Remote steric effect on the regioselectivity of Sharpless asymmetric dihydroxylation

Article abstract of DOI:10.1016/j.tet.2005.03.119

Studies on the regioselectivities for the Sharpless asymmetric dihydroxylation (AD) of conjugated dienoates, trienoates, dienones and dienamides are described. Excellent regioselectivities were obtained in straight chain dienoates, all trienoates, ketones

Full text of DOI:10.1016/j.tet.2005.03.119

Tetrahedron 61 (2005) 6337–6351
Remote steric effect on the regioselectivity of Sharpless
asymmetric dihydroxylation
*
Yan Zhang and George A. O’Doherty
Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA
Received 5 December 2004; revised 14 February 2005; accepted 4 March 2005
Available online 10 May 2005
Abstract—Studies on the regioselectivities for the Sharpless asymmetric dihydroxylation (AD) of conjugated dienoates, trienoates, dienones
and dienamides are described. Excellent regioselectivities were obtained in straight chain dienoates, all trienoates, ketones and amides. The
remote branched iso-propyl and tert-butyl groups of dienoates greatly lowered the normally excellent regiocontrol. This observation is
rationalized in terms of substrate conformational changes, and the steric interaction between the branched methyl group of iso-propyl or tert-
butyl groups and the ethyl group on the (DHQD)2PHAL ligand.
q 2005 Elsevier Ltd. All rights reserved.
The Sharpless asymmetric dihydroxylation reaction has
proven to be one of the most powerful reactions for
asymmetric synthesis.1 Over the years we and others1 have
found the selective use of the asymmetric dihydroxylation
(AD) of polyenes to be a powerful tool for total synthesis.2–4
In particular, we have found the AD reaction of vinylfur-
ans,2 dieneoates3 and trienoates4 provides excellent starting
materials for natural product synthesis.
natural products using a three-step asymmetric hydration of
the g,d-double bond of dienoates7 and the 3,f-double bond
of trienoates.4 Key to this transformation is the regio-
selective dihydroxylation of dienoates and trienoates.
An interesting observation occurred in the course of our
use of this asymmetric hydration procedure for the total
synthesis of the bioactive colletodiol class of natural
products 4a–c (Scheme 2).4 Specifically, we found an
alternative case where a loss of regioselectivity occurred in
the Sharpless dihydroxylation process (Scheme 3).
Not surprisingly, Sharpless has extensively studied the AD
reaction of polyenes5,6 and found the osmium quinuclidine
ligand systems appear to react preferentially with the more
electron rich double bond of a polyene p-system. This is
best exemplified by the asymmetric dihydroxylation of
2,4-dienoates to give regioisomeric diols (1 to 2 or 3,
Scheme 1). In general, Sharpless has found these reactions
occur to give preferentially the conjugated 2-enoate-4,5-diol
2 over the unconjugated 4-enoate-2,3-diol 3. An exception
to this excellent control was seen when the dienoates were
substituted in the 5-position with a phenyl ring as in 1b.
Thus, when 1a was exposed to the Sharpless AD-mix-b
conditions a greater than 20 to 1 ratio of 2a to 3a was
produced. In contrast, when 1b was exposed to the
AD-mix-b conditions only a 5:1 ratio of 2b to 3b resulted.
Sharpless suggested that this lowering of regioselectivity
was a result of the fact that the dihydroxylation reaction
tends to avoid the breaking of conjugation.5
In the course of this synthetic investigation, it was found as
expected that only the g,d-unsaturated double bond under-
went dihydroxylation for the methyl and ethyl dienoates
10b and 10c, providing triols 11b and 11c as the only
regioisomers (Scheme 3). This expected high regiocontrol
was unaffected by a bulky TBS-group on the distal oxygen
as in 10d. When the TBS-ether 10d was reacted with the
AD-mix-b system diol 11d was formed as a single
regioisomer. In contrast, when the ester was changed
to the sterically demanding t-butyl group (10a) the
dihydroxylation became unselective. Thus exposing 10a
to the typical AD-mix-b conditions resulted in a 1:1 ratio
of the products 11a and 12a.
In the previous regioselectivity studies by Sharpless the
observed selectivities were rationalized by a combination of
electronic and steric effects;5,6 however, no such remote
substituent effect has been reported. Therefore, to better
delineate the origins of this peculiar phenomenon, we
decided to further investigate this remote steric effect with
several dienoates, dienones and dienamides. This was done
Recently, we developed several effective routes to various
Keywords: Asymmetric dihydroxylation; Trienoates; Dienones.
*
Corresponding author. Tel.: C1 304 293 3435; fax: C1 304 293 4904;
e-mail: george.odoherty@mail.wvu.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.119

6338
Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
Scheme 1. Regioselectivity of the Sharpless dihydroxylation.
with the hope of gaining a better understanding of the
dihydroxylation mechanism and thus more reliably deliver-
ing these valuable synthetic intermediates.
Because the methyl and t-butyl esters impose a similar
electronic effect on the dienoates, we theorized that the
above observation (10a to 11a/12a) results from a steric
effect on the conformation. That is to say, the larger t-butyl
group may have caused the ester carbonyl to turn out of
plane/conjugation with the diene and thus become less
electron withdrawing. If this assumption were true the same
effect should be seen with other esters, not to mention other
dienes substituted with electron withdrawing groups. To
probe the steric contribution of this conformational effect,
we have chosen to study ethyl, iso-propyl and tert-butyl
dienoates. We also chose to study the Weinreb amide and
methyl ketone. For instance in the case of the Weinreb
amides, they should exist exclusively in one planar
conformation. To investigate the steric effect due to the
ester oxygen atom, we have chosen the thiol ethyl ester
dienoate 13f. To distinguish between steric effects on
conformation and electronic withdrawing effects, we chose
to study methyl, ethyl and tert-butyl trienoates (19a–c),
because we believed the conformational effects should be
identical for the trienoate substrates as the dienoates.
Knowing that the phenyl group lowers the regioselectivity,5
we chose to study dienes with both methyl and phenyl
substitution at the d-position. This substitution should allow
us to modulate the inherent substrate selectivity, and thereby
give us a tunable probe to variably test this distant
substituent effect on regioselectivity.
Scheme 2. Colletodiol retrosynthesis.
Scheme 3. Unusual regioselectivity for t-butyl esters.
1. Results and discussion
All the dienes and trienes were exposed to slight variations
of the Sharpless AD conditions, using both the (DHQ)2-
PHAL (AD-mix-a) and (DHQD)2PHAL (AD-mix-b)
ligands.8 For the dienoates (13a–c, 16a–c) the typical
Table 1. AD of 5-methyl substituted dienes using (DHQD)2PHAL
SM
R
Yield
Ratio (14/15)
%ee 14
%ee 15
13a
13b
13c
13d
13e
13f
OEt
78
45
76
82
68
38
O20:1
9:2
6:1
O20:1
O20:1
O20:1
92
72
76
75
69
92
n.a.
96
n.a.
n.a.
n.a.
n.a.
Oi-Pr
Ot-Bu
N(OMe)Me
Me
SMe

Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
Table 2. AD of 5-phenyl substituted dienes using (DHQD)2PHAL
6339
SM
R
Yield
Ratio (17/18)
%ee 17
%ee 18
16a
16b
16c
16d
16e
16f
OEt
76
50
62
85
68
31
5:1
7:3
5:3
O20:1
w10:1
3.7:1
99
91
91
99
98
99
n.a.
98
99
n.a.
n.a.
99
Oi-Pr
Ot-Bu
N(OMe)Me
Me
SMe
reaction conditions involved exposure of the substrates to
1–5 mol% ligand, 3 equiv K3Fe(CN)6, 3 equiv K2CO3,
1 equiv MeSO2NH2, and 1–5 mol% OsO4 in 1:1 t-butyl
alcohol/ H2O at 0 8C. The other substrates, dienamide 13d/
16d, dineone 13e/16e and dienethioester 13f/16f were much
less reactive and required 10% OsO4 and 11% ligand at
room temperature to give satisfactory yields of diol
products. The absolute configurations of diol products
were determined either by conversion to known compounds,
or by the Mosher method.9 For some minor products the
assignments were based upon the Sharpless mnemonic.1
The ratio of the regioisomers was determined by analysis of
substrate was the more reactive one and thus the major
dihydroxylation products were 14a–f. When one looks at the
series of esters 13a–c, a clear trend can be seen between
increase in steric bulk of the ester substituent and a decrease
in regioselectivity. Interestingly, the less reactive substrates
13d–f all reacted to give essentially one regioisomer 14d–f.
This came as a surprise as it was expected that the amide
substrate 13d would have a similar conformation as the
hindered esters 13b and 13c, and thus have a similar loss of
regiocontrol.
The results for the 5-phenyl substituted diene substrates
16a–f using the (DHQD)2PHAL ligand system are sum-
marized in Table 2. As expected, in all six cases 17a–f
were the major dihydroxylation products formed. Not
surprisingly, the products from the phenyl-substituted
dienes 16a–f afforded products with higher enantiomeric
excess.5 Similarly, we were not surprised to see an across
the board decrease in regioselectivity, with the bulky esters
16b and 16c having product ratio in the range of 2:1. While
the phenyl substituted thioester 16f did have a detectable
amount of the regioisomer 18f (w4:1), we were, once again,
surprised to see the high selectivities for both the amide
(16d) and ketone (16e) substrates.
1
the crude H NMR and isolation of the purified products.
The enantioselectivities were determined by HPLC
(Chiralcel OD column, 1–8% i-PrOH in hexane, 0.8–
1.0 mL/min). The minor regioisomers, 15e and 18e, were
unstable to the reaction conditions and underwent a retro-
aldol reaction to give cinnamaldehyde, integration of which
in the crude 1H NMR was used to determine the
regioselectivities.
The results for the 5-methyl substituted diene substrates
using the (DHQD)2PHAL are summarized in Table 1. As
expected, the more electron rich distal double bond of each
Table 3. AD of 5-methyl substituted dienes using (DHQ)2PHAL
SM
R
Yield
Ratio (14/15)
%ee (ent)-14
%ee (ent)-15
13a
13b
13c
13d
13e
13f
OEt
71
59
57
76
71
24
O20:1
16:1
O20:1
O20:1
O20:1
O20:1
80
79
85
75
65
71
n.a.
96
n.a.
n.a.
n.a.
n.a.
Oi-Pr
Ot-Bu
N(OMe)Me
Me
SMe

6340
Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
Table 5. AD of 7-methyl substituted trienes using (DHQD)2PHAL
The results for the 5-methyl substituted diene substrates
13a–f with the (DHQ)2PHAL ligand system were summar-
ized in Table 3. Interestingly, this remote steric effect on
regioselectivity disappears when the (DHQD)2PHAL ligand
was switched to the pseudo-enantiomeric ligand (DHQ)2-
PHAL. To our surprise, all six substrates 13a–f reacted
under the dihydroxylation conditions using the (DHQ)2-
PHAL ligand to give (ent)-14a–f for all practical purposes
as a single regioisomer, with the iso-propyl ester having
the lowest selectivity that being at the barely detectable
level of 16:1.
R
Ratio
Yield
%ee 20
19a
19b
19c
Me
Et
t-Bu
O20:1
O20:1
O20:1
82
96
78
96
99
96
decrease in regiocontrol only appears when the substituent
has branching (i.e., i-propyl and t-butyl esters and not
amides) and the effect significantly differs depending on
which ligand system is used (i.e., a 9:2 ratio for 13b with
(DHQD)2PHAL and a 16:1 ratio for (ent)-13b with
(DHQ)2PHAL). Thus the origins of this phenomenon must
be the result of a steric interaction between the branched
substitutent and the stereogenic ethyl group that makes
(DHQ)2PHAL and (DHQD)2PHAL diastereomers and not
enantiomers. This steric interaction must be significantly
greater in the (DHQD)2PHAL/Os/dienoate complex than
the (DHQ)2PHAL/Os/dienoate complex.
The results for the 5-phenyl substituted diene substrates
16a–f using the (DHQ)2PHAL are summarized in Table 4.
Once again, the effect of the phenyl groups lowering
regioselectivity can be seen. As in Table 3, the improvement
in regioselectivity for the (DHQ)2PHAL ligand system over
the (DHQD)2PHAL ligand system could be seen; albeit, the
difference in regioselectivity was observed to a much
smaller extent. For example, the t-butyl ester 16c reacted
under the (DHQD)2PHAL reaction condition to give a 5:3
ratio of 17c to 18c (Table 2). In contrast, 16c reacted under
the (DHQ)2PHAL reaction condition to give a 2:1 ratio of
(ent)-17c to (ent)-18c (Table 4). Although this change is
small, the trend is consistent throughout the whole series.
Finally it should be noted that these studies of the AD
reaction on the dienone 16e were complicated by an
isolation problem. This problem introduced some uncer-
tainty to the measurement of regioselectivity. Isolation of
the minor regioisomer 18e for the AD reaction of phenyl
substituted dienone 16e proved problematic due to base
sensitivity. Upon the typical base wash (2 N KOH) to
remove MeSO2NH2 from the reaction mixture, it was noted
that the minor regioisomer 18e underwent a retro-aldol
reaction to give cinnamaldehyde 21 (Scheme 4). Buffering
the reaction mixture with NaHCO3 and skipping the base-
washing can significantly reduce this retro-aldol reaction,
however, a degree of uncertainty in our ability of measure
the ratio of 17e to 18e still remains. Because of our concerns
about the retro-aldol reactions, we skipped the base-washing
step for both the methyl and phenyl substituted dienones 13e
and 16e. The crude 1H NMR spectra for these reactions were
examined for both the minor regioisomers as well as the
retro-aldol products cinnamaldehyde and crotonaldehyde.
The final evidence against our hypothesis that the decrease
of regiocontrol is a result of steric effect on conformation
came from our study of trienoates 19a–c (Table 5).
Regardless of ligand system good yields were obtained for
the AD reaction of methyl, ethyl and tert-butyl trienoates.
Similarly, excellent regiocontrol was observed (i.e., only the
distal double bond underwent a dihydroxylation forming
diols 20a–c). As our initial hypothesis predicted that these
trienoates 19a–c should have similar conformational
populations and electronic polarization as the dienoates
13a–c and thus similar regioselectivities in the dihydrox-
ylation reaction, an alternative explanation was needed
(vide infra).
Our revised hypothesis, for the origins of this unusual
remote steric effect on the regioselectivity of the AD
reaction on dienoates, came from two observations. The
Table 4. AD of 5-phenyl substituted dienes using (DHQ)2PHAL
SM
R
Yield
Ratio (17/18)
%ee (ent)-17
%ee (ent)-18
16a
16b
16c
16d
16e
16f
OEt
73
60
36
61
60
31
6.5:1
9:2
2:1
O20:1
w10:1
7.8:1
99
45
87
98
93
99
n.a.
99
93
n.a.
n.a.
98
Oi-Pr
Ot-Bu
N(OMe)Me
Me
SMe

Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
6341
Scheme 4. Isolation of base sensitive substrates.
While skipping the base washing allowed for the isolation of
diols 14e and 17e, this new procedure did not afford pure
material. To properly gauge the yield of the reaction we
found it easier to convert the crude diol products to
diacetates 22 and 23 (Ac2O/Py/DMAP). Interestingly, the
base sensitive diol products were easily regenerated from
the purified diacetate products upon exposure to Et3N in
CH3OH. No indication of retro-aldol products was observed
under these mildly basic reaction conditions. While no
regioisomers were detected, having pure diol in hand
solvent specified. Flash column chromatography was
performed on ICN reagent 60 (60–200 mesh) silica gel.
Analytical thin-layer chromatography was performed with
˚
pre-coated glass-backed plates (Whatman K6F 60 A, F254
)
and visualized by quenching of fluorescence and by charring
after treatment with p-anisaldehyde or potassium permanga-
nate stain. Rf values are obtained by elution in the stated
solvent ratios (v/v). High resolution mass spectrometric data
analysis was performed by the University of Minnesota
Mass Spectrometry Laboratory. Ether and THF were
distilled from benzophenone and sodium metal. Methylene
chloride, benzene and triethylamine were distilled from
calcium hydride. Unless otherwise noted, solvents were
reagent grade and were used without purification. Commer-
cial reagents were used without purification unless other-
wise noted. Air- and /or moisture-sensitive reactions were
carried out under an atmosphere of nitrogen using oven-
dried glassware and standard syringe/septa techniques.
1
allowed for analysis of crude H NMR (Scheme 5).
In summary, the regioselectivities for the AD reaction of
dienoates, dienones, dienamides and trienoates were
studied. In general, excellent regioselectivities were found
in the ketone and amide cases. The unbranched esters
(methyl, ethyl) gave diol products with good regiocontrol.
In contrast, branched esters (iso-propyl, tert-butyl) gave diol
products with poor regiocontrol. This branching steric effect
can lower regiocontrol by the same magnitude as Sharpless’
previous noted ‘disruption of conjugation’ phenomena. This
can be explained by a steric interaction between the methyls
on the iso-propyl or tert-butyl groups, and the ethyl group
on the (DHQD)2PHAL ligand. This is consistent with the
(DHQ)2PHAL ligand giving higher regiocontrol. This
branched methyl group/ligand interaction is removed by
adding an extra double bond as in the trienoates. Detailed
computational and synthetic studies are ongoing to further
support this new hypothesis.
2.1.1. Ethyl (4S,5S)-4,5-dihydroxy-2-hexenoate ((ent)-
14a). Into a 250 mL round bottom flask was added 60 mL
of t-BuOH, 60 mL of water, K3Fe(CN)6 (41.1 g, 125 mmol),
K2CO3 (17.24 g, 125 mmol), MeSO2NH2 (3.39 g,
35.7 mmol), (DHQ)2PHAL (278 mg, 0.36 mmol), and
OsO4 (45 mg, 0.18 mmol). The mixture was stirred at
room temperature for about 15 min and then cooled to 0 8C.
To this solution was added dienoate 13a (5.00 g,
35.7 mmol) and the reaction was stirred vigorously at 0 8C
overnight. The reaction was quenched with saturated
aqueous sodium sulfite (40 mL) at room temperature.
Ethyl acetate (40 mL) was added to the reaction mixture,
and after separation of the layers, the aqueous phase was
further extracted with the organic solvent (2!30 mL). The
combined organic layers were washed with 2 N KOH
(20 mL) and brine to remove the methanesulfonamide, and
dried over anhydrous sodium sulfate. After removal of the
solvents in vacuo, flash chromatography on silica gel (7:3
(v/v) hexanes/EtOAc) afforded 6.182 g (71% yield) of 14a
as a light yellow oil: [a]D K52.08 (c 1.17, EtOH); IR (neat)
3426, 2978, 1695, 1652, 1464, 1369, 1279, 1179, 1036 cmK
1; 1H NMR (CDCl3, 500 MHz): d 6.92 (dd, JZ16.0, 5.5 Hz,
1H), 6.14 (dd, JZ15.5, 2 Hz, 1H), 4.20 (q, JZ7.5 Hz, 2H),
4.06 (ddd, JZ10.25, 4.5, 1.5 Hz, 1H), 3.73 (dq, JZ10.5,
2. Experimental
2.1. . General methods
1
Melting points are uncorrected. H and 13C NMR spectra
were recorded on Varian VXR-200 (200 MHz), Varian
VXR-300 (300 MHz) or Varian VXR-500 (500 MHz)
spectrometers. Chemical shifts are reported relative to
internal tetramethylsilane (d0.00 ppm) or residual solvent
signal. Infrared (IR) spectra were obtained on a Prospect
MIDAC FT-IR spectrometer. Optical rotations were
measured with a Jasco DIP-370 digital polarimeter in the
Scheme 5. Purification of base sensitive substrates.

6342
Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
6.5 Hz, 1H), 2.89 (br, 1H), 2.59 (br, 1H), 1.29 (t, JZ7.5 Hz,
3H), 1.24 (d, JZ6 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d
166.8, 146.9, 122.6, 75.7, 70.2, 60.7, 19.1, 14.2.
40 mL of t-BuOH, 40 mL of water, K3Fe(CN)6 (18.75 g,
57 mmol), K2CO3 (7.87 g, 57 mmol), MeSO2NH2 (1.81 g,
19 mmol), (DHQD)2-PHAL (296 mg, 0.38 mmol), and
OsO4 (48 mg, 0.19 mmol). The mixture was stirred at
room temperature for about 15 min and then cooled to 0 8C.
To this solution was added dienoate 16a (3.84 g, 19 mmol)
and the reaction was stirred vigorously at 0 8C overnight.
The reaction was quenched with satd aqueous sodium sulfite
(30 mL) at room temperature. Ethyl acetate (40 mL) was
added to the reaction mixture, and after separation of the
layers, the aqueous phase was further extracted with the
organic solvent (2!30 mL). The combined organic layers
were washed with 2 N KOH (20 mL) and brine to remove
the methanesulfonamide, and dried over anhydrous sodium
sulfate. After removal of the solvents in vacuo, flash
chromatography on silica gel (7:3 (v/v) hexanes/EtOAc)
afforded 1.00 g (76% yield) of 17a as a clear oil: [a]D C508
(c 0.97, EtOH); IR (neat) 3426, 3063, 3031, 2983, 2902,
2.1.2. Ethyl (4R,5R)-4,5-dihydroxy-2-hexenoate (14a).
Into a 250 mL round bottom flask was added 60 mL of
t-BuOH, 60 mL of water, K3Fe(CN)6 (41.1 g, 125 mmol),
K2CO3 (17.24 g, 125 mmol), MeSO2NH2 (3.39 g,
35.7 mmol), (DHQD)2-PHAL (278 mg, 0.36 mmol), and
OsO4 (45 mg, 0.18 mmol). The mixture was stirred at room
temperature for about 15 minutes and then cooled to 0 8C.
To this solution was added dienoate 13a (5.00 g,
35.7 mmol) and the reaction was stirred vigorously at 0 8C
overnight. The reaction was quenched with saturated
aqueous sodium sulfite (40 mL) at room temperature.
Ethyl acetate (40 mL) was added to the reaction mixture,
and after separation of the layers, the aqueous phase was
further extracted with the organic solvent (2!30 mL). The
combined organic layers were washed with 2 N KOH
(20 mL) and brine to remove the methanesulfonamide, and
dried over anhydrous sodium sulfate. After removal of the
solvents in vacuo, flash chromatography on silica gel (7:3
(v/v) hexanes/EtOAc) afforded 4.53 g (73% yield) of 14a as
a light yellow oil: [a]D 568 (c 1.0, EtOH); IR (neat) 3426,
2978, 1695, 1652, 1464, 1369, 1279, 1179, 1036 cmK1; 1H
NMR (CDCl3, 500 MHz): d 6.92 (dd, JZ16.0, 5.5 Hz, 1H),
6.14 (dd, JZ15.5, 2 Hz, 1H), 4.20 (q, JZ7.5 Hz, 2H), 4.06
(ddd, JZ10.25, 4.5, 1.5 Hz, 1H), 3.73 (dq, JZ10.5, 6.5 Hz,
1H), 2.89 (br, 1H), 2.59 (br, 1H), 1.29 (t, JZ7.5 Hz, 3H),
1.24 (d, JZ6 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d
166.8, 146.9, 122.6, 75.7, 70.2, 60.7, 19.1, 14.2.
1955, 1888, 1737, 1651, 1495, 1455, 1368, 1279, 1115 cmK1
;
1H NMR (CDCl3, 500 MHz): d 7.36 (m, 5H), 6.75 (dd, JZ
16, 4.5 Hz, 1H), 6.10 (dd, JZ15.5, 1.5 Hz, 1H), 4.57 (d, JZ
7 Hz, 1H), 4.41 (ddd, JZ6.5, 4.5, 2 Hz, 1H), 4.17 (q, JZ
7 Hz, 2H), 2.55 (br, 2H), 1.26 (t, JZ7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d 166.4, 145.5, 139.7, 128.7, 128.6,
126.7, 122.4, 76.8, 75.3, 60.6, 14.2.
2.1.5. i-Propyl (4S,5S)-4,5-dihydroxy-2-hexenoate (ent)-
14b(S,S) and i-propyl (2R,3S)-2,3-dihydroxy-5-phenyl-4-
hexenoate (ent)-15b(R,S). To a 25 mL round bottom flask
was added 1:1 tert-butyl alcohol (5 mL)/water (5 mL),
K3Fe(CN)6 (780 mg, 2.4 mmol), K2CO3 (327 mg,
2.4 mmol), CH3SO2NH2 (75 mg, 0.8 mmol), (DHQ)2-
PHAL (36.9 mg, 6 mol%), OsO4 (10.0 mg, 5 mol%). The
mixture was stirred at room temperature until both phases
were clear, and then cooled to 0 8C. To this solution was
added dienoate 13b (122 mg, 0.8 mmol) and the reaction
was stirred vigorously at room temperature overnight. Satd
aqueous sodium sulfite (5 mL) was added to quench the
reaction while stirring vigorously. Ethyl acetate (10 mL)
was added to the reaction mixture, and after separation of
the layers, the aqueous layer was further extracted with ethyl
acetate (3!5 mL). The combined organic layers were
washed with 2 N KOH (10 mL) and brine (10 mL) to
remove the methanesulfonamide, dried over anhydrous
Na2SO4, and concentrated to afford the crude mixture of
regioisomers ((ent)-14b/(ent)-15bZ94:6 by 1H NMR).
Flash chromatography on silica gel (2:1 (v/v) hexane/
EtOAc) provided regioisomer (ent)-14b (78 mg, 52.8%
yield, 79% ee) and (ent)-15b (9 mg, 6.1% yield, 96% ee),
both as colorless oil. For i-propyl (4S,5S)-4,5-dihydroxy-2-
hexenoate (ent)-14b: RfZ0.05 (4:1 (v/v) hexane/EtOAc);
[a]2D5 K51.08 (c 1.03, EtOH); IR (neat, cmK1) 3411, 2982,
1700, 1659, 1375, 1283, 1181, 985; 1H NMR (CDCl3,
300 MHz): d 6.89 (dd, JZ15.6, 5.1 Hz, 1H), 6.10 (dd, JZ
15.6, 1.5 Hz, 1H), 5.05 (septet, JZ6.3 Hz, 1H), 4.04 (ddd,
JZ5.7, 5.4, 1.5 Hz, 1H), 3.71 (dq, JZ6.6, 6.0 Hz, 1H), 3.00
(br, 2H), 1.26 (d, JZ6.9 Hz, 6H), 1.23 (d, JZ6.6 Hz, 3H);
13C NMR (CDCl3, 125 MHz): d 166.1, 146.4, 122.9, 75.7,
70.3, 68.2, 21.8, 19.1; HRMS (CI) Calcd for [C9H16O4C
NH4]C: 206.1392, Found: 206.1389. The enantiomeric
excess of compound (ent)-14b was determined by HPLC
analysis (Chiralcel OD column), using 3% iPrOH in hexane
at 0.8 mL/min. Retention time (min): S,SZ17.8; R,RZ21.3.
2.1.3. Ethyl (4S,5S)-4,5-dihydroxy-5-phenyl-2-penteno-
ate ((ent)-17a). Into a 250 mL round bottom flask was
added 40 mL of t-BuOH, 40 mL of water, K3Fe(CN)6
(18.75 g, 57 mmol), K2CO3 (7.87 g, 57 mmol), MeSO2NH2
(1.81 g, 19 mmol), (DHQ)2-PHAL (296 mg, 0.38 mmol),
and OsO4 (48 mg, 0.19 mmol). The mixture was stirred at
room temperature for about 15 minutes and then cooled to
0 8C. To this solution was added dienoate 16a (3.85 g,
19 mmol) and the reaction was stirred vigorously at 0 8C
overnight. The reaction was quenched with satd aqueous
sodium sulfite (30 mL) at room temperature. Ethyl acetate
(40 mL) was added to the reaction mixture, and after
separation of the layers, the aqueous phase was further
extracted with the organic solvent (2!30 mL). The
combined organic layers were washed with 2 N KOH
(20 mL) and brine to remove the methanesulfonamide, and
dried over anhydrous sodium sulfate. After removal of the
solvents in vacuo, flash chromatography on silica gel (7:3
(v/v) hexanes/EtOAc) afforded 0.96 g (73% yield) of (ent)-
17a as a clear oil: [a]D K48.78 (c 0.97, EtOH); IR (neat)
3426, 3063, 3031, 2983, 2902, 1955, 1888, 1737, 1651,
1
1495, 1455, 1368, 1279, 1115 cmK1; H NMR (CDCl3,
500 MHz): d 7.36 (m, 5H), 6.75 (dd, JZ16, 4.5 Hz, 1H),
6.10 (dd, JZ15.5, 1.5 Hz, 1H), 4.57 (d, JZ7 Hz, 1H), 4.41
(ddd, JZ6.5, 4.5, 2 Hz, 1H), 4.17 (q, JZ7 Hz, 2H), 2.55 (br,
2H), 1.26 (t, JZ7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d 166.4, 145.5, 139.7, 128.7, 128.6, 126.7, 122.4, 76.8, 75.3,
60.6, 14.2.
2.1.4. Ethyl (4S,5S)-4,5-dihydroxy-5-phenyl-2-penteno-
ate (17a). Into a 250 mL round bottom flask was added

Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
6343
2.1.6. i-Propyl (2R,3S)-2,3-dihydroxy-4-hexenoate (ent)-
15b(R,S). RfZ0.15 (4:1 (v/v) hexane/EtOAc); [a]2D5 K458
(c 1.00, EtOH); IR (neat, cmK1) 3505, 2919, 2852, 1722,
3H), 1.30 (dd, JZ6.0, 5.5 Hz, 6H); 13C NMR (CDCl3,
125 MHz): d 172.5, 129.4, 129.2, 73.8, 73.5, 70.2, 21.79,
21.77, 17.8; HRMS (CI) Calcd for [C9H16O4CNH4]C:
206.1392, Found: 206.1389. The enantiomeric excess of
compound 15b(S,R) was determined by HPLC analysis
(Chiralcel OD column), using 3% iPrOH in hexane at
0.8 mL/min. Retention time (min): R,SZ17.4; S,RZ19.8.
1
1674, 1346, 1290, 1107; H NMR (CDCl3, 300 MHz): d
5.82 (ddq, JZ15.0, 6.5, 1.5 Hz, 1H), 5.63 (ddq, JZ15.3,
6.5, 1.5 Hz, 1H), 5.14 (dseptet, JZ6.5, 2.4 Hz, 1H), 4.33
(ddd, JZ6.5, 5.7, 1.5 Hz, 1H), 4.09 (dd, JZ5.4, 3.0 Hz,
1H), 3.13 (br, 1H), 2.23 (br, 1H), 1.74 (dd, JZ6.5, 1.5 Hz,
3H), 1.31 (dd, JZ6.0, 5.7 Hz, 6H); 13C NMR (CDCl3,
125 MHz): d 172.5, 129.4, 129.2, 73.8, 73.5, 70.2, 21.79,
21.77, 17.8; HRMS (CI) Calcd for [C9H16O4CNH4]C:
206.1392, Found: 206.1390. The enantiomeric excess
of compound (ent)-15b was determined by HPLC
analysis (Chiralcel OD column), using 3% iPrOH in
hexane at 0.8 mL/min. Retention time (min): R,SZ16.9;
S,RZ18.9.
2.1.9. i-Propyl (4S,5S)-4,5-dihydroxy-5-phenyl-2-pen-
tenoate ((ent)-17b(S,S)) and i-propyl (2R,3S)-2,3-dihy-
droxy-5-phenyl-4-pentenoate ((ent)-18b(R,S)). To a
25 mL round bottom flask was added 1:1 tert-butyl alcohol
(5 mL)/water (5 mL), K3Fe(CN)6 (877 mg, 2.7 mmol),
K2CO3 (368 mg, 2.7 mmol), CH3SO2NH2 (84 mg,
0.9 mmol), (DHQ)2-PHAL (41.6 mg, 6 mol%), OsO4
(11.3 mg, 5 mol%). The mixture was stirred at room
temperature until both phases were clear, and then cooled
to 0 8C. To this solution was added dienoate 16b (192 mg,
0.9 mmol) and the reaction was stirred vigorously at room
temperature overnight. Satd aqueous sodium sulfite (5 mL)
was added to quench the reaction while stirring vigorously.
Ethyl acetate (10 mL) was added to the reaction mixture,
and after separation of the layers, the aqueous layer was
further extracted with ethyl acetate (3!5 mL). The
combined organic layers were washed with 2 N KOH
(10 mL) and brine (10 mL) to remove the methanesulfona-
mide, dried over anhydrous Na2SO4, and concentrated to
afford the crude mixture of regioisomers ((ent)-17b/(ent)-
2.1.7. i-Propyl (4R,5R)-4,5-dihydroxy-2-hexenoate
14b(R,R) and i-propyl (2S,3R)-2,3-dihydroxy-5-phenyl-
4-hexenoate 15b(S,R). To a 25 mL round bottom flask was
added 1:1 tert-butyl alcohol (5 mL)/water (5 mL),
K3Fe(CN)6 (767 mg, 2.4 mmol), K2CO3 (322 mg,
2.4 mmol), CH3SO2NH2 (74 mg, 0.8 mmol), (DHQD)2-
PHAL (36.3 mg, 6 mol%), OsO4 (9.9 mg, 5 mol%). The
mixture was stirred at room temperature until both phases
were clear, and then cooled to 0 8C. To this solution was
added dienoate 13b (120 mg, 0.8 mmol) and the reaction
was stirred vigorously at room temperature overnight. Satd
aqueous sodium sulfite (5 mL) was added to quench the
reaction while stirring vigorously. Ethyl acetate (10 mL)
was added to the reaction mixture, and after separation of
the layers, the aqueous layer was further extracted with ethyl
acetate (3!5 mL). The combined organic layers were
washed with 2 N KOH (10 mL) and brine (10 mL) to
remove the methanesulfonamide, dried over anhydrous
Na2SO4, and concentrated to afford the crude mixture of
1
18bZ82:18 by H NMR). Flash chromatography on silica
gel (4:1 (v/v) hexane/EtOAc) provided the pure mixture of
two regioisomers (133 mg, 60.0% combined yield). The two
regioisomers were separated by MPLC (2:1 (v/v) hexane/
EtOAc; flow rate: 6 mL/min) to provide (ent)-17b (95 mg,
42.7% yield, 45% ee) and (ent)-18b (11 mg, 4.9% yield,
99% ee), both as colorless oil. For i-propyl (4S,5S)-4,5-
dihydroxy-5-phenyl-2-pentenoate ((ent)-17b): RfZ0.17
(4:1 (v/v) hexane/EtOAc); [a]2D5 K42.98 (c 0.99, EtOH);
IR (neat, cmK1) 3437, 2981, 1716, 1659, 1306, 1280, 1176,
1
regioisomers (14b/15b)Z82:18 by H NMR). Flash chro-
matography on silica gel (2:1 (v/v) hexane/EtOAc) provided
regioisomer 14b (56 mg, 38.4% yield, 72% ee) and 15b
(9 mg, 6.4% yield, 96% ee), both as colorless oil. For
i-propyl (4R,5R)-4,5-dihydroxy-2-hexenoate (14b(R,R)):
RfZ0.08 (4:1 (v/v) hexane/EtOAc); [a]2D5 C56.08 (c 1.05,
EtOH); IR (neat, cmK1) 3411, 2982, 1700, 1659, 1375,
1
1109, 1053; H NMR (CDCl3, 300 MHz): d 7.35 (m, 5H),
6.74 (dd, JZ15.6, 4.5 Hz, 1H), 6.07 (dd, JZ15.6, 1.8 Hz,
1H), 5.03 (septet, JZ6.3 Hz, 1H), 4.54 (d, JZ6.9 Hz, 1H),
4.38 (ddd, JZ6.3, 4.5, 1.8 Hz, 1H), 3.61 (br, 2H), 1.25 (dd,
JZ6.0, 2.1 Hz, 6H); 13C NMR (CDCl3, 75 MHz): d 165.7,
145.4, 139.7, 128.4, 128.1, 126.7, 122.4, 76.8, 75.2, 67.7,
21.7; HRMS (CI) Calcd for [C14H18O4CNH4]C: 268.1549,
Found: 268.1544. The enantiomeric excess of compound
(ent)-17b(S,S) was determined by HPLC analysis (Chiralcel
OD column), using 8% iPrOH in hexane at 0.8 mL/min.
Retention time (min): S,SZ21.3; R,RZ26.9.
1
1283, 1181, 985; H NMR (CDCl3, 500 MHz): d 6.88 (dd,
JZ15.5, 5.5 Hz, 1H), 6.08 (dd, JZ16.0, 1.5 Hz, 1H), 5.04
(septet, JZ6.0 Hz, 1H), 4.02 (ddd, JZ5.5, 5.0, 1.5 Hz, 1H),
3.70 (dq, JZ6.5, 6.0 Hz, 1H), 3.25 (br, 2H), 1.25 (d, JZ
6.0 Hz, 6H), 1.21 (d, JZ6.0 Hz, 3H); 13C NMR (CDCl3,
125 MHz): d 166.1, 146.4, 122.9, 75.7, 70.3, 68.2, 21.8,
19.1; HRMS (CI) Calcd for [C9H16O4CNH4]C: 206.1392,
Found: 206.1389. The enantiomeric excess of compound
14b(R,R) was determined by HPLC analysis (Chiralcel OD
column), using 3% iPrOH in hexane at 0.8 mL/min.
Retention time (min): S,SZ17.6; R,RZ21.4.
2.1.10. i-Propyl (2R,3S)-2,3-dihydroxy-5-phenyl-4-pen-
tenoate ((ent)-18b(R,S)). RfZ0.17 (4:1 (v/v) hexane/
EtOAc); [a]2D5 K33.08 (c 1.00, EtOH); IR (neat, cmK1
)
1
3458, 2982, 2925, 1730, 1375, 1105, 968, 754, 693; H
NMR (CDCl3, 300 MHz): d 7.33 (m, 5H), 6.71 (dd, JZ15.9,
1.2 Hz, 1H), 6.35 (dd, JZ15.9, 6.6 Hz, 1H), 5.17 (septet,
JZ6.3 Hz, 1H), 4.57 (d, JZ3.0 Hz, 1H), 4.22 (dd, JZ5.7,
3.0 Hz, 1H), 3.19 (br, 1H), 2.43 (br, 1H), 1.30 (dd, JZ6.3,
6.3 Hz, 6H); 13C NMR (CDCl3, 125 MHz): d 172.3, 136.3,
132.5, 128.6, 128.0, 127.5, 126.7, 73.8, 73.6, 70.4, 21.8;
HRMS (CI) Calcd for [C14H18O4C NH4]C: 268.1549,
Found: 268.1541. The enantiomeric excess of compound
(ent)-18b(R,S) was determined by HPLC analysis (Chiralcel
2.1.8. i-Propyl (2S,3R)-2,3-dihydroxy-4-hexenoate
(15b(S,R)). RfZ0.16 (4:1 (v/v) hexane/EtOAc); [a]D25
C458 (c 1.00, EtOH); IR (neat, cmK1) 3505, 2919, 2852,
1722, 1674, 1346, 1290, 1107; 1H NMR (CDCl3, 500 MHz):
d 5.82 (ddq, JZ15.0, 6.5, 1.5 Hz, 1H), 5.63 (ddq, JZ15.5,
6.5, 1.5 Hz, 1H), 5.15 (dseptet, JZ6.5, 2.5 Hz, 1H), 4.33
(ddd, JZ6.5, 5.5, 1.5 Hz, 1H), 4.09 (dd, JZ5.5, 3.0 Hz,
1H), 3.10 (br, 1H), 2.22 (br, 1H), 1.74 (dd, JZ6.5, 1.5 Hz,

6344
Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
OD column), using 5% iPrOH in hexane at 0.8 mL/min.
Retention time (min): R,SZ30.1; S,RZ41.7.
25 mL round bottom flask was added 1:1 tert-butyl alcohol
(5 mL)/water (5 mL), K3Fe(CN)6 (1.80 g, 5.5 mmol),
K2CO3 (756 mg, 5.5 mmol), CH3SO2NH2 (174 mg,
1.8 mmol), (DHQ)2-PHAL (39.7 mg, 2.8 mol%), OsO4
(7.0 mg, 1.5 mol%). The mixture was stirred at room
temperature until both phases were clear, and then cooled
to 0 8C. To this solution was added dienoate 16c (420 mg,
1.8 mmol) and the reaction was stirred vigorously at 0 8C
overnight. Satd aqueous sodium sulfite (5 mL) was added to
quench the reaction and the suspension was warmed to room
temperature while stirring vigorously. Ethyl acetate (10 mL)
was added to the reaction mixture, and after separation of
the layers, the aqueous layer was further extracted with ethyl
acetate (3!5 mL). The combined organic layers were
washed with 2 N KOH (10 mL) and brine (10 mL) to
remove the methanesulfonamide, dried over anhydrous
Na2SO4, and concentrated to afford the crude mixture of
regioisomers ((ent)-17c(S,S)/(ent)-18c(R,S)Z2:1 by 1H
NMR). Flash chromatography on silica gel (15:1–3:1 (v/v)
hexane/EtOAc) provided regioisomer (ent)-17c (131 mg,
27.2% yield, 87% ee) and (ent)-18c (42 mg, 8.7% yield,
93% ee), both as off-white solids. For t-Butyl (4S,5S)-4,5-
dihydroxy-5-phenyl-2-pentenoate ((ent)-17c(S,S)): RfZ
0.12 (4:1 (v/v) hexane/EtOAc); mp: 68–70 8C; [a]D25
K43.38 (c 1.04, EtOH); IR (neat, cmK1) 3550, 2987,
1717, 1456, 1370, 1319, 1157, 1052, 982; 1H NMR (CDCl3,
300 MHz): d 7.38 (m, 5H), 6.68 (dd, JZ15.6, 4.2 Hz, 1H),
6.05 (dd, JZ15.6, 1.8 Hz, 1H), 4.59 (d, JZ6.6 Hz, 1H),
4.42 (ddd, JZ6.6, 4.5, 1.5 Hz, 1H), 2.57 (br, 2H), 1.47 (s,
9H); 13C NMR (CDCl3, 75 MHz): d 165.7, 144.3, 139.8,
128.7, 128.5, 126.8, 124.2, 80.7, 77.0, 75.4, 28.1; HRMS
(CI) Calcd for [C15H20O4CNH4]C: 282.1705, Found:
282.1703. The enantiomeric excess of compound (ent)-
17c(S,S) was determined by HPLC analysis (Chiralcel OD
column), using 5% iPrOH in hexane at 0.8 mL/min.
Retention time (min): S,SZ20.2; R,RZ29.9.
2.1.11. i-Propyl (4R,5R)-4,5-dihydroxy-5-phenyl-2-pen-
tenoate (17b(R,R)) and i-propyl (2S,3R)-2,3-dihydroxy-
5-phenyl-4-pentenoate (18b(S,R)). To a 25 mL round
bottom flask was added 1:1 tert-butyl alcohol (5 mL)/H2O
(5 mL), K3Fe(CN)6 (900 mg, 2.7 mmol), K2CO3 (378 mg,
2.7 mmol), CH3SO2NH2 (87 mg, 0.9 mmol), (DHQD)2-
PHAL (42.6 mg, 6 mol%), OsO4 (11.6 mg, 5 mol%). The
mixture was stirred at room temperature until both phases
were clear, and then cooled to 0 8C. To this solution was
added dienoate 16b (197 mg, 0.9 mmol) and the reaction
was stirred vigorously at room temperature overnight. Satd
aqueous sodium sulfite (5 mL) was added to quench the
reaction while stirring vigorously. Ethyl acetate (10 mL)
was added to the reaction mixture, and after separation of
the layers, the aqueous layer was further extracted with ethyl
acetate (3!5 mL). The combined organic layers were
washed with 2 N KOH (10 mL) and brine (10 mL) to
remove the methanesulfonamide, dried over anhydrous
Na2SO4, and concentrated to afford the crude mixture of
1
regioisomers (17b/18bZ77:33 by H NMR). Flash chro-
matography on silica gel (4:1 (v/v) hexane/EtOAc) provided
the pure mixture of two regioisomers (151 mg, 66.2%
combined yield). The two regioisomers were separated by
MPLC (2:1 (v/v) hexane/EtOAc; flow rate: 6 mL/min) to
provide 17b (91 mg, 39.9% yield, 91% ee) and 18b (23 mg,
10.1% yield, 98% ee), both as colorless oil. For i-propyl
(4R,5R)-4,5-dihydroxy-5-phenyl-2-pentenoate (17b): RfZ
0.26 (4:1 (v/v) hexane/EtOAc); [a]2D5 C46.28 (c 1.02,
EtOH); IR (neat, cmK1) 3437, 2981, 1716, 1659, 1306,
1
1280, 1176, 1109, 1053; H NMR (CDCl3, 500 MHz): d
7.34 (m, 5H), 6.72 (dd, JZ15.5, 4.0 Hz, 1H), 6.06 (dd, JZ
15.5, 2.0 Hz, 1H), 5.02 (septet, JZ6.0 Hz, 1H), 4.54 (d, JZ
6.5 Hz, 1H), 4.37 (ddd, JZ6.5, 4.5, 2.0 Hz, 1H), 2.89 (br,
2H), 1.23 (dd, JZ5.5, 3.5 Hz, 6H); 13C NMR (CDCl3,
75 MHz): d 165.7, 145.4, 139.7, 128.4, 128.1, 126.7, 122.4,
76.8, 75.2, 67.7, 21.7; HRMS (CI) Calcd for [C14H18O4C
NH4]C: 268.1549, Found: 268.1544. The enantiomeric
excess of compound 17b(R,R) was determined by HPLC
analysis (Chiralcel OD column), using 8% iPrOH in hexane
at 0.8 mL/min. Retention time (min): S,SZ21.7; R,RZ26.8.
2.1.14. t-Butyl (2R,3S)-2,3-dihydroxy-5-phenyl-4-pen-
tenoate ((ent)-18c(R,S)). RfZ0.19 (4:1 (v/v) hexane/
EtOAc); mp: 116–119 8C; [a]2D5 K47.18 (c 1.01, EtOH);
IR (neat, cmK1) 3447, 2977, 1735, 1655, 1369, 1161, 968;
1H NMR (CDCl3, 500 MHz): d 7.34 (m, 5H), 6.71 (dd, JZ
16.0, 1.0 Hz, 1H), 6.34 (dd, JZ16.0, 6.0 Hz, 1H), 4.53 (ddd,
JZ6.5, 3.0, 1.0 Hz, 1H), 4.14 (d, JZ3.5 Hz, 1H), 3.16 (br,
1H), 2.36 (br, 1H), 1.52 (s, 9H); 13C NMR (CDCl3, 75 MHz):
d 172.1, 136.4, 132.3, 128.7, 128.0, 127.8, 126.7, 83.6, 73.9,
73.8, 28.1; HRMS (CI) Calcd for [C15H20O4CNH4]C:
282.1705, Found: 282.1705. The enantiomeric excess of
compound (ent)-18c(R,S) was determined by HPLC analysis
(Chiralcel OD column), using 5% iPrOH in hexane at
0.8 mL/min. Retention time (min): R,SZ20.6; S,RZ31.1.
2.1.12. i-Propyl (2S,3R)-2,3-dihydroxy-5-phenyl-4-pen-
tenoate (18b(S,R)). RfZ0.26 (4:1 (v/v) hexane/EtOAc);
[a]2D5 C36.08 (c 1.00, EtOH); IR (neat, cmK1) 3458, 2982,
1
2925, 1730, 1375, 1105, 968, 754, 693; H NMR (CDCl3,
500 MHz): d 7.33 (m, 5H), 6.72 (dd, JZ16.0, 1.0 Hz, 1H),
6.35 (dd, JZ16.0, 6.5 Hz, 1H), 5.17 (septet, JZ6.5 Hz, 1H),
4.58 (d, JZ3.5 Hz, 1H), 4.22 (dd, JZ6.0, 3.0 Hz, 1H), 3.21
(br, 1H), 2.44 (br, 1H), 1.30 (dd, JZ10.5, 7.0 Hz, 6H); 13C
NMR (CDCl3, 125 MHz): d 172.3, 136.3, 132.5, 128.6,
128.0, 127.5, 126.7, 73.8, 73.6, 70.4, 21.8; HRMS (CI)
Calcd for [C14H18O4CNH4]C: 268.1549, Found: 268.1541.
The enantiomeric excess of compound 18b(S,R) was
determined by HPLC analysis (Chiralcel OD column),
using 5% iPrOH in hexane at 0.8 mL/min. Retention time
(min): R,SZ32.3; S,RZ42.2.
2.1.15. t-Butyl (4R,5R)-4,5-dihydroxy-5-phenyl-2-pen-
tenoate (17c(R,R)) and t-butyl (2S,3R)-2,3-dihydroxy-5-
phenyl-4-pentenoate (18c(S,R)). To a 25 mL round bottom
flask was added 1:1 tert-butyl alcohol (5 mL)/water (5 mL),
K3Fe(CN)6 (1.72 g, 5.2 mmol), K2CO3 (720 mg, 5.2 mmol),
CH3SO2NH2 (165 mg, 1.7 mmol), (DHQD)2-PHAL
(27.1 mg, 2 mol%), OsO4 (4.4 mg, 1 mol%). The mixture
was stirred at room temperature until both phases were
clear, and then cooled to 0 8C. To this solution was added
dienoate 16c (400 mg, 1.7 mmol) and the reaction was
stirred vigorously at 0 8C overnight. Satd aqueous sodium
2.1.13. t-Butyl (4S,5S)-4,5-dihydroxy-5-phenyl-2-pen-
tenoate ((ent)-17c(S,S)) and t-butyl (2R,3S)-2,3-dihy-
droxy-5-phenyl-4-pentenoate ((ent)-18c(R,S)). To a

Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
6345
sulfite (5 mL) was added to quench the reaction and the
suspension was warmed to room temperature while stirring
vigorously. Ethyl acetate (10 mL) was added to the reaction
mixture, and after separation of the layers, the aqueous layer
was further extracted with ethyl acetate (3!5 mL). The
combined organic layers were washed with 2 N KOH
(10 mL) and brine to remove the methanesulfonamide, dried
over anhydrous Na2SO4, and concentrated to afford the
crude mixture of regioisomers (17c/18c)Z5:3 by 1H NMR).
Flash chromatography on silica gel (15:1–3:1 (v/v) hexane/
EtOAc) provided regioisomer 17c(R,R) (178 mg, 38.7%
yield, 91% ee) and 18c(S,R) (104 mg, 22.7% yield, 99% ee),
both as off-white solids. For t-Butyl (4R,5R)-4,5-dihydroxy-
5-phenyl-2-pentenoate (17c(R,R)): RfZ0.19 (4:1 (v/v)
hexane/EtOAc); mp: 66–67 8C; [a]2D5 C45.68 (c 1.07,
EtOH); IR (neat, cmK1) 3435, 2978, 1711, 1701, 1660,
yellow oil, as the only product: RfZ0.14 (2:1 (v/v) hexane/
EtOAc); [a]2D5 K43.08 (c 1.04, EtOH); IR (neat, cmK1
)
1
3467, 2977, 2933, 2877, 1666, 1634, 1061, 978; H NMR
(CDCl3, 500 MHz): d 6.83 (dd, JZ15.5, 5.0 Hz, 1H), 6.42
(dd, JZ15.5, 1.5 Hz, 1H), 4.06 (ddd, JZ6.0, 5.0, 2.0 Hz,
1H), 3.72 (dq, JZ6.5, 6.0 Hz, 1H), 2.96 (q, JZ7.0 Hz, 2H),
2.63 (br, 2H), 1.28 (t, JZ7.5 Hz, 3H), 1.25 (d, JZ6.0 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d 190.5, 142.2, 129.0,
75.5, 70.3, 23.4, 19.1, 14.6; HRMS (CI) Calcd for
[C8H14O3SCNH4]C: 208.1007, Found: 208.1015. The
enantiomeric excess of compound (ent)-14f(S,S) was
determined by HPLC analysis (Chiralcel OD column),
using 8% iPrOH in hexane at 0.8 mL/min. Retention time
(min): R,RZ21.7; S,SZ24.2.
2.1.18. S-ethyl (4R,5R)-4,5-dihydroxy-2-hexenoate
(14f(R,R)). To a 25 mL round bottom flask was added
2 mL tert-butyl alcohol, 10 mL water, K3Fe(CN)6 (1.22 g,
3.7 mmol), K2CO3 (513 mg, 3.7 mmol), NaHCO3 (312 mg,
3.7 mmol), CH3SO2NH2 (118 mg, 1.2 mmol), (DHQD)2-
PHAL (106 mg, 11 mol%), OsO4 (31.4 mg, 10 mol%). The
mixture was stirred at room temperature until both phases
were clear, and then cooled to 0 8C. To this solution was
added dienoate 13f (193 mg, 1.2 mmol) and the reaction
was stirred vigorously at room temperature for 20 h. Satd
aqueous sodium sulfite (5 mL) was added to quench the
reaction while stirring vigorously. Ethyl acetate (10 mL)
was added to the reaction mixture, and after separation of
the layers, the aqueous layer was further extracted with ethyl
acetate (3!5 mL). The combined organic layers were
washed with 2 N KOH (10 mL) and brine (10 mL) to
remove the methanesulfonamide, dried over anhydrous
Na2SO4. After removal of the solvents in vacuo, the crude
product was purified by flash chromatography on silica gel
(2:1 (v/v) hexane/EtOAc) to obtain 23 mg 13f (11.9%
starting material recovered) and 14f(R,R) (78 mg, 37.7%
yield, 92% ee), a light yellow oil, as the only product: RfZ
0.19 (2:1 (v/v) hexane/EtOAc); [a]2D5 C59.68 (c 1.06,
EtOH); IR (neat, cmK1) 3467, 2977, 2933, 2877, 1666,
1
1373, 1315, 1153, 1052; H NMR (CDCl3, 300 MHz): d
7.38 (m, 5H), 6.68 (dd, JZ15.6, 4.5 Hz, 1H), 6.05 (dd, JZ
15.6, 1.8 Hz, 1H), 4.59 (d, JZ6.6 Hz, 1H), 4.41 (ddd, JZ
5.4, 4.5, 1.8 Hz, 1H), 2.57 (br, 2H), 1.47 (s, 9H); 13C NMR
(CDCl3, 75 MHz): d 165.7, 144.4, 139.8, 128.7, 128.5,
126.8, 124.2, 80.7, 77.0, 75.4, 28.1; HRMS (CI) Calcd for
[C15H20O4CNH4]C: 282.1705, Found: 282.1710. The
enantiomeric excess of compound 17c(R,R) was determined
by HPLC analysis (Chiralcel OD column), using 5% iPrOH
in hexane at 0.8 mL/min. Retention time (min): S,SZ19.7;
R,RZ30.2.
2.1.16. t-Butyl (2S,3R)-2,3-dihydroxy-5-phenyl-4-pen-
tenoate (18c(S,R)). RfZ0.25 (4:1 (v/v) hexane/EtOAc);
mp: 115–117 8C; [a]2D5 C48.48 (c 1.07, EtOH); IR (neat,
cmK1) 3447, 2988, 1734, 1652, 1373, 1276, 1086; 1H NMR
(CDCl3, 300 MHz): d 7.37 (m, 5H), 6.71 (dd, JZ15.6,
1.2 Hz, 1H), 6.34 (dd, JZ15.9, 6.3 Hz, 1H), 4.53 (ddd, JZ
6.6, 3.0, 1.2 Hz, 1H), 4.14 (d, JZ3.3 Hz, 1H), 3.15 (br, 1H),
2.35 (br, 1H), 1.52 (s, 9H); 13C NMR (CDCl3, 75 MHz): d
172.1, 136.4, 132.3, 128.7, 128.0, 127.8, 126.7, 83.6, 73.9,
73.8, 28.1; HRMS (CI) Calcd for [C15H20O4CNH4]C:
282.1705, Found: 282.1708. The enantiomeric excess of
compound 18c(S,R) was determined by HPLC analysis
(Chiralcel OD column), using 5% iPrOH in hexane at
0.8 mL/min. Retention time (min): R,SZ21.3; S,RZ30.8.
1
1634, 1061, 978; H NMR (CDCl3, 500 MHz): d 6.84 (dd,
JZ16.0, 5.0 Hz, 1H), 6.44 (dd, JZ15.5, 1.5 Hz, 1H), 4.09
(dddd, JZ6.0, 5.0, 4.5, 1.5 Hz, 1H), 3.75 (ddq, JZ6.5, 6.0,
4..5 Hz, 1H), 2.97 (q, JZ7.5 Hz, 2H), 2.44 (br, 1H), 2.11
(br, 1H), 1.30 (t, JZ7.5 Hz, 3H), 1.27 (d, JZ6.5 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d 190.5, 142.2, 129.0, 75.5,
70.3, 23.4, 19.1, 14.6; HRMS (CI) Calcd for [C8H14O3SC
NH4]C: 208.1007, Found: 208.1015. The enantiomeric
excess of compound 14f(R,R) was determined by HPLC
analysis (Chiralcel OD column), using 8% iPrOH in hexane
at 0.8 mL/min. Retention time (min): R,RZ22.9; S,SZ26.2.
2.1.17. S-ethyl (4S,5S)-4,5-dihydroxy-2-hexenoate ((ent)-
14f(S,S)). To a 25 mL round bottom flask was added 3 mL
tert-butyl alcohol, 5 mL water, K3Fe(CN)6 (714 mg,
2.2 mmol), K2CO3 (300 mg, 2.2 mmol), CH3SO2NH2
(69 mg, 0.7 mmol), (DHQ)2-PHAL (62.1 mg, 11 mol%),
OsO4 (18.4 mg, 10 mol%). The mixture was stirred at room
temperature until both phases were clear, and then cooled to
0 8C. To this solution was added dienoate 13f (113 mg,
0.7 mmol) and the reaction was stirred vigorously at room
temperature for 36 h. Satd aqueous sodium sulfite (5 mL)
was added to quench the reaction while stirring vigorously.
Ethyl acetate (10 mL) was added to the reaction mixture,
and after separation of the layers, the aqueous layer was
further extracted with ethyl acetate (3!5 mL). The
combined organic layers were washed with 2 N KOH
(10 mL) and brine (10 mL) to remove the methanesulfona-
mide, dried over anhydrous Na2SO4. After removal of the
solvents in vacuo, the crude product was purified by flash
chromatography on silica gel (2:1 (v/v) hexane/EtOAc) to
obtain (ent)-14f(S,S) (32 mg, 23.5% yield, 78% ee), a light
2.1.19. S-ethyl (4S,5S)-4,5-dihydroxy-5-phenyl-2-pen-
tenoate ((ent)-17f(S,S)) and S-ethyl (2R,3S)-2,3-dihy-
droxy-5-phenyl-4-pentenoate ((ent)-18f(R,S)). To a
25 mL round bottom flask was added 5 mL tert-butyl
alcohol, 10 mL water, K3Fe(CN)6 (1.47 g, 4.5 mmol),
K2CO3 (617 mg, 4.5 mmol), NaHCO3 (375 mg,
4.5 mmol), CH3SO2NH2 (142 mg, 1.5 mmol), (DHQ)2-
PHAL (128 mg, 11 mol%), OsO4 (37.8 mg, 10 mol%).
The mixture was stirred at room temperature until both
phases were clear, and then cooled to 0 8C. To this solution
was added dienoate 16f (325 mg, 1.5 mmol) and the
reaction was stirred vigorously at room temperature for

6346
Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
24 h. Satd aqueous sodium sulfite (5 mL) was added to
quench the reaction while stirring vigorously. Ethyl acetate
(10 mL) was added to the reaction mixture, and after
separation of the layers, the aqueous layer was further
extracted with ethyl acetate (3!5 mL). The combined
organic layers were washed with 2 N KOH (10 mL) and
brine to remove the methanesulfonamide, dried over
anhydrous Na2SO4, and concentrated to afford the crude
mixture of regioisomers (ent)-17f and (ent)-18f. Flash
chromatography on silica gel (4:1 (v/v) hexane/EtOAc)
provided 49 mg 16f (15.4% starting material recovered),
regioisomer (ent)-17f (109 mg, 29.0% yield, 98.6% ee), as a
light yellow oil, and (ent)-18f (6.6 mg, 1.8% yield, 98% ee),
as a off-white solid. For S-ethyl (4S,5S)-4,5-dihydroxy-5-
phenyl-2-pentenoate ((ent)-17f)): RfZ0.18 (4:1 (v/v) hex-
over anhydrous Na2SO4, and concentrated to afford the
crude mixture of regioisomers 17f(R,R) and 18f(S,R). Flash
chromatography on silica gel (4:1 (v/v) hexane/EtOAc)
provided 49 mg 5 (15.4% starting material recovered),
regioisomer 17f(R,R) (96.3 mg, 26.3% yield, 98.7% ee), as a
light yellow oil, and 18f(S,R) (18.3 mg, 5.0% yield, 99%
ee), as a off-white solid. For S-ethyl (4R,5R)-4,5-dihydroxy-
5-phenyl-2-pentenoate (17f(R,R)): RfZ0.11 (4:1 (v/v)
hexane/EtOAc); [a]2D5 C49.78 (c 1.01, EtOH); IR (neat,
cmK1) 3423, 3063, 3032, 2970, 2931, 1666, 1633, 1454,
1
1113, 1051; H NMR (CDCl3, 500 MHz): d 7.38 (m, 5H),
6.65 (dd, JZ15.0, 4.5 Hz, 1H), 6.40 (dd, JZ15.0, 2.0 Hz,
1H), 4.59 (d, JZ6.5 Hz, 1H), 4.44 (ddd, JZ7.0, 4.5, 2.0 Hz,
1H), 2.94 (q, JZ7.5 Hz, 2H), 2.66 (br, 1H), 1.57 (br, 1H),
1.27 (t, JZ7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d
190.4, 141.3, 139.6, 128.8, 128.7, 128.5, 126.8, 77.1, 75.3,
23.3, 14.6; HRMS (CI) Cacld for [C13H16O3SCNH4]C:
270.1164, Found: 270.1171. The enantiomeric excess of
compound 17f(R,R) was determined by HPLC analysis
(Chiralcel OD column), using 2% iPrOH in hexane at
0.8 mL/min. Retention time (min): R,RZ36.7, S,SZ40.4.
ane/EtOAc); [a]2D5 K43.08 (c 1.00, EtOH); IR (neat, cmK1
)
3423, 3063, 3032, 2970, 2931, 1666, 1633, 1454, 1113,
1
1051; H NMR (CDCl3, 500 MHz): d 7.34 (m, 5H), 6.61
(dd, JZ15.5, 4.0 Hz, 1H), 6.35 (dd, JZ15.5, 2.0 Hz, 1H),
4.52 (d, JZ6.5 Hz, 1H), 4.37 (ddd, JZ7.0, 4.5, 2.0 Hz, 1H),
3.22 (br, 2H), 2.90 (q, JZ7.5 Hz, 2H), 1.24 (t, JZ7.5 Hz,
3H); 13C NMR (CDCl3, 125 MHz): d 190.4, 141.3, 139.6,
128.8, 128.7, 128.5, 126.8, 77.1, 75.3, 23.3, 14.6; HRMS
(CI) Cacld for [C13H16O3SCNH4]C: 270.1164, Found:
270.1171. The enantiomeric excess of compound (ent)-
17f(S,S) was determined by HPLC analysis (Chiralcel OD
column), using 2% iPrOH in hexane at 0.8 mL/min.
Retention time (min): R,RZ39.4, S,SZ41.8.
2.1.22. S-ethyl (2S,3R)-2,3-dihydroxy-5-phenyl-4-pen-
tenoate (18f(S,R)). RfZ0.16 (4:1 (v/v) hexane/EtOAc);
mp: 133–134 8C; [a]2D5 K69.18 (c 0.99, EtOH); IR (neat,
cmK1) 3414, 3038, 2927, 2872, 1648, 1448, 1413, 1106,
1
1069, 963; H NMR (CDCl3, 500 MHz): d 7.34 (m, 5H),
6.74 (d, JZ15.5 Hz, 1H), 6.33 (dd, JZ16.0, 6.5 Hz, 1H),
4.73 (dd, JZ6.0, 6.0 Hz, 1H), 4.28 (dd, JZ7.5, 2.5 Hz, 1H),
3.28 (d, JZ7.0 Hz, 1H), 2.98 (dq, JZ7.5, 3.0 Hz, 2H), 2.31
(d, JZ6.0 Hz, 1H), 1.30 (t, JZ7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d 202.3, 133.0, 128.6, 128.2, 128.1,
127.0, 126.7, 80.0, 73.7, 23.2, 14.5; HRMS (CI) Cacld for
[C13H16O3SCNH4]C: 270.1164, Found: 270.1166. The
enantiomeric excess of compound 18f(S,R) was determined
by HPLC analysis (Chiralcel OD column), using 5% iPrOH
in hexane at 0.8 mL/min. Retention time (min): R,SZ54.2,
S,RZ62.1.
2.1.20. S-ethyl (2R,3S)-2,3-dihydroxy-5-phenyl-4-pen-
tenoate ((ent)-18f(R,S)). RfZ0.25 (4:1 (v/v) hexane/
EtOAc); mp: 126–128 8C; [a]2D5 C64.38 (c 0.98, EtOH);
IR (neat, cmK1) 3414, 3038, 2927, 2872, 1648, 1448, 1413,
1
1106, 1069, 963; H NMR (CDCl3, 500 MHz): d 7.37 (m,
5H), 6.74 (d, JZ16.0 Hz, 1H), 6.33 (dd, JZ16.5, 6.5 Hz,
1H), 4.72 (dd, JZ6.0, 6.0 Hz, 1H), 4.28 (dd, JZ7.5, 3.0 Hz,
1H), 3.30 (br, 1H), 2.98 (dq, JZ7.5, 3.0 Hz, 2H), 2.34 (br,
1H), 1.30 (t, JZ7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d 202.3, 133.0, 128.6, 128.2, 128.1, 127.0, 126.7, 80.0, 73.7,
23.2, 14.5; HRMS (CI) Cacld for [C13H16O3SCNH4]C:
270.1164, Found: 270.1166. The enantiomeric excess of
compound (ent)-18f(R,S) was determined by HPLC analysis
(Chiralcel OD column), using 5% iPrOH in hexane at
0.8 mL/min. Retention time (min): R,SZ54.3, S,RZ67.5.
2.1.23. (4S,5S)-4,5-Dihydroxy-2-hexenoic acid methoxy-
methyl-amide ((ent)-14d(S,S)). To a 25 mL round bottom
flask was added 3 mL tert-butyl alcohol, 5 mL water,
K3Fe(CN)6 (481 mg, 1.5 mmol), K2CO3 (202 mg,
1.5 mmol), NaHCO3 (123 mg, 1.5 mmol), CH3SO2NH2
(46 mg, 0.5 mmol), (DHQ)2-PHAL (41.7 mg, 11 mol%),
OsO4 (12.4 mg, 10 mol%). The mixture was stirred at room
temperature until both phases were clear, and then cooled to
0 8C. To this solution was added dienoate 13d (69 mg,
0.5 mmol) and the reaction was stirred vigorously at room
temperature for 27 h. Satd aqueous sodium sulfite (5 mL)
was added to quench the reaction while stirring vigorously.
Ethyl acetate (10 mL) was added to the reaction mixture,
and after separation of the layers, the aqueous layer was
further extracted with ethyl acetate (3!5 mL). The
combined organic layers were washed with 2 N KOH
(10 mL) and brine (10 mL) to remove the methanesulfona-
mide, dried over anhydrous Na2SO4. After removal of the
solvents in vacuo, the crude product was purified by flash
chromatography on silica gel (1:1 (v/v) hexane/EtOAc–9:1
(v/v) EtOAc/MeOH–1:1 (v/v) EtOAc/MeOH) to obtain
(ent)-14d(S,S) (64 mg, 76.0% yield, 65% ee), a light yellow
oil, as the only product: RfZ0.19 (EtOAc); [a]2D5 K40.58 (c
1.05, EtOH); IR (neat, cmK1) 3396, 2977, 2937, 1653, 1617,
2.1.21. S-ethyl (4R,5R)-4,5-dihydroxy-5-phenyl-2-pen-
tenoate (17f(R,R)) and S-ethyl (2S,3R)-2,3-dihydroxy-5-
phenyl-4-pentenoate (18f(S,R)). To a 25 mL round bottom
flask was added 5 mL tert-butyl alcohol, 10 mL water,
K3Fe(CN)6 (1.43 g, 4.4 mmol), K2CO3 (602 mg, 4.4 mmol),
NaHCO3 (366 mg, 4.4 mmol), CH3SO2NH2 (138 mg,
1.5 mmol), (DHQD)2-PHAL (125 mg, 11 mol%), OsO4
(36.9 mg, 10 mol%). The mixture was stirred at room
temperature until both phases were clear, and then cooled to
0 8C. To this solution was added dienoate 16f (317 mg,
1.5 mmol) and the reaction was stirred vigorously at room
temperature for 24 h. Satd aqueous sodium sulfite (5 mL)
was added to quench the reaction while stirring vigorously.
Ethyl acetate (10 mL) was added to the reaction mixture,
and after separation of the layers, the aqueous layer was
further extracted with ethyl acetate (3!5 mL). The
combined organic layers were washed with 2 N KOH
(10 mL) and brine to remove the methanesulfonamide, dried

Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
6347
1419, 1387, 1180, 1117, 1082; 1H NMR (CDCl3, 300 MHz):
d 6.91 (dd, JZ15.6, 5.1 Hz, 1H), 6.69 (d, JZ15.6 Hz, 1H),
4.08 (ddd, JZ5.7, 5.4, 1.5 Hz, 1H), 3.73 (dq, JZ6.3,
6.0 Hz, 1H), 3.71 (s, 3H), 3.24 (s, 3H), 3.12 (br, 2H), 1.22
(d, JZ6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 166.6,
145.9, 119.6, 75.9, 70.3, 61.9, 32.4, 19.0; HRMS (CI) Cacld
for [C8H15NO4CNH4]C: 207.1345, Found: 207.1355. The
enantiomeric excess of compound (ent)-14d(S,S) was
determined by HPLC analysis (Chiralcel OD column),
using 5% iPrOH in hexane at 0.8 mL/min. Retention time
(min): R,RZ34.3, S,SZ37.4.
combined organic layers were washed with 2 N KOH
(10 mL) and brine (10 mL) to remove the methanesulfona-
mide, dried over anhydrous Na2SO4. After removal of the
solvents in vacuo, the crude product was purified by flash
chromatography on silica gel (1:1 (v/v) hexane/EtOAc–9:1
(v/v) EtOAc/MeOH) to obtain (ent)-17d(S,S) (86 mg,
61.2% yield, 98% ee), a light yellow oil, as the only
product: RfZ0.38 (EtOAc); [a]2D5 K40.38 (c 1.00, EtOH);
IR (neat, cmK1) 3410, 2984, 2939, 1663, 1621, 1388, 1195,
1
1052, 1002; H NMR (CDCl3, 300 MHz): d 7.31 (m, 5H),
6.74 (dd, JZ15.3, 4.8 Hz, 1H), 6.51 (d, JZ15.6 Hz, 1H),
4.52 (d, JZ6.9 Hz, 1H), 4.36 (dd, JZ6.6, 4.8 Hz, 1H), 3.60
(br, 2H), 3.53 (s, 3H), 3.15 (s, 3H); 13C NMR (CDCl3,
75 MHz): d 166.4, 144.9, 140.1, 128.5, 128.2, 127.1, 119.9,
77.0, 76.0, 61.8, 43.2; HRMS (CI) Cacld for [C13H17NO4C
NH4]C: 269.1501, Found: 269.1523. The enantiomeric
excess of compound (ent)-17d(S,S) was determined by
HPLC analysis (Chiralcel OD column), using 8% iPrOH in
hexane at 0.8 mL/min. Retention time (min): R,RZ28.4,
S,SZ31.0.
2.1.24. (4R,5R)-4,5-Dihydroxy-2-hexenoic acid methoxy-
methyl-amide (14d(R,R)). To a 25 mL round bottom flask
was added 3 mL tert-butyl alcohol, 5 mL water, K3Fe(CN)6
(741 mg, 2.3 mmol), K2CO3 (311 mg, 2.3 mmol), NaHCO3
(189 mg, 2.3 mmol), CH3SO2NH2 (71 mg, 0.75 mmol),
(DHQD)2-PHAL (64.4 mg, 11 mol%), OsO4 (19.1 mg,
10 mol%). The mixture was stirred at room temperature
until both phases were clear, and then cooled to 0 8C. To this
solution was added dienoate 13d (117 mg, 0.75 mmol) and
the reaction was stirred vigorously at room temperature for
24 h. Satd aqueous sodium sulfite (5 mL) was added to
quench the reaction while stirring vigorously. Ethyl acetate
(10 mL) was added to the reaction mixture, and after
separation of the layers, the aqueous layer was further
extracted with ethyl acetate (3!5 mL). The combined
organic layers were washed with 2 N KOH (10 mL) and
brine (10 mL) to remove the methanesulfonamide, dried
over anhydrous Na2SO4. After removal of the solvents in
vacuo, the crude product was purified by flash chromato-
graphy on silica gel (1:1 (v/v) hexane/EtOAc–9:1 (v/v)
EtOAc/MeOH–1:1 (v/v) EtOAc/MeOH) to obtain 14d(R,R)
(116 mg, 81.7% yield, 75% ee), a light yellow oil, as the
only product: RfZ0.16 (EtOAc); [a]2D5 C46.98 (c 1.18,
EtOH); IR (neat, cmK1) 3396, 2977, 2937, 1653, 1617,
1419, 1387, 1180, 1117, 1082; 1H NMR (CDCl3, 300 MHz):
d 6.85 (dd, JZ15.3, 5.1 Hz, 1H), 6.61 (d, JZ15.3 Hz, 1H),
4.00 (ddd, JZ5.7, 5.4, 1.5 Hz, 1H), 3.99 (br, 2H), 3.63 (s,
3H), 3.63 (dq, dq, JZ6.6, 6.3 Hz, 1H), 3.16 (s, 3H), 1.13 (d,
JZ6.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 166.6,
146.0, 119.4, 76.0, 70.4, 61.9, 32.4, 18.9; HRMS (CI) Cacld
for [C8H15O4NCNH4]C: 207.1345, Found: 207.1363. The
enantiomeric excess of compound 14d(R,R) was determined
by HPLC analysis (Chiralcel OD column), using 5% iPrOH
in hexane at 0.8 mL/min. Retention time (min): R,RZ33.3,
S,SZ38.4.
2.1.26. (4R,5R)-4,5-Dihydroxy-5-phenyl-2-pentenoic
acid methoxy-methyl-amide (17d(R,R)). To a 25 mL
round bottom flask was added 3 mL tert-butyl alcohol,
5 mL water, K3Fe(CN)6 (575 mg, 1.7 mmol), K2CO3
(241 mg, 1.7 mmol), NaHCO3 (147 mg, 1.7 mmol), CH3-
SO2NH2 (55 mg, 0.6 mmol), (DHQD)2-PHAL (50.0 mg,
11 mol%), OsO4 (14.8 mg, 10 mol%). The mixture was
stirred at room temperature until both phases were clear, and
then cooled to 0 8C. To this solution was added dienoate 16d
(127 mg, 0.6 mmol) and the reaction was stirred vigorously
at room temperature for 25 h. Satd aqueous sodium sulfite
(5 mL) was added to quench the reaction while stirring
vigorously. Ethyl acetate (10 mL) was added to the reaction
mixture, and after separation of the layers, the aqueous layer
was further extracted with ethyl acetate (3!5 mL). The
combined organic layers were washed with 2 N KOH
(10 mL) and brine (10 mL) to remove the methanesulfona-
mide, dried over anhydrous Na2SO4. After removal of the
solvents in vacuo, the crude product was purified by flash
chromatography on silica gel (1:1 (v/v) hexane/EtOAc–9:1
(v/v) EtOAc/MeOH) to obtain 17d(R,R) (86 mg, 85.3%
yield, 99.97% ee), a light yellow oil, as the only product:
RfZ0.47 (EtOAc); [a]2D5 C41.88 (c 0.99, EtOH); IR (neat,
cmK1) 3401, 2939, 1663, 1621, 1454, 1195, 1119, 1052,
1
1001; H NMR (CDCl3, 300 MHz): d 7.33 (m, 5H), 6.76
(dd, JZ15.6, 4.8 Hz, 1H), 6.55 (d, JZ15.6 Hz, 1H), 4.55 (d,
JZ6.9 Hz, 1H), 4.39 (dd, JZ6.3, 5.1 Hz, 1H), 3.56 (s, 3H),
3.35 (br, 2H), 3.18 (s, 3H); 13C NMR (CDCl3, 75 MHz): d
166.4, 144.9, 140.1, 128.5, 128.1, 127.1, 119.8, 77.0, 76.0,
61.8, 32.4; HRMS (CI) Cacld for [C13H17O4NCNH4]C:
269.1501, Found: 269.1507. The enantiomeric excess of
compound 17d(R,R) was determined by HPLC analysis
(Chiralcel OD column), using 8% iPrOH in hexane at
0.8 mL/min. Retention time (min): R,RZ26.9, S,SZ32.3.
2.1.25. (4S,5S)-4,5-Dihydroxy-5-phenyl-2-pentenoic acid
methoxy-methyl-amide ((ent)-17d(S,S)). To a 25 mL
round bottom flask was added 3 mL tert-butyl alcohol,
5 mL water, K3Fe(CN)6 (554 mg, 1.7 mmol), K2CO3
(233 mg, 1.7 mmol), NaHCO3 (141 mg, 1.7 mmol), CH3-
SO2NH2 (53 mg, 0.6 mmol), (DHQ)2-PHAL (48.1 mg,
11 mol%), OsO4 (14.3 mg, 10 mol%). The mixture was
stirred at room temperature until both phases were clear, and
then cooled to 0 8C. To this solution was added dienoate 7
(122 mg, 0.6 mmol) and the reaction was stirred vigorously
at room temperature for 25 h. Satd aqueous sodium sulfite
(5 mL) was added to quench the reaction while stirring
vigorously. Ethyl acetate (10 mL) was added to the reaction
mixture, and after separation of the layers, the aqueous layer
was further extracted with ethyl acetate (3!5 mL). The
2.1.27. (5S,6S)-5,6-Dihydroxy-3-en-2-heptanone ((ent)-
14e(S,S)). To a 25 mL round bottom flask was added
3 mL tert-butyl alcohol, 5 mL water, K3Fe(CN)6 (1.07 g,
3.3 mmol), K2CO3 (451 mg, 3.3 mmol), NaHCO3 (274 mg,
3.3 mmol), CH3SO2NH2 (103 mg, 1.1 mmol), (DHQ)2-
PHAL (93.2 mg, 11 mol%), OsO4 (27.6 mg, 10 mol%).
The mixture was stirred at room temperature until both

6348
Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
phases were clear, and then cooled to 0 8C. To this solution
was added dienoate 13e (118 mg, 1.1 mmol) and the
reaction was stirred vigorously at room temperature for
30 h. For workup, no Na2SO3 was added. Ethyl acetate
(10 mL) was added to the reaction mixture, and after
separation of the layers, the aqueous layer was further
extracted with ethyl acetate (3!5 mL). Due to the fact that
the product would decompose in the presence of base, no
base wash was used. Only satd NaCl wash was performed
to the combined organic layers, followed by drying over
anhydrous Na2SO4. After removal of the solvents in vacuo,
the crude product was purified by flash chromatography on
silica gel (hexane/EtOAc 2:1 (v/v)–1:1 (v/v), then EtOAc)
to obtain a light yellow oil (ent)-14e(S,S), together with
unseparatable CH3SO2NH2 (after subtracting the CH3SO2-
NH2 from 1H NMR, the mass of (ent)-14e(S,S) was 72 mg,
46.9% yield, 71% ee): RfZ0.36 (EtOAc); [a]D K57.38 (c
0.75, EtOH); IR (neat, cmK1) 3407, 2984, 2931, 1671, 1642,
1367, 1123, 1080, 988; 1H NMR (CDCl3, 300 MHz): d 6.75
(dd, JZ15.9, 5.1 Hz, 1H), 6.34 (dd JZ15.9, 1.5 Hz, 1H),
4.06 (ddd, JZ6.0, 4.8, 1.5 Hz, 1H), 3.72 (dq, JZ6.3,
6.0 Hz, 1H), 3.23 (br, 2H), 2.26 (s, 3H), 1.21 (d, JZ6.3 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d 199.1, 145.9, 131.0,
75.6, 70.3, 27.6, 19.2; HRMS (CI) Cacld for [C7H12O3C
NH4]C: 162.1130, Found: 162.1137. The enantiomeric
excess of compound (ent)-14e(S,S) was determined by
HPLC analysis (Chiralcel OD column), using 5% iPrOH in
hexane at 0.8 mL/min. Retention time (min): R,RZ25.8,
S,SZ28.9.
using 5% iPrOH in hexane at 0.8 mL/min. Retention time
(min): R,RZ25.1, S,SZ28.8.
2.1.29. (5S,6S)-5,6-Dihydroxy-6-phenyl-3-en-2-hexanone
((ent)-17e(S,S)) and (3R,4S)-3,4-dihydroxy-6-phenyl-5-
en-2-hexanone ((ent)-18e(R,S)). To a 25 mL round bottom
flask was added 3 mL tert-butyl alcohol, 5 mL water,
K3Fe(CN)6 (700 mg, 2.1 mmol), K2CO3 (294 mg,
2.1 mmol), NaHCO3 (179 mg, 2.1 mmol), CH3SO2NH2
(67 mg, 0.7 mmol), (DHQ)2PHAL (60.8 mg, 11 mol%),
OsO4 (18.0 mg, 10 mol%). The mixture was stirred at room
temperature until both phases were clear, and then cooled to
0 8C. To this solution was added dienoate 16e (125 mg,
0.7 mmol) and the reaction was stirred vigorously at room
temperature for 28 h. For workup, no Na2SO3 was added.
Ethyl acetate (10 mL) was added to the reaction mixture,
and after separation of the layers, the aqueous layer was
further extracted with ethyl acetate (3!5 mL). Due to the
fact that the product would decompose in the presence of
base, no base wash was used. The combined oraginc layers
were then washed with satd NaCl wash, dried over
anhydrous Na2SO4 and concentrated to afford the crude
mixture of regioisomers ((ent)-17e(S,S)/(ent)-18e(R,S)Z
11:1 by 1H NMR). Flash chromatography on silica gel
(2:1–1:1 (v/v) hexane/EtOAc) provided regioisomer (ent)-
17e(S,S) (after subtracting the CH3SO2NH2 from 1H NMR,
the mass of (ent)-17e(S,S) was 79 mg, 53.1% yield, 93% ee)
and (ent)-18e(R,S) (after subtracting the CH3SO2NH2 from
1H NMR, the mass of (ent)-18e(R,S) was 5.7 mg, 3.8%
yield), both mixed with unseparatable CH3SO2NH2. For
(5S,6S)-5,6-dihydroxy-6-phenyl-3-en-2-hexanone ((ent)-
17e(S,S)): light yellow oil; RfZ0.10 (2:1 (v/v) hexane/
EtOAc); [a]2D5ZK35.18 (product after protection–deprotec-
tion process, c 1.08, EtOH); IR (neat, cmK1) 3416, 3010,
2925, 1672, 1646, 1361, 1081; 1H NMR (CDCl3, 500 MHz):
d 7.34 (m, 5H), 6.54 (dd, JZ15.0, 4.5 Hz, 1H), 6.28 (dd, JZ
15.5, 1.5 Hz, 1H), 4.54 (d, JZ6.0 Hz, 1H), 4.40 (ddd, JZ
6.5, 5.0, 1.5 Hz, 1H), 2.75 (br, 2H), 2.17 (s, 3H); 13C NMR
(CDCl3, 125 MHz): d 198.9, 144.8, 139.7, 130.7, 128.7,
128.5, 126.8, 77.1, 75.4, 27.4; HRMS (CI) Cacld for
[C12H14O3CNH4]C: 224.1287, Found: 224.1277. The
enantiomeric excess of compound 9(S,S) was determined
by HPLC analysis (Chiralcel OD column), using 5% iPrOH
in hexane at 0.8 mL/min. Retention time (min): R,RZ40.6,
S,SZ42.9.
2.1.28. (5R,6R)-5,6-Dihydroxy-3-en-2-heptanone (14e(R,
R)). To a 25 mL round bottom flask was added 3 mL tert-
butyl alcohol, 5 mL water, K3Fe(CN)6 (1.07 g, 3.3 mmol),
K2CO3 (451 mg, 3.3 mmol), NaHCO3 (274 mg, 3.3 mmol),
CH3SO2NH2 (103 mg, 1.1 mmol), (DHQD)2-PHAL
(93.2 mg, 11 mol%), OsO4 (27.6 mg, 10 mol%). The
mixture was stirred at room temperature until both phases
were clear, and then cooled to 0 8C. To this solution was
added dienoate 13e (120 mg, 1.1 mmol) and the reaction
was stirred vigorously at room temperature for 27 h. For
workup, no Na2SO3 was added. Ethyl acetate (10 mL) was
added to the reaction mixture, and after separation of the
layers, the aqueous layer was further extracted with ethyl
acetate (3!5 mL). Due to the fact that the product would
decompose in the presence of base, no base wash was used.
Only satd NaCl wash was performed to the combined
organic layers, followed by drying over anhydrous Na2SO4.
After removal of the solvents in vacuo, the crude product
was purified by flash chromatography on silica gel (hexane/
EtOAc 2:1 (v/v)–1:1 (v/v), then EtOAc) to obtain a light
yellow oil 14e(R,R), together with unseparatable CH3SO2-
NH2 (after subtracting the CH3SO2NH2 from 1H NMR, the
mass of 14e(R,R) was 46 mg, 29.4% yield, 71% ee): RfZ
2.1.30. (5R,6R)-5,6-Dihydroxy-6-phenyl-3-en-2-hexa-
none (17e(R,R)) and (3S,4R)-3,4-dihydroxy-6-phenyl-5-
en-2-hexanone (18e(S,R)). To a 25 mL round bottom flask
was added 3 mL tert-butyl alcohol, 5 mL water, K3Fe(CN)6
(700 mg, 2.1 mmol), K2CO3 (294 mg, 2.1 mmol), NaHCO3
(179 mg, 2.1 mmol), CH3SO2NH2 (67 mg, 0.7 mmol),
(DHQD)2PHAL (60.8 mg, 11 mol%), OsO4 (18.0 mg,
10 mol%). The mixture was stirred at room temperature
until both phases were clear, and then cooled to 0 8C. To this
solution was added dienoate 16e (122 mg, 0.7 mmol) and
the reaction was stirred vigorously at room temperature for
28 h. For workup, no Na2SO3 was added. Ethyl acetate
(10 mL) was added to the reaction mixture, and after
separation of the layers, the aqueous layer was further
extracted with ethyl acetate (3!5 mL). Due to the fact that
the product would decompose in the presence of base, no
base wash was used. The combined oraginc layers were then
0.37 (EtOAc); [a]D C63.18 (c 1.03, EtOH); IR (neat, cmK1
)
1
3407, 2984, 2931, 1671, 1642, 1367, 1123, 1080, 988; H
NMR (CDCl3, 300 MHz): d 6.76 (dd, JZ15.9, 5.1 Hz, 1H),
6.34 (d, JZ16.2 Hz, 1H), 3.94, (ddd, JZ6.0, 5.1, 1.5 Hz,
1H), 3.72 (dq, JZ6.3, 6.0 Hz, 1H), 3.21 (br, 2H), 2.27 (s,
3H), 1.17 (d, JZ6.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 199.2, 145.9, 131.0, 75.6, 70.3, 27.6, 19.2; HRMS (CI)
Cacld for [C7H12O3CNH4]C: 162.1130, Found: 162.1137.
The enantiomeric excess of compound 14e(R,R) was
determined by HPLC analysis (Chiralcel OD column),

Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
6349
washed with satd NaCl wash, dried over anhydrous Na2SO4
and concentrated to afford the crude mixture of regioisomers
(17e(R,R)/18e(S,R)Z12:1 by H NMR). Flash chromato-
graphy on silica gel (2:1–1:1 (v/v) hexane/EtOAc) provided
yield) as a light yellow oil. RfZ0.29 (2:1 (v/v) hexane/
EtOAc); [a]2D5 C22.68 (c 1.03, EtOH); IR (neat, cmK1
)
2990, 2941, 1742, 1703, 1679, 1637, 1373, 1222, 1061; 1H
NMR (CDCl3, 300 MHz): d 6.63 (dd, JZ16.2, 5.1 Hz, 1H),
6.20 (dd, JZ15.9, 1.5 Hz, 1H), 5.48 (ddd, JZ5.1, 5.1,
1.5 Hz, 1H), 5.11 (dq, JZ6.3, 6.0 Hz, 1H), 2.26 (s, 3H),
2.13 (s, 3H), 2.04 (s, 3H), 1.22 (d, JZ6.6 Hz, 3H); 13C
NMR (CDCl3, 75 MHz): d 197.5, 170.0, 169.6, 139.8,
131.8, 73.2, 69.6, 27.4, 20.9, 20.7, 15.9; HRMS (CI) Cacld
for [C11H16O5CNH4]C: 246.1341, Found: 264.1340.
1
regioisomer 17e(R,R) (after subtracting the CH3SO2NH2
from H NMR, the mass of 17e(R,R) was 89 mg, 60.6%
1
yield, 98% ee) and 18e(S,R) (after subtracting the CH3SO2-
NH2 from 1H NMR, the mass of 18e(S,R) was 4.4 mg,
3.0% yield), both mixed with unseparatable CH3SO2NH2.
For (5R,6R)-5,6-dihydroxy-6-phenyl-3-en-2-hexanone
(17e(R,R)): light yellow oil; RfZ0.56 (4:1 (v/v) hexane/
EtOAc); [a]2D5ZC34.38 (product after protection–deprotec-
tion process, c 1.08, EtOH); IR (neat, cmK1) 3416, 3010,
2925, 1672, 1646, 1361, 1081; 1H NMR (CDCl3, 300 MHz):
d 7.33 (m, 5H), 6.52 (dd, JZ15.9, 4.5 Hz, 1H), 6.27 (dd, JZ
16.2, 1.5 Hz, 1H), 4.53 (d, JZ6.9 Hz, 1H), 4.37 (ddd, JZ
6.6, 5.1, 1.5 Hz, 1H), 3.29 (br, 2H), 2.14 (s, 3H); 13C NMR
(CDCl3, 125 MHz): d 198.9, 144.8, 139.7, 130.7, 128.7,
128.5, 126.8, 77.1, 75.4, 27.4; HRMS (CI) Cacld for
[C12H14O3CNH4]C: 224.1287, Found: 224.1277. The
enantiomeric excess of compound 17e(R,R) was determined
by HPLC analysis (Chiralcel OD column), using 5% iPrOH
in hexane at 0.8 mL/min. Retention time (min): R,RZ43.8,
S,SZ49.2.
2.1.33. Deprotection of diacetate (ent)-22(S,S) to diol
(5S,6S)-5,6-diacetate-6-phenyl-3-en-2-hexanone ((ent)-
14e(S,S)). To a 5 mL round-bottom flask was added the
diacetate (ent)-22(S,S) (45 mg, 0.03 mmol), MeOH (1 mL)
and NEt3 (0.1 mL). The reaction was stirred at room
temperature for 24 h and concentrated. The diol was purified
by flash chromatography on silica gel (2:1 (v/v) hexane/
EtOAc) to yield the pure diol (ent)-14e(S,S) (22 mg, 77.4%
yield) without methanesulfonamide. For the characteriz-
ation of (ent)-14e(S,S), please refer to the previous
dihydroxylation reaction of dienoate 13e.
2.1.34. Deprotection of diacetate 22(R,R) to diol (5R,6R)-
5,6-diacetate-6-phenyl-3-en-2-hexanone (14e(R,R)). To a
5 mL round-bottom flask was added the diacetate 22(R,R)
(40 mg, 0.03 mmol), MeOH (1 mL) and NEt3 (0.1 mL). The
reaction was stirred at room temperature for 24 h and
concentrated. The diol was purified by flash chromato-
graphy on silica gel (2:1 (v/v) hexane/EtOAc) to yield the
pure diol 14e(R,R) (21 mg, 83.1% yield) without methane-
sulfonamide. For the characterization of 14e(R,R), please
refer to the previous dihydroxylation reaction of dienoate
13e.
2.1.31. Protection of diol (ent)-14e(S,S) to diacetate
(5S,6S)-5,6-diacetate-3-en-2-heptanone ((ent)-22(S,S)).
To a solution of (ent)-14e(S,S) (51 mg, 0.7 mmol) in
CH2Cl2 (2 mL) was added excess Ac2O (0.5 mL,
5.3 mmol), pyridine (1 mL) and a catalytic amount of
DMAP (3 mg, 5 mol%). The reaction was stirred for an
hour, after which 2 mL of 1 N sodium bisulfate was added to
remove excess base. The organic layer was washed with
saturated sodium bicarbonate and the aqueous layer was
further extracted with ether (3!2 mL). The combined
organic layers were dried over Na2SO4 and the solvent was
removed in vacuo. The crude product was purified by flash
chromatography on silica gel (4:1 (v/v) hexane/EtOAc) to
yield the diacetate (ent)-22 (47 mg, 58.2% yield) as a light
yellow oil. RfZ0.38 (2:1 (v/v) hexane/EtOAc); [a]D25
K21.28 (c 1.11, EtOH); IR (neat, cmK1) 2990, 2941,
1742, 1703, 1679, 1637, 1373, 1222, 1061; 1H NMR
(CDCl3, 300 MHz): d 6.64 (dd, JZ16.2, 5.1 Hz, 1H), 6.21
(dd, JZ15.9, 1.5 Hz, 1H), 5.48 (ddd, JZ5.1, 5.1, 1.5 Hz,
1H), 5.11 (ddq, JZ6.3, 6.0, 1.5 Hz, 1H), 2.27 (s, 3H), 2.14
(s, 3H), 2.04 (s, 3H), 1.22 (d, JZ6.6 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d 197.5, 170.0, 169.6, 139.8, 131.8, 73.2,
69.6, 27.4, 20.9, 20.7, 15.9; HRMS (CI) Cacld for
[C11H16O5CNH4]C: 246.1341, Found: 246.1340.
2.1.35. Protection of diol (ent)-17e(S,S) to diacetate
(5S,6S)-5,6-diacetate-6-phenyl-3-en-2-hexanone ((ent)-
23(S,S)). To a solution of (ent)-17e(S,S) (142 mg,
0.7 mmol) in CH2Cl2 (2 mL) was added excess Ac2O
(0.5 mL, 5.3 mmol), pyridine (0.8 mL) and a catalytic
amount of DMAP (4 mg, 5 mol%). The reaction was stirred
for an hour, after which 2 mL of 1 N sodium bisulfate was
added to remove excess base. The organic layer was washed
with saturated sodium bicarbonate and the aqueous layer
was further extracted with ether (3!2 mL). The combined
organic layers were dried over Na2SO4 and the solvent was
removed in vacuo. The crude product was purified by flash
chromatography on silica gel (4:1 (v/v) hexane/EtOAc) to
yield the diacetate (ent)-23 (104 mg, 59.9% yield) as a white
solid. RfZ0.20 (5:1 (v/v) hexane/EtOAc); mp: 79–80 8C;
[a]2D5 C27.68 (c 1.04, EtOH); IR (neat, cmK1) 3076, 1747,
2.1.32. Protection of diol 14e(S,S) to diacetate (5S,6S)-
5,6-diacetate-3-en-2-heptanone (22(S,S)). To a solution of
14e(S,S) (47 mg, 0.7 mmol) in CH2Cl2 (2 mL) was added
excess Ac2O (0.5 mL, 5.3 mmol), pyridine (1 mL) and a
catalytic amount of DMAP (3 mg, 5 mol%). The reaction
was stirred for an hour, after which 2 mL of 1 N sodium
bisulfate was added to remove excess base. The organic
layer was washed with saturated sodium bicarbonate and the
aqueous layer was further extracted with ether (3!2 mL).
The combined organic layers were dried over Na2SO4 and
the solvent was removed in vacuo. The crude product was
purified by flash chromatography on silica gel (4:1 (v/v)
hexane/EtOAc) to yield the diacetate 22 (45 mg, 67.2%
1
1636, 1373, 1220, 1027; H NMR (CDCl3, 500 MHz): d
7.35 (m, 5H), 6.44 (dd, JZ16.5, 5.0 Hz, 1H), 6.12 (dd, JZ
16.0, 1.5 Hz, 1H), 5.91 (d, JZ7.0 Hz, 1H), 5.77 (ddd, JZ
6.5, 5.0, 1.5 Hz, 1H), 2.17 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H);
13C NMR (CDCl3, 125 MHz): d 197.4, 169.6, 169.5, 139.6,
135.6, 132.0, 129.0, 128.7, 127.2, 75.4, 73.5, 27.4, 21.0,
20.7; HRMS (CI) Cacld for [C16H18O5CNH4]C: 308.1498,
Found: 308.1496.
2.1.36. Protection of diol 17e(R,R) to diacetate (5R,6R)-
5,6-diacetate-6-phenyl-3-en-2-hexanone (23(R,R)). To a
solution of 17e(R,R) (103 mg, 0.5 mmol) in CH2Cl2 (2 mL)

6350
Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
1
was added excess Ac2O (0.4 mL, 4.2 mmol), pyridine
(0.8 mL) and a catalytic amount of DMAP (3 mg,
0.025 mmol). The reaction was stirred for an hour, after
which 2 mL of 1 N sodium bisulfate was added to remove
excess base. The organic layer was washed with saturated
sodium bicarbonate and the aqueous layer was further
extracted with ether (3!2 mL). The combined organic
layers were dried over Na2SO4 and the solvent was removed
in vacuo. The crude product was purified by flash
chromatography on silica gel (4:1 (v/v) hexane/EtOAc) to
yield the diacetate 23 (80.7 mg, 59.6% yield) as a white
solid. RfZ0.61 (2:1 (v/v) hexane/EtOAc); mp: 80–81 8C;
[a]2D5 K28.88 (c 1.02, EtOH); IR (neat, cmK1) 3076, 1747,
EtOH), H NMR (CDCl3, 500 MHz) d 7.23 (dd, JZ15,
11 Hz, 1H), 6.41 (dd, JZ15, 11 Hz, 1H), 6.06 (dd, JZ15,
6 Hz, 1H), 5.86 (d, JZ15.5, 1H), 3.93 (dd, JZ6.5, 6.5 Hz,
1H), 3.71 (s, 3H), 3.62 (dq, JZ6.5, 6.5 Hz, 1H), 3.33 (br,
2H), 1.14 (d, JZ6.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 167.5, 143.9, 141.3, 129.5, 121.4, 76.5, 70.6, 51.7, 19.0.
2.1.40. t-Butyl (6R,7R)-6,7-dihydroxy-octa-2,4-dienoate
(20c). To a solution of 19c (4.15 g, 21.4 mmol) in t-BuOH
(20 mL) and water (10 mL) was added K3Fe(CN)6 (21.1 g,
64.1 mmol), K2CO3 (8.9 g, 64.1 mmol), NaHCO3 (5.4 g,
64 mmol), (DHQD)2PHAL (332.6 mg, 2 mmol%), and
CH3SO2NH2 (2.03 g, 21.4 mmol). This mixture was cooled
to 0 8C, OsO4 (54.3 mg, 1 mmol%) was then added, and the
solution was stirred at 0 8C for 24 h. The reaction was
quenched with aqueous sodium sulfite (30 mL), and ethyl
acetate (50 mL) was added to the reaction mixture. After the
layers were separated, the aqueous layer was further
extracted with ethyl acetate (2!30 mL). The combined
organic layers were washed with 2 N KOH (20 mL) and
brine (30 mL), and dried over anhydrous sodium sulfate.
After removal of the solvent in vacuo, flash chromatography
on silica gel (20:1–5:1K2:1–1:2 (v/v) hexane/EtOAc)
afforded 20c as a light yellow liquid (3.82 g, 78.5%
yield): Rf 0.16 (2:1 (v/v) hexane/EtOAc); [a]D 22.98 (c
0.85, CHCl3); IR (neat) 3384, 2975, 2933, 1887, 1699,
1644, 1615, 1478, 1455, 1392, 1367, 1307, 1241 cmK1; 1H
NMR (CDCl3, 500 MHz) d 7.17 (dd, JZ15.5, 11 Hz, 1H),
6.44 (dd, JZ16, 12 Hz, 1H), 6.06 (dd, JZ15, 6 Hz, 1H),
5.84 (d, JZ15.0 Hz, 1H), 3.98 (dd, JZ6.5, 6.5 Hz, 1H),
3.68 (dq, JZ6.5, 6.5 Hz, 1H), 1.49 (s, 9H), 1.20 (d, JZ
6 Hz, 3H); 13C NMR (CDCl3, 125 MHz) d 166.4, 142.5,
140.3, 129.8, 124.0, 80.6, 76.7, 70.7, 28.1, 19.0; HRMS
(CI) Calcd for [C12H20O4CNH4]C: 246.1705 Found:
246.1721.
1
1636, 1373, 1220, 1027; H NMR (CDCl3, 500 MHz): d
7.34 (m, 5H), 6.45 (dd, JZ15.5, 5.0 Hz, 1H), 6.11 (dd, JZ
16.0, 1.5 Hz, 1H), 5.91 (d, JZ6.5 Hz, 1H), 5.77 (ddd, JZ
6.5, 5.0, 1.5 Hz, 1H), 2.16 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H);
13C NMR (CDCl3, 125 MHz): d 197.4, 169.6, 169.5, 139.6,
135.6, 132.0, 129.0, 128.7, 127.2, 75.4, 73.5, 27.4, 21.0,
20.7; HRMS (CI) Cacld for [C16H18O5CNH4]C: 308.1498,
Found: 308.1496.
2.1.37. Deprotection of diacetate (ent)-23(S,S) to diol
(5S,6S)-5,6-diacetate-6-phenyl-3-en-2-hexanone ((ent)-
17e(S,S)). To a 5 mL round-bottom flask was added the
diacetate (ent)-23(S,S) (9.3 mg, 0.03 mmol), MeOH
(0.2 mL) and NEt3 (0.1 mL). The reaction was stirred at
room temperature for 24 h and concentrated. The diol was
purified by flash chromatography on silica gel (2:1 (v/v)
hexane/EtOAc) to yield the pure diol (ent)-17e(S,S)
(4.8 mg, 73% yield) without methanesulfonamide. For
the characterization of (ent)-17e(S,S), please refer to the
previous dihydroxylation reaction of dienoate 16e.
2.1.38. Deprotection of diacetate 23(R,R) to diol (5R,6R)-
5,6-diacetate-6-phenyl-3-en-2-hexanone (17e(R,R)). To a
5 mL round-bottom flask was added the diacetate 23(R,R)
(8.4 mg, 0.03 mmol), MeOH (0.1 mL) and NEt3 (0.1 mL).
The reaction was stirred at room temperature for 24 h and
concentrated. The diol was purified by flash chromato-
graphy on silica gel (2:1 (v/v) hexane /EtOAc) to yield the
pure diol 17e(R,R) (6.0 mg, 87% yield) without methane-
sulfonamide. For the characterization of 17e(S,S), please
refer to the previous dihydroxylation reaction of dienoate
16e.
2.1.41. (6S,7S)-6,7-Dihydroxy-octa-2,4-dienoic acid tert-
butyl ester (ent)-20c. To 2.2 g (11.3 mmol) of triene 19 in
30 mL of t-BuOH and 30 mL water was added K3Fe(CN)6
(11.15 g, 33.9 mmol), K2CO3 (4.68 g, 33.9 mmol), (DHQ)2-
PHAL (176 mg, 0.23 mmol), and CH3SO2NH2 (1.07 g,
11.3 mmol). This mixture was cooled to 0 8C, OsO4 (29 mg,
0.113 mmol) was then added, and the solution was stirred
overnight. Ethyl acetate (30 mL) was added to the reaction
mixture, and the reaction was quenched with aqueous
sodium sulfite (30 mL). The layers were separated, and the
aqueous layer was extracted with ethyl acetate (2!30 mL).
The combined organic layers were washed with 2 N KOH
(20 mL) and brine (30 mL), and dried over anhydrous
sodium sulfate. After removal of the solvent in vacuo, flash
chromatography on silica gel afforded diol (ent)-20c
(2.01 g, 78%): [a]D K238 (c 1.0, CHCl3); IR (neat) 3384,
2975, 2933, 1887, 1699, 1644, 1615, 1478, 1455, 1392,
2.1.39. (6R,7R)-6,7-Dihydroxy-octa-2,4-dienoic acid
methyl ester 20a. To 4.2 g (27.6 mmol) of triene 19a in
130 mL of t-BuOH and 130 mL water was added
K3Fe(CN)6 (27.24 g, 82.8 mmol), K2CO3 (11.43 g,
82.8 mmol), (DHQD)2-PHAL (537 mg, 0.69 mmol), and
CH3SO2NH2 (2.62 g, 27.6 mmol). This mixture was cooled
to 0 8C, OsO4 (35 mg, 0.138 mmol) was then added, and the
solution was stirred overnight. Ethyl acetate (50 mL) was
added to the reaction mixture, and the reaction was
quenched with aqueous sodium sulfite (30 mL). The layers
were separated, and the aqueous layer was extracted with
ethyl acetate (2!30 mL). The combined organic layers
were washed with 2 N KOH (20 mL) and brine (30 mL),
and dried over anhydrous sodium sulfate. After removal of
the solvent in vacuo, flash chromatography on silica gel
afforded diol 20a as a white solid (4.0 g, 82%): mp 53–
55 8C; Rf 0.11 (hexane/EtOAc, 3:2), [a]D 73.78 (c 1.3,
1367, 1307, 1241 cmK1; H NMR (CDCl3, 500 MHz) d
1
7.17 (dd, JZ15.5, 11 Hz, 1H), 6.44 (dd, JZ16, 12 Hz, 1H),
6.06 (dd, JZ15, 6 Hz, 1H), 5.84 (d, JZ15.0 Hz, 1H), 3.98
(dd, JZ6.5, 6.5 Hz, 1H), 3.68 (dq, JZ6.5, 6.5 Hz, 1H), 1.49
(s, 9H), 1.20 (d, JZ6 Hz, 3H); 13C NMR (CDCl3,
125 MHz) d 166.4, 142.5, 140.3, 129.8, 124.0, 80.6, 76.7,
70.7, 28.1, 19.0; HRMS (CI) Calcd for [C12H20O4CNH4]C:
246.1705 Found: 246.1721.

Y. Zhang, G. A. O’Doherty / Tetrahedron 61 (2005) 6337–6351
6351
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Acknowledgements
We thank both the Arnold and Mabel Beckman Foundation
and the NIH (1R01 GM63150-01A1) for their generous
support of our research program. Funding for a 600 MHz
NMR by the NSF-EPSCoR (#0314742) is also gratefully
acknowledged.
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