Asymmetric total synthesis of (+)-inthomycin C via O-directed free radical alkyne hydrostannation with Ph3SnH and catalytic Et3B: Reinstatement of the zeeck-taylor (3 R)-Structure for (+)-Inthomycin C

Article abstract of DOI:10.1021/ol5000499

A new pathway to (+)-inthomycin C is reported that exploits an O-directed free radical hydrostannation reaction on (-)-12 and a Stille cross-coupling as key steps. Significantly, the latter process was effected on 19 where a gauche-pentane repulsive inter

Full text of DOI:10.1021/ol5000499

Letter
pubs.acs.org/OrgLett
Asymmetric Total Synthesis of (+)-Inthomycin C via O‑Directed Free
Radical Alkyne Hydrostannation with Ph3SnH and Catalytic Et3B:
Reinstatement of the Zeeck−Taylor (3R)‑Structure for (+)-Inthomycin
C
Karl J. Hale,* Milosz Grabski, Soraya Manaviazar, and Maciej Maczka
The School of Chemistry and 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
S
* Supporting Information
ABSTRACT: A new pathway to (+)-inthomycin C is reported that exploits an
O-directed free radical hydrostannation reaction on (−)-12 and a Stille cross-
coupling as key steps. Significantly, the latter process was effected on 19 where a
gauche-pentane repulsive interaction could interfere. Our stereochemical studies
on the alkynol (−)-12 and the enyne (+)-7 confirm that Ryu and Hatakeyama’s
(3S)-stereochemical revision of (+)-inthomycin C is invalid and that Zeeck and
Taylor’s original (3R)-stereostructure for (+)-inthomycin C is correct.
ome time ago, our group reported1 that propargylically
oxygenated dialkylacetylenes of general structure 1
(Scheme 1) typically undergo highly regio- and stereo-
dialkylacetylenes with Ph3SnH and catalytic Et3B has now
become a stereocontrolled olefination method of genuine
synthetic worth.1,3,4
S
As well as providing many sophisticated examples of
stereodefined trisubstituted olefin synthesis via this approach,1,3
we subsequently went on to employ it for a new and fully
stereocontrolled formal total synthesis of the frog alkaloid,
(+)-pumiliotoxin B,4 by a route which greatly improved and
shortened the original pathway5 to this molecule. Our
(+)-pumiliotoxin B paper4 also presented our expanded
thoughts on the highly complex mechanism6 of this novel
hydrostannation reaction, which is not a simple process by any
means,7 but one that operates through a complex radical
mechanism in which there are multiple competing Ph3Sn
radical addition/elimination and vinylstannane isomerization
events all occurring concurrently and cooperatively,6 with the
result that α-triphenylstannylated alkenes of general structure 2
eventually predominate over time.
As part of our group’s ongoing effort to further define the
synthetic scope and applications8 of this new olefination
method, we recently became interested in establishing its utility
for the creation of chiral trisubstituted allylic alcohols with a β-
quaternary carbon center; structural motifs that can be found in
the anticancer natural products (+)-inthomycin C9 and
(+)-acutiphycin10 (Figure 1). Of course, by employing the O-
directed free radical hydrostannation process to create such
systems, we naturally recognized that we would be forced to
confront the potentially troublesome cross-coupling of an
organometallic with an electronically unactivated (Z)-trisubsti-
Scheme 1. The O-Directed Free Radical Hydrostannation
Route to Trisubstituted Alkenes with Three C−C σ-Bonds
controlled O-directed free radical hydrostannation reactions
with Ph3SnH, catalytic Et3B, and O2 in PhMe at rt, to give
trisubstituted vinyltriphenylstannanes of general structure 2 in
good-to-excellent yield. Our work followed up on, and massively
augmented, a much earlier report by Willem and Gielen2 that 2-
methyl-3-pentyn-2-ol undergoes O-directed α-free radical
hydrostannation with Ph3SnH (1 equiv) and Et3B (1 equiv)
in dry PhMe at rt to provide (Z)-2-methyl-3-triphenylstannyl-3-
pentene-2-ol, as the sole reaction product in 67% yield.
Unfortunately, the latter workers never reported the successful
conversion of their vinyltriphenylstannane product into a
representative target alkene, and it was left to our group to
show that vinyltriphenylstannanes of this sort can efficiently be
transformed into target trisubstituted alkenes 4 by I−Sn
exchange and transition-metal-catalyzed cross-coupling.3 As a
consequence, the O-directed free radical hydrostannation of
Received: January 7, 2014
Published: February 6, 2014
© 2014 American Chemical Society
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Scheme 2. Our Retrosynthetic Planning for (3R)-
(+)-Inthomycin C
Figure 1. (+)-Inthomycin C and (+)-acutiphycin.
tuted vinyl iodide in which multiple gauche-pentane repulsive
interactions could potentially thwart the key oxidative addition
and reductive elimination steps, reactions for which no prior
literature precedent existed, as far as we could tell.
With this in mind, we now present a new and highly
successful application of the O-directed free radical alkyne
hydrostannation reaction with Ph3SnH and catalytic Et3B in
PhMe at rt1 in the total synthesis of (+)-inthomycin C; an
antineoplastic natural product first synthesized by Professor R.
J. K. Taylor and his team in 2008,11 and later resynthesized in
opposite enantiomeric form by Ryu12 and Hatakeyama,13 by
different routes. The latter workers appeared to find a
stereochemical flaw in the originally assigned (3R)-stereo-
structure for (+)-inthomycin C (the Zeeck−Taylor structure, as
we now term it), revising it to the (3S)-configurational
stereoisomer shown in Figure 1, but to us, this stereochemical
revision of Ryu12 and Hatakeyama13 looked potentially unsafe,
since neither team had unambiguously verified the absolute
stereochemistry of the chiral starting materials that they had
employed in their respective syntheses.
Our retrosynthetic analysis of the original Zeeck−Taylor
(3R)-stereoisomer for (+)-inthomycin C is outlined in Scheme
2. It was conceived around the observation that enynols such as
15 generally give rise to poor Z/E-selectivity in the O-directed
free radical hydrostannation reaction with Ph3SnH and catalytic
Et3B in PhMe at rt.6 This suggested that we would almost
certainly encounter extremely poor stereoselectivity in the
hydrostannation of 18 en route to diene (E)-9 (Scheme 2).
Given that we wished for (E)-9 to serve as an advanced
intermediate in our proposed route, we thus elected to prepare
it from the tosylate 10 by E2 elimination, accessing the latter
from the corresponding alcohol, which itself would be obtained
from the vinyltriphenylstannane 11. In turn, 11 would be
secured from the O-directed free radical hydrostannation of 12
with Ph3SnH/cat. Et3B/O2. We envisioned obtaining the
alkynol 12 by asymmetric alkynylation of 14 with alkyne 13,
using Carreira’s methodology.14 Diene (E)-9 would thereafter
be taken forward to Ryu’s claimed (3R)-dienylstannane 612 and
Hatakeyama’s postulated (3R)-enyne 713 to complete formal
and eventually full total syntheses of (+)-inthomycin C,
assuming that the Zeeck−Taylor absolute stereostructure was
indeed correct.
chemical outcome was as depicted, and in complete accord with
Carreira’s model.14 Specifically, the resonance from the
propargylic methylene of the (R)-MTPA ester derived from
(−)-12 was +0.0327 ppm (ca. 13.1 Hz) more shielded than that
for the corresponding (S)-MTPA ester in CDCl3 which,
according to the modified Mosher ester configurational
mnemonic of Riguera,15 was strongly indicative of (R)-absolute
stereochemistry for the C(3)-alcohol in 12 (see the Supporting
Information (SI)).
With the stereochemical integrity of 12 duly established, we
submitted it to our O-directed free radical hydrostannation
procedure, to obtain 11 as the major component of a 46:1
mixture of (Z/E)-α-stannylated geometric isomers in excellent
yield (95%). The purified vinylstannane 11 was subsequently
reacted with excess N-iodosuccinimide (5.0 equiv) in CH2Cl2
to give 19 in 86% yield with complete retention of olefin
geometry. Next, we examined whether 19 would undergo Stille
cross-coupling with Me4Sn successfully, and eventually we
found that it did, as long as Baldwin and Lee’s CsF/CuI-
promoted conditions16 were employed with catalytic Pd-
(PPh3)4 in DMF at 45 °C for 1 h. Following due optimization,
21 was eventually procured in 75% yield. Vinyl iodide 19 was
also transformed into the diene 20 in 61% yield, to show the
wider scope and applicability of the method.
Based upon Carreira’s stereochemical model for asymmetric
alkynylation,14 for which no violation has yet been reported, we
used Zn(OTf)2 (0.3 equiv), Et3N (0.93 equiv), and (−)-N-
methyl ephedrine (0.4 equiv) to mediate the reaction of 13
with 14 in PhMe at 60 °C, a process that took just over 2.5 days
to reach completion, and which cleanly led to the alkynol
(−)-12 in 82% yield and 83% ee (Scheme 3). The absolute
stereochemistry of (−)-12 was confirmed by Mosher ester
configurational analysis,15 which indicated that the stereo-
Returning now to the problem at hand, the hydroxyl group of
21 was next protected as a TBS-ether, and the pendant PMB
group was detached with DDQ. Initially 22 was O-tosylated
under standard conditions to obtain 10 in 79% yield. An E2
elimination was then attempted with KHMDS in THF at −78
°C, but this caused scrambling of the trisubstituted olefin
geometry, presumably due to the reaction being of the E1cb
manifold. Fortunately, this problem could soon be rectified by
performing the elimination on the iodide 23 with 1,8-
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reported by Ryu and co-workers for (−)-6,12 but clearly our
[α]D was of opposite sign and a much lower magnitude than
that recorded by Ryu and his team ([α]D −17.5° (c 0.12
CHCl3)12). Since our previous modified Mosher ester analysis
had supported the absolute stereochemical assignment that we
had made for the Carreira product 12, we concluded that (+)-6
must have (3R)-stereochemistry, which meant that we had
completed a formal total synthesis of the Zeeck−Taylor9a,11
stereostructure for (+)-inthomycin C. Ryu and co-workers had
clearly prepared the enantiomeric (3S)-stereostructure.
However, to help put things beyond any doubt at all, we
decided to examine Ryu’s reported CsF/CuI-mediated Stille
cross-coupling of vinyl iodide 5 with enantiomeric (+)-6
(Scheme 4).12
Scheme 3. Our Formal Synthesis of (+)-Inthomycin C that
Intersects with Ryu’s Claimed Dienylstannane 6 and the
Claimed Enyne 7 of Hatakeyama
Scheme 4. Our Reinvestigation of the Ryu Cross-coupling of
5 with (+)-6 and Our New Simplified Endgame for Securing
the Total Synthesis of (+)-Inthomycin C
While reasonably efficient in terms of chemical yield, it did
not proceed with complete stereocontrol (Scheme 4). Rather,
in our hands, it furnished a 5.9:1 mixture of triene
stereoisomers, in which the desired product 26 predominated;
the precise constitution of this other undesired triene
component has yet to be determined, but this loss of
stereocontrol was not mentioned by Ryu.12 Unfortunately, it
proved extremely difficult to separate this minor (but still
significant) stereoisomer from 26 by multielution preparative
TLC, without also encountering prohibitive reductions in yield.
Indeed, our very best efforts at doing this only managed to
produce 26 as the major component of a 17.1:1 mixture with
considerable material sacrifice (see the SI for this set of NMR
spectra). So, initially, in order to be able to go forward with a
satisfactory amount of material, we decided to proceed with a
partially separated sample that consisted of approximately a 9:1
mixture of isomers. This was subjected to ester hydrolysis with
aqueous LiOH in THF, and the resulting acid was transformed
into 27, whose purity could be further enriched to 9.7:1 in favor
of 27 by preparative TLC. Upon treatment with dry NH3 in
THF, the latter was then very smoothly converted into a 9.7:1
mixture of (+)-inthomycin C and another isomer (see the SI
for our NMR spectra). Unfortunately, because of the high
chemical instability of the inthomycins (a fact already
documented by Whiting in his elegant route to ( )-inthomycin
A19), we found that our purified mixture of (+)-inthomycin C
and this isomeric triene contaminent (ca. 9.7:1) decomposed
within several weeks of storage in the refrigerator under N2,
before we had the opportunity to record its [α]D value!
diazabicycloundec-7-ene (DBU) (3 equiv) in PhMe at 45 °C
for 3 h. Under these conditions, the classical E2-elimination
proceeded cleanly to give the desired (E)-diene 9 exclusively in
95% yield.
Because of the significant steric bulk of the TBS-protecting
group, it proved possible to perform a very clean and highly
regioselective dihydroxylation on (E)-9 with Sharpless’ AD-
mix-β reagent.17 It afforded a mixture of stereoisomers 24, from
which the TBS-group could be successfully removed. There-
after, the resulting triol had its terminal diol cleaved with
aqueous NaIO4 in THF to produce the stereodefined enal 8 in
84% yield. A Hodgson vinylstannation18 was next performed on
8 to secure Ryu’s claimed advanced intermediate 6, whose [α]D
value was found to be +5.3° (c 1.11 in CHCl3). Significantly,
the NMR spectral values for (+)-6 correlated well with those
We therefore repeated the Ryu coupling12 of 5 with (+)-6 to
reobtain the 5.9:1 mixture enriched in 26 (see the SI), and
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without separation (to avoid material losses), we duly took this
forward through the same reaction sequence in the hope that
purification could be effected at the end, by SiO2 flash
chromatography. Unfortunately, it could not, and the [α]D
value that we obtained for the 5.9:1 mixture of (+)-inthomycin
C, contaminated with this inseparable stereoisomeric triene
component, was −8.4° (c 1.0 CHCl3 [Lit. for (+)-inthomycin C
+ 20% tetramethylurea = +25.9° (c 0.27 CHCl3) (Taylor11);
Lit. for pure (−)-inthomycin C reports an [α]D = −34.33° (c
0.1 CHCl3) (Ryu12) and an [α]D = −41.5° (c 0.1 CHCl3)
(Hatakeyama13)]. We attribute the low negative [α]D value
observed for our final (3R)-(+)-inthomycin C sample to the
deleterious presence of this other unidentified triene
component, which arises from use of the Ryu cross-coupling
method.12
ACKNOWLEDGMENTS
We thank QUB and the ACS for financial support.
■
REFERENCES
■
(1) Dimopoulos, P.; Athlan, A.; Manaviazar, S.; George, J.; Walters,
M.; Lazarides, L.; Aliev, A. E.; Hale, K. J. Org. Lett. 2005, 7, 5369.
(2) Willem, R.; Delmotte, A.; De Borger, I.; Biesemans, M.; Gielen,
M.; Kayser, F. J. Organomet. Chem. 1994, 480, 255.
(3) Dimopoulos, P.; Athlan, A.; Manaviazar, S.; Hale, K. J. Org. Lett.
2005, 7, 5373.
(4) Manaviazar, S.; Hale, K. J.; LeFranc, A. Tetrahedron Lett. 2011,
52, 2080.
(5) Lin, N.-H.; Overman, L. E.; Rabinowitz, M. H.; Robinson, L. A.;
Sharp, M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118, 9062.
(6) Dimopoulos, P.; George, J.; Tocher, D. A.; Manaviazar, S.; Hale,
K. J. Org. Lett. 2005, 7, 5377.
Given all of these difficulties and possible ambiguities, we
decided to convert diol 24 into Hatakeyama’s claimed
(−)-inthomycin C intermediate, (−)-713 (see Scheme 3), to
complete an alternate formal total synthesis,20 and although we
did observe an excellent spectral match with the NMR data
quoted by Hatakeyama,13 we found that the optical rotation of
our sample of 7 (prepared in 80−86% ee) was of opposite sign
([α]D = +12.6° (c 0.71 CHCl3)) to the value quoted by
Hatakeyama in his paper for a molecule of allegedly the same
(3R)-absolute stereochemistry [Lit. [α]D = −15.09° (c 1.04
CHCl3)13]. We therefore prepared the (R)- and (S)-MTPA
esters of (+)-7 and used the modified Mosher method15 to
independently confirm our (3R)-absolute stereochemical
assignment (see the SI for more information). The combined
[α]D data for (+)-6 and (+)-7, and our unambiguous
determination of their (3R)-absolute configurations, have
therefore led us to conclude that Hatakeyama13 and Ryu12
must have synthesized (−)-inthomycin C with (3S)-stereo-
chemistry, rather than the (3R)-stereochemistry that they
claimed. Zeeck and Taylor’s original assignment9,11 of (3R)-
stereochemistry for (+)-inthomycin C is therefore correct, and
Taylor’s total synthesis does indeed deliver the (+)-(3R)-
stereostructure as he reported.
Clearly, our new total synthesis of (+)-inthomycin C has
furnished valuable new Mosher ester and optical rotation
evidence that reinstates the originally formulated Zeeck−Taylor
(3R)-stereostructure9 for (+)-inthomycin C and Taylor’s total
synthesis. Our work has also proven the great synthetic worth
of the O-directed free radical hydrostannation process with
Ph3SnH and catalytic Et3B in PhMe for the synthetic
construction of challenging chiral trisubstituted allylic alcohol
motifs possessing a β-geminal dimethyl substituent. Further
work in this direction, in the context of a future projected
(+)-acutiphycin total synthesis, will be reported in the paper
that follows.
(7) Oderinde, M. S.; Organ, M. G. Chem.Eur. J. 2013, 19, 2615.
(8) For Furstner’s spectacular application of the O-directed
̈
hydrostannation method with Ph3SnH during his elegant total
synthesis of isomigrastatin, see: Micoine, K.; Persich, P.; Llaveria, J.;
Lam, M.-H.; Maderna, A.; Loganzo, F.; Furstner, A. Chem.Eur. J.
̈
2013, 19, 7370. Significantly, the cycloalkyne I gave rise to near
enough a single hydrostannation product with Ph3SnH that readily
underwent retentive I/SnPh3 exchange with 1.2 equiv of I2 in CH2Cl2
(0 °C to rt) over 1 h to provide the iodoolefin II:
(9) (a) Inthomycin, C.; Henkel, T.; Zeeck, A. Liebigs Ann. Chem.
1991, 367. (b) For the first inthomycin ((+)-phthoxazolin/
(+)-inthomycin A) to be discovered, see: Omura, S.; Tanaka, Y.;
Kanaya, I.; Shinose, M.; Takahashi, Y. J. Antibiot. 1990, 43, 1034.
(10) Barchi, J. J.; Moore, R. E.; Patterson, G. M. L. J. Am. Chem. Soc.
1984, 106, 8193.
(11) Webb, M. R.; Addie, M. S.; Crawforth, C. M.; Dale, J. W.;
Franci, X.; Pizzonero, M.; Donald, C.; Taylor, R. J. K. Tetrahedron
2008, 64, 4778.
(12) Senapati, B. K.; Gao, L.; Lee, S. I.; Hwang, G.-S.; Ryu, D. H. Org.
Lett. 2010, 12, 5088.
(13) Yoshino, M.; Eto, K.; Takahashi, K.; Ishihara, J.; Hatakeyama, S.
Org. Biomol. Chem. 2012, 10, 8164.
(14) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806. (b) Boyall, D.; Lopez, F.; Sasaki, H.; Frantz, D. E.;
Carreira, E. M. Org. Lett. 2000, 2, 4233. (c) Boyall, D.; Frantz, D. E.;
Carreira, E. M. Org. Lett. 2002, 4, 2605.
(15) (a) Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104,
17. (b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(16) (a) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Angew. Chem., Int. Ed.
2004, 43, 1132. (b) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem.
Soc. 1999, 121, 7600.
(17) (a) Andrus, M. B.; Lepore, S. D.; Sclafani, J. A. Tetrahedron Lett.
1997, 38, 4043. (b) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispino, G. A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.;
Wang, Z. M. J. Org. Chem. 1992, 57, 2768.
(18) Hodgson, D. M.; Foley, A. M.; Boulton, L. T.; Lovell, P. J.;
Maw, G. N. J. Chem. Soc., Perkin Trans. 1 1999, 2911.
(19) For Whiting’s landmark route to ( )-inthomycin A, see: Henaff,
N.; Whiting, A. Org. Lett. 1999, 1, 1137.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, NMR, IR, and mass spectra can be
found in the Supporting Information. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(20) For a recent elegant ( )-inthomycin C formal total synthesis,
see: Souris, C.; Ferbault, F.; Patel, A.; Audisio, D.; Houk, K. N.;
Maulide, N. Org. Lett. 2013, 15, 3242.
*E-mail: k.j.hale@qub.ac.uk.
Notes
The authors declare no competing financial interest.
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