Synthetic studies on lytophilippine A: Synthesis of the proposed structure

Article abstract of DOI:10.1021/ol2007296

Chemical equations presented. Synthesis of the proposed structure of lytophilippine A was accomplished employing SmI₂-mediated 5-exo cyclization of an aldehydo β-alkoxyvinyl sulfoxide and ring-closing metathesis reaction.

Full text of DOI:10.1021/ol2007296

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2476–2479
Synthetic Studies on Lytophilippine
A: Synthesis of the Proposed Structure
Ki Po Jang, Soo Young Choi, Young Keun Chung, and Eun Lee*
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul
151-747, Korea
eunlee@snu.ac.kr
Received March 17, 2011
ABSTRACT
Synthesis of the proposed structure of lytophilippine A was accomplished employing SmI2-mediated 5-exo cyclization of an aldehydo
β-alkoxyvinyl sulfoxide and ring-closing metathesis reaction.
Lytophilippine A is a representative member of the macro-
lactone natural products isolated from the sea hydroid
Scheme 1. Retrosynthetic Analysis
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Lytocarpus philippinus from the Red Sea. Rezanka and co-
workers proposed the structure 1 for lytophilippine A,1
and a recent report2 on a partial synthesis attests to the
current interest in this unique natural product. The most
characteristic feature in the structure of 1 is the macro-
lactone structure incorporating a hydroxyoxolane unit. In
the retrosynthetic analysis, three major fractions appeared
as viable parts in the final assemblage; the hydroxyoxolane
derivative A, the carboxylic acid B, and the side chain
halide C. We intended to obtain the key structural element
A through 5-exo cyclization of an aldehydo β-alkoxyvinyl
sulfoxide D. The stereochemical outcome of the 5-exo cy-
clizations of aldehydo (E)- and (Z)-β-alkoxyvinyl sulfox-
ides derived from a secondary alcohol is well established
from previous studies,3 and the synthesis of (11S,13S,
14R)-A requires use of (Z)-(R)-β-alkoxyvinyl sulfoxide D
(Scheme 1).
In practice, the known diol acetonide 34 was obtained
from D-ribose (2). TBS-protection of 3, mesylation of the
secondary hydroxyl group, TBS-deprotection, and base
treatment afforded epoxide 4. Reaction of 4 with lithiated
dithiane produced the secondary alcohol 5. Reaction of 5
with alkynyl sulfoxide 6 in the presence of ethylmagnesium
bromide and lithium chloride3 led to aldehydo (Z)-β-
alkoxyvinyl sulfoxide 7 after hydrolysis of the dithiane
unit. Reaction of 7 with SmI2 in THFÀmethanol (1:1)5
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(1) Rezanka, T.; Hanus, L. O.; Dembitsky, V. M. Tetrahedron 2004,
60, 12191–12199.
(2) Gille, A.; Hiersemann, M. Org. Lett. 2010, 12, 5258–5261.
(3) Jung, J. H.; Kim, Y. W.; Kim, M. A.; Choi, S. Y.; Chung, Y. K.;
Kim, T.-R.; Shin, S.; Lee, E. Org. Lett. 2007, 9, 3225–3228.
(4) Moon, H. R.; Choi, W. J.; Kim, H. O.; Jeong, L. S. Tetrahedron:
Asymmetry 2002, 13, 1189–1193.
(5) A higher concentration of methanol probably prevented a retro-
Michael reaction, and a higher yield of 8 was obtained.
r
10.1021/ol2007296
Published on Web 04/12/2011
2011 American Chemical Society

yielded mainly (dr 9:1) the 3-hydroxyoxolane product 8,
which was isolated in 72% yield (Scheme 2).
product was reduced by lithium borohydride to yield the
primary alcohol 26.
Scheme 3. Synthesis of the B Fragment
Scheme 2. Synthesis of the A Fragment
The known carboxylic acid 10 was prepared via asym-
metric hydrogenation6 of monomethyl itaconate (9),anddiol
11 was obtained from 10 following the known proce-
dures.7 Aldehyde 12 was prepared from 11 via TBS-protec-
tion and oxidation. Addition of the lithiated dithiane to 12
proceeded under modest stereocontrol (d.r. 4.6:1), and PMB-
protection, TBS-deprotection, and oxidation produced alde-
hyde 13. Wittig olefination of 13 and dithiane hydrolysis led
to aldehyde 14, which reacted with the (Z)-boron enolate
prepared from imide 15.8 The aldol reaction proceeded
stereoselectively (dr >19:1) in high yield, and the product
alcohol 16 was converted to the corresponding TBS or TES
ether (17a and 17b). The B fragment carboxylic acid 18a and
18b were efficiently prepared upon hydrolysis (Scheme 3).
L-Ascorbic acid (19) served as the starting material for
the C fragment, and epoxide 20 was prepared following
the known procedures.9 The secondary alcohol 21 was
obtained via reaction with allylmagnesium bromide in
the presence of cuprous iodide. Chloride substitution of
the hydroxy group in 21 proceeded smoothly to produce
chloride 22, and oxidative cleavage of the terminal double
bond afforded carboxylic acid 23.10 Methylation of the
sodium enolate of the chiral imide 25 prepared from 23 and
oxazolidinone 24 was highly stereoselective, and the
The corresponding aldehyde was obtained from 26
via DessÀMartin oxidation, which reacted under Roush
crotylation conditions11 using the chiral boronate 27 to
produce the secondary alcohol 28 (dr >19:1). TMS-
protection of the hydroxy group in 28 and ozonolysis
produced aldehyde 29, which reacted with the vinyllithium
reagent prepared from the known vinyl iodide 30.12 This
addition proceeded under high stereocontrol (dr 12:1), and
the allylic alcohol 31 was produced in good yield. Acet-
onide protection on 31, TBS-deprotection, and iodide
substitution led efficiently to the C fragment iodide 32
(Scheme 4).
Coupling of the A and B fragments involved Mitsunobu
reaction13 between 8 and 18a, which proceeded efficiently
to produce ester 33. Pummerer rearrangement of 33 and
reductive workup followed by TBS-protection led to a new
diene ester 34. The crucial ring-closing olefin metathesis
(6) (a) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39,
3889–3890. (b) Ostermeier, M.; Brunner, B.; Korff, C.; Helmchen, G.
€
Eur. J. Org. Chem. 2003, 3453–3459. (c) Furstner, A.; Bouchez, L. C.;
ꢁ
Funel, J.-A.; Liepins, V.; Poree, F.-H.; Gilmour, R.; Beaufils, F.;
Laurich, D.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46, 9265–9270.
(7) Betche, H.-J.; Irdam, E. A.; Padilla, A. G.; Pearlman, B.; Perrault,
W. R.; Vanalsten, J.; Franczyk, T. S. WO 2007/010387 A2.
(8) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127–2129.
(11) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterma, R. L. J. Am. Chem. Soc. 1990, 112, 6339–6348.
(12) Kalesse, M.; Chary, K. P.; Quitschalle, M.; Burzlaff, A.; Kasper,
C.; Scheper, T. Chem.;Eur. J. 2003, 9, 1129–1136.
(13) Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc. Jpn. 1967, 40,
2380–2382.
(9) Cho, B. H.; Kim, J. H.; Jeon, H. B.; Kim, K. S. Tetrahedron 2005,
61, 4341–4346.
(10) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936–3938.
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
Org. Lett., Vol. 13, No. 9, 2011
2477

steps. In particular, the TBSO-group at C-3 of 37 appeared
to be the source of the problem.
Scheme 4. Synthesis of the C Fragment
Scheme 5. Synthesis of the Macrolactone Intermediates
The alternative route commenced with the inversion of
stereochemistry at C-13; Mitsunobu reaction on 8 with
p-nitrobenzoic acid and hydrolysis, TBS-protection, and
Pummerer rearrangement afforded the aldehydo hydro-
xyoxolane intermediate 38.16
Treatment of the primary iodide 32 with 2 equiv of tert-
butyllithium and then addition of aldehyde 38 led to the
efficient formation of a mixture (dr 1.6:1) of alcohols
favoring 39.17 Stereoselectivity did not improve under
different reaction conditions. TBS-deprotection of 39 led
to a diol intermediate, which was converted into the diene
ester 40 via reaction with 18b and TBS-protection. The
ring-forming olefin metathesis reaction of 40 proceeded
efficiently (88%) to yield a single macrolactone 41. Finally,
the conversion of 41 to the target structure 1 involved
PMB-deprotection of 41 using DDQ, DessÀMartin oxida-
tion, silyl group deprotection by prolonged exposure to
hydrogen fluorideÀpyridine, and acetonide deprotection
(Scheme 6).
reaction in the presence of the second generation Grubbs
catalyst14 produced a single macrolactone product, and
TBS-deprotection yielded macrolactone 35 efficiently. The
structure of 35 was confirmed via X-ray diffraction
studies.15
Aldehyde 36 was then prepared from 35 via DessÀ
Martin oxidation. Reaction of aldehyde 36 with the orga-
nolithium compound prepared from the primary iodide 32
was sluggish, producing approximately 10% of the cou-
pling productscontaining the secondary alcohol 37and the
corresponding epimer (dr 4:1) (Scheme 5).
The coupling reaction was inefficient, and it was clear
that adjustments should be made in the sequence of mac-
rolactone formation and the side chain addition. Further-
more, difficulties were encountered in the deprotection
Unfortunately, physical data of the final product 1 did
not match the data reported for the natural product.1 The
(16) From previous studies,3 it is known that the present sequence is
more efficient overall than the direct use of (Z)-(S)-β-alkoxyvinyl
sulfoxide.
(17) See the Supporting Information for the stereochemical assign-
ment through the corresponding carbonates.
(15) The structure of 35 was confirmed by X-ray diffraction studies.
CCDC 812839 contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
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Org. Lett., Vol. 13, No. 9, 2011

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structure 1 put forward by Rezanka and co-workers
appears to be in error.18
Scheme 6. Synthesis of the Proposed Structure of 1
In summary, the key hydroxyoxolane fragment of the
proposed structure of lytophilippine A (1) was prepared
through SmI2-mediated 5-exo cyclization of an aldehydo
β-alkoxyvinyl sulfoxide. The 14-membered macrolactone
was synthesized via a ring-closing olefin metathesis reac-
tion. Correction of the structure of lytophilippine A is
necessary, and future studies should focus on finding the
correct structure.
Acknowledgment. This work was supported by a grant
from Marine Biotechnology Program funded by the
Ministry of Land, Transport and Maritime Affairs,
Republic of Korea. This research was also supported by
the National Research Foundation Basic Science Research
Program funded by the Ministry of Education, Science,
and Technology (KRF-2008-314-C00198). BK21 gra-
duate fellowship grants to K.P.J. and S.Y.C. and a
Seoul Science Fellowship grant to S.Y.C. are gratefully
acknowledged.
Supporting Information Available. Experimental pro-
1
cedures and H and 13C NMR spectra of the intermedi-
ates and products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) Comparison of NMR data was problematic, because the origi-
1
nal report by Rezanka and co-workers did not specify the NMR solvent
ꢀ
they used. We recorded NMR spectra of 1 in methanol-d4, acetone-d6,
THF-d8, acetonitrile-d3, pyridine-d5, CDCl3, DMSO-d6, CDCl3À
DMSO-d6 (4:1), and D2O, and none matched the reported data. We
did not yet find any crystalline derivative of 1.
Org. Lett., Vol. 13, No. 9, 2011
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