Silacycle-Templated Intramolecular Diels-Alder Cyclizations for the Diastereoselective Construction of Complex Carbon Skeletons

Article abstract of DOI:10.1021/acs.orglett.1c00340

The utility of the dioxasiline ring as a π-facial directing group in the intramolecular Diels-Alder cyclization is explored. An initial investigation of substrate scope demonstrates that the rigidity of this directing group delivers robust stereocontrol across a number of substrates, affording single diastereomers in moderate to good yields. A mechanistic investigation reveals that the reactive diene is formed through γdeprotonation followed by [1,5] hydride shifts.

Full text of DOI:10.1021/acs.orglett.1c00340

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Letter
Silacycle-Templated Intramolecular Diels−Alder Cyclizations for the
Diastereoselective Construction of Complex Carbon Skeletons
Paul R. Carlson, Alexander S. Burns, Emily A. Shimizu, Shilin Wang, and Scott D. Rychnovsky*
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ABSTRACT: The utility of the dioxasiline ring as a π-facial directing group in the intramolecular Diels−Alder cyclization is
explored. An initial investigation of substrate scope demonstrates that the rigidity of this directing group delivers robust stereocontrol
across a number of substrates, affording single diastereomers in moderate to good yields. A mechanistic investigation reveals that the
reactive diene is formed through γ deprotonation followed by [1,5] hydride shifts.
IMDA reaction in which the dienophile is bound as part of a
siloxacyclopentene. As a result, the two faces of the dienophile
are sterically differentiated, leading to the observed π-facial
selectivity (Scheme 1b).13
he intramolecular Diels−Alder (IMDA) cyclization has
Tproven to be one of the most powerful tools in the
synthetic chemist’s arsenal for the rapid construction of
molecular complexity. Its high degrees of diastereoselectivity
and regioselectivity have made it a key disconnection in a
number of notable total syntheses.1,2 While the primary
strength of the IMDA reaction lies in its easily predictable
stereocontrol over multiple centers, there are certain aspects of
IMDA stereocontrol that remain challenging. For example, the
typical endo selectivity that can be predicted for an
intermolecular Diels−Alder cyclization based on electronic
factors is less certain in the intramolecular domain, especially
for complex intermediates in total synthesis, as more steric and
torsional factors come into play.3−6 The most prominent
selectivity challenge for structurally complex IMDA cycliza-
tions is that of π-facial selectivity, i.e., the face of the diene over
which the dienophile approaches. In the construction of
complex carbon skeletons, π-facial selectivity is crucial in
attaining the desired diastereomer, and as such, a number of
investigations have been dedicated to understanding the π-
facial selectivity of the Diels−Alder reaction in a variety of
specialized systems.7−11
A common strategy for approaching the problem of π-facial
selectivity in the IMDA reaction is to install a directing group
to bias the approach of the dienophile to the desired face. For
example, Boeckman and co-workers have used an alkyl
trimethylsilane as a directing group for the construction of
hydrindene and octalin scaffolds through an IMDA reaction.12
This strategy makes use of A1,3 strain with the bulky silane to
bias one facial approach over the other (Scheme 1a). In an
alternate strategy, Roush and Halvorsen have performed an
The inspiration for the strategy presented herein originated
́
from the work of Belanger in which, similar to Roush’s
siloxacyclopentene work, the rigidity of a dioxasiline ring was
used to direct the facial selectivity of an intramolecular
Vilsmeier−Haack cyclization (Scheme 1c).14 Following this
initial silacycle-directed cyclization, a subsequent azomethine
ylide 1,3 dipolar cycloaddition followed by cleavage of the silyl
group afforded the desired tricyclic core as a single
diastereomer.
Through a similar strategy, our group has recently found
success in directing π-facial selectivity in the IMDA reaction of
A to construct complex tricycle D en route to illisimonin A
(Scheme 2).15 Similar to the work of Belanger, π-facial
́
selectivity was achieved using a dioxasiline ring as a directing
group. The in situ formation of the dioxasiline served the
secondary purpose of forming the reactive Danishefsky-like
diene found in B for the IMDA addition.16 The rigidity of the
silacycle enforced the desired π-facial selectivity, affording D as
a single diastereomer after an HF workup.
Received: January 28, 2021
Published: February 26, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00340
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2183−2188
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without separation. The silacycle directing group is installed in
situ and can be removed with a simple HF workup, adding no
steps to the synthetic sequence. Finally, should a milder
workup be chosen to preserve the silacycle and yield a product
analogous to C, the resulting silyl enol ether is a highly versatile
synthon that allows for further derivatization of the Diels−
Alder adducts.18−22
Scheme 1. Relevant Directing Group Strategies
We began developing our initial success with illisimonin A
into a broader method with an optimization study. The model
substrate chosen for optimization was 1 (Table 1), mainly for
Table 1. Reaction Optimization
temp
yield of
yield of
a
a
entry
R
X
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CH2Cl2
ClCH2CH2Cl
CH2Cl2
(°C)
2
3
1
2
3
4
5
6
7
8
9
Me
tBu
tBu
Ph
Cl
Cl
OTf
Cl
Cl
Cl
Cl
OTf
OTf
40
40
40
40
80
40
80
40
80
40
−
−
−
9
30
65
60
92
78
82
76
9
Ph
−
−
−
−
10
iPr
iPr
iPr
iPr
Scheme 2. Strategy for π-Facial Control in the Synthesis of
Illisimonin A
ClCH2CH2Cl
a
1
As determined by H NMR using 0.5 equiv of 5,6-dibromobenzo-
(1,3)dioxole as an internal standard.
its greater synthetic accessibility compared to that of the
original illisimonin substrate A. The major differences in this
new substrate are in the olefin geometry of the dienophile, the
substitution at the alcohol center, and the identity of the
vinylogous ester protecting group.
In previous studies as part of our synthesis of illisimonin A,
the identity of the base was found to be crucial for this reaction
to proceed; thus, optimization focused on the identity of the
bis-electrophilic silane and the reaction solvent and temper-
ature. Seeing as the original conditions employing the sterically
unencumbered dimethyldichlorosilane gave a poor yield with
our model substrate (Table 1, entry 1), we next employed a
much bulkier silane (entries 2 and 3). However, neither of
these tert-butylsilanes showed improvement over entry 1, with
the first returning starting material and the second giving an
unimpressive NMR yield along with competing elimination to
form 3. Next, we turned to a silane of a more intermediate
steric bulk (entries 4 and 5). This diphenyldichlorosilane
showed a promising increase in yield, which an increased
reaction temperature failed to improve further. Finally, we
discovered that diisopropyl dichlorosilane gave a much
improved 92% NMR yield (entry 6). Neither an increased
reaction temperature (entry 7) nor the corresponding silyl
ditriflate (entries 8 and 9) further improved the results of entry
6.
While individual cases of silacycles directing13 and
initiating17 an IMDA cyclization have been reported, there is
no precedent, to the best of our knowledge, for taking
advantage of both features simultaneously beyond our own
work on illisimonin A. Furthermore, given the skeletal
complexity and number of stereocenters that this directing
group delivered in D, it is evident that the full potential of the
dioxasiline in IMDA cyclizations remains underdeveloped. As
such, we sought to develop our IMDA silacycle directing
strategy into a general method for accessing complex carbon
skeletons.
Some of the promising advantages of this method are as
follows. It allows for complete control of up to six
stereocenters, as highlighted by the formation of D.
Furthermore, the starting materials bear a β-hydroxy carbonyl
oxidation pattern, allowing for their straightforward prepara-
tion through a strategic aldol disconnection. Such an aldol
addition does not need to be syn/anti selective, as the
configuration at the α-carbon is typically ablated in the course
of the reaction, allowing for syn/anti mixtures to be employed
Next, we sought to elucidate the mechanism of this reaction.
Although B (Scheme 2), which ultimately engages in the
observed cycloaddition, would be the direct result of
deprotonation at the α-position of A, it could also result
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from an alternative mechanism involving deprotonation at the
γ-carbon of A followed by facile [1,5] hydride shifts.23,24
To elucidate which of these two plausible pathways was
operative in the case of the formation of D, we sought to access
6a and 6b, deuterated versions of our original system A
(Scheme 3a). If α-deprotonation were the operative mecha-
nism for the formation of the reactive diene, then when 6a or
6b was subjected to the standard IMDA conditions, the
deuterium atom would be removed, yielding fully protiated
product D. Alternatively, if γ-deprotonation were the operative
mechanism, then when 6a or 6b was subjected to the standard
IMDA conditions, the deuterium atom would be retained after
initial deprotonation, after which it would engage in a [1,5]
sigmatropic shift to generate the reactive diene, leaving it at the
γ-position in the final Diels−Alder product (Scheme 3b).
Finally, should both α- and γ-deprotonation compete in some
ratio, we reasoned that the approximate ratio could be deduced
from the extent of deuterium enrichment lost.
Scheme 3. Deuterium Labeling Study
The synthesis of 6a and 6b began with 4, which was
synthesized from the protiated analogue through two rounds of
LDA deprotonation followed by an ethanol-d6 quench, giving
moderate deuterium incorporation (65%) at the α-carbon.
Vinylogous ester 4 underwent an aldol addition with aldehyde
5 to afford diastereomers 6a and 6b with good deuterium
retention (67% and 62%, respectively).
Subjecting 6a and 6b to our original IMDA conditions gave
7a and 7b, respectively, with near-quantitative deuterium
migration to the γ-position (67% and 50% incorporation,
respectively). Furthermore, deuterium migration was diaster-
eospecific, with each aldol diastereomer yielding a unique
epimer at the deuterated carbon.
The high degree of deuterium retention in this experiment
provides compelling evidence that the mechanism of formation
for the reactive diene proceeds primarily through γ-
deprotonation. On the basis of the small deuterium loss
from 6b to 7b, we can reason that <20% of this material
undergoes an α-deprotonation mechanism. For conversion of
Figure 1. Substrate scope of the silacycle-templated IMDA reaction. Standard conditions include iPr2SiCl2 (2 equiv), DBU (6 equiv), dry CH2Cl2,
0−40 °C, and 16 h. Calculated values of ΔG⧧exo − ΔGe⧧ndo using ωB97xd/6-311G(d,p)//ωB97xd/6-31G(d) for each substrate are presented. Entries
5−8 were run in dry Cl2CH2CH2Cl2 from 0 to 80 °C.
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6a to 7a, quantitative deuterium retention suggests that γ-
deprotonation is the sole mechanism involved. Furthermore,
the diastereospecific nature of the deuterium migration
between the two diastereomers strongly suggests that the
migration occurs via a suprafacial [1,5] sigmatropic shift,
leaving the γ-deprotonation route (Scheme 3b) as the most
plausible mechanism.
The IMDA reactions presented herein were modeled using
DFT calculations. For each substrate, the transition state was
identified for the endo and exo product, and the geometries
and energies for starting materials and products were
determined. (The Bn group was replaced by Me in entries
1−4.) For compound 1, the activation energy for the endo
transition state was 17.05 kcal/mol, and the preference for the
endo transition state was 9.70 kcal/mol with respect to the exo
TS. The activation energies for the transition states ranged
from 17 to 21 kcal/mol. The preference for the observed
transition state (endo or exo) is included in Table 1 for each
entry, and full details of the calculations are reported in the
Supporting Information.
Finally, we sought to explore synthetically useful derivatiza-
tions of the products of our silacycle-templated IMDA
cyclizations. To this end, it was desirable to isolate the silyl
enol ether intermediate analogous to C, as this functional
group is a synthon for a number of useful transformations.
Gratifyingly, upon replacement of the typical HF workup with
a mild aqueous workup, silacycle-containing Diels−Alder
adduct 19 was isolated in 62% yield (Scheme 4). This silyl
Our investigation of the substrate scope of our silacycle-
templated IMDA strategy began with some simple modifica-
tions to the original system. First, we report our model
substrate 1 from the optimization study (Figure 1, entry 1).
The desired IMDA proceeded in good recovered yield, albeit
less than our measured NMR yield from Table 1. Nonetheless,
this entry demonstrates that an extension of the dienophile-
bearing chain by one methylene unit can efficiently deliver a
cyclohexyl-fused norbornane skeleton. Exclusive exo selectivity
was achieved from 8, which bears a Z olefin geometry at the
dienophile (entry 2). Entry 3 catalogues an endo selective
IMDA to afford a cyclopentene-fused norbornane scaffold.
Finally, in entry 4, a vinyl sulfone proves to be a competent
dienophile for this reaction, furnishing the corresponding
norbornane in moderate yield. Attempts to expand this
methodology to six-membered vinylogous esters have thus
far proven unsuccessful, as elimination of the β-alcohol
outcompetes the desired Diels−Alder reaction for these
substrates. A detailed table of failed substrates can be found
in the Supporting Information.
Scheme 4. Product Derivatizations
Next, we probed more challenging changes to our system
using substrates that no longer benefit from being highly
activated, Danishefsky-like dienes. It is worth noting that these
substrates required increased temperatures (80 °C in
ClCH2CH2Cl) to reach full conversion, likely as a result of
the lower HOMO energy of the diene. Replacing the cyclic
vinylogous ester of previous substrates with the simple
cyclopentenone in 14 (entry 5) afforded simple norbornane
15-endo in moderate yield. The decrease in yield as compared
to those of the more activated substrates is attributed to a
competing elimination of the alcohol to afford a product
analogous to 3. Interestingly, 16, the constitutional isomer of
14 (entry 6), also afforded 15-endo, albeit in low yield.
Presumably, this convergence is possible as the result of [1,5]
hydride shifts allowing the silacycle intermediate of 16 to
sample all possible reactive dienes for the IMDA. It is worth
noting that substrates such as 16 can be derived from a
strategic Baylis−Hillman disconnection. This outcome high-
lights a practical use of the conclusions drawn from our
mechanistic study.
Finally, entries 7 and 8 present an intriguing mechanistic
case. We initially probed these two substrates anticipating that
their respective Diels−Alder adducts would be epimeric at the
methylene bridge. However, we were surprised to find that
both 17a and 17b afforded 19 in moderate yield.25 One
possible explanation for this outcome arises from regioselective
deprotonations of the different diastereomers. If ketone 17a
were to exclusively undergo an α-deprotonation pathway and
ketone 17b were to exclusively go through γ-deprotonation,
then, after [1,5] hydride shifts, the same diene would be
produced in both cases, which would lead to the observed
product 19. Such a result would not necessarily be at odds with
our mechanistic study given that the additional substitution at
the γ-position may lead to a deprotonation preference different
from that observed in Scheme 3.
enol ether was subsequently employed in a Mukaiyama aldol
reaction that successfully forged an all-carbon quaternary
center and afforded 20 in moderate yield as a mixture of
diastereomers. Less sensitive reactions allowed 19 to be taken
forward without purification, avoiding any hydrolysis of this
sensitive functional group that may occur in the course of silica
gel chromatography. For example, crude 19 was successfully
derivatized as osmate ester 21, allowing for X-ray crystallo-
graphic analysis to confirm our assigned relative configuration
(Figure 2).26−28 Additionally, crude 19 was brominated to
afford tertiary bromide 22 in 50% yield over two steps. Finally,
to target carbon skeletons beyond the cyclopentyl- and
cyclohexyl-fused norbornanes explored thus far, a Baeyer−
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Authors
Paul R. Carlson − Department of Chemistry, University of
California at Irvine, Irvine, California 92697, United States
Alexander S. Burns − Department of Chemistry, University of
California at Irvine, Irvine, California 92697, United States
Emily A. Shimizu − Department of Chemistry, University of
California at Irvine, Irvine, California 92697, United States
Shilin Wang − Department of Chemistry, University of
California at Irvine, Irvine, California 92697, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00340
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Erdwin Orellana [University of California at
Irvine (UCI)] for an initial investigation into the substrate
scope of this transformation. The authors thank Dr. Joe Ziller
(UCI) for determining the X-ray structure of osmate 21. The
National Science Foundation (CHE 1764380) provided
support.
Figure 2. X-ray structure of osmate ester 21.
REFERENCES
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00340.
■
sı
Experimental procedures, characterization data, X-ray
crystallographic data for 21, computational details, and
related NMR spectra for new compounds (PDF)
Accession Codes
CCDC 2059469 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
Scott D. Rychnovsky − Department of Chemistry, University
of California at Irvine, Irvine, California 92697, United
States; orcid.org/0000-0002-7223-4389;
Email: srychnov@uci.edu
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MeOH resulted only in a retro-Michael addition.
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