Assignment and stereocontrol of hibarimicin atropoisomers

Article abstract of DOI:10.1021/ol2017005

A stereochemical feature of the hibarimicins is a central biaryl (HMP-Y6) or aryl-quinone (hibarimicinone) incorporated as a single atropodiastereomer. Herein, a chiral resolution and deracemization process to access optically enriched biaryls aR-3 and aS

Full text of DOI:10.1021/ol2017005

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4538–4541
Assignment and Stereocontrol of
Hibarimicin Atropoisomers
Ian M. Romaine,† Jonathan E. Hempel,† Ganesh Shanmugam,† Hiroshi Hori,§
Yasuhiro Igarashi,‡ Prasad L. Polavarapu,† and Gary A. Sulikowski*,†
Departments of Chemistry and Biochemistry, Vanderbilt Institute of Chemical Biology,
Vanderbilt University, Nashville, Tennessee 37235, United States, Biotechnology
Research Center, Toyoma Prefectural University, Kosugi, Toyama 939-0398, Japan,
and Graduate School of Agriculture, Tamagawa University, Machida, Tokyo 194-8610,
Japan
gary.a.sulikowski@vanderbilt.edu
Received June 24, 2011
ABSTRACT
A stereochemical feature of the hibarimicins is a central biaryl (HMP-Y6) or aryl-quinone (hibarimicinone) incorporated as a single
atropodiastereomer. Herein, a chiral resolution and deracemization process to access optically enriched biaryls aR-3 and aS-3 is described.
From these atropoenantiomers the BCD-EFG ring system of HMP-Y6 is constructed [(þ)-aR-7]. Comparison of CD spectra of aR-7 to HMP-Y6 leads
to the assignment of HMP-Y6 and hibarimicin B atropoisomers as aR and aS, respectively.
The hibarimicins were isolated from the soil microbe
Microbispora rosea during the course of screening natural
product extracts for tyrosine kinase inhibitors.1,2 Structur-
al studies on hibarimicins A, B, C, D, and G concluded
that the five metabolites shared a common aglycone
[hibarimicinone (Figure 1)] conjugated to six deoxy sugars
located at C10/C12 and C100/C120.1b The relative stereo-
chemistry of the aglycone hibarimicinone was assigned as
shown in Figure 1 with the configuration of the C13
tertiary alcohol (H ring) tentative. Kajiura and co-workers
later reported on biosynthetic studies using blocked
mutants of the hibarimicin producer Microbispora rosea
subsp. hibaria TP-A0121 that proved the C13 (H ring) and
C130 (A ring) stereochemistry were identical.3 Key to
clarification of C13 stereochemistry was the isolation of
HMP-Y6 (Figure 1),3c a glycosylated C2-symmetric shunt
metabolite, derived from the oxidative homocoupling of
an aromatic undecaketide followed by glycosylation.
Acidic methanolysis of HMP-Y6 resulted in release of
C10/C12 and C100/C120 deoxy sugars to provide the
aglycone (HMP-Y1, Figure 1). Comparison of the core
biaryl substitution pattern of HMP-Y6 to known atropi-
someric natural products such as biphyscion4 supports an
(3) (a) Hori, H.; Kajiura, T.; Igarashi, Y.; Furumai, T.; Higashi, K.;
Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55,
46–52. (b) Kajiura, T.; Furumai, T.; Igarashi, Y.; Hori, H.; Higashi, K.;
Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55,
53–60. (c) Igarashi, Y.; Kajiura, T.; Furumai, T.; Hori, H.; Higashi, K.;
Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55,
61–70.
† Vanderbilt University.
‡ Toyoma Prefectural University.
§ Tamagawa University.
(4) Hauser, F.; Gauuan, P. Org. Lett. 1999, 1, 671–672.
(1) (a) Kajiura, T.; Furumai, T.; Igarashi, Y.; Hori, H.; Higashi, K.;
Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 1998, 51,
394–401. (b) Hori, H.; Igarashi, Y.; Kajiura, T.; Furumai, T.; Higashi,
K.; Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 1998, 51,
402–417.
(2) Hibarimicin B is identical to previously reported angelmicin B;
see: (a) Uehara, Y.; Li, P.; Fukazawa, H.; Mizuno, S.; Nihei, Y.; Nishio,
M.; Hanada, M.; Yamamoto, C.; Furumai, T.; Oki, T. J. Antibiot. 1993,
46, 1306–1308. (b) Hori, H.; Higashi, K.; Ishiyama, T.; Uramoto, M.;
Uehara, Y.; Oki, T. Tetrahedron Lett. 1996, 37, 2785–2788.
(5) For earlier discussions on hibarimicin atropoisomers, see: (a)
Maharoof, U.; Sulikowski, G. Tetrahedron Lett. 2003, 44, 9021–9023.
(b) Narayan, S.; Roush, W. Org. Lett. 2004, 6, 3789–3792.
(6) Synthetic studies on the hibarimicins. (a) Lee, C.; Audelo, M.;
Reibenpies, J.; Sulikowski, G. Tetrahedron 2002, 58, 4403–4409. (b)
Kim, K.; Maharoof, U.; Raushel, J.; Sulikowski, G. Org. Lett. 2003, 5,
2777–2780. (c) Lambert, W.; Roush, W. Org. Lett. 2005, 7, 5501–5504.
(d) Lee, W.; Kim, K.; Sulikowski, G. Org. Lett. 2005, 7, 1687–1689. (e)
Li, J.; Todaro, L. J.; Mootoo, D. R. Org. Lett. 2008, 10, 1337–1340.
r
10.1021/ol2017005
Published on Web 08/03/2011
2011 American Chemical Society

atropodiastereoslective oxidative homocoupling followed
by oxidation of the BCD ring system leading to hibarimi-
cinone with retention of atropo configuration.5 In connec-
tionwith our pursuitofa totalsynthesisofhibarimicinone6
we describe here a deracemization method providing
atropo-stereocontrol and assignment of configuration of
the central biaryl carbonꢀcarbon bond of HMP-Y6 and
hibarimicin B by spectroscopic correlation further sup-
ported by computational studies.
HMP-Y1 our studies began with a two-directional an-
nulation strategy starting from single atropoenantiomers
of bis-o-tolyl phenyl benzoate.
Figure 2. Biomimetic and two-directional strategies directed
toward HMP-Y1.
Despite the importance of biaryl atropisomers as chiral
ligands and their frequent occurrence in nature, control of
axial chirality remains challenging and no general methods
are currently available to directly produce the required bis-
o-tolyl phenyl benzoate enantioselectively (Figure 2).11
For this reason we considered chiral resolution as it would
provide access to both enantiomers and assist in assigning
the absolute stereochemistry of HMP-Y1. To begin we
examined the Spring oxidative organocuprate homocou-
pling starting from a series of protected phenols (1aꢀc)
(Scheme 1).12 Lithiation, cupration, and oxidation of
methyl ether 1a provided biaryl 2a in yields ranging from
51 to 63%, while cuprates derived from MOM (1b) and
benzyl (1c) ethers oxidatively coupled in slightly lower
yields. Phenyl ester 3 was derived from biaryl 2a by
bromination followed by a lithiumꢀhalogen exchange
and phenyl chloroformate quench. We examined the re-
solution of biaryl intermediates en route to 3 and bis-
phenyl ester 3 by chiral LC using several chiral solid
supports. Resolution of enantiomers was observed only
with bis-phenyl ester 3, which could be separated on
preparative scale. In order to assign the absolute stereo-
chemistry of (þ)- and (ꢀ)-phenyl benzoate 3, bis-phenol
(()-4 [from either MOM ether 2b (HCl, MeOH) or benzyl
ether 2c (H2, Pd/C)] was condensed with an excess of (S)-
Mosher acid to give diastereomers aR-5 and aS-6.
The latter diastereomer was recrystallized from etherꢀ
dichloromethane and subject to single-crystal X-ray ana-
lysis allowing unambigous assignment of stereochemistry.
Phenol aS-4 was derived from Mosher ester aS-6 by LAH
reduction and advanced to aS-3 by a three-step reaction
Figure 1. Structures of hibarimicinone, hibarimicins A-D,
HMP-Y6, and HMP-Y1.
A variety of naturally occurring dimeric quinones, biar-
yls, and binaphthoquinones have been identified and
the subject of synthetic investigations.7 In general two
approaches have been utilized in their assembly: oxidative
biomimetic homocouplings8 and two-directional annu-
lations9 (Figure 2). Nonenzymatic biomimetic homocou-
plings of 2-naphthols have provided diastereoselectivity
under substrate control, but diastereoselective homo-
couplings of 1-naphthols, as required for HMP-Y1
(Figure 2), have not been reported.10 Muller and Steglich
9a,b
€
have employed two-directional MichaelꢀDieckmann
cyclizations of optically active biaryl o-toluate esters
obtained by resolution. For the purpose of assigning
absolute stereochemistry of the central biaryl bond of
(7) (a) Bringmann, G.; Mortimer, A.; Keller, P.; Gresser, M.; Garner,
J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384–5427. (b)
Bringmann, G.; Tasler, S. Tetrahedron 2001, 57, 331–343. (c) Bringmann,
G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111,
563–639.
€
€
(8) (a) Drochner, D.; Huttel, W.; Nieger, M.; Muller, M. Angew.
Chem., Int. Ed. 2003, 42, 931–933. (b) Sperry, J.; Sejberg, J. J. P.;
Stiemke, F. M.; Brimble, M. A. Org. Biomol. Chem. 2009, 7, 2599–2603.
€
(9) (a) Bode, S. E.; Drochner, D.; Mueller, M. Angew. Chem., Int. Ed.
€
2007, 46, 5916–5920. (b) Drochner, D.; Huttel, W.; Bode, S. E.; Mueller,
M.; Karl, U.; Nieger, M.; Steglich, W. Eur. J. Org. Chem. 2007, 1749–
1758. (c) Govender, S.; Mmutlane, E. M.; van Otterlo, W. A. L.; de
Koning, C. B. Org. Biomol. Chem. 2007, 5, 2433–2440.
(11) Wallace, T. W. Org. Biomol. Chem. 2006, 4, 3197–3210.
(12) (a) Surry, D.; Fox, D.; Macdonald, S.; Spring, D. J. Chem. Soc.,
Chem. Commun. 2005, 2589–2590. (b) Surry, D.; Spring, D. Chem. Soc.
Rev. 2006, 35, 218–225.
(10) For examples of stereoselective 2-naphthol homocouplings, see:
(a) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc. Rev. 2009,
38, 3193–3207. (b) Young, S.; Grove, C.; Gozalez, M.; Urgaonkar, S.;
Fettinger, J.; Shaw, J. Angew. Chem., Int. Ed. 2011, 50, 3730–3733.
Org. Lett., Vol. 13, No. 17, 2011
4539

sequence (Scheme 2). Atropoenantiomer aS-3 correlated
with the slower eluting enantiomer in the chiral-LC resolu-
tion of biaryl (()-3 described above.
Scheme 2. Absolute Configuration Assignment and Deracemi-
zation Route to (þ)-aS-3
Scheme 1. Preparation and Resolution of Biaryl 3
Having assigned the absolute configuration of (ꢀ)-aS-3
and (þ)-aR-3, we turned our attention to developing a
method of accessing enantiomerically enriched 3 not rely-
ing on a chiral resolution. We were drawn to reports
describing copper(II)ꢀdiamine complexes to deracemize
C2-symmetric ligands including BINOL, VAPOL, and
VANOL.13 Typically deracemization is accomplished by
in situ generation of copper(II)ꢀ(ꢀ)-sparteine by the
aerobic sonication of CuCl and (ꢀ)-sparteine followed
by exposure of this complex to the racemic biaryl. While
this method has been applied to chiral ligands13a,b and
oligonaphthalenes14 no report of reagent-controlled dera-
cemizationinthe contextofa natural productsynthesis has
appeared.15 We were pleased to observe exposure of
racemic biphenol 4 to the copper(II)ꢀ(ꢀ)-sparteine com-
plex resulted in isolation of (ꢀ)-aS-4 in 93% ee16 and 77%
yield. When (()-4 was treated with copper(II) complexed
to O’Briens diamine17 [(þ)-sparteine surrogate], (þ)-aR-4
was produced in 80% ee (85% yield).
Scheme 3. Bis-annulation Leading to BCDEFG Ring System
the bis-o-toluate anion18 derived from 3 using a series of
deprotonation conditions followed by a D2O quench.19
Interestingly, no deprotonation was observed using 1 or 2
equiv of the LDAꢀTMEDA complex; however use of 4
equiv of LDAꢀTMEDA resulted in generation of the
bis-toluate anion as demonstrated by near complete deu-
terium incorporation. Addition of 2 equiv of cyclohexe-
none to the bis-toluate anion derived from (þ)-aR-3
followed by DDQ oxidation provided (þ)-aR-7 (Scheme 3).
Subsequently racemic (()-7 was resolved using chiral-LC
on a preparative scale to give optically pure (ꢀ)-aS-7 and
(þ)-aR-7.
In order to evaluate the proposed bis-annulation
(Figure 2) we optimized conditions for the generation of
(13) (a) Zhang, Y.; Yeung, S.-M.; Wu, H.; Heller, D. P.; Wu, C.;
Wulff, W. D. Org. Lett. 2003, 5, 1813–1816. (b) Hu, G.; Holmes, D.;
Gendhar, B. F.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 14355–14364.
(c) Lee, W. K.; Park, Y. S.; Beak, P. Acc. Chem. Res. 2009, 42, 224–234.
(14) (a) Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera, P.; Kocovsky,
P. J. Org. Chem. 1992, 57, 1917–1920. (b) Smrcina, M.; Polakova, J.;
Vyskocil, S.; Kocovsky, P. J. Org. Chem. 1993, 58, 4534–4538.
(15) Nelson and Meyers were the first to report on the copper(II)-
mediated deracemization of biaryls under substrate control; see: Nelson,
T. D.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 3259–3262.
(16) Enantiomeric excess was determined by analysis of the derived
bis-menthyl carbonate. See Supporting Information for details.
(17) Dearden, M.; Firkin, C.; Hermet, J.; O’Brien, P. J. Am. Chem.
Soc. 2002, 124, 11870–11871.
Biaryl dimers (ꢀ)-aS-7 and (þ)-aR-7 constitute the
BCD-EFG substructure of HMP-Y6 (Figure 1). Further-
more, since 7 incorporates the chromophore of HMP-Y6
we anticipated that the quantum chemical predictions of
ECD spectra for single enantiomers of 7 and comparison
of the CD spectrum of HMP-Y6 to aS-7 and aR-7 would
(18) (a) Charest, M.; Lerner, C.; Brubaker, J.; Siegel, D.; Myers, A.
Science 2005, 308, 395–398. (b) Mal, D.; Pahari, P. Chem. Rev. 2007, 107,
1892–1918.
(19) Romaine, I. M. Ph.D. Dissertation, Vanderbilt University, 2011.
Org. Lett., Vol. 13, No. 17, 2011
4540

(ECD) spectra of aS-7 and aR-7, along with a quantum
chemical prediction for aR-7, are shown in Figure 3.
A bisignate negative ECD couplet (negative ECD band
on the long wavelength side and positive ECD band on the
short wavelength side) was observed, as also predicted, for
aR-7. The negative ECD couplet predicted by the quantum
chemical calculations for negative torsional angle between
the planes of two biaryl moieties in aR-7 is in agreement
with the same relation predicted for the transition dipole
moments by the empirical exciton coupling model.20
Finally, the CD spectrum of HMP-Y621 correlates with
aR-7 with both having a negative torsional angle between
the planes of two biaryl moieties.
In summary, the axial chirality of HMP-Y6 has been
assigned the aR configuration, and assuming the config-
urationisretainedupon oxidation tohibarimicin, the latter
can be assignedthe aS configuration.22 To date, all isolated
hibarimicins share the same UV and CD spectrum indicat-
ing they also possess the aS configuration. Heating a
methanol solution of hibarimicinone in methanol (60 °C)
resulted in isomerization to the unnatural aR isomer,
indicating the hibarimicinone atropodiastereomer aS is
not a thermodynamic product. This observation will need
tobetaken intoaccountwhendesigning a total synthesisof
hibarimicinone or HMP-Y1.
Acknowledgment. This work was supported by the Na-
tional Institutes of Health (CA 059515), National Science
Foundation (CHE-0804301), and the Vanderbilt Institute
of Chemical Biology. This work was conducted in part
using the resources of the Advanced Computing Center for
Research and Education at Vanderbilt University, Nash-
ville, TN.
Figure 3. ECD and absorption spectra of 7. Top panel: quantum
chemical prediction of ECD spectrum for aR-7 at the B3LYP/6-
31G* level; Middle two panels: experimental ECD and absorp-
tion spectra of aS-7 (blue) and aR-7 (red); Bottom panel:
quantum chemical prediction of absorption spectrum for aR-
7. The inset in the top panel shows the structure of lowest energy
conformation of aR-7 at the B3LYP/6-31G* level.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
allow assignment of configuration of the HMP-Y6 atropi-
somer. The experimental electronic circular dichroism
(21) See Supporting Information.
(22) Note the difference in configurational assignment between
HMP-Y1 (aR) and hibarimicinone (aS) results from a switch in group
priorities in accord with the CahnꢀIngoldꢀPrelog sequence rules.
(20) Harada, N.; Nakanishi, K. Circular dichroic spectroscopy: Ex-
citon coupling in organic stereochemistry; University Science Books: Mill
Valley, CA, 1983.
Org. Lett., Vol. 13, No. 17, 2011
4541