Total syntheses of (Sp)-(+)- and (Rp)-(-)-spiniferin- 1, a pair of unusual natural products with planar chirality

Article abstract of DOI:10.1039/c1cc13650j

(S_p)-(+)-Spiniferin-1 and (R_p)-(-)-spiniferin-1, a pair of unusual marine natural products with planar chirality, were firstly synthesized via a polyfluoroalkanosulfonyl fluoride induced homoallylic carbocation rearrangement reaction

Full text of DOI:10.1039/c1cc13650j

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Total syntheses of (Sp)-(+)- and (Rp)-(ꢀ)-spiniferin-1, a pair of unusual
natural products with planar chiralityw
Yun-Shan Sun, Kai Ding and Wei-Sheng Tian*
Received 20th June 2011, Accepted 14th July 2011
DOI: 10.1039/c1cc13650j
(Sp)-(+)-Spiniferin-1 and (Rp)-(ꢀ)-spiniferin-1,
unusual marine natural products with planar chirality, were
firstly synthesized via polyfluoroalkanosulfonyl fluoride
a pair of
a
induced homoallylic carbocation rearrangement reaction. The
chiral resolution and palladium-catalyzed b-H elimination of
allylic alcohol derivatives were considered as the key steps of
these divergent syntheses.
Bridged-[10]-annulenes have spurred considerable interest in
the chemical community not only because of their aromaticity
but also because of their planar chirality.1 Vogel has synthesized
many artificial bridged-[10]-annulenes in his pioneering work,2
but natural products with the bridged-[10]-annulene structural
unit are rare. Spiniferin-1 (Fig. 1) has been the first and only
known planar-chiral natural product with the skeleton of
1,6-methano[10]annulene up to now.
Scheme 1 Retrosynthetic analysis of Sp-(+)- and Rp-(ꢀ)-spiniferin-1.
Our retrosynthetic strategy to (Sp)-(+)-1 and (Rp)-(ꢀ)-1 is
shown in Scheme 1. The bridged-[10]-annulene structural units
can be easily constructed via a polyfluoroalkanosulfonyl
fluoride induced homoallylic carbocation rearrangement
reaction.6 The preparation of optically pure synthetic precursor
2 (S and R) or its derivatives was considered as the main
challenge for the successful synthesis.
Spiniferin-1 (1) was isolated by Cimino et al. in 1975 from
the Mediterranean sponge Pleraplysilla spinifera, which is
present in the Bay of Naples.3 In 1983, Marshall and Conrow
finished the first total synthesis of racemic spiniferin-1 to
confirm its planar structure.4 Recently, a concise and efficient
total synthesis of racemic spiniferin-1 was also reported by our
group.5 However, the stereochemistry of naturally occurring
spiniferin-1 still remains unclear to date. The interest to determine
the absolute stereochemistry of spiniferin-1 and to study the
biological activities of each of the enantiomers prompted us to
continue the syntheses of the two enantiomers of spiniferin-1.
Herein, we report the first total syntheses of (Sp)-(+)- and
(Rp)-(ꢀ)-spiniferin-1 via the polyfluoroalkanosulfonyl fluoride
induced homoallylic carbocation rearrangement reaction.
Evidently, enantioselective Michael addition is a direct and
concise method for the preparation of optically pure Robinson
annulation product 2.7 However, the b-keto ester 3 displayed
poor reactivity due to the presence of the gem-dimethyl group,
and its addition to methyl vinyl ketone was only promoted by
strong bases such as KOMe or t-BuOK (Scheme 2).
Therefore, we turned our attention to the chiral resolution
of racemic enone 2. Much to our disappointment, the resolution
of enone 2 via formation of an inclusion complex of TADDOL8
only gave less than 30% ee value under optimized conditions.
The chiral ketal of 2 formed by treatment with tartrate ester is
also inseparable by recrystallization or chromatography. The
diastereomeric amides 4 and 40 with (S)-a-methylbenzylamine
as a chiral auxiliary can be readily separated chromato-
graphically, and their absolute stereochemistry was also
determined by X-ray analysis of the hydroxylated derivative
5 from amide 4 (Scheme 2). However, all attempts to cleave the
amide bond of 4 and 5 to regenerate the C–O single bond,
which is necessary for the last step in our strategy, were
fruitless because of the presence of the gem-dimethyl group,
hence precluding the synthesis of enantiomerically pure
spiniferin-1 from amide 4.
Fig. 1 Structure of spiniferin-1.
Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai, China.
E-mail: wstian@mail.sioc.ac.cn; Fax: +86 21 64166128
w Electronic supplementary information (ESI) available: Experimental
procedures, NMR spectra, chiral HPLC data and crystallographic
data for 5. CCDC 838548 and 838549. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1cc13650j
Fortunately, we found that the (S)-mandelic acid esters
9 and 90 of g-hydroxyl enone 7 were easily resolved as well
c
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Chem. Commun., 2011, 47, 10437–10439 10437

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Scheme 2 Robinson-type annulation of b-keto ester 3 and the
resolution of 2 via diastereomeric amide formation. Reagents and
conditions: (a) methyl vinyl ketone, KOMe, 0 1C; K2CO3, MeOH,
reflux, 80%; (b) LiAlH4, THF, rt, 94%; (c) DMSO, (COCl)2, Et3N,
CH2Cl2, ꢀ78 1C–rt, 91%; (d) NaClO2, NaH2PO4ꢂ2H2O, DMSO,
tBuOH/H2O, 0 1C, 75%; (e) DMF, (COCl)2, (S)-a-methylbenzylamine,
ꢀ20 1C–rt, then resolution by chromatography, 4: 39%, 40: 41%; (f) O2,
orthoformic acid triisopropyl ester, p-toluenesulfonic acid, iPrOH,
40 1C, 87%.
Scheme 3 Synthesis of g-hydroxyl enone 7 and chiral resolution.
Reagents and conditions: (a) CH(OCH3)3, p-toluenesulfonic acid,
CH3OH, 0 1C, 78%; (b) oxone, CH3OH, rt, 80%; (c) O-tetrahydro-
pyranyl-S-mandelic acid, DCC, DMAP, CH2Cl2,
0 1C, 85%;
(d) p-toluenesulfonic acid, CH3OH, rt, then resolution by chromatography,
9: 36%, 90: 38%.
(Scheme 3). The g-hydroxyl enone 7 was prepared as a
diastereomerically pure cis-isomer5 from enone 2. Esterification
of (ꢁ)-7 with O-tetrahydropyranyl-S-mandelic acid9 followed
by removal of the THP group afforded more polar ester
9 and less polar ester 90, which can be easily separated by
flash chromatography.10
The absolute configuration of intermediate 9 was assigned
in an indirect manner (Fig. 2).11 The optically pure 9 and 90 are
difficult to recrystallize because of their low melting points.
However, the racemic mixture of 9 and its enantiomer (ent-9),
which was prepared from racemic mandelic acid and 7, had a
higher melting point and could be easily recrystallized. X-Ray
analysis5 of the mixture of 9 and ent-9 confirmed the relative
stereochemistry of three stereocenters in 9. Thus, the absolute
configurations of 9 and 90, derived from (S)-mandelic acid,
were unambiguously assigned to be 1R,4aS,20S and
1S,4aR,20S, respectively, as shown in Scheme 3.
With optically active intermediates 9 (83.6% ee as determined
by HPLC) and 90 (95.5% ee) in hand, we started to synthesize
the two enantiomers of spiniferin-1. Selective hydrolysis of
mandelic acid ester to regenerate enantiopure 7 in the presence
of potassium carbonate or triethylamine12 was unsuccessful
because of the intramolecular transesterification to form a
lactone. However, 9 and 90 can be directly converted into
(S)-10 and (R)-10 in high yields via Pd(PPh3)4-catalyzed
b-H elimination of the allylic alcohol ester (Scheme 4).13
Starting from dienone (S)-10 or (R)-10 the two enantiomers
of spiniferin-1 were prepared smoothly following the previous
Fig. 2 Synthesis and single-crystal X-ray diffraction analysis of the
racemic mixture of 9 and ent-9.5
absolute configuration of (+)-spiniferin-1 was assigned as
Sp and (ꢀ)-spiniferin-1 as Rp.
With the two enantiomers of spiniferin-1 in hand, the
stability of the planar chirality was studied. Consistent with
Vogel’s reports,14 the planar chirality proves to be stable under
neutral conditions. No racemization was observed when the
chiral samples were placed at 0 1C for several months or
at elevated temperature (60 1C) for one hour. The specific
rotation of (ꢀ)-spiniferin-1 had no change with time at room
temperature (Table 1). Compared with the reported data of
1
procedures for the synthesis of (ꢁ)-spiniferin-1. The H and
13C NMR data of (+)-spiniferin-1 and (ꢀ)-spiniferin-1 were both
in agreement with the reported values of racemic spiniferin-1.3–5
Based on the mechanisms of polyfluoroalkanosulfonyl fluoride
induced tandem carbocation rearrangement reaction, the
c
10438 Chem. Commun., 2011, 47, 10437–10439
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preparation of these rare substances for further biological studies.
The biological activities of (ꢁ)-spiniferin-1, (+)-spiniferin-1,
(ꢀ)-spiniferin-1 and their analogues are currently under
investigation.
We gratefully acknowledge financial support of this work by
the NSFC (No. 20772140).
Notes and references
1 (a) E. L. Eliel and S. H. Wilen, Stereochemistry of Organic
Compounds, Wiley-Interscience, 1994, pp. 1170–1172; (b) K. Schlogl,
Top. Curr. Chem., 1984, 125, 27.
2 (a) E. Vogel and H. D. Roth, Angew. Chem., Int. Ed. Engl., 1964,
3, 228; (b) E. Vogel and W. A. Boll, Angew. Chem., Int. Ed. Engl.,
1964, 3, 642; (c) E. Vogel, Pure Appl. Chem., 1982, 54, 1015.
3 (a) G. Cimino, S. De Stefano, L. Minale and E. Trivellone,
Tetrahedron Lett., 1975, 16, 3727; (b) G. Cimino, S. De Stefano,
L. Minale and E. Trivellone, Experientia, 1978, 19, 1425.
4 J. A. Marshall and R. E. Conrow, J. Am. Chem. Soc., 1983,
105, 5679.
5 K. Ding, Y. S. Sun and W. S. Tian, J. Org. Chem., 2011, 76, 1495.
6 (a) W. S. Tian, Z. Lei, L. Chen and Y. Huang, J. Fluorine Chem.,
2000, 101, 305; (b) L. Chen, K. Ding and W. S. Tian, Chem.
Commun., 2003, 838.
7 (a) T. Akiyama, T. Katoh and K. Mori, Angew. Chem., Int. Ed.,
2009, 48, 4226; (b) J. Christoffers, U. Roßler and T. Werner,
Eur. J. Org. Chem., 2000, 701; (c) H. Sasai, E. Emori, T. Arai
and M. Shibasaki, Tetrahedron Lett., 1996, 37, 5561.
8 (a) D. Seebach, A. K. Beck and A. Heckel, Angew. Chem., Int. Ed.,
2001, 40, 92; (b) F. Toda and K. Tanaka, Tetrahedron Lett.,
1988, 29, 551.
Scheme 4 Syntheses of (+)-spiniferin-1 and (ꢀ)-spiniferin-1.
Reagents and conditions: (a) Pd(PPh3)4, Et3N, dioxane, 75 1C, 84%
for (+)-10, 79% for (ꢀ)-10; (b) LDA, ZnCl2, THPOCH2CHO, THF,
ꢀ78 1C, 96% for 11a, 95% for 11b; (c) p-toluenesulfonic acid, THF,
80 1C; (d) LiAlH4, THF, 40 1C; (e) CF3CF2CF2CF2SO2F, DBU,
THF, 0 1C–rt, 35% 3 steps for (+)-spiniferin-1, 31% 3 steps for
(ꢀ)-spiniferin-1.
9 O. Kuisle, E. Quinoa and R. Riguera, J. Org. Chem., 1999,
64, 8063.
10 Chiral HPLC indicated the existence of slight racemization at the
chiral center of the benzylic position in esters 9 and 90, which was
caused by the presence of DMAP during the esterification of
7 as well as the acidic conditions during the THP group removal
step. The racemization led to the decline of the optical purities of
esters 9 and 90. See ESIw for the determination of their optical
purities.
Table 1 Specific rotation of (ꢀ)-spiniferin-1a
0 h
6.5 h
15.5 h
33 h
(ꢀ)-1b
ꢀ364.2
ꢀ365.7
ꢀ372.2
b
ꢀ375.2
11 E. L. Eliel, S. H. Wilen and M. P. Doyle, Basic Organic Stereo-
chemistry, Wiley-Interscience, 2001, pp. 106–115.
12 J. S. Panek and M. A. Sparks, Tetrahedron: Asymmetry, 1990,
1, 801.
a
(ꢀ)-Spiniferin-1: c = 0.905, MeOH, 25 1C. The slight increase of
the specific rotation was due to the slow evaporation of the solvent.
13 (a) J. B. Evarts Jr. and P. L. Fuchs, Tetrahedron Lett., 2001,
42, 3673; (b) J. Tsuji, T. Yamakawa, M. Kaito and T. Mandai,
Tetrahedron Lett., 1978, 24, 2075.
the natural product (ꢀ4.2, concentration and solvent not
given),3a synthetic samples exhibited much higher rotations
(+375, c 1.01 in CHCl3, 80.6% ee and ꢀ432, c 1.06 in CHCl3,
90.8% ee).15 Given the stability of the planar chirality, we
surmised that the natural product existed in a nearly racemic
form (ca. 1% ee).
14 Vogel’s work indicated that the 1,6-methano[10]annulenes were
configurationally stable because of their high bridge inversion
energy barrier. See (a) E. Vogel, T. Schieb, W. H. Schulz,
K. Schmidt, H. Schmickler and J. Lex, Angew. Chem., Int. Ed.
Engl., 1986, 25, 723; (b) J. Scharf, K. Schlogl, M. Widhalm, J. Lex,
W. Tuckmantel, E. Vogel and F. Pertlik, Monatsh. Chem., 1986,
117, 255; (c) E. Vogel, W. Tuckmantel, K. Schlogl, M. Widhalm,
E. Kraka and D. Cremer, Tetrahedron Lett., 1984, 25, 4925;
(d) K. Schlogl, M. Widhalm, E. Vogel and M. Schwamborn,
Monatsh. Chem., 1983, 114, 605; (e) U. Kuffner and K. Schlogl,
Monatsh. Chem., 1972, 103, 1320; (f) U. Kuffner and K. Schlogl,
Tetrahedron Lett., 1971, 12, 1773.
In conclusion, the first total syntheses of Sp-(+)-spiniferin-1
and Rp-(ꢀ)-spiniferin-1 were accomplished and the natural
spiniferin-1 was shown to be nearly racemic. The stereochemical
study of enantiomerically enriched spiniferin-1 indicated that
the naturally occurring planar chirality is stable under mild
conditions. The divergent syntheses of (+)-spiniferin-1 and its
enantiomer in 5.4% and 4.7% respective overall yields over
9 steps could provide an approach for the large scale
15 The low diastereomeric optical purity of ester 9 or 90 accounts for
the low ee value of (+)-spiniferin-1 or (ꢀ)-spiniferin-1 since no
further racemization was observed in all the reactions shown in
Scheme 4. See ESIw for details.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10437–10439 10439