[1,4]-SPh shift cyclisations or [1,2]-SPh-cyclisations as alternative cascade sequences for stereocontrolled synthesis of substituted tetrahydrofurans

Article abstract of DOI:10.1055/s-1999-2815

Treatment of 4-phenylsulfanyl-1,5,7-triols with TsCl in pyridine gives substituted tetrahydrofurans by [1,4]-SPh participation via a five membered sulfonium salt and then capture by a tethered nucleophile. Acid catalysed rearrangement gives other THFs by [1,2]-SPh migration and cyclisations.

Full text of DOI:10.1055/s-1999-2815

LETTER
1215
[1,4]-SPh Shift Cyclisations or [1,2]-SPh-Cyclisations as Alternative Cascade
Sequences for Stereocontrolled Synthesis of Substituted Tetrahydrofurans
Jason Eames,1 Nikolai Kuhnert2 and Stuart Warren*
University Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, England
Fax (01223) 336913; E-mail sw134@cam.ac.uk
Received 3 June 1999
We now report that combining aspects of the two migra-
Abstract: Treatment of 4-phenylsulfanyl-1,5,7-triols with TsCl in
tions in a cascade reaction sequence leads to a new synthe-
pyridine gives substituted tetrahydrofurans by [1,4]-SPh participa-
sis of tetrahydrofurans. The idea was to capture the
tion via a five membered sulfonium salt and then capture by a teth-
ered nucleophile. Acid catalysed rearrangement gives other THFs
intermediate 9 in the [1,4]-SRA migration by a nucleo-
by [1,2]-SPh migration and cyclisations.
philic OH group in the style of the formation of 7 during
[1,2]-SRA migration. Open chain 1,7-diols 8 were re-
quired with a tertiary PhS group at C-4 so that tosylation
would be chemoselective at the primary alcohol and for-
mation of the sulfonium salt 9 by [1,4]-SPh participation
would be followed by cyclisation of the remaining (sec-
ondary) alcohol to give the THF 10. The arrows show
only the direction of cyclisation.
Key words: cyclisations, heterocycles, stereoselective synthesis,
sulfur chemistry, rearrangements
In a series of papers we have reported rearrangements on
diols such as 2 involving stereospecific [1,2]- or [1,4]-
SRA migrations via three-membered 3 or five-membered
1 cyclic sulfonium salts to give single diastereoisomers or
enantiomers of a variety of products.3-7 The two types of
migration can be complementary: heterocycles 4 and 7 as
well as allylic derivatives 5 and 6 are related by the ex-
change of oxygen and sulfur functionality.8
R
R
[1,4]-SPh
1
7
4
TsCl
pyr
HO
HO
OH
S
SPh
Ph
8
9
HO
OH
cyclisation
SRA
S
SPh
R
5
4
O
RA = CH2Ph
RA = Ph RB= H
RB= H
10
HO
Scheme 2
S
RA
The synthesis of the required starting materials is outlined
below. Starting from TBDPS-protected 4-hydroxy-pen-
tan-2-one9 11, aldehyde 13 was obtained by the Jansen
and de Groot methodology10 using pyridine as the base in
the rearrangement step of 12. The aldehyde 13 has previ-
ously been reported.11 Addition of the lithium enolate of
acetone to 13 gave the hydroxy ketone anti-14 as a sepa-
rable mixture of diastereoisomers (94:6 in favour of the
Felkin-Anh product) in moderate yield. Reduction of anti-
14 using either Prasad’s syn-12 or Evans' anti-selective
reagents13 gave the diols anti,anti-15 and syn,anti-15 in
good yields and excellent diastereoselectivities. The extra
hydroxyl group in 15 compared to 8 at C-5 allows control
over the relative stereochemistry at C-4 and C-7 and of-
fers greater versatility in rearrangement.
1
[1,4]-SRA
TsCl
pyridine
OH
RAS
ORB
2
TsOH
[1,2]-SRA
CH2Cl2
RAS
ORB
3
RAS
RAS
ORB
O
Preliminary attempts to effect cyclisation were disap-
pointing, firstly since, after deprotection of diols syn,anti-
15, the corresponding triols could not been isolated in
pure form due to their poor solubility. Secondly our usual
conditions8 for [1,4] PhS migration (TsCl in neat pyri-
RB = H
R
B = SiR3
6
7
Scheme 1
Synlett 1999, No. 8, 1215–1218 ISSN 0936-5214 © Thieme Stuttgart · New York

1216
J. Eames et al.
LETTER
SPh
OHC
PhS
OMe
OTBDPS
11 ; TBDPS =
OTBDPS
MeO
OTBDPS
BuLi
SOCl2
pyridine
O
SPh
OH
13
12; 2:1 mixture of
diastereoisomers
t-butyldiphenylsilyl
OLi
- 100 °C
OH OH
OTBDPS
Me4N [BH(OAc)3]
1:1 MeCN/HOAc
SPh
anti,anti-15, 85%, >98:2
O
OH
OTBDPS
OH OH
SPh
1. Et2B-OMe
2. NaBH4
anti-14
72% yield
94:6 anti:syn
OTBDPS
SPh
3. HOAc
syn,anti-15, 81%, 89:11
Scheme 3
OH
OH OH
1. TBAF (Bu4NF)
OTBDPS
SPh
2. TsCl, pyridine, CH2Cl2
O
SPh
anti,anti-15,>98:2
syn,syn-16, 67%, 95:5
TBAF
OH
OH OH
OH OH
TsCl
pyr
OTs
S
OH
S
OH
Ph
19
SPh
17
Ph
18
OH OH
OH
1. TBAF (Bu4NF)
OTBDPS
SPh
2. TsCl, pyridine, CH2Cl2
SPh
syn,anti-15, 89:11
O
anti,syn-16, 51%, 95:5
Scheme 4
dine) gave only insoluble oligomeric material. However synthesise these compounds as well. Treatment of diols
reaction conditions were found to effect the [1,4] migra- anti,anti-15 and syn,anti-15 under our usual conditions
tion–cyclisation cascade, using dilute reaction mixtures (TsOH in CH2Cl2) gave THFs anti,anti-21 and syn,anti-
(deprotection of the diol 15 with TBAF and in-situ cycli- 21 in almost quantitative yield. The reaction presumably
sation of the triol 17 with TsCl and pyridine all at 0.01 M proceeds via the episulfonium ion 20 and is stereospecific
in CH2Cl2). The THFs syn,syn-16 and anti,syn-16 were with inversion at the migration origin and terminus.
obtained in moderate yield as an inseparable 95:5 mixture Deprotection with TBAF gave alcohol anti,anti-22, which
of diastereoisomers (relative GC-MS area).14
is both a positional isomer (OH and PhS exchanged) of
syn,syn-16 and in a different stereochemical series. This
compound (anti,anti-22) was not identical to either minor
diastereoisomer found in the [1,4]-SPh migration-cyclisa-
tion sequence of reactions.
The reaction presumably proceeds via chemoselective to-
sylation at the primary hydroxyl group, formation of the
five membered sulfonium ion 19 and intramolecular cy-
clisation by the tethered nucleophile. Cyclisation onto the
five membered ring sulfonium ion 19 is a favourable 5- Synthesis of a diol with a tertiary alcohol as potential nu-
exo-tet process (by Baldwin’s rules15). The reaction was cleophile was accomplished using Heathcock’s anti-aldol
shown to be stereospecific with inversion at the migration methodology17 to give the hydroxy ester anti,anti-23 and,
origin and retention at all other stereogenic centres by 500 after further addition of two equivalents of MeMgCl, the
MHz NOESY spectroscopy on syn,syn-16 and anti,syn- diol anti,anti-24. Cyclisation of diol anti,anti-24 with a
16. We believe the minor isomer to be the epimer at the tertiary alcohol as an internal nucleophile gave the THF
tertiary migration origin C-2; epimerisation presumably syn,syn-26 in only poor yield. Moreover overlapping of
occurs by ring opening and reclosing of the sulfonium ion.
the Me-NMR signals (500 MHz) prevented an unambig-
ious assigment of stereochemistry. That this poor result is
partly because of the developing syn stereochemistry in
the migration 25 was shown by the more successful rear-
rangement of anti-27. Yields are still not as good as when
a secondary alcohol is the nucleophile.
In order to exclude the possible isomers resulting from the
rearrangement under [1,2]-SPh participation (we have
previously observed products resulting from acid cataly-
sed [1,2]-SPh participation, presumably due to the pres-
ence of pyH+ in the reaction mixture)16 we decided to
Synlett 1999, No. 8, 1215–1218 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
[1,4]-SPh Shift Cyclisations or [1,2]-SPh-Cyclisations
1217
SPh
OH OH
Ph
TsOH
S
OTBDPS
OTBDPS
OTBDPS
CH2Cl2
R
O
SPh
anti,anti-15,>98:2
OH
20
anti,anti-21,97%
TBAF
SPh
OH OH
SPh
TsOH
OTBDPS
syn,anti-21,96%
OH
CH2Cl2
SPh
O
O
syn,anti-15, 89:11
anti,anti-22,84%
Scheme 5
O
OH
OH OH
O
MeMgCl
1. LDA
ArO
OTBDPS
OTBDPS
2. 13
ArO
Ar = 2,6-
SPh
SPh
dimethylphenyl
anti,anti-23, 92%, >98:2
anti,anti-24, 74%
developing
syn stereo-
chemistry
OH
OH
OH
1. TBAF (Bu4NF)
anti,anti-24
SPh
SPh
S
2. TsCl, pyridine, CH2Cl2
OH OH
O
Ph
25
syn,syn-26, 19%
OH
1. TBAF (Bu4NF)
MeMgCl
anti-14
OTBDPS
2. TsCl, pyridine, CH2Cl2
O
SPh
anti-27, 85%
syn-28, 38%
Scheme 6
(4) Villa, M.-J.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1994,
2953.
(5) Eames, J.; Heras, M. A. d. l.; Jones, R. V. H.; Warren, S.
Tetrahedron Lett. 1996, 37, 1117.
(6) Chibale, K.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1995,
2411.
(7) Coldham, I.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1993,
1637.
In conclusion we have shown that chemoselective tosyla-
tion of 4-PhS-1,5,7-triols takes place at the primary hy-
droxy group and gives, via a five membered cyclic
sulfonium ion and subsequent nucleophilic attack by the
tethered nucleophile, highly substituted tetrahydrofurans
in which three stereogenic centres are built up.
The reaction proceeds with inversion at the migration or-
igin and retention at all other stereogenic centres. Further-
more it was shown that in this reaction, unlike the
cyclisations following [1,2]-SPh participation, secondary
alcohols are better nucleophiles than tertiary alcohols. The
same 4-PhS-1,5,7-triols undergo cyclisation following
[1,2]-SPh shift in acidic conditions to give positional and
diasteroisomeric THFs. All new compounds gave satis-
factory 1H and 13C NMR spectra and MS data.18
(8) (a) Djakovitch, L.; Eames, J.; Jones, R. V. H.; McIntyre, S.;
Warren, S. Tetrahedron Lett. 1995, 36, 1723. (b) Eames, J.;
Jones, R. V. H.; Kuhnert, N.; Warren, S. Tetrahedron Lett.
1998, 39, 1247.
(9) Protection of 4-hydroxy-pentan-2-one turned out in our hands
to be very capricious, since formation of a silylated cyclic
five-membered acetal, resulting from a highly favourable 5-
exo-tet process, was a competing reaction. Protection was
achieved by extremely slow addition of TBDPSCl to a stirred
solution of the alcohol in DMF/imidazole and stirring for 14
days.
(10) (a) Groot, A. d.; Jansen, B. J. M. Synthesis 1985, 434.
(b) Groot, A. d.; Jansen, B. J. M. Tetrahedron Lett. 1981, 22,
887.
(11) McIntyre, S.; Sansbury, F. H.; Warren, S. Tetrahedron Lett.
1991, 32, 5409.
(12) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.;
Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155.
(13) Chapman, K. T.; Evans, D. A.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(14) As an alternative product, an eight membered ring resulting
from a 8-exo-tet cyclisation, would be feasible but could be
excluded by MS data.
Acknowledgement
We thank EPSRC for a grant (to J. E.), RTL and DFG (Deutsche
Forschungsgemeinschaft) for grants (to N. K.), Nick Pryce for 500
MHz NOESY spectra and the Dyson-Perrins Laboratory of the Uni-
versity of Oxford for the use of GC-MS facilities.
References and Notes
(1) New address: Department of Chemistry, Queen Mary and
Westfield College, University of London, London E1 4NS.
(2) New address: Department of Chemistry, University of Surrey,
Guildford GU2 5XH, England.
(3) Aggarwal, V. K.; Coldham, I.; McIntyre, S.; Warren, S. J.
Chem. Soc., Perkin Trans. 1 1991, 451.
(15) Baldwin, J. E. J. Chem. Soc. Chem. Commun. 1976, 734.
Attempted stereoselective [1,4]-PhS migration on the triol 29
gave a 1:1 mixture of the two products of a [1,4]-SPh shift,
Synlett 1999, No. 8, 1215–1218 ISSN 0936-5214 © Thieme Stuttgart · New York

1218
J. Eames et al.
LETTER
131.3, 129.6, 129.0, 127.6, 126.8 (Ar), 82.2 (CO), 72.0
(CHO), 64.0 (COSi), 56.3 (CHSPh), 42.2 (CH2), 33.1 (CH2),
30.4 and 28.2 (CH3) 27.4 (CH2), 27.1 (t-Bu) and 22.1
(CH3CH); m/z 489 (15%, M - CH3), 447 (25, M - t-Bu), 337
(M - t-Bu - PhS) and 110.0 (20, PhSH).
syn- and anti-30, and about 30% of the product of a [1,2]-SPh
shift, the THF anti-31
OH
OH
OH
PhS
PhS
Typical Procedure for [1,4] Cascade: e.g. preparation of syn-
28: TBAF (0.3 mL, 1 M solution in THF, 0.3 mmol) was
added to a solution of diol anti-27 (0.16 g, 0.3mmol) in THF
(3 mL) and stirred for 20 h at r.t. The solvent was removed
under reduced pressure and the residue was redissolved in
CH2Cl2 (30 mL). Pyridine (0.5 mL) and TsCl (54 mg, 0.3
mmol) was added, and the solution was stirred overnight. The
organic phase was washed with HCl (5 mL, 3 M), NaHCO3 (5
mL), brine (5 mL) and dried over MgSO4. The solvent was
removed under reduced pressure and the residue was further
purified by column chromatography (light petroleum (40-
60 °C)/ether 9:1) to give the THF syn-28 (31 mg, 38%) as an
oil; vmax (film, CDCl3)/cm-1 3500-3300 (OH) and 1551 (PhS);
dH(200MHz, CDCl3) 7.44-7.20 (5H, m, SPh), 3.79 (1H, m,
CHOH), 2.92-2.95 (2H, m, CH2SPh), 2.21-2.28 (2H, m,
CH2CHOH), 1.95-2.01 (1H, m, CHAHB), 1.63-1.79 (3H, m,
CHAHB and CH2), 1.21 (6H, s, 2 x, CH3) and 1.19 (3H, s,
CH3); dC(50MHz, CDCl3) 136.5, 128.8, 128.6, 125.7 (SPh),
87.1 (C-O), 82.6 (CO), 82.0 (CHOH), 44.2 (CSPh), 34.7, 32.2,
28.1 and 25.6; m/z 280 (2%, M) and 110 (30, PhS).
TsCl
pyr
OH
OH
SPh
+
O
OH
1:1 syn:anti-30
29
30% anti-31
Scheme 7
(17) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M.
C.; Sohn, J. E.; Lampe, J. J. Org. Chem. 1980, 45, 1066.
(18) Selected experimental and spectroscopic details;
Typical experimental procedure for [1,2] cascade sequence:
e.g. THF syn-anti-21: TsOH (3.4 mg, 0.02 mmol) was added
to a stirred solution of diol syn-anti-15 (52 mg, 0.1 mmol) in
CH2Cl2 (5 mL). The solution was refluxed for 5 min, cooled
to room temperature and filtered through a silica plug. The
solvent was removed under reduced pressure to give the THF
syn-anti-21 (48 mg, 96%) as an oil; vmax (film, CDCl3)/cm-1
1550 (SPh); dH(400MHz, CDCl3) 7.67-7.20 (15 H, m, Ar),
4.07 (1 H, dq J 9.8 and 5.9, CHCH3), 3.65 (2H, t, J 6.2,
CH2OSi), 3.44 (1 H, dd, J 11.0 and 6.8, CHSPh), 2.45 (1 H, q,
J 5.64, CHAHB), 1.70-1.85 (2H, m, CH2), 1.52-1.59 (2H, m,
CH2), 1. 25 (3 H, s, CH3), 1.26 (3 H, d, J 6.13, CH3CH) and
1.03 (9H, s, t-Bu); dC(100MHz, CDCl3) 137.4, 137.2, 135.8,
Article Identifier:
1437-2096,E;1999,0,08,1215,1218,ftx,en;L14699ST.pdf
Synlett 1999, No. 8, 1215–1218 ISSN 0936-5214 © Thieme Stuttgart · New York