Novel stereoselective syntheses of (2E,4E)-4-(4,4-dimethylpent-2-ynylidene)-N1,N5-dimethyl-N1,N5-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-diamine

Article abstract of DOI:10.1016/j.tet.2009.04.095

We report two different synthetic approaches for the stereoselective synthesis of (2E,4E)-4-(4,4-dimethylpent-2-ynylidene)-N¹,N⁵-dimethyl-N¹,N⁵-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-diamine 1, an important im

Full text of DOI:10.1016/j.tet.2009.04.095

Tetrahedron 65 (2009) 5838–5843
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel stereoselective syntheses of (2E,4E)-4-(4,4-dimethylpent-2-ynylidene)-
N1,N5-dimethyl-N1,N5-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-diamine
*
*
Lino Colombo , Marcello Di Giacomo , Massimo Serra, Simone M. Tambini
`
Dipartimento di Chimica Farmaceutica, Universita di Pavia, via Taramelli 12, 27100 Pavia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
We report two different synthetic approaches for the stereoselective synthesis of (2E,4E)-4-(4,4-dime-
thylpent-2-ynylidene)-N1,N5-dimethyl-N1,N5-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-diamine 1, an
important impurity-reference standard for the chemical characterization of terbinafine. The diamine 1
was obtained in only six steps with a good overall yield starting from commercially available glutaconic
acid.
Received 19 February 2009
Received in revised form 8 April 2009
Accepted 30 April 2009
Available online 7 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
diamine 12 (Scheme 1) intended as impurity-reference standard for
the chemical characterization of terbinafine, an orally and topically
Pharmaceutical impurities consist of reaction by-products gen-
erated during the synthesis of active pharmaceutical ingredients
(APIs) and degradation products formed during the formulation
manufacturing process and/or the storage of the APIs. The presence
of these unwanted chemicals, also referred to as ‘related sub-
stances’, even in small amounts may influence the efficacy and
safety of the pharmaceutical products. Indeed, the presence of such
impurities and their levels in the drug products are indicative of the
product quality and can imply a risk to patient safety.
Impurity profiling (i.e., the identity as well as the quantity of the
impurity in the pharmaceuticals) is now receiving important crit-
ical attention from regulatory authorities: limits of impurities
present in the APIs and formulations are incorporated to different
pharmacopoeias. Moreover, the International Conference of Har-
monization (ICH) has formulated a workable guideline regarding
the control of impurities.1 Although these impurities are usually
present at very low levels, it is imperative to characterize their
identities in order to make proactive decisions with respect to
optimization of synthesis routes and formulation development and
ultimately to design a control strategy for manufacturing process.
For this reason, there is a significant demand for impurity-reference
standards along with and the API-reference standards for both
regulatory authorities and pharmaceutical companies. The work
reported here was directed toward the development of two feasible
new synthetic routes to (2E,4E)-4-(4,4-dimethylpent-2-ynylidene)-
N1,N5-dimethyl-N1,N5-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-
active antifungal agent.3
9 steps
6 steps
CO2Et
N
N
N
R
R
R
HO
OH
1
O
O
R = 1-methylnaphthyl
Scheme 1.
terbinafine
2. Results and discussion
Construction of the dienyne system poses a number of synthetic
challenges, the most arduous of which is apparently the stereo-
selective formation of the E-configured trisubstituted double bond.
This stereochemical issue could be obviated starting from the easily
accessible (Z)-ethyl 2,3-dibromoprop-2-enoate 2,4 which has been
shown to undergo two successive coupling reactions to afford in
a highly stereoselective manner 2,3-disubstituted (Z)-propenoates.5
Two consecutive Sonogashira couplings with 3,3-dimethylbut-1-
yne and propargyl alcohol, according to the retrosynthetic pathway
summarized in Scheme 2, should deliver the whole carbon frame-
work to which two molecules of N-methyl-1-(naphthalen-1-yl)me-
thanamine could be simultaneously attached by a substitution
reaction. The use of propargyl alcohol as a coupling agent should play
* Corresponding authors. Tel.: þ39 0382 987366; fax: þ39 0382 422975.
E-mail addresses: lino.colombo@unipv.it (L. Colombo), marcello.digiacomo@
unipv.it (M. Di Giacomo).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.095

L. Colombo et al. / Tetrahedron 65 (2009) 5838–5843
5839
Br
5
H
Ph
O Si
Ph
1
Br
CO2Et
OH
H
3
HO
OH
HO
H H
2
4
3
H
OH
9
Scheme 2. Retrosynthetic analysis of compound 1.
Figure 1. Selected NOEs exhibited by compound 9.
a dual role, allowing the chemo- and stereoselective reduction of the
propargylic triple bond to an E-configured alkene by the action of
sodium bis(2-methoxyethoxy)aluminum dihydride (Red-AlÒ).6
The starting (Z)-ethyl 2,3-dibromoprop-2-enoate 2, readily
available by bromination of ethyl propiolate,4 was coupled with
3,3-dimethylbut-1-yne employing the Pd-modified version of the
Castro–Stephens reaction7 to give the enyne 5 in 64% yield (Scheme
3). Reduction of the ester with DIBALH followed by protection of
the resultant alcohol as a tert-butyldiphenyl silyl ether afforded the
(Z)-vinyl bromide 7 in 31% yield over two steps. Attempts to couple
7 with propargyl alcohol by applying the same experimental con-
ditions as in the first Sonogashira reaction met with failure. Several
reaction variables were investigated including palladium and cop-
per source, catalyst loading, solvent, and base. As a result, the
choice of base proved to have the most significant influence on the
product formation. The use of piperidine,8 all other experimental
conditions being unchanged, led to the desired endiyne 8 in 79%
isolated yield. Stereoselective reduction of the triple bond adjacent
to the hydroxy group with Red-AlÒ afforded in moderate yields the
dienyne 9.
limit its attractiveness, particularly in industrial laboratories. As
a consequence, it seemed to us more useful to design a new synthetic
approach to 1 rather than embark on the usually tedious optimiza-
tion of each single step of the previous synthesis.
Focusing our attention on the key intermediate diol 4, we rea-
soned that its whole carbon skeleton could be assembled through
an aldol condensation between the enolate of a dialkyl pent-2-
enedioate (glutaconate) and 4,4-dimethylpent-2-ynal (Scheme 4).
Dehydration of the resulting propargylic alcohol and reduction of
both ester groups should afford the target diol 4. The most critical
aspect of this simplified sequence is the stereochemical outcome of
the elimination step leading to the trisubstituted double bond.
However, Lewin and Carrol reported that a trisubstituted double
bond with the desired E configuration could be directly formed by
the base-promoted condensation of dimethyl
b-methylglutaconate
and a conjugated aldehyde.9 In practice, reaction at ꢀ78 ꢁC of the
lithium enolate of commercial dimethyl glutaconate 11 with 4,4-
dimethylpent-2-ynal10 followed by warming to 0 ꢁC to drive the
reaction to completion gave directly the dienyne 12 albeit in iso-
lated yields not higher than 43% (Scheme 4).
The E configuration of the newly created double bond was
confirmed by the 16.3 Hz coupling constant correlating the two
relevant hydrogen atoms. The NOESY spectrum of dienyne 9 proved
the E configuration of the trisubstituted double bond. Relevant NOE
correlations are indicated by curved arrows in Figure 1.
Several attempts to further improve yields by varying the base,
temperature, and quenching agents were to no avail. We were able
Removal of the silyl ether protecting group of 9 by reaction with
TBAF afforded the diol 4 in 75% yield. Mesylation under standard
conditions gave a mixture of three products corresponding to the
dichloro compound and an about equimolar mixture of the two
monomesyl-monochloro derivatives. In order to make easier the
purificationprocedure, thereactionwascarriedoutinthepresenceof
TBAC, thus maximizing the formation of the dichloro derivative 10,
that could be isolated in 80% yield. Nucleophilic substitution with
excess N-methyl-1-(naphthalen-1-yl)methanamine in DMF gave the
final product 1 in 90% yield. Although the above synthetic scheme
was shown to be successful within the limits of its purpose, that is the
preparation of a small amount of 1 as a reference standard, the length
of the synthetic sequence (nine linear steps), the use of expensive Pd
catalysts in two steps, and the modest overall yield could strongly
RO
OR
(ii)
(iii)
O
O
t-BuO
Ot-Bu
glutaconic acid R = H
(i)
(3%)
O
O
14 R = t-Bu
11 R = CH3
15
(iv)
4
(ii)
(85%)
O
O
+
(iii)
MeO
OMe
RO
13
O
O
O
H
12
Scheme 4. Reagents: (i) BOC2O, DMAP, t-BuOH (74%); (ii) (t-Bu)C^CCHO, LDA, THF,
ꢀ78 ꢁC (85%); (iii) DIBALH, PhCH3, ꢀ78 ꢁC (85%); (iv) MeOH, H2SO4, 80 ꢁC (95%).
Br
(ii)
(i)
Br
CO2Et
Br
CO2Et
Br
(iii)
CH2OR
6 R = H
7 R = TBDPS
2
5
1
(v)
(iv)
(viii)
CH2OTBDPS
R1H2C
CH2R2
HO
8
9 R1 = OH, R2 = OTBDPS
4 R1 = R2 = OH
(vi)
(vii)
10 R1 = R2 = Cl
Scheme 3. Reagents: (i) (t-Bu)C^CH, Pd(PPh3)4, CuI, (i-Pr)2NH, DMF (64%); (ii) DIBALH, DCM, ꢀ78 ꢁC (64%); (iii) tert-butylchlorodiphenylsilane, Et3N, DMAP, DCM (57%); (iv)
CH^CCH2OH, Pd(PPh3)4, CuI, piperidine, DMF (79%); (v) Red-AlÒ, THF, ꢀ30 ꢁC (26%); (vi) TBAF, THF (75%); (vii) MsCl, TBAC, Et3N, DCM (80%); (viii) N-methyl-1-(naphthalen-1-yl)-
methanamine, DMF (90%).

5840
L. Colombo et al. / Tetrahedron 65 (2009) 5838–5843
to isolate in pure form a major side product (20% yield) identified as
the lactone 13. Although our data do not speak directly to the order
of events governing this overall transformation, an obvious se-
N,N-dimethylaniline, ninhydrin, and KI in an aqueous ethanolic
solution of AcOH. Flash chromatography was performed on Merck
Kieselgel 60 (230–400 mesh). Nuclear magnetic resonance spectra
were acquired at 400 MHz for 1H and 100 MHz for 13C. The
abbreviatons s, d, t, q, br s, and m stand for the resonance multi-
plicities singlet, doublet, triplet, quartet, broad singlet, and multi-
plet, respectively. In the peak listing of 13C spectra abbreviations s
and t refer to zero and two protons attached to the carbons, as
determined by DEPT-135 experiments. Glassware for all reactions
was oven-dried at 110 ꢁC and cooled in a desiccator, or flame-dried
and cooled under a stream of nitrogen or argon prior to use. Liquid
reagents and solvents were introduced by oven-dried syringes
through septa-sealed flasks under an inert atmosphere.
quence could be the
an initial aldol reaction followed by deprotonation of the un-
saturated lactone, -addition of a second aldehyde molecule onto
d-lactonization of the b-alkoxy ester derived by
a
the resulting dienolate, and final E1cB elimination to give 13.
Spectroscopic data (1H and 13C NMR, see S14 and S15 in Sup-
plementary data) indicated that 13 was formed as a single dia-
stereoisomer, but the configuration of the trisubstituted exocyclic
double bond was not assigned as the NOESY spectrum did not give
unambiguous results. The use of sterically more demanding ester
functions could prevent the aforementioned
being a competitive pathway.
d-lactonization from
Thus, when the di-tert-butylester 14 was substituted for the
former dimethyl ester 11, the aldol condensation yields improved to
85% under similar experimental conditions, affording compound
15. However the preparation of the unknown di-tert-butyl glu-
taconate 14 from the corresponding acid was not trivial. After
several attempts11 we eventually found that reaction of glutaconic
acid with di-tert-butyl dicarbonate in t-BuOH with catalytic
DMAP12 afforded the corresponding di-tert-butylester in an ac-
ceptable 74% yield. Unfortunately, the following reduction of di-
ester 15 with DIBALH gave only trace amounts of the desired diol 4,
even under forcing reaction conditions. The use of other reducing
agents gave no better results. This poor reactivity toward hydride
reagents can be ascribed to the steric hindrance of the bulky tert-
butyl group since the correponding dimethyl ester 12 was shown to
undergo smooth DIBALH reduction to the diol 4 in 85% yield. A
somewhat awkward, but high yielding, circumvention was there-
fore inevitable. Transesterification of the di-tert-butylester 15 with
sulfuric acid in methanol gave the corresponding dimethyl ester in
95% yield, pure enough to carry on the next reduction step without
any chromatographic purification. The diol 4, obtained as detailed
above, was identical in all respects to that prepared following the
first synthetic sequence.
4.2. (Z)-Ethyl 2-bromo-6,6-dimethylhept-2-en-4-ynoate (5)
A
solution of (Z)-ethyl 2,3-dibromoprop-2-enoate (2.00 g,
7.75 mmol) in dry DMF (6 mL) was alternatively evacuated and
flushed with nitrogen. The flask was cooled in ice and tetrakis-
(triphenylphosphine) palladium (0.073 g, 0.063 mmol) and cu-
prous iodide (0.098 g, 0.52 mmol) were added in sequence. The
reaction mixture was allowed to warm to room temperature and
a solution of 3,3-dimethylbut-1-yne (1.34 mL, 10.86 mmol) and
diisopropylamine (1.5 mL, 10.86 mmol) in DMF (2 mL) was added.
The color turned from green to orange-red. After 2 h stirring,
additional tetrakis(triphenylphosphine) palladium (0.073 g,
0.063 mmol) and cuprous iodide (0.098 g, 0.52 mmol) were added.
When TLC analysis (hexane/ethyl acetate 97:3, double run) in-
dicated consumption of the starting dibromide, the reaction mix-
ture was poured into a saturated NaHCO3 solution and the mixture
extracted with ethyl acetate. The combined organic layers were
washed with water and brine, dried over Na2SO4, and concentrated
in vacuo to give a brown oil. Flash chromatography with hexane/
diethyl ether (98:2) afforded 1.29 g of 5 as a brown oil (64%). Rf 0.34
(hexane/diethyl ether 98:2). IR (neat, cmꢀ1) 1727, 2193, 2226. 1H
NMR (400 MHz, CDCl3)
d
1.33 (s, 9H), 1.35 (t, J¼7.1 Hz, 3H), 4.31 (q,
3. Conclusion
J¼7.1 Hz, 2H), 7.30 (s,1H). 13C NMR (100 MHz, CDCl3)
d 14.5, 29.3 (s),
30.8, 63.0 (t), 77.1 (s), 116.0 (s), 123.1 (s), 125.5, 162.7 (s). MS (EI) m/z
(% rel intensity)¼258.0 (13.9) [Mþ, 79Br], 260.0 (13.9) [Mþ, 81Br],
229.0 (32.6) [Mþ, 79Br], 231.0 (32.6) [Mþ, 81Br], 149.0 (61.2) [Mþ],
91.0 (100) [Mþ]. Anal. Calcd for C11H15BrO2: C, 50.98; H, 5.83.
Found: C, 50.96; H, 5.81.
In summary, two different syntheses of 1 were developed hav-
ing in common the intermediate diol 4, which could be prepared in
50% yield and only four steps starting from glutaconic acid. The key
step is an aldol condensation followed by in situ stereoselective
E1cB elimination. The alternative approach starting from ethyl
propargylate, based on two consecutive Sonogashira couplings,
required three more synthetic steps and gave an overall lower yield.
Experiments are underway to study the scope of the aldol ad-
dition–elimination process in order to develop a general method-
ology for the stereoselective synthesis of various highly substituted
(E,E) 1,3-diene-4-yne systems.
4.3. (Z)-2-Bromo-6,6-dimethylhept-2-en-4-yn-1-ol (6)
To a solution of the bromo ester 5 (1.00 g, 3.86 mmol) in dry
toluene (19 mL) maintained at ꢀ78 ꢁC under nitrogen was added
dropwise a 1 M CH2Cl2 solution of DIBALH (8.5 mL). When TLC
analysis (hexane/ethyl acetate 8:2) indicated consumption of the
starting ester, typically 1 h, the reaction mixture was allowed to
warm to 0 ꢁC and quenched by addition of a water solution (10 mL)
of tartaric acid (0.30 g). The aqueous layer was extracted with a 1:1
mixture of hexane/ethyl acetate and the combined organic phases
were dried over Na2SO4, filtered, and evaporated in vacuo to give
a yellow oil. Purification by flash chromatography (hexane/ethyl
acetate 82:18) gave pure 6 as a yellow oil (0.538 g, 64%). Rf 0.34
(hexane/ethyl acetate 82:18). IR (neat, cmꢀ1) 1007, 1617, 2208,
4. Experimental section
4.1. General experimental details
Common reagents and materials were purchased from com-
mercial sources and purified by recrystallization or distillation.
Solvents were purified according to the guidelines in Purification of
Laboratory Chemicals.13 Diisopropylamine, diisopropylethylamine,
and triethylamine were distilled from CaH2 prior to use. Yields were
calculated for compounds purified by flash chromatography and
judged homogeneous by thin-layer chromatography, NMR, and
mass spectrometry. Thin-layer chromatography was performed on
Merck Kieselgel 60 F254 plates eluting with solvents indicated, vi-
sualized by a 254 nm UV lamp, and stained with aqueous ceric
molybdate solution or iodine and a solution of 4,40-methylenebis-
2233, 3318. 1H NMR (400 MHz, CDCl3)
d 1.31 (s, 9H), 1.85–2.08 (br s,
1H, exchanges with D2O), 4.33 (s, 2H), 6.25 (t, J¼1.3 Hz, 1H). 13C
NMR (100 MHz, CDCl3)
d 28.8 (s), 31.2, 68.1 (t), 76.1 (s), 106.2 (s),
111.9, 135.3 (s). MS (EI) m/z (% rel intensity)¼216.0 (16.5) [Mþ, 79Br],
218.0 (16.5) [Mþ, 81Br], 201.0 (9.9) [Mþ, 79Br], 203.0 (9.9) [Mþ, 81Br],
137.0 (21.5) [Mþ], 122.0 (100) [Mþ], 91.0 (64.5) [Mþ]. Anal. Calcd for
C9H13BrO: C, 49.79; H, 6.04. Found: C, 49.83; H, 6.06.

L. Colombo et al. / Tetrahedron 65 (2009) 5838–5843
5841
4.4. (Z)-(2-Bromo-6,6-dimethylhept-2-en-4-ynyloxy)(tert-
butyl) diphenylsilane (7)
organic phases were combined, dried with Na2SO4, and evaporated
giving a pale yellow oil. Purification by flash chromatography
(hexane/ethyl acetate 8:2) afforded 0.053 g (26%) of the allyl alcohol
To an ice cooled solution of the alcohol 6 (0.40 g, 1.84 mmol) in
dichloromethane (13 mL) containing distilled triethylamine
(1.29 mL, 9.2 mmol) and DMAP (0.07 g, 0.57 mmol) under nitrogen
was added dropwise tert-butylchlorodiphenylsilane (0.556 mL,
2.21 mmol) dissolved in 5 mL of the same solvent. The mixture was
allowed to warm to room temperature and, after 2 h, an additional
portion of tert-butylchlorodiphenylsilane (0.282 mL, 1.10 mmol)
was added. After 4 h the reaction mixture was quenched by addi-
tion of water (13 mL). The aqueous layer was extracted with a 1:1
mixture of hexane/ethyl acetate and the combined organic phases
were dried over Na2SO4, filtered, and evaporated in vacuo to give
a pale yellow oil. Purification by column chromatography (gradient
elution from 100% hexane to hexane/ethyl acetate 99:1) gave pure 7
as a colorless oil (0.477 g, 57%). Rf 0.34 (hexane/ethyl acetate 99:1).
IR (neat, cmꢀ1) 1105, 1624, 2198, 2225. 1H NMR (400 MHz, CDCl3)
9 as a colorless oil. Rf 0.34 (hexane/ethyl acetate 8:2). IR (neat, cmꢀ1
)
1105, 2198, 2217, 3326. 1H NMR (400 MHz, CDCl3)
d 1.09 (s, 9H), 1.34
(s, 9H), 1.37–1.68 (br s, 1H, exchanges with D2O), 4.21 (d, J¼5.8 Hz,
2H), 4.41 (d, J¼1.6 Hz, 2H), 5.78 (td, J¼5.9, 16.3 Hz, 1H), 6.00 (s, 1H),
6.84 (d, J¼16.3 Hz, 1H), 7.38–7.47 (m, 6H), 7.66–7.72 (m, 4H). 13C
NMR (100 MHz, CDCl3) d 19.7 (s), 27.2, 28.8 (s), 31.5, 63.6 (t), 64.5 (t),
76.6 (s), 106.7 (s), 108.5, 127.7, 128.2, 129.6, 130.2, 133.6 (s), 135.9,
144.9 (s). MS (ESI) m/z¼433.7 [MþH]þ, 455.7 [MþNa]þ. Anal. Calcd
for C28H36O2Si: C, 77.73; H, 8.39. Found: C, 77.85; H, 8.42.
4.7. (2E,4E)-4-(4,4-Dimethylpent-2-ynylidene)pent-2-ene-1,5-
diol (4)
1. By deprotection of the silyl ether 9: an ice cooled solution of 9
(0.080 g, 0.185 mmol) in THF (2 mL) under nitrogen was treated
with 1 M solution of TBAF (1.12 mL, 1.12 mmol) in THF. After 1 h, the
solution was allowed to warm to room temperature and the solvent
removed at reduced pressure. The residue was treated again with
the same TBAF solution (1.12 mL, 1.12 mmol) and reacted for 3 h,
after which time saturated NH4Cl (3 mL) was added and the
aqueous phase extracted with a 1:1 mixture of hexane/ethyl ace-
tate. The combined organic layers were dried (Na2SO4) and evap-
d
1.09 (s, 9H), 1.32 (s, 9H), 4.32 (d, J¼1.8 Hz, 2H), 6.47 (t, J¼1.8 Hz,
1H), 7.38–7.50 (m, 6H), 7.65–7.70 (m, 4H). 13C NMR (100 MHz,
CDCl3) 19.7 (s), 27.2, 28.8 (s), 31.3, 68.4 (t), 76.3 (s), 105.6 (s), 109.9,
d
128.3, 130.4, 133.1 (s), 134.4 (s), 135.9. MS (EI) m/z (% rel
intensity)¼454.1 (1.5) [Mþ, 79Br], 456.1 (1.5) [Mþ, 81Br], 397.0 (14.2)
[Mþ, 79Br], 399.0 (14.2) [Mþ, 81Br], 91.0 (100) [Mþ]. Anal. Calcd for
C25H31BrOSi: C, 65.92; H, 6.86. Found: C, 65.84; H, 6.84.
orated to give
a pale yellow solid. Purification by flash
4.5. (E)-4-((tert-Butyldiphenylsilyloxy)methyl)-8,8-
dimethylnona-4-en-2,6-diyn-1-ol (8)
chromatography (hexane/ethyl acetate 35:65) afforded the diol 4 as
a white solid; mp¼67–68 ꢁC (0.027 g, 75%). Rf 0.36 (hexane/ethyl
acetate 35:65), 0.44 (hexane/ethyl acetate 3:7). IR (neat, cmꢀ1
)
A solution of the vinyl bromide 7 (0.35 g, 0.77 mmol) in dry DMF
(1.5 mL) was alternatively evacuated and flushed with nitrogen. The
flask was cooled in ice and propargyl alcohol (0.054 mL,
0.92 mmol), tetrakis(triphenylphosphine) palladium (0.045 g,
0.039 mmol), cuprous iodide (0.029 g, 0.154 mmol), and piperidine
(0.152 mL, 1.54 mmol) were added in sequence. The reaction mix-
ture was allowed to warm to room temperature and after 4 h under
1051, 2208, 2218, 3255. 1H NMR (400 MHz, CDCl3)
d 1.31 (s, 9H),
1.57–1.68 (br s, 2H, exchanges with D2O), 4.31 (d, J¼5.6 Hz, 2H),
4.36 (s, 2H), 5.73 (s, 1H), 6.11 (td, J¼5.7, 16.2 Hz, 1H), 6.83 (d,
J¼16.3 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 28.8 (s), 31.4, 63.6 (t),
64.2 (t), 76.2 (s), 107.2 (s), 110.4, 127.6, 131.2, 145.4 (s). MS (ESI)
m/z¼195.3 [MþH]þ, 217.3 [MþNa]þ. Anal. Calcd for C12H18O2: C,
74.19; H, 9.34. Found: C, 74.20; H, 9.35.
stirring
a
second aliquot of propargyl alcohol (0.022 mL,
2. By hydrolysis of the dimethyl ester 12: to a solution of the
dimethyl ester 12 (0.400 g, 1.60 mmol) in dry toluene (6.4 mL)
maintained at ꢀ78 ꢁC under nitrogen was added dropwise 1 M n-
hexane solution of DIBALH (6.4 mL). When TLC analysis (hexane/
ethyl acetate 8:2) indicated consumption of the starting ester,
typically 1.5 h, the reaction mixture was allowed to warm to 0 ꢁC
and then quenched by addition of a water solution (5 mL) of tartaric
acid (0.160 g). The aqueous layer was extracted with three portions
of a 1:1 mixture of hexane/ethyl acetate and the combined organic
phases were dried over Na2SO4, filtered, and evaporated in vacuo to
give a pale yellow solid. Purification by flash chromatography
(hexane/ethyl acetate, 35:65) gave pure 4 as a white solid (0.265 g,
85%). Physical and spectroscopic data were identical to those of the
product obtained by the previous synthetic sequence.
0.385 mmol), tetrakis(triphenylphosphine) palladium (0.045 g,
0.039 mmol), and cuprous iodide (0.029 g, 0.154 mmol) were
added. After 24 h, the same amount of reagents as the second ali-
quot were added and the reaction mixture was stirred for further
12 h. The reaction was quenched by treatment with a saturated
NaHCO3 aqueous solution (7 mL). The aqueous layer was extracted
with ethyl acetate (3ꢂ10 mL) and the combined organic phases
were washed with water, dried over Na2SO4, and evaporated to give
a brown oil. Purification by flash chromatography (hexane/ethyl
acetate 85:15) afforded pure 8 as a brown oil (0.261 g, 79%). Rf 0.36
(hexane/ethyl acetate 85:15). IR (neat, cmꢀ1) 1105, 2196, 2220,
3335. 1H NMR (400 MHz, CDCl3)
d 1.09 (s, 9H), 1.33 (s, 9H),1.45–1.54
(br s, 1H, exchanges with D2O), 4.24 (d, J¼2.0 Hz, 2H), 4.43 (s, 2H),
6.24 (t, J¼2.0, 1H), 7.37–7.50 (m, 6H), 7.64–7.70 (m, 4H). 13C NMR
(100 MHz, CDCl3)
d
19.7 (s), 27.2, 28.2 (s), 31.4, 52.0 (t), 65.5 (t), 77.2
4.8. (2E,4E)-Dimethyl 4-(4,4-dimethylpent-2-ynylidene)pent-
(s), 82.9 (s), 94.7 (s), 106.5 (s), 114.8, 128.2, 130.3, 132.2 (s), 133.4 (s),
135.9. MS (ESI) m/z¼431.6 [MþH]þ, 453.6 [MþNa]þ. Anal. Calcd for
C28H34O2Si: C, 78.09; H, 7.96. Found: C, 78.12; H, 7.98.
2-enedioate (12)
1. By aldol condensation: a THF solution (2 mL) of the dimethyl
ester 11 (0.201 g, 1.27 mmol) was added dropwise at ꢀ78 ꢁC to
a 0.2 M solution of LDA (1.27 mmol) in THF, prepared from equi-
molar amounts of diisopropylamine and 1.6 M n-butyllithium in
hexane. After stirring for 30 min, a solution of 4,4-dimethylpent-2-
ynal (0.154 g, 1.40 mmol) in dry THF (1 mL) was added dropwise
and stirring at ꢀ78 ꢁC was continued for 1 h. The reaction was
allowed to warm to 0 ꢁC and then quenched by the addition of wet
silica gel (2.0 g). The suspension was filtered by suction washing
thoroughly with dichloromethane, ethyl acetate, and methanol.
Evaporation of the solvents gave a brown oil that was purified by
flash chromatography (hexane/ethyl acetate 9:1) to afford pure 12
4.6. (2E,4E)-4-((tert-Butyldiphenylsilyloxy)methyl)-8,8-
dimethylnona-2,4-dien-6-yn-1-ol (9)
A solution of the propargyl alcohol 8 (0.207 g, 0.48 mmol) in dry
THF (5 mL) under nitrogen was cooled to ꢀ30 ꢁC and treated with
a 65 wt % solution in toluene of sodium bis(2-methoxyethoxy)-
aluminum dihydride (0.230 mL, 0.77 mmol). After 1 h, the reaction
mixture was allowed to warm to room temperature and stirring
continued for additional 30 min. Saturated NH4Cl (8 mL) was cau-
tiously added and the aqueous layer extracted with Et2O. The

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L. Colombo et al. / Tetrahedron 65 (2009) 5838–5843
(0.137 g, 43%) as a pale yellow oil. 2. By transesterification: a solu-
tion of the di-tert-butylester 14 (0.1 g, 0.30 mmol) in dry MeOH
(10 mL) was treated with a catalytic amount of 96% H2SO4 and the
reaction mixture was heated at 80 ꢁC for 28 h. The solvent was
removed under vacuum and the residue taken up with ethyl ace-
tate, washed with a saturated solution of NaHCO3 and the aqueous
phase extracted with ethyl acetate. The combined organic layers
were dried with Na2SO4 and evaporated to give 0.071 g (95%) of the
dimethyl ester 12. Rf 0.36 (hexane/ethyl acetate 9:1), 0.70 (hexane/
ethyl acetate 7:3). IR (neat, cmꢀ1) 1717, 2189, 2207. 1H NMR
(0.46 mL, 3.30 mmol), freshly distilled methanesulfonyl chloride
(0.225 mL, 2.90 mmol), and solid TBAC (0.734 g, 2.64 mmol). After
1.5 h stirring, the reaction mixture was allowed to warm to room
temperature. Stirring was continued for 2 h, after which time the
reaction mixture was quenched by addition of water (4.8 mL). The
aqueous layer was extracted with CH2Cl2 and the combined organic
phases were dried over Na2SO4, filtered, and evaporated in vacuo to
give a pale yellow oil. The residue was flash chromatographed
(100% hexane) to afford the dichloride 10 as a colorless oil (0.244 g,
80%). Rf 0.30 (100% hexane). IR (neat, cmꢀ1) 1686, 2198, 2218. 1H
(400 MHz, CDCl3)
d
1.34 (s, 9H), 3.80 (s, 3H), 3.83 (s, 3H), 6.90 (s,
NMR (400 MHz, CDCl3) d 1.31 (s, 9H), 4.22–4.27 (m, 4H), 5.80 (s,1H),
1H), 6.92 (d, J¼16.0 Hz, 1H), 7.77 (d, J¼16.2 Hz, 1H). 13C NMR
6.15 (td, J¼7.0, 15.9 Hz, 1H), 6.83 (d, J¼15.9 Hz, 1H). 13C NMR
(100 MHz, CDCl3)
d
29.4 (s), 30.8, 52.1, 52.7, 76.9 (s), 119.4 (s), 123.6,
(100 MHz, CDCl3) d 28.9 (s), 31.2, 44.9 (t), 45.7 (t), 75.8 (s), 109.6 (s),
127.1, 134.8 (s), 137.2, 166.1 (s), 168.1 (s). MS (ESI) m/z¼251.3
[MþH]þ, 273.3 [MþNa]þ. Anal. Calcd for C14H18O4: C, 67.18; H, 7.25.
Found: C, 67.22; H, 7.27.
115.5,128.5, 129.4, 141.6 (s). MS (EI) m/z¼195.0, 197.0 (1:3) [MþꢀCl],
159 [MþꢀClꢀHCl]. Anal. Calcd for C12H16Cl2: C, 62.35; H, 6.98.
Found: C, 62.18; H, 6.96.
4.12. (2E,4E)-4-(4,4-Dimethylpent-2-ynylidene)-N1,N5-
dimethyl-N1,N5-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-
diamine (1)
4.9. (E)-Di-tert-butyl pent-2-enedioate (14)
To a solution of (E)-pent-2-enedioic acid (0.200 g, 1.54 mmol) in
dry t-BuOH (4 mL) under nitrogen, di-tert-butyl dicarbonate
(0.672 mg, 3.08 mmol) and DMAP (0.056 g, 0.456 mmol) were
added sequentially at room temperature. When TLC analysis
(hexane/ethyl acetate 8:2) indicated consumption of di-tert-butyl
dicarbonate (Rf 0.65), typically 3 h, two more equivalents of the
above reagent were added and stirring was continued for 2 h. The
reddish mixture was evaporated under vacuum and the residue
flash chromatographed (hexane/ethyl acetate 85:15) to afford
0.272 g of the di-tert-butylester 14 (74%) as colorless oil. Rf 0.60
A solution of the dichloride 10 (0.125 g, 0.54 mmol) and N-
methyl-1-(naphthalen-1-yl)methanamine (0.370 g, 2.16 mmol) in
freshly distilled DMF (1.5 mL) was stirred under nitrogen for 24 h
and then diluted with saturated aqueous NaHCO3 (15 mL). The
crude mixture was extracted with three portions of ethyl acetate.
The combined organic layers were washed with water, dried
(Na2SO4), and evaporated to give a brownish oil. Purification by
flash chromatography afforded 0.243 g (90%) of the final product 1.
Rf 0.36 (hexane/ethyl acetate 89:11). IR (neat, cmꢀ1) 2194, 2211. 1H
(hexane/ethyl acetate 85:15). IR (neat, cmꢀ1) 1655, 1713, 1732. 1
NMR (400 MHz, CDCl3)
1.47 (s, 9H), 1.49 (s, 9H), 3.13 (dd, J¼1.5,
7.2 Hz, 2H), 5.83 (td, J¼1.5, 15.6 Hz, 1H), 6.89 (td, J¼7.2, 15.6 Hz, 1H).
H
d
NMR (400 MHz, CDCl3)
d 1.29 (s, 9H), 2.19 (s, 3H), 2.20 (s, 3H), 3.17
(d, J¼6.9 Hz, 2H), 3.23 (s, 2H), 3.85 (s, 2H), 3.90 (s, 2H), 5.67 (s, 1H),
6.12 (td, J¼6.7, 15.8 Hz, 1H), 6.80 (d, J¼15.9 Hz, 1H), 7.33–7.53 (m,
8H), 7.70–7.90 (m, 4H), 8.22–8.31 (m, 2H). 13C NMR (100 MHz,
13C NMR (100 MHz, CDCl3)
d 28.4, 28.5, 39.0 (t), 80.8 (s), 81.8 (s),
126.5, 139.4, 165.6 (s), 169.7 (s). MS (ESI) m/z¼243.3 [MþH]þ, 265.3
[MþNa]þ. Anal. Calcd for C13H22O4: C, 64.44; H, 9.15. Found: C,
64.62; H, 9.17.
CDCl3) d 28.8 (s), 31.6, 42.9, 43.1, 60.6 (t), 61.1 (t, 2C), 61.3 (t), 77.0 (s),
106.0 (s), 110.8, 125.2, 125.3, 125.6 (2C), 126.0 (2C), 126.2, 126.3,
127.8, 127.9, 128.3, 128.4, 128.8, 128.9, 130.4, 130.9, 132.9 (s), 133.0
(s), 134.3 (s), 134.4 (s), 135.3 (s), 135.4 (s), 144.8 (s). MS (ESI)
m/z¼501.7 [MþH]þ, 523.7 [MþNa]þ. Anal. Calcd for C36H40N2: C,
86.35; H, 8.05. Found: C, 86.54; H, 8.08.
4.10. (2E,4E)-Di-tert-butyl 4-(4,4-dimethylpent-2-
ynylidene)pent-2-enedioate (15)
A THF solution (1.5 mL) of di-tert-buthylester 14 (0.208 g,
0.86 mmol) was added dropwise at ꢀ78 ꢁC to a 0.2 M solution of
LDA (1.03 mmol), prepared from equimolar amounts of diisopro-
pylamine and 1.6 M n-butyllithium in hexane. After stirring for
30 min, a solution of 4,4-dimethylpent-2-ynal (0.104 g, 0.95 mmol)
in dry THF (0.6 mL) was added dropwise and stirring at ꢀ78 ꢁC was
continued for 1 h. The reaction mixture was allowed to warm to
0 ꢁC and then quenched by the addition of wet silica gel (2.0 g). The
suspension was filtered by suction washing abundantly with
dichloromethane, ethyl acetate, and methanol. Evaporation of the
solvents gave a pale yellow solid that was purified by flash chro-
matography (hexane/ethyl acetate 9:1) to afford pure 15 (0.242 g,
85%) as a white solid, mp¼97–98 ꢁC. Rf 0.70 (hexane/ethyl acetate
9:1). IR (neat, cmꢀ1) 1617, 1710, 2194, 2210. 1H NMR (400 MHz,
Acknowledgements
We thank Dipharma Francis S.r.l. and FAR (Pavia University) for
financial support.
Supplementary data
NOESY spectra of compound 9 and copy of 1H/13C NMR spectra
for products 1, 4–10, and 12–15. Supplementary data associated
with this article can be found in the online version, at doi:10.1016/
j.tet.2009.04.095.
References and notes
CDCl3)
d 1.34 (s, 9H), 1.52 (s, 9H), 1.53 (s, 9H), 6.78 (s, 1H), 6.82 (d,
J¼16.2 Hz, 1H), 7.62 (d, J¼16.2 Hz, 1H). 13C NMR (100 MHz, CDCl3)
1. Roy, J. AAPS PharmSciTech 2002, 3 article 6 and reference cited therein.
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5. (a) Rossi, R.; Bellina, F.; Carpita, A.; Gori, R. Gazzetta 1995, 125, 381–392; (b) Org.
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d
28.5, 28.6, 29.3 (s), 30.9, 77.0 (s), 80.6 (s), 82.2 (s), 117.8 (s), 125.2,
125.9, 136.1, 136.8 (s), 165.0 (s), 166.9 (s). MS (ESI) m/z¼335.4
[MþH]þ, 357.4 [MþNa]þ. Anal. Calcd for C20H30O4: C, 71.82; H, 9.04.
Found: C, 71.83; H, 9.03.
`
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CH2Cl2 (6.6 mL) under nitrogen were added distilled triethylamine

L. Colombo et al. / Tetrahedron 65 (2009) 5838–5843
5843
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11. The following methods were tried starting from glutaconic acid: DCC, t-BuOH; t-
BuOAC, HClO4; t-BuOAC, H2SO4; t-BuOAC, TfOH; Tf2O, t-BuOH; isobutene, H2SO4.
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