2
S. K. Gadakh, A. Sudalai / Tetrahedron Letters xxx (2015) xxx–xxx
OMe
O
OMe
O
O
O
O
RO
O
HO
MeO
4,
O
O
1
, R = H, spirolaxine;
2, R = CH3, spirolaxine methyl ether
3
, spiroketal
phthalide fragment
Figure 1. Structure of spirolaxine (1), its methyl ether (2), spiroketal (3) and phthalide unit (4).
OMe
O
OMe
O
O
O
O
O
RO
O
RO
3
O
HO
3
4
1
, R = H, spirolaxine
2, R = CH3, spirolaxine methyl ether
OMe
TBSO
O
Br
TBSO
3
RO
OTBS
O
5
OH
8
O
O
O
BnO
OEt
OEt
6
7
Scheme 1. Retrosynthetic analysis of spirolaxine methyl ether (2).
esters 6 and 7 by Noyori’s chiral reduction strategy and Grignard
reaction. Phthalide fragment 4 could be obtained by Cu-catalyzed
CN-assisted lactonization of chiral alcohol 8 which can be obtained
by Brown allylation of the corresponding 3,5-dimethoxybenzalde-
hyde 21.
synthesized by the asymmetric reduction of commercially
available ethyl acetoacetate 7 using Noyori’s condition {([(R)-Ru
(BINAP)Cl2]2ÁNEt3, 2 M HCl (0.1 mol %), MeOH, H2 (100 psi),
50 °C)} to produce chiral (R)-ethyl 3-hydroxybutyrate 17 in 94%
yield and 98% enantiomeric excess. Its specific rotation was in close
20
agreement with the reported value [
a
]
D
À45.0 (c 1.0, CHCl3); lit.12
20
[a]
À46.0 (c 1.0, CHCl3)]. Secondary hydroxyl functionality in 17
D
Results and discussion
was protected as its silyl ether 18 in 90% yield. The resulting ester
18 was subjected to complete reduction with DIBAL-H at 0 °C to
provide the corresponding alcohol 19 in 85% yield. Now, free
primary hydroxyl group was converted into the corresponding bro-
mide under Appel reaction protocol (CBr4, Ph3P, CH2Cl2, 0 °C) that
provided alkyl bromide derivative 20 in 89% yield11 (Scheme 3).
Both the fragments 16 and 20 were treated under Grignard con-
ditions that resulted in the formation of alcohol in situ, which was
subsequently oxidized using IBX to furnish keto derivative 5 in 75%
yield for two steps, without affecting the silyl ether functionality.
Finally, acid catalyzed cyclization of keto derivative 5 to spiroketal
moiety 3 was achieved in 76% yield following the literature proto-
col.9f Its specific rotation value was in complete agreement with
The formal synthesis of spirolaxine methyl ether 2 was com-
menced with the construction of the key chiral intermediate
spiroketal 3, which was synthesized from commercially available
1,5-pentanediol (9). Selective benzylation of
9 resulted in
monobenzyl ether 10 in 89% yield followed by its oxidation using
TEMPO and di(acetoxyiodo)benzene conditions furnished aldehyde
11 in 95% yield. Noyori’s asymmetric reduction is a very useful tool
for the chiral reduction of b-keto esters giving b-hydroxy esters in
high enantioselectivity.10
In view of this, we have planned our synthesis to achieve the
chiral b-hydroxy ester 13. Thus, we have treated benzyl protected
aldehyde 11 with ethyl bromoacetate under Reformatsky reaction
conditions (Zn, NH4Cl, THF, 0 °C) that furnished racemic b-hydroxy
ester 12 in 90% yield followed by its oxidation using IBX provided
precursor b-keto ester 6 in excellent yield (87%).
Now, racemic b-keto-ester 6 was subjected to asymmetric
reduction using Noyori’s catalytic conditions: {[(R)-Ru(BINAP)
Cl2]2ÁNEt3, 2 M HCl (0.1 mol %), MeOH, H2 (100 psi), 50 °C} to afford
the corresponding chiral b-hydroxyester 13 with excellent yield
(95%) and enantiopurity (96% ee by chiral HPLC analysis). The
reduction of ester 13 with LiAlH4 resulted in the formation of chiral
1,3-diol 14 in 90% yield. Further, protection of diol 14 as silyl ether
followed by deprotection of benzyl ether to the corresponding
alcohol and its oxidation to aldehyde 16 has been achieved follow-
ing the literature procedure9f (Scheme 2).
+65.2 (c 1.0, CHCl3); lit.9f
[a
]
D
+65.4 (c
20
20
the literature value {[
a
]
D
1.0, CHCl3)} (Scheme 4).
Having synthesized spiroketal 3, our next task was to undertake
the preparation of the phthalide precursor 4, which was crucial for
the total synthesis of spirolaxine methyl ether 2. Recently, we have
developed a general single step protocol for the synthesis of phtha-
lide unit by a simple annulation using CuBr as catalyst and NaCN as
C1 source in stoichiometric amounts.13 This simple synthetic
methodology has been utilized in the synthesis of phthalide precur-
sor 4. Thus, regioselective ortho bromination of 3,5-dimethoxyben-
zaldehyde 21 with NBS gave 2-bromo-3,5-dimethoxybenzaldehyde
followed by its Brown allylation using (À)-Ipc2B(allyl)borane at
À78 °C afforded bromo allylic alcohol 8 in excellent yield and good
enantiomeric excess (89% yield; 87% ee). The Cu(I)-mediated
displacement of bromide with cyanide was achieved using NaCN
With aldehyde fragment 16 in hand, we have turned our
attention toward the synthesis of alkyl fragment 20, which was