Optically Pore Dihydroxy γ-Alkylated γ-Butyrolactones Starting from L-Tartaric Acid: Application to Formal and Total Syntheses of Natural Products

Article abstract of DOI:10.1021/jo970117e

A general and efficient preparation of epimeric optically pure γ-butyrolactones 2 and 3 is described starting from L-tartaric acid (1). These lactones are well-known to be important building blocks in the syntheses of natural products. L-Tartaric acid (1) was transformed into carbonylated chirons (ketones 4 and aldehyde 5). These chirons, when submitted to highly stereoselective reactions (reduction or organometallic addition), led to epimeric dihydroxy γ-butyrolactones 2 and 3 after lactonization and deprotection steps. The resulting optically pure lactones are precursors of biological compounds and have allowed a total synthesis of L-biopterin and formal syntheses of quercus lactone, dodecanolactone, avenaciolide, and tetrahydrocerulenin.

Full text of DOI:10.1021/jo970117e

J . Org. Chem. 1997, 62, 4007-4014
4007
Op tica lly P u r e Dih yd r oxy γ-Alk yla ted γ-Bu tyr ola cton es Sta r tin g
fr om L-Ta r ta r ic Acid : Ap p lica tion to F or m a l a n d Tota l Syn th eses
of Na tu r a l P r od u cts
Anne-Marie Fernandez, J ean-Christophe Plaquevent, and Lucette Duhamel*
Universit e´ de Rouen, UPRES A 6014, et IRCOF, F-76821 Mont-Saint-Aignan Cedex, France
Received J anuary 22, 1997X
A general and efficient preparation of epimeric optically pure γ-butyrolactones 2 and 3 is described
starting from L-tartaric acid (1). These lactones are well-known to be important building blocks in
the syntheses of natural products. L-Tartaric acid (1) was transformed into carbonylated chirons
(
(
ketones 4 and aldehyde 5). These chirons, when submitted to highly stereoselective reactions
reduction or organometallic addition), led to epimeric dihydroxy γ-butyrolactones 2 and 3 after
lactonization and deprotection steps. The resulting optically pure lactones are precursors of
biological compounds and have allowed a total synthesis of L-biopterin and formal syntheses of
quercus lactone, dodecanolactone, avenaciolide, and tetrahydrocerulenin.
In tr od u ction
Ch a r t 1
Optically pure γ-butyrolactones have often played a
key role as building blocks in the syntheses of many types
of natural products including antibiotics, pheromones,
and antifungal and flavor components.1
Consequently, many methods dealing with the syn-
theses of chiral substituted γ-butyrolactones have been
published during the last decade. Regarding γ-alkylated
Indeed, many natural products possess a γ-lactonic
1
1d
9a
moietysnotably,
avenaciolide,
γ-caprolactone,
γ-butyrolactones, the syntheses rely upon using starting2
γ-dodecanolactone, quercus lactone,3 and blastmyci-
9a
material from the chiral pool such as glutamic acid,
none13 sor are synthesized from a γ-butyrolactone as are
levoglucosenone,3 ribonolactone,4 glucose,5 xylose,6 or
1
4
2a
9b
7
chalcogran, sulcatols, and cerulenins (Table 1).
The literature results clearly point out that the con-
trolled construction of the stereogenic center at the γ
carbon is troublesome and that the introduction of the
required alkyl group lacks flexibility.
tartaric acid, while other syntheses have taken advan-
8
9
tage of chiral sulfoxides or propargylic alcohols. Several
resolution procedures have been described,10 as well as
1
1
biochemical accesses using enzymatic hydrolyses or
reductions.12 We have been recently interested in the
stereoselective synthesis of the following γ-alkylated
γ-butyrolactones as intermediates in natural product
syntheses (Chart 1).
On the other hand, L-tartaric acid (1) is a inexpensive
natural product that possesses two asymmetric carbons.
Thus, a highly stereoselective reaction could take advan-
tage of those two centers to induce asymmetry in the
third. Furthermore, a stereodivergent strategy based on
L-tartaric acid (1) could give access to two types of
γ-alkylated γ-butyrolactones 2 and 3 that are epimers
at the C4 level (Scheme 1) and that are pivotal chirons
for the stereospecific syntheses of some natural com-
pounds. We wish to present here a strategy that takes
advantage of the two points presented above. Our
approach puts forth the easy transformation of L-tartaric
acid (1) either to ketoesters 4 or to aldoester 5 which are
themselves convenient precursors of epimeric lactones 2
and 3.
X
Abstract published in Advance ACS Abstracts, May 15, 1997.
(
1) (a) Koch, S. S. C.; Chamberlin, A. R. J . Org. Chem. 1993, 58,
2
1
725. (b) Koch, S. S. C.; Chamberlin, A. R. Stud. Nat. Prod. Chem.
995, 16, 687.
(
2) (a) Mori, K. Tetrahedron 1975, 31, 3011. (b) Ravid, U.; Silver-
stein, R. M.; Smith, L. R. Tetrahedron 1978, 34, 1449.
3) Ebata, T.; Matsumoto, K.; Yoshikoshi, H.; Koseki, K.; Kawakami,
H.; Okano, K.; Matsushita, H. Heterocycles 1993, 5, 1017.
4) (a) Camps, P.; Cardellach, J .; Font, J .; Ortu n˜ o, R. M.; Ponsati,
(
(
O. Tetrahedron 1982, 38, 2395. (b) Cardellach, J .; Font, J .; Ortu n˜ o, R.
M. J . Heterocycl. Chem. 1984, 21, 327.
(5) (a) Ohrui, H.; Emoto, S. Tetrahedron Lett. 1975, 3657. (b)
Anderson, R. C.; Fraser-Reid, B. J . Am. Chem. Soc. 1975, 97, 3870. (c)
Ohrui, H.; Emoto, S. Tetrahedron Lett. 1978, 2095.
(
6) Pougny, J . R.; Sina y¨ , P. Tetrahedron Lett. 1978, 3301.
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2
7, 1079. (b) Rama Rao, A. V.; Reddy, E. R.; J oshi, B. V.; Yadav, J . S.
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Mandville, G.; Ahmar, M.; Bloch, R. J . Org. Chem. 1996, 61, 1122. (c)
Sala u¨ n, J .; Karkour, B. Tetrahedron Lett. 1988, 29, 1537. (d) Tsuboi,
S.; Sakamoto, J .; Sakai, T.; Utaka, M. Chem. Lett. 1989, 1427. (e) Sugai,
T.; Mori, K. Agric. Biol. Chem. 1984, 48, 2497. (f) Takahata, H.; Uchida,
Y.; Momose, T. Tetrahedron Lett. 1994, 35, 4123. (g) Takahata, H.;
Uchida, Y.; Momose, T. J . Org. Chem. 1995, 60, 5628.
(12) (a) Mori, K.; Mori, H.; Sugai, T. Tetrahedron 1985, 41, 919. (b)
Naoshima, Y.; Osawa, H.; Kondo, H.; Hayashi, S. Agric. Biol. Chem.
1983, 47, 1431. (c) Tsuboi, S.; Sakamoto, J .; Sakai, T.; Utaka, M. Synlett
1991, 867. (d) Utaka, M.; Watabu, H.; Takeda, A. J . Org. Chem. 1987,
52, 4363. (e) Kozikowski, A. P.; Murgrage, B. B.; Li, C. S.; Felder, L.
Tetrahedron Lett. 1986, 27, 4817.
Tetrahedron Lett. 1987, 28, 6497. (c) Yoda, H.; Shirakawa, K.; Takabe,
K. Tetrahedron Lett. 1991, 32, 3401. (d) Yoda, H.; Katagiri, T.; Takabe,
K. Tetrahedron Lett. 1991, 32, 6771.
(8) (a) Solladi e´ , G.; Matloubi-Moghadam, F. J . Org. Chem. 1982, 47,
9
1
1
1. (b) Kosugi, H.; Konta, H.; Uda, H. J . Chem. Soc., Chem. Commun.
985, 211. (c) Kosugi, H.; Watanabe, Y.; Uda, H. Chem. Lett. 1989,
865.
(9) (a) Vigneron, J . P.; Bloy, V. Tetrahedron Lett. 1980, 21, 1735.
(
(
b) Vigneron, J . P.; Blanchard, J . M. Tetrahedron Lett. 1980, 21, 1739.
c) Mukaiyama, T.; Suzuki, K. Chem. Lett. 1980, 255. (d) Midland, M.
M.; Tramontano, A. Tetrahedron Lett. 1980, 21, 3549. (e) Noyori, R.;
Tomino, I.; Yamada, M.; Nishizawa, M. J . Am. Chem. Soc. 1984, 106,
6
717.
10) (a) Pirkle, W. H.; Adams, P. E. J . Org. Chem. 1979, 44, 2169.
(13) Cardellach, J .; Font, J .; Ortu n˜ o, R. M. Tetrahedron Lett. 1985,
26, 2815.
(
(
(
b) Fuji, K.; Node, M.; Murata, M. Tetrahedron Lett. 1986, 27, 5381.
c) G u¨ nther, C.; Mosandl, A. Liebigs Ann. Chem. 1986, 2112.
(14) Smith, L. R.; Williams, H. J .; Silverstein, R. M. Tetrahedron
Lett. 1978, 3231.
S0022-3263(97)00117-5 CCC: $14.00 © 1997 American Chemical Society

4
008 J . Org. Chem., Vol. 62, No. 12, 1997
Fernandez et al.
Ta ble 1
Sch em e 2
Sch em e 1
P r ep a r a tion of Keton es 4. Conversion of L-tartaric
acid (1) into ketones 4 required the preliminary synthesis
of thioester 8, which was achieved via either the acid
choride 617 or the acid 7 (Scheme 2). An incomplete
reaction and a partial hydrolysis of 8 during purification
by chromatography on silica gel explained the decreased
yield (75%) obtained by direct conversion of 7 to 8.
Consequently, synthesis of thioester 8 was more efficient
using Mukaiyama’s procedure17 (95% yield from acid
chloride 6). Thioester 8 was submitted to a Grignard
reaction, which introduced the alkyl residues R (Me, Et,
n-Bu, n-Oct) for the preparation of the desired ketones
18
4
a -d (Scheme 2, Table 2).
Syn th esis of Ca r bon yla ted Ch ir on s: Keton es 4
Table 2 summarizes the results.
a n d Ald eh yd e 5. The general method for the prepara-
tion of these chirons is presented in Scheme 2. The
hydroxyl functions of L-tartaric acid (1) were protected
before undergoing further transformation: pivaloyl pro-
tecting groups were preferentially chosen instead of
acetyl groups, the latter having provided unsatisfactory
results.15 Acid choride 6, which can be prepared following
a well-known literature procedure from L-tartaric acid
The addition of Grignard reagents occured exclusively
on the thioester function and not on the ester moiety.
Strict control of the reaction conditions avoided the
1
9
formation of the undesirable dialkylated lactones 9,
which were obtained as byproducts when more drastic
conditions were employed (higher temperaturesTable 2,
entries 1, 4, and 6sor longer reaction timesTable 2,
entries 2 and 7). An incomplete reaction was observed
under more dilute conditions (Table 2, entries 9, 11).
Ketones 4a -c were obtained in 85-90% yield at -15 °C
1
6
(1), is the common precursor of ketones 4 and aldehyde
5
.
(15) (a) Al-Bayati, Y. Th e` se de doctorat, 1989, University of Rouen,
France. (b) Fernandez, A. M. Th e` se de doctorat, 1996, University of
Rouen, France.
(
16) (a) Duhamel, L.; Plaquevent, J . C. Org. Prep. Proced. Int. 1982,
(17) Araki, M.; Sakata, S.; Takei, H.; Mukaiyama, T. Bull. Chem.
Soc. J pn 1974, 47, 1777.
(18) Lloyd, K.; Young, G. T. J . Chem. Soc. C 1971, 2890.
1
4, 347. (b) Duhamel, L.; Herman, T.; Angibaud, P. Synth. Commun.
992, 22, 735.
1

Optically Pure Dihydroxy γ-Alkylated γ-Butyrolactones
Ta ble 2. Syn th esis of Keton es 4a -d fr om Th ioester s 8
J . Org. Chem., Vol. 62, No. 12, 1997 4009
Sch em e 3
dialkylated
c
T
t
ketone 4:
lactone 9:
entry
RMgXa
(°C) (min) yield (%)
b
yield (%)
b
1
2
3
3 M MeMgBr
-5
-15
-15
30
60
45
4a : 60
4a : 68
4a : 90
9a : 20
9a : 12
9a : 5
4
5
1 M EtMgBr
-5
-15
30
45
4b: 70
4b: 90
9b: 6
9b
d
6
7
8
2 M n-BuMgCl
-5
-15
-15
-15
30
75
45
45
4c: 87
4c: 75
4c: 90
9c: 3
9c: 10
d
9c
9c
e
e
d
9
4c: 60
1
1
1
0
1
2
2 M n-OctMgCl -15
75
75
75
no reaction
4d : 50
4d : 85
e
e
9d d
9d
-5
-5
d
a
.1 equiv. After chromatography. c See ref 19. d 9 is not
b
1
e
detected. Diluted medium (0.1 M in THF instead of 1 M in THF
for other entries). Under these conditions, ca. 35% of the starting
material 8 was retrieved after the experiment.
for 45 min (Table 2, entries 3, 5, and 8), whereas 4d was
obtained in 85% yield at -5 °C for 75 min (Table 2, entry
1
2).
P r ep a r a tion of Ald eh yd e 5. This compound was
prepared by reaction of acid chloride 6 with bistriph-
3 2 4
enylphosphine copper borohydride (Ph P) CuBH under
mild conditions20 (Scheme 2). Two equiv of triphenylphos-
phine was added, one to bind to the copper byproduct
and the other to trap liberated BH (eq 1).
3
aldehyde) (Scheme 3). Reduction of ketones 4 led to
alcohols 12, which after a lactonization step, yielded
lactones 10.
2
Ph P,
3
On the other hand, Grignard reactions on aldehyde 5
led directly to lactones 11 (epimers of 10) without
isolation of intermediate alcohols 13. Both series of
lactones were obtained in optically pure form.
Red u ction of Keton es 4. Preliminary experiments
have been run mainly on the ketone 4c (R ) n-Bu) (Table
acetone
8
rt
(
Ph P) CuBH + RCOCl
3
2
4
(
Ph P) CuCl + RCHO + Ph PBH (1)
3
3
3
3
The excess of Ph
3
P was removed by stirring a chloro-
form solution of the crude product with cuprous chloride
and then subjecting the resulting aldehyde 5 to purifica-
tion by flash chromatography on silica gel. The complex
3
8
, entries 1-7) and on ketone 4a (R ) Me) (Table 3, entry
).
Lactone 10c (major product) was directly obtained with
(
Ph
titative yield.
unreactive toward all common functional groups with the
3
P)
3
CuCl may be recycled to (Ph
3
P)
2 4
CuBH in quan-
Zn(BH
in a mixture of solvents (Table 3, entry 2) as well as with
NaBH in THF (Table 3, entry 3). In these cases, yields
4 2
) when used either in THF (Table 3, entry 1) or
2
1
It is noteworthy that the reagent is
4
2
0d
exception of acid halides and iminium salts.
the reagent, which is inert to both oxygen and water, has
an indefinite shelf life.
Finally, aldehyde 5 was obtained without epimeriza-
tion in very good yield after purification (Scheme 2).
Thus, L-tartaric acid (1) has allowed the preparation of
two types of carbonylated chirons: the ketones 4 and the
aldehyde 5. They were obtained in very good yields on
a multigram scale (Scheme 2).
Syn th esis of γ-Alk yla ted γ-Bu tyr ola cton es 10 a n d
1. Development of highly stereoselective reactions was
accomplished by reduction of ketones 4 and by addition
of Grignard reagents to aldehyde 5. A preferential attack
occured on the Si face of carbonyl groups (ketone,
Moreover,
and de were poor.
As is usually observed, the reactivity of NaBH
4
is
dependent on the solvent. In EtOH, ketone 4c was not
reduced at all at -15 °C (Table 3, entry 4) but was totally
reduced into diol i22 at 0 °C (Table 3, entry 5). On the
other hand, excellent results were obtained when NaBH
was used in MeOH, followed by acidic hydrolysis (Table
, entry 6). In this case, alcohol 12c was isolated in both
very good yield and high de. The spontaneous lacton-
ization, which occurred in THF and Et O (Table 3, entries
-3), was not observed because of the protonation of the
intermediate alkoxide by MeOH.
4
3
2
1
1
In a complementary study, we tried to modify the
stereoselectivity at the C4 level by using either cerium
chloride as an additive23 with NaBH
(Table 3, entry 7)
4
(
19) The byproduct 9 resulted from a partial dialkylation of the
or by using another reducing agent (Table 3, entry 8).
However, the expected inversion was not observed. In
thioester 8 in some experiments.
(
22) Formation of diol i, in two cases, during the reduction with
NaBH : (a) NaBH , EtOH, 0 °C (Table 3, entry 5); (b) NaBH , MeOH,
70 °C followed by hydrolysis with H O.
4
4
4
-
2
(
20) (a) Sorrell, T. N.; Pearlman, P. S. J . Org. Chem. 1980, 45, 3449.
b) Sorrell, T. N.; Spillane, R. J . Tetrahedron Lett. 1978, 2473. (c) Fleet,
G. W. J .; Fuller, C. J .; Harding, P. J . C. Tetrahedron Lett. 1978, 1437.
d) Fleet, G. W. J .; Harding, P. J . C. Tetrahedron Lett. 1979, 975.
21) Cariati, F.; Naldini, L. Gazz. Chim. Ital. 1965, 95, 3.
(
(
(

4
010 J . Org. Chem., Vol. 62, No. 12, 1997
Fernandez et al.
Ta ble 3. Red u ction of Keton es 4. P r elim in a r y Exp er im en ts
reducing agent workup
starting
material
major product:
entry
(equiv)
solvent
T, °C (time, h)
conditions (T, °C)
yielda (%) (de (%))
1
2
4c
Zn(BH4)2 (2.5)
THF
Et2O/THF 1/1
-10 (1) and rt (2)
-10 (1) and rt (2)
HCl 3M (0)
HCl 3M (0)
10c: 60 (70)
10c: 50 (60)
3
4
5
6
4c
NaBH4 (0.8)
(1.5)
(2)
THF
-70 (1)
-15 (1)
0 (1)
H2O (-70)
H2O (-15)
H2O (0)
10c: 47 (40)
EtOH
EtOH
MeOH
no reaction
b
d iol i: 50
(1.1)
-70 (45 min)
HCl 3 M (-70)
12c: 85 (>98)
7
4c
4a
NaBH4 (1)
CeCl3-7H2O (1)
MeOH
-70 (1)
H2O (-70)
12c: 60 (>98)
8
NaBH(OAc)3 (2)
CH2Cl2
rt (4)
H2O
12a : 60 (>98)
a
Chromatographed product. b See ref 22.
Ta ble 4. Red u ction of Keton es 4a -d w ith Na BH4.
Ta ble 6. La cton iza tion of Alcoh ols 12a -d . Op tim ized
a
Con d ition sa
Op tim ized Con d ition s
b
c
b
c
R
alcohol 12
t
yield (%)
ee (%)
R
lactone 10
yield (%)
ee (%)
Me
Et
n-Bu
n-Oct
12a
12b
12c
12d
3 h 30 min
1 h
45 min
75 min
80d
85
85
90
>98
>98
>98
>98
Me
Et
n-Bu
n-Oct
10a
10b
10c
10d
97
95
95
90
>98
>98
>98
>98
a
b
a
1 equiv of TsOH, 4 h, rt. b After chromatography. c As checked
1
.1 equiv of NaBH4, MeOH, -70 °C. After chromatography.
c
1
d
by 1H NMR, showing no signals of epimeric lactones 11.
As checked by H NMR. Accompanied by 10% of lactone 10a .
Ta ble 5. La cton iza tion of Alcoh ol 12d . P r elim in a r y
Exp er im en ts
Ta ble 7. Gr ign a r d Rea ction on Ald eh yd e 5
lactone 11:
a
TsOH
RMgX (1.5 equiv)
T (°C)
t (h)
yield (%)
1a : 88
11b: 85
1c: 90
1d : 90
entry
time (h)
(equiv)
products (yield (%))
MeMgBr
3 M in Et2O
-70
and rt
12
2
1
1
2
3
4
24
4
4
1
0.5
1
10d (60), 14d a (20)
10d (70), 12d (30)
b
EtMgBr
1 M in THF
-50
and rt
3
2
10d (90)
10d (80), 14d a (20)
4
2
a
See ref 25. b After chromatography, ee >98%.
n-BuMgCl
M in THF
-25
and rt
2
2
1
2
all cases, the same alcohol was obtained with excellent
de, suggesting a very strong substrate control for the
asymmetric induction.
n-OctMgCl
M in THF
-25
and rt
1
3
1
2
a
After chromatography, ee > 98%, as checked by 1H NMR
(showing no signals of epimeric lactones 10).
The best conditions (NaBH
by acidic hydrolysis) were extended to the other ketones
4
, MeOH, -70 °C, followed
2
). Best conditions were obtained in the presence of 1
4
4
, giving satisfactory results in all cases (Scheme 3, Table
equiv of TsOH (Table 5, entry 3). This method was
applied to the cyclization of other alcohols 12 (Table 6).
Using these conditions, the synthesis of four optically
pure γ-alkylated γ-butyrolactones 10 was achieved
).
Alcohols 12 were obtained with high stereoselectivity
and good yields using the procedure previously described.
In contrast to the literature,24 we observed that the
(
Scheme 3). No epimeric lactones 11 or 14 were detected.
reduction by Zn(BH
NaBH when carried out on our chirons.
La cton iza tion Step of Alcoh ols 12. TsOH in CH
was used for lactonization (Scheme 3). The determi-
4 2
) was less stereoselective than by
The relative configuration of lactones 10 was determined
4
by high-field NMR analysis (NOEDS).26
2
-
Gr ign a r d R ea ct ion on Ald eh yd e 5. After the
search for the best reaction conditions, we observed that
addition of Grignard reagents led to lactones 11 with high
stereoselectivity (ee > 98%) without isolation of the
intermediate alcohols 13 (Scheme 3, Table 7). The
addition step was performed at low temperature, and the
lactonization occurred during warming to rt, yielding
lactones 11 in both good yields (85-90%) and high ee
Cl
2
nation of optimized conditions was carried out using the
alcohol 12d (R ) n-Oct) (Scheme 3, Table 5).
Extended reaction times or excess TsOH resulted in
the formation of lactone 14d (C2 epimer of lactone 10d ,
Table 5). Moreover, incomplete conversion was observed
when less than 1 equiv of TsOH was used (Table 5, entry
(
>98%) (Table 7).
(23) (a) Gemal, A. L.; Luche, J . L. J . Am. Chem. Soc. 1981, 103,
These lactones are the C4 epimers27 of those obtained
5
1
454. (b) Krief, A.; Surleraux, D.; Frauenrath, H. Tetrahedron Lett.
988, 29, 6157. (c) Krief, A.; Surleraux, D. Synlett 1991, 273.
by reduction of ketones 4 (Scheme 3). This approach
(24) (a) Nakata, T.; Oishi, T. Tetrahedron Lett. 1980, 21, 1641. (b)
Nakata, T.; Tanaka, T.; Oishi, T. Tetrahedron Lett. 1981, 22, 4723. (c)
Iida, H.; Yamazaki, N.; Kibayashi, C. J . Org. Chem. 1986, 51, 3769.
(
26) Fernandez, A. M.; J acob, M.; Gralak, J .; Al-Bayati, Y.; Pl e´ , G.;
Duhamel, L. Synlett 1995, 431. Irradiation of the protons on C5 has
led to the unambigous observation of a selective Overhauser effect on
H2 from 3 to 9%.
(25) Lactone 14d , epimer in C2 of the desired lactone 10d , was
observed under the following conditionsslong duration time or excess
of TsOHsduring the lactonization step (Table 5, entries 1-4). Irradia-
tion of the proton H4 led to a selective Overhauser effect on H2 (4%).

Optically Pure Dihydroxy γ-Alkylated γ-Butyrolactones
J . Org. Chem., Vol. 62, No. 12, 1997 4011
Sch em e 4
Sch em e 6a
a
Key: (i) HCl 3 M/dioxane 2/1 reflux, 18 h (except R ) n-Oct,
t ) 48 h)
Sch em e 5
in acidic conditions. In both cases, the lactone 2 was
directly obtained. In the (4S) series, only the lactone 11a
has been deprotected (Scheme 6).
Lactones 2a -c and 3a were obtained following the
same procedure (refluxing in dioxane with HCl 3 M for
1
8 h) (Scheme 6). For the lactone 2d (R ) n-Oct), the
deprotection was more fastidious. The corresponding
protected lactone 10d remained present even when the
reaction time was increased. This slower deprotection
rate may be due to the steric hindrance of the octyl group.
Optical rotations of dihydroxy lactones 2d and 3a were
in total agreement with literature values7
c,31
(see the
constitutes an efficient stereodivergent method to obtain
optically pure γ-butyrolactones (Scheme 3), since the two
complementary routes (via ketones 4 or via aldehyde 5)
yield, in optically pure form, eight epimeric protected
lactones 10 and 11 starting from a single precursor,
L-tartaric acid (1).
Discu ssion for th e Obser ved Selectivity. Results
for the addition and reduction steps are summarized in
Scheme 4.
Experimental Section). Thus, both lactonization and
deprotection were carried out without epimerization.
In this part of the work, five of the eight protected
lactones 10 and 11 have been deprotected, and some of
them are precursors of natural products. The following
part describes the synthetic utility of these compounds.
Syn th etic Ap p lica tion s of Op tica lly P u r e La c-
ton es 2 a n d 3. F or m a l Syn th eses of Na tu r a l P r od -
3
2
u cts Sta r tin g fr om 2c,d . Quercus lactone, dodecano-
lactone,33 avenaciolide, and tetrahydrocerulenin have
been prepared from the corresponding butenolides (Scheme
7). As the synthesis of these butenolides has been carried
out from dihydroxy lactones 2c and 2d , we have realized
the formal syntheses of all these products with overall
yields comparing favorably well with literature syntheses
(Scheme 7).
34
35
The same induction sense and level of selectivity are
observed in reactions of ketones 4 with NaBH and of
4
aldehyde 5 with RMgX. This suggests that the transition
state could be similar. Moreover, it is well-known that
the contribution of the chelated transition state (Cram’s
model,28 Scheme 5) involving the sodium cation is not
2
9
favored, especially in alcohols as solvents. For these
two reasons, Felkin’s model30 is the more appropriate in
Obviously, with the method described here, all these
products can be synthesized in optically pure form. Since
D-tartaric acid is also a cheap commercially available
material, both enantiomeric forms can be prepared with
this method.
both cases (NaBH
4
and RMgX) (Scheme 5). In this
model, the more polar group is located at the side opposite
to the entry of the nucleophile leading to the observed
selectivity in which the attack occurs at the Si face.
Syn th esis of Dih yd r oxy La cton es 2 a n d 3: Dep r o-
tection Step . In the (4R) series, this step has been run
either from alcohols 12 or from lactone 10a (90% yield)
Tota l Syn th esis of L-Biop ter in Sta r tin g fr om 3a .
Through its tetrahydro form, L-biopterin functions as an
essential enzyme cofactor in the metabolism of amino
acids. For example, it plays a well-documented role for
(27) Irradiation of the proton H4 led to a selective Overhauser effect
37
the conversion of phenylalanine to tyrosine, tyrosine to
on H2 (5%).
(
31) Torii, S.; Inokuchi, T.; Masatsugu, Y. Bull. Chem. Soc. J pn
985, 58, 3629.
32) Quercus lactone is identified as a key aroma component of aged
1
(
3
alcoholic beverages such as whisky, brandy, and wines.
9
a
(33) Dodecanolactone is a defensive secretion of rove beetles.
(
34) Avenaciolide is an antifungal agent first isolated from Aspergil-
1
1d
lus avenaceus.
(
35) Tetrahydrocerulenin results of the catalytic hydrogenation of
9b
(
(
(
28) Cram, D. J .; Elhafez, F. A. A. J . Am. Chem. Soc. 1952, 74, 5828.
29) Bartlett, P. A. Tetrahedron 1980, 3.
30) Ch e´ rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
the natural cerulenin.
(36) Yoda, H.; Shirakawa, K.; Takabe, K. Chem. Lett. 1991, 489.
(37) Rembold, H.; Gyure, W. L. Angew. Chem., Int. Ed. Engl. 1972,
1
8, 2199.
11, 1061.

4
012 J . Org. Chem., Vol. 62, No. 12, 1997
Fernandez et al.
Sch em e 7
Sch em e 8
phenylhydrazine in MeOH gave phenylhydrazone 16.
This compound, after acetylation, was allowed to react
with 2,5,6-triamino-4-pyrimidinol and then oxidized with
2
I . Deprotection led to L-biopterin (Scheme 8). This new
synthesis of biopterin exemplifies the strong potential for
the construction of chiral compounds of the γ-butyrolac-
tones prepared herein.
Con clu sion
Starting from L-tartaric acid (1), we developed an
efficient, general, and stereodivergent method of prepa-
ration of γ-alkylated γ-butyrolactones, epimers in the C4
position.
Τwo highly stereoselective reactions on carbonyl chi-
rons allowed the obtention of these lactones with ee >
9
8%. These last compounds are precursors of biological
DOPA,38 melanine synthesis,39 and tryptophan hydroxy-
lation.40 Thus, tetrahydrobiopterin has been proposed as
a remedy for CNS diseases such as phenylketonuria,
Parkinson’s and Alzheimer’s diseases, and depression.
We recently described the first synthesis of L-biopterin
molecules. Thus, formal syntheses of four natural prod-
ucts were realized, and a new total synthesis of L-
biopterin was achieved.
In our strategy, alkyl groups were introduced by means
of Grignard reagents. Thus, because of the wide avail-
ability of organometallic reagents, we think that this
method could be extended to other optically pure γ-func-
tionalized γ-butyrolactones such as â-angelica lactone,
eldanolide, or chrysantemic acid.44
4
1
from L-tartaric acid (1) via the γ-butyrolactone 3a
prepared in this work (Scheme 8).42
The key intermediate, 5-deoxy-L-arabinose (15), was
obtained by reduction of the lactone 3a with DIBALH.42
L-Biopterin was prepared using slight modifications of
literature procedures.42,43 Treatment of lactol 15 with
Exp er im en ta l Section
Physical methods have been described.42 Syntheses of
compounds 3a , 5, 15, 16, and L-biopterin have already been
(
38) (a) Nagatsu, T.; Levitt, M.; Udenfriend, S. J . Biol. Chem. 1964,
39, 2910. (b) Lloyd, T.; Weiner, N. Mol. Pharmacol. 1971, 7, 569.
39) (a) Ziegler, I. Z. Naturforsch. 1963, 18b, 551. (b) Kokolis, N.;
Ziegler, I. Z. Naturforsch. 1968, 23b, 860.
40) (a) Gal, E. M.; Armstrong, J . C.; Ginsberg, B. J . Neurochem.
966, 13, 643. (b) Hosoda, S.; Glick, D. J . Biol. Chem. 1966, 241, 192.
c) Noguchi, T.; Nishino, M.; Kido, R. Biochem. J . 1973, 131, 375.
41) Nagatsu, T.; Matsuura, S.; Sugimoto, T. Med. Res. Rev. 1989,
, 25.
2
(44) These compounds have been prepared using lactones as syn-
thetic intermediates. See, for example: (a) â-Angelica lactone: Camps,
P.; Cardellah, J .; Corbera, J .; Font, J .; Ortu n˜ o, R. M.; Ponsati, O.
Tetrahedron 1983, 39, 395. (b) Eldanolide: Vigneron, J . P.; M e´ ric, R.;
Larchev eˆ que, M.; Debal, A.; Kunesch, G.; Zagatti, P.; Gallois, M.
Tetrahedron Lett. 1982, 23, 5051. Vigneron, J . P.; M e´ ric, R.; Larchev-
eˆ que, M.; Debal, A.; Lallemand, J . Y.; Kunesch, G.; Zagatti, P.; Gallois,
M. Tetrahedron 1984, 40, 3521. Ortu n˜ o, R. M.; Font, J .; Merce, R.
Tetrahedron 1987, 43, 4497. Sarmah, B. K.; Barua, N. C. Tetrahedron
1993, 49, 2253. (c) Chrysantemic acid: Franck-Neumann, M.; Sedrati,
M.; Vigneron, J . P.; Bloy, V. Angew. Chem., Int. Ed. Engl. 1985, 24,
996. Mann, J .; Thomas, A. Tetrahedron Lett. 1986, 3533.
(
(
1
(
(
9
(
(
42) Fernandez, A. M.; Duhamel, L. J . Org. Chem. 1996, 61, 8698.
43) (a) Schircks, B.; Bieri, J . H.; Viscontini, M. Helv. Chim. Acta
1
985, 68, 1639. (b) Mori, K.; Kikuchi, H. Liebigs Ann. Chem. 1989,
267.
1

Optically Pure Dihydroxy γ-Alkylated γ-Butyrolactones
described.42 Acid chloride 6 was obtained following the
literature procedures in 87% yield (oil) from 1. Coupling
constants (J ) are reported in Hz.
J . Org. Chem., Vol. 62, No. 12, 1997 4013
38.8, 52.4, 70.6, 76.1, 166.7, 176.6, 176.8, 203.3; MS (CI/t-BuH)
1
6
+
23
m/ z 429 [M + H] ; [R]
for C23 : C, 64.49; H, 9.41. Found: C, 64.59; H, 9.42.
Red u ction of Keton es 4 w ith Na BH . Gen er a l P r oce-
d u r e. To a solution of ketone 4 (2 mmol) in MeOH (25 mL)
at -70 °C was added, under nitrogen, NaBH (1.1 equiv, 2.2
D
-3.0 (c 20.6, CHCl
3
). Anal. Calcd
40 7
H O
(
2R,3R)-Meth yl-2,3-d ip iva loxy-3-[(2-p yr id in ylth io)ca r -
4
1
6
bon yl]p r op a n oa te (8). To acid chloride 6 (10.0 g, 28.5
mmol) in THF (56 mL), at 0 °C, was added 2-mercaptopyridine
4
(
3.17 g, 28.5 mmol). After the mixture was stirred overnight
at rt, THF was evaporated, and the residue was treated with
Et O (56 mL) and then neutralized with a saturated NaHCO
solution. After extraction with Et O, the organic layer was
dried and evaporated. The crude product was purified by
chromatography on silica gel (PE/Et O 1/1) to give thioester 8
mmol, 84 mg). After the mixture was stirred at -70 °C, during
t, until the starting material had disappeared (TLC), 3 M HCl
was added until pH ) 5 and then distilled water. The reaction
mixture was then allowed to warm to rt. The solvents were
removed by evaporation, the residue treated with ether and
distilled water, and then the organic layer dried and evapo-
rated. After purification on silica gel (PE/Et O 4/1), the single
2
alcohols 12 were obtained in 80-88% yield. Enantiomeric
purities were assumed according to NMR data.
2
3
2
2
-
1
1
(
(
11.5 g, 95%, oil): IR (neat) 1767, 1744, 1709 cm ; H NMR
CDCl ) δ 1.20 (s, 9H), 1.26 (s, 9H), 3.66 (s, 3H), 5.52 (d, 1H,
3
J ) 2.2), 5.89 (d, 1H, J ) 2.2), 7.24 (dd, 1H, J ) 5, 7.7), 7.48
(
4
1
NH
Calcd for C20
5
d, 1H, J ) 7.8), 7.68 (td, 1H, J ) 7.7, 1.9), 8.54 (dd, 1H, J )
Note: The workup must begin with an acidic treatment as
1
3
22
.9, 1.8); C NMR (CDCl
3
) δ 26.8, 38.7, 52.7, 70.9, 75.7, 123.9,
described in order to avoid the formation of diol i.
30.2, 137.4, 149.8, 150.5, 166.4, 176.2, 176.6, 193.8; MS (CI/
(2R ,3S ,4R )-Me t h y l-2,3-d ip iv a lo x y -4-h y d r o x y p e n -
ta n oa te (12a ): t, 3 h 30 min; yield 80%, oil; IR (neat) 3524,
+
26
3
) m/ z 426 [M + H] ; [R]
S: C, 56.46; H, 6.49; N, 3.29. Found: C,
6.52; H, 6.46; N, 3.35.
Syn th esis of Keton es 4. Gen er a l P r oced u r e. To a
D
3
+27.7 (c 3, CHCl ). Anal.
-
1
1
H
27NO
7
1738 cm ; H NMR (CDCl
1H), 3.64 (s, 3H), 3.95 (m, 1H), 5.09-5.15 (m, 2H); C NMR
(CDCl ) δ 18.9, 26.8, 26.9, 38.6, 38.9, 52.4, 66.7, 70.8, 74.7,
167.9, 177.3, 177.6; MS (CI/t-BuH) m/ z 333 [M + H] ; [R]
-17.6 (c 1.2, CHCl ). Anal. Calcd for C16 : C, 57.98; H,
8.49. Found: C, 58.08; H, 8.51.
3
) δ 1.15-1.18 (m, 21H), 2.45 (m,
13
3
+
23
solution of thioester 8 (2.0 g, 4.7 mmol) in THF (56 mL) was
added, under nitrogen, at the temperature T, the appropriate
Grignard reagent (5.2 mmol). The reaction was followed by
TLC until the starting material had disappeared. After the
time t, the reaction mixture was hydrolyzed at the temperature
D
3
28 7
H O
Note: After the chromatography of alcohol 12a , 10% of
lactone 10a was also isolated.
T with a saturated NH
warmed to rt, the organic layer was extracted twice with Et
dried, filtered, and evaporated. The oil was purified by
chromatography on silica gel (PE/Et O 90/10).
Note: the ketone 4a was always present with dialkylated
lactone 9a , which was easily separated under the chromato-
graphic conditions.
4
Cl solution. After the mixture was
(2R ,3S ,4R )-Me t h y l-2,3-d ip iv a lo x y -4-h y d r o x y h e x -
a n oa te (12b): t, 1h; yield 85%, oil; IR (neat) 3538, 1734 cm ;
-
1
2
O,
1
H NMR (CDCl ) δ 0.94 (t, 3H, J ) 7.3), 1.17 (s, 9H), 1.20 (s,
3
2
9H), 1.35-1.52 (m, 2H), 2.15-2.29 (m, 1H), 3.67 (s, 3H), 3.69-
3.71 (m, 1H), 5.16 (dd, 2H, J ) 3.6, 6.9), 5.21 (d, 1H, J ) 3.7);
1
3
C NMR (CDCl ) δ 9.8, 26.0, 26.8, 27.0, 38.6, 38.9, 52.4, 70.9,
3
72.0, 73.3, 168.0, 177.3, 177.5; MS (CI/t-BuH) m/ z 347 [M +
+
25
(
2R,3R)-Meth yl-2, 3-d ip iva loxy-4-oxop en ta n oa te (4a ):
MgBr 3 M in Et O (1.7 mL, 5.2 mmol); T, -15 °C; t, 45
H] ; [R]
D
3 30 7
-10.4 (c 1.8, CHCl ). Anal. Calcd for C17H O :
CH
3
2
C, 58.96; H, 8.67. Found: C, 59.08; H, 8.90.
-1 1
min; yield 80%, oil; IR (neat) 1767, 1740 cm ; H NMR (CDCl
3
)
( 2 R ,3 S ,4 R ) -M e t h y l -2 ,3 -d i p i v a l o x y -4 -h y d r o x y -
octa n oa te (12c): t, 45 min; yield 85%, oil; IR (neat) 3521,
δ 1.20 (s, 9H), 1.23 (s, 9H), 2.16 (s, 3H), 3.70 (s, 3H), 5.51 (d,
H, J ) 2.4), 5,55 (d, 1H, J ) 2.4); 13C NMR (CDCl
7.0, 38.5, 52.5, 70.6, 76.3, 166.6, 176.7, 201.6; MS (CI/NH
) δ 26.7,
-1 1
1
2
3
1738 cm ; H NMR (CDCl
3
) δ 0.83 (t, 3H, J ) 6.3), 1.15-1.21
3
)
(m, 22H), 1.29-1.34 (m, 2H), 2.35-2.45 (m, 1H), 3.66 (s, 3H),
+
26
13
m/ z 331 [M + H] ; [R]
for C16 : C, 58.17; H, 7.93. Found: C, 58.00; H, 7.30.
2R,3S)-2,3-Dip iva loxy-4-d im eth ylbu tyr ola cton e (9a ):
byproduct of 4a ; white solid, 5%; mp 63-66 °C; IR (neat) 1800,
D
-10.0 (c 1.5, CHCl
3
). Anal. Calcd
3.72-3.79 (m, 1H), 5.20-5.25 (m, 2H); C NMR (CDCl ) δ
3
H
26
O
7
13.8, 22.3, 26.8, 27.0, 27.4, 32.5, 38.6, 38.9, 52.4, 70.5, 70.9,
+
(
73.6, 168.0, 177.2, 177.5; MS (CI/t-BuH) m/ z 375 [M + H] ;
[R]23
D
3 34 7
-8.5 (c 2.4, CHCl ). Anal. Calcd for C19H O : C, 60.94;
-
1 1
1
743 cm ; H NMR (CDCl
3
) δ 1.20 (s, 9H), 1.22 (s, 9H), 1.41
H, 9.15. Found: C, 60.95; H, 9.00.
(
s, 3H), 1.53 (s, 3H), 5.30 (d, 1H, J ) 7.9), 5.60 (d, 1H, J ) 8);
(2R ,3S ,4R )-M e t h y l-2,3-d i p i v a lo x y -4-h y d r o x y d o -
d eca n oa te (12d ): t, 75 min; yield 90%, oil; IR (neat) 3524,
1
3
C NMR (CDCl
3
) δ 22.5, 26.8, 27.1, 38.6, 38.7, 71.7, 77.3, 82.5,
+
-1 1
1
68.1, 176.8, 177; MS (CI/t-BuH) m/ z 315 [M + H] , 332 [M
1738 cm ; H NMR (CDCl
3
) δ 0.82 (t, 3H, J ) 6.0), 1.17-1.21
+
4 26 6
] . Anal. Calcd for C16H O : C, 61.15; H, 8.28.
+
NH
Found: C, 60.96; H, 8.48.
2R,3R)-Meth yl-2, 3-d ip iva loxy-4-oxoh exa n oa te (4b):
EtMgBr 1 M in THF (5.2 mL, 5.2 mmol); T, -15 °C; t, 45 min;
(m, 30H), 1.31-1.40 (m, 2H), 2.10-2.13 (m, 1H), 3.67 (s, 3H),
3.71-3.77 (m, 1H), 5.15-5.20 (m, 2H); 13C NMR (CDCl
) δ
3
(
14.0, 22.5, 25.2, 26.8, 27.0, 29.1, 29.3, 29.6, 31.7, 32.9, 38.7,
38.9, 52.4, 70.6, 70.9, 73.6, 168.6, 177.3, 177.5; MS (CI/t-BuH)
-
1
1
+
25
yield 90%, oil; IR (neat) 1769, 1741 cm ; H NMR (CDCl
3
) δ
m/ z 431 [M + H] ; [R]
for C23 : C, 64.16; H, 9.83. Found: C, 64.06; H, 10.07.
La cton iza tion Step . Gen er a l P r oced u r e. To a solution
of alcohol 12 (1 mmol) in CH Cl (15 mL) at rt was added TsOH
D
-9.2 (c 1.6, CHCl
3
). Anal. Calcd
0
.97 (t, 3H, J ) 7.2), 1.17 (s, 9H), 1.21 (s, 9H), 2.36 (dq, 1H, J
42 7
H O
)
2
7
18.8, 7.3), 2.54 (dq, 1H, J ) 18.7, 7.2), 3.68 (s, 3H), 5.54 (s,
13
H); C NMR (CDCl
3
) δ 6.7, 26.7, 26.8, 32.3, 38.6, 38.7, 52.5,
2
2
0.8, 76.1, 166.8, 176.8, 176.9, 204.3; MS (CI/t-BuH) m/ z 345
(1 mmol, 190 mg). After the mixture was stirred for 4 h,
distilled water (10 mL) was added. The aqueous solution was
+
23
[
C
M + H] ; [R]
D
+6.3 (c 3.5, CHCl
: C, 59.30; H, 8.20. Found: C, 59.40; H, 8.16.
2R,3R)-Meth yl-2, 3-d ip iva loxy-4-oxoocta n oa te (4c): n-
3
). Anal. Calcd for
17
H
(
28
O
7
extracted with Et
and evaporated. The lactones 10 were chromatographed on
silica gel (PE/Et O 9/1) to give 90-97% yield. Crude lactones
2
O. The combined organic layers were dried
BuMgCl 2 M in THF (2.6 mL, 5.2 mmol); T, -15 °C; t, 45 min;
2
-
1 1
yield 90%, oil; IR (neat) 1769, 1740 cm ; H NMR (CDCl
3
) δ
10 can be used as such for the deprotection step. No epimeric
lactone 11 can be detected by NMR spectroscopy.
0
1
1
2
7
.86 (t, 3H, J ) 7.2), 1.18 (s, 9H), 1.22 (s, 9H), 1.30 (m, 2H),
.47 (m, 2H), 2.31 (dt, 1H, J ) 17.9, 7.3), 2.46 (dt, 1H, J )
7.9, 7.3), 3.69 (s, 3H), 5.54 (d, 1H, J ) 2.4), 5.57 (d, 1H, J )
(2R,3S,4R)-2,3-Dipivaloxy-4-m eth ylbu tyr olacton e (10a):
-1 1
yield 97%; mp 115-117 °C; IR (neat) 1802, 1742 cm ; H NMR
(CDCl ) δ 1.19 (s, 9H), 1.21 (s, 9H), 1.34 (d, 3H, J ) 6.7), 4.96
(qd, 1H, J ) 6.5, 6.5), 5.39 (dd, 1H, J ) 6.5, 6.5), 5.43 (d, 1H,
1
3
.4); C NMR (CDCl
3
) δ 13.5, 21.9, 24.6, 26.6, 38.4, 38.5, 52.3,
3
0.5, 76.0, 166.6, 176.5, 203.2; MS (CI/t-BuH) m/ z 373 [M +
+
20
13
H] ; [R]
1.27; H, 8.66. Found: C, 61.32; H, 8.96.
2R,3R)-Meth yl-2, 3-d ip iva loxy-4-oxod od eca n oa te (4d ):
n-OctMgCl 2 M in THF (2.6 mL, 5.2 mmol); T, -5 °C; t, 75
D
-2.8 (c 1, CHCl
3
). Anal. Calcd for C19
H
32
O
7
: C,
J ) 6.6); C NMR (CDCl
169.0, 176.9, 177.1; MS (CI/t-BuH) m/ z 301 [M + H] ; [R]
+67.3 (c 0.73, CHCl ). Anal. Calcd for C15 : C, 59.98;
H, 8.05. Found: C, 60.03; H, 8.10.
(2R,3S,4R)-2,3-Dip iva loxy-4-eth ylbu tyr ola cton e (10b):
3
) δ 15.0, 26.8, 38.6, 70.8, 72.9, 75.4,
+
23
6
D
(
3
24 6
H O
-
1 1
min; yield 85%, oil; IR (neat) 1770, 1740 cm ; H NMR (CDCl
δ 0.77 (t, 3H, J ) 6.8), 1.11-1.16 (m, 28H), 1.45 (m, 2H), 2.29
dt, 1H, J ) 17.9, 7.2), 2.44 (dt, 1H, J ) 17.9, 7.3), 3.62 (s,
H), 5.48 (d, 1H, J ) 2.4), 5.50 (d, 1H, J ) 2.4); 13C NMR
CDCl ) δ 13.8, 22.4, 22.6, 26.6, 28.8, 29.1, 31.6, 38.5, 38.6,
3
)
-
1 1
yield 95%; mp 66-68 °C; IR (neat) 1803, 1742 cm ; H NMR
(CDCl ) δ 1.00 (t, 3H, J ) 7.3), 1.14 (s, 9H), 1.16 (s, 9H), 1.63
(qd, 2H, J ) 7.5, 5.7), 4.67 (td, 1H, J ) 6.1, 7.7), 5.37 (d, 1H,
J ) 3.0), 5.39 (dd, 1H, J ) 6.5, 16.2); 13C NMR (CDCl
) δ 9.7,
(
3
3
(
3
3

4
014 J . Org. Chem., Vol. 62, No. 12, 1997
Fernandez et al.
2
2.6, 26.8, 38.7, 71.1, 72.8, 80.3, 169.2, 176.4, 176.6; MS (CI/
Dep r otection Step . Gen er a l P r oced u r e. To alcohols
12a -d or lactones 10a and 11a (1 mmol) were added dioxane
(12 mL) and 3 M HCl (24 mL). After the time t at reflux, the
mixture was cooled to rt and then concentrated. The remain-
ing solids were washed several times with hot AcOEt, and the
washings were filtered, dried, and concentrated by azeotropic
distillation with toluene. After purification on silica gel (PE/
AcOEt 7/3), lactones 2a -d and 3a were obtained in high
yields. Enantiomeric purities were assumed according to NMR
data as well as comparison with literature data reported for
compounds 2d and 3a .
+
22
t-BuH) m/ z 315 [M + H] ; [R]
Calcd for C16 : C, 61.13; H, 8.34. Found: C, 61.20; H,
.38.
2R,3S,4R)-2,3-Dip iva loxy-4-bu tylbu tyr ola cton e (10c):
D
+74.6 (c 0.80, CHCl
3
). Anal.
26 6
H O
8
(
-
1 1
yield 95%; mp 30-33 °C; IR (neat) 1801, 1740 cm ; H NMR
(
CDCl
3
) δ 0.88 (t, 3H, J ) 6.7), 1.20-1.23 (m, 20H), 1.29-
.36 (m, 2H), 1.53-1.61 (m, 2H), 4.77 (td, 1H, J ) 6.0, 6.9),
.42 (d, 1H, J ) 6.1), 5.42 (dd, 1H, J ) 6.5, 12.6); 13C NMR
) δ 13.7, 22.2, 26.8, 27.2, 29.0, 38.6, 71.1, 72.8, 79.1,
1
5
(CDCl
3
+
22
1
+
69.3, 176.9, 177.2; MS (CI/t-BuH) m/ z 343 [M + H] ; [R]
75.0 (c 2.19, CHCl ). Anal. Calcd for C18 : C, 63.13;
H, 8.83. Found: C, 63.38; H, 9.08.
2R,3S,4R)-2,3-Dip iva loxy-4-octylbu tyr ola cton e (10d ):
D
3
30 6
H O
(
2R,3S,4R)-2,3-Dih yd r oxy-4-m eth ylbu tyr ola cton e (2a ):
t, 18 h; yield 80% from alcohol 12a , 90% from the lactone 10a ,
(
-1
1
oil; IR (neat) 3379, 1774 cm ; H NMR (CD
3
OD) δ 1.34 (d,
-
1 1
yield 90%; mp 35-37 °C; IR (neat) 1803, 1740 cm ; H NMR
CDCl ) δ 0.85 (t, 3H, J ) 6.6), 1.18-1.30 (m, 30H), 1.52-
.63 (m, 2H), 4.77 (td, 1H, J ) 5.7, 6.5), 5.41 (dd, 1H, J ) 6.3,
3
2
H, J ) 6.7), 4.19-4.21 (m, 2H), 4.65-4.78 (m, 1H), 4.84 (s,
(
3
13
H); C NMR (CD OD) δ 14.8, 74.0, 75.0, 79.2, 177.2; MS (CI/
22
3
1
1
2
1
+
t-BuH) m/ z 133 [M + H] ; [R]
D
3
+77.2 (c 2.04, CH OH). Anal.
1
3
2.5), 5.41 (d, 1H, J ) 6.2); C NMR (CDCl
3
) δ 14.0, 22.5, 25.2,
Calcd for C : C, 45.46; H, 6.10. Found: C, 45.03; H, 6.34.
5
8 4
H O
6.8, 29.0, 29.2, 29.3, 31.7, 38.7, 71.1, 72.8, 79.2, 169.3, 176.9,
+
23
Note: We observed that the lactone 2a was spontaneously
epimerized at the C2 position, at -20 °C, after 3 days. Thus,
it cannot be stored for more than several hours.
77.2; MS (CI/t-BuH) m/ z 399 [M + H] ; [R]
). Anal. Calcd for C22 : C, 66.30; H, 9.61. Found:
C, 66.41; H, 9.44.
D
+74.5 (c 0.66,
CHCl
3
38 6
H O
Syn th esis of La cton es 11. Gen er a l P r oced u r e. The
appropriate Grignard reagent (15 mmol, 1.5 equiv) was added,
at the temperature T, to a solution of aldehyde 5 (10 mmol, 1
equiv) in THF (70 mL). After being stirred at T for the time
(2R,3S,4R)-2,3-Dih yd r oxy-4-eth ylbu tyr ola cton e (2b): t,
-
1 1
3
18 h; yield 85%, oil; IR (neat) 3414, 1771 cm ; H NMR (CD -
OD) δ 1.02 (t, 3H, J ) 7.5), 1.72 (m, 2H), 4.15 (d, 1H, J ) 5.5),
4.21 (dd, 1H, J ) 5.5, 11.0), 4.46 (td, 1H, J ) 5.1, 9.2), 4.89 (s,
2H); 13C NMR (CD
OD) δ 10.3, 22.9, 74.4, 74.7, 84.7, 177.3;
3
21
t
1
, the mixture was warmed to rt during the time t
lactonization step (TLC control). The mixture was cooled to 0
C and hydrolyzed with a saturated NH Cl solution. THF was
removed, and the residue was extracted with ether. The
organic layer was dried (MgSO ) and evaporated. The crude
product 11 was isolated by chromatography on silica gel (PE/
Et O 90/10) to give the lactones 11a -d in 85-90% yield. No
epimeric lactone 10 can be detected by NMR spectroscopy.
2R,3S,4S)-2,3-Dipivaloxy-4-m eth ylbu tyr olacton e (11a):
MeMgBr 3 M in Et O (5 mL, 15 mmol); T, -70 °C (t , 12 h)
then rt (t , 2 h); yield 88%; mp 65-69 °C; IR (neat) 1804, 1742
cm ; H NMR (CDCl ) δ 1.17 (s, 9H), 1.21 (s, 9H), 1.49 (d,
H, J ) 6.4), 4.42 (qd, 1H, J ) 6.5, 6.5), 5.18 (dd, 1H, J ) 7.1,
.1), 5.48 (d, 1H, J ) 7.3); 13C NMR (CDCl
) δ 18.6, 26.8, 38.6,
2.4, 76.3, 77.1, 168.8, 176.9, 177.3; MS (CI/t-BuH) m/ z 301
2
for
+
MS (CI/t-BuH) m/ z 147 [M + H] ; [R]
D
+84.6 (c 1.02, CH
3
-
°
4
OH). Anal. Calcd for C
49.52; H, 7.04.
6 10 4
H O : C, 49.31; H, 6.90. Found: C,
4
(
2R,3S,4R)-2,3-Dih yd r oxy-4-bu tylbu tyr ola cton e (2c): t,
-1
1
1
8 h; yield 88%; mp 74-76 °C; IR (neat) 3426, 1776 cm ; H
NMR (CD OD) δ 0.93 (t, 3H, J ) 6.9), 1.35-1.85 (m, 6H), 4.14
d, 1H, J ) 3.7), 4.18 (dd, 1H, J ) 5.5, 14.2), 4.53 (td, 1H, J )
.9, 9.2), 4.83 (s, 2H); C NMR (CD
9.5, 74.5, 74.8, 83.4, 177.4; MS (CI/t-BuH) m/ z 157 [M + H
H
2
3
(
(
13
4
2
-
3
OD) δ 14.3, 23.5, 28.9,
2
1
2
+
+
23
2
O] , 175 [M + H] ; [R]
D
+91.5 (c 1.00, CHCl
3
). Anal.
-
1
1
3
Calcd for C
8 14 4
H O
: C, 55.16; H, 8.10. Found: C, 55.20; H, 8.07.
3
7
7
7
c,d
(
2R,3S,4R)-2,3-Dih yd r oxy-4-octylbu tyr ola cton e (2d ):
3
7
d
t, 48 h; yield 60%; mp 66-68 °C (lit. mp 68-70 °C); IR (neat)
3423, 1774 cm ; H NMR (CD
.21-1.85 (m, 14H), 4.15 (d, 1H, J ) 3.8), 4.17 (dd, 1H, J )
3
.3, 14.3), 4.54 (td, 1H, J ) 5, 9), 4.85 (s, 2H); H NMR (CdCl )
-
1
1
+
23
3
OD) δ 0.90 (t, 3H, J ) 6.6),
[
M + H] ; [R]
D
-21.9 (c 1.22, CHCl
: C, 59.98; H, 8.05. Found: C, 60.08; H, 7.97.
2R,3S,4S)-2,3-Dip iva loxy-4-eth ylbu tyr ola cton e (11b):
, 3 h)
, 2 h): yield 85%; mp 59-63 °C; IR (neat) 1806, 1742
cm ; H NMR (CDCl ) δ 1.02 (t, 3H, J ) 7.5), 1.18 (s, 9H),
.22 (s, 9H), 1.81 (qd, 2H, J ) 6.6, 6.6), 4.28 (td, 1H, J ) 6.5,
.8), 5.29 (dd, 1H, J ) 7.2, 7.2), 5.49 (d, 1H, J ) 7.3); 13C NMR
) δ 8.9, 26.1, 26.8, 38.6, 72.6, 75.3, 80.5, 168.9, 176.9,
3
). Anal. Calcd for
1
5
15 24 6
C H O
1
(
δ 0.85 (t, 3H, J ) 6), 1.20-1.50 (m, 12H), 1.7-1.9 (m, 2H),
.73 (m, 2H), 4.43 (m, 1H), 4.49 (m, 2H); 13C NMR (CD
OD) δ
14.2, 23.7, 26.8, 29.8, 30.4, 30.6, 33.0, 74.6, 74.9, 83.5, 177.7;
EtMgBr 1 M in THF (15 mL, 15 mmol); T, -50 °C (t
then rt (t
1
3
3
2
-
1
1
3
1
3
C NMR (CDCl
3
) δ 14 0, 22.6, 26.6, 28.9, 29.1, 29.3, 29.4, 31.8,
1
6
+
22
72.9, 73.7, 81.2, 175.8; MS (CI/t-BuH) m/ z 231 [M + H] ; [R]
D
19
+
71.5 (c 0.8, CHCl
Calcd for C12
.86.
3
) [lit.7d [R]
D
3
+71.9 (c 0.78, CHCl )]. Anal.
(CDCl
3
+
20
22 4
H O : C, 62.58; H, 9.63. Found: C, 62.43; H,
1
77.3; MS (CI/t-BuH) m/ z 315 [M + H] ; [R]
). Anal. Calcd for C16 : C, 61.13; H, 8.34. Found:
C, 61.33; H, 8.15.
2R,3S,4S)-2,3-Dip iva loxy-4-bu tylbu tyr ola cton e (11c):
n-BuMgCl 2 M in THF (7.5 mL, 15 mmol); T, -25 °C (t , 2 h)
D
-25.8 (c 0.52,
9
CHCl
3
26 6
H O
(2R,3S,4S)-2,3-Dih yd r oxy-4-m eth ylbu tyr ola cton e (3a ):
t, 18 h; yield 90% from 11d ; 78% from 5 in one pot; mp
3
1,45
(
124-125 °C (lit.45 mp 125 °C); IR (neat) 3366, 1748 cm ; H
-1
1
1
-
1 1
then rt (t
2
, 2 h); yield 90%, oil; IR (neat) 1808, 1742 cm ; H
) δ 0.89 (t, 3H, J ) 6.9), 1.19-1.22 (m, 20H), 1.32-
.36 (m, 2H), 1.73-1.79 (m, 2H), 4.32 (td, 1H, J ) 7.2, 5.6),
.28 (dd, 1H, J ) 7.2, 7.2), 5.48 (d, 1H, J ) 7.3); 13C NMR
) δ 13.7, 22.2, 26.6, 26.8, 32.8, 38.6, 72.5, 75.8, 79.4,
NMR (CD
8.7), 4.17 (qd, 1H, J ) 6.2, 8.3), 4.32 (d, 1H, J ) 9), 4.82 (s,
2H); 13C NMR (CD
OD) δ 18.1, 75.4, 78.4, 80.5, 176.4; MS (CI/
t-BuH) m/ z 115 [M + H - H
(c 1.10, EtOH) [lit.31 enantiomer (2S,3R,4R) [R]
3
OD) δ 1.41 (d, 3H, J ) 6.2), 3.78 (dd, 1H, J ) 8.8,
NMR (CDCl
1
5
3
3
+
+
21
2
O] , 133 [M + H] ; [R]
D
-37.0
+37.3 (c
5 8 4
H O : C, 45.46; H, 6.10.
13
(CDCl
3
D
+
20
1
-
8
69, 176.9, 177.2; MS (CI/t-BuH) m/ z 343 [M + H] ; [R]
51.0 (c 0.1, CHCl ). Anal. Calcd for C18 : C, 63.13; H,
.83. Found: C, 63.36; H, 8.73.
2R,3S,4S)-2,3-Dip iva loxy-4-octylbu tyr ola cton e (11d ):
n-OctMgCl 2 M in THF (7.5 mL, 15 mmol); T, -25 °C (t , 1 h)
D
1.01, EtOH)]. Anal. Calcd for C
Found: C, 45.64; H, 6.26.
3
30 6
H O
(
Ack n ow led gm en t. We acknowledge Prof. H. Yoda
1
-
1
13
1
1
for providing copies of H and C NMR spectra of
lactone 2d . We thank Prof. G. Pl e´ for high-field NMR
analyses (NOEDS).
then rt (t
2
, 3 h); yield 90%, oil; IR (neat) 1810, 1746 cm ; H
) δ 0.85 (t, 3H, J ) 6), 1.17-1.23 (m, 30H), 1.66-
.82 (m, 2H), 4.31 (td, 1H, J ) 7, 5.9), 5.27 (dd, 1H, J ) 7.2,
.2), 5.48 (d, 1H, J ) 7.3); 13C NMR (CDCl
) δ 14.0, 22.5, 24.6,
5.5, 26.8, 29.1, 29.2, 31.7, 33.1, 38.6, 72.5, 75.8, 79.4, 169,
NMR (CDCl
3
1
7
2
1
3
J O970117E
+
20
76.9, 177.2; MS (CI/t-BuH) m/ z 399 [M + H] ; [R]
). Anal. Calcd for C22 : C, 66.30; H, 9.61.
Found: C, 66.36; H, 9.73.
D
-63.7
(c 0.92, CHCl
3
H
38
O
6
(45) Andrews, P.; Hough, L.; J ones, J . K. N. J . Am. Chem. Soc. 1955,
77, 125.