Total synthesis of herbimycin A

Article abstract of DOI:10.1021/ol5012899

Benzoquinone ansamycin antibiotic herbimycin A was synthesized in 19 linear steps and 4.2% yield. Highlighted is the design of a chiral γ-lactone as the C11-C15 synthon that enabled a facile catalytic asymmetric synthesis of the challenging C8-C20 fragmen

Full text of DOI:10.1021/ol5012899

Letter
pubs.acs.org/OrgLett
Total Synthesis of Herbimycin A
Rui Yan, Chuancai Bian, and Xiaoming Yu*
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical
College & Chinese Academy of Medical Sciences, No. 1 Xiannongtan Street, Beijing 100050, China
S
* Supporting Information
ABSTRACT: Benzoquinone ansamycin antibiotic herbimycin A
was synthesized in 19 linear steps and 4.2% yield. Highlighted is
the design of a chiral γ-lactone as the C11−C15 synthon that
enabled a facile catalytic asymmetric synthesis of the challenging
C8−C20 fragment of the target molecule. The easy access to the
stereogenic centers and high overall yield made the strategy
applicable in the molecular editing of benzoquinone ansamycins.
enzoquinone ansamycins are polyketide antibiotics iso-
the total synthesis of 2 and 1, respectively, using easily available
chiral auxiliaries; Panek accomplished all three natural products
using varied chiral crotylsilanes developed in their own
laboratory, and in other elegant cases, Roush and Brown
asymmetric crotylations as well as Marshall asymmetric
propargylation also played critical roles. In this context, an
asymmetric catalysis based approach to benzoquinone
ansamycin, which is of considerable significance from the
perspective of either academia or practice, is still awaiting
development.
B
lated from bacterial species S. hygroscopicus.1 Geldanamy-
cin (1),2 macbecin I (2),3 and herbimycin A (3)4 are among the
typical members of this natural product family (Figure 1) that
We recently found an L-glutamic acid derived chiral γ-lactone
to be a practically useful C11−C14 synthon for reblastatin, a
compound closely related to 1.12 We also found that, as
demonstrated in the total synthesis of 3 reported herein, a more
sophisticated application of this “γ-lactone” tactic would help
bridge the gap between asymmetric catalysis and chemical
synthesis of benzoquinone ansamycins.
Our retrosynthesis of 3 (Scheme 1) started from seco-amino
acid 4, a three-step precursor Cossy had synthesized.11d This
secondary target was expected to be obtained in its protected
form through a halogen−metal exchange mediated coupling
between 5 and 6 since the Cram chelation model prediction
pointed to the correct configuration at C7.12 We then intended
to build the stereogenic C15 in the C8−C20 fragment 5
through a catalytic asymmetric reduction. To address the C10
and C11 chirality in 5, we assumed a two-step protocol
comprising an asymmetric epoxidation of Z-enyne substituted
γ-lactone 7 and a methyl carbanion effected regioselective
nucleophilic epoxide ring-opening. Owing to the 1,3-cis
geometry of 7 that is accessible by regular hydrogenation,
furanone 8, presumably an easy target of Sharpless AD, arose as
a good starting point for the total synthesis. The synthesis of
C1−C7 aldehyde 6, on the other hand, could be achieved by
following the approach adapted from our previous study using
inexpensive compound 9.
Figure 1. Selected structures of benzoquinone ansamycins.
bear in common a 19-membered macrolactam skeleton,
accommodating six or seven stereogenic carbons, three
geometrically defined CC double bonds, and a p-
benzoquinone subunit. Compounds 1−3 were observed to
exhibit potent anticancer activities upon their isolation, yet the
real fascination lies in their mechanism of action revealed later.
With geldanamycin being the first, all the compounds were
found to be potent inhibitors of heat shock protein 90
(hsp90),5 a newly validated anticancer drug target.6 Benzoqui-
none ansamycins are therefore thought to be valuable lead
structures in seeking novel anticancer drugs,7 and in our view,
an ideal subject for implementation of the “molecular editing”
strategy that might give rise to a deep-seated SAR under-
standing.8
Since the first report in 1989, nearly a dozen successful total
syntheses had been contributed to 1−3 by a number of teams
worldwide,9−11 with each distinguished from others by their
access to the challenging chiral centers, in particular, the tertiary
C10 and C14. For example, Baker, Evans, and Andrus finished
Received: May 6, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5012899 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
As expected, regular hydrogenation of 13 at ambient pressure
and temperature proceeded with high facial selectivity and
smooth removal of the PMB group, giving cis-lactone 14 in 95%
yield. Upon further vicinal diol cleavage using Shing’s silica gel
supported NaIO4,16 aldehyde 15 was obtained and directly
subjected to the Julia−Kocienski reaction with 1617 to give the
desired Z-enyne lactone 7 in 68% yield over two steps. It is
noteworthy that the use of Shing’s reagent is necessary because
15 is highly aqueous soluble, and this reagent helped
circumvent aqueous workup.
Scheme 1. Retrosynthesis of Herbimycin A (3)
The titanium−salan-catalyzed asymmetric epoxidation devel-
oped by Katsuki was then applied.18 With 10 mol % of catalyst
loading, oxidation of 7 using 30% H2O2 gave 18 in 82% yield
without detecting stereoisomers. With this material in hand,
two different methylaluminum-derived reagents, i.e., Me3Al/
H2O, discovered by Maruoka et al.,19 and LiAlMe4, reported by
Kishi,20 were utilized to realize the regioselective SN2 epoxide
ring-opening of 18. Our results indicated that the former was
superior, giving rise to the isolation of expected 19 in 90% yield
accompanied by 7% of an unidentified isomer, whereas the
latter led to complicated reactions.
After successful establishment of the four chiral centers in 19,
we turned our attention to the introduction of the aromatic
moiety, yet prior to that the vinyl iodide function had to be
installed (Scheme 3). Hydrozirconation of the triple bond in 19
Sharpless AD mediated preparation of the chiral furanone
equivalence of 8 proved easy (Scheme 2). The known aldehyde
1013 reacted readily with Ando-modified HWE reagent 1114 to
give Z,E-dienoate 12 in 98% yield (Z/E > 15/1). With the O-
PMB acting as both regio- and enantioselectivity enhancer,15
dihydroxylation of this dienoate using AD-mix-α delivered
spontaneously cyclized furanone 13 in 82% yield and 96% ee.
Scheme 3. Introduction of the Aromatic Subunit
Scheme 2. Preparation of C8−C15 Fragment 15
using Schwartz reagent21 was ineffective due to the preferential
reduction of lactone. Hydrostannylation using the Pd-
(PPh3)2Cl2/Bu3SnH system,22 on the other hand, was chemo-
selective but lacked regioselectivity. This problem was finally
solved by changing the ligand and counteranion to the
palladium catalyst. The Pd(PCy3)2(OAc)2/Bu3SnH system23
exclusively produced C8 stannylated product from 19, and by
treating the resulting vinylstannane with iodine, compound 20
was obtained in excellent yield. Notably, the free hydroxyl in 20
actually offered an opportunity for further derivatization at C11,
but in this study we went on to the trimethylalane-promoted
lactone ring-opening of 20 with N-methoxymethylamine to
afford Weinreb amide 21. After global O-methylation of 21,
resultant 22 was subjected to the Weinreb reaction with the
phenyllithium species generated from 2311d to give ketone 24
in 93% yield.
B
dx.doi.org/10.1021/ol5012899 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
As such, the aromatic ring was introduced at a relatively late
stage, in favor of a diverted synthesis that aims at altering the
benzoquinone substructure. However, the success of such
design still owes much to the subsequent reduction of 24.
A variety of catalytic asymmetric reducing agents were
screened for the diastereoselective reduction of 24 into desired
25. The combination of (R)-B-Me-CBS catalyst with catechol−
borane24 was finally found to be a good option. Under fully
optimized conditions, catecholborane was slowly added to
premixed 24 and 20 mol % of catalyst over 10 h through a
syringe pump at 0 °C, leading to the isolation of 25 as single
diastereomer. Compound 25 was then O-methylated to furnish
26. Lower CBS catalyst loading (10 mol %) in the reduction
also led to a satisfying result if the addition rate of
catecholborane was lowered further.
Scheme 4. Preparation of C1−C7 Fragment 32
The sense of selectivity of the CBS catalyst in this case was
inconsistent with regular prediction model, but easily
rationalized by the two possible catalyst−reactant complexes,
A and B (Figure 2). As has been noted by Corey,25 the o-OMe
Scheme 5. Finale of Herbimycin A (3) Synthesis
Figure 2. Proposed catalyst−reactant complexes for the reduction of
24.
(C21-OMe) in 24 tends to keep the phenyl ring perpendicular
to the carbonyl plane; therefore, the B−Me in complex B only
feels a face-on interaction from the substituted phenyl whereas
that in complex A has to overcome a strong spherical repulsion.
By finishing the aforementioned chemistry, which essentially
constitutes the first example of catalytic asymmetric synthesis of
the challenging C8−C20 fragment of both 2 and 3, we set out
to prepare the C1−C7 fragment (equivalence of 6). Similar to
that reported in our synthesis of reblastatin,12b the known
compound 9 was subjected to a Wittig reaction with stable ylide
27 and then deacetylated with K2CO3/EtOH to provide triol
28 in 83% yield over two steps (Scheme 4). After regioselective
acetonide protection of 28 under standard condition, the
resultant compound 29 was O-methylated with Meerwein’s salt
to give 30. Subsequent acidic hydrolysis of 30 followed by an
oxidative 1,2-diol cleavage successfully delivered aldehyde 32, a
compound that is directly submitted to the next reaction.
To finish the final assembly (Scheme 5), a zincate-mediated
coupling of 26 with 32 was performed using tert-butyllithium
and dimethylzinc26 and resulted in the isolation of 33 in an
optimal yield of 66%. Concomitant O- and N-deallylation of 33
then provided the seco-amino acid 4, the secondary target of
this study. Unfortunately, the compound was not stable enough
to be fully characterized. We therefore directly moved on to the
macrocyclization effected by BOPCl and DIPEA. Upon
isolation of macrolactam 34, installation of the C7-carbamate
and oxidative unmasking of the p-benzoquinone were carried
out as previously described by both Cossy11c and Panek11d to
complete the total synthesis. The optical rotation of our sample
([α]2D0 +222 (c = 0.17, CHCl3)) matched the value reported by
Cossy ([α]2D0 +223 (c = 0.14, CHCl3)), and spectral data was
consistent with previous reports in the literature.
In summary, we described a straightforward total synthesis of
herbimycin A. The synthesis took 19 longest linear steps from
readily available achiral starting materials and a cheap chiral-
pool substance with an overall yield up to 4.2%. The key to
success is the employment of chiral γ-lactone 15 as the C11−
C15 synthon that links the total synthesis to three well-
established catalytic asymmetric reactions. With this achieve-
ment as steping stone, we are now tackling an “edited”
collection of natural and unnatural benzoquinone ansamycin
analogues, and results will be reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, characterization data, and copies of the
NMR spectra of compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
C
dx.doi.org/10.1021/ol5012899 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(17) (a) Bonini, C.; Chiummiento, L.; Videtta, V. Synlett 2006, 2006,
AUTHOR INFORMATION
Corresponding Author
■
2079−2082. (b) Micoine, K.; Furstner, A. J. Am. Chem. Soc. 2010, 132,
̈
14064−14066.
*E-mail: mingxyu@imm.ac.cn.
Notes
(18) (a) Shimada, Y.; Kondo, S.; Ohara, Y.; Matsumoto, K.; Katsuki,
T. Synlett 2007, 2007, 2445−2447. (b) Sawada, Y.; Matsumoto, K.;
Kondo, S.; Watanabe, H.; Ozawa, T.; Suzuki, K.; Saito, B.; Katsuki, T.
Angew. Chem., Int. Ed. 2006, 45, 3478−3480.
The authors declare no competing financial interest.
(19) Abe, N.; Hanawa, H.; Maruoka, K.; Sasaki, M.; Miyashita, M.
Tetrahedron lett. 1999, 40, 5369−5372.
ACKNOWLEDGMENTS
This project received financial support from the National
Natural Science Foundation of China (21272279).
■
(20) Jackson, K. L.; Li, W.; Chen, C. L.; Kishi, Y. Tetrahedron 2010,
66, 2263−2272.
(21) (a) Pischl, M. C.; Weise, C. F.; Muller, M. A.; Pfaltz, A.;
̈
Schneider, C. Angew. Chem., Int. Ed. 2013, 52, 8968−8972. (b) Hu, T.;
Panek, J. S. J. Am. Chem. Soc. 2002, 124, 11368−11378.
(22) (a) Smith, A. B.; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M.
J. Am. Chem. Soc. 2001, 123, 4834−4836. (b) Geist, J. G.; Barth, R.;
Roush, W. R. Org. Lett. 2012, 15, 58−61.
REFERENCES
■
(1) Rascher, A.; Hu, Z.; Buchanan, G. O.; Reid, R.; Hutchinson, C. R.
Appl. Environ. Microbiol. 2005, 71, 4862−4871.
(2) DeBoer, C.; Meulman, P.; Wnuk, R.; Peterson, D. J. Antibiot.
1970, 23, 442.
(3) Tanida, S.; Hasegawa, T.; Higashide, E. J. Antibiot. 1980, 33,
199−204.
(23) (a) Semmelhack, M.; Hooley, R. J. Tetrahedron lett. 2003, 44,
5737−5739. (b) Yuan, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004,
126, 14720−14721.
(4) Omura, S.; Iwai, Y.; Takahashi, Y.; Sadakane, N.; Nakagawa, A.;
Oiwa, H.; Hasegawa, Y.; Ikai, T. J. Antibiot. 1979, 32, 255−261.
(5) (a) Martin, C. J.; Gaisser, S.; Challis, I. R.; Carletti, I.; Wilkinson,
B.; Gregory, M.; Prodromou, C.; Roe, S. M.; Pearl, L. H.; Boyd, S. M.
J. Med. Chem. 2008, 51, 2853−2857. (b) Whitesell, L.; Mimnaugh, E.
G.; De Costa, B.; Myers, C. E.; Neckers, L. M. Proc. Natl. Acad. Sci.
U.S.A. 1994, 91, 8324−8328.
(24) (a) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1989, 30, 6275−
6278. (b) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611−
614.
(25) (a) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 5675−
5678. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986−2012.
(26) Hayashi, Y.; Shoji, M.; Ishikawa, H.; Yamaguchi, J.; Tamura, T.;
Imai, H.; Nishigaya, Y.; Takabe, K.; Kakeya, H.; Osada, H. Angew.
Chem., Int. Ed. 2008, 47, 6657−6660.
(6) For recent review, see: Garcia-Carbonero, R.; Carnero, A.; Paz-
Ares, L. Lancet Oncol. 2013, 14, 358−369.
(7) For recent reviews, see: (a) Kim, T.; Keum, G.; Pae, A. N. Expert
Opin. Ther. Pat. 2013, 23, 919−943. (b) Franke, J.; Eichner, S.;
Zeilinger, C.; Kirschning, A. Nat. Prod. Rep. 2013, 30, 1299−1323.
(c) Kitson, R. R.; Moody, C. J. J. Org. Chem. 2013, 78, 5117−5141.
(8) For reviews, see: (a) Wilson, R. M.; Danishefsky, S. J. J. Org.
Chem. 2006, 71, 8329−8351. (b) Szpilman, A. M.; Carreira, E. M.
Angew. Chem., Int. Ed. 2010, 49, 9592−9628.
(9) For total synthesis of geldanamycin, see: (a) Andrus, M. B.;
Meredith, E. L.; Simmons, B. L.; Soma Sekhar, B.; Hicken, E. J. Org.
Lett. 2002, 4, 3549−3552. (b) Andrus, M. B.; Meredith, E. L.; Hicken,
E. J.; Simmons, B. L.; Glancey, R. R.; Ma, W. J. Org. Chem. 2003, 68,
8162−8169. (c) Qin, H. L.; Panek, J. S. Org. Lett. 2008, 10, 2477−
2479. (d) Hampel, T.; Neubauer, T.; van Leeuwen, T.; Bach, T.
Chem.Eur. J. 2012, 18, 10382−10392 (a two-step precursor).
(10) For the total synthesis of macbecin I, see: (a) Baker, R.; Castro,
J. L. J. Chem. Soc., Chem. Commun. 1989, 378−381. (b) Baker, R.;
Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47−65. (c) Evans, D.
A.; Miller, S. J.; Ennis, M. D.; Ornstein, P. L. J. Org. Chem. 1992, 57,
1067−1069. (d) Panek, J. S.; Xu, F. J. Am. Chem. Soc. 1995, 117,
10587−10588. (e) Belardi, J. K.; Micalizio, G. C. Angew. Chem., Int. Ed.
2008, 47, 4005−4008.
(11) For total synthesis of herbimycin A, see: (a) Nakata, M.; Osumi,
T.; Ueno, A.; Kimura, T.; Tamai, T.; Tatsuta, K. Tetrahedron Lett.
1991, 32, 6015−6018. (b) Nakata, M.; Osumi, T.; Ueno, A.; Kimura,
T.; Tamai, T.; Tatsuta, K. Bull. Chem. Soc. Jpn. 1992, 65, 2974−2991.
(c) Carter, K. D.; Panek, J. S. Org. Lett. 2004, 6, 55−57. (d) Canova,
S.; Bellosta, V.; Bigot, A.; Mailliet, P.; Mignani, S.; Cossy, J. Org. Lett.
2007, 9, 145−148.
(12) (a) Bian, C. C.; Yan, R.; Yu, X. M. Tetrahedron 2014, 70, 2982−
2991. For the original total synthesis of reblastatin, see: (b) Wrona, I.
E.; Gabarda, A. E.; Evano, G.; Panek, J. S. J. Am. Chem. Soc. 2005, 127,
15026−15027. (c) Wrona, I. E.; Gozman, A.; Taldone, T.; Chiosis, G.;
Panek, J. S. J. Org. Chem. 2010, 75, 2820−2835.
(13) García-Fortanet, J.; Murga, J.; Carda, M.; Marco, J. A.; Matesanz,
R.; Díaz, J. F.; Barasoain, I. Chem.Eur. J. 2007, 13, 5060−5074.
(14) (a) Ando, K. J. Org. Chem. 1998, 63, 8411−8416. (b) Ando, K. J.
Org. Chem. 1997, 62, 1934−1939.
(15) Guzman-Perez, A.; Corey, E. J. Tetrahedron Lett. 1997, 38,
5941−5944.
(16) Zhong, Y. L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622−
2624.
D
dx.doi.org/10.1021/ol5012899 | Org. Lett. XXXX, XXX, XXX−XXX