A short synthesis of the C15-C21 segment of (+)-discodermolide, based on an asymmetric approach from achiral 2-methyl-1,3-propanediol to versatile enantiopure stereotriads

Article abstract of DOI:10.1016/S0040-4039(02)01373-4

A new approach was developed to versatile enantiopure stereotriads using chiral oxazaborolidinone-promoted asymmetric aldol reaction of a racemic aldehyde with a bromo silyl nucleophile. A short synthesis of the C₁₅-C₂₁ segment of (+

Full text of DOI:10.1016/S0040-4039(02)01373-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6373–6376
A short synthesis of the C15–C21 segment of (+)-discodermolide,
based on an asymmetric approach from achiral
2-methyl-1,3-propanediol to versatile enantiopure stereotriads
Kazi A. Shahid,a Yong-Nan Li,b Momotoshi Okazaki,a Yoshihiro Shuto,a Fumitaka Gotoc and
Syun-ichi Kiyookab,*
aThe United Graduate School of Agricultural Sciences, Ehime University, Tarumi, Matsuyama 790-8566, Japan
bInstitute for Fundamental Research of Organic Chemistry, Kyushu University, Higashi-ku, Fukuoka 812-8581, Japan
cCellular Technology Institute, Otsuka Pharmaceutical Co., Ltd, Kawauchi-cho, Tokushima 771-0130, Japan
Received 9 June 2002; revised 4 July 2002; accepted 5 July 2002
Abstract—A new approach was developed to versatile enantiopure stereotriads using chiral oxazaborolidinone-promoted
asymmetric aldol reaction of a racemic aldehyde with a bromo silyl nucleophile. A short synthesis of the C15–C21 segment of
(+)-discodermolide was achieved by elongation of one of the stereotriads with further diastereoselective aldol reaction with the
same nucleophile. © 2002 Elsevier Science Ltd. All rights reserved.
(+)-Discodermolide is a polypropionate-derived natural
product known as a potent microtubule-stabilizing
agent which retains activity against Taxol®-resistant
cancer.1 Due to the potential therapeutic development
and the extreme scarcity of the natural product, the
chemical synthesis of this compound is necessary, espe-
cially for making possible its supply in large scale.
Although the total syntheses of (+)- and (−)-isomers
were achieved by several groups to date,2 the highly
stereoselective construction of the complex framework
is still a challenging and attractive target for synthetic
chemists. Our retrosynthetic analysis dissected the
target molecule at both sides of C-14 to generate seg-
ments A and B, which contain the necessary 13 stereo-
genic centers (Scheme 1). A two-carbon unit at C-14 is
incorporated into segment B as a (Z)-vinyl iodide by
15
HO
OH
13
21
21
15
OH OH
O
O
OH
OH
O
C15-C21 Segment A
NH2
14
HO
HO
OH
13
1
O
OH
HO
R
1
O
OH OH OH
C1-C13 Segment B
O
(+)-Discodermolide
HO
OH
O
stereotriads
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01373-4

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K. A. Shahid et al. / Tetrahedron Letters 43 (2002) 6373–6376
the known method2d,2e,3 before the developed palla-
dium(0) cross-coupling reaction between C-13 and C-
14. Segments A and B have similar fragments, as
depicted by squares in Scheme 1, which bound to
stereotriads.4 If an easier synthetic access to enantio-
pure equivalents of the stereotriads is developed, it may
more directly permit a systematic approach to the
stereogenic center at C-3 (>98% ee, determined by
chiral HPLC), which is controlled only by the stereo-
center of promoter D-3 without any influence of the
existing a-chirality of aldehyde 2; the so-called ‘catalyst
(promoter) control in acyclic stereoselection’.10 The
desired 5 was easily separated by silica-gel flash column
chromatography. When a solution of 5 in CH2Cl2 was
exposed to Bu3SnH (5 equiv.) and Et3B (1 equiv.) in the
presence of MgBr2·OEt2 (7 equiv.) at 0°C for 3 h, a
smooth debromination reaction took place to give 2,3-
syn-3,4-anti stereotriad 711 in 80% yield. syn Selection
(chelation control) was observed in a 10:1 ratio of syn
and anti.12 On the other hand, anti selection of the
debromination (Bu3SnH/Et3B/toluene) was achieved
with the corresponding MOM-protected compound in
good selectivity (10:1). Although further improvement
of the debromination processes is being awaited for
excellent diastereoselection, our present method to give
four enantiopure stereotriads, 7ꢀ10, is remarkably
efficient along with easy purification (Scheme 2).
Indeed, when chiral borane L-3 (derived from L-valine)
is applied to the sequence, the other four stereotriads
are available.
synthesis of polyketides containing
a variety of
polypropionate units. Smith has effectively utilized a
stereotriad5 as a common precursor in the total synthe-
sis of (+)-discodermolide.2e We describe herein a ver-
satile asymmetric approach from an achiral diol 1 via a
racemic aldehyde, 2, to enantiopure stereotriads, 7ꢀ10,
and a short synthesis of C15–C21 segment A of (+)-dis-
codermolide by using one of them, which has the same
stereochemistry with different functionality to Smith’s
stereotriad.
Our strategy toward the quite effective enantioselective
synthesis of versatile stereotriads is designed in a
sequence of the chiral oxazaborolidinone-promoted
asymmetric aldol reactions of the racemic aldehyde 2,
derived from the cheap achiral diol 1,6 with silylketene
acetal 47 and the following radical debromination reac-
tion.8 After mono protection of 1 with TBSCl/NaH,
Swern oxidation gave 2 in good yield. In the presence
of a stoichiometric amount of chiral borane D-3, which
was prepared in situ by stirring D-TsVal and BH3·THF
in CH2Cl2 at 0°C, the aldol reaction of 2 with 4 was
carried out at −78°C for 3 h.8 The reaction proceeded
smoothly to give a mixture of products in 85% yield.
The mixture was constituted of an almost 1:1 ratio of
2,3-syn-3,4-anti 5 and 2,3-syn-3,4-syn 6 with a small
amount of isomers at C-2. The 2,3-syn selection, though
considered unnecessary for the sequence, is known to
be characteristic of the chiral oxazaborolidinone-pro-
moted aldol reaction with 4.9 The most important point
of the strategy is the almost complete selection of the
The synthesis of a synthetic equivalent 19 to segment A
is shown in Scheme 3. Alcohol 7 was protected with the
treatment of PMBCO(ꢀNH)CCl3 and TfOH to the
corresponding p-methoxybenzyl ether 13 in 67% yield.
DIBALH reduction of 13 gave directly aldehyde 14.
The BF3·OEt2-mediated diastereoselective aldol reac-
tion (CH2Cl2, −78°C, 1 h) of 14 with 4 resulted in the
highly 3,4-syn selective formation of 2,3-syn-3,4-syn
aldol adduct 1513 in 65% yield along with very high
selection at C-2.14 The following debromination reac-
tion (Bu3SnH, Et3B, CH2Cl2) in the presence of
MgBr2·OEt2 at −78°C for 3 h15 gave the desired 2,3-
syn-3,4-syn-4,5-syn-5,6-anti compound 1716 in 81%
yield (2,3-syn selectivity=7:1). This diastereoselective
sequence using the Mukaiyama aldol reaction and the
O
H
a,b
TBSO
HO
OH
2
1
OH
O
d
4
2
7
TBSO
1
OEt
3
OH
O
O
c
4
2
3
1
OH
O
O
O
TBSO
TBSO
OEt
O
TsN
Br
e
d
B
TBSO
TBSO
TBSO
OEt
OEt
OEt
8
D-3
5
H
OH
OH
Br
OTMS
OEt
9
Me
OH O
4
c
OEt
Br
e
10
6
Scheme 2. Reagents and conditions: (a) TBSCl, NaH, THF, rt, 15 h, 88% yield. (b) (COCl)2, DMSO, CH2Cl2, −78°C, Et3N, 0°C,
82% yield. (c) Chiral oxazaborolidinone-promoted aldol reaction of 2 with 4 in the presence of a stoichiometric amount of D-3
in CH2Cl2 at −78°C for 3 h gave a 1:1 mixture of enantiopure 5 and 6 in 85% yield and then by using flash column
chromatography 5 was easily separated. (d) Bu3SnH, Et3B, MgBr2·OEt2 at 0°C for 3 h: Chelation-controlled debromination
resulted in good 2,3-syn selection. With syn selection (10:1) 7 was obtained in 80% yield. (e) Bu3SnH, Et3B: After MOM protection
of hydroxy group at C-3, 2,3-anti stereoisomer was predominantly obtained.

K. A. Shahid et al. / Tetrahedron Letters 43 (2002) 6373–6376
6375
OH
O
TBSO
O
OEt
HO
OH
1
7
PMBO
PMBO
O
a
b
TBSO
OEt
TBSO
H
13
14
Br
Me
OTMS
OEt
PMBO
OH O
4
c
d
4
3
TBSO
OEt
Br
15 3,4-syn selectivity : ~98% de
TBS
PMBO
OH
O
PMBO
O
O
e
2
3
TBSO
OEt
2,3-syn : anti = 7 : 1
TBSO
OEt
OH
17
19
15
HO
21
OH OH
O
Segment A
Scheme 3. Reagents and conditions: (a) PMBCO(ꢀNH)CCl3, TfOH, Et2O, rt, 15 h, 67% yield. (b) DIBALH, CH2Cl2, −78°C, 3 h,
86% yield. (c) BF3·OEt2, 4, CH2Cl2, −78°C, 1 h, 65% yield. (d) Bu3SnH, Et3B, CH2Cl2, MgBr2·OEt2, −78°C, 3 h, 81% yield. (e)
TBSOTf, 2,6-lutidine, 95% yield.
following debromination reaction apparently turned
out to be effective as an approach to the construction
of polypropionate frameworks. A similar approach also
has been reported.17 Protection of alcohol 17 was car-
ried out without incident to TBS ether 19, which is a
synthetic equivalent of segment A, in 95% yield.18
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; (c) Balachandran, R.; ter
Haar, E.; Welsh, M. J.; Grant, S. G.; Day, B. W.
Anti-Cancer Drugs 1998, 9, 67.
2. (a) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.;
Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 12621; (b)
Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J.
Am. Chem. Soc. 1995, 117, 12011; (c) Harried, S. S.;
Yang, G.; Strawn, M. A.; Myles, D. C. J. Org. Chem.
1997, 62, 6098; (d) Marshall, J. A.; Johns, B. A. J. Org.
Chem. 1998, 63, 7885; (e) Smith, A. B., III; Kaufman, M.
D.; Beauchamp, T. J.; LaMarche, M. J.; Arimoto, H.
Org. Lett. 1999, 1, 1823; (f) Smith, A. B., III;
Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.;
Qiu, Y. P.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J.
Am. Chem. Soc. 2000, 122, 8654; (g) Paterson, I.; Flo-
rence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem., Int.
Ed. 2000, 39, 377; (h) Paterson, I.; Florence, G. J.;
Gerlach, K.; Scott, J. P.; Sereing, N. J. Am. Chem. Soc.
2001, 123, 9535.
In conclusion,
a versatile, systematic asymmetric
approach was developed to enantiopure stereotriads
available for the synthesis of polyketides, based on
catalyst (promoter) control with respect to the chiral
oxazaborolidinone-promoted asymmetric aldol reaction
of racemic aldehyde 2 with 4. The above results suggest
that the sequence of enantioselective and/or
diastereoselectiove aldol reactions with silylketene ace-
tal 4 and the following diastereoselective debromination
reactions surely provide a practical methodology for a
series of polypropionate syntheses. A short synthesis of
the C15–C21 segment of (+)-discodermolide has been
achieved, based on the strategy.
3. Arefolov, A.; Langille, N. F.; Panek, J. S. Org. Lett.
2001, 3, 3281.
Acknowledgements
4. (a) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39,
2054; (b) Arjona, O.; Menchaca, R.; Plumet, J. J. Org.
Chem. 2001, 66, 2400.
This research was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Science, Sports and Culture, Japan.
5. The Weinreb ester of 2,3-syn-3,4-anti isomer was
obtained via a double differential, asymmetric aldol reac-
tion of a chiral aldehyde with a chiral Evans’ nucleophile
in ꢀ50% yield over five steps, according to a similar
procedure of Heathcock, see: Clark, D. L.; Heathcock, C.
H. J. Org. Chem. 1993, 58, 5878.
References
1. (a) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.;
Schulte, G. K. J. Org. Chem. 1990, 55, 4912; (b) ter Haar,

6376
K. A. Shahid et al. / Tetrahedron Letters 43 (2002) 6373–6376
6. 2-Methyl-1,3-propanediol was purchased from Aldrich (1
L, Yꢀ 4.100; 2000–2001 catalog).
7. The silylketene acetal 4 (Z:E=3:1), which accompanies
the corresponding C-silyl ester, by trapping the lithium
enolate with TMSOTf.
8. Kiyooka, S.-i.; Shahid, K. A. Bull. Chem. Soc. Jpn. 2001,
74, 1485 and references cited therein.
9. Kiyooka, S.-i.; Shahid, K. A. Tetrahedron: Asymmetry
2000, 11, 1537.
Compound 5: [h]2D6 +17.5 (c 4.24, CHCl3). IR (neat) 3528,
1
2935, 1720 cm−1. H NMR (CDCl3, 400 MHz) l (ppm)
0.0 (s, 6H), 0.80 (d, J=7.1 Hz, 3H), 0.82 (s, 9H), 1.24 (t,
J=7.1 Hz, 3H), 1.69–1.82 (m, 1H), 1.82 (s, 3H), 3.60 (dd,
J=10.0, 5.84 Hz, 1H), 3.72 (dd, J=10.0, 4.4 Hz, 1H),
3.91 (d, J=3.7 Hz, 1H), 4.10 (dd, J=7.1, 3.68 Hz, 1H),
4.16 (m, 2H). 13C NMR (CDCl3, 100 MHz) l (ppm)
−5.6, −5.6, 13.8, 14.8, 18.2, 22.0, 25.8, 37.9, 62.0, 67.1,
68.0, 78.1, 170.7.
Compound 7: [h]2D9 +10.9 (c 2.58, CHCl3). IR (neat) 3493,
10. Kiyooka, S.-i.; Kira, H.; Hena, M. A. Tetrahedron Lett.
2932, 1732 cm−1. H NMR (CDCl3, 400 MHz) l (ppm)
1996, 37, 2597.
1
11. The stereochemistry of 7 was confirmed by J values and
NOE measurements of 11 and 12.
0.06 (s, 6H), 0.81 (s, 9H), 0.88 (d, J=6.8 Hz, 3H), 1.18
(d, J=7.1 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.68–1.74 (m,
1H), 2.57 (dq, J=6.8, 2.4 Hz, 1H), 3.64 (dd, J=9.8, 6.1
Hz, 1H), 3.72 (d, J=3.7 Hz, 1H), 3.80–3.86 (m, 2H), 4.14
(q, J=7.1 Hz, 2H). 13C NMR (CDCl3, 100 MHz) l
(ppm) −5.7, 10.2, 13.7, 14.1, 18.1, 25.8, 37.0, 42.8, 60.4,
67.5, 76.2, 175.7.
12. Kiyooka, S.-i.; Shahid, K. A.; Hena, M. A. Tetrahedron
Lett. 1999, 40, 6447.
13. The stereochemistry of 15 was determined by J values
and NOE measurements of 16.
Compound 15: [h]2D8 +18.2 (c 0.11, CHCl3). IR (neat)
3539, 2955, 2932, 2858, 1736 cm−1. 1H NMR (CDCl3, 400
MHz) l (ppm) 0.06 (s, 3H), 0.07 (s, 3H), 0.85 (d, J=6.8
Hz, 3H), 0.91 (s, 9H), 0.92 (d, J=6.8 Hz, 3H), 1.34 (t,
J=7.1 Hz, 3H), 1.74–1.83 (m, 2H), 1.88 (s, 3H), 2.73 (d,
J=2.9 Hz, 3H), 3.48 (dd, J=9.0, 2.4 Hz, 1H), 3.60 (dd,
J=9.8, 2.7 Hz, 1H), 3.80 (s, 3H), 3.82 (dd, J=9.8, 4.2
Hz, 1H), 3.17 (dd, J=2.7, 1.2 Hz, 1H), 4.18 (dq, J=7.1,
1.7 Hz, 2H), 4.39 (ABq, J=10.7 Hz, v=37.5 Hz, 2H),
6.88 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H). 13C
NMR (CDCl3, 100 MHz) l (ppm) −5.5, −5.3, 7.7, 14.0,
14.6, 18.3, 23.1, 25.9, 36.5, 38.1, 55.3, 62.1, 64.5, 66.6,
74.4, 78.1, 85.5, 114.0, 129.6, 130.7, 159.4, 170.6.
Compound 19: [h]2D4 +20.0 (c 0.10, CHCl3). IR (neat)
14. Kiyooka, S.-i.; Shahid, K. A.; Murai, K.; Li, Y.-N.;
Okazaki, M.; Shuto, Y. Tetrahedron: Asymmetry 2001,
12, 2343.
15. Even in the presence of non-protected b-OH, the chela-
tion-controlled products can be predominantly obtained
(Ref. 12).
16. The stereochemistry of 17 was determined by J values
and NOE measurements of 18.
2957, 2930, 2857, 1738 cm−1 1H NMR (CDCl3, 400
.
MHz) l (ppm) 0.0 (s, 3H), 0.03 (s, 3H), 0.04 (s, 3H), 0.07
(s, 3H), 0.89 (s, 9H), 0.90 (s, 9H), 0.95 (d, J=6.8 Hz,
3H), 1.02 (d, J=6.8 Hz, 3H), 1.06 (d, J=7.1 Hz, 3H),
1.24 (t, J=7.1 Hz, 3H), 1.91–1.99 (m, 1H), 2.01–2.08 (m,
1H), 2.73 (dq, J=7.1, 5.4 Hz, 1H), 3.39 (t, J=5.6 Hz,
1H), 3.62 (dd, J=10.0, 6.6 Hz, 1H), 3.68 (dd, J=9.8, 3.9
Hz, 1H), 3.80 (s, 3H), 3.88 (t, J=5.4 Hz, 1H), 4.06–4.15
(m, 2H), 4.51 (ABq, J=11.0 Hz, v=51.8 Hz, 2H), 6.86
(d, J=8.5 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H). 13C NMR
(CDCl3, 100 MHz) l (ppm) −5.4, −5.3, −4.1, −3.9, 10.4,
14.2, 14.4, 15.3, 18.3, 18.4, 26.0, 26.1, 38.6, 38.8, 44.8,
55.3, 60.2, 64.4, 74.4, 75.4, 81.8, 113.7, 129.0, 131.5,
159.1, 174.4.
17. In a more simple system, the diastereoselective synthesis
of 2,3-anti-3,4-anti and 2,3-anti-3,4-syn propionates has
recently been reported by using a tandem sequence of
Mukaiyama aldol reaction of a-methyl-b-protected-
oxypropanal with a selenoenoxysilane and the following
hydrogen transfer reaction: Guindon, Y.; Pre´vost, M.;
Mochirian, P.; Gue´rin, B. Org. Lett. 2002, 4, 1019.
18. Spectroscopic data for selected compounds.