Synthesis of tetracyclic heterocompounds as selective estrogen receptor modulators. Part 1. Process development for scale-up of 2,5,8-substituted 5,11 -dihydrochromeno[4,3-c]chromene derivatives

Article abstract of DOI:10.1021/op700020f

Unsymmetrical benzopyranobenzopyran compounds are novel selective estrogen receptor modulators (SERMs). A reproducible and nonchromatographic process was developed to prepare multihundred gram quantities of 5-(4-(2-(piperidin-1-yl) ethoxy)-phenyl)-5,11-di

Full text of DOI:10.1021/op700020f

Organic Process Research & Development 2007, 11, 414−421
Synthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor
Modulators. Part 1. Process Development for Scale-up of 2,5,8-Substituted
5,11-Dihydrochromeno[4,3-c]chromene Derivatives
Xun Li,*,† Michael Reuman,† Ronald K. Russell,† Richard Adams,† Robert Ma,† Sandra Beish,† Shawn Branum,†
Scott Youells,† Jerry Roberts,† Nareshkumar Jain,‡ Ramesh Kanojia,‡ and Zhihua Sui‡
Johnson & Johnson Pharmaceutical Research & DeVelopment, L.L.C., U.S. Research & Early DeVelopment,
1000 Route 202, Raritan, New Jersey 08869
Abstract:
in both Schemes 1 and 2, and Tables 1 and 2).3 A brief
review of this chemistry identified some large-scale synthesis
improvement opportunities: (1) develop a scaleable and safer
route to prepare bulk quantities of 2b, since 2a was not
commercially available and the Discovery preparation of 2a
used highly toxic thallium(III) nitrate;4 (2) reduce or eliminate
the number of chromatographic purifications throughout the
preparation; (3) increase the bromination efficiency of
4-methyl 6a to 4-bromomethyl derivative 7a, since the yields
were generally low (<44% of 7a); (4) look for alternatives
of Grignard reagent 20a, since the preparation was prob-
lematic; and (5) improve the Discovery yield of the Mit-
sunobu cyclization of 11 to 12 (17% after chromatographic
purification). Herein, we report our improved and reproduc-
ible process, which requires no chromatography and is
amendable to large-scale production of 2,8-bis(2,2-dimeth-
ylpropanoate) ester 14.
Unsymmetrical benzopyranobenzopyran compounds are novel
selective estrogen receptor modulators (SERMs). A reproducible
and nonchromatographic process was developed to prepare
multihundred gram quantities of 5-(4-(2-(piperidin-1-yl)ethoxy)-
phenyl)-5,11-dihydrochromeno[4,3-c]chromene-2,8-diyl-bis(2,2-
dimethylpropanoate) (14). The overall yield of this 11-step
synthesis was improved from 0.17% to 7.1% after three scale-
up campaigns.
Introduction
Recently, the Discovery medicinal chemists at Johnson
& Johnson Pharmaceutical R&D reported the preparation of
substituted 5,11-dihydrochromeno[4,3-c]chromene deriva-
tives I (where R ) H, CH3, or COC(CH3)3; R1 ) C6H4-
OCH2CH2N(CH2)5 or other structurally similar substituents;
and n ) 1, 2, 3) as novel selective estrogen receptor
modulators (SERMs).1-3
Results and Discussion
The purpose of the first campaign was to prepare a 10-g
amount of racemic 2,8-diol compound 13 within a limited
time frame and the Discovery synthetic strategy was adopted
with the intention to improve the overall yield. Attention
was focused on the optimizations of the two lowest reaction
yields (steps 8 and 9) as well as to remove the column
chromatographic purifications required for both steps. To
achieve this goal, 3.3 kg of starting material 2a was required
for the synthesis; however, the availability of 2a became an
issue when commercial suppliers had neither material on-
hand nor any plan to make the necessary amounts within
our timeline. The Discovery preparation of 2a was ac-
complished by the conversion of 2-benzyloxy-4-methoxy-
acetophenone (16, another compound which was unavailable
commercially in bulk quantity) using thallium(III) nitrate4
in 52% isolated yield over two steps after chromatographic
purifications (Scheme 3, steps i and ii). These problems were
overcome when a low-cost commercially available 2,4-
dimethoxyacetophenone (17) was used in a modified
Willgerodt reaction5 to prepare 2b from its thioamide
intermediate 18 in 80% overall yield without chromato-
graphic purification (Scheme 3, steps iii and iv). This
modified process was later used by a contract research
organization to prepare bulk quantities of 2b.
As a continuation of this research, large quantities of 5-(4-
(2-(piperidin-1-yl)ethoxy)phenyl)-5,11-dihydrochromeno[4,3-
c]chromene-2,8-diol (13) and its corresponding 2,8-bis(2,2-
dimethylpropanoate) ester 14 were requested for advanced
in vivo biological studies.1c The original Discovery route that
started with the base-catalyzed Perkin condensation of 2,4-
dihydroxyacetophenone (1) and 2-benzyloxy-4-methoxy-
phenylacetic acid (2a) resulted in only 0.17% overall yield
of compound 13, after a 10-step linear synthesis which
required nine chromatographic purifications (Discovery route
* Author for correspondence. Telephone: (908)707-3321. Fax: (908)526-
6469. E-mail: xli6@prdus.jnj.com.
† High Output Synthesis.
‡ Reproductive Therapeutics.
(1) (a) Chen, N.; Jain, N.; Xu, J.; Reuman, M.; Li, X.; Russell, R. K.; Sui, Z.
Tetrahedron Lett. 2006, 47, 5909. (b) Jain, N.; Xu, J.; Sui, Z. WO2006055694,
2006. (c) Jain, N.; Kanojia, R. M.; Xu, J.; Gou, J.-Z.; Pacia, E.; Lai, M.-T.;
Du, F.; Musto, A.; Allan, G.; Hahn, D.; Lundeen, S.; Sui, Z. J. Med. Chem.
2006, 49, 3056.
(2) Kanojia, R. M.; Jain, N.; Xu, J.; Sui, Z. Tetrahedron Lett. 2004, 45, 5837.
(3) Kanojia, R. M.; Jain, N.; Ng, R.; Sui, Z.; Xu, J. WO2003053977, 2003.
(4) McKillop, A.; Swann, B. P.; Taylor, E. C. J. Am. Chem. Soc. 1973, 95, 3340.
(5) King, F. E.; Neill, K. G. J. Chem. Soc. 1952, 4752.
414
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Vol. 11, No. 3, 2007 / Organic Process Research & Development
10.1021/op700020f CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/31/2007

Scheme 1
purification. Silylation of 2,8-dihydroxy 8 with a large excess
of tert-butyldimethylsilyl chloride (TBDMSCl, 5.22 equiv)
afforded its 1,8-bisTBDMS ether 9 in 61% isolated yield
(acetoxy route: steps 1-6). Direct addition of Grignard
reagent 20a to the B-ring lactone carbonyl in THF or Et2O
from -20 to 20 °C were unsuccessful;6 neither a 1,2- nor a
1,4-addition product of 9 was formed,6,7 probably due to
carbonyl conjugation with aromatic A- and D-rings, which
deactivates its electrophilicity.
Although the above results of Grignard addition 20a to
carbonyl were disappointing, a literature survey revealed that
2,4-dialkyl-isoflav-3-enes could be prepared in a moderate
yield (42-50%) by DIBALH reduction of 4-alkyl-3-aryl-
coumarins, a ring system similar to that of compound 9,
followed by in situ addition of a Grignard reagent and acid-
catalyzed cyclization without separation of intermediates.8
Therefore, the carbonyl of 9 was reduced with DIBALH in
toluene to its corresponding bis-silyl lactol 10 in almost
quantitative yield with high chemical purity (95%) (acetoxy
route: step 7 in Scheme 2, Table 2). The bis-silyl lactol 10
was stable at room temperature and did not need to be
protected as its alkyl or aryl ether.9 The Grignard reagent
20a was freshly prepared from the reaction of 19b, a coupling
product of 4-bromophenol with 1-(2-chloroethyl)piperidine
(Scheme 4), with magnesium turnings in the presence of
catalytic amount of CH3I in anhydrous THF.10 Addition of
excess 20a to lactol 10 in anhydrous THF afforded 156%
isolated yield of crude material after workup (the isolated
yield > 100% of theory was due to the crude material
containing solvent residues and other unidentified impurities);
HPLC and 1H NMR analyses indicated that this crude
product contained 65% (area %) of the desired diol 11, ∼30%
of 1-(2-phenoxyethyl)piperidine (19c), plus ∼10% of ho-
mocoupled dimer 19d. However, the presence of 19c and
19d did not impact the B-ring reclosure when a large excess
of acid was used.
Scheme 2
Treatment of crude diol 11 with concentrated HCl in
toluene resulted in 106% isolated yield of crude 12 as a
mixture of 2- and/or 8-monodesilylated products of 12 (3-
5%) and final product 13 (∼1%) (acetoxy route: steps 8, 9,
determined by HPLC and LC/MS analyses compared to
standard reference samples). Interestingly, the byproducts 19c
and 19d were removed as water-soluble HCl salts during
aqueous workup. Desilylation of 12 with tetrabutylammo-
nium fluoride (TBAF) in THF resulted in a 121% isolated
yield of crude product 13,12 which after chromatographic
purification afforded the first batch (14.9 g) of pure 13 in
52% isolated yield over three steps. It was found that when
a large excess of TBAF (such as 5.0 equiv) or long reaction
time (more than 6 h) was used, a lower yield of 13 was
isolated, due to the formation of undesired side products. In
Following the Discovery methods,1,3 coumarin 3b was
prepared by base-catalyzed Perkin condensation of 2,4-
dihydroxyacetophenone (1) and 2b in 55% isolated yield after
silica gel chromatography. Deacetylation and demethylation
of compound 3b using pyridine hydrochloride produced
4-methyl-3-(2,4-dihydroxyphenyl)-7-hydroxycoumarin (4) in
nearly quantitative yield. This trihydroxy coumarin 4 was
converted to its triacetoxy derivative 6a (R ) Ac) in
moderate yield (59%) after chromatographic purification
(acetoxy route in Scheme 1, Table 1). Radical bromination
of 6a with NBS and (BzO)2 resulted in 44% of 4-bromom-
ethyl compound 7a after chromatographic purification.3
Deacetylation and C-ring closure were achieved in a one-
pot reaction by first treatment of 7a with K2CO3 in a mixture
of acetone and methanol, followed by HCl treatment to af-
ford 2,8-dihydroxy-5,11-dihydrochromeno[4,3-c]chromen-5-
one (8) in excellent yield (95%) after chromatographic
(6) Alberola, A.; Ortega, A. G.; Pedrosa, R.; Bragado, J. L. P.; Amo, J. F. R.
J. Heterocycl. Chem. 1983, 20, 715.
(7) Cook, C. E.; Corley, R. C.; Wall, M. E. J. Org. Chem. 1965, 30, 4114.
(8) Cook, C. E.; Twine, C. E., Jr. J. Chem. Soc., Chem. Commun. 1968, 791.
(9) Grese, T. A.; Pennington, L. D. Tetrahedron Lett. 1995, 36, 8913.
(10) Prat, D.; Benedetti, F.; Girard, G. F.; Bouda, L. N.; Larkin, J.; Wehrey, C.;
Lenay, J. Org. Process Res. DeV. 2004, 8, 219.
(11) Li, X.; Jain, N.; Russell, R. K.; Ma, R.; Branum, S.; Xu, J.; Sui, Z. Org.
Process Res. DeV. 2006, 10, 354.
(12) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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415

Table 1. Summary of the reaction conditions and yields for steps 1-5
route
acetoxy routeb
benzoyloxy routec
(2nd campaign)
methoxy routed
(3rd campaign)
step
1
discovery routea
(1st campaign)
2a, Ac2O, Et3N
41% of 3a
2b, Ac2O, Et3N
55% of 3b
2b, Ac2O, Et3N
77% of 3b
2b, Ac2O, Et3N
77% of 3b
2
3a, pyridine‚HCl
>95% of 4
3b, pyridine‚HCl
96% of 4
3b, pyridine‚HCl
99% of 4
2a
3
3b, K2CO3, MeOH
38% of 5
4, Ac2O, pyridine
59% of 6a
4, Ac2O, pyridine
59% of 6a
4, BzCl, Et3N, CH2Cl2
48% of 6b
3a
4
5, K2CO3, DMF, MeI
80% of 6c
6a, NBS, hV, (BzO)2
CCl4, 42% of 7a
6a, NBS, hV, (BzO)2
CCl4, 44% of 7a
6b, LHMDS, Br2, THF
62% of 7b
(plus 38% of 6b)
6c, LHMDS, NBS, THF
91-93% of 7c
(inverse quench)
5
1) 7a, K2CO3, acetone, MeOH
2) HCl, 92% of 8
1) 7a, K2CO3, acetone, MeOH
2) HCl, 95% of 8
1) 7a, K2CO3, acetone, MeOH
2) HCl, 62% of 8
1) 7c, BBr3, CH2Cl2
2) NaOH, 88% of 8
a Four chromatographic purifications were required (steps 1, 3, 4, and 5). b Three chromatographic purifications were required (steps 1, 3, and 4). c Two chromatographic
purifications were required (steps 4 and 5). d Zero chromatographic purification was required.
Table 2. Summary of the reaction conditions and yields from steps 6-11
route
acetoxy routeb
(1st campaign)
benzoyloxy routec
(2nd campaign)
methoxy routed
(3rd campaign)
step
6
discovery routea
8, TBDMSCl, Et3N, CH2Cl2
80% of 9
8, TBDMSCl, Et3N, CH2Cl2
61% of 9
8, TBDMSCl, Et3N, CH2Cl2
19% of 9
8, TBDMSCl, Et3N, CH2Cl2
67% of 9
7
8
9
9, DIBALH, toluene
80% of 10
9, DIBALH, toluene
96% of 10
9, DIBALH, toluene
96% of 10
9, DIBALH, toluene
79% of 10
10, 19a, BrMgCH(CH3)2, THF
22% of 11
10, 19b, Mg, CH3I, THF
11, HCl, toluene
10, 19a, n-BuLi, THF
11, HCl, toluene
10, 19b, n-BuLi, THF
11, HCl, toluene
11, DEAD, P(Ph)3,
Mol. S. 4Å, THF
17% of 12
10
11
12, TBAF, THF.
78% of 13
12, TBAF,THF
52% of 13 (3 steps)
12, TBAF, THF.
12, TBAF, THF.
13, t-BuCOCl, Et3N
40% of 14 (4 steps)
13, t-BuCOCl, Et3N
72% of 14 (4 steps)
a Five chromatographic purifications were required (steps 6-10). b Two chromatographic purifications were required (steps 6 and 10). c One chromatographic purification
was required (step 11). d Zero chromatographic purification was required.
summary, the acetoxy route afforded 3.9% isolated yield of
racemic 2,8-dihydroxy 13 over 10 steps, with the yield of
steps 8-10 significantly improved from 8.7% to 52% and
three chromatographic purifications eliminated. However,
2,8-dihydroxy 13 was found unstable to the ambient condi-
tions after long standing and also decomposed during the
chiral separation process. The pro-drug 14, a 2,8-bis-pivaloyl
ester of 13, was chosen to be used in advanced in vitro and
in vivo tests, which thus far, granted highly reproducible
results (IC50’s) to the biological assays.1c
The second campaign objective was, therefore, changed
to prepare g5.0 g each of (5S)-enantiomer 21 and (5R)-
enantiomer 22, which could be obtained by chiral chromato-
graphic separation of racemate 2,8-bis(2,2-dimethylpro-
panoate) ester 14 (Scheme 5). The focus for this campaign
was to increase the selectivity as well as the yield of the 6a
radical bromination in the acetoxy route (first campaign) and
further reduce the number of chromatographic purifications.
The first goal was achieved after changing the radical
bromination of triacetoxy compound 6a to anionic bromi-
416
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Vol. 11, No. 3, 2007 / Organic Process Research & Development

Scheme 3a
dehydrated to give B-ring cyclized intermediate 12 in 186%
isolated yield, which was used crude in the next step.
Treatment of crude 12 with 2 equiv of TBAF in THF gave
compound 13 in situ, which was then reacted with pivaloyl
chloride in the presence of Et3N to afford a crude reaction
mixture (228% isolated yield) after work up. Chromato-
graphic purification of this crude material afforded the
desired racemate 14 in 40% yield over four steps (benzoyloxy
route: steps 8-11). In summary, the second campaign
demonstrated that anionic bromination of 6b was more
efficient than radical bromination, in terms of reaction time
and isolated yield of the 4-bromomethyl product 7b. In
addition, the number of column chromatographic purifica-
tions was reduced from five in the acetoxy route to three in
this benzoxy route. However, the overall yield for 11 steps
was 0.73%, due to low recovery yield of 9 in step 6.
a Reagents and conditions: i) BnBr, K2CO3, DMF, 20 °C, 18 h, 87%; ii)
Tl(NO3)3, HNO3, MeOH, 20 °C, 18 h, 60%; iii) S, 130 °C, 6 h; iv) NaOH, H2O,
102 °C, 3 h; then HCl, 80% (over two steps).
The above two campaigns (5-20 g scale) provided an
excellent understanding of all intermediates as well as the
final product and allowed for further improvement in the
third campaign, which was for the preparation of at least
250 g of racemate 14 to provide ∼115 g each of (5S)-
enantiomer 21 and (5R)-enantiomer 22. In order to ac-
complish this task, the following problems had to be
solved: (1) the reaction conditions for deacetylation/dem-
ethylation of compounds 3a/3b to trihydroxy 4 were difficult
due to a high reaction temperature (180-210 °C) and a large
volume of gas (CH3Cl) released from the system in a short
time period, (2) the yield of anionic bromination (step 4)
needed to be improved, and (3) two column purifications
(steps 4 and 11 of the benzoyloxy route) needed to be
removed. Since phenol alkyl ethers can be cleaved with a
strong Lewis acid, such as BBr3 or AlCl3,14 an alternative
strategy to 2,8-dihydroxy intermediate 8 was undertaken by
converting 3b to intermediate 5 and then trimethoxy com-
pound 6c. In practice, trimethoxy 6c was prepared in 23.4%
overall isolated yield, starting from compound 1 and 2b
without chromatographic purifications (methoxy route: steps
2a and 3a in Scheme 1, Table 1).11,15 More importantly, the
further improved anionic bromination conditions (which
involving lithiation with LHMDS followed by rapid inVerse
quench with NBS in THF at -76 °C) using 6c successfully
achieved a reproducible quantitative yield of 4-bromomethyl
7c with high chemical purity (91-93%), which could be used
in next step without further purification.11 Treatment of 7c
with BBr3 in CH2Cl2 at 34-36 °C for 24-48 h afforded
88% isolated yield of compound 8 in high chemical purity
Scheme 4a
a Reagents and conditions: i) 19a, K2CO3, acetone, 56 °C, 3 h, 95%; ii) 19b,
K2CO3, acetone, 56 °C, 3 h, 95%; iii) 20a, Mg, CH3I (cat.), THF, > 95%; iv)
20b, n-BuLi, THF, -78 °C, 2 h, > 95%.
nation of tribenzoyloxy derivative 6b as described in a
previous publication, since the preferred protecting group
was Bz (vs SEM and or MOM).11 Therefore, trihydroxy
compound 4 was converted to its tribenzoyloxy derivative
6b in a moderate yield without chromatographic purification.
Treatment of 6b with LHMDS in THF and then quenching
with Br2 afforded 4-bromomethyl compound 7b in 62% yield
along with 38% of recovered starting material 6b after a
column separation (benzoyloxy route: steps 3 and 4 in
Scheme 1, Table 1). Debenzoylation and C-ring cyclization
of 7b was accomplished in the same fashion as in the acetoxy
route (K2CO3, MeOH/acetone) to afford a 62% isolated yield
of 2,8-dihydroxy 8 after column purification. This material
was then also treated with a large excess of TBDMSCl (5.22
equiv) to provide 2,8-bis-silyl ether 9 in only 19% isolated
yield after low-temperature pentane slurry clean up (-10 °C);
albeit, without column chromatographic purification. The
unexpected low yield of 9 here, probably, was due to the
presence of a large amount of TBDMS-related byproducts
in the crude material, which caused more difficulty in
recovering 9 from the purification solvent. The B-ring lactone
of 9 was reduced to lactol 10 in quantitative yield and high
chemical purity (>95%). In the meantime, Discovery chem-
ists demonstrated that the addition of lithium reagent 20b to
lactol 10 afforded a higher yield of diol 11 with less
byproduct 19d. Reagent 20b was easily prepared in an almost
quantitative manner by simply treating iodo compound 19a
with n-BuLi in THF at -78 °C (Scheme 4, step iv).13 After
treatment with concentrated HCl, the crude diol 11 was
1
(90-95%) as determined by both H NMR and HPLC
(methoxy route: steps 4 and 5).1,14
Treatment of 8 with a slight excess of TBDMSCl (2.16
equiv) afforded 2,8-bis-silyl ether 9 in 67% isolated yield
and 95% chemical purity, after slurry of the crude reaction
product in pentane and hexane without additional purifica-
tion. DIBALH reduction of 9 produced crude lactol 10, which
after EtOAc crystallization afforded pure lactol 10 in 79%
yield (methoxy route: steps 6 and 7). One more modification
of Discovery’s preparation of lithium reagent 20b was to
(14) Vickery, E. H.; Pahler, L. F.; Eisenbraun, E. J. J. Org. Chem. 1979, 44,
4444.
(13) Harder, S.; Boersma, J.; Brandsma, L.; Kanters, J. A.; Duisenbery, A. J.
M.; van Lenthe, J. H. Organometallics 1990, 9, 511.
(15) MacKenzie, A. R.; Moody, C. J.; Rees, C. W. Tetrahedron 1986, 42, 3259.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
417

Scheme 5
use the cheaper bromo compound 19b to react with a
stoichiometric amount of n-BuLi (steps iii and iv, Scheme
4). As before, the addition of 20b to lactol 10 in THF at
below -70 °C produced 165% isolated yield (of theory) of
crude diol 11. This crude diol was further treated with
concentrated HCl in toluene and then diluted in EtOAc,
followed by NaHCO3 wash to afford the crude cyclized
product 12 in 106.5% isolated yield, which was used without
further purification (methoxy route: steps 8 and 9). Finally,
treatment of the THF solution of crude 12 with TBAF
resulted quantitatively in bis-hydroxy compound 13, which,
without workup, was reacted with pivaloyl chloride and Et3N
to afford the crude 2,8-bis(2,2-dimethylpropanoate) ester 14
in 73.2% yield. This crude material was crystallized from
IPA to produce the desired racemate 14 as an off-white solid
in 72% isolated yield over four steps. This reaction was
repeated multiple times to afford 569 g of racemate 14 that
was separated by chiral chromatography to produce 257.8 g
of the (5S)-enantiomer 21 and 239.9 g of (5R)-isomer 22.
purification, (4) the yield of bis-silyl ether 9 was improved
to 67% with high purity (>95%) by modifying the workup,
and (5) the racemate 14 was prepared in 72% yield with
high chemical purity (>97%) using crude products in each
step for four consecutive steps. The overall yield of the 11-
step synthesis of racemate 14 was improved from 0.17% to
7.1%, and all chromatographic purifications were eliminated.
This methoxy route was safe, reproducible, lower in cost, and
allowed for multikilogram production of racemates 13/14.
Experimental Section
Starting materials, reagents, and solvents were obtained
from commercial suppliers and were used without further
purification. The melting points are uncorrected and deter-
mined on a MEL-TEMP 3.0 apparatus. 1H NMR spectra were
recorded at 300 MHz on a Bruker Avance-300 instrument,
and mass spectra were recorded on an Agilent Series 180
LC/MS instrument (positive/negative modes). The chemical
purity was determined on an Agilent series 1100 system at
UVmax ) 254 and 340 nm, using a ZORBAX Eclipse XDB-
phenyl column (4.6 mm i.d. × 5 cm, 3.5 µ) at 40 °C with
flow rate of 1.0 mL/min and run time of 10.0 min. Solvent
system: A, 80% H2O + 0.1% TFA; B, 20% CH3CN;
Gradient: B 20% /0.0 min, B 20%/1.0 min, B 90%/6.0 min,
B 90%/8.0 min, B 55%/9.0 min, B 20%/10.0 min. The optical
purity was determined on an Agilent series 1100 system at
UVmax ) 254 and 340 nm, using a CHIRALPAK AD column
(2.1 mm i.d. × 150 mm, 3.5 µ) at 40 °C with flow rate of
0.5 mL/min and run time of 12 min with 2-propanol (IPA,
100%). Rochelle’s solution (40%, wt/vol) was prepared by
dissolving potassium sodium tartrate tetrahydrate (×400 g)
in deionization water (D.I. water, × 1 L) at 20 °C.
Conclusions
Three synthetic routes were used to prepare racemates
13/14, with significant improvements made throughout the
three campaigns. In the acetoxy scale-up route, an economic
and nonchromatographic process was developed to prepare
a large quantity of starting material 2b.5 In addition, a three-
step one-pot synthetic procedure was used to prepare
intermediate 128 and enough of compound 13 in a short time
period. The overall yield of the acetoxy route was increased
to greater than 50% versus the Discovery’s 2.3% over four
steps from intermediate 9, and the number of column
purifications was reduced from nine to five.
In the second campaign, the target product was changed
to the 2,8-bis(2,2-dimethylpropanoate) ester 14. The selective
anionic bromination of benzoyloxy compound 6b produced
better results10 than that of radical bromination, which was
demonstrated by a shorter reaction time and an increased
yield of the desired 4-bromomethyl 7b (62% vs 44%). In
addition, the chromatographic purification steps were further
reduced to three, although the BzCl protection of trihydroxy
4 to 6b and the 2,8-bissilylation of 8 to 9 were problematic
with a low isolated yield (19%) of intermediate 9.
All reactions were carried out in a four-neck round-bottom
flask (RBF, 1-22 L), equipped with a thermocouple control-
ler, an overhead mechanical stirrer, a condenser, and a
pressure-equalization addition funnel and nitrogen inlet/outlet
whenever they were required.
2,4-Dimethoxyphenylaectic acid (2b).5 A 3-L RBF was
charged with 2,4-dimethoxyacetophenone (17) (98%, 333.0
g, 1.848 mol), sulfur (99%, 117.0 g, 3.650 mol), and
morpholine (99%, 319.4 g, 3.666 mol) (the mixing process
was endothermic, and the final temperature of the mixture
was 0 °C). The reaction mixture was heated to reflux (130 °C,
internal temperature) for 6 h, and the progress of the reaction
was monitored by TLC and LC/MS. After completion, the
excess morpholine was removed by distillation under reduced
pressure (40 mmHg) at 136 °C (150 mL of distillate was
collected) to afford the crude thioamide 18 as a viscous oil,
which was used in the next step without further purification.
LC/MS m/z 282 (MH+), 304 (MNa+).
The experience of the first and second campaigns
benefited the third scale-up preparation of 14 in several
ways: (1) a safer process was developed for large-scale
preparation of trimethoxy compound 6c, (2) anionic bromi-
nation of 6c was improved to afford quantitatively 4-bro-
momethyl 7c with high chemical purity (91-93%), (3)
C-ring demethylation/cyclization of 7c using BBr3 produced
2,8-dihydroxy 8 in high yield (88%) without chromatographic
418
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Vol. 11, No. 3, 2007 / Organic Process Research & Development

1
After crude 18 was transferred to a 12-L RBF, D.I. H2O
(4.4 L) and NaOH (591.3 g, 14.78 mol) were added with
rapid stirring (this was an exothermic process, the final
temperature of the solution was about 68 °C). This mixture
was heated to 100-102 °C and refluxed for 3 h (or until
both TLC and LC/MS showed complete hydrolysis). The
H2S gas generated from the reaction was scrubbed through
a bleach solution. After completion, the reaction was cooled
to 25 °C and extracted with CH2Cl2 (1.0 L, 0.5 L) to remove
water-insoluble organic impurities. The aqueous phase was
then cooled to 10 °C in an ice bath and acidified to pH 1 by
dropwise addition of 37% HCl solution (1.1 L) over 1.5 h
with fast agitation. During this addition, the reaction tem-
perature was maintained between 15 and 20 °C. The slightly
yellowish solid was collected by filtration, and the wet cake
was washed with D.I. water (100 mL × 3), air-dried, and
then placed in a vacuum oven at 50 °C for 72 h under house
vacuum. There was obtained 290.7 g (80% yield) of acid
2b as a pale-yellow solid, which was used in the next step
product as it may be a possible skin irritant.) H NMR
(300 MHz, CD3OD) δ 4.79 (br s, 2 H), 5.26 (s, 2 H), 6.39
(s, 1 H), 6.48 (d, J ) 7.8, 1 H), 6.74 (s, 1 H), 6.83 (d, J )
7.6, 1 H), 7.40 (d, J ) 8.0, 1 H), 8.24 (d, J ) 7.9, 1 H).
LC/MS m/z 283 (MH+), 305 (MNa+), 587 (2MNa+).
2,8-Bis(tert-butyldimethylsilyloxy)-11H-chromeno[4,3-
c]chromen-5-one (9).3,16 A 5-L RBF was charged with 2,8-
dihydroxy 8 (410.6 g. 1.45 mol), CH2Cl2 (2 L), and Et3N
(470 mL, 3.37 mol). While the mixture was stirred under
nitrogen, TBDMSCl (473 g, 3.14 mol) was added to the
reaction portionwise (approximately 30 g each at 5-min
intervals), while the internal temperature was maintained
below 36 °C with a cold water bath. After the TBDMSCl
addition, the reaction was allowed to stir at room temperature
for 24 h (the reaction was monitored by HPLC). The mixture
was transferred to a 12-L three-neck separatory flask
equipped with an overhead stirrer and was washed with 0.1
N HCl (1 L × 2) followed by saturated NaHCO3 (1 L). The
organic phase was concentrated to give the crude product
as a tan-brown solid (724 g, 98%). This crude material was
suspended in pentane and filtered (this initial filtration was
difficult, since the filter paper and filter funnel both clogged
with a brown, gummy material). The recovered solid from
the filtration was dissolved in CH2Cl2, reconcentrated, and
then suspended in hexane (500 mL); the solid was collected
by filtration and washed with hexane (500 mL). The product
was dried under vacuum at 40 °C to give 496.0 g (67%
isolated yield) of 2,8-bis-silyl ether 9 as a tan solid, which
was 95% chemically pure by 1H NMR and HPLC. 1H NMR
(300 MHz, CDCl3) δ 0.23 (s, 6 H), 0.25 (s, 6 H), 0.99 (s, 18
H), 5.24 (s, 2 H), 6.47 (d, J ) 2.3, 1 H), 6.58 (dd, J ) 2.4,
8.6, 1 H), 6.82 (d, J ) 8.8, 1 H), 6.84 (s, 1 H), 7.32 (d, J )
8.3, 1 H), 8.43 (d, J ) 8.4, 1 H). LC/MS m/z 511 (MH+),
533 (MNa+).
2,8-Bis(tert-butyldimethylsilyloxy)-11H-chromeno[4,3-
c]chromen-5-ol (10).3,8 A 3-L RBF was charged with CH2-
Cl2 (1.6 L) and lactone 9 (100.0 g, 0.196 mol), and the
mixture was stirred under nitrogen and cooled to -40 °C in a
dry-ice/CH3CN bath. Diisobutylaluminum hydride (DIBALH,
1.0 M solution in toluene, 234.8 mL, 0.2348 mol) was added
dropwise over a 45-min period, while the reaction temper-
ature was maintained at -40 °C. After the addition, the
reaction was stirred at -40 °C for 1.5 h and checked by
TLC and LC/MS. If reaction was not complete, additional
DIBALH was added and allowed to stir an additional 30
min. The reaction was quenched with 40% Rochelle’s
solution (800 mL) (the temperature of mixture increased from
-40 to -6 °C) and was agitated at room temperature for 2
h; then the mixture was transferred to a 12-L separatory flask
equipped with an overhead mechanical stirrer that contained
Rochelle’s solution (7.2 L). After phase separation, the
aqueous phase was extracted with CH2Cl2 (2 × 2.0 L), and
the combined organic phase was washed with Rochelle’s
solution (1 × 1.0 L) and brine (1 × 2.0 L). After
concentration of the solvents, the resulting material (136.9
g) was crystallized from EtOAc (2.2 L). The solution was
gradually cooled to 20 °C and then placed in an ice-water
1
without further purification. H NMR (300 MHz, DMSO-
d6) δ 3.58 (s, 2 H), 3.79 (s, 6 H), 6.44 (d, J ) 7.9, 1 H),
6.47 (s, 1 H), 7.08 (d, J ) 8.0, 1 H), 9.8-10.9 (br s, 1 H).
LC/MS m/z 197 (MH+), 219 (MNa+).
The preparation of substituted coumarins 3a, 3b, 4, 5,
6a-c, and 7a-c was reported in an earlier publication.11
2,8-Dihydroxy-11H-chromeno[4,3-c]chromen-5-one (8).14
A 22-L RBF was charged with 4-bromomethyl 7c (322.1 g,
0.795 mol) and CH2Cl2 (14.7 L). The solution was stirred
under nitrogen while the vessel was evacuated and filled with
nitrogen three times. Boron tribromide (1.05 kg, 4.19 mol)
was added from reagent bottles to the reaction by a cannula
over 10-15 min period under a positive nitrogen pressure
(the BBr3 addition was slightly exothermic, and the internal
temperature increased from 20 °C to 28 °C). The septum
was replaced with a Teflon stopper, and the reaction was
heated gently to just below reflux. The progress of the
reaction was monitored by NMR and HPLC, which was
typically done in 24-48 h.
Two 22-L three-neck separatory flasks equipped with an
overhead stirrer were both charged with saturated NaHCO3
(4 L) and D.I. water (4 L). Approximately half of the contents
of the above reaction mixture was added, in portions, via a
Teflon tube under a positive nitrogen pressure to each of
the separatory flasks with stirring. The reaction flask was
rinsed with a minimal volume of CH2Cl2 and saturated
NaHCO3, and this was added to one of separatory flasks.
The pH of each half-saturated NaHCO3 mixture in each flask
was adjusted to strongly basic (pH >12) by the addition of
10 N NaOH to afford a clean separation of the aqueous and
CH2Cl2 layers. The lower CH2Cl2 layer in each flask was
separated and discarded. The pH of aqueous layer was then
adjusted to acidic (pH ) 1) by the addition of concentrated
HCl; the resulting fine yellow-green precipitate was collected
by filtration, washed with D.I. H2O (4 L), and dried to a
constant weight at 40 °C to afford 197.2 g (88% isolated
yield), of which 1H NMR indicated a 90-95% purity, while
HPLC determined 90% (area %) purity of 2,8-dihydroxy 8.
(All efforts should be taken to avoid contact with this
(16) Kendall, P. M.; Johnson, J. V.; Cook, C. E. J. Org. Chem. 1979, 44, 1421.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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419

bath until the solution temperature was 8 °C. The solids were
collected by filtration, washed with hexanes (200 mL), and
dried in an oven under house vacuum at 40 °C for 20 h.
There was obtained 79.3 g (79% isolated yield) of 2,8-bis-
silyl lactol 10, which was used in the next step without
further purification. 1H NMR (300 MHz, CDCl3) δ 0.23 (s,
12 H), 0.99 (s, 18 H), 3.03 (d, J ) 8.2, 1 H), 5.17 (m, 2 H),
6.36 (d, J ) 8.2, 1 H), 6.43 (d, J ) 2.4, 1 H), 6.47 (dd, J )
2.3, 8.0, 1 H), 6.54 (dd, J ) 2.3, 8.1, 1 H), 6.62 (d, J ) 2.3,
1 H), 6.95 (d, J ) 8.3, 1 H), 7.16 (d, J ) 8.4, 1 H). LC/MS
m/z 495 [(M - OH)H+], 513 (MH+), 535 (MNa+).
2,8-Bis(tert-butyldimethylsilyloxy)-5-[4-(2-(piperidin-
1-yl)ethoxy)phenyl]-5,11-dihydrochromeno[4,3-c]chro-
mene (12).8 A 5-L RBF was charged with the above crude
diol 11 (347.0 g) in toluene (2.9 L) and cooled to 17 °C.
Concentrated HCl (186 mL) was added dropwise via an
addition funnel at a rate to keep the temperature between 20
and 22 °C while cooling with an ice-water bath (LC/MS
analysis indicated that the reaction was complete in 20 min).
The reaction mixture was diluted with EtOAc (1 L) and
transferred to a 22-L three-neck separatory flask along with
additional EtOAc (4 L) and D.I. H2O (5 L). After phase
separation, the organic layer was washed with saturated
NaHCO3 (4 L) followed by brine (4 L) and then dried over
Na2SO4 (500 g). After filtration, the solvent was concentrated
to dryness to give the crude cyclized product 12 (218.0 g,
106.5% isolated yield), which was carried on to the next
step without further purification. 1H NMR (300 MHz, CDCl3)
δ 0.17 (s, 6 H), 0.19 (s, 6 H), 0.93 (s, 9 H), 0.96 (s, 9 H),
1.42 (m, 2 H), 1.58 (m, 4 H), 2.48 (m, 4 H), 2.73 (t, J )
6.0, 2 H), 4.03 (t, J ) 6.0, 2 H), 5.10 (dd, J ) 1.7, 13.8, 1
H), 5.29 (d, J ) 13.9, 1 H), 6.15 (s, 1 H), 6.29 (m, 2 H),
6.38 (m, 2 H), 6.71 (d, J ) 8.3, 1 H), 6.80 (d, J ) 8.4, 2 H),
6.88 (d, J ) 8.2, 1 H), 7.30 (d, J ) 8.6, 2 H). LC/MS m/z
701 (MH+), 723 (MNa+).
2,2-Dimethylpropionic Acid, 8-(2,2-Dimethylpropio-
nyloxy)-5-[4-(2-(piperidin-1-yl)ethoxy)phenyl]-5,11-dihy-
drochromeno[4,3-c]-chromene-2-yl ester (14).12 A 12-L
RBF was charged with a solution of crude 12 (218.0 g) in
THF (2.3 L). TBAF (626 mL, 0.626 mol, 1.0 M in THF)
was added via an addition funnel to the above solution over
20 min (the mixture started as a thick, orange solution and
changed to a red, homogeneous solution). The mixture was
stirred for an additional 30 min; the formation of 2,8-diol
13 was complete by this time as determined by HPLC and
LC/MDS. Pivaloyl chloride (115 mL, 0.93 mol) was added
over 12 min while an ice-water bath was used to maintain
the reaction temperature below 5 °C during this addition,
followed by Et3N (130 mL, 0.93 mol) over 10 min. The
mixture was stirred for an additional 30 min, while the
reaction progress was monitored by HPLC and LC/MS
analyses for the disappearance of 13 and the formation of
2,8-bis(2,2-dimethylpropanoate) 14. The solids were removed
by filtration, and the filtrate was concentrated to give a
mixture of crude 14 with other components (468.0 g). This
crude material 14 was dissolved in CH2Cl2 (5 L), transferred
to a 12-L three-neck separatory flask, and sequentially
washed with D.I. H2O (3 L × 6), saturated NaHCO3 (3.5
L), and brine (3.5 L) (the extraction was followed by LC/
MS to verify the near removal of the residual TBAF). The
CH2Cl2 layer was separated and concentrated to give a 2,8-
bis(2,2-dimethylpropanoate) 14 (184.0 g), which was further
slurried in IPA at 70 °C for 30 min to remove residual TBAF.
The slurry was cooled, and the solid was collected by
filtration. The filter cake was treated with IPA (350 mL),
and the resulting solid was washed with additional IPA (50
mL × 2) and dried under vacuum at 60 °C for 20 h to afford
pure 2,8-bis(2,2-dimethylpropanoate) 14 (133.4 g, 72%
isolated yield). 1H NMR (300 MHz, CDCl3) δ 1.31 (s, 9 H),
2-(4-(Hydroxy(4-(2-(piperidin-1-yl)ethoxy)phenyl)meth-
yl)-7-(tert-butyldimethylsilyloxy-2H-chromen-3-yl)-5-(tert-
butyldimethylsilyloxy)phenol (11). A 12-L Morton RBF
was placed under house vacuum and was heated to 100 °C
for at least 1 h prior to addition of any reagents, while the
attached components were dried with a heat gun. To the
above reaction flask via a cannula under a positive nitrogen
pressure was added 2-(4-bromophenoxy)ethyl piperidine
(19b) (189.25 g, 0.67 mol) followed by the addition of
anhydrous THF (1.5 L). The system was purged with
nitrogen by evacuating and filling with nitrogen (×3). The
addition funnel was charged with n-BuLi (2.5 M in hexane,
240 mL, 0.60 mol) via a cannula; during this time the
reaction flask was chilled in a dry ice-IPA bath. After the
internal temperature reached -75 °C, the n-BuLi was added
at a rate such that the internal temperature did not exceed
-72 °C. After the n-BuLi addition, the reaction was checked
for the extent of the lithium-bromine exchange to form 20b13
1
by H NMR (CDCl3) (used the integration of the starting
bromide doublet at δ 7.35 versus the ether methylene singlet
at δ 4.1), and more n-BuLi was added if the analysis showed
that it was needed. A solution of lactol 10 (150 g, 0.29 mol)
in anhydrous THF (6 L) was transferred to the addition funnel
portionwise (2 L × 3) and then was added at a rate such
that the internal reaction temperature did not exceed -70 °C.
After the addition was complete, the batch was allowed to
stir for 30 min and then was quenched with saturated NH4-
Cl (600 mL). The cooling bath was removed, and the mixture
was stirred while slowly warming to room temperature
overnight. The mixture was filtered to remove salts, and the
phases were separated; the flask and solids were rinsed with
EtOAc (200 mL), and the combined organic phases were
concentrated in vacuo. The resulting oil was diluted with
EtOAc (3 L), transferred to a 12-L separatory flask equipped
with an overhead stirrer, and agitated with D.I. H2O (3 L).
The layers were separated, and the mixture was subjected
to a second water wash followed by a brine (2 L) wash. The
aqueous layers were combined and back extracted with
EtOAc (1.5 L × 2), and the combined EtOAc solution was
concentrated at 60 °C to afford the crude diol 11 (347.0 g,
166.7% isolated yield) as orange oil, which was carried on
1
to the next step without further purification. H NMR (300
MHz, CDCl3) δ 0.15 (s, 6 H), 0.19 (s, 6 H), 0.91 (s, 9 H),
0.96 (s, 9 H), 1.45 (m, 2 H), 1.64 (m, 4 H), 2.53 (m, 4 H),
2.78 (t, J ) 6.0, 2 H), 4.12 (t, J ) 6.2, 2 H), 4.78 (m, 2 H),
5.63 (br s, 1 H), 6.31-6.42 (m, 4 H), 6.70-7.41 (m, 8 H),
7.08 (m, 4 H). LC/MS m/z 718 (MH+), 740 (MNa+).
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Vol. 11, No. 3, 2007 / Organic Process Research & Development

1.33 (s, 9 H), 1.42 (m, 2 H), 1.58 (m, 4 H), 2.47 (m, 4 H),
2.72 (t, J ) 5.8, 2 H), 4.03 (t, J ) 5.7, 2 H), 5.14 (d, J )
13.9, 1 H), 5.37 (d, J ) 14.0, 1 H), 6.20 (s, 1 H), 6.42-6.53
(m, 2 H), 6.61 (d, J ) 2.3, 1 H), 6.63 (dd, J ) 2.4, 8.4, 1
H), 6.77-6.82 (m, 3 H), 7.0 (d, J ) 8.4, 1 H), 7.31 (d, J )
8.5, 2 H). LC/MS m/z 640 (MH+), 662 (MNa+).
gave 34.12 g (121% yield) of crude material, which after
flash chromatographic purification (Si2O, eluted with EtOAc/
hexane/MeOH/NH4OH, 45/45/10/0.2 to 65/20/15/0.5) af-
forded 14.9 g (52% yield, over three steps) of 2,8-diol 13 as
a brown-cherry solid (mp 178-180 °C, decomposition). 1H
NMR (300 MHz, acetone-d6) δ 1.36 (m, 2 H), 1.49 (m, 4
H), 2.42 (m, 4 H), 2.63 (t, J ) 5.6, 2 H), 4.05 (t, J ) 5.8,
2 H), 5.04 (dd, J ) 1.7, 13.9, 1 H), 5.36 (d, J ) 14.0, 1 H),
6.12 (d, J ) 2.4, 2 H), 6.21 (dd, J ) 2.4, 8.3, 1 H), 6.23 (d,
J ) 2.3, 1 H), 6.28 (dd, J ) 2.4, 8.4, 1 H), 6.71 (d, J ) 6.7,
3 H), 7.00 (d, J ) 8.0, 1 H), 7.32 (d, J ) 8.1, 2 H), 7.96-
9.10 (br s, 2 H). LC/MS m/z 472 (MH+), 494 (MNa+).
1-[2-(4-Bromophenoxy)ethyl]piperidine (19b).3,10 A 5-L
RBF was charged with acetone (2.5 L), D.I. H2O (25 mL),
4-bromophenol (98%, 150.0 g, 0.867 mol), 1-(2-chloroethyl)-
piperidine monohydrochloride (98%, 159.6 g, 0.867 mol),
and potassium carbonate (99%, 325 mesh, 239.7 g, 1.734
mol) under nitrogen with agitation. The mixture was heated
to reflux (56 °C) for 3 h. The progress of the reaction was
followed by TLC and LC/MS. After filtration, the solvent
was removed in vacuo, and the resulting oil was diluted in
EtOAc (2 L), washed with 1 N NaOH solution (2 L), and
washed with brine (2 L × 2). Concentration of the solvent
afforded 234.0 g (95% isolated yield) of bromide 19b, which
was placed under high vacuum (∼20 mmHg) at 22 °C for
(5S)-2,2-Dimethylpropionic Acid, 8-(2,2-Dimethylpro-
pionyloxy)-5-[4-(2-(piperidin-1-yl)ethoxy)phenyl]-5,11-di-
hydrochromeno[4,3-c]-chromene-2-yl ester (21). The op-
tical purity was determined on an Agilent series 1100 system
at UVmax ) 254 and 340 nm, using a CHIRALPAK AD
column (2.1 mm i.d. × 150 mm, 3.5 µ) at 40 °C with flow
rate of 0.5 mL/min and run time of 12 min with IPA (100%).
Preparative chiral separation of racemate 14 (569.0 g) was
conducted by using a CHIRALPAK AD column (5 cm i.d.
× 50 cm, 20 µ) at 20 °C with flow rate of 90 mL/min and
run time of 30 min with IPA (100%), which afforded 257.8
g of pure (5S)-21 as beige, amorphous solid with 98.5% of
chemical purity and 99.6% ee optical purity (chiral HPLC
retention time ) 3.83 min), mp 213-214 °C (decomposi-
tion). [R] ) +72.0°, (c ) 0.30 g/100 mL in CHCl3 at 20 °C,
589 nm). LC/MS m/z 640.3 (MH+). Anal. Calcd for C39H45-
NO7: C, 73.22; H, 7.09; N, 2.19. Found: C, 73.00; H, 7.22;
N, 2.13. In addition to the above material, there was obtained
239.9 g of pure (5R)-enantiomer 22 as an off-white
amorphous solid with 99.0% of chemical purity and 99.5%
ee of optical purity (chiral HPLC retention time ) 2.22 min),
mp 208-209 °C (decomposition). [R] ) -73.4°, (c ) 0.31
g/100 mL in CHCl3 at 20 °C, 589 nm). LC/MS m/z 640.3
(MH+). Anal. Calcd for C39H45NO7: C, 73.22; H, 7.09; N,
2.19. Found: C, 73.09; H, 7.17; N, 2.20.
1
18 h and used without further purification. H NMR (300
MHz, CDCl3) δ 1.44 (m, 2 H), 1.61 (m, 4 H), 2.52 (t, J )
5.8, 4 H), 2.74 (t, J ) 6.0, 2 H), 4.08 (t, J ) 6.1, 2 H), 6.78
(d, J ) 8.2, 2 H), 7.34 (d, J ) 8.3, 2 H). LC/MS m/z 284
+
(MH+), 286 [(M + 2)H ].
5-[4-(2-(Piperidin-1-yl)ethoxy)phenyl]-5,11-dihydro-
chromeno[4,3-c]-chromene-2,8-diol (13). A 5-L RBF was
charged with a solution of compound 12 (42.0 g, 0.06 mol)
in anhydrous THF (1.5 L). Tetrabutylammonium fluoride (1.0
M in THF, 120 mL, 0.12 mol) was added dropwise over a
5-min period. The mixture was stirred at 20 °C for 20 min,
while the progress of the reaction was monitored by HPLC
and LC/MS. After completion, an ice-cooled 1 M H3PO4
(1.5 L) solution was added to the above reaction and stirred
vigorously for 3 min. The acidic solution was transferred to
a 12-L three-neck separatory funnel and extracted with
EtOAc (4.0 L, 2.0 L × 2); the organic phases were combined
and washed with brine (1.5 L). Solvent removal in vacuo
Acknowledgment
We thank Mr. Jeffery Proost for technical support in chiral
separation in Beerse, Belgium, and Dr. Andras Horvath for
helpful discussions on the step 1 chemistry.
Note Added after ASAP Publication: There were pro-
duction errors in Table 2 and the Scheme 4 footnote in the
version published on the Web March 31, 2007. The correct
version posted April 5, 2007 and the print version are correct.
Received for review January 26, 2007.
OP700020F
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