A silicon controlled total synthesis of the antifungal agent (+)-preussin

Article abstract of DOI:10.1039/a703387g

A stereoselective total synthesis of (+)-preussin has been achieved from a meso anhydride featuring a dimethyl(phenyl)silyl group as a masked hydroxy group which also restricts elimination reactions, stereodirects hydrogenation and ester enolate alkylation, and facilitates Curtius reaction.

Full text of DOI:10.1039/a703387g

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A silicon controlled total synthesis of the antifungal agent (+)-preussin
Rekha Verma and Sunil K. Ghosh*
Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India
SiMe2Ph
CO2Me
A stereoselective total synthesis of (+)-preussin has been
achieved from a meso anhydride featuring a dimethyl-
i
PhMe2Si
(phenyl)silyl group as a masked hydroxy group which also
restricts elimination reactions, stereodirects hydrogenation
and ester enolate alkylation, and facilitates Curtius reac-
tion.
85%
MeO2C
CO2Me
CO2Me
5
6
ii 97%
SiMe2Ph
SiMe2Ph
(+)-Preussin, (2S,3S,5R)-1-methyl-5-nonyl-2-benzylpyrrolidin-
3-ol (also known as L-657,398), 1 was isolated from the
fermentation broths of Aspergillus ochraceus ATCC 22947 and
Preussia sp.1 This structurally novel pyrrolidine alkaloid has
broader spectrum antifungal activity against both filamentous
fungi and yeasts than the structurally related antibiotic anisomy-
cin. The first total synthesis of (+)-preussin was reported by Pak
and Lee2 taking d-glucose as a substrate. Four more syntheses
have been published subsequently using (S)-phenylalanine3 and
its enantiomer4 as starting materials.
iii–v
92%
MeO2C
CO2Me
O
O
O
4
7
Scheme 2 Reagents and conditions: i, NaOMe, dimethyl malonate, room
temp., 48 h; ii, NaCl, DMSO, H2O, heat, 2.5 h; iii, KOH, MeOH, H2O, room
temp., 48 h; iv, dil. HCl; v, Ac2O, reflux, 2.5 h
mixture of diastereoisomeric acids 9a and 10a (stereochemistry
not determined) (Scheme 3) in 80% yield. In a related study,
Theisen and Heathcock5a have also observed that 3-alkyl
substituted glutaric anhydrides show poor diastereocontrol with
increasing size of the alkyl groups. Alternatively, we opened up
the anhydride with the lithium anion of the Evans’ auxiliary12
11 which quantitatively provided a mixture of diastereoisomeric
acids 9b and 10b in a ratio of ca. 67:33 (analysed as their
methyl esters by NMR spectroscopy). To the best of our
knowledge, this forms the first example of the desymmetriza-
tion of a meso anhydride using an anion of a chiral imide.
Although the selectivity was low, the benzyl esters 12 and 13‡
of these acids were easily separable by chromatography. The
absolute stereochemistry of the major acid 9b was established
by converting it to a known derivative 145b following the
reactions depicted in Scheme 4.
A simple retrosynthetic analysis could be postulated for
1
(+)-preussin 1 from meso anhydride 45 via D -pyrroline 2 as
shown in Scheme 1 (X = OH). However, as pointed out by
Livinghouse,3a an intermediate like 2 is unstable due to the ease
of elimination of the protected or unprotected OH group to
provide a pyrrole derivative. Therefore, a substitute for this
group is desirable which would resist elimination, could be
stereospecifically converted to a hydroxy group when desired,
1
could possibly stereodirect both saturation of the D -pyrroline
system and introduction of the benzyl group, and possibly
facilitate the Curtius reaction of 3. Considering all these
requirements, we envisaged that a dimethyl(phenyl)silyl
(PhMe2Si) group would be an ideal substitute. It is known to be
a poor leaving group and, as shown by Fleming,6 it can be
stereospecifically converted to a hydroxy group with retention
of configuration. They have further shown that b-silyl ester
enolate alkylations occur with high anti stereoselectivity.7
Moreover, we have found that a b-silicon group facilitates the
Curtius reaction of acyl azides‡ in close analogy to silicon
directed Bayer–Villiger oxidation of b-silyl ketones.8
The major acid 9b was converted to the ketone 15 in 60%
yield (88% based on recovered 9b) (Scheme 5), which was
quantitatively protected13 as the acetal and the auxiliary was
removed12 to provide the homochiral methyl ester 16 in 78%
yield.§ We could recover the auxiliary in 78% yield ( > 99%
considering the wrong attack on the auxiliary) without any loss
The starting meso anhydride 4 could easily be obtained in a
few steps from b-silyl acrylate 59 via the triester 6 and
Fleming’s meso diester 710 as depicted in Scheme 2. When 4
was opened up with (±)-naphthylethanol 8, it was expected to
show good diastereocontrol, as observed by Fleming and
Ghosh11 for the opening up of a 3,4-bis-silyl substituted meso
adipic anhydride. However, we obtained an inseparable 85 :15
O
R
O
O
R
O
Nu
+
4
HO
Nu
Nu
OH
9a / 9b R = PhMe2Si
10a /10b R = PhMe2Si
Nu
Reaction
Diastereomeric
ratio
Yield
80%
OH
X
conditions
OH
CH2Cl2, –20 °C
85:15
H19C9
Bn
H19C9
Bn
N
N
DMAP, 2 days
2
Me
1
8
X
X
H19C9
O
THF, 30 °C
24 h
66:33
100%
Bn
CON3
–N
Bn
O
O
O
O
O
4
3
X = OH, SiMe2Ph
Scheme 1
11
Scheme 3
Chem. Commun., 1997
1601

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smoothly† provided the expected benzyloxycarbonyl protected
amine in good yield. The acetal protection was subsequently
removed to give the ketone 19 in overall 75% yield from 17. At
this stage we could easily separate the unwanted minor
diastereoisomer by chromatography. The ketone 19 was
subjected to hydrogenolysis whereupon removal of the benzyl-
oxycarbonyl group took place. The generated amino group
condensed intramolecularly with the carbonyl group sponta-
O
O
O
R
O
BnO
BnO
N
O
O
Bn
13 R = PhMe2Si
i, ii
9b + 10b
(67:33)
+
70%
O
R
O
1
neously to provide the D -pyrroline 2 (X = PhMe2Si) which
was in situ hydrogenated with hydrogens coming from the least
hindered surface, i.e. away from the silicon and benzyl groups,
to provide the pyrrolidine derivative with all three substituents
having cis stereochemistry. Subsequently, the NH group was
protected as ethoxycarbonyl derivative 20 and the silyl group in
the molecule was converted to a hydroxy group6 and then to its
acetate 21.¶ Lithium aluminium hydride reduction of this
acetate provided (+)-preussin 1 in 77% yield. Since we started
with the homochiral methyl ester 16, and the synthetic sequence
does not cause any epimerisation, the enatiomeric purity of
(+)-preussin should undoubtedly be very high ( > 99%). This
was confirmed from its specific rotation value ([a]2D5 + 31.1, c
1, CHCl3) and spectral data.2 The overall yield of (+)-preussin
from the homochiral ester 16 was 17.2%.
OSiMe2But
O
N
O
iii–ix
Bn
12 R = PhMe2Si
34%
PhO
N
H
OMe
14
Scheme 4 Reagents and conditions: i, Et3N, PivCl, 278 to 0 °C, 1 h; ii,
BnOH, DMAP, room temp., 24 h; iii, chromatographic removal of 13; iv,
H2, 10% Pd–C; room temp., 24 h; v, KBr, NaOAc, AcOOH, room temp., 24
h; vi, (S)-phenylethylamine, DCC, DMAP, room temp., 24 h; vii, LiOOH,
THF, 0 °C, 40 min; viii, CH2N2; ix, ButMe2SiCl, DMF, imidazole, room
temp., 15 h
O
O
R
O
i, ii
We acknowledge RSIC, Mumbai for the NMR facility, and
Dr A. Banerji and Dr V. R. Mamdapur for their support.
H19C9
N
O
9b
88%
Bn
15 R = PhMe2Si
Footnotes and References
iii, iv 78%
* E-mail: bod@magnum.barct1.ernet.in
† A silicon group at the b-position enhances the rate of Curtius reaction of
acyl azides; details will be published elsewhere.
‡ We are in the process of converting this diastereoisomer to acetal 16.
§ During the process, an undesired product (about 22%) was also formed by
attack of the methoxide ion on the wrong carbonyl of the auxiliary.
¶ The NMR spectra of 20 and 21 could not be fully interpreted as these are
known to be mixtures of amide geometrical isomers as well as atropi-
somers.
R
O
R
O
v, vi
O
O
O
O
88%
H
19C9
OMe
H19C9
16 R = PhMe2Si
OMe
Bn
17 R = PhMe2Si
vii–ix
75%
R
O
O
R
H
N
x–xii
75%
O
O
OBn
H
19C9
NH2
H19C9
1 R. E. Schwartz, J. Liesch, O. Hensens, L. Zitano, S. Honeycutt,
G. Garrity, R. A. Fromtling, J. Onishi and R. Monaghan, J. Antibiot.,
1988, 41, 1774; R. E. Schwartz, J. C. Onishi, R. L. Monaghan,
J. M. Liesch and O. D. Hensens, US P 4847284, 1989; J. H. Johnson,
D. W. Phillipson and A. D. Kahle, J. Antibiot., 1989, 42, 1184.
2 C. S. Pak and G. H. Lee, J. Org. Chem., 1991, 56, 1128.
3 (a) P. L. McGrane and T. Livinghouse, J. Am. Chem. Soc., 1993, 115,
11 485; (b) M. Overhand and S. M. Hecht, J. Org. Chem., 1994, 59,
4721; (c) W. Deng and L. E. Overman, J. Am. Chem. Soc., 1994, 116,
11 241.
Bn
18 R = PhMe2Si
Bn
19 R = PhMe2
O
Si
xiii, xiv 75%
SiMe2Ph
SiMe2Ph
H19C9
2
Bn
H19C9
Bn
N
H
O
H2N
4 M.Shimazaki, F. Okazaki, F. Nakajima, T. Ishikawa and A. Ohta,
Heterocycles, 1993, 36, 1823.
5 (a) P. D. Theisen and C. H. Heathcock, J. Org. Chem., 1993, 58, 142,
and references cited; (b) D. S. Karanewsky, M. F. Malley and
J. Z. Gougoutas, J. Org. Chem., 1991, 56, 3744.
6 I. Fleming, R. Henning, D. C. Parker, H. E. Plaut and P. E. J. Sanderson,
J. Chem. Soc., Perkin Trans. 1, 1995, 317.
7 R. A. N. C. Crump, I. Fleming, J. H. M. Hill, D. Parker, N. L Reddy and
D. Waterson, J. Chem. Soc., Perkin Trans. 1, 1992, 3277.
8 P. F. Hudrlik, A. M. Hudrlik, T. Yimenu, M. A. Waugh and
G. Nagendrappa, Tetrahedron, 1988, 44, 3791.
9 K. Takeshita, Y. Seki, K. Kawamoto, S. Murai and N. Sonoda, J. Org.
Chem., 1987, 52, 4864.
10 I. Fleming, Stereocontrol in Organic Synthesis Using Silicon Com-
pounds, Conferencias Plenarias de la XXIII Reunio’n Bienal de
Qui’mica, Salamanca, 1990, p. 89.
11 I. Fleming and S. K. Ghosh, J. Chem. Soc., Chem. Commun., 1994,
2285.
SiMe2Ph
Bn
OAc
xv, xvi
60%
xvii
1
H19C9
H19C9
Bn
N
N
77%
CO2Et
CO2Et
21
20
Scheme 5 Reagents and conditions: i, Et3N, PivCl, 278 to 0 °C, 1 h; ii,
C9H19MgBr, 225 °C, 48 h; iii, 1,2-bis(trimethylsilyloxy)ethane, Me3SiO-
SO2CF3, 220 °C, 48 h; iv, MgOMeBr, THF, 30 °C, 18 h; v, LiTMP, THF–
DMPU, 278 °C, 1 h; vi, BnBr, 278 to 210 °C, 60 h; vii, KOH, MeOH,
H2O, 80 °C, 32 h; viii, Im2CO, room temp., 30 min; ix, liq. NH3; x,
Pb(OAc)4, BnOH, DMF, 100 °C, 15 h; xi, TsOH, acetone, H2O, reflux, 2.5
h; xii, chromatographic removal of minor diastereoisomer; xiii, H2, 10%
Pd–C, EtOH, AcOH, 7 h; xiv, EtOCOCl, Et3N, 0 °C, 15 h; xv, KBr, NaOAc,
AcOOH, room temp., 20 h; xvi, Ac2O, DMAP, CH2Cl2, room temp., 20 h;
xvii, LiAlH4, THF, room temp., 24 h
12 D. A. Evans, T. C. Britton, R. L. Dorow and J. F. Dellaria, Jr.,
Tetrahedron, 1988, 44, 5525.
13 T. H. Chan, M. A. Brook and T. Chaly, Synthesis, 1983, 203.
14 H. E. Baumgarten, H. L. Smith and A. Staklis, J. Org. Chem., 1975, 40,
3554.
of optical purity. The ester enolate C-benzylation took place
with high anti selectivity7 (anti:syn = 93:7) to give ester 17
which was resistant to hydrazinolysis. This ester was hydroly-
sed, converted to primary amide 18 via its acid imidazolide and
was subjected to modified Curtius reaction conditions14 which
Received in Cambridge, UK, 16th May 1997; 7/03387G
1602
Chem. Commun., 1997