Studies towards the synthesis of the C29-C51 fragment of altohyrtin A

Article abstract of DOI:10.1055/s-1998-3140

The synthesis of the highly substituted E and F pyran fragment 23 of altohyrtin A 1 from tri-O-benzyl-D-glucal 5 is described. The synthesis of a model compound 31 containing the altohyrtin A triene side-chain outlines the proposed strategy for the elabor

Full text of DOI:10.1055/s-1998-3140

September 1998
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991
Studies Towards the Synthesis of the C29-C51 Fragment of Altohyrtin A
Eduardo Fernandez-Megia, Nelly Gourlaouen, Steven V. Ley* and Gareth J. Rowlands
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Received 3 July 1998
Abstract: The synthesis of the highly substituted E and F pyran
fragment 23 of altohyrtin A 1 from tri-O-benzyl-D-glucal 5 is described.
The synthesis of a model compound 31 containing the altohyrtin A
triene side-chain outlines the proposed strategy for the elaboration of the
F pyran.
The spongipyrans are a new family of marine macrolides which exhibit
1
an extraordinary potency as inhibitors of cancer cell growth. This,
along with their challenging structure, a 51-carbon chain, 42-membered
lactone ring and 6 pyran rings has promoted considerable synthetic
2
interest, culminating in the elegant total synthesis of altohyrtin A
3
4
(spongistatin 1) 1 by Kishi and altohyrtin C by Evans. We have
embarked on a total synthesis of altohyrtin A, the most potent of the
5,6
spongipyrans. In view of recent publications
we report here our
approach to the synthesis of the highly oxygenated EF pyrans and a
strategy for the introduction of the C44-C51 chlorodiene side-chain.
Figure 1
8
chlorine atoms with the ring substituents. The cyclopropane 8 was
obtained from the reductive dehalogenation of 7. All attempts to open
either the dichlorocyclopropane or the analogous dehalogenated
cyclopropane with carbon nucleophiles proved unsuccessful.
Cyclopropane 8 could be opened with methanol and N-iodosuccinimide
to furnish, after reduction of the iodide, the anomeric methoxide 9 in
Scheme 1 outlines the synthesis plan. The highly substituted F pyran
was to be constructed from readily available tri-O-benzyl-D-glucal 5
7
by the stereoselective introduction of C40 methyl group followed by
C-glycosidation and further manipulation to install the methyl ketone.
Stereocontrolled aldol reaction with the C29-C35 aldehyde 6 would
provide 4 which could readily be converted to the hemi-acetal thus
furnishing both the E and F pyran rings. Selective deprotection-
functionalisation of the C44 benzyl group of 4 would allow access to the
methyl ketone 3. In turn 3 could be elaborated by stereocontrolled aldol
coupling to furnish the chlorodiene side-chain and thus complete
synthesis of the C29-C51 fragment 2.
9
82% (for 2 steps).
Formation of the anomeric methoxide 9 provided an opportunity to
10
exploit methodology already developed within our group. We have
previously shown that anomeric sulfones can be readily synthesised,
easily handled and are reactive, versatile reagents in glycosidation and
C-glycosidation reactions. Conversion of 9 to the sulfone 10 by standard
manipulation was followed by displacement with a vinyl zinc reagent
to give 11 as an inconsequential mixture of anomers in good yield
(Scheme 3).
From the outset we were attracted by the idea of installing the C40
methyl group via stereoselective cyclopropanation of a glucal followed
8,9
by ring-opening to introduce functionality at C39. This would allow
The C38 alkene 11 was then converted to the methyl ketone 15 by a
short sequence of manipulations (Scheme 3). Ozonolysis, followed by
silica catalysed epimerisation gave the desired anomeric aldehyde
almost exclusively. Stereoselective addition of acetylene magnesium
bromide in toluene furnished a mixture of C38 alcohols, favouring the
desired R configuration 13. The selectivity was due to chelation of the
Grignard reagent with the ring oxygen. The stereochemistry was
confirmed by comparison of the Mosher's esters. It is possible to recycle
us to utilise a readily available carbohydrate starting material with three
stereocentres already in place. Treatment of tri-O-benzyl-D-glucal 5
under standard Simmons-Smith conditions results in the formation of
the cyclopropane from the wrong face. It is thought that the C41 oxygen
directs the carbene insertion. Using a non-metal induced carbene formed
from the hydrolysis of chloroform gave the desired
dichlorocyclopropane 7 in good yield and excellent selectivity (Scheme
2). The selectivity arises due to the steric interaction of the bulky

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With both fragments 6 and 15 in-hand the aldol coupling was
investigated. Initial studies investigated the use of lithium enolates. The
reaction was found to proceed with moderate yield but high selectivity
(6:1). Attempts to determine the stereochemistry at C35 via Mosher's
ester's were inconclusive. Instead the configuration was established by
n.O.e. studies of the correspondent hemi-acetal obtained by deprotection
of the two TES groups with HF/pyridine. It was shown that the major
product 22 had the wrong configuration.
the undesired S diastereoisomer via Mitsunobu inversion. The alkyne 13
could be hydrolysed in good yield with mercury oxide and sulfuric acid
to give the α-hydroxy ketone 14. Finally, protection of the C38 alcohol
as the triethyl silyl ether gave 15 in good yield. The efficiency of the
route has been demonstrated by the synthesis of multigram quantities of
the methyl ketone 15.
Use of chiral boron enolates was then investigated. Treatment of the
methyl ketone 15 with (-)-DIPCl and triethylamine followed by addition
of the aldehyde gave the desired diastereoisomer exclusively 22
13
(Scheme 5). Deprotection and concomitant cyclisation gave the hemi-
acetal 23 in excellent yield. Further manipulation of 23 will allow us the
introduction of the labile conjugated diene side chain (C45-C51) and
complete the synthesis of 2. The primary C44 benzyl group can be
selectively removed utilising either ferric chloride or acetic anhydride
with iodine. These strategies are currently under investigation.
As outlined before (Scheme 1), we envisioned that this labile side chain
(C45-C51) could be introduced through a aldol coupling between a
methyl ketone at C45 and aldehyde 26. In order to test the feasibility of
this approach it was decided to undertake preliminary studies on a
model ketone 28 that could be synthesised from the readily available
14
glucose derivative 27 that mimics the F-pyran moiety in Altohyrtin A.
Aldehyde 26 was synthesised via a one-pot Swern-Horner-Wadsworth-
15
Emmons olefination from the commercially available alcohol 24.
Thus, oxidation of 24 and treatment of the resulting aldehyde in situ
with triethyl phosphonoacetate-KtBuO gave 25 (100% E) in 33-36%
16
combined yield from 24. Reduction of 25 with DIBAL and Swern
17
oxidation of the resulting alcohol led to 26 in 51% combined yield as a
The C29-C35 aldehyde 6 was readily formed from pentanediol 16 in six
steps (Scheme 4). Monoprotection as the tetrahydropyranyl ether,
followed by oxidation with tetra-n-propylammonium perruthenate
very unstable oil that could be stored under Ar at -60 °C for several days
without loss of purity.
Methyl ketone 28 was obtained from 27 following a three steps
11
18
(TPAP) gave aldehyde 18. Stereoselective aldol coupling with the
sequence. Treatment of 27 with Tf2O led to the corresponding very
12
Evans auxiliary 19 gave the desired syn alcohol 20 which was
stable triflate in 94% yield. Reaction with 2-lithio-2-methyl-1,3-dithiane
18,19
converted to the protected C29-C35 aldehyde 6 via transamination,
protection as the triethyl silyl ether and reductive cleavage of the amide.
(88-94 %),
and deprotection of the resulting dithiane with MeI-
CaCO3 (87-91%) gave the desired ketone 28. The use of a sealed tube in

September 1998
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the deprotection step avoided the sequential additions of MeI as reported
before.
this side chain to the C29-C44 fragment already synthesised 23 are
currently being carried out in our laboratory.
20
Once 26 and 28 were in hand, the boron mediated aldol reaction [(+)-
21
DIP-Cl, Et3N] gave the desired coupling product 29 (diastereomeric
Acknowledgements
ratio 2.3:1 by HPLC) in a 63% yield. The configuration of the new
stereogenic centre in the major isomer was established by reaction with
(R)- and (S)-methoxyphenylacetic acids (DCC, DMAP, DCM) to give
the corresponding diastereomeric esters, both in 67% yield. Application
of the Trost-Mosher method for the determination of the absolute
configuration of secondary alcohols, to these diastereomeric esters,
confirmed the predicted configuration at C47.
N. G. thanks the Association pour la Recherche contre le Cancer, E. F.-
M. thanks the European Union for a Marie Curie Grant and G. J. R.
thanks the Royal Commission for the Exhibition of 1851 for funding.
We are also grateful for support from the BP endowment and the
Novartis Research Fellowship (S. V. L.).
22
References and Notes
From 29 only the methylenation step was required to complete the
synthesis of this model of the C44-C51 side chain of Altohyrtin A.
Several methods are described in the literature to achieve such
transformation, but due to the expected high instability of the C47
1.
Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. H.; Boyd, M. R.;
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23
hydroxy group, the mild Oshima-Lombardo reagent was chosen.
24
Protection of the free hydroxy group in 29 as SEM led to 30 in 76%
yield. When 30 was treated with 350 mol% of a stock solution of the
25
Oshima-Lombardo reagent (TiCl4·CH2Br2·Zn)
product 31 was obtained in 63% yield.
the methylenated
26
6
2.
A few examples are given below: Claffey, M. M.; Heathcock, C.
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In conclusion, we have developed a synthesis of the C29-C44 fragment
and the C44-C51 side chain of Altohyrtin A using pyranoside 27 as a
model system for the latter strategy. Studies towards the incorporation of

994
LETTERS
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1
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3
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1
26. 31: H NMR (CDCl , 600 MHz) δ 7.36-7.28 (15H, m), 6.23 (1H,
3
d, J 15.0 Hz), 6.00 (1H, dd, J 7.2 Hz, J 15.0 Hz), 5.35 (1H, s), 5.29
(1H, s), 4.98 (1H, d, J 10.8 Hz), 4.93-4.91 (3H, m), 4.80 (1H, d, J
10.6 Hz), 4.79 (1H, d, J 12.2 Hz), 4.67-4.59 (4H, m), 4.53 (1H, d,
J 3.5 Hz), 4.31 (1H, c, J 6.9 Hz), 3.98 (1H, t, J 9.2 Hz), 3.78 (1H, t,
J 9.9 Hz), 3.68-3.64 (1H, m), 3.53-3.48 (2H, m), 3.34 (3H, s), 3.19
(1H, t, J 9.1 Hz), 2.63 (1H, d, J 13.9 Hz), 2.42 (1H, dd, J 7.5 Hz, J
14.1 Hz), 2.30 (1H, dd, J 5.9 Hz, J 14.1 Hz), 2.07 (1H, dd, J 10.0
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1
13. 23: H NMR (CDCl , 600 MHz) δ 7.34-7.21 (15H, m), 5.04 (1H,
3
brs), 4.90 (1H, d, J 11.0 Hz), 4.82 (1H, d, J 11.0 Hz), 4.67 (1H, d,
J 11.0 Hz), 4.56 (1H, brs), 4.52 (1H, d, J 11.0 Hz), 4.49 (1H, d, J
12.0 Hz), 4.44 (1H, d, J 12.0 Hz), 4.19 (1H, brd, J 9.0 Hz), 4.10