Studies on the synthesis of chlorothricolide: Diastereo- and enantioselective syntheses of model top-half spirotetronate units

Article abstract of DOI:10.1021/jo980379w

Highly enantio- and diastereoselective syntheses of spirotetronates 9 and 10, corresponding to the top-half fragment of chlorothricolide, are described. Key steps in these syntheses are the Diels-Alder reactions of trienes 11 and 12 with the chiral dienop

Full text of DOI:10.1021/jo980379w

J . Org. Chem. 1998, 63, 5473-5482
5473
Stu d ies on th e Syn th esis of Ch lor oth r icolid e: Dia ster eo- a n d
En a n tioselective Syn th eses of Mod el Top -Ha lf Sp ir otetr on a te
Un its
William R. Roush*,1 and Richard J . Sciotti2
Department of Chemistry, Indiana University, Bloomington, Indiana 47405, and Department of
Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055
Received March 2, 1998
Highly enantio- and diastereoselective syntheses of spirotetronates 9 and 10, corresponding to the
top-half fragment of chlorothricolide, are described. Key steps in these syntheses are the Diels-
Alder reactions of trienes 11 and 12 with the chiral dienophile (R)-6 that provide cycloadducts 18
and 38 with remarkably high stereoselectivity. These reactions exhibit exquisite regioselectivity
for addition across the trisubstituted C(18)-C(21) diene unit; they also proceed with remarkable
orientational control of the dienophile with respect to the C(18)-C(21) diene, as well as with excellent
exo diastereofacial selectivity on the part of the chiral dienophile, (R)-6. Results are presented
indicating that it is not necessary to control the stereochemistry of the C(20)-C(21) trisubstituted
olefin of the triene precursors, as this unit readily isomerizes under the conditions of the Diels-
Alder reaction. Remarkably, the seemingly unreactive (E,E,E)-triene isomers (E,E,E)-11 and
(E,E,E)-12 can be used as the starting material for the Diels-Alder reactions, and the desired
exo-cycloadducts 18 and 38 are still obtained in good yield, without products of competitive Diels-
Alder reactions of the disubstituted C(16)-C(19) dienes being observed.
Chlorothricolide (1) is the aglycon of the spirotetronate
antibiotic chlorothricin that was isolated from Strepto-
myces antibioticus by Keller-Schlierlein and co-workers
in 1969.3,4 Somewhat more complex, but structurally
related, spirotetronate antibiotics kijanimicin,5 tetrocar-
cin,6 and PA-46101 A and B7 have been isolated more
recently. The significant challenges posed by these
structures have stimulated numerous studies on the
synthesis of the aglycons chlorothricolide (1),8-31 kijano-
lide (2), and tetronolide (3).32-50 Total syntheses of
tetronolide44 and 24-O-methylchlorothricolide26 have been
accomplished by Yoshii, and an enantioselective total
synthesis of (-)-chlorothricolide31 and a formal synthesis
of tetronolide50 have been achieved in our laboratory.
We report herein the details of our efforts to define a
(23) Okumura, K.; Okazaki, K.; Takeda, K.; Yoshii, E. Tetrahedron
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(1) Address correspondence to this author at the University of
Michigan.
(2) Taken in part from the1994 Ph.D. Thesis of R.J .S., Indiana
University, Bloomington, IN.
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2071.
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Helv. Chim. Acta 1972, 55, 2094.
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Macfarlane, R. D.; Stephens, R. L. J . Chem. Soc., Perkin Trans. 1 1983,
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J . S.; Moriarty, K. J . J . Org. Chem. 1991, 56, 1192.
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S0022-3263(98)00379-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/21/1998

5474 J . Org. Chem., Vol. 63, No. 16, 1998
Roush and Sciotti
excellent regioselectivity and exo-selectivity, thereby
serving as the key steps in highly stereoselective syn-
thesis of the model top-half spirotetronate fragments 9
and 10.30 The full details of these investigations are
reported herein.
workable strategy for the synthesis of the top-half
spirotetronate fragment of chlorothricolide, 1.30 These
investigations were strongly influenced by the results of
our syntheses of the top-half fragments of kijanolide (2)
and tetronolide (3) via the Diels-Alder reactions of
trienes 440,47 and 546,50 with the chiral dienophile (R)-
6.51-53 These Diels-Alder reactions occurred with excel-
lent site and regioselectivity. Products of addition across
the 4,6-diene unit were observed exclusively in both
cases, and in all products the orientation of the dienophile
and diene was the same as in 7 and 8. Virtually complete
diastereofacial selectivity with respect to the chiral
dienophile (R)-6 was also achieved. Finally, and most
importantly, these reactions also proceeded with remark-
ably high exo-selectivity, as required for the synthesis
of the spirotetronate units of 2 and 3.
Despite this excellent precedent, it was not obvious at
the outset that this Diels-Alder sequence could be
applied as successfully to the synthesis of chlorothricolide
top-half fragments 9 or 10, since the requisite triene
precursors 11 and 12 have two diene units that in
principle can react with (R)-6. Several reports of Diels-
Alder reactions of trienes with substitution patterns the
same as 11 and 12 have indicated that up to 15% of
products resulting from addition to the disubstituted
diene are sometimes obtained.23,54-56 Fortunately, de-
spite these initial concerns, we found that the Diels-
Alder reactions of 11 and 12 with (R)-6 proceed with
Resu lts a n d Discu ssion
Condensation of the known diene aldehyde 1347 with
methyl (triphenylphosphoranylidene)acetate in refluxing
CH2Cl2 provided the trienoate 11 in 90% yield. Initial
Diels-Alder reactions were performed by using racemic
14 as the dienophile.51 A mixture of trienoate 11 and 14
(1.6 equiv) in trichloroethylene (3.0 M in 11) was heated
at 100 °C for 14 h in the presence of BHT as a radical
inhibitor. This provided a 6:1 mixture (1H NMR analysis)
of two cycloadducts 15 and 16 in 84% yield. These
compounds were determined to be diastereofacial iso-
mers, differing with respect to the face of the dienophile
that combined with the diene,51 by methanolysis of each
to the (racemic) R-hydroxy ester 17. Cycloadduct 15 was
subsequently determined to be the product of an exo
Diels-Alder reaction by correlation with cycloadduct
18.57
Because other studies in our laboratory indicated that
dienophile 6 is more diastereofacially selective than 14,
subsequent Diels-Alder reactions were performed with
(R)-6 (1.7 equiv). Surprisingly, whereas the reaction of
11 and 14 proceeded in excellent yield (85%), the analo-
gous reaction of 11 and (R)-6 provided a 15:1 mixture of
cycloadducts 18 (exo) and 19 (endo) in 52-60% yield. Also
(46) Roush, W. R.; Koyama, K. Tetrahedron Lett. 1992, 33, 6227.
(47) Roush, W. R.; Brown, B. B. J . Org. Chem. 1993, 58, 2151.
(48) Roush, W. R.; Brown, B. B. J . Am. Chem. Soc. 1993, 115, 2268.
(49) Boeckman, R. K., J r.; Wrobleski, S. T. J . Org. Chem. 1996, 61,
7238.
(50) Roush, W. R.; Reilly, M. L.; Koyama, K.; Brown, B. B. J . Org.
Chem. 1997, 62, 8708.
(51) Roush, W. R.; Brown, B. B. J . Org. Chem. 1992, 57, 3380.
(52) Roush, W. R.; Essenfeld, A. P.; Warmus, J . S.; Brown, B. B.
Tetrahedron Lett. 1989, 30, 7305.
(53) Mattay, J .; Mertes, J .; Maas, G. Chem. Ber. 1989, 122, 327.
(54) Corey, E. J .; Snider, B. B. J . Am. Chem. Soc. 1972, 94, 2549.
(55) Stork, G.; Nakahara, Y.; Nakahara, Y.; Greenlee, W. J . J . Am.
Chem. Soc. 1978, 100, 7775.
(57) The exo stereochemistry of 15 was also assigned by comparison
of its characteristic 1H NMR data with that of the analogous exo
cycloadduct in the kijanolide series (ref 47).
(56) Vedejs, E.; Ahmad, S. Tetrahedron Lett. 1988, 29, 2291.

Studies on the Synthesis of Chlorothricolide
J . Org. Chem., Vol. 63, No. 16, 1998 5475
obtained was 20-25% of recovered 11 as a 2:1 mixture
of the E,E,E and E,E,Z isomers. An analogous olefin
isomerization has been observed by Yoshii with a related
triene.26 Attempts to suppress the isomerization of the
trisubstituted olefin of 11 by performing the Diels-Alder
reaction with highly purified solvents and reagents, in
the presence of BHT as a radical inhibitor, or in the
presence of potential acid scavengers (e.g., BSA) were
unsuccessful. Accordingly, we resubjected the 2:1 mix-
ture of (E,E,E)- and (E,E,Z)-11 to the reaction conditions,
in anticipation that (E,E,E)-11 would rapidly react with
(R)-6 while (E,E,E)-11 would reequilibrate with (E,E,Z)-
11. This experiment again provided a ca. 15:1 mixture
of 18 and 19 (55-60%) along with additional amounts of
the (E,E,E)- and (E,E,Z)-11 isomer mixture (2:1) that was
recovered in up to 20% yield. In this way, the yield of
cycloadducts 18 and 19 was 62-70% after one recycle of
11. Interestingly, no other cycloadducts were observed,
indicating that (E,E,Z)-11 reacts selectively with (R)-6,
which is surprising given that (E,E,E)-11 contains a
potentially reactive diene unit. Yoshii also has noted that
the trisubstituted olefin of an analogous triene isomerizes
under the conditions of the intramolecular Diels-Alder
reaction employed in his synthesis of 24-O-methylchlo-
rothricolide;26 however, to the best of our knowledge our
results with (E,E,E)- and (E,E,Z)-11 are the first concrete
demonstration that the (E,E,E)-triene is substantially
less reactive than the E,E,Z isomer and that this isomer-
ization can be used productively for preparative purposes.
We subsequently employed this facile isomerization in
our total synthesis of chlorothricolide.31
nOe data summarized in the accompanying three-
dimensional structures, particularly those between the
t-Bu and C(21)-Me (1%) in 18, vs the nOe’s observed
between the t-Bu and H(21) (1.2%) and between H(16)
and H(22ax) in 19.
The stereostructural assignments for cycloadducts 18
and 19 were based initially on spectroscopic correlations
with cycloadducts 7 (exo) and 20 (endo) from the kijano-
lide series.47 In particular, exo cycloadduct 18 exhibited
two small to moderate coupling constants between H(21)
and H(22) (J 21,22(ax) ) 6.6 Hz; J 21,22(eq) ) 3.6 Hz), charac-
teristic of a cycloadduct with an axial C(21)-Me group,
whereas the endo cycloadduct exhibited one large (J 21,22(ax)
) 11.2 Hz) and one moderate (J 21,22(ax) ) 6.2 Hz) coupling
constant between H(21) and H(22). The latter data
require that the C(21)-Me group occupies an equatorial
position in 19. Also, a W-coupling of 1.2 Hz between
H(22eq) and H(18) was observed in the 1H NMR spectrum
of 19, indicating that the unsaturated side chain at C(18)
occupies an axial position with respect to the cyclohexenyl
ring. These J data are completely consistent with the
Cycloadduct 18 was elaborated to the chlorothricolide
top-half fragment 9 as follows. Treatment of 18 with 4
equiv of DIBAL-H in CH2Cl2 at -78 °C provided a 4:1
mixture of hemiacetals 21 in 95% yield. (Attempts to
accomplish the selective reduction of the R,â-unsaturated
ester unit of 18 were unsuccessful.) The primary alcohol
of 21 was selectively protected as a TBS ether using 1.1

5476 J . Org. Chem., Vol. 63, No. 16, 1998
Roush and Sciotti
equiv of TBS-Cl and imidazole in DMF. The hemiacetal
unit was then oxidized using the Swern protocol,58
thereby providing lactone 23 in 78% overall yield. Meth-
anolysis of 23 with K2CO3 in MeOH at 0 °C followed by
DCC coupling59 of the resulting tertiary R-hydroxy ester
with BnOCH2CO2H60 provided 24 in excellent yield. The
same intermediate (albeit racemic) was prepared by an
analogous sequence starting from 15, the major cycload-
duct of the Diels-Alder reaction of 11 and racemic 14.
Finally, closure of the spirotetronate substructure was
accomplished by Dieckmann cyclization8,47 of the lithium
enolate generated from 24. Addition of MOM-Cl and
HMPA directly47 to the Dieckmann reaction mixture
provided 9 in 30-40% yield. However, the chlorothri-
colide top-half fragment 9 was obtained in much better
yield if the intermediate tetronic acid, isolated by an
extractive workup, was treated with MOM-Cl and i-Pr2-
NEt in CH2Cl2. In this way, 9 was obtained in 73% yield
for the two-step sequence.
the synthetic bottom-half fragment (e.g., 27, X ) -SO2-
Ar) was used as the nucleophilic component in an
alkylation reaction with a top-half electrophilic species
28 (X ) Br, I, etc.), we would have to find conditions to
minimize addition of the C(14)-carbanion to the C(1)
carboxylic ester functional group (perhaps best accom-
plished by using 27 with R ) Li). While use of the top-
half fragment as the nucleophilic component (30, W )
SO2Ar) in a reaction with an electrophilic bottom half (29,
X ) leaving group) might pose fewer complications, we
were apprehensive nonetheless about the prospects of
performing this coupling on such highly functionalized
intermediates.
It was apparent that these potential problems could
be avoided if the C(14)-C(15) bond was established
before either of the Diels-Alder reactions were per-
formed. We thus began to focus on hexaenoate 32 as a
key precursor to chlorothricolide. According to this
strategy, it would be necessary to effect a bimolecular
Diels-Alder reaction of (R)-6 with the C(18-21) diene
unit of 32 without addition of (R)-6 to either the C(16-
19) or the C(8-11) dienes. While it seemed probable that
the C(8-11) diene would be consumed rapidly by an
intramolecular Diels-Alder reaction with the C(2,3)-
enoate, it remained to be determined if the absence of
an electron-withdrawing substituent at C(15) of 32 would
influence the site selectivity of the Diels-Alder reaction
of (R)-6 and the C(16-21) triene unit of 32. The
carboalkoxy substituents of 4, 5, and 11 undoubtedly
perturb the FMO coefficients of the reactive triene system
relative to a triene lacking this polarizing substituent,62
and it was not absolutely certain that trienes 4, 5, and
11 were appropriate models for the behavior of 32.
Accordingly, we decided to address this issue by studying
the Diels-Alder reaction of (R)-6 with 12.
The stereochemistry of spirotetronate 9 was verified
by comparison of its characteristic H NMR data with
that for Yoshii’s advanced chlorothricolide intermediate
25, the stereochemistry of which was established by
single-crystal X-ray structure analysis.26
1
Finally, the enantiomeric purity of the series of inter-
mediates deriving from exo cycloadduct 18 was deter-
mined to be 98% ee by NMR analysis of the (S)-MTPA
and (R)-MTPA esters 26a and 26b.61 The 1H NMR
spectrum of 26a in C6D6 showed signals at δ 2.62 (br t,
1 H) and 0.80 (d, 3 H), whereas the corresponding signals
in the spectrum of 26b appeared at δ 2.75 (br t, 1 H) and
0.83 (d, 3 H).
Having completed an efficient, highly diastereo- and
enantioselective synthesis of the chlorothricolide top-half
fragment, we were ready to initiate studies on the
completion of the total synthesis. However, it was readily
apparent that establishing the C(14)-C(15) bond with
the top-half (e.g., 9) and bottom-half intermediates29 in
hand could be a significant challenge.17 For example, if
(58) Tidwell, T. T. Synthesis 1990, 857.
(59) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522.
(60) Manhas, M.; Amin, S.; Chawla, H. P. S.; Bose, A. K. J .
Heterocycl. Chem. 1978, 15, 601.
(61) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(62) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: New York, 1976.

Studies on the Synthesis of Chlorothricolide
J . Org. Chem., Vol. 63, No. 16, 1998 5477
partially isomerized (4-5:1) under these conditions.
Suspecting that this isomerization was promoted by
reversible addition of a “Pd-H” species (conceivably
generated by a competitive, minor Heck pathway)70
across the trisubstituted olefin, we performed the Suzuki
cross coupling in the presence of various Ag(I) salts (e.g.,
AgNO3, AgOAc, Ag2CO3), which are known to be effective
in suppressing olefin isomerizations in Heck reactions.71-73
However, all of these experiments resulted in consider-
ably lower yields of 36 (<5-40%) without suppression
of the olefin isomerization.
Although we were unable to synthesize 36 with the
level of stereoselectivity originally targeted, we pro-
gressed in anticipation that this stereochemical imperfec-
tion would not pose any problems at subsequent stages
of the synthesis (vide supra). Nevertheless, at least
initially, we separated the two isomers by preparative
HPLC (2% ethyl acetate/hexanes) and used isomerically
homogeneous (E,Z,Z)-36 in the subsequent exploratory
steps. The synthesis of the model triene 12 was com-
pleted by protection of the hydroxyl group as a TBS ether,
followed by removal of the bromine substituent via
metal-halogen exchange (n-BuLi, -100 °C, THF).74 This
two-step sequence provided 12 in 86% yield.
The Diels-Alder reaction was performed by heating a
mixture of (E,E,Z)-triene 12 and (R)-6 (1.8 equiv) in
trichloroethylene (2.0 M in 12) at 110 °C for 7 h. This
provided a 14:1 mixture of the exo (38) and endo (39)
isomers in 53% yield. The structural assignments for
these cycloadducts are based on correlations with spec-
troscopic data for the exo (18) and endo (19) adducts
obtained from the trienoate series. In addition to these
two products, a small amount (1-2%) of a third cyclo-
adduct was also isolated from the Diels-Alder reaction
mixture. This compound was tentatively assigned as the
second exo cycloadduct 40, the diastereofacial isomer of
38 resulting from addition of the diene to the more
hindered face of the dienophile.51 Finally, substantially
isomerized triene 12, a 5:1 mixture of the E,E,E and
E,E,Z isomers, was obtained in 44% yield. The latter
mixture was resubjected to the original Diels-Alder
conditions (1.7 equiv of (R)-6, 110 °C, 18 h, 2.0 M in
trichloroethylene), thereby providing an additional 25%
of a 14:1 mixture of cycloadducts 38 and 39 (56% based
on the recycled 12). Thus, the combined yield of 38 was
78% after one such recycle of 12.
It is indeed remarkable that the rate of olefin isomer-
ization of (E,E,E)-12 and the subsequent Diels-Alder
reaction with of (E,E,Z)-12 with (R)-6 is faster than the
Diels-Alder reaction of (R)-6 across the C(16-19) diene
unit of (E,E,E)-12. In fact, we have not detected products
resulting from addition across the disubstituted diene
unit of either triene isomer. The most compelling set of
data in support of this statement derives from an
experiment in which isomerically pure (E,E,E)-12, pre-
pared from the minor E,Z,E isomer of 35 generated in
the Kishi-modified Suzuki coupling, was treated with 2
The synthesis of triene 12 began with the Corey-Fuchs
olefination63 of the known aldehyde 33,47 which provided
dibromoolefin 34 in 81% yield.64 Cross coupling65 of 34
and vinylboronic acid 3566 using Kishi’s modification67
of the Suzuki protocol68,69 provided bromotriene 36 in 72%
yield. Surprisingly, the C(20,21)-trisubstituted olefin was
(63) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(64) Takai olefination of 33 provided the corresponding vinyl iodide
as a ca. 5:1 mixture of (E)- and (Z)-vinyl iodide isomers. We elected,
therefore, to pursue the synthesis of 12 via a cross-coupling reaction
of the dibromoolefin 34 in anticipation that the cross coupling would
be highly regioselective (cf. ref 65) and that subsequent reduction of
the resulting vinyl bromide would also proceed with good stereocontrol.
(65) Roush, W. R.; Moriarty, K. J .; Brown, B. B. Tetrahedron Lett.
1990, 31, 6509.
(69) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J . Am. Chem. Soc. 1989, 111, 314.
(70) Heck, R. Org. React. 1982, 27, 345.
(66) Vinylboronic acid 35 was prepared in 71% yield via the reaction
of 6-heptyn-1-ol with 2 equiv of catecholborane (neat, 75 °C, 14 h),
followed by aqueous workup and chromatographic purification.
(67) Uenishi, J .-i.; Beau, J .-M.; Armstrong, R. W.; Kishi, Y. J . Am.
Chem. Soc. 1987, 109, 4756.
(68) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J . Am.
Chem. Soc. 1985, 107, 972.
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(73) Grigg, R.; Loganathan, V.; Santhakumar, V.; Sridharan, V.;
Teasdale, A. Tetrahedron Lett. 1991, 32, 687.
(74) Parham, W. E.; Bradsher, C. V. Acc. Chem. Res. 1982, 15, 300.

5478 J . Org. Chem., Vol. 63, No. 16, 1998
Roush and Sciotti
In summary, we have demonstrated that the Diels-
Alder reactions of trienes 11 and 12 with the chiral
dienophile (R)-6 exhibit remarkably high diastereofacial
and exo selectivity. These reactions also proceed with
exquisite regioselectivity for addition across the trisub-
stituted C(18)-C(21) diene unit. In no cases were
products observed where the Diels-Alder reactions oc-
curred across the disubstituted C(16)-C(19) diene unit.
This study further demonstrated that it is not necessary
to control the stereochemistry of the C(20)-C(21) trisub-
stituted olefin of the triene precursors, since this unit
readily isomerizes under the conditions of the Diels-
Alder reaction. We have demonstrated that one can use
the seemingly unreactive (E,E,E)-triene isomers (e.g.,
(E,E,E)-12) as the starting materials and still obtain the
desired exo cycloadducts 15 and 38 in good yield. These
studies set the stage for completion of our highly stereo-
selective synthesis of (-)-chlorothricolide.31,75
equiv of (R)-6 at 110-120 °C in the presence of BHT
radical inhibitor. This experiment provided a 14:1
mixture of exo and endo cycloadducts 38 and 39 in 45%
yield. The recovered triene 12 (ca. 45%) was a 4.6:1
mixture of the E,E,E and E,E,Z olefin isomers.
Exp er im en ta l Section 76
Meth yl (2E,4E,6Z)-6-[(ter t-bu tyld ip h en ylsilyloxy)m e-
th yl]octa -2,4,6-tr ien oa te (11). To a solution of diene alde-
hyde 1347 (280 mg, 0.77 mmol) in CH2Cl2 (8.0 mL, 0.1 M) was
added methyl (triphenylphosphoranylidene)acetate (670 mg,
2.0 mmol), and then the mixture was heated to reflux and
allowed to stir for 10 h. The reaction mixture was cooled to
room temperature, diluted with hexanes (3 mL), and filtered
through a plug of silica gel. The filtrate was concentrated in
vacuo, and the crude product was purified by silica gel flash
column chromatography77 (8:1 hexanes-diethyl ether), afford-
ing triene 11 (271 mg, 90%) as a clear oil: TLC Rf ) 0.6 (3:1
1
hexanes-diethyl ether); H NMR (400 MHz, CDCl3) δ 7.70-
7.64 (m, 4 H), 7.45-7.36 (m, 7 H), 6.55 (A of ABX, J ) 15.6,
10.6 Hz, 1 H), 6.54 (B of ABX, J ) 15.6, 0.6 Hz, 1 H), 5.88 (d,
J ) 15.2 Hz, 1 H), 5.89 (q, J ) 7.2 Hz, 1 H), 4.45 (s, 2 H), 3.83
(s, 3 H), 1.65 (d, J ) 7.6 Hz, 3 H), 1.10 (s, 9 H); IR (CDCl3)
1705, 1610 cm-1; HRMS for C26H32O3Si (M+) calcd 420.2121,
found 420.2136 m/z.
(2′R,3R,4S,6R)-Sp ir o-1-[(ter t-b u t yld ip h en ylsilyloxy)-
m et h yl]-3-(3-ca r bom et h oxyp r op -1-en yl)-6-m et h ylcyclo-
h ex-1-en e-[4,5′]-2′-ter t-bu tyl-1′,3′-d ioxola n -4′-on e (18). A
solution of triene (E,E,Z)-11 (225 mg, 0.54 mmol) in degassed
trichloroethylene (134 µL, 4.0 M) that had been purified by
passing through a short column of basic alumina was added
to a presilylated (BSA) resealable Carius tube. To this solution
The enantiomeric purity of exo cycloadduct 38 was
determined to be 98% ee by Mosher ester analysis61 of
the diol obtained by LiAlH4 reduction. Methanolysis of
the dioxolanone system of 38 followed by DCC-mediated
coupling of the resulting R-hydroxy methyl ester with
benzyloxyacetic acid60 provided diester 41 in 76% yield.
Finally, Dieckmann cyclization8 of 41 followed by protec-
tion of the tetronic acid as a MOM ether provided the
targeted spirotetronate 10 in 69% yield.
(75) Roush, W. R.; Sciotti, R. J . J . Am. Chem. Soc. 1998, 119,
submitted for publication.
(76) For general experimental details, see: Roush, W. R.; Koyama,
K.; Curtin, M. L.; Moriarty, K. J . J . Am. Chem. Soc. 1996, 118, 7502.
Unless otherwise noted, all compounds purified by chromatography
are sufficiently pure (>95% by 1H NMR analysis) for use in subsequent
reactions.
(77) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

Studies on the Synthesis of Chlorothricolide
J . Org. Chem., Vol. 63, No. 16, 1998 5479
were added dienophile (R)-651 (145 mg, 0.91 mmol) and a
crystal of BHT (radical inhibitor). The Carius tube was sealed
under an argon atmosphere and heated at 120 °C for 14 h. 1H
NMR analysis (400 MHz) of the crude reaction mixture
revealed a 16:1 mixture of two cycloadducts, along with
residual triene that consisted of a 1:2 mixture of (E,E,Z)-10
and isomerized triene (E,E,E)-10. The reaction mixture was
concentrated in vacuo, and the crude product was purified by
silica gel flash column chromatography (20:1 hexanes-Et2O),
yielding a 16:1 mixture of cycloadducts 18 and 19 (160 mg,
52% yield) along with an inseparable mixture (1:2) of recovered
triene (E,E,Z)-10 and its isomer (E,E,E)-10 (48 mg, 21%).
Cycloadducts 18 and 19 were separated by preparative HPLC
(10% ethyl acetate-hexanes, 4 mL/min, 10 mm Whatman M9
silica gel column, retention time: 18, 14.1 min; 19, 19.4 min).
The recovered triene (48 mg of a 1:2 mixture of (E,E,Z)-10
and (E,E,E)-10) in trichloroethylene (23 µL, 4.0 M; again,
neutralized by elution through basic alumina) was added to a
presilylated (BSA) resealable Carius tube. To this solution
were then added dienophile (R)-6 (25 mg, 0.15 mmol) and a
crystal of BHT. The Carius tube was sealed and the mixture
heated at 120 °C for 28 h. The crude product was purified by
silica gel flash column chromatography (20:1 hexanes-diethyl
ether), giving additional cycloadduct 18 (30 mg, 57% yield).
The yield of adduct 18 (190 mg) was 64% from 11 after one
such recycle.
9 H), 1.06 (s, 9 H), 1.01 (d, J ) 6.8 Hz, 3 H); 13C NMR (100
MHz, CDCl3) (of anomeric mixture) δ 142.8, 141.8, 135.5,
135.4, 133.7, 133.6, 133.5, 133.3, 131.9, 130.8, 129.7, 129.7,
129.4, 127.7, 120.3, 120.0, 112.3, 108.7, 97.6, 85.2, 65.4, 65.1,
63.8, 63.6, 63.2, 42.7, 41.0, 36.3, 33.6, 32.9, 29.9, 29.3, 26.8,
24.2, 24.1, 23.4, 19.6, 19.3, 19.1; IR (CDCl3) 3610, 3430 (broad),
1655, 1585 cm-1; HRMS for C33H46O5Si calcd 550.3114, found
550.3120. Anal. Calcd for C33H46O5Si: C, 71.96; H, 8.42.
Found: C, 71.69; H, 8.12.
TBS Eth er 22. To a 23 °C solution of the lactol 21 (120
mg, 0.22 mmol) in DMF (440 µL, 0.5 M) were added imidazole
(37 mg, 0.55 mmol) and tert-butyldimethylsilyl chloride (43 mg,
0.28 mmol). The mixture was stirred for 14 h and then was
poured into a mixture of 1:1 hexanes-Et2O and 50% aqueous
brine solution. The aqueous layer was extracted with Et2O
(3 × 10 mL). The combined extracts were dried over Na2SO4
and concentrated in vacuo. The crude product was purified
by silica gel flash column chromatography (5:1 hexanes-Et2O),
yielding the mono-TBS ether 22 (125 mg, 89% yield) as an
inseparable 4:1 mixture of hemiacetal anomers: [R] ) -107°
1
(c 0.9, CH2Cl2); TLC Rf ) 0.34 (5:1 hexanes-Et2O); H NMR
(400 MHz, CDCl3) δ 7.69-7.66 (m, 4 H), 7.46-7.36 (m, 6 H),
5.85-5.48 (m, 3 H), 4,99 (d, J ) 8 Hz, 1 H), 4.76 (s, 1 H), 4.25-
4.11 (m, 4 H), 3.02 (m, 1 H), 2.54 (m, 1 H), 2.23 (d, J ) 9.2 Hz,
1 H), 1.77 (ddd, J ) 12.8, 6.0, 1.6 Hz, 1 H), 1.67-1.61 (m, 2
H), 1.06 (s, 9 H), 0.97 (d, J ) 6.8 Hz, 2 H), 0.94 (s, 9 H), 0.91
(s, 9 H), 0.07 (s, 6 H); 13C NMR (100 MHz, CDCl3; of anomeric
mixture) δ 142.5, 135.6, 135.50, 135.45, 133.83, 133.77, 133.7,
132.2, 131.6, 131.0, 129.6, 127.6, 120.4, 108.6, 97.7, 85.3, 65.1,
63.7, 41.2, 39.7, 37.3, 33.6, 33.0, 29.9, 26.8, 26.0, 24.24, 24.17,
19.3, 19.2, 18.4, -5.1; IR (CCl4) 3580, 3450, 1585, 1480, 1470,
1460, 1425, 1360 cm-1; HRMS for C39H60O5Si2 (M+) calcd
664.3979, found 664.4011.
Da ta for exo cycloa d d u ct 18: [R] ) -70.8 (c 1.9, hexanes);
TLC Rf ) 0.64 (2:1 hexanes-Et2O); 1H NMR (400 MHz, CDCl3)
δ 7.69-7.66 (m, 4 H), 7.46-7.36 (m, 6 H), 6.88 (dd, J ) 15.6,
8.8 Hz, 1 H), 5.98 (dd, J ) 15.6, 0.8 Hz, 1 H), 5.45 (dd, J )
2.8, 1.6 Hz, 1 H), 5.09 (s, 1 H), 4.22 (B of AB, J ) 13.6 Hz, 1
H), 4.19 (A of AB, J ) 13.6 Hz, 1 H), 3.76 (s, 3 H), 3.37 (d, J
) 8.8 Hz, 1 H), 2.64 (m, 1 H), 2.11 (dd, J ) 14.0, 6.8 Hz, 1 H),
1.80 (dd, J ) 14.0, 3.2 Hz, 1 H), 1.12 (d, J ) 7.2 Hz, 3 H), 1.06
(s, 9 H), 0.94 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 174.6,
166.3, 145.3, 142.7, 135.5 133.4, 129.7, 127.7, 124.9, 117.1,
109.5, 80.0, 65.4, 51.7, 44.6, 36.4, 34.9, 28.2, 26.8, 23.3, 19.5,
19.3; IR (CCl4) 1795, 1727, 1655, 1590 cm-1; HRMS for
C30H35O6Si (M+ - C4H9) calcd 519.2203, found 519.2203. Anal.
Calcd for C34H44O6Si: C, 70.80; H, 7.69. Found: C, 70.57; H,
7.46.
P a r tia l d a ta for m in or h em ia ceta l a n om er : 1H NMR
(400 MHz, CDCl3) δ 5.82 (ddt, J ) 15.6, 6.8, 1.6 Hz, 1 H), 5.18
(d, J ) 4.4 Hz, 1 H), 4.99 (d, J ) 8.8 Hz, 1 H), 3.36 (m, 1 H),
2.68 (d, J ) 4.8 Hz, 1 H), 2.40 (m, 1 H), 1.02 (d, J ) 6.8 Hz, 1
H), 0.91 (s, 9 H).
(2R,2′R,4S,5R)-Sp ir o-1-[(ter t-b u t yld ip h en ylsilyloxy)-
m eth yl]-2-m eth yl-5-[3-(ter t-bu tyldim eth ylsilyloxy)pr op-1-
en yl]cycloh ex-1-en e-[4,5′]-2′-ter t-b u t yl-1′,3′-d ioxola n -4′-
on e (23). To a -78 °C solution of oxalyl chloride (38 µL, 0.43
mmol) in CH2Cl2 (600 µL, 0.1 M) was added DMSO (42 µL,
0.55 mmol). After 10 min, a solution of lactol 22 (108 mg, 0.16
mmol) in CH2Cl2 (1 mL) was added. The mixture was stirred
for 1 h at -78 °C. Et3N (110 µL, 4.7 equivalents) was added,
and the reaction mixture was allowed to warm to room
temperature. The mixture was poured into saturated NaHCO3
solution (3 mL) and extracted with CH2Cl2 (3 × 15 mL). The
combined extracts were dried over Na2SO4 and concentrated
in vacuo. The crude product was purified by silica gel flash
column chromatography (10:1 hexanes-Et2O), yielding lactone
23 (95 mg, 88% yield) as a colorless oil: [R] ) -57.3° (c 1.86,
CH2Cl2); TLC Rf ) 0.6 (5:1 hexanes-Et2O); 1H NMR (400 MHz,
CDCl3) δ 7.70-7.67 (m, 4 H), 7.46-7.35 (m, 6 H), 5.75 (dt, J
) 15.2, 3.6 Hz, 1 H), 5.67 (dd, J ) 15.2, 8.0 Hz, 1 H), 5.48 (s,
1 H), 5.17 (s, 1 H), 4.20 (m, 4 H), 3.22 (d, J ) 8.0 Hz, 1 H),
2.59 (m, 1 H), 2.14 (dd, J ) 14.0, 7.2 Hz, 1 H), 1.78 (dd, J )
14.0, 2.0 Hz, 1 H), 1.13 (d, J ) 7.2 Hz, 3 H), 1.07 (s, 9 H), 0.94
(s, 9 H), 0.91 (s, 9 H), 0.07 (s, 6 H); 13C NMR (100 MHz, CDCl3)
δ 175.8, 141.0, 135.6, 135.5, 133.7, 133.63, 133.57, 129.6, 127.7,
127.6, 126.6, 120.1, 109.8, 81.0, 65.8, 62.9, 45.2, 36.7, 34.9, 27.9,
Da ta for en d o cycloa d d u ct 19: [R] ) +0.50 (c 0.4, CH2-
1
Cl2); TLC Rf ) 0.60 (2:1 hexanes-Et2O); H NMR (400 MHz,
C6D6) δ 7.69-7.65 (m, 4 H), 7.45-7.35 (m, 6 H), 7.20 (dd, J )
15, 8 Hz, 1 H), 5.93 (dd, J ) 15.5, 1.8 Hz, 1 H), 5.43 (m, 1 H),
4.89 (s, 1 H), 4.13 (A of AB, J ) 13.2 Hz, with additional allylic
coupling, 1 H), 4.01 (B of AB, J ) 13.6 Hz, 1 H), 3.38 (s, 3 H),
2.89 (m, 1 H), 2.45 (m, 1 H), 1.70 (ddd, J ) 13.9, 11.2 Hz, 1
H), 1.62 (dd, J ) 13.9, 6.2, 1.2 Hz, 1 H), 1.2-1.4 (m, 7 H), 1.15
(s, 9 H), 0.85-1.0 (m, 2 H), 0.80 (s, 9 H), 0.65 (d, J ) 6.8 Hz,
3 H); 13C NMR (100 MHz, CDCl3) δ 172.9, 166.3, 145.1, 142.4,
135.6, 135.4, 133.6, 133.4, 129.7, 123.6, 117.5, 107.8, 70.4, 65.1,
51.6, 42.0, 35.0, 34.5, 29.7, 27.5, 26.8, 23.4, 19.3, 18.3; IR (CCl4)
1800, 1730, 1650 cm-1; HRMS for C30H35O6Si (M+ - C4H9)
calcd 519.2203, found 519.2185.
La ctol 21 via DIBAL-H Red u ction of 18. To a -78 °C
solution of optically active lactone 23 (92 mg, 0.16 mmol) in
CH2Cl2 (1.6 mL, 0.1 M) was slowly added diisobutylaluminum
hydride (640 µL of a 1.0 M solution in hexanes, 0.64 mmol).
After 15 min, the reaction mixture was warmed to -15 °C.
The reaction was quenched with saturated Rochelle’s salt
solution (2 mL) and the mixture stirred for 4 h. The mixture
was extracted with CH2Cl2 (4 × 10 mL), and the combined
extracts were dried over Na2SO4 and concentrated in vacuo.
The crude product was purified by silica gel flash column
chromatography (gradient, 3:1 hexanes-Et2O to 1:1 hexanes-
Et2O), affording the lactol 21 (83 mg, 95% yield) as an
inseparable 4:1 mixture of anomers: [R] ) -132° (c 1.0, CH2-
26.9, 25.9, 23.4, 19.6, 19.3, 18.3, -5.3; IR (CCl4) 1795, cm-1
;
HRMS for C39H59O5Si2 (M+ + 1) calcd 663.3901, found 663.3873.
(1S,2R,5R)-1-(2-Ben zyloxya cet oxy)-2-[3-(ter t-b u t yld i-
methylsilyloxy)prop-1-enyl]-4-[(tert-butyldiphenylsilyloxy)-
m eth yl]-1-ca r bom eth oxy-5-m eth ylcycloh ex-3-en e (24). A
mixture of dioxolanone 23 (25 mg, 0.04 mmol) and K2CO3 (2
mg, catalytic) in methanol (0.4 mL, 0.1 M) was stirred for 10
h at ambient temperature. The reaction mixture was concen-
trated in vacuo, and then resultant oil was taken up in CH2-
Cl2 and washed with saturated NH4Cl solution (2 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The
combined extracts were dried over Na2SO4 and then concen-
trated in vacuo. The crude product was purified by silica gel
1
Cl2); TLC Rf ) 0.33 (2:1 hexanes-Et2O); H NMR (400 MHz,
CDCl3) δ 7.67-7.65 (m, 4 H), 7.45-7.36 (m, 6 H), 5.66-5.65
(m, 2 H), 5.62-5.58 (m, 1 H), 4.98 (s, 1 H), 4.75 (s, 1 H), 4.23-
4.12 (m, 4 H), 3.02 (m, 1 H), 2.52 (m, 1 H), 1.86-1.76 (m, 1
H), 1.69-1.59 (m, 1 H), 1.05 (s, 9 H), 0.97 (d, J ) 7.2 Hz, 3 H),
0.94 (s, 9 H); partial 1H NMR data for the minor anomer: δ
5.18 (s, 1 H), 4.92 (s, 1 H), 2.53 (m, 1 H), 2.40 (m, 1 H), 1.08 (s,

5480 J . Org. Chem., Vol. 63, No. 16, 1998
Roush and Sciotti
flash column chromatography (4:1 hexanes-Et2O), providing
the R-hydroxy ester (23 mg, 99% yield) as a colorless oil: [R]
) -42.7° (c 1.6, CH2Cl2); TLC Rf ) 0.24 (5:1 hexanes-Et2O);
1H NMR (400 MHz, CDCl3) δ 7.70-7.64 (m, 4 H), 7.45-7.36
(m, 6 H), 5.67-5.57 (m, 2 H), 5.51 (dd, J ) 1.6, 1.2 Hz, 1 H),
4.24 (B of AB, J ) 13.2 Hz, 1 H), 4.15 (A of AB, J ) 13.2 Hz,
1 H), 4.15 (d, J ) 3.2 Hz, 2 H), 3.77 (s, 3 H), 3.32 (s, 1 H), 2.71
(s, 1 H), 2.53 (m, 1 H), 2.20 (dd, J ) 13.6, 7.2 Hz, 1 H), 1.71
(dd, J ) 13.6, 3.6 Hz, 1 H), 1.13 (d, J ) 7.2 Hz, 3 H), 1.00 (s,
9 H), 0.09 (s, 9 H), 0.06 (s, 6 H); 13C NMR (100 MHz, CDCl3)
δ 176.4, 140.8, 135.6, 135.5, 133.9, 133.8, 133.4, 129.6, 128.4,
127.6, 120.9, 75.7, 66.0, 63.7, 61.5, 52.6, 45.3, 38.3, 29.7, 28.6,
(dd, J ) 14.0, 7.2 Hz, 1 H), 1.50 (d, J ) 14 Hz, 1 H), 1.15 (d,
J ) 7.2 Hz, 3 H), 1.06 (s, 9 H), 0.87 (s, 9 H), 0.04 (s, 3 H), 0.03
(s, 3 H); 13C NMR (100 MHz, CDCl3) δ 168.4, 159.3, 140.7,
136.4, 135.5, 134.0, 133.7, 133.6, 129.7, 128.9, 128.5, 128.4,
127.7, 126.3, 121.6, 120.4, 96.4, 80.6, 77.2, 73.6, 65.8, 63.6, 57.3,
43.1, 37.6, 29.7, 28.1, 26.9, 25.9, 20.1, 19.3, 18.4, -5.15, -5.19;
IR (CDCl3) 1750, 1675 cm-1; HRMS for C40H48O7Si2 (M+
-
C5H12) calcd 696.2939, found 696.2913. Anal. Calcd for
C
45H60O7Si2: C, 70.27; H, 7.86. Found: C, 70.35; H, 7.67.
(3Z)-1,1-Dibr om o-3-[(ter t-bu tyld ip h en ylsilyloxy)m eth -
yl]p en ta -1,3-d ien e (34). To a 0 °C solution of Ph3P (3.1 g,
12 mmol) in CH2Cl2 (7.2 mL, 0.5 M) was slowly added CBr4
(2.0 g, 5.9 mmol).63 The mixture was stirred for 5 min, and
then a solution of aldehyde 3347 (250 mg, 0.74 mmol) in CH2-
Cl2 (1 mL of solution predried over 4 Å molecular sieves) was
added via cannula. The reaction mixture was stirred at 0 °C
for 5 min and then was allowed to warm to room temperature.
The mixture was concentrated in vacuo, and the resultant solid
was washed with hexanes (3 × 150 mL). The combined
extracts were then washed with 50% H2O2 solution to oxidize
residual Ph3P. The extracts were concentrated in vacuo, and
the crude product was purified by silica gel flash column
chromatography (100% hexanes), providing the dibromide 34
(287 mg, 81% yield) as a pale yellow oil: TLC Rf ) 0.81 (10:1
26.9, 26.0, 19.9, 19.3, 18.4, -5.1; IR (CDCl3) 3535, 1725 cm-1
;
HRMS for C35H52O5Si2 (M+) calcd 608.3353, found 608.3337.
Anal. Calcd for C35H52O5Si2: C, 69.03; H, 8.61. Found: C,
69.28; H, 8.84. All physical and spectroscopic data for this
R-hydroxy ester were identical to those of the racemic com-
pound prepared by an analogous manner from 15, except for
the optical rotation.
To a solution of optically active hydroxy ester prepared
above (40 mg, 0.07 mmol) in CH2Cl2 (1.60 mL, 0.04 M) were
added R-benzyloxyacetic acid60 (55 mg, 0.33 mmol), dicyclo-
hexylcarbodiimide (68 mg, 0.33 mmol), and (dimethylamino)-
pyridine (2 mg, catalytic).59 The mixture was stirred for 16 h
1
and then passed through
a
thin plug of silica gel and
hexanes-Et2O); H NMR (400 MHz, CDCl3) δ 7.70-7.64 (m,
concentrated in vacuo. The crude product was purified by
silica gel flash column chromatography (10:1 hexanes-Et2O),
yielding ester 24 (45 mg, 92% yield) as a colorless oil: [R] )
-98.7° (c 18.2, CH2Cl2); TLC Rf ) 0.51 (2:1 hexanes-Et2O);
1H NMR (400 MHz, CDCl3) δ 7.70-7.67 (m, 4 H), 7.43-7.30
(m, 11 H), 5.59 (dt, J ) 15.2, 4.8 Hz, 1 H), 5.55-5.53 (m, 1 H),
5.49 (ddt, J ) 15.2, 8.4, 1.2 Hz, 1 H), 4.62 (B of AB, J ) 11.6
Hz, 1 H), 4.60 (A of AB, J ) 11.6 Hz, 1 H), 4.22-4.02 (m, 6
H), 3.80 (m, 1 H), 3.74 (s, 3 H), 2.40 (m, 1 H), 2.20 (ddd, J )
13.2, 5.8, 0.8 Hz, 1 H), 1.87 (dd, J ) 12.8, 10.4 Hz, 1 H), 1.03
(m, 12H), 0.89 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 171.3, 169.4, 139.2, 137.3, 135.6, 135.5,
133.8, 133.7, 132.8, 129.6, 128.4, 128.0, 127.9, 127.8, 127.7,
127.6, 122.4, 81.9, 73.2, 67.0, 65.4, 63.3, 57.1, 52.4, 43.4, 37.2,
36.0, 29.1, 26.7, 25.9, 19.3, 18.7, 18.3, -5.2; IR (CDCl3) 1755,
1732 cm-1; HRMS for C38H45O7Si (M+ - TBDMS) calcd
641.2934, found 641.2972. Anal. Calcd for C44H60O7Si2: C,
69.80; H, 7.99. Found: C, 69.83; H, 8.14.
4 H), 7.45-7.36 (m, 6 H), 7.03 (s, 1 H), 5.90 (ddq, J ) 14.6,
7.0, 0.8 Hz, 1 H), 4.32 (s, 2 H), 1.51 (dd, J ) 6.8, 0.8 Hz, 3 H),
1.08 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 137.8, 135.6, 135.5,
133.5, 129.7, 129.0, 127.7, 82.2, 60.3, 26.8, 19.2, 13.4; IR
(CDCl3) 3065, 3045, 3010, 2970, 2930, 2855, 1825, 1585 cm-1
;
HRMS for C18H17OSi79Br81Br (M+ - C4H9) calcd 435.9492,
found 435.9477. Anal. Calcd for C22H26OSiBr2: C, 53.45; H,
5.30. Found: C, 53.16; H, 5.32.
(6E,8Z,10Z)-8-Br om o-10-[(ter t-bu tyld ip h en ylsilyloxy)-
m eth yl]d od eca -6,8,10-tr ien -1-ol (36). To a solution of di-
bromoolefin 34 (1.27 g, 2.57 mmol) in degassed THF (25 mL,
0.1 M) was added Pd(PPh3)4 (400 mg, 0.33 mmol). The mixture
was stirred for 5 min, and then a solution of vinylboronic acid
3566 (570 mg, 3.6 mmol) in degassed TlOH solution (12.4 mL
of 0.3 M aqueous solution, 3.6 mmol) was added all at once.67
The reaction mixture was stirred for 20 min and then was
filtered through a plug of Celite. The aqueous layer was
removed and extracted with ethyl acetate (2 × 50 mL). The
combined extracts were concentrated in vacuo. The crude
product was purified by silica gel flash column chromatography
(2:1 hexanes-Et2O with 1% Et3N), giving triene 36 (970 mg,
72% yield) as a ca. 5:1 mixture of olefin isomers at the
trisubstituted double bond. The olefin isomers were separated
by preparative HPLC (29% EtOAc-hexanes, 5 mL/min, 10 mm
Whatman M9 silica gel column), yielding the desired triene
(E,Z,Z)-36 as a pale yellow oil: TLC Rf ) 0.23 (2:1 hexanes-
Et2O); 1H NMR (400 MHz, CDCl3) δ 7.69-7.67 (m, 4 H), 7.44-
7.35 (m, 6 H), 6.42 (s, 1 H), 6.10-6.00 (m, 3 H), 4.35 (s, 2 H),
3.56 (t, J ) 6.4 Hz, 2 H), 2.22 (dt, J ) 12.8, 6.4 Hz, 2 H), 1.64-
1.38 (m, 7 H), 1.55 (d, J ) 7.2 Hz, 3 H), 1.04 (s, 9 H); 13C NMR
(100 MHz, CDCl3) δ 135.7, 135.4, 135.2, 133.7, 130.7, 130.5,
129.6, 129.1, 127.6, 122.6, 62.9, 61.2, 32.6, 32.2, 29.1, 26.8, 25.3,
(5S,6R,9R)-2-Oxo-3-ben zyloxy-6-[3-(ter t-bu tyld im eth yl-
silyloxy)p r op -1-e n yl]-8-[(t er t -b u t yld ip h e n ylsilyloxy)-
m eth yl]-4-m eth oxym eth yloxy-9-m eth yl-1-oxa sp ir o-[4.5]-
d eca -3,7-d ien e (9). To a -78 °C solution of diester 24 (45
mg, 0.06 mmol) in THF (540 µL, 0.1 M) was added lithium
hexamethyldisilazide (120 µL of a 1.0 M solution in hexanes,
0.13 mmol). The reaction mixture was stirred for 2 h at -78
°C and then was allowed to warm to room temperature over a
period of 45 min. The reaction mixture was diluted with brine
(1 mL) and acidified to pH 1 with 2 N HCl. The aqueous layer
was extracted with ethyl acetate (4 × 2 mL), and the combined
extracts were concentrated in vacuo. The crude tetronic acid
was purified by silica gel flash column chromatography (3:1
hexanes-ethyl acetate), yielding the unstable tetronic acid.
The acid was dissolved in 30:1 mixture of CH2Cl2-HMPA (610
µL, 0.1 M) and cooled to 0 °C. Next, i-Pr2NEt (46 µL, 0.27
mmol) and MOM-Cl (11 µL, 0.15 mmol) were added. The
reaction mixture was stirred for 3 h at 0 °C and then was
warmed to room temperature and poured into saturated NH4-
Cl solution (500 mL). The aqueous layer was extracted with
ethyl acetate (4 × 3 mL), and the combined extracts were
concentrated in vacuo. The crude product was purified by
silica gel flash column chromatography (6:1 hexanes-EtOAc),
affording the protected tetronate 9 (33 mg, 73% yield over both
steps) as a white semisolid: [R] ) -46.5° (c 2.2, CH2Cl2); TLC
19.2, 13.5; IR (CCl4) 3630, 3400 (broad), 1640, 1587 cm-1
;
HRMS for C25H30O2SiBr (M+ - C4H9) calcd 469.1198, found
469.1229.
Partial data for (E,Z,E)-36: 1H NMR (400 MHz, CDCl3) δ
7.8-7.85 (m, 4 H), 7.3-7.2 (m, 6 H), 6.23-6.30 (m, 1 H), 6.25
(s, 1 H), 5.98-5.93 (m, 2 H), 4.41 (s, 2 H), 3.31 (t, J ) 6.4 Hz,
2 H), 1.96 (m, 2 H), 1.70 (d, J ) 7.2 Hz, 3 H), 1.4-1.2 (m, 6
H), 1.13 (s, 9 H).
(6E,8Z,10Z)-8-Br om o-1-(ter t-b u t yld im et h ylsilyloxy)-
10-[(ter t-b u t yld ip h en ylsilyloxy)m et h yl]d od eca -6,8,10-
tr ien e (37). To a 0 °C solution of bromotriene (E,Z,Z)-36 (310
mg, 0.59 mmol) in CH2Cl2 (2.5 mL, 0.2 M) was added Et3N
(395 µL, 2.8 mmol). The mixture was stirred for 10 min at 0
°C, and then TBS-OTf (270 mL, 1.2 mmol) was added. The
mixture was stirred for 2 h and then was washed with
saturated NaHCO3 solution. The aqueous layer was extracted
with Et2O (3 × 5 mL). The combined extracts were dried over
Na2SO4 and concentrated in vacuo. The crude product was
1
Rf ) 0.49 (4:1 hexanes-Et2O); H NMR (400 MHz, CDCl3) δ
7.70-7.65 (m, 4 H), 7.45-7.33 (m, 11 H), 5.63 (dt, J ) 15.6,
5.2 Hz, 1 H), 5.50 (s, 1 H), 5.43 (ddt, J ) 15.6, 8.4, 1.2 Hz, 1
H), 5.30 (s, 2 H), 5.11 (A of AB, J ) 10.8 Hz, 1 H), 5.05 (B of
AB, 10.8 Hz, 1 H), 4.22 (B of AB, J ) 13.2 Hz, 1 H), 4.16 (A of
AB, J ) 13.2 Hz, 1 H), 4.10 (dd, J ) 5.2, 1.2 Hz, 2 H), 3.47 (s,
3 H), 3.20 (d, J ) 8.4 Hz, 1 H), 2.58 (t, J ) 7.2 Hz, 1 H), 2.23

Studies on the Synthesis of Chlorothricolide
J . Org. Chem., Vol. 63, No. 16, 1998 5481
purified by silica gel flash column chromatography (2%
EtOAc-hexanes with 1% Et3N), yielding TBS ether 37 (343
mg, 90% yield) as a pale yellow oil: TLC Rf ) 0.81 (15:1
1.26 (m, 4 H), 1.13 (d, J ) 7.2 Hz, 3 H), 1.07 (s, 9 H), 0.94 (s,
9 H), 0.89 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3)
δ 175.9, 140.8, 135.6, 135.5, 135.3, 133.63, 133.61, 129.6,
127.64, 127.59, 127.1, 120.7, 109.9, 81.2, 65.8, 63.1, 45.6, 36.7,
34.9, 32.7, 32.6, 31.6, 28.9, 27.8, 26.8, 26.0, 25.3, 23.4, 22.6,
19.6, 19.3, 18.4, 14.1, -5.3; IR (neat) 1792, 1585 cm-1; HRMS
for C43H67O5Si2 (M++ 1) calcd 719.4527, found 719.4559. Anal.
Calcd for C43H66O5Si2: C, 71.82; H, 9.25. Found: C, 72.10; H,
8.97.
1
hexanes-Et2O); H NMR (400 MHz, CDCl3) δ 7.70-7.68 (m,
4 H), 7.45-7.36 (m, 6 H), 6.42 (s, 1 H), 6.15-6.01 (m, 3 H),
4.35 (s, 2 H), 3.62 (t, J ) 6.8 Hz, 2 H), 2.21 (dt, J ) 12.8, 6.8
Hz, 2 H), 1.59-1.33 (m, 9 H), 1.05 (s, 9 H), 0.91 (s, 9 H), 0.06
(s, 6 H); 13C NMR (100 MHz, CDCl3) δ 135.7, 135.3, 133.7,
130.6, 130.4, 129.6, 129.1, 127.6, 122.7, 63.2, 61.2, 32.7, 32.3,
29.1, 26.8, 26.0, 25.4, 19.3, 18.4, 13.5, -5.2; IR (CCl4) 3070,
3045, 2950, 2930, 2890, 2860, 1587 cm-1; HRMS for C35H53O2-
Si2Br (M+) calcd 640.2768, found 640.2786.
Da ta for en d o cycloa d d u ct 39: [R] ) 66.2° (c 1.3; CH2-
1
Cl2); H NMR (400 MHz, CDCl3) δ 7.70-7.67 (m, 4 H), 7.45-
7.33 (m, 6 H), 5.47-5.40 (m, 2 H), 5.33-5.27 (m, 1 H), 5.30 (s,
1 H), 4.28 (B of AB, J ) 13.2 Hz, 1 H), 4.11 (A of AB, J ) 13.2
Hz, 1 H), 3.58 (t, J ) 6.8 Hz, 2 H), 3.03 (m, 1 H), 2.57 (m, 1
H), 2.02 (m, 2 H), 1.76 (d, J ) 9.6 Hz, 2 H, partially obscured),
1.50 (apparent quintet, J ) 7.0 Hz, 2 H), 1.39-1.25 (m, 4 H),
1.05-1.03 (m, 12 H), 0.97 (s, 9 H), 0.88 (s, 9 H), 0.04 (s, 6 H);
13C NMR (100 MHz, CDCl3) δ 173.4, 140.0, 135.6, 135.5, 134.2,
133.9, 133.6, 130.6, 129.6, 127.8, 127.6, 127.5, 120.6, 107.3,
80.3, 65.5, 63.3, 42.4, 34.9, 34.5, 32.7, 32.5, 29.7, 29.1, 27.4,
26.8, 26.0, 25.3, 23.4, 19.3, 18.4, 18.4, -5.2; IR (CCl4) 1798,
1480 cm-1; HRMS for C39H57O5Si2 (M+ - C4H9) calcd 661.3744,
found 661.3709.
(6E,8E,10Z)-1-(ter t-Bu t yld im et h ylsilyloxy)-10-[(ter t-
bu tyld ip h en ylsilyloxy)m eth yl]d od eca -6,8,10-tr ien e (12).
To a -100 °C solution (Et2O-liquid N2 bath) of bromo triene
37 (301 mg, 0.05 mmol) in THF (4.6 mL, 0.1 M) was added
dropwise n-BuLi (260 µL of a 2.5 M solution in hexanes, 0.07
mmol). The solution immediately turned yellow. After 10 min
at -100 °C, the mixture was diluted with MeOH (1 mL),
warmed to room temperature, and concentrated in vacuo. The
crude product was purified by silica gel flash column chroma-
tography (10:1 hexanes-Et2O with 1% Et3N), yielding triene
12 (252 mg, 95% yield) as a colorless oil: TLC Rf ) 0.67 (15:1
1
hexanes-Et2O); H NMR (400 MHz, CDCl3) δ 7.73-7.70 (m,
P a r tia l d a ta for exo′ cycloa d d u ct 40: [R] ) 37.3° (c 0.3;
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.70-7.66 (m, 4 H),
7.45-7.35 (m, 6 H), 5.51 (dt, J ) 15.6, 6.8 Hz, 1 H), 5.47 (m,
1 H), 5.31 (ddt, J ) 15.6, 8.8, 1.2 Hz, 1 H), 5.14 (s, 1 H), 4.22
(B of AB, J ) 13.2 Hz, 1 H), 4.13 (A of AB, J ) 13.2 Hz, 1 H),
3.58 (t, J ) 6.8 Hz, 2 H), 3.20 (d, J ) 8.4 Hz, 1 H, partially
obscured), 2.54 (m, 1 H), 1.99-1.84 (m, 4 H), 1.49 (m, 2 H),
1.34-1.19 (m, 13 H), 1.08 (d, J ) 6.8 Hz, 3 H), 1.06 (s, 9 H),
4 H), 7.46-7.37 (m, 6 H), 6.37 (dd, J ) 15.2, 10.6 Hz, 1 H),
6.07 (dd, J ) 15.2, 8.8 Hz, 2 H), 5.66-5.56 (m, 2 H), 4.36 (s, 2
H), 3.62 (t, J ) 6.8 Hz, 2 H), 2.11 (dt, J ) 14.4, 7.2 Hz, 2 H),
1.57-1.31 (m, 9 H), 1.05 (s, 9 H), 0.90 (s, 9 H), 0.06 (s, 6 H);
13C NMR (100 MHz, CDCl3) δ 137.8, 135.7, 135.6, 133.8, 132.5,
131.2, 129.5, 128.2, 128.1, 127.6, 63.3, 58.6, 32.81, 32.75, 29.7,
29.2, 26.8, 26.0, 25.4, 19.3, 18.4, 13.8, -5.2; IR (CCl4) 3070,
3045, 3015, 2960, 2935, 2860, 1470, 1460, 1425 cm-1; HRMS
for C31H45O2Si2 (M+ - C4H9) calcd 505.2958, found 505.2947.
(2′R,3R,4S,6R)-Sp ir o-3-[7-(ter t-bu tyld im eth ylsilyloxy)-
h ep t -1-en yl]-1-[(ter t-b u t yld ip h en ylsilyloxy)m et h yl]-6-
m eth ylcycloh ex-1-en e-[4,5′]-2′-ter t-bu tyl-1′,3′-d ioxola n -4′-
on e (38). A solution of triene 12 (250 mg, 0.44 mmol) in
degassed trichloroethylene (220 µL, 2.0 M; the trichloroeth-
ylene was passed through a short column of basic alumina
before use) was added to a presilylated (BSA) resealable Carius
tube. To this solution were added (R)-651 (139 mg, 0.88 mmol)
and a crystal of BHT (radical inhibitor). The Carius tube was
sealed under an argon atmosphere, and the mixture was
heated at 110 °C for 7 h. The reaction mixture was concen-
trated in vacuo. 1H NMR analysis (400 MHz) of the crude
reaction mixture revealed a 16:1 mixture of two major cy-
cloadducts. The product mixture was separated by silica gel
flash column chromatography (20:1 hexanes-Et2O), yielding
a mixture of the three cycloadducts (168 mg, 53% yield), along
with an inseparable (1:5) mixture of recovered triene, consist-
ing of (E,E,E)-30 and isomerized triene (E,E,E)-30 (major in
this mixture) (141 mg, 44%).
0.88 (s, 9 H), 0.04 (s, 6 H); IR (CCl4) 3065, 3045, 1795 cm-1
.
Met h yl (1S,2R,5R)-1-(2-Ben zyloxya cet oxy)-2-[7-(ter t-
b u t yld im e t h ylsilyloxy)h e p t -1-e n yl]-4-[(t er t -b u t yld i-
p h en ylsilyloxy)m eth yl]-5-m eth ylcycloh ex-3-en e ca r box-
yla te (41). A mixture of exo cycloadduct 38 (79 mg, 0.11
mmol) and K2CO3 (16 mg, 0.12 mmol) in a 4:1 mixture of
methanol and THF (1.5 mL, 0.07 M) was stirred for 6 h and
then was concentrated in vacuo. The resultant oil was taken
up in CH2Cl2 and washed with saturated NH4Cl solution. The
aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The
combined extracts were dried over Na2SO4 and concentrated
in vacuo. The crude product was purified by silica gel flash
column chromatography (5:1 hexanes-Et2O), providing the
corresponding tertiary R-hydroxy ester (62 mg, 85% yield) as
a colorless oil: [R] ) -41.9° (c 1.2, CH2Cl2); TLC Rf ) 0.58
1
(3:1 hexanes-Et2O); H NMR (400 MHz, CDCl3) δ 7.70-7.66
(m, 4 H), 7.45-7.36 (m, 6 H), 5.55-5.46 (m, 2 H), 5.35 (ddt, J
) 15.6, 8.0, 1.2 Hz, 1 H), 4.25 (B of AB, J ) 12.8 Hz, 1 H),
4.14 (A of AB, J ) 12.8 Hz, 1 H), 3.76 (s, 3 H), 3.59 (t, J ) 6.4
Hz, 2 H), 3.25 (d, J ) 8.0 Hz, 1 H), 2.54 (m, 1 H), 2.20 (dd, J
) 13.6, 7.2 Hz, 1 H), 2.02 (dt, J ) 13.6, 7.2 Hz, 1 H), 1.71 (dd,
J ) 13.6, 3.2 Hz, 1 H), 1.51 (apparent quintet, J ) 6.4 Hz, 2
H), 1.39-1.26 (m, 6 H), 1.13 (d, J ) 7.6 Hz, 3 H), 1.06 (s, 9 H),
0.89 (s, 9 H), 0.04 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 176.5,
140.5, 135.6, 135.5, 134.9, 133.8, 133.7, 129.6, 127.8, 127.6,
121.4, 75.6, 66.0, 63.2, 52.6, 45.8, 38.0, 32.7, 32.6, 29.2, 28.4,
26.8, 26.0, 25.3, 19.9, 19.3, 18.4, -5.3; IR (neat) 3400 (broad),
1730, 1650 cm-1; HRMS for C35H51O5Si2 (M+ - C4H9) calcd
607.3275, found 607.3218. Anal. Calcd for C39H60O5Si2: C,
70.43; H, 9.09. Found: C, 70.16; H, 8.85.
The recovered triene 30 (141 mg, 0.25 mmol; a 5:1 mixture
favoring the (E,E,E)-isomer) was resubjected to the Diels-
Alder reaction with (R)-6 (78 mg, 0.5 mmol) in trichloroeth-
ylene (125 µL, 2.0 M) at 120 °C for 18 h in the presence of a
crystal of BHT. The crude product mixture was separated by
silica gel flash column chromatography (20:1 hexanes-Et2O),
giving additional quantities of the cycloadduct mixture (83 mg).
The combined yield of the three cycloadducts was 78% (251
mg) overall from 12 after one such recycle of recovered triene.
The individual cycloadducts were separated by preparative
HPLC (3% ethyl acetate-hexanes, 4 mL/min, 10 mm What-
man M9 silica gel column) to give exo cycloadduct 38 (180 mg,
72%), 11.9 min; endo cycloadduct 39 (13 mg, 6.7%), 13.9 min;
and exo′ cycloadduct 40 (3 mg, 1.3%), 16.4 min.
A solution of the above R-hydroxy ester (22 mg, 0.03 mmol)
in CH2Cl2 (820 µL, 0.1 M) was treated with DCC (34 mg; 0.17
mmol), R-benzyloxyacetic acid60 (27 mg, 0.17 mmol), and
catalytic DMAP.59 The mixture was stirred for 16 h at ambient
temperature and then was filtered through a plug of glass
wool. The filtrate was concentrated in vacuo, and the crude
ester was purified by silica gel flash column chromatography
(7:2 hexanes-Et2O), producing 41 (24 mg, 89% yield) as a
colorless oil: [R] ) -108.9° (c 1.0, CH2Cl2); TLC Rf ) 0.76 (3:1
Da ta for th e exo cycloa d d u ct 38: [R] ) -54.7° (c 1.1,
1
CH2Cl2); TLC Rf ) 0.43 (15:1 hexanes-Et2O); H NMR (400
MHz, CDCl3) δ 7.70-7.67 (m, 4 H), 7.46-7.36 (m, 6 H), 5.63
(dt, J ) 15.2, 6.8 Hz, 1 H), 5.43 (d, J ) 1.2 Hz, 1 H), 5.35 (dd,
J ) 15.2, 8.8 Hz, 1 H), 5.12(s, 1 H), 4.23 (B of AB, J ) 13.2
Hz, 1 H), 4.16 (A of AB, J ) 13.2 Hz, 1H), 3.59 (t, J ) 6.8 Hz,
2H), 3.15 (d, 8.8 Hz, 1H), 2.59 (m, 1H), 2.13 (dd, J ) 14.0, 7.2
Hz, 1 H), 2.04 (dt, J ) 13.6, 6.8 Hz, 2H), 1.77 (dd, J ) 14.0,
2.0 Hz, 1H), 1.52 (apparent quintet, J ) 7.2 Hz, 2H), 1.39-
1
hexanes-Et2O); H NMR (400 MHz, CDCl3) δ 7.70-7.68 (m,
4 H), 7.45-7.31 (m, 11 H), 5.51-5.44 (m, 2 H), 5.21 (dd, J )
15.2, 8.8 Hz, 1 H), 4.62 (B of AB, J ) 11.4 Hz, 1 H), 4.61 (A of
AB, J ) 11.4 Hz, 1 H), 4.22 (B of AB, J ) 12.8 Hz, 1 H), 4.11
(B of AB, J ) 16.4 Hz, 1 H), 4.07 (A of AB, J ) 12.8 Hz, 1 H),

5482 J . Org. Chem., Vol. 63, No. 16, 1998
Roush and Sciotti
4.02 (A of AB, J ) 16.4 Hz, 1 H), 3.74 (s, 3 H), 3.58 (t, J ) 6.4
Hz, 2 H), 2.37 (m, 1 H), 2.16 (dd, J ) 12.8, 6.0 Hz, 1 H), 1.96
(dt, J ) 6.8, 6.4 Hz, 2 H), 1.86 (dd, J ) 12.8, 10.8 Hz, 1H),
1.48 (apparent quintet, J ) 6.8 Hz, 2H), 1.36-1.24 (m, 5H),
1.06-1.04 (m, 12H), 0.89 (s, 9 H), 0.04 (s, 6 H); 13C NMR (100
MHz, CDCl3) δ 171.5, 169.3, 138.5, 137.1, 135.5, 135.4, 134.0,
133.8, 133.6, 129.6, 128.4, 128.0, 127.9, 127.63, 127.56, 127.4,
123.2, 81.9, 73.2, 66.9, 65.4, 63.2, 52.4, 43.7, 36.1, 32.7, 32.5,
29.2, 28.9, 26.7, 26.0, 25.4, 19.2, 18.6, -5.3; IR (neat) 1768,
1744 cm-1; HRMS for C44H59O7Si2 (M+ - C4H9) calcd 755.3799,
found 755.3819. Anal. Calcd for C48H68O7Si2: C, 70.89; H,
8.43. Found: C, 70.79; H, 8.18.
(5S,6R,9R)-2-Oxo-3-ben zyloxy-6-[7-(ter t-bu tyld im eth yl-
silyloxy)h ept-1-en yl]-8-[(ter t-bu tyldiph en ylsilyloxy)m eth -
yl]-4-m eth oxym eth yloxy-9-m eth yl-1-oxaspir o[4.5]deca-3,7-
d ien e (10). To a -78 °C solution of 41 (24 mg, 0.03 mmol) in
THF (290 µL, 0.1 M) was added lithium hexamethyldisilazide
(67 µL of a 1.0 M solution in hexanes; 0.07 mmol). The mixture
was stirred for 2 h at -78 °C and then was allowed to warm
to room temperature over a period of 1 h. The reaction was
quenched with brine solution and acidified to pH 1 with 2 N
HCl. The aqueous layer was extracted with EtOAc (4 × 5 mL),
and the combined extracts were dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by
silica gel flash column chromatography (gradient, 4:1 hex-
anes-EtOAc to 2:1 hexanes-EtOAc), yielding the tetronic acid
(16 mg, 70% yield).
in vacuo. The crude product was purified by silica gel flash
column chromatography (4:1 hexanes-EtOAc), affording the
model spirotetronate 10 (17 mg, 98%) as a colorless oil: [R] )
-48.2° (c 2.3, CH2Cl2); TLC Rf ) 0.68 (3:1 hexanes-EtOAc);
1H NMR (400 MHz, CDCl3) δ 7.70-7.65 (m, 4 H), 7.45-7.33
(m, 11 H), 5.49 (dt, J ) 15.2, 6.8 Hz, 1 H), 5.45 (s, 1 H), 5.29
(s, 2 H), 5.19 (dd, J ) 15.2, 8.8 Hz, 1 H), 5.12 (B of AB, J )
10.8 Hz, 1 H), 5.05 (A of AB, J ) 10.8 Hz, 1 H), 4.24 (B of AB,
J ) 13.2 Hz, 1 H), 4.15 (A of AB, J ) 13.2 Hz, 1 H), 3.57 (t, J
) 6.8 Hz, 2 H), 3.47 (s, 3 H), 3.12 (d, J ) 8.8 Hz, 1 H), 2.59
(quintet, J ) 7.2 Hz, 1 H), 2.21 (dd, J ) 14.0, 7.6 Hz, 1 H),
1.97 (q, J ) 7.2 Hz, 2 H), 1.48 (quintet, J ) 6.8 Hz, 2 H), 1.36-
1.26 (m, 5 H), 1.15 (d, J ) 7.6 Hz, 3 H), 1.06 (s, 9 H), 0.88 (s,
9 H), 0.03 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 168.5, 159.5,
140.4, 136.3, 135.5, 135.2, 133.7, 133.6, 129.6, 128.9, 128.5,
128.4, 127.6 (two resonances), 125.8, 121.5, 121.2, 96.3, 90.8,
73.6, 65.9, 63.2, 57.3, 43.5, 37.4, 32.7, 32.5, 29.3, 28.0, 26.9,
26.0, 25.3, 20.1, 19.3, 18.3, -5.3; IR (CCl4) 1760, 1685 cm-1
;
HRMS for C45H59O7Si2 (M+ - C4H9) calcd 767.3799, found
767.3773.
Ack n ow led gm en t. This research was supported by
a grant from the National Institute of General Medical
Sciences (GM 26782).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of 15 and 1H NMR spectra of 10-
12, 19, 22, 23, 36, 37, and 39 (10 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.
A 0 °C solution of the tetronic acid in a 30:1 mixture of CH2-
Cl2 and HMPA (207 µL, 0.1 M) was treated with i-Pr2NEt (16
µL, 0.09 mmol) and MOM-Cl (4 µL, 0.08 mmol). The reaction
mixture was stirred 4 h at 0 °C and then was warmed to room
temperature. The mixture poured into saturated NH4Cl
solution (1 mL) and extracted with EtOAc (4 × 2 mL). The
combined extracts were dried over Na2SO4 and concentrated
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