Palladium asymmetric allylic alkylation of prochiral nucleophiles: Horsfiline

Article abstract of DOI:10.1021/ol060298j

The asymmetric synthesis of the oxindole alkaloid horsfiline is described. A palladium-catalyzed asymmetric allylic alkylation (AAA) is used to set the spiro(pyrrolidine-oxindole) stereogenic center.

Full text of DOI:10.1021/ol060298j

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2027-2030
Palladium Asymmetric Allylic Alkylation
of Prochiral Nucleophiles: Horsfiline
Barry M.Trost* and Megan K. Brennan
Department of Chemistry, Stanford UniVersity, Stanford, California 94305
bmtrost@stanford.edu
Received February 3, 2006
ABSTRACT
The asymmetric synthesis of the oxindole alkaloid horsfiline is described. A palladium-catalyzed asymmetric allylic alkylation (AAA) is used
to set the spiro(pyrrolidine-oxindole) stereogenic center.
(-)-Horsfiline was first isolated in 1991 from the leaves of
the Horsfieldia superba plant by Bodo and co-workers.1
Biologically active alkaloids such as spirotryptostatin A and
B, vincristine, and vinblastine have resulted in increased
interest for oxindole natural products such as horsfiline. The
unique spiro stereogenic center of horsfiline has challenged
synthetic chemists to develop imaginative approaches toward
its construction. As a result, there has been much synthetic
effort toward horsfiline, resulting in several syntheses, three
of which were asymmetric.2 In 1994, Borschberg confirmed
the absolute configuration of horsfiline through the synthesis
of both enantiomers via a diastereoselective oxidative rear-
rangement of an (L)-tryptophan derivative.2i In 1999, Fuji et
al. used a chiral auxiliary for nitro olefination of a substituted
oxindole to set the stereochemistry at the quaternary chiral
center.2h Palmisano and co-workers used an azomethine ylide
cycloaddition reaction to form the pyrrolidine and subse-
quently formed the oxindole by intramolecular cleavage of
the chiral auxiliary.2f
We envisioned constructing the stereogenic quaternary
carbon via a palladium-catalyzed asymmetric allylic alky-
lation (AAA) employing oxindole as the nucleophile. The
use of 3-aryl oxindoles in palladium AAA has been previ-
ously reported;3 however, oxindole nucleophiles with sub-
stituents other than aryl groups have not been employed in
this chemistry. In our proposed synthesis of horsfiline, an
ester or aldehyde substituent in the 3 position would provide
a stabilized, compatible nucleophile for palladium allylic
alkylation (Scheme 1). The carbonyl group also provides a
handle for further manipulation. Oxidative cleavage of the
allyl group followed by reductive amination would introduce
the nitrogen of the pyrrolidine. Cyclization via reductive
amination or SN2 substitution would complete the tricyclic
system.
(1) Jossang, A.; Jossang, P.; Hadi, H.; Sevenet, T.; Bodo, B. J. Org.
Chem. 1991, 56, 6527.
(2) (a) Murphy, J. A.; Tripoli, R.; Khan, T. A.; Mali, U. W. Org. Lett.
2005, 7, 3287. (b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 12,
2209. (c) Lizos, D. E; Murphy, J. A. Org. Biomol. Chem. 2003, 1, 117. (d)
Selvakumar, N.; Azhagan, A. M.; Srinivas, D.; Krishna, G. G. Tetrahedron
Lett. 2002, 43, 9175. (e) Kumar, U.K.; Syam; Illa, H.; Junjappa, H. Org.
Lett. 2001, 3, 4193. (f) Cravotto, G.; Giovenzana, G.; Pilati, T.; Sisti, M.;
Palmisano, G. J. Org. Chem. 2001, 66, 8447. (g) Fischer, C.; Meyers, C.;
Carreira, E. M. HelV. Chim. Acta 2000, 83, 1175. (h) Lakshmaiah, G.;
Kawabata, T.; Shang, M.; Fuji, K. J. Org. Chem. 1999, 64, 1699. (i)
Pellegrini, C.; Stra¨ssler, C.; Weber, M.; Borschberg, H. Tetrahedron:
Asymmetry 1994, 5, 1979. (j) Bascop, S.; Sapi, J.; Laronze, J.; Levy, J.
Heterocycles 1994, 38, 725. (k) Jones, K.; Wilkinson, J. Chem. Commun.
1992, 1767. (l) Chang, M. Y.; Pai, C.-L.; Kung, Y.-H. Tetrahedron Lett.
2005, 46, 8463.
Initially, an aldehyde was installed in the 3 position of
the oxindole following a known procedure using sodium
methoxide and ethyl formate.4 However, the product from
(3) Trost, B. M.; Fredericksen, M. U. Angew. Chem., Int. Ed. 2005, 44,
308.
10.1021/ol060298j CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/21/2006

Scheme 1. Retrosynthetic Analysis of Horsfiline Using Pd
Scheme 2. Synthesis of the Oxindole Core
AAA
the AAA reaction with allyl acetate was unstable to purifica-
tion (Figure 1), resulting in deformylation.
added to generate the enolate anion nucleophile. Initially,
CsF and ligand 2 were investigated with DME as the solvent,
resulting in 77% ee. A significant improvement in ee
occurred by switching the counterion from cesium to tetra-
n-butylammonium. Various conditions were then screened
for optimization (Table 1). Other Trost family ligands, such
as 6 and 7, resulted in lower enantioselectivity.
Figure 1. Deformylation of the initial Pd AAA Adduct
To avoid this decomposition, the aldehyde functionality
was changed to an ester. A rhodium-catalyzed C-H inser-
tion method developed by Padwa and co-workers was used
to build the desired oxindole.5 Refluxing p-anisidine with
2,4-dimethoxybenzaldehyde in toluene followed by reduc-
tion of the imine with sodium borohydride in methanol
resulted in quantitative yield of the desired amine 3 (Scheme
2). Acylation with the acid chloride derivative of ethyl di-
azoacetate in the presence of triethylamine led to for-
mation of amide 4 in 90% yield. Padwa discovered that
Rh2(acac)4 led to â-lactam formation with diazoamides con-
taining benzyl protecting groups, whereas the corresponding
Rh2(CF3CONH2)4 catalyst led to oxindole formation. There-
fore, Rh C-H insertion of amide 4, followed by protection
of the oxindole with TIPSOTf, resulted in 79-86% yield of
5 over two steps varying with the catalyst load from 1 to 3
mol %. Protection of the oxindole was necessary to avoid
hydrolysis.8
Surprisingly, lowering the temperature resulted in a slightly
lower ee (74%). Changing the fluoride source to TBAT and
the solvent to toluene increased the ee to 84%. Moreover,
the major enantiomer could be purified to 98% ee with 69%
yield by recrystallizing out the minor/major enantiomer pair
using heptane or cyclohexane. Furthermore, the yield for this
reaction was 96-100% even when the catalyst loading was
dropped from 1% to 0.25% [Pd(C2H5)Cl]2.
Oxidative cleavage of the allyl group was accomplished
by catalytic osmium tetraoxide and N-methylmorpholine
N-oxide (NMO) followed by cleavage of the diol with lead
tetraacetate in methylene chloride (Scheme 3). Sodium
periodate cleavage required somewhat aqueous conditions,
which led to the formation of the five-membered lactone as
a byproduct. The initial plan to close the pyrrolidine was to
reduce the ester and aldehyde to the diol, followed by bis
mesylation and SN2 substitution with methylamine. Another
route involved reductive amination of the aldehyde and
reduction of the ester to the alcohol followed by intramo-
lecular SN2 substitution. However, all attempts to reduce the
ester resulted in low yields of the alcohol with the major
product resulting from loss of CO.
With the protected oxindole in hand, the next step was
the asymmetric allylic alkylation. A fluoride source was
(4) (a) Wenkert, E.; Bose, A. K.; Reid, T. L. J. Am. Chem. Soc. 1953,
75, 5514. (b) Wenkert, E.; Bhattacharyya, N. K.; Reid, T. L.; Stevens, T.
E. J. Am. Chem. Soc. 1956, 78, 797.
(5) Brown, D. S.; Elliott, M. C.; Moody, C. J.; Mowlem, T. J.; Marino,
J. P.; Padwa, A. J. Org. Chem. 1994, 59, 2447.
2028
Org. Lett., Vol. 8, No. 10, 2006

acid with NaBH3CN led to a number of products, which was
dependent on the amount and order in which the acetic acid
was added to the reaction mixture. Reductive amination in
a two-step procedure, by first forming the imine in dry THF
with MgSO4 and then reducing with NaBH4 in EtOH,6
provided lactam 10 in 65% yield. The byproduct of the
reaction was the lactam alcohol 11, which presumably forms
from cyclization of the hemiaminal onto the ester. Once
lactam 10 was formed, only deprotection and a chemose-
lective reduction remained. The removal of the 2,4-
dimethoxybenzyl group from the oxindole nitrogen was
accomplished in 60% yield using DDQ in refluxing aqueous
methylene chloride.
Table 1. Pd AAA Reaction with Oxindole
entry
1
conditions
ligand
additive
CsF
ee (%)a
77
2.5% [Pd(C2H5)Cl]2
DME, rt
7.5% 2
2
3
2.5% [Pd(C2H5)Cl]2
DME, rt
2.5% [Pd(C2H5)Cl]2
DME, rt
2.5% [Pd(C2H5)Cl]2
DME, 0-4 °C
2.5% [Pd(C2H5)Cl]2
DCM, rt
2.5% [Pd(C2H5)Cl]2
DME, rt
2.5% [Pd(C2H5)Cl]2
toluene, rt
1% [Pd(C2H5)Cl]2
toluene, rt
1% [Pd(C2H5)Cl]2
toluene, rt
0.25% [Pd(C2H5)Cl]2
toluene, rt
7.5% 6
7.5% 7
7.5% 2
7.5% 2
7.5% 2
7.5% 2
3% 2
CsF
21
62
74
61
78
81
84
79
84
The chemoselective reduction of 12 proved to be a difficult
challenge (Table 2). Initially, it was believed that 3 equiv of
CsF
4
CsF
5
CsF
Table 2. Chemoselective Reduction
6
CsF
7
15% TBAT
15% TBAT
5% TBAT
15% TBAT
8
9
3% 2
conditions
3 equiv of DIBLAH, -78 °C
3 equiv of DIBAL-H, -78 °C
yield
no reaction
10
1% 2
reduced oxindole
a 3.0 equiv of CsF was added. b Enantiomeric excess was determined
by HPLC, AD column, 90% heptane/10% PrOH.
1. nBuLi (1 equiv)
2. DIBAL (2 equiv), -78 °Cf0 °C
no reaction
no reaction
i
1. nBuLi (1 equiv)
2. DIBAL (2 equiv) 0 °Cfrt
Reductive amination of the aldehyde using NaBH3CN and
the hydrochloride salt of methylamine resulted in the
formation of the five-membered lactam in low yields (25%).
Switching to a solution of methylamine in THF and acetic
1. nBuLi, -78 °C
2. DIBAL-H/nBuLi, 0 °Cfrt
no reaction
no reaction
BH3 in THF, rt
1. nBuLi/TIPSOTf
2. DIBAL-H (2 equiv)
only SM and
silylated SM
1. nBuLi (1 equiv), -78 °Cf0 °C
2. LAH soln (2H- equiv), -78 °Cf0 °C
20%
Scheme 3. Ring Closure
1. NaH (30 min), rt
2. LAH soln (2H- equiv), -78 °Cf0 °C
<5%
1. nBuLi, -78 °C for 30 min
2. LAHs soln (4H- equiv), -78 °Cf0 °C
0%
1. nBuLi, -78 °C for 30 min
2. LAHs soln (4H- equiv), -78 °Cf0 °C
column (NH3/MeOH/EtOAc)
32%
1. Ph3CLi in DME
2. LAH soln (2H- equiv of DME), rt
48%
DIBAL-H would first deprotonate the secondary amide,
protecting it from further reduction. However, it appeared
that the oxindole was reduced preferentially under these
conditions. Even by initially deprotonating with nBuLi and
then adding DIBAL-H, the desired product was not observed.
(6) Trost, B. M.; Godleski, S. A.; Genet, J. P. J. Am. Chem. Soc. 1978,
100, 3930.
Org. Lett., Vol. 8, No. 10, 2006
2029

Numerous reducing agents and conditions were applied to
both lactams 10 and 12 in an attempt to successfully
differentiate the two amides. Finally, it was found that the
addition of 1 equiv of nBuLi, followed by 2 equiv of LAH
in THF (from a freshly prepared and titrated solution), led
to the desired product in 25-30% yield. Although the nBuLi
was titrated before use,7 low yields could have resulted from
incomplete deprotonation, perhaps due to extraneous water.
To avoid addition of excess base, a solution of trityllithium
in DME was prepared. This solution was then added to the
solution of amide 12 in DME until a slight pink color
remained indicating the complete deprotonation of the
secondary amide. Upon addition of 2 hydride equiv of the
LAH solution at 0 °C, horsfiline was formed in 45% yield.
It is noteworthy that horsfiline, along with other oxindole
natural products, are prone to racemization via a retro-
Mannich reaction that occurs in the presence of acid8
(Scheme 4). Because this synthesis avoids revealing the
Scheme 5. Rationalization of Stereochemistry
p-anisidine and 2,4-dimethoxybenzaldehyde using an oxin-
dole nucleophile in the palladium asymmetric allylic alky-
lation. A new class of prochiral nucleophiles, 3-carbalkoxy-
oxindoles, prove to be good substrates for asymmetric allylic
alkylation. This synthesis circumvents the problems associ-
ated with racemization of the natural product by only
exposing the pyrrolidine ring to a chemoselective reduction
in the final step of the synthesis.
Scheme 4. Racemization Mechanism
pyrrolidine until the last step, this problem is carefully
avoided. Optical rotation verified this and also determined
that the (+)-horsfiline enantiomer had been synthesized.
The enantiomer formed in the Pd AAA reaction can be
rationalized by using the model previously described9
(Scheme 5). The nucleophile prefers to approach underneath
a flap and in an orientation that minimizes steric interactions
with a nearby wall.
Acknowledgment. We thank the National Science Foun-
dation and the National Institutes of Health (GM33049) for
their generous support of our programs. Mass spectra were
provided by the Mass Spectrometry Regional Center for the
University of CaliforniasSan Francisco, supported by the
NIH Division of Research Resources. We thank Novartis
for predoctoral support of M.B. We are indebted to Johnson-
Matthey who generally provided palladium salts.
In conclusion, a concise total synthesis of horsfiline was
achieved in eight steps and 11.1% yield starting from
Supporting Information Available: Full experimental
details and tabulated NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(7) Love, B. E.; Jones, E. C. J. Org. Chem. 1999, 64, 3755.
(8) Brown, R. T. In Heterocyclic Compounds; Saxon, J. E., Ed.; Wiley
Interscience: New York, 1983; Vol 25, part 4, pp 85-97.
(9) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759.
OL060298J
2030
Org. Lett., Vol. 8, No. 10, 2006