The Intramolecular Asymmetric Pauson-Khand Cyclization As A Novel and General Stereoselective Route to Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil)

Article abstract of DOI:10.1021/jo0347720

A general and novel solution to the synthesis of biologically important stable analogues of prostacyclin PGI₂, namely benzindene prostacyclins, has been achieved via the stereoselective intramolecular Pauson-Khand cyclization (PKC). This work illustrates for the first time the synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts issues of individual step stereoselectivity and scalability. The key step in the synthesis involves efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic centers at three carbon atoms (C_3a, C_9a, and C₁).

Full text of DOI:10.1021/jo0347720

Th e In tr a m olecu la r Asym m etr ic P a u son -Kh a n d Cycliza tion a s a
Novel a n d Gen er a l Ster eoselective Rou te to Ben zin d en e
P r osta cyclin s: Syn th esis of UT-15 (Tr ep r ostin il)
Robert M. Moriarty,*,† Neena Rani,‡ Livia A. Enache,§ Munagala S. Rao,§ Hitesh Batra,‡
Liang Guo,‡ Raju A. Penmasta,‡ J ames P. Staszewski,‡ Sudersan M. Tuladhar,‡ Om Prakash,†
David Crich,† Anca Hirtopeanu,†,| and Richard Gilardi
Department of Chemistry (M/ C 111), University of Illinois at Chicago, Chicago, Illinois 60607,
United Therapeutics, Chicago, Illinois 60612, deCODE Genetics, Inc., Chicago, Illinois 60612,
Institute of Organic Chemistry, C.D. Nenitescu, Bucharest, Romania, and Laboratory for the Stucture of
Matter, Naval Research Laboratory, Washington, DC 20375
Received J une 5, 2003
A general and novel solution to the synthesis of biologically important stable analogues of
prostacyclin PGI2, namely benzindene prostacyclins, has been achieved via the stereoselective
intramolecular Pauson-Khand cyclization (PKC). This work illustrates for the first time the
synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent
manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts
issues of individual step stereoselectivity and scalability. The key step in the synthesis involves
efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic
OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed
via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC
product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic
centers at three carbon atoms (C3a, C9a, and C1).
Prostacyclin (PGI2) (1) is an important physiological
prostanoid and occurs as a major metabolic product from
arachidonic acid throughout the vasculature and is
produced in the endothelium and in smooth muscles.1a-r
PGI2 is the most potent endogenous vasodilator in both
systemic and pulmonary circulation. It exerts effects on
vascular smooth muscle cells and inhibits both platelet
aggregation and adhesion.2a-f These biological activities
are relevant to a broad range of cardiovascular diseases
including congestive heart failure, peripheral vascular
disease, myocardial ischemia, and pulmonary hyperten-
sion.3a-r Use of PGI2 as a drug for coronary disease has
not been fruitful because of the fleeting half-life of this
compound (∼10 min at pH 7.6 at 25 °C).4 The ability to
inhibit platelet aggregation in plasma samples is lost
within 5 min.5 Application of PGI2 to disease therapy
presents a typical drug delivery challenge that is dealt
with either mechanically by an appropriate pharmaceuti-
cal device or chemically by synthesizing a hydrolytically
stable analogue that retains the biological activity. The
first option currently is used for the treatment of pulmo-
nary hypertension in which an aqueous solution of PGI2
sodium salt (chemical name, epoprostenol; trade name
Flolan) is pumped continuously and intravenously through
a catheter permanently placed in the patient’s chest via
a portable external pump. PGI2 is light sensitive and
must be stored between 15 and 25 °C, and the formula-
tion in a buffer solution must be prepared by the patient
on a daily basis.6 The PGI2 is thereby introduced directly
* To whom correspondence should be addressed.
† Department of Chemistry (M/C 111), University of Illinois at
Chicago, 845 W. Taylor St., Room 4500.
‡ United Therapeutics.
§ deCODE Genetics, Inc..
| Institute of Organic Chemistry, C.D. Nenitescu.
Naval Research Laboratory.
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J .; Moncada, S. Prostaglandins 1976, 12, 915-928. (c) Vane, J . R.;
Bergstrom, S., Eds. Prostacyclin; Raven Press: New York, 1979. (d)
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10.1021/jo0347720 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/19/2004
1890
J . Org. Chem. 2004, 69, 1890-1902

Synthesis of Treprostinil
into the pulmonary arterial system. This is a difficult
therapy and one can appreciate the strong motivation to
discover an active, stable analogue that could be admin-
istered in a less invasive manner either orally or sub-
cutaneously. From a chemical viewpoint one can readily
understand the hydrolytic lability of PGI2 on the basis
of the presence of the Z-vinyl ether group. Protonation
of 1 yields the oxonium ion 2 followed by ring opening of
the derived hemiketal to yield 6-keto-PGF1R (3).7a Ad-
ditional driving force for the rapid hydrolysis has been
proposed to involve the carboxylate form of 24 and proven
in an elegant kinetic study.7b
intermediate 2 and this compound is called APF-07 4.8
Removal of the C5-6 double bond yields 6â- and 6R-
9a-e
PGI1
or formal removal of the oxygen atom and
replacement by a methylene group generates the class
of analogues called carbaprostacyclins.10a-f These ana-
logues do not possess the reactive vinyl ether system and
prominent examples are iloprost 5,11 cicaprost 5a ,12 and
eptaloprost 5b13a-d which are differentiated by variations
in the side chains. Replacement of the oxygen atom by
sulfur as well as nitrogen has been reported, e.g. (5Z)-
6,9-thiaprostacyclin14a-d and 9-deoxy-9R-nitrilo-PGF1.15a,b
Finally, the Z-vinyl ether can be embedded in an aryl
ether motif as in beraprost (6)16a-e or UT-15 (7).17a-c UT-
15 (7) belongs to a class of stable analogues of PGI2 called
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(17) (a) Aristoff, P. A.; Harrison, A. W.; Aiken, J . W.; Gorman, R.
R.; Pike, J . E. In Advances in Prostaglandin Thromboxane and
Leukotriene Research; Samuelsson, B., Paoletti, R., Ramwell, P. W.,
Eds.; Raven Press: New York, 1983; Vol. 11, pp 267-274. (b) UT-15
has also been variously known as Uniprost, BW-15AU, LRX-15,
U-62840, 15AU81, and finally Remodulin. (c) Sorbera, L. A.; Rabasseda,
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J . Org. Chem, Vol. 69, No. 6, 2004 1891

Moriarty et al.
benzindene prostacyclins that are differentiated by the
structure of their side chains.18a-c
passage through the lungs.20 In further contrast to
Flolan, UT-15 is delivered subcutaneously via a micro-
infusion device thus avoiding the risk of sepsis infection
encountered with catheter delivery. UT-15 (7) retains all
the biological activity of PGI2. UT-15 has been investi-
gated for use in severe congestive heart failure,21a-c
severe intermittent claudication,22a,b and immuno-
suppresion.23a-c Furthermore, UT-15 has an antiprolif-
erative effect on human pulmonary arterial smooth
muscle cells.24 To meet the demands of producing mul-
tikilogram quantities of UT-15 (7) needed in the course
of drug development, an efficient and economical syn-
thesis had to be devised. The essential requirements for
any large-scale, multistep synthesis of a molecule of the
complexity of UT-15 (7) are very high overall stereose-
lectivity, high overall chemical yield, and scalability of
individual steps to multigram quantities. Inspection of
the structure of this molecule reveals the presence of five
chiral centers and the molecule can be viewed as a benzo-
annulated hydrindane with the BC ring system reminis-
cent of the CD ring system of steroids.
Benzindene prostacyclin UT-15 (7), [[(1R,2R,3aS,9aS)-
2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-hydroxy-
octyl]-1-H-benz[f]inden-5-yl]oxy]acetic acid, has been syn-
thesized previously by Upjohn chemists using an ap-
proach in which the AB ring system is introduced in the
form of 5-methoxy-2-tetralone (8), which is converted to
racemic 9, followed by an intramolecular Wadworth-
Emmons-Wittig cyclopentanone annulation using the
homochiral side chain 10 with no stereochemical control
in the creation of the C3a chiral center in 11.25 UT-15 (7)
was synthesized in 14 steps following the route of Scheme
1. Stereochemistry was introduced rather late in the
synthesis in the form of the homochiral side chain 10 in
this general route to benzindene prostacyclins differing
in the C1 side chain. Unfortunately, this low level of
control of stereochemistry in this route led to significant
separation problems in obtaining the final product and
could not be used to fulfill our scale-up needs for
development of UT-15.
Another early route to the benzindene prostacyclin
system and UT-15 (7) used intramolecular alkylation of
the phenolic ring for formation of the B-ring. Homochiral
12 was made in a multistep synthesis and converted to
13 with use of C6H5S(O)(NCH3)CH2MgBr (Scheme 2).
Reductive elimination followed by hydroboration and
To date, UT-15 (7) has proven effective in the treat-
ment of pulmonary hypertension, a debilitating and often
fatal lung disease, for which Flolan mentioned above has
been the main therapy available.19a-f UT-15 (7) has a
longer biological half-life and is not degraded upon
(20) Remodulinsstable form of prostacyclin; United Therapeutics
Corp. Web Site March 23, 2001.
(21) (a) Patterson, J . H.; Adams, K. F., J r.; Gheorghiade, M.; Bourge,
R. C.; Sueta, C. A.; Clarke, S. W.; J ankowski, J . P.; Shaffer, C. L.;
McKinnis, R. A. Am. J . Cardiol. 1995, 75, 26A-33A. (b) Adams, K. F.,
J r.; Patterson, H.; Gheorghiade, M.; Bourge, R. C.; Sueta, C. A.; Clarke,
S. W.; Patel, J . D.; Shaffer, C. Circulation 1992, 86 (4, Suppl.), Abst
1501. (c) Steffen, R. P.; de la Mata, M. Prostaglandins, Leucotrienes
Essent. Fatty Acids 1992, 45, 83. (d) Fink, A. N.; Frishman, W. H.;
Azidad, M.; Argarwal, Y. Heart Dis. 1999, 1, 29-40.
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1258. (b) Aristoff, P. A.; Harrison, A. W. Tetrahedron Lett. 1982, 23,
2067-2070. (c) Aristoff, P. A.; J ohnson, P. D.; Harrison, A. W. J . Am.
Chem. Soc. 1985, 107, 7967-7974.
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E.; Wade, M.; Sehgal, C. M. Vasc. Med. 2000, 5, 231-237. (b) Mohler,
E. R.; Klugherz, B.; Goldman, R.; Fishman, A. P.; Wade, M.; Sehgal,
C. M. J . Am. Coll. Cardiol. 1999, 33 (2, Suppl. A), 277A.
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N. G.; Boyle, M. J .; Kahan, B. D. Transplantation 1993, 55, 1124-
1128. (b) Boyle, M. J .; Dumble, L. J . Cell Transplant 1999, 8, 543-
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1892 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Treprostinil
SCHEME 1
SCHEME 2
SCHEME 3
the intramolecular asymmetric Pauson-Khand cycliza-
tion (PKC) of enynes to cyclopentenones could fulfill both
these requirements.28a-s An enyne of type 18 appeared
to be relatively readily accessible and the powerful
stereodirecting influence of an R-propargylic substituent
at C9 in the intramolecular asymmetric PKC has been
amply demonstrated and productively used in stereose-
lective synthesis.29a-q In the present example the C1 S
configuration of the substituent would create the requi-
site C3aâ-configuration of the hydrogen atom in UT-
15.30a-c Thus, an advanced tricyclic enantiopure inter-
mediate could potentially be obtained from a relatively
simple homochiral precursor. Furthermore, additional
mesylation gave 14 that underwent intramolecular alky-
lation (14 f 15).26a-cA related approach in which the
B-ring of a benzindene prostacyclin was formed by
intramolecular alkylation coupled with conjugate addi-
tion to a vinyl sulfone has also been reported (16 f 17)
(Scheme 3).27a-dReductive cleavage of the phenyl sulfone
group in 17 yielded the cis/trans ring fused product in a
1.9/1 ratio.
These routes, although conceptually appealing, were
deemed inadequate to the task of producing kilogram
quantities of UT-15 (7), and accordingly a novel synthetic
route was required. The principal requirement envisioned
was production of an enantiopure intermediate early in
the synthesis, ideally at the tricyclic stage. In principle,
(28) (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J . Chem.
Rev. 1996, 96, 635-662. (b) Khand, I. U.; Knox, G. R.; Pauson, P. L.;
Watts, W. E.; Foreman, M. I. J . Chem Soc., Perkin Trans. 1 1973, 977-
981. (c) Pauson, P. L. Tetrahedron 1985, 41, 5855-5860. (d) Pauson,
P. L. In Organometallics in Organic Synthesis, Aspects of a Modern
Interdisciplinary Field; de Meijere A., Tom Diek, H., Eds; Springer-
Verlag: Berlin, Germany, 1988; p, 233. (e) Schore, N. E. Chem. Rev.
1988, 88, 1081-1119. (f) Schore, N. E. Org. React. 1991, 40, 1-90. (g)
Schore, N. E. In Comprehensive Organic Synthesis; Trost B. M.,
Fleming, I., Eds., Pergamon Press Ltd.: Oxford, UK, 1991; Vol. 5, p
1037. (h) Schore, N. E. In Comprehensive Organometallic Chemistry
II; Abel, E. W., Stone, F. A., Wilkinson, G., Eds.; Elsevier: New York,
1995; Vol. 12, p 703. (i) Geis, O.; Schmalz, H. G. Angew. Chem., Int.
Ed. 1998, 37, 911-914. (j) Ingate, S. T.; Marco-Contelles, J . Org. Prep.
Proced. Int. 1998, 30, 121-143. (k) J eong, N. In Transition Metals in
Organic Synthesis; Beller M., Molm, C., Eds.; Wiley-VCH: Weinhem,
Germany, 1998; Vol. 1, p 560. (l) Chung, Y. K. Coord. Chem Rev. 1999,
188, 297-341. (m) Buchwald, S. L.; Hicks, F. A. In Comprehensive
Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer Verlag: Berlin, Germany, 1999; Vol. II, p 491. (n) Brummond,
K. M.; Kent, J . L. Tetrahedron 2000, 56, 3263-3283. (o) Khand, I. U.;
Pauson, P. L. J . Chem. Soc., Perkin Trans. 1 1976, 30-32. (p) Pauson,
P. L.; Khand, I. U. Ann. N.Y. Acad. Sci. 1977, 295, 2-14. (q) Bladon,
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Khand, I. U.; Pauson, P. L. J . Chem. Res. Miniprint 1980, 3501. (s)
Fruhauf, H.-W. Chem. Rev. 1997, 97, 523-596.
(26) (a) Aristoff, P. A. US 4306075. (b) Aristoff, P. A. US 4349689.
(c) Aristoff, P. A.; Kelly, R. C.; Nelson, N. A. CH 648017, CH 655308,
FR 2484413, GB 2070596, J P 1990167248, J P 1994145085.
(27) (a) Hardiger, S. A.; J akubowski, J . A.; Fuchs, P. L. Bioorg. Med.
Chem. Lett. 1991, 1, 79-82. (b) Nevill, C. R., J r.; Braish, T. F.;
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P. L. Biomed. Chem. Lett. 1991, 1, 83-86.
J . Org. Chem, Vol. 69, No. 6, 2004 1893

Moriarty et al.
benefits accrue from this approach: cis-stereochemistry
is expected in the heterogeneous catalytic hydrogenation
ence of a catalytic amount of CuI to yield (S)-1-chloro-2-
heptanol (37), which was then converted to the diaster-
eomeric tetrahydropyranyl derivative 38. This compound
was then treated with lithio 1-trimethylsilyl-1-propyne
formed with use of butyllithium at -20 °C and at a
reaction temperature of 0 °C (38 f 39). Cleavage of the
TMS group yielded 5-S-tetrahydropropanoxy-1-decyne
(25).
of the double bond of the enone, resulting in the required
C9a â-configuration; and benzylic hydrogenolysis expect-
edly would remove the unneeded benzylic group while
the carbonyl group at C2 remains available for reduction
to the C2 R-hydroxyl group. All of these preconceptions
proved valid in the synthesis of UT-15 (7) as summarized
in Scheme 4. Individual steps will be discussed in turn.
Resu lts a n d Discu ssion
Syn th esis of En yn e (1,1-Dim eth yleth yl)[[(1S,6S)-
1-[3-m eth oxy-2-(2-p r op en yl)p h en yl]-6-[(tetr a h yd r o-
2H -p y r a n -2-y l)o x y ]-2-u n d e c y n y l]o x y ]d im e t h y l-
sila n e (29). The key feature of enyne 29 is the benzylic
C1 S stereochemistry because this group influences the
creation of the chiral center formed in the PKC at C3a in
the requisite S configuration. It had been shown earlier
that the tert-butyldimethyl silyl ether is a particularly
useful group as the R-propargyl substituent in the PKC.29i
Aldehyde 24 was produced in a straightforward manner.
3-Methoxybenzyl alcohol 20 was protected as the TBDMS
derivative and ortho-allylated (20 f 21 f 22). Depro-
tection and Swern oxidation gave 2-allyl-3-methoxy-
benzaldehyde (24) (22 f 23 f 24).
The further synthesis of enyne involves Grignard
addition of side chain 25 to aldehyde 24 to yield 26. The
diastereomeric side chain 5-S-tetrahydropropanoxy-1-
decyne (25) was synthesized by using an adaptation of
the method of Takano et al.31 (S)-(-)-Epichlorohydrin (36)
was reacted with butylmagnesium chloride in the pres-
3-Methoxy-2-(2-propenyl)-R-[(5S)-5-[(tetrahydro-2H-py-
ran-4-yl)oxy]-1-decynyl]benzenemethanol intermediate
(26), which results from the addition of 25-MgBr to 24,
possesses three chiral centers, one of which is fixed, i.e.,
the S-configuration of the C6 carbon atom. The benzylic
carbon atom and the chiral carbon atom of the THP group
are individually heterochiral. In agreement with expecta-
tion a chiral chromatogram (Daicel Chiralpak AD Col-
umn) of 26 showed four peaks. Diastereomeric 26 was
oxidized with pyridinium chlorochromate to the diaster-
eomeric ketone 27.
For the subsequent stereoselective Pauson-Khand
cyclization, we required the S-configuration of the ben-
zylic (propargylic) carbon bearing the hydroxyl group.
The stereochemistry was obtained by using a stoichio-
metric Corey-type asymmetric reduction of 27 employing
commercially available R-methyloxazaborolidine, borane-
dimethyl sulfide complex, and ketone 27 at -30 °C.32a
The S stereochemical result is in agreement with the
results of Parker and Ledeboer using the same system.32b
Chiral chromatographic analysis of 28 showed the pres-
ence of two diastereomers.
For the Pauson-Khand cyclization, 28 was converted
to the corresponding TBDMS protected alcohol 29 and
subjected to either stoichiometric or catalytic Co2(CO)8
cyclization33 to yield the tricyclic enone 30 in 89% yield.
For assessment of the stereoselectivity of the reaction,
the crude product prior to chromatography was analyzed
with HPLC, which revealed that over 99% of the product
consisted of two peaks of equal intensity corresponding
to >99% creation of the new chiral center at C3a in one
configuration. The two peaks result from the THP dia-
stereomeric center -O-CH-O-.
(29) (a) Mukai, C.; Uchiyama, M.; Sakamoto, S.; Hanaoka, M.
Tetrahedron Lett. 1995, 36, 5761-5764. (b) Xestobergsterol D and E
rings: Krafft, M. E.; Chirico, X. Tetrahedron Lett. 1994, 35, 4511-
4514. (c) Krafft, M. E.; J uliano, C. A.; Scott, I. L.; Wright, C.; McEachin,
M. D. J . Am. Chem. Soc. 1991, 113, 1693-1703. (d) Krafft, M. E. J .
Am. Chem. Soc. 1988, 110, 968-970. (e) Krafft, M. E. Tetrahedron Lett.
1988, 29, 999-1002. (f) (+)-Epoxydicylmene: J amison, T. F.; Sham-
bayati, S.; Crowe, W. E.; Schreiber, S. L. J . Am. Chem. Soc. 1994, 116,
5505-5506. J amison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber,
S. L. J . Am. Chem. Soc. 1997, 119, 4353-4363. (g) (-)-R-Kainic acid:
Yoo, S.; Lee, S. H. J . Org. Chem. 1994, 59, 6968-6972. (h) Pental-
enene: Schore, N. E.; Rowley, E. G. J . Am. Chem. Soc. 1988, 110,
5224-5225. (i) Pentalenic acid, pentalenene: Rowley, E. G.; Schore,
N. E. J . Organomet. Chem. 1991, 413, C5-C9. (j) Siliphene: Rowley,
E. G.; Schore, N. E. J . Org. Chem. 1992, 57, 6853-6861. (k) Kal-
manol: Paquette, L. A.; Borrelly, S. J . Org. Chem. 1995, 60, 6912-
6921. (l) Dendrobine: Cassayre, J .; Zard, S. Z. J . Am. Chem. Soc. 1999,
121, 6072-6073. (m) Coriolin: Exon, C.; Magnus, P. J . Am. Chem.
Soc. 1983, 105, 2477-2478. (n) 9-cis-Retinoic acid: Murray, A.;
Hansen, J . B.; Christensen, B. V. Tetrahedron 2001, 57, 7383-7390.
(o) Quadrone: Magnus, P.; Principe, L. M.; Slater, M. J . J . Org. Chem.
1987, 52, 1483-1486. (p) Hirsuitic acid: Magnus, P.; Exon, C.;
Albaugh-Robertson, P. Tetrahedron 1985, 41, 5861-5869. (q) Carba-
cyclins: Mulzer, J .; Graske, K. D.; Kirste, B. Liebigs Ann. Chem. 1988,
891-897.
Two points are noteworthy in connection with the
Pauson-Khand cyclization of 29. The first is the high
(31) Takano, S.; Yanase, M.; Takahashi, M.; Ogasawara, K. Chem.
Lett. 1987, 2017-2020.
(30) (a) Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26,
4851-4854. (b) Schore, N. E. Pauson-Khand Reaction. In Compre-
hensive Organic Synthesis; Trost, B. M., Ed., Pergamon Press: Oxford,
UK, 1991. (c) J eong, N.; Lee, B. Y.; Lee, S. M.; Chung, Y. K.; Lee, S. G.
Tetrahedron Lett. 1993, 34, 4023-4026.
(32) (a) Helal, C. J .; Magriotis, P. A.; Corey, E. J . J . Am. Chem. Soc.
1996, 118, 10938-10939. (b) Parker, K. A.; Ledeboer, M. W. J . Org.
Chem. 1996, 61, 3214-3217.
(33) Pagenkopf, B. L.; Livinghouse, T. J . Am. Chem. Soc. 1996, 118,
2285-2286.
1894 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Treprostinil
SCHEME 4
J . Org. Chem, Vol. 69, No. 6, 2004 1895

Moriarty et al.
SCHEME 5
chemical yield (89%) and the high degree of chiral
induction of almost 100%. Since these yields are the same
in both the stoichiometric and the catalytic reaction the
results must be mechanistically controlled with steric
effects being determinant. Two factors are operative. The
first is that the phenyl ring forces the enyne system into
the most favorable orientation for annulation by restrict-
ing rotational conformations (18 S 18a ). It has been
observed that â-positioned geminal dialkyl enynes give
relatively higher yields of cyclized products due to a
Thorpe-Ingold-type effect.34a-d This cisoid orientation of
the alkyne Co(CO)6 group and the alkene in 40 is further
enhanced by the ortho CH3O group steric interaction with
the alkyl system.
found this to be the case in 44 f 45 regardless of the
stereochemistry (R or â) of the C1 hydroxyl group.37
According to the mechanism proposed by Magnus and
applied by others, the stereochemical course follows from
the relative energy difference of the transition states
leading to the two diastereomeric metallocycle intermedi-
ates 40 and 42 (Scheme 5) with the latter possessing a
destabilizing 1,3-diaxial interaction that disfavors this
course of reaction.29a-p,30a,b This effect is amplified because
of the large steric bulk of the benzylic TBDMS group.
Catalytic hydrogenation 30 f 31 removed the now
superfluous stereodirecting benzylic TBDMS ether and
the thermodynamically more stable cis-hydrindanone is
formed.35a,b The side chain at C1 existed in both the R-
and â-configurations. Formation of the cis-hydrindanone
appears to concur with expectation; indeed the catalytic
heterogeneous hydrogenation of hydrindenones has been
studied in great detail because of its relationship to the
CD ring of steroids.36 Basically the problem is that the
desired stereochemistry for the CD ring system of ste-
roids is trans but invariably the undesired cis-fused
product is formed by catalytic reduction. Stork and Kahne
In the case of 44a , the â face of the molecule is
hindered by both the allylic angular methyl group and
the homoallylic C1 hydroxyl group and the thermo-
dynamically more stable cis-hydrindanone is formed (44a
f 45a ). Hajos and Parrish succeeded in using the steric
effect of the C1â-substituent to favor formation of the
trans ring fused product by using a tert-butyl ether group
(44b) located homoallylic to the double bond of the enone
resulting in 30% trans product.36 In the case of enone 30
the â face is shielded by the large allylic TBDMS ether,
a circumstance that should favor formation of the un-
desired trans-fused product in the catalytic hydrogena-
tion step as in the above example (44b f 45b). None-
theless cis reduction occurs. This may be taken as
indirect evidence that hydrogenolysis of the OTBDMS
group occurs prior to reduction of the double bond.
(34) (a) De Tar, D. F.; Luthra, N. P. J . Am. Chem. Soc. 1980, 102,
4505-4512. (b) Kirby, A. J . Adv. Phys. Org. Chem. 1980, 17, 208. (c)
Eliel, E. L. Stereochemistry of Carbon Compounds; McGraw-Hill: New
York, 1962; pp 106-202. (d) The majority of the syntheses involve
cyclization of 1,6-enynes to yield bicyclo[3.3.0]octene-3-ones. Applica-
tions to form bicyclo[4.3.0]octene-ones are known: Quattropani, A.;
Anderson, G.; Bernardinelli, G.; Kuendig, E. P. J . Am. Chem. Soc. 1997,
119, 4773-4774 and references therein.
Furthermore, since enones and especially tetrasubsti-
tuted ones undergo H2/Pd-C reduction very slowly (50
(35) (a) Boyce, C. B. C.; Whitehurst, J . S. J . Chem. Soc. 1960, 4547-
4553. (b) Baggaley, K. H.; Brooks, S. G.; Green, J .; Redman, B. T. J .
Chem. Soc. C 1971, 2671-2678.
(37) Stork, G.; Kahne, D. E. J . Am. Chem. Soc. 1983, 105, 1072-
1073.
(36) Hajos, Z. H.; Parrish, D. P. J . Org. Chem. 1973, 38, 3239-3243.
1896 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Treprostinil
psi/43 h and 30 psi/15 h), it is likely that benzylic
dehydrogenation of the TBDMS ether precedes the enone
reduction.
The borohydride reduction of 31 that is a mixture of
exo and endo C1 epimers yields one product, namely, the
exo C1 side chain and endo C2 alcohol.
F IGURE 1. X-ray molecular structure of triol 34.
hydrolyzed with ethanolic potassium hydroxide to yield
UT-15 (7) in 9% overall yield.18c,40
In ethanolic sodium hydroxide equilibration of 31a and
31b occurred while reduction of 31a is slower than that
of 31b, in effect leading to a kinetic resolution of the
desired product. This behavior was observed earlier by
Aristoff et al. in the synthesis of a related benzindene
prostacyclin, namely U-68,215.18c
The stability difference between the exo and the endo
side chain epimers is due to essentially an eclipsed
relationship between the side chain and C9a-C9 for the
endo epimer of the cis-hydrindane ring system versus a
torsional angle of about 120° in the exo orientation
between the side chain and C9a-C9 in the exo configu-
ration. In the sodium borohydride reduction, the hydride
Cleavage of the methyl ether in 33 f 34 with lithium
diphenylphosphine is a problematic step. For a closely
related benzindene prostacyclin a 7-fold excess of lithium
diphenylphosphine was used.18c In the present synthesis,
step 33 f 34, a 7-fold excess likewise proved necessary.
On a weight basis this becomes the most expensive step
in the entire synthesis.
Syn th esis of Ster eoisom er s of UT-15. Since the
stereochemical centers of UT-15 are introduced in the
form of the side chain 25 with (S)-(-)-epichlorohydrin
(39) as the chiral component in 36 f 37 f 38 f 39 f
25 and in the Corey reduction (27 f 28), use of the
opposite configuration of these key chiral reagents will
yield the stereoisomeric product. The synthesis of the
stereoisomer of UT-15 will be the subject of a future
communication.
Com p a r ison of th e Up joh n Rou te of Sch em e 1
w ith th e P a u son -Kh a n d Cycliza tion Rou te.18c The
steps 8 f 9 f 11 of the Upjohn route yield diastereomeric
11 (heterochiral at C3a) that is reduced (H2/Pd-C, EtOH,
K2CO3) to yield an inseparable mixture of ketones (31a ,
31b, 46a , and 46b) in 65% yield. The mixture of ketones
attack occurs in agreement with expectation from the
convex face to yield the R-orientation of the hydroxyl
group.
Deprotection of the side chain THP group gave meth-
oxydiol 33.38 Cleavage of the methoxyl group (33 f 34)
proved problematic because of the presence of the two
secondary hydroxyl groups. Thus TMSI or KI/DMF was
unsuccessful. The reagent C6H5SH/BuLi was successful
on a gram scale but was not scalable. Success was
achieved with lithium diphenylphosphine prepared in
situ from diphenylphosphine and n-butyllithium.39a,b This
step afforded the crystalline triol 34 for which an X-ray
diffraction pattern confirmed the stereochemistry (Figure
1).
Triol 34 was alkylated at the phenolic hydroxyl group
with use of chloroacetonitrile in refluxing acetone with
potassium carbonate (34 f 35) and nitrile 35 was
(38) Corey, E. J .; Niwa, H.; Knolle, J . J . Am. Chem. Soc. 1978, 100,
8031-8034.
(39) (a) Mann, F. G.; Pragnell, M. J . Chem. Ind. (London) 1964, 31,
1386. (b) Ireland, R. E.; Walba, D. M. Tetrahedron Lett. 1976, 14, 1071-
1074. (c) Org. Synth. 1977, 56, 44; Organic Syntheses; Wiley: New
York, 1988; Collect. Vol. VI, pp 567-575.
J . Org. Chem, Vol. 69, No. 6, 2004 1897

Moriarty et al.
is then reduced under equilibrating conditions to give a
mixture of alcohols 32 and 47.
Bicyclo[3.3.0]octenone 58 could potentially be converted
to carbacyclins.10a-f
In conclusion, we advocate the use of the R-propargyl
stereodirecting group, preferably OTBDMS,42 for stereo-
chemical control in the intramolecular PKC.
For the pair of ketones 31a and 31b equilibration (31a
f 31b) and borohydride reduction yields the desired UT-
15 precursor 32. For the ketone pair 46a and 46b
equilibration (46b f 46a ) borohydride reduction yields
47, an undesired stereoisomer. In the asymmetric Pau-
son-Khand cyclization route to 7 (Scheme 4) the num-
ber of stereoisomers is halved, i.e., 31 ) 31a and 31b
and 32 ) 32 uncontaminated with 47. This simplifies
greatly the chromatographic purification up to 32, which
is a common intermediate in the Upjohn and present
PKC routes.
Th e Dia ster eoselectivity of th e In tr a m olecu la r
Asym m et r ic P a u son -Kh a n d Cycliza t ion . Efforts
directed toward controlling the degree of stereoselectivity
in the Pauson-Khand cyclization have used chiral
auxiliaries, chiral catalysts, and chiral amine N-oxide
promoters.41 The present synthesis as well as several
other examples strongly recommend the strategy of an
R-propargyl stereodirecting group for achieving very high
diastereoselectivity.29a-q
The strategy of employing the highly diastereoselective
1,3-asymmetric induction in the PKC using a temporary
and readily removable stereodirecting group results in
an asymmetric synthesis that is superior to other meth-
ods used to date.41 Because of the efficient chemistry
available for deoxygenation of secondary alcohols,43 the
present asymmetric PKC could be generalized to enynes
possessing a nonbenzylic propargylic chiral secondary
alcohol of fixed configuration. The synthetic utility of the
PKC is broadened further by the use of transition metals
other than cobalt.44-49 This encompasses a considerable
range of synthetic targets.
Exp er im en ta l Section
Melting points were determined on a capillary tube melting
point apparatus and are uncorrected. 1H NMR spectra were
recorded on 400- and 300-MHz spectrometers. Tetramethyl-
A second approach is to use a natural product of known
absolute stereochemistry as the source of the R-propargyl
stereodirecting group. Starting from either L-ascorbic acid
(48) or dimethyl L-tartrate (49), 50 was formed and
Pauson-Khand cyclization led to 51 in 100% yield.
(40) Moriarty, R. M.; Penmasta, R.; Guo, L.; Rao, M. S.; Staszewski,
J . P. (United Therapeutics Corp.). Process for stereoselective synthesis
of prostacyclin derivatives. WO 9921830.
(41) For examples of asymmetric PKCs with chiral auxiliaries,
see: (a) Bladon, P.; Pauson, P. L.; Brunner, H.; Eder, R. J . Organomet.
Chem. 1988, 355, 449-454. (b) Castro, J .; Sorensen, H.; Riera, A.;
Morin, C.; Moyano, A.; Pericas, M. A.; Greene, A. E. J . Am. Chem.
Soc. 1990, 112, 9388-9389. (c) Verdaguer, X.; Moyano, A.; Pericas,
M. A.; Riera, A.; Bernardes, V.; Greene, A. E.; Alvarez-Larena, A.;
Piniella, J . F. J . Am. Chem. Soc. 1994, 116, 2153-2154. (d) Hay, A.
M.; Kerr, W. J .; Kirk, G. G.; Middlemiss, D. Organometallics 1995,
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F. A.; Buchwald, S. L. J . Am. Chem. Soc. 1996, 118, 11688-11689.
For use of a chiral amine N-oxide as a promoter see: (i) Kerr, W. J .;
Kirk, G. G.; Middlemiss, D. Synlett 1995, 1085-1086.
Relatedly, Mulzer et al. used this process to form the
same type of homochiral enyne starting from R- and
S-2,3-O-isopropylideneglyceraldehydes 52 and 53, res-
pectively.29q
(42) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
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(43) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans.
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4424-4431.
(47) Molybdenum: (a) Aumann, R.; Weidenhaupt, H.-J . Chem. Ber.
1987, 120, 23-27. (b) Kent, J . L.; Wan, H.; Brummond, K. M.
Tetrahedron Lett. 1995, 36, 2407-2410. (c) J eong, N.; Lee, S. J .; Lee,
B. Y.; Chung, Y. K. Tetrahedron Lett. 1993, 34, 4027-4030.
(48) Iron: Pearson, A. J .; Dubbert, R. A. J . Chem. Soc., Chem.
Commun. 1991, 202-203.
(49) Tungsten: Hoye, T. R.; Suriano, J . Organometallics 1992, 11,
2044-2050.
1898 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Treprostinil
silane (TMS) was used as an internal standard for 1H NMR.
All chemical shifts were reported in parts per million (ppm),
and the coupling constant (J ) values were calculated in hertz
(Hz) based on the chemical shifts. Deuteriochloroform (CDCl3)
was used as solvent for all NMR experiments with residual
chloroform as an internal standard for 13C NMR. IR spectra
were recorded on a FT-IR spectrophotometer. Mass spectra
were obtained by positive chemical ionization (CI) or by fast
atomic bombardment (FAB) technique. Unless otherwise
noted, all reactions were carried out in oven-dried glassware.
Dichloromethane was distilled from calcium hydride. Tetrahy-
drofuran (THF) was freshly distilled from sodium metal/
benzophenone prior to use. All solvents for chromatography
were obtained commercially and used as received. Reactions
were monitored by analytical thin layer chromatographic
(TLC) methods, using silica gel and 230-400 mesh (60A) glass
plates (0.25 mm), and all spots on TLC plates were either
visualized by ultraviolet (UV) light or detected by dipping the
plate into a 5% solution of phosphomolybdic acid in ethanol
and heating. The pure products for characterization were
isolated by flash column chromatography with the use of silica
gel, 230-400 mesh (60A).
3-Meth oxy-O-ter t-bu tyldim eth ylsilylben zyl Alcoh ol (21).
To a stirred solution of 3-methoxybenzyl alcohol (20) (5176 g,
37.46 mol) and imidazole (3035 g, 44.58 mol) in methylene
chloride (40 L) was added portionwise tert-butyldimethylsilyl
chloride (6549 g, 43.45 mol) under argon. After the reaction
was complete as indicated by TLC, the reaction mixture was
washed with water and brine. The organic layer was sepa-
rated, dried (Na2SO4), and concentrated in vacuo to yield crude
compound. The crude compound obtained was chromato-
graphed on silica gel with a gradient solvent of ethyl acetate
in hexanes to yield 8897 g (94%) of 3-methoxy-O-tert-butyldim-
ethylsilylbenzyl alcohol as a yellow oil. IR (neat) 2950, 2930,
and 1600 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.11 (s, 6H), 0.95
(s, 9H), 3.81 (s, 3H), 4.73 (s, 2H), 6.82 (m, 1H), 6.92 (m, 2H),
7.24 (t, 1H, J ) 8 Hz); 13C NMR (CDCl3, 75 MHz) δ -5.1, 18.5,
26.1, 55.2, 64.9, 111.6, 112.5, 118.3, 129.3, 143.3, 159.8. Anal.
Calcd for C14H24O2Si: C, 66.61; H, 9.58. Found: C, 66.62; H,
9.66.
brine, dried (Na2SO4), and filtered. The solvent was removed
in vacuo to yield a dark brown oil that was chromatographed
on silica gel with a solvent gradient of 0-30% ethyl acetate in
hexane to yield 4695 g (57% from 21) of 2-allyl-3-methoxy-
benzyl alcohol (23) as off-white solid; mp 37-38 °C. IR (neat)
3360, 3080, 3000, and 1640 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 3.51 (s, 1H), 3.81 (s, 3H), 4.68 (d, 1H, J ) 6 Hz), 4.96 (m,
1H), 5.98 (m, 1H), 6.87 (d, 1H, J ) 9 Hz), 7.03 (d, 1H, J ) 9
Hz), 7.22 (t, 1H, J ) 9 Hz); 13C NMR (CDCl3, 75 MHz) δ 29.7,
55.8, 63.3, 110.3, 114.6, 120.8, 126.3, 127.4, 137.4, 140.4, 157.7.
2-Allyl-3-m eth oxyben za ld eh yd e (24). To a cooled (-78
°C) and stirred solution of oxalyl chloride (4012 g, 31.61 mol)
in dichloromethane (30 L) was added slowly a solution of
dimethyl sulfoxide (4733 g, 60.58 mol) dissolved in 5 L of
dichloromethane under argon. After being stirred for 30 min,
a solution of 2-allyl-3-methoxybenzyl alcohol (23) (4694 g, 26.34
mol) dissolved in 5 L of dichloromethane was added to this
reaction mixture. After the solution was stirred for 1 h at -78
°C, triethylamine (13327 g, 131.70 mol) was added to quench
the reaction. The reaction mixture was allowed to warm to
room temperature overnight, washed with saturated NH4Cl
and brine, dried (Na2SO4), and filtered. The solvent was
removed in vacuo to yield a dark brown oil that was chro-
matographed on silica gel with a solvent gradient of 0-20%
ethyl acetate in hexane to yield 3997 g (92% pure by GC, 80%
yield) of 2-allyl-3-methoxybenzaldehyde (24) as a pale brown
oil. IR (neat) 3080, 3000, 2760, 1700, and 1640 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 3.88 (s, 1H), 3.90 (s, 3H), 4.90 (dq, 1H, J
) 3, 18 Hz), 5.04 (dq, 1H, J ) 3, 12 Hz), 6.03 (m, 1H), 7.15 (d,
1H, J ) 9 Hz), 7.31 (t, 1H, J ) 9 Hz), 7.44 (dd, 1H, J ) 0.9, 9
Hz), 10.31 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 28.1, 56.1,
115.4, 116.0, 122.6, 127.2, 127.5, 131.0, 135.1, 136.8, 157.9,
192.2.
(S)-1-Ch lor o-2-h ep ta n ol (37). To a solution of (S)-(-)-
epichlorohydrin 36 (3000 g, 32.42 mol) in 25 L of tetrahydro-
furan was added 617 g (3.24 mol) of CuI under argon. The
reaction mixture was cooled to 0 °C, and a solution of 17.02 L
(34.04 mol) of butylmagnesium chloride was added slowly with
stirring. The reaction was allowed to slowly warm to room
temperature, and after the solution was stirred for 15 h, GC
analysis indicated that all starting material was consumed.
The reaction was quenched by adding about 6 L of 15%
aqueous NH4OH saturated with NH4Cl. Solid was removed
by filtration over Celite and washed with ethyl acetate. Filtrate
was washed twice with 15% aqueous NH4OH saturated with
NH4Cl and brine, dried (Na2SO4), filtered, and concentrated
in vacuo to afford 4870 g (80% pure by GC, yield 80%) of (S)-
1-chloro-2-heptanol (37) as a clear yellow oil. IR (neat) 3380,
2960, 1590, 1460, 1430, and 1380 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.89 (t, 3H, J ) 6 Hz), 1.31 (m, 6H), 1.52 (m, 2H), 2.27
(m, 1H), 3.49 (dd, 1H, J ) 6, 12 Hz), 3.80 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 14.0, 22.6, 25.2, 31.7, 34.3, 50.6, 71.5. Anal.
Calcd for C7H15ClO: C, 55.81; H, 10.04. Found: C, 55.66; H,
2-Allyl-3-m eth oxy-O-ter t-bu tyld im eth ylsilylben zyl Al-
coh ol (22). To a stirred solution of 3-methoxy-O-tert-butyldi-
methylsilylbenzyl alcohol (21) (6495 g, 25.65 mol) in anhy-
drous hexane (25 L) was added slowly a solution of n-
butyllithium (11.288 L, 28.22 mol, 2.5 M solution in hexane)
at room temperature under argon. The reaction was stirred
for 2 h at ambient temperature and then cooled to 0 °C. Allyl
bromide (3569 g, 29.50 mol) was added over 30 min. The
reaction was allowed to warm to room temperature and stirred
for 24 h. After this time, the reaction mixture was cooled and
quenched with saturated NH4Cl solution. The organic layer
was washed with H2O and brine, dried (Na2SO4), and filtered
and the solvent was removed in vacuo to yield 2-allyl-3-
methoxy-O-tert-butyldimethylsilylbenzyl alcohol (22) (7393 g,
contains 60% product by GC) as an orange oil. This crude
product was used without further purification. IR (neat) 3080,
10.20. [R]25 2.31 (c 1.1, CHCl3). The compound was taken to
D
the next step without further purification.
(S)-1-Ch lor o-O-tetr a h yd r op yr a n -2-yl-h ep ta n -2-ol (38).
To a solution of 4869 g (32.32 mol) of (S)-1-chloro-2-heptanol
(37) in 30 L of methylene chloride was added 4078 g (48.38
mol, 1.5 equiv) of dihydropyran and 1219 g (4.85 mol, 0.15
equiv) of pyridinium p-toluenesulfonate at room temperature
with stirring. After being stirred for 15 h, the crude reaction
mixture was washed with water and brine. The organic layer
was separated, dried (Na2SO4), filtered, and concentrated in
vacuo. The crude product was chromatographed on silica gel
with 0-10% ethyl acetate in hexanes to yield 6779 g (84% pure
by GC, yield 75%) of (S)-1-chloro-O-tetrahydropyran-2-ylhep-
tan-2-ol (38) as an orange oil. IR (neat) 2940, 2860, 1600, 1470,
1450, 980, and 870 cm-1; 1H NMR(CDCl3, 300 MHz) δ 0.85 (t,
3H, J ) 7 Hz), 1.2-1.9 (m, 14H), 3.44-3.62 (m, 3H), 3.65-
3.79 (m, 1H), 3.81-4.01 (m, 1H), 4.65 (t, 1H, J ) 3 Hz), 4.76
(t, 1H, J ) 6 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.0, 19.6, 19.7,
22.6, 24.7, 25.0, 25.4, 25.5, 30.8, 31.0, 31.8, 31.9, 33.1, 46.1,
3000, and 1640 cm-1 1H NMR (CDCl3, 300 MHz) δ 0.08 (s,
;
6H), 0.98 (s, 9H), 3.53 (d, 2H, J ) 6 Hz), 3.94 (s, 3H), 4.75 (s,
2H), 4.98 (t, 2H, J ) 6 Hz), 6.01 (m, 1H), 6.79 (d, 1H, J ) 8
Hz), 7.01 (d, 1H, J ) 8 Hz), 7.25 (t, 1H, J ) 8 Hz); 13C NMR
(CDCl3, 75 MHz) δ -5.2, 18.5, 26.1, 29.4, 55.8, 62.8, 109.5,
114.4, 119.3, 125.0, 127.0, 136.5, 140.8, 157.3. Anal. Calcd for
C
17H28O2Si: C, 69.81; H, 9.65. Found: C, 69.92; H, 9.75.
2-Allyl-3-m eth oxyben zyl Alcoh ol (23). To a stirred solu-
tion of 2-allyl-3-methoxy-O-tert-butyldimethylsilylbenzyl al-
cohol (22) (13725 g, 46.92 mol) in tetrahydrofuran (10 L) was
added a solution of tetrabutylammonium fluoride (14791 g,
46.92 mol) in THF (28 L) at room temperature under argon.
The reaction was stirred at room temperature until complete
as indicated by TLC and then quenched by adding H2O (5 L).
THF was removed in vacuo, ethyl acetate (30 L) was added,
and the organic layer was separated, washed with water and
J . Org. Chem, Vol. 69, No. 6, 2004 1899

Moriarty et al.
47.3, 62.7, 62.8, 75.5, 77.9, 97.6, 99.5. Anal. Calcd for C12H23
-
6.83-6.86 (d, 1H, J ) 9 Hz), 7.20-7.41 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 14.1, 14.9, 15.5, 19.9, 22.6, 24.7, 25.3, 25.5,
29.5, 31.2, 32.1, 32.7, 33.5, 33.9, 35.1, 55.8, 62.0, 62.1, 62.5,
62.7, 75.3, 75.9, 81.7, 80.3, 87.2, 97.2, 98.0, 110.6, 114.7, 119.3,
125.9, 127.3, 127.4, 137.1, 140.8, 129.9, 136.8, 136.9, 157.6;
UV λmax MeOH, 227 nm; HPLC, Daicel Chiralpak AD column
(4.6 × 250 mm2), 10 µm; flow rate 0.75 mL/min; mobile phase,
hexanes (98%):2-propanol (2%):trifluoroacetic acid (0.1%);
retention time 22, 24, 27, and 34 min (four diastereomers)
(purity 99%). Anal. Calcd for C26H38O4: C, 75.32; H, 9.24.
Found: C, 74.75; H, 9.21.
ClO2: C, 61.39; H, 9.87. Found: C, 60.86; H, 10.09. [R]25
D
-13.54 (c 1.1, CHCl3).
1-(Tr im eth ylsilyl)-O-tetr a h yd r op yr a n -2-yl-1-d ecyn -5-
(S)-ol (39). A solution of 2823 g (25.15 mol, 2.2 equiv) of
1-trimethylsilyl-1-propyne in 20 L of THF was cooled to 0 °C
under argon and treated slowly with butyllithium (6811 g,
24.57 mol, 2.15 equiv, 2.5 M in hexanes). The reaction was
stirred for 3 h at 0 °C and a solution of 2684 g (11.43 mol) of
(S)-1-chloro-O-tetrahydropyran-2-ylheptan-2-ol (38) in 6 L of
THF was slowly added. The reaction mixture was allowed to
slowly warm to room temperature, stirred for 15 h, quenched
with saturated NH4Cl solution, and extracted with ethyl
acetate. The organic layer was washed with water and brine,
dried (Na2SO4), filtered, and concentrated in vacuo to afford
4562 g of a dark oil. IR (neat) 2950, 2940, 2170, 1470, 1450,
and 1020 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.12 (s, 6H), 0.13
(s, 3H), 0.88 (t, 3H, J ) 7 Hz), 1.2-1.9 (m, 16H), 2.26 (t, 1H,
J ) 7 Hz), 2.36 (q, 1H, J ) 7 Hz), 3.4-3.55 (m, 1H), 3.6-3.78
(m, 1H), 3.81-4.0 (m, 1H), 4.65 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 0.2, 14.1, 14.11, 15.8, 16.5, 19.9, 20.1, 22.7, 24.7, 25.2,
25.6, 31.1, 31.2, 32.0, 32.1, 32.7, 33.3, 34.1, 35.0, 62.7, 62.9,
75.1, 76.3, 84.2, 84.6, 97.0, 98.7, 107.4, 107.8. Anal. Calcd for
C18H34O2Si: C, 69.62; H, 11.04. Found: C, 69.83; H, 11.11. This
product was used without further purification.
2-[[(1S)-1-(3-Bu tyn yl)h exyl]oxy]tetr a h yd r o-2H-p yr a n
(25). To a stirred solution of 9443 g (30.41 mol) of 1-(trimeth-
ylsilyl)-O-tetrahydropyran-2-yl-1-decyn-5-(S)-ol (39) in 30 L of
ethanol was added sodium hydroxide (2433 g, 60.82 mol, 2
equiv) at room temperature. After the mixture was stirred for
20 h at room temperature, ethanol was removed in vacuo, and
the crude reaction mixture was partitioned between water and
ethyl acetate. The organic layer was separated, washed with
brine, dried (Na2SO4), filtered, and concentrated in vacuo. The
resulting orange oil was chromatographed on silica gel with
0-10% ethyl acetate in hexanes to afford 7200 g (78% pure
by GC, yield 77% from 38) of 25 as a clear yellow oil. IR (neat)
3310, 2950, 1900, 1450, 1440, 1380, 1250, 1130, 1120, 990, and
840 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.87 (t, 3H, J ) 6 Hz),
1.27-1.86 (m, 17H), 1.92 (m, 1H), 2.22 (dt, 1H, J ) 3, 6 Hz),
2.29-2.36 (m, 1H), 3.44-3.53 (m, 1H), 3.70 (q, 1H, J ) 6 Hz),
3.85-3.92 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 14.1,
14.4, 15.0, 19.8, 20.0, 22.7, 24.7, 25.2, 25.3, 25.6, 31.2, 32.1,
32.6, 33.4, 34.0, 35.0, 35.8, 37.4, 62.7, 62.8, 68.1, 68.4, 68.7,
70.8, 75.2, 76.2, 84.4, 84.8, 97.2, 98.5. Anal. Calcd for
(6S)-1-[3-Meth oxy-2-(2-pr open yl)ph en yl]-6-[(tetr ah ydr o-
2H-p yr a n -2-yl)oxy]-2-u n d ecyn -1-on e (27). To a cooled (0 °C)
and stirred solution of racemic aryl alkynol 26 (6486 g, 15.65
mol) in dichloromethane (40 L) was added PCC (6747 g, 31.3
mol) under argon. The reaction mixture was slowly allowed
to warm to room temperature and stirred under argon for 15
h. Then it was filtered through Celite and the solid was washed
twice with ethyl acetate. The solvents were removed in vacuo
and the crude product was chromatographed on silica gel with
a solvent gradient of 0-20% ethyl acetate in hexanes to give
4846 g (75%) of aryl alkynyl ketone 27 as a light yellow oil. IR
1
2206, 1645, 1456, 1269, and 741 cm-1; H NMR (CDCl3, 300
MHz) δ 0.87 (t, 3H J ) 7 Hz), 1.21-1.92 (m, 16H), 2.49 (t, 1H,
J ) 6 Hz), 2.60 (dt, 1H, J ) 1.7, 6 Hz), 3.42-3.53 (m, 1H),
3.68-3.81 (m, 3H), 3.81-3.93 (m, 4H), 4.58-4.60 (m, 1H),
4.90-5.03 (m, 2H), 5.88-6.05 (m, 1H), 7.05 (d, 1H, J ) 9 Hz),
7.28 (m, 1H), and 7.72 (t, 1H, J ) 9 Hz); 13C NMR (CDCl3, 75
MHz) δ 14.1, 15.1, 15.8, 20.1, 20.3, 22.7, 24.8, 25.2, 25.5, 29.8,
31.2, 31.3, 31.8, 32.0, 32.1, 33.3, 33.7, 35.0, 56.1, 63.1, 63.3,
75.4, 76.2, 81.7, 81.8, 95.4, 96.0, 97.9, 98.7, 114.81, 114.83,
114.87, 114.9, 124.6, 124.8, 126.7, 126.8, 129.91, 129.94, 136.8,
136.9, 137.4, 137.5, 158.10, 158.14, 180.1, 180.2. Anal. Calcd
for C26H36O4: C, 75.69; H, 8.80. Found: C, 75.54; H, 8.78.
(rS)-3-Meth oxy-2-(2-p r op en yl)-r-[(5S)-5-[(tetr a h yd r o-
2H-p yr a n -2-yl)oxy]-1-d ecyn yl]ben zen e Meth a n ol (28). To
a solution of (R)-methyl oxazaborolidine (14.09 L, 1 M in
toluene, purchased from Callery) was added a solution of the
above pale yellow aryl alkynyl ketone 27 (4845 g, 11.74 mol)
in anhydrous THF (23 L) under argon. Then the reaction
mixture was cooled to -30 °C under argon and borane-methyl
sulfide complex (1784 g, 23.48 mol) was added slowly with
stirring. After complete addition the reaction mixture was
stirred at -30 °C for 1 h, then methanol (7 L) was added
carefully with stirring to quench the reaction at -10 to -15
°C. The reaction mixture was allowed to warm to room
temperature and left with stirring overnight (15 h). Then it
was cooled to 0 °C and 5% aqueous solution of ammonium
chloride was added with stirring. The organic layer was
separated and washed with 5% aqueous ammonium chloride
solution and brine. Combined aqueous layers were extracted
with ethyl acetate and washed with brine. Combined organic
layers were dried (Na2SO4) and concentrated in vacuo to yield
S-(+)-aryl alkynol 28 as a viscous oil. The crude viscous oil
was chromatographed on silica gel with a solvent gradient of
0-20% ethyl acetate in hexanes to yield 4141 g (85%) of S-(+)-
aryl alkynol as pale yellow oil. IR 3410, 2227, 1638, 1258, 1027,
and 758 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.88 (t, 3H, J ) 7
Hz), 1.21-1.88 (m, 17H), 2.28 (t, 1H, J ) 7 Hz), 2.33-2.49
(m, 2H), 3.41-3.55 (m, 1H), 3.55-3.63 (m, 1H), 3.63-3.77 (m,
1H), 3.81(s, 3H), 3.82-3.93 (m, 1H), 4.64 (s, 1H), 4.90-4.97
(m, 2H), 5.61(s, 1H), 5.90-6-07 (m, 1H), 6.85 (d, 1H, J ) 8
Hz), and 7.20-7.39 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.1,
14.2, 15.0, 15.5, 19.8, 22.7, 24.7, 25.3, 25.6, 29.5, 31.1, 31.2,
32.0, 32.1, 32.7, 33.5, 34.0, 35.1, 55.8, 61.8, 61.9, 62.6, 75.3,
75.9, 80.5, 80.8, 86.6, 87.0, 97.2, 98.0, 110.5, 114.7, 119.2, 119.3,
125.8, 127.3, 127.4, 137.1, 140.9, 157.7; UV, λmax MeOH, 227
nm; HPLC, Daicel Chiralpak AD column (4.6 × 250 mm2), 10
µm; flow rate, 0.75 mL/min; mobile phase, hexanes (98%):2-
propanol (2%):trifluoroacetic acid (0.1%); retention time 33 and
41 min (two diastereomers) (purity 92%). Anal. Calcd for
C
15H26O2: C, 75.58; H, 10.99. Found: C, 75.51; H, 11.17.
3-Met h oxy-2-(2-p r op en yl)-r-[(5S)-5-[(t et r a h yd r o-2H -
p yr a n -2-yl)oxy]-1-d ecyn yl]ben zen em eth a n ol (26). To a
stirred and refluxing solution of 2-[[(1S)-1-(3-butynyl)hexyl]-
oxy]tetrahydro-2H-pyran (25) (4262 g, 17.88 mol) in anhydrous
THF (30 L) was slowly added a solution of EtMgBr (5.96 L,
17.88 mol, 3 M solution in diethyl ether) under argon. As the
reaction is exothermic heating was stopped during this addi-
tion. After complete addition (about 2 h) the reaction mixture
was further refluxed for 90 min and cooled to 0 °C and then a
solution of 2-allyl-3-methoxybenzaldehyde (24) (3000 g, 17.03
mol) in anhydrous THF (5 L) was added slowly with stirring.
After complete addition (about 30 min), the reaction mixture
was allowed to warm to room temperature and stirred over-
night (15 h). The reaction mixture was cooled again to 0 °C,
and a saturated aqueous solution of NH4Cl was added with
stirring. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate. The combined organic
layers were washed with brine and dried (Na2SO4) and the
solvents were removed in vacuo. The crude viscous liquid was
chromatographed on silica gel with a solvent gradient of
0-20% ethyl acetate in hexanes to give 6487 g (92%) of aryl
alkynol (26). IR 3401, 2227, 1637, 1600, 1470, 913, and 754
cm-1 1H NMR (CDCl3, 300 MHz) δ 0.87 (t, 3H, J ) 6 Hz),
;
1.20-1.40 (m, 6H), 1.41-1.60 (m, 6 H), 1.61-1.80 (m, 5H),
2.26-2.65 (m, 3H), 3.41-3.75 (m, 4H), 3.86 (s, 3H), 4.63-4.65
(m, 1H), 4.95-4.98 (m, 2H), 5.60 (s, 1H), 5.92-6.02 (m, 1H),
C
26H38O4: C, 75.32; H, 9.24. Found: C, 74.80; H, 9.37.
1900 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of Treprostinil
(1,1-Dim e t h yle t h yl)[[(1S ,6S )-1-[3-m e t h oxy-2-(2-p r o-
p en yl)p h en yl]-6-[(t et r a h yd r o-2H -p yr a n -2-yl)oxy]-2-u n -
d ecyn yl]oxy]d im eth ylsila n e (29). TBDMSCl (1807 g, 11.99
mol) was added to a stirred and cooled (0 °C) solution of the
above S-(+)-aryl alkynol 28 (4140 g, 9.99 mol), imidazole (817
g, 11.99 mol), 4-(dimethylamino)pyridine (24 g), and DMF (410
mL) in dichloromethane (40 L) under argon. The reaction
mixture was slowly warmed to room temperature and stirring
was continued for 15 h. The reaction mixture was washed with
water and brine and concentrated in vacuo. The resulting
viscous liquid was chromatographed on silica gel with 0-5%
ethyl acetate-hexanes to yield 4877 g (92%) of 29. IR 2227,
1637, 1587, and 1470 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.09
(s, 3H), 0.12 (s, 3H), 0.83-0.94 (m, 12H), 1.20-1.90 (m, 16H),
2.20-2.40 (m, 2H), 3.40-3.70 (m, 3H), 3.81 (s, 3H), 3.82-3.92
(m, 1H), 4.53-4.69 (m, 1H), 4.91-5.01 (m, 2H), 5.57 (s, 1H),
5.88-6.03 (m, 1H), 6.80 (d, 1H, J ) 9 Hz), 7.20-7.31 (m, 2H);
13C NMR (CDCl3, 75 MHz) δ 14.1, 14.9, 15.5, 18.4, 20.1, 20.3,
22.7, 24.8, 25.6, 26.0, 29.5, 31.2, 32.1, 32.7, 33.4, 34.1, 35.1,
55.8, 62.4, 62.9, 63.1, 75.5, 81.0, 81.4, 85.4, 85.9, 97.4, 98.9,
109.8, 114.5, 118.7, 124.8, 127.1, 136.7, 142.3, 157.4. Anal.
Calcd for C32H52O4Si: C, 72.68; H, 9.91. Found: C, 72.56; H,
9.91.
26.6, 30.4, 30.6, 30.7, 31.3, 31.6, 31.9, 32.1, 33.3, 33.5, 34.8,
35.3, 38.9, 41.7, 45.4, 45.5, 51.6, 51.7, 55.3, 55.4, 57.0, 62.8,
63.1, 97.1, 97.6, 98.0, 107.3, 121.1, 123.4, 124.7, 126.2, 126.4,
136.9, 156.9, 157.6. Anal. Calcd for C27H40O4: C, 75.66; H, 9.41.
Found: C, 75.68; H, 9.10.
(1R,2R,3a S,9a S)-2,3,3a ,4,9,9a -Hexa h yd r o-5-m eth oxy-1-
[(3S)-3-[(tetr a h yd r o-2H-p yr a n -2-yl)oxy]octyl]-1H-ben z[f]-
in d en -2-ol (32). To a cooled (-10 °C) and stirred solution of
tricyclic ketone 31 (3524 g, 8.22 mol, theoretical weight) in
ethanol (30 L) was added a 20% aqueous sodium hydroxide
solution (3288 g in 16.5 L of water, 82.20 mol). The reaction
mixture was stirred for 30 min and then NaBH4 (317 g, 8.38
mol) was added and stirring was continued at -10 °C for 1 h.
Again an additional 1 equiv of NaBH4 (317 g, 8.38 mol) was
added and stirring was continued for another 5 h at -10 °C.
Upon completion, the reaction mixture was quenched carefully
with glacial acetic acid until acidic and the solvent was
removed in vacuo. The crude reaction mixture was dissolved
in ethyl acetate, washed with aq NaHCO3 and brine, dried
(Na2SO4), and concentrated in vacuo to obtain 3201 g of crude
tricyclic alcohol 32 as a viscous liquid. This was used for the
next step without further purification. IR 3448, 1587, 1263,
and 773 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.89 (t, 3H, J ) 6
Hz), 1.09-2.30 (m, 24H), 2.10-2.30 (m, 2H), 2.70-2.90 (m,
2H), 3.43-3.55 (m, 1H), 3.57-3.69 (m, 2H), 3.78 (s, 3H), 3.82-
4.00 (m, 1H), 4.60-4.70 (m, 1H), 6.75 (t, 2H, J ) 9 Hz), and
7.07 (t, 1H, J ) 8 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.1, 14.2,
20.0, 20.3, 20.5, 22.7, 24.9, 25.4, 25.5, 25.6, 25.8, 25.9, 27.6,
28.0, 31.2, 32.1, 32.2, 32.9, 33.6, 33.8, 33.9, 34.9, 41.0, 41.2,
41.3, 52.4, 55.4, 55.3, 55.6, 62.7, 63.4, 97.6, 98.4, 108.4, 120.5,
126.1, 126.2, 127.0, 127.1, 140.6, 140.7, 156.5. Anal. Calcd for
(3a S,9S)-9-[[(1,1-Dim eth yleth yl)d im eth ylsilyl]oxy]-3,-
3a ,4,9-t et r a h yd r o-5-m et h oxy-1-[(3S)-3-[(t et r a h yd r o-2H -
p yr a n -2-yl)oxy]octyl]-2H-ben z[f]in d en -2-on e (30). To a
stirred solution of aryl alkynyl tert-butyldimethylsilyl ether
29 (4876 g, 9.22 mol) in dichloromethane (20 L) was added
dicobalt octacarbonyl (3153 g, 9.22 mol, purity >92%, pur-
chased from Strem Chemicals Inc.) at room temperature under
argon. Stirring was continued for 2 h, then dichloromethane
was removed in vacuo below 40 °C. Residue was dissolved in
acetonitrile (40 L) and the solution was refluxed under argon
for 2 h. Upon cooling, air was bubbled through the reaction
mixture overnight. The reaction mixture was filtered through
Celite and washed with acetone four times. Filtrate was
concentrated in vacuo and the resulting dark viscous liquid
was chromatographed on silica gel with 5-40% ethyl acetate
in hexanes to yield 4580 g (89%) of tricyclic enone 30 as a light
brown oil. IR 1704, 1659, 1788, 1258, 1049, and 777 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 0.06-0.14 (m, 6H), 0.80-0.82 (m,
10H), 1.07-2.49 (m, 22H), 2.69 (dd, 1H, J ) 9, 6 Hz), 3.28-
3.56 (m, 4H), 3.81 (s, 4H), 4.51 (d, 1H, J ) 9 Hz), 5.47 and
5.58 (two s, 1H), 6.80 (dd, 1H, J ) 6, 6 Hz), 6.92 (d, 1H, J )
6, 3 Hz), 7.22 (dd, 1 H, J ) 3, 3 Hz); 13C NMR (CDCl3, 75 MHz)
δ -4.1, -4.0, 14.1, 18.1, 22.6, 24.8, 25.6, 25.7, 32.0, 32.1, 33.5,
42.2, 55.4, 62.8, 63.0, 65.4, 97.8, 109.1, 109.3, 122.0, 122.1,
125.1, 127.4, 137.2, 137.6, 138.2, 156.8, 156.9, 172.6, 172.7,
209.6, 209.2; UV, λmax MeOH, 227 nm; HPLC, Daicel Chiralpak
AD column (4.6 × 250 mm2), 5 µm; flow rate 0.75 mL/min;
mobile phase, hexanes (98%):2-propanol (2%):trifluoroacetic
acid (0.1%); retention time 6 and 8 min (two diastereomers)
(purity 91%). Anal. Calcd for C33H52O5Si: C, 71.18; H, 9.41.
Found: C, 71.24; H, 9.47.
C
27H42O4: C, 75.31; H, 9.83. Found: C, 74.39; H, 9.93.
(1R,2R,3a S,9a S)-2,3,3a ,4,9,9a -Hexa h yd r o-1-[(3S)-3-h y-
d r oxyoctyl]-5-m eth oxy-1H-ben z[f]in d en -2-ol (33). The col-
orless oil 32 was dissolved in methanol (35 L) then cooled (0
°C) and p-TsOH (64 g) was added with stirring under argon.
The reaction mixture was stirred and slowly warmed to room
temperature (15 h). The solvent was removed in vacuo and
the crude product was chromatographed on silica gel with 10-
50% ethyl acetate in hexanes to give 2162 g (76% over three
steps, from tricyclic enone 30) of methoxy benzindene diol 33;
mp 71-72 °C; [R]25 +49.2 (c 1, MeOH). IR 3334, 1471, 1266,
D
1
779, and 732 cm-1; H NMR (CDCl3, 300 MHz) δ 0.90 (t, 3H,
J ) 6 Hz), 1.05-1.98 (m, 17H), 2.08-2.28 (m, 2H), 2.38-2.51
(m, 2H), 2.68-2.88 (m, 2H), 3.52-3.59 (s, 1H), 3.61-3.72 (m,
1H), 3.80 (s, 3H), 6.74 (t, 2H, J ) 6 Hz), 7.08 (t, 1H, J ) 6 Hz);
13C NMR (CDCl3, 75 MHz) δ 14.1, 22.7, 25.5, 25.8, 28.6, 32.0,
32.8, 33.8, 35.1, 37.5, 41.3, 52.3, 55.6, 72.5, 108.4, 120.5, 126.0,
126.2, 127.1, 140.6, 156.5. Anal. Calcd for C22H34O3: C, 76.26;
H, 9.89. Found: C, 75.94; H, 9.82.
(1R,2R,3a S,9a S)-2,3,3a ,4,9,9a -Hexa h yd r o-1-[(3S)-3-h y-
d r oxyoctyl]-1H-ben z[f]in d en -2,5-d iol (34). To a cooled (-20
°C) and stirred solution of diphenylphosphine (8190 g, 43.99
mol) in anhydrous THF (20 L) was added slowly a solution of
n-BuLi (13.84 Kg, 2.5 M in hexanes, 49.92 mol) under argon.
After complete addition (about 2 h) the dark red solution was
stirred at -20 °C for 30 min. Then about a 3/7 portion of this
solution was transferred to another flask containing a solution
of methoxy benzindene diol 33 (2161 g, 6.24 mol) in anhydrous
THF (5 L) and the reaction mixture was refluxed for 2 h under
argon. Heating was stopped, the reaction mixture was cooled
to room temperature, and the remaining 4/7 portion of the
above red solution was added to it. The reaction mixture was
again refluxed for 18 h. The reaction mixture was then cooled
to -10 °C and quenched slowly with 6.5 M aqueous HCl
saturated with NaCl until acidic. The organic layer was
separated and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated in vacuo. The crude product
was chromatographed on silica gel with a solvent gradient of
20-50% ethyl acetate in hexanes to yield benzindene triol 34,
which was further purified by crystallization in dichlo-
(1a S,3a S)-1,3,3a ,4,9,9a -Hexa h yd r o-5-m et h oxy-1-[(3S)-
3-[(tetr ah ydr o-2H-pyr an -2-yl)oxy]octyl]-2H-ben z[f]in den -
2-on e (31). To a solution of tricyclic enone 30 (4579 g, 8.22
mol) in absolute ethanol (11 L) were added anhydrous K2CO3
(229 g, 5% w/w) and 10% Pd/C (1145 g, 50% wet, 25% w/w)
and the mixture was hydrogenated at 90 psi of pressure for
10-15 h at room temperature. The reaction mixture was
filtered through Celite and washed with ethanol. This etha-
nolic solution was used as such in the next step without further
purification. A small sample (about 100 mL) of the solution
was concentrated in vacuo and chromatographed with silica
gel and 5-20% ethyl acetate in hexanes to get pure tricyclic
ketone 31 for characterization. IR 1737, 1588, 1469, 1257, and
1024 cm-1 1H NMR (CDCl3, 300 MHz) δ 0.88 (t, 3H, J ) 6
;
Hz), 1.10-2.00 (m, 20H), 2.13-3.08 (m, 7H), 3.42-3.55 (m,
1H), 3.56-3.70 (m, 1H), 3.81 (d, 3H, J ) 3 Hz), 4.64 (m, 1H),
6.66-6.80 (m, 2H), 7.10-7.20 (m, 1H); 13C NMR (CDCl3, 75
MHz) δ 14.1, 20.0, 20.3, 22.7, 23.9, 24.5, 24.7, 24.8, 25.3, 25.6,
J . Org. Chem, Vol. 69, No. 6, 2004 1901

Moriarty et al.
romethane-hexanes to give 1657 g (80%) of pure product: mp
in vacuo. The resulting solution was diluted with water and
extracted with ethyl acetate (this process removes impurities).
The aqueous layer was acidified to pH 2-3 by addition of 3 M
HCl maintaining the temperature about 20 °C and then
extracted with ethyl acetate. The combined organic layers were
washed with water, dried (Na2SO4), treated with charcoal, and
concentrated in vacuo to yield crude UT-15 (7) as an off-white
solid. This was crystallized by dissolving the solid in ethanol
at 50 °C and adding water (1:1). White needles obtained upon
standing were filtered, washed with 20% ethanol-water, and
dried in a vacuum oven at 55 °C to give 441 g (83%) of pure
113-115 °C; [R]25 +50.8 (c 0.324, MeOH). IR 3415, 3060,
D
2932, 753, and 702 cm-1; H NMR (MeOH, 300 MHz) δ 0.89
1
(t, 3H, J ) 6 Hz), 1.1-2.30 (m, 19H), 2.41-2.45 (m, 2H), 2.64-
2.78 (m, 2H), 3.45-3.54 (m, 1H), 3.55-3.81 (m, 1H), 6.65 (d,
1H, J ) 8 Hz), 6.73 (d, 1H, J ) 8 Hz), 6.99 (t, 1H, J ) 8 Hz);
13C NMR (MeOH, 75 MHz) δ 13.1, 22.4, 25.2, 25.3, 28.3, 31.8,
32.1, 33.3, 34.7, 37.0, 41.0, 51.3, 71.6, 76.3, 112.5, 119.2, 124.7,
125.7, 140.5, 153.8; λmax MeOH, 217 nm; HPLC, Waters
Novopak C18 column (3.9 × 150 mm2), 4 µm; flow rate 2.0 mL/
min; mobile phase, water (57%):acetonitrile (43%):trifluoro-
acetic acid (0.1%); retention tim: 3 min (purity 99.5%). Anal.
Calcd for C21H32O3: C, 75.86; H, 9.70. Found: C, 75.38; H,
9.89.
UT-15 as colorless crystalline solid; mp 126-127 °C; [R]25
D
+52.6 (c 0.453, MeOH), [R]25D + 34.0° (c 0.457, EtOH). IR 3385,
2928, 2856, 1739, 1713, 1585, and 779 cm-1; 1H NMR (CDCl3,
300 MHz) δ 0.87 (t, 3 H, J ) 6 Hz), 1.21-1.86 (m, 13H), 2.02-
2.44 (m, 4H), 3.42-3.76 (m, 3H), 3.81 (s, 2H), 3.82-3.94 (m,
1H), 4.63-4.68 (m, 1H), 4.88-4.92 (m, 1H), 4.94-4.98 (m, 1H),
4.99-5.02 (m, 1H), 5.60 (s, 1H), 5.92-6.06 (m, 1H), 6.85 (d,
1H, J ) 6 Hz), 7.20-7.27 (m, 1H), 7.31-7.37 (m, 1H); 13C NMR
(MeOH, 75 MHz) δ 13.1, 22.4, 25.1, 25.3, 28.3, 31.8, 32.7, 33.2,
34.7, 36.9, 40.7, 41.0, 51.3, 65.2, 71.6, 76.3, 109.5, 121.1, 125.8,
127.4, 140.8, 155.2, 171.5; UV, λmax MeOH, 217 nm; HPLC,
Hypersil ODS column (4.6 × 250 mm2), 5 µm; flow rate 2.0
mL/min; mobile phase A, water (60%):acetonitrile (40%):
trifluoroacetic acid (0.1%), and mobile phase B, water (22%):
acetonitrile (78%):trifluoroacetic acid (0.1%); retention time,
15 min (purity 99.7%). Anal. Calcd for C23H34O5: C, 70.74; H,
8.78. Found: C, 70.41; H, 8.83. Compound 7 was identical in
all respects to an authentic sample of UT-15.50
[[(1R,2R,3a S,9a S)-Hexa h yd r o-2-h yd r oxy-1-[(3S)-3-h y-
d r oxyoctyl]-1H-ben z[f]in d en -5-yl]oxy]a ceton itr ile (35).
To a stirred solution of benzindene triol 34 (452 g,1.36 mol) in
acetone (20 L) were added chloroacetonitrile (433 g, 5.74 mol),
powdered K2CO3 (1145 g, 8.29 mol), and tetrabutylammonium
bromide (39.94 g, 0.12 mol) under argon. The reaction mixture
was refluxed under argon for 8 h, then cooled to room tem-
perature, 10 L of hexanes were added, and the solution was
stirred and filtered over Celite. Celite was washed with ethyl
acetate. The filtrate was concentrated in vacuo and the crude
viscous liquid was chromatographed on silica gel with a solvent
gradient of 20-50% ethyl acetate in hexanes to yield 504 g
(100%) of benzindene nitrile 35. IR 3359, 2931, 2860, 2249,
1
929, and 745 cm-1; H NMR (CDCl3, 300 MHz) δ 0.87 (t, 3H,
J ) 6 Hz), 1.00-2.35 (m, 17H), 2.45-2.60 (m, 2H), 2.75-2.80
(m, 2H), 3.41-3.58 (m, 1H), 3.60-3.80 (m, 1H), 4.68 (s, 2H),
6.77 (d, 1H, J ) 6 Hz), 6.80 (d, 1H, J ) 9 Hz), and 7.09 (t, 1H,
J ) 9 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.2, 22.7, 25.5, 26.1,
28.6, 32.0, 32.7, 33.8, 35.1, 37.5, 41.1, 52.3, 54.6, 72.4, 76.8,
110.6, 115.7, 123.0, 126.4, 128.5, 141.7, 153.7. Anal. Calcd for
Ack n ow led gm en t. Scientific contribution and en-
couragement by Roy A. Swaringen, Ph.D is gratefully
acknowledged. Expert technical assistance was provided
by Zhengzhe Song, Gang Zhao, Rajesh K. Singhal, Oscar
Ivanov, and David Moriarty.
C
23H33NO3: C, 74.36; H, 8.95. Found: C, 74.62; H, 9.73.
[[(1R,2R,3a S,9a S)-2,3,3a ,4,9,9a -Hexa h yd r o-2-h yd r oxy-
Su p p or tin g In for m a tion Ava ila ble: Listing of barium-
(II) induced differential chemical shifts in 25a . This material
is available free of charge via the Internet at http://pubs.acs.org.
1-[(3S)-3-h yd r oxyoct yl]-1-H -b en z[f]in d en -5-yl]oxy]a ce-
tic Acid (UT-15) (7). To a stirred solution of benzindene
nitrile 35 (504 g, 1.36 mol) in methanol (7 L) was added a
solution of aqueous KOH (538 g, 9.6 mol, water 1.8 L, 30%
solution) at room temperature. Then the reaction mixture was
refluxed for 3 h and cooled to 0 °C, then 3 M aqueous HCl
was added until pH 10-12. Most of the solvent was removed
J O0347720
(50) An authentic sample was provided by Shelden Blackburn, Lung
Rx, Research Triangle Park, NC.
1902 J . Org. Chem., Vol. 69, No. 6, 2004