Total synthesis of (+)-azaspiracid-1. An exhibition of the intricacies of complex molecule synthesis

Published on Web 11/12/2008

Total Synthesis of (+)-Azaspiracid-1. An Exhibition of the

Intricacies of Complex Molecule Synthesis

David A. Evans,* Lisbet Kværnø, Travis B. Dunn, Andre´ Beauchemin,

Brian Raymer, Jason A. Mulder, Edward J. Olhava, Martin Juhl, Katsuji Kagechika,

and David A. Favor

Department of Chemistry & Chemical Biology, HarVard UniVersity,

Cambridge, Massachusetts 02138

Received June 18, 2008; E-mail: evans@chemistry.harvard.edu

Abstract: The synthesis of the marine neurotoxin azaspiracid-1 has been accomplished. The individual

fragments were synthesized by catalytic enantioselective processes: A hetero-Diels-Alder reaction to afford

the E- and HI-ring fragments, a carbonyl-ene reaction to furnish the CD-ring fragment, and a Mukaiyama

aldol reaction to deliver the FG-ring fragment. The subsequent fragment couplings were accomplished by

aldol and sulfone anion methodologies. All ketalization events to form the nonacyclic target were

accomplished under equilibrating conditions utilizing the imbedded conﬁgurations of the molecule to adopt

one favored conformation. A ﬁnal fragment coupling of the anomeric EFGHI-sulfone anion to the ABCD-

aldehyde completed the convergent synthesis of (+)-azaspiracid-1.

Introduction

Background. Azaspiracid poisoning is a recent toxic syn-

drome ﬁrst reported in 1995. On this occasion, at least 8 people

in The Netherlands became ill after consuming blue mussels

(Mytilus edulis) harvested in Killary Harbor, Ireland.¹Subse-

quently, intoxications related to azaspiracid poisoning have been

reported in several countries including the U.K., Norway,²Spain,

France,³and Italy⁴as well as Morocco.⁵An active search for

the causative toxin provided the motivation for its isolation by

the Satake group in 1998.⁶Only minute amounts of the active

toxin (2 mg) were obtained as an amorphous solid from 20 kg

of mussel meat collected at Killary Harbor. Extensive NMR

studies of this material resulted in the proposed structural

assignment 1 of azaspiracid-1 (Figure 1). In this nonacyclic

structure, the absolute conﬁguration remained uncertain. In

addition, the ﬂexible methylene bridge at C27 prevented an

unambiguous determination of the relative conﬁgurations be-

tween the ABCDE- and FGHI-domains. All remaining stere-

ochemistries such as the dense acyclic C19-C21 junction

between the D- and the E-rings were assigned based on an

analysis of NOE interactions.⁶A total of 11 azaspiracid

analogues differing slightly in their methylation and hydroxy-

lation patterns have subsequently been described; ﬁve of these

analogues were isolated and characterized by NMR spectro-

Figure 1. Originally proposed structure (1)⁶and correct structure of (-)-

azaspiracid-1 (2).²²

scopy^6,7while the remaining analogues were identiﬁed by

tandem mass spectrometry.⁸

The origin of these toxins has been proposed to be a marine

dinoﬂagellate,⁴and their occurrence has subsequently been

reported in multiple shellﬁsh species including mussels, oysters,

scallops, clams, and cockles.⁹Extensive studies of the azaspi-

(1) McMahon, T.; Silke, J. Harmful Algae News 1996, 14, 2.

(2) James, K. J.; Furey, A.; Lehane, M.; Ramstad, H.; Aune, T.; Hovgaard,

P.; Morris, S.; Higman, W.; Satake, M.; Yasumoto, T. Toxicon 2002,

40, 909–915.

(3) Magdalena, A. B.; Lehane, M.; Krys, S.; Fernandez, M. L.; Furey,

A.; James, K. J. Toxicon 2003, 42, 105–108.

(7) (a) Ofuji, K.; Satake, M.; McMahon, T.; Silke, J.; James, K. J.; Naoki,

H.; Oshima, Y.; Yasumoto, T. Nat. Toxins 1999, 7, 99–102. (b) Ofuji,

K.; Satake, M.; McMahon, T.; James, K. J.; Naoki, H.; Oshima, Y.;

Yasumoto, T. Biosci. Biotechnol. Biochem. 2001, 65, 740–742.

(8) James, K. J.; Sierra, M. D.; Lehane, M.; Magdalena, A. B.; Furey, A.

Toxicon 2003, 41, 277–283.

(4) James, K. J.; Moroney, C.; Roden, C.; Satake, M.; Yasumoto, T.;

Lehane, M.; Furey, A. Toxicon 2003, 41, 145–151.

(5) Taleb, H.; Vale, P.; Amanhir, R.; Benhadouch, A.; Sagou, R.; Chaﬁk,

A. J. Shellﬁsh Res. 2006, 25, 1067–1070.

(6) Satake, M.; Ofuji, K.; Naoki, H.; James, K. J.; Furey, A.; McMahon,

T.; Silke, J.; Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 9967–9968.

(9) Furey, A.; Moroney, C.; Magdalena, A. B.; Saez, M. J. F.; Lehane,

M.; James, K. J. EnViron. Sci. Technol. 2003, 37, 3078–3084.

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2008 American Chemical Society

J. AM. CHEM. SOC. 2008, 130, 16295–16309 16295

A R T I C L E S

Evans et al.

racids have revealed a number of toxic effects such as cytoxicity

in mammalian cell lines,¹⁰teratogenic effects in ﬁnﬁsh,¹¹

pertubation of cell adhesion,¹²disorganization of the Actin

cytoskeleton,¹³and inhibition of the electrical activity of

neuronal networks,¹⁴although the speciﬁc modes of all such

actions of azaspiracids yet remain unclear.¹⁵The scarcity of

azaspiracids from natural sources serves as a further complica-

tion in mechanistic elucidations aiming to better understand their

toxicity and ultimately prevent their hazards to human health.

The intriguing structure of this toxin has furthermore served

to stimulate interest in the chemical community, in particular

by the research groups of Nicolaou,¹⁶Carter,^17,18Forsyth,¹⁹and

others.²⁰The Nicolaou group reported a successful synthesis

of the proposed structure 1 in 2003, only to clearly reveal its

nonidentity to the isolated natural product.²¹Subsequent impres-

sive efforts in the Nicolaou group using a combination of

degradation studies and the synthesis of multiple diastereomers

resulted in a signiﬁcant structural revision of azaspiracid-1 by

total synthesis. These landmark studies allowed the unambiguous

Figure 2. 3D-representation of (-)-azaspiracid-1 (2) highlighting stabilizing

anomeric effects in the molecule.

structural assignment of (-)-azaspiracid-1 (2) in 2004.²²As

highlighted in Figure 1, the position of the A-ring oleﬁn (yellow)

was different, and the relative conﬁgurations of the CD- and

FGHI-domains (green) were opposite in the correctly assigned

natural product 2 compared to the originally proposed structure

1. On the basis of these ﬁndings, an improved synthesis of (-)-

azaspiracid-1 (2) was recently reported by the Nicolaou group.²³

Synthesis Plan. Conformational analysis of azaspiracid-1

suggests that each of the multiple ketals exists in their

thermodynamically favored conﬁguration on the basis of ano-

meric stabilization and steric effects (2, Figure 2). Accordingly,

a number of thermodynamically controlled ketalization events

were incorporated into the synthesis plan under the assumption

that the desired conﬁgurations would be achieved under

equilibrating conditions. Notably, whereas the ABC-bis(spiroket-

al) portion of the originally proposed structure 1⁶contained only

one anomeric effect (not shown), the ABC-moiety of the

corrected (-)-azaspiracid-1 structure (2)²²incorporates two

stabilizing anomeric effects and is presumed to be in its favored

conﬁguration. Thus, a thermodynamically controlled spiroket-

alization should be effective in controlling both spiroketal

stereocenters at C10 and C13. We also anticipated that the FG-

ring bicyclic ketal might also be constructed by an acid-catalyzed

ketalization. Finally, we suspected that the HI-ring spiroaminal

would spontaneously cyclize to provide the desired conﬁguration

at the C36 ring junction from an acyclic precursor with an

unprotected C40 amino group.

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Total Synthesis of (+)-Azaspiracid-1

A R T I C L E S

Scheme 1. Retrosynthetic Analysis of (+)-Azaspiracid-1 (ent-2)^a

^aSee ref 31 for abbreviations.

In our own studies,²⁴we elected to pursue the synthesis of

(+)-azaspiracid-1 (ent-2, Scheme 1). This target required only

minimal changes in our original synthesis plan designed to

pursue the initially proposed structure 1 of (-)-azaspiracid-1.

Thus, the design of a new AB-ring fragment and the synthesis

of the enantiomer of the E-ring fragment were required while

all other regions of the molecule remain unaltered.

Our principal disconnections in the deconstruction of (+)-

azaspiracid-1 (ent-2) are outlined in Scheme 1. In the ﬁnal

fragment coupling, the C21-anion of the anomeric EFGHI-

sulfone 4 was envisioned to be a C20 electrophile such as

aldehyde 3. This strategy could provide a convergent approach

to (+)-azaspiracid-1 since all 9 rings are formed prior to this

ﬁnal sulfone anion addition. Related sulfonyl carbanion additions

have substantial literature precedents, both in the original

investigations from the carbohydrate ﬁeld^25,26and subsequently

in several advanced fragment couplings in some of our previous

total synthesis projects.^27-29

to give the intermediary ketone 5. After retrosynthetic instal-

lation of a sulfone moiety at C12, an addition of this C12-sulfone

anion could provide AB-ring fragment 7 and CD-ring fragment

8 of comparable structural complexity. In the assemblage of

the EFGHI-sulfone 4, ketalization events under equilibrating

conditions were likewise incorporated to give intermediate 9.

The illustrated fragment couplings to construct the C21-C40

chain of 9 would be two aldol addition events: a boron-mediated

aldol addition to form the C26-C27 bond and a chelate-

controlled Mukaiyama aldol addition³⁰to form the C34-C35

bond. Thus, the three fragments 10, 11, and 12 of equal

complexity would represent our initial targets in the synthesis

of the fully elaborated EFGHI-sulfone 4.

The integration of catalytic enantioselective processes into

our synthesis projects has been an ongoing objective in our

research program. In this regard, the Cu-catalyzed hetero-

Diels-Alder reaction to give methyl-substituted dihydropyrans

The plan for the deconstruction of the ABCD synthon 3

involves a thermodynamically controlled spiroketalization event

(30) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011–

1014. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc.

1974, 96, 7503–7509. (c) Mukaiyama, T. Angew. Chem., Int. Ed. 2004,

43, 5590–5614.

(24) For initial communications of this work, see:(a) Evans, D. A.; Kværnø,

L.; Mulder, J. A.; Raymer, B.; Dunn, T. B.; Beauchemin, A.; Olhava,

E. J.; Juhl, M.; Kagechika, K. Angew. Chem., Int. Ed. 2007, 46, 4693–

4697. (b) Evans, D. A.; Dunn, T. B.; Kværnø, L.; Beauchemin, A.;

Raymer, B.; Olhava, E. J.; Mulder, J. A.; Juhl, M.; Kagechika, K.;

Favor, D. A. Angew. Chem., Int. Ed. 2007, 46, 4698–4703.

(31) Abbreviations: Ac ) acetyl, Bn ) benzyl, Boc ) t-butyloxycarbonyl,

CBS ) Corey-Bakshi-Shibata, COD ) 1,5-cyclooctadiene, m-CPBA

) m-chlorperbenzoic acid, Cy ) cyclohexyl, DDQ ) 2,3-dichloro-

5,6-dicyano-1,4-benzoquinone, Dess-Martin periodinane ) 1,1,1-

tris(acetoxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one, DIBALH ) di-

isobutylaluminum hydride, DMAP ) 4-dimethylaminopyridine, DMF

) N,N-dimethylformamide, DMSO ) dimethyl sulfoxide, HMPA )

hexamethylphosphoramide, HPLC ) high pressure liquid chromatog-

raphy, LDA ) lithium diisopropylamide, LiDBB ) lithium di-tert-

butyl biphenylide, LiHMDS ) lithium hexamethyldisilazide, Mes )

2,4,6-trimethylphenyl, pyr ) pyridine, MPLC ) medium pressure

liquid chromatography, PG ) protecting group, PMB ) 4-methoxy-

benzyl, PPTS ) pyridinium p-toluenesulfonate, RaNi ) Raney Nickel,

RT ) room temperature, L-Selectride ) lithium tri-sec-butylborohy-

dride, TBAF ) tetrabutylammonium ﬂuoride, TBAI ) tetrabutylam-

monium iodide, TBDPS ) tert-butyldiphenylsilyl, TBS ) tert-

(25) (a) Ley, S. V.; Lygo, B.; Wonnacott, A. Tetrahedron Lett. 1985, 26,

535–538. (b) Greck, C.; Grice, P.; Ley, S. V.; Wonnacott, A.

Tetrahedron Lett. 1986, 27, 5277–5280.

(26) (a) Beau, J. M.; Sinay, P. Tetrahedron Lett. 1985, 26, 6185–6188. (b)

Beau, J. M.; Sinay, P. Tetrahedron Lett. 1985, 26, 6189–6192. (c)

Beau, J. M.; Sinay, P. Tetrahedron Lett. 1985, 26, 6193–6196.

(27) (a) Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew. Chem., Int. Ed.

1997, 36, 2738–2741. (b) Evans, D. A.; Trotter, B. W.; Cote, B.;

Coleman, P. J. Angew. Chem., Int. Ed. 1997, 36, 2741–2744. (c) Evans,

D. A.; Trotter, B. W.; Cote, B.; Coleman, P. J.; Dias, L. C.; Tyler,

A. N. Angew. Chem., Int. Ed. 1997, 36, 2744–2747.

(28) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Cote, B.; Dias, L. C.;

Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671–8726.

(29) (a) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette,

A. B.; Lautens, M. Angew. Chem., Int. Ed. 1998, 37, 2354–2359. (b)

Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet,

J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540–7552.

butyldimethylsilyl, Tebbe reagent

) (µ-chloro)(µ-methylene)-

bis(cyclopentadienyl)(dimethylaluminum)titanium, Teoc ) 2-(trim-

ethylsilyl)ethoxycarbonyl, TES ) triethylsilyl, TIPS ) triisopropylsilyl,

TMS ) trimethylsilyl, Tr ) trityl (triphenylmethyl), trisyl ) 2,4,6-

trisisopropylbenzenesulfonyl, Ts ) p-toluenesulfonyl.

9

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A R T I C L E S

Evans et al.

(eq 3)³²was speciﬁcally developed for the synthesis of the

azaspiracid E-ring fragment 10. Independently, the glyoxylate-

ene reaction to afford R-hydroxy-γ,δ-unsaturated esters (eq 3)³³

could be used to form the C17 stereocenter of the CD-ring

fragment 8 while the Mukaiyama aldol reaction to furnish

unsaturated lactones featuring 1,2-anti diol arrays (eq 3)³⁴could

be explored to construct the C32-C33 motif of the FG-ring

fragment 11.

Figure 3. Depiction of C6 CO*-orbital in AB-ring fragment 7.

Scheme 2. Synthesis of the C1-C12 Chain of the AB-Ring

Fragment^a

^aReagents and conditions: (a) 27 (5 mol%), CH₂Cl₂, 40 °C, 88%; (b)

PhSH, Et₃N, CH₂Cl₂; (c) allenylMgBr, Et₂O, 0 °C, 96% (2 steps); (d) 29,

n-BuLi, Et₂O, -78 °C, then MgBr₂·OEt₂, then 30, -78 to 0 °C, THF added,

then RT; (e) Ac₂O, DMAP, pyr, CH₂Cl₂, 83% (2 steps). See ref 31 for

abbreviations.

attempted cross metathesis³⁵between alkene 25³⁶and acrylate

26³⁷was low yielding with the Grubbs second-generation

catalyst³⁸(10-35% yield), the more stable Grubbs-Hoveyda

catalyst 27³⁹was considerably more efﬁcient, affording Weinreb

amide 30 in excellent yield (88%). The C7-C12 fragment was

introduced as the racemic acetylene 29, readily prepared from

acrolein by conjugate addition of thiophenol, followed by

addition of the allenyl Grignard reagent (96% yield, 2 steps).

The two fragments were coupled by the selective 1,2-addition

of the dianion derived from acetylene 29 to the unsaturated

Weinreb amide 30. After considerable experimentation, optimum

conditions involved the conversion of acetylene 29 to its derived

Grignard reagent by deprotonation with n-butyllithium and

Results and Discussion

40

transmetalation with MgBr₂·OEt₂followed by the addition

Synthesis of the AB-Ring Fragment 7. In the design of the

azaspiracid AB-ring fragment, the major obstacle was antici-

pated to be the transposed A-ring oleﬁn in the revised azaspi-

racid-1 structure (2), thus creating a labile C6 divinylcarbinol

stereocenter. In order to suppress the lability of this stereocenter,

we selected the C10 lactol methyl ether 7, which includes the

C6 divinylcarbinol in the ketal formation, as our targeted AB-

ring fragment. As depicted in Figure 3, the endocyclic double

bond is taken out of conjugation with the C6 C-O bond in

ketal 7. This eliminates the impact of this π-bond toward

hyperconjugative donation, thus inﬂuencing the stability of the

C6 divinylcarbinol stereocenter in a sufﬁciently positive manner.

In order to preserve the desired oxidation state of the C1

carboxyl terminus, we incorporated the C1 carboxylic acid as

its derived t-Bu ester into our synthesis plan (Scheme 2). While

of THF at a late stage of the reaction to facilitate solubilization.

Since the product of the alkyne addition proved somewhat

unstable, direct acetylation of the unpuriﬁed mixture provided

the C1-C12 ene-ynone 31 in 83% overall yield for the 2 steps.

On the basis of literature precedents for the enantioselective

reduction of ene-ynones,⁴¹the C6-stereocenter was introduced

with high enantioselectivity in a supra-stoichiometric CBS-

reduction⁴²using 2 equiv of oxazaborolidone 32 and BH₃·SMe₂

to afford the desired alcohol 33 (86%, 94-97% ee, Scheme

(35) (a) Choi, T. L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int.

Ed. 2001, 40, 1277–1279. (b) Connon, S. J.; Blechert, S. Angew.

Chem., Int. Ed. 2003, 42, 1900–1923.

(36) Wright, S. W.; Hageman, D. L.; Wright, A. S.; McClure, L. D.

Tetrahedron Lett. 1997, 38, 7345–7348.

(37) Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 1735–1738.

(38) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,

953–956.

(32) (a) Evans, D. A.; Olhava, E. J.; Johnson, J. S.; Janey, J. M. Angew.

Chem., Int. Ed. 1998, 37, 3372–3375. (b) Evans, D. A.; Johnson, J. S.;

Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635–1649.

(33) (a) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay,

S. W. J. Am. Chem. Soc. 1998, 120, 5824–5825. (b) Evans, D. A.;

Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am.

Chem. Soc. 2000, 122, 7936–7943.

(39) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H.

J. Am. Chem. Soc. 1999, 121, 791–799.

(40) Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling,

D. E.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 5583–5601.

(41) (a) Garcia, J.; Lopez, M.; Romeu, J. Synlett 1999, 429–431. (b) Garcia,

J.; Lopez, M.; Romeu, J. Tetrahedron: Asymmetry 1999, 10, 2617–

2626. (c) Yun, H. D.; Danishefsky, S. J. J. Org. Chem. 2003, 68,

4519–4522.

(34) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos,

K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121,

669–685.

9

16298 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Total Synthesis of (+)-Azaspiracid-1

A R T I C L E S

Scheme 4. Initial Synthesis of the CD-Ring Fragment^a

Scheme 3. Synthesis of the AB-Ring Fragment 7^a

^aReagents and conditions: (a) 32 (2 equiv), BH₃·SMe₂, THF, 0 °C, 86%,

94-97% ee; (b) H₂(1 atm), Pd/CaCO₃/Pb (5%), pyr, benzene; (c) TBSCl,

DMAP, imidazole, DMF, 92%, 3-5% C4-C5 alkane (2 steps); (d) K₂CO₃,

MeOH; (e) SO₃·Pyr, DMSO, i-Pr₂NEt, CH₂Cl₂, -25 °C, 91% (2 steps);

(f) HF ·pyr, pyr, THF, 0 °C, 74%; (g) PPTS, HC(OMe)₃, MeOH, CH₂Cl₂,

-10 °C, 92%; (h) H₂O₂, (NH₄)₆Mo₇O₂₄, MeOH, 0 °C, 88%; (i) LiAlH₄,

Et₂O, -20 °C, 92%; (j) TIPSCl, imidazole, DMF, 98%. See ref 31 for

abbreviations.

^aReagents and conditions: (a) NaH, BnBr, CH₂Cl₂, 0 °C to RT, 99%;

(b) DIBALH, toluene, -94 °C; (c) ZnCl₂, 36, 59% (2 steps), dr 93:7; (d)

O₃, MeOH, CH₂Cl₂, -78 °C, then Me₂S, RT, 79%; (e) Et₃SiH, BF₃·OEt₂,

CH₂Cl₂, -78 °C, 82%, dr 90:10. See ref 31 for abbreviations.

3).⁴³Initial attempts to use a catalytic amount of oxazaboroli-

done 32 were detrimental both for the yield and the observed

enantioselectivity in this transformation. Semihydrogenation of

the alkyne under Lindlar conditions proceeded in high yield,

although the product was contaminated with 3-5% of the

undesired C4-C5 alkane that was separated from the major

product by MPLC at a later stage. Subsequent TBS-protection

(92% desired product over two steps) was followed by removal

of the acetate moiety (K₂CO₃, MeOH). In the oxidation to the

ꢀ,γ-unsaturated ketone 34, Dess-Martin periodinane also oxi-

the derived sulfone (H₂O₂, (NH₄)₆Mo₇O₂₄, 88%). In a later

variation on the synthesis plan, the oxidation of the carboxyl

terminus needed to be altered (vide supra). Accordingly, the

ester terminus of this synthon was reduced and protected as its

silyl ether (LiAlH₄, 92%; TIPSCl, 98%), thus concluding the

synthesis of the desired AB-ring fragment 7 and its carboxylate

analogue 34 in 13 linear steps from 25.

dized the phenylsulﬁde to the corresponding sulfoxide.⁴⁴

A

Parikh-Doering oxidation⁴⁵using Et₃N as the base afforded the

product 34 accompanied by approximately 20% of the undesired

R,ꢀ-unsaturated ketone resulting from base-induced oleﬁn

migration. This undesired side reaction was suppressed using

the sterically hindered i-Pr₂NEt as the base to give the desired

ꢀ,γ-unsaturated ketone 34 in good yield (SO₃·pyr, DMSO,

i-Pr₂NEt, 91%, 2 steps).

The stage was now set for the crucial lactol formation of the

C6 alcohol. This was best effected with HF ·pyr buffered with

excess pyridine at 0 °C to give primarily the desired lactol (74%)

accompanied by 20-25% of the undesired conjugated trienone

resulting from elimination of the C6 silyl ether substituent. To

our relief, this lactol was smoothly transformed into the desired

lactol methyl ether in excellent yield (PPTS, MeOH, 92%). This

was the ﬁrst time among various substrates investigated that

the C6 divinylcarbinol moiety proved stable to acidic conditions,

thus validating the anticipated stability of the C6-lactol (Figure

3) and providing us with a credible lead for the anticipated

spiroketalization. Finally, the sulﬁde moiety was oxidized to

Synthesis of the CD-Ring Fragment 8. Initial Synthesis via

a Stereoselective C14-Methylation. The ﬁrst of two syntheses

of this fragment is illustrated in Scheme 4. In our synthesis of

this synthon, we envisioned that the enantioselective Cu²⁺

-

catalyzed glyoxylate-ene reaction developed in these laboratories

could provide the initial C17-stereocenter (eq 3).³³Further

studies with these substrates proved that the reaction could

routinely be conducted on a 20-g scale in good yields and

enantioselectivities using 1 mol% of the bis(aquo)Cu²⁺complex

19⁴⁶(89% yield, 98% ee, Scheme 4). In addition, the Cu²⁺

-

catalyst was sufﬁciently Lewis acidic that commercial ethyl

glyoxalate could be used directly in its polymerized form without

prior distillation to afford the monomeric aldehyde. Whereas

the substrate concentration in these experiments (0.27 M) was

governed by the limited solubility of complex 19 in CH₂Cl₂,

concomitant lowering of the catalyst loading and an increase

of the substrate concentration (0.89 M) allowed for the use of

only 0.1 mol % of catalyst 19. Almost identical results were

obtained (86% yield, 96% ee) although the reaction times to

reach full conversion in the latter case increased considerably

(12 h versus 5 days, respectively).

(42) (a) Hirao, A.; Itsuno, S.; Nakahama, S.; Yamazaki, N. J. Chem. Soc.,

Chem. Commun. 1981, 315–317. (b) Itsuno, S.; Ito, K.; Hirao, A.;

Nakahama, S. J. Chem. Soc., Chem. Commun. 1983, 469–470. (c)

Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109,

5551–5553. (d) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.;

Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925–7926. (e) Corey,

E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1987–2012.

(43) After silylation of the C6-alcohol, the four diastereomers formed in

the reduction step were separable by HPLC and allowed for the

determination of the enantiomeric excess.

(44) Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 575–

578.

(45) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505–

5507.

(46) Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos,

K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541–4544.

9

J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16299

A R T I C L E S

Evans et al.

Scheme 6. Second Synthesis of the CD-Ring Fragment 8^a

The resultant R-hydroxy ester 20 was subsequently benzylated

(NaH, BnBr, 99%) and reduced to the corresponding aldehyde

35 (DIBALH, -94 °C) that was used directly without puriﬁca-

tion in the next step. The zinc homoenolate of siloxycyclopro-

pane 36⁴⁷was then prepared in situ and added stereoselectively

to aldehyde 35 according to the Kuwajima procedure.⁴⁸In

accordance with presumed chelate control exerted by the Zn²⁺

Lewis acid, the resulting protected syn-diol 37 was obtained in

high diastereoselectivity (59%, dr 93:7, two steps). Ozonolysis

of the oleﬁn in the presence of methanol directly afforded the

C19 lactol methyl ethers 38 in 79% yield. The C19 stereocenter

was then established in a stereoselective reduction with Et₃SiH

mediated by BF₃·OEt₂to afford the desired trisubstituted

tetrahydrofuran 39 (82%, dr 90:10). The observed diastereose-

lectivity in this reduction is in good agreement with the

stereoelectronic model 40 for nucleophilic additions to 5-mem-

bered cyclic oxocarbenium ions proposed by Woerpel.⁴⁹

At this stage, our strategy for the stereoselective introduction

of the C14-methyl substituent was inﬂuenced by a report by

Narasaka that acyclic δ-hydroxy esters such as 41 can be

alkylated with high stereoselectivity (eq 4). The presence of

HMPA was proven to be critical for the observed stereoselec-

tivity as silyl-trapping experiments afforded silyl enol ethers

of opposite stereochemistry in the absence and presence of

HMPA, respectively. An 8-membered internal chelate 42 in the

presence of HMPA was invoked as a possibility for explaining

the observed high stereoselectivity.⁵⁰

^aReagents and conditions: (a) MeNH(OMe) ·HCl, Me₃Al, THF, 98%;

(b) PMBBr, NaH, DMF, 0 °C, 95%; (c) 47,⁵³t-BuLi, Et₂O, -78 °C, then

46, 90%; (d) L-Selectride, THF, -78 °C, 96%, dr >95:5; (e) (i) O₃, pyridine,

CH₂Cl₂/MeOH (5:1 v/v), -78 °C, then Me₂S, -78 °C to RT; (ii) PPTS,

MeOH, 90%; (f) Et₃SiH, BF₃·OEt₂, CH₂Cl₂, -78 °C, 84%, dr >95:5; (g)

DDQ, CH₂Cl₂/pH 7 buffer (9:1 v/v), 0 °C, 94%; (h) TESCl, imidazole,

DMF, 97%; (i) LiDBB, THF, -78 °C, 96%; (j) SO₃·Pyr, DMSO, i-Pr₂NEt,

CH₂Cl₂, -30 °C, 97%. See ref 31 for abbreviations.

C14 methyl group (Scheme 6). In this regard, the hydroxy ester

20 derived from the carbonyl ene reaction (Scheme 4) was

converted into the corresponding Weinreb amide⁵²(MeNH-

(OMe)·HCl, Me₃Al, 98%). The C17 hydroxy group was then

protected as its derived PMB ether 46 under standard basic

conditions with no epimerization of the lone stereocenter

(PMBBr, NaH, DMF, 95%), presumably prevented by A^1,3

strain of the Weinreb amide.

Metalation of the readily available iodide 47⁵³with t-BuLi⁵⁴

followed by addition of Weinreb amide 46 then introduced the

remaining 4-carbon subunit (-78 °C, 90%). Notably, optimal

results were obtained when 1.5 equiv of t-BuLi relative to the

iodide 47 were used, while 2 equiv of t-BuLi afforded substantial

amounts of the undesired t-Bu-ketone. The resulting R-alkox-

yketone was then reduced with L-Selectride to afford alcohol

48 as the only detectable diastereomer (96%, dr >95:5). This

stereoselective reduction, presumably the result of Felkin control,

was conﬁrmed by advanced Mosher’s ester analysis.⁵⁵Careful

ozonolysis of the 1,1-disubstituted oleﬁn in the presence of

Sudan III dye as an indicator⁵⁶allowed for the selective

oxidative cleavage of the oleﬁn (O₃, -78 °C, then Me₂S) without

Prior to the actual methylation event, ethyl ester 39 was

converted into its derived amide 44 with the magnesium amide

of morpholine⁵¹(82%, Scheme 5). It was assumed that A^1,3

strain in amide 44 would prevent bis(alkylation), thus allowing

the use of excess external base to achieve full conversion in

the methylation. The subsequent C14-methylation thus pro-

ceeded in excellent yield and moderately good diastereoselec-

tivity to afford the alkylated product 45 (LiHMDS, 96%, dr

86:14).

(47) Nakamura, E.; Shimada, J.; Kuwajima, I. Organometallics 1985, 4,

641–646.

(48) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am.

Chem. Soc. 1987, 109, 8056–8066.

Scheme 5. C14-Methylation^a

(49) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am.

Chem. Soc. 1999, 121, 12208–12209.

(50) Narasaka, K.; Ukaji, Y.; Watanabe, K. Bull. Chem. Soc. Jpn. 1987,

60, 1457–1464.

(51) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,

U. H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461–5464.

(52) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.

(b) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12,

989–993.

^aReagents and conditions: (a) i-PrMgCl, morpholine, THF, -78 to -20

°C, 82%; (b) LiHMDS, MeI, THF, -78 °C, 96%, dr 86:14. See ref 31 for

abbreviations.

(53) (a) Vong, B. G.; Abraham, S.; Xiang, A. X.; Theodorakis, E. A. Org.

Lett. 2003, 5, 1617–1620. (b) Evans, D. A.; Urpi, F.; Somers, T. C.;

Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215–

8216.

(54) (a) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404–

5406. (b) Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem.

1990, 55, 5406–5409.

Improved Synthesis of the CD-Ring Fragment 8 via a

Direct Introduction of a C14-Methylated Fragment. While the

above ﬁndings afforded us a workable route to the CD-ring

fragment, we decided to investigate a modiﬁed approach to the

orthogonally protected CD-fragment 8 (Scheme 1) which would

involve the direct introduction of a fragment incorporating the

(55) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.

Soc. 1991, 113, 4092–4096. (b) Dale, J. A.; Mosher, H. S. J. Am.

Chem. Soc. 1973, 95, 512–519.

(56) Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980, 807–

810.

9

16300 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Total Synthesis of (+)-Azaspiracid-1

A R T I C L E S

Scheme 7. Synthesis of the ABCD-aldehyde 3^a

^aReagents and conditions: (a) 7 (1.6 equiv), LDA, THF, -78 °C; then 8 (1.0 equiv); (b) Dess-Martin periodinane, pyr, CH₂Cl₂, 92% (2 steps); (c) Na/Hg

(5%), NaH₂PO₄, THF/MeOH, -10 °C, 92%; (d) TBAF, THF, -20 °C (workup); (e) PPTS, CH₂Cl₂, 0 °C (83%, 2 steps); (f) TBAF, AcOH, DMF, 86%; (g)

SO₃·Pyr, DMSO, i-Pr₂NEt, CH₂Cl₂, -30 °C, 91%. See ref 31 for abbreviations.

any accompanying oxidation of the benzylic ether protecting

groups. Subsequent ketalization (PPTS, MeOH) afforded the

methyl ketal 49 (90%, 2 steps). In analogy to the reduction to

give 39 described in Scheme 4, stereoselective reduction with

Et₃SiH mediated by BF₃·OEt₂then provided the desired

trisubstituted tetrahydrofuran 50 (84%, dr >95:5) with the

primary byproduct being derived from elimination to the

corresponding undesired furan.

Whereas the observed diastereoselectivity in the 49f50

oxocarbenium ion reduction (dr >95:5) is in agreement with

the stereoelectronic model 40 proposed by Woerpel,⁴⁹it is

noteworthy that the analogous reduction of the O17-TBS

protected methyl ketal 51 proceeded with no diastereoselectivity

to give tetrahydrofuran 52 (dr 1:1, eq 5). This result suggests

that steric factors also play a signiﬁcant role for these sterically

encumbered substrates.

C12-sulfone under the appropriate experimental conditions in the

presence of a C1 t-Bu ester, although the R-protons of esters and

sulfones are of comparable thermodynamic acidity. This expecta-

tion was born out by initial investigations using the sulfone 53,

prepared by essentially the same sequence⁵⁸as previously described

for AB-ring fragment 7, for which the C6 divinylcarbinol moiety

was masked only as its acyclic silyl ether. Thus, selective addition

of sulfone 53 to the C17-TBS-protected aldehyde 54 proceeded to

give a mixture of diastereomeric hydroxysulfones 55 (74% yield,

eq 6).

Since a labile C17-silyl ether was required for the projected

ketalization events, the PMB group was exchanged for a TES

ether by oxidative cleavage with DDQ (94%) and reprotection

under standard conditions (TESCl, 97%, Scheme 6). As this

TES ether proved to be labile to standard palladium-catalyzed

hydrogenolysis conditions, the terminal benzyl ether was

removed under radical anion conditions (LiDBB,⁵⁷96%).

Finally, a Parikh-Doering oxidation⁴⁵afforded aldehyde 8 in

97% yield. Altogether, this second-generation sequence obviates

the need for any diastereomer separation and efﬁciently provided

the desired CD-ring fragment 8.

Union of the AB- and CD-Ring Fragments. With the AB- and

CD-ring fragments in hand, we proceeded to investigate their

coupling and further elaboration into the ABCD-bis(spiroketal).

In the initial synthesis plan, we anticipated that a selective kinetic

deprotonation of the AB-ring fragment might be feasible R to the

Unfortunately, as eluded to earlier in our discussion of Figure

3, adducts 55 incorporating acyclic C6-divinylcarbinol moieties

proved to be too unstable to successfully participate in the

subsequent derivatization into the ABCD-bis(spiroketal) under

a variety of conditions and were abandoned for further studies.

However, much to our surprise, the corresponding addition of

the superﬁcially similar sulfone 56 to C17-TES-protected

aldehyde 8 was nonselective for C12 deprotonation under a

variety of experimental conditions (eq 7). These ﬁndings suggest

that although R-deprotonation of the C12 sulfone moiety may

be kinetically favored over enolization of the C1 ester, subtle

steric differences may have a negative impact on the kinetics

in such desired R-deprotonations.

(57) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924–

1930. (b) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110,

854–860.

Assembly of the ABCD-Aldehyde 3. A simple solution to the

above obstacle was realized using the AB-ring fragment 7 with

9

J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16301

A R T I C L E S

Evans et al.

Scheme 8. syn-1,3-Dimethyl Synthons Embedded in Azaspiracid-1

the C1 terminus protected as its silyl ether (Scheme 7). With

this pattern of orthogonal functionalities, sulfone deprotonation

could readily be effected with LDA as also reported for

structurally similar sulfone anion additions,¹⁸a base which in

previous experiments had displayed inferior kinetic selectivity

for the sulfone moiety (eqs 6 and 7). The addition of the sulfonyl

carbanion derived from 7 (1.6 equiv) to aldehyde 8 proceeded

to give an initial mixture of four C12-C13 hydroxysulfones

mixed with excess sulfone 7. Subsequent Dess-Martin oxidation⁵⁹

afforded the two C12-diastereomeric ketosulfones 6 in 92% yield

for the 2 steps. Subsequent recovery of unreacted sulfone 7 was

achieved in 76% yield. The yield in this step is based on the

limiting aldehyde reaction component. Sodium amalgam exci-

sion of the sulfone moiety under mild conditions (Na/Hg,

NaH₂PO₄)⁶⁰then provided ketone 5 as a single diastereomer in

92% yield.

Scheme 9. Synthesis of the Tetrahydropyran 59^a

In the spirocyclization event, the TES ether was selectively

removed with 1 equiv of TBAF at low temperature to form the

intermediary lactol 57. This step was followed by treatment of

the unpuriﬁed mixture with PPTS in a nonhydroxylic solvent

such as CH₂Cl₂. Under these conditions, the desired bis-

(spiroketal) isomer 58 was obtained in 83% yield (2 steps).⁶¹

The inclusion of a hydroxylic solvent such as MeOH led to the

undesired formation of signiﬁcant amounts of dimethylketals

under otherwise identical spirocyclization conditions. The

desired, thermodynamically favored bis(spiroketal) conﬁguration

in 58 was established by an NOE interaction between H6 and

the methyl group at C14 (see 3D-depiction of 58) as also

previously reported for analogous azaspiracid-derived bis-

(spiroketal) structures.^6,22Finally, the C20 terminus was elabo-

rated by the selective removal of the TBDPS ether⁶²(TBAF,

AcOH, 86%) followed by a Parikh-Doering oxidation⁴⁵

(SO₃·pyr, DMSO, 91%) to furnish the desired aldehyde 3. In

summary, the above convergent sequence afforded the fully

elaborated ABCD-aldehyde.

^aReagents and conditions: (a) KOt-Bu, DMSO, 70 °C, 70%; (b)

2-propenylMgBr, THF/Et₂O, -78 °C, 80%; (c) 15 (2 mol%), 3Å MS, Et₂O,

-40 °C, dr 94:6, 97% ee, 84% 60; (d) H₂(1 atm), Pd/C (5 mol%), EtOAc,

dr 98:2, 95% 59. See ref 31 for abbreviations.

The two components of the hetero-Diels-Alder reaction, 62⁶³

and 64,⁶⁴were readily prepared on multigram scales using slight

modiﬁcations of reported literature procedures (Scheme 9). The

subsequent cycloaddition proceeded readily using low loadings

of the bench-stable hydrated copper complex 15 (2 mol %),

provided it was dehydrated with molecular sieves prior to use.

In contrast to the related cycloadditions reported previously for

which THF was identiﬁed as the optimal solvent,³²these

conditions gave rise to a mixture of cis and trans diastereomers

of dihydropyran 60. Diethyl ether proved to be the optimal

solvent for this particular hetero-Diels-Alder reaction (97% ee,

dr 94:6), and the desired product 60 could be isolated in 84%

yield as a single isomer on a 10-20 g scale. Since neither

propenyl ether 62 nor dihydropyran 60 were observed to

isomerize in control experiments, we believe the less than perfect

diastereomeric ratios in the cycloaddition could potentially be

explained by a stepwise reaction pathway under these Lewis

acid catalyzed conditions. In the subsequent hydrogenation of

the tetrasubstituted oleﬁn, EtOAc proved to be superior to

alcoholic solvents, giving rise to tetrahydropyran 59 in excellent

yield and diastereoselectivity (H₂, Pd/C, EtOAc, dr 98:2, 95%

of 59).

Enantioselective Hetero-Diels-Alder Approach to the

syn-1,3-Dimethyl Synthons of Azaspiracid-1. With a viable route

to the ABCD-portion of azaspiracid-1 established, we turned

our attention to the remaining EFGHI-region of the molecule.

Initially, we focused on synthesizing the E-ring fragment to

investigate potential strategies to form the central C20-C21

bond as will be discussed in the following sections. By

inspection, two syn 1,3-dimethyl synthons of the same conﬁg-

uration are embedded in the E- and the I-rings of azaspiracid-1

(Scheme 8). We were particularly attracted to the possibility of

constructing both of these subunits from the common precursor

59. Tetrahydropyran 59 could potentially be accessible from

dihydropyran 60, which could be prepared using the hetero-

Diels-Alder reaction previously developed in our laboratories

(eq 3)³²for this particular target structure.

Chelate-Controlled Vinylmetal Addition to Form the

Central C20-C21 Bond. With the syn-1,3-dimethyl motif of

the E-ring thus in hand, we turned our attention to the

elaboration of tetrahydroparan 59 into an appropriate E-ring

intermediate that would allow us to establish the crucial

C20-C21 bond. These studies would identify in which order

the remaining EFGHI-region of the molecule should be as-

(58) Ding, P. Y.; Ghosez, L. Tetrahedron 2002, 58, 1565–1571.

(59) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156. (b)

Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.

(60) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R. Tetrahedron

Lett. 1976, 3477–3478.

(61) The selective TES-removal was accompanied by minor loss of the

C1 TIPS protecting group. Since the crude mixture of 60 was subjected

directly to the PPTS-mediated spirocyclization, 76% of 61 was

obtained directly in the spirocyclization event while additional 7% of

61 was obtained after reinstallation of the C1 TIPS substituent.

(62) Crouch, R. D. Tetrahedron 2004, 60, 5833–5871.

(63) Taskinen, E.; Virtanen, R. J. Org. Chem. 1977, 42, 1443–1449.

(64) Rambaud, M.; Bakasse, M.; Duguay, G.; Villieras, J. Synthesis 1988,

564–566.

9

16302 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Total Synthesis of (+)-Azaspiracid-1

A R T I C L E S

Scheme 10. Synthesis of the E-Ring Vinyl Iodide 71^a

Scheme 11. Synthesis of the ABCDE-region 77^a

^aReagents and conditions: (a) t-BuOK, THF, -50 °C, quant.; (b) 1,3-

propanedithiol, BF₃·OEt₂, CH₂Cl₂, 95% (2 steps); (c) LiBH₄, THF, quant;

(d) 2,2-dimethoxypropane, PPTS, CH₂Cl₂, 98%; (e) t-BuLi, HMPA, THF,

-78 °C, then MeI, 92%; (f) Hg(ClO₄)₂, CaCO₃, H₂O, THF, 88%; (g)

trisylhydrazine, THF, 93%; (h) t-BuLi, THF, -78 to 0 °C, then I₂, -78

°C, 86%. See ref 31 for abbreviations.

sembled. One possible option we investigated as a viable

C20-C21 fragment coupling was a chelate-controlled vinyl-

lithium addition^65,66to a D-ring aldehyde synthon 65 (eq 10).

As facile elaboration of the C21-1,1-disubstituted oleﬁn was

thought to be incompatible with the two oleﬁns contained in

the AB-ring fragment 7, this C20-C21 bond construction to

join the CD- and the E-ring fragments was investigated prior

to the introduction of the AB-ring fragment.

^aReagents and conditions: (a) TBAF, AcOH, THF 97%; (b) SO₃·Pyr,

DMSO, i-Pr₂NEt, CH₂Cl₂, -30 °C, 94%; (c) 71 (2 equiv), t-BuLi, Et₂O,

-78 °C, then 72, MgBr₂·OEt₂,⁴⁰CH₂Cl₂, -20 °C, 80%, dr >99:1; (d)

Ac₂O, DMAP, Et₃N, CH₂Cl₂, 96%; (e) (i) O₃, MeOH, CH₂Cl₂, -78 °C,

then Me₂S; (ii) MeOH, HC(OMe)₃, PPTS, 75% (2 steps); (f) TBDPSCl,

imidazole, CH₂Cl₂; (g) DDQ, CH₂Cl₂/pH 7 buffer (9:1 v/v), 0 °C; 78% (2

steps); (h) TESCl, imidazole, CH₂Cl₂, 90%; (i) H₂, RaNi (W-2),⁷¹EtOH,

93%; (j) SO₃·Pyr, DMSO, i-Pr₂NEt, CH₂Cl₂, -30 °C, 75%. See ref 31 for

abbreviations.

was conveniently installed in a Shapiro reaction⁶⁹via an

intermediate trisylhydrazone.⁷⁰Thus, the methyl ketone was

converted into the intermediate trisylhydrazone 70 (trisylhy-

drazine, 93%) which proved slightly unstable in solution but

could be stored neat in the freezer for weeks without any

detectable decomposition. Metalation with t-BuLi followed by

warming to 0 °C generated the intermediate vinyl anion before

an iodine quench at -78 °C furnished vinyl iodide 71 in 86%

overall yield. In summary, this sequence provided the desired

E-ring vinyl iodide 71 in 10 linear steps from the hetero-

Diels-Alder precursors 62/64.

Chelate-Controlled Vinylmetal Addition and Elaboration

into the ABCDE-Region 77. In preparation for the subsequent

chelate-controlled vinyl iodide addition to stereoselectively form

the C20-C21-bond, the CD-ring tetrahydrofuran 50 was desi-

lylated (TBAF, AcOH, 97%) and converted in a Parikh-Doering

oxidation⁴⁵to the corresponding D-ring aldehyde 72 (SO₃·pyr,

DMSO, 94%, Scheme 11). Metal-halogen exchange of the vinyl

iodide fragment 71 was then effected with t-BuLi in Et₂O at

-78 °C followed by cannulation of this vinyllithium solution

into a solution of the aldehyde 72 precomplexed to MgBr₂·OEt₂

(prepared in an Et₂O/toluene solution⁴⁰) in CH₂Cl₂. The

observed diastereoselectivity was excellent at temperatures

ranging from -78 to 0 °C while the best yields were obtained

at -20 °C (80%, dr >99:1). With 2 equiv of vinyl iodide 71

relative to the aldehyde 72, on the order of 0.6-0.7 equiv of

Synthesis of the E-Ring Vinyl Iodide 71. In order to arrive at

an appropriately protected vinyl iodide fragment 66, the ester

substituent of tetrahydropyran 59 was epimerized to its equato-

rial diastereomer (t-BuOK, THF, -50 °C, Scheme 10) prior to

pyran ring opening to give the dithiane 68 (1,3-propanedithiol,

BF₃·OEt₂, 95%, 2 steps). Subsequent ester reduction (LiBH₄)

and acetonide protection proceeded uneventfully in excellent

yields (Me₂C(OMe)₂, PPTS, 98%, 2 steps). In the dithiane

methylation,⁶⁷it was found that a 5-min deprotonation time of

the intermediary dithiane at -78 °C was optimal. This afforded

dithiane 69 in good yield (MeI, t-BuLi, HMPA/THF, 92%).

Longer deprotonation times or higher temperatures afforded

substantial amounts of addition of the reactive dithiane anion

to HMPA as the electrophile. Oxidative removal of the dithiane

moiety under mild conditions revealed the methyl ketone

(Hg(ClO₄)₂, CaCO₃,⁶⁸88%). Finally, the desired vinyl iodide

(65) Peterson, S. L. Ph. D. Thesis, Harvard University, Cambridge, 2006.

(66) (a) Hayward, M. M.; Roth, R. M.; Duffy, K. J.; Dalko, P. I.; Stevens,

K. L.; Guo, J. S.; Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 192–

196. (b) Heathcock, C. H.; McLaughlin, M.; Medina, J.; Hubbs, J. L.;

Wallace, G. A.; Scott, R.; Claffey, M. M.; Hayes, C. J.; Ott, G. R.

J. Am. Chem. Soc. 2003, 125, 12844–12849.

(67) (a) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231–237. (b)

Smith, A. B.; Condon, S. M.; McCauley, J. A.; Leazer, J. L.; Leahy,

J. W.; Maleczka, R. E. J. Am. Chem. Soc. 1997, 119, 947–961.

(68) Bernardi, R.; Ghiringhelli, D. J. Org. Chem. 1987, 52, 5021–5022.

(69) Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc. 1967, 89, 5734–5735.

(70) (a) Chamberlin, A. R.; Stemke, J. E.; Bond, F. T. J. Org. Chem. 1978,

43, 147–154. (b) Chamberlin, A. R.; Bloom, S. H. Org. React. 1991,

45, 1–84.

9

J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16303

A R T I C L E S

Evans et al.

Scheme 12. Synthesis of Cyclic E-Ring Fragments.^a

Scheme 13. Model Studies of Final C20-C21 Sulfone Fragment

Coupling and Product Elaboration^a

^aReagents and conditions: (a) PhSH, BF₃·OEt₂, CH₂Cl₂, -20 °C, dr

96:4, 83% 78; (b) t-BuOK, THF, -50 °C, dr 96:4, 88% 79; (c)

Me(OMe)NH·HCl, i-PrMgCl,⁵¹THF, -78 to -20 °C, 93%; (d) 79,

DIBALH, toluene, -94 to -78 °C, 93%. See ref 31 for abbreviations.

vinyl iodide 71 could additionally be recovered by a ﬁnal I₂-

quench, thus emphasizing the stability of the vinylmetal species

in CH₂Cl₂.

^aReagents and conditions: (a) EtMgBr, THF, -78 °C, 99%; (b)

TMSCH₂Li, THF, -78 °C, 70%; (c) KH, THF, 99%; (d) H₂O₂,

Na₂WO₄·2H₂O,⁷²MeOH, 91%; (e) 81 (1 equiv), LDA (1.2 equiv), THF,

then 82 (1.5 equiv), -78 °C, dr(C21): 6:1, 51% 83; (f) PhSLi, Et₂O, -78

°C, 99%; (g) KHBEt₃, THF, -78 to -20 °C, dr 5-6:1, 56% major isomer;

(h) HgCl₂, pH 7 buffer, MeCN/THF, 0 °C, 86%; (i) KHBEt₃, CH₂Cl₂, -78

to -20 °C, dr 10:1, 91% major isomer. See ref 31 for abbreviations.

Subsequently, the coupled product was acetylated under

standard conditions to give 73 (Ac₂O, 96%). Careful ozonolysis

of the 1,1-disubstituted oleﬁn in the presence of Sudan III as a

color indicator⁵⁶allowed for an almost completely selective

cleavage of the oleﬁn accompanied by only trace amounts of

undesired oxidation of the benzyl ether protecting groups.

Subsequent ketalization in the presence of a mild acid allowed

for the formation of lactol methyl ether 74 (PPTS, MeOH, 75%

of 74, 2 steps). Intermediates observed during investigations of

this ketalization procedure suggested that the product was

partially dehydrated to give the E-ring C21-dihydropyran which

in the presence of strong acids such as p-TsOH could be more

rapidly ketalyzed to give the desired C21 methyl lactol ether,

albeit in only moderate overall yields upon scale-up. A

subsequent series of standard protecting group manipulations

involved TBDPS-protection (TBDPSCl, imidazole), PMB-

removal (DDQ, 78%, 2 steps), and C17 TES installation (TESCl,

imidazole, 90%). The ﬁnal debenzylation in the presence of the

TES silyl ether proceeded readily using W-2 RaNi⁷¹(H₂, RaNi,

EtOH, 93%) followed by a Parikh-Doering oxidation⁴⁵to give

the C13 aldehyde 75 (SO₃·pyr, DMSO, 75%). In preliminary

experiments, aldehyde 75 could be readily elaborated in a ﬁve-

step sequence analogous to the one already discussed in Scheme

7 to give access to the ABCDE-region 77 of azaspiracid-1.

C20-C21 Bond via an Anomeric Sulfone Anion Addition.

Although we had thus established a viable route to form the

C20-C21 bond of azaspiracid-1 as our initial fragment coupling,

we remained attracted to the possibility of performing this

crucial C20-C21 bond formation last. This would constitute a

more convergent approach to azaspiracid-1 since all 9 rings of

the ﬁnal target would be formed prior to such an ultimate

fragment coupling as brieﬂy outlined in Scheme 1.

Synthesis of Cyclic E-ring Fragments Containing a C21

Sulﬁde Moiety. We began these investigations by synthesizing

several E-ring fragments containing a C21-sulﬁde substituent

and different electrophiles at C26 (Scheme 12). Treatment of

tetrahydropyran 59 with one equivalent of thiophenol and a

slight excess of BF₃·OEt₂provided thioglycoside 78 (dr 96:4,

83% of 78) accompanied by minor amounts of the acyclic

dithioacetal as a byproduct. We believe the diastereoselectivity

observed in this reaction is the result of initial formation of the

axial thioglycoside, followed by Lewis acid induced isomer-

ization to the more stable equatorial isomer 78. In support of

this hypothesis, the observed diastereoselectivity at C21 was

inferior when substoichiometric amounts of BF₃·OEt₂were

employed. Subsequent epimerization of the ester substituent to

give the tetrahydropyran 79 with all four substituents occupying

equatorial positions proceeded readily with catalytic amounts

of t-BuOK in THF at low temperature (dr 96:4, 88% of 79).

The only major byproduct in this reaction was the corresponding

t-Bu ester, and its formation was minimized by using only 5

mol % of t-BuOK. Ester 79 could then alternatively be converted

to Weinreb amide 80 (Me(OMe)NH·HCl, i-PrMgCl, 93%) or

reduced directly to aldehyde 10 (DIBALH, 93%). In summary,

this sequence provided the E-ring fragment 10 in 5 steps (54%

yield) from the hetero-Diels-Alder precursors 62/64.

Model Experiments To Form the C20-C21 Bond by an

Anomeric Sulfone Anion Addition. At this stage, we decided

to test the viability of the ﬁnal anomeric sulfone anion addition

to form the C20-C21 bond of azaspiracid-1 using less elaborate

model systems. To the best of our knowledge, the most related

literature precedent for such a fragment coupling can be found

in our altohyrtin synthesis where an anomeric sulfone anion

was added to an N-acylbenzotriazole as the electrophile.^27,28In

a simple azaspiracid model system, the anion of sulfone 81 could

likewise be added to a host of simple activated esters and amides

as exempliﬁed by the N-acylpyrazole 82 (Scheme 13). Although

the yields of these additions to give the slightly unstable C21-ꢀ

ketosulfone 83 were only moderate at this stage, we were more

concerned with the identiﬁcation of sufﬁciently mild conditions

for the subsequent anomeric sulfone excision to arrive at the

desired C21-lactol moiety. Very little is reported about such

anomeric sulfone derivatizations apart from the single altohyrtin

precedent that required forcing conditions for converting one

of the anomeric sulfone anomers,^27,28conditions which were

judged to be too harsh in the present azaspiracid case.

Initially, it was found that the transformation of ketosulfone

83 into ketosulﬁde 84 could be effected with PhSH in the

presence of MgBr₂·OEt₂and i-Pr₂NEt in relatively nonpolar

solvents (CH₂Cl₂or Et₂O, -20 °C, >80% yield). Subsequently,

we discovered that the same transformation could be effected

in quantitative yield under very mild conditions (PhSLi, Et₂O,

(72) Blacklock, T. J.; Butcher, J. W.; Sohar, P.; Lamanec, T. R.; Grabowski,

(71) Mozingo, R. Org. Synth. 1955, 3, 181–183.

E. J. J. J. Org. Chem. 1989, 54, 3907–3913.

9

16304 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Total Synthesis of (+)-Azaspiracid-1

A R T I C L E S

Scheme 14. Model Studies of Final C20-C21 Sulfone Fragment

Coupling via the C20-Aldehyde 3^a

Scheme 15. Synthesis of the FG-Ring Fragment 11^a

^aReagents and conditions: (a) LiAlH₄, Et₂O, -20 °C; (b) TBDPSCl,

imidazole, DMF, 99% (2 steps); (c) m-CPBA, NaHCO₃, CH₂Cl₂, 94%; (d)

87 (2.3 equiv), n-BuLi, THF, -78 °C, then 3 (1.0 equiv), then sat. aq.

NH₄Cl, -78 °C to RT, 65%, 3:1 88:89. See ref 31 for abbreviations.

^aReagents and conditions: (a) O₃, MeOH, CH₂Cl₂, -78 °C, then Me₂S,

61%; then vacuum sublimation, 73%; (b) 10 mol% 93, CH₂Cl₂, -78 °C,

94% conversion, dr >40:1, 97% ee (67% after recrystallization, >99% ee);

(c) H₂(1 atm), 2 mol% [(COD)Ir(PCy₃)(py)]PF₆, CH₂Cl₂, 98%, dr >95:5;

(d) PMBBr, NaH, DMF, -40 to -20 °C, 67%; (e) KHBEt₃, THF, 0 °C to

RT, 94%; (f) TBSCl, imidazole, DMF, 99%; (g) HF ·pyr, THF, -10 °C,

87%; (h) TsCl, DMAP, pyridine, 98%; (i) NaCN, DMSO, 55 °C, 99%; (j)

Boc₂O, DMAP, CH₃CN, 99%; (k) LiBH₄, H₂O, THF, 0 °C to RT, 99%; (l)

TMSCl, imidazole, CH₂Cl₂, 99%; (m) MeLi, Et₂O, 0 °C, 84%; (n) SO₃·Pyr;

DMSO, i-Pr₂NEt, CH₂Cl₂, -30 °C, 99%. See ref 31 for abbreviations.

-78 °C, 99%) in an interesting transformation that proceeds

with complete inversion at the C21 stereocenter. The resulting

ketosulﬁde 84 could be stereoselectively reduced to afford either

C20 alcohol diastereomer utilizing a simple change of solvent

(KHBEt₃in THF or CH₂Cl₂, dr 5-6:1 or 1:10, respectively).

Finally, the phenylsulﬁde moieties could be readily converted

with aqueous HgCl₂into the lactols 85 and 86 for which the

C21 hydroxyl spontaneously occupied an axial position. This

mild reaction sequence was judged to be viable for our more

functionalized azaspiracid target.

As may be noted, the above investigations were performed

with the enantiomer of the Weinreb amide E-ring fragment (ent-

80) since they were part of our early studies targeting the

originally proposed structure of azaspiracid-1 (1). By similar

approaches as depicted in Scheme 13, we additionally synthe-

sized the C19-epimers of lactols 85 and 86, thus providing

access to all four diastereomers of the C19-C20 junction.

Comparison of ¹H NMR data for these four C19-C20 diaster-

eomeric lactols with the published ¹H NMR spectrum of

azaspiracid-1⁶clearly suggested that the acyclic C19-C20

junction between the ABCD- and the E-rings was one likely

region to have been originally miss-assigned. This assumption

was conﬁrmed by Nicolaou in 2004 with the structural revision

of azaspiracid-1 (2).²²

plexation of the aldehyde), and different quenching buffers all

failed to provide a full conversion of aldehyde 3, a goal yet to

be achieved, and did not improve the ratio of desired lactols 88

to dihydropyrans 89. Although by no means optimal, this

coupling experiment depicted in Scheme 15 still provided a

credible lead for the ﬁnal C20-C21 coupling experiments and

established that the C21 lactols 88 could indeed be accessed

directly from ABCD-aldehyde 3 upon appropriate work up

conditions. With this result in hand, a decision was made to

embark on the synthesis of the fully elaborated EFGHI-sulfone

4 (Scheme 1) as will be discussed in the following sections.

Synthesis of the FG-Ring Fragment 11. In the synthesis of

the FG-ring fragment 11, we envisioned that the C32-C33 anti

diol array could be efﬁciently obtained by an extension of our

enantioselective catalytic Mukaiyama aldol reaction of siloxy-

furan 21⁷³and (benzyloxy)acetaldehyde 22⁷⁴(eq 9, entry A).³⁴

In contrast to the original studies where hydrated complex 23

was formed in situ with CuCl₂·2H₂O,³⁴further investigations

revealed that bis(aquo) complex 23 could conveniently be

isolated and stored as a bench-stable solid prior to use. The

inclusion of CF₃CH₂OH as a silicon-scavenging reagent⁷⁵further

increased the observed stereoselectivities and was readily

amenable to reliable large-scale preparations of the desired

product 24 (entry B, 79%, dr 93:7, 97% ee), thus suggesting

the suppression of a racemic silicon-catalyzed background

reaction. However, much inferior stereoselectivities were ob-

Unfortunately, more elaborate model systems in the correct

enantiomeric series of the D-ring that comprised activated esters

and amides derived either from CD-ring aldehyde 72 (Scheme

11) or ABCD-aldehyde 3 (Scheme 7) and the addition of the

anion of E-ring sulfone 87 (Scheme 14) proved signiﬁcantly

less promising under a variety of conditions, also in the

subsequent transformation with PhSLi (not shown). As an

alternative, a signiﬁcantly more rapid entry to the C21-lactol

region of the azaspiracid skeleton would be to utilize aldehyde

3 directly, a strategy with some promising precedent in the

literature.²⁹The well-known competing side reaction in such a

transformation is the sulﬁnate elimination to the corresponding

C21-dihydropyran.^25,28Nevertheless, when this reaction was

carried out with aldehyde 3 and the E-ring model sulfone 87

followed by a quench with slightly acidic buffer at -78 °C,

the desired lactols 88 were preferentially formed over dihydro-

pyrans 89 (3:1 ratio, 65% combined yield). The desired lactols

88 could subsequently be interconverted by an oxidation/

reduction sequence of the C20 moiety to give either C20 alcohol

in high stereoselectivty. A limited number of subsequent studies

with several bases (nBuLi, LDA), additives (HMPA,

MgBr₂·OEt₂), solvents (THF, Et₂O, and CH₂Cl₂for precom-

(73) Casiraghi, G.; Rassu, G. Synthesis 1995, 607–626.

(74) (a) Danishefsky, S. J.; Deninno, M. P. J. Org. Chem. 1986, 51, 2615–

2617. (b) Garner, P.; Park, J. M. Synth. Commun. 1987, 17, 189–194.

(75) (a) Kitajima, H.; Katsuki, T. Synlett 1997, 568–570. (b) Evans, D. A.;

Johnson, D. S. Org. Lett. 1999, 1, 595–598. (c) Evans, D. A.; Rovis,

T.; Kozlowski, M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem.

Soc. 2000, 122, 9134–9142. (d) Evans, D. A.; Scheidt, K. A.; Johnston,

J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480–4491.

9

J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16305

A R T I C L E S

Evans et al.

Scheme 16. Auxiliary-Based Synthesis of the HI-Ring Fragment

12^a

tained in preliminary experiments with the corresponding

methyl-substituted siloxyfuran 90⁷⁶(entry C, dr 80:20, 43% ee),

thus prompting us to investigate alternative conditions for this

particular transformation.

^aReagents and conditions: (a) 104, LiAlH₄, THF, 0 °C, 95%; (b) TsCl,

Et₃N, CH₂Cl₂, 0 ° C to RT, 95%; (c) NaN₃, TBAI, DMF, 60 °C, 93%; (d)

(COCl)₂, DMSO, Et₃N, CH₂Cl₂, -78 °C to RT, 95%. See ref 31 for

abbreviations.

(PCy₃)(py)]PF₆, 98%, dr >95:5). Subsequently, PMB-protection

of the secondary alcohol to give 98 was sufﬁciently chemose-

lective under basic conditions (PMBBr, NaH, 67%) whereas a

variety of acidic conditions afforded both decomposition and

epimerization of the newly set methyl stereocenter.

Further studies revealed that the corresponding Sn(2+)-

catalyzed aldol reaction⁷⁷with Sn(2+)-complex 93 alternatively

afforded optimal results in the desired transformation. Thus,

methyl-substituted siloxyfuran 90 underwent stereoselective

aldol addition with ethyl glyoxalate (92) to give the desired

lactone 94 in excellent yield and selectivities (94%, 95% ee, dr

>50:1, eq 10). During these investigations, it was found that

the ethyl substituents on the chiral ligand were important for

obtaining high stereoselectivities, for reasons that remain

unclear.

The lactone 98 was next reduced to the diol (KHBEt₃, 94%),

persilylated (TBSCl, 99%), and converted into the corresponding

primary alcohol by selective desilylation (HF ·pyr, 87%). We

elected to introduce C28 as a cyano function at this stage of

the synthesis to provide maximal ﬂexibility in subsequent

fragment couplings since the nitrile could be either converted

into an electrophile (an aldehyde) or a nucleophile (a methyl

ketone). This was accomplished in high yield by tosylation of

the primary alcohol and displacement with sodium cyanide to

give nitrile 99 (97% yield, 2 steps). At the other terminus of

the molecule, the N-phenyl amide functionality was reduced in

a two-step sequence involving Boc-activation and reduction with

lithium borohydride to give alcohol 100 in 98% yield for the

two steps. Preliminary investigations of our various fragment

coupling strategies revealed that a C27-methyl ketone was the

most desirable for coupling the FG-ring fragment to the E-ring

fragment 10. The methyl ketone was therefore accessed by a

methyllithium addition to the nitrile in a step that required

transient protection of the primary alcohol to effect full

conversion (TMSCl, 99%). Thus, the nitrile was converted into

the C27 methyl ketone with methyllithium with concomitant

TMS ether hydrolysis during the workup procedure (84%).

Finally, a Parikh-Doering oxidation⁴⁵(SO₃·Pyr, DMSO, 97%)

concluded the synthesis of the FG-ring ketoaldehyde 11.

Another practical variant of this addition process using

N-phenyl glyoxamide 96,⁷⁸readily prepared by ozonolysis of

oleﬁn 95 and dehydration of the intermediary glyoxamide

hydrate by vacuum sublimation, is depicted in Scheme 15 and

afforded adduct 97 (94% conversion, dr >40:1, 97% ee) as a

highly crystalline solid. In this transformation, it was found that

the highest stereoselectivities were observed using a sequential

addition of the reagents in 0.1 equiv increments rather than a

slow addition of either reagent. The resulting lactone 97 could

readily be recrystallized to enantiopurity prior to the subsequent

transformations (99% ee, 67%). Another beneﬁt of the N-phenyl

amide 97 was its propensity to undergo highly diastereoselective

directed hydrogenations to install the methyl-bearing stereo-

center, a goal that was not successfully achieved with the

corresponding ethyl ester 94 under the same range of hydro-

genation conditions. The directed hydrogenation of 97 proved

to be optimal with Crabtree’s catalyst⁷⁹that afforded the

Synthesis of the HI-Ring Fragment 12. Chiral Auxiliary

Approach via Known Intermediate 104. In our initial efforts

aimed at gaining access to the HI-ring fragment 12 for further

studies, we utilized the known hydroxy ester 104 (Scheme 16).

This intermediate is readily available in 8 steps⁸¹based on a

double stereodifferentiating directed hydrogenation⁸²of the

homoallylic oleﬁn 103 synthesized via a chiral auxiliary-based

diastereoselective aldol reaction.⁸³The remaining four trans-

formations comprised ester reduction, selective tosylation of the

resulting lactone as

a single isomer (H₂, [(COD)Ir-

(79) (a) Crabtree, R. Acc. Chem. Res. 1979, 12, 331–338. (b) Crabtree,

R. H.; Davis, M. W. Organometallics 1983, 2, 681–682.

(80) (a) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,

2424–2426. (b) Evans, D. A.; Carter, P. H.; Dinsmore, C. J.; Barrow,

J. C.; Katz, J. L.; Kung, D. W. Tetrahedron Lett. 1997, 38, 4535–

4538.

(76) (a) Yoshii, E.; Koizumi, T.; Kitatsuji, E.; Kawazoe, T.; Kaneko, T.

Heterocycles 1976, 4, 1663–1668. (b) Jefford, C. W.; Sledeski, A. W.;

Rossier, J. C.; Boukouvalas, J. Tetrahedron Lett. 1990, 31, 5741–

5744. (c) Nefkens, G. H. L.; Thuring, J.; Zwanenburg, B. Synthesis

1997, 290–292.

(77) Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am. Chem.

Soc. 1997, 119, 10859–10860.

(81) Evans, D. A.; Dimare, M. J. Am. Chem. Soc. 1986, 108, 2476–2478.

(82) Evans, D. A.; Morrissey, M. M. J. Am. Chem. Soc. 1984, 106, 3866–

3868.

(78) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005, 127, 8006–8007.

9

16306 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Total Synthesis of (+)-Azaspiracid-1

A R T I C L E S

Scheme 17. Catalytic Enantioselective Synthesis of the HI-Ring

Fragment 12^a

Scheme 18. Chelate-Controlled Mukaiyama Aldol Reaction and

Initial Investigations of FG-Ketalization^a

^aReagents and conditions: (a) Et₃SiH, BF₃·OEt₂, CH₂Cl₂, 0 °C, 91%;

(b) LiAlH₄, Et₂O, 0 °C, 91%; (c) I₂, PPh₃, imidazole, CH₃CN/benzene, RT

to 60 °C, 94%; (d) t-BuLi, THF, -78 °C, then TsCl, -78 to 0 °C, 95%;

(e) O₂, PdCl₂, CuCl, H₂O, DMF, 89%; (f) NaN₃, DMSO, 60 °C, 97%. See

ref 31 for abbreviations.

primary alcohol to give 105, azide substitution, and ﬁnally a

Swern oxidation⁸⁴(80%, 4 steps) to deliver the desired keto

azide 12.

^aReagents and conditions: (a) LiHMDS, TMSCl, Et₃N, THF, -78 °C,

89%; (b) MgBr₂·OEt₂, CH₂Cl₂, 0 °C, 93%, dr >95:5; (c) HF, H₂O, CH₃CN,

0 °C, 92%; (d) TBSCl, imidazole, DMF, 99%. See ref 31 for abbreviations.

Catalytic Enantioselective Approach via Hetero-Diels-

Alder Intermediate 59. Alternatively, we envisioned that our

1,3-syn-dimethyl substituted tetrahydropyran 59 generated in

the enantioselective hetero-Diels-Alder reaction could likewise

be utilized to synthesize the acyclic HI-ring fragment 12 by

incorporation of a ring fragmentation. Thus, ester 59 was

converted to alcohol 106 by sequential acetal and ester reduction

(Et₃SiH, BF₃· OEt₂; LiAlH₄, 81% yield), followed by iodine

installation (Scheme 17). Whereas initial investigations of the

latter transformation were frustrated by the lack of reactivity

of intermediate sulfonate esters derived from the primary alcohol

106, the iodide 107 was smoothly obtained by heating of the

intermediate phosphonium salt derived from alcohol 106 to 60

°C (I₂, PPh₃, imidazole,⁸⁵94%). Although the fragmentation

of iodide 107 could be accomplished under a number of

conditions (Zn, MeOH or n-BuLi, Et₂O), the resultant primary

alcohol was too volatile for convenient manipulation. As a

solution, the intermediary lithium alkoxide was formed in THF

and trapped in situ with TsCl to give 108 in 95% yield. The

terminal oleﬁn was smoothly oxidized to the methyl ketone

under standard Wacker conditions (O₂, PdCl₂, CuCl, DMF,

89%), with the remainder of the material consisting of oleﬁn

isomers. Finally, an azide introduction (NaN₃, DMSO, 60 °C,

97%) concluded this catalytic asymmetric synthesis of the HI-

ring fragment 12.

controlled Mukaiyama aldol reaction.³⁰The required enolsilane

109 was readily formed from methyl ketone 12 under standard

conditions (LiHMDS, TMSCl, Et₃N, 89%, Scheme 18). A

careful evaluation of a range of Lewis acids to effect this

transformation established that freshly prepared solid

68,87

MgBr₂·OEt₂

was superior to other Lewis acids such as

TiCl₂(Oi-Pr)₂, TiCl₄, SnCl₄, MgI₂, MgBr₂, Mg(OTf)₂, and

commercial MgBr₂·OEt₂. In addition, a high concentration (0.4

M) was crucial for obtaining a complete conversion with this

mild and selective Lewis acid. Consequently, the desired chelate-

controlled addition of enolsilane 109 to aldehyde 11 proceeded

in excellent yield to afford the desired aldol adduct 110 as a

single diastereomer (93%, dr >95:5). Subsequent model studies

on adduct 110 revealed that treatment with aqueous HF in

acetonitrile⁸⁶smoothly effected the formation of the desired FG

bicyclic ketal 112 in 92% yield.

The aldol addition to form the C26-C27 bond was imple-

mented with Cy₂BCl (2.4 equiv, i-Pr₂NEt) due to its excellent

regioselectivity in the enolization of methyl ketones (Scheme

19).⁸⁸The excess Cy₂BCl is presumed to function as a transient

protecting group for the C34-C36 hydroxyketone moiety and

prevent any retroaldol reactions from taking place as depicted

in the proposed intermediate 113. When treated with a slight

excess of E-ring aldehyde 10, the desired aldol adduct 9 was

formed in near quantitative yield (dr 60:40). When adduct 9

was subsequently exposed to aqueous HF in acetonitrile, the

lone TBS ether was cleaved and the molecule spontaneously

cyclized to form the desired FG bicyclic ketal 114 in excellent

yield (92%, 2 steps). It is noteworthy that the analogous

cyclization of the O34-TBS-protected aldol adduct 111 afforded

a multitude of products.

The lack of diastereoselectively in the boron aldol addition

was inconsequential since the C26 secondary alcohols 114 were

subsequently oxidized to the corresponding ketone 115 with

Dess-Martin periodinane⁵⁹(85%). Pyridine was crucial to buffer

Synthesis of the EFGHI-Sulfone 4. Assembly of the EFGHI

Carbon Skeleton and Formation of the FG Bicyclic Ketal 115.

With the required E-, FG-, and HI-ring fragments in hand as

described above, we proceeded to investigate their assembly to

the pentacyclic EFGHI-sulfone 4. We ﬁrst formed the C34-C35

bond to unite the FG- and the HI-ring fragments in a chelate-

(86) (a) Evans, D. A.; Rieger, D. L.; Jones, T. K.; Kaldor, S. W. J. Org.

Chem. 1990, 55, 6260–6268. (b) Evans, D. A.; Kaldor, S. W.; Jones,

T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001–

7031.

(87) (a) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265–268.

(b) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 1879–1882.

(c) Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50, 3247–3251.

(d) Harwood, L. M.; Manage, A. C.; Robin, S.; Hopes, S. F. G.;

Watkin, D. J.; Williams, C. E. Synlett 1993, 777–780.

(83) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,

2127–2129.

(84) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660.

(85) (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980,

2866–2869. (b) Garegg, P. J.; Johansson, R.; Ortega, C.; Samuelsson,

B. J. Chem. Soc., Perkin Trans. 1 1982, 681–683.

(88) (a) Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B. J. Org.

Chem. 1992, 57, 499–504. (b) Brown, H. C.; Dhar, R. K.; Ganesan,

K.; Singaram, B. J. Org. Chem. 1992, 57, 2716–2721.

9

J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16307

A R T I C L E S

Evans et al.

Scheme 19. Assembly of the EFGHI Carbon Skeleton and

Formation of the FG Bicyclic Ketal 115^a

Figure 4. Key NOEs for spiroaminal 117 (C₆D₆, 500 MHz).

The desired conﬁguration of the spiroaminal 117 was veriﬁed

by the key NOE interactions depicted in Figure 4.

To mask all reactive functionalities in the molecule, we then

elected to protect the spiroaminal nitrogen of 117a as its Teoc

derivative. This transformation proceeded in excellent selectivity

when conducted in THF at high concentrations (TeocCl, 89%,

>97:3 mixture of isomers). Somewhat surprisingly, all Teoc-

protected intermediates proved to be slightly unstable to acidic

conditions while their puriﬁcation was readily executed using

silica gel buffered with organic bases. The stage was now set

for the oleﬁnation of the C26 ketone. We had deliberately

postponed this transformation until after the closure of the FG

bicyclic ketal in our synthesis plan to avoid any intermediates

containing an ꢀ,γ-unsaturated ketone prone to isomerization.

After initial experiments using relatively nonbasic methylene-

dianion equivalents such as the Takai-Nozaki reagent,⁹²the

Tebbe reagent⁹³buffered with pyridine to avoid any C36-

epimerization proved superior in this transformation. The Tebbe

reagent could conveniently be prepared in situ from Cp₂TiCl₂

and AlMe₃⁹⁰and afforded the desired oleﬁnated product in 58%

yield along with 41% of the recovered ketone.⁹¹The yield for

this step could be elevated to 78% after two recycles. The key

NOE interactions of the spiroaminal portion remained un-

changed from those depicted in Figure 4, thus verifying that

the C36 spiroaminal had not epimerized during these latter

transformations. Finally, the oxidation of the C21-phenylsulﬁde

moiety to sulfone 4 proceeded readily (H₂O₂, (NH₄)₆Mo₇O₂₄,

96%) In analogy to the Dess-Martin oxidation described above,

buffering of the reaction mixture with pyridine was crucial to

suppress concomitant loss of the C21-sulfur substituent as an

undesired side reaction. In summary, the above sequence

allowed the efﬁcient synthesis of the EFGHI-sulfone 4.

^aReagents and conditions: (a) Cy₂BCl (2.4 equiv), i-Pr₂NEt, CH₂Cl₂,

-78 °C, then 10 (1.4 equiv), -78 to 0 °C; then H₂O₂, MeOH, pH 7 buffer,

0 °C to RT, dr 60:40; (b) HF, H₂O, CH₃CN, 0 °C, 92% (2 steps); (c) Dess-

Martin periodinane, pyr, CH₂Cl₂, 85%. See ref 31 for abbreviations.

Scheme 20. Completion of the EFGHI-Sulfone 4^a

Sulfone Coupling and Completion. With the desired ABCD-

aldehyde 3 and EFGHI-sulfone 4 in hand, we proceeded to the

ﬁnal fragment coupling to form the C20-C21 bond of azaspi-

racid utilizing the reaction conditions developed during our

model studies (Scheme 14). Thus, the sulfone anion derived

from 4 was generated with nBuLi and added to aldehyde 3

followed by a quench at -78 °C with pH 5 buffer. Gratifyingly,

this procedure afforded a 50% overall yield of the readily

separable lactol diastereomers 118 and 119 in nearly equal

amounts (Scheme 21).⁹⁴Interestingly, the undesired alcohol 118

^aReagents and conditions: (a) DDQ, pH 7 buffer, CH₂Cl₂, 0 °C; (b) H₂

(1 atm), Pd/C, THF, dr >95:5, 77% (2 steps); (c) TeocCl,⁸⁹i-Pr₂NEt, THF,

0 °C, 89%, dr >97:3; (d) Tebbe reagent,⁹⁰pyr, toluene, -40 °C, 55%;⁹¹

(41% recovered ketone); (e) H₂O₂, pyr, (NH₄)₆Mo₇O₂₄, t-BuOH, 96%. See

ref 31 for abbreviations.

this latter oxidation step in order to suppress any overoxidation

and subsequent loss of the C21-phenylsulﬁde moiety, a promi-

nent side reaction observed in initial unbuffered experiments.

Completion of the EFGHI-Sulfone 4. Subsequently, the PMB

ether in ketone 115 was oxidatively removed to afford an

equilibrium mixture of lactols 116 and open-chain tautomers

(DDQ, pH 7 buffer, Scheme 20). Decomposition of this

intermediate upon exposure to silica gel was readily circum-

vented by buffering of the silica gel with Et₃N. With two of

the three functional groups of the HI spiroaminal unmasked,

the terminal azide was reduced to the primary amine. Whereas

Staudinger conditions provided a mixture of isomers, hydro-

genation under standard conditions induced the spontaneous

formation of the thermodynamically favored HI-spiroaminal 117

as a single diastereomer (H₂, Pd/C, 77%, dr >95:5, 2 steps).

(89) Shute, R. E.; Rich, D. H. Synthesis 1987, 346–349.

(90) Cannizzo, L. F.; Grubbs, R. H. J. Org. Chem. 1985, 50, 2386–2387.

(91) At-40 °C, the Tebbe reaction only proceeded to ∼60% conversion

(55% isolated yield) while the residual starting ketone could be

reisolated in high yield. The combined 78% reported yield represents

two recyclings of starting material. At higher temperatures, the

conversions were higher but the amount of decomposition of the

starting ketone was also signiﬁcant, thus giving an overall lower mass

recovery.

(92) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem. 1994,

59, 2668–2670.

(93) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978,

100, 3611–3613.

(94) The majority of the sulfone 4 could be recovered (78% based on the

50% coupling yield) as a mixture of 4 and its C21 epimer.

9

16308 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Total Synthesis of (+)-Azaspiracid-1

A R T I C L E S

Scheme 21. Final Fragment Coupling and Completion of the Synthesis^a

^aReagents and conditions: (a) 4 (2.2 equiv), n-BuLi, -78 °C, then 3 (1.0 equiv), then NaOAc/AcOH buffer, -78 °C to RT, 50% (27% 118, 23% 119);

(b) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, -78 to -20 °C, 63%; (c) LiBH₄(THF), CH₂Cl₂, -40 °C, dr >20:1, 56%; (d) TBAF, THF, 0 °C, 93%; (e) Dess-Martin

periodinane, CH₂Cl₂, 0 °C; (f) NaClO₂, NaH₂PO₄·H₂O, 2-methyl-2-butene, t-BuOH, 90% (2 steps). See ref 31 for abbreviations.

was obtained as an inseparable mixture of the C21-lactol and

the corresponding hydroxyketone, thus suggesting a lower

conﬁgurational stability of this C20 diastereomer. Next, the

undesired lactol 118 was converted into the desired lactol 119

by an oxidation/reduction sequence. Oxidation to the corre-

sponding C20 ketone was best effected under Swern conditions

(oxalyl chloride, DMSO, Et₃N, 63%), a transformation some-

what complicated by the equilibrium between the C21 lactol

and the hydroxyketone, since the latter is oxidized to the

corresponding undesired diketone during the course of the

reaction. A variety of reduction conditions were then evaluated

in the diastereoselective reduction of the C20 ketone to test both

traditional chelation and Felkin control, but unfortunately most

reducing agents selectively provided the undesired lactol 118.

However, LiBH₄in CH₂Cl₂at -40 °C exclusively afforded the

desired C20 diastereomer 119, although in moderate yield (56%,

dr >20:1).

With the desired lactol 119 thus prepared, only a few steps

remained to complete the synthesis. Thus, the two silyl

protecting groups were readily removed with TBAF (93% yield).

Next, the C1 terminus was oxidized in a mild two-step sequence

since initial experiments using TEMPO-type oxidations proved

too harsh for the remainder of the molecule. Interestingly, a

Dess-Martin oxidation at 0 °C chemoselectively afforded the

desired C1 aldehyde even though a large excess of Dess-Martin

periodinane was required to reach a full conversion into the

aldehyde. In contrast, the C20 secondary alcohol of lactol 119

could rapidly be oxidized with Dess-Martin periodinane at room

temperature. Finally, the resulting C1-aldehyde was cleanly

oxidized with NaClO₂to the corresponding carboxylic acid⁹⁵

in the presence of 2-methyl-2-butene as a chlorine scavenger⁹⁶

(90%, 2 steps). This sequence concluded the total synthesis of

(+)-azaspiracid-1 (ent-2) and has allowed us to synthesize 75

mg of the target molecule. The spectroscopic data for (+)-

azaspiracid-1 corresponded with those reported for (-)-azaspi-

racid (2) apart from the optical rotation which was of equal

magnitude but of opposite sign ((+)-azaspiracid-1 (ent-2), [R]²⁴

D

+21.7 (c ) 1.00, MeOH), natural (-)-azaspiracid-1 (2), [R]²⁰

D

-21 (c ) 0.1, MeOH),⁶synthetic (-)-azaspiracid-1 (2), [R]³³

D

-19.0 (c ) 0.07, MeOH)²²).

Conclusions

In projects of this level of complexity, the casual reader is

rarely informed of the intricacies associated with developing a

viable synthesis. For structures such as azaspiracid, assembled

from a number of complex subunits, once the viability of the

successful route has been established, we routinely reanalyze

the individual synthons as a collection of “new targets”. If more

aggressive approaches to the syntheses of these individual

subunits can be perceived, the “ﬁrst-generation” route to that

subunit is re-evaluated as far as the ﬁnal publication is

concerned. In this article, we have attempted to reveal some of

the hidden complexity associated with the reported synthesis

of azaspiracid.

Acknowledgment. Financial support has been provided by the

National Institutes of Health (GM-33328-22), the National Science

Foundation (CHE-0608664), 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 T.B.D. by the National Science Foundation, to A.B. by the

NSERC (Canada), to J.A.M. by the National Institutes of Health,

and to M.J. by the Technical University of Denmark.

Supporting Information Available: Experimental details and

1

analytical data including copies of H and ¹³C NMR spectra

for all new compounds. This material is available free of charge

via the Internet at http://pubs.acs.org.

(95) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888–890.

(96) (a) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175–

1176. (b) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825–4830.

JA804659N

9

J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16309

Article Doi

Total synthesis of (+)-azaspiracid-1. An exhibition of the intricacies of complex molecule synthesis

DOI: 10.1021/ja804659n

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