Remote stereocontrol in [3,3]-sigmatropic rearrangements: Application to the total synthesis of the immunosuppressant mycestericin G

Article abstract of DOI:10.1021/ol203300k

The Ireland - Claisen [3,3]-sigmatropic rearrangement has been used to access biologically important β,β′-dihydroxy α-amino acids. The rearrangement reported is highly stereoselective and offers excellent levels of remote stereocontrol. This strategy has been used to synthesize the natural immunosuppressant mycestericin G and ent-mycestericin G, allowing for a revision of absolute configuration of this natural product.

Full text of DOI:10.1021/ol203300k

ORGANIC
LETTERS
2012
Vol. 14, No. 3
756–759
Remote Stereocontrol in [3,3]-Sigmatropic
Rearrangements: Application to the Total
Synthesis of the Immunosuppressant
Mycestericin G
Nathan W. G. Fairhurst,† Mary F. Mahon,† Rachel H. Munday,‡ and David R. Carbery*,†
Department of Chemistry, University of Bath, Bath, BA2 7AY, United Kingdom, and
AstraZeneca R&D, Charnwood, Bakewell Road, Loughborough LE11 5RH,
United Kingdom
d.carbery@bath.ac.uk
Received December 9, 2011
ABSTRACT
The IrelandꢀClaisen [3,3]-sigmatropic rearrangement has been used to access biologically important β,β0-dihydroxy r-amino acids. The
rearrangement reported is highly stereoselective and offers excellent levels of remote stereocontrol. This strategy has been used to synthesize
the natural immunosuppressant mycestericin G and ent-mycestericin G, allowing for a revision of absolute configuration of this natural product.
The realization that naturally occurring immunosuppres-
sants, such as cyclosporin A,1 greatly reduce the likelihood
of host rejection has made human organ transplantation a
viable medical process.2 Arguably, this medical advance has
profoundly changed society with heart, kidney, lung,
liver, and bone-marrow transplants now being routinely
successful. A large range of natural products have now
been demonstrated to possess immunosuppressive activity3
with recently reported examples seeking to improve biolog-
ical activity or diminish side effects. One of the most
potent immunosuppressant natural products is myriocin
(1, Figure 1) which has been isolated from three different
fungal sources.4ꢀ6 Impressively, myriocin displays a 10ꢀ
100-fold increase in immunosuppressant potency com-
pared with cyclosporin A.6
Figure 1. Myriocin and β,β0-dihydroxy R-amino acids.
† University of Bath.
‡ AstraZeneca R&D.
(1) Petcher, T. J.; Weber, H.-P.; Ruegger, A. Helv. Chim. Acta 1976,
59, 1480.
(2) (a) Calne, R. Y.; White, D. J. G.; Thiru, S.; Evans, D. B.;
McMaster, P.; Dunn, D. C.; Craddock, G. N.; Pentlow, B. D.; Rolles,
K. Lancet 1978, 1323. (b) Powles, R. L.; Barrett, H.; Clink, H. E.; Kay,
H. E. M.; Sloane, J.; McElwain, T. J. Lancet 1978, 1327.
Structureꢀactivity studies have strongly suggested the
crucial structural feature of 1 with respect to biological
activity is the polar β,β0-dihydroxy R-amino acid head
group.7 Accordingly, flexible and efficient synthetic entries
to such β,β0-dihydroxy R-amino acids8 (2, Figure 1) are
€
(3) Mann, J. Nat. Prod. Rep. 2001, 18, 417.
(5) Aragozzini, F.; Manachini, P. L.; Craveri, R.; Rindone, R.;
Scolastico, C. Tetrahedron 1972, 13, 5493. (b) Destro, R.; Colombo, A.
J. Chem. Soc., Perkin Trans. 2 1979, 896.
(6) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.;
Toyama, R.; Chiba, K.; Hoshino, Y.; Okumoto, T. J. Antibiot. 1994, 47,
208.
(4) (a) Kluepfel, D.; Bagli, J.; Baker, H.; Charest, M.-P.; Kudelski,
A.; Sehgal, S. N.; Vezina, C. J. Antibiot. 1972, 25, 109. (b) Bagli, J.;
Kluepful, D.; St-Jacques, M. J. Org. Chem. 1973, 38, 1253. (c) Fujita, T.;
Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.; Toyama, R.; Chiba,
K.; Hoshino, Y.; Okumoto, T. J. Antibiot. 1994, 47, 208.
r
10.1021/ol203300k
Published on Web 01/12/2012
2012 American Chemical Society

potentially important for the discovery of new immuno-
suppressive treatments and related chemical biology
studies.9 In addition, the structurally related natural prod-
ucts, sphingofungin E10 and mycestericins AꢀG,11 contain
this key β,β0-dihydroxy R-amino acid moiety, and high
levels of immunosuppressant activity have also been noted
for both molecules.12
In recent years, we have been developing a program of
researchdirectedtowardthe synthesisof novel amino acids
through IrelandꢀClaisen rearrangements of substrates
rich in heteroatom substitution.13 The IrelandꢀClaisen
[3,3]-sigmatropic rearrangement is a key CꢀC bond form-
ing reaction used in modern organic synthesis14,15 and is
therefore ideally suited to such research efforts. The re-
arrangement offers predictable diastereocontrol, chirality
transfer, and the ability to form congested quaternary
stereocenters. These three key attributes stem from the
preference of acyclic substrates to rearrange via a highly
ordered chair transition state.
Complex serine congeners, suitable for further elabora-
tion to the natural product classes discussed above, might
become accessible through sigmatropic rearrangements on
serine-derived silylketene acetals. The employment of an
IrelandꢀClaisen strategy for the synthesis of substituted
serine analogues would require the generation of an un-
stable serine enolate. To avert this anticipated synthetic
problem, the use of a serine-derived oxazolidine has been
considered. Such a strategy would not only protect the
sensitive β-hydroxy by circumventing degradative E1Cb
elimination16 but also offer the potential to control abso-
lute stereochemistry via the chiral relay strategy pioneered
by Seebach.17 To examine this proposal, model ester sub-
strate 3a was readily synthesized18 and subjected to stan-
dard IrelandꢀClaisen conditions used in our laboratory.13
On treatment with LiHMDS and Me3SiCl at ꢀ78 °C,
the silylketene acetal derivedfrom methyl enol ether 3awas
found to rearrange smoothly, after warming to rt, with
β-methoxy product 4a isolated as a single stereoisomer in
78% yield (Table 1, entry 1). The stereoselectivity is
notable, not only for its magnitude but also because the
controlling stereocenter is two atoms from the forming
(7) For leading references to structureꢀactivity relationships with
respect to 1 and the design of synthetic analogues, see: Kiuchi, M.;
Adachi, K.; Kohara, T.; Minoguchi, M.; Hanano, T.; Aoki, Y.; Mishina,
T.; Arita, M.; Nakao, N.; Ohtsuki, M.; Hoshino, Y.; Teshima, K.;
Chiba, K.; Sasaki, S.; Fujita, T. J. Med. Chem. 2000, 43, 2946.
(8) For reviews concerning the synthesis of natural products contain-
ing β,β0-dihydroxy R-amino acids, see: (a) Ohfune, Y.; Shinada, T. Eur.
J. Org. Chem. 2005, 5127. (b) Kang, S. H.; Kang, S. Y.; Lee, H-S;
Buglass, A. J. Chem. Rev. 2005, 105, 4537.
Table 1. IrelandꢀClaisen Rearrangement of Oxazolidine Enol
Ether Substrates
(9) (a) Miyake, Y.; Kozutsumi, Y.; Nakamura, S.; Fujita, T.; Kawasaki, T.
Biochem. Biophys. Res. Commun. 1995, 211, 396. (b) Chen, J. K.; Lane, W. S.;
Schreiber, S. L. Chem. Biol. 1999, 6, 221.
(10) Horn, W. S.; Smith, T. L.; Bills, G. F.; Raghoobar, S. F.; Helms,
G. L.; Kurts, M. B.; Marrinan, J. A.; Frommer, B. R.; Thornton, R. A.;
Mandara, S. M. J. Antibiot. 1992, 45, 1692.
(11) (a) Sasaki, S.; Hashimoto, R.; Kiuchi, M.; Inoue, K.; Ikumoto, T.;
Hirose, R.; Chiba, K.; Hoshino, Y.; Okumoto, T.; Fujita, T. J. Antibiot. 1994,
47, 420. (b) Fujita, T.; Hamamichi, N.; Kiuchi, M.; Matsuzaki, T.; Kitao, Y.;
Inoue, K.; Hirose, R.; Yoneta, M.; Sasaki, S.; Chiba, K. J. Antibiot. 1996, 49,
846.
(12) For selected recent syntheses of pertinent sphingolipid immu-
nosuppressant natural products, see: (a) Jones, M. C.; Marsden, S. P.
Org. Lett. 2008, 10, 4125. (b) Lee, K.-Y.; Oh, C.-Y.; Kim, Y.-H.; Joo,
J.-E.; Ham, W.-H. Tetrahedron Lett. 2002, 43, 9361. (c) Gan, F.-F.;
Yang, S.-B.; Luo, Y.-C.; Yang, W.-B.; Xu, P.-F. J. Org. Chem. 2010, 75,
2737. (d) Wang, B.; Lin, G.-Q. Eur. J. Org. Chem. 2009, 5038. (e) Li, M.;
Wu, A. Synlett 2006, 2985. (f) Yamanaka, H.; Sato, K.; Sato, H.; Iida,
M.; Oishi, T.; Chida, N. Tetrahedron 2009, 65, 9188. (g) Oishi, T.; Ando,
K.; Inomiya, K.; Sato, H.; Hideyuki, I.; Ida, M.; Chida, N. Bull. Chem.
Soc. Jpn. 2002, 75, 1927. (h) Oishi, T.; Ando, K.; Chida, N. Chem.
Commun. 2001, 1932. (i) Berhal, F.; Takechi, S.; Kumagai, N.; Shibasaki,
M. Chem.;Eur. J. 2011, 17, 1915.
entry
3
R
4
yield (%)
dra
1
3a
3b
3c
3d
3e
3f
Me
Et
4a
4b
4c
4d
4e
4f
78
84
70
71
76b
77
68
73
58
73
75
51c
55c
47c
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
2
3
iPr
allyl
4
5
propargyl
Ph
6
7
3g
3h
3i
PMP
4g
4h
4i
8
p-CF3C6H4
o-IC6H4
Bn
9
10
11
12
13
14
3j
4j
3k
3l
PMB
4k
4l
€
(13) (a) Tellam, J. P.; Kociok-Kohn, G.; Carbery, D. R. Org. Lett.
2008, 10, 5199. (b) Tellam, J. P.; Carbery, D. R. J. Org. Chem. 2010, 75,
7491. (c) Tellam, J. P.; Carbery, D. R. Tetrahedron Lett. 2011, 52, 6027.
(d) Ylioja, P. M.; Mosley, A. D.; Charlot, C. E.; Carbery, D. R.
Tetrahedron Lett. 2008, 49, 1111. (e) Harker, W. R. R.; Carswell,
E. L.; Carbery, D. R. Org. Lett. 2010, 12, 3712. (f) Harker, W. R. R.;
Carswell, E. L.; Carbery, D. R. Org. Biomol. Chem. 201210.1039/
C2OB06853B.
(14) (a) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94,
5897. (b) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc.
1976, 98, 2868. (c) Ireland, R. E.; Wipf, P.; Armstrong, J. D., III. J. Org.
Chem. 1991, 56, 650. (d) Ireland, R. E.; Wipf, P.; Xiang, J. N. J. Org.
Chem. 1991, 56, 3572.
(15) For reviews concerning the IrelandꢀClaisen rearrangement, see:
(a) Castro, A. M. Chem. Rev. 2004, 104, 2939. (b) Chai, Y. H.; Hong,
S. P.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron
2002, 58, 2905. (c) McFarland, C. M.; McIntosh, M. C. The Claisen
Rearrangement; Hiersemann, M. N., Nubbemeyer, U., Eds.; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, Germany, 2007; p 117. (d) Wipf, P.
Claisen Rearrangements; Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Paquette, L. A., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 827.
(e) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Chem. Soc. Rev. 2009, 38, 3133.
o-I-Bn
iBu
3m
3n
4m
4n
Cy
a Diastereomeric ratio stated as syn/anti. Measured by 1H NMR (500
MHz) analysis of crude reaction mixture. b Isolated as TMS alkyne.
c Reaction conducted on unpurified substrates 3lꢀn.
(16) For examples of IrelandꢀClaisen rearrangements in natural
product synthesis using substrates bearing cyclic β-ethereal oxygen
centers, see: (a) Ireland, R. E.; Armstrong, J. D.; Lebreton, J.; Meissner,
R. S.; Rizzacassa, M. A. J. Am. Chem. Soc. 1993, 115, 7152. (b) Bunte,
J. O.; Cuzzupe, A. N.; Daly, A. M.; Rizzacasa, M. A. Angew. Chem., Int.
Ed. 2006, 45, 6376.
(17) (a) Seebach, D.; Aebi, J. D. Tetrahedron Lett. 1984, 25, 2545.
(b) For a review of the self-regeneration chirality strategy, see: Seebach, D.;
Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708.
(18) See Supporting Information for details of substrate synthesis.
Org. Lett., Vol. 14, No. 3, 2012
757

CꢀC bond. This stereocontrol strategy has previously
shown limited efficacy in asymmetric synthesis.14,19
The IrelandꢀClaisen rearrangement reaction of enol
ethers 3aꢀn is general and leads to the formation of
β-alkoxy and β-aryloxy R-amino acid products, isolated
as methyl esters 4aꢀn in good yield and excellent diastereo-
selectivity. The absolute and relative stereochemistry has
been confirmed by XRD of iodoaryl ether 4i (Figure 2).
1ꢀ12 (70ꢀ80%), when the yield of ester formation is taken
into account. The IrelandꢀClaisen rearrangement prod-
ucts 4aꢀn are equivalent to O-alkyl and O-aryl aldols, and
when placed in this context, the power of this rearrange-
ment becomes apparent. Low levels of diastereoselectivity
(dr e2:1) are observed when serine-derived oxazolidine
esters are used in aldol reactions in conjunction with simple
achiral aldehydes.21
The rearrangement is amenable to streamlined prepara-
tive scale (4 mmol of 6) manipulations. For example, when
EDCI mediated coupling of 522 and 6,12a IrelandꢀClaisen
rearrangement, and carboxyl benzylation are conducted
without intermediate purification, 7 is isolated in 81%
yield over three steps (Scheme 1).
Scheme 1. Preparative Scale Rearrangement
Figure 2. ORTEP plot of XRD analysis of 4i (at 30%
probability). Structure deposited with CCDC (CCDC 812147)
and proposed IrelandꢀClaisen rearrangement geometry I.
The observed sense of stereoselectivity is consistent with
transition state geometry I (Figure 2) whereby the enol
ether fragment approaches the silylketene acetal anti to the
oxazolidine tert-butyl group and agrees with reported
stereoselective transformations using this regeneration of
stereocenters tactic.20 Notably, the rearrangement of sub-
strates bearing O-functional handles (entries 4ꢀ5, 9, 13)
and O-protecting groups (entries 4, 7, 10, 12) suggests that
this strategy may be of future synthetic value. This sigma-
tropic transformation is highly stereoselective in each case.
In three instances, however, the substrate proved to be
particularly unstable, necessitating it being used without
purification for conversion to the rearranged allylic ether
products in yields of 47ꢀ55% over two steps (entries
13ꢀ15). It is unclear exactly why these substrates have
proven to be so sensitive. However, we can speculate that
the substantial steric bulk of these alkyl groups (o-iodo-
benzyl, ibutyl, and cyclohexyl) promotes a conformational
restriction of the enol ether oxygen, improving On dona-
tion into the enol ether π-system, ultimately leading to
increased sensitivity. However, it was found that these
systems rearrange as efficiently as that seen in entries
This rearrangement reaction offers a rapid access to
complex and functionalized β,β0-dihydroxy R-amino acid
motifs. To demonstrate the synthetic potential, a synthesis
of mycestericin G (8, Scheme 2) has been examined. This
natural product features a polyhydroxy R-amino acid head
group and a lipophilic tail, offering a potential entry from
the cross-metathesis union of a rearrangement product
7 and a suitable lipophilic olefin partner, such as 9
(Scheme 2). Our envisioned strategy was to examine olefin
homodimer 923 in combination with the second generation
HoveydaꢀGrubbs Ru-carbene catalyst,24 as Grubbs has
previously demonstrated the improved performance of
homodimers25 and the stated catalyst in sterically con-
gested allylic alcohols26 in cross-metathesis reactions.
Scheme 2. Mycestericin G Synthetic Strategy
(19) A chiral glycinate has offered a dr of 11:1 in an IrelandꢀClaisen
rearrangement; see: (a) Matsui, S.; Oka, N.; Hashimoto, Y.; Saigo, K.
Enantiomer 2000, 5, 105. Other examples with poor levels (dr e 3:1) of
remote diastereocontrol, see: (b) Kallmerten, J.; Gould, T. J. J. Org.
Chem. 1986, 51, 1152. (c) Shu, A. Y. L.; Djerassi, C. J. Chem. Soc.,
Perkin Trans. 1 1987, 1291.
(20) For incipient CꢀC bond formation anti to the oxazolidine tert-
butyl group, see: (a) Seebach, D.; Aebi, J. D.; Gander-Coquoz, M.; Naef,
R. Helv. Chim. Acta 1987, 70, 1194. (b) Zhang, J.; Flippen-Anderson,
J. L.; Kozikowski, A. P. J. Org. Chem. 2001, 66, 7555. (c) Brunner, M.;
Saarenketo, P.; Straub, T.; Rissanen, K.; Koskinen, A. M. P. Eur. J. Org.
Chem. 2004, 3879. (d) Brunner, M.; Nissinen, M.; Rissanen, K.; Straub,
T.; Koskinen, A. M. P. J. Mol. Struct. 2005, 734, 177. (e) Ling, T.;
Macherla, V. R.; Manam, R. R.; McArthur, K. A.; Potts, B. C. M. Org.
Lett. 2007, 9, 2289. (f) Ling, T.; Potts, B. C.; Macherla, V. R. J. Org.
Chem. 2010, 75, 3882.
(21) Brunner, M.; Koskinen, A. M. P. Tetrahedron Lett. 2004, 45,
3063.
(22) Ghosez, L.; Yang, G.; Cagnon, J. R.; Le Bideau, F.; Marchand-
Brynaert, J. Tetrahedron 2004, 60, 7591.
€
(23) Scheiper, B.; Bonnekessel, M.; Krause, H.; Furstner, A. J. Org.
Chem. 2004, 69, 3943. See Supporting Information for full details.
(24) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
(25) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder,
R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58.
758
Org. Lett., Vol. 14, No. 3, 2012

The synthesis of mycestericin G was completed after
PMB deprotection of 7, cross metathesis, and hydrogena-
tion, with final N-Boc oxazolidine cleavage furnishing
mycestericin G after chromatography. The 1H NMR data
were in excellent agreement with those reported, but the
optical rotation was opposite in sign, yet of a similar
magnitude, to that quoted (Scheme 3). In contrast, the
parallel synthetic sequence from L-serine produced ent-8,
now with the same sense of optical rotation and compar-
able magnitude to that reported for mycestericin G.
Scheme 3. Total Synthesis of Mycestericin G
Figure 3. Effect of alkene on sense of optical rotation.
rotation data were reported for this synthetic mycestericin G.
Therefore, there is no unequivocal demonstration that the
configuration of the stereocenters in mycestericin E is the
same as the two stereocenters in mycestricin G. The recent
elegant synthesis of mycestericin G by Kumagai and
Shibasaki is of particular interest.12i This effort resulted
in the synthesis of the structure originally reported, how-
ever, with an opposite sense of optical rotation to that in
the original isolation paper. We feel that this observation
offers further credence to a reassignment of configuration
of the natural immunosuppressant mycestericin G.
In conclusion, an IrelandꢀClaisen route to polyhydroxy-
amino acids, using a self-regeneration of stereocenters
strategy, has been developed. It has also been applied in
a succinct synthesis of mycestericin G and ent-mycestericin
G, allowing a reassignment of configuration of this im-
munosuppressant natural product.
To explain this discrepancy, we offer the following
analysis. Hydrogenation of 1 forms dihydromyriocin 10
(Figure 3).27 Key is the realization that hydrogenation of
the seemingly innocuousolefin in 1 leads toa reversal inthe
sense of optical rotation; i.e., myriocin 1 is dextrorotatory
while 10 is levorotatory.
The absolute configuration of mycesterin E (11) has
been determined through the total synthesis.28 This report
also demonstrated that mycestericin G (8) was obtained
from synthetic 11, forming material which was observed to
have identical spectroscopic data. However, no optical
Acknowledgment. We thank The University of Bath,
EPSRC, and AstraZeneca for studentship funding (NWGF).
Supporting Information Available. Full experimental
details and data for all novel compounds. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(26) Sterically demanding allylic alcohols have displayed efficacy in
cross-metathesis reactions using HoveydaꢀGrubbs II metathesis cata-
lysts; see: Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Lett. 2008,
10, 441.
(27) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.;
Toyama, R.;Yoneta, M.;Chiba, K.;Hosshino, Y.;Okumoto, T.J. Antibiot.
1994, 47, 216.
(28) Fujita, T.; Hamamichi, Y.; Matsusaki, T.; Kitao, Y.; Kiuchi, M.;
Node, M.; Hirose, R. Tetrahedron Lett. 1995, 36, 8599.
Org. Lett., Vol. 14, No. 3, 2012
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