Highly Enantioselective Intermolecular Cu(I)-Catalyzed Cyclopropanation of Cyclic Enol Ethers. Asymmetric Total Synthesis of (+)-Quebrachamine

Article abstract of DOI:10.1021/jo9807417

A set of cyclic enol ethers derived from 2,3-dihydrofuran 35 and 3,4-dihydropyran 8 with a varying substitution pattern at the olefinic system were synthesized. Evans's ligand 5 with Cu(I)OTf was found to be an effective catalyst in the cyclopropanation reaction between cyclic enol ethers 14, 19, 28-31, and 33 and ethyl diazoacetate 6 to give diastereoselectivities up to exo/endo = 95:5 and enantioselectivities higher than 95% in nearly all cases. Because of the selective building of a quarternary carbon center and good yields in the formation of bicyclic structures 34c-h, the reaction was used as a key step in the asymmetric synthesis of (+)-quebrachamine 7, an indole alkaloid of the Aspidosperma family. After acid-induced ring opening of bicyclic compound 34f to lactone 40 followed by LiAlH₄ reduction to the masked aldehyde 41, a reaction with tryptamine gave intermediate 42. This alcohol was efficiently converted into the indole alkaloid (+)-quebrachamine 7 in an overall yield of 37% starting from the chiral synthon 34f. Moreover it revealed the absolute configuration of the quarternary center of the cyclopropanation product 34f to be S.

Full text of DOI:10.1021/jo9807417

J . Org. Chem. 1998, 63, 6007-6015
6007
High ly En a n tioselective In ter m olecu la r Cu (I)-Ca ta lyzed
Cyclop r op a n a tion of Cyclic En ol Eth er s. Asym m etr ic Tota l
Syn th esis of (+)-Qu ebr a ch a m in e
Oliver Temme, Shabbir-Ali Taj, and Pher G. Andersson*
Department of Organic Chemistry, Uppsala University, Box 531, S-751 21 Uppsala, Sweden
Received April 21, 1998
A set of cyclic enol ethers derived from 2,3-dihydrofuran 35 and 3,4-dihydropyran 8 with a varying
substitution pattern at the olefinic system were synthesized. Evans’s ligand 5 with Cu(I)OTf was
found to be an effective catalyst in the cyclopropanation reaction between cyclic enol ethers 14, 19,
28-31, and 33 and ethyl diazoacetate 6 to give diastereoselectivities up to exo/endo ) 95:5 and
enantioselectivities higher than 95% in nearly all cases. Because of the selective building of a
quarternary carbon center and good yields in the formation of bicyclic structures 34c-h , the reaction
was used as a key step in the asymmetric synthesis of (+)-quebrachamine 7, an indole alkaloid of
the Aspidosperma family. After acid-induced ring opening of bicyclic compound 34f to lactone 40
followed by LiAlH4 reduction to the masked aldehyde 41, a reaction with tryptamine gave
intermediate 42. This alcohol was efficiently converted into the indole alkaloid (+)-quebrachamine
7 in an overall yield of 37% starting from the chiral synthon 34f. Moreover it revealed the absolute
configuration of the quarternary center of the cyclopropanation product 34f to be S.
In tr od u ction
semicorrins7 3 and bisoxazolines8 4 and 5 as chiral
catalysts in the asymmetric cyclopropanation of alkenes
with diazo esters (Figure 1).
The enantioselective [2 + 1] cycloaddition of carbenes
to olefins is a synthetically useful reaction since two new
carbon-carbon bonds and potentially up to three chiral
centers are formed in one step and the resulting three-
membered ring systems occur in many natural products
and biologically active compounds.1 Moreover, ring open-
ing reactions with the preservation of the stereochemistry
further increases the scope of cyclopropanes as useful
intermediates in organic synthesis.2 The asymmetric
cyclopropanation catalyzed by a chiral transition metal
complex is a very expedient route to enantiomerically
pure cyclopropanes.3 The first example was reported by
Nozaki et al. in 1966 using a copper(II) complex of the
chiral Schiff base 1 as the catalyst in the reaction
between a diazo ester and an alkene to form cyclopro-
panes.4 Then Aratani et al. optimized the ligand design
of the chiral copper(II) complexes and achieved the first
high enantioselectivities in the intermolecular cyclopro-
panation reactions using Schiff base 2.5 Further stud-
ies3,6 have led to a variety of interesting regio- and
stereoselective transition metal catalyzed cyclopropana-
tion reactions. The most important progress was made
with the introduction of Cu(I) chelated by C2-symmetric
Donor-acceptor substituted cyclopropanes have proved
to be excellent building blocks for the synthesis of many
functionalized molecular structures.9 Reissig et al. de-
veloped a highly enantioselective cyclopropanation of silyl
enol ethers10 which led to interesting 1,4-difunctionalized
carbonyl compounds after ring opening of the three-
membered ring.11 Evans’s bisoxazoline ligand 5/Cu(I)-
OTf was found to be the most effective catalyst for the
addition of carbenes to silyl enol ethers. The first and
only studysto the best of our knowledgesof the asym-
metric cyclopropanation of enol ethers was also made by
Reissig et al.12 The reaction between Z1-propenyl ethers
and methyl diazoacetate led to good trans-selectivities,
moderate yields, but low enantioselectivities. Moreover,
(6) Some recent papers: (a) Ashutosh, V. B.; Koroleva, E. B.;
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M.; Garcia, J . I.; Mayoral, J . A.; Tarnai, T. Tetrahedron: Asymmetry
1997, 8, 2089. (d) Bolm, C.; Pupowicz, D. Tetrahedron Lett. 1997, 38,
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Commun. 1997, 1785. (f) Frauenkron, M.; Berkessel, A. Tetrahedron
Lett. 1997, 38, 7175. (g) Haddad, N.; Galili, N. Tetrahedron: Asymmetry
1997, 8, 3367. (h) Pyne, S. G.; Dong, Z.; Skelton, B. W.; White, A. H.
J . Org. Chem. 1997, 62, 2337. (i) Denmark, S. E.; O’Connor, S. P. J .
Org. Chem. 1997, 62, 3390.
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Group; Patai, S., Rappaport, Z., Eds.; Wiley: New York, 1987. (b)
Saluen, J . Chem. Rev. 1989, 89, 1247.
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Hudlicky, T. Chem. Rev. 1989, 89, 165.
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Ed. Engl. 1986, 25, 1005. (b) Frischi, H.; Leuteneggar, U.; Pfaltz A.
Helv. Chim. Acta 1988, 71, 1553.
(3) (a) Singh, K. V.; Datta Goupta, A.; Sekar, G. Synthesis 1997,
137. (b) Doyle, M. P. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
VCH: Weinheim, 1993, 63. (c) Reissig, H. U. In Stereoselective
Synthesis, Houben-Weyl; Helmchen, G., Hoffmann R. W., Mulzer, J .,
Schaumann, E., Eds.; Thieme: Stuttgart 1996; E21, Vol. 5, p 3179.
(d) Doyle, M. P. In Comprehensive Organometallic Chemistry II;
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1966, 5239.
(5) (a) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1975,
1707. (b) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1977,
2599.
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Acta 1991, 74, 232. (b) Lowenthal, R. E.; Aibko, A.; Masamune, S.
Tetrahedron Lett. 1990, 31, 6005. (c) Lowenthal, R. E.; Masamune, S.
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M. M. J . Am. Chem. Soc. 1991, 113, 726. (e) Evans, D. A.; Woerpel, K.
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S0022-3263(98)00741-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/01/1998

6008 J . Org. Chem., Vol. 63, No. 17, 1998
Temme et al.
Sch em e 1a
F igu r e 1. Chiral ligands for Cu(I)-catalyzed asymmetric
cyclopropanations with diazomethane esters.
the absolute configuration of the cyclic products was not
determined.
In this paper we present the first study of the synthesis
and highly stereo- and enantioselective cyclopropanation
of cyclic enol ethers using ethyl diazoacetate 6 and
Evans’s bisoxazoline ligand 5/Cu(I)OTf as the catalyst.
Furthermore, the absolute configuration of the bicyclic
products was determined via the total synthesis of the
natural product (+)-quebrachamine 7.
a
Reagents: (i) Na, diethyl carbonate, H2SO4 concd, 46%; (ii)
acetone, NaI, EtI, K2CO3, reflux, 97%; (iii) ethanol, 2 M NaOH,
reflux, 39%; (iv) THF, DIBAL, 90%; (v) quinoline, p-TsOH, 190
°C, 32%; (vi) CuSO4, N2CHCO2Et, reflux, 90%; (vii) diethyl ether,
LiAlH4, 99%; (viii) 0.5 M H2SO4 in methanol, 60 °C, 60%; (ix) ethyl
acetate, 2.4 mol % PtO2, 120 psi H2, 96%; (x) quinoline, p-TsOH,
190 °C, 92%.
Resu lts a n d Discu ssion
Syn th esis of Cyclic En ol Eth er s a s Cyclop r op a -
n a tion P r ecu r sor s. Enol ethers are useful intermedi-
ates in organic synthesis because they show interesting
behavior in cycloadditions and reactions with electro-
philes due to the unusual polarity of the olefinic system.13
Cyclic enol ethers are by far the most stable compounds
of this class, and 3,4-dihydropyran 8 is even often used
as a protecting group for primary and secondary alcohols
in organic synthesis.14 However, only a few short studies
about the synthesis of cyclic enol ethers with different
substitution patterns have been reported.15 First we
chose two synthetic routes developed by Wenkert et al.16
and Zenk and Wiley17 for the formation of an ethyl-
substituted pyran and furan ring system (Scheme 1) to
compare them in the cyclopropanation with diazo esters.
Enol ether 4-ethyl-2,3-dihydrofuran 14 was synthe-
sized via the alkylated butyrolactone 12 followed by
reduction with DIBALH and elimination via the tosylate.
The 5-ethyl-3,4-dihydropyran 19 was prepared by the
route developed by Wenkert et al. where the alkyl group
is introduced via the cyclopropanation of 3,4-dihydropy-
ran 8 with ethyl diazoacetate. Subsequent reduction
with lithium aluminum hydride, acid-induced ring open-
ing, and hydrogenation of the resulting olefin 17 gave
18 in which the methoxy group was eliminated to afford
the final enol 19. In both cases, for the synthesis of enol
ethers 14 and 19, the overall yield could be improved
after slight changes of the literature procedures.
The main target was to find a short and efficient route
which would allow the preparation of a series of cyclic
enol ethers with different substituents at the olefinic
system. Following a literature procedure,18 4-benzyl-2,3-
dihydrofuran 29 was prepared via a three-step procedure
(Scheme 2). Deprotonation of butyrolactone 9 with LDA
and addition of an electrophile resulted in the alkylated
lactone 21. Subsequent reduction with DIBALH gave
alcohol 25 which was subjected to mesylation and elimi-
nation to give the desired enol ether 29. By variation of
the electrophile (MeI, n-PrI) and the ring size of the
starting lactone 9a ,b a series of alkylated lactones 20-
23 was prepared. The reduction to alcohols 24-27
always resulted in high yields. The final elimination was
either done via the tosylate at high temperatures as in
the case of 28 or via the mesylate under milder conditions
to give enol ethers 29-31. This reaction sequence proved
to be a short and efficient way to 4-substituted dihydro-
furan and 5-substituted dihydropyran structures.
(13) (a) March, J . In Advanced Organic Chemistry, 4th ed.; Wiley:
New York 1992; pp 856 and 871. (b) Carey, F. A.; Sundberg, R. J . In
Advanced Organic Chemistry, 3rd ed.; Plenum Press: New York 1989;
Part B., p 693.
(14) Green, T. W. In Protective Groups In Organic Synthesis;
Wiley: New York, 1981; p 22.
(15) (a) Hall, S. S.; Weber, G. F.; Duggar, A. J . J . Org. Chem. 1978,
43, 667. (b) Longley, R. I.; Emerson, W. S. J . Am. Chem. Soc. 1950,
72, 9. (c) Parham, W. E.; Holmquist, H. E. J . Am. Chem. Soc. 1951,
73, 3. (d) Weber, G. F.; Hall, S. S. J . Org. Chem. 1979, 44, 364. (e)
Botthegi, C.; Consiglio, G.; Ceccarelli, G.; Stefani, A. J . Org. Chem.
1972, 37, 1835. (f) Baird, M. S.; Baxter, A. G. W.; Hoorfar, A.; J efferies,
I. J . Chem. Soc., Perkin Trans. 1 1991, 2575.
Pyrans having a substituent at the 6-position of the
ring was prepared via lithiation of the corresponding five-
or six-membered cyclic enol ether. Following a literature
procedure,19 3,4-dihydropyran 8 was treated with n-BuLi
(16) Wenkert, E.; Buckwalter, B. L.; Sathe, S. S. Synth. Commun.
1973, 261.
(18) Takacs, J . M.; Newsome, P. W.; Kuehn, C.; Takusagawa, F.
Tetrahedron 1990, 46, 5507.
(17) Zenk, P. C.; Wiley: R. A. Chem. Commun. 1984, 695.
(19) Oakes, F. T.; Sebastian, J . F. J . Org. Chem. 1980, 45, 4959.

Asymmetric Total Synthesis of (+)-Quebrachamine
J . Org. Chem., Vol. 63, No. 17, 1998 6009
Sch em e 2a
Sch em e 3
Sch em e 4a
a
Reagents: (i) THF, LDA, 20: MeI, 67%, 21: HMPA, PhCH2Br,
69%, 22: HMPA, n-PrI, 23%, 23: PhCH2Br, 82%; (ii) THF, DIBAL,
90-98%; (iii) 28: quinoline, p-TsOH, 190 °C, 35%, 29-31: ben-
zene, TEA, DMAP, MsCl, 24-63%; (iv) TMEDA, n-BuLi, hexane;
(v) diethyl ether, PhCH2Br, 72%.
to furnish the white lithium salt 32 after removal of the
solvent. A subsequent reaction with MeI has been
described in the literature.19 All our attempts to purify
the product failed. The only enol ether with this substi-
tution pattern which was successfully purified was
6-benzyl-3,4-dihydropyran 33 formed in the reaction
between benzyl bromide and lithium salt 32 (Scheme 2).
Asym m et r ic Cyclop r op a n a t ion of Cyclic E n ol
Eth er s. From the large number of C2-symmetric ligands
for enantioselective intermolecular cyclopropanation (Fig-
ure 1) we selected Evans’s bisoxazoline 3 which had been
proved to be the most effective ligand for Cu(I)OTf in the
reaction of diazo esters with many different olefins.3,8
Following a literature procedure developed by Pfaltz et
al.,20 2 mol % of the active catalyst and a slight excess of
the diazo compound were used in the cyclopropanation
of cyclic enol ethers in CH2Cl2 (Scheme 3, Table 1).
Enol ethers 3,4-dihydropyran 8 and 2,3-dihydrofuran
35 gave the desired cyclopropanes in good yields (77% of
the isolated major diastereomer) and high exo selectivity
(Table 1, entries 1 and 2), but unfortunately without any
asymmetric induction. However, when the alkyl-substi-
tuted enol ethers were used as substrates, the cyclopro-
panation reaction with ethyl diazoacetate 6 proceeded
with high enantioselectivity in nearly all cases. The only
asymmetric cyclopropanations of enol ethers reported so
far by Reissig et al.12 were a reaction between Z1-
propenyl ethers and methyl diazoacetate in the presence
of Evans’s catalyst. Next to moderate yields (48 and 54%)
and a good stereoselectivity (up to 3:97 trans-selectivity)
the enantioselectivity was rather poor (32 and 40% of the
trans-enantiomer). Cyclopropanation of both 4-substi-
tuted dihydrofurans and 5-substituted dihydropyrans
resulted in the formation of 34c-h as the major diaster-
a
Reagents: (i) 10% H2SO4, dioxane, reflux 15 h; (ii) diethyl
ether, DIBAL, -78 °C; (iiia) tryptamine hydrochloride, 10%
aqueous acetic acid; (iiib) 10% aqueous acetic acid, NaBH3CN; (iv)
CHCl3, TEA, MsCl, 40 h, rt; (v) N-methylmorpholine, LiAlH4,
reflux, 13 h (37% overall yield).
eomers in ee’s higher than 95% (Table 1, entries 3-8).
These values are surprisingly high for the enantioselec-
tive formation of a quarternary carbon center compared
to cyclopropanation reactions of corresponding silyl enol
ethers with Evans’s ligand 3/Cu(I)OTf.10 No dependence
between the enantioselectivity and the size of the sub-
stituents could be observed. On the contrary, 1,1-
disubstituted silyl enol ethers which gave good results
in the asymmetric cyclopropanation with Evans’s cata-
lyst10 gave rise to lower selectivities (74%) in the reaction
of 6-benzyl-3,4-dihydropyran 33 with ethyl diazoacetate
6 (Table 1, entry 9). The determination of the enantio-
(20) Leutenegger, U.; Umbricht, G.; Fahrni, C.; Matt, P.; Pfaltz, A.
Tetrahedron 1992, 48, 2143.

6010 J . Org. Chem., Vol. 63, No. 17, 1998
Temme et al.
Ta ble 1. Resu lts of th e Asym m etr ic Cyclop r op a n a tion
Rea ction s
F igu r e 2. Reactive complex A in the asymmetric cyclopro-
panation with Evans’s ligand 3, Cu(I)OTf, and ethyl diazo-
acetate 6.
Ta ble 2. 1H NMR Da ta To P r ove th e Ster eoch em ica l
Ou tcom e of th e Rea ction
F igu r e 3. Application of Pfaltz model on the asymmetric
cyclopropanation between alkyl-substituted pyrans and reac-
tive complex A.
isomer 36 was assigned not only based on the large J AB
(7.7 Hz) but also by NOE difference spectroscopy.
A
strong enhancement of HA was observed upon irridiation
of HB and vice versa. Such an enhancement could not
be observed for the major isomers. In general the pyran
systems showed a higher exo selectivity (up to 95:5) than
the five-membered analogues.
Mech a n istic Asp ects. The cyclic enol ethers showed
a high reactivity in the copper-catalyzed cyclopropanation
with ethyl diazoacetate 6, undoubtedly because the cop-
per carbene complex A (Figure 2) is highly electrophilic
and readily reacts with the electron rich double bond.
Various models have been suggested for the approach
of reactive complex A to alkenes.23 We found our results
to be in accordance with the model proposed by Pfaltz
for asymmetric cyclopropanations.23c Figure 3 shows the
application of this model to a reaction between an alkyl-
substituted pyran and a Cu(I)-complex formed from ethyl
diazoacetate 6 and Evans’s bisoxazoline 3.
meric excesses was carried out by titration with Eu(hfc)3
(Table 1, entries 1-4, 6, 7) and HPLC analysis of the
alcohol derivatives 37-39 (Table 1, entries 5, 8, 9).
The high exo selectivity of the [2 + 1] addition was
expected as similar observations3,8,21 have been reported
for various metal-catalyzed reactions of diazoesters. The
exo orientation of the ester group of 34c-h was deter-
mined on the basis of the proton-proton coupling of the
cyclopropane protons (Table 2). All major isomers showed
a J AB ranging from 1.7 to 3.0 Hz which is consistent with
a trans-coupling for this type of compound.22
In the cyclopropanation of 4-benzyl-2,3-dihydrofuran
29 the minor diastereomer 36 was isolated and deter-
mined to be of an enantiomeric excess greater than 95%.
The endo orientation of the ester moiety of the minor
Pathway a is expected to be favored over b since the
transition state of pathway b shows a strong repulsive
steric interaction between the approaching olefin and the
tBu group of the ligand. This model also indicates that
(21) (a) Demonceau, A.; Noels, A. F.; Hubert, A. J . Tetrahedron 1990,
46, 3889. (b) Doyle, M. P.; Bagheri, T. J .; Wandless, T. J .; Harn, N. K.;
Brinker, D. A.; Eagle, C. T.; Loh, K. L. J . Am. Chem. Soc. 1990, 112,
1906. (c) Maas, G.; Werle, T.; Alt, M.; Mayer, D. Tetrahedron 1993,
49, 881.
(22) Guenther, H. In NMR-Spektroskopie; Thieme: Stuttgart, 1992;
3.Aufl., p 109.
(23) (a) Aratani, T. Pure Appl. Chem. 1985, 57, 1839. (b) Doyle, M.
P. Chem. Rev. 1986, 86, 919. (c) Fritschi, H.; Leutenegger, U.; Pfaltz,
A. Helv. Chim. Acta 1988, 71, 1533.

Asymmetric Total Synthesis of (+)-Quebrachamine
J . Org. Chem., Vol. 63, No. 17, 1998 6011
the high enantioselectivity depends on the structure of
the olefin. In contrast to the alkenes 8 and 35 which
gave no enantioselectivity (Table 1, entries 1 and 2), the
introduction of a third substituent R makes it possible
to control the outcome of the reaction since it is obviously
favorable that the substituent R will be pointing away
from the ligand framework which leads to high enantio-
selectivities. On the basis of this model we assume that
enol ethers having a substituent at the same carbon
bearing the ether function will result in the opposite face-
selection resulting in 34i.
The endo/exo selectivity is expected to be dominated
by the interactions between the substituents at the enol
double bond and the carbenoid moiety. The reaction is
highly exo selective since a furan or pyran ring is
sterically more demanding than a flexible alkyl substitu-
ent. For that reason the heterocycle is pointing away
from the ester function leading to exo cyclopropanes. Due
to the larger ring size, pyrans show higher exo selectivity
than furan structures.
Syn th esis of (+)-Qu ebr a ch a m in e. Deter m in a tion
of th e Absolu te Con figu r a tion of th e Asym m etr ic
Cyclop r op a n a tion P r od u cts. To determine the abso-
lute configuration of the bicyclic products 34, we synthe-
sized an Aspidosperma type indole alkaloid,24 exploiting
a route developed by Wenkert et al.25 Many attempts
have been made to develop an efficient synthesis of the
Aspidosperma alkaloid quebrachamine 726 since this class
of alkaloids possess a variety of important physiological
activities.27 The Pictet-Spengler or the Bischler-Napi-
eralski condensation of tryptamine developed by Kutney
et al.26a is the most frequently used strategy and also the
basis of the enantioselective synthesis of (+)-quebra-
chamine 7 by Fuji et al.28a The second reported enanti-
oselective route to either (+)- or (-)- 7 is based on a
reaction between tryptamine and a chiral template
derived from L-glutamic acid.28b,c
F igu r e 4. Determination of the absolute configuration of
bicyclic cyclopropanation products 34c-h via alkaloid que-
brachamine.
and subsequent reduction with sodium cyanoborohydride
which led to the diastereomeric mixture of alcohols 42.
Kutney et al.26a developed a short two-step synthesis of
(+)/(-)-quebrachamine 7 from alcohol 42 via the quar-
ternary ammonium salt 43 formed spontaneously from
the mesylate with methanesulfonyl chloride and triethyl-
amine followed by a reductive cleavage utilizing LiAlH4
in refluxing N-methylmorpholine. We found that the
yield of this two-step route could be improved from 50 to
67% by avoiding a purification of the intermediate 43.
The final reductive cleavage to a nine-membered hetero-
cyclic ring structure resulted in an overall yield of 37%
of the desired natural product 7 with a single quarternary
center formed in the previous cyclopropanation step. The
positive optical rotation ([R]22 ) +111) manifested the
D
product to be at least 94% enantiomerically pure (+)-
quebrachamine 7 based on the literature value and
revealed the absolute stereochemistry of the quarternary
center of the cyclopropanation product 34f to be S (Figure
4) which is in accordance with the prediction made from
the model in Figure 3.
The chiral center in quebrachamine 7 is a quarternary
carbon with an ethyl group. Wenkert et al. developed a
way to Aspidosperma alkaloids via γ-diketo compounds
derived from oxycyclopropanes.25 The enantiomerically
pure cyclopropane 34f seemed to us a good chiral synthon
for the asymmetric total synthesis of quebrachamine 7.
The acid-induced ring cleavage of 34f gave lactone 40
in 77% yield. Reduction of lactone 40 with DIBALH was
followed by acid-catalyzed condensation with tryptamine
It should also be noted that this strategy gives access
to a number of Aspidosperma and Vincamine alkaloids
in an optical active form since the quarternary am-
monium salt 43 has previously been transformed into
these indole alkaloids.29
Con clu sion s
Catalytic asymmetric cyclopropanation of dihydrofuran
and dihydropyran structures using Cu(I)OTf/Evans’s
bisoxazoline ligand 3 as catalyst and ethyl diazoacetate
6 yielded bicyclic compounds 34c-i with stereoselectivi-
ties up to 95:5 exo and ee’s higher than 95% in nearly all
cases. The excellent control of the absolute configuration
at the key quarternary carbon at C(6) in 34f allowed the
asymmetric total synthesis of (+)-quebrachamine 7 in a
five-step synthesis with an overall yield of 37%.
(24) Some recent papers concerning the total synthesis of Aspi-
dosperma and vincamine alkaloids: (a) Schultz, A. G.; Liping, P. J .
Org. Chem. 1997, 62, 6855. (b) Desmaele, D.; Mekonar, K.; D’Angelo,
J . J . Org. Chem. 1997, 62, 3890. (c) Schultz, A. G.; Malachowski, W.
P.; You, P. J . Org. Chem. 1997, 62, 1223.
(25) Wenkert, E.; Halls, T. D.; Kwart, L. D.; Magnusson, G.;
Showalter, H. D. H. Tetrahedron 1981, 37, 4017.
(26) Racemic syntheses of quebrachamine 7: (a) Kutney, J . P.;
Abdurahman, N.; Le Quesne, P.; Piers, E.; Vlattas, I. J . Am. Chem.
Soc. 1966, 88, 3656. (b) Ban, Y.; Yoshida, K.; Goto, J .; Oishi, T.; Takeda,
E. Tetrahedron 1983, 39, 3657. (c) Ziegler, F. E.; Kloek, J . A.; Zoretic,
P. A. J . Am. Chem. Soc. 1969, 91, 2342. (d) Takano, S.; Hatakeyama,
S.; Ogasawara, K. J . Am. Chem. Soc. 1976, 98, 3022. (e) Giri, V. S.;
Ali, E.; Pakrashi, S. C. J . Heterocycl. Chem. 1980, 17, 1133.
(27) (a) Cordell, G. A. In The Alkaloids; Manske, R. H. F., Rodrigo,
R. G. A., Eds.; Academic Press: New York, 1979; Vol. 17; p 199. (b)
Neuss, N. In Indole and Biogenetically Related Alkaloids; Philipson,
J . D., Zenk, M. H., Eds.; Academic Press: London, 1980. (c) Lohnas-
maa, M.; Tolvanen, A. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York 1992; Vol. 42, p 1.
Exp er im en ta l Section
For general experimental information, see ref 6a. Methyl-
ene chloride was dried over calcium hydride and freshly
distilled under nitrogen. THF and diethyl ether were distilled
(28) Asymmetric syntheses of quebrachamine 7: (a) Manabu, N.;
Nagasawa, H.; Fuji, K. J . Am. Chem. Soc. 1987, 109, 7901. (b) Takano,
S.; Chiba, K.; Yonaga, M.; Ogasawara, K. J . Chem. Soc., Chem.
Commun. 1980, 616. (c) Takano, S.; Chiba, K.; Yonaga, M.; Ogasawara,
K. J . Chem. Soc., Chem. Commun. 1981, 1153.
(29) (a) Kutney, J . P.; Chan, K. K.; Failli, A.; Fromson, J . M.; Gletsos,
C.; Leutwiler, A.; Nelson, V. R.; de Souzu, J . P. Helv. Chim. Acta 1975,
58, 1648. (b) Mokry, J .; Kompis I. Lloydia 1964, 27, 428. (c) Danieli,
B.; Lesma, G.; Palmisano, G. J . Chem. Soc., Chem. Commun. 1981,
908. (d) Lewin, G.; Poisson, J . Tetrahedron 1984, 25, 3813.

6012 J . Org. Chem., Vol. 63, No. 17, 1998
Temme et al.
over sodium/benzophenone under nitrogen. Ethyl diazoacetate
6, (CuOTf)2‚C6H6, 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-
oxazoline] 3, and Eu(hfc)3 were purchased from Aldrich Co.
3,4-Dihydropyran 8, 2,3-dihydrofuran 35, butyrolactone 9a ,
and valerolactone 9b as starting materials were purchased
from Lancaster and freshly distilled just prior use.
distilled (bp 88-92 °C/3 mmHg) to give 15 (11.4 g, 90%) as a
colorless oil. All the physical and spectroscopic data of the
product were in complete agreement with the reported data.16
7-(Hydr oxym eth yl)-2-oxabicyclo[4.1.0]h eptan e (16). To
a suspension of LiAlH4 (5.1 g, 130 mmol) in dry ether (45 mL)
was added a solution of ester 15 (11.4 g, 67 mmol) in dry ether
(25 mL) over a period of 3 h at 0 °C. After additional stirring
at room temperature for 3 h, the reaction was quenched with
H2O (5 mL), 15% aqueous NaOH (5 mL), and H2O (15 mL).
The filtrate was carefully washed with ether, and the organic
layer was concentrated. The crude product was purified by
flash chromatography (pentane/ethyl acetate: 3/1) to give 16
(8.4 g, 99%) as a colorless oil. All the physical and spectro-
scopic data of the product were in complete agreement with
the reported data.16
2-Meth oxy-3-vin yl-3,4,5,6-tetr a h yd r op yr a n (17). Alco-
hol 16 (19.6 g, 153 mmol) was treated with sulfuric acid (43
mL, 0.5 M solution in methanol) at 60 °C for 1.5 h. After
addition of K2CO3 (5 g), the reaction mixture was stirred for
15 min, diluted with brine (50 mL), and extracted with CH2-
Cl2 (4 × 50 mL). The extracts were dried over MgSO4 and
concentrated, and the residue was distilled (bp 75-80 °C) to
give 17 (13.3 g, 61%) as a colorless oil. All the physical and
spectroscopic data of the product were in complete agreement
with the reported data.16
2-Meth oxy-3-eth yl-3,4,5,6-tetr a h yd r op yr a n (18). Olefin
17 (17.3 g, 122 mmol) and PtO2 (0.5 g, 2.4 mol %) in ethyl
acetate (100 mL) were transferred into an autoclave, and the
olefin was stirred under H2 (120 psi) at room temperature for
12 h. The reaction mixture was filtered through a pad of
Celite, and the filtrate was concentrated to give 18 (16.8 g,
96%) as a colorless oil. Physical and spectroscopic data of the
product were in complete agreement with the literature data.16
5-Eth yl-3,4-d ih yd r op yr a n (19). Following the procedure
described for 14, pyran 18 (10.0 g, 69 mmol) gave 19 (4.4 g,
57%) as a colorless oil. Distillation of the quinoline residue
gave another 2.7 g (35%) of pure 19 (bp 139-145 °C). All the
physical and spectroscopic data of the product were in complete
agreement with the reported data.16
3-Ben zyld ih yd r ofu r a n -2-on e (21). To a solution of DIPA
(5.6 g, 55 mmol) in dry THF (45 mL) at -78 °C was added
dropwise n-BuLi (38 mL, 1.6 M solution in hexane, 61 mmol)
over 20 min and stirred at this temperature for another 20
min. Then a solution of butyrolactone (4.3 g, 50 mmol) in dry
THF (50 mL) was added over 30 min. After additional stirring
at -78 °C for 20 min, benzyl bromide (10.3 g, 60 mmol) in
HMPA (10 mL) was added dropwise over 15 min. The reaction
mixture was stirred for 4 h while warming up to -30 °C. The
reaction was allowed to come to room temperature, quenched
by the addition of saturated aqueous NH4Cl (25 mL), diluted
with ether (50 mL), washed with water (20 mL) and brine (20
mL), dried over MgSO4, and concentrated in vacuo. The crude
product was purified by flash chromatography (pentane/ethyl
acetate: 85/15) to give 21 (6.1 g, 69%) as a colorless oil. All
the physical and spectroscopic data of the product were in
complete agreement with the literature data.31
Syn th esis of En ol Eth er s a s Cyclop r op a n a tion P r e-
cu r sor s. 2-Oxotetr a h yd r ofu r a n -3-ca r boxylic Acid Eth yl
Ester (10). To a vigorously stirred solution of sodium (11.5
g, 500 mmol) in diethyl carbonate (123 mL) at 100 °C was
introduced dropwise γ-butyrolactone (43.5 g, 500 mmol) in
diethyl carbonate (40 mL) over 3 h. The cooled reaction
mixture was then poured into a mixture of ice-cold water (450
mL) and concentrated sulfuric acid (21 mL). The phases were
separated, and the aqueous layer was extracted with ether (2
× 50 mL). The combined organic phases were dried and
concentrated in vacuo. Fractional distillation (bp 134-136
°C/8 mmHg) of the crude product afforded 10 (36.1 g, 46%) as
a colorless oil. Physical and spectroscopic data of the product
were in complete agreement with the literature data.30
3-Eth yl-2-oxotetr a h yd r ofu r a n -3-ca r boxylic Acid Eth yl
Ester (11). A solution of lactone 10 (15.8 g, 61 mmol) in
acetone (250 mL) was treated with sodium iodide (30.0 g, 200
mmol), ethyl iodide (31.4 g, 200 mmol), and K2CO3 (34.5 g,
250 mmol) and then refluxed for 17 h. After cooling to room
temperature, the reaction mixture was diluted with hexane
(170 mL), filtered, and concentrated in vacuo. The residue was
dissolved in pentane/ethyl acetate 1/1 and filtered again to give
11 (17.0 g, 97%) after concentration. Physical and spectro-
scopic data of the product were in complete agreement with
the reported data.17
3-Eth yltetr a h yd r ofu r a n -2-on e (12). A solution of lactone
11 (24 g, 130 mmol) in ethanol (100 mL) was treated with 2
M aqueous NaOH (80 mL) and stirred at room temperature
for 6 h. Most of the water and ethanol were removed in vacuo.
The residue was treated with 10% aqueous sulfuric acid (33
mL) and refluxed for 12 h. After the mixture was cooled to
room temperature, the product was extracted with CH2Cl2 (4
× 50 mL). The combined organic phases were washed with
saturated aqueous NaHCO3 and 2 M NaOH, dried over MgSO4,
and concentrated in vacuo to give 12 (5.7 g, 39%) as a colorless
oil. All physical and spectroscopic data of the product were
in complete agreement with the literature values.17
3-Eth yltetr a h yd r ofu r a n -2-ol (13). A solution of lactone
12 (5.0 g, 44 mmol) in dry ether (50 mL) was treated with
DIBALH (50 mL, 1 M solution in THF, 50 mmol) at - 20 °C
and stirred for 1.5 h at this temperature. The resulting
reaction mixture was slowly warmed to room temperature and
then quenched with methanol (35 mL). After filtration,
concentration of the solvent in vacuo afforded 13 (4.6 g, 90%)
as a colorless oil. All the physical and spectroscopic data of
the product were in complete agreement with the reported
data.17
4-Eth yl-2,3-d ih yd r ofu r a n (14). Lactone 13 (4.8 g, 41
mmol) was added dropwise to a solution of p-toluenesulfonic
acid (0.02 g) in quinoline (2.5 mL) at 190 °C over 20 min. The
product was simultaneously distilled out of the reaction
mixture using a microdistillation assembly and collected in a
round-bottom flask containing 2 M NaOH (5 mL). The receiver
was cooled to -78 °C during the distillation. The distillate
was extracted with ether (10 mL), the phases were separated,
and the organic layer was dried over MgSO4 and concentrated
in vacuo to give 14 (1.3 g, 32%) as a colorless oil. All the
physical and spectroscopic data of the product were in complete
agreement with the reported data.17
3-Ben zyltetr a h yd r ofu r a n -2-ol (25). Following the pro-
cedure described for 13, lactone 21 (6.5 g, 37 mmol) gave 25
(6.1 g, 93%) as a colorless oil after flash chromatography
(pentane/ethyl acetate: 3/1). All the physical and spectroscopic
data of the product were in complete agreement with the
reported data.32
4-Ben zyl-2,3-d ih yd r ofu r a n (29). To a solution of lactol
25 (4.0 g, 23 mmol) in benzene (90 mL) at 0 °C were added
dropwise TEA (11.4 g, 112 mmol), methanesulfonyl chloride
(4.2 g, 35 mmol), and 4-DMAP (0.5 g, 4 mmol). The reaction
mixture was warmed to room temperature and stirred over-
night. The solution was filtered, the filter was washed with
ether (50 mL), and the organic layer was concentrated in
vacuo. The crude product was purified by flash chromatog-
7-Ca r beth oxy-2-oxa bicyclo[4.1.0]h ep ta n e (15). To a
refluxing solution of freshly distilled 3,4-dihydropyran 8 (37.8
g, 45 mmol) and CuSO4 (0.6 g) was added slowly a mixture of
ethyl diazoacetate 6 (8.5 g, 85 mmol) and 3,4-dihydropyran 8
(12.6 g, 150 mmol) over 2.5 h. The reaction mixture was
refluxed for additional 2 h. Excess of 3,4-dihydropyran 8 was
removed at atmospheric pressure and the crude product
(31) Tanaka, Y.; Grapsas, I.; Dakoji, S.; Cho, Y.; Mobashery, S. J .
Am. Chem. Soc. 1994, 116, 7475.
(32) Verdaguer, X.; Berk, S. C.; Buchwald, S. L. J . Am. Chem. Soc.
1995, 117, 12641.
(30) Collins, D. J .; J ames, A. M. Aust. J . Chem. 1989, 42, 223.

Asymmetric Total Synthesis of (+)-Quebrachamine
J . Org. Chem., Vol. 63, No. 17, 1998 6013
raphy (pentane/ethyl acetate: 95/5) to give 29 (1.5 g, 42%) as
raphy (pentane/ether: 10/1). Physical and spectroscopic data
of the product were in complete agreement with the literature
values.34
1
a colorless oil. IR (neat, cm-1) 1662, 1091, and 700; H NMR
(300 MHz) δ 2.52 (2 H, t, J ) 13.5 Hz), 3.43 (2 H, s), 4.36 (2 H,
t, J ) 15.1 Hz), 6.19 (1 H, s), and 7.29-7.41 (5 H, m); 13C NMR
(75.5 MHz) δ 140.9, 139.5, 128.4, 128.2, 125.9, 113.6, 69.9, 32.8,
and 31.8; MS (EI) m/z (rel intensity) 160 (M+, 75), 159 (19),
131 (97), 115 (38), 104 (47), 91 (100), and 51 (77). Anal. Calcd
for C11H12O: C, 82.50; H, 7.50. Found: C, 82.59; H, 7.43.
6-Ben zyl-3,4-d ih yd r op yr a n (33). A mixture of 3,4-dihy-
dropyran 8 (7.0 mL, 27.5 mmol) and TMEDA (1.0 g) was
treated with n-BuLi (19.0 mL, 1.6 M solution in hexane, 30.3
mmol) over 5 min. Removal of the hexane afforded a white
solid. A suspension of the dry lithium salt and dry ether (10
mL) was then treated with benzyl bromide (3.3 mL, 27.5 mmol)
at 0 °C. After additional stirring for 1 h, the solution was
washed with water (2 × 20 mL), dried over MgSO4, and
concentrated in vacuo. The crude product was purified by
flash chromatography (pentane/ether: 98/2) to give 33 (3.4 g,
72%) as a slightly yellow oil. Rf 0.15 (pentane/ether: 98/2);
IR (neat, cm-1) 1674, 1061, and 700; 1H NMR (300 MHz) δ
1.78-2.20 (4 H, m), 3.37 (2 H, s), 4.02 (2 H, t, J ) 5.1 Hz),
4.57 (1 H, m), and 7.23-7.44 (5 H, m); 13C NMR (75.5 MHz) δ
153.4, 138.6, 128.7, 128.1, 126.0, 97.1, 66.1, 40.7, 22.2, and
20.2; MS (EI) m/z (rel intensity) 174 (M+, 28), 128 (8), 115 (16),
115 (16), 91 (90), 65 (55), and 55 (100). Anal. Calcd for
3-Meth yld ih yd r ofu r a n -2-on e (20). Following the proce-
dure described for 21 without the use of HMPA, butyrolactone
9a (5.2 g, 60 mmol) and methyl iodide (17.0 g, 120 mmol) gave
20 (4.0 g, 67%) as a colorless oil after flash chromatography
(pentane/ethyl acetate: 3/1). All the physical and spectroscopic
properties of the product were in complete agreement with the
reported data.33
3-Meth yltetr a h yd r ofu r a n -2-ol (24). Following the pro-
cedure described for 13, lactone 20 (4.5 g, 45 mmol) gave pure
24 (4.5 g, 98%) as a colorless oil. Physical and spectroscopic
data of the product were in complete agreement with the
literature data.30
C
12H14O: C, 82.76; H, 8.05. Found: C, 82.75; H, 8.16.
4-Meth yl-2,3-d ih yd r ofu r a n (28). Following the procedure
described for 14, lactone 24 (4.5 g, 44 mmol) gave 28 (1.3 g,
35%) as a colorless oil. All the physical and spectroscopic data
of the product were in complete agreement with the reported
data.15e
Asym m etr ic Cyclop r op a n a tion of En ol Eth er s 34a -i.
Gen er a l P r oced u r e. In a dry 25 mL Schlenk tube under
argon was dissolved (CuOTf)2‚C6H6 (5.1 mg, 0.010 mmol, 2.0
mol % Cu) in dry CH2Cl2 (2 mL) added with 2,2′-isopro-
pylidenebis[(4S)-4-tert-butyl-2-oxazoline] 3 (7.1 mg, 0.024 mmol,
2.4 mol %) in dry CH2Cl2 (1 mL). The slightly yellow solution
was stirred at room temperature for 30 min and then cooled
to 0 °C. A solution of the enol ether (1 mmol) in dry CH2Cl2
(2 mL) was added to the copper complex. To the reaction
mixture was added a solution of ethyl diazoacetate 6 (1.6
mmol) in CH2Cl2 (4 mL) dropwise over 7 h at 0 °C. After
additional overnight stirring at room temperature, the reaction
was quenched with saturated aqueous NH4Cl (5 mL), diluted
with ether (50 mL), washed with H2O (5 mL) and brine (5 mL),
and dried over MgSO4. After concentration, the crude product
was purified by flash chromatography (pentane/ethyl acetate:
95/5).
3-P r op yltetr a h yd r op yr a n -2-on e (22). Following the pro-
cedure described for 21, valerolactone 9b (4.4 g, 44 mmol) and
propyl iodide (13.6 g, 80 mmol) gave 22 (1.4 g, 23%) as a
colorless oil after distillation of the crude product (bp 132 °C,
18 mmHg). All the physical and spectroscopic data of the
product were in complete agreement with the reported data.18b
3-P r op yltetr a h yd r op yr a n -2-ol (26). To a solution of
lactone 22 (1.4 g, 10 mmol) in dry ether (25 mL) was added
DIBALH (11 mL, 1 M solution in hexane, 11 mmol) at - 78
°C over 5 min. After additional stirring for 30 min, the
reaction was quenched with methanol (5 mL) at - 78 °C. The
resulting suspension was warmed to room temperature, and
a saturated aqueous solution of Rochelle’s salt (30 mL) was
added. The resulting suspension was filtered through a pad
of Celite, and the solids were washed carefully with ether. The
filtrate was dried with MgSO4 and concentrated in vacuo to
give pure 26 (1.4 g, 98%) as a colorless oil. All the physical
and spectroscopic data of the product were in complete
agreement with the reported data.18b
(1SR,5SR,6SR)-6-Ca r b et h oxy-2-oxa b icyclo[3.1.0]h ex-
a n e (34a ). The cyclopropanation reaction of 2,3-dihydrofuran
35 afforded cyclopropane 34a (120 mg, 77%) as a colorless oil.
Rf 0.23 (pentane/ethyl acetate: 95/5); IR (neat, cm-1) 2981 and
1
1718; H NMR (300 MHz) δ 1.16 (3 H, t, J ) 7.2 Hz), 1.81-
1.83 (1 H, m), 1.97-2.10 (3 H, m), 3.34-3.47 (1 H, m), 4.00 (2
H, q, J ) 7.2 Hz), 4.10-4.19 (2 H, m); 13C NMR (75.5 MHz) δ
172.1, 66.5, 65.5, 60.1, 27.4, 25.4, 23.0, and 14.0; MS (EI) m/z
(rel intensity) 156 (M+,13), 127 (25), 111 (19), 83 (100), and
55 (93). Anal. Calcd for C8H12O3: C, 61.54; H, 7.69. Found:
C, 61.38; H, 7.59.
5-P r op yl-3,4-d ih yd r op yr a n (30). Following the procedure
described for 29, alcohol 26 (0.7 g, 5 mmol) gave enol ether 30
(0.15 g, 24%) as a colorless oil after flash chromatography
(pentane/ethyl acetate: 10/1). Rf 0.6 (pentane/ethyl acetate:
10/1); IR (neat, cm-1) 1650, 1240, and 1070; 1H NMR (300
MHz) δ 0.86 (3 H, t, J ) 7.3 Hz), 1.30-1.45 (2 H, m), 1.78-
1.95 (6 H, m), 3.87 (2 H, t, J ) 5.6 Hz), and 6.21 (1 H, s); 13C
NMR (75.5 MHz) δ 138.7, 112.5, 65.2, 35.3, 22.9, 22.6, 20.9,
and 13.6; MS (EI) m/z (rel intensity) 126 (M+, 19), 97 (100),
69 (23), and 55 (26). Anal. Calcd for C8H14O: C, 76.19; H,
11.11. Found: C, 76.02; H, 11.26.
(1SR,6SR,7SR)-7-Ca r b et h oxy-2-oxa b icyclo[4.1.0]h ep -
ta n e (34b). The cyclopropanation reaction of 3,4-dihydropy-
ran 8 afforded the bicyclic product 34b (131 mg, 77%) as a
colorless oil. All the physical and spectroscopic data of the
product were in complete agreement with the reported data.16
(1R,5S,6S)-5-Meth yl-6-ca r beth oxy-2-oxa bicyclo[3.1.0]-
h exa n e (34c). Following the general procedure using enol
ether 28 gave cyclopropane 34c (102 mg, 60%) as a colorless
3-Ben zyltetr a h yd r op yr a n -2-on e (23). Following the pro-
cedure described for 21, valerolactone 9b (4.4 g, 44 mmol) and
benzyl bromide (13.7 g, 80 mmol) gave 23 (6.8 g, 82%) as a
colorless oil after flash chromatography (pentane/ether: 2/1).
All the physical and spectroscopic data of the product were in
complete agreement with the reported data.18b
oil. Rf 0.32 (pentane/ethyl acetate: 95/5); [R]25 ) -4.9 (c )
D
1.12, CH2Cl2, >95% ee); IR (neat, cm-1) 1718, 1173, and 1098;
1H NMR (300 MHz) δ 1.12 (3 H, t, J ) 7.0 Hz), 1.20 (3 H, s),
1.96-2.13 (3 H, m), 3.42-3.49 (1 H, m), and 3.97-4.12 (4 H,
m); 13C NMR (75.5 MHz) δ 170.5, 69.8, 66.3, 60.2, 36.1, 32.7,
27.8, 14.3, and 12.4; MS (EI) m/z (rel intensity) 170 (M+, <1),
141 (1), 125 (11), 97 (100), and 69 (27). Anal. Calcd for
C9H14O3: C, 63.53; H, 8.24. Found: C, 63.59; H, 8.37.
(1R,5S,6S)-5-E t h yl-6-ca r b et h oxy-2-oxa b icyclo[3.1.0]-
h exa n e (34d ). Following the general procedure using enol
ether 14 gave cyclopropane 34d (105 mg, 57%) as a colorless
3-Ben zyltetr a h yd r op yr a n -2-ol (27). Following the pro-
cedure described for 26, lactone 23 (2.7 g, 14 mmol) gave pure
27 (2.4 g, 90%) as a colorless oil. All the physical and
spectroscopic data of the product were in complete agreement
with the reported data.18b
oil. Rf 0.28 (pentane/ethyl acetate: 95/5); [R]25 ) -21.0 (c )
5-Ben zyl-3,4-d ih yd r op yr a n (31). Following the procedure
described for 29, alcohol 27 (1.9 g, 10 mmol) gave pure enol
ether 31 (1.1 g, 63%) as a colorless oil after flash chromatog-
D
1.00, CH2Cl2, >95% ee); IR (neat, cm-1) 2967, 1718, 1174, and
1
1099; H NMR (300 MHz) δ 0.90 (3 H, t, J ) 7.5 Hz), 1.20 (3
(33) Ishii, Y.; Yoshida, T.; Yamawaki, K.; Ogawa, M. J . Org. Chem.
1988, 53, 5549.
(34) Barrett, A. G. M.; Betts, M. J .; Fenwick, A. J . Org. Chem. 1985,
50, 169.

6014 J . Org. Chem., Vol. 63, No. 17, 1998
Temme et al.
H, t, J ) 7.2 Hz), 1.61-2.15 (5 H, m), 3.42-3.51 (1 H, m), and
3.98-4.11 (4 H, m); 13C NMR (75.5 MHz) δ 170.3, 69.6, 66.5,
60.1, 39.0, 33.3, 27.2, 20.2, 14.2, and 11.8; MS (EI) m/z (rel
intensity) 184 (M+, 1), 155 (9), 139 (20), 111 (100), 81 (28),
and 55 (58). Anal. Calcd for C10H16O3: C, 65.20; H, 8.70.
Found: C, 64.93; H, 8.71.
(1R,5R,6S)-5-Ben zyl-6-ca r beth oxy-2-oxa bicyclo[3.1.0]-
h exa n e (34e) a n d (1R,5R,6R)-5-Ben zyl-6-ca r beth oxy-2-
oxa bicyclo[3.1.0]h exa n e (36). The cyclopropanation reac-
tion of enol ether 29 afforded the bicyclic products 34e (189
mg, 77%) and 36 in (49 mg, 20%) as colorless oils.
2936, 1720, and 1298; 1H NMR (300 MHz) δ 1.31 (3 H, t, J )
7.1 Hz), 1.78-2.12 (4 H, m), 2.87-3.11 (3 H, m), 3.52 (1 H, d,
J ) 10.7 Hz), 4.07-4.15 (2 H, m), 4.24 (2 H, q, J ) 7.1 Hz),
and 7.18-7.29 (5 H, m); 13C NMR (75.5 MHz) δ 171.8, 138.7,
133.6, 129.3, 128.1, 68.1, 64.7, 61.3, 37.9, 31.3, 26.4, 21.0, 19.1,
and 14.2; MS (EI) m/z (rel intensity) 260 (M+, 7), 231 (3), 185
(13), 115 (10), 91 (100), and 65 (35). Anal. Calcd for
C16H20O3: C, 73.84; H, 7.69. Found: C, 73.85; H, 7.64.
Det er m in a t ion of t h e E n a n t iom er ic E xcess via Al-
coh ol Der iva tives. (1R*,6R*,7R*)-1-Ben zyl-7-(h yd r oxy-
m eth yl)-2-oxa bicyclo[4.1.0]h ep ta n e (39). Ester 34i (260
mg, 1 mmol) in dry ether (5 mL) was added over 5 min to an
ice-cooled suspension of LiAlH4 (76 mg, 2 mmol) in ether (25
mL). After stirring overnight at room temperature, H2O (1
mL) was added. The suspension was filtered, dried over
MgSO4, and concentrated. The residue was purified by using
flash chromatography (pentane/ethyl acetate: 2/1) to afford
39 (180 mg, 82%) as a colorless oil. Rf 0.15 (pentane/ethyl
34e: Rf 0.28 (pentane/ethyl acetate: 95/5); [R]25D ) -73.0 (c
) 1.19, CH2Cl2, >95% ee); IR (neat, cm-1) 1715, 1417, 1178,
and 1100; 1H NMR (300 MHz) δ 1.25 (3 H, t, J ) 7.1 Hz), 1.95-
2.18 (3 H, m), 3.03 (1 H, d, J ) 14.9 Hz), 3.24 (1 H, d, J ) 14.9
Hz), 3.42-3.51 (1 H, m), 3.97-4.04 (1 H, m), 4.12 (2 H, q, J )
7.1 Hz), 4.31 (1 H, d, J ) 1.7 Hz), 7.16-7.31 (5 H, m); 13C
NMR (75.5 MHz) δ 170.5, 139.4, 128.7, 126.1, 69.4, 66.4, 60.3,
38.2, 33.5, 32.7, 27.5, 14.2, and 11.8; MS (EI) m/z (rel intensity)
246 (M+, 4), 173 (40), 155 (100), 127 (44), 115 (23), 91 (76),
and 55 (51). Anal. Calcd for C15H18O3: C, 73.17; H, 7.32.
Found: C, 73.20; H, 7.45.
acetate: 2/1); [R]25 ) +14.8 (c ) 1.00, CH2Cl2, 74% ee); IR
D
(neat, cm-1) 3383, 2929, 1078, and 706; 1H NMR (300 MHz) δ
0.93 (1 H, t, J ) 6.2 Hz), 1.22-1.29 (3 H, m), 1.61-1.78 (1 H,
m), 1.80-1.91 (1 H, m), 2.03 (1 H, s), 2.66-2.77 (2 H, m), 2.92
(1 H, d, J ) 14.6 Hz), 3.37-3.63 (3 H, m), and 7.12-7.29 (5 H,
m); 13C NMR (75.5 MHz) δ 139.1, 129.1, 128.1, 126.1, 64.2,
63.2, 63.1, 39.8, 30.8, 21.7, 21.5, and 19.5; MS (EI) m/z (rel
intensity) 200 (M+ - H2O, 18), 129 (14), 91 (100), 65 (69), and
53 (67). Anal. Calcd for C14H18O2: C, 77.06; H, 8.26. Found:
C, 77.29; H, 8.30.
36: Rf 0.23 (pentane/ethyl acetate: 95/5); [R]25 ) -54.2 (c
D
) 0.50, CH2Cl2, >95% ee); IR (neat, cm-1) 2979, 1716, 1178
1
(film, cm-1); H NMR (300 MHz) δ 1.31 (3 H, t, J ) 7.1 Hz),
1.68 (1 H, d, J ) 7.7 Hz), 2.08-2.21 (1 H, m), 2.50-2.67 (1 H,
m), 2.88-3.07 (2 H, m), 4.09 (1 H, d, J ) 7.7 Hz), 4.16-4.22 (4
H, m), and 7.23-7.35 (5 H, m); 13C NMR (75.5 MHz) δ 169.8,
138.2, 128.9, 128.5, 126.6, 74.2, 68.5, 60.1, 40.5, 37.5, 33.3, 29.9,
and 14.2; MS (EI) m/z (rel intensity) 246 (M+, 3), 173 (35), 155
(100), 127 (41), and 91 (79). Anal. Calcd for C15H18O3: C,
73.17; H, 7.32. Found: C, 73.03; H, 7.36.
(1R,5S,6R)-5-Ben zyl-6-(h yd r oxym eth yl)-2-oxa bicyclo-
[3.1.0]h exa n e (37). Following the procedure described for 39,
ester 34e (300 mg, 1.2 mmol) gave 37 (218 mg, 85%) as a
colorless oil after flash chromatography (pentane/ethyl ac-
etate: 2/1). Rf 0.18 (pentane/ethyl acetate: 2/1); [R]25D ) -10.1
(c ) 1.00, CH2Cl2, 96% ee); IR (neat, cm-1) 3419; 1H NMR (300
MHz) δ 1.62-1.90 (2 H, m), 2.00-2.20 (2 H, m), 3.00-3.07 (2
H, m), 3.56-3.81 (3 H, m), 3.99-4.06 (1 H, m), and 7.26-7.39
(5 H, m); 13C NMR (75.5 MHz) δ 139.8, 128.7, 128.5, 126.2,
67.4, 66.4, 60.4, 35.1, 33.9, 31.8, and 28.2; MS (EI) m/z (rel
intensity) 173 (M+ - CH2OH, 24), 129 (24), 115 (20), 91 (100),
and 65 (54). Anal. Calcd for C13H16O2: C, 76.47; H, 7.84.
Found: C, 76.48; H, 7.99.
(1R,6S,7R)-6-Ben zyl-7-(h yd r oxym eth yl)-2-oxa bicyclo-
[4.1.0]h ep ta n e (38). Following the procedure described for
39, ester 34h (260 mg, 1.0 mmol) gave 38 (183 mg, 84%) as a
colorless oil after flash chromatography (pentane/ethyl ac-
etate: 2/1). Rf 0.09 (pentane/ethyl acetate: 2/1); [R]25D ) +22.2
(c ) 1.00, CH2Cl2, 96% ee); IR (neat, cm-1) 3393, 2933, and
1136; 1H NMR (300 MHz) δ 1.23-1.27 (1 H, m), 1.36-1.47 (3
H, m), 1.69-1.73 (1 H, m), 1.88-1.94 (1 H, m), 2.05-2.31 (2H,
m), 3.16-3.24 (1 H, m), 3.51-3.62 (2 H, m), 3.72-3.85 (2 H,
m), and 7.24-7.38 (5 H, m); 13C NMR (75.5 MHz) δ 139.2,
129.1, 128.4, 126.2, 64.2, 61.9, 61.3, 39.4, 31.0, 25.1, 25.0, and
21.8; MS (EI) m/z (rel intensity) 187 (M+ - CH2OH, 5), 127
(28), 115 (18), 91 (100), and 65 (40). Anal. Calcd for
(1R,6S,7S)-6-E t h yl-7-ca r b et h oxy-2-oxa b icyclo[4.1.0]-
h ep ta n e (34f). Following the general procedure using enol
ether 19 gave cyclopropane 34f (103 mg, 52%) as a colorless
oil. Rf 0.21 (pentane/ethyl acetate: 95/5); [R]25 ) -14.8 (c )
D
1.42, CH2Cl2, >95% ee); IR (neat, cm-1) 1721, 1158, and 1127;
1H NMR (300 MHz) δ 0.86 (3 H, t, J ) 7.3 Hz), 1.24 (3 H, t, J
) 7.2 Hz), 1.45-1.81 (6 H, m), 2.07-2.15 (1 H, m), 3.24-3.32
(1 H, m), 3.56-3.61 (1 H, m), 3.80-3.84 (1 H, m), and 4.10 (2
H, q, J ) 7.3 Hz); 13C NMR (75.5 MHz) δ 171.4, 65.2, 64.2,
60.1, 33.3, 31.1, 25.4, 25.0, 21.9, 14.3, and 10.0; MS (EI) m/z
(rel intensity) 198 (M+, 3), 169 (51), 141 (36), 125 (100), and
95 (67). Anal. Calcd for C11H18O3: C, 66.67; H, 9.10. Found:
C, 66.75; H, 9.27.
(1R,6S,7S)-6-P r op yl-7-ca r beth oxy-2-oxa bicyclo[4.1.0]-
h ep ta n e (34g). Following the general procedure using enol
ether 30 gave cyclopropane 34g (115 mg, 54%) as a colorless
oil. Rf 0.14 (pentane/ethyl acetate: 95/5); [R]25 ) +2.8 (c )
D
0.90, CH2Cl2, >95% ee); IR (neat, cm-1) 1716, 1307, 1180, and
1132; 1H NMR (300 MHz) δ 0.83-1.75 (13 H, m), 1.92 (1 H, d,
J ) 2.9 Hz), 2.92-3.00 (1 H, m), 3.22-3.36 (2 H, m), 3.91-
3.99 (2 H, m) and 4.11 (1 H, d, J ) 2.9 Hz); 13C NMR (75.5
MHz) δ 171.6, 65.5, 64.0, 60.0, 34.7, 32.1, 31.6, 25.7, 22.2, 19.5,
14.3, and 14.2; MS (EI) m/z (rel intensity) 183 (M+-C2H5, 11),
169 (61), 139 (100), 123 (72), 95 (81), 67 (88), and 55(82). Anal.
Calcd for C12H20O3: C, 67.92; H, 9.43. Found: C, 67.71; H,
9.63.
C
14H18O2: C, 77.06; H, 8.26. Found: C, 76.92; H, 8.41.
Syn th esis of (+)-Qu ebr a ch a m in e (7). Deter m in a tion
of th e Absolu te Con figu r a tion of th e Asym m etr ic Cy-
clop r op a n a tion P r od u cts (34c-h ). (3a S,7a R)-3a -Eth yl-
tetr a h yd r ofu r o[2,3-b]p yr a n -2-on e (40). A solution of ester
34f (580 mg, 2.9 mmol) and 10% H2SO4 (11.6 mL) in dioxane
(5.8 mL) was refluxed for 15 h. The dioxane was removed in
vacuo, and the residue was treated with brine (5 mL) and
extracted with ether (4 × 25 mL). The extracts were washed
with brine (5 mL) and saturated aqueous NaHCO3 (5 mL),
dried over MgSO4, and concentrated in vacuo to give 40 (380
mg, 77%) as a colorless oil which was used in the next step
without purification. Rf 0.44 (pentane/ethyl acetate: 3/1);
(1R,6R,7S)-6-Ben zyl-7-ca r beth oxy-2-oxa bicyclo[4.1.0]-
h ep ta n e (34h ). Following the general procedure using enol
ether 31 gave cyclopropane 34h (174 mg, 67%) as a colorless
oil. Rf 0.12 (pentane/ethyl acetate: 95/5); [R]25 ) -31.7 (c )
D
2.50, CH2Cl2, 96% ee); IR (neat, cm-1) 1716 and 1123; 1H NMR
(300 MHz) δ 1.31 (3 H, t, J ) 7.1 Hz), 1.46-1.51 (2 H, m),
1.74-1.85 (1 H, m), 1.93-1.98 (2 H, m), 2.90-3.07 (2 H, m),
3.22-3.31 (1 H, m), 3.60-3.65 (1 H, m), 4.16-4.24 (3 H, m),
and 7.21-7.35 (5 H, m); 13C NMR (75.5 MHz) δ 171.5, 138.8,
129.1, 128.3, 126.2, 64.9, 64.1, 60.4, 37.4, 32.7, 31.2, 25.0, 21.8,
and 14.3; MS (EI) m/z (rel intensity) 260 (M+, 1), 215 (6), 169
(100), 141 (55), 123 (31), and 65 (54). Anal. Calcd for
[R]25 ) -21.7 (c ) 1.00, CH2Cl2); IR (neat, cm-1) 1787, 1190,
D
1165, and 919; 1H NMR (300 MHz) δ 0.90 (3 H, t, J ) 7.6 Hz),
1.44-1.75 (6 H, m), 2.31 (1 H, d, J ) 16.9 Hz), 2.37 (1 H, d, J
) 16.9 Hz), 3.65-3.72 (1 H, m), 3.80-3.86 (1 H, m), and 5.30
(1 H, s); 13C NMR (75.5 MHz) δ 174.0, 105.2, 67.0, 62.1, 40.6,
40.0, 27.3, 27.0, 20.0, and 8.5; MS (EI) m/z (rel intensity) 154
(4), 125 (17), 97 (85), 69 (55), and 55 (100). Anal. Calcd for
C9H14O3: C, 63.53; H, 8.23. Found: C, 63.75; H, 8.18.
C
16H20O3: C, 73.84; H, 7.69. Found: C, 73.94; H, 7.71.
(1R*,6R*,7R*)-1-Ben zyl-7-car beth oxy-2-oxabicyclo[4.1.0]-
h ep ta n e (34i). Following the general procedure using enol
ether 33 gave cyclopropane 34i (117 mg, 45%) as a colorless
oil. Rf 0.20 (pentane/ethyl acetate: 95/5); IR (neat, cm-1) 2981,

Asymmetric Total Synthesis of (+)-Quebrachamine
J . Org. Chem., Vol. 63, No. 17, 1998 6015
(3aS,7aR)-3a-Eth ylh exah ydr ofu r o[2,3-b]pyr an -2-ol (41).
To a solution of lactone 40 (250 mg, 1.5 mmol) in dry ether (5
mL) was introduced dropwise DIBALH (1.6 mL, 1 M solution
in hexane, 1.6 mmol) over 5 min at - 78 °C. After additional
stirring for 1 h at this temperature, the reaction mixture was
slowly warmed to room temperature. The reaction was
quenched with 1 M HCl (5 mL) and extracted with ether (4 ×
5 mL). The combined extracts were washed with saturated
aqueous NaHCO3 (5 mL), dried over MgSO4, and concentrated
in vacuo. The crude product was purified via flash chroma-
tography (pentane/ethyl acetate: 1/1) to give pure acetal 41
(217 mg, 79%) as an unseparable mixture of cis and trans
to give 42 (728 mg, 90%) as a mixture of diastereomers. All
physical and spectroscopic data of the product were in complete
agreement with the literature values.26a
(11S)-11-Eth yl-5,8,9,10,11,12,13,14-octa h yd r o-6H-7,14-
d ia za -7,11-m et h a n ocyclou n d eca [r]in d en e
((+)-Qu e-
br a ch a m in e) (7). The diastereomeric mixture of 42 (210 mg,
0.7 mmol) was dissolved in a mixture of dry TEA (2.5 mL) and
CHCl3 (5 mL) and cooled to - 10 °C. To this stirred solution
was then introduced dropwise via a syringe methanesulfonyl
chloride (500 mg, 4.4 mmol). When the addition was complete,
the reaction mixture was stirred for 40 h at room temperature.
Concentration in vacuo gave a brown oil which was directly
dissolved in dry N-methylmorpholine (50 mL) and treated
portionwise with LiAlH4 (800 mg, 21.1 mmol). The resulting
suspension was heated at reflux for 13 h and then carefully
treated dropwise with water (5 mL) at 0 °C. After filtration
through a pad of Celite and concentration in vacuo the crude
product was purified by flash chromatography on neutral
activated alumina (pentane/ethyl acetate: 10/1) and recrystal-
lized from methanol to give 7 (138 mg, 67%) as white crystals.
[R]22 ) +111 (c ) 0.18, CHCl3) (lit.28 [R]22 ) +117, c ) 0.18,
diastereomers. Rf 0.18 (pentane/ethyl acetate: 1/1); [R]25
)
D
+12.2 (c ) 1.00, CH2Cl2); IR (neat, cm-1) 3416, 2939, 2880,
1
and 1463; H NMR (300 MHz) δ 0.90 (6 H, m), 1.31-2.13 (16
H, m), 3.34-3.38 (1 H, m), 3.48-3.57 (1 H, m), 3.77-3.86 (1
H, m), 3.90-3.98 (2 H, m), 4.12-4.21 (1 H, m), 4.69 (1 H, s),
5.02 (1 H, s), and 5.53-5.68 (2 H, m); 13C NMR (75.5 MHz) δ
105.6, 105.1, 100.0, 97.0, 64.3, 61.7, 44.9, 41.9, 41.1, 38.7, 30.5,
28.1, 27.9, 27.5, 21.1, 20.6, 8.5, and 7.8; MS (EI) m/z (rel
intensity) 171 (M+ - 1, 1), 154 (M+ - H2O, 4), 125 (13), 97
(100), 85 (44), and 69 (60). Anal. Calcd for C9H16O3: C, 62.79;
H, 9.30. Found: C, 62.71; H, 9.43.
(2S,4RS)-3-(2-Eth yl-2,3,5,6,11,11b-h exah ydr o-1H-in doliz-
in o[8,7-b]in d ol-2-yl)p r op a n -1-ol (42). Alcohol 41 (467 mg,
2.7 mmol) was stirred with tryptamine hydrochloride (800 mg,
4.1 mmol) in 10% aqueous acetic acid (5 mL) for 7 h at room
temperature under N2. After the addition of 150 mg of sodium
acetate, the reaction mixture was stirred for another 44 h. The
solution was treated with 10% aqueous Na2CO3 until pH > 7
and extracted with CH2Cl2 (3 × 10 mL). The combined
extracts were dried over MgSO4 and passed through a short
column of neutral alumina to give a yellow foam (832 mg) after
concentration in vacuo. The foam was treated directly with
NaBH3CN (210 mg, 3.3 mmol) in 10% aqueous acetic acid (10
mL). After stirring for 20 min at room temperature, the
solution was extracted with CH2Cl2 (3 × 10 mL), and the
combined extracts were dried over MgSO4 and concentrated
D
D
CHCl3); 1H NMR (300 MHz) δ 0.88 (3 H, t, J ) 7.5 Hz), 1.10-
1.35 (5 H, m), 1.50-1.64 (3 H, m), 1.85-2.01 (1 H, m), 2.21-
2.48 (4 H, m), 2.69-2.95 (4 H, m), 3.27 (1 H, d, J ) 11.9 Hz),
7.09-7.13 (2 H, m), 7.26-7.30 (1 H, m), 7.50-7.53 (1 H, m),
and 7.69 (1 H, s); 13C NMR (75.5 MHz) δ 139.7, 134.7, 128.9,
120.1, 118.6, 117.4, 110.0, 108.7, 56.7, 55.1, 53.4, 53.2, 37.1,
34.7, 33.4, 32.0, 22.7, 22.4, 21.9, and 7.8. All other physical
and spectroscopic data of the product were also in complete
agreement with the reported data.27
Ack n ow led gm en t. We thank the Swedish Natural
Research Council, the Swedish Foundation for Strategic
Research, the Swedish Institute, and Pharmacia and
UpJ ohn for generous financial support.
J O9807417