Structurally and stereochemically diverse tetrahydropyran synthesis through oxidative C-H bond activation

Article abstract of DOI:10.1002/anie.201000033

Simple as pyran: Vinylsilane-substituted tetrahydropyrans, readily accessed through the oxidative C-H bond functionalization of silylallylic or propargylic ethers (see scheme; DDQ = 2,3-dichloro5,6-dicyano-l,4-benzoquinone), are versatile substrates for a wide range of functional group interconversions and stereocontrolled additions. These processes have applications in convergent target- or diversity-oriented synthesis strategies. (Chemical equation presented)

Full text of DOI:10.1002/anie.201000033

Angewandte
Chemie
DOI: 10.1002/anie.201000033
À
C H Activation
Structurally and Stereochemically Diverse Tetrahydropyran Synthesis
À
through Oxidative C H Bond Activation**
Lei Liu and Paul E. Floreancig*
Dedicated to Professor Paul Grieco on the occasion of his 65th birthday
Tetrahydropyrans are core units within a multitude of
biologically active natural products,[1] and methods to prepare
À
these structures, which utilize C H bond functionalization as
À
a prelude to C C bond-formation are desirable. This
approach is both step[2] and atom[3] economical, because the
substrate preparation and reactive intermediate generation
Scheme 1. Vinylsilane classes.
Table 1: Vinylsilane scope.[a]
À
employ unreactive C H bonds, rather than conventional
Entry Substrate
Product
t [h] Yield
leaving groups. We have shown that heterocycles can be
formed with high levels of diastereocontrol from benzylic and
allylic ethers through the DDQ-mediated (2,3-dichloro-5,6-
dicyano-1,4-benzoquinone) oxocarbenium ion formation, and
subsequent intramolecular nucleophilic addition.[4] This
method is highly complementary to Prins-based methods in
the preparation of tetrahydropyrans,[5] and has been validated
through its application to natural product synthesis.[6] Addi-
tional strategic benefits of this approach include the tolerance
of acid labile functional groups towards oxidative condi-
tions,[7] the application of facile etherification reactions to
form stable linkages in segment coupling reactions, and the
access to versatile unsaturated products. We have shown that
this unsaturation provides a route towards a range of
structurally and stereochemically diverse tetrahydropyrans
through post-cyclization manipulations. Vinylsilane- and
alkyne-containing products serve as useful moieties for
application in target- and diversity-oriented synthesis.
[%][b]
1
1
2
3
2
4
18
17
73
94
3
5
4
6
6
82
Vinylsilanes are outstanding precursors for functionally
and stereochemically diverse structures because of their
ability to engage in numerous transformations,[8] and their
well-defined[9] conformational preferences. The cyclization
substrates can be prepared by etherification reactions of the
corresponding silylallylic alcohols.[10] This approach max-
imizes convergency by introducing the silyl group prior to the
fragment coupling, and is therefore applicable in efficient
natural product and other target-oriented syntheses. The class
of silylated ether substrates that were prepared for this study
are depicted in Scheme 1.
7
8
24
8
69[c]
5
9
10
86
6
11
12
18
36
82
–
7
n.r.
The results of the oxidative cyclization reactions for the
silylallylic ethers are shown in Table 1. Both Z- and E-3-
13
[a] Representative procedure: DDQ (4 equiv) was added to a solution
(0.1m) of the substrate, LiClO4 (0.2 equiv), and 2,6-dichloropyridine
(2 equiv) in 1,2-dichloroethane. The reaction mixture was stirred at 458C.
[b] Yields refer to isolated, purified material unless otherwise noted.
[c] Yield of isolated product refers to a 1:1 mixture of alkene stereoiso-
mers. Th=2-thienyl, n.r.=no reaction.
[*] L. Liu, Prof. Dr. P. E. Floreancig
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
Fax: (+1)412-624-8611
E-mail: florean@pitt.edu
[**] We thank the National Institutes of Health (GM062924). We thank
Dr. Steve Geib for crystallographic analysis.
phenyldimethylsilanes 1 and 3 reacted smoothly, and formed
tetrahydropyrones 2 and 4, respectively (entries 1 and 2).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000033.
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When 2-phenyldimethylsilanes 5 and 7 were employed,
products 6 and 8 were afforded, respectively, in good yield
(entries 3 and 4), however, alkene isomerization of the
intermediate radical cation or oxocarbenium ion from 7 was
faster than the cyclization, thus leading to a 1:1 mixture of
alkene isomers. Hetero-arylsilanes are also suitable substrates
for this process as demonstrated by the cyclization of 3-(2-
thienyl)dimethylsilanes 9 and 11 to form 10 and 12, respec-
tively (entries 5 and 6). Consistent with previous studies,[4]
vinylsilane substrates react exclusively to form the 2,6-
cis isomers (entry 6). Benzylsilane 13 was not converted into
the cyclized product (entry 7). This result could be a
consequence of benzylsilane acting as a quenching agent for
the radical cation intermediate, which is in accord with the
known capacity of benzylsilanes to undergo facile single-
electron oxidations.[11] The reactions, although efficient with
respect to yield and stereocontrol, were substantially slower
than reactions of similarly substituted trialkylallylic ethers,
requiring heating to 458C and multiple hours for complete
substrate consumption. These results were consistent with the
observations of Kochi and co-workers,[12] in which sterically
hindered arenes reacted with quinones at a slower rate than
sterically unhindered arenes having similar oxidation poten-
tials because the rate of electron transfer is dependent upon
the ability of the quinone to approach the arene. The bulky
trialkylsilyl groups block the approach of the quinone towards
the alkene, thereby lowering the rate of the reaction.
Scheme 3. Vinylsilane products in cross-coupling reactions. dba=1,5-
diphenyl-1,4-pentadien-3-one.
cyclization. The resulting reaction mixture was treated with
iodobenzene in the presence of Bu4NF and [Pd2(dba)3] to
form 19 in 69% overall yield. Although, this study was not
exhaustive, these results demonstrate the capacity to prepare
diverse structures by combining the oxidative cyclization of
vinylsilane substrates with cross-coupling reactions.
The potential for product diversification led us to explore
propargylic ethers as substrates[10] because the alkynyl groups
of propargylic ethers can be converted into numerous groups
at a later stage in the synthetic sequence. Propargylic ethers
(Scheme 4) were similar in reactivity to the vinylsilane
substrates. For example, the DDQ-mediated cyclization of
alkyne 20 into tetrahydropyran 21 proceeded in 71% yield
after 33 hours at 458C; furthermore, 22 provided 23 in 41%
yield and 24 in 25% yield after 18 hours at 458C. The
similarity of the cyclization rates for silylallylic and prop-
argylic ethers results from alkynes being less sterically
demanding, and also less adept at cation stabilization than
vinylsilanes. Diastereocontrol in the cyclization of 22 was
diminished in comparison to the complete stereocontrol that
had been observed in all previous cyclization reactions. This
result is attributed to the sterically undemanding alkyne
groups which cause a mininal energetic difference between
the intermediate E- and Z-oxocarbenium ions. In contrast,
there is a significant energetic preference for the E geometry
The successful cyclizations of E- and Z-vinylsilane sub-
strates are significant for maximizing the range of products
that can ultimately be accessed through this process. The 1,3-
allylic strain[13] dictates that products 2 and 4 would strongly
prefer to adopt conformations 14 and 15, respectively
(Scheme 2).[14] Conformational restriction will be important
Scheme 2. Conformational control through 1,3-allylic strain minimiza-
tion.
for subsequent studies (see below) because it allows stereo-
chemical complementary functionalization, through directed
reagent delivery from the tetrahydropyranyl oxygen atom.
The capacity of vinylsilanes to engage in cross-coupling
reactions[15] allows the products of the cyclization reactions to
serve as precursors to other alkenes, thus showing that the
products from this study will be useful for natural product and
library syntheses (Scheme 3). The 2-thienyldimethylsilane
group was selected for these reactions to ensure that the
vinylsilane is not cleaved prior to coupling.[16] E-Vinylsilane
10 reacted smoothly with iodobenzene in the presence of
Bu4NF and [Pd2(dba)3], thus affording 16 in 82% yield,
whereas Z-vinylsilane 12 provided 17 in 85% yield. Heter-
oatom substitution on the silicon atom eliminates the concern
of desilylation,[17] therefore vinylsiloxane 18 was prepared
through a platinum-mediated intramolecular hydrosilyla-
tion[18] reaction, and served as a substrate for oxidative
Scheme 4. Cyclization reactions of propargylic ethers. DCE=dichloro-
ethane.
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(ca. 2 kcalmolÀ1)[19] for alkyl- and alkenyl-substituted inter-
mediates.
The wide range of biological activities which tetrahydro-
pyran-containing molecules possess, indicates that preparing
a stereochemically diverse library[20] of these structures would
be an attractive goal, particularly when considering the
growing interest in saturated compounds in drug discovery.[21]
We have achieved this objective by exploiting the accessibility
to cis- and trans-cyclization product, and numerous options
for alkyne functionalization. This approach proceeds through
the non-stereoselective cyclization of 22 into 23 and 24
(Scheme 5). The stereoselective reductions of 23 were ach-
ieved with either NaBH4 (equatorial alcohol product) or
l-Selectride (axial alcohol product). The E vinylsilanes were
then formed by hydrosilylation using PhMe2SiH and [Cp*Ru-
(CH3CN)3PF6],[22] and the Z vinylsilanes were formed by
hydrosilylation using a H2PtCl6 catalyst. The regiocontrol of
the platinum-mediated reaction was lower (ca. 3:1) than
that obtained in the ruthenium-mediated reactions, but
the desired products were isolated in moderate yields
(62–67 %) to complete the synthesis. The resulting vinyl-
silanes 25–28 were reduced using H2 and Crabtreeꢀs cata-
lyst.[23] The stereocontrol in these reactions arises from the
combination of coordination of the catalyst to the tetrahy-
dropyranyl oxygen atom and conformational control of the
vinylsilane, which is in accord with the models from Scheme 2.
The levels of stereocontrol for 25 and 26 were excellent,
whereas substrates 27 and 28 required the conversion of the
free hydroxy group into a silyl ether to achieve complete
stereocontrol; the axial hydroxy group can competitively
deliver H2 from the opposite face of the alkene. Oxidation of
the hydrogenation products under Flemingꢀs conditions,[24]
and subsequent silyl ether cleavage (where necessary)
provided tetrahydropyranols 29–32.
The stereoselective reductions of 2,6-trans-dialkyltetrahy-
dropyran-4-ones are difficult to achieve when the alkyl
substituents are sterically similar because the two possible
chair conformations are energetically similar.[25] However,
2-alkynyl-6-alkyltetrahydropyrans exist preferentially in the
chair conformation, in which the alkynyl group is axially
oriented and the alkyl group is equatorially oriented, because
of the significant difference in the A values (Scheme 6). This
conformational preference should allow predictable additions
to the ketone. Indeed, subjecting 24 to l-Selectride resulted in
reduction from an equatorial trajectory with excellent ste-
reocontrol. Proceeding through the sequence of stereodiver-
gent hydrosilylation, vinylsilane reduction, and Fleming
oxidation provided products 37 and 38. The reduction of 24
with NaBH4 was unselective, because the alkynyl group
blocks the axial approach of the hydride. In contrast, SmI2 and
iPrOH[26] provided the equatorial alcohol as a single isomer in
85% yield. The selective reductions in this series illustrates
that alkynyl substitution could be extremely useful for the
synthesis of 2,6-trans-dialkyltetrahydropyran-containing nat-
ural products. Completion of the sequence allowed the
formation of the final two stereoisomers 39 and 40 with
high selectivity. Furthermore, the triethylsilyl ethers are
sufficiently stable to allow the synthetic sequence to proceed
with similar efficiencies to that employing tert-butyldimethyl-
Scheme 5. Synthesis of a stereochemically diverse library. a) NaBH4,
MeOH, À108C, 85%. b) l-Selectride, THF, À908C, 65% from 23, 89%
from 24. c) PhMe2SiH, [Cp*Ru(NCCH3)3]PF6, acetone, 08C, 91% for
25, 92% for 28, 100% for 33, 86% from 35. d) PhMe2SiH,
H2PtCl6·6H2O, THF, 508C, 65% for 26, 67% for 28, 64% for 34, 62%
for 36. e) TBSCl, imidazole, CH2Cl2 or DMF. f) H2, Crabtree’s catalyst,
CH2Cl2. g) CH3CO3H, KBr, NaOAc, HOAc, 53% from 25, 67% from 26.
h) Bu4NF, THF, 50% from 27, 63% from 28, 67% from 33, 57% from
34, 53% from 35, 58% from 36. i) SmI2, THF, iPrOH, 85%. Cp*=pÀen-
tamethylcyclopentadienyl, Crabtree’s catalyst=[(cod)(py)(Cy3P)I]PF6
l-Selectride=lithium tri(sec-butyl)borohydride, DMF=N,N-dimethyl-
formamide, TBS=tert-butyldimethylsilyl. THF=tetrahydrofuran.
,
Scheme 6. Stereoselective reduction of 2,6-trans isomers.
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We have shown that vinylsilane-substituted tetrahydro-
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stereochemically diverse products. This versatility arises
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and offer multiple options for functional group interconver-
sion, through oxidative or cross-coupling protocols. These
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reactions on silylallylic ethers or on propargylic ethers, and
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exploited to prepare the eight possible diastereomers of a
tetrahydropyran structure. Although, hydrogenation was
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À
diversification. The efficiency of the oxidative C H bond
functionalization protocol, the potential medicinal signifi-
cance of tetrahydropyran structures, and the growing number
of protocols[28] that utilize vinylsilanes as substrates for C C
À
bond-forming reactions indicates that the approach outlined
herein will have broad applications in natural product and
library synthesis.
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Received: January 4, 2010
Revised: February 3, 2010
Published online: March 22, 2010
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[27] Please see the Supporting Information for details on this scheme
and for a crystallographic validation of the hypotheses regarding
the stereochemical outcomes of these reactions. X-ray crystallo-
graphic structure is an analogue of compound 39.
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Keywords: combinatorial synthesis · diastereoselectivity ·
hydrosilylation · molecular diversity · oxidation
.
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