Variable synthesis of the optically active thiotetronic acid antibiotics thiolactomycin, thiotetromycin, and 834-B1

Article abstract of DOI:10.1002/anie.200603562

(Chemical Equation Presented) In seven steps: The antibiotic (+)-thiolactomycin was synthesized in seven steps and with 16% overall yield from 4-acetoxy-2-methyl-2-buten-1-al, an intermediate of the industrial synthesis of vitamin A. Key transformations were the catalytic asymmetric Sharpless epoxidation of an ethoxycarbonyl-substituted pentadienol (93% ee) and a regio- and stereoselective thiolysis of the resulting epoxide (see scheme).

Full text of DOI:10.1002/anie.200603562

Communications
DOI: 10.1002/anie.200603562
Natural Product Synthesis
Variable Synthesis of the Optically Active Thiotetronic Acid
Antibiotics Thiolactomycin, Thiotetromycin, and 834-B1**
Korinna L. Dormann and Reinhard Brückner*
Bacterial infections continue to threaten human life, in
particular because of the increasing number of organisms
resistant to present-day antibiotics.[1] In the development of
new antibacterial agents, one approach is to trace back
antibiotic natural products to “lead structures”and improve
their activity by variation of the substituents. With this
background, the thiotetronic acid (+)-thiolactomycin (1;
Scheme 1), which is produced by the actinomycete Nocardia
sp.[2] and is active against a number of pathogens[2] including
Mycobacterium tuberculosis[3] and the malaria parasite Plas-
of product, and elucidated its configuration.[17] Townsend and
co-workers needed nine steps to transform d-alanine into the
first synthetic specimen of (+)-1 (6% overall yield).[14] Ohata
and Terashima synthesized (+)-1 via a d-phenylalanine-based
enolate and (ꢀ)-1 via its l isomer in eight steps with one
separation by HPLC (22% overall yield).[15] Very recently,
Takabe and co-workers completed a 12-step synthesis of
(+)-1 (3% overall yield) from methyl propionate that
included an enzymatic resolution.[16] Modifications of the
above-mentioned routes,[13,14] spin-off products thereof,[15,17]
or semisyntheses[18] from natural (+)-1 have provided dozens
of racemic[19] or enantiomerically pure[20] thiolactomycin
analogues with non-natural substituents at centers C-3, O-4,
and/or C-5. Nevertheless, in early 2006 medicinal chemists
emphasized that “one of the problems in making progress in
this area is the difficult chemical synthetic route to thiolacto-
mycin analogues”.[6] In this regard, the approach to such
compounds disclosed herein provides new opportunities. One
of its assets is that thiotetronic acids like thiolactomycin are
obtained for the first time through catalytic asymmetric
synthesis. Moreover, our strategy highlights an innovative and
completely diastereoselective way of establishing a stereo-
modium falciparum,[4] became
a source of inspiration
recently. The interest in 1 is spurred by its rapid absorption
in tissues, its effectiveness in mouse infection models,[2,5,6] and
its low toxicity in animals.[2] On a molecular level, 1 is an
inhibitor[5] of the bacterial,[7] but not human, enzymes that
convert malonyl acyl carrier protein (“malonyl-ACP”) and
the acyl-ACP intermediates of growing chain lengths through
b-ketoacyl-ACPs into lipids.[5,8] X-ray analysis of enzyme-
bound thiolactomycin indicates that the latter functions as a
malonyl-ACP surrogate.[9,10]
Since its isolation,[2] racemic thiolactomycin has been
synthesized once,[13] its dextrorotatory isomer three
times,[14–16] and the levorotatory isomer twice.[17,15] The syn-
thesis of (ꢀ)-1 by Thomas and Chambers started from ethyl
l-lactate, comprised 19 linear steps, gave 0.3% overall yield
ꢀ
genic C S bond.
Retrosynthetically, (+)-thiolactomycin (1) was traced
ꢀ
back to the polyfunctional diester 2 with syn-oriented C S
ꢀ
and C OH bonds (Scheme 1) or the diastereomeric diester
ꢀ
with the identical orientation of the C S bond but the
opposite orientation of the C OH bond (not shown). This
ꢀ
plan relied on the feasibility of a vic-didesoxygenation/
Dieckmann condensation sequence for the conversion of
either of these compounds into (+)-1. Specifically, diester
isomer 2 would be the precursor of 1 if vinyl epoxide 4 and
thiocarboxylate 3 underwent a syn-selective SN’ ring-opening
reaction. Conversely, the epimeric diester would become the
precursor of 1 if vinyl epoxide ent-4 and thiocarboxylate 3
combined by an anti-selective SN’ attack. The stereochemistry
of such vinyl epoxide openings has been investigated
almost[22] only with non-sulfur nucleophiles[23a,b] and only[24]
with simpler vinyl epoxides than our sterically hindered and
alkoxycarbonyl-substituted substrates 4 or ent-4; both syn[23]
and anti[23a,b] selectivity as well as no stereoselectivities were
observed. Making up for the incertitude that these findings
implied for our endeavors, either of the vinyl epoxides 4 and
ent-4 would be accessible by the silylation of an appropriately
configured vinyl glycidol. The latter would be obtained from a
Sharpless asymmetric epoxidation[25] (SAE) of the underlying
allyl alcohol in the presence of l- and d-diisopropyl tartrate
(DIPT), for 4 and ent-4, respectively.
Scheme 1. Retrosynthetic analysis of (+)-thiolactomycin (1).
[*] Dipl.-Chem. K. L. Dormann, Prof. Dr. R. Brückner
Institut für Organische Chemie und Biochemie
Universität Freiburg
Albertstrasse 21, 79104 Freiburg (Germany)
Fax: (+49)761-203-6100
E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
The required allyl alcohol was the ethoxycarbonyl-sub-
[**] We are grateful to Prof. Dr. K. Ditrich (BASF AG, Ludwigshafen) for a
donation of aldehyde 5.
stituted pentadienol 7 (Scheme 2), which was synthesized[26]
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Scheme 2. Synthesis of vinyl epoxide 4. a) Addition of 5 to a solution
of 6 (1.1 equiv) in CH2Cl2, 508C, 5 h (Ref. [21]: 85%); b) NaOH
(5 mol%), EtOH, 258C, 12 h; 84% over two steps (Ref. [21]: 91%;
77% over both steps); c) tBuOOH (2.0 equiv), l-(+)-DIPT (12 mol%),
Ti(OiPr)4 (10 mol%), CH2Cl2, 4-Š M.S., ꢀ308C, 12 h; PPh3 (2.0 equiv);
tBuPh2SiCl (1.0 equiv), imidazole (2.2 equiv), CH2Cl2, 258C, 1 h; 83%.
DIPT=diisopropyl tartrate.
by a Wittig reaction between aldehyde 5[27] and phosphorane 6
and a subsequent ethanolysis, as reported previously.[21]
Pentadienol 7 was then subjected to a catalytic[25b] SAE.[28]
The resulting epoxy-alcohol 8 could be protected with tert-
butyldiphenylsilyl chloride without the need for workup in
between. This one-pot procedure afforded the siloxy- and
ethoxycarbonyl-substituted vinyl epoxide 4 in 83% yield and
with 93% ee.[29] Likewise, SAE of pentadienol 7 in the
presence of d-(ꢀ)-DIPT followed by in situ silylation pro-
vided the enantiomeric epoxide ent-4 with 92% ee.[29]
Scheme 3. Optimization of a model thiolysis. a) Reagents (see
Table 1), CH2Cl2, ꢀ788C, 3 h; b) reagents, CH2Cl2, ꢀ78!258C,
60 min; ꢀ788C, addition of 4; ꢀ78!258C, 2 h; c) reagents, CH2Cl2,
ꢀ78!258C, 60 min; addition of epoxide 4 at 258C, 1 h.
Thiolyses of vinyl epoxide 4 were first studied employing
thioacetic acid (Scheme 3 and Table 1), which is commercially
available and was hence a good substitute for the thiopro-
pionic acid to be prepared later from propionyl chloride and
H2S. We expected difficulties in directing the nucleophile
towards position C-2 of our substrate 4 (SN’ reaction) rather
than positions C-3 (conjugate addition) or C-4 or C-5 (SN
reactions). However, site-selectivity was not an issue whereas
the lack of reactivity and/or chemoselectivity was. Thioacetic
acid alone or combined with Na2CO3 led to only incomplete
conversion of 4, while Cs2CO3, triethylamine, Hünigꢀs base, or
Table 1: Reaction conditions and product yields (see Scheme 3).
Conditions Reagents (equiv)
Isolated products
a
BF3·OEt2 (1.0), AcSH (0.0–1.0) up to 50% 10 (51% ee)
b
AlMe3 (4.0), AcSH
(4.0–5.0)
AlMe3 (5.0), AcSH (5.0)
19% 9 + up to 10% 11,
+ up to 10% 12
48% 9
c
dichloromethane at ꢀ788C and the solution was warmed to
room temperature before adding vinyl epoxide 4.[21,32]
pyridine as additives led to its decomposition. Thioacetic acid
The thiolysis conditions from Scheme 3 were readily
applicable to the opening of vinyl epoxide 4 by thiopropionic
acid (Scheme 4, step a). Thus, SN’ 13 was isolated in 60%
yield[33] as a single diastereomer and with 93% ee according to
HPLC analysis. This result proved that there was 100%
[30]
in the presence of Ti(OiPr)4
led to ring opening of
2,3-epoxy-1-hexanol but not of epoxide 4. However, mixtures
of epoxide 4 and thioacetic acid could be activated by other
Lewis acids (see Table 1). This approach furnished the desired
4
2
=
ꢀ
ꢀ
SN’ product 9 with the expected E configuration of the C C
transfer of chirality from the C O bond (broken) to the C
bond (newly established). That the stereostructure of com-
S
bond as well as a seemingly single, although unassigned,
configuration at C-2. Moreover, we obtained some lactone 12,
apparently from an intramolecular transesterification of the
ꢀ
ꢀ
pound 13 was indeed 2, that is, that the C OH and the C S
bond are syn- rather than anti-oriented, followed from the
fact that our synthesis gave dextrorotatory thiolactomycin. As
the latter is R-configured,[17] the corresponding stereocenter
of compound 13 must also have this configuration. This
finding is tantamount to assigning 100% syn selectivity to the
epoxide-opening step, 4!13.
=
isomeric SN’ product iso-9 with the Z-configured C C bond.
In addition, products without incorporation of thioacetic acid
were isolated, namely aldehyde 10 and the conjugated diene
11. Aldehyde 10 appears to result from a semipinacol
rearrangement of the substrate 4, a well-established trans-
formation of silylated epoxy-alcohols.[31] Diene 11 could
originate from substrate 4 by a 1,4-elimination or from
initially formed 9 by a 1,2-elimination. The highest yield of SN’
product 9 (48%) and the best chemoselectivity (almost no by-
products 10–12) were obtained when exactly 5.0 equivalents
each of Me3Al and thioacetic acid were combined in
Proceeding
towards
thiolactomycin
(Scheme 4,
steps b–e), desilylation of compound 13 with the HF/pyridine
complex provided glycol 14 in 85% yield. Initially, glycol 14
was cleaved oxidatively by NaIO4 to afford aldehyde 16 in
90% yield. Surprisingly, olefination of 16 with methylene-
triphenylphosphorane gave the required diene 15 with
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1161

Communications
SAEs of alkoxycarbonyl-substituted pentadienols, anti-selec-
tive SN’ thiolyses of vinyl epoxides, and olefin-forming vic-
didesoxygenations.
Received: August 31, 2006
Revised: September 27, 2006
Published online: December 20, 2006
Keywords: chirality transfer · didesoxygenation · epoxidation ·
.
stereoselective synthesis · vinyl epoxides
[1] a) J. Wang, S. M. Soisson, K. Young, W. Shoop, S. Kodali, A.
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Scheme 4. Total synthesis of (+)-thiolactomycin (1). a) Thiopropionic
acid (5.0 equiv), AlMe3 (5.0 equiv), CH2Cl2, ꢀ78!258C, 60 min;
ꢀ788C; addition of 4, CH2Cl2, ꢀ78!258C, 2 h; 60%; b) HF/pyridine,
THF, 258C, 1.5 h; 85%; c) I2 (4.0 equiv), PPh3 (4.0 equiv), imidazole
(5.0 equiv), toluene, 0!258C, 40 min; 69%; d) NaIO4 (1.0 equiv),
dioxane/H2O, 258C, 20 min; 90%; e) LiHMDS (2.5 equiv), THF,
ꢀ788C, 2.5 h; 65% (Ref. [14]: 70%); f) MePPh3Br (1.3 equiv), nBuLi
(1.1 equiv), THF (degassed), 0!258C, 30 min; addition of 16,
exclusion of light, 258C, 10 min; 55%. LiHMDS=lithium hexamethyl-
disilazide.
variable (2–55%) but mostly low yields (30%). Neither the
exclusion of light, the addition of a radical scavenger, nor the
use of degassed solvents and eluents during and after the
reaction led to an improvement. Fortunately, Garegg and
Samuelssonꢀs reductive vic-didesoxygenation with PPh3, imi-
dazole, and I2[34] applied to glycol 14 avoided this bottleneck.
This transformation afforded diene 15 reproducibly in 69%
yield. Moreover, it shortened our synthesis by one step. The
last step towards (+)-1 (94% ee[29]) involved a Dieckmann
condensation of diester 15 (Scheme 4, step e) as reported by
Townsend and co-workers,[14] It completed the hitherto short-
est synthesis of (+)-thiolactomycin in seven steps from
aldehyde 5 and ylide 6.
The flexibility of our approach was used to synthesize the
analogous thiotetronic acids (+)-17 (92% ee[29]), (+)-18 (95%
ee[29]), and (+)-19 (90% ee[29]) in the same straightforward
fashion (Scheme 5).[35] Thiotetronic acid (+)-17 is a non-
natural homologue of thiolactomycin (1), whereas (+)-18 and
(+)-19 are antibiotics known as 834-B1[36] and thiotetromycin,
respectively.[37] Their syntheses have not been reported
before.
[7] R. J. Heath, S. Jackowski, C. O. Rock in Biochemistry of Lipids,
Lipoproteins and Membranes (Eds.: D. E. Vance, J. E. Vance),
4th ed., Elsevier, 2002, pp. 56 – 63 and 88–89.
[8] J. T. Tsay, C. O. Rock, S. Jackowski, J. Bacteriology 1992, 174,
508 – 513.
[9] A. C. Price, K.-H. Choi, R. J. Heath, Z. Li, S. W. White, C. O.
Rock, J. Biol. Chem. 2001, 276, 6551 – 6559.
[10] If the acidities of thiolactomycin and malonyl-ACP in the
enzyme pocket resemble those of model compounds 20[11]
(pKa = 4.1)[12] and monoethyl malonate (pKa = 3.7)[12] in water,
the enzyme is likely to bind the deprotonated rather than neutral
forms of thiolactomycin (21) and malonyl-ACP (22).
In summary, short asymmetric syntheses of thiotetronic
acid antibiotics were accomplished. Starting with the alde-
hyde intermediate 5 of the technical synthesis of vitamin A,
the natural products thiolactomycin (1), 834-B1 (18), and
thiotetromycin (19) were each synthesized in seven steps and
with overall yields reaching 16%. Key transformations were
[11] K. L. Dormann, Dissertation in preparation, Universität Frei-
burg.
[12] From titrations of 5–10 mm aqueous solutions with 0.1m NaOH
from a Schellbach burette using a membrane pH meter HI 8314
(HANNA instruments) and with graphical interpretation of
data.
[13] C.-L. J. Wang, J. M. Salvino, Tetrahedron Lett. 1984, 25, 5243 –
5246 (11% yield over the five steps from methyl a-propionate).
[14] J. M. McFadden, G. L. Frehywot, C. A. Townsend, Org. Lett.
2002, 4, 3859 – 3862.
Scheme 5. More thiotetronic acids prepared by the strategy shown in
Schemes 2 and 4.
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[15] K. Ohata, S. Terashima, Tetrahedron Lett. 2006, 47, 2787 – 2791.
[16] K.-i. Toyama, T. Tauchi, N. Mase, H. Yoda, K. Takabe,
Tetrahedron Lett. 2006, 47, 7163 – 7166. The authors reported
the synthesis of “R-(ꢀ)”-thiolactomycin but meant R-(+)-
thiolactomycin (personal communication between N.M. and
R.B.).
[29] The ee values of 4 and ent-4 were determined by HPLC on a
chiral stationary phase (L 7100, Merck Hitachi LaChrom;
Chiralpak
OD-H
258C,
column,
UV
n-heptane/iPrOH
detection at
200:1,
230 nm);
0.8 mLminꢀ1
,
tr(S enantiomer) = 8.68 min, tr(R enantiomer) = 10.25 min. The
ee values of (+)-1, (+)-17, (+)-18, and (+)-19 were measured by
the same method but using different absorbents/eluents; in each
case, we found tr(minor enantiomer) < tr(major enantiomer).
[30] Footnote [25] in: M. Caron, K. B. Sharpless, J. Org. Chem. 1985,
50, 1557 – 1560.
[31] a) T. Ooi, H. Yamamoto, J. Am. Chem. Soc. 1989, 111, 6431 –
6432; b) K. Maruoka, S. Nagahara, T. Ooi, H. Yamamoto,
Tetrahedron Lett. 1989, 30, 5607 – 5610; c) M. E. Jung, R.
Marquez, Tetrahedron Lett. 1999, 40, 3129 – 3132.
[17] M. S. Chambers, E. J. Thomas, J. Chem. Soc. Chem. Commun.
1989, 23 – 24.
[18] a) S. M. Sakya, M. Suarez-Contreras, J. P. Dirlam, T. N. OꢀCon-
nell, S. F. Hayashi, S. L. Santoro, B. J. Kamicker, D. M. George,
C. B. Ziegler, Bioorg. Med. Chem. Lett. 2001, 11, 2751 – 2754;
b) P. Kim, Y.-M. Zhang, G. Shenoy, Q.-A. Nguyen, H. I. Boshoff,
U. H. Manjunatha, M. B. Goodwin, J. Lonsdale, A. C. Proce,
D. J. Miller, K. Duncan, S. W. White, C. O. Rock, C. E. Barry III,
C. S. Dowd, J. Med. Chem. 2006, 49, 159 – 171.
[19] Racemic analogues of (+)-1 synthesized since 2003: a) S. J.
Senior, P. A. Illarionov, S. S. Gurcha, I. B. Campbell, M. L.
Schaeffer, D. E. Minnikin, G. S. Besra, Bioorg. Med. Chem. Lett.
2003, 13, 3685 – 3688; b) Ref. [4b]; c) J. M. McFadden, S. M.
Medghalchi, J. N. Thupari, M. L. Pinn, A. Vadlamudi, K. I.
Miller, F. P. Kuhajda, C. A. Townsend, J. Med. Chem. 2005, 48,
946 – 961; d) A. Kamal, A. A. Shaik, R. Sinha, J. S. Yadav, S. K.
Arora, Bioorg. Med. Chem. Lett. 2005, 15, 1927 – 1929; e) P. Kim,
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3451.
[20] Enantiomerically pure analogues of (+)-1: a) M. S. Chambers,
E. J. Thomas, D. J. Williams, J. Chem. Soc. Chem. Commun.
1987, 1228 – 1230; b) Ref. [17]; c) M. S. Chambers, E. J. Thomas,
J. Chem. Soc. Perkin Trans. 1 1997, 417 – 431; d) Ref. [18];
e) Ref. [15]; f) Ref. [19e].
[21] O. Bꢁhnke, Dissertation, Universität Freiburg, 2002.
[22] S nucleophiles such as PhSH (with CuI, AlEt3, or Et3B),
Me3SiSPh (with ZnI2 or a Pd catalyst), and Bi(SPh)3 effect SN’
openings of vinyl epoxides devoid of a possibility of syn- or anti-
selectivity. To the best of our knowledge, the only precedents of
the latter bias stem from SN’ (versus SN) ring openings of vinyl
epoxides with RSH/NEt3; they proceeded with a 1:1 ratio of syn/
anti attack: E. J. Corey, W.-G. Su, Tetrahedron Lett. 1990, 31,
2113 – 2116.
[32] Epoxide opening with Me2AlSAc (prepared as described by E. J.
Corey, D. J. Beames, J. Am. Chem. Soc. 1973, 95, 5829 – 5831):
R. C. Newbold, T. L. Shih, H. Mrozik, M. H. Fisher, Tetrahedron
Lett. 1993, 34, 3825 – 3828.
[33] 13: Thiopropionic acid (1.03 g, 11.4 mmol, 5.0 equiv) in CH2Cl2
(40 mL) was added to AlMe3 (2.0m in heptane, 5.7 mL, 11 mmol,
5.0 equiv) in CH2Cl2 (40 mL) at ꢀ788C over 25 min. The
reaction mixture was allowed to warm to room temperature
during 60 min and then recooled to ꢀ788C. A solution of vinyl
epoxide 4 (93% ee in this experiment; 1.0 g, 2.3 mmol) in CH2Cl2
(40 mL) was then added over 40 min. The resulting mixture was
slowly warmed to room temperature and stirred for 30 min.
After the addition of NaOH (1m, 40 mL) and phase separation,
the aqueous layer was extracted with CH2Cl2 (3 ꢂ 60 mL). The
combined organic phases were washed with H2O (80 mL) and
saturated Na/K tartrate solution (80 mL), dried over MgSO4,
and concentrated under vacuum. The residue was chromato-
graphed on silica gel (eluent cyclohexane/ethyl acetate 7:1) to
give the title compound, namely ethyl (2R,5R)-6-(tert-butyldi-
phenylsiloxy)-5-hydroxy-2,4-dimethyl-2-(propionylsulfanyl)-3-
hexenoate (13; 730 mg, 60%) as a colorless oil. [a]2D5 = + 13.3
(c = 1.03 in CHCl3); 93% ee determined by HPLC on a chiral
stationary phase (L 7100, Merck Hitachi LaChrom; Chiralpak
AD column, n-heptane/EtOH 19:1, 1.0 mLminꢀ1, 258C, UV
detection
at
230 nm);
tr(R enantiomer) = 10.59 min,
1
tr(S enantiomer) = 12.55 min; H NMR (300.1 MHz, TMS inter-
[23] Reviews on non-catalyzed SN’ openings of vinyl epoxides:
a) R. M. Magid, Tetrahedron 1980, 36, 1901 – 1930; b) J. A.
Marshall, Chem. Rev. 1989, 89, 1503 – 1511. Reviews on syn-
selective Pd-catalyzed SN’ openings of vinyl epoxides: c) B. M.
Trost, D. L. Van Vranken, Chem. Rev. 1996, 96, 395 – 422; d) J.
Tsuji, T. Mandai, Synthesis 1996, 1 – 24; e) A. Heumann in
Transition Metals in Organic Synthesis (Eds.: M. Beller, C.
Bolm), Wiley-VCH, Weinheim, 2004, pp. 307 – 320.
nal standard in CDCl3): d = 1.06 (mc, C(CH3)3), 1.11 (t, J3’,2’
7.5 Hz, 3’-H3), 1.22 (t, J2’’,1’’ = 7.1 Hz, 2’’-H3), 1.66 (d, J4-Me,3
=
=
4
1.0 Hz, 4-CH3), 1.84 (s, 2-CH3), 2.48 (q, J2’,3’ = 7.6 Hz, 2’-H2), 2.60
(d, J5-OH,5 = 3.1 Hz, 5-OH), AB signal (dA = 3.53, dB = 3.65, JAB
=
10.2 Hz, in addition split by JA,5 = 7.5 Hz, JB,5 = 4.0 Hz, 6-H2),
4.05 (mc, 5-H), 4.17 (q, J1’’,2’’ = 7.1 Hz, 1’’-H2), 5.72 (br s, 3-H),
7.36–7.47 (m, 4 ꢂ meta-H, 2 ꢂ para-H), 7.64–7.67 ppm (m, 4 ꢂ
ortho-H]); 13C NMR (100.6 MHz, CDCl3 internal standard in
CDCl3): d = 9.55 (C-3’), 14.05 (4-Me, C-2’’), 19.31 (C(CH3)3),
25.94 (2-Me), 26.92 (C(CH3)3), 36.90 (C-2’), 54.72 (C-2), 61.97
(C-1’’), 66.72 (C-6), 76.96 (C-5), 126.09 (C-3), 127.91 (Cmeta),
129.96 and 129.99 (Cpara), 133.06 and 133.10 (Cipso), 135.62
(Cortho), 139.58 (C-4), 172.19 (C-1), 199.30 ppm (C-1’); IR (film):
n˜ = 3510, 2975, 2930, 2860, 1735, 1695, 1460, 1445, 1380, 1115,
1075 cmꢀ1; elemental analysis (%) calcd for C29H40O5SSi (528.8):
C 65.87, H 7.62, S 6.06; found: C 65.70, H 7.59, S 6.09.
[24] With Pd catalysis, alkoxycarbonyl-substituted vinyl epoxides
related to 4 underwent stereoselective ring openings by O nu-
cleophiles, albeit in the SN rather than SN’ mode: B. M. Trost,
J. K. Lynch, S. R. Angle, Tetrahedron Lett. 1987, 28, 375 – 378.
[25] Method: a) Using stoichiometric or near-stoichiometric amounts
of TiIV tartrate: T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc.
1980, 102, 5974 – 5976; b) using molecular sieves and less than
10 mol% of TiIV tartrate: R. M. Hanson, K. B. Sharpless, J. Org.
Chem. 1986, 51, 1922 – 1925; Y. Gao, R. M. Hanson, J. M.
Klunder, S. Y. Ko, H. Masamune, K. B. Sharpless, J. Am. Chem.
Soc. 1987, 109, 5765 – 5780.
[34] Method: P. J. Garegg, B. Samuelsson, Synthesis 1979, 469 – 470.
[35] The ee values of (+)-1, (+)-17, (+)-18, and (+)-19 varied
somewhat (90–95%) because their precursors were derived from
different samples of vinyl epoxide 4 and its a-ethyl analogue.
The enantiopurity of these epoxides depended critically on the
epoxidizing temperature and was not always the same.
[36] T. Sato, K. Suzuki, S. Kadota, K. Abe, S. Takamura, M. Iwanami,
J. Antibiot. 1989, 42, 890 – 896.
[37] S. Omura, Y. Iwai, A. Nakagawa, R. Iwata, Y. Takahashi, H.
Shimizu, H. Tanaka, J. Antibiot. 1983, 36, 109 – 114.
1
[26] All new compounds gave satisfactory H NMR, 13C NMR, and
IR spectra (except 11, 12) and correct combustion analyses
(except 11; low-resolution MS for 10; high-resolution MS for 12,
17–19).
[27] Aldehyde 5 is an intermediate of the industrial synthesis of
vitamin A by BASF.
[28] First SAE of an alkoxycarbonyl-substituted pentadienol:
T. Takahashi, H. Watanabe, T. Kitahara, Tetrahedron Lett.
2003, 44, 9219 – 9222.
Angew. Chem. Int. Ed. 2007, 46, 1160 –1163
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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