Total synthesis of sphingofungin f by orthoamide-type Overman rearrangement of an unsaturated ester

Article abstract of DOI:10.1021/acs.orglett.5b00475

The total synthesis of sphingofungin F through the Overman rearrangement of an unsaturated ester, which is known to be an unsuitable substrate under standard conditions due to the competitive aza-Michael reaction, is described. The developed conditions enabled the ester to be compatible with the original Overman rearrangement, providing quick access to α,α-disubstituted amino acids by minimizing extra protecting group manipulations and redox reactions.

Full text of DOI:10.1021/acs.orglett.5b00475

Letter
pubs.acs.org/OrgLett
Total Synthesis of Sphingofungin F by Orthoamide-Type Overman
Rearrangement of an Unsaturated Ester
†
†
†
†
†
‡
Shun Tsuzaki, Shunme Usui, Hiroki Oishi, Daichi Yasushima, Takahiro Fukuyasu, Takeshi Oishi,
,
†
,†
Takaaki Sato,* and Noritaka Chida*
†Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama
2
23-8522, Japan
‡
School of Medicine, Keio University, 4-1-1, Hiyoshi, Kohoku-ku, Yokohama 223-8521, Japan
S Supporting Information
*
ABSTRACT: The total synthesis of sphingofungin F through the
Overman rearrangement of an unsaturated ester, which is known
to be an unsuitable substrate under standard conditions due to the
competitive aza-Michael reaction, is described. The developed
conditions enabled the ester to be compatible with the original
Overman rearrangement, providing quick access to α,α-disubstituted amino acids by minimizing extra protecting group
manipulations and redox reactions.
s the complexity of target molecules increases in modern
organic synthesis, functional group compatibility is
Scheme 1. Limited Access to Amino Acid Derivatives by
Conventional Overman Rearrangement
A
increasingly recognized as an important concept when
1
developing new reactions. Use of reactions with low functional
group compatibility requires tedious protecting group manipu-
lations, resulting in a decrease in total yield. Our research group is
engaged in a program devoted to incorporating high functional
group compatibility into transformations that are potentially
2
useful, but suffer unsatisfactory compatibility. In this letter, we
succeeded in the integrating ester compatibility with the original
3
Overman rearrangement and developed the direct synthesis of
α,α-disubstituted amino acid derivatives. The reaction was then
applied to the concise total synthesis of a biologically active
natural product.
The trichloroimidate rearrangement, the so-called Overman
rearrangement, is one of the most powerful and widely used
sigmatropic rearrangements in organic synthesis. The reaction
proceeds even with densely functionalized and sterically
hindered molecules. In addition, use of enantiomerically pure
allylic alcohols enables chirality transfer to form the C−N bond
1
a
transformation by exclusion of a number of extra steps
4
1c
stereoselectively via a tight chairlike transition state. If the
including protecting group manipulations and redox reac-
1b
tions.
Overman rearrangement can be applied to unsaturated ester 1,
this reaction will be a useful synthetic tool for amino acid
derivative 3 via imidate 2 (Scheme 1). However, unsaturated
ester 1 has been known to be a longstanding problematic
substrate in the Overman rearrangement due to inherent
competitive aza-Michael addition against the Overman rear-
We suspected that the origin of the competitive aza-Michael
addition against the Overman rearrangement might depend on
the existence of two conformations 2′ and 2″ (Scheme 2). The
aza-Michael addition would be stereoelectronically preferred
from the major conformer 2′ because the ester carbonyl group is
located in the same plane as the olefin. On the other hand, the
Overman rearrangement would proceed from minor conforma-
tion 2″ because the ester carbonyl group is not coplanar with the
olefin, resulting in the suppression of the aza-Michael reaction.
5
rangement (2 → 4). Therefore, synthesis of the amino acid
6
derivative 3 requires an indirect method using additional steps.
In the previous example, unsaturated ester 1 was converted to
5b
protected alcohol 5 prior to the Overman rearrangement. After
the rearrangement (5 → 6 → 7), α-vinyl amino acid derivative 3
could then be obtained through deprotection and reoxidation of
2
We considered that, if a substituent R were installed at the α-
7. In other words, the direct Overman rearrangement of
Received: February 14, 2015
unsaturated esters will become a highly step-economical
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
8
Scheme 2. Working Hypothesis: Induction of the Overman
Rearrangement against the aza-Michael Reaction
4aβ (3%) (entry 1). Unsaturated ester 8a with a methyl group at
the α-position was then heated under identical reaction
conditions (entry 2). Gratifyingly, the aza-Michael reaction was
completely suppressed, giving the rearranged product 9a in 83%
yield. Although the aza-Michael addition was successfully
inhibited, the inductive effect derived from the methyl group of
1,2
8
a might be a dominant factor instead of the A -allylic strain.
Therefore, we prepared electronically similar, but conformation9-
ally different substrates 8b and 8c (entries 3 and 4).
Interestingly, while the reaction of 8b provided 9b in 80%
yield as a single compound, use of unsaturated lactone 8c led to
the aza-Michael addition as a major pathway, probably because
the lactone structure forced the carbonyl group to be situated in
the same plane as the double bond (entry 4). Although the effect
1,2
of the A -allylic strain was not directly proven, these results
indicated that the conformational factor played an important role
in the selectivity.
With the promising rearrangement of unsaturated esters in
hand, we then applied this reaction to allylic vicinal syn-diol 11
(Scheme 3). While sigmatropic rearrangement of a simple allylic
position of unsaturated ester 2, the resulting trisubstituted olefin
1
,2
8
8
would have a large A -allylic strain as shown in conformation
7
1,2
′. This A -allylic strain would promote a conformational
change from 8′ to 8″, leading to the selective Overman
rearrangement. The developed method will be a direct synthetic
method of α,α-disubstituted amino acid 9, embedded in a
number of biologically active natural products.
Scheme 3. Cascade-Type and Orthoamide-Type Overman
Rearrangements of Allylic Vicinal Diol 11
The Overman rearrangement of unsaturated ester 2a with a
hydrogen at the α-position was investigated as a control
experiment to confirm our working hypothesis (Table 1). A
solution of 2a in t-BuPh in a sealed tube was heated to 140 °C,
resulting in the formation of the rearranged product 3a in only
46% yield, along with aza-Michael byproducts 4aα (31%) and
a
Table 1. Overman Rearrangement of Unsaturated Esters
alcohol has been widely investigated, the rearrangement of an
allylic vicinal diol such as 11 had been overlooked until our
10,11
reports.
Treatment of a solution of syn-diol 11 in MeCN with
an excess amount of CCl CN and 2.2 equiv of DBU at −20 °C
3
provided bis(imidate) 12 in 77% yield. Bis(imidate) 12
underwent the cascade-type Overman rearrangement at 220
°C in the presence of MS4 Å (500 wt %), providing bis(amide)
13 in 63% yield. On the other hand, the identical syn-diol 11 was
transformed to cyclic orthoamide 14 in 94% yield upon
treatment with CCl CN (1.3 equiv), DBU (30 mol %), and
3
ZnCl (10 mol %). The orthoamide-type Overman rearrange-
2
ment of 14 underwent the single rearrangement at 220 °C in the
presence of 5 mol % of BHT (butylated hydroxytoluene),
affording 15 in 56% yield. These methods have various salient
features. First, the number of the rearrangement (double or
single) was precisely controlled by selective formation of either
bis(imidate) or cyclic orthoamide. Both reactions took place
through complete chirality transfer of hydroxy groups, giving the
product as a single diastereomer. Furthermore, no aza-Michael
byproduct was observed in either type of rearrangement.
a
b
To demonstrate the utility of our method, we took an interest
in the total synthesis of sphingofungin F (16), which was isolated
from the fermentation broth of Paecilomyces variotii by the Merck
2
or 8, t-BuPh (0.015 M), 140 °C in a sealed tube. Yield of isolated
c
product after purification by column chromatography. The
diastereomeric ratio was 1.5:1.
B
DOI: 10.1021/acs.orglett.5b00475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Total Synthesis of Sphingofungin F (16)
1
2
group in 1992 (Scheme 4). Sphingofungin F (16) is a potent
Table 2. S 2′ Reaction of Trichloroacetamide 21
N
antifungal agent that acts by inhibition of serine palmitoyl-
transferase, blocking the first step of sphingosine biosynthesis.
13
Structurally, it consists of a hydrophobic side chain and a
hydrophilic moiety including an α,α-disubstituted amino acid
and a triol. Its important biological activity and unique structure
have inspired a number of synthetic chemists to work on the total
a
yield (%)
14
15,16
syntheses of sphingofungin F (16) and its congeners.
entry
conditions
22
29
Our central strategy toward the total synthesis of sphingo-
fungin F (16) was utilization of the orthoamide-type Overman
rearrangement of unsaturated ester 20 (Scheme 4). Allylic vicinal
diols are readily available in enantiomerically pure form starting
from naturally occurring monosaccharides. For example, syn-
thesis of sphingofungin F (16) required an anti-diol, which was
prepared from commercially available D-ribose derivative 17.
1
2
3
4
Tf O, pyridine, CH Cl , −20 °C
2
86
37
28
6
2
2
2
PPh , DEAD, toluene, 0 °C
11
15
83
3
P(OEt) , DEAD, toluene, 0 °C
3
PBu , DEAD, toluene, 0 °C
3
a
Yield of isolated product after purification by column chromatog-
raphy.
Reduction of 17 with NaBH , followed by oxidative cleavage of
4
17
the resulting diol, provided lactol 18. The Wittig reaction and
one-pot BOM protection provided the E-unsaturated methyl-
ester, which was exposed to 80% AcOH aq. at 40 °C, giving allylic
vicinal diol 19. Next, cyclic orthoamide 20 was selectively formed
under the optimized conditions in 90% yield. The stage was now
set for the crucial orthoamide-type rearrangement. In contrast to
the syn-diol shown in Scheme 3, the reaction of cyclic orthoamide
triphenylphosphine and DEAD showed a slight anti-selectivity,
use of triethylphosphite resulted in no selectivity (entries 2 and
3
). The highest level of syn-stereoselectivity was achieved when
tributylphosphine was used, giving oxazoline 22 in 83% yield,
along with 29 in 6% yield (entry 4). Although the factors
controlling the selectivities are yet to be clarified, we found that
the unique S 2′ reaction of trichloroacetamide proceeded in
N
20 derived from the anti-diol required a shorter reaction time
either syn- or anti-stereoselectivity by judicious choice of reaction
(
0.5 day vs 2.5 days) and provided sterically hindered α,α-
conditions. As shown in Scheme 4, dihydroxylation of oxazoline
disubstituted amino acid 21 in a higher yield (67% vs 56%). It is
noteworthy that this key transformation achieved three
selectivities simultaneously, including (i) the number of the
rearrangement (single vs double), (ii) the reaction pathway (the
Overman rearrangement vs the aza-Michael reaction), and (iii)
the stereoselectivity through the chirality transfer.
2
2 using a catalytic amount of OsO and NMO in CH Cl at 40
4 2 2
°C provided the desired triol derivative 23, accompanied by
formation of the lactone.
The remaining challenge toward the total synthesis was
installation of the hydrophobic side chain (Scheme 4).
Hydrolysis of oxazoline 23 and the subsequent protection of
the resulting diol in a one-pot sequence gave 24 in 89% yield.
Removal of the BOM group in 24 provided the primary alcohol
25 with concomitant dechlorination. After the Dess-Martin
oxidation of 25, the hydrophobic side chain 27 was successfully
With α,α-disubstituted amino acid 21 in hand, we turned our
attention to construction of the triol (Scheme 4). Unfortunately,
direct dihydroxylation of 21 afforded the unfavorable diaster-
19
14c,f
eoselectivity completely.
This result caused us to attempt
transposition of the double bond in 21 by a syn-type S 2′
installed on aldehyde 26 by the CrCl -mediated Takai coupling
N
2
20
reaction (Table 2). Thus, treatment of 21 with Tf O and pyridine
reaction, which was originally developed by the Kan group for
2
15h
at −20 °C initiated the anti-type S 2′ reaction to give oxazoline
the total synthesis of a sphingofungin derivative.
Finally,
N
2
9 in 86% yield (entry 1). The stereoselectivity of the S 2′
global deprotection of 28 completed the total synthesis of
sphingofungin F (16) in 13 steps in 6.0% total yield from
commercially available D-ribose derivative 17.
N
reaction using Mitsunobu conditions depended highly on the
nature of the phosphines.
1
1c,d,18
Whereas the reaction of 21 with
C
DOI: 10.1021/acs.orglett.5b00475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In conclusion, we have developed a direct method to give α,α-
disubstituted amino acid derivatives by Overman rearrangement
of unsaturated esters. The present study also highlighted the
utility of sigmatropic rearrangements of allylic vicinal diols, which
are readily available in enantiomerically pure form starting from a
monosaccharide. Indeed, we have achieved the concise total
synthesis of sphingofungin F (16), in which the key step was the
orthoamide-type Overman rearrangement of an unsaturated
ester. We successfully demonstrated that incorporation of high
functional group compatibility for the original reactions is a
highly useful approach in regard to the synthesis of complex
molecules such as biologically active natural products and
pharmaceuticals. Efforts to elucidate the mechanistic details to
suppress the aza-Michael reaction in the Overman rearrange-
ment of unsaturated esters are ongoing.
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0cα under the developed conditions at 140 °C resulted in the recovery
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(
1
1
13
(9) H and C NMR spectra showed that the chemical shifts of 8c at
the β-position were slightly more downfield than those of 8b.
(10) For the Overman rearrangement of allylic vicinal diols, see:
(
2
4
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures; copies of H NMR and 13C NMR
■
*
S
1
(11) For the Claisen rearrangements of allylic vicinal diols, see:
(
3
a) Tanimoto, H.; Saito, R.; Chida, N. Tetrahedron Lett. 2008, 49, 358−
spectra of new compounds. This material is available free of
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AUTHOR INFORMATION
Corresponding Authors
■
(12) Horn, W. S.; Smith, J. L.; Bills, G. F.; Raghoobar, S. L.; Helms, G.
*
E-mail: takaakis@applc.keio.ac.jp.
L.; Kurtz, M. B.; Marrinan, J. A.; Frommer, B. R.; Thornton, R. A.;
Mandala, S. M. J. Antibiot. 1992, 45, 1692−1696.
*E-mail: chida@applc.keio.ac.jp.
Notes
(13) Zweerink, M. M.; Edison, A. M.; Wells, G. B.; Pinto, W.; Lester, R.
L. J. Biol. Chem. 1992, 267, 25032−25038.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Hayashi, T.; Nishijima, M.; Hanada, K. J. Am. Chem. Soc. 1998, 120,
This research was supported by a Grant-in-Aid for Scientists
Research (B) from MEXT (26288018). Prof. Toshiaki Miyake
and Dr. Kiyoko Iijima, Institute of Microbial Chemistry, Hiyoshi
BIKAKEN), are acknowledged for the C NMR analysis of the
synthetic sphingofungin F.
9
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DOI: 10.1021/acs.orglett.5b00475
Org. Lett. XXXX, XXX, XXX−XXX