Regio- and enantioselective cyclobutene allylations

Article abstract of DOI:10.1021/ol401033g

Catalytic asymmetric allylation of lactone 1 with allyl boronates leads to functionalized cyclobutenes in high regio- and stereoselectivity.

Full text of DOI:10.1021/ol401033g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Regio- and Enantioselective Cyclobutene
Allylations
Supaporn Niyomchon, Davide Audisio, Marco Luparia, and Nuno Maulide*
Max-Planck-Institut fu€r Kohlenforschung, Kaiser-Wilhelm-Platz 1,
45470 Mu€lheim an der Ruhr, Germany
maulide@mpi-muelheim.mpg.de.
Received April 14, 2013
ABSTRACT
Catalytic asymmetric allylation of lactone 1 with allyl boronates leads to functionalized cyclobutenes in high regio- and stereoselectivity.
The palladium-catalyzed asymmetric allylic alkylation
(AAA), also known as the TsujiÀTrost reaction, is a
powerful synthetic method for the preparation of optically
active compounds. Catalytic AAA allows the formation of
a variety of bond types including CÀH, CÀN, CÀO, CÀS,
or CÀC linkages depending on the nucleophile employed.
The latter are classically categorized as stabilized (“soft”)
and nonstabilized (“hard”) nucleophilic species.1
Under palladium catalysis in particular, stabilized nu-
cleophiles dominate the field while their nonstabilized
counterparts have received less attention. Nevertheless, a
wide range of organometallic reagents have been utilized,
especially featuring aryl and alkenyl derivatives of Al, B,
Mg, Sn, Zn, and Zr.2 Most of them have not yet been
developed into general systems for palladium-catalyzed
AAA.3 Recently, Morken reported a series of elegant
cross-coupling studies between boronates and allylic elec-
trophiles using palladium-catalyzed AAA.4
Recent studies in our laboratory have focused on the
palladium-catalyzed reactions of bicyclic lactone 1 with
stabilized nucleophiles5 (Scheme 1). This strategy has
allowed expeditious access to functionalized cyclobutenes
with high and unusual diastero- and enantioselectivities.
Inspired by the work of Morken,4 we were eager to
investigate the behavior of our system in the presence
of nonstabilized nucleophiles. Herein we report our pre-
liminary results on the catalytic, asymmetric regioselective
allylation of lactones 1 with boronates as well as a mechan-
istic dichotomy that allows those nucleophiles to behave as
(enantioselective) reducing agents.
As depicted in Scheme 1, initial experiments showed that
the combination of lactone 1a and the pinacol ester of
allylboronic acid (allylB(pin) 2a), under palladium cataly-
sis, led to a quantitative yield of the trans-cyclobutene
carboxylic acid 3 as a single diastereoisomer.
To further probe the scope of this transformation, a
diverse array of allylboronates were employed in the
experiments compiled in Table 1.
Comparing the results obtained with methyl-substituted
allyl boronate nucleophiles, where the methyl group occu-
pies either the γ-, β-, or R-position (Table 1, entries 1, 2,
and 3 respectively), it quickly became evident that the
(1) (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395–
422. (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–2943.
(c) Trost, B. M. J. Org. Chem. 2004, 69, 5813–5837. (d) Lu, Z.; Ma, S. M.
Angew. Chem., Int. Ed. 2008, 47, 258–297. (e) Helmchen, G.; Kazmaier,
€
U.; Forster, S. In Catalytic Asymmetric Synthesis, 3rd ed.; Ojima, I., Ed.;
John Wiley & Sons, Inc., Hoboken, NJ, USA, 2010; pp 497À641. (f) Trost,
B. M.; Zhang, T.; Sieber, J. D. Chem. Sci. 2010, 1, 427–440.
(2) Negishi, E.; Liu, F. In Hand book of Organopalladium Chemistry
for Organic synthesis; Nagishi, E., Ed.; John Wiley & Sons, Inc.: Hoboken,
NJ, USA, 2002; pp 551À596.
(3) Asymmetric borylation has been achieved under Cu catalysis; see:
Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem.
Soc. 2007, 129, 14856–14857.
(4) (a) Zhang, P.; A. Brozek, L.; Morken, J. P. J. Am. Chem. Soc.
2010, 132, 10686–10688. (b) Brozek, L. A.; Ardolino, M. J.; Morken,
J. P. J. Am. Chem. Soc. 2011, 133, 16778–16781. (c) Zhang, P.; Le, H.;
Kyne, R. E.; Morken, J. P. J. Am. Chem. Soc. 2011, 133, 9716–9719. (d)
Ardolino, M. J.; Morken, J. P. J. Am. Chem. Soc. 2012, 134, 8770–8773.
ꢀ
(5) (a) Frebault, F.; Luparia, M.; Oliveira, M. T.; Goddard, R.;
Maulide, N. Angew. Chem., Int. Ed. 2010, 49, 5672–5676. (b) Luparia,
M.; Oliveira, M. T.; Audisio, D.; Frebault, F.; Goddard, R.; Maulide, N.
Angew. Chem., Int. Ed. 2011, 50, 12631–12635.
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r
10.1021/ol401033g
XXXX American Chemical Society

Table 1. Scope of the Pd-Catalyzed Allylation of Lactones
1aÀca
Scheme 1. Initial Experiments on the Allylation of Lactone 1
location of the substituent plays a crucial role. Thus,
β-substitution (as in methallyl-pinacolborane (Table 1,
entry 2) led to no reaction while γ-substitution (E-crotyl-
pinacolborane, Table 1, entry 1) provided a mixture of the
branched and linear products 3b and 3c in very low yield.
In contrast, when an R-substituted allyl boronate 2d was
used, the branched allylated cyclobutene 3c was observed
as a single regioisomer in 55% yield with moderate di-
astereoselectivity (Table 1, entry 3).
Surprised by this unanticipated selectivity,4,6 we sub-
jected other R-substituted allylpinacol boranes to the
reaction conditions (Table 1, entries 4À5). The regioselec-
tivity remained high in favor of the branched product,
accompanied by increased levels of diastereoselectivity.
Therefore, allylated cyclobutene 3e bearing a benzyl
branched side chain was obtained in 62% yield and
8:1 d.r. (Table 1, entry 5), suggesting that the diastereo-
selectivity is positively correlated with the steric bulk of the
boronate R-substituent. In addition, allenylpinacol borane
was also a viable nucleophile7 for this transformation
(Table 1, entry 6), allowing the preparation of propargy-
lated cyclobutene 3f in 46% yield.
Targeting the synthesis of cyclobutenes bearing qua-
ternary centers, substituted lactones 1bÀc were prepared
and evaluated in this allylation protocol.8 As shown
(Table 1, entries 7 and 9), allylated products containing
a tolyl- or ethyl-substituted all-carbon quaternary center
were generated in moderate to good yields. The propar-
gylated analogues 3h and 3j could also be prepared
(Table 1, entries 8 and 10).
At this point, we were eager to investigate an asymmetric
variant of this transformation that could enable the quan-
titative deracemization of lactones 1 and the obtention of
valuable enantioenriched allylated cyclobutene building
blocks. A selection of the chiral ligands that were screened
for this purpose is shown in Scheme 2. In the event, only
complex mixtures resulted when (R,R) QuinoxP* (L1)
was employed, and a low 20% yield (albeit with high
enantioselectivity of 90% ee) was obtained upon using
a Yields were determined by NMR spectroscopy (internal standard),
and products were purified as their amide or ester derivatives. The dr
values refer to the center marked with an * and were determined by
NMR analysis of the crude reaction mixture. b Modified conditions were
employed (see Supporting Information for details).
(6) The selectivity observed is actually opposite to that described by
Morken. In those reports, linear (crotyl-like) allylpinacol boranes
afforded the branched product. See ref 4.
(7) (a) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T.; Tan, Z.;
Johnson, C. S.; Lee, H.; Song, J. J.; Yee, N. K.; Senanayake, C. H. Org.
Lett. 2010, 12, 88–91. (b) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T;
Tan, Z.; Tang, W.; Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee, H.;
Yee, N. K; Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600–7601.
(c) Fandrick, D. R.; Saha, J.; Fandrick, K. R.; Sanyal, S.; Ogikubo, J.;
Lee, H.; Roschangar, F.; Song, J. J.; Senanayake, C. H. Org. Lett. 2011,
13, 5616–5619.
(R)-MeO-furyl-biphep (L2) as a ligand. Those ligands
had afforded the best results in the seminal contributions
of Morken.4 On the other hand, our prior success5b with
ꢀ
€
(8) Frebault, F.; Oliveira, M. T.; Wostefeld, E.; Maulide, N. J. Org.
(9) (a) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1993, 32, 566–
568. (b) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769–1772.
Chem. 2010, 75, 7962–7965. See the Supporting Information for details.
B
Org. Lett., Vol. XX, No. XX, XXXX

phosphino-oxazoline (Phox) ligands9 led us to investigate
that class of ligands in the allylation reaction. The sub-
stitution pattern both at phosphorus and at the chiral
center has a marked influence on the results obtained.
For instance, yields and enantioselectivities were directly
affected in a contrasting manner by steric bulk at the
chiral carbon center (cf. L3a, L3b, and L3c). In addition,
replacing the ÀPPh2 moiety with its bulkier counterpart
ÀP(o-tolyl)2 improved the yields but decreased the enantio-
selectivity of the reaction (see L3d, L3e, and L3f).
(see Scheme 3). Lower levels of selectivity were also observed
in the allylation of tolyl- and ethyl-substituted lactone
electrophiles 1b and 1c respectively.12
Scheme 3. Scope of Asymmetric Pd-Catalyzed Allylation of
Lactones 1aÀca
Scheme 2. Ligand Screening for the Catalytic Asymmetric
Allylation
a Yields were determined by NMR spectroscopy (internal standard)
and products were purified as their amide or ester derivatives. The
dr values refer to the center marked with an * and were determined
by NMR analysis of the crude reaction mixture. Ee values were
measured on the corresponding benzyl ester (3a) or N-benzylamide
(3cÀe, 3g, and 3l) derivatives. See Supporting Information for details.
The absolute configuration of the major enantiomers of 3 was not
determined.
b
a The reaction was carried out over 20 h. Yield after optimization
(see Supporting Information for details). Ar = 3,5-di-tert-butyl-4-
c
methoxyphenyl. Yields were determined by NMR spectroscopy
(internal standard). All ee values were measured on the benzyl ester
derivative of 3. See the Supporting Information for details.
The combined use of substituted lactone electrophiles
1bÀ1c and R-substituted allylpinacol boronates led cleanly
to new cyclobutene products that did not, however, con-
tain an allylic substituent (Table 2). To our surprise,
structural elucidation revealed those products to be the
reduced cyclobutenes 4.
Interestingly, this was the observed outcome regardless
of whether Phox or the chiral ligand L3c were employed.
The reduced cyclobutenes 4aÀb could be obtained in high
yields and, when L3c was used, moderate enantio-
selectivities.13 It thus appears that the allylboronate
partner can also function as a formal hydride donor.14
It should be noted that the reduced product 4a was
formed with similar enantioselectivity (Table 2, entries 1À2)
when two different, substituted allylpinacol boronates are
employed.
The phosphoramidite L4a, which was proven highly
cis-selective with stabilized nucleophiles in our previous
work,5b led to trans-allylated cyclobutene 1a with moder-
ate yield but virtually no enantioselectivity along with
traces of the cis-isomer.10 Further refinement of the reac-
tion conditions10 allowed us to obtain good results using
ligands L3bÀc (65À75% yield) while retaining high en-
antioselectivity. The obtention of products with high
(g90%) enantiomeric purity in yields reproducibly higher
than 50% is consistent with a dynamic deracemization
process.11
With suitable conditions in hand, the scope of this cata-
lytic asymmetric allylation was then examined (Scheme 3).
As before, high regioselectivity for the branched product was
observed upon using R-substituted allylpinacol boronates.
However, eroded diastereoselection resulted in those cases
From a mechanistic point of view (Scheme 4), oxidative
addition of the metal catalyst to lactone 1 should lead
to allylmetal complex 5, onto which transmetalation of
the allylpinacol borane fragment may lead to the inter-
mediate 6 (depicted in its η1-allyl form for simplicity).
(10) The use of the BINOL-derived phosphoramidite akin to L4a
afforded no reaction. See the Supporting Information for details and
further experiments.
(12) Asymmetric propargylation of lactone 1 provided the corre-
sponding products in poor yield and enantioselectivity. See the Support-
ing Information for details.
(11) This transformation can be considered an example of DYKAT
Type II. See: (a) Stecher, H.; Faber, K. Synthesis 1997, 1–16. (b) Faber,
K. Chem.;Eur. J. 2001, 7, 5004–5010. (c) Huerta, F. F.; Minidis,
€
(13) Masarwa, A.; Furstner, A.; Marek, I. Chem. Commun. 2009,
5760–5762.
€
A. B. E.; Backvall, J. E. Chem. Soc. Rev. 2001, 30, 321–331. (d)
Steinreiber, J.; Faber, K.; Griengl, H. Chem.;Eur. J. 2008, 14, 8060–
8072.
(14) Keinan, E.; Kumar, S.; Dangur, V.; Vaya, J. J. Am. Chem. Soc.
1994, 116, 11151–11152.
Org. Lett., Vol. XX, No. XX, XXXX
C

to palladium hydride 7. Reductive elimination from this
intermediate accounts for the formation of reduced
cyclobutene products, and also for the observed identi-
cal enantioselectivities regardless of the allylating agent
employed.15
Table 2. Catalytic (Asymmetric) Reduction of Lactones 1bÀc
Using Allylboronatesa
The products obtained are valuable chiral building
blocks (Scheme 5). As shown, both olefinic moieties of
benzyl ester 9 can be simultaneously hydrogenated leading
to the trans-cyclobutane carboxylic acid 10 in 82% yield.
Additionally, thermolysis induces smooth electrocyclic
ring opening to produce the sensitive skipped triene car-
boxylic ester 11, with no traces of the fully conjugated
isomer.16
Scheme 5. Functionalization of the Adducts Obtained
a Yields were determined by NMR spectroscopy (internal standard),
and products were purified as their amide or ester derivatives. All ee
values were measured on the N-benzylamide derivatives of 4. See the
Supporting Information for details. The absolute configuration of the
major enantiomers of 4 was not determined.
In summary, we have developed a regio- and stereose-
lective catalytic asymmetric allylation of cyclobutenes
using allylpinacol boronates. The reaction displays inter-
esting selectivity in favor of branched allylated products
and deposits a versatile allyl substituent, ripe for further
synthetic elaboration, into the cyclobutene framework.
Furthermore, the allylating agent demonstrated reductive
behavior on highly hindered electrophile/nucleophile com-
binations. Studies aimed at broadening the scope of this
and related methodologies as well as applying them to the
synthesis of natural products are currently underway.
Scheme 4. Proposed Mechanism for the Catalytic Allylation
Acknowledgment. We are grateful to the Max-Planck-
€
Society and the Max-Planck-Institut fur Kohlenforschung
for generous support of our research programs. This work
was funded by the Deutsche Forschungsgemeinschaft
(Grant MA 4861/3-1) and the European Research Council
(ERC Starting Grant 278872). We thank Prof. A. Pfaltz
(Univ. Basel, CH) for a very generous donation of several
Phox ligands. The invaluable support of our NMR,
HPLC, and GC Departments is acknowledged.
The obtention of the branched product from R-substituted
allyl boronate nucleophiles, in contrast to prior reports,4
suggests that a normal (rather than a [3,3]-type) reductive
elimination is operative in this system, presumably due
to steric hindrance. As a corollary, the simultaneous
presence of R1 and R2 substituents probably leads to
conformational changes no longer resulting in reductive
elimination14 but rather leading to β-hydrogen elimination
Supporting Information Available. Experimental pro-
cedures, ancillary experiments, and spectroscopic data
for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Posner, G. H.; Crouch, R. D.; Kinter, C. M.; Carry, J.-C. J. Org.
Chem. 1991, 56, 6981–6987.
(15) When the benzyl-substituted allylpinacol boronate 2f was em-
ployed, 1-phenylbutadiene (8 in Scheme 4, R2 = Ph) was detected by
GC-MS and NMR analysis of the crude mixture. See the Supporting
Information for details.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX