Synthesis of optically enriched 1,2-aminoalcohols by [2,3]-Wittig rearrangements of 3-aza-allylic alcohol derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.03.023

[2,3]-Wittig rearrangements of (E)-3-aza-allylic alcohol derivatives can provide access to syn or anti optically enriched 1,2-aminoalcohols by using a chirality transfer or a chiral auxiliary.

Full text of DOI:10.1016/j.tetlet.2008.03.023

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2902–2906
Synthesis of optically enriched 1,2-aminoalcohols by
[2,3]-Wittig rearrangements of 3-aza-allylic alcohol derivatives
Marion Barbazanges, Christophe Meyer *, Janine Cossy
Laboratoire de Chimie Organique, ESPCI, CNRS, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 15 January 2008; revised 5 March 2008; accepted 5 March 2008
Available online 8 March 2008
Abstract
[2,3]-Wittig rearrangements of (E)-3-aza-allylic alcohol derivatives can provide access to syn or anti optically enriched 1,2-amino-
alcohols by using a chirality transfer or a chiral auxiliary.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 1,2-Aminoalcohols; Enamides; [2,3]-Wittig rearrangement; Diastereoselectivity; Chirality transfer
The [2,3]-Wittig sigmatropic rearrangement is a useful
tool in organic synthesis that offers many opportunities
for stereochemical control.1,2 We have recently reported
that propargylic ethers of type B or amides of type C,
derived from the readily available (E)-3-aza-allylic alcohols
A, underwent diastereoselective [2,3]-Wittig rearrange-
ments that led to functionalized anti or syn 1,2-aminoalco-
hols of types D and E, respectively (Scheme 1).3
building blocks for the preparation of chiral catalysts.4,5
Therefore, the control of the absolute configuration of
the two newly heterosubstituted stereocenters, created dur-
ing the [2,3]-Wittig rearrangement of 3-aza-allylic alcohol
derivatives, appeared to be an interesting issue to consider.
To achieve this goal, it was first planned to synthesize 1,2-
amino-alcohols of general formula D0 or E0, by [2,3]-Wittig
rearrangement of the propargylic ethers B0 or amides C0,
respectively, derived from secondary 3-aza-allylic alcohols
of type A0. Indeed, a chirality transfer may enable to con-
trol the absolute configuration of the adjacent stereocenters
in 1,2-aminoalcohols D0 or E0, while creating at the same
time a disubstituted alkene (Scheme 2).
Optically active 1,2-aminoalcohols constitute a wide-
spread structural feature in natural products and/or bio-
logically active compounds and are often used as key
Ts
N
SiR'3
[2,3]
Secondary (E)-3-aza-allylic alcohols of type A0 are read-
ily accessible according to a stereoselective route previously
developed.3 Thus, the protection of but-3-yn-2-ol (1) as a
R
Ts
N
SiR'3
R
Ts
N
O
O
OH
Ts
R
B
C
D
OH
Ts
N
O
R
A
N
O
Ts
N
Ts
N
R
Ts
*
R
N
[2,3]
N
*
G
N
R
R
[2,3]
G
OH
R'
OH
O
E
OH
R'
R'
B'
C'
Scheme 1. [2,3]-Wittig rearrangement of derivatives of (E)-3-aza-allylic
alcohols A.
G =
G =
SiR"3
CONR"2
D'
E'
A'
*
Scheme 2. [2,3]-Wittig rearrangement with chirality transfer from
secondary (E)-3-aza-allylic alcohols of type A0.
Corresponding author. Tel.: +33 1 40795845; fax: +33 1 40794660.
E-mail address: christophe.meyer@espci.fr (C. Meyer).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.023

M. Barbazanges et al. / Tetrahedron Letters 49 (2008) 2902–2906
2903
TMS
silyl ether (TBDPSCl, imidazole, DMF) and bromination
Ts
N
Ts
N
1)
2)
Br
of the terminal alkyne (NBS, cat. AgNO3, acetone) led to
the acetylenic bromide 2 (97%, 2 steps from 1). The latter
compound underwent a copper-catalyzed cross-coupling
with N-benzylsulfonamide (CuSO4ꢀ5H2O (10% mol),
1,10-phenanthroline (20% mol), K3PO4 (2 equiv), toluene,
70 °C) to produce the disubstituted ynamide 3 (99%).6 Sub-
sequent deprotection of the alcohol (n-Bu4NF, THF) and
hydroalumination (Red-Al, THF) afforded alcohol 4
(92%, 2 steps from 3) (Scheme 3).
Bn
Bn
n
-Bu4NHSO4 (20% mol)
35% aq NaOH, toluene, rt
O
OH
Me
n
-BuLi, THF, −78 °C then
TMSCl, −78
Me
°
C to rt
4
5
63%
LDA (1.5 equiv) THF, −78 °C
H
Ts
Bn
TMS
H
N
TMS
O
Me
Ts
Me
87%
OH
The stereoselectivity of the [2,3]-Wittig rearrangement of
the secondary propargylic ether 5 prepared in two steps
from alcohol 4 (HC„CCH2Br, cat. n-Bu4NHSO4, 35%
aq NaOH, toluene; n-BuLi, THF, ꢁ78 °C then TMSCl,
63%) was first examined. Upon treatment with LDA
(1.5 equiv, THF, ꢁ78 °C), compound 5 underwent a diaste-
reoselective [2,3]-Wittig rearrangement and the anti-1,2-
aminoalcohol 6 was isolated in 87% yield (dr = 10/1).
The configuration of the disubstituted alkene in 6 was read-
N
H
6
dr = 10/1
Bn
TS1
Scheme 4.
Ts
N
Ts
N
Br
-Bu4NHSO4 (20% mol)
Bn
Bn
n
OH
O
35% aq NaOH, toluene, rt
91%
1
7
8
ily assigned to (E) by H NMR, and the anti relationship
OPMB
OPMB
1) n-BuLi, THF, −78 °C
between the amino and the hydroxyl groups was confirmed
by a chemical correlation.7 The stereochemical outcome
could be rationalized by considering a five-membered ring
transition state of envelope conformation TS1 in which the
trimethylsilylethynyl group occupies an exo position
whereas the methyl group preferentially adopts a pseudo-
equatorial (endo) position (Scheme 4).8
then TMSCl, −78 °C to rt
76%
2) LDA (2 equiv), −78 °C
(same pot)
Ts
Bn
N
Ts
Bn
cat. H2SO4
cat. HgSO4
O
N
TMS
THF/H2O, rt
87%
10
9
dr = 9/1
PMBO
OH
PMBO
OH
As the [2,3]-Wittig rearrangements of propargylic ethers
of type B0 proceed with a satisfactory level of diastereose-
lectivity, the stage was set to evaluate absolute chirality
Scheme 5.
transfer. The optically active secondary alcohol
7
The behavior of amides of type C0 was next examined.
Compound 4 was alkylated with N-(bromoacetyl)-pyrroli-
dine (11) to afford amide 12 (79%). The latter compound
smoothly underwent [2,3]-Wittig rearrangement by treat-
ment with LiHMDS (2 equiv) in the presence of HMPA
(4 equiv) as an additive (THF, ꢁ78 °C).3 Unfortunately,
the reaction led to a mixture of the diastereomeric
a-hydroxy-b-aminoamides 13 and 14 in an almost stereo-
random fashion (13/14 = 57/43, 72%). The configuration
of the double bond in compounds 13 and 14 was assigned
(ee P 98%)9 was converted to propargylic ether 8 by alkyl-
ation with propargyl bromide (91%). However, after silyla-
tion of the terminal alkyne (n-BuLi, THF then TMSCl,
ꢁ78 °C to rt), the resulting propargylic ether turned out
to be unstable. To avoid isolation of this compound, the
[2,3]-Wittig rearrangement was carried out in the same
pot by the addition of LDA. A satisfactory level of diaste-
reoselection (dr = 9/1) was observed and 1,2-aminoalcohol
9 was isolated in 76% yield (2 steps from 8). The enantio-
meric purity of 9 was determined to be >95%.10 Moreover,
the alkyne in compound 9 underwent hydration (cat.
H2SO4, cat. HgSO4, THF/H2O)11 to afford methyl ketone
10 (87%) without epimerization (Scheme 5).
1
to (E) and (Z), respectively, by H NMR and a chemical
correlation established the syn relative orientation of the
amino and hydroxyl groups in both compounds.12 The
high syn diastereoselectivity of the Wittig rearrangement
of amides of type C has been explained by the more favor-
able endo orientation of the p-acceptor carboxamide moi-
ety in the envelope-like five-membered ring transition
state, due to secondary orbital overlap or electrostatic
interactions with the negatively charged olefinic moiety.8
Whereas transition state TS2 leading to 13, having the
allylic methyl group in an endo position, is destabilized
by steric interactions with the endo carboxamide group
(further enhanced by lithium chelation), the alternative
transition state TS3 leading to 14, wherein the methyl
group lies in the exo position, is destabilized due to interac-
tion between the methyl group and the vinylic hydrogen
close in space.8 Thus, no net stereochemical preference is
1) TBDPSCl, imidazole
DMF, rt
OH
Me
OTBDPS
Me
Br
2) NBS, AgNO3 (10% mol)
acetone, rt
97%
1
2
3
CuSO4.5H2O (10% mol)
1,10-phenanthroline (20% mol)
K3PO4 (2 equiv), toluene, 70 °C
99%
1)
n
-Bu4NF, THF
Ts
N
Ts
Bn
OTBDPS
Me
0 °C to rt
OH
Me
N
Bn
2) Red-Al, THF, rt
92%
4
Scheme 3.

2904
M. Barbazanges et al. / Tetrahedron Letters 49 (2008) 2902–2906
O
the presence of HMPA dramatically improved the syn dia-
stereoselectivity of [2,3]-Wittig rearrangements of amides of
type C,3 the effect of the quantity of this additive was inves-
tigated. In the absence of HMPA, the reaction has to be run
at a higher temperature (ꢁ40 °C to 0 °C) and we confirmed
that a poor syn/anti ratio was observed (18a/19a/20a =
42/54/4) while the anti diastereomer 19a was predominantly
obtained. Gratifyingly, raising the quantity of HMPA from
4 to 10 equiv substantially reduced the amount of the anti
diastereomer 19a (18a/19a/20a = 88/6/6) whereas the use
of a larger amount (30 equiv) again had a slightly beneficial
influence and the ratio of 18a/(19a+20a) finally reached
90/10 (Scheme 8).
Ts
N
O
Ts
N
Br
N
11
-Bu4NHSO4 (20% mol)
Bn
N
Bn
n
O
OH
Me
35% aq NaOH, toluene, rt
79%
Me
12
4
LiHMDS (2 equiv), HMPA (4 equiv)
72%
THF, −78 °C
H
Ts
Bn
H
N
O
O
Me
H
Me
N
Li
OH
13
N
Ts
O
Bn
N
TS2
13/14 = 57/43
+
Ts
Bn
H
Under these optimized conditions, the major diastereo-
mer 18a (dr P 95/5) could be isolated in 77% yield. Simi-
larly, the other amides 17b and 17c underwent [2,3]-
Wittig rearrangement with satisfactory levels of diastereo-
selection (dr = 87/13 and 94/6) and the syn a-hydroxy-
b-amino-amides 18b and 18c (dr P 95/5) were isolated in
65% and 80% yields, respectively. Subsequent cleavage of
the chiral auxiliary was achieved by acidic methanolysis
(35% aq HCl/MeOH, reflux)14 and led to the methyl esters
21a–c in good yields (65–89%), without alteration of the
diastereomeric purity, whereas 1-aminoindan-2-ol could
be recovered (70–80%) (Scheme 9).
Me
N
O
Me
H
Ts
N
N
O
Bn
N
OH
H
Li
14
O
TS3
Scheme 6.
observed during the [2,3]-Wittig rearrangement of amide 12
and the a-hydroxy-b-amino-amides 13 and 14, resulting
from opposite p-facial selectivities, are obtained. There-
fore, an efficient diastereoselective chirality transfer could
not be achieved for such substrates (Scheme 6).
In order to control the absolute configuration of the two
newly created heterosubstituted stereocenters in the [2,3]-
Wittig rearrangement of amides derived from 3-aza-allylic
alcohols of type A, a covalently bond chiral auxiliary could
be used. Thus, the primary 3-aza-allylic alcohols 15a–c3
were alkylated under phase-transfer catalysis conditions,
in the presence of the N-(bromoacetyl)amide 16, derived
from optically active (1R,2S)-1-aminoindan-2-ol13,14 to
afford amides 17a–c (92–97%) (Scheme 7).
Optimization of the reaction conditions for the [2,3]-
Wittig rearrangement was first carried out with substrate
17a. Under our standard conditions (LiHMDS (2 equiv),
HMPA (4 equiv), THF, ꢁ78 °C),3 a mixture of the diaste-
reomeric amides 18a, 19a, and 20a was generated in a
79/17/4 ratio (69%). The structure of 18a was unambigu-
ously fully established by chemical correlations, and the
relative orientation of the hydroxyl and amino groups was
found to be anti in the first minor diastereomer 19a.15,16
Assuming that the p-facial bias exerted by the chiral auxil-
iary was responsible for the formation of both diastereo-
mers 18a and 19a, the problem was to improve the 1,2-syn
diastereoselectivity. As we had previously observed that
Ts
N
O
Bn
XN*
O
17a
LiHMDS (2 equiv)
HMPA (n equiv)
THF, −78 °C
Ts
Bn
Ts
Bn
Ts
Bn
N
O
N
O
N
O
+
+
XN*
XN*
XN*
Yield
OH
18a
OH
OH
20a
n
19a
0*
4
10
30
42
79
88
90
54
17
6
4
4
6
5
66%
69%
89%
83%
5
* The reaction was run from −40 °C to 0 °C
Scheme 8.
R
Ts
Ts
N
O
N
N
O
LiHMDS (2 equiv)
HMPA (30 equiv)
R
XN*
XN*
THF, −78 °C
O
OH
18
O
Ts
N
Ts
N
O
17
Br
35% aq HCl
XN*
R
R
N
MeOH, reflux
16
-Bu4NHSO4 (20% mol)
dr
O
Yields
n
OH
15a R = Bn
(18/19+20)
O
R
Ts
O
35% aq NaOH, toluene, rt
97%
90/10 18a
21a 89%
R = Bn
R = PMB
77%
65%
80%
17a
17b
17c
OMe
65%
87/13 18b
R = Allyl 94/6 18c
21b
15b R = PMB
15c R = Allyl
92%
92%
OH
21
78%
21c
XN*
Scheme 7.
Scheme 9.

M. Barbazanges et al. / Tetrahedron Letters 49 (2008) 2902–2906
2905
We have shown that the [2,3]-Wittig rearrangement of
Bn
Ts
Bn
Ts
N
O
N
O
substituted 3-aza-allylic alcohol derivatives can provide
access to functionalized enantiomerically enriched 1,2-
aminoalcohols either by a chirality transfer17 or by using
a chiral auxiliary.18–20 Applications of this methodology
to natural and/or biologically active compounds will be
examined.
a,b,c
60%
a,b,c
56%
13 + 14
N
N
OH OH
OH
24 (ref. 3)
23
Reagents and conditions: (a) O3, MeOH/CH2Cl2, –78 °C; (b) PPh3, –78 °C
to rt; (c) NaBH4, MeOH, rt.
13. Amide 16 was prepared from (1R,2S)-1-aminoindan-2-ol (86%) by
acylation with bromoacetyl bromide (Et3N, THF, 45 °C) and
ketalization (2-methoxypropene, MsOH, 50 °C), see: Song, Z. J.;
Zhao, M.; Desmond, R.; Devine, P.; Tschaen, D. M.; Tillyer, R.;
Frey, L.; Heid, R.; Xu, F.; Foster, B.; Li, J.; Reamer, R.; Volante, R.;
Grabowski, E. J. J.; Dolling, U. H.; Reider, P. J.; Okada, S.; Kato, Y.;
Mano, E. J. Org. Chem. 1999, 64, 9658–9667.
Acknowledgments
Financial support from Glaxo-Smithkline and the
CNRS (BDI grant to M.B.) is gratefully acknowledged.
14. Kress, M. H.; Yang, C.; Yasuda, N.; Grabowski, E. J. J. Tetrahedron
Lett. 1997, 38, 2633–2636.
References and notes
15. Amide 18a was converted to acetonide 25a and the coupling constant
value between H1 and H2 (3JH1–H2 = 4.9 Hz) was used to assign the
relative configuration. Acidic methanolysis of 19a afforded the methyl
ester 26a, a diastereomer of 21a.
1. (a) Frauenrath, H. In Houben-Weyl (Methods of Organic Chemistry),
Stereoselective Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer,
J., Schaumann, E., Eds.; Thieme: Stuttgart, 1995; Vol. E21d, pp 3301–
3756; (b) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885; (c)
Marshall, J. A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: London, 1991; Vol. 3, pp 908–975; (d)
Nakai, T.; Mikami, K. Org. React. 1994, 46, 105–209.
Bn
Ts
N
O
Bn
Ts
H2
N
O
XN*
H1
XN*
O
O
2. For an organocatalyzed version, see: McNally, A.; Evans, B.; Gaunt,
M. J. Angew. Chem., Int. Ed. 2006, 45, 2116–2119.
4 steps
16%
OH
Ts
3JH1-H2 = 4.9 Hz
18a
25a
3. Barbazanges, M.; Meyer, C.; Cossy, J. Org. Lett. 2007, 9, 3245–3248.
4. (a) Lee, H.-S.; Kang, S. H. Synlett 2004, 1673–1685; (b) Bergmeier, S.
C. Tetrahedron 2000, 56, 2561–2576; (c) Ager, D. J.; Prakash, I.;
Schaad, D. R. Chem. Rev. 1996, 96, 835–875; (d) Cardillo, G.;
Tomasini, C. Chem. Soc. Rev. 1996, 117–128; (e) Cole, D. C.
Tetrahedron 1994, 50, 9517–9582.
Bn
Bn
Ts
N
O
N
O
35% aq. HCl
XN* MeOH, reflux
OMe
OH
OH
26a
19a
16. A chemical correlation was used to assign the absolute configuration
of 21a involving its conversion to the optically active sulfonamide (R)-
27. In parallel, the known amine 28 was transformed to sulfonamide
(S)-27. For the preparation of 28 from D-glyceraldehyde acetonide,
see: Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J. A.
Synthesis 1997, 747–749.
5. (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds., 1st ed.; Springer: Berlin, 1999; (b) Fache, F.;
Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100,
2159–2232.
6. Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L.
Org. Lett. 2004, 6, 1151–1154.
7. Compound 6 was converted to acetonide 22 and the coupling
constant value between H1 and H2 (3JH1–H2 = 10.0 Hz) was used to
assign the relative configuration.
Bn
Ts
Bn
Ts
N
N
O
N
a,b,c,d
68%
OH
OH
Bn
Ts
OMe
N
TMS
Bn
Ts
21a
Bn
(
R
)-27
Ts
OH
H
H2
N
TMS
H1
Bn
Me
N
O
O
e,f,b,c,d
23%
4 steps
11%
3JH1-H2 = 10.0 Hz
OH
O
6
22
O
28
(
S)-27
8. (a) Wu, Y.-D.; Houk, K. N.; Marshall, J. A. J. Org. Chem. 1990, 55,
1421–1423; (b) Mikami, K.; Uchida, T.; Hirano, T.; Wu, Y.-D.;
Houk, K. N. Tetrahedron 1994, 50, 5917–5926.
Reagents and conditions: (a) DIBAL-H, CH2Cl2, –78 °C; (b) H2, cat.
Pd/C, EtOH, rt; (c) NaIO4, THF/H2O, rt; (d) NaBH4, MeOH, rt;
e) TsCl, Pyr, rt; f) 80% aq AcOH, 80 °C.
9. Alcohol 7 was synthesized according to the sequence depicted in
Scheme 3 (5 steps, 79% overall yield) from the corresponding
propargylic alcohol (ee P 98%). For the preparation of the latter
alcohol, see: Yadav, J. S.; Chander, M. C.; Joshi, B. V. Tetrahedron
Lett. 1988, 29, 2737–2740.
17. N-Benzyl-N-[(E)-(R)-1-((S)-1-hydroxy-3-trimethylsilanyl-prop-2-ynyl)-
4-(4-methoxybenzyloxy)but-2-enyl]-4-methylbenzenesulfonamide (9).
To a solution of propargylic ether 8 (419 mg, 0.829 mmol) in THF
(10 mL) at ꢁ78 °C was added dropwise n-BuLi (500 lL, 2.5 M in
hexanes, 1.25 mmol, 1.5 equiv). After 20 min at ꢁ78 °C, TMSCl
(180 lL, 1.41 mmol, 1.7 equiv) was added dropwise and the reaction
mixture was warmed to rt. After 1 h at rt, the reaction mixture was
cooled to ꢁ78 °C and LDA (1.7 mL, from a 1 M freshly prepared
stock solution in THF/hexanes, 1.7 mmol, 2 equiv) was added
dropwise. After 10 min at ꢁ78 °C, the reaction mixture was poured
into a saturated aqueous solution of NH4Cl, acidified (pH 3) by the
addition of 1 M hydrochloric acid and extracted with EtOAc. The
combined organic extracts were washed with a saturated aqueous
solution of NaCl, dried over MgSO4, filtered, and concentrated under
reduced pressure. Analysis of the crude material by 1H NMR
10. The enantiomeric purity and absolute configuration of
9 were
1
determined by analysis of the H NMR spectra of the corresponding
crude diastereomeric (R)- and (S)-O-methyl-mandelates, see: Trost, B.
M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M.;
Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S. L.;
Springer, J. P. J. Org. Chem. 1986, 51, 2370–2374.
11. Ireland, R. E.; Bey, P.; Cheng, K.-F.; Czarny, R. J.; Moser, J.-F.;
Trust, R. I. J. Org. Chem. 1975, 40, 1000–1007.
12. The mixture of 13+14 and the syn-2-amino-1,3-diol 24 was indepen-
dently converted to the same syn-a-hydroxy-b-aminoamide 233 by the
same sequence.

2906
M. Barbazanges et al. / Tetrahedron Letters 49 (2008) 2902–2906
indicated the formation of two diastereomers in a 9/1 ratio (anti/
successively with saturated aqueous solutions of NaCl and LiCl, dried
over MgSO4, filtered, and concentrated under reduced pressure.
Analysis of the 1H NMR spectrum of the crude material indicated a
diastereomeric ratio 18c/(19c+20c) > 94/6. Purification by flash
chromatography (petroleum ether/EtOAc gradient: 80:20 to 70:30)
afforded 96 mg (80%) of 18c as a colorless oil; [a]D ꢁ77.1 (c 1.04,
CHCl3); IR 3385, 1645, 1378, 1331, 1156, 1091, 1052, 930, 815,
syn = 9/1). Purification by flash chromatography (petroleum ether/
EtOAc gradient: 90:10 to 70:30) afforded 114 mg (24%) of a 9/1
mixture of anti/syn diastereomers and 251 mg of pure 9 (52%) as
viscous yellow oils (76% combined yield); [a]D ꢁ10.5 (c 0.97, CHCl3);
IR 3487, 2176, 1613, 1513, 1340, 1249, 1159, 1092, 1033, 844,
817 cmꢁ1 1H NMR (400 MHz, CDCl3) d 7.70 (d, J = 8.3 Hz, 2H),
;
7.34–7.31 (m, 2H), 7.29–7.21 (m, 7H), 6.88 (br d, J = 8.3 Hz, 2H),
5.77 (ddt, J = 15.6, 8.3, 1.3 Hz, 1H), 5.57 (ddd, apparent dt, J = 15.6,
5.3 Hz, 1H), 4.58 (d, AB syst, J = 15.8 Hz, 1H), 4.56 (dd, apparent t,
J = 5.6 Hz, 1H), 4.38 (dd, J = 8.3, 6.0 Hz, 1H), 4.35 (s, 2H), 4.34 (d,
AB syst, J = 15.8 Hz, 1H), 3.90 (br d, J = 5.3 Hz, 2H), 3.81 (s, 3H),
2.39 (s, 3H), 2.06 (d, J = 5.5 Hz, 1H, OH), 0.13 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 159.2 (s), 143.4 (s), 137.3 (s), 137.1 (s), 134.2 (d),
130.1 (s), 129.5 (d, 2C), 129.3 (d, 2C), 128.45 (d, 2C), 128.37 (d, 2C),
127.62 (d), 127.55 (d, 2C), 125.2 (d), 113.8 (d, 2C), 103.7 (s), 92.0 (s),
71.7 (t), 69.3 (t), 65.1 (d), 64.5 (d), 55.3 (q), 50.1 (t), 21.5 (q), ꢁ0.3 (q,
3C); Anal. Calcd for C32H39NO5SSi: C, 66.52; H, 6.80; N, 2.42.
Found: C, 66.27; H, 6.92; N, 2.43.
749, 665 cmꢁ1 1H NMR (400 MHz, CDCl3) d 7.77 (d, J = 8.3 Hz,
;
2H), 7.41 (d, J = 7.2 Hz, 1H), 7.32–7.24 (m, 5H), 6.02 (ddd, J = 17.0,
10.3, 8.5 Hz, 1H), 5.85 (ddt, J = 17.0, 10.1, 6.4 Hz, 1H), 5.36
(d, J = 4.4 Hz, 1H), 5.26 (d, J = 10.1 Hz, 1H), 5.24 (d, J = 17.0 Hz,
1H), 5.15 (dq, J = 17.0, 1.3 Hz, 1H), 5.09 (dq, J = 10.1,1.3 Hz, 1H),
5.02 (dd, J = 9.8, 8.3 Hz, 1H), 4.89 (dd, apparent br t, J = 4.0 Hz,
1H), 4.44 (t, J = 8.4 Hz, 1H), 3.99 (dd, J = 16.0, 6.4 Hz, 1H),
3.87 (dd, J = 16.0, 6.4 Hz, 1H), 3.22 (d, J = 9.8 Hz, 1H, OH), 3.16–
3.13 (m, 2H), 2.42 (s, 3H), 1.57 (s, 3H), 1.34 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 168.5 (s), 143.4 (s), 140.6 (s), 139.9 (s),
137.5 (s), 135.1 (d), 131.6 (d), 129.5 (d, 2C), 128.8 (d), 127.6 (d),
127.5 (d, 2C), 125.9 (d), 124.1 (d), 121.3 (t), 118.0 (t), 97.1 (s), 79.1 (d),
71.3 (d), 66.0 (d), 65.3 (d), 49.8 (t), 36.5 (t), 26.5 (q), 23.7 (q), 21.5 (q);
HRMS (ES+) Calcd for C27H33N2O5S (M+H+): 497.2105. Found:
497.2093.
18. N-Allyl-N-{(E)-3-[2-((3aR,8aS)-2,2-dimethyl-8,8a-dihydro-3aH-
indeno[1,2-d]oxazol-3-yl)-2-oxoethoxy]propenyl}-4-methylbenzene-
sulfonamide (17c). [a]D ꢁ84 (c 1.21, CHCl3); IR 1655, 1425, 1358,
1309, 1244, 1165, 1090, 937, 904, 814, 748, 665 cmꢁ1
;
1H NMR
20. Methyl (2S,3R)-3-[allyl(toluene-4-sulfonyl)amino]-2-hydroxypent-4-
enoate (21c). To a solution of amide 18c (80 mg, 0.16 mmol) in
MeOH (3 mL) was added 35% hydrochloric acid (1 mL). After 5 h
heating at reflux, the reaction mixture was cooled to rt, diluted with
water (5 mL), and extracted with EtOAc. The combined organic
extracts were washed with a saturated aqueous solution of NaCl,
dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography (petroleum ether/EtOAc gra-
dient: 80:20 to 65:35) afforded 43 mg (78%) of 21c as a colorless oil
[a]D ꢁ40.3 (c 2.08, CHCl3); IR 3500, 1742, 1439, 1339, 1287, 1214,
1156, 1090, 1015, 930, 816, 666 cmꢁ1; 1H NMR (400 MHz, CDCl3) d
7.70 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 5.89 (dddd,
J = 17.2, 10.2, 7.0, 5.2 Hz, 1H), 5.63 (ddd, J = 17.2, 10.6, 6.8 Hz, 1H),
5.20 (dq, J = 17.2, 1.4 Hz, 1H), 5.18 (dt, J = 10.6, 1.0 Hz, 1H), 5.15
(dq, J = 10.2, 1.4 Hz, 1H), 5.09 (dt, J = 17.2, 1.0 Hz, 1H), 4.66 (ddt,
J = 7.0, 5.2, 1.0 Hz, 1H), 4.41 (m, 1H), 3.89 (ddt, J = 16.4, 5.2,
1.4 Hz, 1H), 3.81 (s, 3H), 3.77 (ddt, J = 16.4, 7.0, 1.4 Hz, 1H), 3.19 (d,
J = 7.0 Hz, 1H, OH), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) d
172.6 (s), 143.6 (s), 136.8 (s), 135.9 (d), 131.6 (d), 129.6 (d, 2C), 127.5
(d, 2C), 120.6 (t), 117.3 (t), 73.1 (d), 62.2 (d), 52.6 (q), 48.7 (t), 21.5 (q);
HRMS (FAB) Calcd for C16H21NNaO5S (M+Na+): 362.10326.
Found: 362.10277.
(400 MHz, CDCl3) d 7.66 (d, J = 8.3 Hz, 2H), 7.32–7.21 (m, 6H), 7.00
(d, J = 14.2 Hz, 1H), 5.60 (ddt, J = 17.2, 10.4, 5.3 Hz, 1H), 5.37 (d,
J = 4.4 Hz, 1H), 5.16 (dd, J = 17.2, 0.9 Hz, 1H), 5.10 (dd, J = 10.4,
0.9 Hz, 1H), 4.96 (dt, J = 14.2, 7.1 Hz, 1H), 4.88 (dt, J = 4.4, 2.0 Hz,
1H), 4.38 (d, AB syst, J = 13.8 Hz, 1H), 4.34 (d, AB syst, J = 13.8 Hz,
1H), 4.18 (dd, J = 7.1, 0.8 Hz, 2H), 4.01 (br d, J = 5.3 Hz, 2H), 3.13
(apparent d, J = 2.0 Hz, 2H), 2.41 (s, 3H), 1.65 (s, 3H), 1.35 (s, 3H);
13C NMR (100 MHz, CDCl3) d 165.8 (s), 144.0 (s), 140.8 (s), 140.6 (s),
136.1 (s), 131.1 (d), 130.7 (d), 129.8 (d, 2C), 128.5 (d), 127.3 (d), 126.9
(d, 2C), 125.9 (d), 124.4 (d), 118.0 (t), 105.1 (d), 96.9 (s), 79.3 (d), 70.5
(t), 69.3 (t), 64.8 (d), 48.1 (t), 36.3 (t), 26.5 (q), 24.1 (q), 21.5 (q);
HRMS (FAB) Calcd for C27H32O5N2NaS (M+Na+): 519.19241.
Found: 519.19179.
19. N-Allyl-N-{(R)-1-[(S)-2-((3aR,8aS)-2,2-dimethyl-8,8a-dihydro-3aH-
indeno[1,2-d]oxazol-3-yl)-1-hydroxy-2-oxo-ethyl]allyl}-4-methylbenz-
enesulfonamide (18c). To
a solution of amide 17c (120 mg,
0.242 mmol) and HMPA (1.26 mL, 7.26 mmol, 30 equiv) in THF
(5 mL) at ꢁ78 °C was added dropwise LiHMDS (480 lL, 1 M in
THF, 0.480 mmol, 2 equiv). After 30 min at ꢁ78 °C, the reaction
mixture was poured into a saturated aqueous solution of NH4Cl and
extracted with EtOAc. The combined organic extracts were washed