Chirality Transfer from a Chiral Primary Alcohol Equivalent Through Allyl Cyanate-to-Isocyanate Rearrangement: Synthesis of (+)-Geranyllinaloisocyanide

Article abstract of DOI:10.1055/s-0037-1612422

A new approach was developed to construct quaternary stereogenic centers bearing nitrogen substituents in an enantioselective manner. The strategy takes advantage of [1,3]-chirality transfer from a chiral primary alcohol equivalent through an allyl cyanate-to-isocyanate rearrangement. This approach was employed in an efficient eight-step synthesis of the marine natural product, (+)-geranyllinaloisocyanide, in 43percent overall yield.

Full text of DOI:10.1055/s-0037-1612422

SYNTHESIS
0
0
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9
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7
8
8
1
1
4
3
7
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2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–F
paper
A
en
Y. Ichikawa et al.
Paper
Synthesis
Chirality Transfer from a Chiral Primary Alcohol Equivalent
Through Allyl Cyanate-to-Isocyanate Rearrangement: Synthesis
of (+)-Geranyllinaloisocyanide
Yoshiyasu Ichikawa*a
Hirofumi Morimotoa
Toshiya Masudab
O
O
H
C
H
N
O
NH2
[3,3]-sigmatropic
rearrangement
Me
N
C
O
dehydration
SiMe3
R
R
SiMe3
SiMe3
H
a Faculty of Science, Kochi University, Akebono-cho Kochi 780-
8520, Japan
b Graduate School of Human Life Science, Osaka City University,
Osaka 558-8585, Japan
R
H
C
N
ichikawa@kochi-u.ac.jp
(+)-geranyllinaloisocyanide
Received: 20.02.2019
Accepted after revision: 06.03.2019
Published online: 03.04.2019
chiral pool
R1
R3
or
R1
R3
*
*
enantioselective
addition of Et2Zn
R2
OCONH2
R2
OH
DOI: 10.1055/s-0037-1612422; Art ID: ss-2019-f0110-op
I
II
Abstract A new approach was developed to construct quaternary ste-
reogenic centers bearing nitrogen substituents in an enantioselective
manner. The strategy takes advantage of [1,3]-chirality transfer from a
chiral primary alcohol equivalent through an allyl cyanate-to-iso-
cyanate rearrangement. This approach was employed in an efficient
eight-step synthesis of the marine natural product, (+)-geranyllinaloiso-
cyanide, in 43% overall yield.
R1
R2
R3
[3,3]-sigmatropic
rearrangement
R1
R2
R3
R4OH
*
R3
*
R1
*
R2
N
N
C
O
N
C
COOR4
O
H
III
IV
V
Scheme 1 Synthesis of chiral quaternary stereogenic centers bearing
nitrogen substituents through allyl cyanate-to-isocyanate rearrangement
Key words Hoppe reaction, -silyl allyl alcohol, allyl cyanate-to-iso-
cyanate rearrangement, chirality transfer, marine natural products
gives rise to the corresponding carbamate V, which is the
protected form of the corresponding allyl amine. The strate-
gy presented in Scheme 1 has been utilized by us and oth-
ers in the synthesis of natural products and biologically im-
portant compounds.6
Stereoselective construction of quaternary stereogenic
centers poses one of the most difficult challenges in mod-
ern organic synthesis.1 In particular, synthetic methods to
generate nitrogen-substituted quaternary chiral stereogen-
ic centers have attracted our continuing interest due to
their ubiquity in nitrogen-containing natural products and
pharmaceuticals.2 In order to address problems associated
with installation of stereogenic centers of this type, we
have developed methods focusing on allyl cyanate-to-isocy-
anate rearrangement reaction,3 which is a highly stereose-
lective carbon–nitrogen bond forming process at sterically
encumbered positions (Scheme 1).4
In the first step of sequences, a chiral allyl alcohol I is
prepared from a chiral starting material or by enantioselec-
tive addition of diethylzinc to an ,-unsaturated aldehyde
(Scheme 1). The allyl alcohol I is then transformed to the
corresponding allyl carbamate II. Dehydration of II gener-
ates the allyl cyanate III, which undergoes concerted [3,3]-
sigmatropic rearrangement to produce allyl isocyanate IV
with high degree of [1,3]-chirality transfer.5 Treatment of
the resulting allyl isocyanate IV with an alcohol (R4OH)
Our continuing efforts in this area led to the develop-
ment of a new strategy for stereoselective construction of
quaternary stereogenic centers bearing nitrogen substitu-
ents (Scheme 2). In the approach, the chiral primary alcohol
equivalent VI, described earlier by Ireland,7 serves as the
starting material. Rearrangement of the allyl cyanate VII
derived from VI produces the chiral allyl carbamate VIII.
Protodesilylation of the vinylsilane moiety in VIII generates
terminal vinyl compound that would have been formed
from the corresponding achiral primary alcohol. Moreover,
the vinylsilane produced as an intermediate in this se-
quence can be used advantageously in other processes such
as palladium-catalyzed cross-coupling8 and transforma-
tions leading to vinyl halides, ,-unsaturated ketones, and
vinyl boronic esters,9 which would expand the synthetic
utility of this approach. Although chirality transfer of -silyl
allyl alcohol utilizing Ireland–Claisen rearrangement is a
well-known process,10 no reports exist describing its appli-
cation to the allyl cyanate-to-isocyanate rearrangement.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

B
Y. Ichikawa et al.
Paper
Synthesis
R1
R2
R1
R2
SiMe3
R1
SiMe3
SiMe3
C
*
*
*
N
N
R2
OH
(+)-geranyllinaloisocyanide (1)
N
C
O
H
COOR
VIII
VI
VII
Scheme 2 A new approach to synthesize chiral nitrogen-substituted
quaternary stereocenters
Figure 1 Structure of marine natural product (+)-geranyllinaloisocyanide
In order to explore the use of -silyl allyl alcohol in allyl
cyanate-to-isocyanate rearrangement (Scheme 2), we set
up an asymmetric synthesis of (+)-geranyllinaloisocyanide
(1) (Figure 1). This substance was isolated from the marine
sponge Halichondria sp. by Scheuer and Burreson.11 Spec-
troscopic analysis and degradation studies led to elucida-
tion of this marine natural product as an isocyanide ana-
logue of the jasmine constituent, geranyllinalool. The first
racemic synthesis of 1, reported in 1993,12 and the first
asymmetric synthesis, described in 2011,13 were both ac-
complished using routes in which the allyl cyanate-to-iso-
cyanate rearrangement serves as a key step. Although the
first asymmetric synthesis of 1 starting with (–)-lactic acid
methyl ester determined the absolute stereochemistry of
the quaternary stereogenic carbon possessing the isocyano
group as S-configuration, the synthetic route is consider-
ably long (25 steps) and inefficient (5.3% overall yield). As a
result, we were stimulated to explore a new, potentially
more efficient synthetic route to 1 that is based on the
strategy outlined in Scheme 2.
3 was prepared by the reaction of geranylgeraniol (2)15 with
diisopropylcarbamoyl chloride and sodium hydride. Enan-
tioselective lithiation of
3 using n-butyllithium/(–)-
sparteine in toluene at –78 °C in the presence of chloro-
trimethylsilane produced the -silyl geranylgeranyl carba-
mate 5 along with its enantiomer in 94% yield. The stereo-
chemistry of the major enantiomer 5 with R-configuration
was initially assigned based on the analogy to that observed
in the product of Hoppe’s reaction using geranyl N,N-diiso-
propylcarbamate. Treatment of carbamate 5 with excess
DIBAL in THF furnished allyl alcohol 6a in 91% yield.
In order to obtain evidence for the assigned stereochem-
istry and to determine the enantiomeric purity of 6a, we
prepared the corresponding (S)- and (R)-2-methoxy-2-phe-
nyl-2-(trifluoromethyl)acetic acid (MTPA) esters 6b and 6c
(Scheme 4). Stereochemical assignment according to the
modified Mosher–Kusumi MTPA ester analysis method was
made by calculation of the 1H NMR chemical shift differenc-
es (Δ values: Δ = S – R).16 This led to assignment of the R-
configuration to the stereogenic center in 6a, which is the
same as that predicted for 5 based on Hoppe’s observation.
The enantiomeric ratio of (R)/(S)-6a was determined to be
93:7 (86% ee) by 1H NMR analysis of Mosher esters 6b and 6c.17
The synthesis began with the (–)-sparteine-mediated
enantioselective deprotonation and silylation protocol re-
ported by Hoppe (Scheme 3).14 N,N-Diisopropylcarbamate
O
H
N
O
NiPr2
SiMe3
O
NaH, iPr2NCOCl
THF/DMF
DIBAL
THF
N
H
OH
O
NiPr2
(R)
(–)-sparteine (4), n-BuLi
(83%)
(91%)
TMSCl, toluene
(94%)
3
5
2
O
R
O
O
NH2
SiMe3
(CF3CO)2O, iPr2NEt
CH2Cl2
H
Me
[3,3]-sigmatropic
rearrangement
1) Cl3CCONCO, CH2Cl2
N
C
O
SiMe3
SiMe3
R
2) K2CO3, aq MeOH
(97%)
H
8
6a: R = H
C O
7
H
N
H
N
CHO
SiMe3
CHO
N
PPh3, CBr4
LiEt3BH
THF
CsF, DMSO
130 °C, 68 h
Et3N, CH2Cl2
SiMe3
1
(82%)
(93%)
(80%)
12
9
10
Scheme 3 Synthesis of (+)-geranyllinaloisocyanide starting from a chiral primary alcohol equivalent
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

C
Y. Ichikawa et al.
Paper
Synthesis
ed by Ireland were used, no reaction occurred. After screen-
ing a number of conditions [n-Bu4NF or n-Bu4NF(tBuOH)4 in
various solvents,21 CuI/TBAF,22 HF·Et3N], we found that the
use of a large excess of cesium fluoride (10 equiv) in DMSO
at 130 °C for 68 hours led to formation of formamide 12 in
82% yield. Finally, dehydration of 12 employing a modifica-
tion of Appel’s conditions completed the synthesis of (+)-
geranyllinaloisocyanide (1). The spectroscopic properties
(optical rotation, IR, 1H and 13C NMR) of the synthetic mate-
rial 1 match those reported for the natural product and the
previously reported synthetic material (see Supporting In-
formation).
In summary, we have uncovered the first example of al-
lyl cyanate-to-isocyanate rearrangement starting with en-
antiomerically enriched -silyl allyl alcohol. In addition, we
demonstrated that the rearrangement reaction occurs with
a high degree of [1,3]-chirality transfer. This process is
highlighted by its use in an eight-step route for synthesis of
the marine natural product, (+)-geranyllinaloisocyanide (1)
in 43% overall yield. Further applications of this method to
the synthesis of nitrogen-containing natural products are
underway in our laboratory.
CH3 OR2
Si(CH3)3
+0.057
(R)- or (S)-MTPACl
DMAP, Et3N, CH2Cl2
R1
6a
H
–0.095
6b: R2 = (S)-MTPA
6c: R2 = (R)-MTPA
R1=
Scheme 4 Absolute stereochemistry determination by Δ values for
the Mosher ester derivatives
With chiral -silyl alcohol 6a in hand, we next explored
the [1,3]-chirality transfer to install the nitrogen-substitut-
ed quaternary stereogenic center by using allyl cyanate-to-
isocyanate rearrangement (Scheme 3). Treatment of 6a
with trichloroacetyl isocyanate in dichloromethane and
subsequent hydrolysis of the resultant N-trichloroacetyl
carbamate with potassium carbonate in aqueous methanol
afforded allyl carbamate 7 in 97% yield. Dehydration of 7
employing trifluoroacetic anhydride and N,N-diisopropyl-
ethylamine generated allyl cyanate 8,18 which underwent
spontaneous [3,3]-sigmatropic rearrangement. After careful
workup, the formed isocyanate 9 was immediately dis-
solved in THF and treated with lithium triethylborohydride
(LiEt3BH) to produce formamide 10 in 93% overall yield
from 7.19
In order to check the level of [1,3]-chirality transfer in
the rearrangement reaction, allyl isocyanate 9, generated
from 7, was treated with (R)--methylbenzylamine to af-
ford urea 11a and the corresponding diastereomer in a 93:7
ratio (Scheme 5). In a control experiment, 9 was treated
with (±)--methylbenzylamine to afford a 1:1 mixture of
11a and 11b,20 which clearly demonstrates that kinetic res-
olution does not occur in the urea forming process. Consid-
ering the optical purity of 6a, the results of these experi-
ments show that the level of [1,3]-chirality transfer using -
silyl allyl alcohol is quantitative, which may be a conse-
quence of the involvement of a well-defined cyclic transi-
tion state in the [3,3]-sigmatropic rearrangement of 8 in
which the trimethylsilyl group adopts a pseudo-equatorial
position.
Melting points were recorded on a micro melting point apparatus and
are not corrected. Optical rotations were measured at the sodium D
line with a 100 mm path length cell, and are reported as follows:
[]DT, concentration (g/100 mL), and solvent. IR spectra are reported
in wave numbers (cm–1). 1H NMR data are reported with the solvent
resonance as the internal standard relative to CHCl3 ( 7.26) as fol-
lows; chemical shift (), multiplicity (standard abbreviations), cou-
pling constants (J, given in Hz) and integration. 13C NMR chemical
shifts () are recorded in parts per million (ppm) relative to CDCl3 ( =
77.0) as an internal standard. Because formamides 10 and 12 exist as
mixtures of rotamers on the NMR time sale, the 1H and 13C NMR sig-
nals for the minor rotamers are listed in curly brackets and parenthe-
ses, respectively. High-resolution mass spectra (HRMS) are reported
in m/z. Reactions were run under an atmosphere of argon when the
reactions were sensitive to moisture or O2. CH2Cl2 was dried over mo-
lecular sieves 3 Å. Pyridine and Et3N were stocked over anhydrous
KOH. All other commercially available reagents were used as received.
O
O
(2E,6E,10E)-3,7,11,15-Tetramethylhexadeca-2,6,10,14-tetraenyl
Diisopropylcarbamate (3)
(CF3CO)2O
iPr2NEt
CH2Cl2
O
NH2
SiMe3
Ph
SiMe3
HN
O
N
H
H2N
Ph
To a suspension of NaH (510 mg, 60% dispersion in mineral oil,
washed with hexane before use, 13.2 mmol) in THF (10.0 mL) was
added geranylgeraniol (2; 2.40 g, 8.26 mmol). After stirring at r.t. for
30 min, a solution of N,N-diisopropylcarbamoyl chloride (1.62 g, 9.92
mmol) in THF (6.0 mL) and DMF (4.0 mL) were added successively.
The reaction mixture was stirred at r.t. for 2.5 h and then treated cau-
tiously with MeOH and H2O. The separated aqueous layer was ex-
tracted with Et2O, and the combined organic extracts were washed
with brine, dried (anhyd Na2SO4), and then concentrated under re-
duced pressure to afford the residue (3.24 g), which was subjected to
silica gel chromatography (1:10 EtOAc/hexane) to afford carbamate 3;
as a colorless oil yield: 2.87 g (83%).
9
(R)
(88%)
11a
R
R
7
11b
Ph
SiMe3
HN
N
R =
H
R
Scheme 5 Determination of selectivity for allyl cyanate-to-isocyanate
rearrangement
Protodesilylation of 10 was more difficult than we ini-
tially anticipated (Scheme 3). When the conditions using
aqueous tetrafluoroboric acid (HBF4) in acetonitrile report-
IR (KBr): 2967, 2928, 1695, 1438, 1302, 1287, 1050 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

D
Y. Ichikawa et al.
Paper
Synthesis
1H NMR (CDCl3):  = 5.38 (t, J = 6.9 Hz, 1 H), 5.14–5.07 (m, 3 H), 4.60
(d, J = 6.9 Hz, 2 H), 2.12–2.06 (m, 8 H), 1.98–1.95 (m, 4 H), 1.70 (s, 3
H), 1.68 (s, 3 H), 1.61–1.57 (m, 11 H), 1.20 (d, J = 6.9 Hz, 12 H).
HRMS (ESI): m/z calcd for C23H42OSiNa [M + Na]+: 385.2897; found:
385.28955.
13C NMR (125 MHz, CDCl3):  = 155.8, 140.7, 135.3, 134.9, 131.2,
124.3, 124.1, 123.7, 119.5, 61.4, 45.9, 45.5, 39.7, 39.5, 26.7, 26.6, 26.2,
25.6, 21.1, 21.0, 17.6, 16.4, 16.0, 15.9.
HRMS (ESI): m/z calcd for C27H48NO2 [M + H]+: 418.3680; found:
418.3679.
(R,2E,6E,10E)-3,7,11,15-Tetramethyl-1-(trimethylsilyl)hexadeca-
2,6,10,14-tetraenyl Carbamate (7)
To a solution of 6a (1.58 g, 4.36 mmol) in CH2Cl2 (8.0 mL) cooled to –
20 °C was added trichloroacetyl isocyanate (0.56 mL, 4.75 mmol). Af-
ter stirring at –20 °C for 30 min, the solution was treated with a few
drops of MeOH and concentrated under reduced pressure. The result-
ing residue was dissolved in a mixture of MeOH (8.0 mL) and 2 M aq
K2CO3 (8.6 mL). After stirring at r.t. for 90 min, MeOH was evaporated
under reduced pressure. The aqueous layer was extracted with EtOAc
(3 ×), and the combined organic layers were washed with brine, dried
(anhyd Na2SO4), and then concentrated under reduced pressure. Puri-
fication by silica gel chromatography (1:5 EtOAc/hexane) afforded
(R,2E,6E,10E)-3,7,11,15-Tetramethyl-1-(trimethylsilyl)hexadeca-
2,6,10,14-tetraenyl Diisopropylcarbamate (5)
N,N-Diisopropylcarbamate 3 (2.30 g, 5.58 mmol) was dissolved in tol-
uene (ca. 2 mL) in a 50 mL round-bottomed flask and the solvent was
removed azeotropically by rotary evaporation. After drying under
vacuum, the flask was charged with toluene (15.0 mL), (–)-sparteine
(4; 2.18 mL, 9.48 mmol), and chlorotrimethylsilane (1.27 mL, 10.0
mmol, distilled from CaH2 before use). To this solution cooled to –78 °C
with a MeOH/dry ice bath was added n-BuLi (1.64 M solution in hex-
ane, 5.50 mL, 8.92 mmol) dropwise over 5 min. After stirring at –78 °C
for 2 h, a few drops of MeOH were added to quench the reaction and
the cooling bath was removed. Sat. aq NH4Cl and H2O were added and
the separated aqueous layer was extracted with Et2O (3 ×). The com-
bined organic layers were washed with brine, dried (anhyd Na2SO4),
filtered through a cotton plug, and then concentrated to afford the
crude product 5 (3.05 g). Purification by silica gel chromatography
(1:10 EtOAc/hexane) afforded 5 as colorless liquid; yield: 2.57 g (94%);
[]D24 +6.7 (c 1.00, CHCl3).
25
carbamate 7 as a clear oil; yield: 1.72 g (97%); []D +24.7 (c 1.00,
CHCl3).
IR (KBr): 3337, 2962, 2923, 2854, 1717, 1367, 1247 cm–1
.
1H NMR (CDCl3):  = 5.26 (d, J = 10.3 Hz, 1 H), 5.17 (d, J = 10.3 Hz, 1 H),
5.12–5.08 (m, 3 H), 4.52–4.47 (br, 2 H), 2.17–1.94 (m, 12 H), 1.69 (br s,
3 H), 1.68 (br s, 3 H), 1.61–1.58 (m, 9 H), 0.04 (s, 9 H).
13C NMR (125 MHz, CDCl3):  = 157.5, 137.0, 135.2, 134.9, 131.2,
124.3, 124.2, 123.9, 121.7, 68.0, 39.9, 39.7, 39.7, 26.7, 26.6, 26.5, 25.7,
17.6, 16.9, 16.0, 15.9, –3.9.
HRMS (ESI): m/z calcd for C24H44NO2Si [M + H]+: 406.3136; found:
406.3137.
HRMS (ESI): m/z calcd for C24H43NO2SiNa [M + Na]+: 428.2955; found:
428.2956.
IR (KBr): 2965, 2928, 1691, 1435 cm–1
.
1H NMR (CDCl3):  = 5.35 (d, J = 10.3 Hz, 1 H), 5.18 (d, J = 10.3 Hz, 1 H),
5.11–5.09 (m, 3 H), 2.16–1.93 (m, 12 H), 1.69 (s, 3 H), 1.68 (s, 3 H),
1.58–1.61 (m, 9 H), 1.27–1.09 (m, 12 H), 0.05 (s, 9 H).
13C NMR (125 MHz, CDCl3):  = 156.3, 135.8, 135.0, 134.8, 131.2,
124.3, 124.2, 124.0, 122.5, 67.4, 46.4, 44.8, 39.9, 39.7, 39.7, 26.7, 26.6,
25.6, 21.5, 20.8, 17.6, 16.9, 16.0, 15.9, –3.5.
HRMS (ESI): m/z calcd for C30H56NO2Si [M + H]+: 490.4075; found:
490.407118.
HRMS (ESI): m/z calcd for C30H55NO2SiNa [M + Na]+: 512.3894; found:
512.3895.
N-[(S,1E,6E,10E)-3,7,11,15-Tetramethyl-1-(trimethylsilyl)hexade-
ca-1,6,10,14-tetraen-3-yl]formamide (10)
Allyl carbamate 7 (550 mg, 1.36 mmol) was dissolved in toluene (ca. 2
mL) in a 100 mL round-bottomed flask and the solvent was removed
azeotropically by rotary evaporation. After drying under vacuum, the
flask was charged with N,N-diisopropylethylamine (1.42 mL, 8.14
mmol) and CH2Cl2 (10.0 mL). After cooling to –78 °C under argon at-
mosphere, a solution of trifluoroacetic anhydride (1 M solution in
CH2Cl2, 2.70 mL, 2.70 mmol) was added. After stirring for 10 min at
–78 °C, the reaction mixture was warmed to 0 °C. After stirring at 0 °C
for 50 min, the resulting mixture was diluted with hexane and poured
into aq pH 7 phosphate buffer (50 mL). The separated organic layer
was washed with H2O and brine, and dried (anhyd Na2SO4). Concen-
tration under reduced pressure afforded the crude isocyanate 9,
which was immediately dissolved in THF (10.0 mL). The solution was
cooled to 0 °C and then treated with LiEt3BH (1.0 M solution in THF,
4.10 mL, 4.10 mmol). After stirring at 0 °C for 60 min, the reaction
mixture was diluted with Et2O and the Et2O layer was washed with
sat. aq NaHCO3, H2O, and brine. After drying (anhyd Na2SO4), concen-
tration under reduced pressure gave a residue (1.4 g), which was puri-
fied by silica gel chromatography (1:5 EtOAc/hexane) to furnish for-
mamide 10 as a colorless oil; yield: 495 mg (93%); []D22 +0.91 (c 1.00,
CHCl3).
(R,2E,6E,10E)-3,7,11,15-Tetramethyl-1-(trimethylsilyl)hexadeca-
2,6,10,14-tetraen-1-ol (6a)
To a solution of N,N-diisopropylcarbamate 5 (2.41 g, 4.92 mmol) in
THF (25.0 mL) cooled to 0 °C was added DIBAL (1 M solution in hex-
ane, 50.0 mL, 50.0 mmol). After stirring at r.t. for 4 h, the reaction
mixture was cooled to 0 °C, and cautiously treated with MeOH (ca. 3
mL) and sodium potassium tartrate (30.0 g, 106 mmol) in H2O (50
mL). After vigorous stirring at r.t. for 30 min, the separated aqueous
layer was extracted with Et2O (3 ×). The combined organic layers were
washed with brine and dried (anhyd Na2SO4). Concentration under
reduced pressure gave a residue (1.91 g), which was purified by silica
gel chromatography (1: 10 EtOAc/hexane) to afford allyl alcohol 6a as
a colorless oil; yield: 1.62 g (91%); []D26 +39.0 (c 1.00, CHCl3).
IR (KBr): 3239, 2966, 2929, 1682, 1405, 1336 cm–1
.
IR (KBr): 3393, 2962, 2923, 2854, 1245 cm–1
.
1H NMR (CDCl3):  = {8.14 (d, J = 2.3 Hz)}, 8.09 (d, J = 12.0 Hz, 1 H),
{6.01 (d, J = 19.5 Hz)}, 5.97 (d, J = 18.9 Hz, 1 H), 5.82 (d, J = 18.9 Hz, 1
H), {5.63 (d, J = 19.5 Hz)}, 5.13–5.05 (m, 3 H), 2.12–1.90 (m, 10 H),
1.68 (s, 3 H), 1.60 (s, 3 H), 1.59 (s, 3 H), 1.58 (s, 3 H), {1.48 (s)}, 1.38 (s,
3 H), 0.079 (s, 9 H), {0.084 (s)}.
1H NMR (CDCl3):  = 5.28 (d, J = 10.3 Hz, 1 H), 5.12–5.09 (m, 3 H), 4.19
(d, J = 10.3 Hz, 1 H), 2.17–2.03 (m, 8 H), 2.00–1.97 (m, 4 H), 1.68 (s, 3
H), 1.63–1.58 (m, 9 H), 0.04 (s, 9 H).
13C NMR (125 MHz, CDCl3):  = 135.2, 135.1, 134.9, 131.2, 125.9,
124.3, 124.2, 123.9, 64.4, 39.9, 39.7, 39.7, 26.7, 26.6, 25.7, 17.6, 16.7,
16.0, 16.0, –4.1.
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E
Y. Ichikawa et al.
Paper
Synthesis
13C NMR (125 MHz, CDCl3):  = 164.3 (160.4), 149.5 (149.5), 136.1
(135.5), 135.0 (134.9), 131.1, 128.9, 126.6, 124.3 (124.0), 123.9
(123.6), 122.9, 57.6 (58.7), 41.5, 39.6 (39.6), 39.6 (39.2), 26.7, 26.4
(26.5), 26.2, 25.6 (24.9), 22.2 (22.5), 17.6, 15.9 (15.9), 9.9, –1.4 (–1.3).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612421.
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HRMS (ESI): m/z calcd for C24H44NOSi [M + H]+: 390.31874; found:
390.3187.
References
N-[(S,6E,10E)-3,7,11,15-Tetramethylhexadeca-1,6,10,14-tetraen-3-
yl]formamide (12)
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ed with Et2O, the Et2O layer was washed with H2O and brine, and
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residue (101 mg), which was purified by silica gel chromatography
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[]D26 +4.42 (c 2.05, CHCl3).
IR (KBr): 3296, 2967, 2923, 2855, 1687, 1532, 1449 cm–1
.
1H NMR (CDCl3):  = 8.18 (d, J = 12.0 Hz, 1 H), {8.12 (d, J = 1.7 Hz)},
{5.94 (dd, J = 16.9, 10.9 Hz)}, 5.89 (d, J = 16.9, 10.3 Hz, 1 H), 5.22–5.06
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13C NMR (125 MHz, CDCl3):  = 164.1 (160.3), 142.9 (142.3), 136.1
(135.7), 135.0, 131.1, 124.3, 123.9 (124.0), 122.9 (123.5), 114.1
(112.5), 56.4 (57.5), 41.6, 39.6 (39.6), 39.5 (39.5), 26.7, 26.4 (26.4),
25.6 (26.2), 24.5, 22.1 (22.4), 17.6, 15.9 (15.9).
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318.2792.
Geranyllinaloisocyanide (1)
Formamide 12 (33 mg, 0.104 mmol) was dissolved in toluene (ca. 1
mL) in a 30 mL round-bottomed flask and the solvent was removed
azeotropically by rotary evaporation. After drying under vacuum, the
flask was charged with PPh3 (82 mg, 0.31 mmol), Et3N (0.10 mL,
0.73 mmol), and CH2Cl2 (1.0 mL). The flask was cooled in a NaCl/ice
bath at –20 °C. CBr4 (120 mg, 0.36 mmol) in CH2Cl2 (0.50 mL) was
added. After stirring at –20 °C for 20 min, the reaction mixture was
diluted with Et2O. The resulting mixture was washed with 1N KHSO4,
water, sat aq NaHCO3 and brine. After drying (anhyd Na2SO4), concen-
tration under reduced pressure gave a residue (208 mg), which was
purified by silica gel chromatography (1:30 EtOAc/hexane) to afford
1; yield: 25 mg (80%); []D22 +24.6 (c 2.25, CCl4).
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.
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Japan.
1H NMR (CDCl3):  = 5.65 (ddt, J = 16.6, 10.3, 2.6 Hz, 1 H), 5.44 (d, J =
16.6 Hz, 1 H), 5.21 (d, J = 10.3 Hz, 1 H), 5.11–5.08 (m, 3 H), 2.17–1.96
(m, 10 H), 1.68 (br s, 3 H), 1.608 (s, 3 H), 1.602 (s, 3 H), 1.594 (s, 3 H),
1.48 (t, J = 2.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 155.6, 138.1, 136.4, 135.0, 131.2,
124.3, 124.0, 122.3, 114.1, 62.6, 41.4, 39.7, 39.6, 28.4, 26.7, 26.4, 25.7,
22.7, 17.6, 16.0.
HRMS (ESI): m/z calcd for C21H34N [M + H]+: 300.2686; found:
300.2686.
(16) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
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(17) The enantiomeric ratio of (R)/(S)-6a is consistent to that
reported by Hoppe using geranyl N,N-diisopropylcarbamate.
For details, see the reference 14b and Supporting Information.
Acknowledgment
We sincerely thank Professor Hiyoshizo Kotsuki for giving us a 100-
mL bottle of (–)-sparteine.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

F
Y. Ichikawa et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F