A concise route to the highly-functionalized azetidine precursor: The enantioselective synthesis of penaresidin B

Article abstract of DOI:10.1039/c4cc09904d

An efficient and high-yielding synthesis of penaresidin B is disclosed herein. The concise 8-step synthesis of azetidine aldehyde was devised by incorporating our novel strategy for ready access to 3-amino-2,3-dideoxysugars via regio- and stereoselective

Full text of DOI:10.1039/c4cc09904d

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A concise route to the highly-functionalized
azetidine precursor: the enantioselective synthesis
of penaresidin B†
Cite this: Chem. Commun., 2015,
51, 4639
Received 11th December 2014,
Accepted 7th February 2015
Feiqing Ding,‡ Ronny William,‡ Si Min Kock, Min Li Leow and Xue-Wei Liu*
DOI: 10.1039/c4cc09904d
www.rsc.org/chemcomm
An efficient and high-yielding synthesis of penaresidin B is disclosed
herein. The concise 8-step synthesis of azetidine aldehyde was
devised by incorporating our novel strategy for ready access to
3-amino-2,3-dideoxysugars via regio- and stereoselective tandem
hydroamination/glycosylation of glycal as the key step.
Azetidines constitute an important class of azaheterocycles that
have been widely used in drug design as well as in the synthesis
of natural products and pharmacologically active compounds.1,2
In addition, they also serve as versatile building blocks for other
types of nitrogen-containing compounds with potential bio-
logical properties.3 However, azetidine alkaloids structurally
related to phytosphingosines are rare, and only three biologically
active sphingosine-like compounds derived from marine organisms
have been isolated to date (Fig. 1). Penaresidin A (1) and penaresidin
B (2), which exhibited potent actomyosin ATPase-activating activity
when tested as an inseparable mixture, were isolated from an
Okinawan marine sponge Penares sp. by Kobayashi et al.4 The
related compound penazetidine A (3), which showed specific rat
brain protein kinase C inhibitory activity, was isolated from the
Pacific sponge Penaressollasi by Crews and co-workers.5
Fig. 1 Structures of azetidine alkaloids.
asymmetric hydroxylation reactions as the key steps (Scheme 1,
eqn (1)).6i, j In addition, Raghavan and co-workers recently
developed an alternative approach which comprises an 18-step
construction of the azetidine subunit 5 of penaresidin A through
stereoselective addition of the lithio anion of (R)-methyl p-tolyl-
sulfoxide to an unsaturated sulfinylimine (Scheme 1, eqn (2)).6p
Another multistep strategy that consists of a 17-step construction
of the azetidine subunit 6 of penaresidin A, which started from
Interestingly, despite their rare occurrence in nature, azetidine
alkaloids have captured tremendous interest from many
synthetic chemists due to their significant biological activity
and unique structure. To date, several syntheses of such
alkaloid compounds have been reported.6 The current synthetic
strategies rely on the construction of a highly functionalized
azetidine skeleton with the requisite stereogenic centers. For
example, Lin and co-workers reported the enantioselective
synthesis of penaresidin A via a 14-step construction of a highly
functionalized azetidine aldehyde 4 starting from divinyl-
carbinol, using Sharpless asymmetric epoxidation and Sharpless
Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore 637371.
E-mail: xuewei@ntu.edu.sg
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc09904d
Scheme 1 Strategies for construction of azetidine core in synthesis of
azetidine alkaloids.
‡ These authors contributed equally to this work.
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Fig. 2 Our strategy for synthesis of penaresidin B via 3-amino-2,3-
dideoxysugars.
D-galactal and involved Sharpless asymmetric epoxidation, regio-
selective ring-opening of epoxide and azetidine formation via
the SN2 reaction, was most recently accomplished by Reddy’s
group (Scheme 1, eqn (3)).6q Although results from most reports
are encouraging, poor stereoselectivities, low yields and lengthy
synthetic steps present major impediments for the reported
strategies to be widely applied. Hence, a short and straight
forward synthetic route to azetidine with contiguous stereogenic
centers in the enantiomerically pure form has remained a great
and significant challenge for the chemical community.
Scheme 2 Retrosynthetic analysis for a concise synthesis of penaresidin B.
With an aim to refine the synthetic route, we formulated a
novel strategy which incorporates our reported method for
ready access to 3-amino-2,3-dideoxysugars via the regio- and
stereoselective tandem hydroamination/glycosylation of glycal
as shown in Fig. 2.7 By extension of the synthetic utility of this
protocol and its application in the total synthesis of natural
products, we aim to demonstrate the efficient synthesis of
azetidine aldehyde from 3,4,6-tri-O-acetyl-D-galactal via a linear
sequence consisting of only 8 steps. Penaresidin B is envisioned
as the ideal target molecule for this demonstration (Scheme 1,
eqn (4)). Towards the end, the manner by which the above
mentioned general strategy could be exploited to accomplish
the shortest synthesis of azetidine alkaloids using commer-
cially available and inexpensive compounds will be discussed.
As azetidine alkaloids share a similar core structure and differ
mainly along their long alkyl chains, we developed a strategy that
focused on increasing structural and library diversity in a more
Scheme 3 8-Step construction of the core azetidine aldehyde 7.
efficient manner and hence paved the way for potential azetidine of 3,4,6-tri-O-acetyl-D-galactal, benzyl alcohol and p-toluene-
analogues to be synthesized for biological studies. Our retro- sulfonamide in DCE was subjected to treatment with 2.2 equiv.
synthetic analysis of penaresidin B is depicted in Scheme 2. We of BF3ÁOEt2 at room temperature under a nitrogen atmosphere
proposed that our target molecule can be obtained from inter- for 20 min. This led to the formation of benzyl 3-p-toluene-
mediate 8 which in turn could be formed via Julia–Kocienski sulfonamido-4,6-di-O-acetyl-2,3-dideoxy-a-D-galactopyranoside
olefination between azetidine aldehyde 7 and sulfone 9. The 11 in 78% yield with exclusive stereoselectivity. The exclusive
sulfone moiety 9 could be prepared through the Wittig reaction formation of pure diastereomer allowed easy purification of
of 12 with aldehyde 13, while the azetidine core 7, which can also the desired product using SiO2 flash column chromatography.
be regarded as an advanced intermediate for the synthesis of The determination of the chemical structure and stereo-
other azetidine alkaloids, can presumably be constructed from chemical characterization of 11 were achieved by extensive
ester 10 using intramolecular Mitsunobu cyclization. Ester 10 and detailed 1D and 2D NMR studies.8 The described protocol
could in turn be derived from 3-amino-2,3-dideoxygalactoside 11 resulted in an efficient and stereoselective formation of
via the Wittig reaction following removal of the benzyl group. 3-amino-2,3-dideoxygalactoside 11 with great reproducibility
Finally, the 3-amino-2,3-dideoxygalactoside 11 could be accessed on a gram scale synthesis albeit in slightly lower yields.
via regio- and stereoselective tandem hydroamination/glycosylation Sequentially, 11 was treated with Pd(OH)2/C under a hydrogen
of D-galactal in a one-pot manner.
atmosphere to allow the selective deprotection of the benzyl
The proposed synthesis of the key fragment 7 starting from group and this was followed by Wittig olefination of the
D-galactal is detailed in Scheme 3. In the initial step, a mixture resulting aldehyde 14 to form the unsaturated ester 15.
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double bond and removal of the benzyl group, which produced a
90% yield of alcohol 20 in one pot. Subsequently, alcohol 20 was
converted into thioether 22 using 1-phenyl-1H-tetrazole-5-thiol 21 in
the presence of PPh3/DIAD. This was followed by oxidation of
thioether 22 with a molybdenum salt and hydrogen peroxide to
give sulfone 9 with a 73% yield.12 The above mentioned protocol
produced an enantiopure sulfone with the required S-configuration
efficiently and stereoselectively. Additionally, it allows great
reproducibility on various scales.
Fig. 3 NOE correlations of compounds 16 and 18.
With the azetidine aldehyde 7 and sulfone fragment 9
successfully prepared, we embarked on the construction of the
C–C double bond via coupling of these two fragments. Assembly
of the azetidine core structure with the sulfone chain constitutes
the key step in this synthetic route. This was accomplished via
Julia–Kocienski olefination, using KHMDS as a base at À78 1C to
give olefin 8 in 81% yield.13 Sequential desilylation of 8 with
p-TSA in methanol furnished alcohol 22 in 90% yield (Scheme 5)
which was later converted to Ts-protected penaresidin B (23) in
49% yield upon treatment with 10% Pd/C under a hydrogen
atmosphere. In fact, the removal of the two Bn protecting groups
at this point proved rather challenging, as most methods
attempted either resulted in no reaction or caused incomplete
decomposition of the starting material. To our delight, after
numerous attempts, facile deprotection of the two benzyl groups
could be achieved with 10% Pd/C under a hydrogen atmosphere
to afford the desired products, with moderate yield. Ts-protected
penaresidin B (23) could be deprotected to eventually give the
penaresidin B in one step.6h,j,o,q In summary, starting from
the commercially available D-galactal, we have accomplished
the formal synthesis of penaresidin B in a linear sequence of
11 steps with an overall yield of 13%.
Notably, 2-deoxy-b-C-glycoside was obtained by intramolecular
cyclization when the reaction time was prolonged. Successive
treatment of 15 with 10% Pd/C under a hydrogen atmosphere
resulted in the reduction of the C–C double bond to form ester
10 with overall 43% yield in three steps. The subsequent
intramolecular Mitsunobu reaction in the presence of PPh3/
DIAD, which resulted in the conversion of ester 10 to the
azetidine core 16, proceeded smoothly with a 75% yield.9 This
step represents the key step in the present synthetic route as
the core structure azetidine is assembled along with the
requisite contiguous stereogenic centers. Removal of all the
acetyl groups present in 16 followed by protection with benzyl
groups resulted in the formation of compound 18, a benzyl
protected azetidine ester, with a yield of 96%. The determina-
tion of the chemical structure and stereochemical character-
ization of 16 and 18 were established based on extensive and
detailed 1D and 2D NMR studies, which showed a strong NOE
correlation between the protons of C-3 and C-4; and between
the protons of C-3 or C-4 and the protons of C-5; and between
the proton of C-2 and the protons of C-6, and no correlation
for H-2/H-4 (Fig. 3).8 Compound 18 was then subjected to
chemoselective reduction with DIBAL-H to afford azetidine
aldehyde 7 in a quantitative yield and was used directly in
Julia–Kocienski olefination. Azetidine aldehyde 7 is of great
significance in the natural product synthesis, as it comprises
the core structure of several azetidine alkaloids.
Overall, we have developed a short, high-yielding synthetic
approach for the formation of penaresidin B. The eight-step synthesis
of azetidine aldehyde with contiguous stereogenic centers entailed
our novel strategy for ready access to 3-amino-2,3-dideoxysugar via
Next, we shift our focus onto the preparation of the desired
sulfone 9. Wittig olefination of two known fragments, stable ylide
12 (prepared from pentane-1,5-diol in 3 steps)10 and aldehyde 13
(prepared from L-leucine in 4 steps),11 in the presence of n-BuLi,
was first carried out to afford the unsaturated ether 19 in
86% yield (Scheme 4). Treatment of 19 with Pd(OH)2/C under
a hydrogen atmosphere resulted in the reduction of the C–C
Scheme 4 Preparation of sulfone 9 required for Julia–Kocienski olefination.
Scheme 5 Formal synthesis of penaresidin B (2).
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to decrease the number of isolated steps and increase the efficiency of
the synthesis while the Julia–Kocienski olefination was employed to
couple the azetidine and side chain subunit. As three-component
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We gratefully acknowledge Nanyang Technological University
(RG6/13) and the Ministry of Education, Singapore (MOE 2009-
T2-1-030) for the financial support of this research.
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