Synthesis of the C1-C21 southern hemisphere of the originally proposed structure of spirastrellolide A

Article abstract of DOI:10.1055/s-2005-918449

A stereocontrolled synthesis of the C₁-C₂₁ [6,6]-spiro-acetal-containing domain of the originally assigned structure of spirastrellolide A is reported, exploiting asymmetric boron aldol methodology and an alkyne addition to a C₁

Full text of DOI:10.1055/s-2005-918449

PAPER
3225
Synthesis of the C1–C21 Southern Hemisphere of the Originally Proposed
Structure of Spirastrellolide A
S
ynthesia21
s
of the
C
–
1 n
C
Southern He
m
P
S
pir
a
astrellolide
t
A
erson,* Edward A. Anderson, Stephen M. Dalby
University Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336362; E-mail: ip100@cam.ac.uk
Received 8 August 2005
Dedicated to Professor Steven Ley on the occasion of his 60th birthday
premature cell mitosis.3 Synthetic interest in spiras-
trellolide A derives not only from its unique molecular ar-
chitecture,4 but also from its potential development as an
antitumour therapeutic agent. Given the central regulatory
Abstract: A stereocontrolled synthesis of the C1–C21 [6,6]-spiro-
acetal-containing domain of the originally assigned structure of
spirastrellolide A is reported, exploiting asymmetric boron aldol
methodology and an alkyne addition to a C17 aldehyde. Comparison
of the 1H NMR data obtained for this synthetic fragment with that role of PP2A in the cell, it may also have some value as a
for the corresponding region of spirastrellolide suggested some ste-
lead in the treatment of neurological and metabolic disor-
reochemical reassignment was required.
ders.
Key words: total synthesis, spiro compounds, macrolides, aldol
At the outset of our synthetic studies, extensive NMR
reactions, asymmetric synthesis
spectroscopic analysis performed by the Andersen group1
had led to a partial structural assignment of spiras-
trellolide as a 38-membered macrolide, as indicated in 1
Spirastrellolide A, a novel antimitotic macrolide isolated
but without assigning any stereochemistry in the C1–C11
by Andersen and co-workers from the Caribbean sponge
region5 (Scheme 1). The spirastrellolide macrolactone it-
Spirastrella coccinea in 2003,1 is a potent (IC50 = 1 nM)
self was characterized as containing a 2,6-disubstituted
tetrahydropyran (A ring) and two [6,6]-spiroacetals (BC
and selective inhibitor of protein phosphatase 2A
(PP2A).2 As such, it appears to exhibit a similar mode of
and DE rings). Significantly, both spiroacetal motifs ap-
action to other Ser/Thr phosphatase inhibitors, including
pear to benefit from stabilisation by a double anomeric ef-
fostriecin, okadaic acid and the calyculins, which induce
1
OTPS
3
O
OPMB
H
H
H
H
13
21
Spiroacetalisation
OTBS
O
A
O
A
1
17
3
7
7
TPSO
O
O
OPMB
OMe
TBS TBS
Alkyne add'n /
Lindlar red'n
9
21
13
6
O
O
B
OMe
TBSO
C
2
Boron aldol
H
O
OPMB
H
11
13
O
A
9
1
21
17
H
46
HO2C
TPSO
O
O
OPMB
OMe
TBS TBS
OH
OH
7
3
OMe
OH
E
O
1,5-anti
37
O
OH
D
O
1
O
3
H
H
Br
O
A
H
H
10
16
13
O
A
9
H
HO
H
OH
1
Br
7
TPSO
O
O
OPMB
9
13
O
B
O
OH
21
OMe
5
4
C
HO
1: Spirastrellolide A (original assignment)
Scheme 1 Retrosynthetic analysis of the C1–C21 southern hemisphere of the originally proposed structure 1 for spirastrellolide A.1,5
SYNTHESIS 2005, No. 19, pp 3225–3228
x
x.
x
x
.
2
0
0
5
Advanced online publication: 27.10.2005
DOI: 10.1055/s-2005-918449; Art ID: C05505SS
© Georg Thieme Verlag Stuttgart · New York

3226
I. Paterson et al.
PAPER
fect, with all substituents equatorially disposed. alkyne 7 with aldehyde 3. Recognition of a 1,5-anti rela-
Altogether, there are some 19 stereocentres embedded tionship between C9 and C13 guided our choice of a strate-
within this elaborate macrolactone core, along with two gic C9–C10 bond disconnection to reveal the methyl
hydroxyl-bearing stereocentres in the (Z,E)-1,4-diene side ketone 4, containing a masked alkyne functionality, and
chain appended to C37.
the A-ring aldehyde 5. Following precedent set by
ourselves6 and the Evans group,7 a boron-mediated aldol
coupling8 between 4 and 5 was anticipated to install the
desired C9 configuration relative to the inducing C13 stereo-
centre. A subsequent hydroxyl-directed 1,3-anti reduction
should then generate the required C11 stereocentre.
At this early stage in the structural elucidation of spiras-
trellolide, only a partial stereochemical assignment was
available,5 where the relationship between three stereo-
clusters (C1–C7, C9–C24 and C27–C38) was unknown. In
view of this ambiguity, our initial synthetic efforts to-
wards spirastrellolide focussed on constructing the C1–C21 As shown in Scheme 2, the synthesis of the C10–C16 sub-
southern hemisphere segment 2, containing both the [6,6]- unit 4 commenced from our lactate-derived ketone 89 and
spiroacetal and a candidate trans-disubstituted tetrahydro- the aldehyde 9 (prepared from glyoxal10). An anti aldol
pyran, as reported herein.
addition of the kinetically generated (E)-boron enolate (c-
Hex2BCl, Me2NEt) with a solution of freshly prepared al-
dehyde 9 gave the expected b-hydroxy ketone 10,11,12 as
essentially a single isomer (97:3 dr, 91%). Formation of
the PMB ether of aldol adduct 10 [PMBTCA, cat.
Sc(OTf)3] was followed by cleavage of the auxiliary un-
der standard conditions9b to deliver aldehyde 11 in 72%
yield. Corey–Fuchs13 homologation of 11 to the vinyl di-
bromide then proceeded smoothly (98%) to install the la-
tent terminal alkyne moiety. Finally, a Wacker oxidation14
provided the required methyl ketone 4 (41% from 8).
Our retrosynthesis of the C1–C21 segment 2 of spiras-
trellolide, as outlined in Scheme 1, is based on the planned
coupling of three key subunits 3, 4 and 5. We envisaged
that a suitable open-chain precursor 6 to the required
[6,6]-spiroacetal 2 might be derived from the coupling of
c-Hex2BCl, Me2NEt,
Et2O; 9; H2O2, MeOH,
pH 7 buffer
13
OBz
OBz
H
OH
O
O
Efficient access to the C1–C9 subunit 5, containing the
trans-disubstituted tetrahydropyran, was achieved in four
steps from the known15 dihydropyranone 12 (Scheme 2).
Luche reduction of 12, followed by acetylation, gave the
Ferrier rearrangement substrate 13 cleanly (94%). Fol-
lowing previous work within our group,16 treatment of ac-
(91%, 97:3 dr)
O
10
8
9
1. PMBTCA, Sc(OTf)3, PhMe
2. NaBH4, MeOH; K2CO3
3. NaIO4, MeOH, pH 7 buffer
(72%, 3 steps)
Br
16
10
1. PPh3, CBr4, CH2Cl2
H
O
Br
2. O2, PdCl2, CuCl,
DMF/H2O
Br
PMBO
O
OPMB
H
H
13
O
9
H
4
11
(63%, 2 steps)
Br
C10–C16 subunit
TPSO
O
O
OPMB
4
5
H
H
(–)-Ipc2BCl, Et3N, Et2O;
(79%, 97:3 dr) 5, –78 to –20 °C
1. NaBH4, CeCl3⋅7H2O, EtOH
2. Ac2O, Et3N, DMAP, CH2Cl2
O
O
TPSO
TPSO
Br
(94%, 2 steps)
H
H
11
13
OAc
O
12
O
9
Br
13
TPSO
OH
O
OPMB
(i-PrO)2TiCl2
OTBS
16
PhMe, –40 °C
(74%, >95:5 dr)
Me4NBH(OAc)3,
H
H
H
H
MeCN, AcOH, –30 °C
(92%, 95:5 dr)
H2, Pd/C,
EtOAc
O
A
9
H
O
H
O
1
Br
TPSO
O
TPSO
H
H
(94%)
11
O
9
5
14
Br
C1–C9 subunit
TPSO
TPSO
OH OH OPMB
17
1. TBSOTf, 2,6-lut., CH2Cl2
2. n-BuLi, THF, –30 °C
MgBr
(90%, 2 steps)
1.
O
OPMB
OPMB
CuI, THF (93%)
2. NaH, MeI, THF (96%)
H
H
21
O
17
H
O
3. OsO4, NaIO4, THF/H2O
(89%)
OMe
O
O
OPMB
15
3
TBS TBS
C17–C21 subunit
7
Scheme 2 Asymmetric synthesis of the three key subunits 3, 4 and
5.
Scheme 3 Aldol coupling of 4 and 5 followed by elaboration to al-
kyne 7.
Synthesis 2005, No. 19, 3225–3228 © Thieme Stuttgart · New York

PAPER
Synthesis of the C1–C21 Southern Hemisphere of Spirastrellolide A
3227
etate 13 with (i-PrO)2TiCl2 and TBSOCH=CH2 gave the AcOH (3:1) gave the 1,3-anti diol 17 (95:5 dr, 92%).
2,6-trans-dihydropyran 14 as a single isomer, which was Completion of the C1–C16 alkyne subunit 7 proceeded
followed by hydrogenation of the alkene to provide alde- smoothly in 90% yield from diol 17 via bis-TBS ether for-
hyde 5. The remaining C17–C21 subunit 3 was accessed mation (TBSOTf) and treatment with n-BuLi to reveal the
(73%, 3 steps) from the PMB ether 15 of (S)-glycidol terminal alkyne.
(Scheme 2). This involved copper-promoted epoxide
opening with allylmagnesium bromide followed by meth-
yl ether formation and oxidative cleavage of the alkene
using OsO4/NaIO4 to deliver the aldehyde 3.
At this stage, the fully elaborated open-chain precursor 6
for spiroacetal formation could be generated (Scheme 4).
Fragment union was achieved via lithiation of alkyne 7
using n-BuLi, followed by addition of aldehyde 3, to give
adduct 18, as an epimeric mixture at C17. Lindlar hydroge-
H
H
nation of 18 followed by Dess–Martin oxidation gave the
corresponding (Z)-enone 6 cleanly (77%, 3 steps). Grati-
fyingly, treatment of 6 with DDQ in buffered CH2Cl2 ef-
fected clean deprotection of the PMB ethers at C13 and C21
and led initially to the in situ formation of two spiroacetals
that equilibrated to a single isomer 2, which was isolated
in 61% yield. The successful formation of the desired
spiroacetal stereochemistry was readily confirmed by 1H
and 13C NMR analysis.11 A strong NOE enhancement be-
tween H13 and H21ax, also observed in the natural product,
confirmed that the C17 acetal centre of 2 possessed the de-
sired configuration. As shown in Figure 1, a close correla-
O
TPSO
O
O
OPMB
TBS TBS
7
O
OPMB
n-BuLi, THF, –20 °C
(93%)
H
3
OMe
H
H
O
OH
TPSO
O
O
OPMB
17
TBS TBS
18
OPMB
1. H2, Pd/CaCO3/Pb,
quinoline, MeOH (97%)
2. DMP, NaHCO3,
CH2Cl2 (86%)
1
MeO
tion between the H NMR data for the synthetic subunit
and spirastrellolide was observed within the C13–C20
spiroacetal region. In contrast, comparison of the C3–C12
region revealed substantial differences, which suggested
to us that the preliminary structural assignment of spiras-
trellolide as 15 was probably incorrect.
O
OPMB
H
H
13
21
O
17
TPSO
O
O
OPMB
OMe
TBS TBS
6
DDQ, CH2Cl2,
pH 7 buffer, 2 h
(61%)
1
OTPS
OTBS
3
H
H
NOE
O
7
Figure 1 1H NMR chemical shift comparison for the C1–C21 subunit
2 with spirastrellolide methyl ester 22 (Figure 2).
Hax
H
H OMe
21
13
O
17
O
TBSO
H
Around this time, the Andersen group revised the struc-
ture of spirastrellolide to 19 (Figure 2).2 This new struc-
ture features a cis-disubstituted tetrahydropyran (A ring)
and a [6,6]-spiroacetal (BC rings), together with addition-
al stereochemical assignments (cf. circled carbon atoms),
within the southern hemisphere. Furthermore, the north-
ern hemisphere region was subject to more radical struc-
tural revision, now featuring a [5,6,6]-bis-spiroacetal
(DEF rings) appended with a chlorine atom. In support of
this revised structure 19 for spirastrellolide, our subse-
quent studies have led to the synthesis of the C1–C25 sub-
unit 20, incorporating the appropriate stereochemical
changes at C7, C9 and C11, along with the C26–C40 subunit
21.18 Both fragments now show excellent agreement with
the corresponding NMR data obtained for the natural
product.19
2
Scheme 4 Coupling of 7 and 3 followed by elaboration into tricyclic
C1–C21 subunit 2.
With the various subunits in hand, we were now ready to
tackle the fragment coupling steps. We began by explor-
ing the aldol coupling of methyl ketone 4 with aldehyde 5,
involving the installation of the C9 stereocentre
(Scheme 3). Initially, treatment of aldehyde 5 with the di-
cyclohexylboron enolate of 4 (c-Hex2BCl, Et3N) led to
moderate selectivity (3:1 dr) in favour of the expected6
1,5-anti adduct 16. However, this substrate induction
could be significantly enhanced through reagent control,
employing the matched diisopinocampheylboron enolate
of 4 [(–)-Ipc2BCl, Et3N], to deliver adduct 16 as essential-
ly a single isomer (>97:3 dr) in 79% yield. The stereo-
chemical information at C9 could now be relayed to C11
via an Evans–Saksena reduction.17 Thus, treatment of b-
hydroxy ketone 16 with Me4NBH(OAc)3 in MeCN–
In summary, we have completed a highly convergent syn-
thesis of the C1–C21 spiroacetal-containing fragment 2
based on the original structural assignment of spiras-
Synthesis 2005, No. 19, 3225–3228 © Thieme Stuttgart · New York

3228
I. Paterson et al.
PAPER
(5) In addition to the originally proposed structure by Professor
Andersen, as reported in ref. 1, a preliminary stereochemical
assignment was made by us for the C1–C11 region.
(6) (a) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron
Lett. 1996, 37, 8585. (b) Paterson, I.; Collett, L. A.
Tetrahedron Lett. 2001, 42, 1187.
(7) (a) Evans, D. A.; Coleman, P. J.; Côté, B. J. Org. Chem.
1997, 62, 788. (b) Evans, D. A.; Côté, B.; Coleman, P. J.;
Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10893.
(8) Cowden, C. J.; Paterson, I. Organic Reactions, Vol. 51;
Paquette, L. A., Ed.; Wiley: New York, 1997, 1–200.
(9) (a) Paterson, I.; Wallace, D. J.; Velazquez, S. M.
Tetrahedron Lett. 1994, 35, 9083. (b) Paterson, I.; Wallace,
D. J.; Cowden, C. J. Synthesis 1998, 639.
H
O
F
E
OMe
Cl
O
O
D
RO2C
37
O
1
O
OH
3
26
H
O
H
25
HO
H
OH
7
11
9
13
O
B
O
OH
OMe
21
HO
C
19: R = H, Spirastrellolide A
22: R = Me
H
O
OMe
Cl
E
O
(10) Crimmins, M. T.; Kirincich, M. T.; Wells, S. J.; Choy, A. L.
Synth. Commun. 1998, 28, 3675.
40
F
O
D
O
O
(11) All new compounds gave spectroscopic data in agreement
with the assigned structures. Compound 2 had
26
OH
21
[a]D22 = +34.5 (c 0.80, CHCl3); 1H NMR (500 MHz, C6D6):
d = 7.78–7.83 (m, 4 H, ArH), 7.22–7.29 (m, 6 H, ArH), 5.60
(dd, J = 9.9, 2.4 Hz, 1 H, H15), 5.51 (dd, J = 9.9, 1.7 Hz, 1 H,
H16), 4.38 (m, 1 H, H11), 4.22 (m, 1 H, H9), 4.07 (m, 1 H, H3),
4.03 (m, 1 H, H7), 3.94 (m, 1 H, H21eq.), 3.88 (m, 3 H, 2 × H1,
1
OH
OH
H
H
PMBO
25
A
O
HO
H
H21ax.), 3.81 (m, 1 H, H13), 3.15 (m, 1 H, H20), 3.10 (s, 3 H,
O
OH
OMe
O
OMe), 2.12 (m, 1 H, H8), 2.10 (m, 1 H, H2), 2.09 (1H, m,
H10), 2.04 (m, 1 H, H10), 2.02 (m, 1 H, H14), 1.97 (m, 1 H,
B
HO
C
H19ax.), 1.93 (m, 2 H, 2 × H12), 1.84 (m, 1 H, H18eq., H19eq.),
20
1.82 (m, 1 H, H2), 1.76 (m, 1 H, H8), 1.65 (m, 1 H, H6eq.),
1.58 (m, 1 H, H4eq.), 1.50 (m, 1 H, H18ax.), 1.49 (m, 2 H,
2 × H5), 1.36 (m, 1 H, H6ax.), 1.25 (m, 1 H, H4ax.), 1.19 (s, 9
H, SitBu), 1.05 (s, 9 H, SitBu), 1.03 (s, 9 H, SitBu), 0.80 (d,
J = 7.1 Hz, 3 H, Me14), 0.26 (s, 3 H, SiMe), 0.28 (s, 3 H,
SiMe), 0.24 (s, 3 H, SiMe), 0.20 (s, 3 H, SiMe); 13C NMR
(125 MHz, C6D6): d = 135.8, 135.7, 134.2, 134.1, 134.0,
129.7, 129.4, 93.0, 74.9, 71.0, 68.4, 68.3, 67.7, 67.6, 63.7,
61.5, 55.7, 46.6, 43.0, 42.5, 36.3, 34.5, 34.3, 30.8, 29.8, 27.0,
26.1, 26.0, 25.3, 19.3, 18.8, 18.2, 18.1, 17.0, –3.5, –3.7, –3.9,
–4.0; HRMS (ES+): m/z [M + H]+ calcd for C51H87O7Si3:
895.5754; found: 895.5752.
Figure 2 Revised structural assignment of spirastrellolide2 and syn-
thetic fragments prepared.18
trellolide A (16% yield over the longest linear sequence of
14 steps). Key features include the use of asymmetric bo-
ron aldol reactions to configure several stereocentres,
along with the mild and selective conditions employed for
spiroacetalisation. In more recent efforts directed towards
the total synthesis of spirastrellolide A (19), this prelimi-
nary work has already helped guide our strategy for the
construction of the stereochemically revised C1–C25 sub-
unit 20.
(12) The configuration at C13 was confirmed by 1H NMR analysis
using the Kakisawa–Mosher method: Ohtani, I.; Kusumi, T.;
Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092.
(13) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(14) Tsuji, J. Synthesis 1984, 369.
Acknowledgment
(15) (a) Smith, A. B.; Minbiole, K. P.; Verhoest, P. R.; Schelhaas,
M. J. Am. Chem. Soc. 2001, 123, 10942.
We thank the EPSRC (EP/C541677/1), Homerton College, Cam-
bridge (Research Fellowship to E.A.A.) and Merck for support, and
Professor Raymond Andersen (University of British Columbia) for
helpful discussions.
(b) Dihydropyranone 12 was conveniently accessed via a
Jacobsen hetero-Diels–Alder reaction between
Danishefsky’s diene and TPSO(CH2)2CHO in 94% yield and
99% ee.
References
(16) Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron 1995, 51,
9413.
(17) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(1) Williams, D. E.; Roberge, M.; Van Soest, R.; Andersen, R.
J. J. Am. Chem. Soc. 2003, 125, 5296.
(2) Williams, D. E.; Lapawa, M.; Feng, X.; Tarling, T.;
Roberge, M.; Andersen, R. J. Org. Lett. 2004, 6, 2607.
(3) (a) Le, L. H.; Erlichman, C.; Pillon, L.; Thiessen, J. J.; Day,
A.; Wainman, N.; Eisenhauer, E. A.; Moore, M. J. Invest.
New Drugs 2004, 22, 159. (b) Honkanen, R. E.; Golden, T.
Curr. Med. Chem. 2002, 9, 2055.
(4) For reviews on the synthesis of marine macrolides, see:
(a) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041.
(b) Paterson, I.; Yeung, K.-S. Chem. Rev. 2005, 105, in
press.
(18) (a) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O.
Org. Lett. 2005, 7, 4121. (b) Paterson, I.; Anderson, E. A.;
Dalby, S. M.; Loiseleur, O. Org. Lett. 2005, 7, 4125.
(19) For other synthetic studies towards spirastrellolide, see:
(a) Liu, J.; Hsung, R. P. Org. Lett. 2005, 7, 2273.
(b) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O.
Abstracts of Papers 229th National Meeting of the American
Chemical Society, San Diego; ACS: Washington D.C., 2005,
ORGN-331. (c) Wang, C.; Forsyth, C. J. Abstracts of Papers
229th National Meeting of the American Chemical Society,
San Diego; ACS: Washington D.C., 2005, ORGN-414.
Synthesis 2005, No. 19, 3225–3228 © Thieme Stuttgart · New York