Total synthesis of two novel brominated acetylenic diols (+)-diplyne C and E: Stereoselective construction of the (E)-1-bromo-1-alkene

Article abstract of DOI:10.1016/j.tetasy.2005.08.019

The total syntheses of the enantiomers of two novel brominated polyacetylenic natural products diplynes C and E are reported. Pd and Cu(I)-catalyzed coupling reactions were employed to synthesize the diyne and enyne units. The stereochemistry of the terminal (E)-alkenyl bromide in diplyne C was constructed stereoselectively using Brown's hydroboration-bromination procedure. The stereochemistry of the internal (E)-double bond in diplyne E was established using a Takai reaction. The stereocenter was derived from d-mannitol.

Full text of DOI:10.1016/j.tetasy.2005.08.019

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3107–3114
Total synthesis of two novel brominated acetylenic
diols (+)-diplyne C and E: stereoselective construction
of the (E)-1-bromo-1-alkene
*
Benjamin W. Gung, Craig Gibeau and Amanda Jones
Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA
Received 25 July 2005; accepted 9 August 2005
Abstract—The total syntheses of the enantiomers of two novel brominated polyacetylenic natural products diplynes C and E are
reported. Pd and Cu(I)-catalyzed coupling reactions were employed to synthesize the diyne and enyne units. The stereochemistry
of the terminal (E)-alkenyl bromide in diplyne C was constructed stereoselectively using Brownꢀs hydroboration–bromination pro-
cedure. The stereochemistry of the internal (E)-double bond in diplyne E was established using a Takai reaction. The stereocenter
was derived from D-mannitol.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
1,n-diyne unit
R1
Many naturally occurring organobromo compounds
have been reported, most of which are from marine
sources. The first isolation of naturally occurring bro-
R2
OH
OH
1
1
R = Br; R = H
1 2
1 2
minated acetylenic diols from the genus Diplastrella
2 R = H; R = Br
2
was recently reported (Fig. 1). The extract, from which
these novel compounds were isolated, exhibited inhibi-
tory activity against HIV-1 integrase.
Br
OH
OH
3
4
The diplynes differ in structure in the degree of unsatu-
ration on the left hand (vinylbromide end) of the mole-
cules. There is an element of symmetry in both diplynes
A 1 and D 4 in the center portion of the structures as a
Br
Br
OH
OH
1
,n-diyne unit. Recently, we reported the total synthesis
of diplynes A 1 and D 4 by taking advantage of the 1,n-
diyne symmetry and by using Cadiot–Chodkiewicz and
Sonogashira coupling reactions to construct the diyne
OH
OH
3
–5
5
and the enyne units, respectively.
While a similar
strategy allows the construction of the diyne unit com-
mon to all five diplynes, the lack of symmetry in diply-
nes C 3 and E 5 demands a different strategy in the
construction of the left-hand fragment. The presence
of a terminal (E)-alkenyl bromide unit in diplyne C 3
and an internal (E)-double bond in diplyne E 5 requires
Figure 1. Acetylenic diols diplynes A–E 1–5 isolated from the
Philippines sponge Diplastrella sp. The stereocenter in the natural
(
ꢀ)-diplyne A 1 was established to be R by our previous synthesis.
additional synthetic considerations to achieve a stereo-
selective synthesis.
*
0
Corresponding author. Fax: +1 513 529 5715; e-mail: gungbw@
muohio.edu
Initially, we chose to use the Takai reaction for the con-
struction of the (E)-vinyl bromide unit in 3 because the
957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.019

3108
B. W. Gung et al. / Tetrahedron: Asymmetry 16 (2005) 3107–3114
procedure could produce vinyl halide directly (Fig. 2).6
However, the reaction was not chemoselective when
separated by column chromatography. Our attempts to
separate the vinyl bromide from vinyl chloride in sub-
sequent steps were not successful.
6
using a combination of CrCl and CHBr . After experi-
2
3
menting with a few other methods, the (E)-1-bromo-1-
alkene unit of diplyne C 3 was introduced through a
stereoselective hydroboration–bromination procedure.
Based on our experience in acetylenic chemistry,3,7,8 we
anticipated the synthesis of diplyne E 5 to be brief by
means of a Pd(0) and Cu(I) catalyzed coupling reactions.
Since CrBr was not commercially available and our
2
attempted in situ reduction of CrBr with LiAlH did
3
4
not lead to any desired product, we turned our attention
to a potentially selective reduction of the geminal
dibromoalkene 9. A mixture of 9 with diethyl phosphite
was subjected to microwave irradiation for 1 min (Eq.
9
2
). This procedure produced vinyl bromide 10 in 98%
Takai reaction
yield, but with virtually no stereoselectivity. A 1:1 mix-
ture of the (E)- and (Z)-isomers was obtained, which
again could not be separated by column chromatogra-
phy in this or subsequent steps.
Cadiot-Chodkiewicz coupling
Br
OH
OH
3
After encountering chemoselectivity problems with the
Takai reaction and stereoselectivity problems with the
reduction of dibromoalkene, we decided to use a proce-
H
O
OH
OH
1
0,11
Br
dure developed by Brown.
This procedure involved a
stereoselective preparation of the (E)-vinyl bromide start-
ing from a terminal alkyne (Scheme 1). Once this method
was chosen, it became apparent that the element of sym-
metry involving 1,n-diyne also existed here. Starting from
the commercially available 1,11-dodecadiyne 11, a hyd-
Sonogashira coupling
D
-mannitol
roboration reaction using catecholborane gave the desired
Br
10
boronic acid 13 upon workup with H O. In order to re-
2
OH
OH
duce the amount of diboronic acid 14, only 0.25 equiv of
catecholborane was used, which was added slowly over
12 h using a syringe pump. The boronic acids 13 and 14
were obtained as white solids which were subjected to a
5
1,2-dibromoethylene
Figure 2. Retrosynthetic analysis for diplynes C 3 and E 5.
mercuration reaction with Hg(OAc) . The bromination–
2
1
1
demercuration was carried out with Br in pyridine.
2
The three-step pr ocedure afforded the desired ( E)-1-bro-
mo-1-alkene 15 in 60% overall yield based on the recov-
ered starting materials and an (E):(Z) ratio of 96:4.
2
. Results and discussion
The synthesis of diplyne C 3 started with the preparation
of the (E)-1-bromo-1-alkene fragment. Since this
double bond is connected with an Sp carbon, the pre-
Vinyl bromide 15 was then coupled to bromoalkyne 178
in the presence of CuCl to give diyne 18 in 45% yield. Re-
moval of the isopropylidene protecting group using p-
TsOH in MeOH led to the isolation of (+)-diplyne C as
a white solid in 92% yield. All spectroscopic data of the
synthetic sample are consistent with that reported for
the natural product. The synthetic diplyne C 3 had a spe-
3
ferred method of Pd(0)-catalyzed coupling reactions
using 1,2-dibromoethylene could not be employed. We
therefore considered the most direct method of prepar-
6
ing an (E)-vinyl bromide, the Takai olefination. Alde-
hyde 6 was treated with 6 equiv of CrCl and 2 equiv
2
of CHBr in THF producing vinyl bromide 7 in 67%
cific rotation of [a] = +13.3 in MeOH. The positive sign
3
D
yield (Eq. 1). Unfortunately, the reaction gave a mixture
of vinyl bromide and vinyl chloride, which could not be
corresponds to an (S)-configuration since the
stereocenter is derived from D-mannitol. Although the
CrCl , CHBr
X
OTHP
2
3
OTHP
O
ð1Þ
ð2Þ
X = Br 7, (7/8 = 1:1)
X = Cl 8
6
THF, 67%
HP(O)(OEt)2
Br
OTHP
Br
OTHP
NaOEt, EtOH
Microwave 1 min.
trans = 10a, (10a/10b = 1:1)
cis = 10b
Br
9
98%

B. W. Gung et al. / Tetrahedron: Asymmetry 16 (2005) 3107–3114
3109
specific rotation was not available for natural diplyne C 3
due to the small quantity isolated, the natural diplyne A
However, the synthesis of 19 did not proceed as
planned. Carpita and Rossi have studied the reaction
shown in Scheme 2 and concluded that compound 23
is more reactive than the starting material 22 and a sec-
was reported to have a specific rotation of [a] = ꢀ8.7 in
D
2
MeOH. From a common starting material, D-mannitol,
1
3
the synthetic samples of diplynes A, C, D, and E have the
same (+)-sign in specific rotation corresponding to an
ond coupling occurred rapidly to give 24. Since no
attempt was made to improve the yield of 23 by using
excess 22 in the previous study, we conducted the reac-
tion with upto 6 equiv of 22. The results proved dis-
appointing. Rather than producing the desired product
23 as the major product, a mixture of 23 (13%)
and the bis-coupling product 24 (57%) was obtained
(Scheme 2). Therefore, we have confirmed the results
of Carpita and Rossi that 23 is substantially more
reactive than 22. Due to the low yield and the volatility
of 23, the attempt at a convergent synthesis was
abandoned.
(
S)-configuration. It is reasonable to assume that the nat-
ural diplyne C has an (R)-configuration by analogy to
diplyne A because the diplynes are similar in structure
2
,3
and have an identical origin in nature.
Initially, a potentially more efficient convergent route
was attempted for the synthesis of diplyne E 5
(
Fig. 3), which would have involved the synthesis of
the bromine-containing terminal enyne 19 by a Negishi
coupling reaction between trimethylsilyl (TMS) acety-
lene and the commercially available cis/trans mixture
1
2
of 1,2-dibromoethylene. The synthesis of diplyne E 5
would have followed a Pd-catalyzed coupling reaction
between the intermediates 19 and 20.
Our alternative synthetic route (Scheme 3) began with
the reduction of the commercially available 6-heptynoic
acid 25 to alcohol 26, which proceeded in 89% yield. The
O
O
OH
B
BH
1
)
OH
12
13
o
7
0 C, THF
+
OH
B
1
1
2
) H O, 92%
2
OH
HO
B
OH
14
O
O
1
) Hg(OAc) , THF
Br
2
o
15, 60%
-30 C, 1 h
Br
17
+
MeOH, EtNH , H O
2
) Br , Pyridine
Br
2
2
2
Br
o
CuCl, NH OH.HCl
-30 C, 1 h
2
1
6, 8%
o
3
0-40 C, 45%
p-TsOH, MeOH
Diplyne C 3
Br
O
O
5
0oC, 24 h
92%
18
Scheme 1.
Br
19
Br
+
OH
OH
I
5
OH
OH
20
Figure 3. Retrosynthetic analysis for a convergent synthesis of diplyne E 5.

3110
B. W. Gung et al. / Tetrahedron: Asymmetry 16 (2005) 3107–3114
Br
Br
TMS
Br
1
) n-BuLi/Hex/THF
22
2
3, 13%
0
(cis/trans mixture)
-
78 C, 1 h
TMS
H
TMS
ZnCl
+
Pd(PPh3)4
2) ZnCl2
21
TMS
TMS
24, 57%
Scheme 2.
O
O
1) LiAlH , Et O
Br
4
2
O
17
HO
HO
HO
2
) HCl, H O
2
CuCl, Et NH,
25
26
2
.
MeOH, NH OH HCl
8
9%
2
63%
O
(
COCl) , DMSO
2
O
O
O
o
27
Et
3
N, -78 C
2
8
O
87%
I
CrCl , CHI3
2
p-TsOH, MeOH
O
o
THF, 0 C
o
O
50 C, 24 h
29
67% (two steps)
I
TIPS
TIPS
H
OH
OH
OH
OH
Pd(PPh )Cl , CuI,
3
2
i-Pr NH, 74%
31 E:Z = 90:10
30 E:Z = 80:20
2
Br
Br
2
2
TBAF, THF
00%
(
cis/trans mixture)
OH
OH
Diplyne E 5
1
Pd(PPh ) , CuI
TEA, 42%
3
2
3 4
Scheme 3.
cross coupling of 26 with bromoalkyne 17 in the pres-
ence of CuCl led to the desired diyne 27 in 63% yield.
Next, a Swern oxidation of the primary alcohol cleanly
acetylene and a mixture of vinyl iodide 30 (21%)
enriched with the cis isomer was recovered. These find-
ings suggest that the (E)-isomer of vinyl iodide 30
is more reactive towards the coupling reaction and
one could improve the (E)/(Z) ratio of 31 by using
excess vinyl iodide 30.
1
4
produced aldehyde 28 in 87% yield. Takai olefination
was then performed using 2 equiv of CHI and 6 equiv
3
6
of CrCl . The resulting mixture was subjected to treat-
2
ment of p-TsOH in MeOH. This allowed the isolation of
diol 30 in 67% overall yield for the two steps. Vinyl
iodide 30 was isolated as an 80:20 (E:Z) mixture in favor
of the (E)-isomer. The addition of triisopropylsilyl
Next, removal of the TIPS groupusing TBAF pr ovided
terminal enyne 32, quantitatively. A Sonogashira cou-
pling reaction between 32 and four equivalents of the
commercially available mixture of cis/trans dibromoeth-
ylene 22 in the presence of Pd(PPh ) and CuI gave dip-
(
TIPS) acetylene under modified Sonogashira conditions
afforded the TIPS protected enyne 31 in 74% yield
3
4
5
,15
5,16
(
unoptimized).
The (E):(Z) ratio of 31 improved to
lyne E 5 as a pale yellow solid in 42% yield.
As we
9
0:10 following the cross coupling reaction to TIPS
reported previously, the Pd-catalyzed coupling to an

B. W. Gung et al. / Tetrahedron: Asymmetry 16 (2005) 3107–3114
3111
excess mixture of cis/trans dibromoethylene 22 preferen-
tially produces the trans-isomer. However, the syn-
4.2. 2-(11-Bromo-undec-10-enyloxy)-tetrahydro-pyran
10a and 10b
3
thetic sample contained ca. 10% of the internal cis-
double bond isomer originated from the Takai reaction
in the preparation of 30. Except for this contamination,
the synthetic diplyne E 5 exhibited nearly identical spec-
troscopic data to that reported for the natural product
A mixture of EtONa (330 mg, 4.85 mmol), diethyl phos-
phite (0.62 ml), and the dibromoalkene 9 (1.0 g,
2.4 mmol) in EtOH (12 ml) was placed in an Erlenmeyer
flask in a microwave oven, operated at 60% of 1500 W,
and irradiated for 1 min. The reaction mixture was then
cooled to rt. The solvent was removed and the product
was purified over a silica gel column affording the prod-
and gave a specific rotation [a] = +5.9 in MeOH.
D
Again due to the minute amount of the natural diplyne
2
E isolated, no optical activity data were reported. As
described above for diplyne C, the synthetic sample
has an (S)-configuration while the natural diplyne E
should have an (R)-configuration.
ucts as a 1:1 mixture of (E):(Z) isomers (780 mg, 98%).
1
H NMR (300 MHz, CDCl ): d 1.22 (10H, m), 1.30
3
(2H, m), 1.48 (6H, m), 1.62 (1H, m), 1.74 (1H, m),
1
(
.94 (1H, q, J = 6.8 Hz), 2.10 (1H, q, J = 6.8 Hz), 3.29
1H, dt, J = 6.6, 9.5 Hz), 3.41 (1H, m), 3.65 (1H, dt,
J = 6.8, 9.5 Hz), 3.78 (1H, m), 4.50 (1H, t, J = 4.1 Hz),
3. Conclusion
1
3
6
.01 (2H, m). C NMR (75 MHz, CDCl ): d 19.5,
3
We have completed the first total syntheses of (+)-diply-
nes C and E. (+)-Diplyne C was produced in an overall
yield of ca. 22% using Brownꢀs hydroboration–bromina-
tion procedure to establish the (E)-vinyl bromide stereo-
chemistry. (+)-Diplyne E was synthesized stereo-
selectively by means of a Takai olefination and Pd-
catalyzed cross coupling reactions in an overall yield
of ca. 10%.
25.3, 26.0, 27.9, 28.4, 28.7, 28.9, 29.1, 29.2, 29.6, 30.6,
32.7, 62.0, 67.4, 98.6, 107.4, 103.9, 134.8, 138.0.
4.3. Dodec-1-en-11-ynyl-boranediol 13
To diyne 11 (402 mg, 2.46 mmol) was added a 1 M solu-
tion of catecholborane 12 (65 ll, 0.61 mmol) in THF
(0.6 ml). This was added through the aid of a syringe
pump over a period of 15 h, under an atmosphere of
nitrogen in an oil bath at 70 °C. The reaction was
allowed to run for a total of 24 h, yielding boronic ester.
4. Experimental
The solvent was removed and H O (0.6 ml) added and
2
All reactions were carried out under an atmosphere of
nitrogen in oven-dried glassware. Reagents were
purchased from commercial sources and used without
further purification. Flash column chromatographic
separations were performed using silica gel 40–63 lm,
unless otherwise noted. Reactions were monitored with
allowed to stir for 3 h. The solids were filtered, resulting
in boronic acids 13 and 14 (117 mg, 92%) as a mixture of
yellow and white solids.
1
Compound 13: H NMR (300 MHz, CD OD): d 1.30
3
(6H, m), 1.38 (2H, m), 1.48 (4H, m), 1.92 (1H, t,
J = 2.6 Hz), 2.15 (2H, dt, J = 2.6, 6.9 Hz), 2.25 (2H, q,
J = 6.8 Hz), 5.76 (1H, d, J = 18.0 Hz), 7.02 (3H, m),
1
13
TLC and UV light. NMR spectra ( H, C) were
recorded on Bruker 200, 300, and 500 MHz spectrome-
ters with CDCl or CD OD as the solvents. Melting
1
3
7.17 (2H, m). C NMR (75 MHz, CD OD): d 18.2,
3
3
3
points are not corrected.
25.4, 28.0, 28.3, 28.5, 28.6, 28.9, 29.0, 29.2, 35.9, 68.0,
84.5, 112.1 (2), 122.4 (2), 148.2, 157.8.
4
7
.1. 2-(11-Halo-undec-10-enyloxy)-tetrahydropyran
and 8
1
Compound 14: H NMR (300 MHz, CD OD): d 1.30
3
(
8H, m), 1.40 (4H, m), 1.48 (2H, m) 2.14 (5H, m), 5.55
1
3
A suspension of CrCl (11.3 g, 91.7 mmol) in dry THF
(1H, d, J = 17.6), 6.52 (1H, dt, J = 6.5, 17.7 Hz).
C
2
(
38 ml) was allowed to stir at rt under an atmosphere
NMR (75 MHz, CD OD): d 19.0, 29.6, 30.1, 30.2,
3
of nitrogen. To this was added dropwise a solution of
30.2, 30.4, 36.9, 69.3, 85.0, 116.3, 120.9, 153.9.
aldehyde 6 (3.9 g, 15.3 mmol) and CHBr3 (2.67 ml,
3
3
2
0.6 mmol) in dry THF (76 ml) at 0 °C for a period of
0 min. The reaction was allowed to run an additional
h. Upon completion, the mixture was diluted with
4.4. (E)-1-Bromo-dodec-1-en-11-yne 15
To a solution of boronic acids 13 and 14 (99 mg,
0.50 mmol) in THF (0.50 ml) at ꢀ30 °C was added
H O and extracted three times with Et O, and then dried
over Na SO . The resulting solution was filtered, con-
2
2
Hg(OAc) (152 mg, 0.50 mmol). This was allowed to stir
2
4
2
centrated, and purified over a silica gel column to give
for 1 h at ꢀ30 °C. Next, a solution of Br (30 ll,
2
a mixture of the bromo- and chloro-containing products
0.50 mmol) in pyridine (0.50 ml) was added at ꢀ30 °C.
This was allowed to stir for 1 h. The solution was
warmed to rt and slowly poured into an ice cold mixture
of n-pentane and 6 M HCl. The layers were separated
and the aqueous layer extracted twice with n-pentane.
The combined organic layers were then washed with
6 N HCl, saturated aqueous Na S O , then dried over
1
7
and 8 in a ratio of approximately 1:1 (3.4 g, 67%). H
NMR (300 MHz, CDCl ): d 1.22 (8H, m), 1.29 (4H, m),
3
1
.51 (6H, m), 1.65 (1H, m), 1.76 (1H, m), 1.97 (2H, q,
J = 7.4 Hz), 3.32 (1H, dt, J = 6.6, 9.5 Hz), 3.44 (1H,
m), 3.67 (1H, dt, J = 6.8, 9.5 Hz), 3.80 (1H, m), 4.52
1
3
(
1H, t, J = 2.7 Hz), 5.97 (2H, m). C NMR (75 MHz,
2
2
3
CDCl ): d 19.5, 25.4, 26.1, 28.4, 28.7, 28.8, 29.1, 29.3,
MgSO . The resulting solution was filtered, concen-
trated and purified over silica gel column affording com-
pounds 15 (80 mg, 60%) and 16 (9 mg, 8%) as yellow
3
4
2
1
9.4, 30.6, 32.8, 62.1, 67.5, 98.6, 103.9, 116.5, 133.9,
38.1.

3112
B. W. Gung et al. / Tetrahedron: Asymmetry 16 (2005) 3107–3114
1
oils. H NMR (300 MHz, CDCl ): d 1.26 (4H, m), 1.35
HRMS: Calcd for C H BrO +Na, 349.0779: found
16 23 2
3
(
(
(
4H, m), 1.48 (4H, m), 1.91 (1H, t, J = 2.6 Hz), 2.01
2H, q, J = 6.5 Hz), 2.15 (2H, dt, J = 2.8, 6.9 Hz), 5.97
1H, d, J = 13.5 Hz), 6.12 (1H, dt, J = 7.0, 14.0 Hz).
M+Na: 349.0779, M+2+Na: 351.0748.
4
.7. 6-Heptyn-1-ol 27
1
3
C NMR (75 MHz, CDCl ): d 18.3, 28.3, 28.5, 28.6,
3
2
8.8, 28.9, 29.1, 32.8, 68.0, 84.6, 104.0, 138.1. IR: t
To a round bottom flask equipped with a stirring bar
ꢀ
1
cm 3307, 3064, 2929, 2856, 2117, 1620, 1463, 1434,
1
under nitrogen was added LiAlH (903 mg, 23.8 mmol)
4
231, 940.
and anhydrous Et O (75 ml) at 0 °C. Then, a solution
2
of 6-heptynoic acid 25 (1.5 g, 11.9 mmol) in dry Et O
2
4.5. (13E)-4-(14-Bromo-tetradec-13-ene-1,3-diynyl)-2,2-
dimethyl-[1,3]dioxolane 18
(15 ml) was added dropwise with vigorous stirring.
The mixture was then allowed to warm to rt and stirred
for an additional hour. Next, 1 M HCl (40 ml) was
added dropwise and the reaction mixture stirred for an
To a round bottom flask equipped with a stirring bar
and under nitrogen was added MeOH (0.16 ml), a solu-
tion of NH OHÆHCl (16 mg, 0.23 mmol) in 58 ll of
water, 70% aqueous solution of EtNH (0.13 ml), and
CuCl (2 mg, 0.025 mmol). Acetylene 15 (80 mg,
additional 0.5 h before being diluted with Et O. The lay-
2
2
ers were separated and the aqueous layer extracted three
2
times with Et O. The organic layers were combined,
2
dried over MgSO and then filtered. The solvent was
4
0
.32 mmol) was added in one portion. Next, bro-
emoved under reduced pressure and the crude purified
moalkyne 17 (67 mg, 0.32 mmol) was added over a per-
iod of 1 h keeping the temperature between 30 and
3
1
NH Cl (2.5 g) in H O (8 ml) was added with vigorous
stirring. The product was extracted twice with Et O
and the combined organic layers washed with saturated
aqueous NH Cl and then dried over MgSO . The result-
ing solution was filtered, concentrated, and purified over
a silica gel column, affording compound 18 as a pale yel-
low oil (54 mg, 45%) as well as the homocoupling prod-
using a silica gel column to afford the product as a clear
1
oil (1.18 g, 89%). H NMR (300 MHz, CDCl ): d 1.52
3
5 °C. The reaction was allowed to run for an additional
.5 h at 40 °C, then a solution of KCN (0.6 g) and
(
6H, m), 1.91 (1H, t, J = 2.7 Hz), 2.15 (2H, dt,
13
J = 2.5, 6.6 Hz), 3.59 (1H, t, J = 6.4 Hz). C NMR
4
2
(
75 MHz, CDCl ): d 18.74, 25.28, 28.59, 32.54, 63.03,
3
2
6
8.72, 84.83.
4
4
4
1
.8. 9-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-nona-6,8-diyne-
-ol 27
To a round bottom flask equipped with a stirring bar
under an atmosphere of nitrogen was added a solution
of NH OHÆHCl (7.8 mg, 0.11 mmol) in H O (0.10 ml),
uct of compound 17 (21 mg, 17%). [a] = +28.6
D
1
(
MeOH). H NMR (500 MHz, CDCl ): d 1.25 (8H,
3
2
2
m), 1.34 (3H, s), 1.34 (2H, m), 1.46 (3H, s), 1.48 (2H,
m), 2.00 (2H, q, J = 6.7 Hz), 2.24 (2H, t, J = 7.0 Hz),
3
6
MeOH (2.25 ml), a 70% aqueous solution of EtNH2
2.25 ml), and CuCl (11.1 mg, 0.11 mmol). Then, alkyne
6 (251 mg, 2.24 mmol) was added in one portion. Next,
(
2
.91 (1H, dd, J = 1.9, 6.1 Hz), 4.12 (1H, dd, J = 1.6,
.4 Hz), 4.73 (1H, t, J = 6.3 Hz), 5.98 (1H, d,
1
3
a solution of bromoalkyne 17 (505 mg, 2.47 mmol) in
MeOH (1 ml) was added over the course of 0.5 h using
a syringe pump. The resulting mixture was stirred for
an additional 1 h at rt. A solution of KCN (0.43 g)
and NH Cl (1.79 g) in H O (6 ml) was then added with
J = 13.4), 6.14 (1H, dt, J = 7.2, 13.4 Hz). C NMR
(
125 MHz, CDCl ): d 19.2, 25.8, 26.0, 28.0, 28.5, 28.7,
3
2
1
1
8.8, 28.9, 29.1, 32.8, 64.0, 65.8, 69.7, 70.8, 72.7, 82.0,
ꢀ1
04.0, 110.5, 138.1. IR: t cm 3064, 2927, 2855, 2256,
4
2
620, 1458, 1323, 1235, 1065, 939. HRMS: Calcd for
vigorous stirring. The resulting mixture was extracted
C H BrO +Na: 389.1092, found M+Na: 389.1109,
M+2+Na: 391.1082.
1
9
27
2
three times with Et O and the organic layers dried over
2
MgSO . The solution was filtered and the solvent
4
removed under reduced pressure. The crude mixture
4
.6. (+)-Diplyne C 3
was purified over a silica gel column to afford a yellow
1
oil (335 mg, 63%). [a] = +42.9 (c 1.1, MeOH),
H
D
To a round bottom flask equipped with a stirring bar
under nitrogen was loaded a solution of the protected
diol 18 (30 mg, 0.08 mmol) in MeOH (1.6 ml). PTSA
NMR (300 MHz, CDCl ): d 1.35 (3H, s), 1.46 (3H, s),
3
1
.52 (6H, m), 2.78 (2H, t, J = 6.5 Hz), 3.62 (2H, t,
J = 6.2 Hz), 3.91 (1H, dd, J = 6.2, 8.0 Hz), 4.12 (1H,
(
2 mg, 8 lmol) was added at 50 °C. The reaction was
1
3
dd, J = 6.4, 8.0 Hz), 4.73 (1H, t, J = 6.2 Hz).
C
allowed to run for 24 h at 50 °C. Then, NaHCO (17
mg, 0.16 mmol) was added while stirring for 15 min.
The solids were removed by filtration and the product
purified over a silica gel column, affording diplyne C
3
NMR (75 MHz, CDCl ): d 19.64, 25.40, 26.31, 26.51,
3
2
8
2
8.26, 32.56, 63.11, 64.96, 66.25, 70.12, 71.16, 73.30,
2.18, 111.00. HRMS: Calcd for C H O +Na:
59.1310, found M+Na: 259.1305.
1
4
20
3
as
a
white solid (mp61–63 °C, 24 mg, 92%).
1
[
a] = +13.3 (MeOH). H NMR (500 MHz, CD OD):
D
3
d 1.24 (6H, m), 1.32 (4H, m), 1.44 (2H, m), 1.98 (2H,
q, J = 7.0 Hz), 2.20 (2H, m), 3.46 (1H, dd, J = 5.6,
4.9. 9-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-nona-6,8-diynal
28
1
1.0 Hz), 3.51 (1H, dd, J = 6.0, 11.0 Hz), 4.27 (1H, dd,
J = 5.7, 6.0 Hz), 6.05 (1H, d, J = 14.0 Hz), 6.10 (1H,
dt, J = 7.0, 14.0 Hz). C NMR (125 MHz, CD OD): d
To a three-necked round bottom flask equipped with a
1
3
stirring bar under nitrogen was added (COCl)
(0.87 ml, 1.73 mmol) in freshly distilled CH Cl (7 ml).
3
2
1
9.6, 29.2, 29.7, 29.8, 29.9, 30.0, 30.2, 33.7, 64.5, 65.5,
2
2
ꢀ
1
6
7.0, 70.7, 75.7, 81.7, 105.0, 139.4. IR: t cm 3377
This solution was cooled to ꢀ78 °C and DMSO
(
broad), 3054, 2931, 2856, 2254, 1620, 1422, 941, 739.
(0.13 ml, 1.88 mmol) added dropwise over a period of

B. W. Gung et al. / Tetrahedron: Asymmetry 16 (2005) 3107–3114
3113
5
min. After stirring for 10 min, a solution of 27
4.11. 14-Triisopropylsilanyl-tetradec-11-ene-3,5,13-
triyne-1,2-diol 31
(
371 mg, 1.57 mmol) in anhydrous CH Cl (3 ml) was
2
2
added dropwise. After an additional 15 min. at
78 °C, TEA (1.37 ml, 9.73 mmol) was added dropwise
and the reaction mixture was warmed to ꢀ10 °C. Then,
M HCl (5 ml) was added and the aqueous layer
ꢀ
To a round bottom flask equipped with a stirrer bar un-
der nitrogen was added a solution of compound 30
(75 mg, 0.21 mmol) in THF (2 ml). To this solution
was added TIPS acetylene (0.07 ml, 0.31 mmol), CuI
(0.4 mg, 0.002 mmol), and Pd(PPh ) Cl (1.5 mg,
1
extracted twice with Et O. The organic layers were
2
combined and washed once with H O before being dried
2
3 2
2
over MgSO4 and filtered. The solvent was removed
under reduced pressure and the crude mixture purified
0.002 mmol). Next, i-Pr NH (0.06 ml, 0.43 mmol) was
added dropwise. The reaction was allowed to proceed
2
over a silica gel column to afford an orange oil (319
for 3 h before quenching with saturated NH Cl solution
4
1
mg, 87%). [a] = +33.7 (c 0.5, MeOH), H NMR
and diluting with Et O. The organic layer was washed
D
2
(
(
(
300 MHz, CDCl ): d 1.35 (3H, s), 1.46 (3H, s), 1.56
2H, m), 1.70 (2H, m), 2.27 (2H, t, J = 6.8 Hz), 2.44
1H, dt, J = 1.6, 7.1 Hz), 3.91 (1H, dd, J = 6.1,
one time with saturated NaCl, dried over MgSO , and
filtered. The solvent was removed under reduced pres-
sure and the crude mixture purified over a silica gel col-
3
4
8
.1 Hz), 4.12 (1H, dd, J = 6.4, 8.1 Hz), 4.73 (1H, t,
umn to afford an orange oil (64 mg, 74%). [a] = +8.2,
D
1
3
1
J = 6.2 Hz), 9.72 (1H, d, J = 1.5 Hz).
C NMR
(c 0.4, MeOH), H NMR (300 MHz, CDCl ): d 1.05
3
(
4
2
75 MHz, CDCl ): d 19.49, 21.55, 26.29, 26.51, 27.82,
3.62, 65.34, 66.22, 70.10, 71.01, 73.55, 81.47, 111.02,
(21H, m), 1.51 (4H, m), 2.08 (2H, m), 2.27 (2H, m),
3.65 (1H, dd, J = 6.5, 11.3 Hz), 3.72 (1H, dd, J = 2.6,
11.1 Hz), 4.47 (1H, t, J = 5.6 Hz), 5.51 Hz (1H, dt,
3
02.31. HRMS: Calcd for C H O +Na: 257.1154,
1
4
18
3
1
3
found M+Na: 257.1157.
J = 1.4, 15.9 Hz), 6.14 (1H, dt, J = 7.0, 15.9 Hz).
C
NMR (75 MHz, CDCl ): d 11.70, 19.03, 19.47, 27.85,
28.10, 32.80, 64.01, 64.87, 66.71, 71.52, 73.61, 82.07,
3
4
.10. 12-Iodo-dodec-11-ene-3,5-diyne-1,2-diol 30
89.46, 106.14, 110.90, 145.14. HRMS: Calcd for
To a round bottom flask equipped with a stirring bar
under an atmosphere of nitrogen was added CrCl2
C H O Si+Na: 395.2383, found M+Na: 395.2374.
2
3
36
2
(
4.4 g, 35.9 mmol) and THF (60 ml) at 0 °C. Next, a
4.12. Tetradec-11-ene-3,5,13,triyne-1,2-diol 32
solution of aldehyde 28 (1.4 g, 5.98 mmol) and CHI
3
(
4.7 g, 11.9 mmol) in anhydrous THF (30 ml) was added
dropwise. The reaction mixture was stirred at 0 °C for
h before being diluted with H O (150 ml). The layers
To a round bottom flask equipped with a stirrer bar un-
der nitrogen was added a solution of compound 31
(62 mg, 0.17 mmol) in THF (2 ml). TBAF (0.25 ml,
0.25 mmol) was added and the resulting mixture stirred
for 2 h at rt. Next, ice water (10 ml) followed by 1 M
HCl (1 ml) was added and the aqueous layer extracted
4
2
were separated and the aqueous layer extracted four
times with Et O. The combined organic layers were
dried over Na SO and then filtered. The solvent was
2
2
4
removed under reduced pressure and the crude mixture
purified over a silica gel plug to remove any metal to
two times with Et O. The combined organic layers were
2
washed once with H O, dried over MgSO , then filtered.
2
4
afford a mixture of the protected vinyl iodide 29 and
The solvent was removed under reduced pressure and
the crude mixture purified over a silica gel column to af-
1
excess iodoform (2.48 g). H NMR (300 MHz, CDCl ):
3
d 1.24 (3H, s), 1.46 (3H, s), 1.51 (4H, m), 2.04 (2H,
m), 2.27 (2H, m), 3.92 (1H, dd, J = 6.1, 8.1 Hz), 4.13
ford a pale yellow solid (mp 46–48 °C, 36 mg, 100%).
1
[a] = +6.1 (c 0.1, MeOH), H NMR (300 MHz,
D
(
1H, dd, J = 6.4, 8.1 Hz), 5.99 (1H, dt, J = 1.4, 14.4
CDCl ): d 1.51 (4H, m), 2.10 (2H, m), 2.27 (2H, m),
3
Hz), 6.47 (1H, dt, J = 7.1, 14.4 Hz).
2.77 (1H, d, J = 2.2 Hz), 3.66 (1H, dd, J = 6.3,
11.4 Hz), 3.74 (1H, dd, J = 3.9, 11.5 Hz), 4.48 (1H, dd,
The crude mixture containing the protected vinyl iodide
J = 4.0, 6.0 Hz), 5.45 (1H, dq, J = 1.9, 15.9 Hz), 6.20
1
3
2
9 and CHI was dissolved in MeOH (120 ml). Next, p-
(1H, dt, J = 7.0, 15.9 Hz). C NMR (75 MHz, CDCl3):
d 19.44, 27.77, 27.99, 32.75, 64.04, 64.90, 66.73, 71.57,
73.63, 76.31, 82.03, 82.73, 109.50, 146.29. HRMS: Calcd
for C H O +Na, 239.1048: found M+Na: 239.1046.
3
TsOH (114 mg, 0.59 mmol) was added and the mixture
heated to 50 °C while stirring under an atmosphere of
nitrogen. After 24 h, NaHCO (1.27 g, 11.9 mmol)
3
14 16
2
was added, the reaction mixture was cooled to rt, and
the solids were filtered. The solvent was removed under
reduced pressure and the crude mixture was purified
over a silica gel column to afford a pale yellow solid
4.13. (+)-Diplyne E 5
To a round bottom flask equipped with a stirring bar
under nitrogen was added a solution of compound 32
(120 mg, 0.56 mmol), dibromoethylene 22 (413 mg,
(
(
(
mp56–57
°C, 1.29 g, 67% for two steps,
1
E):(Z) = 80:20). [a] = +8.9 (c 0.6, MeOH), H NMR
300 MHz, CDCl ): d 1.50 (4H, m), 2.05 (2H, m),
D
2.22 mmol), Pd(PPh ) (39 mg, 0.034 mmol), and CuI
3
3 4
2
3
1
.27 (2H, t, J = 6.5 Hz), 2.59 (1H, s), 2.92 (1H, s),
.65 (1H, dd, J = 6.5, 11.5 Hz), 3.73 (1H, dd, J = 3.4,
1.6 Hz), 4.46 (1H, t, J = 3.9 Hz), 5.99 (1H, dt,
(13 mg, 0.067 mmol) in TEA (9.3 ml). The resulting mix-
ture was stirred at rt for 16 h, before being diluted with
Et O and filtered over a pad of florisil using excess Et O.
2
2
1
3
J = 1.4, 14.4 Hz), 6.46 (1H, dt, J = 7.1, 14.4 Hz).
C
The solvent was removed under reduced pressure and
the crude mixture purified over a silica gel column to
afford a pale yellow solid (mp 80–82 °C, 74 mg, 42%).
NMR (75 MHz, CDCl3): d 19.44, 27.64, 27.80, 35.82,
4.01, 64.95, 66.70, 71.51, 73.66, 75.44, 81.99, 146.27.
HRMS: Calcd for C H IO +Na: 341.0015, found
6
[a] = +5.9 (c 0.15, MeOH), UV (MeOH): 287, 272,
1
2
15
2
D
1
M+Na: 341.0016.
214 nm. H NMR (500 MHz, CD OD): d 1.53 (4H,
3

3114
B. W. Gung et al. / Tetrahedron: Asymmetry 16 (2005) 3107–3114
m), 2.16 (2H, m), 2.31 (2H, m), 3.54 (1H, dd, J = 6.8,
1.2 Hz), 3.58 (1H, dd, J = 5, 11.2 Hz), 4.36 (1H, t,
3. Gung, B. W.; Gibeau, C.; Jones, A. Tetrahedron: Asym-
metry 2004, 15, 3973–3977.
1
4
. Brandsma L. Preparative Acetylenic Chemistry; 2nd ed.
J = 6.2 Hz), 5.61 (1H, dq, J = 2.0, 15.9 Hz), 6.16 (1H,
dt, J = 7.1, 15.8 Hz), 6.37 (1H, dd, J = 2.1, 14 Hz),
Elsevier: New York, 1988; Vol. 34.
5. Sonogashira, K. J. Organomet. Chem. 2002, 653, 46–49.
1
3
6
.78 (1H, d, J = 14 Hz). C NMR (125 MHz, CD OD):
3
6
. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
08, 7408–7410.
d 19.56, 28.76, 28.90, 33.57, 64.58, 65.79, 67.14, 70.71,
1
7
6.00, 81.51, 85.42, 91.43, 110.79, 118.65, 118.97,
7
. Gung, B. W.; Kumi, G. J. Org. Chem. 2004, 69, 3488–
1
46.42. HRMS: Calcd for C H BrO +Na, 343.0310:
1
6
17
2
3492.
found M+Na: 343.0318, M+2+Na: 345.0272.
8. Gung, B. W.; Dickson, H. Org. Lett. 2002, 4, 2517–2519.
. Kuang, C. X.; Senboku, H.; Tokuda, M. Tetrahedron
002, 58, 1491–1496.
10. Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94,
370–4371.
9
2
Acknowledgement
4
Acknowledgement is made to the donors of the Petro-
leum Research Fund (PRF 36841-AC4) administered
by the American Chemical Society.
11. Brown, H. C.; Larock, R. C.; Gupta, S. K.; Rajagopalan,
S.; Bhat, N. G. J. Org. Chem. 1989, 54, 6079–6084.
1
1
2. Negishi, E. I. Acc. Chem. Res. 1982, 15, 340–348.
3. Carpita, A.; Rossi, R. Tetrahedron Lett. 1986, 27, 4351–
4
354.
1
4. Marx, M.; Tidwell, T. T. J. Org. Chem. 1984, 49, 788–793.
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