A convergent synthesis of the 11-oxa prostaglandin analogue AL-12182

Article abstract of DOI:10.1021/jo048035v

(Chemical Equation Presented) The 11-oxa prostaglandin analogue AL-12182 1 has potent topical ocular hypotensive activity. A convergent and concise general synthesis of this class of prostanoid was developed employing a stereoselective coupling reaction between a tetrahydrofuran core electrophile and a nucleophilic omega side chain component, providing a route that should be suitable for commercial scale production. The tetrahydrofuran core was assembled from dimethyl D-malate using a stereoselective β-hydroxy ester dianion alkylation reaction.

Full text of DOI:10.1021/jo048035v

A Convergent Synthesis of the 11-Oxa Prostaglandin Analogue
AL-12182
Martin E. Fox,* Mark Jackson, Ian C. Lennon, and Raymond McCague
Dowpharma, Chirotech Technology Ltd., A subsidiary of the Dow Chemical Company,
U321 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, United Kingdom
mfox@dow.com
Received November 4, 2004
The 11-oxa prostaglandin analogue AL-12182 1 has potent topical ocular hypotensive activity. A
convergent and concise general synthesis of this class of prostanoid was developed employing a
stereoselective coupling reaction between a tetrahydrofuran core electrophile and a nucleophilic
omega side chain component, providing a route that should be suitable for commercial scale
production. The tetrahydrofuran core was assembled from dimethyl D-malate using a stereoselective
â-hydroxy ester dianion alkylation reaction.
Introduction
4,4-diethoxycrotonate and methylsodium glycolate has
been described,3a but the reported syntheses of enantio-
merically pure compounds of this type3b-f use carbohy-
drate starting materials to provide the four carbon atoms
of the tetrahydrofuran ring and C13 of the ω-chain. Thus,
in the original patent route to AL-12182 1 (Scheme 1),1a
the Corey lactone alcohol equivalent 4 was synthesized
from D-glucose, after which chemistry analogous to the
latter stages of the Corey lactone route to carbocyclic
prostanoids4 was used. A later and more efficient, but
conceptually similar, synthesis of AL-121821b was based
on the route developed by Hanessian3d starting with
D-sorbitol. An essential feature of these routes is a C15
ketone reduction that typically provides the noncrystal-
line final product as a 7:1 mixture of diastereoisomers
that require chromatographic separation.
Of particular concern to us was ensuring rigorous
control of the stereochemistry of the molecule to simplify
any subsequent regulatory submission for pharmaceuti-
cal substance.5 Therefore, we sought an alternative gen-
eral synthesis of 11-oxa prostaglandin analogues with
this consideration in mind.2 Comparing syntheses of
classical (carbocyclic) prostanoids (Scheme 2), introduc-
tion of the ω-chain by a C13-C14 bond-forming step
11-Oxa prostaglandin analogues have been found to
be effective agents for lowering intra-ocular pressure in
the treatment of glaucoma.1 These compounds exhibit
mechanisms similar to PGD2 2 and PGF2R 3 (Figure 1).
An efficient synthesis of a compound of this class, AL-
12182 1, was required with the potential for development
to produce kilogram quantities as a pharmaceutical
product.2 Previous syntheses of 11-oxa prostaglandin
analogues1,3 have utilized (3aR,4S,6aR)-4-hydroxymethyl-
hexahydrofuro[3,4-b]furan-2-one 4, the oxa-analogue of
the Corey lactone alcohol,4 or functionally equivalent
compounds as a key intermediate. The racemic synthesis
of this core tetrahydrofuran unit by reaction of methyl
(1) (a) Selliah, R. H.; Hellberg, M. R.; Klimko, P. G.; Sallee, V. L.;
Zinke, P. W. U.S. Patent 6,197,812; Chem. Abstr. 1997, 127, 135678.
(b) Selliah, R. H.; Hellberg, M. R.; Sharif, A. N.; McLaughlin, M. A.;
Williams, G. W.; Scott, D. A.; Earnest, D.; Haggard, K. S.; Dean, W.
D.; Delgado, P.; Gaines, M. S.; Conrow, R. E.; Klimko, P. G. Bioorg.
Med. Chem. Lett. 2004, 14, 4525-4528.
(2) Fox, M. E.; Jackson, M. EP Patent 1282627; Chem. Abstr. 2001,
135, 371564.
(3) (a) Vlattas, I.; Ong Lee, A. Tetrahedron Lett. 1974, 15, 4451-
4454. (b) Corey, E. J.; Eggler, J. F. DE Patent 2739277; Chem. Abstr.
1978, 89, 5999. (c) Thiem, J.; Lu¨ders, H. Liebigs. Ann. Chem. 1985,
2151-2164. (d) Hanessian, S.; Guindon, Y.; Lavalle´e, P.; Dextraze, P.
Carbohydr. Res. 1985, 141, 221-238. (e) Lourens, G. J.; Koekemoer,
J. M. Tetrahedron Lett. 1975, 43, 3719-3722. (f) Arndt, R. R.;
Koekemoer, J. M.; Lourens, G. J.; Venter, E. M. S.-Afr. Tydskr. Chem.
1981, 34, 121-127.
(5) For a discussion of the issues in commercial scale prostanoid
synthesis see McCague, R.; Lennon, I. C.; Fox, M. E.; Jackson, M. In
Handbook of Chiral Fine Chemicals Second Edition; Ager, D. J., Ed.;
Marcel Dekker: New York, in press; Chapter 30. Commercial Synthesis
of the Antiglaucoma Prostanoid Travoprost.
(4) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis;
Wiley: New York, 1989; p 250-266 and references therein.
10.1021/jo048035v CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/26/2005
J. Org. Chem. 2005, 70, 1227-1236
1227

Fox et al.
FIGURE 1. Structures of AL-12182 1, PGD2 2, and PGF2R 3 and numbering scheme for the prostanoid skeleton.
SCHEME 1. Summary of the Original Synthesis of AL-12182 1
SCHEME 2. Summary of Approaches to Carbocyclic Prostanoids
(disconnection D1) as used in the Corey synthesis suffers
from the requirement that establishment of the C15
stereochemistry is still necessary. On the other hand,
there are alternative approaches that use a C12-C13
bond-forming step (disconnection D2 in Scheme 2) and
thereby allow introduction of the entire ω-chain, stereo-
defined at C15, as a nucleophilic reagent. In addition,
this disconnection affords a more concise and convergent
overall synthesis. The core moiety to which the ω-chain
component is coupled may be a cyclopentenone 5, as in
the three-component coupling route developed by Noyori
and others,6 or a tricycloheptanone 6, as in the route
developed by Roberts and Newton.7 We have used this
latter approach for the development of the manufacturing
route to the prostanoid travoprost marketed by Alcon for
glaucoma and ocular hypertension.5,8
By analogy, we sought to extend this rationale to the
synthesis of AL-12182 (Scheme 3). Application of the
C12-C13 disconnection would entail a stereoselective
C-glycosidation reaction of the lactol 7 requiring activa-
tion of the hydroxyl group to a leaving group and then
displacement with a metalated ω-side chain reagent. We
were attracted to the activation method reported by a
group at Merck to construct 2,5-substituted tetrahydro-
(7) (a) Lee, T. V.; Roberts, S. M.; Dimsdale, M. J.; Newton, R. F.;
Rainey, D. K.; Webb, C. F. J. Chem. Soc., Perkin Trans. 1 1978, 1176-
1178. (b) Newton, R. F.; Roberts, S. M. Tetrahedron 1980, 36, 2163-
2196. (c) Davies, J.; Roberts, S. M.; Reynolds, D. P.; Newton, R. F. J.
Chem. Soc., Perkin Trans. 1 1981, 1317-1320.
(8) Boulton, L. T.; Brick, D.; Fox, M. E.; Jackson, M.; Lennon, I. C.;
McCague, R.; Parkin, N.; Parratt, J. S.; Rhodes, D.; Ruecroft, G. Org.
Process Res. 2002, 6, 138-145.
(6) (a) Noyori, R.; Suzuki, M. Angew. Chem., Int. Ed. Engl. 1984,
23, 847-876. (b) Morita, Y.; Suzuki, M.; Noyori, R. J. Org. Chem. 1989,
54, 1785-1787. (c) Suzuki, M.; Morita, Y.; Koyano, H.; Koga, M.;
Noyori, R. Tetrahedron 1990, 46, 4809-4822. (d) Noyori, R.; Suzuki,
M. Chemtracts Org. Chem. 1990, 3, 173-179.
1228 J. Org. Chem., Vol. 70, No. 4, 2005

A Convergent Synthesis of the 11-Oxa Prostaglandin
SCHEME 3. Retrosynthetic Analysis of AL-12182 1 Based on a C12-C13 Disconnection
furans with a high degree of trans-stereoselectivity and
exemplified on a large scale.9 In this method, the lactol
is silylated, and then the silyl lactol ether is converted
in situ to the 2-bromotetrahydrofuran with trimethylsilyl
bromide. The bromide is displaced with an aryl Grignard
reagent, effecting the desired C-C bond-forming step.
The method gives mainly the trans-diastereoisomer in
high selectivity even though the starting silyl ether was
a mixture of diastereoisomers, the stereoconvergence
suggesting an SN1-like mechanism with stereocontrol
provided by other residues on the tetrahydrofuran. We
reasoned that the presence of two substituents on the
same face of the five-membered ring in 7 would direct
the attack of the side chain nucleophile to the opposite
face in an analogous SN1-like step, thus achieving the
desired diastereocontrol. However, the effect of substit-
uents on the stereochemical outcome of such C-glycosi-
dation reactions of tetrahydrofurans can be subtle.10
We have recently published an efficient synthesis of
the required single enantiomer ω-chain iodide 811 in
which bioresolution of a precursor alkynol is used to
establish the stereocenter. We expected that the lactol 7
could be made by reduction of the lactone 9. Examination
of the open-chain ester equivalent 10 of the lactone 9
reveals an antialdol relationship of the two remaining
stereocenters, which could be established using the
well-precedented protocol of dianion alkylation of the
(R)-â-hydroxy ester 11.12 Hence, in our plan, starting
with a simple chiral building block, both R and ω side
chains would be introduced sequentially in stereoselective
reactions, resulting in a highly convergent overall syn-
thesis with a minimum number of linear steps. The
synthesis of the single isomer hydroxy ester 11 has been
reported by a wide variety of methodologies, including
selective reduction of malic acid,13a oxidative degrada-
tion of L-arabinose,13b enzymatic hydrolysis of 3,4-epoxy-
butyrates,13c and bioreduction13d or asymmetric hydroge-
nation13e-g of the corresponding ketone, although some
of these approaches may only be practical for the
(S)-enantiomer ent-11.
Results and Discussion
Our first objective was to obtain the key lactone
intermediate 9. Starting with dimethyl D-malate 12, the
ester group adjacent to the hydroxyl group was reduced
chemoselectively with borane-dimethyl sulfide complex
(Scheme 4).13a The primary hydroxyl group of the diol 13
was selectively protected with a tert-butyldimethylsilyl
group12d (12:1 primary/secondary protection) to give the
â-hydroxy ester 14 required for the stereoselective alkyl-
ation. In principle, it should be possible to introduce the
entire R-chain in the stereoselective alkylation step using
a suitable homoallylic alkylating agent. However, we
expected this reaction to proceed much more readily if
an activated alkylating agent was used. Therefore, we
chose a stepwise construction of the R-chain, introducing
the first three carbon atoms by alkylation with allyl
bromide or 3-bromo-1-(trimethylsilyl)-1-propyne, both of
which possess functionality suitable for elaboration to the
full R-chain.14 Both alkylating agents gave the antialdols
15 in a 20:1 diastereomeric ratio, but the reaction with
(13) (a) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fuji, T.;
Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389-1392. (b) Bock, K.;
Lundt, I.; Pederson, C. Acta Chem. Scand. Ser. B 1983, 37, 341-344.
(c) Bianchi, D.; Cabri, W.; Cesti, P.; Francalanci, F.; Ricci, M. J. Org.
Chem. 1988, 53, 104-107. (d) Hunt, J. R.; Carter, A. S.; Murrell, J.
C.; Dalton, H.; Hallinan, K. O.; Crout, D. H. G.; Holt, R. A.; Crosby, J.
Biocatalysis and Biotransformations, 1995, 12, 159-178. (e) For a
review on â-ketoester hydrogenation see Ager, D. J.; Laneman, S. A.
Tetrahedron: Asymmetry 1997, 8, 3327-3355. (f) Kitamura, M.;
Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.;
Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 629-
631. (g) Beck, G.; Jendralla, H.; Kesseler, K. Synthesis 1995, 1014-
1018.
(14) For methods of hydration of a terminal alkyne to an aldehyde
see Nicolaou, K. C.; Magolda, R. L.; Sipio, W. J.; Barnette, W. E.;
Lysenko, Z.; Joullie, M. M. J. Am. Chem. Soc. 1980, 102, 3784-3793.
(b) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic
Press: New York, 1988. (c) Nicolaou, K. C.; Duggan, M. E.; Hwang,
C.-K. J. Am. Chem. Soc. 1989, 111, 6676-6682 (b) Tokunaga, M.;
Suzuki, T.; Koga, N.; Fukushima, T.; Horiuchi, A.; Wakatsuki, Y. J.
Am. Chem. Soc. 2001, 123, 11917-11924. (c) Grotjahn, D. B.; Lev, D.
A. J. Am. Chem. Soc. 2004, 126, 12232-12233.
(9) Thompson, A. S.; Tschaen, D. M.; Simpson, P.; McSwine, D. J.;
Reamer, R. A.; Verhoeven, T. R.; Shinkai, I. J. Org. Chem. 1992, 57,
7044-7052.
(10) (a) Larsen, C. H.; Ridgeway, B. H.; Jared, J. T.; Woerpel, K. A.
J. Am. Chem. Soc. 1999, 121, 12208-12209. (b) Smith, D. M.; Tran,
M. B.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 14149-14152.
(11) Fox, M. E.; Jackson, M.; Lennon, I. C.; McCague, R.; Parratt,
J. S. Adv. Synth. Catal. 2002, 344, 50-56.
(12) (a) Fra¨ter, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron 1984, 40,
1269-1277. (b) Barbier, P.; Schneider, F.; Widmer, U. Helv. Chim. Acta
1987, 70, 1412-1418. (c) Muraoka, O.; Tanabe; G.; Sano, K.; Mine-
matsu, T.; Momose, T. J. Chem. Soc., Perkin Trans. 1 1994, 1833-
1845. (d) Thomas, E. J.; Williams, A. C. J. Chem. Soc., Perkin Trans.
1, 1995, 351-358.
J. Org. Chem, Vol. 70, No. 4, 2005 1229

Fox et al.
SCHEME 4. Synthesis of Key Lactones 17a
a Conditions: (a) BH3.DMS, NaBH4 (cat), 89%; (b) TBDMSCl, Et3N, DMAP (cat), CH2Cl2 72%; (c) LDA, THF then 1.3 eq. DMEU then
CH2dCHCH2Br 82% 15a or Me3SiCtCCH2Br 57% 15b; (d) HCl, H2O, DME 92% 16a, 79% 16b; (e) TBDMSCl, imidazole, DMF 76% 17a,
90% 17b.
SCHEME 5. Synthesis of Silylated Lactols 21a
a Conditions: (a) DIBAL-H, toluene quant.; (b) TBDMSCl, imidazole, DMF, then Girard’s reagent T 84%; (c) TMSCl, Et3N, THF 93%
21a, 98% 21b.
allyl bromide was cleaner and the yield was higher.
Removal of the silyl protecting group under acidic condi-
tions gave the lactones 16, after which protection of the
hydroxyl group with a tert-butyldimethylsilyl group gave
the crystalline lactones 17. The presence of a crystalline
intermediate at this stage in the synthesis is of particular
advantage for a large-scale process; given that the early
steps are clean and selective, this minimizes the need
for chromatographic purification. The minor trans-dia-
stereoisomer of the allyl-substituted lactone 17a is a
liquid, ensuring that crystallization is a highly effective
method of purification for this compound. In addition to
being suitable precursors for the cis-4-heptenoyl chain
of AL-12182 1, the allyl and trimethylsilylpropargyl
groups should be versatile precursors for elaboration to
a variety of other substituents. In particular, oxidative
cleavage of the double bond of the allyl substituent should
provide an entry into the synthesis of analogues bearing
a normal prostanoid R-chain with a C5-C6 cis-double
bond.
ω-side chain. The lactones 17 were readily reduced to the
lactols 18 with diisobutylaluminum hydride (Scheme 5).
Silylation of the lactol 18b with the tert-butyldimethyl-
silyl group, as employed by the Merck group,9 gave a
large quantity (15%) of the ring-opened aldehyde 20. We
reasoned that the greater steric crowding of the lactol
18b compared to the Merck substrate slows the silylation
of the lactol form relative to the hydroxy aldehyde form
so that the ring-opened product 20 is favored despite the
overwhelming predominance of the lactol form in the
equilibrium mixture. Further evidence for this equilibra-
tion is provided by the fact that the starting lactols 18
exist as a 2:1 mixture of anomers but the silyl acetal 19
was obtained as a single anomer. The aldehyde 20 was
removable by treatment of the mixture with Girard’s
reagent T. However, a more satisfactory solution to the
problem of obtaining exclusively the silyl acetal form was
to use the less bulky trimethylsilyl group. Thus, silylation
of the lactols 18 with trimethylsilyl chloride gave the
desired lactol silyl ethers 21 (4:1 mixture of anomers).
Having successfully achieved an efficient synthesis of
the key lactones 17, we now turned our attention to the
conversion to a suitable precursor for coupling of the
Next, we turned our attention to the activation and
ω-side chain coupling reaction (Scheme 6). We decided
to focus on the compounds bearing an allyl R-chain
1230 J. Org. Chem., Vol. 70, No. 4, 2005

A Convergent Synthesis of the 11-Oxa Prostaglandin
SCHEME 6. Key Coupling Reactiona
We were pleased to find that the trans-level obtained
in the Wittig reaction using the isopropyl ester 29 was
much lower than with the free carboxylate. Thorough
drying of the phosphonium salt 29 by heating under
vacuum was essential. Both potassium tert-butoxide and
potassium bis(trimethylsilylamide) in THF at -70 °C
were suitable bases, with potassium potassium tert-
butoxide giving 27 with 3.5-4.6% trans and potassium
bis(trimethylsilylamide) giving 27 with 2.1-2.2% trans,
which is well within the acceptable limit for this class of
pharmaceutical product. Removal of the silyl protecting
groups with tetra-n-butylammonium fluoride to give the
oxa prostaglandin analogue 1 was clean and high yield-
ing. Deprotection with acid in the final step would have
been preferred from the point of view of avoidance of toxic
materials in the final step of a pharmaceutical process,
ease of workup, and product purification, but deprotection
of bis-TBDMS ether 27 with HCl in isopropyl alcohol was
much slower than for the corresponding deprotection of
the carbocyclic PGF2R prostaglandin analogue travoprost8
and, in addition, the product 1 suffered slow degradation
under these conditions.
Analysis of the final prostaglandin analogue 1 for
diastereomeric excess and 4,5 cis/trans ratio was best
carried out by HPLC. A 1:1 mixture of epimers at C15
for analytical development was readily made by using
racemic ω-side chain iodide 22. We were surprised to find
that the 15-epi level was typically around 1% because
the ω-side chain iodide 22 used was of >99% ee. However,
on further investigation, we discovered that the com-
mercial dimethyl D-malate used was <98% ee and hence
that the 15-epi impurity observed was in fact the ent-
15-epi isomer. Therefore, use of dimethyl D-malate of as
high an enantiomeric excess as possible as a starting
material is important in this synthesis.
a Conditions: (a) 21a, TMSBr, CH2Cl2, -70 °C; (b) 22, tert-BuLi,
Et2O, -70 °C then LiCu(2-thienyl)CN, THF; (c) add solution from
(a) to (b), -70 °C, 63%.
precursor rather then the trimethylsilylpropargyl group
because of the superior results obtained in the stereose-
lective alkylation step and the advantageous purification
procedure available for the key lactone 17a. The silyl
lactol 21a was treated with trimethylsilyl bromide at low
temperature, after which smooth reaction took place with
a higher order lithium cyanocuprate derived from iodide
2211 at low temperature (<-60 °C) to give the desired
tetrahydrofuran 23 as a single diastereoisomer. Unlike
the previously reported example,9 we were not able to
achieve coupling in our system using Grignard reagents
with or without a copper catalyst.
Completion of the synthesis required elaboration of the
R-chain (Scheme 7). In AL-12182, the R-chain olefin is
transposed one position compared to typical prostanoids.
Clean hydroboration of the terminal double bond of allyl
tetrahydrofuran 23 to the alcohol 24 was achieved with
9-BBN, after which Swern oxidation15 gave the desired
aldehyde 25. Attention was then focused on the Wittig
reaction of the aldehyde 25. A trans level of no more than
3.5% is acceptable in a pharmaceutical product of this
type. Since removal of the trans-isomer from the final
product 1 by chromatography was difficult, ensuring as
high as possible a cis/trans ratio in the Wittig reaction
was paramount. Initially, we used commercially available
(3-carboxypropyl)triphenylphosphonium bromide with
potassium tert-butoxide as the base. In a related Wittig
reaction with the homologous (4-carboxybutyl)triphen-
ylphosphonium bromide, we were routinely able to obtain
a trans-content of 2-3%.8 The acid 26 was converted to
the isopropyl ester 27 with 2-iodopropane and DBU, and
then the silyl protecting groups were removed with tetra-
n-butylammonium fluoride. HPLC analysis of the final
prostaglandin analogue 1 revealed the trans level to be
an unacceptable 11%.
Conclusions
A convergent and concise synthesis of the 11-oxa
prostaglandin analogue AL-12182 1 was demonstrated.
The key steps in this route are a diastereoselective
enolate alkylation and copper-mediated coupling reaction.
With a longest linear sequence of 12 steps and an overall
yield of 12% from dimethyl D-malate, this has the
potential to form the basis for a viable manufacturing
route to this compound. In particular, all of the four
stereogenic centers are rigorously controlled. We expect
this approach to be generally applicable to other 11-oxa
prostaglandin analogues.
Experimental Section
(R)-Methyl 3,4-Dihydroxybutanoate (13).13a Dimethyl
D-malate 12 (50.05 g, 308.7 mmol) was dissolved in dry
tetrahydrofuran (500 mL) under nitrogen. Borane dimethyl
sulfide complex (10 M, 31.5 mL, 315 mmol) was added over
20 min (maintaining the temperature at 12-16 °C using a cold
water bath). The solution was stirred for 1 h. Sodium boro-
hydride (584 mg, 15.4 mmol) was added in five portions over
25 min (using cooling to keep the temperature below 20 °C).
The mixture was stirred for 1 h, after which TLC (MTBE)
showed no starting material. Dry methanol (150 mL) was
added (slowly at first, hydrogen evolved) and the solution was
stirred for 30 min. The solvent was evaporated and the residue
was dissolved in methanol (100 mL). The solvent was evapo-
rated again and the residue was azeotroped with toluene (3 ×
Therefore, we decided to change the order of steps and
use the isopropyl ester 2916 in the Wittig reaction.
Starting with 4-bromobutyric acid, the isopropyl ester 28
was readily prepared by esterification with isopropyl
alcohol and catalytic sulfuric acid (Scheme 8). The
phosphonium salt 29 was formed with triphenylphos-
phine in toluene.
(15) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(16) Thum, O.; Hertweck, C.; Simon, H.; Boland, W. Synthesis 1999,
2145-2150.
J. Org. Chem, Vol. 70, No. 4, 2005 1231

Fox et al.
SCHEME 7. Downstream Steps to AL-12182 1a
a Conditions: (a) 9-BBN then H2O2, NaOH 78%; (b) (COCl)2, DMSO, Et3N, CH2Cl2, -70 °C 92%; (c) Ph3P+CH2CH2CH2COOH Br-,
KOt-Bu, THF; (d) 29, K(N(SiMe3)2, THF 94%; (e) DBU, i-PrI, THF 56%; (f) Bu4N+ F- 84%.
SCHEME 8. Synthesis of Phosphonium Salt 29a
a Conditions: (a) i-PrOH, H2SO4 (cat), reflux 65%; (b) PPh3, toluene, reflux, 57%.
50 mL) to give the crude diol 13 as colorless oil (41.9 g). The
crude product was purified by passing through a pad of silica
(100 g) eluting with ethyl acetate (1 L). The solvent was
evaporated to give the diol 13 as a colorless oil (38.6 g, 274.6
mmol, 89%). 1H NMR (200 MHz, CDCl3): δ 4.10 (m, 1H)
3.8-3.2 (m, 4H), 3.70 (s, 3H), 2.50 (m, 2H).
mL) was added and residual ester was washed in with further
tetrahydrofuran (10 mL) (the addition was exothermic causing
the internal temperature to rise to -47 °C). The cold bath was
removed and the reaction was allowed to warm to 0 °C. The
mixture was then recooled to -60 °C. 1,3-Dimethyl-2-imida-
zolidinone (8.2 mL, 75.6 mmol) was added and after stirring
for 5 min, allyl bromide (7.4 mL, 87.2 mmol) was added. The
mixture was stirred below -50 °C for 30 min. The cold bath
was removed and the reaction was allowed to warm to 10 °C
over 1 h (TLC MTBE/heptane 1:3 showed no starting material).
The reaction was quenched with saturated ammonium chloride
(150 mL) (internal temperature rose to 23 °C). The organic
layer was separated and the aqueous phase was extracted with
MTBE (100 mL). The combined organic phases were washed
with brine (100 mL), dried (MgSO4), filtered, and evaporated.
The crude product was passed through a short silica column
(100 g), eluting with MTBE/heptane 1:6 to give the title
compound 15a as a pale yellow liquid (13.85 g, 48.0 mmol,
82%). [R]D20 +6.5 (c 1.0, CH2Cl2). IR (neat) 3492, 1739 and 1642
Methyl (R)-4-(tert-Butyldimethylsilyloxy)-3-hydroxy-
butanoate (14).12d The diol 13 (38.6 g, 275 mmol) was
dissolved in dichloromethane (500 mL). Triethylamine (50 mL,
357 mmol) was added and the solution was cooled to 0 °C
under nitrogen. A solution of tert-butyldimethylsilyl chloride
(41.4 g, 275 mmol) in dichloromethane (100 mL) was added
over 45 min. The mixture was allowed to warm to room
temperature (over 3.5 h) and stirred overnight. TLC (ethyl
acetate) showed diol 13 still present. (Dimethylamino)pyridine
(1.98 g, 16.2 mmol) was added and the mixture was stirred
for 6 h. Further tert-butyldimethylsilyl chloride (10.0 g, 66
mmol) was added and the mixture was stirred overnight. The
reaction was quenched with water (250 mL). The organic layer
was separated and washed with water (250 mL) and brine (250
mL), dried (MgSO4), filtered, and evaporated. The residue was
chromatographed (MTBE/heptane 1:4 to 1:1) to give the title
compound 14 as a pale yellow liquid (49.7 g, 72%) (12:1 mixture
1
cm-1. H NMR (400 MHz, CDCl3): δ ppm 5.84-5.64 (m, 1H),
5.13-5.00 (m, 2H), 3.83-3.74 (m, 1H), 3.69 (s, 3H), 3.66-3.57
(m, 2H), 2.94 (d, J ) 7 Hz, 1H), 2.74-2.64 (m, 1H), 2.50-2.28
(m, 2H), 0.88 (s, 9H), and 0.05 (s, 6H). EI 231 ([M-tBu]+, 16),
117 (100). Anal. calcd for C14H28O4Si: C, 58.3; H 9.8. Found:
C, 58.5; H, 9.8.
Methyl (2S, 3R)-4-(tert-Butyldimethylsilyloxy)-3-hy-
droxy-2-(1-trimethylsilylpropargyl)butanoate (15b). n-
Butyllithium (2.5 M, 17.7 mL, 44.3 mmol) was added dropwise
to a solution of diisopropylamine (6.75 mL, 48.3 mmol) in
tetrahydrofuran (40 mL) at -10 °C under nitrogen (exother-
mic, temperature maintained at 0 to -5 °C with external
cooling). The solution was stirred at 0 °C for 10 min and then
cooled to -50 °C. A solution of the hydroxy ester 14 (5.0 g,
20.1 mmol) in tetrahydrofuran (10 mL) was added over 5 min
and residual ester was washed in with further tetrahydrofuran
20
of primary/secondary protected). [R]D +9.9° (c 1.0, CH2Cl2).
1H NMR (200 MHz, CDCl3): δ 4.10-4.00 (m, 1H), 3.70 (s, 3H),
3.65-3.50 (m, 2H), 2.88 (d, J ) 5 Hz, 1H), 2.52 (m, 2H), 0.90
(s, 9H), 0.08 (s, 6H).
Methyl (2S, 3R)-2-Allyl-4-(tert-butyldimethylsilyloxy)-
3-hydroxybutanoate (15a). n-Butyllithium (2.5 M, 51.2 mL,
127.9 mmol) was added dropwise to a solution of diisopro-
pylamine (19.5 mL, 139.5 mmol) in tetrahydrofuran (100 mL)
at 0 °C under nitrogen (exothermic, temperature maintained
at 0 to -5 °C with external cooling). The solution was stirred
at 0 °C for 10 min and then cooled to -60 °C. A solution of the
hydroxy ester 14 (14.44 g, 58.1 mmol) in tetrahydrofuran (30
1232 J. Org. Chem., Vol. 70, No. 4, 2005

A Convergent Synthesis of the 11-Oxa Prostaglandin
(5 mL) (the addition was exothermic causing the internal
temperature to rise to -35 °C). The cold bath was removed
and the reaction was allowed to warm to -10 °C. After 10 min,
the mixture was recooled to -50 °C. 1,3-Dimethyl-2-imidazo-
lidinone (2.8 mL, 26.2 mmol) was added and after stirring for
5 min, 3-bromo-1-(trimethylsilyl)-1-propyne (4.7 mL, 30.2
mmol) in tetrahydrofuran (15 mL) was added (immediate color
change from yellow to dark brown) and the reaction was
allowed to warm to room temperature over 3 h (TLC MTBE/
heptane 1:3 showed no starting material). The reaction was
quenched with saturated ammonium chloride (100 mL). The
organic layer was separated and the aqueous phase was
extracted with MTBE (100 mL). The combined organic phases
were washed with water (50 mL) and brine (50 mL), dried
(MgSO4), filtered, and evaporated. The crude product was
chromatographed (MTBE/heptane 1:4) to give the title com-
pound 15b as a light brown liquid (3.95 g, 11.0 mmol, 55%).
IR (neat) 3508, 2178, 1738 cm-1. 1H NMR (200 MHz, CDCl3):
δ 3.94-3.88 (m, 1H), 3.72 (s, 3H), 3.70-3.67 (m, 2H), 2.98 (d,
J ) 7 Hz, 1H), 2.82-2.75 (m, 1H), 2.61-2.58 (m, 2H), 0.90 (s,
9H), 0.11 (s, 9H), 0.08 (s, 6H). EI 301 ([M - tBu]+, 4), 117 (100).
(3S, 4R)-3-Allyl-4-hydroxytetrahydrofuran-2-one (16a).
The 2-allyl hydroxy ester 15a (13.5 g, 46.8 mmol) was dissolved
in 1,2-dimethoxyethane (100 mL). Aqueous hydrochloric acid
(3 N, 60 mL) was added and the mixture was heated at 80 °C
for 1 h (TLC MTBE/heptane 4:1 showed complete reaction).
After cooling to room temperature, the aqueous phase was
saturated with sodium chloride and the mixture was extracted
with ethyl acetate (3 × 70 mL). The combined organic extracts
were dried (MgSO4), filtered, and evaporated. The crude
product (10 g) was filtered through silica (35 g), eluting first
with 30% MTBE in heptane (to remove silicon byproducts) and
then with neat MTBE to afford the lactone 16a (6.11 g, 43.0
mmol, 92%). [R]D20 +67.8 (c 1.0, CH2Cl2). IR (neat) 3444, 1759,
1642 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.90 (m, 1H), 5.25-
5.10 (m, 2H), 4.55 (brs, 1H), 4.30 (m, 2H), 2.70-2.55 (m, 3H),
and 2.50-2.40 (m, 1H). EI 123 (40), 79 (100).
(3S, 4R)-4-Hydroxy-3-(1-trimethylsilylpropargyl)tet-
rahydrofuran-2-one (16b). The hydroxy ester 15b (4.2 g,
11.7 mmol) was dissolved in 1,2-dimethoxyethane (40 mL).
Aqueous hydrochloric acid (2 N, 20 mL) was added and the
mixture was heated at 80 °C for 75 min (TLC MTBE/heptane
3:1 showed complete reaction). After cooling to room temper-
ature, the mixture was extracted with MTBE (2 × 30 mL).
The combined organic extracts were washed with saturated
sodium hydrogencarbonate solution (30 mL) and brine (30 mL),
dried (MgSO4), filtered, and evaporated. Heptane (10 mL) was
added to the oily residue and the mixture was cooled in an ice
bath. The crystalline solid was filtered, washed with heptane
(2 mL), and dried to give the lactone 16b (1.59 g, 7.5 mmol,
64%). mp 75 °C (onset by DSC). IR (Nujol) 3434, 2175, and
1768 cm-1. 1H NMR (200 MHz, CDCl3): δ 4.75 (brs, 1H), 4.38
(m, 2H), 2.90-2.77 (m, 2H), 2.60 (dd, J ) 18, 12 Hz, 1H), 2.46
(brs, 1H), and 0.13 (s, 9H). EI 179 (100).
(3R,4R) diastereoisomer as a colorless oil (456 mg, 1.8 mmol,
20
4%)]. mp 48 °C (onset by DSC). [R]D +88.0° (c 1.0, CH2Cl2).
IR (Nujol) 1763, 1644 cm-1 1H NMR (400 MHz, CDCl3): δ
.
5.94-5.80 (m, 1H), 5.18-5.06 (m, 2H), 4.53 (t, J ) 3.5 Hz, 1H),
4.26 (dd, J ) 10, 3 Hz, 1H), 4.17 (d, J ) 10 Hz, 1H), 2.60-
2.35 (m, 3H), 0.89 (s, 9H), 0.10 (s, 3H), and 0.08 (s, 3H). EI
t
199 ([M - Bu]+, 4), 117 (100). Anal. calcd for C13H24O3Si: C,
60.9; H, 9.4%. Found: C, 61.1; H, 9.5. (3R,4R) diastereoisomer
1H NMR (200 MHz, CDCl3) δ ppm 5.85-5.72 (m, 1H), 5.20-
5.12 (m, 2H), 4.39-4.29 (m, 2H), 4.01-3.95 (m, 1H), 2.60-
2.54 (m, 1H), 2.49-2.30 (m, 2H), 0.88 (s, 9H), 0.08 (s, 3H), and
0.06 (s, 3H).
(3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-(1-trimethyl-
silylpropargyl)tetrahydrofuran-2-one (17b). The hydroxy
lactone 16b (1.57 g, 7.39 mmol) was dissolved in dry dimeth-
ylformamide (4 mL) under nitrogen. Imidazole (755 mg, 11.1
mmol) and then tert-butyldimethylsilyl chloride (1.33 g, 8.9
mmol) were added and the mixture was stirred at room
temperature overnight (TLC MTBE/heptane 1:3 showed com-
plete reaction). The mixture was partitioned between water
(20 mL) and heptane (2 × 30 mL) and the combined organic
phases were dried (MgSO4). The solvent was evaporated and
the residue was passed through a short silica column eluting
with MTBE/heptane 1:8 to give the lactone 17b (2.28 g, 7.0
mmol, 94%). mp 66 °C (onset by DSC). IR (Nujol) 2179, 1765
cm-1. 1H NMR (200 MHz, CDCl3): δ 4.63 (t, J ) 3.51 Hz, 1H),
4.30 (dd, J ) 10, 3 Hz, 1H), 4.20 (d, J ) 10 Hz, 1H), 2.78-
2.67 (m, 2H), 2.52 (dd, J ) 17, 12 Hz, 1H), 0.90 (s, 9H), 0.15
t
(s, 9H), 0.13 (s, 6H). EI 269 ([M - Bu]+, 38), 117 (100).
(3S,4R)-3-Allyl-4(tert-butyldimethylsilyloxy)tetrahy-
drofuran-2-ol (18a). The lactone 17a (5.0 g, 19.50 mmol) was
dissolved in dry toluene (50 mL) and cooled to -70 °C under
nitrogen. Diisobutylaluminum hydride in toluene (1.5M, 19.5
mL, 29.25 mmol) was added over 15 min (temperature was
maintained below -60 °C) and the resulting mixture was
stirred for 1.5 h. The reaction was quenched with methanol
(5 mL) (vigorous frothing initially). Aqueous sulfuric acid (2
N, 75 mL) was added, maintaining the temperature below -30
°C. The mixture was allowed to warm to room temperature
and the organic layer was separated. The aqueous phase was
extracted with toluene (50 mL + 25 mL) (the second extract
contained no product). The combined organic solutions were
washed with aqueous sulfuric acid (2 N, 25 mL), water (3 ×
30 mL, to pH 7), and brine (30 mL). The solution was dried
(MgSO4), filtered, and evaporated to give the lactol 18a as a
colorless oil (5.18 g, 20.04 mmol, 103%), 1.5:1 mixture of
anomers. 1H NMR (200 MHz, CDCl3): δ 5.95-5.80 (m, 1H,
both anomers), 5.30-5.00 (m, 3H, both anomers), 4.46-4.41
(m, 1H, major), 4.30 (t, J ) 3.5 Hz, 1H, minor), 4.16-4.03 (m,
1H, both anomers), 3.90 (dd, J ) 9, 3 Hz, 1H, minor), 3.82-
3.69 (m, 1H, both anomers), 3.50 (brs, 1H, major), 2.42-1.97
(m, 3H, both anomers), 0.92 (s, 9H, both anomers), 0.10 (s,
3H, both anomers), 0.06 (s, 3H, both anomers).
(3S, 4R)-4-(tert-Butyldimethylsilyloxy)-3-(1-trimethyl-
silylpropargyl)tetrahydrofuran-2-ol (18b). The lactone
17b (680 mg, 2.1 mmol) was dissolved in dry toluene (7 mL)
and cooled to -70 °C under nitrogen. Diisobutylaluminum
hydride in toluene (1.5M, 2.0 mL, 3.0 mmol) was added
dropwise and the resulting mixture was stirred for 3 h. The
reaction was quenched with methanol (1 mL) (vigorous froth-
ing initially). Aqueous sulfuric acid (2 N, 10 mL) was added
and the mixture was allowed to warm to room temperature.
The organic layer was separated and the aqueous phase was
extracted with MTBE (2 × 15 mL). The combined organic
solutions were washed with aqueous sulfuric acid (2 N, 10 mL),
water (3 × 10 mL, to pH 7), and brine (10 mL). The solution
was dried (MgSO4), filtered, and evaporated to give the lactol
18b as a colorless oil (680 mg, 99%), 2:1 mixture of anomers.
1H NMR (200 MHz, CDCl3) δ ppm 5.28 (t, 1H, J ) 4 Hz, major),
5.19 (dd, 1H, J ) 12, 4.5 Hz, minor), 4.50 (m, 1H, major), 4.42
(t, 1H, J ) 3.5 Hz, minor), 4.18-4.04 (m, 1H, both anomers),
3.94 (dd, 1H, J ) 10, 3 Hz, minor), 3.75-3.63 (m, 1H, both
(3S, 4R)-3-Allyl-4-(tert-butyldimethylsilyloxy)tetrahy-
drofuran-2-one (17a). The hydroxy lactone 16a (6.0 g, 42.2
mmol) was dissolved in dry dimethylformamide (10 mL) under
nitrogen. Imidazole (4.78 g, 70.2 mmol) and then tert-bu-
tyldimethylsilyl chloride (7.05 g, 46.80 mmol) were added. The
mixture was stirred at room temperature overnight and then
partitioned between water (50 mL) and heptane (2 × 30 mL).
The heptane extracts were dried (MgSO4), filtered, and
evaporated to give the crude product (10.5 g). This was
crystallized from heptane (40 mL) at -15 °C to give the title
compound 17a as a white solid (7.60 g, 29.6 mmol, 70%). The
mother liquors were concentrated and observed to solidify upon
standing. The solid was dissolved in heptane (25 mL) and
cooled in a CO2/acetone bath to induce crystallization. The solid
was filtered and washed with cold heptane (10 mL) to give a
second crop of the lactone 17a (646 mg, 2.5 mmol, 6%). The
residue was chromatographed (MTBE/heptane 1:6 to 1:3) to
give the title compound 17a (746 mg, 2.9 mmol, 7%) [and the
J. Org. Chem, Vol. 70, No. 4, 2005 1233

Fox et al.
anomers), 2.98 (d, 1H, J ) 4 Hz, major), 2.57-2.15 (m, 3H,
both anomers), 0.90 (s, 9H, both anomers), 0.16-0.07 (m, 15
H, both anomers).
in ether (30 mL) was added over 40 min (the internal
temperature was maintained at -60 to -70 °C, a yellow
solution is obtained initially which slowly darkens to orange/
brown). The solution was stirred for a further 40 min after
complete addition. The silyl acetal 21a (4.73 g, 14.3 mmol) was
dissolved in dry dichloromethane (35 mL) and cooled to -60
°C under nitrogen. Trimethylsilyl bromide (1.85 mL, 14.3
mmol) was added and the mixture was stirred for 1 h,
maintaining the temperature below -60 °C. n-Butyllithium
(2.5 M, 7.4 mL, 18.6 mmol) was added to thiophene (1.56 g,
18.6 mmol) in dry tetrahydrofuran (15 mL) at -30 °C under
nitrogen. The thienyllithium solution was stirred for 20 min
and then added to a suspension of copper(I) cyanide (1.66 g,
18.6 mmol) in tetrahydrofuran (15 mL) at -20 °C under
nitrogen. The mixture was allowed to warm until a clear brown
solution was obtained. The lithium 2-thienylcyanocuprate
solution was added to the vinyllithium solution, keeping the
temperature below -60 °C (dark brown solution, some solids
present). After 10 min, the activated bromoether solution was
added to the cuprate solution, keeping the temperature below
-60 °C (clear yellow/brown solution resulted). After 2 h, TLC
(MTBE/heptane 1:15) indicated complete reaction. The reac-
tion was quenched with saturated ammonium chloride solution
(100 mL) and was allowed to warm to room temperature. The
mixture was diluted with water (50 mL) and then filtered
through Celite. The organic layer was separated and the Celite
was washed with MTBE (100 mL). This washing was also used
to extract the aqueous layer. The combined organic phases
were washed with water (50 mL), brine (50 mL), dried
(MgSO4), filtered, and evaporated to give a yellow oil (9.9 g).
This was chromatographed (6% MTBE in heptane) to give the
tetrahydrofuran 23 as a pale yellow oil (5.02 g, 9.1 mmol, 63%).
[R]D20 +43.9 (c 1.0, CH2Cl2). IR (neat) 1595 cm-1. 1H NMR (400
MHz, CDCl3) δ 7.18 (t, J ) 8 Hz, 1H), 6.91 (d, J ) 7.5 Hz,
1H), 6.87 (d, J ) 7 Hz, 1H), 6.76 (dd, J ) 8, 2 Hz, 1H), 5.81-
5.78 (m, 3H), 5.08-4.97 (m, 2H), 4.53 (m, 1H), 4.35 (t, J ) 4
Hz, 1H), 4.15 (m, 1H), 4.03 (dd, J ) 9, 3.5 Hz, 1H), 3.84 (d, J
) 6 Hz, 2H), 3.75 (d, J ) 9 Hz, 1H), 2.30 (m, 1H), 2.05 (m,
(3S,4R)-2,4-(tert-Butyldimethylsilyloxy)-3-(1-trimeth-
ylsilylpropargyl)tetrahydrofuran (19). The lactol 18b (1.18
g, 3.6 mmol) was dissolved in dry dimethylformamide (3 mL)
under nitrogen. Imidazole (369 mg, 5.4 mmol) and then tert-
butyldimethylsilyl chloride (600 mg, 4.0 mmol) were added and
the mixture was stirred at room temperature overnight (TLC
MTBE/heptane 1:3 showed no lactol). The reaction was
quenched with water (15 mL) and extracted with heptane (3
× 15 mL). The combined organic phases were dried (MgSO4),
filtered, and evaporated to give the crude silyl acetal (1.59 g,
99%) as a colorless oil containing approximately 15% aldehyde
27 as an impurity. The silyl acetal 26 was dissolved in ethanol
(25 mL). Girard’s reagent T (300 mg, 1.8 mmol) and water (2
mL) were added and the mixture was stirred for 1 h (TLC
MTBE/heptane 1:15 showed no aldehyde). The reaction mix-
ture was partitioned between heptane (2 × 30 mL) and brine
(30 mL). The combined organic phases were dried (MgSO4).
MTBE (5 mL) was added and the solution was filtered through
silica, washing with 10% MTBE in heptane (50 mL). The
solvent was evaporated to give the pure silyl acetal 19 (1.34
g, 84%) as a single anomer. IR (neat) 2176 cm-1. 1H NMR (200
MHz, CDCl3): δ 5.29 (d, J ) 3 Hz, 1H), 4.54-4.48 (m, 1H),
4.09 (dd, J ) 9, 5 Hz, 1H), 3.63 (dd, J ) 9, 3 Hz, 1H), 2.48-
2.36 (m, 1H), 2.25-2.17 (m, 2H), 0.90 (s, 18H), 0.12-0.08 (m,
t
21H). EI 385 ([M - Bu]+, 7), 117 (64), 73 (100).
(3S,4R)-3-Allyl-4-(tert-butyldimethylsilyloxy)-2-tri-
methylsilyloxytetrahydrofuran (21a). The lactol 18a (5.03
g, 19.50 mmol) was dissolved in dry tetrahydrofuran (50 mL)
under nitrogen and the solution was cooled to 5 °C in an ice
bath. Triethylamine (4.0 mL, 29.25 mmol) was added, followed
by trimethylsilyl chloride (2.60 mL, 20.47 mmol) dropwise over
2 min (internal temperature rose to 7 °C). The mixture was
stirred for 45 min, then allowed to warm to room temperature,
and stirred for a further 75 min (TLC MTBE/heptane 1:4
showed very little lactol). The reaction was quenched with
water (50 mL) and extracted with heptane (2 × 50 mL). The
organic extracts were washed with brine (30 mL), dried
(MgSO4), filtered, and evaporated. The residue was filtered
through a pad of silica, eluting with 5% MTBE in heptane (150
mL) to give the silyl acetal 21a as a colorless oil (6.30 g, 19.05
1H), 1.70 (m, 1H), 0.91 (s, 18H), 0.09 (s, 6H), 0.06 (s, 6H). 13
C
NMR (100 MHz, CDCl3) δ 159.5, 136.9, 134.8, 132.3, 131.7,
130.2, 120.9, 115.7, 114.9, 112.9, 82.4, 75.7, 73.1, 72.4, 71.1,
50.9, 29.0, 25.8, 18.3, 18.0, -4.4, -4.6, -4.7, -5.0. APCI
(positive) 575 ([M35ClNa]+, 2), 421 (48), 156 (69), 114 (100).
Anal. calcd for C29H49ClO4Si2: C, 62.95; H, 8.9. Found: C, 63.0;
H, 8.9.
20
mmol, 98%), approximately a 5:1 mixture of anomers. [R]D
+65.1 (c 1.0, CH2Cl2). IR (neat) 1641 cm-1. 1H NMR (400 MHz,
CDCl3): δ (major anomer) 5.90-5.73 (m, 1H), 5.20-5.00 (m,
3H), 4.48-4.42 (m, 1H), 4.09 (dd, J ) 9, 4.5 Hz, 1H), 3.67 (dd,
J ) 9, 3 Hz, 1H), 2.40-2.27 (m, 1H), 2.15-2.00 (m, 2H), 0.91
(s, 9H), 0.16-0.00 (m, 15H). EI 273 ([M - tBu]+, 1%), 117 (100).
Anal. calcd for C16H34O3Si2: C, 58.1; H 10.4. Found: C, 58.4;
H, 10.35.
[2R, (1E,3R), 3R,4R]-3-{4-tert-Butyldimethylsilyloxy-2-
[3-tert-butyldimethylsilyloxy-4-(3-chlorophenoxy)but-1-
enyl]tetrahydrofuran-3-yl}-propan-1-ol (24). The alkene
23 (2.43 g, 4.39 mmol) was dissolved in dry tetrahydrofuran
(25 mL) under nitrogen. 9-BBN (0.5 M, 10.0 mL, 5 mmol) was
added over 5 min (a cold water bath was used to maintain the
temperature below 20 °C). The mixture was stirred for 2.5 h
(TLC, MTBE/heptane 1:3 showed no starting material). The
reaction was cooled in an ice bath to 5 °C. Sodium hydroxide
solution (3 M, 2.0 mL) and hydrogen peroxide (27.5%, 2.3 mL)
were added in small portions, keeping the temperature below
10 °C (addition of further sodium hydroxide (3 M, 0.2 mL) and
hydrogen peroxide (27.5%, 0.3 mL) showed no further exo-
therm). The mixture was warmed to room temperature and
stirred for a further 30 min. The reaction was poured into
water (50 mL) and extracted with MTBE (3 × 30 mL) [brine
(25 mL) was added to aid separation of phases]. The combined
organic layers were washed with brine (2 × 30 mL), dried
(MgSO4), filtered, and evaporated. The residue was chromato-
graphed (MTBE/heptane 1:4 to 1:2) to give the alcohol 24 as a
(3S,4R)-2,4-(tert-Butyldimethylsilyloxy)-2-trimethyl-
silyloxy-3-(1-trimethylsilylpropargyl)tetrahydrofuran
(21b). The lactol 18b (215 mg, 0.65 mmol) was dissolved in
dry tetrahydrofuran (2 mL) at room temperature under
nitrogen. Triethylamine (0.14 mL, 1.0 mmol) and then tri-
methylsilyl chloride (0.10 mL, 0.78 mmol) were added and the
mixture was stirred for 1 h. The reaction was partitioned
between heptane (20 mL) and water (10 mL). The heptane
layer was washed with brine (10 mL), dried (MgSO4), filtered,
and evaporated to give the silyl acetal 21b as a colorless oil
(241 mg, 0.60 mmol, 93%), approximately a 4:1 mixture of
1
anomers. H NMR (200 MHz, CDCl3) δ (major anomer) 5.29
(d, J ) 3 Hz, 1H), 4.50 (m, 1H), 4.09 (dd, J ) 9, 5 Hz, 1H),
3.61 (dd, J ) 9, 3 Hz, 1H), 2.50-2.42 (m, 1H), 2.30-2.15 (m,
2H), 0.90 (s, 9H), 0.10 (m, 24H).
20
colorless oil (1.96 g, 3.43 mmol, 78%). [R]D +45.1 (c 1.0,
1
CH2Cl2). IR (neat) 3446 cm-1. H NMR (400 MHz, CDCl3) δ
[2R, (1E,3R), 3R,4R]-3-Allyl-4-tert-butyldimethylsi-
lyloxy-2-[3-tert-butyldimethyl-silyloxy-4-(3-chlorophe-
noxy)-1-butenyl]-tetrahydrofuran (23). Anhydrous ether
(20 mL) and tert-butyllithium (1.5 M, 22.8 mL, 34.3 mmol)
were added to a 250-mL three-necked flask at -70 °C under
nitrogen. A solution of the vinyl iodide 2211 (8.16 g, 18.6 mmol)
7.19 (t, J ) 8 Hz, 1H), 6.90 (t, J ) 2 Hz, 1H), 6.86 (t, J ) 2 Hz,
1H), 6.75 (dd, J ) 8, 2 Hz, 1H), 5.77 (m, 2H), 4.53 (m, 1H),
4.34 (m, 1H), 4.05 (m, 1H), 4.01 (dd, J ) 9, 4 Hz, 1H), 3.86 (m,
2H), 3.76 (d, J ) 9.5 Hz, 1H), 3.62 (m, 2H), 1.65-1.4 (m, 4H),
1.25-1.15 (m, 2H), 0.91 (s, 18H), 0.11 (s, 3H), 0.10 (s, 3H),
1234 J. Org. Chem., Vol. 70, No. 4, 2005

A Convergent Synthesis of the 11-Oxa Prostaglandin
0.09 (s, 3H), 0.08 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.5,
134.8, 132.5, 131.8, 130.2, 120.9, 115.0, 112.9, 82.8, 75.8, 73.1,
72.3, 71.0, 63.1, 51.1, 31.2, 25.8, 25.8, 20.7, 18.3, 18.0, -4.9,
-4.6, -4.7, -5.0. APCI positive 595 ([M37ClNa]+, 43), 593
([M35ClNa]+, 100). Anal. calcd for C29H51ClO5Si2: C, 61.0; H,
9.0. Found: C, 60.9; H, 9.0.
Isopropyl [2R, (1E,3R), 3R (4Z), 4R]-7-{4-tert-butyldi-
methylsilyloxy-2-[3-tert-butyl-dimethylsilyloxy-4-(3-chlo-
rophenoxy)but-1-enyl]tetrahydrofuran-3-yl}-hept-4-
enoate (27). The phosphonium salt 29 (3.92 g, 8.32 mmol,
freshly dried by heating under high vacuum) was suspended
in dry tetrahydrofuran (30 mL) and cooled to 0 °C under
nitrogen. Potassium bis(trimethylsilyl)amide (0.5 M in toluene,
16.6 mL) was added dropwise over 5 min (temperature rose
to 3 °C) and the resulting orange solution was stirred for 40
min and then cooled to -72 °C. A solution of the aldehyde 25
(2.37 g, 4.16 mmol) in tetrahydrofuran (30 mL) was added
dropwise over 20 min, maintaining the temperature below -70
°C. The residues were washed in with tetrahydrofuran (5 mL)
and the mixture was stirred for 1.5 h and then allowed to
warm to 0 °C over 2 h. The reaction was quenched with
saturated ammonium chloride solution (50 mL) (temperature
rose to 13 °C) and water (20 mL) to dissolve salts. The organic
layer was separated and the aqueous phase was extracted
with ethyl acetate (50 mL). The combined organic phases
were washed with water (50 mL) and brine (50 mL), dried
(Na2SO4), filtered, and evaporated. The residue was chromato-
graphed (ethyl acetate/heptane 1:10) to give the silyl protected
[2R, (1E,3R), 3R,4R]-3-{4-tert-Butyldimethylsilyloxy-2-
[3-tert-butyldimethylsilyloxy-4-(3-chlorophenoxy)but-1-
enyl]tetrahydrofuran-3-yl}-propionaldehyde (25). A so-
lution of dry dimethyl sulfoxide (0.82 mL, 11.6 mmol) in dry
dichloromethane (10 mL) was added over 5 min to a solution
of oxalyl chloride (2 M in dichloromethane, 2.65 mL) in
dichloromethane (20 mL) at -60 °C under nitrogen. Stirring
was continued for 5 min, and then a solution of the alcohol 24
(2.76 g, 4.83 mmol) in dichloromethane (15 mL) was added
over 5 min (maintaining the temperature below -60 °C). The
alcohol was washed in with dichloromethane (5 mL) and the
reaction was stirred for 40 min. Triethylamine (3.4 mL, 24.2
mmol) was added dropwise and after 15 min the reaction was
allowed to warm to room temperature. Water (50 mL) was
added and the mixture was extracted with heptane (2 × 50
mL). The combined organic phases were washed with hydro-
chloric acid (1 M, 50 mL), water (50 mL), aqueous sodium
carbonate solution (5%, 50 mL), water (50 mL), and brine (50
mL), dried (MgSO4), filtered, and evaporated. The residue was
chromatographed (MTBE/heptane 1:4) to give the aldehyde 25
as a colorless oil (2.55 g, 4.47 mmol, 92%). [R]D20 +47.0 (c 1.0,
20
prostaglandin analogue 27 (2.63 g, 3.88 mmol, 94%). [R]D
+23.9 (c 1.0, CH2Cl2). IR (film) 1731 cm-1. 1H NMR (400 MHz,
CDCl3) δ ppm 7.18 (t, J ) 8 Hz, 1H), 6.91 (d, J ) 8 Hz, 1H),
6.87 (t, J ) 2 Hz, 1H), 6.76 (dd, J ) 8, 2 Hz, 1H), 5.80 (m,
2H), 5.34 (m, 2H), 5.01 (heptet, J ) 6 Hz, 1H), 4.53 (m, 1H),
4.34 (m, 1H), 4.10 (m, 1H), 4.02 (dd, J ) 9, 3.5 Hz, 1H), 3.84
(d, J ) 6 Hz, 2H), 3.75 (d, J ) 9 Hz, 1H), 2.30 (m, 4H), 2.08
(m, 2H), 1.65 (m, 2H), 1.27 (m, 1H), 1.22 (d, J ) 6 Hz, 6H),
0.91 (s, 18H), 0.08 (s, 12H). 13C NMR (100 MHz, CDCl3) δ
172.6, 159.5, 134.8, 132.4, 131.8, 130.7, 130.2, 128.0, 120.9,
114.9, 112.9, 82.7, 75.9, 73.0, 72.4, 71.1, 67.6, 50.7, 34.6, 25.8,
25.6, 24.2, 23.0, 21.9, 18.3, 18.0, -4.3, -4.6, -4.7, -5.0. APCI
705 ([M37ClNa]+, 49), 703 ([M35ClNa]+, 100). Anal. calcd for
C36H61ClO6Si2: C, 63.45; H, 9.0. Found C, 63.45; H, 9.0.
Isopropyl [2R, (1E,3R), 3R (4Z), 4R]-7-{4-tert-butyldi-
methylsilyloxy-2-[3-tert-butyl-dimethylsilyloxy-4-(3-chlo-
rophenoxy)but-1-enyl]tetrahydrofuran-3-yl}-hept-4-
enoate (27) by Wittig Reaction/Ester Formation. 3-Car-
boxypropyltriphenylphosphonium bromide (268 mg, 0.62 mmol)
was suspended in tetrahydrofuran (3 mL) under nitrogen and
cooled to 3 °C. Potassium tert-butoxide (1 M in tetrahydrofu-
ran, 1.25 mL) was added dropwise and the mixture was stirred
for 40 min (a bright orange solution was obtained). The
mixture was cooled to -2 °C and a solution of the aldehyde
25 (237 mg, 0.42 mmol) in tetrahydrofuran (2.5 mL) was added
over 3 min (the residues were washed in with tetrahydrofuran,
0.5 mL). The reaction was stirred for 1 h (TLC MTBE/heptane
1:3 showed complete reaction) and then quenched with satu-
rated ammonium chloride solution (20 mL). Water (10 mL)
was added to dissolve salts and the mixture was extracted with
ethyl acetate (2 × 20 mL). The combined organic phases were
washed with saturated ammonium chloride solution (10 mL)
and brine (10 mL), dried (Na2SO4), filtered, and evaporated
to give a yellow oil (385 mg). The crude heptenoic acid 26 was
dissolved in acetone (2 mL), and DBU (0.31 mL, 2.1 mmol)
was added. After stirring for 5 min, isopropyl iodide (0.21 mL,
2.1 mmol) was added and the solution was stirred overnight
(TLC MTBE/heptane 1:7 showed complete reaction). The
mixture was partitioned between saturated potassium dihy-
drogen orthophosphate solution (15 mL) and ethyl acetate (2
× 20 mL). The organic phases were washed with brine (10
mL), dried (Na2SO4), filtered, and evaporated. The residue was
chromatographed (MTBE/heptane 1:7) to give the title com-
pound 27 (160 mg, 56%) as a colorless oil.
1
CH2Cl2). IR (neat) 1727 cm-1. H NMR (400 MHz, CDCl3) δ
9.72 (m, 1H), 7.18 (t, J ) 8 Hz, 1H), 6.91 (d, J ) 8 Hz, 1 H),
6.86 (t, J ) 2 Hz, 1H), 6.75 (dd, J ) 8, 2 Hz, 1H), 5.82 (m,
2H), 4.53 (m, 1H), 4.32 (m, 1H), 4.12 (m, 1H), 4.04 (dd, J )
10, 4 Hz, 1 H), 3.85 (d, J ) 6 Hz, 2H), 3.75 (d, J ) 9 Hz, 1H),
2.44 (m, 2H), 1.90 (m, 1H), 1.70-1.50 (m, 2H), 0.90 (s, 18H),
0.10 (s, 6H), 0.08 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 201.7,
159.5, 134.8, 133.0, 131.3, 130.2, 120.9, 114.9, 112.9, 82.7, 75.7,
73.0, 72.3, 71.0, 50.2, 42.2, 25.8, 25.7, 18.3, 18.0, 17.2, -4.3,
-4.6, -4.7, -5.0. APCI (positive) 593 ([M37ClNa]+, 18), 591
([M35ClNa]+, 41), 114 (100). Anal. calcd for C29H49ClO5Si2: C,
61.2; H, 8.7. Found: C, 61.35; H, 8.7.
Isopropyl 4-Bromobutyrate (28). 4-Bromobutyric acid
(21.6 g, 129 mmol) was dissolved in 2-propanol (100 mL).
Concentrated sulfuric acid (0.5 mL) was added and the mixture
was heated at reflux for 2 h (TLC MTBE/heptane 1:3 indicated
complete reaction). The solution was cooled to room temper-
ature and concentrated under reduced pressure (70 mL of
solvent was removed). The concentrate was dissolved in MTBE
(150 mL) and washed with saturated sodium hydrogencar-
bonate (50 mL), water (50 mL), and brine (50 mL). The solu-
tion was dried (MgSO4), filtered, and evaporated to give a
yellow liquid (21.7 g, 80%). NMR showed minor impurities
(a more polar spot was visible by TLC). The crude product
was dissolved in heptane (100 mL) and washed with water
(2 × 50 mL) (this removes most of the impurity). The hep-
tane solution was dried (MgSO4) and filtered through a pad
of silica (14 g), washing through with heptane (100 mL). The
solvent was evaporated to give the title compound 28 (17.5 g,
1
65%) as a colorless liquid. H NMR (200 MHz, CDCl3) δ 5.00
(heptet, J ) 6 Hz, 1H), 3.45 (t, J ) 6 Hz, 2 H), 2.45 (t, J ) 7
Hz, 2H), 2.16 (quintet, J ) 7 Hz, 2 H) and 1.22 (d, J ) 6 Hz,
6H).
(3-Isopropoxycarbonylpropyl)triphenylphosphon-
ium Bromide (29).16 Isopropyl 4-bromobutyrate 28 (16.0 g,
76.5 mmol) and triphenylphosphine (20.0 g, 76.5 mmol) in
toluene (160 mL) were heated at reflux under nitrogen for 39
h. The phosphonium salt 29 separated as a white power. The
mixture was allowed to cool (to approximately 40 °C), filtered,
and the solid was washed with toluene (3 × 25 mL). The
product 36 was dried under vacuum to give a white solid (20.7
g, 57%). mp 198 °C (onset by DSC). 1H NMR (200 MHz, CDCl3)
δ 7.85-7.60 (m, 15H), 4.89 (heptet, J ) 6 Hz, 1H), 3.96-3.70
(m, 2H), 2.75 (t, J ) 6 Hz, 2H), 1.95-1.75 (m, 2H), 1.13 (d, J
) 6 Hz, 6H).
Isopropyl [2R (1E,3R), 3S (4Z), 4R)]-7-{tetrahydro-2-
[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-
furanyl}-4-heptenoate (AL-12182) (1).1 The silyl protected
prostaglandin analogue 27 (2.40 g, 3.52 mmol) was dissolved
in tetrahydrofuran (15 mL) (internal temperature 18 °C).
Tetrabutylammonium fluoride (1 M in tetrahydrofuran, 10.5
J. Org. Chem, Vol. 70, No. 4, 2005 1235

Fox et al.
mL) was added (temperature rose to 20 °C over 3 min) and
the mixture was stirred at room temperature under nitrogen
for 4 h (TLC ethyl acetate/heptane 3:1 indicated complete
reaction). Water (50 mL) was added and the mixture was
extracted with ethyl acetate (3 × 30 mL). The combined
organic extracts were washed with water (50 mL) and brine
(50 mL), dried (Na2SO4), filtered, and evaporated. The residue
was chromatographed (ethyl acetate/heptane 7:3) to give a
faintly yellow oil (1.42 g, 3.13 mmol, 89%). Even after drying
under high vacuum, small peaks at δ 0.9 were visible in the
1H NMR spectrum. The product was passed through a short
silica column eluting with neat ethyl acetate to give AL-12182
1 as a clear, colorless oil (1.29 g, 2.85 mmol, 81%). [R]D20 +27.6
(m, 1H), 1.22 (d, J ) 6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ
ppm 173.2, 159.2, 134.9, 132.7, 130.7, 130.6, 130.3, 128.1,
121.4, 115.1, 113.0, 82.2, 75.5, 72.6, 71.8, 70.1, 68.0, 50.9, 34.4,
25.8, 24.6, 22.7, 21.9, 21.9. APCI 477 ([M37ClNa]+, 25), 475
([M35ClNa]+, 69), 247 (100).
Acknowledgment. This work was carried out in
collaboration with Alcon Laboratories Inc., 6201 S.
Freeway, Fort Worth, TX 76134. We are grateful for
Mark DuPriest of Alcon for advice and helpful discus-
sions. Analytical support was provided by Catherine
Hill.
(c 1.0, EtOH). IR (film) 3416 and 1725 cm-1 1H NMR (400
.
MHz, CDCl3) δ 7.19 (t, J ) 8 Hz, 1H), 6.95 (d, J ) 8 Hz, 1H),
6.91 (t, J ) 2 Hz, 1H), 6.78 (dd, J ) 8, 2 Hz, 1H), 5.84 (m,
2H), 5.50-5.30 (m, 2H), 4.99 (heptet, J ) 6 Hz, 1H), 4.56 (m,
1H), 4.41 (m, 1H), 4.14-4.05 (m, 2H), 3.97 (dd, J ) 9, 4 Hz,
1H), 3.93-3.85 (m, 2H), 2.65 (brs, 2H), 2.50 (m, 1H), 2.36-
2.22 (m, 4H), 2.00 (m, 1H), 1.75 (m, 1H), 1.52 (m, 1H), 1.43
Supporting Information Available: HPLC chromato-
grams of AL-12182 1 showing principle impurities. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO048035V
1236 J. Org. Chem., Vol. 70, No. 4, 2005