Rhodium Carbenoid Initiated O-H Insertion/Aldol/Oxy-Cope Cascade for the Stereoselective Synthesis of Functionalized Oxacycles

Article abstract of DOI:10.1021/acs.orglett.6b03229

A novel diazo-cascade approach has been developed for the synthesis of nine-membered oxacycles utilizing readily accessible β-hydroxy vinyl ketones and vinyl diazo esters. The Rh(II)-catalyzed cascade reaction begins with carbene O-H insertion followed by an intramolecular aldol cyclization to provide a substituted tetrahydrofuran intermediate that undergoes an oxy-Cope rearrangement to provide functionalized nine-membered oxacycles with complete stereoselectivity.

Full text of DOI:10.1021/acs.orglett.6b03229

Letter
pubs.acs.org/OrgLett
Rhodium Carbenoid Initiated O−H Insertion/Aldol/Oxy-Cope
Cascade for the Stereoselective Synthesis of Functionalized
Oxacycles
Kiran Chinthapally, Nicholas P. Massaro, and Indrajeet Sharma*
Department of Chemistry and Biochemistry, and Institute of Natural Products Applications and Research Technologies University of
Oklahoma, 101 Stephenson Parkway, Norman, Oklahoma 73071, United States
S
* Supporting Information
ABSTRACT: A novel diazo-cascade approach has been
developed for the synthesis of nine-membered oxacycles
utilizing readily accessible β-hydroxy vinyl ketones and vinyl
diazo esters. The Rh(II)-catalyzed cascade reaction begins with
carbene O−H insertion followed by an intramolecular aldol
cyclization to provide a substituted tetrahydrofuran inter-
mediate that undergoes an oxy-Cope rearrangement to provide
functionalized nine-membered oxacycles with complete stereo-
selectivity.
ascade reactions are valuable tools for installing complex
molecular designs with high efficiency, selectivity, and
C
atom economy.1 Other than being synthetically appealing,
cascade transformations allow for price efficiency in terms of
reagents, catalysts, solvents, and waste management as well as
in time and efforts.2 One of the biggest advantages of cascade
reactions over classical synthetic reactions is the ability to carry
out two or more transformations in a single step under the
same reaction conditions.3 These advantages together make
them ideal to be considered for green chemistry synthesis.4
In continuation of our interest in cascade reactions initiated
by carbene O−H insertion,5 we now report a new approach
involving β-hydroxy vinyl ketones and vinyl diazo esters for the
synthesis of functionalized nine-membered oxacycles, which are
important structural motifs found in many bioactive natural
products.6 There have been several reports in literature for the
synthesis of oxacycles through cyclization of an appropriate
linear precursor (Figure 1a).7 The cyclization step often poses
challenges due to entropic barriers and also requires high
dilution conditions to avoid polymerization.8 Ring expansion
reactions that are insensitive to substrate conformational effects
provide an alternative to the conventional cyclization strategy.9
However, the synthesis of an appropriate precursor for the ring
expansion reactions requires multiple steps and limits the
synthetic utility.
To overcome this chemical challenge, we envision a cascade
approach for the synthesis of oxacycles that utilizes readily
accessible starting materials (Figure 1b). The cascade begins
with carbene O−H insertion followed by an intramolecular
aldol cyclization to provide a substituted tetrahydrofuran
intermediate, which undergoes an oxy-Cope rearrangement to
provide functionalized oxacycles.
Figure 1. Synthetic approaches toward nine-membered oxacycles.
that accommodates varying functionalities including alkenes,
alkynes, and substituted aromatics.10 Additionally, cascade
Our hypothesis was inspired by our recently developed
Received: October 27, 2016
Rh2(esp)2-catalyzed chemoselective carbene O−H insertion
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03229
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactions initiated by carbene O−H insertion have been utilized
for the synthesis of substituted tetrahydrofurans.11 Further-
more, there have been reports of rhodium carbenoid initiated
sigmatropic rearrangements in literature.12
For the initial optimization, vinyl diazo benzoate 1a and β-
hydroxy vinyl ketone 2a were selected as model substrates and
exposed to Rh2(esp)2 in CH2Cl2 at room temperature (rt), and
under refluxing conditions (Table 1, entries 1, 2). To our
Lastly, we also screened the effect of solvent polarity and
reaction temperature with trifluorotoluene (boiling point 102
°C, entry 11) and chlorobenzene (boiling point 131 °C, entry
12) as a solvent respectively, but did not observe any significant
improvement.
With optimized conditions in hand, we then investigated the
scope of the carbene O−H insertion/aldol/oxy-Cope cascade
sequence using Rh2(OAc)4 as a catalyst (Figure 2). Both the
Table 1. Efficiency of Metal Salts in Carbene O−H
a
Insertion/Aldol/Oxy-Cope Cascade
b
entry
reagent
solvent, temp (°C)
product yield (%)
1
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(OAc)4
CH2Cl2, rt
3a, 45
3a, 72
3a, 71
4a, 42
4a, 68
4a, 26
4a, 29
2
CH2Cl2, reflux
DCE, reflux
3
4
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
trifluorotoluene, reflux
chlorobenzene, reflux
5
c
6
Rh2(TFA )4
d
7
Rh2(HFB )4
e
8
Cu(acac)2
Cu(OAc)2
Cu(OTf)
CM
9
CM
10
11
12
CM
Rh2(OAc)4
Rh2(OAc)4
4a, 67
4a, 68
a
All optimization reactions were performed by adding a 0.38 M
solution of 1a (1.5 equiv) into a 0.17 M solution of 2a (1 equiv) with
catalyst (1 mol %) over 3 h via a syringe pump; after the addition of a
diazo compound, all reactions were refluxed for an additional 1 h.
b
c
Isolated yields after column chromatography. TFA = trifluoroacetate.
d
e
HFB = heptafluorobutyrate. CM = complex mixture.
expectations, diazo 1a underwent a chemoselective O−H
insertion followed by an aldol cyclization to yield 3a, but did
not proceed to oxy-Cope rearrangement to complete the third
step of our envisioned cascade sequence. Since the oxy-Cope
rearrangement could be thermally driven13 we focused our
attention toward identifying an appropriate solvent and
temperature that would allow for the oxy-Cope rearrangement
to proceed after yielding 3a to generate the desired nine-
membered oxacycle 4a.
In order to initiate the cascade process at higher temper-
atures, we first attempted 1,2-dichloroethane (DCE, boiling
point 84 °C) as a solvent, but met with a similar outcome to
afford 3a exclusively (entry 3). To our delight, toluene (boiling
point 110 °C) at reflux obtained the desired oxacycle 4a, albeit
in low conversion (entry 4). Encouraged by this findings, we
then screened other Rh(II)-salts to attain nine-membered
oxacycle 4a (entries 5−7). Among them, Rh2(OAc)4 was found
to be the most efficient catalyst for the cascade sequence (entry
5). With hope to achieve the cascade sequence with earth
abundant transition metal catalysts known to effectively form
carbenoid intermediates, we also screened various Cu-salts,14
but observed a complex mixture of different products without
any trace of desired product 3a or 4a (entries 8−10).
Figure 2. Scope of Rh2(OAc)4-catalyzed carbene O−H insertion/
aldol/oxy-Cope cascade sequence; all reactions were performed by
adding a 0.38 M solution of 1 (1.5 equiv) into a 0.17 M solution of 2
(1 equiv) over 3 h via a syringe pump; after the addition of a diazo
a
compound, all reactions were refluxed for an additional 1 h. The
isolated compound 4k was subjected to the reaction conditions
Rh2(OAc)4 in refluxing toluene; no change was observed in the
diastereomeric ratio.
primary and secondary alcohols proceeded in good yield with
high stereoselectivity providing only Z-olefin oxacycles (Figure
2, 4a, 4b). We were pleased to find that the cascade sequence
worked equally well with the substituted vinyl keto alcohols in
good yields (Figure 2, 4c−e). Notably, the cascade reaction
also accommodated additional olefin functionality present in
the starting material vinyl keto alcohol 2f (Figure 2, 4f) and in
the vinyl diazo ester 1b (Figure 2, 4g).
B
DOI: 10.1021/acs.orglett.6b03229
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Organic Letters
Letter
To further explore the generality of this transformation,
substituted vinyl diazoesters were examined with the
substituted vinyl keto alcohols. Remarkably, vinyl diazoester
1b on treatment with substituted vinyl keto alcohols underwent
the desired cascade sequence smoothly to obtain the
corresponding oxacycles in good yields with complete stereo-
selectivity (Figure 2, 4h−j). The stereochemical arrangement of
substituents and Z-configuration of olefin was determined
based on the nuclear Overhauser effect (NOE) correlations and
was further confirmed by the single crystal structure of 4i using
X-ray crystallography (Figure 3, see the Supporting Information
for more details).15
compound 4a suggesting a thermally driven oxy-Cope
rearrangement (Table 2, entry 2).
As oxy-Cope rearrangement could be catalyzed under basic
conditions,16 aldol product 3a was subjected to different bases
known to promote anionic oxy-Cope rearrangement. Unfortu-
nately, we observed a complex mixture without any trace of
desired oxacycle 4a (Table 2, entries 3, 4). We also attempted
acidic conditions to catalyze oxy-Cope rearrangement, but did
not experience success (Table 2, entry 5).
These findings allow us to propose a reaction mechanism as
depicted in the Figure 4.
Figure 4. Proposed reaction mechanism for Rh2(OAc)4-catalyzed
carbene O−H insertion/aldol/oxy-Cope cascade.
Figure 3. X-ray crystal structure of oxacycle 4i.
Interestingly, we observed a decrease in diastereoselectivity
(dr = 3:1) with vinyl keto alcohol 2d bearing a substituent at
the internal position of the olefin double bond (Figure 2, 4k).
This may be attributed to the transannular interaction present
in the enol-form of the nine-membered oxacycle, which
rearranges to the thermodynamically more stable keto-form
as shown in the plausible mechanism (Figure 4).
First, diazo compound 1 is decomposed by the Rh2(OAc)4 to
form a Rh-carbenoid that undergoes a chemoselective O−H
insertion reaction with the alcohol 2. The resulting insertion
intermediate then undergoes an aldol cyclization to provide a
tetrahydrofuran intermediate 3 with high diastereoselectivity.11
The tetrahydrofuran intermediate 3 sets the stage for a
thermally driven concerted oxy-Cope rearrangement with a
boat-type transition state, which results in an enol-form having
both the substituents syn to each other. The enol-form then
rearranges to the thermodynamically more stable keto-form 4.
In conclusion, the reported rhodium carbenoid initiated O−
H insertion/aldol/oxy-Cope cascade sequence is convergent in
nature and uses readily accessible starting materials to access
functionalized nine-membered oxacycles. An important feature
of this transformation is its complete regio- and stereo-
selectivity. Applications of this chemoselective cascade reaction
to the corresponding azacycles are ongoing and will be reported
in due course.
For further insights into the reaction mechanism, additional
experiments were carried out as shown in Table 2. First, the
Table 2. Oxy-Cope Rearrangement of Compound 3a into 4a
a
under Thermal, Basic, and Acidic Conditions
b
entry
reagent
solvent, temp (°C), t
yield (%)
1
2
3
4
5
Rh2(OAc)4
−
KH, 18-crown-6
LiHMDS
CSA
toluene, reflux, 2 h
toluene, reflux, 2 h
THF, 0 °C, 5 min
THF, 0 °C, 15 min
toluene, rt to reflux, 2 h
88
90
ASSOCIATED CONTENT
* Supporting Information
c
■
CM
S
CM
CM
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03229.
a
All optimization reactions were performed with 0.1 M solution of 3a.
b
Isolated yields after column chromatography; CSA = camphor
c
sulfonic acid. CM = complex mixture.
Complete experimental details and relevant spectra for all
important compounds (PDF)
intermediate aldol product 3a, which was isolated as as single
diastereomer, was exposed to Rh2(OAc)4 in refluxing toluene.
As expected, we observed a clean formation of oxy-Cope
rearrangement product 4a in excellent yield (Table 2, entry 1).
Next, 3a was refluxed in toluene without Rh2(OAc)4 to rule out
the involvement of Rh-metal in the oxy-Cope rearrangement.
As expected, the reaction took the same time to afford the
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: isharma@ou.edu.
ORCID
Indrajeet Sharma: 0000-0002-0707-0621
C
DOI: 10.1021/acs.orglett.6b03229
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
D. A.; Stoltz, B. M.; Holubec, A. A.; Dietrich, H.-J. J. Am. Chem. Soc.
1999, 121, 1748−1749.
(13) For thermal oxy-Cope, see: (a) Thies, R. W. J. Am. Chem. Soc.
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(15) CCDC 1510906 (4i) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre (http://www.ccdc.
cam.ac.uk/).
(16) For anionic oxy-Cope, see: (a) Evans, D. A.; Baillargeon, D. J.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Susan Nimmo, Dr. Steven Foster, and Dr.
Douglas R. Powell from the Research Support Services,
University of Oklahoma, for expert NMR, mass spectral, and
X-ray crystallographic analyses, respectively. We would also like
to thank the University of Oklahoma for generous financial
support as startup funds as well as the College of Arts &
Sciences and the Vice President of Research monetary support
through the Junior Faculty Fellowship Award to Dr. Indrajeet
Sharma.
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DOI: 10.1021/acs.orglett.6b03229
Org. Lett. XXXX, XXX, XXX−XXX