Enantiospecific synthesis of trisubstituted butyrolactone natural products and their analogs

Article abstract of DOI:10.1021/jo961171i

A general methodology for the synthesis of highly substituted butyrolactones in enantiomerically pure form has been developed. The application of this process in a highly efficient synthesis of lactone natural products blastmycinone (1), NFX-2 (2), antimycinone (3), and NFX-4 (4) and two lipid metabolites (5, 6) are described. Additionally, the total synthesis of 5-epi-blastmycinone (22), 5-epi-NFX-2 (21b), 5-epi-NFX-4 (21c), and lipid metabolite analogs (19, 20) are also described. The overall yields for the target molecules are the highest reported so far in the literature.

Full text of DOI:10.1021/jo961171i

7848
J . Org. Chem. 1996, 61, 7848-7855
En a n tiosp ecific Syn th esis of Tr isu bstitu ted Bu tyr ola cton e Na tu r a l
P r od u cts a n d Th eir An a logs
Mukund P. Sibi,* J ianliang Lu, and Chelsy L. Talbacka1
Department of Chemistry, North Dakota State University, Fargo, North Dakota 58105-5516
Received J une 21, 1996X
A general methodology for the synthesis of highly substituted butyrolactones in enantiomerically
pure form has been developed. The application of this process in a highly efficient synthesis of
lactone natural products blastmycinone (1), NFX-2 (2), antimycinone (3), and NFX-4 (4) and two
lipid metabolites (5, 6) are described. Additionally, the total synthesis of 5-epi-blastmycinone (22),
5-epi-NFX-2 (21b), 5-epi-NFX-4 (21c), and lipid metabolite analogs (19, 20) are also described.
The overall yields for the target molecules are the highest reported so far in the literature.
In tr od u ction
Development of new methodologies for the synthesis
of butyrolactone natural products has received consider-
able attention from organic chemists.2 This can be
attributed to the wide and potent biological activity
exhibited by many different classes of compounds con-
taining the butyrolactone skeleton. The 3-alkyl-4-hy-
droxy-5-methyl-2(3H)-dihydrofuranone substructure is
found in a wide variety of metabolites with a very
disparate origin.3 Polyketide metabolites blastmycinone4
(1), NFX-25 (2), antimycinone6 (3), and NFX-45 (4) contain
short to medium length carbon chains at the 3-position.
The unusual lipid metabolites 5 and 6 isolated from
Gorgonian coral Plexaura flava are compounds that have
long alkyl chains at the 3-position.3c
The three contiguous chiral centers embodied in these
molecules present a reasonable challenge for the develop-
ment of new methodologies. Control of the relative as
well as absolute stereochemistry of these centers in a
general way would be desirable for the efficient synthesis
of the targets natural products as well as their analogs
for structure-activity studies. Methodologies have been
developed for the synthesis of the targets blastmycinone,7
5-epi-blastmycinone,7i antimycinone,7bb NFX-2,8 and NFX-
47bb and lipid metabolites.9 Some of the strategies include
transformation of chiral natural products,10 enzymatic
resolution,11 oxidative heterocyclization,12 Sharpless oxi-
(7) Racemic synthesis of blastmycinone: (a) Kishikawa, K.; Sankhava-
si, W.; Yamanoto, M.; Kohmoto, S.; Yamada, K. Synth. Commun. 1990,
20, 2339. (b) Ortuno, R. M.; Cardellach, J .; Font, J . J . Heterocycl. Chem.
1987, 24, 79. (c) Cardellach, J .; Font, J .; Ortuno, R. M. Tetrahedron
Lett. 1985, 26, 2815. (d) Kozikowski, A. P.; Ghosh, A. K. J . Org. Chem.
1984, 49, 2762. (e) Nakata, T.; Fukui, M.; Oishi, T. Tetrahedron Lett.
1983, 24, 2657. (f) Heathcock, C. H.; Pirrung, M. C.; Lampe, J .; Buse,
C. T.; Young, S. D. J . Org. Chem. 1981, 46, 2290. (g) Koyama, H.;
Kogure, K.; Mori, K.; Matsui, M. Agric. Biol. Chem. 1973, 37, 915. (h)
Kinoshita, M.; Wada, M.; Umezawa, S. J . Antibiot. 1969, 22, 580. (i)
Mukai, C.; Kataoka, O.; Hanaoka, M. J . Org. Chem. 1993, 58, 2946.
Enantioselective synthesis of blastmycinone: (j) Inghardt, T.; Frejd,
T. Tetrahedron 1991, 47, 6483. (k) Mulzer, J .; Schulze, T.; Strecker,
A.; Denzer, W. J . Org. Chem. 1988, 53, 4098. (l) Ortuno, R. M.; Alonso,
D.; Cardellach, J .; Font, J . Tetrahedron 1987, 43, 2191. (m) Frater,
G.; Mu¨ller, U.; Gu¨nther, W. Helv. Chim. Acta 1986, 69, 1858. (n)
Bernardi, A.; Beretta, M. G.; Colombo, L.; Gennari, C.; Poli, G.;
Scolastico, C. J . Org. Chem. 1985, 50, 4442. (o) Uenishi, J .; Tomozane,
H.; Yamato, M. J . Chem. Soc., Chem. Commun. 1985, 717. (p)
Wasserman, H. H.; Gambale, R. J . J . Am. Chem. Soc. 1985, 107, 1423.
(q) Sayo, N.; Nakai, E.; Nakai, T. Chem. Lett. 1985, 1723. (r) Uchiyama,
H.; Kobayashi, Y.; Sato, F. Chem. Lett. 1985, 467. (s) Fujisawa, T.;
Kohama, H.; Tajima, K; Sato, T. Tetrahedron Lett. 1984, 25, 5155. (t)
Gennari, C.; Bernardi, A.; Cardani, S.; Scolastico, C. Tetrahedron 1984,
40, 4059. (u) Aburaki, S.; Konishi, N.; Kinoshita, M. Bull. Chem. Soc.
J pn. 1975, 48, 1254. (v) Kinoshita, N.; Aburaki, S.; Wada, M.;
Umezawa, S. Bull. Chem. Soc. J pn. 1973, 46, 1279. (w) Kinoshita, N.;
Wada, M.; Aburaki, S.; Umezawa, S. J . Antibiot. 1971, 24, 724. (x)
Nishide, K.; Aramata, A.; Kamanaka, T.; Node, M. Heterocycles 1993,
36, 2237. (y) Nishide, K.; Aramata, A.; Kamanaka, T.; Inoue, T.; Node,
M. Tetrahedron 1994, 50, 8337. (z) de Azevdo, M. B. M.; Greene, A. E.
J . Org. Chem. 1995, 60, 4940. (aa) Wasserman, H. H.; Gambale, R. J .
Tetrahedron 1992, 48, 7059. (bb) Takahata, H.; Uchida, Y.; Momose,
T. J . Org. Chem. 1994, 59, 7201.
X Abstract published in Advance ACS Abstracts, October 1, 1996.
(1) Undergraduate research participant. Recipient of a Ronald E.
McNair Scholarship.
(2) For selected examples on the synthesis of butyrolactones with
biological activity, see: (a) Brown, H. C.; Kulkarni, S. V.; Racherla,
U. S. J . Org. Chem. 1994, 59, 365 and references therein. (b) Shimada,
S.; Hashimoto, Y.; Saigo, K. J . Org. Chem. 1993, 58, 5226. (c) Nagao,
Y.; Dai, W.-M.; Ochiai, M.; Shiro, M. J . Org. Chem. 1989, 54, 5211. (d)
Nakamura, E.; Oshino, H.; Kuwajima, I. J . Am. Chem. Soc. 1986, 108,
3745. (e) Hannesian, S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. J . Am.
Chem. Soc. 1990, 112, 5276. (f) Mandal, A. K.; Mahajan, S. W.
Synthesis 1991, 311. (g) Chan, P. C.-M.; Chong, J . M. Tetrahedron Lett.
1990, 31, 1981. (h) Ohkuma, T.; Kitamura, M.; Noyori, R. Tetrahedron
Lett. 1990, 31, 5509. (i) Sibi, M. P.; Deshpande, P. K.; La Loggia, A. J .
Synlett 1996, 343.
(3) (a) Ortuno, R. M.; Bigorra, J .; Font, J . Tetrahedron 1988, 44,
5139. (b) Martinez, J . C.; Yoshida, V. M.; Gottlieb, O. R. Phytochemistry
1981, 20, 459. (c) Ravi, B. N.; Wells, R. J . Aust. J . Chem. 1982, 35,
105. (d) Silva, R.; Nagem, T. J .; Mesquita, A. A. L.; Gottlieb, O. R.
Phytochemistry 1983, 22, 772. (e) Vieira, P. C.; Yoshida, M.; Gottleib,
O. R.; Filho, H. F. P.; Nagem, T. J .; Filho, R. B. Phytochemistry 1983,
22, 711.
(4) (a) Dictionary of Antibiotics and Related Substances; Bycroft, B.
W., Ed.; Chapman and Hall: London, 1988. (b) Yonehara, H.; Takeuchi,
S. J . Antibiot. 1958, 11A, 254. (c) van Tamelen, E. E.; Dickle, J . P.;
Loomans, M. E.; Dewey, R. S.; Strong, F. M. J . Am. Chem Soc. 1961,
83, 1639. (d) Birch, A. J .; Cameron, D. W.; Harada, Y.; Rickards, R.
W. J . Chem. Soc. 1961, 889. (e) Kinoshita, M.; Aburaki, S.; Umezawa,
S. J . Antibiot. 1972, 25, 373.
(5) Li, W.; Nihira, T.; Sakuda, S.; Nishida, T.; Yamada, Y. J .
Ferment. Bioeng. 1992, 74, 214.
(8) (a) Reference 6. (b) References 7z,bb.
(6) (a) Nishida, T.; Nihira, T; Yamada, Y. Tetrahedron 1991, 47, 6623
(degradation of antimycin A1 to antimycinone).
(9) (a) Reference 7b. (b) Chen, S.-Y.; J oullie, M. M. J . Org. Chem.
1984, 49, 2168. (c) Reference 3a. (d) References 7y,bb.
S0022-3263(96)01171-1 CCC: $12.00 © 1996 American Chemical Society

Trisubstituted Butyrolactone Natural Products
J . Org. Chem., Vol. 61, No. 22, 1996 7849
Sch em e 1
Sch em e 2a
dation,13 and nitrile oxide cycloaddition.7d Of the readily
available chiral starting materials, lactic and tartaric acid
derivatives have found some interesting application in
the synthesis of the stereotriad present in the target
natural products. We have been interested in exploring
aldol reactions between R-alkoxy aldehydes 10 and chiral
N-acyloxazolidinones 9 as a method for the establishment
of the stereotriad. The relative and absolute stereochem-
istries of the stereocenters will then be established by
the nature of the aldol reaction (syn or anti) and by the
resident chirality of the chiral auxiliary and the R-alkoxy
aldehyde (Scheme 1). J oullie´ et al. have used a similar
methodology in the preparation of a butyrolactone inter-
mediate for the total synthesis of didemnins A.14 In this
paper we report the enantiospecific synthesis of blast-
mycinone, NFX-2, antimycinone, and NFX-4 using the
methodology shown in Scheme 1. The first enantio-
specific synthesis of the lipid metabolites 5 and 6, 5-epi-
blastmycinone, 5-epi-NFX-2, 5-epi-NFX-4, and analogs of
the lipid metabolites is also included. The overall yields
for the butyrolactone natural products and analogs by
our methodology are the highest reported so far in the
literature. Additionally, the effect of alkyl chain length
and absolute stereochemistry of the R-alkoxy aldehyde
on aldol yields is discussed.
a
Key: (a) n-BuLi, -78 °C, RCH2COCl; (b) method A, (i)
Bu2BOTf, Et3N CH2Cl2, 0 °C, 1 h, (ii) aldehyde, -78 °C to 0 °C,
24 h, or method B, (i) Bu2BOTf, Me2NPh, Et2O 0 °C, 1 h, (ii)
aldehyde, -78 °C to 0 °C, 24 h.
anion which was quenched with the appropriate acid
chlorides to produce the acylated oxazolidinones 12 in
very high yields (Scheme 2, Table 1).
With the desired starting materials in hand, the key
aldol reactions relied on methodologies developed in the
laboratories of Evans.16 Treatment of the acyloxazolidi-
none 12a with freshly prepared dibutylboron triflate
followed by triethylamine furnished the boron enolate.
This was quenched with freshly prepared (S)-O-TBS-
protected lactaldehyde 1317 to furnish the syn aldol
product 15a (Bu2BOTf, Et3N, CH2Cl2/0 °C/1 h; aldehyde/
-78 °C/30 min/0 °C/1 h). The yields for the aldol product
from several runs only averaged around 60%. We sought
to improve chemical yields by using the modification of
the aldol protocol as reported by Boger.18 Thus, genera-
tion of the boron enolate followed by quenching with the
aldehyde and warming the reaction from -78 to 0 °C over
24 h (Bu2BOTf, Et3N, CH2Cl2/0 °C/1 h; aldehyde/-78 °C
to 0 °C/24 h, method A) (Table 1, entry 1) furnished the
aldol product in 90% yield as a single diastereomer
Resu lts a n d Discu ssion
Our methodology for the synthesis of the butyrolactone
natural and unnatural products started with the attach-
ment of the required side chain to (R)-4-(diphenylmethyl)-
2-oxazolidinone (11). The synthesis and application of
this new chiral oxazolidinone 11 in aldol, Diels-Alder,
and radical reactions have recently been reported from
our laboratory.15 Auxiliary 11 was the substrate of choice
for this work for several reasons: the absolute stereo-
chemistry of the starting material translated to the
natural configuration of the targets; easy availability
from L-serine; easy recovery; crystallinity of the inter-
mediates. Treatment of 11 with n-BuLi produced an
1
(>99% de, by H 400 MHz NMR of the crude reaction
product). In contrast, the use of (S)-O-benzyl-protected
lactaldehyde in place of 13 gave the syn aldol product in
64% chemical yield and 94% diastereomeric excess.19
Thus, for the remainder of the series, the O-TBS-
protected aldehydes were used in the aldol reactions.
Application of method A for the aldol reaction of 12b with
13, however, led to a large decrease in chemical yield
(Table 1, compare entry 1 with entry 2). A similar trend
persisted with increasing chain length for compounds
12c-e (Table 1, entries 3-5 for method A). The syn
diastereoselectivity was still excellent (>99% de) for all
of these substrates.20
(10) (a) Mulzer, J .; Salii, N.; Hartl, H. Tetrahedron: Asymmetry
1993, 4, 457. (b) Suzuki, Y.; Mori, W.; Ishizone, H.; Naito, K.; Honda,
T. Tetrahedron Lett. 1992, 33, 4931. (c) Ebata, T.; Matsumoto, K.;
Yoshikoshi, H.; Koseki, K.; Kawakami, H.; Okano, K.; Matsushita, H.
Heterocycles 1993, 36, 1017. (d) Yoda, H.; Shirakawa, K.; Takabe, K.
Chem. Lett. 1991, 489. (e) Yoda, H.; Shirakawa, K.; Takabe, K.
Tetrahedron Lett. 1991, 32, 3401.
(11) (a) Sibi, M.; Gaboury, J . A. Tetrahedron Lett. 1992, 33, 5681.
(b) J acobs, H. K.; Mueller, B. H.; Gopalan, A. S. Tetrahedron 1992,
48, 8891. (c) Gutman, A. L.; Zuobi, K.; Bravdo, T. J . Org. Chem. 1990,
55, 3546. (d) Sugai, T.; Ohsawa, S.; Yamada, H.; Ohta, H. Synthesis
1990, 1112.
The large differences in chemical yield with variation
in alkyl chain length were puzzling and led us to examine
some of the variables in the aldol reaction. These were
(12) For a review, see: Takahata, H. Yakugaku Zasshi 1993, 113,
737.
(13) Uchiyama, H.; Kobayashi, Y.; Sato, F. Chem. Lett. 1985, 467.
(14) Li, W.-R.; Ewing, W. R.; Harris, B. D.; J oullie´, M. M. J . Am.
Chem. Soc. 1990, 112, 7659.
(15) Synthesis: Sibi, M. P.; Deshpande, P. K.; La Loggia, A. J .;
Christensen, J . W. Tetrahedron Lett. 1995, 36, 8961. Applications: (a)
Sibi, M. P.; Deshpande, P. K.; J i, J . Tetrahedron Lett. 1995, 36, 8965.
(b) Sibi, M. P.; J asperse, C. P.; J i, J . J . Am Chem. Soc. 1995, 117, 10779.
(c) Sibi, M. P.; J i, J . Angew. Chem., Int. Ed. Engl. 1996, 36, 190. (d)
Reference 2i.
(16) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 83.
(17) (a) Cainelli, G.; Giacomini, D.; Mezzina, E.; Panunzio, M.;
Zarantonello, P. Tetrahedron Lett. 1991, 32, 2967. (b) Ito, Y.; Koba-
yashi, Y.; Kawabata, T.; Takase, M; Terashima, S. Tetrahedron 1989,
45, 5767. (c) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J . Org. Chem.
1983, 48, 5180.
(18) Boger, D. L.; Colletti, S. L.; Honda, T.; Menezes, R. F. J . Am.
Chem. Soc. 1994, 116, 5607.
(19) In a similar aldol reaction but using 2-(benzyloxy)-3-methyl-
butanal, J oullie´ et al. obtained a 17:1 diastereoselectivity for the aldol
product. See: ref 14.

7850 J . Org. Chem., Vol. 61, No. 22, 1996
Ta ble 1. Ald ol Rea ction s w ith O-TBS P r otected r-Alk oxy Ald eh yd es
Sibi et al.
acylation
aldol
method A
yield, %a,c
method B
yield, %a,d
aldol
method B
yield, %a,c
entry
substituent R
yield, %a
productb
producte
1
2
3
4
5
12a , R ) (CH2)3CH3
12b, R ) (CH2)5CH3
12c, R ) (CH2)4CH(CH3)2
12d , R ) (CH2)13CH3
12e, R ) (CH2)15CH3
96
99
97
98
95
15a
15b
15c
15d
15e
90
48
45
50
49
88
70
61
68
60
16a
16b
16c
16d
16e
67
45
47
43
42
a
Yields are for isolated and purified materials. b Aldol reaction with (S)-R-alkoxy aldehyde. c Standard Evans aldol protocol and warming
to 0 °C over 24 h after aldehyde addition. Aldol reactions using Me2NPh as the base and ether as the solvent. e Aldol reaction with
d
(R)-R-alkoxy aldehyde.
Sch em e 3a
the extent of enolate formation, solvent, the base used
for enolization, and the nature of the aldehyde partner.
The extent of enolate formation was assessed by a
deuterium quenching experiment (boron enolate genera-
tion followed by quenching with MeOD or CF3COOD and
NMR analysis). Enolate generation using substrate 12a
under Evans conditions and MeOD quenching showed a
90% D incorporation (using CF3COOD, 89% D). This was
consistent with the yield for the aldol reaction. For the
longer alkyl chain substrates, compound 12b was used
a model. Enolate generation using 12b under Evans
conditions and MeOD quenching showed a 60% D ((5%)
incorporation. The extent of the enolate formation was
consistent with the low chemical yield observed for the
aldol reaction with 12b. Several base-solvent combina-
tions were then evaluated for enolate generation with
12b. Of the different solvents evaluated using triethyl-
amine as a base, CH2Cl2 gave 60% D, Et2O gave 72% D,
THF gave 54% D, and toluene gave 0% D. Then several
bases were evaluated using Et2O as a solvent. Of these
dimethylethylamine gave 23% D, diisopropylethylamine
a
Key: (a) HOAc/THF/H2O (3:1:1), rt or 60-65 °C; (b) R1COCl,
DMAP, CH2Cl2, or (R1CO)2O, pyridine, CH2Cl2.
Ta ble 2. Con ver sion of Ald ols fr om (S)-Ald eh yd e to
gave 20% D, 4-(dimethylamino)pyridine gave 15% D, 2,6-
lutidine gave 40% D, and N,N-dimethylaniline gave 88%
D. Subsequently, enolate generation for substrates
12a -e and aldol condensation with 13 was carried out
using the optimized conditions (Bu2BOTf, Me2NPh/Et2O/0
°C/1 h; aldehyde/-78 °C to 0 °C/24 h, method B) and
these results are shown in Table 1, method B column.
As can be evidenced from Table 1, modification of the
reaction conditions led to a reasonable improvement in
chemical yields for the aldol products. The syn diastereo-
selectivity for the aldols was the same using either
method A or B. It is interesting to note that the shorter
chain substrate 12a gave the highest yield under all the
different reaction conditions employed for the aldol
reaction.
La cton es
lactone
yield,
%
acyl
substituent R1
yield,
%
a
a
entry
substituent R
1
2
3
4
5
18a , R ) (CH2)3CH3
2, R ) (CH2)5CH3
4, R ) (CH2)4CH(CH3)2
18d , R ) (CH2)13CH3
18e, R ) (CH2)15CH3
87
84
82
81
89
1, CH2CH(CH3)2
3, CH2CH(CH3)2
86
84
b
c
19, CH3
95
95
c
20, CH3
a
Yields are for isolated and purified materials. b Acylation using
DMAP. c Acetylation using pyridine.
With the aldol reactions successfully completed, the
next step was the removal of the O-TBS protecting group.
Several procedures for the deprotection of the TBS group
in 15 were tried.23 The standard TBAF deprotection
procedure was successful; however, a 1:1 diastereomeric
mixture (diastereomeric at C-3) of lactone products was
obtained. Clean deprotection without any epimerization
was achieved under acidic conditions (HOAc/THF/H2O,
rt or heat) (Scheme 3). Deprotection furnished the
intermediate 17 cleanly, and it underwent spontaneous
lactonization to provide lactones 18. The overall yields
for this two-step one-pot process averaged around 84%
(Table 2, entries 1-5). The chiral auxiliary was also
recovered in >95% yield. The spectral data of 18a were
identical in all respects to that reported in the literature
for blastmycinolactol.24 A similar reaction using 15b and
15c as substrates produced NFX-2 (2) and NFX-4 (4),
respectively, in high yields. The spectral characteristics
Having established the optimal reaction conditions for
aldol reactions with lactaldehyde 13, we turned our
attention to reaction with the enantiomeric compound.
The enantiomeric (R)-O-TBS-protected lactaldehyde 14
was prepared from commercially available (R)-methyl
lactate.21 The aldol reactions were carried out using
method B.22 Table 1 lists the chemical yields for the aldol
products. As can be evidenced from the table, reactions
with 14 were generally less efficient than reactions with
13. However, the syn diastereoselectivities were still
excellent.
(20) The realtive as well as the absolute stereochemsitrry in the syn-
boron aldols using chiral auxiliary 11 has been previously reported
from our laboratory, ref 15a. The stereochemistry of the aldol products
in this study is further established by conversion into the known target
natural products.
(21) Wakabayashi, S.; Ogawa, H.; Ueno, N.; Kunieda, N.; Mandai,
T.; Nokami, J . Chem. Lett. 1987, 875.
(22) Aldol reaction of 12a using either method A or B gave similar
yields. For substrates 12b-e, method B gave slightly higher yields.
(23) (a) Marshall, J . A.; Sedrani, R. J . Org. Chem. 1991, 56, 5496.
(b) Ogilvie, K. K.; Iwacha, D. J . Tetrahedron Lett. 1973, 317. (c) Ganem,
B.; Small, V. R., J r. J . Org. Chem. 1974, 39, 3782.
(24) References 7d,j,l,x.

Trisubstituted Butyrolactone Natural Products
J . Org. Chem., Vol. 61, No. 22, 1996 7851
Sch em e 4a
in their natural configurations. The spectral data of
these compounds matched those reported in the litera-
ture. The overall yields of 5 and 6 over four steps were
31% and 33%.
In conclusion, we have illustrated a short and efficient
method for the preparation of biologically active butyro-
lactone natural products. The generality of the method
allows for the preparation of a variety of natural products
and analogs by a simple change in the starting materials.
Extension of the methodology for the synthesis of more
complex butyrolactone and other natural products is
underway.
a
Key: (a) HOAc/THF/H2O (3:1:1), rt or 60-65 °C; (b) R1COCl,
Exp er im en ta l Section 26
DMAP, CH2Cl2, or (R1CO)2O, pyridine, CH2Cl2.
Gen er a l P r oced u r e for th e Acyla tion of (R)-4-(Dip h en -
ylm eth yl)-2-oxa zolid in on e (11). To a flame-dried 100 mL
three-necked flask under N2 was added a solution of (R)-4-
(diphenylmethyl)-2-oxazolidinone (11) (3.0 g, 11.86 mmol)
dissolved in freshly distilled THF (40 mL). The solution was
cooled to -78 °C in a dry ice/acetone bath. n-BuLi (2.14 M,
5.8 mL, 12.4 mmol) was added in a dropwise fashion via
syringe over a period of 10 min at -78 °C. During this process,
the color of the solution changed from light yellow to orange,
and eventually to red. This red solution was further stirred
at -78 °C for 10 min. The corresponding acid chloride (13.8
mmol) was added slowly over 5 min. The light yellow solution
was stirred at -78 °C for 15 min and at 0 °C for 30 min. The
reaction was quenched with saturated NH4Cl (15 mL) at 0 °C.
The solvent was evaporated under reduced pressure, and the
residue was extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were washed with H2O (40 mL) and brine (40
mL), dried with anhydrous MgSO4, and filtered, and evapora-
tion of the solvent resulted in a white solid. Recrystallization
of the crude product from ethyl acetate and hexane afforded a
white crystalline compound. Purification of the mother liquor
by flash column chromatography (eluted with 20% EtOAc in
hexane) gave another portion of final product. Average yield
is 95-99%.
Ta ble 3. Con ver sion of Ald ols fr om (R)-Ald eh yd e to
La cton es
nat
lactone
yield,
%
prod
yield,
%
acyl
substituent R1
a
a
entry
substituent R
b
1
2
4
4
5
21a , R ) (CH2)3CH3
21b, R ) (CH2)5CH3
88 22, CH2CH(CH3)2 82
84
21c, R ) (CH2)4CH(CH3)2 86
c
c
21d , R ) (CH2)13CH3
21e, R ) (CH2)15CH3
81 5, CH3
89 6, CH3
92
93
a
Yields are for isolated and purified materials. b Acylation using
DMAP. c Acetylation using pyridine.
of these compounds were identical to those reported in
the literature.9 The overall yields for NFX-2 and NFX-4
were 58% and 49%, respectively. This compares very
favorably with the overall yields reported for these two
natural products in the literature.9 The hydroxybutyro-
lactone 18a was converted to natural blastmycinone (1)
by acylation with isovaleryl chloride using a slightly
modified procedure in 86% yield. The overall yield for 1
from our methodology is 64% over four steps. This is the
highest yield reported for the synthesis of blastmy-
cinone.25 The spectral and rotation data of 1 were
identical in all respects to those reported in the literature.7x
NFX-2 was converted to antimycinone (3) in 86% yield
by acylation with isovaleryl chloride. Acetylation of
compounds 18d and 18e using acetic anhydride and
pyridine produced the acetates 19 and 20, respectively,
in excellent yields. Compounds 19 and 20 are diaster-
eomeric analogs of the naturally occurring lipid metabo-
lite 5 and 6.
(-)-(R)-3-(1-Oxoh exyl)-4-(d ip h en ylm eth yl)-2-oxa zolid i-
n on e (12a ): from 11 (3.0 g, 11.9 mmol) was obtained 12a (4.0
g, 11.4 mmol), 96%; mp 95-96.5 °C; Rf 0.35 (80:20 hexane:
EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.89 (t, J ) 7.0 Hz, 3H),
1.23-1.33 (m, 3H), 1.50-1.58 (m, 3H), 2.71-2.85 (m, 2H), 4.37
(dd, J ) 9.1, 2.7 Hz, 1H), 4.41 (dd, J ) 9.1, 6.5 Hz, 1H), 4.68
(d, J ) 6.5 Hz, 1H), 5.33 (ddd, J ) 6.5, 6.5, 2.7 Hz, 1H), 7.10-
7.34 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 173.1, 153.4,
139.5, 138.1, 129.2, 128.9, 128.6, 128.4, 127.8, 127.1, 65.2, 56.2,
51.1, 35.4, 31.2, 23.9, 22.4, 13.9; IR (CDCl3) 2957, 2872, 1780,
1701, 1501, 1496, 1452, 1388, 1249 cm-1; [R]25 ) -105.4° (c
D
1.06, CH2Cl2). Anal. Calcd for C22H25NO3: C, 75.19; H, 7.17;
N, 3.99. Found: C, 75.57; H, 7.35; N, 3.86.
The aldol products from 14 also underwent clean
deprotection and lactonization under acidic conditions.
Thus, deprotection of 16a -e provides intermediates for
the preparation of other targets. The first chiral syn-
thesis of 5-epi-blastmycinone is illustrated in Scheme 4.
Silyl deprotection of 16a furnished 5-epi-blastmycino-
lactol 21a in 88% yield (Table 3). Acylation of the lactol
under standard conditions gave 5-epi-blastmycinone 22
in 82% yield. The spectral data for the final product are
identical to those one reported for racemic material.7i The
overall yield for 22 over four steps was 47%. Analogs of
NFX-2 and NFX-4 (21b and 21c) were readily obtained
in 37% and 39% overall yields from aldols 16b and 16c,
respectively. These compounds have the epi configura-
tion at the 5-position as compared to the natural prod-
ucts. Acidic deprotection followed by acetylation of 16d
and 16e gave the lipid metabolites 5 and 6, respectively,
(-)-(R)-3-(1-Oxooctyl)-4-(d ip h en ylm eth yl)-2-oxa zolid i-
n on e (12b): from 11 (3.0 g, 11.9 mmol) was obtained 12b (4.46
g, 11.8 mmol, 99%); mp 99-100.5 °C; Rf 0.32 (80:20 hexane:
EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.89 (t, J ) 6.7 Hz, 3H),
1.19-1.38 (m, 8H), 1.44-1.62 (m, 2H), 2.70-2.86 (m, 2H), 4.37
(dd, J ) 9.4, 2.9 Hz, 1H), 4.41 (dd, J ) 9.4, 7.3 Hz, 1H), 4.68
(d, J ) 5.9 Hz, 1H), 5.32 (ddd, J ) 7.3, 5.9, 2.9 Hz, 1H), 7.10-
7.38 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 173.0, 153.4,
139.5, 138.1, 129.2, 128.8, 128.6, 128.4, 127.8, 127.1, 65.1, 56.2,
51.1, 35.4, 31.6, 28.9, 24.2, 22.6, 14.1; IR (CDCl3) 3088, 3065,
3032, 2955, 2928, 2859, 1782, 1701, 1601, 1497, 1453, 1387,
1337, 1211, 1096 cm-1; [R]25D ) -96.0° (c 1.00, CH2Cl2). Anal.
Calcd for C24H29NO3: C, 75.96; H, 7.70; N, 3.69. Found: C,
75.59; H, 7.80; N, 3.66.
(-)-(R)-3-(1-Oxo-7-m eth yloctyl)-4-(d ip h en ylm eth yl)-2-
oxa zolid in on e (12c): from 11 (3.0 g, 11.9 mmol) and the acid
(26) 1H and 13C NMR were recorded on J EOL-GSX instruments. IR
spectra were recorded on Mattson Instruments 2020 Galaxy series FT-
IR spectrophotometer. Optical rotations were recorded on a J ASCO-
DIP-370 instrument. For typical experimental protocols, see: Gaboury,
J . A.; Sibi, M. P. J . Org. Chem. 1993, 58, 2173.
(25) The highest yield for blastmycinone reported so far is 22% over
six steps. See ref 7x.

7852 J . Org. Chem., Vol. 61, No. 22, 1996
Sibi et al.
chloride27 was obtained 12c (4.59 g, 11.53 mmol, 97%); mp 88-
90 °C; Rf 0.34 (80:20 hexane:EtOAc); 1H NMR (400 MHz,
CDCl3) δ 0.87 (d, J ) 6.7 Hz, 6H), 1.08-1.20 (m, 2H), 1.20-
1.33 (m, 4H), 1.42-1.61 (m, 3H), 2.71-2.84 (m, 2H), 4.37 (dd,
J ) 9.1, 2.9 Hz, 1H), 4.41 (dd, J ) 9.1, 7.8 Hz, 1H), 4.68 (d, J
) 6.2 Hz, 1H), 5.32 (ddd, J ) 7.8, 6.2, 2.9 Hz, 1H), 7.09-7.39
(m, 10H); 13C NMR (100 MHz, CDCl3) δ 173.0, 153.4, 139.5,
138.1, 129.2, 128.9, 128.6, 128.4, 127.8, 127.1, 65.1, 56.2, 51.1,
38.7, 35.4, 29.3, 27.9, 27.1, 24.2, 22.6; IR (CDCl3) 2955, 2930,
2868, 1782, 1701, 1601, 1497, 1453, 1385, 1339, 1211, 1034,
m eth yl)-2-oxa zolid in on e (15a ): method A (90%), colorless
sticky oil; Rf 0.35 (80:20 hexane:EtOAc); H NMR (400 MHz,
1
CDCl3) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.87-0.89 (m, 12H), 1.07-
1.17 (m, 5H), 1.08-1.30 (m, 2H), 1.57-1.67 (m, 2H), 2.73 (d,
J ) 3.2 Hz, 1H), 3.69 (ddd, J ) 5.9, 5.4, 3.2 Hz, 1H), 3.82 (dq,
J ) 6.4, 5.4 Hz, 1H), 4.00 (ddd, J ) 8.4, 5.9, 5.1 Hz, 1H), 4.36
(dd, J ) 9.7, 7.5 Hz, 1H), 4.42 (dd, J ) 9.7, 1.6 Hz, 1H), 4.78
(d, J ) 5.9 Hz, 1H), 5.32 (ddd, J ) 7.5, 5.9, 1.6 Hz, 1H), 7.14-
7.34 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 175.9, 152.9,
139.6, 137.9, 129.1, 128.9, 128.7, 128.4, 127.9, 127.1, 74.9, 69.0,
64.7, 56.9, 51.1, 43.6, 28.7, 26.9, 25.8, 23.1, 18.9, 17.9, 13.9,
-4.3, -4.9; IR (CDCl3) 3547, 2959, 2931, 2860, 2251, 1784,
1691, 1496, 1464, 1386, 1253, 1207, 1089 cm-1; [R]25D ) -82.5°
(c 1.00, CH2Cl2). Anal. Calcd for C31H45NO5Si: C, 68.98; H,
8.40; N, 2.59. Found: C, 69.11; H, 8.46; N, 2.67.
(-)-[3-(2R,3R,4S),4R]-3-[1-Oxo-2-h exyl-3-h ydr oxy-4-[[(1,1-
d im et h ylet h yl)d im et h ylsilyl]oxy]p en t yl]-4-(d ip h en yl-
m eth yl)-2-oxa zolid in on e (15b): method A (48%), method B
(70%); Rf 0.08 (90:10 hexane:EtOAc); 1H NMR (400 MHz,
CDCl3) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.87-0.92 (m, 12H), 1.10-
1.33 (m, 11H), 1.58-1.72 (m, 2H), 2.71 (d, J ) 3.2 Hz, 1H),
3.70 (ddd, J ) 5.4, 5.4, 3.2 Hz, 1H), 3.82 (dq, J ) 6.2, 5.4 Hz,
1H), 4.00 (ddd, J ) 8.6, 5.4, 4.8 Hz, 1H), 4.36 (dd, J ) 9.4, 8.3
Hz, 1H), 4.43 (dd, J ) 9.4, 2.7 Hz, 1H), 4.78 (d, J ) 5.7 Hz,
1H), 5.31 (ddd, J ) 8.3, 5.7, 2.7 Hz, 1H), 7.12-7.34 (m, 10H);
13C NMR (100 MHz, CDCl3) δ 175.8, 152.9, 139.5, 137.9, 129.1,
128.9, 128.7, 128.3, 127.8, 127.1, 74.9, 69.0, 64.6, 56.8, 50.9,
43.6, 31.6, 29.8, 27.2, 26.6, 25.7, 22.7, 18.9, 17.9, 14.1, -4.3,
-5.0; IR (CDCl3) 3532 (b), 3088, 3063, 2930, 1952, 1784, 1693,
1601, 1497, 1462, 1386, 1209, 968 cm-1; [R]25D ) -75.6° (c 1.00,
CH2Cl2). Anal. Calcd for C33H49NO5Si: C, 69.80; H, 8.70; N,
2.47. Found: C, 69.43; H, 8.46; N, 2.50.
702 cm-1; [R]25 ) -98.1° (c 1.10, CH2Cl2). Anal. Calcd for
D
C25H31NO3: C, 76.30; H, 7.94; N, 3.56. Found: C, 76.14; H,
7.87; N, 3.87.
(-)-(R )-3-(1-O x o h e x a d e c y l)-4-(d ip h e n y lm e t h y l)-2-
oxa zolid in on e (12d ): from 11 (4.0 g, 15.8 mmol) was obtained
12d (7.62 g, 15.5 mmol, 98%); mp 71-73 °C; Rf 0.47 (80:20
hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J ) 6.7
Hz, 3H), 1.26 (bs, 24 H), 1.47-1.62 (m, 2H), 2.70-2.87 (m, 2H),
4.37 (dd, J ) 9.1, 2.7 Hz, 1H), 4.47 (dd, J ) 9.1, 7.5 Hz, 1H),
4.68 (d, J ) 5.9 Hz, 1H), 5.32 (ddd, J ) 7.5, 5.9, 2.7 Hz, 1H),
7.08-7.38 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 173.0, 153.4,
139.5, 138.1, 129.2, 128.9, 128.6, 128.4, 127.8, 127.0, 65.1, 56.2,
51.1, 35.4, 31.9, 29.7, 29.6, 29.5, 29.3, 29.0, 24.2, 22.7, 14.1;
IR (CDCl3) 2928, 2854, 1782, 1699, 1496, 1454, 1397, 1211
cm-1; [R]25D ) -74.9° (c 1.01, CH2Cl2). Anal. Calcd for C32H45
-
NO3: C, 78.17; H, 9.22; N, 2.85. Found: C, 78.18; H, 9.30; N,
3.01.
(-)-(R )-3-(1-O x o o c t a d e c y l)-4-(d ip h e n y lm e t h y l)-2-
oxa zolid in on e (12e): from 11 (2.70 g, 10.67 mmol) was
obtained 12e (5.26 g, 10.13 mmol), 95%; mp 68-70 °C; Rf 0.45
(80:20 hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J
) 6.9 Hz, 3H), 1.08-1.38 (m, 28H), 1.44-1.59 (m, 2H), 2.70-
2.86 (m, 2H), 4.37 (dd, J ) 9.1, 2.6 Hz, 1H), 4.40 (dd, J ) 9.1,
6.9 Hz, 1H), 4.68 (d, J ) 5.9 Hz, 1H), 5.33 (ddd, J ) 6.9, 5.9,
2.6 Hz, 1H), 7.09-7.37 (m, 10H); 13C NMR (100 MHz, CDCl3)
δ 173.0, 153.4, 139.5, 138.1, 129.2, 128.9, 128.6, 128.4, 127.9,
127.1, 65.1, 56.2, 51.1, 35.4, 31.9, 29.7, 29.6, 29.5, 29.3, 29.1,
24.2, 22.7, 14.1; IR (CDCl3) 2926, 2855, 1784, 1703, 1601, 1496,
(-)-[3-(2R,3R,4S),4R]-3-[1-Oxo-2-(5-m eth ylh exyl)-3-h y-
d r oxy-4-[[(1,1-d im eth yleth yl)d im eth ylsilyl]oxy]-p en tyl]-
4-(diph en ylm eth yl)-2-oxazolidin on e (15c): method A (45%),
method B (61%), colorless sticky oil; Rf 0.08 (90:10 hexane:
EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 3H), 0.08 (s,
3H), 0.86-0.92 (m, 15H), 1.08-1.38 (m, 10H), 1.48-1.72 (m,
2H), 2.69-2.75 (bs, 1H), 3.69 (dd, J ) 5.6, 5.4 Hz, 1H), 3.82
(dq, J ) 6.2, 5.6 Hz, 1H), 4.01 (ddd, J ) 8.0, 5.4, 4.0 Hz, 1H,),
4.36 (dd, J ) 9.4, 8.1 Hz, 1H), 4.43 (dd, J ) 9.4, 2.7 Hz, 1H),
4.78 (d, J ) 5.6 Hz, 1H, ), 5.32 (ddd, J ) 8.1, 5.6, 2.7 Hz, 1H),
7.12-7.38 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 175.9, 153.0,
139.7, 138.0, 129.3, 129.0, 128.9, 128.5, 127.9, 127.2, 75.1, 69.2,
64.8, 56.9, 51.2, 43.8, 31.8, 29.9, 27.4, 26.8, 25.9, 22.8, 19.1,
18.0, 14.2, -4.1, -4.8; IR (neat) 3543 (b), 3088, 3063, 3030,
1454, 1386, 1249, 1211, 910, 734, 702 cm-1; [R]25 ) -70.8° (c
D
1.00, CH2Cl2). Anal. Calcd for C34H49NO3: C, 78.57; H, 9.50;
N, 2.69. Found: C, 78.60; H 9.60; N, 2.52.
Gen er a l P r oced u r e for th e Ald ol Rea ction of (R)-N-
Acyl-4-(d ip h en ylm et h yl)-2-oxa zolid in on e (12a -e) w it h
2-[[(1,1-Dim eth yleth yl)d im eth ylsilyl]oxy]p r op a n a l (13,
14). Meth od A. To a flame-dried two-necked 25 mL flask
under N2 was added 12a -e (2.0 mmol) in CH2Cl2 (5 mL), and
the solution was cooled to 0 °C in an ice bath. Dibutylboron
triflate (2.2 mmol) was added slowly over a period of 5 min,
and the resultant brownish solution was stirred for another 5
min. Freshly distilled triethylamine (0.34 mL, 2.6 mmol) was
then added dropwise while the temperature was maintained
at 0 °C. The pale yellow solution was stirred at 0 °C from 45
min to 1 h. The boron enolate solution was then cooled to -78
°C. Freshly prepared 13 or 14 (0.45 g, 2.40 mmol) in 3 mL of
CH2Cl2 was added dropwise over 10 min. The reaction mixture
was warmed gradually to 0 °C over a period of 24 h. The
progress of the reaction was monitored by TLC. The reaction
was quenched slowly with pH ) 7 buffer (2.0 mL), MeOH (6
mL), and MeOH/30% H2O2 ) 2/1 (6 mL). The cloudy mixture
was stirred at 0 °C for 1 h. The aqueous layer was separated
and extracted with CH2Cl2 (4 × 15 mL). The combined
extracts were dried over Na2SO4 and filtered, and the solvent
was evaporated to dryness under reduced pressure. Purifica-
tion of the residue by flash chromatography furnished dia-
stereomerically pure aldol product.
2951, 1950, 1786, 1693, 1601, 1497, 1454, 1383, 953, 833 cm-1
;
[R]25 ) -71.0° (c 1.00, CH2Cl2). Anal. Calcd for C34H51NO5-
D
Si: C, 70.18; H, 8.83; N, 2.41. Found: C, 69.98; H, 8.53; N,
2.81.
(-)-[3-(2R,3R,4S),4R]-3-[1-Oxo-2-tetr a d ecyl-3-h yd r oxy-
4-[[(1,1-d im et h ylet h yl)d im et h ylsilyl]oxy]p en t yl]-4-(d i-
p h en ylm eth yl)-2-oxa zolid in on e (15d ): method A (50%),
method B (68%), colorless sticky oil; Rf 0.12 (90:10 hexane:
EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 3H), 0.08 (s,
3H), 0.85-0.91 (m, 12H), 1.11-1.41 (m, 27H), 1.59-1.80 (m,
2H), 2.72 (d, J ) 3.0 Hz, 1H), 3.70 (ddd, J ) 5.4, 5.4, 3.0 Hz,
1H), 3.82 (dq, J ) 6.2, 5.4 Hz, 1H), 4.00 (ddd, J ) 8.1, 5.4, 3.8
Hz, 1H), 4.36 (dd, J ) 9.4, 7.5 Hz, 1H), 4.43 (dd, J ) 9.4, 2.2
Hz, 1H), 4.78 (d, J ) 5.6 Hz, 1H), 5.32 (ddd, J ) 7.5, 5.6, 2.2
Hz, 1H), 7.14-7.41 (m, 10H); 13C NMR (100 MHz, CDCl3) δ
175.8, 152.9, 139.6, 137.9, 129.1, 128.9, 128.7, 128.4, 127.8,
127.1, 74.9, 69.0, 64.7, 56.8, 51.0, 43.7, 39.9, 30.1, 29.7, 29.6,
29.5, 29.4, 27.2, 26.6, 25.7, 22.7, 19.0, 17.9, 14.1, -4.3, -4.9;
IR (neat) 3532, 3063, 3030, 2933, 2858, 1788, 1692, 1601, 1464,
1387, 1260, 1208, 1094 cm-1; [R]25 ) -60.3° (c 0.98, CH2Cl2).
Meth od B. Same as method A but the reaction was carried
out using Me2NPh (distilled from CaH2) as a base for enoliza-
tion and Et2O as a solvent for the reaction. During the
enolization process, substrates partially precipitated out from
solvent at 0 °C, but eventually dissolved upon the addition of
Bu2BOTf.
D
Anal. Calcd for C41H65NO5Si: C, 72.41; H, 9.63; N, 2.06.
Found: C, 72.51; H, 9.52; N, 1.82.
(-)-[3-(2R,3R,4S),4R]-3-[1-Oxo-2-h exa d ecyl-3-h yd r oxy-
4-[[(1,1-d im et h ylet h yl)d im et h ylsilyl]oxy]p en t yl]-4-(d i-
p h en ylm eth yl)-2-oxa zolid in on e (15e): method A (49%),
method B (60%), colorless sticky oil; Rf 0.12 (90:10 hexane:
EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 3H), 0.08 (s,
3H), 0.85-0.90 (b, 12H), 1.12 (d, 6.2 Hz, 3H), 1.13-1.35 (b,
28H), 1.58-1.74 (m, 2H), 2.72 (d, J ) 3.2 Hz, 1H), 3.70 (ddd,
J ) 5.4, 5.4, 3.2 Hz, 1H), 3.82 (dq, J ) 6.2, 5.4 Hz, 1H), 4.00
(-)-[3-(2R,3R,4S),4R]-3-[1-Oxo-2-bu tyl-3-h ydr oxy-4-[[(1,1-
d im et h ylet h yl)d im et h ylsilyl]oxy]-p en t yl]-4-(d ip h en yl-
(27) The acid chloride was prepared according to a literature
procedure: Kaga, H.; Miura, M.; Orito, K. Synthesis 1989, 864.

Trisubstituted Butyrolactone Natural Products
J . Org. Chem., Vol. 61, No. 22, 1996 7853
(ddd, J ) 7.9, 5.4, 3.9 Hz, 1H), 4.36 (dd, J ) 9.3, 7.7 Hz, 1H),
4.43 (dd, J ) 9.3, 2.8 Hz, 1H), 4.78 (d, J ) 5.7 Hz, 1H), 5.32
(ddd, J ) 7.7, 5.7, 2.8 Hz, 1H), 7.14-7.35 (m, 10H); 13C NMR
(100 MHz, CDCl3) δ 175.8, 152.9, 139.6, 137.9, 129.1, 129.0,
128.7, 128.4, 127.8, 127.1, 74.9, 69.1, 64.7, 56.9, 51.1, 43.7, 31.9,
30.1, 29.7, 29.6, 29.5, 29.4, 27.2, 26.7, 25.8, 22.7, 19.0, 17.9,
14.1, -4.2, -4.9; IR (neat) 3543 (b), 2926, 2855, 1783, 1693,
29.8, 29.6, 22.9, 20.7, 17.9, 14.1, -4.2, -5.1; IR (neat) 3543
(b), 2926, 2854, 1786, 1694, 1601, 1497, 1464, 1386, 1251, 1205,
1093, 835, 775, 702 cm-1; [R]25D ) -72.5° (c 1.00, CH2Cl2). Anal.
Calcd for C41H65NO5Si: C, 72.41; H, 9.63; N, 2.06. Found: C,
72.68; H, 9.30; N, 2.40.
(-)-[3-(2R,3R,4R),4R]-3-[1-Oxo-2-h exa d ecyl-3-h yd r oxy-
4-[[(1,1-d im et h ylet h yl)d im et h ylsilyl]oxy]p en t yl]-4-(d i-
p h en ylm eth yl)-2-oxa zolid in on e (16e): method B (42%); mp
42-44 °C; Rf 0.65 (80:20 hexane:EtOAc); 1H NMR (400 MHz,
C6D6) δ 0.02 (s, 3H), 0.04 (s, 3H), 0.89-0.93 (b, 12H), 1.25-
1.41 (m, 30H), 1.51-1.70 (m, 1H), 1.74-1.90 (m, 1H), 2.21-
2.35 (m, 1H), 2.43 (d, J ) 7.5 Hz, 1H), 3.51 (dd, J ) 9.4, 6.4
Hz, 1H), 3.89 (dd, J ) 9.4, 2.5 Hz, 1H), 3.99 (dq, J ) 6.2, 3.3
Hz, 1H), 4.08 (ddd, J ) 7.5, 6.7, 3.3 Hz, 1H), 4.17 (ddd, J )
7.6, 6.7, 3.7 Hz, 1H), 4.82 (d, J ) 5.6 Hz, 1H), 5.05 (ddd, J )
6.4, 5.6, 2.5 Hz, 1H), 6.85-7.13 (m, 10H); 13C NMR (100 MHz,
C6D6) δ 174.1, 152.9, 139.9, 138.5, 129.3, 128.8, 128.6, 127.9,
127.6, 126.9, 74.9, 70.4, 64.2, 56.7, 51.2, 46.0, 32.1, 30.4, 30.0,
29.9, 29.8, 29.6, 27.6, 26.7, 25.8, 25.7, 22.9, 20.7, 17.9, 14.1,
-4.2, -5.1; IR (neat) 3543, 2925, 2854, 1786, 1693, 1476, 1464,
1691, 1496, 1464, 1387, 1251, 1205, 1093, 835, 775, 702 cm-1
;
[R]25 ) -59.3° (c 1.01, CH2Cl2). Anal. Calcd for C43H69NO5-
D
Si: C, 72.94; H, 9.82; N, 1.98. Found: C, 72.99; H, 9.52; N,
2.27.
(-)-[3-(2R,3R,4R),4R]-3-[1-Oxo-2-bu tyl-3-h ydr oxy-4-[[(1,1-
d im et h ylet h yl)d im et h ylsilyl]oxy]p en t yl]-4-(d ip h en yl-
m eth yl)-2-oxa zolid in on e (16a ): method B (67%), Rf 0.65 (80:
1
20 hexane:EtOAc); H NMR (400 MHz, C6D6) δ 0.02 (s, 3H),
0.04 (s, 3H), 0.82-0.96 (b, 12H), 1.20-1.40 (m, 6H), 1.42-1.53
(m, 1H), 1.71-1.81 (m, 1H), 2.17-2.28 (m, 1H), 2.41 (d, J )
7.5 Hz, 1H), 3.49 (dd, J ) 9.1, 8.1 Hz, 1H), 3.88 (dd, J ) 9.1,
2.2 Hz, 1H), 3.96 (dq, J ) 5.9, 3.8 Hz, 1H), 4.05 (ddd, J ) 7.5,
7.0, 3.8 Hz, 1H), 4.14 (ddd, J ) 7.5, 7.0, 3.2 Hz, 1H), 4.78 (d,
J ) 5.9 Hz, 1H), 5.04 (ddd, J ) 8.1, 5.9, 2.2 Hz, 1H), 6.86-
7.07 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 174.0, 152.9,
138.0, 129.1, 128.9, 128.7, 128.4, 127.8, 127.1, 74.5, 69.7, 64.9,
56.7, 51.1, 45.5, 29.7, 28.3, 26.6, 25.7, 23.0, 20.5, 13.9, -4.0,
-5.1; IR (neat) 3543 (b), 2926, 2854, 1786, 1694, 1601, 1497,
1387, 1251, 1205, 1093, 836, 775, 702 cm-1; [R]25 ) -69.3° (c
D
1.00, CH2Cl2). Anal. Calcd for C43H69NO5Si: C, 72.94; H, 9.82;
N, 1.98. Found: C, 73.35; H, 9.65; N, 2.23.
Gen er a l P r oced u r e for TBS Dep r otection a n d La cton e
F or m a tion . To a 25 mL round bottomed flask under N2 was
added a solution of the aldol product (0.5 mmol) in HOAc (6
mL), THF (2 mL), and H2O (2 mL). This mixture was stirred
at ambient temperature for 24 h or at 60-65 °C for 48 h (for
longer alkyl chain substrates). The reaction was diluted with
H2O (10 mL) and neutralized with Na2CO3 to pH ) 7 at 0 °C.
The mixture was taken up with CH2Cl2 (15 mL) and H2O (5
mL) into a separatory funnel. The aqueous layer was sepa-
rated and extracted with CH2Cl2 (3 × 15 mL). The combined
organic extracts were dried over Na2SO4, and solvent was
evaporated under reduced pressure. The resultant TBS-
deprotected aldol adduct cyclized to the corresponding lactol
in >80% yields during flash column chromatography. The
product was eluted with 30% EtOAc in hexane. The chiral
auxiliary was recovered (ca. 95%) during the chromatographic
purification.
1464, 1386, 1251, 1205, 1093, 835, 775, 702 cm-1; [R]25
)
D
-83.6° (c 1.00, CH2Cl2). Anal. Calcd for C31H45NO5Si: C,
68.98; H, 8.40; N, 2.59. Found: C, 69.01; H, 8.19; N, 2.57.
(-)-[3-(2R,3R,4R),4R]-3-[1-Oxo-2-h e xyl-3-h yd r oxy-4-
[[(1,1-d im e t h yle t h yl)d im e t h ylsilyl]oxy]p e n t yl]-4-(d i-
p h en ylm eth yl)-2-oxa zolid in on e (16b): method B (45%), Rf
1
0.44 (80:20 hexane:EtOAc); H NMR (400 MHz, C6D6) δ 0.02
(s, 3H), 0.04 (s, 3H), 0.87-0.94 (m 12H), 1.27-1.39 (m, 10H),
1.49-1.60 (m, 1H), 1.72-1.86 (m, 1H), 2.16-2.30 (m, 1H), 2.43
(d, J ) 7.4 Hz, 1H), 3.53 (dd, J ) 9.3, 8.5 Hz, 1H), 3.90 (dd, J
) 9.3, 2.5 Hz, 1H), 3.96 (dq, J ) 6.2, 3.7 Hz, 1H), 4.05 (ddd, J
) 7.4, 7.0, 3.7 Hz, 1H), 4.15 (ddd, J ) 7.3, 7.0, 2.4 Hz, 1H),
4.81 (d, J ) 5.6 Hz, 1H), 5.07 (ddd, J ) 8.5, 5.6, 2.5 Hz, 1H),
6.86-7.07 (m, 10H); 13C NMR (100 MHz, C6D6) δ 174.1, 153.0,
139.9, 138.4, 129.3, 128.8, 128.6, 127.9, 127.6, 126.9, 74.9, 70.4,
64.2, 56.7, 51.2, 46.0, 32.0, 30.0, 27.6, 26.6, 25.8, 22.9, 20.7,
17.9, 14.1, -4.2, -5.2; IR (neat) 3522 (b), 3063, 3030, 2955,
2858, 1790, 1694, 1601, 1496, 1454, 1387, 1251, 1211, 1089,
(-)-(3R,4R,5S)-3-Bu t yl-4-h yd r oxy-5-m et h yld ih yd r o-
2(3H)-fu r a n on e [(-)-bla stm ycin ola ctol] (18a ): 15a (0.10
g, 0.185 mmol) gave 18a (22.7 mg, 0.132 mmol, 87%); mp 49-
51 °C; Rf 0.47 (50:50 hexane:EtOAc); 1H NMR (400 MHz,
CDCl3) δ 0.93 (t, J ) 6.9 Hz, 3H), 1.20-1.55 (m, 7H), 1.55-
1.69 (m, 1H), 1.81-1.93 (m, 1H), 2.17-2.29 (bs, 1H), 2.57 (ddd,
J ) 8.6, 7.5, 5.9 Hz, 1H), 3.85 (dd, J ) 8.6, 6.9 Hz, 1H), 4.21
(dq, J ) 6.9, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 176.0,
79.9, 79.1, 48.6, 28.9, 28.1, 22.6, 18.2, 13.8; IR (neat) 3441 (b),
2960, 2933, 2874, 1757, 1456, 1388, 1182, 1107, 1057, 856
cm-1; [R]25 ) -19.4° (c 1.01, CDCl3) {lit.7j [R]20 ) -18.4° (c
968 cm-1; [R]25 ) -81.6° (c 1.15, CH2Cl2). Anal. Calcd for
D
C33H49NO5Si: C, 69.80; H, 8.70; N, 2.47. Found: C, 70.03; H,
8.44; N, 2.52.
(-)-[3-(2R,3R,4R),4R]-3-[1-Oxo-2-(5-m eth ylh exyl)-3-h y-
d r oxy-4-[[(1,1-d im eth yleth yl)d im eth ylsilyl]oxy]p en tyl]-
4-(diph en ylm eth yl)-2-oxazolidin on e (16c): method B (47%),
Rf 0.45 (80:20 hexane:EtOAc); 1H NMR (400 MHz, C6D6) δ 0.02
(s, 3H), 0.05 (s, 3H), 0.87-0.94 (m 15H), 1.18-1.40 (m, 8H),
1.45-1.60 (m, 2H), 1.75-1.88 (m, 1H), 2.18-2.30 (m, 1H), 3.51
(dd, J ) 9.0, 8.7 Hz, 1H), 3.90 (dd, J ) 9.0, 2.5 Hz, 1H), 3.99
(dq, J ) 6.2, 3.5 Hz, 1H), 4.07 (dd, J ) 7.0, 3.5 Hz, 1H), 4.16
(ddd, J ) 7.4, 7.0, 2.4 Hz, 1H), 4.82 (d, J ) 5.7 Hz, 1H), 5.05
(ddd, J ) 8.7, 5.7, 2.5 Hz, 1H), 6.84-7.11 (m, 10H); 13C NMR
(100 MHz, C6D6) δ 174.1, 153.0, 139.9, 138.5, 129.3, 128.8,
128.6, 127.9, 126.9, 74.9, 70.4, 64.2, 56.7, 51.3, 46.0, 39.0, 28.2,
28.1, 27.7, 26.8, 25.8, 25.6, 22.6, 20.7, 17.9, -4.2, -5.2; IR (neat)
3425 (b), 3063, 3030, 2953, 2931, 2856, 1753, 1695, 1601, 1495,
1464, 1386, 1249, 1215, 1060, 835 cm-1; [R]25D ) -79.8° (c 1.01,
CH2Cl2). Anal. Calcd for C34H51NO5Si: C, 70.18; H, 8.83; N,
2.41. Found: C, 70.39; H, 8.67; N, 2.53.
(-)-[3-(2R,3R,4R),4R]-3-[1-Oxo-2-tetr a d ecyl-3-h yd r oxy-
4-[[(1,1-d im et h ylet h yl)d im et h ylsilyl]oxy]p en t yl]-4-(d i-
p h en ylm eth yl)-2-oxa zolid in on e (16d ): method B (43%); mp
63-65 °C; Rf 0.65 (80:20 hexane:EtOAc); 1H NMR (400 MHz,
C6D6) δ 0.02 (s, 3H), 0.05 (s, 3H), 0.90 (b, 12H), 1.15-1.50 (m,
26H), 1.51-1.68 (m, 1H), 1.76-1.89 (m, 1H), 2.20-2.33 (m,
1H), 2.43 (d, J ) 7.5 Hz, 1H), 3.51 (dd, J ) 9.3, 6.3 Hz, 1H),
3.89 (dd, J ) 9.3, 2.4 Hz, 1H), 4.00 (dq, J ) 6.2, 3.4 Hz, 1H),
4.09 (ddd, J ) 7.5, 6.9, 3.4 Hz, 1H), 4.19 (ddd, J ) 7.6, 6.9, 3.7
Hz, 1H), 4.82 (d, J ) 5.5 Hz, 1H), 5.05 (ddd, J ) 6.3, 5.5, 2.4
Hz, 1H), 6.85-7.12 (m, 10H); 13C NMR (100 MHz, C6D6) δ
174.1, 152.9, 139.9, 138.5, 129.3, 128.8, 128.6, 127.9, 127.6,
126.9, 74.9, 70.4, 64.2, 56.7, 51.2, 46.0, 32.1, 30.4, 30.0, 29.9,
D
D
0.98, CD3OD}.
(-)-(3R,4R,5S)-3-H exyl-4-h yd r oxy-5-m et h yld ih yd r o-
2(3H)-fu r a n on e [(-)-NF X-2] (2): 15b (0.2810 g, 0.4966
mmol) gave 2 (0.0831 g, 0.4155 mmol, 84%); mp 56-58 °C; Rf
0.49 (50:50 hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.88
(t, J ) 6.9 Hz, 3H), 1.20-1.38 (b, 6H), 1.39-1.53 (m, 5H),
1.54-1.65 (m, J ) 6.5 Hz, 1H), 1.80-1.90 (m, J ) 4.3 Hz, 1H),
2.20-2.50 (b, 1H), 2.57 (ddd, J ) 8.6, 6.5, 4.3 Hz, 1H), 3.84
(dd, J ) 8.6, 7.3 Hz, 1H), 4.21 (dq, J ) 7.3, 6.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 176.4, 80.0, 78.9, 48.6, 31.5, 29.2,
28.4, 26.6, 22.5, 18.2, 14.0; IR (CDCl3) 3472 (b), 2931, 2860,
1757, 1458, 1390, 1302, 1184, 1109, 1058, 804, 735 cm-1; [R]25
D
) -15.1° (c 1.20, MeOH) {lit.7bb [R]25 ) -13.58° (c 1.23,
D
MeOH)}.
(-)-(3R,4R,5S)-3-(5-Met h ylh exyl)-4-h yd r oxy-5-m et h -
yld ih yd r o-2(3H)-fu r a n on e [(-)-NF X-4] (4): 15c (0.2232 g,
0.38 mmol) gave 4 (0.0684 d, 0.3123 mmol, 82%); mp 61-63
°C; Rf 0.53 (50:50 hexane:EtOAc); 1H NMR (400 MHz, CDCl3)
δ 0.87 (d, J ) 6.7 Hz, 6H), 1.15-1.22 (m, 3H), 1.29-1.38 (m,
2H), 1.40-1.57 (m, 5H), 1.57-1.65 (m, 1H), 1.80-1.91 (m, 1H),
2.20-2.46 (b, 1H), 2.57 (ddd, J ) 8.6, 7.7, 5.8 Hz, 1H), 3.84
(dd, J ) 8.6, 7.3 Hz, 1H), 4.22 (dq, J ) 7.3, 6.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 176.4, 80.1, 78.9, 48.6, 38.7, 28.4,
27.8, 27.3, 26.9, 22.6, 18.2; IR (CDCl3) 3453 (b), 2932, 2866,

7854 J . Org. Chem., Vol. 61, No. 22, 1996
Sibi et al.
1759, 1466, 1387, 1321, 1180, 1059, 920, 729, 650 cm-1; [R]25
1.15, CH2Cl2). Anal. Calcd for C19H36O3: C, 73.03; H, 11.61.
Found: C, 73.37; H, 11.26.
D
) -11.2° (c 1.62, MeOH) {lit.7bb [R]25 ) -12.12° (c 1.825,
D
MeOH)}.
(+)-(3R,4R,5R)-3-Hexa d ecyl-4-h yd r oxy-5-m eth yld ih y-
d r o-2(3H)-fu r a n on e (21e): 16e (0.1776 g, 0.25 mmol) gave
21e (0.0689 g, 0.203 mmol, 81%); mp 73-75 °C; Rf 0.23 (80:20
hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J ) 6.9
Hz, 3H), 1.15-1.62 (m, 32H), 1.67-1.76 (m, 1H), 2.30 (b, 1H),
2.54 (ddd, J ) 7.9, 6.6, 3.2 Hz, 1H), 4.20 (dd, J ) 4.8, 3.2 Hz,
1H), 4.64 (dq, J ) 6.7, 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 177.9, 78.4, 74.0, 49.3, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 28.4,
27.3, 22.7, 14.1, 13.9; IR (CDCl3) 3429, 2920, 2852, 1759, 1736,
(-)-(3R,4R,5S)-3-Tetr a d ecyl-4-h yd r oxy-5-m eth yld ih y-
d r o-2(3H)-fu r a n on e (18d ): 15d (0.4032 g, 0.59 mmol) gave
18d (0.1529 g, 0.48 mmol, 81%); mp 88-90 °C; Rf 0.21 (80:20
hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J ) 6.7
Hz, 3H), 1.10-1.38 (b, 22H), 1.39-1.40 (m, 6H), 1.80-1.92 (m,
1H), 2.37 (d, J ) 4.3 Hz, 1H), 2.57 (ddd, J ) 8.1, 7.5, 5.4 Hz,
1H), 3.84 (ddd, J ) 8.1, 7.0, 4.3 Hz, 1H), 4.21 (dq, J ) 7.0, 5.9
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 176.1, 79.9, 79.0, 48.6,
31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 28.4, 26.7, 22.7, 18.2, 14.1;
IR (CDCl3) 3414 (b), 2955, 2920, 2849, 1734, 1459, 1327, 1058
1454, 1267, 1236, 1136, 1084, 1051, 877, 732, 597 cm-1; [R]25
D
) +39.8° (c 1.42, dioxane). Anal. Calcd for C21H40O3: C, 74.07;
H, 11.84. Found: C, 74.16; H, 11.49.
cm-1; [R]25 ) -12.6° (c 1.17, CH2Cl2). Anal. Calcd for
D
Gen er a l P r oced u r e for th e P r ep a r a tion of 4-(Acyloxy)-
bu tyr ola cton es. Meth od A. To a solution of isovaleryl
chloride (3 mmol) in CH2Cl2 (2 mL) in a 10 mL round bottomed
flask at ambient temperature was added the hydroxy lactone
(0.50 mmol) and DMAP (2 mmol) in CH2Cl2 (2 mL). The
reaction mixture was stirred at rt for 24 h. The reaction was
quenched with H2O (1 mL) and 10% citric acid (1 mL). The
residue was taken up with CH2Cl2 (10 mL) and H2O (5 mL)
into a separatory funnel. The aqueous layer was separated
and extracted with CH2Cl2 (4 × 10 mL). The combined organic
extracts were washed with H2O (15 mL) and brine (20 mL)
and dried over Na2SO4, and the solvent was evaporated under
reduced pressure. Purification of the residue by flash column
chromatography (eluted with 10% EtOAc in hexane) furnished
the butyrolactones.
Meth od B. A solution of hydroxy lactone (0.5 mmol) and
acetic anhydride (7.5 mmol) in pyridine (3 mL) was stirred at
rt for 24 h. The solvent was evaporated under vacuum. The
residue was taken up with CH2Cl2 (10 mL) into a separatory
funnel, and the organic layer was washed with 10% citric acid
(10 mL), H2O (10 mL), and brine (10 mL) and dried over
MgSO4. Flash column chromatography using silica gel gave
the acetylated butyrolactones.
C19H36O3: C, 73.03; H, 11.61. Found: C, 73.09; H, 11.22.
(-)-(3R,4R,5S)-3-Hexadecyl-4-h ydr oxy-5-m eth yldih ydr o-
2(3H)-fu r a n on e (18e): 15e (0.1380 g, 0.19 mmol) gave 18e
(0.0582 g, 0.17 mmol, 89%); mp 91-93 °C; Rf 0.62 (50:50
hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.89 (t, J ) 6.9
Hz, 3H), 1.19-1.30 (b, 26H), 1.40-1.67 (m, 6H), 1.83-1.93 (m,
1H), 2.12 (d, J ) 5.1 Hz, 1H), 2.56 (ddd, J ) 8.6, 7.4, 5.8 Hz,
1H), 3.85 (ddd, J ) 8.6, 7.3, 5.1 Hz, 1H), 4.21 (dq, J ) 7.3, 6.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 175.8, 79.8, 79.1, 48.6,
31.9, 29.7, 29.6, 29.3, 28.5, 26.8, 22.7, 18.3, 18.2, 14.1; IR
(CDCl3) 3414, 2920, 2849, 1734, 1471, 1327, 1286, 1057, 972,
864 cm-1; [R]25D ) -10.7° (c 0.85, CH2Cl2) {lit.3b [R]24D ) -9.6°
(dioxane)}.
(+)-(3R,4R,5R)-3-Bu t yl-4-h yd r oxy-5-m et h yld ih yd r o-
2(3H)-fu r a n on e [(+)-5-epi-bla stm ycin ola ctol] (21a ): 16a
(0.1235 g, 0.2291 mmol) gave 21a (0.0347 g, 0.2017 mmol,
88%); Rf 0.48 (50:50 hexane:EtOAc); 1H NMR (400 MHz,
CDCl3) δ 0.92 (t, J ) 7.3 Hz, 3H), 1.20-1.63 (m, 8H), 1.65-
1.78 (m, 1H), 2.55 (ddd, J ) 8.2, 6.6, 3.2 Hz, 1H), 2.63 (d, J )
4.3 Hz, 1H), 4.21 (ddd, J ) 4.8, 4.3, 3.2 Hz, 1H), 4.65 (dq, J )
6.7, 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.3, 78.6,
73.9, 49.2, 29.3, 28.1, 22.4, 13.9, 13.8; IR (neat) 3443 (b), 2959,
2936, 2874, 1757, 1458, 1383, 1341, 1230, 1186, 1138, 1055,
(+)-(3R,4R,5S)-3-Bu tyl-5-m eth yl-4-((3-m eth ylbu tyr yl)-
oxy)-5-m eth yld ih yd r o-2(3H)-fu r a n on e [(+)-bla stm ycin -
on e] (1): method A; 18a (0.0740 g, 0.43 mmol) furnished 1
as a colorless oil (0.0948 g, 0.37 mmol, 86%); Rf 0.31 (90:10
hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.92 (t, J ) 7.3
Hz, 3H), 0.97 (d, J ) 6.7 Hz, 6H), 1.25-1.57 (m, 7H), 1.59-
1.70 (m, 1H), 1.82-1.92 (m, 1H), 2.11 (m, 1H), 2.23 (d, J ) 7.0
Hz, 2H), 2.69 (ddd, J ) 8.6, 5.9, 5.4 Hz, 1H), 4.37 (dq, J ) 6.5,
4.3 Hz, 1H), 4.95 (dd, J ) 5.4, 4.3 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 175.9, 172.4, 79.4, 78.3, 46.4, 43.1, 29.0, 28.9, 25.7,
22.3, 22.2, 19.4, 13.7; IR (neat) 2959, 2936, 2874, 1784, 1745,
995, 949, 825, 732, 663 cm-1; [R]25 ) +59.8° (c 1.00, CH2Cl2).
D
Anal. Calcd for C9H16O3: C, 62.77; H, 9.36. Found: C, 63.05;
H, 9.10.
(+)-(3R,4R,5R)-3-H exyl-4-h yd r oxy-5-m et h yld ih yd r o-
2(3H)-fu r a n on e [(+)-5-epi-NF X-2] (21b): 16b (0.2689 g,
0.4744 mmol) gave 21b (0.0797 g, 0.3985 mmol, 84%); Rf 0.48
(80:20 hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.85 (t, J
) 6.9 Hz, 3H), 1.20-1.34 (m, 6H), 1.37 (d, J ) 6.6 Hz, 3H),
1.40-1.59 (m, 3H), 1.61-1.74 (m, 1H), 2.52 (ddd, J ) 8.0, 6.5,
3.3 Hz, 1H), 2.82 (b, 1H), 4.16 (dd, J ) 4.8, 3.3 Hz, 1H), 4.61
(dq, J ) 6.6, 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.6,
78.9, 73.9, 49.4, 31.6, 29.1, 28.5, 27.6, 22.6, 14.1, 13.9; IR (neat)
1465, 1369, 1294, 1253, 1176, 1118, 1039, 958 cm-1; [R]25
)
D
+11.3° (c 1.18, CHCl3) {lit.7j [R]20 ) +11.0° (c 2.43, CDCl3)}.
D
3448 (b), 2953, 2933, 1765, 1465, 1340 cm-1; [R]25 ) +47.4°
D
(+)-(3R ,4R ,5S )-3-H e xyl-4-((3-m e t h ylb u t yr yl)oxy)-5-
m eth yld ih yd r o-2(3H)-fu r a n on e [(+)-a n tim ycin on e] (3):
method A; 2 (0.0525 g, 0.26 mmol) yielded 3 (0.0630 g, 0.22
mmol, 84%) as a colorless oil; Rf 0.58 (80:20 hexane:EtOAc);
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J ) 6.8 Hz, 3H), 0.97 (d,
J ) 6.5 Hz, 6H), 1.20-1.36 (b, 6H), 1.37-1.50 (m, 5H), 1.58-
1.68 (m, J ) 8.3 Hz, 1H), 1.80-1.91 (m, J ) 5.6 Hz, 1H), 2.11
(m, 1H), 2.23 (d, J ) 6.7 Hz, 2H), 2.69 (ddd, J ) 8.3, 5.6, 5.6
Hz, 1H), 4.37 (dq, J ) 6.8, 4.6 Hz, 1H), 4.94 (dd, J ) 5.6, 4.6
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 176.0, 172.4, 79.4, 78.3,
46.4, 43.1, 31.5, 29.3, 28.9, 26.7, 25.7, 22.5, 22.3, 19.4, 14.0;
IR (neat) 2958.9, 2933.9, 2872.2, 1788.1, 1745.6, 1465.9,
(c 0.93, CH2Cl2). Anal. Calcd for C11H20O3: C, 65.97; H, 10.07.
Found: C, 66.14; H, 9.88.
(+)-(3R,4R,5R)-3-(5-Met h ylh exyl)-4-h yd r oxy-5-m et h -
yld ih yd r o-2(3H)-fu r a n on e [(+)-5-epi-NF X-4] (21c): 16c
(0.2898 g, 0.509 mmol) gave 21c (0.0959 g, 0.4378 mmol, 86%);
1
Rf 0.45 (80:20 hexane:EtOAc); H NMR (400 MHz, CDCl3) δ
0.85 (d, J ) 6.6 Hz, 6H), 1.12-1.20 (m, 2H), 1.22-1.36 (m,
2H), 1.39 (d, J ) 6.6 Hz, 3H), 1.42-1.61 (m, 4H), 1.62-1.77
(m, 1H), 2.07-2.77 (b, 1H), 2.53 (ddd, J ) 8.1, 6.5, 3.3 Hz,
1H), 4.19 (dd, J ) 5.5, 3.3 Hz, 1H), 4.62 (dq, J ) 6.6, 5.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 177.9, 77.4, 77.1, 49.3, 38.7,
28.5, 28.0, 27.6, 27.2, 22.7, 22.6, 14.0; IR (neat) 3449 (b), 2953,
1369.5, 1292.4, 1251.9, 1174.7, 1118.8, 1039.7, 968.3 cm-1
;
2933, 2865, 1764, 1465, 1385, 1341 cm-1; [R]25 ) +45.5° (c
[R]25 ) +10.8° (c 0.50, CHCl3) {lit.7z [R]21 ) +8° (c 0.50,
D
D
D
1.00, CH2Cl2). Anal. Calcd for C12H22O3: C, 67.26; H, 10.35.
Found: C, 67.45; H, 10.21.
CHCl3)}. Anal. Calcd for C16H28O4: C, 67.57; H, 9.92.
Found: C, 67.61; H, 9.78.
(+)-(3R,4R,5R)-3-Tetr a d ecyl-4-h yd r oxy-5-m eth yld ih y-
d r o-2(3H)-fu r a n on e (21d ): 16d (0.1793 g, 0.26 mmol) gave
21d (0.0640 g, 0.21 mmol, 81%); mp 66-68 °C; Rf 0.26 (80:20
hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J ) 6.7
Hz, 3H), 1.19-1.62 (m, 28H), 1.66-1.78 (m, 1H), 2.18-2.42
(b, 1H), 2.55 (ddd, J ) 8.1, 6.2, 3.2 Hz, 1H), 4.20 (dd, J ) 4.8,
3.2 Hz, 1H), 4.64 (dq, J ) 6.4, 4.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 178.0, 78.4, 73.9, 49.3, 31.9, 29.7, 29.6, 29.5, 29.3,
28.4, 27.3, 22.7, 14.1, 13.9; IR (CDCl3) 3528 (b), 2920, 2852,
(+)-(3R,4R,5S)-3-Tetr a d ecyl-4-O-a cetyl-5-m eth yld ih y-
d r o-2(3H)-fu r a n on e (19): method B; 18d (0.0697 g, 0.22
mmol) furnished 19 (0.0752 g, 0.21 mmol, 95%); mp 48-50
°C; Rf 0.48 (80:20 hexane:EtOAc); 1H NMR (400 MHz, CDCl3)
δ 0.88 (t, J ) 6.9 Hz, 3H), 1.20-1.36 (m, 22H), 1.36-1.52 (m,
5H), 1.57-1.70 (m, 1H), 1.80-1.90 (m, 1H), 2.11 (s, 3H), 2.69
(ddd, J ) 8.1, 5.9, 5.4 Hz, 1H), 4.39 (dq, J ) 6.5, 4.3 Hz, 1H),
4.92 (dd, J ) 5.4, 4.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
175.9, 170.3, 79.4, 78.6, 46.4, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3,
29.2, 26.8, 22.7, 20.9, 19.4, 14.1; IR (CDCl3) 2855, 2926, 1777,
1759, 1736, 1454, 1267, 1236, 1051 cm-1; [R]25 ) +31.4° (c
D

Trisubstituted Butyrolactone Natural Products
J . Org. Chem., Vol. 61, No. 22, 1996 7855
1742, 1466, 1367, 1238, 1180, 1059, 966, 912, 737 cm-1; [R]25
1H), 2.12 (s, 3H), 2.61 (ddd, J ) 8.3, 6.5, 2.7 Hz, 1H), 4.76 (dq,
J ) 6.4, 4.8 Hz, 1H), 5.17 (dd, J ) 4.8, 2.7 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 176.6, 170.1, 76.7, 75.5, 47.1, 31.9, 29.6,
29.5, 29.4, 29.3, 29.2, 28.5, 26.9, 22.7, 20.7, 14.2, 14.1; IR
(CDCl3) 2926, 2854, 1778, 1743, 1460, 1375, 1231, 1192, 1057,
D
) +6.8° (c 1.90, CH2Cl2). Anal. Calcd for C21H38O4: C, 71.15;
H, 10.80. Found: C, 71.33; H, 10.53.
(+)-(3R,4R,5S)-3-Hexadecyl-4-O-acetyl-5-m eth yldih ydr o-
2(3H)-fu r a n on e (20): method B; 18e (0.0270 g, 0.079 mmol)
gave 20 (0.0289 g, 0.75 mmol, 95%); mp 54-56 °C; Rf 0.47 (80:
1020 cm-1; [R]25 ) +37.4° (c 1.92, CH2Cl2) {lit.3c [R]20
)
D
D
1
20 hexane:EtOAc); H NMR (400 MHz, CDCl3) δ 0.86 (t, J )
+36.1° (c 1.9, CH2Cl2)}.
6.8 Hz, 3H), 1.21-1.30 (b, 28H), 1.45 (d, J ) 6.6 Hz, 3H), 1.57-
1.66 (m, 1H), 1.79-1.88 (m, 1H), 2.10 (s, 3H), 2.68 (ddd, J )
8.3, 5.6, 5.4 Hz, 1H), 4.37 (dq, J ) 6.6, 4.5 Hz, 1H), 4.91 (dd,
J ) 5.4, 4.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 176.0,
170.3, 79.5, 78.9, 46.5, 32.0, 29.8, 29.7, 29.6, 29.4, 26.9, 22.8,
20.9, 19.5, 14.2; IR (CDCl3) 2928, 2854, 1777, 1742, 1468, 1367,
(+)-(3R,4R,5R)-3-Hexa d ecyl-4-O-a cetyl-5-m eth yld ih y-
d r o-2(3H)-fu r a n on e (6): method B; treatment of 21e (0.0521
g, 0.15 mmol) yielded 6 (0.0546 g, 0.14 mmol, 93%); mp 42-
44 °C; Rf 0.51 (80:20 hexane:EtOAc); 1H NMR (400 MHz,
CDCl3) δ 0.88 (t, J ) 6.9 Hz, 3H), 1.20-1.32 (b, 26H), 1.34 (d,
J ) 6.5 Hz, 3H), 1.41-1.52 (m, 2H), 1.57-1.68 (m, 1H), 1.70-
1.81 (m, 1H), 2.12 (s, 3H), 2.61 (ddd, J ) 8.3, 6.5, 2.7 Hz, 1H),
4.76 (dq, J ) 6.5, 4.8 Hz, 1H), 5.17 (dd, J ) 4.8, 2.7 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 176.6, 170.1, 76.7, 75.5, 47.1,
31.9, 29.7, 29.6, 29.5, 29.3, 29.2, 28.5, 27.0, 22.7, 20.7, 14.2,
14.1; IR (CDCl3) 2926, 2854, 1778, 1744, 1460, 1375, 1192,
1317, 1240, 1182, 1083, 910, 734 cm-1; [R]25 ) +6.0° (c 1.00,
D
CH2Cl2).
(+)-(3R,4R,5R)-3-Bu tyl-5-m eth yl-4-((3-m eth ylbu tyr yl)-
oxy)-5-m et h yld ih yd r o-2(3H )-fu r a n on e [(+)-5-ep i-b la st -
m ycin on e] (22): method A; 21a (34 mg, 0.198 mmol) fur-
nished colorless oil 22 (42 mg, 0.163 mmol, 82%); Rf 0.47 (80:
1235, 1057, 1020, 835 cm-1; [R]25 ) +31.5° (c 1.30, CH2Cl2)
1
D
20 hexane:EtOAc); H NMR (400 MHz, CDCl3) δ 0.92 (t, J )
{lit.3c [R]20 ) +31.9° (c 1.30, CH2Cl2)}.
D
7.3 Hz, 3H), 0.97 (d, J ) 6.7 Hz, 6H), 1.34 (d, J ) 6.5 Hz, 3H)
1.25-1.41 (m, 2H), 1.42-1.54 (m, 2H), 1.55-1.69 (m, 1H),
1.62-1.84 (m, 1H), 2.11 (m, 1H), 2.23 (s, 1H), 2.25 (d, 1H),
2.59 (ddd, J ) 8.6, 5.9, 2.7 Hz, 1H), 4.77 (dq, J ) 6.5, 4.8 Hz,
1H), 5.18 (dd, J ) 4.8, 2.7 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 176.7, 172.2, 76.7, 75.2, 47.2, 43.0, 29.1, 28.2, 25.6, 22.3, 14.3,
Ack n ow led gm en t. We thank NSF (OSR-9108770),
North Dakota State University, National Institutes of
Health, and FMC Lithium for financial support of our
research programs. C.L.T. thanks the Ronald E. Mc-
Nair program for a fellowship. Partial support for this
work was also provided by the NSF Instrumentation
and Laboratory Improvement Program through Grant
USE-9152532 and by NRICGP (95-37501-2300) for an
upgrade of the NMR data acquisition system.
13.7; [R]25 ) +48.9° (c 1.00, CH2Cl2). Anal. Calcd for
D
C14H24O4: C, 65.60; H, 9.44. Found: C, 65.78; H, 9.11.
(+)-(3R,4R,5R)-3-Tetr a d ecyl-4-O-a cetyl-5-m eth yld ih y-
d r o-2(3H)-fu r a n on e (5): Method B; 21d (0.0454 g, 0.1455
mmol) yielded 5 (0.0475 g, 0.1339 mmol, 92%); mp 31-33 °C;
1
Rf 0.51 (80:20 hexane:EtOAc); H NMR (400 MHz, CDCl3) δ
0.88 (t, J ) 6.9 Hz, 3H), 1.20-1.30 (b, 22H), 1.34 (d, J ) 6.4
Hz, 3H), 1.40-1.52 (m, 2H), 1.57-1.67 (m, 1H), 1.70-1.81 (m,
J O961171I