The formal synthesis of lucentamycin A: Construction of cis-2,3-disubstituted pyrrolidine core by application of SmI2-DMPU system

Article abstract of DOI:10.1016/j.tetlet.2018.02.076

The formal synthesis of lucentamycin A (1) was accomplished in 14 steps from D-serine methyl ester as a starting material. All the requisite stereogenic centers on the pyrrolidine core of 1 were controlled by SmI₂-mediated cyclization. Construc

Full text of DOI:10.1016/j.tetlet.2018.02.076

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
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The formal synthesis of lucentamycin A: Construction of cis-2,3-
disubstituted pyrrolidine core by application of SmI -DMPU system
2
⇑
Kazunori Takahashi , Kei Fukushima, Masayoshi Tsubuki, Toshio Honda
Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The formal synthesis of lucentamycin A (1) was accomplished in 14 steps from D-serine methyl ester as a
Received 8 February 2018
Revised 20 February 2018
Accepted 26 February 2018
Available online xxxx
starting material. All the requisite stereogenic centers on the pyrrolidine core of 1 were controlled by
SmI -mediated cyclization. Construction of the methyl unit at the C9 position of 1 was achieved by decar-
bonylation of lactol 11 with stoichiometric amount of Rh(PPh Cl.
Ó 2018 Elsevier Ltd. All rights reserved.
2
3 3
)
Keywords:
Lucentamycin A
Samarium diiodide
Bromoalkyne
Radical cyclization
Cis-2,3-disubstituted pyrrolidine
Lucentamycin A (1), isolated from marine-derived actinomycete
cis-disubstituted pyrrolidine ring having the desired stereo-
chemistries at the C8 to C10 positions of lucentamycin A (1) with
high diastereoselectivity. Herein, we report the formal synthesis
(
Nocardiopsis lucentensis) by Fenical et al., consists in tripeptide
1
such as proline, homoarginine and leucine (Fig. 1). The geometry
of olefin at C10 of lucentamycin A (1) was revised to E-form as
of lucentamycin A (1) via SmI
2
-mediatated coupling reaction5 as
2
shown in Fig. 1 The structural features of this compound (1) and
a key step.
its analogs are based on the (E)-olefin at the C10, the methyl group
at the C9, and the carbamoyl group at the C8 positions of the pyrro-
lidine ring. Therefore, it is highly desirable to develop a new
methodology constructing three consecutive stereogenic centers,
C8 to C10 positions, stereoselectively, as a key reaction in the syn-
thesis of this class of compounds. If a general procedures for
stereoselective construction of the pyrrolidine core could be estab-
lished, the stereoselective synthesis of lucentamycins B-D would
also be possible by its application. Our own interest in the synthe-
sis of 1 grew out of a desire to develop a novel and general route for
the synthesis of this class of natural products.
The retrosynthetic analysis is shown in Scheme 2. The methyl
unit of Del Valle’s intermediate 2 would be constructed by reduc-
tion of lactone moiety of 3 with DIBAL-H, followed by decarbony-
lation of the resulting lactol. The ethylidene moiety of 3 could be
stereoselectively obtained by Pd-catalyzed coupling reaction of
bromoalkene moiety in 4 with organozinc reagent. The lactone 4
could be synthesized by controlling the stereochemistries of the
2,3
2
fused ring junctures using an intramolecular SmI -mediated cycli-
zaion of the compound 5. The cyclization precursor 5 would easily
be derived from HClÁD-serine methyl ester.
Tosylation of the nitrogen of commercially available HClÁD-ser-
6
Previously, we reported a radical cyclization reaction of chain
ine methyl ester, followed by silylation of the primary hydroxy
7
amides possessing bromoalkyne and
a
,b -unsaturated ester func-
group furnished silyl ether 6 (Scheme 3). Subsequently, alkylation
4
tions with SmI
2
(Scheme 1). The SmI
2
-mediated cyclization devel-
2 3
of silyl ether 6 with propargyl bromide in the presence of K CO
4
a
oped above can control both exo-olefin geometry and adjacent
asymmetric carbon centers as trans, with high diastereoselectivity.
For a synthesis of lucentamycin A (1), it is crucial to control the
stereochemistries at the C8 and C9 positions as cis. We envisaged
that an intramolecular coupling reaction of a bromoalkyne with a
afforded the corresponding alkyne 7 in 99% yield. Reduction of
7 using DIBAL-H, followed by Z selective Ando variant of Horner-
8
Wadsworth-Emmons reaction of the resulting aldehyde with
phosphonate 9 gave 8 in 74% yield over 2 steps.
Although treatment of the ester 8 with p-TsOH in refluxing
MeOH brought about the desired desilylation, and subsequent
heating of the crude product in toluene provided lactone 10, this
procedure was abandoned because of lack of reproducibility
cyclic
a,b-unsaturated lactone would provide a corresponding
⇑
Corresponding author.
E-mail address: takakazu@hoshi.ac.jp (K. Takahashi).
(Scheme 4). Fortunately, we found that the desired lactone 10
https://doi.org/10.1016/j.tetlet.2018.02.076
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0
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2
K. Takahashi et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Fig. 1. Structure of lucentamycins.
2
Scheme 4. Synthesis of lactol 11 via SmI -mediated cyclization.
2
Scheme 1. Radical cyclization of bromoalkyne with SmI .
Scheme 5. Formal synthesis of intermediate 2.
nishing 4 in 64% yield. The stereochemistry of 4 was unambigu-
ously determined by NOE experiment. Thus, we succeeded in
constructing all the stereochemistries in pyrrolidine core of 1. To
accomplish the construction of the ethylidene moiety, the resulting
4
8
was then subjected to Negishi coupling to furnish lactone 3 in
6% yield.
Next, our attention was focused on introducing the methyl
group at the C9 position. Reduction of 3 with DIBAL-H generated
an inseparable mixture of diastereomers 11 in 99% yield. Although
difficulties were initially encountered in obtaining 12 by decar-
1
2
bonylation of 11 under various reaction conditions, we found
that the desired alcohol 12 could be isolated by tretment of 11 with
1
3
Scheme 2. Retrosynthetic analysis of lucentamycin A (1).
stoichiometric amount of Rh(PPh
Scheme 5). The low yield in the formation of 12 might be due to
its instability under the reaction conditions employed, and the ole-
3 3
) Cl in DMA in 34% yield
(
1
4
fin-migration product was isolated by HPLC in trace amounts
together with a number of structurally unidentified decomposed
products. The obtained alcohol 12 was then oxidized using AZA-
Ò
15
DOL -PhI(OAc)
2
system to give carboxylic acid 13 in 79% yield.
Condensation of 13 with l-leucine tert-butyl ester in the presence
2
d,16
of HATU
afforded amide 14 in 77% yield. Finally, the reductive
cleavage of sulfonamide moiety of 14 using Mg was accomplished
in mixed solvent of MeOH and THF, because of the low solubility of
17
compound 14 in MeOH, to provide Del Valle’s intermediate 2 in
1
8
9
9% yield. The spectroscopic data of the synthesized compound
2
were in good agreement with those reported by Del Valle.
Plausible mechanism of the radical cyclization is presented
below (Scheme 6). The observed stereoselectivity affording the
cis-fused bicyclic compound would be rationalized by assuming
that the reaction would proceed through the transition state (TS)
depicted in Scheme 6, where Sm or Sm species might coordinate
to both carbonyl oxygen and bromoalkyne. The corresponding
vinyl anion generated in this cyclization would be protonated from
the convex face of the chelated product to produce (E)-alkene 4
stereoselectively.
Scheme 3. Synthesis of (Z)-a,b -unsaturated ester 8.
could be obtained on treatment with TFA at room temperature for
h in 99% yield. Bromination of terminal alkyne in 10 with NBS-
1
9
II
III
AgNO
be separated from the acetone-derived byproduct. Therefore,
bromination of 10 was conducted in CH CN as a solvent to give 5
in 96% yield. The key radical cyclization of 5 with SmI -HMPA pro-
3
-acetone afforded bromoalkyne 5. However, 5 could not
3
2
10
ceeded smoothly to give the expected bromoalkene 4 in 70%
yield. However, HMPA has been a suspected human carcinogen,
therefore, SmI -DMPU system was applied to this cyclization fur-
2
In conclusion, we have achieved the formal synthesis of lucen-
tamycin A (1) starting from d-serine methyl ester in 14 steps in
1
1
Please cite this article in press as: Takahashi K., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.02.076

K. Takahashi et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
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.3% overall yield. In this synthesis, the desired stereogenic centers
on the pyrrolidine core of 1 were successfully constructed by
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,b-unsaturated system, in one-step. We believe that the strategy
1
1
0. Selected data for compound 4: [
1347, 1163 cm ; 1H-NMR (CDCl3; 400 MHz) d7.68 (2H, d, J = 8.2 Hz), 7.34 (2H,
a
]D23 13.0 (c 1.00, CHCl3); IR n max 1750,
À1
2
d, J = 8.2 Hz), 6.10 (1H, dt, J = 2.0, 1.6 Hz), 4.47 (2H, d, J = 5.0 Hz), 4.32 (1H, dt, J
a
=
3
9.1, 5.0 Hz), 4.08 (1H, dd, J = 15.3, 1.6 Hz), 3.99 (1H, dt, J = 15.3, 2.0 Hz), 3.35-
.26 (1H, m), 2.80 (1H, dd, J = 15.4, 6.9 Hz), 2.67 (1H, dd, J = 15.4, 6.7 Hz), 2.45
developed here will provide an alternative efficient methodology
for the construction of natural product having pyrrolidine ring.
(3H, s); 13C-NMR (CDCl3; 100 MHz) d170.5, 144.6, 141.4, 134.0, 130.1 (2),
27.3 (2), 102.5, 69.5, 56.9, 52.6, 39.8, 30.7, 21.6; mp 163–165 C; HRMS (ESI+)
calcd for C15H16BrNO4S+Na: 407.9881. Found: 407.9894.
1
Acknowledgments
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a
1
For the use of DMPU Mukhopadhyay T, Seebach D. Helv Chim Acta.
982;65:385–391;
The authors thank Prof. Ihara is gratefully acknowledged for
helpful discussions. We also thank Dr. Kasai and Mr. Y. Kato for
determination of MS and HPLC, respectively. This work was sup-
ported in part by Grant-in-Aid for Young Scientists (B) (No.
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1
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4. Selected data for olefin-migration product, ((2S,3R,4R⁄)-3-Methyl-1-tosyl-4-
vinylpyrrolidin-2-yl) methanol: [a]D27 69.58 (c 0.12, CHCl3); IR n max 3566,
1339, 1163 cmÀ1; 1H-NMR (CDCl3; 600 MHz) d 7.74 (2H, d, J = 8.1 Hz), 7.34
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.02.076.
(
2H, d, J = 8.1 Hz), 5.29 (1H, ddd, J = 18.2, 10.1, 8.3 Hz), 5.07 (1H, dd, J = 18.2, 1.4
Hz), 5.04 (1H, dd, J =10.1, 1.4 Hz), 3.85 (1H, d, J = 8.3 Hz), 3.69-3.61 (3H, m), 2.85
1H, dd, J = 10.0, 10.0 Hz), 2.61-2.53 (1H, m), 2.45 (3H, s), 1.50-1.42 (1H, m),
.91 (3H, d, J = 6.9 Hz); 13C-NMR (CDCl3; 150 MHz) d 143.9, 136.6, 133.5,
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Please cite this article in press as: Takahashi K., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.02.076