Stereoselective Total Synthesis of (-)-(2 S,4 R)-3′-Methoxyl Citreochlorol: Preparation and Use of New Proline-Based Auxiliary for Asymmetric Acetate Aldol Reaction

Article abstract of DOI:10.1021/acs.joc.9b03227

The first stereoselective total synthesis of (-)-(2S,4R)-3′-methoxy citreochlorol and (-)-(2S,4S)-3′-methoxy citreochlorol is demonstrated. A proline-based imidazolidinone was synthesized and used as chiral auxiliary for asymmetric acetate aldol reaction to generate initial chirality in the targeted molecule. Geminal dichloromethane functionality was introduced by the addition of in situ generated dichloromethyllithium to Weinreb's amide functional group.

Full text of DOI:10.1021/acs.joc.9b03227

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Article
Stereoselective Total Synthesis of (-)-(2S,4R)-3'-Methoxyl
Citreochlorol: Preparation and Use of New Proline
Based Auxiliary for Asymmetric Acetate Aldol Reaction.
Ranganayakulu Sunnapu, Saikumar Naik Banoth, Reyno R. S.,
Aleena Thomas, Navyasree Venugopal, and Goreti Rajendar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03227 • Publication Date (Web): 12 Feb 2020
Downloaded from pubs.acs.org on February 14, 2020
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The Journal of Organic Chemistry
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Stereoselective Total Synthesis of ()-(2S,4R)-3'-Methoxyl
Citreochlorol: Preparation and Use of New Proline Based
Auxiliary for Asymmetric Acetate Aldol Reaction.
Sunnapu Ranganayakulu, Banoth Saikumar Naik, Reyno R. S., Aleena Thomas, Navyasree Venugopal,
Goreti Rajendar*
School of Chemistry, Indian Institute of Science Education and Research, Thiruvananthapuram, Kerala,
India-695551.
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AUTHOR EMAIL ADDRESS: rajendar@iisertvm.ac.in
OMe
O
OMe
OMe
MeO
+
O
OH
O
OH OH
O
O
N
MeO
Cl
N
MeO
N
N
Ph
Cl
Ph
Ph
Ph
ABSTRACT. First stereoselective total synthesis of ()-(2S,4R)-3`-methoxy citreochlorol, and ()-
(2S,4S)-3`-methoxy citreochlorol is demonstrated. A proline based imidazolidinone was synthesized and
used as chiral auxiliary for asymmetric acetate aldol reaction to generate initial chirality in the targeted
molecule. Geminal dichloromethane functionality was introduced by the addition of in situ generated
dichloromethyllithium to Wienreb`s amide functional group.
Introduction:
In the past 60 years, plethora of halogenated secondary metabolites were isolated from various
natural sources, this number has been gradually increasing day by day by the addition of new molecules.
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These halogen containing compounds have been continuously attracting the scientific community for
their exceptional biological activities and fascinating architectures.1 Chlorinated organic compounds
show range of biological activities like anticancer, anti-biotic, anti-malarial, anti-HIV etc. Compounds
with dichloromethyl and trichloromethyl groups are special class of compounds synthesized in
biological systems by remote C-H chlorination methods using non-Heme iron chloroperoxidase
enzymes.2 gem-Dichlorinated aromatic polyketides (citreovirone) first isolated in 1986 from the mycelia
of Penicillium Citreoviride B (IF0 4692).3 Later, in 1991 compounds with similar structures
(citriochlorol) were isolated from same fungal species.4 Recently, from the same fungal species
Pencillium Sp. that grows on Pinellia ternata, several aromatic polyketide moieties with gem-dichloro
functional group were isolated by Yong et.al. in 2017.5 Structures of these compounds (figure 1) were
identified based on exhaustive NMR and mass spectroscopic studies, the absolute stereochemistry was
determined by [Rh2(OCOCF3)4]-induced ECD experiments and also attributed by the NMR analysis of
their MTPA esters. These molecules are moderately active against several human pathogenic
microorganisms like E.coli and S-aureus (MIC 62.6 and 76.6 μg/ml).
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In this report we are presenting a stereoselective approach for geminal dichlorinated polyketide
molecules. Figure 1 shows two different classes of polyketides4,5 such as citreochlorols, aromatic 1,3-
polyols connected with dichloromethyl group and others are ‘dichlorodiaportals’6 isochromenone
derived polyketides connected with dichloromethyl group. We targeted the synthesis of citreochlorols as
part of our ongoing project on synthesis of polyketide small molecules. Our initial plan for the synthesis
of citreochlorols involves two key steps first is introduction of chirality by the use of auxiliary assisted
acetate aldol reaction and the second is the induction of dichloromethyl functionality in to molecule.
Though, there are several reports available for the synthesis of halogenated biomolecules constituting
monohalomethyl stereogenic center.2d Methods for the synthesis of molecules comprising of geminal
dihalomethyl or trihalomethyl groups are very limited7 and they require selective methods for insertion
of these functional groups. In general, biological system use a direct remote C-H chlorination of
unactivated C-H groups2c,2d to provide halogenated methyl groups however, developing similar
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The Journal of Organic Chemistry
synthetic methods in laboratory is a challenging task and not known to the best our knowledge. Adding
dichloromethyl group adjacent to stereogenic centre is challenging,7b particularly the difficulty increases
when dichloromethyl group is attached with a -hydroxy or -alkoxy stereogenic center.8 Initially we
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planned two distinct approaches to introduce -hydroxy dichloromethyl functionality selectively, first
by addition of dichloromethyl lithium to ester or to amide group7b followed by selective reduction of the
resulted ketone and the second method involves a deoxy dihalogenation of -alkoxy (or) hydroxyl-
aldehyde group.9-12 After extensive studies we realized that the deoxy dihalogenation of -alkoxy
aldehyde is complicated and unproductive under existing methods.13
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OH
OMe
Cl
OH OH
OH OH
OH
O
MeO
Cl
Cl
Cl
MeO
MeO
OH
Cl
Cl
OH
O
( )-citreochlorol 2

( )-(2S,4R)-3'-methoxyl citreochlorol 1

( )-dichlorodiaportal 6

OMe
OR
Cl
MeO
O
OH
OH OH
Cl
Cl
Cl
O
OH
MeO
MeO
Cl
( )-(2R)-3'-methoxyl citreovirone 5
Cl
OR
O

R = H; ( )-(2R,4S) citreochlorol 3

R = H; dichlorodiaporthin 7
R = Me; ( )-(2R,4S)-3-methoxyl
citreochlorol 4

R = Me; 8-Methyl-11-
dichlorodiaporthin 8
“Figure 1: Citreochlorols and dichlorodiaportals, aromatic polyketides with dichloromethylene group.”
Results and Discussions:
The retrosynthetic analysis (Scheme 1) hypothesized for compounds 1 and 2 is depicted in scheme 1.
Both the natural products 1 and 2 share similar structure but differentiating at stereochemistry of diol
system hence both can be readily synthesized from common intermediate 9 by selective reduction
methods. The -hydroxy dichloroketone 9 may be synthesized from aldol adduct 10, where the
dichloromethyl group is expected to be inserted in to the structure by the addition of dichloromethyl
lithium to amide or ester functionality. Compound 10 could be obtained by an asymmetric acetate aldol
reaction from its corresponding aldehyde 11.
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OH
1
2
OH OH
Cl
Cl
3
4
5
6
7
8
9
MeO
MeO
OMe
OMe
Cl
2
OH
O
OH
O
OMe
Cl
MeO
MeO
Ax
Ax = chiral Auxilairy
OH OH
Cl
10
9
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Cl
1
OMe
OMe
O
OMe
MeO
MeO
H
O
12
11
“Scheme 1: Retrosynthetic analysis of ()-citreochlorol and ()-(2S, 4R)-3'-methoxy citreochlorol.”
Synthesis of citreochlorols started with the preparation of aldehyde 11 from commercially available
starting compound 12 (scheme 2). Methylbenzoate 12 (Scheme 2) was homologated to phenylacetic
acid 14 using general functional group transformations in four steps with 85% overall yield (scheme1).
Resulted acid 14 was then subjected for reduction using LAH to provide the alcohol 15 in 97% yield.
Alternatively a twostep method was used starting from 3,5-dimethoxy bromobenzene 16 as starting
material. Bromo compound 16 was subjected to palladium catalyzed C-C coupling reaction using
monopotassium ethylmalonate to provide phenylacetic acid derivative 17 in 65% yield (Scheme 3).14
Ester 17 up on reduction with LAH, provided the alcohol 15 almost in quantitative yield. Oxidation of
alcohol 15 under various oxidation reaction conditions followed by quick column purification provided
aldehyde 11 in poor yields 28-42%. It was observed that because of highly enaolizable nature, the
aldehyde is involving in unwanted self-aldol reactions in presence of water and producing poor yields.
This problem was rectified by oxidation of alcohol 15 using Dess-Martin periodinane, followed by a
water free work up and further purification by hexane trituration provided aldehyde 11 in 90% yield
with sufficient purity to use directly in further aldol reactions.
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The Journal of Organic Chemistry
OMe
OMe
OMe
1. LAH, THF
0 - 80 oC, 4h
NaCN, DMSO
50 oC, 2 h
1
2
3
4
O
OMe
2. SOCl2, Pyridine
Et2O, 0 - 25 oC,4 h
94% 2 steps
NaOH, EtOH:H2O
100 oC, 4 h
Cl
MeO
MeO
OH
MeO
O
13
14
12
91% 2 steps
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6
OMe
OMe
7
8
9
10
11
12
LAH, THF
DMP, CH2Cl2
23 oC, 2 h
O
80 oC, 5 h,
97%
MeO
H
MeO
OH
90%
11
15
“Scheme 2: Preparation of aldehyde 11.”
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O
O
EtO
O-K+
OMe
OMe
OMe
Pd2(allyl)2Cl2, BINAP
DMAP, Mesitylene
O
LAH, THF
80 oC, 5 h
140 oC, 20 h
65%
MeO
Br
MeO
OEt
MeO
OH
99%
16
15
17
“Scheme 3: An alternative two step method for preparation of alcohol 15.”
With the aldehyde 11 in hand, we next moved for installation of first stereogenic center using an
auxiliary assisted asymmetric aldol reaction. Chiral auxiliary assisted aldol reactions have well explored
in total synthesis of several polyketide natural products.15 Many of auxiliaries that work well for
propionate aldol reaction suffer with poor diastereoselectivities in acetate aldol reaction.16 Whereas
Nagao`s thiazolidenethiones provide superior results with -unsubstituted enolates when compared with
other auxiliaries.17 Keeping this in mind we started an acetate aldol reaction of aldehyde 11 with N-
acetyl thiozolidenethione (A1) under modified Evans reaction conditions. The reaction of titanium
enolate of N-acetyl thiozolidenethione A1 with aldehyde 11 provided the aldol adduct 18 in moderate
yields (55%) with poor diastereoselectivity (65: 35 anti:syn) (scheme 4).18 In general the change in
stoichiometry of base alters the stereochemical outcome of aldol adduct as a result of change in
structures of transition state intermediates.18 To our surprise, in present case change in quantity of base
did not alter the ratio of syn- and anti-aldol products, it provided only anti-acetate adduct 18a as major
product. Because of the unsatisfied yields and poor diastereoselectivity we have changed the auxiliary to
Vipin Nair`s N-acetyl imidazolidinone.19 Lithium and titanium enolates of N-acetyl imidazolidinone
with aldehyde 11 failed to give desired aldol product. After that an alternative method to aldol reaction
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i.e asymmetric allylation reaction was performed using catalytic Binol-Ti complex with aldehyde 11 and
allyltributyltin, the reaction provided completely decomposed products without formation of any
homoallylalcohol.18b 20, The poor selectivity and yields were expected due to highly enolizable nature of
aldehyde 11, this was clearly evident for us from its fast self-aldol reaction.21
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OMe
OMe
OMe
O
10
11
12
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S
OH
O
OH
O
S
S
TiCl4, DIPEA
O
N
DCM, -78 oC, 3 h
55%
+
S
MeO
N
MeO
N
+
S
S
MeO
H
Bn
Bn
Bn
A1
11
18a
18s
1.8 : 1
“Scheme 4: Asymmetric acetate aldol reaction under Crimmins protocol.”
As part of second ongoing project on synthesis of proline based chiral ligands and auxiliaries for
application in asymmetric catalysis, we have synthesized a proline based imidazolidinone as a new
chiral auxiliary 23 starting from S-proline and explored in aldol reaction. It was anticipated that N-acetyl
imidazolidinone 24 provides a relatively bulky and less reactive lithium enolate22 hence, it will add to
aldehyde in face selective manner to provide better asymmetric induction in acetate aldol reaction.
Synthesis of imidazolidinone 23 started from commercial methyl prolinate hydrochloride salt 19
(Scheme 5). The amine in compound 19 was protected with benzylbromide in presence of triethylamine
provided N-benzylproline ester, which was subsequently subjected to phenyl Grignard reaction to get
aminol 20 in 92% yield. The alcohol of compound 20 was transformed to amine via acid catalyzed
azidation followed by reduction of resulted azide with LAH produced amine 21 in 91% yield over two
steps. N-benzyl group in compound 21 was removed under hydrogenolysis conditions in presence of
Pd/C using Hunig`s base and methanol as solvent mixture to provide diamine 22 in quantitative yields.23
Overall the diamine 22 was synthesized in five steps with one purification by recrystallization obtained
in 63% overall yield. The diamine further treated with carbonyldiimidazole to get the auxiliary 23, in
84% yield this was further subjected to acetylation using acetyl chloride and sodium hydride to produce
the N-acetyl imidazolidinone 24 in 72% yield along with recovery of remaining starting material in
20%.
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The Journal of Organic Chemistry
1.
NaN3, H2SO4, CHCl3
0 - 25 oC, 24 h
1.
BnBr, Et3N, CH2Cl2
0 - 25 oC, 24 h
1
2
3
4
5
6
Ph
Ph
Ph
OH
Ph
COOMe
N
Cl-
2.LiAlH4, THF
0 - 25 oC, 4 h
91% two steps
N
N
+
NH2
2.
PhMgBr, Et2O
0 - 25 oC, 8 h
92% two steps
H2
Bn
20
Bn
21
19
7
8
9
10
11
12
13
14
Ph
Ph
Ph
Ph
Ph
H2, Pd/C
CDI, CH2Cl2
CH3COCl, NaH
Ph
N
N
N
25 oC, 24 h, 84%
N
MeOH, DIPEA
25 oC, 48 h, 100%
NH
THF, 0 oC, 4 h
92% brsm
NH2
H
O
O
O
22
23
24
“Scheme 5: Preparation of chiral auxiliary 24 from proline ester.”
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The N-acetyl imidazolidinone 24 was treated with LHMDS, the resulted lithium enolate was added the
aldehyde 11 at 78 C and stirred for 12 h to produce aldol adduct 10s in 69% (74% overall yield with
93:7 dr ratio) isolated yield as major product (Scheme 6). Compared to LDA the reaction with LHMDS
and LTMP gave better stereoselection with almost similar yields. The stereochemistry of the newly
generated stereogenic center in compound 10s was confirmed after its hydrolysis to corresponding -
hydroxy carboxylic acid 33 {[]D20 = 5.0 (c 0.5 in CHCl3)}. The spectral and optical properties of the
acid 33 is compared with -hydroxy carboxylic acid24 that was obtained from the hydrolysis of 18a, and
found that both the species are identical. Apart from this, the absolute configuration of newly generated
hydroxyl center in aldol product 10s was confirmed after converting it to the targeted natural product 3
whose structure was confirmed by X-ray crystallographic analysis. After the fruitful results in aldol
reaction with desired aldehyde 11 we further moved to explore the applicability of our new auxiliary
system in aldol reactions of different aldehydes.
OMe
OMe
O
OMe
O
O
OH
O
OH
O
O
LHMDS, THF
-78 oC, 12 h
+
N
O
+
N
N
N
MeO
MeO
N
N
Ph
MeO
74%, dr = 93:7
Ph
Ph
Ph
Ph
Ph
11
10s
10a
“Scheme 6: Asymmetric acetate aldol reaction with proline imidazolidinone.”
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The methodology was extended to diverse aldehyde moieties, reaction of benzaldehyde with auxiliary in
presence of LHMDS provided product 25 in 90% yield with 8.1:1 diastereomeric ratio. The
stereochemistry of the product was also confirmed after the hydrolysis of aldol adduct 25 and compared
the optical rotation of resulted 3-phenyl-3-hydroxy propionic acid with reported value.25 The
methodology works well (Table 1) with aromatic aldehydes (entry 3 & 9), long chain aliphatic
aldehydes (entries 4, 5 & 10), small aliphatic aldehydes (entry 6 & 7) and ,-unsaturated aldehyde
(entry 8) provided good yields with better stereoselectivities. From the results it was observed that the
aldehyde addition is taking place on the convex outer face of the imidazolidinone enolate through a
transition state involves the Si-face addition of aldehyde as shown in figure 2.26, 19
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Entry
conditions
aldol product
yield (%) diasteroemeric
ratio (%)
1. LTMP, -78 oC , THF, 12 h
2. LHMDS, -78 oC , THF, 12 h
3. LHMDS, -78 oC, THF, 12 h
72%
93:7
93:7
89:11
OMe
OH
O
O
MeO
N
N
Ph
Ph
OMe
74%
OH
O
O
MeO
N
N
Ph
Ph
90%17
OH
O
O
N
N
Ph
Ph
25
4. LHMDS, -78 oC , THF, 12 h
80%
86:14
O
O
HO
4
N
N
TBSO
Ph
Ph
26
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The Journal of Organic Chemistry
1
2
3
4
5. LHMDS, -78 oC , THF, 12 h
56%
87:13
O
O
HO
4
N
N
Ph
5
Ph
6
27
7
8
9
6. LHMDS, -78 oC , THF, 12 h
65%27
80: 20
O
O
HO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
N
N
Ph
Ph
28
7. LHMDS, -78 oC, THF, 12 h
8. LHMDS, -78 oC , THF, 12 h
65%28
63:37
83:17
OH
O
O
N
N
Ph
Ph
29
OH
O
O
70%17
N
N
Ph
Ph
30
9. LHMDS, -78 oC, THF, 12 h
O
87%
70:30
82:18
OH
O
N
N
Ph
MeO
Ph
31
10. LHMDS, -78 oC, THF, 12 h
89%17
OH
O
O
N
N
Ph
Ph
32
Table 1: Conditions for acetate aldol reactions with aldehydes.
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H
H
N
H
N
O
O
N
N
H
Li
Li
O
O
R
O
R
O
Re-face addition
non-favoured
Si-face addition
favoured
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“Figure 2: Expected transition structures of aldol reaction.”
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2
3
4
5
6
7
8
9
OMe
OMe
aq.LiOH,THF
O
OH
O
OH
EtOH, H2SO4 (cat)
25 oC, 18 h, 98%
10s
25 oC, 8 h
96%
OH
X
MeO
MeO
33
X = OEt 34
X = N(Me)OMe
ClH2N(Me)OMe
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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60
Me3Al, CH2Cl2
0 oC - rt, 12 h
93%
35
(Cyh)2NLi
CH2Cl2, THF
O
OH
-78 oC, 2 h
82% brsm
Cl
MeO
Cl
9
“Scheme 7: Preparation of key intermediate 9.”
With setting the first stereogenic center we further proceeded for the generation of second
stereogenic center followed by the insertion of dichloromethyl functionality. At first the carboxylic acid
33 was transformed to its corresponding -hydroxy ethyl ester 34 and Wienreb`s amide 35 (Scheme 7).
The carboxylic acid treated with ethanol in presence of catalytic H2SO4 to provide the ester 34 in 98%
yield. The resulted ester was further subjected to amidation with Weinreb`s amine in presence of
trimethyl aluminium to get the amide 35 in 93% yield. For the end game, that is the insertion of
dichloromethyl group, was achieved by in situ generation of dichloro methyllithium and addition either
to ester 34 or to amide 35. Initially, to the ester 34 in dichloromethane and THF solvent mixture was
added excess lithium dicyclohexylamide slowly over a period of 2 h using a syringe pump to provide
dichloromethyl ketone 9 in 54% yield along with 16% recovery of starting material. On the other hand
Weinreb`s amide 35 under same reaction conditions provided ketone 9 selectively in 58% yield along
with 24% recovery of starting amide.
OMe
OMe
OMe
OH
O
OH OH
OH OH
Catecholborane
+
Cl
Cl
Cl
THF, -10 oC
5 h, 96%
MeO
MeO
MeO
Cl
Cl
Cl
1
36
9
(85:15)
“Scheme 8: syn-selective reduction of -hydroxy ketone 9.”
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Reagents
Solvent
Temperature Yeild(%)
anti:syn
40:60
15:85
45:55
44:66
25:75
1
2
3
4
5
6
7
8
DIBAL-H
DCM
-78 oC
-10 oC
-40 oC
-10 oC
-78 oC
96
96
96
97
97
Catechol borane
THF
Et2BOMe/NaBH4
THF/MeOH
9
10
11
12
13
14
15
16
17
18
19
20
OMe
OH
OH
OH OH
Conditions
OH OH
OH OH
Cl
+
Cl
Cl
MeO
MeO
HO
Cl
Cl
Cl
36
37
2
“Scheme 9: Selective demethylation of (2S, 4S)-3'-methoxyl citreochlorol 36.”
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33
34
35
36
37
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With the desired key intermediate 9 in hand which is having all the basic carbon skeleton including the
dichloromethyl functionality we continued for the generation of second stereogenic center. The syn-
selective reduction -hydroxy ketone 9 was achieved by the use of catecholborane to produce
compound 36 as major product (85:15 dr) along with compound 1 as the minor product (Scheme 8).
Attempts for the selective demethylation of (2S,4S)-3'-methoxy citreochlorol 36 to obtain corresponding
demethylated natural product ()-citreochlorol 2 was unsuccessful under several demethylation reaction
conditions (Scheme 9).29
OMe
OMe
OMe
OH
O
OH OH
OH OH
Me4NBH(OAc)3
+
Cl
Cl
Cl
MeO
CH3CN, AcOH
-40 oC, 18 hrs
98%
MeO
MeO
Cl
Cl
Cl
36
1
9
(97:3)
“Scheme 10: Preparation of (2S, 4R)-3'-methoxy citreochlorol 1 by anti-selective reduction of 9.”
Similarly the key intermediate 9 was subjected for anti-selective reduction using tetrabutylammonium
triacetoxy borohydride provided the required anti-isomer i.e. (2S,4R)-3'-methoxy citreochlorol 1 as
colorless needles in 95 % isolated yield as major product along with 3% syn-isomer 36 as byproduct
(Scheme 10). All the spectral data of compound 1 is exactly matched with the reported data.5 The
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magnitude of specific rotation of compound 1 [α]D 15.6 (0.16, MeOH) has little deviation from
25
1
2
3
4
5
reported value [α]D 2.3 (0.16, MeOH), but the absolute structure of the compound 1 was confirmed
25
by its X-ray crystallographic analysis.30
6
7
8
9
In conclusion we have demonstrated a concise, protecting group free first total synthesis of (2S, 4R)-3'-
methoxy citreochlorol and its stereoisomer (2S, 4S)-3'-methoxy citreochlorol. A new proline based
imidazolidinone was prepared and used as chiral auxiliary for application in asymmetric acetate aldol
reactions. Dichloromethyl group was introduced in to the molecule by the addition of dichloromethyl
lithium to ester and to amide functionality. The absolute structure of the natural product (2S,4R)-3'-
methoxy citreochlorol 1 was confirmed by X-ray crystallography analysis.
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EXPERIMENTAL SECTION
General Techniques: All the reactions utilizing air- or moisture sensitive reagents were performed
under an atmosphere of argon or nitrogen. Tetrahydrofuran (THF) and Diethylether were double
distilled from LAH, Dichloromethane (DCM) was distilled from CaH2 before use. Pyridine and i-Pr2NH
were distilled from CaH2 and dried over molecular sieves. Commercially available reagents were used
as received. Reaction used heating conditions were conducted in an oil bath. Reactions were monitored
by thin-layer chromatography (TLC) carried out on 0.25 mm silica gel glass plates (60-F254) that were
analyzed by fluorescence upon 254 nm irradiation or by staining with p-
anisaldeyde/AcOH/H2SO4/EtOH, (NH4)6Mo7O24·4H2O/H2SO4. The products were purified by open
chromatography on silica gel (spherical, neutral, 100−230 μm) column. NMR spectra were recorded
with Avance III-500 (Bruker) (1H: 500 MHz, 13C{1H}: 125 MHz) or a 700 MHz (1 H: 700 MHz,
13C{1H}: 175 MHz) spectrometer and referenced to the solvent peak at 7.26 ppm (1 H) and 77.16 ppm
(13C{1H}) for CDCl3. Infrared spectra were recorded with a Bruker-Alpha (ATR-ZnSe) spectrometer
and reported as wavenumber (cm−1). Single crystal X-ray intensity data were collected on a Bruker
KAPPA APEX-II diffractometer in omega and phi scan mode, MoKα = 0.71073 Å at 298 K. Q-
Exactive benchtop HRMS was used for the high resolution analysis.
Preparation of 1-(chloromethyl)-3,5-dimethoxybenzene (13): To a stirred suspension of LAH (4.8 g,
o
127.4 mmol) in THF (30 mL) under N2 atmosphere at 0 C was added ester 12 (10 g, 50.96 mmol) in
THF (100 mL) via cannula. The reaction mixture was refluxed for 4 hr, and completion of the reaction
was monitored by TLC analysis. The reaction mixture was treated carefully with saturated Na2SO4
solution (5 mL) at 0 oC, ethyl acetate (100 mL) was added. The solids were filtered over celite, washed
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with EtOAc (4 x 100 mL). The filtrate was dried over anhydrous Na2SO4 and concentrated under
vacuum. The crude alcohol (8.5 g, 99%) obtained as white solid, used directly in further steps without
any purification. Rf = 0.15 (20% EtOAc in petroleum ether); 1H NMR (700 MHz, CDCl3) δ 6.55 (d, J =
1
2
3
4
5
6
7
8
13
2.1 Hz, 2H), 6.42 (t, J = 2.1 Hz, 1H), 5.04 (s, 2H), 3.79 (s, 6H). C{1H} NMR (125 MHz, CDCl3) δ
161.3, 143.7, 104.8, 99.9, 65.6, 55.6. IR (neat, cm-1): 3378, 3002, 2939, 1596, 1461, 1320, 1202, 1062.
HRMS (ESI- quadrupole) m/z: [M + Na]+ Calcd for C9H12O3Na 191.0684; Found 191.0679.
9
10
11
12
13
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60
o
To a stirred solution of alcohol (8 g, 47.6 mmol) in Et2O (100 mL) at 0 C under N2 atmosphere was
added pyridine (0.4 mL) and SOCl2 (5.18 mL, 71.4 mmol) dropwise using a pressure equalizing funnel
for 30 min. The reaction mixture was stirred for 4 hr at room temperature, completion of reaction was
confirmed by TLC. The reaction mixture was treated with saturated NaHCO3 solution, the organic layer
was separated and the aqueous layer was extracted with Et2O (3 x 70 mL), the combined organic layers
were washed with H2O, brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude
product was purified using column chromatography (silica gel, 4% EtOAc/hexane) to give chloro
compound 13 (8.5 g, 95%) as a white solid. Rf = 0.75 (20% EtOAc in petroleum ether); 1H NMR (700
13
MHz, CDCl3) δ 6.54 (d, J = 2.1 Hz, 2H), 6.41 (s, 1H), 4.52 (s, 2H), 3.80 (s, 6H). C{1H} NMR (175
MHz, CDCl3) δ 161.2, 139.8, 106.7, 100.7, 55.7, 46.6. HRMS (ESI- quadrupole) m/z: [M + H]+ Calcd
for C9H12ClO2 187.0525; Found 187.0520.
Preparation of 2-(3,5-dimethoxyphenyl)acetonitrile (14): To a stirred solution of compound 13 (3.89
g, 20.9 mmol) in DMSO (40 mL) was added NaCN (1.54 g, 31.26 mmol), the reaction mixture was
o
stirred at 50 C for 2 h. Completion of the reaction was confirmed by TLC, then the reaction mixture
was added water (30 mL) and ethyl acetate (20 mL), organic layer was separated and aqueous layer was
extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with H2O, brine, dried
over anhydrous Na2SO4 and concentrated under vacuum. The cyano compound (3.43 g) obtained as a
colorless oil was directly used for next step without further purification. Rf = 0.2 (10% EtOAc in
petroleum ether); 1H NMR (700 MHz, CDCl3) δ 6.46 (s, 2H), 6.41 (s, 1H), 3.80 (s, 6H), 3.69 (s, 2H).
13C{1H} NMR (175 MHz, CDCl3) δ 161.6, 132.2, 118.0, 106.3, 100.2, 55.7, 24.0. IR (neat, cm-1): 3006,
2960, 2929, 2842, 2251, 1598, 1463, 1204, 1156, 1063. HRMS (ESI- quadrupole) m/z: [M + H]+ Calcd
for C10H12NO2 178.0868; Found 178.0863.
To a stirred solution of cyano compound (3.4 g, 19.19 mmol) in EtOH/H2O (30 mL, 2:1) mixture was
added NaOH (3.1 g, 47.98 mmol). Reaction mixture was stirred at 100 oC for 4 h. The completion of the
reaction was confirmed by TLC, solvent was evaporated under vacuum. To the crude product was added
NaOH solution (20 mL, 2N), aqueous layer was extracted with ether (2 x 20 mL). The aqueous layer
was acidified with 2N HCl until pH 2 and the product was extracted with EtOAc (3 x 20 mL). The crude
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acid 14 (3.43 g, 91%) obtained as a white solid was directly used for next step without further
1
2
3
purification. Rf = 0.2 (30% EtOAc in petroleum ether).
4
5
6
7
Preparation of 2-(3,5-dimethoxyphenyl)ethan-1-ol (15): To a stirred suspension of LAH (2.41 g,
63.71 mmol) in THF (20 mL) under N2 atmosphere at 0 oC was added 14 (5 g, 25.48 mmol) in THF (10
8
9
o
ml) via cannula. The mixture was stirred at 80 C for 4 h and completion reaction was confirmed by
TLC. The reaction mixture was carefully treated with saturated Na2SO4 solution at 0 C and added ethyl
acetate (100 mL). The reaction mixture was filtered over celite, solids were washed with EtOAc (100
mL). The filtrate was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product
was purified using column chromatography (silica gel, 20% EtOAc/hexane) to give 15 (4.5 g, 97%) as a
white solid. Rf = 0.35 (40% EtOAc in petroleum ether); 1H NMR (700 MHz, CDCl3) δ 6.43 (d, J = 2.1
Hz, 2H), 6.38 (t, J = 2.1 Hz, 1H), 3.89 (t, J = 5.6 Hz, 2H), 3.82 (s, 6H), 2.85 (t, J = 6.3 Hz, 2H);
13C{1H} NMR (175 MHz, CDCl3) δ 161.2, 141.1, 107.3, 98.7, 63.7, 55.6, 39.7; IR (neat, cm-1): 3375,
2932, 2842, 1594, 1461, 1429, 1201, 1148, 1048, 830.
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Preparation of 2-(3,5-dimethoxyphenyl)acetaldehyde (11):33 To a stirred solution of alcohol 15 (400
o
mg, 2.195 mmol) in DCM (10 mL) under N2 atmosphere at 0 C was added DMP (1.4 g, 3.293 mmol)
and the reaction mixture was stirred for 2 hr. The completion of the reaction was confirmed by TLC.
The reaction mixture was added NaHCO3 (2 g) stirred for 10 minutes, the suspension was poured into
fast stirring hexane, allowed to settle the solids, filtered and evaporated the solvents. The crude product
was extracted by dichloromethane and hexane (30 mL) trituration, the process was continued for 2 to 3
times until no precipitation observed, to provide compound 11 (352 mg, 90% ) obtained as colorless oil
was directly used for next step without further purification. Rf = 0.5 (20% EtOAc in petroleum ether); 1H
NMR (700 MHz, CDCl3) δ 9.61 (t, J = 2.1 Hz, 1H), 6.28 (t, J = 2.1 Hz, 1H), 6.25 (d, J = 2.1 Hz, 2H),
3.71 (s, 6H), 3.49 (d, J = 2.8 Hz, 2H); 13C{1H} NMR (175 MHz, CDCl3) δ 199.5, 161.5, 134.2107.8,
99.6, 55.6, 51.0; IR (neat, cm-1): 2925, 2849, 1708, 1602, 1205, 1157, 1064, 932. HRMS (ESI-
quadrupole) m/z: [M + H]+ Calcd for C10H13O3 181.0864; Found 181.0857.
Preparation of ester 17:14 To a stirred suspension of Pd2(Allyl)2Cl2 (134.6 mg, 0.36 mmol), BINAP
(688 mg, 1.1 mmol), N,N-dimethylpyridin-4-amine (225 mg, 1.84 mmol) and ethyl potassium malonate
(2.3 g, 13.8 mmol) in xylene (15 mL), was added bromobenzene 16 (2 g, 9.2 mmol). The reaction

mixture was stirred in a preheated oil bath at 140 C for 20 h. The completion of the reaction was
confirmed by the TLC analysis. The reaction mixture was cooled to room temperature and diluted with
diethyl ether, the crude was directly purified using column chromatography (silica gel, 10%
EtOAc/hexane) to give 17 (1.35 g, 65%) as colourless oil. Rf = 0.45 (20% EtOAc in petroleum ether);
1H NMR (500 MHz, CDCl3) δ 6.44 (s, 2H), 6.37 (s, 1H), 4.15 (q, J = 10.0 Hz, 2H), 3.78 (s, 6H), 3.54 (s,
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2H), 1.26 (t, J = 10 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 171.4, 160.8, 136.2, 107.3, 99.2, 60.9,
1
2
3
55.5, 41.7, 14.2. IR (neat, cm-1): 2950, 1732, 1596, 1463, 1295, 1146, 1061, 835.
4
5
6
7

To a stirred suspension of LAH (423 mg, 11.14 mmol) in THF (20 mL) under N2 atmosphere at 0 C
was added 17 (1 g, 4.46 mmol) in THF (10 mL) via cannula. The mixture was stirred at reflux
8
9
temperature for 4 h and completion reaction was confirmed by TLC. The reaction mixture was carefully
o
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treated with saturated Na2SO4 (0.5 ml) solution at 0 C. The reaction mixture was filtered over celite,
solids were washed with EtOAc (20 x 3 mL). The filtrate was dried over anhydrous Na2SO4 and
concentrated under vacuum. The crude product was purified using column chromatography (silica gel,
20% EtOAc/hexane) to give 15 (810 mg, 99%) as a white solid.
Preparation
of
(R)-1-((S)-4-benzyl-2-thioxothiazolidin-3-yl)-4-(3,5-dimethoxyphenyl)-3-
hydroxybutan-1-one (18a): To a stirred solution of auxiliary A1 (312 mg, 1.24 mmol) in CH2Cl2 (10
mL) under N2 atmosphere at -78 oC were added TiCl4 (1.32 mL, 1.32 mmol, 1 M in CH2Cl2) and DIPEA
o
(0.15 mL, 1.48 mmol). After 1 hr at -78 C aldehyde 11 (148 mg, 0.823 mmol) in DCM (10 mL) was
added using a syringe pump for 2 hours. After 1 h, completion of the reaction was monitored by TLC.
The reaction mixture was treated with saturated NH4Cl solution and stirred at RT for 30 minutes. The
organic layer was separated, aqueous layer was extracted with CH2Cl2 (3 x 20 mL), the combined
organic layers were washed with H2O, brine, dried over anhydrous Na2SO4 and evaporated under
vacuum. The crude product was purified by column chromatography (silica gel, 5-12% EtOAc/hexane)
to give aldol adduct 18a and 18s as diastereomeric mixture (65:35).
Compound 18a: (36%, 129 mg) as a pale yellow oil. Rf = 0.5 (20% EtOAc in petroleum ether); [α]D
=
20
–64.88 (c 1.27, CHCl3); 1H NMR (700 MHz, CDCl3) δ 7.38–7.29 (m, 5H), 6.41 (d, J = 2.1 Hz, 2H),
6.36 (t, J = 2.1 Hz, 1H), 5.40–5.37 (m, 1H), 4.34–4.43 (m, 1H), 3.80 (s, 6H), 3.66 (dd, J = 10.5, 17.5
Hz, 1H), 3.42–3.38 (m, 1H), 3.24–3.19 (dd, J = 4.2, 14 Hz, 2H), 3.07–3.04 (dd, J = 10.5, 13.3 Hz, 1H),
2.93–2.90 (dd, J = 8.4, 13.3 Hz, 2H), 2.77–2.74 (dd, J = 7, 13.3 Hz, 1H). 13C{1H} NMR (175 MHz,
CDCl3) δ 201.4, 173.4, 160.8, 141.0, 136.3, 129.4, 128.9, 127.2, 107.5, 98.8, 69.4, 68.1, 55.3, 44.8,
43.3, 36.7, 32.0; IR (neat, cm-1): 3506, 2930, 1691, 1599, 1462, 1345, 1201, 1155, 1062, 703. HRMS
(ESI- quadrupole) calc. for C22H25NO4S2Na [M + Na]+ m/z: 454.1122; found 454.1115.
Compound 18s: (19%, 69 mg) as a pale yellow oil. Rf = 0.4 (20% EtOAc in petroleum ether); [α]D
20
1
+66.6 (c 0.8, CHCl3); H NMR (700 MHz, CDCl3) δ 7.34 (t, J = 10 Hz, 2H), 7.29 (d, J = 4.9 Hz, 3H)
6.40 (d, J = 2.1 Hz, 2H), 6.34 (t, J = 2.1 Hz, 1H), 5.39–5.35 (m, 1H), 4.31 (d, J = 6.7 Hz, 1H), 3.79 (s,
6H), 3.49 (dd, J = 9.2, 17.5 Hz, 1H), 3.40–3.35 (m, 2H), 3.21 (dd, J = 3.8, 13.2 Hz, 2H), 3.15 (bs, 1H),
3.03 (dd, J = 10.5, 13.2 Hz, 1H), 2.89 (dd, J = 5.2, 12.4 Hz 2H), 2.74 (dd, J = 6.9, 13.4 Hz, 1H).
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13C{1H} NMR (175 MHz, CDCl3) δ 201.4, 172.8, 160.9, 139.9, 136.3, 129.4, 128.9, 127.3, 107.5, 98.9,
68.8, 68.3, 55.3, 45.3, 43.1, 36.8, 32.0. IR (neat, cm-1): 3506, 2930, 1691, 1599, 1462, 1345, 1201,
1155, 1062, 703; HRMS (ESI- quadrupole) calc. for C22H25NO4S2Na [M + Na]+ m/z: 454.1122; found
454.1115.
1
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4
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9
Preparation of (S)-(1-benzylpyrrolidin-2-yl)diphenylmethanol 20: To a stirred solution of L-proline
methyl ester hydrochloride 19 (10 g, 60.38 mmol) in dichloromethane (100 mL) in a round-bottomed
flask, trimethylamine (21.1 mL, 150.95 mmol) was added, resulted in the formation of white precipitate
within 5-10 minutes. The precipitate is then filtered off using sintered funnel and the filtrate is collected.
Benzyl bromide (10.8 mL, 90.57 mmol) is then added dropwise to the filtrate in a round-bottomed flask
and stirred for 8 h at room temperature. The reaction mixture was diluted with ethyl acetate (150 mL),
washed with water and brine, dried over anhydrous sodium sulfate. The solvent was evaporated under
reduced pressure to provide the desired benzyl protected proline methyl ester (12.2 g, 100%) as pale
yellow oil. The compound was pure enough to use in further steps without purification. Rf = 0.4 (10%
EtOAc in Pet ether); 1H NMR (500 MHz, CDCl3) δ 7.41-7.23 (m, 5H), 3.89 (d, J = 15 Hz, 1H), 3.65 (s,
3H), 3.58 (d, J = 10 Hz, 1H), 3.25 (dd, J = 5, 10 Hz, 1H), 3.04 (m, 1H), 2.40 (dd, J = 10, 15 Hz, 1H),
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13
2.15 (m, 1H), 1.99-1.91 (m, 2H), 1.81 (m, 1H). C{1H} NMR (175 MHz, CDCl3) δ 170.9, 137.7,
128.9, 128.6, 128.4, 128.2, 60.3, 46.3, 33.4, 20.9, 14.0; IR (neat, cm-1): 3436, 3028, 1599, 1490, 740,
697.
To a stirred solution of compound proline ester (10 g, 45.8 mmol) in dry diethylether (40 mL) was
o
added freshly prepared phenylmagnesium bromide (26.5 g, 146.4 mmol) at 0 C, for 10 minutes. The
reaction was stirred at room temperature for 8 h. The completion of the reaction was confirmed by TLC.
o
The reaction mixture was quenched with saturated NH4Cl at 0 C, diluted with EtOAc (150 ml) and
stirred until there is a clear separation of layers. The organic layer separated and the aqueous layer was
extracted with EtOAc (3 x 100 ml). The organic layer was washed with brine, dried over Na2SO4 and
evaporated under reduced pressure. The crude compound was purified by using recrystallization in
1
MeOH provided compound 20 (11.3 g, 72%) as white solid. Rf = 0.6 (10% EtOAc in Petether). H
NMR (500 MHz, CDCl3) δ 7.75 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 7.4 Hz, 2H), 7.33 – 7.29 (m, 4H), 7.25
(t, J = 5 Hz, 2H), 7.22-7.19 (m, 2H), 7.12 (t, J = 5 Hz, 1H), 7.07 (d, J = 7.3 Hz, 2H), 4.97 (bs, 1H), 4.0
(dd, J = 4.7, 9.5 Hz, 1H), 3.26 (d, J = 12.6 Hz, 1H), 3.06 (d, J = 12.6 Hz, 1H), 2.95 – 2.83 (m, 1H),
13
2.40-2.37 (m, 1H), 2.02-1.96 (m, 1H), 1.81 – 1.77 (m, 1H), 1.70-163 (m, 2H); C{1H} NMR (125
MHz, CDCl3) δ 148.0, 146.7, 139.7, 128.6, 128.1, 128.1, 128.0, 126.8, 126.4, 126.3, 125.6, 125.5, 77.9,
70.6, 60.7, 55.5, 29.8, 24.1; IR (neat, cm-1): 3436, 3028, 1599, 1490, 1031, 740, 697; HRMS (ESI-
quadrupole) m/z: [M + H]+ Calcd for C24H26NO 344.2014; Found 344.2009.
Preparation of (S)-(1-benzylpyrrolidin-2-yl)diphenylmethanamine (21):23
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To a solution of (S)- (1-benzylpyrrolidin-2-yl)diphenylmethanol 20 (6.3 g, 18.26 mmol) in 60 mL
anhydrous chloroform, and sulfuric acid (9 mL, 164.34 mmol) in a round-bottomed flask, was added
solid sodium azide (9.5 g, 146.07 mmol) slowly over a period of 1 h at 0 oC. The reaction mixture was
stirred at room temperature for 24 h. The completion of the reaction was confirmed by TLC, and the
reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted with
dichloromethane (3x60 mL). The organic layer was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure, to obtain azide as yellow oil (5.86 g, 90 %). The azide was pure
enough by TLC, further directly used in the next step without purification. Rf = 0.85 (10% EtOAc in Pet
ether); 1H NMR (500 MHz, CDCl3) δ 7.45-7.06 (m, 15H), 3.95 (t, 1H), 3.72 (d, 1H) 3.23 (d, 1H), 2.70
(t, 1H), 2.19 (d, 1H), 1.99-1.95 (m, 1H), 1.76-1.72 (m, 1H), 1.43 (d, 1H), 0.78 (t, 1H); 13C{1H} NMR
(125 MHz, CDCl3) δ 142.13, 141.87, 128.58, 128.44,128.17, 128.09, 127.96, 127.47, 127.29, 126.64,
70.58, 62.00, 55.03, 30.15, 23.99; IR υmax (neat) 3059, 2974, 2869, 2097, 1599, 1494, 1448, 1383 cm-
1; HRMS (ESI- quadruple) m/z; (M + H)+ calcd for C24H25N4 369.2079, Found 369.2074.
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To a stirred suspension of LiAlH4 (2.94 g, 77.368 mmol) THF (60 mL) azide (7.127 g, 19.342 mmol) in
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THF was added dropwise at 0 C. After 10 minutes reaction mixture was brought to room temperature
and continued stirring for 4 hours. Completion of the reaction was confirmed by TLC and the reaction
was treated with 5 mL of saturated solution of Na2SO4 and diluted with ethyl acetate (50 mL). Solids
were filtered over celite, filtrate was dried over anhydrous Na2SO4 and concentrated under reduced
pressure to obtain compound 21 (6.5 g, 98%) as light yellow color solids in pure form. Rf = 0.3 (5%
EtOAc in Pet ether). Crude compound was directly used for next step without column purification. Rf =
0.6 (EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.47 (dd, J = 4.2, 7.2 Hz, 4H), 7.26-7.19 (m, 2H), 7.16-
7.05 (m, 6H), 6.98 (dd, J = 7.3, 17.5 Hz, 3H), 3.79 (dd, J = 3.4, 9.8 Hz, 1H), 2.87 (d, J = 12.7, 1H),
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2.79 (dd, J = 8.6, 14.3 Hz, 2H), 2.22-1.97 (m, 4H), 1.74-1.62 (m, 1H), 1.60-141 (m, 2H); C{1H}
NMR (125 MHz, CDCl3) δ 147.8, 147.8, 140.4, 128.5, 128.1, 127.9, 127.8, 127.1, 126.8, 126.5, 126.2,
125.9, 71.3, 64.1, 61.6, 55.8, 30.2, 24.9. HRMS (ESI-quadraple) m/z: [M+H]+ Calcd for, C24H27N2
343.2174, Found 343.2157.
Preparation of (S)-diphenyl(pyrrolidin-2-yl)methanamine (22):23
To stirred solution of amine 21 (4 g, 11.67 mmol) in methanol (30 mL) and diisopropylethylamine (40
mL), palladium on activated charcoal was added under nitrogen. The reaction was purged with
hydrogen and stirred under hydrogen atmosphere for 48 hours. The completion of the reaction was
confirmed by TLC. The solids were filtered over celite washed with methanol (3 x 40 mL). Filtrate was
dried over anhydrous Na2SO4 and concentrated under reduced pressure to produce diamine 22 as yellow
color liquid (2.94 g, 100%), Rf = 0.1 (50% EtOAc in Pet ether). The Crude compound was directly used
in next step without column purification.
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Preparation of (S)-1,1-diphenyl hexahydro-3H-pyrrolo[1,2-c]imidazole-3-one (23) :
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To stirred solution of diamine 22 (2 g, 7.93 mmol) in dichloromethane (30 ml), was added solution of
1,1’-carbonyldiimidazole (3.85 g, 23.79 mmol) in DCM (15 ml) at room temperature. The stirring was
continued 24 hours, the completion of the reaction was confirmed by TLC. The reaction was treated
with saturated NH4Cl solution, organic layer was separated and aqueous layer was extracted with DCM
(3 x 20 mL). Combined organic layer was washed with water, brine, dried over sodium sulphate and
evaporated under reduced pressure. The crude compound was purified by column chromatography
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(silica gel 100-200, 5-20% ethyl acetate in hexane) produce imidazolidinone 23 (1.85 g, 84%) as a white
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fluffy solid. Rf = 0.5 (30% EtOAc in Petether); [α]D = 307.5 (c 1, CHCl3); H NMR (500 MHz,
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CDCl3) δ 7.29 – 7.19 (m, 10H), 5.32 (s, 1H), 4.38 (dd, J = 5.4, 10.6 Hz, 1H), 3.68-3.62 (m, 1H), 3.18-
3.13 (m, 1H), 1.85 – 1.81 (m, 1H), 1.76 – 1.66 (m, 2H), 1.04-0.95 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3) 163.6, 146.7, 141.6, 128.7, 128.2, 127.8, 127.4, 126.7, 126.6, 69.8, 65.0, 64.3, 45.6, 29.1, 25.4,
24.6; IR (neat) 3233, 2970, 1758, 1695, 1599, 1493, 1449, 1393 cm-1; HRMS (ESI- quadrupole) m/z:
[M + H]+ Calcd for C18H19N2O 279.1497; Found 279.1491.
Preparation of (S)- 2-acetyl-1,1-diphenylhexahydro-3H-pyrrolo[1,2-c]imidazol-3-one 24: To a
stirred suspension of sodium hydride (287 mg, 0.7.18 mmol, 60% in paraffin pre washed with hexane)
in dry THF (3 mL), was added compound 23 (400 mg, 1.44 mmol) in THF (4 mL) at 0 oC. The reaction
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mixture was stirred for 1 h at 0 C before the addition of the solution of acyl chloride (0.21 mL, 2.88
mmol) in THF (1 mL). After 3 h the completion of reaction was confirmed by TLC and the reaction
mixture was treated with saturated aq. ammonium chloride solution (10 mL). The compound was
extracted with ethyl acetate (3 x 20 mL), organic layer was washed with brine, dried over sodium
sulfate, filtered and evaporated under reduced pressure. The crude compound was purified using column
chromatography (silica gel, eluted with 10% EtOAc in petether) to afford (S)-2-acetyl-1,1-
diphenylhexahydro-3H-pyrrolo[1,2-c]imidazol-3-one, 24 (337 mg, 73%) as white solids along with the
recovery of starting compound 23 (19%, 78 mg). Rf = 0.5 (20% EtOAc in petether); [α]D20 = 144.4 (c
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0.3, CHCl3); H NMR (500 MHz, CDCl3) δ 7.57-7.55 (m, 2H), 7.29-7.19 (m, 6H), 7.06 (t, J = 10 Hz,
2H), 4.20 (dd, J = 5.1, 11 Hz, 1H), 3.71-3.65 (m, 1H), 3.30-3.26 (m, 1H), 2.38 (s, 3H), 1.85-1.79 (m,
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1H), 1.70-1.64 (m, 1H), 1.22-1.18 (m, 1H), 0.68-0.65 (m, 1H); C{1H} NMR (125 MHz, CDCl3) δ
170.3, 158.5, 143.8, 137.7, 129.2, 128.9, 127.8, 127.7, 127.6, 127.0, 70.7, 70.3, 45.2, 30.8, 25.6, 23.7;
HRMS (ESI- quadrupole) m/z: [M + H]+ Calcd for C20H21N2O2 321.1603; Found 321.1591.
General procedure I: Preparation of 2-((R)-4-(3,5-dimethoxyphenyl)-3-hydroxybutanoyl)-1,1-
diphenylhexahydro-3H-pyrrolo[1,2-c]imidazol-3-one (10s): To a stirred solution of HMDS (0.96
mL, 4.6 mmol) in THF (10 ml) at -78 oC, n-BuLi (0.9 M in Hexane, 5.1 ml, 4.6 mmol) was added. After
30 minutes solution of N-acetylated chiral auxiliary 24 (0.5 g, 1.56 mmol) in THF (5 ml) was added
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The Journal of Organic Chemistry

dropwise to the reaction mixture at -78 C. After 1 h solution of aldehyde 11 (423 mg, 2.34 mmol) in
THF (5 ml) was added dropwise and the stirring was continued for 12 hours at same temperature.
Completion of the reaction was confirmed by TLC, the reaction mixture was treated with saturated
solution of aq. NH4Cl. Organic layer was separated, aqueous layer was extracted with ethyl acetate (3 x
15 mL). The combined organic layer was washed with water, brine, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude compound was purified by using column
chromatography (silica gel 200-400; ethyl acetate in hexane) to afford desired aldol adduct 10s (539
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mg, 69%) as white solid along with recovery of auxiliary 24 (94 mg, 19%). [α]D = 209 (c 0.5,
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CHCl3); H NMR (500 MHz, CDCl3 δ 7.54 ( d, J = 7.4 Hz, 2H ), 7.30-7.19 ( m, 6H ), 7.08 (d, J = 7.2
Hz, 2H), 6.27 (d, J = 1.9, Hz, 2H), 6.23 (d, J = 5.2 Hz, 1H) 4.22 (dd, J = 5, 10.9 Hz, 1H), 4.15 (d, J =
5.8 Hz, 1H), 3.72-3.65 (m, 1H), 3.68 (s, 6H), 3.31-3.26 (m, 2H), 2.75 (dd, J = 8.3, 16.7 Hz, 1H), 2.64-
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2.52 (m, 2H), 1.85-1.79 (m, 1H), 1.70-1.59 (m, 2H), 1.24-1.19 (m, 1H), 0.69-0.6 (m, 1H); C{1H}
NMR (125MHz, CDCl3) δ 172.4, 160.7, 158.1, 143.4, 140.6, 137.4, 129.1, 128.0, 127.7, 127.6, 127.2,
107.4, 98.6, 70.8, 70.8, 69.1, 55.2, 45.1, 43.0, 42.8, 30.9, 23.8; IR (neat): 3487, 2927, 1728, 1699, 1599,
1458, 1370, 1269, 1200, 1151, 1063, 837, 701; HRMS (ESI- quadrupole) m/z: [M + H]+ Calcd for
C30H33N2O5 501.2389; Found 501.2376.
Preparation of methyl (R)-4-(3,5-dimethoxyphenyl)-3-hydroxybutanoate 34: To a stirred solution of
aldol adduct 10s (500 mg, 0.998 mmol) in THF and water (4 mL, 1:1), was added LiOH.H2O (251 mg,
6 mmol). The reaction mixture was stirred for 12 h at room temperature. The completion of the reaction
was confirmed by TLC, ethyl acetate (5 mL) is added, and aqueous layer was separated. The aqueous
layer was acidified to pH-5.5, extracted with ethyl acetate (3 x 10 mL), combined organic layer was
washed with brine, dried over anhydrous sodium sulfate, filtered and solvent was removed under
reduced pressure to obtain the hydroxyl acid 33 (230 mg, 96%) as a thick yellow liquid. The acid is pure
enough to use directly in further step without purification. [α]D20 = 5 (c 0.5, CHCl3).
To the stirred solutions of acid 33 (500 mg, 2.08 mmol) in EtOH (5 mL), was added H2SO4 (0.05 mL).
The reaction mixture was stirred at room temperature for 18 h. The completion of the reaction was
confirmed by TLC, the reaction mixture was treated with saturated NaHCO3 solution (5 mL) and the
ethanol was evaporated under reduced pressure. The residue was diluted with H2O (5 mL) and extracted
with ethyl acetate (2 x 10 mL). The combined organic layer was washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified
by column chromatography (silica gel; petroleum ether/ethyl acetate (8:2)) to afford the ester 34 (545
mg, 98%). [α]D20 = 4.6 (c 0.5, CHCl3), 1H NMR (500 MHz, CDCl3) δ: 6.33 (d, J = 2.2 Hz, 2H) 6.29 (t,
J = 4.3 Hz, 1H), 4.25-4.203 (m, 1H), 4.18-4.14 (m, 1H), 3.77 (s, 6H), 2.80 (dd, J = 7.15, 13.5 Hz, 1H),
2.68(dd, J = 6.15, 13.5 Hz, 1H), 2.49 (dd, J = 3.55, 16.35 Hz, 1H), 2.41 (dd, J = 8.7, 16.4 Hz, 1H), 1.25
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(t, J = 8.0 Hz, 3H); C{1H} NMR (500 MHz, CDCl3) δ 172.7, 160.8, 139.9, 107.4, 98.5, 68.9, 60.6,
55.1, 43.2, 40.5, 14.1; IR (neat, cm-1): 3433, 2940, 1723, 1595, 1460, 1295, 1149, 1058, 834: HRMS
(ESI-quadrupole) m/z: [M + H]+ Calcd for C14H21O5 269.1389; Found 269.1375.
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Preparation of (R)-4-(3,5-dimethoxyphenyl)-3-hydroxy-N-methoxy-N-methylbutanamide 35: To a
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stirred suspension of MeONHMe.HCl (180 mg, 1.85 mmol) in THF (5 mL) at -10 C was added a
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solution of AlMe3 (2M solution, 0.93 mL, 1.85 mmol) over a 15 min period. The reaction mixture was
stirred at room temperature for 45 min, then a solution of ester 34 (200 mg, 0.74 mmol) in THF (10 mL)
was added and the resulting mixture was stirred at room temperature for 2 h. Completion of the reaction
was confirmed by TLC, the reaction was treated carefully with saturated NH4Cl solution (5 mL)
followed by addition of EtOAc (10 mL) and saturated solution of Rochelle salt (5 mL). The resulting
mixture was stirred until two layers clearly separated out (3 h). The organic layer was separated and the
aqueous phase was extracted with EtOAc (2 x 10 mL). Combined organic layer was washed with water,
brine, dried over anhydrous Na2SO4, filtered, and evaporated. The crude compound was purified by
column chromatography to obtain the amide 35 (195 mg, 93%) as a light yellow oil. [α]D20 = 29 (c 0.5,
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CHCl3); H NMR (500 MHz, CDCl3) δ 6.40 (d, J = 1.45 Hz, 2H), 6.34 (d, J = 2.1 Hz, 1H), 4.31–4.28
(m, 1H), 3.78 (s, 6H), 3.63 (s, 3H), 3.18 (s, 3H), 2.87 (dd, J = 7.1, 13.5 Hz, 1H), 2.73-2.65 (m, 2H), 2.51
(dd, J = 8.8, 16.4 Hz, 1H); 13C{1H} NMR (175 MHz, CDCl3) δ 173.5, 160.8, 140.5, 107.4, 98.5, 69.0,
61.2, 55.3, 43.2, 37.4, 29.7; IR (neat, cm-1): 2926, 2853, 1644, 1599, 1464, 1389, 1294, 1205, 1153,
1067, 995. HRMS (ESI- quadrupole) m/z: [M + H]+ Calcd for C14H22NO5 284.1497; Found 284.1492.
Preparation of (R)-1,1-dichloro-5-(3,5-dimethoxyphenyl)-4-hydroxypentan-2-one 9: To a stirred
solution of 35 (50 mg, 0.176 mmol) in DCM (10 mL) and THF (10 mL) at -78 oC under N2 atmosphere
was added lithium dicyclohexylamide in THF (generated by treating n-BuLi (0.55 mL, 0.88 mmol) and
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dicyclohexylamine (0.18 mL, 0.88 mmol) in THF 0 C for 15 min) slowly over 1 h using a syringe
pump. The reaction mixture was stirred for additional 1 h, completion of the reaction was confirmed by
TLC. The reaction mixture was treated with saturated NH4Cl solution. The organic layer was separated,
aqueous layer was extracted with EtOAc (3 x 10 mL), and the combined organic layers were washed
with water, 2N oxalic acid, and brine, dried over anhydrous Na2SO4 and concentrated under vacuum.
The crude product was purified by column chromatography (silica gel, 10% EtOAc/hexane) to give 9
(31.5, 58%) as colourless oil along with recovery of starting amide (12.1 mg, 24%). Rf = 0.6 (30%
EtOAc in petroleum ether); [α]D = –0.9 (c 0.975, CHCl3); 1H NMR (700 MHz, CDCl3) δ 6.40–6.36
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(m, 3H), 5.88 (s, 1H), 4.39–4.33 (m, 1H), 3.78 (s, 6H), 3.05–2.96 (m, 2H), 2.77 (d, J = 6.3 Hz, 2H).
13C{1H} NMR (175 MHz, CDCl3) δ 196.3, 161.1, 139.5, 107.4, 98.9, 70.0, 68.6, 55.3, 43.4, 41.8, 29.7;
IR (neat): 2926, 2853, 1734, 1653, 1597, 1449, 1205, 1152, 1070, 994 cm-1. (ESI- quadrupole) m/z: [M
+ H]+ Calcd for C13H17O4Cl2 307.0503; Found 307.0498.
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Preparation of (2S,4S)-1,1-dichloro-5-(3,5-dimethoxyphenyl)pentane-2,4-diol 36: To a stirred
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solution of 9 (10 mg, 0.033 mmol) in THF (0.5 mL) at -10 C was added catecholborane (0.021 mL,
0.195 mmol). The reaction mixture was stirred for 5 hours and completion of reaction was confirmed by
TLC. The reaction mixture was treated carefully with MeOH (0.2 mL) and 0.5 N aqueous sodium
potassium tartrate solution (0.2 mL). The product was extracted with EtOAc (3 x 5 mL), the combined
organic layers were washed with 2N NaOH (2 mL x 3), H2O and brine, dried over anhydrous Na2SO4
and concentrated under vacuum to give 3’-methoxyl citreochlorol 36 (8.6 mg, 85%) as a colourless oil
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with along with the anti-isomer 1 (1 mg, 9.7%) de. Rf = 0.4 (30% EtOAc in petroleum ether); [α]D
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4.3 (c 0.16, MeOH); H NMR (500 MHz, CDCl3) δ 6.37 (s, 1H), 5.71 (d, J = 4.2 Hz, 1H), 4.17–4.14
(m, 1H), 3.79 (s, 6H), 2.80 (dd, J = 3.9, 13.4 Hz, 1H), 2.70 (dd, J = 9, 13.3 Hz, 1H), 2.66-2.45 (bm, 2H),
2.06 (d, J = 14.5 Hz, 1H), 1.86–1.79 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3 + CCl4) δ 161.1, 139.5,
107.4, 98.8, 76.3, 75.5, 72.2, 55.3, 44.7, 37.1, 29.7; IR (neat): 3424, 2926, 1601, 1464, 1296, 1204,
1155, 1071, 837, 780: HRMS (ESI- quadrupole) m/z: [M + Na]+ Calcd for C13H18O4Cl2Na 331.0479;
Found 331.0471.
Preparation of (2S,4R)-1,1-dichloro-5-(3,5-dimethoxyphenyl)pentane-2,4-diol 1: To a stirred
solution of tetramethylammonium triactoxyborohydride (40 mg, 0.15 mmol) in acetonitrile (0.3 mL)
and anhydrous acetic acid (0.3 mL) at -40 oC was added 9 (10 mg, 0.03 mmol) in acetonitrile (0.2 mL).
The reaction mixture was stirred for 18 h and completion of reaction was confirmed by TLC. The
reaction mixture was treated carefully with 0.5 N aqueous sodium potassium tartrate solution (1 mL).
The product was extracted with DCM (3 x 5 mL), the combined organic layers were washed with H2O,
sat. NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and evaporated under vacuum to
give 3’-methoxyl citreochlorol 1 (9.95 mg, 98%) as white needles (HNMR of crude shows dr = 97 : 3).
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Rf = 0.4 (30% EtOAc in petroleum ether); [α]D25 = 15.6 (c 0.16, MeOH); H NMR (500 MHz, CDCl3)
δ 6.37 (s, 3H), 5.76 (d, J = 4.3 Hz, 1H), 4.27 (dd, J = 5, 11.1 Hz, 1H), 4.21 – 4.13 (m, 1H), 3.79 (s, 6H),
2.82 (dd, J = 4, 13.4 Hz, 1H), 2.68 (dd, J = 9, 13.4 Hz, 1H), 2.19 (bs, 2H), 1.9 (t, J = 5 Hz, 2H).
13C{1H} NMR (125 MHz, CDCl3 + CCl4) δ 161.1, 139.9, 107.3, 98.8, 76.5, 73.7, 69.3, 55.3, 44.4, 38.2;
IR (neat): 3424, 2926, 1601, 1463, 1295, 1204, 1155, 1071, 837, 780; HRMS (ESI- quadrupole) m/z:
[M + Na]+ Calcd for C13H18O4Cl2Na 331.0479; Found 331.0471.
Preparation of 2-((S)-3-hydroxy-3-phenylpropanoyl)-1,1-diphenylhexahydro-3H-pyrrolo[1,2-
c]imidazol-3-one 25: Compound 25 was prepared by using General procedure I. The crude compound
was purified by using column chromatography to afford desired compound 25 as light yellow solid (120
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mg, 90%; dr = 89:11). [α]D = 323.2 (c 0.5 CHCl3); Rf = 0.3 (20% EtOAc in pet ether). H NMR
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(500MHz, CDCl3) δ 7.51 (dd, J = 1.3, 8.2 Hz, 2H), 7.28-7.10 (m, 11H), 7.08-7.02 (m, 2H), 5.01 (dd, J =
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2.8, 10 Hz, 1H), 4.23-4.18 m, 1H), 3.76-3.59 (m, 1H), 3.53-3.49 (m, 1H), 3.31-3.25 (m, 1H), 3.06 (bs,
1H) 2.97 (dd, J = 9.2, 16.8 Hz, 2H), 1.90-1.79 (m, 1H), 1.70-1.62 (m, 2H), 1.24 (dd, J = 10, 15 Hz, 1H),
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3486, 3060, 2924.15, 2856, 1726, 1700, 1491, 1449, 1368, 1264, 1092, 1022; HRMS (ESI
 quadrupole) m/z: [M + Na]+ Calcd for C27H26N2O3Na 449.1841; Found 449.1827.
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Preparation of 2-((R)-8-((tert-butyldimethylsilyl)oxy)-3-hydroxyoctanoyl-1,1-diphenylhexahydro-
3H-pyrrolo[1,2-c]imidazol-3-one 26: Compound 26 was prepared by using General procedure I,
1
obtained as thick yellow liquid (137 mg, 80%; dr = 86:14). [α]D = 204.4 (c 0.5, CHCl3); H NMR
20
(500 MHz, CDCl3) δ 7.57 (t, J = 8.1 Hz, 2H), 7.35-7.18 (m, 6H), 7.10 (dd, J = 7.7, 17.3 Hz, 2H), 4.29-
4.18 (m, 1H), 3.89 (bs, 1H), 3.70 (dd, J = 10, 19.4 Hz, 1H), 3.58-3.52 (m, 2H), 3.30 (dd, J = 11, 19.9
Hz, 2H), 2.74-2.59 (m, 1H), 1.92-1.64 (m, 2H), 1.54-1.22 (m, 10H), 0.86 (s, 9H), 0.77-0.63 (m, 1H),
13
0.02 (s, 6H). C{1H} NMR (125MHz, CDCl3 + CCl4 ) δ 172.7, 158.1, 143.4, 137.6, 129.2, 129.1,
128.0, 127.8, 127.7, 127.6, 127.1, 70.8, 70.6, 68.3, 68.2, 63.1, 60.2, 45.2, 43.6, 36.2, 32.8, 30.9, 26.1,
25.8, 25.4, 23.8, 18.4, 4.6; IR (neat, cm-1): 3486, 2930, 1732, 1700, 1449, 1260, 1093, 771; HRMS (ESI
-quadrupole) m/z: [M + H]+ Calcd for C32H47N2O4Si 551.3305; Found 551.3298.
Preparation of 2-((R)-3-hydroxynon-8-enoyl)-1,1-diphenylhexahydro-3H-pyrrolo[1,2-c]imidazol-
3-one 27: Compound 27 was prepared by General procedure I, obtained as yellow color liquid (76 mg,
56%; dr = 87:13). [α]D20 = 263 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.54 (t, J = 9.3 Hz, 2H),
7.30-7.20 (m, 6H), 7.08 (d, J = 10 Hz, 2H), 5.75-5.61 (m, 1H), 4.89 (d, J = 13.6, Hz, 1H), 4.84 (d, J =
13.9 Hz, 1H), 4.23 (dd, J = 5, 11 Hz, 1H), 3.88 (bs, 1H), 3.65 (dd, J = 8.9, 20 Hz, 1H), 3.33-3.23 (m,
2H), 2.66 (dd, J = 8.5, 16.8 Hz, 1H), 1.94 (d, J = 6.2 Hz, 2H), 1.89-1.74 (m, 1H), 1.73-1.62 (m, 1H),
1.38-1.18 (m, 8H), 0.71-0.60 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 172.9, 158.1, 143.3, 138.9,
137.3, 129.0, 127.9, 127.7, 127.6, 127.1, 114.2, 70.8, 70.8, 68.1, 45.1, 43.5, 35.9, 33.6, 30.8, 28.7, 25.1,
23.8; IR (neat, cm-1): 3522, 3456, 3062, 2926, 2855, 1728, 1448, 1371, 1264, 1190, 1264, 1092, 1017;
HRMS (ESI -quadrupole) m/z: [M + H]+ Calcd for C27H33N2O3 433.2491; Found 433.2478.
Preparation of 2-((R)-3-hydroxybutanoyl)-1,1-diphenylhexahydro-3H-pyrrolo[1,2-c]imidazol-3-
one 28: Compound 28 was prepared by following General procedure I. Compound 28 obtained as a
white solid (74.45 mg, 65%; dr = 80:20). [α]D20 = 277.8 (c 0.5, CHCl3); 1H NMR (500MHz, CDCl3) δ
7.55 (t, J = 8.6 Hz, 2H), 7.31-7.19 (m, 6H), 7.08 (d, J = 7.9 Hz, 2H), 4.25-4.21 (m, 1H), 4.09-4.03 (m,
1H), 3.65 (m, 1H), 3.33-3.23 (m, 2H), 2.62 (dd, J = 8.5, 17 Hz, 1H), 1.86-1.83 (m, 1H), 1.73-1.63 (m,
13
1H), 1.23 (m, 1H), 1.05 (d, J = 5 Hz, 3H), 0.70-0.65 (m, 1H). C{1H} NMR (125 MHz, CDCl3) δ
172.8, 158.2, 143.4, 137.4, 129.0, 128.0, 127.8, 127.7, 127.2, 70.8, 64.3, 53.4, 45.1, 45.0, 31.9, 30.9,
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29.7, 23.8, 22.7, 22.0, 14.1. IR (neat): 3434, 2927, 1729, 1698, 1452, 1376, 1264, 1091, 797; HRMS
(ESI- quadrupole) m/z: [M + H]+ Calcd for C22H25N2O3 365.1863; Found 365.1849.
1
2
3
4
5
Preparation of 2-((S)-3-hydroxy-4-methylpentanoyl)-1,1-diphenylhexahydro-3H-pyrrolo[1,2-
6
7
8
9
c]imidazol-3-one 29: Compound 29 was prepared by General procedure I , obtained as a white solid
1
(80 mg, 65%, dr = 63:37). []D = 250.1 (c = 0.5, CHCl3); H NMR (500MHz, CDCl3) δ 7.57-
20
7.53 m, 2H), 7.30-7.18 (m, 6H), 7.11-7.07 (m, 2H), 4.25-4.21 (m, 1H), 3.66-3.61 (m, 1H), 3.31-3.25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(m, 2H), 2.70-2.65 (m, 1H), 1.85-1.80 (m, 1H), 1.71-1.62 (m, 1H), 1.52 (dd, J= 6.6, 13.2 Hz 1H), 1.23
13
(dd, J = 6, 12 Hz, 1H), 0.87-0.75 (m, 7H), 0.71-0.62 (m, 1H); C{1H} NMR (125MHz, CDCl3) δ
173.4, 158.2, 143.4, 137.4, 129.1, 127.9, 127.8, 127.7, 127.6, 127.1, 73.4, 73.0, 70.9, 70.8, 70.7, 45.1,
40.8, 40.8, 33.7, 33.0, 30.9, 30.8, 29.7, 23.8, 23.7, 18.5, 18.3, 17.9, 17.7; IR (neat): 3487, 2960, 1726,
1700, 1371, 1267, 1148, 763, 700. HRMS (ESI- quadrupole) m/z: [M + H]+ Calcd for C24H29N2O3
393.2178; Found 393.2161.
Preparation of 2-((S,E)-3-hydroxy-5-phenylpent-4-enoyl)-1,1-diphenylhexahydro-3H-pyrrolo[1,2-
c]imidazol-3-one 30: Compound 30 was prepared by General procedure I, obtained as yellow colour
1
solid (99 mg, 70%; dr = 83:17). []D20 = 303.8 (c 0.5, CHCl3); H NMR (500MHz, CDCl3) δ 7.55
(dd, J = 7.5, 16 Hz, 2H), 7.29-7.19 (m, 11H), 7.08 ( d, J = 7 Hz, 2H), 6.49 (d, J = 16 Hz, 1H), 6.05 (dd, J
= 6, 16 Hz, 1H), 4.61 (m, 1H), 4.23 (dd, J = 5, 11 Hz, 1H), 3.66 (m, 1H), 3.45 (dd, J = 5, 15 Hz, 1H),
3.31-3.28 (m, 1H), 3.15 (bs, 1H), 2.93-2.88 (m, 1H), 1.86-1.80 (m, 1H), 1.71-1.65 (m, 2H), 1.24 (dd, J
13
= 5, 10.5, 1H), 0.71-0.62 (m, 1H); C{1H} NMR (125MHz, CDCl3) δ 171.8, 157.8, 143.0, 137.0,
136.5, 130.0, 129.8, 128.8, 128.2, 127.7, 127.5, 127.4, 127.2, 126.9, 126.3, 70.7, 70.6, 68.7, 60.1, 44.8,
43.4, 30.6, 23.5, 20.8, 13.9; IR (neat): 3437, 3058, 3029, 2978, 1725, 1363, 1267, 735, 696. HRMS
(ESI- quadrupole) m/z: [M + Na]+ Calcd for C29H28N2O3Na 475.1997; Found 475.1982.
Preparation of (S)-2-((S)-3-hydroxy-3-(4-methoxyphenyl)propanoyl)-1,1-diphenylhexahydro-3H-
pyrrolo[1,2-c]imidazol-3-one 31: Compound 31 was prepared by following the General procedure I,
1
obtained as a white solid (96 mg, 87%; dr = 70:30). [α]D = 180 (c 0.5, CHCl3); H NMR (500MHz,
20
CDCl3) δ 7.54 (dd, J = 7, 16.8 Hz, 2H ), 7.27-7.04 (m, 10H), 6.75 (d, J = 10.6 Hz, 2H), 4.98 (d, J = 7.1
Hz, 1H), 4.21 (dd J = 4.5, 10.5 Hz, 1H), 3.70 (s, 3H), 3.67-3.50 (m, 2H), 3.26 (t, J = 10 Hz, 1H), 3.01
13
(dd, J = 9, 16.8 Hz, 1H), 1.97-1.61 (m, 3H), 0.7-0.63 (m, 1H); C{1H} NMR (125MHz, CDCl3) δ
172.4, 172.1, 158.8, 158.3, 157.9, 143.3, 137.0, 134.7, 129.0, 127.9, 127.7, 127.6, 127.1, 127.0, 113.6,
70.9, 70.7, 70.2, 69.9, 55.2, 45.4, 45.0, 30.8, 29.6, 23.7; IR (neat): 3491, 3060, 2920, 2853, 1725, 1611,
1512, 1449, 1368, 1252, 1179, 1148, 1030, 804, 735, 701.08; HRMS (ESI- quadrupole) m/z: [M + Na]+
Calcd for C28H28N2O4Na 479.1946; Found 479.1933.
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Preparation of 2-((R)-3-hydroxy-5-phenylpentanoyl)-1,1-diphenylhexahydro-3H-pyrrolo[1,2-
c]imidazol-3-one 32: Compound 32 was prepared by General procedure I , obtained as a white solid
(119 mg, 89%; dr = 82:18). [α]D20 = 178 (c 0.5, CHCl3); 1H NMR (500MHz, CDCl3) δ 7.55-7.52 (m,
2H), 7.28-7.19 (m, 8H), 7.09-7.06 (m, 5H), 4.22 (dd, J = 5, 11 Hz, 1H), 3.91-3.88 (m, 1H), 3.67-3.61
(m, 1H), 3.31-3.24 (m, 2H),  (m, 2H), 2.58-2.52 (m, 1H), 1.80 (dd, J = 6.9, 13 Hz, 1H), 1.68-
1
2
3
4
5
6
7
8
13
9
1.56 (m, 3H), 1.21 (dd, J = 5.9, 12.2 Hz, 1H), 0.69-0.6 (m, 1H). C{1H} NMR (125MHz, CDCl3) δ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
172.9, 159.1, 143.3, 142.0, 137.3, 129.0, 128.5, 128.3, 128.0, 127.8, 127.7, 127.6, 125.7, 70.8, 70.8,
67.3, 45.1, 43.5, 37.7, 31.7, 30.8, 23.8; IR (neat): 3422, 3059, 2925, 1726, 1371, 1263, 1089, 1022, 800,
737, 698; HRMS (ESI) Calcd for C29H31N2O3 [M + H]+ m/z: 455.2334; Found 455.2327.
SUPPORTING INFORMATION. The spectral data of compounds and X-ray analysis of compound 1
reported in supporting information.
X-ray crystallographic information for compound 1 is available through CCDC 1968911.
ACKNOWLEDGMENT (Word Style “TD_Acknowledgments”). GR thanks SERB-India for ECRA
funding FILE NO. ECR/2016/001580, Ranganayakulu thanks DST-India for Inspire fellowship.
Authors thank Alex A. for X-Ray Crystallography.
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Ph
Ph
O
O
Conditions
O
O
H
Cl
O
Cl
37
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OMe
O
O
OH
O
O
Ph
LHMDS, THF
Ph
N
N
MeO
N
N
, -78 oC, 4 h
11
20%
Anti : syn = 4: 1
20.
OMe
SnBu3
O
Mixture of unidentified products
S-Binol, Ti(OiPr)4
4A MS, CH2Cl2
MeO
21. TLC analysis shows more polar products. The NMR analysis of crude product confirm the self-
aldol reaction of the aldehyde.
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aldol reactions. Tetrahedron. Asym. 1997, 8, 1193-1206. (b). Practical formal total syntheses of
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9
23. Reyes-Rangel, G.; Vargas-Caporali, J.; Juaristi, E. In search of diamine analogues of the ,-
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10
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44
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60
24. Specific rotation of acid 33: []D25 4.6 (c 1 in CHCl3)
OMe
OMe
OH
O
S
S
THF, H2O
imidazolidine
OH
O
MeO
N
HN
Bn
S
+
S
rt, 14 h, 98%
MeO
OH
Bn
33
25. (a). Specific rotation of -phenyl--hydroxypropionic acid. {[]D 19.2 (c 1 in CHCl3)}. (b).
25
Ankati, H; Zhu, D.; Yang, Y.; Beihl, E. R.; Hua, L. Asymmetric synthesis of both antipodes of
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29. For the various reaction conditions see Table 1 in supporting information.
30. ORTEP structure of (2S, 4R)-3'-methoxy citreochlorol 1.
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31. Qiu, W.W.; Surendra, K.; Yin, L.; Corey E. J. Selective formation of six-membered oxa- and
carbocycles by the In(III)-activated ring closure of acetylenic substrates. Org. Lett. 2011, 13,
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