Total synthesis of the immunosuppressants myriocin and 2-epi-myriocin

Article abstract of DOI:10.1021/ol801709c

(Chemical Equation Presented) Total syntheses of the natural immunosuppressant myriocin (1) and the equipotent unnatural analogue 2-epi-myriocin (in protected form) have been achieved through a common strategy. The key transformations are the efficient synthesis of a quaternary (E)-vinylglycine by asymmetric deconjugative alkylation of a dehydroamino acid and an unusually highly diastereoselective dihydroxylation of the vinylglycine alkene.

Full text of DOI:10.1021/ol801709c

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4125-4128
Total Synthesis of the
Immunosuppressants Myriocin and
2-epi-Myriocin
Matthew C. Jones and Stephen P. Marsden*
School of Chemistry, UniVersity of Leeds, Leeds LS2 9JT, United Kingdom
s.p.marsden@leeds.ac.uk
Received July 25, 2008
ABSTRACT
Total syntheses of the natural immunosuppressant myriocin (1) and the equipotent unnatural analogue 2-epi-myriocin (in protected form) have
been achieved through a common strategy. The key transformations are the efficient synthesis of a quaternary (E)-vinylglycine by asymmetric
deconjugative alkylation of a dehydroamino acid and an unusually highly diastereoselective dihydroxylation of the vinylglycine alkene.
Myriocin (1) is a complex amino acid natural product that
has been isolated independently from three fungal sources.1-3
Initially of interest owing to its antifungal properties,1,2
considerable interest was engendered by the finding that
myriocin is a potent immunosuppressant.3 Myriocin has been
shown to be an inhibitor of serine palmitoyl transferase,4 a
key enzyme in the biosynthesis of sphingolipids. On the basis
of this activity, myriocin has been examined as a potential
antiatherosclerotic agent.5
tive target for total synthesis.6 The first successful total
synthetic approach was achieved in 15 linear steps from
D-fructose, but the quaternary stereocenter was installed by
a Strecker reaction in which the desired diastereoisomer was
the minor component in a 7:2 mixture.7 Subsequent total
and formal synthetic studies have employed a variety of
methods for the stereoselective introduction of the quaternary
stereocenter, including epoxide opening with internal8,9 or
external10,11 nitrogen nucleophiles, aldol reactions on chiral
bislactim ether12 or oxazoline templates,13 Overman re-
The juxtaposition of the quaternary R-amino acid and the
neighboring dihydroxylated alkyl chain within myriocin
represents a challenging motif which, combined with the
interesting biological activity, has made myriocin an attrac-
(6) For a useful review of synthetic approaches to serine palmitoyl
transferase inhibitors, see: Byun, H. S.; Lu, X.; Bittman, R. Synthesis 2006,
2447–2474.
(7) (a) Banfi, L.; Beretta, M. G.; Colombo, L.; Gennari, C.; Scolastico,
C. J. Chem. Soc., Chem. Commun. 1982, 488–490. (b) Banfi, L.; Beretta,
M. G.; Colombo, L.; Gennari, C.; Scolastico, C. J. Chem. Soc., Perkin Trans.
1 1983, 1613–1619. (c) For a synthesis of anhydromyriocin using an
essentially nonselective Strecker reaction, see: Just, G.; Payette, D. R.
Tetrakedron Lett. 1980, 21, 3219–3222.
(1) (a) Kluepfel, D.; Bagli, J.; Baker, H.; Charest, M.-P.; Kudelski, A.;
Sehgal, S. N.; Vezina, C. J. Antibiot. 1972, 25, 109–115. (b) Bagli, J.;
Kluepful, D.; St-Jacques, M. J. Org. Chem. 1973, 38, 1253–1260
.
(2) (a) Aragozzini, F.; Manachini, P. L.; Craveri, R.; Rindone, R.;
Scolastico, C. Tetrahedron 1972, 13, 5493–5498. (b) Destro, R.; Colombo,
A. J. Chem. Soc., Perkin Trans. 2 1979, 896–899
(3) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.; Toyama,
R.; Chiba, K.; Hoshino, Y.; Okumoto, T. J. Antibiot. 1994, 47, 208–215
(4) (a) Miyake, Y.; Kozutsumi, Y.; Nakamura, S.; Fujita, T.; Kawasaki,
T. Biochem. Biophys. Res. Commun. 1995, 211, 396–403. (b) Chen, J. K.;
Lane, W. S.; Schreiber, S. L. Chem. Biol. 1999, 6, 221–235.
(5) Glaros, E. N.; Kim, W. S.; Quinn, C. M.; Jessup, W.; Rye, K.-A.;
Garner, B. J. Lipid. Res. 2008, 49, 324–331.
.
(8) Rao, A. V. R.; Gurjar, M. K.; Devi, T. R.; Kumar, K. R. Tetrahedron
Lett. 1993, 34, 1653–1656.
.
(9) Hatakeyama, S.; Yoshida, M.; Esumi, T.; Iwabuchi, Y.; Irie, H.;
Kawamoto, T.; Yamada, H.; Nishizawa, M. Tetrahedron Lett. 1997, 38,
7887–7890
.
(10) (a) Deloisy, S.; Thang, T. T.; Olesker, A.; Lukacs, G. Tetrahedron
Lett. 1994, 35, 4783–4786. (b) Deloisy, S.; Thang, T. T.; Olesker, A.;
Lukacs, G. Bull. Chim. Soc. Fr. 1996, 133, 581–585
.
10.1021/ol801709c CCC: $40.75
Published on Web 08/23/2008
2008 American Chemical Society

arrangement,14 and photolytic hydroxymethylation of R-car-
chloride. The alkylated product 2 was formed apparently as
18
boxyoximes.15
a single diastereoisomer by H NMR. It should be noted
that the expected16 absolute stereochemistry of the amino
acid center arising from alkylation of 3 (incorporating the
more readily available (-)-enantiomer of the 8-phenylmen-
thol auxiliary) is opposite to that required for myriocin. Our
initial intention was to work in this antipodal series to
optimize the synthetic route and to address the “correct”
stereochemical series later.
1
We recently reported a convenient method for the asymmetric
synthesis of quaternary (E)-vinylglycines based upon the
deconjugative alkylation of chiral dehydroamino acid deriva-
tives.16,17 We reasoned that a quaternary vinylglycine such
as 2 would be an attractive precursor to myriocin, provided
that a diastereoselective dihydroxylation of the alkene could
be achieved under substrate, reagent, or catalyst control
(Figure 1). We report herein the successful application of
Compound 2 could not easily be purified to homogeneity
and so was used directly in the subsequent dihydroxylation
reaction. Reaction of 2 with potassium osmate under slightly
modified Upjohn conditions gave a highly diastereoselective
reaction, furnishing diol 5 in 65% yield (over two steps) as
an inseparable 90:10 mixture of diastereoisomers. Protection
of 5 as an acetonide facilitated separation of the two
diastereoisomers 6a (71%) and 6b (6%) by careful chroma-
tography. At this stage, the identity of the major diastere-
oisomer was confirmed by X-ray crystallographic studies of
a solid derivative.19 This confirmed both the stereochemical
outcome of the alkylation reaction and that dihydroxylation
had occurred selectively syn to the protected amine function.
The syn-1,2-aminoalcohol relationship in 6a is diastere-
omeric to that in myriocin. However, both the relative and
absolute stereochemistries in 6a match those in the non-
natural analogue 2-epi-myriocin 7, which has previously been
prepared by Yoshikawa and shown to be equipotent to
myriocin in the suppression of the mouse allogenic mixed
lymphocyte reaction (IC50 ) 9 nM).20 We therefore elected
to progress 6a to 2-epi-myriocin, providing an alternative
approach to this valuable biochemical tool as well as allowing
us to scope end-game chemistry for a later assault on
myriocin itself.
Figure 1. Schematic retrosynthetic analysis of myriocin.
this strategy to the syntheses of both myriocin and a protected
form of the equipotent non-natural isomer 2-epi-myriocin.
Our first target was the substrate for the deconjugative
asymmetric alkylation, namely, dehydroamino acid 3. This
was readily prepared by Horner-Wadsworth-Emmons
condensation of the previously reported16 phosphonate
reagent 4 (available in two steps from commercial Z-
phosphonoglycinate) with 3-tert-butyldimethylsilanoxybu-
tanal (Scheme 1). Alkylation of 3 was achieved by double
To construct the C6-C7 E-olefin in 7, we elected to use
a Julia-Kocienski olefination.21,22 Thus, removal of the
TBDMS protecting group of 6a was followed by two-step
conversion to the phenyltetrazolyl sulfone 8 according to the
Scheme 1
.
Synthesis and Diastereoselective Dihydroxylation of
Quaternary Vinylglycine 2
(11) (a) Yoshikawa, M.; Yokokawa, Y.; Okuno, Y.; Murakami, N. Chem.
Pharm. Bull. 1994, 42, 994–996. (b) Yoshikawa, M.; Yokokawa, Y.; Okuno,
Y.; Murakami, N. Tetrahedron 1995, 51, 6209–6228
(12) Sano, S.; Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruyama,
S.; Fujita, T.; Nagao, Y. Tetrahedron Lett. 1995, 36, 2097–2100
(13) Lee, K.-Y.; Oh, C.-Y.; Kim, Y.-H.; Joo, J.-E.; Ham, W.-H.
.
.
Tetrahedron Lett. 2002, 43, 9361–9363
.
(14) (a) Oishi, T.; Ando, K.; Chida, N. Chem. Commun. 2001, 1932–
1933. (b) Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N.
Bull. Chem. Soc. Jpn. 2002, 75, 1927–1947
(15) Torrente, S.; Alonso, R. Org. Lett. 2001, 3, 1985–1987
(16) Jones, M. C.; Marsden, S. P.; Mun˜oz-Subtil, D. M. Org. Lett. 2006,
8, 5509–5512
.
.
.
(17) For related approaches to quaternary vinylglycines from dehy-
droamino acids, see:(a) Seebach, D.; Buerger, H. M.; Schickli, C. P. Liebigs.
Ann. Chem. 1991, 669–684. (b) Berkowitz, D. B.; McFadden, J. M.; Sloss,
M. K. J. Org. Chem. 2000, 65, 2907–2918
(18) 2 was inferred to be of 95:5 dr, by reductive cyclization of the
ester and comparison (90% ee) to racemic oxazolidinone. See ref 16
(19) See Supporting Information for details
.
.
.
(20) (a) Yoshikawa, M.; Yokokawa, Y.; Okuno, Y.; Yagi, N.; Murakami,
N. Chem. Pharm. Bull. 1994, 42, 2662–2664. (b) Yoshikawa, M.;
Yokokawa, Y.; Okuno, Y.; Yagi, N.; Murakami, N. Chem. Pharm. Bull.
1995, 43, 1647–1653
(21) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26–28
.
.
(22) For reviews of the Julia-Kocienski olefination, see: (a) Blakemore,
deprotonation with lithium diisopropylamide in the presence
of lithium iodide, followed by addition of benzyloxymethyl
P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585. (b) Plesniak, K.;
Zarecki, A.; Wicha, J. Top. Curr. Chem. 2007, 27, 163–250
.
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Org. Lett., Vol. 10, No. 18, 2008

additionally, examples of preferential dihydroxylation both
syn and anti to the amine are known. In the absence of any
precedent for the origins of the observed stereoselectivity
and how one might overturn it, we therefore embarked on a
screen of different dihydroxylation conditions (Scheme 3).
Scheme 2. Synthesis of 2-epi-Myriocin 7
Scheme 3. Studies on the Diastereoselective Dihydroxylation of 2
We first excluded the possibility of amplification of
stereoselectivity through a “second cycle”-type system26
since the use of stoichiometric osmium tetroxide returned a
ratio of diastereoisomers (in favor of 5a) similar to the
catalytic conditions. We next attempted to use catalyst control
to engineer the desired selectivity. The highly hindered
substrate 2 proved resistant to dihydroxylation under standard
Sharpless AD conditions using either pseudoenantiomeric
catalyst system, even at high catalyst loadings. On moving
to the less sterically demanding monomeric “first-generation”
ligands,27 the reactions were still sluggish but gave sufficient
conversion for the diastereoselectivity to be examined. As
expected, pseudoenantiomeric ligand pairs exhibited matched/
mismatched behavior with the chiral substrate: the dihyd-
roquinidine-derived ligand DHQD-CLB gave exclusively the
undesired syn-diastereomer 5a, in accord with the expected
facial preference of this catalyst system.27 The dihydroqui-
nine-derived variant DHQ-CLB, however, gave a 66:34
mixture of 5a:5b, and this ratio could not be substantially
improved upon with other dihydroquinine ligands. It appears
that the powerful intrinsic bias of the substrate cannot be
overridden by ligand effects.
procedure of Kocienski21 (Scheme 2). Condensation of the
sodium anion of 8 with aldehyde 923 gave the target olefin
10 as a single E-isomer in 59% yield, highlighting the
functional group tolerance as well as the high levels of
stereoselectivity attainable with this reaction.
After extensive studies, deprotection of 10 was achieved
by stepwise removal of the benzyl ether and carbamate by
Birch reduction, acidic hydrolytic cleavage of the acetonide,
and basic hydrolysis of the ester. Since 2-epi-myriocin and
1
myriocin are almost indistinguishable by their H NMR
spectra and no 13C NMR data are reported for the former,20
we elected to isolate the product as the peracetyl lactone
11. This facilitated the efficient isolation of the product in
66% yield over three steps. Compound 11 exhibits different
NMR spectral data from the known14b peracetyl lactone of
myriocin (vide infra). Additionally, we were able to confirm
the relative stereochemistry of the lactone core as corre-
sponding to 2-epi-myriocin by NOE studies.19
(24) (a) Shinada, T.; Ikebe, E.; Oe, K.; Namba, K.; Kawasaki, M.;
Ohfune, Y. Org. Lett. 2007, 9, 1765–1767. (b) Kawasaki, M.; Shinada, T.;
Hamada, M.; Ohfune, Y. Org. Lett. 2005, 7, 4165–4167. (c) (66:34 dr):
Trost, B. M.; Jiang, C.; Hammer, K. Synthesis 2005, 3335–3345. (d)
Avenoza, A.; Busto, J. H.; Corzana, F.; Peregrina, J. M.; Sucunza, D.;
Zurbano, M. M. Tetrahedron: Asymmetry 2003, 14, 1037–1043. (e)
Donohoe, T. J.; Winter, J. G.; Helliwell, M.; Stemp, G. Tetrahedron Lett.
2001, 42, 971–974. (f) Berkowitz, D. B.; Pedersen, M. L. J. Org. Chem.
1995, 60, 5368–5369.
Having established the efficacy of the Julia-Kocienski
olefination as a route to the 2-epi-myriocin structure, we
returned to our approach to myriocin itself and specifically
an examination of the diastereoselective dihydroxylation of
2. A search of the literature revealed scattered examples of
the dihydroxylation of acyclic alkenes substituted with
amine-bearing quaternary asymmetric centers.24,25 The di-
astereoselectivities observed range from 50:50 to 100:0, and
(25) For dihydroxylation of a quaternary vinylglycine bearing a chiral
secondary allylic acetate at the other olefin terminus (70:30 dr), see: Trost,
B. M.; Lee, C. J. Am. Chem. Soc. 2001, 123, 12191–12201.
(26) Wai, J. S. M.; Marko, I.; Svendsen, J. S.; Finn, M. G.; Jacobsen,
E. N.; Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 1123–1125.
(27) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung, J.;
Kawanami, Y.; Lubben, D.; Manoury, E.; Ogino, Y.; Shibata, T.; Ukita, T.
J. Org. Chem. 1991, 56, 4585–4588.
(23) Hayes, C. J.; Bradley, D. M.; Thomson, N. M. J. Org. Chem. 2006,
71, 2661–2665.
Org. Lett., Vol. 10, No. 18, 2008
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We therefore elected to complete our synthesis of myriocin
by performing a formal inversion of the quaternary asym-
metric center, wherein the benzyloxymethyl substituent of
6a ultimately forms the carboxylic acid of myriocin and the
carboxylate becomes the hydroxymethyl side chain. This
approach has the additional advantage that 6a, derived from
the readily available (-)-8-phenylmenthol auxiliary, will
furnish the natural enantiomer of myriocin.
Scheme 4. Total Synthesis of Myriocin 1
Reduction of the ester in 6a with lithium borohydride
followed by base-induced cyclization of the resulting primary
alcohol generates a stable oxazolidinone. Removal of the
TBDMS group under mild acidic conditions gave alcohol
12 in high yield, which was converted to the phenyltetrazolyl
sulfone 13 as before. Reaction of 13 with aldehyde 9 under
the previously utilized conditions (NaHMDS, THF) gave a
poorly selective olefination (86:14 E:Z). A screen of base
countercation, solvent, and reaction conditions (premetalation
or Barbier-type conditions)21 allowed us to identify the use
of KHMDS in THF as optimal. Following removal of the
acetonide, olefin 14 was isolated as a 92:8 mixture of
isomers. This could be improved to 97:3 by recrystallization.
All that remained was to convert the benzyloxymethyl
group to the desired carboxylic acid. It was found necessary
to have all of the other functionality protected as acetyl esters/
amides during the oxidation: other protecting group regimes
gave only product decomposition under a range of oxidative
conditions. Thus, hydrolytic cleavage of the oxazolidinone
was followed by peracetylation and chemoselective depro-
tection of the benzyl ether using boron trichloride. We were
unable to force the latter reaction to completion, using even
large excesses of reagent, but the desired alcohol 15 was
obtained in 36% yield (82% based on 56% recovery of
starting material). Stepwise oxidation of the primary alcohol
(Dess-Martin periodinane followed by Pinnick oxidation)
gave the desired acid. Finally, hydrolysis of the three acetate
esters and acetamide allowed the isolation of myriocin (1)
(Scheme 4). The material had spectroscopic data,14b melting
point,12,13 and optical rotation3,14b in accord with those
reported. As an additional confirmation of structure, we
converted 1 to the known peracetyl lactone 16. Again, the
spectroscopic data14b and optical rotation2a,9 matched
the known values and were distinct from those of the 2-epi-
myriocin peracetyl lactone 11.
are the concise synthesis of quaternary vinylglycine 2 using
our deconjugative asymmetric alkylation methodology and
the highly diastereoselective substrate-controlled dihydroxy-
lation reaction of this olefin to establish the aminodiol
function.
In summary, we have developed a common synthetic
strategy for the synthesis of the natural immunosuppressant
myriocin (1) and a protected form of the equipotent unnatural
variant 2-epi-myriocin (7). The overall efficiencies compare
well with the published routes.28 The key transformations
Acknowledgment. We thank EPSRC (DTA studentship
to M.C.J.) and Colin Kilner (Leeds) for the X-ray structure.
Supporting Information Available: Experimental pro-
1
tocols, spectroscopic data, and H/13C NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(28) 1: 16 linear steps from 4, compared with the shortest previous
stereoselective route of 16 steps from (Z)-but-2-ene-1,4-diol (ref 12). 7: 11
linear steps to 7 (isolated as 11) from 4, compared with 16 steps to 7 from
2-deoxy-D-glucose (ref 20).
OL801709C
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