Total synthesis of (+)-preussin: Control of the stereogenic centers by enantioselective allyltitanations

Article abstract of DOI:10.1055/s-2004-829564

(+)-Preussin was synthesized in ten steps with an overall yield of 6.4% from phenylacetaldehyde. The three stereogenic centers were controlled by enantioselective allyltitanations of aldehydes.

Full text of DOI:10.1055/s-2004-829564

LETTER
1811
Total Synthesis of (+)-Preussin: Control of the Stereogenic Centers by
Enantioselective Allyltitanations
Total
S
ynthesi
o
s
of (+)-Preu
p
ssin hie Canova, Véronique Bellosta, Janine Cossy*
Laboratoire de Chimie Organique, associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
Received 26 March 2004
preparation of structural analogs possessing various
substituents at C2, C3 and C5 for biological screening.
With this aim in view, we envisaged to use enantio-
selective allyltitanations employing the chiral cyclo-
pentadienyl-dialkoxytitanium(IV) complexes5 I and II
(Figure 2) to create the three stereogenic centers present
in (+)-preussin.
Abstract: (+)-Preussin was synthesized in ten steps with an overall
yield of 6.4% from phenylacetaldehyde. The three stereogenic cen-
ters were controlled by enantioselective allyltitanations of alde-
hydes.
Key words: preussin, allyltitanation, cross-metathesis
Preussin (Figure 1), a naturally occuring pyrrolidine
alkaloid has been isolated from fermentation broths of
Aspergillus ochraceus ATCC 22947 and from Preussia
sp., and exhibits antifungal and antibacterial activities.1
Recently, it has been discovered that preussin is a selec-
tive inhibitor for cell growth of the fission yeast ts mutants
defective on cdc2-regulatory genes,2 and its activity in
apoptosis-induction and as a potent inhibitor of cyclin E
kinase in human tumor cells were also reported.3 The
impressive biological activity and interesting structural
features have thus made preussin an attractive target for
synthesis.4 Almost all of the published syntheses employ
a chiral pool starting material to introduce the chirality
except for the syntheses reported by Greene,4j Ghosh,4l
and Rhagavan4s which are enantioselective.
RO
Ti
Ti
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
(R,R)-I
(R,R)-II
R = Me, Et, PMP
Figure 2
Herein, we would like to report the synthesis of
(+)-preussin by employing a double nucleophilic substi-
tution of an activated g-diol by N-methylamine to build
up the pyrrolidine ring and an enantioselective oxyallyl-
titanation of an aldehyde to control at first the C2 and C3
stereogenic centers and then an allyltitanation to control
the C5 stereogenic center. Furthermore, a chain elonga-
tion of A, by using a cross-metathesis reaction has been
envisaged for the installation of the nonyl alkyl side-chain
present at C5 (Scheme 1).
HO
3
Ph
C9H19
5
2
N
Me
(+)-Preussin
Figure 1
HO
OP OH
3
Ph
2
5
C9H19
C9H19
Ph
3
5
2
Among the different methods that allow the formation of
a pyrrolidine ring, the intramolecular nucleophilic dis-
placement of an activated alcohol moiety (e.g. tosylate,
mesylate or triflate) by an amine is certainly one of the
most useful and reliable methods when 2,5-disubstituted
pyrrolidines have to be synthesized. This approach re-
quires that the stereochemistry has already been estab-
lished in the previous steps by using either chiral pool-
derived cyclization precursors or stereoselective C-O and/
or C-N bond formation with the appropriate configura-
tion. Our interest was to develop a versatile route for
preussin, which could be readily extendable to the
N
OH
Me
cross-metathesis
C6H13
OP
3
O
OP
3
OH
5
Allyltitanation
2
2
5
Ph
H
Ph
OP'
OP'
A
Oxyallyltitanation
OP
3
H
2
Ph
Ph
O
OH
SYNLETT 2004, No. 10, pp 1811–1813
0
9
.0
8
.2
0
0
4
Advanced online publication: 15.07.2004
Scheme 1
DOI: 10.1055/s-2004-829564; Art ID: G09604ST
© Georg Thieme Verlag Stuttgart · New York

1812
S. Canova et al.
LETTER
OMOM
Enantioselective oxyallyltitanations with complex of type
I are known to lead to anti-1,2-diols with good diastereo-
selectivity and enantioselectivity.5 The first step of our
synthesis required an oxyallytitanation of phenylacetalde-
hyde 1 to install at this stage a protected alcohol at C3,
which could be easily deprotected at the end of the synthe-
sis. Therefore, we decided to perform the MOM-oxy-
allyltitanation of phenylacetaldehyde 1 with complex
(R,R)-Ia (R = MOM)6 in diethyl ether at –78 °C. The de-
sired anti-1,2-diol 2 was obtained with a 91:9 diastereo-
meric ratio. After purification by flash chromatography,
compound (+)-2 was isolated in 63% yield as a single di-
astereomer with an enantiomeric excess of 90%.7 Protec-
tion of (+)-2 as a benzyl ether (NaH, THF, HMPA, BnBr,
n-Bu4NI) led to compound (+)-3 (87% yield) which was
transformed to the desired primary alcohol (–)-4 in 56%
yield by hydroboration–oxidation (BH3·THF, 0 °C then
NaOH, H2O2). It is noteworthy that the secondary alcohol
4¢ was also formed in 35% yield.8,9 After a Dess–Martin
oxidation of (–)-4 (Dess–Martin periodinane = DMP, py-
ridine), the obtained aldehyde 5 was added directly to the
highly face-selective allyltitanium complex (R,R)-II,5 to
give the homoallylic alcohol (+)-6 with a 96:4 diastereo-
selectivity and in 88% overall yield (for the last two
steps). The next step was the introduction of the alkyl
side chain present at C5 in (+)-preussin, by using a cross-
metathesis reaction (Scheme 2). When homoallylic alco-
hol (+)-6 was treated with the ‘second generation’
Grubbs’ catalyst10 G2 (10 mol%) in refluxing methylene
chloride in the presence of oct-1-ene (20 equiv), the cor-
responding disubstituted olefin (+)-7 was obtained (84%
yield) and hydrogenated (H2, Pd/C, EtOAc–MeOH 4:1) to
produce the mono-protected triol (+)-8 in 73% yield. The
transformation of (+)-8 to pyrrolidine (+)-9 was achieved
in two steps. The monoprotected triol (+)-8 was first treat-
ed with methanesulfonyl chloride (MsCl, Et3N, THF).
The resulting bis-mesylate was reacted slowly with aque-
ous N-methylamine (DMF, 50 °C, 4 d) to produce the
desired cyclized product (+)-9 as a single diastereomer
via two nucleophilic substitution (SN2 and then SNi).
Pyrrolidine (+)-9 was isolated in 48% yield11 (for the last
two steps).
OMOM
3
H
a
2
b
2
3
5
Ph
Ph
Ph
Ph
O
1
OBn
c
OH
(+)-2
(+)-3
MOMO
OH
OMOM
2
3
2
+
5
3
5
Ph
OBn
OBn OH
(−)-4
4'
d
MOMO
OH
MOMO
O
5
e
2
3
2
3
5
Ph
Ph
H
OBn
OBn
5
(+)-6
f
MOMO
OH
5
MOMO
OH
g
C6H13
2
2
3
Ph
5
3
Ph
C9H19
OBn
OH
(+)-8
(+)-7
h
HO
MOMO
3
3
j
Ph
Ph
C9H19
C9H19
5
5
2
2
N
N
Me
Me
(+)-9
(+)-Preussin
MOMO
Ti
O
N
Cl
N
O
Ph
Ph
Ph
Ph
Ru
Cl
O
Ph
PCy3
O
(R,R)-Ia
G2
Scheme 2 (a) (R,R)-Ia, Et2O, –78 °C, 4 h, 63%, ee = 90%; (b) NaH,
HMPA, THF; BnBr, Bu4NI, r.t., 2 h, 87%; (c) BH3·THF, THF, 0 °C
to r.t., 2 h, (–)-4 (56%), 4¢ (35%); (d) DMP, pyridine, CH2Cl2, r.t., 3
h; (e) (R,R)-II, –78 °C, Et2O, 4 h, 88% (2 steps), dr = 96:4; (f) G2 (10
mol%), oct-1-ene (20 equiv), CH2Cl2, reflux, 8 h, 84%; (g) Pd/C 10%,
H2, EtOAc–MeOH (4:1), r.t., 2 h, 73%; (h) i. MsCl, Et3N, THF,
<0 °C, 2 h.; ii. aq MeNH2, DMF, 50 °C, 4 d, 48% (2 steps); (j) 6 N
HCl, THF, r.t., 3 d, 81%.
After acidic removal of the methoxymethyl protecting
group (6 N HCl, THF), (+)-preussin was isolated in 81%
yield. The spectral and physical data of (+)-1 are in accor-
dance with the literature 1b,4m{[a]D25 = +21 (c 0.2, CHCl3),
lit.1b [a]D25 = +22 (c 1.0, CHCl3)]}.
References
(1) (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.; Kahle, A. D. J. Antibiot. 1989, 42,
1184.
(2) Kasahara, K.; Yoshida, M.; Eishima, J.; Takesako, K.;
Beppu, T.; Horinouchi, S. J. Antibiot. 1997, 50, 267.
(3) Achenbach, T. V.; Slater, E. P.; Brummerhop, H.; Bach, T.;
Müller, R. Antimicrob. Agents Chemother. 2000, 44, 2794.
The use of two enantioselective allyltitanations and a
cross-metathesis reaction allowed the synthesis of (+)-
preussin in ten steps with an overall yield of 6.4%. Be-
cause of the biological potential of (+)-preussin, the syn-
thesis of analogs is certainly a topic of current interest and
due to the versatility of the enantioselective allyltitana-
tions and the cross-metathesis reaction, the synthesis of
analogs are still being pursued in our laboratories. The
results along these lines will be reported in due course.
Synlett 2004, No. 10, 1811–1813 © Thieme Stuttgart · New York

LETTER
Total Synthesis of (+)-Preussin
1813
(4) (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.;
Ishikaya, T.; Ohta, A. Heterocycles 1993, 36, 1823.
(d) Deng, W.; Overman, L. E. J. Am. Chem. Soc. 1994, 116,
11241. (e) Overhand, M.; Hecht, S. M. J. Org. Chem. 1994,
59, 4721. (f) Yoda, H.; Yamazaki, H.; Takabe, K.
Tetrahedron: Asymmetry 1996, 7, 373. (g) Beier, C.;
Schaumann, E. Synthesis 1997, 11, 1296. (h) Kadota, I.;
Saya, S.; Yamamoto, Y. Heterocycles 1997, 46, 335.
(i) Dong, H. Q.; Lin, G. Q. Chin. J. Chem. 1998, 16, 458.
(j) Kanazawa, A.; Gillet, S.; Delair, P.; Greene, A. E. J. Org.
Chem. 1998, 63, 4660. (k) Veeresa, G.; Datta, A.
Tetrahedron 1998, 54, 15673. (l) Verma, R.; Ghosh, S. K. J.
Chem. Soc., Perkin Trans. 1 1999, 265. (m) Lee, K.-Y.;
Kim, Y.-H.; Oh, C.-Y.; Ham, W.-H. Org. Lett. 2000, 2,
4041. (n) Bach, T.; Brummerhop, H.; Harms, K. Chem.–
Eur. J. 2000, 6, 3838. (o) Okue, M.; Watanabe, H.;
Kitahara, T. Tetrahedron 2001, 57, 4107. (p) Krasinski, A.;
Gruza, H.; Jurczak, J. Heterocycles 2001, 54, 581.
(q) Cadwell, J. J.; Craig, D.; East, S. P. Synlett 2001, 1602.
(r) Dikshit, D. K.; Goswami, L. N.; Singh, V. S. Synlett
2003, 1737. (s) Raghavan, S.; Rasheed, M. A. Tetrahedron
2003, 59, 10307. (t) Huang, P.-Q.; Wu, T.-J.; Ruan, Y.-P.
Org. Lett. 2003, 5, 4341.
(7) The enantiomeric excess of (+)-3 was determined by 1H
NMR after its derivatization with (S)- and (R)-methoxy-
phenylacetic acid.
(8) Secondary alcohol 4¢ was isolated as a mixture of two
diastereomers in a 75:25 ratio. After debenzylation (H2,
Pd/C, quantitative yield), the resulting 1,3-diols were
transformed to the corresponding acetonides
(dimethoxypropane, PPTS, 90%). According to the 1H NMR
and 13C NMR data, the major product has the anti-anti
structure (Figure 3):
OMOM
2
4
3
Ph
O
O
Figure 3
(9) Decomposition of the starting material or non-reactivity
were observed when other boranes were used [9-BBN,
(Cy)2BH].
(10) Scholl, M.; Ding, S.; Woo Lee, S.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
(11) The formation of tetrahydrofuran B as secondary product
could be observed during the cyclization process (Figure 4).
(5) (a) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-
Streit, P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114,
2321. (b) Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92,
807.
(6) Complex (R,R)-Ia (R = MOM) was formed in situ after
deprotonation of 3-methoxymethoxypropene by s-BuLi and
transmetallation with the correponding chlorocyclo-
pentadienyldialkoxytitanium(IV) complex.
PO
3
Ph
C9H19
5
2
O
B
Figure 4
Synlett 2004, No. 10, 1811–1813 © Thieme Stuttgart · New York