Diastereoselective synthesis of an advanced intermediate of the crocacin family using asymmetric transfer hydrogenation-DKR and Marshall allenylation as key reactions

Article abstract of DOI:10.1016/j.tet.2015.09.057

The natural product of a crocacin-family structural scaffold bearing consecutive anti-anti-syn stereogenic centers was accomplished by means of ATH-DKR and Marshall allenylation reactions with high stereo-control levels. The salient feature of this process is that a single catalytic asymmetric Ru-complex was used for the chirality genesis of pivotal reactions with a high substrate-to-catalyst ratio.

Full text of DOI:10.1016/j.tet.2015.09.057

Accepted Manuscript
Diastereoselective synthesis of an advanced intermediate of the crocacin family using
asymmetric transfer hydrogenation-DKR and Marshall allenylation as key reactions
Kumaraswamy Gullapalli, Vykunthapu Narayanarao, Shanigaram Prakash, Guniganti
Balakishan
PII:
S0040-4020(15)30085-5
10.1016/j.tet.2015.09.057
TET 27154
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 July 2015
Revised Date: 11 September 2015
Accepted Date: 22 September 2015
Please cite this article as: Gullapalli K, Narayanarao V, Prakash S, Balakishan G, Diastereoselective
synthesis of an advanced intermediate of the crocacin family using asymmetric transfer hydrogenation-
DKR and Marshall allenylation as key reactions, Tetrahedron (2015), doi: 10.1016/j.tet.2015.09.057.
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1
ACCEPTED MANUSCRIPT
Graphical Abstract
Diastereoselective synthesis of an advanced intermediate of the
crocacin family using asymmetric transferhydrogenation-DKR
and Marshall allenylation as key reactions
Leave this area blank for abstract info.
Kumaraswamy Gullapalli a b, Vykunthapu Narayanarao a, Shanigaram Prakash a and Guniganti Balakishana
OH
O
Tos
Catalytic asymmetric
transfer hydrogenation
Ph
Ph
N
Marshall
allenylation
Me O
OMe
O
O
Ru
N
N
OMe
H
OMe OMe
Me Me
94 : 6 dr, 98% ee
OMs
N
Ph
1 mol% Cat-B
Me Me
Ph
+
N R1
Ph
H
+
Me Me
HCO2H : Et3N (5 : 2)
DCM, 50 0
24 h
O
Chan alkyne
reduction
C
Me
Me
Crocacin C
TIPS
A single catalytic asymmetric Ru-complex was used for the chirality genesis with high substrate-to-catalyst ratio and elaborated to the synthesis of advanced intermediate
of the crocacin family.

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Diastereoselective synthesis of an advanced intermediate of the crocacin family
using asymmetric transfer hydrogenation-DKR and Marshall allenylation as key
reactions
Kumaraswamy Gullapalli a b, Vykunthapu Narayanarao a, Shanigaram Prakash a and Guniganti Balakishana
a Organic & Biomolecular Chemistry Division,
Indian Institute of Chemical Technology, Hyderabad-500 607, India.
b Academy of Scientific and Innovative Research.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The natural product of a crocacin-family structural scaffold bearing consecutive anti-anti-syn
stereogenic centers was accomplished by means of ATH-DKR and Marshall allenylation
reactions with high stereo-control levels. The salient feature of this process is that a single
catalytic asymmetric Ru-complex was used for the chirality genesis of pivotal reactions with a
high substrate-to-catalyst ratio.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Crocacin
ATH-DKR reaction
Marshall allenylation
Chan alkyne reduction
Propargyl mesylate
Corresponding author. Tel.: + 91-40-27191614; fax: + 91-40-27193275; e-mail: gkswamy_iict@yahoo.co.in

Introduction
and an aldehyde, which expectedly arises from 4. In principle, the
ACCEPTED MANUSCRIPT
key intermediate 4 can be accessed via the ATH-DKR reaction of
racemic α-methylated β-keto Weinreb amide (±)-6. Also, 4 could
be readily prepared from enantioenriched propargyl alcohol
which can be in turn generated with the ATH procedure.
Polyketide natural products with an embedded anti-anti-syn
stereotetrad structural motif were isolated from the
myxobacterium chondromyces crocatus by Jansen et al. in 1994.1
At the same time, they unveiled the relative stereochemistry of
the parent crocacin C (1c) and its congeners A (1a), B (1b) and D
(1d) through a synthesis.2
OMe OMe
Me
3
O
1
11
5
6
8
9
NH2
7
Me
Me
Marshall
allenylation
Me
Catalytic asymmetric
transfer hydrogenation
1c
OMe OMe
O
Me
O
OMe OMe
N
R1
+
H
I
NH2
Me
Me
3
Chan alkyne
reduction
Me
2
Me
R1
=
R1
=
OMe
OH
OH
O
O
O
N
O
N
OMs
H
H
OMe
O
1a, Crocacin A
O
1b, Crocacin B
N
+
Me
5
Me
Me
1c, R1 = H, Crocacin C
R1
=
4
OMe
O
N
O
O
H
O
1d, Crocacin D
OMe +
Me
N
7
TIPS
Me
Me
(+)-6
Figure 1: Natural products of the crocacin family
Scheme 1. Retro-synthetic analysis of crocacin C, 1c.
From a structural viewpoint, the crocacin family is highlighted by
the presence of common scaffold, i.e., polyenic
a
a
Accordingly, the required racemic α-methylated β-keto
Weinreb amide (±)-6 was prepared9 and subjected to the ATH-
DKR reaction. Initially, we planned to exploit the 18-electron
polypropionate carbon skeleton bearing consecutive anti-anti-syn
stereogenic centers with a conjugated (E, E)-dienamide unit. This
critical structural unit is recognized as a crocacin C unit (1c),
while crocacins A, B, and D are additionally attached with
pendant dipeptides of glycine and a 6-aminohexenoic or a 6-
aminohexadienoic acid to the nitrogen atom (Figure 1).
precursor
diphenylethanediamine](ɳ6-p-cymene) cat-A and a formic acid /
triethylamine azeotropic mixture as
hydrogen source.7
RuCl[(1R,
2R)N-p-toluenesulfonyl-1,2-
a
Employing cat-A, the racemic (±)-6 was reduced to
enantiomerically enriched alcohol 4 at a yield of 92% with 92 :
8 d.r. and 96% ee with a substrate-to-catalyst (S/C) ratio of 30
(Table 1, entry 1).
Results and Discussion
The distinctive anti-anti-syn stereotetrad coupled with a
conjugated (E, E)-dienamide structural feature and a broad range
of biological activities3 culminated in a plethora of total
syntheses4 and formal syntheses5 of crocacin C (1c) and its
congeners A (1a), B (1b) and D (1d). These earlier successes
took advantage of a chiral-auxiliary-based aldol reaction to install
initial syn-stereocenters (C8-C9).
Recently, we reported the diastereo-divergent synthesis of an
advanced intermediate of (+)-brevisamide.6 The significant
feature of this methodology is the two contiguous stereogenic
centers generated by a highly efficient catalytic asymmetric
transfer hydrogenation (ATH) process via dynamic kinetic
resolution (DKR). Later, an efficient ATH-DKR of α-methylated
β-keto ester substrates was observed and the respective products
were furnished at a high yield with a remarkable enantiomeric
excess (ee).7 Further, with relevance to showcase this synthetic
methodology coupled with Marshall’s allenylation8 herein, we
describe a concise diastereoselective formal synthesis of (+)-
crocacin C. wherein the challenging anti-anti-syn stereotetrad
(C6-C9) can be envisioned for installation in a highly diastereo-
and enantioselective manner.
Table 1: Synthesis of enantioenriched 4 via the ATH-DKR reaction
O
O
OH
O
1 mol% Cat-B
OMe
OMe
HCO2H : Et3N (5 : 2)
N
N
DCM, 50 0
24 h
C
Me
Me
Me
4, 94% yield
94 :6 dr, 98% ee
Me
(+)-6
-
Tos
Tos
Ph
N
Ph
Ph
N
Ru
Ru
N
N
H H
Cl
Ph
H
Cat-A
Cat-B
Entry
Conditions
Yield (%)b
drc
%ee
(major)
96
1
3 mole% Cat. A
HCO2H : Et3N (5:2)
DCM, rt, 24 h
92
92:8
1 mole% Cat. B
HCO2H : Et3N (5:2)
DCM, rt, 24 h
60
94
68
94:6
94:6
92:8
-
2
3
1 mole% Cat. B
HCO2H : Et3N (5:2)
DCM, 50 °C, 24 h
98
92
1 mole% Cat. B
10 mole% K2CO3
The retrosynthetic analysis is depicted in Scheme 1. Preceding
work suggested that the conjugated (E, E)-dienamide could be
secured through Stille-coupling between vinyliodide 3 and
4
2-Propanol, 50 °C, 48 h
a) All reactions were carried out on a scale of 1.0 mmol. b) Isolated yields but not
optimized. c) The syn : anti ratio was determined by individual isolated weights. e) The
ee value was determined by chiral HPLC (OD-H column, 5% isopropanol in hexane;
flow rate 0.5 mL/min).
vinylstannane, which in turn was obtained from
2 by
hydrostannylation. The critical synthon 2 can be obtained from
Marshall’s allenylation protocol using the propargyl mesylate 5

The major diastereomer was separated through
stereotetrad 8 was isolated at a yield of 21% with an excellent
diastereomeric ratio (95:5) (Scheme 2).
ACCEPcTolEumDn MANUSCRIPT
chromatography and the ee value was determined by chiral
HPLC (OD-H column, 5% isopropanol in hexane; flow rate 0.5
mL/min) by resolving the corresponding racemic 4. The relative
stereochemistry of 4 was assigned based on Noyori’s protocol, 7a
i.e., R, R-diamine-Ru generates the R-configuration and also by
analogy.7b
In order improve the substrate-to-catalyst (S/C) ratio, the chiral
16-electron Ru complexes cat-B was used for the same
transformation. The desired product 4 was isolated at a yield of
94% with 94 : 6 d.r. and 98% ee with a substrate-to-catalyst
(S/C) ratio of 100 (Table 1, entry 3). With 2-propanol as a
hydrogen source, the asymmetric reduction of (±)-6 in the
presence of cat-B and K2CO3 resulted in 4, albeit at a lower yield
and with an inferior ee value (Table 1, entry 4). The optimum
catalyst loading was found to be 1 mol%, while reducing it to 0.5
mol% led to a significant drop in the yield of product 4.
Alternatively, we explored the stereoselective alkyne
reduction11 protocol, which likely ensures C10-C11 E-allylic
alcohol and a primary alcohol. As a result, the reduction of 4 with
LAH led to the expected trans-isomer 9 exclusively at a 91%
isolated yield. The primary alcohol was then formulated as
TBDPS ether 10 (TBDPSCl, imidizole, DCM) at a high yield
(94%). Subsequent etherification of 10 under a basic condition
with MeI followed by fluoride-induced deprotection under
standard conditions provided 11 at a yield of 67% (over two
steps). The Dess-Martin oxidation of 11 furnished the crude
aldehyde which without purification, was directly submitted to
Pd-catalyzed-Zn-mediated addition of a propargyl mesylate 5.
The expected anti-anti-syn stereotetrad 12 was isolated at a yield
of 68% with an excellent diastereomeric ratio (95:5 by crude
NMR) as a separable mixture (Scheme 3). The relative
stereochemistry of stereotetrad 12 was assined tentatively based
on Marshall protocal.8a
OH
OH
OH
O
i) DIBAL-H, DCM
- 78 0C, 2 h
OMs
OMe
The methylation of a secondary alcohol with MeI under
classical conditions resulted in critical intermediate 2 at a yield
74%. Compound 2 is an advanced intermediate used in the
N
Me
Me
Me
4
Me
8, 21% yield
d.r. 95 : 5
ii)
5
Me
synthesis of crocacin C (1c); a comparison of the sign of rotation
Et2Zn, Pd(OAc)2.PPh3
- 78 0C to - 20 0C, 17 h
[4k]
([α]35 + 24.3 (c 1.0, CHCl3) {lit.
([α]23 + 24.8 (c 1.0,
D
D
CHCl3)}) helped to assign its relative configuration of new and
existing stereogenic centers as 3S, 4R, 5S and 6S.
Scheme 2. Synthesis of anti-anti-syn stereotetrad 8
With the enantioenriched stereodefined acetylenic-β-keto-α-
methyl Weinreb amide 4 in hand, we advanced further for the
synthesis of an advanced intermediate of crocacin C. At the
outset, we planned to perform the reduction of 4 to provide
aldehyde with a subsequent Pd-catalyzed-Zn-mediated addition
of propargyl mesylate 5 to ensure the stereotetrad of the
crocacin.5a To this end, with the precursor propargylic mesylate 5
was conveniently prepared10 via the Noyori reduction of 4-TIPS-
3-butyn-2-one, the resulting secondary alcohol was activated as
mesyl ester with MeSO2Cl under basic conditions followed by
the removal of the TIPS group with TBAF. Weinreb amide 4 was
reduced to aldehyde with DIBAL-H at – 78 °C and the crude
aldehyde was directly submitted to the Pd-catalyzed-Zn-mediated
addition of propargyl mesylate 5. Unfortunately, the desired
Additionally, the spectroscopic data of 2 were identical in all
respects with those reported in the literature. In line with a
previous report, employing hydrostannylation and Stille-
coupling, the advanced intermediate 2 can be transformed into
the target which would constitute the total synthesis of crocacin
C (Scheme 3).
Conclusions
In conclusion, we have accomplished the syntheses of critical
intermediates of crocacin C in which four consecutive stereogenic
centers were installed by efficient catalytic asymmetric transfer
hydrogenation (ATH) via dynamic kinetic resolution (DKR) together
OH
O
OH
OMe
LiAlH4
THF
N
OH
Me
Me
4
Me
0 0C to rt, overnight
9, 91% yield
OH
i. NaH, MeI
THF, 0 0C, 3 h
TBDPSCl
imidazole
DCM, 0 0C to rt
3 h
OTBDPS
ii.
TBAF, THF
0 0C to rt, 3 h
Me
10, 94% yield
OMe OH
OMe
i. DMP, DCM
0
0C, 2 h
OH
OMs
Me
Me
Me
11, 67% yield
(over two steps)
ii.
12, 68% yield
(over two steps)
d.r. 95 : 5
5
Me
Et2Zn, Pd(OAc)2.PPh3
- 78 0C to - 20 0C, 17 h
OMe OMe
ref. 8a
Crocacin-C
NaH, MeI
THF, 0 0C, 3 h
Me
Me
2, 74% yield
Scheme 3. Synthesis oftheC20-C21trans-double bond possessing anti-anti-syn stereotetrad 2
with Marshall’s allenylation. This process is significant in how it
demonstrated that using a single Noyori asymmetric catalyst can

generate two variant intermediates with high diastereo- and
85.0, 63.9, 61.2, 40.8, 32.0, 11.6; IR (KBr): 3402, 2926,
ACCEPTED MANUSCRIPT
enantioselectivity. Further, the complementary sense catalyst can
provide a set of distereo-divergent congeners of this family.
Overall, the high catalytic efficiency, enantioselectivity, and
operational convenience can make this process adoptable for
similar strategies. Further optimization and application of this
strategy for the synthesis of crocacin family members and related
natural molecules are at present under investigation in our lab.
2192, 1636, 1448, 1261, 1029, 991, 757 cm-1; MS (ESI) m/z
:
270 (M+Na)+; HRMS: calculated for C14H17O3NNa [M+
Na]+, 270.1101, found 270.1103.
(3
5-diol (8): To a DCM (5.0 mL) solution of
mmol) was added drop wise DIBAL-H (1.0
R
, 4
S
, 5
S
, 6
S
)-4, 6-Dimethyl-1-phenylocta-1, 7-diyne-3,
(500 mg, 2.02
in toluene,
4
M
o
2.43 mL, 2.43 mmol) at -78 C and the resulting reaction
mixture was stirred for 1 h at same temperature. To this
reaction mixture was added saturated sodium potassium
tartrate solution, and the resultant slurry was stirred for 6 h.
The organic layer was separated and aqueous layer was
extracted with ethyl acetate (2 x 30 mL). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4 and concentrated to give crude as colourless oil,
which was directly used for next step without purification.
To a stirring solution of Pd(OAc)2 (30.00 mg, 0.09
mmol, 0.050 equiv) in THF (5.0 mL) at -78 °C was added
PPh3 (24.39 mg, 0.09 mmol, 0.050 equiv), above aldehyde
Experimental Section
General information:
All reactions were conducted under an atmosphere of
nitrogen (IOLAR Grade I). Apparatus used for reactions
were oven dried. THF was distilled over sodium
benzophenone ketyl before use and Dichloromethane
distilled over calcium hydride.
(R)-But-3-yn-2-yl
methanesulfonate was prepared according to the reported
procedure.8c All other chemicals used were commercially
available. Progress of the reactions was monitored by TLC
on pre-coated silica gel 60 F-254. Evaporation of solvents
was performed at reduced pressure on a rotary evaporator.
Column chromatography was carried out with silica gel
(350 mg, 1.86 mmol), and mesylate (R)-5 (413 mg, 2.80
mmol, 1.50 equiv), sequentially. Then, diethylzinc (5.60
mL, 1 M in hexane, 3.00 equiv) was added over 10 min, and
the mixture stirred for 5 min and allowed to warm to -20 °C
and left for overnight stirring. The reaction was quenched
with NH4Cl:Et2O (1:1), and the layers were separated. The
Et2O layer was washed with brine, dried over Na2SO4,
concentrated to give crude residue which was purified by
column chromatography over silicagel using 30% ethyl
acetate : hexane as eluent to give 92 mg (21%, over two
1
grade 60-120 and 100-200 mesh. H NMR spectra were
recorded at 300 & 500 MHz and 13C NMR 75 MHz in
CDCl3. Chemical shifts
(
δ
)
are reported in ppm.
1
Tetramethylsilane (δ = 0.00 ppm for H) and CDCl3 (δ =
77.00 ppm for 13C) were used as the internal standard. Scalar
coupling constants (J) are reported in hertz (Hz). The
following abbreviations are used to designate the
multiplicities: s = singlet, d = doublet, t = triplet, dd =
doublet of doublet, m = multiplet, br.s = broad singlet. The
IR (FT-IR) spectra were measured using KBr pellet or as
film. Mass spectral data were compiled using MS (ESI), and
High resolution mass spectra (HRMS) were recorded by ESI
probe in positive mode using ORBITRAP analyser. Optical
rotations were recorded on high sensitive polarimeter with
1mL cell. The enantiomeric purity was determined by chiral
HPLC using Chiral OD-H, column.
steps) of product 8 as a major diastereomer as a light yellow
oil; Rf 0.50 (30% EtOAC/Hexane), [α]35D = + 11.25 (
c
= 1.4,
1
CHCl3); H NMR (500 MHz, CDCl3): δ 7.46-7.42 (2H, m,
ArH), 7.33-7.29 (3H, m, ArH), 4.86 (1H, d,
C3H), 3.73 (1H, dd, = 9.2 Hz, 2.2 Hz, C5H), 3.58 (1H, br.s,
C3OH), 2.79-2.73 (1H, m, C6H), 2.50 (1H, br.s, C5OH),
2.28-2.19 (1H, m, C4H), 2.16 (1H, d, = 2.5 Hz, CCH), 1.33
(3H, d, = 7.1 Hz, C6CH3), 1.05 (3H, d, = 7.1 Hz, C4CH3);
J = 2.9 Hz,
J
J
J
J
13C NMR (75 MHz): 131.7, 128.4, 128.3, 122.6, 88.3, 86.1,
83.7, 76.6, 71.6, 66.7, 42.5, 30.1, 18.0, 12.9; IR (KBr):
3428, 2923, 2853, 2192, 1744, 1630, 1261, 1102, 1024, 802
cm-1; MS (ESI) m/z: 265 (M+Na)+; HRMS: calculated for
C16H18O2Na [M+ Na]+, 265.1199, found 265.1203.
(
2
R
,
3
R
)-3-Hydroxy-
phenylpent-4-ynamide (4): To a DCM solution (5 mL) of
β-keto-α-methyl weinreb amide (1 mol) (±)- was added
N
-methoxy-
N
,
2-dimethyl-5-
6
pre-dissolved ruthenium catalyst B2 [0.01 mol in CH2Cl2
(2.0 mL)] and formic acid-triethylamine azeotropic mixture
[(5:2), 0.1 mL] successively under argon. While stirring, the
resulting reaction mixture was heated at 55 °C for 24 h.
After which time, the reaction mixture was cooled to rt,
diluted with water and then extracted with ethyl acetate. The
organic solution was washed with aqueous NaHCO3 and
brine. The organic layer was dried over Na2SO4,
concentrated under reduced pressure and the solvent
evaporated under reduced pressure. The crude residue was
purified over silica gel column chromatography using 30%
EtOAc : hexane as eluent to afford 2.27 g (94%) of product
2
4
S
, 3
S, E)-2-Methyl-5-phenylpent-4-ene-1, 3-diol (9): To
(2 g, 8.1 mmol) in THF (30 mL) at 0° C was added
LiAlH4 (2.5 g, 64.8 mmol). The gray solution was stirred at
0° C. for 10 minutes, after which time the cooling bath
removed and stirring continued at room temperature for 12
h. Then, the reaction mixture was cooled to 0 °C and
quenched slowly by dropwise addition of 1
M HCl and the
reaction mixture allowed stirring at room temperature (~ 6
h). Filtered the reaction mixture and extracted with EtOAc.
The organic layer was dried over anhydrous NaSO4, filtered
and concentrated under reduced pressure. The crude residue
was purified over silica gel column chromatography using
50% EtOAc : hexane as eluent afforded 1.42 g (91%) of
4
as a major syn-diastereomer with 98% ee. HPLC analysis
on a Daicel Chiralcel OD-H column: 95/5 -hexane/ -PrOH,
n
i
product
9
. Rf 0.40 (50% EtOAC/Hexane), [α]35D= - 7.5 (
c
=
1
flow rate 1.0 mL/min, λ = 254 nm: major = 29.38 min;
0.9, CHCl3); H NMR (300 MHz, CDCl3): δ 7.41-7.37 (2H,
m, ArH), 7.35-7.29 (2H, m, ArH), 7.27-7.21 (1H, m, ArH),
6.63 (1H, d, J = 15.8 Hz, C5H), 6.29 (1H, dd, J = 15.8 Hz,
minor = 19.75 min; Rf 0.40 (35% EtOAC/Hexane), [α]35D= +
1
8.46 (
c
= 0.9, CHCl3); H NMR (300 MHz, CDCl3): δ 7.18-
7.42 (2H, m, ArH), 7.33-7.27 (3H, m, ArH), 4.95 (1H, d,
3.7 Hz, C2CH), 4.04 (1H, br.s, OH) 3.75 (3H, s, NOMe),
3.26-3.14 (4H, m, OMe, CH), 1.42 (3H, d, = 7.6 Hz, CH3);
13C NMR (75 MHz): 176.5, 131.7, 128.4, 128.2, 122.5, 87.9,
J
=
6.4 Hz, C4H), 4.51-4.47 (1H, m, C3H), 3.78-3.68 (2H, m,
CH2), 2.83 (1H, br.s, C1OH), 2.60 (1H, br.s, C3OH), 2.11-
2.01 (1H, m, C2H), 0.93 (3H, d,
(75 MHz): 131.1, 129.6, 128.6, 127.6, 126.4, 75.8, 66.3,
J
J
= 7.1 Hz, CH3); 13C NMR

40.1, 11.4; IR (KBr): 3428, 2923, 2853, 2192, 1744, 1630,
purified over silica gel column chromatography using 40%
ethyl acetate: hexane as eluent to give compound 11, as
ACCEPTED MANUSCRIPT
1261, 1102, 1024, 802 cm-1; MS (ESI) m/z: 215 (M+Na)+;
HRMS: calculated for C12H16O2Na [M+ Na]+, 215.1043,
found 215.1048.
colourless oil. Yield: 0.235 g, 92%. Rf 0.50 (40%
1
EtOAC/Hexane), [α]35 = + 26.60 (
c
= 1.0, CHCl3); H
D
(3
phenylpent-1-en-3-ol (10): To a stirred DCM solution (10
mL) of (1 g, 5.20 mmol) and imidazole (0.532 g, 7.81
S
, 4
S
,
E
)-5-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1-
NMR (300 MHz, CDCl3): δ 7.46-7.39 (2H, m, ArH), 7.38-
7.30 (2H, m, ArH), 7.30-7.21 (1H, m, ArH), 6.58 (1H, d,
15.8 Hz, C5H), 6.17 (1H, dd, = 15.8 Hz, 7.5 Hz, C4H),
J
=
9
J
mmol) was added TBDPSCl (1.43 g, 5.20 mmol) at 0° C.
The resulting reaction mixture was stirred 3 h at room
temperature, and diluted with saturated NaHCO3 (10 mL)
and extracted with ethyl acetate (2 x 20 mL). The organic
layer was washed with brine, dried over anhydrous Na2SO4
and concentrated under reduced pressure. The crude residue
was purified by column chromatography using 15% ethyl
acetate : hexane as eluent to give 2.1 g (94%) as colourless
3.92-3.84 (1H, m, C3H), 3.77-3.66 (1H, m, C1H), 3.64-3.54
(1H, m, C1H), 3.33 (3H, s, OMe), 2.74 (1H, br.s, OH), 2.16-
2.02 (1H, m, C2H), 0.93 (3H, d,
J
= 7.55 Hz, CH3); 13C
NMR (75 MHz): 136.3, 133.4, 128.5, 127.8, 127.0, 126.4,
85.5, 65.5, 56.6, 39.9, 12.1; ; IR (KBr): 3424, 3027, 2929,
1953, 1723, 1451, 1085, 971, 749, 696 cm-1; MS (ESI) m/z
:
229 (M+Na)+; HRMS: calculated for C13H18O2Na [M+ Na]+,
229.1199, found 229.1195.
oil. Rf 0.40 (15% EtOAC/Hexane), [α]35 = -12.77 (c = 1.2,
(3S, 4S, 5S, 6S, E)-6-methoxy-3, 5-dimethyl-8-phenyloct-
D
1
CHCl3); H NMR (300 MHz, CDCl3): δ 7.74-7.65 (5H, m,
7-en-1-yn-4-ol (12): A dry DCM (10 mL) solution of 11
(500 mg, 2.43 mmol) was treated with NaHCO3 (611 mg, 3
eq) and Dess−Martin periodinane (1.55 g, 3.64 mmol) at 0°
C, and the resulting reaction mixture was allowed to stir 1 h
at same temperature until completion as indicated by TLC
analysis. The reaction was quenched by the sequential
addition of satd. aq Na2S2O3 (5 mL) and satd. aq NaHCO3 (5
mL) and extracted with DCM. The combined organic phases
were washed with brine (10 mL), dried over Na2SO4,
filtered, and concentrated under vacuum to afford aldehyde
as pale yellow oil, which was submitted to next step.
ArH), 7.46-7.36 (7H, m, ArH), 7.36-7.29 (2H, m, ArH),
7.27-7.21 (1H, m, ArH), 6.70 (1H, d,
6.27 (1H, dd, = 15.8 Hz, 5.6 Hz, C4H), 4.55-4.51 (1H, m,
C3H), 3.76-3.67 (2H, m, CH2), 3.29-3.26 (1H, m, OH), 2.11-
2.05 (1H, m, C3H), 1.08 (9H, s, -BuSi), 0.92 (3H, d,
J = 15.8 Hz, C5H),
J
t
J =
7.17 Hz, CH3); 13C NMR (75 MHz): 137.6, 135.6, 134.8,
132.9, 132.8, 130.1, 130.3, 129.8, 128.5, 127.8, 127.4,
126.4, 75.3, 67.7, 40.4, 26.8, 19.1, 11.5; IR (KBr): 3435,
3049, 2929, 1959, 1718, 1470, 1261, 1109, 822, 702 cm-1;
MS (ESI) m/z: 453 (M+Na)+; HRMS: calculated for
C28H34O2SiNa [M+ Na]+, 453.2220, found 453.2229.
To a stirring solution of Pd(OAc)2 (24.8 mg, 0.11 mmol,
0.050 equiv) in THF (5.0 mL) at -78 °C was added PPh3
(28.90 mg, 0.11 mmol, 0.050 equiv), above aldehyde (450
tert-Butyl
phenylpent-4-en-1-yl)oxy)diphenylsilane
suspension of NaH (68 mg, 2.81 mmol) in dry THF (6 mL)
was treated with a THF (5 mL) solution of (1.1 g, 2.56
(((2
S,
3S
,
E
)-3-methoxy-2-methyl-5-
(10a):
A
mg, 2.21 mmol), and mesylate
(R)-5 (490 mg, 3.30 mmol,
9
1.50 equiv), respectively. Then, diethylzinc (6.62 mL, 1
M
mmol), and the resulting mixture was stirred at 0° C for 15
min. The solution was then treated with MeI (0.21 mL, 3.32
mmol) and the resulting reaction mixture was stirred at rt
until TLC analysis indicated reaction completion (12 h). The
reaction was quenched with satd. aq solution of NH4Cl (5
mL), and the layers were separated. The organic layer was
washed with brine (5 mL), and the aqueous layer was
extracted with diethyl ether (3 × 5 mL). The combined
organic extracts were dried over anhydrous Na2SO4, filtered,
and concentrated followed by purification by column
chromatography on silica gel using 10% ethyl acetate :
Hexane gave 820 mg (72.2%) of product 10a; Rf 0.50 (10%
in hexane, 3.00 equiv) was added over 10 min, and after
stirring for 5 min the mixture was warmed to -20 °C and left
overnight stirring. The reaction mixture was quenched with
NH4Cl:Et2O (1:1), and the layers were separated. The Et2O
layer was washed with brine, dried over Na2SO4,
concentrated to give crude residue which was purified by
column chromatography over silicagel using 15% ethyl
acetate : hexane as eluent gave 386 mg (68%, over two
steps) of product 12 as a major diastereomer as a light
yellow oil. Rf 0.40 (15% EtOAC/Hexane), [α]35 = -7.12 (
c
D
1
= 1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 7.44-7.40
(2H, m, ArH), 7.36-7.32 (2H, m, ArH), 7.29-7.24 (1H, m,
EtOAC/Hexane), [α]35D = +19.47 (
(300 MHz, CDCl3): δ 7.71-7.61 (5H, m, ArH), 7.44-7.21
(10H, m, ArH), 6.55 (1H, d, = 15.8 Hz, C5H), 6.09 (1H,
dd, = 15.8 Hz, 7.7 Hz, C4H), 3.91-3.86 (1H, m, C3H), 3.70-
3.65 (1H, m, C1H), 3.63-3.58 (1H, m, C1H), 3.31 (3H, s,
OMe), 1.90-1.82 (1H, m, C2H), 1.06 (9H s, -BuSi), 1.02
(3H, d,
= 6.8 Hz, CH3); 13C NMR (75 MHz): 136.7, 135.6,
c
= 1.2, CHCl3); 1H NMR
ArH), 6.60 (1H, d,
J
= 15.9 Hz, C8H), 6.23 (1H, dd,
J = 16.0
Hz, 7.9 Hz, C7H), 4.09-4.06 (1H, m, C6H), 3.68
(
1H, d,
J =
J
4.70 Hz, OH), 3.52-3.47 (1H, m, C4H), 3.35 (3H, s, OMe),
2.68-2.60 (1H, m, C3H), 2.21-2.15 (1H, m, C5H), 2.11(1H,
J
d,
J
= 2.4 Hz, C1H), 1.33 (3H, d,
J = 7.0 Hz, C3CH3), 0.90
,
t
(3H, d, J
= 7.2 Hz, C5CH3); 13C NMR (75 MHz): 136.3,
J
133.8, 128.6, 127.9, 126.5, 85.4, 84.9, 75.6, 70.3, 56.8, 41.6,
30.2, 18.0, 12.4; IR (KBr): 3430, 2963, 2870, 2361, 1728,
1451, 1085, 971, 749, 696 cm-1; MS (ESI) m/z: 281
(M+Na)+; HRMS: calculated for C17H23O2 [M+ H]+,
259.1693, found 259.1699.
135.5, 133.8, 133.7, 132.5, 129.5, 129.2, 128.5, 127.6,
127.5, 126.5, 83.1, 65.5, 56.5, 41.3, 26.9, 19.3, 12.2; IR
(KBr): 3026, 2926, 2855, 1956, 1737, 1651, 1459, 1108,
968, 701 cm-1; MS (ESI) m/z: 467 (M+Na)+; HRMS:
calculated for C29H36O2SiNa [M+ Na]+, 467.2377, found
467.2389.
((3S, 4R, 5S, 6S, E)-3, 5-Dimethoxy-4, 6-dimethyloct-1-
en-7-yn-1-yl)benzene (2): A THF (2 mL) suspension of
NaH (34 mg, 1.40 mmol)) was treated with a solution of
THF (2 mL) containing 12 (300 mg, 1.16 mmol), and the
resulting mixture was stirred at 0 °C for 15 min. The
solution was then treated with MeI (0.1 mL, 1.51 mmol) and
the resulting reaction mixture was stirred at rt until TLC
analysis indicated reaction completion (12 h). The reaction
(2
S, 3S, E)-3-Methoxy-2-methyl-5-phenylpent-4-en-1-ol
(11): To a THF (10 mL) solution of 10a (0.550 g, 1.24
o
mmol), was added 1.4 mL of TBAF (1
M in THF) at 0 C.
After addition, the reaction mixture was warmed to room
temperature and stirred for 1 h. Then, the solvent was
removed under reduced pressure and resulting residue was

Infante-Rodriguez, L. Domon, P. Breuilles, and D. Uguen, Bull.
mixture was quenched with satd. aq solutAionCoCf ENPHT4CEl D(5 MANUSCRIPT
Chem. Soc. Jpn. 2015, 88, 308-326; (q) A. E. Pasqua, F. D. Ferrari
a, J. J. Crawford, W. G. Whittingham, R. Marquez, Bioorg. Med.
Chem. 2015, 23, 1062–1068.
mL), and the layers were separated. The organic layer was
washed with brine (5 mL), and the aqueous layer was
extracted with diethyl ether (3 × 5 mL). The combined
organic extracts were dried over Na2SO4, filtered, and
concentrated to yield a residue which was purified by
column chromatography over silica gel using 10% ethyl
acetate : hexane as eluent to give 234 mg (74 %) of product
5. (a) M. Besev, C. Brehm and A. Fürstner, Collect. Czech. Chem.
Commun. 2005, 70, 1696-1708; (b) S. Raghavan and S. R. Reddy,
Tetrahedron Lett. 2004, 45, 5593-5595; (c) J. S. Yadav, P. V.
Reddy and L Chandraiah, Tetrahedron Lett. 2007, 48, 145-148;
(d) J. S. Yadav, M. S. Reddy, P. P. Rao and A. R. Prasad, Synlett
2007, 2049-2052.
6. G. Kumaraswamy, A. N. Murthy, V. Narayanarao, S. P. Babu and
B. Jagadeesh Org. Biomol. Chem. 2013, 11, 6751-6765.
7. (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738-8739; (b) Z. Fang and M. Wills, J.
Org. Chem. 2013, 78, 8594-8605.
8. (a) J. A. Marshall, and G. M. Schaaf, J. Org. Chem. 2001, 66,
7825- 7831; (b) J. A. Marshall, M. M. Yanik, N. D. Adams, K. C.
Ellis and H. R. Chobanian, Org. Synth. 2005, 81, 157-170; (c) J.
A. Marshall, P. Eidam and H. M. Eidam, J. Org. Chem. 2006, 71,
4840-4844.
2
. Rf 0.40 (10% EtOAC/Hexane), [α]35 = + 24.3 (
c
= 1.0,
D
1
CHCl3); H NMR (500 MHz, CDCl3): δ 7.42-7.39 (2H, m,
ArH), 7.35-7.30 (2H, m, ArH), 7.26-7.22 (1H, m, ArH), 6.59
(1H, d,
C7H), 4.17-4.14 (C6H, m, 1H), 3.57 (3H, s, C6OCH3), 3.33
(3H, s, C5OCH3), 3.15 (1H, dd, = 9.8 Hz, 2.5 Hz, C4H),
2.80-2.74 (1H, m, C3H), 2.06 (1H, d, = 2.5 Hz, C1H), 1.99-
1.93 (1H, m, C5H), 1.35 (3H, d, = 7.0 Hz, C3CH3), 0.93
(3H, d,
= 7.0 Hz, C5CH3); 13C NMR (75 MHz): 136.8,
J = 16.0 Hz, C8H), 6.20 (1H, dd, J = 16.0 Hz, 7.2 Hz,
J
J
J
9. For the synthesis of (±)-6 See SI.
10. We have used similar protocol described in ref. 8c except loading
of catalyst (0.5 mol% of catalyst).
11. (a) K.-K. Chan, N. Cohen, J. P. De Noble, A. C. Specian Jr., and
G. Saucy, J. Org. Chem. 1976, 41, 3497-3505; (b) M. M. Midland
and J. J. Gabriel, J. Org. Chem. 1985, 50, 1143-1144.
J
132.0, 129.2, 128.7, 127.5, 16.4, 85.1, 84.8, 80.9, 69.9, 61.4,
56.5, 42.8, 29.4, 18.2, 9.9; IR (KBr): 2865, 2963, 2872,
2364, 1451, 1085, 981, 749, 696 cm-1; MS (ESI) m/z: 295
(M+Na)+; HRMS: calculated for C18H24O2Na [M+ Na]+,
295.1669, found 295.1671.
Acknowledgments
We are grateful to Director, IICT, for constant encouragement.
Financial support was provided by the DST, New Delhi, India
(Grant No: SR/S1/OC-08/2011), and ORGIN (CSC-0108)
programme (CSIR) of XII Five year plan. UGC & CSIR (New
Delhi) is gratefully acknowledged for awarding the fellowship to
V. N, S. P and G.B.
Supplementary data
1
Supplementary data: Copies of H and 13C NMR spectras related
to this article can be found at http://.
References and notes
1. B. Kunze, R. Jansen, G. Hofle and H. Reichennach, J. Antibiot.,
1994, 47, 881-886.
2. (a) R. Jansen, P. Washausen, B. Kunze, H. Reichenbach and G.
Hofle, Eur. J. Org. Chem., 1999, 1085-1089; (b) P. J. Crowley, H.
I. Aspinall, K. Gillen, C. R. A. Godfrey, I. M. Devillers, G. R.
Munns, O. A. Sageot, J. Swanborough, P. A. Worthington and J.
Williams, Chimia 2003, 57, 685-691.
3. P. J. Crowley, E. A. Berry, T. Cromarti, F. Daldal, C. R. A.
Godfrey, D.-W. Lee, J. E. Phillips, A. Taylor and R. Viner,
Bioorg. Med. Chem. 2008, 16, 10345-10355.
4. (a) J. T. Feutrill, M. J. Lilly and M. A. Rizzacasa, Org. Lett. 2000,
2, 3365-3367; (b) T. K. Chakraborty, S. Jayaprakash and P.
Laxman, Tetrahedron 2001, 57, 9461-9467; (c) T. K. Chakraborty
and S. Jayaprakash, Tetrahedron Lett. 2001, 42, 497-499; (d) L. C.
Dias and L. G. de Oliveira, Org. Lett. 2001, 3, 3951-3954; (e) J. T.
Feutrill, M. J. Lilly and M. A. Rizzacasa, Org. Lett. 2002, 4, 525-
527; (f) J. T. Feutrill and M. A. Rizzacasa, Aust. J. Chem. 2003,
56, 783-785; (g) C. L. Dias, L. G. de Oliveira, J. D. Vilcachagua
and F. Nigsch, J. Org. Chem. 2005, 70, 2225-2234; (h) J. T.
Feutrill, M. J. Lilly, J. M. White and M. A. Rizzacasa,
Tetrahedron 2008, 64, 4880-4895; (i) G. Sirasani, T. Paul and R.
B. Andrade, J. Org. Chem. 2008, 73, 6386-6388; (j) G. Sirasani,
T. Paul and R. B. Andrade, Bioorg. Med. Chem. 2010, 18, 3648-
3655. (k) M. Candy, G. Audran, H. Bienayme, C. Bressy and J.-
M. Pons, J. Org. Chem. 2010, 75, 1354-1359; (l) A. E. Pasqua, F.
D. Ferrari, J. J. Crawford and R. Marquez, Tetrahedron Lett. 2012,
53, 2114-2116; (m) M. Chen and W. R. Roush, Org. Lett. 2012,
14, 1880-1883; (n) A. E. Pasqua, F. D. Ferrari, C. Hamman, Y.
Liu, J. J. Crawford and R. J. Marquez, J. Org. Chem. 2012, 77,
6989-6997; For a general review on crocacins syntheses see: (o)
R. B. Andrade, Org. Prep. Proced. Int. 2009, 41, 359-383; (p) C.

ACCEPTED MANUSCRIPT
Electronic Supplementary Information (ESI)
Diastereoselective synthesis of an advanced intermediate of the crocacin
family using asymmetric transfer hydrogenation-DKR and Marshall
allenylation as key reactions
Gullapalli Kumaraswamy,* Vykunthapu Narayanarao , Shanigaram Prakash and Guniganti Balakishan.
S2
General Information
S3-S5
Procedure for the synthesis of starting material
S6– S14 1H NMR and 13CNMR Spectra’s
S15-S16 HPLC data
S1

ACCEPTED MANUSCRIPT
General information:
All reactions were conducted under an atmosphere of nitrogen (IOLAR Grade I). Apparatus
used for reactions were oven dried. THF was distilled over sodium benzophenone ketyl before
use and Dichloromethane distilled over calcium hydride. (R)-but-3-yn-2-yl methanesulfonate
was prepared according to the reported procedure1. All other chemicals used were commercially
available. Progress of the reactions was monitored by TLC on pre-coated silica gel 60 F-254.
Evaporation of solvents was performed at reduced pressure on a rotary evaporator. Column
1
chromatography was carried out with silica gel grade 60-120 and 100-200 mesh. H NMR
13
spectra were recorded at 300 & 500 MHz and C NMR 75 MHz in CDCl3. Chemical shifts (δ)
are reported in ppm. Tetramethylsilane (δ = 0.00 ppm for 1H) and CDCl3 (δ = 77.00 ppm for 13C)
were used as the internal standard. Scalar coupling constants (J) are reported in hertz (Hz). The
following abbreviations are used to designate the multiplicities: s = singlet, d = doublet, t =
triplet, dd = doublet of doublet, ddd = doublet of doublet of doublet, m = multiplet, br.s = broad
singlet. Mass spectral data were compiled using MS (ESI), and High resolution mass spectra
(HRMS) were recorded by ESI probe in positive mode using ORBITRAP analyser. Optical
rotations were recorded on high sensitive polarimeter with 1mL cell. The enantiomeric purity
was determined by chiral HPLC using Chiral OD-H, column.
S2

ACCEPTED MANUSCRIPT
Procedure for the synthesis of starting material:
Ethyl 3-phenylpropiolate (A):
To a stirred solution of phenylacetylene (5.00 g, 49.01 mmol, 1.0 eq) in THF (50 mL) at −78 °C
was added dropwise n-butyllithium (2.5 M in hexanes, 31.40 mL, 78.4 mmol, 1.6eq). The
solution was stirred at −78 °C for 45 min, and ethyl chloroformate (6.60 mL, 68.60 mmol, 1.4eq)
was then added dropwise. After an additional 2 h at −78 °C the reaction was quenched by the
dropwise addition of saturated ammonium chloride solution. The solution was extracted with
ethyl acetate, and the combined extracts were dried over Na2SO4 and evaporated. Purification of
the residue by column chromatography on silica gel using hexane/ethyl acetate as eluent (98/2)
gave the title compound A (5.60 g, 66%).
Ethyl 2-methyl-3-oxo-5-phenylpent-4-ynoate (B):
To a solution of diisopropylamine (10.45 mL, 74.71 mmol, 2.6 equiv) in THF (70 mL) was
added a solution of n-BuLi (2.5 M in hexanes, 28.74 mL, 71.82 mmol, 2.5 equiv) dropwise at 0
°C. After stirring for 20 min at this temperature, the reaction mixture was cooled down to -78 °C
and ethyl propionate (8.25 mL, 71.84 mmol, 2.5 equiv) freshly distilled over P2O5 was added
dropwise very slowly, after stirring for 20 min at this temperature and α,β-acetylenic ester (5.0 g,
28.74 mmol, 1.0 equiv) in THF (10 mL) was added dropwise at -78 °C. After stirring for 1 h,
glacial acetic acid (5.0 mL, 86.22 mmol, 3.0 equiv) was added. The resulting suspension was
warmed to 0 °C and hydrolyzed with water (3 x 15 mL). The pH of the aqueous phase was
adjusted to pH ≈ 3 by adding a 3 M HCl aqueous solution and the layers were separated. The
S3

ACCEPTED MANUSCRIPT
aqueous phase was extracted with Et2O (3 x 50 mL) and the combined organic layers were
washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced
pressure. Purification of the residue by column chromatography on silica gel using hexane/ethyl
acetate as eluent (96/4) to gave the β-ketoester B (5.80 g, 87.8%) as a yellow oil.
Ethyl 3-hydroxy-2-methyl-5-phenylpent-4-ynoate (C):
To a stirred solution of compound B (5.0 g, 21.74 mmol, 1eq) in methanol(50.0 ml), NaBH4
o
(0.248 g, 6.52 mmol, 0.3 eq) was added allowed to stir for 15 min at 0 C. The reaction mixture
was quenched with aq.NH4Cl, extracted with EtOAc, dried over Na2SO4, and concentrated to
give crude residue. The crude residue was purified by column chromatography using
hexane/ethyl acetate (90/10) as an eluent to give hydroxyl ester C (4.80 g, 95.2%).
3-hydroxy-N-methoxy-N, 2-dimethyl-5-phenylpent-4-ynamide (D):
To a suspension of N, O-dimethylhydroxylamine hydrochloride (5.30 g, 53.88 mmol, 2.50 eq) in
benzene (40.0 ml), was added trimethyl aluminium (2M in toluene, 26.94 ml, 53.88 mmol, 2.5
o
eq) was added dropwise at 0 C and the resulting solution was stirred at rt for 1 h. To this
compound C (5.0 g, 21.55 mmol, 1eq) in benzene (10.0 ml) was added, and the resulting reaction
mixture was heated to reflux for 3 h. The reaction mixture was cooled to 0 °C, and was quenched
with 1N HCl, extracted with DCM, dried over Na2SO4, and concentrated to give crude residue.
The crude residue was purified by column chromatography using hexane / ethyl acetate (70/30)
as an eluent, to give hydroxy weinrub amide D (3.91 g, 73.5%).
N-methoxy-N, 2-dimethyl-3-oxo-5-phenylpent-4-ynamide (6):
A solution of above hydroxyl wienrub amide D (3.0 g, 12.15 mmol, 1eq) in dry DCM (40 mL)
was treated with NaHCO3 (3.06 g, 36.44 mmol, 3 eq) and Dess−Martin periodinane (10.30 g,
24.30 mmol) at 0° C, and the resulting reaction mixture was allowed to stir 1 h at same
temperature and was quenched by the sequential addition of satd aq Na2S2O3 (30 mL) and satd
aq NaHCO3 (30 mL) and extracted with DCM. The combined organic phases were washed with
brine (30 mL), dried over Na2SO4, filtered, and concentrated to give crude residue. The crude
residue was purified by column chromatography using hexane/ethyl acetate (75/25) as an eluent,
1
to give keto weinrub amide 6 (2.72 g, 91.4%). H NMR (500 MHz, CDCl3): δ 7.56 (2H , d, J=
S4

ACCEPTED MANUSCRIPT
7.32 Hz, ArH), 7.45 (1H, t, J = 7.3 Hz, ArH), 7.37 (2H, t, J = 7.3 Hz, ArH), 3.96 (1H, q, J = 7.3
13
Hz, 6.28 Hz, CH), 3.71 (3H, s, NOMe), 3.24 (3H , s, NMe), 1.48 (3H, d, J = 7.3 Hz, CH3); C
NMR (75 MHz): 183.9, 170.7, 133.3, 131.0, 128.7, 119.7, 86.5, 61.4, 52.1, 32.7, 13.1; IR (KBr):
υ = 2924, 2197, 1659, 1261, 1103, 802 cm-1; MS (ESI) m/z: 268 (M+Na)+.
S5

ACCEPTED MANUSCRIPT
1H NMR and 13CNMR Spectr’s:
1H NMR spectra of, 6 (300 MHz):
10
9
8
7
6
5
4
3
2
1
0
13C NMR of compound 6 (75 MHz):
200
175
150
125
100
75
50
25
0
S6

ACCEPTED MANUSCRIPT
1H NMR spectra of, 4 (300 MHz):
10
9
8
7
6
5
4
3
2
1
0
13C NMR of compound 4 (75 MHz):
200
175
150
125
100
75
50
25
0
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1H NMR spectra of, 8 (300 MHz):
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
13C NMR of compound 8 (75 MHz):
200
175
150
125
100
75
50
25
0
S8

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1H NMR spectra of 9 (300 MHz):
10
9
8
7
6
5
4
3
2
1
0
13C NMR of compound 9 (75 MHz):
200
175
150
125
100
75
50
25
0
S9

ACCEPTED MANUSCRIPT
1H NMR spectra of 10 (300 MHz):
10
9
8
7
6
5
4
3
2
1
0
13C NMR of compound 10 (75 MHz):
200
175
150
125
100
75
50
25
0
S10

ACCEPTED MANUSCRIPT
1H NMR spectra of compound 10a:
10
9
8
7
6
5
4
3
2
1
0
13C NMR of compound 10a:
200
175
150
125
100
75
50
25
0
S11

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1H NMR spectra of 11 (300 MHz):
10
9
8
7
6
5
4
3
2
1
0
13C NMR of compound 11 (75 MHz):
200
175
150
125
100
75
50
25
0
S12

ACCEPTED MANUSCRIPT
1H NMR spectra of 12 (500 MHz):
10
9
8
7
6
5
4
3
2
1
0
13C NMR of compound 12 (75 MHz):
200
175
150
125
100
75
50
25
0
S13

ACCEPTED MANUSCRIPT
1H NMR spectra of 2 (500 MHz):
10
9
8
7
6
5
4
3
2
1
0
13C NMR of compound 2 (75 MHz):
200
175
150
125
100
75
50
25
0
S14

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HPLC SPECTRA OF RACEMIC COMPOUND 4:
S15

ACCEPTED MANUSCRIPT
HPLC SPECTRA OF CHIRAL COMPOUND 4
S16