Total Synthesis of GKK1032A2 via Direct 13-Membered Macrocyclization Using a Nucleophilic Aromatic Substitution of an (η6-Arene)Chromium Complex

Article abstract of DOI:10.1002/asia.201601728

The first enantioselective total synthesis of GKK1032A₂ has been achieved. The key step is a direct construction of the highly strained 13-membered macrocycle of GKK1032A₂ by an intramolecular nucleophilic aromatic substitution (S_NAr) reaction. This is the first successful example of construction of a macrocycle with an aryl ether linkage utilizing an intramolecular S_NAr reaction of an (η⁶-arene)chromium complex.

Full text of DOI:10.1002/asia.201601728

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Total Synthesis of GKK1032A₂ via Direct 13-Membered
Macrocyclization Utilizing Aromatic Nucleophilic Substitution of an
η⁶-Arene Chromium Complex
Authors: Hayato Sugata, Kensuke Inagaki, Toshiaki Ode, Tomoki
Hayakawa, Yuki Karoji, Motoaki Baba, Ryo Kato, Daiju
Hasegawa, Tetsu Tsubogo, and Hiromi Uchiro
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Chemistry - An Asian Journal
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Total Synthesis of GKK1032A2 via Direct 13-Membered
Macrocyclization Utilizing Aromatic Nucleophilic Substitution of
an 6-Arene Chromium Complex
Hayato Sugata,[b] Kensuke Inagaki,[b] Toshiaki Ode,[b] Tomoki Hayakawa,[b] Yuki Karouji,[b] Motoaki
Baba,[b] Ryo Kato,[b] Daiju Hasegawa,[b] Tetsu Tsubogo,[a,b] and Hiromi Uchiro*[a,b]
Abstract: The first enantioselective total synthesis of GKK1032A2
has been achieved. The key step is direct construction of the highly
strained 13-membered macrocycle of GKK1032A2 by an
intramolecular aromatic substitution (SNAr) reaction. To the best of
our knowledge, this is the first successful example of construction of
a macrocycle with an aryl ether linkage utilizing an intramolecular
SNAr reaction of an 6-arene chromium complex.
biosynthesis. In 2003, Oikawa proposed a biosynthetic pathway
for GKK1032A2 (1) based on detailed studies using isotopically
labeled precursors.[7] Nay et al. also discussed several
alternative biosynthetic pathways for the decahydrofluorene
skeleton.[3] Synthetic studies of GKK1032A2 (1) have been
extensively reported by Kuwajima’s, Katoh’s, and Tadano’s
groups.[8-10] These three groups independently achieved the
synthesis of the decahydrofluorene core. Recently, Tadano et al.
has also been successful in the construction of the 13-
membered macrocycle by means of conjugated addition of
nitroalkane to an enone;[10b] however, total synthesis utilizing the
partially functionalized macrocycle has not been reported to date.
The strategy for functional group manipulations after
construction of the macrocycle is also crucial. In the meantime,
we have also achieved synthesis of the decahydrofluorene core
using a sequential retro Diels–Alder and intramolecular Diels–
Alder (retro-DA-IMDA) reaction.[11] In this study, we report the
first total synthesis of GKK1032A2 (1) via direct construction of
the 13-membered macrocycle by intramolecular nucleophilic
aromatic substitution utilizing an 6-arene chromium complex.
Recently, decahydrofluorene-class natural products such as
GKK1032A2 (1), Pyrrocidine
A
(2), Hirsutellone
B
(3),
Embellicine A (4) have been discovered[1,2] (Figure 1). Over a
decade and a half, many researchers have studied the synthesis
of these natural products because of their fascinating biological
activities and synthetically challenging chemical structures.[3]
However, the total synthesis of Hirsutellones have only been
achieved because construction of their highly strained 13-
membered macrocycles with bent benzene rings is still a difficult
problem. In 2009, Nicolaou et al. reported the first total synthesis
of Hirsutellone B (3).[4] In this study, the construction of the 13-
membered macrocycle was achieved by the Ramberg-Bäcklund
reaction of a less strained 14-membered cyclic sulfone. On the
contrary, we achieved the first direct macrocyclization utilizing
intramolecular Ullmann C–O coupling reaction, and the second
total synthesis of Hirsutellone B (3) was reported in 2011.[5]
Thereafter, Sorensen et al. also achieved macrocycle
construction together with formation of a decahydrofluorene
skeleton by their original approach.[6]
Total synthesis of GKK1032A2 (1) is a more difficult problem
because the compound has two quaternary chiral centers at the
C3 and C7 positions, and, in contrast to Hirsutellones, its ether
linkage at the C13 position is on the sterically more hindered -
side of the decahydrofluorene core. GKK1032A2 (1) was
discovered as the first decahydrofluorene class of natural
products with antitumor activity from the culture broth of
Penicillium sp. GKK1032 in 2001 by researchers of Kyowa
Hakko Kogyo Co. Ltd.[1a] Its unique chemical structure has
received much attention from researchers in the field of
Figure 1. Decahydrofluorene-class natural products.
As described above, we have achieved synthesis of the
decahydrofluorene core of GKK1032A2 (1) in 2011.[11] We
then expected that the 13-membered macrocycle could be
constructed in a similar manner to our total synthesis of
Hirsutellone B (3).[5] Actually, an intramolecular Ullmann C-O
coupling reaction[12] of the preliminarily prepared precursor 5
was conducted as shown in Scheme 1.
[a]
[b]
Dr. T. Tsubogo, Prof. Dr. H. Uchiro
Division of Fusion of Regenerative Medicine with DDS, Research
Institute for Science and Technology (RIST)Tokyo University of
Science 2641 Yamazaki, Noda, Chiba 278-8510, Japan
H. Sugata, K. Inagaki, T. Ode, T. Hayakawa, Y. Karouji, M. Baba,
Dr. R. Kato, Dr. D. Hasegawa, Dr. T. Tsubogo, Prof. Dr. H. Uchiro
Faculty of Pharmaceutical Sciences
Tokyo University of Science
2641 Yamazaki, Noda, Chiba 278-8510, Japan
E-mail: uchiro@rs.noda.tus.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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Our retrosynthetic analysis is shown in Figure 3. GKK1032A2 (1)
would be obtained by the formation of the -hydroxylactam
moiety from ketoamide 9, prepared from macrocycle 10 via
several functional group transformations. The 13-membered
macrocycle of 10 would be directly constructed by intramolecular
nucleophilic aromatic substitution between the aliphatic
secondary hydroxyl group at the C13 position and the 6-arene
complexed aryl fluoride moiety. On this cyclization, utilizing
precursor 7 that has an R-configured chiral center at C19
position should be crucially important for stereoselective
construction of the -hydroxylactam moiety. The point chirality at
this position was revealed to be completely transferred to the
point chirality of the -position on the lactam ring via the planar
chirality of the enol ether moiety through the macrocyclization
process of our total synthesis of Hirsutellone B (3), as shown in
Figure 4.[5] The requisite cyclization precursor 7 would be
prepared by Knoevenagel condensation of previously reported
decahydrofluorene compound 12[11] with a Cr(CO)3-complexed
-siloxyaldehyde 13.
Scheme 1. Our preliminary study of construction of the 13-membered
macrocycle of GKK1032A2 (1) by use of an intramolecular Ullmann C-O
coupling reaction.
However, the yield of the desired macrocycle (15%) is lower
than that of our total synthesis of Hirsutellone B (3), likely due to
the poor reactivity of the C13-hydroxyl group on the sterically
hindered -side of the decahydrofluorene core. On the contrary,
through a synthetic study of an unnatural-type isomer of
Hirsutellone B (3),[13] we are convinced that a – interaction on
the precursor between the enol ether moiety and the benzene
ring plays an important role in the 13-membered
macrocyclization by stabilizing its transition state.[14] However,
the energetic benefit may be reduced by the higher reaction
temperature of the Ullmann C–O coupling reaction, leading to
our interest in the intramolecular nucleophilic aromatic
substitution by use of an 6-arene chromium complex. These
types of chromium complexes show higher reactivity for
nucleophilic substitution via an addition/elimination (SNAr)
pathway under the mild condition of room temperature,[15,8] and
their complexed aromatic rings easily create – interactions
with other –electron systems. The observed – interactions
was also applied to an asymmetric reaction[16] and was proved
successful via X-ray crystallographic analysis.[17] The interactive
properies of 6-arene chromium complexes are favorable for our
desired 13-membered macrocyclization because its transition
state would be largely stabilized by an enhanced – interaction
between the enol ether moiety and the complexed aromatic ring
(Figure 2).
Figure 3. Retrosynthetic analysis of GKK1032A2 (1).
Figure 4. Our developed chirality-returning sequence on the total synthesis of
Hirsutellone B (3)
Figure 2. Our straTotal Synthesis of GKK1032A₂ via Direct 13-Membered
Macrocyclization Utilizing Aromatic Nucleophilic Substitution of an η⁶-Arene
Chromium Complextegy for the direct construction of 13-membered
macrocycle.
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First, we commenced the preparation of Cr(CO)3-complexed -
siloxyaldehyde 13[18] (Scheme 2). After p-methoxybenzyl (PMB)
protection[19] of (S)-glycidol 14, the obtained epoxide was
subjected to addition with organocuprate prepared from 1-fluoro-
4-iodobenzene to give alcohol 15. The resulting secondary
hydroxyl group was protected with a tert-butyldimethylsilyl (TBS)
group and subsequent deprotection of the PMB group afforded
primary alcohol 16. Alcohol 16 was transformed into the
corresponding 6-arene complex 17 by a treatment with
chromium hexacarbonyl (Cr(CO)6)[20] in moderate yield, and
subsequent oxidation under Swern conditions to afforded the
desired 6-arene complexed aldehyde 13.
Figure 5. NOESY spectrums of cyclization precursor 7.
With
desired
precursor
7
in
hand,
13-membered
macrocyclization using aromatic nucleophilic substitution
between the C19-hydroxyl group and Cr(CO)3-complexed aryl
fluoride moiety was attempted. We first examined the reaction
under general conditions similar to aromatic substitution of 6-
arene chromium complexes, that is, sodium hydride was used
as a base in THF (Table 1, Entry 1);[15a] however, the desired
macrocyclization did not proceed. We next employed N,N-
dimethylformamide as a more polar solvent (Entry 2), but
decomplexation of the aryl fluoride moiety was exclusively
observed, likely due to instability of the Cr(CO)3 complex in such
a highly coordinating solvent. Therefore, 18-crown-6 was used
with sodium hydride to generate a more nucleophilic naked
anion.[22] As a result, macrocyclization proceeded at high
temperature but the yield of the desired macrocycle 10 was
miserably poor (10%, including the next decomplexation step).
In contrast, use of potassium hydride as a substitute base
resulted in the reaction proceeding smoothly at lower
temperature and the yield of desired macrocycle 10 was greatly
improved, up to 91% (in 2 steps). Although the precise cause of
the observed remarkable improvement has not yet been
revealed, a computational conformation study of the non-
complexed cyclization precursor suggested the existence of a
hydrogen bond between the C13 hydroxyl group and one of the
oxygen atoms of the MOM enol ether moiety. As a result of this
strong hydrogen bonding, undesirable lowering of the acidity of
the C13 hydroxyl group occurred and a stronger base would be
required for deprotonation.[23]
Scheme 2. Synthesis of Cr(CO)3-complexed -siloxyaldehyde 13. PMBCl = p-
methoxybenzyl chloride. TBSCl = tert-butyldimethylsilyl chloride. DDQ = 2,3-
dichloro-5,6-dicyano-p-benzoquinone. TFAA = trifluoroacetic anhydride.
Next, synthesis of cyclization precursor 7 was investigated
(Scheme 3). Previously reported hydroxylester 18[11] was
subjected to condensation with acetonitrile under basic
conditions to afford ketonitrile 12. After Knoevenagel
condensation of ketonitrile 12 with aldehyde 13, the resulting
unsaturated bond was selectively reduced by L-selectride®. The
following enol ether formation under basic conditions gave the
desired cyclization precursor 7 as the E-isomer only. [21]
Table 1. Conditions for the intramolecular SNAr reaction.
Entry
Conditiona
NaH, THF, reflux
Result
NR
1
2
3
4
NaH, DMF, 60°C
decomplexation
10% (2 steps)
91% (2 steps)
NaH, 18-crown-6, THF, reflux
KH, THF, rt
a Reactions were conducted in 0.006[M].
Scheme 3. Synthesis of cyclization precursor 7. LDA = Lithium diisopropyl
amide. MOMCl = Chloromethyl methyl ether.
Several remaining functional group transformations were
conducted to achieve the total synthesis of GKK1032A2 (1)
(Scheme 4). Deprotection of the TBS group at the C19 position
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and following oxidation of the resulting alcohol using Dess–
Martin periodinane afforded the corresponding ketone 20,
quantitatively. The nitrile group of 20 was then converted to the
amide group by treatment with an excess amount of potassium
hydroxide in tert-butanol. In our reaction conditions, an
intramolecular attack of the resulting amide group to the C13-
ketone group afforded the corresponding -hydroxylactam 21.
Importantly, the cyclization process proceeded in a completely
stereoselective manner, similar to our total syntheses of
Hirsutellone B (3) and its unnatural-type isomer[5,13]. Finally,
deprotection of the MOM enol ether moiety was conducted
under acidic conditions and the desired final product was
obtained in high yield. All of the obtained spectroscopic data (1H-
NMR, 13C-NMR, HRMS, IR, and []D) of the final product were in
full agreement with those reported for the naturally occurring
substance.[24] In addition, the positive []D value of our synthetic
sample established the absolute configuration of the natural
product to be as depicted. Thus, the first total synthesis of
GKK1032A2 (1) was successfully accomplished. To the best of
our knowledge, this work is the first successful example of the
construction of a macrocyclic with an aryl ether linkage using
nucleophilic aromatic substitution of an 6-arene-type chromium
complex.
total synthesis are now in progress and will be reported in the
near future.
Experimental Section
The synthetic procedures and characterization of the
compounds studied herein can be found in the Supporting
Information.
Acknowledgements
This work financially supported by JSPS (Japan Society for the
Promotion of Science) for a Grant-in-Aid for Scientific Research
(C) (Grant No. 25460025).
The authors gratefully thank Professor Hideaki Oikawa
(Department of Chemistry, Graduate School of Science,
Hokkaido University) and Kazuo Kubo (Kyowa Hakko Kirin Co.
Ltd.) for the provision of NMR data.
Keywords: gkk1032A2 • total synthesis • direct 13-membered
macrocyclization • Cr(CO)3-arene complex • – interaction
[1]
[2]
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Orlikova, M. U. Kassack, W. Lin, M. Diederich, T. Kurtan, A. Debbab, P.
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Scheme 4. End game of total synthesis of GKK1032A2 (1). TBAF
tetrabutylammonium fluoride. DMP = Dess–Martin periodinane.
=
In conclusion, we developed a new effective method for direct
construction of the highly-strained 13-membered macrocycle of
a decahydrofluorene-class of natural products. The method is
based on the nucleophilic aromatic substitution utilizing an 6-
arene chromium complex, a process not previously used for
macrocyclization of an aryl ether linkage. We believed that the
above described remarkable improvement of the 13-membered
macrocyclization is depend on the enhancement of
intramolecular – interaction between chromium complexed
aromatic ring and enol ether moiety of the cyclization precursor.
Therefore, we would like to prove the existence of the interaction
by further crystallographic or computational investigations. The
developed macrocyclization is strongly thought to be useful for
synthesis of other more complicated decahydrofluorene-class
natural products that have fascinating biologically activities such
as Pyrrocidine A (2) and Embellicine A (4). These challenging
[3]
X.-W. Li, A. Ear, B. Nay, Nat. Prod. Rep. 2013, 30, 765-782, and
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[11] H. Uchiro, R. Kato, Y. Sakuma, Y. Takagi, Y. Arai, D. Hasegawa,
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submitted.
[21] The geometry of the enol ether moiety of cyclization precursor 7 was
determined by noesy spectrum as shown in Scheme 3.
[14] A remarkable contribution of - interaction to construct macrocycle,
see: a) S. K. Collins, Y. El-Azizi, A. R. Schmitzer, J. Org. Chem. 2007,
72, 6397-6408; b) Y. El-Azizi, A. Schmitzer, S. K. Collins, Angew.
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[24] 1H and 13C-NMR spectrum of GKK1032A2 (1) were taken by Kyowa
Hakko Kogyo Co. Ltd. through the courtesy of Professor Hideaki
Oikawa, Hokkaido University.
[15] For example, see: a) S. G. Davies, W. E. Hume, Tetrahedron Lett. 1995,
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29, 383-389.
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COMMUNICATION
Layout 2:
COMMUNICATION
Hayato Sugata,[b] Kensuke Inagaki,[b]
Toshiaki Ode,[b] Tomoki Hayakawa,[b]
Yuki Karouji,[b] Motoaki Baba,[b] Ryo
Kato,[b] Daiju Hasegawa,[b] Tetsu
Tsubogo,[a,b] and Hiromi Uchiro*[a,b]
Page No. – Page No.
The first enantioselective total synthesis of GKK1032A2 has been achieved. The
key step is direct construction of the highly strained 13-membered macrocycle of
GKK1032A2 by a – interaction-assisted intramolecular aromatic substitution
(SNAr) reaction. To the best of our knowledge, this is the first successful example of
construction of a macrocycle with an aryl ether linkage utilizing an intramolecular
SNAr reaction of an 6-arene chromium complex.
Title
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