Spirastrellolide B: Construction of the C(26)-C(40) Northern Hemisphere and a related [5,5,7]-bis-spiroketal analogue

Article abstract of DOI:10.1021/ol301795a

Differential synthetic access to an advanced C26-C40 northern hemisphere fragment of spirastrellolide B and to a related [5,5,7]-bis-spiroketal analogue from a common intermediate has been achieved. Central to this venture is the regiocontrolled functiona

Full text of DOI:10.1021/ol301795a

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3998–4001
Spirastrellolide B: Construction of the
C(26)ꢀC(40) Northern Hemisphere and a
Related [5,5,7]-Bis-spiroketal Analogue
Xiaozhao Wang, Thomas J. Paxton, Ningkun Li, and Amos B. Smith III*
Department of Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, United States
Smithab@sas.upenn.edu
Received June 29, 2012
ABSTRACT
Differential synthetic access to an advanced C26ꢀC40 northern hemisphere fragment of spirastrellolide B and to a related [5,5,7]-bis-spiroketal
analogue from a common intermediate has been achieved. Central to this venture is the regiocontrolled functionalization of a C(31ꢀ32) alkyne,
exploiting different transition metal catalysts (cf. PtII and AuI).
The spirastrellolides A, B, D, and F (1ꢀ4; Figure 1)
comprise a novel family of architecturally complex marine
macrolides isolated by Andersen and co-workers from the
Caribbean marine sponge Spirastrella coccinea.1 Among
this family, spirastrellolide A (1) was found to possess
potent, selective activity as an inhibitor of protein phospha-
tase 2A (PP2A: IC50 = 1 nm; PP1: IC50 = 50 nm).1a,b The
complete structural assignment of spirastrellolide A how-
ever remained unclear, until the isolation of spirastrellolide
B (2), which permitted assignment of the complete relative
and absolute configuration of the macrolide core by single
crystal X-ray analysis.1c In 2007 the remaining stereoche-
mical issue, the C46 stereogenicity, was resolved by chemical
degradation of spirastrellolide D (3) methyl ester.1d
community.2 In 2008 the Paterson group reported an
elegant, first total synthesis of spirastrellolide A methyl
3
ester; later in 2009 and 2011, the Furstner group disclosed
€
their first- and second-generation syntheses of spirastrel-
lolide F (4) methyl ester.4 During the preparation of this
manuscript, the Paterson group also published a second-
generation synthesis of spirastrellolide A methyl ester.3c
Also of note is the Forsyth approach to the northern
hemisphere of spirastrellolide B.2k,l
(2) (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. (c) Paterson, I.; Anderson, E. A.;
Dalby, S. M.; Lim, J. H.; Maltas, P.; Moessner, C. Chem. Commun. 2006,
4186. (d) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Genovino, J.; Lim,
€
J. H.; Moessner, C. Chem. Commun. 2007, 1852. (e) Furstner, A.;
Fenster, M. D. B.; Fasching, B.; Godbout, C.; Radkowski, K. Angew.
Given the potent biological profile, in conjunction with
the complex molecular architecture, the spirastrellolides
have generated considerable interest in the synthetic
€
Chem., Int. Ed. 2006, 45, 5506. (f) Furstner, A.; Fenster, M. D. B.;
Fasching, B.; Godbout, C.; Radkowski, K. Angew. Chem., Int. Ed. 2006,
€
45, 5510. (g) Furstner, A.; Fasching, B.; O’Neil, G. W.; Fenster,
M. D. B.; Godbout, C.; Ceccon, J. Chem. Commun. 2007, 3045. (h)
Liu, J.; Hsung, R. P. Org. Lett. 2005, 7, 2273. (i) Liu, J.; Yang, J. H.; Ko,
C.; Hsung, R. P. Tetrahedron Lett. 2006, 47, 6121. (j) Yang, J.-H.; Liu, J.;
Hsung, R. P. Org. Lett. 2008, 10, 2525. (k) Wang, C.; Forsyth, C. J. Org.
Lett. 2006, 8, 2997. (l) Wang, C.; Forsyth, C. J. Heterocycles 2007, 72,
621. (m) Pan, Y.; De Brabander, J. K. Synlett 2006, 853. (n) Keaton,
K. A.; Phillips, A. J. Org. Lett. 2008, 10, 1083. (o) Chandrasekhar, S.;
Rambabu, C.; Reddy, A. S. Org. Lett. 2008, 10, 4355. (p) Sabitha, G.;
Rao, A. S.; Yadav, J. S. Synthesis 2010, 505. (q) Chen, J. L.-Y.; Brimble,
M. A. Chem. Commun. 2010, 46, 3967. (r) Chen, J. L.-Y.; Brimble, M. A.
J. Org. Chem. 2011, 76, 9417.
(1) (a) Williams, D. E.; Roberge, M.; Van Soest, R.; Andersen, R. J.
J. Am. Chem. Soc. 2003, 125, 5296. (b) Williams, D. E.; Lapawa, M.;
Feng, X.; Tarling, T.; Roberge, M.; Andersen, R. J. Org. Lett. 2004, 6,
2607. (c) Warabi, K.; Williams, D. E.; Patrick, B. O.; Roberge, M.;
Andersen, R. J. J. Am. Chem. Soc. 2007, 129, 508. (d) Williams, D. E.;
Keyzers, R. A.; Warabi, K.; Desjardine, K.; Riffell, J. L.; Roberge, M.;
Andersen, R. J. J. Org. Chem. 2007, 72, 9842. (e) Suzuki, M.; Ueoka, R.;
Takada, K.; Okada, S.; Ohtsuka, S.; Ise, Y.; Matsunaga, S. J. Nat. Prod.
2012, 75, 1192.
r
10.1021/ol301795a
Published on Web 07/24/2012
2012 American Chemical Society

however would be introduction of the carbonyl function-
ality at C31. Access to the alternative carbonyl at C32
would lead to the [5,5,7]-bis-spiroketal, not a completely
unrewarding event, inthataccesstothe latter wouldpermit
construction of novel analogues of the spirastrellolide
skeleton. Exploiting an alkyne to serve as a ketone surro-
gate would also hold promise of an efficient synthetic
sequence by eliminating otherwise required protecting
group manipulations. Construction of the requisite C37
stereogenicity in 7 in turn would entail a chelation-con-
trolled Mukaiyama aldol reaction. Further disconnection
of the C30ꢀC31 σ-bond via an alkyne-epoxide retron
reveals epoxide (ꢀ)-8, alkyne (þ)-9, and aldehyde (ꢀ)-10.
We began with construction of epoxide (ꢀ)-12,2q employ-
ing a two-step sequence from triol (ꢀ)-11, the latter
readily prepared from commercial D-(þ)-ribonic-γ-lactone7
(Scheme 1). Protection of the secondary alcohol as the PMB
ether furnished epoxide (ꢀ)-8, which upon union with the
Scheme 1. Fragment Union of Epoxide (ꢀ)-8 and Alkyne (þ)-9
Figure 1. Structure of spirastrellolide A (1), B (2), D (3), and F
(4). Retrosynthesis of spirastrellolide B northern hemisphere.
Intrigued with the spirastrellolides, we embarked in 2007
on the total synthesis of spirastrellolide B (2) and in
2010 reported the construction of a fully functionalized
C1ꢀC25 southern hemisphere (6).5 We now disclose con-
struction of an advanced C26ꢀC40 northern [5,6,6]-bis-
spiroketal fragment (ꢀ)-5, in conjunction with the [5,5,7]-
bis-spiroketal analogue (ꢀ)-25 (Scheme 3).
anion derived from alkyne 9, the latter prepared by the
method of Baker and Brimble,8 employing BF3•Et2O at low
temperature (ꢀ78 °C), led to (ꢀ)-13. Methylation of the
derived alcohol and removal of the THP protecting group
with PPTS in methanol completed construction of (ꢀ)-14.
The overall yield from (ꢀ)-11 was 28% (six steps).
From the retrosynthetic perspective, we envisioned con-
struction of the requisite [5,6,6]-bis-spiroketal of spiras-
trellolide B (2) to comprise a transition-metal-promoted
spiroketalization reaction (i.e., AuCl),6 involving the
C31ꢀC32-triple bond in 7 (Figure 1). Such a tactic would
require that the alkyne serve as a ketone surrogate. Critical
For the proposed Mukaiyama aldol reaction, a la
Forsyth,2k,l a three-step sequence involving Ley oxidation,9
methyl Grignard addition, and a second Ley oxidation
yielded ketone (ꢀ)-16 (Scheme 2). Kinetic enolization em-
ploying KHMDS at ꢀ78 °C in THF, followed by capture
with TMSCl, then furnished silyl enol ether 18, which in turn
was reacted, in the presence of MgBr2•Et2O, with aldehyde
(ꢀ)-10, prepared in two steps from known epoxide (ꢀ)-17.10
The derived aldol product (ꢀ)-19 was obtained both in
excellent yield and with high selectivity (85% over the two
steps; dr >15:1). The stereochemical outcome was assigned
(3) (a) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Lim, J. H.;
Genovino, J.; Maltas, P.; Moessner, C. Angew. Chem., Int. Ed. 2008,
47, 3016. (b) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Lim, J. H.;
Genovino, J.; Maltas, P.; Moessner, C. Angew. Chem., Int. Ed. 2008, 47,
3021. (c) Paterson, I.; Maltas, P.; Dalby, S. M.; Lim, J. H.; Anderson,
E. A. Angew. Chem., Int. Ed. 2012, 51, 2749. (d) Paterson, I.; Anderson,
E. A.; Dalby, S. M.; Lim, J. H.; Maltas, P.; Loiseleur, O.; Genovino, J.;
Moessner, C. Org. Biomol. Chem. 2012, 10, 5861. (e) Paterson, I.;
Anderson, E. A.; Dalby, S. M.; Lim, J. H.; Maltas, P. Org. Biomol.
Chem. 2012, 10, 5873.
(4) (a) O’Neil, G. W.; Ceccon, J.; Benson, S.; Collin, M.-P.; Fasching,
€
B.; Furstner, A. Angew. Chem., Int. Ed. 2009, 48, 9940. (b) Benson, S.;
Collin, M.-P.; O’Neil, G. W.; Ceccon, J.; Fasching, B.; Fenster, M. D. B.;
(7) Attwood, S. V.; Barrett, A. G. M. J. Chem. Soc., Perkin Trans. 1
1984, 1315.
(8) Baker, R.; Brimble, M. A. Tetrahedron Lett. 1986, 27, 3311.
(9) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(10) Lee, H.; Kim, H.; Baek, S.; Kim, S.; Kim, D. Tetrahedron Lett.
2003, 44, 6609.
(11) Fujisawa, H.; Sasaki, Y.; Mukaiyama, T. Chem. Lett. 2001, 190.
€
Godbout, C.; Radkowski, K.; Goddard, R.; Furstner, A. Angew. Chem.,
Int. Ed. 2009, 48, 9946. (c) Benson, S.; Collin, M.-P.; Arlt, A.; Gabor, B.;
Goddard, R.; Furstner, A. Angew. Chem., Int. Ed. 2011, 50, 8739.
€
(5) (a) Smith, A. B., III; Kim, D.-S. Org. Lett. 2007, 9, 3311. (b)
Smith, A. B., III; Smits, H.; Kim, D.-S. Tetrahedron 2010, 66, 6597.
(6) (a) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845. (b) Liu, B.; De
Brabander, J. K. Org. Lett. 2006, 8, 4907. (c) Aponick, A.; Li, C.-Y.;
Palmes, J. A. Org. Lett. 2009, 11, 121.
Org. Lett., Vol. 14, No. 15, 2012
3999

(ꢀ)-20. The mixture of hemiacetals (7) was then treated
with a catalytic amount of AuCl and PPTS in MeOH at rt.
Unfortunately the only product isolated appeared to be a
furan.12 Reasoning that solvent polarity might play a critical
role in this transformation, we turned to THF, a less polar/
aprotic solvent. Although furan formation again domi-
nated, we were gratified to isolate a bis-spiroketal with the
correct molecular weight, albeit in low (12%) yield.
Scheme 2. Chelation-Controlled Mukaiyama Aldol Reaction
Careful analysis of the high field NMR data (500 MHz)
suggested that the spiroketal appeared to be (ꢀ)-21, possessing
the [5,5,7]- and not the [5,6,6]-bis-spiroketal skeleton. Alter-
natively, treatment of alcohol (ꢀ)-22 to the same reaction
conditions (AuCl, PPTS) employing MeOH as solvent led to
diketone (ꢀ)-23 in 95% yield (Scheme 3). Careful analysis of
1
the 1Hꢀ H COSY data suggested that hydration of the alkyne
had occurred at C32, instead of the desired C31, to deliver
diketone (ꢀ)-23. Importantly, (ꢀ)-23 could be advanced to
bis-spiroketal (ꢀ)-21 in two steps and in 51% yield (i.e.,
removal of PMB ether and PPTS promoted cyclization),
and subseqently to (ꢀ)-25, upon treatment at rt with TASF
in DMF to remove the TBDPS group. The complete structure
of (ꢀ)-25 was assigned by 1D (1H, 13C, and DEPT135) and
2D (COSY, NOESY, HSQC, HMBC, and TOCSY) NMR
studies [see Supporting Information (SI)].
With this information in hand, we reasoned that, in the
conversion of 7 to (ꢀ)-21 (Scheme 4), intramolecular
attack of the C27 hydroxyl on the AuCl-activated alkyne,
involving a six-membered transition state, was not favor-
able (i.e., 5-exo-dig vs 6-exo-dig). Instead the conversion of
(ꢀ)-22 to (ꢀ)-23 more likely proceeds via an intermolecu-
lar pathway (attacked by solvent, i.e., methanol). A solu-
tion to this problem would be to eliminate both the
bimolecular and the five-membered intramolecular reac-
tion pathways by employing monoalcohol (ꢀ)-22 in an
aprotic solvent.
based on a chelation-controlled model.11 The newly gener-
ated hydroxyl group was then protected as methoxy methyl
(MOM) ether to furnish (ꢀ)-20.
To reveal the C27 and C38 hydroxyl groups in (ꢀ)-20 for
the proposed intramolecular alkyne spiroketalization, oxi-
dative cleavage of the PMB ethers with DDQ in CH2Cl2,
employing a pH 7 buffer, cleanly furnished 7 as a mixture of
hemiketals in 70% yield (Scheme 3). Selective, albeit ineffi-
cient removal of the C27 PMB group could also be achieved
upon slow addition of a solution of DDQ in CH2Cl2 at 0 °C
to furnish (ꢀ)-22 in 34% yield, with 40% recovery of
Scheme 3. Synthesis of a [5,5,7]-Bis-spiroketal Analogue of the Spiratrellolide B Northern Hemisphere
4000
Org. Lett., Vol. 14, No. 15, 2012

Scheme 4. Mechanistic Considerations and Possible Solutions
Scheme 5. Synthesis of Spirastrellolide B Northern Hemisphere
To explore this scenario, we first sought to secure a more
reliable, high-yielding route to alcohol (ꢀ)-22. The C27 PMB
hydroxyl protecting group in (ꢀ)-16 was thus interchanged
for a triethylsilyl (TES) group to furnish (ꢀ)-26 (Scheme 5),
which in turn was subjected to the previously developed
chelation-controlled Mukaiyama aldol reaction, followed by
a two-step protecting group reorganization to furnish alcohol
(ꢀ)-22. The overall yield for this six-step sequence was 61% .
With ample quantities of alcohol (ꢀ)-22 in hand, we
turned to the spirocyclization. Unfortunately all attempts
to achieve the desired C31 alkyne hydration employing
AuCl under different solvents/temperature regimes met
with failure.13 However, treatment with a Pt(II) catalyst
effectively led to the desired C31 alkyne functionalization
(Scheme 5).6b The optimal catalyst proved to be
[Cl2Pt(CH2CH2)]2, employed in Et2O in the presence of
comparison to the 1H and 13C NMR data of the natural
product and several previously reported synthetic in-
termediates (see SI). The strong NOE correlations
between H27 and H38 confirmed the double-anomeric
structure of the synthetic northern hemisphere of spir-
astrellolide B.
In summary, we have employed transiton-metal-
mediated regiocontrol to achieve selective alkyne activ-
ation to arrive at an advanced spirastrellolide B north-
ern hemisphere fragment and an intriguing [5,5,7]-bis-
spiroketal analogue from common intermediate (ꢀ)-22.
Studies toward the total synthesis of spirastrellolide
B, as well as possible analogues, continue in our
laboratory.
˚
4 A MS. An aqueous workup furnished a mixture of
hemiacetals 28, which without isolation was subjected to
a deprotection/cyclization sequence employing DDQ in a
mixture of CH2Cl2 and H2O (10:1). Subsequent treatment
with PPTS in CH2Cl2 generated (þ)-5, possessing the
[5,6,6]-bis-spiroketal of spirastrellolide B; the yield was
38% for the three steps from (ꢀ)-22. In addition, a minor
diastereomer (7:1 dr) was isolated (structure not assigned).
Alcohol (þ)-29 was then obtained upon removal of the silyl
protecting group (TBDPS) with TBAF in THF (83%).
Assignment of the complete structure of (þ)-29 was
based on a combination of 2D NMR studies (COSY,
NOESY, HMBC, and HMQC), in conjunction with
Acknowledgment. Financial support was provided by
the National Institutes of Health (Institute of General
Medical Sciences) through Grant GM-29028. We thank
Drs. George Furst and Jun Gu, and Dr. Rakesh Kohli at
the University of Pennsylvania for assistance in obtaining
NMR and high-resolution mass spectra, respectively.
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
€
(12) Furan formation was also observed by the Paterson, Furstner,
and Forsyth group during their synthetic ventures directed toward
construction of the northern hemisphere of the spirastrellolides.
(13) While the reaction in THF was very slow and required an excess
of AuCl reagent, reaction in CH2Cl2 returned a complex mixture, from
which the desired product was not identified.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
4001