Stereoselective cyclization of functionalized 1, n-diynes mediated by [X-Y] reagents [X-Y = R3Si-SnR′3 or (R2N) 2B-SnR′3]: Synthesis and properties of atropisomeric 1,3-dienes

Article abstract of DOI:10.1021/ja105939v

The borylstannane [-N(Me)CH₂CH₂(Me)N-]B-SnMe ₃ is a superior reagent capable of effecting bisfunctionalization- cyclization in several highly functionalized 1,n-diynes, 1,n-enynes, and 1,n-allenynes (including 1,2-dipropargylbenzenes, 2,2′- dipropargylbiphenyls, 4,5-dipropargyldioxolanes, and 1,4-dipropargyl-β- lactams) where the more well-known silylstannanes fail. Variable-temperature NMR studies showed that conformational restraints imposed by selected backbones increase the activation barrier for the helical isomerization in (Z,Z)-dienes that are generated in the cyclization of the diynes. In the biphenyl and dioxolane systems, the reactions proceed with surprisingly good regio-and stereoselectivity. The resulting diazaborolidine derivatives are hydrolytically unstable but can be isolated by recrystallization or precipitation. For further synthetic applications, it is advantageous to convert these compounds in situ into the corresponding dioxaborolidines with either retention of the Me ₃Sn group or replacement of this group via halodestannylation. The configurations of the vinyl moieties are preserved in these reactions. Highly functionalized dibenzocyclooctadienes, which adorn the carbon frames of several important cytotoxic natural products, can be synthesized using this chemistry.

Full text of DOI:10.1021/ja105939v

Published on Web 08/31/2010
Stereoselective Cyclization of Functionalized 1,n-Diynes
Mediated by [X-Y] Reagents [X-Y ) R3Si-SnR′3 or
(R2N)2B-SnR′3]: Synthesis and Properties of Atropisomeric
1,3-Dienes
Ramakrishna Reddy Singidi, Amanda M. Kutney, Judith C. Gallucci, and
T. V. RajanBabu*
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue,
Columbus, Ohio 43210
Received July 14, 2010; E-mail: rajanbabu.1@osu.edu
Abstract: The borylstannane [-N(Me)CH2CH2(Me)N-]B-SnMe3 is a superior reagent capable of effecting
bisfunctionalization-cyclization in several highly functionalized 1,n-diynes, 1,n-enynes, and 1,n-allenynes
(including 1,2-dipropargylbenzenes, 2,2′-dipropargylbiphenyls, 4,5-dipropargyldioxolanes, and 1,4-dipro-
pargyl-ꢀ-lactams) where the more well-known silylstannanes fail. Variable-temperature NMR studies showed
that conformational restraints imposed by selected backbones increase the activation barrier for the helical
isomerization in (Z,Z)-dienes that are generated in the cyclization of the diynes. In the biphenyl and dioxolane
systems, the reactions proceed with surprisingly good regio- and stereoselectivity. The resulting diaz-
aborolidine derivatives are hydrolytically unstable but can be isolated by recrystallization or precipitation.
For further synthetic applications, it is advantageous to convert these compounds in situ into the
corresponding dioxaborolidines with either retention of the Me3Sn group or replacement of this group via
halodestannylation. The configurations of the vinyl moieties are preserved in these reactions. Highly
functionalized dibenzocyclooctadienes, which adorn the carbon frames of several important cytotoxic natural
products, can be synthesized using this chemistry.
Introduction
consequence of the mechanisms of the various organometallic
steps involved, results in the placement of the Si and Sn
Cyclizations of R,ω-diynes and other similar 1,n-π-systems
such as enynes, allenynes, and bisallenes mediated by main-
group bismetallic reagents have attracted considerable attention
because of the ease with which highly functionalized products
with versatile latent functionalities are generated from relatively
simple substrates.1 In initial work in the area, we reported a
facile synthesis of a new class of 1,4-disubstituted (Z,Z)-1,3-
dienes (2) via Pd(0)-catalyzed silylstannylation/cyclization of
1,6-diynes (1) mediated by R3Si-SnR′3 reagents (eq 1).2 The
exceptional control of regio- and stereoselectivity, a necessary
substituents in an “inside” orientation, thus creating a helical
motif. In these reactions, only (Z,Z)-dienes are formed, and
common functional groups such as silyl and alkyl ethers, esters,
amides, nitriles, chlorides, and even free amines and alcohols
in the starting diyne are tolerated. A number of adducts,
including 3-8 (eq 1), were synthesized in good to excellent
yields. The structures and configurations of the (Z,Z)-diene
adducts have been rigorously established by multinuclear (1H,
13C, 119Sn) NMR methods and, in one case, by X-ray crystal-
lographic analysis of a solid derivative. We expected the rate
of the helical isomerization process in these systems (eq 1) to
depend on the size of the groups on Si and Sn and the
substitution pattern around the ring. In solution, this process is
surprisingly facile in monocyclic systems, and the two isomers
are in rapid equilibrium, a process that can be monitored by
variable-temperature (VT) NMR spectroscopy (Figure 1). The
diastereotopic methylene protons (HA and HB) in 3, which appear
as a broad singlet above 298 K but as two AB quartets below
257 K, were used to accurately measure the kinetic parameters
for the enantiomerization by line-shape analysis.3
(1) For recent reviews of multicomponent cyclizations, see: (a) Itoh, K.;
Matsuda, I.; Yamamoto, K. J. Synth. Org. Chem., Jpn. 1999, 57, 912.
(b) Suginome, M.; Ito, Y. Chem. ReV. 2000, 100, 3221. For other
representative examples involving acetylenes, see: (c) Tamao, K.;
Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 6478. (d) Tsuda,
T.; Kiyoi, T.; Miyane, T.; Saegusa, T. J. Am. Chem. Soc. 1988, 110,
8570. (e) Ojima, I.; Donovan, R. J.; Shay, W. R. J. Am. Chem. Soc.
1992, 114, 6580. (f) Chatani, N.; Fukumoto, Y.; Ida, T.; Murai, S.
J. Am. Chem. Soc. 1993, 115, 11614. (g) Kondo, T.; Suzuki, N.; Okada,
T.; Mitsudo, T. J. Am. Chem. Soc. 1997, 119, 6187. (h) Ojima, I.;
Zhu, J.; Vidal, E. S.; Kass, D. F. J. Am. Chem. Soc. 1998, 120, 6690.
(i) Madine, J. W.; Wang, X.; Widenhoefer, R. A. Org. Lett. 2001, 3,
385. (j) Doung, H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004,
126, 11438. (k) Miura, T.; Shimada, M.; Murakami, M. J. Am. Chem.
Soc. 2005, 127, 1094. (l) Brummond, K. M.; You, L. Tetrahedron
2005, 61, 6180. (m) Tsuchikama, K.; Kuwata, Y.; Shibata, T. J. Am.
Chem. Soc. 2006, 128, 13686. (n) Beletskaya, I.; Moberg, C. Chem.
ReV. 2006, 106, 2320. (o) Denmark, S. E.; Liu, J. H.-C. J. Am. Chem.
Soc. 2007, 129, 3737.
The myriad possibilities for further stereoselective function-
alization of the dienes through the use of the vinyl moieties as
well as the potential use of the resident axial chirality for
introduction of new stereocenters provided sufficient impetus
(2) Greau, S.; Radetich, B.; RajanBabu, T. V. J. Am. Chem. Soc. 2000,
122, 8579.
(3) Warren, S.; Chow, A.; Fraenkel, G.; RajanBabu, T. V. J. Am. Chem.
Soc. 2003, 125, 15402.
9
13078 J. AM. CHEM. SOC. 2010, 132, 13078–13087
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Stereoselective Cyclization of Functionalized 1,n-Diynes
A R T I C L E S
(b) how to control the regioselectivity of the [X-Y] addition
in an unsymmetrical 1,n-diyne (see eq 2a); and (c) how to
increase the activation barrier to allow the atropisomer(s) to be
isolated at or near room temperature (eq 2b). For example,
would substitution on the backbone (eq 2b) permit such
isolation? If so, in these reactions, could we bring about
atropselectivity that is dependent on the substrate (diastereose-
lectivity), or even better, on a metal catalyst in the reactions of
a prochiral substrate (enantioselectivity)?
for more work in this area. However, before the contemplation
of any serious synthetic applications of these and other related
[X-Y]-mediated cyclizations, a number of important issues have
to be addressed, among which are the following: (a) identifica-
tion of the most optimal [X-Y] reagent to allow facile
cyclization and subsequent chemistry of the installed functional-
ity for carbon-carbon or carbon-heteroatom bond formations;
While the Pd-catalyzed silylstannylation-cyclization (eq 1)
is a very useful reaction for the synthesis of highly functionalized
cyclyopentanoid compounds from diynes,2,3 allenynes,4,5 and
allenealdehydes,6 its use for the synthesis of carbocyclic and
heterocyclic compounds of other ring sizes is severely limited.
Kinetically unfavorable cyclization reactions are hampered by
the formation of acyclic products via simple 1,2-additions7 and,
in several substrates carrying a coordinating propargylic or
homopropargylic substituent, dimerization of the starting ma-
terial. Two examples of this dimerization are shown in eq 3a,b.8
In these cases, no cyclization products were detected under the
reaction conditions. Likewise, when an internal alkyne is
involved, as shown in eq 3d, only acyclic products (15b and
15c) are formed. In sharp contrast, the corresponding 1,6-diyne
with two terminal alkynes [1 (Z ) NTs, R ) H)] gave a good
yield of the cyclic product 15a (eq 3c). Several other examples
of substrates for which the cyclization reactions failed when
the [Si-Sn] reagent was used are listed in column 5 of Table
1. Examples of more complex substrates that highlight the
limitations of the [Si-Sn] reagents can be seen in ref 7.
The challenges outlined in the previous paragraphs became
immediately apparent as we sought to apply9 these types of
cyclization reactions in a general synthesis of dibenzocyclooc-
tadienes (Figure 2 left),10 a class of compounds with wide-
ranging biological activities. In this paper, we report the results
of our investigations that led to satisfactory resolutions of several
of the issues raised above, including the expanded use of the
(4) Shin, S.; RajanBabu, T. V. J. Am. Chem. Soc. 2001, 123, 8416.
(5) Kumareswaran, R.; Shin, S.; Gallou, I.; RajanBabu, T. V. J. Org.
Chem. 2004, 69, 7157.
(6) (a) Kumareswaran, R.; Gallucci, J.; RajanBabu, T. V. J. Org. Chem.
2004, 69, 9151. (b) Kang, S.-K.; Ha, Y.-H.; Ko, B.-S.; Lim, Y.; Jung,
J. Angew. Chem., Int. Ed. 2002, 41, 343.
(7) Apte, S.; Radetich, B.; Shin, S.; RajanBabu, T. V. Org. Lett. 2004, 6,
4053.
(8) Gallou, I. Selective Pd- and Rh-Catalyzed Processes: I. Enantioselective
Synthesis of Tetrahydroquinolines; II. The Asymmetric Hydroformyl-
ation Reaction. III. Silylstannylation of Diynes and Alleneynes. Ph.D.
Thesis, The Ohio State University, Columbus, OH, 2002.
(9) Singidi, R. R.; RajanBabu, T. V. Org. Lett. 2008, 10, 3351.
Figure 1. VT NMR behavior of (Z,Z)-1,3-diene 3 (only HA and HB are
shown).
9
J. AM. CHEM. SOC. VOL. 132, NO. 37, 2010 13079

A R T I C L E S
Singidi et al.
Scheme 1. Relative Reactivities of [Si-Sn] and [B-Sn] Reagents
surmised that the backbone of a 1,2-bis(alkylidene)cycloalkane
(eqs 1 and 2b) significantly influences the rate of the helical
isomerization process, indicating that it should be possible to
increase the free energy of activation (∆Gq) for this process by
restricting the conformational mobility of this unit. In addition,
this system would permit examination of hitherto unexplored
aspects of stereocontrol via chirality transfer (axial to axial) from
the biphenyl system to a newly created helical moiety. Since
the cyclized product (Scheme 1) has two elements of axial
chirality, it is conceivable that there is some atropselectivity in
the formation of the nonplanar diene, i.e., a preference to form
one of the diastereomers (R*,R*) or (R*,S*).
a
a
a
a
In the event, the exploratory studies of the Pd-catalyzed
silylstannylation of 17 under a variety of conditions [Pd2(dba)3,
THF, 80 °C; Pd2(dba)3/P(C6F5)3, room temperature (rt) to 65
°C; Pd2(dba)3/P(C6H12)3, C6H6, 80 °C; Pd2(dba)3/P(o-tolyl)3,
C6H6, 80 °C; Pd2(dba)3/P(2-furyl)3, C6H6, 80 °C; Pd2(dba)3, dppe,
THF, 65 °C; Pd2(dba)3/P(C6F5)3, rt to 65 °C] gave only trace
amounts of the expected product (Scheme 1). The borylstan-
nylation-cyclization, on the other hand, proceeded in very good
yield under two different sets of conditions, giving exclusively
the product 18 as a single diastereomer in >75% yield. The
reaction could be carried out using PdCl2 ·(PPh3)2 or Pd2(dba)3 ·
[B-Sn] reagent 16 (Figure 2 right).11,12 We found that this
reagent has several advantages in comparison with the [Si-Sn]
reagents, including increased reactivity, better chemo- and
regioselectivity in the reactions of several key substrates, and
broad utility in the use of the adducts in complex molecule
synthesis.13
Results and Discussion
Our initial studies started with an examination of the
cyclization of 2,2′-di-2-propynyl-1,1′-biphenyl (17), as shown
in Scheme 1. The choice of the biphenyl scaffold was based on
two premises besides the obvious similarity to the backbone of
the dibenzocyclooctadienes (Figure 2a), the key targets in our
synthesis efforts. From our dynamic NMR studies,3 we had
(10) For representative references on the isolation and biological activities
of these classes of compounds, see: (a) Chang, J.; Reiner, J.; Xie, J.
Chem. ReV. 2005, 105, 4581. (b) Li, H.; Wang, L.; Yang, Z.; Kitanaka,
S. J. Nat. Prod. 2007, 70, 1999. (c) Chen, D.-F.; Zhang, S.-X.; Kozuka,
M.; Sun, Q.-Z.; Feng, J.; Wang, Q.; Mukainaka, T.; Nobukuni, Y.;
Tokuda, H.; Nishino, H.; Wang, H.-K.; Morris-Natschke, S. L.; Lee,
K.-H. J. Nat. Prod. 2002, 65, 1242. (d) Chen, D.-F.; Zhang, S.-X.;
Xie, L.; Xie, J.-X.; Chen, K.; Kashiwada, Y.; Zhou, B.-N.; Wang, P.;
Cosentino, L. M.; Lee, K.-H. Bioorg. Med. Chem. 1997, 5, 1715. (e)
Kuo, Y.-H.; Wu, M.-D.; Hung, C.-C.; Huang, R.-L.; Kuo, L.-M. Y.;
Shen, Y.-C.; Ong, C.-W. Bioorg. Med. Chem. 2005, 13, 1555. (f) Chen,
D.-F.; Zhang, S.-X.; Chen, K.; Zhou, B.-N.; Wang, P.; Cosentino,
L. M.; Lee, K.-H. J. Nat. Prod. 1996, 59, 1066. (g) Tan, R.; Li, L. N.;
Fang, Q. Planta Med. 1984, 50, 414. (h) Ikeya, Y.; Taguchi, H.;
Yosioka, I. Chem. Pharm. Bull. 1982, 30, 3207. (i) Ikeya, Y.; Taguchi,
H.; Yosioka, I.; Kobayashi, H. Chem. Pharm. Bull. 1979, 27, 2695.
(11) Niedenzu, K.; Rothgery, E. F. Synth. React. Inorg. Met.-Org. Chem.
1972, 2, 1.
(12) Onozawa, S.; Hatanaka, Y.; Choi, N.; Tanaka, M. Organometallics
1997, 16, 5389.
Figure 2. (left) Examples of biologically active dibenzocyclooctadienes.
(right) Stannylborane reagent 16.
(13) Singidi, R. R.; RajanBabu, T. V. Org. Lett. 2010, 12, 2622.
9
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Stereoselective Cyclization of Functionalized 1,n-Diynes
A R T I C L E S
CHCl3/Feringa phosphoramidite (L)14 as a catalyst. The latter
conditions generally gave a cleaner reaction, even though the
product formed was nearly racemic. VT NMR spectroscopy
showed that this molecule (18) or a pinacolboronate derivative
prepared from this molecule (19) does not undergo helical
isomerization up to 55 °C. This aspect will be discussed in
greater detail later.
Scheme 2. Silylstannylation-Cyclization of
2,2′-Dipropargylbiphenyls with Restricted Rotation
We2-5 and others1b,n,12,15 have invested considerable effort
in optimizing the metal/ligand combination for these multicom-
ponent reactions. However, no general trend has emerged, and
each situation demands scouting experiments to identify the most
suitable set of conditions for a particular substrate class.
Gratifyingly, the scouting experiments for these reactions are
remarkably easy to run, since doing so often involves no more
than simply mixing the substrate with the appropriate reagent
in near-stoichiometric amounts in a neutral solvent such as C6D6
and then following the reaction by NMR spectroscopy at room
temperature or slightly above that. The starting materials and
products have unmistakable NMR characteristics, and often one
even has a choice of several nuclei upon which to rely. In the
silylstannylation-cyclization of 1,6-diynes and allenynes, our
early studies2-4 indicated that the use of a combination of Pd(0)
(usually in the form of Pd2dba3) and P(C6F5)3 as the catalyst is
the most suitable when the reaction is carried in a nonpolar
solvent such as benzene. Chelating ligands have generally been
found to be less effective, possibly because the key oxidative
addition of the [X-Y] reagent to these complexes is known to
be slow.15c,e For the borylstannylation-cyclization, we have
most often used the Tanaka conditions12 [PdCl2 ·(PPh3)2, 1-5
mol %, C6H6, rt], even though the most recent studies seem to
suggest that Pd2dba3/ phosphoramidites give cleaner products
at shorter reaction times. The generality of this observation has
yet to be confirmed.
which would be needed for the projected syntheses of diben-
zocyclooctadienes. (i) Diynes carrying a simple unsubstituted
biphenyl backbone, such as 17, have a low barrier (<5 kcal
mol-1) for atrop-interconversion. Generation of an additional
chiral element could in principle proceed with some diastereo-
selectivity if this atropisomerism has a barrier lower than that
of any of the steps involved in the cyclization process and the
products themselves are stable with respect to further equilibra-
tion. Under these conditions, the reaction could be fall in the
Curtin-Hammett regime. (ii) Additionally, if there is a chiral
center present in the chain containing the diynes, such a center
could impact the configuration of the newly created chiral
element (in the case of a diyne cyclization, this would be the
configuration of the newly created, axially chiral diene). In order
to separate these two factors, we chose to restrict the confor-
mational mobility of the biphenyl unit by introducing two
methoxy substituents at the 6 and 6′ positions. A propargylic
substituent (OR in structures 20a-f in Scheme 2) was intro-
duced by acetylide addition to the corresponding biaryl-derived
aldehyde.16 The silylstannylation-cyclization was probed in the
reactions of the diynes 20a-f,16 and the results are shown in
Scheme 2. Even though 21 is formed as a single regio- and
stereoisomer, the reaction is complicated by significant con-
tamination from the acyclic adducts 22 and 23. The protecting
group on the C6 OH group has a pronounced effect on the
regioselectivity of these reactions. In the cyclization product
21, the silyl group is placed exclusively on the terminal carbon
of the unsubstituted propargyl side chain. The unprotected
propargylic alcohol (20a) and the TBS ether (20c) seem to direct
the addition to the proximal alkyne, giving 22a and 22c,
There are two factors that need to be considered in the context
of the cyclization of more complex biaryl-containing alkynes,
(14) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz,
R.; Feringa, B. Tetrahedron 2000, 56, 2865.
(15) For key references dealing with the use of different types of ligands
for palladium in multicomponent additions and cyclizations, see:
Reviews: (a) Burks, H. E.; Morken, J. P. Chem. Commun. 2007, 4717.
(b) Ohmura, T.; Suginome, M. Bull. Chem. Soc. Jpn. 2009, 82, 29. A
theoretical study of [Si-Sn] additions to alkynes: (c) Hada, M.;
Tanaka, Y.; Ito, M.; Murakami, M.; Amii, H.; Ito, Y.; Nakatsuji, H.
J. Am. Chem. Soc. 1994, 116, 8754. Some representative examples of
unique ligand effects in [X-Y]-mediated addition and cyclization
reactions: (d) Use of an isonitrile complex: Suginome, M.; Nakamura,
H.; Ito, Y. J. Chem. Soc., Chem. Commun. 1996, 2777. (e) Ligand
effects on oxidative addition of [B-Sn] reagents to Pd(0): Onozawa,
S.-y.; Hatanaka, Y.; Sakakura, T.; Shimada, S.; Tanaka, M. Organo-
metallics 1996, 15, 5450. Also see: Onozawa, S.; Hatanaka, Y.;
Tanaka, M. Chem. Commun. 1997, 1229. (f) Ligand/metal effects on
[B-Si] additions: Suginome, M.; Matsuda, T.; Nakamura, H.; Ito, Y.
Tetrahedron 1999, 55, 8787. (g) Ligand effects on [Si-Sn]-mediated
enyne cyclization: Mori, M.; Hirose, T.; Wakamatsu, H.; Imakuni,
N.; Sata, Y. Organometallics 2001, 20, 1907. Lautens, M.; Mancuso,
J. Synlett 2002, 394. (h) Use of an N-heterocyclic carbene ligand for
enyne cyclization: Sato, Y.; Imakuni, N.; Mori, M. AdV. Synth. Catal.
2003, 345, 488. Also see: Sato, J.; Imakuni, N.; Hirose, T.; Wakamatsu,
H.; Mori, M. J. Organomet. Chem. 2003, 687, 392. (i) Ligand-free
Pd(0) for silylstannylation of allenes: Jeganmohan, M.; Shanmu-
gasundaram, M.; Chang, K. J.; Cheng, C. H. Chem. Commun. 2002,
2552. (j) A more effective Pd source for [B-Si] additions: Suginome,
M.; Ohmura, T.; Miyake, Y.; Mitani, S.; Ito, Y.; Murakami, M. J. Am.
Chem. Soc. 2003, 125, 11174. (k) Use of a (EtO)3P ligand: Nakano,
T.; Miyamoto, T.; Endoh, T.; Shimotani, M.; Ashida, N.; Morioka,
T.; Takahashi, Y. Appl. Organomet. Chem. 2004, 18, 65. (l) Metal/
ligand effects on [B-CN] addition to alkynes: Suginome, M.;
Yamamoto, A.; Murakami, M. J. Am. Chem. Soc. 2003, 125, 6358.
(m) Electronic effect on regioselectivity of [B-B] addition: Iwadate,
N.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 2548.
(16) Details of the substrate syntheses can be found in the Supporting
Information.
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A R T I C L E S
Singidi et al.
Scheme 3. [B-Sn]-Mediated Cyclization of an Axially Chiral
1,9-Diyne
of diynes, including several instances where the corresponding
silylstannylation-cyclization reactions fail (Table 1). With this
isolation protocol, the functional-group compatibility of the
[B-Sn]-mediated cyclization and its relative advantages in
comparison with the corresponding [Si-Sn]-mediated reaction
can be ascertained.
In addition to the 2,2′-dipropargylbiphenyls 17 and 20b
(Schemes 1 and 3, respectively), the related diynes 20c, 27, and
30 (Table 1, entries 2-4) also undergo the cyclization reaction
with very high chemo-, regio-, and stereoselectivity to give
dibenzocyclooctadienes. The presence of an additional stereo-
genic center, such as the benzylic ether in entries 2-4, does
not erode the regio- or stereoselectivity; formation of a single
isomer was observed in each case, including in the cyclizations
of the enantiomerically pure substrates 27 and 30 (entries 3 and
4). The configurations of 24b and 25b were determined on the
basis of the solid-state structure of a destannylated compound
(26, Scheme 3), while those of the similar compounds 28-31
were deduced from the similarity in the structures of the starting
diynes and from comparison of their 1H NMR parameters with
those of the former set.
These cyclizations and the derivatization protocols are more
broadly applicable. While the dipropargyl-N-tosylamine 33 (R
) H) (Table 1, entry 5) undergoes efficient cyclization with
both [Si-Sn] and [B-Sn] reagents,2,12 the [B-Sn] reagent is
clearly superior for the corresponding 1-methylalkyne 34 (R )
Me). The diyne 34 failed to cyclize with the [Si-Sn] reagents,
giving instead an acyclic adduct.7 In sharp contrast, the [B-Sn]
reagent effected efficient cyclization, giving a highly crystalline
adduct 35. Likewise 1,2-dipropargylbenzene (36) undergoes
borylstannylative cyclization to give 37, which was isolated as
the pinacolboronate 38 in 94% yield (entry 6).
respectively, as the major uncyclized addition products. In these
instances, the putative Pd-C(sp2) intermediates formed in the
first step of the reaction are reluctant to participate in the
cyclization event, leading to early reductive elimination with
the formation of the 1,2-silylstannane. In sharp contrast, the
reactions initiated at the unsubstitued alkynes in 20b, 20d, and
20e lead to substantial cyclization (giving 21b, 21d, and 21e,
respectively).
While screening other similar [X-Y] reagents for the
cyclization of diyne 20b, we again found that it undergoes highly
regio- and stereoselective (atropselective) cyclization upon
reaction with Me3Sn-B[-N(Me)CH2CH2(Me)N-] (16) in the
presence of PdCl2 ·(PPh3)2 to give a single product, 24 (Scheme
3).9 The 1,3-bisazaborolidine 24 is moisture- and air-sensitive,
and in the past, isolation of these compounds has limited the
utility of this otherwise powerful reaction.12,17 We found that
the bis(aza)borolidine is readily converted in situ into air-stable
vinylboronate 25 by treatment with pinacol in the presence of
catalytic amounts of a strong acid.18,19 The structures of the
(Z,Z)-1,2-bis(alkylidene)dibenzocyclooctadienes 24 and 25 were
determined by extensive NMR studies and further confirmed
by X-ray crystallography of the destannylated compound 26
(Figure 3).9
A different mode of chirality transfer was explored with the
cyclization of the C2-symmetric dipropargyl dioxolane 12
derived from (R,R)-tartaric acid. As mentioned above, this
substrate does not undergo the [Si-Sn]-mediated cyclization
(eq 3a).8 Only one of the two possible products is formed in
the generation of a new axially chiral 1,3-diene 40, as
1
determined by H and 13C NMR spectra. The configuration of
As documented in Scheme 3, we initially found that the H+-
catalyzed exchange of the 1,2-diamino ligand on boron for a
1,2-dioxa ligand (24 f 25) using pinacol is generally applicable
to most such adducts, especially those carrying Lewis basic
groups. Formation of the pinacolate from the diazaborolidine
allows purification and isolation of the corresponding 1-boryl-
methylidene-2-stannylmethylidenecycloalkanes from a variety
the nonplanar 1,3-diene has not been established. However, the
corresponding pinacolboronate 41 showed no tendency to
1
undergo atrop-epimerization, as judged by VT H NMR in
toluene-d8 (see below).
Finally, additional functional-group compatibility of the
[B-Sn]-mediated cyclization was explored with diyne 42
containing a sensitive ꢀ-lactam (Scheme 4 and Table 1, entry
8). This substrate is easily assembled from commercially
available ꢀ-lactam 45 (Scheme 4).20 In the cyclization of 42, a
mixture of diastereomeric B/Sn adducts (7:3) were obtained.
The major product (43a) is highly crystalline, and its solid-
state structure was determined by X-ray crystallographic analysis
(Figure 4). The structure of the minor diastereomer has not been
determined conclusively, although from NMR studies on the
corresponding pinacolboronate it appears to be a regioisomer.
Treatment of the mixture of 43a and 43b gave the corresponding
pinacolboronates 44a and 44b, whose structures were rigorously
(17) Weber, L.; Wartig, H. B.; Stammler, H. G.; Stammler, A.; Neumann,
B. Organometallics 2000, 19, 2891.
(18) Biffar, W.; No¨th, H.; Schwertho¨ffer, R. Liebigs Ann. Chem. 1981,
2067.
(19) Suginome, M.; Yamamoto, A.; Murakami, M. Angew. Chem., Int. Ed.
2005, 44, 2380.
Figure 3. Solid-state structure of 26 based on X-ray crystallographic
analysis (hydrogens have been omitted for clarity).
(20) Jiang, B.; Tian, H. Tetrahedron Lett. 2007, 48, 7942.
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Stereoselective Cyclization of Functionalized 1,n-Diynes
A R T I C L E S
Table 1. Pd-Catalyzed Cyclizations of 1,n-Diynes Mediated by [B-Sn] and [Si-Sn] Reagents: A Comparison
a Not isolated, except for 18, 35, 37, and 43a; conversions >90% as estimated by NMR spectroscopy. b Not attempted. c See ref 7. d See ref 8.
established by NMR methods, including extensive correlation
spectroscopy (COSY) and nuclear Overhauser effect spectros-
copy (NOESY) measurements (see the Supporting Information
for details of the NMR analysis). Gratifyingly, the chemical
shifts and coupling constants are highly diagnostic of the
conformation indicated by the solid-state structure of 43a. VT
1H NMR analysis of the major product 44a between 27 and 55
°C showed that these bicyclic compounds do not undergo helical
isomerization under conditions where monocyclic adducts are
known to be fluxional (see below).
As shown in eqs 4-6, this general protocol for the formation
of the pinacolboronate from the corresponding diazaborolidine
is also applicable to other cyclization products derived from
enynes and allenynes.
The superior reactivity of the boron-tin reagent notwith-
standing, these studies indicate that further applications of this
chemistry would have to depend on finding proper derivatization
procedures for easy isolation of useful intermediates from the
1-borylmethylidene-2-stannylmethylidenecycloalkanes because
of their hydrolytic instability. We investigated a number of these
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A R T I C L E S
Singidi et al.
Figure 4. Solid-state structure of 43a (hydrogens have been omitted for
clarity).
Scheme 5. Derivatization Schemes for 1,3-Diazaborolidines
reactions (Scheme 5) in the context of the more prototypical
diene 52,12 which was readily prepared from 1,6-heptadiyne and
16. Adducts with no Lewis basic groups (such as oxygen groups)
on the backbone seem to be more prone to destannylation under
these conditions, and significant contamination by products such
as 54 was seen. For example, adduct 52 gave both stannylated
and destannylated products (53 and 54) competitively (Scheme
5). For this substrate, even without the addition of the strong
acid, the destannylation was competitive. Such uncatalyzed
reactions generally lead to a multitude of products. Terminal
vinylstannanes with more exposed vinyl moieties also appear
to undergo this competitive destannylation.
Another useful derivatization protocol is the bromodestan-
nylation reaction shown in Scheme 5 (52 f 55 f 56), in which
the diazaborolidine-Sn adduct 52 is first treated with 1.5 equiv
of N-bromosuccinimide in chloroform and then the acid-
catalyzed pinacolboronate is formed. In case of the adduct 52,
the halogen-metal exchange takes place cleanly in ∼1 h to
give 55. This resulting compound was not isolated but directly
transformed into 56 by treatment with pinacol and p-toluene-
sulfonic acid (PTS). Diene 56, a stable boronate, was easily
isolated by column chromatography in 80% overall isolated yield
starting from the diyne. It is clear from NOE studies that the
metal exchange takes place with complete retention of stereo-
chemistry. This new derivatization protocol offers a route to
fully substituted 1-borylmethylidene-2-bromomethylidenecy-
cloalkanes, which to the best of our knowledge are new kinds
of bifunctional vinyl derivatives with potential applications as
linchpin reagents.21 Several examples of the formation of these
highly functionalized bisalkylidenes from the corresponding
diynes are shown in Table 2. In general, good to excellent yields
are obtained for the products. Four-, five-, and six-membered-
ring compounds are readily prepared by this method. Nona-
1,8-diyne and deca-1,9-diyne (entry 4) give mostly acyclic 1,2-
adducts.
Scheme 4. Synthesis and Cyclization of a 1,2-Dipropargyl-ꢀ-lactam
Atropisomerism in (Z,Z)-1,2-Bis(alkylidene)cycloalkanes. The
fluxional behavior of the 1,2-bisalkylidenes containing vinyl X
and Y groups (eq 2b), while fascinating from structural and
mechanistic perspectives, is a detraction if these compounds
are to be used for further stereoselective synthesis. As pointed
out earlier, our initial studies strongly suggested that monocyclic
compounds (eq 1, Figure 1) are most likely to be fluxional and
that there was little hope of increasing ∆Gq for the helical
isomerization by simply increasing the size of the X/Y groups.3
The kinetic parameters for the enantiomerization process were
determined for the series of dienes 3-6 via NMR line-shape
analysis, and the results are shown in Figure 5. For all of the
(21) (a) Coleman, R. S.; Lu, X.; Modolo, I. J. Am. Chem. Soc. 2007, 129,
3826. For other similar compounds, see: (b) Coleman, R. S.; Walczak,
M. C. Org. Lett. 2005, 7, 2289. (c) Coleman, R. S.; Walczak, M. C.;
Campbell, E. L. J. Am. Chem. Soc. 2005, 127, 16038.
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13084 J. AM. CHEM. SOC. VOL. 132, NO. 37, 2010

Stereoselective Cyclization of Functionalized 1,n-Diynes
A R T I C L E S
Table 2. Direct Synthesis of
1-Borylmethylidene-2-bromomethylidenecycloalkanes from
1,n-Diynesa
Figure 6. Some fluxional (Z,Z)-4-halodienyl-1-pinacolboronates.
It should be noted that the substitution pattern of the backbone
of the precursor diyne has a strong effect on ∆Gq. For example,
the N-tosyl derivative 7 and N-alkyl derivative 8 in Figure 5
have much lower coalescence temperatures than the correspond-
ing gem-bis(carbomethoxy)methylene compounds 3 and 4. The
cyclic products listed in Tables 1 and 2 add to the list of these
uncommon molecules. Furthermore, we found that by restricting
the conformational mobility of the newly formed ring, either
by having a biphenyl unit as a part of the backbone (Table 1,
entries 1-4) or imposing a bicyclic motif (entries 6-8), the
helical isomerization of the diene can be almost completely
arrested at ambient temperatures.
A typical example of how the helical isomerization can be
monitored by following the changes in the line shapes of the
bisallylic hydrogens in the adducts from symmetric diynes is
shown in Figure 1 for compound 3. In the fast-exchange regime,
because of the pseudoplane of symmetry, the allylic protons
behave like two broad singlets at 279 K. When the exchange is
slow on the NMR time scale, these appear as two AB quartets.
In the context of the [B-Sn] adducts, these limiting cases are
represented by the VT NMR spectra of adduct 38 and the
corresponding iodo and bromo derivatives 66 and 67 (Figure
6).
In compound 38 (Table 1, entry 6, column 4), the bisallylic
hydrogens appeared (in CDCl3) as two distinct AB quartets
centered around δ 3.806 (VA ) 3.978, VB ) 3.634, JAB ) 16.8
Hz) and 3.691 (VA ) 3.814, VB ) 3.568, JAB ) 16.8 Hz). The
vinyl hydrogens in this compound appeared at δ 5.328 [d, J )
1.2 Hz, B-C(sp2)-H] and 5.771 [t, J ) 1.2 Hz, JSn-H ) 76
Hz, Sn-C(sp2)-H]. When a solution of this compound in
toluene-d8 was warmed (27 to 75 °C), very few changes in the
1H NMR spectrum occurred (Figure 7). Only above 50 °C was
there some noticeable broadening in the lines due to the allylic
hydrogens. Of course, the vinyl hydrogens in this compound
would not be expected to undergo any changes, since the helical
isomer is also the enantiomer of the starting material. In the
spectrum of the corresponding iodo derivative 66, the bisallylic
hydrogens appeared as two singlets at δ 3.71 and 3.81 in CDCl3
and at δ 3.50 and 3.57 in toluene-d8. As the toluene solution
a See Scheme 5 for the procedure. b Mostly acyclic adducts.
molecules studied, the ∆Gq values were similar (52-57 kJ mol-1
at 300 K) and well within the range expected from the NMR
spectra. Thus, it has not been possible to synthesize monocyclic
systems in which the helical isomerization is frozen on the NMR
time scale at or near room temperature.
Figure 5. Kinetic parameters for helical isomerization and coalescence temperatures.
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A R T I C L E S
Singidi et al.
1
Figure 7. VT H NMR spectra (toluene-d8) of 38.
1
Figure 9. VT H NMR spectra (toluene-d8) of 41.
product that is formed in a highly atropselective reaction does
not undergo the helical isomerization, as judged by the total
absence of any new peaks in the VT NMR spectra as the
temperature was varied between -50 and 65 °C. The adduct
was dissolved in toluene-d8, and the spectra were recorded at
various temperatures.22 In these cases, axial epimerization would
lead to a different diastereomer, and on the basis of a
considerable body of experimental evidence,3 we should expect
totally different spectra, including the appearance of new vinylic
and benzylic hydrogens. Compound 18 formed from 2,2′-
propargyl-1,1′-biphenyl (17) is typical. It has the following
characteristic peaks: δ 5.874 (s, 1H, JSn-H ) 75 Hz, SnCH),
5.559 (s, 1H, BCH), 3.292 (ABq, VA ) 3.386, VB ) 3.199, JAB
) 12 Hz, 2H, benzylic CH2, CH2CdC(H)B), 3.250-3.358 (m,
1
Figure 8. VT H NMR spectra (toluene-d8) of 66.
was cooled to -65 °C, these peaks underwent changes
reminiscent of the coalescence seen in the spectrum of 3 (Figure
1)3 and below -40 °C appeared as two sets of distinct AB
quartets of equal intensity (Figure 8).
Confirming the dynamic nature of the process in halobor-
onates, we found that in the bromo derivative 67, which
presumably has an even lower barrier for isomerization (because
of the smaller size of Br relative to I), the bisallylic hydrogens
appeared as two sharp singlets at δ 3.41 and 3.45 at room
temperature.
1
d, 2H, benzylic CH2, CH2CdC(H)Sn). VT H NMR analysis
(toluene-d8) showed that the peaks due to the C(sp2) hydrogens
and the benzylic hydrogens exhibited no changes as the
temperature was raised. As the solution was cooled, some line
broadening was observed, which can often be ascribed to
3
1
changes in viscosity of the solvent. VT H NMR spectra of
pinacolboronate 19 also showed no evidence of isomerization.
Adducts from enantiopure D-tartrate-derived diyne 12 (Table
1, entry 7) represent a different class of chiral substrate (C2-
symmetric) for which, as before, the cyclization is atropselective,
with only a single diastereomer formed in the reaction. The 1H
NMR analysis showed only two vinylic hydrogens in product
40 and its boronate derivative 41. The corresponding 13C NMR
spectra also showed only a single set of peaks. Helical
isomerization would lead to a different diastereomer, and it
should be possible to monitor any isomerization reaction from
gross changes in the 1H and 13C NMR spectra. While the
absolute configurations of the [B-Sn] adduct 40 (Table 1, entry
7) and its derivative 41 have not been established, VT 1H NMR
The VT 1H NMR spectra of 56, 57, and 62 (Figure 6, Table
2) also confirmed the low barrier for the bromoboryl deriva-
tives.22 Between 27 and -70 °C there was no change in the
CH2 region except for some broadening. In none of these cases
did we observe the AB pattern characteristic of the evolving
chirality as the temperature is lowered.
The biphenyl scaffolds in diynes 17, 20b, 20c, 27, and 30
(Table 1, entries 1-4) also increase the activation barrier for
the helical isomerization. In each of these substrates, the only
(22) See the Supporting Information for the spectra and other details.
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Stereoselective Cyclization of Functionalized 1,n-Diynes
A R T I C L E S
(16) is a superior reagent capable of effecting bisfunctionaliza-
tion-cyclization in several 1,n-diynes for which the more well-
known silylstannanes fail. These include 1,2-dipropargylben-
zenes, 2,2′-dipropargylbiphenyls, 4,5-dipropargyldioxolanes, and
1,4-dipropargyl-ꢀ-lactams. Conformational restraints imposed
by the backbone increase the activation barrier for the helical
isomerization in (Z,Z)-dienes that are generated in a cyclization
event. In the biphenyl and dioxolane systems, the reactions
proceed with surprisingly good regio- and stereoselectivity. The
diazaborolidine derivatives are hydrolytically unstable but can
be isolated by recrystallization or precipitation. For further
synthetic applications, it is advantageous to convert these
compounds in situ into the corresponding dioxaborolidines with
either retention of the Me3Sn group or replacement of this group
via halodestannylation. The configurations of the vinyl moieties
are preserved in these reactions, and we hope to use the resulting
axially chiral compounds for further stereoselective operations.
Highly functionalized dibenzocyclooctadienes, which adorn the
carbon frames of several key cytotoxic natural products, are
logical targets of this chemistry. Studies directed at the total
syntheses of these compounds will be reported in due course.
1
Figure 10. VT H NMR spectra (toluene-d8) of 44a.
analysis (Figure 9) clearly suggested that the coalescence
temperature for the helical isomerization in this system is
>65 °C.
The major diastereomeric adduct derived from the highly
functionalized ꢀ-lactam 43a and the corresponding pinacolbo-
ronate 44a are also configurationally stable, as judged by VT
NMR studies. The major product 44a, whose structure was
determined by X-ray crystallography, was dissolved in toluene-
d8, and its 1H NMR spectrum was monitored between 23 and 55
°C. There were no apparent changes in the spectrum, confirming
the high barrier for the helical isomerization (Figure 10).
Acknowledgment. Financial assistance for this research from
the National Science Foundation (CHE-0610349) is gratefully
acknowledged.
Supporting Information Available: Full experimental details
for the preparation of the substrates, protocols for the cyclization
and subsequent derivatization reactions, 1H and 13C NMR spectra
of key compounds, and a CIF for 43a. This material is available
free of charge via the Internet at http://pubs.acs.org.
Conclusions
The studies reported in this paper conclusively demonstrate
that the borylstannane [-N(Me)CH2CH2(Me)N-]B-SnMe3
JA105939V
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