Synthesis of the spirofungin a core via a domino strategy consisting of olefinic ester ring-closing metathesis and iodospiroacetalization

Article abstract of DOI:10.1055/s-0030-1259287

Olefination of ester 26 which was obtained from acid 20 and alkenol 25 using a reduced titanium ethylidene reagent led to cyclic enol ether 28 which could be cyclized by iodospiroacetalization to the spiroacetal core of the antifungal compound spirofungin

Full text of DOI:10.1055/s-0030-1259287

LETTER
187
Synthesis of the Spirofungin A Core via a Domino Strategy Consisting of
Olefinic Ester Ring-Closing Metathesis and Iodospiroacetalization
Synthesis
o
of the
S
pirof
c
ungin A Co
h
r
e
en Neumaier, Martin E. Maier*
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax +49(7071)295137; E-mail: martin.e.maier@uni-tuebingen.de
Received 18 October 2010
ed for activity.11 It turned out that the minor isomer,
spirofungin A, is more active in the isoleucyl-tRNA as-
say.11 Therefore, selective approaches to spirofungin A
are in demand.
Abstract: Olefination of ester 26 which was obtained from acid 20
and alkenol 25 using a reduced titanium ethylidene reagent led to
cyclic enol ether 28 which could be cyclized by iodospiroacetaliza-
tion to the spiroacetal core of the antifungal compound spirofungin
A (5).
OH
O
OH
O
R1
Key words: acetal, aldol reaction, natural product, ring-closing
metathesis, spirofungin
R2
R1
9
5
1
O
1 (1,9-anti)
2
R2
The spiroacetal substructure can be found in many biolog-
ically active polyketides.1 Natural products that contain a
[6.6]-spiroacetal result from precursors featuring a 1,9-di-
hydroxynonan-5-one subunit, which in turn are easily ac-
cessible by the polyketide biosynthesis machinery.2 The
spiroacetal provides a unique shape serving as scaffold
that positions side chains in a certain direction. Neglecting
substituents between the 1,9-diol, the relative configura-
tion at the two secondary alcohols determines the config-
uration of the spiroacetal.1d,3 If the two hydroxy groups
are anti like in dihydroxyketone 1 a spiroacetal 2 with two
anomeric effects (ae) will result having both substituents
in equatorial position (Scheme 1). On the other hand, if
they are syn to each other the choice is between a spiroac-
etal with two anomeric effects and one substituent in axial
orientation (acetals 4a) and a spiroacetal with one ano-
meric effect and both substituents in equatorial position
(acetals 4b). If R1 is different from R2 in 4a these acetals
may exist as a mixture of two configurational isomers.
This situation can be found, for example, in the spirofun-
gins A (5) and B (6) which originate from strain Strepto-
myces violaceusniger Tü 4113.4 They appear as a 1:4 (A/
B) mixture of diastereomers at the spiroacetal center. Here
the additional methyl groups on the pyran ring reduce the
number of possible isomers from four to two. Besides the
substituted spiroacetal the spirofungins contain two unsat-
urated side chains terminating in carboxylic groups. These
compounds display good antifungal activity and inhibit
the growth of several human cancer cell lines. The biolog-
ical effects seem to be connected to selective inhibition of
isoleucyl-tRNA synthase.5,6 Up to now four total synthe-
ses for spirofungins have been published.5,7–9 In addition,
several strategies leading to the spiroacetal core are
known.10 Furthermore, various derivatives of reveromy-
cin A and spirofungin A have been prepared and evaluat-
O
R1 R2
H+
O
(S)
(R)
O
O
R2
4a (2 ae, 1 equatorial subst.)
– H2O
R1
R1
OH
O
OH
R2
9
5
1
3 (1,9-syn)
R2
O
O
O
O
R1
R1
R2
(S)
(R)
H+
4b (1 ae, 2 equatorial subst.)
H
2
10
O
15
CO2H
HO2C
O
H
OH
(–)-spirofungin A (5) (15S)
(+)-spirofungin B (6) (15R)
Scheme 1 Stereochemistry of [6.6]-spiroacetals and structure of
spirofungin A (5) and B (6); for the determination of the configuration
of the spiroacetal center, it is assumed that R1 >R2 (higher priority,
CIP)
The wide occurrence of spiroacetals points to a privileged
structure in biology.12 Thus, having access to spiroacetal
scaffolds should allow for the preparation of collections of
interesting natural product analogues. The most common
route to spiroacetals is the internal acetalization of dihy-
droxyketones. Other methods include hetero-Diels–Alder
reactions of enones with methylene pyrans,13 oxidative
cyclization of alcohol containing pyrans,14,15 reductive cy-
clization of cyano acetals,10d transformation of other ace-
tals,16 cyclization of hydroxyalkynones17, gold(I)-
mediated cyclization of alkynediols,18 and spirocycliza-
tion of endocyclic enol ethers [4-(5,6-dihydro-4H-pyran-
2-yl)butan-1-ols].19 Various routes to such dihydropyrans
exist, including ring-closing metathesis of olefinic vinyl
ethers.20,21 We were intrigued by the latter strategy22 in the
SYNLETT 2011, No. 2, pp 0187–0190
x
x.
x
x.
2
0
1
1
Advanced online publication: 23.12.2010
DOI: 10.1055/s-0030-1259287; Art ID: G29110ST
© Georg Thieme Verlag Stuttgart · New York

188
J. Neumaier, M. E. Maier
LETTER
Bn
Bn
context of spirofungin synthesis since the corresponding
substrates should be available by aldol or related strate-
gies (Scheme 2). Accordingly, the spirocyclic core 7 can
be traced back to enol ethers 8 and 9 which in turn lead to
building blocks 10 and 11.
PMBO
PMBO
H
N
O
N
O
Bu2BOTf, Et3N
CH2Cl2, –80 °C
+
O
O
RO
14 R = H
15 R = TBS
PMBO
O
O
O
12
13
TBSOTf
2,6-lutidine
CH2Cl2, 0 °C
(44% from 12)
P2O
H
10
H
O
15
P2O
O
O
PMBO
H
OP1
H
LiBH4, MeOH
OP1
Dess–Martin
CH2Cl2, 0 °C
OH
H
7
8
THF, 0 °C (77%)
OP2
TBSO
OH
TBSO
O
O
16
17
OH
OP1
O
(EtO)2P
PMBO
CO2Et
9
H2, Pd/C
OH
P2O
CO2Et
LiCl, DBU, MeCN
EtOAc (98%)
18
TBSO
(75% from 16)
+
CO2H
OP1
OH
10
11
PMBO
PMBO
20
NaOH
15
CO2H
Scheme 2 Retrosynthetic analysis of the spiroacetal core of spiro-
fungin A based on the domino sequence ester olefination, ring-closing
metathesis and spiroacetalization
CO2Et
EtOH–H2O
(98%)
TBSO
TBSO
19
20
Scheme 3 Synthesis of carboxylic acid 20 via aldol reaction and
chain extension
The synthesis of a carboxylic acid related to 10 started
with the aldol reaction between p-methoxybenzyloxyacet-
aldehyde (12) and chiral propionate23 13, derived from D-
phenylalanine (Scheme 3).24 We found the Evans aldol
reaction25 to be reproducible if aldehyde 12 is prepared
from solketal according to the method of Langlois.26 Silyl
protection of aldol product 14 followed by reduction of 15
with LiBH4 in THF delivered alcohol 16 in good overall
yield. For chain extension, aldehyde 17, obtained by
Dess–Martin oxidation of alcohol 16, was subjected to a
Wittig–Horner reaction using the Roush conditions27
(DBU, LiCl, MeCN) to provide enoate 18. Catalytic hy-
drogenation of the double bond with Pd/C as catalyst in
EtOAc led to ester 19 in almost quantitative yield. Base-
OMs
O
OBn
OH OBn
Pd(OAc)2, Ph3P
+
H
Et2Zn, THF, –20 °C
(70%)
(R)-21
22
23
HO
O
OBn
Ph3PCH3+Br–
1. BH3·SMe2
2. 23, THF, 0 °C
3. NaOOH
KOt-Bu, THF
0 °C (82% from 23)
24
OH OBn
25
induced saponification gave rise to acid 20 corresponding Scheme 4 Synthesis of alkenol 25 via Marshall–Tamaru reaction
to the C15–C20 part of the spirofungins.
successful.34 The same negative result was obtained with
The synthesis of alkenol 25 commenced with a Marshall–
the Tebbe–Petasis reagent (Cp2TiMe2).35 Ultimately, ole-
fination of the ester 26 and ring-closing metathesis could
be achieved in one step using a reduced titanium alky-
lidene, generated from TiCl4 (35 equiv), TMEDA (200
equiv), Zn dust (80 equiv), PbCl2 (5 equiv) and 1,1-dibro-
moethane (40 equiv) in CH2Cl2 at 55 °C.36 Pyran 27 could
be obtained on gram scale in 83% yield. Due to its some-
what sensitive nature cyclic enol ether 27 was chroma-
tographed on Al2O3 and NMR measurements were carried
out in benzene-d6. The secondary alcohol function was
unveiled by treatment of silyl ether 27 with TBAF in THF.
Spiroacetalization of enol ether 28 in the presence of CSA
(2 equiv) delivered a mixture of the two diastereomeric
acetals 29a and 29b. They could be separated by prepara-
tive TLC. The two spiroacetals could be differentiated
based on their characteristic NMR data. In particular, the
11-H/20-H NOESY cross peak in 29a is supportive for the
assignment (Scheme 5). For 29b, a 11-H/17-H NOESY
Tamaru reaction28,29 between benzyloxypropanal30 (22)
and (R)-3-butyn-2-yl mesylate31 21 in the presence of
Pd(OAc)2, Ph3P and diethylzinc (Scheme 4). After a reac-
tion time of 72 hours at –20 °C alkynol 23 was obtained in
70% yield. Analysis by chiral GC–MS (Chirasil-b-Dex
column) indicated a diastereomeric excess (de) of 95.1%
and an enantiomeric excess (ee) of 94.6%. Via hydrobora-
tion of the triple bond with freshly prepared disiamylbo-
rane followed by oxidative workup, hemiacetal 24 was
obtained as an anomeric mixture. Olefination of the crude
hemiacetal by Wittig reaction furnished the desired
alkenol 25 in good yield.
The two key fragments 20 and 25 were condensed under
Yamaguchi conditions32 resulting in olefinic ester 26
(Scheme 5). We initially tried to convert ester 26 into the
corresponding acyclic enol ether using the Tebbe
reagent33 and then to perform a ring-closing metathesis.
However, with substrate 26 this transformation was not
Synlett 2011, No. 2, 187–190 © Thieme Stuttgart · New York

LETTER
Synthesis of the Spirofungin A Core
189
work was carried out within the framework of COST action
CM0804, Chemical Biology with Natural Products.
interaction could be observed. In addition, the spiroacetal
carbon of 29a, featuring two anomeric effects, appears at
slightly higher field (d = 96.8 ppm) as compared to the
corresponding carbon atom in 29b (d = 97.4 ppm).7 Selec-
tive formation of 29a, corresponding to the core structure
of spirofungin A was possible with N-iodosuccinimide
(NIS, 1.5 equiv) in CH2Cl2–MeCN at –90 °C.22 Formation
of 30a is the result of a trans-diaxial attack of electrophile
and nucleophile to the glycal double bond.37 The crude io-
dide 30a was directly subjected to reductive dehalogena-
tion using the combination of tributyltin hydride and
triethylborane38 providing the spiroacetal 29a in 69%
overall yield from substrate 28.
References and Notes
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OH OBn
PMBO
20
15
Cl3C6H2COCl
CO2H
+
25
Et3N, DMAP
TBSO
PMBO
20
toluene (97%)
H
TiCl4, MeCHBr2
PbCl2, Zn
O
O
TBSO
OBn
TMEDA, CH2Cl2
(83%)
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26
PMBO
H
O
CSA, CH2Cl2
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(55%)
(29a/29b = 1:3)
RO
OBn
BnO
27 R = TBS
28 R = H
TBAF
THF, 60 °C
(92%)
BnO
9
14
12
10
10
O
O
O
+
15
16
15
11
11
19
O
PMBO
20
NOE
18
NOE
OPMB
29a
29b
I
OBn
NIS
CH2Cl2–MeCN
10
O
15
Bu3SnH
11
20
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28
29a
O
Et3B, toluene
(69%, 2 steps)
–90 °C, 2 h
OPMB
30a
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Scheme 5 Condensation of acid 20 and alcohol 25 to olefinic ester
26 and its conversion into spiroacetal 29a
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In summary, we could demonstrate that unsaturated ester
26 could be converted in an efficient and highly stereo-
selective manner into spiroacetal 29a which corresponds
to the core structure of spirofungin A. One big advantage
is the convergent nature of this strategy relying on rela-
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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Acknowledgment
Financial support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged. This
Synlett 2011, No. 2, 187–190 © Thieme Stuttgart · New York

190
J. Neumaier, M. E. Maier
LETTER
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PMBO
H
O
Cp2TiMe2, THF, 65 °C or
AlMe3, Cp2TiCl2
toluene–THF, 0 to 60 °C
TBSO
O
OBn
26
PMBO
H
O
O
TBSO
OBn
OBn
26a
AlMe3, Cp2TiCl2
H
toluene–THF, 0 to 60 °C
O
(67%)
O
32
H
O
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O
OBn
31
H
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32
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OBn
65 °C, 16 h
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33
(23%)
Scheme 6
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Tebbe olefination only led to the acyclic enol ether 32
(Scheme 6), whereas the Tebbe–Petasis reagent produced a
mixture of the open and closed enol ethers 32 and 33 (open/
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