Construction of Enantiopure Taxoid and Natural Product-like Scaffolds Using a C-C Bond Cleavage/Arylation Reaction

Article abstract of DOI:10.1021/acs.orglett.5b02797

An approach to construct enantiopure complex natural product-like frameworks, including the first reported synthesis of a C17 oxygenated taxoid scaffold, is presented. A palladium-catalyzed C-C activation/cross-coupling is utilized to access these structu

Full text of DOI:10.1021/acs.orglett.5b02797

Letter
pubs.acs.org/OrgLett
Construction of Enantiopure Taxoid and Natural Product-like
Scaffolds Using a C−C Bond Cleavage/Arylation Reaction
Manuel Weber, Kyle Owens, Ahmad Masarwa,* and Richmond Sarpong*
Department of Chemistry, University of CaliforniaBerkeley, Berkeley, California 94720, United States
S
* Supporting Information
ABSTRACT: An approach to construct enantiopure complex natural product-like
frameworks, including the first reported synthesis of a C17 oxygenated taxoid
scaffold, is presented. A palladium-catalyzed C−C activation/cross-coupling is
utilized to access these structures in a short sequence from (+)-carvone; the scope of
this reaction is explored.
mall, abundant, enantioenriched secondary metabolites
4) through C1−C7 bond cleavage when traditional electro-
S
termed the “chiral pool”1 have long been recognized as
philes (e.g., mCPBA, PPTS or NBS) were applied. Comple-
mentary to this result, several novel cyclohexenone scaffolds
(e.g., 5 and 6) that comprise the core of natural products such
as drummondol (11), suaveolindol (12), and others were
accessed through [Rh(I)]-mediated C1−C6 bond activation.
However, using rhodium catalysts, we were unable to
functionalize the substrates at C6 following C−C bond
activation.13 We sought to overcome this limitation with
palladium-catalyzed cross-coupling chemistry,14 which would
set the stage for accessing a variety of interesting frameworks
such as 7−9.
an excellent starting point for the enantiospecific preparation of
many complex molecules.2 Carvone (1) is one such compound,
which has been shown to undergo a rich assortment of
transformations that have led to the preparation of numerous
natural products3 and their analogues. Recently, synthesis of
natural product inspired compounds, with structures that are
reminiscent of known biologically active compounds, has
provided a way to synthesize compound libraries with increased
opportunities to access a desired biological activity.4,5 Many
applications of chiral pool compounds for complex molecule
synthesis have employed traditional manipulations that retain
the same carbocyclic skeleton.6 Complementary methods that
accomplish the deep-seated reorganization of the carbon
framework would be of great utility in synthetic chemistry.
The products of these rearrangements could facilitate the
synthesis of a wide variety of structures that are only distantly
related to the initial natural product and may possess enhanced
biological activities.
In particular, we hypothesized that arylation at C6 could
provide a rapid route to the cores of taxoids such as taxinine M
(14).15,16 Taxinine M and related taxoids possess a bridging
ether ring that distinguishes them from most taxoid natural
products. No syntheses of these natural products or their core
structures have been reported to date. A straightforward route
to a variety of new taxoid analogues could be useful in drug
discovery efforts to identify more effective chemotherapeutic
agents. With the synthesis of 7−9 in mind, we first sought to
develop a general and broadly applicable ring-opening/aryl
cross-coupling reaction of tricycle 2 (accessible in one step
from 3b) and then of 3c in order to prepare a diverse array of
interesting scaffolds.
Methods that may achieve this goal include selective C−H7
and C−C8 bond activation. The use of nontraditional
functional handles (i.e., C−H and C−C bonds) has become
a powerful tool for the construction of new C−C bonds. While
recent advances in C−H activation/functionalization have
found applications in natural product synthesis,9 the use of
C−C activation is still in its infancy in this respect.10 In this
manuscript, we describe the synthesis of natural product-like
scaffolds including the core of C17 oxygenated taxoids by
applying a Pd-catalyzed C−C activation/arylation reaction to
readily accessible cyclobutanols.11
Under the optimized conditions (Table 1; conditions A),17
we found that the electronic nature of the aryl halide was
inconsequential as the reaction tolerated both electron-
donating and -accepting substituents. Further investigations
revealed that ortho-substituted aryl bromide coupling partners
and heteroaryl bromides bearing Lewis basic groups benefit
Recently we reported a strategy12 to achieve selective C−C
bond cleavage of carvone-derived cyclobutanols 2 and 3
(Scheme 1), providing access to vicodiol-type scaffolds (see
Received: September 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Complementary Strategies To Access Natural Product-Like Scaffolds from (+)-Carvone
Table 1. Substrate Scope of the Ring-Opening/Cross-
Coupling Reaction of 2
in Table 1. On the basis of our hypothesis that an unreactive
palladacycle19 could form under the standard conditions, we
explored conditions to minimize this likelihood.20 Ultimately,
replacing BINAP with monodentate phosphine ligands, which
are known to form highly reactive complexes with a free
coordination site,21 provided the desired cross-coupling
adducts. With P(tBu)3 as the ligand, the ring-opening/cross-
coupling products 16h and 16l were formed in good yields.22
Hydroxylated pinene derivatives 3 have also been studied in
the cross-coupling reaction. In our previous studies of Rh-
catalyzed C−C bond activation, we observed a matched/
mismatched effect depending on the absolute configurations of
the cyclobutanol substrate and ligand that were employed.12 As
such, we surveyed several chiral ligands in the Pd-catalyzed
ring-opening/cross-coupling of 3a and 3c.23
While the cross-coupling of 3c exhibited only a small
preference for (R)-BINAP over (S)-BINAP, the effect was
more pronounced for 3a, which lacks the acyl group on the
primary hydroxyl.17 This acyl group helps prevent decom-
position of the cyclohexenone products via a retro-aldol
pathway. As illustrated in Table 2, the couplings employing
3c are also insensitive to the electronic properties of the aryl
bromide, providing access to products bearing a variety of
electron-donating and -withdrawing groups on the aryl moiety
in good yields. Sterically encumbered and heteroaryl bromides
are also tolerated, yielding cross-coupled compounds (see 17
for a general structure) in good to high yields. Notably, a vinyl
bromide (15p) is also a competent cross-coupling partner,
providing the prenylated product in up to 55% yield.
a
no.
15
R =
cond.
16
yield (%)
1
2
3
4
5
6
7
a
b
c
d
e
f
C6H5
A
A
A
A
A
B
B
E
a
b
c
d
e
f
87
89
85
82
86
93
90
68
70
68
34
59
54
76
4-MeO-C6H4
4-O2N-C6H4
3,5-(MeO)2-C6H3
3-F-5-F3C-C6H3
2-H3C-C6H4
2-iPr-C6H4
g
h
i
g
h
i
b
8
2-Ac-C6H4
9
5-pyrimidinyl
2-thiophenyl
3-furyl
D
C
C
E
10
11
12
13
14
j
j
k
l
k
l
3,5-(MeO)2-6-Ac-C6H2
2-(N-Me)-indoyl
3-pyridyl
m
n
D
D
m
n
a
b
Yield refers to isolated yield after chromatography. 71% on 0.8
mmol scale. Conditions A: 15 (1.25 equiv), Pd(OAc)2/(R)-BINAP (5
mol %), 80 °C, 4 h. Conditions B: 15 (2.0 equiv), Pd(OAc)2/(R)-
BINAP (10 mol %), 80 °C, 22 h. Conditions C: 15 (1.25 equiv),
Pd(OAc)2/(R)-BINAP (5 mol %), 65 °C, 22 h. Conditions D: 15 (1.0
equiv), Pd(OAc)2/(R)-BINAP (15 mol %), 64 °C, 43 h. Conditions E:
15 (2.0 equiv), Pd(OAc)2 (15 mol %), P(tBu)3 (1.5 equiv), 65 °C, 22
h.
We have utilized several of the cross-coupling products (16
and 17) to generate structurally complex, polycyclic, natural
product-like compounds (Scheme 2). For example, nucleo-
philic indoles (see 17m′ and 17o) present opportunities for
further C−C bond forming reactions. Specifically, intra-
molecular conjugate addition of 17m′ using Yb(OTf)3 in
acetonitrile gives tetracyclic product 7 in 83% yield,24 whereas
thermolysis of the Boc group in 17o and subsequent treatment
from slight variations to the standard conditions (compare
conditions A−D, Table 1). The connectivity and absolute
configuration of the products is supported by single crystal X-
ray analysis of 16g.17,18
In order to access the taxoid core, the cross-coupling of 2′-
bromoacetophenones such as 15h and 15l was required. These
substrates proved challenging under conditions A−D described
B
DOI: 10.1021/acs.orglett.5b02797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the desired taxoid scaffold (9) in high yield along with
unreacted starting material (Scheme 3).
Table 2. Substrate Scope of the Ring-Opening/Cross-
Coupling Reaction of 3c
Scheme 3. Synthesis of Enantiopure Taxoid Core 9
a
no.
15
R =
17
yield (%)
1
2
3
4
5
6
7
a
C6H5
a
64
76
74
67
b
c
4-MeO-C6H4
b
c
4-NO2-C6H4
g
2-iPr-C6H4
g
b
m
o
p
2-(N-Me)-indoyl
4-(N-Boc)-indoyl
2-methylprop-1-en-1-yl
m
o
p
59 (29)
81
bc
,
49 (55)
The identity of 9 was unambiguously confirmed by X-ray
analysis.18 This short sequence serves as a highly step-
economical route to the taxoid framework (five steps from
(+)-carvone) and provides access to enantiomerically pure 9.
This constitutes the first synthesis of the core of C17-
oxygenated taxoids such as taxinine M (14),15 taxagifine,27
and taxacin, which contain a bridging ether, that distinguishes
them from other taxoids.28
a
b
c
Yield refers to isolated yield after chromatography. With 3a. With
(S)-BINAP.
Scheme 2. Synthesis of Enantiopure Natural Product-like
Scaffolds
In conclusion, we identified conditions for a sequential, ring-
opening/cross-coupling reaction starting from readily accessible
cyclobutanols. This reaction tolerates a broad range of aryl and
heterocyclic bromides, as well as a vinyl bromide. Various steric
and electronic effects of the aryl substituents are accommo-
dated, providing a short route to several complex frameworks.
In particular, intramolecular conjugate additions provided
access to natural product-like polycycles 7 and 8. The first
synthesis of taxoid scaffold 9 showcases the ability of this
sequence to rapidly build molecular and stereochemical
complexity. Applications of this methodology to the synthesis
of several natural products are currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02797.
with Yb(OTf)3 and an acidic resin yields 8. The structures of 7
and 8 were both confirmed by single crystal X-ray analysis.18
Interestingly, 8 possesses a scaffold reminiscent of the
welwitindolinones (e.g., welwitindolinone B isothiocyanate,
13).25
Finally, we also pursued the cyclization of acetophenone
derivatives such as 16h to access the 6−8−6 tricyclic framework
found in taxoid natural products. However, several challenges
had to be addressed. First, 8-membered rings possess significant
transannular strain that had to be overcome.26 In addition,
ketone 16h is flanked by two tetra-substituted α-positions,
making additions into the carbonyl group difficult.
Experimental details, screening results, complete ana-
lytical data for all new compounds (PDF)
Crystallographic data for 16g (CIF)
Crystallographic data for 9 (CIF)
Crystallographic data for 7 (CIF)
Crystallographic data for 8 (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
We first investigated a Mukaiyama-type cyclization process.
However, after formation of a TMS-enol ether from 16h,
conditions could not be identified to give the desired
cyclization product. Instead, we found that treating 16h directly
with a bis(trimethylsilyl)amide base in THF forms an
equilibrium mixture favoring the open form (16h) over
tetracycle 9. The counterion (i.e., Li+, Na+, or K+) had a
significant impact on the position of the equilibrium. While Na-
and KHMDS formed only trace amounts of 9 (even after 2 h),
an excess of LiHMDS achieved nearly instantaneous formation
of 9. However, upon prolonged reaction, 16h was observed as
the exclusive product. Quenching the reaction mixture by the
addition of water after a short period of time (∼10 min) gave
*E-mail: ahmadm@berkeley.edu (A.M.)
*E-mail: rsarpong@berkeley.edu (R.S.)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the DAAD (German Academic Exchange
Service) for a postdoctoral fellowship to M.W. and the
Rothschild Foundation as well as VATAT (The Israeli Council
for Higher Education) for postdoctoral fellowships to A.M. We
thank Dr. A. DiPasquale (UC Berkeley) and Dr. L. J. Daumann
(UC Berkeley) for solving the crystal structures of 16g, 7, 8,
C
DOI: 10.1021/acs.orglett.5b02797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. Soc. 2003, 125, 8862. (d) Rosa, D.; Nikolaev, A.; Nithiy, N.;
Orellana, A. Synlett 2015, 26, 441. (e) Seiser, T.; Cramer, N. Org.
Biomol. Chem. 2009, 7, 2835.
and 9 (supported by NIH Shared Instrument Grant S10-
RR027172).
(15) Beutler, J. A.; Chmurny, G. M.; Look, S. A.; Witherup, K. M. J.
Nat. Prod. 1991, 54, 893.
(16) Sun, Z.-H.; Chen, Y.; Gui, Y.-Q.; Cui, J.; Zhu, C.-G.; Jin, J.;
Tang, G.-H.; Bu, X.-Z.; Yin, S. Bioorg. Med. Chem. Lett. 2015, 25, 1240.
(17) See the Supporting Information for details.
(18) (a) CCDC 1414897 (16g), 1415152 (7), 1414899 (8), and
1414900 (9) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/
getstructures. (b) See the Supporting Information for visualized
structures.
(19) Vicente, J.; Abad, J.-A.; Martínez-Viviente, E.; de Arellano, M.
C.; Jones, P. G. Organometallics 2000, 19, 752.
(20) Similar reactivity was observed with the corresponding aldehyde,
secondary alcohol, and TBS enol ether as well as the dimethyl and
ethylene glycol acetal substrates.
REFERENCES
■
(1) (a) Handbook of Chiral Chemicals; Ager, D., Ed.; Taylor &
Francis: Boca Raton, FL, 2006. (b) Blaser, H. U. Chem. Rev. 1992, 92,
935.
(2) Hanessian, S. Total Synthesis of Natural Products: The “Chiron”
Approach; Pergamon Press: New York, 1983.
(3) Ho, T.-L. Enantioselective Synthesis: Natural Products from Chiral
Terpenes; Wiley: New York, 1992.
(4) (a) Wetzel, S.; Bon, R. S.; Kumar, K.; Waldmann, H. Angew.
Chem., Int. Ed. 2011, 50, 10800. (b) Koch, M. A.; Schuffenhauer, A.;
Scheck, M.; Wetzel, S.; Casaulta, M.; Odermatt, A.; Ertl, P.;
Waldmann, H. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 17272.
(c) Schuffenhauer, A.; Ertl, P.; Roggo, S.; Wetzel, S.; Koch, M. A.;
Waldmann, H. J. Chem. Inf. Model. 2007, 47, 47.
(5) For recent examples, see: (a) Rafferty, R. J.; Hicklin, R. W.;
Maloof, K. A.; Hergenrother, P. J. Angew. Chem., Int. Ed. 2014, 53, 220.
(b) Huigens, R. W., III; Morrison, K. C.; Hicklin, R. W.; Flood, T. A.,
Jr; Richter, M. F.; Hergenrother, P. J. Nat. Chem. 2013, 5, 195.
(6) Morrison, K. C.; Hergenrother, P. J. Nat. Prod. Rep. 2014, 31, 6.
(7) Selected reviews: (a) Ackermann, L. Acc. Chem. Res. 2014, 47,
281. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res.
2012, 45, 788. (c) Modern Arylation Methods; Ackermann, L., Ed.;
Wiley-VCH: Weinheim, 2009. (d) Bergman, R. G. Science 1984, 223,
902.
(8) (a) Murakami, M.; Ito, Y. Cleavage of Carbon−Carbon Single
Bonds by Transition Metals. In Topics in Organometallic Chemistry;
Murai, S., Ed.; Springer: Berlin, 1999; Vol. 3, p 97. (b) Jun, C.-H.
Chem. Soc. Rev. 2004, 33, 610. (c) Rybtchinski, B.; Milstein, D. Angew.
Chem., Int. Ed. 1999, 38, 870. (d) Marek, I.; Masarwa, A.; Delaye, P.-
O.; Leibeling, M. Angew. Chem., Int. Ed. 2015, 54, 414. (e) C−C Bond
activation. In Topics in Current Chemistry; Dong, G., Ed.; Springer:
Berlin, 2014; Vol. 346. (f) Ruhland, K. Eur. J. Org. Chem. 2012, 2012,
2683. (g) Aïssa, C. Synthesis 2011, 2011, 3389. (h) Murakami, M.;
Matsuda, T. Chem. Commun. 2011, 47, 1100. (i) Park, Y. J.; Park, J.-
W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (j) Murakami, M.;
Makino, M.; Ashida, S.; Matsuda, T. Bull. Chem. Soc. Jpn. 2006, 79,
1315. (k) Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 2005,
1715. (l) Perthuisot, C.; Edelbach, B. L.; Zubris, D. L.; Simhai, N.;
(21) Stambuli, J. P.; Buhl, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
̈
124, 9346.
(22) Competing β-hydride elimination and diminished reactivity
were observed when lower ligand loadings (20−30 mol %) were used.
However, with 1.5 equiv of P(tBu)3, higher reactivity was achieved and
side product formation was reduced (see the Supporting Information
for more details). This may be due to the decreased opportunities for
free coordination sites on the alkyl palladium intermediate. Further
optimization studies to lower the ligand loading are under
investigation.
(23) Substrate 2 was found to undergo the title reaction somewhat
more slowly when (S)-BINAP was used.
(24) The product was formed as a diastereomeric mixture at the
epimerizable α-position.
(25) (a) Stratmann, K.; Moore, R.E.; Bonjouklian, R.; Deeter, J. B.;
Patterson, G.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem. Soc.
1994, 116, 9935. (b) Jimenez, J. I.; Huber, U.; Moore, R. E.; Patterson,
G. J. Nat. Prod. 1999, 62, 569. (c) Weires, N. A.; Styduhar, E. D.;
Baker, E. L.; Garg, N. K. J. Am. Chem. Soc. 2014, 136, 14710.
(26) (a) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881. (b) Petasis,
N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757. (c) Parenty, A.;
Moreau, X.; Niel, G.; Campagne, J.-M. Chem. Rev. 2013, 113, PR1.
(27) Chauvier
̀ ̀
e, G.; Guenard, D.; Pascard, C.; Picot, F.; Potier, P.;
Iverson, C. N.; Muller, C.; Satoh, T.; Jones, W. D. J. Mol. Catal. A:
̈
Prange, T. J. Chem. Soc., Chem. Commun. 1982, 495.
́
Chem. 2002, 189, 157. (m) Souillart, L.; Cramer, N. Chem. Rev. 2015,
115, 9410. (n) Zeng, R.; Dong, G. J. Am. Chem. Soc. 2015, 137, 1408.
(o) Ko, H. M.; Dong, G. Nat. Chem. 2014, 6, 739. (p) Xu, T.; Savage,
N. A.; Dong, G. Angew. Chem., Int. Ed. 2014, 53, 1891. (q) Chen, P.-
H.; Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2014, 53, 1674. (r) Xu, T.;
Ko, H. M.; Savage, N.; Dong, G. J. Am. Chem. Soc. 2012, 134, 20005.
(9) Selected examples and reviews: (a) Chen, D.; Youn, S. W. Chem.
- Eur. J. 2012, 18, 9452. (b) Gutekunst, W. R.; Baran, P. S. Chem. Soc.
Rev. 2011, 40, 1976. (c) Yoshioka, S.; Nagatomo, M.; Inoue, M. Org.
Lett. 2015, 17, 90. (d) Pitts, A. K.; O'Hara, F.; Snell, R. H.; Gaunt, M.
J. Angew. Chem., Int. Ed. 2015, 54, 5451. (e) Fischer, D. F.; Sarpong, R.
J. Am. Chem. Soc. 2010, 132, 5926. (f) Newton, J. N.; Fischer, D. F.;
Sarpong, R. Angew. Chem., Int. Ed. 2013, 52, 1726.
(28) Yoshizaki, F.; Fukuda, M.; Hisamichi, S.; Ishida, T.; In, Y. Chem.
Pharm. Bull. 1988, 36, 2098.
(10) Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2014, 53, 10733.
(11) Bermejo, F. A.; Mateos, A. F.; Escribano, A. M.; Lago, R. M.;
Buron
8933.
́ ́ ́
, L. M.; Lopez, M. R.; Gonzalez, R. R. Tetrahedron 2006, 62,
(12) Masarwa, A.; Weber, M.; Sarpong, R. J. Am. Chem. Soc. 2015,
137, 6327.
(13) For examples of successful alkyl/aryl-Rh functionalization, see:
(a) Ishida, N.; Nakanishi, Y.; Murakami, M. Angew. Chem., Int. Ed.
2013, 52, 11875. (b) Ishida, N.; Ishikawa, N.; Sawano, S.; Masuda, Y.;
Murakami, M. Chem. Commun. 2015, 51, 1882. (c) Yada, A.; Fujita, S.;
Murakami, M. J. Am. Chem. Soc. 2014, 136, 7217.
(14) (a) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 1999, 121,
11010. (b) Waibel, M.; Cramer, N. Angew. Chem., Int. Ed. 2010, 49,
4455. (c) Matsumura, S.; Maeda, Y.; Nishimura, T.; Uemura, S. J. Am.
D
DOI: 10.1021/acs.orglett.5b02797
Org. Lett. XXXX, XXX, XXX−XXX