Sulfoxide-directed stereocontrolled access to 2H-chromans: Total synthesis of the (S,R,R,R)-enantiomer of the antihypertensive drug nebivolol

Article abstract of DOI:10.1002/ejoc.200800201

A homochiral sulfoxide-directed reductive deoxygenation of 2-(p-tolylsulfinyl)methyl-2-chromanols allows the stereoselective formation of 2H-chromans with up to 95:5 diastereoisomeric ratio. This new methodology was applied in a short and convergent enantioselective synthesis of the (S,R,R,R)-enantiomer of the antihypertensive drug Nebivolol. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800201

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800201
Sulfoxide-Directed Stereocontrolled Access to 2H-Chromans: Total Synthesis
of the (S,R,R,R)-Enantiomer of the Antihypertensive Drug Nebivolol
M. Carmen Carreño,*[a] Gloria Hernández-Torres,[a] Antonio Urbano,*[a] and
Françoise Colobert*[b]
Keywords: Chromans / Drug synthesis / Stereoselectivity / Sulfoxides
A homochiral sulfoxide-directed reductive deoxygenation of
2-(p-tolylsulfinyl)methyl-2-chromanols allows the stereo-
selective formation of 2H-chromans with up to 95:5 dia-
stereoisomeric ratio. This new methodology was applied
in a short and convergent enantioselective synthesis of
the (S,R,R,R)-enantiomer of the antihypertensive drug
Nebivolol.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Sulfoxides have been extensively used in asymmetric syn-
thesis due to the excellent asymmetric inductions they pro-
vide in a wide range of reactions.[1] Among them, the dia-
stereodivergent reduction of β-keto sulfoxides has been one
of the most exploited in synthetic applications. We recently
reported[2] an enantioselective access to different sized cis-
α,ω-disubstituted cyclic ethers (II, Scheme 1) based on the
combination of the stereocontrolled reduction of a β-keto
sulfoxide and the reductive cyclization of the resulting β-
hydroxysulfinyl ketone I, in which the stereogenic hydrox-
ylic center was controlling the stereochemical course of the
reaction. Seeking for a short stereoselective approach to the
2H-chroman unit, a structural component of several natu-
ral products and pharmaceuticals, we thought about the di-
rect transformation of enantiopure 4-(2-hydroxyphenyl)-1-
(p-tolylsulfinyl)-2-butanone III into sulfinyl-substituted 2H-
chroman V, in which the homochiral sulfoxide would be
solely responsible for the diastereoselectivity of the reac-
tion. Although important advances in the formation of the
C-2 stereocenter in such systems have been achieved,[3] to
the best of our knowledge, sulfoxides have never been used
as asymmetric inductors to directly generate the 2H-chro-
man moiety from a phenol in a single step.
Scheme 1. Seeking the sulfoxide-directed stereocontrolled access to
2H-chromans.
Herein we describe a novel enantioselective access to the
hydrobenzopyran moiety with a defined stereochemistry at
the C-2 stereogenic center, starting from easily accessible δ-
(o-hydroxyphenyl)-substituted β-keto sulfoxides III, on the
basis of the stereoselective Et3SiH/TMSOTf-promoted de-
oxygenation of the corresponding lactols IV, in equilibrium
with the former. An additional advantage of our method is
the presence of the sulfoxide in the resulting 2H-chromans,
allowing further synthetic exploitation. We illustrate the
efficiency of our approach with a short and convergent syn-
thesis of (S,R,R,R)-Nebivolol, a known antihypertensive
drug currently in clinical use, which has potent and selective
β1-adrenergic antagonist activity.[4]
[a] Departamento de Química Orgánica (C-I), Universidad Autó-
noma de Madrid
Cantoblanco, 28049 Madrid, Spain
Fax: +34-91-4973966
E-mail: carmen.carrenno@uam.es;
antonio.urbano@uam.es
Results and Discussion
[b] Laboratoire de Stéréochimie associé au CNRS, UMR 7509
Université Louis Pasteur, ECPM
The synthesis of β-keto sulfoxide (R)-3a, chosen as a
model, was achieved from reaction of hydrocoumarin 1a
with the LDA-generated lithium anion of (R)-methyl p-tolyl
25 rue Becquerel 67087 Strasbourg Cedex 2, France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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M. C. Carreño, G. Hernández-Torres, A. Urbano, F. Colobert
SHORT COMMUNICATION
sulfoxide [(R)-2][5] (Scheme 2). Under these conditions, 3a
was isolated as an equilibrium mixture with cyclic hemiketal
(R)-4a (mixture of C-2 epimers), in 90% yield. When this
mixture was sequentially treated with Et3SiH and TMSOTf
at 0 °C, a stereoselective reductive deoxygenation process
took place affording, in 86% yield, 2H-chroman (S,R)-5a[6]
in an excellent 95:5 diastereoisomeric ratio. A mechanistic
pathway explaining this result involves the initial formation
of an oxocarbenium intermediate such as A, after ionic
cleavage of the C–OH bond of (R)-4a by activation with
TMSOTf. After coordination of the silane to the sulfinyl
oxygen of A, the attack of the hydride mainly occurred from
the lower face of the dihydrobenzopyran unit in the pre-
ferred six-membered chair-like transition state represented
in Scheme 2, showing the most favorable equatorial disposi-
tion of the bulky p-tolyl substituent of the sulfoxide.
Scheme 2. Highly diastereoselective two-step synthesis of 2H-chro-
man (S,R)-5a.
With this result in hand, we turned our attention to the
total synthesis of the antihypertensive agent (S,R,R,R)-Ne-
bivolol. Although racemic Nebivolol has been prepared by
a number of groups, including several patents,[7] only a few
syntheses of the (S,R,R,R)-enantiomer have been addressed
mainly by using nonstereoselective approaches or multistep
processes.[8] The main challenging and non-well resolved
task has been the efficient generation of the C-2 stereocen-
ters at the 2H-chroman units.
We initiated the synthesis of the left fragment of
(S,R,R,R)-Nebivolol, (S,R)-10, with the addition of the lith-
ium anion of (R)-2 to 6-fluorochroman-2-one (1b)[9] to ob-
tain, in 83% yield, lactol (R)-4b, as a mixture of C-2 epi-
mers (Scheme 3). The treatment of 4b with Et3SiH/
TMSOTf, following the protocol previously established for
4a, afforded, in 75% yield, enantiopure 2H-chroman (S,R)-
5b, after separation of the initially formed 87:13 mixture of
diastereoisomers.
Scheme 3. Convergent total synthesis of the (S,R,R,R)-enantiomer
of the antihypertensive drug Nebivolol hydrochloride starting from
lactone 1b. Reagents and conditions: (a) LDA, THF, –78 °C; (b)
Et3SiH (10 equiv.), TMSOTf (2 equiv.), CH2Cl2, 0 °C; (c) (i) 2,4,6-
collidine, TFAA, CH3CN, 0 °C; (ii) CuCl2, H2O, room temp.; (d)
NaH, BnBr, nBu4NI, THF, room temp.; (e) BnNH2, NaBH-
(OAc)3, 1,2-dichloroethane, room temp.; (f) Ph3PCH3Br, nBuLi,
THF, –78 °C to room temp.; (g) AD-mix-α, tBuOH/H2O, 0 °C; (h)
TsCl, pyridine, 0 °C; (i) NaH, THF, room temp.; (j) EtOH, reflux;
The stereoselective formation of the second chiral carbi-
nol present on the left fragment of (S,R,R,R)-Nebivolol,
was achieved after transformation of sulfoxide (S,R)-5b into (k) (i) H2, Pd/C, EtOH, room temp. (ii) HCl (g), room temp.
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Total Synthesis of the (S,R,R,R)-Enantiomer of Nebivolol
aldehyde (S)-6 through a Pummerer reaction[10] (90% yield, (c = 0.16, MeOH), corresponded to an optical purity
Scheme 3), followed by addition of the lithium anion de- Ͼ99%, measured by chiral HPLC. Thus, the (S,R,R,R)-en-
rived from (S)-methyl p-tolyl sulfoxide [(S)-2][5] to aldehyde antiomer of the antihypertensive drug Nebivolol was pre-
(S)-6. Under these conditions, compound (S,S,S)-7[6] could pared in nine steps for the longest linear sequence, with
be isolated pure in 75% yield, after chromatographic sepa- 11.5% overall yield.
ration of the initially formed 85:15 mixture of epimeric β-
hydroxy sulfoxides. The high diastereoselectivity achieved
Conclusions
can be attributed to the matched double asymmetric induc-
tion process occurring between aldehyde (S)-6 and the nu-
cleophile derived from sulfoxide (S)-2.[11]
The stereoselective reductive deoxygenation of 2-(p-tolyl-
sulfinyl)methyl-2-chromanols was shown to provide an ef-
ficient entry into the challenging generation of the stereo-
genic center at C-2 of the 2H-chroman unit, thus expanding
the known ability of homochiral sulfoxides in asymmetric
synthesis. We have applied such methodology in a new ster-
eoselective synthesis of (S,R,R,R)-Nebivolol by using both
sulfinyl lactols (R)-4b and (S)-4b for the key construction
of the left and right 2H-chroman moieties and by using the
known 6-fluorochroman-2-one (1b) as the common starting
material.
With compound 7 in hand, we undertook the transfor-
mation of the sulfoxide into the required amine present in
the advanced intermediate (S,R)-10. Protection of carbinol
7 (NaH/BnBr/nBu4NI) furnished the O-benzyl derivative
(S,S,S)-8, in 70% yield. Transformation of sulfoxide 8 into
aldehyde (S,S)-9 was again performed through a Pummerer
reaction, in 83% yield. Finally, the reductive amination of
aldehyde 9 by using BnNH2 and NaBH(OAc)3 gave diben-
zyl-protected amino alcohol (S,R)-10, in 73% yield. Thus,
we have achieved the stereoselective synthesis of the left
fragment of (S,R,R,R)-Nebivolol, (S,R)-10, from known
lactone 1b, in seven steps and 18% overall yield.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, NMR spec-
tra, and HPLC data.
The stereoselective preparation of the right fragment of
(S,R,R,R)-Nebivolol, (R,R)-14, started with the formation
of sulfinyl lactol (S)-4b (mixture of C-2 epimers) from the
reaction of lactone 1b and sulfoxide (S)-2 (Scheme 3). The
reductive deoxygenation process (Et3SiH/TMSOTf) of 4b
gave rise to a 89:11 mixture of epimers, from which (R,S)-
5b was isolated pure, in 70% yield. This result demonstrated
that it was possible to obtain both enantiomers of the 2H-
chroman moiety by simply changing the absolute configu-
ration at sulfur of the starting sulfinyl lactol. Sulfoxide 5b
was then transformed into vinyl derivative (R)-11, after
Pummerer reaction (86% yield) followed by Wittig reaction
(78% yield) on the initially formed aldehyde (R)-6. Epoxide
(R,R)-14 was finally obtained from vinyl chroman (R)-11
in a three-step stereoselective sequence. Thus, the Sharpless
asymmetric dihydroxylation of the double bond of (R)-11
with AD-mix-α gave rise, in 97% yield, to a 91:9 mixture
Acknowledgments
We thank the Spanish Ministerio de Ciencia y Tecnología (Grant
CTQ2005-02095/BQU) and the French Ministère de la Recherche
and CNRS for financial support. G. H.-T. wishes to thank the
Spanish Comunidad Autónoma de Madrid for a fellowship.
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Eur. J. Org. Chem. 2008, 2035–2038
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M. C. Carreño, G. Hernández-Torres, A. Urbano, F. Colobert
SHORT COMMUNICATION
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[11]
[12]
[13]
[14]
Nebivolol hydrochloride is marketed in Spain for the treatment
of hypertension under the trade name Lobivon®.
Different values of the optical rotation of (S,R,R,R)-Nebivolol
are reported in the literature: [α]2D0 = +0.040 (c = 0.0027,
MeOH);[8d] [α]2D0 = +0.038 (c = 0.038, MeOH);[8c] [α]2D0 = +20.8
(c = 0.2, MeOH);[8b] [α]2D0 = +0.11 (c = 0.1, MeOH).[8a]
Received: February 21, 2008
Published Online: March 17, 2008
2038
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Eur. J. Org. Chem. 2008, 2035–2038