Synthesis of angularly substituted trans-fused hydroindanes by convergent coupling of acyclic precursors

Article abstract of DOI:10.1021/ja504374j

Angularly substituted trans-fused hydroindanes are now accessible by the direct and convergent union of trimethylsilyl (TMS)-alkynes with 4-hydroxy-1,6-enynes by a process that forges three C-C bonds, one C-H bond, and two new stereocenters. The annulation is proposed to proceed by initial formation of a Ti-alkyne complex (with a TMS-alkyne) followed by regioselective alkoxide-directed coupling with the enyne, stereoselective intramolecular cycloaddition, elimination of phenoxide, 1,3-metallotropic shift, and stereoselective protonation of the penultimate allylic organometallic intermediate. Several examples are given to demonstrate the compatibility of this reaction with substrates bearing aromatic and aliphatic substituents, and an empirical model is presented to accompany the stereochemical observations.

Full text of DOI:10.1021/ja504374j

Communication
pubs.acs.org/JACS
Synthesis of Angularly Substituted Trans-Fused Hydroindanes by
Convergent Coupling of Acyclic Precursors
Valer Jeso, Claudio Aquino, Xiayun Cheng, Haruki Mizoguchi, Mika Nakashige, and Glenn C. Micalizio*
Department of Chemistry, Burke Laboratory, Dartmouth College, Hanover, New Hampshire 03755, United States
S
* Supporting Information
alternative to these classic strategies. Here we describe the
ABSTRACT: Angularly substituted trans-fused hydro-
indanes are now accessible by the direct and convergent
union of trimethylsilyl (TMS)-alkynes with 4-hydroxy-1,6-
enynes by a process that forges three C−C bonds, one C−
H bond, and two new stereocenters. The annulation is
proposed to proceed by initial formation of a Ti−alkyne
complex (with a TMS-alkyne) followed by regioselective
alkoxide-directed coupling with the enyne, stereoselective
intramolecular cycloaddition, elimination of phenoxide,
1,3-metallotropic shift, and stereoselective protonation of
the penultimate allylic organometallic intermediate. Several
examples are given to demonstrate the compatibility of this
reaction with substrates bearing aromatic and aliphatic
substituents, and an empirical model is presented to
accompany the stereochemical observations.
realization of such a method that proceeds from the
intermolecular union of simple acyclic starting materials and
delivers trans-fused hydroindanes bearing up to six substituents,
including an angular methyl group.
We recently described a metallacycle-mediated coupling
reaction between 4-hydroxy-1,6-enynes and internal alkynes
that delivers dihydroindanes possessing two endocyclic
tetrasubstituted alkenes.5 While this method proved useful for
the stereoselective assembly of a variety of substituted
carbocyclic structures where the stereochemistry of the angular
alkyl group (C13, steroid numbering) was reliably set anti to the
hydroxyl group at C16, the annulation reaction did not address
the ring fusion stereochemistry (C14 remained sp2-hybridized).
As illustrated in Figure 2, our efforts to address this different and
unctionalized carbocycles remain challenging targets in
F
modern chemical synthesis despite decades of effort focused
on their synthesis. In fact, campaigns to target such systems often
abandon total synthesis campaigns altogether in favor of natural
product derivatization (semisynthesis).1 Among the great variety
of ubiquitous carbocyclic motifs in natural products and
medicinal agents that continue to represent a significant
challenge are angularly substituted trans-fused hydroindanes
(bicyclo[4.3.0]nonanes; Figure 1). Synthetic strategies for such
Figure 2. Trans-fused hydroindanes by stereoselective metallacycle-
mediated cross-coupling.
more demanding stereochemical challenge (i.e., establishing the
stereochemistry of C14 in concert with the ring-forming process)
have resulted in the discovery of a metallacycle-mediated
annulation reaction that delivers angularly substituted trans-
fused hydroindanes 6 (ds up to 15:1).
Our investigations began with an exploration of the metalla-
cycle-mediated union of enyne 75 with trimethylsilyl (TMS)-
substituted phenylacetylene (8) (Figure 3). Treatment of 8 with
ClTi(Oi-Pr)3 and an ethereal solution of c-C5H9MgCl
(commercially available from Aldrich) in PhMe (−78 to −30
°C) was followed by addition of the lithium alkoxide of 7 as a
solution in Et2O. After the mixture was slowly warmed from −78
°C to rt, this reaction was terminated by addition to a −78 °C
solution containing a proton source. To our great surprise and
delight, the nature of the alcohol used to quench the presumed
organometallic intermediate had a profound effect on the
stereoselectivity of the annulation. Quenching with t-BuOH led
to a 3:2 mixture of annulation products (9a:9b) in 68% yield,
while quenching with i-PrOH showed a significant preference for
the formation of the cis-fused hydroindane 9b (ds = 10:1).7
Finally, quenching of the reaction with MeOH resulted in
Figure 1. Representative examples of natural products that possess
angularly substituted trans-fused hydroindanes.
systems typically embrace key reactions such as cation−olefin
cyclization,2 Robinson annulation,3 and cycloaddition,4 all of
which suffer from substantial challenges associated with either
the synthesis of the appropriately functionalized substrate or the
requirement of numerous reactions after ring formation to
establish the stereochemistry of ring fusion. Thus, a simple
reaction process for the direct and convergent synthesis of highly
substituted trans-fused hydroindanes would be a welcome
Received: May 1, 2014
Published: May 24, 2014
© 2014 American Chemical Society
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Figure 3. Stereoselective access to trans- and cis-fused angularly substituted hydroindanes by coupling of TMS-alkynes with 1,6-enynes.
selective formation of the more strained trans-fused hydroindane
product 9a (ds = 6:1).8 While the mechanistic underpinnings
associated with this shift in stereoselection as a function of the
alcohol employed to terminate the process remain poorly
understood, the core components of the annulation mechanism
are proposed as depicted in the bottom portion of Figure 3.
Alkoxide-directed alkyne−alkyne coupling is reasoned to be an
essential first step in the process,6 delivering the 2-silyl-
substituted titanacyclopentadiene intermediate II. Subsequent
ligand exchange to afford III and stereoselective intramolecular
[4 + 2] cycloaddition is then proposed to deliver bridged bicyclic
metallacyclopentene intermediate IV. Elimination of the distal
phenyl ether then results in the formation of V. Isomerization of
the resulting tertiary allylic metal species (to generate VI) is then
followed by stereoselective protonation via VII or VIII, which
generates the C14 stereocenter and establishes the nature of the
ring fusion (trans or cis). It was recognized that the ability to
selectively establish the stereochemistry of the ring fusion in concert
with annulation represents a significant advance in annulation
chemistry targeting this ubiquitous carbocyclic motif, and
furthermore, the discovery of a path to selectively access the
higher-energy trans-fused isomer was identified as a particularly
compelling characteristic of this reaction process.8
Moving on from these initial observations, our first goal was to
define a reaction procedure that could be run without careful
control of the reaction temperature. While the procedure
summarized in Figure 3 led to the discovery of a process for
selective generation of trans-fused hydroindanes, the exper-
imental details of the reaction were suboptimal. In short, the
temperature profile required (−78 to −30 °C and prolonged
stirring at −30 °C) resulted in a challenging experimental
protocol that was difficult to reproduce. Other characteristics of
this procedure that were unappealing included the use of a mixed
Figure 4. Annulation for the convergent synthesis of trans-fused
PhMe/Et2O solvent system and commercial solutions of
hydroindanes. In eqs 6 and 7, the ratio of products obtained after
ClTi(Oi-Pr)3. With these concerns in mind, we developed an
alternative procedure that employs Ti(Oi-Pr)4/n-BuLi to
execute the metallacycle-mediated annulation reaction in
PhMe.9 These modified reaction conditions proceed between
−78 and 50 °C and avoid prolonged stirring at −30 °C.
1
purification (dr) is given because the H NMR spectrum of the crude
material could not be resolved to determine an accurate ds.
mediated coupling and quenching with MeOH delivered
hydroindane products in 67% yield, favoring the formation of
the trans-fused isomer 9 (ds = 10:1).10 As we have seen in related
As illustrated by eq 1 in Figure 4, initial experiments examined
the reaction of TMS-phenylacetylene 8 with enyne 7. Ti-
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annulation reactions of 4-hydroxy-1,6-enynes,5 the control of
stereochemistry at C13 is quite high (all of the hydroindane
products had a C13 β-Me group; this stereocenter is predictably
set anti to the C16 hydroxy group). Also related to previous
observations, the nature of the protic quench did have an impact
on the product ratio, although the effect here was not as dramatic
as that seen in the annulation reactions promoted by the
combination of ClTi(Oi-Pr)3 and c-C5H9MgCl (Figure 3). In
short, quenching with i-PrOH delivered a 1:1 mixture of
stereoisomers, while quenching with H2O restored the selectivity
for the trans-fused isomer, albeit with a modest drop in
stereoselection (to 5:1). In no case were we able to invert the
selectivity in favor of the cis-fused isomer.
The annulation method is effective with substituted TMS-
phenylacetylenes 10 and 12, delivering trans-fused isomers 11
and 13 with selectivities of 15:1 and 12:1, respectively (eqs 2 and
3). As illustrated in eq 4, C17-furyl substitution, a common
structural feature of liminoids, can be addressed in a
straightforward fashion. Here the coupling between alkyne 8
and enyne 14 selectively delivers the trans-fused isomer 15 (ds =
10:1; 64% combined yield).
Notably, aromatic substitution on the β-face of the hydro-
indane at C17 is not required in order to achieve stereoselection
in this annulation reaction. As illustrated in eq 5, the union of
TMS-alkyne 8 with C17-methyl-substituted enyne 16 delivers
the hydroindane products in 66% yield with 11:1 selectivity in
favor of trans-fused product 17. Notably, substrates devoid of
C17 substitution can also be advanced to trans-fused hydro-
indanes with this method. As depicted in eq 6, the union of 8 with
enyne 18 proceeds in 52% yield and delivers the trans-fused
product 19 with 5:1 dr.
Figure 5. Empirical model for the annulation en route to trans-fused
hydroindanes. Note: The Ph-substituted species was arbitrarily selected
for discussion in the context of the empirical model presented above.
The TMS-alkyne coupling partner can contain substituents
other than Ph and substituted Ph. As illustrated in eq 7, the
reaction of the furyl-substituted alkyne 20 with enyne 7 delivers
the trans-fused hydroindane product 21 with 4:1 dr. Also, as
illustrated in eq 8, coupling of the isopropyl-substituted TMS-
alkyne 22 with enyne 14 delivers the trans-fused hydroindane
product 23 in 46% yield (ds = 11:1).
The stereoselectivity observed in this annulation reaction can
be rationalized as depicted in Figure 5. The central issue is
thought to be preferential positioning of the Ti species on one of
the two faces of the cyclohexadiene, setting up the stereoselective
syn SE′ addition of MeOH. Because of the rather rigid
conformation of the fused bicyclic structure, the substituent at
C9 (steroid numbering) occupies a position in space that is
slightly above the plane of the hydroindane (positioned on the β-
face), and bond rotation is sterically impeded by the presence of
the proximal TMS substituent. Thus, we speculate that a “gearing
effect” would result in preferred positioning of the Ti center
(along with its sterically demanding alkoxide ligands−not
shown) on the α-face, anti to the Ph group (as in structure A).
Subsequent quenching with MeOH by initial coordination to Ti
followed by syn SE′ addition would then deliver the trans-fused
isomer as the major product.11
Figure 6. Metallacycle-mediated annulation reaction for the convergent
synthesis of cis-fused hydroindanes.
While the Ti-mediated annulation proved to be generally
selective for the preparation of trans-fused hydroindanes when
TMS-alkynes containing propargylic branching were employed,
TMS-alkynes lacking this branching were observed to undergo
coupling with a different sense of stereoselection. As illustrated in
Figure 6, the use of benzyl-substituted TMS-acetylene (24) in
coupling reactions with enynes 18 and 7 were moderately
selective for the corresponding cis-fused products 25 and 26
(cis:trans = 3:1; eqs 9 and 10). As demonstrated in eq 11, C9
substitution of a steric nature more substantial than Me appears
to be required for any stereoselectivity in the protic quench. Here
the coupling of TMS-propyne (27) with enyne 14 delivered a 1:1
mixture of stereoisomeric hydroindanes (28).
An empirical model for the cis-selective annulation reaction is
depicted in Figure 6 and is based on the preferential disposition
of the Ph group on the α-face of the cyclohexadiene system (as in
D). Subsequent “gearing” of the metal to avoid steric interactions
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with the Ph group is thought to result in positioning of the Ti
center on the β-face, en route to the cis-fused hydroindane
product by the syn SE′ reaction with MeOH.
AUTHOR INFORMATION
Corresponding Author
glenn.c.micalizio@dartmouth.edu
■
Finally, while propargylic branching in the TMS-alkyne has
been shown to be an important structural component to enable
trans selectivity in the hydroindane-forming process, we note
that long-range steric effects can also be employed in place of
propargylic branching to regain selectivity for the trans-fused
product. For example, as illustrated in Figure 7, the function-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank the NIH NIGMS (GM080266) for financial support,
the Uehara Memorial Foundation for a postdoctoral fellowship
to H.M, and Prof. Peter Jacobi for helpful suggestions during
preparation of the manuscript.
REFERENCES
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(5) Greszler, S. N.; Reichard, H. A.; Micalizio, G. C. J. Am. Chem. Soc.
2012, 134, 2766. The enyne coupling partners used are easily prepared
in a stepwise fashion from epoxy alcohol derivatives or epichlorohydrin
[see the Supporting Information (SI) for details].
(6) Ryan, J.; Micalizio, G. C. J. Am. Chem. Soc. 2006, 128, 2764.
(7) In our initial study aimed at exploring the mechanism of the Ti-
mediated annulation reaction en route to hydroindanes possessing two
endocyclic alkenes,5 an annulation related to that in Figure 3 was
presented in support of a [4 + 2] mechanism for the annulation (rather
than alkene insertion into a metallacyclopentadiene). In that work,
quenching with sat. aq. NH4Cl resulted in cis- and trans-fused
hydroindanes without stereoselection.
(8) AM1 calculations (Spartan 2008) predict that the cis-fused isomer
9b is 3.5 kcal/mol lower in energy than the trans-fused isomer 9a.
(9) (a) Obora, Y.; Moriya, H.; Tokunaga, M.; Tsuji, Y. Chem. Commun.
2003, 2820. (b) Rassadin, V. A.; Six, Y. Tetrahedron 2014, 70, 787. For
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(10) In addition to the trans- and cis-fused isomers (formed in 64%
yield), a small amount of an endocyclic tetrasubstituted alkene
annulation product was formed (18%). Thus, the combined yield of
all annulation products was 82%. In all of the reported examples, a small
amount of this “endo” isomer was also produced; the yields given are
only for the combination of the trans- and cis- hydroindanes. See the SI
for details.
Figure 7. Long-range steric effects for selective access to trans-fused
hydroindanes.
alized benzyl-substituted TMS-alkyne 29 engages enyne 7 in a
trans-selective annulation despite not having propargylic
branching. We speculate that this is due to conformational
biasing of the aryl substituent that results in preferential
positioning on the β-face of the cyclohexadiene. To avoid further
nonbonded steric interactions, the Ti center adopts a position on
the α-face of the carbocycle (as depicted in E), setting up the syn
SE′ reaction with MeOH en route to the trans-fused product 30.
In conclusion, to the best of our knowledge, we have described
the first convergent and stereoselective process for the direct
synthesis of trans-fused hydroindanes from acyclic precursors.
The reaction is thought to proceed by a complex metallacycle-
mediated coupling reaction that features (1) initial alkoxide-
directed coupling between a Ti−alkyne complex and a
homopropargylic alkoxide, (2) stereoselective intramolecular
[4 + 2] cycloaddition to generate a complex bridged tricyclic
organometallic intermediate, (3) elimination of phenoxide, (4)
metallatropic shift, and (5) stereoselective protonation. Our
studies have demonstrated that densely functionalized hydro-
indanes with a variety of substituents at C17 and C9 (steroid
numbering) can be easily accessed. These studies have revealed
an important relationship between the structure of the TMS-
alkyne employed and the ring fusion stereochemistry established
in the product. Finally, an empirical model has been presented to
support the stereochemical observations made. It is based on the
position of the Ti center in the penultimate organometallic
intermediate and protonation via a syn SE′ mechanism.
ASSOCIATED CONTENT
* Supporting Information
Procedures and spectroscopic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(11) This empirical model is proposed only to help understand/
predict the selectivity for annulation reactions. We do not intend to
imply that stereoselective quenching of this intermediate proceeds in a
non-Curtin−Hammett manner.
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