Asymmetric total synthesis and absolute stereochemistry of the neuroactive marine macrolide palmyrolide A

Article abstract of DOI:10.1021/ol300673m

The first asymmetric total synthesis and determination of the absolute configuration for the neuroactive marine macrolide palmyrolide A is described. The highlight of the synthesis is macrocyclization via trans-enamide formation catalyzed by copper(I) iodide and cesium carbonate. Comparison with the authentic spectral data confirms the synthesis of (+)-ent-palmyrolide A.

Full text of DOI:10.1021/ol300673m

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2150–2153
Asymmetric Total Synthesis and Absolute
Stereochemistry of the Neuroactive
Marine Macrolide Palmyrolide A
Rodolfo Tello-Aburto, Emily M. Johnson, Cheyenne K. Valdez, and William A. Maio*
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces,
New Mexico 88003, United States
wmaio@nmsu.edu
Received March 16, 2012
ABSTRACT
The first asymmetric total synthesis and determination of the absolute configuration for the neuroactive marine macrolide palmyrolide A is
described. The highlight of the synthesis is macrocyclization via trans-enamide formation catalyzed by copper(I) iodide and cesium carbonate.
Comparison with the authentic spectral data confirms the synthesis of (þ)-ent-palmyrolide A.
The study of marine organisms continues to provide
natural products with intricate molecular architecture,
unique biological activity, and great potential for use as
modern chemotherapeutics. Recently, Gerwick and co-
workers reported the isolation and structural elucidation
of palmyrolide A (1), a neuroactive macrolide from a
cyanobacterial assemblage comprised of Leptolyngbya
and Oscillatoria species collected at Palmyra Atoll, south
of Hawaii.1 Initial biological studies revealed 1 to be a
potent inhibitor of calcium ion oscillations in murine cere-
brocortical neurons and to possess sodium ion channel
blocking ability in neuroblastoma cells.1 When screened
against human lung adenocarcinoma cells, the authors note
no appreciable cytotoxicity.1
The overall connectivity of (ꢀ)-palmyrolide A was
determined by detailed NMR studies.1 However, due to
the resistance of the lactone to hydrolyze under a variety of
reaction conditions, the authors were unable to degrade
the macrolide into acyclic fragments that would prove
useful in determining the absolute stereochemistry.1 As a
result, the authors performed the Murata J-based config-
urational analysis2 on the macrocycle itself to determine
the relative stereochemistry between the C(5) methyl and
the C(7) tert-butyl centers. These data, in conjunction with
NOE correlations, suggested the relationship between C(5)
and C(7) was syn.1
We became interested in (ꢀ)-palmyrolide A as a syn-
thetic target not only because of its interesting biological
profile but also due to the presence of two unique structur-
al elements: the rare tert-butyl moiety and the trans-N-
methyl enamide. A search of the literature reveals few
examples of isolated natural products that contain a
sterically encumbered tert-butyl group R to the lactone
ester,3 with (ꢀ)-apratoxin A being the sole example con-
firmed by total synthesis.4 It should be noted that, for
apratoxin, the relative stereochemistry between its C(37)
methyl and C(39) tert-butyl is anti.5 In the case of palmyr-
olide A, Gerwick speculates that the tert-butyl structural
(3) (a) Luesch, H.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J.;
Corbett, T. H. J. Am. Chem. Soc. 2001, 123, 5418–5423. (b) Klein, D.;
Braekman, J. C.; Daloze, D.; Hoffmann, L.; Castillo, G.; Demoulin, V.
J. Nat. Prod. 1999, 62, 934–936. (c) Matthew, S.; Salvador, L. A.;
Schupp, P. J.; Paul, V. J.; Luesch, H. J. Nat. Prod. 2010, 73, 1544–1552.
(4) For the most recent total synthesis, see: Numajiri, Y.; Takahashi,
T.; Doi, T. Chem.;Asian J. 2009, 4, 111–125. For the first total
synthesis, see: Chen, J.; Forsyth, C. J. J. Am. Chem. Soc. 2003, 125,
8734–8735.
(1) Pereira, A. R.; Cao, Z.; Engene, N.; Soria-Mercado, I. E.; Murray,
T. F.; Gerwick, W. H. Org. Lett. 2010, 12, 4490–4493.
(2) (a) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.;
Tachibana, K. J. Org. Chem. 1999, 64, 866–876. (b) This method was
successfully applied to the structure elucidation of the (ꢀ)-apratoxin A
macrolide. See ref 3a.
(5) For the apratoxin numbering convention, see ref 3a.
r
10.1021/ol300673m
Published on Web 04/04/2012
2012 American Chemical Society

In the isolation report, the absolute stereochemistry of
the C(10) methyl group was unequivocally assigned to be
in the R configuration.1 Rather than design our synthetic
plan around the known C(10) center, we thought that a
more economical approach would be to target only one of
the two possible C(5)ꢀC(7) anti combinations and then
vary the stereochemistry at C(10). In this way, we would
utilizea common fragment(cf. 2) togainaccesstobothanti
diastereomeric combinations of palmyrolide A (1a and 1b,
Scheme 1) representing one compound from each enantio-
meric set. We chose the C(5)-S, C(7)-S arrangement, based
on guidance from Gerwick,8 to coincide with the absolute
stereochemistry found in apratoxin A.3a
Scheme 1. Retrosynthetic Analysis
Retrosynthetically, we believed that macrocyclization
exploiting a method to unite a primary amide with a vinyl
iodide would prove facile.9,10 A related macrocyclization
has been documented;9j however to the best of our knowl-
edge, there has been no use of this strategy for the
construction of a 15-membered macrocycle, or for the
formation of a trans enamide. Further simplification re-
veals amide alcohol 2, which is common to both
targets, and vinyl iodides 3a and 3b (Scheme 1). These
fragments could be combined in the forward direction
under mild reaction conditions via formation of a mixed
anhydride.
To establish the key anti-stereorelationship between
C(5) and C(7), we relied on elegant chemistry developed
by Cavelier and co-workers during their recent synthesis of
oxoapratoxin,11 an oxazoline analogue of apratoxin A.
The synthesis of fragment 2 commenced with a D-proline
catalyzed asymmetric aldol union between pivaldehyde
and acetone to furnish β-hydroxy ketone (ꢀ)-4, following
the known literature account11 (Scheme 2). In the Cavelier
studies, stereoselective syn-reduction of (ꢀ)-4 was affected
using diethylmethoxyborane/NaBH4,12 which providedan
acceptable mixture of syn and anti diastereomers (95:5).
unit may be evolutionary, developed as a way to prevent
hydrolysis of the bioactive lactone moiety under natural
conditions.1
N-Methyl enamide macrocycles are exceedingly rare
in the natural product literature, with few reported
examples;3b,c none have been confirmed by total synthe-
sis. Interestingly, these compounds all contain a tert-
butyl group R to the lactone ester within their molecular
framework and are likely derived from the same genus of
cyanobacteria.1 A related family of macrolides contains
an N-H enamide,6 although with cis olefin geometry.
Several other compounds have side chains decorated
with N-H enamides;7 however to the best of our knowl-
edge, there is only one that features an N-methyl enam-
ide subunit.7f
Due to uncertainty regarding the absolute configuration
of palmyrolide A,1 at the outset of our synthetic campaign
we decided to target all possible diastereomeric combina-
tions. While Gerwick identified the relative configuration
between the C(5) methyl and the C(7) tert-butyl to be syn,1
based on the apratoxin A literature,3a,4 we believed that the
relationship between these two groups could also be anti.
In order to most efficiently address the unknown absolute
stereochemistry, we decided to exploit a synthetic route
that would allow us to synthesize all diastereomers con-
currently. Herein, we report our work on the C(5)ꢀC(7)
anti series.
(8) Personal communication, 2011.
(9) For copper-catalyzed vinyl halide/amide unions, see: (a) Ogawa,
T.; Kiji, T.; Hayami, K.; Suzuki, H. Chem. Lett. 1991, 1443–1446. (b)
Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333–1336. (c) Shen, R.;
Lin, C. T.; Porco, J. A., Jr. J. Am. Chem. Soc. 2002, 124, 5650–5651. (d)
Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5,
3667–3669. (e) Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett.
2003, 5, 3583–3586. (f) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr. Org.
Lett. 2004, 6, 27–30. (g) Coleman, R. S.; Liu, P.-H. Org. Lett. 2004, 6,
577–580. (h) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809–1812. (i)
Shen, R.; Inoue, T.; Forgac, M.; Proco, J. A., Jr. J. Org. Chem. 2005, 70,
3686–3692. (j) Toumi, M.; County, F.; Evano, G. Angew. Chem., Int. Ed.
2007, 46, 572–575. (k) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev.
2008, 108, 3054–3131.
(10) For a good review of the enamide literature pre-2000, see ref 10b
and references cited therein. For select methods post-2000, see: (a)
(6) (a) For a review article showcasing several examples, see:
Gournelis, D. C.; Laskaris, G. G.; Verpoorte, R. Nat. Prod. Rep.
1997, 14, 75–82. (b) See also: Lin, H.-Y.; Chen, C.-H.; You, B.-J.; Liu,
K. C. S. C.; Lee, S.-S. J. Nat. Prod. 2000, 63, 1338–1343.
€
Furstner, A.; Brehm, C.; Cancho-Grande, Y. Org. Lett. 2001, 3, 3955–
3957. (b) Wallace, D. J.; Klauber, D. J.; Chen, C.-y.; Volante, R. P. Org.
Lett. 2003, 5, 4749–4752. (c) Brice, J. L.; Meerdink, J. E.; Stahl, S. S. Org.
Lett. 2004, 6, 1845–1848. (d) Yudha, S. S.; Kuninobu, Y.; Takai, K. Org.
Lett. 2007, 9, 5609–5611. (e) Bolshan, Y.; Batey, R. A. Angew. Chem.
2008, 120, 2139–2142. (f) Arndt, M.; Salih, K. S.M.; Fromm, A.;
Goossen, L. J.; Menges, F.; Niedner-Schatteburg, G. J. Am. Chem.
Soc. 2011, 133, 7428–7449. (g) Nicolaou, K. C.; Jiang, X.; Lindsay-Scott,
P. J.; Corbu, A.; Yamashiro, S.; Bacconi, A.; Fowler, V. M. Angew.
Chem., Int. Ed. 2011, 50, 1139–1144.
(11) Gilles, A.; Martinez, J.; Cavelier, F. J. Org. Chem. 2009, 74,
4298–4304.
(12) Chen, K. M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.;
Repic, O.; Shapiro, M. J. Chem. Lett. 1987, 1923–1926.
(7) For several examples, see: (a) Erickson, K. L.; Beutler, J. A.;
Cardellina, J. H., II; Boyd, M. R. J. Org. Chem. 1997, 62, 8188–8192. (b)
Galinis, D. L.; McKee, T. C.; Pannell, L. K.; Cardellina, J. H., II; Boyd,
M. R. J. Org. Chem. 1997, 62, 8968–8969. (c) McKee, T. C.; Galinis,
D. L.; Pannell, L. K.; Cardellina, J. H., II; Laakso, J.; Ireland, C. M.;
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J. Org. Chem. 1999, 64, 153–155. (e) Kohno, J.; Koguchi, Y.; Nishio, M.;
Nakao, K.; Kuroda, M.; Shimizu, R.; Ohnuki, T.; Komatsubara, S. J.
Org. Chem. 2000, 65, 990–995. (f) Nogle, L. M.; Gerwick, W. H. Org.
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Org. Lett., Vol. 14, No. 8, 2012
2151

Unfortunately, in our hands this reduction strategy did not
yield a synthetically workable mixture of isomers. Chro-
matographic separation also proved difficult. Pleasingly,
recourse to a stereoselective reduction using 2.5 equiv of
DIBAl-H13 provided the requisite diol in excellent yield
and high diastereoselectivity (Scheme 2). This modifica-
tion also obviated the need for a challenging silica gel
purification step. Next, in two synthetic operations invol-
ving (1) treatment with thionyl chloride in pyridine and (2)
oxidation using RuO4, the syn-diol was easily converted
into cyclic sulfate (ꢀ)-5 in good overall yield.14
It should be noted that during the cross metathesis step,
trace HCl from the acryloyl chloride is sufficient to cleave
some of the silyl ether protecting group. As a result, the
balance in chemical yield is a byproduct arising from free
alcohol esterification with acryloyl chloride. Unfortu-
nately, attempts to hydrolyze the ester were met with no
success. We believe this is due to the steric constraints of
the neighboring tert-butyl group preventing nucleophilic
attack on the ester carbonyl. This result is consistent with
the reported unsuccessful attempts to hydrolyze the lac-
tone of palmyrolide A.1
Withamide alcohol2 inhand, we turnedourattentionto
the fabrication of vinyl iodides 3a and 3b. The syntheses of
these fragments began employing known alcohol 7, pro-
duced in three literature operations from commercially
available 3-butyn-1-ol.19 Alcoholtoiodide interconversion
proceeded in high yield, and the resultant diiodide (8) was
used in the Myers alkylation20 with (S,S)-propionamide 9a
and separately with (R,R)-propionamide 9b (Scheme 4).
Pleasingly, both alkylations proceeded in good yield and in
high diastereoselectivity (>20:1 by 1H NMR). These
yields are consistent with the Myers studies which noted
limitedreactivitywithsubstratesbearingβ-alkylbranching
or alkoxy groups.20 We believe the presence of the β-vinyl
iodide of 8 may be responsible for the diminished yields we
observed relative to unhindered literature examples.20
Subsequent hydrolysis with NaOH provides acids (ꢀ)-3a
and (þ)-3b,21 with negligible loss of stereopurity, and
complete preservation of the trans vinyl iodide unit.22
Scheme 2. Synthesis of Cyclic Sulfate 5
Nucleophilic ring opening of (ꢀ)-515 using a mixed
organometallic species derived from allylmagnesium bro-
mide and copper iodide, following the procedure of
Cavelier,11 and alcohol protection with TESCl provided
alkene (ꢀ)-6, possessing the anti-C(5)-S, C(7)-S stereoche-
mical arrangement we targeted (Scheme 3).16 Of note, the
triethylsilyl group in (ꢀ)-6 is the only protecting group
employed during our synthesis of palmyrolide A.
Union of (ꢀ)-6 with freshly distilled acryloyl chloride17a
employing the HoveydaꢀGrubbs II precatalyst, followed by
in situ addition of ammonium hydroxide, allowed access to the
primary amide. The analogous cross metathesis using acryla-
mide and the Grubbs II precatalyst17b was also tried; however
this process gave good but somewhat inferior results com-
pared to acryloyl chloride (36% vs 58%, respectively). In the
next step, hydrogenation of the R,β-unsaturation occurred
with concomitant loss of the labile triethylsilyl group18 and
provided fragment (ꢀ)-2 in good overall yield (Scheme 3).
Scheme 4. Assembly of Vinyl Iodides 3a and 3b
Scheme 3. Synthesis of Fragment 2
ꢀ
(17) (a) Ferrie, L.; Bouzbouz, S.; Cossy, J. Org. Lett. 2009, 11, 5446–
5448. (b) Choi, T.-L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem.,
Int. Ed. 2001, 40, 1277–1279.
(18) Sajiki, H.; Ikawa, T.; Hattori, K.; Hirota, K. Chem. Commun.
2003, 654–655.
(19) (a) Munakata, R.; Ueki, T.; Katakai, H.; Takau, K.; Tadano,
K.-i. Org. Lett. 2002, 3, 3029–3033. (b) Trend, R. M.; Ramtohul, Y. K.;
Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778–17788. (c) Alcohol 7
can also be prepared in one synthetic step from 3-butyn-1-ol. See:
Huang, Z.; Negishi, E.-i. Org. Lett. 2006, 8, 3675–3678.
(20) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
(21) The yield of (þ)-3b is unoptimized.
(13) Kiyooka, S.-i.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett.
1986, 27, 3009–3012.
(14) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538–
7539. Also see ref 11.
(15) For a review article documenting the reactivity of cyclic sulfates,
see: Byun, H.-S.; He, L.; Bittman, R. Tetrahedron 2000, 56, 7051–7091.
(16) Silyl ether (ꢀ)-6 is a known compound. See ref 11.
(22) Elimination of Z-vinyl iodides readily occurs upon treatment
with NaOMe. For example, see ref 19a.
2152
Org. Lett., Vol. 14, No. 8, 2012

literature values reported by Gerwick. Pleasingly, there
was a complete 1H and 13C NMR match with macrolide
(þ)-1b, where the C(10) methyl group is invertedrelative to
the natural macrolide. Optical rotation comparison con-
firms that we have synthesized the enantiomer of (ꢀ)-
palmyrolide A, (þ)-ent-palmyrolide A {[R]D = þ23 (c =
0.65, CHCl3), lit. [R]D = ꢀ29 (c = 0.9, CHCl3)}.1 The
longest linear sequence is 11 steps from commercially
available starting materials, or 6 steps from known silyl
ether (ꢀ)-6. Importantly, we have confirmed that the
stereochemical relationship between the C(5) methyl
and the C(7) tert-butyl is anti, and not syn, as originally
proposed in the isolation report.1 Also of interest,
the absolute stereochemistry at C(5) and C(7) found
in (ꢀ)-palmyrolide A is opposite that found in
apratoxin A.3a
Scheme 5. Synthesis of Macrocycles 1a and 1b
A full account of this work, including syntheses of the
complementary C(5) methyl, C(7) tert-butyl syn series, and
the synthesis of natural (ꢀ)-palmyrolide A, will be re-
ported in due course.
Acknowledgment. We would like to thank New Mexico
State University for providing financial assistance in terms
of a startup package, as well as the NMSU-MBRS Re-
search Initiative for Scientific Enhancement (NIH
R25GM061222) and NMSU-Howard Hughes Medical
Institute (Grant No. 52006932) programs for providing
salary support (C.K.V. and E.M.J., respectively). Finally,
we would like to thank Professor William Gerwick
(UCSD) and Dr. Alban Pereira (UCSD) for helpful dis-
cussions and for providing FIDs of their palmyrolide A
work. This manuscript is dedicated to Professor Amos B.
Smith, III, with admiration and respect.
Union of the common amide alcohol fragment (2) with
either (ꢀ)-3a or (þ)-3b, exploiting 2,4,6-trichlorobenzoyl
chloride as a coupling agent,23 allowed access to macro-
cyclization precursors (ꢀ)-10a and (ꢀ)-10b, respectively
(Scheme 5). Formation of the 15-membered ring, using a
high-dilution modification (0.01 M) to the copper(I) io-
dide/cesium carbonate conditions developed by Buchwald,9d
afforded the trans-N-H enamide macrocycles in modest
yield. To the best of our knowledge, this is the first use of
the copper-promoted reaction conditions for the formation
of trans-enamide macrocycles. In the final step, treatment of
each macrocycle separately with sodium hydride followed by
iodomethane24 provided the requisite trans-N-methyl enam-
ides (þ)-1a and (þ)-1b (Scheme 5) in excellent yield.
Supporting Information Available. Detailed experimen-
1
tal procedures, as well as scans of H and 13C NMR
spectra are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
At this stage, a comparison with the reported spectra of
palmyrolide A1 was made. Compound (þ)-1a, featuring
the natural C(10)-R stereochemistry, did not match the
(24) Goossen, L. J.; Blanchot, M.; Arndt, M.; Salih, K. S. M. Synlett
2010, 1685–1687.
(23) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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