Asymmetric first total syntheses and assignment of absolute configuration of oxazinin-5, oxazinin-6 and preoxazinin-7

Article abstract of DOI:10.1039/c1ob06320k

Asymmetric first total syntheses of the unprecedented toxins oxazinin-5, oxazinin-6 and preoxazinin-7 have been achieved from a common key intermediate 18, derived from a regiocontrolled Sharpless asymmetric aminohydroxylation and oxa-Michael reaction, which in addition to confirming the structure also established the absolute configuration of the natural products. On the way an expeditious synthesis of a metabolite bursatellin was completed in 8 steps. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06320k

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Asymmetric first total syntheses and assignment of absolute configuration of
oxazinin-5, oxazinin-6 and preoxazinin-7†‡
Dattatraya H. Dethe,* Alok Ranjan and Vijendra H. Pardeshi
Received 3rd August 2011, Accepted 14th September 2011
DOI: 10.1039/c1ob06320k
Asymmetric first total syntheses of the unprecedented toxins
oxazinin-5, oxazinin-6 and preoxazinin-7 have been achieved
from a common key intermediate 18, derived from a re-
giocontrolled Sharpless asymmetric aminohydroxylation and
oxa-Michael reaction, which in addition to confirming the
structure also established the absolute configuration of the
natural products. On the way an expeditious synthesis of a
metabolite bursatellin was completed in 8 steps.
Oxazinins are a new and intriguing class of cytotoxic compounds
which are hazardous to human health and can cause serious loss
to shellfish industries.1 Fattorusso and Ciminiello et al. reported
the isolation and the structural elucidation of the unprecedented
toxins oxazinin-1 (1), -2 (2) -3 (3) and -4 (4) (Fig. 1) from
the digestive glands of Mytilus galioprovincialis,2,3 marine toxins
Fig. 1 Structures of oxazinin-1, -2, -3, -4, -5, -6, preoxazinin-7 and
bursatellin.
from edible mussels of the North Adriatic Sea. The absolute
stereochemistry of both oxazinin-1 (1) and -2 (2) was assigned by
applying the Riguera’s method4 by the same group.5 Subsequently
in 2007 they reported structures and relative stereochemistries
of two more oxazinins (oxazinin-5 (5) and -6 (6)) and a related
linear precursor preoxazinin-7 (7)6 (Fig. 1). Determination of
the structure and the relative stereochemistry of all oxazinins
was based on spectroscopic evidence including extensive 2D
NMR and Molecular Mechanics (MM) calculations. In 1980 a
structurally similar metabolite bursatellin 87 whose structure was
later revised in 19878 was isolated from sea hare Bursatella leachii
pleii. Structurally bursatellin 8 resembles preoxazinin-7 (7) except
that the indole glyoxylic amide moiety in preoxazinin is replaced
by simple formamide functionality. Oxazinin-l (1) was shown to
inhibit the growth of WEHI 164 and 1774 cell lines in vitro.2
Preliminary toxicological studies performed on oxazinins bring to
light that their cytotoxicities are due to the –CN functionality.2
Oxazinins contain three structural units: an indole, a central
morpholinone ring containing two or three substituents, and
a substituted phenol ring. Scarce availability of the oxazinin
compounds limits the evaluation of the extent of threat posed
to human health. Synthetic approaches therefore are crucial to
obtain a quantity of the pure compounds that is sufficient for
comprehensive toxicological studies, indeed synthetic efforts from
Couladouros et al. culminated in the synthesis of a simple member
of this family oxazinin-3 (3).9 Subsequently Baran et al. also
reported an expedient synthesis of oxazinin-3 (3) using the direct
coupling of indole to carbonyl compound in 4 steps from a
known compound.10 In 1990 Sodano et al. reported the semi-
synthesis of bursatellin 8 from chloramphenicol,11 and later in
1995 Hiroshi IRIE et al. reported the total synthesis of bursatellin
8 in 16 steps starting from L-tryptophan,12 but so far there
are no reports in the literature on the synthesis of any other
oxazinins. Herein we report expedient and efficient asymmetric
first total syntheses of preoxazinin-7 (7), oxazinin-5 (5) and -6
(6) using Sharpless asymmetric aminohydroxylation, oxa-Michael
reaction and the intramolecular cyclisation of hydroxyl to form
the central morpholine ring as key steps. The key retrosynthetic
disconnection of our strategy involves the C(2)–O(1) bond. It
was based on the hypothesis that the central morpholinone
ring of the oxazinins might be formed through intramolecular
diastereoselective addition of an appropriate hydroxyl substituent
to a 3-methyleneindolenine (9, Scheme 1), which in turn could
be generated in situ from 3-hydroxymethylindoles 10a,b. Finally,
further disconnection at the amide bondrevealed 3-indoleglyoxylic
acid chloride 11 and tyrosine derivative 12 as appropriate building
blocks. Compound 12 could be obtained from 13, which in
turn could be obtained from p-hydroxybenzaldehyde 14 by HWE
Division of Organic Chemistry, National Chemical Laboratory (CSIR),
Pune, 411 008, India
† Dedicated to Prof. S. Chandrasekaran, Indian Institute of Science,
Bangalore, on the occasion of his 65th birthday.
‡ Electronic supplementary information (ESI) available: Experimental
1
procedures and copies of H NMR, 13C NMR and DEPT spectra of all
new compounds. See DOI: 10.1039/c1ob06320k
7990 | Org. Biomol. Chem., 2011, 9, 7990–7992
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under various reaction conditions also failed to give the expected
product. Finally to our delight the oxa-Michael reaction of
aminophenol 16 with acrylonitrile using a catalytic amount of
Triton-B under reflux conditions gave the desired cyanoethylation
product 12 in 92% yield. The ester group in 12 was then
reduced using lithium borohydride to afford primary alcohol
17. Routine and simple Boc-deprotection proved to be more
complex and led to multiple products and decomposition under
various conditions such as TFA–CH2Cl2,15a TFA–triethylsilane,15b
4M HCl in dioxane,15c CAN,15d TMSOTf,15e and 10% H2SO4
15f
and TMSI.15g Interestingly treatment of 17 with a stoichiometric
amount of Yb(OTf)3 under CH2Cl2 reflux conditions generated
Boc-deprotected amine 18, which upon N-formylation with ethyl
formate followed by removal of the TBS group using TBAF gave
bursatellin 8 in 80% yield as a mixture of rotamers due to restricted
rotation around the N-formyl bond. Its◦spectroscopic properties
(1H, 13C, mass) and [a]D25 value ([a]2D5 -8.6 (c = 0.6, MeOH) were in
good agreement with that of the natural (-)-bursatellin ([a]2D5 -8.8◦
(c = 2.4, MeOH), indicating the accomplishment of the synthesis
of 8 starting from p-hydroxybenzaldehyde.
Scheme 1 Retrosynthetic analysis.
reaction followed by asymmetric aminohydroxylation. An expe-
dient route to building block 12 took advantage of the Sharpless
asymmetric aminohydroxylation reaction, as shown in Scheme 2.
Alternatively coupling of compound 18 with indole glyoxylic
chloride using Et3N generated the TBS-protected preoxazinin-
7 (19) in 70% yield (Scheme 3). Deprotection of TBS group
generated preoxazinin-7 (7) in 78% yield, identical in all respects
(CD, IR, Mass, 1H, 13C) to natural preoxazinin-7.6 For the
synthesis of oxazinin-5 (5) and -6 (6), reduction of the ketone
functionality of the 3-indoleglyoxylic amide 19 by employing
NaBH4 afforded the diastereomeric mixture of diols 10a,b that
upon subsequent treatment with PPTS in refluxing acetonitrile
furnished morpholinones 20a,b as a 3 : 1 mixture of C-2 diastere-
omers. The two diastereomers 20a and 20b were separated by
preparative TLC. Finally individual TBS-deprotection of major
20a and minor 20b isomers provided oxazinin-5 (5) and -6 (6)
respectively along with minor amount of cyanoethyl side chain
Scheme 2 Completion of the synthesis of (-)-bursatellin.
The required starting material for this reaction, the cinnamate
15, was obtained from p-hydroxybenzaldehyde 14 by benzylation
using K2CO3, BnBr and a catalytic amount of TBAI (98%
yield), followed by reaction with PPh3 CHCO2Et (95% yield).
Substrate 15 was used in the Sharpless asymmetric aminohy-
droxylation reaction13 [NaOH, BocNH2, tBuOCl, (DHQD)2AQN,
K2OsO2(OH)4, nPrOH–H2O (1 : 1)], affording directly amino
alcohol 13 in its Boc-protected form in 45% yield and 92% ee
(chiral HPLC). The hydroxy group in 13 was then protected
as its TBS ether (TBSCl, imidazole, 98% yield), followed by
hydrogenolysis [H2, 5% Pd/C, 97% yield] to afford Boc-protected
amino phenol 16.
Attempts at cyanoethylation of the phenolic hydroxyl group in
the aminophenol 16 with acrylonitrile using several kinds of bases
such as NaHCO3, KHCO3, K2CO3 and NaH were unsuccessful as
a result of the retro-Michael fragmentation reaction, as mentioned
by the two independent groups of G. Sodano et al. and Hiroshi
IRIE et al. in their syntheses of bursatellin.11,12 Ph3P/acrylonitrile14
Scheme 3 Synthesis of preoxazinin-7, oxazinin-5 and -6.
Org. Biomol. Chem., 2011, 9, 7990–7992 | 7991
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cleaved compounds 21a and 21b. The synthetic oxazinin-5 (5)
3 P. Ciminiello, C. Dell’Aversano, E. Fattorusso, M. Forino, S. Magno,
F. U. Santelia, V. I. Moutsos, N. Emmanuel, E. N. Pitsinos and E. A.
Couladouros, Tetrahedron, 2006, 62, 7738.
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1
and -6 (6) exhibited IR, H and 13C NMR, and mass spectra,
as well as the sign of the CD curves, identical with those of the
natural oxazinins-5 and -6,6 thus confirming the stereostructure
of the natural products as well as establishing their absolute
configuration.
In conclusion, concise total syntheses of preoxazinin-7 (7),
oxazinin-5 (5), oxazinin-6 (6) and bursatellin 8 were achieved. Our
synthetic route features four highlights: (1) application of a key
intermediate for syntheses of four natural products; (2) application
of Sharpless asymmetric aminohydroxylation; (3) oxa-Michael re-
action for introduction of cyanoethyl side chain; (4) intramolecular
diastereoselective addition of an appropriate hydroxyl substituent
to a 3-methyleneindolenine for the construction of morpholine
ring. The application of this route paves the way for the total
syntheses of other oxazinins and related natural products which
are underway in our laboratory and will be reported in due course.
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13 B. Tao, G. Schlingloff and K. B. Sharpless, Tetrahedron Lett., 1998, 39,
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Acknowledgements
14 H.-L. Liu, H.-F. Jiang and Y.-G. Wang, Chin. J. Chem., 2007, 25,
1023.
AR thanks CSIR, New Delhi, for a junior research fellowship.
This work was funded by department of Science and technology
(DST), project no. GAP 291026.
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7992 | Org. Biomol. Chem., 2011, 9, 7990–7992
This journal is
The Royal Society of Chemistry 2011
©