Facile biomimetic syntheses of the azaspiracid spiroaminal

Article abstract of DOI:10.1016/j.tet.2006.01.112

The azaspiracid natural products display a common spiroaminal-containing terminal domain that has inspired the development of two new methods for spiroaminal syntheses-a Staudinger reduction-aza-Wittig process and a double intramolecular hetero-Michael ad

Full text of DOI:10.1016/j.tet.2006.01.112

Tetrahedron 62 (2006) 5338–5346
Facile biomimetic syntheses of the azaspiracid spiroaminal
*
Son Nguyen, Jianyan Xu and Craig J. Forsyth
Department of Chemistry, University of Minnesota, 139 Smith Hall, 207 Pleasant Street, SE, Minneapolis, MN 55455, USA
Received 13 January 2006; revised 18 January 2006; accepted 20 January 2006
Available online 31 March 2006
Abstract—The azaspiracid natural products display a common spiroaminal-containing terminal domain that has inspired the development of
two new methods for spiroaminal syntheses—a Staudinger reduction–aza-Wittig process and a double intramolecular hetero-Michael addi-
tion. These effective laboratory approaches proceed through imine and enamine intermediates that may reflect transient biogenetic species.
Ó 2006 Elsevier Ltd. All rights reserved.
variable
constant
1. Introduction
Me
40
R1
The azaspiracids are the causative agents of a recently de-
fined class of human poisoning resulting from consumption
of tainted shellfish. As such, intense surveillance programs
have been established to monitor the occurrence and ex-
tent of azaspiracid contamination in edible shellfish. The
archetypal member of this novel class of marine toxins,
azaspiracid-1 (AZA1, Fig. 1), was reported by Yasumoto
and co-workers as an isolate from the cultivated Irish mussel
Mytilus edulis.1 Since then, AZA1 has also been found in the
dinoflagellate Protoperidinium crassipes, which may repre-
sent the primary biogenic source of the azaspiracid toxins.2
Recently, the complete structure of AZA1 was established
by a comprehensive total synthesis—correlation effort by
the Nicolaou group.3 To date, five azaspiracids have been
isolated and structurally elucidated by extensive NMR anal-
ysis and FABMS–MS experiments (AZA1–5),4 and six
others (AZA6–11) have been detected using a combination
of liquid chromatography and multi-tandem mass spectrom-
etry (LC–MSn).5 Among the 11 known azaspiracids, none
show any structural variation within the spiroaminal-termi-
nated C27–C40 domain. Hence, we have focused on devel-
oping efficient synthetic entries to this common portion of
the natural products to support the generation of an ELISA
for environmental monitoring,6 total syntheses of the natural
products, and the laboratory exploration of putative biomi-
metic pathways.7 Here, we summarize the development
and application of two novel methods for the formation of
the common azaspiracid spiroaminal.
8
I
R3
3
HN
O
1
R4
A
O
23
H
O
C
Me
H
Me
HO
R2
H
O
H
B
H22
O G
O
O
H
E
D
O
O
27
28
Me
OH
H
F
Name R1 R2 R3 R4
H
OH
Aza-1 H Me H
Aza-2 Me Me H
Aza-3 H
Aza-4 H
Aza-5 H
H
H
H
Azaspiracids
Me
Me
H
H
H
H
40
OH H
H OH
I
HN
Aza-6 Me H
H H
Common Spiroaminal-
Containing Domain
H
H
Me
Aza-7 H Me OH H
Aza-8 H Me H OH
Aza-9 Me H OH H
Aza10 Me H H OH
Aza11 Me Me OH H
O
H
O G
O
27
R
28
F
Me
Figure 1. Structures of the azaspiracids and the common spiroaminal-
containing domain.
2. Results and discussion
2.1. Synthetic design
Our established route to the dioxabicyclononane system,
comprising the C28–C34 F-G rings of the azaspiracids,
involves a double intramolecular hetero-Michael addition
(DIHMA) upon an ynone.8 Retrosynthetically, the G ring
may be disconnected to enone 1 by a retro-Michael discon-
nection of the C28 ketal releasing a C34 hydroxyl group
(Scheme 1).
A second retro-Michael disconnection of the b-oxyenone re-
veals dihydroxy ynone 2, which, in turn may arise via the
coupling of a C27 acetylide anion equivalent (3) upon a gen-
eralized C26 carbonyl derivative. Advanced intermediate 3
* Corresponding author. Tel.: +1 612 624 0218; fax: +1 612 626 7541;
e-mail: forsyth@chem.umn.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.112

S. Nguyen et al. / Tetrahedron 62 (2006) 5338–5346
5339
Me
conditions to induce an intramolecular aza-Wittig reaction
(S–aW) to form the I ring as an imine (8, Scheme 2), fol-
lowed by engagement of the tethered hydroxyl group to
close the H ring and generate 3. Both kinetic stereoelectronic
and thermodynamic effects should favor the selective forma-
tion of the natural products’ C36 spiroaminal configuration.
Alternatively, liberation of a primary amine by Staudinger
reduction of 7 in the presence of a carbamate-forming
reagent (RX, Scheme 2) might allow formal successive in-
tramolecular hetero-Michael additions upon the a,b-unsatu-
rated ketone (DIHMA) to ensue. In the latter case, an initial
6-exo addition of a carbamate nitrogen upon the ynone would
generate a hydroxy-enamine (9) that could isomerize to spi-
roaminal 10. The residual ketone at C34 of 10 would provide
a functional handle for the stereoselective installation of the
corresponding silyl ether in 3. Although Staudinger reac-
tions are unlikely to be involved in the actual biogenesis of
spiroaminals, the postulated types of hydroxy-imine or
hydroxy-enamine intermediates (8 and 9) derived from
Staudinger reactions in our laboratory syntheses may well be.
Furthermore, these designed Staudinger reaction-initiated
cascade sequences should be accessible under essentially
neutral reaction conditions that are tolerant of the extensive
functionality found in the azaspiracid natural products.
Me
Me
Me
N
H
O
N
R2
OH
O
O
Me
R1
Me
O
O
O
Azaspiracids
Me
R1
1
Me
Me
Me
40
RO
RO
N
R2
34
32
34
O
N
R2
OR
O
O
Me
28
R1
R1
26
32
2
OR
Me
2
Me
27
O
Me
Me
Me
40
Former
40
36
RO
RO
RO
RO
OMe
NBoc
H
34
32
N
34
32
O
O
R2
Trans-
ketalization
28
28
4
3
I
Me
Former
27
Me
27
Staudinger / Aza-Wittig
- ketalization
- carbamate
formation
Present
S-aW
OTES
N
TES TBS
Me
SiR3
O
O
O
Me
R3P
Me
Me
Me
Me
N3
HO
Me
Me Me
OH
O
Me
TBS
36
36
SiR3
40
40
γ-hydroxy-ketone
O
TESO
TBSO
N3
O
HO
34
N3
34
8
3
6
OH
OH
PMBO
32
32
Staudinger / DIHMA
28
28
R
N
TBS
O Me
OTES
SiR3
O
6
5
Me
R3Si
Me
27
Me
O
27
H
OH
N3
O
Me
TBS
SiR3
Me
Me Me
- OR -
S-DIHMA
Me
α'-hydroxy-ynone
Me
7
36
40
R3P
N3
RX
O
34
R
N
R
N
O
OH
TBSO
O
32
Me
Me
O
28
H
O
Me
TBS
Me
O
H
SiR3
Me
O
Me
TBS
SiR3
R3Si
7
Me
27
10
9
Scheme 1. Retrosynthetic analysis for the C27–C40 fragment.
Scheme 2. Two proposed methods for the formation of the azaspiracid
spiroaminal.
contains the piperidine–tetrahydrofuran fused spiroaminal
(H-I rings) and latent nucleophilic oxygens at C32 and
C34 masked as silyl ethers. The previously published assem-
blies of the azaspiracid spiroaminal moiety used a stepwise
sequence of ring-closings.8–10 These involved the initial for-
mation of the C33–C36 H ring as a cyclic mixed methyl
ketal. A C40 terminal azide was then reduced and protected
as a carbamate (cf. 4, Scheme 1). Finally, the spiroaminal
Retrosynthetically, we maintained the same type of triply
convergent approach employed in our previously disclosed
synthesis of the acyclic precursor to the azaspiracid C27–
C40 domain, but with a few significant changes.8 Ynones
6 and 7 could be derived from methyl ketone 11 or alkyne
12, respectively, and the common C34 aldehyde 13 (Scheme
3). A chelation-controlled Mukaiyama aldol reaction was
envisioned to join a silyl enol ether derivative of 11 with
13 while simultaneously setting the C33,C34 syn-stereo-
chemistry in 6. Addition of an acetylide nucleophile derived
from 12 to aldehyde 13 followed by oxidation and PMB
ether cleavage would provide 7. The common aldehyde 13
arises from a Paterson aldol reaction of a boron enolate ob-
tained from ketone 14 and C32 aldehyde 15, with subsequent
oxidative excision of the benzoyl chiral directing moiety
was formed by closure of the C36–C40 piperidine I ring
8,10
upon treatment with a Lewis acid, such as Yb(OTf)3
or
BF3$OEt2.9 We have since designed more facile assemblies
of spiroaminal 3 from acyclic intermediates g-hydroxy-d0-
azidoketone 6 or a-hydroxy-a0,b0-ynone 7.
The appropriately functionalized acyclic intermediate 6
would be subjected to Staudinger reduction under anhydrous

5340
S. Nguyen et al. / Tetrahedron 62 (2006) 5338–5346
OBn
resident in 14. Importantly, a chelating a-p-methoxybenzyl
(PMB) ether was incorporated in aldehyde 13 at the stage
of ketone 14 to effect the desired chelation-controlled
Mukaiyama reaction. This specific protecting group array
would also simplify the functional group manipulations re-
quired to enable the late-stage cyclization cascades via either
the S–aW or the S–DIHMA processes to form the H-I ring.
OH
3 steps
OR
b, c
MeO2C
34
33
34
CO2Me
33
O
O
OH
16 R = H
a
17 R = PMB
OBn
OH
e
d
OPMB
OPMB
OPMB
TES
TBS
34
BzO
BzO
34
BzO
BzO
33
33
33
SiR3
O
O
O
Me
O
OBz
18
OBz
40
40
+
13
13
27
N3
32
34
N3
36
19
36
35
28
OH
Me
Me
Me
Me
11
6
O
OR
32
TES
O
f
TBS
Me
O
SiR3
34
34
O
33
40
35
+
27
OBz O
OBz
14
34
N3
40
32
36
PMB
OH
N3
36
Me Me
20 R = H
21 R = TBS
g
Me Me
12
7
h
TBS
Me
SiR3
27
O
Me
O
SiR3
27
O
O
+
H
32
33
34
TBS
28
TBS
BzO
H 34
32
28
OBz
OPMB
O
O
TES
27
OH
O
TES
OPMB
i
15
33
13
33
14
H
34
BzO
34
OPMB
13
OBz O
Scheme 3. Key disconnections of ynones 6 and 7.
PMB
22
2.2. Preparative chemistry
Scheme 4. Synthesis of the C27–C34 aldehyde. a) NaH, PMBCl, TBAI,
DMF, THF, 0 ꢀC to rt, 6 h (96%); b) CSA (cat.), MeOH, 30 min; c) BzCl,
triethylamine, DMAP, CH2Cl2, 14 h (93% from 17); d) H2, Pd–BaSO4,
EtOAc, 14 h (58%); e) TPAP (cat.), NMO, CH2Cl2, 2 h (78%); f) Chex2BCl,
triethylamine, 0 ꢀC, 2 h, then 15, ꢁ78 ꢀC, 5 h, (69%); g) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 ꢀC, 30 min (83%); h) NaBH4, MeOH, 0 ꢀC, 1 h,
(92%); i) K2CO3, MeOH, 5 h, then AcOH, NaIO4, 30 min (70%).
The synthesis of the C27–C34 aldehyde 13 common to both
spiroaminal formation strategies began with the preparation
of ketone 14, which ultimately provides only carbons 33
and 34 (Scheme 4). However, 14 also bears the essential
a-benzyloxy stereogenic center that defines the absolute
stereochemistry of the ensuant C32 and C33 centers via
the Paterson boron aldol reaction.11 Dimethyl D-tartrate
was converted into primary alcohol 16 according to the pro-
cedure of Ohno.12 The C32 PMB ether was formed at this
stage to generate 17. Cleavage of the acetonide moiety fol-
lowed by bis-benzoylation of the resultant diol provided
18. Selective hydrogenolysis of the benzyl ether of 18 in
the presence of the vicinal PMB was accomplished using
Pd–BaSO4 in ethyl acetate to yield secondary alcohol 19.
Oxidation of the alcohol then delivered ketone 14 in five
steps and 40% overall yield from 16.
of both benzoyl groups was then accomplished by treatment
of 22 with K2CO3 in methanol. Thereafter, the crude triol so-
lution was neutralized with acetic acid and subsequently
treated with NaIO4. This one-pot procedure reliably pro-
vided the desired C27–C34 aldehyde 13.
To implement the S–aW spiroaminal formation strategy,
methyl ketone 115 (Scheme 3), representing C35–C40 of the
azaspiracids, was joined with aldehyde 13 via a chelation-
controlled Mukaiyama aldol reaction. (Scheme 5). For
this, ketone 11 was converted to the TMS vinyl ether 23
by treatment with NaHMDS followed by TMSCl. Various
Lewis acids were screened for the aldol reaction, including
SnCl4, TiCl4, ZnCl2, MgCl2, and MgBr2$OEt2. Among
these, MgBr2$OEt2 best delivered the desired anti-Felkin–
Anh product 24. The absolute configuration of (34R) in 24
was confirmed by application of the advanced Mosher ester
analysis.13 Silylation of the C34 hydroxy group and removal
of the PMB protective group left only the C33 hydroxyl and
C36 ketone of 6 free to participate in spiroaminal formation,
while the latent nucleophilic terminal nitrogen remained
masked as an azide.
A boron-mediated aldol reaction between ketone 14 and
aldehyde 158 following Paterson’s procedure11 proceeded
smoothly to afford the desired syn/anti product 20 (Scheme
1
4) in high yield and diastereoselectivity (ds >9:1, by H
NMR spectroscopy). The anticipated C32,C33 anti-relation-
ship was confirmed by the relatively large coupling constant
(5 MHz) between C32–H and C33–H. It should be noted that
attempts to use the analogous 1,4-bis-(p-methoxybenzy-
l)oxy-3-benzoyl-butanone under the same reaction condi-
tions only resulted in a complicated mixture of inseparable
diastereomeric aldol products. The resultant b-hydroxyl
group in 20 was protected as a TBS ether to give 21. Exhaus-
tive reduction of the ketone and the bis-benzoyloxy groups
in 21 using LiAlH4 resulted in a low yield of the expected
triol. This may be attributed to a net retro-aldol reaction
leading to the fragmentation of the oxy-ketone. A stepwise
approach was thus pursued. Hence ketone 21 was reduced
non-stereoselectively to alcohol 22 using NaBH4. Removal
The anticipated spiroaminal moiety in 26 was initially formed
in moderate yield upon treatment of azide 6 with n-Bu3P
in benzene (Scheme 5). After surveying various conditions
it was found that Et3P in benzene provided better results,
reproducibly giving 26 in ca. 75% yield as a ca. 4:1 ratio
of C36 epimers. The sequence likely proceeds via reaction
of the trialkyphosphine with the azide to generate an

S. Nguyen et al. / Tetrahedron 62 (2006) 5338–5346
5341
OTMS
35
type 7 (Scheme 2). For this, d-azido-aldehyde 28 (Scheme
6) was converted to geminal dibromo-olefin 29 under
Corey–Fuchs conditions. Transformation of 29 to the C35–
C40 lithium acetylide 30 with n-butyllithium allowed addi-
tion to C27–C34 aldehyde 31 to generate propargylic alco-
hols 32. It was determined that Staudinger reduction and
carbamate formation best preceded propargylic alcohol oxi-
dation to yield C27–C40 ynone 33.
a
b
11
40
N3
Me Me
23
TBS
OR1
34
OR2
O
O
Me
TES
N3
Me Me
24 R1 = H, R2 = PMB,
25 R1 = TES, R2 = PMB,
6 R1 = TES, R2 = H
c
O
d
Br
a
b
N3
H
N3
40
36
e
Me Me
Me Me Br
28
TES TBS
Me
29
TES
O
O
O
TBS
Me
Et3P
O
TMS
O
N
Li
35
27
Me Me
OH
H
34
+ N2
40
N3
31
OPMB
Me Me
OTES
N
30
Me
TBS
Me
OH
34
O
TMS
TMS
HO
Me
O
Me
TBS
TES
27
c, d
+ Et3PO
40
N3
36
OPMB
Me Me
32
R
OTES
40
TBS
Me
N
O
O
Me
O
34
TES
O
Me
TBS
H
Me
27
N
Boc
OPMB
36
Me Me
26 R = H
27 R = Cbz
3
f
33
g
Scheme 6. Assembly of the DIHMA precursor. a) CBr4, Ph3P, CH2Cl2
(91%); b) n-BuLi, THF, ꢁ78 ꢀC, then 31 (70%); c) (i) Et3P, toluene, (ii)
BocON, ꢁ10 ꢀC to rt (61%); d) MnO2, pentane (100%).
ref. [8]
Me
Me
To parlay carbamate-ynone 33 into the azaspiracid spiro-
aminal the carbamate nitrogen must conjugatively add to
the ynone and the a-keto PMB ether needs to be cleaved
so that the liberated C33 secondary hydroxyl group may
add to the C34–C36 enone system. An initial attempt to en-
gage in this sequence involved PMB ether cleavage from 33
with DDQ (Scheme 7). Concomitant with removal of the
PMB group under the DDQ reaction conditions, however,
was the conjugate addition of the carbamate nitrogen upon
the ynone to generate hydroxyl enamine 34. Application of
conditions intended to convert the terminal alkynyl silyl
group of 34 into the corresponding iodo-alkyne also led to
an unanticipated secondary transformation—spiroaminal
formation via addition of the C33 hydroxyl upon C36 of
the enamine–enone to result in the target 35. Intramolecular
conjugate addition of the carbamate nitrogen of 33 upon the
ynone system could also be initiated under the influence of
the Lewis acid MgBr2$OEt2 to form enone 36. Thereafter,
cleavage of the PMB ether of 36 revealed the C33 hydroxyl,
which completed the second conjugate addition to form the
spiroaminal. Finally, the direct conversion of C33 PMB
ether–ynone 33 into spiroaminal 36 could be accomplished
in one operation and moderate yield using AgTFA followed
by addition of ethanolic KI. Four functional group trans-
formations are accomplished in this remarkable one-pot
process: hetero-Michael addition of the terminal carbamate
nitrogen upon the C34–C36 ynone, scission of both C27
40
N
O
O
R
Me
1
R
26
O
28
Scheme 5. Spiroaminal assembly via a Staudinger–aza-Wittig process. a)
NaHMDS, THF, ꢁ78 ꢀC, 15 min, then TMSCl, 1 h (w90%, crude); b) 13,
MgBr2$OEt2, CH2Cl2, ꢁ78 ꢀC to ꢁ25 ꢀC, 14 h (66%, 74% borsm); c)
TBSOTf, 2,6-lutidine, CH2Cl2, ꢁ10 ꢀC (92%); d) DDQ, t-BuOH,
˚
CH2Cl2, H2O, 2 h, (82%); e) Et3P, PhH, 6 h (75%); f) CbzCl, K2CO3, 4 A
MS, CH2Cl2, 14 h (73%); g) AgTFA, NIS, DMF (87%).
iminophosphorane that undergoes an intramolecular aza-
WittigreactionwiththeC36ketonetoformthesix-membered
cyclic imine. Addition of the C33 hydroxyl group to the imine
completes the cascade. The spiroaminal nitrogen of 26 was
converted into the corresponding benzylcarbamate 27 for
characterization. 1H NMR experiments, including NOE,
firmly established the relative configuration of the C36 spiro-
aminal center in the major diastereomer as indicated. This
result is consistent with either a kinetically controlled
pseudoaxial addition of the C33 hydroxyl upon the piperidine
imine, or post-addition thermodynamic equilibration, or both.
The alternative DIHMA approach to the azaspiracid spiro-
aminal required the synthesis of a conjugated ynone of

5342
S. Nguyen et al. / Tetrahedron 62 (2006) 5338–5346
terminal alkyne and C33 secondary alcohol protecting
groups, and the stereoselective addition of the C33 oxygen
upon the C36 center to generate spiroaminal 36. Presumably,
the silver cation activates the internal alkyne towards an ini-
tial intramolecular addition of the nitrogen to initiate this
cascade.
under a positive pressure of dry argon or nitrogen and mois-
ture-sensitive solutions and anhydrous solvents were trans-
ferred via standard syringe and cannula techniques. Unless
stated otherwise, all commercial reagents were used as
received. Organic solvents were dried under nitrogen
atmosphere: tetrahydrofuran (THF) and diethyl ether were
distilled over Na-benzophenone; CH2Cl2, N,N-di-iso-
propyl-N-ethylamine, and pyridine were distilled from
CaH2. Flash chromatography was performed using Baker
Flash silica gel 60 (40 mM); analytical TLC was performed
using 0.25 mm EM silica gel 60 F254 plates that were visual-
ized by irradiation (254 nm) or by staining (450 mL of 95%
ethanol, 25 mL concd. H2SO4, 15 mL acetic acid, and 25 mL
anisaldehyde). Optical rotations were obtained using
a JASCO DIP-370 digital polarimeter. IR spectra were re-
corded using a Perkin–Elmer 683 infrared spectrophotome-
ter. NMR spectra were obtained using INOVA 500 and
300 MHz Varian instruments. High-resolution mass spectro-
metric data were obtained using a VG Analytical Sector-
Field mass spectrometer.
Boc
N
OH
TBS
Me
O
O
TMS
a
O
O
Me
TBS
TMS
34
Me
Me
34
H
N
Boc
OPMB
36
Me Me
33
b
b
c
Boc
Me
N
O
Boc
N
OPMB
a, b
OTBS
Me
O
O
O
Me
TBS
TMS
Me
Me
Me
35
36
Scheme 7. Spiroaminal formation via DIHMA. a) DDQ, CH2Cl2, t-BuOH,
pH 7 buffer; b) (i) AgTFA, CH2Cl2, (ii) EtOH, H2O, KI (33 to 35¼56%).
c) MgBr2$OEt2, CH2Cl2.
4.1.1. (2S,3S)-3-(O-Benzyl)-4-(O-[p-methoxy]benzyl)-
1,2,3,4-buaneteteraol-1,2-di-O-acetonide (17). To a stirred
solution of 16 (2.35 g, 9.32 mmol) in THF (95 mL) at 0 C
ꢀ
3. Conclusion
was added in portions NaH (1.12 g, 60% in mineral oil,
28 mmol). The suspension was warmed to rt. After
30 min, PMBCl (2.35 mL, 18.6 mmol) and TBAI (0.68 g,
1.9 mmol) were added sequentially. The reaction mixture
We have developed two complementary second-generation
syntheses of the C27–C40 fragment of the azaspiracids
that are both efficient and stereoselective. Both routes uti-
lize a common C27–C34 aldehyde that is assembled with a
Paterson aldol reaction to establish the C32 and C33 con-
figurations.
ꢀ
was stirred for 24 h, cooled to 0 C, and H2O (30 mL) was
added slowly. The resulting mixture was transferred to a sep-
aratory funnel and extracted with diethyl ether (3ꢂ70 mL).
The combined organic extracts were washed with saturated
aqueous NH4Cl (2ꢂ30 mL) and dried over MgSO4, filtered,
and concentrated in vacuo. Purification of the crude residue
by silica gel column chromatography (hexanes–ethyl ace-
tate, 10:1 to 5:1, v/v) provided 17 (3.32 g, 8.93 mmol, 96%)
as a colorless oil: Rf 0.61 (hexanes–ethyl acetate, 2:1, v/v);
[a]2D3 ꢁ5.8 (c 0.63, CH2Cl2); IR (thin film): 3063–2840,
1612, 1586, 1513, 1455, 1370, 1301, 1251 cmꢁ1; 1H NMR
(CDCl3, 300 MHz): d 7.39–7.28 (m, 5H), 7.24 (d, J¼
8.7 Hz, 2H), 6.87 (d, J¼8.7 Hz, 2H), 4.77 (d, J¼11.4 Hz,
1H), 4.74 (d, J¼11.4 Hz, 1H), 4.47 (d, J¼12 Hz, 1H), 4.42
(d, J¼12 Hz, 1H), 4.26 (q, J¼9.0 Hz, 1H), 3.97 (dd,
J¼8.4, 6.6 Hz, 1H), 3.81 (s, 3H), 3.72 (dd, J¼8.4, 7.4 Hz,
1H), 3.64–3.55 (m, 3H), 1.40 (s, 3H), 1.36 (s, 3H); 13C
NMR (CDCl3, 75 MHz): d 159.2, 138.6, 130.2, 129.3,
128.3, 127.9, 127.5, 113.8, 78.4, 76.9, 73.2, 72.9, 70.0,
65.9, 55.3, 26.6, 25.6; HRMS (ESI) calcd for
[C22H28O5+Na]+ 395.1829, found 395.1833.
For the Staudinger–aza-Wittig-based assembly of the
spiroaminal, the C27–C34 aldehyde was subjected to a che-
lation-controlled Mukaiyama aldol reaction to set the C34
configuration and provide g-hydroxy-d0-azidoketone 6.
Subsequent one-pot formation of the spiroaminal moiety
involved treatment with triethylphosphine to initiate the
cyclization cascade leading to 26. Compound 26 represents
the fully functionalized C27–C40 azaspiracid intermediate
that is amenable to elaboration into the complete F-G-H-I
ring domain via our established DIHMA process. The syn-
thetic sequence leading to 27 via the Staudinger–aza-Wittig
process started with three simple subunits and was com-
pleted in nine linear steps with 11% overall yield.
The complementary DIHMA closure of the azaspiracid spi-
roaminal required an a-hydroxy-a0,b0-ynone (cf. 7) that was
derived from the C27–C34 aldehyde (31) and a C35–C40
acetylide (30). The emergent conjugated ynone 33 could
also be converted into the corresponding spiroaminal in
a one-pot process. In this case, an Ag+ species initiated the
cyclization sequence. Each of these spiroaminal forming
processes demonstrated here in the context of the azaspira-
cids may find broader applications in organic synthesis.
4.1.2. (2R,3S)-2-(O-Benzyl)-1-(O-[p-methoxy]benzyl)-
1,2,3,4-buaneteteraol (17b). To a stirred solution of 17
(1.00 g, 2.68 mmol) in methanol (26 mL) was added Amber-
lite (IR 120H+ C.P., Mallinckrodt; 1.0 g). After the mixture
was stirred for 14 h, the resin was removed by filtration.
The filtrate was evaporated in vacuo to give 17b (0.84 g,
2.5 mmol, 94%) as a colorless oil: Rf 0.32 (hexanes–ethyl ac-
etate, 1:1, v/v); [a]2D3 +17.6 (c 2.13, CH2Cl2); IR (thin film):
3417 (br), 3064, 3032, 2933, 2870, 1613, 1587, 1514, 1456,
4. Experimental
4.1. General
1365, 1302, 1249 cmꢁ1 1H NMR (CDCl3, 500 MHz):
;
d 7.38–7.29 (m, 5H), 7.26 (d, J¼8.5 Hz, 2H), 6.89 (d, J¼
8.5 Hz, 2H), 4.75 (d, J¼11.0 Hz, 1H), 4.55 (d, J¼11.0 Hz,
1H), 4.51 (d, J¼13.0 Hz, 1H), 4.47 (d, J¼13.0 Hz, 1H),
Unless noted otherwise, all oxygen and moisture-sensitive
reactions were executed in oven-dried glassware sealed

S. Nguyen et al. / Tetrahedron 62 (2006) 5338–5346
5343
3.82 (s, 3H), 3.79 (m, 2H), 3.66 (m, 4H), 2.74 (br d,
J¼4.5 Hz, 1H), 2.31 (br s, 1H); 13C NMR (CDCl3,
75 MHz): d 159.3, 137.9, 129.7, 129.5, 128.6, 128.0,
113.9, 78.2, 73.3, 72.7, 71.9, 68.9, 63.5, 55.3; MS (ESI)
calcd for [C19H24O5+Na]+ 355.15, found 355.21.
was transferred to a silica gel column and eluted with
hexanes–ethyl acetate (9:1 to 4:1 to 2:1, v/v) to provide
14 (1.45 g, 3.24 mmol, 87%) as a colorless oil: Rf 0.37
(hexanes–ethyl acetate, 2:1, v/v); [a]2D3 +54.2 (c 0.74, benz-
ene); IR (thin film): 3065, 2956, 2847, 1726, 1611, 1586,
1514, 1452, 1374, 1253 cmꢁ1
;
1H NMR (CDCl3,
4.1.3. (2R,3S)-1,2-Dibenzoyl-3-(O-benzyl)-4-(O-[p-
methoxy]benzyl)-1,2,3,4-buaneteteraol (18). To a stirred
solution of 17b (0.80 g, 2.4 mmol) in CH2Cl2 (24 mL)
were added Et3N (1.33 mL, 9.60 mmol), benzoyl chloride
(0.84 mL, 7.2 mmol), and DMAP (29 mg, 0.24 mmol) se-
quentially. The reaction mixture was stirred for 1.5 h before
saturated aqueous NH4Cl (10 mL) was added. The mixture
was extracted with CH2Cl2 (2ꢂ10 mL). The combined
organic extracts were washed with saturated aqueous NaCl
(10 mL) and dried over MgSO4, filtered, and concentrated
in vacuo. Purification of the crude residue by silica gel
column chromatography (hexanes–ethyl acetate, 4:1 to 2:1,
v/v) provided 18 (1.18 g, 2.25 mmol, 93%) as a colorless
oil: Rf 0.52 (hexanes–ethyl acetate, 2:1, v/v); [a]2D3 +3.3 (c
0.92, CDCl3); IR (thin film): 3065, 3033, 2933, 2864,
1782, 1724, 1611, 1586, 1514, 1453, 1368, 1316,
300 MHz): d 8.05 (d, J¼7.5 Hz, 2H), 7.98 (d, J¼7.5 Hz,
2H), 7.58 (q, J¼7.5 Hz, 2H), 7.44 (q, J¼7.5 Hz, 4H), 7.27
(d, J¼9.0 Hz, 2H), 6.86 (d, J¼9.0 Hz, 2H), 5.89 (t, J¼
4.0 Hz, 1H), 4.87 (d, J¼4.0 Hz, 2H), 4.61 (d, J¼12.0 Hz,
1H), 4.55 (d, J¼12.0 Hz, 1H), 4.38 (d, J¼15.0 Hz, 1H),
4.30 (d, J¼15.0 Hz, 1H), 3.79 (s, 3H; 13C NMR (CDCl3,
75 MHz): d 202.0, 166.0, 165.3, 159.3, 133.7, 133.4,
130.0, 129.7, 128.6, 128.5, 114.0, 102.8, 75.2, 73.4, 73.3,
62.8, 55.3; HRMS (ESI) calcd for [C26H24O7+Na]+
471.1420, found 471.1431.
ꢀ
4.1.6. Aldol adduct (20). To a stirred, 0 C solution of dicy-
clohexylchloroborane (0.79 mL, 3.6 mmol) and triethyl-
amine (0.63 mL, 4.5 mmol) in diethyl ether (40 mL) was
added a solution of 14 (1.34 g, 3.0 mmol) in diethyl ether
(2 mL). The initially colorless solution became a yellow sus-
pension. After 2 h, the reaction mixture was cooled to
1
1253 cmꢁ1; H NMR (CDCl3, 300 MHz): d 8.03 (d, J¼
ꢀ
7.1 Hz, 2H), 7.96 (dd, J¼7.1 Hz, 2H), 7.56 (m, 2H), 7.41
(m, 4H) 7.36–7.27 (m, 5H), 7.25 (d, J¼8.7 Hz, 2H), 6.84
(d, J¼8.7 Hz, 2H), 5.55 (m, 1H), 4.81 (d, J¼11.8 Hz, 1H),
4.69 (d, J¼11.8 Hz, 1H), 4.66 (d, J¼4.2 Hz, 1H), 4.62 (d,
J¼4.2 Hz, 1H), 4.48 (s, 2H), 4.02 (dd, J¼9.9, 5.4 Hz, 1H),
3.79 (s, 3H), 3.72 (d, J¼5.1 Hz, 2H); 13C NMR (CDCl3,
75 MHz): d 166.0, 165.6, 159.0, 137.7, 133.0, 132.9,
129.7, 129.5, 129.3, 128.2, 128.1, 127.8, 127.6, 113.6,
76.3, 73.1, 72.9, 71.3, 68.7, 63.1, 55.1; HRMS (ESI) calcd
for [C33H32O7+Na]+ 563.2041, found 563.2035.
ꢁ78 C, and a solution of 15 (0.49 g, 2.2 mmol) in diethyl
ether (3 mL) was added. After 10 min,ꢀthe reaction mixture
was allowed to warm slowly to ꢁ25 C, and stirring was
continued at this temperature for 4 h. A solution of pH 7
aqueous phosphate buffer (10 mL), methanol (10 mL), and
30% aqueous H2O2 solution (5 mL) were added sequen-
tially. The mixture was allowed to warm to rt and stirred
for 1 h before diethyl ether (20 mL) was added. The aqueous
phase was separated and extracted with diethyl ether
(2ꢂ10 mL), and the combined organic extracts were washed
with saturated aqueous NaCl, dried over MgSO4, filtered,
and concentrated in vacuo. The oily residue was purified
by silica gel column chromatography (hexanes–ethyl ace-
tate, 6:1 to 4:1 to 2:1, v/v) to provide 20 (1.02 g,
1.51 mmol, 69%) as a colorless oil: Rf 0.50 (hexanes–ethyl
acetate, 2:1, v/v); [a]2D3 +37.5 (c 2.5, CH2Cl2); IR (thin
film): 3491.8, 2955.9, 2871.4, 2170, 1727, 1613, 1586,
4.1.4. (2R,3S)-1,2-Dibenzoyl-4-(O-[p-methoxy]benzyl)-
1,2,3,4-buaneteteraol (19). To a solution of 18 (1.00 g,
1.85 mmol) in ethyl acetate (100 mL) was added Pd–
BaSO4 (0.2 g, 10% w/w). The mixture was stirred under
a H2 atmosphere (w1 atm) for 6 h. The catalyst was removed
by filtration and the filtrate was concentrated in vacuo. The
residue was purified by silica gel column chromatography
(hexanes–ethyl acetate, 5:1 to 2:1, v/v) to give recovered
18 (0.25 g, 25%) and the product 19 (0.49 g, 1.1 mmol,
58%) as a colorless oil: Rf 0.33 (hexanes–ethyl acetate,
2:1, v/v); [a]2D3 ꢁ8.7 (c 1.1, CDCl3); IR (thin film): 3489
(br), 3065, 2935, 2865, 1727, 1611, 1586, 1514, 1452,
1514, 1453, 1262 cmꢁ1 1H NMR (CDCl3, 500 MHz):
;
d 8.05 (d, J¼7.5 Hz, 2H), 8.01 (d, J¼7.5 Hz, 2H), 7.58 (q,
J¼7.5 Hz, 2H), 7.44 (q, J¼7.5 Hz, 4H), 7.27 (d, J¼9.0 Hz,
2H), 6.85 (d, J¼9.0 Hz, 2H), 5.93 (dd, J¼4.5, 3.0 Hz, 1H),
4.89 (m, 2H), 4.63 (d, J¼11.5 Hz, 1H), 4.61 (d, 11.5 1H),
4.13 (m, 1H), 4.04 (d, J¼5.5 Hz, 1H), 3.77 (s, 3H), 2.90
(d, J¼7.5 Hz, 1H) 2.29 (dd, J¼12.0, 5.0 Hz, 1H), 2.22 (dd,
J¼12.0, 6.5 Hz, 1H), 2.00 (m, 1H), 1.64 (ddd, J¼14.0, 8.5,
3.5 Hz, 1H), 1.50 (ddd, J¼14.0, 1.0, 5.0 Hz), 1.04 (d,
J¼7.0 Hz, 3H), 0.97 (t, J¼7.5 Hz, 9H), 0.56 (q, J¼7.5 Hz,
6H); 13C NMR (CDCl3, 75 MHz): d 203.1, 166.4, 166.1,
159.7, 133.9, 133.4, 130.2, 130.0, 129.8, 128.6, 114.0,
106.8, 86.7, 72.8, 69.9, 63.0, 55.9, 38.7, 28.9, 26.1, 20.4,
7.6, 4.6; HRMS (ESI) calcd for [C39H48O8Si+Na]+
695.3013, found 695.2990.
1361, 1316, 1255 cmꢁ1 1H NMR (CDCl3, 300 MHz):
;
d 8.04 (d, J¼8.7 Hz, 2H), 7.98 (d, J¼9.0 Hz, 2H), 7.56 (m,
2H), 7.42 (m, 4H), 7.20 (d, J¼8.7 Hz, 2H), 6.82 (d,
J¼8.7 Hz, 2H), 5.62 (ddd, J¼7.0, 4.5, 4.5 Hz, 1H), 4.71
(dd, J¼11.7, 4.5 Hz, 1H), 4.59 (dd, J¼11.7, 6.9 Hz, 1H),
4.46 (s, 2H), 4.17 (m, 1H), 3.78 (s, 3H), 3.65 (dd, J¼9.9,
4.5 Hz, 1H), 3.59 (dd, J¼9.9, 6.3 Hz, 1H), 2.61 (d,
J¼6.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d 166.3,
165.9, 159.3, 133.3, 133.2, 129.8, 129.7, 129.5, 128.4,
113.8, 73.3, 72.1, 70.4, 69.6, 63.2, 55.2; MS (ESI) calcd
for [C26H26O7+Na]+ 473.16, found 473.25.
4.1.7. TBS ether (21). To a soꢀlution of 20 (0.69 g, 1.0 mmol)
in CH2Cl2 (30 mL) at 0 C were added 2,6-lutidine
(0.36 mL, 3.1 mmol) and t-butyldimethylsilyl triflate
(0.47 mL, 2.0 mmol) sequentially. After 1 h, saturated aque-
ous NH4Cl (10 mL) was added slowly. The aqueous phase
was separated and extracted with diethyl ether (2ꢂ10 mL)
and the combined organic extracts were washed with
4.1.5. (3S)-3,4-Dibenzoyl-4-(O-[p-methoxy]benzyl)-1,3,4-
trihydroxybuanone (14). To a solution of 19 (1.67 g,
˚
3.71 mmol) in CH2Cl2 (35 mL) was added 4 A molecular
sieves (0.4 g) and TPAP (65 mg, 0.18 mmol), followed by
NMO (0.65 g, 5.6 mmol). After 30 min, the reaction mixture

5344
S. Nguyen et al. / Tetrahedron 62 (2006) 5338–5346
saturated aqueous NaCl, dried over MgSO4, filtered, and
concentrated in vacuo. The crude residue was purified by
silica gel column chromatography (hexanes–ethyl acetate,
10:1 to 7:1, v/v) to provide 21 (0.66 g, 0.85 mmol, 83%)
as a colorless oil: Rf 0.69 (hexanes–ethyl acetate, 2:1, v/v);
[a]2D3 ꢁ15 (c 0.97, CDCl3); IR (thin film): 2957, 2923,
2875, 2175, 1725, 1613, 1595, 1512, 1446, 1256 cmꢁ1; 1H
NMR (CDCl3, 300 MHz): d 8.05 (d, J¼8.4 Hz, 2H), 7.99
(d, J¼8.4 Hz, 2H), 7.57 (m, 2H), 7.43 (m, 4H), 7.29 (d,
J¼8.7 Hz, 2H), 6.84 (d, J¼8.7 Hz, 2H) 6.06 (dd, J¼5.1,
2.7 Hz, 1H), 4.93 (dd, J¼12.3, 5.1 Hz, 1H), 4.82 (d, J¼
10.8 Hz, 1H), 4.80 (dd, J¼12.3, 2.7 Hz, 1H) 4.58 (d,
J¼10.8 Hz, 1H), 4.26 (m, 2H), 3.78 (s, 3H), 2.30 (dd,
J¼16.8, 3.6 Hz, 1H), 2.01 (dd, J¼16.8, 8.1 Hz, 1H), 1.80
(m, 1H), 1.70–1.60 (m, 2H), 1.03 (d, J¼6.3 Hz, 3H), 0.98
(t, J¼7.8 Hz, 9H), 0.91 (s, 9H), 0.56 (q, J¼7.8 Hz, 6H),
0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (CDCl3, 75 MHz):
d 159.2, 138.6, 130.2, 129.3, 128.3, 127.9, 127.5, 113.8,
78.4, 76.9, 73.2, 72.9, 70.0, 65.9, 55.3, 26.6, 25.6; HRMS
(ESI) calcd for [C45H62O8Si2+Na]+ 809.3881, found
809.3904.
(s, 3H) 13C NMR (CDCl3, 75 MHz): d 203.2, 159.3, 129.5,
129.2, 113.7, 106.0, 86.6, 86.3, 72.3, 72.1, 55.1, 39.8,
28.5, 26.5, 25.7, 19.8, 7.7, 4.4, 0.9, ꢁ4.4, ꢁ4.9; HRMS
(ESI) calcd for [C29H50O4Si2+Na]+ 541.3140, found
541.3138.
4.1.10. TMS enol ether (23). To a solution of 11 (0.30 g,
ꢀ
1.8 mmol) in THF (6 mL) at ꢁ78 C was added NaHMDS
(2.66 mL, 1 M in THF). After 30 min, trimethylsilyl chloride
(0.44 mL, 3.6 mmol) was added. After 1 h, a solution of pH
7 phosphate buffer (6 mL) was added and the reaction mix-
ture was allowed to warm to rt. The separated aqueous phase
was extracted with ether, and the ether extract was washed
with H2O and brine, dried over Na2SO4, filtered, and con-
ꢀ
centrated by rotary evaporation at 20 C. The residue
was passed quickly through a short pad of silica gel with
pentane–ether (3:1 v/v). The solvent was removed by rotary
evaporation to yield 23 as a pale yellow oil (0.49 g). The
product was used for the next step without further purifica-
tion: Rf 9.0 (hexanes–ethyl acetate, 5:1, v/v); 1H NMR
(CDCl3, 300 MHz): d 4.01 (d, J¼0.9 Hz, 1H), 3.96 (s,
1H), 3.17 (dd, J¼12.0, 6.0 Hz, 1H), 3.08 (dd, J¼12.0,
6.9 Hz, 1H), 2.19 (m, 1H), 1.75 (m, 1H), 1.58 (ddd,
J¼13.5, 9.6, 4.5 Hz, 1H), 1.02 (d, J¼6.9 Hz, 3H), 0.95
(d, J¼6.6 Hz, 3H), 0.19 (d, J¼9.9 Hz, 9H); IR (thin
film): 2963, 2097, 1655, 1624, 1461, 1319, 1253, 1092,
ꢀ
4.1.8. Alcohol (22). To a stirred, 0 C solution of 22 (0.80 g,
1.0 mmol) in methanol (11 mL) was slowly added NaBH4
(21 mg, 0.55 mmol). After 1 h, saturated aqueous NH4Cl
(10 mL) was added dropwise and the reaction mixture was
allowed to warm to rt. The aqueous phase was extracted
with CH2Cl2 (3ꢂ10 mL). The combined organic extracts
were washed with saturated aqueous NaCl (5 mL), dried
over MgSO4, filtered, and concentrated. The crude residue
was purified by silica gel column chromatography (hex-
anes–ethyl acetate, 10:1 to 7:1, v/v) to provide the corre-
sponding alcohol 22 (0.73 g, 0.93 mmol, 92%, mixture of
diastereomers) as a colorless oil: Rf 0.48 (hexanes–ethyl
acetate, 5:1, v/v); IR (thin film): 3493, 2954, 2170, 1723,
1611, 1586, 1514, 1454, 1255 cmꢁ1; MS (ESI) calcd for
[C45H64O8Si2+Na]+ 811.39, found 811.45.
1020 cmꢁ1
.
4.1.11. Mukaiyama aldol product (24). To a stirred solu-
tion of 23 (0.49 g) and 13 (144 mg, 355 mmol) in CH2Cl2
ꢀ
(6 mL) at ꢁ78 C was added a fine powder of MgBr2$OEt2
(275 mg, 1.07 mmol). Stirring was continued for 4 h before
the reaction flask was placed in a freezer for 14 h. A solution
of pH 7 phosphate buffer (10 mL) was added and the temper-
ature was allowed to rise to rt. The aqueous phase was ex-
tracted with diethyl ether and the combined organic extract
was washed with brine, dried over Na2SO4, filtered, and con-
centrated by rotary evaporation. The residue was purified by
silica gel column chromatography (hexanes–ethyl acetate,
6:1, v/v) to provide 24 (161 mg, 234 mmol, 66%) as a color-
less oil: Rf 0.19 (hexanes–ethyl acetate, 5:1, v/v); [a]2D3 +25.4
(c 0.51, CH2Cl2); IR (thin film): 3491, 2962, 2933, 2877,
2170, 2100, 1713, 1614, 1514, 1461, 1380, 1356, 1286,
4.1.9. Aldehyde (13). To a solution of 22 (0.73 g,
0.93 mmol) in methanol (5 mL) was added K2CO3 (0.74 g,
5.4 mmol). After 5 h, TLC analysis showed complete con-
version to triol: HRMS (ESI) calcd for [C31H56O6Si2+K]+
619.3253, found 619.3249. To the solution of triol was
slowly added acetic acid (ca. 0.5 mL) to achieve pH 9.
NaIO4 (1.14 g, 5.35 mmol) was then added portion-wise.
After 4 h, saturated aqueous NaHCO3 (5 mL) and CH2Cl2
(15 mL) were added, and stirring was continued for
15 min. The separated aqueous phase was extracted with
CH2Cl2 (4ꢂ10 mL) and the combined organic extracts
were dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel column chromato-
graphy (hexanes–ethyl acetate, 6:1, v/v) to give 13 (3.33 g,
0.65 mmol, 70%) as a colorless oil: Rf 0.58 (hexanes–ethyl
acetate, 4:1, v/v); [a]D23 +30.9 (c 0.55, CDCl3); IR (thin
film): 2956, 2933, 2876, 2172, 1735, 1614, 1587, 1514,
1251, 1177, 1105, 1036 cmꢁ1
;
1H NMR (CDCl3,
300 MHz): d 7.28 (d, J¼8.7 Hz, 2H), 6.89 (d, J¼8.7 Hz,
2H), 4.70 (d, J¼11.4 Hz, 1H), 4.38 (m, 2H), 4.14 (dd,
J¼6.9, 1.8 Hz, 1H), 3.84 (d, J¼1.5 Hz, 1H), 3.82 (s, 3H),
3.30 (m, 1H), 3.20 (dd, J¼12.0, 5.1 Hz, 1H), 3.07 (dd,
J¼12.0, 6.6 Hz, 1H), 2.79 (dd, J¼17.4, 6.3 Hz, 1H), 2.55
(m, 1H), 2.52 (dd, J¼17.1, 5.7 Hz, 1H), 2.29 (dd, J¼16.8,
4.5 Hz, 1H), 2.17 (dd, J¼16.8, 6.0 Hz, 1H), 1.90–1.55 (m,
6H), 1.07 (d, J¼7.5 Hz, 3H), 1.04 (d, J¼6.0 Hz, 3H), 1.00
(t, J¼7.8 Hz, 9H), 0.93 (d, J¼7.2 Hz, 3H), 0.91 (s, 9H),
0.59 (q, J¼7.8 Hz, 6H), 0.15 (s, 3H), 0.12 (s, 3H); MS
(ESI) calcd for [C37H65N3O5Si2+Na]+ 710.43, found
710.43.
1463, 1379, 1302, 1252 cmꢁ1
;
1H NMR (CDCl3,
500 MHz): d 9.64 (d, J¼2.5 Hz, 1H), 7.27 (d, J¼8.7 Hz,
2H), 6.88 (q, J¼8.7 Hz, 2H), 4.58 (d, J¼11.0 Hz, 1H),
4.55 (d, J¼11.0 Hz, 1H), 4.07 (ddd, J¼8.0, 6.0, 2.5 Hz,
1H), 3.81 (s, 3H), 3.64 (dd, J¼2.5, 2.5 Hz, 1H) 2.25 (dd,
J¼16.5, 5.0 Hz, 1H), 2.12 (dd, J¼16.5, 7.0 Hz, 1H), 1.78
(m, 1H), 1.56 (m, 2H), 1.00 (d, J¼5.0 Hz, 3H), 0.98 (t,
J¼8.0 Hz, 9H), 0.57 (q, J¼7.5 Hz, 6H), 0.09 (s, 3H), 0.07
4.1.12. TES ether (25). To a stirredꢀsolution of 10 (32 mg,
47 mmol) in CH2Cl2 (1 mL) at ꢁ10 C were added 2,6-luti-
dine (22 mL, 0.19 mmol) and triethylsilyl triflate (21 mL,
93 mmol). After 30 min, saturated aqueous NaHCO3
(1 mL) was added. The mixture was extracted with
CH2Cl2, dried over MgSO4, filtered, and concentrated. The

S. Nguyen et al. / Tetrahedron 62 (2006) 5338–5346
5345
residue was purified by silica gel column chromatography
(hexanes–ethyl acetate, 6:1, v/v) to provide 25 (35 mg,
43 mmol, 92%) as colorless viscous oil: Rf 0.55 (hexanes–
ethyl acetate, 5:1, v/v); [a]2D3 +15.4 (c 1.4, CH2Cl2); IR
(thin film): 2957, 2877, 2171, 2098, 1715, 1614, 1514,
1461, 1415, 1380, 1250, 1109, 1071, 1018 cmꢁ1; 1H NMR
(CDCl3, 500 MHz): d 7.25 (d, J¼4.2 Hz, 2H), 6.87 (d,
J¼8.0 Hz, 2H), 4.66 (d, J¼11.0 Hz, 1H), 4.47 (d,
J¼11.0 Hz, 1H), 4.36 (m, 1H), 3.98 (ddd, J¼8.5, 4.0,
1.5 Hz, 1H), 3.81 (s, 3H), 3.44 (dd, J¼5.5, 1.5 Hz, 1H),
3.22 (dd, J¼11.5, 5.0 Hz, 1H), 3.07 (dd, J¼11.5, 7.0 Hz,
1H), 2.81 (dd, J¼17.0, 3.5 Hz, 1H), 2.72 (dd, J¼17.0,
7.5 Hz, 1H) 2.58 (septet, J¼7.0 Hz, 1H), 2.30 (dd, J¼16.5,
3.5 Hz, 1H), 2.04 (dd, J¼8.0, 16.5 Hz, 1H), 1.88 (m, 1H),
1.79 (ddd, J¼13.5, 8.5, 6.0 Hz, 1H), 1.66 (m, 1H), 1.48
(ddd, J¼13.5, 9.0, 4.5 Hz, 1H), 1.07 (d, J¼7.0 Hz, 3H),
1.04 (d, J¼6.5 Hz, 3H), 0.99 (t, J¼8.0 Hz, 9H), 0.93 (d,
J¼7.0 Hz, 3H), 0.90 (s, 9H), 0.89 (t, J¼8.0 Hz, 9H), 0.58
(q, J¼8.0 Hz, 6H), 0.54 (q, J¼4.0 Hz, 6H), 0.09 (s, 3H),
0.08 (s, 3H). 13C NMR (CDCl3, 75 MHz): d 211.85,
130.85, 128.99, 113.41, 106.70, 92.68, 83.92, 72.74,
71.56, 68.72, 57.58, 55.11, 45.57, 44.30, 39.57, 36.79,
31.23, 28.69, 25.88, 20.26, 17.81, 16.88, 7.39, 6.86, 4.78,
4.48, ꢁ3.72, ꢁ5.22; HRMS (ESI) calcd for [C43H79N3O5
Si3+Na]+ 824.5220, found 824.5234.
graphy (hexanes–ethyl acetate, 6:1, v/v) to yield 26
(19 mg, 30 mmol, 75%, 4:1 mixture of anomers) as a color-
less oil: Rf 0.23 (hexanes–ethyl acetate, 5:1, v/v); [a]2D3 ꢁ10
(c 0.40, CDCl3); IR (thin film): 2956, 2878, 2173, 1461,
1415, 1378, 1256, 1017 cmꢁ1
;
1H NMR (C6D6,
500 MHz): d 4.29 (dd, J¼12.0, 6.5 Hz, 1H), 4.22 (t,
J¼3.5 Hz, 1H), 3.80 (dd, J¼4.5, 2.5 Hz, 1H), 2.85 (t,
J¼11 Hz, 1H), 2.71 (m, 1H), 2.60 (dd, J¼16.5, 3.5 Hz,
1H), 2.39 (m, 1H), 2.19 (m, 2H), 2.04 (dd, J¼13.5,
4.5 Hz, 1H), 1.95 (m, 2H) 1.81 (m, 2H), 1.73 (d, J¼
13.5 Hz, 1H), 1.48 (m, 1H), 1.33 (d, J¼6.5 Hz, 3H), 1.14
(t, J¼8.0 Hz, 9H), 1.04 (s, 9H), 0.98 (t, J¼7 Hz, 9H),
0.89 (d, J¼6.5 Hz, 3H), 0.85 (d, J¼7.0 Hz, 3H), 0.29 (s,
6H); HRMS (ESI) calcd for [C35H71NO3Si3+H]+
638.4815, found 638.4834.
4.1.15. Carbamate (27). To a stirred solution of 12 (8 mg,
0.1 mmol) in CH2Cl2 (0.5 mL) were sequentially added
˚
powdered 4 A molecular sieves (30 mg), K2CO3 (34 mg,
0.25 mmol, fine powder), and carbobenzyloxy chloride
(7.2 mL, 0.05 mmol). After 14 h, the mixture was applied di-
rectly onto a silica gel column and eluted with hexanes–ethyl
acetate (10:1, v/v). The product collected after evaporation
of the solvents by rotary evaporation was placed under
high vacuum for 2 h to afford 27 as a colorless oil (7 mg,
9 mmol, 73%, 4:1 mixture of anomers): Rf 0.69 (hexanes–
ethyl acetate, 5:1, v/v); [a]2D3 +28 (c 1.0, CH2Cl2); IR (thin
film); 2956, 2876, 2171, 1704, 1460, 1396, 1356, 1259,
4.1.13. Alcohol (6). To a stirred solution of 25 (42 mg,
61 mmol) in CH2Cl2 (3 mL) were added aqueous phosphate
buffer (0.3 mL, pH 7), t-butanol (0.1 mL) and DDQ (42 mg,
0.18 mmol). The reaction mixture turned dark green. After
30 min, saturated aqueous NaHCO3 (3 mL) was added, the
mixture was diluted with CH2Cl2, and transferred to a sepa-
ratory funnel. The separated aqueous phase was extracted
with CH2Cl2 and the combined organic extract was washed
with brine, dried over MgSO4, filtered, and concentrated by
rotary evaporation. The residue was purified by silica gel
column chromatography (hexanes–ethyl acetate, 6:1, v/v)
to give 25 (29 mg, 50 mmol, 82%) as a colorless oil: Rf
0.50 (hexanes–ethyl acetate, 5:1, v/v); [a]2D3 +6.5 (c 0.39,
1174, 1072, 1019 cmꢁ1 1H NMR (CDCl3, 500 MHz):
;
d 7.33 (m, 5H), 5.10 (d, J¼2 Hz, 2H), 4.49 (m, 1H), 4.09
(dd, J¼8.0, 2.5 Hz, 1H), 3.91 (m, 1H), 3.83 (dt, J¼9.5,
2.5 Hz, 1H), 3.76 (dd, J¼13.5, 2.5 Hz, 1H), 3.25 (t,
J¼12.5 Hz, 1H), 2.66 (m, 1H), 2.53 (m, 1H), 2.40 (dd,
J¼16.5, 3.5 Hz, 1H), 1.86 (m, 2H), 1.77 (m, 1H), 1.60 (m,
1H), 1.415 (m, 2H), 1.32 (m, 1H), 1.04 (d, J¼6 Hz, 3H),
0.99 (t, J¼5.5 Hz, 9H), 0.94 (t, J¼8.0 Hz, 9H), 0.91 (s,
9H), 0.80 (d, J¼6.5 Hz, 3H), 0.77 (d, J¼7 Hz, 3H), 0.57
(m, 12H), 0.08 (s, 6H); 13C NMR (CDCl3, 75 MHz):
d 155.61, 137.00, 128.48, 127.77, 127.48, 108.42, 95.62,
85.56, 81.82, 72.33, 70.46, 66.50, 59.60, 49.07, 39.54,
38.01, 31.23, 29.87, 26.08, 21.01, 18.73, 16.81, 7.62, 7.13,
4.79, 1.16, ꢁ4.14; HRMS (ESI) calcd for [C43H77NO5
Si3+Na]+ 794.5007, found 794.4999.
1
CDCl3); H NMR (CDCl3, 300 MHz): d 4.30 (dd, J¼10.2,
5.7 Hz, 1H), 3.77 (dd, J¼12.0, 6.6 Hz, 1H), 3.35 (dd,
J¼10.2, 5.4 Hz, 1H), 3.24 (dd, J¼12.0, 5.4 Hz, 1H), 3.12
(dd, J¼12.0, 6.6 Hz, 1H), 2.80 (dd, J¼16.5, 5.7 Hz, 1H),
2.61 (dd, J¼16.5, 5.4 Hz, 1H), 2.47 (d, J¼6.3 Hz, 1H),
2.32 (dd, J¼16.8, 3.9 Hz, 1H), 2.09 (dd, J¼16.8, 7.2 Hz,
1H), 1.93 (m, 1H), 1.80 (m, 1H), 1.69 (m, 1H), 1.53 (t,
J¼6.6 Hz, 1H), 1.10 (d, J¼6.9 Hz, 3H), 1.06 (d, J¼6.6 Hz,
3H), 0.99 (t, J¼7.1 Hz, 9H), 0.96 (t, J¼7.8 Hz, 9H), 0.90
(s, 9H), 0.64 (q, J¼7.8 Hz, 6H), 0.57 (d, J¼7.8 Hz, 6H),
0.11 (s, 3H), 0.10 (s, 3H); 13C (CDCl3, 75 MHz): d 211.4,
106.7, 82.7, 71.3, 68.1, 57.5, 45.5, 44.5, 38.5, 36.7, 31.2,
29.5, 28.4, 26.3, 25.7, 20.0, 17.8, 16.9, 7.3, 6.7, 4.9, 4.4,
0.8, ꢁ4.2, ꢁ4.3; IR (thin film): 3551, 2957, 2878, 2172,
2099, 1714, 1613, 1514, 1461, 1414, 1380, 1256, 1102,
1019 cmꢁ1; MS (ESI) calcd for [C35H71N3O4Si3+Na]+
704.46, found 704.46.
4.1.16. Alkynyl iodide (3). To a solution of 27 (5 mg,
6.3 mmol) in DMF (0.3 mL) were added N-iodosuccimide
(4 mg, 0.09 mmol) and silver trifluoroacetate (1.5 mg,
6.5 mmol). After 10 min, the reaction mixture was diluted
with diethyl ether and saturated aqueous NaHCO3 was
added. The separated aqueous phase was extracted with di-
ethyl ether. The combined organic extracts were washed
with brine, dried over MgSO4, filtered, and concentrated.
The residue was purified by silica gel column chromato-
graphy (hexanes–ethyl acetate, 6:1, v/v) to provide 3
(4.3 mg, 87%) as a colorless oil: Rf 0.64 (hexanes–ethyl ac-
etate, 5:1, v/v); [a]2D5 +29 (c 0.32, CHCl3); 1H NMR
(500 MHz, CDCl3) d 7.29–7.38 (m, 5H), 5.08 (s, 2H),
4.43–4.50 (m, 1H), 4.09 (dd, J¼9.0, 4.5 Hz, 1H), 3.83 (dt,
J¼4.5, 2.5 Hz, 1H), 3.75 (dd, J¼13.5, 3.5 Hz, 1H), 3.22
(dd, J¼12, 12 Hz, 1H), 2.64 (m, 1H), 2.52 (dd, J¼16,
12 Hz, 1H), 2.46 (dd, J¼16.5, 4.5 Hz, 1H), 2.05 (dd,
J¼17.0, 6.0 Hz, 1H), 1.80–1.96 (m, 2H), 1.51–1.59 (m,
2H), 1.2–1.35 (m, 3H), 0.98 (d, J¼7 Hz, 3H), 0.88–0.91
4.1.14. Spiroaminal (26). To a solution of 6 (28 mg,
41 mmol) in toluene was added triethylphosphine (18 mL,
0.12 mmol). After 14 h, solvent was removed under a stream
of N2 (in a hood—stench). The crude product could be used
for the next step without purification. For characterization,
the residue was purified by silica gel column chromato-

5346
S. Nguyen et al. / Tetrahedron 62 (2006) 5338–5346
(m, 9H), 0.80 (d, J¼7 Hz, 3H), 0.77 (d, J¼7.5 Hz, 3H),
0.55–0.59 (m, 9H), 0.055–0.068 (m, 10H); IR (thin film)
2959 (m), 2929 (m), 2878 (w), 2857 (w), 2361 (m), 1701
(s), 1458 (m), 1397 (m), 1260 (m) cmꢁ1; HRMS (ESI) m/z
calcd for (C37H62INO5Si2+Na)+ 806.3109, found 806.3118.
3.88 (d, J¼4.5 Hz, 1H), 3.80 (s, 3H), 2.98–3.06 (m, 1H),
2.90–2.98 (m, 1H), 2.70–2.78 (m, 1H), 2.23 (dd, J¼16.5,
4.5 Hz, 1H), 2.05 (dd, J¼17.0, 7.0 Hz, 1H), 1.75–1.85 (m,
2H), 1.53–1.62 (m, 3H), 1.43 (s, 9H), 1.22 (d, J¼7.0 Hz,
3H), 1.18–1.21 (m, 1H), 0.99 (d, J¼7.0 Hz, 3H), 0.89 (d,
J¼7.0 Hz, 3H), 0.86 (s, 9H), 0.13 (s, 6H), 0.068 (d,
J¼9.0 Hz, 9H); LRMS m/z calcd for (C39H65INO6Si2+Na)+
722.4, found 722.5.
4.1.17. Ynone (33). To a solution of CBr4 (471 mg,
ꢀ
1.42 mmol) in CH2Cl2 (6 mL) at 0 C under argon was
added triphenylphosphine (745 mg, 2.8 mmol). The result-
ing orange solution was stirred for 30 min before a solution
of aldehyde 28 (110 mg, 0.71 mmol) in CH2Cl2 (6 mL) was
added. After stirring for 10 min, saturated aqueous NaHCO3
(6 mL) was added and the resulting mixture was extracted
with diethyl ether. The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by
flash column chromatography (hexanes–diethyl ether, 5:1,
v/v) to provide dibromide 29 (0.20 g, 0.64 mmol, 91%) as
4.1.18. Spiroaminal (35). To a stirred rt solution of ynone 33
(0.5 mg, 0.7 mmol) in CH2Cl2 (0.3 mL) was added silver tri-
fluoroacetate (1 mg, 5 mmol). After disappearance of start-
ing material 35 by TLC, ethanol (1 mL) and H2O (0.5 mL)
were added, followed by the addition of KI (2 mg). After
stirring for another 5 min, the reaction mixture was applied
to a small silica gel column and eluted to afford 38 (0.2 mg,
1
0.4 mmol, 56%): Rf 0.39 (hexanes–ethyl acetate, 3:1); H
NMR (500 MHz, CDCl3) d 4.48 (d, J¼2.0 Hz, 1H), 4.18–
4.22 (m, 1H), 3.05–3.08 (m, 1H), 2.85–2.97 (m, 1H),
2.76–2.81 (m, 1H), 2.21 (ddd, J¼16.0, 4.5, 2.5 Hz, 1H),
1.98–2.06 (m, 2H), 1.95 (t, J¼2.5 Hz, 1H), 1.75–1.85 (m,
1H), 1.63–1.85 (m, 3H), 1.45–1.50 (m, 1H), 1.43 (s, 9H),
1.25–1.27 (m, 1H), 1.02 (d, J¼6.5 Hz, 3H), 0.93 (d,
J¼6.0 Hz, 3H), 0.87–0.90 (m, 12H), 0.11 (d, J¼1.5 Hz,
6H). HRMS (ESI) m/z calcd for (C18H49NO5Si+Na)+
530.3278, found 530.3191.
1
a yellow oil: Rf 0.75 (hexanes–ethyl acetate, 5:1, v/v); H
NMR (500 MHz, CDCl3) d 6.12 (d, J¼9.5 Hz, 1H), 3.16
(d, J¼6.0 Hz, 2H), 2.56–2.61 (m, 1H), 1.66–1.70 (m, 1H),
1.42–1.48 (m, 1H), 1.14–1.20 (m, 1H), 1.02 (d, J¼7.0 Hz,
3H), 0.98 (d, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 143.6, 104.8, 58.0, 40.7, 36.0, 31.6, 19.9, 17.6; LRMS
(EI) m/z calcd for (C8H13Br2N3–N2–H)+ 280.9, found 280.9.
To a solution of 29 (24 mg, 77 mmol) in THF (0.8 mL)
was added n-butyllithium (65 mmol, 2.5 M in hexane) at
ꢀ
31 (15.1 mg, 31 mmol) in THF (0.2 mL) was added. The re-
sulting mixture was warmed slowly to 0 C over 1 h and
ꢀ
References and notes
ꢁ78 C. After stirring for 20 min, a solution of aldehyde
ꢀ
stirred for another 30 min at 0 C before saturated aqueous
1. 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.
2. James, K. J.; Moroney, C.; Roden, C.; Satake, M.; Yasumoto,
T.; Lehane, M.; Furey, A. Toxicon 2003, 41, 145–151.
3. Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Ling,
T.; Yamada, Y. M. A.; Tang, W.; Frederick, M. O. Angew.
Chem., Int. Ed. 2004, 43, 4318–4324.
4. (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.
5. James, K. J.; Sierra, M. D.; Lehane, M.; Magdalena, A. B.;
Furey, A. Toxicon 2003, 41, 277–283.
6. Nguyen, S.; Xu, J.; Forsyth, C. J. Abstracts of Papers, 229th
ACS National Meeting, San Diego, CA, United States, March
13–17, 2005; ORGN-330.
7. Aiguade, J.; Hao, J.; Forsyth, C. J. Tetrahedron Lett. 2001, 42,
817–820.
8. Forsyth, C. J.; Hao, J.; Aiguade, J. Angew. Chem., Int. Ed. 2001,
40, 3663–3667.
NH4Cl (1 mL) was added. The separated aqueous layer
was extracted with diethyl ether. The combined organic
layers were washed with brine and dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography (hexanes–
diethyl ether, 10:1, v/v) to afford the alcohol 32 (14.6 mg,
23 mmol, 73%): Rf 0.63 (hexanes–ethyl acetate, 3:1, v/v).
To a solution of 32 (7.2 mg, 11 mmol) in toluene (0.6 mL)
under argon was added triethylphosphine (6 mg,
0.05 mmol). The resulting solution was stirred at rt for
ꢀ
50 min and cooled to ꢁ20 C before BocON (7.3 mg,
30 mmol) was added. The reaction mixture was warmed
slowly to rt and stirred for 12 h. Ethyl acetate (2 mL) was
added and the resulting solution was washed with H2O
(3ꢂ1 mL). The organic phase was dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography (hexanes–
ethyl acetate, 10:1, v/v) to provide carbamate alcohol 32b
(4.8 mg, 61%): Rf 0.44 (hexanes–ethyl acetate, 3:1, v/v).
9. Nicolaou, K. C.; Pihko, P. M.; Diedrichs, N.; Zou, N.; Bernal, F.
Angew. Chem. Int. Ed. 2001, 40, 1262–1265.
10. Sasaki, M.; Iwamuro, Y.; Nemoto, J.; Oikawa, M. Tetrahedron
Lett. 2003, 44, 6199–6201.
11. Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998,
639–652.
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Nojima, S. Chem. Pharm. Bull. 1985, 33, 572–582.
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Chem. Soc. 1991, 113, 4092–4096.
Alcohol 32b (3.8 mg, 5.4 mmol) was dissolved in pentane
(0.8 mL) and MnO2 (21 mg, 0.24 mmol) was added. After
stirring for 30 min at rt, the reaction mixture was applied di-
rectly to a silica gel column and purified by flash column
chromatography (hexanes–diethyl ether, 10:1, v/v) to pro-
vide ynone 33 (3.8 mg, 100%): Rf 0.53 (hexanes–ethyl ace-
tate, 3:1); 1H NMR (500 MHz, CDCl3) d 7.26 (d, J¼9.0 Hz,
2H), 6.86 (d, J¼9.0 Hz, 2H), 4.63 (d, J¼11.5 Hz, 1H), 4.46–
4.50 (b, 1H), 4.43 (d, J¼11.5 Hz, 1H), 4.13–4.15 (m, 1H),