Determination of the absolute stereochemistry of (-)-galbonolide A

Article abstract of DOI:10.1021/jo970106l

The absolute stereochemistry of (-)-galbonolide A (1) was assigned by chemical methods. First, 1 was degraded to diol 3. After selective silylation of the primary alcohol, two independent methods were carried out to determine the chirality at C13. Both established its S-configuration. Using the methodology developed in the total synthesis of (-)-galbonolide B, diols 13(S,S) and 13(S,R) were prepared. Their (R)-MTPA esters, 14(S,S,R) and 14(S,R,R), were compared with the analogous (R)-MTPA ester of the degradation product 3, which subsequently established the S-chirality at C8. To determine the chirality at C4, two independent methods were carried out. One involved a comparison with the chirality of C4 of galbonolide B. The other involved a comparison of the degradation product of galbonolide A, 22, with its synthetic equivalents. Both methods confirmed the S-configuration at C4. Since three of the four chiral centers of galbonolides A and B have been confirmed to be identical and since the two galbonolides share very similar conformations as suggested by their ¹H NMR spectra, the configurations at C2 of these two compounds should also be the same.

Full text of DOI:10.1021/jo970106l

3236
J . Org. Chem. 1997, 62, 3236-3241
Deter m in a tion of th e Absolu te Ster eoch em istr y of
(-)-Ga lbon olid e A
Bruno Tse,* Charles M. Blazey, Ben Tu, and J ames Balkovec
Merck Research Laboratories, Department of Medicinal Chemistry, P.O. Box 2000 (RY50G-241),
Rahway, New J ersey 07065-0900
Received J anuary 22, 1997X
The absolute stereochemistry of (-)-galbonolide A (1) was assigned by chemical methods. First, 1
was degraded to diol 3. After selective silylation of the primary alcohol, two independent methods
were carried out to determine the chirality at C13. Both established its S-configuration. Using
the methodology developed in the total synthesis of (-)-galbonolide B, diols 13(S,S) and 13(S,R)
were prepared. Their (R)-MTPA esters, 14(S,S,R) and 14(S,R,R), were compared with the
analogous (R)-MTPA ester of the degradation product 3, which subsequently established the
S-chirality at C8. To determine the chirality at C4, two independent methods were carried out.
One involved a comparison with the chirality of C4 of galbonolide B. The other involved a
comparison of the degradation product of galbonolide A, 22, with its synthetic equivalents. Both
methods confirmed the S-configuration at C4. Since three of the four chiral centers of galbonolides
A and B have been confirmed to be identical and since the two galbonolides share very similar
conformations as suggested by their 1H NMR spectra, the configurations at C2 of these two
compounds should also be the same.
Sch em e 1
Galbonolide A (1) and B (2) were isolated as fungal
metabolites from Micromonospora chalcea by Otake1 and
from Streptomyces galbus by Achenbach2 independently.
They exhibit antifungal activities against a large number
of pathogens such as Candida albicans, Botrytis cinerea,
and Rhodotorula rubra.3 Of these two compounds, gal-
bonolide A is the more potent antifungal agent. Recently,
the first total synthesis of galbonolide B was accom-
plished. In addition, its absolute stereochemistry was
determined.4 Through a translactonization involving the
tertiary alcohol at C4, the secondary alcohol at C13 was
exposed for derivatization. Two independent methods
were carried out to determine its chirality. Both estab-
lished its S-configuration. Together with the relative
stereochemistry determined by its crystal structure, the
absolute stereochemistry was formally established. On
the other hand, there is still no formal establishment of
the absolute stereochemsitry of galbonolide A to our
knowledge, though the connectivities of the atoms have
been confirmed to be the same as that of galbonolide B.1,2
Unlike galbonolide B, however, efforts to obtain an X-ray
structure of galbonolide A or its derivatives have so far
been unsuccessful in our laboratory. Thus, we turned
to chemical methods to determine the absolute stereo-
chemistry. This article describes the assignment of the
absolute stereochemistry of galbonolide A by judicious
modifications of the methodology developed in the total
synthesis of galbonolide B.
and thus most susceptible to ozonolysis. Indeed, selective
cleavage of the C6-C7 olefin was successful. Immediate
reduction of the aldehyde and subsequent treatment with
NaOMe gave diol 3 in 72% yield (Scheme 1). In the
absence of the relatively unstable enol ether moiety, diol
3 would be comparatively easier to handle and thus was
(1) Abe, Y.; Nakayama, H.; Shimazu, A.; Furihata, K.; Ikeda, K.;
Furihata, K.; Seto, H.; Otake, N. J . Antibiot. 1985, 38, 1810.
(2) Achenbach, H.; Muhlenfeld, A.; Fauth, U.; Zahner, H. Tetrahe-
dron Lett. 1985, 26, 6167.
(3) Achenbach, H.; Muhlenfeld, A.; Fauth, U.; Zahner, H. Ann. N.Y.
Acad. Sci. 1988, 544, 128.
Ch ir a lity of C13. Being an enol ether, the C6-C7
double bond was expected to be the most electron-rich
X Abstract published in Advance ACS Abstracts, April 15, 1997.
(4) Tse, B. J . Am. Chem. Soc. 1996, 118, 7094.
S0022-3263(97)00106-0 CCC: $14.00 © 1997 American Chemical Society

Absolute Stereochemistry of (-)-Galbonolide A
J . Org. Chem., Vol. 62, No. 10, 1997 3237
Ta ble 1. Ch em ica l Sh ifts of th e P r oton s Ad ja cen t to th e
(S)- a n d (R)-MTP A Ester s Moieties (p p m ) w ith CDCl3 a s
th e Solven ta
Sch em e 3
compound
C14-H
C15-H
C11-H
C21-H
5
6
1.60-1.78
1.64-1.82
0.80
0.88
5.91
5.83
1.75
1.60
a
In comparison of the chemical shifts of the relevant signals of
5 to 6, the downfield shifts of the protons on C14 and C15 and the
upfield shifts of those on C11 and C21 indicated S-chirality at C13.
Sch em e 2
4
used for the determination of the configurations of C8
and C13. After selective silylation of the primary alcohol
(91%), the secondary alcohol at C13 was derivatized. As
in the case of galbonolide B, two independent methods
were carried out to determine the configuration at C13,
and both methods confirmed its S-chirality.
First, the standard Mosher method was employed,
using the (S)-MTPA and the (R)-MTPA esters.5 From
the comparison of the chemical shifts of the pertinent
signals as tabulated in Table 1, the S-chirality of C13
was indicated.
Ch ir a lity of C4. To determine the chirality of C4, two
independent methods were carried out. The first method
involved a comparison with the chirality of C4 of gal-
bonolide B which had already been established. In the
second method, a degradation product of galbonolide A
containing C4 was prepared synthetically using a simple
modification of the methodology developed in the total
synthesis. A subsequent comparison between the deg-
radation product and the synthetic material could then
allow the assignment of the chirality at C4.
In the second method (Scheme 2), carbamate 7 was
prepared (83% from 4), which was degraded to methyl
ketone 8 (59%). This degradation product was then
compared with synthetic 8(R,R) and 8(S,R) as reported
1
earlier.4 The match of its H NMR with that of 8(S,R)
confirmed the S-chirality at C13.
Compounds 1 and 2 were translactonized to 15 and
16, respectively, upon treatment with NaH and MeI
in DMF (ca. 70%) (Scheme 4). The extra methyl group
at C2 eliminated any complications related to epimer-
ization at C2. Upon ozonolysis, 17 and 18 were formed
(ca. 95%), respectively. The methyl ketone of 18 could
be reduced selectively by LiHAl(Ot-Bu)3 to yield the
corresponding secondary alcohol (95%), which was de-
hydrated to give a mixture of 19 and 20 (∼6:1).6 The
mixture was cleaved oxidatively using Sharpless’s pro-
cedure. After treatment with diazomethane, the product
proved identical to 17 carrying the same optical rotation,
thus establishing the chirality of C4 of galbonolide A to
be the same as that of galbonolide B, i.e., S.
Ch ir a lity of C8. In the total synthesis of galbonolide
B, methyl ketone 10-S was synthesized from 9-R (Scheme
3).4 Similarly, 10-R was prepared from 9-S (ca. 60% over
three steps). Following the same procedure to prepare
12(S,S) from 10-S as in the total synthesis, 12(S,R) was
obtained from 10-R. Both of the SEM and the TBS
groups were cleaved by treatment with Et4NF in DMSO
at 90 °C (ca. 53%) to furnish 13(S,S) and 13(S,R).
1
Despite being diastereomers, H NMR spectra of these
two compounds were identical and thus could not be used
for direct comparison with the degradation product 3.
However, using normal phase HPLC, it was found that
3 coeluted with 13(S,S), not with 13(S,R), indicating that
3 and 13(S,S) were identical and that the chirality of
C8 was S. In addition, when the (R)-MTPA esters of the
primary alcohol were prepared, the two diastereomers
14(S,S,R) and 14(S,R,R) could be easily differentiated
In the second method, an (S)-MTPA ester was first
derived from the C17 primary alcohol of galbonolide A
(80%). Upon translactonization, 21 was obtained (60%),
and was subsequently degraded to 22 by ozonolysis (84%)
(Scheme 5). Compound 22 could be readily synthesized
from the methodology developed in the total synthesis
(Scheme 6). A modification of Seebach’s and Ladner’s
contrasteric enolate chemistry was employed on 24 to
1
by H NMR. When they were compared with the corre-
sponding (R)-MTPA ester prepared from 3, there was a
match of its 1H NMR with that of 14(S,S,R) and a
mismatch with 14(S,R,R). The S-configuration at C8
was thus confirmed.
(6) Since the goal was to convert 18 to 17 regardless of the yield, no
effort to optimize the ratio of 19:20 was carried out.
(5) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.

3238 J . Org. Chem., Vol. 62, No. 10, 1997
Tse et al.
Sch em e 4
Sch em e 6
Sch em e 5
quent oxidative cleavage of the double bond and methy-
lation of the resultant carboxylic acid (62%), 22(S,S) was
obtained. Following the same procedure with the use of
the enantiomer of 23 as the starting material, 22(R,S)
1
was furnished. When the H NMR spectrum of 22 was
compared with those of 22(S,S) and 22(R,S), a match
with the former and a mismatch with the latter were
observed, thus confirming the configuration of C4 to be
S. The results from these two independent methods were
therefore consistent.
Ch ir a lity of C2. Thus, the chiralities of C4, C8 and
C13 of galbonolide A have been assigned and found
identical to those of galbonolide B. Since the asymmetric
center at C2 was rather kinetically labile, no chemical
methods were sought to determine its chirality. How-
ever, upon comparison of the 1H NMR spectra of gal-
bonolide A and galbonolide B and their C2-epimers,10 one
observes that the spectra of the two galbonolides are
extremely similar (Table 2). A striking similarity was
also noticed in the two C2-epimers. Thus, one can
conclude that the two galbonolides share very similar
conformations as do the two C2-epimers. Since the
chiralities of three of the four chiral centers of the two
galbonolides have been confirmed to be identical, the
configurations at C2 of these two compounds should also
be the same. The absolute stereochemistry is, therefore,
fully established to be the structure shown in 1.
install the chiral center at C4 in the total synthesis.7,8
Using allyl bromide as the electrophile in this case, 25
was formed (79%).9 After condensation with the lithium
enolate of ethyl acetate and subsequent methylation at
the C2 position, 27 was furnished (59% over two steps).
Treatment with acid led to hydrolysis of the acetal as
well as lactonization to provide 28 (82%), from which the
(S)-MTPA ester 29 was prepared (89%). Upon subse-
(10) Galbonolides A and B and their C2-epimers did not equilibrate
by themselves at room temperature, thus suggesting that there was
sufficient geometrical constraint imposed by the macrocycle to prevent
isomerization at C2. However, the two galbonolides and their C2-
epimers were found to be in equilibrium in conditions such as DMAP
in CH2Cl2 and pyridine-water mixture and were characterized by Dr.
Mark Greenlee and Ms. Regina Black of this department. Both epi
compounds have also been reported in the literature, e.g., see ref 3.
(7) Seebach, D.; Aebi, J . D.; Gander-Coquoz, M.; Naef, R. Helv. Chim.
Acta 1987, 70, 1194.
(8) Ladner, W. Chem. Ber. 1983, 116, 3413.
(9) The fact that NOE’s were observed between Ha and Hc and
between Hb and Hd’s (Scheme 6) confirmed the configuration of 25.
The diastereoselectivity of the contrasteric attack of the lithium enolate
of 24 on allyl bromide was 12:1.

Absolute Stereochemistry of (-)-Galbonolide A
J . Org. Chem., Vol. 62, No. 10, 1997 3239
Ta ble 2. Ch em ica l Sh ifts (p p m ) w ith CD3OD a s th e
Solven ta
(2H, m), 3.50 (3H, d, J )1.1), 4.86 (1H, s), 5.04, (1H, s), 5.33
(1H, t, J )7.0), 5.91 (1H, s), 7.34-7.38 (3H, m), 7.45-7.49 (2H,
m). 13C NMR (CDCl3) δ -5.4, 9.7, 13.4, 16.2, 18.3, 25.5, 25.9,
34.4, 41.4, 55.2, 67.9, 83.7, 115.8, 123.5, 127.4, 128.3, 129.5,
131.0, 132.5, 134.1, 143.5, 165.8.
1
C2-epi-1
2
C2-epi-2
C9-H
2.04, 2.20
5.62
4.83
1.38
3.59, 3.90
0.73
1.90, 2.25
5.88
4.94
1.17
3.50, 3.66
0.91
2.09, 2.19
5.63
4.82
1.40
3.55, 3.89
0.71
1.92, 2.26
5.87
4.93
1.17
3.52, 3.64
0.87
C11-H
C13-H
C16-H
C17-H
C19-H
C20-H
C15-H
(R)-MTP A Ester 6. The same procedure for the synthesis
of 5 was followed with the use of (S)-MTPA chloride. From
10.0 mg of 4, 13.8 mg (82% yield) of 6 was obtained: [R]25
D
+47.2° (c 0.14, CHCl3). IR 1748. 1H NMR (CDCl3) δ 0.00 (3H,
s), 0.01 (3H, s), 0.79 (3H, d, J ) 6.7), 0.87 (9H, s), 0.88 (3H, t,
J ) 7.6), 1.60 (3H, s), 1.61-1.82 (4H, m), 2.24 (1H, dd, J )
5.3, 13.3), 3.36 (2H, m), 3.55 (3H, s), 4.82 (1H, s), 5.01 (1H, s),
5.27 (1H, t, J ) 7.0), 5.83 (1H, s), 7.32-7.37 (3H, m), 7.46-
7.49 (2H, m). 13C NMR (CDCl3) δ -5.4, -5.4, 9.9, 13.1, 16.3,
18.3, 25.5, 25.9, 34.4, 41.4, 55.5, 67.9, 83.8, 115.7, 123.6, 127.2,
128.3, 129.4, 130.8, 132.6, 133.9, 143.5, 165.7.
4.75, 4.97
0.90
4.87, 5.04
0.85
4.75, 4.98
0.91
4.87, 5.05
0.84
a
The characteristic shifts of signals from galbonolide A (1) to
C2-epi-galbonolide A were also observed from galbonolide B (2) to
C2-epi-galbonolide B.
Ca r ba m a te 7. To a solution of 4 (10.0 mg, 0.032 mmol) in
toluene (3 mL) were added (R)-1-(1-naphthyl)ethyl isocyanate
(0.060 mL, 0.34 mmol) and a catalytic amount of DMAP. The
mixture was refluxed overnight. After concentration in vacuo
and purification by PTLC, 13.5 mg (83% yield) of 7 was
Exp er im en ta l Section
Gen er a l. Reactions sensitive to moisture or air were
performed under nitrogen using anhydrous solvents and
reagents. Reagents and solvents were used as supplied
otherwise. Na2SO4 was used for drying in the aqueous
workups of reactions. 1H and 13C NMR spectra were obtained
at 500 and 125 MHz, respectively. Chemical shifts are
reported in parts per million, and residual solvent peaks were
used as internal references. Coupling constants are reported
in hertz. IR spectra were measured as films and the wave-
numbers are reported in cm-1. Analytical TLC was performed
with E. Merck precoated TLC plates, silica gel 60F-254, layer
thickness 0.25 mm. Preparative TLC (PTLC) separations were
performed on E. Merck precoated TLC plates, silica gel 60F-
254, layer thickness 0.50 mm. Flash chromatography was
performed with E. Merck Kieselgel 60 (230-400 mesh) silica
gel.
obtained: [R]25 +35.7° (c 0.21, CHCl3). IR 1707, 3324. 1H
D
NMR (CDCl3) δ -0.01 (6H, s), 0.78 (3H, d, J ) 6.0), 0.82-
0.88 (3H, m), 0.85 (9H, s), 1.64-1.78 (11H, m), 2.20 (1H, dd, J
) 5.5, 13.3), 3.30-3.37 (2H, m), 4.83 (1H, s), 4.97 (1H, t, J )
6.4), 4.98 (1H, s), 5.62 (1H, s), 5.76 (1H, s), 7.41-7.52 (4H, m),
7.76 (1H, d, J ) 8.0), 7.84 (1H, d, J ) 7.6), 8.08 (1H, d, J )
8.5). 13C NMR (CDCl3) δ -5.4, -5.4, 9.8, 13.8, 16.4, 18.3, 21.5,
25.9, 34.4, 41.5, 46.5, 67.8, 81.0, 115.2, 122.2, 123.3, 125.2,
125.7, 126.4, 128.2, 128.8, 131.2, 133.9, 135.6, 138.9, 143.9,
155.2. HRMS (EI) calcd for C31H47N1O3Si1 509.3325, found
509.3329.
Degr a d a tion P r od u ct 8. To a solution of carbamate 7 (9.0
mg, 0.018 mmol) in CCl4 (1 mL) and CH3CN (1 mL) was added
H2O (1.5 mL), NaIO4 (42.0 mg, 0.20 mmol) and RuCl3 (1 mg,
0.0048 mmol).11 The mixture was stirred at room temperature
for 4 h. After aqueous workup (CH2Cl2) and purification by
PTLC, 3.1 mg (58% yield) of 8 was obtained. Its spectroscopic
data was found to be identical to 8(S,R).
Diol 3. Galbonolide A (100.0 mg, 0.26 mmol) was dissolved
in 3 mL of CH2Cl2 and 8 mL of MeOH. Ozone was periodically
passed through this mixture at -78 °C. The course of the
reaction was carefully monitored by TLC. Upon the comple-
tion of the reaction, nitrogen was passed through the mixture
for 2 min, after which Me2S (1 mL) was added. The mixture
was stirred at -78 °C for 10 min. NaBH4 (500 mg, 13.2 mmol)
was added, and the mixture was stirred at room temperature
for 1 h. NaOMe (3 mL of a 1 M solution in MeOH, 3 mmol)
was added, and the mixture was stirred at room temperature
overnight. After concentration in vacuo, aqueous workup and
(R)-MTP A Ester 14(S,S,R). To a solution of 12(S,S) (5.0
mg, 0.011 mmol) in DMSO (1.5 mL) were added Et4NF (84
mg, 0.56 mmol) and 4 Å powdered molecular sieves (0.5 g).
The mixture was stirred at 90 °C overnight. After acidifica-
tion, aqueous workup (ether), and purification by PTLC, 1.1
mg of the diol was obtained, which was used directly in the
next step. To a solution of this diol (1.1 mg, 0.0056 mmol) in
CH2Cl2 (1.5 mL) were added NEt3 (0.016 mL, 0.12 mmol) and
(S)-MTPA chloride (0.010 mL, 0.053 mmol). The mixture was
stirred at room temperature overnight. After purification by
PTLC, 1.7 mg (36% overall yield) of 14(S,S,R) was obtained:
purification by PTLC, 37.5 mg (72%) of 3 was obtained: [R]25
D
+34.9° (c 0.30, CHCl3). IR 3300. 1H NMR (CDCl3) δ 0.86 (3H,
t, J ) 7.5), 0.87 (3H, d, J ) 6.8), 1.55-1.61 (2H, m), 1.73 (1H,
m), 1.75 (3H, d, J ) 1.4), 1.90 (1H, dd, J ) 6.3, 13.6), 2.21
(1H, dd, J ) 6.2, 13.4), 3.42 (1H, dd, J ) 6.2, 10.5), 3.48 (1H,
dd, J ) 5.7, 10.5), 3.95 (1H, t, J ) 6.5), 4.88 (1H, s), 5.03 (1H,
t, J ) 1.2), 5.78 (1H, s). 13C NMR (CDCl3) δ 10.0, 13.2, 16.5,
27.8, 34.5, 41.9, 68.0, 79.3, 115.2, 126.7, 140.0, 143.8.
[R]25 +63.6° (c 0.082, CHCl3). IR 1744, 3423. 1H NMR
D
(CDCl3) δ 0.85 (3H, t, J ) 7.5), 0.89 (3H, d, J ) 6.4), 1.57 (3H,
m), 1.74 (3H, s), 1.93 (2H, m), 2.14 (1H, m), 3.53 (3H, s), 3.93
(1H, t, J ) 6.7), 4.13 (2H, m), 4.87 (1H, s), 4.96 (1H, s), 5.71
(1H, s), 7.39 (3H, m), 7.49 (2H, m). 13C NMR (CDCl3) δ 10.0,
13.2, 16.7, 27.8, 31.3, 41.4, 55.3, 70.5, 79.2, 116.0, 123.3, 126.2,
127.4, 128.4, 129.6, 132.3, 140.4, 142.7, 166.6. HRMS (EI)
calcd for C22H29O4F3 414.2018, found 414.2005.
TBS Eth er 4. To a solution of diol 3 (35 mg, 0.177 mmol)
in CH2Cl2 (3 mL) were added NEt3 (0.074 mL, 0.531 mmol),
TBSCl (53.3 mg, 0.354 mmol), and a catalytic amount of
DMAP. The mixture was stirred overnight at room temper-
ature. After purification by PTLC, 50.2 mg (91% yield) of 4
was obtained: [R]25D +42.7° (c 0.37, CHCl3). IR 3350. 1H NMR
(CDCl3) δ 0.01 (3H, s), 0.01 (3H, s), 0.82 (3H, d, J ) 6.4), 0.86
(3H, t, J ) 7.4), 0.87 (9H, s), 1.43 (1H, br s), 1.58 (2H, m),
1.64-1.72 (1H, m), 1.75 (3H, d, J ) 1.4), 1.78 (1H, dd, J )
8.8, 13.6), 2.26 (1H, dd, J ) 5.6, 13.4), 3.35 (1H, dd, J ) 6.3,
9.7), 3.40 (1H, dd, J ) 5.1, 9.8), 3.94 (1H, t, J ) 6.5), 4.86 (1H,
s), 5.00 (1H, t, J ) 1.1), 5.77 (1H, s). 13C NMR (CDCl3) δ -5.4,
-5.4, 10.0, 13.1, 16.5, 18.3, 25.9, 27.8, 34.5, 41.7, 67.9, 79.5,
115.1, 127.0, 139.5, 144.0.
(S)-MTP A Ester 5. To a solution of 4 (10.0 mg, 0.032
mmol) in CH2Cl2 (2 mL) were added NEt3 (0.045 mL, 0.32
mmol), (R)-MTPA chloride (0.030 mL, 0.16 mmol), and a
catalytic amount of DMAP. The mixture was stirred at room
temperature overnight. After purification by PTLC, 13.9 mg
(82% yield) of 5 was obtained: [R]25D -7.4° (c 0.18, CHCl3). IR
1746. 1H NMR (CDCl3) δ 0.00 (3H, s), 0.00 (3H, s), 0.79 (3H,
d, J ) 6.6), 0.81 (3H, t, J ) 7.6), 0.87 (9H, s), 1.60-1.80 (4H,
m), 1.75 (3H, d, J ) 1.3), 2.28 (1H, dd, J ) 5.6, 13.4), 3.37
(R)-MTP A Ester 14(S,R,R). To prepare 12(S,R), the same
procedure for the synthesis of 12(S,S) was adopted with the
use of 9-S as the starting material. To prepare 14(S,R,R) from
12(S,R), the same procedure for the synthesis of 14(S,S,R)
from 12(S,S) was adopted. From 6.5 mg of 12(S,R), 1.9 mg
(31% overall yield) of 14(S,R,R) was obtained: [R]25 +33.6°
D
(c 0.15, CHCl3). IR 1744, 3414. 1H NMR (CDCl3) δ 0.84 (3H,
t, J ) 7.5), 0.87 (3H, d, J ) 6.4), 1.57 (3H, m), 1.74 (3H, s),
1.95 (2H, m), 2.13 (1H, m), 3.52 (3H, s), 3.93 (1H, t, J ) 6.5),
4.00 (1H, dd, J ) 5.9, 10.6), 4.24 (1H, dd, J ) 4.7, 10.7), 4.89
(1H, s), 4.99 (1H, s), 5.72 (1H, s), 7.32 (3H, m), 7.49 (2H, m).
13C NMR (CDCl3) δ 9.9, 13.1, 16.7, 27.8, 31.3, 41.5, 55.4, 70.6,
79.3, 115.9, 123.3, 126.2, 127.4, 128.4, 129.6, 132.3, 140.4,
142.7, 166.6. HRMS (EI) calcd for C22H29O4F3 414.2018, found
414.2033.
(11) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.

3240 J . Org. Chem., Vol. 62, No. 10, 1997
Tse et al.
(R)-MTP A Ester of 3. The same procedure for the syn-
thesis of 14(S,S,R) from 13(S,S) was adopted. From 7.4 mg
of 3, 11.6 mg (75% yield) of the corresponding (R)-MTPA ester
was obtained. Its spectroscopic data was identical to that of
14(S,S,R), thus establishing the configuration of C8 to be S.
Tr a n sla cton ized P r od u ct 15. The same procedure for the
preparation of 16 from 2 was followed.4 From 200.0 mg of 1,
152.0 mg (71% yield) of 15 was obtained: [R]25D +74.2° (c 0.43,
CHCl3). IR 1752, 1799, 3525. 1H NMR (CDCl3) δ 0.85 (3H, t,
J ) 7.5), 0.86 (3H, d, J ) 4.6), 1.26 (3H, s), 1.28 (3H, s), 1.56
(2H, m), 1.71 (3H, d, J ) 1.4), 1.98 (2H, m), 2.33 (1H, d, J )
14.9), 2.63 (1H, m), 2.66 (1H, d, J ) 14.8), 3.28 (3H, s), 3.29
(3H, s), 3.46 (1H, d, J ) 10.1), 3.60 (1H, d, J ) 10.1), 3.93
(1H, t, J ) 6.4), 4.58 (1H, d, J ) 9.4), 4.82 (1H, s), 4.95 (1H, t,
J ) 0.9), 5.74 (1H, d, J ) 0.9). 13C NMR (CDCl3) δ 9.9, 13.3,
20.6, 21.2, 21.5, 27.8, 28.9, 34.5, 44.6, 45.5, 56.6, 59.4, 75.2,
79.2, 90.1, 115.2, 124.7, 126.8, 139.5, 143.6, 146.3, 177.6, 213.1.
Degr a d a tion P r od u ct 17. Ozone was passed through a
solution of 15 (150.0 mg, 0.37 mmol) in CH2Cl2 (5 mL) and
MeOH (15 mL) at -78 °C. Upon the completion of the reaction
as monitored by TLC, the excess ozone was removed by passing
nitrogen through the mixture. Me2S (1 mL) was added to the
mixture. Stirring was continued for another 15 min at -78
°C, and the mixture was allowed to warm to room temperature.
After concentration in vacuo and purification by PTLC, 86.0
7.3), 5.91 (1H, s), 7.06 (5H, m), 7.70 (1H, d, J ) 7.8). 13C NMR
(C6D6) δ 10.0, 12.2, 13.5, 23.0, 25.4, 33.1, 37.3, 46.5, 51.1, 55.3,
56.8, 71.5, 76.8, 82.6, 117.4, 124.3, 125.8, 127.9, 128.3, 128.6,
129.7, 132.7, 132.8, 136.0, 144.0, 149.1, 166.1, 172.8, 208.3.
HRMS (EI) calcd for C31H39O8F3 596.2597, found 596.2593.
Tr a n sla cton ized P r od u ct 21. To a solution of the (S)-
MTPA ester of 1 obtained above (13.0 mg, 0.022 mmol) in DMF
(0.5 mL) was added MeI (0.015 mL, 0.24 mmol), followed by
NaH (2.0 mg of a 60% oil dispersion, 0.050 mmol). The
mixture was stirred at room temperature for 2 h. After
concentration in vacuo and purification by PTLC, 8.0 mg (60%
yield) of 21 was obtained: [R]25 +31.5° (c 0.52, CHCl3). IR
D
1675, 1759, 1806, 3484. 1H NMR (CDCl3) δ 0.85 (8H, m), 1.19
(3H, s), 1.56 (4H, m), 1.71 (3H, s), 1.97 (2H, d, J ) 7.1), 2.42
(1H, d, J ) 14.9), 5.33 (1H, d, J ) 14.9), 2.63 (1H, m), 3.28
(3H, s), 3.50 (3H, s), 3.92 (1H, t, J ) 6.5), 4.33 (1H, d, J )
11.9), 4.45 (1H, d, J ) 11.9), 4.59 (1H, d, J ) 9.3), 4.82 (1H,
s), 4.95 (1H, s), 5.73 (1H, s), 7.35 (5H, m). 13C NMR (CDCl3)
δ 9.9, 13.3,. 20.6, 21.0, 21.4, 27.9, 28.9, 35.4, 44.3, 45.4, 55.8,
56.7, 67.2, 79.2, 87.1, 115.3, 123.0, 125.6, 126.6, 126.9, 128.4,
129.8, 131.8, 139.7, 143.4, 145.4, 166.0, 176.7, 211.2.
Degr a d a tion P r od u ct 22. Ozone was passed through a
solution of 21 (6.7 mg, 0.011 mmol) in CH2Cl2 (2 mL) and
MeOH (5 mL) at -78 °C until TLC analysis indicated the
completion of the reaction. Nitrogen was then passed through
the mixture for 5 min to remove the excess ozone. Me2S (0.25
mL) was added, and the mixture was stirred at -78 °C for
another 15 min. After concentration in vacuo and purification
by PTLC, 4.1 mg (84% yield) of 22 was obtained. Its spectro-
scopic data was identical to that of 22(S,S) described below,
thus confirming the configuration of C4 to be S.
mg (96% yield) of 17 was obtained: [R]25 -39.3° (c 0.18,
D
CHCl3). IR 1735, 1756, 1801. 1H NMR (CDCl3) δ 1.50 (3H,
s), 1.36 (3H, s), 2.83 (1H, d, J ) 17.4), 2.98 (1H, d, J ) 17.4),
3.32 (3H, s), 3.52 (1H, d, J ) 10.3), 3.60 (1H, d, J ) 10.1), 3.64
(3H, s). 13C NMR (CDCl3) δ 21.5, 22.3, 37.7, 45.1, 52.4, 59.5,
74.7, 87.8, 168.8, 177.7, 212.9. HRMS (EI) calcd for C11H16O6
244.0947, found 244.0946.
Allyla ted P r od u ct 25. Compound 24 (800.0 mg, 3.2
mmol), which was prepared from the S isomer of 23, was
dissolved in THF (15 mL) and HMPA (5 mL). To this mixture
was added allyl bromide (1.7 mL, 0.020 mol) followed by
LiHMDS (4.8 mL of a 1 M solution in THF, 4.8 mmol) at -78
°C. The mixture was stirred at -78 °C for 1 h. After aqueous
workup (ether) and chromatography, 733.1 mg (79% yield) of
Degr a d a tion P r od u ct 18. The same procedure for the
synthesis of 17 was followed using 16 as the starting material.
From 200.0 mg of 16, 110.5 mg (95%) of 18 was obtained:
[R]25 -20.1° (c 0.29, CHCl3). IR 1720, 1756, 1799. 1H NMR
D
(CDCl3) δ 1.35 (3H, s), 1.59 (3H, s), 2.10 (3H, s), 3.10 (2H, AB
q, J ) 18.6), 3.32 (3H, s), 3.47 (1H, d, J ) 10.3), 3.55 (1H, d,
J ) 10.5). 13C NMR (CDCl3) δ 21.7, 22.6, 29.5, 45.3, 47.0, 59.5,
74.7, 87.4, 177.9, 203.0, 213.0.
25 was obtained: [R]25 -16.2° (c 0.57, CHCl3). IR 1752. 1H
D
NMR (CD3OD) δ 2.17 (3H, s), 2.32 (6H, s), 2.60 (1H, dd, J )
6.4, 14.2), 2.73 (1H, dd, J ) 8.0, 14.2), 3.72 (3H, s), 3.96 (1H,
d, J ) 8.4), 4.13 (1H, d, J ) 8.5), 5.06 (2H, m), 5.74 (1H, m),
6.11 (1H, s), 6.75 (2H, s). 13C NMR (CD3OD) δ 20.3, 21.0, 42.0,
53.0, 73.3, 84.9, 104.4, 119.6, 128.5, 130.9, 133.2, 139.4, 140.3,
174.6.
Con ver sion of 18 to 17. To a solution of 18 (50.0 mg, 0.22
mmol) in THF (5 mL) was added LiHAl(Ot-Bu)3 (0.24 mL of a
1 M solution in THF, 0.24 mmol) at -78 °C. The mixture was
stirred at -78 °C for 2 h. After aqueous workup and purifica-
tion by PTLC, 47.9 mg (95%) of the corresponding alcohol,
which consisted of two diastereomers, was obtained.
Com p ou n d 27. To a solution of EtOAc (1.36 mL, 0.014
mol) in THF (15 mL) at -78 °C was added LiHMDS (15.4 mL
of a 1 M solution in THF, 15.4 mmol). The mixture was stirred
at -78 °C for 10 min. Compound 25 (406.1 mg, 1.40 mmol) in
THF (5 mL) was then added. The mixture was stirred at -78
°C for another 2 h. After aqueous workup (CH2Cl2) and
chromatography, 399.3 mg (82% yield) of 26 was obtained,
which was used directly in the next step.
To a solution of the alcohol obtained above (47.9 mg, 0.21
mmol) in CH2Cl2 (5 mL) was added Martin’s sulfurane reagent
at room temperature until TLC analysis indicated the comple-
tion of the reaction. After purification by PTLC, the insepa-
rable mixture of 19 and 20 (∼6:1) was obtained. To a solution
of this mixture in CCl4 (1 mL) and CH3CN (1 mL) were added
H2O (1.5 mL), NaIO4 (223.0 mg, 1.04 mmol), and RuCl3 (0.011
mmol). The mixture was stirred at room temperature for 4 h.
After aqueous workup (ether), the crude mixture was dissolved
in 10 mL of ether. Ethereal CH2N2 was added until a steady
yellow color was obtained. After stirring for an additional 5
min, the excess CH2N2 was removed by passing nitrogen
through the mixture. After concentration in vacuo and
purification, 7.2 mg (14% yield over three steps) of 17 was
obtained, which was found to have the same optical rotation
and spectroscopic data as the direct ozonolysis product from
15 as mentioned above.
To a solution of 26 (273.8 mg, 0.79 mmol) in DMF (10 mL)
was added t-BuOK (0.79 mL of a 1 M solution in THF, 0.79
mmol) at 0 °C. The mixture was stirred at 0 °C for 5 min.
MeI (0.20 mL, 3.2 mmol) was added, and the mixture was
stirred at 0 °C for 1 h. The same procedure of adding t-BuOK
followed by MeI was repeated three times over a period of 3
h. After aqueous workup and chromatography, 225.7 mg (76%
yield) of 27 was obtained: [R]25 -22.0° (c 0.21, CHCl3). IR
D
1705, 1744. 1H NMR (CD3OD) δ 1.07 (3H, t, J ) 7.1), 1.27
(3H, s), 1.40 (3H, s), 2.17 (3H, s), 2.35 (6H, s), 2.62 (1H, dd, J
) 6.9, 14.1), 2.71 (1H, dd, J ) 7.7, 14.1), 3.89 (1H, d, J ) 9.0),
4.02 (2H, m), 4.14 (1H, d, J ) 8.9), 4.99 (2H, m), 5.65 (1H, m),
6.00 (1H, s), 6.75 (2H, s). 13C NMR (CD3OD) δ 14.2, 21.0, 21.1,
22.3, 23.9, 45.3, 55.0, 62.3, 74.4, 90.2, 105.8, 119.0, 128.9, 131.1,
133.9, 139.1, 140.1, 174.5, 211.4.
(S)-MTP A E st er of 1. To a solution of 1 (65 mg, 0.17
mmol) in CH2Cl2 (7 mL) was added NEt3 (0.48 mL, 3.44 mmol)
and (R)-MTPA chloride (0.32 mL, 1.71 mmol). The mixture
was stirred at room temperature overnight. After aqueous
workup (CH2Cl2) and purification by PTLC, 82 mg (80% yield)
of the corresponding (S)-MTPA ester was obtained: [R]25
La cton e 28. To a solution of 27 (206.7 mg, 0.55 mmol) in
MeOH (10 mL) was added p-TsOH (49.3 mg, 0.26 mmol). The
mixture was stirred at room temperature for 30 min. NEt3
(0.040 mL, 0.27 mmol) was added. After concentration in
vacuo and chromatography, 84.4 mg (82% yield) of 28 was
D
-52.1° (c 0.53, CHCl3). IR 1713, 1729, 1752, 3461. 1H NMR
(C6D6) δ 0.70 (3H, t, J ) 7.5), 0.85 (3H, d, J ) 6.6), 1.28 (3H,
d, J ) 6.9), 1.49 (1H, m), 1.71 (2H, t, J ) 11.9), 1.77 (3H, s),
2.13 (1H, dd, J ) 3.2, 12.8), 2.45 (1H, d, J ) 14.7), 2.72 (1H,
d, J ) 14.9), 2.72 (1H, m), 2.90 (3H, s), 3.45 (3H, s), 3.73 (1H,
q, J ) 7.1), 4.46 (1H, d, J ) 10.3), 4.68 (1H, d, J ) 10.3), 4.86
(1H, d, J ) 8.9), 4.97 (1H, s), 5.02 (1H, s), 5.08 (1H, t, J )
obtained: [R]25 -24.0° (c 0.56, CHCl3). IR 1747, 1796, 3466.
D
1H NMR (CDCl3) δ 1.19 (3H, s), 1.26 (3H, s), 2.44 (2H, m),
3.41 (1H, br s), 3.77 (1H, d, J ) 12.0), 3.82 (1H, d, J ) 12.0),

Absolute Stereochemistry of (-)-Galbonolide A
J . Org. Chem., Vol. 62, No. 10, 1997 3241
5.13 (2H, m), 5.62 (1H, m). 13C NMR (CDCl3) δ 20.1, 20.8,
36.5, 44.7, 65.3, 93.5, 121.6, 129.3, 178.3, 213.9.
66.5, 84.7, 123.0, 126.9, 128.5, 129.9, 131.6, 165.9, 168.5, 176.6,
211.1. HRMS (EI) calcd for C20H21O8F3 446.1189, found
446.1205.
(S)-MTP A Ester 29. To a solution of 28 (33.7 mg, 0.18
mmol) in CH2Cl2 (3 mL) was added NEt3 (0.47 mL, 3.37 mmol)
followed by (R)-MTPA chloride (0.23 mL, 1.23 mmol). The
mixture was stirred at room temperature overnight. After
aqueous workup (CH2Cl2) and purification by PTLC, 58.5 mg
Syn th etic 22(R,S). With the same procedure for the
synthesis of 22(S,S) using the R isomer of 23 as the starting
material, 22(R,S) was obtained: [R]25 +6.9° (c 0.49, CHCl3).
D
IR 1728, 1759, 1806. 1H NMR (CDCl3) δ 1.15, (3H, s), 1.46
(3H, s), 2.98 (2H, AB q, J ) 17.6), 3.47 (3H, s), 3.63 (3H, s),
(89% yield) of 29 was obtained: [R]25 -47.0° (c 2.9, CHCl3).
D
IR 1644, 1759, 1798. 1H NMR (CDCl3) δ 0.80 (3H, s), 1.14
(3H, s), 2.50 (2H, d, J ) 7.1), 3.46 (3H, s), 4.32 (1H, d, J )
11.9), 4.49 (1H, d, J ) 11.9), 5.18 (2H, m), 5.64 (1H, m), 7.32
(5H, m). 13C NMR (CDCl3) δ 19.6, 21.1, 37.6, 44.0, 55.6, 67.0,
88.6, 122.5, 123.1, 126.8, 128.3, 129.7, 131.7, 165.7, 176.4,
211.5.
4.37 (1H, d, J ) 12.1), 4.52 (1H, d, J ) 12.1), 7.41 (5H, m). 13
C
NMR (CDCl3) δ 21.0, 22.6, 38.4, 45.0, 52.6, 55.6, 66.4, 84.9,
123.0, 127.1, 128.6, 130.0, 131.2, 165.9, 168.6, 176.2, 211.2.
HRMS (EI) calcd for C20H21O8F3 446.1189, found 446.1205.
Ack n ow led gm en t. Authentic sample of galbono-
lides A and B were generously supplied by Dr. Guy
Harris of Merck Research Laboratories at Rahway, NJ .
We thank Dr Milton Hammond for his support of this
work, and Ms. Amy Bernick and Ms. Debbie Zink for
providing mass spectral data.
Syn th etic 22(S,S). To a solution of 29 (21.0 mg, 0.051
mmol) in CCl4 (2 mL) and CH3CN (2 mL) were added H2O (3
mL), NaIO4 (54.2 mg, 0.25 mmol), and RuCl3 (1.0 mg, 0.0048
mmol). The mixture was stirred at room temperature for 4 h.
After aqueous workup (CH2Cl2), the crude mixture was dis-
solved in ether (5 mL). Ethereal CH2N2 was added until a
steady yellow color was obtained. The mixture was stirred at
room temperature for 5 min. The excess CH2N2 was removed
by passing nitrogen through the mixture. After concentration
in vacuo and purification by PTLC, 14.0 mg (62% yield) of 22-
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of all key compounds and NOE difference spectra of
25 (51 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.
(S,S) was obtained: [R]25 -87.2° (c 0.12, CHCl3). IR 1729,
D
1759, 1806. 1H NMR (CDCl3) δ 1.04 (3H, s), 1.44 (3H, s), 2.90
(1H, d, J ) 17.4), 3.02 (1H, d, J ) 17.4), 3.53 (3H, s), 3.65
(3H, s), 4.34 (1H, d, J ) 12.1), 4.48 (1H, d, J ) 12.1), 7.38
(5H, m). 13C NMR (CDCl3) δ 21.2, 22.4, 38.4, 44.9, 52.6, 55.8,
J O970106L