Total synthesis of hirsutellone B via ullmann-type direct 13-membered macrocyclization

Article abstract of DOI:10.1021/ol202748e

Total synthesis of Hirsutellone B has been achieved by a convergent synthetic strategy. This synthesis features direct construction of the highly strained 13-membered macrocycle of Hirsutellone B utilizing the Ullmann-type reaction. To the best of our kno

Full text of DOI:10.1021/ol202748e

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6268–6271
Total Synthesis of Hirsutellone B via
Ullmann-Type Direct 13-Membered
Macrocyclization
Hiromi Uchiro,* Ryo Kato, Yuuki Arai, Miki Hasegawa, and Yu Kobayakawa
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki,
Noda-shi, Chiba 278-8510, Japan
uchiro@rs.noda.tus.ac.jp
Received October 13, 2011
ABSTRACT
Total synthesis of Hirsutellone B has been achieved by a convergent synthetic strategy. This synthesis features direct construction of the highly
strained 13-membered macrocycle of Hirsutellone B utilizing the Ullmann-type reaction. To the best of our knowledge, this is the first application of
macrocyclization utilizing an intramolecular Ullmann-type reaction between an aliphatic alcohol and aryl halide.
Recently, several novel decahydrofluorene-class bioac-
tive natural products such as hirsutellones,1 GKK1032s,2
and pyrrocidines3 have been reported. These compounds
have similar structural features including (i) a tricyclic
decahydrofluorene skeleton and (ii) a highly strained
13-membered macrocycle including a γ-hydroxylactam
(Figure 1). However, the reported biological activities
of these compounds are different.1ꢀ3 We therefore
embarked on the total synthesis of this series of compounds
to clarify their mode of action and their structureꢀactivity
relationships.
Hirsutellone B (1) was isolated from the insect patho-
genic fungus Hirsutella nivea BCC 2594 by Isaka et al. in
2005 and exhibits antituberculosis activity against Myco-
bacterium tuberculosis H37Ra, with a minimum inhibitory
concentration (MIC) value of 0.78 μg/mL.1 The struc-
tural novelty and intriguing biological activity of the
hirsutellones have attracted much attention from syn-
thetic chemists and pharmaceutical researchers.
Figure 1. Structures of Hirsutellone
compounds.
B (1) and related
The most difficult and challenging task in the total
synthesis of Hirsutellone B (1) is the construction of the
highly strained 13-membered macrocycle which includes a
bent benzene ring. Therefore, while several projects are
currently underway to synthesize hirsutellones, only one
asymmetric total synthesis has been achieved to date.4
The Nicolaou group achieved the first total synthesis of
(1) Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai, S.;
Thebtaranonth, Y. Tetrahedron 2005, 61, 5577. (b) Isaka, M.; Prathumpai,
W.; Wongsa, P.; Tanticharoen, M. Org. Lett. 2006, 8, 2815.
(2) Koizumi, F.; Hasegawa, A.; Ando, K.; Ogawa, T.; Hara, M. Jpn.
Kokai Tokkyo Koho, JP 2001247574 A2 20010911, 2001; Chem. Abstr.
2001, 135, 209979.
(3) He, H.; Yang, H. Y.; Bigelis, R.; Solum, E. H.; Greenstein, M.;
Carter, G. T. Tetrahedron Lett. 2002, 43, 1633.
r
10.1021/ol202748e
Published on Web 10/31/2011
2011 American Chemical Society

hirsutellone B (1) in 20094c by constructing a 13-membered
intramolecular cyclization and a retro DA-IMDA reac-
tion.5 Therefore, we adopted a similar strategy for the const-
ruction of the decahydrofluorene skeleton 10.
macrocycle from a less strained 14-membered cyclic sul-
€
fone through a RambergꢀBacklund reaction. In contrast,
The first step was the construction of the C-ring (Scheme 1).
Regioselective ozonolysis of (R)-(ꢀ)-citronellene 12 with
reductive workup, followed by TBS protection, gave the
corresponding silyl ether13. Further ozonolysis of 13and a
subsequent Wittig reaction afforded the R,β-unsaturated
ester 14 as a single stereoisomer. DIBAL reduction of the
ester group was carried out, and the resulting allylic
alcohol was then converted to the chiral epoxide 15 by
Sharpless asymmetric epoxidation6 (L-(þ)-DIPT, TBHP,
Ti(Oi-Pr)4, MS4A, CH2Cl2, ꢀ20 °C). After Swern oxida-
tion7 of the primary hydroxyl group of 15, the obtained
aldehyde was transformed to the acetylene by the
SeyferthꢀGilbert homologation reaction utilizing Ohiraꢀ
Bestmann reagent 19.8 After deprotection of the TBS group,
Swern oxidation was carried out to afford the correspond-
ing aldehyde. The silyl enol ether moiety was constructed
from the aldehyde by a vinylogous HWE reaction with R-
siloxyphosphonate 205 in 63% yield in two steps (E/Z =
10:1). With the cyclization precursor in hand, Lewis acid
promoted C-ring formation was carried out. The desired
intramolecular cyclization proceeded smoothly upon
treatment with TMSOTf, and the cyclization product
18 was obtained in 78% yield and in optically pure form
(>99% ee).9
our interest is to develop a direct 13-membered macro-
cyclization approach. In this paper, we report the total
synthesis of Hirsutellone B (1) by using a copper-mediated
Ullmann-type etherification as the key step.
Our retrosynthetic analysis is shown in Figure 2.
Hirsutellone B (1) would be obtained by the formation
of the γ-hydroxylactam moiety from ketoamide 6,
which is prepared from macrocycle 7 via several con-
versions. The 13-membered macrocycle of 7 would be
constructed by intramolecular Ullmann-type etherifica-
tion between the aryl iodide and the aliphatic secondary
alcohol at the C13 position. Cyclization precursor 8
would be prepared by the oxidation of aldol adduct 9
and subsequent enol ether formation. We anticipated
that the stereoselective formation of the E-form of the
enol ether moiety would facilitate the desired intramo-
lecular cyclization by limiting conformational flexibil-
ity. The aldol adduct would be obtained by a coupling
reaction of decahydrofluorene skeleton 10 with an
anion generated from a γ-siloxynitrile 11.
Scheme 1. Synthesis of Cyclization Product 18
Figure 2. Retrosynthetic analysis of Hirsutellone B (1).
Next, the construction of the decahydrofluorene skeleton
was investigated (Scheme 2). The highly reactive γ-keto-
R,β-unsaturated ester moiety was protected prior to mod-
ifications of the acetylene moiety of 18. The protection step
We are also studying the total synthesis of GKK1032s and
previously reported the construction of its decahydro-
fluorene skeleton by utilizing a Lewis acid promoted
(5) Uchiro, H.; Kato, R.; Sakuma, Y.; Takagi, Y.; Arai, Y.;
Hasegawa, D. Tetrahedron Lett. 2011, 47, 6242.
(6) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(7) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2489.
(4) (a) Tilley, S. D.; Reber, K. P.; Sorensen, E. J. Org. Lett. 2009, 11,
701. (b) Huang, M.; Huang, C.; Liu, B. Tetrahedron Lett. 2009, 50, 2797.
(c) Nicolaou, K. C.; Sarlah, D.; Wu, T. R.; Zhan, W. Angew. Chem., Int.
Ed. 2009, 48, 6870. (d) Reber, K. P.; Tilley, S. D.; Sorensen, E. J. Chem.
Soc. Rev. 2009, 38, 3022. (e) Huang, M.; Song, L.; Liu, B. Org. Lett.
2010, 12, 2504. (f) Halvorsen, G. T.; Roush, W. R. Tetrahedron Lett.
2011, 52, 2072. (g) Nicolaou, K. C.; Sun, Y.; Sarlah, D.; Zhan, W.; Wu,
T. R. Org. Lett. 2011, 20, 5708.
€
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Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 6, 521.
(9) An enantiomeric excess was determined by chiral HPLC analysis.
Org. Lett., Vol. 13, No. 23, 2011
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utilizing the intermolecular DielsꢀAlder reaction of 18 with
1,2,3,4,5-pentamethylcyclopentadiene afforded the corre-
sponding norbornene-type compound 21 as a mixture of
inseparable diastereomers. The acetylene moiety of 21
was then converted to the corresponding vinyl iodide
22 via hydrostannylation and subsequent iodination.
A Stille coupling reaction between 22 and indepen-
dently prepared dienyl stannane 2310 under Corey’s
conditions11 afforded the corresponding triene moiety
of 24, and then the hydroxyl group was protected with
a TMS group to give the cyclization precursor 25.
Refluxing of 25 in xylene resulted in the subsequent
desired retro-DA-IMDA reactions, and the IMDA
adduct 26 was obtained in 52% yield.
secondary hydroxyl group, the desired decahydrofluorene
skeleton 32 was successfully obtained.
As another fragment, the chiral γ-siloxynitrile 11 was
prepared (Scheme 4). (R)-Glycidyl tosylate 34 was reacted
witha cuprate prepared from 1,4-diiodobenzene 33, to give
the chiral epoxide 35. Addition of diethyl malonate to
epoxide 35 and subsequent decarboxylation afforded the
lactone 36 with high optical purity (>99% ee).9 The
lactone moiety was then converted to the corresponding
siloxyamide 37 by ammonolysis and subsequent TBS
protection. The amide 37 was dehydrated by treatment
with cyanuric chloride, and the desired γ-siloxynitrile 11
was obtained.
Scheme 3. Further Modifications of IMDA Adduct 26
Scheme 2. Synthesis of Decahydrofluorene Skeleton 26
Further modifications of IMDA adduct 26 were con-
ducted to complete the synthesis of the fully elaborated
decahydrofluorene skeleton of hirsutellone (Scheme 3).
Unfortunately, reduction of the C13 ketone group using
NaBH4 gave the desired alcohol 28 as a minor product
(38% yield), along with its epimer 27 as the major product
(56% yield). The undesired epimer 27 was converted to 26
quantitatively by DessꢀMartin oxidation.12 The obtained
alcohol 28 was protected with the MOM group, followed by
deprotection of the TMS group to give the alcohol 29. The
unnecessary hydroxyl group of 29 was then removed by the
BartonꢀMcCombie procedure13 to give the deoxygenated
compound 30. MOM deprotection of 30 was conducted by
treatment with PTSA. After the three-step modification of
LiAlH4 reduction, selective oxidation of the primary alcohol
using a TEMPO catalyst,14 and TMS protection of the
Scheme 4. Synthesis of γ-Siloxynitrile 11
Thus prepared γ-siloxynitrile 11 was coupled with the
siloxyaldehyde 32 by an aldol reaction. The resulting hydro-
xyl group was oxidized by use of DMP to the corresponding
ketonitrile 38. Ketonitrile 38 was converted to the MOM
enol ether by treatment with Cs2CO3 and MOMCl, and the
TMS group was removed in a one-pot reaction by the
addition of methanol. Then, with the desired cyclization
precursor 8 in hand as a single E-isomer, we tried an
intramolecular Ullmann-type reaction to construct the
ꢀ
(10) Gomez, A. M.; Lopez, J. C.; Fraser-Reid, B. Synthesis 1993,
1993, 943.
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1996, 1996, 1153.
6270
Org. Lett., Vol. 13, No. 23, 2011

Scheme 5. Total Synthesis of Hirsutellone B (1)
highly strained 13-membered macrocycle. Although stan-
dard Buchwald conditions15 were not effective for this
reaction, the desired cyclization product was obtained in
42% yield by increasing the reaction temperature to 160 °C.
To date, several macrocyclization reactions based on the
construction of a biaryl ether linkage utilizing the intramo-
lecular Ullmann-type reaction have been reported.16 How-
ever, to the best of our knowledge, this is the first successful
example of a macrocyclization between an aliphatic alcohol
and an aryl halide.17
Several steps remained to complete the total synth-
esis. The TBS group of 7 was deprotected, and succes-
sive DessꢀMartin oxidations of the resulting hydroxyl
group afforded the ketone 39. The nitrile moiety of 39
was hydrolyzed to the corresponding amide under basic
conditions (refluxed with KOH in t-BuOH). Finally,
the MOM group of 40 was removed by treatment with 1
N HCl aq at 60 °C. Under these reaction conditions, it is
noteworthy that the desired γ-hydroxylactam forma-
tion of the resulting ketoamide 6 also proceeded in
a stereoselective manner. Thus, the total synthesis
of Hirsutellone B (1) was successfully accomplished
(Scheme 5).
In conclusion, we have achieved the total synthesis of
Hirsutellone B (1) via direct construction of the highly
strained 13-membered macrocycle utilizing Ullmann-type
etherification. It is strongly expected that the developed
synthetic strategy will be useful for the synthesis of related
decahydrofluorene-class natural products (i.e., GKK-
1032s and pyrrocidines), aiding structureꢀactivity rela-
tionship studies of these compounds. Further investiga-
tions intothe total synthesisofthisseries of compounds are
now in progress and will be described in the near future.
(15) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org.
Lett. 2002, 4, 973–976.
(16) Some examples of intramolecular Ullmann reaction; Total
synthesis of combretastatin D-2: (a) Boger, D. L.; Sakya, S. M.;
Yohannes, D. J. Org. Chem. 1991, 56, 4204. Total Synthesis of
Vancomycin: (b) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu,
J. M.; Yue, T.-Y.; Natarajan, S.; Chu, X.-J.; Brase, S.; Rubsam, F.
Chem.;Eur. J. 1999, 5, 2584.
Supporting Information Available. Experimental poce-
dures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Review of copper-mediated coupling reactions: Evano, G.;
Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
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