Enantioselective Catalytic Cyclopropanation-Rearrangement Approach to Chiral Spiroketals

Article abstract of DOI:10.1021/acs.orglett.1c01113

A highly enantioselective synthesis of chiral heterobicyclic spiroketals is reported via a "one-pot"cyclopropanation-rearrangement (CP-RA) cascade reaction that is sequentially catalyzed by a chiral Rh(II) catalyst and tetrabutylammonium fluoride (TBAF).

Full text of DOI:10.1021/acs.orglett.1c01113

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Letter
Enantioselective Catalytic Cyclopropanation−Rearrangement
Approach to Chiral Spiroketals
Kuioyng Dong, Raj Gurung, Xinfang Xu,* and Michael P. Doyle*
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ABSTRACT: A highly enantioselective synthesis of chiral heterobicyclic
spiroketals is reported via a “one-pot” cyclopropanation−rearrangement
(CP-RA) cascade reaction that is sequentially catalyzed by a chiral Rh(II)
catalyst and tetrabutylammonium fluoride (TBAF). Exocyclic vinyl
substrates form spirocyclopropanes with tert-butyldimethylsilyl-protected
enoldiazoacetates in excellent yields and with excellent enantioselectiv-
ities when catalyzed by chiral dirhodium(II) carboxylates, and following
desilylation with simultaneous rearrangement in the presence of TBAF,
they give (S)-spiroketals in high yields with excellent chirality retention
(>95% ee).
Scheme 1. Synthetic Asymmetric Heterobicycles via CP-RA
Strategies
iazo compounds are versatile building blocks in synthetic
organic chemistry that have received increasing interest
D
due to their diverse transformations.1 Significant catalytic
asymmetric reactions have been made in cyclopropanation,2
C(X)−H insertion,3 cycloaddition,4 tandem reactions,5 and
other transformations.6 Reactions of diazoacetate esters in the
formation of cyclopropane derivatives were among the first
demonstrations of catalytic asymmetric induction,7 and
cyclopropane derivatives now serve as versatile building blocks
for a variety of bioactive compounds.8
An important application of heteroatom-embodied cyclo-
propanes is their subsequent rearrangement to 2,3-dihydrofur-
ans using a metal catalyst or a strong base; however, chiral
cyclopropanes that undergo this Cloke−Wilson-type rear-
rangement into 2,3-dihydrofurans generally do so with a loss of
enantiopurity (Scheme 1a, path a).9 A stepwise solution was
initially reported by Muller and coworkers. With internal olefin
̈
substrates producing stable chiral donor−acceptor cyclo-
propanes tethered to a silyl enol ether, they were able to
force rearrangement. An intermediate enolate was formed by
treating the donor−acceptor cyclopropane with TBAF
(tetrabutylammonium fluoride), which generated chiral
bicyclic acetals with high ee values. In these cases, a pro-
stereogenic carbon of the enol ether is critical to stereocontrol
in the rearrangement step (Scheme 1a, path b).10 However, for
exocyclic olefins, stereocontrol is more difficult because of its
rapid racemization during the rearrangement step. Recently,
Tang’s group reported a chiral copper/SaBOX complex-
catalyzed asymmetric cyclopropanation−rearrangement (CP-
RA) reaction of exocyclic vinyl enamines that directly provided
(R)-spiroaminals in high yields with excellent enantioselectiv-
ity.11 Encouraged by these results and our continued interest in
rhodium(II)-catalyzed asymmetric reactions, we have inves-
tigated a more challenging transformation with a vinyl ether
Received: March 31, 2021
Published: May 6, 2021
https://doi.org/10.1021/acs.orglett.1c01113
© 2021 American Chemical Society
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and now report a dirhodium(II)-catalyzed stepwise asymmetric
CP-RA reaction, providing (S)-spiroketals with a high level of
enantioselectivity in a “one-pot” reaction.
conditions were achieved with Rh2(S-TCPTTL)4 (91% yield,
99% ee) as the catalyst. Notably, in a one-pot reaction
performed without separating 3aa, direct desilylation occurred,
giving an overall good yield with excellent enantiocontrol (82%
yield, 99% ee).
Notably, the observed high enantioselectivity determined
from the catalytic CP-RA reaction of 2a was not observed with
the corresponding enolizeable diazoacetoacetate (5a) when
reacted under the same conditions without further treatment
with TBAF (eq 1); spiroketal 3aa was directly obtained in
Spiroketals are widely found in natural products, and they
have diverse biological activities.12 Consequently, their
synthetic chemistry has been promoted in recent years.
Among the methods employed, the acid-catalyzed dehydration
of ketodiols is the classical strategy,13 but a variety of
transition-metal-catalyzed strategies have also been devel-
oped.14 However, synthetic access to chiral spiroketals is
rarely reported.15
Our initial exploration was carried out using 4,4-dimethyl-5-
methylene-2-phenyl-4,5-dihydrooxazole 1a and tert-butyldime-
thylsilyl (TBS)-protected enoldiazoacetate 2a as model
substrates in dichloromethane (DCM) at room temperature
(Table 1). A variety of copper, silver, rhodium, and gold
Table 1. Optimization of Reaction Conditions for the
Cyclopropanation−Rearrangement Reaction
higher yield (92 vs 82%) but with only 69% ee. In addition, no
significant improvements were detected from the results of
other chiral dirhodium(II) catalyses and solvents. (See the SI
for details.)The scope of spiroketal syntheses was explored
with Rh2(S-TCPTTL)4 catalysis under the optimum con-
ditions. A variety of 4,4-dimethyl-methlenedihydrooxazoles 1
and enoldiazoacetates 2 were investigated. As presented in
Scheme 2, the reactions proceeded smoothly with different
ester groups of enoldiazoacetates 2. In particular, the
a
3aa
4aa
Scheme 2. Substrate Scope in Asymmetric Catalytic
Cyclopropanation−Rearrangement
a
entry
Rh(II)
yield (%) ee (%) yield (%) ee (%)
1
2
3
4
5
6
7
8
Rh2(OAc)4
Rh2(esp)2
67
88
90
85
92
89
67
NR
92
90
90
93
91
90
88
Rh2(S-PTTL)4
Rh2(S-TFPTTL)4
Rh2(S-TCPTTL)4
Rh2(S-TBPTTL)4
Rh2(S-PTAD)4
Rh2(S-DOSP)4
Rh2(S-TCPTTL)4
96
96
99
97
88
95
96
99
97
85
b
9
82
99
a
Reactions were carried out on a 0.2 mmol scale: To the dirhodium
catalyst (1.0 mol %) and 1a (0.2 mmol) in DCM (2.0 mL) was added
2a (0.3 mmol) in the DCM (2.0 mL) via a syringe pump over 1 h
under an argon atmosphere at room temperature. Desilylation with
TBAF occurred at 0 °C. Isolated yields after flash chromatography.
b
One-pot reaction without separating 3aa. NR, no reaction occurred
over 48 h, and most of 1a and 2a was recovered.
catalysts were surveyed, but only dirhodium(II) carboxylates
gave the desired product. Spiro-cyclopropane 3aa was
generated as the sole outcome with complete diastereocontrol
using dirhodium(II) carboxylate catalysis and easily underwent
desilylation to generate the spiroketal product 4aa (entries 1
and 2). Further improvement of reactivity and selectivity was
investigated by evaluating an array of chiral dirhodium(II)
carboxylate catalysts (entries 3−9). (Structure details are
presented in the SI.) Product formation failed when the
reaction was performed using the chiral prolinate-ligated
catalyst Rh2(S-DOSP)4 (entry 8), possibly because of its
coordination with the basic imine of reactant 1a. However, the
chiral phthalimide-carboxylate-ligated catalyst Rh2(S-PTTL)4
produced 3aa in excellent yield (90%) with excellent
enantioselectivity (entry 3, 96% ee). Remarkably, the spiroketal
product 4aa was formed in high yield with excellent chirality
retention from desilylation (90% yield, 95% ee). Optimized
a
Reactions were carried out at room temperature on a 0.20 mmol
scale of 1 with 0.3 mmol of enoldiazoacetate 2. Isolated yields after
flash chromatography for the two-step procedure. The ee values were
determined by high-performance liquid chromatography (HPLC)
analyses with chiral columns.
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trifluoroethyl ester of 2 gave 4ab in high yield (up 86%) with
excellent enantioselectivity (99% ee). Further exploration
revealed that the reactions exhibited little electronic or steric
influence on the reactivity or selectivity. Comparable yields
(4ac−4ag, up to 81%) with excellent enantioselectivities
(>96% ee) were obtained from different benzyl esters.
Furthermore, enoldiazoacetates containing a γ-substituent
showed a slight effect on the reactivity. Substituents including
methyl (2h), ethyl (2i), and benzyl (2j) produced the target
products in high yields (75−78%) with excellent enantiose-
lectivities (95−97% ee). Modest product yields (4ba−4da,
63−75%) but high enantioselectivities (95−98% ee) were
observed when 1 bearing electron-neutral, electron-rich, or
electron-deficient substituents on the aryl group was tested in
this reaction. The ortho-substituted congeners were also
tolerated under the current conditions (1e and 1f), delivering
the desired products in good yields with excellent enantiose-
lectivities (4ea in 71% yield with 95% ee and 4fa in 81% yield
with 96% ee, respectively). In addition to aryl-substituted
dihydrooxazoles, the desired products (4ga and 4ha) were
smoothly generated in isolated yields above 73% with
enantioselectivities up to 98% ee when 1-naphthyl and
heterocyclic 2-furyl-substituted dihydrooxazoles (1g and 1h)
were employed. The introduction of E-cinnamyl-substituted
dihydrooxazole (1i) resulted in a high yield (4ia, 82%) with
excellent enantioselectivity (4ia, 99% ee) without detecting any
reaction at the cinnamyl group. Changing the substitution at
the 2-position of the dihydrooxazole from an aryl to an
Scheme 3. Control Experiments
the low% ee is due to the rearrangement step rather than
cyclopropanation. The functional group is not stable,10 and it
undergoes spontaneous ring-opening to the zwitterion
intermediate with subsequent recyclization with 0% ee (eq
3). Furthermore, only the acetyl group provides this rearrange-
ment (eq 3). As predicted, when the donor−acceptor diazo
compound 5d was employed in this reaction, the stable
cyclopropane 6ad was generated in high yield with high
enantioselectivity (88% yield, 99% ee) (eq 4), which further
supports our hypothesis that the reaction involves a concerted
and subsequent asynchronous annulation process. However, to
our disappointment, dihydrooxazole 1k without the geminal
dimethyl group failed to give the corresponding spiroketal
product, even though cyclopropane 3ka having a high % ee
value was detected. Because of the driving force to achieve
aromaticity, the racemic proton-transfer product 8ka was
isolated in 78% yield (eq 5). To our surprise, when 1-
methylenetetrahydronaphthalene 1l without a heteroatom was
employed, the desired product 4la was obtained with excellent
enantioselectivity in moderate yield (eq 6, 66% yield, 94% ee),
which has potential implication for similar transformations
with other methylene substrates.
t
aliphatic Bu group was also compatible with this catalytic
process in somewhat lower yield but with excellent
enantioselectivity (4ja, 53% yield and 99% ee). However, an
internal 5-(R)-methylenedihydrooxazole (R = C6H5) without
4,4-dimethyl substitution failed to deliver the target spiroketal
product due to its low reactivity, and decomposition of the
diazo compound 2a was detected only in this reaction. The
structure and absolute configuration of spiroketal (S)-4ai were
established by X-ray diffraction (Figure 1).
A tentative reaction mechanism is proposed in Scheme 4.
Initially, the carbene complex A is formed from diazo
compound 2 in the presence of the Rh(II) catalyst, followed
by cyclopropanation to form B. When R1 is an acetyl group, B
undergoes spontaneous ring-opening to the zwitterion
intermediate C with subsequent recyclization to furnish 4
with low enantiomeric excess. However, when R1 is a silyl enol
ether group, intramolecular C−C bond displacement, triggered
by fluoride-promoted removal of the TBS group, occurs to
generate intermediate E from D, and subsequent protonation
completes the transformation. The aromatic product 8 is
obtained through direct proton transfer of the intermediate D.
In summary, a highly efficient asymmetric CP-RA approach
of enoldiazoacetates with methylenedihydrooxazoles has been
achieved by a one-pot cascade reaction catalyzed by a chiral
Rh(II) catalyst and promoted by TBAF sequentially. Chiral
spiroketals were generated in up to 86% yield with >95% ee
Figure 1. ORTEP diagram of the X-ray crystal structure of (S)-
methyl-7-ethyl-4,4-dimethyl-2-phenyl-1,6-dioxa-3-azaspiro-[4.4]nona-
2,7-diene-8-carboxylate 3a.
To gain insight into the reaction mechanism, we carried out
control experiments (Scheme 3). α-Benzoyldiazoacetate 5b
was reacted with 1a under standard conditions. Unlike α-
acetyldiazoacetate 5a, which directly generated the spiroketal
product 3aa, this diazoacetate formed cyclopropane 6ab as the
major product in 87% yield with 98% ee along with a minor
amount of spiroketal product 7ab in 7% yield with a poor 25%
ee. Further treatment of 6ab at room temperature with or
without Rh(II) catalyst resulted in the same outcome: 85%
yield with 25% ee after 48 h (eq 2). This result indicated that
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Notes
Scheme 4. Proposed Reaction Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the U.S. National Science Foundation (CHE-
1763168) for funding this research. The X-ray diffractometer
used in this research was supported by a grant from the U.S.
National Science Foundation (CHE-1920057).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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Experimental procedure and spectroscopic data for all
new compounds (PDF)
Accession Codes
CCDC 2068308 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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AUTHOR INFORMATION
Corresponding Authors
■
Michael P. Doyle − Department of Chemistry, University of
Texas at San Antonio, San Antonio, Texas 78249, United
States; orcid.org/0000-0003-1386-3780;
Email: michael.doyle@utsa.edu
Xinfang Xu − Guangdong Key Laboratory of Chiral Molecule
and Drug Discovery, School of Pharmaceutical Sciences, Sun
Yat-sen University, Guangzhou 510006, China;
orcid.org/0000-0002-8706-5151; Email: xuxinfang@
mail.sysu.edu.cn
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Kuioyng Dong − Department of Chemistry, University of
Texas at San Antonio, San Antonio, Texas 78249, United
States
Raj Gurung − Department of Chemistry, University of Texas
at San Antonio, San Antonio, Texas 78249, United States
Complete contact information is available at:
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