defined spatial arrangements has resulted in
spiroacetals serving as scaffolds for chemical libraries4 that have
delivered hits for B-cell chronic lymphocytic leukemia treat-
ment,5 apoptosis induction,6 and microtubule disruption.7
Protocols to prepare spiroacetals generally proceed through
the formation of a diol that contains a ketone, or a suitable
surrogate, followed by a cyclization step.8 These routes have
proven to be remarkably versatile for complex molecule
construction. One-pot, convergent approaches to spiroacetal
synthesis, however, would mitigate functional and protecting
group manipulations, thereby increasing step economy9 in the
formation of these structures. We have been exploring
convergent, one-pot approaches to spiroacetal synthesis through
telescoping fragment-coupling processes with oxidative carbon−
hydrogen cleavage. The oxidations generate electrophiles that
cyclize with appended alcohols. We recently reported the
realization of this approach through the use of hetero-Diels−
DDQ-mediated carbon−hydrogen bond cleavage to yield enone
substrates that cyclize under acidic conditions. This manuscript
describes two new formal [n + 1], one-pot oxidative annulation
approaches to form spiroacetals from dihydropyrans. These
processes utilize Ferrier11 and Heck12 reactions in the fragment-
coupling phase. The intermediate allylic ethers that form through
these processes are excellent substrates for oxidative carbon−
hydrogen bond cleavage,13 leading to the cyclization phase that
delivers the desired targets.14 The mild reaction conditions, wide
Received: June 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01736
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Organic Letters
Letter
a b
,
substrate scope, and significant increases in molecular complexity
make these processes extremely attractive for synthesizing these
important structures.
Scheme 3. Annulation Scope
The development of the Ferrier reaction-based annulation
protocol15 is shown in Scheme 2. Allylsilane 3, prepared through
Scheme 2. Ferrier Reaction-Based Approach to Oxidative
Annulation
allylic lithiation of the corresponding alkenol followed by
trapping with Me3SiCl,16 reacts stereoselectively with dihydro-
pyran 4, readily accessed through a hetero-Diels−Alder reaction
between Danishefsky’s diene17 and nonanal followed by a Luche
reduction,18 in the presence of TMSOTf (2 mol %)19 whereby
stereocontrol is dictated by the stereoelectronically favored axial
approach to the intermediate oxocarbenium ion (see the
Supporting Information for structure determination).20 The
resulting allylic ether 5, although containing the unsaturation and
the cation-stabilizing group that we have shown to be essential
for DDQ-mediated carbon−hydrogen bond cleavage,21 proved
to be inert to oxidation. Cleaving the silyl ether with a minimal
amount of aqueous NaHCO3 to yield alcohol 6 followed by the
addition of molecular sieves and DDQ, however, provided
spirocycle 7 in 61% yield as a single stereoisomer for the one-pot
procedure. The stereochemical outcome is consistent with
kinetic control, through addition into the oxocarbenium ion, and
thermodynamic control due to the anomerically favorable
orientation of the spiroacetal. This example illustrates a
convergent approach that employs mild reaction conditions to
generate spiroacetals from readily accessible precursors. The
smooth reactivity of alcohol 6 in contrast to the lack of reactivity
of silyl ether 5 also provides evidence that the DDQ-mediated
carbon−hydrogen bond cleavage requires a rapid and
thermodynamically favorable termination step for starting
material to be consumed, indicating that the oxidation is
reversible.
The scope of the process is illustrated in Scheme 3, where the
nucleophilic and dihydropyran building blocks are shown in
addition to the spiroacetal products. Enantiomerically enriched
dihydropyrans were accessed by using Jacobsen’s protocol22 for
the cycloaddition step, and allylsilanes were prepared through
lithiation/silylation or through the Bunnelle process23 on the
corresponding esters.24 These examples show that dihydropyr-
ans containing tertiary allylic alcohols, prepared through the
addition of the appropriate organometallic reagent into the
hetero-Diels−Alder reaction product and used as inconsequen-
tial mixtures of diastereomers (major diastereomer shown), are
excellent substrates for the procedure. Substrate 16, in which the
tertiary alcohol contains a benzyloxymethyl group, reacts
somewhat less efficiently than substrate 17, in which the tertiary
alcohol contains a methyl group. This can be attributed to the
benzyloxy group’s inductive destabilization of the intermediate
oxocarbenium ion in the oxidative cyclization step. However, the
increased functional group content in the product can be useful
a
Reactions were conducted at rt in accord with Scheme 2 unless
b
c
otherwise noted. R″ = n-C8H17 unless otherwise noted. Cyclization
proceeded at 0 °C. Cyclization was complete within 15 min.
d
in the synthesis of compounds such as 1. This inductive
destabilization is not a significant impediment in the cyclization
when the benzyloxymethyl group is at the 6-position of the
dihydropyran, making compounds with higher functional group
content at that site, such as 23, accessible. Dihydropyrans that
contain a substituent at the 5-position, as required for the
synthesis of 1, could undergo cyclization more slowly than
substrates that are substituted at the 6-position due to the
presence of allylic-1,2 strain25 in the oxocarbenium ion
intermediate. However, spirocycle 26 was accessed in acceptable
yield through the union of 3 and 19. The stereochemical
outcome of this reaction was dictated by allylic strain, with the
benzyl group occupying an axial orientation in the product. The
formation of a minor diastereomer indicates that substituents at
the 5-position of the dihydropyran exert a slightly lower influence
on the stereochemical outcome of the reactions than substituents
at the 6-position.
Allylsilanes that contain secondary alcohols are suitable
nucleophiles for these transformations, as illustrated by the
formation of 24, 25, 33, and 34. This indicates that the method
B
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will be useful for the union of complex fragments for the
construction of functionally dense spiroacetals. Spirocycle 24
was isolated as a 6:1 mixture of diastereomers as a result of
allylsilane 8 being prepared in 74% ee. The formation of the
minor product illustrates that the spirocyclization is applicable to
the preparation of compounds that contain an axially oriented
substituent. Tetrahydrofurans and oxepanes can be fused to
tetrahydropyrans as shown in the preparation of 27 and 28. The
formation of 27 is remarkable because the cyclization occurs in
preference to allylic alcohol oxidation.26 The construction of 28
and 29 shows that dihydropyrans containing tertiary benzylic
alcohols are excellent substrates, illustrating the promise of this
protocol to deliver structurally diverse products. Enolsilanes are
competent nucleophiles that yield ketone-containing products,
as shown in the formation of 29, despite the enhanced inductive
effect from the intermediate ketone in comparison to the alkene
from previous examples. Dihydrothiopyrans can be used to
generate sulfur-containing spirocycles, as shown by the
formation of 30. This result is consistent with our previous
studies27 showing that sulfides react with comparable efficiency
to ethers. Various substitution patterns are tolerated in the
nucleophilic fragment, shown by the formation of 31 with a
branch at the allylic position, 32 with a tertiary ether, and 33 with
a functionalized secondary ether. The alkynyl group in 34 can
serve as an oxidatively stable precursor to alkenyl-substituted
spirocycles such as 1.
rich alkene oxidation29 suggested that the metals from the Heck
coupling inhibit this step. Therefore, the reaction mixture was
filtered through a short pad of silica gel and the filtrate was
subjected to DDQ-mediated oxidation and acid-promoted
cyclization. This process increased the oxidation rate and
improved the reaction yield to 62%.
Other examples of this transformation are shown in Table 1.
Rhamnal derivative 40 (Table 1, entry 1) reacts with
Table 1. Further Examples of Telescoped Heck Coupling and
Oxidative Cyclization
The scope of this process can be expanded through the use of a
broader range of nucleophiles and by retention of oxygenation
during the fragment-coupling stage. These objectives can be
achieved through the use of a Heck reaction to join the subunits.
Telescoping a Heck reaction with oxidative cyclization required
the identification of coupling conditions that proceed in 1,2-
dichloroethane, the optimal solvent for the oxidation step. As
shown in Scheme 4, aryl iodide 35 reacts with glucal derivative 36
a
See Supporting Information for details regarding substrate synthesis,
b
reaction conditions, and product characterization. Yields refer to
isolated, purified materials of the one-pot protocol. Parenthetical
c
yields refer to reactions that were filtered following the Heck reaction.
Parenthetical yield refers to a protocol in which the product from the
d
Scheme 4. Heck Reaction-Based Spirocycle Formation
Heck reaction was purified by flash chromatography.
approximately the same efficiency as 36 to yield 41. Compounds
such as 42 (Table 1, entry 2) with alkyl, rather than silyloxy,
groups at the 5-position are also suitable substrates. Iodoarenes
that contain secondary silyl ethers, such as 44 (Table 1, entry 3),
react smoothly to form spirocycles. The capacity to use
secondary alcohols as nucleophiles significantly expands the
complexity of accessible structures through this route.
Dihydroisobenzofuran structures of the type that are present in
2 can be prepared by shortening the tether between the arene and
the silyl ether. Coupling 36 with iodoarene 46 provided
spirocycle 47, albeit in a modest 32% yield (Table 1, entry 4).
A significant quantity of the dihydropyran starting material was
recovered, indicating that the Heck coupling was not efficient.
When the reactions were conducted separately the Heck reaction
proceeded in 63% yield and the oxidative cyclization proceeded
in 75% yield for an overall yield of 47%. Benzylic alcohol
oxidation was not observed to be competitive with oxidative
cyclization. Despite the modest yield of the transformation, the
facile access to the substrates and the potential for the products
to act as glucose cotransporter 2 inhibitors make the approach
very attractive for developing structure−activity relationships.
Short, efficient syntheses of large, functional group-rich
structures from simple materials require reactions that lead to
significant increases in molecular complexity. Whitlock defines
molecular complexity by the number of rings, stereocenters,
under Ye’s conditions28 to yield intermediate enolsilane 37.
These conditions proved to be optimal for this transformation
though they were originally developed for oxidative Heck
reactions and our reactions are not oxidative processes. The
Pd(0) that is required to initiate the coupling most likely forms
through glycal oxidation. The stereochemical outcome of the
Heck reaction was determined through independent synthesis
(see the Supporting Information) and is consistent with the
classical mechanism of syn-carbopalladation followed by syn-β-
hydride elimination.12
Adding DDQ provided enone 38, which was converted to
spirocycle 39 by the addition of p-TsOH. This transformation
proceeded in 55% yield for the one-pot protocol. The sluggish
rate of the oxidation in comparison to earlier studies on electron-
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(9) For one-pot spiroannulation processes, see: (a) Marko, I. E.;
́
Mekhalfia, A.; Bayston, D. J.; Adams, H. J. Org. Chem. 1992, 57, 2211.
(b) Siau, W.-Y.; Bode, J. W. J. Am. Chem. Soc. 2014, 136, 17726.
(10) Han, X.; Floreancig, P. E. Angew. Chem., Int. Ed. 2014, 53, 11075.
unsaturations, and heteroatoms in a molecule, and by size, as
defined by bond number or molecular weight.30 Therefore,
bimolecular annulation reactions are inherently beneficial
processes for increasing molecular complexity and, therefore,
expediting complex molecule synthesis. We have described
telescoped [n + 1]-annulation processes that couple Ferrier or
Heck fragment-coupling reactions with oxidative carbon−
hydrogen bond cleavage to deliver spiroacetals. The precursors
for these reactions are readily prepared, and the experimental
protocols are facile with no exceptional efforts being required to
eliminate oxygen or water. These factors, coupled with the broad
scope, abundant options for product functionalization, and wide
range of biological activities that spiroacetals exhibit, make this
based approach highly attractive for numerous applications.
(11) For a recent review, see: Gom
́ ́
ez, A. M.; Lobo, F.; Uriel, C.; Lopez,
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́
a recently reported unique approach, see: Donohoe, T. J.; Lipinski, R. M.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectral data for all new compounds,
and synthetic schemes for all substrates. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01736.
■
Angew. Chem., Int. Ed. 2013, 52, 2491.
S
(15) The Brimble group recently reported a variant on this protocol.
See: Hubert, J. G.; Furkert, D. P.; Brimble, M. A. J. Org. Chem. 2015, 80,
2715.
(16) Carlson, R. M. Tetrahedron Lett. 1978, 19, 111.
(17) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807.
(18) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
(19) Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M. Tetrahedron
Lett. 1994, 35, 5673.
AUTHOR INFORMATION
Corresponding Author
■
(20) Danishefsky, S.; Kerwin, J. F., Jr. J. Org. Chem. 1982, 47, 3803.
(21) For a mechanistic analysis of this type of reaction, see: Jung, H. H.;
Floreancig, P. E. Tetrahedron 2009, 65, 10830.
*E-mail: florean@pitt.edu.
Notes
(22) (a) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998,
63, 403. (b) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 1999, 38, 2398.
̊
The authors declare no competing financial interest.
(23) Narayanan, B. A.; Bunnelle, W. H. Tetrahedron Lett. 1987, 28,
6261.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (P50-GM067082)
and the National Science Foundation (CHE-1151979) for
generous support of this work.
(24) Please see the Supporting Information for the preparation of the
subunits and detailed procedures for the spiroannulation reactions.
(25) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(26) Peng, K.; Chen, F.; She, X.; Yang, C.; Cui, Y.; Pan, X. Tetrahedron
Lett. 2005, 46, 1217.
(27) Cui, Y.; Floreancig, P. E. Org. Lett. 2012, 14, 1720.
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(30) Whitlock, H. W. J. Org. Chem. 1998, 63, 7982.
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DOI: 10.1021/acs.orglett.5b01736
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