Studies on the synthesis of quartromicins A3 and D3: Synthesis of the vertical and horizontal bis-spirotetronate fragments

Article abstract of DOI:10.1021/jo061059c

Syntheses of the vertical (3) and horizontal (4) bis-spirotetronate units of quartromicins A₃ and D₃ are described, along with an efficient synthesis of α-hydroxy aldehyde exo-8b, a precursor to the exo-spirotetronate fragments 19 an

Full text of DOI:10.1021/jo061059c

Studies on the Synthesis of Quartromicins A3 and D3: Synthesis of
the Vertical and Horizontal Bis-Spirotetronate Fragments
Tony K. Trullinger,† Jun Qi,† and William R. Roush*,‡
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109, and Department of
Chemistry and Biochemistry, The Scripps Research Institute, Jupiter, Florida 33458
roush@scripps.edu
ReceiVed May 23, 2006
Syntheses of the vertical (3) and horizontal (4) bis-spirotetronate units of quartromicins A3 and D3 are
described, along with an efficient synthesis of R-hydroxy aldehyde exo-8b, a precursor to the
exo-spirotetronate fragments 19 and 21.
Introduction
The quartromicins (Figure 1) are a group of structurally
complex macrocyclic natural products that display activity
against herpes simplex virus (HSV) type 1, influenza, and
HIV.1-3 Quartromicins A3 and D3 possess a novel 32-membered
carbocyclic ring system containing four spirotetronic acid
subunits connected in a head-to-tail arrangement via enone
linkers. Our laboratory has proposed a stereochemical assign-
ment4,5 for the quartromicins, and we have developed chemistry
to access the two distinct spirotetronate subunits of these
complex targets.5,6 We refer to the two spirotetronate fragments
as the endo- (also known as the galacto fragment) and exo (or
the agalacto fragment)-spirotetronate units, by virtue of the
Diels-Alder chemistry that we have employed for their
synthesis.5,6 Other work on the synthesis of the quartromicins
has recently appeared.7
† University of Michigan.
‡ The Scripps Research Institute.
FIGURE 1. Structures of quartromicins A3 (1) and D3 (2).
(1) Kusumi, T.; Ichikawa, A.; Kakisawa, H.; Tsunakawa, M.; Konishi,
M.; Oki, T. J. Am. Chem. Soc. 1991, 113, 8947.
(2) Tsunakawa, M.; Tenmyo, O.; Tomita, K.; Naruse, N.; Kotake, C.;
Miyaki, T.; Konishi, M.; Oki, T. J. Antibiot. 1992, 45, 180.
(3) Tanabe-Tochikura, A.; Nakashima, H.; Murakami, T.; Tenmyo, O.;
Oki, T.; Yamamoto, N. AntiViral Chem. Chemother. 1992, 3, 345.
(4) Roush, W. R.; Barda, D. A. Org. Lett. 2002, 4, 1539.
(5) Roush, W. R.; Barda, D. A.; Limberakis, C.; Kunz, R. K. Tetrahedron
2002, 58, 6433.
The quartromicins are formidable synthetic targets owing to
the presence of contiguous quaternary centers in each of the
spirotetronate fragments (C4/C12 and C4′/C12′ in the exo
fragments; C22/C30 and C22′/C30′ in the endo fragments). The
high steric congestion at these positions greatly complicates
syntheses of the endo- and exo-spirotetronate fragments, much
more so than in syntheses of the spirotetronic acid fragments
of other spirotetronate natural products (e.g., chlorothricolide,8,9
(6) Roush, W. R.; Limberakis, C.; Kunz, R. K.; Barda, D. A. Org. Lett.
2002, 4, 1543.
(7) Bedel, O.; Franxais, A.; Haudrechy, Y. Synlett 2005, 2313.
10.1021/jo061059c CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/09/2006
J. Org. Chem. 2006, 71, 6915-6922
6915

Trullinger et al.
SCHEME 1. Summary of Previous Syntheses of 6 and 8
We have previously accomplished the enantioselective syn-
thesis of 5 via the Lewis acid-catalyzed Diels-Alder reaction
of an acyclic (Z)-1,3-diene.5,6,24 endo-R-Hydroxy aldehyde 6s
a precursor to the endo (or galacto)-spirotetronate fragment of
the quartromicinsswas then easily prepared by the DMDO
epoxidation of the enol silane prepared from 5 (Scheme 1).5
However, conversion of 5 to the exo-R-hydroxy aldehyde 8a
(formally the C(2) epimer of 6 and the targeted precursor of
the exo-spirotetronate subunit of the quartromicins) proceeded
in low overall yield owing to an inefficient inversion of
configuration of the C(2)-Br substituent of 7.5 Consequently,
before initiating work on the synthesis of fragments 3 and 4, it
was necessary to develop a more efficient synthesis of exo-8.
FIGURE 2. Structures of the vertical (3) and horizontal (4) bis-
spirotetronate units of quartromicin D3.
kijanolide,10-16 and tetronolide17-20). Other spirotetronate natural
products that have attracted interest as synthetic targets include
okilactomycin21,22 and tetronothiodin.23
Our synthetic strategy aims to exploit the C2 symmetry of
the natural products by generation of the carbocycle via a late-
stage dimerization of either the vertical (3) or horizontal (4)
exo-endo bis-tetronate fragments (Figure 2). Toward this end,
we have developed and report herein syntheses of the “exo-
endo” bis-spirotetronate units 3 and 4. The vertical “dimer” 3
contains an enone unit linking the two spirotetronate fragments,
whereas the horizontal “dimer” 4 contains a dienone linker.
A significant bottleneck in the synthesis of 3 and 4 is access
to synthetically useful quantities of precursors of the monomeric
endo- and exo-spirotetronate units. While synthesis of the endo
(or galacto) fragment in either racemic or single enantiomeric
form proved to be relatively straightforward, development of a
brief, highly stereoselective synthesis of the exo-spirotetronate
subunit present in the agalacto fragment of quartromicin A3 has
proven to be challenging.5
Results and Discussion
An improved synthesis of exo-R-hydroxy aldehyde 8b began
by converting aldehyde 5 into an enol silyl ether, which was
oxidized under Saegusa conditions25 to give the corresponding
enal (Scheme 2). Reduction of the enal by using DIBAL-H then
gave allylic alcohol 9. All attempts to effect a highly diaste-
reoselective reagent-controlled epoxidation of 9 were unsuc-
cessful (e.g., Sharpless asymmetric epoxidation).26 However,
epoxidation of 9 using VO(acac)2 and t-BuOOH gave the â-face
epoxy alcohol with >20:1 dr.27 Subsequent treatment of the
resulting epoxyalcohol with phenyl isocyanate and triethylamine
furnished urethane 10 in 88% yield over two steps. Exposure
of 10 to BF3‚OEt2 led to rapid and highly diastereoselective
intramolecular epoxide opening28 to furnish carbonate 11,
possessing the C(2) stereochemistry required for the exo-
spirotetronate fragment. Reductive removal of the hydroxyl
group in 11 via Barton deoxygenation29,30 proceeded in >90%
yield. Cleavage of the carbonate with potassium carbonate in
methanol followed by Parikh-Doering oxidation31 of the
primary alcohol furnished aldehyde exo-8b. The overall yield
(8) Takeda, K.; Igarashi, Y.; Okazaki, K.; Yoshii, E.; Yamaguchi, K. J.
Org. Chem. 1990, 55, 3431.
(9) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1998, 120, 7411.
(10) Marshall, J. A.; Grote, J.; Audia, J. E. J. Am. Chem. Soc. 1987,
109, 1186.
(11) Takeda, K.; Yano, S.; Sato, M.; Yoshii, E. J. Org. Chem. 1987, 52,
4135.
(12) Takeda, K.; Yano, S.-g.; Yoshii, E. Tetrahedron Lett. 1988, 29, 6951.
(13) Marshall, J. A.; Xie, S. J. Org. Chem. 1992, 57, 2987.
(14) Roush, W. R.; Brown, B. B. J. Am. Chem. Soc. 1993, 115, 2268.
(15) Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58, 2151.
(16) Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58, 2162.
(17) Takeda, K.; Kawanishi, E.; Nakamura, H.; Yoshii, E. Tetrahedron
Lett. 1991, 32, 4925.
(18) Roush, W. R.; Reilly, M. L.; Koyama, K.; Brown, B. B. J. Org.
Chem. 1997, 62, 8708.
(19) Boeckman, R. K., Jr.; Barta, T. E.; Nelson, S. G. Tetrahedron Lett.
1991, 32, 4091.
(20) Boeckman, R. K., Jr.; Wrobleski, S. T. J. Org. Chem. 1996, 61,
7238.
(21) Paquette, L. A.; Boulet, S. L. Synthesis 2002, 888.
(22) Boulet, S. L.; Paquette, L. A. Synthesis 2002, 895.
(23) Page, P. C. B.; Vahedi, H.; Batchelor, K. J.; Hindley, S. J.; Edgar,
M.; Beswick, P. Synlett 2003, 1022.
(26) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1.
(27) Tanaka, S.; Yamamoto, H.; Nozaki, H.; Sharpless, K. B.; Michael-
son, R. C.; Cutting, J. D. J. Am. Chem. Soc. 1974, 96, 5254.
(28) Roush, W. R.; Brown, R. J.; DiMare, M. J. Org. Chem. 1983, 48,
5083.
(29) Barton, D. H. R.; Jaszberenyi, J. C. Tetrahedron Lett. 1989, 30,
2619.
(24) Roush, W. R.; Barda, D. A. J. Am. Chem. Soc. 1997, 119, 7402.
(25) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(30) Hartwig, W. Tetrahedron 1983, 39, 2609.
(31) Parikh, J. R.; von Doering, E. W. J. Am. Chem. Soc. 1967, 89, 5505.
6916 J. Org. Chem., Vol. 71, No. 18, 2006

Studies on the Synthesis of Quartromicins A3 and D3
SCHEME 2. Synthesis of exo-8b
SCHEME 3. Synthesis of exo-8b via the exo-Selective
Diels-Alder Reaction of 12 and 13
We turned next to elaboration of 8b to exo-spirotetronates
19 and 21 needed for the synthesis of 3 and 4, respectively
(Scheme 4). R-Hydroxy aldehyde exo-8b was oxidized by
SCHEME 4. Elaboration of exo-8b to exo-19 and exo-21
from 5 to 8b (47%) is more than 5 times higher than that from
previous routes. This sequence has been scaled to provide gram
quantities of precursors to 8b.
While the synthesis of 8b summarized in Scheme 2 is
chemically efficient, the length of this sequence is unattractive
(10 steps from 5). This prompted us to develop a more direct
synthesis of exo-8b via the exo-selective Diels-Alder reaction
of 12 and 13, a dienophile that we designed for this purpose.32
Details of the design and synthesis of 13 have been reported
elsewhere.32,33 Thus, the MeAlCl2-mediated Diels-Alder reac-
tion of (Z)-diene 1224 with the conformationally constrained
R-alkoxyacrylate dienophile 13 provided a 5:1 mixture of
cycloadducts favoring exo-14. Reduction of this mixture with
LiAlH4 and then oxidation of the resulting mixture of diols under
Parikh-Doering conditions31 provided the targeted R-hydroxy
aldehyde exo-8b in 51% yield, along with 10% of ent-endo-6
(the enantiomer of endo-6 as presented in Scheme 1), which
were separated chromatographically.
The synthesis of exo-8b summarized in Scheme 3 is more
stepwise efficient than the much longer synthesis summarized
in Scheme 2, starting in both cases from diene 12, the closest
common precursor for both routes.5 The synthesis of exo-8b in
Scheme 3 proceeds in 36% yield over three steps from diene
12, whereas the synthesis of exo-8b from 12 via Scheme 2
proceeds in 23% yield over a 12-step sequence. An implicit
tradeoff, however, is that our current synthesis of dienophile
13 is lengthy (13 steps from commercially available L-valine,
7% overall yield).32,33 Nevertheless, we are using the sequence
of Scheme 3 for bringing up starting materials and have already
prepared ca. 1 g quantities of exo-8b from single runs (see
Experimental Section).
exposure to KOH and I2 in MeOH,34 and then the primary TBS
ether was cleaved by treatment with PPTs in MeOH. The diol
exo-16 was acylated by treatment with Ac2O and catalytic Sc-
(32) Qi, J.; Roush, W. R. Org. Lett. 2006, 8, 2795.
(33) Complete details for the synthesis of dienophile 13 are provided in
the Supporting Information to the paper cited as ref 32.
J. Org. Chem, Vol. 71, No. 18, 2006 6917

Trullinger et al.
SCHEME 6. Synthesis of the Horizontal exo-endo
SCHEME 5. Elaboration of endo-6 to endo-23 and endo-25
Bis-Tetronate 4
(OTf)3,35 and then the primary acetate was selectively cleaved
by treatment with DIBAL-H. The resulting R-acetoxy ester 17
was then elaborated to exo-18 by using our previously published
sequence.5,6 Treatment of 18 with LHMDS in THF-HMPA at
-78 °C followed by addition of NBS provided the 2-bromo
spirotetronic acid. Treatment of this intermediate with CH2N2
afforded the methyl ether derivative exo-19 in 86% yield. This
compound was destined to serve as the nucleophilic component
(after lithium-halogen exchange) in the synthesis of the
horizontal bis-spirotetronate unit 4. Alternatively, standard
Dieckmann cyclization of 18 followed by methylation using
CH2N2 provided 20. Deprotection of the TBS ether of 20 by
treatment with PPTS in methanol followed SO3-pyridine
oxidation31 gave enal exo-21, which ultimately served as the
electrophilic coupling partner in the synthesis of the vertical
bis-spirotetronate fragment 3.
SCHEME 7. Synthesis of the Vertical endo-exo
Bis-Tetronate 3
endo-R-Acetoxy ester 22, derived from endo-6,5,6 was
elaborated to 2-bromo spirotetronate 23 (Scheme 5) by using
the same Dieckmann cyclization-bromination conditions used
for the synthesis of exo-19 from 18 (Scheme 4). Intermediate
23 was designed to serve as the nucleophilic component in the
synthesis of the vertical bis-spirotetronate unit 3. Deprotection
of the primary TBS ether of 24, which derives from the non-
oxidative Dieckmann cyclization of 22,5,6 was accomplished by
treatment with PPTS in MeOH. Oxidation of the resulting
alcohol to the corresponding enal and then olefination with a
stabilized ylide afforded dienal 25 in the endo-spirotetronate
series. The latter compound was targeted to serve as the
electrophilic fragment in a synthesis of the horizontal bis-
spirotetronate 4.
With viable synthetic routes to all four coupling partners in
hand, we were ready to investigate the synthesis of the vertical
and horizontal halves of quartromicin. In previous studies, we
directly metalated endo-24 by treatment with mesityllithium,17and
the resulting R-lithio spirotetronate added in good yield to an
R,â-unsaturated aldehyde.5 However, attempts to apply this
protocol to the metalation of exo-20 under a variety of conditions
met with poor results. Consequently, we elected to generate the
2-lithio-exo-spirotetronate via lithium/halogen exchange36 by
treatment of exo-19 with n-BuLi (Scheme 6).
Unfortunately, while the requisite 2-lithiotetronate was ef-
ficiently generated under these conditions, it failed to add to
dienal 25 in good yield. However, when the 2-lithiotetronate
(generated from 3 equiv of 19) was transmetalated using
CeCl3,37,38 the resulting vinylcerium species underwent smooth
and efficient 1,2-addition to dienal 25 (1 equiv), thus providing
26 in 92% yield (Scheme 6). The addition product 26 was
oxidized to the ketone by using activated MnO2, which provided
the horizontal fragment 4 of quartromicin.
This coupling protocol was also applied to the synthesis of
the vertical fragment 3 (Scheme 7). Thus, sequential treatment
(36) Takeda, K.; Kubo, H.; Koizumi, T.; Yoshii, E. Tetrahedron Lett.
1982, 23, 3175.
(34) Yamada, S.; Morizono, D.; Yamamoto, K. Tetrahedron Lett. 1992,
33, 4329.
(37) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392.
(35) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Am. Chem.
Soc. 1995, 117, 4413.
(38) Conlon, D. A.; Kumke, D.; Moeder, C.; Hardiman, M.; Hutson,
G.; Sailer, L. AdV. Synth. Catal. 2004, 346, 1307.
6918 J. Org. Chem., Vol. 71, No. 18, 2006

Studies on the Synthesis of Quartromicins A3 and D3
at 0 °C. The mixture was stirred at room temperature for 6 h. Diethyl
ether and saturated aq. Rochelle’s salt solution were then added,
and the mixture was further stirred overnight until both layers
became clear. The layers were then separated, and the aqueous layer
was extracted with ether (3×). The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated.
The crude product was then purified by chromatography on silica
gel (50% EtOAc-hexane) providing exo-8b (231 mg, 12%), endo-6
(46 mg, 3%), and a mixture of endo and exo diols (923 mg, 50%
yield).
of 2-bromo-endo-spirotetronate 23 with n-BuLi, CeCl3, and
finally aldehyde exo-21 gave addition product 27 in ca. 65%
yield. The secondary hydroxyl group of 27 was oxidized by
using MnO2 to give the complete vertical fragment 3 of
quartromicin.
In summary, we have developed an improved synthetic route
to exo-R-hydroxy aldehyde 8b via the Diels-Alder reaction of
12 and 13; exo-8b and endo-6 were elaborated into the
corresponding 2-bromo spirotetronates exo-19 and endo-23 and
the unsaturated aldehydes exo-21 and endo-25 needed for the
coupling experiments. Finally, we have shown that both the
vertical (3) and horizontal (4) halves of quartromicins A3 and
D3 can be accessed via the 1,2-addition of organocerium
intermediates derived from 19 and 23 onto the requisite enals
25 and 21, respectively. Attempts to utilize these intermediates
in the completion of the total synthesis of the proposed structure
of quartromicin D3 (2) are in progress and will be reported in
due course.
To a solution of diol mixture (923 mg, 1.5 mmol) in CH2Cl2
(15 mL) were added sequentially DMSO (1.1 mL, 15.5 mmol),
i-Pr2NEt (1.4 mL, 7.8 mmol), and SO3‚pyridine (740 mg, 4.6
mmol). The reaction was judged complete in 15 min by TLC
analysis and was quenched by addition of EtOAc (20 mL) and 1
M aq. HCl (5 mL). The organic layer was separated and washed
with saturated aq. NaHCO3, brine, dried with MgSO4, filtered, and
concentrated. The crude product was purified by flash column
chromatography on SiO2 (10% EtOAc-hexane) to afford the known
R-hydroxy aldehyde exo-8b (694 mg, 75% from the diol mixture;
38% from Diels-Alder adducts 14 and 15) and ent-endo-6 (132
mg, 14% from diol mixture; 7% from 14 and 15). Overall, 925 mg
(51% yield) of exo-8b and 178 mg (10%) of ent-endo-6 were
obtained for the three-step sequence starting with the 5:1 mixture
of Diels-Alder adducts 14 and 15.
Experimental Section39
Spiro(1′R,2′S,5′S,8rR)-6-[2′-[3-(tert-Butyldimethylsilanyl-
oxy)propyl]-4′-(tert-butyldiphenylsilanyloxymethyl)-2′,5′-dimeth-
ylcyclohex-3′-ene]-8r-isopropyldihydrooxazolo[4,3-c][1,4]oxa-
zine-3,5,8-trione (14) and Spiro(1′R,2′R,5′R,8rR)-6-[2′-[3-(tert-
Butyldimethylsilanyloxy)propyl]-4′-(tert-butyldiphenyl-silanyl-
oxymethyl)-2′,5′-dimethylcyclohex-3′-ene]-8r-iso-propyldihydro-
oxazolo[4,3-c][1,4]oxazine-3,5,8-trione (15). To a -78 °C solution
of diene 12 (2.32 g, 4.4 mmol) and dienophile 13 (1.20 g, 5.3 mmol)
in CH2Cl2 was added 5.3 mL of MeAlCl2 (1.0 M solution in
hexanes, 5.3 mmol) over 30 min. The resulting yellow solution
was stirred at -78 °C for 6 days. The reaction was quenched by
the slow addition of saturated aq. NaHCO3 and allowed to warm
to room temperature. The mixture was diluted with diethyl ether
and 1 N HCl, and the layers were separated after the white solids
had dissolved. The aqueous layer was extracted with Et2O (3×).
The combined organic layers were washed with saturated aq.
NaHCO3 and brine, dried over MgSO4, filtered, and concentrated.
The crude product was then purified by chromatography on silica
gel (20% EtOAc-hexane). The mixture of diastereomeric products
so obtained (5:1 mixture, 2.32 g, 70%) was inseparable by silica
gel chromatography (20% EtOAc-hexane) or by HPLC. Data for
Data for exo-8b: Rf 0.56 (10% EtOAc-hexane); [R]23 -2.7°
D
(c 3.1, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 7.66
(m, 4H), 7.40 (m, 6H), 5.52 (br, 1H), 4.27 (d, J ) 13.2 Hz, 1H),
4.18 (d, J ) 13.2 Hz, 1H), 3.57 (m, 2H), 3.27 (s, 1H), 2.46 (m,
1H), 1.92 (dd, J ) 13.9, 11.7 Hz, 1H), 1.65 (dd, J ) 13.9, 7.3 Hz,
1H), 1.51 (m, 4H), 1.08 (s, 7H), 1.05 (d, J ) 6.6 Hz, 3H), 0.89 (s,
9H), 0.82 (s, 3H), 0.04 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
206.5, 138.9, 135.5, 133.6, 133.5, 129.8, 129.3, 127.7, 80.9, 65.4,
63.8, 39.4, 38.2, 34.5, 30.1, 27.0, 26.8, 25.9, 20.5, 19.5, 19.2, 18.3,
-5.3; FT-IR (thin film) 3948, 3070, 2956, 2930, 2857, 1718, 1471,
1427, 1389, 1361, 1333, 1255, 1112, 1006, 934, 835, 775, 738,
701 cm-1; HRMS (ESI) calcd for C35H54O4Si2Na [M + Na]+
617.3458, found 617.3456 m/z.
Data for the minor product ent-endo-6: Rf 0.52 (10% EtOAc-
hexane); [R]23D -9.3° (c 0.8, CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ 9.76 (s, 1H), 7.69 (m, 4H), 7.40 (m, 6H), 5.46 (br, 1H), 4.23 (d,
J ) 13.2 Hz, 1H), 4.14 (d, J ) 13.2 Hz, 1H), 3.55 (m, 2H), 3.16
(s, 1H), 2.53 (m, 1H), 1.80 (m, 2H), 1.53 (m, 4H), 1.06 (s, 7H),
1.02 (d, J ) 6.6 Hz, 3H), 0.99 (s, 3H), 0.87 (s, 9H), 0.03 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 205.5, 138.5, 135.55, 133.51,
133.71, 133.70, 129.63, 129.61, 127.64, 127.60, 127.4, 80.4, 65.5,
63.4, 41.5, 36.0, 35.9, 27.7, 27.2, 26.8, 25.9, 20.5, 19.3, 19.2, 18.3,
-5.3; FT-IR (thin film) 3510, 3071, 3049, 2956, 2930, 2857, 1717,
1589, 1472, 1389, 1361, 1255, 1112, 1006, 938, 835, 775, 740,
701 cm-1; HRMS (ESI) calcd for C35H54O4Si2Na [M + Na]+
617.3458, found 617.3459 m/z. These spectroscopic data matched
previously reported data for endo-(+)-6.5
Synthesis of exo-16. A solution of aldehyde 8b (676 mg, 1.1
mmol) in MeOH (11 mL) was cooled to 0 °C, and methanolic
solutions of potassium hydroxide (11.6 mL of a 0.78 M solution,
9.0 mmol) and iodine (5.8 mL of a 0.78 M solution, 4.5 mmol)
were added successively. The resulting dark brown mixture was
stirred at 0 °C for 45 min, after which time second portions of
potassium hydroxide (2.3 mL, 1.8 mmol) and iodine (1.1 mL, 0.9
mmol) solution were added successively. The starting material was
completely consumed 30 min after the second addition. The reaction
mixture was diluted with 2 N H2SO4 and Et2O and stirred at room
temperature for 30 min. The layer was separated, and the aqueous
layer was extracted with Et2O (3×). The combined layers were
washed with saturated aq. Na2S2O3 and brine, dried over MgSO4,
filtered, and concentrated. The crude product was filtered through
a short column of silica gel (50% EtOAc-hexane) to afford a
mixture of exo-16 and the corresponding TBS ether.
the mixture of 14 and 15: Rf 0.46 (33% EtOAc-hexane); [R]23
D
1
+24.7° (c 1.8, CH2Cl2); H NMR for major diastereomer 14 (500
MHz, CDCl3) δ 7.51 (m, 10H), 5.40 (s, 1H), 4.37 (s, 2H), 4.13
(m, 2H), 3.54 (m, 2H), 2.66 (m, 1H), 2.34 (dd, J ) 13.9, 7.3 Hz,
1H), 2.23 (m, 1H), 1.99 (dd, J ) 13.9, 7.3 Hz, 1H), 1.52 (m, 4H),
1.03 (m, 21H), 0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 165.1, 164.7, 149.5, 137.7, 135.6, 135.5, 135.4, 133.6,
133.5, 129.7, 129.6, 127.7, 127.6, 125.5, 91.6, 66.3, 65.2, 65.0,
63.4, 44.3, 37.7, 37.0, 34.8, 29.0, 27.4, 27.0, 26.8, 26.7, 26.0, 25.9,
21.7, 19.3, 19.2, 18.3, 16.2, 15.7, -5.3; FT-IR (thin film) 2930,
2857, 1822, 1756, 1715, 1472, 1428, 1358, 1297, 1258, 1188, 1111,
1056, 835, 776, 703 cm-1; HRMS (ESI) calcd for C42H61NO7Si2-
Na [M + Na]+ 770.3884, found 770.3903 m/z.
(1R,2S,5S)-2-[3-(tert-Butyldimethylsilanyloxy)propyl]-4-(tert-
butyldiphenylsiloxymethyl)-1-hydroxy-2,5-dimethylcyclohex-3-
enecarbaldehyde (exo-8b) and (1R,2R,5R)-2-[3-(tert-Butyldi-
methylsilanyloxy)propyl]-4-(tert-butyldiphenylsiloxymethyl)-1-
hydroxy-2,5-dimethylcyclohex-3-enecarbaldehyde (endo-6). To
a solution of the 5:1 mixture of 14 and 15 (2.33 g, 3.1 mmol) in
THF (23 mL) was added LiAlH4 (236 mg, 6.2 mmol) portion-wise
(39) New compounds and the isolated intermediates gave satisfactory
1H and 13C NMR, IR, and HRMS data. Yields refer to chromatographically
and spectroscopically homogeneous materials. Tabulations of spectroscopic
data are provided in the Supporting Information.
J. Org. Chem, Vol. 71, No. 18, 2006 6919

Trullinger et al.
To a solution of this mixture in 5 mL of MeOH was added
PPTS (553 mg, 2.2 mmol). The reaction was stirred at room
temperature for 2 h, at which point the TBS ether was fully
deprotected. Water (50 mL) and diethyl ether (50 mL) were added.
The layers were separated, and the aqueous layer was extracted
by Et2O (3×). The combined organic layers were then washed
with brine, dried over MgSO4, filtered, and concentrated. The
product was purified by column chromatography (50% EtOAc-
NBS (0.60 mL, 0.5 M in THF, 0.30 mmol) was then added dropwise
to the -78 °C solution. The flask was wrapped with aluminum
foil and the mixture stirred for 30 min. The reaction was quenched
by addition of EtOAc and aq. 1 M HCl, the solution was allowed
to warm to 23 °C, the layers were separated, and the organic layer
was washed with water (3×), dried over MgSO4, filtered, and
concentrated.
To a 0 °C solution of the tetronic acid in ether (3.0 mL) was
added ethereal CH2N2 (∼10 equiv); gas evolution occurred. The
reaction mixture was allowed to warm to 23 °C and was stirred for
30 min. A few drops of HOAc were added until the yellow color
dissipated, then ether and saturated aq. NaHCO3 were added. The
layers were separated, the aqueous layer was extracted with ether
(2×), and the combined organic extracts were dried over MgSO4,
filtered, and concentrated. Purification of the crude product by
chromatography on SiO2 (20-30% EtOAc-hexane) provided
bromotetronate exo-19 (181 mg, 86%) as an oil. Small amounts of
the regioisomeric methyl tetronate were also detected (ratio ) 10:1
hexane) to afford exo-16 (423 mg, 75%) as a colorless oil: Rf 0.40
1
(50% EtOAc-hexane); [R]23 -16.2° (c 2.5, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 7.70 (m, 4H), 7.39 (m, 6H), 5.36 (s, 1H),
4.27 (d, J ) 12.7 Hz, 1H), 4.09 (d, J ) 12.7 Hz, 1H), 3.71 (s, 3H),
3.59 (t, J ) 5.9 Hz, 2H), 3.54 (br, 1H), 2.64 (m, 1H), 1.98 (dd, J
) 14.2, 6.8 Hz, 1H), 1.78 (dd, J ) 14.2, 8.8 Hz, 1H), 1.56 (m,
5H), 1.06 (m, 12H), 0.93 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
177.3, 138.5, 135.5, 135.4, 133.9, 133.8, 129.6, 129.5, 128.2, 128.1,
127.6, 127.5, 78.7, 66.0, 63.7, 52.5, 52.4, 40.3, 38.3, 34.5, 29.4,
27.6, 26.7, 21.5, 19.3; FT-IR (thin film) 3501, 2955, 2932, 2858,
1716, 1472, 1456, 1428, 1247, 1111, 1062, 824, 738, 702, 614
cm-1; HRMS (ESI) calcd for C30H42O5SiNa [M + Na]+ 533.2699,
found 533.2701 m/z.
favoring 19). Data for 19: Rf 0.28 (20% EtOAc-hexane); [R]27
D
1
+52.3° (c 2.7, CHCl3); H NMR (500 MHz, CDCl3) δ 7.71 (m,
4H), 7.40 (m, 6H), 7.69 (d, J ) 15.6 Hz, 1H), 5.45 (dt, J ) 15.4,
5.1 Hz, 1H), 5.26 (s, 1H), 4.29 (d, J ) 12.4 Hz, 1H), 4.21 (s, 3H),
4.20-4.10 (3H), 2.72 (m, 1H), 1.98 (dd, J ) 13.4, 10.2 Hz, 1H),
1.83 (dd, J ) 13.5, 6.6 Hz, 1H), 1.06 (15H), 0.88 (s, 9H), 0.045 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 176.9, 168.4, 140.5, 135.5,
135.4, 134.7, 133.7, 133.6, 132.0, 129.8, 129.7, 127.7, 127.6, 125.8,
88.4, 79.2, 65.2, 63.8, 59.6, 43.6, 37.6, 29.3, 26.7, 25.9, 21.7, 19.3,
18.9, 18.3, -5.0, -5.1; FT-IR (neat) 2956, 2930, 2857, 1768, 1634,
1258, 1112, 836, 703 cm-1; HRMS (ESI) calcd for C38H53BrO5-
Si2Na [M + Na]+ 747.2513, found 747.2523 m/z.
exo-Spirotetronate 20. To a THF solution (2.0 mL) of exo-R-
acetoxy ester 18 (79 mg, 0.12 mmol) was added HMPA (0.47 mL),
and the resulting solution was cooled to -78 °C. Next, a solution
of LHMDS (0.68 mL, 1.0 M in THF) was added over 2 min. The
solution was stirred for 2 h, at which point complete conversion of
18 to the tetronic acid was observed (TLC analysis). The reaction
was quenched by addition of EtOAc and aq. 1 M HCl, and the
solution was allowed to warm to 23 °C; the layers were separated,
and the organic layer was washed with water (3×), dried over
MgSO4, filtered, and concentrated to give an oil.
To a 0 °C solution of the crude tetronic acid in ether (3.0 mL)
was added ethereal CH2N2 (ca. 10 equiv); gas evolution occurred.
The reaction mixture was allowed to warm to 23 °C and was stirred
for 30 min. A few drops of AcOH were added until the yellow
color dissipated, then ether and saturated aq. NaHCO3 were added.
The layers were separated, the aqueous layer was extracted with
ether (2×), and the combined organic extracts were dried over
MgSO4, filtered, concentrated, and purified by chromatography on
SiO2 (15-30% EtOAc-hexane) to afford the spirotetronate exo-
20 (40 mg pure major diastereomer, and 21 mg which was a 1.7:1
mixture of major and minor tetronate methylation regioisomers for
a 78% total yield) as a clear semisolid. The ratio of the two
Synthesis of exo-17. A solution of diol exo-16 (421.8 mg, 0.83
mmol) in acetic anhydride (6.6 mL) was cooled to 0 °C, and a
CH3CN solution of Sc(OTf)3 (215.4 mg, 0.44 mmol in 1.7 mL of
CH3CN) was added quickly. The resulting solution was stirred at
0 °C for 40 s, after which time saturated aq. NaHCO3 (40 mL)
was added with 10 g of solid NaHCO3. The reaction mixture was
stirred at room temperature overnight and then was diluted with
ether and water. The layer was separated, and the aqueous layer
was extracted with ether (3×). The combined layers were washed
with saturated aq. NaHCO3 and brine, dried over MgSO4, filtered,
and concentrated. The product was purified by column chroma-
tography (25% EtOAc-hexane) to afford the 1°-3° diacetate
intermediate (436 mg, 89%) as a colorless oil; 10% of a triacetate
(derived from deprotection/acylation of the primary TBDPS ether)
was also observed. Data for the diacetate: Rf 0.20 (25% EtOAc-
hexane); [R]23D -48.4° (c 3.2, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 7.68 (m, 4H), 7.38 (m, 6H), 5.43 (s, 1H), 4.19 (d, J ) 13.2 Hz,
1H), 4.13 (d, J ) 13.9 Hz, 1H), 4.02 (t, J ) 6.6 Hz, 2H), 3.71 (s,
3H), 2.47 (m, 2H), 2.34 (m, 1H), 2.03 (s, 3H), 2.02 (s, 3H), 1.78-
1.56 (m, 4H), 1.06 (s, 9H), 0.93 (d, J ) 7.3 Hz, 3H), 0.88 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 171.1, 171.0, 170.2, 138.4, 135.44,
135.41, 133.6, 133.5, 129.6, 129.5, 127.6, 127.6, 124.8, 84.4, 65.6,
65.2, 51.8, 40.1, 31.7, 31.1, 27.6, 26.7, 24.0, 23.8, 21.5, 20.9, 19.4,
19.2; FT-IR (thin film) 3071, 2959, 2934, 2892, 2858, 1739, 1472,
1463, 1429, 1368, 1113, 1072, 1030, 824, 741, 704, 610 cm-1
;
HRMS (ESI) calcd for C34H46O7SiNa [M + Na]+ 617.2911, found
617.2911 m/z.
To a -78 °C solution of the above diacetate (436 mg, 0.73 mmol)
in THF (7.3 mL) was added DIBAL-H (1.96 mL of a 1.5 M solution
in toluene, 2.9 mmol) slowly down the side of the flask. The
resulting solution was stirred at -78 °C for 2 h; pH 7 buffer (10
mL) and ether (20 mL) were then added. The mixture was allowed
to warm to room temperature, diluted with saturated aq. Rochelle’s
salt solution, and stirred for 5 h. The layer was separated, and the
aqueous layer was extracted with ether (3×). The combined layers
were washed with saturated aq. NaHCO3 and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The product was
purified by column chromatography (50% EtOAc-hexane) to afford
exo-17 (410 mg, 99%) as colorless oil: Rf 0.20 (50% EtOAc-
O-methyl tetronates was approximately 7:1. Data for exo-20: Rf
1
0.35 (35% EtOAc-hexane); [R]27 +51.9° (c 0.42, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 7.72 (m, 4H), 7.40 (m, 6H), 5.75 (d, J
) 15.6 Hz, 1H), 5.45, dt, J ) 15.6, 5.6 Hz, 1H), 5.26 (br s, 1H),
5.05 (s, 1H), 4.32 (AB, J ) 12.4 Hz, 1H), 4.16 (m, 2H), 4.13 (AB,
J ) 13.0 Hz, 1H), 3.73 (s, 3H), 2.75 (m, 1H), 2.02 (dd, J ) 13.2,
10.8 Hz, 1H), 1.79 (dd, J ) 13.2, 6.6 Hz, 1H), 1.06 (overlapping
s and d, 12H), 1.01 (s, 3H), 0.88 (s, 9H), 0.049 (s, 3H), 0.047 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 185.4, 171.9, 140.7, 135.5,
133.8, 131.7, 129.7, 129.6, 127.7, 127.6, 125.9, 89.4, 87.7, 65.6,
64.0, 59.1, 43.2, 37.8, 29.7, 29.4, 26.7, 26.0, 21.7, 19.3, 18.8, -5.0;
FT-IR (neat) 2956, 2930, 2856, 1760, 1627, 1361, 1112, 1057, 835,
702 cm-1; HRMS (ESI) calcd for C38H54O5Si2Na [M + Na]+
669.3408, found 669.3411 m/z.
hexane); [R]23 -61.8° (c 1.0, CHCl3); the spectroscopic data for
D
this intermediate were identical to data for the same compound
previously prepared in our laboratory.5
exo-Bromotetronate, exo-19. To a solution of the R-acetoxy
ester exo-18 (196 mg, 0.295 mmol) in THF (6.0 mL) was added
HMPA (1.0 mL). The solution was cooled to -78 °C, and LHMDS
(0.87 mL, 1.0 M in THF, 0.87 mmol) was added. The solution
was stirred for 1.5 h, at which point complete conversion of exo-
18 to the tetronic acid was observed (TLC analysis). A solution of
exo-Enal 21. To a solution of TBS ether exo-20 (48 mg, 0.074
mmol) in MeOH (0.60 mL) and THF (0.10 mL) was added PPTS
(37 mg, 0.15 mmol) in one portion. The reaction was stirred for 2
6920 J. Org. Chem., Vol. 71, No. 18, 2006

Studies on the Synthesis of Quartromicins A3 and D3
h, then the mixture was concentrated to a white precipitate. This
material was purified by chromatography on SiO2 (50% EtOAc-
hexane) to afford the allylic alcohol (33 mg, 83% yield) as a white
foam.
1462, 1428, 1359, 1251, 1113, 836, 777, 703 cm-1; HRMS (ESI)
calcd for C38H54O5Si2Na [M + Na]+ 669.3408, found 669.3385
m/z.
endo-r-Methyl Dienal 25. To a solution of TBS ether and endo-
24 (21.5 mg, 0.33 mmol) in MeOH (0.30 mL) was added PPTS
(25 mg, 0.99 mmol). The reaction mixture was stirred for 2 h then
was concentrated to an oil and titrated with ether. The heterogeneous
solution was filtered through Celite and washed multiple times with
ether. The ether extracts were washed with saturated aq. NaHCO3
(1×), aq. 1 M HCl (1×), and brine (1×), dried over MgSO4, filtered,
and concentrated. This crude material was oxidized by using the
SO3‚pyridine oxidation procedure described for the synthesis of
8b, giving the corresponding enal (12 mg, 68%) as a flaky white
precipitate after purification by chromatography on SiO2 (50-60%
The above allylic alcohol (32 mg, 0.060 mmol) was oxidized
via the SO3‚pyridine protocol described for the synthesis of 8b (see
Supporting Information) to give the crude enal, which was purified
by chromatography on SiO2 (35-50% EtOAc-hexane) to give exo-
21 (28 mg, 71%): Rf 0.38 (50% EtOAc-hexane); [R]27 +95.6°
D
1
(c 2.7, CHCl3); H NMR (500 MHz, CDCl3) δ 9.58 (d, J ) 7.8
Hz, 1H), 7.69 (m, 4H), 7.40 (m, 6H), 6.97 (d, J ) 15.6 Hz, 1H),
6.00 (dd, J ) 15.5, 7.8 Hz, 1H), 5.31 (br s, 1H), 5.12 (s, 1H), 4.29
(AB, J ) 13.2 Hz, 1H), 4.16 (AB, J ) 13.2 Hz, 1H), 3.78 (s, 3H),
2.76 (m, 1H), 1.89 (overlapping dd, 2H), 1.12 (s, 3H), 1.06 (s, 9H),
1.03 (d, J ) 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 193.8,
184.5, 171.1, 161.7, 142.7, 135.4, 135.3, 133.5, 133.4, 133.3, 129.8,
129.7, 127.7, 127.6, 123.2, 89.6, 86.7, 65.1, 59.4, 44.2, 38.2, 29.5,
26.7, 20.9, 19.3, 18.7; FT-IR 2932, 2857, 1761, 1691, 1628, 1361,
1112, 960, 704 cm-1; HRMS (ESI) calcd for C32H38O5SiNa [M +
Na]+ 553.2386, found 553.2378 m/z.
EtOAc-hexane): Rf 0.49 (80% EtOAc-hexane); [R]27 +114.9°
D
1
(c 0.47, CHCl3); H NMR (500 MHz, CDCl3) δ 9.58 (d, J ) 7.9
Hz, 1H), 7.68 (m, 4H), 7.42 (m, 6H), 6.82 (d, J ) 15.6 Hz, 1H),
6.02 (dd, J ) 15.6, 7.5 Hz, 1H), 5.34 (s, 1H), 5.14 (s, 1H), 4.20
(app s, 2H), 3.86 (s, 3H), 2.60 (m, 1H), 1.86 (dd, J ) 14.2, 10.8
Hz, 1H), 1.80 (dd, J ) 14.2, 6.6 Hz, 1H), 1.16 (s, 3H), 1.05 (s,
9H), 0.99 (d, J ) 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
193.7, 182.8, 171.1, 160.7, 141.6, 135.4, 133.3, 133.2, 131.9, 129.7,
127.7, 122.9, 89.7, 85.6, 64.6, 59.5, 44.9, 36.5, 28.6, 26.7, 19.4,
19.2, 18.4; FT-IR (neat) 2955, 2932, 2857, 1756, 1688, 1633, 1428,
1358, 1113, 957, 705 cm-1; HRMS (ESI) calcd for C32H38O5SiNa
[M + Na]+ 553.2386, found 553.2386 m/z.
endo-Bromotetronate 23. The brominative Dieckmann cycliza-
tion of endo-225 (177 mg) was performed using the procedure
described for preparation of exo-19. This gave bromotetronate endo-
23 (111 mg, 58% yield) after purification by chromatography on
SiO2 (30-40% EtOAc-hexane): Rf 0.50 (30% EtOAc-hexane).
Small amounts of the regioisomeric methyl tetronate were also
To a solution of the above enal (12 mg, 0.023 mmol) in toluene
(1.00 mL) was added formylethylidenetriphenylphosphorane (7 mg,
0.023 mmol). The flask was fitted with reflux condenser and heated
to ca. 110 °C overnight (∼16 h). Conversion was only ca. 50%, so
more ylide (7 mg) was added and the reaction was heated for 8 h.
The conversion was not complete, so more ylide (7 mg) was added,
and the reaction was stirred for an additional ca. 16 h. Evaporation
of the solvents and purification of the product by preparative TLC
on SiO2 (80% EtOAc-hexane) gave the dienal endo-25 (8.5 mg,
62%): Rf 0.41 (80% EtOAc-hexane); [R]27D +265° (c 0.3, CHCl3);
1H NMR (500 MHz, CDCl3) δ 9.46 (s, 1H), 7.70 (m, 4H), 7.40
(m, 6H), 6.87 (d, J ) 11.3 Hz, 1H), 6.45 (dd, J ) 15.1, 11.0 Hz,
1H), 6.23 (d, J ) 15.1 Hz, 1H), 5.39 (br s, 1H), 5.13 (s, 1H), 4.23
(app br s, 2H), 3.87 (s, 3H), 2.62 (m, 1H), 1.91 (dd, J ) 13.9, 10.7
Hz, 1H), 1.14 (s, 3H), 1.05 (s, 9H), 1.03 (d, J ) 7.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 194.7, 183.4, 171.3, 148.0, 141.0, 137.6,
135.6, 135.5, 133.6, 133.5, 129.7, 129.7, 127.8, 127.7, 125.7, 124.6,
89.8, 86.4, 65.1, 59.4, 45.3, 36.7, 29.7, 28.8, 26.8, 20.2, 19.3, 18.8,
9.6; FT-IR (neat) 2925, 2854, 1756, 1683, 1630, 1457, 1359, 1179,
1112, 703 cm-1; HRMS (ESI) calcd for C35H42O5SiNa [M + Na]+
593.2699, found 593.2705 m/z.
Synthesis of Horizontal Bis-Tetronate Fragment 4 from 19
and 25. To a solution of exo-bromospirotetronate 19 (35 mg, 0.048
mmol) in THF (0.20 mL) were added cat. 1,10-phenanthroline
indicator and ca. 10 mg of 4 Å molecular sieves. The mixture was
stirred at 23 °C for 30 min then was cooled to -78 °C, and n-BuLi
(2.5 M hex) was added until a deep red/brown color persisted. The
resulting solution was stirred for 30 min, then a suspension of CeCl3
(0.78 mL, 0.68 M THF) was added dropwise. [CeCl3 was activated
as follows.37,38 To powdered CeCl3 (167 mg, 0.677 mmol) (>99+%
anhydrous Aldrich) were added THF (1.00 mL) and H2O (0.002
mL, 0.11 mmol), and the flask was fitted with a reflux condenser
and heated to 70 °C for 2 h. After being cooled to 23 °C, the
suspension was stirred vigorously overnight (ca. 16 h). Microscopy
showed rod-shaped crystals indicative of properly activated CeCl3
as described by Conlon.38] This mixture was stirred for 1 h, then a
solution of the dienal endo-25 (8 mg, 0.016 mmol) in THF (0.20
mL plus 0.10 mL wash) was added dropwise via cannula. The
mixture was stirred at -78 °C for 30 min, at which point TLC
analysis indicated the reaction was complete. Methanol (0.2 mL)
was added to the solution, and after 3 min, the flask was pulled
from the dewer and ether and saturated aq. NH4Cl were added.
The mixture was stirred for 5 min, then EtOAc was added, the
detected (ratio ) 10:1 favoring 23). Data for endo-23: [R]27
D
1
+40.4° (c 2.8, CHCl3); H NMR (500 MHz, CDCl3) δ 7.70 (m,
4H), 7.40 (m, 6H), 5.65 (d, J ) 15.4 Hz, 1H), 5.46 (dt, J ) 15.4,
4.4 Hz, 1H), 5.30 (br s, 1H), 4.30 (s, 3H), 4.19 (4H), 2.56 (m, 1H),
1.96 (dd, J ) 13.6, 10.7 Hz, 1H), 1.72 (dd, J ) 13.9, 6.6 Hz, 1H),
1.04 (s, 12H), 0.98 (d, J ) 7.3 Hz, 3H), 0.91 (s, 9H), 0.069 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 175.7, 168.4, 135.6, 135.5,
134.1, 130.5, 129.7, 129.6, 127.7, 127.6, 125.7, 88.1, 65.1, 63.5,
59.5, 44.6, 36.2, 28.7, 26.8, 25.9, 20.5, 19.3, 18.6, -5.1; FT-IR
(thin film) 2955, 2930, 2857, 1768, 1635, 1601, 1111, 1011, 837,
703 cm-1; HRMS (ESI) calcd for C38H53BrO5Si2Na [M + Na]+
747.2513, found 747.2513 m/z.
endo-Spirotetronate 24. To a THF solution (18 mL) of
endo-R-acetoxy ester 225 (0.54 g, 0.81 mmol) was added HMPA
(2.8 mL), and the resulting solution was cooled to -78 °C. To
this solution was then added a solution of LHMDS (0.41 g, 2.4
mmol, 1.0 M THF) over 2 min. The solution was stirred for 1.5 h,
at which point complete conversion to the tetronic acid was
observed (TLC analysis). The reaction was quenched by addition
of EtOAc and aq. 1 M HCl, the solution was allowed to warm to
23 °C, the layers were separated, and the organic layer was washed
with water (3×), dried over MgSO4, filtered, and concentrated to
give an oil.
To a 0 °C solution of the tetronic acid in ether (10 mL) was
added ethereal CH2N2 (∼10 equiv); gas evolution occurred, and
the solution was allowed to warm to 23 °C. After 30 min, the
reaction was complete (TLC analysis). The solvent was removed
under reduced pressure, and the residue was purified by chroma-
tography on SiO2 (20-30% EtOAc-hexane) to afford spirotetronate
endo-24 (0.36 g, 69%) as a clear semisolid: Rf 0.31 (30% EtOAc-
hexane); [R]27D +42.2° (c 1.1, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 7.72 (m, 4H), 7.43 (m, 6H), 5.69 (dt, J ) 15.4, 1.7 Hz, 1H),
5.47 (dt, J ) 15.4, 4.9 Hz, 1H), 5.34 (app d, J ) 1.5 Hz, 1H), 5.08
(s, 1H), 4.20 (br s, 2H), 4.17 (dd, J ) 4.6, 1.7 Hz, 2H), 3.83 (s,
3H), 2.56 (m, 1H), 1.94 (dd, J ) 13.4, 10.7 Hz, 1H), 1.71 (dd, J
) 13.7, 6.1 Hz, 1H), 1.05 (s, 9H), 1.05 (s, 3 H), 0.98 (d, J ) 7.1
Hz, 3H), 0.91 (s, 9H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl3)
δ 184.0, 171.8, 139.4, 135.5, 135.5, 134.3, 133.7, 133.6, 130.7,
129.6, 129.5, 127.7, 127.6, 125.6, 89.4, 87.1, 65.1, 65.1, 63.5, 59.2,
44.0, 36.4, 28.6, 26.7, 25.9, 20.7, 19.2, 18.6, 18.3, 18.3, -5.2, -5.2;
FT-IR (neat) 3071, 3049, 2956, 2930, 2889, 2856, 1759, 1629, 1590,
J. Org. Chem, Vol. 71, No. 18, 2006 6921

Trullinger et al.
layers were separated, and the aqueous layer was extracted with
EtOAc (1×). The combined organic extracts were combined, dried
over MgSO4, filtered, and concentrated. Purification of the crude
product by chromatography on SiO2 (30-50% EtOAc-hexane)
afforded the exo-spirotetronate 20 (18 mg) and two new spots
corresponding to the two diastereomers of allylic alcohol 26: Rf
a 6:1 mixture (not separable) of addition product 27 and aldehyde
21. On the basis of H NMR integration of this mixture, the yield
of 27 was estimated to be 65% (ca. 12 mg).
1
Treatment of this mixture (13.4 mg) with MnO2 according to
the procedure described for synthesis of 4 provided a crude product
mixture that was separated by chromatography. The mixture was
first purified by conventional chromatography on SiO2, which
provided 6.7 mg of pure 3. The impure fractions were purified by
HPLC to give an additional 2.3 mg of 3 (total 9.0 mg, 78% yield;
1
0.38, 3.7 mg, >90% pure by H NMR analysis, and Rf 0.30, 12.0
mg (50% EtOAc-hexane), 15.7 mg total, 92% yield. To a solution
of allylic alcohol 26 (mixture of both Rf spots from above, 5.5 mg,
0.0045 mmol) in ether (0.15 mL, 0.03 M) at 0 °C was added
activated MnO2 (ca. 10 mg, 25 equiv) in one portion. After 5 min,
the black suspension reaction mixture was allowed to warm to 23
°C and was vigorously stirred for 2 h. This cycle was repeated two
more times until TLC analysis showed complete consumption of
26. Ether (2 mL) was added, and the suspension was filtered through
Celite with washing of the Celite bed (4 × 2 mL). Concentration
of the combined filtrate afforded ketone 4 (3.2 mg, 58%): Rf 0.41
(40% EtOAc-hexane); [R]27D +137.1° (c 0.35, CHCl3); 1H NMR
δ 7.70 (m, 8H), 7.42 (m, 12H), 7.00 (d, J ) 10.3 Hz, 1H), 6.41
(dd, J ) 15.1, 11.0 Hz, 1H), 6.11 (d, J ) 15.2 Hz, 1H), 5.77 (app
d, J ) 15.6 Hz, 1H), 5.48 (dt, J ) 15.4, 5.6 Hz, 1H), 5.40 (app br
s, 1H), 5.30 (br s, 1H), 5.11 (s, 1H), 4.30 (app d, J ) 12.5 Hz,
1H), 4.23 (dd, J ) 20.0, 14.0 Hz, 2H), 4.17 (3H), 3.84 (s, 3H),
3.72 (s, 3H), 2.75 (m, 1H), 2.60 (m, 1H), 2.06 (dd, J ) 13.5, 11.0
Hz, 1H), 1.95 (s, 3H), 1.91 (overlapping dd, 2H), 1.76 (dd, J )
13.9, 6.1 Hz, 1H), 1.15 (s, 3H), 1.14 (s, 3H), 1.05 (s, 21H), 1.02
(d, J ) 7.1 Hz, 3 H), 0.89 (s, 9H), 0.053 (s, 3H), 0.050 (s, 3H);
13C NMR 191.9, 183.4, 181.1, 171.6, 169.4, 148.6, 144.4, 141.0,
136.6, 135.5, 135.1, 133.7, 133.6, 133.5, 133.4, 132.1, 129.7, 127.8,
127.7, 127.6, 126.3, 125.3, 124.1, 104.3, 89.6, 65.4, 64.9, 63.8,
61.1, 59.3, 45.3, 43.7, 37.7, 36.6, 29.7, 29.5, 28.7, 26.8, 26.7, 25.9,
21.9, 20.4, 19.3, 18.8, 18.7, 11.8, -5.0; FT-IR (neat) 2956, 2929,
2856, 1757, 1630, 1456, 1361, 1112, 703; HRMS (ESI) calcd for
C73H94O10Si3Na [M + Na]+ 1237.6053, found 1237.6053 m/z.
Vertical Bis-Tetronate Fragment 3. Bromotetronate endo-23
(30 mg) and enal exo-21 (8.0 mg) were coupled by using the
procedure described for synthesis of 26. This afforded 13.4 mg of
50% overall from 21): Rf 0.38 (40% EtOAc-hexane); [R]27
D
1
+105.5° (c 0.4, CHCl3); H NMR (500 MHz, CDCl3) δ 7.70 (m,
8H), 7.40 (m, 12H), 6.97 (d, J ) 15.7 Hz, 1H), 6.67 (d, J ) 15.6
Hz, 1H), 5.65 (dt, J ) 15.4, 1.5 Hz, 1H), 5.47 (dt, J ) 15.4, 4.8
Hz, 1H), 5.31 (app br s, 2H), 5.09 (s, 1H), 4.35 (app d, J ) 12.7
Hz, 1H), 4.17 (5H), 4.00 (s, 3H), 2.82 (m, 1H), 2.55 (m, 1H), 1.96
(3 overlapping dd, 3H), 1.75 (dd, J ) 13.7, 6.4 Hz, 1H), 1.12 (s +
d overlapping, 6H), 1.07 (s, 3H), 1.06 (s, 9H), 1.04 (s, 9H), 0.98
(d, J ) 7.4 Hz, 3H), 0.90 (s, 9H), 0.063 (s, 3H), 0.060 (s, 3H); 13
C
NMR (125 MHz, CDCl3) δ 186.6, 184.7, 183.8, 171.3, 169.5, 152.5,
142.3, 139.3, 135.6, 135.5, 134.1, 133.7, 133.6, 130.6, 130.2, 129.8,
129.7, 129.6, 129.5, 127.7, 127.6, 125.7, 124.3, 104.8, 89.7, 87.1,
86.3, 65.6, 65.0, 63.6, 62.9, 59.3, 44.6, 44.0, 37.9, 36.2, 29.7, 29.4,
28.6, 26.8, 25.9, 21.0, 20.6, 19.3, 19.2, 18.7, 18.6, -5.1; FT-IR
(neat) 2956, 2929, 2856, 1758, 1660, 1627, 1455, 1360, 1250, 1112,
703 cm-1; HRMS (ESI) calcd for C70H90O10Si3Na [M + Na]+
1197.5740, found 1197.5763 m/z.
Acknowledgment. Financial support by the National Insti-
tutes of Health (GM026782) is gratefully acknowledged. T.K.T.
thanks the NIH for a Postdoctoral Fellowship (GM068298).
Supporting Information Available: Experimental procedures
and full spectroscopic data for all new compounds in Scheme 2.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO061059C
6922 J. Org. Chem., Vol. 71, No. 18, 2006