Atom-Economical Dimerization Strategy by the Rhodium-Catalyzed Addition of Carboxylic Acids to Allenes: Protecting-Group-Free Synthesis of Clavosolide A and Late-Stage Modification

Article abstract of DOI:10.1002/anie.201506618

Natural products of polyketide origin with a high level of symmetry, in particular C₂-symmetric diolides as a special macrolactone-based product class, often possess a broad spectrum of biological activity. An efficient route to this important

Full text of DOI:10.1002/anie.201506618

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International Edition: DOI: 10.1002/anie.201506618
German Edition: DOI: 10.1002/ange.201506618
Natural Products Synthesis
Atom-Economical Dimerization Strategy by the Rhodium-Catalyzed
Addition of Carboxylic Acids to Allenes: Protecting-Group-Free
Synthesis of Clavosolide A and Late-Stage Modification
Alexander M. Haydl and Bernhard Breit*
Abstract: Natural products of polyketide origin with a high
level of symmetry, in particular C2-symmetric diolides as
a special macrolactone-based product class, often possess
a broad spectrum of biological activity. An efficient route to
this important structural motif was developed as part of
a concise and highly convergent synthesis of clavosolide A.
This strategy features an atom-economic “head-to-tail” dime-
rization by the stereoselective rhodium-catalyzed addition of
carboxylic acids to terminal allenes with the simultaneous
construction of two new stereocenters. The excellent efficiency
and selectivity with which the C2-symmetric core structures
were obtained are remarkable considering the outcome under
classical dimerization conditions. Furthermore, this approach
facilitates late-stage modification and provides ready access to
potential new lead structures.
generate branched allylic esters.[13] When we attempted to
extend this methodology to the synthesis of lactones and
macrolactones (in particular, medium-sized lactones) by an
intramolecular addition of carboxylic acids to alkynes, the
“head-to-tail” dimerization product was formed exclusive-
ly.[10b]
To investigate the synthesis of diolides in combination
with the previous findings on the enantioselective addition of
carboxylic acids to terminal allenes,[9] we chose the C2-
symmetric target clavosolide A (1; Scheme 1).[14] The clavo-
solide family and its closely related analogue cyanolide A[15]
N
aturally occurring dimers of polyketide origin have
attracted much attention in the last two decades.[1,2] Aside
from a high level of symmetry, impressive biological activity
can be found in many carbacyclic[1] and oxacyclic[2] dimeric
natural products. In particular, oxacyclic dimers, also known
as diolides, are considered to be a special macrolactone-based
product class and exhibit a broad spectrum of biological
activity,[3] such as immunosuppressive,[4a–c] antipsoriatic,[4d]
antibiotic,[4e–g] anti-HIV,[4h] and various other properties.[4i,j]
Strategic approaches for the construction of such sym-
metrical core structures, besides the classical dimerization
conditions by anhydride-type activation of the seco acid,[5]
have been demonstrated in a number of formal and total
syntheses, including a one-pot double Mitsunobu reaction,[6a]
double transesterification,[6b] double Sakurai allylation,[6c]
double Suzuki cross-coupling,[6d] and alkyne metathesis.[6e]
However, general drawbacks of these reactions with regard
to atom economy are either the requirement of a stoichio-
metric amount of a reagent for the activation of the
monomers, thus leading to the generation of a stoichiometric
amount of waste, or the need for preinstalled stereocenters in
the molecule prior to dimerization. Our research group
recently developed a rhodium-catalyzed[7] atom-economical
and regioselective addition[8] of carboxylic acids to allenes[9]
and alkynes,[10] a method which could be seen as an alternative
to metal-catalyzed allylic substitution[11] and oxidation[12] to
Scheme 1. The polyketides clavosolide A and cyanolide A as examples
of natural products with a C2-symmetric dimeric scaffold.
have garnered significant attention from organic chemists
owing to their high level of molecular complexity; thus,
a large number of formal and total syntheses have been
described in recent years.[16,17] Herein, we report a novel and
highly convergent total synthesis of clavosolide A and various
late-stage modifications in the absence of protecting groups
and premetalated C-nucleophiles. The desired product was
formed in less than half the number of steps required in any
previous approaches by a direct atom-economical diastereo-
selective dimerization strategy for the construction of its 16-
membered macrolide skeleton.
Given the C2-symmetrical dimeric macrodiolide structure
(Scheme 2), we envisioned that a “head-to-tail” addition of
the w-allenyl-substituted carboxylic acid 4 might provide
straightforward access to scaffold 3 with the selective
generation of two of its 22 stereocenters. The proposed
rhodium-catalyzed diastereoselective dimerization is a novel
combination of two methodologies recently described by our
research group.[9a,10b] At the same time, the interim structure 3
should bring a valuable allylester moiety into reach, which
could then be further elaborated either by double cross-
metathesis[18] with (Z)-butene and double stereoselective
Simmons–Smith cyclopropanation[19] for the synthesis of the
targeted natural product 1 or by other late-stage modifica-
tions with only little extra synthetic effort. Our synthetic plan
[*] A. M. Haydl, Prof. Dr. B. Breit
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506618.
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Scheme 3. Synthesis of the tetrasubstituted-pyran precursors. Cited
yields are those of the single diastereomers after silica-gel chromatog-
raphy. Reagents and conditions: a) 6b, 7, pTsOH·H2O (10 mol%),
ꢀ
CH2Cl2, room temperature, 90% (>99% ee); b) HC CCO2Me, quinu-
clidine, TFA, CH2Cl2, 08C then room temperature (d.r. 87:13);
c) K2CO3, MeOH, room temperature, 71% (2 steps); d) LiOH·H2O,
THF/H2O/MeOH (2:1:1), room temperature, 96%; e) 9, MeOTf, MS
(4 Š), Et2O, room temperature, 64% (d.r. 77:23); f) LiOH·H2O, THF/
H2O/MeOH (2:1:1), room temperature, 94%. MS=molecular sieves,
TFA=trifluoroacetic acid, Tf =trifluoromethanesulfonyl, pTs =p-tolue-
nesulfonyl.
Scheme 2. Retrosynthetic disconnection of clavosolide A on the basis
À
of a diastereoselective C O bond-forming addition of carboxylic acids
to allenes as the key step.
for the synthesis of the key fragment 4, either glycosylated or
devoid of any sugar residue, from chiral homoallylic alcohol 5
involved an elegant cascading oxa-Michael/Prins-type cycli-
zation reaction previously described by Willis and co-work-
ers.[20] In any case, this strategic approach to efficiently deliver
symmetrical subunits of polyketide natural products is
considered to be of more general interest, since it shows
enormous potential for late-stage modification by diverted
total synthesis, thus enabling great possibilities for further
biological screening.[21]
methyl triflate.[28] The resulting glycosylated ester 10 was
obtained as a separable 3:1 mixture of diastereomers in favor
of the b anomer. Compound 10 was saponified to give the
corresponding glycosylated w-allenyl-substituted carboxylic
acid 11, which served as one of four substrates for subsequent
investigations on the rhodium-catalyzed addition of carbox-
ylic acids to allenes.
Following on from prior studies,[9] we carried out initial
reactivity assays with 8 and benzoic acid in the presence of
[{Rh(cod)Cl}2] (5.0 mol%) and (R,R)-diop (10 mol%) in
DCE at room temperature (Table 1). We were pleased to
discover that the reaction proceeded well with 8 bearing an
unprotected hydroxy functionality in terms of yield, albeit
with only moderate diastereoselectivity (d.r. 63:37; Table 1,
entry 1). The feasibility of benzoic acid as a benchmark acidic
nucleophile encouraged us to screen a variety of conditions.
To our delight, when the reaction temperature was lowered
and Cs2CO3 (10 mol%) was added (Table 1, entries 2 and 3),
increased diastereoselectivity was observed. However the
drop in reactivity led to incomplete conversion and therefore
a lower yield (62%). Finally, the reaction time was extended,
and complete conversion was observed after 96 h (Table 1,
entry 4). To demonstrate the synthetic utility of the method,
the reaction was performed on a larger scale furnishing 1.43 g
of 12 (79% yield) with good diastereoselectivity (d.r. 93:7;
Table 1, entry 5). Under the optimized reaction conditions,
even 10 bearing a sugar residue attached to the hydroxy group
present in 8 reacted to give 14 in good yield with only slightly
diminished diastereoselectivity (Table 1, entry 7).[29]
Our synthesis proceeded from the menthone-based
Nokami crotyl-transfer reagent[22] 6a by treatment with the
known homoallenyl aldehyde 7[23] (Scheme 3), which could be
readily prepared in multigram quantities in two steps.[24] The
resulting chiral homoallylic alcohol 5 was obtained in good
yield (86%) but with only 72% ee. When we increased the
steric bulk of the chiral transfer agent by introducing a tert-
butyl substituent to create 6b, we obtained 5 in good yield
(90%) with remarkable enantioselectivity (> 99% ee).[25]
A
one-pot oxa-Michael/Prins-type cyclization according to the
method developed by Willis and co-workers[16a,b] then fur-
nished the tetrasubstituted pyran 8 in satisfying yield as
a separable 7:1 mixture of diastereomers. Compound 8 served
as the entry point for the preparation of the precursors 4, 10,
À
and 11 required for the rhodium-catalyzed C O bond-
forming addition of carboxylic acids to allenes, and was
saponified to give the corresponding aglyconic carboxylic acid
4. At this point, the required absolute and relative config-
uration could be confirmed by single-crystal X-ray analysis,
which was in agreement with previous conformation analysis
by NOE experiments on 8.[24] Next, we moved on for the
preparation of the glycosylated carboxylic acid 11. Classic
glycosylation conditions developed by Schmidt and co-work-
ers[26] and used in previous syntheses of clavosolide A and
cyanolide A proved to be incompatible with 8, thus resulting
in a complex product mixture. To circumvent this issue, we
treated 8 with phenyl thioglycoside 9[27] in the presence of
On the basis of these results, we expanded the strategic
approach to investigate the “head-to-tail” dimerization
reaction of the w-allenyl-substituted carboxylic acids 4 and
11 (Table 2). Adapted reaction conditions proved successful
for the transformation of aglycone 4 on a small scale (Table 2,
entry 1). Thus, diolide 15 was obtained exclusively in good
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Table 1: Diastereoselective rhodium-catalyzed addition of benzoic acid
to the terminal allenes 8 and 10.[a]
yield (82%) with extraordinarily high diastereoselectivity
(d.r. > 95:5) in the absence of protecting groups. On a gram
scale, the homodimerization reaction also furnished 15 in
good yield (75%) with excellent diastereoselectivity (d.r.
> 95:5; Table 2, entry 2). Gratifyingly, after this step, purifi-
cation was possible by a single recrystallization of the crude
product without the aid of column chromatography and
provided single crystals for determination of the relative and
absolute configuration by X-ray crystallographic analysis
(Table 2). Subsequent treatment of 15 after catalysis under
previous described glycosidation conditions led to a mixture
of anomers in 85% yield in favor of the b,b-anomeric diolide 3
(d.r. 50:33:17). We further extended the scope of the reaction
to the more complex w-allenyl-substituted carboxylic acid 11
and were pleased to find good reactivity in terms of diolide
formation: Compound 3 was obtained both in good yield
(72%) and with satisfactory diastereoselectivity (d.r. 92:8;
Table 2, entry 4).
Entry
Substrate[b]
Additive
t
Yield [%][c]
d.r.[d]
1[e]
2
3
8 (12)
8 (12)
8 (12)
8 (12)
8 (12)
8 (12)
10 (14)
–
–
18
18
18
96
96
96
96
97
50
62
95
79
94
63
63:37
80:20
95:5
95:5
93:7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
4
5[f]
6[g]
7
For the further synthesis of clavosolide A (1), very little
was known about the proposed conversion of the intermedi-
ate structure 3 by cross-metathesis with either propene or (Z)-
butene to give the corresponding double homologated olefin,
although it seemed to be straightforward (Scheme 4).[30,31]
Instead, approaches involving more than one step, such as
10:90
89:11
[a] General reaction conditions: allene (0.6 mmol), benzoic acid
(0.5 mmol), DCE (5.0 mL), 08C. [b] The corresponding product is
indicated in parenthesis. [c] Yield of the isolated product. [d] The
diastereomeric ratio was determined by 1H NMR spectroscopy of the
crude reaction mixture. The relative configuration was determined by
conversion into 3 (see the Supporting Information for further details).
[e] The reaction was performed at room temperature. [f] Reaction
conditions: allene (6.0 mmol), benzoic acid (5.0 mmol), Cs2CO3
(10 mol%), [{Rh(cod)Cl}2] (5.0 mol%), (R,R)-diop (10 mol%), DCE
(50 mL), 08C, 96 h. [g] The reaction was performed with (S,S)-diop
(10 mol%). Bz=benzoyl, cod=1,5-cyclooctadiene, DCE=1,2-dichloro-
ethane.
À
C C bond-cleaving ozonolysis or Lemieux–Johnson oxida-
tion followed by an olefination reaction, prevail in the
literature.[32] Gratifyingly, double cross-metathesis under
solvent-free conditions in (Z)-butene with the Grubbs II
catalyst furnished a 5:1 mixture of the desired E,E product in
good yield. Subjection of the latter to Simmons–Smith
cyclopropanation conditions,[33] as reported for previous
syntheses,[16a,b] finally led to clavosolide A (1) in only eight
steps from 6b. The synthetic clavosolide A exhibited spectral
properties identical in all respects to those reported for the
natural product.[14] Furthermore, its relative and absolute
configuration could be confirmed by single-crystal X-ray
analysis.
Table 2: Diastereoselective rhodium-catalyzed “head-to-tail” dimeriza-
tion of the W-allenyl-substituted carboxylic acids 4 and 11.
To emphasize the flexibility made possible in late-stage
synthesis by our chosen approach, we subjected 3 to assorted
transformations to generate structural derivatives of clavoso-
lide A (Scheme 4). Double hydroformylation of the terminal
double bonds with our self-assembled ligand 6-diphenylphos-
phanylpyridone (6-DPPon) furnished 16 in high yield and
with high regioselectivity.[34] C1 cleavage by ozonolysis gave 17
in 78% yield.[35] Furthermore, the double bond could readily
be defunctionalized to give the cyanolide A analogue sub-
structure 18.[36]
Entry
Substrate
Product
Yield [%][b]
d.r.[c]
In summary, we have developed a highly atom-econom-
ical diastereoselective rhodium-catalyzed direct homodime-
rization strategy involving the construction of two new
stereocenters in just one step. This methodology proved to
be highly functional-group-tolerant and resulted in a concise
total synthesis of clavosolide A in only eight steps in the
absence of protecting groups and premetalated C-nucleo-
philes. Our synthetic results provide an intriguing glimpse of
how such an approach can be used for the synthesis of
complex polyketide natural products and opens up new routes
to a selection of structural analogues for potential biological
investigations. Further studies towards the generalization of
1[d]
2[e]
3[f]
4[g]
4
4
4
11
15
15
15
3
82
75
80
72
>95:5
>95:5
18:82
92:8
[a] Glycosidation after catalysis: 9, MeOTf, MS (4 Š), Et2O, room
temperature, 85% (43% yield for the b,b-anomer). [b] Yield of the
diastereomeric mixture isolated after silica-gel chromatography. [c] The
diastereomeric ratio was determined by 1H NMR spectroscopy of the
crude reaction mixture. [d] The reaction was performed with 0.5 mmol of
the allene. [e] The reaction was performed with 6.6 mmol of the allene.
[f] The reaction was performed with (S,S)-diop (10 mol%). [g] The
reaction was performed with 0.37 mmol of the allene.
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Scheme 4. Transformation of the core structure 3 into clavosolide A and late-stage
structure modification to give other potentially active derivatives. Reagents and
conditions: a) Grubbs II catalyst (30 mol%) neat in (Z)-2-butene, À788C then 408C,
89% (83:17 E,E/Z,E); b) ICH2Cl, Et2Zn, CH2Cl2, 0!158C, 63%; c) [{Rh(CO)2acac}]
(1.5 mol%), 6-DPPon (30 mol%), CO/H2 (1:1, 20 bar), toluene, 808C, 81% (9:1 l,l/l,b);
d) O3; NaBH4, CH2Cl2/MeOH (2:1), À788C then room temperature, 78%; e) Pd/C
(10 mol%), H2 (1 atm), MeOH, room temperature, 99%. acac=acetylacetonate.
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This research was supported by the DFG and the Interna-
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Reactions for Organic Synthesis” (IRTG 1038). We thank
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Keywords: allenes · allylic compounds · natural products ·
rhodium · total synthesis
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Revised: October 19, 2015
Published online: November 10, 2015
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