Complete Stereocontrol in the Synthesis of Harmonine and Novel Analogues Facilitated by a Grubbs Z-Selective Cross-Metathesis Catalyst

Article abstract of DOI:10.1071/CH15397

(R)-Harmonine was synthesised in 15% overall yield via a six-step sequence exploiting a Z-selective cross-metathesis reaction as its centrepiece. By this strategy, the cis-olefin present in the target could be installed exclusively. The use of an alcohol and an ester as the amine precursors was crucial for isolating the cross-metathesis product from the self-metathesis products. This method was also used to prepare two novel analogues of harmonine.

Full text of DOI:10.1071/CH15397

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2015, 68, 1815–1820
Full Paper
http://dx.doi.org/10.1071/CH15397
Complete Stereocontrol in the Synthesis of Harmonine
and Novel Analogues Facilitated by a Grubbs
Z-Selective Cross-Metathesis Catalyst
A
A
B
Steven-Alan G. Abel, Wesley J. Olivier, Richard L. Pederson,
Alex C. Bissember,
A C
,
A C
,
and Jason A. Smith
A
School of Physical Sciences – Chemistry, University of Tasmania, Hobart, Tas. 7001,
Australia.
B
Materia Inc., 60 N. San Gabriel Boulevard, Pasadena, CA 91107, USA.
C
Corresponding authors. Email: alex.bissember@utas.edu.au; jason.smith@utas.edu.au
(R)-Harmonine was synthesised in 15 % overall yield via a six-step sequence exploiting a Z-selective cross-metathesis
reaction as its centrepiece. By this strategy, the cis-olefin present in the target could be installed exclusively. The use of an
alcohol and an ester as the amine precursors was crucial for isolating the cross-metathesis product from the self-metathesis
products. This method was also used to prepare two novel analogues of harmonine.
Manuscript received: 2 July 2015.
Manuscript accepted: 4 August 2015.
Published online: 3 September 2015.
Introduction
to install the internal alkene. More specifically, we believed that
this could also be achieved stereoselectively utilising a Grubbs
Z-selective cross-metathesis catalyst (Fig. 1).[9] Herein, we
report on the outcomes of our work employing this strategy.
However, it should be noted that while we were completing this
study, two separate six- and five-step stereoselective total
syntheses of (R)-harmonine were disclosed.[10,11] One of these
approaches deployed a Z-selective cross-metathesis reaction to
install the cis-olefin in the target.[10]
The Harlequin ladybird, Harmonia axyridis, is an Asian preda-
tory beetle of the Coccinellidae family (lady beetles) introduced
across Europe and the Americas as a biocontrol agent for pest
insects such as aphids and scale insects.[1] H. axyridis has since
developed into a pest due to its ability to outcompete native
ladybird species due to its resistance to a range of pathogens.[2]
Indeed, wine and fruit growing industries are adversely affected
as H. axyridis consumes soft fruit and taints its flavour by con-
taminating harvests with isopropyl methoxypyrazine, a defence
alkaloid.[1,3] Another undesirable feature of the Harlequin lady-
bird is its tendency to aggregate in buildings during winter
months, which in addition to representing a nuisance, can have
financial implications for businesses and homeowners alike.[3]
When disturbed, Coccinellidae beetles release hemolyph as
small yellow droplets from their leg joints by a process known
as reflex bleeding.[4] The defensive properties of hemolymph
are attributed to the presence of alkaloids in the fluid, the
principal molecule being (R)-harmonine (1) (Fig. 1).[5]
Although harmonine was first isolated and its structure origi-
nally elucidated in 1985,[6] it has recently gained renewed
attention largely due to findings by Wiesner and co-workers.
Significantly, their research illustrated that harmonine exhibits
antibacterial activity against fast-growing Mycobacterium
tuberculosis and antimalarial activity against chloroquine-
resistant Plasmodium falciparum.[7]
Results and Discussion
As part of our initial strategy en route to harmonine, we antic-
ipated that the catalyst 2-mediated cross-metathesis of carba-
mate 4 with a large of excess of carbamate 5 (4 equiv.) would
efficiently furnish target alkene 6 (Scheme 1a). Because car-
bamates 4 and 5 are type I olefins,[12] as expected, the reaction
provided the desired cross-metathesis product 6 in addition to
the two homodimers of 4 and 5. 13C NMR spectroscopy sug-
gested the presence of the trans-isomer of olefin 6. Unfortu-
nately, despite our efforts to optimise this process, this reaction
never proceeded to completion.[13] Furthermore, despite con-
certed efforts, the products of the cross-metathesis were insep-
arable by flash chromatography. This was presumably due to the
similar polarities of the starting materials and the three cross-
metathesis products.[14] Because catalyst 3 is reported to provide
greater (Z)-selectivity (.95 %) and greater turnover numbers
(up to 7000) than catalyst 2 in cross-metathesis processes, we
also briefly investigated the results using this more active cat-
alyst.[9b,15] Thus, in order to test the effectiveness of catalyst 3,
we subjected carbamate 4 to a cross-metathesis reaction and
obtained the homodimer of olefin 4 (di-tert-butyl (2R,17R,Z)-
octadec-9-ene-2,17-diyldicarbamate) in 77 % yield (99 % yield
When we commenced our efforts towards harmonine, only two
total syntheses of the compound had been published: a racemic
19-step approach developed by Braekman and co-workers
and a 15-step enantioselective route reported by Enders and
Bartzen.[8] We anticipated that we could realise the target via a
much shorter sequence by exploiting a cross-metathesis reaction
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

1816
S.-A. G. Abel et al.
N
N
N
O
N
NH2
Ru
O
Ru
O
O
O
ϩ
ϩ
Ϫ
Ϫ
O
N
N
O
O
H2N
1
2
3
Fig. 1. (R)-harmonine (1) and Grubbs Z-selective cross-metathesis catalysts 2 and 3.
(a)
NHBoc
NHBoc
Z-selective
4
cross-metathesis
BocHN
6
BocHN
5
(b)
OH
OH
Z-selective
cross-metathesis
7
8
MeO2C
MeO2C
9
Scheme 1. Strategies for the synthesis of harmonine: (a) original and (b) revised.
based on recovered starting material). Although this reaction
did not proceed to completion, 1H and 13C NMR spectroscopy
indicated that catalyst 3 enabled the formation of the cis-isomer
of di-tert-butyl (2R,17R,Z)-octadec-9-ene-2,17-diyldicarba-
mate exclusively.
9-decenoic acid. When chiral alcohol 7 and olefin 8 (4 equiv.)
were subjected to the pivotal cross-metathesis reaction in the
presence of Grubbs Z-selective catalyst 3 in dichloromethane
the product 9 was obtained in 59 % yield.[18] Importantly, this
transformation enabled the formation of the cis-isomer of alkene
9 exclusively and the trans-isomer was not observed by 1H and
13C NMR spectroscopy. Furthermore, we were pleased to find
that by this approach the three expected products of the reaction
were easily separable by flash chromatography.[19] Next, ester 9
was reduced to diol 12 in 92 % yield. Compound 12 was then
converted into the corresponding dimesylate, which was imme-
diately reacted with NaN3 to afford diazide 13. Finally, reduc-
tion with LiAlH4 furnished (R)-harmonine (1) in 15 % yield over
six steps. All of the spectroscopic data was in accordance with
the data reported in the literature and the trans-isomer was not
It was approximately during this time that Reddy and co-
workers disclosed their approach to harmonine in which this
explicit transformation was successfully undertaken.[10] Indeed,
in this study, catalyst 2 (10 %) was employed to effect the
successful reaction of carbamates 4 (1 equiv.) and 5 (1 equiv.) at
458C, providing the cross-metathesis product 6 in 74 % yield
(90 % Z-selectivity). Interestingly, the authors do not comment
on the formation of the homodimers of 4 and 5 or note the
deviation from expected statistical mixture of all three products
in this process.[12,16] When we repeated the reported procedure,
qualitative analysis of the reaction mixture suggested the for-
mation of all three possible cross-metathesis products.[17]
Instead, because of the above-mentioned issues in the pivotal
cross-metathesis reaction, we decided to substitute the original
pairing of reaction partners (alkenes 4 and 5) in favour of
substrates with sufficient polarity differences that would sim-
plify chromatographic purification while maintaining the step-
efficiency of the synthetic strategy. With this in mind, alcohol
7 and ester 8 were identified as suitable reactants in the key
step (Scheme 1b).
1
observed by gas chromatography (GC) and H and 13C NMR
spectroscopy.[11]
Grubbs Z-selective catalyst 3 was also used to prepare
analogues of harmonine. Specifically, the cross-metathesis of
alkene 8 provided diester 14 (Scheme 3, top). Product 14 was
then reduced and the ensuing diol 15 was converted into
harmonine analogue 17 in three steps via an analogous approach
to the route that furnished harmonine. In a similar fashion, (S)-
dec-9-en-2-ol (7) was subjected to the cross-metathesis reaction
mediated by catalyst 3 to yield olefin 18 (Scheme 3, bottom).
Diol 18 was ultimately elaborated into target diamine 20 by
employing the standard synthetic manipulations that had proved
successful in the previous instances. The respective trans-
In order to test this hypothesis, both reaction partners needed
to be synthesised. To this end, the ring-opening of enantiopure
propylene oxide 10 by the organocuprate derived from Grignard
11 provided (S)-dec-9-en-2-ol (7) (Scheme 2). Ester 8 was
obtained by the straightforward Fischer esterification of
1
isomers of diamines 17 and 20 were not observed by H and
13C NMR spectroscopy.

Complete Stereocontrol in the Synthesis of Harmonine
1817
O
OH
OH
3 (2.6 %)
8 (4 equiv.)
CuBrиSMe2
10
64 % yield
MeO2C
59 % yield
BrMg
Ͼ99 :1 Z :E
9
7
11
LiAlH4 92 % yield
OH
N3
1. MsCl
2. NaN3
LiAlH4
1
85 % yield
50 % yield
over 2
steps
HO
N3
13
12
Scheme 2. Stereoselective total synthesis of (R)-harmonine.
HO
MeO2C
MeO2C
LiAlH4
3 (2.2 %)
8
68 % yield
over 2
steps
HO
15
14
1. MsCl
2. NaN3
49 % yield
over 2 steps
H2N
H2N
N3
N3
LiAlH4
99 % yield
17
16
OMs
OMs
OH
3 (2.7 %)
MsCl
7
74 % yield
68 % yield
19
18
OH
1. NaN3
2. LiAlH4
60 % yield
over 2 steps
NH2
20
Scheme 3. Synthesis of harmonine analogues 17 (top) and 20 (bottom).
NH2
Conclusion
chromatography was carried out using a RevelerisÒ X2 Flash
Chromatography System using silica gel cartridges. All NMR
spectra were recorded on a Bruker NMR spectrometer operating
at 400 (1H) and 100 MHz (13C). All starting materials were
obtained from Sigma–Aldrich, Oakwood chemicals, AK Sci-
entific. Grubbs Z-selective cross-metathesis catalysts 2 (CAS:
1252916-84-7) and 3 (CAS: 1451807-77-4) were obtained from
Materia Inc. Catalyst 2 was also obtained from Sigma–Aldrich.
Solvents were dried using an Innovative Technology Inc. sol-
vent purification system that is based upon technology origi-
nally reported by Grubbs.[21]
After judiciously selecting cross-metathesis substrates, this
strategy was used to synthesise (R)-harmonine (1) in 15 %
overall yield via a six-step sequence. A relatively low catalyst
loading was required in the key step (2.6 % of catalyst 3) and
the cross-metathesis reaction enabled the exclusive formation
of cis-alkene 9. This approach compares favourably to other
recently reported stereoselective total syntheses of the target.
Experimental
Unless otherwise specified, reactions were conducted with
magnetic stirring in oven-dried glassware using anhydrous
solvents under nitrogen. Flash chromatography was performed
using protocols first reported by Still.[20] Automated flash
(S)-Dec-9-en-2-ol (7)
7-Bromohept-1-ene (3.75 mL, 24.6 mmol) was added portion-
wise to a suspension of Mg filings (600 mg, 24.6 mmol) in Et2O

1818
S.-A. G. Abel et al.
(15 mL) (n.b., the addition of a small I2 crystal and heating was
used to initiate this reaction). The mixture was then added to a
mixture of CuBrꢀSMe2 (3.54 g, 17.2 mmol) and (S)-(ꢁ)-pro-
pylene oxide (10) (1.00 g, 17.2 mmol) in THF (25 mL) main-
tained at ꢁ788C via cannula. The reaction mixture was slowly
warmed to room temperature and after 16 h, NH4Cl (35 mL of a
saturated solution) was added and the ensuing mixture was then
extracted with Et2O (3 ꢂ 50 mL). The combined organic extracts
were washed with NaCl (2 ꢂ 50 mL of a saturated solution),
dried (MgSO4), filtered, and concentrated under reduced pres-
sure. The resulting residue was purified by flash chromatography
(0 - 20 % EtOAc/hexane elution) to provide the title compound
as a colourless oil (1.72 g, 64 % yield).[22] dH (400 MHz, CDCl3)
5.81 (ddt, J 6.7, 10.1, 16.9, 1H), 4.97 (complex m, 2H), 3.78
(complex m, 1H), 2.04 (complex m, 2H), 1.22–1.51 (complex m,
11H), 1.19 (d, J 6.2, 3H). dC (100 MHz, CDCl3) 41.5, 39.4, 33.8,
29.6, 29.5, 29.1, 28.9, 25.7, 23.5, 21.1. [a]2D0 þ7.228 (c 1.90 in
CHCl3), [lit. [a]D þ8.78 (c 0.1 in CH2Cl2)].[22]
as a colourless oil (194 mg, 92 % yield).[11] dH (400 MHz,
CDCl3) 5.34 (t, J 4.8, 2H), 3.79 (m, 1H), 3.64 (t, J 6.6, 2H),
2.07–1.93 (complex m, 4H), 1.60–1.24 (complex m, 24 H), 1.18
(d, J 6.2, 3H). dC (100 MHz, CDCl3) 129.9, 129.8, 68.2, 63.1,
39.4, 32.8, 29.71, 29.69, 29.6, 29.5, 29.4, 29.3, 29.3, 27.2, 25.76,
25.74, 23.5. [a]2D0 þ3.228 (c 9.68 in CHCl3), [lit. [a]2D2 þ3.88
(c 1.00 in CHCl3)].[11]
(R,Z)-1,17-Diazidooctadec-9-ene (13)
Methanesulfonyl chloride (130 mL, 1.68 mmol) was added
dropwise to a solution of diol 12 (190 mg, 0.67 mmol) and N,N-
diisopropylethylamine (300 mL, 1.72 mmol) in CH2Cl2 (15 mL)
maintained at 08C. After 0.3 h, Na2CO3 (10 mL of a saturated
aqueous solution) was added. The ensuing organic phase was
then separated, washed with HCl (10 mL of a 2 M aqueous
solution), dried (MgSO4), filtered, and concentrated under
reduced pressure to provide (S,Z)-octadec-9-ene-1,17-diyl
dimethanesulfonate (282 mg) which was used in the step
described immediately below without further purification.
NaN3 (256 mg, 3.92 mmol) was added to (S,Z)-octadec-9-
ene-1,17-diyl dimethanesulfonate (282 mg), obtained as
described above, in DMF (10 mL) at room temperature. After
23 h, water (10 mL) was added and the aqueous layer was
extracted with EtOAc (3 ꢂ 20 mL) and the combined organic
extracts were dried (Na2SO4) and concentrated under reduced
pressure to provide a yellow oil. The ensuing residue was
purified by flash chromatography (0 - 40 % EtOAc/hexane
elution) to provide the title compound as a yellow oil (111 mg,
50 % yield over two steps from diol 12).[10] dH (400 MHz,
CDCl3) 5.35 (m, 2H), 3.42 (m, 1H), 3.25 (t, J 7.0, 2H),
2.08–1.93 (complex m, 4H), 1.60 (complex m, 2H), 1.41–1.26
(complex m, 18H), 1.24 (d, J 6.5, 3H). dC (100 MHz, CDCl3)
129.9, 129.8, 58.0, 51.5, 36.2, 29.7, 29.6, 29.4, 29.3, 29.2, 29.1,
28.8, 27.33, 27.30, 26.9, 26.3, 19.6. [a]2D0 ꢁ20.398 (c 4.34 in
CHCl3), [lit. [a]2D6 ꢁ18.238 (c 1.06 in CHCl3)].[11]
Methyl 9-decenoate (8)
A solution of 9-decenoic acid (5.44 mL, 29.4 mmol) and H2SO4
(1 mL) in MeOH (100 mL) was stirred at room temperature for
24 h. NaHCO3 (40 mL of a saturated aqueous solution) was
added and the ensuing mixture was extracted with CH2Cl2
(3 ꢂ 50 mL). The combined organic extracts were then dried
(MgSO4), filtered, and concentrated under reduced pressure to
provide the title compound as a colourless oil (5.08 g, 94 %
yield).[23] nmax (film)/cmꢁ1 2929, 2856, 1742, 1250, 1245. dH
(400 MHz, CDCl3) 5.80 (ddt, J 6.7, 10.1, 16.9, 1H), 4.95
(m, 2H), 3.66 (s, 3H), 2.30 (t, J 7.6, 2H), 2.03 (q, J 6.9, 2H), 1.62
(t, J 7.4, 2H), 1.42–1.26 (complex m, 8H). dC (100 MHz, CDCl3)
174.1, 139.1, 114.2, 51.4, 34.1, 33.8, 28.9, 28.8, 24.9.
(S,Z)-Methyl 17-hydroxyoctadece-9-enoate (9)
Grubbs Z-Selective cross-metathesis catalyst 3 (18.5 mg,
27.4 mmol) was added to a solution of (S)-dec-9-en-2-ol (7)
(163 mg, 1.04 mmol) and methyl 9-decenoate (8) (768 mg,
4.17 mmol) in CH2Cl2 (500 mL) at room temperature. After 24 h
(n.b., during this time the solvent had evaporated), ethyl vinyl
ether (200 mL) was added and the ensuing mixture was loaded
onto a silica plug and eluted (50 % EtOAc/hexane solution). The
solvent was removed under reduced pressure and the ensuing
colourless oil (860 mg) was purified by flash chromatography
(0 - 15 % EtOAc/hexane elution) to provide the title com-
pound as a colourless oil (191 mg, 59 % yield).[24] dH (400 MHz,
CDCl3) 5.31 (t, J 4.7, 2H), 3.76 (m, 1H), 3.63 (s, 3H), 2.27
(t, J 7.5, 2H), 2.03–1.92 (complex m, 4H), 1.66–1.54 (complex
m, 2H), 1.22–1.49 (complex m, 19H), 1.15 (d, J 6.2, 3H). dC
(100 MHz, CDCl3) 174.3, 129.88, 129.84, 68.1, 51.4, 39.4, 34.1,
29.68, 29.66, 29.5, 29.3, 29.14, 29.12, 29.07, 27.17, 27.16, 25.8,
25.0, 23.5. m/z (HRMS ESI) 335.2550; C18H38 NaN2 [M þ Na]þ
requires 335.2557. [a]2D0 þ2.238 (c 3.70 in CHCl3).
(R)-Harmonine (1)
A solution of (S,Z)-1,17-diazidooctadec-9-ene (13) (108 mg,
0.32 mmol) in THF (10 mL) was added dropwise to a suspension
of LiAlH4 (59 mg, 1.55 mmol) in THF (5 mL) at room temper-
ature. After 1.5 h, Et2O (10 mL) and water (10 mL) were added
and the phases separated. The aqueous layer was further
extracted with EtOAc (3 ꢂ 10 mL) and the combined organic
extracts were dried (Na2SO4), and concentrated under reduced
pressure to provide the title compound as a colourless oil (98 mg,
85 % yield).[11]
n
max (film)/cmꢁ1 2924, 2852, 1558, 1458, 1392, 1319, 680,
650. dH (400 MHz, CDCl3) 5.33 (t, J 4.7, 2H), 2.90 (m, 1H), 2.70
(br s, 2H), 2.43 (br s, 6H), 2.07–1.93 (complex m, 4H),
1.51–1.41 (complex m, 2H), 1.40–1.22 (complex m, 20H),
1.08 (d, J 6.3, 3H). dC (100 MHz, CDCl3) 130.1, 130.0, 47.2,
42.0, 39.7, 33.2, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 27.3, 27.0,
26.4, 23.4. m/z (EI) 282, 266, 250. m/z (HRMS ESI) 283.3109;
C18H39N2 [M þ H]þ requires 283.3108. [a]2D0 ꢁ2.968 (c 2.48 in
C6H6), [lit. [a]2D4 ꢁ3.48 (c 1.04 in C6H6)].[11]
(S,Z)-Octadec-9-ene-1,17-diol (12)
A solution of (S,Z)-methyl 17-hydroxyoctadece-9-enoate (9)
(230 mg, 0.74 mmol) in THF (10 mL) was added dropwise to a
suspension of LiAlH4 (52 mg, 1.37 mmol) in THF (8 mL)
maintained at 08C. After 1 h, water (10 mL) was added and the
ensuing mixture was extracted with EtOAc (3 ꢂ 25 mL). The
combined extracts were then dried (MgSO4), filtered, and con-
centrated under reduced pressure to provide the title compound
(Z)-Octadec-9-ene-1,18-diol (15)
Grubbs Z-selective cross-metathesis catalyst
3 (19.7 mg,
29.1 mmol)wasaddedtoa solutionofester8(246mg, 1.34mmol)
in CH2Cl2 (500mL). After 16h, ethyl vinyl ether (400mL) was
added and the mixture was loaded onto a silica plug and eluted

Complete Stereocontrol in the Synthesis of Harmonine
1819
(100 mL of a 50% EtOAc/hexane solution). The solvent
was removed under reduced pressure to provide (Z)-dimethyl
octadec-9-enedioate (14) as a brown oil (237 mg),[25] which was
used in the step described immediately below without further
purification.
1.28 (s, 23H). dC (100 MHz, CDCl3) 129.9, 42.2, 33.8, 29.7,
29.5, 29.4, 29.2, 27.2, 26.9. m/z (EI) 282, 266. m/z (HRMS ESI)
283.3115; C18H39N2 [M þ H]þ requires 283.3108.
(Z)-Octadec-9-ene-2,17-diol (18)
A
solution of (Z)-dimethyl octadec-9-enedioate (14)
Grubbs Z-selective cross-metathesis catalyst
3 (9.0 mg,
(237 mg), obtained as described above, in Et2O (10 mL) was
added dropwise to a suspension of LiAlH4 (130 mg, 3.42 mmol)
in Et2O at 08C. After 1.7 h, the reaction was quenched with Et2O
and KHSO4 (30 mL of a 0.5 M aqueous solution). The reaction
mixture was extracted with EtOAc (3 ꢂ 20 mL) and the com-
bined organic extracts were dried (MgSO4), filtered, and con-
centrated under reduced pressure to provide a grey solid.
This residue was purified by flash chromatography (50 %
EtOAc/hexane elution) to provide the title compound as a
colourless solid (131 mg, 68 % yield over two steps from ester
8). nmax (film)/cmꢁ1 3300, 1634, 1412, 1360, 1073, 928, 643. dH
(400 MHz, CDCl3) 5.34 (t, J 4.8, 2H), 3.63 (t, J 6.6, 4H),
2.06–1.95 (complex m, 4H), 1.60–1.50 (complex m, 6H), 1.30
(s, 18H). dC (100 MHz, CDCl3) 129.9, 63.1, 32.8, 29.7, 29.48,
29.40, 29.2, 27.1, 25.7.
13.3 mmol) was added to (S)-dec-9-en-2-ol (7) (77 mg,
0.49 mmol) in CH2Cl2 (500 mL) at room temperature. After 16 h,
ethyl vinyl ether (200 mL) was added and the mixture was then
loaded onto a silica plug and eluted (100 mL of a 50 % EtOAc/
hexane solution). The solvent was removed under reduced
pressure and the ensuing residue was purified by flash chro-
matography (50 % EtOAc/hexane elution) to provide the title
compound as a colourless oil (48 mg, 68 % yield). dH (400 MHz,
CDCl3) 5.35 (m, 2H), 3.79 (m, 2H), 2.02 (m, 4H), 1.44 (s, 8H),
1.32 (s, 12H), 1.18 (d, J 6.2, 6H). dC (100 MHz, CDCl3) 130.0,
68.3, 39.5, 29.8, 29.7, 29.4, 27.3, 25.9, 23.6. m/z (HRMS ESI)
307.2608; C18H36NaO2 [M þ Na]þ requires 307.2608. [a]2D0
þ7.338 (c 2.40 in CHCl3).
(Z)-Octadec-9-ene-2,17-diyl dimethanesulfonate (19)
(Z)-1,18-Diazidooctadec-9-ene (16)
Methanesulfonyl chloride (31 mL, 0.40 mmol) was added
dropwise to a solution of N,N-diisopropylethylamine (72 mL,
0.41 mmol) and (Z)-octadec-9-ene-2,17-diol (18) (45 mg,
0.16 mmol) in CH2Cl2 (10 mL) maintained at 08C. After 1.4 h,
Na2CO3 (10 mL of a saturated aqueous solution) was added.
The ensuing organic phase was separated, washed with HCl
(2 ꢂ 10 mL of a 2 M aqueous solution), dried (MgSO4), filtered,
and concentrated under reduced pressure to provide a yellow oil.
This residue was purified by flash chromatography (0 - 50 %
EtOAc/hexane elution) to provide the title compound as a
yellow oil (52 mg, 74 % yield). dH (400 MHz, CDCl3) 5.35 (m,
2H), 4.79 (dt, J 6.3, 2H), 2.99 (s, 6H), 2.0 (m, 4H), 1.71 (m, 3H),
1.58 (m, 4H), 1.41 (d, J 6.3, 6H), 1.31 (s, 17H). dC (100 MHz,
CDCl3) 129.9, 80.5, 38.8, 36.8, 29.7, 29.4, 29.3, 27.3, 25.2, 21.3.
m/z (HRMS ESI) 463.2149; C20H40NaO6S2 [M þ Na]þ requires
463.2159. [a]2D0 þ5.748 (c 1.69 in CHCl3).
Methanesulfonyl chloride (88 mL, 1.14 mmol) was added drop-
wise to a solution of N,N-diisopropylethylamine (208 mL,
1.19 mmol) diol 15 (130 mg, 0.46 mmol) in CH2Cl2 (10 mL)
maintained at 08C. After 1.4 h, Na2CO3 (10 mL of a saturated
aqueous solution) was added. The ensuing organic phase was
then separated, washed with HCl (2 ꢂ 10 mL of a 2 M aqueous
solution), dried (MgSO4), filtered, and concentrated under
reduced pressure to provide (Z)-octadec-9-ene-1,18-diyl
dimethanesulfonate as a yellow solid (211 mg) which was used in
the step described immediatelybelow without further purification.
NaN3 (210 mg, 3.23 mmol) was added to (Z)-octadec-9-ene-
1,18-diyl dimethanesulfonate (211 mg), obtained as described
above, in DMF (10 mL) at room temperature. After 16 h, water
(10 mL) was added and the ensuing mixture was extracted with
EtOAc (3 ꢂ 10 mL). The combined organic extracts were
washed with H2O (2 ꢂ 10 mL) and NaCl (10 mL of a saturated
solution), dried (Na2SO4), filtered, and concentrated under
reduced pressure to provide a brown oil (135 mg). This residue
was purified by flash chromatography (0 - 5 % EtOAc/hexane
elution) to provide the title compound as a colourless oil (76 mg,
49 % yield over two steps from diol 15). nmax (film)/cmꢁ1 2927,
2855, 2360, 2096, 1463, 1261. dH (400 MHz, CDCl3) 5.34
(t, J 4.6, 2H), 3.25 (t, J 7.0, 4H), 2.08–1.94 (complex m, 4 H),
1.65–1.54 (complex m, 4H), 1.30 (s, 20H). dC (100 MHz,
CDCl3) 129.9, 51.5, 29.7, 29.4, 29.2, 29.1, 28.8, 27.2, 26.7.
(Z)-Octadec-9-ene-2,17-diamine (20)
NaN3 (46 mg, 0.71 mmol) was added to dimesylate 19 (52 mg,
0.118 mmol) in DMF (5 mL) at room temperature. After 16 h,
water (5 mL) was added and the ensuing mixture was extracted
with EtOAc (3 ꢂ 5 mL). The combined extracts were washed
with water (2 ꢂ 5 mL) and NaCl (5 mL of a saturated solution),
dried (Na2SO4), filtered, and concentrated under reduced pres-
sure to provide the title compound as a yellow oil (32 mg) which
was used in the step described immediately below without fur-
ther purification.
(Z)-Octadec-9-ene-1,18-diamine (17)
LiAlH4 (15 mg, 0.40 mmol) was added to a solution of
(Z)-2,17-diazidooctadec-9-ene (32 mg), obtained as described
above, in Et2O (5 mL). After 0.75 h, Et2O (5 mL) and H2O
(5 mL) were added and the ensuing mixture was extracted with
EtOAc (3 ꢂ 10 mL). The combined organic extracts were then
dried (Na2SO4), filtered, and concentrated under reduced pres-
sure to provide the title compound as a yellow oil (20 mg, 60 %
yield over two steps from dimesylate 19). nmax (film)/cmꢁ1
2928, 2855, 2361, 2330, 2265, 2636, 1611, 1559, 1516, 1456,
1393. dH (400 MHz, CDCl3) 8.23 (br s, 4H), 5.34 (m, 2H), 3.31
(m, 1H), 2.06–1.95 (complex m, 4H), 1.82 (m, 2H), 1.61 (m, 2H)
1.53–1.20 (complex m, 23H). dC (100 MHz, CDCl3) 130.1, 48.6,
34.9, 29.5, 28.9, 28.6, 26.7, 25.6, 18.9. m/z (EI) 282, 266, 250. m/
A solution of (Z)-1,18-diazidooctadec-9-ene (16) (76 mg,
0.23 mmol) in Et2O (5 mL) was added dropwise to a suspension
of LiAlH4 (35 mg, 0.92 mmol) in Et2O (5 mL) at 08C. After 1 h,
water (3 mL) and NaCl (10 mL of a saturated solution) were
added. The ensuing mixture was extracted with Et2O
(3 ꢂ 10 mL). The combined organic extracts were washed with
NaCl (10 mL of a saturated solution), dried (Na2SO4), filtered,
and concentrated under reduced pressure to provide the title
compound as colourless oil (63 mg, 99 % yield). nmax (film)/
cmꢁ1 3318, 3006, 2920, 2851, 1558, 1556, 1466, 1430, 1327. dH
(400 MHz, CDCl3) 5.33 (t, J 4.6, 2H), 2.67 (br s, 2H), 2.04–1.91
(complex m, 4H), 1.60 (br s, 2H), 1.49–1.37 (complex m, 5H),

1820
S.-A. G. Abel et al.
z (HRMS ESI) 283.3101; C18H39N2 [M þ H]þ requires
283.3108. [a]2D0 ꢁ3.098 (c 0.48 in CHCl3).
[9] (a) B. K. Keitz, K. Endo, P. R. Patel, M. B. Herbert, R. H. Grubbs,
J. Am. Chem. Soc. 2012, 134, 693. doi:10.1021/JA210225E
(b) L. E. Rosebrugh, M. B. Herbert, V. M. Marx, B. K. Keitz, R. H.
Grubbs, J. Am. Chem. Soc. 2013, 135, 1276. doi:10.1021/JA311916M
[10] S. C. Philkhana, P. Dhasaiyan, B. L. V. Prasad, D. S. Reddy, RSC Adv.
2014, 4, 30923. doi:10.1039/C4RA05859C
Di-tert-butyl (2R,17R,Z)-octadec-9-ene-2,17-
diyldicarbamate
Grubbs Z-selective cross-metathesis catalyst 3 (22.6 mg,
33.4 mmol) was added to carbamate 4[10] (377 mg, 1.48 mmol) in
CH2Cl2 (500 mL) at room temperature. After 26 h, ethyl vinyl
ether (400 mL) was added and the mixture was loaded onto a
silica plug and eluted (50 % EtOAc/hexane eluent). The solvent
was removed under reduced pressure and the ensuing residue
was purified by flash chromatography (0 - 20 % EtOAc/
hexane elution) to provide the title compound as a colourless oil
(275 mg, 77 % yield) (n.b., 60 mg of carbamate 4 was also
recovered). dH (400 MHz, CDCl3) 5.32 (t, J 4.7, 2H), 4.33 (br s,
1H), 3.60 (br s, 1H) 2.03–1.95 (complex m, 4H), 1.42 (s, 18H)
1.34–1.23 (complex m, 22H), 1.08 (d, J 6.6, 6H). dC (100 MHz,
CDCl3) 155.4, 129.8, 78.8, 46.5, 37.4, 29.7, 29.4, 29.2, 28.4,
27.2, 26.0, 21.3. [a]2D0 ꢁ1.108 (c 13.8 in CHCl3).
[11] N. C. Nagel, A. Masic, U. Schurigt, W. Boland, Org. Biomol. Chem.
2015, 13, 5139. doi:10.1039/C5OB00461F
[12] A. K. Chatterjee, T.-L. Choi, D. P. Sanders, R. H. Grubbs, J. Am.
Chem. Soc. 2003, 125, 11360. doi:10.1021/JA0214882
[13] Our best results were obtained reacting carbamates 4 (1 equiv) and
5 (4 equiv) with 5 % catalyst 2 in THF at 358C for 16 h. We did not
quantitatively determine reaction conversion.
[14] No reaction was observed when the cross-metathesis was attempted
on dec-9-en-1-amine employing 0.8 % of catalyst 2 in THF at 358C
for 16 h.
[15] For synthetic applications of Grubbs Z-Selective cross-metathesis
catalyst 3 see, for example: (a) J. S. Cannon, R. H. Grubbs, Angew.
Chem. Int. Ed. 2013, 52, 9001. doi:10.1002/ANIE.201302724
(b) B. Morandi, Z. K. Wickens, R. H. Grubbs, Angew. Chem. Int. Ed.
2013, 52, 9751. doi:10.1002/ANIE.201303587
(c) B. L. Quigley, R. H. Grubbs, Chem. Sci. 2014, 5, 501. doi:10.1039/
C3SC52806E
(d) S. L. Mangold, D. J. O’Leary, R. H. Grubbs, J. Am. Chem. Soc.
2014, 136, 12469. doi:10.1021/JA507166G
(e) M. A. Pribisko, T. S. Ahmed, R. H. Grubbs, Polyhedron 2014, 84,
144. doi:10.1016/J.POLY.2014.06.055
Supplementary Material
1H and 13C NMR spectra for compounds 1, 7–9, 12, 13, and
15–20 and GC chromatograms for compounds 1, 17, and 20 are
available on the Journal’s website.
[16] Consequently, the authors also do not comment on any problems arising
from the chromatographic purification of olefin 6 and any co-eluting
products resulting from homodimerisation of carbamates 4 and 5.
[17] Reddy and co-workers note that cross-metathesis product 6 is obtained
via the slow addition of carbamates 4 and 5 to a solution of catalyst 2 in
dichloromethane at 458C. Presumably, this is used to simulate infinite
dilution conditions, which is a viable strategy when the product of the
reaction does not participate in additional metathesis reactions. How-
ever, in this case, it is unclear how this approach works to supress
homodimerisation of carbamates 4 and 5 under the reaction conditions.
[18] Alcohol 7 was completely consumed in this reaction and only a trace
amount of diol 18 was isolated. When this reaction was performed in
THF, GC and 13C NMR spectroscopy suggested the presence of the
trans-isomer of olefin 9.
Acknowledgements
The authors acknowledge the School of Physical Sciences – Chemistry for
financial support and the Central Science Laboratory at University of
Tasmania for access to NMR spectroscopy services. Materia Inc. is thanked
for generously providing cross-metathesis catalysts 2 and 3.
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