Studies towards the synthesis of superstolide A: An aldol-based construction of an advanced C1-C5/C20-C26 segment

Article abstract of DOI:10.1055/s-2004-825619

Based on a boron-mediated syn aldol reaction of an alanine-derived ethyl ketone with an α-chiral aldehyde partner, an advanced intermediate for superstolide A was assembled in a highly stereocontrolled fashion. Controlled 1,3-anti reduction of the resulting β-hydroxy ketone gave the characteristic amino diol stereopentad of superstolide, followed by a Takai olefination and esterification of the C23 hydroxyl to provide the elaborated C1-C5/ C20-C26 segment 3.

Full text of DOI:10.1055/s-2004-825619

LETTER
1359
Studies Towards the Synthesis of Superstolide A: An Aldol-Based
Construction of an Advanced C1–C5/C20–C26 Segment
Studies
T
a
owards the
n
Synthesis of
Supe
P
rstolide
A
aterson,* Angela C. Mackay
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
Fax +44(1223)336362; E-mail: ip100@cam.ac.uk
Received 5 March 2004
Dedicated to Professor Clayton Heathcock
Abstract: Based on a boron-mediated syn aldol reaction of an ala-
nine-derived ethyl ketone with an a-chiral aldehyde partner, an ad-
vanced intermediate for superstolide A was assembled in a highly
stereocontrolled fashion. Controlled 1,3-anti reduction of the result-
ing b-hydroxy ketone gave the characteristic amino diol stereopen-
tad of superstolide, followed by
a Takai olefination and
esterification of the C23 hydroxyl to provide the elaborated C1–C5/
C20–C26 segment 3.
Keywords: macrolide, boron aldol, a-amino ketones, esterification
In recent years, marine macrolides have gained promi-
nence as potent disrupters of cell cycle events, represent-
ing potential new leads for the development of anti-cancer
agents.1 Superstolides A (1) and B (2) are members of a
structurally unique family of cytotoxic macrolides
(Figure 1), isolated by Minale and co-workers from the
New Caledonian sponge Neosiphonia superstes.2 These
highly unsaturated 16-membered macrolides, comprising
a cis-decalin moiety and an N-acetylamino-containing
side chain, were shown to exert potent growth inhibitory
activity against a range of human cancer cell lines, includ-
ing murine leukemia P388 (e.g. IC50 0.003 mg/mL), na-
sopharyngeal and non-small-cell lung carcinomas. Due to
this potent cytotoxicity, combined with a unique molecu-
lar architecture and scarce natural abundance, the super-
stolides have attracted growing synthetic interest.3 To
date, the assembly of the cis-decalin unit was reported ini-
Figure 1
tially by the Roush group,3a followed by studies from sev- coupling of 3 with 6. Both these options required access
eral groups3b–3f focusing on the construction of the to the C20–C26 segment 7, containing the 5 contiguous
characteristic amino diol sequence spanning C20–C26 of stereocentres of the superstolide A structure, along with
superstolide A. As part of a projected total synthesis, we the iodo acid 8.
now report a stereocontrolled synthesis of the advanced
The synthesis of the C20–C26 stereopentad 7 of super-
intermediate 3, incorporating the C1–C5 and C20–C26
stolide A (Scheme 2) started out from the a-amino ethyl
boxed section of superstolide A, based on novel boron-
ketone 9 that was prepared, as described previously,4 in 3
steps and 90% yield from (R)-alanine methyl ester. Based
mediated aldol methodology developed in our group.4
A flexible synthetic plan was adopted, as outlined in on our standard conditions,4,5 the key syn boron aldol re-
Scheme 1, whereby a preassembled cis-decalin moeity, action of ketone 9 was carried out by first forming the (Z)-
e.g. 4, would be attached to the advanced intermediate 3 boron enolate 10, using Bu2BOTf and i-Pr2NEt at –78 °C,
by employing suitable sp2–sp2 cross-coupling reactions. followed by addition of the a-chiral aldehyde 11. In this
Alternatively, a transannular Diels–Alder reaction, form- complex aldol coupling, the strong inherent facial bias of
ing the cis-decalin ring system, was envisaged to follow the enolate is reinforced by the lower level of 1,2-stereo-
on from assembly of the macrocyclic polyene 5 from induction arising from the aldehyde.5 Thus, this matched
reaction led to essentially complete selectivity (40:1 dr)
for formation of the expected4,6 adduct 12 in 98% yield.
SYNLETT 2004, No. 8, pp 1359–1362
Advanced online publication: 04.06.2004
DOI: 10.1055/s-2004-825619; Art ID: Y01704ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
7.
2
0
0
4
To install the remaining C25 stereocentre required for
the C20–C26 sequence, treatment7 of a solution of the

1360
I. Paterson, A. C. Mackay
LETTER
Scheme 1 Retrosynthetic analysis of superstolide A
b-hydroxy ketone 12 in MeCN–HOAc with
Me4NBH(OAc)3 provided the desired 1,3-anti diol,
which was subjected to PPTS in 2,2-dimethoxypropane–
CH2Cl2 to give the corresponding acetonide 13, obtained
in 70% yield. The 13C NMR spectrum of 13 displayed di-
agnostic resonances at d = 100.3, 25.2 and 23.8 ppm, thus
confirming the expected 1,3-anti relationship in the parent
diol.8 At this stage, it remained to manipulate the amine
protection and install the vinyl iodide functionality in or-
der to access the desired intermediate 7.
To liberate the primary amine, acetonide 13 in EtOAc was
exposed to 10% Pd/C under a hydrogen atmosphere, lead-
ing after 20 hours to complete debenzylation. In this in-
stance, the primary amine was not isolated; instead the
crude product was redissolved in CH2Cl2 and treated with
Ac2O/Et3N to afford the acetamide 14 in 83% overall
yield. With 14 in hand, the TBS ether was first removed
using TBAF in THF, followed by oxidation of the result-
ing alcohol on treatment with catalytic TEMPO and
PhI(OAc)2 as the co-oxidant.9 This mild oxidative proce-
dure produced aldehyde 15 cleanly in 95% overall yield,
which was immediately subjected to Takai olefination.10
Employing standard conditions,11 a solution of aldehyde
15 and iodoform in THF–dioxan was treated with CrCl2
providing the desired E-alkene 16 in 57% yield, obtained
as a single geometric isomer (3J20,21 = 14.5 Hz). Comple-
tion of the C20–C26 segment 7 was then achieved in 82%
yield following acetonide removal with PPTS in MeOH.
Scheme 2
Reagents and conditions: (a) Bu2BOTf, i-Pr2NEt,
Access to the d-iodo acid 8, as required for the C1–C5
segment, relied on a Horner–Wadsworth–Emmons olefi-
nation of the b-iodo enal 18, obtained from ethyl-2-bu-
tynoate by treatment with NaI–HOAc,12 followed by
DIBAL reduction and MnO2 oxidation of the resulting
CH2Cl2, –78 °C to 0 °C, 2 h; 11, –78 °C to –20 °C, 18 h; (b)
Me4NBH(OAc)3, MeCN, HOAc, –40 °C to –20 °C, 2.5 h; (c)
(MeO)2CMe2, PPTS, CH2Cl2, reflux, 18 h; (d) Pd/C, H2, EtOAc, r.t.,
20 h; Ac2O, Et3N, CH2Cl2, r.t., 18 h; (e) TBAF, THF, r.t., 4 h; (f)
TEMPO, PhI(OAc)2, CH2Cl2, r.t., 2.5 h; (g) CrCl2, CHI3, THF–
dioxan (1:1), 0 °C, 18 h; (h) PPTS, MeOH, r.t., 20 h.
Synlett 2004, No. 8, 1359–1362 © Thieme Stuttgart · New York

LETTER
Studies Towards the Synthesis of Superstolide A
1361
agreement in the stereopentad region, with deviations
only in the unsaturated regions due to the presence of the
vinyl iodides (Table 1).
Table 1 Comparison of 1H NMR Data for Superstolide A and Ester 3
Protona
Superstolide A (1)
dHb, mult., J (Hz)
C23 Ester 3
d
Hc, mult., J (Hz)
2
3
5.70 d (15.3)
5.97 d (15.3)
7.35 dd (15.3, 10.2)
6.28 d (10.2)
6.15 d (14.4)
6.34 dd (14.4, 8.8)
2.61 m
7.21 dd (15.3, 11.2)
5.92 d (11.2)
6.29 d (15.3)
5.32 dd (15.3, 9.8)
2.71 m
4
20
21
22
23
24
25
26
28-Me
4.79 dd (10.5, 2.0)
1.82 m
4.99 dd (9.7, 1.6)
1.77 m
3.16 dd (10.5, 2.7)
4.18 m
3.10 m
4.18 br qnd (6.7, 2.0)
1.96 s
1.96 s
Scheme 3 Reagents and conditions: (a) NaI, HOAc, 70 °C, 12 h;
(b) DIBAL, CH2Cl2, –78 °C, 1.5 h; (c) MnO2, Et2O, r.t., 4 h; (d)
Ba(OH)2·8H20, (MeO)2P(O)CH2CO2Me, THF, r.t., 16 h; (e) LiOH,
THF–H2O (3:1), r.t., 5 h; (f) EDC, DMAP, CH2Cl2, –20 °C, 20 h; (g)
Ti(Oi-Pr)4, CH2Cl2, r.t., 20 h.
29-Me
33-Me
34-Me
35-Me
NH
1.92 s
2.71 s
1.07 d (6.9)
0.90 d (6.9)
1.05 d (6.9)
6.22 d (8.8)
3.32 d obs.
1.03 d (6.9)
0.88 d (7.0)
1.07 d (6.7)
6.15 obs.
alcohol (Scheme 3). Next, the aldehyde 18 was treated
with activated Ba(OH)2 and trimethyl phosphonoacetate
in THF,13 followed by exposure of the crude product
25-OH
3.96 d (3.7)
a Numbering as in ref.2a
mixture to LiOH in THF–H2O to complete saponification. b Authentic sample of 1 measured at 500 MHz in CDCl3 (ref.2a).
c Sample of fragment 3 measured at 400 MHz in CDCl3
Thus, the desired acid 8 was obtained in 47% yield over 5
steps, where NMR analysis indicated that the E,E-diene
geometry had been installed as required. In earlier work,14
we had found that esterification of hindered 1,3-diols may
be difficult when one of the alcohol functionalities is pro-
tected. To circumvent this problem, esterification of the
In summary, the C1–C5/C20–C26 segment segment 3 of
superstolide A was obtained in 12% yield over 13 steps
from (R)-alanine methyl ester. The synthetic strategy is
convergent and utilises novel syn boron aldol methodolo-
free 1,3-diol can be used to produce a mixture of hydroxy
gy to introduce the C23 and C24 stereocentres as required,
esters, which can then be isomerised under equilibrating
while the C25 stereocentre and the alkenes are also intro-
conditions to afford predominantly the more stable iso-
duced with a high level of control.
mer. To this end, a mixture of diol 7 and acid 8 were treat-
ed with an excess of EDC and DMAP at –20 °C for 20 h,
Acknowledgments
resulting in a 1:1 mixture of esters 3 and 19 in a combined
yield of 68% without any diester formation. Treatment of
this mixture with Ti(Oi-Pr)4 in CH2Cl2 at room tempera-
ture led to isomerisation by transacylation, resulting in
isolation of the esters 3 and 19 as a 7:1 mixture in 90%
yield. Following chromatographic separation, this provid-
ed the desired C23 ester 3, corresponding to the C1–C5/
C20–C26 segment of superstolide A. Unambiguous struc-
tural assignment of the C23 and C25 esters 3 and 19,
respectively, was made by COSY NMR analysis.6 Fur-
We thank the EPSRC, the EC (Network HPRN-CT-2000-0018) and
Pfizer for support.
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Synlett 2004, No. 8, 1359–1362 © Thieme Stuttgart · New York

1362
I. Paterson, A. C. Mackay
LETTER
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MHz, CDCl3): d = 7.41 (1 H, dd, J = 15.3, 10.3 Hz, H3), 6.53
(1 H, dd, J = 14.4, 8.3 Hz, H21), 6.30 (1 H, d, J = 9.9 Hz, H4),
6.12 (1 H, d, J = 14.4 Hz, H20), 6.06 (1 H, d, J = 15.3 Hz,
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2.2 Hz, H25), 4.40 (1 H, br qn, J = 6.8 Hz, H26), 3.27 (1H, dd,
J = 9.2, 2.2 Hz, H23), 2.72 (3 H, s, Me29), 2.53 (1 H, d, J = 4.0
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(1 H, m, H24), 1.15 (3 H, d, J = 6.7 Hz, Me35), 0.96 (3 H, d,
J = 7.0 Hz, Me33), 0.94 (3 H, d, J = 6.9 Hz, Me34). 13C NMR
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121.8, 114.1, 78.8, 75.8, 72.4, 45.8, 43.9, 36.6, 35.0, 23.5,
15.8, 14.1, 8.2. HRMS (ES+): m/z calcd for [M + H]+
C18H28I2NO4: 576.0108; found: 576.0104. MS (CI+): m/z
(%) = 576 (1) [M + H]+, 98 (100).
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Synlett 2004, No. 8, 1359–1362 © Thieme Stuttgart · New York