Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of γ-chiral (Z)-enals

Article abstract of DOI:10.1016/S0040-4039(00)01165-5

The boron-mediated aldol reactions of the (Z)-enals 3 and 7 proceed with high levels of 1,4-stereo-induction arising from the γ-substituent. Reagent control from (+)-Ipc₂BCl can be used effectively to overturn this substrate bias, thus enabling the stereocontrolled formation of (+)-discodermolide (1) and related analogues 15-18. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01165-5

Tetrahedron Letters 41 (2000) 6935±6939
Synthesis of (+)-discodermolide and analogues by control of
asymmetric induction in aldol reactions of g-chiral (Z)-enals
Ian Paterson* and Gordon J. Florence
University Chemical Laboratory, Lens®eld Road, Cambridge CB2 1EW, UK
Received 20 June 2000; accepted 12 July 2000
Abstract
The boron-mediated aldol reactions of the (Z)-enals 3 and 7 proceed with high levels of 1,4-stereo-
induction arising from the g-substituent. Reagent control from (+)-Ipc2BCl can be used e€ectively to
overturn this substrate bias, thus enabling the stereocontrolled formation of (+)-discodermolide (1) and
related analogues 15±18. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: discodermolide; boron aldol; isopinocampheyl; anticancer; remote stereoinduction.
As a potent microtubule-stabilising agent which retains activity against Taxol1-resistant cancer
cells, discodermolide (1, Scheme 1) is a promising candidate for clinical development in cancer
chemotherapy both on its own1a d and in combination with Taxol1.1e However, due to the scarce
supply from its rare sponge source (Discodermia dissoluta),2 access to this novel cytotoxic poly-
ketide is severely limited. We recently disclosed a highly convergent and ¯exible total synthesis,3 5
which has the potential to provide useful quantities of (+)-discodermolide, as well as o€ering a
variety of options for analogue chemistry. This ecient synthesis3 is based on the asymmetric
aldol addition of the enolate 2, which uses chiral ligands on boron (L=Ipc)6 to completely
overturn the intrinsic p-facial bias (for re-face attack) of the (Z)-enal 3. Herein, we report further
studies of this remarkable (C6±C7) aldol coupling step and its application to the stereocontrolled
synthesis of several discodermolide analogues.
Scheme 1.
* Corresponding author: Fax +44 1223 336362; e-mail: ip100@cus.cam.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01165-5

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In planning our synthesis, a late-stage aldol coupling was proposed between the (Z)-enal 3,
containing the entire C7±C24 section of discodermolide, and a suitable enolate derivative 2. While
extensive studies of structurally related boron enolates are available,7,8 the p-facial bias of such an
unusual aldehyde substrate as 3 was an unknown quantity. This led to a detailed examination of
the stereochemical bias of the individual coupling partners and the chiral in¯uence of
isopinocampheyl (Ipc) ligands on boron, as outlined in Scheme 2.
Scheme 2. (a) c-Hex2BCl, Et3N, Et2O, 0ꢀC, 1 h; RCHO, ^78!^20ꢀC, 20 h; H2O2, MeOH, pH 7 bu€er; (b) (+)-
Ipc2BCl, Et3N, Et2O, 0ꢀC, 1 h; RCHO, ^78!^20ꢀC, 20 h; H2O2, MeOH, pH 7 bu€er; (c) (^)-Ipc2BCl, Et3N, Et2O,
0ꢀC, 1 h; RCHO, ^78!^20ꢀC, 20 h; H2O2, MeOH, pH 7 bu€er
The dicyclohexylboron enolate 2 formed from methyl ketone 4 (c-Hex2BCl, Et3N) showed only
modest 1,4-stereoinduction on addition to crotonaldehyde to give a 54:46 mixture of adducts 5
and 6. This 1,4-syn selectivity is much lower than related cases,7,8a but can be easily ampli®ed
using the appropriate chiral boron reagent, i.e. (+)-Ipc2BCl, to generate the desired (7S)-adduct 5
with 91% ds. In a series of boron-mediated aldol additions, the p-facial selectivities of the
aldehyde partner 3,3 along with its truncated version 7,9,10 were then investigated. On reaction
with methyl isopropyl ketone (c-Hex2BCl, Et3N), the (Z)-enal 7 showed unexpectedly high levels
of remote 1,4-stereoinduction in the undesired re-face sense, giving adducts 8 (major) and 9 with

6937
95:5 selectivity.10 This outcome can be attributed to steric control in attack of the enolate on the
re-face of the g-chiral aldehyde, which adopts the s-trans conformation 10 to minimise A (1,3)
allylic strain.11 By using (+)-Ipc2BCl, this substrate-based selectivity could now be reversed to
generate 9 as the major adduct (59% ds).
These results indicated that the boron-mediated C6±C7 aldol coupling of ketone 4 with
aldehydes 3 and 7 would be mismatched situations. In practice, when c-Hex2BCl was employed,
the p-facial bias of the aldehyde component completely overwhelmed the small opposing
in¯uence from the enolate 2, leading to the undesired, preferential formation of 11 over 12 (90:10)
and 13 over 14 (88:12), respectively. This outcome was reinforced using (^)-Ipc2BCl. Gratifyingly,
when (+)-Ipc2BCl was employed, the dominating aldehyde facial selectivity could be overturned
in both cases to produce good yields and useful levels of stereocontrol in favour of 12 (80% ds)
and 14 (84% ds).12 Notably, these represent the ®rst examples of the successful use of the Ipc
reagent to reverse the intrinsic substrate selectivity of a complex aldol coupling between two
chiral carbonyl components. This welcome result permitted the completion of the total synthesis3
of (+)-discodermolide (1) from 14 in two further steps through reduction at C5 and deprotection.
Having generated selectively both epimers at C7 in the key aldol coupling using ketone 4, we
next sought to prepare the three epimeric discodermolides 15±17 as well as the truncated
analogue 18, as shown in Scheme 3. By using c-Hex2BCl and Et3N to initially regenerate the
corresponding boron aldolate from the b-hydroxy ketones 13 and 14, reduction at C5 with LiB-
H3(OMe) proceeded with high 1,3-syn selectivity (>97% ds). Subsequent deprotection and con-
comitant lactonisation under acidic conditions then gave 5-epi-discodermolide (14!15) and
7-epi-discodermolide (13!16) in 41 and 53% yield, respectively. In a complementary fashion,
reduction13 of ketone 13 using Me4NBH(OAc)3 gave predominantly the 1,3-anti diol with 75%
ds. Chromatographic separation and subsequent deprotection led to 5,7-bis-epi-discodermolide
(17) in 63% yield from 13. Finally, the C1±C14 truncated analogue 18 of discodermolide was
Scheme 3. (a) c-Hex2BCl, Et3N, THF, 0ꢀC, 0.5 h; LiBH3OMe, ^78ꢀC, 1.5 h; H2O2, MeOH, pH 7 bu€er; (b) 3N HCl,
MeOH, rt, 72 h; (c) Me4NBH(OAc)3, MeCN, AcOH, ^20!0ꢀC, 4 h

6938
prepared in an analogous fashion from 12, where Me4NBH(OAc)3 reduction gave the
intermediate 1,3-anti diol with >97% ds, which was then followed by deprotection.
In summary, the boron-mediated aldol reactions of the (Z)-enals 3 and 7 have been found to
proceed with unexpectedly high levels of 1,4-stereoinduction arising from the g-substituent.
Reagent control from (+)-Ipc2BCl can be used to overturn the strong facial bias of the aldehyde
component, thus enabling the stereocontrolled formation of (+)-discodermolide (1) and epimeric
analogues at C5 and C7. Further studies are underway to explore the generality and origin of
these e€ects, as well as the tubulin binding and polymerisation activity of the discodermolide
analogues prepared.
Acknowledgements
We thank the EPSRC (GR/M46686 and L41646) and Merck, Sharp & Dohme for support.
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(a) c-Hex2BCl, Et3N, Et2O, 0ꢀC, 3 h; MeCHO, ^78!^20ꢀC, 16 h; H2O2, MeOH, pH 7 bu€er; (b) SmI2, EtCHO,
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1
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