Stereoselective synthesis of anti-1,3-diol units via Prins cyclisation: application to the synthesis of (-)-sedamine

Article abstract of DOI:10.1016/j.tetlet.2006.04.102

The scope of the Prins cyclisation, the higher stereoselective synthesis of multisubstituted tetrahydropyrans from aldehydes and homoallylic alcohols, is expanded. A new approach for the stereoselective synthesis of polyketide precursors containing anti-1

Full text of DOI:10.1016/j.tetlet.2006.04.102

Tetrahedron Letters 47 (2006) 4397–4401
Stereoselective synthesis of anti-1,3-diol units via Prins
cyclisation: application to the synthesis of (ꢀ)-sedamine
J. S. Yadav,* M. Sridhar Reddy, P. Purushothama Rao and A. R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received 6 March 2006; revised 11 April 2006; accepted 20 April 2006
Available online 15 May 2006
Abstract—The scope of the Prins cyclisation, the higher stereoselective synthesis of multisubstituted tetrahydropyrans from alde-
hydes and homoallylic alcohols, is expanded. A new approach for the stereoselective synthesis of polyketide precursors containing
anti-1,3-diols, flanked by a variety of alkyl branches and functional groups is described. The approach is successfully exploited for
the synthesis of (ꢀ)-sedamine.
Ó 2006 Elsevier Ltd. All rights reserved.
OH
1,3-Diol moieties occur as important subunits in a num-
R1
+
R1
R2
ber of biologically active polyketide natural products
and intermediates used for the synthesis of complex
molecules.1 Synthetic access to such subunits has long
been a challenge for synthetic chemists, and a variety
of methodologies have been developed for the synthesis
of 1,3-diols.2 Herein we report a diastereoselective
and convergent approach to the synthesis of such
moieties via highly stereoselective Prins cyclisation
followed by reductive ring opening and have successfully
utilised the method in the synthesis of an alkaloid,
(ꢀ)-sedamine.
OP OH
R2
O
R2
OH
O
1
R
R
2
R1
R1=H
OP OH
OH
R2=Ph
R2
Ph
N
3
4
Me
R1
Scheme 1.
Scheme 2 depicts the synthesis of anti-1,3-diol motifs
present in general structures 2 and 3. Prins cyclisation
using homoallylic alcohol 5 and various aldehydes
resulted in multi substituted pyrans 7 in the presence
of trifluoroacetic acid (TFA)3a in DCM followed by
hydrolysis of the resulting crude trifluoroacetate with
K2CO3 in MeOH. The predominant isomers were iso-
lated by flash column chromatography and were found
to have all substituents in equatorial positions.3a,4a
The 1H NMR spectra of the crude products showed
2–5% of other diastereomers.
Prins cyclisation is effective and useful in the stereoselec-
tive synthesis of tetrahydropyrans (THPs),3 with com-
plex substitution patterns and has been successfully
utilised in the synthesis of several natural products.4
We recently developed a general route to b-hydroxy
d-lactones via Prins cyclisation4a and have begun to ex-
plore the potential of the reaction in the synthesis of acy-
clic frameworks useful in polyketide synthesis. In this
report, we have further extended the scope of the Prins
cyclisation to the synthesis of various polyketide precur-
sors containing anti-1,3-diol units from a common pyr-
an system 1 (Scheme 1). The salient features of our
strategy are: synthesis of 1- or 6-pyranyl methanols from
homoallylic alcohols and aldehydes and iodomethyl- or
chloromethyl-mediated reductive opening of pyrans.
Pyrans 7 were protected either as MOM ethers using
MOM chloride, DMAP and DIPEA as base in DCM
or TBS ethers using TBS chloride, DMAP and imid-
azole, followed by debenzylation using Na or Li in
liquid NH3 to obtain 6-pyranyl methanols 9. Alcohols
9 on treatment with TPP, I2 and imidazole in benzene
gave iodo compounds 10 which on reductive opening
with Zn in refluxing EtOH5 delivered 1-alkenyl anti-
4,6-diols 11.
Keywords: Polyketide; 1,3-Diol; Prins cyclisation; Tetrahydropyrans.
*
Corresponding author. Fax: +91 40 27160512; e-mail: yadavpub@
iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.102

4398
J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 4397–4401
OH
OP
OP
O
R1
R2
R = Bn
ii, iii
R1
R2
R1
R2
R2CHO
i
vi
R1
RO
RO
HO
Cl
OH
O
O
R = Bn, 7
R = H, 8
9
R = Bn, 5
R = H, 6
12
viii
R = H
iv
vii
OP OH
OP
OP
OH
R1
R2
R1
R2
R1
R2
ii
R2
TsO
I
TsO
O
16
O
10
O
14
R1
13
ix, v
ix, v
v
OP OH
OH OH
OP OH
R2
R2
R2
17
R1
R1
R1
15
11
Scheme 2. Reagents and conditions: (i) TFA, rt, 2–3 h then K2CO3, MeOH, rt, 15 min (ii) MOMCl, Hunig’s base, CH2Cl2 or TBSCl, imidazole,
0 °C–rt, 3–4 h (iii) Li or Na in liquid NH3, 3–5 min (iv) TPP, I2, imidazole, 0 °C–rt, 1–2 h (v) Zn, EtOH, reflux, 1 h (vi) TPP, NaHCO3, CCl4, reflux,
1 h (vii) LiNH2, liquid NH3, or LDA, ꢀ78 °C, 1–2 h (viii) TsCl, TEA, 0 °C–rt, 3–4 h (ix) NaI, acetone, reflux, 24 h.
Alternatively, pyranyl methanols 9, when exposed to
TPP and NaHCO3 in refluxing CCl4 produced chloro
compounds 12 which on subjection to LiNH2 or LDA
underwent reductive opening6 furnishing 1-alkynyl
anti-4,6-diols 13. The results are shown in Table 1.
The primary hydroxy group of 8 was tosylated using
1.1 equiv of tosyl chloride and TEA in DCM to produce
14. Treatment of tosylates 14 with NaI in refluxing ace-
tone gave the corresponding iodo compounds, which on
treatment with Zn in refluxing ethanol underwent reduc-
tive opening to furnish 15 with both the hydroxy groups
unprotected.
Having succeeded in preparing partially protected anti-
1,3-diol systems, we sought a route for the synthesis of
unprotected anti-1,3-diols. To achieve this, we selected
the homoallylic alcohol 6, which on subjection to Prins
cyclisation with several aldehydes produced diols 8.
We also synthesised partially protected 1-alkenyl anti-
4,5-diols in a similar way. After tosylation of the pri-
mary alcohol of 8, the secondary alcohol was protected
Table 1. Synthesis of anti-1,3-diol frameworks via Prins cyclisation
Homoallylic alcohol
Aldehyde
Product
Overall yield (%)
55
OMOMOH
BnO
Me
CHO
Et
5a
OH
11a
Me
OMOM OH
5a
53
CHO
11b
Me
OMOM OH
O
OBz
5a
33
53
50
45
OMOM
Me
11c
Me
Me
Et
OMOM OH
BnO
CHO
5b
OH
11d
OMOM OH
5b
n-C11H23CHO
n-C11H23CHO
n-C11H23
11e
OTBS OH
5b
n-C11H23
11f

J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 4397–4401
4399
Table 1 (continued)
Homoallylic alcohol
Aldehyde
Product
Overall yield (%)
OMOMOH
5a
5b
35
42
CHO
Et
Et
13a
Me
OMOMOH
CHO
13b
OMOMOH
5b
n-C11H23CHO
40
30
40
42
35
38
n-C11H23
13c
OTBS OH
5b
n-C11H23CHO
n-C11H23
13d
OH
OH
OH
HO
Me
CHO
Et
OH
6a
6b
15a
Me
OH
HO
n-C6H13
CHO
Et
OH
15b
n-C6H13
OH
OH
HO
n-C11H23CHO
n-C11H23
OH
6c
15c
OH
OH
6c
PhCHO
Ph
15d
OMOMOH
6b
6c
38
35
CHO
Et
17a
n-C6H13
OMOMOH
PhCHO
Ph
17b
either as its MOM ether or its TBS ether to give 16,
which, with NaI in refluxing acetone, afforded the corre-
sponding iodo compound. Reductive opening with Zn in
refluxing ethanol gave the partially protected 1,3-diol
systems 17. The results are summarised in Table 1.
The homoallylic alcohols used were racemic and hence
the products are racemic but diastereomerically pure.
One could obtain the enantiomerically pure products
by using enantiopure homoallylic alcohols.3a,4a
a large family of compounds, many of which exhibit a
wide range of physiological activities, hence much effort
has been devoted to the isolation and structure determi-
nation of such bases and to the development of general
methodologies and routes for their synthesis.7 Sedamine
4 was the first alkaloid isolated from Sedum acre8 and
was obtained later from a number of other Sedum spe-
cies.9 Both levorotatory (ꢀ)-sedamine and its enantio-
mer were found in all of the Sedum species mentioned
above. Numerous syntheses of sedamine have been
reported either in racemic form10 or as a single
enantiomer.11
Finally, having established a general route for the stere-
oselective synthesis of anti-1,3-diol frameworks, we
turned our attention to prove its practicality and thus
extended the method to the synthesis of a piperidine
alkaloid, (ꢀ)-sedamine 4. Piperidine alkaloids constitute
Our synthesis, as summarised in Scheme 3, commenced
from (R)-benzyl glycidyl ether 18.12 Reaction with

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J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 4397–4401
CH2=CHMgBr, CuCN
Li, Liq.NH3
20 min
PhCHO, TFA then
K2CO3, MeOH, rt, 3 h
-78 oC to -40 ºC 4 h
BnO
BnO
HO
O
75%
92%
18
19
52%
20
OH
OH
OTBS
OH
a) NaI, acetone
reflux, 24 h.
OTBS
OH
TEA, TsCl, DCM then
imidazole, DMAP, TBSCl
Ph
0 oC-rt, 3 h
95%
OTs
b) Zn, EtOH
reflux, 1 h
OH
Ph
O
23
Ph
O
21
22
90% (2 steps)
O3, TPP, DCM
a) LiAlH4, THF
0 oC-rt, 2 h
OMOMOTBS
MOMCl, base
0 oC-rt, 4 h
O
OMOM OTBS
then (Ph)3PCHCO2Et
Ph
b) TBAF, THF
0 oC-rt, 4 h
78% (2 steps)
100%
OEt
Ph
78%
24
25
TEA, DMAP, MsCl
0 oC then MeNH2, DMF
reflux, 7 h
Me
OMOM
Me
OH
OMOMOH
HCl, CH3CN,
NaHCO3, rt, 4 h
N
N
OH
Ph
96%
75%
Ph
Ph
26
27
4
Scheme 3.
vinylmagnesium bromide in the presence of CuCN gave
homoallylic alcohol 19, which on treatment with Na or
Li in liquid NH3 underwent debenzylation producing
diol 20. Subjection of 20 and benzaldehyde to Prins cyc-
lisation in the presence of TFA in DCM followed by
hydrolysis of the resulting crude trifluoroacetate with
K2CO3 in MeOH yielded trisubstituted pyran 21. Tosyl-
ation with 1.1 equiv of tosyl chloride in the presence of
TEA in DCM produced the corresponding primary
tosylate which was protected in situ as TBS ether 22
by adding imidazole and TBS chloride to the reaction
medium. Compound 22 on exposure to NaI in refluxing
acetone gave the corresponding iodide which reacted
with Zn in refluxing EtOH to furnish key intermediate
23 with the required anti-1,3-diol system. The newly
created benzyl alcohol of 23 was protected as its
MOM ether 24 in the presence of DIPEA and MOM
chloride in DCM.
works through highly stereoselective Prins cyclisation
and reductive ring opening of pyrans. Proving its practi-
cality, the method was successfully utilised in a synthesis
of an alkaloid, (ꢀ)-sedamine. Further applications of
this methodology are in progress and the results will
be disclosed in due course.
Acknowledgements
M.S.R. thanks CSIR, New Delhi, for the award of
fellowship.
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lit.11h 58–60 °C; ½aꢁD ꢀ83.0 (c 1.40, EtOH), [lit.11h ½aꢁD
ꢀ86.8 (c 1.10, EtOH)]; IR (KBr): mmax 3357, 2932, 2855,
1451, 1363, 1061, 756, 701 cmꢀ1 1H NMR (200 MHz,
;
CDCl3): d 7.20–7.42 (m, 5H), 4.89 (dd, 1H, J = 10.6,
2.6 Hz), 4.70 (br s, 1H), 3.1 (m, 1H), 2.9 (m, 1H), 2.57 (m,
1H), 2.51 (s, 3H), 2.12 (m, 1H), 1.2–1.81 (m, 7H); 13C
NMR (75 MHz, CDCl3): d 20.7, 22.2, 25.9, 39.3, 39.8,
52.4, 61.2, 73.4, 125.4, 127.2, 128.3, 144.7. ESIMS: 220
(M+1)+. HRMS m/z calcd for C14H22NO [M+H]+
220.1701, found 220.1738.