2-Arylcyclopropylmethanol as a substitute for homoallyl aryl alcohol in the construction of cis-2,6-disubstituted tetrahydropyran: Synthesis of (±)-centrolobine

Article abstract of DOI:10.1039/c4cc07796b

The application of 2-arylcyclopropylmethanols as substitutes to homoallyl aryl alcohols and their reactions with aliphatic aldehydes in the presence of SnCl₄ in CH₂Cl₂ leads to an efficient Prins cyclization to generate cis-2,6-disubstituted tetrahydropyrans in high yields. The reaction is free from 2-oxonia-Cope rearrangement. This protocol was used to synthesize (±)-centrolobine in an overall 84% yield over three steps. The protocol holds promise for scaffold generation for medicinal chemistry exploitation. This journal is

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ARTICLE TYPE
2
-Arylcyclopropylmethanol as a substitute for homoallyl aryl alcohol in
the construction of cis-2,6-disubstituted tetrahydropyran. Synthesis of
(±)-centrolobine
a
a
a
b
Veejendra K. Yadav,* Ashish K. Verma, Piyush Kumar and Vijaykumar Hulikal
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
,7a
The application of 2-arylcyclopropylmethanols as a substitute
to homoallyl aryl alcohols and their reactions with aliphatic
agreement with the literature.
Thus, we achieved a facile
synthesis of (±)-centrolobine in 84% yield over three steps in
aldehydes in the presence of SnCl4 in CH Cl leads to an 50 commencing from the cyclopropyl methanol 4 and the aldehyde
2
2
5
. The equatorial orientation of the chlorine atom in 3 was
1
0
efficient Prins cyclization to generate cis-2,6-disubstituted
tetrahydropyrans in high yields. The reaction is free from 2-
oxonia-Cope rearrangement. This protocol was used to
synthesize (±)-centrolobine in an overall 84% yield over three
steps. The protocol holds promise for scaffold generation for
medicinal chemistry exploitation.
ascertained spectroscopically from the observation that the proton
on C4 exhibited a coupling constant of 11.6 Hz due to axial-axial
coupling. This was confirmed further from a single crystal X-ray
structure of 3 (see ESI).
55
1
5
O
O
c
The Prins cyclization is a versatile method for construction of
MeO
Cl
OH
MeO
OBn
OBn
(
±)-1
2
1
the tetrahydropyran ring which is featured in a variety of
2
biologically active natural products. It involves the union of a
CH OH
O
2
homoallyl aryl alcohol and a carbonyl compound in the presence
of a Lewis acid. We have previously reported the reaction of 2-
tert-butyldiphenylsilylmethyl-1-phenylcyclopropyl methanol with
+
b
O
a
MeO
2
2
3
3
4
4
0
5
0
5
0
5
5
MeO
3
OBn
4
carbonyl species in the presence of CF CO H in Prins fashion to
3
2
Scheme 1. Retrosynthesis of (±)-centrolobine. Reagents and reaction
o
generate trifluoroacetates which hydrolyzed to the corresponding
alcohols during the aqueous workup and resulted in the formation
4 2 2
conditions: (a) SnCl , CH Cl , 0 C, 60 min, 95%. (b) n-Bu
3
SnH, AIBN,
6
0
2
toluene, reflux, 2 h, 95%. (c) H , 5 mol% Pd-C, MeOH, 2 h, 98%.
3
of cis-2,6-disubstituted 4-hydroxytetrahydropyrans. We noticed
+
an excellent opportunity in this protocol to construct centrolobine
CH OH
+
2
O
OBn
OBn
1
and the associated analogs. (-)-Centrolobine is a crystalline
MeO
MeO
antibiotic isolated from the heartwood of Centrolobium
MeO
MeO
7
3
4
6
4
5
robustum and stem of Brosinum potabile found in the Amazon
forest. Its absolute configuration was elucidated as 2(S),6(R) from
6
O
OBn
O
its first enantioselective total synthesis. Since then, several
+
Cl
enantioselective and racemic syntheses of centrolobine have
7
MeO
appeared. (-)-Centrolobine shows activity against Leishmania
8
amazonensis promastigotes which has been identified as a major
health risk in Brazil.
Scheme 2. The stepwise progress of the Prins cyclization
We considered replacing CF CO H by SnCl in the hope that this
3
2
4
The overall reaction is likely to proceed through the stable
will introduce a chlorine atom in place of the trifluoroacetoxy
group which could be removed by reductive dechlorination. The
retrosynthetic analysis of our synthetic plan is shown in Scheme
1. Indeed, the union of trans-2-(p-mehoxyphenyl)cyclopropyl
65
benzylic cation 6 which is formed from 4 under the Lewis acid
3
,10
action of SnCl4.
A combination of this cation with 3-(p-
benzyloxyphenyl)propanal 5 will be expected to generate the
oxocarbemium ion 7 which undergoes Prins cyclization followed
8
7g,9
methanol 4 and 3-(p-benzyloxyphenyl)propanal 5
in dry
o
by capture of the resultant cyclohexyl cation 8 by SnCl
-derived
4
CH Cl in the presence of SnCl4 at 0 C generated the 4-
2
2
70
chloride ion to form the 4-chloro-2,6-disubstituted
tetrahydropyran species 3. The entire process is shown in a
stepwise manner in Scheme 2.
chlorotetrahydropyran derivative 3 in 95% yield. Reductive
dechlorination on reflux with n-Bu SnH in toluene furnished 2 in
3
95% yield. Finally, debenzylation of 2 under hydrogenation
conditions produced the racemic centrolobine in 98% yield. The
physical and spectroscopic data obtained for (±)-1 were in full
Alternatively, 4 may combine with 5 in the presence of SnCl to
4
generate the hemiacetal 9, as shown in Scheme 3. The hemiacetal
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1
4
9
can then dehydrate and generate the oxocarbenium ion 10.
an extensive orbital overlap which places the hydrogen at C4 in
the pseudoaxial position and allows a nucleophilic attack along
Cleavage of the cyclopropane’s bond in 10 under the strong
C-C
electron-withdrawing effect of the oxocarbenium ion may now 45 the equatorial trajectory to deliver the observed tetrahydropyran
lead to the formation of the cation 6, and the aldehyde 5 is
regenerated but only to react again with 6 in the manner as
outlined in Scheme 2. This pathway entails dual role of the
3. In 14, the equatorial electron pair orbital on the ring oxygen is
antiperiplanar to and that are rendered electron-
deficient for the positive charge on C4. This premise results in
electron-donation from the electron pair orbital on oxygen to the
5
C2-C3
C5-C6
aldehyde: (a) activation of
bond in cyclopropyl methanol for
C-C
its smooth cleavage and (b) reaction with the cation 6 to form the 50 above two ring
bonds to enable them to stabilize the
1
5
Prins product.
equatorially disposed empty orbital on C4.
OH
OMe
OMe
OMe
CH OH
R
R
OBn
OBn
2
OBn
O
O
+
R
O
MeO
MeO
+
Cl-
3
4
5
9
2
1
O
O
O
6
Cl
5
H 4
H
R
O
13
14
3
+
+
MeO
MeO
Scheme 5. The stereochemical course of the Prins cyclization
10
6
5
The oxocarbenium ion 7 may alternatively be expected to
R = p-BnOC H CH
1
0
6
4
2
7a,16
55
rearrange in 2-oxonia-Cope fashion
to generate yet another
oxocarbenium ion 15 which, on hydrolysis, will lead to the
formation of p-methoxybenzaldehyde 16 and 1-(p-
benzyloxyphenylethyl)-3-buten-1-ol 17, as shown in eqn 1. Now,
the reaction of 16 with the cyclopropyl alcohol 4 in the manner as
60 in Scheme 2 will be expected to generate the symmetrical
tetrahydropyran derivative 18, as depicted in eqn 2. Likewise, the
reaction of 3-(p-benzyloxyphenyl)propanal 5 with the above
generated 1-(p-benzyloxyphenylethyl)-3-buten-1-ol 17 will lead
to the formation of yet another symmetrical tetrahydropyran
Scheme 3. An alternate pathway for the formation of cation 6 required for
the Prins cyclization
+
Cl SnO OH
SnCl /CH Cl
4
4
2
2
4
+
5
0 o
C
MeO
11
.
.
+
.
.
O
OH
O
65
derivative 19, as expressed in eqn 3.
Cl-
3
R2
R2
R2
MeO
12
MeO
7
+
+
1
5
Scheme 4. Another pathway for the Prins cyclization involving cleavage
of the cyclopropane bond under intramolecular S 2 attack by oxy anion
O
O
O
HO
+
(1)
N
R1
R1
R1
7
15
16
17
In yet another approach, the reaction may be considered to
proceed by following the steps shown in Scheme 4. The
combination of 4 and 5 may generate 11 under the Lewis acid
action. Intramolecular reorganization, including cleavage of the
cyclopropane bond under nucleophilic attack of the oxy anion, as
shown, will generate the hemiacetal 12. This hemiacetal may then
dehydrate under the acidic conditions of the reaction to form the
key oxocarbenium species 7 required for the Prins cyclization and
generate 3 as shown in Scheme 2. Obviously, this pathway offers
an excellent scope to generate chiral tetrahydropyrans from chiral
cyclopropyl methanol substrates.
R1
O
O
CH OH
+
+
R1
2
(2)
(3)
R1
R1
Cl
2
2
3
3
4
0
5
0
5
0
16
4
R2
18
R2
O
HO
O
R2
R2
Cl
5
17
19
1
2
R = p-MeOC H , R = PhCH OC H CH CH
6
4
2
6
4
2
2
Scheme 6. The 2-oxonia-Cope rearrangement leading to the formation of
symmetrical tetrahydropyran products
In the event that an 82:18 enantiomeric mixture of the
1
1
cyclopropyl methanol 4 was reacted with 5, a racemic mixture
of 3 was obtained. Clearly, the reaction did not follow the
To our pleasant surprise, 18 and 19 were not formed. Thus, the
pathway shown in Scheme 4. The pathways shown in Schemes 2 70 present protocol to generate the tetrahydropyran skeleton from 2-
and 3 are, therefore, the obvious pathways for the present Prins
arylcyclopropyl methanol is free from 2-oxonia-Cope
rearrangement which has previously been demonstrated to have
plagued many efforts in assembling the said skeleton via the Prins
pathway by using a homoallyl aryl alcohol as the starting
reaction. The enantiomeric compositions of both 3 and 4 were
1
2
ascertained by chiral HPLC.
The factors that control the stereochemical outcome of the above
Prins reaction are two-fold. The intramolecular ring closure of an 75 substrate.
7
a,7d,17
The 2-oxonia-Cope rearrangement has been
alkene onto an oxocarbenium ion proceeds through a chair
transition state resembling 13, as shown in Scheme 5, wherein (i)
the C2 substituent occupies a favorable equatorial position and
the (E)-oxocarbenium ion geometry is preferred over the (Z)-
oxocarbenium ion geometry, leading to the tetrahydropyranyl 80 the present.
cation 14 and (ii) the stereocenter formed at C4 is controlled by
Other researchers have previously used the Prins cyclization of
known to be facilitated by electron-donating substituents, such as
7
a
the methoxy group in the present instance, on the aryl ring. The
genesis of the observed reaction selectivity which excludes
completely the 2-oxonia-Cope rearrangement is not understood at
1
3
2
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7
b,18
8c
homoallyl aryl alcohols,
cross metathesis-cum-reductive
diastereoselective ring rearrangement
metathesis, hetero-Diels-Alder reaction and acid-catalyzed
yield. Thus, commencing from the commercially available p-
anisaldehyde, we have achieved the synthesis of (±)-centrolobine
45 in 67% yield over six steps in all.
7
b,c
etherification,
1
9
20
21
7
g,22
or oxidative
intramolecular etherification as the key steps in
a
MeO
CHO
MeO
5
0
5
0
the synthesis of molecules with tetrahydropyran as the core
skeleton. The use of a 2-aryl-substituted cyclopropyl carbinol as
an in situ substitute for the corresponding homoallyl aryl alcohol
required for the Prins cyclization is a new approach which offers
great promise for the synthesis of a diverse scaffold of
compounds containing tetrahydropyran as the core skeleton for
medicinal chemistry exploitation.
CO Et
2
30
31
b
c
MeO
MeO
CH OH
CH OH
2
2
32
4
Scheme 7. Reagents and reaction conditions: (a) (EtO)
NaH, THF, 0–30 C, 2 h, 94%. (b) DIBAL, toluene, -78–0 C, 3 h, 95%.
2
POCH
2 2
CO Et,
1
1
2
o
o
o
(
2 2 2 2 2
c) CH I , Et Zn, CH Cl , -23 C, 5 h, 90%.
In a rapid deployment of the present methodology, we have
reacted the alcohol 4 with -phenylacetaldehyde 20 and isolated
the 4-chlorotetrahydropyran derivative 21 in 96% yield, eq 4.
Reductive removal of the chlorine atom furnished 22 in 95%
50
In application of the Prins cyclization pathway, the following
syntheses are notable. In a successful attempt to prevent the 2-
oxonia-Cope rearrangement, Rychnovsky commenced with p-
tosyloxybenzaldehyde and synthesized (–)-centrolobine over
yield. The alcohol
methylenedioxyphenyl)acetaldehyde
4
was also reacted with
23 to isolate
-(3,4-
the
7
a
seven steps in 30% overall yield. Lee and Loh have commenced
tetrahydropyran derivative 24 in 95% yield, eq 5. In efforts to 55 from 3-(p-hydroxyphenyl)propanol and synthesized (–)-
7
e
vary the aryl substituent on the cyclopropane ring, the alcohols
centrolobine in 27% overall yield over six steps. The synthesis
involved asymmetric allylation. Dziedzic and Furman used p-
tosyloxybenzaldehyde and 4-(p-benzyloxy)butene as the reactants
8
c
25 and 28 were reacted with the aldehydes 26 and 5 to isolate
2
7 and 29 in 96% and 94% yields, respectively, eqs 6 and 7.
7
h
and synthesized (–)-centrolobine in 10% yield over nine steps.
R
6
0
The synthesis used Sharpless asymmetric dihydroxylation and
hydrostannylation as the key steps. Zhou and Loh have
synthesized (±)-centrolobine in 58% yield over three steps. The
CH2OH
+
(4)
OHC
O
MeO
OMe
18b
4
4
20
2
2
1, R = Cl, 96%
2, R = H, 95%
synthesis employed the reaction of 4-hydroxy-6-(p-
hydroxyphenyl)hexene with p-MeOC H CHO in the presence of
Cl
6
5
CH2OH
CH2OH
O
O
O
+
+
(5)
(6)
65 TMSBr to generate the 4-bromo derivative of (±)-centrolobine.
Reductive removal of bromine with the use of NaBH -InBr
OHC
O
95%
96%
O
24
MeO
Cl
23
4
3
OMe
Cl
generated (±)-centrolobine. Thus, in comparison, the present
synthetic protocol is better than most previously known syntheses
using the Prins cyclization strategy. Additionally, the present
protocol avoids the undesirable 2-oxonia-Cope rearrangement
which makes isolation of the pure desired product very simple.
The authors will like to thank the Department of Science &
Technology and the Council of Scientific & Industrial Research,
Government of India, for funding of the research.
O
OHC
Cl
2
5
26
27
70
Cl
O
O
O
CH2OH
OBn
O
O
+
(7)
OHC
94% BnO
28
5
29
The present protocol, however, is not applicable to aromatic
and vinylogously aromatic aldehydes such as benzaldehyde,
cinnamaldehyde and their p-methoxy derivatives. In all these
instances, the aldehydes were recovered and, in no instance, the
fate of 2-(p-methoxyphenyl)cyclopropyl methanol 4 could be
ascertained for the complex nature of the product mixture. The
cause of this failure is also not understood at the present.
7
5
Notes and references
2
5
a
Department of Chemistry, Indian Institute of Technology, Kanpur
2
08016, India. E-mail: vijendra@iitk.ac.in
Bioorganics & Applied Materials Pvt Ltd, B64/1, III Stage PIA, Peenya,
b
Bangalore 560058, India. E-mail: hulikal.vijay@gmail.com
80 † Electronic Supplementary Information (ESI) available: Experimental
1
13
details, sectroscopic data, H and C NMR spectra, HPLC traces for the
enantio-enriched 4 and the product 3 derived from it and the ORTEP of
the crystal struture of (±)-3. See DOI: 10.1039/b000000x/
3
0
Conclusions
‡
A typical procedure for the synthesis of (±)-centrolobine. A solution of
2-(p-methoxyphenyl)cyclopropyl methanol 4 (0.178 g, 1.0 mmol) and 3-
p-benzyloxyphenylpropanal 5 (0.288g, 1.2 mmol) in dry CH Cl (10 mL)
We have used 2-arylcyclopropyl methanol as an in situ precursor
to aryl-substituted homoallyl alcohol for reaction with aliphatic
aldehydes in Prins manner to generate cis-2,4,6-trisubstituted
tetrahydropyran derivatives in high yields. The strategy was
successfully used for the synthesis of (±)-centrolobine in 84%
yield over three steps. The substrate 4 was prepared by following
the reactions given in Scheme 7 in 80% overall yield. Horner-
Wadsworth-Emmons olefination of the commercially available p-
8
9
9
5
0
5
2
2
0
was cooled to 0 C and mixed with neat SnCl (260 L, 2.2 mmol). The
reaction mixture turned dark red instantaneously. The content was stirred
at 0 C for 60 min before the quench by saturated aqueous NaHCO
4
o
3
(10
3
5
mL) and stirred for an additional 15 min. The organic layer was separated
from the aqueous layer and the aqueous layer was extracted by CH Cl (3
x 5 mL). The combined organic solution was washed by brine (1 x 5 mL),
dried by anhydrous Na SO and concentrated. Purification by silica gel
column chromatography using mixtures of EtOAc and hexanes as the
eluant yielded 3, 0.33 g, solid, mp 80 C, 95% yield. H NMR (400 MHz,
CDCl ): 7.36–7.28 (4H, m), 7.26–7.20 (3H, m), 7.01 (2H, d, J = 8.5
Hz), 6.82 (4H, d, J = 8.7 Hz), 4.96 (2H, s), 4.21 (1H, bd, J = 11.2 Hz),
4.08–4.01 (1H, m), 3.73 (3H, s), 3.40–3.32 (1H, m), 2.72–2.56 (m, 2H),
2
2
2
4
2
3
anisaldehyde 30 furnished the ester 31 in 94% yield. The ester
function in 31 was reduced to the corresponding alcohol 32 on
o
1
4
0
2
4
3
reaction with DIBAL in 95% yield. Finally, cyclopropanation
using CH I and Et Zn furnished the required substrate 4 in 90%
2
2
2
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2
.32–2.60 (1H, m), 2.14–2.08 (m, 1H), 1.92–1.83 (1H, m), 1.75 (1H, dd, J
1999, 77, 1123. (f) H. Kitajima, K. Ito, Y. Aoki and T.
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13
=
23.7, 11.7 Hz), 1.73–1.66 (1H, m), 1.59 (1H, dd, J = 23.7, 11.5 Hz).
NMR (100 MHz, CDCl ): 159.4, 149.6, 138.5, 134.0, 129.5, 128.7,
28.0, 127.6, 127.2, 114.8, 113.9, 78.1, 75.6, 70.1, 56.0, 55.4, 44.1, 42.3,
C
3
9
1
75
80
85
90
95
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-
1
5
0
5
0
5
0
5
0
5
0
5
0
5
0
37.6, 30.7. IR: max cm 1612, 1512, 1455, 1247, 1176, 1070, 1035, 828,
7
4
+
4
40. Calculated m/z for [M + NH ] = 454.2149, observed m/z =
54.2151.
1
(a) B. B. Snider, In The Prins Reaction Carbonyl Ene
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1
1
2
2
3
3
4
4
5
5
6
6
7
12 CHIRALCEL OD-H column (Daicel Chemical Ind. Ltd.) was
used to ascertain the enantiomeric compositions of 4 and 3. 4:
6
8, 7143.
2
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R
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