Hydroxyl-Assisted Carbonylation of Alkenyltin Derivatives: Development and Application to a Formal Synthesis of Tubelactomicin A

Article abstract of DOI:10.1021/acs.orglett.6b01431

Alkenyltin derivatives flanked by a hydroxyl group are subject to methoxycarbonylation when treated with catalytic amounts of Pd(OAc)₂ and Ph₃As in MeOH under a CO atmosphere; key to success is the use of 1,4-benzoquinone as a stoich

Full text of DOI:10.1021/acs.orglett.6b01431

Letter
pubs.acs.org/OrgLett
Hydroxyl-Assisted Carbonylation of Alkenyltin Derivatives:
Development and Application to a Formal Synthesis of
Tubelactomicin A
Heiko Sommer and Alois Furstner*
̈
Max-Planck-Institut fur Kohlenforschung, 45470 Mulheim/Ruhr, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Alkenyltin derivatives flanked by a hydroxyl group
are subject to methoxycarbonylation when treated with catalytic
amounts of Pd(OAc)2 and Ph3As in MeOH under a CO
atmosphere; key to success is the use of 1,4-benzoquinone as a
stoichiometric oxidant in combination with trifluoroacetic acid as
a cocatalyst. The acid lowers the LUMO of the quinone and likely
marshals the critical assembly of the substrates. Under the
optimized conditions, competing proto-destannation is marginal; the method proved compatible with various (acid sensitive)
functional groups and was applied to a short formal total synthesis of the antibiotic tubelactomicin A.
ecent work from this laboratory has shown that the
hydrostannation of propargyl alcohol derivatives A with
Therefore, we turned our attention to a possible alkoxy-
carbonylation of alkenylstannanes of type C. While carbon-
ylative Stille reactions with formation of ketones are well-
known in the literature,7 carbonylations with formation of
carboxylic acid derivatives are exceedingly rare. The few
recorded examples did not look overly promising either:8
while some robust aryltin derivatives of type Ar4Sn could be
converted into the corresponding acid derivatives ArCOOH in
modest yields, electron-rich substrates led to exclusive proto-
destannation; the more common ArSnBu3 derivatives solely
afforded symmetrical ketones.8 Moreover, the literature
procedure uses CuCl2 as an (over)stoichiometric oxidant,
which is known to convert compounds of type C into the
corresponding alkenyl chlorides.5,9 Taken together, it seemed
unlikely that this method applies to the projected case.
R
Bu3SnH catalyzed by [Cp*RuCl]4 or [Cp*RuCl2]n is
distinguished by remarkable levels of regio- and stereocontrol
(Scheme 1).1,2 The reaction follows an unusual trans-addition
mode and faithfully delivers the tin residue to the proximal C
atom of the reacting triple bond.1 Experimental evidence
suggests that this rewarding outcome originates from hydrogen
bonding between the polarized [Ru−Cl] unit and the −OH
group that locks the substrate within the coordination sphere of
the catalyst, while an interligand interaction between the
chloride and the incoming stannane predisposes the
nucleophile for hydride delivery at the distal position;1 in so
doing, a loaded complex of type B evolves most likely via
ruthenacyclopropene intermediates B′ into the unorthodox
trans-addition product C.1,3
The resulting structural motif C is highly useful, given the
many opportunities that a C−Sn bond provides.4 In a first
foray, we explored cross-coupling with MeI, proto-destanna-
tion, or chloride-for-tin exchange; these reactions gave ready
access to the antibiotic 5,6-dihydrocineromycin and synthetic
analogues thereof.5 Another potentially rewarding option is the
conversion of C into trisubstituted enoates of type D, which are
prevalent in nature (Scheme 1).
Although a two-step procedure comprising a tin/iodide
exchange followed by carbonylation of the resulting alkenyl
iodide allows products D to be reached, a direct methoxy-
carbonylation of C was deemed more attractive. Attempts at
reducing this plan to practice, however, by reacting the model
substrate 1 with methyl chloroformate under Stille conditions6
were disappointing. Premature precipitation of palladium black
and hence incomplete conversions, partial disproportionation
of the chloroformate, and competing O-acylation and proto-
destannation of the substrate were troublesome; even allene
formation was observed in some runs.
In the search for viable alternatives, we turned our attention
to a recent report on the alkoxycarbonylation of arylboro-
nates.10 This procedure seemed attractive, as it employs
catalytic Pd(OAc)2/PPh3 in combination with 1,4-benzoqui-
none as the oxidant and proceeds under essentially neutral
conditions in MeOH (or other unhindered alcohols) as the
solvent. Surprisingly though, all attempts at applying this
method to stannane 1 failed completely, even at higher
temperature (Table 1, entry 1). An extensive ligand screening
did not improve the situation by much: although the use of
11
AsPh3 afforded small amounts of the desired product 2 (R =
Me), the conversion remained invariably poor (entries 2, 3).
Since borane derivatives analogous to 1 amenable to
carbonylation under the literature conditions10 are currently
not available by directed trans-hydroboration,12 it was
imperative to understand why alkenylstannanes are reluctant
or even inert. We conjectured that the reoxidation of the Pd0
Received: May 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01431
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Scheme 1. Hydroxyl-Directed trans-Hydrostannation of
Propargyl Alcohols Followed by Methoxycarbonylation;
Representative Natural Products Featuring a Motif of Type
D or an Immediate Derivative Thereof; • = CMe
Scheme 2. (Top) Methoxycarbonylation of an
Organometallic Substrate; (bottom) Rationale for the
Privileged Reactivity of Arylboronates and Mechanistic
Hypothesis How an Acid Cocatalyst Might Enhance the
Reactivity of Stannanes Bearing Protic Functional Groups
organic residue to be transferred. Since organotin derivatives
lack a similarly low-lying empty orbital, they are incapable of
engaging in a similar assembly and are therefore obviously
handicapped.
This shortcoming might be rectified by an acid cocatalyst,
provided it does not lead to competing proto-destannation. It is
tempting to speculate that a carboxylic acid would not only
facilitate the necessary reoxidation of Pd0 but also might play a
more intricate role when working with substrates of type C:
one can conceive a hydrogen bonding network of type G that
fosters oxidative transmetalation by lowering the LUMO of the
quinone, while ensuring the proximity of the reaction partners
at the same time. The high affinity of palladium to the π-
systems of the partners might partly compensate the entropic
cost associated with this assembly, which mimics the proposed
transition state E in the boron series.10
Table 1. Optimization of the Reaction Conditions for the
Methoxycarbonylation of Stannane 1
a
To test this hypothesis, our efforts focused on the use of
b
entry
ligand (mol %)
TFA (mol %)
temp (°C)
1:2:3 (NMR)
trifluoroacetic acid (TFA) as a cocatalyst, which Backvall and
̈
1
2
3
4
5
6
7
Ph3P (12.5)
Ph3As (12.5)
Ph3As (12.5)
Ph3As (10)
Ph3As (10)
Ph3As (10)
Ph3As (5)
−
−
−
20
50
40
40
70
70
20
20
20
20
20
n.r.
co-workers had previously found to be a suitable partner for the
Pd/quinone pair.13,14 Indeed, addition of substoichiometric
amounts of TFA boosted the methoxycarbonylation of
compound 1. A careful screening showed that the use of 40
mol % of TFA was optimal (Table 1, entry 6): lower
concentrations led to incomplete conversions, while higher
amounts resulted in substantial proto-destannation. Under
these conditions, the reaction proved robust and scalable; even
rather acid-sensitive functional groups passed uncompromised
(Table 2). Not only were acetals, tert-alcohols, various silyl
ethers, esters, and a nitrile found stable, but also two otherwise
very sensitive, doubly allylic derivatives reacted without incident
to give the corresponding products 7 and 8 in high yield. The
data also show that the directing hydroxyl group can be
primary, secondary, or tertiary, without much change in the
efficiency of the reaction. The compatibility with unprotected
hydroxyl groups is a distinct advantage over cross-coupling with
chloroformates15 and a desirable attribute in the quest for
target-oriented syntheses that proceed with a minimum of
protecting group manipulations. Particularly noteworthy is the
compatibility of the method with an alkenyl bromide, which is
prone to carbonylation in the presence of Pd0; the fact that this
group remained intact in product 10 suggests that reoxidation
to PdII by the 1,4-benzoquinone/TFA couple is fast enough to
outperform oxidative addition of Pd0 into the C−Br bond.
61:39:0
84:16:0
50:50
0:83:17
0:100:0
14:86:0
a
All reactions were performed with Pd(OAc)2 (5 mol %) and 1,4-
benzoquinone (1.5 equiv) under CO (1 atm) in MeOH. Product
b
1
distribution in the crude material as determined by H NMR.
formed in the first turn of the catalytic cycle might be the
culprit (Scheme 2). It has been shown in the past that
protonation of the quinone carbonyl group is mandatory to
ensure conversion of a [Pd0·quinone] adduct into catalytically
active PdII and hydroquinone.13 Under the premise that only a
proton-coupled electron transfer ensures efficient catalyst
turnover, it seems reasonable that a Lewis acidic boron reagent
has an inherent advantage over an organotin compound. By
virtue of the empty p-orbital at boron, spontaneous
coordination of MeOH used as the solvent will ensue;10 the
formation of an adduct of type E increases the Bronsted acidity
of the alcohol and hence assists the crucial regeneration of PdII
via protonation of the quinone (Scheme 2); at the same time,
adduct formation will enhance the nucleophilicity of the
B
DOI: 10.1021/acs.orglett.6b01431
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various types of mycobacteria, including several drug-resistant
strains.17−19
Table 2. Scope of the Methoxycarbonylation of
Alkenylstannanes Flanked by Hydroxyl Groups
a
One of the reported total syntheses assembles the target
from the decalin building block 17 and the acyclic derivative 16,
which was prepared in 25 steps starting from methyl lactate
(Figure 1).18a,19 We saw an opportunity to streamline the route
Figure 1. Retrosynthetic analysis of the antibiotic tubelactomicin A
reported in ref 18a.
to this particular fragment with the aid of the new method. To
this end, commercial epoxide (R)-18 was opened with lithiated
1-butyne, and the resulting product was subjected to the alkyne
zipper reaction to shift the triple bond to the terminus (Scheme
3).20 Standard O-silylation followed by C-acylation of 19 with
Scheme 3. Formal Total Synthesis of Tubelactomicin A
a
Unless stated otherwise, all reactions were carried out with Pd(OAc)2
(5 mol %), Ph3As (10 mol %), TFA (40 mol %), and 1,4-
b
benzoquinone (1.5 equiv) in MeOH under CO (1 atm) at 20 °C. At
45 °C.
Macrolide 12, formed by methoxycarbonylation, is an analogue
of 5,6-dihydrocineromycin B and hence extends the small
library of non-natural analogues of this antibiotic previously
made by late-stage modification of the very same advanced
organotin intermediate.5 The ready formation of product 13
proves that homoallylic tin derivatives are carbonylated with
spontaneous formation of a densely functionalized α-
alkylidene-γ-butyrolactone ring, a substructure found in a
myriad of bioactive natural products. The generality of this
transformation, however, needs to be explored in more detail,
since an analogous stannane with a terminal CC bond failed
to afford compound 14.
Of mechanistic interest is the fact that the protection of the
−OH group in the model substrate 1 as MOM acetal or TBS
ether did not allow the methoxycarbonylation to proceed (see
products 2b,c). Likewise, alkenylstannanes devoid of an allylic
−OH group do not behave well but rather get decomposed.
Therefore, it is reasonable to assume that the acid additive does
not merely assist the reoxidation of the catalyst but likely
marshals the reaction partners via hydrogen bonding and, in so
doing, assists the surmised proton shuttle in the decisive step of
the catalytic cycle.16
The significance of the new method is further illustrated by
an application to the formal total synthesis of (+)-tubelacto-
micin A.17 This macrolide antibiotic has attracted considerable
attention in the past for its unique and challenging structure as
well as for its potent and specific antimicrobial activities against
methyl chloroformate gave the corresponding ester, which was
subjected to a Claisen condensation to give compound 20 in
high overall yield. A kinetic dynamic resolution under transfer
hydrogenation conditions using complex 21 as a precatalyst
worked well on scale to form the syn-aldol motif of 22 with
excellent diastereoselectivity (dr >20:1).21 Reduction of the
ester set the stage for the key trans-hydrostannation catalyzed
C
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Letter
by [Cp*RuCl2]n:1 as expected, the directing effect of the free
−OH group flanking the triple bond in 23 could be harnessed,
and product 24 be isolated as a single regio- and stereoisomer
in 88% yield on a >3 g scale.
(5) Rummelt, S. M.; Preindl, J.; Sommer, H.; Furstner, A. Angew.
Chem., Int. Ed. 2015, 54, 6241.
̈
(6) (a) Balas, L.; Jousseaume, B.; Shin, H.; Verlhac, J.-B.; Wallian, F.
Organometallics 1991, 10, 366. (b) Jousseaume, B.; Kwon, H.; Verlhac,
J.-B.; Denat, F.; Dubac, J. Synlett 1993, 1993, 117. (c) Dixon, S.;
Gordon, G. J.; Whitby, R. J. Chem. Commun. 2005, 4303. (d) Fujiwara,
S.; Cadou, R.; Yamaoka, Y.; Takasu, K.; Yamada, K. Eur. J. Org. Chem.
2015, 2015, 1264.
(7) (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
50, 1. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4442.
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Jpn. 2001, 74, 1343. (b) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5546.
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Lett. 1991, 32, 6563.
The methoxycarbonylation of the silyl ether derived from 24
also proceeded nicely to furnish the required trisubstituted
enoate 25 in good yield. In order to exactly match fragment 16
previously used in the literature,18,19 25 had to be elaborated in
a stepwise manner, which proceeded uneventfully, including the
final Takai-type olefination with formation of the terminal
alkenylstannane moiety.22,23 With only 14 steps, this approach
to compound 16 is considerably shorter than the existing route
(25 steps)18a,19 and relies on the power of homogeneous
catalysis in its key steps. We like to emphasize that the
sequence could be shortened by several more steps if one were
to accept a slightly different protecting group pattern, which
would, almost certainly, also allow tubelactomicin A to be
reached in the end.
In any case, we are confident that the conceptually new and
exceedingly mild approach to trisubstituted enoates described
herein based on a hydroxyl-directed trans-hydrostannation
followed by methoxycarbonylation is highly enabling, in view of
the many natural products that comprise this particular
structural element or a derivative thereof.24 Further efforts to
showcase this notion will be disclosed in due course.
(10) Yamamoto, Y. Adv. Synth. Catal. 2010, 352, 478.
(11) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(12) Hydroxyl-directed trans-hydroboration of propargyl alcohol
derivatives is currently not possible because pinacol borane reacts
faster with the −OH group than with the triple bond; for trans-
hydroboration of other internal alkynes, see: Sundararaju, B.; Furstner,
̈
A. Angew. Chem., Int. Ed. 2013, 52, 14050.
(13) (a) Grennberg, H.; Gogoll, A.; Backvall, J.-E. Organometallics
̈
1993, 12, 1790. (b) For pioneering work on the use of a Pd/1,4-
benzoquinone couple, see: Hegedus, L. S.; McKearin. J. Am. Chem. Soc.
1982, 104, 2444.
(14) (a) Deng, Y.; Persson, A. K. Å.; Backvall, J.-E. Chem. - Eur. J.
̈
2012, 18, 11498. (b) Backvall, J.-E. Acc. Chem. Res. 1983, 16, 335.
̈
ASSOCIATED CONTENT
* Supporting Information
(15) The synthesis described in ref 6c shows that a lateral sec-OH
group has to be protected prior to the cross-coupling of an
alkenylstannane moiety with methyl chloroformate.
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01431.
(16) Alternatively, one might assume that the −OH group of the
substrate reacts with [L2Pd(tfa)2] to give a transient complex of type
[L2Pd(tfa)(O−CHR−C(SnBu3)CHR)], which undergoes an intra-
molecular palladium-for-tin exchange via a four-membered transition
state; control experiments with overstoichiometric Pd(tfa)2 and Ph3As
in the absence of 1,4-benzoquinone render this explanation unlikely:
the reactions were messy and led to rapid palladium precipitation;
protodestannation largely prevailed over carbonylation.
(17) (a) Igarashi, M.; Hayashi, C.; Homma, Y.; Hattori, S.; Kinoshita,
N.; Hamada, M.; Takeuchi, T. J. Antibiot. 2000, 53, 1096. (b) Igarashi,
M.; Nakamura, H.; Naganawa, J.; Takeuchi, T. J. Antibiot. 2000, 53,
1102.
Experimental procedures, compound characterization
data and copies of spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: fuerstner@kofo.mpg.de.
Notes
(18) (a) Sawamura, K.; Yoshida, K.; Suzuki, A.; Motozaki, T.;
Kozawa, I.; Hayamizu, T.; Munakata, R.; Takao, K.; Tadano, K. J. Org.
Chem. 2007, 72, 6143. (b) Anzo, T.; Suzuki, A.; Sawamura, K.;
Motozaki, T.; Hatta, M.; Takao, K.; Tadano, K. Tetrahedron Lett. 2007,
48, 8442. (c) Hosokawa, S.; Seki, M.; Fukuda, H.; Tatsuta, K.
Tetrahedron Lett. 2006, 47, 2439.
(19) Motozaki, T.; Sawamura, K.; Suzuki, A.; Yoshida, K.; Ueki, T.;
Ohara, A.; Munakata, R.; Takao, K.; Tadano, K. Org. Lett. 2005, 7,
2265.
(20) (a) Wu, Y.; Gao, J. Org. Lett. 2008, 10, 1533. (b) Brown, C. A.;
Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891.
(21) (a) Fang, Z.; Wills, M. J. Org. Chem. 2013, 78, 8594. (b) Hayes,
A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2005,
127, 7318.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by the MPG is gratefully acknow-
ledged. We thank the Analytical Departments of our Institute
for excellent support.
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