Synthesis of a diastereomer of the marine macrolide lytophilippine A

Article abstract of DOI:10.1021/acs.orglett.9b00722

The synthesis of a diastereomer of lytophilippine A required 22 longest linear steps using known building blocks. Cross-metathesis/asymmetric aldol addition and regioselective esterification/ring-closing metathesis served as efficient combi tools for scaffold construction. Detailed NMR investigations in different solvent (systems) provide evidence for a deep-seated configurational misassignment of the molecule named lytophilippine A.

Full text of DOI:10.1021/acs.orglett.9b00722

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of a Diastereomer of the Marine Macrolide Lytophilippine
A
́
̈
Andre Kluppel, Annika Gille, Ceren Ester Karayel, and Martin Hiersemann*
̈
̈
̈
Fakultat fur Chemie und Chemische Biologie, Technische Universitat Dortmund, 44227 Dortmund, Germany
S
* Supporting Information
ABSTRACT: The synthesis of a diastereomer of lytophi-
lippine A required 22 longest linear steps using known
building blocks. Cross-metathesis/asymmetric aldol addition
and regioselective esterification/ring-closing metathesis served
as efficient combi tools for scaffold construction. Detailed
NMR investigations in different solvent (systems) provide
evidence for a deep-seated configurational misassignment of
the molecule named lytophilippine A.
n 2004, Rezanka and co-workers reported the isolation and
structural characterization of the [14]macrolide lytophilip-
pine A (1a) from a sample of the sessile marine animal
Macrorhynchia philippina (alias Lytocarpus philippinus).1 The
stinging hydroid is widely distributed and sometimes
considered invasive.2 However, its natural product chemistry
has been only sparsely investigated.3
The intricate structure of lytophilippine A is distinguished
by the large number of stereogenic carbon atoms (17) relative
to the overall chain length (27) (Figure 1).4,5 Thus,
ensemble including a chlorine-substituted stereogenic carbon
atom C25.6
I
In 2010, some of us reported the synthesis of a C1−C18
building block featuring the originally reported absolute
configuration of 1a.7 The synthesis of a smaller tetrahydrofuran
segment was published by Hodgson and Salik in 2012.8 In
2011, Lee et al. published the total synthesis of 1a;9 however,
the NMR data (CD3OD) for synthetic 1a and the NMR data
(unknown solvent) reported by Rezanka for the molecule
named lytophilipine A did not match. Chemical correlation,
derivatization, as well as NMR studies were originally used to
assign the constitution and configuration of 1a.1 However, the
solvent (system) used for the NMR experiments was not
revealed, and primary data are apparently not available.
Fascinated by the competitiveness of Macrorhynchia
philippina in its natural habitat, and the resulting implications
for its natural product chemistry, we initiated efforts to
contribute to the unfinished quest for structural assignment of
lytophilippine A by total synthesis. Because the credibility of
the isolation report is compromised by an ambiguous
discussion of the results, particularly with respect to the
configurational assignment of the tetrahydrofuran section, we
embarked on a research project aimed at the total synthesis of
all possible diastereomers with respect to the C11−C15 region.
Thus, a stereodivergent synthetic route offering the potential
for full control over the absolute configuration of the C11−
C15 segment was required. Herein, we report the total
synthesis of (11R,13S,14R,15R)-lytophilippine A (1b) as one
possible configurational match for the natural product. We
provide a transparent comparison of our analytical data for 1b
with those published by Lee for 1a and by Rezanka for the
molecule named lytophilippine A. We emphasize the trans-
Figure 1. Lytophilippine A from Macrorhynchia philippina.
lytophilippine A represents a substantial contest for configura-
tional elucidation on one hand and for asymmetric total
synthesis on the other hand. The two sites of unsaturation at
C7/C8 and C18/C19 separate three sections presenting
distinct structural characteristics: the southern C1−C6 γ-keto
ester section is highlighted by a vicinal methyl branching, the
northern C9−C17 section features a skipped and bridged
polyol segment, and the eastern C19−C27 side chain is
decorated by a methylene-separated stereotetrad−stereodyad
1
parent H and 13C NMR assignment and solvent effects on
chemical shifts.
Received: February 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00722
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Our synthesis of the C15−C27 building block 7 commenced
with an aldol reaction between the propionic acid ester 2 of the
Abiko auxiliary10 and the known aldehyde 39,11 (86% de) to
deliver the corresponding anti-β-hydroxy ester contaminated
with inseparable 3 (Scheme 1). The contaminated β-hydroxy
Scheme 2. Elaboration of the C15−C27 Section
Scheme 1. Assemblage of the C15−C27 Section
yield over three steps; the minor diastereomer from the
upstream aldol reaction could be separated by chromatog-
raphy. In terms of structural assignment, it was useful to access
the 20,22-syn aldol 9 by external hydride transfer under Luche
conditions18 to the Re face of the C20 ketone carbonyl group
and, subsequently, the enone 11 as a single diastereomer by
cross-metathesis with methyl vinyl ketone (MVK-CM) in the
presence of catMETium RF3 (10).19 With the alcohol 9 in
hand, we opted for Mosher’s configurational correlation
method20 to assign the absolute configuration of C20.21
Interestingly, reacting the MOM ether with AlCl3 in anisole22
triggered formation of the 1,3-dioxane 12 by intramolecular
transacetalization. Interpretation of NOE experiments on the
methylene acetal 12 supports the assignment of the relative
configuration of the C20−C22 stereotriad.21
The synthesis of 1b was continued by an MVK-CM of 8 to
deliver the C15−C27 building block 13 in 90% yield.
Diastereoface-differentiating aldol reaction of the lithium
enolate of 13 to the Re face of the carbonyl carbon atom of
the aldehyde 1423 followed by diastereoface-differentiating
external hydride transfer24 to the Re face of the C13 ketone
carbonyl carbon atom of the chelated β-hydroxy ketone
delivered the 11,13-diol 15 in 75% yield (dr = 95:5) (Scheme
3).25
With the northern building block 15 available, we advanced
the synthesis by constructing the tetrahydrofuran moiety
within the skipped and bridged polyol C9−C15 segment
(Scheme 4). Thus, subjecting the triene 15 to a regioselective
and stereodiverging Sharpless asymmetric epoxidation (SAE)26
in the presence of (−)-D-diisopropyl tartrate (DIPT) followed
by Brønsted acid mediated diastereomer-differentiating acetal-
ization7 delivered the tetrakisacetal 16 in 24% yield (dr = 94:6)
as well as the diol 17 in 49% yield (dr = 95:5) after separation
by chromatography.27
ester was subjected to MOM protection, and a succeeding
DIBAL-H reduction afforded the primary alcohol 4 in 55%
yield (3.23 g isolated mass) and with a moderate
diastereoselectivity (82:18); auxiliary recovery was accom-
plished with 48% yield. The mixture of diastereomers was
carried downstream until separation by chromatography was
possible. Treatment of the alcohol 4 with 2-iodoxybenzoic acid
(IBX)12 delivered the aldehyde 5 in 93% yield. Chain
elongation in western direction was accomplished by treatment
of 5 with lithiated diethyl ethylphosphonate to yield the
corresponding β-hydroxy phosphonate that was oxidized
according to Swern13 to deliver the corresponding β-keto
phosphonate. Disappointingly, the subsequent condensation14
of the β-keto phosphonate with the α-branched aldehyde 615
proceeded very slowly and sluggishly to afford the α,β-enone 7
in meager yields and still as a mixture of diastereomers (82:18)
from the aldol reaction. Several attempts to enable improve-
ment proved futile.
After passing the bottleneck, we continued with the
structural elaboration of the building block 7 (Scheme 2).
After some experimentation, we found that the removal of the
MOM protecting group could be accomplished using an excess
of ZnBr2 in butanethiol16 as an auxiliary nucleophile; various
alternative conditions were either noneffective or triggered
decomposition. Succeeding substrate-directed internal hydride
transfer by tetrabutylammonium triacetoxyborohydride to the
Si face of the C20 ketone carbonyl group proceeded as
expected to provide the corresponding 20,22-anti-diol.17
Subsequent introduction of the acetonide protecting group
delivered the elaborated C15−C27 building block 8 in 66%
B
DOI: 10.1021/acs.orglett.9b00722
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Scheme 3. Section Fusion by CM and Aldol Addition
Scheme 5. Assemblage of the [14]Macrolactone and
Conclusion of the Total Synthesis
Scheme 4. SAE and Diastereomer Differentiation
full conversion of the starting triene 19; attempts to scale (120
mg) the RCM, however, were hampered by slow and finally
incomplete conversion. In practice at larger scale, two cycles of
RCM were required to achieve complete conversion, and given
the late-stage nature of the RCM, we refrained from further
optimization. In order to achieve global deprotection, we
adapted conditions previously reported for the total synthesis
of 1a.9 Hence, fluoride-mediated cleavage of the TBS ether was
followed by ketal hydrolysis to deliver (11R,13S,14R,15R)-
lytophilippine A (1b) in 45% from the triene 19 as a white
solid which, in our hands, could not be crystallized to deliver
crystals suitable for X-ray crystal structure analysis.
Overall, 84 mg of 1b was made available during our total
synthesis campaign. Aiming to contribute to the quest for
structural assignment, we were well equipped for extensive
NMR investigations. When comparing our NMR data for
(11R,13S,14R,15R)-1b (CD3OD) to those reported by Lee for
(11S,13R,14S,15S)-1a (CD3OD),21 we observed a very good
fit of chemical shifts for protons of the side chain past C18 (Δδ
≤ 0.03 ppm); also in line with our expectations, major
deviations (Δδ) were detected for protons from the skipped
and bridged polyol region with the notable exception of H13
(Δδ = 0.01 ppm). When turning to NMR data comparison
with the natural product named lytophilippine A reported by
Rezanka, we had to deal with an unknown solvent system.
Thus, a selection of deuterated solvents was used for NMR
measurements. For CD3CN, CDCl3, C6D6, and D2O, we
With the protected C8−C27 segment 17 accessible, we
progressed by assembling the [14]macrolactone of lytophi-
lippine A (Scheme 5). Building on previous work,7 we
deployed a remarkably regioselective Shiina esterification28 of
the diol 17 with the acid 18.29 Further following the lead of
our group, the ester was equipped with a TBS ether at C15 in
order to facilitate the envisioned downstream ring-closing
metathesis (RCM). Removal of the PMB protecting group and
succeeding IBX oxidation12 of the corresponding lactonization-
prone γ-hydroxy ester finally delivered the RCM competent γ-
keto ester 19 in 59% yield from 17. At smaller scale (20 mg of
19), the decisive RCM of 19 proceeded uneventfully in the
presence of the second-generation Grubbs precatalyst 2030
(0.2 equiv) to deliver the corresponding [14]macrolide with
1
observed insufficient solubility of 1b. H and 13C NMR data
were then collected in CD3OD, (CD3)2CO,31 (CD3)2SO,32
C5D5N,33 and C5D5N−CD3OD (1:1)34 and compared to the
C
DOI: 10.1021/acs.orglett.9b00722
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data reported by Rezanka for the molecule named
lytophilippine A (Figure 2). From this comparison, it is
available NMR data basis, a global rather than regional
configurational misassignment of the marine macrolide named
lytopilippine A must be concluded.
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.9b00722.
Experimental procedures, configurational assignment,
and comparison of NMR data for 1a and 1b (PDF)
NMR spectra (PDF)
Elemental analyses, MS spectra, and IR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: martin.hiersemann@tu-dortmund.de.
ORCID
Martin Hiersemann: 0000-0003-4743-5733
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support by the DFG (HI628/12-2) and the TU
Dortmund is gratefully acknowledged.
■
REFERENCES
■
(1) Rezanka, T.; Hanus, L. O.; Dembitsky, V. M. Tetrahedron 2004,
60, 12191. The C27 palmitic acid and the C27 oleic acid esters were
also isolated and named lytophilippines B and C. Weak antibacterial
activity against Escherichia coli and Agrobacterium tumefaciens was
reported for the molecule named lytophilippine A.
̈
(2) Cinar, M. E.; Bilecenoglu, M.; Ozturk, B.; Can, A. Aquat.
Invasions 2006, 1, 84.
̈
Figure 2. Comparison of 13C NMR data.
(3) (a) Zlotkowski, K.; Hewitt, W. M.; Yan, P.; Bokesch, H. R.;
Peach, M. L.; Nicklaus, M. C.; O’Keefe, B. R.; McMahon, J. B.;
Gustafson, K. R.; Schneekloth, J. S. Org. Lett. 2017, 19, 1726. (b) Yan,
P.; Ritt, D. A.; Zlotkowski, K.; Bokesch, H. R.; Reinhold, W. C.;
Schneekloth, J. S.; Morrison, D. K.; Gustafson, K. R. J. Nat. Prod.
2018, 81, 1666.
(4) For a review on tetrahydrofuran-containing macrolides from
marine producers, see: Lorente, A.; Lamariano-Merketegi, J.;
Albericio, F.; Alvarez, M. Chem. Rev. 2013, 113, 4567.
(5) For selected recent synthetic work on constitutionally related
marine [14]macrolides, see: (a) Gil, A.; Lamariano-Merketegi, J.;
Lorente, A.; Albericio, F.; Alvarez, M. Org. Lett. 2016, 18, 4485.
(b) Lorente, A.; Gil, A.; Fernandez, R.; Cuevas, C.; Albericio, F.;
Alvarez, M. Chem. - Eur. J. 2015, 21, 150. (c) Schomaker, J. M.;
Borhan, B. J. Am. Chem. Soc. 2008, 130, 12228. (d) Ueda, M.;
Yamaura, M.; Ikeda, Y.; Suzuki, Y.; Yoshizato, K.; Hayakawa, I.;
Kigoshi, H. J. Org. Chem. 2009, 74, 3370.
(6) For examples of polyketides featuring chlorine-substituted
stereogenic sp3 carbon atoms, see: (a) Wyche, T. P.; Piotrowski, J.
S.; Hou, Y.; Braun, D.; Deshpande, R.; McIlwain, S.; Ong, I. M.;
Myers, C. L.; Guzei, I. A.; Westler, W. M.; Andes, D. R.; Bugni, T. S.
Angew. Chem., Int. Ed. 2014, 53, 11583. (b) Du, L.; King, J. B.;
Cichewicz, R. H. J. Nat. Prod. 2014, 77, 2454.
(7) Gille, A.; Hiersemann, M. Org. Lett. 2010, 12, 5258.
(8) Hodgson, D. M.; Salik, S. Org. Lett. 2012, 14, 4402.
(9) Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee, E. Org. Lett. 2011, 13,
2476 For a modified synthetic procedure to 3, see the Supporting
Information. .
immediately evident that extensive global and solvent-
1
independent deviations between the measured H and 13C
chemical shifts of synthetic 1b and those reported for the
molecule named lytophilippine A by Rezanka exist. Further-
more, our extensive NMR studies reveal that Δδ(solvent) is
generally far less pronounced than Δδ(1aRezanka−1b). Hence,
the already reported chemical shift differences for synthetic
and natural 1a Δδ(Rezanka−Lee) are probably not caused by
NMR solvent effects. Consequently, a deep-seated global
configurational misassignment of lytophilippine A by Rezanka
et al. must be concluded. Hence, future attempts to assign the
configuration of lytophilippine A by total synthesis have
probably no prospect of success, and we refrained from
converting 16 to a 11,14-trans-configured tetrahydrofuran
diastereomer of the natural product.35
In conclusion, the total synthesis (11R,13S,14R,15R)-
lytophilippine A (1b), a diastereomer of a [14]macrolide
originally isolated from a sample of the marine animal M.
philippina (alias L. philippinus), was accomplished. A longest
linear sequence consisting of 22 steps from known aldehyde 3
was established. Efforts were made to formulate a robust and
reliable total synthesis, and the sequence consisting of cross-
metathesis−aldol addition−diasteroface-differentiating β-hy-
droxy ketone reduction nicely embodies the agenda. We
provide extensive NMR data for 1b in different solvents and a
transparent chemical shift assignment. According to the thus-
(10) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119,
2586.
D
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Letter
(11) (a) Jaschinski, T. Diploma Thesis, TU Dortmund, 2008.
(b) Stiasni, N. Ph.D. Dissertation, TU Dortmund, 2010.
(12) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
(13) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(14) Paterson, I.; Yeung, K.-S.; Smaill, J. N. Synlett 1993, 1993, 774.
(15) Lin, N.; Overman, L. E.; Rabinowitz, M. H.; Robinson, L. A.;
Sharp, M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118, 9062.
(16) Han, J. H.; Kwon, Y. E.; Sohn, J.-H.; Ryu, D. H. Tetrahedron
2010, 66, 1673.
(17) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(18) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
(19) Kadyrov, R.; Azap, C.; Weidlich, S.; Wolf, D. Top. Catal. 2012,
55, 538.
(20) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(21) See the Supporting Information for details.
(22) Terayama, N.; Yasui, E.; Mizukami, M.; Miyashita, M.;
Nagumo, S. Org. Lett. 2014, 16, 2794.
(23) Moon, H. R.; Choi, W. J.; Kim, H. O.; Jeong, L. S. Tetrahedron:
Asymmetry 2002, 13, 1189.
(24) Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.;
Repic, O.; Shapiro, M. Chem. Lett. 1987, 16, 1923.
(25) The configurational assignment of C11 and C13 rests on
Mosher’s configurational correlation method for C11 and Rychnov-
sky’s [13C]acetonide analysis for C13 in a 20S-configured derivative of
15 accessible from 9 by a sequence consisting of MOM protection,
MVK−CM, aldol reaction with 14, and reduction; see: Rychnovsky,
S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945. Also see the
Supporting Information for details.
(26) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(27) The ratio 16/17 mirrors the mismatched-enforced weak
diastereofacial differentiation of the SAE using (−)-D-DIPT. NOE
studies on 16 and 17 support the assignment of the relative
configuration; see the Supporting Information for details.
(28) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002, 43,
7535. In our hands, Steglich esterification failed and Yamaguchi
esterification was lower yielding.
(29) The constitution was assigned based on NMR−HMBC
experiments.
(30) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
1
(31) H NMR Δδ [(CD3)2CO−CD3OD] in the range from −0.05
to +0.10 ppm.
(32) 1H NMR Δδ [(CD3)2SO−CD3OD] in the range from −0.30 to
−0.01 ppm; general upfield shift.
1
(33) H NMR Δδ [C5D5N−CD3OD] in the range from 0 to +0.85
ppm. With one exception (6′-CH3), significant and general downfield
shift.
(34) Previously used as NMR solvent system by Rezanka et al.; see:
Rezanka, T.; Hanus, L.; Dembitsky, V. M. Eur. J. Org. Chem. 2003,
2003, 4073.
(35) Access to the primary data would be vital to unambiguously
assign the true configuration of the marine polyketide. If indeed it is
not available, reisolation from the natural source appears to be
unavoidable.
E
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