Stereoselective addition of Grignard reagents to sulfinimines derived from tartrate diol (threitol): Generation of chiral building blocks for the collective total synthesis of lentiginosine, conhydrine and methyldihydropalustramate

Article abstract of DOI:10.1016/j.tet.2019.130496

A systematic investigation of the addition of Grignard reagents to sulfinimines derived from tartaric acid diol was undertaken. It was observed that the chirality of the inherent tartrate moiety influences the diastereoselectivity of the resultant sulfinamides formed in the reaction. The formed products serve as excellent building blocks for the synthesis of natural products. This has been demonstrated in the collective total synthesis of lentiginosine, (+)-α-conhydrine and methyldihydropalustramate.

Full text of DOI:10.1016/j.tet.2019.130496

Journal Pre-proof
Stereoselective addition of Grignard reagents to sulfinimines derived from tartrate
diol (threitol): Generation of chiral building blocks for the collective total synthesis of
lentiginosine, conhydrine and methyldihydropalustramate
Kavirayani R. Prasad, Vipin Ashok Rangari
PII:
S0040-4020(19)30823-3
https://doi.org/10.1016/j.tet.2019.130496
TET 130496
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 May 2019
Revised Date: 29 July 2019
Accepted Date: 1 August 2019
Please cite this article as: Prasad KR, Rangari VA, Stereoselective addition of Grignard reagents to
sulfinimines derived from tartrate diol (threitol): Generation of chiral building blocks for the collective total
synthesis of lentiginosine, conhydrine and methyldihydropalustramate, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.130496.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.

Graphical Abstract
Stereoselective Addition of Grignard Reagents to Sulfinimines Derived from Tartrate Diol
(threitol): Generation of Chiral Building Blocks for the Collective Total Synthesis of
Lentiginosine, Conhydrine and Methyldihydropalustramate
Kavirayani R. Prasad* and Vipin Ashok Rangari

Stereoselective Addition of Grignard Reagents to Sulfinimines Derived from Tartrate Diol
(threitol): Generation of Chiral Building Blocks for the Collective Total Synthesis of Lentiginosine,
Conhydrine and Methyldihydropalustramate
Kavirayani R. Prasad* and Vipin Ashok Rangari
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012
E-mail: prasad@iisc.ac.in; FAX: +91-80-23600529
Abstract: A systematic investigation of the addition of Grignard reagents to sulfinimines derived
from tartaric acid diol was undertaken. It was observed that the chirality of the inherent tartrate
moiety influences the diastereoselectivity of the resultant sulfinamides formed in the reaction.
The formed products serve as excellent building blocks for the synthesis of natural products. This
has been demonstrated in the collective total synthesis of lentiginosine, (+)-α-conhydrine and
methyldihydropalustramate.
Key words: Sulfinimines, Chiral pool, Stereoselective addition, Total synthesis, Alkaloids
Introduction:
Polyhydroxy functionalized pyrrolidines, piperidines are important class of compounds
ubiquitously present in aza-sugars and other therapeutically important molecules.1 Owing to the
fact that a large number of polyhydroxy functionalized piperidines, pyrrolidines and other bicyclic
analogues display excellent glycosidase inhibitory activity, there has been a continuing interest in
the development of synthetic strategies for their synthesis.2 The readily available chiral pool
compounds such as carbohydrates and tartaric acid were widely utilized for the synthesis of these
polyhydroxy amine containing compounds. Extensive protection/ deprotection of the functional
groups was required in the synthesis of aza-sugars from carbohydrates,3 while, approaches from
tartaric acid generally involved the stereoselective addition of nucleophiles such as Grignard
reagents to imines or imine equivalents derived from tartrate diol (threitol). Terashima’s group
was the first to study the addition of Grignard reagents to imines derived from tartaric acid. They
found that the addition of cyclohexylmethylmagnesium bromide to the benzylimine 1 derived
from tartaric acid does not form the required product, while, an organocerium reagent prepared
from the Grignard reagent and CeCl3 afforded the product with excellent selectivity.4 Later,
Dondoni’s group studied the nucleophilic addition reactions of nitrones 2 derived from tartrate.5
We reasoned that the formation of sulfinimines 3-4 from the aldehydes derived from tartaric acid
would serve as excellent start point for the synthesis of polyhydroxy functionalized amine
compounds. Sulfinimines are proven reagents for the synthesis of chiral amines with perfect
stereocontrol6 and the ease of deprotection of the sulfinamide group allows the generation of free
amine and further transformations involving the amine functionality. The process would be
beneficial from the conventional use of imine equivalents which involve cumbersome
deprotection of the amine protecting groups. Also, a systematic examination of the addition of
organometallic reagents such as Grignard reagents and organolithium compounds would give the
insight in to the diastereoselectivity associated with the match, mis-match situation of the chiral
sulfinimine and tartrate components. Prior to our work, few examples concerning the addition of
8
CN7 and MeP(O)(OMe)2 on sulfinimine 3 derived from p-toluenesulfinamide and tartrate was
recorded in literature. It is important to note that except for allyl Grignard reagents, the addition
of other Grignard reagents is not possible on the imines derived from p-tolunesulfinamide.
Addition of iodomethyllithium and vinylmagnesium bromide to structurally similar sulfinimine 49,10
prepared from Ellman’s sulfinamide has also been reported. Herein, we describe in detail our
efforts concerning the study of various alkyl/aryl Grignard reagents to the sulfinimine 4 and
1

application of the formed products in the collective total synthesis of natural products
lentiginosine 5, (+)- α-conhydrine 6, methyldihydropalustramate 7 and the piperidine 8; a key
intermediate for the synthesis of CP,99,994, CP-122,721 and LP-733,060, molecules of therapeutic
significance (Fig-1).
Fig.1: Chiral imines derived from tartrate diol (threitol).
Results and Discussion
Accordingly, the study commenced with the synthesis of the sulfinimine from the diol derived
from tartaric acid analogus to a procedure described earlier.10 Addition of MeMgI to the imine
produced the addition product 9a in 92% yield and in >99:1 diastereomeric ratio.11 The addition of
nBuMgBr, PhCH2MgBr also proceeded smoothly to afford the addition products 9b-c in >99:1
i
diastereomeric in good yields. The addition of BuMgBr formed the product 9d in 52% yield (71%
based on the recovery of the starting material) while, the addition of iPrMgBr afforded the product
9e in 68% yield (dr >99:1) along with 14% of the imine reduction product originating from the
addition of the β-hydride of the Grignard reagent. The addition of PhMgBr and 4-OMePhMgBr also
furnished the products 9f-g with excellent diastereoselectivity (>99:1). The addition of pent-4-
enylmagnsium bromide as well as 4-benzyloxybutylmagnesium bromide also gave the products
9h-i with more than >99:1 diastereoselectivity. The addition of vinylmagnesium bromide produced
the product 9j in 74% yield and in >99:1 dr. All these results are summarized in chart-1.
2

Chart-1: Stereoselective addition of Grignard reagents to the sulfinimine 4
Stereochemistry at the newly formed amine center is established by the following. Deprotection
of the sulfinyl group in 9a with methanolic HCl followed by protection as Cbz carbamate
funrnished the Cbz protected amine 10 in 87% yield. Deprotection of the acetonide in 10 yielded
the diol in 75% yield. Treatment of 11 with NaIO4 produced the aldehyde the reduction of which
with NaBH4 afforded the amino alcohol 12 in 86% yield. Comparison of the optical rotation12 of 12
with that obtained from natural amino acid alanine clearly established the stereochemistry as (S)
at the newly formed center bearing the amine group (Scheme-1).
Scheme-1: Determination of the absolute stereochemistry of the amine center in 9a
The sense of induction in the addition reaction was governed by the tartrate moiety rather than
the sulfinimine. Similar outcome was observed by Wang in the addition of vinylmagnesium
bromide to structurally similar sulfinimine.10 It is evident that the major products formed in the
addition of nucleophiles to imine 4 originate from the addition of nucleophiles from a face
opposite to the sulfinyl oxygen of the sulfinimine. Formation of the major products 9a-j can be
explained by a model proposed by Davis13 for the addition of organometallic reagents to
sulfinimines derived from ethylglyoxalate (fig-2).
3

Fig. 2: Proposed model for the observed selectivity
To investigate the effect of match-mismatch situation in the reaction, sulfinimine 4a derived from
D-tartaric acid and Ss-tert-butanesulfinamide was reacted with MeMgI. The formation of both
possible diastereomers 13a and 13b was observed in 3:1 ratio, which were isolated in 59% and
14% respectively (Scheme-2), indicating a mis-match situation. Following a procedure described in
scheme-1, stereochemistry at the newly formed amine center in the major diastereomer 13a was
found to be R.
Scheme-2: Addition of MeMgI to sulfinimine 4a.
After optimizing the conditions for the addition of Grignard reagents and the stereochemistry of
the newly formed stereogenic center, application of the resultant compounds is exemplified in the
synthesis of bio-active natural products. The total synthesis of lentiginosine 5 and conhydrine 6
was accomplished from the sulfinamide as depicted in Scheme-3. Lentiginosine is the smallest aza-
sugar natural product that displayed potent glycosidase inhibitory activity. A plethora of
publications about the synthesis of lentiginosine14 have appeared in literature including the
synthesis originating from tartaric acid.15 In the present sequence, the synthesis of lentiginosine
started with the debenzylation of both benzyl groups in 9i using Li/ naphthalene to furnish the
free diol which was transformed to the bis-tosylate 14 in 61% yield for two steps. Deprotection of
the acetonide as well as the sulfinyl group in 14 was accomplished by reaction with saturated
methanolic HCl. Neutralization of the formed amine hydrochloride with K2CO3 resulted in the
concomitant displacement of both tosyl groups with amine to furnish lentiginosine in 60% yield
(26% overall yield from the sulfinimine in 4 steps). The sulfinamide 9i was also utilized in the
synthesis (+)-α-conhydrine 6, an alkaloid natural product isolated from the seeds and leaves of
Conium maculatum L which was also shown to exhibit glycosidase inhibitory activity.16 For the
synthesis of conhydrine the sulfinyl group in 9i was deprotected and the amine was protected as
the Boc carbamate to yield 15 in 84% yield. Debenzylation of the benzylethers in 15 afforded the
diol 16 which on tosylation of the free hydroxy groups furnished the bis-tosylate 17 in 83% yield.
Reaction of the bis-tosylate 17 with NaH furnished the piperidine 18 in 81% yield. Conversion of
the tosylate 18 to the iodide and subsequent reaction with Zn in EtOH cleanly furnished the allyl
alcohol 19 in 71% yield. Hydrogenation of the olefin in 19 followed by the deprotection of the Boc
group afforded conhydrine 6 in 73% for two steps (Scheme-3). The spectral and physical data of
which is in complete agreement with that reported in literature.17
4

Scheme-3: Total Synthesis of lentiginosine 5 and (+)-α-conhydrine 6 from sulfinamide 9i
After accomplishing the synthesis of lentiginosine and conhydrine, application of the sulfinamide
9f in the synthesis of 8; a key intermediate for the synthesis of therapeutically important
piperidines 21-2318ab (which are shown to act as neurokinin substance P antagonists receptors)
was undertaken. Thus, removal of the sulfinyl group in 9f and further protection of the free amine
as the Boc carbamate furnished 24 in 63% yield. Debenzylation of the benzylether in 24 afforded
the free alcohol 25 (97% yield) which was converted to the tosylate 26 using standard conditions.
N-allylation of the carbamate furnished the product 27 in 60% yield. Conversion of the tosylate in
27 to the iodide and further reaction with zinc in methanol afforded the diene 28 in 91% yield.
Ring closing metathesis (RCM) of the diene 28 with Grubbs’ 2nd generation catalyst and further
hydrogenation of the formed dihydropiperidine with H2/Pd furnished 2-phenyl,3-hydroxy-N-Boc
piperidine 8 in 80% yield. Since conversion of 8 to LP-733,060, CP-99,994 and CP-122,721 is
reported in literature,18a,c the present sequence constitutes a formal synthesis of 21-23 (Scheme-
4).
Ph
Ph
Ph
O
i) HCl in MeOH
0 C, 20 min
ii) (Boc)2O, NaOH
1,4-dioxane, rt, 18 h
63%
S
O
O
O
O
O
O
N
tBu
NHBoc
NHBoc
OH
H2, Pd/C, MeOH
rt, 36 h, 97%
H
25
OBn
24
OBn
9f
Ph
Ph
O
i) NaI, acetone
16 h, 93%
O
NBoc
NHBoc
OTs
TsCl, Et3N, DMAP
NaH, allylbromide
DMF, rt, 3 h, 60%
CH2Cl2, rt, 16 h, 78%
ii) Zn, MeOH
6 h, 91%
O
O
26
27
OTs
Ar
H
O
Ph
N
Ar
i)Grubbs 2nd ge cat
CH2Cl2, rt, 4 h, 80%
ii) H2, Pd/C, EtOAc
rt, 4 h, 80%
OH
Ph
HO
NBoc
N
Ph
N
Ph
H
H
N
LP-733,060 (21)
Ar = 3,5-bis-trifluoro Ar = 2-methoxy-3-
methyl trifluromethoxy = CP-122-721 (23)
Ar = 2-methoxy = CP-99, 994 (22)
Boc
28
8
Scheme-4: Formal synthesis of LP-733,060, CP-99,994 and CP-122,721
5

In another application, total synthesis of methyldihydropalustramate 7,19 a degradation product of
the natural product palustrine and also considered as the intermediate for the synthesis of
palustrine was accomplished from the sulfinamide 9h as depicted in scheme-5. Accordingly,
debenzylation of the benzyl ether in 9h furnished the free alcohol which was converted to the
tosylate 29 under standard reaction conditions in 56% yield for two steps. The tosylate in 29 was
transformed to the iodide which on deprotection of the N-sulfinyl group and further protection of
the free amine with Boc anhydride afforded the Boc-carbamate 30 in 71% yield for two steps.
Elaboration of the olefin in 30 to the unsaturated ester 31 was accomplished by a two-step
process involving ozonolysis of the olefin and subsequent Horner-Wadsworth-Emmons
olefination. Although, olefin cross metathesis of 30 with ethylacrylate also rendered the required
unsaturated ester 31, we preferred the ozonolysis/HWE olefination sequence because of the
better yield. Reaction of 31 with NaH underwent the intramolecular aza Michael addition to form
the 2,6-disubstituted piperidine 32 in 78% yield. Treatment of 32 with zinc in ethanol yielded the
allyl alcohol 33 in 77% yield. K2CO3 mediated trans esterification of the ethyl ester in 33 to the
methyl ester 34 (80% yield) and further hydrogenation formed the Boc-protected epi-
methyldihydropalustramate 35 in almost quantitative yield. Dess-Martin periodinane20 oxidation
of the alcohol in 35 afforded the ketone which on reduction with NaBH4 furnished the Boc-
protected methyldihydropalustramate 36 in 77% yield. TFA mediated deprotection of Boc group in
36 furnished ( −)-methyldihydropalustramate 7 in 72% yield. The spectral and physical data is in
complete agreement with that reported in literature (Scheme-5).19d
Scheme-5: Total synthesis of ( −)-methyldihydropalustramate
In conclusion, a systematic study on the addition of Grignard reagents to the sulfinimines derived
from tartaric acid was reported. It was observed that the diastereoselectivity in the addition
reaction is controlled by inherent tartrate moiety and the sulfinamide group acts as a bulky group.
Slight influence of the match-mismatch like situation was observed in the addition reaction. The
formed sulfinamides serve as excellent building blocks for the synthesis of a number of amine
containing natural products. This was demonstrated in the collective total synthesis of natural
6

products lentiginosine, (+)-α-conhydrine, dihydromethylpalustramate and a key intermediate in
the synthesis of therapeutically important piperidines LP-733,060, CP-99,994 and CP-122,721.
Experimental:
General Information: Column chromatography was performed on silica gel, Acme grade 100−200
mesh. TLC plates were visualized either with UV in an iodine chamber or with phosphomolybdic
acid spray unless noted otherwise. All reagents were purchased from commercial sources and
used without additional purification. THF was freshly distilled over Na-benzophenone ketyl.
Melting points were recorded using melting point apparatus in capillary tubes and are
1
uncorrected. Unless stated otherwise, H (400 MHz) and 13C (100 MHz) spectra were recorded on
400 MHz machine in CDCl3 as solvent with TMS as reference. High-resolution mass spectra (HRMS)
were recorded on a Q-TOF micromass spectrometer using electron spray ionization mode.
Preparation of 4: To a stirred solution of ((4S,5S)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-
4-yl)methanol [4-O-Benzyl-23-O-isopropylidene-L-threotol]21 (1.0 g, 3.96 mmol) dissolved in EtOAc
(15 mL) was added IBX (3.35 g, 11.9 mmol) and the reaction mixture was refluxed for 3 h. After
completion of the reaction (TLC), it was filtered through a short pad of celite, and the solvent was
evaporated off to obtain the crude aldehyde as a colorless oil. The resulting oil was dissolved in
dry THF (10 mL), (S)-tert-butanesulfinamide (0.574 g, 4.75 mmol), and anhydrous Ti(OEt)4 (1.4 mL,
6.6 mmol), were added successively under argon atmosphere and the resulting reaction mixture
was allowed to reflux for 3 h. After completion of the reaction (TLC), it was quenched by addition
of saturated solution of brine (5 mL) and was stirred at rt for 15 min. The resulting solid cake was
filtered through a short pad of celite and was washed with EtOAc (2×20 mL). The solvent was
evaporated off, to obtain crude residue which was purified by silica gel column chromatography
24
using EtOAc:hexane (2:8) as eluent to obtain the imine 4 (1.05 g, 75%) as a colourless oil. [α]
D
+130.6 (c 1.0, CHCl3); IR (neat): 3251, 2985, 1625, 1370, 1080 cm−1; H NMR (400 MHz, CDCl3): δ
8.08 (d, J = 4.8 Hz, 1H), 7.37–7.27 (m, 5H), 4.66 − 4.52 (m, 3H), 4.25−4.16 (m, 1H), 3.72 − 3.58 (m,
2H), 1.48 (s, 3H), 1.43 (s, 3H), 1.12 (s, 9H), 13C NMR (100 MHz, CDCl3).δ: 167.3, 137.6, 128.4 (2C),
127.8 (3C), 111.3, 79.1, 78.2, 73.6, 69.5, 57.0, 26.9, 26.5, 22.3 (3C) HRMS ESI m/z calcd for
C18H27NO4SNa, 376.1558; found 376.1557.
1
Preparation of 4a: Following a similar procedure described above, [4-O-Benzyl-23-O-
24
isopropylidene-D-threotol] furnished the imine 4a (0.73 g, 66%) as colourless oil [α]D + 172.6 (c
1
0.95, CHCl3); IR (neat): 3432, 2985, 1633, 1372 cm−1; H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 4.4
Hz, 1H), 7.40–7.25 (m, 5 H), 4.65−4.55 (dd, J = 6.8 Hz, 5.6 Hz, 3H), 4.30 − 4.22 (m, 1H), 3.70 (ddd, J
= 14.4 Hz, 10.4 Hz, 4.0 Hz, 2H), 1.50 (s, 3H), 1.44 (s, 3H), 1.19 (s, 9H), 13C NMR (100 MHz, CDCl3).δ:
166.7, 137.7, 128.3 (2C), 127.7 (2C), 127.6, 111.2, 78.8, 78.0, 73.5, 69.4, 57.2, 26.8, 26.5, 22.4 (3C),
HRMS ESI m/z calcd for C18H27NO4SNa, 376.1558; found 376.1556.
General Procedure for the Addition of Grignard reagents to Sulfinimine 4: The following
procedure for the preparation of 9a by the addition of MeMgI to sulfinimine 4 is representative: To
7

a stirred solution of the imine 4 (0.08 g, 0.24 mmol) in THF (5 mL) at −78 °C, was added dropwise
methylmagnesium iodide (0.5 M in Et2O, 0.63 mL, 0.33 mmol) under argon atmosphere for 2 min.
The reaction mixture was stirred for 45 min at the same temperature. Progress of reaction was
monitored by TLC, and after completion of the reaction, it was quenched cautiously by addition of
sat. aqueous NH4Cl (5 mL) solution and allowed to warm to room temperature and extracted with
EtOAc (2×10 mL). The combined organic layer was washed with brine (5 mL), dried over Na2SO4
and concentrated. The crude residue thus obtained was purified by silica gel column
chromatography using (1:1) EtOAc:hexane as eluent to yield the compound 9a (0.084 g, 92%) (dr
24
1
99:1). as a colourless oil. [α]D + 20.6 (c 1.4, CHCl3); IR (neat): 3274, 3232, 2927, 1063 cm−1; H
NMR (400 MHz, CDCl3): δ 7.37 – 7.29 (m, 5 H), 4.58 (s, 2H), 4.12 (dd, J = 12 Hz, 6 Hz 1H), 3.97 ( s,
1H), 3.92 (t, J = 6.4 Hz, 1H) 3.64 − 3.61 (m, 2H), 3.52 (dd, J =10, Hz, 5.6 Hz, 1H), 1.41 (s, 3H), 1.38 (s,
3H), 1.20 (s, 3H), 1.18 (s, 9H), 13C NMR (100 MHz, CDCl3).δ 137.5, 128.4 (2C), 127.8 (3C), 109.3,
82.0, 76.6, 73.6, 71.3, 55.4, 51.0, 27.1, 26.9, 22.6 (3C), 16.8; HRMS ESI m/z calcd for C19H31NO4SNa,
392.1872; found 392.1872.
Preparation of 9b: Following the general procedure, addition of n-butylmagnesium bromide (0.25
M in THF, 1.7 mL, 0.43 mmol) to the imine 4 (0.102 g, 0.29 mmol) afforded the compound 9b
24
(0.098 g, 82%) (dr >99:1) as a colourless oil. [α]D + 32.7 (c 0.85, CHCl3); IR (neat): 3415, 2924,
1649, 1219, 1119, cm−1; 1H NMR (400 MHz, CDCl3): δ 7.38 – 7.26 (m, 5 H), 4.58 (s, 2H), 4.17 (q, J =
6.0 Hz, 1H), 4.07 (t, J = 6.4 Hz, 1H) 3.86 (d, J = 5.6 Hz, 1H), 3.67 (dd, J = 9.6 Hz, 5.6 Hz, 1H), 3.53 −
3.46 (m, 1H), 3.41 (t, J = 5.6 Hz, 1H) 1.69 − 1.51 (m, 2H), 1.41 (s, 3H), 1.38 (s, 3H) 1.35 − 1.25 (m,
4H), 1.18 (s, 9H), 0.9 (t, J = 6.4 Hz, 3H), 13C NMR (100 MHz, CDCl3).δ 137.5, 128.3 (2C), 127.72,
127.70 .127.5, 109.2, 81.0, 76.6, 73.5, 71.2, 56.8, 55.7, 30.8, 27.2, 26.9, 26.8, 22.6 (3C), 22.4, 13.9
HRMS ESI m/z calcd for C22H37NO4SNa, 434.2341; found 434.2340.
Preparation of 9c: Following the general procedure addition of benzylmagnesium bromide (0.65 M
in THF, 0.46 mL, 0.33 mmol) to the imine 4 (0.09 g, 0.25 mmol) afforded the compound 9c (0.104g,
92%) (dr 99:1) as colourless oil. [α]D24 + 8.4 (c 1.0, CHCl3); IR (neat): 3244, 2925, 1375, 1067 cm−1;
1H NMR (400 MHz, CDCl3): δ 7.35 – 7.09 (m, 10H), 4.55 (s, 2H), 4.28 (q, J
= 6.4 Hz, 2H), 4.05 (t, J =
6.4, Hz, 1H), 3.85 − 3.65 (m, 3H), 3.51 (dd, J = 9.2 Hz, 7.2 Hz, 1H), 2.98 (dd, J = 14.0, 4.0 Hz, 1H),
2.85 (dd, J = 14.0 Hz, 7.6 Hz, 1H) 1.46 (s, 3H) 1.4 (s, 3H), 1.0 (s, 9H), 13C NMR (100 MHz, CDCl3).δ:
137.7, 137.5, 129.8 (2C), 128.3 (2C), 128.1, 127.8 (2C), 127.7 (2C), 126 2, 109.5, 81.1, 76.7, 73.5,
71.1 ,58.9, 55.8, 37.6, 27.0, 26.9, 22.4 (3C) HRMS ESI m/z calcd for C25H35NO4SNa, 468.2185; found
468.2185.
8

Preparation of 9d: Following the general procedure addition of 2-methyl-propylmagnesium
bromide (0.2 M in THF, 1.0 mL, 0.20 mmol) to the imine 4 (0.049 g, 0.13 mmol) afforded a
24
compound 9d as a colourless oil in 52% yield (0.030 g,) (dr 99:1) [α]D + 20.64 (c 1.4., CHCl3); IR
(neat): 3246, 2928, 1371, 1071 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.34 – 7.27 (m, 5 H), 4.58 (s, 2H),
4.16 − 4.09 (m, 2H), 3.74 (d, J = 6.8, Hz, 1H), 3.67 (dd, J = 9.6 Hz, 4.8 Hz, 1H), 3.58 − 3.42 (m, 2H),
1.80 − 1.70 (m, 1H), 1.42 (s, 3H) 1.38 (s, 3H), 1.34 − 1.27 (m, 2H), 1.19 (s, 9H), 0.93 (d, J = 6.4 Hz,
3H), 0.83 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3).δ: 137.7, 128.4 (2C), 127.8 (2C), 127.7,
109.3, 81.9, 76.3, 73.6, 71.3, 56.0, 55.2, 40.3, 27.0, 26 9, 24.2, 23.4, 22.7 (3C), 21.5; HRMS ESI m/z
calcd for C22H37NO4SNa, 434.2341; found 434.2341.
Preparation of 9e: Following the general procedure addition of isopropylmagnesium chloride (0.3
M in THF, 2.0 mL, 0.61 mmol) to the imine 4 (0.144 g, 0.4 mmol) afforded the compound 9e (0.110
24
g, 68%) (dr >99:1) as a colourless solid. [α]D + 55.2 (c 1.55, CHCl3); mp = 53 °C, IR (KBr): 3261,
2960, 1367, 1055, cm−1; 1H NMR (400 MHz, CDCl3): δ 7.32 – 7.30 (m, 5 H), 4.57 (s, 2H), 4.42 (q, J =
4.8 Hz, 1H), 3.96 − 3.89 (m, 2H); 3.80 (dd, J = 9.2, Hz, 4.4 Hz, 1H), 3.46 − 3.42 (m, 1H), 3.25 (t, J
=6.8 Hz, 1H), 2.10 − 2.03 (m, 1H), 1.41 (s, 3H), 1.37 (s, 3H) 1.13 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H), 0.88
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3).δ 137.4, 128.4 (2C), 127.9 (2C), 127.87, 109.5, 79.7,
77.2, 73.6, 71.3, 63.3, 56.1, 30.1, 27.1, 26.9, 22.9 (3C), 20.2, 15.5; HRMS ESI m/z calcd for
C21H35NO4SNa, 420.2185; found 420.2185. The product 9e’ from the reduction of the imine was
24
1
also formed in 14% yield. [α]D +12.67 (c 0.6, CHCl3); IR (neat): 3420, 2924, 1612, 1371 cm−1; H
NMR (400 MHz, CDCl3): δ 7.40 – 7.24 (m, 5 H), 4.58 (s, 2H), 4.03 (s, 2H), 3.74 − 3.62 (m, 2H), 3.54
(dd, J = 10.8, Hz, 2.4 Hz, 1H), 3.49 (s, 1H), 3.19 (t, J =11.2 Hz, 1H), 1.40 (s, 3H), 1.39 (s, 3H) 1.2 (s,
9H), 13C NMR (100 MHz, CDCl3).δ 137.6, 128.5 (2C), 127.8 (2C), 127.7, 109.4, 78.7, 73.6, 70.4, 56.1,
46.4, 29.7, 27.1, 26.9, 22.7 (3C); HRMS ESI m/z calcd for C18H29NO4SNa, 378.1718; found 378.1718.
Preparation of 9f: Following the general procedure, addition of phenylmagnesium bromide (0.5 M
in THF, 1.2 mL, 0.6 mmol) to the imine 4 (0.144 g, 0.4 mmol) afforded the compound 9f in 87%
yield (0.150 g,) (dr >99:1) as a colourless oil. [α]D24 + 52.0 (c 1, CHCl3); IR (neat): 3231, 2980, 1372,
1
1073 cm−1; H NMR (400 MHz, CDCl3): δ 7.37 – 7.22 (m, 10H), 4.69 (d, J = 5.2 Hz, 1H), 4.44 – 4.36
(m, 3H), 4.20 – 4.16 (m, 1H), 4.14 − 4.08 (m, 1H), 3.18 (dd, J = 9.6 Hz, 5.6 Hz, 1H), 3.0 (dd, J = 9.6
Hz, 4.4 Hz, 1H) 1.39 (s, 3H), 1.36 (s, 3H) 1.22 (s, 9H); 13C NMR (100 MHz, CDCl3).δ 137.5, 137.3,
128.4 (2C), 128.3 (2C), 128.2 (2C), 127.7 (2C), 127.2 (2C), 109.6, 81.1, 76.4 73.5, 70.8, 58.2, 55.7,
27.0, 26.9, 22.6 (3C); HRMS ESI m/z calcd for C24H33NO4SNa, 454.2028; found 454.2028.
9

Preparation of 9g: Following the general procedure addition of 4-methoxyphenylmagnesium
bromide (0.47 M in THF, 0.91 mL, 0.42 mmol) to the imine 4 (0.1 g, 0.28 mmol), afforded the
24
compound 9g in 93% yield (0.120 g) (dr >99:1) as a colourless oil. [α]D + 67.0 (c 0.8, CHCl3); IR
(neat): 3234, 2925, 1512, 1072 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.36 – 7.18 (m, 7H), 6.83 (s, 1H),
6.81 (s, 1H), 4.64 (d, J = 4.8 Hz, 1H), 4.50 − 4.40 (m, 2H), 4.33, (s, 1H), 4.17 (q, J = 5.6 Hz, 1H) 4.07
(t, J = 6.8 Hz, 1H), 3.78 (s 3H), 3.22 (dd, J = 10 Hz, 5.6 Hz, 1H), 3.06 (dd, J =10 Hz, 4.8 Hz, 1H), 1.38
(s, 3H), 1.35 (s, 3H) 1.20 (s, 9H), 13C NMR (100 MHz, CDCl3). δ 159.2, 137.4, 129.3 (2C), 129.0, 128.3
(2C), 127.6 (3C), 113.7 (2C), 109.4, 81.1, 76.3, 73.4, 70.8, 57.6, 55.5, 55.0, 27.0, 26.8, 22.5 (3C),
HRMS ESI m/z calcd for C25H35NO5SNa, 484.2134; found 484.2136.
Preparation of 9h: Following the general procedure addition of pent-4-enyl-1-magnesium bromide
(0.3 M in THF, 1.41 mL, 0.42 mmol) to the imine 4 (0.1 g, 0.28 mmol) afforded the compound 9h
(0.100 g, 83%) with (dr 99:1). as a colourless oil. [α]D24 + 35.5 (c 1.5, CHCl3); IR (neat): 3231, 2931,
1370, 1074 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.40 − 7.20 (m, 5 H), 5.05−4.90 (m, 1H), 4.58 (s, 2H),
4.58 (s, 2H), 4.16 (q, J = 6.0 Hz, 1H), 4.10 − 4.02 (m, 1H), 3.86 (d, J = 5.2 Hz, 1H), 3.68 (dd, J =9.6 Hz,
5.2 Hz, 1H), 3.50 (dd, J = 9.6 Hz, 6.8 Hz, 1H), 3.49 − 3.34 (m, 1H), 2.04 (m, 2H), 1.70−1.5 (m, 3H),
1.49−1.40 (m, 1H) 1.41 (s, 3H), 1.37 (s, 3H),1.18 (s, 9H), 13C NMR (100 MHz, CDCl3).δ: 138.2, 137.4,
128.3 (2C), 127.74 (2C), 127.71, 114.7, 109.3, 81.1, 76.6, 73.5, 71.2 ,56.8, 55.7, 33.7, 30.6, 26.9,
26.8, 24.3, 22.6 (3C); HRMS ESI m/z calcd for C23H37NO4S+H, 424.2522; found 424.2523.
Preparation of 9i: Following the general procedure addition of 4-benzyloxybutylmagnesium
bromide (0.2 M in THF, 18 mL, 3.6 mmol) to the imine 4 (0.85 g, 2.4 mmol) in THF (10 mL) at −78
°C, afforded the compound 9i as a colourless oil in 72% yield (0.9 g,) (dr >99:1). [α]D24 + 20.3 (c 1.1,
1
CHCl3); IR (neat): 3264, 3030, 2932, 1454, cm−1; H NMR (400 MHz, CDCl3): δ 7.37 – 7.29 (m, 8H),
7.28 − 7.22 (m, 2H), 4.56 (s, 2H), 4.48 (s, 2H), 4.15 (dd, J = 12 Hz, 6 Hz,1H), 4.10 – 4.02 (m,1H), 3.87
(d, J = 5.6 Hz, 1H), 3.69 (dd, J = 9.6 Hz, 4.8 Hz, 1H), 3.53 −3.38 (m, 4H), 1.70 − 1.54 (m, 6H), 1.40(s,
3H), 1.36 (s, 3H), 1.17 (s, 9H), 13C NMR (100 MHz, CDCl3). δ 138.5, 137.5, 129.8 (2C), 128.3 (2C),
128.2, 127.75 (2C), 127.71, 127.3, 124.4, 109.3, 81.1, 73.5, 72.7, 71.2, 70.0, 56.9, 55.7, 31.1, 29.5,
27.0, 26.8, 22.6 (3C), 22.4, 21.8 HRMS ESI m/z calcd for C29H43NO5SNa, 540.2760; found 540.2757.
10

Preparation of 9j: Following the general procedure addition of vinylmagnesium bromide (0.28 M in
THF, 1.6 mL, 0.45 mmol), to the imine 4 (0.108 g, 0.30 mmol) afforded the compound 9j in 74%
24
yield (0.084 g) (dr 99:1). as colourless oil. [α]D + 52.2 (c 1.1, CHCl3); IR (neat): 3236, 2984, 1455,
1370, 1074 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.36 – 7.27 (m, 5H), 5.63 (ddd, 17.2 Hz, 10.4 Hz, 8.0
Hz, 1H), 5.34 (d, J
=
16.8 Hz, 1H), 5.27 (d, J = 10.8 Hz, 1H), 4.60 (s, 2H), 4.18 (td, J = 7.6 Hz, 5.2 Hz,
10.0, 5.2 Hz, 1H), 3.52 (dd, J= 10.4 Hz,
1H), 4.09 − 4.05 (m, 1H), 4.02 − 3.97 (m, 2H), 3.59 (dd, J
=
5.2 Hz, 1H) 1.41 (s, 3H), 1.38 (m, 3H), 1.21 (s, 9H); 13C NMR (100 MHz, CDCl3).δ: 137.5, 134.2, 128.3
(2C), 127.7 (3C), 120.0, 109.4, 80.6, 76.3, 73.5, 71.0, 58.1, 55.5, 27.0, 26.8, 22.6 (3C); HRMS ESI m/z
calcd for C20H31NO4SNa, 404.1872; found 404.1872.
Preparation of 13a: Following the general procedure, addition of methylmagnesium iodide (0.5 M
in Et2O, 4.3 mL, 2.15 mmol) to the imine 4a (0.560 g, 1.58 mmol) afforded the separable mixture
of diastereomers 13a and 13b. Data for 13a [α]D24+ 34.4 (c, 1.0 CHCl3);, IR (neat): 3401, 2981,
2927, 1456 , 1070 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.39 – 7.22 (m, 5H), 4.60 (s, 2H), 4.19 (dd, J =
17.2 Hz, 5.2 Hz, 1H), 4.02 (d, J = 4.8 Hz, 1H), 3.82 (t, J = 6.8 Hz, 1H) 3.64 − 3.58 (m, 2H),3.51 (td, J
=12.4 Hz, 6.4 Hz, 1H), 1.42 (s, 3H), 1.40 (s, 3H) 1.19 (s, 9H), 1.15 (d, 4.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3).δ 137.8, 128.4 (2C), 127.7 (3C), 109.4, 81.8, 76.5, 73.5, 70.4, 55.4, 52.1, 27.2 (2C), 22.5 (3C),
18.5; HRMS ESI m/z calcd for C19H31NO4SNa, 392.1872; found 392.1874. Data for 13b [α]D24 +60.63
(c, 1.0 CHCl3); IR (neat): 3441,2986, 2863, 1370 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.38 – 7.25 (m,
5H), 4.57 (s, 2H), 4.06 (dd, J = 12 Hz, 5.6 Hz, 1H), 3.75(t, J = 6.8 Hz, 1H), 3.58 (d, J = 4.4 Hz, 1H),
3.44 (td, J =13.6 Hz, 6.4 Hz, 2H), 3.12 (d, J = 8.8 Hz, 1H), 1.40 (s, 6H), 1.37 (d, J = 6.4 Hz, 3H) 1.15 (s,
9H), 13C NMR (100 MHz, CDCl3).δ 137.7, 128.4 (2C), 127.79 (2C), 127.77, 109.6, 82.0, 78.0, 73.5,
71.1, 56.1, 55.0, 27.14, 27.10, 22.5 (3C), 19.2; HRMS ESI m/z calcd for C19H31NO4SNa, 392.1872;
found 392.1871.
Preparation of 10: To a stirred solution of the compound 9a (0.08 g, 0.21 mmol) in THF (2 mL) was
added a saturated solution of methanolic HCl (1 mL) at 0 °C and stirred at the same temperature
for 20 min, After completion of the reaction (TLC), it was quenched by addition of solid NaHCO3.
The reaction mixture was filtered through a short pad of celite, and the solvent was evaporated
off. The residue was dissolved in CH2Cl2 (5 ml), Et3N (0.16 mL, 0.57 mmol), and CbzCl (0.1 mL, 0.57
mmol) were added successively at 0 °C and the reaction mixture was stirred for 4 h at room
temperature. After completion of the reaction (TLC), the reaction mixture was diluted with EtOAc
(10 mL) and washed with water (5 mL) and brine (5 mL). The organic layer dried over Na2SO4,
solvent was evaporated off, and the residue thus obtained was purified by silica gel column
chromatography using EtOAc:hexane (2:8) as eluent to furnish the compound 10 (0.075 g, 87%).
1
[α]D24−16.8 (c 0.9, CHCl3); IR (neat): 3333, 3202, 1717, 1529 cm−1; H NMR (400 MHz, CDCl3): δ
7.40 – 7.20 (m, 10H), 5.07 (s, 2H), 4.98 (d, J = 6 Hz, 1H), 4.55 (s, 2H), 4.03 (d, J = 4.8 Hz, 1H), 3.90 −
3.75 (m, 2 H), 3.65 − 3.48 (m, 2H), 1.39 (s, 6H), 1.20 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)δ
155, 137.7, 136.5, 128.5 (3C), 128.4, 128.07, 128.05 (3C), 127.71, 127.69, 109.5, 81.0, 77.5, 73.5,
70.8, 66.6, 48.6, 27.0, 26.9, 16.5; HRMS ESI m/z calcd for C23H29NO5Na, 422.1943; found 422.1943.
11

Preparation of 11: To a stirred solution of the compound 10 (0.09 g, 0.22 mmol) in CH2Cl2 (3 mL)
was added TFA (0.3 mL) at 0 °C and stirred at rt for 2 h. After completion of the reaction (TLC), the
solvent was evaporated off and the residue thus obtained was purified by column
chromatography using EtOAc:hexane (1:1) as eluent to furnish the compound 11 (0.06 g, 75%) as
colourless white solid. [α]D24:−2.38 (c 1.05, CHCl3); m.p. 84−87 °C. IR (KBr): 3311, 2870, 1659, 1156
cm−1; 1H NMR (400 MHz, CDCl3): δ 7.33 – 7.28 (m, 10H), 5.16−5.02 (m, 3H), 4.54 (s, 2H), 3.88 −3.81
(m, 1H), 3.77 (dd, J = 14.4 Hz, 7.3 Hz, 1H), 3.59 (d, J = 5.2 Hz, 2H), 3.40 (m, 1H), 3.25−2.50 (m, 2H),
1.22 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3).δ 156.8, 137.7, 136.2, 128.5 (3C), 128.4, 128.17,
127.12, 127.83, 127.80 (3C), 74.35, 73.6, 71.8, 69.03, 66.98, 49.2, 16.9; HRMS ESI m/z calcd for
C20H25NO5Na, 382.1630; found 382.1631.
Preparation of 12: To a stirred solution of the compound 11 (0.060 g, 0.16 mmol) in MeOH:H2O
(2:1) ( 6 mL) was added NaIO4 (0.143 g, 0.66 mmol) and was stirred at rt for 2 h. After completion
of the reaction (TLC), most of the solvent was evaporated off and the residue thus obtained was
dissolved in CH2Cl2 (10 mL) and washed with sat. aq. NaHCO3 (2 mL), brine (2 mL) and dried over
Na2SO4. Solvent was evaporated off and the residue thus obtained was dissolved in MeOH (2 mL),
and NaBH4 (0.019 g , 0.50 mmol) was added and stirred for 1 h at 0 °C. After completion of the
reaction (TLC) acetone (1mL) was added, and the reaction mixture was stirred at rt for 5 min, most
of the volatile were evaporated off, and the residue thus obtained was dissolved in EtOAc (10 mL)
and washed with sat. NaHCO3 (2 mL), and brine (2 mL), successively, dried over sodium Na2SO4.
After the solvent was evaporated off and residue obtained was purified by silica gel column
chromatography using EtOAc:hexane (3:2) as eluent to afford 12 (0.03 g, 86%) as a colourless oil
24
23
[α]D −8.23 (c 0.85, CHCl3); lit12 [ ]D −10.7 (c 0.55, CHCl3), IR (neat): 3309, 2931, 1684, 1532
cm−1; H NMR (400 MHz, CDCl3): δ 7.40 – 7.23 (m, 5 H), 5.09 (s, 2H), 4.98 (d, J = 5.6 Hz, 1H), 3.82
1
(d, J = 4.8 Hz, 1H), 3.64 ( dd, J = 11.2 Hz, 3.6 Hz, 1H), 3.51 (dd , J = 10.8 Hz, 6.0 Hz, 1H), 2.55 (bs,
1H), 1.15 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3).δ 156.6, 136.3, 136.1, 128.5, 128.5, 128.13,
128.0, 66.8 (2C), 49.0, 17.2; HRMS ESI m/z calcd for C11H15NO3Na, 232.0950 found 232.0948.
Preparation of 14: To a suspension of lithium (0.1 g) in THF (20 mL) was added naphthalene (3.5 g)
under argon atmosphere and the reaction mixture was stirred at rt for 2h which resulted in the
dark green colour solution. To a stirred solution of the compound 9i (0.2 g, 0.38 mmol) dissolved
in THF (5 mL) was added the above Li/Napthalide solution at 0 °C, till dark green colour persisted
and the reaction was stirred at rt for 3h. After completion of the reaction (TLC), MeOH (5 mL) was
added dropwise and the solvent was evaporated off. The resulting residue was purified by silica
gel column chromatography using MeOH:EtOAc (5:95) as eluent to obtain the crude diol which
was used as such in the next step. To a solution of the crude diol (obtained above) in dry CH2Cl2 (5
mL), Et3N (0.33 mL, 2.28 mmol), p-toluenesulfonyl chloride (0.36 g, 1.9 mmol) and DMAP (5 mg,
12

0.038 mmol) were added and the reaction mixture was stirred at rt for 6h. After completion of the
reaction (TLC), it was poured into water (5 mL) and was extracted with CH2Cl2 (2×5 mL). Combined
organic layer was washed with brine (5 mL), dried over Na2SO4. Evaporation of solvent gave the
residue which was purified by column chromatography using EtOAc:hexane (7:3) as eluent to
furnish 14 (0.150 g, 61% for 2 steps) as a colourless oil. [α]D24: +31 (c 0.8, CHCl3), IR (KBr): 3128,
2956, 1739, 1598 cm−1 1 H NMR (400 MHz, CDCl3): δ 7.85 − 7.76 (m, 4H), 7.34 (d, J = 7.6 Hz, 4H),
4.46 (dd, J = 11.6 Hz, 3.2 Hz, 1H) 4.22 − 4.11 (m, 1H), 4.11 − 4.39 (m, 4H), 3.76 (d, J = 8.4 Hz, 1H),
3.32 − 3.15 (m, 1H), 2.43 (s, 6H), 1.60 − 1.45 (m, 6H), 1.37 (s, 3H), 1.35 (s, 3H), 1.22 (s, 9H); 13C
NMR (100 MHz, CDCl3).δ 145.1, 145.7, 133.0, 132.5, 129.2 (2C), 129.8 (2C), 127.8 (4C), 109.4, 78.3,
76.8, 70.1, 69.5, 58.9, 56.5, 32.2, 28.5, 27.0, 26.5, 22.8 (3C), 21.58, 21.56, 21.3; HRMS ESI m/z
calcd for C29H43NO9S3Na, 668.1998; found 668.2000.
(+)-Lentiginosine (5): To a stirred solution of 14 (0.070 g, 0.11 mmol) in THF (2 mL) was added
saturated methanolic HCl (2 mL) at 0 °C and stirred at rt for 10 h. After completion of the reaction
(TLC), the solvent was evaporated off and the residue thus obtained was dissolved in CH3CN (3
mL), and K2CO3 (0.14 g, 1.0 mmol) was added to the reaction mixture and stirred at 70 °C for 6 h.
The solvent was evaporated off and residue obtained was dissolved in EtOAc (20 mL) and was
filtered through a short pad of celite. The solvent was evaporated off and the residue thus
obtained was purified by silica gel column chromatography using MeOH:CH2Cl2 (2:8) as eluent to
24
yield lentiginosine 5 (9 mg, 60%) as a white solid. [α]D +2.3 (c 0.3, MeOH), lit22a +2.2 (c.0.28,
MeOH); m.p. 99−103 °C, lit22b 104 °C; IR (KBr): 3387, 2926, 1446, 1134 cm−1 1 H NMR (400 MHz,
CD3OD): δ 3.98 (dd, J = 7.2 Hz, 3.2 Hz, 1H), 3.63 (dd, J = 8.4 Hz, 3.2 Hz, 1H), 3.01(d, J = 10.8 Hz,
1H), 2.90 (d, J = 10.4 Hz, 1H), 2.61(t, J = 9.2 Hz, 1H), 2.08 (t, J = 10.8 Hz, 1H) 2.05 − 1.95 (m, 1H),
1.95 − 1.76 (m, 2H), 1.75−1.45 (m, 2H), 1.45 − 1.18 (m, 2H); 13C NMR (100 MHz, CD3OD).δ 84.9,
77.4, 71.1, 62.6, 54.3, 29.1, 25.5, 24.7; HRMS ESI m/z calcd for C8H15NO2H, 158.1181; found
158.1182.
Preparation of 15: To a stirred solution of 9i (0.437 g, 0.84 mmol) in THF (5 mL) was added
saturated methanolic HCl (2 mL) at 0 °C and stirred for 20 min. The residue obtained after
evaporation of solvent was dissolved in 1,4-dioxan (10 mL) and (Boc)2O (0.4 mL, 1.52 mmol), NaOH
(1M, 2.1 mL, 2.10 mmol), were added at 0 °C. The reaction mixture was stirred at rt for 12 h and
was poured into EtOAc (10 mL), and was washed with water (5 mL) and brine (5 mL). The organic
layer was dried over Na2SO4 and the solvent was evaporated off. The residue obtained after
evaporation of solvent was purified by column chromatography using (1:10) EtOAc:hexane to
furnish the compound 15 (0.365 g, 84%) as a colourless oil. [α]D24 − 2.40 (c 0.75, CHCl3); IR (neat):
3401, 2923, 1655, 1018 cm−1; 1H NMR (400 MHz, CDCl3):δ 7.36 – 7.30 (m, 8H), 7.39 − 7.20 (m, 2H),
4.57 (dd, J = 21.6 Hz, 12.0 Hz, 2H), 4.48 (s, 2H), 4.41 (d, J = 8.4 Hz,1H), 4.11 (s, 1H), 3.80 − 3.60 (m,
1H), 3.60 (dd , J = 10.4 Hz, 4.0 Hz,1H), 3.54 (dd , J = 10.4 Hz, 5.2 Hz, 2H), 3.45 (t, J = 6.4 Hz, 2H),
1.81 − 1.48 (m, 4H), 1.41−1.39 (m, 17H).; 13C NMR (100 MHz, CDCl3).δ: 155.6, 138.6, 137.9, 128.3
(2C), 128.2 (2C), 127.6(2C), 127.59, 127.56 (2C), 127.4, 109.3, 80.1, 79.2, 78.1, 73.4, 72.8, 70.9,
70.0, 52.7, 31.3, 29.5, 28.3 (3C), 27.1, 26.9, 22.2.;HRMS ESI m/z calcd for C30H43NO6Na, 536.2987;
found 536.2988.
13

Preparation of 16: To a stirred solution of the compound 15 (0.365 g, 0.71 mmol) dissolved in
MeOH (5 mL) was added 10% Pd/C (0.07 g) and stirred under H2 atmosphere for 30 h. After
completion of the reaction (TLC), most of the solvent was evaporated off, and the residue
obtained was dissolved in EtOAc (20 mL) and was passed through a short pad of celite. The residue
obtained after evaporation of solvent was purified by silica gel column chromatography using (8:2)
EtOAc:hexane to furnish 16 (0.2 g, 84%) as a white solid. [α]D24: − 24.3 (c, 0.6 acetone); lit23 − 6.9 (c
0.6 acetone). m.p. = 76−80 °C; lit23. m.p. 75 −76 °C.; IR (KBr): 3360, 2928, 1683, 1502, 1072
cm−1.;1H NMR (400 MHz, CDCl3): δ 4.59 (d, J = 8.8 Hz, 1H), 4.06 (t, J = 3.6 Hz, 1H), 3.83 − 3.70 (m,
3H), 3.66 – 3.60 (m, 3H), 2.43 (bs, 1H), 2.04 (bs, 1H), 1.75 − 1.30 (m, 21 H), ;13C NMR (100 MHz,
CDCl3).δ 155.9, 109.8, 79.7, 79.5, 79.3, 62.7, 62.4, 52.7, 32.3, 31.1, 28.3 (3C), 27.1, 27.0, 21.7.
HRMS ESI m/z calcd for C16H31NO6Na, 356.2049; found 356.2043.
Preparation of 17: To a stirred solution of the compound 16 (0.174 g, 0.52 mmol) dissolved in
CH2Cl2 (5 mL) was added Et3N (0.3 mL, 2.08 mmol), p-toluenesulfonyl chloride (0.298 g, 1.57 mmol)
and DMAP (0.032 g, 0.26 mmol). The reaction mixture was stirred at rt for 3 h and after
completion of the reaction (TLC), it was washed with aq. citric acid (aq. 10%) and the aq. layer was
extracted with CH2Cl2 (2×5 mL). Organic layer washed with water (5 mL) and brine (5 mL), and
dried over anhydrous Na2SO4. The residue obtained after evaporation of the solvent was purified
by column chromatography using (3:7) EtOAc:hexane to furnish the compound 17 (0.280 g, 83%)
24
as a white solid. [α]D − 33.3 (c 0.6 acetone); mp = 96 −97 °C.; IR (KBr): 3377, 2949, 1608, 1166
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.80 − 7.77 (m, 4H), 7.36 −7.34 (m, 4H), 4.40 (d, J = 9.6 Hz, ,1H)
4.16 − 4.13 (m, 2H), 4.04 − 4.0 (m, 3H), 3.70 − 3.63 (m, 2H), 2.45 (s, 6H), 1.77 − 1.58 (m, 4H), 1.43
(s, 9H), 1.38 − 1.21 (m, 8H), 13C NMR (100 MHz, CDCl3).δ 155.6, 144.9, 144.7, 133.0, 132.7, 129.84
(2C), 129.80 (2C), 127.9 (2C), 127.8 (2C), 109.6, 79.7, 78.8, 70.2 (2C), 69.3, 52.7, 31.4, 28.5, 28.2
(3C), 27.0, 26.7, 21.5 (2C), 21.2.; HRMS ESI m/z calcd for C30H43NO10S2Na, 664.2226; found
664.2230.
Preparation of 18: To the compound 17 (0.165 g, 0.25 mmol) dissolved in THF (5 mL) was added
NaH (15 mg, 0.37 mmol) at 0 ˚C and the reaction mixture was stirred at rt for 1 h. After completion
of the reaction (TLC), it was quenched by addition of sat. aq. NH4Cl (2 mL). and was extracted with
EtOAc (2×10 mL). Organic layer was washed with brine (5 mL), and dried over anhydrous Na2SO4.
The residue obtained after evaporation of solvent was purified by column chromatography using
(2:8) EtOAc:hexane to furnish the compound 18 (0.098 g, 81%) as a colourless oil. [α]D24 − 51.2 (c
1.3, CHCl3), IR (neat): 2980, 1685, 1367, 1132 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.0 Hz,
2H), 7.33 (d, J = 8.4 Hz, 2H), 4.50 − 3.98 (m, 5H), 3.89 (dd, J = 10.8 Hz, 3.6 Hz, 2H), 2.43 (s, 3H), 1.94
(d, J = 12.4 Hz, 1H), 1.65 − 1.45 (m, 5H), 1.42 (s, 9H), 1.35 (s, 3H), 1.32 (s, 3H); 13C NMR (100 MHz,
14

CDCl3) δ 155.0, 144.9, 132.6, 129.8 (2C), 128.0 (2C), 109.5, 80.0, 77.2, 73.3, 68.9, 52.3, 40.8, 28.3
(3C), 27.1, 26.9, 25.4, 25.1, 21.6, 19.0; HRMS ESI m/z calcd for C23H35NO7SNa, 492.2032; found
492.2032.
Preparation of 19: To a stirred solution of the compound 18 (0.09 g, 0.19 mmol) in acetone (5 ml)
was added NaI (0.285 g, 1.92 mmol) at rt and refluxed for 24 h. After completion of the reaction
(TLC), the solvent was evaporated off, and the residue obtained was dissolved in EtOAc (10 mL),
and was washed with water (5 mL), brine (5 mL) and dried over anhydrous Na2SO4. The residue
obtained after evaporation of the solvent was purified by short path silica gel column using
EtOAc:hexane (1:9). The crude iodide (obtained above) was dissolved in MeOH (5 ml) and zinc dust
was added (0.123 g, 1.92 mmol). It was refluxed for 6 h and after completion of the reaction most
of the solvent was evaporated off and the residue was dissolved in EtOAc (10 mL). It was passed
through a short pad of celite. Evaporation of the solvent followed by purification by silica gel
column chromatography of the residue using EtOAc:hexane (3:7) as eluent, furnished the
compound 19 (0.032 g,71%) as a colourless oil. [α]D24 − 53.3 (c 0.4, CHCl3), IR (neat): 3443, 2903,
1663, 1419 cm−1; 1H NMR (400 MHz, CDCl3): 5.90 (ddd, J = 17.2 Hz, 10 Hz, 7.2 Hz, 1H), 5.27 (d, J =
17.2 Hz, 1H), 5.14 ( d, J = 10.4 Hz, 1H), 4.45 − 4.30 (m, 1H), 4.15 − 4.06 (m, 1H), 3.97 (d, J = 12 Hz,
1H), 2.85 − 2.65 (m, 1H), 2.01 (d, J = 12.8 Hz, 2H), 1.70 − 1.50 (m, 5H), 1.44 (s, 9H ); 13C NMR (100
MHz, CDCl3):δ 155.4, 138.7, 116.6, 79.6, 72.1, 54.9, 40.3, 28.4 (3C), 25.0, 24.3, 19.3. HRMS ESI m/z
calcd for C13H23NO3Na, 264.1576; found 264.1572.
Preparation of 20: To a stirred solution of the compound 19 (25 mg 0.1 mmol) in dry EtOAc (2 mL)
was added 10% Pd/C (5 mg) and the reaction mixture was stirred under H2 atmosphere for 4 h.
After completion of the reaction (TLC), it was passed through a short pad of celite pad. The solvent
was evaporated off to furnish the compound 20 in quantitative yield (0.025g). [α]D24 − 28.7 (c 0.4,
1
CHCl3); IR (Neat): 3427, 2923, 1664, 1420 cm−1; H NMR (400 MHz, CDCl3):4.10−3.90 (m, 2H) 3.81
(bs, 1H), 2.72 (t, J = 12.4 Hz, 1H), 2.01 (d, J = 12.4 Hz, 1H), 1.70−1.50 (m, 6H), 1.45 (s, 9H), 1.24 (s,
2H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): 155.2, 79.5, 71.0, 55.4, 40.3, 28.5 (3C),
26.5, 25.2, 24.5, 19.5, 10.1.; HRMS ESI m/z calcd for C13H25NO3Na, 266.1732; found 266.1729.
(+)-α-conhydrine (6): To a stirred solution of the compound 20 (0.025 g, 0.1 mmol), in CH2Cl2 (2
mL) was added TFA (0.5 mL) at 0 ˚C, and the reaction mixture was stirred for 6 h at room
temperature. After completion of the reaction (TLC), sat. aq. NaHCO3, was added to the reaction
mixture and was extracted with EtOAc (10 mL×3). Organic layer was dried over anhydrous Na2SO4.
The residue obtained after evaporation of the solvent was purified by silica gel column
chromatography using EtOAc:MeOH (8:2) to furnish α-(+)-conhydrine 6 as a white solid (11 mg,
73%). [α]D24 + 7.7 (c 0.35, EtOH); lit.17 [α]D24 + 8.0 (c 1.85, EtOH). mp; 109−113 ˚C; IR (neat): 3538,
3289, 2924, 1452 cm−1; 1H NMR (400 MHz, CDCl3): 3.50−3.39 (m, 1H) 3.20−3.09 ( m, 1H), 2.71(dt, J
15

= 11.6 Hz, 2.8 Hz, 1H), 2.61 (td, J = 10.8 Hz, 3.2 Hz, 1H), 2.40 ( bs, 2H), 1.89−1.80 ( m, 1H),
1.67−1.25 (m, 7H), 0.98 (t, J = 7.6 Hz, 3H). ; 13C NMR (100 MHz, CDCl3): 75.6, 60.2, 46.9, 26.2, 25.4,
24.9, 24.3, 10.5. ;HRMS ESI m/z calcd for C8H17NO+H, 144.1388; found 144.1383.
Preparation of 24: To a stirred solution of the compound 9f (0.312 g, 0.72 mmol) in THF (2 mL) was
added saturated methanolic HCl (1 mL) at 0 °C and stirred for 20 min. After completion of the
reaction, most of the solvent was evaporated off and the residue thus obtained was dissolved in
1,4-dioxane (10 mL). NaOH (1N, 1.8 mL, 1.8 mmol), (Boc)2O (0.3 mL, 1.30 mmol) were added at 0
°C and the reaction mixture was stirred at rt for 18 h. After completion of the reaction (TLC), it was
diluted with EtOAc (20 mL), washed with water (5 mL), brine (5 mL), and dried over anhydrous
Na2SO4. The residue obtained after evaporation of solvent was purified by column
chromatography using EtOAc:hexane (1:9) as eluent to furnish the compound 24 (0.192 g, 63%) as
a white solid. [α]D24−12.42 (c 0.95, CHCl3); m.p. 102−106 °C; IR (KBr): 3370, 2930, 1691, 1165 cm−1;
1H NMR (400 MHz, CDCl3): δ 7.35 – 7.20 (m, 10 H), 5.52 (d, J = 7.6 Hz, 1H), 4.78 (bs, 1H), 4.54 (s, 2
H),4 .12 (t, J = 7.2 Hz, 1H), 3.86 (dt, J = 10 Hz, 5.2 Hz, 1H), 3.57 − 3.45 (m, 2H) 1.38 (s, 9 H), 1.35 (s,
3H) 1.21 (s, 3H); 13C NMR (100 MHz, CDCl3).δ 154.9, 137.6, 128.2 (3C), 127.95, 127.79 (2C), 127.52
(2C), 127.48 (2C), 127.38, 109.5, 80.4, 79.6, 73.5 (2C), 70.2, 55.8, 28.1(3C), 26.8, 26.5; HRMS ESI
m/z calcd for C25H33NO5Na, 450.2256 found 450.2256.
Preparation of 25: To a stirred solution of 24 (0.250 g, 0.58 mmol) in MeOH (5 mL) was added 10%
Pd/C (50 mg) and the reaction was stirred under H2 atmosphere for 36 h. After completion of the
reaction (TLC), most of the solvent was evaporated off and residue thus obtained was dissolved in
EtOAc (20 mL) and passed through a short pad of celite to furnish the compound 25 (0.190 g, 97%)
24
1
as a colourless oil. [α]D + 11.19 (c 1.05, CHCl3); IR (neat): 3317, 2942, 1659, 1020 cm−1; H NMR
(400 MHz, CDCl3): δ 7.34 – 7.24 (m, 5 H), 5.34 (s, 1H), 4.81 (s, 1H), 4.22(t, J = 7.2 Hz, 1H), 3.83 (dd, J
= 8.0 Hz, 4.0 Hz, 1H), 3.75 (d, J = 10.4 Hz, 1H), 3.59 (dd, J = 11.6 Hz, 3.2 Hz, 1H), 2.32 (bs, 1H), 1.40
– 1.38 (s, 12 H), 1.23 (s, 3H); 13C NMR (100 MHz, CDCl3).δ 155.2, 128.3 (2C), 127.9 (2C), 127.8 (2C),
109.3, 79.9, 79.0, 78.5, 62.2, 55.9, 28.7 (3C), 27.1, 26.8; HRMS ESI m/z calcd for C18H27NO5Na,
360.1787 found 360.1785.
Preparation of 26: To a stirred solution of 25 (0.163 g, 0.48 mmol) dissolved in CH2Cl2 (5 mL) was
added Et3N (0.1 mL, 0.72 mmol), DMAP (0.006 g, 0.048 mmol), and p-toluenesulfonyl chloride
(0.139 g, 0.72 mmol), at rt and the resulting reaction mixture was stirred for 16 h. After
completion of the reaction (TLC), it was quenched by addition of water (3 mL). The organic layer
was separated and the water layer was extracted with CH2Cl2 (2×5 mL). The combined organic
layer was washed with brine (5 mL), and dried over anhydrous Na2SO4. The residue obtained after
evaporation of solvent was purified by silica gel column chromatography using EtOAc:hexane (2:8)
to give compound 26 (0.186 g, 78%), as a white solid. [α]D24 − 5.52 (c 0.85, CHCl3); m. p. = 125−130
16

1
°C.; IR (KBr): 3320, 2942, 1661, 1020 cm−1; H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.79 (s, 1H),
7.38 − 7.23 (m, 7H), 5.61 (d, J = 8.4 Hz, 1H), 4.74 (s, 1H), 4.16 − 4.13 (m, 1H), 4.07( d, J = 10 Hz,
1H), 4.02 − 3.98 (m, 1H), 3.92 (s, 1H), 2.46 (s, 3H), 1.40 (s, 9H), 1.30 (s, 3H), 1.23 (s, 3H); 13C NMR
(100 MHz, CDCl3).δ 155.1, 145.1, 140.2, 138.3, 129.9 (3C), 128.4, 128.0 (2C), 127.9, 127.7 (2C),
110.0, 80.0, 78.9, 77.2, 69.0, 67.1, 28.3 (3C), 26.8, 26.8, 21.6; HRMS ESI m/z calcd for C25H33NO7Na,
514.1875 found 514.1875.
Preparation of 27 : To a stirred solution of the compound 26 (0.138 g, 0.28 mmol) in DMF (5 mL)
was added NaH (0.021 g, 0.84 mmol) at 0 °C and stirred at the same temp for 10 min. Allyl
bromide (0.15 mL, 1.68 mmol) was added to the reaction mixture and was stirred for 3 h at rt.
After completion of the reaction (TLC), it was quenched by addition of sat. NH4Cl (1mL) and was
extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (3 mL), dried
over Na2SO4. The residue obtained after evaporation of solvent was purified by silica gel column
chromatography using EtOAc:hexane (1:9) as eluent to give compound 27 (0.09 g, 60%) as a
24
colourless oil. [α]D +11.25 (c 0.8 , CHCl3); IR (neat): 3469, 2981, 1688, 1386, 1177 cm−1; NMR
exhibited rotamers. 1H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.81 (s, 1H), 7.38 − 7.24 (m, 7H), 5.48
− 5.18 (m, 1H), 4.90 − 4.79 (m, 3H), 4.58 (t, J = 8.0 Hz, 1H), 4.31 (bs, 1H), 4.23 (d, J = 10.4 Hz, 1H),
4.01 (d, J = 6.8 Hz, 1H), 3.64 (bs, 1H), 3.44 (bs, 1H), 2.45 (s, 3H), 1.42 (s, 9H), 1.33 (s, 3H), 1.30 (s,
3H); 1H NMR (400 MHz, DMSO at 80 ˚C): δ 7.79 (s, 1H), 7.77 (s, 1H), 7.49 (s, 1H), 7.47 (s, 1H), 7.40 −
7.20 (m, 5H), 5.40 (m, 1H), 5.10 (d, J = 8.8 Hz, 1H), 4.92 − 4.80 (m, 1H), 4.61 (dd, J = 8.8 Hz, 1H),
4.25 − 4.12 (m, 2H), 4.04 (dd, J = 10.8 Hz, 6.4 Hz, 1H), 3.63 (dd, J = 15.6 Hz, 6.4 Hz, 1H), 3.52 (dd, J =
15.6 Hz, 6.0 Hz, 1H), 2.41 (s, 3H), 1.3 (s, 9H), 1.27 (s, 3H), 1.24 (s, 3H); 13C NMR (100 MHz, CDCl3).δ
144.9, 134, 132.6, 132.7, 129.8 (3C), 128.2 (3C), 128.0 (3C), 127.7, 69.3, 28.2 (3C), 26.8, 27.1, 27.0,
21.6. 13C NMR (100 MHz, DMSO at 80 ˚C).δ 154.7, 145.0 (2C), 137.8, 134.4, 132.3, 129.99, 129.94,
128.5, 127.9, 127.4 (3C), 116.4, 109,6, 79.8, 76.6, 75.3, 70.2, 61.1, 47.7, 27.72 (3C) and 27.68 (3C,
rotamer), 26.9 and 26.8 (rotamer), 26.7 and 26.69 (rotamer), 20.9 and 20.8 (rotamer); HRMS ESI
m/z calcd for C28H37NO7Na, 554.2188 found 554.2187.
Preparation of 28: To a stirred solution of 27 (0.118 g, 0.24 mmol) in acetone (10 mL) was added
NaI (0.663 g, 4.44 mmol) and was refluxed for 16 h. After completion of the reaction (TLC), the
solvent was evaporated off, and the residue thus obtained was dissolved in EtOAc (10 mL) and was
washed with water (5 mL), brine (5 mL) and dried over anhydrous Na2SO4. Residue obtained after
evaporation of solvent was purified by silica gel column chromatography using EtOAc:Hexane (1:9)
24
as eluent to give the corresponding iodide (0.1 g, 93%) as a colourless oil. [α]D + 23.52 (c 0.85,
CHCl3) IR (neat): 3399, 3300, 2924, 1688 cm−1; NMR exhibited peaks for a mixture of rotamers) 1H
NMR (400 MHz, CDCl3) δ 7.43 − 7.24 (m, 5H), 5.75 − 5.20 (m, 2H), 5.10 − 4.60 (m, 2H), 4.54 − 5.30
(m, 1H), 4.04 (m, 1H), 3.90 − 3.60 (m, 2H), 3.46 (dd, J = 10.8 Hz, 4.0 Hz, 1H), 3.22 (dd, J = 10.8 Hz,
4.8 Hz, 1H), 1.48 (s, 9H), 1.46 (s, 3H), 1.35 (s, 3H); 13C NMR (100 MHz, CDCl3).δ 134.3 (2C), 128.3
1
(2C), 127.8, 109.7, 79.4, 78.0, 28.3 (3C), 27.6, 27.4 H NMR (400 MHz, DMSO at 80 ˚C): δ 7.42 −
7.21 (m, 5H), 5.44 (ddd, J = 16.4 Hz, 11.2 Hz, 6.4 Hz, 1H), 4.04 (dd, J = 10 Hz, 6.4 Hz, 1H), 5.0 − 4.8
17

(m, 2H), 4.55 (dd, J = 8.8 Hz, 6.4 Hz, 1H), 4.04 ( dd, J = 10, 6.4 Hz, 1H), 3.84 (dd, J = 16.8 Hz, 6.0 Hz,
1H), 3.68 (dd , J = 15.6 Hz, 6.0 Hz, 1H), 3.47 (dd, J = 10.8 Hz, 3.6 Hz, 1H), 3.30 (dd, J = 10.8 Hz, 6.4
Hz, 1H), 1.42 (s, 9H); 13C NMR (100 MHz, DMSO at 80 ˚C).δ 154.3, 137.6, 134.3, 128.3 (2C), 127.6
(2C), 127.0, 115.9, 108.5, 79.5, 78.7, 78.1, 60.7, 27.6 (3C), 27.0, 26.8, 7.7; HRMS calcd for
C21H30INO4Na, 510.1117 found 510.1114.
To a stirred solution of the iodide (0.097 g, 0.19 mmol) (obtained above) dissolved in MeOH (5 mL)
was added Zn dust (0.260 g, 3.98 mmol) and refluxed for 6 h. After completion of the reaction, the
solvent was evaporated off, and the residue thus obtained was dissolved in EtOAc (10 mL) and was
passed through a short pad of celite. The residue obtained after evaporation of the solvent was
purified by silica gel column chromatography using EtOAc:hexane (2:8) as eluent to furnish the
24
diene 28 (0.052 g, 91%), as a colourless oil. [α]D + 31.3 (c 1.15, CHCl3); IR (neat): 3432, 2927,
1
2924, 1650, 1170 cm−1; NMR exhibited rotamers. H NMR (400 MHz, CDCl3): δ 7.45 (s, 1H), 7.42 (s,
1H), 7.40 − 7.24 (m, 3H), 5.99 (ddd, J = 16.4 Hz, 10.4 Hz, 5.6 Hz, 1H), 5.69 − 5.51 (m, 1H), 5.34 (d, J
= 17.2 Hz, 1H), 5.23 (d, J = 10.4 Hz, 1H), 4.99 (s, 1H), 4.96 (d, J = 4.4 Hz, 1H), 4.84 (s, 1H), 3.79 (dd, J
= 15.6 Hz, 6.0 Hz, 1H), 3.6 (bs,1H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3).δ 138.2, 137.5, 134.9,
129.0, 128.4 (2C), 127.7 (2C), 117.1, 116.2, 80.3, 29.6, 28.4 (3C); HRMS calcd for C18H25NO3Na,
1
326.1732 found 322.1732 , H NMR (400 MHz, DMSO at 80 ˚C): 7.45 (s, 1H), 7.43 (s, 1H), 7.35 −
7.25 (m, 2H), 7.26 − 7.20 ( m, 1H), 5.94 (ddd, J = 17.2 Hz, 10.4 Hz, 6.4 Hz, 1H), 5.56 − 3.68 (m, 1H),
5.29 (d, J = 16.8 Hz, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.95− 4.77 (m, 4H), 4.72 (dd , J = 4.8 Hz, 6.4 Hz,
1H), 3.70 (dd, J = 16.0 Hz, 6.4 Hz, 1H), 3.63 (dd, J = 15.6 Hz, 5.6 Hz, 1H), 1.4 (s. 9H),; 13C NMR (100
MHz, DMSO at 80 ˚C).δ 154.4, 139.68, 139.65, 139.0, 135.1, 128.6, 127.3 (2C), 126.4, 115.1, 114.9,
78.6, 70.8, 63.1, 47.4, 27.7 (3C).
Preparation of 8: To a stirred solution of 28 (0.050 g, 0.16 mmol) in CH2Cl2 (0.02 M, 8 mL) was
added Grubb’s 2nd generation catalyst (7 mg, 0.0082 mmol) and the reaction mixture was stirred
at rt for 4 h. After completion of the reaction (TLC), the solvent was evaporated off and the
residue thus obtained was purified by silica gel column chromatography using EtOAc:hexane (3:7)
as eluent to furnish the tetrahydropyridine (0.035g, 80%) as a colourless oil. [α]D24: − 10.0 (c 1.1,
1
CHCl3); IR (neat): 3432, 2927, 2924, 1650, 1170 cm−1; H NMR (400 MHz, CDCl3) δ 7.34 − 7.20 (m,
5H), 6.18 − 6.12 (m, 1H), 5.94 (d, J = 9.6 Hz, 1H), 5.23 (s, 1H), 4.51 (s, 1H), 4.36 (d, J = 19.2 Hz, 1H),
3.45 (d, J = 19.2 Hz, 1H), 2.25 (bs, 1H), 1.51 (s, 9H), 13C NMR (100 MHz, CDCl3).δ 155.8, 138.3,
128.8, 128.4, 127.4 (3C), 126.8, 125.3, 80.5, 77.2, 65.7, 40.7, 28.4 (3C). HRMS ESI m/z calcd for
C16H21NO3Na, 298.1419 found 298.1414. To a stirred solution of the tetrahydropyridine (obtained
above) (0.026 g, 0.094 mmol) dissolved in dry EtOAc (2 mL), was added 10% Pd/C (5 mg) and was
stirred under H2 atmosphere for 4 h. After completion of the reaction (TLC), it was passed through
a short pad of celite, and the solvent was evaporated off to furnish the compound 8 (0.021 g, 80%)
as a colourless oil. [α]D24 + 53.1 (c 1.0, CHCl3). lit24 [α]D20 + 49.4 (c 1.33 , CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.40 − 7.32 (m, 2H), 7.28 − 7.15, (m, 3H), 5.37 (s, 1H), 4.52 (s, 1H), 4.09 (dd, J = 13.6 Hz,
4.0 Hz, 1H), 2.87 (td, J = 13.2 Hz, 3.2 Hz, 1H), 2.25 (d, J = 5.2 Hz, 1H), 2.00 − 1.80 (m, 1H), 1.77 −
1.74 (m, 2H), 1.65−1.56 (m, 1H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3).δ 156.7, 138.1, 128.7 (2C),
126.8 (2C), 126.3, 80.1, 67.5, 60.2, 39.9, 28.3 (3C), 25.9, 18.8; HRMS ESI m/z calcd for
C16H23NO3Na, 300.1576 found 300.1578.
18

Preparation of 29: To a stirred solution of the compound 9h (0.09 g, 0.21 mmol), in THF (10 mL)
was added solution of Li/naphthalide (2 mL) dropwise till the green colour persisted and the
reaction mixture was stirred at rt for 1 h. After completion of the reaction (TLC), it was quenched
by addition of MeOH (4 mL). Most of the solvent was evaporated off and residue thus obtained
was purified by short path silica gel column chromatography using EtOAc:hexane (7:3) to give the
alcohol. The primary alcohol (obtained above) was dissolved in CH2Cl2 (5 mL) and p-toluenesulfonyl
chloride (0.06 g, 0.1 mmol), Et3N (0.1 mL, 0.63 mmol), DMAP (3 mg, 0.021 mmol), were added at 0
˚C. The reaction mixture was stirred at rt for 3 h. After completion of the reaction, it quenched by
addition of water (5 mL) after extraction with EtOAc (2×10 mL) and dried over anhydrous Na2SO4.
Removal of solvent followed by silica gel column chromatography of the residue obtained using
24
EtOAc:hexane (1:1) yielded the compound 29 (0.06 g, 56% for 2 steps) as colourless oil. [α]
D
1
+27.8 (c 1.5, CHCl3); IR (neat): 3314, 2926,1604, 1364; H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4
Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 5.79 (dddd, J = 24.0 Hz, 17.2 Hz, 6.8 Hz, 3.2 Hz, 1H), 5.02 (dd, J =
17.2 Hz, 2.0 Hz, 1H), 4.96 (d, J= 10.0, Hz, 1H), 4.22 (dd, J = 10.4 Hz, 3.6 Hz, 1H), 4.19 − 4.15 ( m, 1H),
4.06 (dd, J = 10.4 Hz, 5.2 Hz, 1H), 3.81 (t, J = 6.8 Hz, 1H), 3.34 (ddd, J = 14.8 Hz, 7.2 Hz, 3.6 Hz, 1H),
3.24 (d, J = 7.2 Hz, 1H), 2.45 (s, 3H), 2.15 − 1.95 (m, 2H), 1.82 − 1.72 (m, 1H), 1.69 − 1.54 (m, 2H),
1.53 − 1.42 (m, 1H), 1.36 (s, 3H), 1.3 (s, 3H), 1.21 (s, 9H).; 13C NMR (100 MHz, CDCl3) δ 145.0, 138.1,
132.6, 129.8 (2 C), 127.9 (2C), 114.9, 110.0, 79.6, 76.6, 69.8, 58.6, 56.2, 33.3, 31.8, 27.2, 26.9, 24.1,
22.6 (3C), 21.5.; HRMS ESI m/z calcd for C23H37NO6S2H 488.2141 found 488.2139.
Preparation of compound 30: To a stirred solution of the compound 29 (0.095 g) in acetone (10
mL), was added NaI (0.48 g, 3.21 mmol), and the resulting solution was refluxed for 48 h. After
completion of the reaction (TLC), most of the solvent was evaporated off, and the residue
obtained was dissolved in water (5 mL), extracted with EtOAc (2×10 mL), washed with sat. sodium
thiosulfate solution (5 mL), water (5 mL) and brine (5 mL) and dried over anhydrous Na2SO4. The
residue obtained after evaporation of solvent was dissolved in THF (2 mL) and saturated ethereal
HCl solution (2 mL), was added dropwise at 0 ˚C and stirred for 30 min at the same temperature.
The solvent was evaporated off, and the residue thus obtained was dissolved in THF:H2O (5 mL,
4:1) and NaHCO3 (0.084 g, 1.05 mmol), (Boc)2O (0.07 mL, 0.31 mmol), were added successively and
stirred at rt for 8 h. After completion of the reaction (TLC), it was extracted with EtOAc (2×10 mL),
and dried over anhydrous Na2SO4. Residue obtained after evaporation of solvent was purified by
silica gel column chromatography using EtOAc:hexane (1:9) to obtain the compound 30 in 71%
yield (0.065 g) for two steps. [α]
24 −26.6 (c 0.75, CHCl3), IR (neat): 3351, 2924,1681, 1528, 1020.;
D
(1H NMR (400 MHz, CDCl3); δ 5.72 (dddd, J = 23.6 Hz, 16.8 Hz, 6.4 Hz, 3.2 Hz, 1H), 4.86 (d, J =17.2
Hz, 1H), 4.90 ( d, J = 10.4 Hz, 1H), 4.32 (d, J = 9.6 Hz, 1H), 3.95 − 3.82 (m, 1H), 3.76 − 3.63 (m , 1H),
3.53 (t, J = 7.2 Hz, 1H), 3.30 (dd, J = 10.8 Hz, 4.8 Hz, 1H), 3.16 (dd, J = 10.8 Hz, 5.2 Hz, 1H), 2.15 −
1.92 (m, 2H), 1.80 − 1.63 (m, 1H), 1.52 − 1.20 (m, 18H).; 13C NMR (100 MHz, CDCl3) δ 155.6, 138.3,
114.9, 109.6, 83.7, 79.7, 78.1, 52.7, 33.4, 31.0, 28.4 (3C), 27.6, 27.4, 24.7, 7.9; HRMS ESI m/z calcd
for C17H30INO4+Na 462.1117 found 462.1120.
19

Preparation of 31: A solution of compound 30 (0.06 g, 0.13 mmol) in CH2Cl2:MeOH (4:1, 5 mL), was
cooled to −78 ˚C, and a stream of O3/O2 was passed for 5 min. The reaction mixture was warmed
to 0 ˚C and Me2S (0.05 mL, 0.65 mmol) was added and stirred for further 1.5 h. The residue
obtained after evaporation of solvent was dissolved in toluene (5 mL), and the ylide (ethyl 2-
(triphenyl-λ5-phosphanylidene)acetate) (0.07 g, 0.2 mmol) was added and refluxed for 6 h. Most of
the solvent was evaporated off and the residue thus obtained was purified by silica gel column
24
chromatography using EtOAc:hexane (2:8) to obtain 31 (0.061 g, 88%), as a white solid. [
α
]
−
D
33.1 (c 1.4, CHCl3); m.p. 75−78 ˚C. IR (neat): 3434, 2923,1715, 1605 cm-1; (1H NMR (400 MHz,
CDCl3) δ 6.94 (ddd, J = 15.6 Hz, 14.0 Hz, 7.2 Hz, 1H), 5.84 (d, J = 15.6 Hz, 1H), 4.45 (d, J = 9.6 Hz,
1H), 4.34 (q, J = 7.2 Hz, 2H), 3.95 (dd, J = 11.2 Hz, 5.2 Hz, 1H), 3.84 − 3.72 (m, 1H), 3.65 − 3.57 (m,
1H), 3.37 (dd, J = 10.8 Hz, 4.8 Hz, 1H), 3.23 (dd, J = 10.8 Hz, 5.2 Hz, 1H), 2.40 − 2.10 (m, 2H), 1.90 −
1.75 (m, 1H), 1.55 − 1.45 (m, 15 H), 1.40 (s, 3H). 1.29 (t, J
=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 166.6, 155.6, 148.4, 121.8, 109.6, 83.6, 79.8, 78.1, 60.1, 52.6, 31.7, 31.1, 28.3 (3C), 27.5, 27.4,
23.9, 14.2, 7.8; HRMS ESI m/z calcd for C20H34INO6+Na 534.1329 found 534.1327.
Preparation of 32: To a stirred solution of the compound 31 (0.060 g, 0.11 mmol) in THF (2 mL)
was added NaH (60%, 10 mg, 0.23 mmol) at 0˚C and was stirred for 10 min and was slowly
warmed to rt and stirred at rt for 45 min. After completion of the reaction, it was quenched by
addition of NH4Cl (2 mL) and was extracted with EtOAc (2×10 mL). The organic layer was washed
with water (5 ml), brine (5 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent gave
the crude residue, which was purified by silica gel chromatography using EtOAc:hexane (5:95) to
furnish the compound 32 (0.047 g, 78%), as a colourless oil. [
2979, 1733,1686, 1169 cm-1; (1H NMR (400 MHz, CDCl3) δ 4.63 (bs, 1H), 4.40 − 4.00 (m, 3H), 3.85 −
10.0 Hz, 5.6 Hz, 1H), 2.65 (bs, 2H), 1.93 (d, J 12.8
α]
24: −68.0 (c 1.4, CHCl3).; IR (Neat):
D
3.15 (m, 2H), 3.55 − 3.45 (m, 1H), 3.24 (dd, J
=
=
Hz, 1H), 1.87 − 1.77 (m, 1H), 1.65 (bs, 2H), 1.55 − 1.40 ( m, 17H), 1.27 ( t, J = 7.2 Hz, 3H).; 13C NMR
(100 MHz, CDCl3) δ 171.7, 155.1, 109.3, 83.8, 80.4, 78.4, 60.4, 48.9, 47.6, 38.7, 28.4 (3C), 28.0,
27.4, 27.3, 23.9, 15.3, 14.2, 7.0; HRMS ESI m/z calcd for C20H34INO6+Na 534.1329 found 534.1330.
Preparation of 33: The iodide 32 (0.075 g, 0.14 mmol) was dissolved in EtOH (5 mL), and Zn dust
(0.095 g, 1.46 mmol) was added at rt and further stirred under reflux for 6 h. After completion of
the reaction (TLC), the solvent was evaporated off and the residue was suspended in EtOAc (20
mL) it was filtered through a short pad of celite and the solvent was evaporated off. The residue
thus obtained was purified by silica gel column chromatography using EtOAc:hexane (1:3), to yield
33 (0.037 g, 77%) as a colourless oil. [α]
24 −29.8 (c 0.8, CHCl3); IR (neat): 3436, 2923,1376, 1609,
D
1370 cm-1 (1H NMR (400 MHz, CDCl3) δ 5.93 (ddd, J = 16.8 Hz, 10.4 Hz, 6.0 Hz, 1H), 5.30 (d, J = 17.2
Hz, 1H), 5.18 (d, J = 10.4 Hz, 1H), 4.73 − 4.58 (m, 1H), 4.34 (dd, J = 10.0 Hz, 5.2 Hz, 1H), 4.25 − 4.00
(m, 3H), 2.83 (bs, 1H), 2.65 (dd, J = 14.0 Hz, 6.0 Hz, 1H), 2.54 (dd, J =13.6 Hz, 8.8 Hz, 1H), 2.05 −
1.94 (m, 1H), 1.80 − 1.65 (m, 2H), 1.55 − 1.35 (m, 12H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
20

CDCl3) δ 172.4, 155.4, 138.9, 116.2, 79.9, 74.1, 60.7, 57.8, 47.1, 40.1, 28.3 (3 C), 28.1, 22.6, 15.6,
14.1; HRMS ESI m/z calcd for C17H29NO5+Na 350.1943 found 350.1940.
Preparation of 34: To a stirred solution of the ester 33 (0.035 g, 0.1 mmol) dissolved in MeOH (5
mL) was added K2CO3 (0.063 g, 4.5 mmol) at rt and stirred for 8 h. After completion of the
reaction, the solvent was evaporated off and the residue was suspended in EtOAc (10 mL). It was
passed through a short pad of celite. The solvent was evaporated off and the residue thus
obtained was purified by silica gel column chromatography using EtOAc:hexane (1:3), to yield the
24
D
compound 34 (0.025 g, 80%) as a colourless oil. [
α
]
− 28.5 (c 1.25, CHCl3); IR (neat): 3435,
2931,1738, 1688, 1170 cm-1. (1H NMR (400 MHz, CDCl3) δ 5.91 (ddd, J = 17.2 Hz, 10.8 Hz, 6.0 Hz,
1H), 5.28 (d, J = 17.2 Hz, 1H), 5.16 (d, J = 12.0 Hz, 1H), 4.62 (dd, J = 12.0 Hz, 6.0 Hz, 1H), 4.37 − 4.30
(m, 1 H), 4.10 − 4.00 (m, 1H), 3.65 (s, 3H), 2.90 (bs, 1H), 2.66 (dd, J = 14.0 Hz, 6.8 Hz, 1H), 2.53 (dd,
J = 14.0 Hz, 8.8 Hz, 1H), 2.05 − 1.90 (m, 1H), 1.78 − 1.65 (m, 2H), 1.50 − 1.35 (m, 12 H).; 13C NMR
(100 MHz, CDCl3) δ 172.8, 155.4, 138.9, 116.1, 80.0, 74.2, 54.8, 51.8, 47.1, 39.9, 28.34 (3C), 28.3,
22.6, 15.6.; HRMS ESI m/z calcd for C16H27NO5+Na 336.1787 found 336.1789.
Preparation of 35: Pd/C (5 mg) was added to a solution of 34 (0.035 g, 0.1 mmol) dissolved in
EtOAc (2 mL) and stirred under H2 atmosphere for 3 h. After completion of the reaction, it was
filtered through a short pad of celite. The residue obtained after evaporation of solvent was
purified by silica gel column chromatography using EtOAc:hexane (3:7) to obtain 35 (0.035 g) in
quantitative yield as a colourless oil. [α]
24 − 22.8 (c 1.25, CHCl3); IR (neat): 3432, 2928,1739, 1688,
D
1172 cm-1. H NMR (400 MHz, CDCl3) δ 4.67 (ddd, J = 14.0 Hz, 7.2 Hz, 2.0 Hz, 1H), 3.98 − 3.90 (m,
1
1H), 3.72 (dd, J = 9.2 Hz, 4.8 Hz, 1H), 3.69 (s, 3H), 2.92 (bs, 1H), 2.68 (dd, J 13.6 Hz, 8.0 Hz, 1H),
=
2.50 (dd, J = 13.6 Hz, 7.6 Hz, 1H), 2.02 − 1.90 (m, 1H), 1.87 − 1.68 (m, 2H), 1.60 − 1.35 ( m, 14H),
1.00 (t, J = 7.6 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 173.1, 155.6, 79.8, 74.4, 55.3, 51.9, 47.1, 40.2,
28.6, 28.3 (3C), 26.8, 22.3, 16.0, 10.9.; HRMS ESI m/z calcd for C16H29NO5+Na 338.1943 found
338.1945.
Preparation of 36: To a stirred solution of 35 (0.110 g, 0.33 mmol) in CH2Cl2 was added Dess-
Martin Periodinane (0.222 g, 0.52 mmol) and NaHCO3 (0.086 g, 1.0 mmol) sequentially at rt. The
resulting reaction mixture was stirred at rt for 1.5 h and after completion of the reaction (TLC), it
was quenched by addition of aqueous sodium thiosulfate solution (10 mL). The aqueous layer was
extracted with Et2O (2×10 mL) and the combined organic layer was dried over anhydrous Na2SO4.
The residue obtained after evaporation of solvent was used as such in next step. To a suspension
of NaBH4 (0.02 g, 0.52 mmol) in THF (2 mL) was added a solution of the crude ketone (obtained
above) dissolved in THF (2 mL). The reaction mixture was cooled to 0 ˚C and MeOH (4 mL) was
added dropwise and stirred at rt for 1 h. After completion of the reaction, most of the solvent was
evaporated off, and the residue was dissolved in water and was extracted with Et2O (2×10 mL).
The combined organic layer was dried over anhydrous Na2SO4. Residue obtained after evaporation
of solvent was purified by silica gel column chromatography using EtOAc:hexane (1:3) to yield the
21

24
D
compound 36 (0.085 g, 77%) as a colourless oil. [
α
]
−30.1 (c 0.6, CHCl3); IR (neat): 3463,
2932,1737, 1684, 1174 cm-1 (1H NMR (400 MHz, CDCl3) δ 4.75 − 4.55 (m, 1H), 4.15 − 4.00 (m, 1H),
3.66 (s, 3H), 3.58 − 3.48 (m, 1H), 2.80 − 2.60 (m, 1H), 2.55 − 2.48 (m, 1H), 1.75 − 1.48 (m, 6H), 1.46
− 1.38 (m, 10H), 1.37 − 1.25 (m, 1H), 1.00 (t, J = 7.2 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 172.7,
157.6, 80.2, 74.5, 54.2, 51.2, 47.4, 38.7, 28.3 (4C), 25.6 (2C), 14.7. 9.7.; HRMS ESI m/z calcd for
C16H29NO5+Na 338.1943 found 338.1946.
(−)Methyldihydropalustramate (7):Compound 36 (0.015 g, 0.047 mmol) was dissolved in CH2Cl2 (2
mL) and TFA (0.5 mL), was added dropwise to it at 0 ˚C, and stirred for 6 h at rt. After completion
of the reaction (TLC), the solvent was evaporated off. The residue obtained was dissolved in water
and was neutralized with aq. sat. NaHCO3 (2 mL) and was extracted with EtOAc (3×10 mL). The
combined organic layer was dried over anhydrous Na2SO4. The residue obtained after evaporation
of solvent was purified by silica gel column chromatography using MeOH:EtOAc (1:4), to yield the
compound 7 (8 mg, 72%) as a colourless oil. [α]
24 −25.4 (c 0.4, MeOH); lit.19b [α]D24:−26.4 (c 0.014,
D
MeOH), lit.19d [α]D24 +26 0 (c 1.35 in MeOH) for the enantiomer; IR (neat) 3401,3370,2921, 1729,
1018 cm-1; (1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.22 (ddd, J = 8.4 Hz, 6.8 Hz, 3.6 Hz, 1 H), 3.01
− 2.87 (m, 1H), 2.46 (ddd, J = 11.2 Hz, 6.8 Hz, 2.4 Hz, 1H), 2.42 − 2.35 (m, 2H), 1.82 (td, J = 12.4 Hz,
1H), 1.67 − 1.50 ( m, 3H), 1.47 − 1.30 (m, 2H), 1.17−1.02 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H);13C NMR
(100 MHz, CDCl3) δ 172.7, 75.6, 60.6, 53.1, 51.5, 41.3, 32.1, 28.4, 26.6, 24.2, 10.0; HRMS ESI m/z
calcd for C11H21NO3+H 216.1600 found 216.1604.
Acknowledgements: We thank Dr. Arava Veera Reddy, Vice-President, Suven Pharma, Hyderabad,
India for a kind gift of the tert-butanesulfinamide used in this investigation. Vipin Rangari (V. A. R.)
thanks the Indian Institute of Science (I. I. Sc.) for a research fellowship.
References:
1.
2.
Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Phytochemistry 2001, 56, 265.
(a) de Melo, E. B.; da Silveira Gomes, A.; Carvalho, I. Tetrahedron 2006, 62, 10277; (b)ꢀ
Compain, P.; Martin, O.R. Eds. Iminosugars: From Synthesis to Therapeutic Applications;
Wiley-VCH: Weinheim, Germany, 2007; (c) Afarankia, K.; Bahar, A. Tetrahedron: Asymmetry
2005, 16, 1239.
3.
(a) Ganem, B. Acc. Chem. Res. 1996, 29, 340; (b) Asano, N.; Nash, R.J.; Molyneux, R. J.;
Fleet, G.W. Tetrahedron Asymmetry 2000, 11, 1645; (c) Tartaric acid and malic acid in
synthesis: A source book of building blocks, ligands, auxiliaries and resolving agents;
Gawronski, J.; Gawronska, K. John Wiley and Sons, 1999.
4.
5.
6.
Kobayashi, Y.; Matsumoto, T.; Takemoto, Y.; Nakatani, K.; Ito, Y.; Kamijo, T.; Harada, H.;
Terashima, S. Chem. Pharm. Bull. 1991, 39, 2550.
Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F. L.; Merino, P.; Tejero, T. J. Org. Chem.
1997, 62, 5497.
(a) Ellman, j. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984; (b) Robak, M. T.;
Herbage, M. A.; Ellman, J. A. Chem. Rev, 2010, 110, 3600; (c) Davis, F. A. J. Org. Chem.
2006, 71, 8993.
7.
8.
Davis, F. A.; Prasad, K. R.; Carol, P. J. J. Org. Chem. 2002, 67, 7802.
Zhou, D.; Staake, M.; Peterson, S. E. Org. Lett, 2008, 10, 2179.
22

9.
Solla, H. R.; Concellon, C.; Alvardo, N.; Llavano, R.; Ganda, S. G.; Diaz, M. R.; Sonegas, R. G.
Synlett, 2013, 181.
10.
11.
Wang, B. J. Org. Chem. 2010, 75, 6012.
Diastereomeric ratio was determined by H NMR of the crude reaction mixture within
1
detectable limits.
12.
13.
14.
Ivkovic, J.; Fadum, C. L.; Breinbauer, R. Org. Biomol. Chem. 2015, 13, 10456.
Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396.
For a comprehensive review on the synthesis of lentiginosine until 2016 see: Michael, J. P.
Simple indolizidine and quinolizidine alkaloids. In The Alkaloids, Knölker, H-J., Ed.; 2016.
For recent synthesis of lentiginosine from tartaric acid see: (a) Shao, J.; Yang, J. S. J. Org.
Chem. 2012, 77, 7891; (b) Zeng, J.; Zhang, Q.; Zhang, H. K.; Chen, A. RSC Adv, 2013, 3,
20298. (c) Du-a-man, S.; Soorukam, D.; Kuharan, C.; Tauchinda, P.; Reutrakul, V.;
Pohmakotr, M.; Eur. J. Org. Chem. 2014, 1708; (d) Lingamurthy, M.; Rajender, A.; Rao, B. V.
Tetrahedron: Asymmetry 2014, 25, 860; (e) Cordero, F. M.; Vurchio, C.; Brandi, A. J. Org.
Chem. 2016, 81, 1661.
15.
16.
For a review on synthesis of conhydrine see: Bhat, C.; Bugde, S. T.; Tilve, S. G. Synthesis,
2014, 46, 2551.
17.
18.
Jamieson, A. G.; Sutherland, A. Org. Lett. 2007, 9, 1609.
For recent synthesis of L-733,060 and CP-122721 see: (a) Liu, Y. –W.; Mao, Z. –Y.; Ma, R. –
J.; Yan, J. –H; Si, C. –M. Tetrahedron, 2017, 73, 2100 references cited there in; For recent
synthesis seen of CP-99,994 see: (b) Yamagiwa, N.; Watanuki, S.; Nishina, T.; Suto, Y.;
Iwasaki, G. Chem. Lett. 2016, 45, 54 and references cited there in. (c) Garrido, N. M.;
Garcia, M.; Sanchez, M. R.; Diez, D.; Urones, J. G. Synlett, 2010, 387.
19.
For early synthesis of 7 see: (a) Muraoka, O.; Zheng, B. Z.; Okumara, K.; Tanabe, G.;
Momose, T.; Eugster, C. J. Chem. Soc. Perkin Trans I, 1996, 1567; (b) Angle, S. R.; Henry, R.
M.; J. Org. Chem. 1998, 63, 7490; (c) Hall, D. G.; Toure, B. B. Angew. Chem. Int. Ed. 2004,
43, 2001; (d) Mayer, C.; Romek, A.; Bach, T. Synlett, 2015, 1505.
20.
21.
22.
Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F. Tetrahedron, 1990, 46, 265.
(a) Cardona, F.; Goti, A.; Sylviane, P. Vogel, P. Brandi, A. J. Carbohyd. Chem. 2000, 19 (4&5),
581. (b) Prasad, K. R.; Pawar, A. B. ARKIVOC, 2004, 15, 565.
23.
24.
Raghavan, S.; Sreekanth, T. Tetrahedron Asymmetry 2004, 15, 565.
Hellal, B.; Ferriera, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. Synlett, 2009, 3115.
23

Highlights of the present work:
•
•
•
Systematic study of the addition of Grignard reagents to Sulfinimines derived from tartaric
acid
Outcome of the diastereoselectivity of the formed product is dependent on the inherent
chirality of the tartrate rather on the sulfinimine.
The formed products are excellent building blocks for the synthesis of natural products:
lentiginosing, methyldihydropalustramate, conhydrine and for the formal synthesis of
Formal synthesis of LP-733,060, CP-99,994 and CP-122,721