A short synthesis of Preussin: Use of allyldimethylsilyl as masked hydroxyl

Article abstract of DOI:10.1055/s-2003-41433

A short and efficient synthesis of Preussin utilizing allyldimethylsilyl group as hydroxyl equivalent via an interesting (3+2) annulation reaction involving non-classical pentavalent silicon cation transition state, has been described.

Full text of DOI:10.1055/s-2003-41433

LETTER
1737
A Short Synthesis of Preussin: Use of Allyldimethylsilyl as Masked Hydroxyl1
A
Short Synthesis
i
of Preu
n
ssin esh K. Dikshit,* Lalit N. Goswami, Vishnu S. Singh
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow – 226 001, India
Fax +91(522)2223405; fax +91(522)2223938; E-mail: dkdikshit@sify.com.
Received X July 2003
rolidine, which might be converted to (2S,3S,5S)-2-
benzyl-1-benzyloxycarbonyl-3-hydroxy-5-hydroxymeth-
yl-pyrrolidine as an en route to Preussin (Scheme 1).
Abstract: A short and efficient synthesis of Preussin utilizing al-
lyldimethylsilyl group as hydroxyl equivalent via an interesting
(3+2) annulation reaction involving non-classical pentavalent sili-
con cation transition state, has been described.
The reaction of allyl trimethylsilane with Cbz-Phe-al gave
Keywords: natural product, antifungal agents, (3+2) annulation, al- as reported, the cis-pyrrolidine 2a in 55% yield along with
open chain syn-alcohol 4 as minor product (<5%).10 How-
lydimethylsilyl, pyrrolidine alkaloid
ever, using allyldimethylphenylsilane under similar con-
dition, no trace of cyclic product 2b was seen and the
allylic alcohol 4 was isolated as the only product. Failure
to obtain cyclic product in this case can be rationalized to
be due to the bulkiness of phenyl substitution in the
crowded transition state involving pentavalent silicon
(Scheme 2).
Isolated originally from Preussia sp. and Aspergillus
ochraceus2a and having strong inhibitory activity as
broad-spectrum antibiotics against filamentous fungi,2b
the pyrrolidine alkaloid Preussin has been the target of
many synthetic endeavors due to its tri-cis-pyrrolidine
structure.3 Recent observations of the role of Preussin in
inhibition of the fission yeast ts mutants defective on
cdc2-regulatory genes,4 apoptosis-induction, inhibition of
cyclin-E kinase,5 and inhibition of programmed-1 riboso-
mal frameshifting,6 have rekindled interest in synthesis of
Preussin and its analogs. Suitably substituted silyl group
can be treated as synthetically equivalent to hydroxyl
function7 and a synthetic approach using dimethylphenyl-
silyl group in place of ring hydroxy function has been re-
ported.8 The possibility that silyl group can be treated as
masked hydroxyl, prompted us to undertake and to report
herein a short and efficient route to Preussin via 2-phenyl-
methyl-3-hydroxy-pyrrolidine-5-carboxaldehyde.
OR'
OH
Ph
Si
CHO
NHCbz
BF3·OEt2
R
Ph
+
Ph
N
+
Si R
NHCbz
Cbz
3
4
2
a, R =Me
b, R = Ph
c, R = allyl
a, R =Me, R' = H
b, R = Ph (not formed)
c, R = allyl, R' = H
Ac2O, Et3N
d, R = allyl, R' = Ac
Scheme 2
Magar et al has shown that allyldimethyl silyl group can
also be used as a hydroxy equivalent.11 Thus using di-
allyldimethylsilane in place of trimethylsilane in the
above reaction gave the cyclic product 2c in good yield.12
2c was converted to its acetate 2d using Ac2O and Et3N.13
Treatment of the acetate 2d first with bromine in CH2Cl2
followed by HF–pyridine as fluoride source13 gave the
corresponding fluorosilane, which was not characterized
and was directly reacted with H2O2–K2CO3 to provide
(2S,3S,5S)-3-acetyl-2-benzyl-benzyloxycarbonyl-5-hy-
droxymethyl-pyrrolidine 5a in good yield.14 During the
oxidative reaction under basic conditions, hydrolysis of
the acetate group also occurred and dihydroxy compound
5b was obtained in small amount. The formation of 5b
could be minimized using preformed H2O2–Na2CO3.
Compound 5a on Swern oxidation gave pyrrolidine alde-
hyde 6 in 60% yield (Scheme 3).15 As a similarly protect-
ed aldehyde has already been converted to Preussin16 in a
few simple steps, this constitutes a formal synthesis of
Preussin.
CHO
OH
OH
Ph
NHCbz
Ph
Ph
Si
+
R
C9H19
N
N
Me
Preussin
1
Cbz
Si R
2
3
Scheme 1
While investigating the Sakurai–Hosomi reaction of allyl-
trimethylsilane with carbonyl compounds in presence of
Lewis acid, Kiyooka et al. have observed an interesting
(3+2) annulation reaction involving non-classical pen-
tavalent silicon cation transition state where cis-2-substi-
tuted
3-hydroxy-5-trimethylsilylmethyl-pyrrolidines
were obtained.9
We envisaged using allyldimethylphenylsilane in place of
allyltrimethylsilane in order to obtain, in a similar reac-
tion, corresponding 5-dimethylphenylsilanylmethylpyr-
Thus, we have accomplished a short and efficient synthe-
sis of the advanced aldehyde intermediate 6 having func-
tionalities of requisite stereochemistry. We feel that this
strategy is general in nature and can serve to give a range
of novel Preussin analogs.
Synlett 2003, No. 11, Print: 02 09 2003. Web: 25 08 2003.
Art Id.1437-2096,E;2003,0,11,1737,1739,ftx,en;U12503ST.pdf.
DOI: 10.1055/s-2003-41433
© Georg Thieme Verlag Stuttgart · New York

1738
D. K. Dikshit et al.
LETTER
OR'
OAc
Ref.16
Ph
Ph
HO
i. Br2 / HF-Pyridine
OHC
Swern
2d
N
1
N
oxidation
ii. H2O2-KHCO3
Cbz
Cbz
5a, R = Ac
6
KOH
b, R = H
Scheme 3
Acknowledgment
OH
OH
OH
Authors are pleased to acknowledge the Department of Science &
Technology, New Delhi for financial assistance. One of us (LNG)
is grateful to Prof. C. S. Mathela, Kumaun University, Nainital for
his encouragement and to the Council of Scientific & Industrial Re-
search, New Delhi for the award of Senior Research Fellowship
(SRF).
Ph
Ph
Si
Ph
t-BuOK
TFA
HN
Cbz
N
N
Cbz
8
Cbz
7
2a
Scheme 4
(11) Magar, S. S.; Fuchs, P. L. Tetrahedron Lett. 1991, 32, 7513.
(12) Synthesis of Compound 2c: To a stirred soln of (S)-2-(N-
benzyloxycarbonylamino)-3-phenyl-propanal (1 g, 3.5
mmol) in 20 mL of freshly dried CH2Cl2 at –10 °C was
added BF3·OEt2 (0.09 mL, 0.4 mmol). After 20 min a
solution of diallyldimethylsilane (0.69 mL, 3.8 mmol) in
freshly dried CH2Cl2 (4 mL) was added to it drop wise over
a period of 10 min, the resultant mixture was stirred for 2 h
at –10 °C, quenched with aq NH4Cl solution (25 mL) and
extracted with CH2Cl2 (50 mL × 3). Combined organic layer
was washed with brine, dried over anhyd Na2SO4 and
concentrated. The crude material was flash
References
(1) Communication no. 6415 from CDRI.
(2) (a) Schwartz, R. E.; Liesch, J.; Hensens, O.; Zitano, L.;
Honeycutt, S.; Garrity, G.; Fromtling, R. A.; Onishi, J.;
Monaghan, R. J. Antibiot. 1988, 41, 1774. (b) Johnson, J.
H.; Phillipson, D. W.; Khale, A. D. J. Antibiot. 1989, 42,
1185.
(3) (a) Pak, C. S.; Lee, G. H. J. Org. Chem. 1991, 56, 1128.
(b) McGrane, P. L.; Livinghouse, T. J. Am. Chem. Soc. 1993,
115, 11485. (c) Shimazaki, M.; Okazaki, F.; Nakajima, F.;
Ishikawa, T.; Ohta, A. Heterocycles 1993, 36, 1823.
(d) Overhand, M.; Hecht, S. M. J. Org. Chem. 1994, 59,
4721. (e) Kanazawa, A.; Gillet, S.; Delair, P.; Greene, A. E.
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(h) Lee, K.-Y.; Kim, Y.-H.; Oh, C.-Y.; Ham, W.-H. Org.
Lett. 2000, 2, 4041. (i) Veeresa, G.; Datta, A. Tetrahedron
1998, 54, 15673.
(4) Kasahara, K.; Yoshida, M.; Eishima, J.; Takasako, K.;
Beppu, T.; Horinouchi, S. J. Antibiot. 1997, 50, 267.
(5) Achenbach, T. V.; Slater, E. P.; Brummerhop, H.; Bach, T.;
Müller, R. Antimicrob. Agents Chemother. 2000, 44, 2794.
(6) Kinzy, T. G.; Harger, J. W.; Schmid, A. C.; Kwon, J.;
Shastry, M.; Justice, M.; Dinman, D. Virology 2002, 300, 60.
(7) (a) Tamao, K.; Ishida, N. Tetrahedron Lett. 1984, 25, 4249.
(b) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M.
Organometallics 1983, 2, 1694. (c) Tamao, K.; Ishida, N. J.
Organomet. Chem. 1984, 269, C37. (d) Fleming, I.;
Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun. 1984,
29. (e) Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett.
1987, 28, 4229. (f) Fleming, I.; Chan, T. H. Synthesis 1979,
762.
(8) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.;
Sanderson, P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 317.
(9) Kiyooka, S.-i.; Shiomi, Y.; Kira, H.; Kaneko, Y.; Tanimori,
S. J. Org. Chem. 1994, 59, 1958.
(10) (a) All the spectral data of compound 2a and 4 matched fully
with that of authentic sample, kindly provided by Prof.
Kiyooka. (b) Our attempts to cleave trimethylsilyl group on
2a to give synthetically useful intermediate met with no
success. Reported TFA catalysed cleavage gave the ring
open product 7: Martin, D.; Gamal, M. Synthesis 1982, 827.
(c) While t-BuOK catalyzed cleavage conditions gave 8
(Scheme 4): Price, C. C.; Sowa, J. C. J. Org. Chem. 1967, 32,
4126.
chromatographed over silica gel using 12% EtOAc–hexane
as eluent to give pure 2c. Data of 2c: Colourless oil (1.03 g,
70%); [a]D = –61.09 (c 0.293, MeOH). IR(neat): 3432,
2956, 1680, 1502,1416 cm–1. 1H NMR (200 MHz, CDCl3):
d = 7.2 (m, 10 H), 5.7 (m, 1 H), 5.0 (d, J = 12 Hz, 2 H), 4.8
(dd, J = 15.8 and 11.0 Hz, 2 H), 4.2 (m, 2 H), 3.8 (m, 1 H),
2.9 (d, J = 5.3 Hz, 2 H), 2.2 (m, 1 H), 1.6 (m, 4 H), 0.81 (dd,
J = 12.9 and 11.7 Hz, 1 H), –0.019 (s, 6 H). 13C NMR (200
MHz, CDCl3): d = 155.1, 139.3, 136.6, 134.6, 129.8, 129.5,
128.39, 128.32, 128.0, 127.9, 126.1, 113.1, 71.4, 66.7, 62.4,
53.9, 39.7, 36.0, 24.1, 23.5, –2.9, –3.2; FABMS: m/z = 424
(M + 1), 383, 292.
(13) Synthesis of Compound 2d: To a solution of 2c (800 mg,
1.89 mmol) in CH2Cl2 (20 mL) at 0 °C were successively
added Et3N (2.6 mL, 18.9 mmol) and Ac2O (0.9 mL, 9.4
mmol) followed by DMAP (50 mg) as catalyst. The resulting
mixture was stirred at r.t. for 4 h, diluted with CH2Cl2 (50
mL), taken in a separating funnel and washed s uccessively
with 5% HCl (25 mL), sat. NaHCO3 (25 mL) and brine (25
mL). The organic layer was dried over anhyd Na2SO4, concd
in vacuo and flash chromatographed over silica gel using 6%
EtOAc–hexane as eluent. Data of 2d: Colorless oil (747 mg,
85%); [a]D = –38.21(c 0.28, MeOH). IR (neat): 3020, 1737,
1690, 1413, 1219 cm–1. 1H NMR (200 MHz, CDCl3): d = 7.2
(m, 10 H), 5.8 (m, 1 H), 5.0 (d, J = 12 Hz, 2 H), 4.9 (m, 1 H),
4.8 (m, 2 H), 4.4 (q, 1 H), 3.9 (m, 1 H), 2.8 (d, J = 8.1 Hz, 2
H), 2.3 (m, 1 H), 1.8 (s, 3 H), 1.7 (m, 2 H), 1.5 (m, 2 H), 0.7
(dd, J = 13.7 and 11.8, 1H), –0.011 (s, 6 H). 13C NMR (200
MHz, CDCl3): d = 170.4, 155.3, 138.9, 136.9, 134.8, 129.8,
128.8, 128.5, 128.4, 128.3, 126.5, 113, 72.7, 67.3, 60.2, 53.8,
37.3, 37.1, 24.5, 23.9, 21.1, –2.4, –2.8. FABMS: m/z = 466
(M + 1), 424.
(14) Synthesis of Compound 5a: To a solution of 2d (500 mg,
1.07 mmol) in CH2Cl2 (30 mL) at 0 °C were added
successively bromine (0.275 mL, 5.3 mmol) and HF–
Synlett 2003, No. 11, 1737–1739 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
pyridine (1.4 mL). The reaction mixture was stirred at r.t. for
A Short Synthesis of Preussin
1739
(bs, 2 H). 13C NMR (200 MHz, CDCl3): d = 157.3, 139.6,
136.5, 129.9, 128.9, 128.7, 128.6, 126.5, 70.7, 67.8, 65.5,
60.2, 58.9, 36.4, 35.0; FABMS: m/z 342 (M + 1), 298.
(15) Synthesis of Compound 6: To a stirred solution of
oxalylchloride (0.06 mL, 0.83 mmol) in CH2Cl2 (10 mL) at
–78 °C under N2 atmosphere was added DMSO (0.1 mL,
1.14 mmol) using a micro syringe. After stirring the mixture
for 30 min, a solution of 5a (200 mg, 0.52 mmol) in CH2Cl2
(2 mL) was added slowly over a period of 10 min. The
reaction mixture was stirred for 30 min at –78 °C and
diisopropylethyl amine (0.455 mL, 2.6 mmol) was added to
it slowly in 10 min. The cooling was discontinued and the
reaction was allowed to warm to r.t., diluted with CH2Cl2 (20
mL), washed with 5% HCl (20 mL), brine and water. The
organic layer was dried over anhyd Na2SO4, concd under
reduced pressure, and flash chromatographed over silica gel
using 25% EtOAc–hexane as eluent to give 6 as viscous oil.
Data of 6: Colourless oil (119 mg, 60%); [a]D = –69.23 (c
0.156, MeOH). IR(neat): 2932, 1740, 1712, 1589, 1224
cm–1. 1H NMR (200 MHz, CDCl3): d = 9.5 (br s, 1 H) 7.2 (m,
10 H), 5.0 (d, J = 12 Hz, 2 H), 4.3 (m, 3 H), 2.7 (dd, J = 13.6
and 9.5 Hz, 2 H), 2.1 (m, 2 H), 1.9 (s, 3 H). 13C NMR (200
MHz, CDCl3): d = 200.5, 169.9, 158, 138, 136.2, 129.6, 129,
128.8, 126.9, 72.7, 68.1, 64.4, 55.8, 33.0, 23.2, 21.1.
FABMS: m/z = 382 (M + 1), 352, 248.
3 h at the end of which excess of HF was destroyed by
pouring the mixture over basic alumina. The resulting slurry
was diluted with CH2Cl2 and filtered. The filtrate was dried
over anhyd Na2SO4 and concentrated in vacuum. The
material thus obtained was dissolved in a mixture of anhyd
THF–MeOH (15 mL each) and KHCO3 (215 mg, 2.15
mmol), KF (124 mg, 2.15 mmol), 30% H2O2 (2.68 mL, 21.5
mmol) were added successively to the soln under stirring.
The resulting mixture was stirred at r.t. for 10 h, sodium
thiosulphate solution (30%, 25 mL) was added to it and the
quenched mixture was extracted with EtOAc (50 mL × 3).
Combined organic layer was washed with brine (30 mL),
dried over anhyd Na2SO4, concentrated in vacuo and flash
chromatographed over silica-gel using 30% EtOAc–hexane
as eluent. Data of 5a: Colorless oil (286 mg, 70%); [a]D =
–40.54 (c 0.259, MeOH). IR(neat): 3350, 3017, 2935, 1679,
1414 cm–1. 1H NMR (200 MHz, CDCl3): d = 7.2 (m, 10 H),
5.1 (d, J = 12.5 Hz, 2 H), 4.4 (m, 1 H), 4.0 (m, 1 H), 3.6 (m,
3 H), 2.8 (d, J = 6 Hz, 2 H), 2.3 (m, 1 H), 1.9 (s, 3 H), 1.7 (m,
1 H). 13C NMR (200 MHz, CDCl3): d = 170.4, 156.1, 138.4,
136.2, 129.7, 128.9, 128.6, 126.7, 72.0, 68.1, 67.2, 60.7,
58.9, 36.7, 31.7,21.0. FABMS: m/z = 384 (M + 1), 340, 248.
Data of 5b: Colorless oil (54.7 mg, 15%); [a]D = –65.71 (c
0.035, MeOH). IR(neat): 3366, 2929, 1686, 1413 cm–1. 1H
NMR (200 MHz, CDCl3): d = 7.2 (m, 10 H), 5.0 (d, J = 12.2
Hz, 2 H), 4.1 (M, 1 H), 4.0 (m, 2 H), 3.9 (dd, J = 11.2 and 3.7
Hz, 1 H), 3.6 (dd, J = 11.2 and 3.7 Hz, 1 H), 3.0 (dd, J = 12.6
and 9.8 Hz, 2 H), 2.2 (m, 1 H), 1.8 (d, J = 13.7 Hz, 1 H), 1.7
(16) (a) Beier, C.; Schaumann, E. Synthesis 1997, 1296.
(b) Krasinski, A.; Gruza, H.; Jurczak, J. Heterocycles 2001,
54, 581.
Synlett 2003, No. 11, 1737–1739 ISSN 1234-567-89 © Thieme Stuttgart · New York