Asymmetric syn-selective aldol reactions of χ-oxygenated vinylogous urethane with a second generation chiral auxiliary: Application in construction of (+)-3-deoxy-d-manno-2-octulosonic acid

Article abstract of DOI:10.1021/jo981916f

Various examples of highly diastereoselective aldol reactions are presented where the nonracemic lithium enolate 6 derived from a C4-oxygenated vinylogous urethane reacts in syn fashion to provide upon intramolecular lactonization useful γ-alkoxy-δ-lactone synthons 12a-f. In one particular example, the result of reaction with an acrolein surrogate, the lactone product 12e is applied in an efficient asymmetric synthesis of (+)-KDO (10 steps, 34% overall yield). Notable transformations include (1) hydrolysis of the vinylogous urethane functionality, (2) stereoselective reduction of the resulting β-keto-lactone 2, (3) stereoselective dihydroxylation of the vinyl side chain of δ-lactone 17, and (4) addition of α-ethoxy-vinyllithium to the lactone carbonyl of 19 to procure the aldulosonic acid residue in 1 upon ozonolysis.

Full text of DOI:10.1021/jo981916f

J . Org. Chem. 1998, 63, 9089-9094
9089
Asym m etr ic Syn -Selective Ald ol Rea ction s of γ-Oxygen a ted
Vin ylogou s Ur eth a n e w ith a Secon d Gen er a tion Ch ir a l Au xilia r y:
Ap p lica tion in Con str u ction of (+)-3-Deoxy-D-m a n n o-2-octu loson ic
Acid
Richard H. Schlessinger† and Liping H. Pettus*,‡
Department of Chemistry, University of Rochester Rochester, New York 14627
Received September 21, 1998
Various examples of highly diastereoselective aldol reactions are presented where the nonracemic
lithium enolate 6 derived from a C4-oxygenated vinylogous urethane reacts in syn fashion to provide
upon intramolecular lactonization useful γ-alkoxy-δ-lactone synthons 12a -f. In one particular
example, the result of reaction with an acrolein surrogate, the lactone product 12e is applied in an
efficient asymmetric synthesis of (+)-KDO (10 steps, 34% overall yield). Notable transformations
include (1) hydrolysis of the vinylogous urethane functionality, (2) stereoselective reduction of the
resulting â-keto-lactone 2, (3) stereoselective dihydroxylation of the vinyl side chain of δ-lactone
17, and (4) addition of R-ethoxy-vinyllithium to the lactone carbonyl of 19 to procure the aldulosonic
acid residue in 1 upon ozonolysis.
In tr od u ction
The merit of four-carbon enolates has been demon-
strated in many prior synthetic applications.1 Enolates
derived from acyclic vinylogous urethanes, in particular,
offer malleable functionality upon aldol and acylation
reactions.2 In a previous communication,3 we disclosed
a highly syn-selective second generation vinylogous ure-
thane (VU), 5, carrying a C4 methyl substituent, which
F igu r e 1.
uses a simple and readily prepared nonracemic auxiliary.
From X-ray work,4 on a species closely related to 7, we
Sch em e 1
had speculated that the lithium enolate possessed the
structure indicated in Figure 1. The unique structure
of these enolate aggregates, in particular their very real
lithium-nitrogen bond, suggested to us that changing
the C4 methyl substituent to an oxygen residue would
not perturb the overall structure of these systems. Thus,
we anticipated that the vinylogous urethane 3 (R′ )
O(CH2)2TMS) would form the enolate structure 6 and
thereby provide syn-products as its alkyl analogue (R′ )
CH3) had in similar aldol reactions.
The contiguous array of hydroxyl residues in (+)-3-
deoxy-D-manno-2-octulosonic acid, (+)-KDO (1), pre-
sented a challenging target to test our proposed modifi-
cation.5,6 Scheme 1 illustrates that the â-keto-lactone 2,
4 by hydrolytic removal of the amine residue, and 4 in
turn would result from a syn-selective aldol reaction of 3
with acrolein. Herein, we describe the aldol reactions of
a potential precursor of 1, might be derived from lactone
† Dedicated to the memory of Professor R. H. Schlessinger, deceased
On December 11, 1997.
‡ Current mailing address: Department of Chemistry, University
of California, Santa Barbara, Santa Barbara, CA 93106.
(1) (a) Evans, D. A.; Ng, H. P.; Clark, S. C.; Rieger, D. L. Tetrahedron
1992, 48, 2127-2142. (b) Evans, D. A.; Kim, A. S. Tetrahedron Lett.
1997, 38, 53-56. (c) Carreira, E. M.; Kruger, J .. J . Am. Soc. Chem.
1998, 120, 837-838.
(2) For selected examples, see: (a) Dankwardt, S. M.; Dankwardt,
J . W.; Schlessinger, R. H. Tetrahedron Lett. 1998, 98, 4983-4986. (b)
Schlessinger, R. H.; Li, Y.-J . J . Am. Soc. Chem. 1996, 118, 3301-3302.
(c) Schlessinger, R. H.; Gillman, K. W. Tetrahedron Lett. 1996, 37,
1331-1334. (d) Schlessinger, R. H.; Tata, J . R.; Springer, J . P.
Tetrahedron Lett. 1987, 28, 5423-5426 and references therein.
(3) Schlessinger, R. H.; Li, Y.-J .; Von Langen, D. J . J . Org. Chem.
1996, 61, 3226.
(5) (+)-KDO occurs in the lipopolysaccharide (LPS) region of the cell
membrane of all Gram-negative bacteria. It provides a unique link
between the hydrophobic lipid A and the hydrophilic polysaccharide
subunits. Interruption of the biosynthesis of 1 leads to a buildup of
LPS precursors and prevents the growth of these types of bacteria.
Anderson, L.; Unger, F. M.; Eds. Bacterial Lipopolysaccharides:
Structure, Synthesis, and Biological Activities; ACS Symposium Series
231; American Chemical Society: Washington, DC, 1983.
(6) For syntheses of KDO, see: (a) Unger, F. M. Adv. Carbohydr.
Chem. Biochem. 1981, 38, 323. (b) Danishefsky, S. J .; Deninno, M. P.;
Chen, S. J . Am Chem. Soc. 1988, 110, 3929. (c) Martin, S. F.; Zinke,
P. W. J . Org. Chem. 1991, 56, 6600. (d) Gao, J .; Harter, R.; Gordon, D.
M.; Whiteside, G. M. J . Org. Chem. 1994, 59, 3714. (e) Kragl, U.; Godde,
A.; Wandrey, C.; Lubin, N.; Auge, C. J . Chem. Soc. Perkins Trans. 1
1994, 1, 119. (f) Pakulski, Z.; Zamojski, A. Tetrahedron 1997, 53, 3723
and references cited therein.
(4) Schlessinger, R. H.; Williard, P. G.; Tata, J . R.; Adams, A. D.;
Iwanowicz, E. J . J . Am. Chem. Soc. 1988, 110, 7901.
10.1021/jo981916f CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/06/1998

9090 J . Org. Chem., Vol. 63, No. 24, 1998
Schlessinger and Pettus
Ta ble 1
Sch em e 2
VU
Lactone 12
R,â-unsaturated
lactone 14
aldehyde RCHO
entry
no.
yield,
%
de,
%
ee,
%
no.
R
no.
no.
1
2
3
4
5
6
11a t-Bu
11b i-Pr
11c Ph
11d (E)-CHdCHCH2CH3 12d
11e (E)-CHdCHSnBu3
11f (Z)-CHdCHSnBu3
12a
12b
12c
93
73
84
78
76
75
14a 97.2 96.5
14b 99.3 96.6
14c 97.9 98.4
14d 98.7 96.5
14e 98.5 96.8
14f 98.9 97.7
12e
12f
Upon establishing that the C4-oxygenated vinylogous
urethane 3 indeed afforded lactone products with excel-
lent de values, we set out to demonstrate the absolute
stereochemistry for these systems by the synthesis of (+)-
KDO. Unfortunately, condensation of the lithium enolate
6 with acrolein resulted in the formation of intractable
tars. Thus, we turned to the use of (E)-3-(tri-n-butyl-
stannyl)-2-propenal, 11e, as an acrolein equivalent.11
Starting with the vinylogous urethane lactone 12e, we
converted this material into the â-keto lactone 2 (in 78%
yield) by HCl hydrolysis of the vinylogous urethane
functionality together with concomitant protodestanny-
lation of the vinyl stannane residue (Scheme 4).
Sch em e 3
Hydride reduction under Luche’s conditions gave the
hydroxy lactol 15 as a single stereoisomer.12 This com-
pound in turn was treated with Ag2CO3 on Celite to
obtain the hydroxy lactone 16 (80%, two steps).13 Many
other reduction conditions were attempted, but none were
found to be both regio- and stereospecific; hence, the
transformation was accomplished in the above two-step
procedure.
We next chose to remove the â-trimethylsilyl ether
protecting group of 16 using BF3‚Et2O and to then protect
the resulting diol product as its corresponding acetonide
17 for easier isolation (78%, two steps). The stage was
now set to install the diol side chain required by 1. Gra-
tifyingly, catalytic osmylation of 17, seemingly distrib-
uted between the two reactive conformers 17a and 17b,
gave 18 as the sole product.14 The diol portion of 18 was
protected as its acetonide to afford 19 (90%, two steps).
Finally, the problem of adding a carboxylic acid to the
lactone carbonyl group of 19 was addressed. After
considerable difficulty with other nucleophilic surrogates,
the R-ethoxy vinyllithium (EVL) was found to smoothly
vinylogous urethane 3 with a variety of aldehydes and
demonstrate potential applications of this methodology
by an asymmetric synthesis of (+)-KDO (1).
Resu lts a n d Discu ssion
Our synthesis of vinylogous urethane 3, Scheme 2,
started with 2-(trimethylsilyl)ethanol which was depro-
tonated with sodium hydride. The resulting sodium
alkoxide coupled with propargyl bromide to afford the
ether 8 (91%).7 Deprotonation of alkyne 8 with n-BuLi
and subsequent treatment with methyl chloroformate
produced the acetylene ester 9 (85%). Last, 9 was reacted
with the nonracemic amine, 10, to afford vinylogous
urethane 3 in 91% yield.8
The enolate 6, obtained by deprotonation of 3 with
LDA/THF (-78 f 0 f -78 °C), was condensed with
aldehydes 11a -f to afford the corresponding vinylogous
urethane lactones 12a -f (Scheme 3). These materials
were then converted into their corresponding R,â-
unsaturated lactone analogues 14a -f in a two-step
sequence for purposes of determining the overall stereo-
selection. Utilizing a Borch reduction, lactones 12a -f
were treated with NaCNBH3 in acidic media to afford
their corresponding â-amino lactone analogues 13a -f.9
These compounds were in turn converted into their
unsaturated lactone counterparts 14a -f by treatment
with m-CPBA and then pyridine. HPLC analyses of
14a -f using normal phase 3 µm Spheriosorb silica gel
and 5 µm Chiralcel OD stationary phases provided both
the diastereomeric and enantiomeric ratios for each
lactone when compared to a racemic standard of syn and
anti products.10 The results are given in Table 1.
(10) The de and ee values of 14a -f and hence of the VU lactones
12a -f were determined by comparison with a racemic mixture of the
syn and anti forms of the lactone 25, which was prepared from
vinylogous urethane 23 as shown below. Under typical conditions,
lactone 24 was produced in 3: 1 syn:anti selectivity. It’s interesting to
note that while the vinylogous urethane derived from pyrrolidine or
dimethylamine is anti-selective, vinylogous urethane derived from tert-
butylamine or diisopropylamine is syn-selective.
(11) (a) J ung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851.
(b) Evans, D. A.; Gage, J . R. J . Org. Chem. 1992, 57, 1957.
(12) (a) Felkin-Ahn reduction predicts hydride addition to occur
opposite the R-axial C-O bond of 2. (Macromodel 3.5a) minimization
of the R-keto lactone 2 predicted the boat form of the lactone with the
adjacent protected hydroxy group at C4 occupying an axial position
on the ring. (b) Gamal, A. L.; Luche, J . L. J . Am. Chem. Soc. 1981,
103, 5454.
(7) When either silicon (OTBS) or allyl (OCH2CHdCH2) or benzyl
(OCH2C5H5) were used as the C4-oxygen protecting group in vinylogous
urethane 3, these systems suffered either from oxygen-oxygen silyl
migration or 2,3-Wittig rearrangements, respectively. Dankwardt, S.
M. Ph.D. Thesis, University of Rochester, 1992.
(8) Enders, D.; Kipphardt, H.; Gerdes, P.; Brenak-Valle, L. J .;
Bhushan, V. Bull. Soc. Chim. Belg. 1988, 97, 691.
(9) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem. Soc.
1971, 93, 2897-2904.
(13) Fetizon, M.; Golfier, M.; Mourgues, P. Tetrahedron Lett. 1972,
4445-4448.

Asymmetric Syn-Selective Aldol Reactions
J . Org. Chem., Vol. 63, No. 24, 1998 9091
Sch em e 4
of (+)-KDO. Noteworthy steps include (a) stereospecific
reduction of â-keto-lactone, (b) stereospecific osmylation
of an olefinic side chain, and (c) the use of ethoxyvinyl-
lithium as a surrogate for a trialkyl orthoformate anion
in the nucleophilic addition to lactone. The high syn-
selectivity (97%-99% de) obtained from the reaction of
lithium enolate derived from vinylogous urethane 3 with
a wide range of aldehydes further substantiates the very
real lithium-nitrogen bond in these types of enolate
systems and suggests that the aggregate 6 is the reacting
species that provides the good enantioselectivities (96%-
98% ee) achieved from this second-generation chiral
auxiliary. It is hoped that these easily accessible mal-
leable systems will find applications in future asymmetric
endeavors.
Exp er im en ta l Da ta
Gen er a l In for m a tion . The following solvents were dis-
tilled directly before use, under a slight positive pressure of
nitrogen. Diethyl ether, tetrahydrofuran, and benzene were
distilled from sodium benzophenone ketyl. tert-Butyl alcohol
was distilled from calcium hydride. The chloroform, methylene
chloride, isopropyl alcohol, and hexanes used for infrared
spectra, HPLC analyses, and optical rotations were labeled
spectroscopic grade by the manufacturer. Melting points were
determined on a Fisher-J ohns melting point apparatus and
are uncorrected. 1H NMR and 13C NMR were recorded at 300
and 75.5 MHz, respectively, and chloroform was used as
internal standard. Infrared spectra were recorded on a Perkin-
Elmer 1600 series Fourier transform infrared spectrometer.
Chiral stationary-phase HPLC analyses were performed with
a Varian 3010 pump and LDC spectromonitor using Chiralcel
OJ columns supplied by J . T. Baker. The spectra was recorded
with a LDC Ultra-Violet/Visible recording spectrometer. Mass
spectra were analyzed by the Midwest Center for Mass
Spectrometry and UCS Mass Spectrometry Facility. Mi-
croanalyses were done by Microlytics, Dr. Greg Dabkowski,
P.O. Box 199, South Deerfield, MA 01373.
â-(Tr im eth ylsilyl)eth yl P r op a r gyl Eth er (8). Sodium
hydride (32.1 mmol, 0.81 g, dry, 95% weight) was suspended
in THF (20 mL) and cooled to 0 °C. 2-(Trimethylsilyl)ethanol
(20.1 mmol, 2.88 mL) was added to above solution dropwise.
Deprotonation continued at 0 °C for 10 min and room tem-
perature for 1 h. Then propargyl bromide (21.0 mmol, 1.87
mL) was added slowly followed by addition of catalytic amount
of tetrabutylammonium iodide. The reaction was continued
at room temperature for 1 h and then refluxed for 4 h. After
this 5 h period, the reaction was quenched with sat. NH4Cl
and extracted with ether. The combined organic layers were
dried with MgSO4 and filtered, the solvent was removed, and
the product 8 distilled (65 °C, 26 mmHg) to yield a colorless
oil (2.85 g, 91% yield). IR (CHCl3) 3306, 2955, 1352, 1250,
1181, 1079. 1H NMR (CDCl3) δ 4.14 (d, 2 H, J ) 2.41 Hz),
3.61 (t, 2 H, J ) 8.32 Hz), 2.42 (t, 1 H, J ) 2.41 Hz), 0.97 (t,
2 H, J ) 8.32 Hz), 0.04 (s, 9 H). 13C NMR (CDCl3) δ 73.8 C,
67.3 CH2, 67.1 CH, 57.3 CH2, 17.9 CH2, -1.4 CH3. Rf ) 0.85
(hexane:EtOAc/2:1). HRMS calcd for C8H16OSi: 156.0970,
molecular ion not observed, found: (M - C3H9Si)+ 83.0496,
(M - C5H7O)+ 73.0471. Anal. Calcd for C 61.48, H 10.32.
Found: C 61.51, H 10.34.
add (1.1 equiv, 0.45 M in THF, -78 °C, 30 min) to lactone
19.15 Reductive ozonolysis provided the ethyl ester 20
(86% overall). Removal of the isopropylidene groups from
20 proceeded in a straightforward manner by treatment
with 90% aqueous acetic acid at 90 °C for 45 min.
Hydrolysis of the ethyl ester (0.1 N NaOH, 2 h), followed
by adjustment of acidity to pH ) 3 (Dowex-50W-X4),
furnished (+)-KDO, 1, isolated as the crystalline am-
monium salt 21 (89% overall yield, mp 123-126 °C, [R]21
D
) +39.5° (c 1.2, H2O)).16 For the purpose of further
characterization and comparison, the ammonium salt 21
was converted to its peracetylated methyl ester 22 ([R]21
D
) +99.7° (c 1.2, MeOH); lit.17 [R]21 ) +101° (c 1.0,
D
MeOH)) according to literature procedure and again
shown to be identical in every spectroscopic respect to
that reported as derived from naturally occurring 1.17
Con clu sion
The pliant functionality of vinylogous urethane-derived
enolates has been demonstrated by a concise synthesis
(14) A Monte Carlo conformational search over a 50 kJ range with
50 steps produced the two minimum energy conformers of 17 to be
that represented by the boat structures 17a and 17b, and predicted
17a to be 2.5 kJ /mol more stable than 17b. 17b in turn was more stable
than the next conformer, which if reactive, would have provided the
unobserved osmylation product. It appeared that dihydroxylation of
either 17a from the convex face, or 17b anti-periplanar to the allylic
C-O bond, would result in the desired side chain alcohol stereochem-
istry represented by 18. The stereoselectivity was assumed to be
greater than 95% as 1H NMR showed only one diastereomer. For
explanation of stereoselectivity, see: (a) Cha, J . K.; Christ, W. J .; Kishi,
Y. Tetrahedron Lett. 1983, 24, 3943. (b) Karabatsos, G. J .; Fenglio, D.
J . Topics in Stereochemistry; Wiley-Interscience: New York, 1970; Vol.
5, p 167.
Meth yl 4-[â-(Tr im eth ylsilyl)eth oxy]-2-bu tyn oa te (9).
Ether 8 (14.5 mmol, 2.27 g) was dissolved in 10 mL of THF
and cooled to -78 °C. n-Butyllithium (15.9 mmol, 10.2 mL,
1.57 M solution in hexanes) was slowly added to the cold
solution. The reaction mixture was warmed to 0 °C and stirred
for 1 h. The mixture was chilled to -78 °C, and methyl
chloroformate (17.4 mmol, 1.40 mL) was added dropwise. The
reaction was stirred for 30 min at -78 °C, warmed to 0 °C,
(15) The R-ethoxy vinyllithium species was prepared in a manner
similar to that described for the R-methoxy vinyllithium species. See
Baldwin, J . E.; Hofle, G. A.; Lever, O. W. J . Am. Chem. Soc. 1974, 96,
7125. For the addition of similar vinyllithium species to ketones, see
Chavdarian, C. G.; Heathcock, C. H. J . Am. Chem. Soc. 1975, 97, 3822.
(16) Authentic Sample from Sigma Co. has mp 122-125 °C, [R ]21
D
) +40.9° (c 0.9, H2O); lit. (see reference 6c) mp 121.5-123 °C, [R]21
(17) Charon, D.; Szabo, L. J . Chem. Soc., Perkin Trans. 1 1979,
2369-2374.
D
) +42.4° (c 1.7, H2O).

9092 J . Org. Chem., Vol. 63, No. 24, 1998
Schlessinger and Pettus
and stirred 45 min. After being warmed to room temperature
and stirred 90 min longer, the reaction was quenched with
excess sat. NH4Cl. The mixture was extracted with ether,
and the combined organic layers were dried over anhydrous
MgSO4. After removal of solvent, the residue was distilled
under vacuum (115 °C, 1 mmHg) to yield compound 9 (2.64 g,
85% yield) as a colorless liquid. IR (CHCl3) 2955, 1715, 1436,
1260. 1H NMR (CDCl3) δ 4.26 (s, 2 H), 3.80 (s, 3 H), 3.62 (t,
2 H, J ) 8.31 Hz), 0.97 (t, 2 H, J ) 8.31 Hz), 0.04 (s, 9 H). 13C
NMR (CDCl3) δ 153.5 CO, 84.1 C, 68.0 CH2, 57.2 CH2, 54.5 C,
52.6 CH3, 17.9 CH2, -1.4 CH3. Rf ) 0.7 (hexane:EtOAc/2:1).
HRMS calcd for C10H18O3Si: 214.1025, molecular ion not
observed. Found: 213.0947 for (M - H)+, 19.0791 for (M -
CH3)+.
CH, 82.1 C, 80.1 CH, 74.1 CH, 67.8 CH2, 64.3 CH, 50.2 CH3,
48.7 CH2, 26.9 CH2, 26.4 CH2, 23.7 CH2, 18.8 CH2, 8.6 CH3,
7.8 CH3, -1.6 CH3. Rf ) 0.44 (hexane:EtOAc/2:1). HRMS
calcd 459.2805 for C26H41NO4Si, found: 459.2808 for M+,
430.2426 for (M - C2H5)+, 73.0475 for (C3H9Si)+.
12d (78% yield): [R]21 ) -90.1° (c 0.9, CHCl3); IR (CHCl3)
D
3023, 2969, 2883, 1665. 1H NMR (CDCl3) δ 6.00 (m, 1 H), 5.7
(m, 1 H), 5.17 (s, 1 H), 4.70 (d, 1 H, J ) 6.40 Hz), 4.03 (d, 1 H,
J ) 2.55 Hz), 3.90 (m, 2 H), 3.65 (m, 2 H), 3.36(m, 1 H), 3.21
(s, 3 H), 2.20-1.52 (m, 10 H), 1.05 (t, 3 H, J ) 7.47 Hz), 0.90
(m, 8 H), -0.00 (s, 9 H). 13C NMR (CDCl3) δ 168.0 CO, 156.5
C, 136.9 CH, 124.2 CH, 123.3 CH, 88.1 CH, 82.1 C, 79.9 CH,
72.2 CH, 63.5 CH2, 50.5 CH3, 48.5 CH2, 27.2 CH2, 26.8 CH2,
26.2 CH2, 24.1 CH2, 21.2 CH2, 19.5 CH2, 13.1 CH3, 8.5 CH3,
7.7 CH3, -1.4 CH3. Rf ) 0.46 (hexane:EtOAc/2:1). Anal.
Calcd for C24H43NO4Si: C 65.86, H 9.90, N 3.20. Found: C
65.86, H 9.92, N 2.99.
12e (75% yield): [R]21D ) -60.1° (c 1.00, CHCl3); IR (CHCl3)
3034, 2958, 1666, 1586, 1463. 1H NMR (CDCl3) δ 6.55 (dd, 1
H, J ) 1.15, 19.16 Hz), 6.16 (dd, 1 H, J ) 5.13, 19.16 Hz),
5.15 (s, 1 H), 4.72 (m, 1 H), 4.11 (d, 1H, J ) 2.39 Hz), 3.87 (m,
2 H), 3.59 (t, 2 H, J ) 8.02 Hz), 3.33 (m, 1 H), 3.19 (s, 3 H),
1.8-2.1 (br, 4 H), 1.75-1.2 (m, 17 H), 0.93-0.8 (m, 22 H),
-0.03 (s, 9 H). 13C NMR (CDCl3) δ 167.9 CO, 156.5 C, 141.3
CH, 132.9 CH, 83.1 CH, 82.1 CH, 81.8 C, 71.9 CH, 65.3 CH2,
64.2 CH, 50.0 CH3, 48.5 CH2, 29.0 CH2, 27.3 CH2, 26.8 CH2,
26.4 CH2, 26.3 CH2, 23.7 CH2, 19.0 CH2, 13.6 CH3, 9.4 CH2,
8.5 CH3, 7.7 CH3, -1.4 CH3. Rf ) 0.72 (hexane:EtOAc/3:1).
Anal. Calcd for C34H65NO4SiSn: C 58.45, H 9.37, N 2.01.
Found: C 58.50, H 9.35, N 1.96.
Vin ylogou s Ur eth a n e 3. A solution of ester 9 (5.60 mmol,
1.20 g) in tert-butyl alcohol (5 mL) was heated to reflux, and
amine 10 (6.44 mmol, 1.10 g) was added. After 2 h, the
reaction was cooled to ambient temperature, and the volatiles
were removed to yield a yellow oil. The oil was Kugelrohr
distilled (3 × 10-6 Torr, 180 °C) to give compound 3 as a very
viscous pale yellow oil (1.96 g, 91% yield). [R]21 ) +222.4° (c
D
1.1, CHCl3); IR (CHCl3) 3019, 2949, 2884, 1681, 1573. 1H NMR
(CHCl3) δ 5.40 (d, 1 H, J ) 11.87 Hz), 4.71 (br, 1 H), 4.50 (d,
1 H, J ) 11.87 Hz), 4.30 (br, 1 H), 3.60 (s, 3 H), 3.55 (m, 2 H),
3.35 (br, 2 H), 3.14 (s, 3 H), 1.78-1.97 (m, 4 H), 1.60-1.43 (m,
4 H), 0.94-0.80 (m, 8 H), 0.05 (s, 9 H). 13C (CHCl3) δ 168.9
CO, 160.5 C, 88.4 CH, 81.6 C, 67.3 CH2, 63.5 CH2, 62.7 CH,
50.7 CH2, 50.1 CH3, 49.8 CH3, 26.6 CH2, 26.3 CH2, 26.1 CH2,
23.6 CH2, 18.4 CH2, 8.2 CH3, 7.6 CH3, -1.4 CH3. Anal. Calcd
for C20H39NO4Si: C 62.30, H 10.19, N 3.63. Found: C 62.44,
H 9.98, N 3.49.
12f (76% yield): [R]21 ) -88.4° (c 0.9, CHCl3); IR (CHCl3)
Gen er a l P r oced u r e for P r ep a r a tion of Vin ylogou s
Ur eth a n e La cton e 12a -f. To a solution of vinylogous
urethane 3 (1.00 mmol, 0.39 g) in anhydrous THF (1 mL) at
-78 °C was added LDA (1.10 mmol, 1.1 mL of 1 M solution in
THF). The mixture was stirred at -78 °C for 30 min and then
warmed to 0 °C for 20 min and finally cooled to -78 °C for 20
min. After this period of 70 min, a solution of aldehyde (1.30
mmol) in anhydrous THF (0.5 mL) was added. Stirring was
continued at -78 °C for 1 h followed by 0 °C for 30 min. The
reaction was quenched with sat. NH4Cl, extracted with
EtOAc, dried over MgSO4, and concentrated. The crude yellow
oil was chromatographed (hexane:EtOAc/2:1 to 3:1) to yield
VU lactone 12a -f as pale yellow oils.
D
3020, 2956, 2928, 1669, 1585, 1463. 1H NMR (CDCl3) d 6.75
(dd, 1 H, J ) 7.25, 13.20 Hz), 6.30 (d, 1 H, J ) 13.18 Hz), 5.14
(m, 1 H), 4.52 (m, 1 H), 3.98 (d, 1 H, J ) 2.19 Hz), 3.91-3.81
(m, 2 H), 3.73-3.62 (m, 2 H), 3.33 (m, 1 H), 3.19 (s, 3 H), 2.13-
1.80 (br, 4 H), 1.75-1.20 (m, 17 H), 0.93-0.8 (m, 22 H), -0.01
(s, 9 H). 13C NMR (CDCl3) δ 166.8 CO, 156.4 C, 142.3 CH,
134.9 CH, 88.4 CH, 82.2 CH, 82.0 C, 72.9 CH, 65.8 CH2, 64.3
CH, 49.6 CH3, 48.4 CH2, 27.0 CH2, 26.8 CH2, 26.7 CH2, 26.6
CH2, 26.3 CH2, 23.6 CH2, 19.0 CH2, 13.3 CH3, 10.8 CH2, 8.3
CH3, 7.6 CH3, -1.5 CH3. Rf ) 0.75 (hexane:EtOAc/3:1). Anal.
Calcd for C34H65NO4SiSn: C 58.45, H 9.37, N 2.01; found: C
58.79, H 9.51, N 2.07.
12a (93% yield): [R]21D ) -73.41° (c 1.7, CHCl3); IR (CHCl3)
3020, 2961, 1660, 1584, 1467. 1H NMR (CDCl3) δ 5.21 (s, 1
H), 4.32 (d, 1 H, J ) 1.65 Hz), 4.07 (m, 1 H), 3.89 (m, 1 H),
3.76 (d, 1 H, J ) 1.95 Hz), 3.64 (m, 1 H), 3.30 (m, 2 H), 3.21 (s,
3 H), 2.1-1.5 (m, 8 H), 1.15 (s, 9 H), 0.90 (m, 8 H), -0.03 (s,
9 H). 13C NMR (CDCl3) δ 169.1 CO, 155.9 C, 88.4 CH, 86.2
CH, 82.1 C, 69.1 CH, 64.4 CH, 62.7 CH2, 50.0 CH3, 48.1 CH2,
34.1 C, 26.9 CH2, 26.4 CH3, 26.1 CH2, 23.7 CH2, 18.9 CH2, 8.5
CH3, 7.7 CH3, -1.5 CH3. Rf ) 0.55 (hexane:EtOAc/2:1). Anal.
Calcd for C24H45NO4Si: C 65.56, H 10.32, N 3.19. Found: C
65.76, H 10.48, N 3.22.
Gen er a l P r oced u r e for P r ep a r a tion of r,â-Un sa tu r -
a ted La cton e 14a -f. At room temperature, sodium cy-
anoborohydride (2.80 mmol, 0.19 g) was added to a solution
of vinylogous urethane lactone 12a -f (0.40 mmol) with a trace
amount of bromocresol in THF (1.0 mL). HCl (0.5 mL of 2 M
solution in THF) was added dropwise, and the deep blue
solution turned yellow. The reaction was continued for 3 h,
and the HCl/THF solution was added periodically to maintain
the yellow color through out this period. Aqueous NaOH (2
M) was added until the solution turned deep blue. The
mixture was extracted with EtOAc. The combined organic
layers were dried over Na2SO4 and concentrated under vaccum
to afford crude 13 as a yellow oil which was used in next step
without further purification.
12b (73% yield): [R]21D ) 119.9° (c 0.90, CHCl3); IR (CHCl3)
3030, 2968, 1661, 1585, 1415. 1H NMR (CDCl3) δ 5.24 (s, 1
H), 4.20 (d, 1 H, J ) 2.40 Hz), 4.08 (m, 1 H), 3.91 (dd, 1 H, J
) 2.42, 8.34 Hz), 3.65 (m, 1 H), 3.45 (m, 1 H), 3.30 (m, 1 H),
3.21 (s, 3 H), 2.2-1.5 (m, 9 H), 1.16 (d, 3 H, J ) 6.57 Hz), 1.04
(d, 3 H, J ) 6.66 Hz), 0.88 (m, 8 H), -0.01(s, 9 H). 13C NMR
(CDCl3) δ 168.5 CO, 155.8 C, 88.7 CH, 85.0 CH, 82.1 C, 68.5
CH, 64.4 CH, 63.3 CH2, 50.1 CH3, 48.3 CH2, 28.8 CH2, 26.8
CH2, 26.4 CH2, 26.3 CH2, 23.8 CH2, 19.5 CH3, 19.0 CH2, 18.7
CH3, 8.6 CH3, 7.7 CH3, -1.4 CH3. Rf ) 0.52 (hexane:EtOAc/
2:1). HREI: calcd 425.2961 for C23H43NO4Si, molecular ion
not observed, found: 410.2744 for (M - CH3)+, 396.2571 for
(M - C2H5)+, 382.2423 for (M-C3H7)+, 73.0473 for (C3H9Si)+.
12c (84% yield): [R]21D ) -132.4° (c 0.83, CHCl3); IR (CHCl3)
3027, 3017, 3005, 2973, 2884, 1669, 1586, 1454. 1H NMR
(CDCl3) δ 7.56-7.28 (m, 5 H), 5.37 (s, 1 H), 5.37 (s, 1 H), 4.14
(m, 2 H), 3.94 (m, 1 H), 3.72 (m, 1 H), 3.44 (m, 1 H), 3.31 (m,
1 H), 3.25 (s, 3 H), 2.15-1.6 (m, 8 H), 0.92 (m, 6 H), 0.64 (t, 2
H, J ) 8.30 Hz), -0.18 (s, 9 H). 13C NMR (CDCl3) δ 168.0
CO, 157.7 C, 136.4 C, 128.3 CH, 128.1 CH, 126.3 CH, 87.6
To a solution of crude 13 in THF (1 mL) at -78 °C was
added m-CPBA (1.2 equiv, 98 mg, 85 wt %). After the reaction
was stirred at -78 °C for 10 min and then 0 °C for 10 min,
pyridine (0.60 mmol, 0.05 mL) was added. The stirring was
continued at 0 °C for 10 min and room temperature for 30 min.
The reaction was quenched with sat. aqueous NaHCO3
solution and extracted with EtOAc. The combined organic
layers were dried with Na2SO4 and concentrated under
reduced pressure. Chromatography of the residue afforded the
R,â-unsaturated lactone 14 as either colorless or pale yellow
oil.
The diastereomeric ratio and enantiomeric ratio of the R,â-
unsaturated lactone 14a -f were analyzed with a Chiralcel OD
and a Sherisorb column 38575 (3 µm), respectively. Since the
R,â-unsaturated lactone was a degradation product of the
vinylogous urethane lactone, the de% and ee% of compounds

Asymmetric Syn-Selective Aldol Reactions
J . Org. Chem., Vol. 63, No. 24, 1998 9093
14a -f represented the diastereoselectivity and enantioselec-
tivity of the aldol reactions of the VU lithium enolate and the
aldehydes.
(m, 2 H), 0.00 (s, 9 H). 13C NMR (CDCl3) δ 163.2 CO, 143.8
CH, 131.7 CH, 122.6 CH, 119.4 CH2, 80.2 CH, 69.8 CH, 67.5
CH2, 18.5 CH2, -1.4 CH3. Rf ) 0.59 (hexane:EtOAc/2:1).
HPLC (λmax ) 210 nm) de% 98.9%, hexane:2-propanol 95:5,
0.6 mL/min, anti 9.59 min, syn 14.10 min; ee% 97.7%, hex-
ane:2-propanol 99.5:0.5, 0.6 mL/min, minor 27.62 min, major
29.01 min. HREI: calcd for C12H20O3Si: 240.1182; molecular
ion not observed, found: 169.0687 for (C8H13O2Si)+, 73.0474
for (C3H9Si)+.
The retention times of the diastereomers (anti and syn) and
enantiomers (minor and major) were assigned by comparing
the HPLC behaviors of the R,â-unsaturated lactones 14a -f
with racemic compound 25 (a degradation product of the
racemic vinylogous urethane lactone 24). Four peaks were
seen when compound 14 was analyzed with the chiral column
due to two anti- and two syn-compounds, while only two peaks
were seen when analyzed with the Sherisorb column due to
anti- and syn-diastereomers.
(3R ,4S )-5-Ke t o-4-[â-(t r im e t h ylsilyl)e t h oxy]-3-vin yl-
oxa cycloh exa n -2-on e (2). To a solution of 12e (1.5 mmol,
1.1 g) in THF (3 mL) was added HCl (2.5 mL of 3 N aqueous
solution, 7.5 mmol) dropwise. Stirring was continued for 3-5
h until the starting material could not be detected from TLC.
The mixture was extracted twice with EtOAc. The combined
organic layers were washed with water, dried over Na2SO4,
and concentrated. The crude yellowed oil was chromato-
graphed (hexane:EtOAc/1.5:1) to yield the â-keto lactone 2 (299
14a (76% yield): [R]21D ) -278.5° (c 1.5, CHCl3). IR (CHCl3)
3021, 2960, 1719, 1261. 1H NMR (CDCl3) δ 7.07 (dd, 1 H, J )
5.73, 9.73 Hz), 6.19 (d, 1 H, J ) 9.94 Hz), 3.98 (dd, 1 H, J )
2.55, 5.55 Hz), 3.90 (d, 1 H, J ) 2.52 Hz), 3.62 (m, 1 H), 3.50
(m, 1 H), 1.13 (s, 9 H), 0.93 (m, 2 H), 0.00 (s, 9 H). 13C NMR
(CDCl3) δ 164.3 CO, 143.2 CH, 123.8 CH, 86.7 CH, 67.4 CH,
66.2 CH2, 34.4 C, 26.6 CH3, 18.8 CH2, -1.4 CH3. Rf ) 0.86
(hexane:EtOAc/2:1). HPLC (λmax ) 214 nm) de% 97.2%,
hexane:2-propanol/95:5, 0.5 mL/min, anti 9.66 min, syn 14.60
min; ee% 96.5%, hexane:2-propanol 99.5:0.5, 0.5 mL/min,
minor 24.80 min, major 32.72 min. Anal. Calcd for C14H26O3-
Si: C 62.18, H 9.69. Found: C 61.81, H 9.75.
mg, 78% yield) as a pale yellow oil. [R]21 ) -44.2° (c 1.2,
D
CHCl3); IR (CHCl3) 3019, 2956, 1740, 1359, 1125. 1H NMR
(CHCl3) δ 5.99 (m, 1 H), 5.45 (m, 2 H), 5.05 (m, 1 H), 4.08 (d,
1 H, J ) 4.15 Hz), 3.86 (m, 1 H), 3.63 (m, 1 H), 3.47 (m, 2 H),
0.99 (t, 2 H, J ) 8.29 Hz), 0.02 (s, 9 H). 13C NMR (CHCl3) δ
192.3 CO, 167.5 CO, 131.0 CH, 119.7 CH2, 79.7 CH, 77.2 CH,
69.6 CH2, 44.2 CH2, 18.2 CH2, -1.4 CH3. Rf ) 0.23 (hexane:
EtOAc 1:1.85). HRMS: calcd 256.1311 for C12H20O4Si, mo-
lecular ion not observed, found: 255.1052 for (M - H)+,
73.0471 for (C3H9Si)+.
14b (75% yield): [R]21D ) -288.9° (c 1.3, CHCl3); IR (CHCl3)
3020, 2958, 2877, 1714, 1262. 1H NMR (CDCl3) δ 7.06 (dd, 1
H, J ) 5.71, 9.74 Hz), 6.19 (d, 1 H, J ) 9.78 Hz), 3.91 (dd, 1
H, J ) 2.66, 5.55 Hz), 3.84 (dd, 1 H, J ) 2.62, 9.72 Hz), 3.67
(m, 1 H), 3.50 (m, 1 H), 2.26 (m, 1 H), 1.12 (d, 3 H, J ) 6.61
Hz), 0.97 (d, 3 H, J ) 6.75 Hz), 0.91 (t, 2 H, J ) 8.06 Hz), 0.00
(s, 9 H). 13C NMR (CDCl3) δ 163.7 CO, 143.1 CH, 124.1 CH,
85.8 CH, 66.2 CH, 66.1 CH2, 28.3 CH, 20.0 CH3, 18.6 CH2,
18.3 CH3, -1.4 CH3. Rf ) 0.81 (hexane:EtOAc/2:1). HPLC
(λmax ) 214 nm) de% 99.3%, hexane:2-propanol 95:5, 0.6 mL/
min, anti 8.08 min, syn 14.23 min; ee% 96.6%, hexane:2-
propanol 99.5:0.5, 0.6 mL/min, minor 24.21 min, major 28.43
min. Anal. Calcd for C13H24O3Si: C 60.90, H 9.43; found: C
61.15, H 9.41.
(3R,4S,5R)-5-h yd r oxy-4-[â-(tr im eth ylsilyl)eth oxy]-3-vi-
n yloxa cycloh exa n -2-on e (16). A solution of â-keto lactone
2 (1.0 mmol, 0.26 g), cerium(III) chloride heptahydrate (1.0
mmol, 0.37 g) in methanol (4.0 mmol, 0.16 mL), and THF (2.5
mL) was cooled to 0 °C and stirred for 10 min. Sodium
borohydride (1.1 mmol, 42 mg) was added in one portion. The
reaction was continued for 30 min at 0 °C and then quenched
with water. The mixture was extracted with EtOAc (2 × 50
mL). The combined organic layers were dried over Na2SO4
and concentrated to afford crude 15 as a yellow oil. To a
solution of crude 15 in benzene (10 mL) was added silver
carbonate on Celite [3.0 mmol, 1.65 g (contains 50 wt %
Ag2CO3)]. The mixture was refluxed for 5-8 h. After the
reaction was completed, the mixture was cooled to room
temperature and filtered through a pad of Celite. The filtrate
was concentrated. The crude brown oil was chromatographed
to yield the â-hydroxy lactone 16 (0.21 g, 80% yield) as a pale
14c (73% yield): [R]21D ) -284.4° (c 1.7, CHCl3). IR (CHCl3)
3027, 3013, 2955, 2897, 1731. 1H NMR (CDCl3) δ 7.52-7.32
(m, 3 H), 7.06 (dd, 1 H, J ) 5.64, 9.69 Hz), 6.21 (d, 1 H, J )
9.75 Hz), 5.45 (d, 1 H, J ) 3.23 Hz), 3.99 (dd, 1 H, J ) 2.85,
5.55 Hz), 3.32 (m, 1 H), 2.94 (m, 1 H), 0.70 (m, 2 H), -0.04 (s,
9 H). 13C NMR (CDCl3) δ 163.5 CO, 143.0 CH, 135.3 C, 128.4
CH, 128.2 CH, 126.9 CH, 123.0 CH, 81.3 CH, 70.2 CH, 68.4
CH2, 18.3 CH2, -1.5 CH3. Rf ) 0.67 (hexane:EtOAc/2:1).
HPLC (λmax ) 216 nm) de% 97.9%, hexane:2-propanol 95:5,
0.6 mL/min, anti 8.45 min, syn 22.13 min; ee% 98.4%, hexane:
2-propanol 99:1, 0.6 mL/min, minor 27.29 min, major 37.18
min. Anal. Calcd for C16H22O3Si: C 66.17, H 7.64. Found:
C 66.16, H 7.71.
yellow oil. [R]21 ) +75.0° (c 1.3, CHCl3). IR (CHCl3) 3566,
D
3020, 2956, 2360, 1739, 1681, 1583. 1H NMR (CDCl3) δ 6.00
(m, 1 H), 5.72 (m, 2 H), 4.68 (dd, 1 H, J ) 0.74, 5.52 Hz), 4.13
(m, 1 H), 3.80 (m, 1 H), 3.73 (m, 2 H), 2.85 (dd, 1 H, J ) 6.63,
17.58 Hz), 2.70 (dd, 1 H, J ) 9.58, 17.58 Hz), 2.48 (d, 1 H, J
) 8.6 Hz), 0.96 (t, 2 H, J ) 8.38 Hz), 0.01 (s, 9 H). 13C NMR
(CDCl3) δ 169.3 CO, 132.9 CH, 132.5 CH2, 80.2 CH, 76.6 CH,
71.1 CH2, 66.2 CH, 35.6 CH2, 18.8 CH2, -1.5 CH3. Rf ) 0.45
(hexane:EtOAc/1:1). HREI: calcd 258.1287 for C12H22O4Si,
molecular ion not observed, found: 173.0639 for (C7H13O3Si)+,
169.0687 for (C8H13O2Si)+, 101.0784 for (C5H13Si)+, 73.0474 for
(C3H9Si)+.
14d (74% yield): [R]21D ) -150.6° (c 1.3, CHCl3). IR (CHCl3)
3020, 2958, 1725, 1630, 1218. 1H NMR (CDCl3) δ 6.92 (dd, 1
H, J ) 4.45, 9.73 Hz), 6.10 (d, 1 H, J ) 9.70 Hz), 5.93 (m, 1
H), 5.76 (m, 1 H), 4.85 (dd, 1 H, J ) 3.89, 7.24 Hz), 4.01 (t, 1
H, J ) 4.09 Hz), 3.64 (m, 2 H), 2.13 (m, 2 H), 1.03 (t, 3 H, J )
7.47 Hz), 0.93 (t, 2 H, J ) 8.08 Hz), 0.02 (s, 9 H). 13C NMR
(CDCl3) δ 163.1 CO, 143.9 CH, 138.7 CH, 122.6 CH, 122.4 CH,
80.7 CH, 70.0 CH, 67.4 CH2, 25.4 CH2, 18.5 CH2, 13.0 CH3,
-1.1 CH3. Rf ) 0.62 (hexane:EtOAc/2:1). HPLC (λmax ) 214
nm) de% 98.7%, hexane:2-propanol 95:5, 0.6 mL/min, anti 8.36
min, syn 13.83 min; ee% 96.5%, hexane:2-propanol 99.5:0.5,
0.6 mL/min, minor 36.27 min, major 39.08 min. Anal. Calcd
for C14H24O3Si: C 62.64, H 9.01. Found: C 62.49, H 9.01.
La cton e 17. â-Hydroxy lactone 16 (0.80 mmol, 206 mg)
was dissolved under nitrogen in dichloromethane (2 mL) at 0
°C, boron trifluoride etherate (1.6 mmol, 0.2 mL) was added,
and the mixture was stirred at 0 °C for 30 min and at room
temperature for 2 h. The volatiles were removed at ca. 5 Torr.
The residue was dissolved in DMF (1 mL) and acetone (0.2
mL), stirred with a catalytic amount of PPTS at room tem-
perature, and 2,2-dimethoxypropane (5.0 mmol, 0.61 mL) was
added and stirred for 12 h. Additional 2,2-dimethoxypropane
(2.5 mmol, 0.31 mL) was added and stirred for another 12 h.
The mixture was then concentrated under reduced pressure.
The crude yellow oil was chromatographed (hexane:EtOAc/
1.5:1) to yield lactone 17 (154 mg, 78% yield) as a colorless
14e (70% yield): [R]21 ) -124.3° (c 1.0, CHCl3). IR, 1H,
D
13C NMR spectra and Rf value were identical with 14f. HPLC
(λmax ) 210 nm) de% 98.5%, hexane:2-propanol 95:5, 0.6 mL/
min, anti 8.99 min, syn 14.33 min; ee% 96.8%, hexane:2-
propanol 99.5:0.5, 0.6 mL/min, minor 26.99 min, major 28.17
min. Anal. Calcd for C12H20O3Si: C 59.96, H 8.39. Found:
C 59.99, H 8.35.
oil. [R]21 ) +48.8° (c 1.0, CHCl3); IR (CHCl3) 3020, 2995,
D
14f (70% yield): [R]21D ) -124.7° (c 1.0, CHCl3). IR (CHCl3)
3028, 2957, 1727, 1630, 1379, 1251, 1212. 1H NMR (CDCl3) δ
6.91 (dd, 1 H, J ) 4.33, 9.90 Hz), 6.09 (m, 2 H), 5.46 (m, 2 H),
4.93 (m, 1 H), 4.10 (t, 1 H, J ) 4.33 Hz), 3.63 (m, 2 H), 0.90
1759, 1455. 1H NMR (CDCl3) δ 6.01 (m, 1 H), 6.45 (m, 2 H),
4.75 (m, 1 H), 4.57 (d, 1 H, J ) 6.30 Hz), 4.45 (dd, 1 H, J )
1.69, 7.71 Hz), 2.92 (dd, 1 H, J ) 2.07, 15.91 Hz), 2.55 (dd, 1
H, J ) 3.62, 15.91 Hz), 1.47 (s, 3 H), 1.35 (s, 3 H). 13C NMR

9094 J . Org. Chem., Vol. 63, No. 24, 1998
Schlessinger and Pettus
(CDCl3) δ 169.0 CO, 131.2 CH, 119.3 CH2, 78.6 CH, 74.5 CH,
71.4 CH, 25.9 CH3, 24.1 CH3. Rf ) 0.73 (hexane:EtOAc/1:1).
Anal. Calcd for C10H14O4: C 60.60, H 7.12; found: C 60.41, H
7.16.
4.37-4.21 (m, 4 H), 4.09-3.97 (m, 2 H), 3.91-3.86 (m, 1 H),
2.49 (dd, 1 H, J ) 6.48, 14.47 Hz), 1.88 (dd, 1 H, J ) 4.77,
14.46 Hz), 1.45 (s, 3 H), 1.41 (s, 3 H), 1.36 (s, 3 H), 1.34 (s, 3
H), 1.30 (t, 3 H, J ) 7.3 Hz). 13C NMR (CDCl3) δ 169.6 CO,
109.3 C, 109.1 C, 94.3 C, 73.9 CH, 71.3 CH, 70.5 CH, 69.9 CH,
66.8 CH2, 62.2 CH2, 32.3 CH2, 27.0 CH3, 26.8 CH3, 25.6 CH3,
25.3 CH3, 14.0 CH3. Rf ) 0.43 (hexane:EtOAc/2:1). Anal.
Calcd for C16H26O8: C 55.48, H 7.56. Found: C 55.27, H 7.49.
La cton e 19. Osmium tetraoxide (0.052 mmol, 42 µL of 2.5
wt % solution in tert-butyl alcohol) was added to a solution of
N-methylmorpholine N-oxide (0.72 mmol, 84 mg), water (2
mL), and acetone (0.4 mL) in THF (0.7 mL). After 10 min,
the olefin 17 (0.65 mmol, 129 mg) in acetone (0.2 mL) and THF
(0.2 mL) was added dropwise. The reaction was completed
after stirring overnight at room temperature. A slurry mixture
of sodium bisulfite (50 mg) and magnesol (100 mg) in water
(0.5 mL) was added and stirred for 10 min, and the solid
was then filtered. The filtrate was adjust to pH 2 with 1 N
H2SO4. The solution was saturated with NaCl and extracted
with EtOAc (3 × 20 mL). The combined organic layers were
dried and concentrated to yield the crude diol 18 as a white
foam. The material was dissolved in DMF (0.8 mL) and
acetone (0.17 mL), stirred with catalytic amount of PPTS at
room temperature, and 2,2-dimethoxypropane (4.0 mmol, 0.49
mL) was added and stirred overnight. A second portion of 2,2-
dimethoxypropane (2.0 mmol, 0.25 mL) was added and stirred
for another 12 h. The mixture was concentrated under
vacuum. The residue was chromatographed (hexane:EtOAc/
1.5:1) to provide lactone 19 (0.16 g, 90% yield) as a white solid.
(+)-KDO Am m om iu n Sa lt (21). A solution of ester 20
(3.81 mmol, 132 mg) in 90% HOAc (12 mL) was heated to 90
°C for 45 min. The solution was cooled to ambient temperature
and then concentrated under vacuum at a temperature not
exceeding 50 °C. To the solution of the residue in water (1
mL) was added NaOH (7 mL of 0.1 N aqueous solution). The
solution was stirred at room temperature for 2 h and then
acidified with Dowex-50W-X4 (20-50 mesh) to pH 3, and the
resin was removed by filtration. The filtrate was concentrated
to yield the crude free KDO, 1, as a white solid. This crude
KDO was dissolved in water (1 mL), and concentrated aqueous
NH3 was added until pH 11. The solution was stirred for 30
min at room temperature and concentrated under vacuum at
a temperature not exceeding 50 °C to yield the crude KDO
ammonium salt as a white solid. Recrystallization from 90%
aqueous ethanol provided the pure KDO ammonium salt (92.5
mg, 89% yield) as a white, fluffy solid. mp 123-126 °C. [R]21
D
[R]21 ) +65.1° (c 1.2, CHCl3). mp 116-118 °C. IR (CHCl3)
D
) +39.5° (c 1.2, H2O); authentic sample from Sigma Co.: mp
2992, 2936, 1762, 1455. 1H NMR (CDCl3) δ 4.72 (m, 1 H), 4.56
(dd, 1 H, J ) 1.17, 7.93 Hz), 4.35 (m, 1 H), 4.05 (m, 2 H), 3.91
(dd, 1 H, J ) 1.05, 8.63 Hz), 2.83 (dd, 1 H, J ) 1.99, 15.88
Hz), 2.51 (dd, 1 H, J ) 3.38, 15.95 Hz), 1.40 (s, 3 H), 1.39 (s,
3 H), 1.34 (s, 3 H), 1.32 (s, 3 H). 13C NMR (CDCl3) δ 168.8
CO, 109.7 C, 109.6 C, 77.7 CH, 72.7 CH, 71.3 CH, 71.2 CH,
66.6 CH2, 34.6 CH2, 27.0 CH3, 25.8 CH3, 25.0 CH3, 24.1 CH3.
Rf ) 0.62 (hexane:EtOAc/1:1). Anal. Calcd for C13H20O6: C
57.34, H 7.39. Found: C 57.16, H 7.45.
122-125 °C, [R]21 ) +40.9° (c 0.9, H2O). The synthetic
D
sample has an identical NMR spectrum and TLC behavior
with the authentic sample: 1H NMR (D2O) δ 4.48-4.35 (m),
4.11-3.94 (m), 3.80-3.70 (m), 3.61-3.52 (m), 2.52 (dd, J )
6.92, 14.14 Hz), 2.31 (m), 2.03-1.79 (m). 13C NMR (D2O) δ
176.7 CO, 96.4 C, 71.1 CH, 69.2 CH, 66.6 CH, 66.2 CH, 62.9
CH2, 33.6 CH2. Rf ) 0.56 (MeOH:CHCl3:H2O/10:10:3). Anal.
Calcd for C8H17NO8: C 35.17, H 7.00, N 5.13; found: C 35.34,
H 6.90, N 5.09.
Ester 20. tert-Butyllithium (0.61 mmol, 0.36 mL of 1.7 M
solution in pentane) was added dropwise to a solution of ethyl
vinyl ether (0.97 mmol, 92 µL) in dry THF (1 mL) at -65 °C
under nitrogen. After removal of the cooling bath the yellow
precipitate redissolved and the solution became colorless
between -5 °C to 0 °C. The solution was recooled to -78 °C.
A solution of lactone 19 (0.55 mmol, 0.15 g) in THF (0.5 mL)
was added. The stirring was continued for 30 min at -78 °C
and then quenched with saturated NH4Cl aqueous solution.
The mixture was extracted with EtOAc (3 × 30 mL). The
combined organic layers were dried and the solvent removed
to yield a pale yellow oil. The material was dissolved in
CH2Cl2 (2.5 mL) and cooled to -60 °C, methanol (0.3 mL) was
added, and the cold mixture was ozonolyzed. After excess of
ozone was removed by N2 stream, 2 equiv of dimethyl sulfide
was added. This mixture was warmed to 0 °C for 20 min and
then concentrated under vacuum to yield the crude product
as a pale yellow oil. This residue was chromatographed to
provide the KDO derivative 20 (0.164 g, 86% yield) as a
colorless oil. [R]21D ) +29.1° (c 1.6, CHCl3). IR (CHCl3) 3524,
2990, 2937, 1737, 1455. 1H NMR (CDCl3) δ 4.49 (m, 1 H),
Com p ou n d 22. The synthetic KDO ammonium salt 21 (45
mg, 0.165 mmol) was peracetylated and esterificated with
diazomethane according to the literature procedure to afford
methyl ester 22 (61 mg, 80% yield) as a colorless oil. [R]21
)
D
+99.7° (c 1.2, MeOH). IR (CHCl3) 2956, 1747, 1370. 1H NMR
(CDCl3) δ 5.38 (m, 1 H), 5.31 (m, 1 H), 5.21 (m, 1 H), 4.46 (dd,
1 H, J ) 2.09, 12.25 Hz), 4.19-4.08 (m, 2 H), 3.80 (s, 3 H),
2.23-2.17 (m, 2 H), 2.13 (s, 3 H), 2.10 (s, 3 H), 5.19 (s, 6 H),
4.49 (s, 3 H). 13C NMR (CDCl3) δ 170.4 CO, 170.2 CO, 169.9
CO, 169.5 CO, 167.9 CO, 166.6 CO, 97.4 C, 69.7 CH, 67.3 CH,
65.9 CH, 63.9 CH, 62.0 CH2, 53.1 CH3, 30.9 CH2, 20.7 CH3,
20.6 CH3. Rf ) 0.51 (hexane:EtOAc/1:1). Anal. Calcd for
C
19H26O13: C 49.35, H 5.66; found: C 49.54, H 5.71.
Ack n ow led gm en t. A Sherman Clarke Fellowship
(to L.H.P.) and financial support from the NIH are
gratefully acknowledged. We thank Dr. Thomas R. R.
Pettus for invaluable help in preparing this manuscript.
J O981916F