A chemo-enzymatic route to differentially protected aryl-naphthalenes

Article abstract of DOI:10.1016/j.bmcl.2012.11.010

Aryl-naphthalene diacetates prepared from bispropargyl sulfones, ethers and amines via Garratt-Braverman Cyclization have been selectively hydrolysed by AK lipase to the monoacetates 12a-c in high yields. The regioisomeric mono acetates 13a-c have been prepared by acetylation of the corresponding diols using the same enzyme. In both cases, the more exposed acetoxymethyl or hydroxy methyl attached to the naphthalene ring binds to the active site of the enzyme and underwent hydrolysis/acetylation. The method provides easy access to differentially protected aryl-naphthalenes which should allow further modifications.

Full text of DOI:10.1016/j.bmcl.2012.11.010

Bioorganic & Medicinal Chemistry Letters 23 (2013) 893–896
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A chemo-enzymatic route to differentially protected aryl-naphthalenes
⇑
Arpita Panja, Deboki Ghosh, Amit Basak
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Aryl-naphthalene diacetates prepared from bispropargyl sulfones, ethers and amines via Garratt–Braverman
Cyclization have been selectively hydrolysed by AK lipase to the monoacetates 12a–c in high yields. The
regioisomeric mono acetates 13a–c have been prepared by acetylation of the corresponding diols using
the same enzyme. In both cases, the more exposed acetoxymethyl or hydroxy methyl attached to the
naphthalene ring binds to the active site of the enzyme and underwent hydrolysis/acetylation. The
method provides easy access to differentially protected aryl-naphthalenes which should allow further
modifications.
Received 28 September 2012
Revised 31 October 2012
Accepted 6 November 2012
Available online 28 November 2012
Keywords:
Chemo-enzymatic
Aryl naphthalene
Lipase
Ó 2012 Elsevier Ltd. All rights reserved.
Transacetylation
Hydrolysis
Garratt–Braverman
Aryl-naphthalene systems have assumed significant importance
in view of their presence in natural biologically active lignans1 as
well as their derivatives possessing wide range of optical and elec-
tronic properties.2 Various methods have been reported for the
synthesis of such skeletons; the most widely used of these is the
intramolecular Friedel–Crafts reaction.3 Recently4 we have re-
ported a Garratt–Braverman Cyclization route to aryl naphthalene
lignans starting from a simple substrate, a bispropargyl ether. In
this Letter, we report an enzymatic route to differentially protected
aryl-naphthalenes. The synthesis allows one to attach functional
group on the naphthalene moiety or on the pendant aryl moiety.
In the process, a novel highly regioselective hydrolysis of aryl-
naphthalene diacetates 1a–c and acetylation of corresponding
aryl-naphthalene diols 2a–c (Fig. 1) have been developed. The re-
sults are described in this Letter.
Candida cylindracea (CCL),9 Porcine pancreatic lipase (PPL)10 and
AK Lipase11 was then attempted. While PPL and CCL did not accept
the diacetates as substrates, AK Lipase was able to hydrolyze the
diacetates to the monoacetates 12a–c having the acetate group at-
tached to the pendant aryl ring. The reaction, which was monitored
by tlc and by recording 1H NMR at different time points, was
usually stopped after 15 h.
Continuation of the reaction even for 48 h did not produce any
trace of the diols. Thus the enzyme hydrolysed only the more ex-
posed acetate which is attached to the naphthalene ring. The re-
sults which are similar for all the substrates 1a–c, are shown in
Table 1.
To access the other set of regioisomeric acetates 13a–c, acetyla-
tion was attempted. In this case, the alcohol attached to the
naphthalene ring should be able to bind to the active site of the
The starting diols 2a–c were prepared by NaBH4 reduction of
the corresponding diesters 11a–b5 and by deprotection of the
THP protected diol 11c.6 The latter, in turn, were obtained from
the bispropargyl sulfone, amine and ether by Garratt–Braverman
Cyclization.7 The diols were then bis acetylated with acetyl chlo-
ride (Scheme 1).
OAc
OH
X
X
The hydrolytic behavior of the aryl-naphthalene bis-acetates
1a–c was then studied. Chemical hydrolysis, even under mild
conditions (LiOH, THF),8 produced a mixture of monoacetates
and continued hydrolysis led to the formation of the diol.
Enzymatic hydrolysis using various hydrolytic enzymes, namely
OAc
OH
1 a-c a. X = SO2
b. X = NTs
2 a-c
c. X = O
⇑
Corresponding author.
E-mail address: absk@chem.iitkgp.ernet.in (A. Basak).
Figure 1. Aryl-naphthalene diacetates and diols used for enzymatic hydrolysis and
acetylation.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.010

894
A. Panja et al. / Bioorg. Med. Chem. Lett. 23 (2013) 893–896
O
O
OH
S
Br
S
I
i
i
i
i
95%
94%
50%
65%
COOMe
COOMe
COOMe MeOOC
COOMe
COOMe MeOOC
10a
3
i
5
4
9
ii
92%
94%
Ts
N
COOMe
COOMe
O
O
NHTs
iv
S
iii
NTs
90%
COOMe MeOOC
90%
COOMe
COOMe
COOMe
11a
11b
10b
6
CH OTHP
2
O
OH
Br
v
O
vi
i
70%
90%
CH OTHP
2
90%
CH OTHP
2
H C
2
CH
CH OTHP
2
2
OTHP
OTHP
8
10c
7
11c
CH OAc
CH OH
2
2
1a, 2a X = SO ,
2
1b, 2b X = NTs,
1c, 2c X = O
vii
11a
X
X
11b
ix
90%
viii
CH OAc
CH OH
2
2
80%
11c
Ts = 4-methylbenzene sulfonyl
THP = Tetrahydropyranyl
85%
2a-c
1a-c
Scheme 1. Synthesis of aryl-naphthalene derivativs 1 and 2. (i) ref. 13; (ii) Et3N, CHCl3, rt; (iii) K2CO3, DMF, 5; (iv) DBU, toluene, reflux; (v) NaH, THF, 7; (vi) KOBut, toluene,
reflux; (vii) NaBH4, THF, MeOH, reflux; (viii) PPTS, EtOH, 50 °C; (ix) AcCl, Et3N, DMAP (cat), CH2Cl2, 0 °C
Table 1
Enzymatic hydrolysis of diacetates 1a–c catalyzed by AK lipase in acetone/phosphate
The structures of the regioisomeric monoacetates were deter-
buffer
mined by 1H NMR. Thus the acetate attached to the pendant phe-
OAc
OH
nyl ring, being in the shielded region of the ring current generated
in the naphthalene ring, appeared at a higher field as compared to
the deshielded acetate attached to the naphthalene. X-ray crystal
structure of two of the monoacetates of each category 12a and
13b could be determined which confirmed its structure (ORTEP
shown in Fig. 2).
a
X
X
OAc
OAc
For a X = SO2
For b, X = NTs
For c, X = O
AK lipase has been shown12 to be effective for hydrolysis/acet-
ylation of molecules with near planar structural features surround-
ing the reactive functionality, namely the acetate or the alcohol.
The enzyme is not suitable for substrates with relatively bulky
moieties close to the acetoxymethyl or hydroxyl methyl centre
and for those which are unable to adopt a planar conformation
around the acetate/hydroxyl group. For the aryl-naphthalenes,
the acetoxy or hydroxyl methyl group attached to the naphthalene
moiety is free of steric constraints and a relatively large portion of
the structure is planar near to this reactive functionality. On the
other hand, the acetate or hydroxyl methyl attached to the phenyl
ring has the near-orthogonal naphthalene moiety nearby and
hence cannot adopt a planar structure suitable for binding. This
can possibly explain the very high regioselectivity shown by the
enzyme to these substrates. The preferred mode of binding to the
active site is shown in Figure 3.
12a-c
1a-c
a = acetone-phosphate buffer (pH 7.00 (1:3 by v/v), A. K. Lipase, r.t., 15 h
Substrate
Product
Enzyme
Yielda (%)
1a
1b
1c
12a
12b
12c
AK lipase
AK lipase
AK lipase
95
96
95
a
Isolated yields after flash chromatography; detection limit at least 95% by NMR.
acyl-enzyme which should then lead to selective acetylation leav-
ing the other hydroxyl group intact. This was found to be the case
when the diols 2a–c were separately treated with vinyl acetate in
presence of AK lipase for ꢀ10 h. The monoacetates 13a–c were iso-
lated in high yield. Again the result is same for the sulfone, ether
and for the amine. As expected, the enzymes CCL or PPL did not
show any acetylation activity. The results are shown in Table 2.
In conclusion, we have achieved a high yielding chemoenzy-
matic route to aryl-naphthalenes, differentially protected as ace-
tates. In future, a plethora of aryl-naphthalenes will be prepared

A. Panja et al. / Bioorg. Med. Chem. Lett. 23 (2013) 893–896
895
Table 2
tone was removed under vacuo. The mixture was partitioned be-
tween water–ethyl acetate (50 mL each). The organic layer was
washed with brine and dried over Na2SO4. Removal of solvent gave
the crude residue from which the monoacetates 10a–c were iso-
lated pure by column chromatography over Si gel, using petroleum
ether/ethyl acetate (1:1) as eluent.
Enzymatic acetylation of diacetates 2a–c catalyzed by AK lipase AK in acetone/
phosphate buffer (1:3 v/v) at room temperature for 15 h
OH
OAc
b
X
X
General procedure for the acetylation of the diol: To the solution of
the diols 2a–c (0.17 mmol) in THF (20 mL) vinyl acetate
(0.34 mmol) and the enzyme AK lipase (22 mg) were added and
stirred at room temperature for 10 h. It was then filtered and
THF was removed under vacuo. The pure monoacetates 13a–c
were isolated by flash column chromatography of the crude resi-
due over Si gel, using petroleum ether–ethyl acetate (1:1) as
eluent.
OH
OH
For a, X = SO2
For b, X = NTs
For c, X = O
13a-c
2a-c
b = vinyl acetate, THF, AK lipase, r.t. 10 h
Selected spectral data: All 1H and 13C NMR spectra were recorded
in CDCl3 at 400 MHz and 100 MHz, respectively.
Substrate
Product
Enzyme
Yielda (%)
For diacetate (1a): State: oil; yield: 80%; dH 8.05 (1H, s), 7.61–
7.59 (2H, m), 7.56–7.49 (2H, m), 7.38 (1H, t, J = 8.4 Hz), 7.29 (1H,
t, J = 8.4 Hz), 7.18 (1H, d, J = 1.6 Hz), 5.58 (2H, s), 4.81, 4.51
(2 Â 1H, ABq, J = 12.4 Hz), 4.65 (2H, s), 4.20, 4.15 (2 Â 1H, ABq,
J = 16.4 Hz), 2.15 (3H, s), 1.89 (3H, s); dC 170.8, 170.6, 137.2,
136.4, 134.1, 132.4, 131.7, 131.4, 130.2, 129.7, 129.3, 129.2,
129.1, 128.9, 128.9, 127.0, 126.5, 121.1, 64.3, 64.1, 57.4, 56.2,
21.0, 20.6.
2a
2b
2c
13a
13b
13c
AK lipase
AK lipase
AK lipase
90
92
90
a
Isolated yields after flash chromatography; detection limit at least 95% by NMR.
For diol (2a): State: white solid; yield: 90%; mp: 230 °C dH 8.21
(1H, s), 7.66 (1H, d, J = 7.6 Hz), 7.54 (2H, t, J = 7.2 Hz), 7.46 (1H, t,
J = 7.6 Hz), 7.36 (1H, t, J = 8.4 Hz), 7.29 (1H, d, J = 8.4 Hz), 7.16
(1H, d, J = 7.2 Hz), 5.16 (2H, s), 4.61 (2H, s), 4.28–4.11 (4H, m); dC
138.7, 136.7, 136.3, 136.2, 132.5, 131.2, 129.5, 129.0, 128.9,
128.8, 128.4, 126.7, 126.6, 126.4, 121.4, 63.9, 62.8, 57.3, 56.1.
For monoacetate (12a): State: oil; yield: 95%; dH 8.21 (1H, s),
7.60–7.49 (4H, m),7.36 (1H, t, J = 8.4 Hz), 7.22 (1H, d, J = 17.2 Hz),
7.18 (1H, d, J = 2 Hz), 5.15 (2H, s), 4.80, 4.52 (2 Â 1H, ABq,
J = 12.4 Hz), 4.63 (2H, s), 4.17 (2H, s), 1.88 (3H, s); dC 170.6,
137.5, 136.4, 136.3, 134.1, 132.4, 131.1, 130.1, 129.7, 129.3,
129.0, 128.9, 128.7, 126.6, 126.6, 126.3, 121.5, 64.2, 63.8, 57.4,
56, 20.6.
For monoacetate (13a): State: oil; yield: 90%, dH 8.05 (1H, s), 7.66
(1H, d, J = 7.6 Hz), 7.60 (1H, d, J = 6.4 Hz), 7.54 (1H, t, J = 7.2 Hz),
7.46 (1H, t, J = 7.2 Hz), 7.39–7.32 (2H, m), 7.16 (1H, d, J = 7.2 Hz),
5.58 (2H, s), 4.63 (2H, s), 4.29–4.11 (4H, m), 2.14 (3H, s); dC
171.1, 138.9, 137.2, 136.3, 132.7, 131.9, 131.6, 129.8, 129.6,
129.4, 129.3, 129.2, 129.0, 128.7, 127.3, 126.8, 121.1, 64.6, 63.1,
57.6, 56.3, 21.3.
Figure 2. ORTEP picture of monoacetate 12a and 13b (CCDC 903459 and 905579
respectively).
Calalytic site
Calalytic site
HL
HL
X
OAc
X
HS
OAc
OAc
HS
Acknowledgment
H
The author A.B. is grateful to DST, Govt. of India, for research
funding and the JC Bose fellowship. A.P. thanks CSIR, Govt. of India
for a research fellowship (NET). DST is also thanked for the funds
for a 400 MHz NMR facility and for the single crystal X-ray facility
under the IRPHA and FIST programmes, respectively.
AcO
(a)
(b)
HS = Small Hydrophobic HL = Large Hydrophobic
Figure 3. Binding of substrate to the active site of AK lipase: (a) preferred, (b) less
preferred.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
11.010.
by selective functional group manipulation and their biological
properties, especially any antitumor activity, will be studied.
Experimental and procedure/spectral data
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