Convenient methods for the synthesis of highly functionalized and naturally occurring chiral allenes

Article abstract of DOI:10.1016/j.tetasy.2014.11.002

A convenient two step procedure to access highly functionalized chiral allenes using chiral N-methylcamphanyl piperazine derivatives is described. In this transformation, chiral propargylamines are obtained in 79-96% yields with up to 99:1 dr by the CuBr catalyzed reactions of chiral piperazine derivatives with 1-alkynes and aldehydes containing functional groups, which are converted into chiral allenes in the presence of zinc bromide, affording the chiral allenes in 59-85% yields and with up to 99% ee. The antifungal agent Sapium japonicum and an allene precursor intermediate for the synthesis of the pheromone of the male dried bean beetle 15 are obtained in 72-78% yields and with up to 98% ee following this methodology.

Full text of DOI:10.1016/j.tetasy.2014.11.002

Tetrahedron: Asymmetry 25 (2014) 1634–1646
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Convenient methods for the synthesis of highly functionalized
and naturally occurring chiral allenes
⇑
Mariappan Periasamy , Polimera Obula Reddy, Nalluri Sanjeevakumar
School of Chemistry, University of Hyderabad, Central University P.O., Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 October 2014
Accepted 3 November 2014
A convenient two step procedure to access highly functionalized chiral allenes using chiral N-methylcam-
phanyl piperazine derivatives is described. In this transformation, chiral propargylamines are obtained in
79–96% yields with up to 99:1 dr by the CuBr catalyzed reactions of chiral piperazine derivatives with 1-
alkynes and aldehydes containing functional groups, which are converted into chiral allenes in the pres-
ence of zinc bromide, affording the chiral allenes in 59–85% yields and with up to 99% ee. The antifungal
agent Sapium japonicum and an allene precursor intermediate for the synthesis of the pheromone of the
male dried bean beetle 15 are obtained in 72–78% yields and with up to 98% ee following this
methodology.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
ral allenes using chiral N-methylcamphanyl piperazine templates
(Scheme 1).4
In recent years, allenes have become highly valuable intermedi-
ates for target-oriented synthesis because they have proven appli-
cation in various transformations with high levels of structural
diversity.1 Hence, 1,3-disubstituted chiral allenes containing func-
tional groups play a significant role in organic synthesis, since they
can be converted under mild conditions into biologically active
compounds.2 Therefore, the introduction of allene as a functional
group into the existing backbone of pharmacologically active com-
pounds could be expected to result in interesting new biological
properties.3 As part of our ongoing research on the synthesis of chi-
ral allenes following the ‘chiral amine approach’, we have recently
reported the enantioselective synthesis of both enantiomers of chi-
Although, this method is useful to access several chiral allenes,
the longer reaction time and higher temperature required may
pose problems in the synthesis of allenes containing sensitive
functional groups. Moreover, methods available for the synthesis
of chiral allenes containing sensitive functional groups are still lim-
ited and many reported methods involve multistep operations
using expensive reagents.5–8 Therefore, it is highly desirable to
develop an efficient and simple method for the synthesis of chiral
allenes containing functional groups. Herein, we describe detailed
studies on the methods of synthesis of highly functionalized chiral
allenes via chiral propargylamine intermediates by using the
N-methylcamphanyl piperazine templates 1 and 2.
ZnBr2 (60 mol%)
ZnBr2 (60 mol%)
N
R2 R2
H
H
N
R2-CHO
R2-CHO
•
•
toluene, 120 o
2- 10 h
C
toluene, 120 oC
2- 10 h
R1
H
R1
N
H
H
N
H
1
(S)-isomer
(R)-isomer
2
+
+
R1
R1
Scheme 1.
⇑
Corresponding author.
E-mail address: mpsc@uohyd.ernet.in (M. Periasamy).
http://dx.doi.org/10.1016/j.tetasy.2014.11.002
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

M. Periasamy et al. / Tetrahedron: Asymmetry 25 (2014) 1634–1646
1635
chiral propargylamines 6ea, 6ec, 6ed, and 6ee in 86–95% yields
with excellent diastereoselectivity (Table 1). Diethyl 2-acetam-
ido-2-propargylmalonate 3g reacts with aldehydes 4a and 4d to
give the corresponding propargylamines 6ga, 6gd in 86–94% yields
and with 96:4, 99:1 dr, respectively. Also, the reaction of N-tosyl
alkyne 3h and with the aldehydes 4a and 4d gives the correspond-
ing propargylamines 6ha and 6hd in 91–96% yields with good dia-
stereoselectivity (Table 1). Similarly, the unprotected 1-alkyne 3k
containing an alcohol functional group reacts with the aldehydes
4a and 4b to give the corresponding propargylamines 6ka, and
6kb with reasonable yields and with good diastereoselectivity.
The configuration at the newly formed stereogenic center in
propargylamines 6 was assigned as (S). We have previously
reported that the chiral bispropargylamine 9 obtained using the
parent chiral camphanylpiperazine 8, had an (R)-configuration at
the new propargyl stereogenic center adjacent to the (S)-campha-
nylamine moiety and an (S)-configuration at the other propargyl
center adjacent to the (R)-camphanylamine moiety, based on sin-
gle crystal X-ray structure analysis (Fig. 1).4b We have also
reported that chiral propargylamine 12, prepared using chiral
N-methylcamphanyl piperazine 1, had an (S)-configuration at the
new propargyl stereogenic center adjacent to the (R)-camphanyl
amine moiety based on single crystal X-ray structure analysis
(Fig. 1).4b These structural assignments are in accordance with
the expected transition states of alkynylzinc addition to the imin-
ium ion intermediates 10 and 11 (Fig. 1). Therefore, the assignment
of the (S)-configuration for the new stereogenic center in propar-
gylamines 6 is in accordance with the expected mechanism of
alkynyl copper addition to the corresponding iminium ion inter-
mediate as this mode of addition would be similar to the addition
2. Results and discussion
We observed that the reaction between ethyl propiolate 3a and
piperazine 1 gives the Michael addition product 5 in 99% yield
(Scheme 2).
Presumably, the formation of the Michael addition product 5 is
due to conjugation between the ester group and the triple bond. To
examine this, we chose methyl-5-hexynoate as the alkyne 3b part-
ner in this reaction. However, in this case, we isolated the amide
derivative 7 in 28% yields along with the propargylamine 6ba in
62% yield with 99:1 dr (Scheme 3).
Very recently, a CuBr promoted method has been reported for
the diastereoselective synthesis of chiral propargylamines which
upon reaction with CuI gave the corresponding chiral allenes.9
We observed that the reaction between methyl-5-hexynoate 3b,
benzaldehyde 4a, and chiral camphanylpiperazine 1 using CuBr
(10 mol %) gives the corresponding propargylamine 6ba in 98%
yield with 99:1 dr (Scheme 4). The procedure is also useful for chi-
ral propargylamines with other sensitive functional groups
(Table 1).
The alkynes containing ester, amide, or alcohol groups are
compatible with the present reaction conditions 3c–3l. Chiral
piperazine 1 reacted with diethyl 2-(prop-2-ynyl)malonate 3c
and t-butyraldehyde 4d to give the corresponding propargylamine
6cd in 81% yield and with up to 99:1 dr (Table 1). The reaction of
chiral piperazine 1 with t-butyraldehyde 4d and dimethyl propar-
gylmalonate 3d yielded the product 6dd in 89% with 97:3 dr. The
reaction is also applicable to substituted dimethyl propargylmalo-
nate as illustrated by the reactions using alkynes 3e and 3f, which
react with aldehydes 4a, 4c, 4d, and 4e to give the corresponding
N
N
ZnCl2 (10 mol%)
EtO2C
H
Ph-CHO
+
+
toluene, 110 oC, 1 h
N
H
N
3a
4a
1
CO2Et
5
99% yield
Scheme 2.
(CH2)3CO2Me
N
N
N
N
N
ZnCl2 (10 mol%)
3b
+
+
toluene, 110 oC, 4 h
N
H
Ph-CHO
4a
1
Ph
O
(CH2)3CO2Me
7
6ba
28% yield
62% yield
99:1dr
Scheme 3.
(CH2)3-CO2Me
N
N
CuBr (10 mol%)
3b
+
toluene, 25 oC,
24 h
N
H
N
Ph-CHO
(S)
4a
1
Ph
6ba
(CH2)3-CO2Me
98% yield
99:1 dr
Scheme 4.

1636
Table 1
M. Periasamy et al. / Tetrahedron: Asymmetry 25 (2014) 1634–1646
Diastereoselective synthesis of propargylamines 6 using chiral piperazine 1, with different 1-alkynes 3 and aldehydes 4 in the presence of copper bromidea,b,c
R2
R1
N
N
X
CuBr (10 mol%)
R1
R3-CHO
H
+
+
Toluene, 25 oC, 24 h
N
N
H
4
R1
3
1
R2
R3
X
6
R1
1
(X= C, R = COOEt, R2 = Me)
3c =
3h= (X= N, R1 = tosyl, R2 = Me)
4a = PhCHO
3d= (X= C, R1 = COOMe, R2 = H)
3e= (X= C, R1 = COOMe, R2 = Me)
3i= (X= N, R1 = tosyl, R2 = benzyl)
3j= (X= N, R1 = SO2C6H4-p-Cl, R2 = Me)
3k= (X= C, R1 = H, R2 = OH)
4b =
p-F-C6H4CHO
4c =
PhCH2CH2CHO
(X= C, R1 = COOMe, R2 = benzyl)
3f =
3g=
4d = t-BuCHO
(X= C, R1 = COOEt, R2 = NHCOCH3)
4e
=
c-C6H11CHO
3l = (X= C, R1 = -(CH2)5-, R2 = OH)
N
N
N
N
N
N
N
N
COOEt
COOMe
COOMe
COOMe
COOMe
COOMe
Ph
COOEt
6ea
6cd
6dd
COOMe
6ed
81% y
89% y
91% y
86% y
99:1dr
97:3 dr
98:2 dr
96:4 dr
N
N
N
N
N
N
N
N
COOMe
COOMe
COOMe
COOMe
COOEt
Ph
COOMe
COOMe
Ph
COOEt
6ec
6ee
6fd
Ph
6ga
NHCOCH3
86% y
95% y
97:3 dr
93% y
94% y
96:4 dr
99:1 dr
99:1 dr
N
N
N
N
N
N
N
N
Ph
TS
COOEt
COOEt
Ph
Ph
N
N
N
TS
TS
6ia
6gd
6hd
6ha
NHCOCH3
86% y
91% y
89% y
96% y
96:4 dr
98:2 dr
98:2 dr
99:1 dr
N
N
N
N
N
N
N
N
SO2C6H4p-Cl
Ph
p-F-C6H4
N
OH
OH
OH
6jd
6ka
6kb
6le
91% y
79% y
82% y
87% y
95:5 dr
98:2 dr
96:4 dr
99:1 dr
a
The reactions were carried out by using chiral piperazine 1 (1.0 mmol), 1-alkyne (1.1 mmol), and aldehyde (1.0 mmol) in toluene (3 mL) with CuBr (10 mol %) at
25 °C for 24 h.
b
dr ratio based on 1H NMR crude sample.
Isolated yield.
c
of alkynylzincs to the iminium intermediate 11, which gave prod-
uct 12 with an (S)-configuration at the new stereogenic center
(Fig. 1).4b,9,10 It is noteworthy that chiral camphanyl propargylam-
We next carried out experiments for the conversion of the chiral
propargylamines into the corresponding chiral allenes. When ZnI2
(50 mol %) was used as the metal salt for the conversion of chiral
propargylamine 6ba in toluene, the expected allene product (R)-
13ba was obtained in 79% yield with 89% ee. We optimized the
ines 6 and 12, which have an (S)-configuration at the propargyl
25
stereogenic center, gave [
a]
values in the range of À29 to À55.
D

M. Periasamy et al. / Tetrahedron: Asymmetry 25 (2014) 1634–1646
1637
Ph
Ph
Similar results were observed with the amide derivatives of prop-
argylamines 6ga and 6gd in 73–85% yields and with 99% ee. Mod-
erate yields and ees were realized in the reaction with alcohol
derivatives 6ka, 6kb, and 6le (Table 3).
Ph
H
Ph
H
(R)
H
N
(R)
All of the optically active allenes obtained by using N-methyl-
camphanyl piperazine 1 are levorotatory, from which the absolute
configurations of the major enantiomer of the allenes were
(R)
(S)
(R)
(S)
N
Zn
N
+
(S)
(R)
(R)
(R)
N
H
N
N
H
(S)
(S)
(S)
Ph
Ph
assigned as (R) by the Lowe–Brewster rule and also by comparison
H
values.12
25
8
(S)
10
with the reported [
a]
D
9
When the reaction was performed with isomeric chiral pipera-
zine 2 with diethyl 2-acetamido-2-propargylmalonate 3g and
benzaldehyde 4a, the desired propargylamine 14ga was isolated
in only 27% yield even after a prolonged reaction time of 48 h. It
was noticed that the chiral piperazine 2 reacted with the substi-
tuted alkyne 3e and aldehyde 4a to give the corresponding propar-
gylamine 14ea with very low yield (22%). From these observations,
it is apparent that the lower reactivity may be due to the steric hin-
drance between the C10 methyl group of camphanyl piperazine 2
and the substituent groups in the alkyne partner. Fortunately,
when the reaction mixture was heated at 45 °C for 24 h, the prop-
argylamine product 14ea was obtained in 89% yield in 99:1 dr
(Scheme 5). The configuration at the newly formed stereogenic
center in propargylamines 14ea and 14ga was assigned as (R) since
the mechanism of the alkynyl copper addition to the corresponding
iminium ion intermediates would be similar to the addition of an
alkynylzinc to the iminium intermediate 10 as outlined in Fig-
ure 1.4b,9,10 It is of interest to note that although the propargylam-
ines 6 and 14 are diastereomers, the propargylamines 6 with an
(S)-configuration at the new propargyl stereogenic center exhibit
(R)
H
N
N
N
(R)
(S)
(R)
(S)
+
(S)
(R)
N
Ph
Zn
Ph
(S)
H
(S)
H
12
Ph
11
Ph
Fig. 1.
Table 2
Conversion of propargylamine 6ba into chiral allene (R)-13ba using different metal
saltsa
H
Ph
H
N
N
metal salts
•
negative [
a
]
25 values in the range of À29 to À55, while propargyl-
D
solvent, time
MeO2C-(H2C)3
amines 14ea and 14ga with an (R)-configuration at the new prop-
argyl stereogenic center gave positive [
(S)
25
13ba
(R)-
a
]
values of +43.6 and
D
Ph
+39.1, respectively.
(CH2)3-CO2Me
We also carried out the conversion of chiral propargylamine
derivatives 14ea and 14ga obtained from piperazine 2 into the cor-
responding chiral allenes (Scheme 5).
The optically active allenes obtained by using N-methylcam-
phanyl piperazine 2 are dextrorotatory from which the absolute
configurations of the major enantiomer of the chiral allenes were
6ba
S. No.
Solvent
Temp
MXn
Mol (%) Time
(h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
CH3CN
Toluene
Toluene
Toluene
Dioxane
120
120
120
50
120
120
120
100
ZnI2
50
50
50
50
50
50
50
50
1
2
79
72
51
35
25
19
5
89
99
99
99
98
99
99
99
ZnBr2
ZnCl2
AgNO3
CuI
CuBr
CuCl
CuI
12
24
12
12
12
18
assigned as (S) by the Lowe–Brewster rule and also by comparison
25
with the reported [
a]
values.12
D
Next, we turned our attention toward the synthesis of naturally
occurring allenes by applying this methodology as none of the bio-
logically active allenes were synthesized so far using chiral propar-
gylamine as precursors.6 We chose the Sapium japonicum 13mf, a
reported antifungal agent containing an allenic moiety as the tar-
get. Several synthetic approaches have been reported for the syn-
thesis of this allene in racemic as well as in enantiomerically
pure form involving an SN2 reaction,6a Claisen rearrangement,6b
and 1,2-elimination of alkenyl halides.6d We observed that chiral
piperazine 1 reacts with 5-oxo-pentanoic acid methyl ester 4f
and TBS alkyne 3m in the presence of 10 mol % CuBr to give the
chiral propargylamine derivate 6mf in 98% yield with 99:1 dr
which upon reaction with ZnBr2 followed by desilylation afforded
(R)-13mf in 78% yield with 98% ee (Scheme 6).6d It is noteworthy
that compound (R)-13mf has previously been synthesized by a
multistep method with low enantioselectivity.
Compound methyl (R,E)-2,4,5-tetradecatrienoate 15 is a phero-
mone component of the male dried bean beetle. We observed that
chiral piperazine 1 reacts with 1-decyne 3n and 4-oxo-butyric acid
methyl ester 4g in the presence of CuBr in toluene to give chiral
propargylamine derivative 6ng in 93% yield with 99:1 dr. This
propargylamine intermediate 6ng reacts with ZnBr2 to give (R)-
13ng allene in 72% yield (Scheme 7). Unfortunately, chiral HPLC
columns available to us failed to separate the enantiomers of
13ng. However, comparison of the specific rotation of
39
a
The reactions were carried out by using propargylamine 6ba (1 mmol) in
solvent (3 mL).
b
Yields are isolated.
The % ee was confirmed by HPLC analysis on chiralcel AS-H.
c
reaction conditions by examining the effect of various metal salts
and solvents for the conversion of chiral into chiral allene (R)-
13ba (Table 2).11
We observed that the use of CuCl, CuBr, and CuI gave poor
results as in these cases, (R)-13ba allene was obtained in only
5–39% yield with 99% ee (entries 5–8, Table 2). Similarly, allene
(R)-13ba was obtained in only 35% yield with 99% ee when AgNO3
was used (entry 4, Table 2). The zinc halides gave the allene in 51–
79% yield with 89–99% ee (entries 1–3, Table 2) while the use of
ZnBr2 (0.5 mmol) gave the optimum results (72% yield with 99%
ee) in a shorter reaction time of 2 h.
Next, we examined the conversion of propargylamine deriva-
tives into chiral allenes by following the conditions optimized for
6ba (Table 2, entry 2). We have observed that the reaction of the
ester derivatives of propargylamines 6cd–6fd with ZnBr2 gave
(R)-allenes 13cd–13fd in 65–77% yields with 90–99% ee (Table 3).

1638
M. Periasamy et al. / Tetrahedron: Asymmetry 25 (2014) 1634–1646
Table 3
ZnBr2 promoted synthesis of chiral allenes from chiral propargylaminesa,b,c
N
H
R3
H
R1
R1
R2
•
ZnBr2 (50 mol%)
N
toluene, 120 o
C
X
R1
R2
R3
X
13
R1
6
6cd = (X= C, R1 = COOEt, R2 = Me, R3
=
t-BuCHO)
6gd = (X= C, R1 = COOEt, R2 = NHCOCH3, R3 = t-BuCHO)
6dd = (X= C, R1 = COOMe, R2 = H, R3 = t-BuCHO)
6ed = (X= C, R1 = COOMe, R2 = Me, R3 = t-BuCHO)
6ha = (X= N, R1 = tosyl, R2 = Me, R3
6hd =
=
PhCHO)
(X= N, R1 = tosyl, R2 = Me, R3
=
t-BuCHO)
6jd = (X= N, R1 = SO2C6H4-p-Cl, R2 = Me, R3 = t-BuCHO)
6ia =
(X= C, R1 = COOMe, R2 = Me, R3 = PhCHO)
6ec = (X= C, R1 = COOMe, R2 = Me, R3 = Ph(CH2)2CHO)
6ee =
6ea =
(X= N, R1 = tosyl, R2 = benzyl, R3 = Ph)
6ka = (X= C, R1 = H, R2 = CH2OH, R3 = PhCHO)
(X= C, R1 = COOMe, R2 = Me, R3 = c-C6H11CHO)
6fd = (X= C, R1 = COOMe, R2 = benzyl, R3 = t-BuCHO))
6ga =
6kb = (X= C, R1 = H, R2 = CH2OH, R3 = p-F-C6H4CHO)
6le = (X= C, R1 = -(CH2)5-, R2 = OH, R3 = c-C6H11CHO)
(X= C, R1 = COOEt, R2 = NHCOCH3, R3 = PhCHO)
H
H
H
H
Ph
H
MeOOC
MeOOC
•
EtOOC
EtOOC
•
MeOOC
MeOOC
•
MeOOC
MeOOC
•
H
H
H
13cd
13ed
13ea
13dd
2 h, 72% y, 99% ee
2 h, 69% y, 96% ee
2 h, 77% y, 99% ee
2 h, 77% y, 96% ee
Ph
H
H
H
Ph
H
MeOOC
MeOOC
•
MeOOC
MeOOC
•
EtOOC
EtOOC
H3COCHN
•
MeOOC
MeOOC
•
H
H
H
H
13ec
13ee
13ga
13fd
Ph
2 h, 65% y, 89% ee
2 h, 85% y, 98% ee
2 h, 68% y, 99% ee
2 h, 71% y, 99% ee
H
H
Ph
H
H
EtOOC
EtOOC
•
•
•
•
13jd
H
TS
N
H
TS
N
H
p-ClC6H4O2SN
H
13ha
13hd
13gd
H3COCHN
3 h, 69% y, 98% ee
2 h, 73% y, 99% ee
3 h, 78% y, 99% ee
3 h, 72% y, 99% ee
H
Ph
H
H
C6H4-p-f
H
Ph
H
H
•
•
•
HO
•
TSN
Ph
H
H
13ia
13ka
13le
HO
HO
13kb
3 h, 73% y, 96% ee
2 h, 65% y, 94% ee
2 h, 59% y, 82% ee
2 h, 72% y, 98% ee
a
b
c
The reactions were carried out by using propargylamine 6 in toluene (3 mL) with ZnBr2 (0.5 mmol).
Isolated yield.
ee was determined by using chiral HPLC.
[
a
]
25 = À61.5 (c 0.73, hexane) observed for product (R)-13ng
intermediate 19. Delivery of the alkynyl group from the bottom
face of the iminium group would lead to a new (S)-stereogenic cen-
ter at the propargylamine product 20 which could complex with
ZnBr2 to give 22 that could then undergo a hydride shift to give chi-
ral allene (R)-8 via the intermediate 23 (Scheme 8).
D
(Scheme 7) with the reported rotation of [
a]
25 = À63.3 (c 2.07, hex-
D
ane) indicates that its purity was 693% ee. This chiral allene (R)-
13ng precursor has been previously converted into pheromone
15 in two steps (Scheme 7).6f
The formation of propargylamines in the reaction of 1-alkynes,
aldehydes, and chiral camphanyl piperazines followed by allene
transformation can be explained by the mechanism outlined in
Scheme 8. Initially chiral piperazine 1 reacts with CuBr to form
the dimeric coper complex 16.10 Then, reaction with 1-alkyne gives
intermediate complex 16, which in turn reacts with the intermedi-
ate imine obtained from the aminal 18, formed in situ by the reac-
tion of the chiral piperazine and aldehyde to generate the
We also found that the imine by-products 24 could be easily
converted in situ to the corresponding chiral piperazines in 69%
yield by simple sodium borohydride reduction.
3. Conclusion
We have developed a method for the synthesis of highly func-
tionalized chiral propargylamine derivatives via the CuBr promoted

M. Periasamy et al. / Tetrahedron: Asymmetry 25 (2014) 1634–1646
1639
COOMe
COOMe
N
N
Ph
H
H
CuBr (10 mol%)
ZnBr2 (50 mol%)
•
COOMe
COOMe
toluene, 120 oC,
1 h
toluene, 45 oC,
24 h
+
N
H
3e
N
(R)
(S)-13ea
Ph-CHO
Ph
2
62% yield
4a
99% ee
COOMe
14ea
COOMe
89% yield,
99:1 dr
COOEt
N
Ph
H
H
N
CuBr (10 mol%)
ZnBr2 (50 mol%)
COOEt
NHCOCH3
•
COOEt
COOEt
toluene, 120 oC,
2 h
toluene, 45 oC,
36 h
N
H
N
+
3g
(R)
NHCOCH3
(S)-13ga
Ph
2
PhCHO
69% yield
COOEt
14ga
99% ee
4a
COOEt
NHCOCH3
78% yield, 99:1 dr
Scheme 5.
N
O
O
N
H
O
1
1) ZnBr2 (50 mol%),
toluene, 120 oC, 1 h
N
H
H
CuBr (10 mol%)
toluene, 25 oC,
24 h
TBSO
•
+
2) desilylation
N
HO
H
O
(S)
O
(R)-13mf
3m
4f
98% ee
6mf
O
78% yield
OTBS
O
Sapium japonicum,
antifungal activity
98% yield
99:1 dr
Scheme 6.
O
O
n-C8H17
3n
N
N
H
N
ZnBr2 (50 mol%)
CuBr (10 mol%)
toluene, 25 oC,
24 h
•
+
toluene
n-C8H17
H
N
H
120 oC, 1 h
(
S
)
O
CHO
O
1
(R)-13ng
4g
O
n-C8H17
6ng
O
72% yield
93% yield
99:1 dr
O
O
H
•
n-C8H17
H
15
dried bean beetles
insect pheromone
Scheme 7.
diastereoselective reaction of 1-alkynes and aldehydes containing
sensitive functional groups using the chiral N-methylcamphanyl
piperazine derivatives 1 and 2. These chiral propargylamine deriv-
atives are converted into chiral allenes using zinc bromide with
high enantiomeric purities. We have also synthesized the naturally
occurring chiral allene Sapium japonicum (R)-13mf and an
advanced allene precursor intermediate (R)-13ng previously used
in the synthesis of the pheromone male dried bean beetle 15 by
using the ‘chiral amine approach’. Accordingly, the methods
described here have considerable potential to access biologically
active chiral allenes containing sensitive functional groups via the
corresponding chiral propargylamines.

1640
M. Periasamy et al. / Tetrahedron: Asymmetry 25 (2014) 1634–1646
R4
H
N
Br
N
N
CuBr
3
Cu
Cu
N
N
H
N
N
H
Br
N
H
H
Cu
Br
1
16
R4
17
H
N
N
R3CHO
+
N
N
H2O
H
4
1
R3
18
OH
N
..
N
N
N
N
N
Cu
R2
Br
R3
H
N
N
H
21
H
R3
H
R4
20
1
19
R1
ZnBr 2
R4
N
N
H
R1
R2
H
1,5-hydride
shift
N
..
+
H
•
+
N
N
H
N
R2
R2
H
ZnBr2
R1
H
22
H
Br-
24
(R)-8
R1
Zn
Br
23
ZnBr
Br
Br-
Scheme 8.
distilled over sodium-benzophenone ketyl before use. Analytical
thin layer chromatographic tests were carried out on glass plates
4. Experimental
4.1. Materials and methods
(3 Â 10 cm) coated with 250
lm acme’s silica gel-G and GF254 con-
taining 13% calcium sulfate as binder. The spots were visualized by
short exposure to iodine vapor or UV light. Column chromatogra-
phy was carried out using acme’s silica gel (100–200 or 230–400
mesh) and neutral alumina.
Melting points were determined using a Superfit capillary point
apparatus. IR (KBr) spectra were recorded on JASCO FT-IR spectro-
photometer Model 5300. The neat IR spectra were recorded on
JASCO FT-IR spectrophotometer Model 5300 and SHIMADZU FT-
IR spectrophotometer Model 8300 with polystyrene as reference.
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded
on Bruker-AC-200 and Bruker-Avance-400 spectrometers, respec-
tively with chloroform-d as solvent and TMS as reference
(d = 0 ppm). The chemical shifts are expressed in d downfield from
the signal of internal TMS. Liquid chromatography (LC) and mass
analysis (LC–MS) were performed on SHIMADZU-LCMS-2010A.
The mass spectral analyses were carried out using Chemical Ioniza-
tion (CI) or Electro spray Ionization (ESI) techniques. Elemental
analyses were carried out using a Perkin–Elmer elemental analyzer
model-240C and Thermo Finnigan analyzer series Flash EA 1112.
Mass spectral analyses for some of the compounds were carried
out on VG 7070H mass spectrometer using EI technique at 70 eV.
Optical rotations were measured on Rudolph Research Analytical
AUTOPOL-II (readability 0.01°) and AUTOPOL-IV (readability
0.001°) automatic polarimeters. The conditions of the polarimeter
were checked by measuring the specific rotation of standard (S)-
(À)-diphenyl prolinol, 99% ee (DPP) which was purchased from
Gerchem Labs (P) Ltd. Hyderabad. Analytical grade ZnCl2 and ZnBr2
purchased from E-Merck, India and Nice Chemicals Pvt Ltd, Indi,
respectively were used. ZnI2 was purchased from Sigma Aldrich.
Powdered zinc halide samples were heated at 120 °C under
reduced pressure (0.001 mm Hg) in a vacuum oven and stored
under dry nitrogen. Toluene supplied by E-Merck, India was freshly
4.1.1. Reaction of 1-alkyne, aldehyde, and the chiral piperazine
1 with CuBr: synthesis of chiral propargylamine 6
To a stirred suspension of chiral piperazine 1 or 2 (0.210 g,
1 mmol), CuBr (0.014 g, 0.1 mmol), and 1-alkyne 3 (1.1 mmol) in
toluene (3 mL), freshly distilled aldehyde 4 (1 mmol) was added
at 25 °C. The contents were stirred at 25 °C for 24 h. Toluene was
then removed after which water (5 mL) and DCM (15 mL) were
added. The DCM layer was washed with saturated NaCl solution,
dried (Na2SO4), and concentrated. The residue was purified by col-
umn chromatography using hexane and ethyl acetate (9:1) as
eluent to isolate the propargyl amines 6.
4.1.2. 7-Phenyl-7-(4,5,9,9-tetramethyl-octahydro-5,8-methano-
quinazolin-1-yl)-hept-5-ynoic acid ethyl ester 6ba
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield:
0.413 g, 98%, [
a
]
25 = À51.1 (c 0.43, CHCl3); IR(neat) 2951, 2874,
D
2793, 2762, 2704, 1739, 1660, 1601, 1531, 1493, 1450, 1338,
1367, 996, 773 cmÀ1 1H NMR (400 MHz, CDCl3, d ppm) 7.61–7.59
;
(d, J = 7.0 Hz, 2H), 7.32–7.23 (m, 3H), 5.00 (s, 1H), 3.70–3.69
(s, 3H), 3.0–2.98 (d, J = 8.0 Hz, 1H), 2.72–2.66 (m, 1H), 2.55–2.41
(m, 5H), 2.27 (s, 3H), 2.14–2.17 (m, 2H), 1.94–1.91 (m, 3H), 1.80–
1.73 (m, 2H), 1.43 (s, 3H), 1.26–1.16(m, 3H), 1.03 (s, 3H), 0.85 (s,
3H); 13C NMR (100 MHz, CDCl3, d ppm) 171.4, 139.0, 129.7, 129.0,
128.2, 127.9, 127.1, 82.4, 79.0, 78.2, 65.3, 57.5, 54.3, 53.5, 52.8,

M. Periasamy et al. / Tetrahedron: Asymmetry 25 (2014) 1634–1646
1641
48.1, 47.3, 47.2, 42.5, 37.2, 26.5, 26.1, 22.2, 20.2, 14.7; HRMS (ESI):
4.1.7. 2-[5,5-Dimethyl-4-(4,5,9,9-tetramethyl-octahydro-5,8-
methano-quinazolin-1-yl)-hex-2-ynyl]-2-methyl-malonic acid
dimethyl ester 6ed
m/z calcd for C27H38N2O4: 422.2933 [M+H+]; found: 423.3085.
4.1.3. 2-[5,5-Dimethyl-4-(4,5,9,9-tetramethyl-octahydro-5,8-
methano-quinazolin-1-yl)-hex-2-ynyl]-2-methyl-malonic acid
diethyl ester 6cd
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield:
0.396 g, 86%, [
a]
25 = À39.7 (c 0.32, CHCl3); IR(neat) 3306, 2951,
D
2874, 2795, 2762, 1739, 1666, 1533, 1454, 1388, 1365, 1294,
Yellow oil; Rf = 0.5 (silica gel, hexane/EtOAc 90:10); yield:
1249,1203, 1111, 1018, 997, 871 cmÀ1 1H NMR (400 MHz, CDCl3,
;
0.396 g, 81%, [
a
]
25 = À52.0 (c 0.35, CHCl3); IR(neat) 2951, 2879,
d ppm) 3.73 (s, 6H), 3.07 (s, 1H), 2.86 (s, 2H), 2.80–2.70 (m, 3H),
2.63–2.53 (m, 2H), 2.25 (s, 2H), 2.19–2.09 (m, 3H), 1.72–1.69
(m, 2H), 1.57 (s, 3H), 1.25 (s, 3H), 1.08–1.01 (m, 2H), 0.96 (s, 1H),
0.93 (s, 9H), 0.76 (s, 3H); 13C NMR (100 MHz, CDCl3, d ppm)
171.5, 81.0, 79.7, 77.7, 66.3, 65.9, 54.5, 53.5, 52.7, 49.9,49.6 48.8,
47.0, 45.7, 36.9, 36.1, 28.2, 26.4, 25.8, 22.6, 22.0, 20.6, 20.1, 14.2;
HRMS (ESI): m/z calcd for C27H44N2O4: 460.3301 [M+H+]; found:
461.3378.
D
2793, 2798, 1738 1599, 1456, 1365, 1294, 1246, 1194, 1107,
1022, 996, 891 cmÀ1 1H NMR (400 MHz, CDCl3, d ppm) 4.21–4.16
;
(m, 1H), 3.07 (s, 1H), 2.80–2.58 (m, 6H), 2.24 (s, 3H), 2.18–2.10
(m, 5H), 1.55 (m, 6H), 1.25–1.23 (m, 10H), 0.96 (s, 3H), 0.93
(s, 9H), 0.76 (s, 3H); 13C NMR (100 MHz, CDCl3, d ppm) 171.0,
80.9, 79.9, 66.3, 65.9, 61.7, 61.4, 54.4, 53.4, 49.9, 49.6, 48.8, 47.0,
45.7, 36.9, 36.1, 28.3, 26.2, 25.8, 22.0, 20.6, 19.9, 14.2, 14.0; HRMS
(ESI): m/z calcd for C29H48N2O4: 488.3614 [M+H+]; found: 489.3692.
4.1.8. 2-[4-Cyclohexyl-4-(4,5,9,9-tetramethyl-octahydro-5,8-
methano-quinazolin-1-yl)-but-2-ynyl]-2-methyl-malonic acid
dimethyl ester 6ee
4.1.4. 2-[5,5-Dimethyl-4-(4,5,9,9-tetramethyl-octahydro-5,8-
methano-quinazolin-1-yl)-hex-2-ynyl]-malonic acid dimethyl
ester 6dd
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield:
0.451 g, 93%, [
a
]
25 = À36.9 (c 0.54, CHCl3); IR(neat) 3302, 2947,
D
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield:
2851, 2795, 2764, 2702, 1739,1657, 1535, 1450, 1388, 1377,
0.383 g, 89%, [
a
]
D
25 = À43.6 (c 0.40, CHCl3); IR(neat) 2953, 2874,
1317, 1292, 1249,1201, 1109, 1022, 997, 817 cmÀ1
;
1H NMR
1743, 1437, 1450, 1388, 1365, 1325, 1292, 1211, 1057, 804 cmÀ1
;
(400 MHz, CDCl3, d ppm) 3.72 (s, 6H), 3.13–3.10 (d, J = 12.0 Hz,
1H), 2.82–2.66 (m, 5H), 2.51–2.46 (m, 1H), 2.25 (s, 3H), 2.16–
1.88 (m, 3H), 1.72–1.69 (m, 2H), 1.54 (s, 3H), 1.43–1.41 (d,
J = 8.0 Hz, 2H), 1.25–1.23 (m, 9H), 1.14–1.08 (m, 3H), 0.97 (s, 1H),
0.89–0.83 (m, 4H), 0.76 (s, 3H); 13C NMR (100 MHz, CDCl3, d
ppm) 171.5, 81.7, 79.2, 78.5, 64.6, 60.2, 54.5, 53.5, 52.7, 50.0,
48.4, 47.6, 47.1, 42.2, 40.6, 37.2, 34.6, 31.6, 30.5, 26.7, 26.3, 26.2,
25.9, 22.6, 22.1, 20.9, 20.1, 14.6; HRMS (ESI): m/z calcd for
1H NMR (400 MHz, CDCl3, d ppm) 3.76 (s, 6H), 3.07 (s, 3H)
3.02–3.01 (d, J = 4 Hz, 1H), 2.92–2.80 (m, 2H), 2.79–2.68 (m, 1H),
2.62–2.57 (m, 2H), 2.25 (s, 3H), 2.19–2.13 (m, 2H), 2.04–2.02
(t, J = 5.3 Hz, 1H), 1.58–1.53 (m, 1H), 1.46–1.40 (m, 1H), 1.24
(s, 3H), 0.96 (s, 3H), 0.93 (s, 9H), 0.77 (s, 3H); 13C NMR (100 MHz,
CDCl3, d ppm) 169.3, 81.6, 78.9, 78.5,77.7, 71.6, 66.3, 66.0, 56.7,
54.5, 53.0, 49.9, 49.6, 48.8, 47.0, 45.8, 36.9, 36.1, 28.2, 25.8, 23.1,
22.8, 22.0, 20.0, 14.3; HRMS (ESI): m/z calcd for C26H42N2O4:
446.3145 [M+K+]; found: 485.3374.
C
29H46N2O4: 486.3458 [M+H+]; found: 487.3536.
4.1.9. 2-Benzyl-2-[5,5-dimethyl-4-(4,5,9,9-tetramethyl-octahydro-
5,8-methano-quinazolin-1-yl)-hex-2-ynyl]-malonic acid dimethyl
ester 6fd
4.1.5. 2-Methyl-2-[4-phenyl-4-(4,5,9,9-tetramethyl-octahydro-5,
8-methano-quinazolin-1-yl)-but-2-ynyl]-malonic acid dimethyl
ester 6ea
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield:
25 = À39.7 (c 0.25, CHCl3); IR(neat) , 2951, 2874,
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield:
0.469 g, 86%, [
a
]
D
0.436 g, 91%, [
a
]
25 = À50.7 (c 0.52, CHCl3); IR(neat) 2953, 2878,
D
2795, 1743,1666, 1533, 1454, 1388, 1377, 1365, 1288,
1248,1211, 1132, 1066, 1018, 966, 889 cmÀ1 1H NMR (400 MHz,
;
2798, 2798, 2766, 2704, 1738 1668, 1601, 1537, 1452, 1388,
1292, 1249,1203, 1109, 1028, 997, 856 cmÀ1 1H NMR (400 MHz,
;
CDCl3, d ppm) 7.27–7.24 (t, J = 12.0 Hz, 3H), 7.18–7.16 (d, J =
8.0 Hz, 2H), 3.73 (s, 6H), 3.42 (s, 2H), 3.18 (s, 1H), 3.10–2.93
(dd, J = 24.0 Hz, 1H), 2.83–2.79 (m, 3H), 2.26 (s, 2H), 2.60–2.58
(m, 3H), 2.26 (s, 3H), 1.72–1.53 (m, 3H), 1.47–1.41 (m, 2H), 1.27
(s, 3H), 1.00 (s, 9H) 0.78 (s, 3H); 13C NMR (100 MHz, CDCl3, d
ppm) 170.2, 135.7, 129.8, 128.4, 127.1, 82.0, 79.9, 77.8, 66.3,
66.0, 58.5, 54.6, 52.6, 50.0, 49.6,48.8, 47.0, 45.8, 37.6, 36.9, 36.2,
28.4, 25.9, 22.6, 22.0, 14.6; HRMS (ESI): m/z calcd for
CDCl3, d ppm) 7.57–7.54 (d, J = 12.0 Hz, 2H), 7.30–7.23 (m, 3H),
4.99 (s, 1H), 3.76–3.70 (s, 6H), 2.98–2.94 (d, J = 16.0 Hz, 3H),
2.48–2.42 (m, 2H), 2.27–2.18 (m, 6H), 1.63 (m, 3H), 1.47–1.43
(m, 6H), 1.20–1.13 (m, 2H), 1.03 (s, 3H), 0.84 (s, 3H); 13C NMR
(100 MHz, CDCl3, d ppm) 171.4, 139.0, 129.7, 129.0, 128.1, 127.9,
82.3, 79.0, 78.2, 65.3, 57.5, 54.3, 53.5, 52.8, 50.3, 48.1, 47.3, 47.2,
42.5,37.2, 26.4, 26.1, 22.2, 21.2, 20.2, 14.6; HRMS (ESI): m/z calcd
for C29H40N2O4: 480.2988 [M+H+]; found: 481.3066.
C
33H48N2O4: 536.3614 [M+H+]; found: 537.3691.
4.1.6. 2-Methyl-2-[6-phenyl-4-(4,5,9,9-tetramethyl-octahydro-5,
8-methano-quinazolin-1-yl)-hex-2-ynyl]-malonic acid dimethyl
ester 6ec
4.1.10. 2-Acetylamino-2-[4-phenyl-4-(4,5,9,9-tetramethyl-
octahydro-5,8-methano-quinazolin-1-yl)-but-2-ynyl]-malonic
acid dimethyl ester 6ga
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield:
Yellow oil; Rf = 0.7 (silica gel, hexane/EtOAc 70:30); yield:
25 = À48.1 (c 0.60, CHCl3); IR(neat) 3296, 2951,
0.517 g, 94%, [a]
25 = À42.1 (c 0.53, CHCl3); IR(neat) 3420, 3302,
0.482 g, 95%, [
a
]
D
D
2874, 2795, 1743, 1666, 1533, 1454, 1388, 1365, 1288, 1248,
3061, 2951, 2876, 2795, 2760, 1749, 1684, 1601, 1494, 1450,
1211, 1132, 1066, 1018, 966 cmÀ1 1H NMR (400 MHz, CDCl3, d
;
1388, 1369, 1302, 1205, 1128, 1057, 854, 734 cmÀ1 1H NMR
;
ppm) 7.29–7.27 (m, 2H), 7.19–7.17 (m, 3H), 3.59–3.55 (t, J =
16.0 Hz, 1H), 2.82 (s, 2H), 2.79–2.57 (m, 5H), 2.28 (s, 3H), 2.19–
2.09 (m, 5H), 1.86–1.80 (q, J = 24.0 Hz, 2H), 1.73–1.61 (m, 5H),
1.55 (s, 3H), 1.46–1.39 (m, 2H), 1.26 (s, 3H), 1.15–1.05 (m, 2H),
0.99 (s, 3H) 0.76 (s, 3H); 13C NMR (100 MHz, CDCl3, d ppm) 171.4,
142.1, 128.4, 128.3, 125.7, 81.9, 79.1, 78.7, 64.7, 54.5, 53.5,53.3,
52.8, 50.0, 48.2, 47.3, 47.1, 42.0, 37.2, 35.5, 32.8, 26.3, 25.8, 22.1,
20.9, 20.0, 14.6; HRMS (ESI): m/z calcd for C31H44N2O4: 508.3301
[M+H+]; found: 509.3652.
(400 MHz, CDCl3, d ppm) 7.53–7.52 (d, J = 4.0 Hz, 2H), 7.32–7.20
(m, 2H), 6.98 (m, 1H), 4.95 (s, 1H), 4.30–4.25 (q, J = 20.0 Hz, 4H),
4.13–4.08 (m, 1H), 2.92–2.90 (d, J = 8.0 Hz, 1H), 2.72–2.62
(m, 1H), 2.47–2.40 (m, 1H), 2.26 (s, 3H), 2.18–2.16 (d, J = 8.0 Hz,
1H), 2.07 (s, 3H), 2.03–2.02 (d, J = 4.0 Hz, 3H), 1.87–1.86
(d, J = 4.0 Hz, 1H), 1.45 (s, 3H), 1.29–1.23 (m, 12H), 1.02 (s, 3H),
0.83 (s, 3H); 13C NMR (100 MHz, CDCl3, d ppm) 169.1, 166.8,
138.8, 129.0, 128.0, 127.9, 127.2, 81.4, 79.2, 78.2, 65.5, 65.3, 62.9,
60.3, 57.5, 54.4, 50.3, 48.2, 47.3, 42.5, 37.2, 26.3, 24.2, 23.0, 22.1,

1642
M. Periasamy et al. / Tetrahedron: Asymmetry 25 (2014) 1634–1646
14.6, 14.2, 14.0; HRMS (ESI): m/z calcd for C32H45N3O5: 551.3359
[M+H+]; found: 552.3447.
(m, 1H), 2.36–2.31 (m, 1H), 2.27 (s, 3H), 2.26 (s, 3H), 2.15–2.13
(d, J = 8.0 Hz, 1H), 2.03–1.98 (m, 2H), 1.76 (s, 2H), 1.44 (s, 3H),
1.21–1.14 (m, 1H), 1.03 (s, 3H), 0.85 (s, 3H); 13C NMR (100 MHz,
CDCl3, d ppm)143.5, 138.2, 134.3, 129.5, 128.0, 127.9, 127.8,
127.2, 126.9, 82.2, 79.8, 78.1, 65.4, 57.5, 54.2, 52.8, 50.3, 48.0,
47.3, 47.1, 46.6, 44.9, 44.8, 42.6, 37.1, 34.4, 32.0, 26.2, 24.5, 22.1,
21.5, 21.1, 20.4, 14.6; HRMS (ESI): m/z calcd for C37H45N3O2S:
595.3232 [M+Na+]; found: 618.3133.
4.1.11. 2-Acetylamino-2-[5,5-dimethyl-4-(4,5,9,9-tetramethyl-
octahydro-5,8-methano-quinazolin-1-yl)-hex-2-ynyl]-malonic
acid dimethyl ester 6gd
Yellow oil; Rf = 0.7 (silica gel, hexane/EtOAc 70:30); yield:
0.456 g, 86%, [
a
]
25 = À36.5 (c 0.45, CHCl3); IR(neat) 3498, 3298,
D
2953, 2874, 2795, 2764, 1736, 1689, 1653, 1535, 1456, 1388,
1377, 1367, 1294, 1246, 1194, 1024, 862 cmÀ1
;
1H NMR
4.1.15. 4-Chloro-N-[5,5-dimethyl-4-(4,5,9,9-tetramethyl-octahy-
dro-5,8-methano-quinazolin-1-yl)-hex-2-ynyl]-N-methyl-ben-
zenesulfonamide 6jd
(400 MHz, CDCl3, d ppm) 6.91 (s, 1H), 4.29–4.25 (m, 4H), 3.15–
3.02 (m, 2H), 3.03–3.01 (m, 1H), 2.92–2.82 (m, 1H), 2.76–2.59
(m, 3H), 2.25 (s, 3H), 2.17–2.08 (m, 2H), 2.06 (s, 3H), 1.66–1.60
(m, 1H), 1.57–1.56 (m, 1H), 1.47–143 (m, 1H), 1.29–1.24 (m,
10H), 0.97 (s, 3H), 0.93 (s, 3H), 0.77 (s, 3H); 13C NMR (100 MHz,
CDCl3, d ppm) 168.9, 166.9, 81.2, 78.7, 77.7, 66.2, 65.6, 62.9,62.8,
54.6, 49.9, 49.5, 48.8, 47.0, 45.7, 36.9, 36.0, 28.2, 25.8, 24.1, 23.0,
22.1, 20.6, 14.2; HRMS (ESI): m/z calcd for C30H49N3O5: 531.3672
[M+H+]; found: 532.3750.
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 75:25); yield:
0.472 g, 91%, [
a
]
25 = À31.7 (c 0.40, CHCl3); IR(neat) 2942, 2876,
D
2794, 1589, 1479, 1397, 1353, 1161, 1095, 1013, 980, 926, 767,
728 cmÀ1
;
1H NMR (400 MHz, CDCl3,
d
ppm) 7.79–7.78
(d, J = 4.0 Hz, 2H), 7.49–7.48 (d, J = 4.0 Hz, 2H), 4.61 (s, 1H), 4.15
(s, 2H), 2.93 (s, 1H), 2.88 (s, 3H), 2.84–2.79 (m, 1H), 2.66–2.61
(m, 4H), 2.53–2.48 (m, 2H), 2.24 (s, 3H), 2.17 (s, 3H), 2.04–1.98
(m, 2H), 1.72–1.63 (m, 1H), 1.52–1.51 (d, J = 4.0 Hz, 2H), 1.48–
1.41 (m, 1H), 1.21(s, 3H), 0.97 (s, 4H), 0.82 (s, 9H), 0.76 (s, 3H);
13C NMR (100 MHz, CDCl3, d ppm) 139.2, 137.3, 136.1, 129.4,
129.3, 129.1, 128.7, 77.3, 66.4, 65.9, 54.4, 50.0, 49.4, 48.7, 47.0,
45.7, 40.1, 36.8, 36.0, 34.2, 29.3, 28.2, 25.9, 21.9, 20.6, 14.2; HRMS
(ESI): m/z calcd for C28H42ClN3O2S: 519.2686 [M+H+]; found:
520.2764.
4.1.12. N-[5,5-Dimethyl-4-(4,5,9,9-tetramethyl-octahydro-5,8-
methano-quinazolin-1-yl)-hex-2-ynyl]-4,N-dimethyl-benzene-
sulfonamide 6hd
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 80:20); yield:
0.454 g, 91%, [
a
]
D
25 = À40.8 (c 0.40, CHCl3); IR(neat) 2947, 2794,
1600, 1457, 1353, 1167, 926, 821, 754 cmÀ1
;
1H NMR (400 MHz,
CDCl3, d ppm) 7.72–7.70 (d, J = 8.0 Hz, 2H), 7.30–7.28 (d, J =
8.0 Hz, 2H), 4.12 (s, 1H), 2.94 (s, 1H), 2.86 (s, 3H), 2.67–2.65
(d, J = 8.0 Hz, 1H), 2.57–2.49 (m, 2H), 2.41 (s, 3H), 2.31 (s, 3H),
2.14–2.11 (d, J = 12.0 Hz, 1H), 2.06–1.98 (m, 2H), 1.68–1.59
(m, 1H), 1.51–1.50 (d, J = 4.0 Hz, 1H), 1.44–1.40 (m, 1H), 1.21
(s, 3H), 0.82 (s, 9H), 0.76 (s, 3H); 13C NMR (100 MHz, CDCl3, d
ppm) 143.4, 134.5, 129.6, 127.7, 84.3, 77.5, 66.2, 66.0, 54.5, 49.5,
49.5, 48.7, 45.7, 40.1, 36.8, 36.0, 34.3, 31.6, 28.2, 25.8, 22.6,
4.1.16. 4-Phenyl-4-(4,5,9,9-tetramethyl-octahydro-5,8-methano-
quinazolin-1-yl)-but-2-yn-1-ol 6ka
Yellow oil; Rf = 0.7 (silica gel, hexane/EtOAc 80:20); yield:
0.299 g, 82%, [
a
]
25 = À49.3 (c 0.75, CHCl3); IR (neat) 3300, 2953,
D
2878, 2795, 1893, 1743, 1655, 1604, 1506, 1451, 1368, 1365,
1332, 1222, 1155, 1128, 1095, 1041, 966, 923, 844 cmÀ1 1H
;
NMR (400 MHz, CDCl3, d ppm) 7.61–7.59 (d, J = 8.0 Hz, 2H),
7.32–7.26 (m, 3H), 5.03 (s, 1H), 3.82–3.79 (t, J = 12.0 Hz, 2H),
2.98–2.96 (d, J = 8.0 Hz, 1H), 2.73–2.69 (m, 3H), 2.52–2.45
(m, 1H), 2.35–2.30 (m, 1H), 2.27 (s, 3H), 2.22–2.19 (t, J = 12.0 Hz,
1H), 2.14–2.07 (m, 1H), 1.93–1.77 (m, 3H), 1.47 (m, 4H), 1.27–
1.09 (m, 3H), 1.04(s, 3H), 0.85 (s, 3H); 13C NMR (100 MHz, CDCl3,
d ppm) 139.1, 128.1, 128.0, 127.2, 84.1, 78.1, 65.6, 61.5, 57.6,
54.4, 50.3, 48.1, 47.4, 47.3, 42.7, 37.2, 26.3, 23.3, 22.2, 21.2, 14.7;
HRMS (ESI): m/z calcd for C24H34N2O: 366.2671 [M+H+]; found:
367.2749.
22.0, 21.5, 20.6; HRMS (ESI): m/z calcd for
C29H45N3O2S:
499.3232[M+H+]; found: 500.3302.
4.1.13. 4,N-Dimethyl-N-[4-phenyl-4-(4,5,9,9-tetramethyl-octa-
hydro-5,8-methano-quinazolin-1-yl)-but-2-ynyl]-benzenesulfon-
amide 6ha
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 80:20); yield:
0.498 g, 96%, [
a
]
25 = À54.2 (c 0.45, CHCl3); IR(neat) 3057, 3030,
D
2958, 2871, 1665, 1600, 1446, 1446, 1336, 1167, 1084, 1024,
926, 816, 734 cmÀ1 1H NMR (400 MHz, CDCl3, d ppm) ; 7.71–
;
7.69 (d, J = 8.0 Hz, 2H), 7.36–7.34 (m, 2H), 7.33–7.21 (m, 3H),
7.19–7.17 (d, J = 8.0 Hz, 2H), 4.80 (s, 1H), 4.21 (s, 2H), 2.89
(s, 3H), 2.78–2.76 (d, J = 8.0 Hz, 1H), 2.71–2.66 (m, 1H), 2.41
(s, 1H), 2.28 (s, 5H), 2.18–2.16 (d, J = 8.0 Hz, 1H), 2.06–1.96
(m, 2H), 1.78 (s, 2H), 1.44–142 (m, 6H), 1.24–1.22 (m, 2H),
1.19–1.09 (m, 3H), 1.03 (s, 4H), 0.82 (s, 3H) 13C NMR (100 MHz,
CDCl3, d ppm) 143.5, 138.2, 134.3, 129.5, 128.5, 128.0, 127.9,
127.8, 127.2, 126.9, 82.2, 79.8, 78.1, 65.4, 57.5, 54.2, 52.9, 50.3,
48.0, 47.3, 47.1, 46.6, 4.9, 44.8, 42.6, 40.2, 37.1, 34.4, 32.4, 26.2,
24.5, 22.1, 21.5, 21.1, 20.4, 17.5, 14.6; HRMS (ESI): m/z calcd for
4.1.17. 4-(4-Fluoro-phenyl)-4-(4,5,9,9-tetramethyl-octahydro-5,
8-methano-quinazolin-1-yl)-but-2-yn-1-ol 6kb
Yellow oil; Rf = 0.7 (silica gel, hexane/EtOAc 80:20); yield:
0.303 g, 79%, [
a
]
25 = À29.9 (c 0.80, CHCl3); IR(neat) 3300, 2953,
D
2878, 2795, 1893, 1743, 1655, 1604, 1506, 1451, 1368, 1365,
1332, 1222, 1155, 1128, 1095, 1041, 966, 923, 844 cmÀ1
;
1H NMR (400 MHz, CDCl3, d ppm) 7.56–7.53 (t, J = 12.0 Hz, 2H),
7.02–6.96 (m, 2H), 4.97 (s, 1H), 4.65 (s, 1H), 3.81–3.77
(t, J = 16.0 Hz, 2H), 2.95–2.93 (d, J = 8.0 Hz, 1H), 2.73–2.61 (m,
3H), 2.31–2.26 (m, 4H), 2.20–2.18 (d, J = 8.0 Hz, 1H), 2.14–2.04
(m, 1H), 1.93–1.89 (m, 3H), 1.80–1.73 (m, 1H), 1.45 (s, 3H),
1.27–1.23 (m, 1H), 1.03 (s, 3H), 0.83 (s, 3H); 13C NMR (100 MHz,
CDCl3, d ppm) 139.1, 128.1, 128.0, 127.2, 84.1, 78.1, 65.6, 61.5,
57.6, 54.4, 50.3, 48.1, 47.4, 47.3, 42.7, 37.2, 26.3, 23.3, 22.2, 21.2,
14.7; HRMS (ESI): m/z calcd for C24H33FN2O: 384.2577 [M+H+];
found: 385.2654.
C
31H41N3O2S: 519.2919 [M+H+]; found: 550.2953.
4.1.14. N-Benzyl-4-methyl-N-[4-phenyl-4-(4,5,9,9-tetramethyl-
octahydro-5,8-methano-quinazolin-1-yl)-but-2-ynyl]-benzene-
sulfonamide 6ia
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 80:20); yield:
0.549 g, 89%, [
a
]
25 = À42.7 (c 0.80, CHCl3); IR(neat) 3063, 3030,
D
2953, 2876, 1704, 1600, 1493, 1452, 1374, 1167, 1096, 926, 898,
4.1.18. 1-[3-Cyclohexyl-3-(5,9,9-trimethyl-octahydro-5,8-meth-
ano-quinazolin-1-yl)-prop-1-ynyl]-cyclohexanol 6le
; d ppm) 7.82–7.80 (d,
739 cmÀ1 1H NMR (400 MHz, CDCl3,
J = 8.0 Hz, 2H), 7.42–7.32 (m, 6H), 7.28–7.26 (m, 3H) 7.18–7.16
(d, J = 8.0 Hz, 2H), 4.79 (s, 1H), 4.47–4.45 (d, J = 8.0 Hz, 2H), 4.19–
4.17 (d, J = 8.0 Hz, 2H), 2.82–2.81 (d, J = 4.0 Hz, 1H), 2.65–2.58
Yellow oil; Rf = 0.7 (silica gel, hexane/EtOAc 80:20); yield:
0.369 g, 87%, [
a
]
D
25 = À49.3 (c 0.63, CHCl3); IR(neat) 3300, 2953,
2878, 2795, 1893, 1743, 1655, 1604, 1506, 1451, 1368, 1365,

M. Periasamy et al. / Tetrahedron: Asymmetry 25 (2014) 1634–1646
1643
1332, 1222, 1155, 1128, 1095, 1041, 966, 923, 844 cmÀ1
;
1H NMR
772 cmÀ1
;
1H NMR (400 MHz, CDCl3,
d
ppm) 3.64 (s, 3H),
(400 MHz, CDCl3, ppm) 3.21–3.19 (d, J = 8.0 Hz, 1H),
d
3.59–3.57 (t, J = 8.0 Hz, 1H), 2.83–2.80 (m, 2H), 2.74–2.71
(m, 1H), 2.58–2.54 (m, 1H), 2.41–2.38 (t, J = 12.0 Hz, 2H), 2.26 (s,
3H), 1.86–1.81 (q, J = 20.0 Hz, 6H), 1.67–1.59 (m, 2H), 1.48–1.38
(m, 5H), 1.27 (s, 9H), 1.22 (s, 3H), 0.97 (s, 3H), 0.88–0.85
(t, J = 20.0 Hz, 4H), 0.75 (s, 3H); 13C NMR (100 MHz, CDCl3, d
ppm) 174.0, 84.8, 78.1, 64.7, 54.4, 52.9, 51.4, 50.0, 48.3, 47.8,
47.0, 41.7, 37.1, 31.8, 30.7, 29.3, 29.0, 28.7, 25.9, 22.6, 22.0, 20.7,
18.5, 14.4, 14.1; HRMS (ESI): m/z calcd for C28H48N2O2: 444.3716,
[M+H+]; found: 445.3785.
2.87–2.85 (d, J = 8.0 Hz, 2H), 2.77–2.66 (m, 1H), 2.66–2.55
(m, 1H), 2.25 (s, 3H), 2.14–2.09 (m, 2H), 2.04–1.96 (m, 3H),
1.93–1.80 (m, 2H), 1.74–1.64 (m, 7H), 1.59–1.51 (m, 5H),
1.47–1.37 (m, 3H), 1.24 (s, 6H), 1.17–1.08 (m, 3H), 0.97 (s, 4H),
0.77 (s, 3H); 13C NMR (100 MHz, CDCl3, d ppm) 139.1, 128.1,
128.0, 127.2, 84.1, 78.1, 65.6, 61.5, 57.6, 54.4, 50.3, 48.1, 47.4,
47.3, 42.7, 37.2, 26.3, 23.3, 22.2, 21.2, 14.7; HRMS (ESI): m/z calcd
for C27H44N2O: 426.3610 [M+H+]; found: 427.3688.
4.1.19. 2-Methyl-2-[4-phenyl-4-(4,5,9,9-tetramethyl-octahydro-
5,8-methano-quinazolin-1-yl)-but-2-ynyl]-malonic acid dimethyl
ester 14ea
4.2. General procedure for the preparation of chiral allenes from
propargylamines
Yellow oil; Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield:
Chiral propargylamines 6 (1 mmol) were added to a stirred sus-
pension of ZnBr2 (0.113 g, 50 mol%) in dry toluene (3 mL) and the
contents were refluxed for 1–2 h at 120 °C under a nitrogen atmo-
sphere. Toluene was removed under reduced pressure and the
crude product was purified by silica gel (100–200 mesh) column
chromatography using hexane as the eluent to isolate the chiral
allenes.
0.427 g, 89%, [
2798, 2798, 2766, 2704, 1738 1668, 1601, 1537, 1452, 1388,
1292, 1249,1203, 1109, 1028, 997, 856 cmÀ1 1H NMR (400 MHz,
a]
25 = + 43.6 (c 0.31, CHCl3); IR(neat) 2953, 2878,
D
;
CDCl3, d ppm) 7.62–7.60 (d, J = 12.0 Hz, 2H), 7.33–7.29 (m, 3H),
4.78 (s, 1H), 3.71 (s, 6H), 3.05–3.03 (d, J = 16.0 Hz, 3H), 2.45–2.42
(m, 1H), 2.27–2.18 (m, 6H), 1.79 (m, 3H), 1.62–1.54 (m, 4H),
1.20–1.13 (m, 4H), 1.03 (s, 3H), 0.84 (s, 3H); 13C NMR (100 MHz,
CDCl3, d ppm) 171.4, 139.6, 128.0, 127.8, 127.0, 80.1, 77.3, 73.3,
68.0, 61.2, 53.4, 53.0, 52.8, 50.4, 48.0, 46.8, 46.0, 45.2, 36.2, 26.6,
26.5, 22.0, 20.5, 20.2, 13.5; HRMS (ESI): m/z calcd for
4.2.1. (R)-8-Phenyl-octa-6,7-dienoic acid ethyl ester 13ba
Colorless liquid, Rf = 0.8 (silica gel, hexane/EtOAc 98:2); yield:
0.262 g, 72%, 99% ee, [
a
]
25 = À214.5 (c 0.57, CHCl3); HPLC using
D
C
29H40N2O4: 480.2988 [M+H+]; found: 481.3144.
chiral column, chiralcel OB-H, hexanes:i-PrOH/97:3; flow rate
0.5 mL/min, 254 nm, retention times: 28.3 min. (R) and 29.7 min.
(S); IR (neat) 3030, 2951, 2854, 1948, 1738, 1597, 1494, 1437,
4.1.20. 2-Acetylamino-2-[4-phenyl-4-(4,5,9,9-tetramethyl-octa-
hydro-5,8-methano-quinazolin-1-yl)-but-2-ynyl]-malonic acid
dimethyl ester 14ga
1363, 1315, 1242, 1155, 1072, 1026, 991, 912 cmÀ1 1H NMR
;
(400 MHz, CDCl3, d ppm) 7.22–7.20 (m, 4H), 7.21–7.17 (m, 1H),
6.18–6.15 (t, J = 12.0 Hz, 1H), 5.59–5.54 (q, J = 20.0 Hz, 1H), 3.67
(s, 3H), 2.42–2.38 (t, J = 16.0 Hz, 2H), 2.22–2.15 (m, 2H), 1.87–
1.82 (q, J = 20.0 Hz, 3H); 13C NMR (100 MHz, CDCl3, d ppm) 205.2,
173.9, 134.7, 128.8, 128.5, 126.7, 126.6, 126.2, 95.1, 94.1, 51.5,
33.4, 28.1, 24.2; HRMS (ESI): m/z calcd for C14H16O2: 216.1150
[M+Na+]; found: 239.0947.
Yellow oil; Rf = 0.7 (silica gel, hexane/EtOAc 70:30); yield:
0.429 g, 78%, [
3061, 2951, 2876, 2795, 2760, 1749, 1684, 1601, 1494, 1450,
1388, 1369, 1302, 1205, 1128, 1057, 854, 734 cmÀ1 1H NMR
a]
25 = + 39.1 (c 0.23, CHCl3); IR(neat) 3420, 3302,
D
;
(400 MHz, CDCl3, d ppm) 7.33–7.31 (m, 2H), 7.09–6.90 (m, 3H),
6.78 (s, 1H), 4.71 (s, 1H), 4.09–4.04 (q, J = 20.0 Hz, 4H), 3.90
(s, 1H), 3.25 (s, 2H), 2.71–2.69 (d, J = 4.0 Hz, 1H), 2.26–2.19
(m, 3H), 2.18–2.16 (d, J = 8.0 Hz, 1H), 2.05 (s, 3H), 1.86–1.82
(m, 6H), 1.24 (s, 3H), 1.08–1.04 (m, 6H), 0.81 (s, 3H), 0.63 (s, 3H);
13C NMR (100 MHz, CDCl3, d ppm) 169.1, 166.8, 139.6, 129.7,
129.0, 128.0, 127.7, 127.1, 81.8, 79.1, 73.4, 67.9, 65.6, 62.6, 62.8,
61.2, 60.3, 53.1, 50.4, 48.0, 46.8, 46.0, 45.2, 36.1, 26.6, 24.2, 23.0,
22.0, 21.0, 20.4, 14.1, 14.0, 13.4; HRMS (ESI): m/z calcd for
4.2.2. (R)-2-(5,5-Dimethyl-hexa-2,3-dienyl)-2-methyl-malonic
acid diethyl ester 13cd
Colorless liquid, Rf = 0.8 (silica gel, hexane/EtOAc 98:2); yield:
0.203 g, 72%, 99% ee, [
a
]
25 = À56.8 (c 0.61, CHCl3); HPLC using chi-
D
ral column, chiralcel AD-H, heptane:i-PrOH/99.5:0.5; flow rate
1.0 mL/min ,210 nm, retention times: 6.7 min. (R) and 7.2 min.
(S); IR (neat) 2962, 2906, 2868, 1961, 1734, 1462, 1377, 1365,
C
32H45N3O5: 551.3359 [M+H+]; found: 552.3437.
1298, 1242, 1190, 1107, 1026, 946, 862 cmÀ1 1H NMR (400 MHz,
;
4.1.21. 8-(tert-Butyl-dimethyl-silanyloxy)-5-(4,5,9,9-etramethyl-
octahydro-5,8-methano-quinazolin-1-yl)-oct-6-ynoic acid methyl
ester 6mf
CDCl3, d ppm) 5.20–5.14 (m, 2H), 3.74–3.73 (s, 6H), 3.51–3.47 (t,
J = 16.0 Hz, 1H), 2.61–2.57 (m, 2H), 1.00 (s, 9H); 13C NMR
(100 MHz, CDCl3, d ppm) 205.9, 171.9, 171.8, 90.7, 85.1, 61.1,
53.8, 35.9, 31.3, 28.4, 22.2, 19.6, 14.0, 13.8; the 13C NMR data were
in agreement with the reported data.5g
Colorless oil; Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield:
0.480 g, 98%, [
a]
25 = À37.4 (c 0.46, CHCl3); IR(neat) 2947, 2931,
D
2854, 1473, 1391, 1358, 1249, 1090, 1002, 936, 843, 772 cmÀ1
;
1H NMR (400 MHz, CDCl3, d ppm) 4.33 (s, 2H), 3.66–3.65 (s, 3H),
2.88–2.83 (m, 2H), 2.78–2.66 (m, 1H), 2.57–2.52 (m, 1H), 2.34–
2.57 (m, 5H), 2.18–2.11 (m, 2H), 1.75–1.55 (m, 6H), 1.42–1.41
(m, 1H), 1.23 (s, 2H), 1.06–1.03 (m, 3H), 0.99 (s, 3H), 0.91 (s, 9H),
0.77 (s, 3H); 13C NMR (100 MHz, CDCl3, d ppm) 173.9, 83.6, 83.1,
78.3, 64.7, 54.4, 53.3, 51.8, 51.4, 50.0, 48.2, 47.5, 47.1, 41.9, 37.1,
33.7, 32.7, 25.8, 22.1, 20.8, 18.3, 14.5; HRMS (ESI): m/z calcd for
4.2.3. (R)-2-(5,5-Dimethyl-hexa-2,3-dienyl)-malonic acid dime-
thyl ester 13dd
Colorless liquid, Rf = 0.8 (silica gel, hexane/EtOAc 98:2); yield:
0.165 g, 69%, 96% ee, [
a
]
25 = À80.8 (c 0.70, CHCl3); HPLC using
D
chiral column, chiralcel AS-H, hexanes:i-PrOH/99:1; flow rate
0.4 mL/min, 220 nm, retention times: 13.2 min. (R) and 14.7 min.
(S); IR (neat) 2959, 2866, 1961, 1739, 1437, 1388, 1340, 1232,
C
28H50N2O3Si: 490.3591, [M+H+]; found: 491.3669.
1078, 1041, 881, 844, 738 cmÀ1 1H NMR (400 MHz, CDCl3, d
;
ppm) 5.10–5.08 (m, 1H), 5.01–4.96 (q, J = 20.0 Hz, 1H), 3.72
(s, 6H), 2.64–2.53 (m, 2H), 1.64 (s, 1H), 1.44 (s, 3H), 1.01 (s, 9H);
13C NMR (100 MHz, CDCl3, d ppm) 201.1, 169.4, 169.3, 104.8,
89.2, 52.5, 52.5, 51.2, 31.7, 29.9, 28.2; the 13C NMR data were in
agreement with the reported data.5g
4.1.22. 4-(4,5,9,9-Tetramethyl-octahydro-5,8-methano-quinazo-
lin-1-yl)-tetradec-5-ynoic acid methyl ester 6ng
Brown liquid; Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield:
0.412 g, 93%, [
a
]
25 = À45.5(c 0.62, CHCl3); IR(neat) 2947, 2931,
D
2854, 1655, 1473, 1391, 1358, 1249, 1090, 1002, 936, 843,

1644
M. Periasamy et al. / Tetrahedron: Asymmetry 25 (2014) 1634–1646
4.2.4. (R)-2-Methyl-2-(4-phenyl-buta-2,3-dienyl)-malonic acid
dimethyl ester 13ea
0.5 mL/min, 210 nm, retention times: 11.2 min. (R) and 12.0 min.
(S); IR (neat) 3078, 2959, 2906, 2866, 1961, 1738, 1641, 1439,
Colorless liquid, Rf = 0.9 (silica gel, hexane/EtOAc 98:2); yield:
1361, 1325, 1282, 1246, 1211, 1076, 922 cmÀ1 1H NMR
;
0.210 g, 77%, 96% ee, [
a
]
25 = À205.9 (c 0.65, CHCl3); HPLC using chi-
(400 MHz, CDCl3, d ppm) 7.28–7.24 (m, 1H), 7.18–7.14 (m, 2H),
5.71–5.61 (m, 1H), 5.13–5.09 (m, 3H), 4.99–4.93 (q, J = 24.0 Hz,
1H), 3.72 (s, 6H), 2.71–2.69 (d, J = 8.0 Hz, 2H), 2.63–2.60 (m, 2H),
2.36 (s, 2H), 1.02 (s, 9H); 13C NMR (100 MHz, CDCl3, d ppm)
203.1, 171.2, 132.3, 129.1, 128.2, 125.3, 119.2, 103.1, 86.4, 57.9,
52.4, 52.3, 36.7, 32.8, 31.6, 30.1; the 13C NMR data were in agree-
ment with the reported data.5g
D
ral column, chiralcel AD-H, hexanes:i-PrOH/99:1; flow rate 0.5 mL/
min, 254 nm, retention times: 20.2 min. (R) and 21.5 min. (S); IR
(neat) 3036, 2997, 2953, 2849, 1950, 1734, 1597, 1494, 1458,
1435, 1379, 1290, 1244, 1203, 1109, 985, 914 cmÀ1 1H NMR
;
(400 MHz, CDCl3, d ppm) 7.33–7.25 (m, 4H), 7.21–7.17 (m, 1H),
6.16–6.13 (m, 1H), 5.49–5.43 (q, J = 24.0 Hz, 1H), 3.75–3.71 (d,
J = 16.0 Hz, 6H), 2.73–2.70 (d, J = 12.0 Hz, 2H), 1.58 (s, 3H); 13C
NMR (100 MHz, CDCl3, d ppm) 206.9, 172.1, 134.1, 128.5, 126.9,
126.8, 94.6, 89.3, 53.7, 52.6, 35.5, 19.9; the 13C NMR data were in
agreement with the reported data.5g
4.2.9. (R)-2-Acetylamino-2-(4-phenyl-buta-2,3-dienyl)-malonic
acid dimethyl ester 13ga
Yellow oil, Rf = 0.7 (silica gel, hexane/EtOAc 90:10); yield:
0.293 g, 85%, 98% ee, [
a
]
D
25 = À192.3 (c 0.55, CHCl3); HPLC using chi-
4.2.5. (R)-2-Methyl-2-(6-phenyl-hexa-2,3-dienyl)-malonic acid
dimethyl ester 13ec
ral column, chiralcel OD-H, hexanes:i-PrOH/100:0; flow rate
1.5 mL/min, 254 nm, retention times: 17.9 min. (R) and 28.1 min.
(S); IR (neat) 3310, 2982, 1950, 1743, 1653, 1518, 1460, 1371,
1309, 1192, 1093, 1062, 1014, 887 cmÀ1; 1H NMR (400 MHz, CDCl3,
d ppm) 7.32–7.28 (m, 2H), 7.25–7.18 (m, 3H), 6.83 (s, 1H),
6.13–6.11 (m, 1H), 5.38–5.32 (q, J = 12.0 Hz, 1H), 4.28–4.11
(m, 4H), 3.18–3.15 (dd, J = 12.0 Hz, 2H), 1.91 (s, 3H), 1.28–1.25
(t, J = 12.0 Hz, 4H), 1.21–1.17 (t, J = 16.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3, d ppm) 207.1, 169.1, 167.5, 134.0, 128.6, 127.1,
126.7, 94.8, 88.1, 66.3, 62.7, 32.1, 22.9, 14.0, 13.9; the 13C NMR data
were in agreement with the reported data.8c
Colorless liquid, Rf = 0.9 (silica gel, hexane/EtOAc 95:5); yield:
0.196 g, 65%, 89% ee, [
a
]
25 = À70.1 (c 0.45, CHCl3); HPLC using
D
chiral column, chiralcel AD-H, hexanes:i-PrOH/99:1; flow rate
0.5 mL/min, 210 nm, retention times: 17.5 min. (R) and 18.2 min.
(S); IR (neat) 3086, 3063, 3026, 2999, 2951, 1963, 1736, 1604,
1531, 1496, 1454, 1435, 1246, 1203, 1156, 1111, 985 cmÀ1 1H
;
NMR (400 MHz, CDCl3, d ppm) 7.28–7.26 (m, 1H), 7.21–7.17
(m, 4H), 5.16–5.10 (m, 1H), 5.00–4.93 (m, 1H), 3.72 (s, 6H), 2.71–
2.68 (t, J = 12.0 Hz, 2H), 2.54–2.52 (m, 2H), 2.32–2.25 (m, 2H),
1.42 (s, 3H); 13C NMR (100 MHz, CDCl3, d ppm) 206.0, 172.2,
141.6, 128.4, 128.3, 125.8, 90.2, 85.6, 53.8, 52.5, 35.8, 35.4, 30.5,
19.7, 14.1; the 13C NMR data were in agreement with the reported
data.5g
4.2.10. 2-Acetylamino-2-(5,5-dimethyl-hexa-2,3-dienyl)-malonic
acid dimethyl ester 13gd
Colorless liquid, Rf = 0.6 (silica gel, hexane/EtOAc 90:10); yield:
0.237 g, 73%, 99% ee, [
a
]
25 = À66.3 (c 0.46, CHCl3); HPLC using
D
4.2.6. (R)-2-(5,5-Dimethyl-hexa-2,3-dienyl)-2-methyl-malonic
acid dimethyl ester 13ed
chiral column, chiralcel AD-H, hexanes:i-PrOH/95:5; flow rate
0.5 mL/min, 210 nm, retention times: 22.8 min. (R) and 26.2 min.
(S); IR (neat) 3382, 3312, 2962, 2905, 2868, 1961, 1743, 1682,
Colorless liquid, Rf = 0.6 (silica gel, hexane/EtOAc 95:5); yield:
25 = À61.9 (c 0.45, CHCl3); HPLC using
D
1502, 1440, 1367, 1304, 1278, 1201, 1093, 1060, 1018, 946 cmÀ1
;
0.202 g, 77%, 99% ee, [
a
]
1H NMR (400 MHz, CDCl3,
d ppm) 6.79 (s, 1H), 5.06–5.03
chiral column, chiralcel AS-H, heptane:i-PrOH/100:0; flow rate
0.25 mL/min, 230 nm, retention times: 37.2 min. (R) and
42.7 min. (S); IR (neat) 2959, 2868, 1961, 1738, 1458, 1435,
(q, J = 12.0 Hz, 1H), 4.92–4.85 (q, J = 28.0 Hz, 4H), 4.28–4.21
(m, 4H), 3.04–3.01 (d, J = 12.0 Hz, 2H), 2.02 (s, 3H), 1.27–1.23
(m, 6H), 0.99 (s, 9H); 13C NMR (100 MHz, CDCl3, d ppm) 203.1,
168.9, 167.7, 167.6, 103.1, 85.6, 66.3, 62.6, 62.5, 33.1, 31.5, 30.1,
23.1, 13.9; the 13C NMR data were in agreement with the reported
data.8c
1377, 1363, 1296, 1246, 1201, 1109, 1020, 935, 877 cmÀ1 1H
;
NMR (400 MHz, CDCl3, d ppm) 5.09–5.08 (m, 1H), 5.01–4.98 (q,
J = 12.0 Hz, 1H), 3.71 (s, 6H), 2.60–2.56 (m, 2H), 1.44 (s, 3H), 1.01
(s, 9H); 13C NMR (100 MHz, CDCl3, d ppm) 203.1, 172.4, 172.3,
102.9, 86.9, 53.8, 52.8, 52.5, 36.3, 31.7, 30.1, 19.8; the 13C NMR data
was in agreement with the reported data.5g
4.2.11. (R)-N-(5,5-Dimethyl-hexa-2,3-dienyl)-4,N-dimethyl-ben-
zenesulfonamide 13hd
4.2.7. 1H and 13C NMR spectra of (R)-2-(4-cyclohexyl-buta-2,3-
dienyl)-2-methyl-malonic acid dimethyl ester 13ee
Colorless liquid, Rf = 0.9 (silica gel, hexane/EtOAc 98:2); yield:
0.202 g, 69%, 98% ee, [
a
]
25 = À92.8 (c 0.46, CHCl3); HPLC using chi-
D
Colorless liquid, Rf = 0.9 (silica gel, hexane/EtOAc 98:2); yield:
ral column, chiralcel OJ-H, hexanes:i-PrOH/ 90:10; flow rate
0.5 mL/min, 210 nm, retention times: 15.8 min. (R) and 16.2 min.
(S); IR (neat) 2959, 2923, 2897, 2861, 1955, 1593, 1464, 1345,
0.190 g, 68%, 99% ee, [
a
]
D
25 = À57.2 (c 0.55, CHCl3); HPLC using chi-
ral column, chiralcel AD-H, hexanes:i-PrOH/99.5:0.5; flow rate
0.5 mL/min, 210 nm, retention times: 37.2 min. (R) and 42.7 min.
(S); IR (neat) 2993, 2926, 2852, 1961, 1736, 1618, 1450, 1377,
1290, 1244, 1201, 1159, 1111, 985 cmÀ1; 1H NMR (400 MHz, CDCl3,
d ppm) 5.08–5.06 (m, 1H), 4.98–4.96 (q, J = 8.0 Hz, 1H), 3.72 (s, 6H),
2.59–2.57 (m, 2H), 1.94–1.93 (m, 1H), 1.72–1.71 (m, 4H), 1.44
(s, 3H), 1.38–1.22 (m, 4H), 1.04–1.00 (s, 1H); 13C NMR (100 MHz,
CDCl3, d ppm) 204.7, 172.3, 96.9, 85.9, 53.8, 52.5, 37.1, 36.2, 33.0,
26.1, 25.9, 22.6, 19.8; the 13C NMR data were in agreement with
the reported data.5g
1303, 1164, 1089, 1086, 977 cmÀ1 1H NMR (400 MHz, CDCl3, d
;
ppm) 7.69–7.67 (d, J = 12.0 Hz, 2H), 7.33–7.31 (d, J = 12.0 Hz, 2H),
5.18–5.16 (m, 1H), 5.05–5.00 (q, J = 20.0 Hz, 1H), 3.72–3.56
(m, 2H), 2.73 (s, 3H), 2.43 (s, 3H), 1.00 (s, 9H); 13C NMR
(100 MHz, CDCl3, d ppm) 202.7, 143.3, 134.6, 129.7, 127.4, 104.6,
88.3, 50.4, 34.2, 31.9, 30.1, 21.5; the 13C NMR data were in agree-
ment with the reported data.8d
4.2.12. (R)-N-Benzyl-4-methyl-N-(4-phenyl-buta-2,3-dienyl)-
benzenesulfonamide 13ia
4.2.8. (R)-2-Benzyl-2-(5,5-dimethyl-hexa-2,3-dienyl)-malonic
acid dimethyl ester 13fd
Colorless liquid, Rf = 0.9 (silica gel, hexane/EtOAc 90:10); yield:
0.283 g, 73%, 96% ee, [
a]
25 = À220.3 (c 0.45, CHCl3); HPLC using
D
Colorless liquid, Rf = 0.9 (silica gel, hexane/EtOAc 96:4); yield:
chiral column, chiralcel AS-H, hexanes:i-PrOH/85:15; flow rate
0.5 mL/min, 254 nm, retention times: 27.8 min. (R) and 29.8 min.
(S); IR (neat) 3058, 3021, 2923, 1955, 1650, 1598, 1490, 1459,
0.234 g, 71%, 99% ee, [
ral column, chiralcel AS-H, hexanes:i-PrOH/99.8:0.2; flow rate
a
]
25 = À64.1 (c 0.55, CHCl3); HPLC using chi-
D

M. Periasamy et al. / Tetrahedron: Asymmetry 25 (2014) 1634–1646
1645
1340, 1091, 910 cmÀ1
;
1H NMR (400 MHz, CDCl3,
d
ppm)
4.2.17. (R)-1-(3-Cyclohexyl-propa-1,2-dienyl)-cyclohexanol 13le
Colorless liquid, Rf = 0.4 (silica gel, hexane/EtOAc 95:5); yield:
7.78–7.76 (d, J = 8.0 Hz, 2H), 7.33–7.13 (m, 13H), 6.04–6.02
(m, 1H), 5.28–5.23 (q, J = 20.0 Hz, 1H), 4.41 (s, 2H), 3.90–3.88
(m, 2H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3, d ppm) 206.2,
143.4, 137.5, 135.8, 133.4, 129.8, 129.8, 128.7, 128.5, 128.1,
127.9, 127.8, 127.3, 126.9, 95.9, 90.0, 50.3, 45.7, 21.5; HRMS
(ESI): m/z calcd for C24H23NO2S: 389.1449 [M+H]; found: 390.1526.
0.158 g, 72%, 98% ee, [
a
]
D
25 = À121.7 (c 0.55, CHCl3); HPLC using chi-
ral column, chiralcel AD-H, hexanes:i-PrOH/95:5; flow rate 0.5 mL/
min 214 nm, retention times: 10.6 min. (R) and 11.2 min. (S); IR
(neat) 3313, 2923, 2849, 1962, 1446, 1399, 1355, 1320, 1264,
1247, 1144, 1100, 1062 cmÀ1 1H NMR (400 MHz, CDCl3, d ppm)
;
5.32–5.31 (d, J = 4.0 Hz, 2H), 2.02–1.97 (m, 1H), 1.78–1.71 (m,
2H), 1.65–1.59 (m, 7H), 1.52–1.47 (m, 4H), 1.36–1.26 (m, 4H),
1.10–1.04 (m, 3H), 0.90–0.85 (m, 1H),; 13C NMR (100 MHz, CDCl3,
d ppm) 199.9, 101.3, 101.0, 70.5, 38.5, 38.3, 37.2, 33.2, 33.1, 25.5,
22.5; the 13C NMR data were in agreement with the reported
data.7c
4.2.13. (R)-4,N-Dimethyl-N-(4-phenyl-buta-2,3-dienyl)-benzene-
sulfonamide 13ha
Colorless liquid, Rf = 0.9 (silica gel, hexane/EtOAc 95:5); yield:
0.244 g, 78%, 99% ee, [
a
]
25 = À232.2 (c 0.50, CHCl3); HPLC using
D
chiral column, chiralcel AS-H, hexanes:i-PrOH/85:15; flow rate
0.5 mL/min, 254 nm, retention times: 30.4 min. (R) and 33.6 min.
(S); IR (neat) 3058, 3021, 2923, 1955, 1650, 1598, 1490, 1459,
4.2.18. (R)-8-Hydroxy-octa-5,6-dienoic acid methyl ester 13mf
Colorless liquid, Rf = 0.4 (silica gel, hexane/EtOAc 98:2); yield:
1340, 1091, 967, 910, cmÀ1 1H NMR (400 MHz, CDCl3, d ppm);
;
0.132 g, 78%, 98% ee, [
a
]
25 = À67.7 (c 0.45, CHCl3); HPLC using chi-
D
7.70–7.68 (d, J = 8.0 Hz, 2H), 7.32–7.28 (m, 5H), 7.23–7.21 (m,
2H), 6.19–6.17 (m, 1H), 5.48–5.43 (q, J = 20.0 Hz, 1H), 3.81–3.77
(m, 2H), 2.78 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3, d
ppm) 206.4, 143.5, 134.6, 133.4, 129.7, 129.1, 128.7, 128.2, 127.3,
127.3, 126.8, 96.1, 90.6, 49.6, 34.4, 21.5; HRMS (ESI): m/z calcd
for C24H34N2O: 313.1136 [M+Na+]; found: 336.1042.
ral column, chiralcel AS-H, hexanes:i-PrOH/95:5; flow rate 0.8 mL/
min 214 nm, retention times: 20.3 min. (R) and 23.8 min. (S). IR
(neat) 3448, 2951, 2869, 1963, 1736, 1439, 1201, 1154,
1054 cmÀ1 1H NMR (400 MHz, CDCl3, d ppm) 5.34–5.32 (m, 1H),
;
5.25–5.22 (m, 1H), 4.11–4.09 (d, J = 8.0 Hz, 2H), 3.66 (s, 3H),
2.38–2.34 (t, J = 16.0 Hz, 2H), 2.06–2.03 (m, 3H), 1.78–1.73 (m,
2H) 13C NMR (100 MHz, CDCl3, d ppm) 203.3, 174.1, 92.5, 92.4,
60.6, 60.4, 51.6, 33.2, 27.8, 24.0. HRMS (ESI): calcd for C9H14O3:
170.0943 [M+H+]; found: 171.1022.
4.2.14. (R)-4-Chloro-N-(5,5-dimethyl-hexa-2,3-dienyl)-N-methyl-
benzenesulfonamide 13jd
Colorless liquid, Rf = 0.9 (silica gel, hexane/EtOAc 95:5); yield:
25 = À83.2 (c 0.62, CHCl3); HPLC using
4.2.19. (R)-Pentadeca-4,5-dienoic acid methyl ester 13ng
Colorless liquid, Rf = 0.4 (silica gel, hexane/EtOAc 98:2); yield:
0.225 g, 72%, 99% ee, [
a]
D
chiral column, chiralcel OD-H, hexanes:i-PrOH/98:2; flow rate
0.5 mL/min, 250 nm, retention times: 16.7 min. (R) and 17.3 min.
(S); IR (neat) 3095, 2958, 2898, 2860, 1961, 1589, 1479, 1402,
0.188 g, 72%, [
a
]
D
25 = À61.5 (c 0.73, CHCl3); IR (neat) 3008, 2900,
2840, 2644, 1960, 1710, 1430, 1280, 1250, 1210, 1170 cmÀ1
.
1H
1347, 1161, 1013, 987, cmÀ1 1H NMR (400 MHz, CDCl3, d ppm)
;
NMR (400 MHz, CDCl3, d ppm) 5.25–5.11 (m, 2H), 3.70–3.67 (s,
3H), 2.45–2.41 (t, J = 16.0 Hz, 2H), 2.32–2.28 (m, 2H), 1.97–1.93
(m, 2H), 1.59 (s, 2H), 1.27 (s, 11H), 0.94–0.86 (t, J = 16.0 Hz, 3H);
13C NMR (100 MHz, CDCl3, d ppm) 203.6, 173.6, 92.6, 89.4, 51.5,
33.2, 31.8, 29.6, 29.4, 29.2, 29.1, 28.8, 23.8, 22.6, 14.0; HRMS
(ESI): calcd for C15H26O2: 238.1933 [M+H+]; found: 239.2012. the
13C NMR data were in agreement with the reported data.6f
7.33–7.32 (d, J = 8.0 Hz, 4H), 5.27–5.22 (q, J = 20.0 Hz, 1H), 5.16–
5.13 (m, 1H), 3.59–3.50 (q, J = 36.0 Hz, 2H), 3.14–3.01 (m, 2H),
2.24 (s, 3H), 1.04 (s, 9H); 13C NMR (100 MHz, CDCl3, d ppm)
202.8, 139.1, 136.3, 129.4, 128.8, 104.8, 88.1, 50.3, 34.2, 31.9,
30.1; the 13C NMR data was in agreement with the reported data.8d
4.2.15. (R)-5-Phenyl-penta-3,4-dien-1-ol 13ka
Acknowledgements
Colorless liquid, Rf = 0.5 (silica gel, hexane/EtOAc 95:5); yield:
0.104 g, 65%, 94% ee, [
a
]
25 = À219.7 (c 0.59, CHCl3); HPLC using
We are thankful to the DST (New Delhi) for a J.C. Bose National
Fellowship Grant to M.P. and also for the FIST and IRPHA programs.
Support of the UGC under UPE and CAS programs is also gratefully
acknowledged. P.O.R. and N.S.K. are thankful to the CSIR (New
Delhi) for a research fellowship.
D
chiral column, chiralcel OD-H, hexanes:i-PrOH/97:3; flow rate
0.5 mL/min, 254 nm, retention times: 34.1 min. (R) and 38.0 min.
(S); IR (neat) 3350, 3063, 3030, 2928, 2879, 1950, 1753, 1701,
1597, 1494, 1458, 1311, 1299, 1203, 1049, 912, 877, cmÀ1 1H
;
NMR (400 MHz, CDCl3, d ppm) 7.32–7.30 (m, 4H), 7.23–7.18 (m,
1H), 6.22–6.18 (q, J = 16.0 Hz, 1H), 5.63–5.58 (q, J = 20.0 Hz, 2H),
3.80–3.78 (t, J = 8.0 Hz, 2H), 2.44–2.38 (m, 3H); 13C NMR
(100 MHz, CDCl3, d ppm) 205.7, 134.4, 128.6, 126.9, 126.6, 95.1,
91.5, 61.9, 32.1; the 13C NMR data were in agreement with the
reported data.5h
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4.2.16. (R)-5-(4-Fluoro-phenyl)-penta-3,4-dien-1-ol 13kb
Colorless liquid, Rf = 0.6 (silica gel, hexane/EtOAc 95:5); yield:
0.105 g, 59%, 82% ee, [
a]
25 = À184.6 (c 0.55, CHCl3); HPLC using chi-
D
ral column, chiralcel OD-H, hexanes:i-PrOH/98:2; flow rate 0.6 mL/
min, 254 nm, retention times: 24.1 min. (R) and 29.0 min. (S); IR
(neat) 3351, 3043, 2928, 2958, 1951, 1738, 1232, 1203, 1153,
912, 750, cmÀ1 1H NMR (400 MHz, CDCl3, d ppm) 7.27–7.24 (m,
;
2H), 7.01–6.99 (t, J = 8.0 Hz, 2H), 6.18–6.16 (m, 1H), 5.63–5.58
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