Enantiopure 1,4-diols and 1,4-aminoalcohols via stereoselective acyclic sulfoxide-sulfenate rearrangement

Article abstract of DOI:10.1021/ol200718y

Chemical equations presented. Treatment of acyclic α-hydroxy and α-tosylamino sulfinyl dienes with amines affords enantiopure 1,4-diol or 1,4-hydroxysulfonamide derivatives in good yields and diastereoselectivities. This one-pot procedure entails a conjugate addition that triggers a diastereoselective sulfoxide-sulfenate [2,3]-sigmatropic rearrangement.

Full text of DOI:10.1021/ol200718y

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2468–2471
Enantiopure 1,4-Diols and 1,4-
Aminoalcohols via Stereoselective
Acyclic SulfoxideꢀSulfenate
Rearrangement
ꢀ
Roberto Fernandez de la Pradilla,* Ignacio Colomer, Mercedes Urena, and Alma Viso
~
´
ꢀ
Instituto de Quımica Organica General, IQOG-CSIC. Juan de la Cierva 3, 28006
Madrid, Spain
iqofp19@iqog.csic.es
Received March 17, 2011
ABSTRACT
Treatment of acyclic R-hydroxy and R-tosylamino sulfinyl dienes with amines affords enantiopure 1,4-diol or 1,4-hydroxysulfonamide derivatives
in good yields and diastereoselectivities. This one-pot procedure entails a conjugate addition that triggers a diastereoselective
sulfoxideꢀsulfenate [2,3]-sigmatropic rearrangement.
The diastereoselective preparation of acyclic 1,4-diols and
1,4-aminoalcohols constitutes an important field in syn-
thetic organic methodology1 and natural product
synthesis.2 In contrast to 1,2-, 1,3-, or 1,5-derivatives, there
are few general methods to prepare these targets. On the
other hand, unsaturated systems have attracted consider-
able attention due to their presence in natural products or
their precursors3 and the potential in being converted into
interesting saturated derivatives. The main strategies
developed to achieve stereocontrol in the synthesis of
acyclic unsaturated 1,4-diols entail the addition of orga-
nometallic reagents,4 or terminal alkynes,5 to carbonyl
derivatives. Alternatively, the stereoselective reduction of
functionalized ketones has also been described, however
with some substrate limitations.6 Other recent methods
have relied on 1,4-hydroxycarbonyl compounds,7 epoxides,8
or 1,3-dienes.9
Comparatively, the diastereoselective preparation of
substituted 2-ene-1,4-aminoalcohol derivatives has been
scarcely documented. Some of the approaches reported
(4) (a) Roush, W. R.; Grover, P. T. Tetrahedron 1992, 48, 1981–
1998. (b) Vettel, S.; Knochel, P. Tetrahedron Lett. 1994, 35, 5849–
5852. (c) Bloch, R.; Brillet, C. Tetrahedron: Asymmetry 1992, 3, 333–
336.
(1) For leading examples on 1,4-diols: (a) Knapp, K. M.; Goldfuss,
n-Matute,
B.; Knochel, P. Chem.;Eur. J. 2003, 9, 5259–5265. (b) Martı
´
€
B.; Edin, M.; Backvall, J.-E. Chem.;Eur. J. 2006, 12, 6053–6061. (c)
ꢀ
´
Bach, J.; Berenguer, R.; Garcıa, J.; Lopez, M.; Manzanal, J.; Vilarrasa,
(5) (a) Amador, M.; Ariza, X.; Garcıa, J.; Ortiz, J. Tetrahedron Lett.
´
2002, 43, 2691–2694. (b) Diez, R. S.; Adger, B.; Carreira, E. M. Tetra-
hedron 2002, 58, 8341–8344.
(6) (a) Molander, G. A.; Bobbitt, K. L. J. Org. Chem. 1994, 59,
´
2676–2678. (b) Bach, J.; Berenguer, R.; Garcıa, J.; Loscertales, T.;
ꢀ
J. Tetrahedron 1998, 54, 14947–14962. (d) Solladie, G.; Huser, N.;
~
Garcıa-Ruano, J. L.; Adrio, J.; Carreno, M. C.; Tito, A. Tetrahedron
´
Lett. 1994, 35, 5297–5300. (e) Burk, M. J.; Feaster, J. E.; Harlow, R. L.
Tetrahedron: Asymmetry 1991, 2, 569–592. (f) Tortosa, M. Angew.
Chem., Int. Ed. 2011 (DOI: 10.1002/anie.201100613). For 1,4-aminoalco-
Manzanal, J.; Vilarrasa, J. Tetrahedron Lett. 1997, 38, 1091–1094. (c)
See ref 1c.
€
hols: Backvall, J. E.; Schink, H. E.; Renko, Z. D. J. Org. Chem. 1990, 55,
826–831.
(7) Hayashi, Y.; Yamaguchi, H.; Toyoshima, M.; Nasu, S.; Ochiai,
K.; Shoji, M. Organometallics 2008, 27, 163–165.
(8) Hodgson, D. M.; Bray, C. D.; Kindon, N. D. Org. Lett. 2005, 7,
2305–2308.
(9) Burks, H. E.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc.
2009, 131, 9134–9135.
€
(2) (a) Konig, C. M.; Gebhardt, B.; Schleth, C.; Dauber, M.; Koert,
U. Org. Lett. 2009, 11, 2728–2731. (b) Kim, H. C.; Kang, S. H. Angew.
Chem., Int. Ed. 2009, 48, 1827–1829.
(3) (a) Kobayashi, Y.; Asano, M.; Yoshida, S.; Takeuchi, A. Org.
Lett. 2005, 7, 1533–1536. (b) Motoyoshi, H.; Ishigami, K.; Kitahara, T.
Tetrahedron 2001, 57, 3899–3908.
r
10.1021/ol200718y
Published on Web 04/06/2011
2011 American Chemical Society

involvePd-catalyzedallylic substitution,10 enantioselective
alkylation of 4-aminoaldehydes,11 or reductive cleavage of
functionalized cycloadducts.12
geometry. The diastereoselective formation of B, influ-
enced by the contiguous chiral centers as well as the
stereochemical outcome of the ensuing [2,3]-sigmatropic
rearrangement would lead, after sulfenate cleavage, to
valuable acyclic 1,4-diol or 1,4-aminoalcohol derivatives
4 and 5. The [2,3]-sigmatropic rearrangement of allylic
sulfoxides has been widely exploited for the preparation of
optically pure allylic alcohols;16 however, relatively few
examples exist of the diastereocontrolled acyclic variant.17
Scheme 1. Proposed Reaction Pathway
Table 1. Solvent Screening for Synthesis of 1,4-Diols
In recent years, readily available dienyl alcohols and
amines 2 and 3 (Scheme 1) have been successfully applied
to the stereoselective synthesis of a wide variety of hetero-
cycles and densely functionalized products.13 Within this
context, and in connection with our interest in the [2,3]-
sigmatropic rearrangement of allylic sulfoxides,14 we envi-
major
anti/syn dr
sioned that
a conjugate addition of a suitable
entry
SM
P
solvent
product
(yield %)a,b,c
nucleophile13d would produce a vinyl sulfoxide A15 that
could undergo base-induced isomerization to allylic sulf-
oxide B with a thermodynamically favored E-alkene
1
2a
3a
2a
3a
2a
3a
6a
7a
6a
7a
6a
7a
H
H
H
H
H
H
EtOH
EtOH
toluene
toluene
DMF
4a
60:40 (89)
55:45 (90)
90:10 (97)
35:65 (78)
80:20 (72)
40:60 (90)
60:40 (88)
90:10 (92)
60:40 (93)
85:15 (92)
82:18 (91)
78:22 (92)
2
ent-4a
4a
3
4
ent-5a
4a
ꢁ
ꢀ
€
(10) (a) Farthing, C. N.; Kocovsky, P. J. Am. Chem. Soc. 1998, 120,
5
€
6661–6672. (b) Backvall, J.-E.; Nystrom, J.-E.; Nordberg, R. E. J. Am.
Chem. Soc. 1985, 107, 3676–3686. (c) Pyne, S. G.; Dong, Z. Tetrahedron
Lett. 1999, 40, 6131–6134.
6
DMF
ent-5a
8a
7
SiBu3
SiBu3
SiBu3
SiBu3
SiBu3
SiBu3
EtOH
EtOH
toluene
toluene
DMF
(11) Lutz, C.; Lutz, V.; Knochel, P. Tetrahedron 1998, 54, 6385–6402.
(12) Martin, S. F.; Hartmann, M.; Josey, J. A. Tetrahedron Lett.
1992, 33, 3583–3586.
8
ent-8a
8a
9
10
11
12
ent-8a
8a
ꢀ
(13) (a) Fernandez de la Pradilla, R.; Castellanos, A.; Osante, I.;
ꢀ
Colomer, I.; Sanchez, M. I. J. Org. Chem. 2009, 74, 170–181. (b) Viso,
DMF
ent-8a
ꢀ
~
A.; Fernandez de la Pradilla, R.; Urena, M.; Colomer, I. Org. Lett. 2008,
ꢀ
10, 4775–4778. (c) Fernandez de la Pradilla, R.; Alhambra, C.; Castel-
lanos, A.; Fernandez, J.; Manzano, P.; Montero, C.; Urena, M.; Viso, A.
ꢀ
~
a Ratio determined by 1H NMR analysis. b Combined yield. c Abso-
lute configuration at C-4 was determined by derivatization with (S)-
MPA.
ꢀ
J. Org. Chem. 2005, 70, 10693–10700. (d) Fernandez de la Pradilla, R.;
Manzano, P.; Montero, C.; Priego, J.; Martınez-Ripoll, M.; Martınez-
Cruz, L. A. J. Org. Chem. 2003, 68, 7755–7767.
´
´
ꢀ
ꢀ
(14) Fernandez de la Pradilla, R.; Lwoff, N.; del Aguila, M. A.;
Tortosa, M.; Viso, A. J. Org. Chem. 2008, 73, 8929–8941.
(15) At short reaction times small amounts of vinyl sulfoxides A are
frequently isolated, leading to 4/5 under reaction conditions.
We began our investigation by submitting alcohols 2a
and 3a,18 epimers at C-1, to treatment with piperidine in
ethanol. Unfortunately, equimolecular mixtures of the
desired 1,4-diols were obtained for both diastereomers
(Table 1, entries 1 and 2). In contrast, the use of toluene
led to a clear improvement of diastereoselectivity for
diastereoisomer 2a that led to 4a in excellent dr (Table 1,
entries 3 and 4). The use of DMF did not improve the
diastereoselectivities found with toluene (Table 1, entries 5
and 6).
~
(16) (a) Arce, E.; Carreno, M. C.; Cid, M. B.; Garcıa Ruano, J. L.
´
J. Org. Chem. 1994, 59, 3421–3426. (b) Grieco, P. A.; Finkelhor, R. S.
J. Org. Chem. 1973, 38, 2245–2247. (c) Vedejs, E.; Wittenberger, S. J.
J. Am. Chem. Soc. 1990, 112, 4357–4364. (d) Evans, D. A.; Andrews,
G. C. Acc. Chem. Res. 1974, 7, 147–155.
(17) (a) Motofumi, M.; Toriyama, M.; Kawakubo, T.; Yasukawa,
K.; Takido, T.; Motohashi, S. Org. Lett. 2010, 12, 3882–3885. (b)
Raghavan, S.; Vinoth Kumar, V.; Raju Chowhan, L. Synlett 2010,
1807–1810. (c) The SPAC (Sulfoxide Piperidine And Carbonyl) reaction
involves the isomerization from vinyl to allylic sulfoxides, followed by
[2,3]-sigmatropic rearrangement in acyclic systems. For leading refer-
ences, see: (d) Nokami, J.; Kataoka, K.; Shiraishi, K.; Osafune, M.;
Hussain, I.; Sumida, S.-I. J. Org. Chem. 2001, 66, 1228–1232. (e)
Having established the viability of the process, we envi-
sioned that protection of the hydroxyl group could improve
ꢀ~
Guerrero de la Rosa, V.; Ordonez, M.; Llera, J. M. Tetrahedron:
Asymmetry 2001, 12, 1089–1094. (f) Domınguez, E.; Carretero, J. C.
´
Tetrahedron Lett. 1990, 31, 2487–2490. Some diastereoselective exam-
ples of this process, see: (g) Trost, B. M.; Grese, T. A. J. Org. Chem. 1991,
56, 3189–3192. (h) Burgess, K.; Cassidy, J.; Henderson, I. J. Org. Chem.
1991, 56, 2050–2058. (i) Burgess, K.; Henderson, I. Tetrahedron 1991, 47,
6601–6616.
(18) Dienyl sulfoxides 1 are available in one step using the procedure
by Craig: Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron 1993,
49, 11263–11304. Lithiation and trapping with aldehydes or sulfoni-
mines lead to the substrates of this study 2/3.
Org. Lett., Vol. 13, No. 9, 2011
2469

the diastereocontrol and lead to differentially protected 1,4-
diols. Thus, silyl ethers 6a and 7a were submitted to the
reaction conditions. In ethanol, while 6a yielded a 60:40
mixture of 1,4-diols 8a and 9a, diastereoisomer 7a, with an S
configuration at C-1, afforded ent-8a with highly improved
diastereoselectivity (90:10, Table 1, entries 7 and 8). The use
of toluene did not significantly alter the results found in
ethanol (Table 1, entries 9 and 10). Finally, 6a (C-1 R) led to
a significant improvement in selectivity in DMF and 7a (C-1
S) gave a slightly less selective mixture (Table 1, entries 11
and 12). In conclusion, each epimer at C-1 (2a and 7a) holds
a favorable array of stereocenters under the appropriate
reaction conditions to afford anti 1,4-diol derivatives with
high yields and selectivities.
use of benzylamine produced ent-8a0 with 90:10 dr
(Table 2, entry 9).
Table 3. Diastereoselective Preparation of 1,4-Aminoalcohols
Table 2. Scope of the Method for Synthesis of 1,4-Diols
major
anti/syn dr
(yield %)a,b,c
entry
SM
solvent
product
1
2
3
4
2e
3e
2e
3e
EtOH
4e
64:36 (85)
60:40 (88)
83:17 (70)
70:30 (79)
EtOH
ent-4e
4e
toluene
toluene
ent-4e
a Ratio determined by 1H NMR analysis. b Combined yield. c Abso-
luteconfiguration at C-4wasdeterminedbyderivatizationwith (S)-MPA.
Toextend the scopeof the method tothe synthesisof 1,4-
hydroxysulfonamides we briefly examined the behavior of
sulfonamides 2eand 3ein EtOH and toluene. While the use
of EtOH led to low diastereocontrol for both isomers
(Table 3, entries 1 and 2), a significant enhancement of
selectivity was found in toluene (Table 3, entries 3 and 4).19
Our proposal to account for the stereochemical outcome
of the process is shown in Scheme 2.20 In toluene, an
intramolecular hydrogen bond between the sulfoxide and
the OH group would determine the major chairlike six-
membered conformation for the allylic sulfoxides gener-
ated from 2, resulting in epimer (1R,2S)-I, that has no
serious 1,3-diaxial interactions, being more favored than
(1R,2R)-I (not shown). Subsequentsigmatropic rearrange-
ment would lead predominantly to anti 1,4-diols 4. The
decreased selectivity found for 1,4-aminoalcohols is con-
sistent with the lower ability of the NH to form a hydrogen
bond with the sulfinyl oxygen. Alternatively, in ethanol,
gauche interactions would be responsible for the relative
stability of allylic sulfoxides (1S,2R)-II vs (1S,2S)-II (not
shown) generated from silyl ethers 7. In reactive conformer
(1S,2R)-II, allylic strain is also minimized by situating H2
and R1 (H or Me) in a 1,3-syn relative disposition and by
positioning the substituents at C1 to reduce the steric
interaction with the sulfur p-tolyl group21 to give anti
ent-8 with high diastereoselectivity.
anti/syn dr
entry
SM
R1
R2
NuH
(yield %)a,b,c
1
2
3
4
5
6
7
8
9
2a
2c
2d
2a
7a
7b
7c
7d
7a
H
Ph
Et
piperidine
piperidine
piperidine
BnNH2
90:10 (97)
85:15 (95)
90:10 (72)
85:15 (90)
90:10 (92)
95:5 (90)
H
Me
H
Ph
Ph
Ph
H
piperidine
piperidine
piperidine
piperidine
BnNH2
H
1-Napht
Et
H
75:25 (91)
90:10 (81)
90:10 (85)
Me
H
Ph
Ph
a Ratio determined by 1H NMR analysis. b Combined yield. c Abso-
luteconfigurationatC-4 wasdetermined byderivatization with(S)-MPA.
The scope of the process was then examined by varying
the nature of R1, R2, and the nucleophile on the stereo-
reinforcing diastereoisomer of the alcohol (2) in toluene.
Thus, ethyl derivative 2c led mainly to diol 4c with slight
erosion of the dr (Table 2, entry 2). The viability of
generating a tertiary alcohol was examined by employing
4-substituted alcohol 2d which led to the desired product
4d in good yield and excellent diastereoselectivity (Table 2,
entry 3). Finally, using benzylamine as the nucleophile did
not significantly affect the reaction, affording 4a0 in good
yield and stereoselectivity (Table 2, entry 4).
Similarly, the behavior of stereoreinforcing silylated
isomer 7 in EtOH was examined, with better results for
7b and with slightly diminished selectivity for 7c (Table 2,
entries 6 and 7). Introduction of a new substituent at C-4
afforded tertiary alcohol ent-8d again in good yield and
excellent diastereoselectivity (Table 2, entry 8). Finally, the
(19) We are currently examining different nucleophiles to extend the
scope of the process and improve the stereocontrol.
(20) For a full discussion see the Supporting Information.
(21) (a) Jones-Hertzog, D. K.; Jorgensen, W. L. J. Am. Chem. Soc.
1995, 117, 9077–9078. (b) Jones-Hertzog, D. K.; Jorgensen, W. L. J. Org.
Chem. 1995, 60, 6682–6683.
2470
Org. Lett., Vol. 13, No. 9, 2011

configuration of the new centers, we synthesized cyclic 1,3-
dioxolane 14, and after inspection of the NMR data, the
coupling constant J1,2 (8.9 Hz) revealed a trans configura-
tion at C1ꢀC2.25
Scheme 2. Stereochemical Outcome
Scheme 3. Stereoselective Epoxidation and Dihydroxylation
To explore upcoming synthetic applications we have
examined the reactivity toward epoxidation and dihydrox-
ylation of diastereomerically pure carbamate 10 (Scheme
3), obtained from silyl ether ent-8a0 (90:10) under standard
conditions. Treatment of 10 with m-CPBA afforded ep-
oxide 11 with high diastereoselectivity (92:8) and excellent
yield.22 Deprotection with TFA and subsequent treatment
with base provided 1,3-oxazin-2-one 12, regio- and stereo-
selectively through a nucleophilic carbamate oxygen at-
tack on the epoxide.23 Alternatively, dihydroxylation of 10
with a nonreinforcing array of stereocenters gave triol 13
with excellent yield and very high dr (94:6). The remark-
able selectivity of this dihydroxylation of an acyclic
substrate is noteworthy.24 A reasonable explanation
for this result, based on steric effects, could be found
in a zigzag arrangement of the carbon chain, where the
bulky silyl group would be in the plane of the chain. Then,
OsO4 would approach from the opposite face of the
hydroxyl group at C-4, in an anti fashion. To secure the
In summary, we have outlined a novel method for the
diastereoselective synthesis of enantiopure unsymmetrical
1,4-diols and 1,4-hydroxysulfonamides from sulfinyl buta-
dienes. This protocol involves a one-pot cascade of events
consisting of an intermolecular conjugate addition, [2,3]-
sigmatropic rearrangement of the in situ generated allylic
sulfoxide, and sulfenate cleavage. We have illustrated the
highly stereoselective dihydroxylation and epoxidation of
our diol derivatives, as well as a regio- and stereoselective
epoxide opening via intramolecular nucleophilic carbamate
attack, leading to valuable enantiopure polyols. We are
currently addressing the application of this process to the
synthesis of natural products.
Acknowledgment. This research was supported by MI-
CINN (CTQ2009-07752). We also thank CM for addi-
tional support to MU and MEC for a fellowship to I.C.
(22) For similar results on m-CPBA epoxidation of 1,4-silyloxyalco-
hols: (a) Uchiyama, M.; Kimura, Y.; Ohta, A. Tetrahedron Lett. 2000,
41, 10013–10017. (b) Johnson, C. R.; Miller, M. W. J. Org. Chem. 1995,
60, 6674–6675. (c) Saito, S.; Itoh, H.; Ono, Y.; Nishioka, K.; Moriwake,
T. Tetrahedron: Asymmetry 1993, 4, 5–8 and references therein.
(23) For related processes, see: (a) Yoshida, M.; Ohshima, M.; Toda,
T. Heterocycles 1993, 35, 623–626. (b) Vanucci, C.; Brusson, X.; Verdel,
V.; Zana, F.; Dhimane, H.; Lhommet, G. Tetrahedron Lett. 1995, 36,
2971–2974. (c) Urabe, H.; Aoyama, Y.; Sato, F. Tetrahedron 1992, 48,
5639–5646.
Supporting Information Available. Experimental pro-
cedures, compound characterization, NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org
(24) For related dihydroxylations of nonreinforcing cyclic substrates,
ꢀ
(25) It is known that vicinal coupling constants for trans-1,3-dioxo-
lanes (8.0ꢀ9.0 Hz) are higher than those for cis isomers (6.0ꢀ7.0 Hz).
See: (a) Anet, F. A. L. J. Am. Chem. Soc. 1962, 84, 747–752. (b)
Adamczeski, M.; Quinoa, E.; Crews, P. J. Am. Chem. Soc. 1988, 110,
~ ꢀ
1598–1602. (c) Adamczeski, M.; Quinoa, E.; Crews, P. J. Am. Chem.
see: (a) Arjona, O.; de Dios, A.; Fernandez de la Pradilla, R.; Plumet, J.
Tetrahedron Lett. 1991, 32, 7309–7312. (b) Arjona, O.; Candilejo, A.; de
ꢀ
Dios, A.; Fernandez de la Pradilla, R.; Plumet, J. J. Org. Chem. 1992, 57,
~ ꢀ
6097–6099. (c) Arjona, O.; de Dios, A.; Plumet, J.; Saez, B. J. Org. Chem.
1995, 60, 4932–4935. (d) Trost, B. M.; Crawley, M. L.; Lee, C. B.
Chem.;Eur. J. 2006, 12, 2171–2187.
Soc. 1989, 111, 647–654 and ref 24d.
Org. Lett., Vol. 13, No. 9, 2011
2471