A catalytic asymmetric total synthesis of (-)-perophoramidine

Article abstract of DOI:10.1039/c4sc01826e

We report a catalytic asymmetric total synthesis of the ascidian natural product perophoramidine. The synthesis employs a molybdenum-catalyzed asymmetric allylic alkylation of an oxindole nucleophile and a monosubstituted allylic electrophile as a key asy

Full text of DOI:10.1039/c4sc01826e

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A catalytic asymmetric total synthesis of
(ꢀ)-perophoramidine†
Cite this: DOI: 10.1039/c4sc01826e
*
B. M. Trost, M. Osipov, S. Kruger and Y. Zhang
¨
We report a catalytic asymmetric total synthesis of the ascidian natural product perophoramidine. The
synthesis employs a molybdenum-catalyzed asymmetric allylic alkylation of an oxindole nucleophile and
a monosubstituted allylic electrophile as a key asymmetric step. The enantioenriched oxindole product
from this transformation contains vicinal quaternary and tertiary stereocenters, and is obtained in high
yield along with high levels of regio-, diastereo-, and enantioselectivity. To install the second quaternary
stereocenter in the target, the route utilizes a novel regio- and diastereoselective allylation of a cyclic
imino ether to deliver an allylated imino ether product in near quantitative yield and with complete
regio- and diastereocontrol. Oxidative cleavage and reductive amination are used as final steps to access
the natural product.
Received 19th June 2014
Accepted 30th July 2014
DOI: 10.1039/c4sc01826e
www.rsc.org/chemicalscience
while that of the communesins is cis. From a biological
perspective, perophoramidine (1) displays cytotoxicity against
Introduction
the HCT116 colon carcinoma cell line with an IC50 of 60 mM.
The combination of its complex, densely functionalized struc-
ture and cytotoxic properties make perophoramidine (1) an
attractive target for asymmetric total synthesis.
In 2002, Ireland and coworkers reported the isolation and
structural elucidation of a novel polycyclic alkaloid, (+)-per-
ophoramidine (1) from the Philippine ascidian organism Per-
ophora namei (Fig. 1).1 The structure of (+)-perophoramidine (1)
was established using multidimensional NMR techniques, and
the molecule was found to contain a densely functionalized
hexacyclic structure containing two vicinal quaternary all-
carbon stereocenters, two amidines, and several points of
halogenation on the aromatic nuclei. The skeletal connectivity
of perophoramidine (1) is related to the Penicillium derived
communesin alkaloids, such as communesin B (2).2 Unlike
perophoramidine (1), the communesin alkaloids contain a
benzazepine ring and bear two aminal functionalities in place
of two amidines. Additionally, the relative relationship of the
vicinal quaternary stereocenters in perophoramidine (1) is trans
Several syntheses of perophoramidine (1) have been repor-
ted. In their synthesis of (ꢁ)-perophoramidine (1), Funk and
coworkers constructed both quaternary stereocenters utilizing a
[4 + 2]-cycloaddition between a 3-alkylindole and 3-bromoox-
indole, which proceeded through an ortho-aza-xylylene inter-
mediate.3 Employing a chiral auxiliary-mediated hetero-Diels–
Alder reaction as a key step, Qin et al. were able to access
(+)-perophoramidine (1) in enantiopure form and also deter-
mined the absolute stereochemistry of the natural product.4
Most recently, Wang and coworkers described a catalytic
asymmetric total synthesis of (+)-perophoramidine (1) using an
alkylation reaction between an indole and a 3-bromooxindole,
similar to that of Funk's.5 Performing the reaction under nickel-
catalysis with chiral diamine ligands, the authors were able to
install both vicinal quaternary stereocenters present in (+)-per-
ophoramidine (1) in a diastereo- and enantioselective fashion.
To date, all perophoramidine (1) syntheses have utilized a
hetero-Diels–Alder-type strategy to access this natural product.
Herein we describe a catalytic asymmetric total synthesis
(ꢀ)–perophoramidine (1) based on a different strategy, which
utilizes a molybdenum-catalyzed asymmetric allylic alkylation
(Mo-AAA) as a key asymmetric step to create one quaternary
stereocenter and an unusual regio- and diastereoselective ally-
lation of an imino ether enolate, which constructs the other
quaternary stereocenter in the target.
Fig. 1 (ꢀ)-Perophoramidine (1) and (ꢀ)-communesin B (2).
Department of Chemistry, Stanford University, Stanford, CA 94305-5580, USA. E-mail:
bmtrost@stanford.edu
† Electronic supplementary information (ESI) available: Details of experimental
procedures, spectroscopic data, and copies of 1H and 13C spectra. See DOI:
10.1039/c4sc01826e
Metal-catalyzed asymmetric allylic alkylations have found
widespread synthetic utility from their ability to construct
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multiple types of bonds, including C–C, C–N, C–O, and C–X formation by a Mitsunobu reaction. Tetracycle 7 could in turn
bonds.6 While palladium catalyzed processes have been studied be formed by reductive cyclization of enantioenriched oxindole
most extensively, these reactions typically lead to linear prod- 8, which would arise from the Mo-AAA reaction between two
ucts when mono-substituted allylic electrophiles are employed.7 simple fragments: cinnamyl electrophile 9 and oxindole 10.
On the other hand, Mo-AAA reactions offer complementary
Oxindole 10 was obtained from tryptophol using a known
regioselectivity, and lead to branched products with mono- route.11 Allylic phosphate 9 was prepared from 4-bromo-2-uo-
substituted allylic electrophiles.8 While other transition metals robenzaldehyde (11) in ve steps detailed in Scheme 2. Nucle-
also offer branched regioselectivity in allylic alkylation reac- ophilic aromatic substitution of aldehyde 11 with sodium azide
tions,6 the low cost of molybdenum and simple structure of the provided an azidoaldehyde,12 which was treated under Horner–
ligands employed make the Mo-AAA an attractive asymmetric Wadsworth–Emmons olenation conditions to deliver azido
process to employ, especially on large scale. Previously, our ester 12. Reduction of the ester- and azido- functionalities with
group has demonstrated that 3-aryl- and 3-alkyloxindoles could excess DIBAL-H provided the corresponding amino alcohol
serve as nucleophiles in the Mo-AAA.9 When mono-substituted product, which was chemoselectively converted to a carbamate
allylic electrophiles were employed in this process, branched by treatment with Boc2O in aqueous dioxane. Allylic phosphate
oxindole products were obtained with vicinal tertiary and 9 was then accessed in 89% yield by treatment of the carbamate
quaternary stereocenters in high yield as well as with excellent with diethylchlorophosphate.
levels of regio-, diastereo-, and enantioselectivity. With this
With both the oxindole nucleophile 10 and allylic electro-
powerful asymmetric methodology in hand, we planned to phile 9 in hand, the Mo-AAA was explored (Scheme 3). The
utilize our Mo-AAA methodology as a key asymmetric step to coupling of oxindole 10 and allylic phosphate 9 could be
construct one of the two quaternary stereocenters in (ꢀ)-per- affected employing 20 mol% Mo(CO)3(C7H8), 30 mol% (S,S)-L1,
ophoramidine (1).
and NaHMDS as base in THF.13 These conditions provided the
desired Mo-AAA product, which was treated with NaOH to
hydrolyze the methyl carbamate to deliver enantioenriched
oxindole 8 in 89% isolated yield, 19 : 1 branched to linear ratio,
8 : 1 dr, and 97% ee. It is noteworthy to mention that the Mo-
AAA reaction could be easily conducted on >10 mmol scale to
provide multigram quantities of enantioenriched oxindole 8,
and that ligand (S,S)-L1 could be recovered at the end of the
transformation.
Enantioenriched oxindole 8 was elaborated to tetracycle 7 via
reductive cyclization (Scheme 4). In order to undergo chemo-
selective reduction, the oxindole carbonyl group required elec-
trophilic activation. For this, we chose to install a sterically
encumbered carbamate at the oxindole nitrogen, which would
favor nucleophilic attack on the oxindole carbonyl group but
can be chemoselectively removed without affecting the pre-
existing Boc group. We elected to utilize the Pd-labile dime-
thylallyl protecting group, which possesses the steric properties
of a Boc group, but can be removed using Pd-catalysis instead of
strong acids.14 Oxindole 8 was deprotonated with NaHMDS and
was treated with nitrophenyl carbonate 13 facilitating the
formation of protected oxindole 14. Reaction of this interme-
diate with LiEt3BH chemoselectively reduced the oxindole
carbonyl group leading to an N,O-hemiaminal intermediate.
Subsequent treatment with Pd(PPh3)4 and morpholine cleaved
the dimethylallyl protecting group and spontaneously cyclized
the N,N-aminal delivering tetracycle 7 in 75% yield over 2 steps.
Results and discussion
Our retrosynthesis for (ꢀ)-perophoramidine (1) is outlined in
Scheme 1. The title compound (1) could be accessed from allyl
imino ether 3 via oxidative cleavage of the olen and a reductive
amination/cyclization sequence. The allyl moiety of 3 would be
installed using a regio- and diastereoselective allylation of
pentacyclic imino ether 4. We realized that this transformation
would be challenging, since little precedent for a regio- and
diastereoselective allylation of an imino ether exists in the
literature.10 Pentacyclic imino ether 4 could be formed in a
straightforward manner from lactam 5, which would derive
from dichlorinated tetracycle 6 by oxidative cleavage of the
olen, oxidation, and amidation. Dichlorinated tetracycle 6
would be accessed by chlorination of tetracycle 7 and azide
Scheme 2 Synthesis of allylic phosphate 9. Reagents and conditions:
(a) NaN3, DMSO, 50 ꢂC, 83%; (b) NaH, THF, triethylphosphonoacetate,
–78 ꢂC, 86%; (c) DIBAL-H, THF, –78 ꢂC, 99%. (d) Boc2O, Na2CO3, H2O/
dioxane, 70 ꢂC, 78%; (e) diethylchlorophosphate, DCM, pyridine, 0 ꢂC,
76%. Boc ¼ tert-butoxycarbonyl.
Scheme 1 Retrosynthesis.
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very sensitive to Brønsted acid, such that variable quantities of
the protiodesilylated primary alcohol product 16 were observed
in the crude reaction mixture by proton NMR. Fortunately,
working up the reaction mixture with CSA protiodesilylated the
silyl ether quantitatively and delivered primary alcohol 16 in
99% yield. Conversion of the primary alcohol to an azide
Scheme 3 Mo-AAA. C7H8 ¼ cycloheptatriene, HMDS ¼ hexame-
thyldisilazide. Yield of mixture of isomers. Both b/l ratio and dr were functionality was accomplished utilizing a Mitsunobu reaction
determined by analysis of the 1H NMR spectrum of the crude reaction
mixture. Enantiopurity determined by HPLC using a chiral stationary
with hydrazoic acid, which provided azide 6 in high yield. To
access lactam 5, the olen functionality had to be cleaved
oxidatively. Attempts to utilize ozonolysis for this trans-
phase.
formation led to decomposition of the starting material. This
likely occurred due to the presence of the electron-rich aminal
functionality, which could undergo competitive oxidation.
Conversely, performing the oxidative cleavage employing
modied Johnson–Lemieux conditions with osmium tetroxide
and sodium periodate, readily provided the desired aldehyde
product.16 Subsequent Pinnick oxidation of the aldehyde inter-
mediate and methylation of the resulting carboxylic acid with
TMSCHN2, delivered methyl ester 17. Treatment of this material
with PMe3 under Staudinger conditions led to the formation of
a primary amine intermediate that underwent spontaneous
lactamization, providing lactam 5 in 47% yield over 4 steps.
To oxidize the aminal functionality to the amidine present in
the natural product, the Boc group had to be removed rst
(Scheme 5). Attempts to cleave this group under Brønsted or
Lewis acidic conditions led to the loss of both Boc and PMB
groups, or decomposition of the starting materials. Previous
work by Rawal and Cava showed that Boc groups were readily
removed from pyrroles and indoles under thermal conditions.17
Analogously, we were able to cleave the Boc group present in
lactam 5 by heating the substrate to 170 ꢂC under high vacuum.
In the same pot, the N–H aminal intermediate could be dis-
solved in a DCM/AcOH mixture and treated with PhI(OAc)2 to
deliver the amidine 18 in 67% yield. To set the stage for the
diastereoselective imino ether allylation, amidine 18 was con-
verted to the requisite imino ether intermediate 4. This was
accomplished in 71% yield employing Meerwein's reagent in
the presence of NaHCO3 as an acid scavenger to afford the O-
alkylation product with complete chemoselectivity.
With imino ether 4 in hand, allylation of this substrate was
explored using allyl iodide as an electrophile (Table 1).
Employing LDA in THF under conditions developed by our
group for the chemoselective C-allylation of imino ethers led to
complete consumption of the starting material and provided C-
and N-allylation adducts, 3 and 19 as a 1 : 10 mixture (entry 1).18
Attempts to thermally rearrange the N-allyl ketene aminal 19 to
allyl imino ether 3 at 150 ꢂC via [3,3] sigmatropic rearrangement
Scheme
4 Synthesis of Lactam 5. Reagents and conditions: (a)
NaHMDS, THF, 0 ꢂC, then 13, 73%; (b) LiEtBH3, THF, –78 ꢂC; (c) 10
mol% Pd(PPh3)4, morpholine, DCM, rt, 74% over 2 steps; (d) NCS,
NaH2PO4, AcOH, rt, 88%; (e) NaHMDS, TBAI, PMB-Br, THF, 0 ꢂC then
CSA, MeOH; (f) HN3, PPh3, DEAD, THF, 0 ꢂC, 82% over 2 steps; (g)
t
OsO4, NaIO4, 2,6-lutidine, dioxane, rt; (h) NaClO2, NaH2PO4, BuOH,
H2O, rt; (i) TMSCHN2, MeOH, PhH, rt; (j) PMe3, THF, rt, 47% over 4
steps. NCS ¼ N-chlorosuccinimide, TBAI ¼ tetra-n-butylammonium
iodide, PMB ¼ p-methoxybenzyl, CSA ¼ (ꢁ)-camphor-10-sulfonic
acid, DEAD ¼ diethyl azodicarboxylate.
At this stage, the two aromatic nuclei of tetracycle 7 were
electronically differentiated to allow for regioselective dichlori-
nation of the more electron-rich indoline ring.15 This trans-
formation was accomplished employing NCS as the
chlorinating agent in AcOH as solvent. In order to obtain high
yields reproducibly, the inclusion of NaH2PO4 as a weak base to
remove HCl was found to be necessary. Under the optimized
reaction conditions, dichloroaminal 15 could be furnished in
88% yield as a single product. To avoid undesired side reac-
tions, the free N–H in dichloroaminal 15 was protected with a
PMB group employing NaHMDS and PMBBr. The inclusion of
catalytic TBAI to form PMBI in situ was found to be crucial in
order to obtain high yields of the product. We discovered that
the primary TBS group in the PMB-protected intermediate was
Scheme 5 Synthesis of imino ether 4. Reagents and conditions: (a) 170
ꢂC, 0.1 mmHg, neat, then PhI(OAc)2, DCM, AcOH, 0 ꢂC to rt, 65%; (b)
Me3OBF4, NaHCO3, DCM, 0 ꢂC, 71%.
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1
Table 1 Allylation of imino ether 3. LDA ¼ lithium diisopropylamide. Conversion and ratio of products determined by H NMR analysis of the
crude reaction mixture
Entry
Conditions
Result
1
2
3
4
LDA, THF, 0 ꢂC then allyl iodide
>95% conversion, 3 : 19, 1 : 10
>95% conversion, 3 : 19, 3 : 1
>95% conversion, 3 : 19, 2 : 1
98% Isolated yield, 3 : 19, >20 : 1
KHMDS, THF, 5 min, 0 ꢂC then allyl iodide
KHMDS, THF, 30 min, 0 ꢂC then allyl iodide
Allyl iodide THF, add KHMDS over 10 min
was unsuccessful. On the other hand changing the base from CSA and subsequent introduction of ozone followed by reduc-
LDA to KHMDS led to a dramatic change in the regiochemical tive basic workup smoothly delivered the desired aldehyde
course of the transformation. Under these conditions, the C- product 20.
and N-allylation products, 3 and 19 products were obtained in a
To install the nal nitrogen atom present in the natural
3 : 1 ratio favoring C-allyl imino ether product 3 (entry 2). While product, aldehyde 20 was converted to amine 21 using a
studying this transformation, it was noted that the ratio of 3 : 19 reductive amination. Attempts to condense methylamine with
eroded to ꢃ2 : 1 when imino ether 4 was treated with KHMDS the aldehyde 20 and subsequent treatment of the imine inter-
ꢂ
and the reaction mixture was allowed to stir for 30 min at 0 C mediate with reducing agents provided the desired amine
prior to the addition of allyl iodide (entry 3). We postulated that product 21 in trace quantities. Instead, the primary alcohol
the 3 : 1 ratio of 3 : 19 could be improved further by the slow product 22 resulting from the reduction of the aldehyde was
addition of KHMDS solution to a mixture of imino ether 4 and observed as the major product. This indicated that the
electrophile, rather than allowing the deprotonated interme- condensation process between aldehyde 20 and methylamine
diate to equilibrate. To our delight, addition of KHMDS to a was not occurring readily. Addition of dehydrating agents to the
solution of imino ether 4 and allyl iodide over 10 min led to reaction mixture to favor imine formation, such as molecular
exclusive formation of C-allyl imino ether 3 in 95% isolated sieves or MgSO4 did not improve the ratio of 21 to 22. However,
yield (entry 4).
employing Ti(OiPr)4 as a Lewis acid to catalyze imine formation
To rationalize the regiochemical outcome of the allylation under conditions developed by Bhattacharyya20 and subsequent
reaction, we propose that the imino ether, like other enolates,19 addition of NaBH4 at 0 ꢂC led to formation of the desired amine
forms an aggregate when deprotonated with strong base. The 21 as the only product, with no observable quantity of the
aggregated enolate form leads to the undesired N-allyl ketene undesired primary alcohol product 22. It is noteworthy to
aminal product 19, while the monomeric form leads to the mention that under these reaction conditions no reduction of
desired C-allyl imino ether 3. Slow addition of base to a solution the imino ether functionality was observed (Scheme 6).
of nucleophile and electrophile reduces the concentration of
In the nal stages of the synthesis, we were le with the tasks
imino ether enolate and the likelihood of aggregation. of cyclizing the amine into the pendant imino ether to afford
Conversely, addition of base to the imino ether and delayed amidine 23 and removal of the PMB protecting group to access
addition of the electrophile favors the formation of aggregates. the natural product (1). Treatment of the amine 21 with
Furthermore, lithium favors the formation of aggregates to a Brønsted acids did not facilitate amidine formation but led to
greater extent than potassium. To rationalize the diaster- acid-mediated hydrolysis of the imino ether functionality to a
eoselectivity for the transformation, we propose that allylation secondary lactam. On the other hand, thermal cyclization of the
occurs from the more accessible bottom face of the molecule amidine proved quite amenable to our system, and heating
such that steric interactions with the aminoethylene chain of amine 21 at 120 ꢂC in either toluene (sealed tube) or anisole as
the adjacent quaternary stereocenter are avoided.
With a method to access allyl imino ether 3, oxidative
cleavage of the allyl moiety was explored. Attempts to utilize
ozonolysis for the transformation led to decomposition of the
starting material. This likely occurred due to the oxidative
lability of the electron-rich amidine present in the molecule. We
postulated that oxidative decomposition could be circumvented
Scheme 6 Synthesis of amine 21. (a) CSA, –78 ꢂC, DCM, then O3, then
MeOH, Me2S, NaHCO3, to rt; (b) Ti(OiPr)4, MeNH2, EtOH, rt, then
NaBH4, 0 ꢂC, 51% over 2 steps.
if the basic amidine in allyl imino ether 3 would be “protected”
via protonation. Indeed, treatment of allyl imino ether 3 with
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2 (a) P. Siengalewicz, T. Gaich and J. Mulzer, Angew. Chem.,
2008, 120, 8290; (b) Z. Zuo and D. Ma, Isr. J. Chem., 2011,
51, 434.
3 J. R. Fuchs and R. L. Funk, J. Am. Chem. Soc., 2004, 126, 5068.
4 H. Wu, F. Xue, X. Xiao and Y. Qin, J. Am. Chem. Soc., 2010,
132, 14052.
5 H. Zhang, L. Hong, H. Kang and R. Wang, J. Am. Chem. Soc.,
2013, 135, 14098.
Scheme 7 Completion of the total synthesis. (a) Anisole, 120 ꢂC, 100%
conversion; (b) TFA, anisole, 90 ꢂC, 100% conversion; (c) Anisole, 120
ꢂC, then 90 ꢂC, TFA, 62%.
6 U. Kazmaier, Transition Metal Catalyzed Enantioselective
Allylic Substitution in Organic Synthesis, in Topics in
Organometallic
Heidelberg, 2011, vol. 38.
Chemistry,
Springer-Verlag
Berlin
solvents furnished PMB-amidine 23. To complete the total
synthesis of (ꢀ)-perophoramidine (1), the PMB group needed to
be removed. Attempts to utilize ceric ammonium nitrate to
cleave this group oxidatively led to decomposition of the start-
ing material. However, PMB cleavage could be performed under
strongly acidic conditions; treatment of PMB-amidine 23 with
7 (a) B. M. Trost, Acc. Chem. Res., 1996, 29, 355; (b) B. M. Trost
and D. L. Van Vranken, Chem. Rev., 1996, 96, 395; (c)
B. M. Trost and F. D. Toste, J. Am. Chem. Soc., 1999, 121,
4545; (d) B. M. Trost, Chem. Pharm. Bull., 2002, 50, 1–14; (e)
B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921;
(f) B. M. Trost, J. Org. Chem., 2004, 69, 5813; (g)
B. M. Trost, T. Zhang and J. D. Sieber, Chem. Sci., 2010, 1,
427; (h) B. M. Trost, Org. Process Res. Dev., 2012, 16, 185.
8 For recent reviews see: (a) O. Belda and C. Moberg, Acc.
Chem. Res., 2004, 37, 159; (b) C. Moberg, Top. Organomet.
Chem., 2012, 38, 209.
9 (a) B. M. Trost and Y. Zhang, J. Am. Chem. Soc., 2006, 128,
4590; (b) B. M. Trost and Y. Zhang, J. Am. Chem. Soc., 2007,
129, 14548; (c) B. M. Trost and Y. Zhang, Chem.–Eur. J.,
2010, 16, 296; (d) B. M. Trost and Y. Zhang, Chem.–Eur. J.,
2011, 17, 2916.
ꢂ
TFA in the presence of anisole at 90 C afforded (ꢀ)-perophor-
amidine (1). Since both the amidine cyclization and PMB
cleavage steps were performed in anisole, we were curious if the
two steps could be coupled into a one-pot process. Indeed,
heating amine 21 in anisole at 120 ꢂC to cyclize the amidine and
then subsequent introduction of TFA at 90 ꢂC to cleave the PMB
group delivered (ꢀ)-perophoramidine (1) in 62% yield for the
single operation (Scheme 7).
Conclusions
In summary, we have developed a catalytic asymmetric total
synthesis of the alkaloid natural product (ꢀ)-perophoramidine
(1). The route utilizes a regio- diastereo- and enantioselective
Mo-AAA to construct one of the two vicinal quaternary carbon
stereocenters present in the target. The second quaternary
carbon stereocenter is constructed employing a regio- and dia-
stereoselective allylation of an imino ether anion, which shows
an unprecedented dependence of regioselectivity on the nature
of the metal cation. With the potassium salt the reaction
proceeds with complete regio- and diastereoselectivity for the
desired product. Manipulation of the allyl moiety via oxidative
cleavage, reductive amination, cyclization and protecting group
cleavage are used to complete the synthesis. The strategy
permits structural exibility particularly at the quaternary
stereocenters for analog synthesis.
10 (a) U. Groth, L. Richter, U. Schoellkopf and J. Zindel, Liebigs
Ann. Chem., 1992, 11, 1179; (b) P. J. M. Taylor, S. D. Bull and
P. C. Andrews, Synlett, 2006, 9, 1347; (c) The bis-lactim
alkylation method developed by Schollkopf is closely
related and allows for the formation of quaternary amino
acids. For a review, see U. Schollkopf, Pure Appl. Chem.,
1983, 55, 1799.
11 B. M. Trost, Y. Zhang and T. Zhang, J. Org. Chem., 2009, 74,
5115.
12 J. Hu, Y. Cheng, Y. Yang and Y. Rao, Chem. Commun., 2011,
47, 10133.
13 When 10 mol% catalyst loadings were employed, b/l ratios
and diastereoselectivities were less reproducible. Typically,
these were around a 9 : 1 b/l ratio and 2.5 dr.
14 J.-K. Lee, Y.-W. Suh, M. C. Kung, C. M. Downing and
H. H. Kung, Tetrahedron Lett., 2007, 48, 4919.
15 Funk and co-workers have demonstrated that dichlorination
of a similar intermediate could be performed with NCS in
AcOH. See: ref. 3.
16 W. Yu, Y. Mei, Y. Kang, Z. Hua and Z. Jin, Org. Lett., 2004, 6,
3217.
Acknowledgements
We thank the NSF (CHE-1145236) and the NIH (GM 033049) for
their generous support of our programs. M.O. thanks The John
Stauffer Memorial Fellowship and Stanford Graduate Fellow-
ship for nancial support. S.K. thanks the ISAP program of
DAAD. We thank Johnson-Matthey for their generous gis of
palladium salts.
17 V. H. Rawal and M. P. Cava, Tetrahedron Lett., 1985, 26, 6141.
18 B. M. Trost and R. A. Kunz, J. Org. Chem., 1974, 39, 2475.
19 L. T. Tomasevich and D. B. Collum, J. Am. Chem. Soc., 2014,
136, 9710.
20 K. A. Neidigh, M. A. Avery, J. S. Williamson and
S. Bhattacharyya, J. Chem. Soc., Perkin Trans. 1, 1998, 1, 2527.
Notes and references
1 S. M. Verbitski, C. L. Mayne, R. A. Davis, G. P. Concepcion
and C. M. Ireland, J. Org. Chem., 2002, 67, 7124.
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