A Method for the Late-Stage Formation of Ketones, Acyloins, and Aldols from Alkenylstannanes: Application to the Total Synthesis of Paecilonic Acid A

Article abstract of DOI:10.1002/anie.201701391

Treatment of alkenylstannanes with Cu(OAc)₂/Et₃N affords the corresponding enol esters or ketones under conditions that proved compatible with many common functionalities; these include groups that would neither survive under the sta

Full text of DOI:10.1002/anie.201701391

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201701391
German Edition: DOI: 10.1002/ange.201701391
Natural Product Synthesis
A Method for the Late-Stage Formation of Ketones, Acyloins, and
Aldols from Alkenylstannanes: Application to the Total Synthesis of
Paecilonic Acid A
Heiko Sommer+, James Y. Hamilton+, and Alois Fꢀrstner*
Abstract: Treatment of alkenylstannanes with Cu(OAc)2/Et3N
affords the corresponding enol esters or ketones under
conditions that proved compatible with many common func-
tionalities; these include groups that would neither survive
under the standard Tamao–Fleming conditions for the oxida-
forming an alkenylstannane of type D as the predominant
isomer. Experimental and computational evidence shows that
this pattern is innately linked to the dual role played by the
ꢀ
polarized [Ru Cl] unit of the catalyst, which serves as
ꢀ
hydrogen bond acceptor for the OH group of substrate A
tion of Csp2 SiR3 bonds nor under the conditions commonly
and, at the same time, steers the incoming R3SnH reagent.[2,6]
These concurrent interactions impose directionality onto the
coordination sphere of the loaded catalyst B and the derived
metallacyclopropene C, which translates into high levels of
selectivity. Although the directing effect gets weaker upon
increasing the distance between the hydroxy group and the
triple bond, it remains appreciable in the conversion of
homopropargylic alcohol F to the corresponding stannane
G.[1,2]
ꢀ
ꢀ
used to oxidize C B bonds. Chiral centers adjacent to the
unveiled carbonyls are not racemized and competing proto-
destannation is marginal, even if the substrate carries unpro-
ꢀ
tected OH groups as internal proton sources. Therefore, the
procedure is well suited for the preparation of acyloin and
aldol derivatives. These enabling virtues are illustrated by
a concise approach to the bicyclic lipid paecilonic acid A.
H
ydrostannation of propargyl alcohols A catalyzed by
The resulting structural motifs D and G provide ample
ꢀ
[Cp*RuCl]4 is distinguished by excellent levels of regio- and
stereocontrol as well as by an exquisite functional group
compatibility (Scheme 1).[1,2] The reaction follows an unusual
trans-addition mode[3–5] and faithfully delivers the tin moiety
to the C-atom of the alkyne proximal to the hydroxy group,
opportunity for downstream functionalization of the C Sn
bond. Ideally, any such method should be compatible with the
ꢀ
OH group in the vicinity, which cannot be taken for granted
since protodestannation is usually facile.[1,7] To this end, our
group has recently developed conditions that allow substrates
of type D to be engaged in Stille-type coupling with MeI,[8]
methoxycarbonylation,[9] or fluoro-destannation reactions.[10]
Conversion of the alkenylstannane entity in D or G to the
corresponding carbonyl is yet another possibility. Attractive
ꢀ
methods for the oxidation of C Sn bonds, however, are
basically unknown, certainly if one expects compatibility with
other functionality and/or additional sites of unsatura-
tion.[11–14] Even the more widely exercised oxidation of C B
ꢀ
ꢀ
and C Si bonds, despite its preparative value, shows only
a limited functional group tolerance.[11,15–19] Rather than
searching for an oxidant with an adequate profile, we
conjectured that formal cross-coupling of the alkenyltin
entity with an appropriate O-nucleophile might be a better
way of securing the desirable orthogonality. Inspiration came
from the formation of ether and ester derivatives by copper-
mediated reactions of organoboron derivatives with different
O-nucleophiles (Chan–Lam–Evans coupling).[20,21] Although
the current mechanistic understanding of this transformation
suggests that organotin compounds also qualify as starting
materials,[22] the few reported examples met with only limited
success. Whereas the somewhat exotic compound Ph3SnCl
was reported to react well with excess phenol in the presence
of Cu(OAc)2 and Et3N as the solvent,[23] the more common
substrates of type ArSnBu3 gave the expected diarylethers in
modest yields, even when they were used in (large)
Scheme 1. Directed trans-hydrostannation/oxidation sequence;
*
denotes a CMe unit.
[*] Dr. H. Sommer,[+] Dr. J. Y. Hamilton,[+] Prof. Dr. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
[+] These authors contributed equally to this work.
excess.[24,25] Likewise, C N bond formation required two
ꢀ
equivalents of ArSnMe3 (rather than the less toxic ArSnBu3)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201701391.
for high conversion.[26]
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All attempts at extending the conditions described in the
literature[23,24] to the model substrate 1[2] using 4-(tert-butyl)-
phenol as nucleophile failed to afford enol ether 4 (Table 1).
Interestingly though, a-acetoxy ketone 2 was present in the
mixture, but alkene 3 prevailed (entry 1). When following up
on this lead, we found that the use of Cu(OAc)2 (2 equiv) and
Et3N (5 equiv)[27] in reagent grade DMSO[28] at slightly
elevated temperature allowed the competing proto-destan-
nation to be curtailed; under these conditions, product 2 was
isolated in 76% yield on a 2.5 mmol scale (entry 4).
Table 1: Attempted coupling of stannane 1 with 4-(tert-butyl)phenol
opened a gateway to O-acylated acyloin derivatives.
Figure 1. Assortment of acyloin derivatives prepared by copper carb-
oxylate-mediated reaction of alkenylstannanes of type D. Unless stated
otherwise, all reactions were performed with Cu(OAc)2 (2 equiv) and
Et3N (5 equiv) in DMSO at 45–508C. [a] Using Cu(tfa)2 (2 equiv)/
NaOBz (4 equiv). [b] No erosion of the optical purity (ee) was
detected. [c] Using Cu(OAc)2 (4 equiv)/Et3N (10 equiv); TBS=tert-
butyldimethylsilyl; tfa=trifluoroacetate.
Entry Cu(OAc)2
(equiv)
Additive
(equiv)
Solvent[a]
T
Conv.[b] 2:3[b]
zation was detected for the diastereomerically pure macrolide
15 (for further examples, see Scheme 2, Scheme 3 and
Scheme 5). For its evident mildness, the new method repre-
sents a serious alternative to the well-established procedures
1
1
tBuC6H4OH CH2Cl2
(2)
–
–
–
RT
78%
42:58
2
3
4
2
2
2
CH2Cl2
DMSO
DMSO
RT
RT
95%
96%
54:46
74:26
ꢀ
for the oxidation of Csp2 M bonds mentioned above, partic-
458C quant. 89:11
ularly when more elaborate compounds have to be addressed.
The procedure is not limited to a-hydroxy-alkenylstan-
nanes of type D leading to acyloin derivatives as products
(Scheme 2). Substrates 16 and 18 devoid of an unprotected
(76%)[c]
[a] All reactions were performed in the presence of Et3N (5 equiv) at
0.125m concentration. [b] Conversion determined by 1H NMR. [c] Iso-
lated yield of analytically pure 2.
ꢀ
allylic OH group afforded the corresponding ketones 17 and
19, respectively, upon treatment with Cu(tfa)2 under other-
wise identical conditions. Likewise, a sequence of hydroxy-
directed trans-hydrostannation of homopropargyl alcohols F
followed by reaction of the resulting b-hydroxylated stan-
An assortment of alkenylstannanes reacted well under
these conditions to give the corresponding acyloin derivatives,
whether they were flanked by primary, secondary, or tertiary
alcohols (Figure 1). The benzoate derivative 8 illustrates the
possibility of directly introducing an ester group other than
acetyl by replacing Cu(OAc)2 with Cu(tfa)2/NaOBz. As
expected, different substituents were tolerated, including
ethers, esters, acetals, chloride, nitrile, and phthalimide. While
the hydroxy groups adjacent to the reacting stannane were
ꢀ
acylated in all cases investigated, remote OH substituents
remained unchanged. Most noteworthy, however, is the
compatibility with functional groups that would not subsist
under the conditions commonly used in Tamao–Fleming
oxidations (HBF4/mCPBA or H2O2/KF/KHCO3): this holds
true for the primary silyl ether in 10, which is endangered in
acidic as well as in fluoride-containing basic medium but
survived under the conditions reported herein. Likewise,
substrates comprising additional sites of unsaturation fall into
this category: while a trisubstituted alkene precludes the use
of mCPBA, an enoate is incompatible with H2O2/KF/KHCO3;
compounds 14 and 15 exemplify that either type of olefin
remained untouched under the present conditions. Moreover,
the ee of an optically active stannane was fully preserved in
the resulting O-acylated hydroxyketone 13, and no epimeri-
Scheme 2. a) Cu(tfa)2 (2 equiv), Et3N (5 equiv), DMSO, 458C, 68%
(17), 70% (19); b) Cu(OAc)2 (2 equiv), Et3N (5 equiv), DMSO, 458C,
57% (21), 59% (23); MOM=methoxymethyl.
2
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variotii living as symbiont in
the inner tissues of the jelly-
fish Nemopilema nomurai.[31]
The challenge of forming the
signature bicyclic core of 34 is
basically reduced to installing
the C12 hydroxy group in 35
by an asymmetric alkynyla-
tion of aldehyde 36; a subse-
quent
trans-hydrostannation
hydroxy-directed
fol-
lowed by oxidation/acetaliza-
tion should open a concise
entry to this interesting
target.[32] Its conquest by syn-
thetic means is important
since the material isolated
from the natural source did
not suffice even for a prelimi-
nary biological evaluation.
Our synthesis started
from the commercial enal
38, which was subjected to
an organocatalytic reaction
cascade resulting in trans-
dihydroxylation/acetaliza-
Scheme 3. a) Bu3SnH, [Cp*RuCl]4 (1.5 mol%), 54% (25), 79% (29); b) Cu(OAc)2 (2 equiv), Et3N (5 equiv),
DMSO, 458C, 58% (26), 65% (30); c) pyridinium-p-toluenesulfonate, wet benzene, 67% (27), 68% (31); d)
Cu(OAc)2 (2 equiv), Et3N (5 equiv), DMSO, 458C, 82% (33), 74% (5); PMB=para-methoxybenzyl.
nanes G with Cu(OAc)2/Et3N provides access to aldol
products H (Scheme 1). This possibility is exemplified by
compounds 21 and 23, although the isolated yields were
moderate.
Another opportunity is shown in Scheme 3, where stan-
ꢀ
nanes 25 and 29, flanked by two OH groups each, furnished
oxetanes 26 and 30, respectively. These transformations show
that an entropically favored intramolecular trapping of the
transient organocopper intermediate can outperform the
coupling with ligated acetate. Oxetanes of this type are
exceedingly rare, since the sensitivity of the exocyclic enol
ether in combination with the high ring strain renders their
preparation difficult;[29] this is particularly true for 30 bearing
an oxidation-prone PMB-ether as well as a highly acid-
sensitive dimethyl acetal. Controlled hydrolysis[30] gave the
corresponding aldols 27 and 31 in good yields. Further studies
into this largely untapped chemotype are underway.
Scheme 4. Retrosynthetic analysis of paecilonic acid A.
A comparison between the reactions of stannane 32a
(R = H) and the corresponding methyl ether 32b (R = Me) is
informative in mechanistic terms (Scheme 3): the fact that
32b provided enol ester 33 as the only product proves that the
reaction is in fact a cross-coupling process, likely involving an
organocopper species of type I as the key reactive intermedi-
ate. Whether O-acetyl acyloin 5 derived from 32a is formed
by transesterification once an enol ester analogous to 33 has
formed or the acyl migration already occurs in the ligand
sphere of [Cu] prior to reductive coupling, as tentatively
shown in J, remains to be firmly established.
tion, which provided product 40 on scale as a single diaste-
reomer with an excellent ee of 97% (Scheme 5).[33] Benzyla-
tion of the alcohols followed by unmasking of the aldehyde
set the stage for chain extension. Though seemingly routine,
=
a standard Wittig reaction of 41 with Ph3P CHCHO led to
either poor conversion or decomposition when more forcing
conditions were applied. The problem was solved by a two-
carbon homologation method based on the transmetalation of
tris(ethoxyvinyl)borane 42 with Et2Zn followed by addition
of the resulting organozinc reagent to aldehyde 41;[34] hydro-
lytic work-up gave enal 43 in 74% yield over two steps.
Chemoselective reduction of the double bond[35] preceded an
The first total synthesis of paecilonic acid A (34) illus-
trates some of the virtues of the new method (Scheme 4). This
unusual fatty acid was isolated from the fungus Paecilomyces
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bonds, including the classi-
cal Tamao–Fleming proto-
col. As it brings enol
esters, ketones, acyloins,
aldols, and even oxetane
derivatives into the reach,
our method is expected to
be
advanced organic synthe-
sis at large. concise
serviceable
for
A
approach to the unusual
fungal metabolite paeci-
lonic acid A bears witness
of this notion, and further
applications to more elab-
orate targets are currently
underway.
Scheme 5. a) (i) 39 (2.5 mol%, Ar=3,5-(F3C)2C6H3-), aq. H2O2, CH2Cl2; (ii) NaOMe, MeOH, 59%, 97% ee.
b) NaH, BnBr, DMF, 08C!RT, 90%. c) Trifluoroacetic acid, CH2Cl2/H2O; d) 42, ZnEt2, toluene, ꢀ788C!RT,
then HCl, 74% (over two steps). e) Et3SiH, Pd/C (1 mol%), aq. H2SO4 (5 mol%), THF, 64%. f) Methyl 10-
undecynoate (37, R=Me), Zn(OTf)2, (ꢀ)-N-methylephedrine, Et3N, 75%. g) Bu3SnH, [Cp*RuCl2]n (2.5 mol%),
CH2Cl2, 83%. h) Cu(OAc)2, Et3N, DMSO, 708C, 77%. i) H2 (1 atm), Pd/C (10 mol%), THF, HCl, 83%. j) eq.
NaOH, MeOH/THF, 95%; Bn=benzyl; TMS=trimethylsilyl.
Acknowledgements
Generous financial sup-
port by the Swiss National
Science Foundation (fel-
lowship to J.Y.H.) and the
MPG
are
gratefully
asymmetric alkynylation under Carreira conditions, which
furnished propargyl alcohol 35 as a single diastereomer.[36]
In the next step, the newly formed secondary alcohol of 35
served as the steering substituent for the ruthenium catalyzed
trans-hydrostannation, which gave stannane 44 as the only
product in high yield. We were pleased to learn that the
subsequent unmasking of acyloin 45 upon treatment of 44
with Cu(OAc)2/Et3N worked well on a > 2 g scale, even
though the reaction temperature had to be raised to 708C. As
expected, no sign of epimerization of the chiral center next to
the unveiled carbonyl was observed. Importantly, the con-
acknowledged. We thank our analytical departments for
expert support.
Conflict of interest
The authors declare no conflict of interest.
Keywords: copper · cross-coupling · natural products ·
synthesis · tin oxidation
ꢀ
current acetylation of the OH group ensures orthogonality
to the benzyl ethers and hence streamlines the final steps.
Specifically, hydrogenolysis of 45 followed by addition of HCl
forged the 6,8-dioxabicyclo[3.2.1.]octane core of the target as
a single isomer in 83% yield over both steps. To complete the
total synthesis, it sufficed to treat compound 46 with aqueous
NaOH in THF/MeOH to cleave the acetate off and saponify
the methyl ester. The spectral data of synthetic paecilonic
acid A (34) matched those of the natural product very well.[31]
Our sample is a colorless material, whereas the authentic
compound was described as a brown solid, which may explain
the disparity in the amplitude of optical rotation between
synthetic and natural 34. With several hundred milligrams of
this peculiar fatty acid obtained in a single run, a detailed
biochemical and biological evaluation is no longer a matter of
material supply.
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nanes with copper(II) carboxylates affords the corresponding
carbonyl derivatives under conditions that ensure compati-
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¯
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Manuscript received: February 8, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Natural Product Synthesis
H. Sommer, J. Y. Hamilton,
A. Fꢁrstner*
&&&& — &&&&
A Method for the Late-Stage Formation of
Ketones, Acyloins, and Aldols from
Alkenylstannanes: Application to the
Total Synthesis of Paecilonic Acid A
Take (it) off: Treatment of alkenylstan-
nanes with Cu(OAc)2/Et3N affords
ketones, acyloins, aldols, and enol deriv-
atives under conditions that proved
compatible with many common func-
tionalities; these include groups that
would neither survive under the standard
Tamao–Fleming conditions for the oxida-
ꢀ
tion of Csp2 SiR3 bonds nor under the
ꢀ
conditions commonly used to oxidize C
B bonds. These virtues are illustrated by
a concise approach to the bicyclic lipid
paecilonic acid A.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!