A straightforward, highly stereoselective construction of eight stereogenic centers in (+)-discodermolide C1-C13 segment, based on a strategy of iterative aldol reactions

Article abstract of DOI:10.1016/S0040-4039(02)01389-8

The eight stereogenic centers were introduced into the C₁-C₁₃ segment of (+)-discodermolide by iterative aldol reactions with quite a high level of selection.

Full text of DOI:10.1016/S0040-4039(02)01389-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6377–6381
A straightforward, highly stereoselective construction of eight
stereogenic centers in (+)-discodermolide C1–C13 segment, based
on a strategy of iterative aldol reactions
Kazi A. Shahid,a Jahan Mursheda,a Momotoshi Okazaki,a Yoshihiro Shuto,a Fumitaka Gotob and
Syun-ichi Kiyookac,*
aThe United Graduate School of Agricultural Sciences, Ehime University, Tarumi, Matsuyama 790-8566, Japan
bCellular Technology Institute, Otsuka Pharmaceutical Co., Ltd, Kawauchi-cho, Tokushima 771-0130, Japan
cInstitute for Fundamental Research of Organic Chemistry, Kyushu University, Higashi-ku, Fukuoka 812-8581, Japan
Received 9 June 2002; revised 4 July 2002; accepted 5 July 2002
Abstract—The eight stereogenic centers were introduced into the C1–C13 segment of (+)-discodermolide by iterative aldol reactions
with quite a high level of selection. © 2002 Elsevier Science Ltd. All rights reserved.
(+)-Discodermolide, (+)-1, is a polypropionate-derived
natural product known as a potent microtubule-stabi-
lizing agent,1 and synthetical supply is necessary for
8 has been described in detail in the preceding paper4 in
connection with dissymmetrization of the starting diol
3. The first chiral borane-promoted aldol reaction quite
effectively resulted in the introduction of the stereo-
utilizing
its
remarkable
characteristics
of
immunosuppression1a and cytotoxicity.1b In addition,
its unique polyketide structure bearing 13 stereogenic
centers is an attractive pure target for synthetic
chemists. Since the absolute configuration of discoder-
molide was determined by Schreiber,2a,b numerous syn-
thetic studies are continuing to date.2,3 However, there
have been few approaches based on Lewis acid-medi-
ated aldol reactions, because no reliable methodology
has been established for diastereoselectively construct-
ing syn- and anti-propionates in sequence. Our syn-
thetic target is the C1–C13 segment, 2, of (+)-1, having
eight stereogenic centers, as shown in Scheme 1, where
the four slant lines present the suitable positions for the
planned bond formations with sequential four aldol
reactions. We disclose herein a unique approach intro-
ducing all the stereocenters of 2 by iterative Lewis
acid-mediated aldol reactions with high stereoselection.
The elaboration to the target 2 was started with the
chiral oxazaborolidinone (L-5)-promoted asymmetric
aldol reaction of racemic aldehyde 4, derived from
achiral diol 3, with tetra-substituted silylketene acetal 6.
The selectivity behavior in the asymmetric transforma-
tion from racemic aldehyde 4 to enantiopure stereotriad
* Corresponding author.
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01389-8

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K. A. Shahid et al. / Tetrahedron Letters 43 (2002) 6377–6381
genic centers at C-11 and C-12 into 2. Conversion of 8
to cyclic compound 9 was required, because 9 is prone
to allow high 2,3-anti diastereoselection through the
so-called ‘exocyclic effect’5 in the debromination pro-
cess. However, acidic deprotection of 3,4-syn 8 unfortu-
nately underwent cyclization to the corresponding
d-valerolactone 10.3a,6 We therefore selected an alterna-
tive route to 2,3-anti-3,4-syn stereotriad 13 by conver-
sion from 2,3-syn-3,4-anti 11, which has the opposite
stereochemistry relative to 13. The preparation of 11
has been reported using D-5 in the preceding paper.4
The switching of the stereochemistry of 11 to the
opposite one, which corresponds to that of 13, would
be realized by replacing the functional groups at both
terminals of 11. Actually, the desired stereotriad 13 was
obtained after the following five-step reaction sequence:
TBS protection, DIBALH reduction to the correspond-
ing alcohol, TBDPS protection, selective deprotection,
and Swern oxidation, in good overall yield (Scheme 2).
Thus, the three stereogenic centers in 2 could be eventu-
Scheme 2. Synthesis of intermediate aldehyde 13: (a) TBSCl, NaH, THF, rt, 15 h, 91%; (b) Swern: (COCl)2, DMSO, CH2Cl2,
−78°C, Et3N, 0°C, 90%; (c) L-TsValine, BH3·THF, 6, −78°C, 10 h, 80%; (d) silica gel column chromatography; (e) PTSA, MeOH,
rt, 1 h, 95%; (f) TBSOTf, 2,6-lutidine, rt, 1 h, 87%; (g) DIBALH, CH2Cl2, −78°C, 3 h, 80%; (h) TBDPSCl, imidazole, CH2Cl2,
rt, 1 h, 92%; (i) PTSA, MeOH, rt, 20 h, 90%; (j) Swern, 87%.
Figure 1. Catalyst (promoter) control on facial selection.

K. A. Shahid et al. / Tetrahedron Letters 43 (2002) 6377–6381
6379
ally introduced by the first aldol reaction coupled with
the following radical debromination reaction.
rior manner of catalyst (promoter) control on facial
selection (Fig. 1).8 The following sequence of TBS
protection, DIBALH reduction, and Swern oxidation
provided the aldehyde 18 in good overall yield. The
third aldol reaction of 18 with the chiral borane L-5
furnished a-bromo ester 19 in 89% yield with almost
complete selection at C-3 with the isomers at C-2
(2,3-syn:anti=10:1). Protection of the hydroxy group at
C-3 of 19 with dimethoxymethane in the presence of
P2O5 eventually gave a cyclic acetal in good yield,
accompanied with deprotection of the neighboring TBS
group. The usual radical debromination resulted in
good anti selection (2,3-anti:syn=25:1) to give 20, pre-
sumably with the exocyclic effect mentioned above.
Thus, the remarkable efficiency of our strategy, com-
prised of the asymmetric aldol reaction coupled with
radical debromination, was ascertained again in estab-
lishing the additional two stereocenters. The last aldol
reaction using a sequence of the Mukaiyama aldol
The aldehyde 13 was converted into the corresponding
Z-enoate in 95% yield (Z:E=25:1), according to the
Still procedure of the Horner–Wadsworth–Emmons
reaction.7 After DIBALH reduction of the Z-enoate,
followed by Swern oxidation to the Z-enal 14, 14 was
subjected to the second aldol reaction using a silyl
nucleophile 15, related to an acetate equivalent, in
order to create the next chiral center. At this stage, the
chiral oxazaborolidinoine-promoted asymmetric aldol
reaction played an extraordinary role in creating the
desired stereocenter in the carbon–carbon bond forma-
tion. When we used D-5, the expected 16 was obtained
with almost complete selection, while L-5 led to the
epimer 17 with the same level of selection. The configu-
ration created at C-3 in these aldol adducts surely came
from the stereocenter of the used promoters in a supe-
Scheme 3. Reagents and conditions: (a) (CF3CH2O)2P(O)CH2COOCH3, 18-crown-6, KHMDS, THF, −78°C, 15 h, 95%; (b)
DIBALH, CH2Cl2, −78°C, 3 h, 90%; (c) Swern, 86%; (d) D-TsValine, BH3·THF, 15, −78°C, 16 h, 86%; (e) TBSOTf, 2,6-lutidine,
rt, 1 h, 87%; (f) DIBALH, CH2Cl2, −78°C, 3 h, 80%; (g) Swern, 90%; (h) L-TsValine, BH3·THF, 6, −78°C, 89%; (i) CH2(OCH3)2,
CHCl3, P2O5, rt, 1 h, 80%; (j) Bu3SnH, Et3B, toluene, −78°C, 3 h, 85%; (k) DIBALH, CH2Cl2, −78°C, 3 h, 90%; (l) TiCl4, 6,
−78°C, 30 min, 78%; (m) Bu3SnH, Et3B, MgBr2·OEt2, −78°C, 15 h, 80%; (n) TBSOTf, 2,6-lutidine, 97%.

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K. A. Shahid et al. / Tetrahedron Letters 43 (2002) 6377–6381
reaction was designed to proceed through a chelation
pathway, and the following radical reduction could be
predicted to be difficult to achieve the expected 2,3-syn-
3,4-anti selection.9 However, contrary to the prediction,
TiCl4-mediated aldol reaction of 21 with 6 was dramat-
ically realized to produce the 3,4-anti product 22 with
excellent anti selection (ꢀ98% de) along with the minor
isomers at C-2 (2,3-syn:anti=ꢀ15:1). After the usual
debromination with Bu3SnH/Et3B in the presence of
MgBr2·OEt2, the last stereogenic center at C-2 was
achieved (2,3-syn:anti=13:1), followed by TBS protec-
tion to give the target equivalent 24 of 2 (Scheme 3).10
Chem. 1998, 63, 817; (g) Misske, A. M.; Hoffmann, H.
M. R. Tetrahedron 1999, 55, 4315; (h) Evans, D. A.;
Halstead, D. P.; Allison, B. D. Tetrahedron Lett. 1999,
40, 4461; (i) Filla, S. A.; Song, J. J.; Chen, L. R.;
Masamune, S. Tetrahedron Lett. 1999, 40, 5449; (j) Pater-
son, I.; Florence, G. J. Tetrahedron Lett. 2000, 41, 6935;
(k) Arefolov, A.; Langille, N. F.; Panek, J. S. Org. Lett.
2001, 3, 3281.
4. The preceding paper: Shahid, K. A.; Li, Y.-N.; Okazaki,
M.; Shuto, Y.; Goto, F.; Kiyooka, S.-i. Tetrahedron Lett.
2002, 43, 6373
5. (a) Guindon, Y.; Yoakim, C.; Lemieux, R.; Boisvert, L.;
Delorme, D.; Lavale´e, J.-F. Tetrahedron Lett. 1990, 31,
2845; (b) Guindon, Y.; Rancourt, J. J. Org. Chem. 1998,
63, 6554; (c) Guindon, Y.; Jung, G.; Gue´rin, B.; Ogilvie,
W. W. Synlett 1998, 213; (d) Guindon, Y.; Houde, K.;
Pre´vost, M.; Cardinal-David, B.; Landry, S. R.; Daoust,
B.; Bencheqroun, M.; Gue´rin, B. J. Am. Chem. Soc. 2001,
123, 8496; (e) Guindon, Y.; Pre´vost, M.; Mochirian, P.;
Gue´rin, B. Org. Lett. 2002, 4, 1019.
In conclusion, the eight stereogenic centers in C1–C13
segment 2 of (+)-discodermolide were introduced by
four aldol reactions with quite a high level of selection.
The strategy, based on the iterative aldol reactions,
turned out to be practically effective for the straightfor-
ward synthesis of polypropionate frameworks.
6. (a) Kiyooka, S.-i.; Li, Y.-N.; Shahid, K. A.; Okazaki, M.;
Shuto, Y. Tetrahedron Lett. 2001, 42, 7299; (b) Kiyooka,
S.-i.; Shahid, K. A. Bull. Chem. Soc. Jpn. 2001, 74, 1485.
7. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
8. In the boron-mediated aldol reactions of similar g-chiral
(Z)-enals, competition between reagent control and sub-
strate control has been observed (Ref. 3j).
Acknowledgements
This research was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan.
9. Even TiCl4 did not serve the expected chelation control in
the reaction of aldehydes having a substituent at the
b-position. See: Evans, D. A.; Dart, M. J.; Duffy, J. L.;
Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322.
10. Spectroscopic data for selected compounds.
References
1. (a) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.;
Schulte, G. K. J. Org. Chem. 1990, 55, 4912; (b) ter Haar,
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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.
Compd 13: [h]2D7 −15.0 (c 2.0, CHCl3). IR (neat) 2959,
2932, 2887, 2858, 1726 cm−1 1H NMR (CDCl3, 400
.
MHz) l (ppm) 0.03 (s, 3H), 0.05 (s, 3H), 0.85 (s, 9H),
0.86 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H), 1.08 (s,
9H), 1.76–1.86 (m, 1H), 2.54–2.62 (m, 1H), 3.50 (dd,
J=10.3, 6.1 Hz, 1H), 3.58 (dd, J=10.2, 7.6 Hz, 1H), 4.16
(dd, J=6.1, 3.2 Hz, 1H), 7.36–7.46 (m, 6H), 7.65 (dt,
J=7.6, 1.4 Hz, 4H), 9.75 (d, J=2.7 Hz, 1H). 13C NMR
(CDCl3, 100 MHz) l (ppm) −4.2. −4.1, 11.1, 11.6, 18.3,
19.2, 26.0, 26.9, 39.7, 50.9, 65.9, 73.4, 127.6, 127.7, 129.6,
129.7, 133.7, 135.5, 135.6, 204.9.
2. Total syntheses: (a) Nerenberg, J. B.; Hung, D. T.;
Somers, P. K.; Schreiber, S. L. J. Am. Chem. Soc. 1993,
115, 12621; (b) Hung, D. T.; Nerenberg, J. B.; Schreiber,
S. L. J. Am. Chem. Soc. 1996, 118, 11054; (c) Smith, A.
B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am.
Chem. Soc. 1995, 117, 12011; (d) Harried, S. S.; Yang,
G.; Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997, 62,
6098; (e) Marshall, J. A.; Johns, B. A. J. Org. Chem.
1998, 63, 7885; (f) Smith, A. B., III; Kaufman, M. D.;
Beauchamp, T. J.; LaMarche, M. J.; Arimoto, H. Org.
Lett. 1999, 1, 1823; (g) 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; (h) Paterson, I.; Florence, G. J.;
Gerlach, K.; Scott, J. P. Angew. Chem., Int. Ed. 2000, 39,
377; (i) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott. J.
P.; Sereing, N. J. Am. Chem. Soc. 2001, 123, 9535.
3. Segment syntheses: (a) Clark, D. L.; Heathcock, C. H. J.
Org. Chem. 1993, 58, 5878; (b) Evans, P. L.; Golec, J. M.
C.; Gillespie, R. J. Tetrahedron Lett. 1993, 34, 8163; (c)
Paterson, I.; Schlapback, A. Synlett 1995, 498; (d)
Miyazawa, M.; Oonuma, S.; Maruyama, K.; Miyashita,
M. Chem. Lett. 1997, 1191; (e) Miyazawa, M.; Oonuma,
S.; Maruyama, K.; Miyashita, M. Chem. Lett. 1997,
1193; (f) Marshall, J. A.; Lu, Z. H.; Johns, B. A. J. Org.
Compd 16: [h]2D6 +19.6 (c 1.43, CHCl3). IR (neat) 3454,
2959, 2930, 2858, 1759, 1595 cm−1. 1H NMR (CDCl3, 400
MHz) l (ppm) 0.02 (s, 3H), 0.07 (s, 3H), 0.87 (s, 9H),
0.88 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H), 1.07 (s,
9H), 1.83 (dq, J=6.8, 3.2 Hz, 1H), 2.40 (d, J=3.4, 1H),
2.69 (dd, J=15.6, 4.9 Hz, 1H), 2.67–2.75 (m, 1H), 2.80
(dd, J=15.8, 8.0 Hz, 1H), 3.46 (dd, J=10.0, 6.6 Hz, 1H),
3.59 (dd, J=10.0, 6.8 Hz, 1H), 3.73 (dd, J=5.4, 3.2 Hz,
1H), 4.82–4.88 (m, 1H), 5.47 (dd, J=10.9, 7.6 Hz, 1H),
5.54 (t, J=10.7 Hz, 1H), 7.09–7.66 (m, 15H). 13C NMR
(CDCl3, 100 MHz) l (ppm) −4.1, −3.2, 11.8, 18.5, 19.1,
19.2, 26.2, 26.9, 36.9, 40.0, 42.2, 64.4, 66.5, 75.7, 121.6,
125.9, 127.6, 129.4, 129.5, 129.6, 130.0, 133.9, 135.6,
136.8, 150.5, 170.2.
Compd 20: [h]2D8 −4.9 (c 1.03, CHCl3). IR (neat) 2959,
2932, 2858, 1738 cm−1 1H NMR (CDCl3, 400 MHz) l
.
(ppm) −0.01 (s, 3H), 0.05 (s, 3H), 0.06 (s, 3H), 0.86 (d,
J=6.8 Hz, 3H), 0.87 (s, 9H), 0.92 (d, J=7.1 Hz, 3H),
1.05 (s, 9H), 1.10 (d, J=7.1 Hz, 3H), 1.27 (t, J=7.1 Hz,
3H), 1.52–1.61 (m, 1H), 1.77–1.90 (m, 2H), 2.61–2.67 (m,

K. A. Shahid et al. / Tetrahedron Letters 43 (2002) 6377–6381
6381
1H), 2.71 (dq, J=8.8, 7.1 Hz, 1H), 3.43 (dd, J=9.8, 6.8
Hz, 1H), 3.56 (dd, J=10.0, 6.4 Hz, 1H), 3.74 (t, J=3.7
Hz, 1H), 3.99 (dt, J=9.3, 3.2 Hz, 1H), 4.17 (d, J=7.1
Hz, 2H), 4.63–4.67 (m, 1H), 4.72 (d, J=6.6 Hz, 1H), 4.82
(d, J=6.6 Hz, 1H), 5.62–5.69 (m, 2H), 7.35–7.45 (m, 6H),
7.63–7.67 (m, 4H). 13C NMR (CDCl3, 100 MHz) l (ppm)
−4.1, −3.7, 12.2, 12.8, 14.2, 18.4, 18.7, 19.3, 26.1, 26.9,
31.6, 37.0, 40.1, 43.9, 60.5, 66.6, 67.7, 73.5, 75.5, 88.0,
126.2, 127.6, 129.5, 129.6, 133.9, 134.0, 135.6, 137.8,
174.4.
0.89 (s, 9H), 0.91 (d, J=6.8 Hz, 3H), 1.05 (s, 9H), 1.14
(d, J=7.1 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.49 (dt,
J=13.7, 2.7 Hz, 1H), 1.76–1.98 (m, 3H), 2.60–2.67 (m,
2H), 3.43 (dd, J=10.0, 6.8 Hz, 1H), 3.54 (dd, J=10.0, 6.6
Hz, 1H), 3.67 (dt, J=10.9, 2.9 Hz, 1H), 3.73 (t, J=3.9
Hz, 1H), 4.09 (q, J=7.1 Hz, 2H), 4.24 (dd, J=5.6, 4.4
Hz, 1H), 4.65–4.73 (m, 1H), 4.70 (d, J=6.3 Hz, 1H), 4.83
(d, J=6.6 Hz, 1H), 5.61 (t, J=10.2 Hz, 1H), 5.71 (dd,
J=11.2, 7.8 Hz, 1H), 7.35–7.44 (m, 6H), 7.61–7.68 (m,
4H). 13C NMR (CDCl3, 100 MHz) l (ppm) −4.4, −4.3,
−4.1, −3.7, 10.5, 12.0, 13.6, 14.1, 18.2, 18.4, 18.5, 19.3,
25.9, 26.1, 26.9, 33.8, 37.1, 40.0, 42.0, 43.4, 60.3, 66.7,
67.9, 72.1, 72.6, 75.3, 87.9, 126.4, 127.6, 129.4, 129.5,
133.9, 134.0, 135.6, 137.3, 175.8.
Compd 24: [h]2D8 −20.5 (c 0.44, CHCl3). IR (neat) 2959,
2932, 2856, 1734 cm−1 1H NMR (CDCl3, 400 MHz) l
.
(ppm) −0.02 (s, 3H), 0.04 (s, 6H), 0.07 (s, 3H), 0.85 (d,
J=6.8 Hz, 3H), 0.86 (s, 9H), 0.87 (d, J=6.8 Hz, 3H),