Enantioselective syntheses of (+)-sertraline and (+)-indatraline using lithiation/borylation-protodeboronation methodology

Article abstract of DOI:10.1021/ol202251p

The lithiation/borylation-protodeboronation of a homoallyl carbamate was applied to the synthesis of (+)-sertraline and (+)-indatraline. Due to the presence of the alkene, significant modifications of the methodology were required (use of 12-crown-4, TMSCl, H₂O), or a solvent switch to CHCl₃, to achieve high yields and high selectivities.

Full text of DOI:10.1021/ol202251p

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5740–5743
Enantioselective Syntheses of
(þ)-Sertraline and (þ)-Indatraline Using
Lithiation/BorylationꢀProtodeboronation
Methodology
Stefan Roesner, Javier Mansilla Casatejada, Tim G. Elford, Ravindra P. Sonawane,
and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K.
V.Aggarwal@bristol.ac.uk
Received August 19, 2011
ABSTRACT
The lithiation/borylationꢀprotodeboronation of a homoallyl carbamate was applied to the synthesis of (þ)-sertraline and (þ)-indatraline. Due to
the presence of the alkene, significant modifications of the methodology were required (use of 12-crown-4, TMSCl, H2O), or a solvent switch to
CHCl3, to achieve high yields and high selectivities.
The enantioselective synthesis of gem-diarylalkyl com-
pounds, a motif which is present in many therapeutically
important molecules,1 is challenging due to the lack of
proximal functional groups. Examples of these com-
pounds include (þ)-sertraline (1, Zoloft), (þ)-indatraline
(2, Lu 19-005), tolterodine, and podophyllotoxin (Figure 1).
In this paper we describe the application of our lithiation/
borylation2ꢀprotodeboronation methodology3 to the
synthesis of both (þ)-sertraline (1) and (þ)-indatraline
(2), although unexpected but significant hurdles were
encountered en route that required significant changes to
our standard protocol.
(1) Selim, K. B.; Matsumoto, Y.; Yamada, K.; Tomioka, K. Angew.
Chem., Int. Ed. 2009, 48, 8733–8735 and references therein.
(2) (a) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K.
Nature 2008, 456, 778–783. (b) Bagutski, V.; French, R. M.; Aggarwal,
V. K. Angew. Chem., Int. Ed. 2010, 49, 5142–5145. These reactions are
based on the seminal studies by Hoppe on the lithiation and trapping of
Figure 1. Therapeutically important molecules containing the
gem-diarylalkyl substructure.
€
secondary benzylic carbamates. See: (c) Hoppe, D.;Carstens, A.;Kramer,
T. Angew. Chem., Int. Ed. Engl. 1990, 29, 1424–1425. (d) Carstens, A.;
Hoppe, D. Tetrahedron 1994, 50, 6097–6108.
(3) Nave, S.; Sonawane, R. P.; Elford, T. G.; Aggarwal, V. K. J. Am.
(þ)-Sertraline (1) is a potent competitive selective ser-
otonin reuptake inhibitor (SSRI), which has become a
commonly prescribed pharmaceutical for the treatment of
Chem. Soc. 2010, 132, 17096–17098.
r
10.1021/ol202251p
Published on Web 10/13/2011
2011 American Chemical Society

depression and other anxiety-related disorders.4 In 2004,
sertraline was the ninth top-selling drug worldwide ($3.36
billion).5 (þ)-Sertraline has become a popular target for
asymmetric synthesis due to its small but challenging
structure.6
protodeboronation leads to the tertiary stereogenic center.
These processes have been found to be highly stereo-
selective, occurring with retention of stereochemistry in
the lithiation/borylation reaction2 and again retention
of stereochemistry in the protodeboronation reaction.3
The related molecule, (þ)-indatraline (2), is a potent
psychoactive compound that acts as a monoamine reup-
take inhibitor and affects the dopamine and the serotonin
transporter.7 To date, only three asymmetric syntheses of
trans (þ)/(ꢀ)-2 have been reported.8
Scheme 2. Synthesis of Olefin 3 via Lithiation/Borylationꢀ
Protodeboronation Sequencea
Scheme 1. Retrosynthetic Scheme for the Synthesis of Sertraline
(1) and Indatraline (2)a
a Cb = 2,2-diisopropylcarbamoyl, pin = pinacolato.
Our synthesis began with commercially available homo-
allylic alcohol 7, a substrate which can also be prepared in
98% ee either by enzymatic resolution of the racemate9 or
by asymmetric allylation of benzaldehyde using the (R,R)-
Leighton reagent.10 The secondary alcohol 7 was initially
converted into chiral carbamate 4 in 83% yield (Scheme 2).
Thereafter, carbamate 4 was subjected to the lithiation/
borylation reaction by treatment with 1.3 equiv of sec-
butyllithium and a subsequent reaction with 1.5 equiv of
aryl pinacol boronic ester 5 (Table 1). The formation of a
boron-ate complex between 4 and 5 and its conversion to 6
was monitored by 11B NMR. However, under our stan-
dardreaction conditions, no1,2-migration occurred, either
upon warming to ambient temperature or even by heating
thereactionmixtureunderreflux(Table1, entry 1). The ate
complex stubbornly remained.
To determine whether the problem was related to steric
effects, the related propylcarbamate 8 was tested in the
lithiation/borylation reaction and this led to the homo-
logated boronic ester 9 in 72% yield and 99% es under
standard conditions (Scheme 3). Like previous extensive
examples,2 the 1,2-migration occurred simply upon warm-
ing fromꢀ78°C toambient temperature. This showed that
the problem was not steric in origin.
a Cb = 2,2-diisopropylcarbamoyl, pin = pinacolato.
Our retrosynthetic analysis of both (þ)-sertraline and
(þ)-indatraline led us toacommonprecursor, diarylalkene
3 (Scheme 1). We envisaged that this intermediate could be
obtained from our recently reported methodology of
lithiation/borylationꢀprotodeboronation using carba-
mate 4 and boronic ester 5.2,3 This reaction sequence
occurs via an intermediate boron-ate complex, which
undergoes a stereospecific 1,2-metalate rearrangement to
afford a homologated tertiary boronic ester 6. Subsequent
(4) (a) Koe, K. B.; Weisman, A.; Welch, W. M.; Broune, R. G. J.
Pharmacol. Exp. Ther. 1983, 226, 686–700. (b) Welch, W. M.; Kraska,
A. R.; Sarges, R.; Koe, K. B. J. Med. Chem. 1984, 27, 1508–1515.
(5) Maggon, K. Drug Discovery Today 2005, 10, 739–742.
(6) For recent asymmetric examples (2005ꢀpresent), see: (a) Dockendorff,
C; Sahli, S.; Olsen, M.; Milhau, L.; Lautens, M. J. Am. Chem. Soc. 2005,
127, 15028–15029. (b) Wang, G.; Zheng, C.; Zhao, G. Tetrahedron:
Asymmetry 2006, 17, 2074–2081. (c) Han, Z.; Wang, Z.; Zhang, X.;
Ding, K. Angew. Chem., Int. Ed. 2009, 48, 5345–5349. (d) Ohmiya, H.;
Makida, Y.; Li, D.; Tanabe, M.; Sawamura, M. J. Am. Chem. Soc. 2010,
132, 879–889. (e) Garcia, A. E.; Ouizem, S.; Cheng, X.; Romanens, P.;
These initial results indicated that the alkene was inter-
fering in the lithiation/borylation process, and we consid-
ered the possibility that a Liꢀπ coordination complex may
be forming (B, Figure 2),11 which would stabilize the ate
complex. In this complex, 1,2-metalate rearrangement
would be disfavored as the migrating group is not aligned
€
Kundig, E. P. Adv. Synth. Catal. 2010, 352, 2306–2314. (f) Krumlinde,
€
P.; Bogar, K.; Backvall, J. E. Chem.;Eur. J. 2010, 16, 4031–4036. (g)
Chen, F.; Wang, T.; He, Y.; Ding, Z.; Li, Z.; Xu, L.; Fan, Q. H. Chem.;
Eur. J. 2011, 17, 1109–1113. (h) Barluenga, J.; Florentino, L.; Aznar, F.;
ꢀ
Valdes, C. Org. Lett. 2011, 13, 510–513.
(9) Master, H. E.; Nevadkar, R. V.; Rane, R. A.; Kumar, A.
Tetrahedron Lett. 1996, 37, 9253–9254.
(10) (a) Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42,
946–948. (b) Kim, H.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011,
133, 6517–6520.
(11) Monje, P.; Paleo, M. R.; Garcıa-Rıo, L.; Sardina, F. J. J. Org.
Chem. 2008, 73, 7394–7397.
(7) (a) Bøgesø, K. P.; Christensen, A. V.; Hyttel, J.; Liljefors, T. J.
Med. Chem. 1985, 28, 1817–1828. (b) Hyttel, J.; Larsen, J. J. J.
Neurochem. 1985, 44, 1615–1622.
(8) Asymmetric indatraline syntheses: (a) Davies, H. M. L.; Gregg,
T. M. Tetrahedron Lett. 2002, 43, 4951–4953. (b) Yoo, K.; Kim, H.; Yun,
J. Chem.;Eur. J. 2009, 15, 11134–11138. (c) Taylor, J. C.; Correia,
C. R. D. J. Org. Chem. 2011, 76, 857–869.
Org. Lett., Vol. 13, No. 21, 2011
5741

migration of the aryl group in the ate complex was
observed (entry 2). However, this issue was ultimately
solved by the addition of both TMSCl (1.2 equiv) and
water (0.1 equiv). Under these conditions, the desired
product 6 was indeed obtained with high es and high yield
(entry 3). The necessity of each component was established
since without the H2O (entry 4) or the crown ether (entry 5),
or TMSCl (entry 6), lower yields or lower es were obtained.12
Table 1. Optimization of the Lithiation/Borylation Reaction
Conditionsa
yield
(%)
es
entry
conditions
64 h, rt or 16 h, reflux
(%)b
1
2
3
0
0
ꢀ
ꢀ
12-crown-4, 16 h, rt
(i) 12-crown-4, 0.1 equiv H2O, 1 h, ꢀ78 °C
(ii) TMSCl, 16 h, rt
81
100
4
5
6
(i) 12-crown-4, 1 h, ꢀ78 °C
(ii) TMSCl, 16 h, rt
65
31
31
80
99
96
Figure 2. Structure of boron-ate complex with and without
proposed Liꢀπ complexation.
(i) 0.1 equiv H2O, 1 h, ꢀ78 °C
(ii) TMSCl, 16 h, rt
(i) 12-crown-4, 0.1 equiv H2O, 1 h, ꢀ78 °C
(ii) 16 h, rt
During mechanistic studies to probe the structure of the
intermediate boron-ate complex, we surprisingly discov-
ered that, after carrying out a solvent exchange from Et2O
to dry CHCl3, complete migration of the aryl group
occurred, leading to tertiary boronic ester 6 in high yield
and high es (entry 7). Of the solvents explored for the
exchange (CH2Cl2, PhCH3, and PhCF3), PhCF3 also worked
well, albeit with lower es (entry 8). Thus, the simple expediency
of carrying out a solvent exchange provides an alternative
method for effecting the 1,2-metalate rearrangement in this
case. The use of a nonpolar solvent is essential in this process,
where it may now begin to favor the lithiated complex A
required for 1,2-metalate rearrangement over complex B.
7
8
Remove Et2O, add CHCl3, rt, 16 h
Remove Et2O, add PhCF3, rt, 16 h
62
57
98
91
a Reaction conditions: 4 (0.3 M in diethyl ether), sBuLi (1.3 M
in cyclohexane/hexane 98:2), 5 (0.9 M in toluene). Where applicable,
1.2 equiv of 12-crown-4 and/or 1.2 equiv of TMSCl were used. The
enantiomeric excess was determined after oxidation of an aliquot of the
tertiary boronic ester by chiral HPLC (see Supporting Information).
b es = (product ee/starting material ee) ꢁ 100.
Scheme 3. Lithiation/Borylation of Carbamate 4 and 8
Table 2. Optimization for the Amount of Water in the Proto-
deboronation Reaction of 6a
entry
amount of H2O
yield (%)
es (%)b
1
2
3
4
5
6
7
8
0 equiv
88
93
92
88
87
81
76
12
16
79
82
94
97
97
97
88
antiperiplanar to the carbamate leaving group. Without
the alkene, the lithium ion could coordinate to both
oxygens of the pinacol ester which in turn places the
migrating group antiperiplanar to the carbamate leaving
group leading to facile 1,2-metalate rearrangement (A,
Figure 2). Indeed, it has been reported that a π-bond can
contribute a similar level ofstabilization asan ether oxygen
to a Liþ complex (ca. 1.7 kcal molꢀ1).11 By adding 12-
crown-4 to the reaction mixture, we hoped to break up the
complex by sequestering the lithium ions and, therefore,
allow the 1,2-migration to occur. Unfortunately, still no
1.1 equiv
1.5 equiv
2.0 equiv
2.5 equiv
3.0 equiv
4.0 equiv
8.0 equiv
a Reaction conditions: 0.1 M in CH2Cl2, 1.5 equiv of CsF and
specified equiv of water, room temperature, overnight. b es = (product
ee/starting material ee) ꢁ 100. Determined by chiral HPLC (see Sup-
porting Information).
5742
Org. Lett., Vol. 13, No. 21, 2011

With the lithiation/borylation problem solved, we fo-
cused on the next step: protodeboronation of tertiary
boronic ester 6. Unfortunately, our standard conditions
fordiarylalkylboronic esters(1.5 equivofCsF;1.1 equiv of
H2O, 1,4-dioxane)3 led to partial racemization of the
stereocenter. Through a systematicinvestigation, wefound
that controlling the amount of water was crucial for this
reaction, since the reactivity of fluoride in organic solvents
is fundamentally dependent on the water content in the
reaction mixture.13 For optimization, the protodeborona-
tion reaction was performed in dichloromethane with
1.5 equiv of predried cesium fluoride and varying amounts
of water (Table 2). While a certain threshold amount of water
was critical for obtaining high enantioselectivity (entries
1ꢀ4), the best results were obtained with 2.5 and 3.0 equiv
of water (entries 5, 6). Further increasing the equivalents of
water resulted in diminished yields and reduced es (entries
7ꢀ8). Consequently, by performing the protodeboronation
with 2.5 equiv of water, olefin 3could be obtained in excellent
yield with almost complete retention of configuration.14
With diarylbutene 3 in hand, the double bond was oxidized
by a sequence of hydroboration and Jones oxidation to
provide carboxylic acid 10 in 98% yield (Scheme 4). Subse-
quent intramolecular FriedelꢀCrafts acylation15 of the chiral
carboxylic acid using chlorosulfonic acid afforded known
tetralone 11 in 93% yield and 94% ee (99% es from 3), which
was converted to (þ)-sertraline by reductive amination in
47% yield with a cis/trans ratio of 96.5:3.5.16 Thus, sertraline
(þ)-1 was synthesized in eight steps from readily accessible
homoallylic alcohol 7 with an overall yield of 28%.
Scheme 4. Syntheses of (þ)-Sertraline and (þ)-Indatralinea
a 9-BBN = 9-borabicyclo[3.3.1]nonane, Ms = methanesulfonyl.
For the synthesis of (þ)-indatraline (Scheme 4),
oxidation17 of olefin 3 with in situ generated osmium
tetroxide gave the desired aldehyde, which was further
oxidized by a Pinnick oxidation to furnish carboxylic acid
12. Intramolecular FriedelꢀCrafts acylation gave inde-
none 13 in 93% ee (99% es from 3) and nearly quantitative
yield.18 The ee of 13 could be improved to >98% by
recrystallization from hot heptane. Indenone 13 was re-
duced to the alcohol, which was subsequently converted to
(þ)-indatraline (2) in 76% yield for both steps.8a,19 Thus,
(þ)-indatraline 2 was synthesized in eight steps with an
overall yield of 42% starting from alcohol 7.
diaryl compounds in high enantioselectivity. For our
homoallylic carbamate, it was found to be necessary to
break up the lithium/boron-ate complex with a crown
ether or to carry out a solvent exchange to achieve 1,2-
metalate rearrangement in order to obtain the tertiary
boronic ester in high yield and high es.
Acknowledgment. We thank the European Research
Council (FP7/2007-2013, ERC Grant No. 246785) for
financial support. V.K.A. thanks EPSRC for a Senior
Research Fellowship. We thank Inochem-Frontier Scien-
tific for the generous donation of boronic acids and
boronic esters.
In conclusion, lithiation/borylation and subsequent pro-
todeboronation give access to functionalized chiral 1,1-
(12) The optimized conditions found here are specific to this sub-
strate. Application of these conditions to the saturated carbamate 8 gave
the corresponding tertiary alcohol in low yield (26% over two steps) and
with reduced chirality transfer (91% es).
(13) Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050–
2051.
(14) Protodeboronation of tertiary boronic ester 9 under the pre-
viously reported conditions (1.5 equiv of CsF, 1.1 equiv of H2O, 1,4-
dioxane) gave the protodeboronated product in 67% es. Using the
current conditions (1.5 equiv of CsF (predried), 2.5 equiv of H2O,
CH2Cl2) gave the protodeboronated product in 97% es. We believe that
different batches of CsF contain different amounts of water and so
recommend drying it prior to use and then adding controlled amounts of
water (2.5 equiv) in order to get consistently high enantioselectivity.
(15) Ohmiya, H.; Makida, Y.; Li, D.; Tanable, M.; Sawamura, M.
J. Am. Chem. Soc. 2010, 132, 879–889.
Supporting Information Available. Detailed experi-
mental procedures and characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ꢀ
(16) Vukics, K.; Fodor, T.; Fischer, J.; Fellegvari, I.; Levai, S. Org.
ꢀ
Process Res. Dev. 2002, 6, 82–85.
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3217–3219.
(18) Pastre, J. C.; Correia, C. R. D. Adv. Synth. Catal. 2009, 351,
1217–1223.
(19) Froimowitz, M.; Wu, K.-M.; Moussa, A.; Haidar, R. M.; Jurayj,
J.; George, C.; Gardner, E. L. J. Med. Chem. 2000, 43, 4981–4992.
Org. Lett., Vol. 13, No. 21, 2011
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