2
K. R. Ganesh et al. / Tetrahedron Letters xxx (2016) xxx–xxx
OH
In a similar way hydroxy-c-butyrolactones have been widely
O
O
HO
O
used as chiral synthons in the synthesis of several biologically
active molecules. There are several approaches reported in the lit-
erature for the synthesis of key starting material, lactone 6, specif-
ically with (3S,4R) absolute configuration and the structural
similarities are observed between this lactone and PGE2. An enan-
tioselective synthesis of 6 was developed starting with protected
R-glyceraldehyde (10).
O
O
O
O
HO
HO
O
O
HO
HO
HO
OH
OCH3
OCH3
1
2a
Vittrilide-A (
)
OH
O
O
O
HO
OH
O
HO
Thus the synthesis of 6 began with protected R-glyceraldehyde
(10). The latter was subjected to allylation under the standard con-
ditions using Zn dust and allyl bromide in THF, the 11 hydroxy ole-
fin anti and syn was obtained as diastereomeric mixture (dr = 96:4,
93% yield).9 Thus obtained secondary alcohol (11) was protected as
corresponding p-methoxy benzyl ether (12).7 The required PMBBr
for OH protection of 11 was synthesized using the literature proce-
dure4 and proceeded for OH protection, however due to the unsta-
ble PMBBr, 12 was obtained in 54% of yield against 75%, reported in
the literature. Then the terminal olefin of compound 12 was dihy-
droxylated using OsO4 and the corresponding diol in situ was oxi-
dized to aldehyde (13).10 The aldehyde was oxidized under Pinnick
oxidation conditions to afford the corresponding carboxylic acid
(14).11 As reported in the literature for Pinnick reaction the reac-
tion mass was quenched with 2-methyl-2-butene which afforded
the product in good yield. Finally the carboxylic acid 14 was lac-
tonized to afford compound 6. Initially under the catalytic amount
of camphor sulfonic acid12 the acetonide deprotection resulted in
diol intermediate and eventually the secondary alcohol displaced
the OH of carboxylic acid to cyclize as per the Baldwin rules in 5-
exo-trig to afford compound 6 in an overall yield of 28% over 5
steps starting from compound 10 (Scheme 2).
HO
PGE2 prostaglandin (
OH
Ferulic acid (3)
4
2b)
O
O
HO
OH
O
PMBO
PMBO
OCH
35
6
Figure 1.
product from commercially available (R)-2,2-dimethyl-1,3-diox-
olane-4-carbaldehyde as an inexpensive chiral pool material. In
the present work, herewith we reported the successful first total
synthesis and absolute stereo chemical assignment of 1.
Results and discussion
The synthesis of 5-O-feruloyl-2-deoxy-
was commenced by coupling reaction of two key intermediates
protected Ferulic acid (5) and -ribono lactone (6). The synthesis
D-ribono-c-lactone (1)
D
of 5 was achieved as per the literature procedure via O-PMB pro-
tection, wherein o-benzyl protection is reported. The reaction con-
ditions for O-PMBBr preparation was optimized using p-methoxy
benzyl alcohol and PBr3,4 then subsequently it was subjected
in situ to O-PMB protection.5
After successful synthesis of optically pure compound 6, it was
coupled with ferulic acid derivative 5 using EDCꢀHCl, HOBT, and
DMAP as base. This resulted in the formation of a novel intermedi-
ate 2-deoxy-D-ribono-c-lactone cinnamic acid derivative (15) in
trans-Cinnamic acids are useful synthons in organic chemistry
and are part of several industrial products. Notably these are
required in the production of cosmetics and hair protection agents.
Because of these significant uses in industry as well as organic syn-
thesis, there has been considerable interest for developing facile
and efficient processes for their production. Several methods have
been reported for synthesis of cinnamic acids, prominent of which
the Claisen–Schmidt condensation of aldehydes with acetates,6 the
Knoevenagel reaction of aldehydes with malonic acid,7 the Wittig
64% of yield. The compound was characterized by spectral data
such as 1H NMR, 13C NMR, Mass analysis, and IR. Further the com-
pound 15 was subjected to O-PMB deprotection, the deprotection
was screened with various conditions using DDQ13 as oxidizing
agent. Attempted various solvents and solvent combinations such
as DCM, acetonitrile, and buffer conditions, but the reaction did
not proceed. Further the deprotection was carried out using ceric
ammonium nitrate14 in water and acetonitrile, unsuccessful results
were observed. Therefore attempted a combination of Mn(OAc)3
and DDQ15 in DCM and observed deprotection O-PMB of lactone
but aromatic O-PMB remained intact. Finally attempted Marcantoni
conditions for selective deprotection of p-methoxy benzyl ether
using CeCl3ꢀ7H2O and NaI.16 Initially aliphatic deprotection prefer-
ably was observed and further during the course of the reaction
both aliphatic and aromatic deprotection was observed in 90:10
ratio in 1 h. Further when it was continued for 24 h a 30:70 ratio
reaction of aldehydes with a phosphorus ylide derived from a-bro-
moacetate and also there are other simple and efficient approaches
reported in the literature. But for now we required this trans-cin-
namic acid as a key intermediate in the total synthesis of com-
pound 1. Hence we have utilized Wittig chemistry8 followed by
O-PMB protection and saponification and synthesized the O-PMB
protected ferulic acid (5) in three steps with overall 40% yield
(Scheme 1).
Me
Me
Me
Me
Me
Me
O
O
a
b
O
O
O
O
O
CHO
CHO
Me
OH
11
OPMB
12
a
OCH2CH3
b
10
HO
HO
OCH3
Me
Me
OCH3
c
Me
7
8
O
O
O
O
O
e
HO
d
c
O
O
O
OCH2CH3
OH
COOH
OPMB
14
CHO
OPMB
PMBO
PMBO
PMBO
13
6
OCH3
OCH3
9
5
(a) Zn, allyl bromide, THF, 0°C, 2h, 93%; (b) PMB-Br, NaH, THF, rt, 2h, 54%;
(c) OsO4, Toluene, Pb(OAc)4, rt, 3h, 83%; (d) NaClO2, Phosphate buffer, t-butanol,
2-Methyl-2-butene, rt, 2h, 88%; (e) CSA, DCM:MeOH (10:1), rt, 1h, 75%.
(a) PPh3=CH-COOEt, Toluene, reflux, 4h, 95%; (b) PMB-Br, NaH,
DMF, 0°C to rt, 2h, 56%; (c) NaOH, MeOH,65°C, 4h, 75%.
Scheme 1. Synthesis of compound 5.
Scheme 2. Synthesis of compound 6.