A diastereoselective intramolecular hydroamination approach to the syntheses of (+)-, (±)-, and (-)-pinidinol

Article abstract of DOI:10.1021/jo015603n

A diastereoselective, lanthanocene-catalyzed, intramolecular hydroamination reaction was applied to the preparation of 2,6-disubstituted piperidines. Various metal/ligand arrays in the catalysts were examined using a model substrate to allow optimization of the diastereoselectivity. It was determined that the relationship between metal size and ligand bulk plays an integral role in the transformation. The complex Cp*₂NdCH(TMS)₂ converted 2-substituted 8-nonen-4-amines to 2,6-disubsituted piperidines with greater than 100: 1 selectivity for the formation of the cis isomer. A short synthesis of pinidinol, an alkaloid isolated from various pine and spruce species, was then carried out to exploit this stereoselective reaction.

Full text of DOI:10.1021/jo015603n

4344
J . Org. Chem. 2001, 66, 4344-4347
A Dia ster eoselective In tr a m olecu la r Hyd r oa m in a tion Ap p r oa ch to
th e Syn th eses of (+)-, (()-, a n d (-)-P in id in ol
Gary A. Molander,* Eric D. Dowdy, and Shawn K. Pack
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323
gmolandr@sas.upenn.edu
Received March 1, 2001
A diastereoselective, lanthanocene-catalyzed, intramolecular hydroamination reaction was applied
to the preparation of 2,6-disubstituted piperidines. Various metal/ligand arrays in the catalysts
were examined using a model substrate to allow optimization of the diastereoselectivity. It was
determined that the relationship between metal size and ligand bulk plays an integral role in the
transformation. The complex Cp*2NdCH(TMS)2 converted 2-substituted 8-nonen-4-amines to 2,6-
disubsituted piperidines with greater than 100:1 selectivity for the formation of the cis isomer. A
short synthesis of pinidinol, an alkaloid isolated from various pine and spruce species, was then
carried out to exploit this stereoselective reaction.
In tr od u ction
The formation of polysubstituted heterocycles is an
important endeavor in synthetic organic chemistry, and
approaches to many naturally occurring and biologically
important molecules would benefit by the development
of diastereoselective ring-forming reactions. A highly
selective preparation of 2,5-disubstituted pyrrolidines
employing the intramolecular hydroamination of substi-
tuted aminopentenes was reported by Marks and co-
workers (eq 1).1 In a thorough study, they elucidated the
F igu r e 1. Proposed transition structure for the formation of
2,6-disubstituted piperidines via the intramolecular hydroami-
nation reaction.
(Picea) species, pinidinol is also absorbed by parasitic
plants feeding on the roots of these trees. Although
specific biological activity information is lacking, a crude
alkaloid extract containing 1 has shown moderate to high
antifeedant activity against Eastern spruce budworms.
Pinidinol was recently synthesized by the double
alkylation of benzylamine with an appropriately func-
tionalized ditosylate (eq 2).2c The stereocenters in the
molecule were established using asymmetric dihydroxy-
lation reactions. Prior to its isolation from a natural
source, 1 was prepared in racemic fashion as an inter-
mediate in the synthesis of pinidine by the reduction of
a 2,6-disubstituted pyridine (eq 3).2d The former synthesis
effects of catalyst structure and reaction conditions on
the diastereoselectivity of the intramolecular reaction.
The major diastereomer obtained (trans) in the olefin
insertion process was rationalized by considering a chair-
like transition structure that minimized steric interac-
tions during the cyclization.
Left unanswered was the stereochemistry of the pro-
cess exhibited during the formation of disubstituted
piperidines under similar reaction conditions. A simple,
one methylene extension of the chairlike model proposed
above predicts the formation of cis-2,6-disubstituted
piperidines (Figure 1). However, the well-known differ-
ences between five- and six-membered rings would most
likely require tuning of the steric and electronic environ-
ments about the catalyst to achieve useful selectivity.
Consequently, the current study was undertaken to
determine these optimal conditions and to apply it to the
synthesis of a natural product.
was 11 steps with a low overall yield (1.25%). Although
not targeted at the preparation of 1, the latter synthesis
A simple alkaloid bearing this structural feature is (-)-
pinidinol (1) (eq 2).2 Isolated from a variety of spruce
(2) (a) Schneider, M. J .; Montali, J . A.; Hazen, D.; Stanton, C. E. J .
Nat. Prod. 1991, 54, 905. (b) Schneider, M. J .; Stermitz, F. R.
Phytochemistry 1990, 29, 1811. (c) Takahata, H.; Yotsui, Y.; Momose,
T. Tetrahedron 1998, 54, 13505. (d) Leete, E.; Carver, R. A. J . Org.
Chem. 1975, 40, 2151.
(1) Gagne´, M. R.; Stern, C. L.; Marks, T. J . J . Am. Chem. Soc. 1992,
114, 275.
10.1021/jo015603n CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/16/2001

Synthesis of Pinidinol
J . Org. Chem., Vol. 66, No. 12, 2001 4345
Sch em e 1a
Sch em e 2a
a
Key: (a) 4-Pentenylmagnesium bromide, 83%. (b) Phthalimide,
Ph3P, DEAD, 56%. (c) Aqueous MeNH2, THF, 55%.
Ta ble 1. F in e Tu n in g of th e Ca ta lyst
a
Key (racemic yields): (a) n-BuLi. (b) (i) TBDPSCl, imidazole,
DMAP; (ii) HgCl2; (iii) NaBH4, 3.7:1, 74% (65%). (c) Phthalimide,
Ph3P, DEAD, 78% (45%). (d) NaBH4 then HOAc, 72% (45%).
entry
catalyst
time (h) temp (°C) ratio
1
2
3
4
Me2SiCpCp′′YCH(TMS)2
[CpTMS2YMe]2
Cp*2YMe‚THF
Cp*2NdCH(TMS)2
∼12
rt
rt
80
rt
7:1
10:1
17:1
much bulkier ligand array (Cp* ) C5Me5)8 provided
another gain, although heating was required to push the
reaction to completion in a synthetically useful time
(entry 3). As the heating could have eroded the selectivity
imparted by the hindered ligands, a complex based on a
metal with a larger ionic radius (entry 4)9 was used with
the hope that the reaction would proceed under milder
conditions. This combination of very hindered Cp* ligands
and a large lanthanide metal (Nd) provided a satisfactory
level of diastereoselectivity. The identity of the major
isomer was confirmed by conversion of this material to
the corresponding picrate salt (7) and X-ray diffraction
analysis of the resulting crystalline solid. As expected,
the major isomer was found to be cis. This result can be
rationalized from the proposed chairlike transition struc-
ture (Figure 1) where both the isopropyl and the incipient
methyl group occupy equatorial orientations in the
developing six-membered ring.
48
48
∼12
115:1
generated an inseparable mixture of enantiomers and
diastereomers in the reduction step.
A straightforward retrosynthesis based on the in-
tramolecular hydroamination reaction (eq 4) provides an
interesting approach to this synthetic target and a means
to probe the stereochemical preferences of the key
transformation.
Resu lts a n d Discu ssion
With reaction conditions established for the prepara-
tion of cis-2,6-disubstituted piperidines, an enantioselec-
tive route to (-)-pinidinol was devised utilizing appro-
priately functionalized cyclization substrates (Scheme 2).
To assess the enantiomeric purity of the final target, an
approach was utilized that allowed the synthesis of the
enantiomerically pure product as well as the racemate.
The synthetic scheme began with a lynchpin reaction,10
coupling the dithiane 8 to the epoxide 9 and iodopentene
10 in a single pot. The 5-iodo-1-pentene (10) was syn-
thesized from the commercially available 5-bromo-1-
pentene via a Finkelstein reaction.11 Without purification,
11 was converted to 12 by protecting the alcohol with
tert-butyldiphenylsilyl chloride, removing the dithiane
with HgCl2,12 and stereoselectively reducing the siloxy
ketone with NaBH4. A 3.7:1 ratio of chromatographically
separable diastereomers was obtained, with the major
isomer being syn. A Mitsunobu reaction,4 followed by a
NaBH4 reduction,13 was then used to generate the
substrate 14 for cyclization.
A model system that mimics the steric demands of
pinidinol was prepared to allow easy optimization of the
cyclization conditions and to provide a rapid assessment
of the stereochemical preference of the reaction (Scheme
1). The carbon framework of the model substrate was
constructed by the addition of pentenylmagnesium bro-
mide to isobutyraldehyde (2).3 The primary amine was
installed by Mitsunobu inversion with phthalimide4
followed by deprotection with methylamine.5
A series of catalysts were surveyed in this hydroami-
nation reaction, with improved diastereoselectivity
achieved by modifying the structure of the catalyst (Table
1). Although varying reaction conditions were required,
all catalysts used were active in the cyclization, and gas
chromatography (GC) analysis indicated complete con-
sumption of starting material and clean conversion to
product. The least selective catalyst proved to be the
bridged and lightly substituted yttrium complex de-
scribed in entry 1 (Cp′′ ) C5Me4).6 By using a catalyst
with slightly bulkier ligands (entry 2),7 a modest im-
provement in the diastereoselectivity was observed. A
(8) den Haan, K. H.; de Boer, J . L.; Teuben, J . H.; Smeets, W. J .;
Spek, A. L. J . Organomet. Chem. 1987, 327, 31.
(3) Hwa, J . C. H.; Sims, H. Organic Syntheses; Wiley and Sons: New
York, 1973; Collect. Vol. V, p 608.
(4) Mulzer, J .; Brand, C. Tetrahedron 1986, 42, 5961.
(5) Wolfe, S.; Hasan, S. K. Can. J . Chem. 1970, 48, 3572.
(6) Molander, G. A.; Dowdy, E. D.; Noll, B. C. Organometallics 1998,
17, 3754.
(9) J eske, G.; Lauke, H.; Mauermann, H.; Swepston, P. N.; Schu-
mann, H.; Marks, T. J . J . Am. Chem. Soc. 1985, 107, 8091.
(10) Bracher, F.; Schulte, B. Org. Prep. Proced. Int. 1995, 27, 682.
(11) Kuwajima, I.; Hirokazu, U. Organic Syntheses; Wiley and
Sons: New York, 1993; Collect. Vol. VIII, p 486.
(12) Corey, E. J .; Crouse, D. J . Org. Chem. 1968, 33, 298.
(13) Osby, J . O.; Martin, M. G.; Ganem, B. Tetrahedron Lett. 1984,
25, 2093.
(7) Schumann, H.; Keitsch, M. R.; Demtschuk, J .; Molander, G. A.
J . Organomet. Chem. 1999, 582, 70.

4346 J . Org. Chem., Vol. 66, No. 12, 2001
Molander et al.
Sch em e 3a
Sch em e 5
a
Key (racemic yields): (a) 9% Cp*2NdCH(TMS)2, rt, 90% (89%).
(b) (i) KOH in MeOH then HCl; (ii) KOH, 66% (36%).
Sch em e 4a
Conversion of 19 to (+)-1 was accomplished using the
general procedures outlined in Schemes 2 and 3, without
the isolation of the HCl salt, in 38.5% overall yield. The
spectra of the product obtained matched that of the
natural material, with the optical rotation being similar
in magnitude but opposite in sign, thus confirming the
synthesis of (+)-pinidinol.
The role of the siloxy stereocenter on the diastereose-
lectivity of the hydroamination was explored in greater
detail by converting 23 to piperidine 24 (Scheme 5). The
synthesis of 23 was achieved by using the above-men-
tioned procedures from the alcohol 22. The alcohol was
isolated as the minor isomer in the reduction of 19. The
hydroamination proceeded with greater than 100:1 se-
lectivity for the 1,3-cis isomer, indicating little or no
dependence of the diastereoselectivity on the size or
stereochemistry of additional stereocenters in the pen-
dant group.
a
Key: (a) Baker’s yeast, 50%, 96% ee. (b) TBDPSCl, imidazole,
DMAP, 84%.
F igu r e 2. Mosher’s esters formed from alcohol 18.
The cyclization of 14 proceeded smoothly, providing
piperidine 15 with good diastereoselectivity (>100:1) and
with good yield after silica gel chromatography (Scheme
3). The protecting group was removed by boiling in
methanol with KOH.14 Purification of (-)-1 and (()-1 was
achieved by generating the crystalline HCl salts 16. The
spectra of the material obtained matched those reported
in the literature for (-)- and (()-pinidinol.2 Chiral GC
using the racemate as a standard confirmed the enan-
tiomeric purity of the natural product as being 99.9+%
ee.
An enantioselective synthesis of (+)-pinidinol was
carried out by another route. The synthesis began with
the known diketone 17 (Scheme 4), itself prepared by the
alkylation of the dianion of 2,4-pentanedione.15 Enantio-
selective introduction of the hydroxyl group was achieved
by a selective baker’s yeast reduction of the desired ke-
tone.16 The enantioselectivity of the reaction was estab-
lished by conversion of the material to the corresponding
Mosher’s ester 20 (Figure 2).17 As 18 contained small
amounts of isomeric impurities resulting in similar 1H
NMR resonances, an authentic sample of (()-18 was
prepared.18 Formation of Mosher’s ester from the racemic
alcohol gave 21, and NMR analysis allowed the identi-
fication of the appropriate peaks in the NMR spectrum
of 20, revealing the enantiomeric excess of the material
to be 96%.
Con clu sion s
The stereoselectivity exhibited during the construction
of 2,6-disubstituted piperidines from substituted amino-
hexenes using the intramolecular hydroamination reac-
tion was determined and optimized. A steric model that
minimizes the interactions between the 2,6 substituents
of the incipient ring, with only the amine stereocenter
determining the outcome, can be used to rationalize the
observed (cis) product. The variability of the lanthanide
metallocene scaffold provided a means to maximize the
diastereoselectivity of the reaction. The high diastereo-
selectivity achieved upon tuning was then used for the
enantioselective synthesis of (+)- and (-)-pinidinol as
well as (()-pinidinol. A brief and efficient synthetic
scheme was used for the substrate synthesis with the
absolute stereochemistry introduced by the readily avail-
able, enantiomerically pure, propylene oxide and by a
highly enantioselective baker’s yeast reduction. Cycliza-
tion using the optimized catalyst followed by deprotection
yielded (-)-1 in 10 steps in 19% yield, (+)-1 in 7 steps
from the known diketone 17 in 16% yield, and (()-1 in
10 steps in 3.3% yield (unoptimized).
Exp er im en ta l Section
Rea gen ts. Et2O, tetrahydrofuran (THF), and C6D6 were
distilled from sodium benzophenone ketyl. C6D6 was degassed
prior to use. Cp*2NdCH(TMS)2 was prepared by a literature
procedure9 and handled in a nitrogen-filled glovebox. All other
reagents were used as received. GC conditions: 60 °C for 5
min, 10 °C/min ramp, max temp ) 250 °C; HP Ultra 2, cross-
linked 5% phenylmethyl silicone, 25 m × 0.32 mm.
(14) Malik, A. A.; Cormier, R. J .; Sharts, C. M. Org. Prep. Proced.
Int. 1986, 18, 345.
(15) Huckin, S. N.; Weiler, L. J . Am. Chem. Soc. 1974, 96, 1082.
(16) (a) Bolte, J .; Gourcy, J . G.; Veschambre, H. Tetrahedron Lett.
1986, 27, 565. (b) Fauve, A.; Veschambre, H. J . Org. Chem. 1988, 53,
5215. (c) Dauphin, G.; Fauve, A.; Veschambre, H. J . Org. Chem. 1989,
54, 2238.
(17) (a) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969,
34, 2543. (b) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95,
512.
(2R,2′R,6′R)-1-(6′-Met h ylp ip er id in -2′-yl)-2-ter t-b u t yl-
d ip h en ylsilyloxyp r op a n e [(-)-15]. Gen er a l P r oced u r e
for In tr a m olecu la r Hyd r oa m in a tion . In a nitrogen-filled
glovebox, a vial was charged with 10 mg (17 µmol) of
(18) Bernardi, R.; Ghiringhelli, D. J . Org. Chem. 1987, 52, 5021.

Synthesis of Pinidinol
J . Org. Chem., Vol. 66, No. 12, 2001 4347
Cp*2NdCH(TMS)2 and 100 mg of C6D6. A solution of (+)-14
was prepared by dissolving 73 mg (180 µmol) in 200 mg of
C6D6. The amine solution was charged to the green catalyst
solution followed by a 200-mg C6D6 rinse. The brown/green
solution was allowed to stand overnight at rt. The vial was
removed from the glovebox and charged with 2 mL of hexanes.
The catalyst solution was allowed to oxidize for ca. 1 h. The
yellow/brown slurry was then filtered through 2 g of flash silica
gel. The product was eluted with 2 mL of hexanes followed by
10 mL of 10% EtOAc/hexanes. The combined fractions were
concentrated to give 63.6 mg of a pale yellow oil. 1H NMR (500
MHz, CDCl3): δ 7.70-7.64 (m, 4H), 7.42-7.33 (m, 6H),
3.99-3.90 (m, 1H), 2.79-2.66 (m, 1H), 2.52-2.40 (m, 1H),
1.75-1.65 (m, 2H), 1.64-1.38 (m, 5H), 1.30-1.27 (m, 1H),
1.10-1.04 (m, 12H), 1.00-0.97 (m, 1H), 0.96-0.94 (d, J ) 6.3
Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 136.14, 136.07, 134.90,
134.22, 129.84, 129.72, 127.82, 127.65, 66.94, 53.32, 52.40,
46.98, 34.28, 32.91, 27.26, 25.11, 24.17, 23.11, 19.46. IR
(neat): 3344.0, 3070.6, 1589.7 cm-1. HRMS: (M + H)+ calcd
for C25H38NOSi, 396.2644; found, 396.2732. LRMS m/z : (EI+)
according to the general procedure for intramolecular hy-
droamination given above. After the reaction was complete,
the mixture was added directly to a silica gel column. The
product was eluted using a 74/25/1 mixture of hexanes/EtOAc/
Et3
N. The title compound was obtained as a viscous oil in 90%
yield. The NMR was similar to that of (-)-15. [R]20 +0.7 (c
D
0.55, CHCl3).
(+)-P in id in ol [(+)-1]. A MeOH solution of (+)-15 (0.063
g, 0.159 mmol) was treated with an excess of KOH (∼2 g). The
mixture obtained was heated to reflux overnight. After being
cooled, the mixture was poured onto H2O and made acidic with
concentrated HCl. The aqueous layer was washed with Et2O
before it was made basic with solid NaOH. The aqueous layer
was extracted four times with CH2Cl2. The combined organic
phase was dried over K2CO3 and concentrated after filtration.
The title compound (0.023 g, 0.146 mmol, 92%) was obtained
as a white solid. mp 68-69 °C, literature2c 70.5-72 °C. 1H
NMR (500 MHz, CDCl3): δ 4.13-4.07 (m, 1H), 2.94-2.90 (m,
1H), 2.60-2.54 (m, 1H), 1.80-1.74 (m, 1H), 1.61-1.41 (m, 5H),
1.39-1.30 (m, 2H), 1.14 (d, J ) 6.4 Hz, 3H), 1.01 (d, J ) 6.4
Hz, 3H), 0.99-0.96 (m, 1H), 0.93-0.81 (m, 1H). 13C NMR (125
MHz, CDCl3): δ 65.10, 55.04, 52.55, 43.76, 33.85, 30.28, 24.68,
23.68, 23.14. IR (neat): ∼3200 (br) cm-1. HRMS: (M + H)+
calcd for C9H19NO, 157.1467; found, 157.1475. LRMS m/z :
437 (5), 393 (5), 396 (100). [R]27 -1.4 (c 0.55, CHCl3).
D
(2R ,2′R ,6′R )-1-(6′-Me t h y lp ip e r id in iu m -2′-y l)-2-h y -
d r oxyp r op a n e, HCl Sa lt [(-)-16]. Gen er a l P r oced u r e for
th e HCl Sa lt F or m a tion of P in id in ol. A 10-mL round-
bottom flask equipped with a nitrogen line, reflux condenser,
and magnetic stirrer was charged with 58.1 mg (150 µmol) of
(-)-15, 1.5 mL of MeOH, and 347 mg of KOH. The mixture
was heated to reflux and stirred overnight, ca. 9 h. The solution
was cooled to rt and charged with 1 mL of water and 2 mL of
CH2Cl2. The mixture was separated, and the aqueous layer
was extracted with 5 × 2 mL of CH2Cl2. The combined organic
layers were dried over K2CO3. The solvents were removed
under vacuum and replaced with 0.5 mL of MeOH and 2 mL
of ether. The solution was cooled to 0 °C and charged with 25
µL of concentrated HCl (300 µmol). The solution was stirred
for ca. 30 min at 0 °C. The product was crystallized with the
addition of 15 mL of ether. The slurry was stirred for ca. 2 h
before collecting 21 mg of white, birefringent, needlelike solids
(EI+) 157 (5), 142 (25), 112 (6), 98 (100). [R]26 +11.7 (c 0.535,
D
CHCl3), literature2c [R]26 -15.0 (c 0.55, CHCl3) for (-)-1.
D
(2S,2′R,6′R)-1-(6′-Met h ylp ip er id in -2′-yl)-2-ter t-b u t yl-
d ip h en ylsilyloxyp r op a n e (24). Prepared from 23 according
to the general procedure for intramolecular hydroamination
given above. After the reaction was complete, the mixture was
added directly to a silica gel column. The product was eluted
using a 74/25/1 mixture of hexanes/EtOAc/Et3N. The title
compound was obtained as a viscous oil in 90% yield. 1H NMR
(500 MHz, CDCl3): δ 7.69-7.66 (m, 4H), 7.42-7.33 (m, 6H),
3.97-3.91 (m, 1H), 2.66-2.60 (m, 1H), 2.54-2.48 (m, 1H),
1.75-1.58 (m, 3H), 1.52-1.49 (m, 1H), 1.42-1.35 (m, 2H),
1.27-1.18 (m, 2H), 1.03 (s, 9H), 1.00 (d, J ) 6.2 Hz, 3H), 0.97
(d, J ) 6.4 Hz, 3H), 0.95-0.84 (m, 1H). 13C NMR (125 MHz,
CDCl3): δ 135.92, 135.83, 134.75, 134.19, 129.54, 129.43,
127.54, 127.39, 68.54, 54.88, 52.35, 47.42, 34.22, 32.44, 27.02,
24.84, 24.48, 22.94, 19.26. IR (neat): 3349.3, 3071.0, 1589.8
cm-1. HRMS: (M + H)+ calcd for C25H36NOSi, 394.2566; found,
394.2551. LRMS m/z : (EI+) 394 (2), 338 (50), 199 (15), 98
(73%). mp 218-220 °C. 1H NMR (500 MHz, CDCl3):
δ
9.15-8.55 (s, 2H), 4.80-4.45 (s, 1H), 4.35-4.20 (m, 1H),
3.38-3.23 (m, 1H), 3.23-3.02 (m, 1H), 2.20-2.08 (m, 1H),
2.00-1.71 (m, 6H), 1.70-1.60 (s, 1H), 1.59-1.47 (m, 4H),
1.39-1.15 (d, J ) 6.3 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ
62.81, 55.28, 54.19, 41.27, 30.30, 28.60, 23.19, 22.91, 19.69.
IR (solid): 3396 (s), 2845, 2530, 2458 cm-1. HRMS: (M + H,
CI+) calcd for C9H20NO, 158.1545; found, 158.1549. LRMS m/z :
(EI+) 159 (10), 158 (100), 140 (10). [R]26D -22.4 (c 0.29, CHCl3).
(-)-P in id in ol [(-)-1]. Gen er a l P r oced u r e for th e F r ee-
Ba se F or m a tion of P in id in ol. A 10-mL round-bottom flask
equipped with a nitrogen line and magnetic stirrer was
charged with 9.9 mg (63 µmol) of (-)-16, 1 mL of MeOH, and
100 mg of KOH. The mixture was stirred for 30 min. The
solution was charged with 1 mL of water and 2 mL of CH2Cl2.
The mixture was separated, and the aqueous layer was washed
with 4 × 2 mL of CH2Cl2. The combined organic layers were
dried over K2CO3, and the solvents were removed under
vacuum, resulting in the isolation of 7.1 mg of white, needlelike
solids (88.8%). mp 70-72 °C, literature2c 70.5-72 °C. The
spectral data matched that given in the literature. [R]27D -14.2
(100). [R]20 -6.5 (c 0.505, CHCl3).
D
Ack n ow led gm en t. We thank Dr. Bruce Noll for the
X-ray structure determination of 7. We gratefully
acknowledge the National Institutes of Health (Grant
GM48580), Merck & Co., and NATO for their generous
support of this research. E.D.D. thanks Smith Kline-
Beecham for their support in the form of a graduate
fellowship administered by the Organic Division of the
American Chemical Society. S.K.P. thanks the Process
R&D group of Bristol-Myers Squibb for their generous
financial support and study leave.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for all compounds not described within the text.
HRMS, LRMS, 1H and, 13C NMR spectra of representative
compounds. X-ray data for 7. This material is available free
of charge via the Internet at http://pubs.acs.org.
(c 0.55, CDCl3), literature2c [R]26 -15.0 (c 0.55, CHCl3).
D
99.9+% ee by chiral GC: 80 °C for 2 min, 0.1 °C/min ramp,
220 °C max temp, Supelco â-dex 120, 15 m × 0.25 mm.
Retention times (min): (-)-1: 36.46, (+)-1: 35.33.
(2S,2′S,6′S)-1-(6′-Met h ylp ip er id in -2′-yl)-2-ter t-b u t yl-
d ip h en ylsilyloxyp r op a n e [(+)-15]. Prepared from (-)-14
J O015603N