Synthesis of (E,Z)-5-bromo-1,1-dimethoxy-5-trimethylsilyl-4-pentene, an upper chain allenic prostaglandin building block

Article abstract of DOI:10.1081/SCC-120023984

This work explores the synthetic route to allenic prostaglandins. In a search for more efficient and reliable methods for the introduction of the allene moiety into the side chains of prostaglandins, the synthons, the (E) and (Z) isomers of 1-bromo-5,5-dimethoxy-1-trimethylsilyl-1-pentene (13a) and (13b), have been prepared and converted to R,S-1,1-dimethoxy-6-phenyl-4,5-hexadiene (16), a prostaglandin analog.

Full text of DOI:10.1081/SCC-120023984

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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 19, pp. 3271–3283, 2003
Synthesis of (E,Z )-5-Bromo-1,1-dimethoxy-5-
trimethylsilyl-4-pentene, an Upper Chain Allenic
Prostaglandin Building Block
2
Antonio Guzman-Duran,1, Esther Guzman,
*
Keith H. Pannell,3 and Winston D. Lloyd3
1Contributio of Centro de Investigacion en Materiales
Avanzados, Chihuahua, Chihuahua, Mexico
2University of Texas, Houston Health Science Center,
Houston, Texas, USA
3Department of Chemistry, University of Texas at
El Paso, El Paso, Texas, USA
ABSTRACT
This work explores the synthetic route to allenic prostaglandins. In
a search for more efficient and reliable methods for the introduction
of the allene moiety into the side chains of prostaglandins, the syn-
thons, the (E ) and (Z) isomers of 1-bromo-5,5-dimethoxy-1-tri-
methylsilyl-1-pentene (13a) and (13b), have been prepared and
converted to R,S-1,1-dimethoxy-6-phenyl-4,5-hexadiene (16),
prostaglandin analog.
a
*Correspondence: Antonio Guzman-Duran, Contributio of Centro de Investi-
gacion en Materiales Avanzados, 31109 Chihuahua, Chihuahua, Mexico.
3271
DOI: 10.1081/SCC-120023984
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3272
Guzman-Duran et al.
INTRODUCTION
The luteolytic activity of 4,5-dehydro PGF2a, 1, has been shown to
[1]
be greater than that of PGF2a in several animal species. Allenic pros-
taglandins with the allenic moiety in both the superior[1,2] and inferior[1]
chains have been prepared. Compound 1 has the greater luteolytic
effect.[3] All previous syntheses of 1 have employed a cuprate induced
conversion of a propargyllic acetate to an allene as the key step in the
construction of the allene containing side chain.[1–3] Crabbe and
Carpio,[2] for example, added the acetate of 4-pentyne-1-ol to Corey’s
lactol[2,4–8] and generated the propadiene unit from the resulting
propargylic acetate using lithium dimethyl cuprate. Here we seek a
simpler strategy for the synthesis of 1, which would avoid the subsequent
oxidation and reduction steps, which are problematic in the reported[1]
synthesis of 1.
An attractive route for the introduction of the allene group is via
difunctional olefin 2, in which A serves as a nucleophyllic site for addition
to Corey’s lactol and B is a functional group capable of generating a
double bond in the resulting allylic alcohol.[9–22]
The silyl bromo olefin (where A is a trimethyl silyl group and B is a
bromine) appeared to be an ideal synthon for this purpose. Halogen
metal exchange could generate the needed nucleophile and the Peterson
reaction[15] could deliver the allenic group with the other portions of the
molecule at the proper oxidation level. In this work we show that the
protected derivatives of 5-trimethylsilyl-4-pentynoic acid do not survive
the hydroalumination reaction. This makes it impossible to prepare 1 by
this route.
Since acetals are more resistant to reduction than esters or ortho
esters and are easily converted to the readily oxidizable aldehydes,
the synthesis of the corresponding acetal was undertaken to provide an
intermediate that can be used in the preparation of 1 (Sch. 2)
A
CO CH
OH
B
2
3
B
OH
2
CH
CO
H
CO
3
2
2
+
OH
OH
O
O
H
O H
1
1
O
H
O
H
Scheme 1. A retrosynthetic analysis of the route to prostaglandin 1.

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Synthetic Route to Allenic Prostaglandins
3273
OH
O
OH
Si
H
Si
OC
OCH
3
H
OC
1
B
3
r
OC
H
3
14
+
OH
Li
Scheme 2. The use of an acetal in the preparation of 1.
RESULTS AND DISCUSSION
In order to conserve the oxidation state of the carboxylic acid group,
protection by converting it to an orthoester was investigated. Following
the route of Whiting et al.[23] who have prepared a homolog of 9 with
lower yield, 4-butyne-1-ol was mesylated to 3 and treated with sodium
cyanide to give 4-cyanobutyne, 4 (85%, overall yield). The cyano group
of 4 was converted to the ester group of 5 by treatment with methanol,
HCl, and water (Sch. 3).
Since the ester could be subject to reduction in the subsequent
reactions an attempt was made to protect it by preparing the bicyclic
ortho ester,[26] 6. The 4-cyanobutyne, 4, was treated with dry HCl in
methanol followed by triethylamine and 1,1,1-tris(hydroxymethyl)ethane
to give the bicyclic orthoester, 1-(3-butynyl)-4-methyl-2[2,2,2]octane, 6
(Sch. 4). Despite several attempts to silylate this compound by treatment
with DBU followed by TMSCl and AgCl no silylated orthoester was
obtained. This approach was therefore abandoned.
Treatment of 4-cyanobutyne, 4, with gaseous HCl in anhydrous
methanol gave iminoester, 7, which on treatment with methanol in
hexane gave trimethyl ortho-4-pentynoate, 8 (Sch. 5).
The ease of hydrolysis of orthoesters was confirmed by the observa-
tion that percolation of compound 8 through silica gel converted it to the
corresponding ester, 5.
Silylation of orthoester, 8, with DBU, silver chloride, and TMSCl,
gave the silyl orthoester 9. Alternatively 4 could be silylated and then
converted to silyl orthoester 10 by a similar procedure but the overall
yield was lower.[24,25] Treatment of the silylated orthoester, 9, with silica
gel gave methyl 5-trimethylsilyl-4-pentynoate, 10, in quantitative yield
(Sch. 6).

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3274
Guzman-Duran et al.
N(Et)
O
3
O
S
Me
OH
MeSO
Cl
3
O
3 (95%)
NaCN
N
HCl
O
C
MeOH
Me
O
5 (58%)
4 (69%)
Scheme 3. The conversion of 4-butyne-1-ol to ester (5).
1 MeOH, HCl
O
O
CN
2 NEt
3 CH
3
O
4
6 (19%)
OH)
C (CH
2
3
3
Scheme 4. Preparation of the bicyclic orthoester (6).
HCl
MeOH
2 days
O
N
H
O
CN
_
MeOH
O
O
Me
4
8 (83%)
7 (80%)
Scheme 5. Preparation of trimethyl ortho-4-pentynoate (8).
1. DBU
2. TMSCl & AgCl
Silica gel
O
O
Si
O
Si
O
O
O
O
O
10 (100%)
9 (67%)
8
Scheme 6. Preparation of methyl 5-trimethylsilyl-4-pentynoate (10).
Reduction of 10 with one equivalent of DIBALH converted it to the
corresponding aldehyde, 11. Aldehyde, 11, was protected by conversion
to acetal 12 in quantitative yield by treatment with absolute methanol
and tosic acid. Acetal 12 was readily hydrolyzed to aldehyde 11 (Sch. 7).

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Synthetic Route to Allenic Prostaglandins
3275
The use of acetal 12 as a synthon for the introduction of an allyl
group into prostaglandins was tested by treating it with DIBALH and
quenching with bromine to give a mixture of the two bromoalkenyl
derivatives 13a and 13b (Sch. 8). The work of Zweifel et al.[9,18,24]
shows that the treatment of silylated acetylenes by the use of DIBALH
and bromine gives the E isomer as the major product and the Z isomer as
the minor product. These products were separable by chromatography.
Reductive removal of bromine from the mixture of bromo-alkylated
intermediate 13b was effected by treatment of the compound with
one equivalent of tBuLi. Quenching the lithiated intermediate
with methanol gave silylated acetals 14a and 14b (Sch. 9). No attempt
was made to separate these two isomers and it was not possible to
establish the ratio.
Quenching the lithiated intermediate with benzaldehyde gave
isomeric oily alcohols, 15a and 15b (Sch. 10), which were separable by
preparative thin layer chromatography.
Treatment of 15a with KH in THF as suggested by Peterson[15] gave
a mixture of racemic allene 16 (30%) and alkyne 17 (24%) (Sch. 11).
MeOH, pTsOH
DIBALH
O
O
O
Si
Si
O
Si
O
H
11 (85%)
10
12 (100%)
H O, pTsOH
2
(50%)
Scheme 7. Preparation and reversible hydrolysis of the silylated acetal (10).
O
Si
O
Br
13a (38%)
1. DIBALH
2. Br2
Si
O
+
O
O
Br
Si
O
12
13b (16%)
Scheme 8. The reductive bromination of the acetal (12).

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3276
Guzman-Duran et al.
O
H
O
Si
14(a/b)
O
O
1. tBuLi
Br
Si
14(a+b) (44%)
2. MeOH
13b
+
O
Si
H
O
14(b/a)
Scheme 9. Preparation of the mixed E and Z isomers of 1,1-dimethoxy-4-
pentene, 14(a/b).
O
O
O
O
O
H
Si
Br
Si
15(a/b) (52%)
1. tBuLi
2.
13a (70%)
CH=O
+
+
Si
O
O
O
O
Br
HO
Si
13b (39%)
15(b/a) (11%)
Scheme 10. The preparation of a racemic E and Z mixture of 6-hydroxy-1,1-
dimethoxy-6-phenyl-5-trimethylsilyl-4-hexene, (15a/b).
The NMR spectra of the silylated acetylenic compounds and the
allenic compound clearly show that there is restricted rotation about
the C2 to C3 bond. This makes extracting the NMR parameters difficult.
The J 4 and J5 values reported for the allenic system are typical. The
overall yield of E and Z isomers of 5-bromo-1,1-dimethoxy-5-trimethyl-
silyl-4-pentene (13a) and (13b) based on 3-butynol was 13%.

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Synthetic Route to Allenic Prostaglandins
3277
Si
HO
O
H
O
O
O
H
16 (30%)
KH
15a
+
O
or
O
HO
Si
O
17 (24%)
O
H
Scheme 11. The dehydrosilylation of compound (15a/b).
EXPERIMENTAL
Reagents were used as purchased from Aldrich or they were dried
appropriately before use. HCl (g) was dried by sparging through conc.
H2SO4 and was then passed through a Dryerite trap. TLC was performed
on Silica Gel 60 F254 plates from Merck and visualized by UV and/or
iodine vapor. Column chromatography was carried out on 70–230 mesh
silica gel from Merck and Flash chromatography was also done on
70–230 mesh silica gel from Merck. The solvents used as eluants were
concentrated using a cold trap equipped rotary evaporator to facilitate
proper disposal of used solvents. Infrared spectra were recorded on a
Perkin Elmer 1600 series FTIR spectrometer.
NMR spectra were recorded on a Bruker Aspect 3000 200 MHz
instrument in either CDCl3 or in C6D6 or on a Varian EM390 90 MHz
instrument. Shifts are relative to internal Me4Si. The use of the verb
‘‘concentrated’’ refers to evaporation under reduced pressure (water
aspirator) using a rotary evaporator. Mass spectra and elemental
analyses were determined by Galbraith Laboratories, Knoxville, TN.
Methyl 3-butyne-1-sulfonate (3). A solution of 3-butyne-1-ol (225 g,
0.357 mol) in CH2Cl2 was placed in a round-bottomed flask and the
stirred mixture was cooled to ꢀ10ꢁC. Triethylamine (70 mL, 51 g,
0.50 mol) was added and then mesyl chloride (49 g, 0.427 mol) was
added dropwise with stirring. After 3 h at ꢀ10ꢁC the solution was allowed
to warm to room temperature, extracted with saturated NaHCO3, dried

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3278
Guzman-Duran et al.
(Na2SO4) and concentrated to give a reddish-black oil. This oil was
purified by chromatography over silica gel (benzene, an attempt to use
toluene was unsuccessful). Concentration gave 3, a reddish viscous oil
(50 g, 0.34 mol, 95%). Spectral data for 3. IR (neat) 3310, 3020, 1980,
1365, 1345, 1180, 995, 965, 907, 820, 710, 655 cmꢀ1. 1H NMR (200 MHz,
C6D6): ꢀ 4.15 (t, 2H, J ¼ 6.4 Hz), 2.8 (s, 3 H), 2.52 (td, 2H, J ¼ 6.4,
2.7 Hz), 2.13 (t, 1H, J ¼ 2.7). 13C NMR (200 MHz, C6D6): ꢀ 79.9 (d,
J ¼ 14.6 Hz), 71.5 (d, J ¼ 73.1 Hz), 68.1 (t, J ¼ 22.2 Hz), 37.0 (q,
J þ 33 Hz), 19.4 (t, J ¼ 34.6 Hz). Anal. calcd. for C5H8O3S: C, 40.53; H,
5.44. Found: C, 40.54; H, 5.34.
4-Cyano-1-butyne (4). A solution of 3 (110 g, 0.7 mol) and sodium
cyanide (175 g, 3.57 mol) in DMF (300 mL) was stirred at room tempera-
ture for 2 h. A deep brown oil (48 g) was obtained after purification by
Flash column chromatography (CH2Cl2). Distillation (80ꢁC/35 Torr)
gave 4, a colorless oil (40 g, 0.506 mol, 69%). Spectral data for 4. IR
(CH2Cl2) 3306, 2918, 2238, 2114, 1340, 1323. cmꢀ1
.
1H NMR
(200 MHz, C6D6): ꢀ 2.2 (m, 4H), 2.09 (s, 1H). 13C NMR (200 MHz,
C6D6): ꢀ 118.9 (s,), 80.8 (d, J ¼ 8 Hz), 71.3 (d, J ¼ 51 Hz), 17.2 (t,
J ¼ 30 Hz), 15.5 (t, J ¼ 29 Hz). Anal. calcd. for C5H5N: C, 75.92;
H, 6.37. Found: C, 75.76; H, 6.58.
Methyl 4-pentynoate (5). A solution of nitrile 4 (32.52 g, 0.412 mol) in
absolute MeOH (27.7 mL, 0.648 mol) was cooled to ꢀ10ꢁC and saturated
with dry HCl (g, H2SO4, Dryerite). After concentration water (7.42 mL,
0.412 mol) was added and the ester, 5 (26.8 g, 0.24 mol, 58%), was
extracted into ether. An insoluble residue of 4-pentynoic acid (6.68 g,
0.068 mol, 10%) remained. Spectral data for 5. IR (neat) 3299, 2960,
2131, 1738, 1439, 1367 cmꢀ1 1H NMR (200 MHz, C6D6): ꢀ 3.27 (s,
.
3H), 2.14 (m, 4H), 1.79 (m, 1H). 13C NMR (200 MHz, C6D6): 171.5 (s),
82.7 (d, J ¼ 2.7 Hz), 69.4 (d, J ¼ 84.4 Hz), 51.2 (q, J ¼ 159.0 Hz), 33.1 (t,
J ¼ 40.0 Hz), 14.5 (t, J ¼ 40.5 Hz).
1-(3-Butynyl)-4-methyl-2,6,7-trioxobicyclo[2.2.2]octane (6). A solution
of nitrile 4 (9.0 g, 0.114 mol) in dry methanol (5.2 mL) was cooled to
ꢀ10ꢁC and the solution was saturated with dry HCl. After 10 min
addition of dry THF (50 mL) caused the intermediate to precipitate.
The pH was raised to 5.0 by the addition of anhydrous triethylamine
and 1,1,1-tris(hydroxymethyl)ethane (11 g, 0.092 mol) was added. Stirring
was continued for 16 h at room temperature. Concentration gave a resi-
due which was extracted with CH2Cl2.. After drying (Na2SO4) con-
centration gave a white crystalline solid (5 g) which was purified by
sublimation (3 mmHg, bath temperature 71ꢁC) to afford 6 (5.0 g,
0.022 mol, 19%) as a white crystalline solid. Spectral data for 6. IR
(neat) 3302, 2121, 1060 cmꢀ1
.
1H NMR (200 MHz, C6D6): ꢀ 3.61

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Synthetic Route to Allenic Prostaglandins
3279
(s, 6H), 2.7 (m, 2H), 2.4 (m, 2H), 1.87 (t, 1H, J ¼2.7 Hz), 0.16 (s, 3H).
13C NMR (200 MHz, C6D6): ꢀ 108.5 (s), 84.3 (d, J ¼ 39 Hz), 72.4 (t,
J ¼ 54 Hz), 36.8 (t, J ¼ 88 Hz), 30.0 (s), 13.8 (q, J ¼ 110 Hz), 13.4 (t,
J ¼ 90).
Methyl 4-pentynoateiminoester (7). A solution of nitrile 4 (2.0 g,
0.025 mol) and dry methanol (1.125 mL, 3.9 g, 0.0278 mol) in ether
(6.8 mL) was prepared, stirred for 5 min and then cooled to ꢀ10ꢁC.
The solution was saturated with dry HCl gas which caused the tempera-
ture to rise to 40ꢁC. It was again cooled to ꢀ10ꢁC, hexane was added and
the solution was concentrated. On cooling to Dry Ice temperature white
crystals of 7 (3.0 g. 0.020 mol, 80%) formed. These crystals were washed
with dry ether until the pH of the ether was 7.0. The white crystalline
solid was held 24 h in an evacuated dessicator over KOH, NaOH, and
P2O5 before it was used in subsequent reactions. Spectral data for 7. IR
(CDCl3) 3310, 2227, 1663, 1472, 1412 cmꢀ1. 1H NMR (200 MHz, CHCl3):
ꢀ 4.33 (s, 3H), 4.19 (s, 1H), 2.99 (t, 2H, J ¼ 7.0 Hz), 2.67 (t, 2H
J ¼ 7.0 Hz), 2.07 (s, 1H). 13C NMR (200 MHz, CHCl3): ꢀ 178 (s), 79 (s),
71 (d, J ¼ 75 Hz), 60.8 (q, J ¼ 19 Hz), 32 (t, J ¼ 30 Hz), 15 (t, J ¼ 3 Hz).
Trimethyl ortho-4-pentynoate (8). A solution of iminoester 7 (2.00 g,
0.025 mol) and methanol (1.95 g, 2.4 mL, 0.61 mol) in dry hexane was
stirred for three days at room temperature under nitrogen.
Concentration gave 8 (2.67 g, 0.0169 mol, 83%) as a colorless oil.
Spectral data for 8. IR (neat) 3280, 2950, 2840, 2120, 1419, 1328, 1219,
1149, 1040 cmꢀ1. 1H NMR (90 MHz, CHCl3): ꢀ 3.27 (s, 9H), 2.2 (m, 3H),
2.12 (s, 1H), 1.92 (m, 2H).
Methyl 4-pentynoate (5) from 8. A solution of orthoester 8 (100 mg,
0.633 mmol) in CH2Cl2, C6H14 (4:1) was percolated through a silica gel
column (2.15 g, 70–230 mesh). The major fraction on concentration gave
5 (71 mg, 100%). Spectral data for 5. As reported above.
Trimethyl ortho-5-trimethylsilyl-4-pentynoate (9). A mixture of
orthoester 8 (4.7 g, 0.030 mol), DBU (5.5 g, 0.036 mol), and AgCl
(0.86 g, 0.006 mol) in CH2Cl2 (124 mL) was heated to reflux and
TMSCl (3.9 g, 0.036 mol) was added. After 25 h at reflux the solution
was concentrated and the residue was extracted with hexane. The
hexane solution was filtered through Celite and concentrated to give a
colorless oil (7.0 g). Distillation (82ꢁC/1 mmHg) gave 9 (4.6 g, 67%).
Spectral data for 9. IR (neat) 2950, 2830, 2170, 1740, 1670, 1438, 1245,
1
1100, 1045, 965, 919, 842 cmꢀ1. H NMR (90 MHz, CHCl3): ꢀ 3.15 (s,
9H), 2.2 (m, 2H), 2.0 (m, 2H), 0.15 (s, 9H).
Methyl 5-trimethylsilyl-4-pentynoate (10). A solution of orthoester 9
(17.48 g, 0.076 mol) in CH2Cl2, C6H14 (4:1) was percolated through a
silica gel column (450 g, 70–230 mesh). This solution on concentration

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Guzman-Duran et al.
gave 10 (13.0 g, 0.076 mol, 100%). Spectral data for 10. IR (neat) 2962,
1
2183, 1740, 1440, 1368, 1205, 1175 cmꢀ1. H NMR (200 MHz, CDCl3): ꢀ
3.55 (s, 3H), 2.44 (m, 4H), 0.15 (s, 9H). 13C NMR (200 MHz, C6D6):
ꢀ 171.5 (s), 105.7 (s), 85.0 (s), 51.2 (q, J ¼ 88 Hz), 33.1 (t, J ¼ 100 Hz),
15.9 (t, J ¼ 99 Hz), 0.12 (q, J ¼ 105 Hz). Anal. calcd. for C9H16O2Si: C,
58.65; H, 8.75. Found: C, 58.68; H, 8.79.
Methyl 5-trimethylsilyl-4-pentynoate (10) from 5. A mixture of ester 5
(26.8 g, 0.24 mol), AgCl (6.9 g, 0.048 mol), and DBU (51.0 g, 0.336 mol)
in anhydrous CH2Cl2 (500 mL) was brought to reflux then TMSCl
(31.2 g, 0.288 mol) was added and refluxing was continued for 25 h.
Concentration gave a colorless oil which was extracted into hexane,
filtered through Celite and concentrated to 10 (30.1 g, 0.16 mol, 69%).
Spectral data for 10. See above.
5-Trimethylsilyl-4-pentynal (11). A stirred solution of 10 (23.5 g,
0.13 mol) in toluene was maintained at ꢀ65 to ꢀ70ꢁC during the
addition of a solution of DIBALH (20.3 g, 0.143 mol) in toluene
(25 mL) with stirring. After 23 min MeOH (50 mL) was added and the
reaction was allowed to warm to room temperature. After filtration
through a sintered glass funnel, concentration gave a yellowish oil
(18 g) which was purified by flash column chromatography (50 g,
hexane). Concentration gave a colorless oil, 11 (17.0 g, 0.111 mol,
85.4%). Spectral data for 11. IR (neat) 2950, 2170, 1745, 1230 cmꢀ1
.
1H NMR (200 MHz, C6D6): ꢀ 9.8 (s, 1H), 2.6 (m, 4H) 0.2 (s, 9H);
13C NMR (200 MHz, C6D6): ꢀ 199.7 (d, J ¼ 129 Hz), 175.4 (s), 85.3 (s),
105.7 (s), 85.3 (s), 42.6 (t, J ¼ 93 Hz), 14.1 (t, J ¼ 98.4 Hz), 0.2 (s, 9H,
J ¼ 104). 29Si NMR (200 MHz, C6D6): ꢀ ꢀ19.7 (s). MS m/z 139 (Mþ),
109, 85, 83, 73, 61, 59, 53. Anal. calcd. for C8H14OSi: C, 62.28; H, 9.15.
Found: C, 58.68; H, 9.70.
1,1-Dimethoxy-5-trimethylsilyl-4-pentyne (12). Anhydrous pTsOH
(300 mg) was added to a solution of 11 (6.0 g, 0.039 mol) in absolute
methanol. The reaction mixture was stirred for 1 h at room temperature.
The solution was concentrated and the residue was dissolved in CH2Cl2
and washed with aqueous NaHCO3. After drying (Na2SO4) concen-
tration gave 12 (7.8 g, 0.039 mol, 100%). Spectral data for 12. IR (neat)
2950, 2836, 2176, 1250, 1110, 1060, 840 cmꢀ1. 1H NMR (200 MHz, C6D6):
ꢀ 4.29 (t, 1H, J ¼ 5.8 Hz), 3.08 (s, 6H), 2.11 (t, 2H, J ¼ 6.4 Hz), 1.65
(q, 2H, J ¼ 6.0 Hz), 0.04 (s, 9H). 13C NMR (200 MHz, C6D6): ꢀ 106.9
(s), 103.4 (d, J ¼ 65.4 Hz), 84.4 (s), 52.4 (q, J ¼ 88.8 Hz), 31.8 (t,
J ¼ 103.0 Hz), 15.5 (t, J ¼ 96.0 Hz), 0.18 (q, J ¼ 103.5 Hz). 29Si NMR
(200 MHz, C6D6) ꢀ ꢀ19.7. MS m/z; ms 199, 169, 127, 111, 97, 89, 75,
73). Anal. calcd. for C10H20O2Si: C, 59.95; H, 10.06. Found: C, 59.68;
H, 10.27.

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Synthetic Route to Allenic Prostaglandins
3281
5-Trimethylsilyl-4-pentynal (11) from 12. A solution of 12 (155 mg,
0.775 mmol) in 95% THF and a trace of pTsOH was refluxed for 12 h.
The solution was cooled and extracted with hexane. Concentration gave
11 (60 mg, 0.389 mmol, 50%), a colorless oil. Spectral data for 11. As
reported above.
E and Z Isomers ocf 5-Bromo-1,1-dimethoxy-5-trimethylsilyl-4-pentene
(13a) and (13b). A stirred solution of 12 (5.0 g, 0.025 mol) in anhydrous
hexane (10 mL) was cooled to ꢀ50ꢁC. A solution of DIBALH (7.1 g,
0.050 mol) in anhydrous hexane (5 mL) was added dropwise at ꢀ50ꢁC.
After stirring for 45 min at ꢀ50ꢁC the reaction mixture was allowed to
warm to room temperature. Concentration gave an oil which was
dissolved in anhydrous THF (12 mL). This solution was cooled to
ꢀ70ꢁC and bromine (12 g, 0.075 mol) in anhydrous CH2Cl2 was added
with stirring at that temperature. After this solution had warmed to
room temperature it was contacted with a solution of NaOH (24 g,
0.6 mol) in water (100 mL) with vigorous stirring. After drying
(Na2SO4), concentration gave a colorless oil (8.2 g) that was dissolved in
ether and purified by column chromatography over silica gel (500g, elution
with CH2Cl2). The major fraction was isomer , 13a (2.6 g, 9.4 mmol, 38%),
and the minor fraction was isomer, 13b (1.1 g, 0.4 mmol, 16%). Spectral
data for 13a. IR (neat) 1600, 840 cmꢀ1. 1H NMR (90 MHz, CDCl3): ꢀ 6.7
(t, 1H, J ¼ 8 Hz), 4.3 (t, 1H, J ¼ 6 Hz), 3.3 (s, 6H), 2.2 (m, 2H), 1.7 (m, 2H),
0.3 (s, 3H), 0.2 (m, 6H). MS m/e 248, 207, 201, 169. Spectral data for 13b.
IR (neat) 1600, 840 cmꢀ1 1H NMR (90 MHz, CDCl3): ꢀ 6.3 (t, 1H,
.
J ¼ 7 Hz), 4.4 (t, 1H, J ¼ 6 Hz), 3.3 (s, 6H), 2.2 (m, 2H), 1.8 (m, 2H), 0.3
(s, 3H), 0.2 (s, 6H). MS m/e 248, 209, 207, 201, 169. Anal. calcd. for
C10H21O2BrSi: Br, 28.47. Found: Br, 24.0.
Mixed E and Z Isomers of 1,1-Dimethoxy-5-trimethylsilyl-4-pentene
(14a and b). A stirred solution of 13b (0.32 g, 1.4 mmol) in anhydrous
THF (5 mL) was cooled to ꢀ78ꢁC and the temperature was kept below
ꢀ65ꢁC during the addition of a 1.5 M solution of tBuLi (1.6 mL,
2.4 mmol). After 5 min at ꢀ65ꢁC the temperature was allowed to rise to
ꢀ20ꢁC and was held at that temperature for 1 h 18 min. Methanol
(10 mL) was added. Concentration gave a mixture of 14a and b (0.10 g,
0.5 mmol, 44%). The ratio of isomers in this oily liquid could not be
established by chromatography or from the spectra. Spectral data for
1
14a and b. IR (neat) 2950, 1605, 1240, 1120, 860, 833 cmꢀ1. H NMR
(90 MHz, CDCl3): ꢀ 6.3 (m, 2H), 4.4 (t, 1H, J ¼ 5Hz), 3.3 (m, 6H), 2.2 (m,
2H), 1.7 (m, 2H), 0.1 (s, 3H), 0.04 (s, 6H).
E and Z isomers of R,S-6-Hydroxy-1,1-dimethoxy-6-phenyl-5-tri-
methylsilyl-4-hexene (15a) and (15b). A solution of the mixed isomers
13a and 13b (1.3 g, 4.6 mmol) in anhydrous THF (25 mL) was cooled

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3282
Guzman-Duran et al.
to ꢀ78ꢁC under nitrogen and 1.5 M tBuLi (6.7 mL, 9.7 mmol) was added
with stirring. After 1 h at ꢀ78ꢁC benzaldehyde (0.5 g, 0.5 mL 4.6 mmol)
was added. Extraction with CH2Cl2 and concentration gave a colorless
oil. This material was purified by preparative TLC (hexane 95%, EtOAc
5%). The major fraction was the isomer, 15a (0.74 g, 2.4 mmol, 52%) and
the minor fraction was the isomer, 15b (0.15 g, 0.5 mmol, 11%). Spectral
data for 15a. IR (neat) 3450, 1600, 1100 cmꢀ1 1H NMR (90 MHz,
.
CDCl3): ꢀ 7.3 (m, 5H), 5.9 (t, 1H, J ¼ 7.5 Hz), 5.8 (s, 1H), 4.4 (t, 1H,
J ¼ 6 Hz), 3.3 (s, 6H), 3.2 (s, 1H), 2.2 (m, 2H), 1.8 (m, 2H), 0.1 (s, 9H).
MS m/z 307, 218.
Spectral data for 15b. IR (neat) 3400, 1600, 1240, 1120, 833 cmꢀ1
.
1H NMR (90 MHz, CDCl3) ꢀ 7.35 (m, 5H), 5.6 (m, 1H), 4.9 (m, 2H), 3.3
(s, 6H), 1.8 (m, 4H), 0.1 (s, 9H). MS m/e 307, 218.
R,S-1,1-Dimethoxy-6-phenyl-4,5-hexadiene (16) and 1,1-dimethoxy-
6-phenyl-5-hexyne (17). Potassium hydride (0.48 g, 12 mmol) was rinsed
with anhydrous hexane and suspended in anhydrous THF. To this
solution was added 15a (1.08 g, 3.5 mmol) in anhydrous THF (5 mL).
The reaction mixture was stirred for 2.5 h. TLC indicated that the
reaction was complete at this time. Excess of MeOH (5 mL) was added
and the mixture was concentrated to give 1.48 g of a colorless oil. This
material was extracted into CH2Cl2 and purified by preparative TLC (95%
hexane, 5% EtOAc). The less polar fraction was 16 (0.22 g, 1.0 mmol,
30%) and the more polar fraction was 17 (0.17 g, 0.8 mmol, 24%).
Spectral data for 16. IR (neat) 1940, 1600, 1100 cmꢀ1 1H NMR
.
(90 MHz, CDCl3): ꢀ 7.3 (m, 5H), 6.2 (quintet, 1H, J 4 ¼ 6.4, J5 ¼ 3.2),
5.6 (q, 1H, J ¼ 6 Hz), 4.4 (t, 1H, J ¼ 5 Hz), 3.3 (s, 6H), 2.2 (m, 2H), 1.8
(m, 2H). MS m/e 218, 186, 143. Spectral data for 17. IR (neat) 2804, 1600,
1490, 1125, 1065, 760, 695 cmꢀ1 1H NMR (90 MHz, CDCl3): ꢀ 7.29
.
(m, 5H), 4.4 (t, 1H, J ¼ 5 Hz), 3.3 (s, 6H), 2.5 (t, 2H, J ¼ 6H), 1.7 (m, 4H).
ACKNOWLEDGMENT
We would like to acknowledge support from the National Institutes
of Health during this investigation.
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Synthetic Route to Allenic Prostaglandins
3283
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Received in the USA March 18, 2003

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