Synthesis of the Verapamil Intermediate through the Quaternary Carbon-Constructing Allylic Substitution

Article abstract of DOI:10.1055/s-0036-1588518

In the present study, the key secondary allylic picolinate was synthesized via Pd(PPh ₃) ₄ -catalyzed coupling of the TBS ether of (R, Z)-4-iodo-5-methylhex-3-en-2-ol with allyl-MgBr. Allylic substitution of the picolinate with the copper reagent derived from 3,4-(MeO) ₂ C ₆ H ₃ MgBr and Cu(acac) ₂ in a 2:1 ratio afforded the anti S _N 2′ product with complete chirality transfer and 91% regioselectivity. Synthetic manipulation of the olefin moiety led to the nitrile group, generating the intermediate for the synthesis of (S)-verapamil.

Full text of DOI:10.1055/s-0036-1588518

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
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A
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Y. Kobayashi et al.
Letter
Synlett
Synthesis of the Verapamil Intermediate through the Quaternary
Carbon-Constructing Allylic Substitution
Yuichi Kobayashi*
Ryohei Saeki
(3)
(4)
(1)
Red-Al
then I2
(Sia)2BH then [O]
PyCO2H, DCC
(2) CH2=CHCH2MgBr
Pd(PPh3)4 cat.
OTBS
Py
OH
Yutaro Nanba
Yuta Suganuma
Masao Morita
Keita Nishimura
O
O
TBSO
3,4-(MeO)2C6H3MgBr
Cu(acac)2
OMe
Department of Bioengineering, Tokyo Institute of Technology,
Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama
226-8501, Japan
R: CH=CHMe
R: CN
OMe
(Mg/Cu = 2:1)
R
ykobayas@bio.titech.ac.jp
14.6% yield over 12 steps from the alcohol
Received: 08.05.2017
Accepted after revision: 04.07.2017
Published online: 08.08.2017
reactions is generally dependent on substituents, an alter-
native method was developed, as shown in Scheme 2. The
Red-Al reduction/iodination5 of C (R1 = (CH2)2OPMB, R3 = Et)
gave D regio- and stereoselectively. However, palladium-
catalyzed coupling of D (R1 and R3 as above, R = TBS,
Me(EtO)CH) with n-BuZnCl produced proton-quenched ole-
fin F (E/F = 75:25) as a byproduct, and when n-BuMgBr was
used, F was obtained as the major product. This side reac-
tion was observed with alkyl metal compounds6 except for
methyl metals.4,7
DOI: 10.1055/s-0036-1588518; Art ID: st-2017-u0341-l
Abstract In the present study, the key secondary allylic picolinate was
synthesized via Pd(PPh3)4-catalyzed coupling of the TBS ether of (R,Z)-
4-iodo-5-methylhex-3-en-2-ol with allyl-MgBr. Allylic substitution of
the picolinate with the copper reagent derived from 3,4-
(MeO)2C6H3MgBr and Cu(acac)2 in a 2:1 ratio afforded the anti SN2′
product with complete chirality transfer and 91% regioselectivity. Syn-
thetic manipulation of the olefin moiety led to the nitrile group, gener-
ating the intermediate for the synthesis of (S)-verapamil.
OH
Key words allylic substitution, quaternary carbon, verapamil, pico-
linate, copper, palladium
Red-Al
R2-M
R2
OR
I
OR
R3
*
then NIS
R3
R3
Pd cat.
R1
R1
R1
*
*
E
C
D
Recently, we reported the allylic substitution of γ,γ-
disubstituted secondary allylic picolinates A (Scheme 1), in
which the use of a picolinoxy leaving group (PyCO2) afford-
ed anti SN2′ products B in good yields with high regio- and
stereoselectively.1 This protocol is advantageous over previ-
ous methods using other esters2 and has been applied to
the synthesis of mesembrine3 and sporochnol.4
OR
R3
byproduct:
R1
R2 in R2–M:
previously, n-Bu, (CH2)2CH=CH2
presently, i-Pr, "(CH2)3OH" equiv
F
Scheme 2 Method for synthesizing γ,γ-disubstituted secondary allylic
alcohol derivatives
R2
OCOPy
R3
R2 Ar
R1
Although the formation of F was inevitable, the strategy
based on the combination of the methods shown in
Schemes 1 and 2 is a useful tool in organic synthesis. In or-
der to clarify the steric influence of the substituents on this
strategy we attempted the preparation of nitrile 2, the key
intermediate for the synthesis of verapamil (1)8 (Figure 1),
which was envisaged to be constructed from the corre-
sponding allylic product B via oxidative cleavage of the dou-
ble bond.9 The present method would be applicable to the
synthesis of structurally similar nitriles such as those
shown in Figure 1.
ArMgBr, Cu(acac)2
anti SN2'
R3
R1
A
B
Scheme 1 Quaternary C–C bond formation by allylic substitution
To date, compounds A bearing methyl, alkoxymethyl,
and/or primary alkyl substituents (R1, R2, and R3) on the al-
lylic moiety have been examined, whereas the effect of
bulky substituents on the allylic substitution has not been
investigated. The γ,γ-disubstituted secondary allylic alcohol
derivatives have been prepared by Wittig or Horner–
Wadsworth–Emmons olefination of carbonyl compounds
R1R2C=O. However, because the stereoselectivity of these
The racemic form of verapamil is clinically used as a cal-
cium ion channel blocker. However, its enantiomers exhibit
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
Y. Kobayashi et al.
Letter
Synlett
to the presence of 8a derived from proton-quenching of the
Al intermediate. An attempted palladium-catalyzed cou-
pling of 6a with i-PrZnCl derived from i-PrMgBr and ZnCl2
was slow even at 50 °C, a temperature higher than that used
for the coupling with n-BuZnCl.3 Worse than that, the major
product was the n-Pr derivative 7b, which was accompa-
nied by byproduct 8a (7b/8a = 63:37 determined by 1H
NMR analysis; Scheme 3, study 1). The 1H NMR spectrum of
7b was identical to that of the authentic sample prepared
by coupling of 6a and n-PrZnCl (r.t., 22 h), which also pro-
duced 8a (7b/8a = 83:17; Scheme 3, footnote a). These re-
sults indicate that the formation of propene–Pd–H complex
12 occurred more rapidly than reductive elimination of the
i-Pr–Pd complex 11 probably because of steric effects, and
that complex 12 was in equilibrium with n-Pr–Pd complex
13 through reversible β-H elimination and reinsertion, re-
leasing 8a and 7b, respectively (Scheme 4).
OMe
OMe
MeO
MeO
Me
OMe
HO
N
OMe
CN
CN
(S)-verapamil (1)
key intermediate 2
Ar1
F
N
N
Me
Ar2
CN
N
Ph
O
CN
emopamil (3): Ar1 = Ar2 = Ph
gallopamil (4): Ar1 = Ar2 = 3,4,5-(MeO)3C6H2
E2050 (5)
Figure 1 Biologically active nitriles with a quaternary stereogenic cen-
ter
significantly different biological actions to each other: the
S-isomer 1 is the more potent blocker, while the R-isomer
deactivates the sodium pumps.8a Verapamil has been syn-
thesized in enantiomerically enriched form by optical and
enzymatic resolutions.10 Moreover, an asymmetric acyla-
tion reaction using a chiral catalyst has been developed for
the synthesis of verapamil, which was, however, obtained
in somewhat low enantiomeric purity.11
Preliminary results of our studies on the synthesis of al-
lylic picolinates are summarized in Scheme 3. First, a race-
mic iodide 6a as a model compound was reproducibly syn-
thesized in good yields by Red-Al reduction/iodination of
the corresponding propargylic alcohol followed by silyla-
tion with TBSCl. The chemical purity of 6a was 93–96%, due
Next, the coupling of 6a (6a/8a
= 96:4) with
CH2=C(Me)ZnCl followed by hydrogenation was studied
(Scheme 3, study 2). The coupling at room temperature for
21 hours gave a mixture of 7c and 6a in a 1:1 ratio, indicat-
ing a lower reactivity of the vinyl zinc reagent than that of
n-Pr- and n-BuZnCl. Fortunately, the reaction at 50 °C was
complete within three hours to afford 7c along with small
1
amount of 8a (7c/8a = 94:6, determined by H NMR analy-
sis). However, reduction of the desilicated alcohol 7d under
hydrogen in the presence of RhCl(PPh3)3 catalyst in MeOH12
proceeded with low substrate selectivity, producing a mix-
< study 1 >
i-PrMgBr (4 equiv)
ZnCl2 (5 equiv)
OTBS
I
OTBS
OTBS
OTBS
+
+
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
Pd(PPh3)4 (10 mol%)
THF, 50 °C, 60 h
7a
7ba
8a
6a
93% purity over 8a
quant.
7a/7b/8a = 0:63:37
< study 2 >
CH2=C(Me)MgBr (3 equiv)
OR
ZnCl2 (4.3 equiv)
+
(7c/8a = 94:6)
6a
8a, 5%
Ph(CH2)3
Pd(PPh3)4 (10 mol%)
THF, 50 °C, 3 h
96% purity
over 8a
7c, R = TBS, 85%
7d, R = H
TBAF
84%
OH
OH
H2, RhCl(PPh3)3 (cat.)
+
Ph(CH2)3
Ph(CH2)3
MeOH, r.t.
low product selectivity
9
7e
< study 3 >
CH2=CHCH2MgBr (2 equiv)
Pd(PPh3)4 (20 mol%)
OTBS
I
OR
OTBS
+
THF, reflux, overnight
8f
7f
6f, R = TBS
HO
83%, 7f/8f = 94:6
OTBS
(Sia)2BH then H2O2, NaOH
76%
96% purity over 8f
cf. 10, R = Hb
7g
Scheme 3 Preliminary results of Pd-catalyzed coupling reaction. a Coupling of 6a (6a/8a = 96:4) with n-PrZnCl at r.t. for 22 h gave 7b and 8a in an
83:17 ratio quantitatively. b Coupling of 10 under similar conditions was unsuccessful.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
Y. Kobayashi et al.
Letter
Synlett
R-enantiomer of 6f) with allylMgBr proceeded smoothly
even in the presence of commonly used Pd(PPh3)4 in reflux-
ing THF to afford the desired product 7f in 83% yield with
94% product selectivity (Scheme 3, study 3).15 Finally, hyd-
roboration of 7f followed by oxidation gave alcohol 7g in
76% yield.
Pd
OTBS
Pd(0)
+
6a
i-PrZnCl
Ph(CH2)3
11
H
Pd
OTBS
Pd
OTBS
In summary, CH2=C(Me)ZnCl and allylMgBr proved to be
useful reagents for the palladium-catalyzed coupling of vi-
nyl iodides derived from secondary propargylic alcohols.
Moreover, the CH2=C(Me) and allyl groups provide synthet-
ic handles for further functional-group manipulation. For
instance, the allyl moiety could be converted into a 3-hy-
droxypropyl group in the synthesis of enantiomerically en-
riched 2, as discussed later. Recently, a one-pot synthesis of
allyl-substituted allylic alcohols from propargylic alcohols
was reported, involving Red-Al reduction, transformation to
methyl alanates with MeLi, transmetalation to organocop-
per compounds, and coupling with allyl (or allylic) bro-
mides.16 Hence, our study is complementary to the report-
ed method.
On the basis of our results, the synthesis of verapamil
intermediate 2 in an optically active form was undertaken
starting with the conversion of aldehyde 14 to ketone 1517
in 63% yield (Scheme 5). Asymmetric hydrogen-transfer re-
action18 of the ketone afforded alcohol (R)-16 in 80% yield
with 96% ee as determined by HPLC analysis of the derived
Ph(CH2)3
Ph(CH2)3
13
12
8a
7b
Scheme 4 Plausible mechanism
tures of 7e (desired product), 9 (over-reduced product), and
7d (starting material) in a ratio of 11:13:76 after three
hours and 23:29:48 after eight hours.
The formation of small amounts of allene–Pd–H species
in the coupling with CH2=C(Me)ZnCl prompted us to inves-
tigate the reaction of allyl-metal compounds with iodide 6f
(racemic) bearing a bulky i-Pr group. The coupling of allyl-
MgBr with sterically unhindered iodoolefins in the pres-
ence of PdCl2(dppf) or PdCl2(MeCN)2 as a catalyst has been
previously reported.13,14 In this work, the reaction of race-
mic 6f (6f/8f = 96:4; see Scheme 5 for the synthesis of the
O
OH
1) CBr4, Ph3P
2) BuLi, MeCHO
I
OR
Ru cat.a
CH2=CHCH2MgBr
Red-Al
CHO
then NIS
i-PrOH
Pd(PPh3)4 (cat.)
3) PCC
63%
14
15
(R)-16
96% ee
80%
(R)-10, R = H
(R)-6f, R = TBS
TBSCl, imidazole
89% from (R)-16
HO
TBSO
TBSO
OR
OCOPy
OH
OTBS
(Sia)2BH then
H2O2, aq NaOH
PyCO2H
TBSCl, imidazole
[N-Me-2-ClC5H4N]+ I–
DMF, –60 °C
84%
96%
19
18
(R)-7f
(R)-7g, R = TBS
17, R = H
TBAF
RO
55% from (R)-6f
OMe
MeO
OMe
OMe
OMe
OMe
TBSO
3,4-(MeO)2C6H3MgBr (20) (12 equiv)
Cu(acac)2 (6 equiv), THF, –20 °C
O3 then
TBSO
+
CHO
100% CT, 91% rs
Me2S
(other attempts, see Table 1)
24
21, R = TBS
cf. 23, R = H, 97% ee
22
OMe
OMe
RO
TBSO
CDI
NH2OH, NaOAc
OMe
OMe
THF, reflux
CN
N
OH
26, R = TBS
2, R = H, 37% from 19
TBAF
25
Scheme 5 Synthesis of the verapamil intermediate 2. a RuCl(p-cymene)[(R,R)-TsDPEN].
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
Y. Kobayashi et al.
Letter
Synlett
benzoate. Red-Al reduction/iodination of (R)-16 gave iodo
alcohol (R)-10, which was converted into TBS ether (R)-6f
in 89% yield from (R)-16 along with 8f in a 96:4 ratio. Palla-
dium-catalyzed coupling of (R)-6f with allylMgBr afforded
(R)-7f with (R)-7f/8f in a 96:4 ratio. Hydroboration/oxida-
tion of this product gave (R)-7g, which upon desilylation
with TBAF afforded diol 17 in 55% yield from iodide (R)-6f.
Regioselective protection of 17 with TBSCl followed by es-
terification of the resulting hydroxyl group with PyCO2H
gave picolinate 19 in good yield. Similarly, racemic pico-
linate rac-19 (the exact structure not shown) was prepared
for a preliminary study of the allylic substitution.
Table 1 Allylic Substitution
3,4-(MeO)2C6H3MgBr (20), Cu(acac)2
ZnI2 (0 or 1.5 equiv) THF, –20 °C
+
22
19
21
Entry
20
(equiv)
Cu(acac)2
(equiv)
ZnI2
(equiv)
21c/22/19 CTd
1a
2a
3b
4b
3
6
1.5
3
–
39:5:56
68:6:26
–
–
–
4.7
12
1.5
6
1.5
–
93:7:0
91:9:0
41
100
a Racemate rac-19 was used.
b 96% ee.
Firstly, we examined the allylic substitution of rac-19
with the copper reagent derived from 3,4-(MeO)2C6H3MgBr
and Cu(acac)2 in a 2:1 ratio, according to the procedure1a
described for the reaction of a simple picolinate A (R1 = R2 =
Me, R3 = (CH2)3Ph) with PhMgBr/Cu(acac)2 (2:1) at –40 °C to
–20 °C for two hours (Scheme 1). With the reported
amount of the copper reagent (1.5 equiv), the reaction was
slow and incomplete even after 14 hours (Table 1, entry 1);
doubling the reagent amount also gave unsatisfactory con-
version (Table 1, entry 2). These results clearly indicate that
the i-Pr group hampered the substitution. In an early study,
the PhMgBr/Cu(acac)2/ZnI2 reagent system in a 3:1:1 ratio
proved to be as effective as PhMgBr/Cu(acac)2 (2:1) in terms
of yield and regioselectivity, although chirality transfer (CT)
was not determined.1a On the basis of these findings, a new
reagent system consisting of 20/Cu(acac)2/ZnI2 (3:1:1) was
applied to the allylic substitution of rac-19. Notably, the
original amount of the copper reagent (1.5 equiv) was suffi-
cient to afford rac-21 with 93% regioselectivity as deter-
mined by 1H NMR spectroscopy.19 A similar regioselectivity
(91%) was achieved with 19 derived from 96% ee of 16 (Ta-
ble 1, entry 3). Following the steps shown in Scheme 5,
compound 21 was then converted into the target 2 in 35%
overall yield but only with low CT of 41% (39.5% ee by HPLC
analysis) and low specific rotation {[α]D20 –4 (c 1.0, CHCl3);
cf. lit.10a –12.6 (c 3.84, CHCl3)}. A low ee value was reproduc-
ibly obtained. Probably, elimination of the PyCO2 group was
accelerated by acidity of the reagent mixture consisting of
ZnI2, 3,4-(MeO)2C6H3MgBr, Cu(acac)2, and MgBr2 (formed in
situ) to afford stable allylic carbocation. Because racemiza-
tion was unlikely to occur during the steps following the al-
lylic substitution,20 we went back to the original ZnI2-free
protocol using six equivalents of the reagent, with which
the reaction proceeded to completion to afford 21 with 91%
regioselectivity over 22 (entry 4; cf. entry 2). To determine
the enantiomeric purity, 21 (synthesized again from 19 of
the same lot) was converted into alcohol 23 in 52% yield,
which showed 97% ee by HPLC analysis. As described above,
compound 21 was converted into 2 in 37% yield from pico-
linate 19 with a specific rotation of [α]D20 –11 (c 1.0, CHCl3),
similar to the literature value mentioned above. The total
yield was 7.4% over 15 steps from 14.21
c Product 21 in entries 3 and 4 was transformed to 2 in 35% and 37% yields
from 19.
d Defined as (% ee of 21) × 100 / (% ee of 19).
In conclusion, the scope of the strategy based on the
combination of the reactions in Schemes 1 and 2 was ex-
panded to sterically hindered allylic picolinate 19 bearing
the bulky i-Pr group next to the reacting olefin carbon. In
addition, allylMgBr and CH2=C(Me)MgBr were demonstrat-
ed to be good reagents for the palladium-catalyzed coupling
of vinyl iodides.
Funding Information
This work was supported by JSPS KAKENHI Grant Number 26410111
and the Kobayashi International Scholarship
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Supporting information for this article is available online at
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References and Notes
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Youn, B. H. Tetrahedron: Asymmetry 1999, 10, 3759.
(e) Bannister, R. M.; Brookes, M. H.; Evans, G. R.; Katz, R. B.;
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(20) Strong activation of the PyCO2 group by ZnI2 is a likely step for
the racemization through the carbocation.
(21) To an ice-cold suspension of Cu(acac)2 (437 mg, 1.67 mmol) in
THF (10 mL) was added a solution of 3,4-3,4-(MeO)2C6H3MgBr
(20, 0.46 M in THF, 7.12 mL, 3.28 mmol) dropwise. The mixture
was stirred at 0 °C for 30 min and cooled to –40 °C. A THF solu-
tion (2 mL) of picolinate 19 (107 mg, 0.273 mmol) derived from
(R)-16 of 96% ee was added to the mixture, which was warmed
to –20 °C over 2 h, stirred at –20 °C overnight, and diluted with
sat. NH4Cl. The product 21 was extracted with EtOAc three
times and passed through a short silica gel column (hex-
ane/EtOAc) to afford 21. 1H NMR (400 MHz, CDCl3): δ = 0.71 (d, J
= 6.8 Hz, 3 H), 0.84 (d, J = 6.8 Hz, 3 H), 1.81 (d, J = 5.1 Hz, 3 H),
3.46 (t, J = 6.3 Hz, 2 H), 5.52 (dq, J = 16.0, 5.1 Hz, 1 H), 5.58 (d, J =
16.0 Hz, 1 H). Further conversion of 21 into 2 (28 mg, 37% from
picolinate 19) was described in the Supporting Information:
[α]D –11 (c 0.56, CHCl3); cf. lit.10b [α]D –12.6 (c 3.84, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 0.80 (d, J = 6.8 Hz, 3 H), 1.19 (d, J
= 6.8 Hz, 3 H), 1.20–1.50 (m, 2 H), 1.55–1.68 (m, 1 H), 1.92 (ddd,
J = 13.6, 12.0, 4.4 Hz, 1 H), 2.08 (sept, J = 6.8 Hz, 1 H), 2.21 (ddd, J
= 13.6, 12.0, 4.4 Hz, 1 H), 3.59 (dt, J = 2.0, 6.0 Hz, 2 H), 3.88 (s, 3
H), 3.89 (s, 3 H), 6.84 (d, J = 8.4 Hz, 1 H), 6.86 (s, 1 H), 6.92 (dd, J
= 8.4, 2.4 Hz, 1 H). 13C-APT NMR (100 MHz, CDCl3): δ = 18.6 (+),
19.0 (+), 29.0 (–), 34.3 (–), 38.0 (+), 53.3 (–), 55.97 (+), 56.04 (+),
62.3 (–), 109.6 (+), 111.1 (+), 118.8 (+), 121.5 (–), 130.5 (–),
148.3 (–), 149.1 (–). The 1H NMR and 13C NMR spectra of 2 were
consistent with those reported.10d
20
20
(11) Mermerian, A. H.; Fu, G. C. Angew. Chem. Int. Ed. 2005, 44, 949.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E