Asymmetric Garratt-Braverman cyclization: A route to axially chiral aryl naphthalene-amino acid hybrids

Article abstract of DOI:10.1021/jo500771g

We report the first example of a highly diastereoselective Garratt-Braverman cyclization leading to the synthesis of chiral aryl naphthalene-amino acid hybrids in excellent yields. The stereogenecity in the amino acid has induced high diastereoselectivity for the reaction. Computations based on density functional theory indicated a lower activation free energy barrier for the M isomer as compared to that for the P diastereomer (ΔΔG = 3.48 kcal/mol). Comparison of the recorded CD spectrum of the product with the calculated one also supported the preferential formation of the M diastereomer.

Full text of DOI:10.1021/jo500771g

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Article
Asymmetric Garratt-Braverman Cyclization: A Route
to Axially Chiral Aryl Naphthalene-Amino Acid Hybrids
Tapobrata Mitra, Saibal Jana, Sharmila Pandey, Prabuddha
Bhattacharya, Uttam Khamrai, Anakuthil Anoop, and Amit Basak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo500771g • Publication Date (Web): 26 May 2014
Downloaded from http://pubs.acs.org on June 2, 2014
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The Journal of Organic Chemistry
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Asymmetric Garratt-Braverman Cyclization: A Route to
Axially Chiral Aryl Naphthalene-Amino Acid Hybrids
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Tapobrata Mitra, Saibal Jana, Sharmila Pandey, Prabuddha Bhattacharya, Uttam K. Khamrai,
Anakuthil Anoop* and Amit Basak*
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Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302 India
absk@chem.iitkgp.ernet.in; anoop@chem.iitkgp.ernet.in
Abstract: We report the first example of a highly diastereoselective Garratt-Braverman cyclization
leading to the synthesis of chiral aryl naphthalene-amino acid hybrids in excellent yields. The
stereogenecity in the amino acid has induced high diastereoselectivity for the reaction. Computations
based on Density Functional Theory indicated a lower activation free energy barrier for the M isomer as
compared to that for the P diastereomer (G = 3.48 kcal/mol). Comparison of the recorded CD
spectrum of the product with the calculated one also supported the preferential formation of the M
diastereomer.
Key Words: Garratt-Braverman Cyclization, Diastereoselective, Aryl-naphthalene, Amino acid,
Hybrid, Axially Chiral and Cotton effect
Introduction
Garratt-Braverman (GB) cyclization,1 discovered in the 70’s of the last century, has recently
drawn keen interest, specifically focusing on two aspects: finding additional support for the biradical
mechanism2 and exploration of its synthetic potential.3 While many elegant studies are there in pursuit
of the mechanistic aspects of the reaction, synthetic endeavours exploiting the reaction have started to
appear only in recent years.4 Some of the advantages of GB cyclization in organic synthesis include
formation of two carbon-carbon bonds, as depicted in Scheme 1, in high yields (especially from aryl
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Page 2 of 22
substituted systems) and the easy availability of starting materials. However, at the same time, the
reaction suffers from some selectivity issues which can lower its synthetic potential to a large extent.
1
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3
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7
8
9
O
O
O
O
O
O
S
S
S
O
O
O
S
O
S
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C
C
Scheme 1: GB cyclization of bis-propargyl sulfone
One common selectivity problem encountered in case of GB cyclization of unsymmetrical
sulfones is the formation of four possible products (excluding atropisomerism) arising from
participation of both the aryl rings. Even for some symmetrical sulfones, two products can be obtained
as the aryl double bond can participate in two possible orientations. All these possibilities are shown in
Scheme 2. Recently,4a by a judicious choice of aryl groups with distinctly different electronic
characters, the number of possible products have been minimised and one product has been made the
predominant one. However, until now, to the best of our knowledge there is no report of asymmetric GB
reaction which leads to only one stereoisomeric axially chiral aryl naphthalenes. In this communication,
we report the first example of a highly diastereoselective GB reaction that led to the synthesis of aryl
naphthalene-amino acid hybrids4b in high yields.
S
S
R1
R1
R1
R2
O
O
O
O
B
A
R1
R2
R1
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
S
R2
R1
R1
R1
R1
R1
R2
R2
R1
G
H
F
E
D
C
Scheme 2: Various possible products of GBC of unsymmetrical (A) and symmetrical (B) sulfones
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The Journal of Organic Chemistry
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S
I
S
S
K
O
O
O
O
O
O
O
O
O
O
NH
R*
HN
*R
HN
J
NH
N
N
O
O
R*
*R
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O
S
O
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N
S
S
O
O
O
O
O
O
O
N
N
N
N
COR* *ROC
L
*R
R*
N
Q
N
O
Scheme 3: Reactivity of sulfones with different amide linkages
Results and Discussion
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The idea behind making the aryl naphthalene-amino acid hybrid was two-fold: firstly, to exploit
the influence of chirality of the amino acid moiety on the axial chirality of the biaryl system and
secondly, the use of such skeletons as privileged structure for combinatorial drug design.5 Previously,6,7
we have shown that the substrates I and J, upon base-treatment, did not follow the GB reaction
pathway; instead these produced products arising from intramolecular nucleophilic addition (INA) or
6-electrocyclization (6-EC) as shown (Scheme 3). In order to suppress these non-GB pathways, we
made a tertiary amide K involving piperidine. Expectedly, K produced only the GB product in high
yield when treated with Et3N.
Having sorted out the structural requirement of o-amido propargyl sulfones to undergo GB
pathway using a 3o-amide, we incorporated different chiral oxazolidinones at the o-position of propargyl
sulfones (1a-c) and studied the diastereoselectivity of the resulting GB process (Scheme 4). However, in
none of these cases, the distereoselectivity was found to be satisfactory. The best ratio (1.8:1) was
obtained with phenylalanine derived oxazolidinone in benzene (entry 10, Table 1). The structure of the
major isomer from 1c was confirmed by single crystal X-ray crystallography8 and its absolute
configuration was determined to be M. Use of a chiral base or performing the reaction in different
solvents and temperatures to enhance the selectivity did not improve the scenario. Attempt to raise the
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rotational barrier between the two atropisomers by placing a substituent at C-4 of the starting bis-aryl
propargyl ether (2a-b) (that ultimately ended up at C-8 of the final aryl naphthalene 4a-b) was only
marginally successful (compare entries 14, 15 vis-a-vis entries 1 and 2).
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2
3
4
5
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7
8
*ROC
Me
Me
COR*
9
O
O
O
O
S
S
O
O
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S
S
O
COR*
O
*ROC
Me
COR*
COR*
Me
*ROC
COR*
1a-c
2a-b
3a-c
4a-b
O
N
R1 = CHMe2 (a), Ph (b), CH2Ph (c)
R1 = CHMe2 (a), Ph (b)
O
R =
R1
Scheme 4: Reactivity of sulfones with oxazolidinone auxiliaries
Entry
1
Starting
sulfone
Base
Et3N
Solvent
CHCl3
Temperature
rt
Product
Ratio of
diastereomers
1a
3a
1.7:1
2
3
4
5
6
1b
1c
1c
1c
1c
Et3N
Et3N
Et3N
Et3N
Et3N
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
rt
3b
3c
3c
3c
3c
1:1
1.65:1
rt
0 ºC
65 ºC
-20 ºC
1.61:1
1.63:1
No reaction
7
8
9
1c
1c
1c
Et3N
Et3N
Et3N
PhMe
DMSO
CH3CN
-4 ºC
rt
rt
3c
3c
3c
1.64:1
Decomposed
1:1
10
11
1c
1c
Et3N
C6H6
C6H6
rt
rt
3c
3c
1.8:1
1.5:1
(-)-Spartein
12
13
1c
1c
(+)-Cinchonine
C6H6
C6H6
rt
rt
3c
3c
1.7:1
(-)-
Cinchonidine
Et3N
1.65:1
14
15
2a
2b
C6H6
rt
rt
4a
4b
2:1
Et3N
CHCl3
1.14:1
Table 1: Result of GBC of different sulfones
As attempts to increase the distereoselectivity via the oxazolidinone approach failed, we turned
our attention to a different strategy. Retrospection of the reactivity of previously synthesized o-amido
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sulfones which underwent intramolecular addition or 6-EC indicated generation of highly stabilized
indole or isochromene systems to be the probable cause for such type of reactivity (computational
analysis described later). We reasoned that incorporation of a methylene linker in the form of a
homologous amide will remove the possibility of such processes occurring as those cannot lead to a
stabilized aromatic system (Scheme 5). These molecules are thus expected to follow the GB cyclization
pathway. Computations (as described later) also supported such an assertion and showed a difference of
12.64 kcal/mol between the GB process and intramolecular nucleophilic addition. It also predicted an
activation energy difference of 3.48 kcal/mole between the two possible diastereomers, with M having
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lower activation energy.
NHCOR1*
O
O
S
S
C
C
O
O
GBC
O
S
O
Spacer
HN
O
O
NH
R1*
HN
O
O
NH
R1*
NHCOR1*
R1*
R1*
Z
5a-e
6a-e
N as nucleophile
6-exo-dig
O as nucleophile
8-exo-dig
R1*
R
N
R1* =
H
O
COR1*
N
NHBoc
R = Me, CHMe2,
CH2CHMe2, CH2Ph,
CH2-C6H4-p-OMe
O
O
S
O S
O
O
N
COR1*
R1*
N
X
Y
Scheme 5: Reactivity of N-Boc amino acylated o-aminomethyl bispropargyl sulfones with different amino acids
To check the validity of our prediction, a series of N-Boc aminoacylated o-aminomethyl
bispropargyl sulfones 5a-e were prepared using different amino acids (Scheme 6) starting from o-iodo
aminoacyl benzylamine derivatives 8a-e.9 Sonogashira coupling with propargyl alcohol followed by
functional group transformation provided the bromide 9a-e. The latter on treatment with Na2S followed
by oxidation with m-CPBA furnished the sulfones 5a-e which were then subjected to GB conditions
(Et3N in CHCl3). To our expectation, the reaction followed only the GB pathway; no non-GB product
could be isolated. The other striking feature of the reaction was the excellent diastereoselectivity in
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addition to the high yield (de> 90%, yield >95%). The results are compiled in Table 2. The structure of
1
2
3
1
the GB products was confirmed by comparing the H-NMR with those made from the diamine 13 via
4
5
6
7
8
HATU-mediated coupling with the Boc-amino acids. Incidentally, the diamine 13 was prepared from the
diester 10 for which an X-ray structure was available8 (Scheme 7). The de’s were calculated from the
hplc analysis. The absolute configuration of the major diastereomer could not be determined by single
crystal X-ray because none of the diastereomers gave crystals which met the quality and size required
for such analysis. In view of that, we chose to compare the Electronic Circular Dichroism (ECD)
Spectra with the experimental one10 (Figure 1). The computed CD spectrum showing positive Cotton
effect for the M diastereomer matched with that observed experimentally for the diastereomer 6d. A
negative Cotton effect was computationally predicted for the other diastereomer P. For M, the major
positive rotatory strength is at 386 nm and for P at 426 nm. Lowest excited state (π → π* transiton from
HOMO to LUMO) contributed the Cotton effect.
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BocHN
Br
S
I
R
O
O
O
O
i
HN
S
iii
O
v
NHBoc
NH
O
R
NH
O
R
NH
HN
R
O
ii
O
R
NH
iv
R
95%
85-90%
88-95%
NHBoc
NHBoc
5a-e
NHBoc
O
NHBoc
9a-e
8a-e
6a-e (M)
+
BocHN
HN
R = Me (a) , CHMe2 (b), CH2CHMe2(c), Bn
(d) , CH2-C6H4-p-OMe (e)
R
O
O
S
O
NHBoc
NH
R
i) Propargyl alcohol, PdCl2(PPh3)2, CuI, Et3N, rt, 8 h ii) (a) MsCl, Et3N,
THF, 0 oC, 0.5 h (b) LiBr, 4 h iiii) Na2S/MeOH iv) m-CPBA, DCM v) NEt3,
CHCl3, rt, 48-72 h.
O
7a-e (P)
Scheme 6: Synthesis and GBC of 5a-e
Substrate
Amino acid
Overall Yield (%)
Diastereomeric ratio
5a
5b
5c
5d
5e
Ala
Val
Leu
97
97
95
95
97
95:5 (6a:7a)
98:2 (6b:7b)
95:5 (6c:7c)
97:3 (6d:7d)
97:3 (6e:7e)
Phe
MeO-tyr
Table 2: Result of diastereselective GBC
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1
2
3
4
MeO2C
N3
CH2OH
CO2Me
O
O
O
iii
i
ii
S
S
S
O
O
O
S
O
N3
iv
O
80%
5
95%
CH2OH
CO2Me
6
90%
7
8
CO2Me
10
11
5f
12
9
10
11
Me
NHBoc
O
H2N
NH
BocHN
12
13
v
vi
O
O
O
S
S
S
O
NH2
O
O
20%
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75%
NHBoc
NH
Me
O
13a
NHBoc
13
6a/7a
o
i) NEt3, CHCl3, rt, 2 h; ii) NaBH4, THF, MeOH, 80 C, 4 h; iii)
CH2Cl2, MsCl, Et3N, 0 oC, 1h; iv) NaN3, DMF, 6 h; v) THF-H2O,
PPh3, 6 h; vi) HOBt, N-Boc alanine, HATU, DIPEA DMF, 72 h
(13 was characterized as
its di-Boc derivative 13a)
Scheme 7: Alternate synthesis of GB products 5a-e
1.5
1.0
0.5
0.0
2.5
2.0
1.5
1.0
0.5
0.0
0.00
426 nm
-0.25
mdeg
mdeg
mdeg
-0.50
-0.75
386 nm
375
350 400 450 500 550
Wavelength (nm)
300
325
350
400
300
305
310
315
Wavelength (nm)
A
B
WCavelength (nm)
Figure 1:(A) Computed electronic CD spectrum of 6d (M; rotatory strength is shown at 386 nm); (B)
Computed electronic CD spectrum of 7d (P; rotatory strength is shown at 426 nm); (C) Experimentally
recorded CD spectrum of the cyclized product of 5d.
As the complexity of the system increases, the rule of thumb predictions based on electronic or
steric effects becomes highly difficult. In our system complexity arises from multitude of possible
intramolecular interactions between aromatic groups and among the N-H…O hydrogen bonds, and also
from the various possible conformations of the substrate. Therefore, we tried to understand the energy
requirements for the possible reaction pathways by computational methods. In order to address the
conformational space, we have made Short Molecular Dynamics Conformational Search for the
bisallenic sulfones Z, the active species for the cyclization (Scheme 4).10 Conformations resulted from
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the MD runs were further fully optimized with Density Functional Theory calculations. Most stable
1
2
3
conformations were chosen for further calculation for each of the substrates (I, J, K and 5a).
4
5
The conformational geometry has very important role on the course of the subsequent steps in
the reaction. In our system, ortho-substituted bisallenic sulfones may undergo biradical GB cyclization,
6π-EC or INA. For I and J, from the computed energies, it is observed, that the allenyl moieties are
away from each other in most stable bisallenic sulfones geometries. Such substrate conformations with
distant allenyl groups will have lesser tendencies for GB cyclization. We have calculated the activation
free energy for the competitive pathways. I has a barrier of 25.61 kcal/mol for INA, whereas for GB
cyclization, the barrier is twice (51.07 kcal/mol) as the barrier for INA. Similarly for J the barriers are
12.69 and 22.20 kcal/mol for 6π-EC and GB cyclization respectively. Such large differences in barriers
for competitive reactions indicate exclusive non-GB cyclizations for I and J. But for K, the situation is
reversed; the barrier is 10.73 kcal/mol for GB cyclization and 16.8 kcal/mol for intramolecular
nucleophilic addition, showing the preference for GB cyclization pathway. Since there is no H attached
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A
B
Figure 2:A) Free energy profile (∆G in kcal/mol; BP86-D3/def2-SVP) of INA and GB cyclization
reaction of 5a. Red colored line describes the energy diagram for INA, and the blue colored line stands
for GB cyclization. Here the energy of substrate conformation was taken as reference; B) Relative free
energies of activation (at BP86-D3/def2-SVP level; in kcal/mol) for the first intermediate formation
from bisallenic sulfones in different mechanistic pathways. Blue colored bars stand for free activation
barrier of GB cyclization, and the red colored bars are for INA or 6π-EC. The energy of the most stable
bisallenic sulfone was taken as the reference (0.0 kcal/mol) for each case.
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to N, it cannot participate in aromatization. Therefore, there was no driving force for intramolecular
nucleophilic addition. For further study, we have performed similar calculation on the methylene linked
molecule 5a. Again, 5a has the option of undergoing GB cyclization and intramolecular nucleophilic
addition. But the activation free energy for GB cyclization is 21.70 kcal/mol, which is much lower than
the required activation energy for intramolecular nucleophilic addition (34.34 kcal/mol). Such high
energy difference will lead to the formation of exclusive GB cyclization. The energy profiles for the
competing processes are shown in Figure 2.
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Axial chirality arises from unsymmetrically substituted aryl rings, e. g. ortho-substitution at the
phenyl rings attached to the terminal alkyne systems. If both the ortho substituent are same,
bispropargyl sulfones can produce two GB cyclized product under base treatment, which are
diastereomers with axial chirality. When the ortho substituent is large, geometry of the active substrate
(bisallenic form) conformation determine the selection of pathways for the GB cyclization. The
rearrangement after the first step is unlikely when ortho-substituted group is bulky and therefore the
Figure 3: Optimized geometry of bisallenic sulfones of 5a. (A) and (B) are two conformations, where
(A) is more stable than (B). For clarity hydrogen atoms are not shown.
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P/M conversion is not possible. Two of the stable substrate conformations are shown in Figure 3. The
conformation A leads to M isomer and B leads to P isomer. Conformation A is 9.58 kcal/mol more
stable than the conformation B, and the energy of the transition state for the reaction from A is lower by
3.48 kcal/mol than that from conformation B. This is because of greater-stacking interactions between
the aryl rings of the two propargyl arms. Thus based on computation results, the reaction should prefer
to form the isomer with M axial chirality which corresponded to the experimental result. The activation
barrier for the conversion from M to P for 6a/7a pair was estimated from relaxed surface scan to be
50.67 kcal/mol, which is too high for a conversion at the reaction conditions.
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In conclusion, we have successfully carried out an asymmetric GB reaction leading to the
synthesis of aryl naphthalene-amino acid hybrids with predominantly one axial chirality. To the best of
our knowledge this is the first example of an asymmetric GB reaction. Computational results nicely
supported the observed selectivity. Considering the importance of aryl naphthalene skeleton, the
strategy to have access to the latter in one chiral form should be of importance to the synthetic
community.
Experimental
All the reactions were monitored by TLC using polygramR SILG/UV254 precoated (0.25 mm)
silica gel TLC plates. Column chromatography was done with silica gel (60-120 or 230-400 mesh).
NMR data were obtained with 200 MHz and 400 MHz NMR instruments. Proton and carbon spectra
were referenced internally to solvent signals, using values of δ = 7.26 ppm for proton and δ = 77.0 for
carbon (middle peak) in CDCl3. The following abbreviations are used to describe peak patterns where
appropriate: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, app. = apparently and bs =
broad signal. All coupling constants (J) are given in Hz.
Synthesis of sulfones 1a-c, 2a-b, 5a-f: To an ice-cold solution of the sulfide (0.05 mmol, 1.0 eq.) in dry
DCM (2ml), m-CPBA (2.0 eq., 75%, 0.1 mmol, 45 mg) was added under inert condition. After 20
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minutes the ice was removed and the reaction mixture was left to attain the room-temperature. The
reactions were complete within 10-15 mins. The reactions were quenched by diluting the reaction
mixture with water and DCM and washed with saturated solutions of Na2SO3 and Na2CO3 successively.
DCM layers were dried over anh. Na2SO4 and the solutions were concentrated and subjected to column
chromatography (Si-gel, pet ether-ethyl acetate mixture as eluent).
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Compound 1a: White solid; Yield 90% (27 mg), mp 180-182 C,δH (400 MHz): 7.56-7.32 (m, 8H),
4.67-4.59 (m, 2H), 4.45 (t, J = 8.6 Hz, 2H, 4.27-4.16 (m, 6H), 2.63-2.47 (m, 2H), 0.97 (d, J = 2.6 Hz,
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6H), 0.93 (d, J = 2.6 Hz, 6H), C{1H} (50 MHz): 168.1, 153.3, 138.2, 132.4, 129.8, 129.1, 126.7,
118.6, 85.1, 79.6, 79.6, 63.8, 58.7, 44.2, 28.4, 17.9, 14.8. HRMS: m/z [M + Na+] Calcd. for
C32H32N2O3SNa 627.1777; Found 627.1782.
Compound 1b: White solid; Yield 90% (30 mg), mp mp 183-185 C,δH (400 MHz): 7.51-7.23 (m,
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18H), 5.65-5.56 (m, 2H), 4.92-4.67 (m, 4H), 4.24-4.13 (m, 4H), C{1H} (50 MHz): 167.5, 153.0,
138.7, 137.6, 132.4, 130.1, 129.2, 129.1, 128.7, 127.0, 126.1, 118.9, 85.3, 79.7, 70.4, 58.0, 44.3. HRMS:
m/z [M + Na+] Calcd for C38H28N2O8SNa 695.1464; Found 695.1467.
Compound 1c: White solid; Yield 90% (31 mg), mp 190-192 C,δH (400 MHz): 7.43-7.24 (m, 18H),
4.94-4.85 (m, 2H), 4.45-4.32 (m, 4H), 4.24-4.15 (4H), 4.49 (dd, J = 3.2 Hz, 13.2 Hz, 2H), 2.98 (dd, J =
9.4 Hz, 13.3 Hz, 2H), 13C{1H} (50 MHz): 168.2, 152.9, 137.8, 135.4, 132.6, 130.2, 129.5, 129.2, 129.0,
127.3, 127.2, 119.0, 85.2, 79.6, 66.7, 55.4, 44.3, 37.6. HRMS: m/z [M + Na+] Calcd for
C40H32N2O8SNa 723.1777; Found 723.1781.
Compound 2a: White solid; Yield 92% (29 mg), mp 194-195 C,δH (400 MHz): 7.76 (d, J = 1.6 Hz,
2H), 7.57 (dd, J = 8.0 Hz, 1.6 Hz, 2H), 7.32-7.28 (m, 4H), 4.71-4.66 (m, 2H), 4.4-4.39 (m, 6H), 4.29-
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4.26 (m, 2H), 2.53 (s, 6H), 2.52-2.47 (m, 2H), 0.97 (d, J = 7.2 Hz), C{1H} (100 MHz): 168.7, 153.7,
145.6, 133.0, 130.9, 129.8, 129.2, 121.2, 86.0, 80.5, 63.5, 58.6, 44.4, 28.2, 20.9, 17.8, 15.1. HRMS: m/z
[M + Na+] Calcd for C34H36N2O8SNa [M + Na+] 655.2090; Found 655.2088.
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Compound 2b: White solid; Yield 92% (32 mg), mp 205-207 C, δH (400 MHz): 7.77 (s, 2H), 7.59 (d,
J = 8.0 Hz, 2H), 7.42-7.28 (m, 10H), 7.28 (s, 4H), 5.61 (t, J = 7.2 Hz, 2H), 4.77 (t, J = 8.0 Hz, 2H), 4.36
(s, 4H), 4.32 (t, J = 8.0 Hz, 2H), 2.50 (t, J = 10.0 Hz), 13C{1H} (100 MHz): 168.3, 153.8, 146.3, 137.7,
133.5, 130.2, 129.5, 129.2, 126.6, 126.3, 121.5, 86.2, 80.8, 70.1, 59.0, 44.8, 21.2. HRMS: m/z [M +
Na+] Calcd for C40H32N2O8SNa [M + Na+] 723.1777; Found 723.1779.
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Compound 5a: White solid; Yield 90% (31 mg), mp 125-126 C, δH (200 MHz): 7.42 (d, J = 7.6 Hz,
2H), 7.32-7.29 (m, 4H), 7.23-7.19 (m, 2H), 5.27 (bs, 2H), 4.54-4.45 (m, 8H), 4.21-4.11 (bs, 2H), 1.36
(s, 18H), 0.89-0.83 (m, 3H); 13C{1H} (50 MHz): 172.9, 155.5, 140.8, 132.5, 129.6, 128.4, 127.4, 120.4,
86.1, 80.6, 79.9, 49.9, 45.1, 42.1, 25.2, 18.5. HRMS (ESI-TOF) m/z [M + Na+] Calcd for
C36H46N4O8SNa 717.2934; Found 717.2937.
Compound 5b: White solid; Yield 90% (34 mg), mp 120-122 C; δH (200 MHz): 7.41 (d, J = 7.6 Hz,
2H), 7.35-7.26 (m, 6H), 7.18 (t, J = 7.6 Hz, 2H), 5.28 (d, J = 6.4 Hz, 2H), 4.58-4.40 (m, 8H), 3.96 (bs,
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2H), 2.05-2.02 (m, 2H), 1.35 (s, 18H), 0.91-0.85 (bm, 12H); C{1H} (50 MHz): 172.2, 156.2, 141.2,
132.7, 129.8, 128.9, 127.5, 120.6, 86.4, 80.9, 79.9, 60.1, 45.1, 42.3, 31.2, 28.4, 19.5, 18.1; HRMS m/z
[M + Na+] Calcd for C40H54N4O8SNa 773.3560; Found 773.3562.
Compound 5c: White solid; Yield 88% (34 mg); mp 118-120 C; δH (200 MHz): 7.60 (bs, 1H), 7.41 (d,
J = 7.6 Hz, 2H), 7.33-7.26 (m, 3H), 7.19-7.17 (m, 2H), 5.28-5.27 (m, 1H), 4.65-4.62 (m, 1H), 4.51-4.35
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(m, 5H), 4.23 (bs, 1H), 1.67-1.48 (m, 6H), 1.32 (bs, 18H), 0.95-0.81 (bs, 12H); C{1H} (50 MHz):
173.4, 156.1, 141.2, 132.7, 129.8, 128.1, 127.4, 120.5, 86.1, 81.1, 80.0, 53.3, 45.0, 42.1, 41.6, 28.4,
24.1, 23.2; HRMS (ESI-TOF) m/z [M + Na+] Calcd for C42H58N4O8SNa 801.3873; Found 801.3877.
Compound 5d: White solid; Yield 90% (38 mg); mp 125-127 C; δH (200 MHz): 7.40-7.08 (m, 20H),
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5.27 (d, J = 6.8 Hz, 2H), 4.50-4.22 (m, 10H), 3.03-2.98 (m, 4H), 1.28 (s, 18H); C{1H} (50 MHz):
155.7, 140.8, 136.8, 132.7, 129.8, 129.5, 128.6, 127.5, 126.9, 120.5, 86.3, 80.9, 55.8, 45.0, 42.3, 38.9,
28.4; HRMS (ESI-TOF) m/z [M + Na+] Calcd for C48H54N4O8SNa 869.3560; Found 869.3566.
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Compound 5e: White solid; Yield 90% (40 mg), mp 120-122 C; δH (200 MHz): 7.4 (d, J = 7.2 Hz,
2H), 7.25-6.99 (m, 12H), 6.71 (d, J = 8.0 Hz, 4H), 5.32-5.27 (m, 2H), 4.56-4.53 (m, 2H), 4.39-4.28 (m,
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132.6, 129.7, 128.8, 127.5, 120.6, 114.1, 86.3, 80.9, 80.1, 55.3, 45.0, 42.2, 38.0, 28.4; HRMS (ESI-
TOF) m/z [M + Na+] Calcd for C50H58N4O10SNa 929.3771; Found 929.3774.
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Compound 5f: Yellowish white solid: Yield 95% (19 mg), mp 124-125 C, δH (200 MHz): 7.93 (dd, J
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= 7.2 Hz, 1.3Hz, 2H), 7.59-7.33 (m, 6H), 4.61 (s, 4 H), 3.90 (s, 6H); C{1H} (50 MHz): 166.1, 134.5,
132.0, 131.9, 130.4, 128.8, 86.1, 81.6, 52.5, 44.7; HRMS (ESI-TOF) m/z [M + H]+ Calcd for C22H19O6S
411.0902; Found 411.0910.
Synthesis of aryl naphthalenes 3a-c, 4a-b, 6a-e and 10 by Garratt-Braverman cyclization:
The aryl naphthalenes were obtained simply by treating the sulfones (0.05 mmol, 1.0 eq.) with
triethylamine (0.05 mmol, 7 l as a solution in CHCl3, 1.0 equiv.) in CHCl3 (2 ml). The time for the
completion of the reactions varied from 48 h to 72 h for different substrates. The reaction mixtures after
evaporation to dryness, were directly subjected to column chromatographic purification (Si-gel, hexane-
ethyl acetate 1:1 mixture as eluent).
Compound 3a (diastereomeric mixture): White solid; Combined yield 80% (24 mg); δH (400 MHz):
8.30 (d, J = 4.0 Hz), 8.95 (s, major diastereomer), 8.89 (s, minor diastereomer), 7.77-7.71 (m), 7.66-7.61
(m), 7.59-7.52 (m), 7.49-7.43 (m), 7.35-7.32 (m), 6.77 (m), 4.80-4.78 (m), 4.59-4.53 (m), 4.47-4.42 (m),
4.36-4.31 (m), 4.15 (t, J = 16.0 Hz), 4.06-4.04 (m), 3.97-3.74 (m), 2.71-2.65 (m), 1.96 (bs), 1.09-1.06
(m), 0.75 (d, J = 7.2 Hz), 0.62 (d, J = 6.8 Hz); HRMS (ESI-TOF) m/z [M + Na+] Calcd for
C32H32N2O8SNa 627.1777; Found 627.1778.
Compound 3b (diastereomeric mixture) : White solid; Combined yield 85% (28 mg); δH (400 MHz):
8.28 (s, characteristic of one axial diastereomer), 8.26 (s, characteristic of another axial distereomer),
7.76-7.71 (m), 7.65-7.23 (m), 7.13-7.07 (m), 6.76 (s), 6.66 (bs), 6.62 (bs), 5.79-5.73 (m), 5.68 (bs),
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5.02-4.75 (m), 4.73 (t, J = 8.8 Hz), 4.48-4.16 (m), 4.05-4.01 (m), 3.94-3.90 (m); HRMS (ESI-TOF) m/z
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[M + Na+] Calcd for C38H28N2O8SNa 695.1464; Found 695.1464.
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Compound 3c (P): White crystalline solid; Yield 45% (16 mg); δH (400 MHz): 7.91 (s, 1H), 7.64-7.59
(m, 4H), 7.51-7.49 (m, 1H), 7.44-7.09 (m, 10H), 7.08 (d, J = 6.8 Hz, 2H), 5.03-5.00 (m, 1H), 4.62-4.50
(m, 3H), 4.40-4.36 (m, 1H), 4.31-4.23 (m, 2H), 4.17 (d, J = 16.4 Hz, 1H), 3.85-3.82 (m, 1H), 3.73-3.69
(m, 1H), 3.59 (dd, J = 16.0 Hz, 2.8 Hz, 1H), 3.03 (dd, J = 13.2 Hz, 9.6 Hz, 1H), 2.94 (d, J = 12.0 Hz,
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1H); C{1H} (100 MHz): 169.0, 168.4, 152.7, 152.4, 135.6, 135.3, 134.9, 134.8, 134.6, 132.0, 131.3,
131.0, 130.5, 130.2, 129.9, 129.7, 129.5, 129.4, 129.3, 129.1, 128.8, 128.4, 128.2, 127.6, 127.2, 125.6,
121.8, 76.6, 66.4, 57.0, 55.9, 55.5, 54.8, 37.7, 36.9, 29.6; HRMS (ESI-TOF) m/z [M + H+] Calcd for
C40H33N2O8S 701.1958; Found 701.1959.
Compound 3c (M): White solid; Yield 52% (18 mg); δH (400 MHz): 7.91 (s, 1H), 7.76 (d, J = 8.8 Hz,
1H), 7.69-7.56 (m, 4H), 7.52-7.48 (m, 1H), 7.41-7.31 (m, 6H), 7.22-7.15 (m, 3H), 7.00-6.98 (m, 2H),
5.04-4.98 (m, 1H), 4.54-4.48 (m, 3H), 4.44-4.36 (m, 1H), 4.32-4.29 (m, 1H), 4.15-4.11 (m, 2H), 3.75-
3.73 (m, 2H), 3.59 (dd, J = 13.2 Hz, 3.2Hz, 1H), 3.06 (dd, J = 12.8 Hz, 9.6 Hz, 1H), 2.68 (d, J = 12.8
Hz, 1H); 13C{1H} (100 MHz): 168.0, 168.6, 152.6, 152.5, 135.7 (2C), 135.0, 134.7, 134.3, 132.1, 131.4,
130.8, 130.4, 130.3, 129.8, 129.5, 129.2, 129.1, 128.7, 128.6, 127.9, 127.6, 127.2, 127.0, 125.7, 121.7,
66.5, 66.4, 56.8, 55.8, 55.3, 55.0, 37.8, 36.4; HRMS (ESI-TOF) m/z [M + H+] Calcd for C40H33N2O8S
701.1958; Found 701.1957.
Compound 4a (One diastereomer; axial stereochemistry is undetermined): White solid; Yield 27% (8
mg); δH (400 MHz): 8.08 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz,
1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 4.61 (s, 2H), 4.53-4.50 (m, 1H), 4.38 (t, J = 1.2
Hz, 1H), 4.32-4.28 (m, 2H), 4.02 (d, J = Hz, 1H), 4.92-4.90 (m, 2H), 3.68 (d, J = Hz, 1H), 2.77 (s, 3H),
2.70 (bs, 1H), 2.22 (bs, 1H), 1.66 (s, 3H), 1.01 (d, J = 8.0 Hz, 3H), 0.96 (d, J = 8.0 Hz, 3H), 0.89-0.83
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(m, 6H); C{1H} (100 MHz): 169.3, 168.7, 153.5, 152.9, 144.2, 136.6, 136.5, 135.7, 133.1, 132.1,
131.4, 130.7, 130.6, 129.4, 129.2, 128.0, 127.4, 126.7, 126.2, 122.3, 62.8, 62.4, 58.1, 57.3, 57.2, 56.3,
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27.7, 27.6, 20.4, 20.3, 18.0, 17.7, 14.8, 14.3; HRMS (ESI-TOF) m/z [M + Na+] Calcd for
C34H36N2O8SNa 655.2090; Found 655.2090.
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Compound 4a (Another diastereomer; axial stereochemistry is undetermined): White solid; Yield 54%
(17 mg); δH (400 MHz): 8.08 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 12.0 Hz, 8.0 Hz, 2H), 7.35
(s, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.69 (sex, J = 4.0 Hz, 1H), 4.64, 4.58 (ABq, J = 16.0 Hz, 2H), 4.32-
4.26 (m, 2H), 4.19-4.13 (m, 2H), 3.93 (dd, J = 12.0, 4.0 Hz, 1H), 3.77 (d, J = 16.0 Hz, 1H), 3.62 (t, J =
4.0 Hz, 1H), 2.75 (s, 3H), 2.38-2.30 (m, 2H), 2.17 (s, 3H), 0.90 (m, 6H), 0.83 (d, J = 8.0 Hz, 6H);
13C{1H} (100 MHz): 169.3, 168.7, 153.5, 152.9, 144.2, 136.6, 136.5, 135.7, 133.1, 132.1, 131.4, 130.7,
130.6, 129.4, 129.2, 128.0, 127.43, 126.7, 126.2, 122.3, 62.8, 62.4, 58.1, 57.3, 57.2, 56.3, 27.7, 27.6,
20.4, 20.3, 18.0, 17.7, 14.8, 14.3; HRMS (ESI-TOF) m/z [M + Na+] Calcd for C34H36N2O8SNa
655.2090; Found 655.2090.
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Compound 4b (diastereomeric mixture): White solid; Combined yield 80% (28 mg); mp 200-205 C;
δH (400 MHz): 8.10 (s), 8.08 (s), 7.84-7.77 (m), 7.57 (s), 7.45 (d, J = 7.6 Hz), 7.46-7.26 (m), 7.11 (d, J =
6.8 Hz), 6.98 (d, J = 7.6 Hz), 5.75 (t, J = 8.8 Hz, minor diastereomer), 5.63 (t, J = 8.8 Hz, major
diastereomer), 4.82-4.57 (m), 4.40-4.33 (m), 4.29-4.22 (m), 4.12 (q, J = 7.2 Hz), 4.00-3.97 (m), 3.90 (t,
J = 9.2 Hz), 3.81 (d, J = 4.8 Hz), 3.76 (d, J = 4.8 Hz), 3.58 (q, J = 4.4 Hz), 2.76 (s), 2.07 (s), 2.05 (s),
1.74 (s); HRMS (ESI-TOF) m/z [M + Na+] Calcd for C40H32N2O8SNa 723.1777; Found 723.1777.
Compounds 6a and 7a: White solid; Yield 95% (33 mg); mp 120-125 C; δH (Acetone-d6, 400 MHz):
8.23 (s, 1H), 7.72 (bs, 1H), 7.59-7.57 (m, 2H), 7.49-7.37 (m, 4H), 7.24 (d, J = 8.0 Hz, 1H), 7.17 (d, J =
7.2 Hz, 1H), 6.16 (bs, 1H), 6.06 (bs, 1H), 4.92 (m, 2H), 4.69-4.64 (m, 2H), 4.30-3.94 (m, 6H), 1.42-1.28
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(m, 24H); C{1H} (100 MHz): 174.0, 173.7, 155.8, 155.7, 137.0, 136.9, 136.1, 134.5, 131.9, 130.8,
130.1, 129.2, 128.7, 127.6, 127.4, 126.5, 126.4, 125.2, 120.8, 79.0, 56.7, 55.4, 50.4, 50.1, 40.7, 40.6,
40.0, 28.6, 17.4; [α]25 -65.3 (c 0.25, CHCl3); HRMS (ESI-TOF) m/z [M + Na+] Calcd. for
D
C36H46N4O8SNa 717.2934; Found 717.2939.
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Compounds 6b and 7b: White solid; Yield 95% (36 mg); mp 115-117 C; δH (Acetone-d6, 400
MHz):8.24 (s, 1H), 7.81 (bs, 1H), 7.59-7.55 (m, 3H), 7.49-7.35 (m, 3H), 7.25-7.23 (m, 1H), 7.14 (d, J =
7.2 Hz, 1H), 6.00 (bs, 1H), 5.90 (bs, 1H), 4.91 (bs 2H), 4.73-4.61 (m, 2H), 4.35-4.27 (m, 1H), 4.12-3.85
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MHz): 171.5, 171.4, 155.7, 137.5, 136.2, 136.2, 136.1, 134.9, 132.1, 131.0, 130.3, 129. 4, 129.3, 128.5,
127.5, 127.4, 126.7, 126.4, 125.4, 125.3, 121.0, 78.2, 60.0, 56.8, 55.5, 40.8, 40.1, 30.8, 30.5, 29.5, 29.3,
29.1, 28.9, 28.7, 28.5, 28.3, 27.6, 18.9, 17.4, 17.3; [α]25D -67.6 (c 0.25, CHCl3); HRMS (ESI-TOF) m/z
[M + Na+] Calcd for C40H54N4O8SNa 773.3560; Found 773.3562.
Compound 6c and 7c: White solid; Yield 95% (37 mg); mp 118-120 C; δH (Acetone-d6, 400 MHz):
8.21 (s, 1H), 7.82 (d, J = 5.6 Hz, 1H), 7.59-7.54 (m, 3H), 7.48-7.33 (m, 3H), 7.22 (d, J = 6.0 Hz, 1H),
7.14 (d, J = 6.8 Hz, 1H), 6.18 (bs, 1H), 6.10 (bs, 1H), 4.90-4.88 (m, 2H), 4.73-4.62 (m, 2H), 4.33-4.21
(m, 2H), 4.12-4.08 (m, 2H), 4.01-3.93 (m, 2H), 1.72-1.63 (m, 2H), 1.39-1.35 (m, 18H), 0.92-0.84 (m,
13
12H); C{1H} (100 MHz): 172.6, 172.5, 155.6, 137.6, 137.5, 136.2, 135.0, 132.1, 131.0, 130.3, 129.3,
129.2 (2C), 128.5, 127.4, 126.5, 126.3 (2C), 120.9, 120.9, 78.3, 56.9, 55.5, 53.2, 53.1, 41.2, 41.0, 40.9,
40.8, 40.1 (2C), 27.7, 24.5 (2C), 22.5 (2C), 21.1; [α]25 -75.2 (c 0.25, CHCl3); HRMS (ESI-TOF) m/z
D
[M + Na+] Calcd for C42H58N4O8SNa 801.3873; Found 801.3869.
Compounds 6d and 7d: White solid; Yield 95% (40 mg), mp 116-118 C; δH (Acetone-d6, 400 MHz):
8.22 (s, 1H), 7.80 (bs, 1H), 7.46-7.16 (m, 17H), 6.15 (bs, 1H), 6.05 (s, 1H), 4.90-4.88 (m, 2H), 4.68-
4.66 (m, 2H), 4.43 (bs, 1H), 4.29-4.26 (m, 2H), 4.14-4.07 (m, 2H), 3.98-3.87 (m, 2H), 2.95-2.87 (m,
13
4H), 1.31 (s, 18H); C{1H} (100 MHz): 172.3, 155.8, 137.6, 137.3, 137.2, 136.4, 136,3, 132.2, 131.2,
130.4, 129.5, 129.4, 129.3, 128.9, 128.4, 128.3, 128.1, 127.8, 127.7, 126.6, 126.5, 125.5, 121.2, 79.2,
57.1, 56.2, 56.1, 55.7, 40.9, 40.4, 40.3, 38.2, 38.0, 29.9, 29.7, 29.5, 29.4, 29.2, 28.9, 28.8, 27.8; [α]25
-
D
72.3 (c 0.25, CHCl3); HRMS (ESI-TOF) m/z [M + Na+] Calcd for C48H54N4O8SNa 869.3560; Found
869.3562.
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Compounds 6e and 7e: White solid; Yield 95% (43 mg); mp 123-125 C; δH (Acetone-d6, 400 MHz):
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8.21 (s, 1H), 7.78 (bs, 1H), 7.45-6.73 (m, 15H), 6.12 (bs, 1H), 6.01 (bs, 1H), 4.86 (bs, 2H), 4.60-4.65
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(m, 2H), 4.37-3.9 (m, 6H), 3.77 (s, 6H), 3.06 (bs, 1H), 2.98-2.92 (m, 4H), 1.32 (s, 18H); C{1H} (100
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MHz): 171.4, 158.4, 158.3, 155.4, 155.2, 137.4, 137.3, 136.3, 136.2, 134.8, 132.0, 129.4, 129.3, 128.5,
128.1, 127.7, 127.5, 127.4, 126.5, 126.4, 125.2, 120.8, 113.6, 113.5, 78.4, 56.8, 56.2, 55.5, 55.3, 54.5,
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54.4, 40.7, 40.1, 37.2, 37.1, 36.9, 29.5, 29.3, 29.1, 28.9, 28.7, 28.5, 28.3, 27.6; [α]25 -68.9 (c 0.25,
D
CHCl3); HRMS (ESI-TOF) m/z [M + Na+] Calcd for C50H58N4O10SNa 929.3771; Found 929.3771.
Synthesis of compounds 9a-e:
0.5 mmol of the product of Sonogashira coupling between 8a-e and propargyl alcohol was taken in 15
ml anh. THF and cooled in an ice-bath. Et3N (2.0 eq., 1.0 mmol, 140l) and MsCl (1.1 eq., 0.55 mmol,
as a solution of 45 l in 1.0 ml CH2Cl2) were added in succession. The progress of the reaction was
monitored by TLC. After the completion of the reaction (maximum 30 min) anh. LiBr (2.5 mmol, 5.0
eq., 215 mg) was added and the reaction was sirrred at rt for 4 h. The reaction mixture was concentrated
and the product was purified by column chromatography (Si-gel 60-120 mesh, PE: EA = 4:1).
Compound 9a: Colourless liquid; Yield 90% (175 mg); δH (200 MHz): 7.38-7.13 (m, 4H), 6.78 ( bs,
1H), 5.12 -5.14 (m, 1H), 4.51 (d, J=5.8, 2H), 4.15 (s, 2H), 1.35 (s, 9H), 1.24-1.21 (m, 3H); 13C{1H} (50
MHz): 172.7, 155.6, 140.4, 132.5, 129.3, 128.2, 127.4, 121.2, 89.3, 84.6, 80.2, 42.1, 29.7, 28.3, 18.5,
15.2; HRMS (ESI-TOF) m/z [M + H+] Calcd for C18H24BrN2O3 395.0970; Found 395.0972.
Compound 9b: Colourless liquid; Yield 90% (190 mg); δH (200 MHz): 7.41-7.15 (m, 4H), 6.73( bs,
1H), 5.19(d, J=8.2, 1H), 4.53 (d, J=5.8, 2H), 4.17 (m, 2H), 3.98-3.91 (m, 1H), 1.38 (s, 9H), 0.93-0.85
13
(m, 6H); C{1H} (50 MHz): 171.8, 156.1, 140.4, 132.6, 129.4, 128.4, 127.5, 121.3, 89.3, 84.7, 42.2,
31.0, 28.5, 19.5, 17.9, 15.3; HRMS (ESI-TOF) m/z [M + H+] Calcd for C20H28BrN2O3 423.1283; Found
423.1285.
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Compound 9c: Colourless liquid; Yield 90% (195 mg); δH (200 MHz): 7.36-7.21 (m, 4H), 5.46 (d,
J=7.8, 1H), 4.47-4.36 9m, 2H), 4.14 (s, 2H), 1.64-1.48 (m, 3H), 1.36(s, 9H), 0.89-0.87 (m, 6H);
13C{1H} (50 MHz): 173.0, 155.8, 140.4, 132.3, 129.2, 127.5, 127.1, 120.9, 89.23, 84.4, 79.7, 53.1, 41.7,
41.4, 28.3, 24.7, 22.9, 22.0, 15.2; HRMS (ESI-TOF) m/z [M + H+] Calcd for C21H30BrN2O3 437.1440;
Found 437.1443.
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Compound 9d: Colourless liquid; Yield 90% (210 mg); δH (200 MHz): 7.35-7.32 (m, 1H), 7.22-7.07
(m, 8H), 6.59 (m,1H), 5.23 (bs, 1H), 4.41-4.31 (m, 3H), 4.09 (s, 2H), 3.58 (t, J=6.4, 1H), 2.99 (d,
J=6.6, 2H), 1.37 (s, 9H); 13C{1H} (50 MHz): 171.4, 155.6, 140.2, 136.7, 132.5, 129.4, 128.7,
18.3,127.4, 126.9, 121.2, 89.3, 84.6, 80.5, 61,8, 42.0, 38.8, 28.4, 15.3; HRMS (ESI-TOF) m/z [M + H+]
Calcd for C24H28BrN2O3 471.1283; Found 471.1285.
Compound 9e: Colourless liquid; Yield 85% (212 mg); δH (200 MHz): 7.34-7.22 (m, 3H), 7.05 (d,
J=7.8, 3H), 6.76-6.69 (m, 3H), 5.36-5.32 (m, 1H), 4.51-4.36 (m, 3H), 4.14 (s, 2H), 3.75(s, 3H), 2.99(d,
13
J=6.6, 2H), 1.38(s, 9H); C{1H} (50 MHz): 171.5, 158.5, 155.5, 140.2, 130.4, 129.2, 128.7, 128.1,
127.3, 121.1, 114.1, 89.3, 84.5, 80.1, 55.3, 41.9, 37.9, 28.4, 15.2; HRMS (ESI-TOF) m/z [M + H+]
Calcd for C25H30BrN2O3 501.1389; Found 501.1391.
Compound 10: White crystalline solid; Yield 95% (19 mg); m.p. 225-227C; δH (400 MHz): 9.02 (s,
1H), 8.21 (d, J = 6.8 Hz, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.71-7.67 (m, 1H), 7.63-7.59 (m, 1H), 7.45 (d, J
= 8.4 Hz, 1H), 7.40-7.36 (m, 1H), 7.25 (d, J = 6.8 Hz, 1H), 4.67, 4.62 (ABq, J = 16.2 Hz, 1H), 4.16,
4.07 (ABq, J = 16.2 Hz, 1H), 4.01 (s, 3H), 3.50 (s, 3H); 13C{1H} (100 MHz): 167.8, 166.6, 138.3, 137.8,
132.9, 132.5, 131.6, 131.2, 131.0, 131.0, 130.5, 130.3, 129.0, 128.4, 127.0, 125.6, 122.8, 105.3, 57.6,
56.2, 52.5, 52.3; HRMS (ESI-TOF) m/z [M + H+] Calcd for C22H19O6S 411.0902; Found 411.0900.
Synthesis of compound 11:
A solution of 10 (0.5 mmol, 205 mg) in THF (15 ml) was taken in a two-neck r.b. flask. 8 eq. of finely
ground NaBH4 (4 mmol, 152 mg) was added. Drop wise addition of 10 mL of MeOH followed at 60 C
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for 4 h. The reaction was quenched with NH4Cl (aq.), extracted with EtOAc, dried over anh. Na2SO4,
concentrated and subjected to column chromatographic purification (Si-gel 60-120 mesh, PE:EA=1: 1).
Isolated as white solid; Yield 80% (140 mg); mp 230-232 C; δH (400 MHz): 8.21 (s, 1H), 7.66 (d, J =
7.6 Hz, 1H), 7.56-7.52 (m, 2H), 7.48-7.45 (m, 1H), 7.38-7.35 (m, 1H), 7.30-7.26 (m, 1H), 7.16 (d, J =
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7.2 Hz, 1H), 5.16 (s, 2H), 4.61 (s, 2H), 4.28-4.11 (m, 4H); C{1H} (100 MHz): 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.
HRMS (ESI-TOF) m/z [M + H+] Calcd for C20H19O4S 355.1004; Found 355.1006.
Synthesis of compound 12: The diol 11 (0.5 mmol, 177 mg) was treated with 3.0 eq. of mesyl chloride
(1.5 mmol, 115 l in 1 ml CH2Cl2) and 3.0 eq. of Et3N (1.5 mmol, 210 l) in CH2Cl2 at 0 C for 15 min.
The solvent was evaporated in vacuum and the reaction crude was directly treated with 5.0 eq. of NaN3 (
2.5 mmol, 162 mg) in anh. DMF for 6 h. The reaction mixture was poured into water and extracted with
EtOAc, washed with brine, dried over anh. Na2SO4, evaporated in vacuum and purified by column
chromatography (Si-gel 60-120 mesh, PE: EA = 2:1). Isolated as colourless viscous liquid; Yield 90%
(180 mg); δH (400 MHz): 8.08 (s, 1H), 7.56-7.22 (m, 7H), 4.79 (s, 2H), 4.65 (s, 2H), 4.15 (s, 2H), 4.04,
13
3.89 (ABq, J = 13.6 Hz, 2H); C{1H} (100 MHz): 136.9, 136.2, 134.1, 133.4, 131.4, 131.1, 130.0,
129.8, 129.4, 129.2, 128.4, 126.9, 126.6, 121.3, 57.2, 56.0, 53.0, 52.6; HRMS (ESI-TOF) m/z [M + H+]
Calcd for C20H17N6O2S 405.1134; Found 405.1137.
Synthesis of compound 13: The diazide 12 (0.05 mmol, 20 mg) was treated with 3.0 eq. of TPP (0.15
mmol, 40 mg) in 5 ml THF-H2O (10:1) for 6 h at room temperature. The product was purified by
column chromatography (Si-gel 60-120 mesh, DCM: MeOH = 4:1). Isolated as brown viscous oil; Yield
75% (13 mg); δH (400 MHz): 8.06 (s, 1H), 7.51-7.02 (m, 7H), 4.53 (s, 2H), 4.28 (bs, 2H), 4.05 (s, 2H),
3.36-3.53 (m, 3H).
Synthesis of compound 13a: The diazide 12 (0.5 mmol, 200 mg) was treated with 3.0 eq. of TPP (1.5
mmol, 400 mg) in 15 ml THF-H2O (10:1) for 6 h at room temperature. 2.0 eq of Et3N (1.0 mmol, 140
l) and 2.2 eq. of Boc anhydride (1.1 mmol, 240 l) were added in succession at rt and stirred for 4 h.
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The product was purified by column chromatography (Si-gel 60-120 mesh, PE: EA = 2:1). Isolated as
white solid; Yield 45% (125 mg); mp 140-142 C; δH (400 MHz): 8.13 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H),
7.51-7.40 (m, 3H), 7.34 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 6.8 Hz, 1H), 4.89 (bs,
1H), 4.78 (s, 2H), 4.60 (bs, 3H), 4.16-4.07 (m, 2H), 3.86-3.83 (m, 2H), 1.49 (s, 9H), 1.35 (s, 9H);
13C{1H}(100 MHz) 155.8 (2 signals), 137.5, 137.1, 136.4, 134.9, 132.7, 131.5, 129.8, 129.5, 129.3,
128.8, 128.3, 127.7, 127.0, 126.4, 121.4, 80.1, 79.8, 57.7, 56.3, 43.3, 42.4, 28.6, 28.5; HRMS (ESI-
TOF) m/z [M + H+] Calcd for C30H37N2O6S 553.2372; Found 553.2369
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Procedure of HATU mediated coupling for synthesis of 6a/7a: A solution of N-Boc L-alanine (95
mg, 0.5 mmol, 2.0 eq), HATU (2.0 eq, 0.5 mmol, 190 mg) and HOBt (2.0 eq, 0.5 mmol, 70 mg) was

prepared in anh. DMF (2 mL) at 0 C and an ice-cold solution of the diamine (1.0 eq, 0.25 mmol, 88
mg) and anh. DIPEA (4 eq, 1.0 mmol, 175 l) in anh. DMF (2 mL) was added drop wise to it. The
reaction was left for 72 h to gradually attain the room temperature. The work-up of the reaction was
done according to the usual procedure with water and EtOAc. The reaction product was purified by
column chromatography (Si-gel 60-120 mesh, PE: EA = 1:1). Isolated yield was 35 mg (20% ).
Acknowledgement
DST is acknowledged for the J C Bose Fellowship grant to AB which supported the research. TM and
SJ are grateful to CSIR and UGC, Government of India, respectively, for research fellowships. The
NMR facility has been provided at IIT Kharagpur by DST under the IRPHA programme. Prof. S. Hajra
is thanked for helping with the hplc analysis.
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Supporting Information Available: Spectral data for all new compounds;various H- and C-NMR
spectra, crystallographic data and computational details. This information is available free of charge via
the Internet at http://pubs.acs.org.
References and Notes
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1. (1) (a) Garratt, P. J.; Neoh, S. B. J. Org. Chem. 1979, 44, 2667. (b) Cheng,Y. S. P.; Garratt, P. J.;
Neoh, S. B.; Rumjanek, V. H. Isr. J. Chem. 1985, 26, 101. (c) Braverman, S.; Duar, Y.; Segev, D.
Tetrahedron Lett. 1976, 17, 3181. (d) Zafrani, Y.; Gottlieb, H. E.; Sprecher, M.; Braverman, S. J. Org.
Chem. 2005, 70, 10166. (e) Mitra, T.; Das, J.; Maji, M.; Das, R.; Das, U. K.; Chattaraj, P. K.; Basak, A.
RSC Advances 2013, 3, 19844. (f) Mondal, S.; Basak, A.; Jana, S.; Anoop, A. Tetrahedron 2012, 68,
7202. (g) Mukherjee, R.; Basak, A. Synlett 2012, 23, 877. (h) Mukherjee, R.; Mondal, S.; Basak, A.;
Mallick, D.; Jemmis, E. D. Chem. Asian J. 2012, 7, 957. (i) Addy, P. S.; Dutta, S.; Biradha, K.; Basak,
A.Tetrahedron Lett. 2012, 53, 19. (j) Basak, A.; Das, S.; Mallick, D.; Jemmis, E. D. J. Am. Chem. Soc.
2009, 131, 15695. (k) Das, J.; Mukherjee, R.; Basak, A. J. Org. Chem. 2014, 79, 3789.
(2) Maji, M.; Mallick, D.; Mondal, S.; Anoop, A.; Bag, S. S.; Basak, A.; Jemmis, E. D. Org. Lett. 2011,
13, 888.
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(3) Mondal, S.; Maji, M.; Basak, A. Tetrahedron Lett. 2010, 52, 1183.
(4) (a) Mondal, S.; Mitra, T.; Mukherjee, R.; Addy, P. S.; Basak, A. Synlett 2012, 23, 2582.(b) Hybrid
molecules are defined as chemical entities with two (or more than two) structural domains having
different biological functions. Meunier, B. Acc. Chem. Res. 2008, 41, 69.
(5). (a) Ecker, D. J.; Crooke, S. T. Nat. Biotechnol. 1995, 13, 351. (b) Gordon, E. M.; Barrett, R. W.;
Dower, W. J.; Fodor, S. P. A.; Gallop M. A. J. Med. Chem., 1994, 37, 1385. (c) Houghten, R. A.;
Pinilla, C.; Blondelle, S.E.; Appel, J. R.; Dooley, C. T.; Cuervo, J.H. Nature 1991, 354, 84.
(6) Mitra, T.; Das, S.; Basak, A. Tetrahedron Lett. 2009, 50, 5846.
(7) Mitra, T.; Dutta, S.; Basak, A. Tetrahedron Lett. 2010, 51, 2828.
8. CCDC Numbers for compound 3c and for compound 10 are 943869 and 943891 respectively.
9. The aminoacyl o-iodobenzylamine derivatives were prepared from o-iodobenzylamine via EDC (1-
Ethyl-3-(3-dimethylaminopropyl) carbodiimide) mediated coupling with various Boc-amino acids.
10. Experimental condition of the ECD measurement: c. 250 M in MeOH, pathlength 0.1 cm,
bandwidth 1.0 nm, data pitch 0.5 nm, temperature 25 C.
11. For computational details and references see ESI.
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TOC
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=========================================================================
5
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BocHN
S
BocHN
HN
R
O
O
O
S
R
O
O
S
O
HN
O
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O
NHBoc
NH
O
R
NH
NHBoc
HN
R
O
NHBoc
NH
+
R
R
NHBoc
O
O
5a-e
7a-e (SSaS)
6a-e (SRaS)
R = Me, CHMe2, CH2CHMe2, Bn, CH2-C6H4-p-OMe
Substrate Diastereomeric ratio
5a
5b
5c
5d
5e
95:5 (6a:7a)
98:2 (6b:7b)
95:5 (6c:7c)
97:3 (6d:7d)
97:3 (6e:7e)
==========================================================================
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