Stereoselective Synthesis of the Proposed C79-C104 Fragment of Symbiodinolide

Article abstract of DOI:10.1002/chem.201503880

Stereoselective and streamlined synthesis of the proposed C79-C104 fragment 2 of symbiodinolide (1), a polyol marine natural product with a molecular weight of 2860, was achieved. In the synthetic route, the proposed C79-C104 fragment 2 was synthesized by utilizing a Julia-Kocienski olefination and subsequent Sharpless asymmetric dihydroxylation as key transformations in a convergent manner. Detailed comparison of the ¹³C NMR chemical shifts between the natural product and the synthetic C79-C104 fragment 2 revealed that the stereostructure at the C91-C99 carbon chain moiety of symbiodinolide (1) should be reinvestigated.

Full text of DOI:10.1002/chem.201503880

DOI: 10.1002/chem.201503880
Full Paper
&
Organic Synthesis |Very Important Paper|
Stereoselective Synthesis of the Proposed C79–C104 Fragment of
Symbiodinolide
Hiroyoshi Takamura,*[a] Takayuki Fujiwara,[a] Yohei Kawakubo,[a] Isao Kadota,[a] and
Daisuke Uemura[b]
Abstract: Stereoselective and streamlined synthesis of the
proposed C79–C104 fragment 2 of symbiodinolide (1),
a polyol marine natural product with a molecular weight of
2860, was achieved. In the synthetic route, the proposed
C79–C104 fragment 2 was synthesized by utilizing a Julia–
Kocienski olefination and subsequent Sharpless asymmetric
dihydroxylation as key transformations in a convergent
manner. Detailed comparison of the 13C NMR chemical shifts
between the natural product and the synthetic C79–C104
fragment 2 revealed that the stereostructure at the C91–C99
carbon chain moiety of symbiodinolide (1) should be rein-
vestigated.
Introduction
A variety of biologically active secondary metabolites have
been isolated from marine origin.[1] Among them, polyether
and polyol marine natural products, such as brevetoxins, cigua-
toxins, halichondrins, and palytoxins, are attractive molecules
in natural product, synthetic, and medicinal chemistry due to
their extraordinary structures and potent biological activities.[2]
Their structural feature is a long carbon backbone that is
highly functionalized by oxygen atoms.
We previously reported the isolation of symbiodinolide (1,
Figure 1) from the symbiotic marine dinoflagellate Symbiodini-
um sp. in 2007.[3] Symbiodinolide (1) is a 62-membered polyol
macrolide with a molecular weight of 2860 and 61 stereogenic
centers. This natural product displays voltage-dependent N-
type Ca2+ channel-opening activity at 7 nm and COX-1 inhibito-
ry effect at 2 mm (65% inhibition). In addition, 1 ruptures the
tissue surface of the acoel flatworm Amphiscolops sp. at
2.5 mm. The gross structure of 1 was established by extensive
2D NMR analysis[3] and partial stereochemistries of 1 were elu-
cidated by the degradation of the natural product[3,4] and
chemical synthesis of each fragment[5] by our group. However,
the complete configurational elucidation of 1 remains an un-
solved issue because of its huge and complicated molecular
structure. In the C91–C99 carbon chain moiety, the stereoche-
Figure 1. Structure of symbiodinolide (1).
stants and NOE observations.[3] In this article, we first describe
the stereoselective synthesis of the C79–C104 fragment 2 pos-
sessing the proposed stereostructure. Furthermore, the
13C NMR chemical shifts were compared between the natural
product and the synthetic product 2, which indicates that the
stereochemical determination of the C91–C99 carbon chain
domain of 1 needs to be re-examined.[6]
3
mistries were determined by the analysis of JH,H coupling con-
[a] Prof. Dr. H. Takamura, T. Fujiwara, Y. Kawakubo, Prof. Dr. I. Kadota
Department of Chemistry, Graduate School of Natural Science
and Technology, Okayama University
3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530 (Japan)
E-mail: takamura@cc.okayama-u.ac.jp
Results and Discussion
[b] Prof. Dr. D. Uemura
Department of Chemistry, Faculty of Science, Kanagawa University
2946 Tsuchiya, Hiratsuka 259-1293 (Japan)
Retrosynthetic analysis of 2
Our retrosynthetic analysis of the proposed C79–C104 frag-
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/chem.201503880.
ment 2 is shown in Scheme 1. We envisioned that the target
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Scheme 1. Retrosynthetic analysis of 2. P=protective group; PT=1-phenyl-
1H-tetrazol-5-yl.
molecule 2 could be synthesized by the Julia–Kocienski olefi-
nation[7] between 1-phenyl-1H-tetrazol-5-yl (PT)-sulfone 3 and
aldehyde 4 and subsequent stereoselective introduction of the
syn-diol moiety at the C93- and C94-positions by utilizing
Sharpless asymmetric dihydroxylation.[8] The carbon framework
of the coupling precursor 3 could be stereoselectively con-
structed through the thermodynamically controlled spiroace-
talization of dihydroxyketone 5. On the other hand, tetrahydro-
pyran fragment 4 could be synthesized by the reaction of di-
thiane 6 and aldehyde 7.
Scheme 2. Synthesis of 15. TBS=tert-butyldimethylsilyl, DMAP=4-dimethyl-
aminopyridine, mCPBA=m-chloroperbenzoic acid, Bn=benzyl, TPAP=tetra-
n-propylammonium perruthenate, NMO=N-methylmorpholine oxide,
MS=molecular sieves, CSA=camphorsulfonic acid, NOE=nuclear Overhaus-
er effect, DEAD=diethyl azodicarboxylate.
Synthesis of aldehyde 29
With the coupling precursor 15 in hand, we next examined the
stereocontrolled synthesis of the C94–C104 fragment aldehyde
29,[17] which is the coupling partner of 15. We first investigated
the stereoselective construction of the tetrahydropyran moiety.
Thus, deprotonation of furan 16[18] with nBuLi and subsequent
reaction with aldehyde 17[19] gave racemic furyl alcohol 18
(Scheme 3). Oxidation of the alcohol 18 with Ac2O/DMSO[20]
followed by asymmetric transfer hydrogenation of the result-
ing furyl ketone by using HCO2H/Et3N as the hydrogen source
in the presence of 2 mol% of (S,S)-ruthenium catalyst 19[21]
provided optically active furyl alcohol 20 quantitatively as
a single stereoisomer.[22] Achmatowictz rearrangement[23] of 20
was initiated with NBS in aqueous THF at 08C to yield the cor-
responding hemiacetals as a 1:1 diastereomeric mixture at the
C103-position, which were quite unstable and, therefore, react-
ed immediately with (MeO)3CH/BF3·OEt2 in Et2O at 08C to
afford the desired methyl acetal 21 and its 103-epimer in 67
and 10% yields in two steps, respectively. Next, the stereose-
lective introduction of the vicinal diol moiety at the C101- and
C102-positions was examined. We first carried out the OsO4-
catalyzed dihydroxylation of enone 21; however, unfortunately,
the reaction did not proceed at all and the enone 21 was re-
covered quantitatively. Plietker et al. reported that RuO4-cata-
lyzed dihydroxylation in the presence of a Lewis acid was effi-
cient for the electron-deficient alkenes.[24] Therefore, according
to their protocol, enone 21 was treated with RuCl3/NaIO4 in
Synthesis of PT-sulfone 15
First, we investigated the stereoselective synthesis of the C79–
C93 fragment PT-sulfone 15.[9] The synthesis commenced from
optically pure epoxide 8, which was prepared from l-aspartic
acid by the known procedure (Scheme 2).[10] The epoxide 8
was treated with 3-butenylmagnesium bromide/CuI[11] to afford
the desired secondary alcohol. The resulting alcohol was pro-
tected with TBSCl to provide silyl ether 9. Alkene 9 was oxi-
dized with mCPBA to give terminal epoxide 10 as a 1:1 diaste-
reomeric mixture. The coupling between epoxide 10 and
alkyne 11[5a,12] with nBuLi/BF3·OEt2 proceeded smoothly to
[13]
produce alcohol 12 in 92% yield. Hydrogenation of alkyne 12
followed by tetra-n-propylammonium perruthenate (TPAP) oxi-
dation[14] of the resulting alcohol gave ketone 13. Global de-
protection of the three TBS groups of 13 and spiroacetalization
with CSA in MeOH were performed in one-pot to provide alco-
hol 14 in 95% yield in three steps as a single stereoisomer.[15]
The absolute configuration of 14 was unambiguously estab-
lished by the NOE correlations between H-83 and H-91. The
stereochemical outcome in the spiroacetalization can be ra-
tionalized by the thermodynamic stability of 14 due to its
double anomeric effect. Treatment of the alcohol 14 with
1-phenyl-1H-tetrazole-5-thiol/diethyl azodicarboxylate (DEAD)/
PPh3 and subsequent oxidation of the resulting PT-sulfide with
H2O2/MoVI[16] furnished PT-sulfone 15 in 95% yield in two steps.
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Scheme 3. Synthesis of 23. Ts=toluenesulfonyl, NBS=N-bromosuccinimide,
AIBN=2,2’-azobisisobutyronitrile.
Scheme 4. Synthesis of 29. DBB=4,4’-di-tert-butylbiphenylide, pyr=pyridine,
PMB=p-methoxybenzyl, DMP=Dess–Martin periodinane, DIBAL-H=diiso-
butylaluminum hydride, NCS=N-chlorosuccinimide.
the presence of CeCl3 as a Lewis acid to produce the desired
diol 22 in 51% yield. After the detailed investigation, the use
of ZnCl2 as a Lewis acid was found to be effective to furnish
22 in 84% yield as the sole product. The stereostructure of the
diol 22 was elucidated by NMR spectroscopy. Thus, the stereo-
chemistry at the C103-position resulting in the transformation
from 20 to 21 was verified by the NOE correlations between
H-99 and OCH3-103. The NOE observations of H-99/H-101 and
the small magnitude of the coupling constant (3J101,102 =3.6 Hz)
confirmed that H-99, H-101, and H-102 were oriented in the
syn relationship to each other. Although the detailed confor-
mational analysis of 21 was not carried out, the 103-methoxy
group seems to sterically prevent the RuO4-approaching from
the a-face. After the diol 22 was protected with Me2C(OMe)2,
the resulting ketone was reduced with NaBH4 to produce the
corresponding b-alcohol, presumably due to the steric repul-
sion between the acetonide moiety and the reagent. The abso-
lute configuration at the C100-position of the resulting b-alco-
from 25, to the aldehyde 24 is understandable by a Felkin–
Anh model[29] as shown in TS1. Unfortunately, the stereochem-
istry at the C98-position was undesired; therefore, the stereoin-
version at the C98-position of 26 was performed by Dess–
Martin oxidation[30] and subsequent diastereoselective reduc-
tion with DIBAL-H at À958C to furnish alcohol 27 bearing the
desired configuration in 84% yield in two steps as the sole
product. After the hydrolysis of the dithiane moiety of 27 with
NCS/AgNO3/2,6-lutidine in aqueous MeCN,[31] the resulting a-
hydroxy ketone was reduced diastereoselectively with Zn(BH4)2
through the chelated transition state[32] to afford the desired
anti-diol 28 as a single diastereomer.[22] Acetonide protection
of 28, removal of the p-methoxybenzyl (PMB) group by hydro-
genation, and TPAP oxidation[14] provided the aldehyde 29.
3
hol was determined by the J99,100 coupling constant (5.5 Hz).
The hydroxy moiety at the C100-position was removed
through a Barton–McCombie deoxygenation[25] by way of the
(S)-methyl dithiocarbonate to afford tetrahydropyran 23.
Synthesis of the proposed C79–C104 fragment 2.
After having synthesized both coupling precursors 15 and 29,
we next focused on the connection of these two fragments by
the Julia–Kocienski olefination (Table 1).[7] When we treated the
PT-sulfone 15 with LDA as a base and reacted it with the alde-
hyde 29, the (E)- and (Z)-alkenes 30 and 31 were obtained in
95% combined yield as an inseparable mixture in a 2.8:1 dia-
stereomeric ratio (Table 1, entry 1).[33] The resulting configura-
We next turned our attention to the introduction of the
C94–C97 moiety. Thus, deprotection of the benzyl group of 23
with lithium 4,4’-di-tert-butylbiphenylide (LiDBB)[26] followed by
Parikh–Doering oxidation[27] gave aldehyde 24 (Scheme 4). De-
protonation of dithiane 25 with nBuLi, which was synthesized
from commercially available (S)-3-hydroxy-2-methylpropionate
by the known procedure,[28] and addition of the aldehyde 24
led to the formation of alcohol 26 as a single stereoisomer.[22]
The stereoselective addition of the anion, which was formed
3
tions at the C93- and C94-positions were verified by the J93,94
coupling constants, respectively (15.3 Hz in 30 and 10.2 Hz in
31). Although we obtained the desired coupling product 30,
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Table 1. Julia–Kocienski olefination between 15 and 29.
Table 2. 13C NMR chemical shifts and their deviations of natural symbiodi-
nolide (1) and the synthetic product 2.[a]
Position
1[b]
2[c]
D(d1Àd2)[d]
83
87
91
92
93
94
95
95-Me
96
97
70.3
97.0
67.1
42.0[e]
68.7
80.9
33.5
19.0
38.7
70.5
78.5
68.8
30.7
67.1
70.4
97.2
67.2
41.8
69.1
80.9
33.1
17.3
37.7
70.1
78.1
69.4
31.1
67.3
À0.1
À0.2
À0.1
+0.2
À0.4
0.0
+0.4
+1.7
+1.0
+0.4
+0.4
À0.6
À0.4
À0.2
Entry
Conditions[a]
Yield [%][b]
Ratio (30/31)[c]
98
99
100
101
1
2
3
LDA, À78 to 08C
KHMDS, À788C
KHMDS, À1008C
95
80
70
2.8:1
8:1
>20:1
[a] LDA=lithium diisopropylamide, KHMDS=potassium hexamethyldisila-
[a] Chemical shifts are reported in ppm with reference to the internal re-
sidual solvent (CD3OD, d=49.0 ppm). [b] Data from ref. [3]. Recorded at
200 MHz. [c] Recorded at 150 MHz. [d] d1 and d2 are chemical shifts of
natural symbiodinolide (1) and the synthetic product 2, respectively.
[e] We previously reported the C92 chemical shift (d=46.4 ppm) in
ref. [3]. In this work, after the careful and detailed reinvestigation of the
13C NMR data, we have revised the chemical shift assignment (d=
42.0 ppm).
zide. [b] Isolated yield. [c] Determined by analysis of the 1H NMR spectra.
E/Z selectivity was quite low. When we used KHMDS as the
base, the E/Z ratio was increased to 8:1 (entry 2). Finally, lower-
ing the reaction temperature to À1008C, we could obtain the
(E)-alkene 30 in 70% yield as a single diastereomer (entry 3).
Further transformation from 30 to the target molecule 2 is
depicted in Scheme 5. The alkene 30 was exposed to the
Sharpless asymmetric dihydroxylation[8] with AD-mix-b to pro-
duce diol 32 possessing the expected and desired stereoche-
mistries.[22] Finally, deprotection of the benzyl group by hydro-
genation followed by simultaneous removal of the acetonide
and TBS moieties with HCl in MeOH furnished the proposed
C79–C104 fragment 2 in 79% yield in two steps.
Conclusion
Stereoselective and streamlined synthesis of the C79–C104
fragment 2 with the originally assigned stereostructure of sym-
biodinolide (1) was examined. Acid-catalyzed thermodynami-
cally controlled spiroacetalization was used as a key step to
afford stereoselectively the coupling precursor 15. The other
coupling precursor 29 was synthesized by utilizing the Achma-
towicz reaction for the tetrahydropyran construction and the
dithiane addition to the aldehyde for the introduction of the
C94–C97 moiety. The PT-sulfone 15 and the aldehyde 29 were
coupled by Julia–Kocienski olefination and subsequent Sharp-
less asymmetric dihydroxylation produced the target molecule
2. In addition, comparison of the 13C NMR chemical shifts be-
tween the natural product and synthesized 2 suggests that the
relative configuration at the C91–C99 region of symbiodinolide
(1) needs to be reinvestigated. Further our effort toward the
stereostructural elucidation of this moiety of 1 will be reported
in the following article.[36]
Experimental Section
Scheme 5. Synthesis of 2.
Experimental details, compound data, and copies of NMR spectra
of new compounds can be found in the Supporting Information.
Next, we compared the 13C NMR data of the synthetic prod-
uct 2 with those of the corresponding moiety of natural sym-
biodinolide (1).[34] The 13C NMR chemical shifts and their devia- Acknowledgements
tions of 1 and 2 are summarized in Table 2. Unexpectedly, the
13C NMR chemical shifts of the synthetic 2 did not match those
of the natural product. Especially, their chemical shift deviation
was critical at the C95-Me group. These findings clearly indi-
cate that the stereostructure at the C91–C99 carbon chain
region of symbiodinolide (1) should be re-surveyed.[35]
We are grateful to the Division of Instrumental Analysis, Okaya-
ma University, for the NMR measurements. We appreciate the
JGC-S Scholarship Foundation, The Naito Foundation, The Su-
mitomo Foundation, and The Uehara Memorial Foundation for
their financial support. This research was supported by
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[17] For our preliminary communication on the synthesis of the C94–C104
fragment, see ref. [5h].
[18] S. Celanire, F. Marlin, J. E. Baldwin, R. M. Adlington, Tetrahedron 2005,
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a Grant-in Aid for Scientific Research (no. 24710250) from the
Japan Society for the Promotion of Science (JSPS).
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[20] J. D. Albright, L. Goldman, J. Am. Chem. Soc. 1965, 87, 4214–4216.
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[22] For the stereochemical determination, see the Supporting Information.
[23] O. Achmatowicz Jr., P. Bukowski, B. Szechner, Z. Zwierzchowska, A. Za-
mojski, Tetrahedron 1971, 27, 1973–1996.
[24] B. Plietker, M. Niggemann, J. Org. Chem. 2005, 70, 2402–2405.
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Keywords: macrocycles
stereoselective synthesis · structure elucidation
·
natural products
·
polyols
·
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Published online on December 11, 2015
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