Total syntheses of natural pseurotins A, F2, and azaspirene

Article abstract of DOI:10.1246/bcsj.77.1703

We describe the total syntheses of natural pseurotins A and F₂, inhibitors of chitin synthase, both of which possess an unusual 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione ring system. The total syntheses of these spiro-hetereocyclic natural produ

Full text of DOI:10.1246/bcsj.77.1703

ꢀ 2004 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 77, 1703–1716 (2004) 1703
Total Syntheses of Natural Pseurotins A, F2, and Azaspirene
ꢀ
Shin-ya Aoki, Takahiro Oi, Kazuya Shimizu, Ryota Shiraki, Ken-ichi Takao, and Kin-ichi Tadano
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522
Received March 10, 2004; E-mail: tadano@applc.keio.ac.jp
We describe the total syntheses of natural pseurotins A and F2, inhibitors of chitin synthase, both of which possess
an unusual 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione ring system. The total syntheses of these spiro-hetereocyclic nat-
ural products feature: 1) a stereoselective preparation of two segments, i.e., a 2,3-dihydroxylated heptenal derivative and
a highly functionalized ꢀ-lactone, each from D-glucose, 2) the connection of the two segments via an aldol-type carbon–
carbon bond formation, 3) spirocyclic ring formation from the aldol adduct through convenient 3(2H)-furanone forma-
tion, 4) the transformation of a spirocyclic ꢀ-lactone into a ꢀ-lactam hemiaminal derivative, and 5) conversion of the
benzyl substituent in the ꢀ-lactam ring into a benzoyl group via a cyclic enamide followed by m-CPBA oxidation in the
final stage of the total synthesis. In the initial stage, the quaternary spiro-carbon center in the target molecules was ef-
ficiently constructed by a stereochemically exclusive vinyl Grignard addition to the D-glucose-derived 3-ulose. Further-
more, the preparation of the ꢀ-lactone included a stereo- and regioselective Cu(I)-mediated benzyl Grignard addition to
aldehyde. We have also completed the total synthesis of a structurally related novel angiogenesis inhibitor, azaspirene,
using the analogous reaction sequence.
Over the past three decades, structurally as well as biologi-
cally intriguing hetero-spirocyclic ꢀ-lactam-type antibiotics
have been found in nature. Pseurotin A (1) (Fig. 1), isolated
from the culture filtrate of Pseudeurotium ovalis (Ascomy-
cetes) by Tamm et al. in 1976,1a is a representative example
of this class of secondary microbial metabolites. The structure
of pseurotin A (1), including its relative and absolute stereo-
chemistries, was determined by a combination of spectroscop-
ic analysis and chemical modification,1a and finally by a sin-
gle-crystal X-ray analysis of its 12,13-dibromo derivative.1b
Pseurotin F2 (8-O-demethylpseurotin A) (2) was first isolated
from Aspergillus fumigatus DSM 6598 as an antagonist of apo-
morphine.2 Compound 2 was also isolated from A. fumigatus
strain HA 57-88 as an inhibitor of both the solubilized and
membrane-bound forms of chitin synthase, along with 1.3 Lat-
er, compound 1 was reported as a novel neurite-forming sub-
stance for rat PC12 pheochromocytoma cells, and was thus ex-
pected to be a useful tool for investigating the mechanism of
neurite formation of neuronal cells.4 Some other hetero-spiro-
cyclic ꢀ-lactams related to pseurotins were reported. Synera-
zol (3) was isolated from a cultured broth of A. fumigatus
SANK 10588 as an antifungal antibiotic.5 FD-838 (4) was iso-
lated from A. fumigatus fresenius F-838, which induces the dif-
ferentiation of leukemia in culture and inhibits the growth of
certain Gram-positive bacteria and fungi.6 All of these natural
products, 1–4, were characterized structurally by their unusual
1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione core skeleton, in-
cluding three contiguous stereogenic centers, in addition to
an oxygenated olefinic side chain (for 1–3) or a furan ring
(for 4) at C2 and a benzoyl group at C8 (for 1–4). Recently,
azaspirene (5) was isolated from the fungus Neosartorya sp.
by Osada and co-workers as a novel angiogenesis inhibitor
of the endothelial migration induced by a vascular endothelial
growth factor.7 Although the core framework of 5 is similar to
those of 1–4, the structure of 5 is characterized by an E,E-con-
jugate hexadiene side chain at C2 and a benzyl group instead
of the benzoyl group at C8. In regard to synthetic studies on
these natural products, some approaches toward the pseurotins
family have been reported so far by the Tamm group8 and by
us.9 In 2002, Hayashi and co-workers reported the first total
synthesis of natural (ꢁ)-azaspirene (5).10 We describe here
the details of our total syntheses of natural 1, 2, and 5.11 Quite
recently, Hayashi’s group reported the asymmetric total syn-
theses of 1 and 2.12
OH
O
O
O
2
O
O
NH
O
O
O
NH
8
OH
Me
Ph
Me
Ph
Me
Me
Me
OR
O
OH
OMe
NH
OH
Pseurotin A (1): R = Me
Pseurotin F2 (2): R = H
Synerazol (3)
Results and Discussion
O
O
O
O
Me
Our initial synthetic approach to 1 and 2 is outlined in
Scheme 1. We envisioned that the pseurotins 1 and 2 would
be obtained from ꢀ-benzoylated ꢀ-lactone 6, which contains
all of the requisite carbon skeleton with correct stereogenic
centers, via construction of the spiro-3(2H)-furanone substruc-
ture, transformation of the ꢀ-lactone to a ꢀ-lactam, and final
adjustment of the oxidation level at C8. This advanced inter-
NH O
Ph
O
Ph
Me
O
Me
OH
OMe
O
OH
OH
Azaspirene (5)
FD-838 (4)
Fig. 1. Structures of the spiro-heterocyclic ꢀ-lactam natural
products 1–5.
Published on the web September 10, 2004; DOI 10.1246/bcsj.77.1703

1704 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Total Syntheses of Pseurotins and Azaspirene
Bu4NI,14 provided ꢀ-lactone-ꢁ,ꢂ-diol 13. The cis-diol in 13
was protected as an isopropylidene acetal 14, which was treat-
ed with LiAlH4 to provide a ring-opened diol 15. A three-step
protection/deprotection process from 15 via a trityl ether pro-
vided an acyclic suitably protected intermediate 16. Dess–
Martin oxidation15 of 16 produced the aldehyde 17.
PO
O
PO
PO
O
O
O
8
Pseurotins A, F2 (1, 2)
HO
Me
Me
OP
6
P=suitable protecting groups
The introduction of a benzoyl equivalent into 17 was next
investigated. First, we chose 2-phenyl-1,3-dithiane (18) as a
benzoyl equivalent (Scheme 3). However, the addition of the
2-lithio-1,3-dithiane generated from 18 to 17 did not proceed
cleanly. On the other hand, the reaction of 17 with 1-lithiated
1-phenylethene, prepared from 1-bromo-1-phenylethene (19)
and t-BuLi (2 molar amt.) in Et2O at ꢁ78 ꢂC, proceeded
smoothly to produce the 2-phenylallyl alcohol 20 as a single
stereoisomer. The introduced (R)-stereogenic center in 20
was determined by NOE experiments of 22. As shown in
Scheme 3, this diastereoselective nucleophilic addition of the
1-lithiated 1-phenylethene to 17 can be explained on the basis
that the lithium-ion-associated five-membered chelate forma-
tion occurs between the aldehyde oxygen and one of the acetal
oxygens in 17, to which the nucleophile attacks from the less-
hindered ꢂ-side, leading to 20. The simultaneous ozonolytic
cleavage of the two carbon–carbon double bonds in 20, fol-
lowed by acidic hydrolysis of the acetal moiety, spontaneously
formed a five-membered hemiacetal 21, which was oxidized
with NIS to ꢀ-benzoyl-ꢀ-lactone-ꢁ,ꢂ-diol 22. The tertiary hy-
droxy group in 22 could be selectively protected as a triethyl-
silyl (TES) ether to provide 23. We suppose that this selective
protection of the tertiary hydroxy group may be attributable to
the electric effect of both the ꢀ-lactone carbonyl and the ben-
zoyl carbonyl, although a steric reason can not be excluded.
Hydrogenolysis of the benzyl group in 23, accompanied by
the reduction of the benzoyl carbonyl, followed by oxidation
using 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX)16
in DMSO, provided 24. Then, the secondary hydroxy group
in 24 was protected as a methoxymethyl (MOM) ether to give
25 (P = TES and MOM in 7), the substrate for the aldol reac-
tion.
O
OP
Me
PO
O
O
O
CHO
OP
Me
Ph
OP
OP
+
7
9
PO
PO
CHO
O
O
O
Me
Me
8
Me
Me
3
HO
10
D-Glucose
Scheme 1.
mediate 6 would be prepared by the aldol-type connection of a
ꢀ-lactone 7 equipped with an ethyl ketone moiety to a seven-
carbon olefinic aldehyde 8 corresponding to the left-side chain.
The preparation of the side-chain equivalent 8 was originally
reported by the Tamm group.8a The aldol partner 7 could be
obtained from an acyclic hexose derivative 9 via the installa-
tion of a benzoyl group, followed by the formation of the ꢀ-
lactone via an oxidative cleavage of the vinyl group. This
functionalized branched deoxy hexose 9 could be prepared
via the stereoselective introduction of a vinyl group at C3 in
the 3-ulose prepared from known 5,6-dideoxy-1,2-O-isopro-
pylidene-ꢁ-D-xylo-hexofuranose (10), in turn prepared from
D-glucose in six convenient steps.13
The synthesis of 17, a suitably protected form of acyclic
5,6-dideoxy-aldohexose 9, from 10 is summarized in
Scheme 2. The oxidation of 10 with pyridinium chlorochro-
mate (PCC), followed by the usual vinyl Grignard addition
to the resultant 3-ulose 11, provided the adduct 12 as a single
diastereoisomer. The vinyl nucleophile attacked exclusively
from the convex face of the trioxabicyclo[3.3.0]octane struc-
ture of 11. The acidic hydrolysis of the acetal moiety in 12,
and subsequent chemoselective oxidation of the hemiacetal
carbon with N-iodosuccinimide (NIS) in the presence of n-
The coupling partner for the aldol reaction of 25, the alde-
hyde 29 (P = MOM in 8), was synthesized from D-glucose ac-
cording to the reported procedure8a with an improvement of
the Z-olefin introduction. For preparing the known compound
26, we used potassium bis(trimethylsilyl)amide (KHMDS) as a
O
O
O
O
Me
Me
b
Me
O
O
c, d
e
a
Me
Me
Me
Me
10
O
O
O
OR
OR
OH
11
12
13: R = H
14: R = isopropylidene
OR
OBn
OH
Me
j
CHO
Me
f
14
O
O
O
O
Me
Me
Me Me
15: R = H
17
g − i
16: R = Bn
Scheme 2. Reagents and conditions: (a) PCC, MS4A, CH2Cl2; (b) CH2=CHMgBr, THF, ꢁ18 ꢂC (83% for 2 steps); (c) 80% aque-
ous AcOH, 80 ꢂC; (d) NIS, n-Bu4NI, CH2Cl2 (95% for 2 steps); (e) Me2C(OMe)2, Me2CO, CSA, reduced pressure (ca. 300 hPa),
40 ꢂC (79%); (f) LiAlH4, THF, 0 ꢂC (91%); (g) TrCl, DMAP, pyr, reflux; (h) BnBr, NaH, DMF; (i) CSA, MeOH, EtOAc (84% for
3 steps); (j) Dess–Martin periodinane, CH2Cl2 (96%).

S. Aoki et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1705
Me
OBn
O
O
Li
S
H
S
OBn
OH
Ph
18
x
Me
O
Ph
S
Li
17
O
S
O
Me
17
Me
a
Ph
Br
19
OBn
OH
O
HO
RO
Me
O
HO
OH
b, c
O
Ph
O
Me
Ph
Ph
Me
Ph
O
BnO
OH
BnO
O
OH
21
Me
Me
20
O
O
RO
TESO
O
O
f, g
O
O
d
O
21
Me
Me
h
Ph
BnO
OH
22: R = H,
23: R = TES
OR
24: R = H
25: R = MOM
e
Scheme 3. Reagents and conditions: (a) 19 (2.0 equiv), t-BuLi (4.0 mol. amt.), Et2O, ꢁ78 ꢂC; then 17 (94%); (b) O3, CH2Cl2, ꢁ78
ꢂC; Ph3P; (c) 60% aqueous TFA; (d) NIS, n-Bu4NI, CH2Cl2 (57% from 20); (e) TESOTf, pyr (91%); (f) H2, 10% Pd on C, EtOAc;
(g) IBX, DMSO (87% for 2 steps); (h) CH2(OMe)2, P2O5, CH2Cl2 (98%).
Me
OBn
OH
OBn
OH Me
Me
Me
O
BnMgCl
Ref. 8a
17
O
+
OH
D-Glucose
O
O
Me
O
O
Me
Me
30
31
Me
Me
26
R1O
MOMO
MOMO
R1O
OR2
a, b
e, f
CHO
MgCl
O
R
R
Me
c, d
Me
29
27: R1 = H, R2 = MPM
28: R1 = MOM, R2 = H
MgCl
O
Me
H
O
O
O
OBn
O
Me
R =
Me
Me
Me
Scheme 4. Reagents and conditions: (a) MPMCl, NaH,
DMF; (b) Amberlyst 15 (Hþ), MeOH (91% for 2 steps);
(c) MOMCl, i-Pr2NEt, CH2Cl2; (d) DDQ, CH2Cl2/H2O
(15:1, v/v); (e) separation of the geometrical isomers on
silica gel (Z-isomer: 88% from 27, E-isomer: 7% from
27); (f) (COCl)2, DMSO, CH2Cl2; Et3N, ꢁ78 ꢂC to rt
(89%).
Scheme 5.
benzoyl moiety caused the instability of the substrate 25 under
the basic conditions. We concluded that a more reliable syn-
thetic approach would be to replace the benzoyl group with
a benzyl group.
base for the Wittig olefination of the intermediary aldehyde to
introduce a carbon–carbon double bond. Under our conditions,
the selectivity was significantly improved (Z:E = 14:1)
(Scheme 4). Swern oxidation17 of 26 provided the aldehyde
(not shown), which was unstable on silica gel to purify. Thus,
we planned to prepare a more stable aldol partner by changing
the acetal protecting group in 26 to vicinal O-MOM groups.
The transformation of 26 to di-O-MOM ether 28 via O-p-
methoxyphenylmethyl (MPM) ether 27 was conducted
straightforwardly. At this stage, the E-geometrical isomer
was cleanly removed. The Swern oxidation of the Z-isomer
28 provided 29. We attempted the aldol connection of 25 with
29 under a variety of reaction conditions. Unfortunately, all of
the cases examined resulted in the formation of a complex
mixture of products, or the decomposition of 25. Although
lacking firm evidence, we considered that the presence of the
For the introduction of a benzyl group as a synthetic precur-
sor of a benzoyl group, we investigated the benzyl Grignard
addition to the aldehyde 17. Using excess benzylmagnesium
chloride in THF at room temperature, we obtained a mixture
of the desired benzyl adduct 30 (14%) and the undesired and
abnormal 2-methylphenyl (ortho-tolyl) adduct 31 (51%) along
with a 9% recovery of 17 (Scheme 5). As shown, the 2-methyl-
phenyl adduct 31 was formed via a Mg(II)-mediated six-mem-
bered transition state, in which the ortho-carbon of the benzyl
Grignard reagent attacked the aldehyde, as previously pro-
posed.18 The formation of the desired adduct 30 was slightly
19
improved by the addition of an equal amount of CeCl3 in
the reaction mixture (26% of 30, 36% of 31, and 22% recovery
of 17). We were pleased to find that the addition of
CuBr Me2S in a mixed solution of THF and Me2S20 dramati-
cally increased the yield of 30. As a result, the benzyl adduct
ꢃ

1706 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Total Syntheses of Pseurotins and Azaspirene
30 was isolated in 89% yield along with a small amount (2%)
of 31. It was considered that the addition of the Cu(I) salt sup-
pressed the formation of the six-membered transition state;
thus, the expected normal addition occurred preferentially.
Similar to the case involving the formation of 20, the configu-
ration of a newly introduced secondary alcohol carbon in 30
was determined as shown, after converting to the ꢀ-lactone 32.
The ozonolysis of 30 and successive hydrolytic removal of
the acetal, followed by the chemoselective oxidation of the re-
sultant ꢀ-lactol with NIS, eventually provided ꢀ-lactone 32
(Scheme 6). We examined the selective protection of the terti-
ary hydroxy group in 32, as we had done in the case of 22. Un-
fortunately, all attempts to protect the tertiary hydroxy group
selectively, as O-TBS, O-TES, O-TMS, O-MOM or O-THP,
failed. In the case of the O-TES protection, we obtained the de-
sired mono-O-TES ether in a less-practical yield of 66% along
with the di-O-TES derivative 33 in 24% yield (4.5 mol. amts.
of TESOTf, lutidine, CH2Cl2, ꢁ40 to ꢁ20 ꢂC). From this
mono-O-TES derivative, we prepared the aldol substrate corre-
sponding to 25 (not shown, a benzyl group in place of the ben-
zoyl). Contrary to our expectation, the aldol reaction of this
substrate with 29 did not provide any aldol adduct. Conse-
quently, we selected di-O-TES derivative 33 as a synthetic pre-
cursor of the aldol substrate 35. Thus, two hydroxy groups in
32 were protected as vicinal di-O-TES ether to provide 33
using slightly excess of TESOTf at 50 ꢂC. Deprotection of
the benzyl group in 33 by hydrogenolysis, followed by Dess–
Martin oxidation of the resultant 34, provided ethyl ketone 35.
The aldol reaction of 35 and aldehyde 29 was best achieved
usingꢂ 1.0 molar amount of KHMDS as a base in THF at
ꢁ78 C to produce the aldol product 36 with a high level of
diastereoselectivity.21 We did not determine the stereochem-
istry of the aldol adduct. Exposure of 36 to a dilute solution
of hydrogen fluoride–pyridine complex in pyridine22 selective-
ly cleaved the TES group attached to the tertiary alcohol, giv-
ing 37. Dess–Martin oxidation of 37, followed by dehydration
of the resultant spirocyclic five-membered hemiketal ꢀ-lactone
38 with thionyl chloride, provided the desired spirocyclic
3(2H)-furanone 39.
In Scheme 7, the final steps for the total syntheses of 1 and 2
are illustrated. We examined the installation of a ꢀ-lactam ni-
trogen atom to 39 by a variety of reagents, such as aqueous
ammonia, ammonium acetate with catalytic sodium cyanide,23
or 1,1,1,3,3,3-hexamethyldisilazane.24 None of these condi-
tions gave useful results. Finally, we found that a treatment
of 39 with saturated NH3 in i-PrOH resulted in a ꢀ-lactone
ring-opened amidation accompanied by cleavage of the TES
group. Therefore, the TES group in 39 was replaced by an
MOM group prior to ammonolysis.25 After de-O-silylation of
39, followed by etherification under acidic conditions provided
the MOM ether 40 in good yield. The ammonolysis of 40 with
saturated NH3 in i-PrOH, followed by Dess–Martin oxidation,
provided the ring-opened amide ketone 41. By exposing 41 to
saturated aqueous Na2CO3, an intramolecular attack of the
amide-nitrogen to the carbonyl occurred to form the hemiami-
nal 42 (a ꢀ-hydroxy-ꢀ-lactam) as the predominant ꢁ-anomer,
O
O
TESO
HO
RO
O
f
a-c
O
e
30
Me
Me
d
Ph
Ph
BnO
OTES
34
OR
32: R = H
33: R = TES
MOMO
MOMO
O
O
29
RO
O
TESO
i
O
g
O
HO
Me
Me
Ph
Ph
Me
O
OTES
OTES
35
36: R = TES
37: R = H
h
MOMO
MOMO
MOMO
O
OH
O
MOMO
O
O
O
j
O
O
Ph
Ph
Me
Me
Me
Me
OTES
O
OTES
39
38
Scheme 6. Reagents and conditions: (a) O3, CH2Cl2, ꢁ78
ꢂC; Ph3P; (b) 60% aqueous TFA; (c) NIS, n-Bu4NI,
CH2Cl2 (84% from 30); (d) TESOTf, pyr, 50 ꢂC (95%);
(e) H2, 10% Pd on C, EtOH (94%); (f) Dess–Martin peri-
odinane, CH2Cl2 (98%); (g) KHMDS (1.0 mol. amt.),
ꢂ
THF, ꢁ78 C; then 29 (3.0 mol. amt.); (h) HF pyr, pyr,
ꢃ
THF; (i) Dess–Martinꢂ periodinane, CH2Cl2 (46% from
35); (j) SOCl2, pyr, 0 C (97%).
MOMO
O
O
O
NH2
MOMO
O
O
f
O
e
c, d
NH
O
O
8
Ph
Ph
Ph
Me
Me
Me
Me
OH
OMOM
O
O
OR
O
OMOM
39: R = TES
40: R = MOM
41
42
a, b
OH
O
O
O
O
O
O
O
O
O
O
O
NH
NH
i
g, h
NH
OH
Me
Ph
Ph
Ph
Me
Me
j
Me
OH
OMOM
OR
OH
OMOM
43
Pseurotin F2 (2): R = H
Pseurotin A (1): R = Me
44
ꢂ
Scheme 7. Reagents and conditions: (a) HF pyr, pyr, THF; (b) CH2(OMe)2, P2O5, CH2Cl2, 0 C (98% for 2 steps); (c) saturated
ꢃ
NH3 in i-PrOH; (d) Dess–Martin periodinane, CH2Cl2; (e) saturated aqueous Na2CO3 (42: 81% for 3 steps, C8-ꢂ-isomer: 16%
ꢂ
for 3 steps); (f) 5% AcOH in i-PrOH, 70 C; (g) m-CPBA, NaHCO3ꢂ, CH2Cl2; (h) Dess–Martin periodinane, CH2Cl2 (37% for
3 steps); (i) 6 M HCl/MeOH (1:1, v/v) (89%); (j) CSA, MeOH, 40 C (41%).

S. Aoki et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1707
along with the ꢂ-anomer (not shown) in a ratio of approxi-
mately 5:1. The anomers were separable by column chroma-
tography on silica gel. The stereochemistry of the ꢁ-anomeric
carbon (C8) in 42 was determined by NOE experiments. After
some experimentation, we found that the dehydrated enamide
43 was formed as an inseparable E,Z-mixture by heating 42 in
5% acetic acid in i-PrOH.26,27 The ꢂ-isomer of 42 also provid-
ed a mixture of the E,Z-enamides 43 under similar acidic con-
ditions. To our delight, the formation of the desired ꢀ-hy-
droxy-ꢀ-lactam, carrying a benzoyl side-chain, was success-
fully achieved by the regioselective epoxidation of the enam-
ide double bond in 43 with m-CPBA,28 followed by Dess–
Martin oxidation of the resulting benzylic alcohols, which
were presumably formed by the ring-opening of the intermedi-
ary epoxide by the attack of water. We could not isolate the
intermediary epoxide. On the other hand, the treatment of 43
with dimethyldioxirane29 gave undesired overoxidation prod-
ucts. In this case, epoxidation of the left-hand side-chain dou-
ble bond was observed. Osmium tetraoxide in alcoholic sol-
vents30 provided a mixture of degradation products. Singlet
oxygen31 provided 42 via the hydration of the enamide moiety.
47. The Dess–Martin oxidation of 47, followed by dehydration
of the resultant ꢀ-lactone hemiketal with thionyl chloride,
provided the desired 1,7-dioxaspiro[4.4]non-2-ene-4,6-dione
48, along with a 2,8-dioxabicyclo[4.3.0]non-3-ene-5,7-dione
49.35 The spirocyclic ꢀ-lactone 48 was converted into the
hemiaminal 51 (a ꢀ-oxgenated-ꢀ-lactam) via the O-MOM
ether 50 by the same reaction sequence used for the conversion
of 39 into 42. Hydrolysis of the O-MOM group in 51 complet-
ed the total synthesis of azaspirene (5). Synthetic 5 was iden-
tical to an authentic sample of natural 5 in all respects (mp,
1
½ꢁꢄD, IR, H and 13C NMR, HRMS, TLC).7
In conclusion, we completed the total syntheses of natural
pseurotins A (1) and F2 (2) using D-glucose as an enantiomeric
pure starting material. The spiro-carbon in 1 and 2 was con-
structed by the stereoselective vinyl Grignard addition at C3
of the D-glucose-derived ulose 11. The synthesis of an ad-
vanced intermediate 39, a highly functionalized 1,7-dioxaspi-
ro[4.4]non-2-ene-4,6-dione, featured 1) the Cu(I)-mediated
benzyl Grignard addition to a functionalized hexanal deriva-
tive 17 and 2) the aldol reaction of a keto ꢀ-lactone 35 with
a seven-carbon aldehyde 29. Transformation of the ꢀ-lactone
40 derived from 35 to the ꢀ-oxygenated-ꢀ-lactam 42, followed
by benzylic oxidation, eventually provided pseurotins F2 (2),
and then A (1). By a similar synthetic venture including the al-
dol reaction of the common intermediate 35 with LiBr-coordi-
nated dienal 45, the total synthesis of natural azaspirene (5)
was also completed.
Potassium permanganate in the presence of CuSO4 5H2O32
ꢃ
did not work. Removal of all the O-MOM groups in 44 by
acidic hydrolysis completed the total sysnthesis of natural
pseurotin F2 (2). The spectroscopic data of synthetic 2 matched
well with those reported for natural 2.3 Furthermore, methyl
acetalization of 2 with CSA in MeOH provided natural pseur-
otin A (1). Synthetic 1 was identical to an authentic sample of
natural 1 in all respects (mp, ½ꢁꢄD, IR, 1H and 13C NMR,
HRMS, TLC).
Experimental
General Methods. Melting points are uncorrected. Specific
1
Our next concern focused on the total synthesis of azaspi-
rene (5). The total synthesis was accomplished starting from
the union of the intermediate 35 and commercially available
(2E,4E)-2,4-heptadienal (45) (Scheme 8). Deprotonation of
35 with KHMDS in THF at ꢁ78 ꢂC, followed by the addition
of 45 in the presence of 5.0 molar amounts of LiBr,33 provided
the aldol adduct 46 as a sole product. The stereochemistry of
46 was not determined. When the reaction was conducted in
the absence of LiBr, 46 was not formed.34 Exposure of 46 to
rotations were measured in a 10 mm cell. H NMR spectra were
recorded at 270 MHz or at 300 MHz in a CDCl3 solution with
tetramethylsilane as an internal standard. 13C NMR spectra were
recorded at 75 MHz in a CDCl3 solution. Thin-layer chromatog-
raphy (TLC) was performed on Merck Kieselgel 60 F254 plates.
The crude reaction mixtures and extractive materials were purified
by chromatography on Daisogel IR-60 (Daiso) or Wakogel C-300
(Wako). Combined organic extracts were concentrated under re-
duced pressure using an evaporator with a water bath at 35–45 ꢂC.
(2R,3R,4R,5R)-5-Ethyl-4-hydroxy-2,3-isopropylidenedioxy-
4-vinyltetrahydrofuran (12). To a cooled (0 ꢂC) stirred solution
a dilute solution of HF pyridine complex in pyridine selective-
ly cleaved the O-TES group on the tertiary alcohol to provide
ꢃ
O
O
35
RO
O
Me
O
O
Me
a
+
HO
Me
Ph
Ph
Me
Me
CHO
O
OTES
O
OR
45
46: R = TES
47: R = H
48: R = TES
b
e, f
c, d
50: R = MOM
+
OTES
O
O
O
O
O
NH
Me
g − i
Me
50
O
Me
Me
OH
OR
O
H
Ph
51: R = MOM
Azaspirene (5): R = H
49
j
Scheme 8. Reagents and conditions: (a) KHMDS (1.0 mol. amt.), THF, ꢁ78 ꢂC; then 45 (5.0 mol. amt.), LiBr (5.0 mol. amt.); (b)
HF pyr, pyr, THF (59% from 35); (c) Dess–Martin periodinane, CH2Cl2; (d) SOCl2, pyr, 0 ꢂC (42% for 48 and 24% for 49 from
ꢃ
47); (e) HF pyr, pyr, THF; (f) CH2(OMe)2, P2O5, CH2Cl2, 0 ꢂC (72% for 2 steps); (g) saturated NH3 in i-PrOH; (h) Dess–Martin
periodinane, CH2Cl2; (i) saturated aqueous Na2CO3 (85% for 3 steps); (j) 6 M HCl/MeOH (1:1, v/v) (51%).
ꢃ

1708 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Total Syntheses of Pseurotins and Azaspirene
of 10 (14.4 g, 76.6 mmol) in CH2Cl2 (300 mL) were added PCC
(67.4 g, 313 mmol) and molecular sieves 4A (67.6 g). The mixture
was stirred at room temperature for 10 h, followed by elution
through a short column of silica gel to remove inorganic salts.
The column was eluted with excess Et2O. The combined eluates
were concentrated in vacuo to give crude 3-ulose 11 (14.6 g),
which was used directry in the next step. Theꢂfollowing reaction
was carried out under Ar. To a cooled (ꢁ18 C) stirred solution
of crude 3-ulose 11 (14.6 g) in THF (100 mL) was added dropwise
vinylmagnesium bromide (1.0 M solution in THF, 121 mL, 121
mmol). After being stirred for 1 h at ꢁ18 ꢂC, the solution was
quenched with saturated aqueous NH4Cl (50 mL), diluted with
EtOAc (1 L) and washed with saturated aqueous NH4Cl (300
mL) and saturated brine (300 mL ꢅ 2). The organic layer was
dried and concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel (EtOAc/hexane, 1:40) to pro-
vide 13.6 g (83% from 10) of 12 as colorless crystals: mp 59.6–
rated brine (200 mL). The organic layer was dried and concentrat-
ed in vacuo. The residue was purified by column chromatography
on silica gel (EtOAc/hexane, 1:30) to provide 5.25 g (79%) of 14
27
as a colorless oil: TLC Rf 0.53 (EtOAc/hexane, 1:3); ½ꢁꢄD þ6:5
(c 2.72, CHCl3); IR (neat) 1790 cmꢁ1; 1H NMR (300 MHz) ꢃ 1.02
(t, 3H, J ¼ 7:3 Hz), 1.31–1.48, 1.65–1.81 (2 m, each 1H), 1.42,
1.44 (2 s, each 3H), 4.44 (dd, 1H, J ¼ 3:7, 9.8 Hz), 4.66 (s,
1H), 5.42 (dd, 1H, J ¼ 1:1, 10.7 Hz), 5.58 (dd, 1H, J ¼ 1:1,
17.1 Hz), 5.98 (dd, 1H, J ¼ 10:7, 17.1 Hz); 13C NMR (75 MHz)
ꢃ 9.8, 26.1, 27.7, 27.9, 78.0, 87.0, 88.3, 114.2, 118.3, 133.3,
173.7; HRMS calcd for C11H16O4 (Mþ) m=z 212.1049, found
212.1064.
(2S,3R,4R)-2,3-Isopropylidenedioxy-3-vinylhexane-1,4-diol
(15). To a cooled (0 ꢂC) stirred solution of 14 (2.99 g, 14.1
mmol) in THF (60 mL) was added LiAlH4 (1.61 g, 42.4 mmol).
After being stirred for 2 h at 0 ꢂC, the mixture was quenched with
H2O (5 mL). The resulting gels were removed by filtration
through a Celite-pad and washed well with EtOAc. The combined
filtrate and washings were concentrated in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/hexane,
1:3) to provide 2.77 g (91%) of 15 as colorless crystals: mp 80.1–
23
60.7 ꢂC; TLC Rf 0.35 (EtOAc/hexane, 1:10); ½ꢁꢄD þ54:6 (c
1
1.32, CHCl3); IR (neat) 3480 cmꢁ1; H NMR (300 MHz) ꢃ 0.98
(t, 3H, J ¼ 7:3 Hz), 1.36, 1.60 (2 s, each 3H), 1.49 (quint, 2H, J ¼
7:3 Hz), 2.68 (s, 1H, OH), 3.70 (t, 1H, J ¼ 7:3 Hz), 4.20 (d, 1H,
J ¼ 3:9 Hz), 5.28 (dd, 1H, J ¼ 1:7, 11.0 Hz), 5.49 (dd, 1H,
J ¼ 1:7, 17.3 Hz), 5.75 (dd, 1H, J ¼ 11:0, 17.3 Hz), 5.80 (d,
1H, J ¼ 3:9 Hz); 13C NMR (75 MHz) ꢃ 10.5, 21.8, 26.4, 26.5,
80.1, 83:5 ꢅ 2, 103.3, 112.3, 115.5, 134.4; HRMS calcd for
C11H18O4 (Mþ) m=z 214.1205, found 214.1198. Anal. Calcd for
C11H18O4: C, 61.66; H, 8.47%. Found: C, 61.53; H, 8.58%.
(2R,3R,4R)-4-Ethyl-2,3-dihydroxy-3-vinyl-4-butanolide
(13). Compound 12 (7.32 g, 34.2 mmol) was dissolved in 80%
aqueous AcOH (120 mL). The solution was stirred at 80 ꢂC for
11 h and concentrated in vacuo with the aid of EtOH and toluene
to give a crude ꢀ-lactol derivative (6.99 g), which was used in the
next step without further purification. The following reaction was
carried out in the dark. To a cooled (0 ꢂC) stirred solution of crude
ꢀ-lactol derivative (6.99 g) in CH2Cl2 (100 mL) were added n-
Bu4NI (18.9 g, 51.2 mmol) and NIS (19.2 g, 85.4 mmol). The
mixture was stirred at room temperature for 20 h, diluted with
EtOAc (800 mL), and washed with saturated aqueous Na2S2O3
(300 mL), saturated aqueous NaHCO3 (300 mL), and saturated
brine (300 mL). The organic layer was dried and concentrated
in vacuo, followed by elution through a short column of silica
gel. The column was eluted with EtOAc/hexane (1:2). The com-
bined eluates were concentrated in vacuo and the residue was pu-
rified by column chromatography on silica gel (EtOAc/hexane,
1:4) to give 5.60 g (95% from 12) of 13 as colorless crystals:
27
80.3 ꢂC; TLC Rf 0.20 (EtOAc/hexane, 1:3); ½ꢁꢄD þ86:0 (c 2.53,
CHCl3); IR (neat) 3400 cmꢁ1; 1H NMR (270 MHz) ꢃ 0.99 (t, 3H,
J ¼ 7:3 Hz), 1.18–1.30, 1.74–1.88 (2 m, each 1H), 1.39, 1.44 (2 s,
each 3H), 2.54 (br s, 1H, OH), 3.67 (dd, 1H, J ¼ 2:2, 10.3 Hz),
3.92–4.06 (m, 3H), 5.26 (dd, 1H, J ¼ 2:0, 11.0 Hz), 5.49 (dd,
1H, J ¼ 2:0, 17.2 Hz), 6.14 (dd, 1H, J ¼ 11:0, 17.2 Hz);
13C NMR (75 MHz) ꢃ 10.7, 24.1, 26.0, 28.3, 60.1, 73.7, 82.9,
85.8, 107.8, 115.6, 136.0; HRMS calcd for C10H13O4 (Mþ
CH3) m=z 201.1127, found 201.1130.
ꢁ
(2S,3R,4R)-4-Benzyloxy-2,3-isopropylidenedioxy-3-vinyl-
hexan-1-ol (16). To a stirred solution of 15 (5.55 g, 25.7 mmol)
in pyridine (100 mL) were added DMAP (6.27 g, 51.3 mmol) and
trityl chloride (14.3 g, 51.3 mmol). The solution was refluxed for 4
h, diluted with EtOAc (500 mL), and washed with saturated aque-
ous NaHCO3 (200 mL), saturated aqueous NH4Cl (200 mL), and
saturated brine (200 mL). The organic layer was dried and concen-
trated in vacuo, followed by elution through a short column of sili-
ca gel. The column was eluted with EtOAc/hexane (1:15, contain-
ing 1 v/v% Et3N). The combined eluates were concentrated in va-
cuo to give crude trityl ether (17.8 g), which wasꢂused in the next
step without further purification. To a cooled (0 C) stirred solu-
tion of crude trityl ether (17.8 g) in DMF (50 mL) were added
NaH (60% emulsion in mineral oil, 10.3 g, 257 mmol) and benzyl
bromide (15.3 mL, 129 mmol). After being stirred for 8 h at room
temperature, the mixture was quenched with H2O (30 mL) at 0 ꢂC,
diluted with EtOAc (500 mL), and washed with saturated aqueous
NaHCO3 (300 mL), saturated aqueous NH4Cl (300 mL), and satu-
rated brine (300 mL). The organic layer was dried and concentrat-
ed in vacuo, followed by elution through a short column of silica
gel. The column was eluted with EtOAc/hexane (1:20, containing
1 v/v% Et3N). The combined eluates were concentrated in vacuo
to give crude benzyl ether (22.6 g), which was used in the next
step without further purification. To a stirred solution of crude
benzyl ether (22.6 g) in MeOH (100 mL) was added CSA (59.6
mg, 0.257 mmol). The solution was stirred at room temperature
for 2 days, diluted with EtOAc (500 mL), and washed with satu-
rated aqueous NaHCO3 (200 mL ꢅ 2) and sturated brine (200
mL). The organic layer was dried and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:8 to 1:6) to provide 6.59 g (84% from
15) of 16 as a colorless oil: TLC Rf 0.28 (EtOAc/hexane, 1:6);
21
mp 71.0–72.1 ꢂC; TLC Rf 0.39 (EtOAc/hexane, 1:1); ½ꢁꢄD
þ106 (c 1.07, CHCl3); IR (neat) 3440, 1780, 1640 cmꢁ1; 1H NMR
(300 MHz) ꢃ 1.03 (t, 3H, J ¼ 7:3 Hz), 1.42–1.57, 1.64–1.77 (2 m,
each 1H), 3.60 (br s, 2H, OH ꢅ 2), 4.30 (dd, 1H, J ¼ 3:7, 10.7
Hz), 4.56 (s, 1H), 5.42 (dd, 1H, J ¼ 0:7, 10.7 Hz), 5.60 (dd,
1H, J ¼ 0:7, 17.1 Hz), 5.93 (dd, 1H, J ¼ 10:7, 17.1 Hz);
13C NMR (75 MHz) ꢃ 10.4, 25.0, 71.7, 78.6, 88.6, 118.8, 134.5,
175.2; HRMS calcd for C8H12O4 (Mþ) m=z 172.0736, found
172.0736. Anal. Calcd for C8H12O4: C, 55.81; H, 7.02%. Found:
C, 55.74; H, 7.03%.
(2R,3R,4R)-4-Ethyl-2,3-isopropylidenedioxy-3-vinyl-4-bu-
tanolide (14). To a stirred solution of 13 (5.40 g, 31.4 mmol) in
acetone/Me2C(OMe)2 (1:1 v/v, 100 mL) was aꢂdded CSA (2.19 g,
9.41 mmol). After being stirred for 6 h at 40 C under reducing
pressure (300 hPa), the solution was neutralized with saturated
aqueous NaHCO3 at 0 ꢂC, diluted with EtOAc (500 mL), and
washed with saturated aqueous NaHCO3 (200 mL ꢅ 2) and satu-

S. Aoki et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1709
29
½ꢁꢄD þ64:2 (c 2.18, CHCl3); IR (neat) 3500 cmꢁ1
;
1H NMR
rt for an additional 1 h. The solvent was removed by evaporation
in vacuo to provide a crude aldehyde derivative (2.03 g), which
was used directly in the next step. The crude aldehyde (2.03 g)
was dissolved in 60% aqueous CF3CO2H (20 mL). After being
stirred for 10 h at room temperature, the solution was neutralized
with 5 M (1 M = 1 mol dmꢁ3) aqueous NaOH, diluted with
EtOAc (200 mL), and washed with saturated brine (80 mL ꢅ
2). The organic layer was dried and concentrated in vacuo. The
residue was eluted through a short column of silica gel with
EtOAc/hexane (1:2), and the combined eluates were concentrated
in vacuo to provide crude ꢀ-lactol 21 (890 mg), which was used in
the next step without further purification. The following reaction
was carried out in the dark. To a cooled (0 ꢂC) stirred solution
of crude ꢀ-lactol 21 (890 mg) in CH2Cl2 (10 mL) were added
n-Bu4NI (620 mg, 1.68 mmol) and NIS (633 mg, 2.81 mmol).
The solution was stirred at room temperature for 24 h, and addi-
tional NIS (633 mg ꢅ 2, 2.81 mmol ꢅ 2) was added every 12
h. The solution was stirred for a total of 48 h, diluted with Et2O
(200 mL), and washed with saturated aqueous Na2S2O3 (80 mL)
and saturated aqueous NaHCO3 (80 mL ꢅ 2). The organic layer
was dried and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (EtOAc/hexane, 1:3 to
1:2) to give 352 mg (57% from 20) of 22 as a colorless oil:
(300 MHz) ꢃ 1.03 (t, 3H, J ¼ 7:7 Hz), 1.41, 1.47 (2 s, each
3H), 1.60–1.74, 1.84–1.99 (2 m, each 1H), 2.37 (br s, 1H, OH),
3.57 (dd, 1H, J ¼ 3:7, 5.1 Hz), 3.79 (d, 2H, J ¼ 6:6 Hz), 3.98
(t, 1H, J ¼ 6:6 Hz), 4.37, 4.69 (AB q, each 1H, J ¼ 10:7 Hz),
5.19 (dd, 1H, J ¼ 2:0, 10.7 Hz), 5.53 (dd, 1H, J ¼ 2:0, 17.1
Hz), 6.17 (dd, 1H, J ¼ 10:7, 17.1 Hz), 7.25–7.38 (m, 5H);
13C NMR (75 MHz) ꢃ 11.9, 22.2, 25.9, 28.2, 60.6, 71.0, 80.8,
84.2, 85.8, 108.1, 114.7, 127:8 ꢅ 2, 127.9, 128:5 ꢅ 2, 137.1,
137.4; HRMS calcd for C18H26O4 (Mþ) m=z 306.1831, found
306.1833.
(2R,3R,4R)-4-Benzyloxy-2,ꢂ3-isopropylidenedioxy-3-vinyl-
hexanal (17). To a cooled (0 C) stirred solution of 16 (6.50 g,
21.2 mmol) in CH2Cl2 (100 mL) was added Dess–Martin period-
inane (9.90 g, 23.3 mmol). The mixture was stirred for 3 h at room
temperature, diluted with EtOAc (500 mL), and washed with satu-
rated aqueous Na2S2O3 (300 mL) and saturated aqueous Na2CO3
(300 mL ꢅ 2). The organic layer was dried and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:20) to provide 6.17 g (96%) of 17
28
as a colorless oil: TLC Rf 0.48 (EtOAc/hexane, 1:6); ½ꢁꢄD
ꢁ17:5 (c 1.76, CHCl3); IR (neat) 1730 cmꢁ1
;
1H NMR (300
MHz) ꢃ 1.01 (t, 3H, J ¼ 7:7 Hz), 1.42, 1.59 (2 s, each 3H),
1.53–1.67, 1.71–1.85 (2 m, each 1H), 3.40 (t, 1H, J ¼ 5:1 Hz),
4.19, 4.50 (AB q, each 1H, J ¼ 11:0 Hz), 4.35 (s, 1H), 5.31
(dd, 1H, J ¼ 1:7, 11.0 Hz), 5.61 (dd, 1H, J ¼ 1:7, 17.3 Hz),
6.27 (dd, 1H, J ¼ 11:0, 17.3 Hz), 7.24–7.37 (m, 5H), 9.51 (s,
1H); 13C NMR (75 MHz) ꢃ 11.6, 22.3, 26.0, 28.1, 71.0, 80.4,
87.8, 88.9, 110.2, 115.9, 127.6, 127:8 ꢅ 2, 128:3 ꢅ 2, 135.7,
137.7, 192.5; HRMS calcd for C18H24O4 (Mþ) m=z 304.1675,
found 304.1676.
25
TLC Rf 0.58 (EtOAc/hexane, 1:1); ½ꢁꢄD þ31:6 (c 1.18, CHCl3);
1
IR (neat) 3450, 1790, 1695 cmꢁ1; H NMR (300 MHz) ꢃ 1.07 (t,
3H, J ¼ 7:3 Hz), 1.67–1.95 (m, 2H), 3.87 (dd, 1H, J ¼ 3:9, 8.5
Hz), 4.58 (d, 1H, J ¼ 2:8 Hz), 4.70, 5.15 (AB q, each 1H, J ¼
10:0 Hz), 5.76 (d, 1H, J ¼ 2:8 Hz), 7.26–7.40, 7.42–7.47 (2 m,
3H + 2H), 7.52 (t, 2H, J ¼ 7:1 Hz), 7.67 (t, 1H, J ¼ 7:1 Hz),
8.07 (d, 2H, J ¼ 7:1 Hz); 13C NMR (75 MHz) ꢃ 10.2, 23.4,
75.0, 75.4, 78.3, 78.8, 80.7, 127.9, 128:4 ꢅ 2, 128:5 ꢅ 2,
128:9 ꢅ 2, 129:3 ꢅ 2, 134.6, 134.7, 138.1, 174.2, 195.2; HRMS
calcd for C21H22O6 (Mþ) m=z 370.1416, found 370.1418. NOE
experiment; 10.2% enhancement of the H-4 (ꢃ 5.76) was observed
when H-3 (ꢃ 4.58) was irradiated, and 8.0% enhancement of H-3
was observed when H-4 was irradiated.
(3R,4S,5R,6R)-6-Benzyloxy-4,5-isopropylidenedioxy-2-phen-
yl-5-vinyloct-1-en-3-ol (20). The following reaction was carried
out under Ar. To a cooled (ꢁ78 C) solution of 1-bromo-1-phen-
ꢂ
ylethene (19) (0.48 mL, 3.70 mmol) in Et2O (10 mL) was added
dropwise tert-butyllithium (1.57 M solution in pentane, 4.71 mL,
7.39 mmol). The solution was stirred at ꢁ78 ꢂC for 30 min, and a
solution of 17 (566 mg, 1.86 mmol) in Et2O (0.5 mL) was added.
After being stirred at ꢁ78 ꢂC for 30 min, the solution was
quenched with H2O (1 mL), diluted with Et2O (100 mL), and
washed with saturated brine (80 mL ꢅ 3). The organic layer
was dried and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (EtOAc/hexane, 1:30)
to provide 715 mg (94%) of 20 as a colorless oil: TLC Rf 0.55
(2S,3S,4S)-4-Benzoyl-2-[(1R)-1-(benzyloxy)propyl]-3-hy-
droxy-2-triethylsiloxy-4-butanolide (23). The following reac-
ꢂ
tion was carried out under Ar. To a cooled (0 C) stirred solution
of 22 (198 mg, 0.535 mmol) in pyridine (10 mL) was added drop-
wise triethylsilyl trifluoromethanesulfonate (0.18 mL, 0.80 mmol).
After being stirred for 2 h at room temperature, the solution was
quenched with saturated aqueous NaHCO3 (1 mL) at 0 ꢂC, diluted
with EtOAc (50 mL), and washed with saturated aqueous
NaHCO3 (30 mL), saturated aqueous NH4Cl (30 mL), and saturat-
ed brine (30 mL). The organic layer was dried and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:7) to give 236 mg (91%) of 23 as a
18
(EtOAc/hexane, 1:6); ½ꢁꢄD þ82:2 (c 0.720, CHCl3); IR (neat)
3540 cmꢁ1
;
1H NMR (300 MHz) ꢃ 1.01 (t, 3H, J ¼ 7:6 Hz),
1.29, 1.52 (2 s, each 3H), 1.56–1.70, 1.75–1.90 (2 m, each 1H),
3.16 (br s, 1H, OH), 3.93 (t, 1H, J ¼ 5:0 Hz), 3.84 (d, 1H, J ¼
1:5 Hz), 4.66 (s, 2H), 5.07 (dd, 1H, J ¼ 1:7, 11.0 Hz), 5.24 (br
s, 1H), 5.33 (dd, 1H, J ¼ 1:7, 17.3 Hz), 5.35–5.37 (m, 1H),
5.44 (d, 1H, J ¼ 1:2 Hz), 6.13 (dd, 1H, J ¼ 11:0, 17.3 Hz),
7.18–7.43 (m, 10H); 13C NMR (75 MHz) ꢃ 12.2, 23.2, 26.2,
28.0, 68.2, 71.6, 81.4, 83.0, 86.0, 108.1, 113.1, 114.4,
126:7 ꢅ 2, 127.3, 127:4 ꢅ 2, 127.6, 128:27 ꢅ 2, 128:34 ꢅ 2,
137.9, 139.0, 139.9, 150.0; HRMS calcd for C26H32O4 (Mþ)
m=z 408.2301, found 408.2302.
(2S,3S,4S)-4-Benzoyl-2-[(1R)-1-(benzyloxy)ꢂpropyl]-2,3-di-
hydroxy-4-butanolide (22). To a cooled (ꢁ78 C) stirred solu-
tion of 20 (686 mg, 1.68 mmol) in CH2Cl2 (10 mL) was bubbled
ozone (O2 containing ca. 3% O3) for 15 min until a light blue col-
or persisted. To this solution was added Ph3P (1.10 g, 4.19 mmol),
and the solution was stirred for 30 min at ꢁ78 ꢂC and warming to
20
colorless oil: TLC Rf 0.45 (EtOAc/hexane, 1:3); ½ꢁꢄD þ16:2
(c 1.40, CHCl3); IR (neat) 3460, 1790, 1700 cmꢁ1 1H NMR
;
(300 MHz) ꢃ 0.33–0.43 (m, 6H), 0.79 (t, 9H, J ¼ 7:9 Hz), 1.06
(t, 3H, J ¼ 7:3 Hz), 1.49–1.61, 1.69–1.82 (2 m, each 1H), 3.79
(dd, 1H, J ¼ 2:4, 9.7 Hz), 4.66, 5.17 (AB q, each 1H, J ¼ 10:0
Hz), 4.70 (d, 1H, J ¼ 3:4 Hz), 5.85 (d, 1H, J ¼ 3:4 Hz), 7.28–
7.39, 7.44–7.49 (2 m, 3H + 2H), 7.51 (t, 2H, J ¼ 7:3 Hz), 7.63
(t, 1H, J ¼ 7:3 Hz), 8.04 (d, 2H, J ¼ 7:3 Hz); 13C NMR (75
MHz) ꢃ 5:0 ꢅ 3, 6:6 ꢅ 3, 10.1, 23.6, 75.7, 77.8, 78.6, 79.2,
83.3, 127.9, 128:4 ꢅ 2, 128:7 ꢅ 2, 128:7 ꢅ 2, 129:0 ꢅ 2, 134.1,
135.2, 138.1, 174.2,193.4; HRMS calcd for C25H31O6Si (Mþ
ꢁ
CH2CH3) m=z 455.1890, found 455.1891. NOE experiment;
14.0% enhancement of the H-4 (ꢃ 5.85) was observed when H-3
(ꢃ 4.70) was irradiated, and 9.7% enhancement of the H-3 was

1710 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Total Syntheses of Pseurotins and Azaspirene
observed when H-4 was irradiated.
171 mL, 85.5 mmol). The mixture was stirred at room temperature
for 1.5 h, and 2,3-ethylidenedioxy-D-erythrofuranose8a (5.01 g,
34.3 mmol) was added. After being stirred at room temperature
for 1.5 h, the mixture was quenched with saturated aqueous
NH4Cl (10 mL) at 0 ꢂC, diluted EtOAc (300 mL), and washed
with saturated aqueous NH4Cl (70 mL), saturated aqueous
NaHCO3 (70 mL), and saturated brine (70 mL). The organic layer
was dried and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1:4) to pro-
vide 5.56 g (94%) of 26 (Z/E = ca. 14:1, determined by 1H NMR
analysis) as a colorless oil. Spectroscopic data for 26; see Ref. 8a.
(2R,3S,4Z)-1-(4-Methoxybenzyloxy)hept-4-ene-2,3-diol (27)
(2S,3S,4S)-4-Benzoyl-3-hydroxy-2-(1-propanoyl)-2-triethyl-
siloxy-4-butanolide (24). A solution of 23 (231 mg, 476 mmol)
in EtOAc (5 mL) was stirred under atmospheric H2 in the presence
of 10% Pd on charcoal (41.0 mg) for 1 day, and an additional 10%
Pd on charcoal (41.0 mg ꢅ 2) was added every 1 day. The mixture
was stirred for a total of 3 days, and the catalyst was removed by
filtration through a Celite-pad and washed well with EtOAc. The
combined filtrate and washings were concentrated in vacuo to give
crude triol (201 mg), which was used in the next step without fur-
ther purification. To a solution of crude triol (201 mg) in DMSO
(5 mL) was added 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide
(IBX) (399 mg, 1.42 mmol). The solution was stirred for 12 h, and
additional IBX (399 mg, 1.42 mmol) was added. The solution was
stirred for 11 h at room temperature, diluted with EtOAc (100
mL), and washed with saturated aqueous Na2S2O3 (40 mL) and
saturated aqueous Na2CO3 (40 mL ꢅ 2). The organic layer was
dried and concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel (EtOAc/hexane, 1:8) to pro-
vide 194 mg (87%) of 24 as colorless crystals: mp 114.8–115.0
and 4E-Isomer.
To a cooled (0 ꢂC) stirred solution of 26
(4.12 g, 23.9 mmol) in DMF (10 mL) were added NaH (60%
emulsion in mineral oil, 2.30 g, 57.4 mmol) and 4-methoxybenzyl
chloride (3.89 mL, 28.7 mmol). After being stirred at room tem-
perature for 5 h, the mixture was quenched with H2O (5 mL) at
0
ꢂC, diluted with EtOAc (100 mL), and washed with saturated
aqueous NaHCO3 (70 mL), saturated aqueous NH4Cl (70 mL),
and saturated brine (70 mL). The organic layer was dried and con-
centrated in vacuo to give crude 4-methoxybenzyl ether (10.3 g),
which was used directly to the next step. To a stirred solution of
crude 4-methoxybenzyl ether (10.3 g) in MeOH (15 mL) was add-
ed Amberlite IR-120 (Hþ) (1.10 g). The mixture was stirred for 20
h, and the resin was removed by filtration and washed well with
MeOH. The combined filtrate and washings were concentrated
in vacuo, and the residue was purified by column chromatography
on silica gel (EtOAc/hexane, 2:3) to provide 5.80 g (91% from
20
ꢂC; TLC Rf 0.62 (EtOAc/hexane, 1:5); ½ꢁꢄD þ64:5 (c 2.02,
CHCl3); IR (neat) 3440, 1790, 1715, 1700 cmꢁ1; H NMR (300
1
MHz) ꢃ 0.09–0.31 (m, 6H), 0.69 (t, 9H, J ¼ 7:8 Hz), 1.13 (t,
3H, J ¼ 7:1 Hz), 2.79, 2.84 (2 dq, each 1H, J ¼ 15:4, 7.1 Hz),
4.84 (br s, 1H, OH), 5.03 (d, 1H, J ¼ 7:6 Hz), 6.14 (d, 1H, J ¼
7:6 Hz), 7.53 (t, 2H, J ¼ 7:8 Hz), 7.66 (t, 1H, J ¼ 7:8 Hz), 7.96
(d, 2H, J ¼ 7:8 Hz); 13C NMR (75 MHz) ꢃ 4:1 ꢅ 3, 6:4 ꢅ 3,
7.2, 33.4, 79.4, 80.5, 83.0, 128:5 ꢅ 2, 128:9 ꢅ 2, 134.3, 135.7,
171.9, 192.5, 204.2; HRMS calcd for C20H28O6Si (Mþ) m=z
392.1655, found 392.1653. NOE experiment; 10.8% enhancement
of the H-4 (ꢃ 6.14) was observed when H-3 (ꢃ 5.03) was irradiat-
ed, and 13.4% enhancement of the H-3 was observed when H-4
was irradiated.
1
26) of 27 (Z/E = ca. 14:1, determined by H NMR analysis) as
colorless crystals: mp 54.3–55.7 ꢂC; TLC Rf 0.33 (EtOAc/hexane,
22
1:1); ½ꢁꢄD þ26:6 (c 1.38, CHCl3); IR (neat) 3290, 1615 cmꢁ1
;
1H NMR (300 MHz) ꢃ 0.98 (t, 3H, J ¼ 7:6 Hz), 1.96–2.23 (m,
2H), 2.59 (br s, 2H, OH ꢅ 2), 3.56 (dd, 1H, J ¼ 4:2, 9.8 Hz),
3.60 (dd, 1H, J ¼ 5:9, 9.8 Hz), 3.74 (dt, 1H, J ¼ 5:9, 4.2 Hz),
3.80 (s, 3H), 4.47 (s, 2H), 4.53 (dd, 1H, J ¼ 4:2, 9.3 Hz), 5.36
(dd, 1H, J ¼ 9:3, 11.0 Hz), 5.60 (dt, 1H, J ¼ 11:0, 7.6 Hz),
6.85–6.91, 7.22–7.28 (2 m, 2H + 2H); 13C NMR (75 MHz) ꢃ
14.2, 21.2, 55.2, 69.3, 70.9, 72.5, 73.3, 113:8 ꢅ 2, 127.1,
129:5 ꢅ 2, 129.7, 136.1, 159.3; HRMS calcd for C15H22O4
(Mþ) m=z 266.1518, found 266.1518.
(2S,3S,4S)-4-Benzoyl-3-methoxymethoxy-2-(1-propanoyl)-
2-triethylsiloxy-4-butanolide (25). To a cooled (0 ꢂC) stirred
suspension of P2O5 (185 mg, 1.30 mmol) in CH2(OMe)2 (5
mL) was added a solution of 24 (139 mg, 0.354 mmol) in CH2Cl2
(1 mL). After being stirred at 0 ꢂC for 1.5 h, the mixture was
quenched with saturated aqueous Na2CO3 (5 mL), diluted with
EtOAc (50 mL), and washed with saturated aqueous Na2CO3
(20 mL) and saturated brine (20 mL). The organic layer was dried
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:4) to provide
131 mg (98%) of 25 as a colorless oil: TLC Rf 0.64 (EtOAc/hex-
(2R,3S,4Z)-2,3-Bis(methoxymethoxy)hept-4-en-1-ol (28) and
4E-Isomer. To a cooled (0 ꢂC) stirred solution of 27 (4.25 g,
15.9 mmo) in CH2Cl2 (15 mL) were added i-Pr2NEt (11.7 mL,
67.2 mmol) and chloromethyl methyl ether (2.54 mL, 33.4 mmol).
The solution was stirred at room temperature for 8 h, diluted with
EtOAc (250 mL), and washed with saturated aqueous NaHCO3
(100 mL) and saturated brine (100 mL ꢅ 2). The organic layer
was dried and concentrated in vacuo to give crude 2,3-bis(meth-
oxymethyl ether) (5.78 g), which was used directly in the next
step. To a cooled (0 ꢂC) stirred suspension of crude methoxymeth-
yl ether (5.78 g) in CH2Cl2/H2O (15:1 v/v, 16 mL) was added
DDQ (4.34 g, 19.1 mmol). After being stirred at room temperature
for 12 h, the mixture was quenched with saturated aqueous
NaHCO3 (10 mL) at 0 ꢂC, and diluted with saturated aqeous
NaHCO3 (300 mL). The whole was extracted with CH2Cl2 (150
mL ꢅ 4), and the combined extracts were dried and concentrated
in vacuo. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:3) to provide 3.29 g (88% from 27) of
28 and 260 mg (7%) of 4E-isomer. The Z-isomer 28 was obtained
17
ane, 1:5); ½ꢁꢄD þ74:7 (c 0.385, CHCl3); IR (neat) 1790, 1720,
1705 cmꢁ1 1H NMR (300 MHz) ꢃ 0.15–0.36 (m, 6H), 0.73 (t,
;
9H, J ¼ 8:1 Hz), 1.09 (t, 3H, J ¼ 7:1 Hz), 2.56, 3.21 (2 dq, each
1H, J ¼ 20:0, 7.1 Hz), 3.36 (s, 3H), 4.70, 4.94 (AB q, each 1H,
J ¼ 6:8 Hz), 4.98 (d, 1H, J ¼ 3:7 Hz), 5.81 (d, 1H, J ¼ 3:7
Hz), 7.52 (t, 2H, J ¼ 7:3 Hz), 7.65 (t, 1H, J ¼ 7:3 Hz), 8.02 (d,
2H, J ¼ 7:3 Hz); 13C NMR (75 MHz) ꢃ 4:4 ꢅ 3, 6:5 ꢅ 3, 6.9,
36.0, 56.9, 79.3, 83.9, 84.0, 94.4, 128:8 ꢅ 2, 129:0 ꢅ 2, 134.2,
134.9, 169.9, 192.0, 204.0; HRMS calcd for C22H32O7Si (Mþ)
m=z 436.1917, found 436.1912. NOE experiment; 16.4% enhance-
ment of the H-4 (ꢃ 5.81) was observed when H-3 (ꢃ 4.98) was ir-
radiated, and 15.8% enhancement of the H-3 was observed when
H-4 was irradiated.
(2R,3S,4Z)-2,3-(Ethylidenedioxy)hept-4-en-1-ol (26) and 4E-
Isomer. The following reaction was carried out under Ar. To a
stirred suspension of propyltriphenylphosphonium bromide (33.0
g, 85.7 mmol) in THF (100 mL) was added dropwise potassium
bis(trimethylsilyl)amide (KHMDS) (0.5 M solution in toluene,
23
as a colorless oil: TLC Rf 0.30 (EtOAc/hexane, 1:1); ½ꢁꢄD þ162
(c 1.14, CHCl3); IR (neat) 3480 cmꢁ1; 1H NMR (300 MHz) ꢃ 0.99
(t, 3H, J ¼ 7:6 Hz), 2.04–2.22 (m, 2H), 3.38, 3.43 (2 s, each 3H),

S. Aoki et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1711
3.64 (dt, 1H, J ¼ 9:5, 4.9 Hz), 3.63–3.74 (m, 2H), 4.50–4.57 (m,
1H), 4.53, 4.67 (AB q, each 1H, J ¼ 6:6 Hz), 4.73, 4.75 (AB q,
each 1H, J ¼ 6:8 Hz), 5.25–5.34 (m, 1H), 5.73 (dt, 1H,
J ¼ 10:7, 7.6 Hz); 13C NMR (75 MHz) ꢃ 14.1, 21.1, 55.4, 55.7,
62.7, 70.9, 82.1, 93.3, 97.0, 125.1, 137.8; HRMS calcd for
C11H22O5 (Mþ) m=z 234.1467, found 234.1454. The 4E-isomer
7.31, (m, 10H); 13C NMR (75 MHz) ꢃ 11.9, 22.7, 26.1, 28.1,
41.5, 68.8, 71.5, 81.2, 85.6, 85.7, 107.6, 114.8, 126.1,
127:4 ꢅ 2, 128:2 ꢅ 2, 128:3 ꢅ 2, 129:3 ꢅ 3, 137.7, 138.2, 138.5;
HRMS calcd for C25H32O4 (Mþ) m=z 396.2301, found
396.2305. Compound 31 was obtained as a colorless oil: TLC
24
Rf 0.41 (EtOAc/hexane, 1:15); ½ꢁꢄD ꢁ10:7 (c 1.20, CHCl3);
was obtained as a colorless oil: TLC Rf 0.29 (EtOAc/hexane,
23
IR (neat) 3440 cmꢁ1
;
1H NMR (300 MHz) ꢃ 1.05 (t, 3H, J ¼
1:1); ½ꢁꢄD þ168 (c 1.00, CHCl3); IR (neat) 3460, 1730 cmꢁ1
;
7:6 Hz), 1.37, 1.59 (2 s, each 3H), 1.60–1.75, 1.80–1.96 (2 m, each
1H), 2.12 (s, 3H), 3.28 (br s, 1H, OH), 3.96 (s, 1H), 3.98 (t, 1H,
J ¼ 4:9 Hz), 4.71 (s, 2H), 5.20 (dd, 1H, J ¼ 2:0, 11.0 Hz), 5.49
(dd, 1H, J ¼ 2:0, 17.2 Hz), 5.53 (s, 1H), 6.31 (dd, 1H,
J ¼ 11:0, 17.2 Hz), 7.05–7.37, 7.45–7.48 (2 m, 8H + 1H);
13C NMR (75 MHz) ꢃ 12.1, 19.1, 23.2, 26.5, 28.1, 65.7, 71.6,
81.1, 85.2, 86.3, 108.4, 114.5, 125.8, 126.0, 127.19, 127.24,
127:3 ꢅ 2, 128:2 ꢅ 2, 130.3, 134.7, 138.1, 139.0, 141.5; HRMS
calcd for C25H32O4 (Mþ) m=z 396.2301, found 396.2305. NOE
experiment; 10.7% enhancement of the H-1 (ꢃ 5.53) and 6.7%
enhancement of the H-2 (ꢃ 3.96) were observed when CH3 of
the tolyl group (ꢃ 2.12) was irradiated.
1H NMR (300 MHz) ꢃ 1.01 (t, 3H, J ¼ 7:6 Hz), 2.04–2.15 (m,
2H), 3.38, 3.43 (2 s, each 3H), 3.61–3.66, 3.69–3.72 (2 m, 1H
+ 2H), 4.11 (dd, 1H, J ¼ 4:4, 8.3 Hz), 4.54, 4.71 (AB q, each
1H, J ¼ 6:6 Hz), 4.73, 4.76 (AB q, each 1H, J ¼ 6:8 Hz), 5.32–
5.41 (m, 1H), 5.79 (dt, 1H, J ¼ 15:6, 6.3 Hz); 13C NMR (75
MHz) ꢃ 13.3, 25.3, 55.5, 55.7, 62.7, 76.8, 82.1, 93.3, 96.9,
124.8, 138.5; HRMS calcd for C11H21O4 (Mþ ꢁ OH) m=z
217.1440, found 217.1439.
(2S,3S,4Z)-2,3-Bis(methoxymethoxy)hept-4-enal (29). The
following reaction was carried out under Ar. To a coold (ꢁ78
ꢂC) solution of oxalyl chloride (0.60 mL, 6.88 mmol) in CH2Cl2
(5 mL) was added dropwise DMSO (0.98 mL, 13.8 mmol) slowly.
(2S,3S,4R)-4-Benzyl-2-[(1R)-1-(benzyloxy)propyl]-2,3-dihy-
ꢂ
ꢂ
The solution was stirred at ꢁ78 C for 1 h, and a solution of 28
droxy-4-butanolide (32). To a cooled (ꢁ78 C) stirred solution
(539 mg, 2.30 mmol) in CH2Cl2 (1 mL) was added dropwise. Af-
ꢂ
of 30 (1.47 g, 3.70 mmol) in CH2Cl2 (15 mL) was bubbled ozone
(O2 containing ca. 3% O3) for 1 h until a light-blue color persist-
ed. To this solution was added Ph3P (971 mg, 3.70 mmol), and the
solution was stirred at ꢁ78 ꢂC for 30 min and for an additional 1 h
warming to room temperature. The solvent was removed by evap-
oration in vacuo to provide a crude aldehyde derivative (2.76 g),
which was used directly in the next step. The crude aldehyde (2.76
g) was dissolved in 60% aqueous CF3CO2H (15 mL). After being
stirred at room temperature for 9 h, the solution was neutralized
with 5 M aqueous NaOH, diluted with EtOAc (200 mL), and
washed with saturated brine (50 mL ꢅ 2). The organic layer
was dried and concentrated in vacuo. The residue was eluted
through a short column of silica gel with EtOAc/hexane (1:2),
and the combined eluates were concentrated in vacuo to provide
the crude ꢀ-lactol derivative (1.21 g), which was used in the next
step without further purification. The following reaction was car-
ried out in the dark. To a cooled (0 ꢂC) stirred solution of crude ꢀ-
lactol derivative (1.21 g) in CH2Cl2 (20 mL) were added n-Bu4NI
(2.05 g, 5.55 mmol) and NIS (2.08 g, 9.24 mmol). The solution
was stirred at room temperature for 24 h, and additional NIS
(416 mg ꢅ 2, 1.85 mmol ꢅ 2) was added every 24 h. The solution
was stirred for total 72 h, diluted with EtOAc (200 mL), and wash-
ed with saturated aqueous Na2S2O3 (100 mL) and saturated aque-
ous NaHCO3 (100 mL). The organic layer was dried and concen-
trated in vacuo. The residue was purified by column chromatogra-
phy on silica gel (EtOAc/hexane, 1:3) to give 1.11 g (84% from
ter being stirred at ꢁ78 C for 1 h, Et3N (2.89 mL, 20.7 mmol)
was added dropwise to the mixture, which was then warmed to
room temperature. The mixture was stirred for an additional 30
min, diluted with EtOAc (100 mL), and washed with saturated
brine (50 mL ꢅ 3). The organic layer was dried and concentrated
in vacuo. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:4) to provide 474 mg (89%) of 29 as
22
a colorless oil: TLC Rf 0.39 (EtOAc/hexane, 1:3); ½ꢁꢄD þ125 (c
3.18, CHCl3); IR (neat) 1740 cmꢁ1; 1H NMR (300 MHz) ꢃ 0.98 (t,
3H, J ¼ 7:6 Hz), 1.98–2.22 (m, 2H), 3.36, 3.42 (2 s, each 3H),
4.04 (dd, 1H, J ¼ 2:0, 4.6 Hz), 4.53, 4.67 (AB q, each 1H, J ¼
6:8 Hz), 4.74, 4.78 (AB q, each 1H, J ¼ 6:6 Hz), 4.73–4.77 (m,
1H), 5.34–5.43 (m, 1H), 5.76 (dt, 1H, J ¼ 11:0, 7.3 Hz), 9.67
(d, 1H, J ¼ 2:0 Hz); 13C NMR (75 MHz) ꢃ 14.0, 21.1, 55.5,
55.9, 70.5, 83.6, 93.2, 96.9, 123.7, 138.5, 201.3; HRMS calcd
for C10H17O5 (Mþ ꢁ CH3) m=z 217.1076, found 217.1080.
(2R,3S,4R,5R)-5-Benzyloxy-3,4-isopropylidenedioxy-1-phen-
yl-4-vinylheptan-2-ol (30) and (1R,2S,3R,4R)-4-Benzyloxy-2,3-
isopropylidenedioxy-1-(2-methylphenyl)-3-vinylhexan-1-ol
(31). The following reaction was carried out under Ar. To a
cooled (0 ꢂC) solution of 17 (6.17 g, 20.3 mmol) and CuBr Me2S
ꢃ
(20.8 g, 101 mmol) in THF/Me2S (2:1 v/v, 300 mL) was added
dropwise benzylmagnesium chloride (2.0 M solution in THF,
ꢂ
101 mL, 202 mmol). After being stirred for 30 min at 0 C, the
mixture was quenched with saturated aqueous NH4Cl (50 mL).
The resulting mixture was diluted with EtOAc (500 mL), and
washed with saturated aqueous NH4Cl (300 mL), saturated aque-
ous NaHCO3 (300 mL), and saturated brine (300 mL). The organ-
ic layer was dried and concentrated in vacuo. The residue was pu-
rified by column chromatography on silica gel (EtOAc/hexane,
1:30 to 1:20) to provide 7.12 g (89%) of 30 and 125 mg (2%)
of 31. Compound 30 was obtained as a colorless oil: TLC Rf
30) of 32 as a colorless oil: TLC Rf 0.34 (EtOAc/hexane, 1:3);
22
½ꢁꢄD þ76:1 (c 2.89, CHCl3); IR (neat) 3440, 1780 cmꢁ1
;
1H NMR (300 MHz) ꢃ 1.03 (t, 3H, J ¼ 7:3Hz), 1.64–1.75 (m,
2H), 2.61, 3.63 (2 br s, each 1H, OH ꢅ 2), 2.99 (dd, 1H, J ¼
7:3, 13.9 Hz), 3.17 (dd, 1H, J ¼ 7:3, 13.9 Hz), 3.78 (t, 1H, J ¼
6:3 Hz), 3.97 (br d, 1H, J ¼ 2:9 Hz), 4.64, 5.08 (AB q, each
1H, J ¼ 10:3 Hz), 4.92 (dt, 1H, J ¼ 2:9, 7.3 Hz), 7.20–7.42 (m,
10H); 13C NMR (75 MHz) ꢃ 10.4, 23.7, 34.1, 74.5, 75.4, 79.4,
79.7, 82.4, 126.9, 127.9, 128:39 ꢅ 2, 128:44 ꢅ 2, 128:8 ꢅ 2,
129:1 ꢅ 2, 135.9, 138.0, 175.5; HRMS calcd for C21H25O5 (Mþ
+ H) m=z 357.1702, found 357.1707. NOE experiment; 9.6% en-
hancement of the H-4 (ꢃ 4.92) was observed when H-3 (ꢃ 3.97)
was irradiated, and 7.5% enhancement of the H-3 was observed
when H-4 was irradiated.
22
0.27 (EtOAc/hexane, 1:15); ½ꢁꢄD þ35:5 (c 1.53, CHCl3); IR
(neat) 3500 cmꢁ1
;
1H NMR (300 MHz) ꢃ 1.00 (t, 3H, J ¼ 7:6
Hz), 1.41, 1.54 (2 s, each 3H), 1.56–1.72, 1.77–1.91 (2 m, each
1H), 2.78 (dd, 1H, J ¼ 8:3, 13.7 Hz), 2.90 (dd, 1H, J ¼ 5:4,
13.7 Hz), 3.74 (d, 1H, J ¼ 3:9 Hz), 3.78 (t, 1H, J ¼ 4:9 Hz),
4.26 (ddd, 1H, J ¼ 3:9, 5.4, 8.3 Hz), 4.56, 4.66 (AB q, each
1H, J ¼ 11:2 Hz), 5.17 (dd, 1H, J ¼ 2:0, 11.0 Hz), 5.45 (dd,
1H, J ¼ 2:0, 17.2 Hz), 6.19 (dd, 1H, J ¼ 11:0, 17.2 Hz), 7.16–
(2R,3S,4R)-4-Benzyl-2-[(1R)-1-(benzyloxy)propyl]-2,3-bis-

1712 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Total Syntheses of Pseurotins and Azaspirene
(triethylsiloxy)-4-butanolide (33). The following reaction was
carried out under Ar. To a cooled (0 ꢂC) stirred solution of 32
(3.03 g, 8.50 mmol) in pyridine (100 mL) was added dropwise
triethylsilyl trifluoromethanesulfonate (4.04 mL, 17.9 mmol). Af-
ter being stirred at 50 ꢂC for 12 h, the solutꢂion was quenched with
saturated aqueous NaHCO3 (50 mL) at 0 C. The resulting mix-
ture was diluted with EtOAc (300 mL), and washed with saturated
aqueous NaHCO3 (200 mL ꢅ 2) and saturated brine (200 mL).
The organic layer was dried and concentrated in vacuo. The resi-
due was purified by column chromatography on silica gel
(EtOAc/hexane, 1:30) to provide 4.70 g (95%) of 33 as a colorless
(5S,8R,9S)-8-Benzyl-2-[(1S,2S,3Z)-1,2-bis(methoxymethoxy)-
3-hexenyl]-2-hydroxy-3-methyl-9-triethylsiloxy-1,7-dioxaspiro-
[4.4]nonane-4,6-dione (38). The following reaction was carried
ꢂ
out under Ar. To a cooled (ꢁ78 C) stirred solution of 35 (43.5
mg, 88.3 mmol) in THF (2 mL) was added dropwise potassium
bis(trimethylsilyl)amide (KHMDS) (0.5 M solution in toluene,
ꢂ
0.19 mL, 95 mmol). The solution was stirred at ꢁ78 C for 1 h,
and a solution of 29 (80.3 mg, 0.346 mmol) in THF (0.5 mL)
was added. After being stirred at ꢁ78 ꢂC for 1 h, the solution
was quenched with CSA (33.1 mg, 0.143 mmol) and H2O (1.5
mL), diluted with EtOAc (50 mL), and washed with saturated
brine (20 mL ꢅ 2). The organic layer was dried and concentrated
in vacuo. The residue was eluted through a short column of silica
gel with EtOAc/hexane (1:8), and the combined eluates were con-
centrated in vacuo to provide crude 36 (65.7 mg), which was used
in the next step without further purification. To a coold (0 ꢂC) stir-
red solution of crude 36 (65.7 mg) in pyridine (2 mL) was added a
20
oil: TLC Rf 0.69 (EtOAc/hexane, 1:15); ½ꢁꢄD þ81:1 (c 1.87,
1
CHCl3); IR (neat) 1780 cmꢁ1; H NMR (300 MHz) ꢃ 0.60–0.77
(m, 12H), 0.91 (t, 9H, J ¼ 7:9 Hz), 1.03 (t, 9H, J ¼ 7:8 Hz),
1.06 (t, 3H, J ¼ 7:3 Hz), 1.78–1.89, 1.90–2.06 (2 m, each 1H),
2.80 (dd, 1H, J ¼ 3:2, 15.1 Hz), 2.90 (dd, 1H, J ¼ 10:3, 15.1
Hz), 3.72 (dd, 1H, J ¼ 4:2, 7.6 Hz), 4.56 (d, 1H, J ¼ 7:1 Hz),
4.65, 4.82 (AB q, each 1H, J ¼ 11:2 Hz), 4.75 (ddd, 1H,
J ¼ 3:2, 7.1, 10.3 Hz), 6.97–7.01, 7.1–7.45 (2 m, 2H + 8H);
13C NMR (75 MHz) ꢃ 4:9 ꢅ 3, 5:8 ꢅ 3, 6:9 ꢅ 3, 12.0, 23.0,
35.5, 73.2, 79.8, 80.9, 81.2, 82.1, 126.3, 127:3 ꢅ 2, 127:6 ꢅ 2,
128:1 ꢅ 2, 128:3 ꢅ 2, 129.1, 138.2, 138.5, 174.3; HRMS calcd
for C33H52O5Si2 (Mþ) m=z 584.3353, found 584.3353.
dilute solution of HF pyridine complex in pyridine (1:25 v/v, 2
ꢃ
mL). The solution was stirred at room temperature for 30 min,
and additional solution of HF pyridine complex in pyridine
ꢃ
(1:25 v/v, 2 mL ꢅ 4) was added every 30 min. The solution
was stirred for total 2.5 h, and quenched with saturated aqueous
ꢂ
NaHCO3 (5 mL) at 0 C. The resulting mixture was diluted with
(2R,3S,4R)-4-Benzyl-2-[(1R)-1-hydroxypropyl]-2,3-bis(tri-
ethylsiloxy)-4-butanolide (34). A solution of 33 (2.20 g, 3.76
mmol) in EtOH (100 mL) was stirred under atmospheric H2 in
the presence of 10% Pd on charcoal (220 mg) for 3 days, and
the catalyst was removed by filtration through a Celite-pad and
washed well with EtOAc. The combined filtrate and washings
were concentrated in vacuo. The residue was purified by column
chromatography on silica gel (Et2O/hexane, 1:30) to provide
1.75 g (94%) of 34 as a colorless oil: TLC Rf 0.54 (EtOAc/
EtOAc (50 mL), and washed with saturated aqueous NaHCO3 (20
mL) and saturated brine (20 mL ꢅ 2). The organic layer was dried
and concentrated in vacuo. The residue was eluted through a short
column of silica gel with excess EtOAc/hexane (1:3), and the
eluates were concentrated in vacuo to provide crude 37 (32.4
mg), which was used in the next step without further purification.
To a cooled (0 ꢂC) stirred solution of crude 37 (32.4 mg) in
CH2Cl2 (2 mL) was added Dess–Martin periodinane (33.7 mg,
79.5 mmol). The mixture was stirred at room temperature for 6
h, diluted with EtOAc (50 mL), and washed with saturated aque-
ous Na2S2O3 (20 mL) and saturated aqueous Na2CO3 (20 mL ꢅ
2). The organic layer was dried and concentrated in vacuo. The
residue was purified by column chronatography on silica gel
(EtOAc/hexane, 1:6) to provide 23.6 mg (46% form 35) of 38
as white crystals: mp 77.5–78.1 ꢂC; TLC Rf 0.41 (EtOAc/hexane,
20
hexane, 1:15); ½ꢁꢄD þ74:8 (c 1.44, CHCl3); IR (neat) 3540,
1
1770 cmꢁ1; H NMR (300 MHz) ꢃ 0.57–0.74 (m, 12H), 0.90 (t,
9H, J ¼ 7:6 Hz), 1.02 (t, 9H, J ¼ 7:8 Hz), 1.05 (t, 3H, J ¼ 7:3
Hz), 1.46–1.77 (m, 2H), 2.85 (dd, 1H, J ¼ 2:4, 14.9 Hz), 3.03
(dd, 1H, J ¼ 10:5, 14.9 Hz), 3.35 (br s, 1H, OH), 3.88 (dd, 1H,
J ¼ 1:5, 10.7 Hz), 4.27 (d, 1H, J ¼ 4:6 Hz), 4.87 (ddd, 1H,
J ¼ 2:4, 4.6, 10.5 Hz), 7.21–7.35 (m, 5H); 13C NMR (75 MHz)
ꢃ 5:1 ꢅ 3, 5:8 ꢅ 3, 6:9 ꢅ 6, 10.4, 22.4, 35.9, 72.9, 79.6, 80.9,
83.0, 126.7, 128:6 ꢅ 2, 129:0 ꢅ 2, 137.4, 176.1; HRMS calcd
for C26H46O5Si2 (Mþ) m=z 494.2884, found 494.2883.
21
1:3); ½ꢁꢄD þ45:9 (c 1.45, CHCl3); IR (neat) 3440, 1800, 1770
cmꢁ1 1H NMR (300 MHz) ꢃ 0.64–0.73 (m, 6H), 0.96–1.02 (m,
;
12H), 1.18 (d, 3H, J ¼ 6:8 Hz), 2.08–2.28 (m, 2H), 3.03–3.10
(m, 1H), 3.19 (dq, 1H, J ¼ 1:5, 6.8 Hz), 3.36, 3.40 (2 s, each
3H), 3.41–3.51 (m, 1H), 3.74 (d, 1H, J ¼ 8:3 Hz), 4.51, 4.53 (2
d, each 1H, J ¼ 6:8 Hz), 4.69–4.80 (m, 4H), 5.07–5.14 (m, 1H),
5.24–5.33 (m, 1H), 5.62 (d, 1H, J ¼ 1:5 Hz, OH), 5.83 (dt, 1H,
J ¼ 11:0, 7.3 Hz), 7.20–7.34 (m, 5H); 13C NMR (75 MHz) ꢃ
4:6 ꢅ 3, 6:7 ꢅ 4, 14.0, 21.1, 35.7, 49.1, 56.5, 56.6, 69.8, 75.2,
77.7, 82.2, 86.0, 92.7, 98.1, 106.5, 125.3, 126.5, 128:5 ꢅ 2,
129:3 ꢅ 2, 137.8, 139.5, 170.0, 206.5; HRMS calcd for
C31H48O10Si (Mþ) m=z 608.3017, found 608.3017. NOE experi-
ment; 4.3% enhancement of the H-1 of the side chain at C-2 (ꢃ
3.74) was observed when CH3 at C-3 (ꢃ 1.18) was irradiated.
(5S,8R,9S)-8-Benzyl-2-[(1S,2S,3Z)-1,2-bis(methoxymethoxy)-
3-hexenyl]-3-methyl-9-triethylsiloxy-1,7-dioxaspiro[4.4]non-2-
ene-4,6-dione (39). To a cooled (0 ꢂC) sttired solution of 38 (996
mg, 1.64 mmol) in pyridine (50 mL) was added thionyl chloride
(2S,3S,4R)-4-Benzyl-2-propanoyl-2,3-bis(triethylsiloxy)-4-
butanolide (35). To a cooled (0 ꢂC) solution of 34 (3.25 g, 6.57
mmol) in CH2Cl2 (50 mL) was added Dess–Martin periodinane
(3.34 g, 7.87 mmol). The mixture was stirred at room temperature
for 9 h, diluted with EtOAc (300 mL), and washed with saturated
aqueous Na2S2O3 (200 mL) and saturated aqueous Na2CO3 (200
mL ꢅ 2). The organic layer was dried and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(Et2O/hexane, 1:30) to provide 3.17 g (98%) of 35 as a colorless
23
oil: TLC Rf 0.56 (EtOAc/hexane, 1:15); ½ꢁꢄD þ104 (c 2.11,
CHCl3); IR (neat) 1790, 1720 cmꢁ1 1H NMR (300 MHz) ꢃ
;
0.57–0.78 (m, 12H), 0.94 (t, 9H, J ¼ 7:8 Hz), 1.00 (t, 9H, J ¼
8:3 Hz), 1.09 (t, 3H, J ¼ 7:1 Hz), 2.71, 2.82 (2 dq, each 1H,
J ¼ 19:3, 7.1 Hz), 2.85 (dd, 1H, J ¼ 2:5, 14.9 Hz), 3.08 (dd,
1H, J ¼ 11:0, 14.9 Hz), 4.52 (d, 1H, J ¼ 6:8 Hz), 4.74 (ddd,
1H, J ¼ 2:5, 6.8, 11.0 Hz), 7.20–7.35 (m, 5H); 13C NMR (75
MHz) ꢃ 4:7 ꢅ 3, 5:8 ꢅ 3, 6:6 ꢅ 3, 6:9 ꢅ 3, 7.0, 33.5, 35.0, 80.0,
82.4, 85.6, 126.6, 128:5 ꢅ 2, 129:2 ꢅ 2, 137.7, 172.3, 209.0;
HRMS calcd for C26H44O5Si2 (Mþ) m=z 492.2727, found
492.2713.
ꢂ
(0.24 mL, 3.3 mmol). After being stirred at 0 C for 10 min, the
solution was quenched with saturated aqueous NaHCO3 (10
mL), diluted with EtOAc (200 mL), and washed with saturated
aqueous NaHCO3 (100 mL) and saturated brine (100 mL). The or-
ganic layer was dried and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/hexane,

S. Aoki et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1713
1:8) to provide 954 mg (97%) of 39 as colorless crystals: mp 56.0–
21
The residue was purified by column chromatography on silica gel
(EtOAc/hexane, 1:2) to provide 110 mg (81% from 40) of 42 and
21.1 mg (16%) of 8S-isomer. Compound 42 was obtained as a
colorless oil: TLC Rf 0.26 (EtOAc/hexane, 1:2); ½ꢁꢄD ꢁ79:2
56.3 ꢂC; TLC Rf 0.20 (EtOAc/hexane, 1:5); ½ꢁꢄD þ23:0 (c 2.09,
CHCl3); IR (neat) 1790, 1715, 1640 cmꢁ1; 1H NMR (300 MHz) ꢃ
0.51–0.69 (m, 6H), 0.94, (t, 9H, J ¼ 8:1 Hz), 1.01 (t, 3H, J ¼ 7:6
Hz), 1.79 (s, 3H), 2.09–2.27 (m, 2H), 3.19 (dd, 1H, J ¼ 2:7, 15.4
Hz), 3.31, 3.39 (2 s, each 3H), 3.65 (dd, 1H, J ¼ 11:0, 15.4 Hz),
4.57–4.68 (m, 5H), 4.71–4.78 (m, 1H), 4.83 (ddd, 1H, J ¼ 2:7,
7.3, 11.0 Hz), 5.00 (d, 1H, J ¼ 7:3 Hz), 5.35 (dd, 1H, J ¼ 9:5,
11.0 Hz), 5.78 (dt, 1H, J ¼ 11:0, 7.3 Hz), 7.21–7.35 (m, 5H);
13C NMR (75 MHz) ꢃ 4:5 ꢅ 3, 5.7, 6:6 ꢅ 3, 14.0, 21.2, 36.3,
55.8, 56.0, 71.1, 72.7, 74.2, 82.7, 89.1, 94.5, 95.1, 114.9, 125.5,
126.6, 128:5 ꢅ 2, 129:3 ꢅ 2, 137.6, 138.6, 166.3, 183.4, 195.4;
HRMS calcd for C30H43O8Si (Mþ ꢁ OCH3) m=z 559.2727, found
559.2722.
23
(c 1.02, CHCl3); IR (neat) 3280, 1730, 1680, 1620 cmꢁ1; 1H NMR
(300 MHz) ꢃ 1.00 (t, 3H, J ¼ 7:3 Hz), 1.81 (s, 3H), 2.07–2.25 (m,
2H), 2.97 (d, 1H, J ¼ 13:7 Hz), 3.30, 3.36, 3.41 (3 s, each 3H),
3.36 (d, 1H, J ¼ 13:7 Hz), 4.50 (s, 1H), 4.54–4.61, 4.64–4.75 (2
m, 3H + 4H), 4.76 (dd, 1H, J ¼ 7:6, 9.5 Hz), 5.33 (dd, 1H,
J ¼ 9:5, 11.0 Hz), 5.79 (dt, 1H, J ¼ 11:0, 7.6 Hz), 5.97 (br s,
1H, OH), 6.30 (br s, 1H, NH), 7.28–7.38 (m, 5H); 13C NMR (75
MHz) ꢃ 5.6, 14.0, 21.3, 43.6, 55.6, 56.0, 56.2, 71.3, 74.0, 79.0,
84.7, 92.9, 94.2, 95.3, 96.6, 114.2, 125.2, 127.6, 128:7 ꢅ 2,
130:5 ꢅ 2, 134.5, 138.9, 163.2, 187.5, 199.9; HRMS calcd for
C27H35NO9 (Mþ ꢁ H2O) m=z 517.2311, found 517.2305. NOE
experiment; 10.1% enhancement of the H-9 (ꢃ 4.50) was observed
when CHHPh (ꢃ 2.97) was irradiated, and 5.8% enhancement of
the CHHPh was observed when H-9 was irradiated. 8S-Isomer
was obtained as a colorless oil: TLC Rf 0.11 (EtOAc/hexane,
(5S,8R,9S)-8-Benzyl-2-[(1S,2S,3Z)-1,2-bis(methoxymethoxy)-
3-hexenyl]-9-methoxymethoxy-3-methyl-1,7-dioxaspiro[4.4]-
non-2-ene-4,6-dione (40). To a cooled (0 ꢂC) stirred solution of
39 (153 mg, 259 mmol) in pyridine (10 mL) was added dropwise
HF pyridine complex (1 mL). After being stirred at room temper-
ꢃ
20
ature for 3 h, the solution was quenched with saturated aqueous
NaHCO3 (10 mL), diluted with EtOAc (80 mL), and washed with
saturated aqueous NaHCO3 (30 mL) and saturated brine (30 mL).
The organic layer was dried and concentrated in vacuo to give a
crude alcohol derivative (139 mg), which was used directly in
the next step. To a cooled (0 ꢂC) stirred suspension of P2O5
(185 mg, 1.30 mmol) in CH2(OMe)2 (5 mL) was added a solution
of crude alcohol derivative (139 mg) in CH2Cl2 (1 mL). After be-
ing stirred at 0 ꢂC for 1.5 h, the mixture was quenched with satu-
rated aqueous Na2CO3 (5 mL), diluted with EtOAc (50 mL), and
washed with saturated aqueous Na2CO3 (20 mL) and saturated
brine (20 mL). The organic layer was dried and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:4) to provide 131 mg (98% from
39) of 40 as a colorless oil: TLC Rf 0.66 (EtOAc/hexane, 1:1);
1:2); ½ꢁꢄD þ32:3 (c 0.500, CHCl3); IR (neat) 3400, 3260,
1
1730, 1690, 1635 cmꢁ1; H NMR (300 MHz) ꢃ 1.01 (t, 3H, J ¼
7:6 Hz), 1.81 (s, 3H), 2.09–2.27 (m, 2H), 3.14 (dd, 1H, J ¼
13:9 Hz), 3.31, 3.37, 3.39 (3 s, each 3H), 3.90 (dd, 1H, J ¼
13:9 Hz), 4.57–4.75 (m, 8H), 4.78 (dd, 1H, J ¼ 7:8, 9.5 Hz),
5.35 (dd, 1H, J ¼ 9:5, 11.0 Hz), 5.78 (dt, 1H, J ¼ 11:0, 7.3
Hz), 5.97 (br s, 1H, OH), 7.27–7.38 (m, 5H); 13C NMR (75
MHz) ꢃ 5.6, 14.1, 21.3, 42.2, 55.6, 55.9, 56.3, 71.2, 73.8, 85.5,
86.5, 91.3, 94.2, 95.1, 97.1, 114.2, 125.4, 127.4, 128:8 ꢅ 2,
130:8 ꢅ 2, 134.5, 138.7, 163.2, 184.7, 197.6; HRMS calcd for
C27H35NO9 (Mþ ꢁ H2O) m=z 517.2311, found 517.2319.
(5S,8S,9R)-8-Benzoyl-2-[(1S,2S,3Z)-1,2-bis(methoxymeth-
oxy)-3-hexenyl]-8-hydroxy-9-methoxymethoxy-3-methyl-1-oxa-
7-azaspiro[4.4]non-2-ene-4,6-dione (44). A solution of 42 (24.5
mg, 45.7 mmol) in 5% AcOH in i-PrOH (5 mL) was stirred at 70
ꢂC for 66 h, and concentrated in vacuo to provide crude enamide
43 (27.7 mg) as a 5:4 geometric mixture (1H NMR analysis),
which was used directly in the next step. In a small-scale experi-
ment, a pure inseparable geometric mixture of 43 was obtained by
column chromatography on silica gel (EtOAc/hexane, 2:5) as a
colorless oil: TLC Rf 0.27 (EtOAc/hexane, 1:2); IR (neat) 3260,
21
½ꢁꢄD þ38:5 (c 0.60, CHCl3); IR (neat) 1790, 1710, 1640
cmꢁ1
;
1H NMR (300 MHz) ꢃ 1.01 (t, 3H, J ¼ 7:6 Hz), 1.83 (s,
3H), 2.08–2.26 (m, 2H), 3.30, 3.31, 3.37 (3 s, each 3H), 3.31
(dd, 1H, J ¼ 3:4, 15.1 Hz), 3.64 (dd, 1H, J ¼ 10:0, 15.1 Hz),
4.53–4.63 (m, 5H), 4.67 (d, 1H, J ¼ 6:6 Hz), 4.69 (d, 1H, J ¼
7:1 Hz), 4.71–4.78 (m, 1H), 4.91 (d, 1H, J ¼ 7:8 Hz), 4.98
(ddd, 1H, J ¼ 3:4, 7.8, 10.0 Hz), 5.33 (dd, 1H, J ¼ 9:5, 11.0
Hz), 5.79 (dt, 1H, J ¼ 11:0, 7.6 Hz), 7.21–7.35 (m, 5H); 13C NMR
(75 MHz) ꢃ 5.7, 14.1, 21.3, 36.5, 55.7, 56.0, 56.5, 71.2, 73.5, 78.1,
81.2, 88.3, 94.1, 95.3, 97.2, 114.5, 125.2, 126.7, 128:5 ꢅ 2,
129:4 ꢅ 2, 137.2, 138.9, 165.9, 184.3, 195.6; HRMS calcd for
C26H33O9 (Mþ ꢁ OCH3) m=z 489.2124, found 489.2118.
1750, 1695, 1635 cmꢁ1
;
1H NMR (300 MHz) ꢃ 0.99 (t, 3H ꢅ
4/9, J ¼ 7:3 Hz), 1.02 (t, 3H ꢅ 5/9, J ¼ 7:3 Hz), 1.81 (s, 3H ꢅ
5/9), 1.82 (s, 3H ꢅ 4/9), 2.12–2.26 (m, 2H), 3.32, 3.33,
3.38, 3.40, 3.43 (5 s, 3H ꢅ 4/9 + 3H ꢅ 5/9 + 3H ꢅ 4/9 + 3H +
3H ꢅ 5/9), 4.53–4.83 (m, 8H), 4.91 (s, 1H ꢅ 4/9), 5.28 (d, 1H ꢅ
5/9, J ¼ 1:7 Hz), 5.32–5.42 (m, 1H), 5.80 (dt, 1H, J ¼ 10:7,
7.3 Hz), 5.93 (s, 1H ꢅ 4/9), 5.96 (d, 1H ꢅ 5/9, J ¼ 1:7 Hz),
7.24–7.31, 7.35–7.41 (2 m, 3H + 2H), 7.79 (br s, 1H ꢅ 4/9,
NH), 7.81 (br s, 1H ꢅ 5/9, NH); HRMS calcd for C27H35NO9
(Mþ) m=z 517.2311, found 517.2307. The following reaction
was carried out under Ar. To a stirred solution of crude enamide
43 (27.7 mg) in CH2Cl2 (2 mL) was added a 50 mM m-CPBA
solution in CH2Cl2 (3.66 mL, 183 mmol). After being stirred at
room temperature for 5 h, the solution was diluted with EtOAc
(15 mL), and washed with saturated aqueous Na2SO3 (5 mL), sat-
urated aqueous NaHCO3 (5 mL) and saturated brine (5 mL). The
organic layer was dried and concentrated in vacuo. The residue
was eluted through a short column on silica gel with EtOAc/hex-
ane (1:1), and the combined eluates were concentrated in vacuo to
give a crude product (10.5 mg), which was used in the next step
without further purification. To a cooled (0 ꢂC) stirred solution
of crude benzyl alcohol (10.5 mg) in CH2Cl2 (2 mL) was added
(5S,8R,9R)-8-Benzyl-2-[(1S,2S,3Z)-1,2-bis(methoxymethoxy)-
3-hexenyl]-8-hydroxy-9-methoxymethoxy-3-methyl-1-oxa-7-
azaspiro[4.4]non-2-ene-4,6-dione (42) and 8S-Isomer. To a
stirred solution of 40 (131 mg, 252 mmol) in i-PrOH (10 mL)
was added saturated NH3 in i-PrOH (6 mL). After being stirred
at room temperature for 3 h, the solution was concentrated in va-
cuo to provide a crude amide derivative (140 mg), which was used
ꢂ
directly in the next step. To a cooled (0 C) stirred solution of a
crude amide derivative (140 mg) in CH2Cl2 (10 mL) was added
Dess–Martin periodinane (132 mg, 311 mmol). The mixture was
stirred for 6 h at room temperature, diluted with EtOAc (100
mL), and washed with saturated aqueous Na2S2O3 (40 mL) and
saturated aqueous Na2CO3 (40 mL ꢅ 2). Saturated aqueous
Na2CO3 (50 mL) was added to the resulting organic layer, and
the mixture was vigorously stirred for 10 h. The layers were sep-
arated and the organic layer was dried and concentrated in vacuo.

1714 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Total Syntheses of Pseurotins and Azaspirene
Dess–Martin periodinane (16.1 mg, 38.0 mmol). The mixture was
stirred for at room temperature for 11 h, diluted with EtOAc (10
mL), and washed with saturated aqueous Na2S2O3 (5 mL) and sat-
urated aqueous Na2CO3 (5 mL ꢅ 2). The organic layer was dried
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 2:5) to provide
9.3 mg (37% from 42) of 44 as a colorless oil: TLC Rf 0.49
1H, NH), 8.32 (d, 2H, J ¼ 7:3 Hz); 13C NMR (75 MHz) ꢃ 6.1,
14.1, 21.4, 51.7, 70.6, 70.9, 73.0, 90.3, 92.8, 113.4, 126.4,
128:7 ꢅ 2, 130:7 ꢅ 2, 132.3, 134.8, 136.8, 166.6, 185.8, 195.1,
196.3; HRMS calcd for C21H21NO7 (Mþ ꢁ CH3OH) m=z
399.1318, found 399.1318. NOE experiment; 4.5% enhancement
of the H-2,6 of the benzoyl group (ꢃ 8.32) was observed when
H-9 (ꢃ 4.70) was irradiated, and 5.4% enhancement of the H-9
was observed when H-2,6 of the benzoyl group was irradiated.
No enhancement of the H-9 (ꢃ 4.70) was observed when OCH3
(ꢃ 3.44) was irradiated.
(2S,3S,4R)-4-Benzyl-2-hydroxy-2-[(4E,6E)-3-hydroxy-2-
methylnona-4,6-dienoyl]-3-triethylsiloxy-4-butanolide (47).
The following reaction was carried out under Ar. To a cooled
(ꢁ78 ꢂC) stirred solution of 35 (251 mg, 509 mmol) in THF (8
mL) was added dropwise potassium bis(trimethylsilyl)amide
(KHMDS) (0.5 M solution in toluene, 1.0 mL, 0.51 mmol). The
solution was stirred at ꢁ78 ꢂC for 1 h, and a solution of
(2E,4E)-2,4-heptadienal (45) (355 mL, 2.54 mmol) and anhydrous
LiBr (265 mg, 3.05 mmol) in THF (2 mL) were added. After being
stirred at ꢁ78 ꢂC for 1 h, the solution was quenched with saturated
aqueous NH4Cl (5 mL). The resulting mixture was diluted with
EtOAc (50 mL), and washed with saturated aqueous NH4Cl (30
mL) and saturated brine (30 mL). The organic layer was dried
and concentrated in vacuo. The residue was eluted through a short
column of silica gel with excess EtOAc/hexane (1:30), and the
combined eluates were concentrated in vacuo to provide a crude
aldol product 46 (261 mg), which was used in the next step with-
out further purification. To a cooled (0 ꢂC) stirred solution of
crude aldol product 46 (261 mg) in pyridine (5 mL) was added
25
(EtOAc/hexane, 1:1); ½ꢁꢄD ꢁ68:7 (c 0.225, CHCl3); IR (neat)
3260, 1750, 1695, 1680, 1620 cmꢁ1 1H NMR (300 MHz) ꢃ
;
1.01 (t, 3H, J ¼ 7:6 Hz), 1.86 (s, 3H), 2.07–2.27 (m, 2H), 3.17,
3.32, 3.38 (3 s, each 3H), 4.56–4.69 (m, 6H), 4.74 (d, 1H, J ¼
6:8 Hz), 4.80 (dd, 1H, J ¼ 6:8, 9.5 Hz), 5.13 (s, 1H), 5.36 (dd,
1H, J ¼ 9:5, 11.0 Hz), 5.80 (dt, 1H, J ¼ 11:0, 7.6 Hz), 6.61 (s,
1H, OH), 6.83 (br s, 1H, NH), 7.49 (t, 2H, J ¼ 7:3 Hz), 7.62 (t,
1H, J ¼ 7:3 Hz), 8.34 (d, 2H, J ¼ 7:3 Hz); 13C NMR (75 MHz)
ꢃ 5.7, 14.0, 21.3, 55.7, 56.0, 56.4, 71.5, 74.1, 75.8, 87.9, 92.6,
94.2, 95.3, 96.5, 114.3, 125.2, 128:6 ꢅ 2, 130:9 ꢅ 2, 133.1,
134.1, 138.9, 163.0, 188.3, 192.2, 199.8; HRMS calcd for
C27H34NO10 (Mþ ꢁ OH) m=z 532.2183, found 532.2183. NOE
experiment; 1.7% enhancement of the H-2,6 of the benzoyl group
(ꢃ 8.34) was observed when H-9 (ꢃ 5.13) was irradiated, and 1.4%
enhancement of the H-9 was observed when H-2,6 of the benzoyl
group was irradiated.
(5S,8S,9R)-8-Benzoyl-2-[(1S,2S,3Z)-1,2-dihydroxy-3-hex-
enyl]-8,9-dihydroxy-3-methyl-1-oxa-7-azaspiro[4.4]non-2-ene-
4,6-dione (Pseurotin F2) (2). Compound 44 (9.3 mg, 17 mmol)
was dissolved in 6 M HCl/MeOH (1:1 v/v, 1 mL). After being stir-
red at room temperature for 8 h, the solution was concentrated in
vacuo. The residue was purified by column chromatography on sili-
ca gel (EtOAc/hexane, 1:1) to provide 6.3 mg (89%) of 2 as color-
less crystals: mp 94.4–95.0 ꢂC; TLC Rf 0.29 (acetone/PhMe, 1:2);
a dilute solution of HF pyridine complex in pyridine (1:125 v/
ꢃ
v, 2 mL). The solution was stirred at room temperature for 1 h,
and an additional solution of HF pyridine complex in pyridine
25
20
½ꢁꢄD þ78:0 (c 0.165, CHCl3); ½ꢁꢄD ꢁ31:4 (c 0.100, MeOH); IR
(neat) 3380, 3300, 1730, 1695, 1630 cmꢁ1; 1H NMR (300 MHz) ꢃ
1.01 (t, 3H, J ¼ 7:6 Hz), 1.69 (s, 3H), 2.03–2.24 (m, 2H), 4.64 (d,
1H, J ¼ 4:2 Hz), 4.78 (dd, 1H, J ¼ 4:2, 8.9 Hz), 4.87 (s, 1H), 5.16
(dd, 1H, J ¼ 8:9, 11.0 Hz), 5.57 (dt, 1H, J ¼ 11:0, 7.3 Hz), 6.83
(s, 1H, OH), 7.49 (t, 2H, J ¼ 7:3 Hz), 7.64 (t, 1H, J ¼ 7:3 Hz),
8.40 (d, 2H, J ¼ 7:3 Hz), 8.55 (br s, 1H, NH); 13C NMR (75
MHz) ꢃ 6.3, 14.1, 21.4, 70.8, 71.6, 71.7, 89.1, 94.8, 113.0,
126.2, 128:6 ꢅ 2, 131:4 ꢅ 2, 133.0, 134.6, 136.5, 164.8, 188.9,
193.8, 198.8; HRMS calcd for C21H21NO7 (Mþ ꢁ H2O) m=z
399.1318, found 399.1318. NOE experiment; 2.1% enhancement
of the H-2,6 of the benzoyl group (ꢃ 8.40) was observed when
H-9 (ꢃ 4.87) was irradiated, and 2.6% enhancement of the H-9
was observed when H-2,6 of the benzoyl group was irradiated.
(5S,8S,9R)-8-Benzoyl-2-[(1S,2S,3Z)-1,2-dihydroxy-3-hexen-
yl]-9-hydroxy-8-methoxy-3-methyl-1-oxa-7-azaspiro[4.4]non-
2-ene-4,6-dione (Pseurotin A) (1). To a stirred solution of 2 (5.2
mg, 13 mmol) in MeOH (1 mL) was added CSA (4.3 mg, 19
mmol). After being stirred at 40 ꢂC for 8 h, the solution was neu-
tralized with saturated aqueous NaHCO3, diluted with saturated
brine (5 mL), and extracted with EtOAc (5 mL ꢅ 5). The com-
bined extracts were dried and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (EtOAc/
hexane, 1:1) to provide 2.2 mg (41%) of 1 as colorless crystals:
ꢃ
(1:125 v/v, 2 mL ꢅ 2) was added every 1 h. The solution was stir-
red for a total of 3 h, and quenched with saturated aqueous
NaHCO3 (15 mL). The resulting mixture was diluted with EtOAc
(100 mL), and washed with saturated aqueous NaHCO3. The res-
idue was purified by column chromatography on silica gel
(EtOAc/hexane, 1:20 to 1:6) to provide 146 mg (59% from 35)
of 47 as a colorless oil: TLC Rf 0.19 (EtOAc/hexane, 1:6);
26
½ꢁꢄD þ83:8 (c 1.99, CHCl3); IR (neat) 3300, 1790, 1720
cmꢁ1 1H NMR (300 MHz) ꢃ 0.64–0.75 (m, 6H), 0.95–1.06 (m,
;
15H), 2.06–2.19 (m, 2H), 2.91 (dd, 1H, J ¼ 2:5, 14.7 Hz), 3.18
(dd, 1H, J ¼ 10:5, 14.7 Hz), 3.88 (dq, 1H, J ¼ 5:0, 6.8 Hz),
4.27 (dd, 1H, J ¼ 5:0, 9.2 Hz), 4.72 (ddd, 1H, J ¼ 2:5, 8.2,
10.5 Hz), 4.76 (d, 1H, J ¼ 8:2 Hz), 5.48 (dd, 1H, J ¼ 9:2, 14.9
Hz), 5.82 (dt, 1H, J ¼ 14:9, 6.6 Hz), 6.06 (dd, 1H, J ¼ 10:5,
14.9 Hz), 6.20 (dd, 1H, J ¼ 10:5, 14.9 Hz), 7.19–7.34 (m, 5H);
13C NMR (75 MHz) ꢃ 4:6 ꢅ 3, 6:6 ꢅ 3, 12.3, 13.2, 25.6, 34.7,
45.3, 76.8, 77.9, 82.2, 84.4, 126.3, 126.5, 128.0, 128:4 ꢅ 2,
129:3 ꢅ 2, 135.8, 137.9, 138.9, 174.1, 211.0; HRMS calcd for
C27H40O6Si (Mþ) m=z 488.2594, found 488.2599.
(5S,8R,9S)-8-Benzyl-2-[(1E,3E)-hexa-1,3-dienyl]-3-methyl-
9-triethylsiloxy-1,7-dioxaspiro[4.4]non-2-ene-4,6-dione (48)
and (1S,6R,9R)-9-Benzyl-3-[(1E,3E)-hexa-1,3-dienyl]-4-meth-
yl-6-triethylsiloxy-2,8-dioxabicyclo[4.3.0]non-3-ene-5,7-dione
(49). To a cooled (0 ꢂC) stirred solution of 47 (160 mg, 326
mmol) in CH2Cl2 (5 mL) was added Dess–Martin periodinane
(277 mg, 653 mmol). The mixture was stirred at room temperature
for 3 h, diluted with EtOAc (50 mL), and washed with saturated
aqueous Na2S2O3 (15 mL) and saturated aqueous NaHCO3 (15
mL ꢅ 2). The organic layer was dried and concentrated in vacuo.
The residue was eluted through a short column of silica gel with
25
mp 126.0–126.9 ꢂC; TLC Rf 0.50 (acetone/PhMe, 1:1); ½ꢁꢄD
24
þ70:8 (c 0.110, CHCl3); ½ꢁꢄD ꢁ8:1 (c 0.110, MeOH); IR (neat)
3400, 3280, 1730, 1680, 1635 cmꢁ1; H NMR (300 MHz) ꢃ 0.99
1
(t, 3H, J ¼ 7:6 Hz), 1.68 (s, 3H), 2.05–2.24 (m, 2H), 3.44 (s, 3H),
4.59 (d, 1H, J ¼ 4:4 Hz), 4.70 (s, 1H), 4.75 (dd, 1H, J ¼ 4:4, 9.0
Hz), 5.28 (dd, 1H, J ¼ 9:0, 11.0 Hz), 5.60 (dt, 1H, J ¼ 11:0, 7.6
Hz), 7.49 (t, 2H, J ¼ 7:3 Hz), 7.65 (t, 1H, J ¼ 7:3 Hz), 8.27 (br s,

S. Aoki et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1715
EtOAc/hexane (1:10), and the combined eluates were concentrat-
ed in vacuo to provide a crude mixture of 1,7-dioxaspiro[4.4]no-
nane derivative and 2,8-dioxabicyclo[4.3.0]nonane derivative
(121 mg), which was used in the next step without further purifi-
4H); 13C NMR (75 MHz) ꢃ 5.8, 12.9, 26.3, 36.5, 56.2, 77.8,
81.0, 88.1, 96.9, 110.8, 114.8, 126.6, 128.4, 128:5 ꢅ 2,
129:4 ꢅ 2, 137.4, 140.3, 147.2, 167.1, 179.5, 194.3; HRMS calcd
for C23H26O6 (Mþ) m=z 398.1729, found 398.1729.
ꢂ
cation. To a cooled (0 C) stirred solution of a crude mixture of
1,7-dioxaspiro[4.4]nonane derivative and 2,8-dioxabicyclo[4.3.0]-
nonane derivative (121 mg) in pyridine (3 mL) was added thionyl
(5S,8R,9R)-8-Benzyl-2-[(1E,3E)-hexa-1,3-dienyl]-8-hydroxy-
9-methoxymethoxy-3-methyl-1-oxa-7-azaspiro[4.4]non-2-ene-
ꢂ
4,6-dione (51). To a cooled (0 C) stirred solution of 50 (29.1
mg, 73.0 mmol) in i-PrOH (2 mL) was added saturated NH3 in
i-PrOH (4 mL). After being stirred at 0 C for 1 h, the solution
ꢂ
chloride (48.0 mL, 658 mmol). After being stirred at 0 C for 30
ꢂ
min, the solution was quenched with saturated aqueous NaHCO3
(3 mL), diluted with EtOAc (50 mL), and washed with saturated
aqueous NaHCO3 (15 mL) and saturated brine (15 mL). The or-
ganic layer was dried and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (EtOAc/
hexane, 1:30) to provide 63.5 mg (42% from 47) of 48 and 36.7
mg (24%) of 49. Compound 48 was obtained as a colorless oil:
was concentrated in vacuo to provide a crude amide derivative
(31.8 mg), which was used directly in the next step. To a cooled
(0 ꢂC) stirred solution of a crude amide derivative (31.8 mg) in
CH2Cl2 (3 mL) was added Dess–Martin periodinane (62.0 mg,
146 mmol). The mixture was stirred for 4 h, diluted with EtOAc
(50 mL), and washed with saturated aqueous Na2S2O3 (10 mL)
and saturated aqueous Na2CO3 (10 mL ꢅ 2). A saturated aqueous
Na2CO3 (20 mL) was added to the resulting organic layer, and the
mixture was vigorously stirred for 3 h. The layers were separated
and the organic layer was dried and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(EtOAc/hexane, 1:3) to provide 25.8 mg (85% from 50) of 51
as yellow crystals: mp 141.7–142.2 ꢂC; TLC Rf 0.41 (EtOAc/
24
TLC Rf 0.39 (EtOAc/hexane, 1:6); ½ꢁꢄD þ18:0 (c 1.58, CHCl3);
IR (neat) 1790, 1695, 1680, 1650, 1635, 1615 cmꢁ1 1H NMR
;
(300 MHz) ꢃ 0.48–0.57 (m, 6H), 0.88 (t, 9H, J ¼ 7:8 Hz), 1.08
(t, 3H, J ¼ 7:3 Hz), 1.78 (s, 3H), 2.20–2.36 (m, 2H), 3.30 (dd,
1H, J ¼ 3:4, 15.4 Hz), 3.75 (dd, 1H, J ¼ 10:7, 15.4 Hz), 4.84
(ddd, 1H, J ¼ 3:4, 8.1, 10.7 Hz), 5.03 (d, 1H, J ¼ 8:1 Hz),
6.17–6.37 (m, 3H), 7.16 (dd, 1H, J ¼ 9:3, 15.1 Hz), 7.27–7.34
(m, 5H); 13C NMR (75 MHz) ꢃ 4:4 ꢅ 3, 5.6, 6:4 ꢅ 3, 12.8, 26.2,
36.3, 74.1, 82.5, 89.1, 110.9, 114.8, 126.5, 128:4 ꢅ 3, 129:4 ꢅ 2,
137.9, 139.9, 146.8, 167.5, 179.2, 194.2; HRMS calcd for
C27H36O5Si (Mþ) m=z 468.2332, found 468.2332. Compound
49 was obtained as a colorless oil: TLC Rf 0.31 (EtOAc/hexane,
21
hexane, 1:1); ½ꢁꢄD ꢁ87:4 (c 0.450, CHCl3); IR (neat) 3280,
1730, 1715, 1680, 1615 cmꢁ1 1H NMR (300 MHz) ꢃ 1.06 (t,
;
3H, J ¼ 7:6 Hz), 1.78 (s, 3H), 2.18–2.29 (m, 2H), 3.00, 3.35
(AB q, each 1H, J ¼ 13:7 Hz), 3.33 (s, 3H), 4.46 (s, 1H), 4.66
(s, 2H), 6.22–6.36 (m, 3H), 7.27–7.39 (m, 6H); 13C NMR (75
MHz) ꢃ 5.7, 12.8, 26.3, 43.6, 56.2, 79.4, 84.8, 92.3, 96.9, 110.7,
114.6, 127.5, 128.4, 128:7 ꢅ 2, 130:5 ꢅ 2, 134.6, 141.4, 148.0,
164.8, 182.1, 198.0; HRMS calcd for C23H27NO6 (Mþ) m=z
413.1838, found 413.1847.
28
1:6); ½ꢁꢄD þ126 (c 0.620, CHCl3); IR (neat) 1790, 1690, 1680,
1650, 1630, 1610 cmꢁ1 1H NMR (300 MHz) ꢃ 0.56–0.68 (m,
;
6H), 0.95 (t, 9H, J ¼ 7:9 Hz), 1.09 (t, 3H, J ¼ 7:6 Hz), 1.76 (s,
3H), 2.20–2.32 (m, 2H), 2.93 (dd, 1H, J ¼ 4:1, 14.9 Hz), 3.22
(dd, 1H, J ¼ 9:3, 14.9 Hz), 4.48 (d, 1H, J ¼ 3:3 Hz), 5.31 (ddd,
1H, J ¼ 3:3, 4.1, 9.3 Hz), 6.17–6.39 (m, 3H), 7.22–7.35 (m,
6H); 13C NMR (75 MHz) ꢃ 4:7 ꢅ 3, 5.8, 6:7 ꢅ 3, 12.8, 26.3,
35.3, 74.3, 82.4, 89.6, 110.0, 114.6, 126.8, 128.4, 128:6 ꢅ 2,
129:2 ꢅ 2, 136.5, 140.9, 147.4, 168.0, 179.9, 195.7; HRMS calcd
for C27H36O5Si (Mþ) m=z 468.2332, found 468.2334.
(5S,7R,8R)-8-Benzyl-2-[(1E,3E)-hexa-1,3-dienyl]-8,9-dihy-
droxy-3-methyl-1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione
(Azaspirene) (5). Compound 51 (4.4 mg, 11 mmol) was dis-
solved in 6 M HCl/MeOH (1:1 v/v, 1 mL). After being stirred
at room temperature for 10 h, the solution was concentrated in va-
cuo. The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:2, then MeOH/CHCl3, 1:25) to provide 2.0
(5S,8R,9S)-8-Benzyl-2-[(1E,3E)-hexa-1,3-dienyl]-9-methoxy-
methoxy-3-metꢂhyl-1,7-dioxaspiro[4.4]non-2-ene-4,6-dione (50).
To a cooled (0 C) stirred solution of 48 (50.0 mg, 107 mmol) in
ꢂ
mg (51%) of 5 as yellow crystals: mp 165.5–166.0 C; TLC Rf
23
0.38 (EtOAc/hexane, 1:1); ½ꢁꢄD ꢁ204 (c 0.100, MeOH); IR
1
pyridine (5 mL) was added dropwise HF pyridine complex (0.5
(KBr) 3250, 1735, 1715, 1675, 1610 cmꢁ1; H NMR (300 MHz)
ꢃ
mL). After being stirred at room temperature for 6 h, the solution
was quenched with saturated aqueous NaHCO3 (10 mL), diluted
with EtOAc (80 mL), and washed with saturated aqueous
NaHCO3 (30 mL) and saturated brine (30 mL). The organic layer
was dried and concentrated in vacuo to provide a crude alcohol
derivative (38.8 mg), which was used directly in the next step.
To a cooled (0 ꢂC) stirred suspension of P2O5 (75.7 mg, 533
mmol) in CH2(OMe)2 (3 mL) was added a solution of crude alco-
hol derivative (38.8 mg) in CH2Cl2 (1 mL). After being stirred at
ꢃ 1.07 (t, 3H, J ¼ 7:3 Hz), 1.76 (s, 3H), 2.24 (dq, 2H, J ¼ 4:6,
7.3 Hz), 2.96, 3.27 (2 d, each 1H, J ¼ 13:9 Hz), 2.98 (d, 1H, J ¼
10:0 Hz, OH), 4.50 (d, 1H, J ¼ 10:0 Hz), 6.02 (br s, 1H, OH),
6.23–6.36 (m, 3H), 6.56 (br s, 1H, NH), 7.25–7.38 (m, 6H);
13C NMR (75 MHz) ꢃ 5.6, 12.8, 26.3, 42.8, 74.7, 84.5, 93.2,
110.6, 114.6, 127.6, 128.4, 128:8 ꢅ 2, 130:4 ꢅ 2, 134.2, 142.1,
148.3, 165.0, 183.3, 198.4; HRMS calcd for C21H23NO5 (Mþ)
m=z 369.1576, found 369.1572.
0
ꢂC for 2 h, the mixture was quenched with saturated aqueous
We thank Nippon Kayaku Co., Ltd. for providing us copies
of the spectra and a sample of natural pseurotin A (1). We
thank Drs. Hiroyuki Osada and Hideaki Kakeya (RIKEN) for
providing us copies of the spectra and a sample of natural aza-
spirene (5). We also thank Taisho Pharmaceutical Co., Ltd. for
participating in useful discussions.
Na2CO3 (5 mL), diluted with EtOAc (50 mL), and washed with
saturated aqueous Na2CO3 (15 mL) and saturated brine (15
mL). The organic layer was dried and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:5) to provide 30.5 mg (72% from 48) of
28
50 as a colorless oil: TLC Rf 0.51 (EtOAc/hexane, 1:2); ½ꢁꢄD
þ81:3 (c 0.335, CHCl3); IR (neat) 1790, 1695, 1615 cmꢁ1
;
1H NMR (300 MHz) ꢃ 1.07 (t, 3H, J ¼ 7:3 Hz), 1.81 (s, 3H),
2.17–2.30 (m, 2H), 3.25 (s, 3H), 3.34 (dd, 1H, J ¼ 4:4, 15.1
Hz), 3.72 (dd, 1H, J ¼ 9:5, 15.1 Hz), 4.54 (s, 2H), 4.90–5.03
(m, 2H), 6.20–6.37 (m, 3H), 7.13–7.24, 7.28–7.34 (2 m, 2H +
References
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8
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Preliminary communication on part of the results described
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1
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34 We also explored the following reaction conditions for this
aldol coupling. After treating 35 with 1.0 molar amount of
KHMDS, 5.0 molar amounts of 45 were added with 5.0 molar
equiv of chlorotriethylsilane33a,b in THF or THF/PhMe (1:1 v/
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J. Org. Chem., 47, 1243 (1982). c) C. Bernardon and A. Deberly,
J. Chem. Soc., Perkin Trans. 1, 1980, 2631.
35 We suppose that the O-TES group in 47 migrated to the
tertiary hydroxy group in the oxidation step. Then the liberated
secondary hydroxy group attacked to the formed carbonyl, pro-
ducing 49 after dehydration. To suppress the formation of 49,
we examined a variety of oxidation conditions. However, the ratio
of 48 to 49 was approximately 2:1 in all cases.