Synthesis of ent-Ketorfanol via a C-H Alkenylation/Torquoselective 6π Electrocyclization Cascade

Article abstract of DOI:10.1002/anie.201505604

The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A Rh^I-catalyzed intramolecular C-H alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2-dihydropyridin

Full text of DOI:10.1002/anie.201505604

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201505604
German Edition: DOI: 10.1002/ange.201505604
Alkaloid Synthesis
Synthesis of ent-Ketorfanol via a C–H Alkenylation/Torquoselective 6p
Electrocyclization Cascade
Eric M. Phillips, Tehetena Mesganaw, Ashay Patel, Simon Duttwyler, Brandon Q. Mercado,
Kendall N. Houk,* and Jonathan A. Ellman*
Abstract: The asymmetric synthesis of ent-ketorfanol from
simple and commercially available precursors is reported. A
I
À
Rh -catalyzed intramolecular C H alkenylation/torquoselec-
tive 6p electrocyclization cascade provides a fused bicyclic 1,2-
dihydropyridine as a key intermediate. Computational studies
were performed to understand the high torquoselectivity of the
key 6p electrocyclization. The computational results demon-
strate that a conformational effect is responsible for the
observed selectivity. The ketone functionality and final ring
are introduced in a single step by a redox-neutral acid-
catalyzed rearrangement of a vicinal diol to give the requisite
carbonyl, followed by intramolecular Friedel–Crafts alkyla-
tion.
O
xycodone[1] and related semisynthetic opioid ligands are
effective and pervasively used medications for the manage-
ment of pain. However, these compounds have significant
liabilities that include dependency, tolerance, which results in
increasing doses being required to maintain efficacy, and the
serious side effects of higher doses, such as respiratory failure.
The recently reported high-resolution structures of a number
of opioid receptor ligands in complex with several receptor
subtypes provide an exceptional opportunity for the struc-
ture-based design of new opioid ligands with reduced draw-
backs.[2] However, access to different structural variants is
constrained by reported synthetic routes to the approved
semisynthetic opioid ligands, which rely on morphine, the-
baine, and other morphinoid natural products as heavily
functionalized starting materials.[3,4]
Scheme 1. Retrosynthetic analysis of ent-Ketorfanol.
tion of intermediate 2.[6] This intermediate could potentially
be obtained in situ from 3 under the acidic reaction conditions
via a speculative redox-neutral process[7] proceeding through
ionization of the allylic oxygen functionality followed by
a hydrogen shift (see below). Fused bicyclic tetrahydropyr-
idine 3 would then be obtained through reduction of
dihydropyridine 4 under mildly acidic reductive amination
conditions. In the key step, bicyclic intermediate 4 should be
À
Our recently developed Rh-catalyzed C H functionaliza-
tion/6p electrocyclization cascade[5] should enable direct and
rapid entry to this important class of alkaloids from readily
available achiral precursors. Herein, we demonstrate this
approach with the asymmetric synthesis of ent-ketorfanol (1),
the nonregulated enantiomer of the semisynthetic opioid drug
ketorfanol (Scheme 1). ent-Ketorfanol should be accessible
through acid-catalyzed intramolecular Friedel–Crafts cycliza-
À
accessible via an intramolecular Rh-catalyzed syn C H bond
addition to the alkyne, followed by electrocyclization, which
should hopefully proceed with high torquoselectivity owing to
remote asymmetric induction provided by the isopropylidine
protected diol.[8–10] The precursor for this cascade reaction,
imine 6, should be readily accessible from ester 7 through
straightforward functional-group transformations. Ester 7
should be obtainable by regioselective Sharpless asymmetric
dihydroxylation,[11] isopropylidene protection, and alkyne
benzylation of the achiral dienoate 8.
[*] E. M. Phillips, T. Mesganaw, S. Duttwyler, B. Q. Mercado,
Prof. Dr. J. A. Ellman
Department of Chemistry, Yale University
225 Prospect St., New Haven, CT 06520 (USA)
E-mail: jonathan.ellman@yale.edu
A. Patel, Prof. Dr. K. N. Houk
Department of Chemistry and Biochemistry
University of California, Los Angeles
Los Angeles, CA 90095-1569 (USA)
E-mail: houk@chem.ucla.edu
The synthesis commenced with Swern oxidation of 4-
pentyn-1-ol (9) and subsequent Horner–Wadsworth–
Emmons reaction (Scheme 2) to furnish dienoate 10 (60%
yield, 2 steps). A highly regio- and enantioselective Sharpless
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505604.
12044
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 12044 –12048

Angewandte
Chemie
I
À
Scheme 3. The Rh -catalyzed C H insertion reaction. Reagents and
conditions: a) [{RhCl(coe)2}2] (2.5 mol%), 4-(diethylphosphino)-N,N-
dimethylaniline (5 mol%), toluene, 658C; b) NaHB(OAc)3, AcOH,
EtOH, 0!238C.
rates vicinal diol stereocenters that are distant from the
stereocenter to be formed. Exposure of imine 15 to 2.5 mol%
of [{RhCl(coe)2}2] and 5 mol% of the electron-rich ligand 4-
(diethylphosphino)-N,N-dimethylaniline at 658C led to highly
selective formation of dihydropyridine 16 in excellent yield
1
(84% by H NMR analysis). While this tandem reaction was
found not to be overly sensitive to concentration, reaction
temperature is important, with higher temperatures resulting
in lower yields and the formation of isomeric byproducts.
Intermediate 16 was reduced without isolation by using
NaHB(OAc)3 and AcOH to provide tetrahydropyridine 17 in
65% overall yield and greater than 20:1 d.r., thereby
confirming the high torquoselectivity of the reaction.
To determine the origins of the torquoselectivity observed
in the RhI-catalyzed cascade sequence, computional studies of
the key aza-electrocyclization were conducted using the
wB97x-D density functional with the 6-31 + G(d,p) basis set.
Table 1 illustrates the truncated substrates modeled computa-
tionally as well as the kinetic diastereoselectivities of ring
closures of these compounds. The sense and level of the
torquoselectivities computed are consistent with the exper-
imental results. The discussion of the stereoinduction (see
below) emphasizes the results of our computational studies on
E, the 1-azatriene that most closely resembles the exper-
imental substrate 5.
Scheme 2. Synthesis of imine 15. Reagents and conditions: a) (COCl)2,
DMSO, Et3N, CH2Cl2, À788C; b) nBuLi, iPr2NH, (E)-ethyl-4-(diethoxy-
phosphoryl)but-2-enoate, À78!08C; c) AD-mix-a, MeSO2NH2,
tBuOH, H2O, 08C; d) 2,2-dimethoxypropane, pTsOH (10 mol%),
CH2Cl2, 08C; e) 3-TBSOPhCH2Cl, PdCl2(CH3CN)2 (5 mol%), XPhos
(15 mol%), Cs2CO3, THF, 658C; f) DIBAL, CH2Cl2, À788C; g) Dess–
Martin periodinane, pyridine, CH2Cl2, 08C; h) cyclopropylmethyl
amine, toluene, 3 Š MS. DMSO=dimethyl sulfoxide, TsOH=4-tolue-
nesulfonic acid, TBS=tert-butyldimethylsilyl, THF=tetrahydrofuran,
DIBAL=diisobutylaluminium.
asymmetric dihydroxylation was performed on the olefin
distal to the ester (81% yield, 95% ee).[11] Diol 11 was
immediately protected using 2,2-dimethoxypropane and
pTsOH to furnish acetonide 12 in 94% yield. X-ray structural
analysis of 11 was also carried out to confirm that its absolute
configuration was consistent with that predicted for AD-mix-
a.[12]
Alkyne 12 was next benzylated by CuI-mediated coupling
to give a moderate yield of product 13 (50–70%).[13] However,
this process was plagued by long reaction times (4 days), the
need for stoichiometric CuI, and difficulty in obtaining pure
material. Ultimately, the efficient Pd-catalyzed method
developed by Buchwald and co-workers[14] enabled the
coupling of benzyl chloride and terminal alkyne 12 in 75%
yield (Scheme 2). DIBAL reduction and Dess–Martin period-
inane oxidation afforded a,b-unsaturated aldehyde 14 (54%
yield, 2 steps). Condensation with cyclopropylmethyl amine
gave our key imine substrate 15 in 95% yield.
With a,b-unsaturated imine 15 in hand, we attempted the
crucial tandem RhI-catalyzed intramolecular alkenylation/
6p electrocyclization (Scheme 3).[5] Notably, while previously
reported examples of diastereoselective electrocyclizations of
azatrienes rely on stereogenic centers directly attached to the
two atoms involved in ring closure,[8–10] azatriene 5 incorpo-
Table 1: 1-Aza-3,5-trienes modeled computationally, computed activa-
tion free energy differences, and computed torquoselectivities.
Compound R1
R2
R3
G° [kcalmolÀ1
]
Torquoselectivity[a]
A
B
C
D
E
H
H
H
Me
H
H
H
3.1
3.3
3.6
187:1
262:1
435:1
187:1
221:1
Me Me
H
Me Me Me 3.2
Me Me 3.1
[a] Free energies and torquoselectivities determined assuming a stan-
dard state of 1 atm and 298.15 K.
Angew. Chem. Int. Ed. 2015, 54, 12044 –12048
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12045

.
Angewandte
Communications
The torquoselectivity of the electrocyclization is con-
trolled by the transition-state conformational preferences of
the six-membered ring appended to the 1-azatriene. In the
favored transition structure c-tsE, the six-membered ring
adopts a distorted chair-like arrangement, whereas this ring is
forced into a twist boat arrangement in tb-tsE, thereby
destabilizing this transition structure by 3.2 kcalmolÀ1. Argu-
ments first proposed to rationalize electrophilic additions to
cyclohexenes and their corresponding oxides[15] can be
extended to rationalize these conformational differences.
The favored mode of disrotation forces C5 of the triene
moiety to pyramidalize “downwards” (as shown in Figure 1),
Figure 1. wB97x-D/6-31+G(d,p)-optimized transition structures and
their relative free energies (in kcalmolÀ1).
thus allowing the six-membered ring to adopt a chair-like
conformation; pyramidalization of this carbon in the opposite
direction is responsible for the twist-boat arrangement found
in tb-tsE. This effect is likely general and could be exploited
to perform diastereoselective electrocyclizations of similar
chiral cyclic trienes.[16]
Figure 2. Free-energy diagram of the electrocyclization of 1-aza-3,5-
triene E and the computed structures of the reactant conformers of E.
Free energies (in kcalmolÀ1) and structures were determined using
wB97x-D/6-31+G(d,p).
Figure 2 depicts the free energy surface of both modes of
disrotatory electrocyclization as well as the reactant con-
formers of E. The global minimum conformer of E is c-E1,
which features a chair-like six-membered ring and an s-trans
arrangement of the azatriene moiety. tb-E1 has a relative
energy of 4.1 kcalmolÀ1 and leads to the disfavored transition
structure. The helical arrangement of the azatriene in this
structure forces the fused ring to adopt the less stable twist-
boat conformation, thus demonstrating that the geometry
required to form tb-tsE is inherently strained. The reactive
conformers c-E2 and tb-E2 also differ in energy by approx-
imately 4 kcalmolÀ1, suggesting that the magnitude of this
conformational effect is similar in the ground and transition
states.
With the concise asymmetric synthesis of intermediate 17
accomplished, the stage was set for completing the synthesis
of ent-ketorfanol (1). The remaining tasks included cleavage
of the silyl ether and ketal protecting groups, intramolecular
Friedel–Crafts alkylation, and transformation of the diol into
the desired ketone moiety. All of these steps could theoret-
ically be accomplished under acidic conditions. We therefore
attempted to carry out this sequence in a single step by
subjecting 17 to phosphoric acid at elevated temperature,
which resulted in a 2:1 inseparable mixture of 18 and ent-
ketorfanol (1), favoring 18 in a combined 69% yield
(Scheme 4). Under these strongly acidic conditions, rapid
cleavage of the ketal and silyl protecting group occurs along
Scheme 4. Intramolecular Friedel–Crafts alkylation with concomitant
redox-neutral diol-to-ketone interconversion.
with ionization to give the stabilized 28/38 allylic carbocation
19, which upon hydrogen migration affords ketone 20. This
ketone intermediate accumulates as determined by NMR
reaction monitoring. Subsequent intramolecular Friedel–
Crafts alkylation of 20 then provides regioisomers 18 and 1.
The poor regioselectivity of the Friedel–Crafts reaction
was not unexpected but did pose a significant challenge. An
effective solution to this problem would be to block the
12046 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 12044 –12048

Angewandte
Chemie
position para to the hydroxy group on the aromatic ring.
However, a silicon blocking group would likely not survive
the strongly acidic conditions necessary for the Friedel–Crafts
cyclization and a bromine blocking group would likely be
À
incompatible with the C H functionalization conditions
[17]
À
owing to competitive C Br insertion.
We therefore tar-
geted a substrate with a chloride para to the hydroxy group
(Scheme 5). Benzyl chloride 21 was readily coupled with
terminal alkyne 12 according to our previously described
alkynylation conditions. Transformation of the a,b-unsatu-
rated ester 22 into the required imine 24 then proceeded
without incident.
We were now ready to subject imine 24 to our RhI-
À
catalyzed C H functionalization conditions (Scheme 6). At
558C within 3 h, dihydropyridine 25 was produced in excel-
lent yield as a single diastereomer (> 95:5 d.r.). Subsequent
reduction with NaHB(OAc)3 provided tetrahydropyridine 26
in 69% yield of isolated product. Although the deactivating
nature of the chloride substitution in 26 necessitated a higher
temperature for the phosphoric acid mediated Friedel–Crafts
alkylation compared to the des-chloro compound, cyclization
to give 27 proceeded with excellent levels of regio- and
diastereocontrol. Hydrodehalogenation of the aryl chloride in
27 with H2 in the presence of Pd/C and NaHCO3 cleanly
afforded ent-ketorfanol (1). The structure and absolute
configuration were rigorously established by X-ray crystal-
lography.[12]
The asymmetric total synthesis of ent-ketorfanol was
accomplished in 11 steps and 9% overall yield from commer-
cially available achiral starting materials. In contrast, the only
published routes to ketorfanol proceed through multistep
degradations of morphine or naltrexone.[3] The RhI-catalyzed
alkenylation/6p electrocyclization cascade rapidly furnishes
a bicyclic 1,2-dihydropyridine that serves as a key intermedi-
ate in the synthesis. The electrocyclization is highly torquo-
selective and thus enables the use of a Sharpless asymmetric
dihydroxylation to readily produce either enantiomer of
Scheme 6. Synthesis of ent-ketorfanol (1). Reagents and conditions:
a) [{RhCl(coe)2}2] (5 mol%), 4-(diethylphosphino)-N,N-dimethylaniline
(10 mol%), toluene, 558C; b) NaHB(OAc)3, AcOH, EtOH, 0!238C;
c) 85% phosphoric acid, 1258C; d) H2, Pd/C, NaHCO3, EtOH.
ketorfanol. The acid-catalyzed tandem pinacol rearrange-
ment/Friedel–Crafts alkylation not only provides the multi-
cyclic drug framework but also converts the diol that served as
the stereocontrolling element to the requisite ketone moiety
in an efficient redox-neutral process.
In previous reports, we have demonstrated the versatility
I
À
of our Rh -catalyzed C H functionalization, electrocycliza-
tion, and reduction sequence for the regio- and stereoselec-
tive incorporation of diverse substituents into tetrahydropyr-
idines.[5c–h] For this reason, the synthetic route reported herein
should enable the straightforward preparation of a variety of
ketorfanol analogues and thus provide an avenue for improv-
ing drug properties.
Acknowledgements
This work was supported by NIH Grant GM069559 (to
J.A.E.). E.M.P. also acknowledges support from an NRSA
postdoctoral fellowship (F32GM090661), and S.D. is grateful
to the Swiss National Science Foundation for a postdoctoral
fellowship (PBZHP2-130-966). We gratefully acknowledge
Dr. Michael Takase for solving the crystal structure of 1·HCl.
We also acknowledge the financial support of the NIH (GM-
36700 and CHE-1351104 to K.N.H.) A.P. thanks the Chem-
ical-Biology Interface Training Program for its support (T32
GM 008496). A.P acknowledges the University of California,
Los Angeles for financial support. Density functional theory
computations were performed using the Extreme Science and
Engineering Discovery Environment (XSEDE)ꢀs Gordon
supercomputer (OCI-1053575) at the San Diego Supercom-
puting Center.
Scheme 5. Synthesis of imine 24. Reagents and conditions: a) PdCl2-
(CH3CN)2 (5 mol%), XPhos (15 mol%), Cs2CO3, THF, 658C;
b) DIBAL, THF, À788C; c) Dess–Martin periodinane, pyridine, CH2Cl2,
08C; d) cyclopropylmethyl amine, toluene, 3 Š MS.
Angew. Chem. Int. Ed. 2015, 54, 12044 –12048
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12047

.
Angewandte
Communications
À
[7] A discussion on redox economy in synthesis: N. Z. Burns, P. S.
Baran, R. W. Hoffmann, Angew. Chem. Int. Ed. 2009, 48, 2854 –
2867; Angew. Chem. 2009, 121, 2896 – 2910.
Keywords: alkaloids · asymmetric synthesis · C H activation ·
heterocycles · torquoselectivity
[8] A recent review on asymmetric electrocyclization reactions: S.
Thompson, A. G. Coyne, P. C. Knipe, M. D. Smith, Chem. Soc.
Rev. 2011, 40, 4217 – 4231.
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12044–12048
Angew. Chem. 2015, 127, 12212–12216
[9] a) R. P. Hsung, L. L. Wei, H. M. Sklenicka, C. J. Douglas, M. J.
McLaughlin, J. A. Mulder, L. J. Yao, Org. Lett. 1999, 1, 509 – 512;
b) K. Tanaka, S. Katsumura, J. Am. Chem. Soc. 2002, 124, 9660 –
9661; c) H. M. Sklenicka, R. P. Hsung, M. J. McLaughlin, L. I.
Wei, A. I. Gerasyuto, W. B. Brennessel, J. Am. Chem. Soc. 2002,
124, 10435 – 10442; d) N. Sydorenko, R. P. Hsung, E. L. Vera,
Org. Lett. 2006, 8, 2611 – 2614; e) T. Kobayashi, K. Takeuchi, J.
Miwa, H. Tsuchikawa, S. Katsumura, Chem. Commun. 2009,
3363 – 3365; f) T. Sakaguchi, S. Kobayashi, S. Katsumura, Org.
Biomol. Chem. 2011, 9, 257 – 264.
[10] Recent reports of remote stereocontrol of triene electrocycliza-
tion: a) Z.-X. Ma, A. Patel, K. N. Houk, R. P. Hsung, Org. Lett.
2015, 17, 2138 – 2141; b) A. Patel, G. A. Barcan, O. Kwon, K. N.
Houk, J. Am. Chem. Soc. 2013, 135, 4878 – 4883; c) G. A. Barcan,
A. Patel, K. N. Houk, O. Kwon, Org. Lett. 2012, 14, 5388 – 5391.
[11] D. Q. Xu, G. A. Crispino, K. B. Sharpless, J. Am. Chem. Soc.
1992, 114, 7570 – 7571.
[12] Synthetic details, characterization, and molecular structures
obtained by X-ray structural analysis of compounds are
described in the Supporting Information. CCDC 1404582 (11)
and 1404583 (1·HCl) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
[13] K. A. Davies, R. C. Abel, J. E. Wulff, J. Org. Chem. 2009, 74,
3997 – 4000.
[14] C. H. Larsen, K. W. Anderson, R. E. Tundel, S. L. Buchwald,
Synlett 2006, 2941 – 2946.
[1] Typing the name of these drug and drug candidates into the
NCGC Pharmaceutical Collection database provides compound
structure, bioactivity, a full list of literature, and access to
ongoing clinical trials, applications, and usage.
[2] a) M. Filizola, L. A. Devi, Nature 2012, 485, 314 – 317; b) A.
Manglik, A. C. Kruse, T. S. Kobilka, F. S. Thian, J. M. Mathiesen,
R. K. Sunahara, L. Pardo, W. I. Weis, B. K. Kobilka, S. Granier,
Nature 2012, 485, 321 – 326; c) H. X. Wu, D. Wacker, M. Mileni,
V. Katritch, G. W. Han, E. Vardy, W. Liu, A. A. Thompson, X. P.
Huang, F. I. Carroll, S. W. Mascarella, R. B. Westkaemper, P. D.
Mosier, B. L. Roth, V. Cherezov, R. C. Stevens, Nature 2012, 485,
327 – 332; d) S. Granier, A. Manglik, A. C. Kruse, T. S. Kobilka,
F. S. Thian, W. I. Weis, B. K. Kobilka, Nature 2012, 485, 400 – 404.
[3] Synthesis of ketorfanol from the degradation of heavily func-
tionalized natural product starting materials: a) A. Manmade,
H. C. Dalzell, J. F. Howes, R. K. Razdan, J. Med. Chem. 1981, 24,
1437 – 1440; b) Y. Ida, T. Nemoto, S. Hirayama, H. Fujii, Y. Osa,
M. Imai, T. Nakamura, T. Kanemasa, A. Kato, H. Nagase,
Bioorg. Med. Chem. 2012, 20, 949 – 961.
[4] Reviews and leading references on the syntheses of morphine
and related natural products: a) J. W. Reed, T. Hudlicky, Acc.
Chem. Res. 2015, 48, 674 – 687; b) U. Rinner, T. Hudlicky, Top.
Curr. Chem. 2012, 300, 33 – 66; c) N. Chida, Top. Curr. Chem.
2011, 299, 1 – 28; d) M. Tissot, R. J. Phipps, C. Lucas, R. M. Leon,
R. D. M. Pace, T. Ngouansavanh, M. J. Gaunt, Angew. Chem. Int.
Ed. 2014, 53, 13498 – 13501; Angew. Chem. 2014, 126, 13716 –
13719; e) M. Ichiki, H. Tanimoto, S. Miwa, R. Saito, T. Sato, N.
Chida, Chem. Eur. J. 2013, 19, 264 – 269; f) J. Li, G.-L. Liu, X.-H.
Zhao, J.-Y. Du, H. Qu, W.-D. Chu, M. Ding, C.-Y. Jin, M.-X. Wei,
C.-A. Fan, Chem. Asian J. 2013, 8, 1105 – 1109; g) V. Varghese, T.
Hudlicky, Angew. Chem. Int. Ed. 2014, 53, 4355 – 4358; Angew.
Chem. 2014, 126, 4444 – 4447; h) A. Kimishima, H. Umihara, A.
Mizoguchi, S. Yokoshima, T. Fukuyama, Org. Lett. 2014, 16,
6244 – 6247.
[15] A. Fürst, P. A. Plattner, Helv. Chim. Acta 1949, 32, 275 – 283.
[16] Computations of the electrocyclic reaction of carbatriene
analogue of E predict a similar level of torquoselectivity.
[5] a) D. A. Colby, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.
2008, 130, 3645 – 3651; b) S. Duttwyler, C. Lu, A. L. Rheingold,
R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2012, 134, 4064 –
4067; c) S. Duttwyler, S. Chen, M. K. Takase, K. B. Wiberg, R. G.
Bergman, J. A. Ellman, Science 2013, 339, 678 – 682; d) M. A.
Ischay, M. K. Takase, R. G. Bergman, J. A. Ellman, J. Am. Chem.
Soc. 2013, 135, 2478 – 2481; e) S. Duttwyler, S. Chen, C. Lu, B. Q.
Mercado, R. G. Bergman, J. A. Ellman, Angew. Chem. Int. Ed.
2014, 53, 3877 – 3880; Angew. Chem. 2014, 126, 3958 – 3961; <
lit f > T. Mesganaw, J. A. Ellman, Org. Process Res. Dev. 2014,
18, 1097 – 1104; g) T. Mesganaw, J. A. Ellman, Org. Process Res.
Dev. 2014, 18, 1105 – 1109.
[17] A leading reference: J. C. Lewis, A. M. Berman, R. G. Bergman,
J. A. Ellman, J. Am. Chem. Soc. 2008, 130, 2493 – 2500.
[6] Intramolecular Friedel – Crafts alkylation has been used to form
this ring system, but not in the presence of the acid-labile allylic
alchol functionality. R. Grewe, A. Mondon, Chem. Ber. 1948, 81,
279 – 286.
Received: June 17, 2015
Published online: August 17, 2015
12048 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 12044 –12048