A stereocontrolled route to 2-substituted chromans

Article abstract of DOI:10.1016/S0040-4039(00)01530-6

A two-step synthesis of 2-substituted chromans of high enantiomeric purity is described. Mitsunobu reaction of homochiral halopropanols 10 with 2-bromophenol (9), followed by treatment with n-butyllithium under Parham cycloalkylation conditions generates

Full text of DOI:10.1016/S0040-4039(00)01530-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8655–8659
A stereocontrolled route to 2-substituted chromans
Kevin J. Hodgetts*
Department of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
Received 14 August 2000; accepted 12 September 2000
Abstract
A two-step synthesis of 2-substituted chromans of high enantiomeric purity is described. Mitsunobu
reaction of homochiral halopropanols 10 with 2-bromophenol (9), followed by treatment with n-butyl-
lithium under Parham cycloalkylation conditions generates 2-substituted chromans 7. The methodology
was applied to the synthesis of the natural product tephrowatsin E (5) and the antiviral BW683C (6).
© 2000 Elsevier Science Ltd. All rights reserved.
The chroman ring system occupies a prominent position among oxygen heterocycles, occur-
ring naturally with a variety of substituents at C-2.1 Disubstituted examples include a-toco-
pherol (vitamin E) (1)2 and the psychotropic tricycle D9-tetrahydrocannabinol (2).3
Monosubstituted examples include the anti-HIV agent calanolide A (3),4 the antibiotic LL-
D253a (4),5 and the plant product tephrowatsin E (5).6 In addition, many biologically active
synthetic chromans have been reported, for example racemic 4%,6-dichloroflavan (BW683C) (6),
a potent in vitro inhibitor of rhinovirus replication.7
* Corresponding author. Present address: Neurogen Corporation, 35 Northeast Industrial Road, Branford, CT 06405,
USA. Tel: 1-203-488-8201; fax: 1-203-483-7027; e-mail: khodgetts@nrgn.com
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01530-6

8656
While there is extensive literature on the synthesis of chromans, most efforts are specifically
directed to the synthesis of the tocopherol and tetrahydrocannabinol ring systems. We required
access to a series of homochiral 2-aryl and 2-alkyl monosubstituted chromans for which there
are few general routes. Knight8 has recently reported a chroman ring synthesis based on the
intramolecular trapping by alcohols of benzynes generated from 7-substituted-1-aminobenzo-
triazoles. Trost’s synthesis of calanolide A (3) utilizes an asymmetric O-alkylation of a phenol
followed by functionalization and an aromatic ring closure to the chromanol 3.4 Routes to
2-alkylchroman-4-ones reported in the literature include the diastereoselective conjugate addi-
tion of lithium dimethylcuprate to (S)-3-(p-tolylsulphinyl)chromanones reported by Wallace,9 as
well as an approach based on the Houben–Hoesch reaction reported by Rama Rao.10
Our approach is outlined in Scheme 1. Parham11 cyclization of an aryl bromide 8 should give
the chroman ring system 7. The aryl bromide 8 should be accessible via a Mitsunobu12 inversion
reaction between 2-bromophenol (9) and the appropriately substituted halopropanol 10.13 Chiral
propanols 10 are either commercially available or readily prepared via asymmetric reduction of
the corresponding ketone.14
Scheme 1.
Our preliminary results are shown in Table 1. Commercially available (R)-(+)-3-chloro-1-
phenyl-1-propanol (12)15 was treated with 2-bromophenol (11) under standard Mitsunobu
inversion conditions to give, following chromatography, the (S)-phenyl ether 13a in 78% yield
Table 1
n
Reaction conditions: (i) PPh3, DEAD, THF, rt, 8–36 h; (ii) BuLi, THF, −50°C to rt
Entry
R1
R2
R3
R4
R
X
Yield 13 (%)
Yield (%)
a
b
c
d
e
f
H
H
H
H
H
MeO
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Me
Ph
Cl
Cl
Cl
Cl
Br
Cl
78
82
81
64
67
76
14a
14b
14c
14d
14e
5
83
77
78
74
81
78
Me
Cl
H
H
H
ꢀ(CH)4ꢀ
H
MeO
H
H

8657
(entry a, Table 1). Initially, we subjected 13a to the cyclization conditions originally described
by Parham, but these led to only moderate yields of the 2-phenylchroman (14a).11 Optimal
conditions for the Parham cyclization were found to be a modified version of those recently
described by Spoors16 for the cyclization of 2-(o-bromophenoxy)ethyl bromides to benzodihy-
drofurans; addition of 13a to one equivalent of n-butyllithium in THF at −50°C and allowing
the reaction to warm to room temperature. Under these conditions, (2S)-(−)-phenylchroman
(14a), [h]D=−15 (c 3.0 in CHCl3) [lit.17 [h]D=−15.3 (c 3.48 in CHCl3)] was obtained. The sign
and magnitude of rotation confirmed that the Mitsunobu reaction occurred with inversion and
the two steps without significant racemization. A single recrystallization from methanol gave
material of >99% e.e. by HPLC analysis.18 In order to investigate the utility of the methodology,
a variety of readily available substituted bromophenols 11 (entries b, c, d and f) were studied in
the reaction with (R)-(+)-3-chloro-1-phenyl-1-propanol (12). The Mitsunobu reaction and
cyclization all proceeded in good yields and without significant racemization to furnish the
(2S)-phenylchromans 14b, 14c, 14d, and 5, respectively. Tephrowatsin E (5) was previously
isolated from the aerial parts of Tephrosia Watsoniana.6 The spectral properties of our synthetic
sample were in close agreement with the reported spectral data.6 Replacement of the 2-phenyl
substituent with an alkyl substituent was possible by repeating the sequence with 2-bromophenol
(11) and (S)-4-bromobutane-2-ol (12e)19, which gave (2R)-methylchroman (14e) in 54% yield
over the two steps (entry e).
The range of potential substituents located at the chroman 2-position can be extended further
by taking advantage of the asymmetric reduction of suitable prochiral ketones,14 as exemplified
by the first synthesis of enantiomerically pure (R)-4%,6-dichloroflavan (6) (Scheme 2). Catalytic
asymmetric reduction of 3,4%-dichloropropiophenone (15) with (R)-oxazaborolidine and borane,
under the conditions described by Corey,20 gave (S)-3-chloro-1-(4-chlorophenyl)-1-propanol (16)
1
in 91% yield and 94% e.e. as judged by H NMR analysis of the MTPA (Mosher) ester.21
Mitsunobu reaction of 16 with 2-bromo-4-chlorophenol and cyclization with one equivalent of
n-butyllithium gave, following recrystallization from methanol, BW683 (6) of >99% e.e. by
HPLC analysis.18 Racemic BW683C (6) is a potent in vitro inhibitor of rhinovirus replication
and was previously isolated in enantiomerically pure form following preparative HPLC using
the chiral stationary phase cellulose tris(3,5-dimethylphenylcarbamate).22
Scheme 2. Reaction conditions: (i) BH3, (R)-oxazaborolidine, THF, 0°C, 91%; (ii) 2-bromo-4-chlorophenol, PPh3,
n
DEAD, THF, rt, 16 h, 85%; (iii) BuLi, THF, −50°C to rt, 78%
Bradsher has examined the selectivity of n-butyllithium towards aromatic dibromides in the
Parham cyclization.23 It was reported that the bromide adjacent to the ether preferentially reacts
with one equivalent of n-butyllithium to initiate cyclization between −100 and −78°C. The
second bromide was then exchanged by the addition of further n-butyllithium at −100°C
followed by in situ trapping with an electrophile. As expected, replication of these conditions
with the dibromide 17 was complicated by the relatively slow cyclization step and a mixture of

8658
products was obtained. Treatment of the dibromide 17 (entry a, Table 2) with one equivalent of
n-butyllithium, under our modified conditions, gave the 6-bromo-2-phenylchroman (18a) in 84%
yield, confirming the selectivity for the ortho-bromide described by Bradsher. This reaction was
repeated, but when the cyclization was judged to be complete, the reaction mixture was
re-cooled to −50°C and two equivalents of n-butyllithium were added followed by an excess of
DMF. This time the desired 6-carbaldehyde-2-phenylchroman (18b) was isolated in 81% yield
(entry b). A range of other electrophiles were screened in the double lithiation reaction and each
gave the desired 6-substituted-2-phenylchroman 18 in good to moderate yields (entries c, d and
e). Repeating the sequence with the 2,6-dibromoether 17 (entries f and g) gave the expected
8-bromo-2-phenylchroman (18f) and 8-carbaldehyde-2-phenylchroman (18g) in good yields,
further extending the synthetic utility of this procedure.
Table 2
n
n
Reagents and conditions: (i) BuLi, THF, −50°C to rt 2 h; (ii) −50°C, BuLi, 30 min; (iii) E+ (4–6 equivalents),
−50°C to rt
Dibromide
R2
Product
R2
Entry
R1
Electrophile
R1
Yield (%)
a
b
c
d
e
f
Br
Br
Br
Br
Br
H
H
H
H
H
H
Br
Br
–
Br
H
H
H
H
H
Br
CHO
84
81
78
80
57
79
76
DMF
CO2 (g)
MeI
(CH2O)n
–
CHO
CO2H
Me
CH2OH
H
g
H
DMF
H
In conclusion, we have developed a general and flexible synthesis of 2-substituted chromans
of high enantiomeric purity from readily available starting materials. A natural product
tephrowatsinE (5) and a biologically active synthetic compound BW683 (6) were prepared using
the methodology. Further studies in this area will be the subject of future reports.
Acknowledgements
University College Dublin and Schering-Plough (Avondale) are thanked for the funding of
this research under the Newman Fellowship program and the Department of Chemistry at
University College Dublin are thanked for the use of facilities during this research.

8659
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