Efficient, divergent synthesis of cryptophycin unit A analogues

Article abstract of DOI:10.1039/c2cc32417b

A flexible and divergent synthesis of cryptophycin unit A analogues is described. This method relies on iridium-catalysed stereo- and enantioselective crotylation and chemoselective one-pot oxidative olefination to access common intermediate 8. Heck, cros

Full text of DOI:10.1039/c2cc32417b

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Efficient, divergent synthesis of cryptophycin unit A analoguesw
Kyle L. Bolduc, Scott D. Larsen* and David H. Sherman*
Received 3rd April 2012, Accepted 1st May 2012
DOI: 10.1039/c2cc32417b
A flexible and divergent synthesis of cryptophycin unit A
analogues is described. This method relies on iridium-catalysed
stereo- and enantioselective crotylation and chemoselective one-pot
oxidative olefination to access common intermediate 8. Heck, cross
metathesis, and Suzuki-Miyaura reactions are illustrated for the
generation of methyl ester unit A analogues 10a–d.
production of unit A analogues varied in the phenyl region to
support development of improved cryptophycins for the treat-
ment of cancer.
We initially envisioned a synthetic route modelled closely on
that of Eggen et al.13 (Scheme 1), which was attractive for
utilising Heck coupling for the late-stage installation of the
phenyl ring in unit A. This coupling was ideal for derivatisa-
tion of the unit A phenyl ring using diverse aryl iodides.
However, development of this route in our laboratory for
higher throughput proved to be problematic. The Brown
crotylboration was the most significant hindrance to large-
scale synthesis, as it proceeded in poor yield with competing
decomposition of aldehyde I–3. In addition, protecting group
exchange (I–4 to I–6 and I–8 to I–9) was inefficient, and the
second round of oxidation provided a volatile silyl ether
aldehyde (I–6) whose isolation was problematic. The complexity
and low-throughput (0.12% over 11 steps to I–9; data not
shown) of this route hindered our ability to access the desired
quantities of unit A and its analogues.
The cryptophycins are a family of lichen-derived cyanobacterial
peptides1–3 that represent some of the most potent microtubule
stabilising agents discovered to date. Effective at levels significantly
lower than either vinblastine or paclitaxel, cryptophycins have
proven to be powerful cytostatic agents capable of arresting the
growth of P-glycoprotein-expressing multidrug resistant (MDR)
human carcinoma cell lines.4,5 However, pronounced neurotoxi-
city precluded development of cryptophycin 52 (Fig. 1), a synthetic
analogue of cryptophycin 1 that had been identified as the most
promising clinical candidate.6 As a result, extensive medicinal
chemistry efforts have been undertaken in the search for new
analogues with improved therapeutic profiles.7,8
Facing these initial obstacles, we sought a new route to unit
A analogues that was both short and enabled diversification
as a terminal, divergent step. Recent advances in crotylation
technology pioneered in the Krische laboratory14–17 created the
opportunity for a catalytic process with the potential for recovery
and recycling of the expensive iridium-based reactive complex.18
Of the four subunits that comprise the cryptophycins
(Fig. 1), unit A is the only subunit where significant structural
modification has been performed and shown to be tolerated.9–11
As noted by Corbett and coworkers,12 substituted phenyl ring
analogues of unit A have displayed antitumor activity with
promising pharmacological profiles. Therefore, we were motivated
to establish a selective, scalable, and efficient method for the
Fig. 1 Cryptophycins 1 and 52 with subunits A, B, C, and D highlighted.
Life Sciences Institute and Departments of Medicinal Chemistry,
Chemistry, and Microbiology & Immunology, University of Michigan,
Ann Arbor, MI 48109, United States. E-mail: sdlarsen@umich.edu;
davidhs@umich.edu
w Electronic Supplementary Information (ESI) available: Spectro-
scopic data and experimental details for the preparation of all new
compounds. See DOI: 10.1039/c2cc32417b
Scheme 1 Original synthetic route to unit A and analogues developed
from Eggen et al.
c
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Table 1 Heck route to unit A analoguesa
Aryl iodide
Product
Yield (%)b
9a
9b
9c
9d
10a
10b
10c
10d
31
28
38
30
a
Reaction conditions: Pd(OAc)2 (1.6 mol%), 1.1 eq. aryl iodide,
b
10 eq. Et3N, CH3CN, 85 1C, 18 h. Isolated yields.
Scheme 2 Our efficient synthesis developed for common intermediate 8.
This crotylation was also highly efficient, as it eliminated the
need for a separate aldehyde generation and isolation step.
Furthermore, an Eli Lilly process chemistry report19 suggested
that tedious protection and deprotection steps through the
final alcohol oxidation would not be necessary, and that an
in situ olefination could further shorten the synthetic route.
Thus, we sought to pursue analogue synthesis through olefin
cross metathesis (CM), Heck coupling, and Suzuki-Miyaura
cross coupling.
Table 2 CM route to unit A analoguesa
Styryl fragment
Product
Yield (%)b
11a
11b
11c
11d
10a
10b
10c
10d
30
23
26
8
Our synthesis of intermediate 8, which would serve as the
common intermediate for unit A and analogues, is summarised
in Scheme 2. Starting from 1,3-propanediol, monosilylated
alcohol 4 was prepared as previously reported in excellent
yield.20 Treatment of 4 with the Ir complex 5, prepared and
isolated as described,16 in the presence of a-methyl allyl acetate
afforded the expected crotyl alcohol 6 in a 6 : 1 dr that was
sufficiently pure to carry forward without purification. Mosher
ester analysis21,22 of the diastereomeric mixture of 6 confirmed
the correct stereochemistry (3S, 4R) and revealed a 95 : 5 er.z
Precipitation with pentane and filtration allowed recovery of
the catalyst, while the filtrate containing 6 was concentrated and
treated with TBAF to liberate crotyl diol 7 in good yield from 4.
With 7 in hand, a one-pot oxidation/olefination sequence was
employed to effect chemoselective conversion of the primary
alcohol to unsaturated ester 8 (420 : 1 E/Z).23 The terminal
alkene on 8 was then employed as the handle to generate unit A
analogues.
a
Reaction conditions: Hoveyda-Grubbs II (5 mol%), 4.0 eq. styryl
b
fragment, DCM, reflux, 2 h. Isolated yields.
at reflux temperature with a set of para-substituted styrenes
(11a–d).27–29 CM was successful in providing the desired
analogues 10a–d, but competitive insertion of the a,b-unsaturated
methyl ester prevented higher yields (Table 2). However, we expect
this route could be further optimised to utilise the full spectrum of
styryl building blocks available.
The final route developed for unit A analogue synthesis
employed Suzuki-Miyaura cross coupling. For this method,
the boronic ester 12 was first prepared through CM
(Table 3).30,31 Aryl iodides 9a–d were then coupled with 12
using Pd2(dba)3 in a mixture of water and glyme to afford
Table 3 Suzuki-Miyaura cross coupling to unit A analoguesa
A series of phenyl moieties (4-H, 4-trifluoromethyl, 4-methoxy,
and 4-cyano) was chosen to demonstrate the flexibility of the
reported synthetic scheme. This series was developed for the wide
range of electron demand presented and for structural replication
of non-native cryptophycins produced through precursor-directed
biosynthesis.3
As previous methods utilised Heck coupling for appending
the phenyl on unit A, this was the first route explored for
analogue creation (Table 1). Phosphine-free Pd catalysis with
aryl iodides 9a–d in acetonitrile proved to be the most versatile
for reactions with the terminal olefin of 8, but also likely to
induce reactivity with the a,b-unsaturated methyl ester.24–26
Decomposition was evident, likely due to extended heating
times, but yields were acceptable for analogues 10a–d.
The second route investigated for flexible analogue generation
was CM (Table 2). In this case, olefin 8 underwent metathesis in
the presence of Hoveyda-Grubbs II catalyst in dichloromethane
Aryl iodide
Product
Yield (%)b
9a
9b
9c
9d
10a
10b
10c
10d
42
55
53
63
a
Reaction conditions: [Pd2(dba)3] (2 mol%), PCy3 (4.8 mol%), 1.7 eq.
b
K3PO4, DME/H2O (2 : 1), 85 1C, 2 h. Isolated yields from 12.
c
Chem. Commun.
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electron donating or withdrawing substituents (Table 3).32
Reactivity could also be achieved with aryl bromides and
chlorides with increased heating times and temperatures,
proving this Suzuki-Miyaura route to be the most efficient
for future analogue generation.
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Suzuki-Miyaura coupling, the remaining transformation
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13a–d. This was accomplished with LiOH in a 1 : 1 : 0.5
mixture of methanol/water/tetrahydrofuran (Scheme 3). The
presence of the free acid now allows attachment of these
novel unit A analogues to linear depsipeptide precursors of
cryptophycin.33
In summary, we have established a short and efficient
synthesis to intermediate 8 (4 steps, 34% overall yield) from
which flexible coupling methods, particularly Suzuki-Miyaura
cross coupling, provide access to a broad range of phenyl or
more highly functionalised aromatic moieties in the synthesis
of unit A analogues. With this strategy in place, the remaining
objective involves coupling of the analogues to units B, C,
and D to generate seco-cryptophycin intermediates. Our
laboratory has previously demonstrated that solid phase
synthesis34 followed by Crp thioesterase and epoxidase-
mediated chemoenzymatic assembly3,35,36 enable rapid production
of cryptophycin anticancer agents. We expect the versatile unit A
synthetic strategy reported herein will open new opportunities
to produce unique cryptophycin analogues for on-going drug
development efforts.
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We are grateful to Russell L. Betts, PhD and Jeffrey D.
Kittendorf, PhD of Alluvium Biosciences for expert technical
assistance and helpful discussion. Karoline Chiou is thanked
for QTOF-MS analysis. This work was supported by NIH
grant RO1 CA108874 and the Hans W. Vahlteich Professorship
(to DHS). Additional financial support for this work was provided
by an NIH Phase I STTR grant (R41CA135869) awarded to
Alluvium Biosciences and a Fred W. Lyons Fellowship and a
Rackham Graduate Research grant (to KLB).
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Notes and references
z The MTPA ester was synthesised from purified
6 using
(S)-(+)-MTPA acid chloride in anhydrous pyridine at 60 1C for
24 h. The 19F NMR spectra of esters prepared from 6 and its
enantiomer (from (S)-(ꢀ)ꢀ5) were compared to determine the er
(Supporting Informationw).
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.