Synthesis of both syn and anti diastereoisomers of Boc-dolaproine from (S)-proline through DKR using ruthenium-catalyzed hydrogenation: A dramatic role of N-protecting groups

Article abstract of DOI:10.1016/j.tet.2004.07.043

The natural (2R,3R)-Boc-dolaproine and its unnatural (2S,3S) diastereoisomer were synthesized involving as key transformation the Ru(II)-promoted hydrogenation of the β-keto-α-methyl ester derived from (S)-N-Boc-proline. Interestingly, the asymmetric hydrogenation of this β-keto ester N-protected as an amine hydrochloride salt, provided the corresponding anti (2S,3R)- and (2R,3S)-β-hydroxy-α-methyl esters with significant level of selectivities through dynamic kinetic resolution. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.07.043

Tetrahedron 60 (2004) 9715–9723
Synthesis of both syn and anti diastereoisomers of Boc-dolaproine
from (S)-proline through DKR using ruthenium-catalyzed
hydrogenation: a dramatic role of N-protecting groups
*
Celine Mordant, Sebastien Reymond, Virginie Ratovelomanana-Vidal and Jean-Pierre Genet
*
ˆ
´
´
` ´
Laboratoire de Synthese Selective Organique et Produits Naturels, E.N.S.C.P., UMR 7573, 11 rue P. et M. Curie,
F-75231 Paris Cedex 05, France
Received 18 June 2004; revised 2 July 2004; accepted 6 July 2004
Available online 11 September 2004
Abstract—The natural (2R,3R)-Boc-dolaproine and its unnatural (2S,3S) diastereoisomer were synthesized involving as key transformation
the Ru(II)-promoted hydrogenation of the b-keto-a-methyl ester derived from (S)-N-Boc-proline. Interestingly, the asymmetric
hydrogenation of this b-keto ester N-protected as an amine hydrochloride salt, provided the corresponding anti (2S,3R)- and (2R,3S)-b-
hydroxy-a-methyl esters with significant level of selectivities through dynamic kinetic resolution.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Reformatsky synthesis of Dap was also described by Pettit
et al.14 Another strategy was recently developed based on a
Baylis–Hillman reaction between N-Boc-L-prolinal and
methylacrylate which provided 91% of a diastereoisomeric
mixture of syn/anti esters (83/17) after diastereoselective
hydrogenation of the Baylis–Hillman adduct.15
Naturally occurring (2R,3R)-dolaproine 1a (Dap) is a key
unit of dolastatin 10 originally isolated in 1987 from the
Indian Ocean sea hare Dolabella auricularia. Dolastatin 101
is a potent inhibitor of microtubule assembly which
displayed remarkable antineoplastic activity and is actually
in phase II human cancer clinical trials (Fig. 1).2,3
Following our ongoing research devoted to the synthesis of
natural products and industrially relevant molecules16–19
using Ru-catalyzed hydrogenation reactions through
dynamic kinetic resolution (DKR),20–22 we have previously
described a multigram-scale preparation of anti Boc-(2S,3R)-
iso-dolaproine23 with an excellent level of diastereoselectivity
(d.e. 85%). This synthesis involving as key step the
hydrogenation of the b-keto-a-methyl ester derived from
the hydrochloride salt of (S)-proline turned out to be the first
Several groups have turned their attention towards the
synthesis of dolaproine, which is the most complex unit of
this marine natural product. The pioneering work of Pettit et
al. was based on an aldol reaction of N-Boc-L-prolinal with
the magnesium enolate of a chiral propionate leading to all
four diastereoisomers in moderate yields and selectivities.4,5
Subsequent efforts were focused on devising stereoselective
and practical syntheses of dolaproine and its diastereo-
isomers. Shioiri et al. reported an efficient synthetic route to
the synthesis of dolaproine6–9 using Evans aldol methodo-
logy and condensation of N-Boc-L-prolinal with a chiral
oxazolidinone in the presence of dibutylboron triflate,
providing the desired syn compound with a complete
diastereoselection.10 Other syntheses of dolaproine involved
aldol condensation with an achiral Z-boron enolate of
thiophenyl propionate11 or Z-crotylboronate12 with mode-
rate yields, while the use of benzyl propionate furnished
a syn/anti mixture.13 A convenient cobalt-mediated
Keywords: Dolaproine; DKR; Asymmetric hydrogenation; Ruthenium.
* Corresponding authors. Tel.: C33-0144276743; fax: C33-0144071062;
e-mail: genet@ext.jussieu.fr
Figure 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.043

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C. Mordant et al. / Tetrahedron 60 (2004) 9715–9723
diastereoisomers Boc-(2S,3S)-iso-dolaproine and Boc-
(2R,3S)-iso-dolaproine is reported.
2. Results and discussion
The retrosynthetic approach for the required diastereo-
isomers of Boc-dolaproine 1b was designed as follows
(Scheme 1). Target compound 1b would be obtained from
the N-protected b-hydroxy esters 3. The b-hydroxy-a-
methyl esters 3 would be synthesized from the correspond-
ing N-protected b-keto-a-methyl esters 2a or 2b by catalytic
asymmetric hydrogenation.
The hydrogenation substrates 2a and 2b were easily
prepared from the readily available (S)-N-Boc-proline.23
The key hydrogenation was performed with the b-keto ester
2a derived from the hydrochloride salt of (S)-proline
(pathway B, Scheme 2). On the basis of our previous
work (pathway A, Scheme 2),23 we expected to obtain an
anti diastereoselectivity.
Scheme 1.
example of an efficient DKR of a b-keto ester a-substituted
by an alkyl group, bearing at the g-position a stereogenic
center. We have also recently disclosed a general method
for the stereoselective synthesis, from the same common
intermediate, of syn and anti a-amino-b-hydroxy esters,24,25
precursors of medically important compounds. Whereas the
hydrogenation of a-amido-b-keto esters led to the syn
adducts, DKR of these b-keto esters a-substituted by a
NH2$HCl group provided the corresponding anti b-hydroxy
esters with excellent selectivities.
The b-keto-a-methyl ester 2a was hydrogenated under
10 bar at 50 8C for 48 h in ethanol with the in situ generated
[Ru((R)-MeO-BIPHEP)Br2] catalyst according to our con-
venient procedure.26 Unlike the results described for the
synthesis of Boc-(2S,3R)-iso-dolaproine involving the
ligand of (S)-configuration,23 we were surprised to find
that the hydrogenation reaction with (R)-MeO-BIPHEP
as ruthenium ligand proceeded rather slowly; 3 mol% of
catalyst were required to ensure complete conversion. A
moderate selectivity in favor of the anti b-hydroxy-a-
methyl ester hydrochloride salt (2R,3S)-3a was observed.
This lower diastereoselectivity could be the result of the
following mismatched pair: chirality of the proline moiety
and configuration of the ligand, as previously described in
the literature.27,28
In connection with our efforts to synthesize dolastatin 10
and its analogs required for biological trials, an attractive
solution would be to develop a practical stereoselective
route to all diastereoisomers of dolaproine from the same
b-keto-a-methyl ester intermediate derived from (S)-pro-
line. We thus anticipated that the nature of the N-protecting
group of the (S)-proline fragment might influence the
stereochemical outcome of the hydrogenation reaction.
Spectroscopy analysis (1H NMR in D2O) of the crude
hydrogenated product showed that the desired diastereo-
isomer (2R,3S)-3a was obtained in mixture with two other
In this paper, a simple and direct preparation of the naturally
occurring Boc-(2R,3R)-dolaproine 1b and its related
Scheme 2.

C. Mordant et al. / Tetrahedron 60 (2004) 9715–9723
9717
diastereoisomers, (2S,3S)-3a and (2S,3R)-3a, in a 71:24:5
diastereoisomeric ratio. This mixture was enriched up to
85:15 [(2R,3S)-3a:(2S,3S)-3a] by recrystallization in ethyl
acetate.
cyclized into the bicyclic lactam 5 by using potassium
carbonate in a ethanol/water mixture (Scheme 4). The
stereochemistry (2R,3S) of 3 was then assigned by NMR on
the basis of NOE and COSY experiments.
The synthesis of anti Boc-(2R,3S)-iso-dolaproine was
achieved by saponification of the ethyl ester function with
sodium hydroxide (Scheme 3). Unfortunately, this reaction
provided a mixture of the desired Boc-(2R,3S)-iso-dap and
its isomerized diastereoisomer Boc-(2S,3S)-iso-dap.29
Treatment of this mixture with Boc2O in the presence of
triethylamine afforded the corresponding N-protected com-
pounds Boc-(2R,3S)-3 and Boc-(2S,3S)-3 which could not
be separated by chromatography on silica gel. However the
resulting 83:17 mixture was engaged in the O-methylation
reaction with Me3OBF4 and proton sponge.5 At this stage,
optically pure anti Boc-(2R,3S)-4 was isolated in 51% yield
after flash chromatography (Scheme 3).
Although the origin of the anti diastereoselectivity is not
clear at present, a chelated model could be speculated in
which the substrate is coordinated to the metal by both its
carbonyl oxygen functions (Scheme 5). Obviously, the
chirality of (R)-MeO-BIPHEP as ruthenium ligand controls
efficiently the stereofacial discrimination at the carbonyl
function since the (3S) configuration is predominantly
obtained, in agreement with the general sense of asymmetric
hydrogenation.30,31 Chair-like transition state TS1, where
the methyl group adopts a pseudo-equatorial position is
more favored than transition state TS2 exhibiting an axial
methyl group. This could explain the predominant for-
mation of the anti product.
In order to confirm the stereochemistry of the diastereo-
isomer 3 obtained, Boc-(2R,3S)-4 was treated with TFA and
Thus, we have demonstrated that the asymmetric Ru(II)-
promoted hydrogenation reaction of the b-keto-a-methyl
ester 2a derived from the hydrochloride salt of (S)-proline
provided the anti products (2R,3S)-3 and (2S,3R)-323 as
major diastereoisomers with moderate to good diastereo-
selectivities (41 and 85% d.e., respectively). The stereo-
genic center at the g-position of the substrate seems to
influence deeply the stereochemical outcome of the DKR.
Scheme 3. (a) Me3OBF4, proton sponge, CH2Cl2, 48 h, 51% yield. (b)
NaOH, EtOH/H2O, overnight.
According to our previous results obtained for the general
synthesis of syn and anti a-amino-b-hydroxy esters,24,25 we
postulated that by simply changing the protecting group of
the amine function of the proline moiety, the stereochemical
course of the DKR of b-keto-a-methyl ester 2b protected as
Scheme 4.
Scheme 5.

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C. Mordant et al. / Tetrahedron 60 (2004) 9715–9723
3 mol%, affording the corresponding crude product Boc-
(2S,3S)-3 with an excellent control of the syn diastereo-
selectivity (entry 4, 87% d.e) (pathway C, Scheme 2). After
chromatography on silica gel, Boc-(2S,3S)-3 was isolated in
88% yield and 96% d.e. (Scheme 6).
Scheme 6.
The reversal of diastereoselectivity observed in the
hydrogenation of the N-Boc protected proline derivative
2b could be justified with the transition states proposed
below (Scheme 7). As expected, the chirality of (R)-MeO-
BIPHEP as ruthenium ligand controls the (3S) configuration
of the product,29,30 which was predominantly produced.
Chair-like transition state TS3 having the methyl group and
the bulky N-Boc-proline moiety in an 1,2 axial–equatorial
relationship is rather favored compared to transition state
TS4 where the methyl group adopts a pseudo-equatorial
position. Even if at this stage we have no clear evidence,
these suggested transition states TS3 and TS4 could explain
the predominant formation of the syn Boc-(2S,3S)-3.
its N-Boc derivative would be in favor of the syn product as
required for the dolaproine unit. In this context, we decided
to examine the hydrogenation reaction of 2b protected with
a tert-butyloxycarbonyl group. Thus, we turned our
attention to the synthesis of Boc-(2R,3R)-dolaproine 1b
(Dap) and its related diastereoisomer Boc-(2S,3S)-
dolaproine.
The hydrogenation reaction of the b-keto ester derivative 2b
was first carried out in the presence of 1 mol% [Ru((R)-
MeO-BIPHEP)Br2] (Scheme 5, Table 1) at 50 8C under
95 bar of hydrogen pressure for 96 h. We were pleased to
notice a remarkable reversal of the diastereoselectivity
(entry 1). The syn (2S,3S) diastereoisomer was produced
with high d.e. (entry 1, 83% d.e. on the crude product) but
with a moderate conversion (66%). Thus we tried to
optimize this reaction (Table 1). A complete conversion was
ensured by increasing hydrogen pressure to 130 bar and the
substrate/catalyst ratio to 5 and 3 mol% but unfortunately,
lower chiral inductions were observed (entries 2 and 3, 72
and 77% d.e. on the crude product). Finally, the reaction was
performed under 100 bar of hydrogen pressure at 50 8C with
Considering the excellent asymmetric induction observed in
the presence of [Ru((R)-MeO-BIPHEP)Br2)], we focused
our attention on the synthesis of the naturally occurring
dolaproine (2R,3R)-Dap-1b which should be obtained
by catalytic hydrogenation of 2b with the opposite
configuration of the ruthenium ligand ([Ru((S)-MeO-
BIPHEP)Br2)]). The hydrogenation reaction was conducted
under 130 bar of hydrogen pressure at 50 8C for 96 h in
ethanol with 5 mol% of catalyst. The reaction was not
Scheme 7.
Table 1. Asymmetric hydrogenation of compound 2b using [Ru((R)-MeO-BIPHEP)Br2]
Entry
[Ru] (mol%)
P(H2) (bar)
Conv. (%)
d.e. (2S,3S) (%)a
1
2
3
4
1
5
3
3
95
66
83
72
77
87
130
130
100
100
100
100
a
d.e. determined on the crude product by 1H NMR (300 MHz).

C. Mordant et al. / Tetrahedron 60 (2004) 9715–9723
9719
complete and the desired syn product Boc-(2R,3R)-3 was
obtained in mixture with the starting material 2b (30–40%)
and with the three other diastereoisomers. After flash
chromatography, Boc-(2R,3R)-3 was isolated in mixture
with anti Boc-(2S,3R)-3. The conversion could be improved
(up to 72%) and the proportion of the minor diastereo-
isomers syn Boc-(2S,3S)-3 and anti Boc-(2R,3S)-3
decreased (until 8%) by using the in situ generated
catalyst simply prepared by mixing [Ru(p-cymene)Cl2]2
and (S)-SYNPHOSw ligand recently developed in our group
(pathway D, Scheme 2).32 However syn Boc-(2R,3R)-3 and
anti Boc-(2S,3R)-3 could not be separated and after
chromatography on silica gel, a 2:1 d.r. was obtained in a
55% yield. The (3R) configuration is predominantly
obtained suggesting that the ligand of (S) configuration
controls quite well the enantiofacial discrimination; but in
this case, the DKR is less efficient. Once again, the influence
of the asymmetric center at the g-position of the substrate is
important for the control of selectivity.
Scheme 9. (a) Me3OBF4, proton sponge, CH2Cl2, rt, 24 h, 68% yield. (b)
NaOH, EtOH/H2O, 30 8C, 24 h, 73% yield. (c) (1) LHMDS, HMPA, THF,
K78 8C, 25 min; (2) MeOTf, K20 8C, 15 min; 45% yield. (d) LiOH,
EtOH/H2O, overnight, 59% yield.
The absolute configuration of the N-Boc-Dap (2R,3R)-1b
has been found to be identical to the previously synthesized
compounds. All spectrometric data were in agreement with
those reported in the literature (Scheme 9).5
Afterwards, the b-hydroxy esters Boc-(2S,3S)-3 and Boc-
(2R,3R)-3 were subjected to the next synthetic steps:
O-methylation and saponification (Scheme 9). The synthesis
of N-Boc-iso-Dap (2S,3S)-1 was achieved by O-methyl-
ation5 followed by saponification of 6 to yield N-Boc-
(2S,3S)-iso-Dap whose stereochemistry was unambiguously
confirmed by X-ray analysis (Scheme 8).
3. Conclusions
In conclusion, we have succeeded in the synthesis of
naturally occurring Boc-dolaproine 1b and both (2S,3S)-
and (2R,3S)-iso-dolaproine derivatives by developing a
catalytic approach based on the ruthenium-promoted
hydrogenation reaction via DKR as key transformation.
The protecting group of the proline moiety turned out to
play a crucial role in the stereochemical outcome of the
asymmetric hydrogenation. The synthesis of dolastatin 10
and analogues is currently underway in our group and will
be reported in due course.
After treatment of Boc-(2R,3R)-3 with LHMDS in HMPA
and MeOTf, the methoxy derivative Boc-(2R,3R) which led
to the naturally occurring Boc-(2R,3R)-dolaproine 1b, was
isolated optically pure in a 45% yield after chromatography
on silica gel, without any trace of anti (2R,3S) compound.11
4. Experimental
4.1. General methods
Dichloromethane was distilled from calcium hydride and
tetrahydrofuran and diethyl ether from sodium-benzo-
phenone. Acetone for the catalyst preparation was distilled
over potassium carbonate. Other solvents were used without
any purification. Triethylamine was distilled from potas-
sium hydroxide. All air and/or water sensitive reactions
were carried out under an argon atmosphere unless
otherwise noted. 1H NMR spectra were recorded on an
Avance 300 at 300 MHz or an Avance 400 at 400 MHz; 13C
NMR spectra were recorded on an Avance 300 at 75 MHz or
an Avance 400 at 100 MHz. Chemical shifts (d) are reported
in ppm downfield relative to internal Me4Si. Coupling
constants (J) are reported in Hz and refer to apparent peak
multiplicities (recorded as s, singlet; d, doublet; t, triplet; q,
quadruplet; qu, quintet; o, octet; m, multiplet; and br,
broad). Mass spectra were determined on a Nermag R10-
10C instrument. Ionization was obtained by chemical
ionization with ammonia (DCI/NH3) or by electrospray
(on a API 3000 PE Sciex instrument). Optical rotations were
measured on a Perkin–Elmer 241 polarimeter at 589 nm
(sodium lamp). GC analyses of compounds 3 were
¨
Scheme 8. ORTEP drawing of Boc-(2S,3S)-iso-Dap (ellipsoıds, probability
˚
50%)—selected bond distances (A): C1–C2Z1.518(5); C2–C4Z1.538(6);
C2–C3Z1.529(5); C3–O3Z1.427(4); O3–C5Z1.378(5); C3–C20Z
1.542(5). Selected angles (8): C6–N1–C20Z124.6(3); C6–N1–C50Z
119.4(3); C50–N1–C20Z113.8(3); C5–O3–C3Z115.6(3). Selected dihe-
dral angles (calculated) (8): C30–C20–C3–O3ZK64.7; O3–C3–C2–
C4ZK51.5. Nitrogen hybridization: (N1) (8)Z357.8.

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C. Mordant et al. / Tetrahedron 60 (2004) 9715–9723
performed on a Agilent 6850 series equipped with a HP01
column capillary column (30 m, : 0.25 mm): 70–210 8C,
5 8C/min, flow: 4 mL/min (He).
was purified by silica gel column chromatography using
cyclohexane–ethyl acetate (9:1) as eluent to give the N-Boc
b-hydroxy ester (295 mg, 98% yield) as a pale yellow oil
in a 83:17 mixture of (2R,3S):(2S,3S) diastereoisomers
confirmed by GC analysis (tR (2R,3S) 22.0, tR (2S,3S) 22.7).
1H NMR (CDCl3, 300 MHz, 24 8C): d 4.16 (q, JZ7.1 Hz,
2H), 4.08 (app dt, JZ3.6, 7.9 Hz, 1H), 3.56 (dd, JZ3.8,
7.9 Hz, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.65 (dq, JZ3.8,
7.1 Hz, 1H), 1.60–2.05 (m, 4H), 1.46 (s, 9H), 1.28 (d, JZ
7.1 Hz, 3H), 1.26 (t, JZ7.1 Hz, 3H); 13C NMR (CDCl3,
75 MHz, 24 8C): d broad peaks (conformers) 174.2, 155,
80.3, 68.2, 60.4, 59.8, 47.2, 43.2, 28.4, 24.0, 23.5, 14.2; MS
(DCI, NH3): m/z 302 (100%, [MCH]C), 263 (6%, [MK
C4H8CNH4]C), 246 (25%, [MKC4H8CH]C); [a]2D1Z
K67.8 (cZ1.01, CHCl3).
4.2. Typical procedure for hydrogenation
(S)- or (R)-MeO-BIPHEP (0.011 mmol, 1.1 equiv, 6.4 mg)
and (cod)Ru(2-methylallyl)2 (0.01 mmol, 1 equiv, 3.2 mg)
were placed in a 15 mL flask and 1 mL of anhydrous
acetone previously degassed was added. A methanolic
solution of HBr (0.022 mmol, 2.2 equiv, 141 mL of a
0.156 N solution prepared by added 48% aqueous HBr in
degassed methanol) was added to the resulting suspension
and the reaction mixture was stirred at room temperature for
30 min. The solvent was thoroughly evaporated under
vacuum. The orange solid residue was used directly as
catalyst (1 mol%) for the hydrogenation reaction. A solution
(previously degassed) of the b-keto ester (1 mmol) in
ethanol (1 mL) was added via canula to the catalyst and the
reaction vessel was placed then in a 500 mL stainless steel
autoclave, under argon. The autoclave was pressurized to
the suitable pressure of hydrogen, heated at 50 8C and the
reaction was allowed to proceed until completion. The crude
reaction mixture was evaporated.
4.2.3. Ethyl (2S,3S,4S)-3-(N-tert-butoxycarbonyl-20-pyrro-
lidinyl)-3-hydroxy-2-methyl-propanoate Boc-(2S,3S)-3.
Obtained from ethyl (4S)-3-(N-tert-butoxycarbonyl-20-
pyrrolidinyl)-3-oxo-2-methyl-propanoate23 (2 mmol, 598 mg)
according to the general procedure with the catalyst [Ru((R)-
MeO-BIPHEP)Br2] (0.03 mmol, 3 mol) under 100 bar of
1
hydrogen for 96 h. H NMR analysis of the crude product
showed a complete conversion and a diastereoisomeric
excess of 87%. Purification by silica gel column chromato-
graphy using cyclohexane–ethyl acetate (9:1) led to the
b-hydroxy ester (435 mg, 88% yield) as a slightly yellow
4.2.1. Ethyl (2R,3S,4S)-3-(20-pyrrolidinyl)-3-hydroxy-2-
methyl-propanoate hydrochloride (2R,3S0)-3a. The title
compound was obtained from ethyl (4S)-3-(2 -pyrrolidinyl)-
3-oxo-2-methyl-propanoate hydrochloride23 (2 mmol,
472 mg) according to the general procedure with the
catalyst [Ru((R)-MeO-BIPHEP)Br2] (0.06 mmol, 3 mol%)
under 10 bar of hydrogen for 48 h. 1H NMR analysis of the
crude product (brown oil) showed a complete conversion
and a 71:24:5 mixture of (2R,3S), (2S,3S) and (2S,3R)
diastereoisomers (d.e. (2R,3S) 42%). After recrystallization
in ethyl acetate, this mixture was enriched up to a 85:15
mixture of (2R,3S):(2S,3S) diastereoisomers. 1H NMR
(D2O, 300 MHz, 24 8C): d (major diastereoisomer) 4.10
(q, JZ7.1 Hz, 2H), 3.80 (dd, JZ5.3, 7.1 Hz, 1H), 3.72 (dq,
JZ7.3, 9.5 Hz, 1H), 3.24 (app t, 2H, JZ7.3 Hz), 2.69 (dq,
1H, JZ5.3, 7.1 Hz), 2.11–2.20 (m, 1H), 1.88–2.08 (m, 2H),
1.63–1.77 (m, 1H), 1.18 (t, JZ7.1 Hz, 3H), 1.13 (d, JZ
7.1 Hz, 3H); d (minor diastereoisomer) identical except 4.05
(m, 1H), 3.55 (app q, JZ7.7 Hz, IH), 1.07 (d, JZ7.1 Hz,
3H); 13C NMR (D2O, 75 MHz, 24 8C): d (major diastereo-
isomer) 175.7, 72.3, 62.5, 62.0, 45.4, 43.3, 26.9, 23.4, 13.3,
13.1; d (minor diastereoisomer) 176.3, 71.2, 62.9, 62.2,
45.2, 42.8, 26.8, 23.4, 13.3, 9.3; MS (DCI, NH3): m/z 202
(100%, [MCH]C).
1
oil. H NMR analysis showed a 98:2 mixture of (2S,3S):
(2R,3S) diastereoisomers confirmed by GC analysis (tR
(2S,3S) 22.7, tR (2R,3S) 22.0). 1H 1H NMR (CDCl3,
300 MHz, 24 8C): d 5.05 (br s, 1H, OH), 4.16 (dq, JZ2.4,
7.2 Hz, 2H), 3.95 (m, 2H), 3.50 (m, 1H), 3.30 (ddd, JZ5.5,
6.9, 10.9 Hz, 1H), 2.31 (dq, JZ1.8, 6.9 Hz, 1H), 1.62–1.95
(m, 4H), 1.46 (s, 9H), 1.26 (t, JZ7.2 Hz, 3H), 1.20 (d, JZ
6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz, 24 8C): d 174.4,
158.0, 80.8, 76.1, 60.6, 60.4, 47.1, 42.9, 28.4, 28.4, 24.1,
14.2, 8.9; MS (DCI, NH3): m/z 302 (100%, [MCH]C), 263
(7%, [MKC4H8CNH4]C), 246 (48%, [MKC4H8CH]C);
[a]2D1ZK76.2 (cZ0.97, CHCl3).
4.2.4. Ethyl (2R,3R,4S)-3-(N-tert-butoxycarbonyl-20-pyr-
rolidinyl)-3-hydroxy-2-methyl-propanoate Boc-(2R,3R)-
3. A solution of ethyl (4S)-3-(N-tert-butoxycarbonyl-20-
pyrrolidinyl)-3-oxo-2-methyl-propanoate23 (3 mmol, 897 mg)
in absolute ethanol (6 mL) was degassed by three vacuum-
argon cycles at room temperature and added via canula to
the mixture (5 mol%) [Ru(p-cymene)Cl2]2 (0.075 mmol,
46 mg)C(S)-SYNPHOSw (0.165 mmol, 105 mg). The
Schlenk vessel was then placed under argon in a 250 mL
stainless steel autoclave. The argon atmosphere was
replaced with hydrogen by three cycles of pressurizing
and the pressure adjusted to 130 bar. The autoclave was
heated at 50 8C and stirring was maintained for 96 h. After
cooling, the reaction mixture was concentrated under
reduced pressure to afford the crude b-hydroxy ester as a
brown oil. 1H NMR analysis showed a 72% conversion. The
crude product was purified by silica gel column chromato-
graphy using cyclohexane–ethyl acetate (9:1) as eluent to
give the b-hydroxy ester (500 mg, 55% yield) as a slightly
yellow oil. GC analysis showed a 2:1 mixture of (2R,3R):
(2S,3R) diastereoisomers (tR (2R,3R) 21.8, tR (2S,3R) 21.9).
1H NMR (CDCl3, 300 MHz, 24 8C): d 5.01 (br s, 1H, OH),
4.14 (q, JZ7.1 Hz, 2H), 3.99 (app t, JZ4.9 Hz, 1H), 3.95
4.2.2. Ethyl (2R,3S,4S)-3-(N-tert-butoxycarbonyl-20-pyr-
rolidinyl)-3-hydroxy-2-methyl-propanoate Boc-(2R,3S)-
3. Tri-ethylamine (1.2 mmol, 1.2 equiv, 0.17 mL) and di-
tert-butyl dicarbonate (1.05 mmol, 1.05 equiv, 229 mg)
were added to a stirred solution of ethyl (2R,3S,4S)-3-(20-
pyrrolidinyl)-3-hydroxy-2-methyl- propanoate hydrochloride
(1 mmol, 238 mg) in ethanol (2 mL). After being stirred
overnight at room temperature, the mixture was concen-
trated under reduced pressure. Tetrahydrofuran (10 mL)
was added to the residue and the mixture was stirred for
15 min. The resulting precipitate was removed by filtration
on a celite pad and washed with tetrahydrofuran. The filtrate
was concentrated under reduced pressure and the residue

C. Mordant et al. / Tetrahedron 60 (2004) 9715–9723
9721
(m, 1H), 3.50 (m, 1H), 3.25 (m, 1H), 2.54 (m, 1H), 1.71–
1.97 (m, 4H), 1.46 (s, 9H), 1.25(m, 6H); 13C NMR (CDCl3,
75 MHz, 24 8C): d broad peaks (conformers) 175.6, 155
(br), 79.9 (br), 73.8 (br), 60.5, 59.4, 47.3, 42.1, 28.5, 25.2,
24.3, 14.6, 14.1; MS (DCI, NH3): m/z 302 (100%, [MC
H]C), 263 (4%, [MKC4H8CNH4]C), 246 (13%, [MK
C4H8CH]C); [a]2D1ZK47.7 (cZ1.0, CHCl3).
4.2.7. Ethyl (2R,3R,4S)-3-(N-tert-butoxycarbonyl-20-
pyrrolidinyl)-3-methoxy-2-methyl-propanoate (2R,3R)-4.
A solution of ethyl (2R,3R,4S)-3-(N-tert-butoxycarbonyl-20-
pyrrolidinyl)-3-hydroxy-2-methyl-propanoate Boc-(2R,3R)-3
(2 mmol, 602 mg) in tetrahydrofuran (6 mL) was added to a
solution of LHMDS (1 M in THF, 2.8 mmol, 1.4 equiv,
2.8 mL) in HMPA (3.2 mmol, 1.6 equiv, 557 mL) and
tetrahydrofuran (3.2 mL) at K78 8C. The stirring was
maintained for 25 min at K78 8C before the addition at
K20 8C of MeOTf (6.0 mmol, 3.0 equiv, 679 mL). The
mixture was stirred at K20 8C for an additional 15 min. The
reaction was then quenched with saturated aqueous
ammonium chloride. After extraction with ethyl acetate,
the organic layer was washed with saturated aqueous
sodium chloride, dried over sodium sulfate and concentrated
under reduced pressure. The residue was purified by silica
gel column chromatography using petroleum ether–ethyl
acetate (9:1) as eluent to give the N-Boc b-methoxy ester
4.2.5. Ethyl (2R,3S,4S)-3-(N-tert-butoxycarbonyl-20-
pyrrolidinyl)-3-methoxy-2-methyl-propanoate (2R,3S)-
4. To a solution of ethyl (2R,3S,4S)-3-(N-tert-butoxycarbonyl-
20-pyrrolidinyl)-3-hydroxy-2-methyl-propanoate Boc-(2R,3S)-
3(0.5 mmol, 150 mg) in dichloromethane (3 mL) was added
1,8-bis(dimethyl-amino)-naphtalene "proton sponge"
(1 mmol, 2 equiv, 214 mg) followed by trimethyloxonium
tetrafluoroborate (1.1 mmol, 2.2 equiv, 163 mg). The mix-
ture was then stirred at room temperature for 24 h before
a further addition of proton sponge (0.5 mmol, 1 equiv,
107 mg) and trimethyloxonium tetrafluoroborate (0.55 mmol,
1.1 equiv, 81 mg). The stirring was maintained for an
additional 22 h before being filtered on a celite pad. The
filtrate was washed successively with saturated aqueous
citric acid and water, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was
purified by silica gel column chromatography using
petroleum ether–ethyl acetate (9:1) as eluent to give the
N-Boc b-methoxy ester (80 mg, 51% yield) as a colorless
1
(282 mg, 45% yield) as a colorless oil. H NMR (CDCl3,
300 MHz, 24 8C): d 4.14 (br q, 2H, JZ7.1 Hz), 3.70–3.95
(m, 2H), 3.53 (m, 1H), 3.41 (s, 3H), 3.22 (m, 1H), 2.47 (m,
1H), 1.80–2.05 (m, 3H), 1.65–1.77 (m, 1H), 1.49 (m, 9H),
1.25 (t, JZ7.1 Hz, 3H), 1.23 (d, JZ7.2 Hz, 3H); 13C NMR
(CDCl3, 75 MHz, 24 8C): d 174.6, 154.4 (br), 83.4, 79.6
(br), 61.0 (br), 60.4, 59.6 (br), 46.6 (br), 43.1, 28.5, 26.2 (br),
24.0 (br), 14.2, 13.6; MS (DCI, NH3): m/z 333 (7%, [MC
NH4]C), 316 (100%, [MCH]C), 277 (7%, [MKC4H8C
NH4]C), 260 (34%, [MKC4H8CH]C); [a]2D1ZK50.8 (cZ
1.2, CHCl3).
1
oil. H NMR (CDCl3, 300 MHz, 24 8C): d 4.05–4.20 (m,
3H), 3.67 (m, 1H), 3.25–3.50 (m, 2H), 3.45 (s, 3H), 2.64 (dq,
JZ2.6, 7.0 Hz, 1H), 1.75–2.02 (m, 4H), 1.47 (m, 9H), 1.26
(t, JZ7.1 Hz, 3H), 1.13 (br d, JZ7.0 Hz, 3H); 13C NMR
(CDCl3, 100 MHz, 24 8C): d broad peaks (conformers)
175.1, 154.5 (br), 84.0 (br), 79.2 (br), 60.2, 59.0 (br), 57.1,
47.5 (br), 42.8, 28.5, 29.6, 27.2, 14.6, 14.2; MS (DCI, NH3):
m/z 333 (3%, [MCNH4]C), 316 (100%, [MCH]C), 277
(7%, [MKC4H8CNH4]C), 260 (21%, [MKC4H8CH]C);
[a]2D1ZK51.2 (cZ0.16, CHCl3).
4.2.8. (2R,3S,4S)-hexahydro-3-methoxy-2-methyl-1-
pyrrolizinone 5. To an ice-cooled solution of ethyl
(2R,3S,4S)-3-(N-tert-butoxycarbonyl-20-pyrrolidinyl)-3-
methoxy-2-methyl-propanoate (0.16 mmol, 50 mg) in
dichloromethane (3 mL) was added trifluoroacetic acid
(500 mL). After 15 min at 0 8C, the mixture was stirred 1 h at
room temperature. The solvant was thoroughly evaporated
under vacuum. 3 mL of a mixture ethanol–water (1:2) was
added to the residue and the resulting solution was cooled to
0 8C. Potassium carbonate (0.48 mmol, 3 equiv, 66 mg) was
added portionwise and after 15 min at 0 8C, the stirring was
maintained for 4 h at room temperature. The reaction
mixture was then diluted and extracted with dichloro-
methane (3!25 mL) after the addition of saturated aqueous
sodium chloride (10 mL). The combined organic layers
were dried over sodium sulfate and concentrated under
reduced pressure to give the bicyclic lactam as a slightly
yellow oil which crystallized upon standing. 1H NMR
(CDCl3, 400 MHz, 24 8C): d 3.86 (m, 1H), 3.75 (app t, JZ
4.4 Hz, 1H), 3.45 (m, 1H), 3.35 (s, 3H), 3.03 (m, 1H) 2.82
(m, 1H), 1.95–2.08 (m, 2H), 1.74–1.85 (m, 2H), 1.14 (d, JZ
7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz, 24 8C): d 175.0,
81.2, 64.3, 59.7, 46.1, 41.2, 26.8, 23.7, 8.6.
4.2.6. Ethyl (2S,3S,4S)-3-(N-tert-butoxycarbonyl-20-
pyrrolidinyl)-3-methoxy-2-methyl-propanoate (2S,3S)-
4. To a solution of ethyl (2S,3S,4S)-3-(N-tert-butoxycarbonyl-
20-pyrrolidinyl)-3-hydroxy-2-methyl-propanoate Boc-(2S,3S)-3
(1.20 mmol, 360 mg) in dichloromethane (5 mL) was added
1,8-bis(dimethyl-amino)-naphtalene ‘proton sponge’
(2.40 mmol, 2.0 equiv, 515 mg) followed by trimethyl-
oxonium tetrafluoroborate (2.64 mmol, 2.2 equiv, 391 mg).
The mixture was then stirred at room temperature for 24 h
and then filtered over a celite pad and washed with
dichloromethane. The filtrate was washed successively
with saturated aqueous citric acid and water, dried over
magnesium sulfate and concentrated under reduced pres-
sure. The residue was purified by silica gel column
chromatography using cyclohexane–ethyl acetate (9:1) as
eluent to give the N-Boc b-methoxy ester (257 mg, 68%
yield) as a slightly yellow oil. 1H NMR (CDCl3, 300 MHz,
24 8C): d 4.00–4.20 (m, 3H), 3.72–3.88 (m, 1H), 3.35–3.50
(m, 4H), 3.20 (m, 1H), 2.48 (m, 1H), 1.58–1.95 (m, 4H),
1.47 (m, 9H), 1.25 (t, JZ7.1 Hz, 3H), 1.13 (d, JZ6.9 Hz,
3H); 13C NMR (CDCl3, 75 MHz, 24 8C): d 174.8, 154.1
(br), 82.1, 79.4, 60.4, 59.6, 58.0, 47.3 (br), 41.0, 28.4, 26.9
(br), 23.9, 14.2, 13.9; MS (DCI, NH3): m/z 316 (100%,
[MCH]C), 277 (2%, [MKC4H8CNH4]C); 260 (21%,
[MKC4H8CH]C); [a]D21ZK64.0 (cZ0.25, CHCl3).
4.2.9. (2R,3S,4S)-3-(N-tert-butoxycarbonyl-20-pyrrol-
idinyl)-3-methoxy-2-methylpropanoic acid Boc-(2R,3S)-
iso-dolaproine. To an ice-cooled solution of ethyl
(2R,3S,4S)-3-(N-tert-butoxycarbonyl-20-pyrrolidinyl)-3-
methoxy-2-methyl-propanoate (0.6 mmol, 190 mg) in etha-
nol (5 mL) was added 1 N aqueous sodium hydroxide
(1.80 mmol, 3 equiv, 1.8 mL). The mixture was stirred at
0 8C for 30 min then room temperature for 21 h. After
further addition of 1 N aqueous sodium hydroxide

9722
C. Mordant et al. / Tetrahedron 60 (2004) 9715–9723
(2.43 mmol, 3 equiv, 2.43 mL), the mixture was stirred
overnight at 30 8C. The resulting solution was acidified to
pH 4 by adding 1 N aqueous hydrochloric acid and then
extracted with a mixture ethyl acetate–toluene (1:1) (3!
30 mL). The organic extracts were washed with 1 M
aqueous potassium hydrogen sulfate (20 mL) and saturated
aqueous sodium chloride (30 mL), dried over sodium sulfate
and concentrated under reduced pressure to give the crude
product as a mixture of the desired (2R,3S)-Boc-iso-
dolaproine and the isomerized stereoisomer (2S,3S)-Boc-
aqueous hydrochloric acid and then extracted with ethyl
acetate followed by dichloromethane. The combined
organic layers were dried over sodium sulfate and
concentrated under reduced pressure to give the desired
1
product as a colorless viscous oil (132 mg, 59% yield). H
NMR (CDCl3, 400 MHz, 24 8C): d 4.11 (m, 1H), 3.62 (m,
1H, 3.47 (s, 3H), 3.44–3.51 (m, 1H), 3.06 (m, 1H), 2.65 (m,
1H), 1.89–1.96 (m, 2H), 1.76–1.88 (m, 2H), 1.47 (s, 9H),
1.26 (d, JZ6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz,
24 8C): d 179.8 (br), 154.3 (br), 83.0, 79.9, 61.2, 59.4, 46.6,
42.8, 28.5, 26.1, 24.0, 13.5; MS (DCI, NH3): m/z 305 (4%,
[MCNH4]C), 288 (100%, [MCH]C), 249 (14%, [MK
C4H8CNH4]C), 232 (30%, [MKC4H8CH]C); HRMS
(DCIC): m/z calcd for C14H26O5N: 288.1811, found:
288.1804; [a]2D4ZK60.0 (cZ1.03, MeOH).
1
iso-dolaproine. H NMR (CDCl3, 300 MHz, 24 8C): d 4.11
(m, 1H), 3.50–3.72 (m, 1H), 3.47 (s, 3H), 3.30 (m, 1H), 2.68
(m, 1H), 1.80–1.97 (m, 2H), 1.60–1.72 (m, 2H), 1.47 (s,
9H), 1.24 (d, JZ6.7 Hz, 3H); 13C NMR (CDCl3, 75 MHz,
24 8C): d 178.3, 155.0 (br), 83.8, 79.3 (br), 60.0, 57.4, 47.0
(br), 42.0, 28.4, 27.1 (br), 23.5 (br), 15.4; MS (DCI, NH3):
m/z 288 (100%, [MCH]C), 249 (11%, [MKC4H8C
NH4]C), 232 (32%, [MKC4H8CH]C); HRMS (DCIC):
m/z calcd for C14H26O5N: 288.1811, found: 288.1809;
[a]2D4ZK37.0 (cZ0.6, CHCl3).
Acknowledgements
We thank Dr. R. Schmid and Dr. M. Scalone (Hoffmann-La
Roche) for samples 0of (R)- and (S)-MeO-BIPHEPZ(S)-(K)-
6,60-dimethoxy-2,2 -bis(diphenylphosphino)-1,10-biphenyl.
A fellowship from C.N.R.S./D.G.A. (C. Mordant) is grate-
fully acknowledged. Dr. S. Reymond is grateful to C.N.R.S.
for a post-doctoral fellowship.
4.2.10. (2S,3S,4S)-3-(N-tert-butoxycarbonyl-20-pyrrol-
idinyl)-3-methoxy-2-methylpropanoic acid Boc-(2S,3S)-
iso-dolaproine. To an ice-cooled solution of ethyl
(2S,3S,4S)-3-(N-tert-butoxycarbonyl-20-pyrrolidinyl)-3-
methoxy-2-methyl-propanoate (0.81 mmol, 257 mg) in
ethanol (5 mL) was added 1 N aqueous sodium hydroxyde
(2.43 mmol, 3 equiv, 2.43 mL). The mixture was stirred at
0 8C for 30 min then heated at 30 8C overnight. After further
addition of 1 N aqueous sodium hydroxide (2.43 mmol,
3 equiv, 2.43 mL), the mixture was stirred at 30 8C for an
additional 6 h. The resulting solution was acidified to pH 4
by adding 1 N aqueous hydrochloric acid and then extracted
with a mixture ethyl acetate–toluene (1:1) (3!30 mL). The
organic extracts were washed with 1 M aqueous potassium
hydrogen sulfate (20 mL) and saturated aqueous sodium
chloride (30 mL), dried over sodium sulfate and concen-
trated under reduced pressure to give the crude product. The
residue was purified by silica gel column chromatography
using cyclohexane–ethyl acetate (7:3) as eluent to give the
desired Boc-iso-dolaproine as an amorphous white powder
(170 mg, 73% yield). 1H NMR (CDCl3, 400 MHz, 54 8C): d
4.11 (m, 1H), 3.62 (m, 1H), 3.47 (s, 3H), 3.44–3.51 (m, 1H),
3.06 (m, 1H), 2.65 (m, 1H), 1.89–1.96 (m, 2H), 1.76–1.88
(m, 2H), 1.47 (s, 9H), 1.26 (d, JZ6.9 Hz, 3H); 13C NMR
(CDCl3, 75 MHz, 24 8C): d 175.9, 157.2 (br), 86.5, 81.0,
61.8, 58.8 (br), 48.3 (br), 44.2, 28.3, 26.9, 23.8, 13.9; MS
(DCI, NH3): m/z 288 (100%, [MCH]C), 249 (10%, [MK
C4H8CNH4]C), 232 (16%, [MKC4H8CH]C); calcd for
C14H25NO5: C 58.52, H 8.77, N 4.87; found C 58.85, H
8.77, N 4.71; [a]D24ZK57.0 (cZ0.75, CHCl3).
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