Flexible tetrahydropyran synthesis from homopropargylic alcohols using sequential Pd-Au catalysis

Article abstract of DOI:10.1021/acs.orglett.6b03532

A flexible synthetic method toward highly substituted tetrahydropyran is reported. The key transformation involves atom-efficient sequential metal catalysis consisting of Pd-catalyzed addition of homopropargylic alcohols to alkoxyallene and the subsequent

Full text of DOI:10.1021/acs.orglett.6b03532

Letter
pubs.acs.org/OrgLett
Flexible Tetrahydropyran Synthesis from Homopropargylic Alcohols
Using Sequential Pd−Au Catalysis
Jungjoon Kim, Wook Jeong, and Young Ho Rhee*
Department of Chemistry, Pohang University of Science and Technology, Hyoja-dong San 31, Pohang, Kyungbuk 790-784, Republic
of Korea
S
* Supporting Information
ABSTRACT: A flexible synthetic method toward highly substituted tetrahydropyran is reported. The key transformation
involves atom-efficient sequential metal catalysis consisting of Pd-catalyzed addition of homopropargylic alcohols to alkoxyallene
and the subsequent gold(I)-catalyzed cycloisomerization. Notably, this method gives access to both 2,6-cis- and 2,6-trans-
tetrahydropyrans possessing diverse substitution patterns.
etrahydropyran is a common structural core that can be
easily found in numerous bioactive natural products and
intermediate B/B′ may suggest unique solution to this
T
challenging problem (Scheme 1).9−11 Furthermore, the enol
pharmaceutical candidates.1 As illustrated by some representa-
tive examples (Figure 1), a notable feature of the tetrahydropyran
Scheme 1. Basic Concept: Sequential Catalysis
Figure 1. Tetrahydropyran-containing natural products.
ether moiety in the product C/C′ should be easily converted into
numerous functional groups. The O,O-acetals A/A′ may be
prepared by the ligand-driven Pd-catalyzed diastereodivergent
addition of chiral homopropargylic alcohols to alkoxyallene.12,13
Because O,O-acetals are configurationally unstable under acidic
conditions, we reasoned that the key issue would be to find the
optimal structure of O,O-acetal (R2 group) that would work for
both chemoselective metal catalyzed reactions.
core is highlighted by the stereochemical diversity with regard to
the substituents at the 2,6-positions. This feature in the diversity
is further enriched by the wealth of the substitution patterns in
the tetrahydropyran ring. The natural products possessing
tetrahydropyran core have a wide range of biological activities.
Thus, a flexible synthetic approach allowing access to the diverse
structure should be highly powerful. However, this challenging
divergent strategy has not been easily accomplished by the well-
known methods such as hetero-Diels−Alder2 reaction, intra-
molecular nucleophilic addition,3 Petasis−Ferrier rearrange-
ment,4 Prins cyclization,5 and other metal-catalyzed reactions.6
Based upon our recent reports in the related area,7,8 we
envisioned that the Au-catalyzed stereoretentive cycloisomeriza-
tion of the chiral O,O-acetals A/A′ mediated by formation of
Indeed, the structure of the alkoxy moiety in the allene proved
critical for the metal catalyzed reactions (Table 1). Based upon
our recent studies on the Pd-catalyzed asymmetric hydro-
Received: November 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03532
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acetal 4b again proceeded in high yield and selectivity when the
ligand ent-2 was used. Interestingly, the gold(I)-catalyzed
cycloisomerization reaction turned out to be significantly slower
than the that of syn-diastereomer 4a.17 In this case, using complex
5 as well as 6 gave the dihydropyran product trans-8 in much
lower yield and selectivity (entries 5 and 6). After extensive
variation of the reaction condition, we discovered that the use of
electron poorer gold complex 7 (3 mol %) gave trans-8 in
moderate yield with low selectivity cis-8 (entry 7).18−20 Using
higher catalyst loading along with the molecular sieve (4 Å)
significantly improved both the yield and the selectivity of the
cycloisomerization reaction (entry 8). In this case, the trans-8
was obtained in 81% isolated yield along with small amount of cis-
8.
Table 1. Optimization
Using the optimized conditions established in Table 1, we
tested an array of homopropargylic alcohols for the stereo-
divergent synthesis of dihydropyran cyclic ethers (Table 2). In
general, the homopropargylic alcohol substrates gave the
corresponding O,O-acetal with high ligand-driven diastereose-
lectivity as with the optimization studies.21 In addition, cis-enol
ether products were obtained in excellent yield with near-
complete chirality transfer from the O,O-acetals; whereas the
trans-enol ethers were obtained with formation of small amount
of the cis-diastereomer. The reaction was compatible with benzyl
ether 9 (entries 1 and 2) and silyl ether 11 (entries 3 and 4). In
addition, substrate possessing benzyl group 13 also worked
smoothly to give the cyclic ether products 14 (entries 5 and 6).
The unique chemoselectivity of the reaction was also illustrated
by the benzylic alcohol substrate 15 (entries 7 and 8).
Both Pd-catalyzed and gold-catalyzed reaction worked
smoothly to give the diastereomeric products 16 in good to
excellent yield. In addition to the terminal alkynes discussed
above, internal alkyne 17 also proved efficient for the sequential
catalysis to give the products 18 in high yield (entries 9 and 10).
Also, the allylic ether substrate 19 gave the dihydropyran
compound 20 in high yields with no interference from the
gold(I)-catalyzed enyne cyclization. These examples further
address the chemoselectivity of the proposed gold(I)-catalyzed
cycloisomerization reaction.
Having established the generality of the sequential metal
catalysis, we then investigated the synthetic transformation of the
enol ether products. As described in Scheme 2, cis-10 was
successfully converted into the cyclic ketal 21 in 85% yield upon
treatment with excess TMSCl and ethylene glycol. Under the
analogous condition, the trans-10 was also converted into the
trans-ketal 2222 in 91% yield with no formation of the cis-
diastereomer 21.
In addition to the simple ketal formation described above,
highly electron rich enol ether moiety in the product should
allow for introduction of more dense functional groups into the
tetrahydropyran ring. As an illustrative example, we examined the
Os-catalyzed dihydroxylation of compound cis-8. As depicted in
Scheme 2, the reaction proceeded smoothly. However, the
hydroxyketone product 23 could not be easily isolated due to the
undesired dimerization.23 This problem was successfully avoided
by the acetate formation from the crude 23 to generate 24 in 58%
yield (over two steps).24 Notably, complete chemoselectivity in
the dihydroxylation was observed; the terminal olefin remained
intact in the dihydroxylation. Unlike cis-8, the trans-10 gave the
desired hydroxyketone 25 only in low yield because of the poor
chemoselectivity. To our delight, alternative epoxidation with
DMDO followed by in situ treatment with catalytic CSA
produced 25 in 76% yield with high stereoselectivity (∼10:1) and
a
b
Isolated yield of mixture. dr was determined by integration of the
c
d
crude NMR. Isolated yield of the major diastereomer. Not
determined. ent-2 was used as the ligand. In this case, 1.8 mol %
of 2,6-di-tert-butylpyridine was used along with 4 Å molecular sieve.
e
f
alkoxylation reaction,7a we first examined the cyclohexyl-
substituted oxyallene. The reaction of this allene (2.0 equiv)
with alcohol 1 in the presence of Pd2(dba)3 (1.5 mol %), ligand 2
(3 mol %), and triethylamine (0.1 equiv) proceeded in near-
quantitative yield to produce the product 3a virtually as single
diastereomer.14 However, the gold(I)-catalyzed cycloisomeriza-
tion reaction of desilylated alcohol 4a gave the product cis-8 only
in trace yield when gold complex 5 was used (entry 1),
presumably because the large alkoxy moiety slowed the
formation of the intermediate B (Scheme 1).15 Varying the
gold complexes and other reaction conditions little improved the
results. Using the smaller n-pentyloxyallene, however, signifi-
cantly lowers the selectivity of the Pd-catalyzed hydroalkox-
ylation reactions (entry 2). In light of these disappointing results,
we reasoned that the size of the alkoxy moiety should be
elaborately modified to maintain the high stereoselectivity in the
Pd-catalyzed reaction without too much slowing of the gold
catalysis. Based upon this analysis, we then tested benzylox-
yallene. However, the dr was still low for the Pd-catalyzed
reaction (entry 3). A notable improvement arises when
cyclohexylmethyl-substituted allene16 was used (R = CH2(c-
C6H11), entries 4−8). For example, the Pd-catalyzed reaction for
this allene gave the corresponding O,O-acetals in 99% yield with
high (∼20:1) selectivity. In addition, the gold-catalyzed
cycloisomerization of 4a using complex 5 gave the corresponding
cyclic ether cis-8 in 94% yield with no indication of formation of
trans-8 (entry 4). Thus, the stereochemical information on the
acetal 4a is completely retained in the cycloisomerization
reaction. As shown in entry 5, synthesis of diastereomeric O,O-
B
DOI: 10.1021/acs.orglett.6b03532
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Organic Letters
Letter
Table 2. Scope of Stereodivergent Dihyropyran Synthesis
Scheme 2. Synthetic Transformation of Enol Ether Products
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03532.
Experimental details and spectral data; 1H and 13C scan of
all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yhrhee@postech.ac.kr.
ORCID
Young Ho Rhee: 0000-0002-2094-4426
Notes
a
b
The authors declare no competing financial interest.
Isolated yield of mixture. Isolated yield of the major diastereomer.
c
Determined by the integration of the crude NMR after the second
ACKNOWLEDGMENTS
step (Au catalysis). In all cases, the diastereomeric ratio of the first step
■
d
(Pd catalysis) was determined to be >20:1. 5 mol % of Pd/10 mol %
This work was supported by the National Research Foundation
funded by the Korean government (Nano-Material Technology
Development Program and NRF-2013R1A2A2A01068684).
e
f
of ligand was used. 14 mol % of 7 was used. The ratio was
determined after purification using column chromatography.
REFERENCES
■
chemoselectivity.25 The transformations depicted in Scheme 2
illustrates the potential utility of the proposed method in the
divergent synthesis of tetrahydropyran natural products.
In summary, we reported a new and highly flexible synthesis of
tetrahydropyran structure based upon the use of sterodefined
O,O-acetals as the key moiety. Notably, a variety of
tetrahydropyran structure could be accessed by the chemo-
selective sequential Pd/Au metal catalysis. This new reaction
significantly broadens the synthetic scope of the sterodefined
O,O-acetals. Currently, we are working on the total synthesis of
bioactive tetrahydropyran natural products as well as further
expansion of the utility of the sterodefined O,O-acetals based on
chemoselective metal catalysis.
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Letter
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(14) Alkynyl alcohol substrates were generally prepared by BF3-
promoted addition of lithium acetylide to epoxides; see Supporting
Information for details.
(15) In this case, extensive formation of alcohol 1 by way of the
cleavage of the acetal was observed as the major event.
(16) Alkoxyallenes were prepared by potassium tert-butoxide catalyzed
isomerization of the corresponding alkyl propargyl ethers; see
Supporting Information for details.
(17) This rate difference may be explained by the increased steric
hindrance in formation of the oxonium ion intermediate B/B′ chiral
acetal A/A′.
(18) For detailed list of optimization, see the SI.
(19) Partial epimerization was observed for the slower-reacting trans-
acetals such as 4b, when the reaction was stopped before full conversion.
Thus, the lower selectivity can be explained by the competing
epimerization.
D
DOI: 10.1021/acs.orglett.6b03532
Org. Lett. XXXX, XXX, XXX−XXX