Rearrangement of spirocyclic oxindoles with lithium amide bases

Article abstract of DOI:10.1021/ol8016885

(Chemical Equation Presented) Spirocyclohexa-2,5-dienes were shown to rearrange at -40 °C, when treated with 1 equiv of LDA. Alkyl halides and aldehydes then reacted with the resulting phenanthridinone lithium enolate intermediates, with distinct regioselectivities and high diastereocontrol, to afford functionalized dearomatized phenanthridinones which were elaborated further. A mechanistic scheme involving a diisopropylamine-mediated proton transfer was proposed to rationalize the rearrangement.

Full text of DOI:10.1021/ol8016885

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4441-4444
Rearrangement of Spirocyclic Oxindoles
with Lithium Amide Bases
Ge´raldine Rousseau,† Fre´de´ric Robert,† Kurt Schenk,‡ and Yannick Landais*,†
UniVersity Bordeaux 1, Institut des Sciences Mole´culaires, UMR-CNRS 5255, 351,
cours de la libe´ration, 33405 Talence cedex 05, France, and UniVersity of Lausanne,
Institut de Cristallographie, BCP, CH-1015 Dorigny-Lausanne, Switzerland
y.landais@ism.u-bordeaux1.fr
Received July 24, 2008
ABSTRACT
Spirocyclohexa-2,5-dienes were shown to rearrange at -40 °C, when treated with 1 equiv of LDA. Alkyl halides and aldehydes then reacted
with the resulting phenanthridinone lithium enolate intermediates, with distinct regioselectivities and high diastereocontrol, to afford functionalized
dearomatized phenanthridinones which were elaborated further. A mechanistic scheme involving a diisopropylamine-mediated proton transfer
was proposed to rationalize the rearrangement.
Spirocyclic oxindoles (e.g., I, Scheme 1) constitute the core
skeleton of several naturally occurring alkaloids isolated from
Scheme 1. Spirocyclic Oxindole Core in Gelsemium Alkaloids
Gelsemium semperVirens, including gelsemine 1,1 one of the
most active constituents of this plant. This simple tricyclic
skeleton is also present as a key fragment in various
biologically relevant synthetic targets2 and as such constitutes
a versatile intermediate in organic synthesis.3 In the course
of our ongoing interest in desymmetrization processes
involving 1,4-diene systems,4 we became recently interested
in the chemistry of spirocyclohexa-2,5-dienes of type II,
containing the spirooxindole moiety.
The desymmetrization of cyclohexa-1,4-dienes (e.g., II)
implies the differentiation of both diastereotopic faces and
an enantiotopic group, a challenging task, which has recently
attracted a great deal of interest.4,5 The spiro-type structure
of II exhibits attractive features in this context, including
electronically well-differentiated diastereotopic faces with a
polar amide functional group on one face and an apolar aryl
substituent on the other face. It was envisioned that the
propensity of the amide functional group to lead to hydrogen
bonding6 and metal binding7 could be exploited to differenti-
ate diastereotopic faces. The desymmetrization process could
† University Bordeaux 1.
‡ University of Lausanne.
(1) Lin, H.; Danishefsky, S. Angew. Chem., Int. Ed. 2003, 42, 36–51,
and references cited therein.
(2) (a) Venkatesan, H.; Davis, M. C.; Altas, Y.; Snyder, J. P.; Liotta,
D. C. J. Org. Chem. 2001, 66, 3653–3661. (b) Chande, M. S.; Verma, R. S.;
Barve, P. A.; Khanwelkar, R. R.; Vaidya, R. B.; Ajaikumar, K. B. Eur.
J. Med. Chem. 2005, 40, 1143–1148.
(3) (a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6477–6487. (b) Mao, Z.; Baldwin, S. W. Org. Lett.
2004, 6, 2425–2428.
(4) (a) Beniazza, R.; Dunet, J.; Robert, F.; Schenk, K.; Landais, Y. Org.
Lett. 2007, 9, 3913–3916. (b) Lebeuf, R.; Robert, F.; Schenk, K.; Landais,
Y. Org. Lett. 2006, 8, 4755–4558, and references cited therein.
10.1021/ol8016885 CCC: $40.75
Published on Web 09/11/2008
2008 American Chemical Society

then be performed through deprotonation of the dienyl
system, followed by transmetalation with a suitable chiral
metal complex (e.g., ML*dTi(OR*)4,...) and reaction of the
resulting pentadienyl-metal complex with various electro-
philes.5b-d
Spirocyclic oxindoles were prepared using a methodology
based on a SmI2-mediated aryl cyclization process. Tanaka
et al.8 recently reported that SmI2-HMPA was able to
mediate the radical cyclization of iodoamides 2 to afford the
spirocyclic skeleton of 3, provided that an ortho substituent
was present on the arene (Scheme 2). 2 (R ) R′ ) H) was
of the base. n-BuLi and s-BuLi were shown to afford a
complex mixture of products, while LiHMDS, NaH, and
t-BuOLi led to recovered starting material in essentially
quantitative yield. In contrast, metalation with t-BuOK
followed by addition of MeI led to a mixture of the C-4
methylated spiro oxindole (20%) and the 2,4-isomerized spiro
oxindole (53%). More attractive results were obtained when
LDA was used as a base. When 5a was treated with LDA at
-78 °C, no reaction took place. However, upon warming to
-40 °C, the reaction mixture turned rapidly deep purple, a
color which rapidly vanished upon addition of MeI. To our
surprise, a rearranged product 6a, possessing a new 1,4-
cyclohexadienyl ring substituted at C-3, was formed without
a trace of the expected methylated spiro oxindole (Table 1).
Scheme 2. Preparation of Spirocyclic Oxindoles 5a,b
Table 1. LDA-Mediated Rearrangement of Spiro Oxindoles
5a,b, Followed By Alkylation
entry spiro oxindole
R′
RX
MeI
AllylBr Allyl
MOMCl MeOCH2
R
diene yielda
1
2
3
4
5a
5a
5a
5b
H
H
H
Me
6a
6b
6c
6d
67
48
30
42
OMe MeI
Me
a Isolated yield of 6a-d after chromatography.
effectively shown to provide the desired oxindole 5a, along
with large amounts of the unseparable phenanthridinone 4.
In contrast, the expected spiro compounds 3a,b were
obtained in reasonable to good yields from amides 2a,b
having a bulky silyloxy group (OTBDMS) in the ortho
position. Silyloxycyclohexadienes 3a,b were then trans-
formed into the desired cyclohexadienes 5a,b following a
two-step procedure, including the conversion of 3a,b into
the corresponding triflates (not shown), using a fluoride
source and PhN(Tf)2,9 followed by a palladium-mediated
hydrogenation of the latter with formic acid.10
Varying the nature of the electrophile, a range of alkylated
products 6a-d was obtained in moderate to good isolated
yields but in all cases as a single regioisomer (C3). Reactions
were generally clean (crude yield >90%), the isolated yield
not reflecting the efficiency of the process due to the
sensitivity of dienes 6a-d to rearomatization. The structure
of regioisomers 6a-d was assigned based on the X-ray
structure determination of a derivative of 6a (vide infra).
Metalation and methylation of spiro oxindole 5b also led to
rearranged product 6d after methylation. Other electrophiles
such as aldehydes also reacted, providing alcohols 7a-d with
complete regiocontrol and in most cases with high diaste-
reocontrol (Table 2). Surprisingly and in contrast with
alkylation above, reaction with aldehydes took place at C-5.11
The stereochemistry of 7a-d was assigned based on X-ray
diffraction studies performed on alcohol 7a.12 Reaction of
5a with formaldehyde invariably led to the formation of the
phenanthridinone 4 and no trace of the desired alcohol.
Interestingly, cinnamaldehyde reacted with rearranged 5a
in a 1,4-fashion to give the aldehyde 8 with complete regio-
With spirocyclic oxindoles 5a,b in hand, we then turned
our attention toward the metalation step, varying the nature
(5) (a) Abd Rahman, N.; Landais, Y. Curr. Org. Chem. 2002, 6, 1369–
1395. (b) Studer, A.; Schleth, F. Synlett 2005, 3033–3041. (c) Maji, M. S.;
Frohlich, R.; Studer, A. Org. Lett. 2008, 10, 1847–1850. (d) Umeda, R.;
Studer, A. Org. Lett. 2007, 9, 2175–2178. (e) Butters, M.; Elliott, M. C.;
Hill-Cousins, J.; Paine, J. S.; Walker, J. K. E. Org. Lett. 2007, 9, 792–803,
and references cited therein.
(6) Epoxidation of II (R ) Me, R′ ) H) using CF3CO3H was shown to
lead exclusively to the expoxidation syn relative to the CdO group, likely
as a result of the amide functional group directing effect: Rousseau, G.;
Robert, F.; Landais, Y. unpublished results.
(7) Clayden, J. Organolithiums: Selectivity for Synthesis. Tetrahedon
Organic Chemistry Series; Elsevier Science: Oxford, 2002; Vol. 23.
(8) (a) Ohno, H.; Iwasaki, H.; Eguchi, T.; Tanaka, T. Chem. Commun.
2004, 2228–2229. (b) Iwasaki, H.; Eguchi, T.; Tsutsui, N.; Ohno, H.;
Tanaka, T. J. Org. Chem. 2008, 73, 7145–7152.
(11) (a) Snider, B. B.; Phillips, G. B.; Cordova, R. J. Org. Chem. 1983,
48, 3003–3010. (b) Ballester, P.; Costa, A.; Garcia-Raso, A.; Gomez-
Solivellas, A.; Mestres, R. Tetrahedron Lett. 1985, 26, 3625–3628.
(12) The relative configuration of alcohol 7a results from an ul-addition,
involving the Si-face of the enolate and the Re-face of the aldehyde, through
a transition state in which the aldehyde carbonyl group is likely coordinated
to the lithium cation. Seebach, D.; Prelog, V. Angew. Chem., Int. Ed. Engl.
1982, 21, 654–660.
(9) Mi, Y.; Schreiber, V.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
11290–11291.
(10) Mori, R.; Nakanishi, M.; Kajishima, D.; Sato, Y. J. Am. Chem.
Soc. 2003, 125, 9801–9807.
4442
Org. Lett., Vol. 10, No. 20, 2008

Table 2. LDA-Mediated Rearrangement of Spiro Oxindole 5a,b,
Followed By Addition of Aldehydes
Scheme 4. Functionalization of Rearranged Products 6a and 7a
entry
R
alcohol
dra
yieldb
1
2
3
4
Ph
i-Pr
t-Bu
4-OMePh
7a
7b
7c
7d
>95:5
85:15
>95:5
>95:5
60
63
61
30
a Estimated from the 1H NMR of the crude reaction mixture. b Isolated
yields of 7a-d after chromatography.
and stereocontrol (Scheme 3). Its relative configuration was
assigned based on the assumption that the topicity of the
process is similar to that proposed above for the addition of
aldehydes.12
from an approach of the dienophile anti relative to the
benzylic alcohol moiety of the diene partner.
This unprecedented rearrangement of spirocyclo oxindoles
5a,b was rationalized invoking the general pathway depicted
in Figure 1. LDA abstraction of the bisallylic protons of 5a,b
Scheme 3. Synthesis of Aldehyde 8
Dienes were then functionalized further, demonstrating that
despite their sensitivity they represent valuable intermediates
for organic synthesis. Hydrogenation of 6a also occurred
regioselectively on the C4-C5 double bond, leaving R,ꢀ-
unsaturated amide 9 in 75% yield (Scheme 4). 6a was shown
to react selectively with m-CPBA, affording epoxide 10 as
a single diastereomer. X-ray crystallography was used to
establish the stereochemistry of 10, indicating that approach
of the peracid has occurred anti relative to the methyl group
on the resident C3-stereogenic center. Dihydroxylation of
6a, followed by diol protection, occurred similarly to afford
acetonide 11 as a unique anti-diastereomer, for which
stereochemistry was assigned through NMR experiments.
Finally, alcohol 7a was shown to react with maleimide,
providing, with complete diastereocontrol, Diels-Alder
cycloadduct 12 having six stereogenic centers installed in
only two steps. The stereochemistry of 12 was determined
through NOESY experiments and confirmed by X-ray
diffraction studies. This indicates that the endo-adduct results
Figure 1. Tentative mechanism of the anionic rearrangement of
5a,b.
likely generates a pentadienyl lithium intermediate i13 that
rearranges at -40 °C into an amide-stabilized7 lithiated
Org. Lett., Vol. 10, No. 20, 2008
4443

carbanion iii through transition state ii.14 The structure of
products 6a-d and 7a-d implies that an enolate such as W
is involved at a late stage of the process. Reaction of W with
aldehydes occurs at C-5 and probably involves a complex-
ation of the carbonyl group with the lithium cation of the
enolate. In constrast, the alkylation reaction takes place at
C-3. The origin of this regiochemical change remains
presently unclear. The conversion of iii into W was rational-
ized, invoking an equilibrium between these two species, as
a result of the presence in the medium of diisopropylamine
issued from LDA. Diisopropylamine would protonate iii at
C-6 to provide iW. The regenerated LDA would then abstract
the acidic proton at C-1 on the latter to give W. Diisopropy-
lamine would thus serve as a proton transfer agent to shift
the equilibrium toward the thermodynamically more stable
lithium enolate W. Two observations support this hypothesis.
First, when the reaction was performed in the presence of
chiral amide base 13,15 6a was formed in low to modest
yield (10-47%) but with significant enantiocontrol (6-20%
e.e.), indicating that the secondary chiral amine is located
in close proximity to the lithium enolate.16 Second, when
repeating the same experiment, but adding to the medium, a
second equivalent of n-Buli at -78 °C before warming to
-40 °C, cis-dimethylated product 14,17 was formed as the
major compound in 40% yield. This indicates that when the
proton transfer agent (R2NH) is “removed” from the medium
the conversion of iii into iW does not take place and iii may
be alkylated at C-6. Deprotonation of 6-Me-iii by LDA then
generates the corresponding enolate that is alkylated at C3
to afford 14. The role of diisopropylamine in this process is
thus central and would explain the failure observed during
reaction of 5a with alkyllithium bases (n-BuLi and s-BuLi).
In summary, we have described along these lines an
unprecedented LDA-mediated rearrangement of spirocyclic
oxindoles. Ring strain is likely a driving force in this
rearrangement, which is only observed in the presence of
lithium amide bases for the reasons given above. The reaction
displays a broad scope of applications, giving rise to highly
functionalized phenanthridinones that represent valuable
intermediates for organic synthesis. Preliminary experiments
show that an enantioselective version is at hand by using
chiral amide bases or chiral ligands. DFT calculations are
currently carried out to get a deeper insight into the
mechanism of this rearrangement and will be reported in due
course.
Acknowledgment. We thank the MNERT and CNRS for
financial support and a grant for GR. We are grateful to B.
Kauffmann (IECB, Bordeaux) for X-ray diffractions studies
and J. C. Lartigues and N. Pinaud (ISM, University Bor-
deaux-1) for NMR experiments.
(13) (a) Clayden, J.; Dufour, J.; Grainger, D. M.; Helliwell, M. J. Am.
Chem. Soc. 2007, 129, 7488–7489. (b) Liu, L.; Wang, Z.; Zhao, F.; Xi, Z.
J. Org. Chem. 2007, 72, 3484–3491.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Involvement of anionic species such as aryllithium or acyllithium
intermediates formed through C1-C3 or C1-C2 bond breaking should not
be ruled out. These would then recombine to afford iii.
(15) (a) Whitesell, J. K.; Felman, S. W. J. Org. Chem. 1980, 45, 755–
756. (b) Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins, N. S.
Tetrahedron 1990, 46, 523–544.
OL8016885
(17) The relative configuration of 14 was determined through X-ray
diffraction analysis (see Supporting Information).
(16) O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439–1457.
4444
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