Synthesis of bicyclic proline derivatives by the aza-Cope-Mannich reaction: Formal synthesis of (±)-acetylaranotin

Article abstract of DOI:10.1002/chem.201405811

Herein we suggest an approach to oxygenated bicyclic amino acids based on an aza-Cope-Mannich rearrangement. Seven distinct amino acid scaffolds analogous to the natural products were prepared on a gram scale with precise control of stereochemistry. Successful implementation of our strategy resulted in the formal synthesis of acetylaranotin.

Full text of DOI:10.1002/chem.201405811

DOI: 10.1002/chem.201405811
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&
Organic Synthesis
Synthesis of Bicyclic Proline Derivatives by the Aza-Cope–Mannich
Reaction: Formal Synthesis of (ꢀ)-Acetylaranotin
Dmitry S. Belov,*[a, b] Nina K. Ratmanova,[a] Ivan A. Andreev,[a] and Alexander V. Kurkin*[a, b]
Dedicated to Maria Andreeva on the occasion of her 13th birthday
Abstract: Herein we suggest an approach to oxygenated
bicyclic amino acids based on an aza-Cope–Mannich re-
arrangement. Seven distinct amino acid scaffolds analogous
to the natural products were prepared on a gram scale with
precise control of stereochemistry. Successful implementa-
tion of our strategy resulted in the formal synthesis of
acetylaranotin.
Introduction
Oxygenated bicyclic amino acids constitute an important class
of secondary metabolites. Many of these nonproteinogenic
amino acids[1] are subunits of structurally diverse natural prod-
ucts (Figures 1 and 2).[2,3] Epidithiodiketopiperazines (ETPs) and
Figure 2. Natural products with oxygenation at 5 and 5’-positions.
stimulated numerous synthetic efforts toward compounds 3–8.
Total syntheses of epicoccin G, 8,8’-epi-ent-rostratin B, and
related ETPs were reported by the Nicolaou group.[5] Brꢀse
reported a unified synthetic strategy toward diketopiperazine
cores, present in all of these natural products.[6] Recently, the
groups of Reisman[7] and Tokuyama[8] completed total
syntheses of acetylaranotin. The work in this area stimulated
the development of various synthetic methods, such as
sulfenylation[9] of 2,5-diketopiperazines, syntheses of bicyclic
amino acids,[10] and preparation of diketopiperazines.[11] More-
over, successful efforts were taken to find biologically active
analogues of these natural products.[5b,12]
Figure 1. Natural products derived from oxygenated bicyclic amino acids.
bis(methylthio)diketopiperazines with oxygenation at the C5
and C5’-positions and the cis-fused ring junction, which are
represented by four groups of natural products (epicoccins,
epicorazines, rostratins, and brocazines), deserve additional at-
tention (Figure 2).[3] The intriguing structural features of these
fungal metabolites together with their antiviral, antibacterial,
antiallergic, antimalarial, and cytotoxic properties[3,4] have
We began planning the synthesis of the above-mentioned
scaffolds with the retrosynthetic simplification of compounds
4–8 to the less-oxidized[13] C2-symmetric diketopiperazine inter-
mediate 9 (Scheme 1), which in turn could arise from the
dimerization of 10. It was envisioned that stereoselective for-
mation of cis-fused bicyclic amino acid 10 could be achieved
by the aza-Cope–Mannich reaction.[14] The requisite building
block 11 could in turn be obtained by diastereoselective
Grignard addition to a suitably protected a-amino ketone 12.
Although the preparation of proline derivatives by the aza-
Cope–Mannich reaction is known in the literature,[15] no such
chemical transformation has ever been applied to derivatives
[a] Dr. D. S. Belov, N. K. Ratmanova, I. A. Andreev, Dr. A. V. Kurkin
Lomonosov Moscow State University, Department of Chemistry
1/3 Leninskie Gory, Moscow, 119991 (Russia)
E-mail: kurkin@direction.chem.msu.ru
dimonmsuchem@mail.ru
Homepage: www.chem.msu.ru
[b] Dr. D. S. Belov, Dr. A. V. Kurkin
EDASA Scientific srls., Via Stingi, 37, 66050 San Salvo (CH) (Italy)
Homepage: www.edasascientific.com
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405811.
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thetic strategy (Scheme 2).[16] The ring-opening of cyclopen-
tene oxide with benzylamine produced 13, and N-allylation,
followed by the Swern oxidation,[20] afforded ketone 15 in 75%
yield over three steps. Ketone 15 was found to be
unstable even upon storage at reduced temperature and was
immediately consumed in the next stage. After the formation
of a nonbasic[21] vinylcerium species, 15 was added at ꢁ788C
to give the tertiary allylic alcohol 16 in 93% yield as a single
isomer (cis-amino alcohol). It is noteworthy that ketone 15 is
added to the preformed vinylmagnesium bromide–cerium(III)
chloride reagent, otherwise the yield and the diastereoselectiv-
ity of the reaction would be greatly diminished.[22] The careful
control of the reaction temperature is also important, because
alkenylcerium reagents are unstable above ꢁ208C.[23] The re-
moval of the allyl group under the action of 1,3-dimethylbarbi-
turic acid (NDMBA) in the presence of catalytic amounts of
[PdCl2(Ph3P)2] gave the required cis-amino alcohol 17.[24] The
successive treatment of 17 with a freshly distilled ethyl glyoxy-
late in the presence of camphorsulfonic acid (CSA, 0.1 equiv)
furnished the oxazolidine 18 in an excellent yield. The configu-
ration of the C2 stereocenter was not determined in 18 and
related oxazolidines (vide infra), because this center was
destroyed in the following reaction. Finally, the aza-Cope–
Mannich reaction proceeded smoothly at ꢁ788C upon
treatment of 18 with BF3·Et2O to provide a bicyclic amino
ester 20 as a single diastereomer in 83% yield (8.3 g scale).
After the Luche reduction and debenzylation, the relative
stereochemistry of 20 was unambiguously confirmed by X-ray
crystallographic analysis (Scheme 3).[25]
Scheme 1. Retrosynthetic analysis.
of octahydroindol-2-carboxylic acid or other bicyclic amino
acids. In addition, recent studies from our group showed that
the aza-Cope–Mannich reaction can be easily scaled up to
decagram quantities and even more, therefore providing an
adequate supply of material for both biological and synthetic
studies.[16,17] Moreover, even substrates with a-stereocenters
that are prone to epimerization can be used in the rearrange-
ment.[18]
In principle, thiodiketopiperazines (acetylaranotin, gliotoxin)
without C5 oxygenation can be prepared from diketopipera-
zine 9 or amino acid 10 by appropriate keto-group manipula-
tions, oxidation[8] of the carbon framework and sulfenylation[19]
(Scheme 1). Herein, we disclose the preparation of amino acid
10 and structural analogues thereof as well as the implementa-
tion of our strategy for the formal synthesis of acetylaranotin.
The use of methyl glyoxylate[26] instead of ethyl ester and
following with BF3-catalyzed rearrangement effectively
provided amino ester 21 (34% from 17), the N-benzyl group of
which was exchanged for an N-Cbz group by hydrogenation
and sequential treatment with benzyloxycarbonyl chloride in
the presence of base (DIPEA). The two-step procedure,
Results and Discussion
Synthesis of octahydroindol-2-carboxylic esters
Our studies commenced with the preparation of cis-amino
alcohol 17 in accordance with the previously developed syn-
Scheme 2. Synthesis of cis-fused amino esters: a) BnNH2 (3 equiv), 1508C, 81%; b) AllylBr (1.5 equiv), K2CO3 (2 equiv), MeCN, D, 100%; c) DMSO, (COCl)2, Et3N,
dichloromethane, ꢁ788C, 92%; d) vinylmagnesium bromide, 1m in THF (1.5 equiv), CeCl3 (1 equiv), THF, ꢁ788C, 93%; e) N,N’-dimethylbarbituric acid (3 equiv),
[PdCl2(PPh3)2] 1 mol%, dichloromethane, D, 88%; f) ethyl glyoxylate (2 equiv), dichloromethane, CSA 10 mol%, (R=Et, 90%, R=Me, 93%); g) BF3·Et2O
(2 equiv), dichloromethane, ꢁ788C to RT, (R=Et, 83%, R=Me, 37%); h) 1) 10% Pd/C, H2, EtOAc; 2) CbzCl, DIPEA, EtOAc, 62%; i) TMSOTf (3 equiv), DIPEA
(4 equiv), dichloromethane; j) Pd(OAc)2 (2 equiv), MeCN, 43% over two steps. Cbz=carbobenzyloxy; DIPEA=N,N-diisopropylethylamine.
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Scheme 3. Synthesis of 26: a) NaBH4 (1 equiv), CeCl3·7H2O (1 equiv), ꢁ788C,
66%; b) 10% Pd/C, H2, EtOH, 94%.
Scheme 5. Transition-state geometry of [3,3]-sigmatropic rearrangements of
iminium ions; R=H, Me; R1, R2 =H, CO2Et.
featuring silyl enol formation and Saegusa–Ito[27] oxidation,
intercepted an intermediate in Tokuyama’s[8] acetylaranotin
synthesis, successfully completing our formal synthesis studies.
It is a well-known fact that methylated compounds, especial-
ly amino acids, are of considerable interest to medicinal
chemists due to the “magic methyl effect”.[28] Thus, the scope
of the reaction was further extended to structures containing
methyl substituents (as well as a quaternary stereocenter) at
the ring junction. To this end, aminoethanol 28 was prepared
(Scheme 4) from ketone 15 by employing the same two-step
intermediate iminium ion (Scheme 5).[14] When the substituent
at the nitrogen atom is large (CH2Ph) and R=H, the configura-
tion-determining [3,3]-sigmatropic rearrangement (32!33)
occurs preferentially via the (Z)-iminium ion to furnish amino
esters 20 and 21 (Scheme 2).[31,32] The replacement of vinyl by
an isopropenyl group leads to an almost equal stability of (E)-
and (Z)-iminium ions (30/31 1.1:1, Scheme 4), due to the steric
interactions between Me (R) and the ester groups (R1). How-
ever, when an aldehyde substituent decreases in size
(CHOCO2H vs. CHOCO2Et, Scheme 12), the (Z)-iminium ion
again becomes more favorable (68/67 9.6:1 vs. 1.1:1,
Scheme 12).
Synthesis of decahydrocyclohepta[b]pyrrole-2-carboxylic
esters
The sequence en route to octahydroindoles was further
extended to the synthesis of decahydrocyclohepta[b]pyrrole-2-
carboxylic acids. These substrates can be viewed as full-carbon
analogues of acetylaranotin or conformationally constrained
analogues of proline:[33] the related amino acid was found to
be a useful intermediate in the total synthesis of didehydro-
stemofoline.[34] Both cis- and trans-fused amino acids can be
prepared.
Scheme 4. Synthesis of cis-fused amino esters: a) 2-propenylmagnesium
bromide, 0.5m in THF (1.5 equiv), CeCl3 (1 equiv), THF, ꢁ788C, 73%; b) N,N’-
dimethylbarbituric acid (3 equiv), [PdCl2(PPh3)2] 1 mol%, dichloromethane, D,
94%; c) ethyl glyoxylate 50% in toluene (2 equiv), CSA 10 mol%, dichloro-
methane.
To synthesize cis-fused analogues, we have considered an
azido group as an ammonia surrogate in place of benzyl-
amine.[35] This tactic was expected to obviate the need for
protection–deprotection (e.g. 13!14, 16!17, Scheme 2) and
debenzylation steps. The sequence commenced with Swern
oxidation[20] of readily available trans-2-azido-cyclohexanol 35
(Scheme 6).[36] As the resulting ketone is quite volatile, all
manipulation (workup, chromatography) was conducted using
low-boiling solvents (dichloromethane, Et2O, pentane) to
ensure high yield (96%). The following Grignard addition
proved to be more challenging than anticipated:[37,38] the treat-
ment of 36 with vinylmagnesium bromide in THF at 08C pro-
vided a 3.5:1 mixture of trans- and cis-azidoalcohols 37 and 38
in a 52% combined yield. The isomers obtained are readily
separable by column chromatography even on a large scale
(>10 g).Decreasing the reaction temperature to ꢁ788C led to
an increase of both the combined yield (71%) and the diaste-
reomeric ratio of the products (5.5:1 in favor of 38). Using a cer-
ium(III)mediated addition[21] further improved the yield to 85%
but also dramatically reduced the d.r. to 2:1 in favor of the
trans isomer. Ketone 36 showed an analogous behavior in the
procedure as for 17. In this way, the treatment of 28 with ethyl
glyoxylate in the presence of camphorsulfonic acid (CSA,
0.1 equiv) furnished not only the oxazolidine 29 but also two
rearranged products, 30 and 31, in 19, 26, and 41% yield,
respectively. The rearrangement of 29 under the action of
BF3·Et2O at ꢁ788C gave a 1:1 mixture of 30 and 31. To over-
come the formation of a complex mixture, we have applied
more forcing conditions to 28 (i.e., refluxing in 1,2-DCE), thus
achieving the complete consumption of 28 and 29; however,
the yields of 30 and 31 were slightly lower (35 and 24%,
respectively). Further extension of the reaction time up to 3
days at an ambient temperature in dichloromethane resulted
in a full conversion with improved yields (30: 38%, 31: 33%).
The relative configuration of 30 and 31 was assigned on the
basis of NMR spectroscopic studies (NOESY). It should be
emphasized that 30 and 31 are readily separable by column
chromatography (>1 g scale). Compound 30 can, in principle,
be transformed to simplified lycoposerramine-S analogues.[29,30]
It is well-known that the stereochemical outcome of an aza-
Cope–Mannich reaction is controlled by steric effects in the
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Scheme 6. Synthesis of cis-fused amino esters: a) NaN3 (2.5 equiv), H2O/acetone, D, 99%; b) DMSO (2.5 equiv), (COCl)2 (1.5 equiv), Et3N (5 equiv), dichlorome-
thane, ꢁ788C, 96%; c) vinylmagnesium bromide, 1m in THF (1.5 equiv), THF, ꢁ788C, 71%; d) 2-propenylmagnesium bromide, 0.5m in THF (1.5 equiv), CeCl3
(1 equiv), THF, ꢁ788C, 80%; e) LiAlH4 (2 equiv), Et2O, 97% for 40, 93% for 41; f) ethyl glyoxylate, 50% in toluene (1.1 equiv), CSA 10 mol%, dichloromethane;
g) BF3·Et2O (2 equiv), dichloromethane, ꢁ788C, 72% over two steps; h) TsCl (1 equiv), Et3N (1 equiv), DMAP (cat.), dichloromethane, 88%; i) ethyl glyoxylate,
50% in toluene (1.1 equiv), CSA 0–95 mol%, dichloromethane, 95%. DMAP=4-dimethylaminopyridine.
reaction with 2-propenylmagnesium bromide (33% at 08C,
55% at ꢁ788C, CeCl3 80%); however, only minor quantities of
trans-azidoalcohol were observed (d.r.=20: 1). The subsequent
reduction of azides 38 and 39 with LiAlH4 in Et2O led smoothly
to amino alcohols 40[39] and 41 in 97 and 93% yields, respec-
tively. Next, the reaction of 40 with ethyl glyoxylate in the
presence of 3 ꢂ molecular sieves gave an oxazolidine (not
shown on scheme), which was treated in a one-pot fashion
with two equivalents of BF3·Et2O. After mild basic workup
(NaHCO3), amino ester 42 was obtained in 72% yield as
a single isomer (1 g scale). We have noted that 42 forms an in-
Scheme 7. Transition-state geometry of [3,3]-sigmatropic rearrangements of
iminium ions; R=H, Et; R1 =H, Me; R2, R3 =H, CO2Et.
separable mixture of epimers upon storage (weeks). However,
tosylation (TsCl, Et3N, DMAP cat.) provides a stable crystalline
compound 43, the relative stereochemistry of which was de-
termined by X-ray crystallographic analysis.[25] In contrast, no
Lewis or protic acid was needed to initiate the aza-Cope–Man-
nich rearrangement of 41: two products were formed, and the
diastereoselectivity of the reaction was found to be dependent
on the reaction conditions. Thus, 44 was the major product
when the reaction was conducted in the presence of
0.95 equivalents of CSA in dichloromethane (44/45=5:1). In
contrast, 45 was formed predominantly in CHCl3 without any
acidic catalysis (44/45=1: 3.3). The relative configurations of
44 and 45 were unambiguously confirmed on the basis of
COSY and NOESY spectra. Despite significant differences in
their chromatographic mobility, compounds 44 and 45 cannot
be fully separated by means of column chromatography.
Formation of 45 is surprising and cannot be explained fully by
steric interactions in the transition iminium ion (Scheme 7).
The synthesis of the trans-fused amino acid commenced
Scheme 8. Synthesis of trans-fused amino ester 55: a) Benzylamine (2 equiv),
with a preparation of trans-amino alcohol 51 by performing
LiClO4 (1.5 equiv), MeCN, 608C, 91%; b) H2, Pd/CaCO3, EtOH, 96%; c) ethyl
the previously described two-step procedure:[17,40] the nucleo-
glyoxylate (3 equiv), CSA 30 mol%, dichloromethane, 63%; d) 10% Pd/C, H2,
philic ring-opening of the commercially available oxirane 49
followed by the partial reduction of the triple bond in the
presence of Lindlar’s catalyst furnished the amino alcohol 51 in
80% yield (Scheme 8). The subsequent treatment of 51 with
freshly distilled ethyl glyoxylate mediated by CSA (0.3 equiv)
furnished a mixture of compounds 52–54.The relative configu-
ration of the main product 54 was determined by X-ray crystal
structural analysis based on its derivative 56. The N-alkylation
HCl (1 equiv), EtOH, 87%; e) p-BrC6H4COCl (1 equiv), Et3N (1 equiv), dichloro-
methane, 95%.
of aminoester 42 with benzyl chloride furnished a product
with the same NMR spectra as 53 (Scheme 6). Unfortunately,
we failed to increase the yield of 54. When more forcing
conditions were applied to ensure the full consumption of
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alkene 51 and oxazolidines 52, the diastereoselectivity of the
reaction decreased.
The rearrangements of iminium ions derived from cyclo-
hexanols with cis-oriented amine and vinyl groups are quite
complex, because two chair transition states are possible
(Scheme 9). In both cases, the carboethoxy group is placed in
Scheme 10. Synthesis of cis-fused amino acids.
Scheme 9. Transition-state geometry of [3,3]-sigmatropic rearrangements of
iminium ions; E=CO2Et, R=Bn.
Scheme 11. Synthesis of trans-fused amino acids: a) glyoxylic acid monohy-
drate (1.1 equiv), MeOH, 69%; b) NH3/MeOH, 608C, 61%; c) H2, Pd/CaCO3,
EtOH, 92%; d) glyoxylic acid monohydrate (1.1 equiv), MeOH, 48%.
a pseudoequatorial position (57, 59), but conformation 57 is
higher in energy than 59 due to steric interactions between
the bulky benzyl group and the cyclohexane ring. As was re-
ported earlier by our group, this steric interaction is one of the
major factors contributing to high trans-stereoselectivity.[17] It
has been previously demonstrated by Overman that alkene
substitution is also very important for the stereochemical out-
come of the reaction, that is, when an aryl substituent is intro-
duced, the rearrangement gives the cis-product analogous to
53 exclusively.[41] It is worth noting that cis- and trans-substitut-
ed amino cyclohexanols can be transformed to the respective
cis- and trans-fused decahydrocyclohepta[b]pyrroles; in
contrast, both cis- and trans-substituted amino cyclopentanols
rearrange to cis-fused octahydroindoles.[32b]
with a rapid reaction rate might be a result of intramolecular
acidic catalysis.[15a]
In analogy with the reactions shown in Scheme 10, the
treatment of 51 with glyoxylic acid in MeOH resulted in fast
precipitation of a single product—N-benzyl amino acid 63
(69%, Scheme 11). N-unsubstituted trans-amino acid 66 was
prepared from epoxide 49 in three steps (Scheme 11). The
aza-Cope–Mannich rearrangement was also fast, but the dia-
stereoselectivity was modest (5:1 in favor to trans-fused
product, see Scheme 9).
In contrast to the observed behavior of the compounds 37,
39, and 51, the treatment of 28 with glyoxylic acid in MeOH
(Scheme 12) provided a 3:1 mixture of diastereomeric amino
acids 67 and 68 in 74% combined yield (separable by column
chromatography).[15,43] The d.r. was sharply improved to 9.6:1
in favor of 68 by employing trifluoroethanol as a solvent. The
reaction of aminoethanol 17 with glyoxylic acid led to a
complex mixture under a variety of conditions.
Synthesis of amino acids
For further modification, including diketopiperazine formation,
both an N-deprotected aminoester and N-protected amino
acid are needed. With these considerations in mind, we
attempted to prepare N-protected amino acids by ester hydrol-
ysis. The reaction proved very challenging, and under most
conditions, extensive epimerization/decomposition was ob-
served. Preliminary results suggested Ba(OH)2·8H2O in metha-
nol as a most suitable hydrolyzing reagent.[42] After these un-
successful experiments, we switched to directly preparing the
amino acids by reacting amino ethanols with glyoxylic acid.[15a]
In comparison to the reaction with ethyl glyoxylate
(Scheme 6), no diastereomeric mixtures were formed during
the reaction of both 37 and 39 with glyoxylic acid in MeOH.
Hence, within a few minutes, precipitates of pure amino acids
61 and 62 were formed in 45 and 81% yields, respectively
(>1 g scale, Scheme 10).[15] High diastereoselectivity along
Scheme 12. Synthesis of cis-fused amino acids: a) glyoxylic acid monohy-
drate (1.1 equiv), CF3CH2OH, 74%; b) glyoxylic acid monohydrate (1.1 equiv),
MeOH, 69%.
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Conclusions
We have developed a practical method for the preparation of
unnatural bicyclic proline analogues by a tandem cationic aza-
Cope rearrangement–Mannich cyclization reaction. Herein, we
have prepared seven distinct amino acid scaffolds that could
be of interest to medicinal chemists. The experimental simplici-
ty of our procedures allows us to prepare gram quantities of
the requisite compounds. Finally, we have demonstrated the
applicability of our route to the synthesis of complex natural
products by formal synthesis of acetylaranotin. Although our
synthesis was less efficient than reported by others[7,8] and
intercepted only a racemic intermediate, it demonstrates that
diketopiperazine natural products can be accessed by an
aza-Cope–Mannich rearrangement. We believe that our route
to the diketopiperazine scaffold can be much more efficient
when applied to the synthesis of analogues of amino ester 24
for biological examination.
Experimental Section
All the experimental details are gathered in the Supporting
Information.
Acknowledgements
This study was supported by the Russian Foundation for Basic
Research (RFBR), Russia (Projects No. 14-03-31685, 14-03-31709,
14-03-01114). We thank Maria A. Andreeva for the drawing of
the graphical abstract.
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Keywords: amino acids
products · rearrangement · total synthesis
· medicinal chemistry · natural
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Published online on && &&, 0000
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FULL PAPER
Rearrangement mimics fungi: An
approach to oxygenated bicyclic amino
acids based on an aza-Cope–Mannich
rearrangement is described. Seven
distinct amino acid scaffolds analogous
to the natural products were prepared
on a gram scale with precise control of
stereochemistry. Successful implementa-
tion of our strategy resulted in the
formal synthesis of acetylaranotin (see
scheme).
&
Organic Synthesis
D. S. Belov,* N. K. Ratmanova,
I. A. Andreev, A. V. Kurkin*
&& – &&
Synthesis of Bicyclic Proline
Derivatives by the Aza-Cope–Mannich
Reaction: Formal Synthesis of (ꢀ)-
Acetylaranotin
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Chem. Eur. J. 2015, 21, 1 – 8
www.chemeurj.org
8
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!