Tandem nucleophilic addition/oxa-michael reaction for the synthesis of cis-2,6-disubstituted tetrahydropyrans

Article abstract of DOI:10.1002/ejoc.201402199

A Lewis acid catalyzed tandem nucleophilic addition/oxa-Michael reaction was developed for the synthesis of cis-2,6-disubstituted tetrahydropyran (THP) derivatives in good yields with excellent diastereoselectivities. The strategy was successfully used in the construction of THP derivatives with three stereocenters in a highly stereoselective fashion. Copyright

Full text of DOI:10.1002/ejoc.201402199

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402199
Tandem Nucleophilic Addition/Oxa-Michael Reaction for the Synthesis of
cis-2,6-Disubstituted Tetrahydropyrans
Santosh J. Gharpure,*[a,b][‡] J. V. K. Prasad,[a] and Kalisankar Bera[a]
Keywords: Oxygen heterocycles / Michael addition / Lewis acids / Domino reactions / Nucleophilic addition
A Lewis acid catalyzed tandem nucleophilic addition/oxa-
Michael reaction was developed for the synthesis of cis-2,6-
disubstituted tetrahydropyran (THP) derivatives in good
yields with excellent diastereoselectivities. The strategy was
successfully used in the construction of THP derivatives with
three stereocenters in a highly stereoselective fashion.
In this context, the synthesis of THPs by using tandem re-
actions has been the focus of some recent studies; the most
notable among these are a tandem allylic oxidation/oxa-
conjugate addition reaction, domino olefin cross-metathe-
sis/intramolecular oxa-conjugate addition reaction, redox
isomerization/oxa-conjugate addition reaction, and tandem
Suzuki coupling/oxa-conjugate addition reaction.[6] Most
recently, Zhao et al. reported the stereoselective synthesis of
2,6-cis-substituted tetrahydropyrans by using one-pot se-
quential catalysis involving a Henry reaction and an oxa-
Michael reaction catalyzed by the addition of a Brønsted
acid.[7a] In continuation of our efforts on developing strate-
gies for the stereoselective synthesis of cyclic ethers,[10] par-
ticularly by using tandem reactions, herein we describe a
Lewis acid catalyzed tandem nucleophilic addition/oxa-
Michael reaction for the stereoselective synthesis of cis-2,6-
disubstituted THPs.
We envisioned that 2,6-disubstituted THP derivatives 1
could be readily synthesized from alcohol 2 by intramolecu-
lar oxa-Michael addition. It was reasoned that if alcohol 2
was prepared by Lewis acid catalyzed addition of nucleo-
phile 3 to the aldehyde functionality of 4, which also bears
an appropriately tethered Michael acceptor, it should lead
to 2,6-disubstituted THP derivatives 1 by in situ oxa-
Michael addition. This will obviate the need to isolate
alcohol 2 (Scheme 1).
Introduction
Tetrahydropyrans (THPs) are omnipresent in nature and
form common structural motifs of a vast number of biolo-
gically active molecules. Natural products such as marine
toxins, acid ionophores, which are commonly known as
polyether antibiotics, and pheromones possess a THP moi-
ety in their molecular architecture.[1] Owing to their wide
occurrence and biological activity, a variety of synthetic
methods have been developed to assemble THPs.[2] Among
the general methods developed for the synthesis of THP
derivatives;[3] intramolecular oxa-Michael addition to en-
oates has been well studied and has been widely utilized in
the synthesis of complex natural products.[4–7] Both the
base-catalyzed as well as the Brønsted acid catalyzed intra-
molecular oxa-Michael addition is well established for the
synthesis of THPs.[5,7,8] Interestingly, Lewis acid catalyzed
intramolecular oxa-Michael additions for the stereoselective
synthesis of THPs is relatively less explored. In the majority
of cases, the synthesis of the precursors for this intramo-
lecular oxa-Michael addition involves several steps, includ-
ing the generation of the alcohol, protection of the alcohol,
installation of the appropriate Michael acceptor, and depro-
tection of the alcohol followed by the Michael addition. A
tandem reaction sequence that will obviate such a multistep
synthesis thus looks very attractive.
Tandem reactions are highly desirable in present day syn-
thesis because they enhance molecular complexity in a “sin-
gle pot”, which thereby minimizes the number of steps re-
quired and the quantities of chemicals and solvents used.[9]
[a] Department of Chemistry, Indian Institute of Technology
Madras,
Chennai 600036, India
Scheme 1. Retrosynthesis of the 2,6-disubstituted THP derivatives.
[b] Department of Chemistry, Indian Institute of Technology
Bombay,
Powai, Mumbai 400076, India
http://www.chem.iitb.ac.in/people/Faculty/prof/sjg.html
[‡] Present address: Indian Institute of Technology, Bombay
E-mail: sjgharpure@iitb.ac.in
Results and Discussion
To test the feasibility of the strategy, aldehyde 4a, pre-
pared by mono-Wittig olefination of glutaraldehyde with
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402199.
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Tandem Nucleophilic Addition/Oxa-Michael Reaction
Table 1. Tandem nucleophilic addition/oxa-Michael reaction: screening of Lewis acids.
Entry
Nucleophile
Lewis Acid
Equiv.
Solvent
T [°C]
Time [h]
Yield [%][a]
dr[b]
1
2
3
4
5
6
7
3a
3a
3a
3a
3a
3b
3b
BF3·OEt2
TiCl4
TMSOTf
FeCl3
BiBr3
BF3·OEt2
BF3·OEt2
1.5
1.5
1.5
1.5
1.5
1.5
0.1
CH2Cl2
CH2Cl2
CH2Cl2
MeNO2
CH2Cl2
CH2Cl2
CH2Cl2
–78 to r.t.
0 to r.t.
–78 to r.t.
r.t.
0 to r.t.
–78 to r.t.
–78 to r.t.
4
66
13
10
32
Ն19:1
Ն19:1
–
3:1
5:1
Ն19:1
Ն19:1
0.5
2.5
8.5
5
2.5
5.5
60
90
20[c]
[a] Yield of isolated product. [b] In all the cases, the diastereomeric ratio (dr) was determined by analysis of the crude reaction mixture
1
by H NMR spectroscopy. [c] Uncyclized alcohol was isolated in 33% yield.
[(phenylcarbonyl)methylene]triphenylphosphorane,
was ployed.[8,11,12] In contrast, aldehyde 4e, bearing a more reac-
treated with allyl-organometallic reagents 3a and 3b in the tive alkylidine malonate as Michael acceptor, was found to
presence of various Lewis acids, and the results are summa- work efficiently, and corresponding cis-THP derivative 1eb
rized in Table 1. Upon using BF3·OEt2 (1.5 equiv.) as the was formed in good yield with good diastereoselectivity
Lewis acid along with allyltrimethylsilane (3a) as the nu- (Table 2, entry 4).
cleophile, desired cis-2,6-disubstituted THP derivative 1aa
was obtained in 66% yield with excellent diastereoselectiv-
strate scope.
Table 2. Tandem nucleophilic addition/oxa-Michael reaction: sub-
ity (Table 1, entry 1). The stereochemistry of the 2,6-substit-
uents was found to be cis on the basis of NOE experiments.
Upon using more reactive allyltributylstannane (3b) as the
nucleophile, cis-2,6-disubstituated THP 1aa was obtained in
90% yield with excellent diastereoselectivity (Table 1, en-
try 6). The use of a catalytic amount (10 mol-%) of
BF3·OEt2 resulted in a poor yield (20%) of THP derivative
1aa, along with uncyclized alcohol 2aa in 33% yield
(Table 1, entry 7). For other Lewis acids such as TiCl4, tri-
methylsilyl trifluoromethanesulfonate (TMSOTf), FeCl3,
and BiBr3, THP product 1aa was formed in very poor
yields with only moderate diastereoselectivities (Table 1, en-
tries 2–5). Thus, BF3·OEt2 was found to be the best Lewis
acid in the tandem nucleophilic addition/oxa-Michael reac-
tion for the synthesis of cis-2,6-disubstituated THP deriva-
tives.
To study the scope of the tandem nucleophilic addition/
oxa-Michael reaction for the stereoselective synthesis of cis-
2,6-disubstituated THP derivatives, aldehydes 4b–e bearing
different Michael acceptors were prepared and subjected to
the optimized reaction conditions. The results are summa-
rized in Table 2. Treatment of aryl- and methyl-substituted
enones 4b and 4c tethered to an aldehyde functionality with
allyltributylstannane (3b) under the optimized reaction con-
ditions gave corresponding THPs 1bb and 1cb in good
yields with excellent diastereoselectivities (Table 2, entries 1
[a] Yield of isolated product. [b] In all cases, the dr was determined
and 2). Interestingly, if an α,β-unsaturated ester was used
by analysis of the crude reaction mixtures by 1H NMR spec-
troscopy. [c] The uncyclized alcohol was isolated.
as the Michael acceptor (cf. aldehyde 4d), the second step
of this tandem sequence, that is, the oxa-Michael addition,
did not take place, and uncyclized alcohol 2db was obtained
To study the scope of the nucleophiles in the tandem nu-
in 80% yield (Table 2, entry 3). This was perhaps the result cleophilic addition/oxa-Michael reaction, aldehyde 4a was
of the low reactivity of the α,β-unsaturated ester as the con- treated with nucleophiles 3c–k, and the results are summa-
jugate acceptor under the reaction conditions em- rized in Table 3. Tin-based reagents such as allenyltributyl-
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S. J. Gharpure, J. V. K. Prasad, K. Bera
SHORT COMMUNICATION
Table 3. Tandem nucleophilic addition/oxa-Michael reaction: nucleophile scope.
[a] Yield of isolated product. [b] In all the cases, the dr was determined by analysis of the crude reaction mixtures by 1H NMR spec-
troscopy.
stannane (3c) and allyltin reagent 3d added successfully to B (Figure 1). In the first step, the nucleophile chemoselec-
aldehyde 4a to give THPs 1ac and 1ad, respectively, in good tively adds to aldehyde to generate an alcohol bound to the
yields with excellent diastereoselectivities (Table 3, entries 1 Lewis acid. During the second step, that is, the oxa-Michael
and 2). If TMSCN (3e) was used as the nucleophile, 2,6- addition, the bulky substituent (nucleophile) occupies the
disubstituted THP derivative 1ae was obtained in good pseudoequatorial position to avoid 1,3-diaxial interactions.
yield but with 1:1 diastereoselectivity (Table 3, entry 3). Because the incipient acylmethylene group is bulkier than
Silyl enol ethers or silyl ketene acetals 3g–k were found to hydrogen, it tends to adopt a pseudoequatorial orientation
be good nucleophiles, and products 1ag–ak were obtained (A of Figure 1) rather than a pseudoaxial orientation (B of
in good yields with good diastereoselectivities (Table 3, en- Figure 1) to avoid 1,3-diaxial interaction, which results in
tries 5–9). Upon using the silyl enol ether of cyclohexanone the cis product.[13]
3f as the nucleophile, product 1af was obtained as a 1:1
mixture of diastereomers (Table 3, entry 4). It is pertinent
to note that the diastereoselectivity of the first Mukaiyama
aldol step was poor rather than that of the oxa-Michael
addition step.
The stereochemical outcome of these reactions can be
explained on the basis of transition-state structures A and Figure 1. Explanation for stereochemical outcome of the reaction.
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Tandem Nucleophilic Addition/Oxa-Michael Reaction
This transition-state structure also explains the poor Et3SiH in the presence of BF3·OEt2 to furnish THP deriva-
selectivity in the case of THP derivative 1ae in which CN tives 8 and 9 in good yields with good diastereoselectivities
was the nucleophile; in this case, because CN is small, it (Scheme 4).
does not have any preference to be in the axial or equatorial
position in comparison to hydrogen.
After successfully exploring the scope of the tandem nu-
cleophilic addition/oxa-Michael reaction for the synthesis
of 2,6-disubstituted THPs, it was decided to add hydride as
a nucleophile. Thus, treatment of aldehyde 4a with Et3SiH
in the presence of BF3·OEt2 in dry CH2Cl2 resulted in the
formation of THP 6 in 63% yield rather than ketone 5
(Scheme 2). THP 6 is clearly a product of over-reduction
(reduction of the keto group) of intermediate ketone 5.
Scheme 4. Synthesis of THP derivatives: one-pot allylation/oxa-
Michael addition/reduction sequence.
Conclusions
In conclusion, we developed a Lewis acid catalyzed tan-
Scheme 2. Tandem nucleophilic addition/oxa-Michael reaction: hy-
dem nucleophilic addition/oxa-Michael reaction for the
dride as nucleophile; PCC = pyridinium chlorochromate, MS =
synthesis of cis-2,6-disubstituted THP derivatives in good
yields with excellent diastereoselectivities. The reaction
worked well with good Michael acceptors. Various nucleo-
philes added successfully to the aldehydes to give rise to
THP derivatives. The developed strategy was amenable to
designing sequential reactions and was successfully used in
the “one-pot” construction of THP derivatives bearing
three stereocenters in a highly stereoselective fashion.
molecular sieves.
To ascertain the over-reduction of ketone with Et3SiH
under the ionic hydrogenation conditions, cis-2,6-disubsti-
tuted THP derivative 1aa was subjected to the reaction with
Et3SiH in the presence of BF3·OEt2. The reaction indeed
led to the formation of alcohol 7; however, it was only a
minor product. The major product formed in this reaction
was THP 8, which was the outcome of the reduction of
the benzylic hydroxy group under the ionic hydrogenation
conditions employed.
Again, control of the reaction was found to be difficult;
hence, the reaction was performed with an excess amount
of Et3SiH, which furnished THP 8 as the sole product in
84% yield (Scheme 3). In contrast, if 2,6-disubstituted THP
derivative 1ca bearing a methyl ketone rather than an aryl
ketone was treated with Et3SiH in the presence of
BF3·OEt2, alcohol 9 was obtained in 66% yield as a single
diastereomer.[14]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data along with
copies of the 1H NMR and 13C NMR spectra for all new com-
pounds.
Acknowledgments
The authors thank the Council of Scientific and Industrial Re-
search (CSIR), New Delhi and the Department of Science and
Technology (DST), New Delhi, for financial support. The authors
are grateful to CSIR for the award of a research fellowship to
J. V. K. P.
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SHORT COMMUNICATION
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Received: March 5, 2014
Published Online: April 30, 2014
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