(-)-lytophilippine a: Synthesis of a C1-C18 building block

Article abstract of DOI:10.1021/ol1023008

The convergent enantioselective synthesis of a protected C1-C18 building block for the total synthesis of (-)-lytophilippine A was achieved. A catalytic asymmetric Gosteli-Claisen rearrangement and an Evans aldol reaction served as key C/C-connecting transformations during the assembling of the C1-C7 subunit (10 steps from 4, 29%). The synthesis of the C8-C18 segment was achieved utilizing d-galactose as inexpensive ex-chiral-pool starting material (15 steps, 15%). The merger of the subunits was accomplished by a remarkably efficient sequence consisting of esterification and ring-closing metathesis (five steps, 56%).

Full text of DOI:10.1021/ol1023008

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5258-5261
(-)-Lytophilippine A: Synthesis of a
C1-C18 Building Block
Annika Gille* and Martin Hiersemann*
Fakulta¨t Chemie, Technische UniVersita¨t Dortmund, 44227 Dortmund, Germany
annika.gille@tu-dortmund.de; martin.hiersemann@udo.edu
Received September 24, 2010
ABSTRACT
The convergent enantioselective synthesis of a protected C1-C18 building block for the total synthesis of (-)-lytophilippine A was achieved.
A catalytic asymmetric Gosteli-Claisen rearrangement and an Evans aldol reaction served as key C/C-connecting transformations during the
assembling of the C1-C7 subunit (10 steps from 4, 29%). The synthesis of the C8-C18 segment was achieved utilizing D-galactose as
inexpensive ex-chiral-pool starting material (15 steps, 15%). The merger of the subunits was accomplished by a remarkably efficient sequence
consisting of esterification and ring-closing metathesis (five steps, 56%).
Marine organisms continue to be a prolific source for
structurally novel and pharmacologically active natural
products.1 Members of the macrolide family of polyketides
display a wide range of biological activities and have been
prominent targets for total synthesis.2
of the absolute configuration was accomplished. The 27-
carbon atom backbone of 1 features 17 stereogenic carbon
atoms and is characterized by two domains: the C1-C13
macrolactone and the C14-C27 side chain. Attracted by the
architectural challenges presented by the complex structure
of 1, we devised a general retrosynthetic strategy that leads
to three building blocks of comparable molecular complexity
(Figure 1). In this paper, we report robust and scalable
syntheses of the C1-C7 segment 2 and the C8-C18 segment
3 as well as their assembly to an orthogonally protected
C1-C18 building block.
The isolation of the complex macrolide (-)-lytophilippine
A (1) from the stinging hydroid Lytocarpus philippinus was
ˇ
reported in 2004 by Rezanka and co-workers (Figure 1); an
in vivo antitumor activity has been suggested for 1.3 The
gross structure of 1 was deduced from a combination of
extensive NMR, IR, and mass spectroscopic techniques. The
assignment of the relative configuration rests on NOESY
studies as well as on empirical rules relating to chemical
shifts and coupling constants. Finally, derivatization (Mosher
esters, acetonides), oxidative degradation, and chemical
correlation provided the basis from which the determination
Key to our synthesis of the C1-C7 segment 2 is the
enantiomerically pure R-keto ester 6 which was accessed by
the catalytic asymmetric Gosteli-Claisen rearrangement4 of
the known allyl vinyl ether 45 in the presence of [Cu{(S,S)-
(1) Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.; Northcote,
P. T.; Prinsep, M. R. Nat. Prod. Rep. 2009, 26, 170–244.
(4) (a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem.,
Int. Ed. 2001, 40, 4700–4703. (b) Abraham, L.; Ko¨rner, M.; Schwab, P.;
Hiersemann, M. AdV. Synth. Catal. 2004, 346, 1281–1294.
(2) (a) Jackson, K. L.; Henderson, J. A.; Phillips, A. J. Chem. ReV. 2009,
109, 3044–3079. (b) Roy, M.; Kalesse, M. Nat. Prod. Rep. 2008, 25, 862–
870. (c) Colby, E. A.; Jamison, T. F. Org. Biomol. Chem. 2005, 3, 2675–
2684. (d) Yeung, K.-S.; Paterson, I. Chem. ReV. 2005, 105, 4237–4313.
(5) Compound 4 has been prepared on 20 g scale in five steps from
commercial 2-butyn-1-ol according to the published procedure; see: Rehbein,
J.; Leick, S.; Hiersemann, M. J. Org. Chem. 2009, 74, 1531–1540. The
synthesis requires access to preparative HPLC for the separation of vinyl
ether double bond isomers.
ˇ
(3) Rezanka, T.; Hanusˇ, L. O.; Dembitsky, V. M. Tetrahedron 2004,
60, 12191–12199.
10.1021/ol1023008  2010 American Chemical Society
Published on Web 10/25/2010

Scheme 1
Figure 1. Synthetic strategy toward (-)-lytophilippine A 1. TPS
) t-BuPh2Si.
t-Bu-box}(H2O)2](SbF6)2 (5,6 0.05 equiv) in CH2Cl2 at room
temperature (Scheme 1). This operationally simple and robust
procedure is amenable to multigram scale without loss of
chemo- or stereoselectivity.7
The matched doubly diastereoselective reduction of the
R-keto ester 6 employing the Me-Corey-Bakshi-Shibata
(CBS) catalyst (R)-7 provided the R-hydroxy ester 8 as single
diastereomer after flash chromatography.8 Inversion of the
configuration at C2 was accomplished by Mitsunobu reac-
tion,9 and subsequent reduction with LiBH410 delivered the
diol 9. Transacetalization of the dimethyl acetal of p-methoxy
benzaldehyde with the diol 9 under Brønsted acid catalysis
afforded the corresponding cyclic acetal, which was reduc-
tively cleaved, and the resulting primary alcohol was
subsequently oxidized to provide the aldehyde 10.11,12 The
missing stereogenic carbon atoms were then set by a matched
doubly diastereoselective Evans aldol reaction between the
R-chiral aldehyde 10 and the acylated Evans auxiliary 11.13,14
The short route to 2 finally was completed by the introduction
of a TBS protecting group and the removal of the chiral
auxiliary.15,16
We continued our synthetic endeavor with the elaboration
of D-galactose (13) as an ex-chiral-pool building block in
the context of the present purpose (Scheme 2).17 Hence, the
bis(acetonide) of 13 was prepared and the remaining hy-
droxyl group was subjected to the conditions of a redox
condensation to afford the iodide 14.18 Subsequent ꢀ-elim-
ination in the presence of Zn and catalytic amounts of vitamin
B1219 delivered a cyclic hemiacetal which was reduced to
provide the diol 15.17 Regioselective tosylation20 of the
primary hydroxyl group introduced a capable leaving group
for a Kolbe nitrile synthesis. The resulting nitrile was
converted into the silyl ether 16 and then reduced21 to afford
(6) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem.
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(7) For selected applications of the catalytic asymmetric Gosteli-Claisen
rearrangement in natural product synthesis, see: (a) Pollex, A.; Hiersemann,
M. Org. Lett. 2005, 7, 5705–5708. (b) Ko¨rner, M.; Hiersemann, M. Org.
Lett. 2007, 9, 4979–4982.
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1998, 39, 4363–4366
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.
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109, 5551–5553. Reduction in the presence of (R)-7 provided (2S)-8 in
87% (dr ) 93:7). Treatment with K-Selectride also delivered (2S)-8 (81%,
dr ) 85:15), albeit with limited scalability (1 g). Far inferior yields (60%)
and diastereoselectivities (dr ) 4:1) were obtained with (S)-7.
(9) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380–2382. (b) Mitsunobu, O. Synthesis 1981, 1–28.
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103, 2127–2129
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Org. Lett., Vol. 12, No. 22, 2010
5259

construction of the tetrahydrofuran had to be put into practice
(Scheme 2). At first, the absolute configuration at C13 was
set by a CBS reduction of the enone 19 which delivered the
corresponding allylic alcohol in 72% yield (dr >95/5) after
chromatographic separation of the minor diastereomer (crude
product dr ) 9/1). Chemoselective cleavage of the TBS ether
then provided the diol 20 which was epoxidized with
m-CPBA25 to deliver a 3/2 mixture of the corresponding
diastereomeric oxiranes in 95% yield. Attempts to improve
the diastereoselectivity of the substrate-directed epoxidation
were unsuccessful; the VO(acac)2/t-BuOOH epoxidation26
favored the formation of the undesired diastereomer (dr )
15:85), and the outcome of a Katsuki-Sharpless asymmetric
epoxidation (SAE)27 (L-(+)-DIPT, Ti(O-i-Pr)4, t-BuOOH)
was dedicated by an unfortunate divergent interplay of
substrate- and catalyst-induced diastereoselectivity (dr ) 1:1).
Subsequent treatment of the 3/2 diastereomeric mixture from
the Prileschajew epoxidation with (+)-10-camphorsulfonic
acid (CSA)28 in acetone provided, after chromatographic
separation, the desired C8-C18 segment 3 (55%) as well
as the acetonide 21 (37%); 21 was formed from the diol
which resulted from the SNi ring-opening of the undesired
diastereomer of the epoxidation. The configuration of the
newly generated stereogenic carbon atoms was deduced from
NOE experiments.
Scheme 2
In order to gain insights into the reason(s) for the
remarkable diastereomer-differentiating acetalization, DFT
calculations using the functionals B1B95,29 M05-2X30
(hybrid meta-GGA), and B3LYP31 (hybrid GGA) were
performed for the model systems II and III (Figure 2).32
Geometry optimization and harmonic vibrational frequency
calculations were realized using the 6-311++G(d,p) basis
set. System II represents a simplification of the experimen-
tally observed acetonide 21, and system III was used as a
model for the inaccessible acetonide of the diol 3; in both
cases, the C8-C10 and the C16-C18 appendixes were
replaced by a methyl group in order to limit the computa-
tional cost. In support of the experimental observation, the
B3LYP calculations then demonstrate that the cis-
bicyclo[4.3.0]nonane-like model II is 1.6 kcal/mol more
stable than the trans-annulated model acetal III. Notably,
our B3LYP computations predict a more pronounced dipole
moment for the cis-annulated acetal II (2.4 D) compared to
III (1.3 D); therefore, the enthalpic preference for the
the corresponding aldehyde. Using the aldehyde as an
electrophile toward lithiated trimethyl phosphonate furnished
a ꢀ-hydroxy phosphonate that was oxidized12 to deliver the
ꢀ-keto phosphonate 17. Subsequent HWE reaction between
17 and the aldehyde 1822,23 (TPS ) t-BuPh2Si) using
Paterson conditions24 afforded the C8-C18 building block
19 in a remarkable yield.
(25) Prileschajew, N. Ber. Dtsch. Chem. Ges. 1909, 42, 4811–4815.
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6136–6137.
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5976.
With a concise synthesis of the carbon backbone of the
C8-C18 segment 3 in place, the projected key steps for the
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1979, 101, 260–262. (b) Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 2000,
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Filla, S. A.; Masamune, S. Angew. Chem., Int. Ed. Engl. 1994, 33, 673–
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(22) Prepared in four steps from 11; see: (a) Lin, N.-H.; Overman, L. E.;
Rabinowitz, M. H.; Robinson, L. A.; Sharp, M. J.; Zablocki, J. J. Am. Chem.
Soc. 1996, 118, 9062–9072. (b) Mulzer, J.; Langer, O. J. Org. Chem. 2000,
65, 6540–6546 (enantiomer). (c) Evans, D. A.; Bender, S. L.; Morris, J.
J. Am. Chem. Soc. 1988, 110, 2506–2526. (d) Gramatica, P.; Manitto, P.;
Monti, D.; Speranza, G. Tetrahedron 1988, 44, 1299–1304. Experimental
details are provided in the Supporting Information.
(29) Becke, A. D. J. Chem. Phys. 1996, 104, 1040–1046.
(30) Zhao, Y.; Truhlar, D. G. Org. Lett. 2006, 8, 5753–5755.
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Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785–789.
(32) The calculations were carried out with Gaussian03, see: Frisch,
M. J. Gaussian 03, reVision E.01; Gaussian, Inc.: Wallingford, CT, 2004.
Full reference given in the Supporting Information.
(23) Keyling-Bilger, F.; Schmitt, G.; Beck, A.; Luu, B. Tetrahedron
1996, 52, 14891–14904
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5260
Org. Lett., Vol. 12, No. 22, 2010

Scheme 3
Figure 2. Structural models and relative enthalpies (kcal/mol)
of model acetals predicted by DFT calculations at the B3LYP/
6-311++G(d,p), (B1B95/6-311++G(d,p)), and [M05-2X/6-
311++G(d,p)] level.
formation of II would be even more significant in the
condensed phase.33
Having accomplished the synthesis of 2 and 3, we were
able to address the merger of the subunits to create the
desired 14-membered macrolide (Scheme 3). Toward this
end, we selected a sequence consisting of esterification and
subsequent ring-closing metathesis. To our delight and
surprise, esterification of the acid 2 with the diol 3 under
the conditions reported by Shiina (MNBA ) 2-methyl-6-
nitrobenzoic anhydride) proceeded completely regioselective
to deliver the ester 22 (94%)!34 Even more impressive was
the efficiency of the subsequent ring-closing metathesis
(RCM) event provided that the C15 hydroxyl group was
protected first. Hence, following the uneventful introduction
of a TBS protecting group, the RCM using the second-
generation Grubbs precatalyst 2535 at elevated temperatures
delivered the macrolide 23 in very good yield (90%).36 The
final obstacle was the chemoselective cleavage of the primary
TPS ether in the presence of two secondary TBS ethers. After
extensive experimentation we found that a large excess of
NH4F37 (100 equiv) in hexafluoroisopropanol (HFIP) pos-
sessed the well-balanced reactivity required and subsequent
oxidition of the resulting alcohol afforded the aldehyde 24
which could be purified by chromatography.
In summary, we have established a highly convergent
synthesis of the aldehyde 24 which would seem to represent
a promising building block for further elaboration. We are
now directing our attention to the synthesis of segment I
and, subsequently, the completion of the total synthesis of
(-)-lytophilippine A (1).
Acknowledgment. Financial support of this work was
provided by the Deutsche Forschungsgemeinschaft (HI 628/
11, HI628/4) and the Technische Universita¨t Dortmund. We
are grateful for a donation of L-tert-leucine by Evonik
Degussa GmbH. Computer time was provided by the IT
& Medien Centrum of the TU Dortmund. A.G. thanks
Alexandra Ho¨lemann (TU Dortmund) for advice related to
carbohydrate chemistry and Claudia God as well as Sandra
Bo¨rding (both TU Dortmund) for skillful technical assistance.
(33) Single-point self-consistent reaction field (SCRF) calculations using
the PCM solvation model as implemented in Gaussian 03 (PCM, solvent
) acetone) at the PCM//B3LYP/6-311++G(d,p) level support this notion
and predict a free energy difference of 4.0 kcal/mol in favor of II.
(34) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org. Chem.
2004, 69, 1822–1830.
(35) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
Supporting Information Available: Computational de-
(36) The vicinal 3J coupling constant of the vinylic protons of 23 (16.1
Hz) is in good accordanced with reported value for the natural product
(15.2 Hz).
tails, experimental procedures, spectral and analytical data,
1
and copies of H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(37) NH4F in MeOH, see: Zhang, W.; Robins, M. J. Tetrahedron Lett.
1992, 33, 1177–1180. However, attempts to perform the reaction in MeOH
or various other alcohols, including CF3CH2OH, were not successful.
OL1023008
Org. Lett., Vol. 12, No. 22, 2010
5261