Homoallylic alcohols and trichloroacetamides as hydrogen bond donors for directed dihydroxylation

Article abstract of DOI:10.1016/S0040-4039(01)01999-2

The synthesis and directed dihydroxylation of a series of homoallylic alcohols and trichloroacetamides is described. Using the combination of OsO₄ and TMEDA, moderate to high levels of stereoselectivity were obtained, depending upon the structu

Full text of DOI:10.1016/S0040-4039(01)01999-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8951–8954
Homoallylic alcohols and trichloroacetamides as hydrogen bond
donors for directed dihydroxylation
Timothy J. Donohoe,a,* Lee Mitchell,a Michael J. Waring,a Madeleine Helliwell,a,† Andrew Bellb and
Nicholas J. Newcombec
aDepartment of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
bPfizer Limited, Sandwich, Kent CT13 9NJ, UK
cAstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Received 19 September 2001; revised 20 October 2001; accepted 24 October 2001
Abstract—The synthesis and directed dihydroxylation of a series of homoallylic alcohols and trichloroacetamides is described.
Using the combination of OsO4 and TMEDA, moderate to high levels of stereoselectivity were obtained, depending upon the
structure of the substrate. Proof of the structure of two osmate esters was obtained through X-ray crystallography. © 2001
Elsevier Science Ltd. All rights reserved.
The concept of using a substrate to direct a reaction
with an external reagent is an extremely useful one in
organic chemistry.1 While many diverse Lewis acid/base
interactions between reagent and substrate have been
the origin of such a directing effect, perhaps the most
common and useful type of association is based on
hydrogen bonding.
accomplishes the directed dihydroxylation of allylic
alcohols2 and amides3 (Scheme 1). We believe that
TMEDA forms a bidentate, and reactive, complex with
OsO4 in situ. In each case, it was suggested that hydro-
gen bonding between the oxo-ligands of the oxidant
(hydrogen bond acceptor) and the allylic group (hydro-
gen bond donor) was responsible for the high levels of
syn selectivity that were observed. Importantly, such
control during the oxidation event leads to a sense of
stereoselectivity that cannot be obtained without the
OsO4/TMEDA reagent (see condition (i) versus condi-
tion (ii), Scheme 1).4
It has been recently shown that combination of osmium
tetroxide with TMEDA produces a reagent which
* Corresponding author. Present address: Dyson Perrins Laboratory,
South Parks Road, Oxford OX1 3QY, UK; e-mail:
timothy.donohoe@chem.ox.ac.uk
Positioning a hydrogen bond donor in the homoallylic
position of substrates has also been investigated as a
device for controlling stereoselective reactions and, with
regard to peracid epoxidation, it was shown that effec-
tive hydrogen bonding can occur.6 However, it is fair to
† Author to whom correspondence regarding the X-ray crystal struc-
ture should be addressed. Crystal data: C11H24N2O5Os syn-2M=
454.52, orthorhombic, a=11.0606 (17), b=14.287 (3), c=9.0546
3
,
,
(14) A, V=1430.8 (4) A , T=296 K, space group P212121(no. 19),
Z=4, v(Cu Ka)=17.017 mm−1, 1679 independent reflections which
were used in all calculations. The final ꢀR(F2) was 0.0937 (all
data). R(F) was 0.0350 using 1629 reflections with I>2|(I). The
structure was solved using the Patterson method, C-9 was disor-
dered over two sites, A and B, whose occupancies were constrained
to sum to 1.0. Full-matrix least-squares refinement was carried out
on F2.
XH
XH
XH
OH
OH
OH
OH
(i) or (ii)
+
Crystal data: C13H24Cl3N3O5Os syn-13M=598.90, monoclinic, a=
condition (i) 8:1 (98%)
condition (ii) 1:12 (94%)
XH= OH
,
11.19 (2), b=11.405 (10), c=15.857 (10) A, i=102.57 (4)°, V=
3
,
1976 (4) A , T=296 K, space group P21/c (no. 14), Z=4, v(Mo
condition (i) 20:1 (98%)
condition (ii) 1:3 (99%)
XH= Cl3CCONH
Ka)=6.888 mm−1, 3844 independent reflections which were used in
all calculations. The final ꢀR(F2) was 0.0629 (all data). R(F) was
0.0240 using 3605 reflections with I>2|(I). The structure was solved
using direct methods, and refined on F2 using full-matrix least-
squares.
Scheme 1. Reagents and conditions: (i) OsO4 (1 equiv.),
TMEDA (1 equiv.), CH2Cl2, −78°C, then MeOH, H+; (ii)
OsO4 (cat.), NMO, acetone/water, rt.5
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01999-2

8952
T. J. Donohoe et al. / Tetrahedron Letters 42 (2001) 8951–8954
say that the scope and nature of homoallylic directing
groups has not been extensively developed in compari-
son to the corresponding allylic systems. Perhaps the
main reason for this is the lack of readily available
substrates on which to test out new reactions.
syn-2 and both compounds anti-4 and anti-10 are
known in the literature. The syn and anti stereochem-
istry of both syn-6 and syn-8 was assigned by analogy.
Proof of the involvement of hydrogen bonding during
oxidation was sought in the preparation and dihydroxy-
lation of 11, which is without a hydrogen bond donor
(Scheme 3). In this case, the bulky OsO4/TMEDA
oxidant approaches the alkene from the face opposite
to the two acetoxy groups, thus confirming our
hypothesis.
Therefore, we set out to synthesise and dihydroxylate a
series of cyclic compounds with both alcohol and
trichloroacetamide functionality in the homoallylic
position. This type of remote stereocontrol should be a
useful way to prepare stereochemically defined
molecules suitable for use in synthesis.
AcO
OAc
OAc
AcO
AcO
OAc
OAc
(i) (ii)
Scheme 2 shows the results obtained from oxidation of
a series of five- and six-membered cyclic homoallylic
alcohols.7 The substrates were prepared using standard
synthetic transformations including metathesis (1 and
3),8 Birch reduction (5)9 hydroboration and dihydroxyl-
ation (9).10 The results show that, generally, oxidation
under standard conditions (UpJohn5) gives low
stereoselectivity for the anti diastereoisomer, while oxi-
dation with OsO4/TMEDA gives contra-steric selectiv-
ity for the syn diastereoisomer.
+
AcO
OAc
OAc
1:15 (78%) anti-10
11
syn-10
Scheme 3. Reagents and conditions: (i) OsO4 (1 equiv.),
TMEDA (1 equiv.), CH2Cl2, −78°C, then MeOH, H+; (ii)
Ac2O, py.
We then prepared a set of homoallylic trichloroac-
etamides and studied directed dihydroxylation reactions
under OsO4/TMEDA conditions (Scheme 4). The sub-
strates were prepared by a variety of synthetic routes
including metathesis (12 and 14), Birch reduction chem-
istry (16)9 and Curtius rearrangement (18).
The stereochemistry of the products was determined by
a number of methods. For example, X-ray crystallogra-
phy was used to solve the structure of derivatives of
OH
OAc
OAc
AcO
AcO
(i) or (ii)
then (iii)
+
1
syn-2
anti-2
NHCOCCl3
NHCOCCl3
NHCOCCl3
AcO
AcO
(i) or (ii)
then (iii)
condition (i) 25:1 (71%)
condition (ii) 2:1 (82%)
+
AcO
OAc
AcO
OAc
12
syn-13
anti-13
AcO
OAc
AcO
OAc
condition (i) 25:1 (94%)
condition (ii) 1:7 (65%)
(i) or (ii)
then (iii)
+
O
O
O
anti-4
syn-4
3
H
H
H
AcO
OAc AcO
OAc
OH
OAc
OAc
(i) or (ii)
then (iii)
condition (i) 1:1 (55%)
condition (ii) 1:4 (75%)
+
O
O
O
O
H
H
H
NHCOCCl3
NHCOCCl3
NHCOCCl3
anti-15
AcO
OAc
AcO
OAc
14
syn-15
condition (i) 2:1 (72%)
condition (ii) 1:4 (82%)
(i) or (ii)
then (iii)
+
O
O
O
syn-6
5
anti-6
OH
OAc
OAc
OAc
AcO
OAc AcO
OAc
condition (i) 6:1 (83%)
condition (ii) 1:2 (79%)
(i) or (ii)
then (iii)
+
O
O
NHCOCCl3
OH
AcO
AcO
AcO
AcO
OAc
NHCOCCl3
NHCOCCl3
(i) or (ii)
then (iii)
+
16
syn-17
anti-17
condition (i) 20:1 (88%)
condition (ii) 1:3 (70%)
7
syn-8
anti-8
condition (i) 3:1 (92%)
condition (ii) 1:1 (88%)
NHCOCCl3
NHCOCCl3
NHCOCCl3
(i) or (ii)
then (iii)
OH
OH
AcO
AcO
OAc
OAc
AcO
OAc
+
(i) or (ii)
then (iii)
+
AcO
AcO
AcO
syn-10
OAc
OAc
OAc
anti-19
18
syn-19
anti-10
9
condition (i) 12:1 (82%)
condition (ii) 1:2 (86%)
condition (i) 1:1 (92%)
condition (ii) 1:1 (99%)
Scheme 2. Reagents and conditions: (i) OsO4 (1 equiv.),
TMEDA (1 equiv.), CH2Cl2, −78°C, then MeOH, H+; (ii)
OsO4 (cat.), NMO, acetone/water, rt; (iii) Ac2O, py.
Scheme 4. Reagents and conditions: (i) OsO4 (1 equiv.),
TMEDA (1 equiv.), CH2Cl2, −78°C, then MeOH, H+; (ii)
OsO4 (cat.), NMO, acetone/water, rt; (iii) Ac2O, py.

T. J. Donohoe et al. / Tetrahedron Letters 42 (2001) 8951–8954
8953
Again, it can be seen that choice of the conditions
Acknowledgements
enables the synthesis of predominantly the syn or the
anti diastereoisomer.
We are grateful to the EPSRC, Pfizer and AstraZeneca
Pharmaceuticals for financial support of this project.
Examination of the results illustrated in Schemes 2 and
4 leads us to conclude that the directing effect is
strongest when the hydrogen bond donor is positioned
directly on the ring (compare the oxidation of 1 with 3
and 12 with 14); presumably this is a steric effect
whereby the exocyclic methylene chain prevents
directed dihydroxylation. We can also see that five-
membered rings tend to yield higher stereoselectivities
than their six-membered counterparts (compare 1 with
7 and 12 with 18).
References
1. Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev.
1993, 93, 1307.
2. (a) Donohoe, T. J.; Moore, P. R.; Waring, M. J.; New-
combe, N. J. Tetrahedron Lett. 1997, 38, 5027; (b) Ling,
R.; Mariano, P. S. J. Org. Chem. 1998, 63, 6072; (c)
Harris, J. M.; Keranen, M. D.; O’Doherty, G. J. Org.
Chem. 1999, 64, 2982.
3. (a) Donohoe, T. J.; Blades, K.; Moore, P. R.; Winter, J.
J. G.; Helliwell, M.; Stemp, G. J. Org. Chem. 1999, 64,
2980; (b) Donohoe, T. J.; Winter, J. J. G.; Stemp, G.
Tetrahedron Lett. 2000, 41, 4701.
4. (a) Cha, J. K.; Christ, W.; Kishi, Y. Tetrahedron Lett.
1983, 24, 3943; (b) Cha, J. K.; Christ, W.; Kishi, Y.
Tetrahedron Lett. 1983, 24, 3947; (c) Cha, J. K.; Christ,
W.; Kishi, Y. Tetrahedron 1984, 40, 2247; (d) Cha, J. K.;
No-Soo, K. Chem. Rev. 1995, 95, 1761.
Furthermore, one can conclude that, generally, homoal-
lylic trichloroacetamides give superior levels of syn
selectivity in the dihydroxylation, presumably because
of their increased hydrogen bond donor ability when
compared to the corresponding homoallylic alcohols.
However, in this regard, the non-selective oxidation of
18 was surprising (especially when compared to the
alcohol 7) and we assume that this is because the
hydrogen bond acceptor group must adopt an axial
position in order to deliver the oxidant. Evidently, the
bulky amide group resists reaction through this confor-
mation. This requirement for an axial directing group
would also explain why 9 (which must have one axial
hydroxyl group) is oxidised more selectively than 7.
5. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron
Lett. 1976, 1973.
6. (a) Derby, A. C.; Henbest, H. B.; McClenaghan, I. J.
Chem. Ind. 1962, 462; (b) Bingham, K. D.; Meakins, J.
D.; Wicha, J. J. Chem. Soc. (C) 1969, 510; (c) Rotella, D.
P. Tetrahedron Lett. 1989, 30, 1913; (d) de Sousa, S. E.;
Kee, A.; O’Brien, P.; Watson, S. T. Tetrahedron Lett.
1999, 40, 387; (e) Barrett, S.; O’Brien, P.; Steffens, H. C.;
Towers, T. D.; Voith, M. Tetrahedron 2000, 56, 9633; (f)
See also Ref. 1.
The stereochemistry of a derivative of syn-13 was
proven by X-ray crystallography and that of syn-15
and syn-17 by NOE experiments.
In fact, we were able to obtain crystal structures of
osmate esters derived from the two five-membered ring
compounds syn-2 and syn-13 (Fig. 1); both structures
show the chelated nature of the TMEDA ligand and
the osmium metal.
7. Representative experimental procedure: To a solution of
9 (50 mg, 0.44 mmol) and TMEDA (56 mg, 0.48 mmol)
in dichloromethane (10 mL) precooled to −78°C was
added a solution of OsO4 (114 mg, 0.45 mmol) in
dichloromethane (ꢀ1 mL). The solution turned deep red
then brown–black. The solution was stirred until com-
plete (TLC analysis, ca. 1 h) before being allowed to
warm to room temperature. The solution was then con-
centrated under reduced pressure and the resulting
residue redissolved in methanol (10 mL). Hydrochloric
acid (conc. three drops) was then added and the solution
stirred for 2 h. The solution was then concentrated under
reduced pressure and the product was redissolved in
pyridine (5 mL) and acetic anhydride (5 mL) and N,N-
dimethylaminopyridine (5 mg, cat.) was added. The mix-
ture was then heated at 80°C for 12 h. It was then
allowed to cool and was diluted with diethyl ether (100
mL). The solution was then filtered through Celite® and
washed with dilute hydrochloric acid (100 mL, 2 M),
potassium carbonate solution (saturated, 100 mL) and
brine (100 mL). The ethereal layer was then dried
(MgSO4) and then concentrated under reduced pressure
to yield the crude mixture of peracetylated products
which were then purified by flash chromatography
(EtOAc) to afford syn-10 as a colourless solid (114 mg,
82%); mp 65–66°C; lH (300 MHz; CDCl3) 5.11–5.03 (4H,
m), 2.35 (2H, dt, J=14 and 7), 2.06 (12H, s), 1.84 (2H,
dt, J=14 and 3); lC (75 MHz, CDCl3) 170, 67.9, 28.0,
20.9.
Figure 1. X-Ray crystal structures of osmate esters from
syn-2 and syn-3.
To conclude, we have shown that a range of homoal-
lylic alcohols and trichloroacetamides are potentially
useful hydrogen bond donors for the directed dihydroxyl-
ation reaction. Access to both triols and amino diol
derivatives with defined stereochemistry is now possible
and we aim to use this methodology in synthesis.

8954
T. J. Donohoe et al. / Tetrahedron Letters 42 (2001) 8951–8954
Other representative data is as follows:
4.72 (2H, m), 2.04 (3H, s), 1.98 (3H, s), 1.86 (3H, s),
2.05–1.45 (6H, m); lC (75 MHz, CDCl3) 170 (3), 69.5,
69.3, 67.9, 31.4, 25.3, 24.7, 21.1, 20.9, 20.8.
syn-2: lH (300 MHz; CDCl3) 5.16–5.02 (3H, m), 2.35
(2H, dt, J=14 and 7), 2.08 (6H, s), 2.06 (3H, s), 1.95 (2H,
dt, J=14 and 4); lC (75 MHz, CDCl3) 171, 170, 72.1,
70.4, 35.5, 35.4, 20.8.
8. For a pertinent review, see: Armstrong, S. K. J. Chem.
Soc., Perkin Trans. 1 1998, 371.
syn-6: lH (300 MHz; CDCl3) 5.43 (1H, q, J=5), 5.17
(1H, d, J=5), 4.26–4.09 (3H, m), 3.89 (1H, dd, J=10, 5),
2.10 (6H, s), 2.08 (3H, s), 1.36 (3H, s); lC (75 MHz,
CDCl3) 171, 170 (2), 80.8, 76.2, 71.2, 68.9, 65.3, 22.3,
20.6, 20.4, 18.3.
9. (a) Birch, A. J.; Slobbe, J. Tetrahedron Lett. 1975, 627;
(b) For a review, see: Donohoe, T. J.; Guyo, P. M.;
Raoof, A. Target. Heterocyclic Syst. 1999, 3, 117 (Italian
Society of Chemistry).
10. Maras, A.; Secen, H.; Suetbeyaz, Y.; Balci, M. J. Org.
Chem. 1998, 63, 2039.
syn-8: lH (300 MHz; CDCl3) 5.17–5.11 (1H, m), 4.84–