Enantioselective synthesis of cyclopropane aminoalcohols containing quaternary stereogenic centers

Article abstract of DOI:10.1016/S0957-4166(99)00463-2

Some title compounds have been synthesized in enantiomerically pure form starting from D- or L-glyceraldehyde as chiral precursors. A new synthesis of (+)-(Z)-methanohomoserine, one of the key intermediates employed, is also described. The target molecule

Full text of DOI:10.1016/S0957-4166(99)00463-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4245–4260
Enantioselective synthesis of cyclopropane aminoalcohols
containing quaternary stereogenic centers
Joan Rifé and Rosa M. Ortuño ∗
Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
Received 18 October 1999; accepted 20 October 1999
Abstract
Some title compounds have been synthesized in enantiomerically pure form starting from D- or L-glyceraldehyde
as chiral precursors. A new synthesis of (+)-(Z)-methanohomoserine, one of the key intermediates employed, is
also described. The target molecules are densely functionalized. Thus, in addition to one or two hydroxyl groups on
a side-chain, an amino group is attached to a quaternary carbon of the cyclopropane ring, and the fourth substituent
of such a stereogenic center contains a halogen atom, an alkyl group, or an alcohol, thioether or ester function.
Some of these compounds are useful precursors in the synthesis of new cyclopropane nucleosides. © 1999 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Compounds containing an amine function and one or more hydroxyl groups are of great interest due
either to their intrinsic properties or for use as powerful synthetic intermediates. The 1,2-aminoalcohol
function is present in the widely consumed drug propanolol, a β-blocking agent, and in the structure of
serine protease inhibitors.1 Aminoalcohols bearing a cyclic moiety in their structure have been described
as displaying relevant activities. Thus, for instance, chiral pyrrolidines with amino and hydroxymethyl
groups inhibit α-glycosidases.2 Six-membered ring molecules containing 1,2- and 1,3-aminoalcohol
functions have been used for phosphodiester recognition allowing aminoglycoside antibiotics with
activity against HIV to be designed.3 Moreover, 1,2-, 1,3-, and, less frequently, 1,4-aminoalcohols
are useful as chiral ligands for catalysts4 or as chiral auxiliaries in asymmetric synthesis.5 Some
representantives of these different types of compounds are shown in Fig. 1. Finally, aminoalcohol
molecules containing a cyclopropane ring have been employed as key intermediates in the synthesis
of carbocyclic nucleosides.6
∗
Corresponding author. E-mail: rosa.ortuno@uab.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00463-2

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Figure 1.
In this paper we describe stereoselective synthetic routes to several types of enantiomerically pure
cyclopropane aminoalcohols 1–4 and some conveniently protected derivatives (Fig. 2). All these com-
pounds contain one or two hydroxyl groups and one amino group in 1,2- or 1,3-relative positions.
Figure 2.
Moreover, these molecules contain a quaternary carbon in the cyclopropane ring linked to an amino
group and to a substituent containing different chemical functions. These structures are, therefore,
densely functionalized and highly sterically constrained. gem-Disubstitution in conformationally re-
stricted cyclopropane derivatives is a structural feature present in NMDA receptor antagonists related to
Milnacipran®.7 Furthermore, some gem-disubstituted cyclopropane carbocyclic nucleosides have been
recently revealed to be potent anti-HIV agents.8
The syntheses achieved in this work are highly efficient and versatile, since divergent pathways from
common precursors lead to different types of products. Some of these compounds have been prepared in
both enantiomeric forms starting, alternatively, from (+)- and (−)-(Z)-methanohomoserine derivatives 5
and 6, respectively. A new synthesis of free amino acid (+)-14 (Scheme 1) is reported herein starting from
L-glyceraldehyde as the chiral precursor. (Z)-Methanohomoserine is a useful precursor in the synthesis of
other cyclopropane amino acids,9 and it is also an analogue of the precursor to the plant growth hormone
ethylene, being processed by the in vivo ethylene-forming enzyme (EFE) to produce allylic alcohol.10 In
addition to the free aminoalcohols, some partially protected derivatives have also been prepared, these
products being convenient synthetic building blocks.
2. Results and discussion
The main targets and precursors are shown in Fig. 2. Aminoalcohol 1 as well as its N-Boc derivative
15 (Scheme 1) have been obtained from protected (+)-(Z)-methanohomoserine 5. This product and

J. Rifé, R. M. Ortuño / Tetrahedron: Asymmetry 10 (1999) 4245–4260
4247
Scheme 1.
amino acid 14 have been synthesized from L-glyceraldehyde prepared, in turn, from L-gulonolactone.11
The enantiomeric aminodiol 2, aminoalcohol 3, and some derivatives have been synthesized from 6.
Finally, the latter compound and aminoalcohols 4 result from the common precursor 7 obtained from
D-glyceraldehyde.
2.1. Synthesis of aminodiol 1 and (+)-(Z)-methanohomoserine 14
The synthetic pathway is depicted in Scheme 1, the key common intermediate being compound 5 that,
after deprotection, affords free amino acid 14 and, in addition, is susceptible of reduction to diol 15 which
is the immediate precursor of aminodiol 1.
Compound 5 was prepared by using the same methodology earlier employed in our laboratory for
the synthesis of its enantiomer from D-glyceraldehyde.9 Actually, L-glyceraldehyde was condensed with
phosphonate 8,9 in the presence of potassium tert-butoxide, affording aminopentenoate 9 as the major
isomer (85% yield). Cyclopropanation of the double bond was accomplished by highly stereoselective
1,3-dipolar cycloaddition of diazomethane to 9 followed by photolysis of the resultant pyrazoline. In
this way, cyclopropane 10 was obtained in 87% yield for the two steps. Hydrolysis of the acetonide
and subsequent oxidative cleavage of diol 11 gave aldehyde 12 which was reduced to alcohol 5 with
NaBH4. The free amino acid 14 was prepared by saponification of the methyl ester with methanolic
sodium hydroxide followed by hydrolysis of the carbamate with 1 M HCl and subsequent treatment
with propylene oxide as acid captor. (+)-(Z)-Methanohomoserine was thus obtained in 50% overall yield
from L-glyceraldehyde. It is noteworthy that this synthetic sequence competes advantageously with other
methods previously described for the preparation of this amino acid.10
Following a divergent route, compound 5 was reduced by LiBH4 giving diol 15 in 88% yield which was

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deprotected by hydrolysis of the carbamate with 1 M HCl followed by treatment with sodium bicarbonate.
Aminodiol 1 was thus obtained in 43% overall yield from L-glyceraldehyde.
2.2. Synthesis of aminoalcohols 2, 3, and some derivatives
The starting materials were compounds 7a,b (Scheme 2) prepared from D-glyceraldehyde by using the
same protocol explained above for the synthesis of 10.
Scheme 2.
Hydrolysis of the acetonide followed by diol oxidation afforded aldehydes 16a,b which were reduced
to alcohols 6a,b, respectively.9 Compound 6b is, in turn, the precursor of aminoalcohol 3. Thus, the ester
group in 6b was reduced with DIBAL affording diol 17b in 77% yield. Diols 17a,b were also obtained

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4249
from 6a,b in 95% when LiBH4 was used as reducing agent. Nevertheless, the yield was improved and
the synthetic sequence shortened when one-pot reduction of both aldehyde and ester groups in 16a was
achieved with LiBH4, obtaining 17a in 95% yield. Hydrolysis of the N-Boc group by the usual method
gave free aminodiol 2 in 66% yield from 7a (49% yield from D-glyceraldehyde).
Derivatives 18–20 were also prepared in order to dispose of selectively protected products. Thus,
reaction of 17a with 2.5 equivalents of benzoyl chloride in the presence of pyridine, at room temperature
for 16 h, afforded 18 that led to 19 after hydrolysis with HCl. Treatment of 19 with sodium bicarbonate
liberated the amine which was an unstable oil being, therefore, characterized as the hydrochloride. In
addition, diol 17a was chemoselectively monoprotected by reaction with 1 equivalent of benzoyl chloride
at room temperature for 3 h to afford 20 in 88% yield, thus showing the different reactivity of the two
hydroxyl groups.
The protected (−)-(Z)-methanohomoserine derivative 6b was the key intermediate in the synthesis
of aminoalcohol 3. The required chemical transformations involve reduction of the methyl ester to
methyl group and deprotection of the amine. Previously, the hydroxyl group in 6 was protected as tert-
butyldiphenylsilyl ether in almost quantitative yield. Then, ester 21 was reduced with LiBH4 and the
resultant alcohol 22 was converted into mesylate 23 under standard conditions with 93% yield for the two
steps. The instability of this compound under the usual purification conditions forced the use of the crude
product in subsequent transformations. This fact, as well as the low reactivity observed for 23, could
account for the unsatisfactory results obtained when it was reacted with several nucleophiles, and for
the modest yield (50%) in its reduction to furnish 24. Compound 24 is orthogonally protected and leads,
alternatively, to products 25 and 26 in which only the amino or the hydroxyl group is free, conferring on
these molecules the ability to be selectively elaborated in further transformations. Thus, hydrogenation
under two atmospheres pressure, in the presence of palladium hydroxide as catalyst, gave amine 25. On
the other hand, treatment of 24 with n-Bu4NF afforded alcohol 26. Finally, reductive carbamate-removal
led to the free aminodiol 3.
2.3. Synthesis of aminodiols 33–36
Compound 7a was the precursor of these products (Scheme 3). The synthetic goal involved specific
chemical transformation of the ester group into the desired substituents, while keeping the amine and the
diol functions conveniently protected.
Methyl ester in 7a was reduced with LiBH4 in nearly quantitative yield affording alcohol 27 which
was reacted with mesyl chloride to produce mesylate 28. Alternatively, reaction between 27 and benzoyl
chloride gave benzoate 32 which, after hydrolysis, yielded diol 36. Mesylate 28 was the common
precursor to the target diols 33–35 through acetonides 29–31. Thus, 28 afforded compound 29 by
reduction with LiBH4. In turn, thioether 30 was obtained when mesylate 28 was reacted with sodium
thiomethoxide at room temperature for 20 h. On the other hand, the reaction between 28 and lithium
bromide in THF was performed in order to prepare 31, a mixture of this product along with diol 35
being unexpectedly obtained, even when both the solvent and the reactant were previously dried and
experiments were run in anhydrous conditions. The mixture was treated with 5% HCl to afford compound
35 in 64% yield for the two steps.
Moreover, we tried to explore the usefulness of these diols to prepare other related compounds such
as 1,2-amino acids and 1,3-aminoalcohols. However, the oxidative cleavage of the diol function by using
sodium or tetra-n-butylammonium periodate, or ruthenium oxide, was not successful, always yielding
products for which spectroscopic data revealed the absence of the cyclopropane ring and of the expected
carbonyl function. The product resulting from the oxidation of 36 with sodium periodate could be isolated

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Scheme 3. Reagents: (a) LiBH4; (b) NaSMe; (c) LiBr
1
and purified yielding a solid, mp 93–95°C, [α]D=0. Its IR and H and 13C NMR spectroscopic data
as well as the microanalysis were in accordance with the dihydrofuran structure 37 (Scheme 3). We
propose the arrangement to take place at the aldehyde level, this intermediate evolving rapidly towards
a zwitterionic open-chain species in which the carbocation would be stabilized by resonance with the
nitrogen lone-pair. Attack of the enolate oxygen to the charged carbon led to the five-membered ring
with concomitant racemization. Similar processes must occur in the attempted oxidation of substrates
33–35.
3. Conclusions
Versatile synthetic strategies, through simple and efficient protocols, have been used for the preparation
of a variety of cyclopropane aminoalcohols from common precursors. Since the starting materials
are available in both enantiomeric forms, by using alternatively D- or L-glyceraldehyde as sources of
chirality, the two enantiomeric series of products are available.
Some of the synthesized products are being evaluated for their possible biological activities and others
have been used as key intermediates in the synthesis of novel cyclopropane carbocyclic nucleosides.12
4. Experimental
Flash column chromatography was carried out on silica gel (240–400 mesh) unless otherwise stated.
Baker-silica® (40 µm) was used for the chromatography of acid-sensitive products. Melting points were
1
determined on a hot stage and are uncorrected. H NMR and 13C NMR spectra were recorded at 250

J. Rifé, R. M. Ortuño / Tetrahedron: Asymmetry 10 (1999) 4245–4260
4251
and 62.5 MHz, respectively. Electron-impact mass spectra were recorded at 70 eV. Compounds 5, 9–14
were prepared following the same procedures as those previously reported for their enantiomers, whose
spectroscopic data and physical constants, except specific rotation, were in good accord with the data
obtained for 5, 9–14.9 Therefore, only specific rotation and microanalysis values, for the new compounds,
are given herein for these products.
4.1. Methyl (R)-Z-2-N-tert-butoxycarbonylamino-3-(20 ,20-dimethyl-10,30-dioxolan-4-yl)-
2-propenoate 9
Yield: 800 mg (53%). [α]D=+10.9 (c 4.40, CHCl3) (lit.9 [α]D=−10.8 (c 2.10, CHCl3) for the
enantiomer). Anal. calcd for C14H23O6N: C, 55.80%; H, 7.69%; N: 4.65%. Found: C: 55.72%; H, 7.81%;
N, 4.57%.
4.2. Methyl (1R,2S,40R)-(+)-1-N-tert-butoxycarbonylamino-2-(20 ,20-dimethyl-10,30-dioxolan-40-yl)-
cyclopropanecarboxylate 10
Yield: 640 mg (87% for the two steps). [α]D=+69.0 (c 1.10, CHCl3) (lit.9 [α]D=−68.9 (c 1.03, CHCl3)
for the enantiomer). Anal. calcd for C15H25NO6: C, 57.13%; H, 7.99%; N, 4.44%. Found: C, 57.05%; H,
7.74%; N, 4.41%.
4.3. Methyl (1R,2S,10R)-(+)-1-N-tert-butoxycarbonylamino-2-(10 ,20-dihydroxyethyl)cyclopropane-
carboxylate 11
Yield: 476 mg (95%). [α]D=+54.3 (c 1.50, MeOH) (lit.9 [α]D=−54.6 (c 1.08, MeOH) for the
enantiomer). Anal. calcd for C12H21O6N: C, 52.35%; H, 7.69%; N, 5.09%. Found: C, 52.27%; H, 7.58%;
N, 4.72%.
4.4. Methyl (1R,2S)-(+)-1-N-tert-butoxycarbonylamino-2-formylcyclopropanecarboxylate 12
Yield: 341 mg (85% yield). [α]D=+189.0 (c 1.00, CHCl3) (lit.9 [α]D=−190.7 (c 0.96, CHCl3) for the
enantiomer). Anal. calcd for C11H17O5N: C, 54.31%; H, 7.04%; N, 5.76%. Found: C, 54.14%; H, 6.73%;
N, 5.85%.
4.5. Methyl (1R,2S)-(+)-1-N-tert-butoxycarbonylamino-2-hydroxymethylcyclopropanecarboxylate 5
Yield: 316 mg (92%). [α]D=+33.9 (c 0.80, MeOH) (lit.9 [α]D=−34.1 (c 0.67, MeOH) for the
enantiomer).
4.6. (1R,2S)-(+)-1-N-tert-Butoxycarbonylamino-2-hydroxymethylcyclopropanecarboxylic acid 13
Yield: 127 mg (91%). [α]D=+38.0 (c 1.00, MeOH) (lit.10 [α]D=+37.8 (c 0.45, MeOH)).
4.7. (+)-(Z)-Methanohomoserine 14
Yield: 67 mg (100%). [α]D=+74.7 (c 1.05, H2O) (lit.10 [α]D=+73.8 (c 0.48, H2O)).

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4.8. (1R,2S)-(+)-1-N-tert-Butoxycarbonylamino-1,2-bis(hydroxymethyl)cyclopropane 15
A 2 M solution of LiBH4 in THF (2.2 mL, 5.7 mmol) was slowly added to a solution of ester 5 (175 mg,
0.7 mmol) in anhydrous THF (5 mL) at −78°C. The mixture was allowed to reach room temperature and
then stirred for 18 h. The excess hydride was destroyed by slow addition of methanol, and solvents were
removed at reduced pressure. The residue was dissolved in water and extracted with dichloromethane
(4×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was evaporated. The
residue was chromatographed (ethyl acetate) to afford diol 15 as a colorless oil. Yield: 137 mg (88%).
[α]D=+18.7 (c 0.80, CHCl3). IR (film) 3600–3100, 1685 cm−1. 1H NMR (CDCl3) 0.42 (t, H3, J=J0=5.8
00
Hz), 0.90 (dd, H3, J=9.5 Hz, J0=5.8 Hz), 1.41–1.50 (complex absorption, C(CH3)3+H2), 3.12 (t, H1 a
,
0
0
0
00
J=J =10.9 Hz), 3.36 (d, H1 , J=11.6 Hz), 3.53 (d, H1 , J=11.6 Hz), 3.93 (m, H1 b), 5.31 (broad s, NH).
13C NMR (methanol-d4) 14.80 (C3), 25.36 (C2), 28.65 (C(CH3)3), 39.78 (C1), 62.78 (CH2O), 67.31
(CH2O), 80.74 (C(CH3)3), 159.57 (CO). Anal. calcd for C10H19NO4: C, 55.28%; H, 8.81%; N, 6.45%.
Found: C, 55.20%; H, 8.83%; N, 6.28%.
4.9. (1R,2S)-(+)-1-Amino-1,2-bis(hydroxymethyl)cyclopropane 1
A solution of 15 (120 mg, 0.5 mmol) and 1 M HCl (5 mL) in THF (5 mL) was stirred at room
temperature for 8 h. Then saturated aqueous sodium bicarbonate was added to reach neutral pH and
THF was removed. The aqueous solution was extracted with ethyl acetate (8×5 mL) and the combined
organic extracts were dried over MgSO4. The solvent was removed at reduced pressure and the residue
was purified by elution through a C18-reverse phase cartridge using 1:1 methanol:water as eluent. In
this way, pure aminodiol 1 was obtained as a colorless oil. Yield: 58 mg (90%). [α]D=+16.2 (c 1.15,
MeOH). IR (film): 3500–3000 cm−1. 1H NMR (methanol-d4) 0.96–1.09 (complex absorption, H3a+H3b),
0
0
00
1.27–1.41 (m, H2), 3.57 (d, H1 a, J=12.2 Hz), 3.66 (d, H1 b, J=12.2 Hz), 3.78 (dd, H1 a, J=11.7 Hz,
J0=5.8 Hz), 4.00 (dd, H1 b, J=11.7 Hz, J0=4.0 Hz). 13C NMR (methanol-d4) 11.33 (C3), 22.27 (C2),
00
40.97 (C1), 59.31 (CH2O), 65.90 (CH2O). Anal. calcd for C5H11NO2: C, 51.26%; H, 9.46%; N, 11.96%,
Found: C, 51.42%; H, 9.28%; N, 11.74%.
4.10. (1S,2R)-(−)-1-N-tert-Butoxycarbonylamino-1,2-bis(hydroxymethyl)cyclopropane 17a
This product is a colorless oil that was synthesized alternatively by reduction of alcohol 6a or aldehyde
16a with LiBH4, following a similar protocol to that described above for the synthesis of 15 (yield 631
mg, 95%). Spectroscopic data are in good agreement with those of its enantiomer 15. [α]D=−18.9 (c 1.05,
CHCl3). Anal. calcd for C10H19NO4: C, 55.28%; H, 8.81%; N, 6.45%. Found: C, 54.99%; H, 8.91%; N,
6.74%.
4.11. (1S,2R)-(+)-1-N-Benzyloxycarbonylamino-1,2-bis(hydroxymethyl)cyclopropane 17b
This diol is a colorless oil which was synthesized from ester 6b by the standard procedure described
1
above (yield: 592 mg, 94%). [α]D=+6.4 (c 2.20, CHCl3). IR (film) 3650–3100, 1699 cm−1. H NMR
0
0
00
(CDCl3) 0.46 (t, H3, J=J =5.8 Hz), 0.87 (dd, H3, J=9.5 Hz, J =5.8 Hz), 1.33 (m, H2), 3.09 (t, H1 ,
0
0
0
J=J =10.9 Hz), 3.46 (d, H1 , J=11.7 Hz), 3.54 (d, H1 , J=11.7 Hz), 3.85 (complex absorption, 3H), 5.04
(s, CH2Ph), 6.07 (broad s, NH), 7.28 (s, 5H). 13C NMR (CDCl3) 14.54 (C3), 25.27 (C2), 39.24 (C1),
61.70 (CH2O), 67.18 (CH2Ph), 68.06 (CH2O), 128.07, 128.23, 128.49, 135.84 (Cipso), 158.37 (CO).
Anal. calcd for C13H17NO4: C, 62.14%; H, 6.82%; N: 5.57%. Found: C, 62.15%; H, 6.98%; N, 5.42%.

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4.12. (1S,2R)-(−)-1-Amino-1,2-bis(hydroxymethyl)cyclopropane 2
A mixture of 17a (90 mg), 5 mL of 1 M HCl and THF (5 mL) was stirred at room temperature for 8
h. Then saturated aqueous sodium bicarbonate was added to reach neutral pH. THF was removed, and
the aqueous solution was extracted with ethyl acetate (8×5 mL). The combined organic extracts were
dried over MgSO4 and the solvent was evaporated at reduced pressure. Crude aminodiol 2 was purified
by elution through a C18-reverse phase cartridge using 1:1 methanol:water as eluent to afford pure 2 as a
colorless oil (yield: 39 mg, 81%). Spectroscopic data are in good accordance with those described above
for its enantiomer 1. [α]D=−16.4 (c 1.05, MeOH). Anal. calcd for C5H11NO2: C, 51.26%; H, 9.46%; N,
11.96. Found: C, 51.54%; H, 9.68%; N, 11.69.
4.13. (1S,2R)-(+)-1,2-bis(Benzoyloxymethyl)-1-N-(tert-butoxycarbonylamino)cyclopropane 18
To an ice-cooled solution of 17a (232 mg, 1.1 mmol) in dry dichloromethane (12 mL) anhydrous
pyridine (530 µL, 6.5 mmol) and benzoyl chloride (320 µL, 2.7 mmol) was added under a nitrogen
atmosphere. The mixture was stirred at room temperature for 16 h, then dichloromethane (5 mL) was
added and the solution was subsequently washed with 5% HCl (3×8 mL) and saturated aqueous sodium
bicarbonate (2×8 mL). The organic phase was dried over MgSO4 and the solvent was evaporated at
reduced pressure to afford 18 as a solid which was purified by crystallization (yield: 312 mg, 81%).
Crystals, mp 126–128°C (from EtOAc/pentane). [α]D=+6.95 (c 1.15, CHCl3). IR (KBr) 3500–3100,
1
1790, 1718 cm−1. H NMR (CDCl3) 0.96 (dd, H3b, J=6.2 Hz, J0=5.5 Hz), 1.31 (dd, H3a, J=9.5 Hz,
J0=5.5 Hz), 1.44 (s, C(CH3)3), 1.57 (m, H2), 4.02 (d, HαO, J=11.7 Hz), 4.24 (dd, HαO, J=11.7 Hz,
J0=9.5 Hz), 4.56 (d, HαO, J=11.7 Hz), 4.61 (d, HαO, J=11.7 Hz), 5.91 (broad s, NH), 7.20–7.97
(complex absorption, 10H). 13C NMR (CDCl3) 16.38 (C3), 22.27 (C2), 28.32 (C(CH3)3), 36.64 (C1),
64.10 (CH2O), 69.42 (CH2O), 79.83 (C(CH3)3), 128.17 (Cm), 128.33 (Cm), 129.55 (Co), 129.61 (Co),
129.85 (Cipso), 130.52 (Cipso), 132.81 (Cp), 133.04 (Cp), 155.95 (NHCO), 166.35 (CO), 166.74 (CO).
MS, m/e (%) 326 (M−Boc, 8), 230 (8), 203 (35), 105 (PhCO, 100), 77 (Ph, 33), 57 (C(CH3)3, 100), 41
(28). Anal. calcd for C24H27NO6: C, 67.75%; H, 6.40%; N, 3.29%. Found: C, 67.68%; H, 6.53%; N,
3.32%.
4.14. (1S,2R)-(+)-1-Amino-1,2-bis(benzoyloxymethyl)cyclopropane hydrochloride 19
A mixture of 18 (62 mg, 0.1 mmol) and 6 M HCl (1.5 mL) in THF (1.5 mL) was stirred at room
temperature overnight. The solution was evaporated to dryness to afford a solid which was purified
by crystallization (yield: 30 mg, 63%). Crystals, mp 179–181°C (MeOH/ether). [α]D=+34.8 (c 1.15,
MeOH). IR (KBr) 3209, 3000–2600, 1715, 1701, 1602 cm−1. 1H NMR (methanol-d4) 1.23 (t, H3b, J=7.3
Hz), 1.47 (dd, H3a, J=10.2 Hz, J0=6.9 Hz), 1.97 (m, H2), 4.23 (d, HαO, J=13.1 Hz), 4.31 (dd, HαO
,
J=12.8 Hz, J0=10.2 Hz), 4.73 (d, HαO, J=13.1 Hz), 4.77 (dd, HαO, J=11.7 Hz, J0=4.4 Hz), 7.29–8.03
(complex absorption, 10 H). 13C NMR (methanol-d4) 13.60 (C3), 22.67 (C2), 39.39 (C1), 63.36 (CH2O),
68.83 (CH2O), 129.49 (Cm), 129.52 (Cm), 130.70 (2Co), 130.77 (2Cipso), 133.04 (2Cp), 167.52 (CO),
168.24 (CO). MS, m/e (%) 326 (M−36, 1), 204 (10), 203 (1), 105 (PhCO, 100), 82 (36), 77 (Ph, 42),
41 (7). Anal. calcd for C19H20ClNO4C: 63.07%; H, 5.57%; N, 3.87%. Found: C, 62.95%; H, 5.60%; N,
3.84%.

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4.15. (1S,2R)-(+)-1-Benzoyloxymethyl-1-N-tert-butoxycarbonylamino-2-hydroxymethylcyclopropane
20
To an ice-cooled solution of 17a (60 mg, 0.3 mmol) in dry dichloromethane (5 mL) anhydrous pyridine
(75 µL, 0.9 mmol) and benzoyl chloride (35 µL, 0.3 mmol) was added under a nitrogen atmosphere. The
mixture was stirred at room temperature for 3 h, then dichloromethane (5 mL) was added and the solution
was subsequently washed with 5% HCl (3×8 mL) and saturated aqueous sodium bicarbonate (2×8 mL).
The organic phase was dried over MgSO4, the solvent was evaporated at reduced pressure and the residue
was chromatographed (1:2, ethyl acetate:hexane) (yield: 78 mg, 88%). Crystals, mp 110–112°C (from
EtOAc/pentane). [α]D=+11.3 (c 0.80, CHCl3). IR (KBr) 3468 (N–H), 3359 (O–H), 1693 (C_O) cm−1.
1H NMR (CDCl3) 0.47 (dd, H3b, J=6.2 Hz, J0=5.5 Hz), 1.04 (dd, H3a, J=9.5 Hz, J0=5.5 Hz), 1.42 (s,
C(CH3)3), 1.60 (m, H2), 3.16 (t, OH, J=J0=11.0 Hz), 3.75 (d, CH2OH, J=11.7 Hz), 3.94 (dt, CH2OH,
J=J0=11.7 Hz, J00=3.6 Hz), 4.04 (d, CH2OBz, J=11.7 Hz), 4.66 (d, CH2OBz, J=11.7 Hz), 5.11 (sa NH),
7.43 (dd, 2Hm, J=8.0 Hz, J0=7.3 Hz), 7.54 (dt, Hp, J=8.0 Hz, J0=1.5 Hz), 8.45 (dd, 2Ho, J=7.3 Hz, J0=1.5
Hz). 13C NMR (CDCl3) 14.35 (C3), 26.70 (C2), 28.23 (C(CH3)3), 36.80 (C1), 61.67 (CH2OH), 69.35
(CH2OBz), 81.00 (C(CH3)3), 128.38 (Cm), 129.73 (Co), 130.11 (Cipso), 133.05 (Cp), 157.41 (NHCO),
166.44 (OCOPh). MS, m/e (%) 322 (M+1, 49), 266 (M−PhCO, 18), 222 (M−Boc, 31), 105 (PhCO, 63),
77 (Ph, 27), 57 (C(CH3)3, 100), 41 (34). Anal. calcd for C17H23NO5: C, 63.54%; H, 7.21%; N, 4.36%.
Found: C, 63.34%; H, 7.29%; N, 4.32%.
4.16. Methyl (1S,2R)-(+)-1-N-benzyloxycarbonylamino-2-(tert-butyldiphenylsilyloxymethyl)cyclo-
propanecarboxylate 21
tert-Butyldiphenylsilyl chloride (395 µL, 1.5 mmol) was added to a stirred and ice-cooled solution
of 6b (210 mg, 0.8 mmol) and dimethylaminopyridine (313 mg, 2.6 mmol) in dichloromethane (5 mL).
The mixture was stirred at 0°C for 25 min and saturated aqueous NH4Cl (5 mL) was added. Layers
were separated and the organic phase was washed with water (1×8 mL) and dried over MgSO4. The
solvent was removed and the residue was chromatographed (1:9 ethyl acetate:hexane) to afford pure 21
(yield: 403 mg, 97%). [α]D=+8.8 (c 3.20, CHCl3). IR (film) 3600–3250, 1734 cm−1. 1H NMR (CDCl3)
1.03 (s, (CH3)3), 1.03–1.22 (m, H3a), 1.77 (m, H3b), 1.94 (m, H2), 3.48 (t, H1 a, J=J0=10.7 Hz), 3.70 (s,
0
CH3), 4.02 (dd, H1 b, J=10.7 Hz, J0=5.1 Hz), 5.12 (s, CH2Ph), 7.35–7.64 (complex absorption, 15H). 13
C
0
NMR (CDCl3) 19.07 (C(CH3)3), 21.89 (C3), 26.77 (C(CH3)3), 29.80 (C2), 38.12 (C1), 52.50 (OCH3),
0
63.50 (C1 ), 66.59 (CH2Ph), 127.75, 127.81, 127.99, 128.40, 129.84, 133.11, 135.40, 135.46, 136.37,
156.87 (NHCO), 172.92 (CO). Anal. calcd for C30H35NO5Si: C, 69.60%; H, 6.81%; N, 2.71%. Found:
C, 69.50%; H, 6.94%; N, 2.72%.
4.17. (1S,2R)-(+)-1-N-Benzyloxycarbonylamino-2-tert-butyldiphenylsilyloxymethyl-1-hydroxymethyl-
cyclopropane 22
Ester 21 was reduced with LiBH4 following the standard procedure described above for the preparation
1
of 15 (yield: 1.3 g, 93%). [α]D=+11.0 (c 2.00, CHCl3). IR (film) 3600–3100 cm−1. H NMR (CDCl3)
0.74 (dd, H3, J=7.9 Hz, J0=5.8 Hz), 1.04 (s, SiC(CH3)3), 1.18 (m, H3), 1.25 (m, H2), 3.45 (complex
0
0
0
absorption, CH2OH), 3.68 (d, H1 , J=11.7 Hz), 3.97 (dd, H1 , J=11.7 Hz, J =5.5 Hz), 5.09 (s, CH2Ph),
5.74 (broad s, NH), 7.33–7.39 (complex absorption, 11H), 7.61–7.67 (complex absorption, 4H). 13C
NMR (CDCl3) 17.45 (C3), 19.08 (SiC(CH3)3), 25.55 (C2), 26.85 (SiC(CH3)3), 39.18 (C1), 64.05
(CH2OSi), 66.96 (CH2Ph), 70.15 (CH2OH), 127.79 (4Co), 128.01 (2Co), 128.50 (2Cp), 129.83 (4Cp),

J. Rifé, R. M. Ortuño / Tetrahedron: Asymmetry 10 (1999) 4245–4260
4255
133.19 (2Cipso), 135.44 (Cm), 135.52 (Cm), 158.34 (NHCO). Anal. calcd for C29H35NO4Si: C, 71.13%;
H, 7.20%; N, 2.86%. Found: C, 71.27%; H, 7.09%; N, 2.73%.
4.18. (1S,2R)-1-N-Benzyloxycarbonylamino-2-tert-butyldiphenylsilyloxymethyl-1-methanesulfonyloxy-
cyclopropane 23
Triethylamine (240 µL, 2.0 mmol) and mesyl chloride (140 µL, 2.0 mmol) were subsequently added to
a stirred and ice-cooled solution of alcohol 22 (0.5 g, 1.0 mmol) in dry dichloromethane (10 mL) under
nitrogen atmosphere. The mixture was stirred at 0°C for 30 min and water (8 mL) was added. Layers
were separated and the aqueous phase was extracted with dichloromethane (2×8 mL). The combined
organic extracts were dried over MgSO4 and the solvent was evaporated at reduced pressure to afford
1
quantitatively mesylate 23 (580 mg) which was used in the next step without further purification. H
NMR (CDCl3) 0.88 (t, H3, J=J0=6.6 Hz), 1.05 (s, C(CH3)3), 1.09 (m, H3), 1.40 (m, H2), 2.90 (s,
CH3), 3.48 (dd, CH2OSi, J=11.0 Hz, J0=8.7 Hz), 3.83 (d, CH2OH, J=10.9 Hz), 4.00 (dd, CH2OSi,
J=11.0 Hz, J0=5.1 Hz), 4.58 (d, CH2OH, J=10.9 Hz), 5.09 (s, CH2Ph), 5.63 (broad s, NH), 7.32–7.40
(complex absorption, 11H), 7.60–7.72 (complex absorption, 4H). 13C NMR (CDCl3) 17.70 (C3), 19.12
(SiC(CH3)3), 24.96 (C2), 26.82 (SiC(CH3)3, 36.27 (C1), 37.43 (CH3), 63.67 (CH2OSi), 66.75 (CH2Ph),
74.23 (CH2OH), 127.76 (4Co), 128.01 (2Co), 128.48 (2Cp), 129.81 (4Cp), 133.08 (2Cipso), 135.38 (Cm),
135.49 (Cm), 156.24 (NHCO).
4.19. (1S,2R)-(+)-1-N-Benzyloxycarbonylamino-2-tert-butyldiphenylsilyloxymethyl-1-methylcyclo-
propane 24
Mesylate 23 was reduced with LiBH4 according to a similar protocol to that described above for the
synthesis of 15. Crude 24 was purified by column chromatography on Baker-silica® (5:1, hexane:ether) to
afford a colorless oil (yield: 240 mg, 50%). [α]D=+15.0 (c 2.70, CHCl3). IR (film) 3423, 3339 (broad),
1
1725 cm−1. H NMR (CDCl3) 0.69 (t, H3, J=J0=5.1 Hz), 0.85 (dd, H3, J=8.0 Hz, J0=5.1 Hz), 1.07
(complex absorption, C(CH3)3+H2), 1.39 (s, CH3), 3.47 (t, CH2OSi, J=J0=10.9 Hz,), 4.01 (dd, CH2OSi,
J=10.9 Hz, J0=5.8 Hz), 5.09 (s, CH2Ph), 5.50 (broad s, NH), 7.35–7.43 (complex absorption, 11H),
7.60–7.68 (complex absorption, 4H). 13C NMR (CDCl3) 19.12 (C(CH3)3), 19.68 (C3), 24.12 (C2), 26.24
0
(CH3), 26.85 (C(CH3)3), 33.32 (C1), 64.91 (C1 ), 66.23 (CH2Ph), 127.70, 127.91, 128.41, 129.73, 133.2,
135.47, 135.55, 136.76, 156.41 (NHCO). Anal. calcd for C29H35NO3Si: C, 73.53%; H, 7.45%; N, 2.96%.
Found: C, 73.50%; H, 7.84%; N, 2.75%.
4.20. (1S,2R)-(−)-1-Amino-2-tert-butyldiphenylsilyloxymethyl-1-methylcyclopropane 25
A stirred mixture of 24 (100 mg, 0.2 mmol) and 20% Pd(OH)2/C (16 mg) in methanol (10 mL) was
hydrogenated under two atmospheres pressure for 24 h. The catalyst was removed by filtration through
Celite and the solvent was evaporated. The residue was chromatographed on Baker-silica® giving a
colorless oil (yield: 54 mg, 76%). [α]D=−34.6 (c 0.75, CHCl3). IR (film) 3600, 3100 (broad) cm−1.
1H NMR (CDCl3) 0.27 (t, H3, J=J0=5.1 Hz), 0.47 (dd, H3, J=9.1 Hz, J0=4.7 Hz), 0.94 (m, H2), 1.03 (s,
C(CH3)3), 1.26 (s, CH3), 3.70 (dd, CH2OSi, J=10.9 Hz, J0=8.4 Hz), 3.94 (dd, CH2OSi, J=10.9 Hz, J0=5.1
Hz), 7.35–7.39 (complex absorption, 6H), 7.66–7.69 (complex absorption, 4H). 13C NMR (CDCl3) 18.64
(C(CH3)3), 19.20 (C3), 26.88 (C(CH3)3), 27.18(C2), 28.62 (CH3), 34.32 (C1), 64.16 (CαO), 127.59 (Co),
129.50 (Cp), 134.19 (Cipso), 135.60 (Cm). Anal. calcd for C21H29NOS: C, 74.28%; H, 8.61%; N, 4.13%.
Found: C, 74.49%; H, 8.89%; N, 3.89%.

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4.21. (1S,2R)-(−)-1-N-Benzyloxycarbonylamino-2-hydroxymethyl-1-methylcyclopropane 26
A 1 M solution of tetrabutylammonium fluoride in THF (270 µL, 0.3 mmol) was added to a solution
of 24 (88 mg, 0.2 mmol) in THF (2 mL). The mixture was stirred at room temperature for 1 h,
then the solvent was evaporated at reduced pressure and the residue was chromatographed (1:1, ethyl
acetate:hexane) to afford pure 26 (yield: 43 mg, 100%). Crystals, mp 47–50°C (from EtOAc/pentane).
1
[α]D=−19.1 (c 1.70, CHCl3). IR (KBr) 3600–3100 (broad), 1725 cm−1. H NMR (CDCl3) 0.34 (t, H3,
J=J0=5.8 Hz), 0.70 (dd, H3, J=8.8 Hz, J0=5.8 Hz), 1.29 (m, H2), 1.36 (s, CH3), 3.08 (t, OH, J=J0=11.0
Hz), 3.50 (d, CH2OH, J=11.0 Hz), 3.88 (dd, CH2OH, J=11.0 Hz, J0=2.9 Hz), 5.08 (s, CH2Ph), 5.33
(broad s, NH), 7.32 (s, 5H). 13C NMR (CDCl3) 16.51 (C3), 23.85 (C2), 28.34 (CH3), 33.72 (C1),
0
62.70 (C1 ), 67.05 (CH2Ph), 128.03, 128.20, 128.51, 135.47, 135.96, 157.74 (NHCO). Anal. calcd for
C13H17NO3: C, 66.36%; H, 7.28%; N, 5.95%. Found: C, 66.64%; H, 7.39%; N, 5.78%.
4.22. (1S,2R)-(−)-1-Amino-2-hydroxymethyl-1-methylcyclopropane 3
Compound 26 was hydrogenated according to the procedure described above for the preparation of 25.
Aminoalcohol 3 was purified by elution through a C18-reverse phase cartridge affording an oil (yield: 22
mg, 95%). [α]D=−23.4 (c 0.55, CHCl3). IR (film) 3600–3000 (broad) cm−1. 1H NMR (methanol-d4) 0.28
(t, H3, J=J0=5.8 Hz), 0.65 (dd, H3, J=8.9 Hz, J0=5.8 Hz), 1.29 (m, H2), 1.36 (s, CH3), 3.71 (dd, J=11.7
Hz, J0=5.7 Hz), 3.96 (dd, J=11.7 Hz, J0=4.2 Hz). 13C NMR (methanol-d4) 14.93 (C3), 22.59 (C2), 28.01
(CH3), 37.43 (C1), 59.98 (CH2O). Anal. calcd for C5H11NO: C, 59.37%; H, 10.96%; N, 13.85%. Found:
C, 59.54%; H, 10.85%; N, 13.69%.
4.23. (1S,2R,40S)-(−)-1-N-tert-Butoxycarbonylamino-2-(20 ,20-dimethyl-10,30-dioxolan-40-yl)-1-
hydroxymethylcyclopropane 27
Ester 7a was reduced with LiBH4 following the same procedure as that described above for the
synthesis of 15 (yield: 450 mg, 99%). Crystals, mp 92–94°C (from EtOAc/pentane). [α]D=−60.6 (c 1.65,
1
CHCl3). IR (KBr) 3500–3000 (broad), 1719 cm−1. H NMR (CDCl3) 0.82 (t, H3a, J=J0=5.8 Hz), 1.03
(dd, H3b, J=8.8 Hz, J0=5.8 Hz), 1.23 (complex absorption, H2+CH3), 1.31 (s, CH3), 1.40 (s, C(CH3)3),
0
0
0
3.34 (d, CH2OH, J=11.0 Hz), 3.75 (complex absorption, H5 +CH2OH), 3.84 (m, H4 ), 4.06 (dd, H5 ,
J=8.0 Hz, J0=5.8 Hz), 5.08 (broad s, NH). 13C NMR (CDCl3) 16.76 (C3), 25.51 (CH3), 26.09 (C2),
0
0
26.73 (CH3), 28.17 ((CH3)3), 39.01 (C1), 69.85 (CH2OH), 70.03 (C5 ), 76.47 (C4 ), 80.57 (C(CH3)3),
+
0
108.59 (C2 ), 157.55 (NHCO). MS, m/e (%) 231 (M −56, 1), 172 (M−Boc, 29), 113 (10), 112 (12), 101
(13), 86 (33), 59 (14), 57 (100), 43 (21), 42 (25). Anal. calcd for C14H25NO5: C, 58.52%; H, 8.77%; N,
4.87%. Found: C, 58.42%; H, 8.84%; N, 5.09%.
4.24. (1S,2R,40S)-(−)-1-N-tert-Butoxycarbonylamino-2-(20 ,20-dimethyl-10,30-dioxolan-40-yl)-1-
methanesulfonyloxycyclopropane 28
This compound was synthesized following the same procedure as that described above for the
preparation of 23. Crude mesylate 28 was purified by crystallization (yield: 1.5 g, 88%). Crystals,
1
mp 118–120°C (from CH2Cl2/pentane). [α]D=−42.0 (c 1.50, CHCl3). IR (KBr) 1685 cm−1. H NMR
(CDCl3) 0.99 (m, H3a), 1.20 (m, H3b), 1.31 (s, CH3), 1.42 (complex absorption, CH3+H2+C(CH3)3),
0
0
2.98 (s, SO2CH3), 3.78 (complex absorption, 3H), 4.05 (dd, H5 , J=8.0 Hz, J =5.8 Hz), 4.58 (d,
CH2OMs, J=10.9 Hz), 4.97 (broad s, NH). 13C NMR (CDCl3) 16.45 (C3), 25.36 (CH3), 26.65 (C2), 26.71

J. Rifé, R. M. Ortuño / Tetrahedron: Asymmetry 10 (1999) 4245–4260
4257
0
0
(CH3), 28.21 (C(CH3)3), 36.54 (C1), 39.01 (CH3SO2), 69.82 (CH2OH), 74.06 (C5 ), 75.91 (C4 ), 80.41
+
0
(C(CH3)3), 108.70 (C2 ), 155.34 (NHCO). MS, m/e (%) 345 (M −20, 4), 344 (16), 235 (12), 179 (100),
164 (13), 107 (18), 99 (19), 94 (15), 73 (22), 57 (98), 43 (22), 41 (22). Anal. calcd for C15H27NO7S: C,
49.30%; H, 7.45%; N, 3.83%; S, 8.77%. Found: C, 49.64%; H, 7.55%; N, 3.77%; S, 8.48%.
4.25. (1S,2R,40S)-(−)-1-N-tert-Butoxycarbonylamino-2-(20 ,20-dimethyl-10,30-dioxolan-40-yl)-1-
methylcyclopropane 29
Mesylate 28 was reduced with LiBH4 according to the standard procedure (yield: 150 mg, 50%).
1
Crystals, mp 80–81°C (from CH2Cl2/pentane). [α]D=−80.0 (c 1.00, CHCl3). IR (KBr) 1691 cm−1. H
NMR (CDCl3) 0.71 (t, H3a, J=J0=5.8 Hz), 0.82 (dd, H3b, J=8.8 Hz, J0=5.8 Hz), 0.96 (m, H2), 1.31 (s,
0
0
0
0
2×CH3), 1.40 (s, CH3), 1.41 (s, C(CH3)3), 3.69 (m, H5 ), 3.79 (t, H5 , J=J =7.3 Hz), 4.10 (dd, H4 , J=8.0
Hz, J0=5.8 Hz), 4.76 (broad s, NH). 13C NMR (CDCl3) 18.33 (C3), 23.72 (C2), 25.48 (CH3), 26.83
0
0
(CH3), 28.27 (C(CH3)3), 28.51 (CH3), 33.49 (C1), 70.21 (C5 ), 77.50 (C4 ), 79.41 (C(CH3)3), 108.14
+
0
(C2 ), 155.37 (NHCO). MS, m/e (%) 214 (M −57, 156 (12), 101 (28), 96 (19), 70 (43), 57 (100). Anal.
calcd for C14H25NO4: C, 61.97%; H, 9.29%; N, 5.16%. Found: C, 61.98%; H, 9.41%; N, 5.04%.
4.26. (1S,2R,40S)-(−)-1-N-tert-Butoxycarbonylamino-2-(20 ,20-dimethyl-10,30-dioxolan-40-yl)-1-
(methylthiomethyl)cyclopropane 30
A solution of sodium thiomethoxide (122 mg, 1.7 mmol) in anhydrous THF (5 mL) was added to
a solution of mesylate 28 (426 mg, 1.2 mmol) in THF (10 mL) and the mixture was stirred at room
temperature for 20 h. Then the solvent was removed, the residue was poured into water (20 mL), and the
resulting solution was extracted with dichloromethane (5×20 mL). The combined organic extracts were
dried over MgSO4 and the solvent was evaporated at reduced pressure. The residue was chromatographed
(1:2, ethyl acetate:hexane) to furnish pure 30 (yield: 173 mg, 47%). Crystals, mp 87–88°C (from
1
CH2Cl2/pentane). [α]D=−58.0 (c 1.35, CHCl3). IR (KBr) 1687 cm−1. H NMR (CDCl3) 0.84 (t, H3a,
J=J0=5.8 Hz), 0.96–1.14 (complex absorption, H2+H3b), 1.30 (s, CH3), 1.40 (complex absorption,
CH3+C(CH3)3), 2.11 (s, SCH3), 2.31 (d, HαS, J=13.9 Hz), 3.10 (d, HαS, J=13.9 Hz), 3.67–3.83 (complex
0
absorption, 2H5 ), 4.07 (dd, H4 , J=8.0 Hz, J =5.8 Hz), 5.04 (broad s, NH). 13C NMR (CDCl3) 16.80
0
0
(SCH3), 17.86 (C3), 25.51 (CH3), 26.86 (C2), 27.92 (CH3), 28.30 ((CH3)3), 37.50 (C1), 42.00 (CH2SMe),
0
0
0
70.03 (C5 ), 77.00 (C4 ), 79.97 (C(CH3)3), 108.43 (C2 ), 155.40 (NHCO). Anal. calcd for C15H27NO4S:
C, 56.75%; H, 8.57%; N, 4.41%; S, 10.10%. Found: C, 56.59%; H, 8.65%; N, 4.33%; S, 9.83%.
4.27. (1S,2R,40S)-(−)-1-Benzoyloxymethyl-1-N-tert-butoxycarbonylamino-2-(20 ,20-dimethyl-10,30-
dioxolan-40-yl)cyclopropane 32
A solution of alcohol 27 (680 mg, 2.4 mmol), benzoyl chloride (345 µL, 3.0 mmol), and anhydrous
pyridine (570 µL, 7.1 mmol) in dry dichloromethane (16 mL) was stirred under a nitrogen atmosphere
at room temperature for 1 h. The reaction mixture was washed with saturated aqueous ammonium
chloride (2×10 mL) and the organic phase was dried over MgSO4. The solvent was evaporated at
reduced pressure and the residue was chromatographed (1:3, ether:hexane) (yield: 907 mg, 2.3 mmol).
Crystals, mp 94–96°C (from ether/pentane). [α]D=−29.1 (c 1.55, CHCl3). IR (KBr) 1717, 1684 cm−1. 1H
NMR (CDCl3) 0.94 (t, H3a, J=J0=5.8 Hz), 1.24 (complex absorption, H2+H3b), 1.28 (s, CH3), 1.41 (s,
C(CH3)3), 1.43 (s, CH3), 3.82 (ac, 2H), 4.06 (d, CH2OBz, J=11.7 Hz), 4.12 (dd, HαO, J=8.0 Hz, J0=5.8
Hz), 4.57 (d, CH2OBz, J=11.7 Hz), 4.93 (s, NH), 7.42 (t, 2Hm, J=J0=7.3 Hz), 7.54 (t, Hp, J=J0=7.3

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J. Rifé, R. M. Ortuño / Tetrahedron: Asymmetry 10 (1999) 4245–4260
Hz), 8.01 (d, 2Ho, J=7.3 Hz). 13C NMR (CDCl3) 16.29 (C3), 25.46 (CH3), 26.46 (CH3), 26.85 (C2),
0
0
0
28.26 (C(CH3)3), 36.74 (C1), 68.80 (CH2OBz), 70.02 (C5 ), 76.47 (C4 ), 80.10 (C(CH3)3), 108.56 (C2 ),
128.34 (2Cm), 129.62 (2Co), 129.95 (Cipso), 133.02 (Cp), 155.30 (NHCO), 166.25 (CO). Anal. calcd for
C21H29NO6: C, 64.43%; H, 7.47%; N, 3.58%. Found: C, 64.72%; H, 7.25%; N, 3.55%.
4.28. (1S,2R,10S)-1-N-tert-Butoxycarbonylamino-2-(10 ,20-dihydroxyethyl)-1-methylcyclopropane 33
HCl (5%=four drops) was added to a solution of 29 (157 mg, 0.6 mmol) in methanol (8 mL) and the
mixture was stirred at room temperature for 90 min. The reaction mixture was evaporated to dryness and
the residue was crystallized (yield: 110 mg, 0.5 mmol). Crystals, mp 87–89°C (from CH2Cl2/pentane).
[α]D=−31.1 (c 1.15, CHCl3). IR (KBr) 3650–3000 (broad), 1693 cm−1. 1H NMR (acetone-d6) 0.71–0.82
0
(complex absorption, 2H3), 1.27 (s, CH3), 1.38 (complex absorption, H2+C(CH3)3), 3.26 (m, H5 ), 3.61
0
(t, H5 , J=J =5.8 Hz,), 4.00 (m, H4 ), 6.24 (broad s, NH). 13C NMR (acetone-d6) 18.15 (C3), 23.94 (C2),
0
0
0
0
28.12 (C(CH3)3), 28.53 (CH3), 33.94 (C1), 66.55 (C5 ), 72.00 (C4 ), 79.52 (C(CH3)3), 156.48 (NHCO).
Anal. calcd for C11H21NO4: C, 57.12%; H, 9.15%; N, 6.06%. Found: C, 57.48%; H, 9.38%; N, 5.89%.
4.29. (1S,2R,10S)-1-N-tert-Butoxycarbonylamino-2-(10 ,20-dihydroxyethyl)-1-(methylthiomethyl)cyclo-
propane 34
HCl (5%=four drops) was added to a solution of 30 (90 mg, 0.3 mmol) in methanol (8 mL) and the
mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness and
the residue was chromatographed (ethyl acetate) (yield: 57 mg, 77%). Crystals mp 99–101°C (from
1
CH2Cl2/pentane). [α]D=−12.0 (c 0.68, CHCl3). IR (KBr) 3500–3100 (broad), 1692 cm−1. H NMR
(CDCl3) 0.95–1.04 (complex absorption, 2H3+H2), 01.42 (s, C(CH3)3), 2.17 (s, SCH3), 2.60 (d, HαS
,
J=14.0 Hz), 2.83 (d, HαS, J=14.0 Hz), 3.51 (m, H1 ), 3.70 (m, 2H2 ), 5.41 (broad s, NH). 13C NMR
(CDCl3) 16.76 (SCH3), 18.48 (C3), 27.99 (C2), 28.29 ((CH3)3), 38.08 (C1), 42.43 (CH2SMe), 66.54
0
0
0
(C5 ), 71.59 (C4 ), 80.08 (C(CH3)3), 155.93 (NHCO). Anal. calcd for C12H23NO4S: C, 51.96%; H,
8.36%; N, 5.05%; S, 11.56%. Found: C, 51.86%; H, 8.58%; N, 4.89%; S, 11.71%.
4.30. (1S,2R,10S)-1-Bromomethyl-1-N-tert-butoxycarbonylamino-2-(10 ,20-dihydroxyethyl)cyclo-
propane 35
A mixture of mesylate 28 (375 mg, 1.0 mmol) and lithium bromide (175 mg, 2.0 mmol) in THF (15
mL) was stirred at room temperature for 4 days. The solvent was removed, the residue was poured into
water and the resultant aqueous solution was extracted with dichloromethane. The combined organic
extracts were dried over MgSO4 and the solvent was evaporated at reduced pressure. The residue was
poured into methanol (10 mL) and 5% HCl (4 drops) was added. The solution was stirred at room
temperature for 20 min, then evaporated to dryness. The residue was chromatographed (ethyl acetate)
to afford diol 35 as a solid (yield: 253 mg, 64%). Crystals, mp 95–96°C (from MeOH/CH2Cl2/pentane).
1
[α]D=−23.0 (c 1.00, CHCl3). IR (KBr) 3700–3100 (broad), 1692 cm−1. H NMR (CDCl3) 1.15–1.19
(complex absorption, 2H3+H2), 1.42 (s, C(CH3)3, 2.55 (complex absorption, 2HαBr,), 3.45–3.70 (com-
plex absorption, H1 +2H2 ), 5.44 (broad s, NH). 13C NMR (CDCl3) 20.48 (C3), 28.27 (C(CH3)3), 30.71
0
0
0
0
(C2), 39.09 (C1), 42.48 (CH2Br), 66.47 (C5 ), 71.47 (C4 ), 80.53 (C(CH3)3), 155.69 (NHCO). Anal.
calcd for C11H20BrNO4: C, 42.59%; H, 6.50%; N, 4.52%; Br, 25.76%. Found: C, 42.62%; H, 6.57%; N,
4.53%; Br, 25.59%.

J. Rifé, R. M. Ortuño / Tetrahedron: Asymmetry 10 (1999) 4245–4260
4259
4.31. (1S,2R,10S)-(−)-1-Benzoyloxymethyl-1-N-tert-butoxycarbonylamino-2-(10 ,20-dihydroxyethyl)-
cyclopropane 36
Following the same procedure as that described above for the synthesis of 34, diol 36 was obtained
as a solid (yield: 742 mg, 98%). Crystals, mp 124–126°C (from CH2Cl2/pentane). [α]D=−24.7 (c 1.00,
CHCl3). IR (KBr) 3600–3100 (broad), 1722, 1675 cm−1. 1H NMR (CDCl3) 1.01 (t, H3a, J=J0=5.1 Hz),
1.18–1.29 (complex absorption, H2+H3b), 1.41 (s, C(CH3)3), 2.15 (s, OH), 2.35 (broad s, OH), 3.35
(m, H), 3.70 (complex absorption, 2H), 4.32 (s, CH2OBz), 5.28 (broad s, NH), 7.43 (t, 2Hm, J=J0=7.3
Hz), 7.56 (t, Hp, J=J0=7.3 Hz), 8.03 (d, 2Ho, J=7.3 Hz). 13C NMR (CDCl3) 17.10 (C3), 27.91 (C2),
0
0
28.58 (C(CH3)3), 37.42 (C1), 67.42 (C5 ), 70.08 (CH2OBz), 72.27 (C4 ), 79.12 (C(CH3)3), 129.31 (2Cm),
130.35 (2Co), 131.41 (Cipso), 133.71 (Cp), 156.52 (NHCO), 166.75 (CO). Anal. calcd for C18H25NO6:
C, 61.52%; H, 7.17%; N, 3.99%. Found: C, 61.15%; H, 7.29%; N, 3.81%.
4.32. 2-Benzoyloxymethyl-2-N-tert-butoxycarbonylamino-2,3-dihydrofuran 37
Sodium periodate (40 mg, 3.0 mmol) was added in small portions to a solution of diol 36 (100 mg,
0.3 mmol) in THF–water (3.5+1.5 mL). The mixture was stirred at room temperature for 15 min, then
evaporated to dryness. The residue was poured into water (5 mL) and the aqueous solution was extracted
with dichloromethane (4×5 mL). The combined organic extracts were dried over MgSO4 and the solvent
was removed. The residue was chromatographed (1:3, ether:hexane) to afford 37 as a solid (yield: 47
1
mg, 51%). Crystals, mp 93–95°C (from ether/pentane). IR (KBr) 3385, 1724, 1625 cm−1. H NMR
(CDCl3) 1.41 (s, C(CH3)3), 2.74 (dt, H3, J=16.1 Hz, J0=J00=2.20 Hz), 3.01 (d, H3, J=16.1 Hz), 4.45 (d,
CH2OBz, J=11.7 Hz), 4.57 (d, CH2OBz, J=11.7 Hz), 4.95 (d, H4, J=2.20 Hz), 5.50 (broad s, NH), 6.29
(d, H5, J=2.20 Hz), 7.41 (t, 2Hm, J=J0=7.3 Hz), 7.54 (t, Hp, J=J0=7.3 Hz), 8.00 (d, 2Ho, J=7.3 Hz). 13
C
NMR (CDCl3) 28.21 (C(CH3)3), 37.46 (C3), 66.30 (CH2OBz), 80.41 (C(CH3)3), 93.40 (C2), 99.17 (C4),
128.31 (2Cm), 129.45 (Cipso), 129.70 (2Co), 133.19 (Cp), 144.08 (C5), 153.53 (NHCO), 166.08 (CO).
Anal. calcd for C18H25NO6: C, 63.94%; H, 6.63%; N, 4.39%. Found: C, 64.21%; H, 6.44%; N, 4.51%.
Acknowledgements
J.R. thanks the CIRIT (Generalitat de Catalunya) for a predoctoral fellowship. Financial support from
DGESIC through the project PB97-0214 is gratefully acknowledged.
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