Divergent synthesis of functionalized carbocycles through organosilane-directed asymmetric alkyne-alkene reductive coupling and annulation sequence

Article abstract of DOI:10.1021/ja3083945

An organosilane-directed alkyne-alkene reductive coupling of readily available propargylsilanes is used to access densely functionalized chiral allylsilanes. The divergent reactivity of the allylsilanes can be controlled to afford a range of novel carbocy

Full text of DOI:10.1021/ja3083945

Article
pubs.acs.org/JACS
Divergent Synthesis of Functionalized Carbocycles through
Organosilane-Directed Asymmetric Alkyne−Alkene Reductive
Coupling and Annulation Sequence
Jie Wu, Yi Pu, and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University,
Boston, Massachusetts 02215, United States
S
* Supporting Information
ABSTRACT: An organosilane-directed alkyne−alkene reduc-
tive coupling of readily available propargylsilanes is used to
access densely functionalized chiral allylsilanes. The divergent
reactivity of the allylsilanes can be controlled to afford a range
of novel carbocyclic ring systems through an intramolecular allyla-
tion, [3+2] annulation, and Sakurai-like homodimerization.
In our continuing interests in developing chiral silane reagents
capable of delivering useful levels of asymmetric induction with
activated CX π-bonds,9 we envisioned that an extension of the
reductive coupling using enantioenriched propargylsilanes should
allow access to highly functionalized chiral allylsilanes. While it is
well known that chiral allylsilane reagents generally exhibit
excellent stereocontrol in reactions with electronically activated
CX π-bonds, we were interested in whether useful selectivity
can be achieved in new reactions of propargyl homologues.
In this article we detail an efficient procedure for the pre-
paration of densely functionalized allylsilanes from readily acces-
sible enantioenriched propargylsilane building blocks 1,10 that has
broadened the substrate scope for the diastereoselective alkyne−
alkene reductive coupling. The experiments described herein mark
a substantial advance in generating complex allylsilanes, which may
be used as an entry point to access carbocycles with considerable
skeletal variation in a convergent and highly selective manner
(Scheme 1).
1. INTRODUCTION
Allylsilanes enjoy a privileged role in the realm of organic syn-
thesis owing to their ease of preparation, handling and rela-
tively low toxicity, allowing their use as powerful reagents for the
synthesis of complex organic molecules and natural products.1 In
that context, a number of strategies have been developed to syn-
thesize these reagents,2,3 including the silylcupration of allenes,1a
Claisen rearrangement,1d allylic C−OH functionalization,2b
carbenoid Si−H insertion,2c,h allylic substitution,2d Pd-catalyzed
intramolecular bis-silylation,2f and alkyne−alkene reductive cross-
coupling.3 Given this background, generation of allylsilanes from
propargylsilanes, a seemingly straightforward approach, has not
been realized but restricted to partial hydrogenation and/or
hydride reduction.4
Transition metal-mediated reductive coupling reactions have
proven to be extraordinarily useful transformations due to the
inherent atom- and step-economical principles, thereby avoid-
ing alkene prefunctionalization.5 In that context, alkyne−alkene
reductive coupling represents a potentially significant and
difficult case due to the sluggish reactivity and control of regio-
and stereoselectivity. Further complications arise when a 1,2-
disubstituted olefin is used, as a new stereocenter will be created.
However, the majority of previous work in this area has been
restricted to racemic variants of this important bond construction.6
A significant breakthrough was recently documented by the
Micalizio group concerning the development of a bimolecular
alkyne−alkene reductive coupling with unactivated olefins.3,7b
That study described a double asymmetric coupling where the
newly formed allylic stereocenter appeared to be controlled
by A1,3-strain8 derived from a (Z)-homoallylic alcohol coupling
partner. However, the limited alkene substrate scope reported
for the diastereoselective version thus far presents an opportunity
for further development in this area.7
2. RESULTS AND DISCUSSION
2.1. Silane-Directed Asymmetric Alkyne−Alkene Re-
ductive Coupling. Formation of the Alkyne−Titanium
Complexes. Our initial investigation focused on the efficiency
of generating the alkyne−titanium complex from propargylsi-
lane 1, the key to a successful reductive coupling.5b,11 The plau-
sible bicyclic metallacyclopropene intermediate I may not be
favored due to excessive ring strain associated with a fused
bicyclic [3.1.0] system. Therefore, dimer II or higher order
oligomers may play a significant role in the subsequent carbo-
metalation (Figure 1).12
Received: August 28, 2012
Published: October 11, 2012
© 2012 American Chemical Society
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Scheme 1. Silane-Directed Alkyne−Alkene Reductive
Coupling and Annulation Sequence
Scheme 2. Silane-Directed Alkyne−Alkene Reductive
Coupling with Monosubstituted Olefins
Figure 1. Proposed monomeric and dimeric alkyne−titanium com-
a
b
plexes (higher order oligomeric structures are not shown).
Isolated yield after purification on SiO2. Regioselectivity was based on
1
analysis of the crude H NMR spectra; r.r. = ratio of regioselectivity.
Although attempted formation of titanocyclopropene failed
in toluene (Table 1, entry 3), treatment of propargylsilane 1a
determined to be alkene 2 and homodimer 7 derived from pro-
pargylsilane 1. In the cases of 2,3-aryl-substituted bis-homoallylic
alcohols, the coupling reactions also proceeded effectively to
furnish products in excellent regioselectivity (4c and 4e). However,
the pyridyl-substituted olefin resulted in product 4d in low yield,
presumably due to the incompatibility of the starting alkene in the
presence of nBuLi. Alkyne−alkene couplings with allylic or tris-
homoallylic alcohols only resulted in complex product mixtures.
Alkyne−Alkene Reductive Coupling with Disubstituted
Olefins. This strategy also proved to be effective in the coupling
of 1,2-disubstituted olefins at higher temperature (room tem-
perature vs 0 °C), which allowed C−C bond formation between
the two π-systems accompanied by the formation of a new allylic
stereogenic center. The reaction of a bis-homoallylic alkoxide
derived from cis-4-hexen-1-ol 8a with the in situ formed alkyne−
titanium complex of 1a was highly selective, delivering the
coupled product 4f as the only regioisomer with good di-
astereoselectivity (Scheme 3, entry 1). Notably, the reaction
between trans-4-hexen-1-ol 8b and silane 1a afforded the same
major diastereomer 4f in similar yield and selectivity (entry 2). In
a similar manner, reactions of 1b with both cis-3-hexen-1-ol 8c
and trans-3-hexen-1-ol 8d afforded the same major product 3c in
good selectivity (entries 3 and 4). The n-butyl-substituted alkene
could be coupled with good selectivity and yield using the same
condition (entry 5). Furthermore, the styrene-like reaction
partner (entry 6) and silyl variant (entries 7 and 8) were suitable
for the coupling to give products 4g−4i with excellent selectivity,
albeit in lower yield, most likely due to steric interactions
associated with the substrates. Slightly larger amounts of by-
products 2 and 7 were detected compared to reactions with
monosubstituted olefins. Allylsilanes 3e and 4j were produced in
modest yield using gem-disubstituted olefins 8h and 8i; however,
diastereoselectivity was not observed in these cases (entries 9
and 10). The absolute stereochemistry of 4f and 3c was un-
ambiguously assigned by X-ray crystallography and NOE
measurements of the corresponding [3+2] annulation product
9f and the cyclization derivative 10c′ (Scheme 4). The remaining
cases in Scheme 3 were assigned by analogy to 4f and 3c.
Table 1. Optimization for Metallacyclopropene Complex
Generation
a
b
entry
solvent
additive
temp (°C)
2a:1a
yield (%)
d
1
2
3
4
5
6
Et2O
Et2O
toluene
Et2O
Et2O
Et2O
none
−78 to −20
−78 to −20
−78 to −20
0 to −78 to −20
−78 to 0
1:4
4:1
0:1
nd
nBuLi
nBuLi
nBuLi
nBuLi
nd
0
c
na
0
1:0
80
none
−78 to 0
1:4
nd
a
b
c
1
Ratios based on crude H NMR spectra. Isolated yield. na = not
d
available. nd = not determined.
with nBuLi (1 equiv), Ti(OiPr)3Cl (2 equiv), and cyclopentyl-
magnesium chloride (4 equiv, from −78 to 0 °C) using Et2O as
the solvent delivered the (Z)-crotylsilane 2a in 80% yield after
hydrolysis (entry 5), suggesting a clean formation of the titano-
cyclopropene intermediate. The presence of nBuLi was essential
for generation of an alkoxide (entry 6), which would undergo a
rapid ligand exchange to afford the polycyclic intermediate I or
II.12 Both allylic and propargylic silanes were well tolerated in the
reaction, and no trace of Peterson elimination or protiodesily-
lation byproducts were detected.
Alkyne−Alkene Reductive Coupling with Monosubstituted
Olefins. Monosubstituted terminal olefins were evaluated in the
coupling with the in situ generated alkyne−titanium complex.13
As depicted in Scheme 2, homoallylic alcohols as well as bis-
homoallylic alcohols reacted smoothly to deliver the coupled
products in good yield and regioselectivity, with new C−C bond
formation selectively taking place at the carbon γ to the silyl group.
The major byproducts isolated from these reactions were
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Scheme 3. Silane-Directed Alkyne−Alkene Reductive
Coupling with Disubstituted Olefins
Scheme 4. Assignment of Absolute Configuration
a
The crystal structure was obtained as the monohydrate of 9f.
Scheme 5. Reductive Coupling with an E/Z Mixture of
Disubstituted Olefins
Scheme 6. Reductive Coupling Using a Phenyl-Substituted
Internal Alkyne
a
b
Isolated yield after purification on SiO2. Selectivities were based on
1
analysis of the crude H NMR spectra; r.r. = ratio of regioselectivity;
d.r. = diastereomeric ratio.
Mechanistic Proposal. A plausible mechanistic explanation
of the observed stereochemical outcome rests on a three-
dimensional shape of the polycyclic metallacycle II, which
shows a clearly defined concave nature that is influenced by the
size of the silyl substituent (Scheme 7).14 A rapid and reversible
ligand exchange between alkyne−titanium complex II and
the in situ generated alkoxide would deliver intermediate III.
The subsequent transformation likely proceeds by engaging the
Ti−C δ bond in a carbometalation event. Given the geometric con-
straints imposed by the sp2-like nature of the metallacyclopro-
pene, the developing bond should ensue from interaction of
the alkene π system of the homoallylic alcohol partner with the
C−Ti δ bond in an orientation that best accommodates the hybrid-
ization of the CC bond of the metallacycle (intermediate IV).
Thus, with the π system of the alkene coupling partner facing the
Ti−C δ bond positioned in-plane with the metallacycle, the
terminal substituent of the alkene may prefer to be oriented
outside of the concave fused metallacyclic system (syn to the silyl
substituent). In this manner, the intramolecular carbometalation
will afford the metallacyclopentene V, followed by quenching
with water to furnish the allylsilane product.15
For the cases studied, the stereochemical course of the
reaction appears to be independent of the olefin configuration,
as both cis- and trans-olefins afforded coupled products with
the same stereochemistry, and we anticipated that the coupl-
ing should occur in a stereoselective manner even with E/Z
isomeric mixtures of alkenes. A control experiment was con-
ducted using a 1:1 mixture of E/Z olefin isomers (8c and 8d)
to couple with propargylic silane 1b. As expected, the major
diastereomer 3c was obtained in good yield and with high
selectivity (Scheme 5). Therefore, the coupled products could
be obtained in a stereoselective manner even starting with iso-
meric mixtures of alkenes.
In an effort to expand the scope of this transformation, experi-
ments were conducted using alkyne 11 (phenyl group replaced
silyl group) and cis- and trans-3-hexen-1-ols (Scheme 6). Both
reactions proceeded smoothly to achieve the same major product
12 in good yield and diastereoselectivity and as a single regio-
isomer. This control experiment also indicated that the phenyl
group had sufficient steric bulk to influence the stereochemical
course of the reaction.
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the chiral silyl group. As shown in Scheme 9, the intramolecular
reaction is consistent with an antiperiplannar transition state
Scheme 7. Proposed Mechanism for Silane-Directed
Alkyne−Alkene Reductive Coupling
Scheme 9. Rationale for the Stereochemical Course of [3+2]
Annulations
2.2. Silane-Directed Asymmetric Annulation. Though
the intermolecular allylsilylation has been widely documented,9
the substrate scope for intramolecular process was limited,16
most likely due to a lack of reliable methods to prepare complex
allylsilanes. With an efficient synthesis of highly functionalized
allylsilanes now accessible, we sought to demonstrate their syn-
thetic utility. It is well documented that access to a single asym-
metric quaternary carbon is regarded as a challenging problem in
organic synthesis.17 In this context, we anticipated that silyl alde-
hydes 14 and 13, derived from alcohols 4 and 3 respectively,18
could be undertaken to achieve various cyclic compounds
bearing quaternary stereocenters and would present significant
opportunities for structural variation.
[3+2] Annulations. As described earlier in Scheme 4, upon
treatment of aldehyde 14f with BF3·OEt2 at −30 °C, 9f was
obtained through a [3+2] annulation as the only detectable
diastereomer. Thus, silyl aldehydes of type 14 with different
alkyl or aryl substituents, which were originally derived from bis-
homoallylic alcohols, were evaluated in the [3+2] annulation to
establish the generality of this transformation to deliver stereo-
defined, angularly substituted perhydrobenzofurans (Scheme 8).
(intermediate VI). However, elimination of the dimethylphe-
nylsilyl group is superseded by a [1,2]-silyl migration presumably
through trapping of the silacyclopropylium cation VII, which
delivers the bicyclic product 9. However, simply raising the
reaction temperature to 0 °C resulted in the production of cyclo-
hexanol 15, suggesting that the perhydrobenzofuran product
may undergo a Peterson elimination at higher temperature to
afford vinyl-substituted cyclohexanols.9b The in situ generation
and trapping of the derived iminium ion of 14a could also access
perhydroindole 9k through this strategy.
Furthermore, the silyl-substituted heterocycles 9 participated
in a Tamao oxidation19 or protiodesilylation,20 thereby enhanc-
ing the diversity element of the [3+2] annulation pathway
(Scheme 10). Perhydrobenzofurans bearing a fully substituted
Scheme 10. Further Diversification of [3+2] Annulation
Products
a
Scheme 8. [3+2] Annulation
stereocenter are common structural fragments integrated into a
large number of natural products. For instance, desilylated
product 17 has the same stereochemistry of the BC ring fusion
as natural subglutinol B and asporyzin A,21 underscoring a
potential route for their preparation.
Intramolecular Allylation. Alternatively, treatment of
aldehydes of type 13, originally generated from homoallylic
alcohols, with a Lewis acid afforded highly substituted cyclo-
pentanols 10 through an intramolecular exo-trig cyclization and
without detection of the [3+2] annulation product. To
optimize the reaction condition, a variety of Lewis acids were
screened using aldehyde 13a, and BF3·OEt2 proved to be the
a
Isolated yield after purification on SiO2 is given. Diastereoselectivity was
based on analysis of the crude 1H NMR spectra. w/o = with or without.
In all cases, the resulting annulation products were obtained in
moderate to good yield and with exceptional selectivity. The
diastereoselectivity can be attributed to the stereocontrol effect of
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most effective promoter of the annulation (Table 2). Moreover,
using MeCN as the solvent resulted in a cleaner reaction than
CH2Cl2 (entries 2 and 3).
Scheme 12. Stereochemical Model for Intramolecular
Allylation
Table 2. Optimization for the Intramolecular Allylation
a
b
entry
Lewis acid
solvent
temp (°C)
yield (%)
d.r.
1
2
3
4
5
6
7
TMSOTf
BF3·OEt2
BF3·OEt2
TiCl4
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
−78
−30
−30
−78
0
25
50
>20:1
>20:1
>20:1
>20:1
na
61
<20
0
afford aminocyclopentane 10f in good yield and complete
stereoselectivity (Scheme 11).
MeAlCl2
In(OTf)3
Sc(OTf)3
0
<20
0
>20:1
na
Sakurai-like Dimerization. In an effort to further explore the
skeletal diversity with the generated allylsilane reagents, we
evaluated the reactivity of bis-silyl reagents 14h and 14i.
Gratifyingly, when the bis-silyl reagents were treated with
BF3·OEt2 (2 equiv) in CH2Cl2 (0.1 M) at −50 °C, Sakurai-type
dimerization22 products 19 with desilylation of the TMS group
were obtained as single stereoisomers, without any monomer
20 detected, probably owing to the conformational rigidity and
strain in cyclization of mono-oxonium ion intermediates XI
(Scheme 13).23 The dimerization may proceed through either
0
a
b
Isolated yield after purification on SiO2. Diastereoselectivity based
on the crude H NMR spectra analysis.
1
With optimal conditions now defined, reactions of five differ-
ent aldehydes of type 13 proceeded effectively in the intra-
molecular allylation, affording the cyclopentane products as a
single diastereomer based on the starting aldehyde (Scheme 11,
Scheme 11. Stereocontrolled Synthesis of
Vinylcyclopentanes
a
Scheme 13. Sakurai-like Dimerization
a
Isolated yield after purification on SiO2. Diastereoselectivity was
1
based on the crude H NMR spectra analysis. w/o = with or without.
b
Reaction for 10f was conducted in CH2Cl2 instead of MeCN.
10a−10e). The chirality of the emerging stereocenter solely
originated from and was controlled by the nature of the silicon-
bearing stereocenter, which was consistent with the well-
established antiperiplanar transition state (Scheme 12). In
contrast to the [3+2] process that proceeds through a bridged
silyl cation intermediate as observed in the cases of aldehyde
14f, the β-silyl cation in the reaction with aldehyde 13 was
terminated by elimination of the silyl group to form an alkene.
This result was most likely due to the high energy barrier that must
be overcome for the Lewis acid-coordinated alkoxide to trap the
bridged silyl cation IX via formation of a strained trans-fused
bicyclic [3.3.0] ring system 18.
the bis-oxonium ion intermediates X or a stepwise procedure
involving the intermediates XII and XIII.
The stereochemical course of the process maybe controlled
by both TMS and dimethylphenylsilyl groups. In the proposed
transition state, the TMS group appeared to be perpendicular
and orientated antiperiplanar to the oxonium ion (Scheme 14).
The dimethylphenylsilyl group occupied the pseudoequatorial
position to give the most stable conformation, which led to
the final product 19. The configuration of 19a was deter-
mined by NOE measurement. The dimer products could
efficiently undergo oxidative cleavage or protiodesilylation as
well to enhance the synthetic utility of this dimerization
process (Scheme 15).
To extend the utility of this methodology, an in situ gen-
erated iminium ion was subjected to intramolecular allylation to
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Prof. John A. Porco, Jr., Prof. Aaron Beeler (BU-CMLD), and
Mr. Jihoon Lee in Boston University for helpful discussion. We
thank Dr. Paul Ralifo, Dr. Norman Lee, and Dr. Jeff Bacon
(Boston University) for assistance with NMR spectroscopy,
HRMS, and X-ray measurements.
Scheme 14. Stereochemical Explanation for Sakurai-like
Dimerization
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Scheme 15. Further Diversification of Dimers
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3. CONCLUSION
In summary, a sterically influenced and economical alkyne−alkene
reductive coupling has been developed to generate a range of
novel chiral allylsilanes that participated in Lewis acid-promoted
carbocyclization with excellent levels of selectivity. Readily available
chiral propargylsilanes are shown to be versatile building blocks
for the construction of complex allylsilanes by reductive coupling,
where the silyl group exhibits a significant steric influence on the
stereochemical course of the reaction. Our study paved the way for
rapid access to densely functionalized allylsilanes through an alkyne
reductive coupling (e.g., alkyne−alkyne, alkyne−aldehyde). More-
over, silane-directed asymmetric alkyne−alkene reductive couplings
exhibit an enhanced alkene substrate scope, achieving products
with useful selectivity even from isomeric mixtures of alkenes. The
subsequent annulations underscore the reliability of a silyl group
with C-centered chirality as a stereocontrol element and establish a
concise pathway for the convergent assembly of complex
carbocycles with potential pharmacological value.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org. Crystallographic data have also
been deposited with the Cambridge Crystallographic Data
Centre under CCDC 869781.
AUTHOR INFORMATION
Corresponding Author
Panek@bu.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the NIGMS
CMLD initiative (P50-GM067041). We are grateful to
■
(10) For details concerning the preparation of propargylsilanes 1, see
Supporting Information. Also see: Lowe, J. T.; Panek, J. S. Org. Lett.
2005, 7, 3231.
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Journal of the American Chemical Society
Article
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chiral alkyne (methyl-substituted) with an achiral monosubstituted
alkene has been reported in Micalizio’s synthesis of dictyostatin with
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(14) The authors are grateful to a referee for suggesting the possible
empirical model of the titanium-mediated diastereoselective reductive
coupling.
(15) The proposed empirical model for the coupling reaction has
been described as a “Class III” alkoxide-directed coupling process in
Micalizio’s review of regioselective metallacycle-mediated alkyne
coupling reactions; see ref 5b.
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(23) See Supporting Information for control experiments to support
the dimerization process.
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