An indium-mediated allylative/transesterification DFT-directed approach to chiral C(3)-functionalized phthalides

Article abstract of DOI:10.1021/ol301566f

A one-pot synthesis of chiral C₍₃₎-substituted phthalides via an indium-mediated allylation/transesterification reaction is described. The development of this reaction was facilitated through the applied use of DFT calculations to rationalize the stereoselection of a chiral In-mediated process. It was discovered that the enantiomeric excess of this reaction depended upon the steric size, chain length, and substitution of the aldehyde employed.

Full text of DOI:10.1021/ol301566f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
An Indium-Mediated Allylative/
Transesterification DFT-Directed
Approach to Chiral C(3)-Functionalized
Phthalides
Roya Mirabdolbaghi and Travis Dudding*
Department of Chemistry, Brock University, 500 Glenridge Avenue, St. Catharines,
Ontario, Canada L2S 3A1
tdudding@brocku.ca
Received June 12, 2012
ABSTRACT
A one-pot synthesis of chiral C(3)-substituted phthalides via an indium-mediated allylation/transesterification reaction is described. The develop-
ment of this reaction was facilitated through the applied use of DFT calculations to rationalize the stereoselection of a chiral In-mediated process.
It was discovered that the enantiomeric excess of this reaction depended upon the steric size, chain length, and substitution of the aldehyde
employed.
The ability of a catalyst or single reagent to promote a
desired cascade of reaction events in a single reaction flask
with high enantioselectivity in useful yields represents an
efficient strategy for assembling complex synthetic targets,
such as natural products. In this context, we were recently
attracted by the possibility of employing a chiral indium
reagent or catalyst as a resource for preparing optically
enriched, value added chemicals and/or synthetic precur-
sors of natural products. Driving this interest was the low
toxicity, functional group compatibility, and tolerance to
air and moisture of inidium which remains underutilized
in synthesis at this time (especially in the field of asym-
metriccatalysis), apartfrom a few notableexamples.1ꢀ4 To
this end, the development of an enantioselective, indium-
mediated, synthetic approach to C(3)-chiral substituted
phthalides, which are a widely distributed structural motif
within a number of biologically active natural products
and medicinally important pharmaceuticals, appeared an
ideal challenge. For instance, the structurally related spiro-
laxines CJ-12,954 (1) and CJ-13,014 (2) are reported to
lower cholesterol and exhibit cytotoxicity against endo-
thelial (BMEC and Huvec) and tumor (LoVo, HL60)
cell lines,5 while the Apium plant seed extract (S)-3-n-
butylphthalide (3) has recognized potential as a treatment
for stroke and pretreatment for Parkinson’s disease (PD)
(Figure 1).6,7
Given their therapeutic properties, it is perhaps not
surprising that a number of efficient synthetic routes to
(5) (a) Blaser, M. J. Clin. Infect. Dis. 1992, 15, 386–393. (b) Bava, A.;
Clericuzio, M.; Giannini, G.; Malpezzi, L.; Meille, S. V.; Nasini, G. Eur.
J. Org. Chem. 2005, 11, 2292–2296. (c) Radcliff, F. J.; Fraser, J. D.;
Wilson, Z. E.; Heapy, A. M.; Robinson, J. E.; Bryant, C. J.; Flowers,
C. L.; Brimble, M. A. Bioorg. Med. Chem. 2008, 16, 6179–6185.
(6) Xiong, N.; Huang, J.; Chen, C.; Zhao, Y.; Zhang, Z.; Jia, M.;
Zhang, Z.; Hou, L.; Yang, H.; Cao, X.; Liang, Z.; Zhang, Y.; Sun, S.;
Lin, Z.; Wang, T. Neurobiol. Aging 2012, 33, 1777–1791.
(7) For more examples see: (a) Robinson, J. E.; Brimble, M. A.
Chem. Commun. 2005, 1560–1562. (b) Nannei, R.; Dallavalle, S.;
Merlini, L.; Bava, A.; Nasini, G. J. Org. Chem. 2006, 71, 6277–6280.
(c) Keaton, K. A.; Phillips, A. J. Org. Lett. 2007, 9, 2717–2719. (d)
Arnone, A.; Assante, G.; Nasini, G.; Depava, O. V. Phytochemistry
1990, 29, 613–616. (e) Tianpanich, K.; Prachya, S.; Wiyakrutta, S.;
Mahidol, C.; Ruchirawat, S.; Kittakoop, P. J. Nat. Prod. 2011, 74, 79–81.
(1) Hirayama, L. C.; Gamsey, S.; Knueppel, D.; Steiner, D.; DeLaTorre,
K.; Singaram, B. Tetrahedron Lett. 2005, 46, 2315–2318.
(2) Yus, M.; Gonzalez-Gomez, J. C.; Foubelo, F. Chem. Rev. 2011,
111, 7774–7854.
(3) Kargbo, R. B.; Cook, G. R. Curr. Org. Chem. 2007, 11, 1287–1309.
(4) Loh, T. P.; Zhou, J. R.; Yin, Z. Org. Lett. 1999, 1, 1855–1857.
r
10.1021/ol301566f
XXXX American Chemical Society

augment experimental development, we initially turned
to DFT calculations to discern to what, if any, extent this
process would afford enantioselection. Thus, working under
the assumption that allylation was the (R)- vs (S)-enantio-
selective-determining step of this reaction, the addition of 4
to 1 was modeled using the Gaussian 09 suite of programs
at the B3LYP/LanL2DZ level of theory with the IEFPCM
dielectric continuum solvation model and the default
parameters for THF (ε = 7.6).
Figure 1. Examples of natural products containing C(3)-chiral-
substituted phthalides.
optically enriched C(3)-chiral phthalides have been reported.8
Nevertheless, there remains a pressing need for sythetic
routes to C(3)-chiral phthalides, as the majority of the re-
ported approaches are limited in substrate scope, use
expensive and/or toxic rare earth transition metals, and
provide low levels of enantioselection.
Scheme 1. Envisioned Mechanistic Cycle for the Synthesis of
C
(3)-Substituted Phthalides
Fully aware of these limitations, we were drawn toward
the possibility of developing a more robust and syn-
thetically efficient strategy for preparing optically enriched
C(3)-chiral phthalides. Accordingly, we describe here a
target-oriented assembly of chiral C(3)-substituted phtha-
lides via the orchestrated use of rational forethought (i.e.,
density functional theory (DFT) calculations) in prelude to
experimental practice. Notably, this work has also pro-
vided theoretical models for rationalizating the enantioin-
duction of the reactions, and the ligand component used
was easily recoverable after the reaction. This work has
led to a revision of the stereochemical assignment of the
allylation products reported by Singaram et al. (vide infra).
At the outset of this work, with the goal of developing an
In-mediated protocol for preparing C(3)-chiral phthalides,
we envisioned using a reaction scenario such as that out-
lined in Scheme 1. In this mechanistic proposal, a highly
reactive In-allyl species, 4, is generated in situ from 3,
inexpensive indium metal, and allyl bromide (step 1).
Intermediate 4 then reacts with methyl-2-formylbenzoate
1 (step 2) to give allyl intermediate 5, which subsequently
undergoes a dual In-metal/pyridium salt (pyr-Hþ) cata-
lyzed intramolecular transesterification to afford (R)-3-
allylisobenzofuran-1(3H)-one 2 (step 3). However, because
of the frequently observed erosion in the enantioseletion
of catalytic asymmetric allylations of ortho-substituted
substrates,9ꢀ11 we were concerned if this process would
in fact impart enantioselectivity.12 For this reason, in
keeping with our philosophy of utilizing computation to
Surfacing from these calculations were a number of
insightful features with respect to the first-order saddle
points, (R)-TS1 and (S)-TS2, governing the (R)- vs (S)-
enantioselective allylation (Figure 2). A particularly domi-
nant feature of these transition states was the presence of a
bidentate mode of (LUMO-lowering) aldehdye activation
by the two In-metal centers (In(1) O(1) and In(2) O(1)),
3 3 3
3 3 3
which interestingly, because of geometric constraints, only
occurred in the two lowest transition structures, (R)-TS1
and (S)-TS2. A second notable feature of these two transi-
tion structures is that the In(1)-metal center resides within
the plane of the 5-membered ring system containing the
N- and O-atoms of the ligand, while the In(2)-metal center
resides below the plane of this same 5-membered ring
system and trans to the bulky phenyl substituents of the
ligand. Geometrically, this in-plane/below the plane rela-
tionship of the two In-metals with respect to the sterically
bulky vicinal phenyl groups of the ligand component in
(R)-TS1 and (S)-TS2 shields the top face of these struc-
tures, forcing allylation to take place on the bottom face in
a synclinal manner via a chairlike transition state.
(8) (a) Asami, M.; Mukaiyama, T. Chem. Lett. 1980, 17–20. (b) Meyers,
A. I.; Hanagan, M. A.; Trefonas, L. M.; Baker, R. J. Tetrahedron 1983,
39, 1991–1999. (c) Ohkuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett.
1990, 31, 5509–5512. (d) Watanabe, M.; Hashimoto, N.; Araki, S.; Butsugan,
Y. J. Org. Chem. 1992, 57, 742–744. (e) Zhang, H.; Zhang, S.; Liu, L.; Luo,
G.; Duan, W.; Wang, W. J. Org. Chem. 2010, 75, 368–374. (f) Phan, D. H. T.;
Kim, B.;Dong, V. M.J. Am. Chem. Soc. 2009, 131, 15608–15609. (g) Huang,
X.; Pan, X.; Lee, G.; Chen, C. Adv. Synth. Catal. 2011, 353, 1949–1954.
(9) Mirabdolbaghi, R.; Dudding, T. Tetrahedron 2012, 68, 1988–
1991.
Importantly, these structural differences reduce the ac-
tivation barrier for Re-stereofacial addition by 2.15 kcal/
mol with respect to the Si-stereofacial mode of addi-
tion (ΔGq = 4.13 (Re-addition, (R)-TS1) vs 6.28 kcal/mol
(Si-addition, (S)-TS1), which translates to 98% en-
antioselectivity, agreeing well with experiment (see the
Supporting Information for additional details). The spe-
cific origin of this enantiofacial selectivity appears to result
(10) Yus, M.; Gonzalez-Gomez, J. C.; Foubelo, F. Chem. Rev. 2011,
111, 7774–7854.
(11) (a) Haddad, T. D.; Hirayama, L. C.; Singaram, B. J. Org. Chem.
2010, 75, 642–649. (b) Hrdina, R.; Valterova, I.; Hodacova, J.; Cisarova,
I.; Kotora, M. Adv. Synth. Catal. 2007, 349, 822–826.
(12) Knepper, K.; Ziegert, R. E.; Brase, S. Tetrahedron 2004,
60, 8591–8603.
B
Org. Lett., Vol. XX, No. XX, XXXX

64% ee, whereas with tert-butyl 2-formylbenzoate, 1m, no
reaction occurred (Table 1, entries 12 and 13). Lastly, to
investigate the effect of performing the reaction on a solid
support, Merrifield resin bound 2-formylbenzoic acid was
then reacted,12 which disappointingly only afforded race-
mic phthalide 2a.
Table 1. Indium-Mediated Enantioselective Allylationa/Intra-
molecular Transestrification of Functionalized Aldehydes
yield ee
product (%)b (%)c
entry
R1
R2
Figure 2. DFT (B3LYP/LanL2DZ)-computed enantioselective
transition states (R)-TS1 and (S)-TS2.
1
2
3
4
5
6
7
8
9
1a CH3
1b CH3
1c CH3
1d CH3
1e CH3
1f CH3
1g C2H5
H
2a
2b
2c
2d
2e
2f
77
67
68
69
65
67
62
58
60
55
57
78
0
80
77
45
69
69
68
79
76
71
65
50
64
OCH3
NO2
Br
from the presence of a shorter In(1)
O(1) distance in (R)-
3 3 3
˚
˚
isobutyl- CO2NH
TS1 (d = 2.11 A) vs (S)-TS2 (d = 2.19 A) and increased
Pitzer and Baeyer strain in (S)-TS2. This strain is attributed
to the half-chair transition state assembly for allylation in
(S)-TS2, while in (R)-TS1, allylation proceeds through a
less strained, chair-type transition state; see Figure 2 (red
atoms).
Ph
H
H
H
H
H
H
H
H
2a
2a
2a
2a
2a
2a
1h CH2Ph
1i C5H11
10 1j C6H13
11 1k 12H25
C
12 1l CH(CH3)2
13 1m C(CH3)3
Charged with this insight as a proof of concept, our
efforts then turned toward the experimental realization of
our rationally designed C(3)-chiral phthalide forming reac-
tion sequence. In this vein, methyl 2-formylbenzoate 1a
(1 equiv) was reacted with allyl bromide (2 equiv), indium
powder (2 equiv), (1R,2S)-(ꢀ)-2-amino-1,2-diphenyletha-
nol (2 equiv), and anhydrous pyridine (2 equiv) in THF
at ꢀ78 °C, which to our delight, as predicted, afforded 2a in
a respectable 80% ee (Scheme 2). Encouraged by this result,
a more extensive scan of the substrate scope of this reaction
was then explored. Arising from the reaction of electron-
rich substrate (methyl 2-formyl-5-methoxybenzoate) 1b,
we isolated phthalide 2b in ee comparable to that of 2a
(Table 1, entries 1 and 2). Disappointingly, however, the
electron-deficient methyl 2-formyl-5-nitrobenzoate sub-
strate 1c resulted in a dramatic decrease in product ee
(Table 1, entry 3). Furthermore, the reactions of the bromo-,
carbamate-, and phenyl-5-substituted substrates 1dꢀf simi-
larly afforded phthalides of moderate ee, which is somewhat
interesting considering the electronic and structural differ-
ences existing between these substrates (Table 1, entries 4ꢀ6).
We then examined the dependence of this reaction on
the chain length and steric bulk of the ester group. The
resulting trends indicated an increase in ee with diminish-
ing n-alkyl carbon chain length (Table 1, entries 7ꢀ11). We
believe these results may originate from substrate aggrega-
tion and potential micelle formation. With respect to
changes in steric bulk of the ester group, it was found that
increased branching led to erosion of ee. For instance,
isopropyl 2-formylbenzoate, 1l, afforded the product in
d
d
ꢀ
ꢀ
14 1n solid supporte
2a
52
0
a Allyl bromide, indium powder, (1R, 2S)-(ꢀ)-2-amino-1,2-dipheny-
lethanol, and anhydrous pyridine in THF at ꢀ78 °C. b Yields of isolated
products after flash chromatography. c Enantiomeric excess was deter-
mined by HPLC analysis. d ꢀ, not applicable. e Merrifield resin was used.
At that stage, the product 2a obtained from our reac-
tion was assigned as the (R)-enantiomer by comparison
of its optical rotation with that previously reported by
Pedrosa et al. (Supporting Information) which notably
was in agreement with the computationally predicted
stereochemical outcome. Consequently, to determine if
the ortho-ester group of our substrates might potentially
flip the absolute sense of (R)- vs (S)-enantioinduction
observed in our reaction, we reacted benzaldehyde with
allyl bromide under the conditions used throughout this
work (Scheme 2). To this end, it was instructively found
that we had formed the (R)-enantiomer of 6, as this prod-
uct hadthe samedirection ofoptical rotation[R]20D = þ37
(c = 1, CHCl3) as previously reported by several groups
also as the (R)-enantiomer (Supporting Information).
As such, this finding was surprising to us considering we
had applied the same conditions previously employed by
Singaram for the In-mediated allylation of benzaldehyde,
with the exception that the enantiomeric antipode of the
ligand was used, and yet we observed the same sign of
optical rotation reported by Singaram as the (S)-enantiomer
([R]25D = þ48.67 (c = 0.42, benzene)).11 Thus, it would
Org. Lett., Vol. XX, No. XX, XXXX
C

appear based upon these results that the ortho-ester group
present in our substrates did not flip the absolute sense of
(R)- vs (S)-enantioinduction observed in our reaction.
of InBr3 (derived in situ from Br2 and In) product forma-
tion was observed and the reaction had gone to ∼40%
completion after 6 h (conditions B). Similarly, when
pyridium salt pyr-Hþ (conditions C) was employed as
the sole catalyst, a marked product formation was again
observed. However, unfortunately when the reaction was
performed in the dual catalytic presence of In/Br2 and pyr-
Hþ, the formation of an intractable mixture of byproduct
resulted (conditions D). Given these trends, we believe that
further investigation is warranted to better understand the
outcome of this reaction under the catalytic action of both
In/Br2 and pyr-Hþ (i.e., conditions D).
Scheme 2. Synthesis of (R)-1-Phenylbut-3-en-1-ol via an Indium-
Mediated Enantioselective Allylation Reaction
Taken together, we have disclosed here an In-promoted
one-pot allylation/intramolecular transesterification se-
quence and accompanying DFT rationale of stereoselection
that provides enantioenriched C(3)-functionalized chiral
phthalides (2aꢀl). Notably, to the best of our knowledge,
this work presents the first example of a DFT-drafted
stereochemical model for rationalizing the observed enan-
tioselectivity of a reaction. Moreover, an interesting depen-
dence of the ee of this reaction upon the steric size and chain
length of the ester appendage undergoing transesterification
during this reaction dynamic was revealed. Ongoing efforts
in our laboratory focus on the expansion and integrated use
of this protocol in total synthesis.
Finally, as a last mechanistic probe, we set out to deter-
mine the catalytic role of indium and the in situ generated
pyridinium salt (pyr-Hþ) on the transesterification step of
this reaction. In order to do this, we began by modeling the
corresponding transition states for C(3)-chiral phthalide
forming ring closure, both in the presence ((R)-TS3 and
(S)-TS4) and absence ((R)-TS5 and (S)-TS6) of pyr-Hþ
and the indium bound complex generated from allylation
(see the Supporting Information.). Encouragingly, the
resultswereconsistentwith ourinitialmechanistic premise,
in that the indium and pyr-Hþ catalyzed transition states
wereenergeticallyfavored overthecontroltransitionstates
in which no catalyst was present. The free energies of
activation for transesterification in presence of indium
and pyr-Hþ were 5.8 kcal/mol ((R)-TS3) and 4.5 kcal/mol
((S)-TS4), while those for the uncatalyzed ring closure
were 31.4 and 37.5 kcal/mol for (R)-TS5 and (S)-TS6,
respectively.
Acknowledgment. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
(NSERC) for funding of thisresearch. Wethank Dr. Costa
Metallinos and Joshni John of Brock University for use of
equipment.
Furthermore, to experimentally substantiate this theo-
retical model, we carried out four separate, representative,
intermolecular reactions between 2-propanol and methyl
phenylacetate (conditions AꢀD); see the Supporting In-
formation for details. Under conditions A wherein no
indium species or pyr-Hþ was present, product formation
was not observed by NMR after 6 h, while in the presence
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data for all new compounds,
and computational details. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX