Formation of (S)-5-cyclohexyl-5-phenyl-1,3-dioxolane-2,4-dione: A key intermediate in the synthesis of (S)-oxybutynin hydrochloride

Article abstract of DOI:10.1021/op100021w

The synthesis of the drug candidate (S)-oxybutynin hydrochloride 1 is described. The procedure involves initial activation of (S)-cyclohexylmandelic acid 2, using isobutylchloroformate, followed by reaction of the resulting intermediate with 4-(diethylami

Full text of DOI:10.1021/op100021w

Organic Process Research & Development 2010, 14, 921–925
Formation of (S)-5-Cyclohexyl-5-phenyl-1,3-dioxolane-2,4-dione: A Key Intermediate
in the Synthesis of (S)-Oxybutynin Hydrochloride†
Charles P. Vandenbossche, Philomen de Croos, Surendra P. Singh,* Roger P. Bakale,§ and Thomas R. Wagler
Chemical Process Research and DeVelopment, Sepracor Inc., 84 Waterford DriVe, Marlborough, Massachusetts 01752, U.S.A.
Abstract:
The synthesis of the drug candidate (S)-oxybutynin hydrochloride
1 is described. The procedure involves initial activation of (S)-
cyclohexylmandelic acid 2, using isobutylchloroformate, followed
by reaction of the resulting intermediate with 4-(diethylamino)but-
2-yn-1-ol, 3. In this reaction, (S)-5-cyclohexyl-5-phenyl-1,3-diox-
olane-2,4-dione 7 was identified as a key transient intermediate
leading to 1. On the basis of the in situ IR spectroscopy data
collected, the sequence of chemical events involved in the formation
of intermediate 7, and its conversion to product and byproducts
are described.
Figure 1. (S)-Oxybutynin hydrochloride.
Scheme 1. Synthesis of 1
Introduction
Urge urinary incontinence (UUI) is caused by hyperactivity
of the detrusor muscle and is widely treated by muscarinic
receptor antagonists, particularly acting at the M3 subtype.
However, side effects such as dry mouth, tachycardia, and
mydriasis often result from the nonselective binding with other
M subtypes or with M3 subtypes, which are not bladder specific
such as those located in the salivary glands and pupils.1
Enantiopure (S)-oxybutynin2 1 (Figure 1) has the potential to
reduce urinary frequency and incontinence episodes while
reducing the side effects associated with the racemic compound.
Scheme 2. Reaction of 2 with IBCF
6-8 h, at 65-70 °C, to afford 1 (83-85% assay yield). After
aqueous workup, the organic layer containing 1 as the free base,
is distilled to remove isobutyl alcohol and water prior to
crystallization. Product 1 is isolated as the HCl salt in 78-80%
yield from 2 by crystallization from MTBE/toluene (Scheme
1).
A number of other activating reagents such as DCC, CDI,
SOCl2, phosphoryl chloride, and 2-fluoro-1-methylpyridinium
p-toluenesulfonate were also evaluated in the laboratory.
However, IBCF was selected as the reagent of choice on the
basis of reaction performance, cost, stability, and commercial
availability. In order to track and obtain a better understanding
of the chemical events throughout the course of this reaction,
we sought to monitor the activation of 2 with IBCF as well as
the formation of 1 using HPLC and in situ IR spectroscopy.
The reaction of 2 with NMP (2 equiv) and IBCF (1 equiv)
at 23 °C affords intermediate 4 (along with 2-3 area % 5) as
detected by HPLC and by in situ IR spectroscopy3 (Scheme
2). All attempts to isolate a pure sample of intermediate 4 were
unsuccessful due to its inherent instability resulting in partial
Results and Discussion
An efficient and scalable coupling protocol for the synthesis
of multikilogram quantities of the target molecule 1 has been
developed, starting from carboxylic acid 2. The two-step, one-
pot procedure involves the initial activation of 2 using isobu-
tylchloroformate (IBCF) and N-methylpiperidine (NMP) in
toluene, at ambient temperature. The resulting intermediate is
subsequently reacted with 4-(diethylamino)but-2-yn-1-ol 3 over
† Part of this work was presented at the 224th National Meeting of the
American Chemical Society, Boston, MA, August 18-22, 2002; ORGN 419.
* Corresponding author. Telephone (508)-357-7451. Fax (508)-357-7808.
E-mail: surendra.singh@sepracor.com.
§ Current address: Cephalon Inc.
(1) Reitz, A. B.; Gupta, S. K.; Huang, Y.; Parker, M. H.; Ryan, R. R. Med.
Chem. 2007, 3, 543, and references therein.
(2) (a) Shuji, M.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2002, 43, 8647. (b) Gupta, P.; Fernandes, R. A.; Kumar, P. Tetrahedron
Lett. 2003, 24, 351. (c) Shuji, M.; Suzuki, M.; Kanai, M.; Shibasaki,
M. Tetrahedron Lett. 2004, 60, 10497. (d) Trost, B. M.; Xu, J.; Reichle,
M. J. Am. Chem. Soc. 2007, 129, 282. For the synthesis of (S)-
cyclohexylmandelic acid see: (e) Senanayake, C. H.; Fang, K.; Grover,
P. T.; Bakale, R. P.; Vandenbossche, C. P.; Wald, S. A. Tetrahedron
Lett. 1999, 40, 819. (f) Grover, P. T.; Bhongle, N. N.; Wald, S. A.;
Senanayake, C. H. J. Org. Chem. 2000, 65, 6283. (g) Tokuda, O.; Kano,
T.; Gao, W.; Ikemoto, T.; Maruoka, K. Org. Lett. 2005, 7, 5103. (h)
Roy, S.; Sharma, A.; Chattopadhyay, N.; Chattopadhyay, S. Tetrahedron
Lett. 2006, 47, 7067.
(3) In situ IR spectra were obtained using a ReactIR 1000 instrument, from
ASI Applied Systems, equipped with a SiComp probe.
(4) (a) Rhee, S. W.; Ryan, K. J.; Tracy, M.; Kelson, A. B.; Clizbe, L. A.;
Chang, M.-H.; Park, J.-S.; Roh, J.-K.; Kong, J.-Y.; Yang, J.; Kim, W.-
B.; Ok, K.-D. J. Label. Compds. Radiopharm. 1997, 39, 773. (b) Kim,
H.; Olsen, R. K.; Choi, O. J. Org. Chem. 1987, 52, 4531.
10.1021/op100021w  2010 American Chemical Society
Published on Web 06/16/2010
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Scheme 3. Formation of intermediate 4
Scheme 4. Conversion of intermediate 4 to the transient
intermediate 7
Figure 2. Three-dimensional waterfall plot (solvent subtracted)
of the reaction depicted in Scheme 2, monitored over time by
in situ IR. Absorptions: 2 1733 cm-1 (CdO); 2 carboxylate 1644
cm-1 (CdO); 4 1752 and 1652 cm-1 (CdO); 5 1829, 1811, and
1760 cm-1 (CdO).
spectroscopy under the reaction conditions nor at -78 °C with
a collection rate of three spectra per second. Initial formation
of the mixed anhydride 6, followed by the rapid intramolecular
transfer of the isobutoxycarbonyl moiety to the R-hydroxyl, is
believed to be the mechanism leading to the formation of
intermediate 4. This is based on the finding that the methyl ester
of 2 has been found to remain unreacted when subjected to the
same reaction conditions.
decomposition of 4 to 2 and isobutyl alcohol as evident by crude
1H and 13C NMR. Instead, intermediate 4 was trapped as the
methyl ester, using diazomethane, was isolated, and was fully
characterized.
Intermediate 4, when heated to 65-70 °C in toluene, was
observed to slowly undergo intramolecular ring closure to afford
the 5-cyclohexyl-5-phenyl-1,3-dioxolane-2,4-dione intermediate
7 and isobutyl alcohol (Scheme 4). This conversion is evident
by the appearance of the absorption at 1815 cm-1 (CdO stretch)
and 1900 cm-1 (carbonate CdO stretch), followed by the
corresponding decrease in absorptions related to the disappear-
ance of intermediate 4 (Figure 3).
The addition of a second equivalent of IBCF (2 equiv total)
afforded exclusively intermediate 5 as evident by HPLC and
by IR. This intermediate was isolated and fully characterized.
Intermediates similar to 5, resulting from the reaction of
R-hydroxy acids with IBCF (2 equiv), have been proposed by
Rhee4a et al. for the 14C-radiolabeled synthesis of anthracycline,
an anticancer agent, and employed as intermediates by Olsen
et al. for the preparation of ꢀ-keto esters.4b
The in situ IR absorptions observed for intermediate 7 were
found to be consistent with the IR spectrum of a synthetic
sample prepared from 2 using trichloromethylchloroformate.6
Intermediate 7 appears to be the final intermediate along the
pathway to forming product 1. Conversely, by allowing the
reaction to proceed further at 65-70 °C in the absence of 3,
consumption of the two carbonyl stretches resulting from
reaction of intermediate 7 with isobutyl alcohol is observed
along with the simultaneous increase in the absorption at 1725
cm-1, resulting in the formation of the byproduct, isobutyl ester7
In situ IR spectroscopy was utilized to observe the conver-
sion of 2 to intermediates 4 and 5 (Figure 2). Accordingly, NMP
(2 equiv) was added to a suspension of 2 in toluene at 23 °C,
resulting in a homogeneous solution. The deprotonation of 2
resulting from the addition of the amine base to afford the
carboxylate salt can be observed. The absorption at 1733 cm-1
2, carboxylic acid (CdO stretch) disappears upon addition of
the base, while the broad absorption at 1644 cm-1 (carboxylate
salt CdO stretch), subsequently appears. Addition of IBCF (1
equiv) at 23 °C resulted in a thin suspension by activation of
the carboxylate salt, resulting in the formation of intermediate
4 as evidenced by the appearance of the absorption at 1752
cm-1 (carbonate CdO stretch) along with retention of the broad
absorption at 1652 cm-1 (carboxylate salt CdO stretch).
Likewise, addition of a second equivalent of IBCF (2 equiv
total), resulting in the formation of intermediate 5, was also
observed. The two absorptions at 1752 cm-1 and 1652 cm-1
corresponding to intermediate 4 disappear, while the absorptions
at 1829, 1811, and 1760 cm-1 (CdO stretches) simultaneously
appear, resulting from the formation of intermediate 5. Similar
mixed anhydrides5 of this type are reported to absorb at
1827-1810 and 1775-1750 cm.-1
Formation of intermediate 4 is believed to proceed through
the mixed anhydride intermediate 6 (Scheme 3); however, no
sign of this intermediate 6 was observed by in situ IR
Figure 3. Three-dimensional waterfall plot (solvent subtracted)
of the partially completed reaction, depicted in Scheme 4,
monitored over time by in situ IR. Absorptions: 4 1752, and
1652 cm-1 (CdO); 7 1900, and 1815 cm-1 (CdO); 8 1725 cm-1
(CdO).
(5) Colthup, N. B.; Daly, L. H.; Wiberley, S. E. Introduction to Infrared
and Raman Spectroscopy, 3rd ed.; Academic Press: San Diego, CA,
1990; p 312.
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Scheme 5. Generation of intermediate 7 using
trichloromethylchloroformate
safety, cost, and scalability prohibited the consideration of
trichloromethylchloroformate for further development and scale
up.
The cyclization of 4 to cyclic intermediate 7 occurs only at
or above 40 °C when isobutylchloroformate is used as evident
by in situ IR, but 7 can be made and subsequently converted to
1 at room temperature when trichloromethylchloroformate is
used instead. Also, under the standard reaction conditions, upon
heating intermediate 4 in the presence of 1.3 equiv of 3, no
observable level of intermediate 7 is detected by in situ IR.
However, only by starving the reaction mixture of 3, at 65-70
°C, allowed sufficient quantity of intermediate 7 to be detected
in order to confirm its presence in the reaction mixture. On the
basis of these findings it is concluded that among the series of
chemical events in the synthesis of 1 from 2 (Scheme 6), the
formation of 7 from 4 may be the rate-limiting step.
The fate of intermediate 5, generated using 2.0 equiv of
IBCF, throughout the course of the coupling reaction was also
investigated. Under these conditions, a significant increase in
the amount of the undesirable byproduct, isobutyl ester 8, was
produced upon reaction completion (15 vs 5 area % by HPLC
under reaction conditions, when 1.0 equiv of IBCF was used).
In this case, intermediate 4 is formed along with carbonate
8 (Figure 3). This is consistent with the literature report about
that dioxalane-2,4-diones, similar to 7, though less hindered,
were prepared and converted to esters by Grieco and Deng.8
The use of trichloromethylchloroformate as an alternative
reagent was also evaluated for this coupling process. The benefit
of using this reagent, over IBCF, was the possible gain in yield
resulting from the reduction in the amount of the isobutyl ester
8 produced (Scheme 5). Formation of the same reactive
intermediate 7 was observed at 23 °C by in situ IR when
trichloromethylchloroformate was used as an activating reagent
instead of IBCF. The reaction trending profile (Figure 4) clearly
indicates the formation of 2 carboxylate anion, which is
consumed by formation and build up of intermediate 7. When
intermediate 7 is treated with 3 (at ∼3 h) it undergoes reaction
to produce 1 (free base). Despite the advantage in yield increase
due to elimination of byproduct 8, major concerns regarding
Figure 4. Absorption profile for the reaction depicted in Scheme 5, as determined by in situ IR spectroscopy.
Scheme 6. Proposed reaction mechanism
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byproduct9 9 by the reaction of intermediate 5 with 3 (Scheme
6). Formation of byproduct 9 ultimately diminishes the amount
of available 3 in solution. In the absence of a sufficient amount
of 3, the isobutyl alcohol (generated from the formation of
intermediate 7 from 4), reacts with 7, resulting in a significant
increase of the isobutyl ester 8 along with 1. Since all three
pathways are irreversible and the products of each are not
interconvertible, the relative distribution of products is kineti-
cally controlled.
(75 MHz, CDCl3): δ 25.6, 25.7, 25.9, 26.7, 46.4, 92.8, 124.7,
129.1, 129.6, 132.9, 148.0, 168.3. HRMS Calcd for C15H16O4
(M + Na)+ 283.0946; found 283.0942.
(S)-4-(Diethylamino)but-2-ynyl 2-cyclohexyl-2hydroxy-
2-phenyl Acetate Hydrochloride, 1. To a suspension of
compound 2 (30.0 g, 128 mmol) in toluene (180 mL) under
argon was added NMP (25.3 g, 256 mmol, 2.0 equiv) at 23
°C. Isobutylchloroformate was added over 10 min (17.5 g, 128
mmol, 1.0 equiv) at 23 °C. The reaction mixture was stirred at
ambient temperature for 30 min before 4-(diethylamino)but-2-
yn-1-ol, 3 was added (23.6 g, 166 mmol, 1.3 equiv), and the
reaction mixture was stirred at 70 °C for 4 h. A second portion
of isobutyl chloroformate (3.8 g, 25.6 mmol, 0.2 equiv) was
added at 70 °C, and the reaction mixture was stirred at 70 °C
for 3 h. At this point, HPLC analysis showed starting material
2 and intermediate 4 each were less than 1 area %. The reaction
mixture was cooled to ambient temperature and quenched by
the addition of NaH2PO4 (10%, 192 g) before separating the
organic layer. The organic layer was washed with NaH2PO4
(10%, 192 g) and DI water (192 g). HPLC analysis showed
the desired product was obtained in 86% assay yield (39.4 g).
The resulting yellow solution was subjected to azeotropic
distillation to remove isobutanol and lower the water content
of the mixture to <0.2% by weight. The batch was concentrated
to a final volume of 110 mL, and diluted to a final volume of
250 mL with fresh toluene. MTBE (184 mL) was added as
cosolvent. Hydrogen chloride gas (4.4 g) was added via
subsurface addition over 20 min at 25 °C. The clear solution
was heated to 50 °C, and crystallization was initiated by seeding.
After seeding, the resulting slurry was allowed to stir at 50 °C
for 2 h. The batch was cooled to ambient temperature over 1 h
and agitated, at 20-25 °C, for 2 h. The slurry was filtered
through a glass filter, and the cake was washed with MTBE
(157 g) and oven-dried at 40-45 °C, under reduced pressure,
for 12 h to afford 1 (40.2 g, 80.0% yield) as white needles, mp
Conclusion
In summary, in situ IR spectroscopy combined with HPLC
was found to be an effective tool for determining and tracking
the chemical events of this reaction. Using in situ IR allowed
for a better understanding of the chemical process. The
formation and build up of transient intermediates, starting
material disappearance, and product and byproduct formation
were effectively followed during the course of the reaction using
both techniques. This process has been scaled up to produce
multiton quantities of 1. Presumably, other R-hydroxy acids
react with chloroformates in a similar manner to afford esters
and amides.
Experimental Section
General. A Water 2690 HPLC system equipped with Waters
2487 UV detector was used for in-process assays. The HPLC
data were reported in area % and were not adjusted to weight
%. The formation of intermediates 4 (17.8 min) and 5 (19.9
min), from 2 (13.6 min), and product 1 (8.8 min) were
monitored using gradient HPLC @ 220 nm (Zorbax RX C-8,
mobile phase: A ) 0.05 M NaH2PO4 (pH 2.5)/methanol (40:
60, v/v), B ) methanol). Linear ramp from 100% A to 100%
B from 0 to 10 min; held at 100% B for 10 to 25 min; re-
equilibration with 100% A for 15 min prior to next injection.
Typically, up to 2-3 HPLC A% of 5 along with 4 was observed
even when only 1.0 equiv of IBCF was used.
1
117-118 °C. H NMR (400 MHz, DMSO-d6): δ 0.9 to 1.1
5-Cyclohexyl-5-phenyl-1,3-dioxolane-2,4-dione, 7. NMP
(0.7 mL, 10.2 mmol. 2.0 equiv) was added over 30 s to a stirred
solution of 2 (1.17 g, 5.0 mmol) in anhydrous THF (10 mL) at
ambient temperature. After 10 min, trichloromethylchlorofor-
mate (0.7 mL, 5.8 mmol, 1.2 equiv) was added dropwise over
one minute while maintaining the reaction temperature e30 °C.
After being stirred for 12 h at room temperature, the reaction
mixture was concentrated to a viscous oil under reduced
pressure. Hexanes (20 mL) was added to the oil, and the mixture
was allowed to stand at 5 °C for 2 h. The resulting solid (amine
salt) was filtered and washed with hexane (10 mL). The hexane
solution was concentrated, and the crude product was purified
by flash chromatography using hexane eluent to give pure
(m, 4H), 1.1 to 1.2 (m, 7H), 1.3 (m, 1H), 1.4 (m, 1H), 1.6 (m,
2H), 1.7 (m, 1H), 2.9 (d, 4H), 4.1 (s, 2H), 4.8 (s, 2H), 5.7 (s,
1H), 7.2 (m, 1H), 7.3 (m, 2H), 7.5 (m, 2H), 11.4 (s, 1H). 13
C
NMR (100 MHz, DMSO-d6): δ 8.9, 25.2, 25.1, 25.8, 25.9, 25.9,
40.5, 45.7, 46.8, 52.4, 75.4, 80.9, 83.8, 125.7, 127.2, 127.9,
141.1, 173.5.
Cyclohexyl-isobutoxycarbonyloxy-phenyl Acetic Acid
Methyl Ester. NaOH (5 N, 19.8 mL) was added dropwise to
a solution of 1-methyl-1-nitroso-1-nitro guanidine (4.4 g, 30
mmol) (caution! diazomethane is potentially toxic and carci-
nogenic; all operations should be carried out in fumehood) in
diethyl ether (100 mL) and H2O (16.5 mL) at 0 °C. The two-
phase reaction mixture was allowed to stir for approximately
2 h at 0 °C. The bottom aqueous layer was separated and
discarded. The bright-yellow organic layer was maintained at
0 °C prior to use (solution A). To a suspension of compound
2 (5.0 g, 21.3 mmol) in toluene (30 mL) under argon was added
NMP (5.2 mL, 42.6 mmol, 2.0 equiv) at 23 °C. Isobutyl
chloroformate (2.7 mL, 21.3 mmol, 1.0 equiv) was added over
approximately 10 min at 23 °C. The reaction mixture was
allowed to stir at ambient temperature for 1 h and was then
quenched with aqueous NaH2PO4 (10%, 75 mL) and diluted
1
product 7 (1.0 g, 79% yield). IR (film) 1807, 1900 cm-1. H
NMR (300 MHz, CDCl3): δ 1.14 to 1.46 (m, 6H), 1.70 to 1.89
(m, 4H), 2.20 to 2.28 (m, 1H), 7.4 to 7.6 m, 5H). 13C NMR
(6) Toyooka, K.; Takeuchi, Y.; Kubota, S. Heterocycles 1989, 29, 975.
(7) Mndzhoyan, A. L.; Bagdasaryan, E. R. Arm. Khim. Zh. 1970, 23, 617.
(8) Moher, E. D.; Grieco, P. A.; Collins, J. L. J. Org. Chem. 1993, 58,
3789. Grieco, P. A.; Collins, J. L.; Moher, E. D.; Thomas, J. F.; Gross,
R. S. J. Am. Chem. Soc. 1993, 115, 6078. Tang, L.; Deng, L. J. Am.
Chem. Soc. 2002, 124, 2870.
(9) For a review article on organic carbonates see: Shaikh, A.-A.; Sivaram,
S. Chem. ReV. 1996, 96, 951.
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1
with toluene (30 mL). The organic phase (solution B) was
separated and washed with DI water (50 mL). Solution A was
added dropwise to solution B at 0 °C, resulting in a colorless
solution. The reaction mixture was allowed to stir at 0 °C for
1 h and then at ambient temperature overnight. The organic
layer was concentrated under reduced pressure to afford a
yellow oil. The crude product was purified using flash chro-
matography; Rf ) 0.33 (eluent: 93:7 hexane/EtOAc) to afford
Isobutyl 2-cyclohexyl-2-hydroxy-2-phenylacetate, 8. H
NMR (400 MHz, CDCl3): δ 0.85 to 1.0 (m, 6H), 1.0 to 1.40
(m, 6H), 1.45 (m, 2H), 1.65 (m, 2H), 1.83 (m, 1H), 1.99 (m,
1H), 2.25 (m, 1H), 3.98 (m, 2H), 7.27 to 7.40 (m, 3H), 7.68 to
7.70 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 19.2, 25.7, 26.4,
26.5, 26.6, 27.6, 27.8, 45.9, 72.6, 81.1, 126.2, 127.5, 128.2,
141.0, 175.9.
4-(Diethylamino)but-2-yn-1-ol Isobutyl Carbonate, 9.
Authentic sample of 9 was prepared by reacting 3 with
isobutylchloroformate (1.2 equiv) in the presence of triethy-
lamine (1.2 equiv) in toluene at room temperature for 12 h.
The product, as an oil, was isolated in 48% yield after removal
of toluene under vacuum followed by flash chromatography
using 20% (v/v) ethyl acetate in hexane. 1H NMR (300 MHz,
CDCl3): δ 0.95 (m, 6H), 1.05 (m, 6H), 2.0 (m, 1H), 2.55 (q, J
) 7.5 Hz, 4H), 3.48 (br s, 2H), 3.98 (d, J ) 3 Hz, 2H), 4.85
(br s, 2H). 13C NMR (75 MHz, CDCl3): δ 12.8, 19.1, 28.0,
41.1, 47.4, 55.9, 74.6, 78.4, 82.8, 155.1. Anal. Calcd for
C13H23NO3: C, 64.70; H, 9.61; N, 5.80. Found: C, 64.56; H,
9.79; N, 5.70.
1
the desired product as a colorless oil. H NMR (300 MHz,
CDCl3): δ 0.86 to 1.30 (m (2d, J ) 2.7 and 3.0 Hz), 11H),
1.50 to 2.25 (m, 7H), 3.80 (s, 3H), 3.95 (dd, J ) 8.9, 6.9 Hz,
2H), 7.28 to 7.39 (m, 3H), 7.56 to 7.60 (m, 2H). 13C NMR (75
MHz, CDCl3): δ 19.0, 26.2, 26.4, 26.3, 27.5, 28.0, 28.1, 47.4,
52.4, 74.4, 88.2, 126.4, 127.8, 127.9, 137.4, 154.0, 170.4.
HRMS Calcd for C20H28O5 (M + Na) 371.1834; found
371.1850.
Cyclohexylisobutyloxycarbonyloxyphenyl Acetic Acid
Isobutylcarbonic Anhydride, 5. To a suspension of 2 (5.0 g,
21.3 mmol) in cyclohexane (100 mL) was added triethylamine
(7.4 mL, 53.3 mmol, 2.5 equiv) and isobutylchloroformate (5.5
mL, 42.6 mmol, 2.0 equiv) while maintaining the reaction
temperature between 20-30 °C. The reaction mixture was
allowed to stir at ambient temperature for 1 h and was then
quenched with aqueous NaH2PO4 (10%, 50 mL). The organic
phase was separated and washed with aqueous NaH2PO4 (10%,
50 mL) and DI water (50 mL). The organic layer was dried
over anhydrous MgSO4, concentrated in vacuo, and purified
using flash chromatography; Rf ) 0.20 (eluent: 95:5 hexane/
EtOAc) to afford the desired product (2.5 g, 27% yield
unoptimized) as a colorless oil. IR (film) 1825, 1809, 1761,
Acknowledgment
We thank Dr. Chris H. Senanayake (currently at Boehringer-
Ingelheim, Ridgefield, CT, U.S.A.) for his valuable suggestions
and Dr. Hal Butler for analytical support.
Supporting Information Available
1
1273 cm-1. H NMR (300 MHz, CDCl3): δ 0.94 (d, J ) 6.9
Experimental procedures and spectral data of all new
compounds described in the paper (1H, 13C NMR, and FTIR if
applicable). This material is available free of charge via the
Internet at http://pubs.acs.org.
Hz, 6H), 0.99 (d, J ) 6.9 Hz, 6H), 1.10 to 2.40 (m, 13H), 3.94
(dd, J ) 10.5, 6.3 Hz, 1H), 3.99 (dd, J ) 10.5, 6.3 Hz, 1H),
4.09 (d, J ) 6.9 Hz, 2H), 7.27 (m, 3H), 7.58 (m, 2H). 13C NMR
(75 MHz, CDCl3): δ 18.7, 25.9, 26.1, 26.2, 26.8, 27.6, 27.7,
46.7, 74.6, 75.6, 87.3, 126.1, 127.9, 128.0, 135.7, 148.5, 153.6,
164.4. HRMS Calcd for C24H34O7, (M + Na) 457.2205; found
457.2176.
Received for review January 27, 2010.
OP100021W
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