First enantioselective total synthesis of both (+)- and (-)-metachromin A

Article abstract of DOI:10.1002/1099-0690(200102)2001:4<647::AID-EJOC647>3.0.CO;2-6

The antineoplastic agent (-)-metachromin A (1) from Hippospongia metachromia has been synthesized in enantiomerically pure form in 13% overall yield. A general convergent synthetic strategy for different metachromins using a 2-alkyloxy-3-sulfonyl-l,3-oxazolidine as a chiral dithienium equivalent is presented.

Full text of DOI:10.1002/1099-0690(200102)2001:4<647::AID-EJOC647>3.0.CO;2-6

FULL PAPER
First Enantioselective Total Synthesis of Both (؉)- and (؊)-Metachromin A
Markus Brüggemann,[a] Christiane Holst,[a][‡] and Dieter Hoppe*[a]
Dedicated to Professor Günter Helmchen on the occasion of his 60th birthday
Keywords: Total synthesis / Natural products / Chiral 1,3-oxazolidines / Terpenoids / Quinones
The antineoplastic agent (−)-metachromin A (1) from Hip-
pospongia metachromia has been synthesized in enantiomer- kyloxy-3-sulfonyl-1,3-oxazolidine as
synthetic strategy for different metachromins using a 2-al-
chiral dithienium
a
ically pure form in 13% overall yield. A general convergent
equivalent is presented.
Introduction
cently, an enantioenriched intermediate of this synthesis has
also been prepared.[2b] Our retrosynthetic disassembly is
shown in Scheme 1. The two key intermediates 2 and 3 can
be elaborated from silyl enol ether 4 and 1,2,4,5-tetrameth-
oxybenzene (5), respectively.
The purple-coloured Okinawan marine sponge Hip-
pospongia metachromia is the source of a number of struc-
turally related sesquiterpenoid quinones and phenols
named metachromins AϪH[1] (Figure 1). Due to their inter-
esting biological profiles[1] Ϫ exhibiting cytotoxicity against
murine leukemia cells and human epidermoid carcinoma
cells as well as remarkable coronary vasodilating activity
Ϫ these compounds represent attractive synthetic targets in
medicinal chemistry.
Scheme 1. Retrosynthetic analysis of (Ϫ)-metachromin A (1)
Figure 1. Structures of metachromins
Results and Discussion
With the exception of metachromin C, all metachromins
contain the same chiral fragment R* as part of their biogen-
etically unusual carbon skeletons. Consequently, a retrosyn-
thetic scission of the C-7ϪC-8 bond offers a general conver-
gent synthetic strategy suitable for the preparation of seven
different metachromins. As a first synthetic target, we chose
(Ϫ)-metachromin A (1), which has previously been synthe-
sized by Correia et al. as a racemic mixture.[2a] More re-
To introduce the stereochemical information into the key
intermediate 2, an enantiomerically pure 2-alkyloxy-3-sul-
fonyl-1,3-oxazolidine 6 was used as a chiral dithienium
equivalent. The well-known Lewis acid mediated reaction
of chiral, non-racemic 2-alkyloxy-3-sulfonyl-1,3-oxazolid-
ines[3] with prochiral silyl enol ethers generally affords a 1:1
mixture of epimers when it is used for the construction of
quaternary carbon centres.[3e,3f] In order to obtain en-
hanced selectivities, prior conversion of the silyl enol ether
4[4] into a titanium enolate[5] was essential (Scheme 2).
Without further addition of a Lewis acid, this new method
provided 79% of an easily separable mixture (dr ϭ 81:19)
[a]
Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität,
Corrensstrasse 40, 48149 Münster, Germany
Fax: (internat.) ϩ 49-251/833-9772
E-mail: dhoppe@uni-muenster.de
[‡]
X-ray structure analysis.
Eur. J. Org. Chem. 2001, 647Ϫ654
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0204Ϫ0647 $ 17.50ϩ.50/0
647

M. Brüggemann, C. Holst, D. Hoppe
FULL PAPER
of two epimers at the quaternary carbon centre favouring oxygen by aggregation and complexation, forcing the
the desired diastereomer cu-7. Presumably, coordination of methyl group into the axial position via a chair-like trans-
the oxazolidine 6 at the trichlorotitanium enolate and reac- ition state.
tion via a cyclic transition state similar to that involved in
corresponding aldol reactions[5bϪ5d] is responsible for the
increased selectivity. We plan to study this reaction in more
detail in the future.
Figure 2. Proposed transition states for the methylation of the enol-
ate of cu-7
Olefination of the strongly sterically hindered ketone 8
under the conditions established by Fitjer[7] furnished
product 9 in 93% yield. Only traces of epi-9, formed by
epimerization at C-3Ј under the basic conditions, were de-
tected by NMR (dr Ͼ 96:4). This epi-9 could not be re-
moved from 9 by FCC, but was lost during the ensuing
steps. The relative and absolute configuration of the inter-
mediate 9 was elucidated by X-ray crystal structure ana-
lysis[8] (Figure 3), which showed the desired trans arrange-
ment of the two methyl groups at the cyclohexane moiety.
Finally, thiolysis[3d] with 1,3-propanedithiol resulted in the
formation of 2 (93%). The chiral auxiliary, sulfonamide 10,
was recovered in 84% yield. Interestingly, the last two steps
could be performed in reverse order. Because of the steric
hindrance at the cyclohexane ring in 8, selective thiolysis of
the oxazolidine group was possible, leading to ketone 11
(82%); unfortunately, subsequent olefination afforded the
product 2 in only 52% yield as a mixture of epimers (dr ϭ
Scheme 2. Reagents and conditions: (a) 6, ZnCl2·Et2O, CH2Cl2, 0
80:20). Following the first route, the key intermediate 2 was
°C, 15 min, 85%, dr ϭ 45:55; (b) TiCl4, CH2Cl2, Ϫ78 °C, 15 min,
synthesized in enantiomerically pure form from the silyl
enol ether 4 in only four steps in 46% overall yield.
room temp., 45 min, then 6, Ϫ78 °C Ǟ room temp., 15 h, 79%,
dr ϭ 81:19; (c) LDA, THF, Ϫ78 °C, 1 h, then MeI, 0 °C Ǟ room
temp., 15 h, 54%, dr ϭ 27:73 (ϩ35% cu-7); (d) KOtBu, 18-crown-
6, THF, Ϫ40 °C Ǟ room temp., 1 h, then MeI, Ϫ78 °C Ǟ room
temp., 15 h, 86%, dr ϭ 96:4; (e) MePPh3Br, KOtBu, toluene, reflux,
4 h, 93%, dr Ͼ 96:4; (f) H2C(CH2SH)2, BF3·Et2O, CH2Cl2, 0 °C,
2 h, 93% 2 ϩ 84% 10; (g) H2C(CH2SH)2, BF3·Et2O, CH2Cl2, 0 °C,
2 h, 82%; (h) MePPh3Br, KOtBu, toluene, reflux, 4 h, 52%, dr ϭ
81:19 (ϩ18% 11); LDA ϭ lithium diisopropylamide, THF ϭ tetra-
hydrofuran, Ts ϭ 4-toluenesulfonyl
After separation by flash column chromatography (FCC)
on silica gel, the diastereoselective methylation of cu-7 with
methyl iodide was efficiently achieved using potassium tert-
butylate/18-crown-6 for deprotonation (86%, dr ϭ 96:4);
other bases, such as lithium diisopropylamide (LDA) in
THF, gave lower yields and led preferentially to the un-
desired diastereomer epi-8 (54%, dr ϭ 27:73). By exposing
the thermodynamically unfavoured diastereomerically pure
epi-8 to the same conditions as used for the formation of 8
(KOtBu/18-crown-6/MeI, then epi-8, THF, Ϫ78 °C Ǟ room
Figure 3. X-ray structure analysis of 9
The five steps required for the elaboration of the second
temp., 15 h), it was shown that no epimerization occurred. fragment 3 from 1,2,4,5-tetramethoxybenzene (5)[9] gave an
This result suggests that it is the alkylation step which is overall yield of 47% (Scheme 3). ortho-Lithiation of 5 with
responsible for the observed selectivity. Most probably, in- n-butyllithium and subsequent reaction with oxirane pro-
teraction between the alkylating agent and the quasi-axial duced the alcohol 12 in 80% yield. Only a Swern oxida-
methyl group[6c] at C-2 favours the formation of 8 when a tion[10] at Ϫ30 °C afforded the aldehyde 13 in a satisfactory
free enolate is employed (Figure 2). In this case, ‘‘equator- yield of 79%. Other methods, such as pyridinium chloro-
ial’’ attack via a twist-boat-like transition state leads to the chromate (PCC)[11] or DessϪMartin periodinane (DMP)
product.[6] When LDA is used for deprotonation, the li- oxidation,[12] gave lower yields (52% and 56%, respectively).
thium presumably creates a steric demand at the enolate The (E)-configured trisubstituted double bond moiety
648
Eur. J. Org. Chem. 2001, 647Ϫ654

First Enantioselective Total Synthesis of Both (ϩ)- and (Ϫ)-Metachromin A
FULL PAPER
could
be
introduced
by
either
a
HornerϪ tylstannane/2,2Ј-azobisisobutyronitrile (AIBN) in ben-
WadsworthϪEmmons reaction[13] with phosphonate 15 zene[21] at 80 °C for 12 h (80%). Consequently, much more
[92%, (E)/(Z) ϭ 95:5] or a Wittig reaction[14] with the com- vigorous conditions of neat tributylstannane at 120 °C for
mercially available ylide 16 [92%, (E)/(Z) ϭ 98:2] furnishing 30 h (addition of AIBN every two hours) were required,
the ester 14. An NOE of 3% between the signals of the under which the desired precursor 19 was obtained in excel-
methyl group at C-2 and the C-4 methylene group proved lent yield (95%). Unfortunately, the final oxidation with
the (E) configuration of the double bond. Subsequent cerium(IV) ammonium nitrate (CAN)[9] in acetonitrile/
chemoselective reduction with diisobutylaluminium hy- water produced only 37% of (Ϫ)-metachromin A (1) along
dride[15] (DIBAL-H) and bromination of the resulting alco- with 34% of the known[1] methyl ether 20. Isolation and
hol 17 via the mesylate with lithium bromide led to the allyl separation of the two products was accomplished by FCC
bromide 3 in good yield (82% over two steps).
on RP-18 silica gel. All attempts to achieve a selective de-
methylation[9,22] of 20 have hitherto met with failure.
Scheme 4. Reagents and conditions: (a) tBuLi, HMPTA, THF, Ϫ78
°C, 2.5 h, then 3, Ϫ78 °C, 3 h, 85%; (b) Bu3SnH, AIBN, 120 °C,
30 h, 95%; (c) CAN, MeCN/H2O, 70:30, Ϫ7 °C, 1.5 h, room temp.,
2 h, 37% 1 ϩ 34% 20; HMPTA ϭ hexamethylphosphoric triamide,
AIBN ϭ 2,2Ј-azobisisobutyronitrile, CAN ϭ cerium(IV) ammo-
nium nitrate
Scheme 3. Reagents and conditions: (a) nBuLi, LiCl, THF, 0 °C,
30 min, then ethylene oxide, Ϫ78 °C, 30 min, room temp., 3 h, 80%;
(b) DMP, CH2Cl2, room temp., 2 h, 56%; (c) PCC, NaOAc,
CH2Cl2, room temp., 5 h, 52%; (d) (COCl)2, DMSO, CH2Cl2, Ϫ60
°C Ǟ Ϫ30 °C, 1 h, then NEt3, room temp., 1 h, 79%; (e) (EtO)2-
P(O)CH(Me)COOEt (15), LiCl, DBU, MeCN, room temp., 1 h,
92%, (E)/(Z) ϭ 95:5; (f) Ph3PϭC(Me)COOEt (16), CH2Cl2, reflux,
3 h, 92%, (E)/(Z) ϭ 98:2; (g) DIBAL-H, CH2Cl2, Ϫ78 °C, 2.5 h,
92%; (h) CBr4, PPh3, CH2Cl2, 0 °C, 30 min, 83%; (i) MsCl, NEt3,
CH2Cl2, Ϫ40 °C, 1.5 h, then LiBr, THF, 0 °C, 2.5 h, 89%; DMP ϭ
DessϪMartin periodinane, PCC ϭ pyridinium chlorochromate,
DMSO ϭ dimethyl sulfoxide, DBU ϭ 1,8-diazabicyclo[5.4.0]undec-
7-ene, DIBAL-H ϭ diisobutylaluminium hydride, Ms ϭ meth-
anesulfonyl
An exact mass, a correct elemental analysis, and the melt-
ing point proved the correct molecular formula and high
purity of the synthesized (Ϫ)-metachromin A (1). The spec-
troscopic data (1H NMR, 13C NMR, IR) were identical in
all respects to those provided by Prof. Correia.[2] The spe-
cific optical rotation [α]2D7 ϭ Ϫ17.6 of the synthetic 1 was
higher than the value reported[1] for natural 1 ([α]D27 ϭ Ϫ11).
Starting from the 2-alkyloxy-1,3-oxazolidine ent-6, (ϩ)-me-
tachromin A (ent-1, [α]2D7 ϭ ϩ17.3) was similarly synthe-
sized.
With the required building blocks in hand, their coupling
could be accomplished by alkylation of the lithiated dithi-
ane 2 with the bromide 3 (85%) (Scheme 4). Selective
lithiation of the neopentylic dithiane[16] moiety without
concomitant deprotonation at the allylic position was
achieved using tert-butyllithium/hexamethylphosphoric tri-
Conclusion
A general convergent synthetic strategy for the stereocon-
amide (HMPTA) at low temperature.[16e] As expected, the trolled preparation of different metachromins is presented.
selective desulfuration of the product 18 caused some diffi- As an example, (Ϫ)-metachromin A (1) has been synthe-
culties due to the dithiane ring being adjacent to a quatern- sized in enantiomerically pure form in seven steps from the
ary carbon centre and the presence of two reactive double silyl enol ether 4 in 13% overall yield. The use of a 2-alk-
bonds. The use of Raney nickel (W2,[17] freshly prepared), yloxy-3-sulfonyl-1,3-oxazolidine 6 as a chiral dithienium
even after its deactivation in boiling acetone,[18] led to re- equivalent, which constitutes a new method for the stereo-
duction and isomerization of the double bonds but not to selective construction of quaternary carbon centres, allowed
complete desulfuration. Treatment with hydrazine[19] re- the efficient preparation of the common chiral part of seven
sulted in complete decomposition of the compound. Birch of the metachromins.
conditions,[20] at the temperature of boiling ammonia as
Thus, the alkylation of chiral dithianes, in turn obtained
well as at Ϫ50 °C, led to reduction of the electron-rich ben- from enantiomerically pure 3-sulfonyl-1,3-oxazolidines, and
zene ring, while at Ϫ78 °C a mixture of compounds with subsequent reduction (or hydrolysis) represents a valuable
only one reductively cleaved CϪS bond was detected. The strategy for the enantioselective synthesis of natural prod-
same mixture was obtained when 18 was treated with tribu- ucts.
Eur. J. Org. Chem. 2001, 647Ϫ654
649

M. Brüggemann, C. Holst, D. Hoppe
FULL PAPER
was slowly added. The resulting mixture was allowed to warm to
room temperature over a period of 15 h. The reaction was then
stopped by the addition of 2  HCl (250 mL) and the aqueous layer
was extracted with CH2Cl2 (4 ϫ 150 mL). The combined organic
layers were stirred with K2CO3 (3.00 g) for 15 min, then the suspen-
sion was filtered and the solvent was removed in vacuo to leave the
crude product {cu-7/cl-7, 81:19 [1H NMR (2Ј-H)]}. Purification by
FCC (1130 cm3 SiO2, gradient Et2O/PE, 1:5 Ǟ Et2O/PE, 1:4)
yielded diastereomerically pure cu-7 (5.93 g, 16.2 mmol, 65%) as
colourless crystals. Ϫ Rf ϭ 0.37 (SiO2, Et2O/PE, 1:1). Ϫ M.p.
97.0Ϫ98.5 °C (Et2O/PE, 1:4). Ϫ [α]2D0 ϭ Ϫ24.8 (c ϭ 1.30, CH2Cl2);
ent-cu-7: [α]2D0 ϭ ϩ25.6 (c ϭ 0.94, CH2Cl2). Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 0.84 (t, 3J ϭ 7.4 Hz, 3 H, 2ЈЈ-H3), 1.08 (s, 3 H, 2-
CH3), 1.42Ϫ1.57 (m, 2 H, 3-H2, 1ЈЈ-H2), 1.61Ϫ1.79 (m, 3 H, 5-H2,
4-H2, 1ЈЈ-H2), 1.83Ϫ1.99 (m, 2 H, 5-H2, 4-H2), 2.28Ϫ2.53 (m, 3 H,
6-H2, 3-H2), 2.38 (s, 3 H, 4ЈЈЈ-CH3), 3.05Ϫ3.11 (m, 1 H, 5Ј-H2),
3.50Ϫ3.57 (m, 2 H, 4Ј-H, 5Ј-H2), 5.36 (s, 1 H, 2Ј-H), 7.28Ϫ7.37
(m, 2 H, 3ЈЈЈ-H, 5ЈЈЈ-H), 7.68Ϫ7.77 (m, 2 H, 2ЈЈЈ-H, 6ЈЈЈ-H). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 10.8 (q, C-2ЈЈ), 20.7 (q, 2-CH3), 21.0
(t, C-4), 21.6 (q, 4ЈЈЈ-CH3), 25.9 (t, C-5), 27.4 (t, C-1ЈЈ), 34.3 (t, C-
3), 39.5 (t, C-6), 52.8 (s, C-2), 62.2 (d, C-4Ј), 69.4 (t, C-5Ј), 93.6 (d,
C-2Ј), 128.2 (d, C-2ЈЈЈ, C-6ЈЈЈ), 129.9 (d, C-3ЈЈЈ, C-5ЈЈЈ), 134.4 (s,
C-4ЈЈЈ), 144.2 (s, C-1ЈЈЈ), 212.1 (s, C-1). Ϫ IR (KBr): ν˜ ϭ 2900 s,
2850 s, 1690 s, 1585 w, 1430 m, 1330 s, 1150 s, 1100 s, 975 s, 800
w, 650 s cmϪ1. Ϫ EI-MS: m/z (%) ϭ 364 (0.1) [Mϩ Ϫ H], 254 (100),
210 (43), 155 (64), 91 (76). Ϫ C19H27NO4S (365.50): calcd. C 62.44,
H 7.45, N 3.83; found C 62.36, H 7.46, N 3.60. Ϫ cl-7 (1.32 g,
3.61 mmol, 14%, colourless crystals). Ϫ Rf ϭ 0.32 (SiO2, Et2O/PE,
1:1). Ϫ M.p. 136.5Ϫ137.5 °C (Et2O/PE, 1:4). Ϫ [α]2D0 ϭ Ϫ23.8 (c ϭ
0.96, CH2Cl2); ent-cl-7: [α]2D0 ϭ ϩ22.2 (c ϭ 0.94, CH2Cl2). Ϫ 1H
Experimental Section
General Remarks: All solvents were dried and purified prior to use:
Et2O and toluene were distilled from sodium benzophenone ketyl.
THF was distilled from potassium benzophenone ketyl. CH2Cl2,
NEt3, and DMSO were distilled from CaH2. MeCN was distilled
from P4O10. All commercially available reagents were used without
purification. LiCl and LiBr were dried for 15 h at 150 °C under
reduced pressure. All reactions were performed under Ar in flame-
dried glassware and were monitored by thin-layer chromatography
(TLC, silica gel 60 F254 or RP-18 F254s, Merck). Ϫ Flash column
chromatography (FCC) was performed on Merck silica gel 60,
0.040Ϫ0.063 mm, or LiChroprep RP-18, 0.040Ϫ0.063 mm; PE ϭ
light petroleum ether, b.p. 36Ϫ46 °C. Ϫ NMR: Bruker ARX 300,
AM 360 (NOE experiments), and AMX 400 (2D spectra); Varian
Unity Plus 600 (2D spectra); for 1H NMR, CDCl3 as solvent (δH ϭ
7.24); for 13C NMR, CDCl3 as solvent (δC ϭ 77.0). Ϫ IR: Nicolet
5DXC. Optical rotations: PerkinϪElmer polarimeter 341. Ϫ MS:
Finnigan MAT 8200. Ϫ Elemental analysis: Heraeus CHN-O-
Rapid. Ϫ Melting points: Gallenkamp MFB 595, uncorrected
values. Ϫ GC: HewlettϪPackard 6890, HP1701.
(؉)-(2R,4S)-4-Ethyl-2-ethyloxy-3-[(4-methylphenyl)sulfonyl]-1,3-
oxazolidine (6): To a solution of (S)-2-aminobutanol (5.00 g,
56.1 mmol) and NEt3 (8.40 mL, 60.3 mmol) in CH2Cl2 (75 mL), a
solution of pTsCl (11.0 g, 57.7 mmol) in CH2Cl2 (75 mL) was
slowly added at 0 °C. After stirring at room temperature for 18 h,
the reaction mixture was washed with aqueous
2  HCl
(3 ϫ 150 mL), dried (Na2SO4), and concentrated in vacuo. The
crude tosylate was dissolved in triethyl orthoformate (150 mL),
three drops of MsOH were added, and the mixture was stirred for
3 h at room temperature. K2CO3 (1.00 g) was then added and the
resulting suspension was stirred for 10 min. Filtration and removal
of the triethyl orthoformate in vacuo gave the crude products 6 and
epi-6 as a viscous oil {16.2 g, 54.1 mmol, 96%, 6/epi-6 ϭ 85:15 [1H
NMR (2-H)]}. The epimeric mixture was dissolved in hexanes at
50 °C and the resulting solution was cooled to Ϫ30 °C for 4 h.
Filtration gave diastereomerically pure 6 (13.5 g, 45.1 mmol, 80%,
dr ϭ 99:1) as colourless crystals. Ϫ Rf ϭ 0.43 (SiO2, Et2O/PE, 1:1).
Ϫ M.p. 57.9Ϫ58.7 °C (hexanes). Ϫ [α]2D0 ϭ ϩ15.9 (c ϭ 0.90,
CH2Cl2); ent-6: [α]2D0 ϭ Ϫ15.4 (c ϭ 1.00, CH2Cl2). Ϫ 1H NMR
3
NMR (300 MHz, CDCl3): δ ϭ 0.78 (t, J ϭ 7.6 Hz, 3 H, 2ЈЈ-H3),
1.21 (s, 3 H, 2-CH3), 1.36Ϫ1.63 and 1.65Ϫ1.93 (2 m, 3 H and 4 H,
5-H2, 4-H2, 3-H2, 1ЈЈ-H2), 2.05Ϫ2.16 (m, 1 H, 3-H2), 2.41 (s, 3 H,
4ЈЈЈ-CH3), 2.42Ϫ2.53 (m, 1 H, 6-H2), 2.59Ϫ2.71 (m, 1 H, 6-H2),
3.23Ϫ3.31 (m, 1 H, 5Ј-H2), 3.55Ϫ3.66 (m, 2 H, 4Ј-H, 5Ј-H2), 5.69
(s, 1 H, 2Ј-H), 7.28Ϫ7.36 (m, 2 H, 3ЈЈЈ-H, 5ЈЈЈ-H), 7.70Ϫ7.79 (m,
2 H, 2ЈЈЈ-H, 6ЈЈЈ-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 10.8 (q,
C-2ЈЈ), 20.1 (q, 2-CH3), 20.8 (t, C-4), 21.6 (q, 4ЈЈЈ-CH3), 26.7 (t, C-
5), 27.0 (t, C-1ЈЈ), 34.7 (t, C-3), 39.6 (t, C-6), 53.6 (s, C-2), 62.1 (d,
C-4Ј), 70.1 (t, C-5Ј), 94.3 (d, C-2Ј), 128.5 (d, C-2ЈЈЈ, C-6ЈЈЈ), 129.9
(d, C-3ЈЈЈ, C-5ЈЈЈ), 134.9 (s, C-4ЈЈЈ), 144.3 (s, C-1ЈЈЈ), 212.8 (s, C-1).
Ϫ IR (KBr): ν˜ ϭ 2920 s, 2850 s, 1680 s, 1585 w, 1440 m, 1330 s,
1150 s, 970 s, 800 w, 655 s cmϪ1. Ϫ EI-MS: m/z (%) ϭ 364 (0.1)
[Mϩ Ϫ H], 254 (92), 210 (19), 155 (55), 91 (100). Ϫ C19H27NO4S
(365.50): calcd. C 62.44, H 7.45, N 3.83; found C 62.35, H 7.41,
N 3.77.
3
(300 MHz, CDCl3): δ ϭ 0.87 (t, J ϭ 7.6 Hz, 3 H, 2Ј-H3), 1.22 (t,
3J ϭ 6.9 Hz, 3 H, 2ЈЈ-H3), 1.51Ϫ1.66 (m, 1 H, 1Ј-H2), 1.82Ϫ1.96
(m, 1 H, 1Ј-H2), 2.41 (s, 3 H, 4ЈЈЈ-CH3), 3.53Ϫ3.72 (m, 3 H, 1ЈЈ-
H2, 4-H), 3.74Ϫ3.89 (m, 2 H, 5-H2), 6.02 (s, 1 H, 2-H), 7.26Ϫ7.30
(m, 2 H, 3ЈЈЈ-H, 5ЈЈЈ-H), 7.69Ϫ7.73 (m, 2 H, 2ЈЈЈ-H, 6ЈЈЈ-H). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 9.8 (q, C-2Ј), 14.9 (q, C-2ЈЈ), 21.4 (q,
4ЈЈЈ-CH3), 27.4 (t, C-1Ј), 59.4 (t, C-1ЈЈ), 61.6 (d, C-4), 70.3 (t, C-5),
108.0 (d, C-2), 127.5 (d, C-2ЈЈЈ, C-6ЈЈЈ), 129.7 (d, C-3ЈЈЈ, C-5ЈЈЈ),
135.6 (s, C-4ЈЈЈ), 144.3 (s, C-1ЈЈЈ). Ϫ IR (KBr): ν˜ ϭ 2980, 2900,
1560, 1360, 1170, 815 cmϪ1. Ϫ EI-MS: m/z (%) ϭ 299 (0.6) [Mϩ],
254 (99), 196 (58), 155 (60), 91 (100). Ϫ C14H21NO4S (299.39):
calcd. C 56.17, H 7.07, N 4.68; found C 56.24, H 7.08, N 4.92.
(؉)-(2R,6R)-2-{(2S,4S)-4-Ethyl-3-[(4-methylphenyl)sulfonyl]-1,3-
oxazolidin-2-yl}-2,6-dimethylcyclohexan-1-one (8) and (؊)-(2R,6S)-
2-{(2S,4S)-4-Ethyl-3-[(4-methylphenyl)sulfonyl]-1,3-oxazolidin-2-
yl}-2,6-dimethylcyclohexan-1-one (epi-8): A solution of 18-crown-6
(6.39 g, 24.2 mmol) and KOtBu (2.71 g, 24.1 mmol) in THF
(80 mL) was cooled until the onset of cloudiness (ca. Ϫ40 °C). The
ketone cu-7 (5.90 g, 16.1 mmol) in THF (40 mL) was then added
at such a rate that the mixture did not solidify during the course
of the addition. The orange solution thus obtained was stirred at
room temperature for 1 h. It was then cooled to Ϫ78 °C, where-
upon MeI (10.1 mL, 162 mmol) was added. After allowing the mix-
(؊)-(2R)-2-{(2S,4S)-4؊Ethyl-3-[(4-methylphenyl)sulfonyl]-1,3-oxa-
zolidin-2-yl}-2-methylcyclohexan-1-one (cu-7) and (؊)-(2S)-2-
{(2S,4S)-4-Ethyl-3-[(4-methylphenyl)sulfonyl]-1,3-oxazolidin-2-yl}-
2-methylcyclohexan-1-one (cl-7): To a cold (Ϫ78 °C) solution of si-
lyl enol ether 4[4] (4.61 g, 25.0 mmol) in CH2Cl2 (200 mL), TiCl4 ture to warm to room temperature over a period of 15 h, satd.
(2.75 mL, 25.1 mmol) was added dropwise. After stirring for 15 min
at Ϫ78 °C, the reaction mixture was allowed to warm to room
aqueous NH4Cl (150 mL) was added and vigorous stirring was
maintained. The aqueous layer was subsequently extracted with
temperature and stirred for a further 45 min. The deep-red solution Et2O (5 ϫ 150 mL). The combined organic layers were dried with
was then cooled to Ϫ78 °C once more, whereupon a solution of 2-
alkyloxy-1,3-oxazolidine 6 (7.49 g, 25.0 mmol) in CH2Cl2 (50 mL)
Na2SO4 and the solvents were removed in vacuo. The crude prod-
uct {8/epi-8, 96:4 [1H NMR (2ЈH)]} was subjected to FCC (1130
650
Eur. J. Org. Chem. 2001, 647Ϫ654

First Enantioselective Total Synthesis of Both (ϩ)- and (Ϫ)-Metachromin A
cm3 SiO2, gradient Et2O/PE, 1:5 Ǟ Et2O/PE, 1:3). The diastereom-
4.94 (s, 1 H, 2Ј-CH2), 5.41 (s, 1 H, 2-H), 7.28Ϫ7.38 (m, 2 H, 3ЈЈЈ-H,
FULL PAPER
erically pure product 8 (5.10 g, 13.4 mmol, 83%) was obtained as a 5ЈЈЈ-H), 7.70Ϫ7.80 (m, 2 H, 2ЈЈЈ-H, 6ЈЈЈ-H). Ϫ 13C NMR (75 MHz,
resinous colourless oil. Ϫ Rf ϭ 0.38 (SiO2, Et2O/PE, 1:1). Ϫ [α]2D0ϭ
ϩ35.5 (c ϭ 2.90, CH2Cl2); ent-8: [α]2D0ϭ Ϫ35.1 (c ϭ 0.73, CH2Cl2).
CDCl3): δ ϭ 10.9 (q, C-2ЈЈ), 18.0 (q, 3Ј-CH3), 19.4 (q, 1Ј-CH3),
21.3 (t, C-5Ј), 21.5 (q, 4ЈЈЈ-CH3), 27.3 (t, C-1ЈЈ), 34.1 (d, C-3Ј), 37.0
Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.84 (t, 3J ϭ 7.5 Hz, 3 H, 2ЈЈ- and 37.2 (2 t, C-4Ј, C-6Ј), 46.2 (s, C-1Ј), 62.1 (d, C-4), 70.5 (t, C-
H3), 1.00 (d, 3J ϭ 6.4 Hz, 3 H, 6-CH3), 1.07 (s, 3 H, 2-CH3), 5), 97.8 (d, C-2), 105.3 (t, 2Ј-CH2), 128.5 (d, C-2ЈЈЈ, C-6ЈЈЈ), 129.8
1.35Ϫ1.40 (m, 2 H, 5-H2, 3-H2), 1.50Ϫ1.56 (m, 1 H, 1ЈЈ-H2),
1.68Ϫ1.74 (m, 2 H, 4-H2, 1ЈЈ-H2), 2.03Ϫ2.09 (m, 2 H, 5-H2, 4-H2),
(d, C-3ЈЈЈ, C-5ЈЈЈ), 134.7 (s, C-4ЈЈЈ), 144.0 (s, C-1ЈЈЈ), 157.0 (s, C-
2Ј). Ϫ IR (KBr): ν˜ ϭ 2950 s, 2910 s, 2860 s, 1650 m, 1590 m, 1330
2.58Ϫ2.66 (m, 2 H, 6-H, 3-H2), 2.43 (s, 3 H, 4ЈЈЈ-CH3), 3.07 (dd, s, 1160 s, 1100 s, 970 s, 890 s, 810 m, 660 s cmϪ1. Ϫ EI-MS: m/z
2
2J ϭ 8.6 Hz, 3J ϭ 6.1 Hz, 1 H, 5Ј-H2), 3.53 (dd, J ϭ 8.6 Hz, 3J ϭ
(%) ϭ 254 (100), 173 (5), 155 (53), 123 (4), 91 (75). Ϫ C21H31NO3S
2.6 Hz, 1 H, 5Ј-H2), 3.54Ϫ3.60 (m, 1 H, 4Ј-H), 5.46 (s, 1 H, 2Ј-H), (377.55): calcd. C 66.81, H 8.28, N 3.71; found C 66.80, H 8.25,
7.31Ϫ7.38 (m, 2 H, 3ЈЈЈ-H, 5ЈЈЈ-H), 7.71Ϫ7.78 (m, 2 H, 2ЈЈЈ-H, 6ЈЈЈ-
H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 10.8 (q, C-2ЈЈ), 15.0 (q,
6-CH3), 19.3 (q, 2-CH3), 20.9 (t, C-4), 21.6 (q, 4ЈЈЈ-CH3), 26.9 (t,
C-1ЈЈ), 35.8 (t, C-5), 36.6 (t, C-3), 43.1 (d, C-6), 53.6 (s, C-2), 62.5
(d, C-4Ј), 69.7 (t, C-5Ј), 93.3 (d, C-2Ј), 128.2 (d, C-2ЈЈЈ, C-6ЈЈЈ),
130.0 (d, C-3ЈЈЈ, C-5ЈЈЈ), 134.1 (s, C-4ЈЈЈ), 144.4 (s, C-1ЈЈЈ), 213.1 (s,
C-1). Ϫ IR (film): ν˜ ϭ 2920 m, 2850 m, 1700 s, 1590 w, 1450 m,
1340 s, 1160 s, 1120 m, 1080 m, 1000 m, 855 w, 820 m, 700 m, 660
s cmϪ1. Ϫ EI-MS: m/z (%) ϭ 254 (100), 224 (14), 173 (5), 155 (45),
91 (65). Ϫ C20H29NO4S (379.52): calcd. C 63.30, H 7.70, N 3.69;
found C 63.45, H 7.92, N 3.88. Ϫ epi-8 (205 mg, 0.54 mmol, 3.3%,
colourless solid). Ϫ Rf ϭ 0.48 (SiO2, Et2O/PE, 1:1). Ϫ M.p.
71.8Ϫ72.6 °C (Et2O/PE, 1:3). Ϫ [α]2D0 ϭ Ϫ78.6 (c ϭ 0.74, CH2Cl2);
ent-epi-8: [α]2D0 ϭ ϩ74.5 (c ϭ 0.96, CH2Cl2). Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 0.90 (t, 3J ϭ 7.4 Hz, 3 H, 2ЈЈ-H3), 1.08 (d,
3J ϭ 6.5 Hz, 3 H, 6-CH3), 1.18 (s, 3 H, 2-CH3), 1.46Ϫ1.61 (m, 2
H, 5-H2, 1ЈЈ-H2), 1.68Ϫ1.87 (m, 4 H, 4-H2, 3-H2, 1ЈЈ-H2),
1.91Ϫ2.01 (m, 1 H, 5-H2), 2.29Ϫ2.39 (m, 1 H, 3-H2), 2.44Ϫ2.59
(m, 1 H, 6-H), 2.40 (s, 3 H, 4ЈЈЈ-CH3), 3.09Ϫ3.15 (m, 1 H, 5Ј-H2),
3.50Ϫ3.59 (m, 2 H, 4Ј-H, 5Ј-H2), 5.39 (s, 1 H, 2Ј-H), 7.30Ϫ7.37
(m, 2 H, 3ЈЈЈ-H, 5ЈЈЈ-H), 7.70Ϫ7.80 (m, 2 H, 2ЈЈЈ-H, 6ЈЈЈ-H). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 10.7 (q, C-2ЈЈ), 15.2 (q, 6-CH3), 20.9
(t, C-4), 21.2 (q, 2-CH3), 21.5 (q, 4ЈЈЈ-CH3), 27.9 (t, C-1ЈЈ), 33.6 (t,
C-5), 34.4 (t, C-3), 41.5 (d, C-6), 52.2 (s, C-2), 62.0 (d, C-4Ј), 69.2
(t, C-5Ј), 94.4 (d, C-2Ј), 128.3 (d, C-2ЈЈЈ, C-6ЈЈЈ), 129.8 (d, C-3ЈЈЈ,
C-5ЈЈЈ), 134.5 (s, C-4ЈЈЈ), 143.9 (s, C-1ЈЈЈ), 214.4 (s, C-1). Ϫ IR
(KBr): ν˜ ϭ 2920 m, 2850 m, 1690 s, 1590 w, 1450 m, 1340 s, 1160
s, 1090 m, 1080 m, 1000 m, 820 m, 660 s. Ϫ EI-MS: m/z (%) ϭ 254
(100), 224 (60), 173 (5), 155 (48), 125 (9), 91 (71). Ϫ C20H29NO4S
(379.52): calcd. C 63.30, H 7.70, N 3.69; found C 63.57, H 7.47,
N 3.66.
N 3.93.
X-ray Structure Analysis of 9:[8] Data were collected on an
EnrafϪNonius CAD4 diffractometer. C21H31NO3S, crystal size
0.35 ϫ 0.25 ϫ 0.20 mm, Mr ϭ 377.53 gmolϪ1, orthorhombic, space
group P212121 (No. 19), a ϭ 11.534(1), b ϭ 12.404(1), c ϭ 14.629(1)
A, V ϭ 2092.9(3) A , Z ϭ 4, ρcalcd. ϭ 1.198 g cmϪ3, λ ϭ 1.54178
3
˚
˚
A, T ϭ 223 K, µ ϭ 1.522 mmϪ1, empirical absorption correction
˚
based on ψ scan data (0.618 Յ C Յ 0.751), ω/2θ scans, total no.
of reflections collected (ϩh, Ϫk, Ϫl) 2418, [sinΘ/λ]max ϭ 0.62 A
Ϫ1
˚
,
2418 independent reflections and 2279 observed reflections [I Ն
2σ(I)], 240 refined parameters, R ϭ 0.040, Rw2 ϭ 0.114, max. resid-
ual electron density ρ ϭ 0.33 (Ϫ0.33) eAϪ3, Flack parameter
˚
Ϫ0.01(2).
(؉)-(2S,6R)-2-(1,3-Dithian-2-yl)-2,6-dimethylcyclohexan-1-one (11):
To a solution of oxazolidine 8 (975 mg, 2.57 mmol) and 1,3-pro-
panedithiol (0.52 mL, 5.2 mmol) in CH2Cl2 (50 mL), BF3·Et2O
(0.64 mL, 5.1 mmol) was added dropwise at 0 °C. After 2 h at this
temperature, satd. aqueous NaHCO3 (50 mL) was added and the
aqueous layer was extracted with CH2Cl2 (3 ϫ 50 mL). The com-
bined organic layers were dried (Na2SO4) and the solvent was re-
moved in vacuo. FCC (440 cm3 SiO2, gradient Et2O/PE, 1:10 Ǟ
Et2O/PE, 1:3) gave 11 (518 mg, 2.12 mmol, 82%) as a colourless
solid. Ϫ Rf ϭ 0.43 (SiO2, Et2O/PE, 1:1). Ϫ [α]2D0 ϭ ϩ160 (c ϭ 1.18,
CH2Cl2). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.99 (d, 3J ϭ 6.2 Hz,
3 H, 6-CH3), 1.13 (s, 3 H, 2-CH3), 1.24Ϫ1.35 (m, 2 H, 3-H2, 5-
H2), 1.55Ϫ1.64 (m, 1 H, 4-H2), 1.72Ϫ1.94 (m, 2 H, 4-H2, 5Ј-H2),
2.00Ϫ2.13 (m, 2 H, 5-H2, 5Ј-H2), 2.37 (dq, 2J ϭ 14.1 Hz, 3J ϭ
3.3 Hz, 1 H, 3-H2), 2.61Ϫ2.75 (m, 1 H, 6-H), 2.84Ϫ2.95 (m, 4 H,
4Ј-H2, 6Ј-H2), 4.63 (s, 1 H, 2Ј-H). Ϫ 13C NMR (75 MHz, CDCl3):
δ ϭ 15.0 (q, 6-CH3), 19.2 (q, 2-CH3), 20.6 (t, C-4), 26.4 (t, C-5Ј),
31.5 and 31.6 (2 t, C-4Ј, C-6Ј), 36.6 (t, C-5), 38.1 (t, C-3), 41.6 (d,
C-6), 53.8 (s, C-2), 54.9 (d, C-2Ј), 213.1 (s, C-1). Ϫ IR (KBr): ν˜ ϭ
2940 s, 1709 s, 1450 m, 1420 m, 1380 m, 1280 m cmϪ1. Ϫ EI-MS:
m/z (%) ϭ 244 (27) [Mϩ], 121 (25), 119 (100), 106 (13). Ϫ
C12H20OS2 (244.42): calcd. C 58.97, H 8.25; found C 59.01, H 8.44.
(؊)-(2S,4S)-2-[(1S,3R)-1,3-Dimethyl-2-methylenecyclohexyl]-4-
ethyl-3-[(4-methylphenyl)sulfonyl]-1,3-oxazolidine (9): A mixture of
MePPh3Br (7.15 g, 20.0 mmol) and KOtBu (2.22 g, 19.8 mmol) in
toluene (80 mL) was refluxed for 1 h. Most of the solvent was then
distilled off and a solution of ketone 8 (5.00 g, 13.2 mmol) in tolu-
ene (50 mL) was slowly added to the boiling mixture. Again, most
of the toluene was removed and the concentrated mixture was re-
(؊)-2-[(1S,3R)-1,3-Dimethyl-2-methylenecyclohexyl]-1,3-dithiane
(2). ؊ Method A: To a stirred solution of oxazolidine 9 (4.11 g,
fluxed for 4 h. After cooling to room temperature, brine (150 mL) 10.9 mmol) and 1,3-propanedithiol (2.21 mL, 22.0 mmol) in
was added and the aqueous layer was extracted with CH2Cl2
(4 ϫ 150 mL). The combined organic layers were dried (MgSO4)
CH2Cl2 (200 mL), BF3·Et2O (2.75 mL, 21.7 mmol) was added
dropwise at 0 °C. After stirring for 2 h, satd. aqueous NaHCO3
and the solvent was evaporated. The crude product {9/epi-9, Ͼ 96:4 (50 mL) was added and the aqueous layer was extracted with
[1H NMR (2-H)]} was purified by FCC (1130 cm3 SiO2, Et2O/PE,
CH2Cl2 (4 ϫ 100 mL). The combined organic layers were dried
1:5) to give 9 together with traces of epi-9 (4.65 g, 12.3 mmol, 93%, with Na2SO4 and the solvents were removed in vacuo. Purification
dr Ͼ 96:4) as colourless crystals. Ϫ Rf ϭ 0.55 (SiO2, Et2O/PE, 1:1).
of the crude product by FCC (780 cm3 SiO2, gradient PE Ǟ Et2O/
PE, 1:10 Ǟ Et2O) yielded 2 (2.46 g, 10.1 mmol, 93%) as a volatile
Ϫ M.p. 174.9Ϫ175.5 °C (Et2O/PE, 1:5). Ϫ [α]2D0 ϭ Ϫ44.7 (c ϭ 0.68,
CH2Cl2); ent-9: [α]2D0 ϭ ϩ44.1 (c ϭ 1.00, CH2Cl2). Ϫ 1H NMR oil and amino alcohol 10 (2.22 g, 9.12 mmol, 84%) as a white solid.
(300 MHz, CDCl3): δ ϭ 0.85 (t, 3J ϭ 7.6 Hz, 3 H, 2ЈЈ-H3), 1.02 (d,
3J ϭ 6.7 Hz, 3 H, 3Ј-CH3), 1.08 (s, 3 H, 1Ј-CH3), 1.46Ϫ1.61 and KOtBu (245 mg, 2.18 mmol) in toluene (20 mL) was refluxed for
1.61Ϫ1.88 (2 m, 2 H and 6 H, 3Ј-H, 4Ј-H2, 5Ј-H2, 6Ј-H2, 1ЈЈ-H2), 1 h. Most of the solvent was then distilled off and a solution of
Ϫ Method B: A mixture of MePPh3Br (785 mg, 2.20 mmol) and
2.25Ϫ2.42 (m, 1 H, 6Ј-H2), 2.43 (s, 3 H, 4ЈЈЈ-CH3), 3.25Ϫ3.31 (m, ketone 11 (355 mg, 1.45 mmol) in toluene (10 mL) was slowly ad-
1 H, 5-H2), 3.56Ϫ3.68 (m, 2 H, 4-H, 5-H2), 4.81 (s, 1 H, 2Ј-CH2), ded to the boiling mixture. Again, most of the toluene was distilled
Eur. J. Org. Chem. 2001, 647Ϫ654
651

M. Brüggemann, C. Holst, D. Hoppe
FULL PAPER
off and the concentrated mixture was refluxed for 4 h. After cooling
to room temperature, brine (30 mL) was added and the aqueous
layer was extracted with CH2Cl2 (3 ϫ 50 mL). The combined or-
ganic layers were dried (MgSO4) and the solvent was evaporated.
The crude product [1H NMR (2-H): 2/epi-2, 81:19] was purified by
FCC (250 cm3 SiO2, gradient Et2O/PE, 1:10 Ǟ Et2O/PE, 1:5) to
(2.15 g, 8.95 mmol, 79%) as a colourless oil. Ϫ Rf ϭ 0.27 (SiO2,
Et2O/PE, 1:1). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 3.70 (s, 8 H,
2-H2, 2Ј-OCH3, 6Ј-OCH3), 3.85 (s, 6 H, 3Ј-OCH3, 5Ј-OCH3), 6.50
(s, 1 H, 4Ј-H), 9.68 (t, 3J ϭ 1.5 Hz, 1 H, 1-H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 39.5 (t, C-2), 56.4 (q, 3Ј-OCH3, 5Ј-OCH3),
60.8 (q, 2Ј-OCH3, 6Ј-OCH3), 98.9 (d, C-4Ј), 121.2 (s, C-1Ј), 141.2
1
give a mixture of 2 and epi-2 (183 mg, 0.75 mmol, 52%, dr ϭ 80:20) (s, C-2Ј, C-6Ј), 148.9 (s, C-3Ј, C-5Ј), 199.5 (d, C-1). Ϫ IR (film):
as a volatile colourless liquid, along with diastereomerically pure ν˜ ϭ 2920 s, 1710 s, 1590 m, 1480 s, 1340 m, 1225 s, 1070 s, 1000
11 (65 mg, 0.26 mmol, 18%). Ϫ Rf ϭ 0.64 (SiO2, Et2O/PE, 1:1). Ϫ m, 960 w, 845 w. Ϫ EI-MS: m/z (%) ϭ 240 (100) [Mϩ], 225 (38),
[α]2D0 ϭ Ϫ3.1 (c ϭ 0.80, CH2Cl2); ent-2: [α]2D0 ϭ ϩ1.75 (c ϭ 1.10,
196 (28), 182 (72), 167 (20), 153 (23). Ϫ C12H16O5 (240.26): calcd.
CH2Cl2). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.06 (d, 3J ϭ 6.7 Hz, C 59.99, H 6.71; found C 60.14, H 6.80.
3 H, 3Ј-CH3), 1.05Ϫ1.20 (m, 1 H, 4Ј-H2), 1.23 (s, 3 H, 1Ј-CH3),
Ethyl
(E)-2-Methyl-4-(2,3,5,6-tetramethoxyphenyl)-2-butenoate
1.49Ϫ1.74 (m, 4 H, 4Ј-H2, 5Ј-H2, 6Ј-H2), 1.75Ϫ1.90 (m, 2 H, 5-
H2, 6Ј-H2), 2.02Ϫ2.10 (m, 1 H, 5-H2), 2.30Ϫ2.43 (m, 1 H, 3Ј-H),
(14): Ylide 16 (2.55 g, 7.03 mmol) was treated with a solution of
aldehyde 13 (1.30 g, 5.41 mmol) in CH2Cl2 (70 mL) and the re-
sulting mixture was refluxed for 3 h. Satd. brine (100 mL) was then
added, the aqueous layer was extracted with CH2Cl2 (3 ϫ 100 mL),
and the combined organic layers were dried (Na2SO4) and concen-
trated in vacuo. FCC (440 cm3 SiO2, gradient Et2O/PE, 1:3 Ǟ
Et2O/PE, 1:2) furnished ester 14 [1.61 g, 4.96 mmol, 92%, (E)/(Z) ϭ
98:2 (GC)] as a colourless solid. Ϫ Rf ϭ 0.32 (SiO2, Et2O/PE, 1:1).
Ϫ M.p. 54.7Ϫ55.3 °C (Et2O/PE, 1:2). Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 1.22 (t, 3J ϭ 7.2 Hz, 3 H, 2ЈЈ-H3), 1.99 (d, 4J ϭ 1.2 Hz,
2
2.84Ϫ2.92 (m, 4 H, 4-H2, 6-H2), 4.32 (s, 1 H, 2-H), 4.92 (d, J ϭ
1.4 Hz, 1 H, 2Ј-CH2), 5.11 (s, 1 H, 2Ј-CH2). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 19.7 (q, 3Ј-CH3), 20.8 (t, C-5Ј), 24.3 (q, 1Ј-CH3), 26.4
(t, C-5), 31.8 and 32.0 (2 t, C-4, C-6), 34.9 (d, C-3Ј), 35.9 (t, C-4Ј),
37.4 (t, C-6Ј), 44.9 (s, C-1Ј), 60.4 (d, C-2), 108.5 (t, 2Ј-CH2), 154.3
(s, C-2Ј). Ϫ IR (film): ν˜ ϭ 3080 w, 2900 s, 1620 m, 1440 m, 1410
m, 1270 m, 1180 w, 1050 w, 900 s, 770 m cmϪ1. Ϫ EI-MS: m/z
(%) ϭ 242 (8) [Mϩ], 121 (9), 119 (100), 106 (3). Ϫ C13H22S2
(242.44): calcd. C 64.40, H 9.15; found C 64.83, H 9.28.
3
3 H, 2-CH3), 3.52 (dd, J ϭ 7.2 Hz, J ϭ 0.9 Hz, 2 H, 4-H2), 3.74
(s, 6 H, 2Ј-OCH3, 6Ј-OCH3), 3.82 (s, 6 H, 3Ј-OCH3, 5Ј-OCH3), 4.22
(q, J ϭ 7.2 Hz, 2 H, 1ЈЈ-H2), 6.44 (s, 1 H, 4Ј-H), 6.74 (m, 1 H, 3-
2-(2,3,5,6-Tetramethoxyphenyl)ethan-1-ol (12):
A
solution of
3
1,2,4,5-tetramethoxybenzene[9] (5) (1.98 g, 10.0 mmol) and LiCl
(1.27 g, 30.0 mmol) in THF (100 mL) was cooled to 0 °C, where-
upon a 1.6  solution of nBuLi in hexane (6.90 mL, 11.0 mmol)
was added dropwise. After stirring at room temperature for 30 min,
the reaction mixture was cooled to Ϫ78 °C and transferred by
means of a cannula into a solution of ethylene oxide (ca. 5 g,
114 mmol) in THF (30 mL). The resulting mixture was stirred at
Ϫ78 °C for 30 min and thereafter at room temperature for a further
3 h. 2  aqueous HCl (50 mL) was then added at 0 °C and the
heterogeneous mixture was stirred for 30 min. The aqueous layer
was subsequently extracted with Et2O (4 ϫ 150 mL), the combined
organic layers were dried (MgSO4), and the solvents were evapor-
ated in vacuo. FCC (850 cm3 SiO2, gradient Et2O/PE, 2:1 Ǟ Et2O)
provided alcohol 12 (1.94 g, 8.00 mmol, 80%) as a waxy solid. Ϫ
H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 12.4 (q, C-2ЈЈ), 14.2 (q,
2-CH3), 24.3 (t, C-4), 56.3 (q, 3Ј-OCH3, 5Ј-OCH3), 60.3 (t, C-1ЈЈ),
60.8 (q, 2Ј-OCH3, 6Ј-OCH3), 97.8 (d, C-4Ј), 127.2 and 127.4 (2 s,
C-2, C-1Ј), 140.6 (d, C-3), 141.17 (s, C-2Ј, C-6Ј), 148.9 (s, C-3Ј, C-
5Ј), 168.2 (s, C-1). Ϫ IR (KBr): ν˜ ϭ 2910 s, 1695 s, 1630 w, 1590
w, 1480 s, 1340 m, 1230 s, 1050 s, 960 w, 800 w cmϪ1. Ϫ EI-MS:
m/z (%) ϭ 323 (100) [Mϩ Ϫ H], 308 (5), 292 (4), 278 (12), 247 (11),
235 (59), 220 (18). Ϫ C17H24O6 (324.38): calcd. C 62.95, H 7.46;
found C 63.01, H 7.68.
(E)-2-Methyl-4-(2,3,5,6-tetramethoxyphenyl)-2-buten-1-ol (17):
A
1.0  solution of DIBAL-H in CH2Cl2 (28.4 mL, 28.4 mmol) was
added dropwise to a solution of ester 14 (1.84 g, 5.67 mmol) in
CH2Cl2 (50 mL) at Ϫ78 °C. After stirring for 2.5 h at this temper-
ature, the reaction mixture was hydrolyzed by the addition of H2O
(15 mL) and allowed to warm to room temperature. 2  aqueous
HCl (100 mL) was added and the aqueous layer was extracted with
CH2Cl2 (3 ϫ 150 mL). The combined organic layers were dried
(Na2SO4) and the solvent was evaporated in vacuo. Purification of
the crude product by FCC (500 cm3 SiO2, Et2O/PE, 3:1) yielded
alcohol 17 (1.47 g, 5.21 mmol, 92%) as a colourless oil. Ϫ Rf ϭ
1
Rf ϭ 0.23 (SiO2, Et2O). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 2.04
3
(s, 1 H, 1-OH), 2.94 (t, J ϭ 6.6 Hz, 2 H, 2-H2), 3.76 (s, 6 H, 2Ј-
OCH3, 6Ј-OCH3), 3.77 (t, 3J ϭ 6.6 Hz, 2 H, 1-H2), 3.83 (s, 6 H,
3Ј-OCH3, 5Ј-OCH3), 6.44 (s, 1 H, 4Ј-H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 28.0 (t, C-2), 56.3 (q, 3Ј-OCH3, 5Ј-OCH3), 60.9 (q,
2Ј-OCH3, 6Ј-OCH3), 63.4 (t, C-1), 97.9 (d, C-4Ј), 126.9 (s, C-1Ј),
141.3 (s, C-2Ј, C-6Ј), 149.0 (s, C-3Ј, C-5Ј). Ϫ IR (film): ν˜ ϭ 3400 s,
2920 s, 1590 m, 1480 s, 1360 s, 1230 s, 1080 s, 850 w cmϪ1. Ϫ EI-
MS: m/z (%) ϭ 242 (100) [Mϩ], 227 (45), 211 (9), 195 (37), 181
(35), 166 (11), 153 (60), 139 (18), 125 (16). Ϫ C12H18O5 (242.27):
calcd. C 59.49, H 7.48; found C 59.57, H 7.38.
1
0.29 (SiO2, Et2O). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.34 (s, 1
H, 1-OH), 1.82 (d, 4J ϭ 0.3 Hz, 3 H, 2-CH3), 3.39 (d, 3J ϭ 7.2 Hz,
2 H, 4-H2), 3.74 (s, 6 H, 2Ј-OCH3, 6Ј-OCH3), 3.82 (s, 6 H, 3Ј-
3
4
OCH3, 5Ј-OCH3), 3.95 (s, 2 H, 1-H2), 5.45 (td, J ϭ 7.2 Hz, J ϭ
0.3 Hz, 1 H, 3-H), 6.41 (s, 1 H, 4Ј-H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 13.7 (q, 2-CH3), 23.3 (t, C-4), 56.3 (q, 3Ј-OCH3, 5Ј-
OCH3), 60.8 (q, 2Ј-OCH3, 6Ј-OCH3), 68.9 (t, C-1), 97.3 (d, C-4Ј),
125.0 (d, C-3), 129.1 (s, C-1Ј), 134.6 (s, C-2), 141.0 (s, C-2Ј, C-6Ј),
148.9 (s, C-3Ј, C-5Ј). Ϫ IR (film): ν˜ ϭ 3400 s, 2910 s, 1590 m, 1450
s, 1340 m, 1230 s, 1050 s, 830 w cmϪ1. Ϫ EI-MS: m/z (%) ϭ 282
(100) [Mϩ], 249 (8), 233 (16), 209 (12), 202 (20), 181 (11), 178 (16).
Ϫ C15H22O5 (282.34): calcd. C 63.81, H 7.85; found C 63.71, H
7.92.
2-(2,3,5,6-Tetramethoxyphenyl)ethanal (13): To a cooled (Ϫ60 °C)
solution of (COCl)2 (2.00 mL, 22.9 mmol) in CH2Cl2 (100 mL), a
solution of DMSO (3.24 mL, 45.7 mmol) in CH2Cl2 (20 mL) was
added dropwise and the resulting mixture was stirred for 15 min.
Then, a solution of alcohol 12 (2.76 g, 11.4 mmol) in CH2Cl2
(30 mL) was slowly added. The reaction mixture was allowed to
warm to Ϫ30 °C over a period of 1 h, NEt3 (12.7 mL, 91.1 mmol)
was added, and the resulting solution was stirred for 1 h at room
temperature. 2  aqueous HCl (100 mL) was then added and the
aqueous layer was extracted with CH2Cl2 (3 ϫ 100 mL). The com- 3-[(E)-4-Bromo-3-methyl-2-butenyl]-1,2,4,5-tetramethoxybenzene
bined organic layers were dried (Na2SO4) and the solvents were
evaporated. The crude product was purified by FCC (850 cm3 SiO2,
gradient Et2O/PE, 1:2 Ǟ Et2O/PE, 1:1) to furnish aldehyde 13
(3): To a solution of alcohol 17 (1.00 g, 3.54 mmol) in CH2Cl2 at
Ϫ40 °C, NEt3 (0.78 mL, 5.6 mmol) followed by MsCl (0.36 mL,
4.7 mmol) were added. After stirring for 1.5 h, a solution of LiBr
652
Eur. J. Org. Chem. 2001, 647Ϫ654

First Enantioselective Total Synthesis of Both (ϩ)- and (Ϫ)-Metachromin A
FULL PAPER
(1.23 g, 14.2 mmol) in THF (25 mL) was added and the resulting
subjected to FCC (500 cm3 SiO2, Et2O/PE, 1:9) to yield 19 (560 mg,
1.39 mmol, 95%) as a resinous colourless oil. Ϫ Rf ϭ 0.47 (SiO2,
mixture was stirred for 2.5 h at 0 °C. It was then poured into PE
(250 mL) and extracted with H2O (4 ϫ 200 mL). Drying (Na2SO4) Et2O/PE, 1:1). Ϫ [α]2D0 ϭ Ϫ15.2 (c ϭ 0.79, CH2Cl2); ent-19: [α]2D0
ϭ
1
of the organic layer and evaporation of the solvents afforded an
adequately pure crude product (1.20 g, 3.48 mmol, 98%). FCC (310
ϩ15.2 (c ϭ 0.86, CH2Cl2) . Ϫ H NMR (300 MHz, CDCl3): δ ϭ
0.81Ϫ1.00, 1.10Ϫ1.30, 1.40Ϫ1.75, and 1.75Ϫ1.80 (4 m, 1 H, 1 H,
cm3 SiO2, Et2O/PE, 1:2) provided the bromide
3 (1.09 g, 5 H, and 1 H, 4ЈЈ-H2, 5ЈЈ-H2, 6ЈЈ-H2, 5Ј-H2), 0.99 (s, 3 H, 1ЈЈ-CH3),
3.16 mmol, 89%) as a colourless oil. Ϫ Rf ϭ 0.40 (SiO2, Et2O/PE,
1.00 (d, 3J ϭ 6.4 Hz, 3 H, 3ЈЈ-CH3), 1.79 (s, 3 H, 3Ј-CH3),
1.93Ϫ2.00 (m, 2 H, 4Ј-H2), 2.26Ϫ2.34 (m, 1 H, 3ЈЈ-H), 3.37 (d,
1
4
1:1). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.90 (d, J ϭ 0.3 Hz, 3
H, 3Ј-CH3), 3.38 (d, 3J ϭ 7.2 Hz, 2 H, 1Ј-H2), 3.73 (s, 6 H, 2- 3J ϭ 6.4 Hz, 2 H, 1Ј-H2), 3.74 (s, 6 H, 2-OCH3, 4-OCH3), 3.82 (s,
OCH3, 4-OCH3), 3.82 (s, 6 H, 1-OCH3, 5-OCH3), 3.93 (s, 2 H, 4Ј-
6 H, 1-OCH3, 5-OCH3), 4.65 (s, 1 H, 2ЈЈ-CH2), 4.67 (s, 1 H, 2ЈЈ-
3
4
H2), 5.63 (td, J ϭ 7.2 Hz, J ϭ 0.3 Hz, 1 H, 2Ј-H), 6.42 (s, 1 H, CH2), 5.13Ϫ5.23 (m, 1 H, 2Ј-H), 6.41 (s, 1 H, 6-H). Ϫ 13C NMR
6-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 14.7 (q, 3Ј-CH3), 24.0 (75 MHz, CDCl3): δ ϭ 16.3 (q, 3Ј-CH3), 19.6 (q, 3ЈЈ-CH3), 21.8 (t,
(t, C-1Ј), 41.8 (t, C-4Ј), 56.3 (q, 1-OCH3, 5-OCH3), 60.8 (q, 2-
C-5ЈЈ), 23.7 (t, C-1Ј), 24.7 (q, 1ЈЈ-CH3), 34.0 (d, C-3ЈЈ), 39.2 (s, C-
OCH3, 4-OCH3), 97.5 (d, C-6), 128.1 (s, C-3), 130.0 (d, C-2Ј), 131.4 1ЈЈ), 34.0, 37.2, 38.7, and 40.1 (4 t, C-4Ј, C-5Ј, C-4ЈЈ, C-6ЈЈ), 56.4
(s, C-3Ј), 141.0 (s, C-2, C-4), 148.9 (s, C-1, C-5). Ϫ IR (film): ν˜ ϭ (q, 1-OCH3, 5-OCH3), 60.8 (q, 2-OCH3, 4-OCH3), 97.4 (d, C-6),
2905 s, 1580 m, 1450 s, 1345 m, 1200 s, 1050 s, 1000 w, 830 w cmϪ1
.
103.4 (t, 2ЈЈ-CH2), 122.9 (d, C-2Ј), 130.2 (s, C-3), 135.8 (s, C-3Ј),
141.3 (s, C-2, C-4), 149.0 (s, C-1, C-5), 159.8 (s, C-2ЈЈ). Ϫ IR (film):
Ϫ EI-MS: m/z (%) ϭ 344/346 (100/98) [Mϩ], 265 (69), 250 (32),
234 (56), 219 (20), 203 (20), 191 (20), 187 (18). Ϫ C15H21O4Br ν˜ ϭ 2930 s, 2850 s, 1639 w, 1604 m, 1487 s, 1467 s, 1425 s, 1343 m,
(345.24): calcd. C 52.19, H 6.13; found C 52.24, H 6.30.
1246 s, 1095 s, 1088 s, 1019 m, 978 w, 895 w cmϪ1. Ϫ EI-MS: m/z
(%) ϭ 402 (100) [Mϩ], 278 (59), 263 (24), 247 (29), 233 (37), 211
(70), 196 (66), 191 (33), 181 (35), 171 (34), 123 (33), 109 (57), 95
(66). Ϫ HRMS (C25H38O4): calcd. 402.2770; found 402.2780.
(؉)-2-[(1S,3R)-1,3-Dimethyl-2-methylenecyclohexyl]-2-[(E)-2-
methyl-4-(2,3,5,6-tetramethoxyphenyl)-2-butenyl]-1,3-dithiane (18):
A 1.7  solution of tBuLi in pentane (1.23 mL, 2.09 mmol) was
slowly added to a solution of dithiane 2 (485 mg, 2.00 mmol) in
THF (40 mL) and HMPTA (1.04 mL, 5.98 mmol) at Ϫ78 °C. The
yellow mixture thus obtained was stirred for 2.5 h and then a solu-
tion of bromide 3 (691 mg, 2.00 mmol) in THF (8 mL) was added
dropwise. After stirring for a further 3 h at Ϫ78 °C, MeOH/H2O
(1:1, 10 mL) was added and the reaction mixture was allowed to
warm to room temperature. The mixture was passed through a pad
of silica gel eluting with Et2O/PE, 1:1, so as to remove HMPTA,
the solvents were evaporated, and the residue was subjected to FCC
(500 cm3 SiO2, Et2O/PE, 1:10). The dithiane 18 (864 mg,
1.70 mmol, 85%) was obtained as a resinous colourless oil. Ϫ Rf ϭ
0.40 (SiO2, Et2O/PE, 1:1). Ϫ [α]2D0 ϭ ϩ31.1 (c ϭ 0.63, CH2Cl2);
(؊)-Metachromin A (1): To a solution of compound 19 (474 mg,
1.17 mmol) in MeCN (10 mL), a solution of CAN (1.61 g,
2.94 mmol) in MeCN/H2O (7:3, 10 mL) was added over a period
of 1.5 h (syringe pump) at Ϫ7 °C. The resulting reaction mixture
was stirred at room temperature for 2 h. The organic layer was
then washed with H2O (2 ϫ 20 mL) and the aqueous layers were
extracted with Et2O (3 ϫ 20 mL). The combined organic phases
were dried (Na2SO4) and the solvents were removed in vacuo. FCC
(80 cm3 RP-18, gradient MeCN/H2O, 2:1 Ǟ MeCN/H2O, 3:1) af-
forded metachromin A (1, 154 mg, 0.43 mmol, 37%) and the methyl
ether 20 (162 mg, 0.40 mmol, 34%) as orange oils. Both compounds
were crystallized from Et2O/PE to give orange needles. Ϫ Rf ϭ
0.43 (RP-18, MeCN/H2O, 9:1). Ϫ M.p. 80.7Ϫ81.2 °C (Et2O) (ref.[1]
1
ent-18: [α]2D0 ϭ Ϫ28.8 (c ϭ 0.86, CH2Cl2). Ϫ H NMR (300 MHz,
80Ϫ82 °C). Ϫ [α]2D7 ϭ Ϫ17.6 (c ϭ 0.94, CHCl3) {ref.[1] [α]2D7
Ϫ11.0 (c ϭ 1.00, CHCl3)}; ent-1: [α]2D7 ϭ ϩ17.3 (c ϭ 0.55, CHCl3).
1H NMR (400 MHz, CDCl3): δ ϭ 0.87Ϫ1.02, 1.13Ϫ1.22,
ϭ
CDCl3): δ ϭ 0.83Ϫ1.04, 1.55Ϫ1.80, 1.80Ϫ1.98, and 2.05Ϫ2.15
(4 m, 1 H, 5 H, 1 H, and 1 H, 4ЈЈ-H2, 5ЈЈ-H2, 6ЈЈ-H2, 5-H2), 0.96
(d, 3J ϭ 6.4 Hz, 3 H, 3ЈЈ-CH3), 1.34 (s, 3 H, 1ЈЈ-CH3), 2.14 (s, 3 H,
2Ј-CH3), 2.16Ϫ2.31 (m, 1 H, 3ЈЈ-H), 2.46Ϫ2.61, 2.61Ϫ2.85, and
2.85 Ϫ3.05 (3 m, 1 H, 3 H, and 2 H, 4-H2, 6-H2, 1Ј-H2), 3.39 (d,
3J ϭ 6.9 Hz, 2 H, 4Ј-H2), 3.76 (s, 6 H, 2ЈЈЈ-OCH3, 6ЈЈЈ-OCH3), 3.81
(s, 6 H, 3ЈЈЈ-OCH3, 5ЈЈЈ-OCH3), 4.94 (d, 2J ϭ 1.4 Hz, 1 H, 2ЈЈ-
CH2), 5.53Ϫ5.62 (m, 2 H, 2ЈЈ-CH2, 3Ј-H), 6.41 (s, 1 H, 4ЈЈЈ-H). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 19.3 (q, 2Ј-CH3), 19.9 (q, 3ЈЈ-
CH3), 20.4 (q, 1ЈЈ-CH3), 22.3, 22.7, 27.2, and 27.9 (4 t, C-4, C-5,
C-6, C-5ЈЈ), 24.0 (t, C-4Ј), 34.0 and 36.9 (2 t, C-4ЈЈ, C-6ЈЈ), 34.8 (d,
C-3ЈЈ), 47.5 (t, C-1Ј), 54.3 (s, C-1ЈЈ), 56.4 (q, 3ЈЈЈ-OCH3, 5ЈЈЈ-
OCH3), 60.8 (q, 2ЈЈЈ-OCH3, 6ЈЈЈ-OCH3), 66.7 (s, C-2), 97.6 (d, C-
4ЈЈЈ), 108.7 (t, 2ЈЈ-CH2), 129.6 and 131.7 (2 s, C-2Ј, C-1ЈЈЈ), 129.9
(d, C-3Ј), 141.4 (s, C-2ЈЈЈ, C-6ЈЈЈ), 148.9 (s, C-3ЈЈЈ, C-5ЈЈЈ), 153.4 (s,
C-2ЈЈ). Ϫ IR (film): ν˜ ϭ 2980 s, 1580 w, 1450 m, 1335 w, 1210 m,
1045 m cmϪ1. Ϫ EI-MS: m/z (%) ϭ 506 (14) [Mϩ], 383 (45), 241
(49), 211 (50), 196 (37), 181 (21), 153 (20), 133 (23), 125 (27), 123
(31), 119 (43). Ϫ HRMS (C28H42O4S2): calcd. 506.2524; found
506.2526. Ϫ C28H42O4S2 (506.78): calcd. C 66.36, H 8.35; found C
66.96, H 8.29.
Ϫ
1.41Ϫ1.65, and 1.65Ϫ1.75 (4 m, 1 H, 1 H, 5 H, and 1 H, 1-H2, 2-
H2, 3-H2, 7-H2), 0.98 (s, 3 H, 14-H3), 0.99 (d, 3J ϭ 6.4 Hz, 3 H,
12-H3), 1.73 (s, 3 H, 15-H3), 1.91Ϫ1.96 (m, 2 H, 8-H2), 2.27Ϫ2.32
3
(m, 1 H, 4-H), 3.13 (d, J ϭ 7.2 Hz, 2 H, 11-H2), 3.82 (s, 3 H, 22-
H3), 4.65 (s, 1 H, 13-H2), 4.67 (s, 1 H, 13-H2), 5.13 (td, 3J ϭ 7.2 Hz,
4J ϭ 1.0 Hz, 1 H, 10-H), 5.81 (s, 1 H, 19-H), 7.26 (s, 1 H, OH). Ϫ
13C NMR (100 MHz, CDCl3):[23] δ ϭ 16.3 (q, C-15), 19.6 (q, C-
12), 21.8 (t, C-11), 24.7 (q, C-14), 34.0 (d, C-4), 39.2 (s, C-6), 21.8,
34.0, 37.2, 38.7, and 40.0 (5 t, C-1, C-2, C-3, C-7, C-8), 56.7 (q, C-
22), 102.2 (d, C-19), 103.3 (t, C-13), 118.3 (s, C-9), 118.8 (d, C-10),
138.3 (s, C-16), 151.2, 159.2, and 161.1 (3 s, C-5, C-17, C-20), 181.4
and 183.0 (2 s, C-18, C-21). Ϫ IR (film): ν˜ ϭ 3346 s, 2920 s, 2856
s, 1649 s, 1607 s, 1450 w, 1387 m, 1308 m, 1230 m, 1202 m, 1039
w cmϪ1. Ϫ EI-MS: m/z (%) ϭ 358 (16) [Mϩ], 234 (13), 219 (40),
207 (38), 189 (68), 180 (48), 170 (54), 168 (81), 133 (22), 123 (31),
119 (33), 109 (100), 95 (69). Ϫ HRMS (C22H30O4): calcd. 358.2144;
found 358.2149. Ϫ C22H30O4 (358.48): calcd. C 73.71, H 8.44;
found C 73.45, H 8.71.
(؊)-3-{(E)-5-[(1R,3R)-1,3-Dimethyl-2-methylenecyclohexyl]-3-
methyl-2-pentenyl}-1,2,4,5-tetramethoxybenzene (19): Dithiane 18
(740 mg, 1.46 mmol) was dissolved in Bu3SnH (5.80 mL,
21.6 mmol) and the resulting solution was heated to 120 °C for
30 h. Initially, and then at intervals of 2 h, 1 mg portions of solid
AIBN were added. The crude reaction mixture was subsequently
Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft is
gratefully acknowledged. MB wishes to thank Mrs. Ute Janz and
Mrs. Karin Gottschalk for technical assistance and the Graduier-
tenkolleg ‘‘Hochreaktive Mehrfachbindungssysteme’’ for a fellow-
Eur. J. Org. Chem. 2001, 647Ϫ654
653

M. Brüggemann, C. Holst, D. Hoppe
FULL PAPER
for ent-9. Copies of the data can be obtained free of charge
on application to the CCDC, 12 Union Road, Cambridge
CB2 1EZ, U.K. [Fax: (internat.) ϩ 44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
ship. We thank Prof. C. R. D. Correia (Universidade Federal de
Rio de Janeiro, Brazil) for kindly providing spectra of racemic
metachromin A.
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Programs used: data collection: Express (Nonius B.V., 1994);
data reduction and absorbtion correction: MolEN (K. Fair,
Enraf؊Nonius B.V., 1990); structure solution: SHELXS-86
and SHELXS-97 (G. M. Sheldrick, Acta Crystallogr. 1990,
A46, 467؊473); structure refinement: SHELXL-97 (G. M.
Sheldrick, Universität Göttingen, 1997), graphic presentation:
MoPict 3.0 (M. Brüggemann, Universität Münster, 2000).
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC-147881 for 9 and CCDC-147882
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J. Pfeifer, H. Gerlach, Liebigs
At variance with ref.[1], we did not detect any 13C resonance at
δ ϭ 28.6. We observed two triplet signals at δ ϭ 21.8 rather
than one, and found the signal at δ ϭ 33.9 to be a doublet
rather than a triplet. All other shifts were in accordance with
the literature. The results of DEPT, 1H-1H COSY, HMQC, and
HMBC spectra confirm the structure of metachromin A (1).
Received August 17, 2000
[23]
[O00416]
654
Eur. J. Org. Chem. 2001, 647Ϫ654