Catalytic asymmetric amination of N-nonsubstituted α-alkoxycarbonyl amides: Concise enantioselective synthesis of mycestericina F and G

Article abstract of DOI:10.1002/chem.201002874

In an attempt to explore the synthetic utility of a ternary asymmetric catalyst comprising La(NO₃)₃·6H₂O, amide-based ligand (R)-L1, and D-valine tert-butyl ester H-D-Val-OtBu, we investigated a catalytic, asymmetric amination of functionalized N-nonsubstituted α-alkoxycarbonyl amides using di-tert-butyl azodicarboxylate as an electrophilic aminating reagent. A highly functionalized, cyclic N-nonsubstituted α-alkoxycarbonyl amide delivered the desired amination product in up to 96% enantiometric excess, with the requisite functionalities of the polar heads of sphingosines with the appropriate stereochemical arrangement. The rapid asymmetric assembly of these functional groups allowed a concise enantioselective synthetic route to sphingosines to be established with a broad flexibility towards derivative synthesis. These studies have culminated in an efficient catalytic enantioselective total synthesis of immunosuppressive fungal metabolites mycestericina F (3a) and G (3b).

Full text of DOI:10.1002/chem.201002874

FULL PAPER
DOI: 10.1002/chem.201002874
Catalytic Asymmetric Amination of N-Nonsubstituted a-Alkoxycarbonyl
Amides: Concise Enantioselective Synthesis of Mycestericin F and G
Farouk Berhal,[a, b] Sho Takechi,[a, b] Naoya Kumagai,*[a, b] and Masakatsu Shibasaki*[a, b]
Abstract: In an attempt to explore the
synthetic utility of a ternary asymmet-
ric catalyst comprising LaACHTUNRTGNE(UNG NO3)3·6H2O,
amide-based ligand (R)-L1, and d-
valine tert-butyl ester H-d-Val-OtBu,
we investigated a catalytic, asymmetric
amination of functionalized N-nonsub-
stituted a-alkoxycarbonyl amides using
di-tert-butyl azodicarboxylate as an
stituted a-alkoxycarbonyl amide deliv-
ered the desired amination product in
up to 96% enantiometric excess, with
the requisite functionalities of the
polar heads of sphingosines with the
appropriate stereochemical arrange-
ment. The rapid asymmetric assembly
of these functional groups allowed a
concise enantioselective synthetic route
to sphingosines to be established with a
broad flexibility towards derivative
synthesis. These studies have culminat-
ed in an efficient catalytic enantioselec-
tive total synthesis of immunosuppres-
sive fungal metabolites mycestericin F
(3a) and G (3b).
Keywords: amide-based ligands
asymmetric catalysis · asymmetric
synthesis cooperative effects
natural products
·
·
·
electrophilic aminating reagent.
A
highly functionalized, cyclic N-nonsub-
Introduction
2 (Scheme 1). The cooperative stereocontrol that operates
through both metal coordination and hydrogen bonding was
proposed to be a key element in the high enantioselectivity
with these substrates, which are seldom employed in asym-
The catalytic, asymmetric electrophilic a-amination of car-
bonyl compounds has received growing attention as a robust
methodology that provides functionalized a-amino acid de-
rivatives.[1–3] We recently developed a unique ternary catalyt-
ic system comprising LaACTHNUTRGNE(NUG NO3)3·6H2O, amide-based ligand
(R)-L1, and d-valine tert-butyl ester H-d-Val-OtBu, in which
the three catalyst components are in dynamic equilibrium
and work in a synergistic manner.[4–6] This catalytic system
was specifically identified as being efficient for catalytic
asymmetric amination of highly coordinative substrates ex-
hibiting multiple coordination modes, such as succinimide
derivative 1 and N-nonsubstituted a-alkoxycarbonyl amides
[a] Dr. F. Berhal, S. Takechi, Dr. N. Kumagai, Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry
Tokyo, 3-14-23 Kamiosaki
Shinagawa-ku, Tokyo 141-0021 (Japan)
Fax : (+81)3-3447-7779
E-mail: mshibasa@bikaken.or.jp
nkumagai@bikaken.or.jp
[b] Dr. F. Berhal, S. Takechi, Dr. N. Kumagai, Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku
Tokyo 113-0033 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002874.
Scheme 1. A ternary catalytic system for asymmetric amination of 1 and
2. Boc=tert-butoxycarbonyl, ee=enantiomeric excess.
Chem. Eur. J. 2011, 17, 1915 – 1921
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1915

metric catalysis because multiple coordination modes usual-
ly compromise the enantioselection.[4c] A particular advant-
age of using these substrates in asymmetric catalysis is the
ability to rapidly assemble functional groups in a stereocon-
trolled manner; this provides a powerful methodology with
which to construct certain types of densely functionalized
stereogenic substructures. In this context, the polar head
groups of mycestericins drew our attention. Mycestericins
were isolated from the culture broth of Mycelia sterilia and
identified as potent immunosuppressants;[7,8] their mode of
action is closely related to that of myriocin.[9] The character-
istic densely functionalized a-trisubstituted amine motif,
with adjacent carboxylic acid and hydroxyl groups, is acces-
sible by catalytic asymmetric amination of functionalized N-
nonsubstituted a-alkoxycarbonyl amides. Therefore, we en-
visioned exploiting our ternary catalytic system for a concise
enantioselective total synthesis of mycestericin F (3a) and G
(3b),[10–12] which would also contribute to the production of
several useful analogues containing stereochemical diversity.
The synthesis of this class of compounds was hampered by
the difficulty in the stereoselective construction of the polar
head group, because the known synthetic routes require
lengthy transformations. Herein, we present details of a cat-
alytic asymmetric amination of functionalized N-nonsubsti-
tuted a-alkoxycarbonyl amides and its application to the
total synthesis of 3a and 3b.
Scheme 2. Retrosynthetic analysis of mycestericin F (3a) and G (3b).
tive elaboration of the amination product. Initially, we de-
signed the functionalized N-nonsubstituted a-alkoxycarbon-
yl amides 6a–6d as candidate substrates for the catalytic
asymmetric amination for the synthesis of 3a and 3b
(Scheme 3). Although a-alkoxycarbonyl amide 6a, with a
Scheme 3. Candidate substrates for catalytic asymmetric amination in the
synthesis of mycestericin F (3a) and G (3b).
pendant O-protected a-hydroxylmethyl group, was a viable
substrate to give the requisite functionalities quickly at the
stereogenic tetrasubstituted carbon, all attempts to prepare
these compounds resulted in failure due to a tendency of
the 2-hydroxymethyl-1,3-dicarbonyl framework to undergo
dehydration. This result prompted us to examine substrates
with sp2 a-substituents that are amenable to oxidation to in-
troduce the requisite hydroxyl group. However, attempts at
catalytic asymmetric aminations of 6b–6d under the stan-
dard amination conditions[4c] suffered from poor catalytic
performance and undesired side reactions leading to com-
plex mixtures. For example, asymmetric amination of 6d
gave the desired product 7d in low yield, albeit in 85% ee,
at 08C after 43 h together with several unidentified products
Results and Discussion
Design of N-nonsubstituted a-alkoxycarbonyl amides 6 and
catalytic asymmetric amination with the ternary catalyst:
The clear structural features of sphingosines, including my-
cestericins, led us to divide the structure of mycestericins
into two parts, an aliphatic tail 4 and a polar head 5, which
we anticipated would be coupled by cross-metathesis
(Scheme 2). The stereogenic tetrasubstituted carbon atom of
the polar head group can be constructed through catalytic
asymmetric amination of functionalized N-nonsubstituted a-
alkoxycarbonyl amides 6. Clear differentiation between the
amide carbonyl and the ester carbonyl allowed stereoselec-
1916
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Synthesis of Mycestericin F and G
FULL PAPER
(Scheme 4a). Even worse results came from reactions with
6b or 6c, in which none of the desired amination products
were obtained. A previous study revealed that the present
cyclic compound 6h is sufficiently stable under both acidic
and basic conditions, probably as a result of conformational
restriction of the a-hydroxymethyl group, which prevents b-
elimination. Catalytic asymmetric amination of the lactam-
type substrate 6h proceeded smoothly at room temperature,
affording 7h in 90% yield and 84% ee after 3 h
(Scheme 4c). The synthesis of 6h commenced with commer-
cially available b-propiolactone (8), the ring opening of
which proceeded quantitatively with concentrated aqueous
ammonia to give b-hydroxypropionamide, followed by intra-
molecular protection/cyclization using 2,2-dimethoxypro-
pane in the presence of p-toluenesulfonic acid, affording
2,2-dimethyl-1,3-oxazin-4-one (9) in 58% yield in two steps
(Scheme 6). Unsuccessful installation of a methoxycarbonyl
Scheme 6. Synthesis of lactam-type substrate 6h for asymmetric amina-
tion. a) Aq 25% NH3, RT, 18 h; b) 2,2-dimethoxypropane, p-toluenesul-
fonic acid, toluene, reflux, 20 h, 58% (two steps); c) Boc2O, 4-dimethyla-
minopyridine (DMAP), Et3N, CH3CN, reflux, 48 h, 96%; d) lithium diiso-
propylamide (LDA), methyl chloroformate, THF, À788C, 2 h, 86 %;
e) trifluoroacetic acid (TFA), CH2Cl2, RT, 2 h, 78%.
Scheme 4. Selected results of catalytic asymmetric amination of function-
alized a-alkoxycarbonyl amides.
ternary catalytic system recognizes the a-alkoxycarbonyl
group with 9 led us to protect the lactam nitrogen. After in-
stallation of the N-Boc protecting group under standard
conditions in 96% yield, methoxycarbonylation of the lithi-
um enolate of 10, generated by LDA, proceeded smoothly
with methyl chloroformate in 86% yield. Subsequent Boc
removal of compound 11 using TFA in dichloromethane
gave the amination substrate 6h in 78% yield.
À
amide motif with a trans-N H proton as a privileged sub-
structure to promote the reaction in a highly enantioselec-
tive manner (Scheme 5).[4c] Indeed, a-alkoxycarbonyl amide
6e, which has such a trans-NH proton, afforded the desired
amination product in 83% yield with 99% ee, whereas the
reaction of neither N-methyl nor N,N-dimethyl analogues 6 f
or 6g, both lacking
a
trans-NH proton, proceeded
Further optimization of the catalytic asymmetric amina-
tion of 6h was the next focus; the results are summarized in
Table 1. The catalyst was prepared by mixing the three com-
(Scheme 4b). To both minimize the steric bias and comply
with the privileged structure, including a trans-amide NH
proton, we designed the lactam-type substrate 6h, with the
requisite oxygen functionality incorporated into a 1,3-oxa-
ponents of LaACTHNUTRGNEUNG
(NO3)3·6H2O (US$392.5/500 g, Aldrich),[13]
amide-based ligand (R)-L1,[14] and d-valine tert-butyl ester
H-d-Val-OtBu in a ratio of 1:1:3 in ethyl acetate. The reac-
tion temperature could be lowered from room temperature
to 08C to increase the enantioselectivity to 96% ee while
maintaining high catalytic efficiency (Table 1, entries 1 and
2). The absolute configuration of the amination product 7h
was temporarily assigned by analogy to other acyclic N-non-
substituted a-alkoxycarbonyl amides, assuming that a similar
transition state was operative for the lactam-type substrate
6h (Scheme 7).[4c] The catalyst loading was successfully re-
duced to 3 mol% after an extended period of reaction time
(Table 1, entry 3). In some cases, adjunctive triethylamine
accelerated the reaction in this catalytic system by enhanc-
ing the formation of the La/(R)-L1/H-d-Val-OtBu ternary
ACHTUNGTRENNUNGzinane ring system (Scheme 5). In contrast to acyclic 6a, the
Scheme 5. Privileged structure in the catalytic asymmetric amination with
the ternary catalytic system.
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N. Kumagai, M. Shibasaki et al.
Table 1. Catalytic asymmetric amination of 6h with La
d-Val-OtBu ternary catalyst.
G
Table 2. Catalytic asymmetric amination of 6h with known catalysts.
x
Conditions
Yield
[%]
ee
[%]
1
2
3
4
1.0 L2 (10 mol%), 1,1,2-trichloroethane, RT
1.05 L3 (20 mol%), CH2Cl2, À258C
0.91 L4 (10 mol%), toluene, RT
0
0
ND
ND
Cat. concentration [mol%]
T [8C]
t
Yield[a]
[%]
ee[b]
[%]
w
x
y
z
[h]
40[a]
53
63[b]
1.6 La
À408C
1.2 Cu(OTf)2/L6 (10 mol%), CH2Cl2, RT
A
1
1
2
3
4
5
6
7
8
9
10
10
3
10
10
3
30
30
9
0
0
0
9
0
0
0
0
0
RT
0
0
0
0
0
0
0
0
3
3
90
96
83
81
92
84
96
92
88
95
5
A
quant.
95
24
24
24
24
24
24
24
3
3
9
[a] Based on tert-butyl azodicarboxylate. [b] ent-7h was obtained as the
major enantiomer.
3
2
3
2
12
8
76
82
0
10
10
10
10
0
30
0
30
trace
trace
63
ND[c]
ND[c]
4
[a] Yield of the isolated product. [b] Determined by chiral stationary
phase HPLC analysis. [c] ND=not determined.
Scheme 7. Proposed transition state for the asymmetric amination of 6h
and the assumed absolute configuration of 7h.
enantioselection (1% ee; Table 2, entry 4). Catalyst L6
(10 mol%)[2a] gave the desired product 7h in quantitative
yield with 95% ee at room temperature (Table 2, entry 5),
indicating that the Cu catalyst was similarly effective for the
amination of 6h.
complex in equilibrium; however, this was not the case for
this specific substrate (Table 1, entry 4). Instead, additional
use of H-d-Val-OtBu (4 equiv relative to La) increased both
the chemical yield and the ee value, whereas at least
3 mol% of La was essential to achieve satisfactory catalytic
efficiency (Table 1, entries 5 and 6). Further studies con-
Enantioselective total synthesis of mycestericin F and G: By
harnessing metal coordination/hydrogen-bond cooperative
catalysis for stereocontrol and substrate activation exerted
by our ternary catalyst system, we succeeded in the asym-
metric amination of the functionalized a-alkoxycarbonyl
amides 6h to afford amination product 7h with the requisite
functionality for the synthesis of mycestericins in high yield
and excellent enantioselectivity with a minimum catalyst
loading of 3 mol%. We then set out to achieve the enantio-
selective total synthesis of 3a and 3b. The di-Boc hydrazine
moiety of 7h was first converted into amine 12 in a two-step
sequence (Scheme 8). Whereas an attempt at removing the
Boc groups with a small excess (6 equiv) of TFA in dichloro-
methane led to the formation of considerable amounts of
byproducts, a large excess (130 equiv) of TFA allowed clean
conversion into the deprotected hydrazine TFA salt. The hy-
firmed that every catalyst component LaACTHNUGTRNEUNG(NO3)3·6H2O, (R)-
L1, and H-d-Val-OtBu was indispensable for the promotion
of the reaction with a high level of stereocontrol (Table 1,
entries 7–9).
Taking the particular functional group arrangement of
substrate 6h into account, we examined the amination reac-
tion of 6h using other known organocatalysts and metal-
based catalysts for asymmetric amination. A series of orga-
nocatalysts, L2 (10 mol%, RT),[3k] L3; (20 mol%,
À258C),[3b] or L4 (10 mol%, RT),[3d] were evaluated under
the recommended reaction conditions; however, the catalyt-
ic efficiency was unsatisfactory, with no reaction at all being
observed with L2 or L3, and only 40% yield and 63% ee
being obtained with L4 (Table 2, entries 1–3). On the other
hand, metal-based catalysts exhibited better performance in
the amination. Catalyst L5[2f] (10 mol%) gave the desired
product 7h in 53% yield at À408C, albeit with almost no
À
drogenative conditions used for cleavage of the N N bond
with Raney nickel were unsuccessful for this specific sub-
strate.[15] Moreover, none of the transition-metal catalysts,
including palladium on carbon,[16] palladium hydroxide,[17] or
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Chem. Eur. J. 2011, 17, 1915 – 1921

Synthesis of Mycestericin F and G
FULL PAPER
lowed by selective 1,4-addition to the resulting vinyl
ketone.[23] Ester 13 underwent twofold alkylation under Lu-
bellꢂs conditions with a slight modification, delivering the
desired g,d-unsaturated ketone 14 in 81% yield with
10 equivalents of vinylmagnesium bromide and a stoichio-
metric amount of copper(I) cyanide. When the amounts of
Grignard reagent and copper(I) cyanide were reduced, the
yield of 14 decreased significantly and the product was ac-
companied by the formation of unidentified byproducts.
The aliphatic tail group of mycestericins with a terminal
olefin was synthesized in three steps from commercially
available n-heptanoyl chloride (15) following the reported
procedure (Scheme 9).[24] Formation of the Weinreb amide
Scheme 8. Conversion of the amination product 7h. a) TFA, CH2Cl2,
08C, 3 h; b) H2 (1 atm), Rh/C, MeOH, RT, 18 h, 96%; c) acetyl chloride,
Et3N, CH2Cl2, RT, 98%; d) vinylmagnesium bromide (10 equiv), CuCN,
THF, À458C to RT, 18 h, 81%.
Scheme 9. Synthesis of the aliphatic tail bearing
a terminal olefin.
a) MeONHMe·HCl, pyridine, CH2Cl2, RT, 3 h, 88%; b) 7-octen-1-ylmag-
nesium bromide, THF, 08C, 2 h, 93%; c) ethylene glycol, p-toluenesulfon-
ic acid, toluene, reflux, 18 h, quant.
platinum oxide,[18] achieved the reaction. A two-step se-
quence of di-trifluoroacetylation/SmI2 treatment[19] resulted
in the formation of a complex reaction mixture. Eventually,
16 followed by alkylation with freshly prepared 7-octen-1-yl-
magnesium bromide gave the C15 linear chain 17, with C=O
and C=C functionalities at the requisite positions, in high
yield. The ketone was protected as the dioxolane under
standard conditions to give the aliphatic tail substrate 18 in
quantitative yield, which was used for the coupling reaction.
Cross-metathesis of 14, which was composed of the polar
head group attached to the aliphatic tail with the terminal
olefin, with 18 was then examined (Table 3). Among the
readily available Ru-based metathesis catalysts tested, the
Grubbs first generation catalyst exhibited the best perfor-
mance to give the coupling product 19.[25] The NMR spec-
trum suggested that a trace amount of the coupling product
with Z-configured olefin was also formed; however, the
olefin geometry is not an issue for the synthesis of 3a and
3b with a saturated alkyl chain.
The next objective was the diastereoselective reduction of
the ketone of 19. We anticipated that the rigid structure of
the neighboring six-membered lactam with densely located
polar functional groups could induce high diastereoselectiv-
ity (Scheme 10). Hydride reduction with NaBH4 in methanol
either at room temperature or at 08C produced the desired
homoallylic alcohol in favor of the S-configured secondary
alcohol 20a with 9:1 diastereoselectivity determined by
1H NMR spectroscopic analysis of the crude mixture. Use of
the sterically demanding l-selectride in THF at À788C sig-
nificantly enhanced the diastereoselectivity to afford 20a in
93% yield as a single diastereomer. Chelate formation with
CeCl3 at the 1,3-dicarbonyl moiety altered the stereochemi-
cal course of the reduction with NaBH4 to provide R-config-
ured alcohol 20b.[26] Whereas the reaction at room tempera-
ture in methanol gave the reduced product as a diastereo-
À
the N N bond cleavage was effected by using rhodium on
carbon under a hydrogen atmosphere.[20] By using 30 wt%
of 5% Rh/C as catalyst, a mixture of starting material and
amine 12 was obtained with concomitant formation of some
byproducts, but with 60 wt% of the catalyst a very clean
conversion was observed and amine 12 was obtained as the
TFA salt[21] in 96% overall yield from 7h. The free amino
group of 12 was then capped with an acetyl group to give 13
in 98% yield before the subsequent alkylation. The absolute
configuration was unequivocally determined at this stage by
single-crystal X-ray crystallographic analysis of ent-13, which
was derived from the catalyst prepared from (S)-L1.[22]
Installation of the 3-butenyl group at the ester carbonyl to
provide g,d-unsaturated ketone 14, which is a requisite
handle for the attachment of the aliphatic tail of mycesteri-
cins, was the next focus. The multiple coordinative function-
al groups in the periphery of the ester carbonyl hampered
the introduction of a C4 alkyl chain. Moreover, potential
overalkylation of the ester by using organometallic reagents
to give a tertiary alcohol was also an issue that needed to be
addressed. An attempted reaction using commercially avail-
able 3-butenylmagnesium bromide resulted in the formation
of the desired product 14 in 30% yield together with a
number of byproducts, most notably the tertiary alcohol, be-
cause of overalkylation. We turned our attention to the use
of a less sterically demanding nucleophile and applied the
protocol reported by Lubell and co-workers, who developed
a sequential addition of vinylmagnesium bromide on esters
in the presence of a copper salt to afford the g,d-unsaturated
ketones through collapse of the tetrahedral intermediate fol-
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1919

N. Kumagai, M. Shibasaki et al.
Table 3. Cross-metathesis of the polar head group 14 and the aliphatic
tail group 18.
Scheme 11. Final global deprotection to produce 3a and 3b. a) H2
(1 atm), Pd/C, MeOH, RT, 18 h, quant (for 18a and 18b); b) aq 6m HCl,
reflux, 18 h, 61% (for 3a), 69% (for 3b).
Catalyst[a]
t [h]
Isolated yield [%]
62
1
2
24
Conclusion
18
24
46
54
We have achieved an efficient asymmetric total synthesis of
mycestericin F (3a) and G (3b), which are sphingosine-like
fungal metabolites that exhibit immunosuppressive activity.
A lanthanum/amide-based ligand (R)-L1/H-d-Val-OtBu ter-
nary catalyst system for asymmetric amination developed by
our group was crucial for the construction of the tetrasubsti-
tuted stereogenic center that is a requisite for this class of
compounds. The design of an amination substrate 6h with
3
4
18
46
À
an a-alkoxycarbonyl amide motif with a trans-amide N H,
which is a privileged structural motif required for specific
recognition by the catalyst, allowed for rapid stereoselective
assembly of functional groups in the polar head group. Con-
tinuing efforts will be devoted to the synthesis of several an-
alogues and sphingosines based on this synthetic methodolo-
gy. The results, including biological evaluation, will be re-
ported in due course.
[a] Mes=mesityl.
Acknowledgements
This work was financially supported by a Grant-in-Aid for Scientific Re-
search (S). N.K. thanks the Daiichi-Sankyo Foundation for Life Science
for financial support. Dr. Motoo Shiro is gratefully acknowledged for per-
forming the X-ray crystallographic analysis of compound ent-13. We
thank Dr. Ryuichi Sawa and Ms.Yumiko Kubota at the Institute of Mi-
crobial Chemistry, Tokyo, for technical assistance. We thank Professor
Tetsuro Fujita for fruitful discussions.
Scheme 10. Diastereoselective reduction of 19. a) l-Selectride, À788C,
THF, 93%; b) NaBH4 (1 equiv), CeCl3 (10 equiv), MeOH, À788C, 91%.
[1] For reviews of catalytic asymmetric electrophilic amination of car-
bonyl compounds, see: a) R. O. Duthaler, Angew. Chem. 2003, 115,
1005; Angew. Chem. Int. Ed. 2003, 42, 975; b) C. Greck, B. Drouil-
lat, C. Thomassigny, Eur. J. Org. Chem. 2004, 1377; c) J. M. Janey,
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4292; d) C. Cativiela, M. OrdꢃÇez, Tetrahedron: Asymmetry 2009,
20, 1.
[2] For selected examples using metal-based catalysts, see: a) M.
Marigo, K. Juhl, K. A. Jørgensen, Angew. Chem. 2003, 115, 1405;
Angew. Chem. Int. Ed. 2003, 42, 1367; b) S. Ma, N. Jiao, Z. Zheng,
Z. Ma, Z. Lu, L. Ye, Y. Deng, G. Chen, Org. Lett. 2004, 6, 2193;
c) C. Foltz, B. Stecker, G. Marconi, S. Bellemin-Laponnaz, H. Wade-
pohl, L. H. Gade, Chem. Commun. 2005, 5115; d) L. Bernardi, W.
Zhuang, K. A. Jørgensen, J. Am. Chem. Soc. 2005, 127, 5772;
e) Y. K. Kang, D. Y. Kim, Tetrahedron Lett. 2006, 47, 4565; f) J. Co-
melles, A. Pericas, M. Moreno-MaÇas, A. Vallribera, G. Drudis-Solꢄ,
meric mixture in favor of 20b (20a/20b=35:65), isomer 20b
was obtained exclusively in 91% yield without any trace of
20a when the same transformation was performed at
À788C. Both 20a and 20b were hydrogenated at room tem-
perature under atmospheric pressure using palladium on
charcoal to give 21a and 21b, with saturated alkyl chains, in
quantitative yield (Scheme 11). Global deprotection and hy-
drolysis of the amides was achieved in a single-step proce-
dure by treatment with 6m aqueous hydrochloric acid at
reflux temperature for 15 h. With this procedure, com-
pounds 21a and 21b were successfully transformed into 3a
1
and 3b, respectively. H NMR spectra of the final products
were in full accord with the reported data.[22]
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Synthesis of Mycestericin F and G
FULL PAPER
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Received: October 5, 2010
Published online: January 12, 2011
Chem. Eur. J. 2011, 17, 1915 – 1921
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