Total synthesis of (+)-yatakemycin

Article abstract of DOI:10.1021/ja0619455

A convergent total synthesis of (+)-yatakemycin was accomplished in a 20-step sequence in an overall yield of 13%. The synthesis features the regioselective ring opening of (S)-epichlorohydrin with 2,6-dibromophenyllithium species, the mild copper-mediated aryl amination utilizing the combination of CuI and CsOAc, and the efficient deprotection of benzyl groups of aryl benzyl ether with BCl₃ in the presence of pentamethylbenzene. Copyright

Full text of DOI:10.1021/ja0619455

Published on Web 05/12/2006
Total Synthesis of (+)-Yatakemycin
Kentaro Okano,† Hidetoshi Tokuyama,†,‡ and Tohru Fukuyama*,†
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, PRESTO, Japan Science and Technology
Agency, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received March 21, 2006; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Scheme 1. Retrosynthetic Analysis of (+)-Yatakemycin
(+)-Yatakemycin (1), which was isolated from a culture broth
of Streptomyces sp. TP-A0356 by Igarashi in 2003,1 is an antitumor
antibiotic that has a characteristic dienone cyclopropane ring found
in duocarmycin SA,2 duocarmycin A,3 and CC-1065.4 These
compounds possess remarkable antitumor activity through a
sequence-selective DNA alkylation at the activated cyclopropane.
Among these compounds, yatakemycin has been found to exhibit
the most potent activity and, therefore, has attracted a great deal
of attention regarding the nature of its interaction with DNA.5a The
first total synthesis of this compound has recently been reported
by Boger and co-workers, who also revised its structure and
determined the absolute configuration.5b
Scheme 2. Synthesis of the Middle Segmenta
As outlined in the retrosynthetic analysis (Scheme 1), we planned
to form the highly reactive spirocyclopropane by ring contraction
of the hydroxytetrahydroquinoline at a later stage in the synthesis.
Disconnections at the two amide bonds should then lead to three
segments 2-4. Key synthetic issues here would be the effective
preparation of these highly functionalized nitrogen-containing
heterocycles and the order in which these segments are assembled
without affecting the sensitive thiol ester functionality. For the
synthesis of these segments, we intended to use the exceptionally
mild copper-mediated aryl amination reaction developed in our
laboratories.6 We describe herein a highly convergent and efficient
total synthesis of 1 featuring the construction of all of the aryl-
nitrogen bonds by means of our variant of a copper-mediated aryl
amination reaction.
Synthesis of the middle segment 2 commenced with the
regioselective ring opening of (S)-epichlorohydrin (6) with 2,6-
dibromophenyllithium species, which was prepared by iodoselective
lithiation of 2,6-dibromoiodobenzene derivative 5 (Scheme 2).7
Cleavage of the epoxide in 6 proceeded smoothly in the presence
of BF3‚OEt2 to provide exclusively the desired chlorohydrin 7.8
We then converted 7 to the amination precursor 8 in a three-step
sequence involving the introduction of an azide group, the
Staudinger reaction,9 and finally in situ treatment of the resultant
primary amine with NsCl.10 The crucial intramolecular amination
proceeded uneventfully to give the desired tetrahydroquinoline 9
with complete retention of the other bromo group.11 Heck reaction12
of this hindered bromide with a dehydroalanine derivative 1013 was
performed successfully using a combination of Pd2(dba)3 and 2-di-
(t-Bu)phosphino-1,1′-biphenyl. After removal of the nosyl group,
a bromo substituent was regioselectively introduced and the second
amination reaction at the highly sterically hindered position was
examined. A high-yielding process could be realized by using a
stoichiometric amount of CuI at ambient temperature to furnish
the middle segment 2.11
a Reagents and conditions: (a) n-BuLi (1.0 equiv), toluene, -78 °C, 10
min; BF3‚OEt2, 6, -78 °C, 5 min, 93%; (b) NaN3, DMF, 90 °C, 9 h; (c)
TBSCl, imidazole, DMAP, DMF, 50 °C, 6 h, 99% (2 steps); (d) P(n-Bu)3,
THF, rt, 30 min; H2O, rt, 2 h; NsCl, NaHCO3 aq., rt, 24 h, 89%; (e) CuI
(0.5 equiv), CsOAc (5.0 equiv), DMSO, 60 °C, 24 h, 83%; (f) 10, Pd2(dba)3
(5 mol %), 2-di(t-Bu)phosphino-1,1′-biphenyl (20 mol %), Et3N, LiCl, DMF,
90 °C, 1 h, 89%; (g) PhSH, Cs2CO3, MeCN, rt, 30 min, 99%; (h) NBS,
CH2Cl2, 0 °C, 20 min, 90%; (i) CuI (1.0 equiv), CsOAc (2.5 equiv), DMSO,
rt, 12 h, quant.
Dibromination of 1314 in the presence of FeCl3,15 removal of the
trifluoroacetyl group, and subsequent oxidation provided dihy-
droisoquinoline 14, which was readily converted to hemiaminal 15
by treatment with NsCl and then with water. The cyclization
precursor 16, obtained by reductive opening of hemiaminal 15, was
subjected to the first amination reaction using 10 mol % of CuI to
give the desired indoline 17 with retention of the other bromo group.
After conversion of 17 to the dehydroalanine derivative 19 by
oxidation and Horner-Wadsworth-Emmons reaction,16 the second
amination was performed to provide dihydropyrroloindole 20 in
good yield.11 The Ns group and benzyl ester in 20 were then
converted to a Fmoc group and a methanethiol ester, respectively.
Finally, an Fmoc-directed, regioselective demethylation was per-
formed with BCl3 to furnish the left segment 3.17 The right-hand
The copper-mediated aryl amination proved to be highly effective
for the facile construction of the left-hand segment 3 (Scheme 3).
† University of Tokyo.
‡ PRESTO. Current address: Graduate School of Pharmaceutical Sciences,
Tohoku University, Aoba, Sendai 980-8578, Japan.
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J. AM. CHEM. SOC. 2006, 128, 7136-7137
10.1021/ja0619455 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Synthesis of the Left Segmenta
instability of the amine derived from 3. After extensive optimization,
we were able to overcome this problem by carrying out the
deprotection of the Fmoc group and subsequent condensation with
23 in one pot. The benzyl groups were then removed by BCl3 in
the presence of pentamethylbenzene, which served as a scavenger
of benzyl cation.19 Finally, spirocyclopropanation was effected by
treatment with NaHCO3 in aqueous DMF5b to furnish (+)-
yatakemycin (1), which is identical in all respects to the natural
product.
In conclusion, we have accomplished a highly efficient total
synthesis of (+)-yatakemycin (1) based on the novel coupling of
(S)-epichlorohydrin (6) with 2,6-dibromophenyllithium species and
the copper-mediated construction of all five aryl-nitrogen bonds
in 1. The present strategy consisting of these two technologies
allowed us to conduct a sub-gram-scale preparation of 1 in 13%
overall yield over 20 steps (longest linear steps) and should be
generally applicable to the synthesis of this class of compounds.
a Reagents and conditions: (a) Br2, FeCl3, 0 °C, 30 min, 88%; (b) K2CO3,
MeOH, rt, 6 h; (c) MnO2, CH2Cl2, rt, 18 h, 90% (2 steps); (d) NsCl, THF,
0 °C, 5 min; rt, 1 h; NaHCO3 aq., rt, 30 min; (e) NaBH4, MeOH, 0 °C, 1
h, 78% (2 steps); (f) CuI (10 mol %), CsOAc (2.5 equiv), DMSO, 80 °C,
24 h; (g) TPAP (2 mol %), NMO, MS 4 Å, CH2Cl2, rt, 1 h, 85% (2 steps);
(h) 18, 1,1,3,3-tetramethylguanidine, CH2Cl2, rt, 6 h, 84%; (i) CuI (1.0
equiv), CsOAc (5.0 equiv), DMSO, rt, 12 h, 77%; (j) PhSH, Cs2CO3, MeCN,
rt, 3 h, 95%; (k) FmocCl, NaHCO3, THF-H2O (3:1), rt, 10 min, 91%; (l)
Pd/C, H2, THF-EtOH (1:1), rt, 3 h; (m) MeSH, WSCD‚HCl, DMAP, DMF,
0 °C, 3 h, 76% (2 steps); (n) BCl3, CH2Cl2, 0 °C, 20 min, 97%.
Acknowledgment. We thank Dr. Yasuhiro Igarashi (Toyama
Prefectural University) for providing natural (+)-yatakemycin,
Grant-in-Aid from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan for the financial support, and JSPS
(predoctoral fellowship for K.O.).
Supporting Information Available: Experimental details and
spectroscopic data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Scheme 4. Completion of the Total Synthesisa
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pentamethylbenzene (10 equiv), CH2Cl2, -78 °C, 15 min, 83%; (f)
NaHCO3, DMF-H2O (2:1), rt, 2 h, 94%.
segment 4 was also prepared in a straightforward manner by using
the aryl amination strategy.18
Having synthesized the requisite three segments, we then turned
to the facile assembly of these compounds (Scheme 4). After
coupling of the middle segment 2 with the right-hand segment 4
by acylation, the TBS ether was converted into a mesylate.
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of the Cbz group then provided 23. Initially, the crucial coupling
with the left-hand segment met with limited success due to the
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(18) For the preparation, see Supporting Information.
(19) In the absence of pentamethylbenzene, 25 was obtained in low yield.
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