Dihydrothiophenes containing quaternary stereogenic centres by sequential stereospecific rearrangements and ring-closing metathesis

Article abstract of DOI:10.1039/c4cc02596b

Stereospecific [3,3]-sigmatropic rearrangement of O-substituted thiocarbamate derivatives of enantiopure allylic alcohols provides allylic thiocarbamates as single enantiomers. Intramolecular arylation by rearrangement of their allyllithium derivatives provides allylic tertiary thiols. Allylation and ring-closing metathesis gives 2,5-dihydrothiophenes containing sulfur-bearing quaternary centres. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02596b

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Dihydrothiophenes containing quaternary
stereogenic centres by sequential stereospecific
rearrangements and ring-closing metathesis†‡
Cite this: Chem. Commun., 2014,
50, 6754
Received 8th April 2014,
Accepted 6th May 2014
Gaelle Mingat, Joseph J. W. McDouall and Jonathan Clayden*
¨
DOI: 10.1039/c4cc02596b
www.rsc.org/chemcomm
Stereospecific [3,3]-sigmatropic rearrangement of O-substituted
thiocarbamate derivatives of enantiopure allylic alcohols provides
allylic thiocarbamates as single enantiomers. Intramolecular arylation
by rearrangement of their allyllithium derivatives provides allylic
tertiary thiols. Allylation and ring-closing metathesis gives 2,5-dihydro-
thiophenes containing sulfur-bearing quaternary centres.
Dihydrothiophenes and tetrahydrothiophenes are important
motifs in the context of natural products, biologically active
compounds, and materials chemistry.1 Nevertheless, their
stereoselective synthesis has received little attention.1a,b Earlier
diastereoselective methods1d–f were recently enhanced by the
report from Xu and co-workers of an enantioselective synthesis
of 2,5-dihydrothiophene-3-carbaldehydes by domino thia-Michael/
aldol condensation reactions.1c,2 Dihydrothiophenes containing a
quaternary chiral center provide a motif of particular interest for
pharmaceutical applications3 which occurs in the thiotetronic
acid antibiotics3a–c including (R)-thiolactomycin,3b,4 and in
dideoxyspirothio nucleoside analogues with antiviral and anti-
cancer properties.3d
Scheme 1 Dihydrothiophenes from allylic alcohols.
thiocarbamates, but that the stereospecificity of the rearrange-
ment (which involves N to C migration of an aryl or vinyl group)
was typically compromised by the incomplete configurational
instability of the allyllithium intermediate.
Reasoning that dipole-stabilised11 allyllithiums bearing
g-substituents typically should show greater configurational
stability than those substituted only at the a-position,12 we
explored the possibility of using the migration of an aryl ring
from N to C within substituted thiocarbamates 4 as a means of
obtaining tertiary allylic thiols 3 with reliable stereospecificity.
Three pairs of allylic thiocarbamates 4 bearing p electron-donating
groups (Scheme 2) were deprotonated with LDA in order to
compare the behaviour of the substituted and unsubstituted series,
and the results are shown in Table 1.
It is evident that the more substituted allyllithium inter-
mediates 4dLi–4fLi rearrange in higher yield and with higher
stereospecificity—almost complete in the formation of 6e and
6f. Only the p-OMe-substituted thiocarbamate 4d still failed to
rearrange efficiently in the more substituted case. 4a failed to
rearrange, but NMR of the reaction mixture showed that the
In this paper we report the construction of enantiomerically
enriched 2,5-dihydrothiophenes 1 by ring-closing metathesis of
doubly allylic sulfides5
2 derived from tertiary thiols 3
(Scheme 1), themselves made from readily-obtained chiral allylic
alcohols by a pair of tandem stereospecific rearrangements.
The synthesis of five- and six-membered heterocycles by
ring-closing metathesis is well established,6,7 but for the synthesis
of sulfur heterocycles its use is rare and reportedly problematic.5,8
Nonetheless, coordination to sulfur has been proposed to enhance
Ru-promoted cross-metathesis of allyl sulfides.9
We have previously shown10 that certain allylic thiols 3
required as precursors for such an approach may be made by
rearrangement of the anionic derivatives of a class of allylic
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL,
UK. E-mail: clayden@man.ac.uk
† Dedicated to Professor Richard Taylor in celebration of his 65th birthday.
‡ Electronic supplementary information (ESI) available: Full experimental details
for new compounds. See DOI: 10.1039/c4cc02596b
Scheme 2 Stereospecificity in the rearrangement of allylic thiocarbamates.
6754 | Chem. Commun., 2014, 50, 6754--6757
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 1 The effect of a g-substituent on the stereospecificity of the
arylation of allylic thiocarbamates
R2 = H
SM
R2 = cyclohexyl
X
6, yield
er
SM
6, yield
er
MeO
Me
F
4a
0
—
57 : 43
70 : 30
4d
4e
4f
6d, 24
6e, 76
6f, 82
—
91 : 9
94 : 6
4ba
4ca
6b, 11
6c, 40
a
Data from ref. 10a.
Scheme 4 Stereospecific aryl migration in cyclohexyl-substituted allylic
thiocarbamates 4.
intermediate organolithium 4aLi was nonetheless formed,13
indicating that the poor performance of 4a–4c was indeed
due to the slow migration of the aryl ring to the less substituted,
and therefore less reactive, allyllithium.
Substituted thiocarbamates 4 may be synthesised by stereo-
specific [3,3]-sigmatropic rearrangement of enantiopure allylic
alcohols 5.14 Given that the terminal substituent R2 is lost in
the final metathesis step leading to 1, we elected to start with the
readily accessible cyclohexyl-substituted substrates 5a and 7.
Ketone 7 was reduced enantioselectively to the allylic alcohol
(S)-5a using Noyori’s catalyst 8,15 and (ꢀ)-5a underwent Sharpless
kinetic resolution to leave behind (R)-5a in lower yield but higher
e.r.16 (Scheme 3, Methods A and B).
Treatment of either (S)- or (R)-5a with thiocarbonyl-
diimidazole 9 formed imidazole derivatives 10 directly by
acylation of the allylic alcohol and in situ [3,3]-sigmatropic
rearrangement of the resulting O-allylthiocarboxylimidazole
species.17 This rearrangement was fully enantiospecific, and
nucleophilic displacement of the imidazole group in 10 with
N-methylanilines17 11 gave a series of S-allylthiocarbamates 4
in enantiomerically enriched form (Scheme 3 and Table 2).
The thiocarbamates 4 were treated with LDA at ꢁ78 1C in
order to form their allyllithium derivatives, which on warming
to ꢁ60 1C underwent intramolecular N to C aryl migration to
yield the tertiary thiocarbamates 6 (Table 2). Quenching the
anionic products with propionic acid at low temperature prior
to work-up avoided partial hydrolysis of the products. Rear-
ranged products were obtained with both electron-rich and
electron-deficient migrating rings, and in contrast with the
rearrangements of less substituted allyllithiums10 stereospeci-
ficity was uniformly high.
Basic hydrolysis of thiocarbamates 6 revealed tertiary thiols 3,
which were S-allylated under standard conditions to yield the
sulfides 2 (Scheme 4 and Table 2). Despite the presence of the
sulfur atom and the adjacent quaternary centre, the allyl sulfides
2 underwent ring-closing metathesis5 to dihydrothiophenes 1 in
the presence of 125,18a or 1318b in 63–94% yield (Scheme 5).
The absolute configuration of the dihydrothiophenes 1 was
confirmed by comparison of experimental and calculated circular
dichroism (CD) spectra of (R)-1e. The geometry of (R)-1e was
optimised at the B3LYP/6-311G(d,p) level and electronic CD
spectra were generated, within the time-dependent density func-
tional formalism, for conformations at 101 intervals about the
aryl-dihydrothiophene bond.19 These spectra were Boltzmann
weighted according to the potential energy of the conformation
to give the calculated CD spectrum shown along with the experi-
mental spectrum of (R)-1e in methanol in Fig. 1. The matching
form of the spectra leads us to assign R configuration to the
stereogenic centre of (R)-1e.
The CD spectra of (R)-1m and (R)-1n took a similar form to
that of (R)-1e, while those of (S)-1h and (S)-1i were inverted.
Scheme 3 Synthesis of enantiomerically enriched thiocarbamates 4 by
stereospecific in situ [3,3]-sigmatropic rearrangement.
Table 2 Synthesis of enantioenriched allylsulfides by stereospecific aryl migration
Entry
X
4 (er, S : R)
6, yield (er, S : R)
3, yield
2, yield
1
2
3
4
5
6
7
8
9
4-Me
4-Me
4-F
4-Cl
3-OMe
2-OMe
(S)-4e (94 : 6)
(R)-4e (13 : 87)
(S)-4f (94 : 6)
(S)-4g (95 : 5)
(S)-4h (95 : 5)
(S)-4i (94 : 6)
(R)-4j (14 : 86)
(S)-4k (94 : 6)
(S)-4l (95 : 5)
(S)-6e, 76 (91 : 9)
(R)-6e, 100 (13 : 87)
(S)-6f, 82 (94 : 6)
(S)-6g, 63 (94 : 6)a
(S)-6h, 100 (95 : 5)
(S)-6i, 100 (94 : 6)
(R)-6j, 71 (15 : 85)
(S)-6k, 30 (93 : 7)
(S)-6l, 41 (90 : 10)
—
—
(R)-3e, 91
(S)-3f, 56
3g,b 56
(S)-3h, 72
(S)-3i, 61
(R)-3j, 90
—
(R)-2e, 76
—
—
(S)-2h, 100
(S)-2i, 98
(R)-2j, —c
—
2,3-Benzo [Ar = 1-naphthyl]
– [Ar = 2-pyridyl]
N-Boc-3,4-pyrrolo [Ar = N-Boc-6-indolyl]
3l,b,d 58
2l,b 53
a
b
c
d
At ꢁ50 1C. Using racemic material. Inseparable from by-product 2j0: see ESI. (R)-3l was obtained in 39% yield from (R)-6l.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 6754--6757 | 6755

View Article Online
ChemComm
Communication
2 N. Baricordi, S. Benetti, C. De Risi, M. Fogagnolo, G. P. Pollini and
V. Zanirato, Lett. Org. Chem., 2009, 6, 593.
3 (a) C. Rapp, G. Jung, C. Isselhorst-Scharr and H. Zahner, Liebigs Ann.
¨
Chem., 1988, 1043; (b) K.-i. Toyama, T. Tauchi, N. Mase, H. Yoda and
K. Takabe, Tetrahedron Lett., 2006, 47, 7163; (c) P. Kim, Y.-M. Zhang,
G. Shenoy, Q.-A. Nguyen, H. I. Boshoff, U. H. Manjunatha,
M. B. Goodwin, J. Lonsdale, A. C. Price, D. J. Miller, K. Duncan,
S. W. White, C. O. Rock, C. E. Barry and C. S. Dowd, J. Med. Chem.,
2006, 49, 159; (d) L. A. Paquette, F. Fabris, F. Gallou and S. Dong,
J. Org. Chem., 2003, 68, 8625.
4 H. N. T. Oishi, H. Sasaki, K. Suzuki, T. Hayashi, H. Okazaki, K. Ando
and M. Sawada, J. Antibiot., 1982, 391.
5 G. Spagnol, M.-P. Heck, S. P. Nolan and C. Mioskowski, Org. Lett.,
2002, 4, 1767 and references therein.
6 For recent examples, see: (a) C. Gazon, M. Attolini and M. Maffei, Eur.
J. Org. Chem., 2013, 3653; (b) E. Benedetti, M. Lomazzi, F. Tibiletti,
J.-P. Goddard, L. Fensterbank, M. Malacria, G. Palmisano and
A. Penoni, Synthesis, 2012, 3523; (c) E. Ascic, S. T. Le Quement,
M. Ishoey, M. Daugaard and T. E. Nielsen, ACS Comb. Sci., 2012,
14, 253; (d) O. Pavluk, H. Teller and M. C. McMills, Tetrahedron Lett.,
2009, 50, 2716; (e) P.-A. Fournier and S. K. Collins, Organometallics,
2007, 26, 2945; ( f ) R. Pathak, J.-L. Panayides, T. D. Jeftic, C. B. de
Konig and W. A. L. van Otterlo, S. Afr. J. Chem., 2007, 60, 1;
(g) R. Grigg, W. Martin, J. Morris and V. Sridharan, Tetrahedron,
2005, 61, 11380; (h) T. S. Cooper, A. S. Larigo, P. Laurent, C. J. Moody
and A. K. Takle, Org. Biomol. Chem., 2005, 3, 1252; (i) W. Chao,
M. L. Meketa and S. M. Weinreb, Synthesis, 2004, 2058; ( j) For a
review, see: K. C. Majumdar, S. Muhuri, R. U. Islam and
B. Chattopadhyay, Heterocycles, 2009, 78, 1109.
Scheme 5 Ring-closing metathesis of allylsulfides 2 to yield dihydrothio-
phenes 1. a Prepared by the method of ref. 10a. b Using catalyst 12. c Yield
not determined as the starting material contained an impurity. d Using
catalyst 13.
7 For reviews, see: (a) P. Merino, T. Tejero, G. Greco, E. Marca,
I. Delso, A. Gomez-SanJuan and R. Matuta, Heterocycles, 2012,
84, 75; (b) H. M. A. Hassan, Chem. Commun., 2010, 46, 9100;
(c) T. J. Donohoe, L. P. Fishlock and P. A. Procopiou, Chem. – Eur.
J., 2008, 14, 5716; (d) T. J. Donohoe, A. J. Orr and M. Bingham,
Angew. Chem., Int. Ed., 2006, 45, 2664; (e) R. C. D. Brown and
V. Satcharen, Heterocycles, 2006, 70, 705; ( f ) H. Villar, M. Frings
and C. Bolm, Chem. Soc. Rev., 2007, 36, 55; (g) M. Arisawa, A. Nishida
and M. Nakagawa, J. Organomet. Chem., 2006, 691, 5109;
(h) A. Gradillas and J. Perez-Castells, Angew. Chem., Int. Ed., 2006,
45, 6086; (i) A. Deiters and S. F. Martin, Chem. Rev., 2004, 104, 2199.
8 M. D. McReynolds, J. M. Dougherty and P. R. Hanson, Chem. Rev.,
2004, 104, 2239.
9 (a) Y. A. Lin, J. M. Chalker, N. Floyd, G. J. L. Bernardes and
B. G. Davis, J. Am. Chem. Soc., 2008, 130, 9642; (b) A. Fu¨rstner and
K. Langemann, Synthesis, 1997, 792.
10 (a) G. Mingat, P. MacLellan, M. Laars and J. Clayden, Org. Lett., 2014,
16, 1252; (b) J. Lefranc, A. M. Fournier, G. Mingat, S. Herbert,
T. Marcelli and J. Clayden, J. Am. Chem. Soc., 2012, 134, 7286.
11 M. C. Whisler, S. MacNeil, V. Snieckus and P. Beak, Angew. Chem.,
Int. Ed., 2004, 43, 2206.
Fig. 1 Experimental and calculated CD spectra of (R)-1e and experimental
CD spectra of (R)- and (S)-2,5-dihydrothiohenes 1.
These results (in conjunction with the established suprafacial
stereospecificity of the [3,3]-sigmatropic rearrangement giving
10) confirm that the migration of the aryl ring proceeds with
retention of absolute configuration, as observed in related
benzylic thiocarbamates.20
In summary, enantiomerically enriched dihydrothiophenes
may be synthesised from enantiomerically enriched allylic
alcohols by intramolecular arylation of their allylic thiocarbamate
derivatives followed by ring closing metathesis. The work expands
the scope of heterocyclic synthesis by ring-closing metathesis,7
allowing the incorporation both of sulfur,5,8 and of a sterically
hindered quaternary stereogenic centre.18,21
12 We expected anion-destabilising g-substitution to increase the
localisation of the C–Li bond at the a-carbon of the allyl system.
See: M. C. Whisler and P. Beak, J. Org. Chem., 2003, 68, 1207.
13 The 1H NMR spectrum of 4aLi generated under the conditions of
the reaction was consistent with the formation of an allyllithiumin
(Comprehensive carbanion chemistry, Part A Structure and Reactivity,
ed. E. Buncel and T. Durst, Elsevier, Amsterdam, 1980, ch. 6, II,
p. 274): disappearance of the q at d 3.98 arising from the proton a to
sulfur, reduction in multiplicity from ddd to dd for the signal of the
central (b) allylic proton without significant change of chemical
shift (d 5.84 to 6.09) and considerable upfield shift of both signals of
the allylic g-protons (d 5.12, 4.97 to d 2.75, 2.59 ppm).
This work was funded by the EPSRC (studentship to GM).
¨
14 (a) F. Marr, R. Frohlich and D. Hoppe, Org. Lett., 1999, 1, 2081;
¨
(b) F. Marr, R. Frohlich, B. Wibbeling, C. Diedrich and D. Hoppe, Eur.
Notes and references
J. Org. Chem., 2002, 2970; (c) K. C. Nicolaou and R. D. Groneberg, J. Am.
Chem. Soc., 1990, 112, 4085; (d) K. C. Nicolaou and D. Clark, Angew.
Chem., Int. Ed. Engl., 1992, 31, 855; (e) R. D. Groneberg, T. Miyazaki,
N. A. Stylianides, T. J. Schulze, W. Stahl, E. P. Schreiner, T. Suzuki,
Y. Iwabuchi, A. L. Smith and K. C. Nicolaou, J. Am. Chem. Soc., 1993,
115, 7593; ( f ) K. C. Nicolaou, C. W. Hummel, M. Nakada, K. Shibayama,
E. N. Pitsinos, H. Saimoto, Y. Mizuno, K.-U. Baldenius and A. L. Smith,
J. Am. Chem. Soc., 1993, 115, 7625; (g) R. C. Schnur and M. L. Corman,
J. Org. Chem., 1994, 59, 2581; (h) D. Yang, G.-S. Jiao, Y.-C. Yip, T.-H. Lai
and M.-K. Wong, J. Org. Chem., 2001, 66, 4619.
1 (a) N. Morita and N. Krause, Angew. Chem., Int. Ed., 2006, 45, 1897;
(b) S. Benetti, C. De Risi, G. P. Pollini and V. Zanirato, Chem. Rev.,
2012, 112, 2129; (c) J. Tang, D. Q. Xu, A. B. Xia, Y. F. Wang,
J. R. Jiang, S. P. Luo and Z. Y. Xu, Adv. Synth. Catal., 2010,
352, 2121; (d) V. V. Dotsenko, S. G. Krivokolysko, A. N. Chernega
and V. P. Litvinov, Russ. Chem. Bull., 2007, 56, 1431; (e) A. V. Samet,
A. M. Shestopalov, V. N. Nesterov and V. V. Semenov, Synthesis, 1997,
623; ( f ) A. M. Shestopalov, O. P. Bogomolova and V. P. Litvinov,
Synthesis, 1991, 277.
6756 | Chem. Commun., 2014, 50, 6754--6757
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
15 (a) T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa,
K. Murata, E. Katayama, T. Yokozawa, T. Ikariya and R. Noyori,
J. Am. Chem. Soc., 1998, 120, 13529; (b) For a review, see: R. Noyori
and T. Ohkuma, Angew. Chem., Int. Ed., 2001, 40, 40.
16 Y. Gao, J. M. Klunder, R. M. Hanson, H. Masamune, S. Y. Ko and
K. B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765.
T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark,
J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith,
R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant,
S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli,
J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski,
G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels,
O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski and D. J. Fox, Gaussian
09, Revision B.01, Gaussian, Inc., Wallingford CT, 2010.
17 G. Mingat and J. Clayden, Synthesis, 2012, 2723.
18 (a) I. C. Stewart, T. Ung, A. A. Pletnev, J. M. Berlin, R. H. Grubbs and
Y. Schrodi, Org. Lett., 2007, 9, 1589; (b) I. C. Stewart, C. J. Douglas
and R. H. Grubbs, Org. Lett., 2008, 10, 441.
19 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, 20 (a) P. MacLellan and J. Clayden, Chem. Commun., 2011, 47, 3395;
J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson,
H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino,
G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, 21 T. Vorfalt, S. Leuthaußer and H. Plenio, Angew. Chem., Int. Ed., 2009,
(b) D. Castagnolo, D. J. Foley, H. Berber, R. Luisi and J. Clayden, Org.
Lett., 2013, 15, 2116.
¨
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
48, 5191.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 6754--6757 | 6757