Addition of Lithium Anion of (Acetylmethylene)triphenylphosphorane to Nonracemic Sulfinimines: Total Synthesis of (+)-241D and Formal Total Synthesis of (+)-Preussin

Article abstract of DOI:10.1021/acs.orglett.0c02608

The addition of lithium anion of (acetylmethylene)triphenylphosphorane to nonracemic sulfinimines was investigated. It was found that the addition proceeded with good diastereoselectivity and further reaction of the formed sulfinimidophosphorane with seve

Full text of DOI:10.1021/acs.orglett.0c02608

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Letter
Addition of Lithium Anion of
(
Acetylmethylene)triphenylphosphorane to Nonracemic
Sulfinimines: Total Synthesis of (+)-241D and Formal Total Synthesis
of (+)-Preussin
Sopan P. Khandare, Polimera Obula Reddy, and Kavirayani R. Prasad*
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ABSTRACT: The addition of lithium anion of (acetylmethylene)triphenylphosphorane to nonracemic sulfinimines was
investigated. It was found that the addition proceeded with good diastereoselectivity and further reaction of the formed
sulfinimidophosphorane with several aldehydes afforded the β-sulfinamido substituted enones in good yields. The resultant enones
were elaborated to the synthesis of alkaloid (+)-241D, to the formal total synthesis of (+)-preussin, and to the synthesis of
aminocyclopentenol.
ubstituted piperidines, piperidinones, and pyrrolidines are
prepared from simple methyl vinyl ketone did not proceed at
all. Similarly, the addition of 5 to sulfinimines obtained from
α,β-unsaturated aldehydes was futile. This prompted us to
identify a suitable synthetic equivalent for procuring building
blocks which are otherwise not accessible by conventional
methods. Herein, we disclose the addition of the lithium anion
of the Wittig ylide acetylmethylenetriphenylphosphorane
S
structural units frequently found in several alkaloid natural
1
products. These alkaloids are shown to exhibit diverse
biological activities, which led to the development of different
strategies for their synthesis. One of the key approaches
reported for the synthesis of 2,6-disubstituted piperidin-4-ones
is the intramolecular Michael addition of suitably substituted
2
3
4
β-amino ketones containing unsaturation. The Davis, Troin,
(
MeCOCHPPh ) 7 to nonracemic Davis−Ellman sulfini-
3
5
and Sutherland groups independently studied the synthesis of
7
mines and application of the formed enones in the synthesis
of alkaloid (+)-241D, in the formal total synthesis of
pyrrolidine alkaloid preussin and in the synthesis of amino
cyclopentenol, a useful intermediate in the synthesis of
carbocyclic nucleosides (Scheme 1).
2
from suitably N-protected β-keto phosphonates derived from
corresponding β-amino acid esters. We recently disclosed the
stereoselective synthesis of β-sulfinamido substituted ketones 6
from nonracemic sulfinimines 4 using a vinylogous Mukaiyama
reaction and showcased their utility in the synthesis of
The study commenced with the addition of lithium anion of
6
quinolizidine and piperidinone alkaloids. The synthesis of
n
7
(generated by the deprotonation of 7 with BuLi) to the
amino enones from the keto phosphonates 1 had two
drawbacks. (i) Preparation of simple enones devoid of
substitutions on the alkene by Wittig reaction of 1 with
formaldehyde was not possible perhaps because of the
elimination of the amino group. (ii) The synthesis of
phosphonates was mostly restricted to derivatives of aspartic
acid, β-alanine, and β-phenylalanine. Although the addition of
silylenol ethers derived from several substituted methyl ketones
sulfinimine 4a. The reaction furnished the required addition
Received: August 4, 2020
5
to sulfinimines was successful, the addition of silylenol ether
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c02608
A
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Scheme 1. Synthesis of β-Aminoenones
Scheme 2. Addition of Phosphorane 7 to Sulfinimine 4a and
Further Reaction with Aldehdyes
product 8 in 36% yield along with the product arising from the
n
addition of BuLi to the sulfinimine 4a. Employing LiHMDS
or KHMDS as the base did not yield any product. However,
the use of LDA as a base resulted in the formation of the
sulfinamidophosphorane 8, admixed with the unreacted
phosphorane. At this stage, it was difficult to estimate the
diastereomeric ratio of the product phosphorane 8 by NMR
analysis. Hence, we treated the crude sulfinimidophosphorane
8
with aldehydes to yield the enones 6a−h. The diastereomeric
ratio of the chromatographically purified product enones was
1
8
estimated by H NMR spectroscopy. Thus, reaction of 8 with
formaldehyde produced the unsubstituted enone 6a in 63%
yield and with >99:1 diastereomeric ratio. The reaction of
phosphorane 8 with other aldehydes afforded the β-
sulfinamido enones 6b−h with diastereoselectivities ranging
from 83:17 to >99:1 and in good yields. Reaction with
aliphatic aldehydes acetaldehyde and propanaldehyde afforded
the corresponding enones 6b and 6c in 71 and 74% yield,
respectively. Reaction with benzaldehyde and 4-methoxy
benzaldehyde formed the products 6d and 6e in 62% (dr
properties of product enones with the known compounds
reported in the literature and also by single crystal X-ray
structure analysis of the enone 6q (see the Supporting
Information for the crystal structure). The addition of a
nucleophile is from a face opposite to the sulfinyl group which
can be explained by the transition state proposed by Davis and
9
3:7) and 69% (dr 89:11) yield, respectively. Reaction with
aromatic aldehydes containing heteroatoms such as furan-2-
carbaldehyde and thiophene-2-carbaldehyde furnished the
products 6f and 6g in 60 and 49% yields, respectively, with
9
Ellman (Figure 1; Scheme 2). The present synthetic strategy
>
99:1 diastereomeric ratio. Reaction with functionalized
aldehyde such as ethylglyoxalate afforded the product 6i in
2% yield with 93:7 diastereomeric ratio. Similarly, reaction of
overcomes the drawbacks associated with other synthetic
methods for the synthesis of simple β-amino enones.
After accomplishing the synthesis of the amino enones,
deprotection of the sulfinyl group and subsequent aza-Michael
reaction to form the 2,6-disubstituted piperidine-4-one was
examined. Thus, deprotection of the sulfinyl group in 6a−l by
reaction with saturated ethereal HCl followed by neutralization
4
the phosphorane 8 with chiral aldehydes obtained from lactic
acid and D-tartaric acid also yielded the corresponding enones
6
j and 6k in 59 and 69% yields, respectively. Reaction with
cinnamaldehyde yielded the product 6l in 65% yield. The
varied diastereoselectivity in the formation of product enones
clearly indicate that the preliminary addition of ylide 7 to
sulfinimine 4a is non-diastereoselective. Observation of >99:1
dr in some of the product enones is a consequence of the
diastereomeric enrichment during the column chromatography
purification. All of the results are summarized in Scheme 2.
Further generalization of the protocol was exemplified by the
synthesis of several unsubstituted enones 6m−t obtained by
the reaction of phosphorane 7 with different sulfinimines
derived from alkyl, aryl, substituted aryl, and alkenyl aldehydes
and further reaction with formaldehyde. In all cases, the
reaction afforded the products with good selectivity and yields
with Et N furnished the corresponding piperidinones in good
3
yield. Reaction of enones 6b−h, 6k, and 6l furnished a
separable mixture of cis and trans piperidinones 9a−17a and
10
9b−17b, respectively. Enones 6f and 6i comprising a 2-furyl
group and an ester moiety failed to produce the piperidinones
and decomposed during the reaction. Enone 6j furnished the
piperidinone 16 in 78% yield. The reaction of unsubstituted
enones 6a and 6m−u (obtained from the reaction of
sulfinimines with phosphorane 7 formaldehyde) exhibited an
interesting trend. The enones 6a, 6t, and 6u containing an
alkyl substituent at the carbon bearing the amino group cleanly
furnished the corresponding 2-substitued piperidin-4-ones 18,
19, and 20 in 71, 73, and 81% yields, respectively. However, all
of the other amino enones 6m−q having aryl, substituted aryl,
(
Scheme 3). Stereochemistry of the newly formed stereogenic
center was established by comparison of the physical
B
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Scheme 3. Synthesis of Simple β-Amino Enones from
Sulfinimines
Scheme 4. Synthesis of Substituted Piperidin-4-ones from
the Enones 6a−u
and alkenyl substitution failed to produce the piperidinones.
We believe that the hydrochloride salt formed after
deprotection of the sulfinyl group in 6m−q with saturated
ethereal HCl underwent an elimination of the amino group in
a
Yields refer to isolated yields after silica gel column chromatography.
Enones 6f, 6i, and 6m−6q did not yield any piperidinone and
b
the subsequent neutralization with Et N instead of the aza-
3
Michael reaction. Such an elimination is mitigated in the
reaction of enones 6a, 6t, and 6u containing an alkyl
substitution at the amino group (Scheme 4).
decomposed during the reaction.
Scheme 5. Total Synthesis of (+)-241D
The formed piperidinones serve as excellent building blocks
for the synthesis of alkaloids. The alkaloid (+)-241D 24 was
isolated from the skin of the Panamanian poison frog
1
1
Dendrobates specious by Daly and co-workers. Several
syntheses of this alkaloid in enantiopure form were recorded
1
2
in the literature. We envisioned the synthesis of (+)-241D by
the reduction of the corresponding 4-piperidinone, which in
turn can be obtained by the aza-Michael cyclization of suitably
substituted enone. Accordingly, reaction of sulfinimine 4j with
the phosphorene 7 and further reaction with acetaldehyde
afforded the enone 21 in 79% yield. Deprotection of the
sulfinyl group in 21 with ethereal HCl and neutralization with
Et N furnished a separable mixture of cis- and trans-2,6-
3
disubstituted piperidin-4-ones 22 and 23 in 65 and 20% yield,
respectively. Formation of the cis and trans isomers was
confirmed by comparison of the spectral and optical rotation
13
data with that reported by Sutherland’s group. Piperidinone
3 on reduction with NaBH led to the formation of the
alkaloid (+)-241D 24 as a single diastereomer in 90% yield
2
4
Thus, reduction of the enone 6u under Luche reduction
conditions furnished the β-sulfinamido alcohol 25 in 94%
yield. Deprotection of the sulfinyl group in 25 and further
protection of the free amine as the Boc carbamate afforded 26
in 82% yield. The free hydroxy group in 26 was protected as its
TBS ether 27 in 86% yield. The transformation of 27 to
(
Scheme 5).
15
After the successful completion of the synthesis of alkaloid
+)-241D, the strategy was extended for the formal synthesis
(
of the substituted pyrrolidine alkaloid (+)-preussin 28, a
14
natural product which is an inhibitor of cyclin-E-kinase.
C
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preussin involving carboamination/arylation and reduction of
the Boc group was reported by the Wolfe group. Hence, the
present synthesis constitutes a formal synthesis of preussin
Wittig olefination reaction with aldehydes; synthesis of
6a−u and 21; general procedure for the synthesis of 2,6-
disubstituted piperidinones using the intramolecular aza-
Michael cyclization reaction; synthesis of 9a−20;
synthesis of (+)-241D; formal total synthesis of
preussin; synthesis of aminocyclopentenol derivative
16
(Scheme 6).
Scheme 6. Formal Total Synthesis of (−)-Preussin
3
1b; and X-ray crystal data (PDF)
Copies of the H and 13C NMR spectra of all new
1
compounds and the X-ray crystal structure data of 6q
(PDF)
Accession Codes
CCDC 2017135 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
We also utilized the enone 6r as the building block in the
synthesis of aminocyclopentenol derivative 31, an intermediate
for the synthesis of therapeutically important carbonucleo-
Kavirayani R. Prasad − Department of Organic Chemistry,
Indian Institute of Science, Bangalore 560012, India;
orcid.org/0000-0003-1453-9798; Email: prasad@iisc.ac.in
1
7
sides. For this purpose, the enone 6u was subjected to Luche
reduction to furnish the sulfinamido alcohol 29 in 80% yield.
Removal of the sulfinyl group and protection of free amine as
its Boc carbamate furnished 30 in 88% yield. Ring closing
Authors
Sopan P. Khandare − Department of Organic Chemistry,
Indian Institute of Science, Bangalore 560012, India
Polimera Obula Reddy − Department of Organic Chemistry,
Indian Institute of Science, Bangalore 560012, India
1
8
metathesis of 30 using Hoveyda−Grubbs second generation
1
9
(
2.5 mol %) catalyst
led to the formation of the
aminocyclopentenol 31 in 85% yield (Scheme 7).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02608
Scheme 7. Synthesis of Boc-Protected Aminocyclopentenol
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Science and Engineering Research Board (SERB,
Grant No. CRG/2018/001332) for funding the project. S.P.K.
thanks the Council of Scientific and Industrial Research
(
CSIR) India for a research fellowship. P.O.R. thanks the
University Grants Commission, New Delhi, for the Dr. D. S.
Kothari postdoctoral fellowship. We thank Dr. A. Veera Reddy
of Suven Lifesciences, Hyderabad, India, for a generous gift of
the tert-butyl sulfinamide. We thank Prof. Parthasarathi
Mukherjee and Dr. Rupak Saha of the Department of
Inorganic and Physical Chemistry, Indian Institute of Science,
Bangalore, for their help in X-ray structure determination of
In conclusion, the addition of lithium enolate of the ylide
acetylmethylene)triphenylphosphorane to nonracemic sulfini-
(
mines and further Wittig reaction with several aldehydes to
yield β-sulfinamido ketones was accomplished with good
diastereoselectivity. The formed sulfinamido enones serve as
excellent precursors for the synthesis of piperidine and
pyrrolidine alkaloids (+)-241D and preussin and also for the
synthesis of aminocyclopentenol, a useful intermediate for the
synthesis of carbonucleosides.
6
q.
DEDICATION
■
Dedicated with warmth and respect to Dr. K. Nagarajan,
Founder-Member of the National Organic Symposium Trust,
India, on the occasion of his 90th birthday.
ASSOCIATED CONTENT
sı Supporting Information
■
REFERENCES
*
■
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(
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5
(
(
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(
9
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(
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(
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1
E
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