Total synthesis of korormicin

Article abstract of DOI:10.1002/1099-0690(200105)2001:10<1873::AID-EJOC1873>3.0.CO;2-O

Recently, we have assigned the (5S,3′R,9′S,10′R) stereochemistry to planar korormicin (1) on the basis of the specific rotations of the four possible diastereoisomers [i.e., (5S,3′R,9′S,10′R), (5S,3′S,9′S,10′R), (5S,3′S,9′R,10′S), and (5S,3′R,9′R,10′S) isomers], which were prepared by a total synthesis. In this article, we describe the synthetic aspects in detail. The intermediates in the synthesis are enamino lactone (5S)-4 and both enantiomers of acid 5 and of boronate ester 7. Lactone (5S)-4 and boronate 7 with (9′S,10′R) and (9′R,10′S) chiralities were prepared through asymmetric dihydroxylation of olefins 11 and 30, respectively, with AD-mix-α or -β. Compounds (3′R)- and (3′S)-5 were prepared by kinetic resolution of rac-19 with asymmetric epoxidation. Condensation of (5S)-4 and (3′R)- or (3′S)-5 with DCC in the presence of DMAP and PPTS furnished the advanced intermediate 6 with (5S,3′R) and (5S,3′S) chiralities in good yields. Addition of PPTS was important to prevent formation of acyl urea 24. A nickel-catalyzed coupling reaction between 6 and 8 [prepared in situ from (9′S,10′R)- or (9′R, 10′S)-7 and MeLi] produced 9, which upon deprotection with Bu₄NF furnished the four diastereoisomers of korormicin (1).

Full text of DOI:10.1002/1099-0690(200105)2001:10<1873::AID-EJOC1873>3.0.CO;2-O

FULL PAPER
Total Synthesis of Korormicin
Yuichi Kobayashi,*[a] Shinya Yoshida,[a] and Yuji Nakayama[a]
Keywords: Borates / Korormicin / Nickel / Total synthesis / Marine natural products
Recently, we have assigned the (5S,3ЈR,9ЈS,10ЈR) stereo-
mix-α or -β. Compounds (3ЈR)- and (3ЈS)-5 were prepared by
chemistry to planar korormicin (1) on the basis of the specific kinetic resolution of rac-19 with asymmetric epoxidation.
rotations of the four possible diastereoisomers [i.e.,
(5S,3ЈR,9ЈS,10ЈR), (5S,3ЈS,9ЈS,10ЈR), (5S,3ЈS,9ЈR,10ЈS), and
(5S,3ЈR,9ЈR,10ЈS) isomers], which were prepared by a total
Condensation of (5S)-4 and (3ЈR)- or (3ЈS)-5 with DCC in the
presence of DMAP and PPTS furnished the advanced inter-
mediate 6 with (5S,3ЈR) and (5S,3ЈS) chiralities in good yields.
synthesis. In this article, we describe the synthetic aspects in Addition of PPTS was important to prevent formation of acyl
detail. The intermediates in the synthesis are enamino lac-
tone (5S)-4 and both enantiomers of acid 5 and of boronate
urea 24. A nickel-catalyzed coupling reaction between 6 and
8 [prepared in situ from (9ЈS,10ЈR)- or (9ЈR,10ЈS)-7 and MeLi]
ester 7. Lactone (5S)-4 and boronate 7 with (9ЈS,10ЈR) and produced 9, which upon deprotection with Bu4NF furnished
(9ЈR,10ЈS) chiralities were prepared through asymmetric di-
hydroxylation of olefins 11 and 30, respectively, with AD-
the four diastereoisomers of korormicin (1).
Introduction
EtOH)}.[1a] The construction of the chiral centers of the
conjugated diene and the enaminolactone moiety is highly
efficient, and hence all of the stereoisomers can be obtained
stereospecifically. Herein, we would like to describe the syn-
thesis in detail.
Recently, Yoshikawa isolated korormicin from the bac-
terium Pseudoalteromonas sp. F-420. Korormicin has an in-
hibitory activity towards the growth of marine Gram-nega-
tive bacteria, whereas it is inactive against terrestrial micro-
organisms.[1] According to the authors, this unique activity
and specificity are of a sufficient level for use as a probe for Results and Discussion
the classification of unidentified marine bacteria. In addi-
Strategy for the Synthesis
tion, korormicin could be of use as a lead compound in the
development of effective drugs for fish in aquaculture
against diseases caused by Gram-negative bacteria. The
planar structure and geometries of the diene and the epox-
ide parts of korormicin were determined by the authors on
the basis of NMR and MS data as depicted in 1 (Fig-
ure 1).[1a] Consequently, clarification of the proposed struc-
ture and the absolute configuration was an urgent issue in
order to develop the potential of korormicin.
Since natural korormicin was not available to us, we used
the spectroscopic data (1H NMR and 13C NMR taken in
[D6]DMSO) and the specific rotation data published by
Yoshikawa. Eight stereoisomers exist in total for koror-
micin, and therefore four signals from any proton(s) and/or
carbon atom(s) should be detected separately in the NMR
spectra in order to differentiate the four possible diastereo-
isomers. We examined this by means of the NMR spectra
of korormicin synthesized as a diastereoisomeric mixture
from racemic fragments. In addition, the diastereoisomers
listed in Figure 2 were selected for comparison of their [α]D
values with that of natural korormicin.
Figure 1. Planar structure of korormicin (1)
Recently, we[2] and another group[3] have succeeded in the
determination of the chiral centers in korormicin. In our
investigation, a stereoselective synthesis of korormicin was
first developed, and then the specific rotations of the four
possible diastereoisomers were compared with the reported
value for natural korormicin {[α]2D6 ϭ Ϫ24.4 (c ϭ 0.29,
[a]
Department of Biomolecular Engineering,
Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
Fax: (internat.) ϩ 81-45/924-5789
E-mail: ykobayas@bio.titech.ac.jp
Figure 2. Possible stereoisomers of (5S)-korormicin
Eur. J. Org. Chem. 2001, 1873Ϫ1881
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0510Ϫ1873 $ 17.50ϩ.50/0
1873

Y. Kobayashi, S. Yoshida, Y. Nakayama
FULL PAPER
Recently, we reported a nickel-catalyzed coupling reac- whereas reaction of the lithium enolate derived from 15 and
tion between bulky alkenyl halides 2 and alkenyl borates 3 LDA with CBr4 at Ϫ78 °C resulted in dibromination. This
[Equation (1)],[4] and the reaction was applied to the con- is certainly caused by the fast proton transfer of α-bromo-
struction of the key intermediates in the synthesis of 10,11- lactone 16 to the enolate anion derived from lactone 15 com-
dihydroleukotriene B4 and related compounds.[5] The react- pared with the slow nucleophilic reaction of the enolate
ivity and the almost neutral character of the borates are with CBr4. Accordingly, nonnucleophilic conditions were
synthetic advantages of this reaction.[6,7] Accordingly, we examined, that is, enolate trapping of the lithium enolate
envisioned a sequence as in Scheme 1 to synthesize the dia- with TMSCl followed by reaction with Br2. Fortunately, the
stereoisomers of korormicin (Figure 2). In the following reaction proceeded cleanly at Ϫ78 °C as monitored by TLC
paragraphs, preparation of the requisite intermediates and to furnish α-bromolactone 16, which was a 1:1 diastereo-
1
synthesis of korormicin are described.
isomeric mixture by H NMR spectroscopy. Subsequently,
reaction of 16 with NaN3 in refluxing EtOH overnight af-
forded azide 17 which, upon treatment with NaOEt (0.1
equiv.) in EtOH, produced 4 in 58% yield from lactone 15.
(1)
Synthesis of the Key Intermediates
Synthesis of enaminolactone (5S)-4 was accomplished
successfully by a route summarized in Scheme 2[8] in which
the crucial step is construction of the enamine moiety onto
the lactone 15 by the method of Kraatz.[9] The
JohnsonϪClaisen rearrangement of 10 with MeC(OEt)3 at
150 °C afforded ester 11 stereoselectively.[10] Asymmetric di-
hydroxylation[11] (AD) of 11 with AD-mix-β produced diol
12,[12] which under the given basic conditions underwent
lactonization to yield lactone 13 with 95% ee[13] in good
yield. The hydroxy group in 13 was transformed into the
xanthate ester moiety, and the latter was removed under
radical conditions[14] to afford lactone 15 in 75% yield from
11.[15] Attempted bromination of 15 with the method of
Kraatz[9] (Br2 and PBr3 at 130 °C) gave a complex mixture, 15)
Scheme 2. (a) MeC(OEt)3 (5 equiv.), EtCO2H (10 mol-%), 150 °C,
3 d (81%); (b) AD-mix-β, MeSO2NH2, tBuOH/H2O, 0 °C; (c) CS2,
imidazole (cat.), NaH, THF then MeI (82% from 11); (d) Bu3SnH,
AIBN (cat.), toluene, reflux (92%); (e) (i) LDA, THF, Ϫ78 °C, (ii)
TMSCl, (iii) Br2; (f) NaN3, EtOH; (g) NaOEt, EtOH (58% from
Scheme 1. Strategy for synthesis of (5S)-korormicin
1874
Eur. J. Org. Chem. 2001, 1873Ϫ1881

Total Synthesis of Korormicin
FULL PAPER
Preparation of (3ЈR)-5 was previously reported by Sato
as a communication (Scheme 3).[16] The key alcohol (R)-19
in his synthesis is prepared by the kinetic resolution of rac-
19 using the Sharpless reagent[17] [tBuOOH, Ti(OPr)4, -
(ϩ)-diisopropyl tartrate (-(ϩ)-DIPT)]. In our research,
(R)- as well as (S)-19 with 99% ee were prepared in 38%
and 40% yields based on rac-19 with -(ϩ)- or -(Ϫ)-DIPT,
respectively. Both enantiomers of 19 were transformed into
(3ЈR)- and (3ЈS)-5 in good yields without any problems.
Scheme 4
nished the desired amide 26 and the acyl urea 27 in a ratio
of 9:1, a similar result to that described above. Formation
of such acyl ureas was reported by Keck[20] in their macro-
lactonization and intermolecular esterification under high-
dilution conditions. The problem was solved by addition of
DMAP·HCl which efficiently delivers a proton to the nitro-
gen anion before the rearrangement. This idea has also been
applied successfully in the synthesis of macrosphelides with
camphorsulfonic acid (CSA).[21] In our case, the condensa-
tion partner 4 is not an alcohol but an amine. Consequently,
it seemed important to find a selective acid, which effici-
ently quenches the nitrogen anion in 23 before the re-
arrangement and which does not protonate the nitrogen
atom in 4. With pTsOH or CSA, the reaction did not take
place, while the mild acid PPTS (0.3Ϫ0.5 equiv.) produced
26 in 63% yield without contamination with 27. Other re-
agents such as DCC/HOSu, EDC·HCl in CH2Cl2 or DMF,
EDC·HCl/Et3N in CH2Cl2 or DMF, (EtO)2P(ϭO)CN, and
2-ClϪN(Me)-Pyϩ·IϪ did not afford amide 26 perhaps be-
cause of the low reactivity of the intermediate toward the
nitrogen atom in 4, which is of low nucleophilicity due to
the conjugation of the enamine moiety with the carbonyl
group. The above conditions with PPTS were then applied
to the real partners [i.e., (5S)-4 with (3ЈR)- or (3ЈS)-5], and
(5S,3ЈR)- and (5S,3ЈS)-6 were obtained as sole products in
82% and 76% yields, respectively. Similarly, rac-4 and -5
produced 6 as a diastereomeric mixture in 70% yield.
Scheme 3. (a) LiCH2CO2Bu, Ϫ78 °C (93%); (b) tBuOOH, Ti-
(OPr)4, -(ϩ)-DIPT, Ϫ20 °C (38%); (c) 1  NaOH, THF/Et2O/
MeOH (1:1:1); (d) I2, NaHCO3 aq., THF/Et2O/MeOH (1:1:1) [94%
from (R)-19]; (e) Bu4NF, THF, Ϫ10 °C; (f) TBSCl, imidazole,
DMF; (g) K2CO3, MeOH, room temp., 1 h (78% from 20); (h)
tBuOOH, Ti(OPr)4, -(Ϫ)-DIPT, Ϫ20 °C (40%)
The reaction conditions for DCC condensation to yield
amide 6 (Scheme 1) were explored by using the racemic
partners, that is, enamine rac-4 and acid rac-5, as it was
feared that the intramolecular attack of the nitrogen anion
of 23 on to the carbonyl carbon atom would produce the
acyl urea 24 as a by-product (Scheme 4). In practice, the
amide 6 was produced in 84% yield by means of the proced-
ure of Steglich[18] [DCC (1.2 equiv.) and 4-dimethylamino-
pyridine (DMAP, 0.2 equiv.) in CH2Cl2] with approximately
10% of the acyl urea 24,[19] and these products were insepar-
able by chromatography on silica gel. To make matters
worse, transformation of 6 to diene 9 and subsequently to
korormicin (1) was contaminated by the compounds de-
rived from urea 24, as compound 24 and amide 6 have the
same iodovinyl moiety. Chromatographic separations of the
desired products (9 and 1) and the by-products after the
coupling reaction and after the subsequent deprotection
were found to be difficult.
(2)
In order to circumvent this situation, condensation of
rac-4 and acid 25 was studied as a model system [Equa-
tion (2)]. The conditions of Steglich[18] (DCC/DMAP) fur-
Eur. J. Org. Chem. 2001, 1873Ϫ1881
1875

Y. Kobayashi, S. Yoshida, Y. Nakayama
FULL PAPER
Both enantiomers of boronate ester 7 were prepared ac-
cording to the sequence illustrated in Scheme 5, the neces-
sary chiral centers were constructed on olefin 30 by using
AD-mix-α or -β.[11] Nonanal (28) was converted into alco-
hol 29 in 89% yield[22] by Wittig reaction with (EtO)2P(ϭ
O)CH2CO2Et followed by reduction with DIBAL. Chlor-
ination[23] of allylic alcohol 29 and subsequent dihy-
droxylation of 30 using AD-mix-α afforded syn-diol 31 in
good yield. Without purification, 31 was exposed to
crushed NaOH in THF to produce epoxy alcohol 32 in 90%
ee.[13] Mesylation of 32 and subsequent epoxide ring open-
ing[24] with the reagent derived from TMSCϵCLi and
BF3·OEt2 gave the unstable acetylenic alcohol 34 which, on
treatment with K2CO3 in MeOH, underwent the epoxide
ring formation and, concomitantly, desilylation to produce
epoxide 35 in 69% yield from epoxy alcohol 32. Trans-
formation of the acetylenic part of 35 into the vinyl-
boronate moiety was accomplished stereoselectively by hy-
droboration with (Ipc)2BH (Ipc: isopinocampheyl) followed
by oxidation with excess MeCHO according to the
SuzukiϪMiyaura reaction.[25] Ligand exchange of the re-
sulting diethyl boronate ester 36 with 2,2-dimethyl-1,3-pro-
panediol furnished (9ЈS,10ЈR)-7 in 64% yield from epoxide
35.
The synthesis of (9ЈR,10ЈS)-7 was performed with the
same methodology through epoxide ent-32 derived from
diol ent-31 which, in turn, was prepared by AD reaction of
olefin 30 using AD-mix-β. The enantiomeric purity of ep-
oxide ent-32 was Ͼ 99% ee.[13] In addition, racemic diol rac-
31 was prepared from 30 with OsO4 (cat.) and NMO in
95% yield, and was transformed into racemic epoxide rac-7
(structures of rac-31 and -7 are not shown).
Synthesis of Korormicin
Scheme 5. (a) (EtO)2P(ϭO)CH2CO2Et, NaH, THF; (b) DIBAL,
Ϫ70 °C (89% from 28); (c) CCl4, PPh3 (81%); (d) AD-mix-α,
MeSO2NH2, 0 °C; (e) NaOH (5 equiv.), THF, room temp., 30 min
(32, 84% from 30; ent-32, 73%); (f) MsCl, NEt3, CH2Cl2, 0 °C; (g)
(i) TMSCϵCH (1.7 equiv.), nBuLi (1.5 equiv.), (ii) BF3·OEt2 (1.7
equiv.), Ϫ78 °C, (iii) 33, Ϫ78 °C, 30 min; (h) K2CO3 (3 equiv.),
MeOH, room temp., 4 h (35, 69% from 32; ent-35, 58% from ent-
32); (i) (Ipc)2BH (1.2 equiv.), THF, then MeCHO (15 equiv.), 40 °C
(reflux), overnight; (j) HOCH2C(Me)2CH2OH, THF [(9ЈS,10ЈR)-
7, 64% from 35; (9ЈR,10ЈS)-7, 76% from ent-35]; (k) AD-mix-β,
MeSO2NH2, 0 °C
We were now ready for the coupling reaction proposed
in Scheme 1 to furnish korormicin (1). First, the racemic
intermediates were used in order to examine the reaction
conditions and to check whether the NMR method men-
tioned above met our requirements. Concomitant trans-
formation of boronate ester rac-7 (1.4 equiv. per 6) and
NiCl2(PPh3)2 (15 mol-%) into lithium borate rac-8 and a
Ni0 catalyst was effected by addition of MeLi (1.6 equiv.)
(0 °C, 15 min) and a subsequent coupling reaction with a
diastereoisomeric mixture of iodide 6 at room temperature
as described before[4] to afford diene 9. No contamination solved into four peaks corresponding to the four diastereo-
of the geometric isomers or formation of other by-prod- isomers. Several carbon atom signals of 1 and 9 in the 13C
uct(s) which might be produced by attack of MeLi on the NMR spectra and the C(5) methyl proton signals of 9 in
epoxide function of 7 occurred. The cis,trans geometry of 1H NMR spectrum were actually resolved, but only into
the diene was confirmed by the coupling constants in the two lines with ∆δ Ͻ 0.2 ppm for the carbon atoms and Ͻ
1H NMR spectrum: J4ЈϪ5Ј ϭ 11 Hz, J6ЈϪ7Ј ϭ 15 Hz. Finally, 0.02 ppm for the protons. These results indicate that the
1
reaction of 9 with Bu4NF induced deprotection to afford 1 NMR approach at 300 MHz (for H) is insufficient for de-
as a mixture of diastereoisomers in 35% yield from iodide termination of the stereochemistry.
1
6. The H (300 MHz) and 13C NMR spectra of synthetic
Next, the synthesis of the diastereoisomers listed in Fig-
product 1 in [D6]DMSO were fully consistent with the data ure 2 was carried out with the enantiomerically enriched
reported for natural 1.[1a]
intermediates prepared in Schemes 3, 5, and 6 for the se-
We then carefully scanned the expanded spectra of 1 in cond study, that is, a comparison of their [α]D values with
[D6]DMSO and CDCl3 and those of 9 in CDCl3 to find that for natural korormicin. The results are summarized in
any signals of proton(s) and/or carbon atom(s) clearly re- Scheme 6.
1876
Eur. J. Org. Chem. 2001, 1873Ϫ1881

Total Synthesis of Korormicin
FULL PAPER
Scheme 6. Synthesis of the four diastereoisomers of 1; specific rotations are calculated from the measured [α]D values shown in parentheses
based on the (R)/(S) chirality ratio at each of the chiral centers: (a) 7 (1.5 equiv. based on 6), MeLi (1.8 equiv.), NiCl2(dppf) (10Ϫ15
mol-%), THF, 0 °C, 15 min; (b) 6, room temp., 4 h (46Ϫ56% based on 6); (c) Bu4NF (2 equiv.), THF, room temp., 30 min (76Ϫ94%)
Since the stereoisomeric purity of boronate esters 7 and reaction for the synthesis of sterically congested conjugated
iodide 6 did not exceed 99%, the measured [α]D values given olefin systems frequently seen in other natural products
in the parentheses are corrected for the pure stereoisomers such as fostriecin and didemnilactone.
by a linear calculation of the measured values after consid-
eration of the (R)/(S) chirality ratio at each of the chiral
centers. The value obtained from the (5S,3ЈR,9ЈS,10ЈR) iso-
Experimental Section
mer (Ϫ24.5) is the closest to that for natural korormicin
(Ϫ24.4)[1a] and all the other values are outside the range of
General: The following solvents were distilled before use: THF
error of Ϯ 2 degrees; hence, this isomer is the natural koror-
micin.
(from Na/benzophenone), Et2O (from Na/benzophenone), and
CH2Cl2 (from CaH2). N,N-Dimethylformamide (DMF) was dried
with CaH2. Routinely, organic extracts were dried with MgSO4 and
concentrated using a rotary evaporator to leave residues, which
were purified by chromatography on silica gel purchased from
Merck (Silicagel 60). Ϫ Infrared (IR) spectra are reported in wave
numbers (cmϪ1). Ϫ The 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were measured in CDCl3 with SiMe4 (δ ϭ 0) and
the center line of CDCl3 triplet (δ ϭ 77.1) as internal standards, re-
spectively.
Conclusion
In summary, the synthesis of korormicin has been estab-
lished. The three key intermediates shown in Scheme 1 have
been prepared efficiently by the AD reaction of 11 and 30
with AD-mix-α and/or -β or the kinetic resolution of rac-
19 using asymmetric epoxidation to give high enantiomeric
excess of 95% for (5S)-4, 99% for (3ЈR)- and (3ЈS)-5, 90%
for (9ЈS,10ЈR)-7, and Ͼ 99% for (9ЈR,10ЈS)-7. Other olefins
with similar structures to 11, rac-19, and 30 may also un-
dergo these key reactions to provide synthetic analogues of
1, and give useful compounds useful in the research field(s)
of biochemistry. In addition, the construction of the diene
by coupling reaction of iodide 6 and boronate ester 7 with
Ethyl (E)-Methylhex-4-enoate (11): To an ice-cold solution of
MeMgI in Et2O (67 mL, 1.98 , 133 mmol), methacrolein (8.47 g,
121 mmol), dissolved in Et2O (60 mL), was added dropwise. After
the addition, the solution was stirred at 0 °C for 30 min and the
mixture was poured into a mixture of 1  HCl and Et2O. The layers
were separated, and the aqueous layer was extracted with Et2O.
The combined extracts were washed with NaHCO3 and dried. The
solvent was removed by distillation at 1 atm to leave a residue
which was distilled at reduced pressure to afford 10 (8.3 g, 80%).
the Ni catalyst demonstrates the potential usefulness of this Ϫ B.p. 70 °C (50 Torr). Ϫ 13C NMR: δ ϭ 149.1, 109.6, 71.6, 21.6,
Eur. J. Org. Chem. 2001, 1873Ϫ1881 1877

Y. Kobayashi, S. Yoshida, Y. Nakayama
FULL PAPER
1
17.8. Ϫ The H NMR spectrum is identical with that reported[10]
resulting mixture was warmed up to 0 °C over 1 h to produce the
and is updated: δ ϭ 1.25 (d, J ϭ 7 Hz, 3 H), 1.72 (s, 3 H), 1.9 (br. silyl enol ether, which was used for the next reaction without isola-
s, 1 H), 4.20Ϫ4.25 (m, 1 H), 4.76 (s, 1 H), 4.93 (s, 1 H). Ϫ A tion. Ϫ The above solution was cooled again to Ϫ78 °C and Br2
mixture of 3-methyl-2-butanol (10) (7.5 g, 87 mmol), MeC(OEt)3
(2.23 g, 14.0 mmol) was added. The mixture was allowed to warm
(70.8, 436 mmol), and EtCO2H (650 mg, 8.6 mmol) in a sealed tube up to room temperature over 30 min and then the solution was
was stirred at 150 °C for 3 d and poured into 1  HCl. The resulting
mixture was extracted with EtOAc three times, and the combined
extracts were dried and concentrated to afford a residue, which was
poured into a mixture of saturated NaHCO3 and EtOAc with vig-
orous stirring. The organic layer was separated and the aqueous
layer was extracted with EtOAc three times. The combined organic
distilled to give 11 (11.02 g, 81%). Ϫ B.p. 130 °C (20 Torr) [ref.[10] layers were washed with aqueous Na2S2O3 and dried. Evaporation
90 °C (0.5 Torr)]. Ϫ The 1H NMR spectrum of the product is ident-
of the solvents gave a residue which was semi-purified by chromato-
ical with the data reported.[10]
Ϫ
13C NMR: δ ϭ 173.8, 134.2, graphy (hexane/EtOAc) to afford α-bromolactone 16. Ϫ IR (neat):
1
119.4, 60.3, 34.7, 33.2, 15.5, 14.2, 13.3.
ν˜ ϭ 1770, 945 cmϪ1. Ϫ H NMR: δ ϭ 0.95 and 0.98 (2t, J ϭ 7.5
and 7.5 Hz, 3 H), 1.37 and 1.55 (2s, 3 H), 1.60Ϫ1.95 (m, 2 H), 2.37
and 2.44 (2dd, J ϭ 14, 6 and 15, 8 Hz, 1 H), 2.64 and 2.76 (2dd,
J ϭ 14, 9 and 15, 9 Hz, 1 H), 4.57 and 4.64 (2dd, J ϭ 9, 6 and 9,
8 Hz, 1 H). Ϫ 13C NMR: δ ϭ 172.7 and 172.5, 87.0 and 86.8, 43.4
and 43.1, 38.2 and 38.0, 34.1 and 33.8, 25.7 and 25.1, 8.02 and
7.99. Ϫ A mixture of the above bromide, NaN3 (2.28 g, 35.1 mmol),
and EtOH (20 mL) was stirred overnight under reflux and filtered
through a pad of Celite with EtOAc. The filtrate was concentrated
to give a residue, which was diluted with brine. The resulting mix-
ture was extracted three times with EtOAc. The combined extracts
were dried and concentrated to afford a somewhat unstable α-azi-
dolactone 17, which was used for the next reaction without further
purification. Ϫ To a solution of NaOEt in EtOH, prepared from
sodium (50 mg, 0.0022 g-atom) and EtOH (20 mL), was added a
solution of unpurified 17, dissolved in EtOH (10 mL). After 30
min of stirring at room temperature, the solvent was removed by
evaporation to give a residue, which was suspended in saturated
NH4Cl. The resulting mixture was extracted three times with
EtOAc, and the combined organic layers were dried and concen-
trated. The residual viscous oil was purified by chromatography
(hexane/EtOAc) to afford enaminolactone (5S)-4 (0.96 g, 58% from
15). Ϫ [α]2D6 ϭ Ϫ25 (c ϭ 0.96, CHCl3). Ϫ IR (nujol): ν˜ ϭ 3448,
3359, 1739, 1668 cmϪ1. Ϫ 1H NMR: δ ϭ 0.82 (t, J ϭ 7.5 Hz, 3 H),
1.38 (s, 3 H), 1.58Ϫ1.81 (m, 2 H), 3.71 (br. s, 2 H), 5.79 (s, 1 H).
S-Methyl
(1R,2ЈR)-O-[1-(2Ј-Methyl-5Ј-oxotetrahydrofuran-2-yl)-
ethyl]dithiocarbonate (14): To an ice-cold mixture of AD-mix-β
(27 g) and MeSO2NH2 (1.83 g, 19.2 mmol) in tBuOH (100 mL) and
H2O (100 mL), 11 (3.00 g, 19.2 mmol) was added dropwise. The
mixture was stirred at 0 °C overnight and the excess reagent was
destroyed with NaHSO3 (25 g, 240 mmol). The resulting mixture
was extracted twice with EtOAc and the combined extracts were
dried and concentrated. The residue was semi-purified after pas-
sage through a short column of silica gel first with hexane and then
with CHCl3 to afford lactone 13, 95% ee by 1H NMR spectroscopy
of the derived MTPA ester. Product 13 was used for the next reac-
tion without further purification, and an analytically pure sample
was obtained by chromatography (hexane/EtOAc). Ϫ 1H NMR:
δ ϭ 1.23 (d, J ϭ 6 Hz, 3 H), 1.37 (s, 3 H), 1.86Ϫ1.98 (m, 1 H),
2.20Ϫ2.32 (m, 1 H), 2.32Ϫ2.54 (m, 1 H), 2.56Ϫ2.73 (m, 2 H),
3.71Ϫ3.80 (m, 1 H). Ϫ 13C NMR: δ ϭ 177.3, 88.9, 72.9, 30.5, 29.3,
21.1, 17.0. Ϫ To an ice-cold solution of the above lactone 13, CS2
(4.41 g, 57.9 mmol), and imidazole (65 mg, 0.95 mmol) in THF
(40 mL), NaH (1.7 g, 50% suspension in mineral oil, 35 mmol) was
added in portions. The ice/water bath was removed and stirring was
continued for 1 h. The mixture was immersed into an ice/water bath
again, and MeI (6.84 g, 48.2 mmol) was added. The resulting mix-
ture was stirred at room temperature for 30 min and poured into
saturated NH4Cl with EtOAc. The product was extracted with
EtOAc repeatedly, and the combined extracts were dried and con-
centrated to give a residue which was purified by chromatography
(hexane/EtOAc) to afford 14 (3.69 g, 82% from 11). Ϫ [α]2D9 ϭ ϩ49
(c ϭ 0.86, CHCl3). Ϫ IR (nujol): ν˜ ϭ 1759, 1045 cmϪ1. Ϫ 1H
NMR: δ ϭ 1.39 (d, J ϭ 7 Hz, 3 H), 1.46 (s, 3 H), 2.00 (ddd, J ϭ
13 Hz, 10, 8 Hz, 1 H), 2.23 (ddd, J ϭ 13 Hz, 10, 6 Hz, 1 H), 2.56
(s, 3 H), 2.48Ϫ2.73 (m, 2 H), 5.77 (q, J ϭ 6.5 Hz, 1 H). Ϫ 13C
NMR: δ ϭ 215.7, 176.6, 86.4, 83.7, 31.1, 29.1, 23.9, 19.2, 13.9.
Ϫ
13C NMR: δ ϭ 170.8, 132.6, 119.7, 86.5, 32.5, 24.9, 8.1. Ϫ
C7H11NO2 (141.2): calcd. C 59.56, H 7.85; found C 59.80, H 7.85.
Butyl (E)-3-Hydroxy-5-trimethylsilyl-4-pentenoate (rac-19): To an
ice-cold solution of iPr2NH (2.86 g, 28.2 mmol) in THF (50 mL)
was added nBuLi (10.3 mL, 2.50  in hexane, 25.8 mmol). The mix-
ture was stirred for 15 min, and then the solution was cooled to
Ϫ78 °C and n-butyl acetate (3.00 g, 25.8 mmol) was added. The
solution was stirred at Ϫ78 °C for 30 min, and aldehyde 18[26]
(3.00 g, 23.4 mmol) was added. The resulting solution was stirred
at Ϫ78 °C for 10 min and poured into a mixture of Et2O and
saturated NH4Cl with vigorous stirring. The layers were separated,
and the aqueous layer was extracted three times with EtOAc. The
combined organic layers were dried and concentrated to leave an
oil, which was purified by chromatography to afford alcohol rac-
19 (5.32 g, 93%). Ϫ IR (neat): ν˜ ϭ 3448, 1738, 867, 839 cmϪ1. Ϫ
1H NMR: δ ϭ 0.05 (s, 9 H), 0.92 (t, J ϭ 7 Hz, 3 H), 1.36 (sext,
J ϭ 7 Hz, 2 H), 1.60 (quint, J ϭ 7 Hz, 2 H), 2.48 (dd, J ϭ 16,
8 Hz, 1 H), 2.58 (dd, J ϭ 16, 4 Hz, 1 H), 3.03 (d, J ϭ 5 Hz, 1 H),
4.10 (t, J ϭ 7 Hz, 1 H), 4.45Ϫ4.55 (m, 1 H), 5.93 (dd, J ϭ 19,
1 Hz, 1 H), 6.03 (dd, J ϭ 19, 4 Hz, 1 H). Ϫ 13C NMR: δ ϭ 172.7,
146.0, 130.5, 70.4, 64.7, 41.0, 30.6, 19.1, 13.6, Ϫ1.50.
(S)-4-Methyl-4-hexanolide (15):
A
mixture of 14 (3.98 g,
17.0 mmol), Bu3SnH (7.45 g, 25.5 mmol), and AIBN (30 mg,
0.18 mmol) in toluene (200 mL) was stirred overnight under reflux
and concentrated to leave an oil, which was purified by chromato-
graphy (hexane/EtOAc) followed by distillation to afford 15 (2.0 g,
92%). Ϫ B.p. 150 °C (10 Torr). Ϫ [α]2D9 ϭ Ϫ9.5 (c ϭ 0.80, CHCl3).
Ϫ IR (neat): ν˜ ϭ 1770, 1165, 937 cmϪ1. Ϫ H NMR: δ ϭ 0.93 (t,
1
J ϭ 7.5 Hz, 3 H), 1.34 (s, 3 H), 1.56Ϫ1.77 (m, 2 H), 1.94 (ddd, J ϭ
13 Hz, 10, 7 Hz, 1 H), 2.04 (ddd, J ϭ 13 Hz, 10, 9 Hz, 1 H), 2.53
(ddd, J ϭ 18, 9, 7 Hz, 1 H), 2.60 (ddd, J ϭ 18, 9, 8 Hz, 1 H). Ϫ
13C NMR: δ ϭ 177.1, 87.2, 33.5, 32.3, 29.1, 25.0, 8.0. Ϫ C7H12O2
(128.2): calcd. C 65.60, H 9.44; found C 65.31, H 9.48.
(S)-2-Aminohex-2-en-4-olide [(5S)-4]: To an ice-cold solution of
iPr2NH (1.78 g, 17.6 mmol) in THF (15 mL) was added nBuLi
(6.2 mL, 2.26  in hexane, 14 mmol). The solution was stirred for
30 min, and then cooled to Ϫ78 °C, and lactone 15 (1.50 g,
11.7 mmol) was added. The solution was stirred at Ϫ78 °C for a
further 1 h, and then TMSCl (1.91 g, 17.6 mmol) was added. The
Kinetic Resolution of rac-19: To a solution of Ti(OiPr)4 (5.83 g,
20.5 mmol) in CH2Cl2 (200 mL) at Ϫ20 °C was added -(ϩ)-DIPT
(5.77 g, 24.6 mmol). The solution was stirred at Ϫ20 °C for 10 min,
and rac-19 (5.01 g, 20.5 mmol) was added to the solution. Stirring
was continued at Ϫ20 °C for 10 min, and tBuOOH (6.5 mL, 4.74
1878
Eur. J. Org. Chem. 2001, 1873Ϫ1881

Total Synthesis of Korormicin
FULL PAPER
 in CH2Cl2, 30.8 mmol) was added slowly to the solution. The
solution was left at Ϫ20 °C overnight and the reaction was termin-
Amide (5S,3ЈR)-6: To
0.56 mmol, 99% ee), (5S)-4 (76 mg, 0.54 mmol, 95% ee), DMAP
a
solution of acid (3ЈR)-5 (200 mg,
ated by the addition of Me2S (4.4 g, 68 mmol). After 30 min at Ϫ20 (13 mg, 0.11 mmol), and PPTS (40 mg, 0.16 mmol) in CH2Cl2
°C, 10% aqueous tartaric acid (20 mL), NaF (20 g, 476 mmol), and
Celite (20 g) were added to the solution. The resulting mixture was
stirred at room temperature overnight and filtered through a pad
of Celite with Et2O. The filtrate was concentrated and the residue
was purified by chromatography to afford (R)-19 (1.90 g, 38%
(1 mL) was added a solution of DCC (130 mg, 0.63 mmol) in
CH2Cl2 (0.7 mL). The resulting mixture was stirred at room tem-
perature overnight and concentrated to leave an oil, which was
purified by chromatography (hexane/EtOAc) to afford (5S,3ЈR)-6
(209 mg, 82%). Ϫ [α]2D8 ϭ Ϫ25 (c ϭ 0.978, CHCl3). Ϫ IR (neat):
1
1
based on rac-19), which was 99% ee by H NMR spectroscopy of
ν˜ ϭ 3319, 1751, 1693, 1655 cmϪ1. Ϫ H NMR: δ ϭ 0.09 (s, 6 H),
the derived MTPA ester.
0.85 (t, J ϭ 7.5 Hz, 3 H), 0.87 (s, 9 H), 1.47 (s, 3 H), 1.7Ϫ1.9 (m,
2 H), 2.52 (dd, J ϭ 14, 7 Hz, 1 H), 2.61 (dd, J ϭ 14, 4 Hz, 1 H),
4.79 (dt, J ϭ 4, 7 Hz, 1 H), 6.26Ϫ6.37 (m, 2 H), 7.34 (s, 1 H), 8.23
(br. s, 1 H). Ϫ 13C NMR: δ ϭ 169.3, 169.2, 142.2, 134.0, 124.8,
88.4, 82.1, 73.3, 43.7, 32.0, 25.7, 24.4, 17.9, 8.1, Ϫ4.5, Ϫ5.1. Ϫ
C18H30INO4Si (479.4): calcd. C 45.09, H 6.31; found C 45.26, H
6.45.
(3R,4R,5R)- and (3R,4S,5S)-3-Hydroxy-5-iodo-5-trimethylsilyl-4-
pentanolide (20): A mixture of alcohol (R)-19 (1.49 g, 6.10 mmol),
THF (6 mL), Et2O (6 mL), MeOH (6 mL), and 1  NaOH (9.0 mL,
9.0 mmol) was stirred at room temperature overnight and 1  HCl
(ca. 15 mL) was added dropwise until the solution became acidic.
The mixture was extracted with CHCl3 repeatedly and the com-
bined organic layers were dried and concentrated to furnish the
corresponding acid, which was used for the next reaction without
further purification. Ϫ To an ice-cold mixture of the above acid,
THF (6 mL), Et2O (6 mL), MeOH (6 mL), and saturated NaHCO3
(15 mL), crushed I2 (2.33 g, 9.2 mmol) was added. The mixture was
stirred at 0 °C for 30 min and poured into a mixture of CHCl3 and
aqueous Na2S2O3. The layers were separated, and the aqueous
layer was extracted with CHCl3 three times. The combined organic
layers were dried and concentrated to give a yellow solid, which
was purified by chromatography to furnish iodolactone 20 [1.80 g,
94% from (R)-19] as a diastereomeric mixture. Ϫ 1H NMR: δ ϭ
0.22 (s, 9 H), 2.48 and 2.59 (dd and d, J ϭ 19, 4 and 18 Hz, 1 H),
2.77 and 2.97 (2dd, J ϭ 18, 5 and 19, 8 Hz, 1 H), 3.09 and 3.59
(2d, J ϭ 5 and 5 Hz, 1 H, OH), 3.28 and 3.39 (2d, J ϭ 6 and
12 Hz, 1 H), 4.31 and 4.51 (2dd, J ϭ 6, 3 and 12, 3 Hz, 1 H),
4.37Ϫ4.45 and 4.68Ϫ4.74 (2m, 1 H). Ϫ 13C NMR: δ ϭ 176.5 and
175.5, 88.3 and 85.8, 72.5 and 69.3, 39.0 and 38.5, 20.5 and 12.3,
Ϫ1.14 and Ϫ1.37.
Amide (5S,3ЈS)-6: According to the above procedure, the title com-
pound was prepared from (5S)-4 and (3ЈS)-5 in 77% yield. Ϫ
1
[α]2D7 ϭ Ϫ1 (c ϭ 1.02, CHCl3). The H and 13C NMR spectra are
superimposed with those of (5S,3ЈR)-6.
Ethyl (E)-2-Undecenoate: To an ice-cold suspension of NaH
(3.10 g, 55% suspension in mineral oil, 71.0 mmol) in THF
(100 mL) was added triethyl phosphonoacetate (21.5 g, 95.8 mmol)
and the mixture was warmed up to room temperature over 30 min
with stirring. 1-Nonanal (28) (8.30 g, 58.4 mmol) was added, and
the mixture was stirred at room temperature for 10 min. Brine was
added and the resulting mixture was extracted three times with
Et2O. The combined extracts were dried and concentrated to give
an oily residue, which was purified by chromatography to afford
ethyl (E)-2-undecenoate as an oil, the 1H NMR spectrum of which
is identical with those reported previously.[22] The 1H NMR and
other spectroscopic data of the ester are updated. Ϫ IR (neat): ν˜ ϭ
1724, 1655 cmϪ1. Ϫ 1H NMR: δ ϭ 0.86 (t, J ϭ 7 Hz, 3 H),
1.18Ϫ1.38 (m, 13 H), 1.38Ϫ1.49 (m, 2 H), 2.17 (dq, J ϭ 2, 7 Hz,
2 H), 4.17 (q, J ϭ 7 Hz, 2 H), 5.79 (dt, J ϭ 15, 2 Hz, 1 H), 6.95
(dt, J ϭ 15, 7 Hz, 1 H). Ϫ 13C NMR: δ ϭ 167.0, 149.7, 121.4, 60.1,
32.2, 31.8, 29.3, 29.2, 29.1, 28.0, 22.6, 14.2, 14.0.
(3R,4Z)-[3-(tert-Butyldimethylsilyl)oxy]-5-iodo-4-pentenoic
Acid
[(3ЈR)-5]: To a solution of lactone 20 (1.51 g, 4.81 mmol) in THF
(20 mL) was added dropwise TBAF (7.2 mL, 1.0  in THF,
7.2 mmol) at Ϫ10 °C. The solution was stirred at Ϫ10 °C for 1 h
and poured into a mixture of CHCl3 and 1  HCl with vigorous
stirring. The layers were separated and the aqueous layer was ex-
tracted with CHCl3 repeatedly. The combined organic layers were
dried and concentrated to afford acid 21 as a viscous oil, which
was used for the next reaction without further purification. Ϫ A
mixture of acid 21, TBSCl (1.84 g, 12.2 mmol), imidazole (0.98 g,
14.4 mmol), and DMF (10 mL) was stirred at room temperature
overnight. Brine and hexane were added. The resulting mixture was
stirred for 1 h and extracted with hexane three times. The combined
organic layers were dried and concentrated to give silyl ester 22,
which was used for the next reaction without further purification.
Ϫ A mixture of the silyl ester 22 and K2CO3 (1.00 g, 7.24 mmol)
in MeOH (20 mL) was stirred at room temperature for 1 h and
diluted with EtOAc. The resulting mixture was acidified slightly by
addition of 1  HCl and the product was extracted with EtOAc
repeatedly. The combined organic layers were dried and concen-
trated to give an oily residue, which was purified by chromato-
graphy to furnish a mixture of acid (3ЈR)-5 and TBSOH. The
quantity of the products was calculated by using the 1H NMR
(E)-2-Undecen-1-ol (29): To a solution of the above ethyl ester, dis-
solved in THF (100 mL), DIBAL (154 mL, 0.95  in toluene,
146 mmol) was added dropwise at Ϫ70 °C. The mixture was stirred
at Ϫ70 °C for 1 h, and the solution was poured into a mixture of
EtOAc and 1  HCl at 0 °C with vigorous stirring. The layers were
separated and the aqueous layer was extracted with EtOAc three
times. The combined organic layers were dried and concentrated to
furnish an oily residue, which was purified by distillation to afford
1
alcohol 29 (8.86 g) in 89% yield from 28. The H NMR spectrum
of 29 is identical with the data reported.[22] Other data of 29 are
provided. Ϫ B.p. 150 °C (5 Torr). Ϫ IR (neat): ν˜ ϭ 3325, 970 cmϪ1
Ϫ
.
13C NMR: δ ϭ 133.8, 129.0, 63.9, 32.2, 31.9, 29.5, 29.3, 29.2,
29.1, 22.7, 14.1.
(E)-1-Chloro-2-undecene (30): A mixture of 29 (3.00 g, 17.6 mmol),
PPh3 (6.92 g, 26.4 mmol), and CCl4 (9 mL) was stirred at room
temperature for 4 d, diluted with hexane, and filtered through a
pad of Celite with hexane. The filtrate was concentrated to give an
oil, which was purified by chromatography (hexane) to afford 30
1
(2.68 g, 81%). Ϫ IR (neat): ν˜ ϭ 1250, 966 cmϪ1. Ϫ H NMR: δ ϭ
integration. (3ЈR)-5 (1.33 g, 78% yield from iodolactone 20) and
TBSOH (125 mg). Ϫ (3ЈR)-5: H NMR: δ ϭ 0.07 and 0.10 (2 s, 6 H), 4.03 (dt, J ϭ 7, 1 Hz, 2 H), 5.61 (dt, J ϭ 15, 7 Hz, 1 H), 5.76
H), 0.86 (s, 9 H), 2.49Ϫ2.61 (m, 2 H), 4.83 (q, J ϭ 6 Hz, 1 H),
6.25Ϫ6.34 (m, 2 H). Ϫ This mixture was used for the next reaction
without further purification.
0.88 (t, J ϭ 7 Hz, 3 H), 1.20Ϫ1.44 (m, 12 H), 2.05 (q, J ϭ 7 Hz, 2
1
(dt, J ϭ 15, 7 Hz, 1 H). Ϫ 13C NMR: δ ϭ 136.5, 126.0, 45.6, 32.1,
31.9, 29.4, 29.2, 29.1, 28.8, 22.7, 14.1. Ϫ C11H21Cl (188.7): calcd.
C 70.00, H 11.21; found C 70.28, H 11.34.
Eur. J. Org. Chem. 2001, 1873Ϫ1881
1879

Y. Kobayashi, S. Yoshida, Y. Nakayama
FULL PAPER
(2R,3S)-1-Chloroundecane-2,3-diol (31): To an ice-cold mixture of
AD-mix-α (28 g) and MeSO2NH2 (1.90 g, 20.0 mmol) in tBuOH
(100 mL) and H2O (100 mL), 30 (3.78 g, 20.0 mmol) was added
dropwise. The mixture was stirred at 0 °C for 24 h and the excess
reagent was destroyed with NaHSO3 (28 g, 270 mmol) at 0 °C for
30 min. The product was extracted with EtOAc twice. The com-
bined extracts were washed with 2  KOH to remove most of the
MeSO2NH2. The mixture was then dried, and concentrated to fur-
nish diol 31, which was used for the next reaction without further
purification. An enantiomeric excess of 90% was later determined
at the stage of epoxy alcohol 32 (vide infra). Analytically pure 31
was obtained by chromatography. Ϫ IR (nujol): ν˜ ϭ 3367, 3275
18.5, 14.1. Ϫ C13H22O (194.3): calcd. C 80.35, H 11.41; found C
80.02, H 11.42.
(1ЈE,4ЈS,5ЈR)-2-(4Ј,5Ј-Epoxy-1Ј-tridecenyl)-5,5-dimethyl-1,3,2-
dioxaborinane [(9ЈS,10ЈR)-7]: To an ice-cold solution of BH3·SMe2
(3.0 mL, 2.0  in THF, 6.0 mmol) was added (Ϫ)-α-pinene (2.05 g,
15.0 mmol). After stirring at 0 °C for 1 h, a white precipitate was
observed. The ice bath was removed and the mixture was stirred
for an additional 2 h to ensure complete formation of (Ipc)2BH.
The mixture was cooled to Ϫ30 °C and acetylene 35 (928 mg,
4.78 mmol) was added. The resulting mixture was allowed to warm
up to 0 °C over 2 h with stirring to complete the hydroboration.
To this solution acetaldehyde (3.31 g, 75.1 mmol) was added and
the solution was heated under gentle reflux (bath temperature ca.
40 °C) overnight. The volatile compounds were removed in vacuo
to leave 36 as a viscous oil, which was used for the next reaction
without further purification. Ϫ A solution of 36 and 2,2-dimethyl-
1,3-propanediol (575 mg, 5.52 mmol) in THF (10 mL) was stirred
at room temperature for 3 h, and concentrated to furnish a mixture
of the desired product and Ipc-OH, from which Ipc-OH was re-
moved by bulb-to-bulb distillation [100Ϫ110 °C (1 Torr), 1Ϫ2 h].
Finally, the residue was purified by chromatography (hexane/
EtOAc) to afford (9ЈS,10ЈR)-7 (940 mg, 64%). Ϫ [α]2D6 ϭ ϩ21 (c ϭ
0.928, CHCl3). Ϫ IR (neat): ν˜ ϭ 1639, 1090, 999 cmϪ1. Ϫ 1H
NMR: δ ϭ 0.87 (t, J ϭ 7 Hz, 3 H), 0.96 (s, 6 H), 1.20Ϫ1.58 (m,
14 H), 2.26 (ddt, J ϭ 15, 1.5, 6 Hz, 1 H), 2.45 (ddt, J ϭ 15, 1.5,
6 Hz, 1 H), 2.89Ϫ2.97 (m, 1 H), 3.02 (dt, J ϭ 4, 6 Hz, 1 H), 3.63
(s, 4 H), 5.49 (dt, J ϭ 18, 1.5 Hz, 1 H), 6.55 (dt, J ϭ 18, 6 Hz, 1
H). Ϫ C18H33BO3 (308.3): calcd. C 70.13, H 10.79; found C 69.88,
H 10.60.
1
cmϪ1. Ϫ H NMR: δ ϭ 0.87 (t, J ϭ 7 Hz, 3 H), 1.17Ϫ1.58 (m, 14
H), 2.4 (br. s, 1 H), 2.9 (br. s, 1 H), 3.54Ϫ3.72 (m, 4 H). Ϫ 13C
NMR: δ ϭ 73.8, 71.6, 46.8, 33.6, 31.8, 29.52, 29.49, 29.2, 25.5,
22.6, 14.0. Ϫ C11H23ClO2 (222.8): calcd. C 59.31, H 10.41; found
C 59.46, H 10.53.
(2S,3S)-1,2-Epoxyundecan-3-ol (32): To a solution of the above diol
31, dissolved in THF (40 mL), was added crushed NaOH (3.93 g,
98.3 mmol). The mixture was stirred at room temperature for 30
min, and diluted with brine. The resulting mixture was extracted
with EtOAc three times, and the combined extracts were dried and
concentrated to afford a residue. Purification by chromatography
(hexane/EtOAc) afforded 32 (3.17 g, 84% from chloride 30), which
1
was 90% ee by H NMR spectroscopy of the derived MTPA ester.
Ϫ 32: IR (neat): ν˜ ϭ 3421 cmϪ1. Ϫ 1H NMR: δ ϭ 0.85 (t, J ϭ
7 Hz, 3 H), 1.16Ϫ1.62 (m, 14 H), 2.26 (t, J ϭ 6 Hz, 1 H), 2.69 (dd,
J ϭ 5, 3 Hz, 1 H), 2.80 (dd, J ϭ 5, 4 Hz, 1 H), 2.95 (ddd, J ϭ 5.5,
4, 3 Hz, 1 H), 3.39 (quint, J ϭ 5.5 Hz, 1 H). Ϫ 13C NMR: δ ϭ
71.8, 55.5, 45.2, 34.3, 31.8, 29.6, 29.4, 29.2, 25.3, 22.6, 14.0. Ϫ
C11H22O2 (186.3): calcd. C 70.92, H 11.90; found C 70.75, H 12.13.
(1ЈE,4ЈR,5ЈS)-2-(4Ј,5Ј-Epoxy-1Ј-tridecenyl)-5,5-dimethyl-1,3,2-
dioxaborinane [(9ЈR,10ЈS)-7]: According to the procedure described
above, the title compound ([α]2D6 ϭ Ϫ23 (c ϭ 1.03, CHCl3) was
prepared from ent-35 of Ͼ 99% ee ([α]2D9 ϭ Ϫ46 (c ϭ 0.982, CHCl3).
(4S,5R)-4,5-Epoxytridecan-1-yne (35): To an ice-cold solution of 32
(1.00 g, 5.37 mmol) and Et3N (1.73 g, 17.1 mmol) in CH2Cl2
(14 mL), MsCl (918 mg, 8.01 mmol) was added dropwise. The mix-
ture was stirred at 0 °C for 30 min, and diluted with EtOAc and
saturated NaHCO3. After separation of the organic layer, the aque-
ous layer was extracted three times with EtOAc. The combined
organic layers were dried and concentrated to give mesylate 33,
which was used for the next reaction without further purification.
Ϫ To a solution of trimethylsilylacetylene (1.01 g, 10.3 mmol) in
THF (15 mL) was added nBuLi (4.0 mL, 2.03  in hexane,
8.12 mmol) at Ϫ78 °C. The mixture was stirred at Ϫ78 °C for 30
min, then BF3·OEt2 (1.30 g, 9.13 mmol) was added and, after 10
min of stirring, a solution of 33 in THF (7.5 mL) was added. The
mixture was stirred between Ϫ78 and Ϫ60 °C for 30 min and
poured into saturated NH4Cl. The product was extracted with
EtOAc three times. The combined extracts were dried and concen-
trated to leave the acetylenic alcohol 34, which was somewhat un-
stable and used immediately for the next reaction without further
purification. Ϫ To the above acetylene 34 in MeOH (16 mL),
K2CO3 (2.26 g, 16.1 mmol) was added in portions. The mixture was
stirred at room temperature for 8 h and poured into saturated
NH4Cl with EtOAc. The resulting mixture was extracted three
times with EtOAc, and the combined organic layers were dried and
concentrated to give an oil, which was purified by chromatography
(hexane/EtOAc) to afford epoxy acetylene 35 (724 mg, 69% from
epoxy alcohol 32 of 90% ee). Ϫ [α]2D8 ϭ ϩ42 (c ϭ 1.002, CHCl3).
TBS Ether of (5S,3ЈR,9ЈS,10ЈR)-Korormicin (1) [(5S,3ЈR,9ЈS,10ЈR)-
9]: To an ice-cold mixture of (9ЈS,10ЈR)-7 (97 mg, 0.31 mmol, 90%
ee), NiCl2(dppf) (22 mg, 0.032 mmol), and THF (0.2 mL), MeLi
(0.24 mL, 1.58  in Et2O, 0.38 mmol) was added. The resulting
dark red solution was stirred at 0 °C for 15 min to generate the
corresponding borate 8 and an active Ni0 species. To this solution
was added (5S,3ЈR)-6 (100 mg, 0.21 mmol, 94% ds) at 0 °C. The
cooling bath was removed and the mixture was stirred at room
temperature for 4 h. Saturated NH4Cl was added, and the resulting
mixture was extracted with Et2O three times. The combined or-
ganic layers were dried and concentrated to furnish a brown res-
idue, which was purified by chromatography to afford
(5S,3ЈR,9ЈS,10ЈR)-9 (56 mg, 49%) as a viscous oil. Ϫ IR (neat): ν˜ ϭ
1
3321, 1765, 1701, 1655, 837, 779 cmϪ1. Ϫ H NMR: δ ϭ 0.04 (s,
3 H), 0.05 (s, 3 H), 0.8Ϫ0.9 (m, 15 H), 1.47 (s, 3 H), 1.1Ϫ1.6 (m,
12 H), 1.70Ϫ1.88 (m, 2 H), 2.24Ϫ2.59 (m, 4 H), 2.92Ϫ3.00 (m, 2
H), 4.95Ϫ5.04 (m, 1 H), 5.35 (dd, J ϭ 11, 8 Hz, 1 H), 5.78 (dt, J ϭ
15, 7 Hz, 1 H), 5.97 (t, J ϭ 11 Hz, 1 H), 6.39 (dd, J ϭ 15, 11 Hz,
1 H), 7.33 (s, 1 H), 8.15 (br. s, 1 H). Ϫ 13C NMR: δ ϭ 169.9, 169.3,
133.8, 132.3, 131.3, 129.0, 126.9, 124.9, 88.3, 66.6, 57.1, 55.9, 45.9,
32.0, 31.8, 31.5, 29.51, 29.50, 29.2, 27.7, 26.6, 25.7, 24.4, 22.6, 18.0,
14.1, 8.1, Ϫ4.4, Ϫ5.2. Ϫ C31H53NO5Si (547.8): calcd. C 67.96, H
9.75; found C 67.77, H 9.44.
1
Ϫ IR (neat): ν˜ ϭ 3313, 2120 cmϪ1. Ϫ H NMR: δ ϭ 0.87 (t, J ϭ
(5S,3ЈR,9ЈS,10ЈR)-Korormicin (1) (Natural Type): To the silyl ether
7 Hz, 3 H), 1.18Ϫ1.58 (m, 14 H), 2.04 (t, J ϭ 3 Hz, 1 H), 2.27 9 (100 mg, 0.18 mmol), dissolved in THF (1 mL), Bu4NF (0.36 mL,
(ddd, J ϭ 17, 7, 3 Hz, 1 H), 2.58 (ddd, J ϭ 17, 6, 3 Hz, 1 H), 2.96 1.0  in THF, 0.36 mmol) was added dropwise. The solution was
(dt, J ϭ 4, 6 Hz, 1 H), 3.14 (ddd, J ϭ 7, 6, 4 Hz, 1 H). Ϫ 13C stirred at room temperature for 1 h and poured into buffer (pH ϭ
NMR: δ ϭ 79.5, 70.4, 57.0, 54.8, 31.8, 29.5, 29.2, 27.5, 26.4, 22.6, 5) and Et2O with vigorous stirring. The organic layer was separated
1880
Eur. J. Org. Chem. 2001, 1873Ϫ1881

Total Synthesis of Korormicin
FULL PAPER
of (R)-iii is reported by Vlad.[8b] However, it was later found
that (R)-iii is not available even though both the enantiomers of
and the aqueous layer was extracted with Et2O twice. The com-
bined organic layers were dried and concentrated to afford an oily
residue, which was purified by chromatography to afford
(5S,3ЈR,9ЈS,10ЈR)-1 (67 mg, 86%). Ϫ [α]3D0 ϭ Ϫ24.5 (c ϭ 0.828,
EtOH) {ref.[1a] [α]2D6 ϭ Ϫ24.4 (c ϭ 0.29, EtOH)}. Ϫ The 1H and
13C NMR spectra of synthetic 1 in [D6]DMSO are identical with
those reported.[1a] The following spectroscopic data were obtained
iii are found in the Merck Index.[8c] Major companies including
[8b]
Merck now produce it as a racemic form. Ϫ
P. Vlad, M.
Soucek, Coll. Czech. Chem. Commun. 1962, 27, 1726Ϫ1729. Ϫ
[8c] The Merck Index, 12th ed. (Ed.: S. Budavari), Merck & Co.,
Inc., Whitehouse Station, NJ, 1996, 5520 Linalool.
U. Kraatz, W. Hasenbrink, H. Wamhoff, F. Korte, Chem. Ber.
1971, 104, 2458Ϫ2466.
[9]
1
[10]
in CDCl3. Ϫ H NMR: δ ϭ 0.86 (t, J ϭ 7 Hz, 3 H), 0.88 (t, J ϭ
N.-h. Ho, W. J. le Noble, J. Org. Chem. 1989, 54, 2018Ϫ2021.
[11] [11a] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem.
Rev. 1994, 94, 2483Ϫ2547. Ϫ [11b] K. B. Sharpless, W. Amberg,
Y. L. Bennani, G. A. Crispino, J. Hartung, K.-S. Jeong, H.-L.
7 Hz, 3 H), 1.47 (s, 3 H), 1.1Ϫ1.6 (m, 12 H), 1.68Ϫ1.92 (m, 2 H),
2.28Ϫ2.41 (m, 2 H), 2.57 (dd, J ϭ 16, 3.5 Hz, 1 H), 2.62 (dd, J ϭ
16, 8 Hz, 1 H), 2.91Ϫ3.01 (m, 2 H), 3.08 (br. s, 1 H), 4.98Ϫ5.08
(m, 1 H), 5.39 (dd, J ϭ 11, 9 Hz, 1 H), 5.81 (dt, J ϭ 15, 7 Hz, 1
H), 6.06 (t, J ϭ 11 Hz, 1 H), 6.45 (dd, J ϭ 15, 11 Hz, 1 H), 7.36
(s, 1 H), 8.46 (br. s, 1 H). Ϫ 13C NMR: δ ϭ 170.7, 169.5, 134.4,
132.8, 130.9, 129.9, 127.0, 124.8, 88.6, 64.7, 57.2, 55.9, 43.4, 32.0,
31.8, 31.4, 29.5, 29.2, 27.7, 26.5, 24.2, 22.6, 14.0, 8.2.
Kwong, K. Morikawa, Z.-M. Wang, D. Xu, X.-L. Zhang, J.
[11c]
Org. Chem. 1992, 57, 2768Ϫ2771. Ϫ
E. Keinan, S. C.
Sinha, A. Sinha-Bagchi, Z.-M. Wang, X.-L. Zhang, K. B.
Sharpless, Tetrahedron Lett. 1992, 33, 6411Ϫ6414. Ϫ [11d] K. P.
M. Vanhessche, Z.-M. Wang, K. B. Sharpless, Tetrahedron
Lett. 1994, 35, 3469Ϫ3472.
[12]
The corresponding racemic diol was obtained by oxidation
with OsO4 (cat.) and NMO in 87% yield. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 1.06 (s, 3 H), 1.12 (d, J ϭ 7 Hz, 3 H),
1.23 (t, J ϭ 7 Hz, 3 H), 1.67Ϫ1.87 (m, 2 H), 2.39Ϫ2.48 (m, 2
H), 2.6Ϫ2.8 (m, 2 H), 3.53Ϫ3.62 (m, 1 H), 4.11 (q, J ϭ 7 Hz,
2 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 175.0, 74.2, 72.9,
60.7, 33.3, 28.7, 20.0, 17.2, 14.1.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports, and Culture, Gov-
ernment of Japan.
Enantiomeric excess was determined by 1H NMR spectroscopy
of the derived MTPA ester.
[13]
[14] [14a]
D. H. R. Barton, S. W. McCombie, J. Chem. Soc., Perkin
[14b]
I 1975, 1574Ϫ1585. Ϫ
S. Iacono, J. R. Rasmussen, Org.
[1] [1a]
Synth., Collect. Vol. 1990, 7, 139Ϫ141.
Alternatively, the following method afforded 15 in 17% yield
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K. Yoshikawa, T. Takadera, K. Adachi, M. Nishijima, H.
[15]
[1b]
Sano, J. Antibiot. 1997, 50, 949Ϫ953. Ϫ
K. Yoshikawa, Y.
Nakayama, M. Hayashi, T. Unemoto, K. Mochida, J. Antibiot.
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[2]
[3]
[4]
[5]
[6]
[7]
Y. Kobayashi, Y. Nakayama, S. Yoshida, Tetrahedron Lett.
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Y. Kobayashi, Y. Nakayama, R. Mizojiri, Tetrahedron 1998,
54, 1053Ϫ1062.
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[16]
Y. Kitano, S. Okamoto, F. Sato, Chem. Lett. 1989, 2163Ϫ2164.
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[17b]
6237Ϫ6240. Ϫ
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[7a]
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845Ϫ855.
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[18]
B. Neises, W. Steglich, Angew. Chem. Int. Ed. Engl. 1978, 17,
[8] [8a]
Preparation of 15 by another route shown below was also
522Ϫ524.
[19] 1H NMR (300 MHz, CDCl3) of 24: δ ϭ 2.42 (dd, J ϭ 13.5,
4 Hz, 1 H), 2.86 (dd, J ϭ 13.5, 11 Hz, 1 H), 3.62Ϫ3.72 (m, 1
H), 4.07Ϫ4.24 (m, 1 H), 4.92Ϫ5.03 (m, 1 H), 6.25 (t, J ϭ 8 Hz,
1 H), 6.35 (d, J ϭ 8 Hz, 1 H).
studied with racemic compounds. This route is shorter than
that of Scheme 2, and preparation of (S)-ii by hydrogenation
[20]
E. P. Boden, G. E. Keck, J. Org. Chem. 1985, 50, 2394Ϫ2395.
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T. Sunazuka, T. Hirose, Y. Harigaya, S. Takamatsu, M.
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Supporting information of: J. A. Marshall, H. Jiang, J. Org.
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M. E. Jung, B. Gaede, Tetrahedron 1979, 35, 621Ϫ625.
Received November 10, 2000
[O00569]
Eur. J. Org. Chem. 2001, 1873Ϫ1881
1881