Total synthesis of pteridic acids A and B

Article abstract of DOI:10.1002/chem.200600134

Pteridic acid A (1) is a spirocyclic octaketide produced by the phytoepiphytic actinomycete Streptomyces hygroscopicus TP-A0451 and possesses potent plant-growth-promoting activity comparable to that of indole-3-acetic acid. The enantioselective total syn

Full text of DOI:10.1002/chem.200600134

DOI: 10.1002/chem.200600134
Total Synthesis of Pteridic Acids A and B
Takashi Nakahata, Shohei Fujimura, and Shigefumi Kuwahara*[a]
Abstract: Pteridic acid A (1) is a spiro-
cyclic octaketide produced by the phy-
toepiphytic actinomycete Streptomyces
hygroscopicus TP-A0451 and possesses
potent plant-growth-promoting activity
comparable to that of indole-3-acetic
acid. The enantioselective total synthe-
sis of this natural product was achieved
ma acetylenic coupling reaction as the
libration of an anomerically favored
spirocyclic intermediate used for the
synthesis of 1 brought about partial ep-
imerization of the spirocenter to give
the corresponding anomerically disfa-
vored epimer, which was converted
into pteridic acid B (11-epi-1), another
plant-growth promoter of the same mi-
crobial origin.
À
key C C bond-forming steps producing
1 through a 14-step sequence in 22%
overall yield from a known oxazolidi-
none derivative. MgBr2-mediated equi-
Keywords:
natural products
aldol
reaction
polyketides
·
·
·
by employing the SnACTHRE(UNG OTf)2-mediated
Evans aldol reaction and the Fukuya-
pteridic acid · total synthesis
Introduction
extensive spectroscopic analyses including HMBC and
NOESY experiments.[1] These two epimeric octaketides both
exhibited potent promoting activity in the formation of ad-
ventitious roots in the hypocotyls of kidney beans compara-
ble to that of indole-3-acetic acid (a natural plant hormone,
auxin) at an extremely low concentration of 1 nm. This is the
lowest value so far reported for the plant-growth-promoting
activity of microbial secondary metabolites,[2] which might
allow us to envisage the presence of a symbiosis-like interre-
lationship between phytoepiphytic actinomycetes and their
host plants by secondary metabolites.[3] Our interest in such
substantial biological roles of secondary metabolites of mi-
crobial origin in the natural ecosystem and in complex mo-
lecular architectures featuring a spiroacetal ring bearing
eight stereogenic centers around it prompted us to embark
on the total synthesis of pteridic acids, and our synthetic ef-
forts recently culminated in the first enantioselective total
synthesis of pteridic acid A (1).[4] We describe herein a full
account of our synthetic study on 1, together with the con-
version of its synthetic intermediate into the other plant-
growth promoter, pteridic acid B (2).
In the course of screening for plant-growth regulators pro-
duced by epiphytic microorganisms on live plants, Igarashi
and co-workers discovered two novel spirocyclic polyketides,
pteridic acids A (1) and B (2, 11-epi-1), from the fermenta-
tion broth of the actinomycete Streptomyces hygroscopicus
TP-A0451, isolated from the stems of the bracken Pteridium
aquilinum and determined their structures on the basis of
Our retrosynthetic analysis of pteridic acid A (1) is shown
in Scheme 1. The conjugated diene carboxylic acid moiety
incorporated in 1 was considered to be readily installable by
using the Horner–Wadsworth–Emmons olefination of alde-
hyde 3 with known phosphonate 4. The spiroacetal 3 could
be obtained either by the addition of an alkenyl anion de-
rived from iodide 6a or by the addition of an acetylide
anion derived from 6b to carbonyl compound 5 (X=H or
an appropriate leaving group), followed by some additional
[a] T. Nakahata, S. Fujimura, Prof. Dr. S. Kuwahara
Laboratory of Applied Bioorganic Chemistry
Graduate School of Agricultural Science
Tohoku University, Tsutsumidori-Amamiyamachi
Aoba-ku, Sendai 981–8555 (Japan)
Fax : (+81)22-717-8783
E-mail: skuwahar@biochem.tohoku.ac.jp
Supporting information for this article is available on the WWW
1
under http://www.chemeurj.org/ or from the author and contains H
and 13C NMR spectra for all important compounds.
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FULL PAPER
considerably high diastereose-
lectivity (7,9-anti/7,9-syn ap-
proximately 10:1). The protec-
tion of diol 10 as acetonide 11
and subsequent reductive re-
moval of the chiral auxiliary
with LiBH4 afforded stereo-
chemically homogeneous alco-
hol 12 in 75% yield from 10
after chromatographic purifica-
tion. The 7,9-anti relative ster-
eochemistry of 12 was readily
confirmed by analyzing its
13C NMR spectrum, in which
the signals assignable to the
Scheme 1. Retrosynthetic analysis of pteridic acid A (1). PMB=p-methoxybenzyl.
quaternary carbon and the two
transformations. Finally, retrosynthetic disconnection of the
methyl carbon atoms of the acetonide moiety were observed
at d=100.6, 24.9, and 23.5 ppm, respectively, in good ac-
cordance with a general rule proposed for the assignment of
the relative stereochemistry of 1,3-syn- and 1,3-anti-diol ace-
tonides.[8] Finally, oxidation of 12 with Dess–Martin periodi-
nane (DMP) completed the preparation of the C5–C11 frag-
ment 13.
À
C7 C8 bond in 5 enabled us to think of its construction
through an asymmetric aldol reaction between ketone 7 and
aldehyde 8. On the other hand, the synthesis of pteridic acid
B (2), the 11-epimer of 1, was anticipated to be more diffi-
cult due to its anomerically disfavored conformation at the
spirocenter.[1] This potential difficulty was, however, success-
fully overcome by applying a MgBr2-promoted epimeriza-
tion reaction to a spirocyclic synthetic intermediate of 1 as
described later in this paper.
Preparation of the C12–C16 fragment 18 and its attempted
coupling with 13: Next, we set about the preparation of al-
kenyl iodide 18 (compound 6a in Scheme 1, R4 =EE), one
of the candidates for the coupling partner of 13 (Scheme 3).
Results and Discussion
Preparation of the C5–C11 fragment 13: The preparation of
our subtarget 13 (compound 5 in Scheme 1; X=H, R1 and
R2 =acetonide) began with the diastereoselective aldol reac-
tion of known aldehyde 8[5] with b-keto imide derivative 7
developed by Evans et al.,[6] which produced an inseparable
13:1 mixture of the desired 7,8-syn-8,10-anti-aldol 9 and its
1
(7R,8S)-diastereomer, as judged by the H NMR analysis of
the reaction product (Scheme 2). The mixture then under-
went hydroxyl-directed diastereoselective reduction by
[7]
treatment with NaBHACHTRE(UGN OAc)3 to give 7,9-anti-diol 10 with
Scheme 3. Preparation of the C12–C16 fragment 18 and its coupling with
13: a) CH2=CHOEt, PPTS, CH2Cl2, RT, 24 h (quant); b) DIBAL,
CH2Cl2, À788C, 24 h (quant); c) DMSO, (COCl)2, Et3N, À788C, 1 h
(quant); d) (Ph3PCH2I)+IÀ, NaHMDS, THF, À208C, 3 h (68%);
e) tBuLi, THF, À788C, 12 h; f) CrCl2, NiCl2, DMSO, DMF, RT, 24 h.
EE=ethoxyethyl, PPTS=pyridinium p-toluenesulfonate; DIBAL=diiso-
butylaluminum hydride; HMDS=hexamethyldisilazide.
Protection of known hydroxy ester 14[9] as its ethoxyethyl
ether 15 was followed by reduction of the ester functionality
to give alcoholic intermediate 16, which was then exposed
to Swern oxidation conditions to furnish protected aldehyde
17. (Z)-Selective Wittig olefination of 17 with Ph3P=CHI
proceeded smoothly to afford 18 with >20:1 Z/E selectivi-
ty.[10]
Scheme 2. Preparation of the C5–C11 fragment 13: a) Sn
CH2Cl2, À788C, 2 h (82%); b) NaBH(OAc)3, AcOH, RT, 1.5 h (92%);
c) Me2C(OMe)2, TsOH·H2O, acetone, RT, 24 h (96%); d) LiBH4, MeOH,
ACHTRE(UGN OTf)2, Et3N, 8,
AHCTREUNG
ACHTREUNG
THF, RT, 3 h (78%); e) DMP, CH Cl2, RT, 24 h (94%). DMP=Dess–
2
Martin periodinane.
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S. Kuwahara et al.
The coupling of 18 with aldehyde 13 was examined in two
ways: 1) addition of the alkenyllithium reagent prepared
from 18 to 13[11] and 2) direct coupling of the two compo-
nents under the Nozaki–Hiyama–Kishi coupling condi-
tions.[12] Under the former conditions, however, the only
isolable product was the b-elimination product 20, while
under the latter conditions, no detectable product was ob-
tained, resulting only in the recovery of the substrates.
We also attempted the coupling of Weinrebꢁs amide 23
and the alkenyllithium reagent derived from 25a
(Scheme 4), which in turn was obtained from 14 by the same
Scheme 5. Preparation of the C12–C16 fragment 27 and its coupling with
13: a) CBr4, P hP , P y, CHCl2, 08C, 1.5 h (64%); b) nBuLi, THF, À788C,
3
2
24 h (79%); c) nBuLi, 13, À788C, 24 h (40%); d) DMP, CH Cl2, 08C,
2
24 h (94%).
lithium acetylide was reacted successfully with aldehyde 13
to give a 40% yield of desired coupling product 28, which
was then oxidized to ketone 29. In this coupling reaction,
again, the main byproduct was the b elimination product 20
(approximately 40% yield). Use of the less basic magnesium
acetylide prepared by treating 27 with EtMgBr in THF was
not successful, resulting only in the recovery of 13 and 27.
The unexpected problems in this coupling step with alde-
hyde 13 as a precursor of 29 made us seek an alternative
Scheme 4. Preparation of the C5–C11 fragment 23 and its coupling with
25a: a) TBSOTf, 2,6-lutidine, CH2Cl2, À58C, 24 h; b) AlMe3, (MeO)-
MeNH·HCl, THF, À208C, 24 h; c) TBSOTf, 2,6-lutidine, CH2Cl2, À788C,
24 h (30% from 10); d) 25a, tBuLi, THF, À788C, 2.5 h. TBS=tert-butyl-
silyl; Tf=triflate.
À
protocol for the formation of the C11 C12 linkage.
À
Construction of the C11 C12 bond via thiol ester intermedi-
ate 30: Although we could secure a,b-acetylenic ketone 29,
which was a requisite for the installation of the spiroacetal
ring, by oxidation of 28 as just described, the low chemical
yield (40%) and the formation of a substantial amount of
byproduct 20 (approximately 40%), stemming from the b
elimination of aldehyde 13 in the coupling step, called on us
to alter our synthetic plan to a small extent. We envisaged
obtaining 29 without the intervention of 13. Among numer-
ous methodologies so far reported for the preparation a,b-
acetylenic ketones,[15] we adopted a protocol recently devel-
oped by Fukuyama and co-workers, which could effect the
coupling of a variety of thiol esters and terminal acetylenes
procedure as described for 18 except for the protection step
(TBSOTf/2,6-lutidine/CH2Cl2 instead of CH2=CHOEt/
À
PPTS/CH2Cl2). To prepare 23, the C7 OH group of diol 10
was protected as its mono-TBS ether 21, followed by the re-
placement of the chiral auxiliary with a methoxymethylami-
no group under conventional conditions to give 22.[13] Final-
ly, TBS-protection of the remaining hydroxyl at the C9 posi-
tion produced the desired amide 23 in about 30% overall
yield from 10 (the chemical yield was not optimized). The
nucleophilic substitution of 23 with the alkenyl anion pre-
pared by treating 25a with tBuLi to form olefinic ketone 24,
however, did not proceed at all, giving only the starting
amide 23 along with deiodinated terminal olefin 25b gener-
ated from 25a.
in the presence of [PdCl2ACHTREU(NG dppf)] and CuI under mild reac-
tion conditions (Scheme 6).[16] Thus, oxazolidinone deriva-
Preparation of the C12–C16 fragment 27 and its coupling
with 13: To circumvent the difficulties encountered in the
coupling reaction with alkenyl iodides 18 or 25a, we turned
our attention to the utilization of terminal acetylene 27
(compound 6b in Scheme 1; R4 =EE) for the construction
À
of the C11 C12 bond (Scheme 5). The acetylenic segment
was readily prepared by dibromomethylenation of aldehyde
17 in the presence of pyridine and subsequent treatment of
the resulting dibromoolefin 26 with nBuLi.[14] The presence
of pyridine as an additive was essential in this case, as its ab-
sence brought about complete deprotection of the ethoxy-
ethyl group. After treatment of 27 with nBuLi, the resulting
Scheme 6. Preparation of the C5–C11 fragment 30 and its coupling with
27: a) n-C12H25SH, nBuLi, À78–À208C, 5 h (77%); b) [PdCl
2ACHTRE(UGN dppf)], CuI,
(2-furyl)3P , EtN, 27, DMF, 508C, 3 h (83%, 3 cycles). dppf=bis(diphe-
3
nylphosphino)ferrocene.
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Pteridic Acids A and B
FULL PAPER
tive 11 was first converted into the corresponding dodecane-
thiol ester 30 by treatment with lithium dodecanethiolate in
THF.[16b] Gratifyingly, the palladium-catalyzed coupling reac-
tion of 30 with terminal acetylene 27 (approximately
2 equiv) produced 29 cleanly, without the formation of any
other products arising from 30. This transformation was,
however, accompanied by an oxidative homocoupling reac-
tion of the acetylenic substrate 27 to afford the correspond-
ing Glaser-type diyne compound 31,[17] which competitively
consumed 27 and, as a result, precluded the reaction from
proceeding to completion. Thus, the chemical yield of this
coupling reaction was approximately 40–45% per single op-
eration, but the thiol ester substrate 30 could be recovered
almost quantitatively, which made it possible to obtain an
83% yield of 29 in total by repeating the same operation
two more times with recovered 30. This alteration of the
coupling protocol enabled us to not only reduce the number
of synthetic steps, but also to improve the overall yield of 29
(five steps, 46% overall yield from 7).
Completion of the synthesis of pteridic acid A (1): The suc-
cessful assembly of the C5–C16 segment 29 set the stage for
the formation of the spiroacetal ring and subsequent four-
carbon elongation toward the total synthesis of pteridic acid
A (1, Scheme 7). Simultaneous removal of the two types of
acetal-protecting groups of 29 in acidic methanol below 08C
brought about the formation of cyclic acetal 32 as an insepa-
rable 3:1 diastereomeric mixture in 91% yield. Keeping the
reaction temperature below 08C was essential to obtain re-
producibly high yields, as elevating the reaction temperature
to 258C resulted in considerably low yields (53–78%), pro-
ducing unidentified byproducts. Exposure of 32 to catalytic
semihydrogenation conditions followed by acidic treatment
of the resulting olefin 33 afforded spiroacetal 34 as a single
stereoisomer. The stereochemistry of the spirocenter of 34
was tentatively assigned based on the amomeric effect and
the similarity in the 1H NMR spectrum between 34 and
pteridic acid A (1), and was eventually confirmed by its con-
version to 1. After protection of the hydroxyl group of 34 as
its acetate 35, the PMB-protecting group was removed by
DDQ oxidation to give 36 without any epimerization at the
spirocenter. In our previous communication,[4] we reported
the occurrence of partial epimerization at the C11 spirocen-
ter during the oxidation step, producing a 6:1 mixture of 36
and 11-epi-36. This small degree of epimerization, however,
could be avoided by immediately conducting chromato-
graphic purification of the crude reaction mixture. This find-
ing made us suspect that the ring-opening/closure process
leading to the epimeric mixture might have taken place as a
result of exposure of the initially formed spiroacetal 36 to a
high concentration of the considerably acidic 2,3-dichloro-
5,6-dicyanohydroquinone generated from the oxidizing re-
agent DDQ, as in our previous experiment,[4] the crude reac-
tion product was left to stand overnight at room tempera-
ture without purification after the evaporation of the
EtOAc employed for extraction.
Scheme 7. Completion of the synthesis of pteridic acid A (1): a) CSA,
MeOH, CH2Cl2, 08C, 3 d (91%); b) Lindlarꢁs catalyst, 1-hexene, EtOAc,
RT, 15 min (89%); c) PPTS, toluene, RT, 1 h (99%); d) Ac2O, DMAP,
Py, RT, 24 h (quant); e) DDQ, H2O, CH2Cl2, 08C, 1 h (86%); f) DMP, Py,
CH2Cl2, 08C, 24 h (91%); g) 4, LiHMDS, THF, À788C, 3 h (94%);
h) K2CO3, MeOH, RT, 3 h (83%); i) KOH, H2O, MeOH, 6 h (99%);
j) (R)-MTPACl, Py. CSA=camphorsulfonic acid; DMAP=4-dimethyl-
aminopyridine;
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone;
MTPA=a-methoxy-a-(trifluoromethyl)phenylacetyl.
The oxidation of alcohol 36 with DMPproceeded un-
eventfully to give aldehyde 37, for which four-carbon elon-
gation with phosphonate 4 furnished geometrically pure 38
possessing all the carbon atoms and stereochemically correct
asymmetric centers of pteridic acid A (1). Finally, deprotec-
tion of the acetyl group by methanolysis to 39 and subse-
quent hydrolysis of the methyl ester moiety gave 1 ([a]2D4 =
+24 (c=0.15 in CHCl3); lit.[1] [a]D24 =+22.3 (c=1.0 in
1
CHCl3)). H and 13C NMR spectra were identical to those of
natural pteridic acid A.[1] The enantiomeric homogeneity of
our synthetic pteridic acid A was confirmed by directly com-
1
paring the H NMR spectrum of the (S)-MTPA ester (40)
derived from 39 with those of the (S)- and (R)-MTPA esters
prepared previously by Igarashi from natural pteridic acid
A.[1]
Synthesis of pteridic acid Bthrough epimerization of inter-
mediate 39: With the enantioselective total synthesis of 1
completed, we attempted the epimerization of the spirocen-
ter of an appropriate synthetic intermediate for 1 to obtain
pteridic acid B (2), the C11 epimer of pteridic acid A (1).
As reported in our previous communication,[4] the epimeri-
zation must have occurred at the stage of the formation of
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S. Kuwahara et al.
36 when the crude reaction product was exposed to a high
concentration of the phenolic byproduct generated from
DDQ, giving an inseparable 6:1 mixture of 36 and 11-epi-
36; this epimeric mixture was converted through a three-
step sequence into a separable mixture of 39 and 11-epi-39,
the former of which was then successfully transformed into
pteridic acid A (1) by saponification. Although the previous
synthetic efforts failed to produce 2 in its chemically pure
form due to its paucity,[4] the observation that 39 and 11-epi-
39 were separable, helped us chose 39 as a suitable epimeri-
zation substrate for the synthesis of 2. Our literature search
for reaction conditions used for analogous conversions sug-
gested the utilization of MgBr2, which had previously been
employed as catalyst for the epimerization of a spiroacetal
intermediate in the total synthesis of pinnatoxin A by Kishi
et al.[18] Gratifyingly, treatment of a solution of 39 in CH2Cl2
with 3–4 equivalents of anhydrous MgBr2 at room tempera-
ture brought about clean equilibration to give a separable
3:2 mixture of 39 and 11-epi-39 without formation of any
other detectable product (Scheme 8). Increasing the amount
Scheme 9. A plausible mechanism for the formation of the anomerically
disfavored spiroacetal, 11-epi-39.
keeping the anomerically favored conformation at the spiro-
center. Quenching the equilibrium mixture with aqueous
NaHCO3 would then have led to the irreversible 3:2 mixture
of the starting spiroacetal 39 and the epimerization product
(11-epi-39, generated by an additional conformational
change at the tetrahydropyran ring of 41 after the basic
workup), probably reflecting the equilibrium ratio between
some kind of magnesium complex of 39 and the chelation-
stabilized intermediate 41. Chromatographic separation of
the mixture enabled us to isolate 39 (60%) and 11-epi-39
(40%), the latter of which was then hydrolyzed to furnish
pteridic acid B (2, [a]2D4 =À20.2 (c=0.05 in CHCl3); lit.[1]
[a]D24 =À20.8 (c=0.68 in CHCl3)). The 1H and 13C NMR
spectra of 2 were identical to those of natural pteridic acid
B.[1]
Scheme 8. Synthesis of pteridic acid B (2) by epimerization of intermedi-
ate 39: a) MgBr2, CH2Cl2, RT, 3 h (40% for 11-epi-39, 60% for 39);
b) KOH, H2O, MeOH, 6 h (99%).
Conclusion
The enantioselective total synthesis of pteridic acid A (1)
of the Lewis acid catalyst did not improve the outcome, but
merely promoted the gradual decomposition of the products,
as judged by TLC monitoring. This successful equilibration
yielding a considerably high proportion of anomerically dis-
favored 11-epi-39 is in sharp contrast to the exclusive forma-
tion of anomerically favored spirocyclic compound 34 on
treatment of 33 with a protic acid (PPTS in toluene,
Scheme 7), which might allow us to assume some kind of
positive participation of Mg2+ to promote the production of
11-epi-39. It might be possible to presume the intervention
of a chelation-stabilized species, such as 41, which could be
formed from 39 through Lewis acid catalyzed epimerization
at the spirocenter and conformational change at both of the
two rings (Scheme 9). The conformation of 41 should be
suitable for the formation of the magnesium chelate be-
tween the C9- and the C15-oxygen functionalities while
employing the SnACHTRE(UNG OTf)2-mediated Evans aldol reaction of
oxazolidinone 7 with aldehyde 8 and the Fukuyama cou-
pling reaction of thiol ester intermediate 30 with acetylene
À
27 as the key C C bond-forming steps was accomplished in
22% overall yield from 7 through a considerably short 14-
step sequence. MgBr2-mediated equilibration of the spirocy-
clic intermediate 39 brought about partial epimerization of
the spirocenter to give anomerically disfavored 11-epi-39,
which was then converted into pteridic acid B (2).
Experimental Section
General methods: IR spectra were measured by a Jasco FTIR-4100 spec-
trometer. NMR spectra were recorded with TMS as an internal standard
in CDCl3 by a Varian Gemini 2000 spectrometer (300 MHz for 1H and
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Chem. Eur. J. 2006, 12, 4584 – 4593

Pteridic Acids A and B
FULL PAPER
75 MHz for 13C NMR spectra), a Varian UNITY plus-500 spectrometer
(500 MHz for 1H and 125 MHz for 13C NMR spectra), or a Varian
UNITY plus-600 spectrometer (600 MHz for 1H and 150 MHz for
13C NMR spectra). Optical rotation values were measured with a Jasco
DIP-371 polarimeter, and mass spectra were obtained with a Jeol JMS-
700 spectrometer operated in the EI or FAB mode. Merck silica gel 60
(70–230 mesh) was used for silica gel column chromatography. Solvents
for reactions were distilled prior to use: THF from Na and benzophe-
none, MeOH from Mg and I2, CH2Cl2 and DMF from CaH2, and toluene
from LiAlH4. All air- or moisture-sensitive reactions were conducted
under a nitrogen atmosphere.
(S)-4-Benzyl-3-((S)-2-{(4R,5R,6S)-6-[(S)-2-(4-methoxybenzyloxy)-1-meth-
ylethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl}propanoyl)oxazolidin-2-one (11):
TsOH·H2O (25 mg, 0.13 mmol) was added to a stirred solution of 10
(665 mg, 1.33 mmol) and 2,2-dimethoxypropane (5 mL) in acetone
(5 mL) at room temperature. After 24 h, the reaction was quenched with
saturated aqueous NaHCO3, and the resulting mixture was extracted
with EtOAc. The extract was washed with brine, dried (MgSO4), filtered,
and concentrated in vacuo. The residue was chromatographed over silica
gel (hexane/EtOAc 3:1) to give 11 (688 mg, 96%) as a pale yellow oil.
[a]2D4 =+37.1 (c=1.10 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.93
(d, J=6.9 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 1.26 (s, 3H), 1.27 (d, J=
7.1 Hz, 3H), 1.29 (s, 3H), 1.76–1.88 (m, 1H), 1.88–1.99 (m, 1H), 2.76 (dd,
J=13.5, 9.9 Hz, 1H), 3.32 (dd, J=13.5, 3.0 Hz, 1H), 3.38 (dd, J=8.5,
6.0 Hz, 1H), 3.53 (dd, J=8.5, 3.0 Hz, 1H), 3.56–3.64 (m, 2H), 3.80 (s,
3H), 4.01 (dq, J=4.7, 7.1 Hz, 1H), 4.09–4.20 (m, 2H), 4.41 (s, 2H), 4.59–
4.67 (m, 1H), 6.86 (deformed d, J=8.8 Hz, 2H), 7.20–7.38 ppm (m, 7H);
13C NMR (75 MHz, CDCl3): d=11.6, 11.8, 13.2, 23.6, 24.9, 33.7, 34.8,
37.7, 41.2, 55.2, 55.8, 66.0, 70.0, 72.1, 72.8, 75.7, 100.6, 113.7, 127.4, 129.0,
129.2, 129.5, 131.1, 135.5, 153.3, 159.1, 175.0 ppm; IR (film): n˜ =3060 (w),
1780 (vs), 1700 (s), 1615 (m), 1515 (s), 1250 (s), 760 cmÀ1 (s); HRMS
(FAB): m/z: calcd for C31H42NO7: 540.2961; found: 540.2961 [M+H]+.
(2S,4R,5S,6S)-1-[(S)-4-Benzyl-2-oxooxazolidin-3-yl]-5-hydroxy-7-(4-me-
thoxybenzyloxy)-2,4,6-trimethylheptane-1,3-dione (9): Et3N (1.21 mL,
8.71 mmol) was added to a stirred suspension of stannous triflate (3.03 g,
7.26 mmol) in CH2Cl2 (30 mL) at room temperature. The resultant pale
yellow slurry was immediately cooled to À208C and stirred for 10 min
before a solution of 7 (1.40 g, 4.84 mmol) in CH2Cl2 (12 mL) was added
dropwise over 5 min. The resulting almost clear solution was stirred at
À208C for 1 h and then cooled to À788C. A solution of 8 (1.13 g,
5.81 mmol) in CH2Cl2 (5 mL) was then added to the solution, and the re-
sulting mixture was stirred at À788C for a further 2 h before being
(R)-2-{(4S,5S,6S)-6-[(S)-2-(4-Methoxybenzyloxy)-1-methylethyl]-2,2,5-tri-
methyl-1,3-dioxan-4-yl}-1-propanol (12): LiBH4 (63 mg, 2.89 mmol) was
added portionwise to a stirred solution of 11 (788 mg, 1.45 mmol) and
MeOH (0.12 mL) in THF (3 mL) at 08C, and the resulting mixture was
warmed to room temperature and stirred for 3 h. The reaction was
quenched with saturated aqueous Rochelleꢁs salt, and the mixture was
extracted with EtOAc. The extract was washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. The residue was chromato-
graphed over silica gel (hexane/EtOAc 10:1) to give 12 (411 mg, 78%) as
a pale yellow oil. [a]2D4 =+0.55 (c=1.37 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=0.87 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.97 (d, J=
6.9 Hz, 3H), 1.27 (s, 3H), 1.34 (s, 3H), 1.76–1.95 (m, 3H), 2.42–2.53 (brs,
1H; OH), 3.39 (dd, J=8.8, 6.0 Hz, 1H), 3.48–3.55 (m, 2H), 3.57–3.68 (m,
3H), 3.80 (s, 3H), 4.41 (s, 2H), 6.88 (deformed d, J=8.5 Hz, 2H),
7.26 ppm (deformed d, J=8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=
10.7, 12.1, 13.4, 23.5, 24.9, 33.7, 34.1, 37.6, 55.2, 67.0, 70.2, 72.0, 72.8, 77.8,
100.6, 113.6, 129.1, 130.9, 159.0 ppm; IR (film): n˜ =3420 (m), 1610 (m),
1510 (s), 1250 (vs), 1220 (s), 1035 (s), 760 cmÀ1 (s); HRMS (FAB): m/z:
calcd for C21H35O5: 367.2484; found: 367.2487 [M+H]+.
poured into
a vigorously stirred mixture of CH2Cl2 (200 mL) and
NaHSO4 (1m, 200 mL) at 08C. The mixture was stirred for 30 min and
extracted with CH2Cl2. The extract was washed with saturated aqueous
NaHCO3, dried (MgSO4), filtered, and concentrated in vacuo. The resi-
due was chromatographed over silica gel (hexane/EtOAc 10:1) to give 9
(1.98 g, 82%) as a pale yellow oil. The 1H NMR spectrum indicated that
the product was a mixture of 9 and its (4S,5R)-diastereomer. [a]D24
=
+36.3 (c=1.60 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.90 (d, J=
6.9 Hz, 3H), 1.18 (d, J=7.1 Hz, 3H), 1.47 (d, J=7.2 Hz, 3H), 1.85–1.95
(m, 1H), 2.76 (dd, J=13.5, 9.6 Hz, 1H), 2.91 (dq, J=3.0, 7.1 Hz, 1H),
3.30 (dd, J=13.5, 3.6 Hz, 1H), 3.42 (d, J=2.6 Hz, 1H; OH), 3.54 (d, J=
5.8 Hz, 2H), 3.80 (s, 3H), 3.90 (ddd, J=8.8, 3.0, 2.6 Hz, 1H), 4.11–4.24
(m, 2H), 4.45 (s, 2H), 4.67–4.76 (m, 1H), 4.94 (q, J=7.2 Hz, 1H), 6.87
(deformed d, J=8.5 Hz, 2H), 7.18–7.37 ppm (m, 7H); 13C NMR
(75 MHz, CDCl3): d=9.0, 13.4, 13.9, 35.9, 37.9, 47.4, 50.9, 55.3, 55.4, 66.4,
73.1, 74.1, 74.5, 113.8, 127.4, 129.0, 129.3, 129.4, 130.0, 135.0, 153.6, 159.2,
170.5, 210.4 ppm; IR (film): n˜ =3475 (m), 3050 (w), 3020 (w), 1770 (vs),
1710 (s), 1690 (s), 1610 (m), 1510 (s), 1240 (s), 755 cmÀ1 (s); HRMS
(FAB): m/z: calcd for C28H35NO7Na: 520.2311; found: 520.2313 [M+Na]+.
(S)-2-{(4R,5R,6S)-6-[(S)-2-(4-Methoxybenzyloxy)-1-methylethyl]-2,2,5-
trimethyl-1,3-dioxan-4-yl}propanal (13): Dess–Martin periodinane
(463 mg, 1.09 mmol) was added portionwise to a stirred solution of 12
(286 mg, 0.78 mmol) in CH2Cl2 (3 mL) at 08C. The solution was then
warmed to room temperature and stirred for 24 h. The reaction was
quenched with saturated aqueous Na2S2O3, and the resulting mixture was
extracted with EtOAc. The extract was washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. The residue was chromato-
graphed over silica gel (hexane/EtOAc 10:1) to give (267 mg, 94%) of 13
(S)-4-Benzyl-3-[(2S,3R,4R,5S,6S)-3,5-dihydroxy-7-(4-methoxybenzyloxy)-
2,4,6-trimethylheptanoyl]oxazolidin-2-one (10): To stirred acetic acid
(neat, 80 mL) was added portionwise NaBH4 (1.87 g, 50 mmol) at 08C.
After hydrogen evolution ceased, the mixture was warmed to room tem-
perature, and stirred for 1 h. To this solution was added a solution of 9
(2.40 g, 4.95 mmol) in acetic acid (28 mL) over a period of 5 min, and the
resulting mixture was stirred for 1.5 h, and then concentrated in vacuo.
The resulting oily product was diluted with toluene, concentrated again
in vacuo to remove residual acetic acid, and finally mixed with saturated
aqueous NaHCO3. The mixture was extracted with CH2Cl2, and the ex-
tract was dried (Na2SO4), filtered, and concentrated in vacuo. The residue
was chromatographed over silica gel (hexane/EtOAc 3:1) to give 10
as
a
pale yellow oil. [a]D24 =+22.0 (c=0.50 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=0.91 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.9 Hz, 3H),
1.15 (d, J=6.9 Hz, 3H), 1.25 (s, 3H), 1.32 (s, 3H), 1.79–1.95 (m, 2H),
2.42 (ddq, J=1.1, 3.3, 6.9 Hz, 1H), 3.41 (dd, J=8.4, 6.0 Hz, 1H), 3.52
(dd, J=8.4, 3.3 Hz, 1H), 3.62 (dd, J=10.7, 4.4 Hz, 1H), 3.75 (dd, J=7.4,
3.3 Hz, 1H), 3.81 (s, 3H), 4.41 (s, 2H), 6.87 (deformed d, J=8.8 Hz, 2H),
7.25 (deformed d, J=8.8 Hz, 2H), 9.70 ppm (d, J=1.1 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=7.8, 11.8, 13.3, 23.4, 24.6, 33.6, 34.5, 49.0,
55.2, 70.1, 72.0, 72.9, 74.1, 100.9, 113.7, 129.2, 131.1, 159.2, 204.6 ppm; IR
(film): n˜ =2720 (w), 1725 (s), 1610 (m), 1510 (s), 1250 (s), 1220 cmÀ1 (s);
HRMS (FAB): m/z: calcd for C21H32O5Na: 387.2147; found: 387.2148
[M+Na]+.
1
(2.28 g, 92%) as a colorless oil. The H NMR spectrum indicated that the
product contained the (5R)-isomer of 10 (10/(5R)-10 approximately 10:1)
together with a minute amount of other diastereomers. [a]2D4 =+30.0 (c=
1
1.40 in CHCl3); H NMR (300 MHz, CDCl3): d=0.72 (d, J=7.2 Hz, 3H),
0.96 (d, J=7.2 Hz, 3H), 1.32 (d, J=6.9 Hz, 3H), 1.26 (s, 1H; OH), 1.67–
1.76 (m, 1H), 1.93–2.05 (m, 1H), 2.78 (dd, J=13.4, 9.3 Hz, 1H), 3.27 (dd,
J=13.4, 3.3 Hz, 1H), 3.46 (t, J=9.1 Hz, 1H), 3.57 (dd, J=9.1, 3.8 Hz,
1H), 5.59 (d, J=4.9 Hz, 1H; OH), 3.80 (s, 3H), 3.89–4.06 (m, 3H), 4.13–
4.22 (m, 2H), 4.42 (d, J=11.4 Hz, 1H), 4.48 (d, J=11.4 Hz, 1H), 4.62–
4.70 (m, 1H), 6.88 (deformed d, J=8.5 Hz, 2H), 7.16–7.37 ppm (m, 7H);
13C NMR (75 MHz, CDCl3): d=9.3, 11.6, 12.9, 35.6, 36.5, 37.6, 40.2, 55.2
(two overlapping peaks), 66.0, 69.6, 73.1, 74.2, 76.1, 113.9, 127.4, 129.0,
129.4, 129.5, 129.6, 135.2, 153.0, 159.4, 177.5 ppm; IR (film): n˜ =3450 (m),
3050 (w), 1770 (vs), 1685 (s), 1605 (s), 1505 (s), 1240 (s), 750 cmÀ1 (s);
HRMS (FAB): m/z: calcd for C28H37NO7Na: 522.2468; found: 522.2471
[M+Na]+.
Methyl (2R,3R)-3-(1-ethoxyethoxy)-2-ethylbutanoate (15): Ethyl vinyl
ether (1.48 g, 20.5 mmol) was added dropwise to a stirred solution of 14
(1.00 g, 6.84 mmol) and PPTS (0.17 g, 0.68 mmol) in CH2Cl2 (5 mL) at
08C. The solution was then warmed to room temperature and stirred for
24 h. After this time, the reaction was quenched with saturated aqueous
NaHCO3 at 08C, and the resulting mixture was extracted with EtOAc.
The extract was washed with brine, dried (Na2SO4), filtered, and concen-
Chem. Eur. J. 2006, 12, 4584 – 4593
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4589

S. Kuwahara et al.
trated in vacuo. The residue was chromatographed over silica gel
(hexane/EtOAc 6:1) to give (1.49 g, quant) of 15. [a]2D4 =À5.51 (c=1.70
in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.89 (t, J=7.4 Hz, 1.5H),
0.90 (t, J=7.4 Hz, 1.5H), 1.15 (d, J=6.3 Hz, 1.5H), 1.18 (t, J=7.0 Hz,
1.5H), 1.19 (t, J=7.0 Hz, 1.5H), 1.22 (d, J=6.3 Hz, 1.5H), 1.23 (d, J=
5.5 Hz, 1.5H), 1.29 (d, J=5.5 Hz, 1.5H), 1.50–1.61 (m, 2H), 2.36–2.47 (m,
1H), 3.41 (dq, J=9.2, 7.0 Hz, 0.5H), 3.49 (dq, J=9.2, 7.0 Hz, 0.5H), 3.60
(dq, J=9.2, 7.0 Hz, 0.5H), 3.61 (dq, J=9.2, 7.0 Hz, 0.5H), 3.69 (s, 3H),
3.80 (dq, J=8.1, 6.3 Hz, 0.5H), 3.91 (dq, J=8.1, 6.3 Hz, 0.5H), 4.68 (q,
J=5.5 Hz, 0.5H), 4.75 ppm (q, J=5.5 Hz, 0.5H); 13C NMR (75 MHz,
CDCl3): d=11.8, 11.9, 15.1, 15.2, 17.6, 18.8, 20.3, 20.5, 21.1, 21.2, 51.2
(two overlapping peaks), 54.2, 54.3, 59.8, 60.0, 72.0, 75.2, 97.9, 100.7,
174.9, 175.7 ppm; IR (film): n˜ =1730 (s), 1190 (m), 1080 cmÀ1 (m);
HRMS (FAB): m/z: calcd for C11H22O4Na: 241.1416; found: 241.1422
[M+Na]+.
with EtOAc. The extract was washed with brine, dried (MgSO4), filtered,
and concentrated in vacuo. The residue was chromatographed over silica
gel (hexane/EtOAc 20:1) to give 18 (0.18 g, 68%) as a pale yellow oil.
[a]2D4 =+33.1 (c=2.63 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.90
(t, J=7.5 Hz, 1.5H), 0.91 (t, J=7.5 Hz, 1.5H), 1.09 (d, J=6.3 Hz, 1.5H),
1.15 (d, J=6.3 Hz, 1.5H), 1.20 (t, J=7.2 Hz, 1.5H), 1.21 (t, J=7.2 Hz,
1.5H), 1.29 (d, J=5.2 Hz, 1.5H), 1.31 (d, J=5.2 Hz, 1.5H), 1.38–1.54 (m,
1H), 1.54–1.70 (m, 1H), 2.39–2.50 (m, 1H), 3.42–3.58 (m, 1H), 3.58–3.70
(m, 1H), 3.71 (dq, J=3.3, 6.3 Hz, 0.5H), 3.80 (dq, J=3.3, 6.3 Hz, 0.5H),
4.736 (q, J=5.2 Hz, 0.5H), 4.743 (q, J=5.2 Hz, 0.5H), 6.03 (dd, J=9.9,
7.2 Hz, 0.5H), 6.06 (dd, J=9.9, 7.2 Hz, 0.5H), 6.346 (d, J=7.2 Hz, 0.5H),
6.353 ppm (d, J=7.2 Hz, 0.5H); 13C NMR (75 MHz, CDCl3): d=11.6,
11.7, 15.1, 15.2, 17.6, 18.5, 20.4, 20.6, 22.6, 23.1, 52.06, 52.11, 59.97, 60.00,
72.4, 74.8, 84.0, 84.2, 97.7, 100.0, 142.2, 142.3 ppm; IR (film): n˜ =3070
(w), 1610 (w), 1130 (s), 1085 (s), 1055 cmÀ1 (s); HRMS (EI): m/z: calcd
for C11H21IO2: 312.0587; found: 312.0589 [M]+.
ACHTREUNG(2S,3R)-3-(1-Ethoxyethoxy)-2-ethyl-1-butanol (16): DIBAL (1m in
hexane, 20 mL, 20 mmol) was added dropwise to a stirred solution of 15
(1.50 g, 6.87 mmol) in CH2Cl2 (10 mL) at À788C. After 24 h, the reaction
was quenched with saturated aqueous potassium sodium tartrate and the
mixture was warmed gradually to room temperature and stirred for 24 h.
After this time, the mixture was extracted with EtOAc, and the extract
was washed with brine, dried (Na2SO4), filtered, and concentrated in
vacuo. The residue was chromatographed over silica gel (hexane/EtOAc
10:1) to give 16 (1.56 g, quant). [a]2D4 =À28.3 (c=2.03 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.96 (t, J=7.2 Hz, 3H), 1.20 (t, J=
7.0 Hz, 1.5H), 1.20 (d, J=6.0 Hz, 1.5H), 1.22 (t, J=7.0 Hz, 1.5H), 1.28
(d, J=6.0 Hz, 1.5H), 1.31 (d, J=5.2 Hz, 1.5H), 1.32 (d, J=5.2 Hz, 1.5H),
1.30–1.48 (m, 3H), 2.70 (dd, J=6.6, 5.1 Hz, 0.5H; OH), 3.17 (dd, J=8.1,
5.1 Hz, 0.5H; OH), 3.44–3.68 (m, 3H), 3.68–3.81 (m, 1H), 3.84–3.97 (m,
1H), 4.69 (q, J=5.2 Hz, 0.5H), 4.70 ppm (q, J=5.2 Hz, 0.5H); 13C NMR
(75 MHz, CDCl3): d=11.7, 11.8, 15.1 (two overlapping peaks), 18.3, 19.4,
20.3, 20.5, 21.0, 21.2, 47.6, 48.0, 60.3, 60.9, 61.6, 62.5, 74.4, 77.2, 98.2,
100.5 ppm; IR (film): n˜ =3425 (m), 1130 (s), 1080 (s), 1050 cmÀ1 (s);
HRMS (FAB): m/z: calcd for C10H23O3: 191.1647; found: 191.1651
[M+H]+.
ACHTRE(UGN 3S,4R)-1,1-Dibromo-4-(1-ethoxyethoxy)-3-ethyl-1-pentene (26): A solu-
tion of CBr4 (2.22 g, 6.69 mmol) in CH2Cl2 (5 mL) was added dropwise to
a stirred mixture of Ph3P(3.51 g, 13.0 mmol) and pyridine (1.1 mL) in
CH2Cl2 (10 mL) at 08C, and the mixture was stirred for 15 min. A solu-
tion of 17 (600 mg, 3.19 mmol) in CH2Cl2 (5 mL) was then added, and
the resulting mixture was stirred at 08C for 1.5 h before being diluted
with CH2Cl2. The solution was washed with saturated aqueous NaHCO3,
dried (Na2SO4), filtered, and concentrated in vacuo. The residue was
chromatographed over silica gel (hexane/EtOAc 20:1) to give 26
(700 mg, 64%) as a pale yellow oil. [a]2D4 =+18.0 (c=1.82 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.91 (t, J=7.2 Hz, 1.5H), 0.92 (t, J=
7.2 Hz, 1.5H), 1.10 (d, J=6.3 Hz, 1.5H), 1.17 (d, J=6.3 Hz, 1.5H), 1.20
(t, J=7.0 Hz, 3H), 1.29 (d, J=5.2 Hz, 1.5H), 1.30 (d, J=5.2 Hz, 1.5H),
1.35–1.51 (m, 1H), 1.51–1.66 (m, 1H), 2.31–2.42 (m, 1H), 3.43–3.54 (m,
1H), 3.57–3.68 (m, 1H), 3.69 (dq, J=3.6, 6.3 Hz, 0.5H), 3.79 (dq, J=3.6,
6.3 Hz, 0.5H), 4.69 (q, J=5.2 Hz, 0.5H), 4.73 (q, J=5.2 Hz, 0.5H), 6.30
(d, J=9.9 Hz, 0.5H), 6.33 ppm (d, J=9.9 Hz, 0.5H); 13C NMR (75 MHz,
CDCl3): d=11.7, 11.8, 15.19, 15.24, 17.9, 19.0, 20.3, 20.5, 23.1, 23.4, 51.66,
51.68, 59.8, 59.9, 71.9, 74.5, 89.2, 89.4, 97.6, 100.3, 139.8, 140.0 ppm; IR
(film): n˜ =1130 (s), 1090 (s), 1060 (m), 760 (s), 670 cmÀ1 (m); HRMS
(EI): m/z: calcd for C11H2079Br2O2: 341.9830; found: 341.9837 [M]+.
ACHTREUNG(2R,3R)-3-(1-Ethoxyethoxy)-2-ethylbutanal (17): A solution of dimethyl
sulfoxide (1.53 g, 19.6 mmol) in CH2Cl2 (5 mL) was added dropwise to a
stirred solution of oxalyl chloride (1.24 g, 9.81 mmol) in CH2Cl2 (10 mL)
at À788C, and the mixture was stirred for 30 min. After this time, a solu-
tion of 16 (1.56 g, 8.17 mmol) in CH2Cl2 (10 mL) was added dropwise to
the mixture at À788C. After 1.5 h, Et3N (4.56 mL, 32.7 mmol) was added
dropwise, and the resulting mixture was stirred for 1 h. The reaction was
quenched with saturated aqueous NH4Cl, and the mixture was extracted
with EtOAc. The extract was washed with brine, dried (Na2SO4), filtered,
and concentrated in vacuo. The residue was chromatographed over silica
gel (hexane/EtOAc 10:1) to give 17 (1.56 g, quant). [a]2D4 =À27.0 (c=1.60
in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.93 (t, J=7.5 Hz, 3H), 1.19
(t, J=7.1 Hz, 1.5H), 1.196 (d, J=6.3 Hz, 1.5H), 1.198 (t, J=7.1 Hz,
1.5H), 1.26 (d, J=6.3 Hz, 1.5H), 1.286 (d, J=5.2 Hz, 1.5H), 1.288 (d, J=
5.2 Hz, 1.5H), 1.51–1.65 (m, 1H), 1.65–1.80 (m, 1H), 2.18–2.32 (m, 1H),
3.41–3.54 (m, 1H), 3.54–3.67 (m, 1H), 3.94 (quin, J=6.3 Hz, 0.5H), 4.06
(quin, J=6.3 Hz, 0.5H), 4.72 (q, J=5.2 Hz, 0.5H), 4.77 (q, J=5.2 Hz,
0.5H), 9.69 (d, J=3.3 Hz, 0.5H), 9.70 ppm (d, J=3.3 Hz, 0.5H);
13C NMR (75 MHz, CDCl3): d=11.59, 11.64, 15.1, 15.2, 17.9, 18.7, 19.1,
19.2, 20.1, 20.3, 59.4, 59.6, 59.8, 59.9, 70.6, 73.0, 97.5, 100.2, 204.9,
205.1 ppm; IR (film): n˜ =2720 (w), 1720 (s), 1135 (s), 1080 (s), 1060 cmÀ1
(m); HRMS (FAB): m/z: calcd for C10H19O3: 187.1334; found: 187.1348
[MÀH]À.
AHCTRE(UNG 3S,4R)-4-(1-Ethoxyethoxy)-2-ethyl-1-pentyne (27): nBuLi (1.6m in
hexane, 5.11 mL, 8.18 mmol) was added dropwise to a stirred solution of
26 (700 mg, 2.05 mmol) in THF (4 mL) at À788C, and the solution was
stirred for 24 h. After this time, the reaction was quenched with saturated
aqueous NH4Cl, and the resulting mixture was extracted with EtOAc.
The extract was washed with brine, dried (MgSO4), filtered, and concen-
trated at atmospheric pressure. The residue was chromatographed over
silica gel (pentane/ether 20:1) to give 27 (297 mg, 79%) as a pale yellow
oil. [a]2D4 =+22.2 (c=1.65 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
1.040 (t, J=7.4 Hz, 1.5H), 1.044 (t, J=7.4 Hz, 1.5H), 1.195 (t, J=7.1 Hz,
1.5H), 1.203 (t, J=7.1 Hz, 1.5H), 1.21 (d, J=6.2 Hz, 1.5H), 1.26 (d, J=
6.2 Hz, 1.5H), 1.31 (d, J=5.2 Hz, 1.5H), 1.32 (d, J=5.2 Hz, 1.5H), 1.36–
1.55 (m, 1H), 1.55–1.71 (m, 1H), 2.08 (d, J=2.5 Hz, 0.5H), 2.09 (d, J=
2.5 Hz, 0.5H), 2.35–2.47 (m, 1H), 3.45–3.56 (m, 1H), 3.58–3.71 (m, 1H),
3.79 (dq, J=4.2, 6.2 Hz, 0.5H), 3.83 (dq, J=4.2, 6.2 Hz, 0.5H), 4.77 (q,
J=5.2 Hz, 0.5H), 4.78 ppm (q, J=5.2 Hz, 0.5H); 13C NMR (75 MHz,
CDCl3): d=12.0, 12.1, 15.2 (two overlapping peaks), 16.9, 18.0, 20.3, 20.5,
22.4, 22.6, 39.8, 40.0, 59.8, 60.2, 70.5 (two overlapping peaks), 72.4, 74.3,
85.2, 98.3, 99.9 ppm; IR (film): n˜ =3300 (m), 2250 (w), 2110 (w), 1125 (s),
1080 (s), 1060 (s), 760 cmÀ1 (vs); HRMS (FAB): m/z: calcd for C11H19O2:
183.1385; found: 183.1386 [MÀH]À.
S-Dodecyl (S)-2-{(4R,5R,6S)-6-[(S)-2-(4-methoxybenzyloxy)-1-methyleth-
yl]-2,2,5-trimethyl-1,3-dioxan-4-yl}propanethioate (30): nBuLi (1.6m in
hexane, 0.66 mL, 1.06 mmol) was added dropwise to a stirred solution of
dodecanethiol (225 mg, 1.11 mmol) in THF (3.5 mL) at À58C. After
30 min, the reaction mixture was cooled to À788C and a solution of 11
(150 mg, 0.278 mmol) in THF (1 mL) was added. The resulting solution
was stirred for 2 h at À788C and was then gradually warmed to 08C over
a period of 3 h before being quenched with saturated aqueous NH4Cl.
The mixture was extracted with AcOEt, and the extract was washed with
brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue
A
(1m in THF, 1.03 mL, 1.03 mmol) was added dropwise to a stirred sus-
pension of iodomethyltriphenylphosphonium iodide (0.55 g, 1.03 mmol)
in THF (3.9 mL) at room temperature. After 10 min, a solution of 17
(0.16 g, 0.82 mmol) in THF (1 mL) was added dropwise at À208C and
the resulting mixture was stirred for 3 h before being gradually warmed
to room temperature. Hexane (5 mL), Celite (1.5 g) and water (0.5 mL)
were then successively added to the mixture and the resulting slurry was
stirred for a few minutes. After filtration, the filtrate was concentrated in
vacuo and the resulting residue was diluted with water and extracted
4590
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4584 – 4593

Pteridic Acids A and B
FULL PAPER
was chromatographed over silica gel (hexane/EtOAc 20:1) to give 30
(120 mg, 77%) as a pale yellow oil. [a]2D4 =+18.2 (c=6.35 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.87 (d, J=6.9 Hz, 3H), 0.88 (t, J=
6.6 Hz, 3H), 0.93 (d, J=6.9 Hz, 3H), 1.22 (d, J=6.9 Hz, 3H), 1.18–1.37
(m, 21H), 1.31 (s, 3H), 1.48–1.60 (m, 2H), 1.75–1.93 (m, 2H), 2.72 (quin,
J=6.9 Hz, 1H), 2.82 (dt, J=13.2, 7.1 Hz, 1H), 2.91 (dt, J=13.2, 7.1 Hz,
1H), 3.39 (dd, J=8.8, 6.3 Hz, 1H), 3.53 (dd, J=8.8, 2.7 Hz, 1H), 3.58
(dd, J=6.9, 5.8 Hz, 1H), 3.62 (dd, J=10.7, 4.1 Hz, 1H), 3.81 (s, 3H), 4.41
(s, 2H), 6.87 (deformed d, J=8.8 Hz, 2H), 7.25 ppm (deformed d, J=
8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=11.9, 12.6, 13.2, 14.0, 22.6,
23.7, 24.9, 28.7, 28.8, 29.0, 29.2, 29.4 (two overlapping peaks), 29.48, 29.53
(two overlapping peaks), 31.8, 33.6, 35.4, 52.4, 55.2, 69.9, 72.1, 72.8, 76.2,
100.8, 113.7, 129.2, 131.1, 159.2, 201.9 ppm; IR (film): n˜ =1680 (s), 1610
(m), 1510 (s), 1250 (s), 1220 cmÀ1 (s); HRMS (EI): m/z: calcd for
C33H56O5S: 564.3848; found: 564.3852 [M]+.
(2R,3S,4R,5S,6S)-2-[(1Z,3S,4R)-3-Ethyl-4-hydroxy-1-pentenyl]-2-me-
thoxy-6-[(S)-2-(4-methoxybenzyloxy)-1-methylethyl]-3,5-dimethyltetrahy-
dropyran-4-ol (33): A mixture of 32 (28 mg, 0.062 mmol), Lindlarꢁs cata-
lyst (approximately 200 mg) and 1-hexene (0.5 mL) in EtOAc (1 mL) was
vigorously stirred for 15 min at room temperature under a hydrogen at-
mosphere. After this time, the mixture was filtered through a Celite pad
and concentrated in vacuo. The residue was chromatographed over silica
gel (hexane/EtOAc 5:1) to give 33 (25 mg, 89%) as a pale yellow oil.
1
[a]2D4 =À62.6 (c=1.65 in CHCl3); H NMR (300 MHz, CDCl3): d=0.87 (t,
J=7.5 Hz, 3H), 0.96 (d, J=6.9 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H), 1.03 (d,
J=6.6 Hz, 3H), 1.19 (d, J=6.0 Hz, 3H), 1.50–1.81 (m, 4H; H-3+OH),
1.88–2.05 (m, 2H), 2.60–2.73 (m, 1H), 3.04 (brs, 1H; OH), 3.15 (s, 3H),
3.41 (dd, J=7.7, 6.0 Hz, 1H), 3.51–3.58 (m, 2H), 3.71–3.88 (m, 2H), 3.79
(s, 3H), 4.36 (d, J=11.5 Hz, 1H), 4.40 (d, J=11.5 Hz, 1H), 5.36 (dd, J=
12.1, 10.9 Hz, 1H), 5.72 (d, J=12.1 Hz, 1H), 6.86 (deformed d, J=
8.5 Hz, 2H), 7.23 ppm (deformed d, J=8.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=5.1, 11.4, 12.0, 13.3, 21.9, 24.5, 35.1, 35.6, 41.9, 48.2, 48.6, 55.2,
69.4, 71.9, 72.3, 72.4, 72.6, 102.7, 113.7, 129.2, 130.9, 133.4, 137.1,
159.1 ppm; IR (film): n˜ =3425 (m), 1610 (m), 1510 (s), 1250 (s), 1035 (s),
760 cmÀ1 (s); HRMS (FAB): m/z: calcd for C26H42O6Na: 473.2879; found:
473.2882 [M+Na]+.
ACHTREUNG(2S,6S,7R)-7-(1-Ethoxyethoxy)-6-ethyl-2-{(4R,5R,6S)-6-[(S)-2-(4-methoxy-
benzyloxy-1-methylethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl]-4-octyn-3-one (29):
A solution of 30 (120 mg, 0.212 mmol) in DMF (0.5 mL) was added to a
stirred mixture of [PdCl
2ACHTRE(UGN dppf)] (17 mg, 0.020 mmol), CuI (69 mg,
0.36 mmol), tri(2-furyl)phosphine (12 mg, 0.050 mmol), and Et3N
ACHTREUNG
(0.3 mL) in DMF (1.0 mL) at room temperature. A solution of 27
(74 mg, 0.404 mmol) in DMF (0.3 mL) was then added at 508C, and the
resulting mixture was stirred for 3 h. After this time, the mixture was di-
luted with EtOAc and brine, and was filtered through a Celite pad. The
filtrate was extracted with EtOAc, and the extract was washed with
brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue
was chromatographed over silica gel (hexane/EtOAc 20:1) to give 29
(45 mg, 39%) as a pale yellow oil together with recovered 30 (74 mg,
61%). The recovered thiol ester was retreated with same reaction condi-
tions to give a mixture of 29 and 30, the latter of which was, after chro-
matographic separation, treated once more to the same operation to
(2S,3S,4R,5S,6R,8R,9S)-9-Ethyl-2-[(S)-2-(4-methoxybenzyloxy)-1-methyl-
ethyl]-3,5,8-trimethyl-1,7-dioxaspiroACTHRE[UNG 5.5]undec-10-en-4-ol (34): A catalyt-
ic amount of PPTS was added to a stirred solution of 33 (25 mg,
0.056 mmol) in toluene (1.5 mL) and the mixture was stirred at room
temperature for 1 h. After this time, the reaction was quenched with sa-
turated aqueous NaHCO3 and the resulting mixture was extracted with
EtOAc. The extract was washed with brine, dried (MgSO4), filtered, and
concentrated in vacuo. The residue was chromatographed over silica gel
(hexane/EtOAc 5:1) to give 23 mg (99%) of 34 as a pale yellow oil.
1
[a]2D4 =À5.3 (c=1.55 in CHCl3); H NMR (300 MHz, CDCl3): d=0.89 (d,
J=6.9 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H), 0.941 (d, J=6.9 Hz, 3H), 0.944
(t, J=7.4 Hz, 3H), 1.26 (s, 1H; OH), 1.31 (d, J=6.6 Hz, 3H), 1.47 (quin,
J=7.4 Hz, 2H), 1.55–1.71 (m, 2H), 1.87–1.97 (m, 1H), 1.97–2.07 (m,
1H), 3.29 (dd, J=8.9, 7.2 Hz, 1H), 3.58 (dd, J=8.9, 3.3 Hz, 1H), 3.77–
3.87 (m, 2H), 3.80 (s, 3H), 3.93 (q, J=6.6 Hz, 1H), 4.36 (s, 2H), 5.53 (dd,
J=10.3, 1.3 Hz, 1H), 5.99 (ddd, J=10.3, 5.4, 0.8 Hz, 1H), 6.86 (deformed
d, J=8.6 Hz, 2H), 7.24 ppm (deformed d, J=8.6 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=4.3, 11.8, 12.4, 13.3, 21.7, 26.1, 35.3, 36.0, 40.2, 40.9,
55.2, 71.2, 71.9, 72.5 (three overlapping peaks), 96.8, 113.7, 127.9, 129.3,
130.1, 131.0, 159.1 ppm; IR (film): n˜ =3450 (m), 3030 (w), 1610 (m), 1510
(s), 1250 (s), 1030 cmÀ1 (s); HRMS (FAB): m/z: calcd for C25H38O5Na:
441.2617; found: 441.2623 [M+Na]+.
eventually provide a maximum yield of 29 (96 mg, 83% in total). [a]D24
=
+11.4 (c=4.65 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.92 (d, J=
6.3 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 1.05 (t, J=7.4 Hz, 3H), 1.16–1.37
(m, 18H), 1.45–1.96 (m, 4H), 2.52–2.65 (m, 2H), 3.39 (dd, J=8.8, 6.0 Hz,
1H), 3.44–3.65 (m, 4H), 3.76–3.95 (m, 2H), 3.81 (s, 3H), 4.41 (s, 2H),
4.75 (q, J=5.4 Hz, 0.5H), 4.76 (q, J=5.4 Hz, 0.5H), 6.87 (deformed d,
J=8.8 Hz, 2H), 7.25 ppm (deformed d, J=8.8 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=9.5, 11.6, 12.2, 13.3, 15.2, 17.2 (0.5C), 18.3 (0.5C),
20.2 (0.5C), 20.4 (0.5C), 22.0 (0.5C), 22.4 (0.5C), 23.5, 24.6, 33.7, 35.1,
40.4 (0.5C), 40.7 (0.5C), 51.6, 55.2, 59.8 (0.5C), 60.0 (0.5C), 70.0, 72.1,
72.9, 73.3 (0.5C), 73.6 (0.5C), 75.0, 77.2, 96.1, 98.1 (0.5C), 99.9 (0.5C),
100.8, 113.7, 129.2, 131.0, 159.2, 186.2 ppm; IR (film): n˜ =2200 (m), 1670
(s), 1610 (m), 1510 (vs), 1250 (vs), 1225 (vs), 1080 cmÀ1 (vs); HRMS
(FAB): m/z: calcd for C32H50O7Na: 569.3454; found: 569.3459 [M+Na]+.
(2S,3R,4R,5S,6R,8R,9S)-9-Ethyl-2-[(S)-2-(4-methoxybenzyloxy)-1-meth-
ylethyl]-3,5,8-trimethyl-1,7-dioxaspiroCAHTRE[UNG 5.5]undec-10-en-4-yl acetate (35):
Acetic anhydride (20 mL, 0.21 mmol) and a catalytic amount of DMAP
was added to a stirred solution of 34 (10 mg, 0.024 mmol) in pyridine
(0.3 mL) at room temperature. After 24 h, the mixture was diluted with
saturated aqueous NH4Cl and extracted with EtOAc. The extract was
washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was chromatographed over silica gel (hexane/EtOAc 10:1)
to give 35 (11 mg quant) as a pale yellow oil. [a]2D4 =À17.0 (c=1.65,
CHCl3); 1H NMR (300 MHz, CDCl3): d=0.78 (d, J=6.6 Hz, 3H), 0.88
(d, J=6.9 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H), 0.93 (t, J=7.4 Hz, 3H), 1.29
(d, J=6.8 Hz, 3H), 1.40–1.51 (m, 2H), 1.61–1.70 (m, 1H), 1.80 (dq, J=
11.6, 6.6 Hz, 1H), 1.84–1.95 (m, 1H), 2.06 (s, 3H), 2.11–2.20 (m, 1H),
3.27 (dd, J=8.7, 7.5 Hz, 1H), 3.59 (dd, J=8.7, 3.3 Hz, 1H), 3.80 (s, 3H),
3.88 (dd, J=10.5, 2.1 Hz, 1H), 3.94 (q, J=6.8 Hz, 1H), 4.36 (s, 2H), 5.07
(dd, J=11.6, 4.7 Hz, 1H), 5.54 (dd, J=10.2, 1.4 Hz, 1H), 6.00 (ddd, J=
10.2, 5.8, 0.8 Hz, 1H), 6.86 (deformed d, J=8.8 Hz, 2H), 7.24 ppm (de-
formed d, J=8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=5.2, 11.8, 12.4,
13.3, 21.0, 21.7, 26.0, 33.4, 35.3, 38.0, 40.8, 55.2, 71.2, 71.3, 72.5 (two over-
lapping peaks), 75.4, 96.7, 113.7, 127.5, 129.2, 130.6, 131.0, 159.1,
170.7 ppm; IR (film): n˜ =3020 (w), 1735 (s), 1610 (m), 1510 (s),
1230 cmÀ1 (s); HRMS (FAB): m/z: calcd for C27H40O6Na: 483.2723;
found: 483.2727 [M+Na]+.
(2S,3S,4R,5S,6S)-2-[(3S,4R)-3-Ethyl-4-hydroxy-1-pentynyl]-2-methoxy-6-
[(S)-2-(4-methoxybenzyloxy)-1-methylethyl]-3,5-dimethyltetrahydropyr-
an-4-ol (32): Camphorsulfonic acid (1.3 mg, 5.5 mmol) was added to a stir-
red solution of 29 (12 mg, 22 mmol) and MeOH (0.2 mL) in CH2Cl2
(1.5 mL) at 08C, and the resulting mixture was stirred at 08C for 3 d.
After this time, the reaction was quenched with saturated aqueous
NaHCO3, and the resulting mixture was extracted with EtOAc. The ex-
tract was washed with brine, dried (Na2SO4), filtered, and concentrated
in vacuo. The residue was chromatographed over silica gel (hexane/
EtOAc 5:1) to give 32 (9.0 mg, 91%) as a pale yellow oil. The 1H NMR
spectrum indicated that the product was a 3:1 mixture of 32 and its C2-
epimer. [a]2D4 =À65.4 (c=1.65 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=0.92 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 1.05 (t, J=7.2 Hz,
3H), 1.13 (d, J=6.9 Hz, 3H), 1.27 (d, J=6.9 Hz, 3H), 1.50–1.64 (m. 3H),
1.75–1.95 (brs, 2H; 2”OH), 1.88–2.03 (m, 2H), 2.32–2.41 (m, 1H), 3.25
(s, 3H), 3.52–3.58 (m, 3H), 3.72–3.81 (m, 2H), 3.81 (s, 3H), 4.41 (s, 2H),
6.87 (deformed d, J=8.8 Hz, 2H), 7.25 ppm (deformed d, J=8.8 Hz,
2H); 13C NMR (75 MHz, CDCl3): d=4.3, 11.9, 12.3, 13.1, 21.2, 24.3, 34.7,
35.5, 41.7, 42.3, 50.2, 55.2, 69.0, 71.7, 71.9, 72.2, 72.7, 81.7, 84.1, 98.8,
113.7, 129.1, 130.9, 159.1 ppm; IR (film): n˜ =3400 (s), 2230 (w), 1610 (s),
1510 (s), 1250 cmÀ1 (s); HRMS (FAB): m/z: calcd for C26H40O6Na:
471.2723; found: 471.2727 [M+Na]+.
(2S,3R,4R,5S,6R,8R,9S)-9-Ethyl-2-[(S)-2-hydroxy-1-methylethyl]-3,5,8-
trimethyl-1,7-dioxaspiroACTHRE[UNG 5.5]undec-10-en-4-yl acetate (36): DDQ (25 mg,
Chem. Eur. J. 2006, 12, 4584 – 4593
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4591

S. Kuwahara et al.
0.11 mmol) was added to a stirred mixture of 35 (36.0 mg, 0.078 mmol)
and water (0.2 mL) in CH2Cl2 (1 mL) at 08C. After 1 h, the mixture was
diluted with water and extracted with EtOAc. The extract was washed
with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resi-
due was chromatographed over silica gel (hexane/EtOAc 30:1) to give
23 mg (86%) of 36 as a pale yellow oil. [a]2D4 =À21.9 (c=1.15 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.77 (d, J=6.8 Hz, 3H), 0.80 (d, J=
6.8 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H), 1.26 (brs,
1H; OH), 1.39 (d, J=6.8 Hz, 3H), 1.37–1.53 (m, 2H), 1.68–1.77 (m, 1H),
1.83 (dq, J=11.5, 6.8 Hz, 1H), 1.90–2.01 (m, 1H), 2.07 (s, 3H), 2.12–2.22
(m, 1H), 3.45 (brd, J=10.7 Hz, 1H), 3.64 (dd, J=10.7, 8.5 Hz, 1H), 3.99
(brq, J=6.8 Hz, 1H), 4.01 (dd, J=10.2, 2.5 Hz, 1H), 5.09 (dd, J=11.5,
4.8 Hz, 1H), 5.54 (dd, J=10.2, 1.4 Hz, 1H), 6.03 ppm (ddd, J=10.2, 5.5,
0.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=5.4, 11.6, 12.3, 12.7, 21.0,
21.2, 25.9, 33.7, 36.3, 38.1, 40.6, 68.5, 71.7, 74.7, 76.9, 97.0, 126.9, 131.6,
170.7 ppm; IR (film): n˜ =3500 (m), 1720 (s), 1240 (s), 1030 (s), 990 (s),
760 cmÀ1 (vs); HRMS (FAB): m/z: calcd for C19H33O5: 341.2328; found:
341.2333 [M+H]+.
(MgSO4), filtered, and concentrated in vacuo. The residue was chromato-
graphed over silica gel (hexane/EtOAc 30:1) to give 39 (9.0 mg, 83%) as
a pale yellow oil. [a]2D4 =+23.4 (c=0.55 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=0.90 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 0.93 (t, J=
7.2 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H), 1.25 (d, J=6.6 Hz, 3H), 1.46 (quin,
J=7.2 Hz, 2H), 1.54–1.67 (m, 2H), 2.01–2.11 (m, 1H), 2.42–2.51 (m,
1H), 3.72 (s, 3H), 3.75 (dd, J=9.9, 2.1 Hz, 1H), 3.84 (dd, J=11.1, 4.7 Hz,
1H), 3.91 (q, J=6.6 Hz, 1H), 5.51 (dd, J=10.4, 1.5 Hz, 1H), 5.78 (d, J=
15.3 Hz, 1H), 5.96 (dd, J=10.4, 5.7 Hz, 1H), 6.17 (dd, J=15.3, 10.2 Hz,
1H), 6.18 (dd, J=15.3, 7.0 Hz, 1H), 7.19 ppm (dd, J=15.5, 10.2 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=4.4, 11.8, 12.4, 15.1, 22.8, 26.1, 36.2, 38.4,
40.3, 40.8, 51.4, 71.6, 72.4, 74.5, 96.9, 118.9, 127.0, 127.6, 130.3, 145.6,
149.1, 167.9 ppm; IR (film): n˜ =3475 (m), 1700 (s), 1640 (s), 1620 (m),
1270 (s), 1220 (s), 1150 (s), 1030 (s), 1000 (s), 760 cmÀ1 (vs); HRMS
(FAB): m/z: calcd for C22H35O5: 379.2484; found: 379.2485 [M+H]+.
(S)-6-[(2S,3S,4R,5S,6R,8R,9S)-9-Ethyl-4-hydroxy-3,5,8-trimethyl-1,7-
dioxaspiroACHTRE[UGN 5.5]undec-10-en-2-yl]-2,4-heptadienoic acid (1): A solution of
KOH (0.5m in MeOH, 0.2 mL, 0.1 mmol) was added to a mixture of 39
(7.0 mg, 0.018 mmol) and water (0.1 mL), and the resulting mixture was
stirred at room temperature for 6 h. After this time, the mixture was ex-
tracted with ether and the aqueous layer was acidified to pH 2 with aque-
ous HCl (0.5m) and then extracted with EtOAc. The extract was washed
with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resi-
(2R,3R,4R,5S,6R,8R,9S)-9-Ethyl-3,5,8-trimethyl-2-[(R)-1-methyl-2-oxo-
ethyl]-1,7-dioxaspiroACHTREUNG[5.5]undec-10-en-4-yl acetate (37): Dess–Martin pe-
riodinane (43 mg, 0.10 mmol) was added to a stirred solution of 36
(23 mg, 0.068 mmol) and pyridine (30 mL) in CH2Cl2 (2 mL) at 08C. The
resulting solution was warmed to room temperature and stirred for 24 h.
The reaction was quenched with saturated aqueous Na2S2O3, and the re-
sulting mixture was extracted with EtOAc. The extract was washed with
brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue
was chromatographed over silica gel (hexane/EtOAc 10:1) to give 37
(21 mg, 91%) as a pale yellow oil. [a]2D4 =À40.9 (c=1.05 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.80 (d, J=6.8 Hz, 3H), 0.925 (t, J=
7.4 Hz, 3H), 0.929 (d, J=7.1 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H), 1.23 (d,
J=6.9 Hz, 3H), 1.39–1.50 (m, 2H), 1.61–1.71 (m, 1H), 1.84 (dq, J=11.7,
6.8 Hz, 1H), 2.08 (s, 3H), 2.14–2.24 (m, 1H), 2.55 (ddq, J=10.4, 3.2,
6.9 Hz, 1H), 3.96 (q, J=6.9 Hz, 1H), 4.24 (dd, J=10.4, 2.2 Hz, 1H), 5.10
(dd, J=11.7, 4.9 Hz, 1H), 5.53 (dd, J=10.4, 1.4 Hz, 1H), 6.00 (ddd, J=
10.2, 5.8, 1.1 Hz, 1H), 9.73 ppm (d, J=3.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=5.3, 9.6, 11.7, 12.3, 21.0, 22.2, 26.0, 33.2, 38.1, 40.7, 47.6, 71.4,
71.5, 74.7, 97.1, 126.9, 131.0, 170.6, 205.2 ppm; IR (film): n˜ =3030 (w),
1735 (s), 1730 (s), 1240 (s), 990 cmÀ1 (s); HRMS (FAB): m/z: calcd for
C19H31O5: 339.2172; found: 339.2177 [M+H]+.
due was purified by using preparative TLC (Merck silica gel 60 F254
,
0.5 mm thick; CHCl3/EtOAc 20:1) to give 1 (6.7 mg (99%) as a colorless
1
oil. [a]2D4 =+24 (c=0.15 in CHCl3); H NMR (500 MHz, CDCl3): d=0.90
(d, J=6.8 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H), 1.00
(d, J=6.8 Hz, 3H), 1.24 (d, J=6.8 Hz, 3H), 1.46 (quin, J=7.3 Hz, 2H),
1.56–1.67 (m, 2H), 2.03–2.10 (m, 1H), 2.49 (ddq, J=9.8, 6.8, 6.8 Hz, 1H),
3.75 (dd, J=9.8, 2.0 Hz, 1H), 3.85 (dd, J=11.2, 4.9 Hz, 1H), 3.91 (brq,
J=6.8 Hz, 1H), 5.51 (d, J=10.3 Hz, 1H), 5.78 (d, J=15.1 Hz, 1H), 5.96
(dd, J=10.3, 5.4 Hz, 1H), 6.19 (dd, J=15.4, 10.0 Hz, 1H), 6.25 (dd, J=
15.4, 6.8 Hz, 1H), 7.25 ppm (dd, J=15.1, 10.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3): d=4.5, 11.9, 12.5, 15.2, 22.9, 26.2, 36.2, 38.5, 40.3,
40.8, 71.6, 72.5, 74.5, 96.8, 118.1, 126.8, 127.5, 130.2, 147.5, 150.1,
171.0 ppm; IR (film): n˜3400 (m), 3020 (w), 2960 (s), 2925 (s), 2875 (s),
2650 (w), 1680 (s), 1635 (m), 1610 (m), 1455 (m), 1370 (w), 1300 (w),
1270 (m), 1200 (w), 1020 (m), 990 (s), 960 cmÀ1 (m); HRMS (FAB): m/z:
calcd for C21H32O5Na: 387.2147; found: 387.2151 [M+Na]+.
Methyl (S)-6-[(2S,3R,4R,5S,6R,8R,9S)-4-acetoxy-9-ethyl-3,5,8-trimethyl-
Methyl (S)-6-[(2S,3S,4R,5S,6S,8R,9S)-9-ethyl-4-hydroxy-3,5,8-trimethyl-
1,7-dioxaspiro
A
1,7-dioxaspiroACHERT[UNG 5.5]undec-10-en-2-yl]-2,4-heptadienoate (11-epi-39): An-
(1m in hexane, 36 mL, 0.036 mmol) was added dropwise to a stirred solu-
tion of 4 (8.7 mg, 0.037 mmol) in THF (0.3 mL) at À788C. After 20 min,
37 (6.0 mg, 0.018 mmol) in THF (0.5 mL) was added and the resulting
mixture was stirred at À788C for 3 h. After this time, the reaction was
quenched with saturated aqueous NH4Cl and the mixture was extracted
with EtOAc. The extract was washed with brine, dried (MgSO4), filtered,
and concentrated in vacuo. The residue was chromatographed over silica
gel (hexane/EtOAc 50:1) to give 38 (7.0 mg, 94%) as a pale yellow oil.
[a]2D4 =+17.3 (c=0.75 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.78
(d, J=6.9 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), 0.97
(d, J=6.9 Hz, 3H), 1.24 (d, J=6.9 Hz, 3H), 1.38–1.49 (m, 2H), 1.58–1.68
(m, 1H), 1.80 (dq, J=11.7, 6.9 Hz, 1H), 2.07 (s, 3H), 2.15–2.25 (m, 1H),
2.37–2.50 (m, 1H), 3.73 (s, 3H), 3.84 (dd, J=9.9, 2.1 Hz, 1H), 3.93 (q, J=
6.9 Hz, 1H), 5.06 (dd, J=11.7, 4.8 Hz, 1H), 5.52 (dd, J=10.2, 1.2 Hz,
1H), 5.78 (d, J=15.3 Hz, 1H), 5.97 (ddd, J=10.2, 5.8, 1.0 Hz, 1H), 6.10–
6.23 (m, 2H), 7.18 ppm (dd, J=15.3, 10.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=5.2, 11.8, 12.3, 15.1, 21.0, 22.7, 26.1, 33.5, 38.0, 38.3, 40.8, 51.3,
71.5, 73.7, 75.3, 96.8, 118.9, 127.1, 127.2, 130.8, 145.5, 148.8, 167.9,
170.7 ppm; IR (film): n˜ =3020 (w), 1720 (vs), 1640 (s), 1620 (m), 1240
(vs), 1000 (vs), 760 cmÀ1 (vs); HRMS (FAB): m/z: calcd for C24H37O6:
421.2590; found: 421.2594 [M+H]+.
hydrous MgBr2 (9.0 mg, 0.049 mmol) was added to a stirred solution of
39 (5.0 mg, 0.013 mmol) in CH2Cl2 (2 mL) at room temperature. After
3 h, the reaction was quenched with saturated aqueous NaHCO3 and the
mixture was extracted with EtOAc. The extract was washed with brine,
dried (Na2SO4), filtered, and concentrated in vacuo. The residue was
chromatographed over silica gel (hexane/EtOAc 20:1) to give 11-epi-39
(2.0 mg, 40%) as a pale yellow oil together with recovered 39 (3.0 mg,
1
60%). [a]2D4 =À22.3 (c=0.10 in CHCl3); H NMR (300 MHz, CDCl3): d=
0.88 (t, J=7.4 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H),
0.97 (d, J=7.1 Hz, 3H), 1.16–1.28 (m, 1H), 1.22 (d, J=6.0 Hz, 3H), 1.44–
1.55 (m, 1H), 1.78 (dq, J=11.3, 6.9 Hz, 1H), 1.81–1.90 (m, 1H), 1.95–
2.12 (m, 2H; H-1+OH), 2.52 (ddq, J=9.8, 6.6, 6.6 Hz, 1H), 3.26 (dd, J=
9.8, 1.6 Hz, 1H), 3.69 (dd, J=11.0, 4.7 Hz, 1H), 3.73 (s, 3H), 3.90 (dq,
J=9.8, 6.0 Hz, 1H), 5.77 (d, J=15.4 Hz, 1H), 5.89 (d, J=11.2 Hz, 1H),
5.93 (dd, J=11.2, 1.6 Hz, 1H), 6.09 (dd, J=15.4, 6.6 Hz, 1H), 6.21 (dd,
J=15.4, 10.4 Hz, 1H), 7.20 ppm (dd, J=15.4, 10.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=4.8, 9.9, 11.4, 15.3, 19.5, 23.3, 36.2, 38.2, 40.7, 42.2,
51.4, 68.1, 74.3, 75.6, 97.9, 118.8, 123.5, 127.6, 134.0, 145.7, 148.3,
168.0 ppm; IR (film): n˜ =3450 (m), 3030 (w), 1720 (s), 1640 (s), 1260 (m),
1000 cmÀ1 (s); HRMS (FAB): m/z: calcd for C22H35O5: 379.2484; found:
379.2489 [M+H]+.
Methyl (S)-6-[(2S,3S,4R,5S,6R,8R,9S)-9-ethyl-4-hydroxy-3,5,8-trimethyl-
(S)-6-[(2S,3S,4R,5S,6S,8R,9S)-9-Ethyl-4-hydroxy-3,5,8-trimethyl-1,7-
1,7-dioxaspiro
A
dioxaspiroACHTRE[GNU 5.5]undec-10-en-2-yl]-2,4-heptadienoic acid (2): By the same
amount of K2CO3 was added to
a
protocol as that described for the preparation of 1, 11-epi-39 (2.0 mg,
5.3 mmol) was converted into 2 (1.9 mg, 99%, colorless oil). [a]2D4 =À20.2
(c=0.05 in CHCl3); 1H NMR (600 MHz, CDCl3): d=0.87 (t, J=7.5 Hz,
3H), 0.92 (d, J=6.6 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.7 Hz,
0.029 mmol) in MeOH (1 mL) and the mixture was stirred at room tem-
perature for 3 h. After this time, the mixture was diluted with water and
extracted with EtOAc. The extract was washed with brine, dried
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Chem. Eur. J. 2006, 12, 4584 – 4593

Pteridic Acids A and B
FULL PAPER
3H), 1.16–1.25 (m, 1H), 1.22 (d, J=6.2 Hz, 3H), 1.45–1.54 (m, 1H), 1.78
(dq, J=11.2, 6.6 Hz, 1H), 1.82–1.88 (m, 1H), 2.04–2.10 (m, 1H), 2.53
(ddq, J=9.8, 6.8, 6.8 Hz, 1H), 3.26 (dd, J=9.8, 1.8 Hz, 1H), 3.69 (dd, J=
11.2, 4.7 Hz, 1H), 3.89 (dd, J=9.8, 6.2 Hz, 1H), 5.77 (d, J=15.5 Hz, 1H),
5.89 (d, J=11.0 Hz, 1H), 5.93 (dd, J=11.0, 2.1 Hz, 1H), 6.14 (dd, J=
15.4, 6.8 Hz, 1H), 6.24 (dd, J=15.4, 10.9 Hz, 1H), 7.26 ppm (dd, J=15.5,
10.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=4.7, 9.8, 11.4, 15.2, 19.4,
23.3, 36.1, 38.3, 40.7, 42.2, 68.1, 74.2, 75.6, 97.9, 118.2, 123.5, 127.5, 134.1,
147.8, 149.5, 171.7 ppm; HRMS (FAB): m/z: calcd for C21H31O5:
363.2172; found: 363.2175 [MÀH]À.
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We are grateful to Prof. Igarashi (Toyama Prefectural University) for
providing us with copies of the NMR spectra for pteridic acid A (1),
pteridic acid B (2), 39, and 40. We also thank Ms. Yamada (Tohoku Uni-
versity) for measuring NMR and MS spectra. This work was supported,
in part, by a Grant-in-Aid for Scientific Research (B) from the Ministry
of Education, Culture, Sports, Science and Technology of Japan (No.
16380075).
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Received: January 31, 2006
Published online: March 28, 2006
Chem. Eur. J. 2006, 12, 4584 – 4593
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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