Towards the synthesis of (+)-discodermolide

Article abstract of DOI:10.1016/S0040-4039(01)00799-7

An approach to the asymmetric synthesis of fragments corresponding to C1-C7 and C15-C24 of (+)-discodermolide is reported. Key elements of the successful strategy include elaboration of two advanced fragments from a common precursor.

Full text of DOI:10.1016/S0040-4039(01)00799-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4713–4716
Towards the synthesis of (+)-discodermolide†
J. S. Yadav,a,* Sunny Abraham,a M. Muralidhar Reddy,a Gowravaram Sabitha,a A. Ravi Sankarb
and A. C. Kunwarb
aDivision of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bCentre for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad, India
Received 2 April 2001; revised 2 May 2001; accepted 11 May 2001
Abstract—An approach to the asymmetric synthesis of fragments corresponding to C1ꢀC7 and C15ꢀC24 of (+)-discodermolide is
reported. Key elements of the successful strategy include elaboration of two advanced fragments from a common precursor.
© 2001 Elsevier Science Ltd. All rights reserved.
(+)-Discodermolide 1 was isolated from the Caribbean
sponge Discodermia dissoluta by Gunasekera and co-
workers.1 The structure of (+)-discodermolide com-
prises a linear polypropionate backbone punctuated by
(Z)-olefinic linkages at C(8–9), C(13–14) and C(21–22).
By virtue of its potent immunosuppressive and poten-
tial antitumor activity and in view of its limited
availability, interest in the chemical synthesis of this
natural product continues unabated.1,2
Several synthetic approaches towards discodermolide
have been disclosed.3,4 We chose to adopt a highly
convergent strategy to the synthesis of (+)-discoder-
molide (1), disconnecting the carbon backbone at C(8–
9) and C(13–14) Z alkenes thus dividing the target into
three key subunits, 2, 3 and 4. In this letter we detail
our efforts towards the enantio- and diastereoselective
synthesis of 2 and 4 from a common precursor 5. The
advantages of making use of such a common bicyclic
Scheme 1.
Keywords: (+)-discodermolide; common precursor; desymmetrization.
* Corresponding author. Fax: +91-040-7170512; e-mail: yadav@iict.ap.nic.in
† IICT Communication No. 4757.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00799-7

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while C-2 and C-4 of 5 can be correlated to C-16 and
C-18 of 1. The bicyclic compound 5 has five stereogenic
centres and two prostereogenic sp2 sites, which could
facilitate further functionalization (Scheme 1).
We initiated our synthesis from precursor 5, which we
had developed and utilized for the synthesis of a
rifamycin-S fragment wherein, we had exploited the
desymmetrization approach to create six stereogenic
centres at once.5 Asymmetric hydroboration of the
olefin 5 using (+)-diisopinocampheylborane gave 6
(96%) in high optical purity as reported by us.5 By
Scheme 2. (a) (+)-Ipc2BH, −23°C, 24 h, 3N NaOH, 30%
H2O2, rt, 6 h; (b) PCC, DCM, rt, 3 h; (c) m-CPBA, NaHCO3,
DCM, rt, 10 h.
precursor are manifold. The relative stereochemistry at
C-4 of the precursor 5 can be correlated to C-4 of 1,
Scheme 3. (a) LAH, THF, 0°C–rt, 4 h; (b) TBDPS-Cl, imidazole, DCM, 0°C–rt, 2 h; (c) DEAD, TPP, p-NO2C6H4-COOH, THF,
0°C–rt; (d) Dess–Martin periodinane, DCM, rt, 2 h; (e) NaBH4, MeOH/THF, 0°C–rt, 1 h; (f) TBAF, THF, rt, 1.5 h; (g) IBX,
DMSO/DCM, rt, 6 h; (h) NaCNBH3, MeOH/AcOH, pH 5.5, rt, 1 h; (i) TBDMS-Cl, imidazole, DCM, 0°C–rt, 1.5 h; (j) 1%
NaOH, THF, 3 h, H+, CH3COONa, Ac2O, warm, 5 min.
Scheme 4. (a) Me3CCOCl, Py, DCM, 0°C–rt, 4 h; (b) 10% Pd-C/H2, rt, EtOH, 5 h; (c) DEAD, TPP, p-NO2C6H4-COOH, THF,
rt; (d) acetone, PTSA, rt, 2 h; (e) IBX, DMSO/DCM, rt, 1 h; (f) allyl triphenylphosphonium bromide salt, n-BuLi, −78°C, 45 min.

J. S. Yada6 et al. / Tetrahedron Letters 42 (2001) 4713–4716
4715
modifying our earlier conditions, the alcohol 6 was
converted to the lactone 7 by a two-step sequence, PCC
oxidation followed by Baeyer–Villiger oxidation of the
resulting ketone as shown in Scheme 2.6
80% yield, which was characterized by the presence of
an aldehyde proton at l 9.79 in the 1H NMR spectrum.
The IR spectrum revealed absorption bands at 3400
cm−1 for the hydroxyl group and 1730 cm−1 for the
carbonyl group. The terminal Z-diene was installed via
Wittig olefination of the aldehyde 23 using the ylide
generated from allyltriphenylphosphonium bromide salt
and n-BuLi in anhydrous THF at −78°C to afford
compound 24 and its trans isomer in the ratio 73:27,
which was determined from 1H NMR spectrum9
(Scheme 4).
Synthesis of the C1ꢀC7 fragment
Having obtained the bicyclic lactone 7 with all the
functionality for elaboration of the C1ꢀC7 fragment of
2, our attention was directed to the opening of the
bicyclic ring. It was felt that reduction of the lactone
with LAH would be the most ideal route to obtain the
triol 8. The primary hydroxyl groups of the triol 8 were
then protected as their TBDPS ethers (83%). Inversion
of the hydroxyl group configuration at C-5 of the
intermediate 9 to obtain the stereochemistry for C-5 of
(+)-discodermolide employing the Mitsunobu protocol7
failed. Alternatively, we explored an oxidation reduc-
tion strategy. Oxidation using Dess–Martin periodinane
gave the corresponding keto compound 11 in 95%
yield. It was found that reduction of the keto group of
11 using NaBH4 in MeOH:THF (4:1) afforded the
required b isomer 12 as the major isomer (12:9=9:1,
91%). That the alcohol 12 was the C-5 epimer of
alcohol 9 was unambiguously shown by oxidation of 12
to afford 11. It is pertinent to note that the C5-H of 12
resonated upfield (l 3.85) relative to C5-H of 9 (l 4.15)
indicating an anti relationship between the CH3 group
at C-4 and OH at C-5. The required b isomer 12 was
separated by column chromatography. This was fol-
lowed by deprotection of the TBDPS ethers using
TBAF, to afford the triol 13 in 88% yield. It was then
proposed to transform the triol to the lactone 14.
Towards this end, oxidation of the triol 13 using IBX
resulted in the lactone 14 (71%) via the lactol. The next
step called for epimerization of the C-2 methyl group.
To circumvent the possibility of unwanted side reac-
tions involving the reactive aldehyde group, we reduced
it with NaCNBH3 followed by protection of the result-
ing alcohol as a TBS ether 15. Epimerization of 15
using 1% NaOH in tetrahydrofuran afforded the
required product 168 in 55% yield along with minor
amounts of the a,b-unsaturated analogue 17 (15%)
arising from 1,2-elimination (Scheme 3).
In summary we have completed the highly stereocon-
trolled synthesis of the C1ꢀC7 and C15ꢀC24 fragments
of (+) discodermolide. Studies towards completing the
total synthesis of discodermolide using the subunits 16
and 24 are now underway.
Acknowledgements
The authors S.A. and M.M.R. thank CSIR for the
award of the fellowship.
References
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Synthesis of C-15–C-24 fragment
For the synthesis of the C-15–C-24 fragment we pre-
pared the precursor 18 by our earlier method.5 The
primary hydroxyl of the compound 18 was protected as
its pivalate ester (85%). The steps required for the
elaboration of 18 to the target fragment 4 included an
inversion at C-17 and elaboration of the diene moiety.
For the inversion at C-17 we deprotected the benzyl
ether of compound 19 by Pd-C/H2, followed by a
Mitsunobu reaction. The yield of Mitsunobu reaction
to invert the sterically hindered hydroxy stereochem-
istry was only 15%. We therefore changed our strategy
and initially explored elaboration of the diene moiety
that is the C-21–C-24 fragment of (+)-discodermolide.
Acetonide deprotection of compound 19 gave the diol
22 in 93% yield. Selective oxidation of the primary
hydroxyl group using IBX afforded the aldehyde 23 in

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J. S. Yada6 et al. / Tetrahedron Letters 42 (2001) 4713–4716
1998, 63, 7885; (f) Paterson, I.; Florence, G. J.; Gerlach,
H-4), 2.88 (dq, J=3.8, 7.5 Hz, 1H, H-2), 3.41 (dd, J=3.3,
3.8 Hz, 1H, H-3), 3.80 (m, 2H, H7), 4.53 (ddd, J=9.5, 9.1,
2.8 Hz, 1H, H-5), 4.48 (d, J=11.6 Hz, 1H, -OCH2), 4.64
(d, J=11.6 Hz, 1H, -OCH2), 7.28–7.37 (m, 5H, ArH). [h]2D0
+12.10 (c=0.40, CHCl3).
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9. 1H NMR of compound 24 (500 MHz, CDCl3): l 0.91 (d,
J=6.7 Hz, 3H), 1.02 (d, J=7.1 Hz, 3H), 1.10 (d, J=6.7
Hz, 3H), 1.23 (s, 9H), 1.98 (m, 1H), 2.23 (m, 1H), 2.31 (m,
1H) 3.44 (dd, J=2.7, 9.6 Hz, 1H), 3.66 (t, J=4.2 Hz, 1H),
4.10 (dd, J=3.2, 6.0 Hz, 1H), 4.25 (dd, J=3.4, 5.2 Hz,
1H), 4.58 (d, J=10.6 Hz, 1H), 4.65 (d, J=10.6 Hz, 1H),
5.14 (ddd, J=2.1, 10.3, 1.1 Hz, 1H), 5.21 (ddd, J=2.1,
16.9, 1.1 Hz, 1H), 5.37 (ddd, J=10.1, 11.2, 1.1 Hz,
7. Mitsunobu, I. Synthesis 1981, 1–28.
8.
-CH
-CHꢁCH
-CHꢁCH-CH
6
ꢁCH-CHꢁ), 6.10 (ddd, J=11.2, 11.3, 1.1 Hz,
-CHꢁ), 6.65 (dddd, J=10.3, 11.3, 16.9, 1.1 Hz,
ꢁ), 7.3–7.4 (m, 5H, ArH). [h]D20 −11.8 (c=
6
NMR studies of the compound 16 showed NOEs between
Me-2 and H4. This observation confirmed the configura-
tion at C2 centre of 16 as ‘R’. H NMR of compound 16
(500 MHz, CDCl3): l 0.050 (s, 3H, Si-Me), 0.052 (s, 3H,
Si–Me), 0.88 (s, 9H, C(CH3)3), 1.07 (d, J=6.6 Hz, 3H,
C4-CH3), 1.30 (d, J=7.5 Hz, 3H, C2-CH3), 1.73 (m, 1H,
H6), 1.91 (m, 1H, H6), 2.07 (ddq, J=9.5, 3.3, 6.6 Hz, 1H,
6
1
0.12, CHCl3). The olefinic protons for the ‘E’ isomer of
the compound 24 appeared at l 5.45 (ddd, J=9.3, 15.3,
0.70 Hz, -CH
Hz, -CHꢁCH-CHꢁ), 6.28 (dddd, J=10.3, 10.9, 16.95, 0.70
Hz, -CHꢁCH-CHꢁ).
6 ꢁCH-CHꢁ), 6.13 (ddd, J=10.3, 15.3, 0.70
6
6
.