Total synthesis of (+)-azaspiracid-1. Part I: Synthesis of the fully elaborated ABCD aldehyde

Article abstract of DOI:10.1002/anie.200701515

(Chemical Equation Presented) Has aspirations: The total synthesis of (+)-azaspiracid-1 has been realized. The ABCD fragment was synthesized in 20 linear steps and 16% overall yield through the enantioselective syntheses of the AB sulfone and the CD aldeh

Full text of DOI:10.1002/anie.200701515

Angewandte
Chemie
DOI: 10.1002/anie.200701515
Azaspiracid (1)
Total Synthesis of (+)-Azaspiracid-1. Part I: Synthesis of the Fully
Elaborated ABCD Aldehyde**
David A. Evans,* Lisbet Kværnø, Jason A. Mulder, Brian Raymer, Travis B. Dunn,
AndrØ Beauchemin, Edward J. Olhava, Martin Juhl, and Katsuji Kagechika
Dedicated to Professor Dieter Seebach on the occasion of his 70th birthday
(À)-Azaspiracid-1 (2, Figure 1) is a structurally complex
assignment 1, in which the relative configurations between the
ABCDE and FGHI domains, as well as the absolute config-
uration, remained uncertain.[2] The intriguing chemical struc-
ture of azaspiracid-1, in combination with its scarcity in
nature, has spurred considerable interest among the chemical
community.[3] These efforts resulted in a synthesis of the
proposed structure 1 in 2003 by the research group of
Nicolaou with the finding that this structure did not match
that of the natural product.[4] Subsequent efforts in the
research group of Nicolaou involving numerous degradation
studies and the synthesis of multiple diastereomers resulted in
a significant structural revision that allowed the unambiguous
structural assignment of (À)-azaspiracid-1 (2) in 2004.[5]
Based on these impressive studies, an improved total syn-
thesis of azaspiracid-1 in 39 linear steps was recently reported
by Nicolaou and co-workers.[6]
marine neurotoxin that is implicated in seafood poisoning.
Herein and in the following Communication,[7] we de-
scribe our efforts, which culminated in a synthesis of (+)-
azaspiracid-1 (ent-2, Scheme 1). This target requires only
minimal changes in our original synthesis plan that targeted
the originally proposed structure 1 of (À)-azaspiracid-1,
namely the design of a newAB ring fragment and the
synthesis of the enantiomer of the E ring fragment. Herein we
Figure 1. Originally proposed structure (1)[2] and correct structure of
(À)-azaspiracid-1 (2).[5]
Outbreaks of azaspiracid poisoning were first reported in
1995[1] and in 1998 the causative toxin was isolated in minute
amounts from blue mussels (Mytilus edulis). Extensive NMR
spectroscopic studies resulted in the proposed structural
[*] Prof. D. A. Evans, Dr. L. Kværnø, Dr. J. A. Mulder, B. Raymer,
T. B. Dunn, Dr. A. Beauchemin, E. J. Olhava, M. Juhl, Dr. K. Kagechika
Department of Chemistry & Chemical Biology
Harvard University
Cambridge, MA 02138 (USA)
Fax: (+1)617-495-1460
E-mail: evans@chemistry.harvard.edu
[**] Financial support has been provided by the National Institutes of
Health (GM-33328-20), the Merck Research Laboratories, Amgen,
and Eli Lilly. Fellowships were provided to L.K. by the Villum Kann
Rasmussen and the Carlsberg Foundations (Denmark), to J.A.M. by
the National Institutes of Health, to T.B.D. by the National Science
Foundation, to A.B. by the NSERC (Canada), and to M.J. by the
Technical University of Denmark.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. Retrosynthetic analysis of the ABCD aldehyde 3 of (+)-
azaspiracid-1 (ent-2). See Ref.[9] for abbreviations.
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address the asymmetric syntheses of the AB and CD ring
fragments and their assembly into the fully elaborated
ABCD portion of this natural product.
thesis[10] of alkene 8[11] and unsaturated Weinreb amide 9,[12]
which proceeded smoothly in the presence of the Grubbs–
Hoveyda catalyst 10[13] to provide unsaturated Weinreb amide
13 (88%). The remaining six-carbon-atom fragment was
introduced as the racemic alkyne 12, which was readily
prepared from acrolein (96%, 2 steps) and added chemo-
selectively as its dianion to the unsaturated Weinreb amide
13. This alkyne addition required some experimentation
before it was eventually found that transmetalation in the
presence of MgBr2·OEt2[14] as a mild Lewis acid, as well as the
addition of THF at a late stage of the reaction, were both
crucial in achieving the desired transformation. Thus, after
acetylation of the unpurified mixture, ene-ynone 14 was
obtained in 83% yield (2 steps).
Introduction of the stereocenter at C6 was then effected in
high yield and enantioselectivity using a stoichiometric CBS
reduction[15] (15, BH3·SMe2, 86%, 94–97% ee) to afford
alcohol 16. The subsequent semihydrogenation of the
alkyne under Lindlar conditions proceeded readily, although
the product was contaminated with 3–5% of the undesired
alkane that was separated from the major product at a later
stage. After protection of the alcohol as a TBS ether under
standard conditions (92%, 2 steps), the acetate was removed
(K2CO3, MeOH), and a subsequent Parikh–Doering oxida-
tion[16] gave the bisallylic silyl ether 17 (SO3·py, DMSO, 91%,
2 steps). The crucial formation of the lactol was subsequently
effected with HF·pyridine buffered with excess pyridine
(74%). To our relief, this lactol was smoothly transformed
into the desired lactol methyl ether in excellent yield (PPTS,
MeOH, 92%), thus validating the anticipated stability of the
lactol at C6 to acidic conditions (vide infra). Finally, the
sulfide moiety was oxidized to the derived sulfone (H2O2,
[(NH4)6Mo7O24], 88%) to conclude the synthesis of the
desired AB ring fragment 7 in 11 linear steps and 32% overall
yield.
The corrected (À)-azaspiracid structure (2)[5] contains an
ABC bis(spiroketal) synthon, nowcontaining two stabilizing
anomeric effects, that is presumed to be in its favored
configuration (Figure 1). Accordingly, a thermodynamically
controlled spiroketalization should be effective in controlling
both the spiroketal stereocenters at C10 and C13. The plan for
the deconstruction of the ABCD synthon 3 is outlined in
Scheme 1 and affords fragments 6 and 7 of comparable
complexity. The selection of the lactol methyl ether 7 rather
than an equivalent acyclic divinylcarbinol synthon was made
in response to the extreme lability of the hydroxy group at C6
in acyclic intermediates under a range of conditions.[8] It was
reasoned that the inclusion of the hydroxy group at C6 as its
corresponding lactol methyl ether 7 would influence its
stability in a positive manner. As depicted in Scheme 1, the
double bond in the ring is taken out of conjugation with the
À
C O bond at C6 in ketal 7, thus eliminating the impact of this
p bond toward hyperconjugative donation and chemical
labilization.
To preserve the desired oxidation state of the carboxy
terminus, the synthesis plan included the AB ring fragment 7
with the carboxylic acid protected as its tert-butyl ester
(Scheme 2). The synthesis was initiated with the cross-meta-
In the synthesis of the CD ring fragment 6, the enantio-
selective Cu2+-catalyzed glyoxylate-ene reaction reported by
our research group[17] provided the first stereocenter at C17
[Eq. (1), Scheme 3]. This reaction could routinely be con-
ducted on a 20 g scale in good yields and enantioselectivities
using 1 mol% of the Cu2+ complex 18 (89% yield, 98% ee).
In the presence of 0.1 mol% of 18, almost identical results
were obtained (86% yield, 96% ee) although the reaction
times to reach full conversion in the latter case increased
considerably (5 days compared with 12 h). Subsequently, the
resultant hydroxy ester 19 was converted into the correspond-
ing Weinreb amide[18] (MeNH(OMe)·HCl, Me3Al, 98%) for
which A1,3 strain is presumed to allowfor a PMB protection
under standard basic conditions (PMBBr, NaH, 95%) with no
detrimental epimerization of the stereocenter at C17
(Scheme 3).
Scheme 2. Synthesis of the AB Ring Fragment 7. Reagents and
conditions: a) 10 (5 mol%), CH2Cl2, 408C, 88%; b) PhSH, Et3N,
CH2Cl2; c) allenylMgBr, Et2O, 08C, 96% (2 steps); d) 12, nBuLi, Et2O,
À788C, then MgBr2·OEt2, then 13, À78 to 08C, THF added, then RT;
e) Ac2O, DMAP, py, CH2Cl2, 83% (2 steps); f) 15 (2 equiv), BH3·SMe2,
THF, 08C, 86%, 94–97% ee; g) H2 (1 atm), Pd/CaCO3/Pb (5%), py,
benzene; h) TBSCl, DMAP, imidazole, DMF, 92%, 3–5% alkane
(2 steps); i) K2CO3, MeOH; j) SO3·py; DMSO, iPr2NEt, CH2Cl2, À258C,
91% (2 steps); k) HF·py, py, THF, 08C, 74%; l) PPTS, HC(OMe)3,
MeOH, CH2Cl2, À108C, 92%; m) H2O2, [(NH4)6Mo7O24], MeOH, 08C,
88%. See Ref. [9] for abbreviations.
Metalation of the known iodide 21[19] with tBuLi[20]
provided the remaining four-carbon-atom subunit (À788C,
90%). The resulting a-alkoxyketone was reduced with L-
Selectride with Felkin control to afford alcohol 22 as the only
detectable diastereomer (96%, d.r. > 95:5). Careful ozonol-
ysis of the 1,1-disubstituted olefin in the presence of Sudan III
dye as an indicator[21] allowed for the selective oxidative
cleavage of the olefin (O3, À788C, then Me2S) without any
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As a silyl ether protecting group at C17 was required for
the global synthesis plan, the next two transformations of
tetrahydrofuran 24 (Scheme 3) comprised an oxidative
removal of the PMB group (DDQ, 94%) and a silylation of
the secondary alcohol at C17 (TESCl, 97%). Finally, the
benzyl group was best removed under radical anion con-
ditions (LiDBB,[23] 96%), followed by a Parikh–Doering
oxidation[16] to give aldehyde 6 (97%). Altogether, this
sequence efficiently provided the desired CD ring fragment
6 in 12 steps and 46% overall yield.
Although the a protons of the C1-ester and C12-sulfone
termini of the AB ring fragment are of comparable thermo-
dynamic acidity, we anticipated that a selective kinetic
deprotonation a to the sulfone might be feasible under the
appropriate experimental conditions. This expectation was
indeed borne out by experiment in the selective addition of
sulfone 27 to the TBS-protected aldehyde 28 [74% yield,
Eq. (3)]. Unfortunately, adduct 29 proved too unstable to
successfully participate in the subsequent derivatization into
the ABCD bis(spiroketal) and was abandoned for further
studies.[8] However, much to our surprise, the corresponding
addition of the lactol derivative 7 to aldehyde 6 was very
unselective for deprotonation at C12 under a variety of
experimental conditions [Eq. (4)]. These findings thus suggest
that although a deprotonation of the sulfone is generally
kinetically favored, subtle steric differences may have a
negative impact on the kinetics in such a deprotonations.
Scheme 3. Synthesis of the CD ring fragment 6. Reagents and con-
ditions: a) MeNH(OMe)·HCl, Me3Al, THF, 98%; b) PMBBr, NaH,
DMF, 95%; c) 21,[19] tBuLi, Et2O, À788C, 90%; d) L-Selectride, THF,
À788C, 96%; e) 1. O3, py, CH2Cl2/MeOH (5:1 v/v), À788C, then Me2S,
À788C to RT; 2. PPTS, MeOH, 90%; f) Et3SiH, BF3·OEt2, CH2Cl2,
À788C, 84%; g) DDQ, CH2Cl2/pH 7 buffer, 08C (9:1 v/v), 94%;
h) TESCl, imidazole, DMF, 97%; i) LiDBB, THF, À788C, 96%;
j) SO3·py, DMSO, iPr2NEt, CH2Cl2, À308C, 97%. See Ref. [9] for
abbreviations.
undesired oxidation of the benzylic ether
protecting groups. Subsequent ketalization
(PPTS, MeOH) afforded the methyl ketal 23
(90% yield, 2 steps). The desired trisubsti-
tuted tetrahydrofuran 24 could be readily
obtained by stereoselective reduction with
Et3SiH mediated by BF3·OEt2 (84% yield,
d.r. > 95:5), with the primary by-product
derived from an elimination reaction to the
corresponding undesired furan.
The observed diastereoselectivity in the
reduction of the oxocarbenium ion of 23 to give 24 is in good
agreement with the model for nucleophilic additions to five-
membered cyclic oxocarbenium ions proposed by Woerpel
and co-workers.[22] It is noteworthy that the analogous
reduction of the methyl ketal 25 with TBS protection at
O17 proceeded with no diastereoselectivity to give the
tetrahydrofuran 26 [Eq. (2)], which suggests that steric factors
also play a significant role for these sterically rather
encumbered substrates.
A solution to this obstacle was the reduction of the
carboxy terminus of 7 and protection as its silyl ether 30, as
depicted in Scheme 4 (LiAlH4, 92%; TIPSCl, 98%). Subse-
quent sulfone deprotonation with LDA and addition to
aldehyde 6 readily proceeded to give the two C12-diastereo-
meric ketosulfones 31 after Dess–Martin oxidation[24] of the
initial mixture of the four hydroxy sulfones (92% yield,
2 steps). Sodium amalgam excision of the sulfone moiety[25]
then provided ketone 32 as a single diastereomer in excellent
overall yield for the fragment coupling sequence (92%).
In the crucial spirocyclization event, optimal yields were
obtained when the TES ether was selectively removed with
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Communications
Scheme 4. Synthesis of the ABCD aldehyde 35. Reagents and conditions: a) LiAlH4, Et2O, À208C, 92%; b) TIPSCl, imidazole, DMF, 98%; c) 6,
LDA, THF, À788C; d) DMP, py, CH2Cl2, 92% (2 steps); e) Na/Hg (5%), NaH2PO4, THF/MeOH, À108C, 92%; f) TBAF, THF, À208C (workup);
g) PPTS, CH2Cl2, 08C (83%, 2 steps); h) TBAF, AcOH, DMF, 86%; i) SO3·py; DMSO, iPr2NEt, CH2Cl2, À308C, 91%. See Ref. [9] for abbreviations.
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one equivalent of TBAF at lowtemperature to form the
intermediary lactol 33, followed by treatment of the unpuri-
fied mixture with PPTS in a nonpolar solvent such as CH2Cl2.
Thus, the major and desired bis(spiroketal) isomer 34 was
obtained in overall 83% yield (2 steps).[26] The desired
bis(spiroketal) configuration of 34 was established by a key
NOE interaction between H6 and the methyl group at C14, as
also previously reported for analogous azaspiracid-derived
bis(spiroketal) structures.[2,5] Finally, chemoselective removal
of the TBDPS ether[27] (TBAF, AcOH, 86%) and subsequent
Parikh–Doering oxidation[16] (91%) afforded the desired
tetracyclic aldehyde 35.
In summary, the convergent sequence afforded the fully
elaborated ABCD aldehyde 35 in 20 linear steps and
16% overall yield. These advances led to the completion of
the synthesis of (+)-azaspiracid-1 (ent-2) as detailed in the
following Communication.[7]
Received: April 6, 2007
Keywords: ene reaction · natural products ·
.
nucleophilic addition · spiroketalization · total synthesis
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[26] The selective removal of the TES group was accompanied by
minor loss of the TIPS protecting group at C1. Since the crude
mixture of 33 was subjected directly to the PPTS-mediated
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DMP = Dess–Martin periodinane, DMSO = dimethylsulfoxide,
LDA = lithium diisopropylamide, LiDBB = lithium di-tert-butyl
biphenylide, Mes = 2,4,6-trimethylphenyl, Nu = nucleophile,
PMB = 4-methoxybenzyl, PPTS = pyridinium p-toluenesulfo-
nate, py = pyridine, TBAF = tetrabutylammonium fluoride,
TBDPS = tert-butyldiphenylsilyl, TBS = tert-butyldimethylsilyl,
TES = triethylsilyl, TIPS = triisopropylsilyl.
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