Studies on the asymmetric dihydroxylation of advanced bryostatin C-ring segments

Article abstract of DOI:10.1055/s-2004-822400

The asymmetric dihydroxylation reaction of early stage and advanced Bryostatin C-ring precursors was evaluated. For homoallylic ethers and alcohols, several AD ligands were investigated including a novel class of quinidine-alkynes.

Full text of DOI:10.1055/s-2004-822400

PAPER
1391
Studies on the Asymmetric Dihydroxylation of Advanced Bryostatin C-Ring
Segments
Asymmetric
Dihydrox
a
ylation of
A
r
dvance
d
t
Bryos
i
tatin C-
n
Ring Segments C. Seidel, René Smits, Christian B. W. Stark,1 Jens Frackenpohl,2 Oliver Gaertzen,3 H. Martin R. Hoffmann*
Department of Organic Chemistry, University of Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: hoffmann@mbox.oci.uni-hannover.de
Received 15 April 2004
Dedicated to Professor Teruaki Mukaiyama on the auspicious occasion of his 77th anniversary with respect and admiration
construction of vicinal diols in the laboratory and also in
Abstract: The asymmetric dihydroxylation reaction of early stage
industrial settings.13 Common trans-disubstituted double
bonds tend to react with exceptional stereoselectivity. Re-
and advanced Bryostatin C-ring precursors was evaluated. For ho-
moallylic ethers and alcohols, several AD ligands were investigated
cent examples of applications in natural product chemis-
try, however, reveal that the asymmetric dihydroxylation
of complex substrates remains an important challenge.
Thus, only moderate selectivities were achieved in syn-
thetic approaches toward Zaragozic acid C14 and
Apoptolidin15 and in the time-consuming optimization of
the synthesis of Cryptophycin.16 However, in these exam-
ples no ligands other than the standard PHAL-derivative
were tested.
including a novel class of quinidine-alkynes.
Key words: asymmetric dihydroxylation, Bryostatin, quinidine-
based ligands, double stereoinduction, Cinchona alkynes
The Bryostatins (Figure 1) are a class of highly oxygenat-
ed marine macrolides with a polyacetate backbone, which
exhibit exceptional therapeutic antineoplastic activities.4
Since their discovery and structure elucidation in the early
1980’s by Pettit et al.,5 three total syntheses (S. Masam-
une, D. A. Evans, S. Yamamura) and several partial syn-
theses have been published.6
25
O
OH
OH
(R,R)
O
26
25
+
26
O
25 OH
(S,S)
26
OH
Equation 1 Dihydroxylation reaction
We herein describe a detailed investigation on the asym-
metric dihydroxylation of advanced Bryostatin C-ring
segments (construction of the C25/C26 diol subunit, cf.
Equation 1) using a set of commercially available dihy-
droxylation ligands. In addition, preliminary results em-
ploying novel alkyne-Cinchona alkaloids as ligands for
asymmetric dihydroxylation are presented.
Figure 1 Bryostatin 1 (R1 = H, R2 = OMe) and 3 (R1 = R2 = O)
Of special interest is the southern C17–C27 segment, both
as a seat of the pharmacophoric groups7 and as a synthetic
challenge. For approaching the C17–C27 fragment, we
planned to establish the C25/C26 vicinal diol unit by
Sharpless’ asymmetric dihydroxylation8 (AD) of a suit-
able E-alkene precursor. Hitherto, this diol unit was taken
from the chiral pool,9 constructed via stereoselective
reduction10 or built up by AD reaction of simple sub-
strates.11 The dihydroxylation of an advanced C-ring ana-
logue proved to be unsatisfactory due to low selectivity.12
Systematic Investigation on the Asymmetric Dihy-
droxylation of Advanced C-Ring Substrates
Our initial experiments were focused on lactol 1
(Figure 2), as a simple first generation model of the south-
ern segment of Bryostatin 1. In order to determine the in-
trinsic reactivity and stereo-preference, the first
dihydroxylation attempts were carried out in the absence
of any chiral ligand (Table 1, entry 1). In these experi-
ments a slight preference for the desired R,R-diastereomer
could be detected. Since DHQD-derived ligands in-
creased this margin a matched situation seems likely (en-
try 3), whereas the DHQ-ligand gave the undesired S,S-
diol in only slight excess, representing a mismatched pair
(entry 2). Using AD-mix-b at 0 °C a good selectivity of
7.5:1 in favor for the desired R,R-isomer was obtained. As
expected, other commercially available ligands [e.g.
The asymmetric dihydroxylation developed by Sharpless
and co-workers has evolved as standard technique for the
SYNTHESIS 2004, No. 9, pp 1391–1398
x
x
.
x
x
.2
0
0
4
Advanced online publication: 08.06.2004
DOI: 10.1055/s-2004-822400; Art ID: C12704SS
© Georg Thieme Verlag Stuttgart · New York

1392
M. C. Seidel et al.
PAPER
(DHQD)2PYR and the monomeric (DHQD)CLB; entries the open chain substrates. Closed and acyclic derivatives
5 and 6, respectively] gave lower stereoinduction. These can be classified further into Bryostatin 1 (R1 = H) and
results are in accord with the generally observed high se- Bryostatin 3 C-ring precursors in order to investigate the
lectivity for trans double bonds using the steric influence of the substituent at C22 (R1 = OR).
(DHQD)2PHAL-ligand.
Dihydroxylation of cyclic southern half mimic 2a in the
presence of (DHQD)2PHAL ligand led to a disappointing
HO
O
MeO
BnO
O
selectivity (2.7:1 at 20 °C and 3.7:1 at 0 °C, Table 2). The
use of (DHQD)2PYR ligand, however, afforded a strongly
increased stereoselectivity (11.5:1). This finding is sur-
prising since the PYR-ligand is generally believed to be
the ligand of choice for terminal and tetrasubstituted dou-
ble bonds and not for trans disubstituted olefins.19 In-
creasing the amount of ligand up to 50 mol% did not give
any further improvement. The use of less OsO4 had a mi-
nor influence on the stereoselectivity (Table 2, entries 6
and 8). Other commercially available ligands [i.e.
(DHQD)2AQN and (DHQD)CLB (Figure 3)] gave lower
selectivities.
2a: R1 = H
2b: R1 = OH
2c: R1 = OBn
BnO
R1
OBn
2
1
OBn
BT-S
OMe
O
OBn R1
26
O
19
22
BnO
OBn
25
O
OH
OR2
3
4
OBn
OBn
4a: R1 = H, R2 = H
4b: R1 = OBn, R2 = H
4c: R1 = H, R2 = TBDMS
4d: R1 = H, R2 = TIPS
Table 2 AD-Reactions of Second Generation Bryostatin C Mimics
2 and 3
O
Ph
PhO2S
Entry Alkene Ligand (mol%)/
Methoda
Temp Time YieldbR,R:S,Sb
(° C) (h)
O
OTIPS
OBn
(%)
73
70
64
80
79
77
97
99
99
99
99
75
88
90
98
97
89
90
5
1
2
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
2c
2c
2c
3
None/A
20
20
0
14
15
15
14
20
24
14
14
16
16
9
1.3:1
2.7:1
3.7:1
2.7:1
5.2:1
8.0:1
8.1:1
11.5:1
7.8:1
8.4:1
1.2:1
3.0:1
4.5:1
15:1
Figure 2 Cyclic and acyclic Bryostatin C-ring precursors as AD
substrates (BT = benzothiazol-2-yl)
(DHQD)2PHAL/B
(DHQD)2PHAL/B
(DHQD)CLB (10)/C
(DHQD)2AQN (10)/C
(DHQD)2PYR (10)/C
(DHQD)2PYR (50)/C
(DHQD)2PYR (10)/D
(DHQD)2PYR (10)/D
(DHQD)2AQN (10)/D
None/A
3
Table 1 AD-Reactions of Alkene 1 as First Generation Bryostatin
4
0
C Model
5
0
Entry Alkene Ligand/Methoda
Temp Time Yieldb R,R:S,Sb
(° C) (h)
(%)
62
63
59
75
63
60
6
0
1
2
3
4
5
6
1
1
1
1
1
1
none/A
20
20
2
36
24
48
24
24
1.2:1
1:1.4
5.5:1
7.5:1
4.0:1
3.2:1
7
0
(DHQ)2PHAL/B
8
0
(DHQD)2PHAL/B 20
9
0
(DHQD)2PHAL/B
(DHQD)2PYR/C
(DHQD)CLB/C
0
20
20
10
11
12
13
14
15
16
17
18
0
20
0
(DHQD)2PHAL/B
(DHQD)2PYR (10)/D
(DHQD)2AQN (10)/D
(DHQD)2PHAL (10)/E
(DHQD)CLB (10)/E
(DHQD)2PYR (10)/E
(DHQD)2AQN(10)/E
11
6
a A: OsO4 (0.01 equiv, 2.5 wt% solution in t-BuOH), NMO (3 equiv),
THF–H2O (10:1); B: 1.4 g AD-mix-a or b/mmol substrate, OsO4
(0.05 equiv), MeSO2NH2 (1 equiv), t-BuOH–H2O (1:1); C: OsO4
(0.01 equiv, 2.5 wt% solution in t-BuOH), ligand (0.1 equiv),
MeSO2NH2 (1 equiv), K3FeCN6 (3 equiv), K2CO3 (3 equiv), t-BuOH–
H2O (1:1).
0
0
7
0
46
37
25
26
2.1:1
3.2:1
3.1:1
7.2:1
b Yields refer to the corresponding compound used for the determina-
tion of diastereomeric ratios via 1H NMR (see ref.17).
3
0
3
0
3
0
We then turned our attention to the AD-reaction of ad-
vanced and more challenging C-ring fragments. Several
a A: OsO4 (0.1 equiv, 2.5 wt% solution in t-BuOH), NMO (3 equiv),
cyclic and open chain substrates18 with increasing com- THF–H2O (10:1); B: 1.4 g AD-mix-b/mmol substrate, OsO4 (0.05
equiv), MeSO2NH2 (1 equiv), t-BuOH–H2O (1:1); C: OsO4 (0.1
equiv), MeSO2NH2 (1 equiv), K3FeCN6 (3 equiv), K2CO3 (3 equiv),
t-BuOH–H2O (1:1); D: See C, OsO4 (0.01 equiv); E: See C, OsO4
plexity were tested to evaluate at which stage of the syn-
thesis the asymmetric dihydroxylation is most suitable.
Due to higher flexibility of linear substrates (4 and 5 in
Figure 2) and the greater steric demands of cyclic deriva-
(0.01 equiv), t-BuOH–THF–H2O (2:1:3).
b Ratio was determined via 1H NMR.
tives (2 and 3 in Figure 2) best results were expected for
Synthesis 2004, No. 9, 1391–1398 © Thieme Stuttgart · New York

PAPER
Asymmetric Dihydroxylation of Advanced Bryostatin C-Ring Segments
1393
(DHQD)2PYR
(DHQD)2AQN
(DHQD)CLB
Cl
Et
O
Ph
RO
OR
O
RO
OR
O
CLB
N
O
N
N
Ph
DHQD
R = DHQD
OCH3
N
Figure 3 Structures of some commercially available AD-ligands
While the pyrimidine core-containing ligand was appar- workers noted in their original communication slightly
ently most suitable for Bryostatin 1 C-ring model 2a, giv- improved selectivities for the AQN-ligand compared to
ing high selectivity (11.5:1; entry 8) ratios dropped with the PHAL-ligand. Apparently this finding has not to led to
the introduction of the proximal C22 substituent (Bryosta- applications in complex natural product synthesis.22 It is
tin 3 precursors 2b,c, entries 9–14). In these cases the therefore worth noting that the AQN-ligand is significant-
AQN-ligand was superior thus being the ligand of choice ly superior to the classical PHAL-ligand. The measure of
for the Bryostatin 3 series. An increase of the steric bulk improvement on these structurally complex substrates is
at C22 leads to a decrease in selectivity using the PYR- noteworthy.
ligand. Interestingly, the same increase in bulk led to an
increase in selectivity using the AQN-ligand. With fully
Investigation of Novel Alkyne-Cinchona Alkaloids as
functionalized Bryostatin 3 precursor 3 a similar tendency
Ligands for Asymmetric Dihydroxylation
was observed, although selectivities were generally re-
duced (Table 2, entries 17 and 18). For acyclic C-ring pre- The above results demonstrate the utility of modern dihy-
cursors again the standard PHAL ligand displayed poor droxylation chemistry but at the same time reveal ‘certain
selectivities (1.9:1 to 2.7:1; Table 3, entries 1 and 11). In gaps’ for structurally complex substrates. In this context,
accord with the above findings for cyclic C-ring mimics 2, our recent experimental finding that as a class of bicyclic
the open chain fragments of Bryostatin 1 (lacking the C22
substituent, 4a,c,d and 5) suited the (DHQD)2PYR ligand
best, whereas (DHQD)2AQN favored the derivatives of
the C22 oxygenated form (see Table 3). As expected
building up steric hindrance at the C23 hydroxy function
(in homoallylic position) led to an inevitable decrease of
selectivities.20
Table 3 AD-Reactions of Acyclic Bryostatin C Segments 4 and 5
Entry Alkene Ligand (mol%)/
Methoda
Temp Time Yieldb R,R:S,S
(° C) (h) (%)
1
2
4a
4a
4a
4a
4b
4b
4c
4d
4d
5
(DHQD)2PHAL (10)/A
(DHQD)CLB (10)/A
(DHQD)2AQN (10)/A
(DHQD)2PYR (10)/B
(DHQD)2AQN (10)/B
(DHQD)2PYR (10)/B
(DHQD)2PYR (10)/A
(DHQD)2PYR (10)/A
(DHQD)CLB (10)/A
None/C
0
0
16
15
14
16
10
7
85
87
87
97
91
95
81
99
96
86
92
83
74
97
2.7:1b
2.6:1b
2.9:1b
4.9:1b
10:1b
Interim summing up: Our work represents a systematic in-
vestigation of the AD reaction on advanced Bryostatin C-
ring fragments using commercially available ligands.
Whereas on simple C-ring model 1 the standard AD-mix
b gave satisfactory results (7.5:1); the same ligand failed
to give good diastereoselectivities on more advanced sub-
strates. In fact, a diastereoselection of 3.7:1 was not ex-
ceeded, leading to a disappointing isolated yield of 50%
for the desired isomer. An increase in ligand loading did
not lead to any improvement. Interestingly other commer-
cially available ligands (i.e. the PYR- and the AQN-
ligand) displayed a significantly higher selectivity of up to
15:1. Best dihydroxylation results for the Bryostatin 1 se-
ries were obtained using the PYR-ligand with substrate 2a
(11.5:1). Conversely for the Bryostatin 3 series (carrying
a substituent in homoallylic position) best results were
achieved using the AQN-ligand for substrate 2c (15:1).
The dihydroxylation results of the acyclic Bryostatin 1
3
0
4
0
5
0
6
0
3.4:1b
1.6:1c
1.3:1c
2.3:1c
1.1:1c
1.9:1c
1.4:1c
2.2:1c
2.7:1c
7
0
14
15
14
4
8
0
9
0
10
11
12
13
20
0
5
(DHQD)2PHAL (10)/A
(DHQD)2PYR (10)/A
(DHQD)CLB (10)/A
(DHQD)CLB (20)/A
24
6
5
0
5
20
0
6
precursors (Table 3, entries 1–4) could not compete with 14
those obtained for the cyclic form. In this study the best
result was achieved employing the AQN-ligand. This
class of ligands is generally used for the AD reaction of
5
60
a A: OsO4 (0.1 equiv, 2.5 wt% solution in t-BuOH), MeSO2NH2 (1
equiv), K3FeCN6 (3 equiv), K2CO3 (3 equiv), t-BuOH–H2O (1:1); B:
see A, OsO4 (0.01 equiv); C: OsO4 (0.1 equiv), NMO (3 equiv), THF–
terminal double bonds.21 When trans disubstituted stan- H2O (10:1).
b Ratio was determined via separation of AD-products.
dard substrates were dihydroxylated, Sharpless and co-
c Ratio was determined via 1H NMR.
Synthesis 2004, No. 9, 1391–1398 © Thieme Stuttgart · New York

1394
M. C. Seidel et al.
PAPER
R
OMe
H
6a R = Ph
6b R = I
6c R = quinolyl
OH
8
9
1
N
H
HO
O
N
BnO
i
10
OBn
H
H
Figure 4 Substrates for novel Cinchona-alkyne AD ligands
R
7a R = Ph
7b R = I
7c R = quinolyl
N
R
N
H
N N
Table 4 AD-Reactions of Alkenes 8–10 and First Generation Bry-
ostatin C Model 1
O
O
H
MeO
OMe
Entry Alkene Ligand/Methoda
Temp Time Yield R,R:S,S
(° C) (h)
N
(%)
89
86
83
82
88
86
82
82
87
83
62
63
59
75
47
37
27
N
1
2
8
8
(DHQD)2PHAL/A
7a/A
0
0
24
24
24
22
14
16
16
16
14
16
2
39:1b
65:1b
65:1b
49:1b
8:1b
Equation 2 Synthesis of novel Cinchona alkaloid AD ligands.
Reagents and conditions: i) 1,4-dichlorophthalazine, K2CO3, KOH,
toluene, 14 h reflux, 59–66%.
3
8
7b/A
0
3-ethynylquinuclidines shows enhanced basicity and po-
larity and also crystallize readily is of practical and heu-
ristic value as it potentially gives rise to a novel class of
AD ligands. Hitherto, synthetic efforts to modify Cincho-
na-based AD ligands have focused on the replacement of
the spacer or linker23 and transformations of the quinoline
motif,24 leaving the quinuclidine moiety and its side-chain
aside. The ethynyl function coexists with OsO4 when it is
substituted, unlike the vinyl group of conventional Cin-
chona alkaloids, which has to be hydrogenated for prepa-
ration of AD mixes. Based on X-ray data Cinchona-
alkynes show only little twist of the azabicyclic cage al-
lowing better orbital overlap of the N(sp3) lone pair with
the antiperiplanar s bond(s) and the alkyne function.25
Due to their different electronic properties alkyne-quinu-
clidines appear to bind OsO4 more tightly. Thus, we de-
cided to explore the efficiency of these Cinchona-alkynes
in AD reactions.
4
8
7c/A
0
5
9
(DHQD)2PHAL/A
7a/A
0
6
9
0
7:1b
7
9
7b/A
0
5.4:1b
1.1:1b
3.1:1b
2:1b
8
9
7c/A
0
9
10
10
1
(DHQD)2PHAL/A
7a/A
0
10
11
12
13
14
15
16
17
0
None/B
20
20
20
0
1.2:1c
1:1.4c
5.5:1c
7.5:1c
>9:1c
7.3:1c
4.0:1c
1
(DHQ)2PHAL/C
(DHQD)2PHAL/C
(DHQD)2PHAL/C
7a/A
36
24
48
24
24
48
1
1
1
0
PHAL-alkyne ligands 7a–c were easily synthesized in one
step from 10,11-didehydroquinidine derivatives 6a–c,26
following a standard protocol (Equation 2).8b Ligands
containing the PHAL-spacer represent the most widely
employed and best studied class of AD-ligands. Applica-
tions of these ligands in the catalytic dihydroxylation of
selected alkenes are summarized in Table 4. Initial studies
using trans-stilbene as a substrate were promising. The
enantiomeric excesses obtained with the novel ligands
were comparable to or even better than those observed for
the standard PHAL-ligand. In the dihydroxylation reac-
tion of C-ring model 1, Cinchona-alkyne ligand 7a was
again slightly superior to the (DHQD)2PHAL ligand. In
the case of terminal or trisubstituted double bonds (sub-
strates 9 and 10, Figure 4) the alkyne-Cinchona ligands
were less efficient.
1
7b/A
0
1
7c/A
0
a A: OsO4 (0.01 equiv, 2.5 wt% solution in t-BuOH), ligand (0.1
equiv), MeSO2NH2 (1 equiv), K3FeCN6 (3 equiv), K2CO3 (3 equiv),
t-BuOH–H2O (1:1); B: OsO4 (0.01 equiv, 2.5 wt% solution in t-BuOH),
NMO (3 equiv), THF–H2O (10:1); C: 1.4 g AD-mix-a or b/mmol sub-
strate, OsO4 (0.05 equiv), MeSO2NH2 (1 equiv), t-BuOH–H2O (1:1).
b Ratio was determined by GC analysis.
c Yields refer to the corresponding compound used for the determina-
tion of diastereomeric ratios (see ref.17).
should, however, be noted that although alkyne ligand 7a
provided the diol products in higher stereoselectivity iso-
lated yields were reduced. This effect was especially no-
ticeable in the case of structurally more complex
substrates. At present, the reason for the diminished
chemical yields remains unclear.27
In all cases alkyne-Cinchona ligand 7a was superior to
ligands 7b and 7c, suggesting that the remote sidechain of
the quinuclidine moiety has a considerable impact on the
facial selectivity of the dihydroxylation reaction. It
In conclusion, we have investigated the asymmetric dihy-
droxylation reactions of complex natural product frag-
Synthesis 2004, No. 9, 1391–1398 © Thieme Stuttgart · New York

PAPER
Asymmetric Dihydroxylation of Advanced Bryostatin C-Ring Segments
Dihydroxylated Alkene 2a
1395
ments. The dihydroxylation represents a key step in our
intended synthesis of Bryostatin thus introducing one of
the important pharmacophoric groups. In these experi-
ments it was shown that the PYR-ligand was more favor-
able for Bryostatin 1 precursors, whereas AQN was best
suited for the Bryostatin 3 series. With closed Bryostatin
C-ring mimics better optical purities were achieved than
with their open chain derivatives. Homoallylic alcohols
and higher homologues as well as their protected deriva-
tives represent common AD substrates in natural product
synthesis. We therefore believe that our findings are of
general interest and will be useful in future synthetic ap-
plications. Especially the tendencies observed for sterical-
ly demanding substrates carrying substituents in homo- or
bis-homoallylic position and the remarkable stereoselec-
tivities obtained with the AQN-ligand are most notable.
IR (neat): 3412, 2911, 1715, 1496, 1454, 1381, 1315, 1268, 1194,
1132, 1071, 1043, 958, 866, 737, 714, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.42–7.22 (m, 10 H, Ph-H), 5.71–
5.63 (m, 1 H, CHCH2OBn), 4.76 (d, J = 1.4 Hz, 1 H, H-19), 4.59 (d,
J = 12.2 Hz, 1 H, CH2-Ph), 4.53 (s, 2 H, CH2-Ph), 4.33 (d, J = 12.2
Hz, 1 H, CH2-Ph), 4.15 (dd, J = 12.4, 6.8 Hz, 1 H, CHCH2OBn),
4.10 (dd, J = 12.4, 6.2 Hz, 1 H, CHCH2OBn), 4.06–3.98 (m, 1 H,
H-23), 3.71–5.56 (m, 2 H, H-25, H-26), 3.59 (d, J = 1.4 Hz, 1 H,
H-20), 3.37 (s, 3 H, OCH3), 2.79 (d, J = 4.5 Hz, 1 H, OH), 2.41 (br
s, 1 H, OH), 2.25 (d, J = 6.5 Hz, 2 H, H-22), 1.75 (ddd, J = 14.4, 9.2,
2.6 Hz, 1 H, H-24a), 1.60 (ddd, J = 14.4, 9.4, 2.7 Hz, 1 H, H-24b),
1.18 (d, J = 6.2 Hz, 3 H, H-27).
13C NMR (100 MHz, CDCl3): d = 138.1, 137.9, 134.2, 128.4, 128.4,
127.9, 127.8, 127.7, 127.6, 127.3, 101.1, 78.6, 72.6, 71.0, 72.1,
69.2, 66.4, 65.1, 54.9, 38.7, 30.9, 19.4.
HR–MS: m/z = 411.2170 [M+ – MeO].
In addition to studying commercially available AD-
ligands, we tested a set of alkyne-Cinchona ligands. This
novel class of ligands exhibited remarkable selectivities
on trans disubstituted double bonds. Ligand 7a gave high-
er enantioselectivity compared to the well established
Dihydroxylated Alkene 2b
IR (neat): 3364, 2917, 1454, 1364, 1327, 1137, 1074, 961, 908, 735,
698 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.28 (m, 10 H, Ph-H), 6.20–
6.16 (m, 1 H, CHCH2OBn), 4.74 (s, 1 H, H-19), 4.61 (d, J = 12.4
(DHQD)2PHAL ligand. Other ligands (cf. 7b and 7c) dif- Hz, 1 H, CH2-Ph), 4.51, 4.47 (d, J = 11.9 Hz, 2 × 1 H, CH2-Ph), 4.32
(d, J = 12.4 Hz, 1 H, CH2-Ph), 4.24 (s, 1 H, H-20), 4.22 (d, J = 9.4
Hz, 1 H, H-22), 4.04 (dd, J = 11.9, 7.3 Hz, 1 H, CHCH2OBn), 3.96
(dd, J = 11.9, 6.3 Hz, 1 H, CHCH2OBn), 3.74 (dt, J = 8.4, 3.5 Hz, 1
H, H-23), 3.68–3.61 (m, 2 H, H-25, H-26), 3.52, 3.45 (br s, 1 H,
OH), 3.35 (s, 3 H, OCH3), 2.89 (br s, 1 H, OH), 2.05 (ddd, J = 13.3,
9.7, 3.4 Hz, 1 H, H-24a), 1.82 (dd, J = 13.3, 7.9 Hz, 1 H, H-24b), 1.21
(d, J = 4.6 Hz, 3 H, H-27).
fering in the substitution of the alkyne were less selective,
clearly indicating an influence of the remote substituent
on the alkyne. At present, the major drawback of this class
of ligands appears to be the low isolated yields of dihy-
droxylation product. This undesirable effect is currently
under investigation in our laboratories.
13C NMR (100 MHz, CDCl3): d = 138.0, 137.8, 136.7, 128.4, 128.4,
127.75, 127.71, 127.69, 127.66, 124.1, 100.0, 72.74, 72.67, 72.37,
72.16, 71.1, 69.5, 69.3, 65.4, 54.7, 36.4, 19.4.
Catalytic Asymmetric Dihydroxylation; General Procedure
To a stirred solution of ligand (0.01 mmol, 10 mol%), K3Fe(CN)6
(99 mg, 0.3 mmol, 3.0 equiv), K2CO3 (41 mg, 0.3 mmol, 3.0 equiv),
methanesulfonamide (9.5 mg, 0.1 mmol, 1.0 equiv) and OsO4 (125
mL, 0.01 mmol, 0.1 equiv, 2.5 wt% solution in t-BuOH), in
t-BuOH–H2O (1:1, 0.05 M) the alkene (0.1 mmol in t-BuOH) was
added at 0 °C. The resulting mixture was stirred vigorously at 0 °C
until completion of the reaction as indicated by TLC. The reaction
mixture was quenched with Na2SO3 and then allowed to warm to r.t.
and stirred for 1 h. After dilution with CH2Cl2 and H2O the organic
phase was separated and the aqueous phase was extracted three
times with CH2Cl2. The combined organic extract was dried over
Na2SO4, concentrated in vacuo and the resultant residue was puri-
fied by silica gel chromatography. All spectroscopic data corre-
spond to the R,R-diols.
ESI: m/z = 481.2206 [M+ + Na].
Dihydroxylated Alkene 2c
IR (neat): 3417, 3030, 2922, 2863, 1454, 1365, 1202, 1134, 1089,
1074, 1028, 960, 908, 731, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.24 (m, 15 H, Ph-H), 6.15–
6.12 (m, 1 H, CHCH2OBn), 4.70 (d, J = 11.2 Hz, 1 H, CH2-Ph), 4.69
(s, 1 H, H-19), 4.58 (d, J = 12.3 Hz, 1 H, CH2-Ph), 4.50, 4.46 (d,
J = 11.9 Hz, 2 × 1 H, CH2-Ph), 4.46 (d, J = 11.2 Hz, 1 H, CH2-Ph),
4.32 (d, J = 12.3 Hz, 1 H, CH2-Ph), 4.27 (s, 1 H, H-20), 4.07 (dd,
J = 12.3, 7.8 Hz, 1 H, CHCH2OBn), 4.03 (d, J = 10.0 Hz, 1 H,
H-22), 3.96 (dd, J = 12.3, 6.4 Hz, 1 H, CHCH2OBn), 3.88 (dt, J =
8.3, 2.6 Hz, 1 H, H-23), 3.58–3.52 (m, 2 H, H-25, H-26), 3.32 (s, 3
H, OCH3), 2.87, 2.47 (br s, 2 × 1 H, OH), 1.94 (ddd, J = 14.4, 9.4,
2.8 Hz, 1 H, H-24a), 1.70 (dd, J = 14.4, 8.2 Hz, 1 H, H-24b), 1.13
(d, J = 5.8 Hz, 3 H, H-27).
Dihydroxylated Lactol 1
Spectroscopic data refer to lactone 11.17
13C NMR (100 MHz, CDCl3): d = 138.3, 137.8, 137.5, 134.2, 128.4,
128.36, 128.2, 128.0, 127.75, 127.73, 127.69, 127.6, 124.5, 100.3,
76.3, 73.6, 73.0, 72.8, 72.3, 71.8, 71.0, 69.5, 65.5, 54.8, 34.9, 19.2.
1H NMR (400 MHz, CDCl3): d = 7.33 (m, 10 H, Ph-H), 5.05, 4.83,
4.64, 4.61 (d, J = 12.2 Hz, 4 × 1 H, CH2Ph), 4.42 (dd, J = 4.8, 2.7
Hz, 1 H, H-23), 4.18 (d, J = 3.2 Hz, 1 H, H-20), 4.14 (ddd, J = 7.6,
3.2 Hz, 1 H, H-21), 3.81 (ddd, J = 10.3, 8.4, 1.7 Hz, 1 H, H-25), 3.67
(dd, J = 8.4, 6.0 Hz, 1 H, H-26), 2.29 (ddd, J = 14.8, 7.5, 4.9 Hz, 1
H, H-22a), 1.92 (ddd, J = 14.8, 11.2, 3.0 Hz, 1 H, H-22b), 1.88 (ddd,
J = 14.4, 9.6, 1.7 Hz, 1 H, H-24a), 1.61 (ddd, J = 14.4, 10.3, 2.6 Hz,
1 H, H-24b), 1.38, 1.34 [s, 2 × 3 H, O2C(CH3)2], 1.25 (d, J = 6.0 Hz,
3 H, H-27).
Dihydroxylated Alkene 3
IR (neat): 3408, 3030, 2926, 2869, 1454, 1426, 1380, 1362, 1309,
1275, 1238, 1206, 1075, 1043, 991, 937, 912, 752, 736, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.79 (d, J = 8.2 Hz, 1 H, Ar-H),
7.69 (d, J = 7.4 Hz, 1 H, Ar-H), 7.39–7.23 (m, 17 H, Ph-H, Ar-H),
6.15–6.12 (m, 1 H, CHCH2OBn), 4.66 (d, J = 11.5 Hz, 1 H, CH2-
Ph), 4.58, 4.53 (d, J = 11.9 Hz, 2 × 1 H, CH2-Ph), 4.48 (d, J = 11.6
Hz, 1 H, CH2-Ph), 4.43 (s, 1 H, H-20), 4.41 (d, J = 11.4 Hz, 1 H,
CH2-Ph), 4.28 (d, J = 11.6 Hz, 1 H, CH2-Ph), 4.30–4.24 (m, 1 H,
CHCH2OBn), 4.08 (dd, J = 12.4, 5.6 Hz, 1 H, CHCH2OBn), 4.04 (d,
13C NMR (100 MHz, CDCl3): d = 169.8, 138.1, 137.3, 128.5, 128.3,
127.9, 127.8, 127.5, 127.6, 108.3, 77.9, 76.9, 76.4, 72.7, 72.3, 72.6,
72.4, 38.8, 35.8, 27.3, 27.2, 17.0.
Synthesis 2004, No. 9, 1391–1398 © Thieme Stuttgart · New York

1396
M. C. Seidel et al.
PAPER
J = 9.6 Hz, 1 H, H-23), 3.81 (d, J = 11.9 Hz, 1 H, H-17a), 3.80–3.78
(m, 1 H, H-24), 3.78–3.72 (m, 1 H, H-26), 3.73 (d, J = 11.9 Hz, 1
H, H-17b), 3.63 (t, J = 6.3 Hz, 1 H, H-25), 3.35 (s, 3 H, OCH3), 2.60
(br s, 2 H, OH), 1.98 (ddd, J = 14.4, 10.1, 2.4 Hz, 1 H, H-24a), 1.74
(ddd, J = 14.4, 9.0, 2.5 Hz, 1 H, H-24b), 1.23 (d, J = 6.2 Hz, 3 H,
H-27), 1.18, 1.15 [s, 2 × 3 H, C(CH3)2].
13C NMR (100 MHz, CDCl3): d = 169.6, 153.2, 138.3, 137.6, 137.4,
134.8, 135.0, 128.4, 128.41, 128.39, 128.3, 128.0, 127.8, 127.73,
127.68, 127.66, 125.9, 123.9, 123.4, 121.2, 120.8, 103.4, 76.8, 75.7,
75.3, 72.8, 72.5, 72.4, 71.2, 69.9, 65.8, 52.2, 42.8, 36.3, 27.0, 23.7,
23.2, 19.5.
(br s, 1 H, OH), 2.50 (d, J = 7.4 Hz, 2 H, H-22), 1.68, 1.50 (m, 2 H,
H-24), 1.51 (d, J = 6.5 Hz, 3 H, PhCHCH3), 1.41, 1.35 [s, 2 × 3 H,
C(CH3)2], 1.12 (d, J = 6.3 Hz, 3 H, H-27), 1.07 {s, 21 H,
Si[CH(CH3)2]3}.
13C NMR (100 MHz, CDCl3): d = 208.0, 141.8, 141.5, 137.9, 133.4,
131.5, 129.1, 128.5, 128.4, 128.3, 128.1, 127.7, 127.7, 127.5, 126.9,
84.7, 75.9, 71.1, 72.8, 69.9, 72.7, 66.6, 64.7, 47.6, 38.3, 36.2, 25.4
24.3, 22.8, 18.9, 18.2, 18.1, 12.7, 12.6.
MS–FAB: m/z = 817 [M+ + Na], 807 (16), 795 (65), 691 (20), 621
(74), 583 (31), 539 (78).
Synthesis of Ligands 7a–c; General Procedure
Dihydroxylated Alkene 4a
Didehydroquinidine derivatives 6a–c were synthesized according
to literature procedures.24 Typically, 6a–c (1 equiv) were then dis-
solved in anhyd toluene and K2CO3 (1.5 equiv) and 1,4-dichloro-
phthalazine (0.5 equiv) were added, and the reaction mixture was
refluxed in a Dean-Stark apparatus for 2 h. After cooling down to
r.t., finely powdered KOH (1.5 equiv) was added and refluxing was
continued for 12 h. The resulting reaction mixture was cooled to r.t.,
aq NaHCO3 was added, and the aqueous layer was extracted with
CHCl3. The combined organic layer was dried (MgSO4), filtered
and concentrated, affording a yellowish residue, which was purified
by column chromatography (EtOAc–MeOH, 10:1) to afford desired
PHAL-bridged ligands 7a–c.
IR (neat): 3378, 2974, 2931, 1722, 1496, 1454, 1390, 1366, 1314,
1253, 1205, 1137, 1060, 1028, 943, 908, 850, 738, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.23 (m, 10 H, Ph-H), 5.89–
5.82 (m, 1 H, CHCH2OBn), 4.57 (d, J = 11.8 Hz, 1 H, CH2-Ph), 4.53
(d, J = 11.8 Hz, 1 H, CH2-Ph), 4.39 (d, J = 11.3 Hz, 1 H, CH2-Ph),
4.21 (d, J = 11.3 Hz, 1 H, CH2-Ph), 4.15 (dd, J = 12.0, 7.0 Hz, 1 H,
CHCH2OBn), 4.10 (dd, J = 12.0, 5.8 Hz, 1 H, CHCH2OBn), 4.07–
3.98 (m, 1 H, H-23), 3.82 (d, J = 8.6 Hz, 1 H, H-19), 3.75–3.65 (br
s, 2 H, OH), 3.71 (d, J = 8.6 Hz, 1 H, H-20), 3.62–3.54 (m, 2 H,
H-25, H-26), 2.88 (br s, 1 H, OH), 2.45 (dd, J = 14.4, 10.3 Hz, 1 H,
H-22a), 2.21–2.13 (m, 1 H, H-22b), 2.05 (br s, 1 H, OH), 1.63 (ddd,
J = 14.3, 7.8, 3.3 Hz, 1 H, H-24a), 1.56 (ddd, J = 14.3, 8.3, 3.0 Hz,
1 H, H-24b), 1.36 [s, 9 H, C(CH3)3], 1.17, 1.15 [s, 2 × 3 H, C(CH3)2],
1.11 (d, J = 5.8 Hz, 3 H, H-27).
(3R,3¢¢R,4S,4¢¢S,8R,8¢¢R,9S,9¢¢S)-1,4-Bis[11-phenyl-10,11-dide-
hydro-6¢-methoxy-cinchonanyl-9-oxy]-phthalazine (7a)
Compound 6a (650 mg, 1.63 mmol, 1 equiv) was allowed to react
according to the general procedure with K2CO3 (338 mg, 2.45
mmol, 1.5 equiv), KOH (137 mg, 2.45 mmol, 1.5 equiv) und 1,4-
dichlorophthalazine (163 mg, 0.82 mmol, 0.5 equiv) to afford
dimeric ligand 7a (63%, 486 mg, 0.51 mmol).
13C NMR (100 MHz, CDCl3): d = 176.8, 138.7, 137.7, 137.5, 131.3,
128.5, 128.2, 127.94, 127.87, 127.7, 86.4, 80.5, 74.9, 73.5, 72.7,
70.6, 70.3, 68.4, 66.1, 46.3, 39.4, 35.2, 27.9, 23.9, 21.2, 19.0.
HR–MS: m/z = 595.3273 [M+ – OC(CH3)3].
1H NMR (400 MHz, CDCl3): d = 8.47 (m, 2 H), 8.33 (m, 2 H), 8.03
(m, 2 H), 7.59 (m, 2 H), 7.50–7.40 (m, 6 H), 7.39–7.25 (m, 6 H),
7.24–7.17 (m, 4 H), 6.78 (m, 2 H), 3.84 (s, 6 H), 3.43–3.25 (m, 4 H),
3.07–2.99 (m, 2 H), 2.97–2.88 (m, 2 H), 2.73–2.59 (m, 4 H), 2.14–
2.08 (m, 2 H), 1.63–1.41 (m, 6 H), 1.22–1.13 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 157.8, 156.3, 147.2, 144.6, 144.2,
132.2, 131.8, 131.5, 128.3, 127.8, 127.7, 126.6, 123.7, 122.9, 122.1,
118.3, 101.5, 93.1, 81.6, 76.6, 59.2, 55.5, 50.7, 49.8, 28.9, 28.5,
25.6, 25.1.
Dihydroxylated Alkene 4b
IR (neat): 3378, 3030, 2974, 2929, 1724, 1497, 1454, 1366, 1253,
1131, 1055, 1028, 910, 850, 735, 697 cm–1.
1H NMR (500 MHz, CD3C6H5, 350 K): d = 7.30–7.00 (m, 15 H,
Ph-H), 6.33–6.37 (m, 1 H, H-12), 4.61 (d, J = 11.5 Hz, 1 H, CH2Ph),
4.56 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.47 (s, 2 H, CH2Ph), 4.47–4.44
(m, 1 H, H-13a), 4.44–4.40 (m, 2 H, H-4, H-6), 4.36–4.30 (m, 1 H,
H-13b), 4.34 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.33 (d, J = 11.5 Hz, 1
H, CH2Ph), 4.24 (d, J = 8.8 Hz, 1 H, H-3), 4.14 (dt, J = 6.1 Hz, J =
1.8 Hz, 1 H, H-7), 3.84 (br s, 2 H, OH), 3.62–3.55 (m, 1 H, H-9),
3.51–3.42 (m, 1 H, H-10), 2.99 (br s, 1 H, OH), 1.99 (ddd, J = 14.4,
8.6, 3.1 Hz, 1 H, H-8a), 1.77 (ddd, J = 14.4, 7.8, 3.1 Hz, 1 H, H-8b),
1.34 [s, 9 H, CO2C(CH3)3], 1.32, 1.28 (s, 3 H, H-14), 1.02 (d, J = 6.0
Hz, 3 H, H-11).
IR (CHCl3): 3000, 2948, 2876, 2836, 2224, 1620, 1596, 1552, 1508,
1472, 1432, 1380, 1352, 1304, 1228, 1164, 1092, 1032, 988, 844
cm–1.
MS–FAB: m/z = 945 (7) [M+ + Na], 923 (28) [M+ + 1], 636 (7), 543
(11), 399 (9), 381 (100).
13C NMR (125 MHz, CD3C6H5, 350 K): d = 176.2, 140.0, 139.1,
138.8, 137.4, 138.5, 129.3, 128.7, 128.6, 128.5, 128.5, 128.0, 127.9,
80.0, 78.4, 74.4, 73.2, 72.4, 72.1, 72.0, 72.0, 71.1, 70.8, 66.8, 47.4,
35.8, 28.2, 27.2, 23.2, 19.5.
(3R,3¢¢R,4S,4¢¢S,8R,8¢¢R,9S,9¢¢S)-1,4-Bis[11-iodo-10,11-didehy-
dro-6¢-methoxy-cinchonanyl-9-oxy]-phthalazine (7b)
Compound 6b (520 mg, 1.16 mmol, 1 equiv) was allowed to react
according to the general procedure with K2CO3 (240 mg, 1.74
mmol, 1.5 equiv), KOH (98 mg, 1.74 mmol, 1.5 equiv) and 1,4-
dichlorophthalazine (115 mg, 0.58 mmol, 0.5 equiv) to yield dimer-
ic ligand 7b (59%, 349 mg, 0.34 mmol).
ESI: m/z = 701.3646 [M+ + Na].
Dihydroxylated Alkene 5
IR (neat): 3478, 3064, 3032, 2926, 2865, 1712, 1586, 1495, 1449,
1368, 1308, 1256, 1210, 1151, 1086, 1067, 1028, 1015, 884, 861,
738, 701, 687 cm–1.
IR (CHCl3): 3096, 2948, 2880, 2836, 2112, 1620, 1596, 1552, 1508,
1472, 1432, 1380, 1356, 1300, 1264, 1228, 1164, 1092, 1032, 844
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.83 (d, J = 4.6 Hz, 2 H), 8.63 (m,
2 H), 8.06, 8.00 (d, J = 9.2 Hz, 2 H), 7.96 (m, 2 H), 7.49 (d, J = 2.6
Hz, 2 H), 7.42–7.34 (m, 4 H), 7.12 (m, 2 H), 3.88 (s, 6 H), 3.57–3.49
(m, 2 H), 3.40–3.24 (m, 2 H), 3.07–2.92 (m, 4 H), 2.89–2.77 (m, 2
H), 2.50–2.41 (m, 1 H), 2.15–2.10 (m, 2 H), 2.03–1.91 (m, 2 H),
1.70–1.43 (m, 6 H).
1H NMR (400 MHz, CDCl3): d = 7.84 (m, 2 H, o-Ph-H), 7.61 (m, 1
H, p-Ph-H), 7.52 (m, 2 H, m-Ph-H), 7.37–7.26 (m, 10 H, Ph-H),
5.93 (dd, J = 6.5, 6.2 Hz, 1 H, CHCH2OBn), 4.64 (s, 1 H, H-20),
4.59 (d, J = 11.9 Hz, 1 H, CH2-Ph), 4.55 (d, J = 11.9 Hz, 1 H, CH2-
Ph), 4.52 (q, J = 6.5 Hz, 1 H, PhCHCH3), 4.29 (m, 1 H, H-23), 4.22
(dd, J = 12.6, 6.5 Hz, 1 H, CHCH2OBn), 4.18 (dd, J = 12.6, 6.2 Hz,
1 H, CHCH2OBn), 3.60, 3.49 (m, 2 H, H-25, H-26), 3.51 (d, J = 13.9
Hz, 1 H, PhSO2CH2), 3.34 (d, J = 13.9 Hz, 1 H, PhSO2CH2), 2.61
Synthesis 2004, No. 9, 1391–1398 © Thieme Stuttgart · New York

PAPER
Asymmetric Dihydroxylation of Advanced Bryostatin C-Ring Segments
1397
13C NMR (100 MHz, CDCl3): d = 157.9, 156.4, 147.8, 144.6, 144.1,
132.1, 131.6, 127.0, 125.7, 122.5, 121.3, 118.5, 101.0, 87.6, 78.9,
76.3, 59.6, 55.8, 49.6, 47.8, 28.2, 27.9, 25.1, 22.9.
(10) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.;
Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121,
7540.
(11) Hale, K. J.; Lennon, J. A.; Manaviazar, S.; Javaid, M. H.
Tetrahedron Lett. 1995, 36, 1359.
(12) Wender, P. A.; Baryza, J. L.; Bennett, C. E.; Bi, F. C.;
Brenner, S. E.; Clarke, M. O.; Horan, J. C.; Kan, C.; Lacote,
E.; Lippa, B.; Nell, P. G.; Turner, T. M. J. Am. Chem. Soc.
2002, 124, 13648.
(13) (a) Markó, I. E.; Svendsen, J. E. In Comprehensive
Asymmetric Catalysis, Vol. II; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, 1999, 713–787.
(b) Bolm, C.; Hildebrand, J. P.; Muñiz, K. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000, 399–428. (c) Beller, M.; Sharpless, K. B.
In Applied Homogeneous Catalysis with Organometallic
Compounds, 2nd ed.; Cornils, B.; Herrmann, W. A., Eds.;
Wiley-VCH: Weinheim, 2002, 1149–1164. (d) See also ref.
8b
(14) Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1994, 116,
10825.
(15) Nicolaou, K. C.; Li, Y.; Sugita, K.; Monenschein, H.;
Guntupalli, P.; Mitchell, H. J.; Fylaktakidou, K. C.;
Vourloumis, D.; Giannakakou, P.; O’Brate, A. J. Am. Chem.
Soc. 2003, 125, 15443.
(16) Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J. Org.
Chem. 2000, 65, 3143.
(17) To determine the ratio of diastereoselectivity for the
dihydroxylated lactol of 1 the diol was first transformed into
the corresponding acetonide, followed by oxidation to
lactone 11 (Equation 3).
MS–FAB: m/z = 1024 (5) [M+ + 2], 924 (9), 794 (10), 772 (32), 449
(100), 305 (98), 292 (26).
(3R,3¢¢R,4S,4¢¢S,8R,8¢¢R,9S,9¢¢S)-1,4-Bis[11-quinolinyl-10,11-di-
dehydro-6¢-methoxy-cinchonanyl-9-oxy]phthalazine (7c)
Compound 6c (420 mg, 0.94 mmol, 1 equiv) was allowed to react
according to the general procedure with K2CO3 (194 mg, 1.40
mmol, 1.5 equiv), KOH (79 mg, 1.40 mmol, 1.5 equiv) and 1,4-
dichlorophthalazine (93 mg, 0.47 mmol, 0.5 equiv) to afford dimer-
ic ligand 7c (66%, 316 mg, 0.31 mmol).
IR (CHCl3): 3068, 2956, 2872, 2220, 1668, 1620, 1600, 1568, 1508,
1472, 1432, 1380, 1348, 1228, 1164, 1092, 1032, 984, 840 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.91 (m, 2 H), 8.63 (m, 2 H), 8.46
(m, 2 H), 8.17 (m, 2 H), 8.09 (m, 2 H), 8.01 (m, 2 H), 7.80–7.65 (m,
6 H), 7.63–7.60 (m, 2 H), 7.58–7.51 (m, 2 H), 7.45–7.32 (m, 4 H),
6.35–6.25 (m, 2 H), 3.86 (s, 6 H), 3.54–3.38 (m, 4 H), 3.05–2.96 (m,
2 H), 2.81–2.74 (m, 2 H), 2.62–2.50 (m, 4 H), 2.39 (m, 2 H), 1.84–
1.47 (m, 6 H), 1.30–1.22 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 157.8, 156.4, 152.4, 146.9, 146.6,
144.2, 143.8, 138.3, 132.0, 131.9, 129.4, 129.2, 127.5, 127.4, 127.2,
127.2, 127.0, 122.4, 121.9, 117.9, 117.8, 101.8, 96.3, 78.9, 72.0,
56.9, 55.7, 50.7, 49.7, 29.2, 28.8, 27.3, 22.7.
MS–FAB: m/z = 1026 (17) [M+ + 2], 603 (8), 595 (22), 577 (28),
551 (42), 450 (23), 432 (100).
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft, the Volkswagen
foundation and the Fonds der Chemischen Industrie for their sup-
port. In addition we appreciate the generous gift of Cinchona alka-
loids from Buchler GmbH, Braunschweig.
References
Equation 3
(1) New address: Christian B. W. Stark, Department of Organic
Chemistry, Freie Universität Berlin, Takustr. 3, 14195
Berlin, Germany.
(2) New address: J. Frackenpohl, Bayer CropScience GmbH,
Chemistry Frankfurt, G836, Industriepark Höchst, 65926
Frankfurt am Main, Germany.
(18) The synthesis of these fragments will be presented in due
course.
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PAPER
(26) Frackenpohl, J.; Braje, W.; Hoffmann, H. M. R. J. Chem.
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(27) Although complete conversion was noted in these
experiments, the yield of isolated product was generally low
when structurally complex substrates were converted. Thus
far, no degradation products could be isolated, implying the
formation of highly water-soluble side-products.
Synthesis 2004, No. 9, 1391–1398 © Thieme Stuttgart · New York