Remote 1,5-stereoinduction in boron aldol reactions of methyl ketones: Application to the convergent assembly of the 1,3-polyol sequence of (+)-roxaticin

Article abstract of DOI:10.1016/S0040-4039(00)02205-X

By exploiting 1,5-anti stereoinduction in the boron aldol coupling of the β-alkoxy methyl ketones 6 and 8 with aldehydes 7 and 9, the convergent synthesis of 2, corresponding to the fully protected polyol sequence of the 30-membered macrolide, (+)-roxaticin (1), was achieved in an efficient manner (15 steps and 24.0% yield from ketone 15).

Full text of DOI:10.1016/S0040-4039(00)02205-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1187–1191
Remote 1,5-stereoinduction in boron aldol reactions of methyl
ketones: application to the convergent assembly of the 1,3-polyol
sequence of (+)-roxaticin
Ian Paterson* and Lynne A. Collett
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
Received 9 November 2000; accepted 29 November 2000
Abstract—By exploiting 1,5-anti stereoinduction in the boron aldol coupling of the b-alkoxy methyl ketones 6 and 8 with
aldehydes 7 and 9, the convergent synthesis of 2, corresponding to the fully protected polyol sequence of the 30-membered
macrolide, (+)-roxaticin (1), was achieved in an efficient manner (15 steps and 24.0% yield from ketone 15). © 2001 Elsevier
Science Ltd. All rights reserved.
As potent antifungal agents, the polyene macrolides
constitute an important class of polyketide metabo-
lites.1 Their highly oxygenated structures have stimu-
lated synthetic efforts towards the development of
general approaches to the asymmetric construction of
stereodefined 1,3-polyols.2 In the case of roxaticin (1), a
30-membered macrolide first isolated from a cultured
soil streptomycete by Maehr et al. at Roche in 1989,3
total syntheses have been completed by the Rychnovsky
(ent-1) and Mori groups.4 By using boron aldol
reactions5 for achieving remote acyclic stereocontrol,
we now report an expedient synthesis of the C10–C29
subunit 2, which comprises the full 1,3-polyol sequence
of (+)-roxaticin containing all ten stereocentres.
The boron-mediated aldol reaction of chiral ketones is
now well established as a powerful tool for polyketide
synthesis. However, due to the lower stereoselectivities
observed in the aldol reactions of methyl versus ethyl
ketones, application to acetate-derived polyketides usu-
ally requires reagent control using chiral ligands on
boron.5 A notable exception is the aldol reaction of
certain b-alkoxy methyl ketones with aldehydes, as in
3“4“5 in Scheme 1, which are found to proceed with
remarkably high levels of 1,5-anti stereoinduction under
substrate control.6,7 Access to stereodefined 1,3,5-triol
sequences,6 as found in the polyene macrolides, can
then be realised by suitable reduction (3,5-syn or anti )
of the b-hydroxy ketones 5.
Keywords: roxaticin; boron aldol; macrolide; antifungal; remote stereoinduction.
* Corresponding author. Fax: +44 1223 336362; e-mail: ip100@cus.cam.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02205-X

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I. Paterson, L. A. Collett / Tetrahedron Letters 42 (2001) 1187–1191
A convergent synthesis of the 1,3-polyol subunit 2 for
(+)-roxaticin was planned, following the route outlined
in Scheme 1. The pivotal 1,5-anti aldol reaction was
intended to be used twice, i.e. for the coupling of the
simpler fragments 6 with 7 and 8 with 9. To ensure a
useful level of 1,5-stereoinduction, suitable protecting
groups, such as PMB (by analogy with 3), for the C15
and C21 hydroxyls were incorporated into the methyl
ketones 6 and 8, respectively. Following our synthetic
studies on spongistatin, we planned to prepare the
methyl ketone 6 using a 1,3-syn aldol reaction of ace-
tone with the b-siloxy aldehyde 10.6b
the required C10–C18 subunit 6 (80%). The enal 9,
incorporating C25–C29, was obtained using the comple-
mentary syn aldol chemistry9a,c of the ketone 15, having
a benzyl ether in place of the benzoate. Thus, the
syn-configured aldehyde 16 was readily prepared from
the aldol adduct 17, followed by chain extension4a to
produce 9 (91%). The final C19–C24 subunit, i.e. methyl
ketone 8, was obtained in 95% ee by Brown allybora-
tion
of
aldehyde
18
using
B-allylbis(2-iso-
caranyl)borane,13 followed by PMB protection and
Wacker oxidation of the alkene.
The controlled aldol coupling of the three subunits,
followed by suitable manipulation was now addressed.
In the first 1,5-anti coupling step between equimolar
amounts of 8 and 9 (Scheme 3), use of c-Hex2BCl and
Et3N led, after oxidative work-up, to the adduct 19
with 95% ds in 86% yield. By combining this step with
an in situ reduction6a,14 of the intermediate dicyclo-
hexylboron aldolate using LiBH4, the C23 and C25
stereocentres could be introduced efficiently, generating
the 1,3-syn diol 20 (95% ds) in 90% yield. The C25
The preparation of the three key subunits 6, 8 and 9 is
outlined in Scheme 2.8 Following standard condi-
tions,9a,b the boron aldol reaction (c-Hex2BCl,
Me2NEt) of the lactate-derived9b ketone 11 with 3-(ben-
zyloxy)propanal proceeded with ]97% ds, giving the
anti adduct 12 (88%). Protection as a TIPS ether,
followed by LiAlH4 reduction and oxidative glycol
cleavage with Pb(OAc)4 then gave 13 (86%). Next, the
vinyl iodide was introduced (E:Z=96:4) by Takai
olefination10 using CHI3 and CrCl2, followed by deben-
zylation (BCl3·SMe2)11 and Dess–Martin oxidation to
produce aldehyde 10 (67% from 13). Using (−)-Ipc2BCl
and Et3N,12 the aldol addition of acetone to 10 pro-
ceeded with ]97% ds to give 1,3-syn adduct 14 (99%).
As expected,6b the moderate 1,3-stereoinduction from
the b-siloxy aldehyde 10 is reinforced here by the chiral
boron reagent. Protection as the PMB ether then gave
1
configuration was established as (R) by H NMR spec-
troscopy (through use of the advanced Mosher
method15 on the (R)- and (S)-MTPA esters of 19),
while that at C25 was determined in turn by 13C NMR
analysis16 of the acetonide 21. Selective deprotection of
the primary TBS ether in 21 with TBAF was then
followed by Swern oxidation to give aldehyde 7 (93%).
Scheme 1. Retrosynthetic analysis based on identification of 1,5-anti stereorelationships in 2.

I. Paterson, L. A. Collett / Tetrahedron Letters 42 (2001) 1187–1191
1189
Scheme 2. Reagents and conditions: (a) c-Hex2BCl, Me2NEt, Et2O, 0°C, 2 h; BnOCH2CH2CHO, −78“−20°C, 16 h; H2O2,
MeOH, pH 7 buffer; (b) TIPSOTf, 2,6-lutidine, CH2Cl2, −78“0°C, 3 h; (c) LiAlH4, −78“0°C, 3 h; (d) Pb(OAc)4, Na2CO3,
CH2Cl2, 0.5 h; (e) CHI3, CrCl2, THF, dioxane, 8 h; (f) BCl3·SMe2, CH2Cl2, 45 min; (g) Dess–Martin periodinane, CH2Cl2, 1–3
h; (h) Me2CO, (−)-Ipc2BCl, Et3N, Et2O, 0°C, 35 min; 10, −78°C, 1 h; H2O2, MeOH, pH 7 buffer; (i) PMB–TCA, cat TfOH, Et2O,
0°C, 3 h; (j) c-Hex2BCl, Et3N, Et2O, −78“0°C, 80 min; i-PrCHO, −78“−20°C, 16 h; H2O2, MeOH, pH 7 buffer; (k) TBSOTf,
2,6-lutidine, CH2Cl2, −78°C, 1 h; (l) H2, Pd(OH)2/C, EtOAc, 1 h; (m) NaIO4, aq. MeOH, 40 min; (n) Ph3PꢀCHCO2Me, MeCN,
84°C, 20 h; (o) DIBAL, Et2O, −78“20°C, 1.5 h; (p) (2-dIcr)2Ballyl, Et2O, −78°C, 3 h; H2O2, NaOH; (q) PMB–TCA,
Ph3CBF4,THF, 0°C, 16 h; (r) PdCl2, CuCl, O2, aq. DMF, 25 h.
Scheme 3. Reagents and conditions: (a) c-Hex2BCl, Et3N, Et2O, 0°C, 10 min; 9, −78“−20°C, 18 h; H2O2, MeOH, pH 7 buffer;
(b) c-Hex2BCl, Et3N, Et2O, 0°C, 10 min; 9, −78“−20°C, 18 h; LiBH4, 2 h; H2O2, MeOH, pH 7 buffer; (c) (MeO)2CMe2, PPTS,
CH2Cl2, 16 h; (d) TBAF, THF, 1.5 h; (e) (COCl)2, DMSO, CH2Cl2, −78°C, 30 min; Et3N, −78“0°C, 1 h.
In the more challenging, second 1,5-anti aldol coupling
(Scheme 4), enolisation of ketone 6 with c-Hex2BCl and
Et3N, followed by addition of aldehyde 7, gave the
desired adduct 22 (75% ds), along with 19-epi-22. After
chromatographic separation, the major adduct 22 was
isolated in 53% yield. By treatment of each of the aldol
products with DDQ, the formation of the correspond-
ing PMP acetals, with concomitant deprotection of the
C15 PMB ether, was achieved.17 Subsequent NOE anal-
ysis of 23, along with the 19-epi system 24, enabled the
unambiguous assignment of the C19 configuration aris-
ing from the aldol coupling. In the analogous reaction
of methyl ketone 6 with the simple aldehyde 25, the
1,5-anti adduct 26 was obtained in 69% ds, while alde-
hyde 7 showed low selectivity (61% ds) in reaction with
the dicyclohexylboron enolate of acetone. Therefore, we
attribute the moderate 75% ds achieved in the forma-
tion of 22 (cf. 9+10“19 in 95% ds) to a reduced level of
1,5-stereoinduction from the ketone component 6 (as
opposed to a mismatched coupling situation). This may
be a consequence of steric congestion, arising from the
bulky C11 TIPS ether, adversely affecting the conforma-

1190
I. Paterson, L. A. Collett / Tetrahedron Letters 42 (2001) 1187–1191
Scheme 4. Reagents and conditions: (a) c-Hex2BCl, Et3N, Et2O, 0°C, 10 min; 7 or 25, −78“−20°C, 16 h; H2O2, MeOH, pH 7
buffer; (b) DDQ, CH2Cl2, pH 7 buffer, 6 h; (c) Me4NBH(OAc)3, MeCN, AcOH, −30“20°C, 18 h; (d) (MeO)2CMe2, PPTS,
CH2Cl2, 15 h.
tion of the stereodirecting PMB ether at C15. In com-
parison, the corresponding lithium and Mukaiyama
aldol reactions of 6 with 7 gave much poorer stereose-
lectivity for 22.
Commonwealth Trust and Merck, Sharp & Dohme for
support.
Finally, a hydroxyl-directed reduction of aldol adduct
22, employing Me4NBH(OAc)3,18 led to the 1,3-anti
diol 27 with 96% ds, which was transformed into the
bis-acetonide 28 in 81% overall yield (allowing confir-
mation of the stereochemistry by 13C NMR analysis16).
This contains all ten stereocentres of the 1,3-polyol
sequence of (+)-roxaticin, with a vinyl iodide appended
at C10 for a subsequent Pd-mediated coupling to intro-
duce the polyene unit and close the macrolide ring.
References
1. Omura, S.; Tanaka, H. In Macrolide Antibiotics; Omura,
S., Ed.; Academic Press: Orlando, FL, 1984; pp. 351–396.
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3. Maehr, H.; Yang, R.; Hong, L.-N.; Liu, C.-M.; Hatada,
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5. For a review on asymmetric aldol reactions using boron
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In summary, the asymmetric synthesis of bis-acetonide
2, corresponding to the fully protected 1,3-polyol
sequence for (+)-roxaticin (1) and containing all ten
stereocentres, has been achieved in 15 steps and high
overall yield (24.0%) from ketone 15 (three steps from
ethyl (S)-lactate9a). By exploiting the 1,5-anti boron
aldol coupling protocol, a convergent synthesis using
equimolar amounts of the individual subunits 6, 8 and
9 was realised. Further studies are underway to explore
the generality and origin of these, and other, remote
induction effects in boron aldol reactions.19
Acknowledgements
8. All new compounds gave spectroscopic data in agreement
with the assigned structures. 2 had: [h]2D0 −22.5 (c 1.5,
CHCl3); 1H NMR (400 MHz, CDCl3) l 7.27 (2H, d,
J=8.6 Hz, ArH), 7.23 (2H, d, J=8.7 Hz, ArH), 6.88
We thank the EPSRC (GR/L41646), the Cambridge

I. Paterson, L. A. Collett / Tetrahedron Letters 42 (2001) 1187–1191
1191
(2H, d, J=8.6 Hz, ArH), 6.87 (2H, d, J=8.7 Hz, ArH),
6.53 (1H, dd, J=14.5, 8.5 Hz, H11), 5.86 (1H, d, J=14.5
Hz, H10), 5.64 (1H, dd, J=15.6, 8.0 Hz, H27), 5.39 (1H,
dd, J=15.6, 6.4 Hz, H26), 4.50 (1H, d, J=10.6 Hz,
9. (a) Paterson, I.; Wallace, D. J.; Vela´zquez, S. M. Tetra-
hedron Lett. 1994, 35, 9083; (b) Paterson, I.; Wallace, D.
J.; Cowden, C. J. Synthesis 1998, 639; (c) Paterson, I.;
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E. Synlett 1993, 663.
12. Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann,
R. C.; McClure, C. K.; Norcross, R. D. Tetrahedron
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13. Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz,
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Chem. Soc. 1988, 110, 3560.
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6935.
OCH
4.46 (1H, d, J=10.6 Hz, OCHAHB
H25), 4.29 (1H, d, J=11.4 Hz, OCHAHB
6
AHBAr), 4.47 (1H, d, J=11.4 Hz, OCHA
Ar), 4.28–4.34 (1H, m,
Ar), 3.99–4.14
6 HBAr),
6
6
(2H, m, H15, H23), 3.92–3.98 (1H, m, H21), 3.81–3.90 (1H,
m, H13), 3.80 (3H, s, OMe), 3.80 (3H, s, OMe), 3.75–3.82
(1H, m, H19), 3.42–3.52 (1H, m, H17), 3.27 (1H, dd,
J=4.9, 4.9 Hz, H29), 2.27–2.36 (1H, m, H28), 2.10–2.18
(1H, m, H12), 1.88–1.96 (1H, m, H20A), 1.70–1.80 (2H, m,
H
20B, H30), 1.25–1.70 (10H, m, H14, H16, H18, H22, H24),
1.46 (3H, s, OC(Me)(Me)O), 1.42 (3H, s, OC(Me)(Me)O),
1.38 (3H, s, OC(Me)(Me)O), 1.36 (3H, s, OC(Me)(Me)O),
1.06 (21H, s, Si(CHMe2)3), 1.06 (3H, d, obscured, C12-
Me), 0.98 (3H, d, J=6.8 Hz, C28-Me), 0.91 (9H, s,
SiCMe3), 0.88 (3H, d, J=6.9 Hz, C30-MeA), 0.84 (3H, d,
J=6.7 Hz, C30-MeB), 0.03 (6H, s, SiMe2) ppm; 13C NMR
(100.6 MHz, CDCl3) l 159.2, 159.1, 148.1, 136.2, 131.0,
130.8, 129.5, 129.4, 129.2, 113.9, 113.6, 100.2, 98.5, 80.9,
74.9, 72.3, 72.1, 71.9, 71.8, 70.2, 69.8, 65.2, 63.4, 63.3,
55.3 (×2), 44.7, 42.9, 42.3, 40.6 (×2), 40.2, 39.3, 37.7, 31.6,
30.4, 26.2 (×2), 25.2, 20.5, 20.0, 18.4, 18.3, 17.7, 16.6,
15.9, 12.9, −3.5, −3.8 ppm; HRMS (+ESI) calcd for
C62H105O10NaSi2I [M+Na]+ 1215.6183, found 1215.6091.
.