Practical asymmetric synthesis of a γ-secretase inhibitor exploiting substrate-controlled intramolecular nitrile oxide-olefin cycloaddition

Article abstract of DOI:10.1021/jo060033i

A practical asymmetric synthesis of the γ-secretase inhibitor (-)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspect

Full text of DOI:10.1021/jo060033i

Practical Asymmetric Synthesis of a γ-Secretase Inhibitor Exploiting
Substrate-Controlled Intramolecular Nitrile Oxide-Olefin
Cycloaddition
Jeremy P. Scott,*,† Steven F. Oliver,*,† Karel M. J. Brands,† Sarah E. Brewer,†
Antony J. Davies,† Andrew D. Gibb,† David Hands,† Stephen P. Keen,† Faye J. Sheen,†
Robert A. Reamer,‡ Robert D. Wilson,† and Ulf-H. Dolling‡
Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road,
Hoddesdon, Hertfordshire EN11 9BU, United Kingdom, and Department of Process Research,
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065
jeremy_scott@merck.com; steVen_oliVer@merck.com
ReceiVed January 6, 2006
A practical asymmetric synthesis of the γ-secretase inhibitor (-)-1 is described. As the key transformation,
a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole
core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an
isoxazole to form a cis-γ-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct
a sultam ring, and the R-alkylation of a sultam with excellent diastereoselectivity. In each instance, the
relative stereochemistry was evolved by way of substrate-based induction with g96% ds. Kilogram
quantities of the targeted drug candidate (-)-1 were obtained, without recourse to chromatography, by
way of 10 isolated intermediates and in 13% overall yield.
Introduction
development. We report herein an efficient and practical
asymmetric synthesis of 1 that is amenable to multikilogram
operation.
Alzheimer’s disease (AD) is a progressive and chronic
neurodegenerative disease that leads to loss of intellect and
memory in those afflicted. AD affects around 4.5 million people
in the U.S. and 18 million people worldwide, and with the
limited therapies currently available, this represents a major
unmet medical need. One of the main pathological characteristics
of this disease is the production of the 40-42 amino acid
amyloid-â (Aâ) peptide,1 in which the protease enzyme γ-secre-
tase plays a critical role through cleavage of the â-amyloid
precursor protein (âAPP). γ-Secretase, therefore, represents a
potential target for AD therapeutic intervention, and as part of
a program at Merck directed toward the identification of
inhibitors of this enzyme,2 (-)-1 was selected for further
Results and Discussion
Retrosynthetic Analysis. γ-Secretase inhibitor 1 represents
a significant synthetic challenge (Scheme 1). Key structural
elements include a trisubstituted octahydro-1H-2,1-benzothiaz-
ine-2,2-dioxide core and an uncommon, sulfone-bearing carbon
as one of four stereogenic centers. Our approach to the synthesis
sought to exploit the tertiary sulfone stereocenter to control all
relative stereochemistry in the molecule (Scheme 1).
† Merck Sharp & Dohme Research Laboratories.
‡ Merck Research Laboratories.
(1) (a) Jhee, S.; Shiovitz, T.; Crawford, A. W.; Cutler, N. R. Expert Opin.
InVest. Drugs 2001, 10, 593-605. (b) Sambamurti, K.; Grieg, N. H.; Lahiri,
D. K. NeuroMol. Med. 2002, 1, 1-31. (c) Hardy, J.; Higgins, G. A. Science
1992, 256, 184-185. (d) Tsai, J.-Y.; Wolfe, M. S.; Xia, W. Curr. Med.
Chem. 2002, 9, 1087-1106.
10.1021/jo060033i CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/11/2006
3086
J. Org. Chem. 2006, 71, 3086-3092

Synthesis of a γ-Secretase Inhibitor
a
SCHEME 1. Retrosynthetic Analysisa
SCHEME 2
a Conditions: (a) 2 M NaOH, EtOH, T e 15 °C. (b) H2O2, AcOH, 40
°C.
SCHEME 3 a
a Ar1 ) 4-trifluoromethylphenyl; Ar2 ) 2,5-difluorophenyl.
With late-stage construction of the sultam ring and substrate-
controlled installation of the pendant ethyl substituent, γ-amino
alcohol derivative 2 was identified as a key intermediate. This
γ-amino alcohol enables an intramolecular [3+2] nitrile oxide-
olefin cycloaddition (INOC)3 disconnection by way of isox-
azoline 3, generated from oximes 4. These in turn would be
accessible from the dioxolane-bearing tertiary sulfone 5, itself
available by sequential alkylations of benzylaryl sulfone 6. In
the forward sense, analysis of the likely stereochemical outcome
of the three key diastereoselective transformations (INOC,
isoxazoline reduction, and ethylation) led us to expect the desired
stereochemistry to evolve with substrate control relative to the
tertiary sulfone in 5. The enantioselective synthesis of 1 would,
therefore, require either the preparation of a single enantiomer
of 5 or a classical resolution.
Construction of the Cycloaddition Precursor. Our synthesis
began with the alkylation of commercially available 4-trifluo-
romethylthiophenol with 2,5-difluorobenzyl bromide (Scheme
2). A highly practical procedure involving the generation of the
sodium thiolate with NaOH in aqueous EtOH and the addition
of the bromide led to the desired sulfide 7 in excellent yield
(99%). Oxidation to the corresponding sulfone 6, using H2O2
a Conditions: (a) KOt-Bu, 2-(2-bromoethyl)-1,3-dioxolane, DMSO, T
< 20 °C. (b) KOt-Bu, allyl bromide, DMSO, T < 25 °C. Ar1
4-trifluoromethylphenyl; Ar2 ) 2,5-difluorophenyl.
)
in AcOH, proceeded in high yield (98%). In both of these
processes, the crystalline product is filtered directly from the
reaction mixture without extractive workup.
The screening of solvent, base, and reagent stoichiometry led
to the rapid definition of a practical one-pot procedure for the
preparation of rac-5 (Scheme 3). Exposing benzylaryl sulfone
6 to KOt-Bu in DMSO at ambient temperature, followed by
the addition of 2-(2-bromoethyl)-1,3-dioxolane, afforded
monoalkylated 8. This intermediate was not isolated but was
directly alkylated further by the formation of the anion with
KOt-Bu in DMSO and quenching with allyl bromide. On
addition of water, the desired rac-5 could be crystallized directly
from the reaction mixture in 79% overall yield. A reverse-
addition protocol for the allylation step minimized the formation
of the diene byproduct 9, which was otherwise significant (up
to 35%). Symmetrical dialkylated products 10 and 11 were only
formed at low levels (<2%).
Several approaches to an enantioselective synthesis of 5 were
investigated in parallel, with emphasis on the asymmetric
allylation of alkyl sulfone 8. Despite the wealth of Pd- and Mo-
catalyzed asymmetric allylic alkylation processes reported,4,5
no examples relate to chiral tertiary sulfone formation. Following
an extensive ligand and precatalyst screen, Pd-catalyzed bond
(2) (a) Shaw, D. E.; Best, J. D.; Dinnell, J.; Nadin, A.; Shearman, M.
S.; Pattison, C.; Peachey, J.; Reilly, M. A.; Williams, B. J.; Wrigley, J. D.
J.; Harrison, T. Biorg. Med. Chem. Lett. Submitted for publication. (b)
Churcher, I.; Beher, D.; Best, J. D.; Castro, J. L.; Clarke, E. E.; Gentry, A.;
Harrison, T.; Hitzel, L.; Kay, E.; Kerrad, S.; Lewis, H. W.; Morentin-
Gutierrez, P.; Mortishire-Smith, R.; Oakley, P. J.; Reilly, M.; Shaw, D. E.;
Shearman, M. S.; Teall, M. R.; Williams, S.; Wrigley, J. D. J. Biorg. Med.
Chem. Lett. 2006, 16, 280-284. (c) Teall, M.; Oakley, P.; Harrison, T.;
Shaw, D.; Kay, E.; Elliot. J.; Gerhard, U.; Castro, J. L.; Shearman, M.;
Ball, R. G.; Tsou, N. N. Biorg. Med. Chem. Lett. 2005, 15, 2685-2688.
(d) Churcher, I.; Ashton, K.; Butcher, J. W.; Clarke, E. E.; Harrison, T.;
Lewis, H. D.; Owens, A. P.; Teall, M. R.; Williams, S.; Wrigley, J. D. J.
Biorg. Med. Chem. Lett. 2003, 13, 179-183. (e) Churcher, I.; Williams,
S.; Kerrad, S.; Harrison, T.; Castro, J. L.; Shearman, M. S.; Lewis, H. D.;
Clarke, E. E.; Wrigley, J. D. J.; Beher, D.; Tang, Y. S.; Liu, W. J. Med.
Chem. 2003, 46, 2275-2278.
(4) (a) Trost, B. M. J. Org. Chem. 2004, 69, 5813-5837. (b) Trost, B.
M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921. (c) Trost, B. M.; Lee, C.
B. In Catalytic Asymmetric Synthesis II; Ojima, I., Ed.; Wiley-VCH: New
York, 2000; Chapter 8E, pp 593-650. (d) Pfaltz, A.; Lautens, M. In
ComprehensiVe Asymmetric Catalysis II; Jacobsen, E. N., Pfaltz, A.,
Yamomoto, H., Eds.; Springer: Berlin, 1999; Chapter 24, pp 833-884.
(5) (a) Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104-
1105. (b) Trost, B. M.; Dogra, K.; Franzini, M. J. Am. Chem. Soc. 2004,
126, 1944-1945. (c) Belda, O.; Moberg, C. Acc. Chem. Res. 2004, 37,
159-167.
(3) Reviews: (a) Jager, V.; Colinas, P. A. In Synthetic Applications of
1,3-Dipolar Cycloaddition Chemistry Towards Heterocycles and Natural
Products; Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons: New
Jersey, 2003; Chapter 6. (b) Kozikowski, A. P. Acc. Chem. Res. 1984, 17,
410-416. (c) Kanemasa, S.; Tsuge, O. Heterocycles 1990, 30, 719-736.
J. Org. Chem, Vol. 71, No. 8, 2006 3087

Scott et al.
SCHEME 4 a
SCHEME 5 a
a Conditions: (a) DIBAH, THF, -5 °C, and then 50 °C. Ar1
4-trifluoromethylphenyl; Ar2 ) 2,5-difluorophenyl.
)
ous cycloaddition. The addition of water then allowed for direct
crystallization of the desired cis-isoxazoline 3 in 84% yield for
this unprecedented four-step one-pot sequence.12 An examination
of the crude reaction mixtures indicated that even at 50 °C 3
was formed with 96% ds,13 and the diastereocontrol observed
was consistent with the expected preferred transition state TS-1
(Scheme 4).14
a Conditions: (a) NH2OH‚HCl, EtOH, H2O, 70 °C. (b) Chloramine-T
hydrate, EtOH, H2O, 50 °C. Ar1 ) 4-trifluoromethylphenyl; Ar2 ) 2,5-
difluorophenyl.
formation to afford 5 was found to be possible under both neutral
and basic conditions, however, all products were racemic.6
Phase-transfer-catalyzed allylation of rac-8 was also evaluated
without significant success.7 As a final approach, it was
speculated that possible low-temperature configurational stabil-
ity8 of anions derived from (R)- or (S)-8 would allow for
allylation with minimal racemization. In studies using discrete
enantiomers of 8,9 complete racemization was observed at -78
°C within 1 min under a range of conditions (solvent, additive,
and concentration).10 The in situ generation of the anion in the
presence of allyl bromide also yielded racemic product. In the
absence of a route to chiral 5, attention shifted to employing a
classical resolution of amino alcohol 2 to define the absolute
stereochemistry.
Intramolecular Nitrile Oxide-Olefin Cycloaddition (INOC)
and Amino Alcohol Synthesis. Formation of isoxazoline 3 from
tertiary sulfone 5 was envisaged by the deprotection of the
dioxolane functionality, a conversion to the corresponding
oximes 4, an oxidation to the nitrile oxide, and a subsequent
cycloaddition (Scheme 4). Initial studies of the acid-catalyzed
deprotection of dioxolane 5 were problematic, with incomplete
conversions and competitive degradation of aldehyde 12. It was,
however, found that exposing 5 to NH2OH‚HCl in EtOH/H2O
at 70 °C for 2 h led directly to oximes 4 (1:1 E/Z), obviating
the need to isolate 12. Interestingly, on cooling to 50 °C and
adding chloramine-T11 to this product mixture, an in situ
oxidation to the nitrile oxide occurred, followed by a spontane-
A diastereoselective reduction of 3 to give amino alcohol 2
was expected to ensue through a sterically preferred exo
approach to the isoxazoline of 3, provided the imine moiety
was reduced prior to the N-O bond cleavage. While LiBH4,
BH3‚Me2S, and Red-Al were promising, DIBAH proved to be
the optimum reagent for this purpose, and a practical one-pot
process was developed (Scheme 5).15 The exposure of 3 to
DIBAH (2.25 equiv) in THF at T < 0 °C afforded N-
aluminoisoxazolidine 13 with excellent diastereocontrol (98.6%
ds).13 Heating this mixture to 50 °C then triggered N-O bond
cleavage to afford 2 in 82% yield, following an aqueous workup
to remove aluminum residues.16
With racemic 2 in hand, a survey of readily available chiral
acids for a classical resolution was performed. Both dibenzoyl-
and ditoluoyltartaric acids were promising leads, and the former
was evaluated in detail (Table 1).17 The dibenzoyl-D-hemitartrate
salt of 2 was found to be the best. The performance of the
resolution proved to be critically dependent on the use of
ethereal solvents such as THF or DME (entries 2 and 5),
possibly as the result of solvate formation.18 Interestingly, amino
alcohol 2 could also be successfully resolved using just 0.25
equiv of dibenzoyl-D-tartaric acid, however, yields were sig-
nificantly reduced (entries 3 and 6).
Sultam Ring Synthesis and Final Elaboration. Our pro-
posed routes to the sultam ring of 1 were based on methodology
(6) Summary of Pd-screening results: The diphosphines (S,S)-Et-DuPhos,
(S,S)-Chiraphos, (S,S)-Diop, (S,S)-Dipamp, t-BuJOSIPHOS, and (R,R)-
Norphos with LHMDS, Pd(allyl)2, and allyl acetate afforded conversion to
5 (57-80%) in all cases racemically.
(7) (a) O’Donnell, M. J. In Catalytic Asymmetric Synthesis, 2nd ed.;
Oijima, I., Ed.; Wiley-VCH: New York, 2000; Chapter 10, pp 727-755.
(b) Lygo, B. Rodd’s Chemistry of Carbon Compounds; Elsevier: Oxford,
U.K., 2001; Vol. 5, pp 101-149. (c) Jones, R. A. Quaternary Ammonium
Salts. Their Use in Phase-Transfer Catalysis; Academic Press: London,
2001.
(8) (a) Gais, H.-J.; Hellmann, G.; Gunther, H.; Lopez, F.; Lindner, H.
J.; Braun, S. Angew. Chem., Int. Ed. Engl. 1989, 28, 1025-1027. (b) Raabe,
G.; Gais, H.-J.; Flesichhauer, J. J. Am. Chem. Soc. 1996, 118, 4622-4630.
(c) Corey, E. J.; Konig, H.; Lowry, T. H. Tetrahedron Lett. 1962, 84, 515-
520.
(9) A preparative separation of the enantiomers of 8 was accomplished
using 5% IPA in supercritical CO2 (Chiralcel OD-H, 70 mL/min, 35 °C,
100 bar).
(12) Low levels (<1%) of competitive dehydration of the oximes 4 to
the corresponding nitrile were observed in this process, and the latter was
the major product when operating in EtOH in the absence of added water.
(13) Diastereoselection was determined by a reverse-phase HPLC assay
of unpurified samples of the reaction mixtures. The undesired diastereoi-
somer remained in the mother liquors such that the isolated solid was >99%
de.
(14) Related diastereocontrol in an INOC has been reported: Kozikowski,
A. P.; MaloneyHuss, K. E. Tetrahedron Lett. 1985, 26, 5759-5762.
(15) Although the one-pot diastereoselective reduction of an isoxazoline
to the corresponding γ-amino alcohol has been reported, an N-metalloisox-
azolidine intermediate was not explicitly implicated: Burri, K. F.; Cardone,
R. A.; Chen, W. Y.; Rosen, P. J. Am. Chem. Soc. 1978, 100, 7069-7071.
(16) Compound rac-14 can be prepared using 1.2 equiv of DIBAH in
CH2Cl2 (-50 °C). This solvent efficiently suppresses any subsequent N-O
bond cleavage, which occurs on extended aging in THF.
(17) Other chiral acids that were screened (malic, tartaric, abietic, aspartic,
glutamic, CSA, and mandelic) led to no crystalline material or the isolated
salt was racemic.
(18) Whilst the microscope examination of the intially formed slurries
indicated crystalline material with needle morphology, the dry solid (45
°C in vacuo) is amorphous by XRPD, likely a result of desolvation.
(10) The extent of the deprotonation of enantioenriched 8 (as determined
by deuterium quenching) was found to closely correlate with the ee of the
recovered 8, and in situ trapping with allyl iodide afforded only rac-5.
(11) Hassner, A.; Rai, K. Synthesis 1989, 57-59.
3088 J. Org. Chem., Vol. 71, No. 8, 2006

Synthesis of a γ-Secretase Inhibitor
TABLE 1. Study of Dibenzoyl-D-tartaric Acid Stoichiometry with rac-2 in THF and DME
equiv of
dibenzoyl-D-tartaric acid
solvent
isolated yield (%)
of hemitartrate salt
ee of isolated
solida (%)
entry
(mL g-1
)
1
2
3
4
5
6
1.0
0.5
0.25
1.0
0.5
THF (10)
THF (10)
THF (10)
DME (10)
DME (10)
DME (10)
38
42
36
44
42
36
73
87
94
95
98
98
0.25
a Enantiomeric excess determined by acetylation and HPLC assay.
SCHEME 6. Proposed Sultam Ring Constructionsa
SCHEME 7 a
a Ar1 ) 4-trifluoromethylphenyl; Ar2 ) 2,5-difluorophenyl.
a Conditions: (a) NaOH, CH2Cl2, 25 °C, and then Ms2O, Et3N, T < 10
°C. (b) NaBr, DMF, 85 °C. Ar1 ) 4-trifluoromethylphenyl; Ar2 ) 2,5-
difluorophenyl.
previously reported from these laboratories for the construction
of sultams via sulfonamide dianion alkylation (Scheme 6).19 In
route A, diastereoselective R-ethylation of sultam 15, or an
appropriate N-protected derivative, would be required to arrive
at 1.20,21 This would be preceded by the cyclization of the N,C-
dianion generated from γ-bromomethanesulfonamide 16, in turn
derived from γ-amino alcohol 2. In the more convergent
approach (route B), a diastereoselective cyclization of an N,C-
dianion of propanesulfonamide derivative 17 would be required.
Despite extensive efforts, the latter cyclizations (17: X ) Br,
Cl, I, OTs, or benzenesulfonate) were found to be only
moderately diastereoselective (e69% ds).
SCHEME 8 a
a Conditions: (a) LDA, THF, T < -45 °C. (b) H2O, and then PMBCl,
DMAc, NaI, 25 °C. Ar1 ) 4-trifluoromethylphenyl; Ar2 ) 2,5-difluoro-
phenyl.
formation. No azetidine byproduct 20 was detected in the
preparation of 16.
The desired sultam ring precursor was prepared from γ-amino
alcohol 2 by O- and N-mesylation, followed by bromide
displacement (Scheme 7).19 Thus, exposure of the resolved
hemitartrate salt of 2 to a biphasic mixture of NaOH and CH2-
Cl2, separation of the free base containing organic layer,
followed by the addition of methanesulfonic anhydride and Et3N
afforded bismesylate 18. This was not isolated, but aged with
NaBr at elevated temperature following a solvent exchange to
DMF. The addition of H2O then allowed the direct crystallization
of 16 from the reaction mixture in excellent yield (91%). The
cyclization behavior of 16 had been demonstrated to be superior
to 19,22 and our use of Ms2O over MsCl was, therefore, guided
by our desire to suppress the formation of 19. Chloride 19 was
always observed during the bromide displacement if MsCl had
been employed (as a result of presumed chloride carry over)
and was found to be responsible for downstream byproduct
The addition of a THF solution of bromide 16 to LDA at T
< -45 °C led to a clean cyclization to N-lithiosultam 21 with
no competitive formation of azetidine 20 (Scheme 8).23 Previ-
ously, we had shown that the direct ethylation of a dianion
derived from sultam 15 was not viable to access 1.24 For this
reason, 21 was protected in situ as the p-methoxybenzyl (PMB)
derivative by quenching the excess LDA with a minimum of
H2O, followed by the addition of 4-methoxybenzyl chloride and
sodium iodide in N,N-dimethylacetamide (DMAc). After over-
night aging at ambient temperature, the conversion of 21 was
complete and sultam 22 could be isolated in 89% yield.
The introduction of the final ethyl substituent was initially
problematic due to significant degradation of the anion of 22
at -40 °C. This instability was compounded by a slow
alkylation rate with EtI and unsatisfactory diastereoselection at
this temperature. An in situ trapping protocol was, therefore,
pursued, in which the EtI was added prior to any base. A striking
(19) Lee, J.; Zhong, Y.-L.; Reamer, R. A.; Askin, D. Org. Lett. 2003, 5,
4175-4177.
(20) Kaiser, E. M.; Knutson, P. L. A. J. Org. Chem. 1975, 40, 1342-
1346.
(23) Azetidine 20 can be readily prepared by the cyclization of 16 with
KOt-Bu in THF at 40 °C.
(21) Thompson, M. E. J. Org. Chem. 1984, 49, 1700-1703.
(22) Bromide 16 undergoes cyclization a temperature 20 °C cooler (-50
compared to -30 °C) than chloride 19 using LDA, affording a consequently
improved impurity profile in isolated 22.
(24) An attempted direct ethylation of sultam 15 was thwarted by our
inability to prepare the N,C-dianion, as indicated by deuterium incorporation
studies. Profiles of deprotonations were also unsatisfactory at higher
temperatures, presumably a result of competing aryl C-H abstraction.
J. Org. Chem, Vol. 71, No. 8, 2006 3089

Scott et al.
SCHEME 9 a
alcohol by sequential imine and N-O bond reduction (3 f 2);
and (3) acidic deprotection of a PMB-protected sulfonamide
using thioglycolic acid as an efficient cation scavenger. The
developed route is notable for the control of relative stereo-
chemistry, with the three diastereoselective transformations
proceeding with g96% ds under substrate-based induction in
each instance.
Experimental Section
1,4-Difluoro-2-({[4-(trifluoromethyl)phenyl]thio}methyl)-
benzene (7). 4-Trifluoromethylthiophenol (10.0 kg, 56.1 mol) was
dissolved in EtOH (20.5 L) and cooled to 13 °C. Aqueous sodium
hydroxide (2 M, 37.6 L, 75.2 mol) was added over 30 min,
maintaining T e 15 °C. The resultant solution was aged for 15
min at 15 °C, and then a solution of 2,5-difluorobenzylbromide
(11.4 kg, 55.1 mol) in EtOH (9.0 L) was added dropwise over 1 h,
with T e 15 °C. The resultant slurry was cooled to 13 °C, and
water (41.0 L) was added over 15 min at e15 °C. Filtration,
washing of the product cake with EtOH/H2O (1:2, 23.0 L) and water
(2 × 23.0 L), and drying in vacuo at 40 °C for 18 h furnished the
a Conditions: (a) NaHMDS, EtI, THF, T < 1 °C. (b) MsOH, HSCH2CO2H,
CH2Cl2, T < 5 °C. Ar1 ) 4-trifluoromethylphenyl; Ar2 ) 2,5-difluorophenyl.
metal counterion effect was observed. With the slow addition
of NaHMDS at T < 1 °C to a THF solution of 22 and EtI, 24
formed with excellent diastereoselectivity (99.4% ds; Scheme
9). Following an aqueous workup and crystallization, pure 24
could be isolated in 90% yield. In contrast, the substitution of
NaHMDS with LHMDS in the identical process led to formation
of 10% of the undesired diastereomer 25. Although the sense
of diastereoselection is consistent with the sterically most
favorable exo approach to the cis-bicyclic core, the origin of
the dramatic counterion effect is currently not understood in
detail.25
To control the final impurity levels, a robust procedure for
the cleavage of the PMB group from 24 was required. An initial
survey of acid-mediated deprotection in aprotic solvents indi-
cated that, although high yields of 1 were readily obtained, they
were typically accompanied by a myriad of PMB-derived
byproducts. Speculating that an inefficient capture of the cation
resulting from the PMB cleavage was occurring, a screen of
sulfur-containing additives was initiated.26 Thioglycolic acid
(HSCH2CO2H) performed particularly well, and exposing 24
to 4.0 equiv of this additive with 3.0 equiv of MsOH in CH2-
Cl2 cleanly afforded 1 in quantitative assay yield (Scheme 9).
This procedure had the additional benefit that the resulting
byproduct 26 could be efficiently removed by a simple wash
with aqueous base. Following crystallization, the desired drug
candidate 1 could be isolated in 89% yield as an analytically
pure compound.27,28
1
title compound as a white solid (16.6 kg, 99%). H NMR (400
MHz, DMSO-d6) δ 7.64 (2H, d, J ) 8.3 Hz), 7.55 (2H, d, J ) 8.3
Hz), 7.27 (2H, m), 7.16 (1H, m), 4.36 (2H, s); 13C NMR (100 MHz,
DMSO-d6) δ 158.3 (dd, J ) 2.2, 241.0 Hz), 156.9 (dd, J ) 2.4,
242.1 Hz), 141.9 (q, J ) 1.5 Hz), 128.4, 126.2 (q, J ) 3.8 Hz),
126.7 (q, J ) 32.0 Hz), 124.5 (q, J ) 271.7 Hz), 126.4 (dd, J )
8.4, 17.6 Hz), 117.7 (dd, J ) 4.0, 24.8 Hz), 117.4 (dd, J ) 8.8,
24.6 Hz), 116.4 (dd, J ) 8.6, 24.0 Hz), 29.7; mp 52-54 °C; Anal.
Calcd for C14H9F5S: C, 55.26; H, 2.98. Found: C, 54.85; H, 2.94.
1,4-Difluoro-2-({[4-(trifluoromethyl)phenyl]sulfonyl}methyl)-
benzene (6). To a stirred solution of sulfide 7 (12.2 kg, 40.1 mol)
dissolved in acetic acid (58 L) at ambient temperature was added
hydrogen peroxide (5.05 kg, 27.5% w/t, 40.1 mol) over 35 min.
The reaction was heated to 30 °C and aged at this temperature for
3 h. Further hydrogen peroxide (12.1 kg, 27.5% w/t, 96.2 mol)
was added over 30 min, and then the mixture was aged at 40 °C
for 18 h. The resultant slurry was cooled to <35 °C, and water (98
L) was added over 30 min. The slurry was aged 30 min at 25 °C
and then filtered. The cake was washed with water (5 × 31 L) and
then dried in vacuo at 45 °C to afford the title compound as a white
solid (13.3 kg, 98%). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (2H,
d, J ) 8.7 Hz), 7.99 (2H, d, J ) 8.7 Hz), 7.24 (2H, m), 7.15 (1H,
m), 4.86 (2H, s); 13C NMR (100 MHz, DMSO-d6) δ 157.9, (dd, J
) 2.2, 240.7 Hz), 157.5 (dd, J ) 2.4, 245.1 Hz), 142.4, 134.2 (q,
J ) 32.6 Hz), 129.8, 126.9 (q, J ) 3.8 Hz), 123.7 (q, J ) 272.7
Hz), 119.8 (dd, J ) 3.4, 25.0 Hz), 118.2 (dd, J ) 8.7, 24.0 Hz),
117.8 (dd, J ) 9.0, 18.0 Hz), 117.5 (dd, J ) 9.0, 24.8 Hz), 54.7;
mp 119-120 °C; Anal. Calcd for C14H9F502S: C, 50.00; H, 2.70.
Found: C, 49.92; H, 2.72.
In summary, we have developed a practical asymmetric route
to the γ-secretase inhibitor 1, proceeding by way of 10 isolated
intermediates (13% overall yield) and exploiting a diastereo-
selective INOC as key step. Aspects of the route which are of
potentially more general synthetic utility follow: (1) the use of
a dioxolane moiety as a masked nitrile oxide, exemplified by
the transformation of 5 f 3; (2) conditions for the one-pot
diastereoselective reduction of an isoxazoline to the γ-amino
2-(3-(2,5-Difluorophenyl)-3-{[4-(trifluoromethyl)phenyl]-
sulfonyl}hex-5-en-1-yl)-1,3-dioxolane (5). Sulfone 6 (12.70 kg,
37.8 mol) in DMSO (33.8 L) was added to a solution of potassium
tert-butoxide (4.66 kg, 41.5 mol) in DMSO (17 L) maintaining T
< 25 °C. The resultant mixture was cooled to 15 °C, and 2-(2-
bromoethyl)-1,3-dioxolane (7.85 kg, 43.4 mol) was added while
maintaining T < 20 °C. The reaction mixture was aged at ambient
temperature for 105 min and then cooled to 15 °C, and a solution
of potassium tert-butoxide (6.77 kg, 60.3 mol) in DMSO (23.8 L)
was added. The mixture was aged for 30 min and then added to a
solution of allyl bromide (16.0 kg, 132 mol) in DMSO (34.8 L)
while maintaining T < 25 °C. Water (36.0 L) was added at ambient
temperature. The resultant slurry was filtered, and the solid was
washed with a 2:1 mixture of DMSO/H2O (16 kg) and then water
(2 × 15 kg). Drying in vacuo afforded the title compound as a
(25) The observed diastereoselection is kinetic in origin under the
conditions used, as prolonged aging in the presence of the 0.4 equiv of
excess LHMDS or NaHMDS employed does not lead to any change in the
ratio of 24:25. In addition, under conditions of thermodynamic equilibration
(KOt-Bu/t-BuOH, 80 °C), a 1:1 mixture of 24 and 25 afforded only a 97:3
ratio favoring 24.
(26) Other trapping agents evaluated were thiourea, thiosemicarbazide,
2-thiobenzoic acid, L-methionine, and thioanisole. The use of protic solvents
EtOH or IPA with 6 or 12 M HCl afforded high assay yields of 1, however,
impurity profiles were unsatisfactory.
(27) The PMB ether can also be removed by catalytic hydrogenolysis
using a Degussa E101 NE/W, 20% Pd, 50% H2O catalyst (70 psi, MeOH/
AcOH, 10% w/t dry basis relative to 24).
(28) The absolute stereochemistry of (-)-1 was confirmed by X-ray
crystallography. See Supporting Information.
1
white solid (14.2 kg, 79%). H NMR (400 MHz, CDCl3) δ 7.67
(d, J ) 8.0 Hz, 2H), 7.57 (d, J ) 8.0 Hz, 2H), 7.07 (m, 2H), 6.82
(ddd, J ) 4.8, 9.0, 12.2 Hz, 1H), 5.92 (m, 1H), 5.28 (dq, J ) 1.6,
3090 J. Org. Chem., Vol. 71, No. 8, 2006

Synthesis of a γ-Secretase Inhibitor
17.0 Hz, 1H), 5.20 (dq, J ) 1.4, 10.2 Hz, 1H), 4.91 (t, J ) 4.4 Hz,
1H), 3.93 (m, 4H), 3.30 (m, 1H), 3.12 (m, 1H), 2.51 (m, 2H), 2.02
(m, 1H), 1.58 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.4 (dd,
J ) 2.0, 243.5 Hz), 158.1 (dd, J ) 2.6, 249.0 Hz), 138.9 (m), 135.5
(q, J ) 33.2 Hz), 131.8, 130.9, 125.5 (q, J ) 3.6 Hz), 123.0 (dd,
J ) 7.2, 11.6 Hz), 123.0 (q, J ) 273.1 Hz), 119.9, 118.7 (dd, J )
4.2, 25.8 Hz), 118.1 (dd, J ) 8.6, 29.2 Hz), 118.0 (dd, J ) 10.0,
23.8 Hz), 103.6, 71.9 (dd, J ) 1.2, 4.6 Hz), 65.0 (d, J ) 6.2 Hz),
36.2 (d, J ) 6.6 Hz), 28.1, 25.5 (d, J ) 5.6 Hz); mp 93-94 °C;
Anal. Calcd for C22H21F504S: C, 55.46; H, 4.44. Found: C, 55.31;
H, 4.38.
(m, 1H), 7.45-7.42 (m, 2H), 7.25-6.95 (m, 3H), 5.89 (s, 1H),
3.75-3.52 (m, 2H), 3.49-3.42 (m, 1H), 2.85-2.80 (m, 1H), 2.58-
2.45 (m, 1H), 2.40-2.30 (m, 2H), 2.08-1.98 (m, 1H), 1.73-1.53
(m, 2H); 13C NMR (100 MHz, DMSO-d6, 70 °C) δ 168.7, 165.5,
159.0 (d, J ) 250.0 Hz), 158.5 (d, J ) 241.2 Hz), 139.7, 134.3 (q,
J ) 32.0 Hz), 133.4, 131.3, 130.6, 129.6, 128.8, 126.4 (q, J )
3.6), 123.7 (q, J ) 273), 121.2 (m), 118.9 (3C, m), 72.7, 72.2 (m),
62.6, 46.0, 39.2, 27.6, 26.4, 24.0; mp 167-168 °C; [R]20 +5.35
D
(c 1.0, MeOH, >99% ee); enantiopurity was determined via
supercritical fluid chromatography (Chiralpak AD, 0.7 mL/min, 150
bar CO2, t ) 0 min @ 11% MeOH, t ) 12 f 20 min @ 17%
MeOH, tR ) 11.0-11.7 and 12.1-12.7 min) following acetylation
(MTBE/NaOH, concentrate MTBE extract, and dissolve in MeOH/
Ac2O).
cis-5-(2,5-Difluorophenyl)-5-{[4-(trifluoromethyl)phenyl]sul-
fonyl}-3,3a,4,5,6,7-hexahydro-2,1-benzisoxazole (3). Dioxolane
5 (28.0 kg, 58.8 mol) and hydroxylamine hydrochloride (5.31 kg,
76.0 mol) in a mixture of ethanol (140 L) and water (28 L) were
aged at 70 °C for 2 h and then cooled to 50 °C. A solution of
chloramine-T hydrate (20.1 kg, 88.2 mol) in a mixture of water
(56 L) and ethanol (196 L) was then added, and the mixture was
aged at 50 °C for 2 h before cooling to ambient temperature. The
resultant slurry was filtered, and the solid was washed with a 4:1
mixture of EtOH/H2O (20 L). Drying in vacuo furnished the title
N-((1R,2S,4S)-2-Bromomethyl-4-(2,5-difluorophenyl)-4-{[4-
(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)methanesulfon-
amide (16). To a slurry of ((1R,2S,5R)-2-amino-5-(2,5-difluorophe-
nyl)-5-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)methanol D-
dibenzoyl hemitartrate (4.10 kg, 3.3 mol) in CH2Cl2 (76.0 kg) was
added 0.4 N NaOH (23.5 kg, 9.4 mol), and the resultant mixture
was aged for 45 min. The lower organic layer was separated, washed
with water (13 kg), and then reduced in volume to 12 L by
distillation at atmospheric pressure. Triethylamine (1.67 kg, 16.5
mol) was added, followed by a solution of methanesulfonic
anhydride (2.83 kg, 16.3 mol) in methylene chloride (11 kg) while
maintaining T < 10 °C. DMF (30 kg) was then added, and the
mixture was distilled to remove the CH2Cl2 and to reach a volume
of 34 L. Sodium bromide (1.34 kg, mol) was added, and the batch
was heated to 85 °C for 7 h. DMF (7 kg) was added, followed by
water (35 L), to crystallize the product. The resultant slurry was
filtered, and the solid was washed with water (2 × 5 L). Drying in
vacuo furnished the title compound as an off-white solid (3.49 kg,
1
compound as a tan solid (21.4 kg, 84%). H NMR (600.1 MHz,
DMF-d7, 350 K) δ 7.97 (d, J ) 8.3 Hz, 2H), 7.77 (d, J ) 8.3 Hz,
2H), 7.38-7.34 (om, 2H), 7.19 (m, 1H), 4.50 (dd, J ) 10.2, 7.9
Hz, 1H), 3.88 (dd, J ) 10.2, 7.9, 1H), 3.33 (ddd, J ) 13.2, 5.3, 3.4
Hz, 1H), 3.30-3.17 (om, 2H), 2.85 (m, 1H), 2.25-2.18 (om, 2H),
2.13 (td, J ) 12.8, 1.5 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
δ 159.0 (dd, J ) 2.0, 249.3 Hz), 158.7 (dd, J ) 2.5, 241.7 Hz),
157.4, 139.0, 134.8 (q, J ) 32.4 Hz), 131.5, 126.5 (q, J ) 3.6 Hz),
123.6 (q, J ) 273.2 Hz), 119.9 (dd, J ) 7.8, 11.4 Hz), 119.3 (3C,
m), 72.9, 71.0 (m), 45.2, 35.1 (d, J ) 6.4 Hz), 30.4 (d, J ) 7.0
Hz), 21.3; mp 212-214 °C; Anal. Calcd for C20H16F5N03S: C,
53.93; H, 3.62; N, 3.14. Found: C, 53.68; H, 3.60; N, 3.04.
((1R,2S,5R)- and ((1S,2R,5S)-2-Amino-5-(2,5-difluorophenyl)-
5-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)methanol (2).
Isoxazoline 3 (50.0 g, 112 mmol) was slurried in tetrahydrofuran
(300 mL) and cooled to -5 °C. Diisobutylaluminum hydride (20
% w/t in toluene, 212 mL, 252 mmol) was added while maintaining
T < -3 °C. The resultant solution was aged for 1.5 h, warmed to
50 °C for 1.5 h, and then recooled to 0 °C. Methanol (10 mL) was
added while maintaining T < 15 °C, and then aqueous sodium
hydroxide (2 M, 300 mL) was added. The mixture was stirred for
14 h, and then the layers were separated. The organic layer was
distilled to a volume of 250 mL while toluene (250 mL) was added.
The mixture was allowed to cool. The resultant slurry was filtered,
and the solids were washed with toluene (50 mL). Drying in vacuo
1
91%, >99% ee). H NMR (400 MHz, DMSO-d6, 80 °C) δ 7.89
(d, J ) 8.4 Hz, 2H), 7.67 (d, J ) 8.4 Hz, 2H), 7.28 (m, 1H), 7.15
(d, J ) 7.3 Hz, 1H), 7.10 (m, 2H), 3.68 (m, 1H), 3.62 (dd, J ) 6.6,
10.1 Hz, 1H), 3.52 (br t, J ) 8.2 Hz, 1H), 2.97 (s, 3H), 2.79 (br m,
1H), 2.60 (br m, 1H), 2.45 (m, 1H), 2.22 (t, J ) 13.5 Hz, 1H),
2.03 (m, 1H), 1.82 (m, 1H), 1.43 (m, 1H);13C NMR (100 MHz,
DMF-d7, 5 °C) δ 158.9 (dd, J ) 2.8, 247.5 Hz), 158.6 (dd, J )
2.0, 239.5 Hz), 138.9 (m), 134.5 (q, J ) 33.0 Hz), 131.5, 126.3
(m), 123.6 (q, J ) 273.1), 120.7 (m), 118.9 (3C, m), 70.9 (d, J )
3.9 Hz), 49.9, 40.6, 39.7, 35.4, 28.6 (m), 24.2, 23.9 (m); mp 200-
201 °C; [R]20 -26.9 (c 1.0, MeOH, >99% ee); Anal. Calcd for
D
C21H21BrF5N04S2: C, 42.72; H, 3.59; N, 2.37. Found: C, 42.81;
H, 3.55; N, 2.24. The separation of the enantiomers was ac-
complished by HPLC analysis (Chiralpak AD, 2.0 mL/min, 90%
hexane, 10% EtOH, tR ) 13.2, 17.9 min).
1
furnished the title compound as a white solid (40.9 g, 82%). H
NMR (400 MHz, DMSO-d6, 80 °C) δ 7.88 (d, J ) 8.3 Hz, 2H),
7.67 (d, J ) 8.3 Hz, 2H), 7.26 (m, 1H), 7.08 (m, 2H), 3.40 (m,
2H), 3.08 (m, 1H), 2.47 (m, 2H), 2.40 (d, J ) 12.8 Hz, 1H), 2.25
(t, J ) 12.8 Hz, 1H), 1.69 (m, 1H), 1.36 (m, 2H); 13C NMR (100
MHz, DMSO-d6) δ 158.9 (dd, J ) 2.8, 248.1 Hz), 158.5 (dd, J )
2.1, 241.3 Hz), 139.8, 134.3 (q, J ) 32.4 Hz), 131.3, 126.3 (q, J )
3.8 Hz), 123.7 (q, J ) 272.9 Hz), 121.9 (dd, J ) 7.2, 12.4 Hz),
119.2 (dd, J ) 4.6, 25.8 Hz), 118.9 (dd, J ) 9.0, 29.2 Hz), 118.5
(dd, J ) 10.0, 23.8 Hz), 72.6 (m), 63.7, 45.2, 40.7, 30.6, 26.1 (m),
23.7 (d, J ) 7.4 Hz); mp 212-214 °C; Anal. Calcd for C20H20F5-
N03S: C, 53.45; H, 4.49; N, 3.12. Found: C, 53.24; H, 4.41; N,
2.99.
((1S,2R,5S)-2-Amino-5-(2,5-difluorophenyl)-5-{[4-(tri-
fluoromethyl)phenyl]sulfonyl}cyclohexyl)methanol D-Dibenzoyl
Hemitartrate. To a solution of rac-2 (7.5 kg, 16.7 mol) in THF
(56.3 L) was added a solution of dibenzoyl-D-tartaric acid (2.99
kg, 8.34 mol) in IPAc (56.3 L) while maintaining T < 25 °C. The
resultant mixture was aged overnight and filtered, and the solids
were washed with THF/IPAc (1:1, 22.5 L), followed by THF (22.5
L). Drying in vacuo furnished the title compound as a white solid
(4.05 kg, 39%, 96% ee). 1H NMR (400 MHz, MeOH-d4) δ 8.18-
8.13 (m, 2H), 7.83-7.80 (m, 2H), 7.63-7.60 (m, 2H), 7.59-7.51
(4aS,6S,8aR)-6-(2,5-Difluorophenyl)-1-(4-methoxybenzyl)-6-
{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-ben-
zothiazine 2,2-Dioxide (22). THF (14.7 kg) was cooled to less than
-60 °C, and hexyllithium (5.2 kg of a 2.28 M solution in hexane,
16.8 mol) was added at T < -20 °C. Diisopropylamine (1.78 kg,
17.6 mol) was then added while maintaining T < -20 °C. The
resultant solution was cooled to -60 °C, and then a solution of 16
(3.22 kg, 5.45 mol) in THF (4.8 kg) was added while maintaining
T < -45 °C. The resultant solution was aged for 3 h, and then
water (0.11 kg, 6.15 mol) was added while maintaining T < -40
°C. The solution was allowed to warm to -20 °C, and a solution
of NaI (0.42 kg, 2.80 mol) in DMAc (8.66 kg) was added, followed
by para-methoxybenzyl chloride (1.58 kg, 10.1 mol). The mixture
was warmed to room temperature and aged to reach full conversion.
A solution of HCl [1.64 L of concentrated HCl (specific gravity
1.18) diluted with 17 L of water, 19.4 mol] was added while
maintaining T < 50 °C. Toluene (44.3 kg) was added, and the layers
were separated. The organic layer was washed with water (3 ×
8.9 kg) and then distilled to reach a volume of 22.5 L, adding
toluene as necessary to reach a residual THF content of <2 mol %
(1H NMR). Heptane (12.6 kg) was added, and the resultant slurry
was filtered and washed with a 1:1 mixture of toluene and heptane
J. Org. Chem, Vol. 71, No. 8, 2006 3091

Scott et al.
(2.8 kg of each), followed by heptane (2.8 kg). Drying in vacuo
furnished the title compound as tan solid (3.05 kg, 89%, >99%
ee). 1H NMR (400 MHz, DMSO-d6, 85 °C) δ 7.85 (d, J ) 8.2 Hz,
2H), 7.57 (d, J ) 8.1 Hz, 2H), 7.37 (d, J ) 8.4 Hz, 2H), 7.30-
7.23 (m, 1H), 7.13-7.05 (m, 2H), 6.92 (d, J ) 8.5 Hz, 2H), 4.53
(d, J ) 16.6 Hz, 1H), 4.11 (d, J ) 16.6 Hz, 1H), 3.82 (s, 3H), 3.50
(br s, 1H), 3.35 (dt, J ) 3.7, 13.7 Hz, 1H), 3.25-3.18 (m, 1H),
2.69-2.60 (m, 1H), 2.48-2.40 (m, 1H), 2.38-2.25 (m, 1H), 2.21-
2.11 (m, 2H), 2.10-2.01 (m, 1H), 1.79-1.68 (m, 2H), 1.40-1.28
(m, 1H); 13C NMR (100 MHz, DMSO-d6, 85 °C) δ 159.2 (d, J )
247 Hz), 159.1, 158.7 (d, J ) 240 Hz), 139.5, 134.5 (q, J ) 32
Hz), 131.3, 130.8, 129.4, 126.2 (q, J ) 3.0 Hz), 123.8 (q, J ) 272
Hz), 121.5 (dd, J ) 7.0, 12.0 Hz), 119.5-118.6 (3C, overlapping
resonances), 114.5, 71.8, 58.3, 55.8, 45.5, 44.9, 32.4, 28.7 (d, J )
Anal. Calcd for C31H32F5N05S2: C, 56.61; H, 4.90; N, 2.13.
Found: C, 56.50; H, 4.89; N, 2.06. Separation of enantiomers was
accomplished by HPLC analysis (Chiralpak AD, 0.7 mL/min, 60%
hexane, 40% EtOH, tR ) 10.5, 14.5 min).
(3R,4aS,6S,8aR)-6-(2,5-Difluorophenyl)-3-ethyl-6-{[4-
(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzo-
thia-zine 2,2-Dioxide (1). To a stirred solution of 24 (2.74 kg, 4.16
mol) in CH2Cl2 (18 L) at 0 °C was added thioglycolic acid (1.53
kg,16.6 mol). A solution of methanesulfonic acid (1.21 kg, 12.5
mol) in CH2Cl2 (2 L) was added while maintaining T < 5 °C. The
reaction was then aged 30 min, and then a 2 M NaOH solution (18
L, 36 mol) was added while maintaining T < 10 °C. The lower
organic layer was diluted with IPAc (35 L), and the combined
organic layers were washed sequentially with 2 M NaOH (18 L,
36 mol) and water (17 L). The organic layer was distilled to a
volume of 15 L, and further IPAc (20 L) was added. The solution
was again distilled to a volume of 15 L, and then heptane (12.5 L)
was added to crystallize the product. The solid was isolated by
filtration and washed with a 2:1 heptane/IPAc mixture (5 L). Drying
in vacuo furnished the title compound as a white solid (1.97 kg,
7.0 Hz), 28.1, 25.3, 24.5; mp 230-231 °C; [R]20 -7.58 (c 1.0,
D
CH3CN, >99% ee); Anal. Calcd for C29H28F5N05S2: C, 55.32; H,
4.48; N, 2.22. Found: C, 55.20; H, 4.48; N, 2.15. Separation of
enantiomers was accomplished by HPLC analysis (Chiralpak AD,
1.0 mL/min, 60% hexane, 40% EtOH, tR ) 9.8, 16.9 min).
(3R,4aS,6S,8aR)-6-(2,5-Difluorophenyl)-3-ethyl-1-(4-methoxy-
benzyl)-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-
2,1-benzothiazine 2,2-Dioxide (24). A solution of 22 (2.97 kg,
4.7 mol) and ethyl iodide (1.03 kg, 6.60 mol) in THF (26.3 kg)
was cooled to -5 °C. Sodium bis(trimethylsilylamide) (1.0 M in
THF, 5.97 kg, 6.60 mol) was then added while maintaining T < 1
°C. The mixture was aged for 80 min, and then an aqueous citric
acid solution (0.55 kg citric acid, 2.84 mol in 28.3 kg water) was
added while maintaining T < 8 °C. Methyl tert-butyl ether (22 kg)
was added, and the layers were allowed to settle. The organic layer
was washed with water (8.91 kg) and then distilled at atmospheric
pressure to a volume of 34 L. The mixture was further distilled,
adding 2-propanol (80.2 kg) to reach a final volume of 34 L. The
resultant slurry was cooled and filtered, and the solid was washed
with 2-propanol (2.70 kg). Drying in vacuo furnished the title
1
89%, >99 wt %, >99% ee). H NMR (400 MHz, DMSO-d6, 85
°C) δ 7.88 (2H, d, J ) 7.9 Hz), 7.65 (d, J ) 7.6 Hz, 2H), 7.30-
7.23 (m, 1H), 7.22-7.05 (m, 2H), 7.00-6.95 (m, 1H), 3.48-3.40
(m, 1H), 2.96-2.89 (m, 1H), 2.63-2.38 (m, 4H), 2.10-1.95 (m,
1H), 1.90-1.79 (m, 3H), 1.65-1.35 (m, 3H), 1.05 (t, J ) 7.6 Hz,
3H); 13C NMR (100 MHz, DMSO-d6, 85 °C) δ 159.2 (d, J ) 248
Hz), 158.4 (d, J ) 240 Hz), 139.6, 134.5 (q, J ) 32.0 Hz), 131.3,
126.3 (q, J ) 3.0 Hz), 123.8 (q, J ) 272 Hz), 121.3 (dd, J ) 7.0,
90 Hz), 119.5-118.5 (3C, overlapping resonances), 72.3 (d, J )
4.0 Hz), 55.7, 52.1, 35.1, 31.9, 38.0 (d, J ) 7.0 Hz), 26.6, 24.0,
21.9, 11.2; mp 247-248 °C; [R]20 -52.6 (c 1.0, MeOH, >99%
D
ee); Anal. Calcd for C23H24F5N04S2: C, 51.39; H, 4.50; N, 2.61.
Found: C, 51.28; H, 4.47; N, 2.54. Separation of enantiomers was
accomplished by HPLC analysis (Chiralpak AD, 1.5 mL/min, 60%
hexane, 40% EtOH, tR ) 4.3, 10.4 min).
1
compound as a white solid (2.74 kg, 90%, >99% ee). H NMR
(400 MHz, DMSO-d6, 85 °C) δ 7.87 (d, J ) 8.0 Hz, 2H), 7.56 (d,
J ) 7.2 Hz, 2H), 7.40 (d, J ) 8.0 Hz, 2H), 7.31-7.25 (m, 1H),
7.18-7.03 (m, 2H), 6.94-6.90 (d, J ) 8.0 Hz, 2H), 4.55 (d, J )
17.2 Hz, 1H), 4.17 (d, J ) 16.8 Hz, 1H), 3.81 (s, 3H), 3.49-3.48
(m, 1H), 3.28-3.19 (m, 1H), 2.70-2.61 (m, 1H), 2.52-2.43 (m,
1H), 2.20-1.92 (m, 5H), 1.75-1.67 (m, 2H), 1.60-1.49 (m, 1H),
1.38-1.28 (m, 1H), 1.10 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6, 85 °C) δ 159.2 (d, J ) 245 Hz), 159.1, 158.7 (d, J )
241 Hz), 139.5, 134.5 (q, J ) 32.0 Hz), 131.3, 130.9, 129.4, 126.3
(d, J ) 3.0 Hz), 123.8 (q, J ) 272 Hz), 121.4 (dd, J ) 12.0, 20.0
Hz), 119.5-118.5 (3C, overlapping resonances), 114.5, 71.9, 57.7,
56.2, 55.8, 45.0, 34.0, 33.0, 29.0 (d, J ) 6.1 Hz), 25.3, 24.5, 21.7,
Acknowledgment. We thank Andrew Kirtley, Sophie Aillaud,
Mirlinda Biba, Jennifer Chilenski, Arlene McKeown, Jimmy
Dasilva, Christopher J. Welch, and Peter Yehl for technical support.
We thank Mike S. Ashwood, Khateeta M. Emerson, John S.
Edwards, and Adrian Goodyear for pilot plant support.
Supporting Information Available: Details of the stereochem-
ical assignment of 3 and the X-ray structure of 1. This material is
available free of charge via the Internet at http://pubs.asc.org.
11.0; mp 188-189 °C; [R]20 -23.9 (c 1.0, MeOH, >99% ee);
JO060033I
D
3092 J. Org. Chem., Vol. 71, No. 8, 2006