Enantioselective Approach to (-)-Hamigeran B and (-)-4-Bromohamigeran B via Catalytic Asymmetric Hydrogenation of Racemic Ketone to Assemble the Chiral Core Framework

Article abstract of DOI:10.1021/acs.orglett.6b00369

A new strategy featuring an iridium-catalyzed asymmetric hydrogenation of a racemic ketone via dynamic kinetic resolution to generate a cyclopentanol with three contiguous stereocenters and a SmI₂-promoted pinacol coupling to install the six-me

Full text of DOI:10.1021/acs.orglett.6b00369

Letter
pubs.acs.org/OrgLett
Enantioselective Approach to (−)-Hamigeran B and (−)-4-
Bromohamigeran B via Catalytic Asymmetric Hydrogenation of
Racemic Ketone To Assemble the Chiral Core Framework
Han Lin,† Li-Jun Xiao,† Min-Jie Zhou,† Hong-Ming Yu,† Jian-Hua Xie,*,† and Qi-Lin Zhou*,†,‡
‡
†State Key Laboratory and Institute of Elemento-organic Chemistry and Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A new strategy featuring an iridium-catalyzed
asymmetric hydrogenation of a racemic ketone via dynamic
kinetic resolution to generate a cyclopentanol with three
contiguous stereocenters and a SmI2-promoted pinacol
coupling to install the six-membered ring with correct
stereochemistry has been described for the enantioselective
total synthesis of (−)-hamigeran B (19 steps, 10.6% overall
yield) and (−)-4-bromohamigeran B (19 steps, 12.3% overall
yield).
atural products continue to inspire the development of
asymmetric catalysts for enantioselective synthesis.1 The
hamigerans, a family of biologically active molecules isolated
from the sponge Hamigera tarangaensis, have drawn much
attention from synthetic chemists owing to their unique
[6,6,5]- and [6,7,5]-tricyclic carbon skeletons bearing three or
four contiguous stereogenic centers (Figure 1).2 In 2001,
auxiliary to construct the chiral quaternary stereocenter. Taber
and Tian6 described an enantioselective strategy involving the
use of optically pure citronellol and an intramolecular C−H
insertion of an α-aryl-α-diazoketone followed by a Friedel−
Crafts cyclization to install the chiral core structure. Trost et al.7
used a Pd-catalyzed asymmetric allylic alkylation followed by an
intramolecular Heck reaction to install the quaternary carbon
center. Jiang et al.8 reported a formal synthesis involving the
construction of the chiral quaternary stereocenter by means of
Pd-catalyzed oxidative resolution of a racemic aryl-substituted
cyclopentenol combined with a reductive Claisen rearrange-
ment. Recently, Stoltz et al.9 reported a Pd-catalyzed
asymmetric decarboxylative allylic alkylation to access the
quaternary carbon center as part of an asymmetric formal
synthesis of (+)-hamigeran B. In addition, there have been
other reports on the synthesis of racemic hamigeran B10 and on
the nonenantioselective construction of the core tricyclic
carbon skeleton of various hamigerans.11
N
We recently developed several methods for highly efficient
asymmetric hydrogenation with the goal of improving the
efficiency of enantioselective syntheses of the core frameworks
of naturally occurring bioactive molecules.12 These successes
encouraged us to devote more effort to the development of new
efficient asymmetric hydrogenations for facile enantioselective
synthesis of other challenging targets. We noted that the
hamigerans have a chiral core consisting of an aryl-substituted
cyclopentane framework and that almost all of the chiral centers
are located on the cyclopentane ring. Inspired by this unique
structural characteristic, we set out to investigate the use of
asymmetric hydrogenation of racemic 2-(3-methoxy-2,5-
dimethylphenyl)-3-(ethoxycarbonyl)cyclopentanone (2) via
Figure 1. Molecular structures of selected hamigerans.
Nicolaou et al.3 reported the first synthesis of hamigerans, by
means of photoenolization of racemic or optically active
substituted benzaldehydes and subsequent Diels−Alder trap-
ping of the generated hydroxyl-o-quinodimethanes to construct
the chiral core framework in racemic or enantiomerically pure
form, respectively. Since then, several other syntheses have
been developed, and most of them have focused on the
synthesis of hamigeran B,4 which has strong in vitro activity
against herpes and polio viruses but little cytotoxicity.2 Clive
and Wang5 synthesized (−)-hamigeran B by using Meyer’s
Received: February 4, 2016
© XXXX American Chemical Society
A
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Letter
dynamic kinetic resolution (DKR) to access the chiral core
framework. We herein report that chiral iridium complexes Ir−
(R)-SpiroPAP 1, which have a spiro pyridine−aminophosphine
ligand,13 efficiently catalyzed the transformation of 2 to chiral
cyclopentanol 3, allowing us to achieve enantioselective total
syntheses of (−)-hamigeran B and its 4-bromo analogue
(Scheme 1).
Scheme 3. Enantioselective Synthesis of Ketone 4
Scheme 1. Enantioselective Synthesis of (−)-Hamigeran B
and (−)-4-Bromohamigeran B via a Catalytic Asymmetric
Hydrogenation of Racemic Ketone
afforded cyclopentanone 2 in 78% as a trans isomer yield for
the two steps.
Our retrosynthetic analysis of (−)-hamigeran B is outlined in
Scheme 2. Our strategy was to focus on the construction of the
The asymmetric hydrogenation of racemic ketone 2 via DKR
to afford optically active cyclopentanol 3, with its three
contiguous stereocenters, was the key step of our strategy. First,
we investigated the ruthenium complex RuCl2−(S)-Xyl-SDP/
(R,R)-DPEN (11), which efficiently catalyzes the hydro-
genation of racemic α-arylcycloketones,20 and we found that
it gave 3 in only moderate yield and enantioselectivity (ethyl
ester, 46% yield, 76% ee; isopropyl ester, 30% yield, 82% ee),
but with high diastereoselectivity (trans/cis > 99:1). Next, we
studied chiral iridium complexes 1, which bear a spiro
pyridine−aminophosphine ligand,13 and found that (R)-1c
catalyzed the production of (+)-3 in 97% yield with 97% ee and
>99:1 trans/cis selectivity (for details, see the Supporting
Information). The hydrogenation is through the direct
reduction of one of the enantiomers of cis-2, which are
generated by base-promoted epimerization of trans-2. The
observation of a minor amount of cis,cis-3 in the hydrogenation
system provides evidence to support this conclusion. The
longer reaction time favored the epimerization of cis,cis-3 to
trans,cis-3, resulting high diastereoselectivity. The absolute
configuration of (+)-3 was assigned as (1S,2S,3S) by inference
from the X-ray crystal structure of lactone 16 (Scheme 4). The
hydrogenation of racemic ketone 2 could be performed on a
gram scale without reduction in either the yield or the
selectivity. The hydroxyl group was then protected with tert-
butylchlorodimethylsilane (TBSCl) at room temperature;21
subsequent treatment of the protected compound with lithium
diisopropylamide in THF at −78 °C and trapping with methyl
iodide yielded methylated product 13 in 94% yield. Compound
13 was oxidized with pyridinium dichromate/trimethylsilyl
chloride according to Palomo’s procedure22 to afford ketone 4
in 85% yield; no epimerization of the α-arylated stereogenic
center was observed. Note, however, that 4 was unstable and
had to be stored at 0 °C for no more than a week. Thus, we
accomplished the enantioselective synthesis of key chiral
intermediate 4, which has the necessary adjacent chiral
quaternary and aryl-substituted stereocenters.
Scheme 2. Retrosynthetic Analysis of (−)-Hamigeran B
chiral aryl-substituted cyclopentane framework. We expected
that catalytic asymmetric hydrogenation would provide chiral
cyclopentanol 3, which has three contiguous stereocenters, and
that subsequent methylation with methyl iodide would generate
the quaternary carbon center. The resulting methylated product
would be oxidized to cyclopentanone 4, which would serve as a
precursor for installation of the isopropyl group. Several
subsequent functional transformations, including benzylic
oxidation,14 would provide dialdehyde 5. An intramolecular
SmI2-mediated reductive cyclization of the dialdehyde15 would
provide tricyclic intermediate 6. Finally, by using the Ir-
catalyzed hydrogenation method developed by Trost et al.7
followed by Swern oxidation and several other transformations,
we would convert 6 to the target molecule.
The Suzuki coupling of 2-iodocyclopent-2-enone (7)16 and
arylboronic acid 8,17 both known compounds, in the presence
of 1 mol % of Pd2(dba)3·CHCl3 and 4 mol % of MePhos
yielded α-aryl-substituted cyclopentenone 9 in 99% yield
(Scheme 3).18 1,4-Addition of Me3SiCN to cyclopentenone 9
according to Chen’s procedure,19 followed by conversion of the
nitrile group of the addition product 10 to an ester group,
The introduction of the bulky isopropyl group adjacent to
the aryl group on the cyclopentane ring with the correct
B
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Scheme 4. Attempts To Introduce Isopropyl Group
Scheme 5. Enantioselective Synthesis of Dialdehyde 5
stereochemistry had previously been demonstrated to be a
challenge in the synthesis of hamigeran B.4 Initially, we
attempted to install the isopropyl group by using transition-
metal-catalyzed cross-coupling reactions (Scheme 4). Reaction
of ketone 4 with lithium 2,2,6,6-tetramethylpiperidide and
trimethylsilyl chloride yielded a silyl enol ether, which was
converted to enol triflate 14 in 51% yield (two steps) by
reaction with N-phenylbis(trifluoromethanesulphonimide) by
means of Corey’s method.23 However, coupling of enol triflate
14 with isopropylmagnesium chloride or isopropylzinc chloride
catalyzed by either a palladium or a nickel catalyst did not
afford desired product 15. Thus, we tried to introduce the
isopropyl group by addition of a Grignard reagent and
elimination of the resulting hydroxyl group. In the presence
of cerium chloride, ketone 4 reacted with isopropylmagnesium
chloride to provide lactone 16 in 92% yield, and X-ray
diffraction analysis of a crystal of 16 showed its absolute
configuration to be (1R,4R,7R). However, elimination of the
ester group of 16 to form a trisubstituted olefin was
unsuccessful. Lactone 16 could be reduced to diol 17 with
LiAlH4, but subsequent elimination of the tertiary hydroxyl
group with Burgess reagent to 18 failed.
Scheme 6. Enantioselective Syntheses of (−)-Hamigeran B
and (−)-4-Bromohamigeran B
Instead, lactone 16 was oxidized with potassium persulfate in
the presence of copper sulfate to give aldehyde 19 in 73% yield
according to a literature method14 (Scheme 5). Aldehyde 19
was reduced to alcohol 20 with LiAlH4, and the hydroxyl group
was protected with TBSCl to yield 21 in 82% yield over two
steps. Note that 21 was synthesized from ketone 4 in four steps
without purification of the intermediates and a higher overall
yield (57%). We were delighted to find that reaction of 21 with
Burgess reagent afforded tetrasubstituted olefin 22a and
trisubstituted olefin 22b in 26% and 73% yields, respectively.
After removal of the TBS group of 22b with tetrabutylammo-
nium fluoride, olefins 23 were isolated in 82% yield. Olefin 23
was oxidized with Dess−Martin periodinane to dialdehyde 5 in
85% yield. In summary, dialdehyde 5 was synthesized in seven
steps from ketone 4 in 21.9% overall yield. We also attempted
the direct hydrogenation of olefin 23 to diol 24 using various
catalysts, but without success.
hydrogenation,7 6 was converted to diol 25 in 99% yield with
the correct stereochemistry of the isopropyl group. The cis-
oriented isopropyl group and aryl group on the five-membered
ring and the trans-orientated hydroxyl groups on the six-
membered ring were confirmed by nuclear Overhauser
enhancement spectroscopy. Diol 25 was subjected to Swern
oxidation5 and subsequent demethylation with BBr3 to produce
diketone 27 in 85% yield for two steps.3 Finally, selective
bromination of diketone 27 with a slight excess of N-
bromosuccinimide in the presence of diisopropylamine afforded
(−)-hamigeran B in 82% yield.7 With 2.2 equiv of N-
bromosuccinimide, (−)-4-bromohamigeran B was obtained in
95% yield.10a The NMR spectroscopic data and the optical
rotations of our synthetic (−)-hamigeran B ([α]2D6 −167.3 (c
0.15, CH2Cl2)) and (−)-4-bromohamigeran B ([α]2D6 −80.0 (c
0.10, CH2Cl2)) were identical to those of the corresponding
natural products ([α]2D5 −151.1 (c 0.15, CH2Cl2) and [α]2D5
−81.2 (c 0.37, CH2Cl2),2 respectively). Thus, we accomplished
the enantioselective total syntheses of (−)-hamigeran B (19
Dialdehyde 5 was subjected to pinacol coupling mediated by
SmI2 to generate tricyclic product 6 as a single diastereomer in
88% yield (Scheme 6). By means of Ir-black-catalyzed
C
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steps and 10.6% overall yield)24 and (−)-4-bromohamigeran B
(19 steps, 12.3% overall yield).
(9) Mukherjee, H.; McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. Org.
Lett. 2011, 13, 825−827.
(10) (a) Lau, S. Y. W. Org. Lett. 2011, 13, 347−349. (b) Miesch, L.;
Welsch, T.; Rietsch, V.; Miesch, M. Chem. - Eur. J. 2009, 15, 4394−
4401.
In conclusion, we developed a new strategy for the
enantioselective construction of the chiral core framework of
the hamigeran family of natural products. The strategy features
an iridium-catalyzed asymmetric hydrogenation of a racemic
ketone via DKR to afford a cyclopentanol moiety with three
contiguous stereocenters as well as a SmI2-promoted pinacol
coupling to install the six-membered ring with the correct
stereochemistry. With this efficient strategy, the enantioselec-
tive total syntheses of (−)-hamigeran B and (−)-4-
bromohamigeran B were achieved.
(11) (a) Cai, Z.; Harmata, M. Org. Lett. 2010, 12, 5668−5670.
(b) Arnaiz, E.; Blanco-Urgoiti, J.; Abdi, D.; Domínguez, G.; Castells, J.
́
P. J. Organomet. Chem. 2008, 693, 2431−2437. (c) Madu, C. E.;
Lovely, C. J. Org. Lett. 2007, 9, 4697−4700. (d) Sperry, J. B.; Wright,
D. L. Tetrahedron Lett. 2005, 46, 411−414. (e) Mehta, G.; Shinde, H.
M. Tetrahedron Lett. 2003, 44, 7049−7053.
(12) For reviews, see: (a) Xie, J.-H.; Zhou, Q.-L. Huaxue Xuebao
2014, 72, 778−797. (b) Xie, J.-H.; Zhou, Q.-L. Aldrichimica Acta 2015,
48, 33−40. For selected papers, see: (c) Liu, S.; Xie, J.-H.; Li, W.;
Kong, W.-L.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2009, 11, 4994−
4997. (d) Chen, J.-Q.; Xie, J.-H.; Bao, D.-H.; Liu, S.; Zhou, Q.-L. Org.
Lett. 2012, 14, 2714−2717. (e) Xie, J.-H.; Guo, L.-C.; Yang, X.-H.;
Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2012, 14, 4758−4761. (f) Zhang,
Q.-Q.; Xie, J.-H.; Yang, X.-H.; Xie, J.-B.; Zhou, Q.-L. Org. Lett. 2012,
14, 6158−6161. (g) Liu, C.; Xie, J.-H.; Li, Y.-L.; Chen, J.-Q.; Zhou, Q.-
L. Angew. Chem., Int. Ed. 2013, 52, 593−596. (h) Cheng, L.-J.; Xie, J.-
H.; Chen, Y.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2013, 15, 764−767.
(i) Li, G.; Xie, J.-H.; Hou, J.; Zhu, S.-F.; Zhou, Q.-L. Adv. Synth. Catal.
2013, 355, 1597−1604.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00369.
Experimental procedures, characterization of the prod-
ucts, and X-ray data for compound 16 (PDF)
X-ray crystallographic data for 16 (CIF)
(13) (a) Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L.
Angew. Chem., Int. Ed. 2011, 50, 7329−7332. (b) Xie, J.-H.; Liu, X.-Y.;
Yang, X.-H.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed.
2012, 51, 201−203. (c) Yang, X.-H.; Xie, J.-H.; Liu, W.-P.; Zhou, Q.-L.
Angew. Chem., Int. Ed. 2013, 52, 7833−7836. (d) Yang, X.-H.; Xie, J.-
H.; Zhou, Q.-L. Org. Chem. Front. 2014, 1, 190−193. (e) Yang, X.-H.;
Wang, K.; Zhu, S.-F.; Xie, J.-H.; Zhou, Q.-L. J. Am. Chem. Soc. 2014,
136, 17426−17429.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: jhxie@nankai.edu.cn
*E-mail: qlzhou@nankai.edu.cn
Notes
(14) Hauser, F. M.; Ellenberger, S. R. Synthesis 1987, 1987, 723−724.
(15) Szostak, M.; Fazakerley, N. J.; Parmar, D.; Procter, D. J. Chem.
Rev. 2014, 114, 5959−6039.
The authors declare no competing financial interest.
(16) One step from cyclopent-2-enone, see: Krafft, M. E.; Cran, J. W.
Synlett 2005, 1263−1266.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China,
the National Basic Research Program of China
(2012CB821600), and the “111” project (B06005) of the
Ministry of Education of China for financial support.
(17) Four steps from 2,5-dimethylphenol, see: Gore, M. P.; Gould, S.
J.; Weller, D. D. J. Org. Chem. 1992, 57, 2774−2783.
(18) Wolfe, J. P.; Singer, R. A.; Yang, B.-H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550−9561.
(19) (a) Yang, J.-Y.; Wang, Y.-X.; Wu, S.-X.; Chen, F.-X. Synlett 2009,
2009, 3365−3367. (b) Yang, J.-Y.; Shen, Y.-B.; Chen, F.-X. Synthesis
2010, 2010, 1325−1333.
REFERENCES
■
332.
(1) Mohr, J. T.; Krout, M. R.; Stoltz, B. M. Nature 2008, 455, 323−
(20) (a) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Fan, B.-M.; Duan,
H.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125, 4404−4405. (b) Xie,
J.-H.; Liu, S.; Huo, X.-H.; Cheng, X.; Duan, H.-F.; Fan, B.-M.; Wang,
L.-X.; Zhou, Q.-L. J. Org. Chem. 2005, 70, 2967−2973.
(21) Bartoszewicz, A.; Kalek, M.; Nilsson, J.; Hiresova, R.; Stawinski,
J. Synlett 2008, 2008, 37−40.
(2) (a) Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.; Bergquist,
P. R. J. Nat. Prod. 2000, 63, 79−85. (b) Singh, A. J.; Dattelbaum, J. D.;
Field, J. J.; Smart, Z.; Woolly, E. F.; Barber, J. M.; Heathcott, R.; Miller,
J. H.; Northcote, P. T. Org. Biomol. Chem. 2013, 11, 8041−8051.
(c) Dattelbaum, J. D. A.; Singh, J.; Field, J. J.; Miller, J. H.; Northcote,
P. T. J. Org. Chem. 2015, 80, 304−312.
(3) (a) Nicolaou, K. C.; Gray, D.; Tae, J. Angew. Chem., Int. Ed. 2001,
40, 3675−3678. (b) Nicolaou, K. C.; Gray, D.; Tae, J. Angew. Chem.,
Int. Ed. 2001, 40, 3679−3683. (c) Nicolaou, K.; Gray, D. L. F.; Tae, J.
J. Am. Chem. Soc. 2004, 126, 613−627.
(4) For reviews, see: (a) Clive, D. L.; Wang, J. Org. Prep. Proced. Int.
2005, 37, 1−35. (b) Miesch, M.; Welsch, T.; Rietsch, V.; Miesch, L.
Total Syntheses of Hamigeran B. In Strategies and Tactics in Organic
Synthesis; Harmata, M., Ed.; Elsevier Ltd., 2013; Vol. 9, pp 203−229.
(5) (a) Clive, D. L. J.; Wang, J. Angew. Chem., Int. Ed. 2003, 42,
3406−3409. (b) Clive, D. L. J.; Wang, J. Tetrahedron Lett. 2003, 44,
7731−7733. (c) Clive, D. L. J.; Wang, J. J. Org. Chem. 2004, 69, 2773−
2784.
(22) Cossfo, F. P.; Aizpurua, J.; Palomo, C. Can. J. Chem. 1986, 64,
225−231.
(23) Mi, Y.; Schreiber, J. V.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
11290−11291.
(24) This synthesis is comparable to the best result achieved by Trost
et al. (for (−)-hamigeran B, 10% overall yield, 15 steps); see ref 7.
(6) Taber, D. F.; Tian, W. J. Org. Chem. 2008, 73, 7560−7564.
(7) (a) Trost, B. M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, G.
M. J. Am. Chem. Soc. 2004, 126, 4480−4481. (b) Trost, B. M.; Pissot-
Soldermann, C.; Chen, I. Chem. - Eur. J. 2005, 11, 951−959.
(8) Jiang, B.; Li, M.-M.; Xing, P.; Huang, Z.-G. Org. Lett. 2013, 15,
871−873.
D
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