Synthetic Study on Pactamycin: Stereoselective Synthesis of the Cyclopentane Core Framework

Article abstract of DOI:10.1021/acs.orglett.7b01257

The cyclopentane core framework 23 of pactamycin (1) was synthesized in 14 steps from symmetric cyclohexadiene 11. Our synthetic strategy features Rh-mediated catalytic desymmetrization of 10 via aziridination and then regioselective ring-opening reaction

Full text of DOI:10.1021/acs.orglett.7b01257

Letter
pubs.acs.org/OrgLett
Synthetic Study on Pactamycin: Stereoselective Synthesis of the
Cyclopentane Core Framework
†
†
†
†
†
†
Atsumi Goto, Satoshi Yoshimura, Yuta Nakao, Makoto Inai, Tomohiro Asakawa, Masahiro Egi,
†
‡
,†
Yoshitaka Hamashima, Mitsuru Kondo, and Toshiyuki Kan*
†
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Graduate School of Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan
‡
*
S Supporting Information
ABSTRACT: The cyclopentane core framework 23 of pactamycin (1) was synthesized in 14 steps from symmetric
cyclohexadiene 11. Our synthetic strategy features Rh-mediated catalytic desymmetrization of 10 via aziridination and then
regioselective ring-opening reaction of sulfonylaziridine 9 with NaN , ring-contraction of cyclohexene 14 by ozonolysis followed
3
by intramolecular aldol reaction, and stereoselective construction of the sequential tetrasubstituted carbons by dihydroxylation
and methylation reaction. Stereospecific incorporation of amine on tetrasubstituted carbon was achieved by Curtius
rearrangement and subsequent carbamide formation.
actamycin (1), which was isolated from the fermentation
broth of Streptomyces pactum var. pactum by the former
by desymmetrization of the diene 2 via asymmetric
bromolactonization and regioselective olefination of the
dialdehyde derived from 3, as shown in Scheme 1. Inspired
P
4b
Upjohn Company in 1961, exhibits antitumor, antiviral, and
antiprotozoal activities as well as cytotoxicity toward Gram-
1
−3
Scheme 1. Previous Synthesis of Sphingofungin E (5)
positive and Gram-negative bacteria.
Structurally, pactamy-
cin (1) is one of the most complex aminocyclopentitol
antibiotics, featuring six contiguous stereogenic centers with
three consecutive tetrasubstituted carbons on a heteroatom-rich
cyclopentene core, a urea unit, and two aromatic rings (Figure
1).
During the course of our synthetic studies of biologically
active natural products, we have realized that efficient syntheses
of complex natural products can sometimes be achieved by
by this result, we envisioned that aziridine derivative 9, which is
analogous to 3, could be used to generate the sequential amino
functionalities of pactamycin (1). Herein, we report a
stereocontrolled synthesis of cyclopentane core 23 as a part
of our strategy for the total synthesis of 1.
4
utilizing latent symmetry. For example, we used this strategy to
accomplish an efficient total synthesis of sphingofungin E (4)
Our synthetic plan for pactamycin (1) is illustrated in
Scheme 2. The introduction of two aromatic rings of 1 could be
carried out by transition-metal-mediated aromatic amination
and esterification in a late stage of the synthesis. Thus, we saw
the aminocyclopentitol 5 as a key intermediate for the synthesis
of 1. Since incorporation of a urea group on tetrasubstituted
carbon could be carried out by a combination of Curtius
rearrangement and nucleophilic attachment of dimethylamine
Received: April 26, 2017
Figure 1. Structure of pactamycin (1).
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01257
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthetic Strategy of Pactamycin (1)
Scheme 3. Synthesis of Cyclopentenol 17 via Ring-
Contraction Reaction
5
to the isocyanate intermediate, the tetra-substituted carbons of
5
would be constructed by stepwise functionalization of 6.
Although it is well-known that stereoselective functionalization
of a cyclopentane ring derivative is difficult compared to that of
a cyclohexane ring, we envisioned that the polyfunctional
cyclopentane ring would be fixed in an appropriate
conformation. Furthermore, construction of the cyclopentane
ring of 2 between sterically crowded positions is expected to be
difficult, so ring contraction reaction of cyclohexene 8 to
cyclopentene 6 by oxidative cleavage of the double bond and
intermolecular aldol reaction of dialdehyde 7 would be
desirable. We envisioned that trans-diaminocyclohexene 8
would be synthesized from symmetric cyclohexadiene 10 by
means of desymmetric aziridination and stereoselective ring
opening reaction with azide.
With the desired allyl alcohol 17 in hand, we next focused on
stereoselective construction of the tetrasubstituted carbons at
C-4 and C-5 on the cyclopentane ring, as shown in Scheme 4.
Conversion of the trisubstituted double bond of 17 to the exo-
olefin 20 was performed by epoxidation with mCPBA,
mesylation, and treatment of 18 with a large excess of NaI in
MeCN. This olefin formation reaction presumably results from
SN2 reaction of mesylate 18 with NaI and subsequent attack of
iodonium anion on the iodoepoxide intermediate 19 to provide
20 without decomposition of the azide group. Upon treatment
with DMDO, the epoxidation reaction proceeded smoothly to
As shown in Scheme 3, allyl alcohol 17 was synthesized from
symmetric cyclohexadiene 11, which we had used as a synthetic
4b
intermediate of sphingofungin E (4). Conversion from the
primary alcohol 11 to the corresponding sulfamate 10 was
performed by treatment with in situ generated ClSO NH2
2
(
1
derived from CSI and HCO H) in DMA. Upon treatment of
2
0 with a catalytic amount of Rh (OAc) in the presence of
2 4
PhI(OAc) , the desired aziridination proceeded smoothly to
2
6
12
provide 9 as a single diastereomer in high yield. Next, the
give β-epoxide 21. Conversion of 21 to cyclopentanone 22
13
stereospecific ring-opening reaction of aziridine 9 was carried
was carried out by AZADO-mediated Iwabuchi oxidation.
out by treatment with NaN ; nucleophilic attack occurred at
the C-2 position to afford the desired azide 12a predominantly.
Upon treatment of 22 with methylmagnesium bromide,
alkylation proceeded smoothly to provide the α-alcohol 23
predominantly. Interestingly, nucleophilic attack on cyclo-
pentane rings 20 and 22 occurred from the β-side exclusively.
In this alkylation reaction, addition of CH Cl played a key role
3
A similar regioselective ring-opening reaction was reported by
7
Du Bois et al. The stereochemistry of 12a was confirmed by X-
8
,9
ray analysis of the p-bromobenzyl ester 12b (Scheme 3). The
azide 12a was converted to ester 14 in a three-step sequence
involving protection with a Boc group, basic hydrolysis of cyclic
sulfamate, and protection with a TBDPS group. Since isolation
and purification of labile dialdehyde 15 were difficult, we chose
to employ a one-pot ozonolysis/cyclization. In this conversion,
the addition of pyridine was advantageous since reducing
2
2
14
for enhancement of the reactivity and selectivity. The
stereochemistry of 23 was confirmed by X-ray analysis after
conversion to the corresponding p-bromobenzamide 24. The
15
stereochemistry was identical to that of 1.
As shown in Scheme 5, incorporation of the amino
functionality onto the α-trisubstituted carbon was accomplished
by Curtius rearrangement as employed in our α-substituted α-
10
reagents were not required. After oxidative cleavage of the
double bond of 14 and in situ treatment with DBU,
regioselective intramolecular aldol reaction proceeded smoothly
4
amino acid synthesis. After removal of the TBDPS group, the
resulting diol group of 25 was converted to methoxybenzyli-
dene acetal. One-step incorporation of the dimethyl urea group
was performed by the combination of Curtius rearrangement
and addition of methylamine. After hydrolysis of the methyl
11
to provide enal 16. Subsequent treatment of 16 with NaBH4
resulted in smooth 1,2-reduction to provide the stable key
cyclopentenol derivative 17.
B
DOI: 10.1021/acs.orglett.7b01257
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Organic Letters
Letter
5
Scheme 4. Stereoselective Synthesis of Cyclopentane 23
ester of 26 and treatment of the carboxylic acid with DPPA,
the desired rearrangement proceeded smoothly to afford the
isocyanate intermediate 27. In this reaction, monitoring the
disappearance of carboxylic acid and subsequent addition of
dimethylamine provided methyl urea 28. Next, dihydroxylation
of 28 with OsO and NMO afforded the desired diol 29. The
4
oxidation reaction occurred from the convex face of 28 to
provide the β-diol 29. The stereochemistry of 29 was confirmed
16
by X-ray crystallography analysis (see Scheme 5).
In conclusion, the cyclopentane core framework 23 of
pactamycin (1) was synthesized in 14 steps from symmetric
cyclohexadiene 11.
Our synthetic strategy features a Rh-mediated catalytic
desymmetrization of 10 via aziridination followed by
regioselective aziridine ring-opening reaction with NaN and
3
construction of the cyclopentane ring by ozonolysis followed by
intermolecular aldol reaction. Subsequent stereoselective
construction of three sequential tetrasubstituted carbons was
accomplished by Curtius rearrangement, dihydroxylation, and
methylation reaction. Further conversion of 23 and/or 29 to
pactamycin (1) and synthesis of optically active 9 by
employment of a chiral catalyst are under investigation in our
laboratory.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01257.
Experimental details and spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Scheme 5. Incorporation of Urea 28 by Curtius
Rearrangement
*
E-mail: kant@u-shizuoka-ken.ac.jp.
ORCID
Toshiyuki Kan: 0000-0002-9709-6365
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by MEXT/JSPS
KAKENHI Grant Nos. JP23390007 and JP17H03973,
Grants-in-Aid for Scientific Research on Priority Areas
JP26102736, JP26105751, and JP16H01160 from the Ministry
of Education, Culture, Sports, Science and Technology
(
MEXT) of Japan, and a Platform Project for Supporting in
Drug Discovery and Life Science Research (Platform for Drug
Discovery, Informatics and Structural Life Science) from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT).
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D
DOI: 10.1021/acs.orglett.7b01257
Org. Lett. XXXX, XXX, XXX−XXX