Iterative synthesis of deoxypropionate units: The inductor effect in acyclic conformation design

Article abstract of DOI:10.1021/jo061098o

Conjugate addition of lithium dimethylcuprate to acyclic α,β-unsaturated esters of varying lengths bearing terminal alkyl or phenyl groups leads to a preponderance of syn 1,3-adducts when one methyl is already present. Conversion to enoates, and iteration of cuprate additions also favors syn adducts to give contiguous deoxypropionate units in a growing chain. The effect of end-group variation (Me, i-Pr, phenyl, tert-butyl) in conjunction with the nature of the ester group (Me, tert-butyl, etc.) on the diastereoselectivity of syn and anti products was studied. The results are rationalized in terms of inductor effects related to the minimization of the 1,5-pentane interactions in energetically favored folded conformations and corroborated by homodecoupling NMR studies.

Full text of DOI:10.1021/jo061098o

Iterative Synthesis of Deoxypropionate Units: The Inductor Effect
in Acyclic Conformation Design
Stephen Hanessian,* Navjot Chahal, and Simon Giroux
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128,
Station Centre-Ville Montre´al, P.Q. H3C 3J7
stephen.hanessian@umontreal.ca
ReceiVed May 29, 2006
Conjugate addition of lithium dimethylcuprate to acyclic R,â-unsaturated esters of varying lengths bearing
terminal alkyl or phenyl groups leads to a preponderance of syn 1,3-adducts when one methyl is already
present. Conversion to enoates, and iteration of cuprate additions also favors syn adducts to give contiguous
deoxypropionate units in a growing chain. The effect of end-group variation (Me, i-Pr, phenyl, tert-
butyl) in conjunction with the nature of the ester group (Me, tert-butyl, etc.) on the diastereoselectivity
of syn and anti products was studied. The results are rationalized in terms of inductor effects related to
the minimization of the 1,5-pentane interactions in energetically favored folded conformations and
corroborated by homodecoupling NMR studies.
The deoxypropionate motif is prevalent in many natural
products that are biosynthetically derived from the so-called
polypropionate pathway.1 These units, consisting of an array
of alternating C-methyl groups on an acyclic chain, are deployed
in one of two relative orientations for a single deoxypropionate
unit. Syn- and anti-methyl group orientations of a single
deoxypropionate triad2 originate from two propionate biosyn-
thetic units, and they are present in a number of natural
products.3 On the other hand, two contiguous deoxypropionate
units consisting of three alternating C-methyl groups on an
acyclic chain within a molecule are much less prevalent. For
example, a syn/syn-deoxypropionate unit can be found in only
three natural products, TMC-151A,4 pectinatone,5 and sipho-
narienone (and its congeners),6 and one macrocyclic lactone,
doliculide.7 Another macrocyclic lactone, borrelidin, harbors the
only example of four alternating C-methyl groups with a syn/
syn/anti orientation.8 There are also two exceptions to the syn/
syn “rule”, in the C4-C8 segment of ionomycin9 and in the
segments of the cuticular hydrocarbon from cane beetle,10 which
have two and three contiguous deoxypropionate units with syn/
anti orientations, respectively (Chart 1).
(6) Isolation: see ref 5b. Total synthesis: (a)Abiko, A.; Masamune, S.
Tetrahedron Lett. 1996, 37, 1081. (b) Magnin-Lachaux, M.; Tan, Z.; Liang,
B.; Negishi, E.-I. Org. Lett. 2004, 6, 1425.
(7) Structure: (a) Ishiwata, H.; Nemoto, M.; Ojika, M.; Yamada, K. J.
Org. Chem. 1994, 59, 4710. Total synthesis: (b) Ishiwata, H.; Sone, H.;
Kigoshi, H.; Yamada, K. Tetrahedron 1994, 50, 12853. (c) Ghosh, A. K.;
Liu, C. Org. Lett. 2001, 3, 635. (d) see also ref 12.
(8) Isolation: (a) Berger, J.; Jampolsky, L. M.; Goldberg, M. W. Arch.
Biochem. 1949, 22, 476. (b) Lumb, M.; Macey, P. E.; Spyvee, J.; Whitmarsh,
J. M.; Wright, R. D. Nature 1965, 206, 263. Structure: (c) Anderson, B.
F.; Herlt, A. J.; Rickards, R. W.; Robertson, G. B. Aust. J. Chem. 1989,
42, 717. Total synthesis: (d) Duffey, M. O.; LeTiran, A.; Morken, J. P. J.
Am. Chem. Soc. 2003, 127, 1458. (e) Vong, B. G.; Kim, S. H.; Abraham,
S.; Theodorakis, E. A. Angew. Chem., Int. Ed. 2004, 43, 3947. (f) Nagamitsu,
T.; Takano, D.; Fukuda, T.; Otoguro, K.; Kuwajima, I.; Harigaya, Y.;
Omura, S. Org. Lett. 2004, 6, 1865. (g) see also 13.
(9) Isolation: Liu, C.-M.; Hermann, T. E. J. Biol. Chem. 1978, 253, 5892.
Synthesis: (a) Hanessian, S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. J. Am.
Chem. Soc. 1990, 112, 5276. (b) Evans, D. A.; Dow, R. L.; Shih, T. L.;
Takacs, J. M.; Zahler, R J. Am. Chem. Soc. 1990, 112, 5290. (c) Lautens,
M.; Colucci, J. T.; Hiebert, S.; Smith, N. D.; Bouchain, G. Org. Lett. 2002,
4, 1879.
(1) (a) Khosla, C. Chem. ReV. 1997, 97, 2577. (b) Katz, L. Chem. ReV.
1997, 97, 2557.
(2) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054.
(3) Hanessian, S.; Giroux, S.; Mascitti, V. Synthesis 2006, 1057.
(4) Kohno, J.; Nishio, M.; Sakurai, M.; Kawano, K.; Hajime, H.; Kameda,
N.; Kishi, N.; Yamashita, T.; Okuda, T.; Komatsubara, S. Tetrahedron 1999,
55, 7771.
(5) Isolation: (a) Biskupiak, J. E.; Ireland, C. M. Tetrahedron Lett. 1983,
24, 3055. Structure: (b) Norte, M.; Cataldo, F.; Gonzalez, A. G.; Rodriguez,
M. L.; Ruiz-Perez, C. Tetrahedron 1990, 46, 1669. Total synthesis (c)
Birkbeck, A. A.; Enders, D. Tetrahedron Lett. 1998, 39, 7823.
10.1021/jo061098o CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/16/2006
J. Org. Chem. 2006, 71, 7403-7411
7403

Hanessian et al.
CHART 1. Representative Examples of Deoxypropionate Natural Products
The apparent preference for syn/syn deployment of C-methyl
groups has been rationalized on the basis of conformation design
in acyclic systems,2,11 where 1,5-pentane interactions are
minimized. Indeed the solid-state crystal structures of deoxy-
propionate-containing natural products such as pectinatone5 and
borrelidin8 clearly show the nonstaggered orientation of the
alternating C-methyl groups on the respective carbon frame-
works. We have used a virtual diamond lattice to qualitatively
visualize the three-dimensional structures of such deoxypropi-
onate arrays.12,13 The virtual superposition of the carbon chain
backbone of such deoxypropionate arrays on the diamond lattice
is also matched by NMR data.12,13
There are several methods for the iteratiVe construction of
deoxypropionate units with predisposed stereochemical orienta-
tions.3 Until recently these methods relied on asymmetric
induction due to resident chirality12,13 or the presence of a chiral
auxiliary.14 Negishi15 and Feringa16 have now reported elegant
catalytic methods for the elaboration of deoxypropionate units.
Extension of these catalytic methods to the synthesis of complex
polyfunctional natural products will no doubt follow.
Our approach to the iterative synthesis of the syn oriented
deoxypropionate units found in borrelidin, doliculide, and
siphonarienal relied on the conjugate addition of lithium
dimethylcuprate to a “starter” enantiopure γ-alkoxy-R,â-
unsaturated enoate.17 The product resulting from a 1,2-induction
obtained in very high diastereomeric purity, was extended to a
second iteration via a 3-step sequence. A second cuprate addition
took place to give a syn product in a ratio of 80:20. Surprisingly,
a third iteration gave a seven carbon acid harboring three
alternating syn/syn-C-methyl groups with a 91:9 diastereose-
lection (for the third addition). Thus, three stereocontrolled
cuprate additions were done in an iterative manner on a growing
acyclic chain. In the course of these studies, we introduced the
1-methyl-1-cyclopentyl (MCP) ester group, as a constrained
steric variant to the tert-butyl group, which allowed the
attainment of high syn selectivity compared to other esters.12
We attributed this to an “ester” effect, which in conjunction
with another anchoring group at the other extremity of the
enoate, leads to energetically favorable folded conformations
in which intervening 1,5-pentane interactions in the main carbon
chain are minimized.13
(10) Isolation and structure: (a) Chow, S.; Fletcher, M. T.; Lambert, L.
K.; Gallagher, O. P.; Moore, C. J.; Cribb, B. W.; Allsopp, P. G.; Kitching,
W. J. Org. Chem. 2005, 70, 1808. (b) Fletcher, M. T.; Chow, S.; Lambert,
L. K.; Gallagher, O. P.; Cribb, B. W.; Allsopp, P. G.; Moore, C. J.; Kitching,
W. Org. Lett. 2003, 5, 5083.
(11) (a) Hoffmann, R. W.; Gottlich, R.; Scho¨pfer, U. Eur. J. Org. Chem.
2001, 1865. (b) Hoffmann, R. W.; Stahl, M.; Scho¨pfer, U.; Frenking, G.
Chem.sEur. J. 1998, 4, 559.
In this paper, we studied the effect of placing different ester
groups and a chain extremity “inductor” anchoring group, on
the stereoselectivity of conjugate additions with lithium dim-
ethylcuprate on a set of enoates. In this context, we also studied
the effects of varying the nature of the alkoxy ether group
(Figure 1).
(12) Hanessian, S.; Mascitti, V.; Giroux, S. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 11996.
(13) Hanessian, S.; Yang, Y.; Giroux, S.; Mascitti, V.; Ma, J.; Raeppel,
F. J. Am. Chem. Soc. 2003, 125, 13784.
We initially chose an isopropyl group as an anchoring
extremity. Once the first C-methyl is introduced, it could, in
principle, avoid a 1,5-pentane interaction with the two methyl
groups of the isopropyl group in one or more energetically
favored conformations by placing a hydrogen atom opposite to
the C-methyl in the main chain (Figure 1, A versus B and C).
It was anticipated that subsequent cuprate additions on iterated
enoates would involve priviledged folded conformations which
would undergo stereoselective syn additions in each cycle
(Figure 1).
(14) Auxiliary-mediated organocuprate chemistry: (a) Williams, D. R.;
Nold, A. L.; Mullins, R. J. J. Org. Chem. 2004, 69, 5374. (b) Williams, D.
R.; Kissel, W. S.; Li, J. J.; Mullins, R. J. Tetrahedron Lett. 2002, 43, 3723.
(c) Breit, B.; Demel, P. Tetrahedron 2000, 56, 2833. (d) Ogawa, T.;
Suemune, H.; Sakai, K. Chem. Pharm. Bull. 1993, 41, 1652. (e) Oppolzer,
W.; Maretti, R.; Bernardelli, G. Tetrahedron Lett. 1986, 27, 4713. Auxiliary-
mediated alkylations: (a) Abiko, A.; Masamune, S. Tetrahedron Lett. 1996,
37, 1081. (b) Nicolaou, K. C.; Yue, E. W.; Naniwa, Y.; De Riccardis, F.;
Nadin, A.; Leresche, J. E.; La Greca, S.; Yang, Z. Angew. Chem., Int. Ed.
Engl. 1994, 33, 2184. Auxiliary-mediated Cope rearrangement: Tomooka,
K.; Nagasawa, A.; Wei, S.-Y.; Nakai, T. Tetrahedron Lett. 1997, 37, 8895.
(15) (a) Novak, T.; Tan, Z.; Liang, B.; Negishi, E.-I. J. Am. Chem. Soc.
2005, 127, 2838. (b) Tan, Z.; Negishi, E.-I. Angew. Chem., Int. Ed. 2004,
43, 2911. (c) Magnin-Lachaux, M.; Tan, Z.; Liang, B.; Negishi, E.-I. Org.
Lett. 2004, 6, 1425. (d) Negishi, E.-I.; Tan, Z.; Liang, B.; Novak, T. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5782. (e) Kondakov, D.; Negishi, E.-I.
J. Am. Chem. Soc. 1996, 118, 1577. (f) Kondakov, D.; Negishi, E.-I. J.
Am. Chem. Soc. 1995, 117, 10771.
Chemistry. The readily available 2R-hydroxy-3-methyl bu-
tyrate 117a was protected as the BOM ether, reduced, then
(17) (a) Hanessian, S.; Ma. J.; Wang, W.; Gai, Y. J. Am. Chem. Soc.
2001, 123, 10200. (b) Hanessian, S.; Wang, W.; Gai, Y.; Olivier, E. J. Am.
Chem. Soc. 1997, 119, 10034. (c) Hanessian, S.; Gai, Y.; Wang, W.
Tetrahedron Lett. 1996, 37, 7473. (c) Hanessian, S.; Wang, W.; Gai, Y.
Tetrahedron Lett. 1996, 37, 7477. (d) Hanessian, S.; Raghavan, S. Bioorg.
Med. Chem. Lett. 1994, 4, 1697. (e) Hanessian, S.; Sumi, K. Synthesis 1991,
1083.
(16) Des Mazery, R.; Pullez, M.; Lopez, F.; Harutyunyan, S. R.;
Minnaard, A. J. Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966.
7404 J. Org. Chem., Vol. 71, No. 19, 2006

IteratiVe Synthesis of Deoxypropionate Units
FIGURE 1. Functional group effects in enoate additions and possible preferred conformations of adducts.
SCHEME 1. Synthesis of 5a-ea
a (a) BOMCI, NEt(iPr)2, CH2Cl2, 85%; (b) Dibal-H, CH2Cl2, -78 °C, 92%; (c) DMSO, (COCl)2, NEt3, CH2Cl2, -78 °C, 97%; (d) PPh3dC(H)CO2Me,
CH2Cl2, E/Z > 20:1, 91%; (e) MeLi‚LiBr, CuI, TMSCl, THF, -78 °C, syn/anti > 15:1, 96%; (f) repeat b, 93%; (g) repeat c, 97%, (h) PPh3dC(H)CO2R,
CH2Cl2, for 4a, 96%; 4b, 85%; 4c, 64%; 4d, 91%; 4e, 74%; (i) repeat i, see Table 1 for yields and syn/anti ratios. MCP ) 1-methyl-1-cyclopentyl.
SCHEME 2. Synthesis of 9a-ea
TABLE 1. Diastereoselective Cuprate Additions to Enoates 4a-e:
The Ester Effect
entry
compd
product
R
syn/antia
yieldb
1
2
3
4
5
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
Me
i-Pr
75:25
77:23
78:22
89:11
91:9
80
96
93
87
89
neoPent
t-Bu
MCPc
a Determined by 13C inverse gated NMR. b Isolated yields after chro-
matography. c MCP: methylcyclopentyl.
extended to the enoate 2 in an overall yield of 70% (Scheme
1). The addition of lithium dimethylcuprate in the presence of
TMSCl at -78 °C17a gave the anti product 3 as a single isomer
in quantitative yield.
a (a) H2, 1 atm, Pd/C, MeOH, 99%; (b) Dibal-H, CH2Cl2, -78 °C; (c)
PPh3dC(H)CO2t-Bu, CH2Cl2, E/Z > 20:1, 61% two steps; (d) for 8a,
Me3OBF4, proton sponge, CH2Cl2, 60%; for 8b, MOMCl, NEt(iPr)2,
CH2Cl2, 82%; for 8c, MEMCl, NEt(iPr)2, DMAP (catalyst), CH2Cl2, 74%;
for 8d, benzoyl peroxide, dimethylsulfide, 48%; for 8e, TESOTf, 2,6-
lutidine, CH2Cl2, 44%; (e) MeLi‚LiBr, CuI, TMSCl, THF, -78 °C, see
Table 2 for yields and syn/anti ratios.
A three-step extension was done with the appropriate phos-
phorane to give the corresponding enoates 4a-e containing
esters of increasing steric bulk. Cuprate additions afforded the
corresponding adducts 5a-e as mixtures of syn and anti
diastereomers. The ratio increased in favor of the syn adduct in
going from a methyl ester to the 1-methyl-1-cyclopentyl ester
(MCP) without unduly affecting the yields (Table 1).
in the presence of proton sponge18 afforded the methyl ether
8a in 61% yield. Other ethers 8b-d were prepared under
standard conditions from 7. Addition of lithium dimethylcuprate
to the individual enoates gave good to excellent yields of adducts
with more or less the same diastereoselectivities favoring the
syn isomers by a ratio of ca. 4:1 (Table 2). The methyl and
BOM ethers were found to give a slightly higher ratio (Table
2, entries 1 and 6).
We next studied the influence of the alkoxy group on the
diastereoselectivity of conjugate addition. The required sub-
strates were prepared from precursor 3 by exchanging the BOM
group (Scheme 2). Hydrogenolysis of 3 led to the lactone 6
which was partially reduced to the hemiacetal, and the latter
was treated with tert-butyl(triphenylphosphoranylidene)acetate
to afford the trans-enoate 7. Attempted O-methylation in the
presence of sodium hydride led to intramolecular cyclic ether
formation. Alternatively, methylation with Meerwein’s reagent
Having established that a bulky ester and a removable
protective group such as a BOM ether were best suited to favor
(18) Diem, M. J.; Burow, D. F.; Fry, J. L. J. Org. Chem. 1977, 42, 1801.
J. Org. Chem, Vol. 71, No. 19, 2006 7405

Hanessian et al.
TABLE 2. Diastereoselective Cuprate Additions to Enoates 8a-f:
The terminal tert-butyl variant was also studied in a racemic
substrate (Scheme 5, Table 5). Thus, pivalic aldehyde 21 was
converted to (()-enoate 22 in four uneventful steps. Cuprate
addition to 22 followed by extension to 23a-c, and a second
iteration gave 24a-c in relatively high diastereoselectivities (see
Table 5). The third cuprate addition on the separated syn isomer
was performed on the (()-tert-butyl enoate 25 only, to give
the corresponding adduct 26 in a 82:18 syn/anti ratio.
Finally, the effect of the chain extremity inductor group in
these enoates was studied with the methyl series. Thus (S)-ethyl
lactate 27 was converted to the enoates 28a-c, and the latter
was subjected to conjugate addition in the usual manner to give
the corresponding adducts 29a-c as single isomers in excellent
yields after purification (Scheme 6). Extension of the tert-butyl
ester to the enoate 30 and the addition of lithium dimethylcuprate
gave the adduct 31 as a 2:1 mixture of syn and anti isomers
(Table 6).
Iterative conjugate additions to enoates can also be extended
in a bidirectional mode (Scheme 7). Thus, alcohol 3213 was
elaborated to enoate 33 and subjected to a “third” cuprate
conjugate addition in a bidirectional way. The anticipated 1,2-
induction by the O-BOM group led to an excellent anti/syn ratio
of >20:1 in 34. A three-step extension, followed by conjugate
addition, reduction to the corresponding alcohol, and removal
of the minor isomer by chromatography led to enantiopure 35
(88:12, syn/anti). A similar extension led to 36 which was
subjected to a third cuprate addition affording an 88:12 syn/
anti ratio of tert-butyl ester 37. All in all, five cuprate additions
were effected starting from an enoate precursor of 32.13
Conversion of the O-BOM to the alcohol 38 by hydrogenolysis
and treatment with MsCl in the presence of NEt3 led to 39.
Subsequent treatment with LiAlH4 with concomitant formation
of the terminal alcohol, followed by etherification with MOMCl
afforded the nonmeso compound 40 in addition to the minor
anti isomer.
The Alkoxy Effect
entry
compd
product
Rc
Me
MOM
MEM
TES
syn/antia
yieldb
1
2
3
5
6
8a
8b
8c
8d
4d
9a
9b
9c
9d
5d
90:10
86:14
86:14
82:18
89:11
60
78
81
84
87
BOM
a Determined by 13C inverse gated NMR. b Isolated yields after chro-
matography. c MOM, methoxymethyl ether; MEM, methoxyethoxyether;
TES, triethylsilyl ether; BOM, benzyloxymethyl ether.
TABLE 3. Cuprate Additions to Enoates 11a-c and 13a-b: The
Third and Fourth Iterations
entry
compd
product
R
syn/antia
yieldb
1
2
3
4
5
11a
11b
11c
13a
13b
12a
12b
12c
14a
13b
Me
67:33
87:13
83:17
85:15
83:17
84
97
91
78
92
t-Bu
MCP
t-Bu
MCP
a Determined by 13C inverse gated NMR. b Isolated yields after chro-
matography.
the highest ratio of the syn adducts, we turned our attention to
a third iteration. Thus, compound 5d was reduced to the
corresponding alcohol 10 and the pure syn isomer was oxidized
and then treated with the appropriate phosphoranylidene ester
to give 11a-c (Scheme 3). Cuprate addition gave excellent
yields of the corresponding adducts 12a-c with diastereose-
lectivities favoring the syn/syn isomer (Table 3). After separation
of the pure syn isomer, a fourth iteration was tried with tert-
butyl and MCP esters 13a and 13b leading to diastereoselec-
tivities in favor of the syn/syn/syn isomers 14a and 14b with
average ratios of 4.2:1 (Table 3).
Our next objective was to probe the influence of the chain
extremity “inductor” anchoring group on the stereoselectivity
of cuprate addition on a γ-BOM enoate. Conjugate addition of
lithium dimethylcuprate to the enoates 15a-c obtained from
(R)-mandelic acid led to 16a-c in high selectivities17d and
excellent yields (Scheme 4, Table 4).
A three-step chain extension of 16a-c to the corresponding
enoates 17a-c, followed by cuprate addition gave the syn
adducts 18a-c in high selectivity. Separation of the syn isomer
and further extension of the tert-butyl and MCP esters gave
the pure syn isomers 19a and 19b. A third cuprate addition gave
the corresponding syn/syn adducts 20a and 20b and the
corresponding syn/anti adducts in ca. 4:1 diastereomeric ratio,
respectively.
Deuterium Labeling and Isomer Ratios. The highly non-
polar nature of the cuprate adducts differing in the syn or anti
dispositions of pendant C-methyl groups on growing acyclic
chains rendered the determination of isomer ratio difficult by
analytical methods such as HPLC or GC. 13C inverse gated
NMR spectroscopy which was used routinely in previous
studies12,13 was found to be a reliable method to estimate relative
ratios of diastereomers. We sought to develop a method that
1
would exploit H NMR as an expedient method to determine
isomer ratios and to corroborate the 13C inverse gated NMR
results. We surmised that incorporation of a deuterium atom
on the carbon chain bearing each C-methyl group would
SCHEME 3. Third and Fourth Iterationsa
a (a) Dibal-H, CH2Cl2, -78 °C, 74%; (b) DMSO, (COCl)2, NEt3, CH2Cl2, -78 °C; (c) PPh3dC(H)CO2R, CH2Cl2, for 11a, 90% two steps, for 11b, 94%
two steps for 11c, 85% two steps; (d) MeLi‚LiBr, CuI, TMSCl, THF, -78 °C, see Table 3; (f) repeat a with 12b, 60%; (g) repeat b and c, for 14a, 71% two
steps, for 14b, 70%; (h) repeat d, see Table 4. Iterations done on pure syn isomers.
7406 J. Org. Chem., Vol. 71, No. 19, 2006

IteratiVe Synthesis of Deoxypropionate Units
SCHEME 4. Cuprate Additions in the Phenyl Seriesa
a (a) MeLi‚LiBr, CuI, TMSCl, THF, -78 °C, see Table 4; (b) Dibal-H, CH2Cl2, -78 °C, 75%; (c) DMSO, (COCl)2, NEt3, CH2Cl2, -78 °C; (d)
PPh3dC(H)CO2R, CH2Cl2, for 17a, 75% two steps, for 17b, 87% two steps, for 17c, 89% two steps; (e) repeat a, see Table 4; (f) repeat step b with 17a,
60%; (g) repeat c and d, for 19a, 99% two steps, for 19b, 89% two steps; (h) repeat a, see Table 4. Iterations done on pure syn isomers.
TABLE 4. Cuprate Additions in the Phenyl Series
C-methyl groups in the growing acyclic chain is operative for
third and fourth cuprate additions so as to favor the syn adduct
(Scheme 3). Detailed NMR studies12,13 of first and second stage
enoates such as 4a and 11a have corroborated this hypothesis,
since homodecoupling measurements indicated the presence of
a time-averaged folded conformation at 25 °C in each case that
was in excellent agreement with values obtained from X-ray
studies of natural products.4 An overlay of the presumed folded
conformation on a virtual diamond lattice provides a useful
visual tool in such correlations in these new examples (Figure
2).
entry
compd
product
R
syn/antia
yieldb
1
2
3
4
5
6
7
8
15a
15b
15c
17a
17b
17c
19a
19b
16a
16b
16c
18a
18b
18c
20b
20c
Me
94:6
95:5
95:5
69:31
84:16
85:15
79:21
79:21
97
92
89
86
85
86
90
74
t-Bu
MCP
Me
t-Bu
MCP
t-Bu
MCP
a Determined by 13C inverse gated NMR. b Isolated yields after chro-
matography.
There is a clear “ester” effect in the conjugate additions to
enoates, where syn isomers are favored over anti. Small ester
moieties such as methyl lead to increasing amounts of anti
adducts. tert-Butyl esters and 1-methyl-1-cyclopentyl (MCP)
esters appear to be the best in favor of the syn isomers (Table
1, entry 5). This effect was more pronounced when the extremity
was a CH2OTBDPS group (t-Bu 4:1, MCP 8:1).12 Syn prefer-
ence is also manifested in the third and fourth cuprate additions,
especially in the presence of tert-butyl and MCP esters with
ratios > 4:1 (Tables 3 and 4).
The chain extremity “inductor” effect was also studied with
different anchoring groups. Diastereoselective preference for
syn/syn over syn/anti isomers remained at > 4:1 especially with
the tert-butyl and MCP esters. In substituting an isopropyl to a
tert-butyl group as the chain extremity, we had anticipated a
substantial drop in diastereoselectivity since a 1,5-pentane
interaction could already exist with the first C-methyl group in
the chain and one of the tert-butyl methyls (Figure 2, 23a).
However, a 9:1 selectivity for the second cuprate addition in
the isopropyl series dropped only to 4:1 for the tert-butyl case
(Scheme 5, Table 6, entries 1-3). The persistent syn selectivity
in this case, despite potentially unavoidable 1,5-pentane interac-
tions of C-methyl groups in the first and second stage cuprate
additions may be rationalized by the existence of alternative
conformations compared to the isopropyl series (Figure 2, 23a).
Indeed, homodecoupling studies showed a time-averaged cou-
pling constant favoring folded conformation A (Figure 2, JF-E
) < 2.0 Hz), in which the tert-butyl group adopts a different
orientation compared to B where the 1,5-pentane interaction is
expected to be at a maximum (JF-E expected > 9.0 Hz, see
Figure 2, 4a and 11a). A potential tert-butyl/methyl and chain
C-C interaction may still be operative in conformation A
(Figure 2, 23a red bonds). To corroborate these assumptions
considerably simplify the interpretation of the 1H spectra at the
iterated enoate stage. Indeed, integration of methine peaks
(bearing a C-methyl group and a deuterium atom), provided
syn/anti ratios that were in excellent agreement with those
determined by inverse gated 13C NMR (Scheme 8).19
Discussion. The insightful studies by Hoffmann2,11 demon-
strated the importance of conformational design in acyclic
carbon chains and the effect of a substituent like a C-methyl
group as an “inductor group”. Thus, a resident C-methyl group
in an acyclic chain can serve as an inductor for an incoming
second C-methyl group, leading to a preferred folded conforma-
tion which is best accommodated by an isotactic-type relation-
ship of substituents. This observation was rationalized on the
basis of the destabilization of those conformers where higher
energy-level 1,5-pentane interactions are possible.2,11 Accord-
ingly, deoxypropionate units harboring two or more alternating
C-methyl groups in a growing chain should adopt conformations
favoring staggered orientations of such groups. We have
extended this concept to the iterative synthesis of syn oriented
deoxypropionates in functionalized enoates which were used
as advanced intermediates in the total synthesis of doliculide12
and borrelidin.13 Thus, an enoate bearing an anchoring group
at the extremity of the acyclic chain will adopt a conformation
in solution allowing a preferential approach of the cuprate to
give a syn adduct as the major isomer. Low energy conforma-
tions in which 1,5-pentane interactions are minimized in the
main chain as well as with the extremity group will prevail,
especially at low temperature. Despite the growing entropy of
the system, and the presence of coordinating sites, this encoded
bias for preferred folded conformations harboring predisposed
(19) See Supporting Information.
J. Org. Chem, Vol. 71, No. 19, 2006 7407

Hanessian et al.
SCHEME 5. Cuprate Additions in the tert-Butyl Seriesa
a (a) VinylMgBr, THF, 0 °C; (b) BOMCl, NEt(i-Pr)2, CH2Cl2, 50% two steps; (c) OsO4, NaIO4, THF/H2O; (d) PPh3dC(H)CO2Me, CH2Cl2, 54% two
steps; (e) MeLi‚LiBr, CuI, TMSCl, THF, -78 °C, 80%; (f) Dibal-H, Ch2Cl2, -78 °C, 82%; (g) DMSO, (COCl)2, NEt3, CH2Cl2, -78 °C; (h) PPh3dC(H)CO2R,
CH2Cl2, for 23a, 92%; for 23b, 92%; for 23c, 82%; (i) repeat e, see Table 5; (j) repeat f with 24a, 64%; (k) repeat g; (l) repeat h with R ) t-Bu, 70% two
steps; (m) repeat e, syn/anti 82:18, 77%. Iterations done on pure syn isomers.
TABLE 5. Cuprate Additions in the t-Butyl Series
in energies of conformers may be less significant than with
bulkier esters such as tert-butyl or MCP. The nature of the
alkoxy ether group is not important (Table 2), and it probably
adopts a preferred orientation which exerts, however, only minor
influence to the inductor effect of the chain extremity group. It
is clear that the nature of the bulky ester overrides the effects
of the chain extremity group, since syn selectivity up to four
cuprate iterations was still observed in going from isopropyl,
to phenyl, to tert-butyl (Schemes 3-5, Tables 3-6). These
results are remarkable, considering the purely acyclic nature of
the substrates.
entry
compd
product
R
syn/antia
yieldb
1
2
3
23a
23b
23c
24a
24b
24c
Me
t-Bu
MCP
63:37
82:18
82:18
76
85
73
a Determined by 13C inverse gated NMR. b Isolated yields after chro-
matography.
based on NMR data, we also analyzed the methyl chain
extremity analogue 30 (Figure 2). Here, coupling constants for
FE protons are intermediate between vicinal and anti reflecting
on the prevalence of equally populated conformations of the
enoates A and B. Consequently, ratios of adducts are clearly
diminished compared to branched extremity groups. It is
reasonable to assume that at -78 °C, such energetically favored
folded conformations are even more prevalent.
The mechanism of organocuprate additions to enoates is
complex.20 It is generally agreed that an initial π-complex A
evolves to a â-cuprio(III) species B that delivers the alkyl methyl
group. Thus, steric nonbonded interactions are manifested early
in the transition states of a significant population of favorably
folded conformations as depicted for the isopropyl series (4e
and 11c, Figure 3). With methyl esters, the relative differences
Experimental Section
General Procedure for DIBAL-H Reduction (Procedure A).
To a solution of the ester in CH2Cl2 cooled to -78 °C, DIBAL-H
(3 equiv) was added. The reaction was stirred at -78 °C for 4 h
before being quenched with a saturated Na/K tartrate solution. The
reaction mixture was diluted with ethyl acetate and stirred for 30
min at room temperature until a clear biphasic solution was
observed. The aqueous layer was extracted three times with EtOAc.
The combined organic extracts were washed with brine, dried over
Na2SO4, and filtered. After concentration, the resulting residue was
purified by flash chromatography. Syn isomers were separated and
used in the next step.
General Procedure for Swern Oxidation (Procedure B).
Oxalyl chloride (2.5 equiv) was slowly added to a solution of
DMSO (5 equiv) in CH2Cl2 cooled to -78 °C. The reaction mixture
was allowed to stir at -78 °C for 20 min before the addition of a
solution of the alcohol in CH2Cl2. After 45 min, NEt3 (10 equiv)
was added, and the reaction was warmed to room temperature. The
reaction was quenched with a saturated solution of NH4Cl, the
aqueous layer was extracted three times with EtOAc, and the
combined organic layers were dried over Na2SO4, filtered, and then
concentrated. Flash chromatography afforded the desired aldehyde.
General Procedure for Wittig Olefination (Procedure C). A
solution of the aldehyde in CH2Cl2, was charged with Ph3Pd
CHCO2R (1.5 equiv). The reaction mixture was stirred at room
temperature for 18 h and then evaporated to dryness. The crude
solid was triturated with hexanes/Et2O (3:1), and the resulting slurry
was filtered over a pad of Celite. The filtrate was concentrated and
purified by flash chromatography affording the enoate.
(20) For mechanistic discussions see the following: (a) Bertz, S. H.;
Carlin, C. M.; Deadwyler, D. A.; Murphy, M. D.; Ogle, C. A.; Seagle, P.
H. J. Am. Chem. Soc. 2002, 124, 13650. (b) Woodward, S. Chem. Soc.
ReV. 2000, 29, 393. (c) Frantz, D. E.; Singleton, D. A. J. Am. Chem. Soc.
2000, 122, 3288. (d) Canisius, J.; Gerold, A.; Krause, N. Angew. Chem.,
Int. Ed. 1999, 38, 1644. (e) Bertz, S. H.; Chopra, A.; Eriksson, M.; Ogle,
C. A.; Seagle, P. Chem.sEur. J. 1999, 5, 2680. (f) Nakamura, E.; Mori,
S.; Morokuma, K. J. Am. Chem. Soc. 1997, 119, 4900. (g) Snyder, J. P. J.
Am. Chem. Soc. 1995, 117, 11025. (h) Dorigo, A. E.; Wanner, J.; von Rague
Schleyer, P. Angew. Chem., Int. Ed. 1995, 34, 476. (i) Krause, N.; Wagner,
R.; Gerold, A. J. Am. Chem. Soc. 1994, 116, 381. (j) Bertz, S. H.; Smith,
R. A. J. Am. Chem. Soc. 1989, 111, 8276. (k) Dorigo, A, E.; Morokuma,
K. J. Am. Chem. Soc. 1989, 111, 6524. (l) Christensen, B.; Olsson, T.;
Ullenius, C. Tetrahedron 1989, 45, 523. (m) Hallnemo, G.; Olsson, T.;
Ullenius, C. J. Organomet. Chem. 1985, 282, 133. (n) Corey, E. J.; Boaz,
N. W. Tetrahedron Lett. 1984, 25, 3063. (o) Krauss, S. R.; Smith, S. G. J.
Am. Chem. Soc. 1981, 103, 141. For a recent discussion on selectivity see
the following: Kireev, A. S.; Manpadi, M.; Kornienko, A. J. Org. Chem.
2006, 71, 2630. For the effect of TMSCl see (a) Bertz, S. H.; Miao, G.;
Rossiter, B. E.; Snyder, J. P. J. Am. Chem. Soc. 1995, 117, 11023. (b)
Lipshutz, B. H.; Dimock, S. H.; James, B. J. Am. Chem. Soc. 1993, 115,
9283. (c) Horiguchi, Y.; Komatsu, M.; Kuwajima, I. Tetrahedron Lett. 1989,
30, 7087. (d) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015,
6019. (e) Corey, E. J.; Hannon, F. J.; Boaz, N. W. Tetrahedron 1989, 45,
545.
General Procedure for Cuprate Addition (Procedure D). To
a slurry of CuI (6 equiv) in THF at -15 °C was added MeLi‚LiBr
(12 equiv). The resulting colorless solution was stirred at this
temperature for 20 min and then cooled to -78 °C. Dropwise
addition of TMSCl (18 equiv) was followed by cannulation of a
7408 J. Org. Chem., Vol. 71, No. 19, 2006

IteratiVe Synthesis of Deoxypropionate Units
SCHEME 6. Cuprate Additions in the Methyl Seriesa
a (a) BOMCl, NEt(i-Pr)2, CH2Cl2, 75%; (b) Dibal-H, CH2Cl2, -78 °C, 91%; (c) PPh3dC(H)CO2R, CH2Cl2, for 28a, 96%; for 28b, 94%; (d) MeLi‚LiBr,
CuI, TMSCl, THF, -78 °C, see Table 6; (e) Dibal-H, CH2Cl2, -78 °C, 89% with 29a; (f) Dess-Martin Periodinane, CH2Cl2; (g) PPh3dC(H)CO2-t-Bu,
CH2Cl2, 52% two steps; (h) MeLi‚LiBr, CuI, TMSCl, THF, -78 °C, 90% 2:1 syn/anti. Iterations done on pure syn isomers.
TABLE 6. Cuprate Additions in the Methyl Series
g, 93%) after flash chromatographic purification with 10% EtOAc/
hexanes. Following general procedures B and C, oxidation of the
alcohol (1.55 g, 5.82 mmol) afforded the desired aldehyde (1.31 g,
81%) and further Wittig homologation of the aldehyde (0.20 g,
0.77 mmol) gave 4d (0.24 g, 85%) as a colorless oil after flash
chromatography with 2% EtOAc/hexanes: [R]D -6.2 (c 0.40,
CHCl3). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.34 (m, 5H), 6.87
(m, 1H), 5.77 (d, 1H, J ) 15.5 Hz), 4.82 (d, 1H, J ) 6.9 Hz), 4.80
(d, 1H, J ) 6.8 Hz), 4.69 (d, 1H, J ) 11.9 Hz), 4.65 (d, 1H, J )
11.9 Hz), 3.11 (t, 1H, J ) 5.4 Hz), 2.52 (m, 1H), 2.02 (m, 1H),
1.90 (m, 2H), 1.49 (s, 9H), 0.95 (m, 9H). 13C NMR (100 MHz,
CDCl3): δ (ppm) 166.4, 147.7, 138.3, 128.8 (2C), 128.5 (2C),
128.0, 124.6, 97.2, 89.7, 80.4, 70.6, 35.6, 35.2, 30.8, 28.6 (3C),
entry
compd
product
R
syn/antia
yieldb
1
2
3
4
28a
28b
28c
30
29a
29b
29c
31
Me
73:27
85:15
80:20
66:33
99
91
92
90
t-Bu
MCP
t-Bu
a Determined by 13C inverse gated NMR. b Isolated yields after chro-
matography.
solution of the R,â-unsaturated ester in THF at -78 °C. The reaction
mixture was stirred at -78 °C for 3 h and quenched with solution
of NH4OH/NH4Cl (1:1). The mixture was diluted with Et2O and
warmed to room temperature. The aqueous layer was extracted three
times with Et2O, and the combined organic extracts were washed
with NH4OH/NH4Cl (1:1) and brine and dried over Na2SO4. The
solution was filtered and concentrated in vacuo. The resulting
residue was purified by flash chromatography.
20.7, 18.0, 17.5. IR (thin film): 2967, 1712, 1651, 1455, 1366 cm-1
.
HRMS (EI): m/z 363.2533 (calcd for C22H34O4, 363.2535).
(3R,5S,6R)-6-Benzyloxymethoxy-3,5,7-trimethyloctanoic Acid
tert-Butyl Ester (5d). Compound 4d (0.10 g, 0.28 mmol) was
subject to a cuprate addition following general procedure D. Flash
chromatographic purification of the product with 2% EtOAc/
hexanes afforded the products syn-5d and anti-5d (0.091 g, 87%
combined yield) in a ratio of 89:11 syn/anti. [R]D -14.0 (c 0.60,
CHCl3). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.31 (m, 5H), 4.82
(d, 1H, J ) 6.9 Hz), 4.79 (d, 1H, J ) 6.9 Hz), 4.69 (d, 1H, J )
12.0 Hz), 4.65 (d, 1H, J ) 12.0 Hz), 3.09 (t, 1H, J ) 5.2 Hz), 2.30
(dd, 1H, J ) 4.4, 14.3 Hz), 2.01 (m, 1H), 1.87 (m, 2H), 1.77 (m,
1H), 1.49 (m, 1H) 1.46 (s, 9H), 1.12 (m, 1H), 0.94 (m, 12H). 13C
NMR (100 MHz, CDCl3): δ (ppm) 173.2 (173.9), 138.5, 128.8
(2C), 128.1 (2C), 128.0, 97.1, 97.0, (90.6) 90.1, 80.4, 70.4, (44.9)
42.5, 39.6 (38.8), 33.5 (33.2), (30.7) 30.6, 28.5 (3C), 21.7, 21.0
(20.8), (19.2) 18.8, 17.7 (17.3). IR (thin film): 2963, 2932, 2875,
1729, 14.56, 1367, 1257 cm-1. HRMS (EI): m/z 379.2861 (calcd
for C23H38O4, 379.2848).
General Procedure for Swern Oxidation Followed by Wittig
Reaction (Procedure E). Oxalyl chloride (2.5 equiv) was added
to a solution of DMSO (5 equiv) in CH2Cl2 at -78 °C. After 15
min, a solution of the alcohol in CH2Cl2 was added and stirred at
-78 °C for 45 min. Triethylamine (10 equiv) was then added, and
the reaction mixture was warmed to room temperature over 45 min.
A saturated solution of NH4Cl was added, and the layers were
separated. The aqueous layer was extracted three times with EtOAc.
The combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated. The crude aldehyde was added
to a solution of Ph3PdCHCO2R (1.5 equiv) in CH2Cl2, and the
reaction was stirred at room temperature for 18 h and then
evaporated to dryness. The crude solid was triturated with hexanes/
Et2O (3:1), and the resulting slurry was filtered over a pad of Celite.
The filtrate was concentrated and purified by flash chromatography.
(3S,4R)-4-Benzyloxymethoxy-3,5-dimethyl-hexanoic Acid Meth-
yl Ester (3). Following general procedure A, enoate 217a (2.5 g,
8.98 mmol) was subject to a cuprate addition providing product 3
(2.54 g, 96%): [R]D -18.22 (c 1.10, CHCl3). 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.37 (m, 5H), 4.82 (d, 1H, J ) 6.86 Hz), 4.79
(d, 1H, J ) 6.89 Hz), 4.70 (d, 1H, J ) 11.90 Hz), 4.65 (d, 1H, J
) 11.84 Hz), 3.69 (s, 3H), 3.14 (t, 1H, J ) 5.39 Hz), 2.63 (dd, 1H,
J ) 14.91, 3.21 Hz), 2.22 (m, 1H), 2.18 (dd, 1H, J ) 9.76, 14.89
Hz), 1.79 (m, 1H), 1.00 (m, 9H). 13C NMR (100 MHz, CDCl3) δ
(ppm) 174.49, 137.51, 128.81 (2C), 128.16 (2C), 128.03, 97.15,
89.34, 70.59, 51.82, 37.60, 33.31, 30.92, 20.55, 18.26, 18.05. IR
(thin film): 2962, 2877, 1738, 1497, 1455, 1436, 1384, 1366, 1253,
1194, 1163 cm-1. HRMS (EI): m/z 295.1917 (calcd for C17H26O4,
295.1909).
(3R,5S,6R)-6-Benzyloxymethoxy-3,5,7-trimethyloctan-1-ol (10).
Following general procedure A, 5d (1.04 g, 2.76 mmol) was reduced
to give a mixture of diastereomeric alcohols. Careful chromato-
graphic separation provided syn-10 (0.63 g, 74%) as a colorless
1
oil. [R]D -20.5 (c 0.73, CHCl3). H NMR (400 MHz, CDCl3): δ
(ppm) 7.34 (m, 5H), 4.85 (d, 1H, J ) 6.9 Hz), 4.81 (d, 1H, J ) 6.9
Hz), 4.71 (d, 1H, J ) 11.9 Hz), 4.67 (d, 1H, J ) 11.9 Hz), 3.70
(m, 2H), 3.11 (t, 1H, J ) 5.3 Hz), 1.87 (m, 2H), 1.69 (m, 2H),
1.49 (m, 2H), 1.27 (m, 1H), 1.10 (m, 1H), 0.97 (m, 12H). 13C NMR
(100 MHz, CDCl3): δ (ppm) 138.5, 128.8 (2C), 128.1 (2C), 128.0,
97.0, 90.3, 70.5, 61.5, 40.3, 39.0, 33.4, 30.6, 27.7, 21.5, 21.1, 18.8,
17.84. IR (thin film): 3402 2960, 2931, 2875, 1456, 1382, 1158
cm-1. HRMS (ESI): m/z 331.2238 (calcd for C19H32O3Na+,
331.2243).
(E)-(5S,7S,8R)-8-Benzyloxymethoxy-5,7,9-trimedec-2-enoic
Acid tert-Butyl Ester (11b). Following general procedure E,
alcohol 10 (1.00 g, 3.24 mmol) provided 11b ((E)- 1.07 g, (Z)-
0.150 g, 94%) after flash chromatographic purification with 2%
(E)-(5S,6R)-6-Benzyloxymethoxy-5,7-dimethyloct-2-enoic Acid
tert-Butyl Ester (4d). Following general procedure A, reduction
of 3 (1.51 g, 5.13 mmol) afforded the corresponding alcohol (1.26
J. Org. Chem, Vol. 71, No. 19, 2006 7409

Hanessian et al.
SCHEME 7. Bidirectional Cuprate Additionsa
a (a) MOMCl, NEti-Pr2, CH2Cl2, 93%; (b) TBAF, THF, 73%; (c) (COCl)2, DMSO, NEt3, CH2Cl2, -78 °C; (d) PPh3dC(H)CO2Me, CH2Cl2, 93% for two
steps; (e) MeLi‚LiBr, CuI, TMSCl, THF, -78 °C, anti/syn > 20:1, 88%; (f) Dibal-H, CH2Cl2, -78 °C, 87%; (g) repeat c; (h) PPh3dC(H)CO2t-Bu, CH2Cl2,
69% for two steps; (i) repeat e, syn/anti > 10:1, 91%; repeat f, 72%; (j) repeat c and repeat d, 96% two steps; (k) repeat e syn/anti > 10:1, 83%; (l) H2, 1
atm, Pd/C, MeOH/AcOH (4:1), 86%; (m) MsCl, NEt3, CH2Cl2, 0 °C; (n) LiAlH4, THF, 0 °C, 71% two steps; (o) repeat a, 73%. Iterations done on pure syn
isomers.
SCHEME 8. Deuterium Labeling
1
EtOAc/hexanes. [R]D -9.0 (c 0.63, CHCl3). H NMR (500 MHz,
CDCl3): δ (ppm) 7.36 (m, 5H), 6.87 (m, 1H), 5.78 (d, 1H, J )
15.5 Hz), 4.85 (d, 1H, J ) 6.7 Hz), 4.82 (d, 1H, J ) 6.8 Hz), 4.71
(d, 1H, J ) 11.9 Hz), 4.68 (d, 1H, J ) 11.9 Hz) 3.12 (t, 1H, J )
5.2 Hz), 2.31 (m, 1H), 1.97-1.90 (m, 3H), 1.64 (m, 1H), 1.52 (s,
9H), 1.53-1.52 (m, 1H), 1.14 (m, 1H), 0.99 (m, 12H). 13C NMR
(100 MHz, CDCl3): δ (ppm) 166.4, 147.2, 138.5, 128.7 (2C), 128.1
(2C), 128.0, 124.7, 97.0, 90.2, 80.3, 70.5, 39.5, 38.6, 33.4, 30.6,
30.5, 28.6 (3C), 21.5, 21.0, 18.8, 17.8. IR (thin film): 2961, 2931,
127.4, 96.3, (90.3) 90.0, 79.8, 69.9, (44.7) 44.2, (43.1) 42.8, 40.0,
33.4 (33.1), 29.9 (2C), 28.0 (3C), 27.6, 21.1, 20.9, 20.6, (19.3) 18.9,
17.8 (17.5). IR (thin film): 2961, 2931, 2874, 1729, 1456 cm-1
.
(E)-(5R,7S,9S,10R)-10-Benzyloxymethoxy-5,7,9,11-tetra-
methyldodec-2-enoic Acid tert-Butyl Ester (13a). Following
general procedure A, 12b (0.23 g, 0.54 mmol) was reduced to give
a mixture of diastereomeric alcohols. Careful chromatographic
purification (2% EtOAc/hexanes) provided the pure all syn-alcohol
(0.11 g, 60%) as a colorless oil. The alcohol obtained was then
subject to general procedure E, providing 13a (0.068, 71% over
two steps) after flash chromatographic purification with 2% EtOAc/
hexanes. [R]D -17.9 (c 1.02, CHCl3). 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.32 (m, 5H), 6.89 (m, 1H), 5.76 (d, 1H, J )
15.5 Hz), 4.85 (d, 1H, J ) 6.9 Hz), 4.81 (d, 1H, J ) 6.9 Hz), 4.71
(d, 1H, J ) 11.9 Hz), 4.67 (d, 1H, J ) 11.9 Hz), 3.11 (t, 1H, J )
5.1 Hz), 2.24 (m, 1H), 1.86 (m, 4H), 1.57 (m, 1H), 1.50 (s, 9H),
1.42 (m, 1H), 1.32 (m, 1H), 1.06 (m, 1H), 0.93 (m, 16H). 13C NMR
(100 MHz, CDCl3): δ (ppm) 165.6, 146.3, 137.7, 128.0 (2C), 127.4
(2C), 127.2, 123.9, 96.1, 89.3, 79.6, 69.7, 43.2, 39.8, 38.0, 32.6,
29.7, 29.5, 27.9 (3C), 27.4, 20.9, 20.5, 20.4, 18.1, 17.1. IR (thin
film): 2960, 2930, 1715, 1653, 1457, 1368, 1321, 1288, 1250, 1158
1715, 1653, 1457, 1368, 1321, 1256 cm-1
.
(3R,5S,7S,8R)-8-Benzyloxymethoxy-3,5,7,9-tetramethylde-
canoic Acid tert-Butyl Ester (12b). Compound 11b (0.055 g, 0.14
mmol) was subject to a cuprate addition following general procedure
D. Flash chromatographic purification with 2% EtOAc/hexanes
afforded the products syn-12b and anti-12b (0.054 g, 97% combined
yield) in a ratio of 87:13 syn/anti. [R]D -21.10 (c 1.10, CHCl3).
1H NMR (400 MHz, CDCl3): δ (ppm) 7.33 (m, 5H), 4.85 (d, 1H,
J ) 6.9 Hz), 4.81 (d, 1H, J ) 6.9 Hz), 4.71 (d, 1H, J ) 11.9 Hz),
4.67 (d, 1H, J ) 11.9 Hz), 3.12 (t, 1H, J ) 5.1 Hz), 2.29 (dd, 1H,
J ) 4.8, 14.3 Hz), 2.08 (m, 1H), 1.85 (m, 3H), 1.47 (s, 9H), 1.33
(m, 2H), 1.08 (m, 2H), 0.94 (m, 16H). 13C NMR (100 MHz,
CDCl3): δ (ppm) 173.2 (172.9), 138.0, 128.2 (2C), 127.6 (2C),
cm-1
.
7410 J. Org. Chem., Vol. 71, No. 19, 2006

IteratiVe Synthesis of Deoxypropionate Units
FIGURE 2. Possible conformations of enoates 4a, 11a, 23a, and 30 on the basis of homodecoupling studies.
FIGURE 3. Proposed enoate/cuprate π-complexes, the corresponding â-cuprio(III) intermediates, and adducts. Cuprates are shown as monomers
for simplicity: L ) TMSCl or THF, M ) Li or TMS.
(3R,5R,7S,9S,10R)-10-Benzyloxymethoxy-3,5,7,9,11-penta-
methyldodecanoic Acid tert-Butyl Ester (14a). Compound 13a
(0.067 g, 0.15 mmol) was subject to a cuprate addition following
general procedure D. Flash chromatographic purification with 2%
EtOAc/hexanes afforded the products syn-14a and anti-14a (0.057
g, 78% combined yield) in a ratio of 86:14 syn/anti. [R]D -19.5 (c
1.20, CHCl3). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.34 (m, 5H),
4.85 (d, 1H, J ) 6.9 Hz). 4.81 (d, 1H, J ) 6.9 Hz), 4.70 (d, 1H,
J ) 11.9 Hz), 4.67 (d, 1H, J ) 11.9 Hz), 3.12 (m, 1H), 2.28 (dd,
1H, J ) 4.9, 14.2 Hz), 2.02 (m, 1H), 1.89 (m, 2H). 1.82 (m, 1H),
1.57 (m, 1H), 1.47 (s, 9H), 1.40 (m, 1H), 1.26 (m, 3H), 1.04 (m,
1H), 0.99-0.87 (m, 19H). 13C NMR (100 MHz, CDCl3): δ (ppm)
172.5 (172.2), 137.8, 128.0 (2C), 127.4 (2C), 127.2, 96.1, (89.3)
89.2, 79.5, 69.6, (44.6) 44.4, (44.0) 43.7, 39.8, 32.7 (32.6), 29.7,
(29.7) 29.6, 27.8 (3C), 27.7, 27.4, 27.3, 21.2, (20.9) 20.9, 20.6,
20.4, (18.7) 18.2, 17.0 (16.8). IR (thin film): 2960, 2930, 1730,
1456, 1367 cm-1
.
Acknowledgment. We thank NSERC and FCAR for finan-
cial assistance.
Supporting Information Available: Typical experimental
procedures for key reactions and copies of selected 1H and 13C NMR
spectras. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO061098O
J. Org. Chem, Vol. 71, No. 19, 2006 7411