Stereocontrolled total synthesis of sphingofungin e

Article abstract of DOI:10.1002/ejoc.201301065

We describe herein the asymmetric total synthesis of sphingofungin E, which has potent immunosuppressive activity. Key steps include asymmetric desymmetrization by bromolactonization, stereocontrolled construction of four contiguous stereogenic centers through allylic C-H oxidation and epoxide ring opening, regioselective elongation of a dialdehyde, and Hofmann rearrangement by using PhI(OCOCF₃)₂. The asymmetric total synthesis of sphingofungin E, which has potent immunosuppressive activity, is described. Key steps include asymmetric desymmetrization by bromolactonization, stereocontrolled construction of four contiguous stereogenic centers through allylic C-H oxidation and epoxide ring opening, regioselective elongation of a dialdehyde, and Hofmann rearrangement by using PhI(OCOCF₃) ₂; TIPS = triisopropylsilyl. Copyright

Full text of DOI:10.1002/ejoc.201301065

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301065
Stereocontrolled Total Synthesis of Sphingofungin E
Kazutada Ikeuchi,[a] Moemi Hayashi,[a] Tomohiro Yamamoto,[a] Makoto Inai,[a]
Tomohiro Asakawa,[a] Yoshitaka Hamashima,[a] and Toshiyuki Kan*[a]
Dedicated to Professor Robert M. Williams on the occasion of his 60th birthday
Keywords: Asymmetric synthesis / Olefination / Oxidation / Rearrangement / Amino acids
We describe herein the asymmetric total synthesis of sphingo- ous stereogenic centers through allylic C–H oxidation and
fungin E, which has potent immunosuppressive activity.
Key steps include asymmetric desymmetrization by bromo-
lactonization, stereocontrolled construction of four contigu-
epoxide ring opening, regioselective elongation of a dialde-
hyde, and Hofmann rearrangement by using PhI(OCOCF3)2.
the synthesis of various derivatives is still required. Given
that sphingosines and related compounds often possess
interesting biological activities,[7] exploration of their struc-
ture–activity relationships would be useful for further drug
discovery. Herein, we report a stereocontrolled (stereodiv-
ergent) total synthesis of 1 on the basis of our original syn-
thetic methodology.
Introduction
α-Substituted α-amino acids, both natural and synthetic,
are of interest because of their unique structures and impor-
tant bioactivities.[1] During the course of our synthetic in-
vestigations on α-substituted α-amino acids,[2] we com-
pleted the total synthesis of ent-myriocin (2,[3] Figure 1) fea-
turing epoxide intermediate 7, which can potentially be
converted into numerous stereoisomers (see below). We en-
visioned that further development of the reported pro-
cedures[2,3] would provide an efficient route to sphingofun-
gin E (1),[4] which possesses an α-disubstituted α-amino
acid skeleton with four contiguous stereogenic centers.
Results and Discussion
The heart of our synthetic plan of 1 is illustrated in
Scheme 1. As Hofmann rearrangement could incorporate a
nitrogen atom onto the quaternary carbon atom of 1 at the
C-2 position, the polar amine functionality would be intro-
duced at a late stage of the total synthesis. Regioselective
incorporation of a long alkyl chain into dialdehyde 4 at the
C-6 position would be a crucial step. Dialdehyde 4 would
be obtained from cyclohexene 5 by oxidative cleavage of the
double bond. Furthermore, highly functionalized cyclohex-
Figure 1. Structures of sphingofungin E (1) and myriocin (2).
Sphingosine derivatives such as sphingofungin E (1)[4]
and myriocin (2)[5] show potent immunosuppressive activity
through inhibition of serinepalmitoyl transferase (SPT).
There have been numerous synthetic studies of the sphingo-
fungin family, but most of them have relied on chiral start-
ing materials, which limits access to various stereoisomers.
Although some total syntheses of 1 have been reported,[6]
a
versatile and flexible method that would be applicable to
[a] School of Pharmaceutical Sciences, University of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka, Japan
E-mail: kant@u-shizuoka-ken.ac.jp
http://w3pharm.u-shizuoka-ken.ac.jp/~yakuzo/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301065.
Scheme 1. Synthetic strategy of 1.
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T. Kan et al.
SHORT COMMUNICATION
ene 5 would be constructed by regioselective ring opening was accomplished efficiently. Chemoselective reduction of
of epoxide 6 at the C-3 position. Recently, we developed an the nitro group of the PNP ether was achieved by Pd/C-
efficient synthesis of epoxide 7 prepared by catalytic asym- catalyzed hydrogenolysis in the presence of Et3N.[15] Treat-
metric bromolactonization.[8] Thus, installation of the oxy- ment of the resultant p-aminophenol ether with cerium(IV)
gen atom of 6 at the C-5 position by C–H oxidation of 7 ammonium nitrate (CAN) afforded alcohol 11. After incor-
would also be a key step in our total synthesis.
poration of a MOM group into 11, oxidative cleavage of
As shown in Scheme 2, dialdehyde 12 was synthesized the double bond of the cyclohexene derivative was per-
from original epoxide 8 (90%ee), which was prepared by formed by ozonolysis to give dialdehyde 12.
catalytic asymmetric bromolactonization.[8,9] We began to
With desired dialdehyde 12 in hand, we next turned our
investigate allylic C–H oxidation and a regioselective epox- attention to regioselective elongation of the alkyl chain
ide ring-opening reaction. After numerous attempts,[10] we (Scheme 3). During investigation of this reaction, we found
found that a combination of MnIII-catalyzed oxidation and that the right-side aldehyde at the C-2 position was less re-
NaBH4 reduction gave satisfactory results. The desired all- active than the aldehyde at the C-6 position, as it was steri-
ylic C–H oxidation proceeded under Shing’s conditions,[11] cally more crowded. After numerous attempts at selective
and subsequent treatment with Et3N[12] provided the enone olefination,[16] we found that the divalent chromium-medi-
in excellent yield. Next, the chemo- and stereoselective re- ated Takai reaction[17] gave the most satisfactory results.
duction of the enone was carried out with NaBH4 in the Upon treatment of dialdehyde 12 with alkyl diiodide 13[18]
presence of (MeO)3B[13] at –78 °C to give 9 in good yield. and CrCl2 in the presence of DMF, the coupling reaction
Throughout this oxidation and reduction sequence, no de- proceeded smoothly to give 14 with predominantly trans
composition of the epoxide was observed. After inversion configuration. In this step, all carbon units within 1 were
of the secondary alcohol of 9 by Mitsunobu reaction with incorporated with the correct stereochemistry. However,
p-nitrophenol (PNPOH),[14] regioselective ring opening of oxidation of the remaining aldehyde to the corresponding
the epoxide was carried out. Upon treatment of the epoxide carboxylic acid was found to be troublesome.[19] This might
with BF3·OEt2, intramolecular 6-exo cyclization from the be related to the low reactivity of the aldehyde with nucleo-
carbonyl oxygen atom of the tert-butoxycarbonyl (Boc) philes to generate hemiacetal intermediates as a result of
group occurred smoothly to afford cyclic carbonate 10 with steric hindrance. We speculated that the oxidation might oc-
the correct contiguous stereogenic centers of sphingofun-
gin E (1). Recrystallization afforded 10 in optically pure
form (Ͼ99%ee). After basic hydrolysis of the carbonate
group of 10, the resultant triol was protected as a meth-
oxymethyl (MOM) ether. In the Mitsunobu reaction, we
selected PNPOH because it is a sufficiently acidic nucleo-
phile and the ether bond is high stabile under basic as well
as acidic conditions. Although the removal of the PNP
group required a two-step procedure, the transformation
Scheme 2. Synthesis of dialdehyde 12. Reagents and conditions:
(a) Mn(OAc)3·2H2O, TBHP, EtOAc, 4 Å molecular sieves, Et3N
(87%). (b) NaBH4, (MeO)3B, MeOH, –78 °C (93%, dr = 27:1).
(c) PNPOH, DEAD, Ph3P, toluene. (d) BF3·OEt2, CH2Cl2, 0 °C; Scheme 3. Completion of the total synthesis of 1. Reagents and
TFA (79% two steps). (e) NaH, MeOH, 0 °C. (f) MOMCl,
iPr2NEt, 1,2-dichloroethane, 60 °C. (g) H2, Pd/C, Et3N, EtOAc.
(h) CAN, MeCN/buffer (pH 7.6), 0 °C. (i) MOMCl, iPr2NEt,
CH2Cl2 (63% five steps). (j) O3, CH2Cl2; Me2S, –78 °C to r.t.
TBHP = tert-butyl hydroperoxide, DEAD = diethyl azodicarboxyl-
ate, TFA = trifluoroacetic acid.
conditions: (a) 13, CrCl2, DMF, THF (61%, two steps).
(b) TMSCN, Et3N, CH2Cl2; NH4F, EtOH, 0 °C. (c) AZADO,
PhI(OAc)2, CH2Cl2. (d) aq. NH3, 0 °C (59%, three steps). (e) PhI-
(OCOCF3)2, toluene, 60 °C (18/19 = 3:2). (f) 6 m HCl, MeOH.
(g) 3 m NaOH, MeOH, 75 °C; Amberlite IRC-76 (63%, three
steps).
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Stereocontrolled Total Synthesis of Sphingofungin E
suggestion regarding regioselective olefination of 12 in the presence
of DMF.
cur if the secondary alcohol could be formed by the ad-
dition of a suitable nucleophile to the aldehyde. Indeed,
treatment of 14 with TMSCN and Et3N followed by ad-
dition of NH4F gave cyanohydrin 15 in good yield as a [1] For recent reviews, see: a) Y. Ohfune, K. Sakaguchi, T. Shin-
ada, ACS Symp., Ser. 2009, 1009, 57–88; b) Y. Ofune, T. Shin-
mixture of diastereomers. To our delight, oxidation of 15
ada, Eur. J. Org. Chem. 2005, 5127–5143; c) T. Ooi, K. Ma-
was promoted by 2-azaadamantane-N-oxyl (AZADO)[20]
ruoka, Aldrichim. Acta 2007, 40, 77–86; d) S. H. Kang, S. Y.
Kang, H.-S. Lee, A. Buglass, Chem. Rev. 2005, 105, 4537–4558.
and PhI(OAc)2 without difficulty. Given that generated acyl
nitrile intermediate 16 was unstable, 16 was converted into
desired amide 17 in situ by adding aqueous ammonia. This
result suggests that the hydrocyanation/oxidation combina-
tion is potentially applicable to the oxidation of other steri-
cally hindered aldehydes to the corresponding carboxylic
acids.[21]
[2] a) T. Kan, T. Fujimoto, S. Ieda, Y. Asoh, H. Kitaoka, T. Fuku-
yama, Org. Lett. 2004, 6, 2729–2731; b) T. Kan, Y. Kawamoto,
T. Asakawa, T. Furuta, T. Fukuyama, Org. Lett. 2008, 10, 169–
171; c) S. Ieda, T. Kan, T. Fukuyama, Tetrahedron Lett. 2010,
51, 4027–4029.
[3] M. Inai, T. Goto, T. Furuta, T. Wakimoto, T. Kan, Tetrahe-
dron: Asymmetry 2008, 19, 2771–2773.
[4] W. S. Horn, J. L. Smith, G. F. Bills, S. L. Raghoobar, G. L.
Helmes, M. B. Kurta, J. A. Marrina, B. R. Frommer, R. A.
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[5] a) D. Kluepfel, J. F. Bagli, H. Baker, M. Charest, A. Kudelski,
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R. Craveri, B. Rindone, C. Scolastico, Tetrahedron 1972, 28,
5493–5498.
Having synthesized a Hofmann rearrangement precur-
sor, we finally focused on the construction of the α-disubsti-
tuted α-amino acid moiety. Upon treatment of amide 17
with PhI(OCOCF3)2, the desired Hofmann rearrangement
and oxazolidinone formation proceeded smoothly to give a
3:2 mixture of 18/19. This oxazolidinone formation reaction
presumably results from attack of the neighboring MOM
ether on the isocyanate intermediate. Finally, reaction of
the mixture of 18/19 with 6 m HCl,[22] followed by exposure [6] For the total synthesis of sphingofungin E, see: a) B. Wang,
X.-M. Yu, G.-Q. Lin, Synlett 2001, 904–906; b) B. M. Trost,
to 3 m NaOH in MeOH solution removed all of the MOM
C.-B. Lee, J. Am. Chem. Soc. 2001, 123, 12191–12201; c) T.
groups and hydrolyzed the oxazolidinone ring. Subsequent
Nakamura, M. Shiozaki, Tetrahedron Lett. 2001, 42, 2701–
neutralization with Amberlite IRC-76 gave sphingofungin E
2704; d) T. Nakamura, M. Shiozaki, Tetrahedron 2002, 58,
(1) in neutral form. The spectroscopic data (1H NMR, 13C
8779–8791; e) T. Oishi, K. Ando, K. Inomiya, H. Sato, M. Iida,
N. Chida, Org. Lett. 2002, 4, 151–154; f) T. Oishi, K. Ando,
K. Inomiya, H. Sato, M. Iida, N. Chida, Bull. Chem. Soc. Jpn.
2002, 75, 1927–1947; g) B. Wang, G.-Q. Lin, Eur. J. Org. Chem.
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manováa, S. Slaninková, J. Kuchár, Carbohydr. Res. 2010, 345,
2427–2437.
NMR, IR, HRMS, and [α]D) were in full agreement with
those of the natural product.
Conclusions
[7] FTY 720 (Fingomolide), which was developed from 1 as a lead
compound, has recently been marketed as an immunomodulat-
ing drug by the Mitsubishi Tanabe Pharma Corporation and
Novartis International AG. For details of FTY 720, see: a) K.
Adachi, T. Kohara, N. Nakao, M. Arita, K. Chiba, T. Mishina,
S. Sasaki, T. Fujita, Bioorg. Med. Chem. Lett. 1995, 5, 853–
856; b) K. Chida, N. Yoshii, Nippon Yakurigaku Zasshi 2012,
139, 265–274; c) K. Chida, K. Adachi, Pharmaceuticals 2012,
5, 514–528; d) K. Adachi, Farumashia 2012, 48, 526–530.
[8] K. Ikeuchi, S. Ido, S. Yoshimura, M. Inai, T. Asakawa, Y.
Hamashima, T. Kan, Org. Lett. 2012, 14, 6016–6019.
[9] We already reported the large-scale synthesis of 8. For details,
see ref.[8] and the Supporting Information.
In conclusion, the enantioselective total synthesis of
sphingofungin E (1), starting from benzoic acid, was ac-
complished in 22 steps. Our synthetic strategy features all-
ylic C–H oxidation, regioselective Takai olefination of dial-
dehyde 12 to give (E)-olefin 14, and PhI(OCOCF3)2-medi-
ated Hofmann rearrangement of amide 17 to provide the α-
disubstituted α-amino acid moiety. Given that the synthetic
intermediates are readily convertible into other stereoiso-
mers,[23] the present synthetic method should be suitable for
the preparation of various derivatives of 1, as well as other
natural products.[1d] Further investigations are underway in
our laboratories.
[10] The allylic oxidation of 8 by using other reagents is shown
below:
Supporting Information (see footnote on the first page of this arti-
1
cle): Full experimental details and copies of the H NMR and 13C
NMR spectra for all new compounds.
Acknowledgments
This research was financially supported in part by a Grant-in-Aid
for Scientific Research on Priority Areas 12045232 and a Grant-
in-Aid for Scientific Research on Innovative Areas “Advanced Mo-
lecular Transformations by Organocatalysts” from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT) of
Japan and a grant from Uehara Memorial Foundation. The au-
thors thank Professor Kazuhiko Takai (Graduate School of Natu-
ral Science and Technology, Okayama University) for his kind
[11] T. K. M. Shing, Y.-Y. Yeung, P. L. Su, Org. Lett. 2006, 8, 3149–
3151.
[12] In this oxidation reaction, the addition of Et3N was important
for the conversion of the tert-butyl peroxide intermediate into
the ketone.
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T. Kan et al.
SHORT COMMUNICATION
[13] A. Murai, N. Tanimoto, N. Sakamoto, T. Masamune, J. Am.
Chem. Soc. 1988, 110, 1985–1986.
[14] D. L. Hughes, Org. React. 1992, 42, 335–656.
[15] In this reduction, Et3N is likely to poison the Pd catalyst. In
the absence of Et3N, concomitant reduction of the cyclohexene
proceeded; see: a) H. Sajiki, H. Kuno, K. Hirota, Tetrahedron
Lett. 1998, 39, 7127–7130; b) H. Sajiki, K. Hirota, Tetrahedron
1998, 54, 13981–13996.
[16] Investigation of the regioselective olefination reaction of 20 un-
der other reaction conditions is described in the Supporting
Information.
[17] K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc. 1986, 108,
b) For the quaternary carbon center, a combination of reduction
and oxidation of 22 resulted in inversion of the carboxylic acid
and the primary alcohol to provide 25.
7408.
[18] Diiodide dodecanone 13 was prepared from 2-hexyl-2-(6-
iodohexyl)-1,3-dioxolane in two steps. For more details, see the
Supporting Information.
[19] For the direct conversion of aldehyde 14 into the carboxylic
derivative, the following oxidations were tested: Jones oxi-
dation, Kraus oxidation, and AZADO oxidation. However,
these standard reactions gave unsatisfactory results. The start-
ing material decomposed in the Jones oxidation, whereas it was
recovered in the other two reactions.
[20] M. Shibuya, M. Tomizawa, I. Suzuki, Y. Iwabuchi, J. Am.
Chem. Soc. 2006, 128, 8412–8413.
[21] E. J. Corey, N. W. Gilman, B. E. Ganem, J. Am. Chem. Soc.
1968, 90, 5616–5617.
[22] Removal of the three MOM ethers from oxazolidinone deriva-
tives 18 and 19 occurred efficiently under acidic conditions,
whereas deprotection of tetrakis-MOM ether derivatives, ob-
tained from the reaction with PhI(OAc)2, resulted in a retro-
aldol reaction. For details, see the Supporting Information.
[23] Various stereoisomers are accessible through the following
transformations of synthetic intermediates. Combinations of
these reactions would potentially provide numerous derivatives:
a) For the diastereomer of the diol part, regioselective ring
opening of benzoate 20 occurred at the other site to give diol
21.
Received: July 17, 2013
Published Online: September 19, 2013
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