Synergistic factors ensue high expediency in the synthesis of menaquinone [K2] analogue MK-6: Application to access an efficient one-pot protocol to MK-9

Article abstract of DOI:10.1016/j.tet.2020.131696

Here we report a practical and efficient method for the synthesis of menaquinone vitamin (K₂) analog MK-6 in all trans forms through “1 + 5 convergent synthetic approach” of pentaprenyl chloride with monoprenyl menadione derivative. In the synergistic factors, less efficient leaving group/more efficient nucleophile (Cl) in the substrate makes it more prominent reaction by eliminating all S_n^2’ side reaction products. Further, the addition of acetic acid in the last step (desulfonation) of reaction sequence removes the limitations of the reactions in terms of cyclized side product (multiple reactions of pentaprenyl alcohol with Et₃B), byproduct (Et₃B, incendiary compound) formations and their interruption in the tricky purification processes. The utility of this method was further extended to find an efficient one-pot synthesis to MK-9 to the gram scale synthesis. This approach is economical and efficient and avoids the awkward chromatographic separation processes.

Full text of DOI:10.1016/j.tet.2020.131696

Journal Pre-proof
Synergistic Factors Ensue High Expediency in the Synthesis of Menaquinone [K ]
2
Analogue MK-6: Application to Access an Efficient One-Pot Protocol to MK-9
Nanaji Yerramsetti, Lavanya Dampanaboina, Venugopal Mendu, Satyanarayana
Battula
PII:
S0040-4020(20)30909-1
https://doi.org/10.1016/j.tet.2020.131696
TET 131696
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 September 2020
Revised Date: 9 October 2020
Accepted Date: 13 October 2020
Please cite this article as: Yerramsetti N, Dampanaboina L, Mendu V, Battula S, Synergistic Factors
Ensue High Expediency in the Synthesis of Menaquinone [K ] Analogue MK-6: Application to Access an
2
Efficient One-Pot Protocol to MK-9, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131696.
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Graphical Abstract
Synergistic Factors Ensue High Expediency
in the Synthesis of Menaquinone [K2]
Analogue MK-6: Application to Access an
Efficient One-Pot Protocol to MK-9
Leave this area blank for abstract info.
Nanaji Yerramsetti,a* Lavanya Dampanaboina,a Venugopal Mendu,a Satyanarayana Battulab*
aFiber and Biopolymer Research Institute, Department of Plant and Soil Science, Texas Tech University,
Lubbock, Texas 79409-2122, USA.
bDepartment of Chemistry, Uka Tarsadia University, Bardoli, Gujarat, India-394350.
Here we report a practical and efficient method for the synthesis of menaquinone vitamin (K2) analog
MK-6 in all trans forms through “1+5 convergent synthetic approach” of pentaprenyl chloride with monoprenyl
menadione derivateive. In the synergistic factors, less efficient leaving group/ more efficient nucleophile (Cl) in
2’
the substrate makes it more prominent reaction by eliminating all Sn side reaction products. Further, the
addition of acetic acid in the last step (desulfonation) of reaction sequence removes the limitations of the
reactions in terms of cyclized side product (multiple reactions of pentaprenyl alcohol with Et3B), byproduct
(Et3B, incendiary compound) formations and their interruption in the tricky purification processes. The utility of
this method was further extended to find an efficient one-pot synthesis to MK-9 to the gram scale synthesis.
This approach is economical and efficient and avoids the awkward chromatographic separation processes.

Graphical Abstract
Synergistic Factors Ensue High Expediency
in the Synthesis of Menaquinone [K2]
Analogue MK-6: Application to Access an
Efficient One-Pot Protocol to MK-9
Leave this area blank for abstract info.
Nanaji Yerramsetti,a* Lavanya Dampanaboina,a Venugopal Mendu,a Satyanarayana Battulab*
aFiber and Biopolymer Research Institute, Department of Plant and Soil Science, Texas Tech University,
Lubbock, Texas 79409-2122, USA.
bDepartment of Chemistry, Uka Tarsadia University, Bardoli, Gujarat, India-394350.

1
Tetrahedron
journal homepage: www.elsevier.com
Synergistic Factors Ensue High Expediency in the Synthesis of Menaquinone [K2]
Analogue MK-6: Application to Access an Efficient One-Pot Protocol to MK-9
Nanaji Yerramsetti,a* Lavanya Dampanaboina,a Venugopal Mendu,a and Satyanarayana Battulab*
aFiber and Biopolymer Research Institute, Department of Plant and Soil Science, Texas Tech University, Lubbock, Texas 79409-2122, USA.
bDepartment of Chemistry, Uka Tarsadia University, Bardoli, Gujarat, India-394350. *satyanarayana.battula@utu.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Here we report a practical and efficient method for the synthesis of menaquinone vitamin (K2)
analog MK-6 in all trans forms through “1+5 convergent synthetic approach” of pentaprenyl
chloride with monoprenyl menadione derivateive. In the synergistic factors, less efficient
leaving group/ more efficient nucleophile (Cl) in the substrate makes it more prominent reaction
by eliminating all Sn2’ side reaction products. Further, the addition of acetic acid in the last step
(desulfonation) of reaction sequence removes the limitations of the reactions in terms of cyclized
side product (multiple reactions of pentaprenyl alcohol with Et3B), byproduct (Et3B, incendiary
compound) formations and their interruption in the tricky purification processes. The utility of
this method was further extended to find an efficient one-pot synthesis to MK-9 to the gram
scale synthesis. This approach is economical and efficient and avoids the awkward
chromatographic separation processes.
Available online
Keywords:
Vitamin K2
MK-6
MK-9
Chlorine nucleophile
AcOH quenching
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
which have important significance in the treatment of
Parkinson’s disease and vitamin K2 insufficiency may cause
diseases such as osteoporosis.8-10 Isolation of the vitamin from a
natural source is complex and evidently it presents in low
quantities.11 The metabolic process of vitamin K2 production by
microorganism fermentation is very lengthy and with the overall
low synthesis efficiency, besides the complicated purification
process causes difficulties for the large-scale synthesis.
Vitamin K family consists of a common core structure 2-
methyl-1,4-naphthoquinone and the nature of side chain attached
to its C-3 position vary among the members resulting in
antibacterial, anti-inflammatory and anticancer activity
activities.1 There are two natural forms (Figure 1) of vitamin K’s
exist in nature. The plant derived vitamin K1 (phylloquinone)
contains phytin residue at 3rd position and it presents high
concentration in green leafy vegetables e.g. broccoli, iceberg
lettuce, spinach and some plant oils.2 The latter, bacterium
derived vitamin K2 (menaquinones) is a group of related
compounds differ in their polyprenyl side chains (4-13) attached
at the third position (C-3) of 1,4-naphthoquinone and are
designated as MK-n (n: number of isoprenoid residues in the side
chain). The vitamin K2 naturally present in various vegetables,
eggs, meet and fermented foods such as natto, cheese, yogurt and
sauerkraut.3 In general, vitamin K2 mainly exists in prokaryotes,
serves as a component of the electron transport in the cell
membranes and also utilized for various functions in the human
body. Vitamin K2 promotes bone formation process through γ-
carboxylation and that was initiated by the side chain of vitamin
K2 (geranylgeraniol). In addition, it also inhibits bone resorption
caused by osteoclasts and acts as a unique characteristic drug.4-7
Further, vitamin K2 promotes the blood clotting and improves
arteriosclerosis condition. Emerging evidence shows that vitamin
K2 has the potential for liver cancer therapy. Studies have
confirmed its inhibitory effect on growth and proliferation of
human hepatoma cells and induction of damaged nerve cells,
Figure 1. Natural vitamin K structures.
Moreover, the biological synthesis result in the preparation of
mixture of different menaquinones rather than to produce pure
menaquinones. Owing to these facts, vitamin K2 is currently
being synthesized by chemical methods, but most of these
protocols facing problems such as lower yields, formation of
isomers and various byproducts.12 All natural menaquinones
contains all trans configurations for the appropriate side chain
double bonds, majority of these vitamins are being used as
dietary supplements.13 To meet the requirements of mankind, an
effective and stereoselective method is desirable for preparing

2
Tetrahedron
high purity menaquinones. In this context, the present
discovery offers an efficient and productive approach for
the synthesis of vitamin MK-6 and MK-9 which contains
six and nine double bonds with trans configuration
respectively. This present process perhaps eliminates the
limitations in the synthesis sequence of vitamin K2, such
2
as the formation of Sn ' side reaction products in the
synthesis wherein polyprenyl halide is involved as well as
cyclized products in desulfonation reaction. Further, this
method was successfully applied to the gram scale
synthesis of MK-9 molecule in one-pot approach.
2. Results and discussion
Here, we report the development of a simple strategy
for the synthesis of menaquinone (MK-6 and MK-9)
analogues with appreciable yields (up to 90%) and
stereoselectivity (de up to > 99%). Our study commenced
with the synthesis of vitamin MK-6 (1). MK-6 contains
Scheme 1. Retrosynthetic strategy of Menaquinone-6 (MK-6).
by treatment with Ac2O under base presence (Et3N, DMAP) in
all six trans double bonds in the side chain. Basesd on the
retrosynthetic strategy, vitamin MK-6 can be obtained by “1+5”
convergent synthetic coupling approach (Scheme 1). Reported
literature suggests that,14 the title compound 1 can be generated
by the reaction of protected monoprenyl menadiol derivative 2
with all-trans-pentaprenyl halide 3 in the following retro
synthetic strategy.
DCM at 0 °C to rt for 24 h, it produced the geranyl acetate 9.
Further, it was subjected to a stereoselective allylic oxidation at
the terminal methyl group,16 by using 0.5 equiv of SeO2, 2.0
equiv of tBuOOH in the presence of 12 mol% of salicylic acid
and it followed by reduction with NaBH4 to give allylic alcohol
10 in 60% yield. In the next step, hydroxyl group in 10 was
replaced by chloride with PCl3 in DMF at 0 °C to produce the
corresponding diprenyl chloride 6 (Scheme 2).
In this study, the substrate 2 was planned to synthesize from
In order to synthesize triprenyl sulfone, (E,E)-farnesol 11 was
treated with PBr3 in DMF at 0 °C for 3 h to generate the
corresponding bromide compound 12,17 later it was subjected to
sulfonation without purification by sodium benzenesulphinate to
the reaction of substituted naphthyl bromide 4 and phenyl
2
sulfonyl monoprenyl halide
5
through Sn nucleophilic
substitution reaction by converting
4
into organometallic
Gillmans reagent. Subsequently, pentaprenyl halide 3 can be
prepared from commercially available terpenes (eg. geraniol,
farnesol) through “2+3” strategy. It was planned to synthesize via
coupling of diprenyl halide derivative 6 with triprenyl sulfone 7
to generate sulfonated polyprenol derivative and followed by its
selective reduction of sulfonyl group. The sulfonyl coupling
group was chosen due to ease in preparation and removal after
reaction.15
2
13. In the next step, the reaction of Sn type nucleophilic
substitution of diprenyl chloride 6 was occurred with sulfur-
stabilized allylic carbon nucleophiles generated from sulfone 13
in the presence of t-BuOK in THF at 0 °C and it was followed by
deacetylation to generate the corresponding sulfonated
polyprenol derivative 14 in almost quantitative yields. The last
one, desulfonation reaction, which is crucial to the synthesis of
MK-6, and this reaction was carried out by using lithium
triethylborohydride in presence of Pd(dppf)Cl2 as a catalyst in
anhydrous THF in acetic acid at 0 °C to rt for 5 h (Scheme 3).
The current strategy requires, oxidation at the head of the
isoprenoid skeleton. For this purpose, geraniol 8 was acetylated
Scheme 2. Synthetic route to O-acetyl diprenyl chloride 6
Scheme 3. Synthetic route to pentaprenyl chloride 3

3
In Scheme 3, the Sn2 halogenation of pentaprenol 15 to 3 is an
important step that influence various factors including reaction
2
yield and formation of side products, viz., Sn ' reaction product,
and cyclized products (multiple reactions of 15 with Et3B) and
that perhaps interrupt the purification process. To probe the effect
of the nucleophilic group on the reaction, this halogenation
reaction studied for Br (PBr3) and Cl (PCl3/MsCl) nucleophiles at
the various reaction conditions (at different basic conditions,
temperatures, solvents & time). Out of these experiments, the
best condition for the reaction was found to occur with PCl3 in
DMF solvent at ˗10 to 0 °C for 3 h to produce pentaprenyl
chloride 3 (Table 1). Based on these results, we conclude that, the
strength of Cl nucleophile suitable to trigger the reaction without
2
involvement of Sn ' side reaction, thereby, the reaction was more
efficient.
Table 1. Synthesis of halides from pentaprenyl alcohol
Scheme 4. Synthetic route to menaquinone MK-6 1
The usefulness of chlorine nucleophiles in the synthesis of
menaquinone MK-6, prompted us to the synthesis of other
menaquinone analog, MK-9.18 To make this method as a more
attractive synthetic methodology, a domino as well as one-pot
(stepwise) protocol for the synthesis of menaquinone MK-9 was
performed (Scheme 5). This one-pot protocol involves the
reaction between solanesol 18, Ghosez reagent and Diels-Alder
adduct of menadione 19 (as a menadione molecular surrogate) at
the proposed reaction conditions. This reaction proceeds through
the chlorination of solanesol 18 by Ghosez reagent to generate
solanesyl chloride A, and then its coupling with menadione
adduct produces compound B. Later, it undergoes retro Diels-
Alder reaction to generate MK-9 by the elimination of
cyclopentadiene. The corresponding menaquinone MK-9 was
obtained as yellow solid and exclusive diastereomer with
appreciable yield (77%, 99.9% purity by chiral HPLC). In
addition, we accomplished successfully this one-pot method to
20 mmol level reaction for the synthesis of MK-9.
entrya RH
Solvent
Base
T (°C)
T
Yield
(%)b
82
1
2
3
4
5
6
7
8
PBr3
PBr3
PBr3
MsCl
PCl3
PCl3
PCl3
PCl3
DMF
No
-10 to 0
4 h
4 h
4 h
4 h
3 h
3 h
3 h
3 h
THF
No
0
80
75
65
95
85
65
80
Toluene
DMF
Et3N
-5
Collidine/LiCl -20
DMF
No
-10 to 0
DMF/ THF
Et2O
No
-10
-20
Rt
Et3N
C6H12/DMF No
a) All reactions were carried out with 15 (1.0 mmol), PBr3 (0.5 mmol), PCl3
(0.5 mmol), MsCl (1.2 mmol), Et3N (1.4 mmol), Solvent (30 mL) under
argon, at -10 oC to 0 oC for 5 h. RH: Reagent for halogenation
b) Yields of isolated products.
The synthesis of another intermediate phenyl sulfone
derivative of monoprenyl menadiol 2 was carried out through a
four-step protocol (Scheme A, Supp Material). To synthesize the
final product MK-6, a reaction was performed between phenyl
sulfone derivative of monoprenyl menadiol 2 with pentaprenyl
halide 3 (Table A, Supp Material). The desulfonation process is
important and crucial in the synthesis of MK-6 1 and also has the
same role in pentaprenyl halide 3 preparation. This desulfonation
reaction was studied with a hydride source (Na/EtOH, Li/EtNH2,
and super hydride) in presence of various Pd catalysts (Table B,
Supp Material). After completion of the reaction, while it was
quenched with either water/20% NH4Cl/alcohol/ hydrogen
peroxide (33% w/v) in alkaline solution, a significant amount of
triethyl borane (Et3B) was released and that could cause to auto-
oxidation and leading to generation of radical based side
reactions. Owing to highly inflammable nature of Et3B (fuel in
turbojet engine and rocket), it caught the fire while concentrating
the reaction mixture in rotavapor. The quenching process of Et3B
was discussed clearly in Table C & Scheme B (Supp Material).
Scheme 5. One-pot synthetic strategy for the synthesis of
menaquinone MK-9 and its mechanism
To procure the best reaction for MK-9, we studied the reaction
at various conditions (Table 2). Initially, we studied the reaction
between 18 & 19 (entry 1 & 2) in DMF solvent with PCl3/ PBr3
After successful desulfonation from carbon skeleton of
menaquinone MK-6 (16) with LiEt3BH, Pd(dppf)Cl2, and acetic
acid to produce the compound 17, it was proceeded further to the
oxidation by cerium(IV) ammonium nitrate (CAN) gave the
target product MK-6 (1) as a yellow solid (Scheme 4). After
purification by column chromatography using 100-200 mesh
grade of silica gel, the MK-6 was obtained with 99% purity.
19
respectively (the best condition in Table 1). Unfortunately, we
couldn’t get good yield for the reaction, apparently due to the
20
formation of complex between PBr3/ PCl3 with DMF, that
perhaps interrupted further coupling reaction with menadione

4
Tetrahedron
3. Conclusion
surrogate 19 & eventually produced lower yields of MK-9.
Then we thought to find a halogenation reagent such as, which by
itself or it’s by product should not interfere in further reaction
with 19. In this contextual survey, we obtained the best results
(entry 3-7) when the same reaction was conducted with Ghosez
halogenation reagents21 (Cl, Br) where in the by-products did not
disturb further reaction. Among the tested reactions with Ghosez
reagents, the reaction conducted with chlorine based Ghosez
reagent in toluene solvent at 0 C - 120 C for 6 h was produced
the best yields (77%) of the MK-9 (entry 4). On the other hand,
at the same reaction conditions bromine based Ghosez based
reagent gave lower yields (65%, entry 5). However, we tested the
reaction with DCM and THF solvents but not found appreciable
yields (entry 6, 7).
In conclusion, we developed an efficient protocol to the
synthesis of MK-6 and MK-9. In addition, the synthesis MK-9
was achieved by a one-pot approach and it was further developed
to the gram scale synthesis. Here, we found the utility of
isoprenyl chlorides as the choice of substrates to the synthesis of
MK-6 & MK-9 than compared to their bromo analogs, due to
2'
o
o
their less leaving efficiency from the substrates prevent the Sn
side reaction. Furthermore, we also developed the AcOH/ MeOH
mediated desulfonation quenching process, which offers the
quenching of excess super hydride in the reaction and in situ
formed Et3B. Both these synergistic factors support to the
synthesis of MK-6 & MK-9 through the elimination of tedious
separation/ chromatographic processes
Table 2. Study of the one-pot reaction of MK-9[a]
4. Experimental section
Analytical thin layer chromatography (TLC) was carried out
using silica gel 60 F254 pre-coated plates. Visualization was
accomplished with UV lamp or I2 stain. Silica gel 230−400 mesh
size was used for flash column chromatography using the
combination of ethyl acetate and petroleum ether as eluent.
Unless noted, all reactions were carried out in oven-dried
glassware under an atmosphere of nitrogen/argon using
anhydrous solvents. Where appropriate, all reagents were purified
prior to use following the guidelines of Perrin and Armerego.22
All commercial reagents were used as received. Proton nuclear
magnetic resonance (1H-NMR) spectra were recorded at 400
MHz/ 500 MHz. Chemical shifts were recorded in parts per
million (ppm, δ) relative to the standard proton tetramethyl silane
entry
HR
solvent
T (°C)
t (h)
Yieldc
1
PBr3
DMF
-5 to 120
4 h
25
2
3
PCl3
DMF
DCM
-5 to 120
0 to 120
5 h
4 h
35
25
Cl
Cl
N
N
4
toluene
0 to 120
6 h
77
1
(δ 0.00). H-NMR splitting patterns are designated as singlet (s),
doublet (d), doublet of doublet (dd), triplet (t), quartet (q), and
multiplet (m). Carbon nuclear magnetic resonance (13C-NMR)
spectra were recorded at 100 MHz/ 125 MHz. Mass spectra (MS)
were obtained using ESI mass spectrometers. IR spectra were
recorded as neat for liquid and in KBr for solids. Melting points
were determined using a hot stage apparatus and are uncorrected.
Optical rotations were measured using a 2.0 mL cell with a 1.0
dm path length and are reported as [α] 25 D (c in g per 100 mL
solvent) at 25 °C. Enantiomeric ratios (er) were determined by
HPLC using chiralpak AD-H analytical column (detection at 254
nm). Diastereomeric ratios (dr) were determined by 1H-NMR.
5
toluene
-5 to 120
6 h
65
Cl
6
7
THF
THF
0 to 120
6 h
6 h
69
60
N
-5 to 120
[a]All reactions were carried out with 23 (1.0 mmol), Ghosez reagent (1.2
mmol) [halogenation agent: PBr3 (0.35-0.5 mmol), PCl3 (0.35-0.5 mmol),
Ghosez reagent (1.2 mmol) tested], toluene (30 mL) under argon. Yields
c
4.1 Experimental procedures
of isolated products (%).
Procedure for (E)-1,4-dimethoxy-2-methyl-3-(3-methyl-4-
(phenylsulfonyl)but-2-en-1-yl) Naphthalene (2). Powdered
copper(l) bromide (157.8 mg, 1.1 mmol) was added to a stirred
solution of the Grignard reagent prepared from 19 (281.1 mg, 1.0
mmol) in tetrahydrofuran (30 mL) at 10-15 °C and stirring was
continued for 50 min. Then, a solution of (E)-4-chloro-2-methyl-
1-phenylsulfony l-2-butene 20 (244.7 mg, 1.0 mmol) in
tetrahydrofuran (30 mL) was added and stirring was continued at
20 °C for 2 h. The mixture was then poured into saturated
ammonium chloride solution (30 ml) and extracted with ethyl
acetate (3 × 80 ml). The extract was dried with magnesium
sulfate and evaporated. The residual product was crystalized from
methanol without column chromatography, to afford the pure
products 2 (340 mg, 0.83 mmol, 83%). Rf = 0.23 (hexane/EtOAc,
7:3); Mp 155−157 °C; 1H-NMR (400 MHz, CDCl3, ppm): δ
(ppm) 8.08−7.98 (m, 2H), 7.77−7.71 (m, 2H), 7.51−7.41 (m,
2H), 7.38−7.32 (m, 1H), 7.29−7.26 (m, 2H), 5.01 (t, J = 6.7 Hz,
1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.73 (s, 2H), 3.47 (d, J = 6.6 Hz,
2H), 2.19 (s, 3H), 1.99 (s, 3H).
Scheme 6. Scale-up protocol for MK-9
Next, we sought to evaluate the utility of this one-pot protocol
to the gram scale synthesis of MK-9 by using optimized
condition to further confirm the efficiency and robustness of the
present protocol. The reaction was studied with 20 mmol of
solanesol which produced 77% product yield (12.2 g) as depicted
in Scheme 6.

5
(2E,6E)-8-Hydroxy-3,7-dimethylocta-2,6-dienyl Acetate (10).
A suspension of selenium dioxide (5.6 mg, 1.0 mmol) tert-butyl
hydroperoxide (0.24 mL, 2.5 mmol), salicylic acid (12 mol%,
16.6 mg) in anhydrous dichloromethane (20 mL) was stirred for
20 min at room temperature, and then silica gel (230-400 mesh,
72.0 mg) was added. After 30 min, the geranyl acetate (196.3 mg,
1.0 mmol) was slowly added. The mixture was stirred for 26 h,
filtered through celite, and washed with 10% potassium
hydroxide and brine. The extract was dried over Na2SO4 and
concentrated under vacuum. The resulting dark orange residue
was dissolved in 4 mL of ethanol and cooled to 0 °C, and sodium
borohydride (37.8 mg, 1.0 mmol) was added in several portions.
After 30 min, a saturated solution of NH4Cl (5 mL), brine, and
ethyl acetate was added. The mixture was extracted with ethyl
acetate and once with dichloromethane, dried, and concentrated.
The residue was purified by flash chromatography eluting with
hexane/AcOEt (9/1, v/v) to give alcohol 10 as a yellow oil (160.0
solution of 2 (410.5 mg, 1.0 mmol) and 3 (413.7 mg, 1.1 mmol)
o o
in THF (20 mL) at -20 C. The stirring was continued at -20 C
for 4 h and reaction was monitored by TLC and quenched with
saturated NH4Cl solution (20 mL). The aqueous layer was
extracted with EtOAc (3 × 15.0 mL). The combined organic
extract was washed with H2O (3×15.0 mL) and brine (20.0 mL)
and dried over Na2SO4. The solvent was removed under reduced
pressure to give crude product which was purified by flash
column chromatography on silica gel (230-400 mesh) using ethyl
acetate in petroleum ether to afford the pure products 16 (650
mg, 0.865 mmol, 87%) as
a colorless oil Rf = 0.30
1
(hexane/EtOAc, 7:2); Rf = 0.31 (hexane/EtOAc, 7:0); H-NMR
(400 MHz, CDCl3): δ (ppm) 8.10−8.01 (m, 4H), 7.73-7.65 (m,
3H), 7.48−7.41 (m, 2H), 5.43−4.84 (m, 6H), 3.96 (m, 3H), 3.88
(s, 3H), 3.77-3.72 (m, 1H), 3.38−3.32 (m, 2H), 2.88−2.62 (m,
3H), 2.18-2.16 (m, 3H), 2.10−1.88 (m, 20H), 1.80-1.75 (m, 3H),
1.68-1.61 (m, 3H), 1.60-1.48 (m, 10H).
1
mg, 75%). H-NMR (400 MHz, CDCl3): δ (ppm) 5.38-5.28 (m,
2H), 4.55 (2H, d, J = 7.2), 3.96 (2H, s), 2.28-2.06 (5H, m), 2.05
(3H, s), 1.70 (3H, s), 1.60 (3H, s).
Procedure for 2-((2E,6E,10E,14E,18E)-3,7,11,15,19,23-
hexamethyltetracosa-2,6,10,14,18,22-hexaen-1-yl)-1,4-
dimethoxy-3-methylnaphthalene
(17).
Lithium
(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-
triethylborohydride (2.2 mL, 2.2 mmol) was added dropwise over
yl)sulfonyl)benzene (13). To solution of (2E,6E)-1-bromo-3,7,11-
trimethyldodeca-2,6,10-triene 12 (285.3 mg,1.0 mmol) in 25.0
mL DMF was added to benzene sulfinic acid sodium salt 196.9
mg (1.2 mmol) was added in one portion at room temperature.
The suspension was stirred at room temperature for overnight.
The mixture was poured into ice water. The layers were separated
and the aqueous layer was extracted with EtOAc. The combined
organic extracts were washed with ice water and icecold brine,
dried over Na2SO4, filtered and concentrated. The residue was
purified by flash chromatography eluting with hexane/AcOEt
(9/1, v/v) to give sulfone 13 as a colorless oil yield (310.0 mg,
0.5 h to a solution of 16 (751.1 mg, 1.0 mmol) and
bis(diphenylphosphino)
propanepalladium(II)
dichloride
[Pd(dppp)Cl2] (36.6 mg, 0.05 mmol) in THF (20 mL) at -10 °C.
Then the reaction mixture was stirred at -10 °C for 6 h and
reaction was monitored by TLC and quenched with MeOH (0.15
mL) ans acetic acid (0.57 mL). The reaction mixture was further
stirred for 24 h at RT. When ethane gas was completely evolved,
solvent was removed from reaction mixture, and then ethyl
acetate was added to the reaction mixture followed by water. The
aqueous layer was extracted with EtOAc (3 × 15.0 mL). The
combined organic extract was washed with H2O (3 × 15.0 mL)
and brine (20.0 mL) & dried over Na2SO4. The solvent was
removed under reduced pressure to give crude product which was
purified by flash column chromatography on silica gel (230-400
mesh) using ethyl acetate in petroleum ether to afford the pure
products 17 (510 mg, 0.83 mmol, 83%) as a white solid. Rf =
0.33 (hexane/EtOAc, 7:3); 1H NMR (400 MHz, CDCl3): δ (ppm)
8.18−7.98 (m, 2H), 7.48-7.40 (m, 2H), 5.18−5.02 (m, 6H), 3.88
(s, 3H), 3.85 (s, 3H),3.55 (d, J =8.0, 2H) 2.35 (s, 3H), 2.11−18
(m, 18H), 1.82 (s, 3H), 1.65 (s, 3H), 1.61−1.51 (m, 17H).
1
89%). H NMR (400 MHz, CDCl3): δ 7.88-7.86 (m, 2H), 7.65-
7.59 (m, 1H), 7.56-7.42 (m, 2H), 5.20-5.18 (m, 1H), 5.08-5.01
(m, 2H), 3.78 (d, J = 7.2, 2H), 2.18-1.91 (m, 8H), 1.65 (3H, s),
1.56 (3H, s), 1.25 (3H, s).
Procedure
for
(2E,6E,10E,14E)-3,7,11,15,19-
(15). Lithium
pentamethylicosa-2,6,10,14,18-pentaen-1-ol
triethylborohydride (super-hydride) (3.2 mL, 3.2 mmol) was
added drop wise over 0.5 h to a solution of 14 (498.8 mg, 1.0
mmol) and bis(diphenylphosphino) propanepalladium(II)
dichloride [Pd(dppp)Cl2] (14.6 mg, 0.05 mmol) in THF (1 mL)
at -10 °C. Then the reaction mixture was stirred at -10 °C for 6 h
and the reaction was monitored by TLC and quenched with
MeOH (4 mmol, 0.15 mL) and acetic acid (10 mmol, 0.57 mL).
The reaction mixture was further stirred for 24 h at RT. When
ethane gas was completely evolved, solvent was removed from
reaction mixture, and then ethyl acetate was added to the reaction
mixture followed by water. The aqueous layer was extracted with
EtOAc (3 × 15.0 mL). The combined organic extract was washed
with H2O (3 × 15.0 mL) and brine (20.0 mL) and dried over
Na2SO4. The solvent was removed under reduced pressure to give
crude product which was purified by flash column
chromatography on silica gel (230-400 mesh) using ethyl acetate
in petroleum ether to afford the pure product 15 (302 mg, 0.84
Procedure for 2-((2E,6E,10E,14E,18E)-3,7,11,15,19,23-
hexamethyltetracosa-2,6,10,14,18,22-hexaen-1-yl)-3-
methylnaphthalene-1,4-dione (1), m.p.: 49.4-51.4 °C. A solution
of ceric ammonium nitrate (1.6 g, 3.0 mmol) in CH3CN (16 mL)
and H2O (4 mL) was slowly added to a stirred solution of 17
(611.0 mg, 1.0 mmol) in a mixture of CH3CN (8 mL) and CH2Cl2
(8 mL) at -15 °C for 50 min and reaction was monitored by TLC.
The reaction mixture was poured into ice cold water (10 mL) and
extracted with CH2Cl2 (3 x 25 mL). The combined organic layers
were washed with brine and water, dried over anhydrous Na2SO4,
filtrated and The solvent was removed under reduced pressure to
give crude product which was purified by flash column
chromatography on silica gel (230-400 mesh) using ethyl acetate
in petroleum ether to afford the pure product 1 (490.0 mg, 0.84
1
1
mmol, 84%) as a colorless oil. H-NMR (400 MHz, CDCl3): δ
mmol, 84%) as a yellow solid. H-NMR (400 MHz, CDCl3): δ
(ppm) 5.51 (t, J = 8.3, 8.4 2H), 5.15-5.05 (m, 4H), 4.01 (d, J =
7.6 Hz, 2H), 2.15-1.95 (m, 15H), 1.89-1.65 (m, 9H), 1.63-1.55
(m, 11H).
(ppm) 8.09−8.04 (m, 2H), 7.65−7.69 (m, 2H), 5.10−4.98 (m,
6H), 3.3 (d, J = 7.2 Hz, 2H), 2.18 (s, 3H), 2.09−1.88 (m, 19H),
1.77 (s, 3H), 1.65 (s, 3H), 1.58-1.48 (m, 16H).
Procedure for 2-((2E,6E,10E,14E,18E)-3,7,11,15,19,23-
hexamethyl-4-phenylsulfonyl)tetracosa-2,6,10,14,18,22-hexaen-
1-yl)-1,4-dimethoxy-3-methylnaphthalene (16). t-BuOK (123.2
mg, 1.1 mmol) and 18-crown-6 (13.2 mg) were added to a stirred
Procedure
for
2-methyl-3-
((2E,6E,10E,14E,18E,22E,26E,30E)-3,7,11,15,19,23,27,31,35-
nonamethylhexatriaconta-2,6,10,14,18,22,26,30,34-nonaen-1-
yl)naphthalene-1,4-dione (MK-9). 1-Chloro-N,N,2-trimethyl-1-

6
Tetrahedron
propenylamine (0.146 mL, 1.1 mmol) was added dropwise over
References
20 min to a solution of 18 (631.1 mg, 1.0 mmol) in toluene (30
mL) at 15 °C. Then the reaction mixture was stirred at 15 °C for
6 h and after halogination of solanesol, 4a-methyl-1,4,4a,9a-
tetrahydro-1,4-methanoanthracene-9,10-dione 19 (290.0 mg, 1.01
mmol), t-BuOK (123.2 mg, 1.1 mmol) and 18-crown-6 (13.2 mg,
0.05 mmol) were added to reaction mixture at 0 °C for 6 h. after
6 h, acetic acid follewed by tributylmethylammonium bromide
(14.0 mg, 0.05 mmol) was added to reaction mixture at 120 °C.
The stirring was continued at 120 ºC until completion of the
reaction and reaction was monitored by TLC and then ethyl
acetate was added to the reaction mixture followed by water. The
aqueous layer was extracted with EtOAc (3 × 15.0 mL). The
combined organic extract was washed with H2O (3 × 15.0 mL)
and brine (20.0 mL) and dried over Na2SO4. The solvent was
removed under reduced pressure to give crude product which was
purified by flash column chromatography on silica gel (230-400
mesh) using ethyl acetate in petroleum ether to afford the pure
products MK-9 (1a) (610 mg, 0.77 mmol, 77%) as a yellow
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(m, 2H), 5.22−4.98 (m, 9H), 3.36 (d, J = 7.2 Hz, 2H), 2.80 (s,
3H), 2.18−1.88 (m, 37H), 1.78 (s, 3H), 1.66 (s, 3H), 1.60-1.48
(m, 19H).
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Large scale synthesis (MK-9)
Procedure
for
2-methyl-3-
((2E,6E,10E,14E,18E,22E,26E,30E)-3,7,11,15,19,23,27,31,35-
nonamethylhexatriaconta-2,6,10,14,18,22,26,30,34-nonaen-1-
yl)naphthalene-1,4-dione (1a): 1-Chloro-N,N,2-trimethyl-1-
propenylamine (3.0 mL, 22.0 mmol) was added dropwise over 20
min to a solution of 18 (12.6 g, 20.0 mmol) in toluene (600 mL)
at 15 °C. Then the reaction mixture was stirred at 15 °C for 6 h
and after halogination of solanesol, 4a-methyl-1,4,4a,9a-
tetrahydro-1,4-methanoanthracene-9,10-dione 19 (4.8 g, 20.2
mmol), t-BuOK (2.46 g, 22.0 mmol) and 18-crown-6 (264.0 mg,
1.0 mmol) were added to reaction mixture at 0 °C for 6 h. after 6
h, acetic acid follewed by tributylmethylammonium bromide
(240.0 mg, 0.1 mmol) was added to reaction mixture at 120 °C.
The stirring was continued at 120 ºC until completion of the
reaction and reaction was monitored by TLC and then ethyl
acetate was added to the reaction mixture followed by water. The
aqueous layer was extracted with EtOAc (3 × 300.0 mL). The
combined organic extract was washed with H2O (3 × 300.0 mL)
and brine (400.0 mL) and dried over Na2SO4. The solvent was
removed under reduced pressure to give crude product which was
purified by flash column chromatography on silica gel (230-400
mesh) using ethyl acetate in petroleum ether to afford the pure
products MK-9 (1a) (12.2 g, 15.4 mmol, 77%) as a yellow solid.
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Cheng, W.-C. J. Org. Chem. 2008, 73, 7197.
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Acknowledgments
Thank to Prof. Mendu for providing his lab to do the work,
also thank to Department of Chemistry, Uka Tarsadia University.
Click here to remove instruction text...

Title of the Manuscript
“Synergistic Factors Ensue High Expediency in the Synthesis of Menaquinone [K2] Analogue
MK-6: Application to Access an Efficient One-Pot Protocol to MK-9”
Highlights in the present work:
1. It provides an efficient and practical method for the synthesis of menaquinone vitamin
(K2) analog MK-6 in all trans forms through “1+5 convergent synthetic approach driven
by important synergistic factors.
2. The synergistic factors includes,
1) Less efficient leaving group/more efficient nucleophile (Cl) in the substrate
(isoprenyl chlorides; as the choice of substrates compare to their bromo analogs for the
2'
synthesis of MK-6 & MK-9) makes it more prominent reaction by eliminating all SN
side reaction products.
2) In the desulfonation process (key reaction in the synthesis of MK-6 & MK-9),
addition of acetic acid removes the limitations of the reactions in terms of cyclized side
product, byproduct (Et3B, incendiary compound) formations and interruption in the tricky
purification processes.
3. The utility of this method was further extended successfully to find an efficient one-pot
synthesis to MK-9 to the gram scale synthesis.
4. Owing to this synergistic effect, the present method successfully eliminates the tedious
separation/ chromatographic processes.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: