Convenient syntheses of (2R,3S,4R)-3-(tert-butyldimethylsilanyloxy)-2,4-dimethyl-5-oxopentanoic acid methoxymethylamide from methacrolein. Preparation of C1-C7 and C17-C24 fragments of (+)-discodermolide

Article abstract of DOI:10.1016/S0957-4166(02)00261-6

Two new highly stereoselective routes to (2R,3S,4R)-3-(tert-butyldimethylsilanyloxy)-2,4-dimethyl-5-oxopentanoic acid methoxymethylamide, an important intermediate in natural product synthesis, are described. Both schemes are considerably shorter and less

Full text of DOI:10.1016/S0957-4166(02)00261-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1161–1165
Convenient syntheses of (2R,3S,4R)-3-(tert-butyldimethylsilanyl-
oxy)-2,4-dimethyl-5-oxopentanoic acid methoxymethylamide from
methacrolein. Preparation of C1–C7 and C17–C24 fragments of
(
+)-discodermolide
†
Billy W. Day,* Cyrous O. Kangani and Kwasi S. Avor
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
Received 22 March 2002; accepted 2 May 2002
Abstract—Two new highly stereoselective routes to (2R,3S,4R)-3-(tert-butyldimethylsilanyloxy)-2,4-dimethyl-5-oxopentanoic acid
methoxymethylamide, an important intermediate in natural product synthesis, are described. Both schemes are considerably
shorter and less expensive than methods previously reported. The title compound was then converted to direct precursors of
C1–C7 and C17–24 fragments of the potent microtubule stabilizer (+)-discodermolide. © 2002 Elsevier Science Ltd. All rights
reserved.
1
. Introduction
Its mechanism of action, however, was first predicted
computationally, then shown biochemically and in cell
culture to involve potent induction of tubulin assembly
The unique natural product (+)-discodermolide is a
C24:4 fatty acid lactone bearing three (Z)-double
bonds, four hydroxy groups, eight methyl substituents,
a carbamate moiety and thirteen stereogenic centers
Fig. 1). It was originally isolated from the Caribbean
deep sea sponge Discodermia dissoluta and was ini-
5,6
and stabilization of microtubules, properties that lead
7
–10
to cell cycle arrest at mitosis and death by apoptosis.
The microtubule-based actions of (+)-discodermolide
are superior to those of other mechanistically-related
agents like paclitaxel (Taxol). This, coupled with its
effectiveness against paclitaxel- and other multidrug-
resistant cancers, make it a promising candidate for
(
1
2–4
tially proposed to be a potential immunosuppressant.
9
,11,12
clinical development as a chemotherapeutic agent.
+)-Discodermolide is, however, present in only minute
(
quantities in the sponge, which is itself difficult to
obtain. Several ingenious total syntheses of both (+)-
discodermolide and its less active (−)-enantiomer have
13–22
been reported.
The development of an economical
synthetic route to (+)-discodermolide, as well as to
simpler and more diverse analogs, is therefore an
important goal in the medicinal chemistry of this agent.
Smith et al. achieved the herculean task of preparing
(
+)-discodermolide on gram scale by constructing a
common precursor [(−)-CP: (2R,3S,4S)-3-hydroxy-5-(4-
methoxybenzyloxy)-2,4-dimethylpentanoic acid
Figure 1.
methoxymethylamide] to all three subunits of the
molecule. In one branch of their synthesis, (−)-CP was
further elaborated by TBS protection, PMB group
*
Corresponding author. Tel.: +1 412 648 9706; fax: +1 412 624 1850;
e-mail: bday@pitt.edu
Present address: TransTech Pharma Inc., High Point, North Caro-
lina, USA.
17
†
removal by hydrogenolysis with catalytic Pd(OH) /C
2
0
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00261-6

1
162
B. W. Day et al. / Tetrahedron: Asymmetry 13 (2002) 1161–1165
1
7
and subsequent oxidation of the resulting primary alco-
hol to furnish (2R,3S,4R)-3-(tert-butyldimethylsilanyl-
oxy)-2,4-dimethyl-5-oxopentanoic acid methoxymethyl-
amide 1. Their routes to 1 from the starting material,
in their hydrogenolysis reaction. Oxidation of alcohol
6a with SO ·pyridine then afforded aldehyde 1. Com-
3
pound 1 was identical in all respects with that reported,
with the only exception being a minor difference in
1
8
(
S)-3-hydroxy-2-methylpropionic acid methyl ester (aka
optical rotation ([h] −54.1 (c 0.79, CHCl ) for one
D
3
18
17
23
‘
Roche ester’), were performed in seven or eight steps
batch, [h]D −57.0 (c 13.5, CHCl ) for another; lit. [h]D
3
with a very respectable overall yield of 45–50%. Having
repeated these methods at various molar scales, we
found them to possess certain drawbacks, including,
−65.0 (c 1.38, CHCl )).
3
This ‘second generation’ five-step preparation of 1 was
achieved in an overall yield of 50% with no attempts to
optimize reaction conditions. This is comparable to the
yields reported previously, but is at least two steps
shorter. Furthermore, using prices from the most com-
mon chemical vendors in the calculation, the route in
Scheme 1 via 6a allows the synthesis of 1 for one-half
the cost necessary to prepare 1 by the method reported
in Ref. 17.
2
3,24
among others,
the fact that the starting Roche ester
is expensive. We envisaged 1 to be an important inter-
mediate in our preparation of various versions of the
left side lactone and right side diene displays of (+)-dis-
codermolide for analogue building, and therefore
sought a more efficient and economical synthesis of 1.
17
2
. Results and discussion
The d-lactone 6b from the hydroboration reaction was
easily ‘recycled’ to 1 by reproducible ring-opening
Weinreb amide formation followed by oxidation with
We reasoned that all stereochemistry in the target
molecule could be selectively and reliably installed, and
originate entirely from the easily recyclable chiral auxil-
iaries developed by Evans. Thus, the boron enolate
derived from the acylated oxazolidinone derivative of
1S,2R)-norephedrine was reacted with inexpensive
methacrolein 2 to give the desired aldol product 3 in
5% yield as the sole diastereomer (Scheme 1). Reac-
3
3
SO ·pyridine. The formation of 6b, which is a solid, in
3
24
the hydroboration reaction led to the supposition that
the Weinreb amide formation could be postponed in
the synthesis of 1. We reasoned that the more easily
displaced Evans auxiliary might, if used in place of a
Weinreb amide, lead directly to 6b during hydrobora-
tion. Therefore, the auxiliary-bearing aldol adduct 3
was TBS protected to give intermediate 7. Compound 7
was converted, as envisioned, directly and in high yield
(95%) by reaction with 9-BBN to 6b (Scheme 2), which
was converted to 1 by the methods outlined above.
Thus, this ‘third generation’ route to 1 via 6b is also a
five-step preparation that leads to an overall yield of
60%, again without attempts to optimize yields, and at
a lower cost even than our ‘second generation’
synthesis.
(
2
5
8
2
6,27
tion of 3 with Me Al and Me(OMe)NH·HCl
yielded
3
the Weinreb amide 4, whose secondary hydroxyl group
28
was silyl protected with TBSOTf to give compound 5.
gem-Disubstituted olefins can be converted to primary
alcohols with high levels of anti or syn diastereoselectiv-
ity between the newly formed and pre-existing stereo-
centers by using 9-borabicyclo[3.3.1]nonane (9-BBN) or
catecholborane/RhCl(Ph P)
(Wilkinson’s catalyst),
3
3
2
9–32
respectively.
Hydroboration of the terminal alkene
moiety in 5 with 9-BBN in THF therefore gave the
desired anti intermediate 6a in good yield (85%) as a
:1–11:1 mixture with a minor product 6b, a d-lactone
also encountered in the Smith synthesis as a byproduct
9
Compound 1 was then elaborated to the direct precur-
sors of the C1–C7 and C17–C24 fragments of (+)-disco-
dermolide (Scheme 3). Allyltrimethylsilane was added
with anti-Felkin selectivity (>50:1) to 1 in a TiCl -pro-
4
17
moted reaction. The product was cyclized with TFA
in hexane/CH Cl to afford the left side, C1–C7 frag-
2
2
1
8
ment of (+)-discodermolide, lactone 8 ([h] +13.8 (c
D
17
23
3 3
1
.30, CHCl ); lit. [h]D +14.2 (c 0.12, CHCl )) in 85%
yield from 1.
As further proof of principle, 1 was converted to the
right side C17–C24 fragment of (+)-discodermolide in
three steps. Compound 1 was transformed to the (Z)-
3
4
vinyl iodide 9 in 61% yield by Stork’s procedure, then
to diene 10 in 88% yield via palladium-catalyzed reac-
35
tion with vinyl zinc bromide. The Weinreb amide was
then readily cleaved with DIBALH to give aldehyde 11
in 81% yield.
Scheme 1. New ‘second generation’ synthesis of 1.
Scheme 2. ‘Third generation’ synthetic route.

B. W. Day et al. / Tetrahedron: Asymmetry 13 (2002) 1161–1165
1163
4
. Experimental
4
.1. General procedures
Reactions were carried out under a dry nitrogen atmo-
sphere in anhydrous solvents using oven-dried glass-
ware. Solvents and bases were distilled from CaH and
2
stored under argon over 4 A molecular sieves or CaH2.
,
Methacrolein was distilled immediately prior to use.
Melting points were determined on a Fisher–Johns
1
13
open stage apparatus and are uncorrected. H and
C
NMR spectra were recorded on Varian Mercury 400
spectrometer at 400 and 100 MHz, respectively, with
compounds dissolved in CDCl . Chemical shifts are
3
reported in ppm downfield from tetramethylsilane with
the solvent resonance acting as the internal standard
1
(
residual CHCl in CDCl l 7.26 ppm in H spectra;
3
3
13
CDCl l 77.0 ppm in C spectra). Data are reported as
3
follows: chemical shift, multiplicity (s=singlet, d=dou-
blet, t=triplet, q=quartet, br=broad, m=multiplet),
Scheme 3. Elaboration of 1 to the lactone and diene displays
of (+)-discodermolide.
13
coupling constant (Hz), integration. C NMR spectra
were recorded with complete proton decoupling. Gas
chromatography–mass spectrometry (GC–MS) was car-
ried out on a Hewlett Packard 5890 Series II gas
chromatograph equipped with a 30 m HP-5 (5% phenyl
methylsilicone) Hewlett Packard capillary column and a
Hewlett Packard 5971 mass selective detector in the
3. Conclusions
Methods used in previous syntheses of discodermolide
subunits have all relied upon an enantiomerically pure
substrate, most often the Roche ester, as a starting
material for stereoselective introduction of substituents
by various methodologies. Schreiber’s group utilized
the separate additions of Roush’s (E)- and (Z)-crotyl
positive chemical ionization (PCI) mode using CH as
4
the reagent bath gas. Low and high resolution electron
ionization (EI) mass spectra (LRMS and HRMS) were
determined on a Micromass Autospec double focusing
instrument by direct insertion probe at the High Reso-
lution Mass Spectrometry Facility at the Department of
Chemistry, University of Pittsburgh. Optical rotations
were recorded on a Perkin–Elmer 241 digital polarime-
13,14
boronates to the Roche ester in their synthesis.
Marshall and Johns used chiral allenyl metal reagents
in homoaldol reactions with the Roche ester to prepare
ter with a sodium lamp at ambient temperature and are
1
9
°C
l
alkyne intermediates to the subunits. Paterson et al.
prepared early intermediates in their recent full synthe-
sis through boron-mediated anti-selective aldol reaction
of chiral ketones built from the Roche ester and (S)-
reported as follows: [h]
(cg/100 mL). Only new enti-
ties are described below. All data reported is from
chromatographically homogeneous compounds.
2
0–22
ethyl lactate.
cedure,
With the exception of the Smith pro-
4.1.1. (3R,4S,5S)-4-(tert-Butyldimethylsilanyloxy)-3,5-
dimethyltetrahydropyran-2-one 6b. A solution of 9-BBN
(132 mL, 66 mmol, 0.5 M in THF) was treated with
(4R,5S) - 3 - [(3R,4R) - 3 - (tert - butyldimethylsilanyloxy)-
2,4-dimethylpent-4-enoyl]-4-methyl-5-phenyloxazolidin-
2-one 7 (9.2 g, 22 mmol) in THF (60 mL). The reaction
mixture was stirred at rt for 24 h, then treated sequen-
tially with 1:1 EtOH–THF (8 mL), 50 mM phosphate
buffer (pH 7, 8 mL) and 30% aq. H O (8 mL) and then
1
5–17
all other methods have suffered at least one
point in the synthetic scheme from the appearance of a
substantial level of undesired diastereomers. The meth-
ods reported here rely solely on the Evans auxiliary for
introduction of all stereochemistry and, at least for
preparation of left- and right-side arrays of discoder-
molide, give no undesired diastereomer output.
2
2
In summary, we have achieved two less costly and more
expedient syntheses of an important intermediate in the
preparation of (+)-discodermolide displays. These two
new stereoselective routes have several advantages,
including an overall shortening of the number of opera-
tions required to synthesise 1, the elimination of the
costly Roche ester from the synthetic scheme, and
provide alternatives for the timing of introduction of
the Weinreb amide protecting group. These improve-
ments are noteworthy and could significantly lower the
cost of producing 1 and the products derived from it.
These routes and displays will be useful in the medicinal
chemistry of (+)-discodermolide, a rare natural product
with exciting anti-cancer potential.
stirred for 12 h at rt. The mixture was extracted with
diethyl ether (3×30 mL). The combined organic layers
were washed with H O (20 mL) and saturated aq. NaCl
2
(20 mL) then dried over MgSO . Filtration, concentra-
4
tion in vacuo and purification by flash chromatography
(4:1 hexanes–ethyl acetate) gave 6b as a white crys-
talline solid (5.4 g, 94%). Mp: 55–55.5°C (pentane);
1
8
1
[h] +20.4 (c 0.22, CHCl ); H NMR l 4.30 (m, 1H),
D
3
4.12 (m, 1H), 3.66 (t, J=3.7, 1H), 2.68 (dq, J=7.9,
1H), 2.14 (m, 1H), 1.25 (d, J=7.9, 3H), 0.93 (d, J=7.5,
1
3
3H), 0.85 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); C NMR
l 173.7, 73.5, 70.1, 43.6, 30.3, 25.7, 17.9, 16.2, 12.0;
GC–MS (PCI) m/z (relative abundance, %): 259 ([M+
+
H] , 26), 157 (18), 145 (17), 127 (95), 115 (39), 99 (15),

1
164
B. W. Day et al. / Tetrahedron: Asymmetry 13 (2002) 1161–1165
+
8
3 (100), 75 (59); LRMS (EI) m/z (relative abundance,
m/z (relative abundance, %): 342 ([M+H] , 45), 326
(58), 284 (61), 260 (57), 210 (100); LRMS (EI) m/z
+
’
): 201 (M−C H , 15), 171 (7), 157 (70), 145 (93), 115
4 9
%
+
’
(
86), 101 (9), 99 (10), 85 (11) 75 (100), 73 (49), 59 (37);
(relative abundance, %): 341 (M , 1) 326 (4), 284 (66),
+
’
HRMS (EI) m/z 201.0947 found (M−C H ), 201.0941
calculated for C H O Si.
260 (73), 204, 149, 73; HRMS (EI) m/z: 341.2398 found
4
9
+
’
(M ), 341.2386 calculated for C H NO Si.
18 35 3
9
17
3
4
.1.2. (2R,3S,4S,5Z)-3-(tert-Butyldimethylsilanyloxy)-6-
iodo-2,4-dimethylhex-5-enoic acid methoxymethylamide
. A suspension of (iodomethyl)triphenylphosphonium
4
.1.4. (2R,3S,4S,5Z)-3-(tert-Butyldimethylsilanyloxy)-
,4-dimethylocta-5,7-dienal 11. A solution of amide 10
2
9
(
0.45 g, 1.32 mmol) in THF (10 mL) was treated with
iodide (2.90 g, 5.36 mmol) in THF (15 mL) was treated
with NaHMDS (1.0 M in THF, 5.36 mL, 5.36 mmol)
and the resulting solution was stirred for 20 min at
rt. The resulting dark red solution was cooled to
DIBALH (1 M in hexanes, 2.77 mL) at −78°C. The
solution was stirred at −78°C for 2 h, then treated with
CH OH (2 mL) followed by saturated aqueous solution
of Rochelle’s salt (10 mL). The mixture was diluted
with ethyl acetate (20 mL) and stirred for 3 h at
ambient temperature. The organic phase was separated,
washed with saturated aq. NaHCO and saturated aq.
NaCl, dried over MgSO , filtered and concentrated
under vacuum. Flash chromatography of the residue
3
−
78°C and HMPA (1.2 mL) was added followed
by (2R,3S,4R)-3-(tert-butyldimethylsilanyloxy)-2,4-di-
methyl-5-oxopentanoic acid methoxymethylamide 1
3
(
0.85 g, 2.68 mmol) in THF (5 mL). After 20 min of
4
stirring at −78°C, the reaction mixture was warmed to
rt and stirred for an additional 1 h. The mixture was
diluted with hexane (20 mL), filtered through silica gel
(
20:1 hexane–diethyl ether) provided 11 (300 mg, 81%).
18 1
D 3
[h] −16.7 (c 1.30, CHCl ) H NMR l 9.76 (s, 1H),
(
60 g), and concentrated in vacuo. Chromatography of
6
1
5
.51 (ddd, J=16.8, 10.7, 10.6 Hz, 1H ), 6.0 (dd, J=
1.0, 11.0 Hz, 1H ), 5.44 (dd, J=10.7, 10.7 Hz, 1H),
7
the resulting residue (10:1 hexane–diethyl ether)
6
1
8
afforded 9 (720 mg, 61%). [h] +65.9 (c 1.0, CHCl3);
D
.23 (d, J=16.8 Hz, 1H), 5.12 (d, J=10.2 Hz, 1H), 3.99
1
H NMR l 6.35 (dd, J=7.3, 8.7 Hz, 1H), 6.20 (d,
(
dd, J=4.7, 4.7 Hz, 1H), 2.85 (m, 1H), 2.52–2.46 (m,
J=7.3 Hz, 1H), 3.97 (d, J=9.6 Hz, 1H), 3.7 (s, 3H),
3
2
0
2
1
H), 1.08 (d, J=7.0 Hz, 3H), 1.04 (d, J=6.7 Hz, 3H),
.18 (s, 3H), 2.82 (unresolved m, 1H), 2.63 (ddq, J=
0.3, 3.3, 7.0 Hz, 1H), 1.14 (d, J=7.0 Hz, 3H), 1.01 (d,
13
.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); C NMR l
1
04.2, 133.2, 132.1, 130.4, 118.2, 75.9, 51.5, 36.2, 25.9,
J=6.9 Hz, 3H), 0.94 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H).
8.7, 18.2, 9.5, −4.1, −4.2; GC–MS (PCI) m/z (relative
1
3
C NMR l 142.5, 82.7, 76.3, 61.2, 44.4, 26.2, 22.6,
+
abundance, %): 283 ([M+H] , 3), 267 (8), 225 (100),
1
8.4, 17.4, 15.4, −3.4, −3.5; GC–MS (PCI) m/z (relative
2
01, (19), 151 (25), 123 (18), 107 (27), 95 (7), 93 (14), 81
+
abundance, %): 442 ([M+H] , 31), 426 (32), 384 (74),
(
11), 75 (6), 73 (4); LRMS (EI) m/z (relative abun-
310 (55), 260 (100), 57 (79); LRMS (EI) m/z (relative
+
’
dance, %): 225 (M−C H9 , 52), 201 (73), 173 (44), 145
4
+
’
abundance, %): 441 (M , 1), 426 (3), 384 (7), 188 (18),
81 (28), 75 (56), 73 (60), 59 (45), 57 (100); HRMS (EI)
(
33), 115 (77), 93 (32), 81 (30), 75 (65) 73 (100), 59 (45);
1
+
’
9
HRMS (EI) m/z: 225.1302 found (M−C H ),
2
4
+
’
m/z: 441.1212 found (M ), 441.1196 calculated for
25.1311 calculated for C H O Si.
12 21 2
C H NO SiI.
16
32
3
4
2
1
6
6
.1.3. (2R,3S,4S,5Z)-3-(tert-Butyldimethylsilanyloxy)-
,4-dimethylocta-5,7-dienoic acid methoxymethylamide
0. Vinylmagnesium bromide (1.0 M in THF, 6.35 mL,
Acknowledgements
.35 mmol) was added to a solution of ZnBr (1.43 g,
2
Supported by grants from the National Cancer Institute
CA78039 and CA88833). We thank Professor Amos
Smith for providing a spectrum of compound 8 for
comparison. We sincerely thank Professors Dennis Cur-
ran and Peter Wipf and their research groups, particu-
larly Drs. Nakyen Choy and Jose Minguez and Mr.
Jonathan T. Reeves, for invaluable discussions.
.35 mmol) in THF (5 mL) under argon and the white
(
slurry was stirred for 15 min at rt. The resulting gray
reaction mixture was cooled to 0°C and treated with
vinyl iodide 9 (0.70 g, 1.59 mmol) in THF (3 mL)
followed by addition of Pd(PPh ) (0.18 g, 0.16 mmol)
in THF (8 mL). The mixture was stirred and allowed to
warm to rt. After 24 h at rt, the reaction was quenched
3
4
by the addition of saturated aq. NH Cl (30 mL). The
4
aqueous layer was separated and extracted with hexane
(
3×20 mL). The combined organic layers were washed
References
with saturated aq. NaCl (30 mL), dried over anhydrous
MgSO , and concentrated in vacuo. Flash chromatog-
1. Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.;
Schulte, G. K. J. Org. Chem. 1990, 55, 4912–4915; correc-
tion: ibid. 1991, 56, 1346.
2. Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasek-
era, M.; Gunasekera, S. P. Transplantation 1991, 52,
650–656.
3. Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasek-
era, M.; Gunasekera, S. P. Transplantation 1991, 52,
656–661.
4. Longley, R. E.; Gunasekera, S. P.; Faherty, D.; McLane,
J.; Dumont, F. Ann. NY Acad. Sci. 1993, 696, 94–107.
4
raphy of the residue (20:1 diethyl ether–hexane) pro-
1
8
1
vided 10 (480 mg, 88%). [h] +53.2 (c 0.01, CHCl ); H
D
3
NMR l 6.50 (ddd, J=16.7, 10.6, 10.2 Hz, 1H ), 6.01
7
(
dd, J=11.4, 11.4 Hz, 1H ), 5.62 (dd, J=10.4, 10.4 Hz,
6
1
1
3
H), 5.17 (d, J=17.0 Hz, 1H), 5.07 (d, J=10.7 Hz,
H), 3.93 (d, J=10.8 Hz, 1H), 3.61 (s, 3H), 3.13 (s,
H), 2.85–2.78 (m, 2H), 1.13 (d, J=7.2 Hz, 3H), 1.03
(
3
2
d, J=7.0 Hz, 3H), 0.94 (s, 9H), 0.02 (s, 3H), 0.01 (s,
H); C NMR l 133.9, 132.7, 129.6, 117.1, 61.0, 36.7,
6.2, 26.1, 19.4, 18.5, 15.4, −3.4, −3.5; GC–MS (PCI)
13

B. W. Day et al. / Tetrahedron: Asymmetry 13 (2002) 1161–1165
1165
5. Ter Haar, E.; Rosenkranz, H. S.; Hamel, E.; Day, B. W.
Bioorg. Med. Chem. 1996, 4, 1659–1671.
23. Walkup, R. D.; Kahl, J. D.; Kane, R. R. J. Org. Chem.
1998, 63, 9113–9116.
6
. Ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M.;
Longley, R. E.; Gunasekera, S. P.; Rosenkranz, H. S.;
Day, B. W. Biochemistry 1996, 35, 243–250.
24. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77–82.
25. Smith et al. prepared 3 in comparable yield with the same
reactants during their full synthesis of (+)-trienomycins A
and F: Smith, A. B., III; Barbosa, J.; Wong, W.; Wood,
J. L. J. Am. Chem. Soc. 1996, 118, 8316–8328.
7
8
9
. Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. Chem.
Biol. 1994, 1, 67–71.
. Hung, D. T.; Chen, J.; Schreiber, S. L. Chem. Biol. 1996,
2
2
2
6. Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun.
982, 12, 989–993.
7. Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc.
988, 110, 2506–2526.
8. This pathway to 5, with the exception of our use of
TBSOTf, is therefore a mixture of methods used, for
different targets, in Ref. 25 and in: Sch o¨ ning, K.-W.;
Wittenberg, R.; Kirschning, A. Synlett 1999, 1624–1626.
Sch o¨ ning et al. also reported a preparation of compound
3
, 287–293.
1
. Kowalski, R. J.; Giannakakou, P.; Gunasekera, S. P.;
Longley, R. E.; Day, B. W.; Hamel, E. Mol. Pharmacol.
1
1
997, 52, 613–622.
1
0. Balachandran, R.; ter Haar, E.; Welsh, M. J.; Grant, S.
G.; Day, B. W. Anti-Cancer Drugs 1998, 9, 67–76; corri-
gendum ibid. 1998, 9, 369.
1
1. Balachandran, R.; Grant, S. G.; Welsh, M. J.; Day, B.
W. Breast J. 1998, 4, 409–419.
4, but gave no physical or spectral data. We found that,
1
2. Martello, L. A.; McDaid, H. M.; Regl, D. L.; Yang, C.
P.; Meng, D.; Pettus, T. R.; Kaufman, M. D.; Arimoto,
H.; Danishefsky, S. J.; Smith, A. B., III; Horwitz, S. B.
Clin. Cancer Res. 2000, 5, 1978–1987.
3. Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber,
S. L. J. Am. Chem. Soc. 1993, 115, 12621–12622.
4. Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am.
Chem. Soc. 1996, 118, 11054–11080.
after precipitating the auxiliary with 1:1 diethyl ether–
hexanes at 4°C overnight and evaporation of solvent
from the filtrate, the resulting oil yielded 4 as a white
solid (mp 73–74°C) on standing at rt for 10 min.
1
1
1
1
2
3
3
3
9. Still, W. C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105,
2487–2489.
0. Evans, D. A.; Fu, G. C.; Hoveyda, A. H. A. J. Am.
Chem. Soc. 1992, 114, 6671–6679.
1. Evans, D. A.; Fu, G. C.; Anderson, B. A. J. Am. Chem.
Soc. 1992, 114, 6679–6685.
2. Burgess, K.; Donk, W. A.; Westcott, S. A.; Marder, T.
B.; Baker, R. T.; Calabrese, J. C. J. Am. Chem. Soc.
5. Smith, A. B., III; Qin, Y.; Jones, D. R.; Kobayashi, K. J.
Am. Chem. Soc. 1995, 117, 12011–12012.
6. Smith, A. B., III; Kaufman, M. D.; Beauchamp, T. J.;
LaMarche, M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823–
1
826; correction: ibid. 2000, 2, 1983.
1992, 114, 9350–9359.
1
7. Smith, A. B., III; Beauchamp, T. J.; LaMarche, M. J.;
Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654–8664.
8. Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J.
Org. Chem. 1997, 62, 6098–6099.
18
3
3. Mp 55–55.5°C (pentane); [h]D +20.4 (c 0.22, CHCl3).
Smith et al. reported formation of 6b in Ref. 17, but gave
no physical or spectral data. Its enantiomer has been
reported in detail by: (a) Paterson, I.; Patel, S. K.; Porter,
1
1
2
2
2
23
J. R. 1983, 24, 3395–3396 (mp: 59.5–60°C; [h] −23.1 (c
9. Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63,
D
1
.73, CHCl )); and (b) Stork, G.; Paterson, I.; Lee, F. K.
7
885–7892.
3
C. J. Am. Chem. Soc. 1982, 104, 4686–4688 (mp: 52–
0. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.
Angew. Chem., Int. Ed. Engl. 2000, 39, 377–380.
1. Paterson, I.; Florence, G. J. Tetrahedron Lett. 2000, 41,
25
5
5°C; [h]D −19 (c 0.8, CHCl )).
3
3
4. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173–
174.
2
6
935–6939.
2. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.;
35. Gardette, M.; Jabri, N.; Alexakis, A.; Normant, J. F.
Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535–9544.
Tetrahedron 1984, 40, 2741–2750.