Asymmetric allylation/ring closing metathesis: One-pot synthesis of benzo-fused cyclic homoallylic amines. Application to the formal synthesis of Sertraline derivatives

Article abstract of DOI:10.1021/ol4017113

A one-pot asymmetric allylation/ring closing metathesis (RCM) sequence for the synthesis of cyclic homoallylic amines has been developed. A library of six- and seven-membered benzo-fused products has been synthesized in good yields and complete diastereoselectivity. The new methodology has been applied to the formal syntheses of the antidepressant Sertraline and the epimeric Norsertraline. The methodology is amenable for the synthesis of analogs.

Full text of DOI:10.1021/ol4017113

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Asymmetric Allylation/Ring Closing
Metathesis: One-Pot Synthesis of
Benzo-fused Cyclic Homoallylic Amines.
Application to the Formal Synthesis of
Sertraline Derivatives
†
†
†
†,‡
Santos Fustero,*,†,‡ Ruben Lazaro, Lidia Herrera, Elsa Rodrıguez, Natalia Mateu,
ꢀ
ꢀ
´
and Pablo Barrio*,†
´
Departamento de Quımica Organica, Universidad de Valencia, E-46100 Burjassot,
Spain, and Laboratorio de Moleculas Organicas, Centro de Investigacion Prıncipe
ꢀ
ꢀ
ꢀ
ꢀ
´
Felipe, E-46012 Valencia, Spain
Santos.fustero@uv.es; pablo.barrio@uv.es
Received June 17, 2013
ABSTRACT
A one-pot asymmetric allylation/ring closing metathesis (RCM) sequence for the synthesis of cyclic homoallylic amines has been developed. A
library of six- and seven-membered benzo-fused products has been synthesized in good yields and complete diastereoselectivity. The new
methodology has been applied to the formal syntheses of the antidepressant Sertraline and the epimeric Norsertraline. The methodology is
amenable for the synthesis of analogs.
Arguably, the asymmetric allylation of imines is the most
important method for the synthesis of homoallylic amines
which are versatile building blocks in organic synthesis.1
Among existing methods, the diastereoselective addition
of allylzinc bromide to Ellman’s tert-butylsulfinimines pre-
sents a number of advantages: a high degree of diaster-
eocontrol and chemical yields, reliability, and functional
group compatibility, among others.2 On the other hand,
ring closing metathesis (RCM) is one of the most reliable
methods for the construction of medium-sized rings.3
The combination of these two powerful strategies enables
the rapid construction of cyclic homoallylic amines. Our
group4 as well as others5 have used this reaction sequence
for the synthesis of cyclic amino acid derivatives, pyrro-
loazepines, or pharmaceutical compounds, respectively.
However, it has never been applied to the synthesis of
benzo-fused systems.
Several years ago, in the context of diversity oriented
synthesis (DOS), we launched a research program to study
the use of ortho-substituted aromatic tert-butylsulfinyl imi-
nesfor the asymmetricsynthesisofa variety of benzo-fused
carbo- and heterocyclessuchasfluorinated isoindolines6a,b
and isoquinolines6b or indanones,6c respectively (Scheme 1).
Among benzo-fused systems, the tetrahydronaphtha-
lene core belongs to the so-called privileged structures,
† Universidad de Valencia.
‡
ꢀ
´
Centro de Investigacion Prıncipe Felipe.
(1) For reviews on asymmetric allylation, see: (a) Yus, M.; Gonzalez-
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Gomez, J. C; Foubelo, F. Chem. Rev. 2011, 111, 7774. (b) Ding, H.;
Friestad, G. K. Synthesis 2005, 2815. (c) Yamamoto, Y.; Asao, N. Chem.
Rev. 1993, 93, 2207.
(2) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600.
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(4) (a) Fustero, S.; Sanchez-Rosello, M.; Rodrigo, V.; del Pozo, C.;
(3) (a) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073. (b)
Blanchard, N.; Eustache, J. Synthesis of Natural Products Containing
Medium-size Carbocycles by Ring-closing Alkene Metathesis. In Me-
tathesis in Natural Product Synthesis; Cossy, J., Arseniyadis, S., Meyer, C.,
Eds.; Wiley-VCH: Weinheim, 2010; pp 1À43.
ꢀ
Sanz-Cervera, J. F.; Simon, A. Org. Lett. 2006, 8, 4129. (b) Fustero, S.;
~
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Sanz-Cervera, J. F.; Acena, J. L.; Sanchez-Rosello, M. Synlett 2009, 525.
(5) Grainger, R. S.; Welsh, E. J. Angew. Chem., Int. Ed. 2007, 46,
5377.
r
10.1021/ol4017113
XXXX American Chemical Society

chromatographic purifications, resulting in the optimiza-
tion of the amount of solvents, energy, and working time.
The design of such one-pot processes requires the careful
evaluation of functional groups, solvents, and reactant
compatibility. Very recently, we have reported a relay
catalysis approach to cyclic homoallylic alcohols.9 Our
interest in benzo-fused systems prompted us to design an
analogous strategy for the synthesis of the parent amines.
Scheme 1. DOS Strategy on 2-Halobenzaldehyde
Scheme 2. Scope of the Stepwise Allylation/RCM Sequence
i.e. structures more commonly found in natural products
or drugs (Figure 1).
Figure 1. Tetrahydronaphthalene containing natural products
and pharmaceuticals.
An example of such tetrahydronaphthalene derivatives
is Sertraline (Figure 1, 1), a selective serotonine reuptake
inhibitor (SSRI) antidepressant.7 Sertraline has attracted a
great deal of interest, and several asymmetric syntheses
have been reported in the literature.8 However, only a few
analogs have been described; specifically, no derivative on
the tetrahydronaphthalene ring has been reported. On the
other hand, the development of one-pot processes is of
pivotal importance in modern organic synthesis, as they
entail a minimum number of manipulations, including
a Overall yield for the two steps; experiments were typically carried
out in a 0.30 mmol scale (for details on the yields for each step see
b
Supporting Information).
For the RCM step, formation of the
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ꢀ
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(6) (a) Fustero, S.; Moscardo, J.; Sanchez-Rosello, M.; Rodrı
´
~
guez,
corresponding iminium salt by pretreatment with PTSA in refluxing
DCM was required.
E.; Barrio, P. Org. Lett. 2010, 12, 5494. (b) Fustero, S.; Ibanez, I.; Barrio,
P.; Maestro, M. A.; Catalan, S. Org. Lett. 2013, 15, 832. (c) Fustero, S.;
Rodrıguez, E.; Herrera, L.; Asensio, A.; Maestro, M. A.; Barrio, P. Org.
ꢀ
´
Lett. 2011, 13, 6564.
Readily available sulfinimes 2aÀi were submitted to the
stepwise protocol10 giving rise to the desired products in
good overall yields, in most of the cases, and complete
diastereoselectivity (Scheme 2).11 Electron-donating (2d,f),
electron-withdrawing (2e), and fluorine substituents (2b,c)
(7) (a) Welch, W. M.; Kraska, A. R.; Sarges, R.; Koe, B. K. J. Med.
Chem. 1984, 27, 1508. (b) Williams, M.; Quallich, G. Chem. Ind.
(London) 1990, 10, 315. (c) Quallich, G. J.; Woodall, T. M. Tetrahedron
1992, 48, 10239. (d) Corey, E. J.; Gant, T. G. Tetrahedron Lett. 1994, 35,
5373. (e) Johnson, B. M.; Chang, P.-T. L. Anal. Profiles Drug Subst.
1996, 24, 443.
(8) For some selected examples, see: (a) Lee, S. H.; Kim, I., S.; Li,
Q. R.; Dong, G. R.; Jeong, L. S.; Jung, Y. H. J. Org. Chem. 2011, 76,
10011. (b) Ohmiya, H.; Makida, Y.; Li, D.; Tanabe, M.; Sawamura, M.
J. Am. Chem. Soc. 2010, 132, 879. (c) Han, Z.; Wang, Z.; Zhang, X.;
Ding, K. Angew. Chem., Int. Ed. 2009, 48, 5345. (d) Alexakis, A.; Hajjaji,
S. E.; Polet, D.; Rathgeb, X. Org. Lett. 2007, 9, 3393. (e) Dockendorff,
C.; Sahli, S.; Olsen, M.; Milhau, L.; Lautens, M. J. Am. Chem. Soc. 2005,
127, 15028. (f) Nair, V.; Rajan, R.; Rath, N. P. Org. Lett. 2002, 4, 1575.
(g) Lautens, M.; Rovis, T. Tetrahedron 1999, 55, 8967. (h) Corey, E. J.;
Gant, T. G. Tetrahedron Lett. 1994, 35, 5373.
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(9) Fustero, S.; Rodriguez, E.; Lazaro, R.; Herrera, L.; Catalan, S.;
Barrio, P. Adv. Synth. Catal. 2013, 355, 1058.
(10) For optimization of the experimental conditions, see Supporting
Information.
(11) S absolute configuration was assumed for all products in agree-
ment with Ellman’s proposed transitionstate; see: Cogan, D. A.; Liu, G.;
Ellman, J. A. Tetrahedron 1999, 55, 8883.
B
Org. Lett., Vol. XX, No. XX, XXXX

are tolerated on the aromatic ring. Moreover, heteroaro-
matic imines are also compatible with the reaction condi-
tions (2g,h). Finally, the introduction of an allyl chain in
the ortho position allows for the synthesis of seven-mem-
bered benzo-fused products (2i).
Scheme 3. One-Pot Procedures
In order to increase the efficiency of the methodology,
we studied the one-pot procedure. For this goal, several
compatibility issues have to be addressed, namely: (1)
functional groups present in the starting materials 2 and
the intermediates 3 are compatible with all the reactants;
(2) both steps (allylation and RCM) have been described in
common solvents such as THF and DCM;12 (3) both steps
are clean and conversion takes place inanefficient manner,
avoiding the formation of byproducts, which could inter-
fere in the next reaction step. Our major concern was the
compatibility between organozinc species and ruthenium
metathesis catalysts, which has never been described to the
best of our knowledge. Hence, the one-pot procedure was
tested in both DCM and THF as solvents using 2a as the
model substrate (Scheme 3, equation a).
To our delight, the one-pot procedure in THF gives rise
to product 4a in an excellent 95% yield and equally high
diastereoselectivity. Despite the apparent complete com-
patibility between the allylzinc species and the ruthenium
catalyst, a higher catalyst loading is required and the
reaction is much slower (20 vs 4 h). In addition, the catalyst
must be loaded in three 5 mol % portions, as deactivation
is observed.13 Thus, some kind of interaction between the
two organometallic species is actually taking place.
To show the applicability of this one-pot procedure, it
was used in the synthesis of the new seven-membered
analogue4jinaglobal 56% yield, inthree steps(Scheme4).
Scheme 4. Application of the One-Pot Strategy for the Synthesis
of the Seven-Membered Analog 4j
In a further development stage, we tested the one-pot
procedure starting from aldehyde 5a as the compatibility
of titanium alkoxyde with both organozinc reagents14 and
ruthenium based metathesis catalysts15 as well as the use of
THF as solvent for the condensation step have been
reported.16 Our initial experimental conditions lead to a
promising 45% yield for the three steps. In view of the
excellent yield obtained for the allylation/RCM sequence
(see Scheme 3, equation a) the drop in chemical yield may
be caused by the interaction between the excess Ti(OEt)4
and the allylzinc bromide. Therefore, an optimization of
the number of equivalents of Ti(OEt)4 was carried out17
showing that the use of 2 equiv led to an improved 60%
yield comparable with the 63% obtained in the stepwise
procedure but only requiring one isolation step and one
chromatographic purification resulting in time, solvent,
and personnel optimization (Scheme 3, equation b).
Deprotection under standard conditions was carried out
on representative products 4a and 4i giving rise to the
corresponding chlorohydrates 6a and 6i in excellent yields
(Scheme 5).
Scheme 5. Deprotection of Some Representative Substrates
(12) For examples of allylations in DCM and THF, see: (a) van der
Sluis, M.; Broxterman, Q. B. Org. Lett. 2001, 3, 3943. (b) Sun, X. W.; Xu,
M. H.; Lin, G. Q. Org. Lett. 2006, 8, 4979. For examples of RCM in
DCM and THF, see: (c) Leduc, A. B.; Kerr, M. A. Angew. Chem., Int.
Ed. 2008, 47, 7945. (d) Grainger, R. S.; Welsh, E. J. Angew. Chem., Int.
Ed. 2007, 46, 5377.
Finally, the methodology was challenged in the formal
synthesis of the antidepressant Sertraline and the epimeric
Norsertraline (Scheme 6). During the scale-up, we found
out that an improved yield of 4a (85%) could be obtained
by using crude 2a in the allylation/RCM one-pot proce-
dure. After some fruitless efforts aimed at the introduc-
tion of the 3,4-dichlorophenyl moiety by means of an
(13) At a larger reaction scale (10 mmol) 3 Â 2 mol % portions may be
used without affecting the final yield.
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(14) Forrat, V. J.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry
2009, 20, 65.
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(15) Fustero, S.; Monteagudo, S.; Sanchez-Rosello, M.; Flores, S.;
Barrio, P.; del Pozo, C. Chem.;Eur. J. 2010, 16, 9835.
(16) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278.
(17) For details, see Supporting Information.
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C

sequence lead to cross-coupling counterpart bromoolefin
8a,b. The success of this step required protecting group
exchange from tert-butylsulfinyl to either Boc or Ac; other-
wise partial deprotection of the amine was observed.18 A
thorough optimization allowed us to identify high yield-
ing Suzuki coupling conditions under microwave irradia-
tion for the introduction of the 3,4-dichlorophenyl moiety.19
Heterogenous hydrogenation of the double bond on Boc
protected derivative 9a gives rise to 10, an intermediate in
Chandrasekar’s total synthesis of sertraline,20 in poor 2:1
diastereoselectivity.21 On the other hand, homogeneous
Scheme 6. Formal Total Syntheses of Sertraline and
Norsertraline
hydrogenation of the acetylated derivative 9b, an inter-
22
€
mediate in Backvall’s total synthesis of norsertraline,
using Crabtree’s cataysts has been reported to proceed in
excellent diastereoselectivity.23
In conclusion, a one-pot procedure for the asymmetric
synthesis of cyclic benzo-fused homoallylic amines by
diastereoselective allylation of Elllman’s sulfinylimines
followed by RCM has been developed. The methodology
shows broad scope and is amenable for the three-step one-
pot protocol starting from the corresponding aldehyde.
While other syntheses of sertraline are very limited with
respect to the introduction of functionalities in the aromatic
ring of the tetrahydronaphthalene ring, our methodology is
suitable for the preparation of analogs bearing substitution
at the aromatic ring of the tetrahydronaphthalene core.
Acknowledgment. We would like to thank the Spanish
ꢀ
Ministerio de Ciencia e Innovacion (CTQ2010-19774) and
Generalitat Valenciana (PROMETEO/2010/061) for their
financial support. P.B. expresses his thanks for a Juan de la
Cierva contract, E.R. thanks the Universidad de Valencia,
and R.L. thanks the Spanish goverment for pre-doctoral
fellowships.
Supporting Information Available. Detailed experimental
procedures, optimization tables, and complete character-
1
ization data including H, 13C, and 19F NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
intermolecular Heck reaction (see Supporting Information),
a more conservative double bond preactivation strategy
was adopted. Hence, a dibromination/debromination
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(22) Thalen, L. K.; Zhao, D.; Sortais, J.-B.; Paetzold, J.; Hoben, C.;
€
Backvall, J. E. Chem.;Eur. J. 2009, 15, 3403.
(23) Compound 9b is obtained in four steps from 5a in 26% global
(18) Overoxidation of the chiral auxiliary by bromine seems to be
responsible for this undesired side reaction.
(19) See Supporting Information for details.
(20) Chandrasekhar, S.; Reddy, M. V. Tetrahedron 2000, 56, 1111.
(21) Compound 10 is obtained in five steps from 5a in 23% global
yield (2:1 dr), while in Chandraserkar’s synthesis the global yield is 22%
(9:1 dr) for seven steps starting from phenylglycine limiting its applic-
ability for the synthesis of analogs.
€
yield, while in Backvall’s synthesis the global yield is 31% for four steps
starting from racemic 1,2,3,4-tetrahydro-1-naphthylamine which is in
turn acetylated under chemoenzymatic dynamic kinetic resolution
(DKR) conditions. Once again, the applicability of this strategy for
the synthesis of derivatives is limited.
The authors declare no competing financial interest.
D
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