Synthesis of N-Boc-β-aryl alanines and of N-Boc-β-methyl-β-aryl alanines by regioselective ring-opening of enantiomerically pure N-Boc- aziridines

Full text of DOI:10.1021/jo981140i

8574
J . Org. Chem. 1998, 63, 8574-8578
Sch em e 1
Syn th esis of N-Boc-â-Ar yl Ala n in es a n d of
N-Boc-â-Meth yl-â-a r yl Ala n in es by
Regioselective Rin g-Op en in g of
En a n tiom er ica lly P u r e N-Boc-Azir id in es
Eva Medina, Albert Moyano, Miquel A. Perica`s,*,† and
Antoni Riera*,‡
Unitat de Recerca en S´ıntesi Asime`trica (URSA),
Departament de Quı´mica Orga`nica, Universitat de
Barcelona, c/ Martı´ i Franque`s, 1-11.
08028-Barcelona, Spain
Received J une 15, 1998
alcohols used in the Sharpless epoxidation, (b) the
benzylic nature of the C-3 carbon in the epoxides 2 (R )
aryl), which efficiently controls the regioselectivity of the
ring opening process, and (c) the crystalline nature of the
N-Boc-3-amino-1,2-diols 1 (R ) aryl) which allows, if
necessary, an easy enantioenrichment.
In tr od u ction
The stereoselective synthesis of unnatural R-amino
acids1 is currently a subject of enormous interest mainly
due to the increasing biological and therapeutic applica-
tions of modified peptides.2 Over the last few years, we
have been involved in a project devoted to the enantio-
selective synthesis of several structural types of N-Boc
amino acids and dipeptide isosteres.3,4 Our approach,
which is based on the intermediacy of enantiomerically
pure N-Boc-3-amino-1,2-diols 1, readily available from
allyl alcohols through Sharpless epoxidation5 followed by
a regio- and stereospecific ring-opening by a convenient
ammonia equivalent6 (Scheme 1), has even found ap-
plication at the industrial level.7
As an application of this methodology, we have recently
reported a more convenient synthesis of N-Boc arylgly-
cines 3.8 In that particular case, our approach benefits
from several aspects that make it attractive in front of
possible alternatives: (a) the easy availability of aromatic
carbaldehydes which are the precursors of the allyl
However, if the procedure described in Scheme 1 had
to be applied to the synthesis of the even more interesting
â-aryl alanines 4,9,10 these advantages would be at least
partially lost. In particular, the strict regiocontrol in the
epoxide ring-opening derived from the benzylic nature
of the attacked carbon atom would be no longer operating.
To circumvent this difficulty, we planned to accede the
â-aryl alanines from N-Boc-3-aryl-3-amino-1,2-propane-
diols (1 R) aryl), but introduce in the sequence a 1,2-
nitrogen shift instead of the degradative oxidation step.
This would be done through the intermediacy of N-Boc
aziridines 5 (Scheme 2), which present a benzyl type
carbon for nucleophilic attack and offer the additional
bonus of easily allowing the preparation of â-substituted
derivatives 6.
We report here a new and simple procedure for the
preparation of optically pure â-aryl alanines (4) and
â-alkyl-â-aryl alanines (6), from readily available N-Boc-
3-aryl-3-amino-1,2-propanediols (1, R ) aryl).
† E-mail: mpb@ursa.qo.ub.es.
‡ E-mail: are@ursa.qo.ub.es.
(1) (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539-1650. (b) Ohfune,
Y. Acc. Chem. Res. 1992, 25, 360-366 (c) Williams, R. M. Synthesis of
Optically Active R-Amino Acids; Pergamon Press: Oxford, 1989. (d)
O’Donnell, M. J ., Ed. Tetrahedron 1988, 44, 5253-5614.
(2) (a) Begley, D. J . J . Pharm. Pharmacol. 1996, 48, 136-146. (b)
McMartin, C. Handb. Exp. Pharmacol. 1994, 110, 371-382 (c) Crom-
melin, D. J . A.; Storm, G. Eur. J . Pharm. Sci. 1994, 2, 17-18. (d)
Kompella, U. B.; Lee, V. H. L. Adv. Drug Delivery Rev. 1992, 8 (1),
115-162.
(3) (a) Poch, M.; Alco´n, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 1993, 34, 7781-7784. (b) Pasto´, M.; Moyano, A.;
Perica`s, M. A.; Riera, A. Tetrahedron: Asymmetry 1995, 6, 2329-2342.
(c) Castejo´n, P.; Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 1995, 36, 3019-3022. (d) Castejo´n, P.; Moyano, A.;
Perica`s, M. A.; Riera, A. Chem. Eur. J . 1996, 2, 1001-1006. (e)
Castejo´n, P.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron 1996,
52, 7063-7086. (f) Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron: Asymmetry 1996, 7, 243-262. (g) Pasto´, M.; Castejo´n,
P.; Moyano, A.; Perica`s, M. A.; Riera, A. J . Org. Chem. 1996, 61, 6033-
6037. (h) Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron
Lett. 1998, 39, 1233-1236. (i) Aguilar, N.; Moyano, A.; Perica`s, M. A.;
Riera, A. J . Org. Chem. 1998, 63, 3560-3567.
(4) Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera, A. J . Org. Chem.
1997, 62, 8425-8431.
(5) (a) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780. (b)
Katsuki, T.; Mart´ın, V. S. Org. React. 1996, 48, 1-299.
(6) Canas, M.; Poch, M.; Verdaguer, X.; Moyano, A.; Perica`s, M. A.;
Riera, A. Tetrahedron Lett. 1991, 32, 6931-6934.
(7) Shum, W. P.; Cannarsa, M. J . In Chirality in Industry II; Collins,
A. N., Sheldrake, G. N., Crosby, J ., Eds.; J ohn Wiley & Sons Ltd.: New
York, 1997; pp 363-379.
(8) Medina, E.; Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera,
A. Tetrahedron: Asymmetry 1997, 8, 1581-1586.
Resu lts a n d Discu ssion
Phenyl and 1-naphthyl were selected as representative
aryl groups for our study. In both cases, the preparation
(9) Selected examples of modified peptides wiith naphthyl ala-
nines: (a) Rodriguez, M.; Bernad, N.; Galas, M. C.; Lignon, M. F.; Laur,
J .; Aumelas, A.; Martinez, J . Eur. J . Med. Chem. 1991, 26, 245-253.
(b) Prochazka, Z.; Slaninova, J . Collect. Czech. Chem. Commun. 1995,
60, 2170-2177. (c) Ranjalahy-Rasoloarijao, L.; Lazaro, R.; Daumas,
P.; Heitz, F. Int. J . Pept. Protein Res. 1989, 33, 273-280. (d) Lammek,
B.; Konieczna, E.; Trzeciak, H. I.; Kozlowski, A.; Szymkowiak, J .;
Stojko, R.; Kupryszewski, G. J . Pharm. Pharmacol. 1996, 48, 316-
319. (e) Lammek, B.; Czaja, M.; Derdowska, I.; Rekowski, P.; Trzeciak,
H. I.; Sikora, P.; Szkrobka, W.; Stojko, R.; Kupryszewski, G. J . Pept.
Res. 1997, 49, 261-268. (f) Mierke, D. F.; Said-Nejad, O. E.; Schiller,
P. W.; Goodman, M. Biopolymers 1990, 29, 179-196. (g) Schmidt, R.;
Wilkes, B. C.; Chung, N. N.; Lemieux, C.; Schiller, P. W. Int. J . Pept.
Protein Res. 1996, 48, 411-419. (h) Yabe, Y.; Miura, C.; Baba, Y.;
Sawano, S. Chem. Pharm. Bull. 1978, 26, 993-997.
(10) Some references of asymmetric synthesis of â-aryl alanines: (a)
Chan, A. S. C.; Hu, W.; Pai, C.-C.; Lau, C.-P.; J iang, Y.; Mi, A.; Yan,
M.; Sun, J .; Lou, R.; Deng, J . J . Am. Chem. Soc. 1997, 119, 9570-
9571. (b) Zhu, G.; Cao, P.; J iang, Q.; Zhang, X. J . Am. Chem. Soc. 1997,
119, 1799-1800. (c) Kolar, P.; Petric, A.; Tisler, M. J . Heterocycl. Chem.
1997, 34, 1067-1098. (d) Meiwes, J .; Schudok, M.; Kretzschmar, G.
Tetrahedron: Asymmetry 1997, 8, 527-536. (e) Tararov, V. I.; Saveleva,
T. F.; Kuznetsov, N. Y.; Ikonnikov, N. S.; Orlova, S. A.; Belokon, Y.
N.; North, M. Tetrahedron: Asymmetry 1997, 8, 79-83. (f) J ackson,
R. F. W.; Wythes, M. J .; Wood, A. Tetrahedron Lett. 1989, 30, 5941-
5944.
10.1021/jo981140i CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/28/1998

Notes
J . Org. Chem., Vol. 63, No. 23, 1998 8575
Sch em e 2
subsequent oxidation of the primary alcohol in 10a ,b with
PDC in DMF afforded the target â-aryl alanines 4a ,b in
58-67% overall yield from aziridines 5a ,b (Scheme 3).
To check the enantiomeric purity of these amino acids,
the corresponding methyl esters, prepared by treatment
with methyl iodide and potassium hydrogen carbonate
in DMF, were analyzed by HPLC (Chiracel OD). In both
cases the enantiomeric purity was very high (>99% ee
for 4a and >98% ee for 4b), in full agreement with the
optical purity of the starting N-Boc-3-amino-1,2-diols 1.
As we have already mentioned, the ring opening of
N-Boc-aziridines 5 by carbon nucleophiles could lead to
â-substituted â-aryl alanines which are important bio-
active compounds. In particular, several â-methyl-â-aryl
alanines have been incorporated into peptides in order
to confer conformational restrictions to the molecule12 and
modify their biological activities.13 The demand for
flexible stereoselective methods allowing the preparation
of any desired diastereomer of such amino acids has only
recently met a satisfactory answer4 in the case of â-meth-
yl-phenylalanine.14 In this context, the planned ring
opening of the N-Boc-aziridines with carbon nucleophiles
could be the key step of a new and practical synthesis of
such amino acids with anti configuration.
Sch em e 3a
Although the protection of the aziridine nitrogen with
a tert-butoxycarbonyl group is well-known,15 the activa-
tion of the aziridine ring by this group has received very
little attention.16 Notwithstanding, the reaction of 5a ,b
with lithium dimethylcuprate took place cleanly to afford
with regioselectivity and with excellent yields the pro-
tected 2-amino-3-arylbutanols 11a ,b (Scheme 4). The
conversion of these intermediates into the target amino
acids 6a ,b was easily performed by a sequence of fluoride-
induced deprotection (75-93% yield) and oxidation of the
intermediate alcohols 12a ,b with PDC in DMF (77-83%),
as for the â-unsubstituted analogues.
The so-prepared anti-N-Boc-â-methylphenylalanine 6a
was spectroscopically identical to the one previously
obtained by us,4 and its optical purity was determined
to be greater than 99% ee by HPLC analysis of its methyl
ester. On the other hand, the previously unreported anti-
N-Boc-â-methyl-â-naphthyl alanine 6b was completely
characterized, and its optical purity was also checked by
HPLC (>97% ee). This new compound has a great
potential interest for structural and biological studies,
since it combines two of the most usual modifications of
phenylalanine used in peptides: replacement of the
phenyl group for a naphthyl and alkyl substitution at the
â-position.17
a
Reagents and conditions: (a) ButMe2SiCl, imidazole, DMF, rt;
(b) CH3SO2Cl, Et3N, 4-DMAP, CH2Cl2; (c) HNa, THF; (d) H2, Pd/
C, AcEt; (e) TBAF, THF; (f) PDC, DMF.
of the corresponding enantiomerically pure N-Boc-3-
amino-1,2-diols3a,3f,8 is well documented and can be very
easily performed. Starting from these aminodiols (1a ,b),
the primary alcohol was first protected (Scheme 3) as a
tert-butyldimethylsilyl ether under standard conditions
to afford 7a ,b with excellent yield (85-89%) and complete
chemoselectivity. The conversion of these ethers into the
derived N-Boc aziridines 5a ,b was then attempted using
Mitsunobu conditions (DEAD, PPh3),11 but probably due
to the low nucleophilicity of the carbamate nitrogen atom,
the cyclization yields were rather low (20-34%). Quite
gratifyingly, this cyclization could be conveniently per-
formed by mesylation of the secondary alcohol, leading
to 8a ,b, and subsequent generation of the anion of the
carbamate with sodium hydride. In this way, N-Boc-
aziridines 5a ,b were obtained in 62-71% yield.
(12) (a) Burgess, A. W. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 2649-
2653. (b) Hruby, V. J . Biopolymers 1993 33, 1073-1082. (c) Hruby, V.
J .; Al-Obeidi, F.; Kazmierski, W. Biochem. J . 1990, 268, 249-262. (d)
Shenderovich, M. D.; Ko¨ve´r, K. E.; Nikiforovich, G. V.; J iao, D.; Hruby,
V. J . Biopolymers 1996, 38, 141-56.
(13) (a) Hruby, V. J .; Toth, G.; Gherig, C. A.; Kao, L.-F.; Knapp, R.;
Lui, G. K.; Yamamura, H. I.; Kramer, T. H.; Davis, P.; Burks, T. F. J .
Med. Chem. 1991, 34, 1823-1830. (b) Qian, X.; Shenderovich, M. D.;
Ko¨ve´r, K. E.; Davis, P.; Horva´th, R.; Zalewska, T.; Yamamura, H. I.;
Porreca, F.; Hruby, V. J . J . Am. Chem. Soc. 1996, 118, 7280-7290.
(14) (a) Dharanipragada, R.; Nicolas, E.; Toth, G.; Hruby, V. J .
Tetrahedron Lett. 1989, 30, 6841-6844. (b) Dharanipragada, R.;
VanHulle, K.; Bannister, A.; Bear, S.; Kennedy, L.; Hruby, V. J .
Tetrahedron 1992, 48, 4733-4748. (c) Burk, M. J .; Gross, M. F.;
Martinez, J . P. J . Am. Chem. Soc. 1995, 117, 9375-9376. (d) Davis,
F. A.; Liang, C.-H.; Liu, H. J . Org. Chem. 1997, 62, 3796-3797.
(15) (a) Wessig, P.; Schwarz, J . Synlett 1997, 893-894 (b) McCort,
I.; Dure´ault, A.; Depezay, J .-C. Tetrahedron Lett. 1996, 37, 7717-7720.
(c) Ziegler, F. E.; Belema, M. J . Org. Chem. 1994, 59, 7962-7967.
(16) (a) Righi, G.; Franchini, T.; Bonini, C. Tetrahedron Lett. 1998,
39, 2385-2388. (b) Ezquerra, J .; Pedregal, C.; Lamas, C.; Pastor, A.;
Alvarez, P.; Vaquero, J . J . Tetrahedron Lett. 1996, 37, 683-686.
With the key aziridines 5 in hand, reductive conversion
to â-aryl alanine precursors was first studied by catalytic
hydrogenation. To our satisfaction, the reaction took
place in excellent yield and with complete regioselectivity,
affording the protected amino alcohols 9a ,b. Then, a
selective deprotection of the silyl ether (TBAF/THF) and
(11) Osborn, H. M. I.; Sweeney, J . Tetrahedron: Asymmetry 1997,
8, 1693-1715.

8576 J . Org. Chem., Vol. 63, No. 23, 1998
Notes
Sch em e 4a
aqueous solution and dried over MgSO4, and the solvents were
evaporated in vacuo. The crude product was purified by chro-
matography (AcOEt/hexane 0-5%) yielding 365 mg of 7a as a
white solid (85% yield). [R]D ) -25.9 (c 2.1, CHCl3). Mp: 43-
45 °C. IR (film) νmax: 3410, 2960, 1700, 1500 cm-1
.
1H NMR
(200 MHz, CDCl3) δ 0.04 (s, 3H), 0.06 (s, 3H), 0.93 (s, 9H), 1.41
(s, 9H), 2.7 (broad s, 1H, OH), 3.4 (dd, J ) 10.4 Hz, J ) 4.2 Hz,
1H), 3.6 (dd, J ) 10.4 Hz, J ) 3.8 Hz, 1H), 3.8 (m, 1H), 4.9 (m,
1H), 6.1 (broad d 1H, NH), 7.3 (s, 5H) ppm. 13C NMR (50 MHz,
CDCl3) δ -5.6 (CH3) 18.0 (C), 25.8 (CH3), 28.3 (CH3), 58 (CH),
63.9 (CH2), 72.8 (CH), 79.3 (C), 126.8 (CH), 127.3 (CH), 128.4
(CH), 139.3 (C), 155.5 (C) ppm. Anal. Calcd for C20H35NO4Si:
C, 62.95%; H, 9.25%; N, 3.67%. Found: C, 63.14%; H, 9.23%;
N, 3.62%.
(2R,3R)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-[(ter t-bu toxy-
ca r bon yl)a m in o]-3-(1-n a p h th yl)-2-p r op a n ol, 7b. The pro-
cedure described in the preparation of 7a but starting from 0.93
g (2.93 mmol) of 1b afforded 1.13 g of 7b as a white solid (89%
yield). [R]D ) +15.0 (c 1.0, CHCl3). Mp: 71-72 °C. IR (KBr)
νmax
:
3401, 2931, 1692, 1506 cm-1
.
1H NMR (200 MHz,
CDCl3): δ 0.14 (s, 6H), 1.03 (s, 9H), 1.34 (s, 9H), 2.89 (d J ) 8.8
Hz, 1H, OH), 3.59 (dd, J ) 10.6 Hz, J ) 3.2 Hz, 1H), 3.66 (dd,
J ) 10.6 Hz, J ) 3.0 Hz, 1H), 4.1 (broad s, 1H), 5.9 (broad s,
1H), 6.5 (broad d, 1H), 7.5-8.25 (m, 7H) ppm. 13C NMR (50
MHz, CDCl3) δ -5.7 (CH3) 18.2 (C), 25.8 (CH3), 28.3 (CH3), 55.3
(CH), 63.9 (CH2), 71.2 (CH), 79.3 (C), 122.8 (CH), 123.2 (CH),
125.2 (CH), 125.6 (CH), 126.3 (CH), 128.0 (CH), 128.8 (CH), 130.5
(C), 134.3 (C), 136.3 (C), 155.3 (C) ppm. EM (CI-NH3) m/e )
a
Reagents and conditions: (a) Me2CuLi, THF; (b) TBAF, THF;
(c) PDC, DMF.
In summary, we have developed a new procedure for
the synthesis of enantiomerically pure â-aryl alanines
and â-alkyl substituted â-aryl alanines. Our methodol-
ogy takes advantage of the convenient preparation of
optically pure N-Boc-3-aryl-3-amino-1,2-diols using the
Sharpless epoxidation as a source of chirality and is
based on the conversion of these compounds into optically
active N-Boc-aryl aziridines, which can be regioselectively
hydrogenated or opened by a organocuprate. Extension
of this methodology to the stereocontrolled preparation
of other â-substituted alanines is underway in our
laboratories and will be reported in due term.
432 (M+ + 1, 51), 376 (100), 332 (23). Anal. Calcd for C24H37
NO4Si: C, 66.78%; H, 8.64%; N, 3.24%. Found: C, 66.82%; H,
8.78%; N, 3.37%.
-
Meth a n esu lfon ic Acid (1R,2R)-2-[(ter t-Bu toxyca r bon yl)-
a m in o]-1-[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-2-p h en yl-
eth yl Ester , 8a . To a solution of 7a (1.86 g, 4.88 mmol) in
CH2Cl2 (5 mL) at -15 °C were added triethylamine (0.75 mL,
5.37 mmol), 4-(N,N-dimethylamino)pyridine (30 mg, 0.24 mmol),
and methanesulfonyl chloride (0.41 mL, 5.37 mmol). The
mixture was allowed to warm to room temperature under
stirring, and the reaction progress was monitored by TLC. When
no starting material could be detected (ca. 5 h), water (10 mL)
was added and the aqueous phase was extracted with CH2Cl2
(3 × 15 mL). The combined organic phases were washed with
cold 10% aq HCl, NaHCO3 satd solution and water, dried over
MgSO4, concentrated in vacuo, and purified by column chroma-
tography (AcOEt/hexanes 10-15%) to afford 1.87 g (83% yield)
of 8a as an oil. [R]D ) -9.6 (c 2.0, CHCl3). IR (KBr) νmax: 3400,
Exp er im en ta l Section
Gen er a l Meth od s. Optical rotations were measured at room
temperature (23 °C) (concentration in g/100 mL). Melting points
were determined in open capillary tubes and are uncorrected.
Infrared spectra were recorded using NaCl film or KBr pellet
techniques. 1H NMR were recorded at 200 MHz (s ) singlet, d
) doublet, t ) triplet, q ) quartet, dt ) double triplet, m )
multiplet, b ) broad, and bd ) broad doublet). 13C NMR were
recorded at 50.3 or 75.4 MHz. Carbon multiplicities have been
assigned by distortionless enhancement by polarization transfer
(DEPT) experiments. High-resolution mass spectra (CI) were
performed by the Servicio de Espectrometr´ıa de Masas, Univer-
sidad de Co´rdoba. Elemental analyses were performed by the
Servei d’Ana`lisis Elementals del CSIC de Barcelona. Chromato-
graphic separations were carried out using NEt3-pretreated
(2.5% v/v) SiO2 (70-230 mesh). Chromatographic analyses were
performed on a instrument equipped with a Chiralcel OD (25
cm) column. THF and diethyl ether were distilled over metallic
sodium/benzophenone. DMF and methylene chloride were
distilled over calcium hydride.
(2R,3R)-3-(ter t-Bu t oxyca r bon yla m in o)-3-ph en yl-1,2-pr o-
panediol 1a 3f and (2R,3R)-3-(tert-butoxycarbonylamino)-3-(1-
naphthyl)-1,2-propanediol 1b8 were prepared according to de-
scribed procedures.
(2R,3R)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-[(ter t-bu toxy-
ca r bon yl)a m in o]-3-p h en yl-2-p r op a n ol, 7a . To a solution of
(2R,3R)-3-[(tert-butoxycarbonyl)amino]-3-phenyl-1,2-propane-
diol 1a (300 mg, 1.12 mmol) in dimethylformamide (5 mL) were
added tert-butyldimethylsilyl chloride (186 mg, 1.23 mmol) and
imidazole (168 mg, 2.47 mmol). The reaction was monitored by
TLC. After 24 h, water (8 mL) was added, and the aqueous
phase was extracted with diethyl ether (3 × 6 mL). The
combined organic phases were washed with saturated NH4Cl
2960, 1710, 1500 cm-1
.
1H NMR (200 MHz, CDCl3) δ 0.05 (s,
3H), 0.08 (s, 3H), 0.93 (s, 9H), 1.42 (s, 9H), 3.00 (s, 3H), 3.62
(dd, J ) 12 Hz, J ) 4.1 Hz, 1H), 3.74 (dd, J ) 12 Hz, J ) 3.7
Hz, 1H,), 4.87 (m, 1H), 5.10 (broad s, 1H), 6.15 (broad d, 1H,
NH), 7.34 (s, 5H) ppm. 13C NMR (50 MHz, CDCl3) δ -5.7 (CH3)
18.0 (C), 25.7(CH3), 28.2 (CH3), 38.6 (CH3), 56.2 (CH), 62.9 (CH2),
79.4 (C), 82.0 (CH), 127.2 (CH), 128.6 (CH), 128.0 (CH), 137.4
(C), 155.1 (C) ppm. EM (CI-NH3) m/e ) 477 (M+ + 18, 100),
460 (M+ + 1, 15), 421 (18).
Meth a n esu lfon ic Acid (1R,2R)-2-[(ter t-bu toxyca r bon yl)-
a m in o]-1-[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-2-(1-n a p h -
th yl)eth yl Ester , 8b. The procedure described in the prepa-
ration of 8a but starting with 1.0 g (2.31 mmol) of 7b afforded
1.02 g of 8b as a colorless oil (87% yield). [R]D ) +38.3 (c 1.0,
CHCl3). IR (KBr) νmax: 3411, 2932, 1717, 1503 cm-1 1H NMR
.
(200 MHz, CDCl3) δ 0.03 (s, 6H), 0.92 (s, 9H), 1.38 (s, 9H), 3.03
(s, 3H), 3.55 (dd, J ) 12 Hz, 1H), 3.70 (dd, J ) 12 Hz, J ) 2.4
Hz, 1H), 5.01 (s, 1H), 6.09 (dd, J ) 7.6, J ) 4.8 Hz, 1H), 6.65
(broad d 1H, NH), 7.4-8.2 (m, 7H) ppm. 13C NMR (50 MHz,
CDCl3) δ -5.8 (CH3), 18.0 (C), 25.6 (CH3), 28.1 (CH3), 38.7 (CH3),
53.0 (CH), 63.0 (CH2), 79.3 (C), 79.3 (CH), 122.4 (CH), 123.9
(CH), 125.1 (CH), 125.7 (CH), 126.7 (CH), 128.5 (CH), 128.7 (CH),
130.6 (C), 134.1 (C), 134.2 (C), 155.6 (C) ppm. EM (CI-NH3)
m/e ) 510 (M+ + 1, 50), 454 (100), 410 (21).
(2S,3R)-1-(ter t-Bu toxyca r bon yl)-2-[[(ter t-bu tyld im eth yl-
silyl)oxy]m eth yl]-3-p h en yla zir id in e, 5a . To a suspension of
sodium hydride (13.05 mmol, from 392 mg of a 80% mixture with
paraffin washed with anhydrous hexane under nitrogen) in THF
(7 mL) was added a solution of 8a (1.5 g, 3.26 mmol) in THF (10
mL). After 3 h of stirring at room temperature, ethyl acetate (5
mL) and some drops of methanol were added to the mixture to
(17) The synthesis of four isomers of â-methyl-3-(2-naphthyl)alanine
has been reported recently: Yuan, W.; Hruby, V. J . Tetrahedron Lett.
1997, 38, 3853-3856.

Notes
J . Org. Chem., Vol. 63, No. 23, 1998 8577
Mp:73-75 °C. IR (film) νmax: 3357, 1686, 1528 cm-1 1H NMR
remove any trace of unreacted hydride. The solvent was
removed at reduced pressure, and the crude mixture was treated
with a 1:1 mixture of H2O/AcOEt. The aqueous phase was
extracted with ethyl acetate (3 × 7 mL), and the combined
organic phases were dried (MgSO4) and concentrated. Purifica-
tion of the crude mixture by column chromatography (AcOEt/
hexanes 3%) gave 0.89 g of aziridine 5a as a colorless oil (75%
yield). [R]D ) -54.6 (c 1.1, EtOH). IR (film) νmax: 2931, 1721
.
(200 MHz, CDCl3) δ: 1.4 (s, 9H), 2.35 (s, broad, 1H, OH), 2.84
(d, J ) 6.8 Hz, 2H), 3.52-3.69 (m, 2H), 3.87 (m, 1H), 4.75 (broad
d, J ) 8.4 Hz, 1H, NH), 7.2-7.35 (m, 5H) ppm. 13C NMR (50
MHz, CDCl3) δ 28.3 (CH3), 37.4 (CH2), 53.7 (CH), 64.3 (CH2),
79.7 (C), 126.5 (CH), 128.5 (CH), 129.3 (CH), 137.8 (C), 156.5
(C) ppm. EM (CI-NH3) m/e ) 286 (M+ + 35, 4), 269 (M+ + 18,
100), 252 (M+ + 1, 83). Anal. Calcd for C14H21NO3: C, 66.91%,
H, 8.42%; N, 5.57%. Found: C, 66.86%; H, 8.51%; N, 5.52%.
(2S)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-3-(1-n a p h t h yl)-1-
p r op a n ol, 10b. Following the procedure described in the
preparation of 10a but starting with 68 mg (0.16 mmols) of 9b,
cm-1 1H NMR (200 MHz, CDCl3): δ 0.09 (s, 3H), 0.11 (s, 3H),
.
0.92 (s, 9H), 1.39 (s, 9H), 2.8 (m, 1H), 3.5 (d, J ) 3.4 Hz, 1H),
3.92 (dd, J ) 11.5 Hz, J ) 3.7 Hz, 1H), 4.05 (dd, J ) 10.4 Hz, J
) 11.5 Hz, J ) 3.2 Hz, 1H), 7.3 (s, 5H) ppm. 13C NMR (50 MHz,
CDCl3) δ -5.2 (CH3), 18.4 (C), 25.9 (CH3), 28.0 (CH3), 41.5 (CH),
46.6 (CH), 60.3 (CH2), 81.0 (C), 126.7 (CH), 127.6 (CH), 128.3
46 mg of 10b was obtained as a white solid (93% yield). [R]D
-55.7 (c 1.0, CHCl3). Mp: 122-123 °C. IR (KBr) νmax: 3367,
2975, 1684, 1532 cm-1 1H NMR (200 MHz, CDCl3) δ 1.4 (s,
)
(CH), 136.6 (C), 160.7 (C) ppm. EM (CI-NH3) m/e ) 381 (M+
+
.
18, 5), 364 (M+ + 1, 60), 325 (100). HRMS (CI) calcd for
9H), 3.1 (broad s, 1H, OH), 3.3 (m, 2H), 3.58 (dd, J ) 11 Hz, J
) 4.8 Hz, 1H), 3.67 (dd, J ) 11 Hz, J ) 4.8 Hz, 1H), 4-4.09 (m,
1H), 4.9 (broad s, 1H), 7.3-8.2 (m, 7H) ppm. 13C NMR (50 MHz,
CDCl3) δ 28.3 (CH3), 34.5 (CH2), 53.1 (CH), 64.1 (CH2), 79.5 (C),
123.8 (CH), 125.4 (CH), 125.6 (CH), 126.2 (CH), 127.4 (CH), 127.5
(CH), 128.7 (CH), 131.6 (C), 133.9 (C), 134.0 (C), 157.8 (C) ppm.
EM (CI-NH3): m/e ) 302 (M+ + 1, 29), 319 (M+ + 18, 100).
Anal. Calcd for C18H23NO3: C, 71.73%; H, 7.69%; N, 4.64%,
Found: C, 72.01%; H, 7.71%; N, 4.65%.
C
20H34O3NSi: 364.2308. Found: 364.2317.
(2S,3R)-1-(ter t-Bu toxyca r bon yl)-2-[[(ter t-bu tyld im eth yl-
silyl)oxy]m eth yl]-3-(1-n a p h th yl)-a zir id in e, 5b. The proce-
dure described in the preparation of 5a but starting with 460
mg of 8b afforded 309 mg of aziridine 5b as a white solid (82%
yield). [R]D ) -67.2 (c 0.97, CHCl3). Mp: 63-65 °C. IR (KBr)
ν
max: 2933, 1719 cm-1 1H NMR (200 MHz, CDCl3) δ 0.15 (s,
.
6H), 0.96 (s, 9H), 1.37 (s, 9H), 2.84 (m, 1H), 3.92 (dd, J ) 11.4
Hz, J ) 4.6 Hz, 1H), 4.05 (d, J ) 3.4 Hz), 4.27 (dd, J ) 11.4 Hz,
J ) 3.4 Hz, 1H), 7.4-8.4 (m, 7H) ppm. 13C NMR (50 MHz,
CDCl3) δ -5.3 (CH3) 18.6 (C), 25.9 (CH3), 27.9 (CH3), 40.6 (CH),
45.2 (CH), 60.9 (CH2), 81.0 (C), 123.9 (CH), 124.2 (CH), 125.4
(CH), 125.8 (CH), 126.1 (CH), 128.1 (CH), 128.4 (CH), 132.1 (C),
132.7 (C), 133.3 (C), 159.7 (C) ppm. EM (CI-NH3) m/e ) 431
(M+ + 18, 100), 414 (M+ + 1, 68), 375 (100), 376 (29). Anal.
N-Boc-(L)-P h en yla la n in e 4a . To a solution of 10a (50 mg,
0.2 mmol) was added under nitrogen at room temperature a
solution of PDC (374 mg, 1.0 mmol) in DMF (0.75 mL). After
24 h of stirring, water (10 mL) and diethyl ether (10 mL) were
added. The aqueous phase was extracted with diethyl ether (3
× 7 mL), and the combined organic phases were dried (MgSO4)
and evaporated. The crude product was taken with AcOEt and
extracted with NaHCO3 satd solution. The aqueous layer was
washed with AcOEt, acidified with 2 N HCl, and extracted with
AcOEt. The organic phases were then dried (MgSO4) and
evaporated yielding 43 mg of N-Boc-phenylalanine 4a (81% yield)
spectroscopically identical to a commercial sample (Propeptide).
Determination of the enantiomeric purity: To a mixture of 4a
(61 mg, 0.23 mmol) and KHCO3 (46 mg, 0.46 mmol) in DMF
(0.4 mL) was added CH3I (43 µL,0.69 mmol) by syringe. After
24 h of stirring water (2 mL) was added, and the aqueous phase
was extracted with diethyl ether (3 × 3 mL). The combined
organic phases were washed with water (2 × 2 mL), 5% aqueous
Na2SO3 (2 × 2 mL) and brine (2 × 2 mL), dried (MgSO4), and
evaporated under vacuum. The crude product was chromato-
graphed (AcOEt/hexanes 0-5%) yielding 44 mg of N-Boc-(L)-
phenylalanine methyl ester (69% yield). Chiral HPLC analy-
sis: only one peak at 18.9 min (> 99% ee) was observed under
the following conditions: CHIRALCEL OD (25 cm) column, 30
°C, hexane/2-propanol 90/10, 0.3 mL/min, λ ) 254 nm. Racemic
sample: tR(2R) ) 17.6 min, tR(2S) ) 19.0 min.
Calcd for
C24H35NO3Si: C, 69.69%; H, 8.52%; N, 3.38%.
Found: C, 69.71%; H, 8.60%; N, 3.32%.
(2S)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-1-[(ter t-Bu t yld i-
m eth ylsilyl)oxy]-3-p h en ylp r op a n e, 9a . A solution of aziri-
dine 5a (205 mg, 0.56 mmol) in ethyl acetate (3 mL) was added
to a stirred suspension of 10% Pd/C (30 mg) in ethyl acetate (1.2
mL) under hydrogen. The mixture was hydrogenated at atmo-
spheric pressure (hydrogen balloon) until no starting material
could be detected by TLC (ca. 4 h). Then, the suspension was
filtered through Celite, washing the filtrate thoroughly with
AcOEt and MeOH. The solvents were evaporated at reduced
pressure yielding 206 mg of a crude product that was spectro-
scopically pure (quantitative yield). [R]D ) -22.8 (c 1.1, CHCl3).
IR (film) νmax: 3452, 2930, 1719, 1497, 1254, 1171, 837 cm-1
.
1H NMR (200 MHz, CDCl3) δ 0.05 (s, 6H), 0.92 (s, 9H), 1.42 (s,
9H), 2.8 (d, J ) 7 Hz, 2H), 3.45-3.57 (m, 2H), 3.82 (s, 1H), 4.73
(broad s, 1H, NH), 7.2-7.35 (m, 5H) ppm. 13C NMR (50 MHz,
CDCl3) δ -5.2 (CH3), 18.4 (C), 25.9 (CH3), 28.3 (CH3), 37.3 (CH2),
53.0 (CH), 62.8 (CH2), 81.0 (C), 126.2 (CH), 128.3 (CH), 129.4
(CH), 139.9 (C), 154.0 (C) ppm. EM (CI-NH3) m/e ) 383 (M+
+
N-Boc-(L)-(1-Na p h th yl)a la n in e, 4b. The procedure de-
scribed in the preparation of 4a but starting with 76 mg (0.25
mmol) of 10b afforded 56 mg of 4b (71% yield), spectroscopically
identical to a commercial sample (Sigma). Determination of the
enantiomeric purity: Chiral HPLC analysis of the methyl ester
prepared as described in the preparation of 4a . A major peak
at 15.4 min (>98% ee) was observed under the following
conditions: CHIRALCEL OD (25 cm) column, 30 °C, hexane/2-
propanol 90/10, 0.5 mL/min, λ ) 254 nm. Racemic sample: tR-
(2R) ) 13.7 min, tR(2S) ) 15.4 min.
18, 9), 366 (M+ + 1, 100). HRMS (CI) calcd for C16H30NOSi (M+
- Boc): 280.2097. Found: 280.2089.
(2S)-2-[(t er t-b u t oxyca r b on yl)a m in o]-1-[(t er t-Bu t yld i-
m eth ylsilyl)oxy]-3-(1-n a p h th yl)p r op a n e, 9b. The procedure
described in the preparation of 9a but starting with 5b (76 mg,
0.18 mmol) afforded after chromatographic purification (AcOEt/
hexanes 0-2%) 68 mg of 9b (88% yield). [R]D ) -35.0 (c 0.8,
CHCl3). IR (KBr) νmax: 3450, 2931, 1713, 1491 cm-1 1H NMR
.
(200 MHz, CDCl3) δ 0.05 (s, 3H), 0.06 (s, 3H,), 0.96 (s, 9H), 1.44
(s, 9H), 3.15-3.5 (m, 4H), 4.01 (s, broad, 1H), 4.95 (broad d, 1H),
7.3-8.4 (m, 7H) ppm. 13C NMR (50 MHz, CDCl3) δ -5.4 (CH3)
18.4 (C), 25.9 (CH3), 28.4 (CH3), 34.4 (CH2), 52.2 (CH), 62.6
(CH2), 78.9 (C), 124.2 (CH), 125.3 (CH), 125.5 (CH), 126.1 (CH),
127.1 (CH), 127.7 (CH), 128.6 (CH), 132.3 (C), 133.7 (C), 134.5
(C), 155.5 (C) ppm. EM (CI-CH4): m/e ) 416 (M+ + 1, 92), 360
(100), 316 (33).
(2S,3S)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-[(ter t-bu toxy-
ca r bon yl)a m in o]-3-p h en ylbu ta n e, 11a . To a stirred slurry
of CuI (171 mg) in anhydrous diethyl ether (3 mL) at 0 °C was
added MeLi (1.12 mL, 1.6 M in diethyl ether), and the mixture
was stirred at this temperature several minutes. A solution of
aziridine 5a (109 mg, 0.30 mmol) in diethyl ether (3 mL) was
added via cannula to the lithium dimethylcuprate solution at 0
°C, and the reaction was stirred under N2 and monitored by TLC.
When no starting material could be detected (ca. 2 h), a 8:1
mixture of saturated aqueous NH4Cl and NH4OH (6 mL) was
added to the reaction, and the organic layer was extracted with
diethyl ether (3 × 6 mL). The combined organic phases were
dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash chromatography (AcOEt/hexanes 0-2%) yield-
ing 90 mg of 11a (80% yield) as an oil: [R]D ) -17.0 (c 1.0,
(2S )-2-[(t er t -Bu t oxyca r b on yl)a m in o]-3-p h e n yl-1-p r o-
p a n ol, 10a . To a solution of 9a (120 mg, 0.33 mmol) in THF
(1.7 mL) at 0 °C was added a solution of tetrabutylammonium
fluoride monohydrate (0.17 g, 0.65 mmol) in THF (1 mL). The
reaction was stirred at room temperature and monitored by TLC.
After 60 min, the solution was washed with water and the
organic layer extracted with ether. The combined organic phases
were dried over MgSO4 and concentrated in vacuo. The residue
was purified by chromatography (AcOEt/hexane), yielding 68 mg
(83% yield) of 10a as a white solid. [R]D ) -25.0 (c 1.0, CHCl3).
CHCl3). IR (film): νmax: 3452, 2930, 1719, 1497 cm-1
.
1H NMR
(200 MHz, CDCl3) δ 0.048 (s, 6H), 0.92 (s, 9H), 1.27 (s, 9H), 1.39

8578 J . Org. Chem., Vol. 63, No. 23, 1998
Notes
(d, J ) 9.6 Hz, 3H), 3.1 (m, 1H), 3.4-3.6 (m, 2H), 3.7 (m broad,
1H), 4.4 (broad s, 1H), 7.1-7.3 (m, 5H) ppm. 13C NMR (50 MHz,
CDCl3) δ -5.5 (CH3), 18.2 (C), 18.2 (CH3), 25.9 (CH3), 28.3 (CH3),
39.6 (CH), 56.1 (CH), 62.8 (CH2), 78.8 (C), 126.3 (CH), 128.2
(CH), 129.4 (CH), 143.0 (C), 154.5 (C) ppm. EM (CI-NH3) m/e
) 397 (M+ + 18, 4), 380 (M+ + 1, 100).
s, 1H), 7.4-8.2 (m, 7H) ppm. 13C NMR (50 MHz, CDCl3) δ 18.3
(CH3), 28.1 (CH3), 34.2 (CH), 57.1 (CH), 63.3 (CH2), 79.7 (C),
123.1 (CH), 123.9 (CH), 125.3 (CH), 125.4 (CH), 126.0 (CH), 127.0
(CH), 128.9 (CH), 132.0 (CH), 133.9 (CH), 139.4 (CH), 156.0 (C)
ppm. EM (CI-NH3): m/e ) 333 (M+ + 18, 17%), 316 (M+ + 1,
100%), 277 (38%), 260 (24%), 216 (6%). HRMS (CI) calcd for
(2S,3S)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-[(ter t-bu toxy-
ca r bon yl)a m in o]-3-(1-n a p h th yl)bu ta n e, 11b. To a solution
of aziridine 5b (100 mg, 0.24 mmol) in diethyl ether (2.4 mL)
was added via cannula at -20 °C a solution of lithium dimeth-
ylcuprate (0.60 mmol) in diethyl ether prepared as described in
the preparation of 11a . After 4 h of stirring at this temperature,
the reaction was worked up as described in the preparation of
11a affording after chromatographic purification (AcOEt/
hexanes 0.5%) 70 mg of 11b (68% yield). [R]D ) +12.4 (c 1.1,
C
19H25O3N: 315.1834. Found: 315.1814.
(2S,3S)-2-[(ter t-Bu toxycar bon yl)am in o]-3-ph en ylbu tan o-
ic Acid (N-Boc-(L)-â-Meth yl-â-p h en yla la n in e), 6a . The pro-
cedure described in the preparation of 4a but starting with 114
mg (0.43 mmol) of 12b afforded 93 mg of 6a (77% yield),
spectroscopically identical to the product described in the
literature.4 Determination of the enantiomeric purity: Chiral
HPLC analysis of the methyl ester, prepared as described for
4a : Only one peak at 20.1 min (>99% ee) was observed under
the following conditions: CHIRALCEL OD (25 cm) column, 30
°C, hexane/2-propanol 90/10, 0.3 mL/min, λ ) 254 nm. Racemic
sample: tR(2R,3R) ) 22.6 min, tR(2S, 3S) ) 20.5 min.
CHCl3). IR (KBr) νmax: 3454, 2931, 1715, 1495 cm-1 1H NMR
.
(200 MHz, CDCl3) δ 0.042 (s, 3H), 0.06 (s, 3H), 0.94 (s, 9H), 1.27
(s, 9H), 1.43 (d, J ) 6.6 Hz, 3H), 3.57-3.8 (m, 2H), 4.1 (m, 2H),
4.64 (broad d), 7.4-8.4 (m, 7H) ppm. 13C NMR (50 MHz, CDCl3)
δ -5.4 (CH3), 18.5 (CH3), 18.3 (C), 25.9 (CH3), 28.3 (CH3), 33.9
(CH), 55.8 (CH), 62.8 (CH2), 78.8 (C), 123.3 (CH), 124.1 (CH),
125.2 (CH), 125.4 (CH), 125.8 (CH), 126.7 (CH), 128.7 (CH), 132.2
(C), 133.7 (C), 139.7 (C), 155.3 (C) ppm. EM (CI-NH3) m/e )
(2S,3S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-(1-n a p h th yl)-
bu ta n oic Acid [N-BOC-â-Meth yl-(L)-(1-n a p h th yl)a la n in e],
6b. The procedure described in the preparation of 4a but
starting with 53 mg (0.17 mmol) 12b afforded 43 mg of 6b (83%
yield). [R]D ) +66.7 (c 0.9, MeOH). IR (film) νmax: 3051, 2979,
447 (M+ + 18, 1), 430 (M+ + 1, 100). HRMS (CI) calcd for C25H40
NO3Si (M+ + 1): 430.2777. Found: 430.2761.
-
1717, 1600, 1397, 1163, 779 cm-1 1H NMR (200 MHz, CDCl3)
.
δ 1.37 (s, 9H), 1.5 (d, J ) 6.8 Hz, 3H), 4.2 (m, 1H), 4.65 (m, 1H),
4.9 (broad d, 1H), 7.2-7.8 (m, 7H) ppm. 13C NMR (50 MHz,
CDCl3) δ 18.4 (CH3), 28.2 (CH3), 35.9 (CH), 58.2 (CH), 80.5 (C),
122.8 (CH), 124.1 (CH), 125.3 (CH), 125.5 (CH), 126.2 (CH), 127.5
(CH), 128.9 (CH), 131.7 (C), 133.8 (C), 137.1 (C), 155 (C), 176
(2S ,3S )-2-[(t er t -B u t o x y c a r b o n y l)a m i n o ]-3-p h e n y l-
bu ta n ol, 12a . The procedure described in the preparation of
10a , but starting with 112 mg (0.30 mmols) of 11a , afforded 60
mg of 12a (80% yield) as a white solid. [R]D ) -2.3 (c 1.0,
CHCl3). Mp 49-51 °C. IR (film) νmax: 3363, 2973, 1684 cm-1
.
(C) ppm. EM (CI-NH3) m/e ) 347 (M+ + 18, 100), 330 (M+
+
1H NMR (200 MHz, CDCl3) δ 1.27 (d, J ) 5.4 Hz, 3H), 1.35 (s,
9H), 2.75 (s, broad, 1H, OH), 3.05-3.2 (m, 1H), 3.5-3.9 (m, 3H),
4.7 (broad d, 1H, NH), 7.15-7.3 (m, 5H) ppm. 13C NMR (50
MHz, CDCl3) δ 18.3 (CH3), 28.3 (CH3), 40.2 (CH), 57.3 (CH), 64.0
(CH2), 80.5 (C), 127.9 (CH), 128.5 (CH), 128.7 (CH), 142.8 (C),
156.5.0 (C) ppm. EM (CI-NH3): m/e ) 266 (M+ + 1, 100%),
1, 26), 291 (40). HRMS (CI) calcd for C14H16NO2 (M+ - Boc):
230.1181. Found: 230.1190. Determination of the enantiomeric
purity: Chiral HPLC analysis of the methyl ester prepared as
described in the preparation of 4a . A major peak at 31.7 min
(>97% ee) was observed under the following conditions: CHIRAL-
CEL OD (25 cm) column, 30 °C, hexane/2-propanol 99/1, 0.45
mL/min, λ ) 254 nm. Racemic sample: tR(2R,3R) ) 37.3 min,
tR(2S, 3S) ) 31.7 min.
283 (M+ + 18, 92%), 300 (M+ + 35, 4%). Anal. Calcd for C15H23
-
NO3: C, 67.89%; H, 8.73%; N, 5.28%. Found: C, 67.78%; H,
8.89%; N, 5.00%.
(2S,3S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-(1-n a p h th yl)-
bu ta n ol, 12b. The procedure described in the preparation of
10a , but starting with 115 mg (0.27 mmols) of 11b, afforded 79
mg of 12b as a colorless oil (93% yield). [R]D ) +29.1 (c 1.1,
Ack n ow led gm en t. Financial support from DGICYT
(PB95-0265) and from CIRIT (GRQ93-1083 and
1996SGR-00013) is gratefully acknowledged. E.M. thanks
Universitat de Barcelona for a predoctoral fellowship.
CHCl3). IR (KBr) νmax: 3429, 2977, 1694, 1511 cm-1 1H NMR
.
(200 MHz, CDCl3) δ 1.3 (s, 9H), 1.45 (d, J ) 6.6 Hz, 3H), 2.3
(broad s, 1H, OH), 3.6-3.8 (m, H), 3.9-4.1 (m, 3H), 4.6 (broad
J O981140I