Total syntheses of squamocin A and squamocin D, bi-tetrahydrofuran acetogenins from Annonaceae

Article abstract of DOI:10.1002/(SICI)1099-0690(200005)2000:10<1889::AID-EJOC1889>3.0.CO;2-R

The total syntheses of the Annonaceous acetogenins squamocin A and squamocin D have been achieved. The synthesis follows a modular strategy, wherein a left-side chain, the central bis-THF core and the right-side chain are assembled together. Key reactions are additions of organomagnesium compounds to bi-THF aldehydes. At the end of the synthesis the butenolide moiety was introduced. This modular synthetic approach should be useful for the synthesis of other related natural products as well as pharmacologically interesting analogs.

Full text of DOI:10.1002/(SICI)1099-0690(200005)2000:10<1889::AID-EJOC1889>3.0.CO;2-R

FULL PAPER
Total Syntheses of Squamocin A and Squamocin D, Bi-tetrahydrofuran
Acetogenins from Annonaceae
Ulrich Emde[a] and Ulrich Koert*[a]
Keywords: Total synthesis / Natural products / Squamocin A / Squamocin D
The total syntheses of the Annonaceous acetogenins squam-
compounds to bi-THF aldehydes. At the end of the synthesis
ocin A and squamocin D have been achieved. The synthesis the butenolide moiety was introduced. This modular syn-
follows a modular strategy, wherein a left-side chain, the
central bis-THF core and the right-side chain are assembled
together. Key reactions are additions of organomagnesium
thetic approach should be useful for the synthesis of other
related natural products as well as pharmacologically inter-
esting analogs.
Introduction
The acetogenins from Annonaceae are a class of natural
products with remarkable biological properties, e.g. as anti-
tumor agents, immunosuppressants or pesticides.[1] More
than 250 compounds from various plant species have been
isolated and characterised.[1] Among them is a subclass con-
taining a bi-THF subunit as a characteristic structural fea-
ture. Furthermore, these compounds have in common a left
alkyl side chain and a right alkyl side chain. A butenolide
is located at the end of the right-side chain. The bi-THF
acetogenins show the most promising in vitro activity and
selectivity against cancer cell lines. Studies concerned with
the mode of action indicate a blockage of mitochondrial
complex I (NADH-ubiquinone oxidoreductase).[2] The left
alkyl side chain seems to be important for membrane fixa-
tion. The membrane-bound conformation of Annonaceous
acetogenins and its relation to complex I inhibition has
been investigated.[3] In addition, these compounds inhibit
an NADH oxidase, which is overexpressed in the plasma
membrane of tumors but not in normal cells.[4] The acetog-
enins induce a decrease of the tumor-cell ATP level, which
has an inhibitory effect on multiple drug resistance caused
by ATP-driven transporter systems.
Figure 1. Structures of selected bi-THF-acetogenins
Representative members of the bi-THF acetogenins with
a threo-anti-threo configuration are squamocin A, squamo-
cin D, squamocin G and squamocin H (Figure 1).[5] De-
pending on the plant source different names were given in
the past for the same compound. Squamocin A[5] is syn-
onymous to annonin I[6] and rollinicin.[7] Its relative and
absolute configuration was assigned by a combination of
X-ray structure analysis and spectroscopic methods.[5]Ϫ[7]
Squamocin D[5] corresponds to asiminacin[8] and squamo-
cin G[5] is known as bullatacin[9] or rolliniastatin-2.[10] Squa-
mocin H[5] is called asimicin[11] or annonastatin.[12]
(adjacent THF-THP,[13] nonadjacent THF-THP,[14] tri-
THF,[15] adjacent bi-THF,[16] nonadjacent bi-THF,[17]
mono-THF,[18] other acetogenins[19]). Here we report in de-
tail on the total syntheses of squamocin A and squamocin
D.[16d]
Results and Discussion
Our retrosynthetic analysis of squamocin A and D leads
to an introduction of the butenolide unit at the end of the
synthesis (Scheme 1). A protected hydroxy group at C1 in
1 and 2 is a suitable precursor for the butenolide. Oxidation
of the hydroxy group to the corresponding carboxylic acid
and reaction with propene oxide would result in a butyrol-
actone. Introduction of the C2ϪC35 double bond could
Numerous contributions highlight the importance of an
efficient synthetic access to the Annonaceous acetogenins
[a]
Institut für Chemie der Humboldt-Universität zu Berlin
Hessische Straße 1Ϫ2, 10115 Berlin, Germany
Fax: (internat.) ϩ 49-(0)30/2093-7266
E-mail: koert@lyapunov.chemie.hu-berlin.de
Eur. J. Org. Chem. 2000, 1889Ϫ1904
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0510Ϫ1889 $ 17.50ϩ.50/0
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U. Emde, U. Koert
FULL PAPER
Scheme 1. Retrosynthetic analysis of squamocin A and squamo-
cin D
then give rise to the target substructure. The next retrosyn-
thetic steps involve the disconnection at C15ϪC16 and
C23ϪC24 leading to the corresponding organometallic side
chains 3 and 5 and to the dialdehyde 4. In the synthetic
sequence it would be advantageous to subsequently gener-
ate and react the two aldehyde functions. The resulting
strategy has a common entry to both squamocins with a
bifurcation point at the addition of the left-side chain.
The starting point for the synthesis of the bi-THF core
was bromide 6[20] (Scheme 2). An optimized route[21,22] to
the bi-THF diol 13[23] was followed. Alkylation of bromide
6 with acetylene gave alkyne 7 in 82% yield, which was al-
lowed to react again with the bromide 6 to yield the C2-
symmetric alkyne 8. It was found that the solvent combina-
tion NH3/THF/DMSO (2.5:1:1) and rapid addition of
Scheme 2. (a) LiCϵCH en, NH3/THF (2.5:1), Ϫ33 °C, 2 h, 82%;
(b) nBuLi, 6, NH3/THF/DMSO (2.5:1:1), Ϫ33 °C, 4 h, 85%; (c)
LiCϵCH en, nBuLi, NH3/THF (2.5:1), Ϫ33 °C, 3 h, then nBuLi,
with addition of DMSO as a co-solvent, 6, Ϫ33 °C, 4 h, 45%; (d)
Na, NH3/THF (5:1), Ϫ33 °C, 4 h, 92%; (e) K2CO3, K3[Fe(CN)6],
K2OsO4 H2O, (DHQ)2PHAL, CH3SO2NH2, tBuOH/H2O (1:1), 0
°C, 18 h, 91%, ds ϭ 98:2; (f) pTsCl, py, CH2Cl2, 0 °C, 12 h, 86%;
(g) HOAc/H2O (5:1), room temp., 12 h, 99%; (h) NaH, THF, 0 °C,
4 h, 92%; (i) TBDMSCl, imidazole, CH2Cl2, 0 °C, 2 h, 43% and
diprotected bifuran 40%; (j) (COCl)2, DMSO, NEt3, CH2Cl2, Ϫ60
Ǟ Ϫ40 °C, 1.5 h, 91%; TBDMS ϭ tert-butyldimethylsilyl, pTs ϭ
p-toluenesulfonyl, py ϭ pyridine, en ϭ ethylenediamine
nBuLi were crucial for obtaining a high yield (85%) in the Mono-TBDMS protection of 14 followed by Swern oxida-
second alkylation step. An one-pot double alkylation of 6 tion provided the bi-THF aldehyde 15.
to 8 was possible in 45% yield. An (E)-selective reduction
The right-side chain was prepared from the dicarboxylic
of alkyne 8 to the corresponding alkene followed by a acid 16 (Scheme 3). Borane reduction furnished a diol,
Sharpless dihydroxylation[24] gave, with a ‘‘self-mixedЈЈ AD- which was monobenzylated to the monoalcohol 17. The lat-
mix α, the two diastereomeric diols 9 and 10 in a ratio ter was transformed via the tosylate into the bromide 18.
greater than 98:2. On using a commercially available AD- Next, the Grignard reagent prepared from 18 was allowed
mix α, a diastereoselectivity between 90:10 and 98:2 was to react with aldehyde 15. A PCC oxidation of the resulting
observed. The two diastereomers 9 and 10 were difficult to alcohol and a subsequent stereoselective -selectride re-
distinguish by their NMR spectra. Therefore, the selectivity duction[25] of the ketone led to the alcohol 19. The stereo-
was determined at the bis(tosylate) stage. Double tosylation selectivity of the -selectride reduction was 98:2, as deter-
of 9/10 gave the acetonide-protected bis(tosylates) 11 and mined by NMR spectroscopy. Protection of the secondary
12. Depending on the diastereoselectivity of the dihy- hydroxy group in 19 followed by the selective (89%) depro-
droxylation step, varying amounts of the minor epimer 12 tection of the primary TBDMS group using CSA in
were chromatographically separated at this stage. Double CH2Cl2/MeOH gave the alcohol 20. The latter could be
deprotection of 11 gave the tetrahydroxy bis(tosylate) 13. A converted into the aldehyde 21 by a Swern oxidation.
5-ring selective multiple Williamson reaction[21,22] of 13
gave the trans-threo-trans bi-THF diol 14 in 92% yield. 28. The elaboration of this partial structure (Scheme 4) was
The left-side chain contains a stereogenic center at C-
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Eur. J. Org. Chem. 2000, 1889Ϫ1904

Total Syntheses of Squamocin A and Squamocin D
FULL PAPER
on a 30-mmol scale, it was necessary to reflux the catalyst
with molecular sieves for 90 min before adding further re-
agents. The (S) configuration of the new chiral center was
proven by conversion of the alcohol 23 into the acetate 24
followed by comparison of the chiroptical data for 24 and
ent-24[27] {found: [α]D20 ϭ Ϫ23.5 (c ϭ 0.23, CHCl3), ref.[27]
:
[α]2D0 ϭ ϩ 23.7 for ent-24 (c ϭ 1.0, CHCl3)}. A TBDMS
protection of 23 and a subsequent hydroboration with 9-
BBN gave the primary alcohol 25, which was then con-
verted via its tosylate into bromide 26.
For the attachment of the left-side chain, bromide 26 was
converted into the corresponding Grignard reagent
(Scheme 5). Reaction of this Grignard reagent with alde-
hyde 21 gave the two epimers, 27 and 28, in a 2:1 ratio. The
two epimers could be separated by column chromatography.
The stereochemical assignment of the two epimers was
based on the 13C-NMR chemical shift[6] of the new ste-
reocenter (27: δ ϭ 74.0; 28: δ ϭ 71.2).
Scheme 3. (a) BH3 Me2S, THF, room temp. Ǟ 50 °C, 4 h, 98%; (b)
BnCl, KOH, 110 °C, 5 h, 61%; c) pTsCl, py, CH2Cl2, 0 °C, 12 h,
93%; (d) LiBr, THF, 0 °C Ǟ 45 °C, 5 h, 88%; (e) Mg, 18, 1,2-
dibromoethane, Et2O, room temp. Ǟ 40 °C, 1 h, then 15, Et2O,
˚
Ϫ40 °C Ǟ room temp., 3 h, 76%; f) PCC, 4 A molecular sieves,
room temp., 1 h, 72%; (g) -selectride , THF, Ϫ100 °C Ǟ Ϫ70 °C,
2 h, 96%, ds ϭ 98:2; (h) TBDMSCl, imidazole, CH2Cl2, 0 °C, 12 h,
87%; (i) CSA, CH2Cl2/MeOH (1:1), 2 h, Ϫ10 °C Ǟ 0 °C, 89%; (j)
(COCl)2, DMSO, NEt3, CH2Cl2, Ϫ60 Ǟ Ϫ40 °C, 1.5 h, 90%; Bn ϭ
benzyl, PCC ϭ pyridiniumchlorochromate, CSA ϭ camphorsul-
fonic acid
Scheme 5. (a) Mg, 26, 1,2-dibromoethane, Et2O, room temp. Ǟ 40
°C, 1 h, then CuBr Me2S, 21, Et2O, Ϫ60 °C Ǟ room temp., 12 h,
80%; separation of the two compounds by CC, ds 2:1 in favour of
epimer 27
Now that the two side chains had been attached to the
bi-THF subunit, the introduction of the butenolide re-
mained to be accomplished. For the synthesis of squamocin
D, the alcohol 27 was further elaborated (Scheme 6).
TBDMS protection followed by hydrogenolysis of the
benzyl ether function provided alcohol 29. A two-step ox-
idation (Swern/chlorite) of 29 gave the carboxylic acid 30.
Treatment of the dianion of 30 with (S)-propylene oxide[28]
afforded a hydroxy carboxylic acid, which was cyclized via
a mixed anhydride to the butyrolactone 31. It was found
that the addition of LiCl to the solvent was necessary for a
good turnover in the reaction of the dianion with the epox-
ide. The dilithium salt of the carboxylic acid may form an
intramolecular complex with the bi-THF moiety, resulting
in a decreased reactivity of the dianion. An indication for
this situation came from model studies for the introduction
of the butenolide (Scheme 7). Here, the carboxylic acid 33
was converted with good turnover into the butyrolactone
˚
Scheme 4. (a) (R)-BINOL, Ti(OiPr)4, 4 A molecular sieves, allyltri-
butylstannane, CH2Cl2, Ϫ25 °C, 5 d, 90%, ee 99:1 (determined by
chiral GC); (b) Ac2O, py, cat. DMAP, room temp., 36 h, 52%; (c)
TBDMSCl, imidazole, CH2Cl2, 0 °C, 12 h, 98%; (d) 9-BBN, THF,
0 °C Ǟ room temp., 18 h, 91%; (e) pTsCl, py, CH2Cl2, 0 °C, 12 h,
82%; (f) LiBr, THF, 0 °C Ǟ 35 °C, 30 h, 93%; DMAP ϭ 4-di-
methylaminopyridine, 9-BBN ϭ 9-borabicyclo[3.3.1]nonane, BI-
NOL ϭ 2,2Ј-dihydroxy-1,1Ј-binaphthyl
accomplished by an enantioselective allylation of heptanal 34. The addition of LiCl was not necessary in this case,
22 to the homoallylic alcohol 23 using Keck’s procedure.[26] where the complexing bi-THF subunit is absent. Com-
R-BINOL/Ti(OiPr)4 was used as the chiral Lewis acid. The pound 34 was transformed into the butenolide 35 by selen-
enantioselectivity of the allylation was 99:1, as determined ation and subsequent syn elimination of the corresponding
by GC analysis. In order to obtain such a high selectivity selenium oxide.
Eur. J. Org. Chem. 2000, 1889Ϫ1904
1891

U. Emde, U. Koert
FULL PAPER
Scheme 7. (a) (COCl)2, DMSO, NEt3, CH2Cl2, Ϫ60 Ǟ Ϫ40 °C,
1.5 h, 94%; (b) NaOCl2, NaH2PO4 2 H2O, 2-methyl-2-butene/
tBuOH/H2O (1:3:5), 2.5 h, 99%; (c) LDA, THF, 0 Ǟ 20 °C, 40 min,
then (S)-propylene oxide, 0 °C Ǟ room temp., 2.5 h; (d) PivCl,
NEt3, CH2Cl2, room temp., 30 min, 64% from 33; (e) KHMDS,
THF, 0 °C Ǟ room temp., 50 min, then PhSeCl, 2.5 h; (f) MMPP,
THF/MeOH (1:1), room temp., 20 min, 70% from 34
Scheme 6. (a) TBDMSOTf, 2,6-lutidine, CH2Cl2, Ϫ20 °C, 45 min,
91%; (b) H2 (1 atm), 10% Pd/C, ethyl acetate/iPrOH (1:1), room
temp., 3 h, 99%; (c) (COCl)2, DMSO, NEt3, CH2Cl2, Ϫ60 Ǟ Ϫ40
°C, 1.5 h; (d) NaOCl2, NaH2PO4 2 H2O, 2-methyl-2-butene/
tBuOH/H2O (1:3:5), 2.5 h, 95% from 29; (e) LDA, THF saturated
with LiCl, 0 Ǟ 20 °C, 40 min, then (S)-propylene oxide, 0 °C Ǟ
room temp., 2.5 h; (f) PivCl, NEt3, CH2Cl2, room temp., 30 min,
52% from 30; (g) KHMDS, THF, 0 °C Ǟ room temp., 50 min, then
PhSeCl, 2.5 h; (h) MMPP, THF/MeOH (1:1), room temp., 20 min,
40% from 31; (i) 5% HF in CH3CN, THF, room temp., 2 h, 79%;
MMPP ϭ magnesium monoperoxophthalate
The C2ϪC35 double bond of the natural product was
introduced by the same method (Scheme 6). Selenation of
31 followed by syn elimination of the selenium oxide re-
sulted in the butenolide derivative 32. Cleavage of the silyl
protecting groups in 32 provided squamocin D ([α]2D1 ϭ ϩ20
(c ϭ 0.097 in CHCl3), which was found to be identical with
the naturally occurring product in respect to the spectro-
scopic data.
Scheme 8. (a) TBDMSOTf, 2,6-lutidine, CH2Cl2, Ϫ20 °C, 2 h; (b)
H2 (1 atm), 10% PdϪC, ethyl acetate/iPrOH (1:1), room temp.,
12 h, 75% from 28; (c) (COCl)2, DMSO, NEt3, CH2Cl2, Ϫ60 Ǟ
Ϫ40 °C, 1.5 h; (d) NaOCl2, NaH2PO4 2 H2O, 2-methyl-2-butene/
tBuOH/H2O (1:3:5), 12 h, 89% from 36; (e) LDA, THF saturated
with LiCl, room temp., 20 min, then (S)-propylene oxide, room
temp., 12 h; (f) PivCl, NEt3, CH2Cl2, room temp., 30 min, 58%
from 37; (g) LDA, THF, room temp., 30 min, then PhSeCl, 0 °C
Ǟ room temp., 2.5 h; (h) MMPP, THF/MeOH (1:1), room temp.,
30 min, 40% from 38; (i) 5% HF in CH3CN, THF, room temp.,
6 h, 82%
On using the same reaction sequence the alcohol 28 was
converted into squamocin A (Scheme 8). Compound 28 was
converted via the alcohol 36 into the carboxylic acid 37.
The latter was transformed into the butyrolactone 38. In-
troduction of the double bond and removal of the TBDMS
Conclusion
A modular strategy for the assembly of squamocin A and
protecting groups gave the target compound squamocin A. D is presented. One noteworthy aspect is the stereodiverg-
1892
Eur. J. Org. Chem. 2000, 1889Ϫ1904

Total Syntheses of Squamocin A and Squamocin D
FULL PAPER
MgSO4. Removal of the solvents in vacuo and purification by CC
(500 cm3 SiO2, PE/MTBE, 10:1) gave alkyne 8 (14.12 g, 50.0 mmol,
85%) as a colorless liquid. Ϫ Rf ϭ 0.13 (SiO2, PE/MTBE, 10:1). Ϫ
[α]2D4 ϭ ϩ7.1 (c ϭ 1.80, CHCl3). Ϫ IR (KBr): ν˜ ϭ 2985 , 2936,
2871 s (CH), 1454 m, 1379 s, 1370 s, 1245 s, 1215 s, 1157 m, 1073
ent step 26 Ǟ 27 ϩ 28, which allows the synthesis of both
natural products from a common precursor. Squamocin G
and squamocin H, as well as pharmacologically important
analogs, should be accessible using the same strategy.
1
s, 855 m cmϪ1. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.29 (s, 6 H,
acetonide-H3), 1.34 (s, 6 H, acetonide-H3), 1.58Ϫ1.76 (m, 4 H, 3-
H2, 8-H2), 2.16Ϫ2.22 (m, 4 H, 4-H2, 7-H2), 3.50 (dd, J ϭ 7.9,
6.8 Hz, 2 H, 1-HЈ, 10-HЈ), 4.00 (dd, J ϭ 7.9, 6.0 Hz, 2 H, 1-HЈЈ,
10-HЈЈ), 4.07Ϫ4.14 (m, 2 H, 2-H, 9-H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 15.3 (C-4, C-7), 25.7 (acetonide-C), 26.9 (acetonide-
C), 33.1 (C-3, C-8), 69.1 (C-1, C-10), 74.9 (C-2, C-9), 79.6 (C-5, C-
6), 108.7 (acetal-C). Ϫ C16H26O4 (282.38): calcd. C 68.06, H 9.28;
found C 67.89, H 9.01.
Experimental Section
General: All boiling points and melting points are uncorrected
values. Ϫ IR: PerkinϪElmer FT-IR 1600, Biorad FTS 3000MX. Ϫ
NMR: Bruker AC-300, DPX-300 and AMX-600. For 1H NMR,
CDCl3 as solvent (δH ϭ 7.24); for 13C NMR, CDCl3 as solvent
(δC ϭ 77.0). Ϫ Elemental analysis: CHNS-932 Analyser (Leco). Ϫ
HRMS: Finnigan MAT 95. All reactions were performed under Ar
in oven- or flame-dried glassware. Ϫ GC: Shimadzu GC-14A, C-
R4AX. Dry solvents: THF, Et2O, benzene, xylene and toluene were
distilled from sodium benzophenone ketyl. Pyridine, triethylamine
and CH2Cl2 were distilled from CaH2. All commercially available
reagents were used without purification unless stated otherwise. All
reactions were monitored by thin-layer chromatography (TLC) car-
ried out on Merck F-254 silica glass plates visualized with UV light
and/or heat-gun treatment with 5% phosphomolybdic acid in eth-
anol. Ϫ Column chromatography (CC) and flash column chroma-
tography (FCC) were performed with Merck silica gel 60 (70Ϫ200
mesh and 230Ϫ400 mesh). PE: light petroleum ether, bp 40Ϫ60 °C.
MTBE: tert-butyl methyl ether.
Alternative Preparation of (2R,9R)-1,2;9,10-Di-O-isopropylidene-5-
decyne-1,2,9,10-tetraol (8): LiCϵCH en complex (90%, 2.74 g,
26.8 mmol) was suspended in liquid ammonia (100 mL) at Ϫ78 °C.
A solution of bromide 6 (4.08 g, 19.5 mmol) in THF (20 mL) was
added quickly. The mixture was refluxed for 3 h at Ϫ33 °C. Under
vigorous stirring nBuLi (2.5 mmol/mL, 10.0 mL, 25.0 mmol) was
added as quickly as possible. The mixture was stirred for 10 min at
Ϫ78 °C and the cooling bath was removed. After 5 min, DMSO
(35 mL) was added and 5 min later rapid addition of a solution of
bromide 6 (6.19 g, 29.6 mmol) in THF (20 mL) followed. The mix-
ture was refluxed for 4 h with vigorous stirring at Ϫ33 °C. The
condensed ammonia was allowed to evaporate overnight. After ad-
dition of sat. aqueous NH4Cl (75 mL) the aqueous layer was ex-
tracted twice with MTBE (75 mL). The combined organic layers
were washed with sat. aqueous NaCl (75 mL) and dried with
MgSO4. After purification by CC (300 cm3 SiO2, PE/MTBE, 10:1)
alkyne 8 (2.48 g, 8.79 mmol, 45%) was obtained as a colorless li-
quid.
(2R)-1,2-O-Isopropylidene-5-hexyne-1,2-diol (7): LiCϵCH en com-
plex (90%, 8.03 g, 78.5 mmol) was suspended in liquid ammonia
(100 mL) at Ϫ78 °C. A solution of bromide 6 (12.63 g, 60.38 mmol)
in THF (40 mL) was added quickly. The mixture was refluxed for
2 h at Ϫ33 °C. The condensed ammonia was allowed to evaporate
overnight. After addition of sat. aqueous NH4Cl (100 mL), the
aqueous layer was extracted twice with MTBE (100 mL). The com-
bined organic layers were washed with sat. aqueous NaCl (100 mL)
and dried with MgSO4. Removal of the solvents in vacuo and puri-
fication by CC (375 cm3 SiO2, PE/MTBE, 10:1) yielded alkyne 7
(7.61 g, 49.4 mmol, 82%) as a colorless liquid. Ϫ Rf ϭ 0.43 (SiO2,
PE/MTBE, 10:1). Ϫ bp: 63 °C (14 mbar). Ϫ [α]2D4 ϭ ϩ7.8 (c ϭ
1.89, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3295 s (CϵCH), 2986 s, 2937 m,
2874 w (CH), 2118 w (CϵC), 1454 s, 1380 m, 1371 m, 1246 m,
1216 m, 1156 m, 1074 s, 854 m, 638 m cmϪ1. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 1.29 (s, 3 H, acetonide-H3), 1.34 (s, 3 H,
acetonide-H3), 1.67Ϫ1.77 (m, 2 H, 3-H2), 1.90 (t, J ϭ 2.7 Hz, 1 H,
6-H), 2.21Ϫ2.28 (m, 2 H, 4-H), 3.51 (dd, J ϭ 7.9, 6.9 Hz, 1 H, 1-
HЈ), 4.01 (dd, J ϭ 7.9, 6.0 Hz, 1 H, 1-HЈЈ), 4.10Ϫ4.16 (m, 1 H, 2-
H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 15.0 (C-4), 25.6 (aceton-
ide-C), 26.9 (acetonide-C), 32.6 (C-3), 68.7 (C-6), 69.0 (C-1), 74.7
(C-2), 83.5 (C-5), 108.8 (acetal-C).
(2R,5S,6S,9R)-1,2;9,10-Di-O-isopropylidenedecane-1,2,5,6,9,10-
hexaol (9). ؊ 1. Reduction of the Alkyne: Na (2.92 g, 127.1 mmol)
was dissolved in liquid ammonia (100 mL) at Ϫ78 °C (the typical
dark-blue color appeared). A solution of alkyne 8 (13.01 g,
46.08 mmol) in THF (20 mL) was added. The mixture was refluxed
with vigorous stirring for 4 h at Ϫ33 °C. The condensed ammonia
evaporated overnight. Under argon at 0 °C the mixture was treated
dropwise with 2-propanol (50 mL) and then with sat. aqueous
NH4Cl (100 mL). The aqueous layer was extracted twice with
MTBE (100 mL). The combined organic layers were washed with
sat. aqueous NaCl (75 mL) and dried with MgSO4. Purification by
CC (350 cm3 SiO2, PE/MTBE, 10:1 and 5:1) afforded the alkene
(11.99 g, 42.22 mmol, 92%) as a colorless liquid.
(2R,5E,9R)-1,2;9,10-Di-O-isopropylidene-5-decene-1,2,9,10-tetraol:
Rf ϭ 0.41 (SiO2, PE/MTBE, 5:1). Ϫ [α]2D2 ϭ Ϫ23.2 (c ϭ 1.07,
CHCl3). Ϫ IR (KBr): ν˜ ϭ 2985, 2935, 2867 s (CH), 1620 w (Cϭ
C), 1378 s, 1369 s, 1248 s, 1216 s, 1157 m, 1066 s, 971 w (trans-Cϭ
C), 857 m cmϪ1. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.28 (s, 6
H, acetonide-H3), 1.33 (s, 6 H, acetonide-H3), 1.46Ϫ1.51 (m, 2 H,
3-HЈ, 8-HЈ), 1.61Ϫ1.66 (m, 2 H, 3-HЈЈ, 8-HЈЈ), 1.95Ϫ2.05 (m, 4 H,
4-H2, 7-H2), 3.43 (t, J ϭ 7.2 Hz, 2 H, 1-HЈ, 10-HЈ), 3.93Ϫ4.03 (m,
4 H, 1-HЈЈ, 2-H, 9-H, 10-HЈЈ), 5.37 (dt, J ϭ 3.5, 2.0 Hz, 2 H, 5-H,
6-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 25.7 (acetonide-C), 26.9
(acetonide-C), 28.7 (C-4, C-7), 33.3 (C-3, C-8), 69.3 (C-1, C-10),
75.5 (C-2, C-9), 108.5 (acetal-C), 129.8 (C-5, C-6). Ϫ C16H28O4
(284.40): calcd. C 67.57, H 9.92; found C 67.63, H 9.84.
(2R,9R)-1,2;9,10-Di-O-isopropylidene-5-decyne-1,2,9,10-tetraol (8):
Alkyne 7 (9.08 g, 58.9 mmol) was dissolved in liquid ammonia
(100 mL) and THF (30 mL) at Ϫ78 °C. Under vigorous stirring
nBuLi (2.4 mmol/mL, 25.0 mL, 60.0 mmol) was added as quickly
as possible. After 15 min of stirring at Ϫ78 °C, the cooling bath
was removed and, after another 5 min, DMSO (50 mL) was added.
The solution solidified. Very rapid addition of a solution of brom-
ide 6 (15.2 g, 72.6 mmol) in THF (20 mL) redissolved the reaction
mixture immediately. The color of the solution turned to yellow-
green. The mixture was refluxed for 4 h with vigorous stirring at
Ϫ33 °C. The ammonia was allowed to evaporate overnight. After
addition of sat. aqueous NH4Cl (100 mL) the aqueous layer was
extracted twice with MTBE (100 mL). The combined organic layers
were washed with sat. aqueous NaCl (100 mL) and dried with
2. Dihydroxylation: K2CO3 (17.51 g, 126.7 mmol), K3[Fe(CN)6]
(41.72 g, 126.7 mmol), K2OsO4 2 H2O (73 mg, 0.2 mmol) and
(DHQ)2PHAL (362 mg, 0.5 mmol) were dissolved in tBuOH
Eur. J. Org. Chem. 2000, 1889Ϫ1904
1893

U. Emde, U. Koert
FULL PAPER
(215 mL) and H2O (215 mL). After addition of MeSO2NH2
(4.12 g, 43.28 mmol), the mixture was cooled to 0 °C. A yellow-
red precipitate appeared. The mixture was charged with the alkene
(11.99 g, 42.16 mmol) and stirred for 18 h. Addition of Na2S2O3
(62.1 g) stopped the reaction. The aqueous layer was extracted
three times with ethyl acetate (150 mL). The combined organic
1-HЈ, 10-HЈ), 3.77Ϫ3.90 (m, 4 H, 1-HЈЈ, 2-H, 9-H, 10-HЈЈ),
4.58Ϫ4.67 (m, 2 H, 5-H, 6-H), 7.34 (d, J ϭ 8.3 Hz, 4 H, tosyl-H),
7.78 (d, J ϭ 8.3 Hz, 4 H, tosyl-H). Ϫ 13C NMR (75 MHz, CDCl3):
δ ϭ 21.7 (tosyl-CH3), 25.0 (C-4, C-7), 25.6 (acetonide-CH3), 26.9
(acetonide-CH3), 29.1 (C-3, C-8), 69.1 (C-1, C-10), 74.9 (C-2, C-
9), 80.0 (C-5, C-6), 108.9 (acetal-C), 128.2, 129.0, 133.0, 145.2
layers were washed separately with 2  NaOH (150 mL), sat. aque- (tosyl-C). Ϫ HRMS (EI): calcd. 611.1985 (M Ϫ CH3)ϩ; found
ous NaHCO3 (200 mL) and sat. aqueous NaCl (100 mL) and dried
with MgSO4. Removal of the solvents and purification by CC (600
cm3 SiO2, ethyl acetate/PE, 3:1) gave diol 9 (12.26 g, 38.52 mmol,
91%, ds 98:2) as colorless crystals. Ϫ Rf ϭ 0.18 (SiO2, ethyl acetate/
PE, 3:1). Ϫ M.p. 85 °C. Ϫ [α]2D3 ϭ Ϫ28.2 (c ϭ 0.33, CHCl3). Ϫ IR
(KBr): ν˜ ϭ 3402 bs, 3286 s (OH), 2986, 2944, 2868 s (CH), 1400 s,
611.1984.
5,6-Bis-p-toluenesulfonate 13 of (2R,5S,6S,9R)-Decane-1,2,9,10-
tetraol: Bis(tosylate) 11 (20.45 g, 32.63 mmol) was dissolved in
conc. HOAc (250 mL) and H2O (50 mL). The solution was stirred
for 12 h. After treatment with H2O (50 mL), the solvents were re-
moved in vacuo. The residue was treated three times with toluene
(75 mL) and the solvents were, in each case, removed in vacuo. The
crude product, tetraol 13 (17.77 g, 32.50 mmol, 99%), was obtained
as a colorless, viscous oil. Ϫ Rf ϭ 0.14 (SiO2, CHCl3/MeOH, 10:1).
1
1370 s, 1219 s, 1158 m, 1113 m, 1064 s, 860 m cmϪ1. Ϫ H NMR
(300 MHz, CDCl3): δ ϭ 1.33 (s, 6 H, acetonide-H3), 1.39 (s, 6 H,
acetonide-H3), 1.47Ϫ1.61 (m, 2 H, 3-HЈ, 8-HЈ), 1.63Ϫ1.77 (m, 6
H, 3-HЈЈ, 8-HЈЈ, 4-H2, 7-H2), 2.70 (d, J ϭ 4.4 Hz, 2 H, OH),
3.42Ϫ3.53 (m, 4 H, 1-HЈ, 2-H, 9-H, 10-HЈ), 4.01Ϫ4.10 (m, 4 H, 1-
HЈЈ, 5-H, 6-H, 10-HЈЈ). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 25.7
(acetonide-CH3), 26.9 (acetonide-CH3), 29.5 (C-4, C-7), 29.9 (C-3,
C-8), 69.5 (C-1, C-10), 74.1 (C-2, C-9), 76.2 (C-5, C-6), 109.0 (ace-
tal-C). Ϫ C16H30O6 (318.41): calcd. C 60.36, H 9.50; found C 60.06,
H 9.40.
1
Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.98Ϫ1.17 (m, 2 H, 3-HЈ, 8-
HЈ), 1.18Ϫ1.34 (m, 2 H, 3-HЈЈ, 8-HЈЈ), 1.45Ϫ1.63 (m, 2 H, 4-HЈ,
7-HЈ), 1.73Ϫ1.91 (m, 2 H, 4-HЈЈ, 7-HЈЈ), 2.41 (s, 6 H, tosyl-CH3),
3.22Ϫ3.34 (m, 2 H, 1-HЈ, 10-HЈ), 3.35Ϫ3.75 (m, 4 H, 1-HЈЈ, 2-H,
9-H, 10-HЈЈ), 4.61 (m, 2 H, 5-H, 6-H), 7.31 (d, J ϭ 7.9 Hz, 4 H,
tosyl-H), 7.73 (d, J ϭ 8.3 Hz, 4 H, tosyl-H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 21.7 (tosyl-CH3), 25.3 (C-4, C-7), 28.3 (C-3, C-8),
66.2 (C-1, C-10), 71.6 (C-2, C-9), 81.0 (C-5, C-6), 128.1, 129.9,
5,6-Bis-p-toluenesulfonate 11 of (2R,5S,6S,9R)-1,2;9,10-Di-O-iso-
propylidenedecane-1,2,9,10-tetraol and 5,6-Bis-p-toluenesulfonate 12 132.9, 145.3 (tosyl-C).
of (all-R)-1,2;9,10-Di-O-isopropylidenedecane-1,2,9,10-tetraol: Diol
(all-R)-5,5Ј-Bis(hydroxymethyl)octahydro-2,2Ј-bifuran (14): Tetraol
9/10 (12.09 g, 37.96 mmol) was dissolved in CH2Cl2 (150 mL). Pyr-
idine (60.0 mL, 743 mmol) and pTsCl (56.70 g, 297.4 mmol) were
added at 0 °C. The solution was stirred overnight. Sat. aqueous
NaHCO3 (35 mL) was added to destroy excess pTsCl and the mix-
ture was stirred for 1 h. The mixture was treated with H2O (50 mL)
and acidified with 1  HCl (pH ϭ 3Ϫ4). The aqueous phase was
extracted twice with CH2Cl2 (100 mL). The combined organic
layers were washed with sat. aqueous NaHCO3 (200 mL) and sat.
aqueous NaCl (100 mL) and dried with MgSO4. Removal of the
solvents in vacuo and purification by CC (1100 cm3 SiO2, PE/
MTBE, 1:1) gave ditosylate 11 (20.53 g, 32.75 mol, 86%) as a color-
less oil, which later partially crystallized. Note: Depending on the
diastereoselectivity of the previous reaction (AD reaction), in some
cases the minor diastereomer 12 was also obtained.
13 (4.00 g, 7.31 mmol) was dissolved in THF (80 mL). At 0 °C
NaH (95%, 0.97 g, 40.33 mmol) was added. The mixture was
stirred for 4 h at 0 °C. Under argon at 0 °C HOAc (100%, 2.8 mL,
44.3 mmol) in THF (100 mL) was added cautiously. The mixture
solidified. Treatment with THF (100 mL) redissolved the residue.
The solvents were removed in vacuo. The residue was treated three
times with toluene (75 mL) and the solvents were, in each case,
removed in vacuo. Purification by CC (200 cm3 SiO2, CHCl3/
MeOH, 10:1) afforded bi-THF diol 14 (1.36 g, 6.73 mmol, 92%) as
a colorless, viscous oil. Ϫ Rf ϭ 0.25 (SiO2, CHCl3/MeOH, 10:1).
Ϫ [α]2D3 ϭ Ϫ16.6 (c ϭ 0.79, CHCl3). Ϫ IR (film): ν˜ ϭ 3373 bs (OH),
2931 m, 2872 m (CH), 1457 w, 1382 w, 1327 w, 1194 w, 1043 s, 969
w, 938 w, 883 w, 617 w cmϪ1. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
1.48Ϫ2.10 (m, 8 H, 3-H2, 4-H2, 3Ј-H2, 4Ј-H2), 2.89 (br. s, 2 H, OH),
3.40Ϫ3.51 (m, 2 H, 1ЈЈ-HЈ, 1ЈЈЈ-HЈ), 3.61Ϫ3.76 (m, 2 H, 1ЈЈ-HЈЈ,
1ЈЈЈ-HЈЈ), 3.79Ϫ3.91 (m, 2 H, 2-H, 2Ј-H), 4.04Ϫ4.15 (m, 2 H, 5-H,
11: Rf ϭ 0.32 (SiO2, PE/MTBE, 1:1). Ϫ m.p.: 70 °C. Ϫ [α]2D4
Ϫ31.7 (c ϭ 0.63, CHCl3). Ϫ IR (KBr): ν˜ ϭ 2987 m, 2935 w, 2889
ϭ
w (CH), 1598 w (aryl), 1399 m, 1357 s (SO2), 1190 s, 1176 s (SO2), 5Ј-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 27.3 (C-3, C-3Ј), 28.8
928 m, 911 m, 882 m, 818 m, 677 m, 666 s, 552 s cmϪ1. Ϫ 1H NMR
(C-4, C-4Ј), 64.5 (C-1ЈЈ, C-1ЈЈЈ), 80.1 (C-5, C-5Ј), 82.3 (C-2, C-2Ј).
(300 MHz, CDCl3): δ ϭ 1.04Ϫ1.18 (m, 2 H, 3-HЈ, 8-HЈ), 1.22Ϫ1.52 Ϫ HRMS (EI): calcd. 202.1205 (Mϩ); found 202.1208.
(m, 4 H, 3-HЈЈ, 4-HЈ, 7-HЈ, 8-HЈЈ), 1.26 (s, 6 H, acetonide-H3), 1.31
(all-R)-[5Ј-(5ЈЈ-(tert-Butyldimethylsilyloxy)methyltetrahydrofuran-
(s, 6 H, acetonide-H3), 1.71Ϫ1.84 (m, 2 H, 4-HЈЈ, 7-HЈЈ), 2.43 (s, 6
2ЈЈ-yl)tetrahydrofuran-2Ј-yl]carbaldehyde (15). ؊ 1. TBDMS Pro-
H, tosyl-CH3), 3.28 (t, J ϭ 6.8 Hz, 2 H, 1-HЈ, 10-HЈ), 3.77Ϫ3.92
tection: To a solution of bi-THF diol 14 (6.19 g, 30.60 mmol) in
(m, 4 H, 1-HЈЈ, 2-H, 9-H, 10-HЈЈ), 4.55 (d, J ϭ 10.6 Hz, 2 H, 5-H,
CH2Cl2 (200 mL) at 0 °C was added imidazole (17.0 g, 249 mmol)
6-H), 7.33 (d, J ϭ 8.3 Hz, 4 H, tosyl-H), 7.76 (d, J ϭ 8.3 Hz, 4 H,
and TBDMSCl (50% in toluene, 9.68 g, 32.1 mmol). The mixture
tosyl-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 21.6 (tosyl-CH3),
was stirred for 2 h at room temp. The reaction was quenched with
24.8 (C-4, C-7), 25.5 (acetonide-CH3), 26.8 (acetonide-CH3), 29.2
sat. aqueous NH4Cl (100 mL). The aqueous layer was extracted
(C-3, C-8), 68.9 (C-1, C-10), 75.1 (C-2, C-9), 80.6 (C-5, C-6), 108.9
(acetal-C), 128.1, 129.9, 133.0, 145.2 (tosyl-C). Ϫ C30H42O10S2
twice with CH2Cl2 (75 mL). The combined organic layers were
washed with sat. aqueous NaCl (100 mL) and dried with MgSO4.
(626.77): calcd. C 57.49, H 6.75; found C 57.37, H 6.76.
Removal of the solvents and purification by CC (300 cm3 SiO2, PE/
12: Rf ϭ 0.18 (SiO2, PE/MTBE, 1:1). Ϫ [α]2D4 ϭ ϩ29.7 (c ϭ 0.37,
CHCl3). Ϫ IR (film): ν˜ ϭ 3020 w, 2985 w, 2935 w, 2875 w (CH),
1598 w (aryl), 1454 w, 1369 s (SO2), 1216 m, 1177 s (SO2), 1096 w,
MTBE, 1:1) afforded bis-TBDMS-protected bifuran (4.33 g,
10.1 mmol, 33%, yield based on conversion: 40%) and the desired
mono-TBDMS-protected alcohol (3.45 g, 10.9 mmol, 36%, yield
1058 w, 910 w, 869 w, 817 w, 757 s, 669 m, 615 w cmϪ1. Ϫ 1H based on conversion: 43%) as colorless liquids. The combined aque-
NMR (300 MHz, CDCl3): δ ϭ 1.05Ϫ1.18 (m, 4 H, 3-H2, 8-H2),
ous layers were extracted three times with CHCl3/2-propanol (2:1)
1.28 (s, 6 H, acetonide-H3), 1.32 (s, 6 H, acetonide-H3), 1.58Ϫ1.74 (100 mL). The combined organic layers were dried with MgSO4.
(m, 4 H, 4-H2, 7-H2), 2.44 (s, 6 H, tosyl-CH3), 3.25Ϫ3.33 (m, 2 H,
Removal of the solvents and purification of the residue by CC (150
1894
Eur. J. Org. Chem. 2000, 1889Ϫ1904

Total Syntheses of Squamocin A and Squamocin D
FULL PAPER
cm3 SiO2, CHCl3/MeOH, 10:1) was performed to reisolate bi-THF
diol 14 (1.06 g, 5.22 mmol).
were removed in vacuo. This procedure was repeated twice. The
residue was crystallized from MTBE and yielded the desired diol
(13.1 g, 57.0 mmol, 98%) as colorless crystals.
(all-R)-[5Ј-(5ЈЈ-(tert-Butyldimethylsilyloxy)methyltetrahydrofuran-
2ЈЈ-yl)tetrahydrofuran-2Ј-yl]methanol: Rf ϭ 0.15 (SiO2, PE/MTBE,
1:1). Ϫ [α]2D3 ϭ ϩ2.8 (c ϭ 0.89, CHCl3). Ϫ IR (film): ν˜ ϭ 3416 bm
1,14-Tetradecanediol: Rf ϭ 0.17 (SiO2, PE/MTBE, 1:1). Ϫ m.p.: 81
°C. Ϫ IR (KBr): ν˜ ϭ 3414 bs (OH), 2923 s, 2848 s (CH), 1661 m,
(OH), 2952, 2929, 2858 m (CH), 1636 m, 1471 m, 1387 w, 1254 w, 1558 m, 1480 w, 1462 w, 1400 w, 1357 w, 1333 w, 1212 w, 1052 m,
1
1065 m, 909 s, 837 m, 734 s, 650 m cmϪ1. Ϫ H NMR (300 MHz,
1017 m, 972 w, 728 w, 616 bm cmϪ1. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 1.25Ϫ1.29 (m, 20 H, 3-H2 to 12-H2), 1.50Ϫ1.59 (m,
CDCl3): δ ϭ Ϫ0.03 (s, 6 H, SiCH3), 0.82 [s, 9 H, SiC(CH3)3],
1.47Ϫ1.77 (m, 4 H, 3Ј-HЈ, 4Ј-HЈ, 3ЈЈ-HЈ, 4ЈЈ-HЈ), 1.84Ϫ2.01 (m, 4 4 H, 2-H2, 13-H2), 3.62 (t, J ϭ 6.6 Hz, 4 H, 1-H2, 14-H2). Ϫ 13C
H, 3Ј-HЈЈ, 4Ј-HЈЈ, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ), 2.41 (br. s, 1 H, OH), 3.37Ϫ3.54 NMR (75 MHz, CDCl3): δ ϭ 25.7 (C-7, C-8), 29.4 (C-6, C-9), 29.5
(m, 2 H, 1-HЈ, 1ЈЈЈ-HЈ), 3.57Ϫ3.66 (m, 2 H, 1-HЈЈ, 1ЈЈЈ-HЈЈ),
3.78Ϫ3.88 (m, 2 H, 5Ј-H, 2ЈЈ-H), 3.95Ϫ4.11 (m, 2 H, 2Ј-H, 5ЈЈ-H). C-14). Ϫ C14H30O2 (230.39): calcd. C 72.99, H 13.12; found C
13C NMR (75 MHz, CDCl3):
Ϫ5.4 (SiCH3), 18.2 73.16, H 12.90.
(C-5, C-10), 29.6 (C-3,C-4,C-11,C-12), 32.8 (C-2, C-13), 63.1 (C-1,
Ϫ
δ ϭ
[SiC(CH3)3], 25.8 [SiC(CH3)3], 27.4, 28.27, 28.32, 28.6 (C-3Ј, C-4Ј,
C-3ЈЈ, C-4ЈЈ), 64.5 (C-1), 65.7 (C-1ЈЈЈ), 79.75, 79.77 (C-2Ј, C-5ЈЈ),
82.06, 82.12 (C-5Ј, C-2ЈЈ). Ϫ HRMS (EI): calcd. 301.1835 (M Ϫ
CH3)ϩ; found 301.1839. Ϫ C16H32O4Si (316.51): calcd. C 60.72, H
10.19; found C 60.29, H 10.28.
2. Monoprotection: A mixture of diol (22.2 g, 96.4 mmol), BnCl
(11.1 mL, 96.4 mmol) and powdered KOH (5.4 g, 96.4 mmol) was
stirred for 5 h at 110 °C. Treatment with ice/water (300 mL) and
CHCl3 (400 mL) stopped the reaction. The aqueous layer was ex-
tracted twice with CHCl3 (200 mL). The combined organic layers
(all-R)-5,5Ј-Bis(tert-butyldimethylsilyloxy)methyloctahydro-2,2Ј- were washed with sat. aqueous NaCl (250 mL) and dried with
bifuran: Rf ϭ 0.75 (SiO2, PE/MTBE, 1:1). Ϫ [α]2D1 ϭ ϩ13.1 (c ϭ
1.73, CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.00 (s, 6 H,
SiCH3), 0.84 [s, 9 H, SiC(CH3)3], 1.54Ϫ1.76 (m, 4 H, 3-HЈ, 4-HЈ,
MgSO4. Removal of the solvents in vacuo and purification by CC
(800 cm3 SiO2, PE/MTBE, 5:1, 1:1 and MTBE) yielded alcohol 17
(12.4 g, 38.8 mmol, 61% based on turnover) as colorless crystals. Ϫ
3Ј-HЈ, 4Ј-HЈ) 1.84Ϫ2.03 (m, 4 H, 3-HЈЈ, 4-HЈЈ, 3Ј-HЈЈ, 4Ј-HЈЈ), Rf ϭ 0.48 (SiO2, PE/MTBE, 1:1). Ϫ M.p.: 41 °C. Ϫ IR (KBr): ν˜ ϭ
3.44Ϫ3.53 (m,
2
H, CHЈOTBDMS), 3.61Ϫ3.68 (m,
2
H, 3428 bm, 3371 bm (OH), 3066 w, 2920 s, 2848 s (CH), 1469 m,
1454 m, 1400 w, 1369 w, 1356 w, 1117 m, 1094 w, 1060 m, 1028 w,
CHЈЈOTBDMS), 3.81Ϫ3.89 (m, 2 H, 2-H, 2Ј-H), 3.94Ϫ4.07 (m, 2
H, 5-H, 5Ј-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ5.4 (SiCH3), 1004 w, 983 w, 757 w, 736 m, 722 w, 702 w, 696 w cmϪ1. Ϫ 1H
17.9 [SiC(CH3)3], 25.9 [SiC(CH3)3], 28.2 (C-4, C-4Ј), 28.5 (C-3, C- NMR (300 MHz, CDCl3): δ ϭ 1.24Ϫ1.33 (m, 20 H, 3-H2 to 12-
3Ј), 65.8 (CH2OTBDMS), 79.7 (C-5, C-5Ј), 81.9 (C-2, C-2Ј). Ϫ
H2), 1.52Ϫ1.62 (m, 5 H, 2-H2, 13-H2 and OH), 3.44 (t, J ϭ 6.6 Hz,
C22H46O4Si2 (430.78): calcd. C 61.34, H 10.76; found C 61.14, H 2 H, 14-H2), 3.61 (t, J ϭ 6.6 Hz, 2 H, 1-H2), 4.48 (s, 2 H, PhCH2O),
10.41.
7.25Ϫ7.33 (m, 5 H, phenyl-H). Ϫ 13C NMR (75 MHz, CDCl3):
δ ϭ 25.7, 26.2, 29.41, 29.47, 29.57, 29.61 (C-3 to C-12), 29.8 (C-
13), 32.8 (C-2), 63.1 (C-1), 70.5 (C-14), 72.8 (PhCH2O), 127.4,
127.6, 128.3, 138.7 (phenyl-C). Ϫ C21H36O2 (320.51): calcd. C
78.70, H 11.32; found C 78.58, H 11.05.
2. Swern Oxidation: (COCl)2 (360 µL, 4.13 mmol) was dissolved in
CH2Cl2 (20 mL). The solution was cooled to Ϫ60 °C and DMSO
(710 µL, 10.0 mmol) dissolved in CH2Cl2 (3 mL) was added. At
Ϫ50 °C
a solution of the bi-THF monoalcohol (522 mg,
1.65 mmol) in CH2Cl2 (3 mL) was added. After 45 min at Ϫ45 °C,
the mixture was treated with Et3N (2.05 mL, 14.7 mmol). After
14-Benzyloxytetradecane Bromide (18). ؊ 1. Tosylation: To a solu-
tion of alcohol 17 (4.4 g, 13.7 mmol) in CH2Cl2 (100 mL) was ad-
5 min, the temperature was allowed to rise to 0 °C and H2O ded pyridine (6.0 mL, 74.2 mmol). The mixture was treated with
(10 mL) was added to stop the reaction. The aqueous layer was
extracted twice with CH2Cl2 (15 mL). The combined organic layers
were washed with sat. aqueous NaCl (15 mL) and dried with
MgSO4. Removal of the solvents in vacuo and purification by CC
(150 cm3 SiO2, PE/MTBE, 1:1) yielded aldehyde 15 (471 mg,
pTsCl (4.5 g, 23.7 mmol) at 0 °C. The reaction mixture was stirred
overnight. H2O (50 mL) was added to destroy excess pTsCl at 0 °C
and the mixture was stirred for 1 h. The aqueous layer was ex-
tracted twice with MTBE (75 mL). The combined organic layers
were washed with 2  HCl (100 mL), sat. aqueous NaHCO3
1.50 mmol, 91%) as a liquid. Ϫ Rf ϭ 0.25 (SiO2, PE/MTBE, 1:1). (200 mL) and sat. aqueous NaCl (100 mL) and dried with MgSO4.
Ϫ [α]2D1ϭ ϩ25.4 (c ϭ 1.32, CHCl3). Ϫ IR (film): ν˜ ϭ 3030 w, 2970
Removal of the solvents in vacuo afforded the crude tosylate (6.0 g,
m, 2872 s (CH), 2719 w, 1733 s (CϭO), 1496 w, 1454 w, 1365 w, 12.7 mmol, 93%, Rf ϭ 0.36 [SiO2, PE/MTBE, 5:1] as colorless crys-
1314 w, 1273 w, 1202 w, 1070 s, 938 w, 883 w, 819 w, 739 m, 699
tals.
1
m, 609 w cmϪ1. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.02 (s, 6 H,
2. Bromination: To
a solution of the crude tosylate (6.0 g,
SiCH3), 0.86 [s, 9 H, SiC(CH3)3], 1.56Ϫ1.82 (m, 3 H, 4Ј-HЈ, 3ЈЈ-
HЈ, 4ЈЈ-HЈ), 1.89Ϫ2.05 (m, 4 H, 3Ј-HЈ, 4Ј-HЈЈ, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ),
2.17Ϫ2.30 (m, 1 H, 3Ј-HЈЈ), 3.45Ϫ3.72 (m, 2 H, 1ЈЈЈ-H2), 3.78Ϫ4.16
(m, 3 H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-H), 4.28Ϫ4.38 (m, 1 H, 2Ј-H), 9.66 (d,
J ϭ 1.9 Hz, 1 H, CHO). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ5.3
(SiCH3), 18.3 [SiC(CH3)3], 25.9 [SiC(CH3)3], 27.4 (C-3Ј), 27.9, 28.3,
28.4 (C-4Ј, C-3ЈЈ, C-4ЈЈ), 65.8 (C-1ЈЈЈ), 80.0 (C-5ЈЈ), 81.7 (C-2ЈЈ),
83.3 (C-2Ј), 83.4 (C-5Ј), 203.0 (CHO). Ϫ HRMS (EI): calcd.
315.1992 (M ϩ H)ϩ; found 315.1995.
12.7 mmol) in THF (200 mL) was added LiBr (9.0 g, 105 mmol) at
0 °C. The mixture was stirred for 5 h at 50 °C. Treatment with H2O
(100 mL) stopped the reaction. The aqueous layer was extracted
twice with MTBE (75 mL). The combined organic layers were
washed with sat. aqueous NaCl (100 mL) and dried with MgSO4.
Removal of the solvents and purification by CC (250 cm3 SiO2,
PE/MTBE, 10:1) yielded bromide 18 (4.3 g, 11.2 mmol, 88%) as
colorless crystals. Ϫ Rf ϭ 0.73 (SiO2, PE/MTBE, 5:1). Ϫ M.p.: 31
°C. Ϫ IR (KBr): ν˜ ϭ 3030 w, 2921 s, 2851 s (CH), 1641 w, 1497 w,
1468 w, 1455 w, 1400 w, 1367 w, 1356 w, 1206 w, 1125 m, 1107 m,
14-Benzyloxytetradecanol (17). ؊ 1. Reduction: Dicarboxylic acid
16 (15.0 g, 58.1 mmol) was dissolved in THF (300 mL). BH3 Me2S
1076 w, 1029 w, 1017 w, 992 w, 972 w, 906 w, 739 m, 697 m cmϪ1
.
complex (10 mmol/mL in THF, 13.9 mL, 139 mmol) was added Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.18Ϫ1.35 (m, 20 H, 3-H2 to
and the solution was stirred for 4 h at 50 °C. Cautious treatment
12-H2), 1.50Ϫ1.55 (m, 2 H, 13-H2), 1.73Ϫ1.78 (m, 2 H, 2-H2), 3.33
with MeOH (200 mL) at 0 °C stopped the reaction. The solvents (t, J ϭ 7.0 Hz, 2 H, 1-H2), 3.39 (t, J ϭ 6.6 Hz, 2 H, 14-H2), 4.41
Eur. J. Org. Chem. 2000, 1889Ϫ1904
1895

U. Emde, U. Koert
(s, 2 H, PhCH2O), 7.17Ϫ7.25 (m, 5 H, phenyl-H). Ϫ 13C NMR for 1 h and then treated with H2O (50 mL) and MTBE (50 mL).
FULL PAPER
(75 MHz, CDCl3): δ ϭ 26.2, 28.2, 28.8, 29.42, 29.47, 29.51, 29.57,
29.60 (C-3 to C-12), 29.8 (C-13), 32.8 (C-2), 34.0 (C-1), 70.5 (C-
The aqueous layer was extracted twice with MTBE (50 mL). The
combined organic layers were washed with sat. aqueous NaHCO3
14), 72.8 (PhCH2O), 127.4, 127.6, 128.3, 138.7 (phenyl-C). Ϫ (75 mL) and sat. aqueous NaCl (75 mL) and dried with MgSO4.
C21H35BrO (383.41): calcd. C 65.79, H 9.20, Br 20.84; found C
65.80, H 8.93, Br 21.00.
Removal of the solvents and purification by CC (150 cm3 SiO2, PE/
MTBE, 3:1) afforded alcohol 19 (850 mg, 1.37 mmol, 96%) as a
colorless oil. The stereoselectivity was determined to be better than
98:2 by 13C-NMR analysis. Ϫ Rf ϭ 0.27 (SiO2, PE/MTBE, 3:1). Ϫ
[α]2D2 ϭ ϩ8.2 (c ϭ 0.96, CHCl3). Ϫ IR (film): ν˜ ϭ 3450 bm (OH),
2926, 2854 s (CH), 1463 w, 1360 w, 1251 w, 1102 m, 1070 w, 836
m, 776 w, 734 w, 697 w cmϪ1. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
0.03 (s, 6 H, SiCH3), 0.87 [s, 9 H, SiC(CH3)3], 1.21Ϫ1.42 (m, 26 H,
2-H2 to 14-H2), 1.53Ϫ1.66 (m, 4 H, 3Ј-HЈ, 4Ј-HЈ, 3ЈЈ-HЈ, 4ЈЈ-HЈ),
1.88Ϫ2.04 (m, 4 H, 3Ј-HЈЈ, 4Ј-HЈЈ, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ), 2.33 (br. s, 1
H, OH), 3.33Ϫ3.39 (m, 1 H, 1-H), 3.44 (t, J ϭ 7.2 Hz, 2 H, 15-
H2), 3.55 (dd, J ϭ 4.6, 9.4 Hz, 1 H, 1ЈЈЈ-HЈ), 3.66 (dd, J ϭ 4.6,
9.4 Hz, 1 H, 1ЈЈЈ-HЈЈ), 3.77Ϫ3.91 (m, 3 H, 2Ј-H, 5Ј-H, 2ЈЈ-H),
4.01Ϫ4.10 (m, 1 H, 5ЈЈ-H), 4.48 (s, 2 H, PhCH2O), 7.22Ϫ7.33 (m,
5 H, phenyl-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ5.3 (SiCH3),
18.3 [SiC(CH3)3], 25.9 [SiC(CH3)3], 25.6, 26.2, 28.31, 28.33, 28.5,
28.9, 29.46, 29.58, 29.60, 29.63, 29.72, 29.75, 33.5 (C-2 to C-14, C-
3Ј, C-4Ј, C-3ЈЈ, C-4ЈЈ), 65.8 (C-1ЈЈЈ), 70.5 (C-15), 72.8 (PhCH2O),
74.0 (C-1), 79.9 (C-5ЈЈ), 81.9, 82.0 (C-5Ј, C-2ЈЈ), 82.9 (C-2Ј), 127.4,
127.6, 128.3, 138.7 (phenyl-C). Ϫ HRMS (EI): calcd. 619.4758 (M
ϩ H)ϩ; found 619.4759.
(all-R)-1-[5Ј-(5ЈЈ-(tert-Butyldimethylsilyloxy)methyltetrahydrofuran-
2ЈЈ-yl)tetrahydrofuran-2Ј-yl]-15-benzyloxypentadecan-1-ol (19). Ϫ 1.
Grignard Reaction and Oxidation: A three-necked flask (100 mL),
equipped with a dropping funnel, a reflux condenser and a mag-
netic stirring bar, was flame-dried in vacuo and, after cooling to 20
°C, flushed with argon. The flask was charged with Mg (1.44 g,
59.2 mmol) and the same drying procedure was repeated. Et2O
(5 mL) was added and the mixture was stirred vigorously. The
dropping funnel was charged with a solution of bromide 18 (5.13 g,
13.4 mmol) in Et2O (30 mL) and 1,2-dibromoethane (250 µL,
2.90 mmol). 7 mL of the solution was added quickly to the vigor-
ously stirred mixture. After warming the mixture slightly with a
heat gun, the Grignard reaction started. The remaining bromide
solution was added over 20 min and the mixture was stirred for 1 h
at 35 °C. The Grignard solution was transferred by cannula into a
Schlenk flask (100 mL) and was cooled to Ϫ40 °C. A precipitate
that could be stirred was obtained. A solution of aldehyde 15
(832 mg, 2.65 mmol) in Et2O (8 mL) was added dropwise. Over 3 h
the reaction mixture was stirred and the temperature was allowed
to rise to room temp. Addition of sat. aqueous NH4Cl (25 mL) and
Et2O (25 mL) stopped the reaction. The aqueous layer was ex-
tracted twice with Et2O (25 mL). The combined organic layers were
washed with sat. aqueous NaCl (50 mL) and dried with MgSO4.
(all-R)-[5Ј-(5ЈЈ-(1ЈЈЈ-tert-Butyldimethylsilyloxy-15ЈЈЈ-benzyloxy-
pentadec-1ЈЈЈ-yl)tetrahydrofuran-2ЈЈ-yl)tetrahydrofuran-2Ј-yl]-
methanol (20): ؊ 1. TBDMS Protection: To a solution of alcohol
19 (737 mg, 1.19 mmol) in CH2Cl2 (25 mL) at 0 °C was added imid-
Removal of the solvents in vacuo and purification by CC (250 cm3 azole (795 mg, 11.7 mmol) and TBDMSCl (50% in toluene, 1.65 g,
SiO2, PE/MTBE, 3:1, 2:1) afforded a mixture (1:1 by 13C NMR)
of the epimeric alcohols [1.25 g, 2.02 mmol, 76%, Rf ϭ 0.56 and
0.59 (SiO2, PE/MTBE, 1:1)] as a colorless liquid. The epimeric al-
5.46 mmol). The mixture was stirred overnight at room temp. The
reaction was quenched with sat. aqueous NH4Cl (25 mL). The
aqueous layer was extracted twice with CH2Cl2 (25 mL). The com-
cohols (1.23 g, 1.98 mmol) were dissolved in CH2Cl2 (20 mL). Mo- bined organic layers were washed with sat. aqueous NaCl (20 mL)
˚
lecular sieves (4 A, 1.37 g) and PCC (1.30 g, 6.02 mmol) were ad-
ded. The mixture was stirred for 1 h at room temp., then diluted
with MTBE (50 mL) and filtered through a pad of Celite. The solv-
ents were removed in vacuo. Purification by CC (200 cm3 SiO2, PE/
MTBE, 4:1, 2:1) gave the desired ketone (879 mg, 1.43 mmol, 72%)
as a colorless liquid.
and dried with MgSO4. Removal of the solvents in vacuo and puri-
fication by CC (150 cm3 SiO2, PE/MTBE, 20:1) afforded bis-
TBDMS-protected diol (753 mg, 1.03 mmol, 87%) as a colorless li-
quid.
(all-R)-1-[5Ј-(5ЈЈ-(tert-Butyldimethylsilyloxy)methyltetrahydrofuran-
2ЈЈ-yl)tetrahydrofuran-2Ј-yl]-1-tert-butyldimethylsilyloxy-15-
(all-R)-1-[5Ј-(5ЈЈ-(tert-Butyldimethylsilyloxy)methyltetrahydrofuran-
benzyloxypentadecane: Rf ϭ 0.36 (PE/MTBE, 20:1). Ϫ [α]2D2
ϭ
2ЈЈ-yl)-tetrahydrofuran-2Ј-yl]-15-benzyloxypentadecan-1-one: Rf
ϭ
ϩ18.6 (c ϭ 0.37, CHCl3). Ϫ IR (film): ν˜ ϭ 2927, 2855 s (CH),
0.42 (SiO2, PE/MTBE, 4:1). Ϫ [α]2D2 ϭ ϩ20.4 (c ϭ 0.26, CHCl3).
1462 w, 1361 w, 1252 m, 1100 m, 1005 w, 939 w, 836 m, 776 m, 733
Ϫ IR (film): ν˜ ϭ 2927, 2855 cmϪ1 s (CH), 1717 m (CϭO), 1461 w, 697 w cmϪ1. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.02, 0.025,
1
m, 1363 w, 1254 w, 1098 bm, 839 m, 777 w, 736 w, 697 w. Ϫ 1H
NMR (300 MHz, CDCl3): δ ϭ 0.03 (s, 6 H, SiCH3), 0.87 [s, 9 H, 1.19Ϫ1.52 (m, 26 H, 2-H2 to 14-H2), 1.53Ϫ1.74 (m, 4 H, 3Ј-HЈ, 4Ј-
SiC(CH3)3], 1.20Ϫ2.10 (m, 34 H, 2-H2 to 14-H2, 3Ј-H2, 4Ј-H2, 3ЈЈ- HЈ, 3ЈЈ-HЈ, 4ЈЈ-HЈ), 1.78Ϫ2.04 (m, 4 H, 3Ј-HЈЈ, 4Ј-HЈЈ, 3ЈЈ-HЈЈ, 4ЈЈ-
H2, 4ЈЈ-H2), 3.42 (t, J ϭ 6.5 Hz, 2 H, 15-H2), 3.50Ϫ3.70 (m, 2 H, HЈЈ), 3.44 (t, J ϭ 6.8 Hz, 2 H, 15-H2), 3.52 (dd, J ϭ 5.9, 10.4 Hz,
1ЈЈЈ-H2), 3.80Ϫ4.00 (m, 4 H, 2Ј-H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-H), 4.48 (s, 2 H, 1 H, 1ЈЈЈ-HЈ), 3.60Ϫ3.69 (m, 2 H, 1-H, 1ЈЈЈ-HЈЈ), 3.81Ϫ4.08 (m, 4
0.03 (3 ϫ s, 12 H, SiCH3), 0.86, 0.87 [2 ϫ s, 18 H, SiC(CH3)3],
PhCH2O), 7.22Ϫ7.33 (m, 5 H, phenyl-H). Ϫ 13C NMR (75 MHz, H, 2Ј-H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-H), 4.48 (s, 2 H, PhCH2O), 7.22Ϫ7.33
CDCl3): δ ϭ Ϫ5.3 (SiCH3), 18.3 [SiC(CH3)3], 25.9 [SiC(CH3)3],
23.1, 26.2, 28.0, 28.4, 29.3, 29.5, 29.6, 29.8, 38.1 (C-2 to C-14, C-
(m, 5 H, phenyl-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ5.3,
Ϫ4.6, Ϫ4.3 (SiCH3), 18.2, 18.3 [SiC(CH3)3], 25.91, 25.94
3Ј, C-4Ј, C-3ЈЈ, C-4ЈЈ), 65.9 (C-1ЈЈЈ), 70.5 (C-15), 72.8 (PhCH2O), [SiC(CH3)3], 26.2, 26.9, 28.2, 28.43, 28.45, 29.48, 29.60, 29.65,
80.0, 81.6, 83.0, 83.9 (C-2Ј, C-5Ј, C-2ЈЈ, C-5ЈЈ), 127.4, 127.6, 128.3, 29.67, 29.8, 29.9, 32.1 (C-2 to C-14, C-3Ј, C-4Ј, C-3ЈЈ, C-4ЈЈ), 65.9
138.7 (phenyl-C), 212.9 (C-1). Ϫ HRMS (EI): calcd. 616.4523
(C-1ЈЈЈ), 70.5 (C-15), 72.8 (PhCH2O), 74.6 (C-1), 79.8 (C-5ЈЈ), 81.8,
81.9 (C-5Ј, C-2ЈЈ), 82.1 (C-2Ј), 127.4, 127.6, 128.3, 138.7 (phenyl-
C). Ϫ C43H80O5Si2 (733.27): calcd. C 70.43, H 11.00; found C
70.39, H 10.83.
(M)ϩ; found 616.4527.
2. Reduction: To a solution of the ketone (879 mg, 1.43 mmol) in
THF (20 mL) at Ϫ100 °C was added -selectride (1 mol/L in
THF, 3.0 mL, 3.0 mmol), which had been precooled at Ϫ78 °C.
2. Monodeprotection: Bis-TBDMS-protected diol (685 mg, 934
The mixture was stirred for 2 h. During that period the temperature µmol) was dissolved in CH2Cl2 (10 mL) and MeOH (2 mL). At
was allowed to rise to Ϫ70 °C. At 0 °C, 2  NaOH (10 mL) and Ϫ10 °C, CSA (22 mg, 95 µmol) was added. The mixture was stirred
30% H2O2 (10 mL) were added carefully. The mixture was stirred
for 2 h. During that period the temperature was allowed to rise to
1896
Eur. J. Org. Chem. 2000, 1889Ϫ1904

Total Syntheses of Squamocin A and Squamocin D
FULL PAPER
0 °C. When a TLC spot of the dideprotected side product started
for 90 min. After cooling down to room temp. the mixture was
to appear, the mixture was treated with phosphate buffer solution charged with heptanal (22) (4.30 mL, 30.8 mmol) and stirred for
(pH ϭ 7, 10 mL) to stop the reaction. The aqueous layer was ex-
tracted twice with CH2Cl2 (25 mL). The combined organic layers
1 h. At Ϫ78 °C allyltributylstannane (10.5 mL, 33.9 mmol) was ad-
ded. The suspension was stirred for 30 min at Ϫ78 °C and the flask
were dried with MgSO4. Removal of the solvents in vacuo and was allowed to stand at Ϫ25 °C for 5 d. The reaction was quenched
purification by CC (150 cm3 SiO2, PE/MTBE, 5:1, 4:1, 1:1) af-
forded reisolated bis-TBDMS-protected diol (250 mg, 341 µmol)
and primary alcohol 20 (327 mg, 528 µmol, 57%, yield based on
turnover: 89%) as a colorless viscous oil. In the refrigerator (Ϫ30
°C) alcohol 20 solidified to a colorless wax. Ϫ Rf ϭ 0.22 (SiO2,
by adding sat. aqueous NaHCO3 (50 mL) and stirred for 1 h. The
reaction mixture was filtered through a pad of Celite and the pad
was washed with H2O (50 mL) and CH2Cl2 (50 mL). The aqueous
layer was extracted twice with CH2Cl2 (50 mL). The combined or-
ganic layers were washed with sat. aqueous NaCl (50 mL) and
PE/MTBE, 2:1). Ϫ M.p.: 20Ϫ 25 °C. Ϫ [α]2D2 ϭ ϩ8.9 (c ϭ 0.70, dried with MgSO4. Removal of the solvents in vacuo and purifica-
CHCl3). Ϫ IR (film): ν˜ ϭ 3453 bm (OH), 3030 w, 2926, 2854 s
tion by CC (600 cm3 SiO2, PE/MTBE, 10:1) yielded heptanal
(CH), 1463 m, 1361 w, 1251 m, 1102 s, 1070 w, 836 s, 776 m, 734 (365 mg, 3.20 mmol) and the alcohol 23 (3.90 g, 25.0 mmol, 81%,
1
w, 697 w cmϪ1. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.03 (s, 3 H, yield based on turnover: 90%) as a colorless liquid. The enantiose-
SiCH3), 0.04 (s, 3 H, SiCH3), 0.86 [s, 9 H, SiC(CH3)3], 1.20Ϫ1.51
(m, 26 H, 2ЈЈЈ-H2 to 14ЈЈЈ-H2), 1.53Ϫ1.76 (m, 4 H, 3Ј-HЈ, 4Ј-HЈ,
lectivity was determined by chiral GC and found to be 99:1 in favor
of the desired isomer. Note: The reaction was although done with
3ЈЈ-HЈ, 4ЈЈ-HЈ), 1.83Ϫ2.00 (m, 4 H, 3Ј-HЈЈ, 4Ј-HЈЈ, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ), 0.1 equiv. (R)-BINOL and 0.1 equiv. Ti(OiPr)4. Use of heptanal
3.41Ϫ3.50 (m, 3 H, 15ЈЈЈ-H2, 1-HЈ), 3.61Ϫ3.71 (m, 2 H, 1ЈЈЈ-H, 1- (1.61 g, 14.1 mmol) afforded alcohol 23 (1.48 g, 9.48 mmol, 68%,
HЈЈ), 3.81Ϫ3.99 (m, 3 H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-H), 4.05Ϫ4.15 (m, 1 H,
yield based on conversion: 85%) with an enantioselectivity of 99:1
2Ј-H), 4.48 (s, 2 H, PhCH2O), 7.22Ϫ7.34 (m, 5 H, phenyl-H). Ϫ determined by chiral GC. Ϫ Rf ϭ 0.19 (SiO2, PE/MTBE, 10:1). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ Ϫ4.7, Ϫ4.3 (SiCH3), 18.2 GC: Rt [(S) enantiomer)]: 8.08 min, Rt [(R) enantiomer)]: 8.50 min
[SiC(CH3)3], 25.9 [SiC(CH3)3], 26.2, 26.9, 27.4, 28.6, 28.7, 29.47, [chiral column β-3p, 25 m, temperature program: start temp.: 95
29.59, 29.63, 29.75, 29.9, 32.1 (C-2ЈЈЈ to C-14ЈЈЈ, C-3Ј, C-4Ј, C-3ЈЈ, °C (hold for 12 min), end temp.: 180 °C (hold for 5 min), heating
C-4ЈЈ), 64.6 (C-1), 70.5 (C-15ЈЈЈ), 72.8 (PhCH2O), 74.5 (C-1ЈЈЈ), rate: 10 °C/min, pressure: H2 (0.5 kg/cm2)]. Ϫ [α]2D5 ϭ Ϫ9.1 (c ϭ
79.7 (C-2Ј), 82.0, 82.1, 82.2 (C-5Ј, C-2ЈЈ, C-5ЈЈ), 127.4, 127.6, 128.3,
0.72, CHCl3). Ϫ IR (film): ν˜ ϭ 3356 bs (OH), 3077 w, 2956, 2929,
138.7 (phenyl-C). Ϫ HRMS (EI): calcd. 562.4054 (M Ϫ C4H8)ϩ; 2857 s (CH), 1641 m (CϭC), 1466 m, 1436 m, 1378 w, 1341 w,
found 562.4055. Ϫ C37H66O5Si (619.01): calcd. C 71.79, H 10.75;
found C 71.60, H 11.04.
1228 w, 1125 m, 1069 m, 1036 m, 994 m, 912 s, 877 s, 724 w, 666
1
w cmϪ1. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.85 (t, J ϭ 6.8 Hz,
3 H, 10-H3), 1.18Ϫ1.48 (m, 10 H, 5-H2 to 9-H2), 1.70 (br. s, 1 H,
OH), 2.04Ϫ2.16 (m, 1 H, 3-HЈ), 2.21Ϫ2.31 (m, 1 H, 3-HЈЈ),
3.54Ϫ3.66 (m, 1 H, 4-H), 5.04Ϫ5.13 (m, 2 H, 1-H2), 5.71Ϫ5.87 (m,
1 H, 2-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 14.0 (C-10), 22.6
(C-9), 25.6, 29.3, 31.8 (C-6, C-7, C-8), 36.8 (C-5), 41.9 (C-3), 70.6
(C-4), 117.9 (C-1), 134.9 (C-2). Ϫ C10H20O (156.27): calcd. C 76.86,
H 12.90; found C 76.59, H 12.72.
(all-R)-[5Ј-(5ЈЈ-(1ЈЈЈ-tert-Butyldimethylsilyloxy-15ЈЈЈ-benzyloxy-
pentadec-1ЈЈЈ-yl)tetrahydrofuran-2ЈЈ-yl)tetrahydrofuran-2Ј-yl]carbal-
dehyde (21): (COCl)2 (170 µL, 1.95 mmol) was dissolved in CH2Cl2
(5 mL). The solution was cooled to Ϫ60 °C and DMSO (340 µL,
4.79 mmol) dissolved in CH2Cl2 (3 mL) was added. At Ϫ50 °C, a
solution of alcohol 20 (475 mg, 767 µmol) in CH2Cl2 (3 mL) was
added. After 45 min at Ϫ45 °C, the mixture was treated with Et3N
(1.00 mL, 7.18 mmol). After 5 min, the reaction mixture was al-
(4S)-4-Acetoxy-1-decene (24): To a solution of alcohol 23 (144 mg,
lowed to warm up to 0 °C and H2O (10 mL) was added to stop 920 µmol) in CH2Cl2 (4 mL) was added pyridine (270 µL,
the reaction. The aqueous layer was extracted twice with CH2Cl2
(10 mL). The combined organic layers were washed with sat. aque-
3.34 mmol), DMAP (7 mg, 57 µmol) and Ac2O (205 µL,
2.17 mmol). The mixture was stirred for 36 h at room temp. The
ous NaCl (10 mL) and dried with MgSO4. Removal of the solvents solvents were removed in vacuo and the residue was purified by
and purification by CC (75 cm3 SiO2, PE/MTBE, 3:1, 1:1) yielded
aldehyde 21 (424 mg, 687 µmol, 90%) as a colorless liquid. Ϫ Rf ϭ
0.17 (SiO2, PE/MTBE, 3:1). Ϫ [α]2D1 ϭ ϩ23.3 (c ϭ 0.51, CHCl3).
Ϫ IR (film): ν˜ ϭ 2926, 2854 s (CH), 1733 (CϭO), 1463 m, 1361 w,
CC (25 cm3 SiO2, PE) to afford acetate 24 (92 mg, 474 µmol, 52%)
as a colorless liquid. Rf ϭ 0.48 (SiO2, PE/MTBE, 20:1). Ϫ [α]2D0
ϭ
Ϫ23.5 (c ϭ 0.23, CHCl3). Ϫ IR (film): ν˜ ϭ 3079 cmϪ1 w, 2955,
2930, 2858 s (CH), 1740 s (CϭO), 1642 w (CϭC), 1466 w, 1437 w,
1252 w, 1102 s, 836 m, 776 m, 734 w, 697 w cmϪ. Ϫ 1H NMR 1373 m, 1240 s, 1128 w, 1023 m, 994 w, 915 w, 830 w, 724 w, 666
1
(300 MHz, CDCl3): δ ϭ 0.03 (s, 3 H, SiCH3), 0.04 (s, 3 H, SiCH3),
w. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.87 (t, J ϭ 6.7 Hz, 3 H,
0.86 [s, 9 H, SiC(CH3)3], 1.20Ϫ2.25 (m, 34 H, 2ЈЈЈ-H2 to 14ЈЈЈ-H2, 3-H3), 1.18Ϫ1.33 (m, 8 H) and 1.44Ϫ1.56 (m, 2 H, 5-H2 to 9-H2),
3Ј-H2, 4Ј-H2, 3ЈЈ-H2, 4ЈЈ-H2), 3.44 (t, J ϭ 6.6 Hz, 2 H, 15ЈЈЈ-H2), 1.99 (s, 3 H, acetate-CH3), 2.21Ϫ2.30 (m, 2 H, 3-H2), 4.88 (quint,
3.58Ϫ3.66 (m, 1 H, 1ЈЈЈ-H), 3.84Ϫ4.04 (m, 3 H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-
H), 4.28Ϫ4.35 (m, 1 H, 2Ј-H), 4.48 (s, 2 H, PhCH2O), 7.21Ϫ7.33
J ϭ 6.2 Hz, 1 H, 4-H), 4.98Ϫ5.07 (m, 2 H, 1-H2), 5.63Ϫ5.78 (m, 1
H, 2-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 14.0 (C-10), 21.2
(m, 5 H, phenyl-H), 9.65 (d, J ϭ 6.3 Hz, 1 H, CHO). Ϫ 13C NMR (acetate-CH3), 22.5 (C-9), 25.2, 29.1, 31.7 (C-6, C-7, C-8), 33.5 (C-
(75 MHz, CDCl3): δ ϭ Ϫ4.6, Ϫ4.3 (SiCH3), 18.2 [SiC(CH3)3], 25.9
5), 38.6 (C-3), 73.3 (C-4), 117.5 (C-1), 133.8 (C-2), 170.7 (CϭO).
[SiC(CH3)3], 25.8, 26.2, 27.1, 27.4, 27.8, 28.5, 29.45, 29.57, 29.60, Ϫ C12H22O2 (198.31): calcd. C 72.68, H 11.18; found C 72.59, H
29.73, 29.84, 32.4 (C-2ЈЈЈ to C-14ЈЈЈ, C-3Ј, C-4Ј, C-3ЈЈ, C-4ЈЈ), 70.5 10.97.
(C-15ЈЈЈ), 72.8 (PhCH2O), 74.6 (C-1ЈЈЈ), 81.3, 82.4, 83.2, 83.3 (C-
(4S)-4-tert-Butyldimethylsilyloxy-1-decanol (25). ؊ 1. TBDMS Pro-
tection: To a solution of alcohol 23 (3.21 g, 20.6 mmol) in CH2Cl2
(75 mL) at 0 °C was added imidazole (12.59 g, 185 mmol) and
TBDMSCl (50% in toluene, 18.2 g, 60.5 mmol). The mixture was
stirred overnight at room temp. The reaction was quenched with
sat. aqueous NH4Cl (100 mL) and the aqueous layer was extracted
twice with CH2Cl2 (50 mL). The combined organic layers were
washed with sat. aqueous NaCl (50 mL) and dried with MgSO4.
2Ј, C-5Ј, C-2ЈЈ, C-5ЈЈ), 127.4, 127.6, 128.3, 138.7 (phenyl-C), 202.9
(C-1). Ϫ HRMS (EI): calcd. 560.3897 (M Ϫ C4H8)ϩ; found
560.3894.
(4S)-1-Decen-4-ol (23): (R)-BINOL (1.75 g, 6.12 mmol) was dis-
˚
solved in CH2Cl2 (50 mL). Molecular sieves (4 A, 17.83 g), which
had been rinsed out with CH2Cl2 (10 mL), and Ti(OiPr)4 (1.80 mL,
6.10 mmol) were added. The orange-red suspension was refluxed
Eur. J. Org. Chem. 2000, 1889Ϫ1904
1897

U. Emde, U. Koert
FULL PAPER
Removal of the solvents in vacuo and purification by CC (350 cm3
SiO2, PE) afforded the TBDMS-protected alkene (5.43 g,
20.1 mmol, 98%) as a colorless liquid.
5), 71.1 (C-1), 71.4 (C-4), 127.9, 129.8, 133.2, 144.6 (tosyl-C). Ϫ 2.
Bromination: To a solution of the tosylate (3.95 g, 8.92 mmol) in
THF (100 mL) was added LiBr (2.40 g, 27.74 mmol) at 0 °C. The
mixture was stirred for 32 h at 35 °C. Treatment with H2O
(100 mL) and MTBE (100 mL) stopped the reaction. The aqueous
layer was extracted twice with MTBE (75 mL). The combined or-
ganic layers were washed with sat. aqueous NaCl (100 mL) and
dried with MgSO4. Removal of the solvents in vacuo and purifica-
tion by CC (100 cm3 SiO2, PE) yielded bromide 26 (2.91 g,
8.29 mmol, 93%) as a colorless liquid. Rf ϭ 0.23 (SiO2, PE). Ϫ [α]D22
ϭ ϩ2.7 (c ϭ 1.18, CHCl3). Ϫ IR (film): ν˜ ϭ 2955, 2929, 2856
cmϪ1 s (CH), 1462 m, 1377 w, 1360 w, 1255 m, 1133 m, 1099 m,
1005 w, 939 w, 835 m, 774 s, 665 m. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 0.02 (s, 6 H, SiCH3), 0.84Ϫ0.88 [m, 12 H, 10-H3,
SiC(CH3)3], 1.18Ϫ1.34 (m, 8 H, 6-H2 to 9-H2), 1.35Ϫ1.45 (m, 6 H,
5-H2), 1.46Ϫ1.63 (m, 2 H, 3-H2), 1.82Ϫ1.95 (m, 2 H, 2-H2), 3.39
(t, J ϭ 6.8 Hz, 2 H, 1-H2), 3.50Ϫ3.74 (quint, J ϭ 5.6 Hz, 1 H, 4-
H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ4.5, Ϫ4.4 (SiCH3), 14.1
(C-10), 18.1 [SiC(CH3)3], 25.9 [SiC(CH3)3], 28.6 (C-2), 22.6, 25.2,
29.5, 31.9 (C-6, C-7, C-8, C-9), 34.4 (C-1), 35.4 (C-3), 37.1 (C-5),
71.5 (C-4). Ϫ C16H35BrOSi (351.44): calcd. C 54.68, H 10.04, Br
22.74; found C 54.93, H 9.86, Br 22.73.
(4S)-4-tert-Butyldimethylsilyloxy-1-decene: Rf ϭ 0.49 (SiO2, PE). Ϫ
[α]2D6 ϭ Ϫ14.8 (c ϭ 1.26, CHCl3). Ϫ IR (film): ν˜ ϭ 3077 w, 2956,
2929, 2857 s (CH), 1641 m, 1472 m, 1463 m, 1434 w, 1388 w, 1361
m, 1255 s, 1127 m, 1070 m, 1005 m, 938 m, 912 s, 836 s, 809 m,
773 s, 722 w, 666 w cmϪ1. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
0.03 (s, 6 H, SiCH3), 0.82Ϫ0.89 [m, 12 H, 10-H3, SiC(CH3)3],
1.17Ϫ1.47 (m, 10 H, 5-H2 to 9-H2), 2.11Ϫ2.23 (m, 2 H, 3-H2), 3.66
(quint, J ϭ 5.6 Hz, 1 H, 4-H), 4.97Ϫ5.05 (m, 2 H, 1-H2), 5.72Ϫ5.87
(m, 1 H, 2-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ4.5, Ϫ4.4
(SiCH3), 14.1 (C-10), 18.2 [SiC(CH3)3], 22.6 (C-9), 25.9
[SiC(CH3)3], 25.3, 29.5, 31.9 (C-6, C-7, C-8), 36.8 (C-5), 42.0 (C-3),
72.0 (C-4), 116.5 (C-1), 135.5 (C-2). Ϫ C16H34OSi (270.53): calcd. C
71.04, H 12.67; found C 71.29, H 12.47.
2. Hydroboration: The alkene (5.65 g, 20.90 mmol) was dissolved in
THF (80 mL) and cooled to 0 °C. 9-BBN (0.5 mmol/mL in THF,
54.3 mL, 26.9 mmol) was added dropwise. The mixture was stirred
for 18 h at room temp. At 0 °C first 2  NaOH (50 mL) and then
30% H2O2 (50 mL) was added slowly. The mixture was stirred for
5 h. During that period the temperature was allowed to rise to
room temp. After addition of sat. aqueous NH4Cl (75 mL) the
aqueous layer was extracted twice with MTBE (50 mL). The com-
bined organic layers were washed with sat. aqueous NaCl (50 mL)
and dried with MgSO4. Removal of the solvents in vacuo and puri-
fication by CC (500 cm3 SiO2, PE/MTBE, 5:1) afforded alcohol 25
(5.47 g, 19.0 mmol, 91%) as a colorless liquid. Rf ϭ 0.24 (SiO2, PE/
MTBE, 5:1). Ϫ [α]2D4 ϭ ϩ4.0 (c ϭ 2.12, CHCl3). Ϫ IR (film): ν˜ ϭ
3331 bs (OH), 2929 s, 2857 s (CH), 1472 m, 1463 m, 1407 w, 1377
w, 1360 m, 1255 s, 1127 m, 1058 s, 1005 m, 939 m, 906 m, 835 s,
811 m, 714 s, 722 w, 666 w cmϪ1. Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ 0.03 (s, 6 H, SiCH3), 0.82Ϫ0.89 [m, 12 H, 10-H3, SiC(CH3)3],
1.17Ϫ1.33 (m, 8 H, 6-H2 to 9-H2), 1.36Ϫ1.67 (m, 6 H, 2-H2, 3-H2,
5-H2), 2.23 (br. s, 1 H, OH), 3.50Ϫ3.74 (m, 3 H, 1-H2, 4-H). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ Ϫ4.5 (SiCH3), 14.1 (C-10), 18.1
[SiC(CH3)3], 22.6 (C-9), 25.9 [SiC(CH3)3], 25.4, 29.5, 31.8 (C-6, C-
7, C-8), 28.1 (C-2), 33.4 (C-3), 36.5 (C-5), 63.2 (C-1), 72.1 (C-4).
Ϫ C16H36O2Si (288.55): calcd. C 66.60, H 12.57; found C 66.47,
H 12.32.
(1R,5S,2ЈR,5ЈR,2ЈЈR,5ЈЈR,1ЈЈЈR)-1-[5Ј-(5ЈЈ-(1ЈЈЈ-tert-Butyldimeth-
ylsilyloxy-15ЈЈЈ-benzyloxypentadec-1ЈЈЈ-yl)tetrahydrofuran-2ЈЈ-
yl)tetrahydrofuran-2Ј-yl]-5-(tert-butyldimethylsilyloxy)-
undecan-1-ol (27) and (1S,5S,2ЈR,5ЈR,2ЈЈR,5ЈЈR,1ЈЈЈR)-1-[5Ј-(5ЈЈ-
(1ЈЈЈ-tert-Butyldimethylsilyloxy-15ЈЈЈ-benzyloxypentadec-1ЈЈЈ-yl)-
tetrahydrofuran-2ЈЈ-yl)tetrahydrofuran-2Ј-yl]-5-(tert-butyldimethyl-
siloxy)undecan-1-ol (28): A three-necked flask (100 mL), equipped
with a dropping funnel, a reflux condenser and a magnetic stirring
bar, was carefully flame-dried in vacuo and, after cooling to 20
°C, flushed with argon. The flask was charged with Mg (984 mg,
40.5 mmol) and the drying procedure was repeated twice. Dry, oxy-
gen-free Et2O (5 mL) was added and the mixture was stirred vigor-
ously. The dropping funnel was charged with a solution of bromide
26 (1.61 g, 4.59 mmol) in Et2O (25 mL) and 1,2-dibromoethane (70
µL, 812 µmol). 7 mL of the solution was added quickly to the vig-
orously stirred mixture. After slight warming with a heat gun the
Grignard reaction started. The remaining bromide solution was ad-
ded over 10 min and the mixture was stirred for an additional 1 h
at 35 °C. The Grignard solution was transferred by cannula into a
Schlenk flask (50 mL), diluted with Et2O (10 mL) and cooled to
Ϫ60 °C. A precipitate that could be stirred was obtained. The flask
was charged with CuBr Me2S (75 mg, 365 µmol) and the mixture
stirred for 15 min at Ϫ60 °C. A solution of aldehyde 21 (424 mg,
687 µmol) in Et2O (7 mL) was added. The reaction mixture was
stirred overnight. During that period the temperature was allowed
to rise to room temp. Addition of sat. aqueous NH4Cl (25 mL)
and MTBE (25 mL) stopped the reaction. The aqueous layer was
extracted twice with MTBE (25 mL). The combined organic layers
were washed with sat. aqueous NaCl (50 mL) and dried with
MgSO4. The solvents were removed in vacuo. Purification by CC
(250 cm3 SiO2, PE/MTBE, 5:1, 3:1) afforded reisolated aldehyde 21
(61 mg, 99 µmol) and the separated epimeric alcohols 27 (276 mg,
310 µmol) and 28 (141 mg, 159 µmol) (stereoselectivity ca. 2:1,
68%; yield based on conversion: 80%) as viscous oils.
(4S)-4-tert-Butyldimethylsilyloxy-1-decyl Bromide (26). ؊ 1. Tosyl-
ation: To an ice-cooled solution of the alcohol 25 (5.38 g, 18.6
mmol) in CH2Cl2 (120 mL) was added pyridine (7.5 mL,
93.0 mmol). To this solution was added pTsCl (8.86 g, 46.5 mmol)
at 0 °C. The reaction mixture was stirred overnight. Sat. aqueous
NaHCO3 (50 mL) was added to destroy excess pTsCl at 0 °C and
the mixture was stirred for 1 h. The aqueous layer was extracted
twice with MTBE (80 mL). The combined organic layers were
washed with sat. aqueous NH4Cl (80 mL) and sat. aqueous NaCl
(80 mL) and dried with MgSO4. Removal of the solvents in vacuo
and purification by CC (300 cm3 SiO2, PE/MTBE, 10:1) afforded
the desired tosylate (6.75 g, 15.3 mmol, 82%) as a colorless liquid.
(4S)-4-tert-Butyldimethylsilyloxy-1-decyl-p-toluenesulfonate: Rf
ϭ
0.39 (SiO2, PE/MTBE, 10:1). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
Ϫ0.04 (s, 3 H, SiCH3), Ϫ0.02 (s, 3 H, SiCH3), 0.82Ϫ0.89 [m, 12
H, 10-H3, SiC(CH3)3], 1.17Ϫ1.45 (m, 12 H, 3-H2, 5-H2 to 9-H2),
1.59Ϫ1.73 (m, 2 H, 2-H2), 2.42 (s, 3 H, tosyl-CH3), 3.50Ϫ3.59 (m, 27: Rf ϭ 0.58 (SiO2, PE/MTBE, 3:1). Ϫ [α]1D8 ϭ ϩ9.8 (c ϭ 0.40,
1 H, 4-H), 4.01 (t, J ϭ 6.6 Hz, 2 H, 1-H2), 7.32 (d, J ϭ 7.9 Hz, 2 H,
CHCl3). Ϫ IR (film): ν˜ ϭ 3410 bm (OH), 2928, 2856 s (CH), 1463
tosyl-H), 7.76 (d, J ϭ 8.3 Hz, 2 H, tosyl-H). Ϫ 13C NMR (75 MHz,
m, 1377 w, 1254 w, 1069 m, 836 m, 774 w, 733 w, 698 w cmϪ1. Ϫ
CDCl3): δ ϭ Ϫ4.6 (SiCH3), Ϫ4.4 (SiCH3), 14.1 (C-10), 18.0 1H NMR (300 MHz, CDCl3): δ ϭ 0.02, 0.03, 0.06 (3 ϫ s, 12 H,
[SiC(CH3)3], 21.6 (tosyl-CH3), 22.6 (C-9), 24.7 (C-2), 25.8
[SiC(CH3)3], 25.1, 29.4, 31.8 (C-6, C-7, C-8), 32.5 (C-3), 37.0 (C-
SiCH3), 0.80Ϫ0.89 [m, 21 H, 11-H3, SiC(CH3)3], 1.19Ϫ1.46 (m, 42
H, 2ЈЈЈ-H2 to 14ЈЈЈ-H2, 2-H2 to 4-H2, 6-H2 to 10-H2), 1.55Ϫ1.71
1898
Eur. J. Org. Chem. 2000, 1889Ϫ1904

Total Syntheses of Squamocin A and Squamocin D
FULL PAPER
(m, 4 H, 3Ј-HЈ, 4Ј-HЈ, 3ЈЈ-HЈ, 4ЈЈ-HЈ), 1.82Ϫ1.98 (m, 4 H, 3Ј-HЈЈ, (C-3 to C-14, C-3Ј, C-4Ј, C-3ЈЈ, C-4ЈЈ, C-7ЈЈЈ to C-9ЈЈЈ), 32.5, 33.7
4Ј-HЈЈ, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ), 2.42 (d, J ϭ 3.8 Hz, 1 H, OH), 3.30Ϫ3.39
(C-2, C-2ЈЈЈ), 37.0, 37.2 (C-4ЈЈЈ, C-6ЈЈЈ), 70.5 (C-15), 72.4 (C-5ЈЈЈ),
(m, 1 H, 1-H), 3.44 (t, J ϭ 6.6 Hz, 2 H, 15ЈЈЈ-H2), 3.54Ϫ3.61 (m, 72.8 (PhCH2O), 74.8 (C-1ЈЈЈ), 74.9 (C-1), 81.5, 81.6, 82.2, 82.3 (C-
2 H, 5-H, 1ЈЈЈ-H), 3.74Ϫ3.93 (m, 4 H, 2Ј-H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-H), 2Ј, C-5Ј, C-2ЈЈ, C-5ЈЈ), 127.4, 127.6, 128.3, 138.7 (phenyl-C). Ϫ
4.48 (s, 2 H, PhCH2O), 7.23Ϫ7.33 (m, 5 H, phenyl-H). Ϫ 13C NMR HRMS(EI): calcd. 1001.7845 (M Ϫ H)ϩ; found 1001.7835.
(75 MHz, CDCl3): δ ϭ Ϫ4.7, Ϫ4.43, Ϫ4.38, Ϫ4.2 (SiCH3), 14.1
2. Deprotection: The all-TBDMS-protected benzyl ether (213 mg,
212 µmol) was dissolved in ethyl acetate (5 mL) and iPrOH (5 mL).
After adding Pd (10% on activated carbon, 22.7 mg) the mixture
was evacuated and filled with H2 (1 bar). This procedure was re-
peated four times. The mixture was stirred for 3 h at room temp.
The reaction mixture was filtered through a pad of Celite and the
pad was washed with CH2Cl2 (25 mL). Removal of the solvents
and purification by CC (75 cm3 SiO2, PE/MTBE, 10:1, 5:1) af-
forded alcohol 29 (193 mg, 211 µmol, 99%) as a colorless oil. Ϫ
Rf ϭ 0.18 (SiO2, PE/MTBE, 10:1). Ϫ [α]1D8 ϭ ϩ18.0 (c ϭ 0.35,
CHCl3). Ϫ IR (film): ν˜ ϭ 3359 bm (OH), 2954 m, 2928 s, 2856 s
(C-11), 18.1, 18.3 [SiC(CH3)3], 25.9, 26.0 [SiC(CH3)3], 21.6 (C-3),
22.6 (C-10), 25.3, 25.8, 26.2, 27.0, 27.4, 28.4, 28.7, 28.8, 29.49,
29.51, 29.63, 29.65, 29.76, 29.86, 31.9 (C-3ЈЈЈ to C-14ЈЈЈ, C-3Ј, C-
4Ј, C-3ЈЈ, C-4ЈЈ, C-7 to C-9), 32.5, 33.7 (C-2ЈЈЈ, C-2), 37.1, 37.3 (C-
4, C-6), 70.5 (C-15ЈЈЈ), 72.4 (C-5), 72.8 (PhCH2O), 74.0 (C-1), 74.9
(C-1ЈЈЈ), 81.6, 81.7, 82.5, 82.8 (C-2Ј, C-5Ј, C-2ЈЈ, C-5ЈЈ), 127.4,
127.6, 128.3, 138.7 (phenyl-C). Ϫ HRMS (EI): calcd. 870.6953 (M
Ϫ H2O)ϩ; found 870.6955.
28: Rf ϭ 0.45 (SiO2, PE/MTBE, 3:1). Ϫ [α]1D9 ϭ ϩ17.0 (c ϭ 0.50,
CHCl3). Ϫ IR (film): ν˜ ϭ 3412 bm (OH), 2928, 2855 s (CH), 1460
m, 1377 w, 1254 w, 1187 w, 1069 m, 836 m, 774 w, 733 w, 698 w
cmϪ1. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.01, 0.02, 0.04 (3 ϫ s,
12 H, SiCH3), 0.83Ϫ0.88 [m, 21 H, 11-H3, SiC(CH3)3], 1.19Ϫ1.48
(m, 42 H, 2ЈЈЈ-H2 to 14ЈЈЈ-H2, 2-H2 to 4-H2, 6-H2 to 10-H2),
1.55Ϫ1.69 (m, 4 H, 3Ј-HЈ, 4Ј-HЈ, 3ЈЈ-HЈ, 4ЈЈ-HЈ), 1.76Ϫ1.99 (m, 4
H, 3Ј-HЈЈ, 4Ј-HЈЈ, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ), 2.11 (br. s, 1 H, OH), 3.44 (t,
J ϭ 6.6 Hz, 2 H, 15ЈЈЈ-H2), 3.57Ϫ3.69 (m, 2 H, 5-H, 1ЈЈЈ-H),
3.79Ϫ3.99 (m, 5 H, 1-H, 2Ј-H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-H), 4.48 (s, 2 H,
PhCH2O), 7.23Ϫ7.33 (m, 5 H, phenyl-H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ Ϫ4.6, Ϫ4.44, Ϫ4.41, Ϫ4.3 (SiCH3), 14.1 (C-11), 18.1,
18.2 [SiC(CH3)3], 25.9 [SiC(CH3)3], 21.7 (C-3), 22.6 (C-10), 24.5,
25.3, 25.87, 26.01, 26.2, 26.8, 28.5, 28.7, 29.49, 29.51, 29.63, 29.66,
29.76, 29.9, 31.9 (C-3ЈЈЈ to C-14ЈЈЈ, C-3Ј, C-4Ј, C-3ЈЈ, C-4ЈЈ, C-7 to
C-9), 32.0, 32.6 (C-2, C-2ЈЈЈ), 37.0, 37.1 (C-4, C-2), 70.52 (C-15ЈЈЈ),
71.2 (C-1), 72.2 (C-5), 72.8 (PhCH2O), 74.5 (C-1ЈЈЈ), 82.2, 82.3,
82.4, 82.5 (C-2Ј, C-5Ј, C-2ЈЈ, C-5ЈЈ), 127.4, 127.6, 128.3, 138.7
(phenyl-C). Ϫ HRMS (EI): calcd. 832.6432 (M Ϫ C4H8)ϩ; found
832.6437.
(CH), 1472 w, 1463 w, 1254 m, 1094 m, 1005 w, 835 s, 774 m cmϪ1
.
1
Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.01, 0.02, 0.04 (3 ϫ s, 18 H,
SiCH3), 0.82Ϫ0.89 [m, 21 H, 11ЈЈЈ-H3, SiC(CH3)3], 1.19Ϫ1.76 (m,
46 H, 2-H2 to 14-H2, 3Ј-HЈ, 4Ј-HЈ, 3ЈЈ-HЈ, 4ЈЈ-HЈ, 2ЈЈЈ-H2 to 4ЈЈЈ-
H2, 6ЈЈЈ-H2 to 10ЈЈЈ-H2), 1.79Ϫ1.90 (m, 4 H, 3Ј-HЈЈ, 4Ј-HЈЈ, 3ЈЈ-
HЈЈ, 4ЈЈ-HЈЈ), 3.55Ϫ3.65 (m, 5 H, 1-H2, 15-H, 1ЈЈЈ-H, 5ЈЈЈ-H),
3.81Ϫ3.96 (m, 4 H, 2Ј-H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ Ϫ4.62, Ϫ4.59, Ϫ4.45, Ϫ4.38, Ϫ4.23
(SiCH3), 14.1 (C-11ЈЈЈ), 18.1, 18.2 [SiC(CH3)3], 25.9, 26.0
[SiC(CH3)3], 21.8 (C-3ЈЈЈ), 22.6 (C-10ЈЈЈ), 25.2, 25.8, 25.87, 27.1,
27.2, 28.4, 29.4, 29.54, 29.59, 29.61, 29.64, 29.9, 31.9 (C-3 to C-13,
C-3Ј, C-4Ј, C-3ЈЈ, C-4ЈЈ, C-7ЈЈЈ to C-9ЈЈЈ), 32.4, 32.7 (C-14, C-2ЈЈЈ),
32.8 (C-2), 37.0, 37.6 (C-4ЈЈЈ, C-6ЈЈЈ), 63.1 (C-1), 72.4 (C-5ЈЈЈ),
74.76 (C-1ЈЈЈ), 74.83 (C-15), 81.53, 81.58, 82.17, 82.19 (C-2Ј, C-
5Ј, C-2ЈЈ, C-5ЈЈ). Ϫ HRMS (EI): calcd. 856.6828 (M Ϫ C4H8)ϩ;
found 856.6829.
(15R,2ЈR,5ЈR,2ЈЈR,5ЈЈR,1ЈЈЈR,5ЈЈЈS)-15-[5Ј-(5ЈЈ-(1ЈЈЈ,5ЈЈЈ-Bis(tert-
butyldimethylsilyloxy)undec-1ЈЈЈ-yl)tetrahydrofuran-2ЈЈ-yl)tetra-
hydrofuran-2Ј-yl]-15-(tert-butyldimethylsilyloxy)pentadecanoic
Acid (30): (COCl)2 (50 µL, 585 µmol) was dissolved in CH2Cl2
(2 mL). The solution was cooled to Ϫ60 °C and DMSO (100 µL,
1.37 mmol) dissolved in CH2Cl2 (3 mL) was added. At Ϫ50 °C, a
solution of alcohol 29 (174 mg, 190 µmol) in CH2Cl2 (5 mL) was
added. After 45 min at Ϫ45 °C, the mixture was treated with Et3N
(325 µL, 2.33 mmol). After 5 min the temperature was allowed to
rise to 0 °C and H2O (5 mL) was added to stop the reaction. The
aqueous layer was extracted three times with CH2Cl2 (5 mL). The
combined organic layers were washed with sat. aqueous NaCl
(10 mL) and dried with MgSO4. Removal of the solvents afforded
the crude aldehyde (Rf ϭ 0.73; SiO2, PE/MTBE, 5:1), which was
dissolved in tBuOH (3 mL) and 2-methyl-2-butene (1 mL). The
mixture was treated with a solution of NaClO2 (80%, 137 mg,
1.2 mmol) and NaH2PO4 2 H2O (255 mg, 1.6 mmol) in H2O (5 mL)
at 0 °C. The mixture was stirred vigorously at room temp. for 2 h
30 min. MTBE (10 mL) and H2O (10 mL) were added. The aque-
ous layer was extracted three times with MTBE (20 mL). The com-
(15R,2ЈR,5ЈR,2ЈЈR,5ЈЈR,1ЈЈЈR,5ЈЈЈS)-15-[5Ј-(5ЈЈ-(5ЈЈЈ-(tert-Butyldi-
methylsilyloxy)undec-1ЈЈЈ-yl)-tetrahydrofuran-2ЈЈ-yl)tetrahydro-
furan-2Ј-yl]-15-(tert-butyldimethylsilyloxy)pentadecan-1-ol (29): Ϫ
1. TBDMS Protection: To a solution of alcohol 27 (231 mg, 260
µmol) in CH2Cl2 (10 mL) at Ϫ20 °C was added 2,6-lutidine (250
µL, 2.15 mmol) and TBDMSOTf (140 µL, 610 µmol). The mixture
was stirred for 45 min at Ϫ20 °C. The reaction was quenched with
sat. aqueous NH4Cl (10 mL). The aqueous layer was extracted
twice with CH2Cl2 (10 mL). The combined organic layers were
washed with sat. aqueous NaCl (10 mL) and dried with MgSO4.
The solvents were removed in vacuo. Purification by CC (100 cm3
SiO2, PE/MTBE, 20:1) afforded the all-TBDMS-protected benzyl
ether (237 mg, 236 µmol, 91%) as a colorless liquid.
(1R,2ЈR,5ЈR,2ЈЈR,5ЈЈR,1ЈЈЈR,5ЈЈЈS)-1-[5Ј-(5ЈЈ-(1ЈЈЈ,5ЈЈЈ-Bis(tert-
butyldimethylsilyloxy)undec-1ЈЈЈ-yl)tetrahydrofuran-2ЈЈ-yl)tetra-
hydrofuran-2Ј-yl]-1-tert-butyldimethylsilyloxy-15-benzyloxypenta-
decane: Rf ϭ 0.50 (SiO2, PE/MTBE, 20:1). Ϫ [α]2D0 ϭ ϩ26.1 (c ϭ
0.33, CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.01, 0.02, 0.03,
0.04 (4 ϫ s, 18 H, SiCH3), 0.81Ϫ0.88 [m, 21 H, 11ЈЈЈ-H3, bined organic layers were dried with MgSO4 and the solvents re-
SiC(CH3)3], 1.17Ϫ1.70 (m, 46 H, 2-H2 to 14-H2, 3Ј-HЈ, 4Ј-HЈ, 3ЈЈ-
HЈ, 4ЈЈ-HЈ, 2ЈЈЈ-H2 to 4ЈЈЈ-H2, 6ЈЈЈ-H2 to 10ЈЈЈ-H2), 1.80Ϫ1.95 (m,
moved in vacuo. Purification by CC (75 cm3 SiO2, PE/MTBE, 3:1,
MTBE) yielded acid 30 (168 mg, 181 µmol, 95% over two steps) as
4 H, 3Ј-HЈЈ, 4Ј-HЈЈ, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ), 3.44 (t, J ϭ 6.6 Hz, 2 H, 15- a colorless oil. Ϫ Rf ϭ 0.38 (SiO2, PE/MTBE, 3:1). Ϫ [α]2D0 ϭ ϩ15.8
H2), 3.55Ϫ3.65 (m, 3 H, 1-H, 1ЈЈЈ-H, 5ЈЈЈ-H), 3.82Ϫ3.93 (m, 4 H,
(c ϭ 0.38, CHCl3). Ϫ IR (film): ν˜ ϭ 3366 bm (OH), 2928, 2856 s
2Ј-H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-H), 4.48 (s, 2 H, PhCH2O), 7.23Ϫ7.33 (m, 5 (CH), 1711 m (CϭO), 1463 w, 1360 w, 1254 m, 1096 m, 1071 w,
1
H, phenyl-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ4.6, Ϫ4.46, 1005 w, 836 m, 774 m cmϪ1. Ϫ H NMR (300 MHz, CDCl3): δ ϭ
Ϫ4.37, Ϫ4.2 (SiCH3), 14.1 (C-11ЈЈЈ), 18.2 [SiC(CH3)3], 26.0
[SiC(CH3)3], 21.6 (C-3ЈЈЈ), 22.6 (C-10ЈЈЈ), 25.2, 25.8, 26.2, 27.0,
27.4, 28.4, 28.6, 28.8, 29.50, 29.55, 29.62, 29.67, 29.77, 29.9, 31.9
0.01, 0.02, 0.04 (3 ϫ s, 18 H, SiCH3), 0.82Ϫ0.89 [m, 21 H, 11ЈЈЈ-
H3, SiC(CH3)3], 1.19Ϫ1.75 (m, 44 H, 3-H2 to 14-H2, 3Ј-HЈ, 4Ј-HЈ,
3ЈЈ-HЈ, 4ЈЈ-HЈ, 2ЈЈЈ-H2 to 4ЈЈЈ-H2, 6ЈЈЈ-H2 to 10ЈЈЈ-H2), 1.79Ϫ1.93
Eur. J. Org. Chem. 2000, 1889Ϫ1904
1899

U. Emde, U. Koert
FULL PAPER
(m, 4 H, 3Ј-HЈЈ, 4Ј-HЈЈ, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ), 2.32 (t, J ϭ 7.5 Hz, 2-
µmol) was dissolved in THF (200 µL). A mixture of the lactone 31
H2), 3.55Ϫ3.64 (m, 3 H, 15-H, 1ЈЈЈ-H, 5ЈЈЈ-H), 3.81Ϫ3.96 (m, 4 H, (19.2 mg, 19.8 µmol) dissolved in THF (300 µL) was added at 0
2Ј-H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ °C. The mixture was stirred for 30 min at 0 °C and 20 min at room
Ϫ4.61, Ϫ4.58, Ϫ4.45, Ϫ4.37, Ϫ4.22 (SiCH3), 14.1 (C-11ЈЈЈ), 18.1,
18.2 [SiC(CH3)3], 26.0 [SiC(CH3)3], 21.8 (C-3ЈЈЈ), 22.7 (C-10ЈЈЈ),
24.7, 25.2, 25.9, 27.0, 27.1, 27.2, 28.4, 29.1, 29.2, 29.4, 29.55, 29.60,
temp. A solution of PhSeCl (107 mg, 559 µmol) in THF (400 µL)
was added. The mixture was stirred for 1 h at 0 °C and 1 h 30 min
at room temp. The reaction was quenched by adding phosphate
29.63, 29.9, 31.9 (C-3 to C-13, C-3Ј, C-4Ј, C-3ЈЈ, C-4ЈЈ, C-7ЈЈЈ to buffer (pH ϭ 7, 2 mL) and MTBE (3 mL). The aqueous layer was
C-9ЈЈЈ), 32.4, 32.7 (C-14, C-2ЈЈЈ), 33.9 (C-2), 37.0, 37.6 (C-4ЈЈЈ, C- extracted four times with MTBE (10 mL). The combined organic
6ЈЈЈ), 72.4 (C-5ЈЈЈ), 74.76 (C-1ЈЈЈ), 74.84 (C-15), 81.54, 81.59, 82.17, layers were dried with MgSO4 and the solvents were removed in
82.20 (C-2Ј, C-5Ј, C-2ЈЈ, C-5ЈЈ), 178.87 (C-1). Ϫ HRMS (EI): calcd. vacuo. Purification by CC (75 cm3 SiO2, n-hexane/MTBE, 8:1, 6:1)
926.7246 (M)ϩ; found 926.7258.
yielded the selenyllactone (C-3 epimers; Rf ϭ 0.24 and 0.26; SiO2,
n-hexane/MTBE, 8:1), which was dissolved in THF (500 µL) and
MeOH (500 µL). At 0 °C, MMPP (85%, 40 mg, 69 µmol) was ad-
ded. The yellow mixture was stirred for 20 min at room temp. The
yellow color disappeared. The reaction was quenched by addition
of phosphate buffer (pH ϭ 7, 1 mL), sat. aqueous NH4Cl (1 mL)
and MTBE (3 mL). The aqueous layer was extracted four times
with MTBE (10 mL). The combined organic layers were dried with
MgSO4 and the solvents were removed in vacuo. Purification by
CC (30 cm3 SiO2, n-hexane/MTBE, 6:1) yielded the α,β-unsatur-
ated lactone 32 (7.7 mg, 8.0 µmol, 40% over two steps) as a color-
less oil. Ϫ Rf ϭ 0.23 ( SiO2, n-hexane/MTBE, 5:1). Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 0.01, 0.02, 0.04 (3 ϫ s, 18 H, SiCH3),
0.82Ϫ0.89 [m, 21 H, 11ЈЈЈЈ-H3, SiC(CH3)3], 1.19Ϫ1.45 and
1.59Ϫ1.72 (2 ϫ m, 42 H, 2Ј-H2 to 12Ј-H2, 3ЈЈ-HЈ, 4ЈЈ-HЈ, 3ЈЈЈ-HЈ,
4ЈЈЈ-HЈ, 2ЈЈЈЈ-H2 to 4ЈЈЈЈ-H2, 6ЈЈЈЈ-H2 to 10ЈЈЈЈ-H2) with 1.38 (d, J ϭ
6.8 Hz, 3 H, CH3-lactone), 1.79Ϫ1.90 (m, 4 H, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ,
3ЈЈЈ-HЈЈ, 4ЈЈЈ-HЈЈ), 2.24 (t, J ϭ 7.2 Hz, 2 H, 1Ј-H2), 3.55Ϫ3.64 (m,
3 H, 13Ј-H, 1ЈЈЈЈ-H, 5ЈЈЈЈ-H), 3.81Ϫ3.96 (m, 4 H, 2ЈЈ-H, 5ЈЈ-H, 2ЈЈЈ-
H, 5ЈЈЈ-H), 4.97 (dd, J ϭ 7.2, 1.5 Hz, 1 H, 5-H), 6.96 (d, J ϭ 1.5 Hz,
1 H, 4-H). Ϫ 13C NMR (75 MHz; CDCl3): δ ϭ Ϫ4.62, Ϫ4.59,
Ϫ4.45, Ϫ4.37, Ϫ4.22 (SiCH3), 14.1 (C-11ЈЈЈЈ), 18.1, 18.20, 18.22
[SiC(CH3)3], 19.2 (CH3-lactone), 25.95, 25.97 [SiC(CH3)3], 21.8 (C-
3ЈЈЈЈ), 22.6 (C-10ЈЈЈЈ), 25.2, 25.9, 27.1, 27.2, 27.4, 28.4, 29.2, 29.3,
29.5, 29.6, 29.9, 31.9, 32.4, 32.7 (C-1Ј to C-12Ј, C-3ЈЈ, C-4ЈЈ, C-3ЈЈЈ,
C4ЈЈЈ, C-2ЈЈЈЈ, C-7ЈЈЈЈ to C-9ЈЈЈЈ), 37.0, 37.6 (C-4ЈЈЈЈ, C-6ЈЈЈЈ), 72.4
(C-5ЈЈЈЈ), 74.76, 74.83 (C-13Ј, C-1ЈЈЈЈ), 77.4 (C-5), 81.55, 81.59,
82.17, 82.20 (C-2ЈЈ, C-5ЈЈ, C-2ЈЈЈ, C-5ЈЈЈ), 134.4 (C-3), 148.8 (C-4),
173.9 (C-2).
(3Θ,5S,13ЈR,2ЈЈR,5ЈЈR,2ЈЈЈR,5ЈЈЈR,1ЈЈЈЈR,5ЈЈЈЈS)-3-[13Ј-(5ЈЈ-(5ЈЈЈ-
(1ЈЈЈЈ,5ЈЈЈЈ-Bis(tert-butyldimethylsilyloxy)undec-1ЈЈЈЈ-yl)tetra-
hydrofuran-2ЈЈЈ-yl)tetrahydrofuran-2ЈЈ-yl)-13Ј-(tert-butyldimethyl-
silyloxy)tridec-1-yl]-5-methyldihydrofuran-2(3H)-one (31): To
a
freshly prepared solution of LDA (2.0 mmol/mL in THF, 1.45 mL,
2.9 mmol) was added LiCl (previously dried for 15 h at 150 °C
under reduced pressure; 64 mg, 1.51 mmol) and the mixture was
stirred for 30 min at room temp. A 10-mL flask was charged with
carboxylic acid 30 (28.5 mg, 30.7 µmol), cooled to 0 °C and the
previously prepared LDA solution (sat. with LiCl, 2.0 mmol/mL in
THF, 200 µL, 400 µmol) was added dropwise. The yellow solution
was stirred for 20 min at room temp. (S)-propylene oxide (100 µL,
1.42 mmol) was then added. The mixture was stirred overnight at
room temp. The reaction was quenched with sat. aqueous NH4Cl
(2 mL). The aqueous layer was extracted three times with MTBE
(10 mL). The combined organic layers were dried with MgSO4. The
solvents were removed in vacuo and the residue was redissolved in
CH2Cl2 (750 µL). Et3N (100 µL, 717 µmol) and PivCl (50 µL, 406
µmol) were added at 0 °C. The mixture was stirred for 30 min at
room temp. The reaction was quenched with sat. aqueous NH4Cl
(1 mL). The aqueous layer was extracted three times with CH2Cl2
(15 mL). The combined organic layers were dried with MgSO4 and
the solvents were removed in vacuo. Purification by CC (20 cm3
SiO2, n-hexane/MTBE, 5:1) afforded lactone 31 (mixture of C-3
epimers, 15.8 mg, 16.3 µmol, 53% over two steps) as a colorless oil.
Ϫ Rf ϭ 0.40 and 0.44 (SiO2, PE/MTBE, 5:1). Ϫ IR (film): ν˜ ϭ
2928, 2856 s (CH), 1775 m (CϭO), 1465 m, 1385 w, 1253 m, 1096
m, 1071 w, 836 m, 774 m cmϪ1. Ϫ H NMR (300 MHz, CDCl3):
1
Squamocin D (Asiminacin): Unsaturated lactone 32 (7.7 mg, 8.0
µmol) was dissolved in THF (1 mL). HF (5% in MeCN, 2.0 mL,
5.0 mmol) was added and the mixture was stirred for 2 h at room
temp. The reaction was quenched with sat. aqueous NaHCO3
(3 mL) and CH2Cl2 (2 mL). The aqueous layer was extracted three
times with CH2Cl2 (15 mL). The combined organic layers were
dried with MgSO4. Removal of the solvents in vacuo and purifica-
tion by CC (10 cm3 SiO2, MTBE, MTBE/MeOH, 100:1, 20:1,
CHCl3/MeOH, 10:1) afforded squamocin D (3.9 mg, 6.3 µmol,
79%) as a colorless solid. Ϫ Rf ϭ 0.29 (MTBE/MeOH, 100:1). Ϫ
δ ϭ 0.01, 0.02, 0.04, 0.05 (4 ϫ s, 18 H, SiCH3), 0.84Ϫ0.88 [m, 21
H, 11ЈЈЈЈ-H3, SiC(CH3)3], 1.19Ϫ1.48 and 1.57Ϫ1.73 (2 ϫ m, 44 H,
1Ј-H2 to 12Ј-H2, 3ЈЈ-HЈ, 4ЈЈ-HЈ, 3ЈЈЈ-HЈ, 4ЈЈЈ-HЈ, 2ЈЈЈЈ-H2 to 4ЈЈЈЈ-
H2, 6ЈЈЈЈ-H2 to 10ЈЈЈЈ-H2, 4-H2 epimers) with 1.34 and 1.39 (2 ϫ d,
J ϭ 6.2 Hz, 3 H, CH3-lactone epimers), 1.77Ϫ1.89 (m, 4 H, 3ЈЈ-
HЈЈ, 4ЈЈ-HЈЈ, 3ЈЈЈ-HЈЈ, 4ЈЈЈ-HЈЈ), 1.98Ϫ2.09 and 2.40Ϫ2.62 (2 ϫ m,
1 H, 3-H epimers), 3.54Ϫ3.64 (m, 3 H, 13Ј-H, 1ЈЈЈЈ-H, 5ЈЈЈЈ-H),
3.80Ϫ3.96 (m, 4 H, 2ЈЈ-H, 5ЈЈ-H, 2ЈЈЈ-H, 5ЈЈЈ-H), 4.39Ϫ4.49 and
4.58Ϫ4.68 (2 ϫ m, 1 H, 5-H epimers). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ Ϫ4.63, Ϫ4.61, Ϫ4.46, Ϫ4.38, Ϫ4.24 (SiCH3), 14.1 (C-
11ЈЈЈЈ), 18.11, 18.18, 18.21 [SiC(CH3)3], 25.94, 25.96 [SiC(CH3)3],
21.0, 21.2 (CH3-lactone), 21.8 (C-3ЈЈЈЈ), 22.6 (C-10ЈЈЈЈ), 25.2, 25.9,
27.1, 27.2, 27.4, 28.3, 29.3, 29.44, 29.49, 29.53, 29.56, 29.62, 29.9,
30.7, 31.9, 32.3, 32.7, 35.1 (C-1Ј to C-12Ј, C-3ЈЈ, C-4ЈЈ, C-3ЈЈЈ, C-
4ЈЈЈ, C-2ЈЈЈЈ, C-7ЈЈЈЈ to C-9ЈЈЈЈ, C-2), 37.0, 37.6 (C-4ЈЈЈЈ, C-6ЈЈЈЈ),
39.3, 41.5 (C-3), 72.4 (C-5ЈЈЈЈ), 74.7, 74.8 (C-13Ј, C-1ЈЈЈЈ), 74.9, 75.0
(C-5), 81.55, 81.59, 82.16, 82.19 (C-2ЈЈ, C-5ЈЈ, C-2ЈЈЈ, C-5ЈЈЈ), 179.1,
179.4 (C-1). Ϫ HRMS (EI): calcd. 910.6933 (M Ϫ C4H8)ϩ; found
910.6919.
1
[α]2D1 ϭ ϩ20 (c ϭ 0.095, CHCl3). Ϫ H NMR (300 MHz, CDCl3):
δ ϭ 0.86 (t, J ϭ 6.4 Hz, 3 H, 34-CH3), 1.21Ϫ1.69 (m, 42 H, 4-H2
to 14-H2, 17-HЈ, 18-HЈ, 21-HЈ, 22-HЈ, 25-H2 to 27-H2, 29-H2 to
33-H2), 1.38 (d, J ϭ 6.8 Hz, 3 H, 37-H3), 1.91Ϫ2.01 (m, 4 H, 17-
HЈЈ, 18-HЈЈ, 21-HЈЈ, 22-HЈЈ), 2.24 (tt, J ϭ 7.9, 1.5 Hz, 3-H2),
3.33Ϫ3.42 (m, 2 H, 15-H, 24-H), 3.55Ϫ3.60 (m, 1 H, 28-H),
3.78Ϫ3.89 (m, 4 H, 16-H, 19-H, 20-H, 23-H), 4.97 (qq, J ϭ 6.8,
1.5 Hz, 1 H, 36-H), 6.96 (q, J ϭ 1.5 Hz, 1 H, 35-H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 14.1 (C-34), 19.2 (C-37), 21.7 (C-26), 22.6
(C-33), 25.2 (C-3), 25.64, 25.65, 27.40, 28.40, 28.93, 28.96,
(5S,13ЈR,2ЈЈR,5ЈЈR,2ЈЈЈR,5ЈЈЈR,1ЈЈЈЈR,5ЈЈЈЈS)-3-[13Ј-(5ЈЈ-(5ЈЈЈ-(1ЈЈЈЈ, 29.1Ϫ29.7 signal overlap, 29.72, 31.8 (C-4 to C-13, C-17, C-18, C-
5ЈЈЈЈ-Bis(tert-butyldimethylsilyloxy)undec-1ЈЈЈЈ-yl)tetrahydrofuran-
2ЈЈЈ-yl)tetrahydrofuran-2ЈЈ-yl)-13Ј-(tert-butyldimethylsilyloxy)tridec-
1-yl]-5-methylfuran-2(5H)-one (32): KHMDS (95%, 53 mg, 252
21, C-22, C-30 to C-32), 33.3, 33.5 (C-14, C-25), 37.32, 37.54 (C-
27, C-29), 71.8 (C-28), 73.9, 74.1 (C-15, C-24), 77.4 (C-36), 81.76,
81.83 (C-19, C-20), 83.0, 83.2 (C-16, C-23), 134.4 (C-2), 148.8 (C-
1900
Eur. J. Org. Chem. 2000, 1889Ϫ1904

Total Syntheses of Squamocin A and Squamocin D
35), 173.9 (CϭO). Ϫ HRMS (EI): calcd. 604.4703 (M Ϫ H2O)ϩ; 1.29 mmol) and PivCl (100 µL, 812 µmol) were added at 0 °C. The
FULL PAPER
found 604.4705.
mixture was stirred for 45 min at room temp. The reaction was
quenched with sat. aqueous NH4Cl (15 mL). The aqueous layer
was extracted twice with CH2Cl2 (25 mL). The combined organic
layers were washed with sat. aqueous NaCl (25 mL) and dried with
MgSO4. Purification by CC (100 cm3 SiO2, PE/MTBE, 3:1) af-
forded a mixture of the epimeric lactones 34 (138 mg, 367 µmol,
64%) as a colorless wax. Ϫ Rf ϭ 0.39 and 0.42 (PE/MTBE, 3:1).
Ϫ M.p.: 20Ϫ25 °C. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.21Ϫ2.10
(m, 24 H, 1Ј-H2 to 11Ј-H2, 4-H2) with 1.34 and 1.39 (2 ϫ d, J ϭ
6.4 Hz, 3 H, CH3 epimers), 2.39Ϫ2.63 (m, 1 H, 3-H epimers), 3.44
(t, J ϭ 6.8 Hz, 2 H, 12Ј-H2), 4.48 (s, 2 H, PhCH2O), 4.57Ϫ4.68
(m, 1 H, 5-H), 7.23Ϫ7.33 (m, 5 H, phenyl-H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 21.0, 21.2 (CH3 epimers), 26.2, 27.3, 29.3,
29.39, 29.44, 29.50, 29.53, 29.7, 30.3, 30.7 (C-1Ј to C-11Ј), 35.0,
37.0 (C-4), 39.3, 41.5 (C-3), 70.5 (C-12Ј), 72.8 (PhCH2O), 74.9, 75.0
(C-5), 127.4, 127.6, 128.3, 138.7 (phenyl-C), 179.1, 179.4 (C-2).
14-Benzyloxytetradecanoic Acid (33): 1. Swern Oxidation: (COCl)2
(770 µL, 8.83 mmol) was dissolved in CH2Cl2 (20 mL). The solu-
tion was cooled to Ϫ60 °C and DMSO (1.50 mL, 21.1 mmol) dis-
solved in CH2Cl2 (2 mL) was added. At Ϫ55 °C, a solution of alco-
hol 17 (1.10 g, 3.45 mmol) in CH2Cl2 (20 mL) was added. After
45 min at Ϫ50 °C, the mixture was treated with Et3N (4.50 mL,
32.3 mmol). After 5 min, the temperature was allowed to rise to 0
°C and H2O (50 mL) was added to stop the reaction. The aqueous
layer was extracted twice with CH2Cl2 (50 mL). The combined or-
ganic layers were washed with 1  HCl (50 mL), sat. aqueous
NaHCO3 (50 mL) and sat. aqueous NaCl (50 mL) and dried with
MgSO4. After evaporation of the solvents, the crude aldehyde
(1.06 g, 3.31 mmol, 94%) was obtained as a yellow liquid.
14-Benzyloxytetradecanal: Rf ϭ 0.60 (PE/MTBE, 5:1). Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 1.22Ϫ1.40 (m, 18 H, 4-H2 to 12-H2),
1.52Ϫ1.67 (m, 4 H, 3-H2, 13-H2), 2.39 (dt, J ϭ 7.5, 1.9 Hz, 2 H,
2-H2), 3.44 (t, J ϭ 6.8 Hz, 2 H, 14-H2), 4.48 (s, 2 H, PhCH2O),
7.21Ϫ7.30 (m, 5 H, phenyl-H), 9.73 (t, J ϭ 1.9 Hz, 1 H, CHO). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 22.1, 26.2, 29.1, 29.3, 29.37,
29.45, 29.52, 29.54, 29.56 (C-3 to C-12), 29.8 (C-13), 43.9 (C-2),
70.5 (C-14), 72.8 (PhCH2O), 127.4, 127.6, 128.3, 138.7 (phenyl-C),
202.9 (CHO).
(5S)-3-(12Ј-Benzyloxydodecyl)-5-methylfuran-2(5H)-one
(35):
KHMDS (95%, 105 mg, 528 µmol) was dissolved in THF (0.5 mL).
A solution of lactone 34 (38.8 mg, 104 µmol) in THF (0.5 mL) was
added at 0 °C. The mixture was stirred for 30 min at 0 °C and
20 min at room temp. A solution of PhSeCl (164 mg, 856 µmol) in
THF (1 mL) was added. The mixture was stirred for 2 h at room
temp. The reaction was quenched by adding phosphate buffer
(pH ϭ 7, 5 mL), sat. aqueous NH4Cl (5 mL) and MTBE (10 mL).
The aqueous layer was extracted twice with MTBE (25 mL). The
combined organic layers were washed with sat. aqueous NaCl
(50 mL) and dried with MgSO4. Purification by CC (50 cm3 SiO2,
PE/MTBE, 5:1) yielded the epimeric selenyllactones, which were
dissolved in THF (2 mL) and MeOH (2 mL). At 0 °C, MMPP
(85%, 506 mg, 870 µmol) was added. The yellow mixture was
stirred for 1 h at room temp. The reaction was quenched by addi-
tion of sat. aqueous NH4Cl (5 mL) and MTBE (10 mL). The aque-
ous layer was extracted twice with MTBE (25 mL). The combined
organic layers were washed with sat. aqueous NaCl (15 mL) and
dried with MgSO4. Purification by CC (30 cm3 SiO2, PE/MTBE,
3:1) yielded the unsaturated lactone 35 (27.2 mg, 73.0 µmol, 70%)
as a colorless wax. Rf ϭ 0.31 (PE/MTBE, 3:1). Ϫ M.p.: 20Ϫ25 °C.
Ϫ [α]2D0 ϭ ϩ12.0 (c ϭ 0.25, CHCl3). Ϫ IR (KBr): ν˜ ϭ 2926, 2854
cmϪ1 s (CH), 1756 s (CϭO), 1650 w (CϭC), 1454 w, 1362 w, 1318
2. Chlorite Oxidation:
A solution of the aldehyde (1.06 g,
3.31 mmol) in tBuOH (25 mL) and 2-methyl-2-butene (10.0 mL)
was treated with a mixture of NaClO2 (80%, 1.19 g, 10.5 mmol)
and NaH2PO4 2 H2O (2.18 g, 14.0 mmol) in H2O (25 mL) at 0 °C.
The mixture was stirred vigorously at room temp. for 5 h. MTBE
(50 mL) and H2O (50 mL) were added and the phases were separ-
ated. The aqueous layer was extracted twice with MTBE (50 mL).
The combined organic layers were washed with sat. aqueous NaCl
(75 mL) and dried with MgSO4. Purification by CC (200 cm3 SiO2,
PE/MTBE, 3:1) yielded acid 33 (1.09 g, 3.27 mmol, 99%) as color-
less crystals. Ϫ Rf ϭ (PE/MTBE, 3:1). Ϫ M.p.: 49 °C. Ϫ IR (KBr):
ν˜ ϭ 3438 bw (OH), 3029 w, 2916, 2849 s (CH), 2793 w, 2677 w,
1703 s (CϭO), 1496 w, 1471 w, 1463 w, 1454 w, 1360 w, 1321 w,
1302 m, 1255 w, 1207 w, 1188 w, 1103 m, 1046 w, 1026 w, 992 w,
944 w, 913 w, 748 m, 698 m cmϪ1. Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ 1.20Ϫ1.39 (bm, 18 H, 4-H2 to 12-H2), 1.53Ϫ1.67 (m, 4 H, 3-
H2, 13-H2), 2.32 (t, J ϭ 7.6 Hz, 2 H, 2-H2), 3.45 (t, J ϭ 6.6 Hz, 2
H, 14-H2), 4.49 (s, 2 H, PhCH2O), 7.22Ϫ7.34 (m, 5 H, phenyl-H).
1
w, 1100 m, 1027 w, 858 w, 736 w, 671 w. Ϫ H NMR (300 MHz,
CDCl3): δ ϭ 1.22Ϫ1.64 (m, 20 H) with 1.38 (d, J ϭ 6.8 Hz, 3 H,
CH3-lactone) and 2.20Ϫ2.28 (m, 2 H) (1Ј-H2 to 11Ј-H2), 3.44 (t,
J ϭ 6.6 Hz, 2 H, 12Ј-H2), 4.48 (s, 2 H, PhCH2O), 4.92Ϫ5.01 (m, 1
H, 4-H), 6.96 (dd, J ϭ 3.4, 1.7 Hz, 1 H, 3-H), 7.22Ϫ7.33 (m, 5 H,
phenyl-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 19.2 (CH3), 25.1,
26.2, 27.4, 29.2, 29.27, 29.45, 29.47, 29.52, 29.54, 29.8 (C-1Ј to C-
11Ј), 70.5 (C-12Ј), 72.8 (PhCH2O), 77.4 (C-5), 127.4, 127.6, 128.3
(phenyl-C), 134.2 (C-3), 138.7 (phenyl-C), 148.8 (C-4), 173.9 (C-
2). Ϫ C24H36O3 (372.55): calcd. C 77.38, H 9.74; found C 77.13,
H 9.72.
Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 24.7, 26.2, 29.0, 29.2, 29.39,
29.45, 29.51, 29.54 (C-3 to C-12), 29.7 (C-13), 34.0 (C-2), 70.5 (C-
14), 72.8 (PhCH2O), 127.4, 127.6, 128.3, 138.6 (phenyl-C), 179.5
(COOH). Ϫ C21H34O3 (334.50): calcd. C 75.41, H 10.24; found C
75.35, H 10.25.
(3Θ,5S)-3-(12Ј-Benzyloxydodecyl)-5-methyldihydrofuran-2(3H)-one
(34): A solution of diisopropylamine (280 µL, 2.00 mmol) in THF
(5 mL) was treated with nBuLi (2.51 mmol/mL in n-hexane, 600
µL, 1.51 mmol) at Ϫ40 °C. The temperature was allowed to rise to
0 °C during 20 min. At 0 °C a solution of carboxylic acid 33
(190 mg, 569 µmol) in THF (5 mL) was added dropwise. The yel-
low solution was stirred for 45 min at 0 °C. (S)-Propylene oxide
(500 µL, 7.14 mmol) was then added. The mixture was stirred
15 min at 0 °C and for a further 2 h at room temp. The reaction
(15R,2ЈR,5ЈR,2ЈЈR,5ЈЈR,1ЈЈЈS,5ЈЈЈS)-15-[5Ј-(5ЈЈ-(1ЈЈЈ,5ЈЈЈ-Bis(tert-
butyldimethylsilyloxy)undec-1ЈЈЈ-yl-tetrahydrofuran-2ЈЈ-yl)tetra-
hydrofuran-2Ј-yl]-15-(tert-butyldimethylsilyloxy)pentadecan-1-ol
(36): To a solution of alcohol 28 (130 mg, 146 µmol) in CH2Cl2
(10 mL) at Ϫ20 °C were added 2,6-lutidine (220 µL, 1.89 mmol)
and TBDMSOTf (120 µL, 523 µmol). The mixture was stirred for
was quenched with sat. aqueous NH4Cl (10 mL). The aqueous 2 h at Ϫ20 °C. The reaction was quenched with sat. aqueous
layer was extracted twice with MTBE (25 mL). The combined or- NH4Cl (10 mL). The aqueous layer was extracted twice with
ganic layers were washed with sat. aqueous NaCl (25 mL) and CH2Cl2 (10 mL). The combined organic layers were washed with
dried with MgSO4. The solvents were removed in vacuo and the
residue was redissolved in CH2Cl2 (3 mL). Et3N (180 µL,
sat. aqueous NaCl (10 mL) and dried with MgSO4. Removal of the
solvents in vacuo and purification by CC (75 cm3 SiO2, PE/MTBE,
Eur. J. Org. Chem. 2000, 1889Ϫ1904
1901

U. Emde, U. Koert
FULL PAPER
20:1) afforded the all-TBDMS protected benzyl ether (Rf ϭ 0.43;
PE/MTBE, 20:1; 131 mg, 131 µmol, 90%) as a colorless liquid,
18.11, 18.14, 18.22 [SiC(CH3)3], 25.92, 25.97 [SiC(CH3)3], 21.1 (C-
3ЈЈЈ), 22.6 (C-10ЈЈЈ), 24.7, 25.3, 25.9, 27.2, 28.41, 28.45, 29.1, 29.2,
which was redissolved in ethyl acetate (5 mL) and iPrOH (5 mL). 29.4, 29.51, 29.55, 29.6, 29.9, 31.9 (C-3 to C-13, C-3Ј, C-4Ј, C-3ЈЈ,
After adding Pd (10% on activated carbon, 15.7 mg), the flask was C-4ЈЈ, C-7ЈЈЈ to C-9ЈЈЈ), 32.3, 35.1 (C-14, C-2ЈЈЈ), 34.0 (C-2), 37.0,
evacuated and filled with H2 (1 bar). The procedure was repeated
four times. The reaction mixture was then stirred overnight at room
temp., filtered through a pad of Celite and washed with CH2Cl2
(25 mL). Removal of the solvents and purification by CC (30 cm3
SiO2, PE/MTBE, 5:1) afforded the primary alcohol 36 (100 mg, 109
µmol, 75% over two steps) as a colorless oil. Ϫ Rf ϭ 0.22 (PE/
MTBE, 5:1). Ϫ [α]2D1 ϭ ϩ12.4 (c ϭ 0.34, CHCl3). Ϫ IR (film): ν˜ ϭ
3387 cmϪ1 bm (OH), 2952, 2928, 2856 s (CH), 1462 w, 1253 m,
37.4 (C-4ЈЈЈ, C-6ЈЈЈ), 72.2 (C-5ЈЈЈ), 73.6 (C-1ЈЈЈ), 74.7 (C-15), 81.36,
81.42, 82.15, 82.18 (C-2Ј, C-5Ј, C-2ЈЈ, C-5ЈЈ), broad CϭO signal
not seen. Ϫ HRMS(EI): calcd. 851.6437 (M Ϫ C4H9. Ϫ H2O)ϩ;
found 851.6439.
(3Θ,5S,13ЈR,2ЈЈR,5ЈЈR,2ЈЈЈR,5ЈЈЈR,1ЈЈЈЈS,5ЈЈЈЈS)-3-[13Ј-(5ЈЈ-(5ЈЈЈ-
(1ЈЈЈЈ,5ЈЈЈЈ-Bis(tert-butyldimethylsilyloxy)undec-1ЈЈЈЈ-yl)tetra-
hydrofuran-2ЈЈЈ-yl)tetrahydrofuran-2ЈЈ-yl)-13Ј-(tert-butyldimethyl-
1
silyloxy)tridec-1-yl]-5-methyldihydrofuran-2(3H)-one (38): To
a
1070 m, 836 m, 775 m. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.01,
freshly prepared solution of LDA in THF (2.0 mmol/mL, 1.45 mL,
2.9 mmol) was added LiCl (previously dried for 15 h at 150 °C
under reduced pressure, 64 mg, 1.51 mmol) and the mixture was
stirred for 30 min at room temp. A 10-mL flask was charged with
carboxylic acid 37 (25.0 mg, 26.9 µmol), cooled to 0 °C and the
previously prepared LDA solution in THF (sat. with LiCl,
2.0 mmol/mL, 200 µL, 400 µmol) was added dropwise. The yellow
solution was stirred for 20 min at room temp. (S)-Propylene oxide
(250 µL, 3.57 mmol) was added. The mixture was stirred overnight
at room temp. The reaction was quenched with sat. aqueous NH4Cl
(2 mL). The aqueous layer was extracted three times with MTBE
(10 mL). The combined organic layers were dried with MgSO4. The
solvents were removed in vacuo and the residue was redissolved in
CH2Cl2 (750 µL). Et3N (100 µL, 717 µmol) and PivCl (50 µL, 406
µmol) were added at 0 °C. The mixture was stirred for 30 min at
room temp. The reaction was quenched with sat. aqueous NH4Cl
(1 mL). The aqueous layer was extracted three times with CH2Cl2
(15 mL). The combined organic layers were dried with MgSO4 and
the solvents were removed in vacuo. Purification by CC (20 cm3
SiO2, n-hexane/MTBE, 5:1) afforded lactone 38 (epimeric mixture
at C-3, 15.1 mg, 15.6 µmol, 58% over two steps) as a colorless oil.
Rf ϭ 0.20 and 0.25 (PE/MTBE, 5:1). Ϫ IR (film): ν˜ ϭ 2928, 2856
s (CH), 1777 m (CϭO), 1462 m, 1361 w, 1253 m, 1096 m, 1070 w,
1006 w, 836 m, 774 m, 725 w cmϪ1. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 0.00, 0.01, 0.03, 0.04 (4 ϫ s, 18 H, SiCH3), 0.83Ϫ0.89
[m, 21 H, 11ЈЈЈЈ-H3, SiC(CH3)3], 1.20Ϫ1.49 and 1.58Ϫ1.73 (2 ϫ m,
44 H, 1Ј-H2 to 12Ј-H2, 3ЈЈ-HЈ, 4ЈЈ-HЈ, 3ЈЈЈ-HЈ, 4ЈЈЈ-HЈ, 2ЈЈЈЈ-H2 to
4ЈЈЈЈ-H2, 6ЈЈЈЈ-H2 to 10ЈЈЈЈ-H2, 35-H2 epimers) with 1.34, 1.38
(2 ϫ d, J ϭ 6.3 Hz, 3 H, CH3-lactone epimers), 1.77Ϫ1.90 (m, 4
H, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ, 3ЈЈЈ-HЈЈ, 4ЈЈЈ-HЈЈ), 2.02Ϫ2.61 (m, 1 H, 3-H epi-
mers), 3.54Ϫ3.65 (m, 2 H, 13Ј-H, 5ЈЈЈЈ-H), 3.70Ϫ3.77 (m, 1 H,
0.02, 0.04 (3 ϫ s, 18 H, SiCH3), 0.82Ϫ0.89 [m, 21 H, 11ЈЈЈ-H3,
SiC(CH3)3], 1.19Ϫ1.45 and 1.49Ϫ1.71 (2 ϫ m, 46 H, 2-H2 to 14-
H2, 3Ј-HЈ, 4Ј-HЈ, 3ЈЈ-HЈ, 4ЈЈ-HЈ, 2ЈЈЈ-H2 to 4ЈЈЈ-H2, 6ЈЈЈ-H2 to 10ЈЈЈ-
H2), 1.76Ϫ1.91 (m, 4 H, 3Ј-HЈЈ, 4Ј-HЈЈ, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ), 3.55Ϫ3.65
(m, 4 H, 1-H2, 15-H, 5ЈЈЈ-H), 3.71Ϫ3.77 (m, 1 H, 1ЈЈЈ-H),
3.79Ϫ3.94 (m, 4 H, 2Ј-H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ Ϫ4.7, Ϫ4.5, Ϫ4.45, Ϫ4.38, Ϫ4.2 (SiCH3),
14.1 (C-11ЈЈЈ), 18.12, 18.15, 18.24 [SiC(CH3)3], 25.93, 25.98
[SiC(CH3)3], 21.1 (C-3ЈЈЈ), 22.6 (C-10ЈЈЈ), 25.3, 25.7, 25.9, 26.1,
27.2, 28.4, 29.4, 29.5, 29.62, 29.64, 29.9, 31.9 (C-3 to C-13, C-3Ј,
C-4Ј, C-3ЈЈ, C-4ЈЈ, C-7ЈЈЈ to C-9ЈЈЈ), 32.4, 32.8 (C-14, C-2ЈЈЈ), 35.1
(C-2), 37.0, 37.5 (C-4ЈЈЈ, C-6ЈЈЈ), 63.1 (C-1), 72.2 (C-5ЈЈЈ), 73.7 (C-
1ЈЈЈ), 74.8 (C-15), 81.36, 81.43, 82.17, 82.20 (C-2Ј, C-5Ј, C-2ЈЈ, C-
5ЈЈ). Ϫ HRMS (EI): calcd. 855.6750 (M Ϫ C4H9)ϩ; found
855.6749.
(15R,2ЈR,5ЈR,2ЈЈR,5ЈЈR,1ЈЈЈS,5ЈЈЈS)-15-[5Ј-(5ЈЈ-(1ЈЈЈ,5ЈЈЈ-Bis(tert-
butyldimethylsilyloxy)undec-1ЈЈЈ-yl)tetrahydrofuran-2ЈЈ-yl)tetra-
hydrofuran-2Ј-yl]-15-(tert-butyldimethylsilyloxy)pentadecanoic
Acid (37): (COCl)2 (50 µL, 550 µmol) was dissolved in CH2Cl2
(2 mL). The solution was cooled to Ϫ60 °C and DMSO (90 µL,
1.30 mmol), dissolved in CH2Cl2 (1 mL), was added. At Ϫ50 °C a
solution of alcohol 36 (99 mg, 108 µmol) in CH2Cl2 (2 mL) was
added. After 45 min at Ϫ45 °C, the mixture was treated with Et3N
(300 µL, 2.15 mmol). After 5 min, the temperature was allowed to
rise to 0 °C and H2O (5 mL) was added to stop the reaction. The
aqueous layer was extracted three times with CH2Cl2 (5 mL). The
combined organic layers were washed with sat. aqueous NaCl
(10 mL) and dried with MgSO4. Removal of the solvents afforded
the crude aldehyde (Rf ϭ 0.83; PE/MTBE, 3:1), which was dis-
solved in tBuOH (3 mL) and 2-methyl-2-butene (1 mL). The mix-
ture was treated with a solution of NaClO2 (80%, 95 mg, 840 µmol)
and NaH2PO4 2 H2O (190 mg, 1.22 mmol) in H2O (5 mL) at 0 °C.
The mixture was stirred vigorously at room temp. overnight.
MTBE (10 mL) and H2O (10 mL) were added and the layers were
separated. The aqueous layer was extracted three times with MTBE
(20 mL). The combined organic layers were dried with MgSO4 and
the solvents were removed in vacuo. Purification by CC (50 cm3
SiO2, n-hexane/MTBE, 5:1, MTBE) yielded acid 37 (89 mg, 96
µmol, 89% over two steps) as a colorless oil. Ϫ Rf ϭ 0.29 (PE/
MTBE, 3:1). Ϫ [α]2D0 ϭ ϩ11.4 (c ϭ 0.90, CHCl3). Ϫ IR (film): ν˜ ϭ
2928, 2856 s (CH), 1712 m (CϭO), 1472 w, 1463 w, 1362 w, 1254
m, 1096 m, 1072 w, 1005 w, 836 m, 774 m, 723 w, 663 w cmϪ1. Ϫ
1H NMR (300 MHz, CDCl3): δ ϭ 0.01, 0.03, 0.04 (3 ϫ s, 18 H,
SiCH3), 0.82Ϫ0.94 [m, 21 H, 11ЈЈЈ-H3, SiC(CH3)3], 1.18Ϫ1.48 and
1ЈЈЈЈ-H), 3.80Ϫ3.95 (m,
4 H, 2ЈЈ-H, 5ЈЈ-H, 2ЈЈЈ-H, 5ЈЈЈ-H),
4.19Ϫ4.66 (m, 1 H, 5-H epimers). Ϫ 13C NMR (75 MHz, CDCl3):
δ ϭ Ϫ4.6, Ϫ4.4, Ϫ4.3, Ϫ4.2 (SiCH3), 14.1 (C-11ЈЈЈЈ), 18.1, 18.2,
18.25 [SiC(CH3)3], 25.95, 26.0 [SiC(CH3)3], 21.0, 21.1, 21.2 (CH3-
lactone epimers, C-3ЈЈЈЈ), 22.6 (C-10ЈЈЈЈ), 24.6, 25.2, 25.9, 27.2,
28.4, 28.5, 29.0Ϫ29.7 signal overlap, 29.9, 30.8, 31.9, 32.3, 32.7,
35.1 (C-1Ј to C-12Ј, C-3ЈЈ, C-4ЈЈ, C-3ЈЈЈ, C-4ЈЈЈ, C-2ЈЈЈЈ, C-7ЈЈЈЈ to
C-9ЈЈЈЈ, C-2 epimers), 37.0, 37.5 (C-4ЈЈЈЈ, C-6ЈЈЈЈ), 39.3, 41.5 (C-3
epimers), 72.2 (C-5ЈЈЈЈ), 73.6 (C-1ЈЈЈ), 74.8 (C-13Ј), 74.9, 75.0 (C-5
epimers), 81.3, 81.4, 82.15, 82.2 (C-2ЈЈ, C-5ЈЈ, C-2ЈЈЈ, C-5ЈЈЈ), 179.1,
179.4 (C-2 epimers). Ϫ HRMS(EI): calcd. 909.6855 (M Ϫ C4H9)ϩ;
found 909.6839.
Squamocin A (Annonin I, Rollinicin): ؊ 1. Introduction of the
1.56Ϫ1.74 (2 ϫ m, 44 H, 3-H2 to 14-H2, 3Ј-HЈ, 4Ј-HЈ, 3ЈЈ-HЈ, 4ЈЈ- Double Bond: To a solution of lactone 38 (8.5 mg, 8.8 µmol) in
HЈ, 2ЈЈЈ-H2 to 4ЈЈЈ-H2, 6ЈЈЈ-H2 to 10ЈЈЈ-H2), 1.77Ϫ1.93 (m, 4 H, 3Ј- THF (300 µL) was added freshly prepared LDA (2.0 mmol/mL,
HЈЈ, 4Ј-HЈЈ, 3ЈЈ-HЈЈ, 4ЈЈ-HЈЈ), 2.32 (t, J ϭ 7.5 Hz, 2-H2), 3.55Ϫ3.66 350 µL, 700 µmol) at 0 °C. The mixture was stirred at room temp.
(m, 2 H, 15-H, 5ЈЈЈ-H), 3.72Ϫ3.78 (m, 1 H, 1ЈЈЈ-H), 3.80Ϫ3.95 (m,
for 30 min. PhSeCl (250 mg, 1.31 mmol) was added at 0 °C. The
4 H, 2Ј-H, 5Ј-H, 2ЈЈ-H, 5ЈЈ-H). Ϫ 13C NMR (75 MHz, CDCl3): mixture was stirred for 1 h at 0 °C and 1 h 30 min at room temp.
δ ϭ Ϫ4.7, Ϫ4.52, Ϫ4.46, Ϫ4.39, Ϫ4.2 (SiCH3), 14.1 (C-11ЈЈЈ), The reaction was quenched by adding phosphate buffer (pH ϭ 7,
1902
Eur. J. Org. Chem. 2000, 1889Ϫ1904

Total Syntheses of Squamocin A and Squamocin D
FULL PAPER
D. J. Morre, R. de Cabo, C. Farley, N. H. Oberlies, J. L.
[4]
´
2 mL) and MTBE (3 mL). The aqueous layer was extracted four
times with MTBE (10 mL). The combined organic layers were
dried with MgSO4. The solvents were removed and the residue was
redissolved in THF (500 µL) and MeOH (500 µL). At 0 °C, MMPP
(85%, 30 mg, 59 µmol) was added. The yellow mixture was stirred
for 30 min at room temp. The reaction were quenched by addition
of phosphate buffer (pH ϭ 7, 1 mL), sat. aqueous NH4Cl (1 mL)
and MTBE (3 mL). The aqueous layer was extracted four times
with MTBE (10 mL). The combined organic layers were dried with
MgSO4 and the solvents were removed in vacuo. Purification by
CC (20 cm3 SiO2, n-hexane/MTBE, 6:1) yielded the corresponding
butenolide (3.4 mg, 3.5 µmol, 40% over two steps) as a colorless oil
(Rf ϭ 0.45, PE/MTBE, 4:1).
McLaughlin, Life Sci. 1995, 56, 343.
[5] [5a]
M. Sahai, S. Singh, M. Singh, Y. K. Gupta, S. Akashi, R.
Yuji, K. Hirayama, H. Asaki, H. Araya, N. Hara, T. Eguchi,
K. Kakinuma, Y. Fujimoto, Chem. Pharm. Bull. 1994, 42,
[5b]
1163Ϫ1174. Ϫ
Squamocin A ϭ squamocin, see Y. Fujim-
oto, T. Eguchi, K. Kakinuma, N. Ikekawa, M. Sahai, Y. K.
Gupta, Chem. Pharm. Bull. 1988, 36, 4802Ϫ4806.
[6]
L. Born, F. Lieb, J. P. Lorentzen, H. Moeschler, M. Nonfon,
R. Söllner, D. Wendisch, Planta Med. 1990, 56, 312Ϫ316.
[7] [7a]
T. T. Dabrah, A. Sneden, J. Nat. Prod. 1984, 47, 652Ϫ657.
[7b]
Ϫ
T. T. Dabrah, A. Sneden, Phytochemistry 1984, 23,
2013Ϫ2016.
[8]
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2. Deprotection: The protected squamocin A (3.4 mg, 3.5 µmol) was
dissolved in THF (1 mL). HF (5% in MeCN, 1.0 mL, 2.5 mmol)
was added and the mixture was stirred for 6 h at room temp. The
reaction was quenched with sat. aqueous NaHCO3 (1 mL) and
CHCl3 (1 mL). The aqueous layer was extracted three times with
CH2Cl2 (10 mL). The combined organic layers were dried with
MgSO4. Removal of the solvents in vacuo and purification by CC
(5 cm3 SiO2, CHCl3 Ǟ CHCl3/MeOH, 10:1) afforded squamocin
A (1.8 mg, 2.9 µmol, 82%) as a colorless solid. Rf ϭ 0.44 (MTBE/
MeOH, 20:1). Ϫ [α]2D2 ϭ ϩ15 (c ϭ 0.080, CHCl3). Ϫ IR (KBr): ν˜ ϭ
3450 bs (OH), 2923 m, 2852 m, 1752 (CϭO), 1654 (CϭC), 1507
m, 1399 w, 1047 m, 809 w, 669 m cmϪ1. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 0.86 (t, J ϭ 6.8 Hz, 3 H, 34-H3), 1.22Ϫ1.68 (m, 42
H, 4-H2 to 14-H2, 17-HЈ, 18-HЈ, 21-HЈ, 22-HЈ, 25-H2 to 27-H2, 29-
H2 to 33-H2), 1.38 (d, J ϭ 6.8 Hz, 3 H, 37-H3), 1.91Ϫ2.02 (m, 4
H, 17-HЈЈ, 18-HЈЈ, 21-HЈЈ, 22-HЈЈ), 2.24 (t, J ϭ 7.2 Hz, 3-H2),
3.33Ϫ3.42 (m, 1 H, 15-H), 3.55Ϫ3.66 (m, 2 H, 24-H, 28-H),
3.79Ϫ3.94 (m, 4 H, 16-H, 19-H, 20-H, 23-H), 4.97 (qq, J ϭ 6.8,
1.9 Hz, 1 H, 36-H), 6.96 (q, J ϭ 1.5 Hz, 1 H, 35-H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 14.1 (C-34), 19.2 (C-37), 22.0 (C-26), 22.6
(C-33), 25.2 (C-3), 24.8, 25.63, 25.66, 27.4, 28.4, 28.9, 29.1Ϫ29.7
signal overlap, 29.72, 31.8 (C-4 to C-13, C-17, C-18, C-21, C-22,
C-30 to C-32), 32.5 (C-25), 33.4 (C-14), 37.3, 37.5 (C-27, C-29),
71.4 (C-24), 71.8 (C-28), 74.1 (C-15), 77.4 (C-36), 82.3, 82.5, 82.8,
83.3 (C-16, C-19, C-20, C-23), 134.3 (C-2), 148.8 (C-35), 173.9 (Cϭ
O). Ϫ HRMS (EI): calcd. 623.4887 (M ϩ H)ϩ; found 623.4897.
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Acknowledgments
This work was supported by the Deutsche Forschungsgemein-
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1903
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Received November 22, 1999
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1904
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