A General Diastereoselective Strategy for Both cis- and trans-2,6-Disubstituted Tetrahydropyrans: Formal Total Synthesis of (+)-Muconin

Article abstract of DOI:10.1021/acs.orglett.8b03053

A protocol for general diastereoselective tandem dihydroxylation followed by S_N2 cyclization was developed for the convenient and efficient synthesis of cis- and trans-2,6-disubstituted tetrahydropyrans from ζ-mesyloxy α,β-unsaturated esters. T

Full text of DOI:10.1021/acs.orglett.8b03053

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A General Diastereoselective Strategy for Both cis- and trans-2,6-
Disubstituted Tetrahydropyrans: Formal Total Synthesis of
(+)-Muconin
Beduru Srinivas, D. Srinivas Reddy, N. Arjunreddy Mallampudi, and Debendra K. Mohapatra*
Organic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India
S
* Supporting Information
ABSTRACT: A protocol for general diastereoselective tandem dihydroxylation followed by SN2 cyclization was developed for
the convenient and efficient synthesis of cis- and trans-2,6-disubstituted tetrahydropyrans from ζ-mesyloxy α,β-unsaturated
esters. The application of this novel method was demonstrated through the concise formal synthesis of (+)-muconin, a
nonclassical acetogenin, with sequential THP−THF ring formation.
etrahydropyran (THP) rings are an important structural
motif present in an array of natural products such as
reported the synthesis of cis- and trans-2,5-disubstituted
tetrahydrofurans by tandem dihydroxylation followed by SN2
cyclization (Scheme 1a).4 From these results, we envisioned
that it could be possible to synthesize both cis- and trans-2,6-
disubstituted pyrans following the above conditions. Herein we
describe the development of the reagent-controlled synthesis
of both cis- and trans-2,6-disubstituted tetrahydropyrans
starting from common substrates (Scheme 1b) and the
application of the developed synthetic method to the formal
synthesis of (+)-muconin.
We initiated our study with the synthesis of cyclization
precursor 16 as a model substrate. For this, commercially
available aldehyde 12 was converted to chiral epoxide 13 under
Corey−Chaykovsky conditions5 followed by hydrolytic kinetic
resolution using Jacobsen’s catalyst,6 [(R,R)-CoIII(salen)-
(OAc)], for 24 h at room temperature in 48% yield with
96% ee. Chiral epoxide 13 was treated with 4-bromo-1-butene
in the presence of Mg and CuI at −40 °C to produce olefin 14
in 92% yield7 (Scheme 2). The cross-metathesis reaction of
olefin 14 with ethyl acrylate using Grubbs’ second-generation
catalyst afforded hydroxy ester 15 in 79% yield.8 Finally, the
mesylation of secondary alcohol in 15 was carried out with
mesyl chloride and Et3N in CH2Cl2 to obtain ζ-mesyloxy-α,β-
unsaturated ester 16 in 93% yield (Scheme 2).4 After the
development of a general synthetic route for the preparation of
T
marine toxins, polyether antibiotics, and pheromones (Figure
1). THP-ring-containing natural products have diverse and
potent biological activities and have attracted significant
attention in recent years.1 Over the past few decades,
increasing numbers of natural products with THP backbones
have been isolated from different sources.1 The importance of
their biological activities and structural architecture has led to a
significant development in synthetic strategies for the
preparation of both cis- and trans-2,6-disubstituted pyrans.2a−d
To our knowledge, very few reports are available on the
synthesis of both cis- and trans-2,6-disubstituted pyrans from a
common substrate.2e−j Very recently, Nicolaou et al.2e
reported a stereoselective and practical method for construct-
ing both cis- and trans-2,6-disubstituted dihydro- and
tetrahydropyran ring systems following a Heck/Saegusa−Ito/
oxa-Michael cyclization sequence. As very few methods are
currently available, the development of an efficient and highly
stereocontrolled protocol for the preparation of substituted
tetrahydropyrans is highly desirable.
Our group has also developed several new synthetic
strategies for the synthesis of cis- and trans-2,6-disubstituted
pyrans and applied these to the synthesis of many natural
products.3 Continuing our research on developing method-
ologies for the synthesis of either cis- or trans-tetrahydropyran
rings, we were interested in developing a protocol that could
be used to synthesize both cis- and trans-tetrahydropyran rings
starting from a common precursor. In 2005, Marshall’s group
Received: September 24, 2018
© XXXX American Chemical Society
A
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Letter
common mesylate precursors, the synthesis of cis- and trans-
2,6-disubstituted tetrahydropyrans was initiated.
Accordingly, unsaturated mesylate 16 was treated under
Sharpless reaction conditions4 using AD-mix-α to furnish the
desired product 18 in only 10% yield, and the intermediate diol
17 was formed in 70% yield. However, treatment of diol 17
with excess K2CO3 (3 equiv) in tBuOH did not improve the
conversion of 17 to the desired product, even after 24 h.
Interestingly, when the same reaction mixture was heated to 60
°C for another 12 h, the yield of the desired pyran product was
increased to 74% (Scheme 3). Then the same reaction was
Scheme 3. Optimization of the Synthesis of cis- and trans-
2,6-Disubstituted Tetrahydropyrans from a Common
a
Substrate
Figure 1. Representatives structures of natural products containing
2,6-disubstituted pyrans.
Scheme 1. Background and Present Work
a
Reaction conditions A: 16 (1 mmol), K3[Fe(CN)6] (3 mmol),
K2OsO2(OH)4 (0.005 mmol), (DHQ)2PHAL (0.01 mmol), K2CO3
(6 mmol), and CH3SO2NH2 (1 mmol) in tBuOH/H2O (1:1) at 0 °C
for 12 h and then at 60 °C for 12 h, unless otherwise mentioned.
Conditions B: 16 (1 mmol), K3[Fe(CN)6] (3 mmol), K2OsO2(OH)4
(0.005 mmol), (DHQD)2PHAL (0.01 mmol), K2CO3 (6 mmol),
CH3SO2NH2 (1 mmol) in tBuOH/H2O (1:1) at 0 °C for 12 h and
then at 60 °C for 12 h, unless otherwise mentioned.
repeated under the AD-mix-α conditions with excess K2CO3 (6
equiv) for 12 h at 0 °C and then heated to 60 °C to obtain cis-
tetrahydropyran derivative 18 in 86% yield with a 99:1
diastereomeric ratio (as analyzed by HPLC). Similarly, when
mesylate 16 was treated with AD-mix-β under the optimized
conditions, the corresponding trans product 19 was obtained
in 90% yield (Scheme 3). Both products were characterized by
spectral (1H and 13C NMR) and analytical data, and the cis and
trans orientations at the pyran rings of compounds 18 and 19
were confirmed through 2D NOE experiments. These results
confirm that the cyclization reaction took place in an SN2
manner.
Scheme 2. Synthesis of ζ-Mesyloxy α,β-Unsaturated Esters
With the optimized conditions, further studies were
designed to investigate the scope and stereochemical outcomes
of cyclization (Table 1). ζ-Mesyloxy α,β-unsaturated esters
16a−i were well-designed and prepared to have a variable
carbon side chain containing OBn (entry 2), OPMB (entries 3
and 5), long chain (entries 4 and 5), methyl (entry 6), OMOM
(entry 7), and substituted aryl (entries 8−10) groups in the
corresponding cyclic products.
One-pot cyclization was carried out on these substrates
under standard conditions A or B to furnish the corresponding
cis- or trans-2,6-disubstituted pyrans in moderate to good
yields (Table 1). Unfortunately, substrate 16f did not give the
cyclic product under conditions B (entry 7). This might have
B
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Table 1. Substrate Scope for the Synthesis of cis- and trans-
2,6-Disubstituted Tetrahydropyrans
Scheme 4. Synthesis of Chloro Compounds 16g−i
a
demonstrate the synthetic utility and generality of this novel
methodology using the readily available required building
blocks for the synthesis of the complex biologically active
natural product (+)-muconin (11), a nonclassical acetogenin
with sequential THP−THF ring systems. In 1996, McLaughlin
et al.10f isolated 11 from the leaves of Rollinia mucosa (Jacq.)
Baill. (Annonaceae) and showed it to have potent in vitro
cytotoxicity against human pancreatic and breast tumor cells.
The key structural features of muconin contain sequential THF
and THP rings attached between a long carbon chain and a
2,4-disubstituted α,β-unsaturated-γ-lactone of which six out of
eight stereogenic centers are found in the middle part (THF/
THP rings).10 Scheme 5 outlines our retrosynthetic approach
Scheme 5. Retrosynthetic Analysis
for the formal synthesis of (+)-muconin.10a We planned that
the sequential THP−THF rings could be achieved using
tandem dihydroxylation, SN2 cyclization, and intramolecular
nucleophilic ring opening of the epoxide in compound 23,
which in turn could be synthesized by cross-metathesis of
epoxide 24 and mesylate 26. Epoxide intermediate 24 was
prepared from commercially available pent-4-en-1-ol (25), and
mesylate intermediate 26 was obtained from D-mannitol.
The formal synthesis of (+)-muconin was initiated with the
stereoselective synthesis of epoxide fragment 24 from 25
(Scheme 6). Unsaturated ester 28 was synthesized from 25 by
sequential Swern oxidation and Wittig olefination in one pot in
75% yield.4 Next, α,β-unsaturated ester 28 was reduced with
DIBAL-H at −78 °C to furnish allyl alcohol 29 in 85% yield.
Asymmetric Sharpless epoxidation of alcohol 29 using
a
Reaction conditions A and B are the same as reported in Scheme 3,
unless otherwise mentioned.
been due to the steric strain of the MOM group on the
transition state, which could have prevented cyclization from
happening. It is noteworthy that mesylation of substrates 15g−
i gave only chloro-substituted products 16g−i in yields of 78−
85%, rather than the mesylated products with the inverted
orientation (Scheme 4).9 Interestingly, these substrates also
gave the cyclic products 18g−i and 19g−i (entries 8−10)
smoothly under same reaction conditions in good yields.
Empowered by our newly developed synthetic strategy and
successful study of the scope of cyclization, we were able to
C
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With the two required olefin partners in hand, we next
focused on the key cross-metathesis reaction. Subjecting epoxy
olefin 24 and mesylate 26 to cross-metathesis using Grubbs’
second-generation catalyst8 in CH2Cl2 under reflux conditions
furnished the desired fragment 23 in 55% yield along with the
homocoupled product 34 in 8% yield (Scheme 8). The
Scheme 6. Synthesis of Epoxide Fragment 24
Scheme 8. Formal Synthesis of (+)-Muconin
(+)-DIPT, Ti(OiPr)4, and TBHP in CH2Cl2 at −20 °C
furnished epoxy alcohol 30 in 89% yield,11 which was
protected as its TBDPS ether with TBDPSCl and imidazole
in CH2Cl2 to get compound 24 in 92% yield with 92% ee (as
analyzed by HPLC) (Scheme 6).
After obtaining a good quantity of epoxy olefin 24, we
synthesized the other olefin partner 26 required for the
Grubbs’ cross-metathesis reaction (Scheme 7). Commercially
Scheme 7. Synthesis of Mesylate Fragment 26
intermediate compound 23 having the reactive epoxide, olefin,
and mesyl functionalities was then ready for the crucial one-pot
dihydroxylation followed by SN2 cyclization and intramolecular
nucleophilic ring opening of the epoxide. Accordingly,
intermediate 23 was treated with AD-mix-β under the standard
optimized conditions (conditions B) to obtain the required
THF−THP compound 35 in 42% yield. The structure of
compound 35 was confirmed by 2D NOE studies, and the key
NOE correlations are shown in Figure 2.
Finally, deprotection of the TBDPS ether was achieved with
TBAF in THF to afford known (+)-muconin fragment 22 in
92% yield (Scheme 8).10a The spectral (1H and 13C NMR) and
available D-mannitol was converted to aldehyde 31 in
quantitative yield by following a known protocol in two
steps.12 31 was then subjected to the Grignard reagent
generated from 5-bromopent-1-ene and magnesium in THF to
afford a diastereomeric mixture of alcohols 32 and 33 in a 3:1
ratio (Scheme 7) in 87% yield.13 The two alcohols were easily
separated through silica gel column chromatography, and the
absolute stereochemistry of the newly generated hydroxyl
group in both compounds was assigned by modified Mosher’s
ester analysis.14 Esterification of minor alcohol 33 with both
(S)- and (R)-methoxy-α-(trifluoromethyl)phenylacetic acid
(MTPA) showed positive chemical shift differences [Δδ =
(δS − δR) × 103] for protons on C5 through C2, while protons
on C7 through C10 showed negative chemical shift differences,
which confirmed that C6 bears an R configuration (see the
Supporting Information). After the absolute configuration was
confirmed, the undesired major alcohol 32 was inverted to the
required alcohol 33 by Mitsunobu inversion15 using TPP,
DIAD, and 4-nitrobenzoic acid followed by ester hydrolysis
with K2CO3 in MeOH in 72% yield over the two steps. Alcohol
33 was then treated with methanesulfonyl chloride in the
presence of Et3N in CH2Cl2 to obtain mesylate 26 in 90%
yield.4
Figure 2. (a) Key NOE correlations in 35. (b) Energy-minimized
structure of 35.
D
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Letter
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In conclusion, we have developed a practical and stereo-
selective synthesis of both cis- and trans-2,6-disubstituted
tetrahydropyrans utilizing in situ Sharpless asymmetric
dihydroxylation followed by intramolecular SN2 cyclization of
substituted ζ-mesyloxy α,β-unsaturated esters. The reaction
featured good substrate scope and proceeded efficiently in
moderate to good yields. This synthetic method was also
demonstrated for the formal synthesis of (+)-muconin in a
concise and highly stereoselective manner. The key reactions
involved in this formal synthesis were Sharpless asymmetric
epoxidation, Mitsunobu inversion, Grubbs’ cross-metathesis,
and one-pot Sharpless asymmetric dihydroxylation/SN2
cyclization/intramolecular nucleophilic epoxide ring opening.
The strategy opens up new avenues for the preparation of
novel bioactive natural products with a similar structure.
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■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03053.
Detailed experimental procedures and spectral data (1H,
13C and 2D-NMR) for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mohapatra@iict.res.in.
ORCID
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Chem. Lett. 2012, 22, 1655.
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Debendra K. Mohapatra: 0000-0002-9515-826X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for financial support as
part of the XII Five Year Plan Programme under the title
ORIGIN (CSC-0108; Manuscript Communication Number
IICT/Pubs/2018/297). B.S., D.S.R., and N.A.M. thank CSIR
and UGC, New Delhi, India, for financial assistance in the
form of fellowships. This paper is dedicated to our wonderful
colleague, Dr. Tadikamalla Prabhakar Rao, Centre for NMR
and Structural Chemistry, CSIR-IICT, who recently passed
away, for his support for 2D NMR studies.
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