Stereocontrolled total synthesis of (+)-UCS1025A

Article abstract of DOI:10.1002/anie.201207800

Under control: A stereocontrolled total synthesis of (+)-UCS1025A, a potent telomerase inhibitor, was achieved. The synthesis features an intramolecular Diels-Alder reaction, a tandem Staudinger/aza-Wittig reaction, and stereoselective construction of the hemiaminal moiety facilitated by neighboring-group participation. Copyright

Full text of DOI:10.1002/anie.201207800

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Angewandte
Communications
DOI: 10.1002/anie.201207800
Natural Product
Stereocontrolled Total Synthesis of (+)-UCS1025A**
Kenji Uchida, Takahiro Ogawa, Yoshinori Yasuda, Hiraku Mimura, Teppei Fujimoto,
Tohru Fukuyama, Toshiyuki Wakimoto, Tomohiro Asakawa, Yoshitaka Hamashima, and
Toshiyuki Kan*
UCS1025A (1), an antitumor antibiotic alkaloid isolated from
Acremonium sp. KY4917 by Yamashita et al. in 2000,[1] was
shown to inhibit telomerase and have antimicrobial activity.[2]
This remarkable biological activity coupled with its highly
complex structure makes 1 an attractive target for total
synthesis; several synthetic studies on this family of com-
pounds have been published.[3] Three total syntheses have
been reported to date: these were by the groups of
Danishefsky,[4] Hoye,[5] and Christmann.[6] A crucial step in
the total synthesis of 1 is the construction of a pyrrolizidinone
(azabicyclo [3.3.0] octanone) skeleton possessing a hemiami-
nal moiety at the ring-fusion position. Consequently, stereo-
selective construction of the hemiaminal moiety should be
a significant task in the chemical synthesis of 1.[7] Herein, we
Scheme 1. Structure and synthetic strategy of 1. PMP=para-methox-
yphenyl.
report a stereocontrolled total synthesis of 1.
Scheme 1 illustrates the basis of our synthetic plan. As
a detailed structure–activity relationship (SAR) study is
important for drug discovery and this requires the synthesis
of a diverse range of analogues, it would be advantageous if
the construction of the carbon framework of 1 could be
performed by condensation of 2 and 3 in a convergent manner
during the later stage of the total synthesis. The trans-fused
octahydronaphthalene skeleton of 3 could be formed by an
intramolecular Diels–Alder reaction[8] of 4, and the labile
aminal moiety of 2 could be prepared by stereocontrolled
transannular cyclization of 5. Furthermore, the construction
of the eight-membered lactam of 5 could be accomplished by
an intramolecular Staudinger/aza-Wittig reaction with Pfp
(pentafluorophenyl) ester, which is a method developed by
our group.[9] The precursor 6 could be prepared from l-
diethyl malate 7, an inexpensive starting material.
As shown in Scheme 2, the synthesis of the right segment
14 commenced from aldehyde 8, which was readily prepared
from cyclohexene.[10] The stepwise elongation of 8 was
achieved by a Wittig reaction with phosphonium salt 9,
a Horner–Wadsworth–Emmons reaction with phosphonate
10,[11] and subsequent isomerization of the double bond at the
C8-C9 position by heating with PhSSPh[12] to provide triene
11. After extensive investigation, treatment with EtAlCl2 at
08C resulted in the construction of the trans decalin skeleton
by the crucial intramolecular Diels–Alder reaction to afford
[*] Dr. K. Uchida, T. Ogawa, Y. Yasuda, Dr. T. Asakawa,
Dr. Y. Hamashima, Prof. Dr. T. Kan
School of Pharmaceutical Sciences
University of Shizuoka and Global COE Program
52-1 Yada, Suruga-ku, Shizuoka 422-8526 (Japan)
E-mail: kant@u-shizuoka-ken.ac.jp
H. Mimura, Dr. T. Fujimoto, Prof. Dr. T. Fukuyama, Dr. T. Wakimoto
Graduate School of Pharmaceutical Sciences, University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
[**] The authors thank Dr. Shinji Nara and Dr. Yutaka Kanda (Kyowa
Hakko Kirin Co. Ltd) for providing a natural sample of 1. This work
was financially supported by the Takeda Science Foundation, the
Naito Foundation, the Uehara Memorial Foundation, the Nagase
Science and Technology Foundation, MEXT/JSPS KAKENHI Grant
Number 23390007, and a Grant-in-Aid for Scientific Research on
Priority Areas 12045232 from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of Japan.
Scheme 2. Synthesis of the right segment 14 by an intramolecular
Diels–Alder reaction: a) 9, LHMDS, THF, 08C to RT (85%; trans/
cis=1:1); b) 1m HCl, THF; c) 10, Et3N, LiCl, MeCN (59% in 2 steps);
d) PhSSPh, THF, 658C (84%; trans/cis=5:1); e) EtAlCl2, CH2Cl2, 08C
(80%); f) LiAlH4, THF, 08C, (90%); g) Jones reagent, acetone, 08C
(90%); h) (COCl)2, DMF, CH2Cl2, 08C then benzotriazole, Et3N (85%).
DMF=N,N’-dimethylformamide, LHMDS=lithium hexamethyldisila-
zide, THF=tetrahydrofuran.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207800.
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the desired bicycle 12 in 80% yield with complete diastereo-
control. Next camphorsultam 12 was converted into acylben-
zotriazole 14 through a three-step sequence involving reduc-
tion to 13,[13,14] Jones oxidation, and incorporation of benzo-
triazole[15] through the corresponding acid chloride.
As shown in Scheme 3, the left segment, a pyrrolizidinone
skeleton, was synthesized from 15, which was readily synthe-
sized from commercially available l-diethyl malate 7 accord-
Scheme 4. Stereocontrolled synthesis of the left segment 30: a) H2,
Pd(OH)2/C, MeOH; b) TBDPSCl, iPr2NEt, DMAP, CH2Cl2/iPrOH (87%
in 2 steps); c) TPAP, NMO, CH2Cl2; d) 25, CSA, toluene, 08C;
e) TBAF, THF; f) Bz2O, Et3N, MeCN (94% in 3 steps); g) 25, CSA,
toluene, 08C (82%); h) LiOH·H2O, MeOH (88%); i) TBSCl, imidazole,
CH2Cl2 (95%). Bz=benzoyl, CSA=camphorsulfonic acid, NMO=N-
methylmorpholine N-oxide, TBDPS=tert-butyldiphenylsilyl, TBS=tert-
butyldimethylsilyl, TPAP=tetrapropylammonium perruthenate.
improve the diastereoselectivity, incorporation of bulky
alcohol 25,[23] which would be readily deprotected under
mild conditions, was investigated. Treatment of 24 with 25 in
the presence of CSA gave 26 as a single isomer, albeit with the
opposite configuration to that in 1 at the C4 hemiaminal
position. Interestingly, the opposite relative configuration
could be established by using substrate 27, in which the
neighboring primary alcohol is protected by a benzoyl group
rather than a tert-butyldiphenylsilyl group. After switching
the protecting group from a TBDPS to a benzoyl group,
quantitatively, treatment of 27 under the similar reaction
conditions gave 29 with the desired relative configuration at
the C4 position. The high diastereoselectivity of this reaction
suggested that the reaction proceeds via intermediate 28, in
which the acyliminium cation might interact with the carbonyl
group of the benzoate[24] and the alcohol 26 would attack from
the less-hindered b-face of 28. The benzoate of 29 was
changed to TBS ether to provide 30.[25]
With the both desired segments in hand, we next focused
on condensation of 14 and 30 (Scheme 5). Upon treatment of
the acyl donor 14 and 30 with LHMDS, the acylation reaction
produced the desired b-diketone, which contains all the
carbon atoms composing the skeleton of 1, in 96% yield.
Although the obtained diketone was a mixture of stereoiso-
mers and tautomers, a subsequent reaction with PhSCl
proceeded from the convex face of the bicyclo[3.3.0]octanone
skeleton to give 31 predominantly. After removal of the TBS
group, 1-Me-AZADO-mediated Iwabuchi oxidation[26]
directly produced the carboxylic acid. Subsequent protection
with an allyl group gave 32, which was converted into aminal
36 through a three-step sequence involving DDQ-mediated
removal of the dimethoxybenzyl group,[27] DMP oxidation of
the resulting alcohol 33, and treatment of aldehyde 34 with
pyrrolidine and acetic acid. The formed enamine 35 was
converted into 36 by a retro-Michael-type reaction. The
Scheme 3. Stereocontrolled synthesis of the eight-membered lactam
22: a) 16, IBX, CH2Cl2, M.S. (4ꢀ), reflux (85%); b) O3, CH2Cl2/MeOH,
À788C then NaBH4, À78 to 08C; c) NaBH4, NiCl2, MeOH, 08C (67%
in 2 steps); d) DPPA, DBU, toluene, 808C (80%); e) LiOH·H2O, THF/
MeOH/H2O; f) PfpOH, EDCI, DMAP, CH2Cl2 (88% in 2 steps);
g) nBu3P, toluene, 808C; h) MeCN/H2O, reflux (81% from 19).
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene), DMAP=4-dimethylamino
pyridine, DPPA=diphenylphosphoryl azide, EDCI=1-ethyl-3-(3-dime-
thylaminopropyl)carbodiimide, IBX=2-iodoxybenzoic acid, M.S.=mo-
lecular sieves, Pfp=pentafluorophenyl.
ing to the protocol reported by Tadano and co-workers.[16]
One-pot olefination of primary alcohol 15 was accomplished
by IBX oxidation in the presence of ylide 16.[17] Chemo-
selective ozonolysis of 17 and subsequent 1,4-reduction[18] in
the presence of NiCl2 with NaBH4 gave alcohol 18. After
incorporation of the azide group into 18 by DPPA[19] and
DBU, hydrolysis and subsequent condensation of the resul-
tant carboxylic acid with pentafluorophenol gave ester 19.
Upon treatment of 19 with nBu3P in hot toluene, the desired
cyclization reaction proceeded smoothly to provide eight-
membered imino ether 21 through an intramolecular Stau-
dinger[20]/aza-Wittig reaction.[21] Hydrolysis of the isolated 21
in MeCN/H2O under reflux afforded the desired eight-
membered lactam 22 in 81% yield from 19.[22]
With the lactam 22 in hand, we then focused on
construction of the azabicyclo[3.3.0]octanone skeleton
(Scheme 4). After the removal of the benzylidene acetal of
22 under hydrogenolysis conditions and protection of the
primary alcohol, TPAP-mediated oxidation of the secondary
alcohol invoked a spontaneous transannular cyclization,to
give bicyclic aminal 24 as a 1:1 mixture of distereoisomers. To
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Keywords: alkaloids · Diels-Alder reaction · hemiaminal ·
.
Staudinger/aza-Wittig reaction · total synthesis
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[11] Phosphonate 10 was prepared from sultam in two steps: a) NaH;
BrCH2COBr, toluene; b) P(OMe)3, 1208C, (84% in 2 steps); see
the Supporting Information for details. For sultam: W. Oppolzer,
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Scheme 5. Completion of the total synthesis of 1: a) LHMDS, THF,
08C (96%); b) NaHMDS, PhSCl, THF, 08C (71%); c) TBAF, AcOH,
THF, RT (96%); d) 1-Me-AZADO, PhI(OAc)2, CH2Cl2/phosphate buffer,
08C; e) allyl bromide, K2CO3, acetone, RT, (61% in 2 steps); f) DDQ,
CH2Cl2-H2O, RT (73%); g) DMP, CH2Cl2, RT; h) pyrrolidine, AcOH,
CH2Cl2, RT (74% in 2 steps); i) Pd(PPh3)4, pyrrolidine, MeCN, RT
(88%); j) DMDO, CH2Cl2, 08C; k) CaCO3, toluene, 708C (45% in 2
steps). DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMDO=di-
methyldioxirane, DMP=Dess–Martin periodinane, 1-Me-AZADO=1-
methyl-azaadamantane N-oxyl.
dimethoxybenzyl ether protecting group was readily removed
under mild reaction conditions without the decomposition of
hemiaminal moiety. After deprotection of the allyl ester of 36,
DMDO-mediated oxidation of 37 gave the sulfoxide. Finally,
the activated double bond of 38 was formed by the thermal
b elimination of the generated sulfoxide and a subsequent
intramolecular oxy-Michael reaction gave (+)-UCS1025 A
(1); the spectral data (1H NMR, 13C NMR, IR, HRMS and
[a]D) were in full agreement with those of the natural product.
In conclusion, we achieved a stereocontrolled total syn-
thesis of (+)-UCS1025A (1) in a convergent manner. Our
synthesis features an intramolecular Diels–Alder reaction to
readily access the octahydronaphthalene skeleton of 14, an
intramolecular Staudinger-aza/Wittig reaction to give the
eight-membered lactam 22, and stereoselective construction
of the labile hemiaminal moiety using the neighboring
participation effect, and our novel aminal protecting group.
Further modifications of the present route to prepare
analogues are currently underway in our laboratories.
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Received: September 27, 2012
Published online: November 9, 2012
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[22] To construct the lactam ring of 22, the fixation of the
conformation of 19 by benzylidene acetal was essential. The
reaction of a linear derivative of 22 did not provide the desired
eight-membered ring.
[23] Primary alcohol 25 was prepared from 3,4-dimethoxybenzalde-
hyde in two steps: a) 1,3-propanediol, CSA, benzene, 808C;
b) Diisobutylaluminium hydride, Et2O, 0 8C (80% in two steps);
see the Supporting Information for details
510; b) T. J. Boltje, T. Buskas, G.-J. Boons, Nat. Chem. 2009, 1,
611 – 622.
[25] The protection group of the primary alcohol should be optimized
for each conversion, because the oxidation of the benzoate
derivatives of 23 caused b elimination, and the condensation of
29 with the right segment resulted in a low yield. The relative
configuration was determined by nOe difference spectroscopy;
see the Supporting Information.
[24] A similar neighboring group participation for the direction of
the stereochemical outcome has been observed in the glyco-
sylation reaction of 2-acylhexose derivatives, see: a) L. K.
Mydock, A. V. Demchenko, Org. Biomol. Chem. 2010, 8, 497 –
[26] M. Shibuya, M. Tomizawa, I. Suzuki, Y. Iwabuchi, J. Am. Chem.
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