Practical formal total syntheses of the homocamptothecin derivative and anticancer agent diflomotecan via asymmetric acetate aldol additions to pyridine ketone substrates

Article abstract of DOI:10.1021/jo060928v

(Chemical Equation Presented) Two practical, efficient, and scalable asymmetric routes to DE ring fragment 7, a key building block in the synthesis of the homocamptothecin derivative diflomotecan 4, are described. The "acetal route" starts from 2-chloro-4

Full text of DOI:10.1021/jo060928v

Practical Formal Total Syntheses of the Homocamptothecin
Derivative and Anticancer Agent Diflomotecan via Asymmetric
Acetate Aldol Additions to Pyridine Ketone Substrates
Rene´ Peters,*,†,§ Martin Althaus,† Christian Diolez,‡ Alain Rolland,‡ Eric Manginot,| and
Marc Veyrat|
F. Hoffmann-La Roche Ltd., Pharmaceuticals DiVision, Safety & Technical Sciences, Synthesis and
Process Research, Grenzacherstr. 124, CH-4070 Basel, Switzerland, Ipsen, aVenue du Canada, F-91966
Les Ulis, France, and Expansia, route d’AVignon, F-30390 Aramon, France
peters@org.chem.ethz.ch
ReceiVed May 4, 2006
Two practical, efficient, and scalable asymmetric routes to DE ring fragment 7, a key building block in
the synthesis of the homocamptothecin derivative diflomotecan 4, are described. The “acetal route” starts
from 2-chloro-4-cyanopyridine 8 and represents an enantioselective and optimized modification of the
original racemic discovery chemistry synthesis. The inefficient optical resolution procedure was replaced
by an efficient asymmetric acetate aldol addition (dr 87:13) to a ketone substrate as the key step generating
the (R)-configured quaternary stereocenter with high stereoselectivity. 7 was finally obtained in 8.9%
overall yield (er 99.95:0.05) over nine steps, avoiding chromatographic purifications and comparing
favorably with the initial procedure. In the related “amide route” starting from 2-chloroisonicotinic acid
41, a secondary amide directing group was used to facilitate the ortho lithiation of the pyridine 3-position.
The key step of this protocol again consists of a practical asymmetric acetate aldol addition (dr ) 87:
13). The DE ring building block 7 was thus obtained in 11.1% overall yield (er > 99.95:0.05) over nine
steps requiring only one chromatographic purification.
Introduction
pentacyclic system, which was determined in 1966,3 contains a
highly electrophilic R-hydroxy-δ-lactone ring (ring E), which
rapidly hydrolyzes in basic and neutral media yielding the open-
chain carboxylate form 2 (Scheme 1), which is biologically
almost inactive.
The alkaloid camptothecin (CPT, 1), which was first isolated
in 1958 by Wani and Wall1 from the Chinese tree Camptotheca
accuminata, shows potent antiproliferative activity and continues
to serve as a very attractive and challenging lead structure for
the development of new anticancer drugs.2 The structure of the
(2) Selected CPT review articles: (a) Thomas, C. J.; Rahier, N. J.; Hecht,
S. M. Bioorg. Med. Chem. 2004, 12, 1585. (b) Du, W. Tetrahedron 2003,
59, 8649. (c) Kawato, Y.; Terasawa, H. Prog. Med. Chem. 1997, 34, 69.
(d) Jew, S.-s.; Kim, M. G.; Kim, H.-J.; Roh, E.-Y.; Park, H.-g. Korean J.
Med. Chem. 1996, 6, 263. (e) Hutchinson, C. R. Tetrahedron 1981, 37,
1047. (f) Schultz, A. G. Chem. ReV. 1973, 73, 385.
† F. Hoffmann-La Roche Ltd.
§ Current address: ETH Zu¨rich, Laboratory of Organic Chemistry, Wolfgang-
Pauli-Str. 10, Ho¨nggerberg HCI E 111, CH-8093 Zu¨rich, Switzerland.
‡ Ipsen.
| Expansia.
(1) Wall, M. E. In Chronicles of Drug DiscoVery; Lednicer D., Ed.;
American Chemical Society: Washington D. C., 1993; Vol. 3, p 327.
(3) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A.
T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888.
10.1021/jo060928v CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
J. Org. Chem. 2006, 71, 7583-7595
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Peters et al.
SCHEME 1. Hydrolysis of CPT Leading to Biologically
Almost Inactive 2
SCHEME 2. Coupling Strategy of DE Fragment 7 with AB
Quinoline Derivatives 6
This strategy was previously developed by Comins et al. for
the total synthesis of (S)-CPT (1).6 Because of its convergent
character and the robustness of two finishing steps, we decided
to maintain this concept for the production of kilogram amounts
of 4 for clinical trials.
This equilibrium is shifted toward the carboxylate form 2 in
human plasma thus explaining the lower efficacy of most CPT
analogues in clinical trials compared to the stunning results
obtained with Xenograft models.4 The development of homo-
camptothecins (hCPT, Figure 1), which are CPT analogues
entailing a seven-membered â-hydroxy-ꢀ-lactone ring, addressed
this issue: although it was previously generally accepted that
an R-hydroxylactone is an indispensable structural feature for
anticancer activity of CPT derivatives, Lavergne, Bigg, et al.5
investigated a modification of the CPT lactone ring, which
retains the TOPO I mediated activity and at the same time
displays enhanced stability against hydrolysis. hCPT provided
an excellent template for the preparation of new TOPO I
inhibitors with high cytotoxicity toward solid tumor cell lines.
The most promising hCPT derivative so far is diflomotecan (4),
possessing two fluorine atoms attached to ring A.
The discovery chemistry synthesis of the DE ring system 7
is shown in Scheme 3.5 As a key step, the quaternary stereo-
center was generated in racemic form by a Reformatsky addition
to ketone 15 as an acceptor component. The subsequent optical
resolution of (rac)-17 by crystallization using quinidine as a
resolving reagent was not efficient on a large scale because the
undesired enantiomer crystallized. The desired enantiomer was
isolated from the mother liquid with the consequence of a
relatively low enantiomeric ratio (er) of 85:15 and a purity of
only 70% as determined by quantitative HPLC. Key intermediate
7 was thus obtained from 8 over 13 linear steps in 1.3% overall
yield and requiring four chromatographic purifications.7,8
Search for a Scalable Synthesis of DE Ring Fragment 7.
(a) Acetal Approach. Herein, we present a practical, efficient,
and scalable enantioselective modification of the discovery
chemistry synthesis. To circumvent the inefficient optical resolu-
tion of â-hydroxycarboxylic acid (rac)-17, a stoichiometric
asymmetric aldol addition protocol was developed. To this end,
the steps leading to ketone 15 were modified to obtain 15 in
the high purity required for an efficient and selective asymmetric
aldol addition reaction. Furthermore, this task should be realized
avoiding any chromatographic purification.
Our approach started by methanolysis of 2-chloro-4-cyano-
pyridine (8) with 1.2 equiv of NaOMe in acetonitrile (Scheme
4) providing 2-methoxy pyridine 20, which was purified by
Soxhlet extraction.9 Grignard addition to the cyano group gener-
ated ethyl ketone 21, which was then protected by 1,3-dioxane
formation furnishing 11 isolated in 40% yield over three steps
after high vacuum distillation. The subsequent metalation of
the pyridine 3-position is ortho directed by the methoxy and
the acetal moiety in 11.10 The intermediate carbanion, which
was generated by using mesityllithium, was trapped by addition
FIGURE 1. hCPT derivative diflomotecan (4).
The convergent discovery chemistry synthesis was based on
the coupling strategy of DE fragment 7 with AB quinoline
derivatives 6 via a Mitsunobu alkylation followed by a Heck
cyclization thus forming ring C of the pentacycle (Scheme 2).5
(4) Cao, Z.; Harris, N.; Kozielski, A.; Vardemann, D.; Stehlin, J. S.;
Giovanella, B. J. Med. Chem. 1998, 41, 31.
(5) (a) Lavergne, O.; Demarquay, D.; Bailly, C.; Lanco, C.; Rolland,
A.; Huchet, M.; Coulomb, H.; Muller, N.; Baroggi, N.; Camara, J.; Le
Breton, C.; Manginot, E.; Cazaux, J.-B.; Bigg, D. C. H. J. Med. Chem.
2000, 43, 2285. (b) Lavergne, O.; Harnett, J.; Rolland, A.; Lanco, C.;
Lesueur-Ginot, L.; Demarquay, D.; Huchet, M.; Coulomb, H.; Bigg, D. C.
H. Bioorg. Med. Chem. Lett. 1999, 9, 2599. (c) Lavergne, O.; Lesueur-
Ginot, L.; Pla Rodas, F.; Kasprzyk, P. G.; Pommier, J.; Demarquay, D.;
Pre´vost, G.; Ulibarri, G.; Rolland, A.; Schiano-Liberatore, A.-M.; Harnett,
J.; Pons, D.; Camara, J.; Bigg, D. C. H. J. Med. Chem. 1998, 41, 5410. (d)
Lavergne, O.; Lesueur-Ginot, L.; Pla Rodas, F.; Bigg, D. C. H. Bioorg.
Med. Chem. Lett. 1997, 7, 2235.
(6) (a) Comins, D. L.; Hong, H.; Saha, J. K.; Jinhua, G. J. Org. Chem.
1994, 59, 5120. (b) Comins, D. L.; Hong, H.; Jinhua, G. Tetrahedron Lett.
1994, 35, 5331. (c) Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem.
Soc. 1992, 114, 10971.
(7) Application of this chemistry to produce kilogram amounts of 4
resulted in decreased yields: 7 was typically obtained in 0.5% yield starting
from 8.
(8) For an alternative reported total synthesis of hCPT in 1.4% overall
yield (longest linear sequence of 15 steps), see: Gabarda, A. E.; Du, W.;
Isarno, T.; Tangirala, R. S.; Curran, D. P. Tetrahedron 2002, 58, 6329.
(9) All purification attempts of 20 by crystallization or trituration failed.
7584 J. Org. Chem., Vol. 71, No. 20, 2006

Formal Total Syntheses of Homocamptothecin
SCHEME 3. Beaufour-Ipsen Discovery Chemistry Route to DE Ring Fragment 7
of DMF giving rise to aldehyde 12. All attempts to replace
mesityllithium (MesLi) with other bases, which would be
commercially available and easier to handle, failed. Whereas
alkyllithiums, such as n-, s-, or tert-butyllithium, as well as
aryllithiums such as phenyllithium smoothly undergo addition
to the pyridine 6-position of 11, lithium (LHMDS, LDA, LTMP)
and potassium amide bases (KHMDS) did not deprotonate the
aromatic heterocycle. This forced us to significantly improve
the practicality of the mesityllithium preparation procedure. tert-
BuLi was successfully replaced by n-BuLi for halogen-lithium
exchange with mesitylbromide, and in this context, we found
that it is essential to use a 2.5 M n-BuLi solution in hexane
(instead of the more common 1.6 M n-BuLi in hexane) to reduce
the amount of hexane thereby increasing the solubility of MesLi.
Aldehyde 12 was purified by silica gel filtration to remove
mesityl side products and unreacted starting material as well as
several side products. The most prominent side product was
identified by LC-MS and NMR as the mesityl addition product
to the pyridine 6-position.
by an alternative base. In addition to the safety issue related to
NaH, we encountered formation of considerable amounts of
high-boiling dibenzyl ether as a side product depending on the
NaH quality. Furthermore, even under activation by addition
of catalytic amounts of tetrabutylammonium iodide, conversion
was incomplete. Interestingly, even only marginally nucleophilic
bases such as potassium or sodium tert-butoxide led to not yet
fully rationalized degradation reactions of primary alcohol 13
to form aldehyde 12 and acetal 11 in equal amounts (Scheme
5). In the absence of oxygen, 50% of starting material 13 was
already decomposed after 2 h at room temperature (9% decom-
position after 5 min, 35% decomposition after 1 h).
Using lithium tert-butoxide, the degradation was negligible,
but benzylation was extremely slow. However, the nonnucleo-
philic base LHMDS was successfully employed for clean pre-
formation of the corresponding lithium alkoxide. By addition
of 10 mol % of dry tetrabutylammonium iodide (dried to
constant weight in high vacuum prior to use to avoid formation
of dibenzyl ether as the side product), the alkylation proceeded
without decomposition at 65 °C furnishing benzyl ether 14 in
high purity. To remove excess benzyl bromide, pyrrolidine was
added after almost complete conversion and the resulting tertiary
benzylamine was removed by extraction with aqueous HCl.
Reduction of the aldehyde group in 12 with NaBH4 provided
13 in high yield and purity after trituration with heptane. In the
subsequent benzylation step, it was desirable to replace NaH
(10) Review about the directed metalation of π-deficient azaaromatics:
Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. AdV. Heterocycl.
Chem. 1991, 52, 187.
The acetal cleavage of 14 in TFA/water (1:1 or 2:1) was com-
pleted within 24 h at room temperature. However, product 15
J. Org. Chem, Vol. 71, No. 20, 2006 7585

Peters et al.
SCHEME 4. Practical Asymmetric Synthesis of DE Ring Fragment 7 (Acetal Route)
SCHEME 5. Unexpected Decomposition of Benzylic Alcohol
13 with tert-Butoxide Bases
to ketones as acceptor substrates are a largely unexplored field.
Only two auxiliaries, namely, 2412 (dr ) 65:35 to 79:21) and
2513 (dr ) 82:18), have been reported in the literature to provide
reasonable stereoselectivities in the addition reaction to aceto-
phenone or similar phenylalkyl ketones. With 15 as the substrate,
no addition reaction took place using either 24 or 25, presumably
because the di- or trianions formed from 24 or 25 are too basic
and preferentially deprotonate ketone 15. Monolithiated acetates
26-31 suffer from either low conversion or low diastereo-
selectivity.14 The relatively high dr of 85:15 obtained for acetate
29 derived from 8-phenylmenthol is exceptional in this series.
The most promising auxiliaries were the chiral oxazolidinones
(ent)-22 and 32-40 (acylated Evans-type auxiliaries). The
highest selectivities were obtained with auxiliaries bearing bulky
R1 groups. An R2 substituent cis to R1 seems to be advanta-
geous in terms of both conversion and selectivity, whereas an
R3 group trans to R1 appears to exhibit a negative influence.
Two auxiliaries proved synthetically exceptionally useful: (4S)-
4-tert-butyloxazolidin-2-one providing acetate 33 and (4S,5R)-
4,5-diphenyloxazolidin-2-one (ent-22). Auxiliary cleavage re-
vealed that the (S)-isomer of 17 was preferentially formed using
(4S)-configured oxazolidinones 32-37.15 (4R)-Configured ox-
azolidinones are therefore required to obtain 17 with (R)-
configuration. This configurational outcome is in agreement with
the results obtained by Evans et al. for aldehyde electrophiles.16
Whereas the commercial availability of kilogram amounts of
(4R)-4-tert-butyloxazolidin-2-one is uncertain (annual produc-
was not pure enough to achieve high conversion in the sub-
sequent asymmetric aldol addition reaction. A highly pure
product 15 was however directly obtained by utilizing a catalytic
amount of para-toluenesulfonic acid (0.2 equiv) in EtOH/water
(4:1) for the acetal cleavage.
The key step of this synthesis is the asymmetric acetate aldol
addition reaction 15 f 17. Eighteen chiral acetate derivatives
were screened (Scheme 6). The best results were obtained with
3-acetyl-(4S,5R)-4,5-diphenyloxazolidin-2-one ((ent)-22). The
screening was performed on a 100 mg scale adding a solution
of ketone 15 to the corresponding chiral lithium enolates at
-78 °C. Monitoring of the reactions proved problematic due
to the thermal instability of the intermediate lithium alkoxides
undergoing rapid retro-aldol reactions during sampling with a
syringe. However, the additions generally took place very
rapidly and no significant difference in conversion was observed
when reactions were quenched either after 10 min or after 1 h.
In contrast to propionate aldol additions, which often provide
excellent stereoselectivities, stoichiometric asymmetric acetate
aldol addition reactions usually suffer from low diastereoselec-
tivities.11 Furthermore, stereoselective acetate aldol additions
(11) Review: Palomo, C.; Oiarbide, M.; Garc´ıa, J. M. Chem.-Eur. J.
2002, 8, 36.
(12) Dongala, E. B.; Dull, D. L.; Mioskowski, C.; Solladie´, G. Tetra-
hedron Lett. 1973, 4983.
(13) Braun, M.; Devant, R. Tetrahedron Lett. 1984, 5031.
(14) The configuration of the generated stereocenter has not been assigned
using 26-31.
(15) Conversion of (ent)-17 to (ent)-7 and comparison with a sample of
(R)-7 by chiral HPLC.
7586 J. Org. Chem., Vol. 71, No. 20, 2006

Formal Total Syntheses of Homocamptothecin
SCHEME 6. Screening of the Asymmetric Acetate Aldol Addition to Ketone 15
tion of only ca. 1 kg, Degussa: 23 000 ꢀ/kg), (4R,5S)-4,5-
diphenyloxazolidin-2-one is produced in ton amounts each year
(ChemPacific: 2000 USD/kg). On this basis, (4R,5S)-4,5-
diphenyloxazolidin-2-one was selected as the auxiliary of choice.
The efficiency of Evans-type auxiliaries for the acetate aldol
reaction described is rather surprising because it has been
reported in the literature that even with aldehyde acceptors the
chiral acetyl oxazolidinone 32 led to moderate or almost no
diastereoselectivity. Thus, the corresponding boron enolate
provided disappointing results with acetaldehyde (dr ) 72:28)
or with isobutyraldehyde (dr ) 52:48).16
Scale-up experiments at -78 °C (acetone/dry ice cooling
bath) revealed that the stereoselectivity of the initial aldol
product dropped with increasing reaction scale presumably due
to less-efficient cooling of the reaction mixture upon addition
of the ketone substrate. For that reason, the addition was
performed under optimized conditions at -95 °C (MeOH, liquid
N2 cooling) and the ketone solution was slowly added using a
syringe pump.
reaction mixture after treatment with LiOH and H2O2 followed
by recrystallization from toluene (yield of recovered auxiliary
was 90%; the auxiliary was reused successfully multiple times
without significant changes in selectivity and yield) and (ii) the
ease of product isolation/purification by pH-dependent extrac-
tion.17
For the formation of the Li enolate, it is important to add the
LHMDS solution to a solution of chiral auxiliary 22 because
the opposite order of addition can result in crystallization of 22
in the syringe during the addition.
â-Hydroxy carboxylic acid 17 was then treated with aqueous
HBr in DME resulting in both methyl and benzyl ether cleavage
as well as in lactone formation. Gratifyingly, the er was signifi-
cantly increased due to preferential crystallization of the (R)-7
out of the reaction mixture. The key building block 7 was thus
obtained with an er of 99.95:0.05 (chiral HPLC). The yield of
the final step highly depends on the er of 17 because the mother
liquid contains the almost racemic product. Therefore, a starting
material 17 with an er of 87.2:12.8 could in principle lead to a
maximum yield of 100 - (2 × 12.8) ) 74.4% () ee value of
17). In conclusion, the optically active key intermediate 7 was
thus synthesized over nine linear steps avoiding any chromato-
graphic purification (and requiring only one chromatographic
filtration) in 8.9% overall yield, which compares favorably with
the discovery chemistry route. The experiments described in
the experimental part have been performed on either a 40 g
scale (8 f 11) or a 5 g scale (11 f 7).
Cleavage of the auxiliary was found to proceed in the same
pot by addition of aqueous LiOH and H2O2. The (R)-configured
product 17 was isolated in 75% yield starting from 15 with an
er of 87.2:12.8. This aldol addition step is practical because of
(i) the ease of auxiliary recycling by simple filtration from the
(16) (a) Evans, D. A.; Bartoli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. See also: (b) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett.
1985, 26, 3788. (c) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986,
108, 6757. (d) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem.
Soc. 1982, 104, 1737. (e) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J.
S.; Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215. (f) Evans, D. A.;
Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141.
(17) The result described here for the formation of 17 was achieved with
22, which had been prepared from an auxiliary having been recycled already
five times.
J. Org. Chem, Vol. 71, No. 20, 2006 7587

Peters et al.
SCHEME 7. Practical Asymmetric Synthesis of DE Ring Fragment 7 (Amide Route)
(b) Amide Approach. Because the asymmetric acetate aldol
addition reaction to ketone substrate 15 worked unexpectedly
well regarding stereoselectivity and conversion, an alternative
route toward a suitable ketone substrate was sought to avoid
the use of MesLi generating the problem of the formation of
high-boiling mesityl side products only removable by silica gel
filtration. For this purpose, a more efficient ortho-directing group
in the pyridine 4-position other than the 1,3-dioxane moiety was
required.
of NaBH4 because the reducing agent is more stable in this
solvent mixture than in EtOH (in EtOH, the reduction was not
complete even with 4 equiv of NaBH4, which was added in
four portions).
Ethyllithium addition to lactone 45 provided lactol 46, which
is in equilibrium with the open hydroxyketone form (lactol/
hydroxyketone ca. 6:1 in CDCl3). With EtMgCl, Et3ZnLi, Et4-
ZnLi2, and Et3ZnMgX, lactol 46 was not accessible because
the ethyl addition occurred faster to 46 than to 45. EtMgBr
provided complex mixtures, whereas EtMgBr in combination
with CeCl3 gave almost no conversion. Ethyllithium was there-
fore the reagent of choice. Although the addition works almost
quantitatively on a 100 mg scale, it was difficult to obtain high
conversion on a multigram scale. The reasons are manifold: the
ethyllithium reagent is purchased as a 0.5 M solution in benzene/
cyclohexane, which rapidly freezes in the syringe upon dropwise
addition to the cooled solution of lactone 45. For that reason, a
solution of 45 was added to an EtLi suspension. On the other
hand, 45 also rapidly crystallizes from concentrated THF
solutions. For that reason, the dilution factor should be at least
25. During the addition of 45, there is initially a large excess
of reagent causing some double addition. An improved version
involves a combination of triethylaluminum (1.1 equiv) and
ethyllithium (2 × 1.1 equiv). Equimolar amounts of AlEt3 (1.1
equiv) and EtLi are precoordinated at 0 °C followed by the rapid
addition of the solution of the starting material 45 at -40 °C.
To reach high conversion, a second equivalent of EtLi is
required, which is slowly added at -40 °C. The reaction mixture
is then allowed to slowly warm to -15 °C and is stirrable at
any time (in contrast to the version without AlEt3). Surprisingly,
there was no conversion when AlEt3 was precoordinated with
the 2 equiv of EtLi (potential formation of Et5AlLi2). For that
reason, we suggest that EtLi is still the reactive species and
that Et4AlLi might help to activate the lactone toward the
nucleophilic addition acting as a Lewis acid. Although the yield
of 46 could thus be increased to 53%, product purification still
requires column chromatography.
2-Methoxy-4-isopropylamide 43 was identified to be a suit-
able intermediate for a more practical metalation procedure of
the 3-pyridine position (Scheme 7). 43 was prepared over two
steps starting from 2-chloroisonicotinic acid 41, which was
obtained via reaction of the corresponding acid chloride with
isopropylamine. The 2-chloro substituent in 42 was subsequently
substituted by a methoxy group using NaOMe. Metalation of
the 3-position of 43 was already achieved with n-BuLi in the
presence of TMEDA or LiCl. Gratifyingly, no butyl addition
to the pyridine 6-position was observed for this substrate,
presumably due to electronic deactivation of the pyridine nucleus
toward an addition reaction caused by deprotonation of the
secondary isopropylamide functionality. Although the regio-
selectivity is low in THF (3-Li/5-Li ) ca. 3:1) regardless of
the metalation temperature, metalation of the 3-position is
significantly favored in TBME. This might be rationalized by
the weaker donor ability of TBME, thus enhancing the effect
of the coordinating and directing methoxy group. No reaction
occurred with n-BuLi in the absence of the activating additives
TMEDA or LiCl. The use of s-BuLi does not require these
additives, but the regioselectivity is lower than with n-BuLi.
The lithiated species was trapped by DMF yielding N,O-
hemiacetal 44. The crude product, which still contained large
amounts of DMF, was reduced by NaBH4 in 2-propanol/water
to the corresponding hydroxyamide, which was then cyclized
in the same pot by addition of aqueous HCl furnishing lactone
45 which was purified by trituration. The choice of 2-propanol/
water for the reduction step is important to reduce the amount
7588 J. Org. Chem., Vol. 71, No. 20, 2006

Formal Total Syntheses of Homocamptothecin
TABLE 1. Screening of Asymmetric Acetate Aldol Additions to Ketones 47, 50, and 51
equiv
(auxiliary)
ketone
oxazolidinone
T/°C
conversion/%c
drc
47
47
47
47
47
47
47
47
47
47
47
47
47
47
47
51
51
51
51
51
51
50
50
50
50
50
22 (R1 ) Ph, R2 ) Ph)
39 (R1 ) Ph, R2 ) H)
39 (R1 ) Ph, R2 ) H)
39 (R1 ) Ph, R2 ) H)
39 (R1 ) Ph, R2 ) H)
39 (R1 ) Ph, R2 ) H)
39 (R1 ) Ph, R2 ) H)
39 (R1 ) Ph, R2 ) H)
38 (R1 ) Bn, R2 ) H)
(ent)-32 (R1 ) iPr, R2 ) H)
40 (R1/2 ) C6H4CH2)
(ent)-33 (R1 ) tBu, R2 ) H)
(ent)-33 (R1 ) tBu, R2 ) H)
1.1
1.1
1.1
1.1
2.0
2.0
3.0
3.0
1.1
3.0
3.0
1.1
1.5
2.0
2.5
3.0
3.0
3.0
4.0
3.0
2.5
1.1
2.0
1.1
1.1
1.1
-78
-78
-78
-95
-95
-95
-95
-95
-78
-78
-78
-95
-95
-95
-78
-78
-95
-95
-78
-78
-78
-95
-95
-95
-95
-95
25
40
40
41
57
51
72
88
45
23
64
60
78
87
81
63
75
54
90
58
76
62
84
48
59
54
66:34
78:22
50:50a
78:22
80:20
85:25b
82:18
87:13b
73:27
77:23
62:38
90:10
93:7
(ent)-33 (R1 ) tBu, R2 ) H)
91:9
e
52:48
82:18
85:15
57:43
80:20
82:18
67:33
62:38
62:38
68:32
61:39d
72:28
39 (R1 ) Ph, R2 ) H)
39 (R1 ) Ph, R2 ) H)
22 (R1 ) Ph, R2 ) Ph)
38 (R1 ) Bn, R2 ) H)
(ent)-32 (R1 ) iPr, R2 ) H)
e
39 (R1 ) Ph, R2 ) H)
39 (R1 ) Ph, R2 ) H)
22 (R1 ) Ph, R2 ) Ph)
38 (R1 ) Bn, R2 ) H)
(ent)-32 (R1 ) iPr, R2 ) H)
a In the presence of 1.1 equiv of LiCl. b Slow ketone addition by syringe pump. c Determined from crude 1H NMR. d Determined by HPLC. e 8-Ph-
menthol was used as the chiral auxiliary.
To obtain a suitable ketone substrate for the asymmetric aldol
addition reaction, 46 had to be opened by an appropriate
electrophile. Attempts failed to synthesize 15 using, e.g., BnO-
(HNd)CCCl3 (DCM, cat. TfOH, or TMSOTf, 0 °C) due to
decomposition, incomplete conversion, and formation of only
trace amounts of 15. Similar results were obtained for tritylation
with trityl chloride (NEt3, DMAP, DCM, rt to 50 °C), methoxy-
methylation with formaldehyde dimethyl acetal (TFA, DCM,
0 °C), ethoxyethylation with ethyl vinyl ether (PTSA, DCM),
acetylation with acetic anhydride (pyridine, 0 °C), or 2-bromo-
acetylation with bromo acetyl bromide (2,6-lutidine, DCM,
-78 °C) as electrophilic components. However, the intended
strategy was finally realized using silyl chlorides and worked
especially well with TBSCl (tert-butyldimethylsilyl chloride)
and TBDPSCl (tert-butyldiphenylsilyl chloride); TMSCl (tri-
methylsilyl chloride) failed to give the desired product, and
TESCl (triethylsilyl chloride) resulted in formation of significant
amounts of a side product formed by silylation of the tertiary
lactol hydroxy group. The workup of the TBS and TBDPS ether
formation benefits from the solubility of the lipophilic silyl
ethers in heptane. As a result, the polar components DMF and
imidazole were completely removed by aqueous workup and
the crude ketone product 47 was isolated with excellent purity.
Unfortunately, the protecting group on the primary benzylic
oxygen, although rather remote from the reacting carbonyl
carbon, exerts a major influence on conversion and selectivity
of the asymmetric aldol addition reaction. To obtain high con-
versions, an enolate excess of ca. 2-3 equiv was necessary.18
The chiral enolate formed from (4R,5S)-3-acetyl-4,5-diphenyl-
oxazolidin-2-one (22) led to disappointingly low diastereo-
selectivities for all silyl ethers, thus necessitating an additional
auxiliary screening for each derivative (Table 1). As a general
trend, it may be concluded that the conversion decreases with
increasing steric bulk of the silyl protecting group while the
diastereoselectivity increases. Thus, TBS evolved as the best
compromise. Slow addition of the ketone solution to the chiral
Li enolate generally increased conversion and the diastereomeric
ratio. Under optimized conditions, lithiated (R)-4-phenyloxazo-
lidinone (39) (3.0 equiv) was reacted with TBS ketone 47 at
-95 °C resulting in 88% conversion and a dr of 87:13. The
auxiliary was recycled in 87% yield. Less auxiliary (2.0 equiv)
is required when (R)-3-acetyl-4-tert-butyl-oxazolidinone (33)
is used (conversion 87%). Moreover, the diastereoselectivity
increased to 91:9. However, because of the low annual produc-
(18) We assume that the lower reactivity of 47 as compared to 15 might
be best rationalized by steric and not by electronic reasons. In accordance
with this hypothesis, conversions (as determined by 1H NMR) using chiral
lithium enolates were generally higher for TES derivative 50 than for TBS
ether 47 and the TBDPS ether 51 (eq 1, Table 1). This illustrates that the
lower conversion as compared to 15 cannot be mainly attributed to a weak
Si‚‚‚OdC interaction and a resulting enhanced acidity of the R-CH2 group
because in this case lower conversions with smaller silyl protecting groups
such as, e.g., TES would be expected.
J. Org. Chem, Vol. 71, No. 20, 2006 7589

Peters et al.
heptane/ethyl acetate (1:1). Mp: 98 °C. 1H NMR (300 MHz,
CDCl3): δ 8.31 (d, 1H, J ) 5.1 Hz), 7.07 (dd, 1H, J ) 5.1 Hz,
J ) 1.2 Hz), 6.99 (br. s, 1H), 3.97 (s, 3H) ppm. 13C NMR (100
MHz, CDCl3): δ 164.2, 148.5, 122.4, 117.5, 116.5, 114.2, 54.0
ppm. IR (ATR-FTIR) 2922, 2853, 2238, 1601, 1547, 1480, 1476,
1450, 1387, 1313, 1151, 1041, 843 cm-1. MS (EI) m/z (rel intensity)
134 (95), 133 (100), 104 (71). HRMS (ESI POS) calcd for C7H7N2O
(MH+) 135.0558, found 135.0559. Anal. Calcd for C7H6N2O: C,
62.68; H, 4.51; N, 20.88. Found: C, 62.54; H, 4.57; N, 20.84.
Synthesis of 1-(2-Methoxy-pyridin-4-yl)-propan-1-one (21).
A stirred suspension of 20 (25.44 g, 189.7 mmol) in TBME (380
mL) was cooled to 0 °C, and a solution of ethylmagnesium chloride
(114 mL, 2.0 M in THF, 228.0 mmol, 1.20 equiv) was added within
45 min. Stirring was continued at 0 °C. After 3 h 40 min, additional
ethylmagnesium chloride (5 mL, 10.0 mmol, 0.05 equiv) was added
at 0 °C. The reaction was monitored by HPLC. After 4.5 h, the
reaction was quenched at 0 °C by addition of water (300 mL). The
resulting suspension was stirred for 16 h at room temperature and
was then diluted with toluene (200 mL). The aqueous phase was
extracted with toluene (400 mL), and the combined organic phases
were washed with saturated aqueous NH4Cl (500 mL) and brine
(500 mL), dried over Na2SO4 (50 g, 30 min), and filtered. The
filter cake was washed with toluene (100 mL). After evaporation
of solvent in a rotary evaporator (40 °C/10 mbar), the crude product
(28.64 g, 91 wt %) was obtained as an orange solid. An analytical
sample (white solid) was obtained by Kugelrohr distillation (85
tion of (R)-3-acetyl-4-tert-butyl-oxazolidinone, we selected 39
as the chiral reagent of choice.
Treatment of 48 with aqueous LiOH/H2O2 in THF resulted
in rapid cleavage of the chiral oxazolidinone furnishing the
corresponding carboxylic acid. Because purification of the free
acid by pH-dependent extraction was hampered by the insolu-
bility of the corresponding lipophilic silyl ether in aqueous
media, we chose to simultaneously cleave the silyl ether protec-
ting group in the same pot using aqueous NaOH at room
temperature. Although TES and TBS were removed easily under
these conditions, cleavage of the TBDPS group proceeded very
slowly finally resulting in massive decomposition. Because of
the hydrophilic nature of the highly polar carboxylic acid diol
49 preventing its extraction into dichloromethane, a more polar
dichloromethane/EtOH (4:1) mixture was used for its isolation.
The dihydroxy acid 49 lactonizes slowly during solvent evapo-
ration and also when stored at ambient temperature. However,
when 49 was treated with acid prior to isolation, lactone
formation was sluggish and did not go to completion. Unfor-
tunately, the er of 49 (80.5:19.5) was determined to be signif-
icantly lower than the dr of 48 (87:13).
Methyl ether cleavage as well as formation of the seven-
membered lactone ring were accomplished by 2.1 equiv of
aqueous HBr in DME furnishing target molecule 7 in optically
pure form (er > 99.95:0.05, chiral HPLC). DE ring building
block 7 was thus synthesized over nine linear steps in 11.1%
overall yield utilizing one column chromatography.
1
°C, 0.6 mbar). Mp: 38 °C. H NMR (300 MHz, CDCl3): δ 8.30
(d, 1H, J ) 5.3 Hz), 7.30 (dd, 1H, J ) 5.3 Hz, J ) 1.3 Hz), 7.18
(br. s, 1H), 3.98 (s, 3H), 2.96 (q, 2H, J ) 7.2 Hz), 1.22 (t, 3H, J )
7.2 Hz) ppm, 13C NMR (100 MHz, CDCl3): δ 200.0, 165.1, 148.0,
145.9, 114.0, 109.4, 53.9, 32.3, 7.8 ppm. IR (ATR-FTIR) 2978,
1690, 1603, 1559, 1479, 1391, 1311, 1170, 1038, 1017, 848 cm-1
.
Summary
MS (EI) m/z (rel intensity) 165 (98), 164 (75), 136 (100), 108 (43).
HRMS (ESI POS) calcd for C9H12NO2 (MH+) 166.0868, found
166.0870. Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71; N, 8.48.
Found: C, 65.22; H, 6.55; N, 8.50.
In conclusion, we have described two practical routes to DE
ring fragment 7, which have the potential to serve as the basis
for a technical synthesis of this key building block required for
the synthesis of homocamptothecin derivatives such as diflomo-
tecan 4. The two approaches, the “acetal route” and the “amide
route”, starting from both commercially available and inexpen-
sive pyridine building blocks rely on unprecedented efficient
and practical asymmetric acetate aldol additions to ketone
substrates whereby the auxiliary can be easily recycled in high
yield. Optically pure 7 is obtained after the final lactonization
step in 8.9% yield via the acetal approach (nine linear steps, no
chromatographic purification, one silica gel filtration) or in
11.1% overall yield via the amide approach (nine linear steps,
one chromatography required).
Synthesis of 4-(2-Ethyl-[1,3]dioxan-2-yl)-2-methoxy-pyridine
(11). Sulfuric acid (96%, 473 µL, 4.63 mmol, 0.02 equiv), para-
toluenesulfonic acid monohydrate (99%, 889 mg, 4.63 mmol, 0.02
equiv), and 1,3-propanediol (100 mL, 1.39 mol, 6.0 equiv) were
added to a stirred solution of 21 (38.23 g, 231.4 mmol) in toluene
(575 mL). The reaction mixture was heated for 72 h (NMR control)
to reflux (oil bath temperature 160 °C). After cooling to room
temperature, saturated aqueous NaHCO3 (500 mL) was added and
the phases were separated. The organic phase was washed with
brine (2 × 250 mL) and was then dried over Na2SO4 (50 g, 30
min) and filtered. The filter cake was washed with toluene (100
mL). After evaporation of solvent in a rotary evaporator (50 °C/10
mbar), the crude product (40.31 g, 78 wt %) was obtained as a
brown oil. Purification was achieved using a high-vacuum distilla-
tion (bp 95 °C at 0.056 mbar, oil bath temperature 125 °C, 40 cm
Vigreux column) furnishing product 11 (31.80 g, 142.4 mmol, 62
wt %) as a colorless liquid. Bp: 95 °C (0.056 mbar).1H NMR (300
MHz, CDCl3): δ 8.19 (dd, 1H, J ) 5.2 Hz, J ) 0.8 Hz), 6.91 (dd,
1H, J ) 5.3 Hz, J ) 1.5 Hz), 6.78 (dd, 1H, J ) 1.4 Hz, J ) 0.8
Hz), 3.96 (s, 3H), 3.89 (m, 2H), 3.75 (m, 2H), 2.09 (m, 1H), 1.72
(q, 2H, J ) 7.5 Hz), 1.26 (m, 1H), 0.81 (t, 3H, J ) 7.5 Hz) ppm.
13C NMR (100 MHz, CDCl3): δ 164.9, 152.3, 147.2, 115.9, 109.8,
101.2, 61.4, 53.5, 36.8, 25.4, 7.1 ppm. IR (ATR-FTIR) 2970, 2870,
1606, 1559, 1477, 1385, 1314, 1141, 1083, 1041, 840 cm-1. MS
(EI) m/z (rel intensity) 223 (2), 194 (100), 136 (44). HRMS (ESI
POS) calcd for C12H18NO3 (MH+) 224.1287, found 224.1285. Anal.
Calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.27;
H, 7.78; N, 6.05.
Experimental Section
Synthesis of 2-Methoxy-isonicotinonitrile (20).19 A stirred
suspension of NaOMe (17.86 g, 330.7 mmol, 1.22 equiv) in
acetonitrile (95 mL) was cooled to 0 °C, and a solution of 2-chloro-
4-cyano pyridine (8, 37.56 g, 271.1 mmol) in acetonitrile (225 mL)
was added over 45 min. Stirring was continued at room temperature
for 23 h (HPLC control). Potassium dihydrogen phosphate (11.1
g, 81.56 mmol, 0.30 equiv) was added at 0 °C, and stirring was
continued for 3 h at room temperature. The reaction mixture was
then evaporated to dryness in a rotary evaporator (40 °C/10 mbar)
yielding the crude product (64.94 g, 179 wt %) as a brown solid.
The crude product was extracted with toluene (900 mL) for 18 h
at reflux temperature using a Soxhlet extraction apparatus yielding
product 20 (25.65 g, 71 wt %) as an orange solid. An analytical
sample (white solid) was obtained by column chromatography with
Synthesis of 4-(2-Ethyl-[1,3]dioxan-2-yl)-2-methoxy-pyridine-
3-carbaldehyde (12). A stirred solution of 2-bromomesitylene
(98%, 6.87 mL, 44.78 mmol, 2.0 equiv) in THF (44 mL) was cooled
to -45 °C. n-Butyllithium (35.8 mL, 2.5 M in hexanes, 89.56 mmol,
4.0 equiv) was added within 20 min. The resulting white suspension
(19) Known compound: Walpole, C. S. J.; Wrigglesworth, R.; Bevan,
S.; Campbell, E. A.; Dray, A.; James, I. F.; Perkins, M. N.; Reid, D. J.;
Winter, J. J. Med. Chem. 1993, 36, 2362.
7590 J. Org. Chem., Vol. 71, No. 20, 2006

Formal Total Syntheses of Homocamptothecin
was then allowed to warm to 0 °C within 2.5 h. At -10 °C, the
reaction mixture became a clear solution. Stirring was continued
for an additional hour at 0 °C. The solution was cooled to -10 °C,
and a solution of 11 (5.00 g, 22.39 mmol) in THF (15 mL) was
added over 15 min under vigorous stirring. The resulting brown
suspension was allowed to warm to 10 °C within 2.5 h. The cooling
bath was then removed, and stirring was continued at room tem-
perature for an additional hour. The clear brown solution was then
cooled to -23 °C, and DMF (5.19 mL, 67.17 mmol, 3.0 equiv)
was added. The mixture was allowed to slowly warm to room
temperature overnight. The reaction was quenched by addition of
saturated aqueous NH4Cl (100 mL). After 15 min, water (50 mL)
was added. The mixture was extracted with TBME (3 × 150 mL).
The combined organic phases were washed with brine (2 × 300
mL), dried over Na2SO4 (20 g, 30 min), and filtered. The filter
cake was washed with TBME (40 mL). After evaporation of solvent
in a rotary evaporator (40 °C/10 mbar), the crude product (12.048
g, 214 wt %) was obtained as a brown oil, which was then purified
by silica gel filtration using a gradient elution with heptane/ethyl
acetate (30:1) (to elute mesityl products and 11) and heptane/ethyl
acetate (5:1). Evaporation to dryness of the second fraction in a
rotary evaporator (40 °C/10 mbar) yielded product 12 (3.832 g,
subsequently added, and the mixture was heated to 65 °C. The
reaction was monitored by HPLC. After 16 h at 65 °C, pyrrolidine
(875 µL, 7.55 mmol, 0.7 equiv) was added at room temperature.
After 3.5 h, the mixture was poured into heptane (600 mL) and the
organic phase was washed with aqueous HCl (0.5 M, 2 × 400 mL)
and subsequently with water (500 mL). The organic phases were
dried over Na2SO4 (20 g, 30 min) and filtered. The solid was washed
with heptane (40 mL). After evaporation of solvent in a rotary
evaporator (40 °C/10 mbar), the crude product (4.985 g, 96 wt %)
was obtained as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.12
(d, 1H, J ) 5.5 Hz), 7.25-7.41 (m, 5H), 6.98 (d, 1H, J ) 5.4 Hz),
4.73 (s, 2H), 4.63 (s, 2H), 3.98 (s, 3H), 3.85 (m, 4H), 2.09 (m,
1H), 1.80 (q, 2H, J ) 7.5 Hz), 1.24 (dm, 1H, J ) 13.0 Hz), 0.84
(t, 3H, J ) 7.4 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ 164.6,
150.4, 146.2, 138.7, 128.3, 127.9, 127.5, 118.9, 117.4, 102.3, 73.4,
63.5, 61.9, 53.8, 36.7, 25.4, 7.3 ppm. IR (film) 2969, 1592, 1562,
1387, 1311, 1153, 1013, 984, 737 cm-1. MS (EI) m/z (rel intensity)
343 (6), 252 (10), 234 (100), 176 (45), 91 (46). HRMS (ESI POS)
calcd for C20H26NO4 (MH+) 344.1862, found 344.1865. Anal. Calcd
for C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found: C, 69.90; H,
7.24; N, 4.03.
Synthesis of 1-(3-Benzyloxymethyl-2-methoxy-pyridin-4-yl)-
propan-1-one (15). para-Toluenesulfonic acid monohydrate (99%,
461 mg, 2.40 mmol, 0.2 equiv) was added at room temperature to
a stirred solution of 14 (4.120 g, 12.00 mmol) in ethanol (96 mL)
and water (24 mL). The mixture was subsequently heated to 80 °C,
and the reaction was monitored by HPLC. After 6.25 h at 80 °C,
the solution was cooled to room temperature and poured into hep-
tane (600 mL). The organic phase was washed with water (600 mL),
subsequently with aqueous NaHCO3 solution (600 mL, 0.1 M), and
again with water (600 mL). The organic phase was dried over Na2-
SO4 (20 g, 30 min) and filtered. The solid was washed with heptane
(40 mL). After evaporation of solvent in a rotary evaporator (40
°C/10 mbar), the crude product (3.302 g, 96 wt %) was obtained
as a light yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.14 (d, 1H,
J ) 5.1 Hz), 7.29-7.37 (m, 5H), 6.75 (d, 1H, J ) 5.3 Hz), 4.62 (s,
2H), 4.50 (s, 2H), 3.95 (s, 3H), 2.74 (q, 2H, J ) 7.2 Hz), 1.06 (t,
3H, J ) 7.2 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ 206.0,
161.8, 150.7, 146.4, 137.7, 128.4, 128.0, 127.8, 117.0, 113.7, 73.4,
63.6, 53.8, 36.2, 7.5 ppm. IR (ATR-FTIR) 2943, 1706, 1594, 1561,
1450, 1386, 1355, 1303, 1068, 1017, 735, 697 cm-1. MS (EI) m/z
(rel intensity) 286 (2), 194 (100), 179 (41), 176 (81), 91 (32). HRMS
(ESI POS) calcd for C17H20NO3 (MH+) 286.1443, found 286.1442.
Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found:
C, 71.44; H, 6.69; N, 4.94.
1
15.2 mmol, 68 wt %). H NMR (300 MHz, CDCl3): δ 10.33 (s,
1H), 8.25 (d, 1H, J ) 5.5 Hz), 6.96 (d, 1H, J ) 5.3 Hz), 3.98 (s,
3H), 3.83 (m, 2H), 3.61 (m, 2H), 2.09 (m, 1H), 1.86 (q, 2H, J )
7.5 Hz), 1.29 (m, 1H), 0.92 (t, 3H, J ) 7.5 Hz) ppm. 13C NMR
(100 MHz, CDCl3): δ 192.2, 161.7, 151.7, 148.8, 120.2, 116.2,
101.2, 61.2, 54.0, 36.3, 24.8, 7.1 ppm. IR (ATR-FTIR) 2972, 2871,
1706, 1583, 1562, 1376, 1306, 1137, 1079, 1051, 859 cm-1. MS
(EI) m/z (rel intensity) 251 (9), 222 (12), 192 (100), 164 (30).
HRMS (ESI POS) calcd for C13H18NO4 (MH+) 252.1236, found
252.1238. Anal. Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57.
Found: C, 62.30; H, 6.76; N, 5.48.
Synthesis of [4-(2-Ethyl-[1,3]dioxan-2-yl)-2-methoxy-pyridin-
3-yl]-methanol (13). Sodium borohydride (96%, 134.6 mg, 3.416
mmol, 0.27 equiv) was added at 0 °C to a stirred solution of 12
(3.178 g, 12.65 mmol) in 2-propanol (95 mL) and water (15.8 mL).
The reaction (grey suspension) was monitored by HPLC. After 30
min, acetone (11 mL) was added and stirring was continued for 30
min at room temperature. Saturated aqueous NH4Cl (190 mL) was
added, and the mixture was extracted with dichloromethane (3 ×
180 mL). The combined organic phases were dried over Na2SO4
(20 g, 30 min) and filtered. The solid was washed with dichloro-
methane (40 mL). After evaporation of solvent in a rotary evaporator
(40 °C/10 mbar), the crude product (3.184 g, 99 wt %) was obtained
as a yellow oil. Purification was achieved by trituration with heptane
(16 mL) for 24 h at room temperature and subsequent standing for
4 days at -20 °C. After cold filtration and removal of residual
solvent in a rotary evaporator (40 °C/10 mbar), product 13 (2.827
g, 11.2 mmol, 88 wt %) was obtained as white crystals. Mp: 79 °C.
1H NMR (300 MHz, CDCl3): δ 8.11 (d, 1H, J ) 5.3 Hz), 7.01 (d,
1H, J ) 5.3 Hz), 4.93 (d, 2H, J ) 6.6 Hz), 4.04 (s, 3H), 3.93 (m,
2H), 3.77 (m, 2H), 2.83 (t, 1H, J ) 7.2 Hz), 2.10 (m, 1H), 1.81 (q,
Asymmetric Aldol Addition: Synthesis of (4R,5S)-3-[(R)-3-
(3-Benzyloxymethyl-2-methoxy-pyridin-4-yl)-3-hydroxy-penta-
noyl]-4,5-diphenyl-oxazolidin-2-one (52). A solution of 22 (108.4
mg, 0.385 mmol, 1.1 equiv) in THF (650 µL) was slowly added
(addition time: 5 min) at -78 °C to a solution of lithium bis-
(trimethylsilyl)amide (389.4 µL, 1.0 M in THF, 0.385 mmol, 1.1
equiv). During the addition, the color changed from colorless to
bright yellow. After 2 h at -78 °C, the solution was cooled to
-95 °C and 15 (100.0 mg, 0.350 mmol) dissolved in THF (400
µL) was slowly added (addition time: 5 min). The solution was
kept for an additional 30 min at -95 °C and then for 45 min at
-78 °C. Subsequently, the reaction was quenched by addition of
aqueous 0.5 M HCl (5 mL). The mixture was extracted with
dichloromethane (3 × 10 mL), and the combined extracts were
dried over sodium sulfate (1 g, 30 min) and filtered. The filter cake
was washed with dichloromethane (2 mL). After removal of solvent
in a rotary evaporator (40 °C/5 mbar), the crude product was
obtained as a colorless oil (206.7 mg, 104 wt %, dr ) 92:8 (1H
NMR)). An analytical sample (dr > 30:1 (1H NMR), white solid)
was obtained by column chromatography with heptane/ethyl acetate
2H, J ) 7.5 Hz), 1.30 (m, 1H), 0.85 (t, 3H, J ) 7.4 Hz) ppm. 13
C
NMR (100 MHz, CDCl3): δ 163.8, 148.7, 145.5, 122.0, 117.6,
102.3, 61.6, 56.9, 53.8, 36.3, 25.2, 7.2 ppm. IR (Nujol) 3333, 2923,
2855, 1595, 1557, 1464, 1388, 1309, 1152, 1079, 837 cm-1. MS
(EI) m/z (rel intensity) 254 (7), 224 (100), 194 (19), 166 (36), 115
(42). HRMS (ESI POS) calcd for C13H20NO4 (MH+) 254.1392,
found 254.1395. Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56;
N, 5.53. Found: C, 61.63; H, 7.28; N, 5.47.
Synthesis of 3-Benzyloxymethyl-4-(2-ethyl-[1,3]dioxan-2-yl)-
2-methoxy-pyridine (14). Lithium bis(trimethylsilyl)amide (16.6
mL, 1.0 M in THF, 16.62 mmol, 1.1 equiv) was added within 10
min at -78 °C to a stirred solution of 13 (3.828 g, 15.11 mmol) in
THF (21 mL). After an additional 10 min at -78 °C, stirring was
continued for 10 min at 0 °C and for 15 min at room temperature.
Benzylbromide (2.56 mL, 21.15 mmol, 1.4 equiv) and dry tetra-
butylammonium iodide (98%, 570 mg, 1.51 mmol, 0.1 equiv) were
20
1
(7:3). [R]D (c ) 0.7417 /dL, CHCl3) ) -23.9. Mp: 61 °C. H
NMR (300 MHz, CDCl3): δ 7.99 (d, 1H, J ) 5.6 Hz), 6.83-7.33
(m, 15H), 6.57 (d, 1H, J ) 5.6 Hz), 5.79 (d, 1H, J ) 7.7 Hz), 5.51
(d, 1H, J ) 7.7 Hz), 5.31 (s, 1H), 4.89 (d, 1H, J ) 10.5 Hz), 4.81
J. Org. Chem, Vol. 71, No. 20, 2006 7591

Peters et al.
(d, 1H, J ) 10.6 Hz), 4.42 (d, 1H, J ) 11.6 Hz), 4.35 (d, 1H, J )
16.8 Hz), 4.33 (d, 1H, J ) 11.8 Hz), 3.90 (s, 3H), 3.22 (d, 1H, J )
16.8 Hz), 1.92 (q, 2H, J ) 7.1 Hz), 0.80 (t, 3H, J ) 7.4 Hz) ppm.
13C NMR (100 MHz, CDCl3): δ 171.1, 163.8, 156.2, 153.6, 145.9,
138.5, 133.9, 132.6, 128.5, 128.3, 128.1, 128.1, 128.0, 127.9, 127.4,
126.3, 126.3, 117.8, 115.7, 80.3, 78.0, 71.9, 63.1, 62.7, 53.7, 46.0,
36.3, 7.8 ppm. IR (ATR-FTIR) 3444, 2923, 1779, 1694, 1592, 1555,
1455, 1377, 1243, 1185, 1133, 1060, 836, 760, 724 cm-1. MS (ESI)
m/z 567.4 (MH+). HRMS (ESI POS) calcd for C34H35N2O6 (MH+)
567.2495, found 567.2493. Anal. Calcd for C34H34N2O6: C, 72.07;
H, 6.05; N, 4.94. Found: C, 71.87; H, 6.31; N, 4.54.
product crystals appeared. The reaction was monitored by HPLC.
After 27 h at 50 °C, the reaction was cooled to room temperature.
The mixture was allowed to stir at room temperature for 72 h and
was then filtered. The solid was washed with TBME (2 × 2.2 mL)
and subsequently washed with acetone (2.2 mL), water (2 × 2.2
mL), and finally with acetone (2 × 2.2 mL). After drying in vacuo,
product 7 (1.040 g, 4.66 mmol, 54 wt %, er ) 99.95:0.05 [chiral
HPLC; sample preparation: ethanol solution; Chiralcel-ODH col-
umn, 250 × 4.6; temperature of 25 °C; mobile phase, 75% heptane,
25% ethanol/trifluoroacetic acid (99:1); flow of 0.8 mL/min; injec-
tion volume of 5 µL, detection, UV 308 nm; retention time, 9.68
20
min (S)-7, 13.28 min (R)-7]) was obtained as white crystals. [R]D
Asymmetric Aldol Addition: Synthesis of (R)-3-(3-Benzyl-
oxymethyl-2-methoxy-pyridin-4-yl)-3-hydroxy-pentanoic Acid
(17). A solution of 22 (4.733 g, 16.82 mmol, 1.2 equiv) in THF
(19 mL) prepared at 65 °C was cooled to -78 °C, and lithium
bis(trimethylsilyl)amide solution (17.00 mL, 1.0 M in THF, 16.82
mmol, 1.2 equiv) was slowly added (addition time: 10 min). During
the addition, the color changed from colorless to bright yellow.
After 2 h at -78 °C, the clear solution was cooled to -95 °C. A
solution of 15 (4.00 g, 14.02 mmol) in THF (16 mL) was slowly
added (syringe pump, addition time: 30 min), and the solution was
kept for an additional 30 min at -95 °C and then for 45 min at
-78 °C. Subsequently, aqueous LiOH solution (87.6 mL, 0.8 M,
70.1 mmol, 5.0 equiv) and aqueous H2O2 solution (7.01 mL, 10 M,
70.1 mmol, 5.0 equiv) were added, and stirring of the resulting
suspension was continued at 0 °C for 30 min and at room temper-
ature for 1 h. The precipitated auxiliary was collected by filtration,
and the solid was washed with water (15 mL). The filtrate was
poured on aqueous NaOH solution (200 mL, 2.0 M). A second
portion of precipitated auxiliary was collected by filtration, and
the solid was washed with water (3 mL) [Auxiliary recycling: the
combined filter cakes (4.16 g) were triturated at reflux temperature
in toluene (20.8 mL, 30 min). After cooling to room temperature
overnight while stirring, 3.63 g of auxiliary was recycled (15.17
mmol, 90 wt %, white crystals).] The filtrate was extracted with
TBME (3 × 200 mL) to remove unreacted 15, unprecipitated
auxiliary, and impurities. The aqueous phase was then acidified
with aqueous HCl (2.0 M) until pH 3. The resulting white
suspension was extracted with dichloromethane (2 × 200 mL). The
combined dichloromethane extracts were washed with saturated
aqueous NH4Cl (80 mL) and brine (16 mL) and were subsequently
dried over sodium sulfate (20 g, 30 min) and filtered. The solid
was washed with dichloromethane (40 mL). After removal of
solvent in a rotary evaporator (40 °C/5 mbar), the crude product
was obtained as a light yellow oil (3.61 g, 75 wt %, er ) 87.2:12.8
[chiral HPLC; sample preparation: ethanol solution: Chiralcel-
ODH column, 250 × 4.6; temperature of 25 °C; mobile phase,
99.9% heptane/ethanol (24:1); 0.1% trifluoroacetic acid; flow of
0.8 mL/min; injection volume of 5 µL; detection, UV 275 nm;
(c ) 1.1000 g/dL, DMSO) ) +134.4. Mp: >270 °C (decomp).
1H NMR (300 MHz, DMSO): δ 11.67 (br. s, 1H), 7.34 (d, 1H,
7.2 Hz), 6.33 (d, 1H, 7.2 Hz), 5.72 (br. S, 1H), 5.34 (d, 1H, J )
15.1 Hz), 5.21 (d, 1H, J ) 15.1 Hz), 3.32 (d, 1H, J ) 13.5 Hz),
2.98 (d, 1H, J ) 13.7 Hz), 1.68 (m, 2H), 0.80 (t, 3H, J ) 7.5 Hz)
ppm. 13C NMR (100 MHz, DMSO): δ 171.9, 161.1, 155.6, 133.7,
122.6, 104.9, 72.7, 61.0, 42.2, 35.7, 8.1 ppm. IR (ATR-FTIR) 3279,
3106, 2968, 1742, 1621, 1562, 1528, 1422, 1281, 1177, 1040, 1020,
879, 809, 798 cm-1. MS (EI) m/z (rel intensity) 223 (26), 205 (3),
194 (17), 181 (10), 166 (18), 163 (26), 152 (100). Anal. Calcd for
C11H13NO4: C, 59.19; H, 5.87; N, 6.27. Found: C, 58.95; H, 5.73;
N, 6.24.
Synthesis of (4R,5S)-3-Acetyl-4,5-diphenyl-oxazolidin-2-one
(22).20 n-Butyllithium (13.65 mL, 1.5 M in pentane, 20.47 mmol,
0.98 equiv) was added at -78 °C during 6 min to a stirred suspen-
sion of (4R,5S)-(+)-cis-4,5-diphenyl-2-oxazolidinone (98%, 5.100
g, 20.89 mmol, recycled material) in THF (102 mL). The resulting
dark red solution was stirred for an additional 70 min at -78 °C.
During this period, the solution became colorless. Stirring was
continued for 15 min at -25 °C, before it was cooled again to
-78 °C. A solution of acetyl chloride (1.536 mL, 21.31 mmol,
1.02 equiv) in THF (15.3 mL) was then added within 5 min. After
50 min, the mixture was poured on water (510 mL) and the product
was extracted with dichloromethane (3 × 305 mL). The combined
organic phases were washed with aqueous NaHCO3 (715 mL, 1.0
M) and with brine (715 mL). The solution was dried over sodium
sulfate (25 g, 30 min) and filtered. The filter cake was washed
with dichloromethane (50 mL). After removal of solvent in a rotary
evaporator (40 °C/30 mbar), the crude product (5.899 g, 100 wt
%) was obtained as a white solid. Purification was accomplished
by recrystallization from toluene (13 mL). The heterogeneous
mixture was heated to reflux until a clear solution was obtained,
which was then allowed to slowly cool to room temperature. After
2 days, product 22 was collected by filtration as white crystals
20
(5.157 g, 18.332 mmol, 88%). [R]D (c ) 0.453 g/dL, CHCl3) )
1
+80.4. Mp: 142 °C. H NMR (300 MHz, CDCl3): δ 7.11 (m,
6H), 6.97 (m, 2H), 6.86 (m, 2H), 5.91 (d, 1H, J ) 7.5 Hz), 5.67
(d, 1H, J ) 7.5 Hz), 2.62 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3): δ 169.5, 154.0, 134.4, 132.8, 128.5, 128.3, 128.2, 128.1,
126.6, 126.1, 80.3, 62.7, 23.9 ppm. IR (ATR-FTIR) 2923, 1778,
1712, 1702, 1604, 1497, 761, 699 cm-1. MS (EI) m/z (rel intensity)
281 (3), 237 (39), 149 (100), 132 (78), 107 (95), 43 (35). HRMS
(ESI POS) calcd for C17H15NO3Na (MNa+) 304.0950, found
304.0950. Anal. Calcd for C17H15NO3: C, 72.58; H, 5.37; N, 4.98.
Found: C, 72.78; H, 5.53; N, 4.75.
20
retention time of 12.75 min (S)-17, 14.51 min (R)-17]). [R]D
1
(c ) 0.9884 g/dL, CHCl3) ) -23.3 (for ee ) 100%). H NMR
(300 MHz, CDCl3): δ 8.08 (d, 1H, J ) 5.5 Hz), 7.35 (m, 5H),
6.78 (d, 1H, J ) 5.5 Hz), 6.16 (s, 1H), 4.97 (d, 1H, J ) 11.3 Hz),
4.86 (d, 1H, J ) 11.3 Hz), 4.65 (d, 1H, J ) 11.7 Hz), 4.60 (d, 1H,
J ) 11.7 Hz), 3.93 (s, 3H), 2.96 (d, 1H, J ) 15.5 Hz), 2.84 (d, 1H,
J ) 16.1 Hz), 1.86 (m, 2H), 0.76 (t, 3H, J ) 7.5 Hz) ppm. 13C
NMR (100 MHz, CDCl3): δ 173.7, 163.5, 155.3, 146.4, 137.2,
128.5, 128.4, 128.1, 128.1, 117.1, 115.7, 72.8, 63.2, 54.0, 46.3,
35.8, 7.9 ppm. IR (ATR-FTIR) 3455, 2968, 2600, 1709, 1593, 1555,
Synthesis of 2-Chloro-N-isopropyl-isonicotinamide (42).21
Thionyl chloride (99%, 11.77 mL, 160.2 mmol, 1.3 equiv) and DMF
(762 µL, 9.86 mmol, 0.08 equiv) were added to a stirred suspension
of 2-chloroisonicotinic acid (97%, 20.00 g, 41, 123.2 mmol) in
acetonitrile (200 mL). The mixture was heated to reflux (clear dark
red solution) and was monitored by HPLC (sample preparation:
5 µL of the reaction mixture was added to 0.2 mL of MeOH). After
1453, 1383, 1312, 1191, 1061, 1027, 1006, 824, 736, 698 cm-1
.
MS (ESI) m/z 344.2 (M - H+). HRMS (ESI POS) calcd for C19H24-
NO5 (MH+) 346.1654, found 346.1658. Microanalysis: C was not
in the range <0.4%, even after purification by preparative HPLC
(HPLC purity 100.0%).
Synthesis of (R)-5-Ethyl-5-hydroxy-2,5,6,9-tetrahydro-8-oxa-
2-aza-benzocycloheptene (7). Aqueous HBr (2.01 mL, 48%, 17.89
mmol, 2.06 equiv) was added to a stirred solution of 17 (3.00 g,
8.69 mmol) in 1,2-dimethoxyethane (11 mL). After 15 min at room
temperature, the solution was heated to 50 °C. After 4 h, the first
(20) The enantiomer is known: Ferroci, M.; Inesi, A.; Palombi, L.;
Sotgiu, G. J. Org. Chem. 2002, 67, 1719.
(21) Known compound: Pavlova, M. V.; Mikhalev, A. I.; Kon’shin, M.
E.; Vasilyuk, M. V.; Kotegov, V. P. Pharm. Chem. J. 2002, 36, 425.
7592 J. Org. Chem., Vol. 71, No. 20, 2006

Formal Total Syntheses of Homocamptothecin
60 min, the reaction mixture was cooled to room temperature and
all volatiles were removed in a rotary evaporator (40 °C/10 mbar).
The residual oil was dissolved in dichloromethane (200 mL), and
the solution was cooled to 0 °C. Triethylamine (20.6 mL, 147.8
mmol, 1.20 equiv) and isopropylamine (99.5%, 11.7 mL, 135.5
mmol, 1.10 equiv) were subsequently added, and stirring was
continued for 2 h at 0 °C (almost black solution). The mixture was
poured on water (200 mL), and the phases were separated. The
organic phase was washed with brine (200 mL), dried over sodium
sulfate (15 g, 30 min), and filtered. The filter cake was washed
with dichloromethane (30 mL). After removal of solvent in a rotary
evaporator (40 °C/20 mbar), the crude product (24.83 g, 102 wt
%) was obtained as a brown solid. Mp: 99 °C (decomp). 1H NMR
(300 MHz, CDCl3): δ 8.50 (dd, 1H, J ) 4.9 Hz, J ) 0.6 Hz), 7.62
(dd, 1H, J ) 1.3 Hz, J ) 0.6 Hz), 7.51 (dd, 1H, J ) 5.1 Hz, J )
1.5 Hz), 5.94 (br. s, 1H), 4.27 (m, 1H), 1.28 (d, 6H, J ) 6.6 Hz)
ppm. 13C NMR (100 MHz, CDCl3): δ 163.4, 152.4, 150.4, 145.1,
122.0, 119.8, 42.5, 22.6 ppm. IR (Nujol) 3278, 3061, 2969, 1636,
1532, 1460, 1365, 1297, 1077, 905 cm-1. MS (ESI) m/z 199.1
(MH+). HRMS (ESI POS) calcd for C9H12ClN2O (MH+) 199.0638,
found 199.0639. Anal. Calcd for C9H11ClN2O: C, 54.42; H, 5.58;
N, 14.10. Found: C, 54.21; H, 5.71; N, 14.10.
(100 MHz, CDCl3): δ 165.3, 159.3, 149.2, 143.1, 124.6, 110.8,
79.9, 53.9, 44.4, 21.8, 20.1 ppm. IR (Nujol) 3290, 2921, 1684, 1667,
1605, 1468, 1418, 1329, 1082, 1047, 868, 854 cm-1. MS (EI) m/z
(rel intensity) 222 (6), 207 (80), 164 (100). HRMS (ESI POS) calcd
for C11H14N2O3 (M+) 222.1004, found 222.1005. Anal. Calcd for
C11H14N2O3: C, 59.45; H, 6.35; N, 12.60. Found: C, 59.26; H,
6.31; N, 12.53.
Synthesis of 4-Methoxy-3H-furo[3,4-c]pyridin-1-one (45).
Sodium borohydride (96%, 5.160 g, 130.9 mmol, 1.5 equiv) was
added to a stirred solution of crude 44 (19.40 g, 87.29 mmol) in
2-propanol (300 mL) and water (100 mL) at room temperature.
The reaction was monitored by HPLC. After 3 h 10 min, the
reduction was quenched at 0 °C by addition of acetone (34.0 mL,
474.4 mmol, 5.3 equiv) and stirring was continued for 35 min at
room temperature. The mixture was poured on aqueous 2 M HCl
(415 mL, 829.3 mmol, 9.5 equiv) at 0 °C, and stirring was continued
for 20 min at room temperature. The mixture was then heated to
50 °C overnight and was subsequently cooled to 0 °C. Dipotassium
hydrogen phosphate was added to adjust the pH to 3.0, and ca.
95% of the 2-propanol was removed in a rotary evaporator (40
°C/10 mbar). Water was added until the salts were dissolved, and
the mixture was extracted with dichloromethane (3 × 300 mL).
The combined organic phases were dried over Na2SO4 (50 g, 30
min) and filtered. The solid was washed with dichloromethane (100
mL). After evaporation of solvent in a rotary evaporator (40 °C/25
mbar), the crude product (9.963 g, 69 wt %) was obtained as a
light brown solid. Purification was achieved by trituration with ethyl
acetate (30 mL) for 24 h at room temperature and subsequent
addition of heptane (60 mL). The suspension was then allowed to
stand for 24 h at 5 °C yielding the product (5.486 g, 33.22 mmol,
Synthesis of N-Isopropyl-2-methoxy-isonicotinamide (43).
NaOMe (95%, 27.82 g, 489.3 mmol, 5.0 equiv) was added to a
stirred solution of 42 (19.44 g, 97.86 mmol) in methanol (165 mL)
in four equal portions over 60 min. The solution was then heated
to 80 °C (oil bath temperature), and the reaction was monitored by
HPLC. After 23 h, the mixture was cooled to room temperature
and quenched by addition of saturated aqueous NH4Cl (200 mL).
The product was extracted with dichloromethane (3 × 150 mL).
The combined organic phases were dried over sodium sulfate (40 g,
30 min) and filtered. The filter cake was washed with dichlo-
romethane (80 mL). After removal of solvent in a rotary evaporator
(40 °C/22 mbar), the crude product (15.856 g, 83 wt % (84% over
two steps from 41)) was obtained as a white solid. An analytical
sample was obtained by column chromatography with heptane/ethyl
1
40 wt % (68% over two steps)) as a beige solid. Mp: 90 °C. H
NMR (300 MHz, CDCl3): δ 8.35 (d, 1H, J ) 5.1 Hz), 7.36 (d,
1H, J ) 5.3 Hz), 5.29 (s, 2H), 4.07 (s, 3H) ppm. 13C NMR (100
MHz, CDCl3): δ 169.6, 159.3, 148.1, 136.3, 129.0, 111.7, 68.1,
54.0 ppm. IR (ATR-FTIR) 1785, 1769, 1606, 1465, 1441, 1402,
1360, 1256, 1173, 1036, 845 cm-1. MS (EI) m/z (rel intensity) 165
(100), 164 (61), 136 (35). HRMS (ESI POS) calcd for C8H7NO3
(M+) 165.0426, found 165.0429. Anal. Calcd for C8H7NO3: C,
58.18; H, 4.27; N, 8.48. Found: C, 57.89; H, 4.39; N, 8.57.
Synthesis of 1-Ethyl-4-methoxy-1,3-dihydro-furo[3,4-c]pyri-
din-1-ol (46). Ethyllithium (40.0 mL, 0.5 M in cyclohexane/
benzene, 20.0 mmol, 1.1 equiv) was added dropwise to a triethyl-
aluminum solution (10.5 mL 1.9 M in toluene, 20.0 mmol, 1.1
equiv) at 0 °C. After 15 min at 0 °C, THF (50 mL, precooled to
-40 °C) was added rapidly via a cannula. A solution of 45 (3.000
g, 18.17 mmol) in THF (75 mL) was subsequently added rapidly
at -40 °C (orange suspension). After 10 min at -40 °C, additional
ethyllithium (40.0 mL, 20.0 mmol, 1.1 equiv) was added slowly
(clear yellow-orange solution). The mixture was allowed to warm
to -15 °C within 3 h, and the reaction was afterward quenched by
addition of methanol (3.68 mL, 100 mmol, 5 equiv). After 30 min,
the mixture was poured in saturated aqueous potassium sodium
tartrate (1.5 L) and was extracted with dichloromethane (3 × 500
mL). The combined organic phases were dried over Na2SO4 (100
g, 30 min) and filtered. The solid was washed with dichloromethane
(200 mL). After evaporation of solvent in a rotary evaporator (40
°C/10 mbar), the crude product (3.77 g, 106 wt %) was obtained
as a brown oil, which was purified by column chromatography with
heptane/ethyl acetate (7:3) yielding product 46 (1.877 g, 9.61 mmol,
53 wt %) as yellow solid. Mp: 145 °C. 1H NMR (300 MHz, CDCl3)
lactol-form: δ 8.15 (d, 1H, J ) 5.3 Hz), 6.90 (d, 1H, J ) 5.2 Hz),
5.13 (d, 1H, J ) 13.2 Hz), 4.95 (d, 1H, J ) 13.2 Hz), 3.99 (s, 3H),
2.86 (s, 1H), 2.06 (m, 2H), 0.86 (t, 3H, J ) 7.4 Hz) ppm. 1H NMR
(300 MHz, CDCl3) hydroxy-ketone-form: δ 8.21 (d, 1H, J ) 5.3
Hz), 6.99 (d, 1H, J ) 5.2 Hz), 4.63 (d, 2H, J ) 7.2 Hz), 4.00 (s,
3H), 3.07 (t, 1H, J ) 7.1 Hz), 2.92 (q, 2H, J ) 7.1 Hz), 1.21 (t,
3H, J ) 7.1 Hz) ppm. 13C NMR (100 MHz, CDCl3) lactol-form:
δ 159.9, 151.9, 146.9, 121.6, 110.7, 110.6, 69.4, 53.5, 32.2, 8.0
ppm. IR (ATR-FTIR) 3280, 1597, 1473, 1458, 1411, 1340, 1096,
1
acetate (7:3). Mp: 100 °C. H NMR (300 MHz, CDCl3): δ 8.24
(dd, 1H, J ) 5.3 Hz, J ) 0.6 Hz), 7.15 (dd, 1H, J ) 5.3 Hz, J )
1.3 Hz), 7.02 (dd, 1H, J ) 1.3 Hz, J ) 0.6 Hz), 5.89 (br. s, 1H),
4.28 (m, 1H), 3.96 (s, 3H), 1.26 (d, 6H, J ) 6.6 Hz) ppm. 13C
NMR (100 MHz, CDCl3): δ 165.34, 165.26, 148.3, 145.6, 114.5,
109.1, 54.3, 42.7, 23.2 ppm. IR (Nujol) 3297, 2924, 1633, 1616,
1539, 1466, 1450, 1394, 1234, 1156, 1133, 1050, 895, 801 cm-1
.
MS (ESI) m/z 195.3 (MH+). HRMS (ESI POS) calcd for C10H14N2O2
(M+) 194.1055, found 194.1055. Anal. Calcd for C10H14N2O2: C,
61.84; H, 7.27; N, 14.42. Found: C, 61.61; H, 7.12; N, 14.38.
Synthesis of 3-Hydroxy-2-isopropyl-4-methoxy-2,3-dihydro-
pyrrolo[3,4-c]pyridin-1-one (44). TMEDA (99.5%, 17.2 mL, 113.3
mmol, 2.2 equiv) was added to a stirred suspension of 43 (10.00 g,
51.40 mmol) in TBME (300 mL) at room temperature resulting
in the formation of a clear solution, which was then cooled to
-78 °C. Subsequently, n-butyllithium (102.8 mL, 1.5 M in hexane,
154.4 mmol, 3.0 equiv) was added over 35 min and stirring was
continued at the same temperature for an additional 3 h and
subsequently at -22 °C for another 3 h. DMF (13.9 mL, 180.0
mmol, 3.5 equiv) was added to the slightly brown suspension, at
-78 °C. The resulting suspension was quenched after 16 h 45 min
by addition of saturated aqueous NH4Cl (200 mL). The mixture
was extracted with dichloromethane (3 × 150 mL). The combined
organic phases were dried over Na2SO4 (20 g, 30 min) and filtered.
The filter cake was washed with dichloromethane (40 mL). After
evaporation of solvent in a rotary evaporator (40 °C/20 mbar), the
crude product (19.400 g, 170 wt %, regioselectivity: 11.68:1 (1H
NMR)) was obtained as a brown oil. An analytical sample was
obtained by silica gel chromatography (heptane/ethyl acetate ) 1:1).
Mp: 117 °C. 1H NMR (300 MHz, CDCl3): δ 8.33 (d, 1H, J ) 5.1
Hz), 7.26 (dd, 1H, J ) 5.1 Hz), 6.05 (d, 1H, J ) 7.5 Hz), 4.40
(sept, 1H, J ) 6.8 Hz), 4.07 (s, 3H), 2.44 (d, 1H, J ) 8.5 Hz),
1.44 (d, 3H, J ) 6.8 Hz), 1.42 (d, 3H, J ) 6.8 Hz) ppm. 13C NMR
J. Org. Chem, Vol. 71, No. 20, 2006 7593

Peters et al.
1003, 917, 823 cm-1. MS (EI) m/z (rel intensity) 195 (11), 178
(10), 166 (100), 136 (27). HRMS (ESI POS) calcd for C10H14NO3
(MH+) 196.0974, found 196.0973. Anal. Calcd for C10H13NO3: C,
61.53; H, 6.71; N, 7.17. Found: C, 61.38; H, 6.78; N, 7.06.
Synthesis of 1-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-2-
methoxy-pyridin-4-yl]-propan-1-one (47). TBSCl (3.475 g, 23.05
mmol, 3.0 equiv) was added to a solution of 46 (1.500 g, 7.68
mmol) and imidazole (1.831 g, 26.89 mmol, 3.5 equiv) in DMF
(12.5 mL) at 0 °C. The solution was allowed to slowly warm to
room temperature overnight. Heptane (285 mL) was added, and
the solution was washed with water (445 mL). The organic phase
was separated, dried over Na2SO4 (20 g, 30 min), and filtered. The
solid was washed with heptane (40 mL). After evaporation in a
rotary evaporator (40 °C/10 mbar) and subsequently under high
vacuum (40 °C, 0.01 mbar), product 47 (2.34 g, 7.56 mmol, 98 wt
%) was obtained as a slighty yellow oil. 1H NMR (300 MHz,
CDCl3): δ 8.11 (d, 1H, J ) 5.1 Hz), 6.72 (d, 1H, J ) 5.2 Hz),
4.77 (s, 2H), 3.96 (s, 3H), 2.82 (t, 2H, J ) 7.1 Hz), 1.16 (t, 3H,
J ) 7.2 Hz), 0.88 (s, 9H), 0.07 (s, 3H), 0.00 (s, 3H) ppm. 13C
NMR (100 MHz, CDCl3): δ 205.1, 160.2, 149.2, 144.8, 118.6,
112.9, 56.3, 52.7, 35.4, 24.9, 17.6, 6.7, -6.6 ppm. IR (ATR-FTIR)
(7 × 100 mL) to remove unreacted 47 and the auxiliary. [Auxiliary
recycling: the TBME extracts were evaporated to dryness in a rotary
evaporator (40 °C/5 mbar) yielding a yellow semisolid (1.61 g),
which was purified by dissolving in ethyl acetate (3 mL) at reflux
temperature and subsequent dropwise addition of heptane (7.5 mL).
The resulting suspension was filtered, and the isolated crystals were
washed with heptane (2 mL) yielding the pure auxiliary (1.07 g,
87 wt %).] The aqueous phase was acidified with aqueous HCl
(2.0 M) to adjust the pH to 3.0 and was extracted with dichloro-
methane/ethanol (4:1, 9 × 100 mL). After evaporation in a rotary
evaporator (40 °C/5 mbar), product 49 was obtained as a colorless
semisolid (700 mg, 2.74 mmol, 45 wt % (85% over two steps from
47), er ) 80.5:19.5) (chiral HPLC method, sample preparation:
ethanol solution; Chiralpak-ADH column, 250 × 4.6; temperature
of 25 °C; mobile phase, 90% heptane, 10% ethanol/trifluoroacetic
acid (99:1); flow of 0.8 mL/min; injection volume of 5 µL, detec-
tion, UV 308 nm; retention time, 22.20 min (R)-49, 24.78 min
(S)-49). 49 lactonizes partly during solvent evaporation and also
when stored at ambient temperature, thus ruling out a correct micro-
analysis. [R]D20 (c ) 1.3154 g/dL, CHCl3) ) +9.1. 1H NMR (300
MHz, CDCl3): δ 8.03 (d, 1H, J ) 5.5 Hz), 6.76 (d, 1H, J ) 5.4
Hz), 5.04 (d, 1H, J ) 12.2 Hz), 4.89 (d, 1H, J ) 12.2 Hz), 3.97 (s,
3H), 3.07 (d, 1H, J ) 16.2 Hz), 2.85 (d, 1H, J ) 16.2 Hz), 1.92
(br. q, 2H, J ) 7.5 Hz), 0.82 (t, 3H, J ) 7.4 Hz) ppm. 13C NMR
(100 MHz, CDCl3): δ 175.6, 163.5, 154.2, 145.5, 120.9, 115.3,
77.4, 56.5, 54.1, 44.7, 35.3, 8.1 ppm. IR (ATR-FTIR) 3404, 2949,
1725, 1596, 1567, 1450, 1370, 1267, 1188, 1044 cm-1. MS (EI)
m/z (rel intensity) 237 (19), 208 (20), 166 (100). HRMS (ESI POS)
calcd for C12H17NO5Na (MNa+) 278.1004, found 278.1004. HRMS
(ESI POS) calcd for C12H18NO5 (MH+) 256.1185, found 256.1184.
Microanalysis: C was not in the range <0.4%, even after purifica-
tion by preparative HPLC (HPLC purity 100.0%).
2952, 1710, 1594, 1561, 1450, 1371, 1252, 1066, 1018, 835 cm-1
.
MS (EI) m/z (rel intensity) 309 (2), 252 (100), 178 (52), 75 (18).
HRMS (ESI POS) calcd for C16H28NO3Si (MH+) 310.1840, found
310.1838. Anal. Calcd for C16H27NO3Si: C, 62.10; H, 8.79; N,
4.53. Found: C, 62.12; H, 8.83; N, 4.47.
Synthesis of (R)-3-{3-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-
2-methoxy-pyridin-4-yl]-3-hydroxy-pentanoyl}-(R)-4-phenyl-ox-
azolidin-2-one (48). A solution of 39 (1.989 g, 9.69 mmol, 3.0
equiv) in THF (7.5 mL) was slowly added (addition time: 10 min)
to a solution of lithium bis(trimethylsilyl)amide (9.79 mL, 1.0 M
in THF, 9.69 mmol, 3.0 equiv) at -78 °C. Upon addition, the color
changed from colorless to bright yellow. After 2 h at -78 °C, the
solution was cooled to -95 °C and 47 (1.000 g, 3.231 mmol)
dissolved in THF (6.7 mL) was slowly added (addition time: 60
min) using a syringe pump. The solution was kept for an additional
30 min at -95 °C and then for 1 h at -78 °C. Subsequently, the
reaction was quenched by addition of aqueous 0.5 M HCl (50 mL).
The mixture was extracted with dichloromethane (3 × 50 mL),
and the combined extracts were dried over sodium sulfate (10 g,
30 min) and filtered. The filter cake was washed with dichlo-
romethane (20 mL). After removal of solvent in a rotary evaporator
(40 °C/5 mbar), the crude product was obtained as an orange solid
(3.12 g, 188 wt %, dr ) 87:13 (1H NMR)). An analytical sample
(dr > 50:1; colorless oil) was obtained by semipreparative HPLC
(Extend C18, 21.2 × 150 mm). [R]D20 (c ) 0.285 g/dL, CHCl3) )
-98.1. 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H, J ) 5.4 Hz),
7.23 (m, 3H), 7.03 (m, 2H), 6.67 (d, 1H, J ) 5.5 Hz), 5.42 (s, 1H),
5.35 (dd, 1H, J ) 8.7 Hz, J ) 4.0 Hz), 4.97 (d, 1H, J ) 11.6 Hz),
4.93 (d, 1H, J ) 11.6 Hz), 4.62 (t, 1H, J ) 8.7 Hz), 4.18 (dd, 1H,
J ) 8.6 Hz, J ) 4.2 Hz), 4.07 (d, 1H, J ) 16.2 Hz), 3.91 (s, 3H),
3.23 (d, 1H, J ) 16.2 Hz), 1.90 (m, 2H), 0.87 (s, 9H), 0.78 (t, 3H,
J ) 7.4 Hz), 0.06 (s, 3H), 0.01 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3): δ 170.6, 162.8, 155.4, 153.7, 145.3, 138.4, 129.0, 128.4,
125.4, 120.3, 115.5, 78.1, 69.8, 57.5, 56.5, 53.5, 46.0, 36.4, 25.9,
18.3, 7.9, -5.3, -5.4 ppm. IR (MTIR) 3480, 2928, 1779, 2698,
1380, 1249, 1044, 1003, 835, 762, 696 cm-1. MS (EI) m/z (rel
intensity) 515 (2), 457 (2), 439 (1), 365 (31), 262 (96), 252 (54),
202 (100), 178 (69). HRMS (ESI POS) calcd for C27H38N2O6NaSi
(MNa+) 537.2397, found 537.2396. Anal. Calcd for C27H38N2O6-
Si: C, 63.01; H, 7.44; N, 5.44. Found: C, 62.68; H, 7.62; N, 5.44.
Synthesis of (R)-3-Hydroxy-3-(3-hydroxymethyl-2-methoxy-
pyridin-4-yl)-pentanoic Acid (49). An aqueous solution of LiOH
(37.8 mL, 0.8 M, 30.2 mmol, 5.0 equiv) and an aqueous solution
of H2O2 (3.02 mL, 10 M, 30.2 mmol, 5.0 equiv) was added to a
solution of crude 48 (3.11 g, 6.04 mmol) in THF (35 mL) at 0 °C.
After 30 min, aqueous NaOH solution (220 mL, 2.0 M) was added
and the ice bath was removed. The reaction was monitored by
HPLC. After 2 h, the resulting emulsion was extracted with TBME
Synthesis of (R)-5-Ethyl-5-hydroxy-2,5,6,9-tetrahydro-8-oxa-
2-aza-benzocycloheptene (7). Aqueous HBr (48%, 1.01 mL, 9.0
mmol, 2.1 equiv) was added to a stirred solution of 49 (1.097 g,
4.298 mmol) in 1,2-dimethoxyethane (15 mL). After 15 min at room
temperature, the solution was heated to 50 °C. After 18 h at 50 °C,
the resulting suspension was allowed to stir at room temperature
for an additional 24 h and subsequently to stand at 5 °C for 18 h.
The precipitate was collected by filtration using no vacuum and
was subsequently washed with TBME (2 × 2.6 mL), then with
acetone (2.6 mL), water (2 × 3.2 mL), and finally again with
acetone (2 × 2.6 mL). After evaporation of residual solvent in a
rotary evaporator (40 °C/10 mbar), product 7 (418.1 mg, 1.873 mmol,
44 wt %, er > 99.95:0.05 (chiral HPLC, sample preparation:
ethanol solution; Chiralcel-ODH column, 250 × 4.6; temperature
of 25 °C, mobile phase, 75% heptane, 25% ethanol/trifluoroacetic
acid (99:1); flow of 0.8 mL/min; injection volume of 5 µL;
detection, UV 308 nm; retention time, 9.68 min (S)-7, 13.28 min
20
(R)-7)) was obtained as white crystals. [R]D (c ) 1.178 g/dL,
DMSO) ) +127.9. Mp: >270 °C (decomp). 1H NMR (300 MHz,
DMSO): δ 11.67 (br. s, 1H), 7.34 (d, 1H, 7.2 Hz), 6.33 (d, 1H,
7.2 Hz), 5.72 (br. S, 1H), 5.34 (d, 1H, J ) 15.1 Hz), 5.21 (d, 1H,
J ) 15.1 Hz), 3.32 (d, 1H, J ) 13.5 Hz), 2.98 (d, 1H, J ) 13.7
Hz), 1.68 (m, 2H), 0.80 (t, 3H, J ) 7.5 Hz) ppm. The other
analytical data are in accordance with those described above.
Synthesis of (R)-3-Acetyl-4-phenyl-oxazolidin-2-one (39).22
n-Butyllithium (21.0 mL, 1.5 M in pentane, 31.53 mmol, 1.05 equiv)
was added to a stirred suspension of (4R)-(-)-4-phenyl-2-oxazo-
lidinone (98%, 5.000 g, 30.03 mmol) in THF (100 mL) at 0 °C
within 10 min. The resulting colorless solution was stirred for an
additional 50 min at 0 °C. Acetyl chloride (2.57 mL, 36.0 mmol,
1.2 equiv) was then added within 1 min. After 3 h 30 min, the
reaction was stopped by addition of saturated aqueous NH4Cl
(25 mL) and the mixture was extracted with ethyl acetate (75 mL).
The organic phase was washed with aqueous NaHCO3 (50 mL,
(22) Known compound: Ferroci, M.; Inesi, A.; Palombi, L.; Rossi, L.;
Sotgiu, G. J. Org. Chem. 2001, 66, 6185.
7594 J. Org. Chem., Vol. 71, No. 20, 2006

Formal Total Syntheses of Homocamptothecin
1.0 M) and with brine (50 mL). The solution was dried over sodium
sulfate (5 g, 30 min) and filtered. The filter cake was washed with
ethyl acetate (10 mL). After removal of solvent in a rotary evapo-
rator (40 °C/18 mbar), the crude product (6.13 g, 100 wt %) was
obtained as white crystals. Purification was achieved by dissolving
in 10.6 mL of ethyl acetate at reflux temperature and subsequent
dropwise addition of heptane (26.6 mL). The resulting suspension
was allowed to slowly cool to 5 °C, and after standing overnight,
the precipitate was collected by filtration. After washing with
heptane (3 mL), product 39 (5.26 g, 25.6 mmol, 85 wt %) was
obtained as white crystals. [R]D20 (c ) 0.083 g/dL, CHCl3) ) -58.8.
(100), 43 (77). HRMS (ESI POS) calcd for C11H12NO3 (MH+)
206.0817, found 206.0818. Anal. Calcd for C11H11NO3: C, 64.38;
H, 5.40; N, 6.83. Found: C, 64.25; H, 5.39; N, 6.75.
Acknowledgment. We thank Dr. Martin Karpf for valuable
discussions and Mr. Thomas Naber and Mrs. Se´ve´rine Baum-
gartner for skillful experimental work. We also thank the
members of the analytical services of F. Hoffmann-La Roche
Ltd., Basel, especially the mass spectroscopy group of Dr.
Andreas Sta¨mpfli, for efficiently and persistently providing the
physical data of all compounds described.
1
Mp: 94 °C. H NMR (300 MHz, CDCl3): δ 7.25-7.42 (m, 5H),
5.42 (dd, 1H, J ) 8.8 Hz, J ) 3.5 Hz), 4.69 (t, 1H, J ) 8.8 Hz),
4.29 (dd, 1H, J ) 8.8 Hz, J ) 3.5 Hz), 2.53 (s, 3H) ppm. 13C
NMR (100 MHz, CDCl3): δ 169.7, 153.9, 139.1, 129.2, 128.8,
126.0, 70.0, 57.5, 23.8 ppm. IR (Nujol) 2923, 1789, 1707, 1332,
769, 703 cm-1. MS (EI) m/z (rel intensity) 205 (7), 162 (47), 161
Supporting Information Available: General experimental meth-
ods and 1H/13C NMR spectra of all key compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO060928V
J. Org. Chem, Vol. 71, No. 20, 2006 7595