Synthesis of Vitamin K and Related Naphthoquinones via Demethoxycarbonylative Annulations and a Retro-Wittig Rearrangement

Article abstract of DOI:10.1021/acs.orglett.5b02920

Anionic annulations of 3-nucleofugal phthalides with α-alkyl(aryl)acrylates involving a demethoxycarbonylation provide a succinct synthesis of vitamin K and related naphthoquinones. Also reported is a new cascade reaction stemming from a Cope-retro-Wittig rearrangement. This cascade leads to direct formation of 1-hydroxy-4-prenyloxynaphthalene-2-carboxylates from the corresponding α-prenyl acrylate acceptors.

Full text of DOI:10.1021/acs.orglett.5b02920

Letter
pubs.acs.org/OrgLett
Synthesis of Vitamin K and Related Naphthoquinones via
Demethoxycarbonylative Annulations and a Retro-Wittig
Rearrangement
Dipakranjan Mal,* Ketaki Ghosh, and Supriti Jana
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
S
* Supporting Information
ABSTRACT: Anionic annulations of 3-nucleofugal phthalides
with α-alkyl(aryl)acrylates involving a demethoxycarbonylation
provide a succinct synthesis of vitamin K and related
naphthoquinones. Also reported is a new cascade reaction
stemming from a Cope−retro-Wittig rearrangement. This
cascade leads to direct formation of 1-hydroxy-4-prenylox-
ynaphthalene-2-carboxylates from the corresponding α-prenyl
acrylate acceptors.
are denoted as MK-n, where n indicates the number of
unsaturated isoprene units. In Figure 1 are presented the
structures of the vitamin K series and some biologically
important natural 1,4-naphthoquinones 4−7 which show
antimicrobial,7 anti-inflammatory,8 antimalarial,9 and cardiotonic
activities. Vitamin K3 (1) is a synthetic compound sometimes
used as a nutritional supplement. It is widely used as a blood
coagulating agent due to its anti-hemorrhagic effects and is a key
intermediate in the synthesis of the other vitamins of group K.
On an industrial scale, vitamin K3 is produced by stoichiometric
oxidation of 2-methylnaphthalene by CrO3 in sulfuric acid. This
method produces about 18 kg of toxic inorganic waste per 1 kg of
target product.10 Alternatively, a one-pot synthesis of vitamin K2
from 3-phenylthioisobenzofuranone and alkenyl phenyl sulfone
via anionic cycloaddition process lacks environmental efficiency
as well as atom economy.11 Direct coupling involving allylsilanes,
allylstannanes, and stanylquinones was investigated in detail in
the 1990s. More recently, Lipshutz et al. used a Ni(0)-catalyzed
coupling between vinylalanes and chloromethylated 1,4-
naphthoquinones as a route to vitamin K1 and K2.12 Thus, the
development of an environmentally friendly method for the
production of substituted quinones continues to be a challenging
goal.
itamin K, a family of natural products, is of importance in
Vmany key biochemical processes of living systems, including
blood coagulation, bone metabolism, and cell growth.1,2 It is
established that vitamin K is essential for proper formation of
prothrombin which converts blood fibrinogen to fibrin that
results in blood clots.3 Vitamin K is also involved in a number of
other biological processes, namely, maintenance of bone, early
development of skeletal4 and cellular growth.5 In addition,
vitamin K is shown to inhibit the growth of a number of tumor
cell lines.6 Structurally, the vitamin K series is menadione (1)
with a divergent substitution at the C-3 position (Figure 1). For
example, vitamin K1 or phylloquinone (3) contains a 3-phytyl
substituent, whereas vitamin K2 or menaquinone (2) has
repeating unsaturated isoprene units at C-3 position and they
In a recent report,13 we described a demethoxycarbonylative
annulation of α-substituted acrylates with phthalides for the
regiocontrolled synthesis of polysubstituted 1-naphthols, where-
in the demethoxycarbonylation occurred under base-promoted
reaction conditions. In an extension of this study, we considered
the use of a 3-nucleofugal phthalide (e.g., 8) in the annulation for
a direct entry to naphthoquinones. Since the nucleofugal group
at C-3 increases the oxidation level, the resulting products would
be 1,4-naphthoquinols, which, in turn, would be expected to yield
1,4-naphthoquinones on aerial oxidation. This study was
Figure 1. Vitamin K genre and some naturally occurring naphthoqui-
nones.
Received: October 8, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02920
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Organic Letters
Letter
undertaken with the aim of achieving an efficient synthesis of
vitamin K and similar naphthoquinones. Although the extension
is perceptible in terms of tandem Michael−Dieckmann
condensation, its success much depends on suppressing the
competing reactions such as Michael addition and 1,2-addition
that lead to dimerization. Sometimes, exceptional stability of the
incipient carbanion of the phthalides leads to failure of the
desired initial Michael addition.14 Furthermore, the choice of
bases and reaction conditions play crucial roles. For example,
Brimble et al. and Donner et al. performed thorough studies to
achieve successful annulations.15 Initially, the reactivities of
phthalides 8 with methyl methacrylate 9a in the presence of
LiOBu-t in dry THF at −78 °C (Table 1) were explored. The
removal of lithium cyanide to produce dihydronaphthoquinone
12. The nucleophilic attack of tert-butoxide anion at the ester
carbonyl proceeds to effect demethoxycarbonylation and
concomitant fragmentation to yield intermediate 13. This then
undergoes enolization to produce 1,4-naphthoquinol 14, which
transforms to quinone 1 via an aerial oxidation.
Enthused by our success in the above demethoxycarbonylative
annulation (Scheme 1), we established the generality of the
reaction with different phthalides and acrylates (Table 2). To
Table 2. Benzannulation of Substituted Acrylates with 3-
a
Cyanophthalides
Table 1. Bases Screened for the Annulation of 8e
entry
base/conditions (°C)
product
%yield
1
2
3
4
LiOBu-t/−60 to rt
LiHMDS/−78 to rt
LDA/−78 to rt
NaH/0 to rt
1
1
1
64
20
23
intractable mixture
reaction of readily accessible 3-methoxyphthalide (8a) with
methyl methacrylate (9a) in the presence of LiOBu-t resulted in
direct formation of the expected menadione (1) in 30% yield. As
shown in Scheme 1, the reactions with phenylsulfonylphthalide
Scheme 1. Annulation Reaction of 3-Nucleofugal Phthalides
with Acrylates and Base Screening
8b and phenylthiophthalide 8c also gave menadione (1) in 23%
and 20% yields, respectively. With the recently developed 3-
isocyanophthalide (8d),16 the yield of 1 was slightly higher. From
the base screening study (Table 1), 3-cyanophthalide (8e) was
found to be the best donor.
The formation of 2-methylnaphthoquinone (1) is explained
by the electron-arrow mechanism shown in Scheme 2. At low
temperature, the incipient phthalide anion 10 adds to the acrylate
9a in Michael addition mode to form new anion 11. This anion
11 then attacks at the phthalide carbonyl group resulting in
a
b
Reaction conditions: LiOBu-t, dry THF, −78 °C to rt, 6−7 h. 10%
2-phenyl-3-cyanonaphthoquinone was obtained as a byproduct along
with 27.
evaluate the sensitivity of the dealkoxycarbonylation step to steric
effects, we reacted butyl methacrylate (15) with 3-cyanoph-
thalide (8e) (Table 2, entry 1). With LiOBu-t as base, it gave the
desired menadione (1) in 50% yield. The lower yield suggests
sensitivity of the annulation to steric effects. Under similar
reaction conditions, cyanophthalide 16 underwent annulation
with methyl methacrylate (9a) to produce methoxynaphthoqui-
none 17 in 70% yield (Table 2, entry 2).17 Likewise, 2-methyl-8-
methoxynaphthoquinone (19)18 was formed in 62% yield when
the annulation was carried out with 7-methoxycyanophthalide
1819 (Table 2, entry 3). When methyl tiglate 20 was reacted with
3-cyanophthalide 8e in the presence LiOBu-t, dimethylnaph-
thoquinone 21 was formed in 67% yield (Table 2, entry 4). On
the other hand, naphthoate 23 was formed in 74% yield when 2-
methylmaleate 22 was subjected to annulation with cyanoph-
thalide 8e, and the corresponding demethoxycarbonylated
product was not detected (Table 2, entry 5).
Scheme 2. Probable Mechanism for the Formation of 2-
Methylnaphthoquinone
B
DOI: 10.1021/acs.orglett.5b02920
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Letter
Attempted demethoxycarbonylation of a purified sample of 23
with an excess amount of bases LiOBu-t, LiHMDS, or LDA was
unsuccessful. A similar attempt, however, was successful when its
O-methyl derivative was treated with LiOBu-t.20 The contrasting
reactivity of 23 and O-methyl derivative to LiOBu-t-promoted
demethoxycarbonylation can be explained by the electrostatic
repulsion of the oxyanion of 23 to addition of tert-butoxide anion
to the ester carbonyl groups. With dimethyl itaconate (24), the
desired naphthoquinone 25 was obtained in 57% yield (Table 2,
entry 6). The reaction of 2-phenyl acrylate 26 with 3-
cyanophthalide 8e provided 2-phenylnaphthoquinone 27 in
62% yield (Table 2, entry 7).
For an entry to vitamin K structures, we developed a general
synthesis of α-alkenyl acrylates 28a−f in 2 steps starting from
corresponding alkenyl bromides 29a−c. Allylic bromides 29a−c
were treated with methyl 2-(diethoxyphosphoryl)acetate 30 in
the presence of KOBu-t in dry DMF at 0 °C to rt for 20 h to give
phosphonoacetates 31a−c in 70−80% yields.
Wittig−Horner reaction of 31a−c with paraformaldehyde or
acetaldehyde in the presence of NaH furnished α-alkenyl
acrylates 28a−f in good yields (Scheme 3). When the simplest
However, an interesting result emerged when α-prenyl
acrylate 28b was subjected to this annulation. 4-Prenyloxynaph-
thoate 32 (Scheme 4, Table 3, entry 2) was exclusively formed
Scheme 4. Unusual Formation of 3-Prenyloxynaphthoate 32
a
40% (with LDA); 52% (with LiHMDS); 32% (with NaHMDS);
Structure of 32 was confirmed by an independent synthesis. Methyl
b
1,4-dihydroxy-2-naphthoate was first synthesized22 by Hauser
annulation of 8e and methyl acrylate. It was then selectively prenylated
with prenyl bromide and K2CO3.
(83%) in place of the expected naphthoquinone. Similarly, the
reaction of α-geranyl acrylate 28c with phthalide 8e under
identical reaction conditions, produced 3-geranyloxynaphthoate
34a and 2-geranyl-1,4-naphthoquinone 34b23 in a 5:4 ratio
(Table 3, entry 3).
Formation of 3-prenyloxynaphthoate 32 can be explained by
the mechanistic proposal in Scheme 5. Intermediate 35 is
Scheme 3. Synthesis of α-Alkenylacrylates via Wittig−Horner
Reactions
Scheme 5. Plausible Mechanism for the Formation of 4-
Prenyloxynaphthoate 32
allyl acrylate 28a was reacted with the 3-cyanophthalide 8e in the
presence of LiOBu-t, 2-allyl-1,4-naphthoquinone21 (33) was
obtained in 65% yield (Table 3, entry 1).
produced by the Michael addition followed by Dieckmann
cyclization of 3-cyanophthalide 8e and α-prenyl methacrylate
28b. Thereafter, a Cope rearrangement of intermediate 36
occurs to form the oxy-anion 37. A retro-Wittig rearrangement of
anion 37 furnishes 32 after protonation. It appears that C-5 gem-
substitution is one of the driving forces of the retro-Wittig
rearrangement. The stability of the final product could be
another.
Table 3. Annulation of 8e with α-Allyl/Prenyl/Geranyl
a
Acrylates 28a−c
The above rearrangement (Scheme 4) was prevented when an
acrylate (28d−f) carried a β-methyl group. For all three cases
studied, tetrahydronaphthoates (39, 41, 43) were intercepted.
Under the reaction conditions, in situ demethoxycarbonylation
did not occur. However, treatment of the tetrahydronaphthoates
39, 41, and 43 with LiOBu-t in refluxing THF furnished expected
quinones 4024 and 4225 and vitamin K2/menaquinone 2,26
respectively (Table 4, entries 1−3). For the naphthoquinone 40,
the yield was 45% and for prenyl analogue 42, 55%. The overall
yield of menaquinone (2) (5:3 mixture of E and Z isomer) was
26%.
In summary, we have shown that demethoxycarbonylative
annulation of 3-nucleofugal phthalides with α-substituted
acrylates produces a succinct route to 1,4-naphthoquinones,
including vitamin K2. This one-pot synthetic approach is
a
Reaction conditions: donor 8e, base LiOBu-t, dry THF, −78 °C to rt,
6−7 h.
C
DOI: 10.1021/acs.orglett.5b02920
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Organic Letters
Letter
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regiospecific. With further refinements, such a method would be
industrially viable. More notably, α-prenyl/geranyl acrylates
display an unprecedented cascade reaction involving Cope
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02920.
■
S
Synthesis, analytical data, and NMR spectra (PDF)
(20) Attempted demethoxycarbonylation of 23 with an excess amount
of base LiOBu-t, LiHMDS, or LDA was unsuccessful. However, a similar
attempt was successful when its O-methyl derivative was treated with
LiOBu-t, and methyl 4-hydroxy-1-methoxy-3-methyl-2-naphthoate was
obtained in 55% yield.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dmal@chem.iitkgp.ernet.in.
Notes
(21) (a) Mal, D.; Pahari, P.; Senapati, B. Tetrahedron Lett. 2005, 46,
2097. (b) Yadav, J. S.; Reddy, B. V.; Swamy, S. T. Tetrahedron Lett. 2003,
44, 4861.
The authors declare no competing financial interest.
(22) (a) Yamamoto, Y. Org. Lett. 2009, 11, 717. (b) Adams, S. P. J. Org.
Chem. 1981, 46, 3474.
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(b) Araki, S.; Katsumura, N.; Butsugan, Y. J. Organomet. Chem. 1991,
415, 7.
(24) Syper, L.; Kloc, K.; Mlochowski, J. Tetrahedron 1980, 36, 123.
(25) Teitelbaum, A.; Scian, M.; Nelson, W.; Rettie, A. Synthesis 2015,
47, 944.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Council of Science & Industrial
Research, New Delhi for financial support. K.G. is thankful to the
University Grand Commission, New Delhi, for her research
fellowship and contingency grant. We are also thankful to DST-
FIST for financial support for establishing NMR facility.
(26) (a) Fujii, F.; Shimizu, A.; Takeda, N.; Oguchi, K.; Katsurai, T.;
Shirakawa, H.; Komai, M.; Kagechika, H. Bioorg. Med. Chem. 2015, 23,
2344. (b) Yamago, S.; Hashidume, M.; Yoshida, J. Tetrahedron 2002, 58,
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D
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