Asymmetric synthesis of (+)-tetrahydropseudodistomin

Article abstract of DOI:10.1016/j.tetlet.2007.01.143

An efficient asymmetric synthesis of (+)-tetrahydropseudodistomin is described. The important synthetic features include a Maruoka asymmetric allylation and a Sharpless asymmetric dihydroxylation as key steps for the generation of chirality at C-2, -4, and -5 of the trisubstituted piperidine ring.

Full text of DOI:10.1016/j.tetlet.2007.01.143

Tetrahedron Letters 48 (2007) 2373–2375
Asymmetric synthesis of (+)-tetrahydropseudodistominI
S. Chandrasekhar,* S. Shameem Sultana, N. Kiranmai and Ch. Narsihmuluꢀ
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 22 November 2006; revised 18 January 2007; accepted 24 January 2007
Available online 30 January 2007
Abstract—An efficient asymmetric synthesis of (+)-tetrahydropseudodistomin is described. The important synthetic features include
a Maruoka asymmetric allylation and a Sharpless asymmetric dihydroxylation as key steps for the generation of chirality at C-2, -4,
and -5 of the trisubstituted piperidine ring.
Ó 2007 Elsevier Ltd. All rights reserved.
The Okinawan tunicate Pseudodistoma sp. is a rich
source of bioactive piperidine alkaloids, the most
remarkable of these being pseudodistomins A–F. These
isomeric alkaloids contain a 2-substituted 5-amino-4-
piperidinol as a common core and only differ in the
stereochemistry of the stereogenic carbons and in the
nature of the side chain (Fig. 1). Pseudodistomins A–C
were isolated from Pseudodistoma kanoko by Kobayashi
et al. and exhibited potent in vitro inhibitory effects on
calmodulin activated brain phosphodiesterase. In addi-
tion, they also displayed cytotoxicity against both mur-
ine leukemia and human epidermoid carcinoma KB
cells.1 In addition, the extract of Pseudodistoma mega-
larva provided pseudodistomins D–F which were found
to be active in a cell-based assay for DNA damage
induction.2
OH
OH
OH
In view of their promising biological activity, pseudodis-
tomins have attracted extensive synthetic studies.3 In
NH2
NH2
NH2
this article, we report
a practical synthesis of
R
N
H
R
N
H
R
N
H
(2R,4R,5S)-tetrahydropseudodistomin 1. Our primary
objective was to delineate a strategy that would allow
installation of the three asymmetric centers at C-2, C-
4, and C-5 with flexibility so as to enable syntheses of
other stereo analogs as well. The vicinal 1,2-amino alco-
hol functionality and piperidine skeleton are privileged
functionalities and novel methods for their construction
are welcome.
A: R=R1
B: R=R2
F: R=R4
E: R=R2
C: R=R4
D: R=R2
Tetrahydropseudodistomin R=R3 (1)
R1=
R2=
R3=
Accordingly, the retrosynthetic analysis envisioned the
installment of the three stereogenic centers of 1 through
application of a Maruoka asymmetric allylation and a
Sharpless asymmetric dihydroxylation as key reactions,
starting from tetradecanol 4 (Scheme 1).
R4=
Figure 1.
As illustrated in Scheme 2, Swern oxidation of tetradec-
anol 4 gave aldehyde 5, which was subjected to an enan-
tioselective Maruoka allylation by treatment with
titanium complex (R,R)-I and allyltri-n-butyltin using
known reaction conditions4 to afford homoallylic alco-
hol 3 in 86% yield with excellent enantioselectivity,
98% ee (determined by chiral HPLC).5
Keywords: Marouka asymmetric allylation; Sharpless asymmetric
dihydroxylation.
q IICT Communication No. 061121.
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
27160512; e-mail: srivaric@iict.res.in
ꢀ Present address: Centre for Drug Design, University of Minnesota,
Minneapolis, USA.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.143

2374
S. Chandrasekhar et al. / Tetrahedron Letters 48 (2007) 2373–2375
Ozonolysis of the double bond in 7 provided the corre-
OH
sponding aldehyde, which was elaborated by Wittig
olefination to a,b-unsaturated ester 8, obtained as a sin-
gle isomer (E) in 76% yield, ready for the installation of
vicinal chirality. Sharpless asymmetric dihydroxylation
using AD-mix b was explored to generate the C-4, C-5
stereogenic centers and the expected diol 2 was obtained
in good yield and diastereoselectivity (9:1). The diaste-
reomers were easily separated by column chromato-
graphy. The azido group at C-5 was introduced by a
two-step reaction sequence. First, regioselective a-tosyl-
ation7 of diol 2 using TsCl and DIPEA in CH2Cl2 affor-
ded the mono-tosylated product 9, which was treated
with NaN3/DMF to provide azido alcohol 10 in 67%
yield.
NHBoc
n =9
OH
NH2
CO2Et
n
2
N
H
n
OH
1
n =9
OH
OH
n
n
4
3
n =9
n =9
Scheme 1.
Homoallylic alcohol 3 was then converted to the corre-
sponding homoallylic azide 6 via Mitsunobu inversion6
using diphenylphosphoryl azide (DPPA) in 71% yield.
Azido compound 6 was reduced using Staudinger reac-
tion conditions (TPP, THF:H2O) in the presence of
(Boc)2O to provide the N-Boc protected amine 7 in
68% yield.
Completion of the synthesis of 1 and its N,N0,O-triace-
tate 12 involved cyclization of 10 using TFA:DCM
(1:1) to give azidolactam 11 in 87% yield and concomi-
tant reduction of both the azide and amide functional-
ities in 11 using LiAlH4 albeit, in a poor yield. Thus, a
sequential reduction strategy was adopted. Stepwise
O
OH
b
a
c
OH
H
n
n
n
(R,R)-I
4
3
5
n =9
n =9
n =9
N3
NHBoc
NHBoc
e, f
d
CO2Et
n
n
n
7
6
n =9
8
n =9
n =9
NHBoc OH
NHBoc OH
j
i
g
CO2Et
CO2Et
n
n
N3
R
n =9
10
n =9
2
9
R=OH
R=OTs
h
OAc
OH
OH
NHAc
NH2
N3
O
k, l
m
N
N
H
n
N
H
n
n
Ac
1
n =9
n =9
12
11 n =9
O
Oi-Pr
Ti
O
O
O
Ti
i-PrO
O
(R,R)-I
Scheme 2. Reagents, conditions, and yields: (a) (COCl)2, DMSO, CH2Cl2, ꢀ78 °C, 2 h, 87%; (b) (R,R)-I (10 mol %), Bu3SnCH2CH@CH2, CH2Cl2,
ꢀ15 °C to 0 °C, 24 h, 86%; (c) DPPA, TPP, DEAD, THF, 0 °C, 12 h, 71%; (d) TPP, THF:H2O, (Boc)2O, rt, 24 h, 68%; (e) O2, DMS, ꢀ78 °C; (f)
PPh3@CHCO2Et, benzene, rt, 3 h, 76%; (g) AD-mix b, MeSO2NH2, tBuOH–H2O (1:1), 0 °C, 24 h, 78%; (h) TsCl, DIPEA, CH2Cl2, 0 °C, 12 h, 70%;
(i) NaN3, DMF, 60 °C, 6 h, 67%; (j) TFA:DCM (1:1), 0 °C, 3 h, 87%; (k) Pd(OH)2/C, H2, MeOH, rt; (l) BH3ÆTHF, THF, reflux, 12 h; (m) Ac2O,
pyridine, CH2Cl2, 1 h, 55% (for 3 steps).

S. Chandrasekhar et al. / Tetrahedron Letters 48 (2007) 2373–2375
2375
Kiguchi, T. J. Chem. Soc., Perkin Trans. 1 1994, 773–775;
(h) Knapp, S.; Hale, J. L. J. Org. Chem. 1993, 58, 2650–
2651; (i) Naito, T.; Yuumoto, Y.; Ninomiya, I.; Kiguchi, T.
Tetrahedron Lett. 1992, 33, 4033–4036; (j) Utsunomiya, I.;
Ogawa, M.; Natsume, M. Heterocycles 1992, 33, 349–
356.
reduction of 11 with Pd/C, H2 resulted in selective
reduction of the azide to an amine. Amide reduction
to diamino alcohol 1 was achieved using excess (5 equiv)
BH3ÆTHF. Triacetyl derivative 12 was synthesized to en-
able comparison with the known data. Treatment of 1
with Ac2O/pyridine gave triacetate 12,8 which showed
spectral and physical data consistent with the literature
4. (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am.
Chem. Soc. 2003, 125, 1708–1709; (b) Chandrasekhar, S.;
Narsihmulu, Ch.; Sultana, S. S. Tetrahedron Lett. 2004, 45,
9299–9301.
25
23
{½aꢁD 31.6 (c 0.5, MeOH), lit. ½aꢁD 33 (c 1.0, MeOH)}.1a
In conclusion, we have achieved the asymmetric synthe-
sis of (+)-tetrahydropseudodistomin 1 using Maruoka
asymmetric allylation and Sharpless asymmetric dihydr-
oxylation reactions as key steps. Application of the pres-
ent strategy to the asymmetric synthesis of other
pseudodistomins is in progress and will be reported in
due course along with their biological profiles.
5. (a) Homoallyl alcohol 7 was converted to its 4-nitrobenzo-
ate for determination of the ee by chiral HPLC {Chiralcel
OB-H, iPrOH/hexane (1:99), flow rate 0.4 ml/min,
tR = 8.36 (minor), tR = 9.26 (major)}; (b) Chen, J.; Li, Y.;
Cao, X. P. Tetrahedron: Asymmetry 2006, 17, 933–941.
6. Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K.
Tetrahedron Lett. 1977, 23, 1977–1980.
7. Denis, J.-N.; Correa, A.; Green, A. E. J. Org. Chem. 1990,
55, 1957–1980.
8. Representative analytical data: Compound 3: Waxy
25
white solid; ½aꢁD ꢀ5.43 (c 1.1, CHCl3). 1H NMR
Acknowledgements
(300 MHz, CDCl3): d 5.86–5.72 (m, 1H), 5.12 (m, 2H),
3.64–3.54 (m, 1H), 2.31–2.32 (m, 1H), 2.15–2.05 (m, 1H),
1.43–1.38 (m, 2H), 1.35–1.25 (m, 22H), 0.88 (t, 3H,
J = 6.7 Hz). 13C NMR (75 MHz, CDCl3): d 134.9, 118.0,
70.6, 41.9, 36.8, 31.9, 29.6–29.3, (overlapping signals) 25.6,
22.6, 14.1. (ESI-MS): m/z 277 [M+Na]. HRMS calcd for
C17H34ONa: 277.2507 (M++Na), found: 277.2517.
S.S.S. thanks the CSIR, New Delhi and N.K. thanks the
UGC, New Delhi, for financial support and S.C. thanks
the DST, New Delhi, for a grant.
25
References and notes
Compound 11: White solid mp 92–94 °C; ½aꢁD 90.38 (c 0.8,
CHCl3). 1H NMR (300 MHz, CDCl3): d 6.44 (br s, 1H),
4.18–4.13 (m, 1H), 3.96 (d, 1H, J = 3.4 Hz), 3.77–3.71 (m,
1H), 2.54 (m, 1H), 2.18–2.11 (m, 2H), 1.51–1.25 (m, 24H),
0.88 (t, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): d
169.0, 66.0, 62.1, 48.3, 36.3, 33.5, 31.8, 29.6–29.2 (overlap-
ping signals), 25.0, 22.6, 14.0. (ESI-MS): m/z 361 [M+Na].
HRMS calcd for C18H35N4O2: 339.2760 (M++1), found:
339.2774.
1. (a) Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.;
Hirata, Y.; Kobayashi, J. J. Org. Chem. 1987, 52, 450–453;
(b) Kobayashi, J.; Naitoh, K.; Doi, Y.; Deki, K.; Ishibashi,
M. J. Org. Chem. 1995, 60, 6941–6945.
2. Freyer, A. J.; Patil, A. D.; Killmer, L.; Troupe, N.;
Mentzer, M.; Carte, B.; Faucette, L.; Johnson, R. K. J.
Nat. Prod. 1997, 60, 986–990.
3. (a) Haddad, M.; Larcheveque, M.; Tong, H. M. Tetrahe-
dron Lett. 2005, 46, 6015–6017; (b) Trost, B. M.; Fandrick,
D. R. Org. Lett. 2005, 7, 823–826; (c) Langlois, N. Org.
Lett. 2002, 4, 185–187; (d) Kiguchi, T.; Ikai, M.; Shirak-
awa, M.; Fujimoto, K.; Ninomiya, I.; Naito, T. J. Chem.
Soc., Perkin Trans. 1 1998, 893–899; (e) Naito, T.;
Yuumoto, Y.; Kiguchi, T.; Ninomiya, I. J. Chem. Soc.,
Perkin Trans. 1 1996, 281–288; (f) Doi, Y.; Ishbashi, M.;
Kobayashi, J. Tetrahedron 1996, 52, 4573–4580; (g) Naito,
T.; Ikai, M.; Shirakawa, M.; Fujimoto, K.; Ninomiya, I.;
25
Compound 12: Colorless liquid; ½aꢁD 31.6 (c 0.5, MeOH).
1H NMR (500 MHz, CDCl3): d 5.86 (d, 1H, J = 6.6 Hz),
5.14 (m, 1H), 4.91 (br s, 1H), 4.34 (br s, 1H), 3.93 (d, 1H,
J = 14.2 Hz), 3.27 (d, 1H, J = 14.2 Hz), 2.05 (s, 3H), 2.04
(s, 3H), 2.02 (s, 3H), 1.71–1.61 (m, 2H), 1.29 (br s, 24H),
0.88 (t, 3H, J = 6.6 Hz). 13C NMR (75 MHz, CDCl3): d
170.3, 170.0, 169.7, 66.9, 47.6, 47.0, 43.9, 32.0, 30.2, 29.7–
29.2 (overlapping signals), 28.3, 26.3, 23.2, 22.8, 21.8, 21.0,
14.2. (ESI-MS): m/z 447 [M+Na]. HRMS calcd for
C24H44N2O4Na: 447.3198 (M++Na), found: 447.3213.