Total Synthesis of Haliclonin A

Article abstract of DOI:10.1002/anie.202016343

The total synthesis of haliclonin A was accomplished. Starting from 3,5-dimethoxybenzoic acid, a functionalized cyclohexanone fused to a 17-membered ring was prepared through a Birch reduction/alkylation sequence, ring-closing metathesis, intramolecular cyclopropanation, and stereoselective 1,4-addition of an organocopper reagent to an enone moiety. Reductive C?N bond formation via an N,O-acetal forged the 3-azabicyclo[3.3.1]nonane core. The allyl alcohol moiety was constructed by a sequence involving stereoselective α-selenylation of an aldehyde via an enamine, syn-elimination of a selenoxide, and allylation of the aldehyde with an allylboronate. Formation of the 15-membered ring containing a skipped diene was achieved by ring-closing metathesis, and final transformations led to the synthesis of haliclonin A.

Full text of DOI:10.1002/anie.202016343

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 9666–9671
International Edition:
German Edition:
doi.org/10.1002/anie.202016343
doi.org/10.1002/ange.202016343
Natural Products
Total Synthesis of Haliclonin A
Yuan Jin, Kensuke Orihara, Fumiki Kawagishi, Tatsuya Toma, Tohru Fukuyama, and
Satoshi Yokoshima*
Abstract: The total synthesis of haliclonin A was accom-
plished. Starting from 3,5-dimethoxybenzoic acid, a function-
alized cyclohexanone fused to a 17-membered ring was
prepared through a Birch reduction/alkylation sequence,
ring-closing metathesis, intramolecular cyclopropanation, and
stereoselective 1,4-addition of an organocopper reagent to an
enone moiety. Reductive CÀN bond formation via an N,O-
structure is a 3-azabicyclo[3.3.1]nonan-2,7-dione that is fused
to 17- and 15-membered rings. The 17-membered ring has
a formamide moiety and shares a quaternary carbon with the
bicyclic core. The 15-membered ring contains a skipped diene
and an allyl alcohol moiety. Huang and co-workers reported
[
4]
the first total synthesis of haliclonin A in 2016. The synthesis
featured an asymmetric conjugate addition of nitromethane
to construct the quaternary carbon, a palladium-mediated
carbonyl-enone coupling to form the 3-azabicyclo-
[3.3.1]nonane core, and an alkyne metathesis to form the
15-membered ring. Recently, Ishihara and co-workers report-
ed a formal synthesis of haliclonin A that features a tandem
radical reaction of a selenocarbamate to form the 3-
azabicyclo[3.3.1]nonane core and to install a carbon unit for
acetal forged the 3-azabicyclo[3.3.1]nonane core. The allyl
alcohol moiety was constructed by a sequence involving
stereoselective a-selenylation of an aldehyde via an enamine,
syn-elimination of a selenoxide, and allylation of the aldehyde
with an allylboronate. Formation of the 15-membered ring
containing a skipped diene was achieved by ring-closing
metathesis, and final transformations led to the synthesis of
haliclonin A.
[
5]
the 17-membered ring. We also reported our synthetic
[
6]
studies toward haliclonin A in 2018. In that report, we
succeeded in constructing the 3-azabicyclo[3.3.1]nonane core
via an unexpected 1,5-hydride shift. However, there were
challenges in forming the 15-membered ring. After continu-
ous efforts, we completed the synthesis of haliclonin A not via
the 1,5-hydride shift to form the 3-azabicyclo[3.3.1]nonane
core and with successfully constructing the allyl alcohol
moiety, as well as the skipped diene, in the 15-membered ring.
Herein we disclose our total synthesis of haliclonin A.
Introduction
A variety of natural products that contain a nitrogen-
containing polycyclic core fused to macrocyclic rings, have
[
1]
been isolated from sponges. These characteristic structures
of the natural products have attracted the attention of
chemists and spurred the proposal of elegant biosynthetic
pathways that can explain the relationship between each
[
2]
structure. Haliclonin A (1), one of the natural products, was
[
3]
isolated from Haliclona sp. in 2009 (Figure 1). The core
Results and Discussion
Our synthesis commenced with Birch reduction of 3,5-
dimethoxybenzoic acid (2) followed by alkylation with 6-
[
6]
bromo-1-hexene (A, Scheme 1). The resultant carboxylic
acid 3 was treated with 2.05 equivalents of n-butyllithium to
generate a dianion, which stereoselectively reacted with alkyl
[
7]
bromide B to afford 4 as the sole isomer. After methylation
with iodomethane, the resulting methyl ester 5 was reduced
with lithium aluminum hydride to afford alcohol 6. Ring-
closing metathesis with the Grubbs second-generation cata-
Figure 1. Structure of haliclonin A.
[8]
lyst, followed by hydrogenation, furnished 7.
The next task was introduction of a carbon unit on C1. We
found that installation of a carbon unit on C1 was problematic
after construction of the 3-azabicyclo[3.3.1]nonane core,
[
*] Y. Jin, Dr. K. Orihara, Dr. T. Toma, Prof. Dr. T. Fukuyama,
Prof. Dr. S. Yokoshima
Graduate School of Pharmaceutical Sciences, Nagoya University
Furo-cho, Chikusa-ku, Nagoya, 464-8601 (Japan)
E-mail: yokosima@ps.nagoya-u.ac.jp
[4a]
consistent with a published report.
The problem was
partially attributed to the steric hindrance of the quaternary
carbon adjacent to C1. To address this issue, we chose to
conduct an intramolecular cyclopropanation at this stage to
deliver the carbon unit. Alcohol 7 was converted into
Dr. F. Kawagishi
Graduate School of Pharmaceutical Sciences, The University of Tokyo
[
9]
diazoacetate 8. Upon treatment with a catalytic amount of
copper complex, 8 underwent an intramolecular cyclopropa-
7
-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 (Japan)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016343.
[10]
nation to afford tetracyclic lactone 9, thereby generating
the C1–C10 bond.
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Table 1: Asymmetric cyclopropanation.
Entry
Catalyst
T
Yield [%]
Enantiomer ratio
1
2
3
4
5
6
7
L1, Cu(OTf)
L2, Cu(OTf)
L3, Cu(OTf)
L4, Cu(OTf)
M1
rt
rt
rt
6
3
2
27
34
32
45
52:48
48:52
45:55
60:40
35:65
34:66
21:79
[a]
rt
758C
758C
758C
M2
M3
[
a] Instead of toluene, dichloromethane was used as a solvent.
Scheme 1. Synthesis of 9 via Birch reduction, ring closing metathesis,
and intramolecular cyclopropanation.
Compound 8, the substrate for the cyclopropanation, is
symmetric, and therefore cyclopropanation employing chiral
[11]
catalysts would afford enantioenriched cyclopropane 9. We
screened catalysts for asymmetric cyclopropanation (Table 1).
Reactions with the oxazoline ligands L1–3 gave almost
[12]
racemic products in low yields (entries 1–3).
Reactions
with the binaphthyl ligand L4 slightly induced enantioselec-
[
13]
tivity (entry 4). Employing M1–3 as a catalyst improved the
enantioselectivity, and a reaction of 8 in the presence of M3
[14]
produced 9 in 45% yield with an enantiomer ratio of 21:79.
These results showed the possibility of the asymmetric
synthesis, and development of novel ligands or catalysts will
lead to high yield and enantioselectivity; however, we decided
[15]
to proceed our synthesis in racemic form.
Attempted acidic treatment of 9 produced an inseparable
mixture of 10 and 11 (Scheme 2). Acidic hydrolysis of the enol
ether and the subsequent cleavage of the cyclopropane ring
between C2 and C10 would produce 10, whereas cleavage of
the cyclopropane ring prior to the hydrolysis of the enol ether
would produce 11. To control the reaction sequence, we
attempted to open the lactone ring to reduce the ring strain of
the cyclopropane. Thus, 9 was treated with sodium hydroxide
to give carboxylic acid 12, which was treated with 10-
camphorsulfonic acid (CSA) in dichloromethane, resulting
Scheme 2. Hydrolysis of the enol ether and cleavage of the cyclo-
propane ring.
One of the factors affecting the selective transformation
of 9 into 10 was the decrease in the ring strain of the
[
17]
cyclopropane by the lactone opening. More importantly,
the carboxy group in 12 worked as both an acid and
a nucleophile. The proximity of the carboxy group would
promote protonation of the enol ether moiety in 12, and the
[16]
in selective formation of 10 in 92% yield over 2 steps.
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Scheme 3. Proposed mechanism for the selective formation of 10.
resultant oxocarbenium ion would be attacked by the carboxy
group (Scheme 3). Indeed, upon standing in CDCl at room
3
temperature, carboxylic acid 12 was slowly converted into
lactone 14 even without external acid. By adding an acid, the
lactone formation occurred more smoothly, and the primary
hydroxy group in 15 subsequently attacked the lactone
intramolecularly to liberate a ketone moiety with elimination
of methanol. The resultant lactone 16, which restored the
strained ring system, underwent cleavage of the cyclopropane
ring to give 10. Intermediates 14 and 16 could be isolated and
be converted into compound 10 in 85% and 92% yields,
respectively. The reaction sequence shown in Scheme 3 could
also be detected by a reaction conducted in a NMR tube
1
Figure 2. H NMR spectra in CDCl . Conversion of 14 into 10 via
3
intermediate 16 by treatment with 0.1 equivalent of CSA.
(
Figure 2).
The vinylogous ester and lactone moieties in 10 were
simultaneously reduced with diisobutylaluminum hydride
(
(
DIBAL) to give, after acidic hydrolysis, enone 17
Scheme 4). The hemiacetal moiety in 17 was then converted
into cyclic enol ether 18 by treatment with methanesulfonyl
chloride and triethylamine. Upon treatment of 18 with
vinylmagnesium chloride in the presence of copper(I) iodide,
the 1,4-addition of a vinyl group to the enone moiety and
protonation of the resultant enolate on workup occurred
stereoselectively from the less hindered side, the side opposite
to the bridge of the 17-membered ring, to furnish 19 in 61%
yield as the sole isomer. The conversion of the hemiacetal
moiety in 17 into the cyclic enol ether was essential for the 1,4-
addition. Indeed, when 20 or 21 was used as a substrate, the
1
,4-addition did not proceed, or provided the corresponding
product only in low yield with poor reproducibility. Being flat,
the cyclic enol ether might decrease the steric hindrance
during the 1,4-addition.
We next constructed the 3-azabicyclo[3.3.1]nonane skel-
eton (Scheme 5). Ketone 19 was stereoselectively reduced
Scheme 4. Stereoselective 1,4-addition of a vinyl group.
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Scheme 5. Construction of the 3-azabicyclo[3.3.1]nonane skeleton.
with DIBAL, and the resultant secondary alcohol was
protected with an acetyl group. After acidic hydrolysis of
cyclic enol ether 22, the resultant hemiacetal 23 was
reductively cleaved with sodium borohydride to afford diol
stereochemical outcome of 37 can be explained by consider-
ing the following factors: (a) enamine 34 has a conformation
in which the allylic strain is minimized; (b) the reaction of the
enamine with phenylselenyl chloride occurs from the less-
hindered side that is opposite to the quaternary carbon; and
(c) syn-elimination of the selenoxide occurs. Subsequent
allylation of the enal with alylboronic acid pinacol ester
occurred via a chair-like transition state 39, in which the enal
assumed the s-trans conformation to avoid steric repulsion
with the quaternary carbon at C6 and the allylboronate
approached from the opposite side of the bridge to give
secondary alcohol 40 in 71% yield with a diastereoselectivity
of 7.9:1. After protection of the hydroxy group with a TBS
group, ring-closing metathesis was conducted with the Grubbs
first generation catalyst to afford an E,Z-mixture of product
2
4, and both hydroxy groups were protected with TBS groups.
Ozonolysis of the vinyl group in 25 followed by oxidation with
[18]
sodium chlorite produced carboxylic acid 26, which was
[19]
condensed with amine 27.
Removal of the TBS groups
under acidic conditions was followed by Swern oxidation to
[20]
afford dialdehyde 30. Attempted isolation of the dialde-
hyde with silica gel resulted in low yield because of its
instability. Therefore, the crude mixture was immediately
treated with pyridinium p-toluenesulfonate (PPTS) in reflux-
ing dichloromethane. Under these conditions, sequential
formation of a hemiaminal and a hemiacetal occurred,
leading to construction of the 3-azabicyclo[3.3.1]nonane
system fused to a cyclic hemiacetal. Product 31 was stable
enough to be purified with silica gel and was isolated in 90%
yield over 2 steps. Reduction of 31 with sodium cyanobor-
ohydride in the presence of chlorotrimethylsilane as an acid
[23]
42 in 56% yield. The geometrical isomer were separable
after removal of the acetyl group. The tosyl group of Z-isomer
43 was cleaved with sodium naphthalenide, and a formyl
group was installed on the resultant secondary amine 44.
Oxidation of the secondary alcohol moiety in 46 followed by
cleavage of the TBS group with TASF afforded haliclonin A
(1).
[
21]
afforded 32.
The remaining task was construction of the allyl alcohol
moiety and the macrocyclic ring containing a skipped diene.
[22]
Dess–Martin oxidation of alcohol 32 afforded aldehyde 33,
which was converted into enamine 34 by a reaction with Conclusion
piperidine (Scheme 6). The E configuration of the enamine
1
was confirmed by H NMR, which showed the coupling
constant to be 13.7 Hz. Reaction of the enamine with
phenylselenyl chloride, followed by oxidation with hydrogen
peroxide afforded the desired (E)-enal 37, the configuration
of which was confirmed by the NOESY spectrum. The
We have achieved the total synthesis of haliclonin A
starting from 3,5-dimethoxybenzoic acid. A Birch reduction/
alkylation sequence and ring-closing metathesis were used to
construct a cyclohexane ring fused to a 17-membered ring.
Intramolecular cyclopropanation formed a CÀC bond at
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Scheme 6. Completion of the synthesis.
a sterically congested position adjacent to a quaternary Acknowledgements
carbon. 1,4-addition of an organocopper reagent to an enone
moiety introduced a carbon unit, with the stereochemistry
completely controlled by a bridge in the 17-membered ring.
Reductive CÀN bond formation via an N,O-acetal construct-
This work was financially supported by JSPS KAKENHI
(Grant Number JP17H01523 and JP18H04399) and by the
Platform Project for Supporting Drug Discovery and Life
Science Research (Basis for Supporting Innovative Drug
Discovery and Life Science Research: BINDS) from the
Japan Agency for Medical Research and Development
(AMED) under Grant Number JP20am0101099.
ed the 3-azabicyclo[3.3.1]nonane core. The allyl alcohol
moiety was introduced by a sequence involving the stereose-
lective a-selenylation of an aldehyde via an enamine, syn-
elimination of a selenoxide, and allylation of the aldehyde
with an allylboronate. The stereochemistry of the allylation
was also controlled by the bridge fused to the cyclohexane,
leading to the stereoselective formation of the allyl alcohol. Conflict of interest
The 15-membered ring containing a skipped diene was
constructed via ring-closing metathesis, and five more steps
completed the synthesis.
The authors declare no conflict of interest.
Keywords: alkaloids · macrocycles · marine natural products ·
metathesis · stereoselective reactions
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7
625; e) A. Cornejo, J. M. Fraile, J. I. García, M. J. Gil, C. I.
[
1] a) J.-F. Hu, M. T. Hamann, R. Hill, M. Kelly in The Alkaloids:
Chemistry and Biology, Vol. 60, Academic Press, New York,
Herrerías, G. Legarreta, V. Martínez-Merino, J. A. Mayoral, J.
Mol. Catal. A 2003, 196, 101 – 108.
2
003, pp. 207 – 285; b) B. Delpech in The Alkaloids: Chemistry
[13] a) H. Suga, T. Fudo, T. Ibata, Synlett 1998, 933 – 935; b) H. Suga,
A. Kakehi, S. Ito, T. Ibata, T. Fudo, Y. Watanabe, Y. Kinoshita,
Bull. Chem. Soc. Jpn. 2003, 76, 189 – 199.
[14] a) T. Aratani, Y. Yoneyoshi, T. Nagase, Tetrahedron Lett. 1975,
16, 1707 – 1710; b) T. Aratani, Y. Yoneyoshi, T. Nagase, Tetrahe-
dron Lett. 1977, 18, 2599 – 2602; c) K. Suenobu, M. Itagaki, E.
Nakamura, J. Am. Chem. Soc. 2004, 126, 7271 – 7280; d) M.
Itagaki, K. Suenobu, Org. Process Res. Dev. 2007, 11, 509 – 518.
[15] For other trials of asymmetric cyclopropanation, see the
Supporting Information.
and Biology, Vol. 73 (Ed.: H.-J. Knçlker), Academic Press, New
York, 2014, pp. 223 – 329; c) M. Amat, M. PØrez, R. Ballette, S.
Proto, J. Bosch in The Alkaloids: Chemistry and Biology, Vol. 74
(
1
Ed.: H.-J. Knçlker), Academic Press, New York, 2015, pp. 159 –
99; for synthetic studies on related natural products, see: d) B.
Cheng, J. Reyes, Nat. Prod. Rep. 2020, 37, 322 – 337; e) S.
Yokoshima, Chem. Lett. 2021, 50, 96 – 102; f) Z. Meng, A.
Fürstner, J. Am. Chem. Soc. 2020, 142, 11703 – 11708.
[
2] a) J. E. Baldwin, R. C. Whitehead, Tetrahedron Lett. 1992, 33,
2
059 – 2062; b) J. E. Baldwin, T. D. W. Claridge, A. J. Culshaw,
[16] Impurities, which could not be separated by silica gel column
chromatography, were formed in the transformation of 8 into 9,
F. A. Heupel, V. Lee, D. R. Spring, R. C. Whitehead, R. J.
Boughtflower, I. M. Mutton, R. J. Upton, Angew. Chem. Int. Ed.
and therefore, in a large-scale preparation, the yield of
1
998, 37, 2661 – 2663; Angew. Chem. 1998, 110, 2806 – 2808;
compound 10 was calculated to be 61% as the overall yield in
3 steps from compound 8. In small-scale reactions, the impurities
could be separated by preparative TLC. For details, see the
Supporting Information.
c) J. E. Baldwin, T. D. W. Claridge, A. J. Culshaw, F. A. Heupel,
V. Lee, D. R. Spring, R. C. Whitehead, Chem. Eur. J. 1999, 5,
3
154 – 3161.
[
[
3] K. H. Jang, G. W. Kang, J.-e. Jeon, C. Lim, H.-S. Lee, C. J. Sim,
K.-B. Oh, J. Shin, Org. Lett. 2009, 11, 1713 – 1716.
[17] DFT calculations suggested that the C2–C10 bond becomes
longer by forming the lactone ring. For details, see the Support-
ing Information. The change in the bond length might be
attributed to the fixed conformation of the lactone, in which the
C2–C10 bond can interact with the p* orbital of the carbonyl
group.
[18] a) B. O. Lindgren, T. Nilsson, Acta Chem. Scand. 1973, 27, 888 –
890; b) G. A. Kraus, M. J. Taschner, J. Org. Chem. 1980, 45,
1175 – 1176; c) G. A. Kraus, B. Roth, J. Org. Chem. 1980, 45,
4825 – 4830; d) B. S. Bal, W. E. Childers, H. W. Pinnick, Tetrahe-
dron 1981, 37, 2091 – 2096.
[19] For preparation of amine unit 27, see the Supporting Informa-
tion.
[20] The removal of the TBS groups with hydrochloric acid was
quenched within 10 minutes. A prolonged reaction time induced
formation of a lactone between the amide moiety and the
primary alcohol.
4] a) L.-D. Guo, X.-Z. Huang, S.-P. Luo, W.-S. Cao, Y.-P. Ruan, J.-L.
Ye, P.-Q. Huang, Angew. Chem. Int. Ed. 2016, 55, 4064 – 4068;
Angew. Chem. 2016, 128, 4132 – 4136; b) S.-P. Luo, L.-D. Guo, L.-
H. Gao, S. Li, P. -Q. Huang, Chem. Eur. J. 2013, 19, 87 – 91; c) S.-P.
Luo, X.-Z. Huang, L.-D. Guo, P.-Q. Huang, Chin. J. Chem. 2020,
3
8, 1723 – 1736.
[
[
[
5] K. Komine, Y. Urayama, T. Hosaka, Y. Yamashita, H. Fukuda, S.
Hatakeyama, J. Ishihara, Org. Lett. 2020, 22, 5046 – 5050.
6] K. Orihara, F. Kawagishi, S. Yokoshima, T. Fukuyama, Synlett
2
018, 29, 769 – 772.
7] a) N. J. Bennett, M. C. Elliott, N. L. Hewitt, B. M. Kariuki, C. A.
Morton, S. A. Raw, S. Tomasi, Org. Biomol. Chem. 2012, 10,
3
5
859 – 3865; b) E. Koch, A. Studer, Angew. Chem. Int. Ed. 2013,
2, 4933 – 4936; Angew. Chem. 2013, 125, 5033 – 5036.
[
[
8] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
53 – 956.
9] T. Toma, J. Shimokawa, T. Fukuyama, Org. Lett. 2007, 9, 3195 –
197.
9
[21] a) R. Johansson, B. Samuelsson, J. Chem. Soc. Perkin Trans.
1 1984, 2371 – 2374; b) A. Fürstner, T. Nagano, J. Am. Chem. Soc.
2007, 129, 1906 – 1907.
3
[
[
10] E. J. Corey, A. G. Myers, Tetrahedron Lett. 1984, 25, 3559 – 3562.
11] For selected reviews on cyclopropanation, see: a) H. Lebel, J.-F.
Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003, 103,
[22] a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155 – 4156;
b) D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277 –
7287.
[23] a) P. Schwab, R. H. Grubbs, J. W. Ziller, J. Am. Chem. Soc. 1996,
118, 100 – 110. Attempted subjection of 41 to the Z-selective
ring-closing metathesis resulted in no production of 42 and the
substrate 41 was recovered. b) B. K. Keitz, K. Endo, P. R. Patel,
M. B. Herbert, R. H. Grubbs, J. Am. Chem. Soc. 2012, 134, 693 –
699; c) V. M. Marx, M. B. Herbert, B. K. Keitz, R. H. Grubbs, J.
Am. Chem. Soc. 2013, 135, 94 – 97.
9
77 – 1050; b) M. Honma, H. Takeda, M. Takano, M. Nakada,
Synlett 2009, 1695 – 1712; c) P. Tang, Y. Qin, Synthesis 2012, 44,
2
2
969 – 2984; d) G. Bartoli, G. Bencivenni, R. Dalpozzo, Synthesis
014, 46, 979 – 1029; e) A. Ford, H. Miel, A. Ring, C. N. Slattery,
A. R. Maguire, M. A. McKervey, Chem. Rev. 2015, 115, 9981 –
1
1
0080; f) C. Ebner, E. M. Carreira, Chem. Rev. 2017, 117, 11651 –
1679.
[
12] a) R. Ida, M. Nakada, Tetrahedron Lett. 2007, 48, 4855 – 4859;
b) M. Honma, T. Sawada, Y. Fujisawa, M. Utsugi, H. Watanabe,
A. Umino, T. Matsumura, T. Hagihara, M. Takano, M. Nakada,
J. Am. Chem. Soc. 2003, 125, 2860 – 2861; c) D. A. Evans, K. A.
Woerpel, M. M. Hinman, M. M. Faul, J. Am. Chem. Soc. 1991,
Manuscript received: December 9, 2020
Revised manuscript received: January 18, 2021
Accepted manuscript online: February 8, 2021
Version of record online: March 11, 2021
1
13, 726 – 728; d) J. M. Fraile, J. I. García, V. Martínez-Merino,
J. A. Mayoral, L. Salvatella, J. Am. Chem. Soc. 2001, 123, 7616 –
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