Synthesis of the C(7)-C(22) Sector of (+)-Acutiphycin via O-directed double free radical alkyne hydrostannation with Ph3SnH/Et3B, double I-Sn exchange, and double stille coupling

Article abstract of DOI:10.1021/ol500050p

Herein a new double O-directed free radical hydrostannation reaction is reported on the structurally complex dialkyldiyne 11. Through our use of a conformation-restraining acetal to help prevent stereocenter-compromising 1,5-H-atom abstraction reactions b

Full text of DOI:10.1021/ol500050p

Letter
pubs.acs.org/OrgLett
Synthesis of the C(7)−C(22) Sector of (+)-Acutiphycin via O‑Directed
Double Free Radical Alkyne Hydrostannation with Ph3SnH/Et3B,
Double I−Sn Exchange, and Double Stille Coupling
̌
,
‡
̌
̌
̌
̌
Karl J. Hale,* Maciej Maczka, Amarjit Kaur, Soraya Manaviazar, Mehrnoosh Ostovar, and Milosz Grabski
̌
The School of Chemistry & Chemical Engineering and the Centre for Cancer Research and Cell Biology (CCRCB), the Queen’s
University Belfast, Stranmillis Road, Belfast BT9 5AG, Northern Ireland, United Kingdom
‡The Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom
S
* Supporting Information
ABSTRACT: Herein a new double O-directed free radical hydro-
stannation reaction is reported on the structurally complex
dialkyldiyne 11. Through our use of a conformation-restraining
acetal to help prevent stereocenter-compromising 1,5-H-atom
abstraction reactions by vinyl radical intermediates, the two
vinylstannanes of 10 were concurrently constructed with high
stereocontrol using Ph3SnH/Et3B/O2. Distannane 10 was thereafter
elaborated into the bis-vinyl iodide 9 via O-silylation and double I−
Sn exchange; double Stille coupling of 9, O-desilylation, and
oxidation thereafter furnished 8.
n the preceding paper,1 we unveiled a new total synthesis of
(+)-inthomycin C, in which we documented the first
Kiyooka and Hena,3e alongside other noteworthy synthetic
efforts from the laboratories of Miftakhov3f and Leger.3g
The two stereodefined olefins of (+)-acutiphycin present a
special challenge for construction by the O-directed free radical
hydrostannation method,4 due to the fact that a conformation-
ally unrestrained diyne of general structure 1 could give rise to a
range of intermediary vinyl radicals5 that could potentially
engage in stereocenter-compromising 1,5-H-atom abstraction
processes,6 with two possible adverse outcomes shown in
Scheme 1.
Given these issues, we considered that the positioning of a
conformation-restraining acetal within 1 could be highly
beneficial, since it would severely constrain the approach of
the different vinyl radicals to the various stereocenters present
within the carbon chain. A high concentration of stannane
would also favor the rapid quenching of these vinyl radicals.
Together, these combined tactics could be expected to promote
the desired double O-directed hydrostannation event on 1
without causing a loss of stereocenter integrity from within the
product.
I
successful use of the O-directed alkylacetylene free radical
hydrostannation reaction with Ph3SnH and catalytic Et3B/O2
for the synthetic construction of a chiral trisubstituted allylic
alcohol with a geminal dimethyl substituent positioned directly
next to the OH. In this accompanying Organic Letter, we now
report on the further augmentation of that methodology, in the
context of our development of a new synthetic route to the
C(7)−C(22)-sector of the antitumor macrolide, (+)-acutiphy-
cin. Specifically, we record here the first example of a new O-
directed double free radical hydrostannation process for the
simultaneous creation of two structurally distinct trisubstituted
olefins within the same target molecule, a reaction that
proceeds efficiently and without deleterious vinyl radical 1,5-
H-atom abstraction events compromising the newly introduced
stereocenters present within the C(7)−C(22) sector of the
target.
(+)-Acutiphycin is a pyranylated macrolide of significant
pharmaceutical interest on account of its pronounced growth
inhibitory effects against human KB nasopharyngeal carcinoma
in vitro and its ability to counteract murine Lewis lung
carcinoma in vivo.2 It is, however, no longer produced by the
blue green alga from which it was first isolated (Oscillatoria
acutissima), which means that all future clinical supply will have
to be met by total synthesis, unless a new source of
(+)-acutiphycin can be found. So far, only two total syntheses
of (+)-acutiphycin have been completed: one by the team of
Smith at Penn,3a,b the other by Jamison’s group3c,d at MIT.
Both stand out for their elegance and clever synthetic design, as
well as for their excellent levels of stereocontrol. A notable
asymmetric aldol approach has also been formulated by
Accordingly, we selected the O-isopropylidenated enal 8 as
an advanced intermediate for our proposed route (Scheme 2).
It would be prepared via a multistep sequence involving double
O-directed free radical hydrostannation on the bis-propargyli-
cally oxygenated diyne 11 with Ph3SnH and cat. Et3B/O2 in
PhMe. O-Silylation of 10 and retentive I−Sn exchange would
thereafter ensue to furnish the bis-iodoolefin 9 ready for two-
directional Stille cross-coupling with Me4Sn. O-Desilylation and
Received: January 7, 2014
Published: February 6, 2014
© 2014 American Chemical Society
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Letter
Scheme 1. Deleterious 1,5-H-Atom Transfer Events that
Could Potentially Occur in an Acyclic Precursor 1 after α-
Addition of a Ph3Sn Radical and β-Vinyl Radical Formation
Scheme 3. Our O-Directed Free Radical Hydrostannation
Strategy for the C(12)−C(24) Sector of (+)-Acutiphycin
Scheme 2. Our O-Directed Double Free Radical Stannation
Strategy for the C(7)−C(22) Sector of (+)-Acutiphycin
alternative, in the event of the desired double hydrostannation
event later faltering.
Accordingly, we commenced our synthesis of 14 with the
preparation of terminal epoxide 17 (Scheme 3). For this, we
exploited Smith’s excellent Sharpless AD protocol on 1-
heptene3a,b to obtain the diol 19, which was shown to be of
80−84% ee by Mosher ester NMR analysis, a protocol that
concurrently confirmed the absolute configuration of 19. The
latter was then selectively O-tosylated to obtain 20, which was
converted through to 17 by treatment with NaH in Et2O. Due
to the high volatility of this epoxide, it was generally found best
to use it crude for the subsequent epoxide ring-opening step
with the lithium acetylide−EDTA complex in THF/HMPA,
which provided the volatile homopropargylic alcohol 21 in 64%
yield for the two steps. Compound 21 was thereafter protected
with PMB-trichloroacetimidate, and the alkyne 15 was used for
a Carreira asymmetric alkynylation with the β-aldehydo ester
16.1 The latter reaction proceeded cleanly and with high
stereocontrol to deliver 14 as essentially a single, diastereomeri-
cally pure, compound in 79% yield after SiO2 flash
chromatography, which removed the minor diastereomer that
inevitably arose from the use of an alkyne of 80−84% ee.
Mosher ester analysis of the (R)- and (S)-MTPA acid esters
confirmed the absolute stereochemistry of the newly induced
asymmetric center, showing it to be fully in accord with the
predictions of the Carreira stereochemical model,7 so
reinforcing the earlier work done on (+)-inthomycin C.1 The
propargylic alcohol 14 was thereafter subjected to O-directed
oxidation would subsequently provide 8. Carreira asymmetric
alkynylation7 between 15 and 16 and Marshall asymmetric
allenylzinc addition8 between aldehyde 13 and the O-mesylate
128b were thereafter envisioned for the obtention of 11.
Initially we decided to carry out a model study to help
establish whether the alkynol 14 would undergo O-directed free
radical hydrostannation with Ph3SnH and catalytic Et3B/O2
with good regio- and stereocontrol. I−Sn exchange and Stille
cross-coupling were subsequently envisaged for securing 25
(Scheme 3). Success in this endeavor would not only give us a
good indication of whether our proposed double O-directed
free radical hydrostannation strategy would be likely to create
10 stereoselectively but also provide us with a viable synthetic
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free radical hydrostannation with Ph3SnH and catalytic Et3B/
O2 in PhMe for 7 h 40 min;4a,5 it provided the (Z)-configured
vinyltriphenylstannane 22, which smoothly engaged in I−Sn
exchange4b,9 to give 23 in 84% yield. While it proved difficult to
estimate the precise level of stereo- and regiocontrol that had
manifested itself in the hydrostannation step by NMR, due to
22 giving rise to rotamers,10 following I−Sn exchange with N-
iodosuccinimide (NIS) in CH2Cl2,4b the regio- and stereo-
control could be seen to be near total. Again, very minor
rotameric equilibria were evident for 23. However, unlike with
22, the effects were now not sufficiently severe to prevent a
reliable stereochemical estimate of hydrostannation perform-
ance. Following O-silylation, 24 was subjected to the Baldwin−
Lee CsF/CuI variant of the Stille cross-coupling conditions
with Me4Sn,11 which successfully converted it into 25 in 61%
yield, albeit, after the reactants had been heated in DMF at 60
°C for the rather lengthy period of 15 days! It will be noted that
24 and 25 both had identical mobilities on TLC, which made
reaction progress extremely difficult to monitor. Nevertheless,
after multielution TLC, 24 and 25 could be distinguished by
their differing colors upon staining with anisaldehyde/H2SO4
stain. In our experience, TLC behavior of this sort is quite
common for this type of Stille coupling, and we now alert the
community to this fact.
Scheme 4. Our Conformationally Restricted O-Directed
Double Free Radical Hydrostannation Route to the C(7)−
C(22) Sector of (+)-Acutiphycin
With the viability of the aforementioned chemistry
established, we now embarked on the double O-directed
hydrostannation strategy that we had retrosynthetically mapped
out in Scheme 2. This initially entailed us O-silylating alcohol
14 (Scheme 4), reducing the O-silylated ester to the alcohol 26
and oxidizing the latter to the aldehyde 13 with iodosobenzene
diacetate and TEMPO.12 This set up a Pd(0)-mediated
Marshall allenylzinc addition8 for the obtention of 27. Although
two products were invariably formed in this process, 27 always
predominated. The reaction also never usually reached
completion, but it did come quite close on a number of
occasions. Following SiO2 flash chromatography, 27 could
typically be isolated pure in 51% yield, alongside a 7% yield of
the diastereomeric C(11)-alcohol epimer. The O-silylated ether
27 was next treated with TBAF to obtain the 1,3-diol 28, which
was O-acetalated. O-Depivaloylation subsequently afforded the
propargylic alcohol 11 in 84% overall yield for the three steps.
Alkynol 11 underwent double O-directed free radical hydro-
stannation over 14 h to give the bisvinylstannane 10 as the
primary reaction product in 84% yield. Once more, accurate
evaluation of the level of diastereoselectivity that had
manifested itself at this stage was thwarted by the existence
of a complex rotameric equilibrium induced by the combined
presence of the hydroxymethyl and Ph3Sn subunits. Our
attempts at implementing the I−Sn exchange reaction on 10
also gave rise to problems. Nevertheless, after O-silylation, I−
Sn exchange could eventually be accomplished on 29 with
NIS4b in MeCN, in the presence of 2,6-lutidine13 and catalytic
hydroquinone. It gave rise to the desired bis-vinyl iodide 9 as
essentially a single compound in 40% yield, which suggested
that the hydrostannation event had proceeded with very high
regio- and stereocontrol, as is now customary for these
reactions.5,9 Another set of highly useful I−Sn exchange
conditions that we identified utilized NIS/I2/2,6-lutidine and
DMAP in MeCN/CH2Cl2 at 35−40 °C to bring about the
same transformation. The conversion of 29 into 9 is by far the
most complex I−Sn exchange ever performed on a vinyltri-
phenylstannane substrate, and the 30−40% yield of 9 that was
obtained by both methods essentially translates to a 55−63%
yield for each respective vinylstannane I−Sn cleavage step,
which is not bad at all when one considers the high degree of
steric hindrance around both alkenes in the bis-vinyltriphenyl-
stannane 29, a factor which, in this rather unusual instance,
required multiple phenyl groups to be cleaved from around the
central Sn-atoms, to allow the desired electrophilic cleavages of
the vinyl-Sn bonds to proceed satisfactorily to produce 9. This
requirement to cleave multiple more sterically accessible Ph−Sn
bonds before vinyl iodide formation could occur almost
certainly accounted for why such a large excess of the N-
iodosuccinimide/2,6-lutidine or the NIS/I2/2,6-lutidine/
DMAP was needed to bring about this overall conversion.
Our study of this reaction also highlighted the critical role
played by 2,6-lutidine (and DMAP) in bringing these
proceedings to a successful conclusion. In this regard, I2
alone in CH2Cl2 caused extensive decomposition when applied
on 29, an outcome that contrasted sharply with the many
successful I−Sn exchanges that we4b,9 and others14 have
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Letter
performed on less hindered vinyltriphenylstannane substrates.
Possibly, I2 alone cleaves the syn-1,3-acetal without the lutidine
or DMAP present.
ACKNOWLEDGMENTS
■
We thank QUB for studentships (M.M. and M.G.), the
Government of India for a Boyscast Postdoctoral Fellowship
(A.K.), and the ACS and QUB for additional financial support
of our work.
All of these issues notwithstanding, the fact that this I−Sn
exchange could eventually be accomplished allowed us to
investigate the double Stille cross-coupling of vinyl diiodide 9
with Me4Sn. Fortunately, this reaction proceeded successfully
when it was conducted under the Baldwin−Lee conditions11
with CuI, catalytic (Ph3P)4Pd, and CsF as additives in DMF at
60 °C over 24 h. The bis-olefin 30, so formed, was produced in
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plished with commercial TBAF in THF to give the alcohol 31.
Oxidation of 31 with MnO2 in CHCl3 subsequently completed
our pathway to the enal 8. Overall, these two transformations
proceeded in 52% combined yield. Efforts are currently
underway to use 8 to help us complete a new total synthesis
of (+)-acutiphycin, and further results will be reported as and
when additional progress is made.
However, of significance for now, the present work has
demonstrated, for the very first time, that it is possible to
perform a double O-directed free radical hydrostannation on a
nonsymmetric, bis-propargylically oxygenated, dialkyl-diyne to
predictably set two structurally distinct trisubstituted vinyltri-
phenylstannanes within the same molecule, with very high
stereo- and regiocontrol. We have also shown the viability of
doing two-directional I−Sn exchange and double Stille cross-
coupling in complex highly crowded systems that possess acid-
sensitive functionality. We have additionally revealed the
occasional need to cleave off multiple more sterically accessible
phenyl groups from a Ph3Sn moiety, in order to effect an I−Sn
exchange in a vinyltriphenylstannane where the constituent
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expanded the synthetic utility of the O-directed free radical
hydrostannation reaction with Ph3SnH/cat. Et3B. We have also
laid down important markers for the future application of this
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effective acetal-tethering tactic for preventing deleterious
stereocenter-compromising 1,5-H-atom abstraction events
from destroying the chirality present within acyclic vinyl-
stannane products. Clearly, by applying the Ph3SnH/cat. Et3B
O-directed alkyne free radical hydrostannation process on
highly challenging target molecules such as (+)-acutiphycin and
(+)-inthomycin C,1 we have gained new strategic insights into
how to deploy this powerful and mechanistically complex5
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ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental procedures and copies of the H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
(14) Micoine, K.; Persich, P.; Llaveria, J.; Lam, M.-H.; Maderna, A.;
Loganzo, F.; Furstner, A. Chem.Eur. J. 2013, 19, 7370.
̈
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: k.j.hale@qub.ac.uk.
Notes
The authors declare no competing financial interest.
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