Total synthesis of the nonadjacent bis-tetrahydrofuran Annonaceous acetogenin squamostatin-D

Article abstract of DOI:10.1021/jo981103r

A total synthesis of the Annonaceous acetogenin squamostatin-D is described. Key adjacent stereocenters were introduced through enantioselective addition of chiral oxygenated allylic tin and indium reagents to aldehyde subunits. The isolated stereocenter at C12 was constructed through addition of a functionalized organozinc reagent to an aldehyde subunit in the presence of a chiral bis-sulfonamide-titanium catalyst.

Full text of DOI:10.1021/jo981103r

7066
J . Org. Chem. 1998, 63, 7066-7071
Tota l Syn th esis of th e Non a d ja cen t Bis-Tetr a h yd r ofu r a n
An n on a ceou s Acetogen in Squ a m osta tin -D
J ames A. Marshall* and Hongjian J iang
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901
Received J une 9, 1998
A total synthesis of the Annonaceous acetogenin squamostatin-D is described. Key adjacent
stereocenters were introduced through enantioselective addition of chiral oxygenated allylic tin
and indium reagents to aldehyde subunits. The isolated stereocenter at C12 was constructed
through addition of a functionalized organozinc reagent to an aldehyde subunit in the presence of
a chiral bis-sulfonamide-titanium catalyst.
Several years ago, Fujimoto et al. described the isola-
ployed for the synthesis of adjacent bis-THF acetogenins
and prototypes.4c,6 As a further test of this methodology
for the nonadjacent counterparts, we formulated a plan
for the total synthesis of squamostatin-D (Figure 3). The
plan is modular in nature. Key stereocenters are intro-
duced by means of (1) Sharpless asymmetric dihydroxy-
lation (C19/C20),7 (2) BF3-promoted addition of a γ-alkoxy
allylic stannane (C23/C24),6 (3) addition of a γ-alkoxy
allylic indium chloride (C15/C16),6 and (4) addition of an
organozinc reagent catalyzed by a chiral titanium triflic
amide (C12).8 The C36 methyl stereocenter is derived
from (S)-lactic acid. Since all stereocenters are intro-
duced by chiral reagents at positions remote from other
stereocenters, it should be possible to prepare all possible
stereoisomers of any of the squamostatins by this ap-
proach.
Aldehyde 1, the eventual C16-C23 segment of squa-
mostatin-D, was secured as previously described4c through
Sharpless asymmetric dihydroxylation of an unsaturated
precursor, obtained by an ortho ester Claisen rearrange-
ment. Addition of the (R)-γ-alkoxy allylic stannane 2 in
the presence of BF3‚OEt2 afforded the syn adduct 3 as
the sole product (Scheme 1).9 The tosylate 4 was
converted to the eventual threo,trans,threo C16-C34
segment 5 of squamostatin-D upon treatment with TBAF
in THF. Protection of the C19 OH in 5 as the MOM ether
6 and hydrogenation over Pd-C afforded the debenzy-
lated dihydro product 7. Oxidation by the Dess-Martin
protocol10 proceeded smoothly affording aldehyde 8,
which was treated with the (S)-R-alkoxy allylic stannane
9 in the presence of InCl3 to yield the ultimate C12-C34
segment, anti adduct 10.11 This addition could also be
performed with InBr3 in ether, but with some decomposi-
tion of the aldehyde, especially when the reaction was
performed on more than 100 mg of material. Alcohol
adduct 10 was protected as the MOM ether 11. Hydro-
tion and structure elucidation of five nonadjacent bis-
tetrahydrofuran Annonaceous acetogenins, squamost-
atins A-E (Figure 1).1 The structure assignments were
made on the basis of mass spectral fragmentation pat-
1
terns and detailed H and, especially, 13C NMR analyses.
The absolute stereochemistry of the C36 center (buteno-
lide CH3) was assigned by analogy with other known
numbers of the Annonaceous acetogenin family. The
absolute stereochemistry of the remaining centers was
not assigned.
These natural products are part of a small subgroup
of a large class of related compounds, most of which
possess one or two tetrahydrofuran rings with flanking
hydroxyl groups near the midpoint of an unbranched
chain of (usually) 32 or so carbon atoms which terminates
with a γ-methylbutenolide moiety attached at the R-posi-
tion to the carbon chain.2 The family has attracted a
great deal of interest because of its wide range of
biological activities. Most thoroughly studied have been
the adjacent bis-tetrahydrofuran subgroup in which the
two furan rings are directly attached at the C2 (R)
positions (Figure 2). Many of these show extremely high
levels of cytotoxicity toward human tumor cell lines.3 A
number of total syntheses of these compounds have been
reported.4 Less well studied are the nonadjacent bis-THF
acetogenins exemplified by the squamostatins and their
relatives.2 To date, the only reported synthesis of any
representative of this subgroup has been the 21-step
conversion of (-)-muricatacin, an acetogenin artifact, into
4-deoxygigantecin.5
We have recently shown that chiral γ-oxygenated
allylic tin and indium reagents can be effectively em-
(1) Fujimoto, Y.; Murasaki, C.; Shimada, H.; Nishioka, S.; Kaki-
numa, K.; Singh, S.; Singh, M.; Gupta, Y. K.; Sahai, M. Chem. Pharm.
Bull. 1994, 42, 1175.
(2) Reviews: Cave´, A.; Figade´re, B.; Laureno, A.; Cortes, D. in
Progress in the Chemistry of Natural Products; Hery, W., Kirby, G.
W., Moore, R. E., Steglich, W., Tamm, Ch., Eds. Springer, New York,
1997; Vol. 70, pp 81-288. Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.;
Gu, Z.-M.; He, K.; McLaughlin, J . L. Nat. Prod. Rep. 1996, 275.
(3) Cf. Hopp, D. C.; Zeng, Z.; Gu, J . L.; McLaughlin, J . L. J . Nat.
Prod. 1996, 59, 97. He, K.; Zhao, G.-X.; Chao, J .-F.; McLaughlin, J . L.
Bioorg. Med. Chem. 1997, 5, 501. Oberlies, N. H.; Chang, C.; McLaugh-
lin, J . L. J . Med. Chem. 1997.
(4) (a) Figade´re, B. Acc. Chem. Res. 1995, 28, 359. (b) Hoye, T. R.;
Ye, Z. J . Am. Chem. Soc. 1996, 118, 1801. (c) Marshall, J . A.; Hinkle,
K. W. Tetrahedron Lett. 1998, 39, 1303 and references cited. (d) Schaus,
S. E.; Branalt, J .; J acobsen, E. N. J . Org. Chem. 1998, 63, 4876.
(5) Makabe, H.; Tanaka, A.; Oritan, T. Tetrahedron 1998, 54, 6329.
(6) Cf. Marshall, J . A.; Hinkle, K. W. J . Org. Chem. 1996, 61, 4247.
(7) Cf. J acobsen, E. N.; Marko´, I.; Mungall, W. S.; Schro¨der, G.;
Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 1968.
(8) Lutz, C.; Knochel, P. J . Org. Chem. 1997, 62, 7895.
(9) Stannane 2 was prepared by treatment of the R-alkoxy isomer
with BF3‚OEt2 as previously described. Marshall, J . A.; J iang, H.
Tetrahedron Lett. 1998, 39, 1493. The R-hydroxy stannane precursor
of 2 was judged to be enantiomerically pure within the limits of
analysis by means of the 1H NMR spectra of the (R)- and (S)-O-methyl
mandelates.6
(10) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. Meyer,
S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.
(11) Marshall, J . A.; Garofalo, A. W. J . Org. Chem. 1996, 61, 8732.
S0022-3263(98)01103-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/11/1998

Total Synthesis of the Squamostatin-D
J . Org. Chem., Vol. 63, No. 20, 1998 7067
F igu r e 1. Squamostatin subgroup of nonadjacent bis-tetrahydrofuran Annonaceous acetogenins.
absolute and relative configuration as shown. The (R)-
and (S)-Mosher ester derivatives showed significant
differences in the 4.8-5.4, 3.8-4.0, and 3.4-3.6 regions
1
of the H NMR spectra. Each of these spectra showed
no extraneous peaks in these regions. Accordingly, we
surmize that our synthetic material is of >90% ee.
The present synthesis confirms the utility of γ-oxygen-
ated allylmetal additions to aldehydes for the synthesis
of acetogenin natural products. This methodology in
combination with the organozinc chemistry has the
potential to produce any member of the family as well
as stereoisomers and analogues.
F igu r e 2. Asimicin subgroup of adjacent bis-tetrahydrofuran
Annonaceous acetogenins.
Exp er im en ta l Section
(9E)-(11S,12S,15R,16R)-19-Ben zyloxy-15,16-d i[(ter t-bu -
tyldim eth ylsilyl)oxy]-11-(m eth oxym eth oxy)-9-n on adecen -
12-ol (3). To a mixture of 0.50 g (0.99 mmol) of γ-stannane 2
and 0.49 g (0.99 mmol) of aldehyde 1 in 8 mL of CH2Cl2 at
-78 °C was added 0.13 mL (1.0 mmol) of BF3‚OEt2. The
reaction mixture was stirred at -78 °C for 30 min, quenched
with saturated NaHCO3, and diluted with ether. The aqueous
layer was extracted with ether, and the combined extracts
were dried over MgSO4. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatography on silica gel (elution with 8% EtOAc in
hexane) to afford 0.62 g (88%) of alcohol 3: [R]D +58.5 (c 1.19,
CHCl3); IR (film) 3510, 2950, 2916, 2855 cm-1; 1H NMR (CDCl3
300 MHz) δ 7.33 (m, 5 H), 5.72 (m, 1 H), 5.25 (q, J ) 8.5 Hz,
1 H), 4.75 (d, J ) 6.9 Hz, 1 H), 4.54 (d, J ) 6.9 Hz, 1 H), 4.50
(s, 2 H), 3.79 (q, J ) 8.1 Hz, 1 H), 3.42-3.61 (m, 3 H), 3.38 (s,
F igu r e 3. Synthetic strategy for squamostatin-D.
genation over Rh-on-alumina followed by desilylation
then led to the primary alcohol 13.
Introduction of the C12 stereocenter along with the
C1-C11 chain of squamostatin-D was conveniently
achieved through addition of the zinc reagent 15, pre-
pared from unsaturated ester 14, in the presence of the
titanate catalyst generated in situ from the (S,S)-1,2-
diaminocyclohexane triflamide 17 and titanium isopro-
poxide.8 The enantioselectivity of this addition was
judged to be >90% by comparison of the 1H NMR spectra
of the O-methyl mandelates 19 and 20. The absolute
stereochemistry at C12 is assigned by analogy to related
additions by Lutz and Knochel.8 Protection of the C12
alcohol as the TBS ether was followed by hydrogenolysis
of the C15 BOM acetal. The derived tosylate 23 cyclized
upon treatment with TBAF to afford the bis-THF ester
24.
3 H), 1.12-2.17 (m, 22 H), 0.87 (m, 21 H), 0.03 (m, 12 H); 13
C
NMR (CDCl3, 75 MHz) δ 138.7, 137.5, 128.3, 127.5, 127.4,
126.2, 93.3, 80.9, 75.8, 75.4, 74.3, 72.7, 70.7, 55.6, 32.4, 31.8,
30.3, 29.4, 29.2, 29.0, 27.1, 26.7, 26.4, 25.9, 22.6, 18.0, 14.1,
-4.1, -4.2, -4.5, -4.6. Anal. Calcd for C40H76O6Si2: C, 67.74;
H, 10.80. Found: C, 67.66; H, 10.88.
Tosyla te 4. To a solution of 1.66 g (2.40 mmol) of alcohol
3 in 2 mL of pyridine was added 2.68 g (14.0 mmol) of p-TsCl.
The reaction mixture was stirred for 12 h, quenched with
water, and extracted with ether. The extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel (elution with 10% EtOAc in hexane) to afford 1.94 g
(96%) of tosylate 4: [R]D +38.6 (c 1.17, CHCl3); IR (film) 2912,
The butenolide segment of squamostatin-D was intro-
duced by a modification of Yao and Wu’s method.12
Accordingly OTBS-protected (S)-lactaldehyde 25 con-
densed with the lithio enolate of ester 24 to afford the
aldol product. Subsequent treatment with TBAF led to
the lactone diasteromers 26 in 78% overall yield. Dehy-
dration to the butenolide 27 was best achieved through
treatment with trifluoroacetic anhydride and triethyl-
amine. Cleavage of the MOM ethers with aqueous HCl
in THF-methanol afforded squamostatin-D, [R]D +8.4
(lit1 +7.9), mp 112-113 °C (lit.1 mp 112-113.5 °C), in
1
2855 cm-1; H NMR (CDCl3, 300 MHz) δ 7.78 (d, J ) 8.1 Hz,
2 H), 7.34 (m, 5 H), 7.26 (d, J ) 8.1 Hz, 2 H), 5.71 (m, 1 H),
5.20 (q, J ) 8.5 Hz, 1 H), 4.60 (d, J ) 6.5 Hz, 1 H), 4.55 (m, 1
H), 4.51 (s, 2 H), 4.44 (d, J ) 6.5 Hz, 1 H), 4.10 (m, 1 H), 3.32-
3.73 (m, 4 H), 3.28 (s, 3 H), 2.38 (s, 2 H), 1.00-2.06 (m, 22 H),
0.86 (m, 21 H), 0.01 (m, 12 H).
(9E )-(11S ,12R ,15R ,16R )-19-Be n zyloxy-11-(m e t h oxy-
m eth oxy)-12,15-oxid o-9-n on a d ecen -16-ol (5). To a solution
of 1.93 g (2.23 mmol) of tosylate 4 in 50 mL of THF was added
11.1 mL (11.1 mmol) of TBAF (1.0 M in THF) at room
temperature. The reaction mixture was stirred at 50 °C for
12 h, quenched with brine and extracted with ether. The
extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by
column chromatography on silica gel (elution with 25% EtOAc
in hexane) to afford 0.91 g (88%) of mono-THF alcohol 5: [R]D
1
near-quantitative yield. The H and 13C NMR spectra
were identical to the spectra of the natural product as
1
was the H spectrum of the (R)-Mosher ester derivative
29.1 In view of these comparisons, we can assign the
(12) Yao, Z.-J .; Wu, Y.-L. Tetrahedron Lett.1994, 35, 157.
+73.4 (c 1.59, CHCl3); IR (film) 3466, 2916, 2855 cm-1 1H
;

7068 J . Org. Chem., Vol. 63, No. 20, 1998
Marshall and J iang
Sch em e 1
Sch em e 2
NMR (CDCl3, 300 MHz) δ 7.32 (m, 5 H), 5.70 (m, 1 H), 5.31
(q, J ) 8.1 Hz, 1 H), 4.72 (d, J ) 7.3 Hz, 1 H), 4.55 (d, J ) 7.3
Hz, 1 H), 4.50 (s, 2 H), 4.04 (m, 2 H), 3.80 (m, 1 H), 3.33-3.56
(m, 3 H), 3.36 (s, 3 H), 1.16-2.11 (m, 22 H), 0.88 (t, J ) 7.9
Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 138.4, 136.7, 128.2,
127.5, 125.7, 93.3, 83.2, 81.2, 78.4, 73.5, 72.7, 70.1, 55.2, 32.3,
31.8, 30.1, 29.3, 29.2, 29.0, 28.1, 27.4, 25.8, 22.5, 14.0. Anal.
Calcd for C28H46O5: C, 72.69; H, 10.02. Found: C, 72.76; H,
10.12.
(elution with 15% EtOAc in hexane) to afford 0.90 g (92%) of
olefin 6: [R]D +79.8 (c 1.48, CHCl3); IR (film) 2925, 2846, 1448
1
cm-1; H NMR (CDCl3, 300 MHz) δ 7.33 (m, 5 H), 5.68 (m, 1
H), 5.29 (q, J ) 7.3 Hz, 1 H), 4.82 (d, J ) 6.9 Hz, 1 H), 4.71 (d,
J ) 6.9 Hz, 1 H), 4.66 (d, J ) 6.9 Hz, 1 H), 4.55 (d, J ) 6.9 Hz,
1 H), 4.50 (s, 2 H), 4.00 (m, 3 H), 3.49 (m, 3 H), 3.38 (s, 3 H),
3.36 (s, 3 H), 1.19-2.10 (m, 22 H), 0.88 (t, J ) 6.9 Hz, 3 H);
13C NMR (CDCl3, 75 MHz) δ 138.5, 136.1, 128.2, 127.5, 127.4,
126.2, 96.6, 93.5, 82.0, 81.2, 79.2, 78.5, 72.7, 70.2, 55.6, 55.1,
32.3, 31.8, 29.3, 29.2, 29.0, 28.0, 27.6, 27.1, 25.8, 22.6, 14.0.
Mon o-THF Olefin 6. To a mixture of 0.89 g (1.92 mmol)
of alcohol 5 and 1.40 mL (7.68 mmol) of diisopropylethylamine
in 5.0 mL of CH2Cl2 was added 0.30 mL (3.82 mmol) of
MOMCl. The reaction mixture was stirred at room temper-
ature for 12 h, quenched with water, and extracted with ether.
The extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel
(4R,5R,8R,9S)-4,9-Di(methoxymethoxy)-5,8-oxido-1-nona-
d eca n ol (7). A mixture of 0.81 g (1.60 mmol) of olefin 6 and
0.80 g of Pd-C (5%) in 8 mL of EtOH was placed under a H2
atmosphere. The reaction mixture was stirred for 12 h and
filtered through Celite. The solvent was removed under
reduced pressure and the residue was purified by column
chromatography on silica gel (elution with 40% EtOAc in

Total Synthesis of the Squamostatin-D
J . Org. Chem., Vol. 63, No. 20, 1998 7069
hexane) to afford 0.65 g (97%) of alcohol 7: [R]D +19.0 (c 1.28,
CHCl3); IR (film) 3449, 2925, 2855 cm-1; 1H NMR (CDCl3, 300
MHz) δ 4.85 (d, J ) 6.9 Hz, 1 H), 4.77 (d, J ) 6.9 Hz, 1 H),
4.68 (d, J ) 6.9 Hz, 1 H), 4.65 (d, J ) 6.9 Hz, 1 H), 3.97 (m, 2
H), 3.66 (t, J ) 5.8 Hz, 2 H), 3.53 (m, 1 H), 3.40 (s, 3 H), 3.38
(s, 3 H), 1.17-2.02 (m, 26 H), 0.87 (t, J ) 6.5 Hz, 3 H); 13C
NMR (CDCl3, 75 MHz) δ 96.7, 96.6, 81.7, 81.4, 79.5, 78.6, 62.8,
55.7, 55.6, 31.8, 29.7, 29.5, 29.2, 28.6, 27.7, 26.6, 25.5, 22.6,
14.0. Anal. Calcd for C23H46O6: C, 65.99; H, 11.08. Found:
C, 65.89; H, 10.99.
(4R,5R,8R,9S)-4,9-Di(m eth oxym eth oxy)-5,8-oxid on on a -
d eca n a l (8). To a solution of 0.60 g (1.43 mmol) of alcohol 7
in 6 mL of CH2Cl2 was added 0.78 g (1.83 mmol) of Dess-
Martin periodinane.10 The reaction mixture was stirred at
room temperature for 60 min, quenched with Na2S2O3, and
extracted with ether. The extracts were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column chroma-
tography on silica gel (elution with 20% EtOAc in hexane) to
afford 0.55 g (92%) of aldehyde 8: [R]D +30.6 (c 1.14, CHCl3);
IR (film) 2925, 2855, 1719 cm-1; 1H NMR (CDCl3, 300 MHz) δ
9.79 (t, J ) 1.5 Hz, 1 H), 4.80 (d, J ) 6.5 Hz, 1 H), 4.76 (d, J
) 6.5 Hz, 1 H), 4.65 (d, J ) 1.9 Hz, 1 H), 4.63 (d, J ) 1.9 Hz,
1 H), 3.95 (m, 2 H), 3.65 (m, 1 H), 3.49 (m, 1 H), 3.38 (s, 6 H),
2.59 (dt, J ) 1.1, 7.3 Hz, 2 H), 1.20-2.05 (m, 24 H), 0.87 (t, J
) 6.5 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 202.0, 96.9, 96.6,
81.7, 81.4, 78.8, 78.6, 55.8, 55.6, 40.0, 31.8, 29.7, 29.5, 29.2,
28.5, 26.5, 25.4, 23.6, 22.6, 14.0. Anal. Calcd for C23H44O6:
C, 66.31; H, 10.65. Found: C, 66.38; H, 10.60.
oxid otr icosa n e (12). A mixture of 0.41 g (0.52 mmol) of olefin
11 and a catalytic amount of Rh-Al2O3 (5%) in 6 mL of EtOAc
was placed under a H2 atmosphere. The reaction mixture was
stirred for 4 h and filtered through Celite. The solvent was
removed under reduced pressure, and the residue was purified
by column chromatography on silica gel (elution with 15%
EtOAc in hexane) to afford 0.39 g (95%) of dihydro product
1
12: [R]D +8.1 (c 0.70, CHCl3); H NMR (CDCl3, 300 MHz) δ
7.33 (m, 5 H), 4.56-4.91 (m, 10 H), 3.94 (m, 2 H), 3.55-3.76
(m, 5 H), 3.45 (m, 1 H), 3.78 (m, 9 H), 1.21-1.99 (m, 30 H),
0.88 (m, 12 H), 0.03 (s, 6 H); 13C NMR (CDCl3, 75 MHz) δ 137.9,
128.3, 127.8, 127.6, 96.7, 96.0, 94.0, 81.8, 81.4, 79.9, 79.2, 78.9,
78.6, 69.6, 63.0, 55.7, 55.6, 31.9, 29.7, 29.6, 29.4, 29.3, 28.6,
28.0, 26.9, 26.6, 25.9, 25.6, 25.5, 22.6, 18.3, 14.1, -5.3.
(4R,5S,8R,9R,12R,13S)-4-[(Ben zyloxym eth )oxy]-5,8,13-
tr i(m eth oxym eth oxy)-9,12-oxid o-1-tr icosa n ol (13). To a
solution of 0.054 g (0.07 mmol) of TBS ether 12 in 1 mL of
THF was added 0.30 mL (0.30 mmol) of TBAF (1.0 M in THF).
The mixture was stirred at room temperature for 2 h,
quenched with brine, and extracted with ether. The extracts
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (elution with 70% EtOAc in
hexane) to afford 0.045 g (98%) of alcohol 13: [R]D +18.1 (c
1
0.63 CHCl3); IR (film) 3466, 2925, 2846, 1457 cm-1; H NMR
(CDCl3 300 MHz) δ 7.33 (m, 5 H), 4.56-4.92 (m, 10 H), 3.92
(m, 2 H), 3.57-3.78 (m, 5 H), 3.46 (m, 1 H), 3.38 (s, 3 H), 3.37
(s, 6 H), 1.15-1.98 (m, 30 H), 0.87 (t, J ) 6.5 Hz, 3 H); 13C
NMR (CDCl3, 75 MHz) δ 137.7, 128.2, 127.6, 127.5, 96.7, 96.6,
96.0, 93.9, 81.3, 79.7, 79.0, 78.8, 78.5, 69.6, 62.5, 55.6, 55.5,
55.4, 31.7, 29.6, 29.4, 29.1, 29.0, 28.5, 27.8, 26.7, 26.6, 26.4,
25.4, 22.5, 14.0.
(2E)-(4R,5S,8R,9R,12R,13S)-4-[(Ben zyloxym eth )oxy]-1-
[(ter t-bu tyld im eth ylsilyl)oxy]-8,13-d i(m eth oxym eth oxy)-
9,12-oxid o-2-tr icosen -5-ol (10). A mixture of 0.26 g (1.18
mmol) of InCl3 in 20 mL of EtOAc was sonicated for 15 min,
and to it was added a solution of 0.49 g (1.18 mmol) of aldehyde
8 in 0.5 mL of EtOAc. The mixture was cooled to -78 °C, and
a solution of 1.15 g (1.88 mmol) of stannane 9 in 0.5 mL of
EtOAc was slowly added. The mixture was allowed to warm
to room temperature (2 h), quenched with NaHCO3, and
extracted with ether. The extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel
(elution with 20% EtOAc in hexane) to afford 0.79 g (90%) of
alcohol 10: [R]D -35.6 (c 1.26, CHCl3); IR (film) 3466, 2925,
(4R,5S,8R,9R,12R,13S)-4-[(Ben zyloxym eth )oxy]-5,8,13-
tr i(m eth oxym eth oxy)-9,12-oxid otr icosa n a l (16). To a so-
lution of 0.13 g (0.19 mmol) of the alcohol 13 in 1.5 mL of
CH2Cl2 was added 0.15 g (0.35 mmol) of Dess-Martin perio-
dinane.10 The reaction mixture was stirred at room temper-
ature for 60 min, quenched with Na2S2O3, and extracted with
ether. The extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel (elution with 20% EtOAc in hexane) to afford 0.12 g
(92%) of aldehyde 16: [R]D +26.0 (c 0.62, CHCl3); IR (film)
1
1
2864,1448 cm-1; H NMR (CDCl3, 300 MHz) δ 7.34 (m, 5 H),
2925, 2855, 1719 cm-1; H NMR (CDCl3, 300 MHz) δ 9.74 (s,
5.83 (dt, J ) 5.0, 15.4 Hz, 1 H), 5.65 (q, J ) 7.7 Hz, 1 H),
4.46-4.90 (m, 10 H), 4.20 (s, 1 H), 4.19 (s, 1 H), 4.08 (m, 1 H),
3.94 (m, 2 H), 3.65 (m, 2 H), 3.49 (m, 1 H), 3.38 (s, 6 H), 1.18-
2.04 (m, 26 H), 0.90 (m, 12 H), 0.06 (s, 6 H); 13C NMR (CDCl3
75 MHz) δ 137.7, 135.5, 128.4, 127.9, 127.7, 124.8, 96.8, 96.7,
92.1, 82.0, 81.3, 80.1, 78.7, 73.9, 69.7, 62.9, 55.7, 55.6, 31.9,
29.7, 29.6, 29.3, 28.7, 28.2, 28.0, 26.6, 25.9, 25.5, 22.6, 18.3,
14.1, -5.3. Anal. Calcd for C41H74O9Si: C, 66.63; H, 10.09.
Found: C, 66.74; H, 10.07.
1 H), 7.33 (m, 5 H), 4.58-4.89 (m, 10 H), 3.95 (m, 2 H), 3.67
(m, 3 H), 3.44 (m, 1 H), 3.39 (s, 3 H), 3.38 (s, 3 H), 3.37 (s, 3
H), 2.58 (m, 2 H), 1.19-2.00 (m, 28 H), 0.88 (t, J ) 6.9 Hz, 3
H); 13C NMR (CDCl3, 75 MHz) δ 202.0, 137.7, 128.4, 127.6,
96.7, 96.6, 96.1, 94.0, 81.7, 81.3, 79.7, 78.7, 78.6, 78.4, 69.9,
55.7, 55.6, 55.5, 40.3, 31.8, 29.7, 29.5, 28.5, 27.7, 27.0, 26.5,
25.5, 22.6, 22.4, 14.0. Anal. Calcd for C37H64O10: C, 66.44;
H, 9.64. Found: C, 66.62; H, 9.66.
Eth yl (12R,15R,16S,19R,20R,23R,24S)-15-[(Ben zyloxy-
m et h )oxy]-12-h yd r oxy-16,19,24-t r i(m et h oxym et h oxy)-
20,23-oxid otetr a tr ia con ta n oa te (18). To 0.41 g (1.93 mmol)
of ethyl undecylenate 14 was slowly added 0.32 mL (1.20
mmol) of Et2BH (3.7 M in ether) at -10 °C. The reaction
mixture was allowed to warm to room temperature and stirred
for 2 h. Solvent and other volatiles were removed under
vacuum to afford the hydroboration product. To this organo-
borane was added 0.30 mL (2.93 mmol) of Et2Zn at 0 °C. After
30 min, the excess Et2Zn and Et3B were removed under
vacuum (1.0 mmHg, 50 °C, 3 h). The resulting dialkylzinc was
diluted with 0.5 mL of toluene. A suspension of 0.007 g (0.01
mmol) of (1S,2S)-1,2-bis(trifluoromethanesulfonamido)cyclo-
hexane and 0.11 mL (0.32 mmol) of Ti(O-i-Pr)4 in 0.5 mL of
toluene was heated at 50 °C for 30 min and cooled to -60 °C.
The dialkylzinc solution was added, and the mixture was
allowed to warm to -20 °C. After 20 min, a solution of 0.11 g
(0.16 mmol) of aldehyde 16 in 0.5 mL of toluene was added
and the reaction mixture was stirred for 12 h at this temper-
ature. The reaction was quenched with 1.0 M HCl and
extracted with ether. The extracts were washed with brine,
dried over MgSO4, and concentrated under reduced pressure.
Purification by columm chromatography afforded 0.091 g (63%)
(2E)-(4R,5S,8R,9R,12R,13S)-4-[(Ben zyloxym eth )oxy]-1-
[(ter t-bu tyldim eth ylsilyl)oxy]-5,8,13-tr i(m eth oxym eth oxy)-
9,12-oxid o-2-t r icosen e (11). To a mixture of 0.13 g (0.18
mmol) of alcohol 10 and 0.13 mL (0.72 mmol) of diisopropyl-
ethylamine in 1 mL of CH2Cl2 was added 0.03 mL (0.36 mmol)
of MOMCl. The mixture was stirred at room temperature for
12 h, quenched with water, and extracted with ether. The
extracts were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
was purified by column chromatography on silica gel (elution
with 15% EtOAc in hexane) to afford 0.16 g (90%) of olefin 11:
[R]D -43.4 (c 0.62, CHCl3); IR (film) 2925, 2855, 1457 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.32 (m, 5 H), 5.80 (dt, J ) 4.6,
15.8 Hz, 1 H), 5.63 (dd, J ) 7.3, 17.0 Hz, 1 H), 4.48-4.87 (m,
10 H), 4.19 (m, 3 H), 3.92 (m, 2 H), 3.63 (m, 2 H), 3.43 (m, 1
H), 3.37 (s, 9 H), 1.14-2.00 (m, 26 H), 0.88 (m, 12 H), 0.05 (s,
6 H); 13C NMR (CDCl3, 75 MHz) δ 137.9, 134.7, 128.3, 127.8,
127.6, 125.8, 96.7, 96.3, 91.8, 81.8, 81.3, 79.8, 79.6, 78.6, 78.1,
69.4, 63.0, 55.7, 55.6, 31.9, 29.7, 29.6, 29.3, 28.7, 27.6, 26.9,
26.6, 25.9, 25.5, 22.6, 18.3, 14.1, -5.3.
(4R,5S,8R,9R,12R,13S)-4-[(Ben zyloxym eth )oxy]-1-[(ter t-
bu tyldim eth ylsilyl)oxy]-5,8,13-tr i(m eth oxym eth oxy)-9,12-

7070 J . Org. Chem., Vol. 63, No. 20, 1998
Marshall and J iang
of hydroxy ester 18: [R]D +8.2 (c 0.45, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 7.34 (m, 5 H), 4.58-4.92 (m, 10 H), 4.11 (q, J )
7.3 Hz, 2 H), 3.93 (m, 2 H), 3.51-3.77 (m, 4 H), 3.44 (m, 1 H),
3.38 (s, 3 H), 3.37 (s, 6 H), 2.27 (t, J ) 7.3 Hz, 2 H), 1.11-2.00
(m, 51 H), 0.87 (t, J ) 7.3 Hz, 3 H); 13C NMR (CDCl3, 75 MHz)
δ 173.8, 137.8, 128.3, 127.7, 127.6, 96.7, 94.1, 81.7, 79.8, 79.4,
79.2, 78.6, 73.3, 72.0, 69.7, 60.0, 55.7, 55.6, 55.5, 37.6, 34.3,
33.9, 31.8, 30.2, 29.7, 29.6, 29.5, 29.3, 29.2, 29.1, 29.0, 28.5,
27.9, 26.9, 26.5, 25.6, 24.9, 22.6, 14.2, 14.0. Anal. Calcd for
Bis-THF Ester 24. To a solution of 0.039 g (0.038 mmol)
of tosylate 23 in 1 mL of THF was added 0.15 mL (0.15 mmol)
of TBAF (1.0 M in THF). The reaction mixture was stirred at
50 °C for 12 h, quenched with brine, and extracted with ether.
The extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by
column chromatography on silica gel (elution with 15% EtOAc
in hexane) to afford 0.020 g (72%) of bis-THF ester: [R]D -6.0
(c 0.38, CHCl3); IR (film) 2925, 2855, 1728 cm-1 1H NMR
;
C
50H90O12: C, 67.99; H, 10.27. Found: C, 67.75; H, 10.10. The
(CDCl3, 300 MHz) δ 4.61-4.88 (m, 6 H), 4.12 (q, J ) 6.9 Hz,
2 H), 3.80-4.02 (m, 4 H), 3.65 (m, 1 H), 3.45 (m, 2 H), 3.38
(m, 9 H), 2.28 (t, J ) 7.7 Hz, 2 H), 1.00-2.05 (m, 51 H), 0.87
(t, J ) 6.9 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 173.8, 96.7,
96.6, 81.7, 80.8, 79.8, 79.2, 78.7, 60.1, 55.7, 55.6, 35.8, 34.3,
32.2, 31.9, 30.1, 30.0, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2,
29.1, 28.6, 28.5, 27.3, 27.1, 26.6, 25.5, 24.9, 22.6, 14.2, 14.1.
1
ee of this alcohol was judged to be >90% by H NMR analysis
of the (R)- and (S)-O-methyl mandelates (Supporting Informa-
tion).
Eth yl (12R,15R,16S,19R,20R,23R,24S)-15-[(Ben zyloxy-
m eth )oxy]-12-[(ter t-bu tyld im eth ylsilyl)oxy]-16,19,24-tr i-
(m eth oxym eth oxy)-20,23-oxid o-tetr a tr ia con ta n oa te (21).
To a mixture of 0.178 g (0.20 mmol) of alcohol 18 and 0.060 g
(0.88 mmol) of imidazole in 2 mL of DMF was added 0.076 g
(0.50 mmol) of TBSCl. The mixture was stirred at room
temperature for 12 h, quenched with water, and extracted with
ether. The extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel (elution with 10% EtOAc in hexane) to afford 0.190
g (95%) of TBS ether 21: [R]D +4.4 (c 0.5, CHCl3); IR (film)
Alcoh ol 26. To a solution of 0.02 mL (0.14 mmol) of
diisopropylamine in 0.5 mL of THF at 0 °C was added 0.04
mL (0.10 mmol) of BuLi. The mixture was stirred at 0 °C for
10 min and cooled to -78 °C. To it was added a solution of
0.016 g (0.02 mmol) of ester 24 in 0.5 mL of THF. The reaction
mixture was stirred at -78 °C for 60 min, and a solution of
0.006 g (0.03 mmol) of aldehyde 25 in 0.5 mL of THF was
added. After 30 min, the reaction was quenched with satu-
rated NH4Cl and extracted with ether. The extracts were
dried over MgSO4 and concentrated under reduced pressure.
To the residue was added 1 mL of THF followed by 0.1 mL
(0.10 mmol) of TBAF (1.0 M in THF). The reaction mixture
was stirred at room temperature for 30 min, quenched with
brine, and extracted with ether. The extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography (elution
with 40% EtOAc in hexane) to afford 0.013 g (78% for two
steps) of alcohol 26: 1H NMR (CDCl3, 300 MHz) δ 4.61-4.86
(m, 6 H), 4.18 (m, 1 H), 3.77-4.03 (m, 4 H), 3.65 (m, 1 H),
3.44 (m, 2 H), 3.38 (m, 9 H), 2.55 (m, 1 H), 1.03-2.10 (m, 51
H), 0.87 (t, J ) 6.9 Hz, 3 H).
2925, 2846, 1736, 1457 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
7.34 (m, 5 H), 4.57-4.91 (m, 10 H), 4.12 (q, J ) 6.0 Hz, 2 H),
3.94 (m, 2 H), 3.64 (m, 4 H), 3.44 (m, 1 H), 3.38 (m, 9 H), 2.28
(t, J ) 7.7 Hz, 2 H), 1.13-1.98 (m, 51 H), 0.88 (m, 12 H), 0.03
(s, 6 H); 13C NMR (CDCl3, 75 MHz) δ 173.8, 137.9, 128.3, 127.7,
127.6, 96.7, 96.0, 94.0, 81.8, 81.4, 79.9, 79.5, 79.3, 78.6, 72.5,
69.6, 60.1, 55.8, 55.7, 55.6, 37.3, 34.4, 33.7, 31.9, 30.2, 30.0,
29.8, 29.4, 29.3, 29.2, 29.1, 28.6, 28.0, 26.7, 26.6, 25.9, 25.5,
25.2, 25.0, 24.8, 22.6, 18.1, 14.2, 14.1, -4.4.
Eth yl (12R,15S,16S,19R,20R,23R,24S)-12-[(ter t-Bu tyld i-
m e t h y ls ily l)o x y ]-15-h y d r o x y -16,19,24-t r i(m e t h o x y -
m eth oxy)-20,23-oxid otetr a tr ia con ta n oa te (22). A mixture
of 0.080 g (0.08 mmol) of ester 21 and 0.080 g of Pd-C (5%) in
1.5 mL of EtOAc-EtOH (3:1) was placed under an H2
atmosphere. The mixture was stirred for 12 h and filtered
through Celite. The solvent was removed under reduced
pressure and the residue was purified by column chromatog-
raphy on silica gel (elution with 20% EtOAc in hexane) to
afford 0.060 g (86%) of alcohol 22: [R]D +15.1 (c 0.37, CHCl3);
MOM-P r otected Squ a m osta tin -D 27. To a mixture of
0.012 g (0.016 mmol) of alcohol 26 and 0.025 mL (0.16 mmol)
of Et3N in 1.5 mL of CH2Cl2 at 0 °C was added 0.005 mL (0.035
mmol) of (CF3CO)2O. The reaction mixture was stirred at
room temperature for 16 h, quenched with saturated NaHCO3,
and extracted with ether. The extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel (elution with 60% Et2O in hexane) to afford 0.011 g
(94%) of MOM-protected squamostatin-D 27: IR 2925, 2837,
IR (film) 3466, 2925, 2846, 1728 cm-1; H NMR (CDCl3, 300
1
MHz) δ 4.59-4.86 (m, 6 H), 4.11 (q, J ) 6.0 Hz, 2 H), 3.95 (m,
2 H), 3.67 (m, 2 H), 3.47 (m, 3 H), 3.40 (s, 3 H), 3.38 (s, 6 H),
2.28 (t, J ) 7.7 Hz, 2 H), 1.11-2.00 (m, 51 H), 0.88 (m, 12 H),
0.04 (s, 6 H); 13C NMR (CDCl3, 75 MHz) δ 173.8, 144.4, 134.5,
129.6, 127.8, 96.8, 96.7, 96.2, 85.3, 81.8, 81.4, 79.7, 78.6, 78.5,
71.9, 60.1, 55.8, 55.6, 37.2, 34.4, 32.8, 31.9, 29.8, 29.7, 29.6,
29.4, 29.3, 29.2, 29.1, 28.6, 27.6, 27.1, 26.6, 25.8, 25.5, 25.1,
25.0, 22.6, 21.6, 18.0, 14.2, 14.1, 10.0, -4.5, -4.6.
1
1754 cm-1; H NMR (CDCl3, 300 MHz) δ 6.98 (s, 1 H), 4.99
(m, 1 H), 4.61-4.88 (m, 6 H), 3.79-4.05 (m, 4 H), 3.66 (m, 1
H), 3.45 (m, 2 H), 3.38 (m, 9 H), 2.26 (t, J ) 7.7 Hz, 2 H),
1.17-2.07 (m, 46 H), 1.40 (d, J ) 6.5 Hz, 3 H), 0.87 (t, J ) 7.3
Hz, 3 H).
Squ a m osta tin -D (28). A mixture of 0.010 g (0.013 mmol)
of the MOM-protected sqamostatin D 27 in 1.25 mL of 6 N
HCl-THF-CH3OH (1:2:2) was stirred for 12 h at room
temperature. The reaction mixture was quenched with water
and extracted with ether. The extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel (elution with 80% EtOAc in hexane) to afford 0.008
g (97%) of squamostatin-D 28: mp 112-113 °C (EtOAc-
hexane; lit.1 mp 112-113.5 °C); [R]D +8.4 (c 0.40, MeOH); lit.1
Tosyla te 23. To a solution of 0.053 g (0.06 mmol) of alcohol
22 in 0.5 mL of pyridine was added 0.070 g (0.35 mmol) of
p-TsCl. The mixture was stirred at room temperature for 12
h, quenched with water, and extracted with ether. The
extracts were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
was purified by column chromatography on silica gel (elution
with 20% EtOAc in hexane) to afford 0.059 g (95%) of tosylate
23: [R]D +10.9 (c 0.49, CHCl3); IR (film) 2916, 2846, 1728 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J ) 8.9 Hz, 2 H), 7.31
(d, J ) 8.9 Hz, 2 H), 4.48-4.84 (m, 7 H), 4.12 (q, J ) 7.3 Hz,
2 H), 3.93 (m, 2 H), 3.61-3.76 (m, 2 H), 3.51 (m, 1 H), 3.41
(m, 1 H), 3.38 (s, 3 H), 3.36 (s, 3 H), 3.34 (s, 3 H), 2.43 (s, 3 H),
2.28 (t, J ) 8.1 Hz, 2 H), 1.04-2.01 (m, 51 H), 0.87 (t, J ) 6.2
Hz, 3 H), 0.94 (s, 9 H), -0.01 (s, 3 H), -0.03 (s, 3 H); 13C NMR
(CDCl3, 75 MHz) δ 173.8, 97.0, 96.7, 83.8, 81.8, 81.4, 80.8, 79.8,
78.6, 77.2, 76.8, 73.2, 72.4, 60.1, 55.8, 55.6, 47.7, 36.9, 34.3,
33.7, 31.9, 30.2, 30.1, 30.0, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3,
29.2, 29.1, 28.6, 27.6, 26.6, 25.9, 25.5, 25.3, 25.0, 22.6, 18.1,
15.2, 14.2, 13.9, 10.0, -4.45.
+7.9 (c 0.51, MeOH); IR (film) 3423, 2907, 2846, 1736 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 6.98 (s, 1 H), 4.99 (m, 1 H), 3.84
(m, 5 H), 3.41 (m, 2 H), 2.26 (t, J ) 6.9 Hz, 2 H), 1.40 (d, J )
6.5 Hz, 3 H), 1.15-2.10 (m, 46 H), 0.88 (t, J ) 7.3 Hz, 3 H);
13C NMR (CDCl3 300 MHz) δ 173.9, 148.9, 134.3, 82.3, 82.2,
82.0, 79.3, 74.6, 74.4, 71.5, 35.6, 32.5, 32.4, 31.9, 29.7, 29.6,
29.5, 29.4, 29.3, 29.1, 28.6, 28.4, 27.4, 26.2, 26.0, 25.1, 22.7,
19.2, 14.1. Tr i-(R)-Mosh er ester : 1H NMR (CDCl3, 300 MHz)
δ 7.30-7.64 (m, 15 H), 6.97 (d, J ) 1.6 Hz, 1 H), 5.26 (m, 1 H),
4.99 (dd, J ) 1.5, 6.8 Hz, 1 H), 4.91 (m, 2 H), 3.97 (m, 1 H),
3.89 (q, J ) 6.9 Hz, 1 H), 3.75 (m, 1 H), 3.69 (q, J ) 7.4 Hz, 1

Total Synthesis of the Squamostatin-D
J . Org. Chem., Vol. 63, No. 20, 1998 7071
H), 3.58 (s, 3 H), 3.52 (s, 3 H), 3.47 (s, 3 H), 2.26 (tt, J ) 1.6,
7.1 Hz, 1 H), 1.10-1.93 (m, 46 H), 0.88 (t, J ) 7.0 Hz, 3 H).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of stannane 2 and 1H NMR spectra
for intermediates (28 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
Ack n ow led gm en t. This research was supported by
a research grant from the NIH (R01GM56769). We
thank Professor Fujimoto for comparison spectra of
squamostatin-D and the Mosher ester derivative.
J O981103R